Organic Reactions || Transition-Metal-Catalyzed α-Arylation of Enolates

CHAPTER 2

TRANSITION-METAL-CATALYZED α-ARYLATION OF ENOLATES

DAMIEN PRIM, SYLVAIN MARQUE, AND ANNE GAUCHER

Universite de Versailles-Saint-Quentin-en-Yvelines, Institut Lavoisier deVersailles UMR CNRS 8180, 45, Avenue des Etats-Unis, F-78035

Versailles, France

JEAN-MARC CAMPAGNE

Ecole Nationale Superieure de Chimie de Montpellier, 8, Rue de I’EcoleNormale, 34296, Montpellier Cedex, France

CONTENTSPAGE

ACKNOWLEDGMENTS . . . . . . . . . . . . . 50INTRODUCTION . . . . . . . . . . . . . . 50MECHANISM AND STEREOCHEMISTRY . . . . . . . . . . 53SCOPE AND LIMITATIONS . . . . . . . . . . . . 59

Palladium-Catalyzed α-Arylation . . . . . . . . . . 59α-Arylation of Ketones . . . . . . . . . . . 59α-Arylation of Aldehydes . . . . . . . . . . . 64α-Arylation of Amides . . . . . . . . . . . 64α-Arylation of Esters . . . . . . . . . . . . 67α-Arylation of Amino Acids and Derivatives . . . . . . . 68α-Arylation of Nitriles . . . . . . . . . . . 70α-Arylation of Active Methylene Compounds . . . . . . . 71Vinylogy, Phenylogy. Site Selectivity in γ/ω-Arylation . . . . . 73α-Arylation via α-Stannylmethyl Carbonyl Compounds . . . . . 74α-Arylation of Silyl Enol Ethers and Ketene Acetals . . . . . . 75

Copper-Catalyzed α-Arylation . . . . . . . . . . 77Nickel-Catalyzed α-Arylation . . . . . . . . . . 78

APPLICATIONS TO SYNTHESIS . . . . . . . . . . . 79COMPARISON WITH OTHER METHODS . . . . . . . . . . 81

Palladium-Catalyzed α-Arylation via α-Halomethyl Carbonyl Compounds . . 81Stoichiometric Transition-Metal- and Metal-Promoted α-Arylation . . . . 81

Copper-Mediated α-Arylation . . . . . . . . . . 81Magnesium- and Titanium-Mediated α-Arylation . . . . . . 83

[email protected] Reactions, Vol. 76, Edited by Scott E. Denmark et al.© 2012 Organic Reactions, Inc. Published 2012 by John Wiley & Sons, Inc.

49

50 ORGANIC REACTIONS

Bismuth-Mediated α-Arylation . . . . . . . . . . 83Lead-Mediated α-Arylation . . . . . . . . . . 84

Miscellaneous α-Arylation Methods . . . . . . . . . 85EXPERIMENTAL CONDITIONS . . . . . . . . . . . 87EXPERIMENTAL PROCEDURES . . . . . . . . . . . 87

2-(2-Bromophenyl)cyclohexanone [Palladium-Catalyzed α-Arylation of a Ketone] 871-Phenyl-2-arylpropan-1-one [α-Arylation of a Ketone Using an N-Heterocyclic

Carbene-Based Catalytic System] . . . . . . . . . 881-Vinyl-3-tert-butyl-1H -isochromene [Palladium-Catalyzed α-Arylation of a Ketone] 88tert-Butyl 2-Phenyl-2,3-dihydro-1H -isoindole-1-carboxylate [Palladium-Catalyzed

Intramolecular α-Arylation of an α-Amino Acid Ester] . . . . . 891-Benzyloxindole [Preparation of an Oxindole by Palladium-Catalyzed Intramolecular

α-Arylation of an Amide] . . . . . . . . . . . 90(1-Nitroethyl)benzene [Palladium-Catalyzed α-Arylation of Nitroethane] . . 90Diethyl 2-Phenylmalonate [Palladium-Catalyzed α-Arylation of a Malonate with an

Aryl Bromide] . . . . . . . . . . . . . 91Ethyl 2-(2-Methylphenyl)cyanoacetate [Palladium-Catalyzed α-Arylation of Ethyl

Cyanoacetate] . . . . . . . . . . . . . 91(R)-(+)-2-Methyl-2-(4-anisyl)-5-(N-methylanilinomethylene)cyclopentanone

[Palladium-Catalyzed Asymmetric α-Arylation of a Ketone Enolate] . . . 92(–)-3-(3-Methoxyphenyl)-3-methyldihydrofuran-2-one [Nickel-Catalyzed Asymmetric

α-Arylation of a Lactone] . . . . . . . . . . . 93(S)-Ethyl 2-Methyl-3-oxo-2-[2-(2,2,2-trifluoroacetamido)phenyl]butanoate

[Copper-Catalyzed Enantioselective α-Arylation of an Acetoacetate] . . . 94TABULAR SURVEY . . . . . . . . . . . . . 94

Chart 1. Structures of Ligands Used in Tables . . . . . . . 96Chart 2. Structures of Palladacycles and Palladium Complexes Used

in Tables . . . . . . . . . . . . . . 98Chart 3. Structures of Polymer-Supported Catalysts Used in Tables . . . 99Table 1. Arylation of Aldehydes, Ketones, and Enol Ethers . . . . . 100Table 2. Arylation of Esters, Amides, Lactones, Lactams, Nitriles, Ketene Acetals, and

Preformed Enolates . . . . . . . . . . . . 168Table 3. Arylation of 1,3-Dicarbonyls and Cyanoacetates . . . . . 241

REFERENCES . . . . . . . . . . . . . . 276

ACKNOWLEDGMENTS

The authors are greatly indebted to Professors Dale L. Boger, Stuart W.McCombie, Peter Wipf, Engelbert Ciganek, and Scott E. Denmark for helpfulguidance and insightful comments.

INTRODUCTION

The last three decades have witnessed increasing efforts to develop highlyefficient and selective tools for the catalyzed formation of carbon–carbon and car-bon–heteroatom bonds. Among the latter, outstanding results have been obtainedin the field of soft, non-organometallic nucleophiles.1 The formation of car-bon–oxygen, –nitrogen, –sulfur, –phosphorus, –boron, or –silicon bonds hasbecome as widely used as the well-known Suzuki, Corriu–Kumada–Tamao,

TRANSITION-METAL-CATALYZED α-ARYLATION OF ENOLATES 51

Stille, Negishi, Hiyama, and Sonogashira cross-coupling reactions. One of themajor challenges is the α-arylation of soft carbon nucleophiles such as stabilizedcarbon enolates and related functional groups. Although α-arylated carboxylicacids (and keto derivatives) are prevalent in natural products (for example,lucuminic acid,2 welwistatin,3 and chloropeptin and vancomycin4) and are impor-tant building blocks in a number of drugs (such as the anti-inflammatory agentsNaproxen and Ibuprofen,5 the anesthetic Scopolamine,6 and p-malonylphenylal-anine (Pmf,7 a potent phosphotyrosine mimetic), catalytic α-arylation of stabilizedcarbon enolates had, until recently, been described only rarely (Fig. 1).

MeO

CO2H

Naproxenanti-inflammatory agent

CO2H

Ibuprofenanti-inflammatory agent

lucuminic acid

CH2OH

O O

MeN

O

Scopolamineanesthetic

CO2HH2N

HO2C

CO2H

p-malonylphenylalanine (Pmf)phosphotyrosine mimetic

welwistatinmultidrug resistance reverser

OHOHO

HOOHO

HOHO

CO2H

Ph

O

O

SCNO

NMe

HO

Cl

H

Figure 1. Natural products and drugs bearing α-arylated carboxylic acid derivatives.

The first examples of both inter- and intramolecular arylation of ketone eno-lates were reported in 1973 by Semmelhack using a nickel catalyst.8 The reactionof the oxidative addition product of bromobenzene and Ni(PPh3)4 with the lithiumenolate of acetophenone afforded the arylated ketone in modest yield (Eq. 1). Anintramolecular version was also reported as the key step of the total synthesisof cephalotaxinine. The natural product was obtained in only 30% yield andrequired the use of a stoichiometric amount of Ni(cod)2.8

O

Br OLi+ Ni(PPh3)4

DMF, –78°(65%)

(Eq. 1)

This pioneering work was followed by several examples of transition-metal-mediated α-arylations of ketones or their derivatives including the catalyzedarylation of vicinal bromotrimethylsilylalkenes9 and acetonyltributyltin (Eq. 2),10


as well as the arylation of 2-trimethylsilyloxyallyl halides with stoichiometricreagents.11

OSnBu3

PdCl2[P(o-tol)3]2 (10 mol %)

toluene, 100°, 5 h

O+ (78%)Br

(Eq. 2)

One variant of these reactions involves the site selective arylation of silylenol ethers of methyl ketones with aryl halides under palladium catalysis in thepresence of trialkyltin fluorides (Eq. 3).12,13 The latter are assumed to generatetin enolates in situ via silyl/stannyl exchange followed by arylation with the arylhalide.

Me3SiO Bu3SnF

PdCl2[P(o-tol)3]2 (3 mol %),benzene, reflux, 5 h

Bu3SnO

OMe

Br

OOMe

(86%)

(Eq. 3)

Later, the use of malonate-type nucleophiles in the palladium-catalyzed α-arylation of ketones in inter- and intramolecular modes was reported (Eq. 4).14,15

(PPh3)4Pd (10 mol %)

NaH (1.2 equiv), DMF, 130°, 6 h

O

OI

O

O

(68%)

(Eq. 4)

In 1997, five seminal papers dealing with inter- and intramolecular palladium-catalyzed arylation of ketones appeared.16 – 20 This method could then be extendedto ketones and esters under milder conditions and with a wider scope (Eq. 5).

t-Bu

Br

O

+

NaOt-Bu (1.3 equiv),Pd2(dba)3 (1.5 mol %), BINAP (3.6 mol %)

THF, 70°

t-Bu

O

(67%)

dba = dibenzylideneacetone

(Eq. 5)


The more recent developments of this method concern not only the use ofa large number of related nucleophiles such as amides, lactones and lactams,malonates, cyanoacetates, aldehydes, α-amino esters, nitriles, sulfones, and nitro-alkanes, but also activated benzylic and vinylogous γ-arylations. Current effortsare mainly devoted to multiple arylation sequences, intramolecular α-arylations,and enantioselective α-arylations. Although palladium-catalyzed reactions havereceived a great deal of attention, several other efficient, competitive, and enan-tioselective nickel-, copper-, or ruthenium-based catalytic systems have recentlyemerged.

In addition, the transition-metal-catalyzed introduction of aromatic groups atthe position α to enolizable moieties has found applications in the total syn-thesis of natural products, demonstrating the utility of this general syntheticmethod. The aim of this chapter is to present an up-to-date overview of thetransition-metal-catalyzed α-arylation of enolates and their derivatives. Becausepalladium is the transition metal predominantly employed, this chapter focuseson palladium-assisted synthetic transformations. However, the most relevant α-arylations involving other catalytic systems are also detailed. Several accountshave recently appeared covering some aspects of palladium-catalyzed α-aryl-ations.21 – 23 The literature up to the beginning of 2008 is covered in the TabularSurvey.

MECHANISM AND STEREOCHEMISTRY

Palladium is the most widely used transition metal in catalyzed α-arylations.Relevant mechanistic studies are almost exclusively carried out with this metal.The main features of reactions mediated by other transition metals are discussedin the corresponding sections.

The general mechanism of the palladium-catalyzed arylation of enolates israther classical involving the well-known oxidative addition, transmetalation, andreductive elimination sequence (Scheme 1).23 Although the general mechanismis well accepted, a number of questions about particular aspects of the catalyticcycle are still under discussion.

The first issue concerns the number of phosphines coordinated to the palladiumatom. Initially, bidentate phosphines such as dppf (1) or BINAP (2) (Fig. 2) wereused to form strongly chelated intermediates to prevent β-elimination.16 However,during further synthetic and mechanistic studies, a monochelated intermediateinvolving the DtBPF ligand (3) was observed by 31P NMR spectroscopy.23 Thisobservation led to the introduction of very efficient mono- and bidentate ligands4–11 (Fig. 2). Such bulky, electron-rich monodentate ligands are involved in theformation of monoligated (12 electrons) [PdL] species that can undergo rapidoxidative additions with ArX, including aryl chlorides.24,25 Ligandless reactionsare also possible in some non-demanding reactions.18

The second issue concerns the nature of the palladium species undergoingreductive elimination in the catalytic cycle. In general, main group metal and earlytransition metals favor the O-bound enolate whereas late transition metals favor


ArX

R1

R2

Ar(Ln)PdO

R1

R2

OPd(Ln)Ar

R1

R2

OAr(Ln)Pd

ArR1

O

R2

R1, base

O

R2

ArPd(Ln)X

(Ln)Pd(0)

oxidative addition

transmetalation

reductive elimination

Scheme 1

Fe

PR2

PR2

RPht-Bu

Ligand1 3

FeP(Cy)2

PPh2

4

P(R1)2

R2

R1

t-But-BuCyCyCy

R2

HMeHMei-Pr

Ligand

7891011

R1

PPh2

P(p-tol)2

NMe2

R2

PPh2

P(p-tol)2

P(t-Bu)2

Ligand

256

R1

R2

Figure 2. Phosphine ligands for palladium-catalyzed α-arylations.

the C-bound form.23 Indeed, with the exception of hindered α,α′-disubstitutedketones and complexes where the enolate oxygen is located trans with respectto the aryl group, the C-bound isomers are favored.23 Competition experimentsinvolving isolated palladium enolates showed that their relative stability is con-trolled by the number of substituents on the α-position of the keto group (Fig. 3).23


[Pd]O

R> [Pd]

O

R>

O[Pd]

R

Figure 3. Relative stability of palladium enolates.

The reductive elimination step was investigated for various isolated C- andO-bound palladium enolates.26 By comparison of the elimination rates, alterna-tive mechanisms (such as isomerization to the enol or migratory insertion couldbe ruled out and the classical concerted reductive elimination was confirmed(Scheme 2).23,27

[Pd]O

R

Ar

ArO

R

R

O[Pd]

Ar

ArR

O[Pd]

[Pd]R

OHAr

ArR

OH


migratoryinsertion

isomerizationto enol


Scheme 2

The influence of electronic effects was also investigated. As illustrated inFig. 4, acyl substituents (aryl, alkoxy, amino) on the palladium enolates havelittle influence on the reductive elimination rates.28 In these cases, the observeddifferences in reactivity in the palladium-catalyzed arylation of ketones, esters,and amides must result from the rate of formation of the α-palladated species.On the other hand, striking differences are observed in the reductive eliminationsof methyl, ketomethyl, cyanomethyl, and malonyl arylpalladium complexes.23,29

Increasing the electron-withdrawing ability of the substituent lowers the reductiveelimination rate. This effect is particularly impressive in malonate-type complexeswhere no reductive elimination is observed. In such reactions, this effect must becounteracted by ligands that are efficient in promoting reductive elimination, suchas bulky, electron-rich monophosphines, as exemplified by the DPPBz ligand (12)(Fig. 4).23,29

Because enantiomerically enriched α-substituted carbonyl compounds areimportant structural features in drugs and natural products, the creation of tertiaryand quaternary stereogenic centers α to carbonyl groups through the asymmetricarylation of enolates is of significant interest. Initial attempts employed BINAP-type ligands for this transformation.30 Modest enantioselectivities are obtainedusing 10 to 20 mol % of palladium precatalyst, and 12 to 24 mol % of ligands2 or 13 (Eq. 6).


L2PdO

Ph

ArL2Pd

O

Ot-Bu

ArL2Pd

O

NMe2

Ar

PPh2

PPh2

L2PdO

alkyl

Ar

CNL2PdAr CO2RL2Pd

Ar

CO2RMe

L2PdAr

Half-life (90°): t1/2 = 31 min t1/2 = 44 min t1/2 = 31 min

L2 =

< 5 min 3 h 60 h no reductive elimination

Reductive elimination

time:

12

Figure 4. Electronic effects on the rate of reductive elimination.

OO

n

n = 1, 2

Pd(OAc)2 (10–20 mol %), (S)-2 or (S)-13 (12–24 mol %)

P(o-tol)2

P(o-tol)2

(S)-13

nO

OO

OBr

n12

(79%)(61–88%)

% ee70

40–66

+NaOt-Bu, toluene, 100°

(Eq. 6)

These transformations require the use of an excess of the aryl halide to ensurecomplete conversions because of the competitive homocoupling of the aryl bro-mide to afford biphenyl derivatives.30a In addition, these arylations are restrictedto the formation of quaternary stereocenters. The acidity of the remaining pro-ton in the tertiary arylation products leads to lower enantioselectivities underbasic conditions.30a The arylation reactions proceed with high yields and highto excellent enantioselectivities in the case of blocked α-methylcyclopentanones(Eq. 7).31 In such substrates, the use of a methylene group that can be easilyremoved can prevent arylation at the less substituted carbon of α-methylcyclopen-tanones. Toluene and sodium tert-butoxide is the most suitable combination ofsolvent and base in these transformations. Whereas arylations using m- and p-substituted aryl bromides generally proceed with high enantioselectivities(80–94% enantiomeric excess), the o-substituted derivatives react with low yieldsand enantioselectivities. Similar enantiomeric excesses (88–93%) are observedin couplings of ketones bearing methyl, n-propyl, and n-pentyl α-substituents,


indicating that enantiomeric excesses are insensitive to the size of the α-alkylmoiety.30a Although BINAP is often used, reactions using palladium catalystsbased on dialkyl monophosphines such as 14 can be employed under milderconditions (room temperature) and are more efficient in terms of substrate rangeand precatalyst loadings. As exemplified in Eq. 7, best results are obtained usingmonophosphine ligands. Although attempts to rationalize the sense of asymmetricinduction are still inconclusive, it should be noted that reversed stereoselectivity isobserved using diphosphine-type ligands such as BINAP.30a These observationssuggest an asymmetric induction mechanism that is significantly different formonophosphine and diphosphine ligands, respectively, depending on the chela-tion mode in the enantiodetermining step.

NMe

OPd2(dba)3 (1 mol %), (R)-14 (2.5 mol %)

PCy2

NMe2

(72%) 58% ee

(R)-14

+BrO

NMe

Ph

(S)

NaOt-Bu, toluenePh

(Eq. 7)

An interesting alternative approach involves the use of chiral N-heterocycliccarbene (NHC) ligands in intramolecular arylation reactions for the asymmetricsynthesis of oxindoles. Ligands 15 and 16, derived from (–)-isopinocampheyl-amine and (+)-norbornylamine, respectively, display complementary inductionunder mild conditions, and afford products of opposite absolute configuration(Eq. 8).32

N N+

BF4–

N N+

BF4–

Br

NBn

O

NBn

O

Pd(OAc)2 (10 mol %), 15 or 16 (10 mol %)

15

16

Ligand1516

(88%)(80%)

% ee6771

rt, 24 h

(Eq. 8)


In addition to palladium-catalyzed asymmetric arylations, nickel- and copper-catalyzed processes have recently emerged as alternative approaches.33 Substitu-tion of palladium(0) with nickel(0) catalysts leads to very efficient, enantioselec-tive α-arylation of γ-butyrolactones. The use of Ni(BINAP) catalytic systemsprovides the products in modest to good yields, but with high enantiomericexcesses (Eq. 9).33 The increase in the enantioselectivity is attributed to thegreater influence of the ligand in the stereodetermining step resulting from thesmaller nickel-center. Interestingly, aryl chlorides can be used instead of bro-mides with comparable reaction rates.34 Moreover, addition of substoichiometricamounts of zinc salts increases the reaction rate. Zinc halide species are assumedto act as Lewis acids to facilitate halide abstraction from the oxidative additionproduct, thus generating a more reactive cationic complex at an early stage ofthe transmetalation step (Eq. 10).33

O

O

O

ONi(cod)2 (5 mol %), (S)-BINAP 2 (8 mol %)

(76%) 94% ee

OMeOMe

Cl+

ZnBr2 (15 mol %), NaHMDS

(Eq. 9)

(BINAP)Ni(Ar)(Br)ZnBr2

[(BINAP)Ni(Ar)]+ ZnBr3– (Eq. 10)

The highly enantioselective arylation of ketones using ligand 17 and electron-poor aryl triflates in the presence of nickel-based catalysts, or electron-richaryl triflates in the presence of palladium-based complexes, has been recentlydescribed (Eq. 11).34

O

O

CN

OTf

CN

+M(0) (5–10 mol %), 17 (6–12 mol %)

NaOt-Bu (2 equiv), toluene, 80–100°

O

O

O

O

F

F

F

F

PPh2

PPh2

17

M(0)Ni(cod)Pd(dba)2

% ee9578

(84%)(79%)

(Eq. 11)

Highly enantioselective nickel-catalyzed α-arylations of ketone enolatesinvolving the Ni-P-Phos catalytic system (P-Phos = structure 18) have beenapplied to the 2-methylindanone, -tetralone, and -benzosuberone series leadingto the formation of quaternary centers with enantiomeric excesses up to 98%(Eq. 12).35


O Ni(cod)2 (2 mol %), (R)-18 (5 mol %)

(R)-18

n123

(69–80%)(59–94%)(70–74%)

% ee67–8870–9860–73

O

NaOt-Bu (2 equiv), toluenen n

N

PPh2

OMe

OMeN

MeO

MeO

Ph2P

Ar

+ ArBr

(Eq. 12)

Copper-catalyzed arylations of acetoacetates in the presence of L-trans-4-hydroxyproline as the ligand proceed in high yield (29–87%) and enantiomericexcesses (60–93%) (Eq. 13).36 It is worth noting that traces of water in thesolvents are beneficial to the reaction rates, allowing the reactions to proceedsmoothly at low temperature. Temperatures as low as −45◦ provide the car-bon–carbon bond formation with enhanced enantiomeric composition.36

NHCOCF3

I

OO

t-BuO

CuI (10 mol %),L-trans-4-hydroxyproline (20 mol %)

NHCOCF3O

Ot-BuO

(79%) 93% ee

NaOH, DMF, H2O, –45°+

(Eq. 13)

SCOPE AND LIMITATIONS

Palladium-Catalyzed α-Arylationα-Arylation of Ketones. This section focuses mainly on the direct, catalyzed

arylation of ketone enolates; recent developments on the use of stoichiometricreagents37 – 39 are not covered. In the period since their seminal 1997 papers,Hartwig, Buchwald, and Miura have tried to develop “universal conditions” fora wide range of substrates under mild reaction conditions.

On the basis of their mechanistic studies (see above), the Hartwig grouphas reported a simple and active catalytic system for the arylation of ketones:3/Pd(dba)2 or (t-Bu)3P/Pd(OAc)2 (in a 1:1.25 Pd/L ratio) in THF (Eq. 14).40

These conditions allow the reaction of a wide range of aryl bromides and chlo-rides (including electron-rich ones) to take place. One example of the couplingof an aryl tosylate with propiophenone is also described, but requires the use ofligand 19 at 70◦ (Eq. 15).40 Under these conditions, monoarylated ketones can beobtained in good yields starting from cyclohexanone, 3-methyl-2-propanone, ace-tophenone, propiophenone, and isobutyrophenone. The limits of these conditionsare found with methyl alkyl ketones, which form diarylated compounds.

Pd(OAc)2 (2 mol %), (t-Bu)3P (2.5 mol %),

NaOt-Bu (1.5–2.2 equiv)

Ph

OPh

O

Ph

(78%)THF, 70°

Cl

+(Eq. 14)


FeP(t-Bu)2

PPh2

19

Pd(OAc)2 (2 mol %),19 (2.5 mol %),

NaOt-Bu (2.2 equiv)

Ph

O Ph

O

(60%)

OTs

+THF, 70°

(Eq. 15)

Buchwald et al. have developed electron-rich monophosphine ligands 7–11(Fig. 2) and 20–23 (Fig. 5) that possess a biphenyl skeleton. These ligands facil-itate rapid oxidative additions with aryl halides, including aryl chlorides.41

P(R1)2

R2R3

R1

Pht-BuCyCy

R2

NMe2

NMe2

NMe2

OMe

R3

HHHOMe

Ligand

20212223

Figure 5. Electron-rich monophosphine ligands.

A wide range of substrates (electron-rich, electron-poor, and 2-substituted arylbromides and chlorides with aromatic, aliphatic, and cyclic ketones) can be suc-cessfully combined under typical conditions: Xantphos (24), Pd(OAc)2, NaOt-Bu,70◦ in toluene (Eq. 16).42 For reactions involving base-sensitive substrates, amilder base such as K3PO4 can be used in the presence of 24/Pd2(dba)3.43 Mostof the non-demanding reactions (typically propiophenone and pinacolone witharyl bromides) can be carried out in the absence of a ligand. However, the useof bidentate ligands such as Xantphos (24) is essential in α-arylations of ketonesbearing two enolizable methylene or methyl groups.42 A major limitation ofthis method is the use of cyclopentanone, where self-aldolization is the majorprocess (for an example where the cyclopentanone enolate is generated in situthrough a 1,4-addition, see Ref. 44). The α-arylations of methyl or cyclic ketoneswith 2-halonitroarenes require the use of a substoichiometric amount (20%) of4-methoxyphenol to be efficient.45

Br

+O Pd(OAc)2 (0.1 mol %),

24 (0.2 mol %)

O

(70%)

NMe2NMe2

OPPh2PPh2

24

NaOt-Bu (1.3 equiv), toluene, 85°

(Eq. 16)


Miura et al. have mainly focused their efforts on multiple arylations of phenylketone derivatives. Benzyl phenyl ketones undergo a triarylation sequence: theexpected α-arylation but also two o-arylations (Eq. 17).46 With alkyl aryl ketones,multiple arylation is also observed: after the initial α-arylation process, a secondpalladium-enolate is formed, which undergoes a β-elimination to form a doublebond. This double bond then reacts further through a Heck reaction (Eq. 18), ora vinylogous γ-arylation (Eq. 19).47

OPh

O

Ph

Ph

Ph

Ph

Cl Cl

(59%)

Pd(PPh3)4 (0.5 mol %),Cs2CO3 (3–5 equiv)

PhBr

(4 equiv)

+o-xylene, 160°

(Eq. 17)

Ph

OPh

O

PhPh

(59%) 2:1 (E)/(Z)

PhPh

OPd(OAc)2 (5 mol %),

Ph3P (20 mol %)

Cs2CO3 (4 equiv),o-xylene, 160°

PhBr

(4 equiv)

+

(Eq. 18)

Ph

O

Ph

O

Ph

Pd(OAc)2 (10 mol %),(o-tol)3P (40 mol %)

PhPh

O

Ph

Ph

(78%)

Ph

OPh

(14%)

Cs2CO3 (4 equiv), o-xylene, 160°

+

PhBr

(4 equiv)

+

(Eq. 19)

Robust catalytic systems capable of practical (industrial) applications, espe-cially with aryl chlorides, are of great value. The use of the n-BuP(adamantyl)2

electron-rich phosphine,48 palladacycles possessing a tertiary phosphine, such as25,49 or secondary phosphines 26–28,49 NHC ligand 29,50,51 or palladacycle 3052

provide efficient arylation of non- and deactivated aryl chlorides (Eqs. 20, 21).

NPd

MeMe

RP(Cy)3

PH(Cy)2

PH(t-Bu)2

PH(2-norbornyl)2

Palladacyle25262728

Cl

palladacycle (0.5 mol %)

NaOt-Bu (1.2 equiv), toluene, 110°

OO

+

(99%)(69%)(60%)(100%)

Cl

R

(Eq. 20)


BF4–

N N+

i-Pr

i-Pr

i-Pr

i-Pr

29

NPd

MeMe

Cl

NN

R

R

R = 2,6-(i-Pr)2C6H3

30

O O

Cl+

[(allyl)PdCl]2 (1 mol %), 29 or 30 (1 mol %)

with 29 (67%)with 30 (97%)

NaOt-Bu (1.1 to 1.5 equiv), dioxane, 60°

(Eq. 21)

The selective mono-arylation of 1,2-diarylethanones has been studied, andbyproducts (o-arylation, multiple arylation, and dehalogenation) can be mini-mized by a careful choice of reaction conditions (Eq. 22). Originally, homoge-neous conditions (Pd(OAc)2, Ph3P, Cs2CO3) were described, but these reactionscan also be performed with polystyrene-derived catalyts 31–33 (Eq. 23).53 – 55

More recently, the same group has also described the use of phosphinite PCP-pincer complexes.56 In addition, arylations on solid supports have been describedusing immobilized 4-bromobenzamide.57

O+

OMeOMe

OMe

OMe

O

OMeOMe

OMe

OMe

Br

Pd(OAc)2 (2 mol %), Ph3P (5 mol %)

(85%)Cs2CO3 (2.5 equiv),

DMF, 150°

(Eq. 22)

PPd

O

O

O

O

PPd

O

O

O

O

PPd

O

O

N

31 32 33

Catalyst313233

Br catalyst (5 mol %),K2CO3 or Cs2CO3 (3 equiv) OO

+

(43%)(16%)(85%)

toluene or DMF, 130° or 150°

(Eq. 23)


In some instances, either the ketone enolate or the aryl palladium species canbe generated from alternative precursors. In Eq. 24, the ketone enolate is obtainedin situ through a cyclopropanol ring-opening reaction.58 Biphenylene can also beused as an aryl halide surrogate in the presence of p-cresol (Eq. 25).59

TBSO

Ph CO2Me

I

(PPh3)4Pd (20 mol %)

Bu4NF (3 equiv), THF, rt

MeO2C

PhO

(61%)

(Eq. 24)

+R

O(PPh3)4Pd (5 mol %),p-cresol (10 mol %)

(84%)(94%)(88%)

R

O

Pd(OAr)Ln

RPh2-thienylt-Bu

C6D6, 120°

(Eq. 25)

Using 1,2-dibromobenzenes, tandem reactions can be envisioned through twosuccessive palladium-catalyzed reactions. In the formation of benzofurans fromaryl benzyl ketones, the mechanism involves first an α-arylation followed bya second deprotonation of the more acidic proton and finally the intramolecu-lar arylation of the O-enolate intermediate 34 (Eq. 26).60 An extension of thismethod to non-aromatic cyclic and acyclic ketones has been described usingDPEphos (35).61,62 A tandem alkylation of the O-enolate intermediate is reportedin the synthesis of a small library of 1-vinyl-1H -isochromene derivatives as illus-trated in Eq. 27.63 Two carbon–carbon single bond formations are also possibleas illustrated in Eq. 28.60

PhO

OMeBr

Br

Pd(OAc)2 (5 mol %),Ph3P (20 mol %)

O

Ph

OMe

O–

OMePh

Br

(75%)

34

+Cs2CO3 (2 equiv),

o-xylene, 160°

(Eq. 26)


OPPh2PPh2

35

Br

OTBS

+

O

OMe

Pd2(dba)3, 35

LHMDS, DME(60%)

O

OMe

(Eq. 27)

PhO

Ph

Br

Br

+


Ph

Ph

O (71%)K2CO3 (4 equiv), o-xylene, 160°

(Eq. 28)

α-Arylation of Aldehydes. Because of the propensity of aldehydes to under-go aldol self-condensations under basic conditions, arylation of aldehydes hasreceived less attention. In the intramolecular arylation of aldehydes, a mixture ofα-arylation and carbonyl-arylation is obtained (Eq. 29).64

CHO

O OBr

PdCl2(CH3CN)2 (10 mol %),Cs2CO3 (3 equiv)

O O

OHC

O O

OH

(50%) 1:1.6

toluene or THF, 100°+

(Eq. 29)

In intermolecular, α-selective arylation of aldehydes (Eq. 30), the use of diox-ane and (t-Bu)3P are essential to prevent aldolization and to promote the reaction(no reaction is observed in the presence of Cy3P).65

CHO

Ph

Br

+

Pd(OAc)2 (5 mol %),(t-Bu)3P (10 mol %)

CHO

Ph

(36%)Cs2CO3 (1.2 equiv), dioxane, 110°

(Eq. 30)

α-Arylation of Amides. On the basis of the arylation of ketones and alde-hydes, several groups have explored the extension of the method to carboxylicacid derivatives. In these studies and in contrast to ketones, the arylation ofamides and esters is not plagued by site selectivity and such reactions wouldappear to be less challenging. Disappointingly, the first attempts to arylate amidesgave rather low yields, even in intramolecular versions. This lack of reactivitycan be attributed to the higher pKa’s of the amide moiety compared to that of


ketones,66 requiring the use of stronger bases. KHMDS is more efficient thanLiTMP (lithium 2,2,6,6-tetramethylpiperidide) and the more classical NaOt-Bu.The α-arylation of N ,N-dialkylacetamide has been reported in moderate to goodyields.67 Side-products such as diarylated amides and/or dehydrohalogenatedarenes are observed along with the expected arylation products (Eq. 31).

NMe2

O+

NMe2

ONMe2

O

(70%) (9%)

Pd(dba)2 (5 mol %),2 (7.5 mol %)

Br

+

KHMDS (2.0 equiv),dioxane, 100° (Eq. 31)

The scope of the reaction is limited by the use of strongly basic conditionsthat preclude the use of base-sensitive and/or electrophilic substituents and leadto catalyst deactivation or decomposition. The aforementioned problems haverecently been overcome by moving to the less basic zinc enolates. The higherfunctional group tolerance of these nucleophiles allows an extended scope of suchcoupling processes. Indeed, ketone, nitrile, ester, and nitro derivatives can be usedas substrates in one-pot procedures starting from N ,N-dialkylamides or α-bromoN ,N-dialkylamides.68 Under these conditions (Pd(dba)2, 36), no side-productsfrom diarylation of the enolate are observed (Eq. 32).

NMe2

O+

1. s-BuLi (1.2 equiv), THF, –78°, 1 h2. ZnCl2 (2.4 equiv), rt, 10 min NMe2

O

R

R4-CO2Me2-CN4-CN4-COPh4-NO2

(95%)(84%)(89%)(92%)(90%)

R

Br

Fe

P(t-Bu)2

Ph

PhPh

PhPh

36

3. Pd(dba)2 (1 mol %), 36 (1 mol %), rt

(Eq. 32)

Apart from the use of zinc enolates, the α-arylation of amides has been lim-ited to intramolecular reactions and/or lactam substrates. Intramolecular reactionshave been used in the synthesis of oxindoles and tetrahydroisoquinoline deriva-tives. In the oxindole series, a wide range of aryl substituents (with respect toboth steric and electronic properties) are tolerated in these intramolecular reac-tions. Standard conditions involving BINAP and NaOt-Bu are used, but sterically


hindered alkyl phosphines67 or hindered imidazolium carbene precursors like3732,69,70 generate more active catalytic systems, providing higher arylation rates(Eq. 33).

Br

NMe

O

NMe

OPd(OAc)2 (5 mol %), 37 (5 mol %)

NaOt-Bu (1.5 equiv), dioxane, 50°(93%)

37

N N+ BF4–

(Eq. 33)

In the tetrahydroisoquinoline series, more disparate yields have been observed.Poor yields (5%) of the expected cyclized product from a non-stabilized enolateusing the Pd(dba)2, BINAP, NaOt-Bu catalytic system are observed (Eq. 34).67

In contrast, stabilization of the enolate allows yields ranging from 54 to 81%(Eq. 35).71

BrMeN O

Pd(dba)2 (5 mol %), 2 (7.5 mol %)

NaOt-Bu (1.5 equiv), dioxane, 100° NMe

O(5%)

(Eq. 34)

BrMeN O

MeO

Pd(dba)2 (10 mol %), dppe (15 mol %)

KOt-Bu (1.5 equiv), dioxane, 100°

NMe

OMeO

OBn

BnO

(81%)

BnO

BnO

(Eq. 35)

Arylation of lactams is also possible. N-Methylpyrrolidinone (NMP) reactswith bromobenzene to give the expected arylation product in 49% yield, alongwith 9% of the diarylation product (Eq. 36).67

(49%)

Pd(dba)2 (5 mol %),2 (7.5 mol %)

NMe

ONMe

O

Ph

(9%)

NMe

O

PhPh

+KHMDS (2.0 equiv),

dioxane, 100°

+Br

(Eq. 36)

Arylpiperidones can also be prepared by palladium-assisted α-arylation of thederived zinc enolates (Eq. 37).72 No diarylation byproducts are observed. Theα-arylation process seems not to be dependent on the nitrogen atom substitution.In contrast, steric hindrance around the aryl halide has a significant impact on


yields: a modest 46% yield is observed with 2-methylbromobenzene whereas noarylation occurs with 2,6-dimethylbromobenzene.

NTs

O

NTs

O

(78%)

1. LiHMDS (2.5 equiv), THF, –20°2. ZnCl2 (2.2 equiv), THF, –20°

3. PhBr, Pd(dba)2 (5 mol %), 21 (7.5 mol %), THF, 65°

(Eq. 37)

α-Arylation of Esters. α-Arylation of methyl phenyl acetate, which involvesa doubly-stabilized anion, using a PdCl2 –Ph3P catalytic system and Cs2CO3 asthe base, affords the expected arylated ester in a modest 56% yield (Eq. 38).73

OMe

OPh

PhI, PdCl2 (5 mol %),Ph3P (10–20 mol %)

OMe

OPh

Ph

(56%)Cs2CO3 (1.2 equiv), DMF, 100°

(Eq. 38)

The use of hindered phosphines (Eq. 39), bidentate phosphines, or carbene-based ligands (Eq. 40) has been extended to the α-arylation of ester substrates.74,75

tert-Butyl acetate or propionate reacts with a wide range of aryl bromides at roomtemperature in high yields. Although 2.2 to 2.5 equivalents of base are necessaryto ensure complete conversion, diarylated byproducts are not observed.

Ot-Bu

O+

Pd(OAc)2 (3 mol %), 22 (6 mol %)

LHMDS (2.5 equiv), toluene, rt

(84%)

Ot-Bu

O

Br

(Eq. 39)

Ot-Bu

O

Pd(dba)2 (0.2–1 mol %), (t-Bu)3P or 29 (0.5–5 mol %)

(88%)

Ot-Bu

O+

CF3BrCF3 LHMDS or NaHMDS (2.2 equiv),toluene, rt

(Eq. 40)

Generation of the enolate prior to the coupling with a stronger hindered amidebase, such as LiNCy2, greatly improves the reaction and allows the formation ofquaternary carbon atoms (Eq. 41).23,74 Heterocycles such as furans, thiophenes,and pyridines are well-tolerated using this method. Moreover, high yields aregenerally obtained using low catalyst loadings and slight excesses of both esterand base.

(97%)OMe

O

OMe

O

Et

PhBr, Pd(dba)2 (1 mol %),(t-Bu)3P (1 mol %)

EtLiNCy2 (1.3 equiv), toluene, rt

(Eq. 41)


For aryl halides bearing base-sensitive or electrophilic substituents, the use ofzinc enolates again improves the yield (Eq. 42).76 In addition, these conditionsalso prove satisfactory for aryl halides bearing acidic and basic substituents, suchas bromophenols, bromoanilines, and substituted pyridines.

Ot-Bu

OPd(dba)2 (1 mol %), 36 (1 mol %)

THF or dioxane, rt+[Zn]

Ot-Bu

O

(96%)

Br

NO2NO2 (Eq. 42)

The arylation of lactones under palladium catalysis appears in a single report;however, only modest yields are obtained using the Pd/BINAP, NaHMDS cat-alytic system (Eq. 43).33

Pd(dba)2 (2.5 mol %), 2 (15 mol %)

NaHMDS, toluene, 50°OO

+

OO

OMe(31%)

MeO

Br

(Eq. 43)

More successful nickel-catalyzed α-arylations of esters have been developed,and this point will be discussed below.

α-Arylation of Amino Acids and Derivatives. Ethyl N ,N-dimethylglycin-ate (38) undergoes facile α-arylation even when using K3PO4 as the base(Eq. 44).77

OEt

OMe2N

Pd(dba)2 (2 mol %),(t-Bu)3P (2 mol %)

+

OEt

OMe2N

t-Bu

(84%)

t-Bu

Br

38K3PO4 (2.3 equiv), 100°

(Eq. 44)

Amino acids with more common nitrogen protecting groups have been evalu-ated subsequently. Because of their convenient preparation, imino esters derivedfrom benzophenone and benzaldehyde are of particular value. Under the afore-mentioned conditions ((t-Bu)3P, Pd(dba)2, K3PO4), imino ester derivatives arearylated in high yields (Eq. 45).77 Coordination of the substrate nitrogen atom isassumed to assist both the formation of the enolate and the arylation reaction.


OEt

ON

MeO

F(67%)

OEt

ON

MeO

F

Br

+

Pd(dba)2 (2 mol %), (t-Bu)3P (4 mol %)

K3PO4 (3 equiv), toluene, 100°

(Eq. 45)

Intramolecular α-arylation of α-amino acid esters provides easy access to 5-and 6-membered dihydroisoindole and tetrahydroisoquinoline derivatives in goodto excellent yields using a Pd2(dba)3/20 or 22 and LiOt-Bu catalytic system(Eq. 46). In these reactions, LiOt-Bu is superior to other bases such as NaOt-Bu, NaHMDS, phosphates, or carbonates (which cause decomposition of thestarting material or lead to poor conversion).78 In addition, this method allowsflexible access to fused tricyclic systems in fair to good yields. Although quater-nary carbon centers are accessible via the aforementioned intramolecular route,the analogous intermolecular α-arylation of α-alkyl α-amino acid derivatives isstill unreported.

(66%)

NMe

CO2t-Bu

MeO

MeO

Br

MeO

MeO

MeN

CO2t-Bu

Pd2(dba)3 (2.3 mol %), 20 (2.5 mol %)

LiOt-Bu (2 equiv), dioxane, 100°

(Eq. 46)

An elegant route to quaternary amino acids, involving a cyclodehydration–arylation–hydrolysis sequence, has been described (Scheme 3).79 α-Alkyl α-amino acids are first transformed into azalactones. In the second step, thepalladium-catalyzed α-arylation affords quaternary carbon centers in good yields

N

O O

R

PhPh N

HCO2H

RO cyclization

aza-lactone

Pd-assisted α-arylation

N

O O

R

Ph

aza-lactone(40–85%)

ArPh N

H

ROhydrolysisOH

O

Ar

P(t-Bu)

39

2P(n-Bu)

40

2

Scheme 3


(40–85%). Subsequent hydrolysis gives rise to the quaternary amino acids. Thehighest yields and fastest rates occur with catalytic systems based on 5 mol %Pd(dba)2 or Pd(OAc)2, 10 mol % of ligand 39 or 40 and 3.3 equivalents ofK2CO3 or K3PO4.

α-Arylation of Nitriles. Aliphatic nitriles are less acidic than ketones26,66

and thus require the use of stronger bases. For these substrates, the developmentof catalytic systems was first based on the general method established for ketonesand amino acid derivatives. However, hindered alkyl phosphines are less effectivethan the more common BINAP ligand 2. Thus, arylation of nitriles is possibleusing the Pd(OAc)2/2 catalytic system and affords high to quantitative yields ofthe expected arylated nitriles (Eq. 47).26

CN

Pd(OAc)2 (1 mol %),2 (1 mol %)

(89%)NaHMDS (1.3 equiv),

toluene, 100°

+Br CN

(Eq. 47)

A major limitation to this method is the arylation of linear nitriles. Only thediarylated product is obtained under the previously described conditions becauseof the increased acidity of the α-CH of the monoarylated product compared tothe starting material (Eq. 48).26

CN

CN

(69%)

Pd(OAc)2 (1 mol %),2 (1 mol %)

NaHMDS (1.3 equiv),toluene, 100°

+Br

(Eq. 48)

One elegant solution that circumvents the formation of diarylation byproductsis the coupling of aryl halides with silylaceto- or propionitriles.80 Under these con-ditions, monoarylation occurs selectively in the presence of Pd2(dba)3/(t-Bu)3P or24 and ZnF2 (Eq. 49). Highly hindered silyl derivatives fail to react under theseconditions and require the use of a stronger fluoride source such as KF. Indeed,α-arylation of α-trimethylsilylcyclohexanecarbonitrile occurs in good yields withvarious aryl bromides as exemplified by Eq. 50.

Pd2(dba)3 (2 mol %),(t-Bu)3P or 24 (2–4 mol %)

CN

(84%)

CNMe3Si+

EtO2C

Br

EtO2C ZnF2 (0.5 equiv), DMF, 90°

(Eq. 49)

NC SiMe3 24 (2 mol %), KF (1 equiv) NC(68%)

DMF, 90°+

Br

Pd2(dba)3 (2 mol %),

(Eq. 50)


α-Arylation of Active Methylene Compounds. Along with ketones andcarboxylic acid derivatives, active methylene compounds such as malonates,β-cyanoesters, malononitriles, and β-diketones represent an important class ofnucleophiles that can be arylated, thus considerably expanding the scope of themetal-assisted α-arylation reaction. An example of α-arylation of malononitrilesis shown in Eq. 51. The mechanism is assumed to proceed as described in Scheme1.14,81

Br+

CN

CN

PdCl2(Ph3P)2 (3–10 mol %)

NaH (1.5 equiv), THF, reflux

CN

CN (69%) (Eq. 51)

Recent work has significantly expanded the range of nucleophiles and nowallows malonates, acetoacetates, as well as β-cyanoesters to couple with aromatichalides in both an intra- and intermolecular fashion. Complete conversions areobtained using (t-Bu)3P, 3, 36, or 41 as ligands (with a palladium to ligand ratioof 1:1 or 1:2) in association with mild bases such as NaH or K3PO4 (Eq. 52).43,82

EtO OEt

O O+

EtO OEt

O O

(83%)

Pd(dba)2 (2 mol %), 41 (4 mol %), NaH (1 equiv)

Br

41P(t-Bu)2

THF, 70°

(Eq. 52)

With a view to industrial applications where catalyst and purification costsare of economic importance, the use of heterogeneous conditions has also beenexplored. Although the results do not rival the most recent developments inhomogeneous catalysis, [Pd(NH3)4]-zeolite in combination with NaOt-Bu, andPdCl4−2 in combination with Ba(OH)2, allow the arylation of diethyl malonatesin yields ranging from 38–84% and 93–99%, respectively.83,84 It is worth notingthat no diarylated products are observed.

The formation of quaternary carbon centers can be achieved starting fromfluoro malonates as shown in Eq. 53.40 However, attempts to couple alkyl-substituted malonates failed. This lack of reactivity is mainly attributed to sterichindrance, which inhibits the formation of the carbon-bound palladium–malonatecomplex. This limitation is overcome through a sequential arylation–alkylationprocess (Eq. 54).40

EtO OEt

O O

EtO OEt

O O

(88%)


F F PhNaH (1 equiv), THF, 70°

+ PhBr

(Eq. 53)


EtO OEt

O O+

EtO OEt

O O

(89%)

1. Pd2(dba)3 (1 mol %), (t-Bu)3P (4 mol %), K3PO4 (4.5 equiv), toluene, 70°

2. MeI

Br

(Eq. 54)

α-Arylation of 1,3-diketones can also be carried out. 1,3-Cyclohexanedioneand 1,3-cyclopentanedione undergo monoarylation using the aforementioned pro-cedure (Eq. 55).43

(96%)

O

O

Pd(OAc)2 (1 mol %),8 (2 mol %)

O

O

K3PO4 (2.3 equiv),dioxane, 100°

Br CO2Me+

CO2Me(Eq. 55)

Intramolecular arylation of 1,3-diketones has been described (Eq. 56). Al-though this strategy requires relatively high temperatures, precluding the useof thermally sensitive substrates, these results paved the way to more recentdevelopments.15,85

O

OI

O

O

(PPh3)4Pd (5 mol %)

NaH, DMF, 135°(76%) (Eq. 56)

Palladium-catalyzed α-arylations of β-keto esters are rare. However, the keystep of an elegant synthesis of the N-methylwelwitindolinone skeleton is based onan intramolecular palladium-catalyzed α-arylation of a β-keto ester (see below).86

Moreover, arylacetic acid esters can be prepared through a one-pot two-step strat-egy involving a palladium-catalyzed α-arylation of acetoacetate followed by an insitu base-catalyzed deacylation of the arylacetoacetate intermediate 42 (Eq. 57).87

(55%)O

Pd2(dba)3 (1 mol %),(t-Bu)3P (2 mol %)

CO2Et

OCO2Et

42

CO2Et

K3PO4 (2.5 equiv), toluene, 90°

Br

+

(Eq. 57)

Although the arylation of cyanoacetates using Pd(PPh3)2Cl2/KOt-Bu as thecatalytic system in 1,2-dimethoxyethane (monoglyme) proceed in low to goodyields (8–88%),88,89 recent advances allow selective access to monoarylated as


well as symmetrical and unsymmetrical diarylated cyanoacetates. Optimizationusing high-throughput screening led to the development of a high-yielding aryl-ation of cyanoacetates using Pd(dba)2/(t-Bu)3P (Eq. 58).90 However, reactionsof aryl halides bearing electron-withdrawing groups generate varying amountsof diarylated side products. The selectivity of this method can be improved byswitching from (t-Bu)3P to ligand 36, without a noticeable decrease in the aryl-ation yield. The reaction of 2 equivalents of aryl halide and ethyl cyanoacetateproduces symmetrical diarylcyanoesters (Eq. 59) and the reaction of 1 equiva-lent of aryl halide with monoarylcyanoacetates cleanly affords the correspondingunsymmetrical diarylated cyanoacetates (Eq. 60).90

+(87%)

Pd(dba)2 (1 mol %),(t-Bu)3P or 36 (4 mol %)

EtO

OCN

EtO

OCNCl

Na3PO4 (3.0 equiv), toluene, 70°

(Eq. 58)

(90%)EtO

OCN

EtO

OCN


Na3PO4 (3.0 equiv),toluene, 70°

(2 equiv)

Br

+

(Eq. 59)

(93%)EtO

OCN


EtO

OCN

Br+

Na3PO4 (3.0 equiv), toluene, 70°

(Eq. 60)

Vinylogy, Phenylogy. Site Selectivity in γ/ω-Arylation. In substratesincorporating vinyl and phenyl groups, arylation may occur at the γ- and ω-position according to vinylogy and phenylogy principles.91 In α,β-unsaturatedcarbonyl substrates, where both α- and γ-positions are prone to arylation, only γ-arylation occurs even in substrates having hydrogen available for syn-β-elimina-tion (Eq. 61).92 Arylation at the β-position (Heck reaction) is not observed. Cyclicenones are also good substrates for γ-arylation (Eq. 62).92 Mono- or diarylatedcompounds can be obtained selectively by changing the amount of aryl bromide.

CHOPd(OAc)2 (5 mol %),

Ph3P (10 mol %)(79%)

CHOCHOγ α

Pd

–

Cs2CO3 (1.2 equiv), DMF, 120°

Br

+

(Eq. 61)


(58%)

O

n-C5H11

O

n-C5H11

Cs2CO3 (1.2 equiv), DMF, 120°


Br+

(Eq. 62)

Alkylated nitroaromatic compounds undergo arylation in the side chains(Eq. 63).93 Although good yields are obtained, the arylation process often affordsmixtures of mono- and diarylated products. It is worth noting that selective diaryl-ation may occur when 2 equivalents of the aryl bromide are used. However, thisreaction is sensitive to steric factors and depends on the aromatic substitutionpattern. Indeed, despite the use of 2 equivalents of the aryl bromide, selectivemonoarylation is obtained in the presence of neighboring substituents in eitherthe aromatic halide or the nitro-substrate, or at the benzylic position.

NO2 Pd(OAc)2 (5 mol %),Ph3P (10 mol %)

NO2

(70%)Cs2CO3 (1.2 equiv),

DMF, 120°

Br+

(1.2 equiv)

(Eq. 63)

α-Arylation via α-Stannylmethyl Carbonyl Compounds. α-Stannylmethylketones are usually considered masked tin enolates. Although this strategy alsorequires the preparation of the stannylated coupling partner (in some cases suchtin derivatives can be prepared in situ), α-aryl ketones are cleanly obtained inyields ranging from 51–91% in the presence of PdCl2[P(o-tol)3]2 (Eq. 64).10

OSnBu3


toluene, 100°O

+

(74%)

NMe2

Br

NMe2

(Eq. 64)

Products arylated at the γ-position of α,β-unsaturated esters have been obtainedfrom the corresponding tin derivatives (Eq. 65). The reaction takes place at thecarbon directly bonded to tin. The allylic transposition product (α-arylation) isnot detected.94,95

SnBu3

CO2Et

+


CO2Et

γα

(30%)

α

O

OEt–

OMe

Br

OMe

toluene, reflux

γ

(Eq. 65)


A similar strategy introduces an aromatic group on an acetate moiety.96,97

Indeed, the preparation of the arylacetic fragment of elisabethin A involvesarylation of an acetate ester through tin–zinc transmetallation and a subsequentNegishi-type coupling (Eq. 66).

EtO

OSnBu3


ZnBr2 (1.4 equiv), DMF, 80°+

(71%)

Br

OTBS

OTBS

OMeOTBS

OTBS

OMe

EtO

O

(Eq. 66)

α-Arylation of Silyl Enol Ethers and Ketene Acetals. The α-arylation ofsilyl enol ethers with aryl halides requires the use of a stoichiometric amount ofBu3SnF as an additive. The reaction is assumed to proceed by in situ generationof tin enolate 43 via silicon–tin exchange followed by a palladium-catalyzedα-arylation (Eq. 67).12,13

PhBr,PdCl2[P(o-tol)3]2 (3 mol %)

n-C7H15

OSiMe3

n-C7H15

O(65%)

43

Bu3SnF (1.05 equiv)

n-C7H15

OSnBu3

benzene, reflux

(Eq. 67)

Interestingly, good selectivity is observed in substrates bearing two silyl enolether groups. Steric interactions between large alkyl groups and the approach-ing tin fluoride have been postulated to explain the observed selective arylation(Eq. 68).12,13

exclusive arylation

PdCl2[P(o-tol)3]2 (4.5 mol %)

Bu3SnF (2 equiv), benzene, reflux

O

OSiMe3

AcO

Br

AcO+

7

OSiMe3

OSiMe3

7

(—)

(Eq. 68)


α-Arylation of silyl ketene acetals also requires the use of additives, such asBu3SnF or CuF2 (Eq. 69).98

Ot-Bu

OTBS PdCl2[P(o-tol)3]2 (5 mol %)

CuF2 (2 equiv), THF, reflux+ CO2t-Bu (81%)

OMeBr

OMe

(Eq. 69)

More recently, a general α-arylation procedure for silyl ketene acetals thatuses catalytic amounts of a Lewis acid promoter was reported. Thus, 0.25–0.50equivalents of ZnF2 or Zn(Ot-Bu)2 allows complete reaction and arylation in highyields (Eq. 70). Since transmetalation products or accumulation of zinc enolatescould not be detected, the exact role of the zinc-based additives is still unclear.99

Ot-Bu

OSiMe3

Pd(dba)2 (1 mol %), (t-Bu)3P (2 mol %)

+ CO2t-Bu (75%)

CNBr

CNZnF2 (0.5 equiv), DMF, 80°

(Eq. 70)

This method has been extended to ketimines and silyl ketene acetals bearingchiral auxiliaries and thus to the diastereoselective formation of tertiary stere-ogenic centers (Eqs. 71 and 72).

O N

OSiMe3O

O N

O

(78%) 92:8 dr


O

Br+

ZnF2 (0.5 equiv), DMF, 80°

(Eq. 71)

(67%) >50:1 dr

OO

OMe

OMeMe3SiO

OO

OMe

OMeO

PhHO

OMe

Odeprotection

>99.5% ee


ZnF2 (0.5 equiv), DMF, 80°

Ph

+ PhBr

(Eq. 72)

The requirement for metal-based additives can be avoided by the use of aryltriflates. In the presence of palladium(II) and lithium acetate, α-arylated estersare often obtained in high yields (Eq. 73).100


OMe

OSiMe3

1 (8 mol %),(η3-C4H7PdOAc)2 (2 mol %)

CO2Me(53%)

LiOAc (2 equiv), THF, reflux

OTf+

(Eq. 73)

Copper-Catalyzed α-ArylationAlthough palladium complexes are the most studied catalytic systems for α-

arylation of enolates, nickel and copper catalysts were initially used. Reaction ofvarious halobenzoic acids in the presence of CuBr allows the formation of theexpected arylation product (Eq. 74).101

CO2H

Br

O O+

CO2H

O

OCuBr (6 mol %)

NaH (2 equiv)(74%)

Br Cu

O

O

NuBr

–O

O

Cu

COO–

Nu

+ CuBr

(Eq. 74)

The arylation is assumed to proceed through a copper-assisted nucleophilicdisplacement of the bromide anion. This strategy is limited to active methy-lene compounds and requires the presence of an ortho carboxylic acid group.This protocal has been extended to the arylation of malononitriles and relatedsubstrates,102 and to the formation of benzofuran-2-ones.103 The α-arylation ofmalononitrile and its derivatives proceeds in the presence of a catalytic amountof CuI as shown in Eq. 75.102

CuI (10 mol %)

K2CO3 (8 equiv)(80%)NC CN

NC CN

+

Br

(Eq. 75)

Catalytic amounts of CuBr promote the reaction between dimethyl malonateand 2-bromophenols to afford the corresponding benzofuran-2-ones in one step(Eq. 76). Access to benzofurans from the copper-catalyzed arylation of β-ketoesters has also been described (Eq. 77).104

+CuBr (20 mol %)

NaH (2 equiv)

(60%)

O O

MeO OMe

Br

HO

OO

OOMe

–O

O

O

MeO

OMe

(Eq. 76)


I

Br

+OEt

O O CuI (10 mol %), K2CO3 (1.5 equiv)

THF, 100°O

CO2Et

(83%)

(Eq. 77)

The use of CuI in combination with 2-phenylphenol105 or 2-nicotinic acid106

as the ligand allows mild arylations of malonates in high to excellent yields atroom temperature (Eq. 78).

+

CuI (5 mol %),

(90%)O O

EtO OEt

O O

EtO OEt

PhHO (10 mol %)

OMe

OMe

IOMe

OMe

Cs2CO3 (1.5 equiv)

(Eq. 78)

The efficient copper-catalyzed enantioselective α-arylation of β-keto esters waspresented earlier (Eq. 13).36

Nickel-Catalyzed α-ArylationUntil the recent development of a Ni–BINAP catalytic, enantioselective α-

arylation of lactones (Eq. 9) and the N-heterocyclic carbene-based nickel com-plex 44 promoted α-arylation of acyclic ketones (Eq. 79),107 examples of nickel-catalyzed arylations of enolates were rare. Two papers independently describedthe arylation of lithium (Eq. 80)108 and zinc enolates (Eq. 81).109

Br

+

O44 (10 mol %), NaOt-Bu (1.3 equiv)

toluene, 100°O

(87%)

N N

Ni ClCl

PPh3

44 (Eq. 79)

NiBr2 (100 mol %),n-BuLi (20 mol %)

(73%)LiO

Ot-Bu

O

Ot-Bu+

I THF, –78° to rt

(Eq. 80)


+Ni(PPh3)4 (10 mol %)

dimethoxymethane/HMPA (1:1)

(69%)

BrZnO

OEt

O

OEtBr

(Eq. 81)

Although the nature of the catalytic system (n-BuLi–NiBr2) is still unclear,the arylation of preformed lithium ester enolates with aryl halides occurs inmodest to high yields and is viable for both arylation and vinylation reactions(Eq. 80).108 Preformed zinc enolates (Reformatsky-type reagents) can also bearylated in the presence of nickel(0) catalysts. However, the use of unstable andair sensitive Ni(PPh3)4, even at 10 mol % loading, affords good yields of theexpected arylated products (Eq. 81).109

An efficient α-arylation of malononitrile has also been described usingNi(PPh3)4 (generated in situ from NiBr2(PPh3)2, Ph3P, and zinc) as the catalyst(Eq. 82).110

I

NC CN +

NiBr2(PPh3)2 (20 mol %), Ph3P (40 mol %), Zn (60 mol %)

NC CN

(70%)KOt-Bu (2.2 equiv), THF, 60°

(Eq. 82)

APPLICATIONS TO SYNTHESIS

Transition-metal-catalyzed α-arylations of carbonyl compounds have foundmany useful synthetic applications,15,111 particularly in the synthesis of naturalproducts and biologically active substances. Bonjoch and Wills have describedapproaches to the syntheses of bridged azabicyclic and 1-vinyl-1H -isochromenecompounds, respectively (Fig. 6).63,112,113 As previously discussed, access tobenzofurans (Eq. 26) and benzothiophenes is possible through a C-arylation,O-arylation sequence.61,62,64

RN

O

RN

O

O

R

Figure 6. Palladium-assisted bond formation.

An efficient synthesis of trileptal, one of the most widely prescribed drugs forthe treatment of epilepsy, involves a palladium-catalyzed α-arylation followed bya palladium-catalyzed N-arylation (Eq. 83).114


NHTs

O

BrBr

Pd(OAc)2 (4.4 mol %),23 (8.5 mol %)

NHTs

O

Br

NH

OPd-catalyzedα-arylation

Pd-catalyzedN-arylation

+

(85%)

1. H2SO4, rt2. Pd(OAc)2 (4.9 mol %), 2 (7.9 mol %)

(91%)

Cs2CO3 (1.4 equiv),toluene, H2O, 120°

K3PO4 (1.97 equiv),toluene, H2O, 130°

N

NH2O

O

trileptal

1. ClSO2NCO, CHCl3, rt

2. H2O, rt

(Eq. 83)

The key step in an approach to the N-methylwelwitindoline skeleton involvesan intramolecular palladium-catalyzed α-arylation of a cyclic β-keto ester deriva-tive (Eq. 84).86

MeO

O O

NMe

Br

Pd(OAc)2 (30 mol %),(t-Bu)3P (60 mol %)

MeO

O O

NMe

(74%) N-methylwelwitindolinone C isothiocyanate

SCNO

NMe

HO

H

KOt-Bu (2 equiv), toluene, 70°

H

(Eq. 84)

Efficient syntheses of cherylline and latifine use the intramolecular α-arylationof amides (Eq. 85),71 and a total synthesis of lennoxamine (Eq. 86) employsintramolecular α-arylation of an α-amido ketone.115

Br

BnO

MeOMeN

OOBn

NMe

O

BnO

MeO

OBn

Pd(dba)2 (5 mol %), dppe (5 mol %)

NMeBnO

MeO

OH

cherylline

(81%)

KOt-Bu (1.1 equiv), dioxane, 100°

(Eq. 85)


NO

O

O

OOMe

OMeBr

Pd2(dba)3 (5 mol %), 2 (10 mol %) N

O

O

O

O

OMe

OMe(65%)

NO

O

O

OMe

OMe

lennoxamine

KOt-Bu (1.5 equiv),dioxane, 100°

(Eq. 86)

COMPARISON WITH OTHER METHODS

The arylation of enolates has been a challenging subject of research formore than fifty years. The advent of transition-metal-catalyzed carbon–carbonbond formation overcomes many of the drawbacks of existing methods. How-ever, some catalytic, stoichiometric, and metal-free methods represent useful,complementary strategies that also allow the α-arylation of enolates. The follow-ing section focuses on: (1) palladium-catalyzed α-arylation from α-halomethylketones, (2) α-arylation involving the stoichiometric use of transition metals ormetals, (3) miscellaneous methods including photo-induced α-arylation, iodo-nium salt α-arylation, and nucleophilic aromatic substitution using enolates.

Palladium-Catalyzed α-Arylation via α-Halomethyl Carbonyl CompoundsAs shown in Eq. 87, oxidative addition of α-chloro ketones to a palladium(0)

species affords C-bound “palladium enolates”, some of which have been iso-lated and fully characterized.116 Adducts of this type, such as that derived fromethyl bromoacetate, are able to couple with arylboronic acids under Suzuki-typereaction conditions (Pd(OAc)2, P(1-naphthyl)3, K3PO4) to give the correspond-ing arylated acetic acid ester derivatives (Eq. 88).117 The main drawback of thisstrategy is the required preparation of α-halo carbonyl compounds prior to thecoupling reaction.

OCl (PPh3)4Pd

toluene

OPd(PPh3)2Cl (Eq. 87)

OEt


(1-Naphthyl)3P (9 mol %)+

(74%)

BrOEt

OOHC

B(OH)2

OHC

K3PO4 (5 equiv), THF, 20°

(Eq. 88)

Stoichiometric Transition-Metal- and Metal-Promoted α-ArylationCopper-Mediated α-Arylation. Stoichiometric, copper-mediated α-arylation

of ketones and other carbonyl derivatives has been known for almost a century.


Early reports deal with arylation of acetylacetone, ethyl malonate, and activemethylene anions in the presence of copper-bronze or copper acetate.118 – 120

More recently, reactions of α-halo tosylhydrazones with an excess of phenylcop-per (Eq. 89)121 or a bromination–phenylation sequence on enamines (Eq. 90)122

smoothly afford the products, which are converted into the corresponding α-phenyl cycloalkanones.

NNHTs

Cl1. PhCu, THF, –60°

2. BF3•Et2O, Me2CO, H2O

O

Ph (72%) (Eq. 89)

NBr2, Et3N

O

Ph (65%)

O

N

O

Br

Ph2CuLi

THF, –23°(Eq. 90)

α-Chloromethyl trimethylsilyl enol ethers also undergo arylation using lithiumdiarylcuprate. Depending on the reaction temperature, the arylated silyl enol ether45 or the corresponding arylated ketone 46 may be obtained (Eq. 91).11

OSiMe3

Cl

OSiMe3

Ph

OPh

(79%)

45

46

Ph2CuLi

Et2O, 0°, 5.5 h(78%)

Ph2CuLi

Et2O, 0°, 5 h;then rt, 4 h

(Eq. 91)

Activation of symmetrical and unsymmetrical active methylene compoundswith 1.2 to 1.3 equivalents of CuBr in refluxing dioxane allows the arylation ofmalonates (Eq. 92).123,124

EtO OEt

O O PhBr, CuBr (1.2–1.3 equiv)

dioxane, 100°EtO OEt

O O

(70%) (Eq. 92)

CuI is used as a stoichiometric coupling agent in arylation reactions of unsym-metrical, phosphonyl-stabilized carbanions (Eq. 93). Two equivalents of both CuIand the active methylene reactant are required to obtain good to high yields.125

(EtO)2P SO2MeO PhBr, CuI (2 equiv)

DMF or HMPA(58%)

(EtO)2P SO2MeO

(2 equiv)

(Eq. 93)


Magnesium- and Titanium-Mediated α-Arylation. Although stoichiomet-ric magnesium- or titanium-based arylations are rare, their use allows easy accessto arylated ketones or diarylated esters in some cases. An example is the reactionof 2-chlorocyclohexanone with phenylmagnesium bromide (Eq. 94).126

+

OCl

O

(58%)Et2O

BrMg(Eq. 94)

The reaction of α-arylacetic esters with tertiary arylamines in the presence ofstoichiometric amounts of TiCl4 affords the corresponding α,α-diarylated ester(Eq. 95).127 The proposed mechanism involves both the titanium ester enolate 47and aryltitanium species 48.

+NMe2

O

OEt TiCl4 (1.35 equiv)

CH2Cl2, 0° to rt

(89%)

O

OEt

NMe2

NMe2

TiCl3

O

OEt

TiCl347

48

+

(Eq. 95)

Bismuth-Mediated α-Arylation. Ketones, active methylene derivatives,silyl enol ethers, and silyl ketene acetals are arylated under basic or neutralconditions using stoichiometric amounts of polyarylbismuth(V) compounds suchas pentaphenylbismuth, tetraphenylbismuth chloride or triphenylbismuth dichlo-ride as phenylating agents.128,129 The postulated mechanism involves the O–Bibonded intermediate 49 (Eq. 96). Internal ligand coupling between the aryl groupand the enolate carbon accounts for the observed α-arylated products.

OH

Ph

Ph

O

PhPhPh

Ph

49

(69%)Ph5Bi, AcOHO

Ph

Ph

[Bi]O

(Eq. 96)


α,β-Unsaturated carbonyl derivatives undergo site selective α-arylation withconcomitant deconjugation of the olefinic moiety (Eq. 97).37,130

LDA (2.2 equiv), Ph3BiCl2 (2.2 equiv)

OEt

O

OEt

O OEt

O

Ph

(63%)[Bi]

Ph

HMPA (2.2 equiv), THF, –78°(Eq. 97)

Cyclic α,β-unsaturated ketones react with arylbismuth reagents in the presenceof tributylphosphine and Hunig’s base to afford α-arylation products (Eq. 98).The reaction likely proceeds by formation of phosphonium intermediate 50 fol-lowed by the generation of Bi-enolate 51, the α-arylation reaction, and subsequentelimination of the phosphine.38

OO–

PBu3+

Ph[Bi]O

PBu3+

[Bi]Ph

PBu3

O

Ph

50 51(70%)

PBu3

i-Pr2NEt

(Eq. 98)

Lead-Mediated α-Arylation. Aryllead triacetates effect the construction ofα-aryl carbonyl compounds under mild conditions. As shown in Fig. 7, thismethod introduces aryl groups into various substrates, including β-dicarbonyls,active methylene compounds, lactones, dihydroindoles, benzofurans, and neo-flavones.131 – 135 In most cases, 1.1 equivalents of the aryllead derivative, obtainedthrough Hg–Pb or Sn–Pb exchange, are required to ensure complete transforma-tion. Reaction rates are significantly enhanced by the use of additional ligandssuch as 1,10-phenanthrolines.136

O O

O OAr

RN NR

O OAr

O

RO2C Z

Ar

Z = CO2R, CN

O2N alkyl

Ar

Z

O

Ar

Z = NR, O

O

Ar

O

O

RO2C ArO

Figure 7. α-Aryl carbonyl compounds formed with aryllead triacetates.


Asymmetric coupling of aryllead reagents with β-keto esters is achieved byreplacement of one or more of the labile acetate ligands with enantiomeri-cally pure carboxylic acids such as 52 or the binaphthyl dicarboxylic acid 53(Eq. 99).133,137

OCO2Me +

OMe

Pb(OAc)3

52 or 53 (3 equiv)

CHCl3, –20°

CO2HCO2H

O

CO2Me

OMe

(74%) 43% ee

53

OO

OOH

OO

OHO

52

(Eq. 99)

Miscellaneous α-Arylation MethodsIntroduction of aryl groups at the α-carbon of carbonyl compounds may also

be accomplished through several non-metallic procedures. The following sectionbriefly illustrates the most relevant ones, including nucleophilic or photo-inducedaromatic substitution and α-arylation using iodonium salts.

Nucleophilic aromatic substitution of activated aryl halides by carbon nucleo-philes proceeds through Meisenheimer-type intermediates and is followed byrearomatization. This process requires the presence of strong electron-withdrawinggroups or complexation of the aromatic system with metallic fragments suchas Cr(CO)3. In this context, efficient arylation of ketone hydrazones with η6-(chlorobenzene)Cr(CO)3 followed by decomplexation and hydrolysis has beenreported (Eq. 100).138

Cr(CO)3 (64%)Ph

NNMe2

Cl

2. air, hν3. H+

Ph

O

1. BuLi (1.1 equiv)

Ph

N

2

1.

2. CuI (1.2 equiv), THF, –5°

NMe2

CuLi

(Eq. 100)

In addition, the diastereoselective arylation of protected mandelic acids withfluoronitrobenzenes under basic conditions affords the expected arylated products(Eq. 101).139

OO

O

Pht-Bu

H LDA (1.2 equiv)

THF, –78°+ O

O

O

Pht-Bu

H

NO2

(27–85%)F NO2 (Eq. 101)


Photo-stimulated formation of carbon–carbon bonds between aromatics andenolate equivalents has also received considerable attention. Photo-induced gen-eration of phenyl cations and subsequent reaction with enamines, silyl enol ethers,or ketene silyl acetals afford the corresponding α-arylated carbonyl compounds(Eqs. 102 and 103).96,140,141

NMe2

Cl

hνNMe2

+

OTES

NMe2

(63%)

O

Et3N (20 mol %), MeCN(Eq. 102)

OSiMe3

MeO

NMe2

MeO2C

(60%)hν

Et3N (20 mol %), MeCN

NMe2

Cl

+ (Eq. 103)

An alternative strategy involves the use of diaryliodonium salts as the “phenylcation” species. Such species exploit the excellent nucleofugality of the phenylio-donium group, which is about 10 times higher than that of triflate.142 Thetreatment of silyl enol ethers with diaryliodonium fluorides affords the expectedarylated ketones. Although the mechanism is still unclear, it might involve atrivalent iodine intermediate 54 as suggested in Eq. 104.143,144

OSiMe3O

I OPh

54

(20%)Ph2I+F–

THF

PhPh

(Eq. 104)

A second alternative, involving deprotonation of cyclic ketones followed bygeneration of a copper enolate and subsequent coupling using diaryliodoniumsalts, is shown in Eq. 105.145

1. LDA, –78°2. CuCN, –78° to –35°

O O

(55%)3. Ph2I+OTf–, –78° to rt

(Eq. 105)

A recent synthesis of (–)-epibatidine employs a chiral amide base to desym-metrize 4-substituted cyclohexanone derivatives, which then react with a diarylio-donium salt to give the arylated products in high yields, and modest dr and ee(Eq. 106).146


O

OTBS

O

OTBS

1. Ph NLi

Ph, –118°

2. (pyridyl)2 I+Cl–, –45°

(70%)90% ee, 2:1 dr

N

ClN

Cl

HN

epibatidine

(Eq. 106)

EXPERIMENTAL CONDITIONS

An attractive aspect of the transition-metal-catalyzed α-arylation of enolates isits experimental simplicity. Although the use of a glove-box was initially recom-mended, most of the reactions can be carried out efficiently using normal Schlenktechniques in anhydrous solvents. As discussed above, a wide variety of differentconditions (palladium source, ligand, base, solvent) have been developed, but itappears that Pd2(dba)3 [(or Pd(OAc)2), (t-Bu)3P in dioxane (or toluene)] in thepresence of an excess of NaOt-Bu [(NaHMDS or LiNCy2 in the arylation ofesters and amides)] are often the first experimental conditions to be tried.

EXPERIMENTAL PROCEDURES

O

I

Pd2(dba)3 (0.5 mol %),24 (1.2 mol %)

O

BrBrCs2CO3, toluene, 80°

OPPh2PPh2

24

(78%)+

2-(2-Bromophenyl)cyclohexanone [Palladium-Catalyzed α-Arylation of aKetone].62 Cesium carbonate (4.570 g, 14.00 mmol) was added to a flaskcharged with Pd2(dba)3 (0.030 g, 0.033 mmol) and Xantphos (24) (0.040 g,0.080 mmol) under nitrogen. The reagents were suspended in anhydrous dioxane(6.4 mL); 1-Bromo-2-iodobenzene (1.80 g, 6.37 mmol, 0.82 mL) and cyclohex-anone (1.25 g, 12.74 mmol, 1.3 mL) were added under nitrogen, and the reactionmixture was heated at 80◦ for 24 h. After cooling, the reaction mixture wasdiluted with Et2O (ca. 10 mL), filtered through Celite, and the solvents wereremoved in vacuo. The residue was purified by flash column chromatography(5–10% Et2O/petroleum ether) to give 1.26 g (78% yield) of the title product:mp 57–58◦ (MeOH); IR (Nujol) 2920, 2855, 1709, 1566 (w), 1462, 1377, 1281,1196, 1121, 1070, 1027, 977, 940, 769, 746, 722, 674 cm−1; 1H NMR (300 MHz,CDCl3) δ 7.56 (td, J = 7.9, 1.5 Hz, 1H, Ar–H), 7.31 (td, J = 7.9, 1.1 Hz, 1H,


Ar–H), 7.21 (dd, J = 7.9, 1.9 Hz, 1H, Ar–H), 7.12 (ddd, J = 7.9, 7.2, 1.9 Hz,1H, Ar–H), 4.11 (app. dd, J = 12.4, 5.3 Hz, 1H, Ar–CH), 2.89–2.51 (m, 2H,CH2CO), 2.35–2.15 (m, 2H, ArCHCH2), 2.10–1.71 (m, 4H, CH2); 13C NMR(75 MHz, CDCl3) δ 208.3, 137.8, 132.1, 128.9, 127.8, 126.8, 124.6, 56.0, 41.8,33.6, 27.1, 25.1; LRMS (CI+, NH3) m/z: [M + NH4]+ 270, [M + H:79Br]+ 253,[M − 79Br]+ 173, [M − 79Br–CO]+ 145, [M − 79Br–CO–C2H4]+ 115; HRMS(ES+): [M + H]+ calcd for C12H14BrO, 253.0223; found, 253.0225.

O(IPr)Pd(OAc)2 (1 mol %)

NaOt-Bu, dioxane, 60°

O

RR

Cl

+

1-Phenyl-2-arylpropan-1-one [α-Arylation of a Ketone Using an N -Hetero-cyclic Carbene-Based Catalytic System].51 In a drybox, 1.5 mmol of base(typically NaOt-Bu) was added to a screw-cap vial charged with 1 mol % of[N ,N ′-(2,6-diisopropyl phenyl)imidazol-2-ylidene]Pd(OAc)2 complex. Dioxane(1.5 mL) was added and the vial sealed with a rubber septum. Outside the drybox,propiophenone (1.2 mmol) followed by the aryl halide (1 mmol) were injectedinto the vial with a syringe. The reaction mixture was shaken on a Lab-LineOrbit Shaker at 60◦ (J-Kem Scientific, Kem-Lab Controller) or stirred over amagnetic plate in an oil bath set at 60◦ for the indicated time. The reactionswere monitored by gas chromatography. After reaching maximum conversion,the reaction mixture was allowed to cool to rt and it was then quenched withwater. The water layer was extracted with methyl tert-butyl ether or Et2O anddried over magnesium sulfate. The solvent was then evaporated in vacuo. Whennecessary the product was purified by flash chromatography on silica gel.

O

t-BuBr

OTBS

Pd2(dba)3 (5 mol %), 1 (10 mol %)

O

t-Bu

Fe

PPh2

PPh21

LHMDS, dioxane, 100°+ (71%)

1-Vinyl-3-tert-butyl-1H -isochromene [Palladium-Catalyzed α-Arylation ofa Ketone].63 A solution of LiHMDS (1 M in THF, 3 equiv) was treatedslowly with a solution of 3,3-dimethylbutan-2-one (2 equiv) at 5◦. A solution ofPd2(dba)3 (5 mol %) and dppf (1) (10 mol %) in solvent was added at rt, followedby a solution of (E/Z)-tert-butyldimethyl[3-(2-bromophenyl)allyloxy]silane (1equiv). The reaction mixture was heated at 100◦ overnight and quenched with 1M HCl solution at rt. The mixture was twice extracted with CH2Cl2, the combined


organic layers were dried, and the solvent was evaporated under reduced pres-sure yielding the crude product, which was purified by chromatography (detailsnot reported) to give the title compound in 71% yield: IR (NaCl) 2954, 1638,1085, 914, 750 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.30–6.90 (m, 4H), 6.15(ddd, J = 17.1, 10.4, 6.6 Hz, 1H), 5.67 (s, 1H), 5.46 (d, J = 6.6 Hz, 1H), 5.16(dt, J = 17.1, 1.3 Hz, 1H), 5.23 (dt, J = 10.4, 1.3 Hz, 1H), 1.16 (s, 9H); 13CNMR (75 MHz, CDCl3) δ 164.2, 136.7, 132.0, 129.4, 128.5, 126.2, 124.9, 123.8,118.2, 97.7, 79.3, 35.5, 28.3; MS (EI) m/z: M+ 214, 187, 129; HRMS (EI) m/z:calcd for C15H18O, 214.135765; found, 214.136173.

NPh

CO2t-Bu

NPh

CO2t-BuBr

Pd2(dba)3 (2.25 mol %), 22 (5 mol %)

LiOt-Bu (2 equiv), dioxane (0.2 M)(78%)

PCy2

NMe2

22

tert-Butyl 2-Phenyl-2,3-dihydro-1H -isoindole-1-carboxylate [Palladium-Catalyzed Intramolecular α-Arylation of an α-Amino Acid Ester].78 Anoven-dried resealable Schlenk tube containing a magnetic stir bar was evacu-ated and purged with argon while cooling to ambient temperature. The Schlenktube was charged with LiOt-Bu (2.0 equiv), Pd2(dba)3 (2.25 mol %), and 2-(dicyclohexylphosphino)-2′-(N ,N-dimethylamino)biphenyl (5 mol %). The reac-tion vessel was evacuated, backfilled with argon, and dioxane (2 mL) was addedvia syringe under argon. The mixture was stirred for 5 min at rt, followed byaddition of a solution of dodecane (0.045 mL, 0.2 mmol) and the substrate (0.188g, 0.5 mmol) in dioxane (0.5 mL) via syringe. The solution was 0.2 M in dioxaneas solvent. The Schlenk tube was sealed and placed in a preheated oil bath at85◦ for 1 h. After complete conversion, as judged by either GC or TLC analy-sis, the reaction mixture was cooled to ambient temperature. The crude mixturewas filtered through a silica gel plug, and the plug then washed thoroughly withether. The filtrate was concentrated and further purified by flash column chro-matography (hexanes/ether 15:1) to give 0.115 g (78% yield) of the title product:mp 72◦; IR (CH2Cl2) 3043, 2979, 2933, 2875, 2840, 1740, 1603, 1505, 1468,1368, 1146, 1094, 1036, 1003, 955, 839, 750, 690 cm−1; 1H NMR (400 MHz,C6D6) δ 7.47–7.41 (m, 1H), 7.32–7.26 (m, 2H), 7.10–7.03 (m, 2H), 6.97–6.91(m, 1H), 6.86–6.81 (m, 1H), 6.70–6.55 (m, 2H), 5.36–5.33 (d, J = 3.5 Hz, 1H),4.59–4.53 (dd, J = 3.5, 12.9 Hz, 1H), 4.36–4.31 (d, J = 12.9 Hz, 1H), 1.19 (s,9H); 13C NMR (100 MHz, C6D6) δ 171.2, 146.9, 139.1, 138.0, 130.0, 128.7,127.8, 123.4, 123.0, 117.7, 112.8, 81.5, 68.3, 57.8, 54.3, 28.1. Anal. Calcd forC19H21NO2: C, 77.26; H, 7.17. Found: C, 77.12; H, 7.17.


Br

NBn

O

NBn

OPd(dba)2 (5 mol %), 2 (7.5 mol %)

KOt-Bu (1.5 equiv), dioxane, 100°(66%)

PPh2

PPh2

2

1-Benzyloxindole [Preparation of an Oxindole by Palladium-CatalyzedIntramolecular α-Arylation of an Amide].67 In a drybox, Pd(dba)2 (57.5 mg,0.10 mmol), BINAP (2) (93.4 mg, 0.15 mmol), and potassium tert-butoxide(288 mg, 3.00 mmol) were combined in a round-bottom flask. Dioxane (18 mL)was added, and the flask was sealed with a septum. After removing the flaskfrom the drybox, 2-bromo-N-benzylacetanilide (609 mg, 2.00 mmol) was added.The flask was placed in an oil bath at 100◦ for 3 h. The reaction mixture waspoured into 50 mL of saturated NH4Cl solution and extracted (3 × 30 mL) withether. The combined ether extracts were washed with brine (50 mL), dried overMgSO4, and filtered. The solvent was removed under vacuum, and the resultingcrude product was purified by flash chromatography on silica gel (hexanes/EtOAc85:15); recrystallization from hexanes gave 0.297 g (66% yield) of the title prod-uct as pale yellow needles: mp 66.5–67◦; FTIR (neat, NaCl plate) 1717 cm−1;1H NMR (500 MHz, CDCl3) δ 7.34–7.33 (m, 3H), 7.30–7.26 (m, 2H), 7.19 (t,J = 7.8 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.94 (s,2H), 3.65 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 175.3, 144.4, 135.9, 128.8,127.9, 127.7, 127.4, 124.5, 124.5, 122.5, 109.2, 43.8, 35.8. Anal. Calcd forC15H13NO: C, 80.68; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.92; N, 6.16.

Pd2(dba)3 (3 mol %), 8 (6 mol %)

Cs2CO3 (1.2 equiv), DME, 50º

NO2

NO2

(90%)

P(t-Bu)2

8

Br+

(1-Nitroethyl)benzene [Palladium-Catalyzed α-Arylation of Nitro-ethane].147 A dried, resealable Schlenk tube containing a magnetic stir bar wascharged with Pd2(dba)3 (27.4 mg, 0.03 mmol, 3 mol %), 2-(di-tert-butylphos-phino)-2′-methylbiphenyl (8) (19.2 mg, 0.06 mmol, 6 mol %), and 1.2 equiv ofCs2CO3. The reaction vessel was capped with a rubber septum, evacuated, and


backfilled three times with argon, and 1.0 mmol of bromobenzene, dimethoxy-ethane (5 mL), and 1.0–2.0 equiv of nitroethane were added sequentially viasyringe under argon. The mixture was stirred vigorously for 1 min at rt, theSchlenk tube was sealed and placed in a preheated oil bath at 50◦ for 8–30 h.After completion of the reaction, as judged by either GC or TLC analysis, thereaction mixture was allowed to cool to ambient temperature. The crude mixturewas quenched with a solution of saturated aqueous NH4Cl (2 × 2 mL, two times),the aqueous phase was extracted with ether (2 mL), and the combined organicphases were washed with brine. The solvent was removed, and the remain-ing oil was purified by flash silica gel column chromatography (hexanes/Et2O20:1) to provide 0.136 g (90% yield) of the title product: 1H NMR (300 MHz,CDCl3) δ 7.48–7.40 (m, 5H), 5.62 (q, J = 6.9 Hz, 1H), 1.89 (d, J = 6.9 Hz,3H); 13C NMR (75 MHz, CDCl3) δ 135.7, 129.9, 129.1, 127.5, 86.3, 19.5.

EtO OEt

O O EtO OEt

O OPd(dba)2 (2 mol %),(t-Bu)3P (4 mol %)

NaH, THF, 70°(87%)

Br

+

Diethyl 2-Phenylmalonate [Palladium-Catalyzed α-Arylation of a Mal-onate with an Aryl Bromide].53,82 To a screw-capped vial in a dry box contain-ing diethyl malonate (176 mg, 1.1 mmol) was added tetrahydrofuran(1.0 mL) followed by NaH (1.1 mmol). Upon completion of hydrogen evolution(ca. 2 min), bromobenzene (157 mg, 1.00 mmol), (t-Bu)3P (0.040 mmol),Pd(dba)2 (0.020 mmol), and THF (2.0 mL) were added. The vial was sealed witha cap containing a PTFE septum and removed from the drybox. The homoge-neous reaction mixture was stirred at 70◦ and monitored by GC. After completeconversion of the aryl halide, the crude reaction mixture was filtered througha plug of Celite and concentrated in vacuo. The residue was purified by col-umn chromatography on silica gel (hexanes/CH2Cl2 2:1) to give 0.204 g (87%yield) of the title compound: 1H NMR (CDCl3) δ 7.43–7.34 (m, 5H), 4.62 (s,1H), 4.27–4.18 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3) δ 168.17,132.81, 129.27, 128.59, 128.20, 61.80, 57.96, 14.01.

EtO

OPd(dba)2 (2 mol %),(t-Bu)3P (4 mol %)

CNEtO

OCN

(88%)Na3PO4, toluene, 70°

Br

+

Ethyl 2-(2-Methylphenyl)cyanoacetate [Palladium-Catalyzed α-Arylationof Ethyl Cyanoacetate].82 Into a screw-capped vial containing ethylcyanoacetate (125 mg, 1.10 mmol) and 2-bromotoluene (172 mg, 1.00 mmol),


were added (t-Bu)3P (40 μL, 1.0 M in toluene, 0.040 mmol), Pd(dba)2 (3.7 mg,0.010 mmol), and Na3PO4 (3.0 mmol), followed by toluene (3.0 mL). The vialwas sealed with a cap containing a PTFE septum and removed from the drybox.The heterogeneous reaction mixture was stirred at 70◦ and monitored by GC.After complete conversion of the aryl bromide, the reaction mixture was filteredthrough a plug of Celite and concentrated in vacuo. The residue was purifiedby chromatography on silica gel (hexanes/CH2Cl2, 3:1) to give the title product(88% yield): 1H NMR (CDCl3) δ 7.47–7.45 (m, 1 H), 7.32–7.22 (m, 3H), 4.89(s, 1H), 4.31–4.19 (m, 2H), 2.40 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR(CDCl3) δ 165.03, 136.23, 131.24, 129.34, 128.93, 128.62, 127.05, 115.90, 63.25,41.06, 19.42, 13.92.

Pd2(dba)3 (5 mol %),(S)-BINAP (12.5 mol %)

NMe

O

Ph

OMe(74%) 57% ee

O

NMe

Ph NaOt-Bu (2 equiv), toluene, 100°

Br

OMe

+

(R)-(+)-2-Methyl-2-(4-anisyl)-5-(N -methylanilinomethylene)cyclopenta-none [Palladium-Catalyzed Asymmetric α-Arylation of a Ketone Enolate].41

An oven-dried Schlenk tube equipped with a rubber septum was evacuated andbackfilled with argon. The tube was charged with tris(dibenzylideneacetone)dipalladium (0.005 mmol), (S)-BINAP (0.125 mmol), and (E)-2-methyl-5-((methyl(phenyl)amino)methylene)cyclopentanone (0.50 mmol). The tube wasevacuated and backfilled three times with argon. Toluene (2 mL) was addedand the mixture was stirred for 15 min at rt. 4-Bromoanisole (1.00 mmol) andsodium tert-butoxide (96 mg, 1.00 mmol) were added to the tube. The tube wascapped with a septum, purged with argon, and additional toluene (1 mL) wasadded through the septum. The mixture was stirred at rt until the starting ketonehad been completely consumed as judged by GC analysis. The reaction mixturewas quenched with saturated aqueous ammonium chloride (10 mL) and dilutedwith ether (20 mL). The aqueous layer was extracted with ether (20 mL) andthe combined organic layers were washed with brine (20 mL), dried over anhy-drous magnesium sulfate, filtered, and concentrated in vacuo. The crude materialwas purified by silica gel chromatography (10–20% EtOAc/hexanes) to givethe title product (74% yield, 57% ee): [α]20+1.53 (c 10.0, CHCl3); 1H NMR(300 MHz, CDCl3) δ 7.62 (t, J = 1.5 Hz, 1H), 7.33–7.29 (m, 4H), 7.13–7.08(m, 3H), 6.85–6.80 (m, 2H), 3.75 (s, 3H), 3.45 (s, 3H), 2.56–2.32 (m, 3H),1.89–1.79 (m, 1H), 1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.5, 157.8,146.1, 142.4, 136.1, 129.1, 127.4, 124.6, 121.1, 113.6, 108.0, 55.3, 51.9, 40.1,


36.6, 25.4, 24.9; MS (EI) m/z: M+ 321. Anal. Calcd for C21H23NO: C, 82.58;H, 7.59. Found: C, 82.53; H, 7.68.

O O

O O

Ni(cod)2 (5 mol %), (S)-2 (8.5 mol %),ZnBr2 (15 mol %)

(86%) 96% ee

Cl

OMe

+NaHMDS (2.3 equiv)

PPh2

PPh2

(S)-2

OMe

(–)-3-(3-Methoxyphenyl)-3-methyldihydrofuran-2-one [Nickel-CatalyzedAsymmetric α-Arylation of a Lactone].33 An oven-dried, resealable Schlenktube containing a magnetic stir bar was allowed to cool to rt and was then chargedwith (S)-BINAP (2) (13.2 mg, 21.3 μmol). The tube was sealed, evacuated,and backfilled with argon. From a freshly prepared, yellow, homogeneous stocksolution of Ni(cod)2 (0.05 M, toluene), 250 μL (12.5 μmol) was added by syringewhile purging with argon. The tube was sealed and heated to 60◦ for 5 min duringwhich time the solution turned dark red. The reaction vessel was removed fromthe oil bath, and sequentially α-methyl-γ-butyrolactone (47.0 μL, 0.5 mmol),dodecane (50 μL, internal standard) and NaHMDS (105.4 mg, 0.575 mmol) wereadded under argon. From a stock solution, ZnBr2 (0.51 M in THF, 250 μL37.5 μmol) was added by syringe while purging with argon; the mixture wasthen stirred for 5 min at rt. 3-Chloroanisole (0.25 mmol) was added by syringefollowed by toluene (500 μL) while purging with argon. The tube was sealedand heated at 60◦ for 20 h. After complete conversion had been accomplished,as judged by GC analysis, the reaction mixture was allowed to cool to rt andwas then filtered through a pad of silica gel, eluting with EtOAc. The eluatewas concentrated under reduced pressure, followed by chromatography of theresidue on silica gel (1.5 × 30 cm, EtOAc/hexanes), to give 42.6 mg of the titlecompound (86% yield, 96% ee) as a colorless oil: HPLC (OD-col., 10% i-PrOH/hexanes, 0.7 mL/min) tr (major) = 13.7 min, tr (minor) = 17.0 min; [α]20

−7.3 (c 2.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 18.30 (m, 1H), 6.99 (m,2H), 6.84 (m, 1H), 4.34 (ddd, J = 9.0, 7.8, 3.9 Hz, 1H), 4.16 (ddd, J = 8.9,8.9, 6.5 Hz, 1H), 3.82 (s, 3H), 2.69 (ddd, J = 12.9, 6.5, 3.9 Hz, 1H), 2.41 (ddd,J = 12.9, 8.7, 7.8 Hz, 1H), 1.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 180.3,160.3, 143.0, 130.3, 118.5, 112.8, 112.6, 66.7, 65.5, 55.7, 47.9, 38.5, 25.9. Anal.Calcd. for C12H14O2: C, 69.88; H, 6.84. Found: C, 69.58; H, 6.91.


NHCOCF3

I

COMe

CO2Et+

CuI (40 mol %),trans-4-hydroxy-

L-proline (80 mol %)NHCOCF3

EtO2C

COMe

(80%) 71% ee

NaOH, DMF, H2O, –45°

(S )-Ethyl 2-Methyl-3-oxo-2-[2-(2,2,2-trifluoroacetamido)phenyl]butanoate[Copper-Catalyzed Enantioselective α-Arylation of an Acetoacetate].36 ASchlenk tube was charged with 2-(2,2,2-trifluoroacetamido)phenyliodide (0.5mmol), CuI (19 mg, 0.2 mmol), trans-4-hydroxy-L-proline (26 mg, 0.4 mmol),and NaOH (80 mg, 2 mmol), evacuated and backfilled with argon. After injectionof H2O (5 μL) and DMF (1 mL), the tube was immersed in a cooling bath andethyl 2-methylacetoacetate (0.75 mmol) was injected. The reaction mixture wasstirred at −45◦ until the conversion was complete as monitored by TLC. The mix-ture was partitioned between EtOAc and saturated NH4Cl; the organic layer waswashed with brine, dried over Na2SO4, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (petroleum ether/EtOAc50:1 to 20:1) to provide the title product (80% yield, 71% ee): HPLC (Chiral-pak AD, 95:5 hexanes/i-PrOH, 0.7 mL/min) tr (major) = 10.2 min, tr (minor)= 9.7 min; [α]20+191 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 10.27 (brs, 1H), 7.71–7.34 (m, 4H), 4.32–4.20 (m, 2H), 1.95 (s, 3H), 1.88 (s, 3H), 1.31(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.2, 173.0, 155.8, 134.2,131.8, 129.6, 127.5, 127.5, 127.0, 114.5, 63.9, 63.1, 24.5, 20.3, 13.9; ESI-MSm/z: [M + Na]+ 354; HRMS: [M + Na]+ calcd for C15H16NO4F3Na, 354.0924;found, 354.0920.

TABULAR SURVEY

The tabular survey includes all examples found in the literature through mid-2008. The literature survey was conducted by computer search of Beilstein andSciFinder and by direct inspection of the literature.

Table 1 compiles the arylation of ketones, aldehydes, and enol ethers. Table 2lists the arylation of esters, amides, lactones, lactams, nitriles, ketene acetals, andpreformed enolates. Table 3 compiles the arylation of 1,3-dicarbonyl compoundsand cyanoacetates; other types of active methylene compounds can be found inTables 1 and 2.

In all the tables, the examples are listed according to the nucleophiles involved,in order of increasing total number of carbon atoms. Protecting groups areincluded in the carbon count. Intramolecular couplings are included in the tablesand are given after intermolecular reactions for the same carbon count. Arylcompounds are ordered according to the class of the structure in the followingorder: phenyl- > naphthyl- > heteroaromatic compounds. Within the same arylclass, the entries are ordered according to the nature of the leaving group in orderof, Cl > Br > I > OTf. Entries of the same aryl halide are further ordered by


increasing number of substituents and then by the position of those substituents(2 > 3 > 4). Finally, if all other functionalization of the aryl compound isthe same, the entries are arranged by the substituent attached to the aryl ring,heteroatom-substituted (by increasing atomic number) > carbon-substituted. Asub-table contains examples where a comparison between halides was possible,following the same ordering rules as previously stated. The entry containing thesub-table is placed within the aryl compound ordering based on the first entry inthe subtable.

Unreported yields are indicated using “(—) ”. There are a number of entrieswhere ee or de values are reported but for which the authors did not report theabsolute configuration of the created center. In several entries substituents (“R”)or halide (“X”) functions were not reported. All these entries are faithful to theoriginal literature data.

The following abbreviations are used in the tables:

Ad adamantylAll allylbiPh biphenylp-cresol 4-methylphenolCy cyclohexyldba dibenzylideneacetonediglyme diethylene glycol dimethyl etherdioxane 1,4-dioxanedppb 1,4-bis(diphenylphosphino)butanedppe 1,2-bis(diphenylphosphino)ethanedppp 1,3-bis(diphenylphosphino)propaneeq equivalentsether diethyl etherLiHMDS lithium bis(trimethylsilyl)amideLiTMP lithium 2,2,6,6-tetramethylpiperididemonoglyme ethylene glycol dimethyl etherMS molecular sievesNap naphthylTBDPS tert-butyldiphenylsilyltol methylphenylxyl dimethylphenyl

CHART 1. STRUCTURES OF LIGANDS USED IN TABLES

Fe

PR2

PR2

R

Ph

o-tol

t-Bu

Cy

Ligand

L1

L2

L3

L4

FeR1

R2

R1

OMe

NMe2

PPh2

PCy2

PCy2

P(t-Bu)2

NMe2

Fe

P(t-Bu)2

Ph

PhPh

PhPh

L12

P(R1)2

R2R3

R1

Ph

t-Bu

t-Bu

t-Bu

Cy

Cy

Cy

Cy

Cy

R2

NMe2

NMe2

H

Me

NMe2

H

Me

OMe

i-Pr

R3

H

H

H

H

H

H

H

OMe

i-Pr

Ligand

L13

L14

L15

L16

L17

L18

L19

L20

L21

R3

R2

PPh2

P(t-Bu)2

PCy2

PPh2

PCy2

P(o-tol)2

PPh2

R3

H

H

H

H

H

H

PPh2

Ligand

L5

L6

L7

L8

L9

L10

L11

R1

PPh2

P(o-tol)2

P(p-tol)2

NMe2

NMe2

NMe2

OH

OMe

—OP(NEt2)O—

R2

PPh2

P(o-tol)2

P(p-tol)2

P(t-Bu)2

PPh(t-Bu)

PCy2

PPh2

PPh2

Ligand

L23

L24

L25

L26

L27

L28

L29

L30

L31

R1

R2

O

O

O

O

PPh2

PPh2

F

F

F

F

L22O

PPh2PPh2

L32

P(t-Bu)2

L33

P(t-Bu)

L34

2

P(n-Bu)

L35

2

96

OP(i-Pr)2

OP(i-Pr)2

EtO2C OPPh2

OPPh2

EtO2C

L36 L37

O

O

OOH

O

O

OHO

L38

PPh2

PPh2

L39

P

PEt

Et

Et

Et

L40

PPh2 N

O

L41

PPh2

L42

PPh

L43

O

PNtert-Bu

Me

Ph

L44

R

NH

O

HN

R

O

L45 R = PPh2

N N+ R2 X–R1

R1

Bu

2,6-(i-Pr)2C6H3

R2

Bu

2,6-(i-Pr)2C6H3

Ligand

L46

L47

X

PF6

BF4

N N+

i-Pr

i-Pr

i-Pr

i-Pr

Cl–

L51

N N+ Br–

L52

Br

N N+ BF4–

L48 L49

N N+ BF4–

L50

N N+ BF4–

97

CHART 2. STRUCTURES OF PALLADACYCLES AND PALLADIUM COMPLEXES USED IN TABLES

N

Pd

Me

Me

Cl

NN

R

R

Pd cat 1

R = 2,6-(i-Pr)2C6H3

N

Pd

Me

Me

Cl

PCy3 NHPd

PCy2Cl

Pd

N N

Pd

N N N N+ +

+

Cl

ClPd

Cl

N N+

PdCl

Pd

N N+

Cl

i-Pr

i-Pri-Pr

Pd cat 2 Pd cat 3

Pd cat 4 Pd cat 5

Pd cat 7

Pd cat 6

Pd cat 8

98

CHART 3. STRUCTURES OF POLYMER-SUPPORTED CATALYSTS USED IN TABLES

PPd

O

O

O

O

PPd

O

O

O

O

O

O

PPd

N

Pd cat 9 Pd cat 10 Pd cat 11

99

Substrate Refs.Conditions Product(s) and Yield(s) (%)

TABLE 1. ARYLATION OF ALDEHYDES, KETONES, AND ENOL ETHERS

Aryl Compound


P(t-Bu)3 (10 mol %),

LiHMDS, dioxane, 90°, 3 h

63

C3

C4

Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),

Cs2CO3 (1.2 eq), dioxane, 4 h

65

65

Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),


Pd(OAc)2 (2 mol %), L23 (3 mol %),


148

Br

OTBS

t-Bu

Br

O

(55)

t-Bu

HH

O

O

(54)

PhO

H

(—)(—)

+

OTBS

O

OTBS

O OTBS

Ph

Br

Ph

BrH

O

(43)

PhO

H

100


P(t-Bu)3 (10 mol %),


63

Br

OTBSO

(—)(—)

+

OTBS

O

OTBS

O

OTBS

O

OTBS

+

(—)

i-PrH

O148

C5

O48

Pd(OAc)2 (1 mol %),

L35 (2 mol %), K3PO4 (2.2 eq),

dioxane, 100°, 20 h

(51)

(50)

(61)

(64)

(58)

(65)

R

i-Pr

H

O

Cl

Cl

(58)

ClO

R

MeO

MeS

t-Bu

MeO

MeS

t-Bu

X

Cl

Cl

Cl

Br

Br

Br

R

X

Catalyst, ligand, Cs2CO3 (1.2 eq),

dioxane, 80–100°

Catalyst

Pd cat 3

Pd cat 3

Pd cat 3

[Pd(allyl)Cl]2

Pd(OAc)2

Pd(OAc)2

Ligand

none

none

none

L32

L32

L32

101


TABLE 1. ARYLATION OF ALDEHYDES, KETONES, AND ENOL ETHERS (Continued)

Aryl Compound

43

Pd(OAc)2 (0.1 mol %),

L19 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 70°, 24 h

(74)

MeO

Cl

MeOO

O

C5

Pd cat 4 (1 mol %), NaOt-Bu (1.05 eq),

THF, 60°, 0.5 h

(68) 50

Pd(OAc)2 (1 mol %),

L35 (2 mol %), K3PO4 (2.2 eq),


(55) 48Cl

O

Br

O

O

45

Pd2(dba)3, L17, K3PO4 (2.2 eq),

PhOH or PhOK (0.2 eq), toluene,

50°, 14 h

(—)

1. CH2=C=O

2. Bu3SnOMe (1 eq),

PdCl2[P(o-tol)3]2 (0.7 mol %),

toluene, 100°, 5 h

(60) 149Br

Br

NO2

O

NO2

O

Pd(OAc)2 (0.1 mol %),

L19 (0.2 mol %), NaOt-Bu (2 eq),

THF, 70°, 24 h

43

Cl

OH

O

OH

(88)

102

C6


P(t-Bu)3 (10 mol %),


63

O Pd(OAc)2 (5 mol %),

P(t-Bu)3 (20 mol %),

Cs2CO3 (1.2 eq), DMF, 60°, 7 h

O

47(—)

(—)

HH

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %),

NaOt-Bu (1.3 eq), THF, 70°16(76)Br

O

O

Br

O

O

O

OTBS

O

O

Br

OTBS

Pd(OAc)2 (5 mol %),

PPh3 (0.1 eq), base (y eq), DMF

Ph

O

92H

Pd(OAc)2 (5 mol %),

P(t-Bu)3 (10 mol %),

Cs2CO3 (2 eq), DMF

(45) 60

Base

Cs2CO3

Cs2CO3

Cs2CO3

K2CO3

Na2CO3

Cs2CO3

X

Br

Br

Br

Br

Br

I

Temp (°)

120

60

120

120

120

60

Time (h)

1

4

1

4

5

4

(84)

(80)

(96)

(69)

(12)

(34)

X

Br

Br

H

O

Ph

Ph

x eq

x

1.0

1.0

2.0

2.0

2.0

1.0

y

1.2

1.2

2.0

2.0

2.0

1.2

103



Aryl Compound

R2

R1

148

R1

H

Me

Me

Me

X

Cl

Cl

Br

Br


dioxane, 80–100°

Catalyst

Pd cat 3

Pd cat 3

Pd(OAc)2

[Pd(allyl)Cl]2

Ligand

none

none

L32

L32

(45)

(62)

(65)

(84)

R2

OCH2CO2Et

NMe2

NMe2

OCH2CO2Et

R1

H


L32 (1.2 mol %), NaOt-Bu (1.3 eq),

THF, 70°, 12 h

(74) 43

Pd2(dba)3 (1.5 mol %),

L23 (3.6 mol %),

NaOt-Bu (1.3 eq), THF, 70°16

45

(64)

BrF

Br

N

Ph

Ph N

Ph

PhO

F

O

X

O

HO

C6

45Pd2(dba)3, L17, K3PO4 (2.5 eq),

PhOH (0.2 eq), toluene, 50°, 24 h

(65)O

NO2

Cl

NO2

EtO2CO

Pd2(dba)3, L17, K3PO4 (2.5 eq),

PhOH (0.2 eq), toluene, 50°, 24 h

(67)

NO2

MeO

Br

NO2

MeOO

EtO2C

R2

104

45

Pd2(dba)3, L17 (4 mol %),

PhOH (0.2 eq), K3PO4 (2.5 eq),

toluene, 50°, 24 h

(63)


L23 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°, 16 h

(72) 43

Pd2(dba)3 (0.5 mol %),

L32 (0.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°, 17.5 h

(72) 43

1. CH2=C=O

2. Bu3SnOMe (1 eq),


toluene, 100°, 5 h

(64) 149Br

O

NO2

F

Br

O

O

OMe

MeO

Br

MeO

BrMeO

NO2

FO

OMe

MeOO

MeOO

MeO

23

X

Cl

Br

(82)

(83)

Pd(dba)2, P(t-Bu)3, NaOt-Bu, Rt to70°

Solvent

toluene

THF

MeO X

O O

MeO

Pd(OAc)2 (0.1 mol %),

L17 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 90°, 16 h

(79) 43

Cl

t-Bu t-BuO

105



Aryl Compound

40

Pd(dba)2 (2 mol %), L3 (2.5 mol %),

70°, 12 h

I

(92)

I (83)

Pd(OAc)2 (1 mol %),

P(t-Bu)3 (2.5 mol %), 50°, 12 h 40

O

MeO Br MeO

O

Pd(OAc)2 (0.1 mol %),

L17 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 85°, 24 h (70) 43

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70° 16(93)

Br

Me2N

Br

Ph PhO

Me2NO

O Pd cat 4 (1 mol %), NaOt-Bu (1.05 eq),

THF, 60°, 1 h (91) 50Cl

O

17

Pd(dba)2 (7.5 mol %), L2 (9 mol %),

KHMDS (2.2 eq), THF, reflux,

0.75 h (51)Br

I

O

1. CH2=C=O

2. Bu3SnOMe (1 eq),


toluene, 100°, 5 h

149I (86)Br

C6

MeO Br

OMe OMe

106

23

R

2-MeO

3-MeO

4-t-Bu

4-Ph

(87)

(88)

(92)

(92)

Pd(dba)2, P(t-Bu)3 or L47,

LiHMDS or NaHMDS, rt

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°16(78)

Br

O

Br

N

Ph

Ph N

Ph

PhO

(98) 23Pd(dba)2, P(t-Bu)3 or L47,

LiHMDS or NaHMDS, rtBr

O

(65) 59Pd(PPh3)4 (5 mol %),

p-cresol (10 mol %), C6D6, 120°

OPh

R R

Pd(OAc)2 (1 mol %),

NaOt-Bu (1.3 eq), toluene,

80°, 6 h

(68) 43

BrMeO MeO

O

Br

(90) 23Pd(dba)2, P(t-Bu)3 or L47,

LiHMDS or NaHMDS, rt

O

107



Aryl Compound

R

H

MeO

EtO2C

t-Bu

(72)

(71)

(54)

(75)

44

1. CuCl (1 mol %), (S)-L25 (1 mol %),

NaOt-Bu (1 mol %),

Ph2SiH2 (0.51 eq),

THF/pentane (1:1), –78°2. Pd(OAc)2 (5 mol %),

L15 (10 mol %), CsF (1.1 eq),

THF, rt, 18 h

O

Br

R RO

dra

96.5:3.5

97:3

97.5:2.5

96.5:3.5

Pd cat 2 (1 mol %), NaOt-Bu, dioxane,

70°, 2 h

(97) 52

I

Cl

OO

C6

Pd(OAc)2 (1 mol %), L35 (2 mol %),

K3PO4, dioxane, 100°, 20 h

48I (59)

Pd(OAc)2 (1 mol %), L51 (1 mol %),

NaOt-Bu (1.5 eq), dioxane, 60°, 2 h

51I (67)

Pd(dba)2 (2 mol %), L3 (2.5 mol %),

NaOt-Bu, THF, 70°, 12 h

O

(70)

Pd(OAc)2 (1 mol %),

P(t-Bu)3 (1.25 mol %), NaOt-Bu,

THF, 50°, 3 h

40

40

I

I (73)

Pd(dba)2, L3, NaOt-Bu, rt to 70° I (70) 23

Br

Ph

Cl

Cl

Br

Br

108

PdCl2(cod), ligand, Cs2CO3,

DMF, 153°, 1 h

(88)

(83)

Ligand

L36

L37

56Br

Br

1. CH2=C=O

2. Bu3SnOMe (1 eq),


toluene, 100°, 5 h

149I (54)

Pd2(dba)3 (0.5 mol %),

L24 (1 mol %), Cs2CO3,

toluene, 80°, 24 h

(—) 62

Br

Br

OBr


ligand (1.1 mol %), K3PO4,

toluene, 80°, 15 h

(70)

(74)

43

Ligand

L19

L23

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°(83) 16

MeO2C

Br

Br

t-Bu

O

O

MeO2C

t-Bu

(78) 61

Pd(dba)2 (0.5 mol %),

L32 (1.2 mol %), Cs2CO3,

toluene, 80°

Br

I

OBr

I

109



Aryl Compound

C6 O Pd2(dba)3 (0.5 mol %),

ligand (1 mol %), Cs2CO3,

toluene, 80°, 24 h

Ligand

L1

L3

L9

L15

L16

L17

L23

L24

(—)

(25)

(—)

(—)

(—)

(9)

(78)

(—)

62

Br

I

OBr

17

Pd(dba)2 (7.5 mol %), L2 (9 mol %),


0.75 h

(57)Br

O

Pd(OAc)2 (1 mol %), L51 (1 mol %),

NaOt-Bu (1.5 eq), dioxane,

60°, 12 h

(13) 51Cl

O

17

Pd(dba)2 (7.5 mol %), L2 (9 mol %),


0.75 h

(68)

Pd(dba)2, L1 or L3, KHMDS, 70° I (68) 23

I

O

Br

(75) 59Pd(PPh3)4 (5 mol %),

p-cresol (10 mol %), C6D6, 120°

OPh

O

Br

O

O

S

O

S

S

S

110

OSiMe3Pd(dba)2 (3 mol %),

P(t-Bu)3 (5.4 mol %), ZnF2 (1.4 eq),

MnF2 (1.4 eq), DMF, 70°(68) 150

Br

O

C7


dioxane, 80–100°148

X

Cl

Br

Catalyst

Pd cat 3

Pd(OAc)2

Ligand

none

L22

(51)

(54)

X

O

O O

O

CHOH

O

O

H

R

Me2N

MeO

MeS

Me2N

MeO

MeS


dioxane, 80–100°

Catalyst

Pd cat 3

Pd cat 3

Pd cat 3

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Ligand

none

none

none

L20

L20

L20

X

Cl

Cl

Cl

Br

Br

Br

(54)

(60)

(63)

(68)

(65)

(59)

148

X

RR

CHO

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°(88) 16

OCl

Br

ClO

111



Aryl Compound

C7

O

1. CuCl (1 mol %), (S)-L25 (1 mol %),

NaOt-Bu (0.01 eq),

Ph2SiH2 (0.51 eq),

THF/pentane (1:1), –78°2. Pd(OAc)2 (5 mol %), L15 (10 mol %),

CsF (1.1 eq), THF, rt, 18 h

(42), 96:4 drb 44

(52), 97:3 drb 44

Pd(OAc)2 (0.05 eq), PPh3 (0.1 eq),

Cs2CO3 (1.2–4 eq), DMF, 60°, 2 h Ph

(50) 92Br

O

Br

EtO2CEtO2C

O

O

Br

1. CuCl (1 mol %), (S)-L25 (1 mol %),

NaOt-Bu (0.01 eq),

Ph2SiH2 (0.51 eq),

THF/pentane (1:1), –78˚

2. Pd(OAc)2 (5 mol %), L15 (10 mol %),


O Pd(OAc)2 (0.5 mol %),

L19 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 85°, 24 h

(61) 43

O Pd(OAc)2 (0.5 mol %),

L19 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 70°, 23 h

(61) 43

t-Bu

Br

Br

t-BuO

O

112

Pd(OAc)2 (1 mol %), L51 (1 mol %),


51(—)Cl

O

OMe

O

OMe

O

Pd2(dba)3, ligand, THF, 80°

Ligand

L32

L19

43

R

NC

t-Bu

(72)

(81)

Time (h)

16

17

Br

R

R

O

(46)

Pd(dba)2, L1 or L3, KHMDS, 70°

I

23

Pd(OAc)2, ligand, NaOt-Bu (1.3 eq),

toluene

43

Ligand

L18

L19

(66)

(80)

Temp (°)

60

45

Time (h)

18.5

20

Br

O

O

O

OO

ClPd(OAc)2 (1 mol %), L51 (1 mol %),


51

(79)Br

I (79) 17

Pd(dba)2 (7.5 mol %), L3 (9 mol %),


0.75 h

O

MeN

O

MeN

O

MeN

Ph

Br

113



Aryl Compound

C8

Bu

O

47Pd(OAc)2, PPh3, Cs2CO3

(—) (—)

H+

O

HBr

Et

O

Et

Pd(OAc)2 (5 mol %),

P(t-Bu)3 (0.2 eq),

Cs2CO3 (1.2 eq), DMF, 7 h, 60°47(—)H

Pd(OAc)2 (0.05 eq), PPh3 (0.1 eq),

Cs2CO3 (1.2–4 eq), DMF

92

R

H

MeO

Cl

Me

(80)

(60)

(64)

(69)

Temp (°)

120

60

60

60

Time (h)

1

2

4

5

Ph

O

Et

HPh

EtBr

Br

R

R

Et

Et

O

H

Pd(OAc)2 (5 mol %), ligand,

Cs2CO3 (2 eq), DMF, 80°, 4 hEt

O

60R

R

HBr

R

R

BrEt

(12)

(—)

(77)

(50)

R

H

H

H

Me

Ligand

PPh3

P(o-tol)3

P(t-Bu)3

P(t-Bu)3

Bu

Ph

Ph

O

H

Bu

Ph

PhPh

114

n-C6H13

H

O

R

MeO

MeO

X

Cl

Cl

Br

Br


dioxane, 80–100°

Catalyst

Pd cat 3

Pd cat 3

[Pd(cinnamyl)Cl]2

[Pd(allyl)Cl]2

Ligand

none

none

L32

L32

(50)

(65)

(56)

(70)

148

NBocN

NBocN

X

RR

n-C6H13

H

O

Pd(OAc)2 (0.05 mol %),

ligand (10 mol %), base (1.2 eq),

110°65

Ligand

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

PPh3

PPh3

PPh3

PCy3

PCy3

n-C6H13

HPh

n-C6H13

Ph

n-C6H13H

n-C6H13

n-C6H13H

I II

III

I

(49)

(53)

(77)

(70)

(0)

(0)

(0)

(0)

(0)

+

Base

Cs2CO3

Cs2CO3

Cs2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Time (h)

2

2

2

24

2

2

23

2

21

OO

OSolvent

DMF

dioxane

dioxane

dioxane

DMF

dioxane

dioxane

dioxane

dioxane

II

(20)

(1)

(1)

(2)

(45)

(6)

(32)

(4)

(46)

III

(31)

(2)

(5)

(12)

(22)

(15)

(11)

(18)

(10)

Br+x eq

x

2.0

1.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

115



Aryl Compound

C8

R

OMe

Me

Ph

(61)

(67)

(59)

Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),


65

H Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),


65(56)

O

CO2Et 45

Pd2(dba)3, L17 (4 mol %),

K3PO4 (2.5 eq), PhOH (0.2 eq),

toluene, 50°, 23 h

(65)


P(t-Bu)3 (10 mol %), LiHMDS,

dioxane, 90°, 3 h

63(—)

Br

R

Br

O

H

Br

NO2

NO2

O

CO2EtO

Br

OTBSOTBS

O

n-C6H13

H

O R

n-C6H13

H

O


THF, 0.5 hX

R1

H

H

MeO

Me

H

R2

H

Me

H

H

MeO

X

Cl

Cl

Cl

Cl

OTf

(93)

(90)

(78)

(88)

(80)

R2R1

Ph

OR2R1

50

O

O

116

48Pd(dba)2, ligand, base, 20 h

I

I

(70)

(0)

(40)

(16)

(22)

(0)

(16)

(59)

(9)

(0)

(33)

(17)

(31)

(17)

II

Ligand

L35

L35

L35

L35

L35

L35

L35

L35

P(t-Bu)2(n-Bu)

P(t-Bu)3

PCy3

PCy2(n-Bu)

PCy2Ph

PCy2(biPh)

Base

NaOt-Bu

Na2CO3

K2CO3

K3PO4

Cs2CO3

CaO

K3PO4

K3PO4

K3PO4

K3PO4

K3PO4

K3PO4

K3PO4

K3PO4

Solvent

toluene

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

Temp (°)

120

100

100

100

100

100

100

100

100

100

100

100

100

100

II

(—)

(0)

(25)

(51)

(62)

(0)

(51)

(31)

(20)

(19)

(32)

(3)

(31)

(19)

ClPh

Ph

OPh

Ph

O

Ph

+

Pd(dba)2 (0.1 mol %), L35, NaOt-Bu,

toluene, 120°, 20 h

48I (70)Cl

Pd(OAc)2, L35, K3PO4, dioxane,

100°, 20 h

(57)

(23)

Cl

F F

Ph

O

F

Ph

O

F48+

117



Aryl Compound

C8

O

Pd(OAc)2, L35, K3PO4, dioxane,

100°, 20 hCl

MeO

(57)

Ph

OPh

O

48

MeO

OMe

MeO

(25)

Pd2(dba)3 (1 mol %), L17 (4 mol %),

K3PO4 (2.5 eq), p-methoxy-

phenol (20%), toluene, 35–50°, 22 h

R1

R2

NO2

X

R1

R2

R1

EtO2C

Me

MeO

R2

H

H

MeO

X

Cl

Br

Br

(61)

(90)

(65)

45

NO2O

Ph

Catalyst, ligand, base, toluene,

130°56

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

R

H

H

H

H

MeO

MeO

F

F

(>99)

(94)

(>99)

(88)

(>99)

(93)

(>99)

(94)

Ligand

L36

L37

L36

L37

L36

L37

L36

L37

Base

K3PO4

K3PO4

Cs2CO3

Cs2CO3

K3PO4

K3PO4

K3PO4

K3PO4

Br

R RO

Ph

+

118

53

Pd(OAc)2 (1 mol %), PPh3 (8 mol %),

Cs2CO3 (2.5 eq), DMF, 150°,

0.5–1 h

R1

H

MeO

R2

H

MeO

(96)

(85)Br

R1

R2

R1

R2

R1

R2

O

Ph

I

R2

+ 54, 55See table

X

R1

R2

R1

O

Ph

X

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

R1

H

H

H

H

H

H

H

H

H

H

H

H

H

R2

H

H

H

H

H

H

H

H

H

H

MeO

MeO

MeO

Catalyst

Pd/C (5 mol %)

PdCl2 (3 mol %)

Pd(OAc)2

Pd(OCOCF3)2 (5 mol %)

Pd(PPh3)4 (1 mol %)

Pd cat 9 (5 mol %)

Pd cat 10 (1 mol %)

Pd cat 10 (2 mol %)

Pd cat 10 (2 mol %)

Pd cat 11

Pd cat 11 (5 mol %)

Pd(OAc)2

Pd(OAc)2

Ligand

none

PPh3

PPh3

PPh3

none

none

none

none

none

none

none

P(t-Bu)3

PPh3

Base

Na2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

K2CO3

K2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Solvent

DMF

DMF

DMF

DMF

xylene

toluene

toluene

xylene

DMF

DMF

DMF

THF

DMF

Temp (°)

150

130

153

150

153

130

130

153

153

153

153

80

153

II

(3)c

(—)c

(—)

(4)c

(2)c

(43)c

(16)c

(44)c

(3)c

(—)

(2)c

(70)c

(—)

I

(2)c

(11)c

(91)

(82)c

(71)c

(8)c

(45)c

(15)c

(—)c

(89)

(85)c

(5)c

(71)

I

II

119



Aryl Compound

O

C8

R2

R1

H

H

H

F

F

MeO

MeO

H

Catalyst

Pd(OCOCF3)2 (5 mol %)

Pd(PPh3)4 (1 mol %)

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd cat 11 (7 mol %)

I II

+ 54, 55See table (cont. from previous page)

Base

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

R2

MeO

MeO

MeO

H

H

MeO

MeO

H

X

Br

Br

Br

Br

Br

Br

Br

I

Ligand

PPh3

none

none

PPh3

none

PPh3

none

PPh3

Solvent

DMF

xylene

DMF

DMF

DMF

DMF

DMF

DMF

Temp (°)

150

150

153

153

153

153

153

100

II

(11)c

(—)c

(—)

(—)

(—)

(—)

(—)

(—)

I

(54)c

(25)c

(79)

(63)

(73)

(61)

(80)

(49)c

X

R1

R2

R1

O

Ph

R2

R1

O

Ph

R1

R2

R2

55I + II

Br

R1

See table

R1

H

H

H

H

R2

H

H

H

H

Catalyst

Pd(PPh3)4 (0.5 mol %)

Pd(OAc)2 (5 mol %)

Pd(OAc)2 (5 mol %)

Pd(OAc)2 (5 mol %)

Ligand

none

PEt3

P(o-tol)3

P(o-tol)3

Base

Cs2CO3

Cs2CO3

Cs2CO3

NaOt-Bu

Solvent

DMF

DMF

DMF

THF

Temp (°)

150

150

153

80

I

(18)c

(27)c

(8)c

(80)

II

(1)c

(—)c

(22)c

(—)

120

Pd cat 9 (1 mol %)

Pd cat 10 (5 mol %)

Pd cat 10 (1 mol %)

Pd cat 9 (5 mol %)

Pd cat 10

Pd(OAc)2

Pd cat 10

Pd cat 10

none

none

none

none

none

PPh3

none

none

K2CO3

NaOt-Bu

K2CO3

K2CO3

NaOt-Bu

Cs2CO3

NaOt-Bu

NaOt-Bu

toluene

toluene

xylene

toluene

THF

DMF

THF

THF

130

85

130

130

85

153

85

85

(13)c

(87)

(17)c

(32)c

(92)

(—)

(80)

(91)

(4)c

(—)

(32)c

(6)c

(—)

(63)

(—)

(—)

H

H

H

H

H

F

F

MeO

H

H

H

MeO

MeO

H

H

MeO

121



Aryl Compound

C8

17

Pd(dba)2 (7.5 mol %), ligand,

KHMDS (2.2 eq), THF,

reflux, 0.75 h

X

Br

Br

Br

Br

Br

Br

I

X

R3

R1

R2

R3

R1

R2

O

Ph

R1

H

H

Me

H

H

H

H

R2

H

H

H

NC

H

H

H

R3

H

H

H

H

t-Bu

MeO

H

Ligand

L2

L1

L2

L2

L2

L2

L2

(84)

(76)

(94)

(73)

(85)

(69)

(79)

O

46Pd(PPh3)4 (0.5 mol %),

Cs2CO3 (3–5 eq), o-xylene, 23 h

(61)

Ar = m-ClC6H4BrCl

O

Ar

Ar

Ar

Ar

OSiMe3Pd2(dba)3 (2.5 mol %),

P(t-Bu)3 (6 mol %), Bu3SnF (2 eq),

benzene, reflux, 26 h

(70)

C9

148Pd(OAc)2 (2 mol %), L20 (3 mol %),

Cs2CO3 (1.2 eq), dioxane, 100°(—)

151

MeO

Br

THPO

Br

MeOO

O

H

O

H

OH

122

Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),


(45) 65

Ph

BrH

O H

O

Ph

(43) 65



dioxane, 90°, 3 h

63

(—)

(—) +

Ph

Br

O

n-C7H15

Br

OTBS OTBS

O

n-C7H15

OTBS

Pd(OAc)2 (0.05 mol %),

P(t-Bu)3 (10 mol %),


O

H

O

H

Ph

O

n-C7H15

Pd(OAc)2, PPh3 or P(t-Bu)3, Cs2CO3

(—)

47+

O

BrPh

Ph

O

(—)

Ph

Ph

O

Ph

TBSO

123



Aryl Compound

C9

Pd(OAc)2 (0.05 eq), PPh3 (10 mol %),

Cs2CO3, DMF

(56)

(56)

92

Ph

OO

Br

R

R

Br

Br

Pd(OAc)2, PPh3 (5 mol %),

Cs2CO3 (4 eq), DMF, 80°, 5–6 h

R

H

Me

(94)

(80)

60R

R

O

I

II

+ 55

Catalyst

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd(OAc)2

Pd cat 10

Pd cat 11

Ligand

PPh3

none

none

PPh3

none

none

PPh3

none

none

PPh3

none

none

Base

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Solvent

DMF

THF

DMF

DMF

THF

DMF

DMF

THF

DMF

DMF

THF

DMF

Temp (°)

153

85

153

153

85

153

153

85

153

153

85

153

I

(—)

(86)

(—)

(—)

(86)

(—)

(—)

(74)

(—)

(—)

(82)

(—)

II

(91)

(—)

(93)

(71)

(—)

(75)

(63)

(—)

(80)

(61)

(—)

(92)

R1

H

H

H

H

H

H

F

F

F

MeO

MeO

MeO

R2

H

H

H

MeO

MeO

MeO

H

H

H

MeO

MeO

MeO

O R2

Br

R1

R1

O

R2

R2

R1

R1

O

R2

See table

Temp (º)

60

80

Time (h)

6

5

124

R2

54Catalyst, ligand, Cs2CO3, DMF, 153°

R2

H

H

MeO

MeO

H

H

MeO

MeO

Catalyst

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

(87)

(93)

(69)

(75)

(68)

(80)

(60)

(92)

R1

H

H

H

H

F

F

MeO

MeO

Ligand

PPh3

none

PPh3

none

PPh3

none

PPh3

none

Br

R1

R1

O

R2

R2

R1

Catalyst, ligand, K3PO4, toluene, 130° 56

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

R

H

H

MeO

MeO

F

F

(>99)

(90)

(>99)

(90)

(>99)

(91)

Ligand

L36

L37

L36

L37

L36

L37

Br

RR

O

125



Aryl Compound

C9

Pd(OAc)2 (1 mol %), L51 (1 mol %),

base, 60°51

(71)

(94)

(90)

(71)

(81)

(90)

(77)

(85)

(87)

(84)

(82)

(96)

(85)

(60)

(85)

(78)

(10)

(27)

(69)

(88)

(83)

Solvent

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

toluene

DME

dioxane

THF

MTBE

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

dioxane

R

H

2-MeO

2-Me

2-CF3

3-MeO

4-MeO

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-Me

4-CF3

4-Me

4-Me

X

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Br

I

Time (h)

6

1

2

12

1

3

1

2

1

1

1

3

4

5

2

12

3

3

12

1

1

Base

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

KOt-Bu

KOMe

NaH

KH

Cs2CO3

K3PO4

NaOt-Bu

NaOt-Bu

NaOt-Bu

R

X

ROO

126

(89)

(78)

(90)

Pd cat 1 (1 mol %), NaOt-Bu, dioxane,

70°, 2 hZ

52

X

Z

OR

R

Me

Me

H

Z

CH

CH

N

X

Cl

OTf

Cl

R

Catalyst (1 mol %), NaOt-Bu, THF

(100)

(91)

(95)

(95)

(93)

(99)

(80)

(87)

(88)

(81)

(71)

(72)

(91)

(93)

(60)

50Z

R4

R2

R1

X

R3

Z

R4

R2

R1

R3

O

Catalyst

Pd cat 4

Pd cat 4

Pd cat 5

Pd cat 6

Pd cat 7

Pd cat 8

Pd cat 4

Pd cat 4

Pd cat 4

Pd cat 4

Pd cat 4

Pd cat 4

none

none

Pd cat 4

R1

H

H

H

H

H

H

H

H

H

H

H

Me

H

H

H

R2

H

H

H

H

H

H

MeO

Me

H

H

H

Me

H

H

H

R3

H

H

H

H

H

H

H

H

MeO

H

H

H

H

H

H

Z

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

N

X

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Br

OTf

OTf

Cl

R4

H

H

H

H

H

H

H

H

H

CF3

PhC(O)

Me

H

Me

H

Temp (°)

70

50

70

70

70

70

60

60

70

70

70

60

60

60

50

127



Aryl Compound

ClPd(dba)2 (x mol %), L35, base, 20 h

(40)

(41)

(97)

(100)

(90)

48

x

0.01

0.01

0.05

0.1

1

Solvent

toluene

toluene

toluene

toluene

dioxane

Base

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

K3PO4

Temp (°)

80

120

80

80

100

OO

Pd(OAc)2 (0.5 mol %),

L19 (0.2 mol %), NaOt-Bu (1.3 eq),

80°, toluene

43

R

CN

CO2Me

(78)

(76)

Time (h)

18

16

Cl

RR

O

Pd(dba)2, L1 or L3, KHMDS, 70° (71) 23

17

Pd(dba)2 (7.5 mol %), ligand,

KHMDS (2.2 eq), THF,

reflux, 0.75 h

I

Ligand

L2

L1

(71)

(47)

Br

O

C9

IBr

128

Catalyst (x mol %),

NaOt-Bu (1.3 eq), toluene

43

(74)

(84)

(76)

(93)

R1

H

H

Me

Me

R2

H

MeO

H

H

Catalyst

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd2(dba)3

Time (h)

24

3

2.3

14

x

0.001

1.0

1.0

1.0

Temp (°)

120

80

80

80

R1

R1 Br

R2

R1

R1

R2

O

Br

Pd(OAc)2 (5 mol %),

ligand (10 mol %),

NaOt-Bu (2.3 eq), 80°

Ligand

L9

L9

L9

L9

L9

L9

L9

L9

L9

L14

L15

L16

L18

L19

Solvent

THF

DME

dioxane

DMF

DMA

t-BuOH

DCE

toluene

toluene

toluene

toluene

toluene

toluene

toluene

152

(85)

(78)

(84)

(54)

(37)

(45)

(0)

(64)

(97)

(42)

(30)

(0)

(0)

(62)

O

OH OH129



Aryl Compound

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°16(91)

OMe

Br

O

OMeC9

Pd2(dba)3 (5 mol %), LiHMDS,

P(t-Bu)3 (10 mol %), dioxane,

90°, 3 h

63(—)

O

Pd(OAc)2 (1 mol %), L51 (1 mol %),

NaOt-Bu, dioxane, 60°, 12 h

(42) 51

Pd(OAc)2 (1 mol %), L51 (1 mol %),


(36) 51

S Cl

S

Cl

O

MeO

OTBS

O

OMe

OTBS

Br

Pd(OAc)2 (0.5 mol %),

L19 (0.2 mol %), NaOt-Bu (1.3 eq),

toluene, 70°, 17 h

(83) 43

t-Bu

Br

t-Bu

OMe

O

O

S

OS

Pd(OAc)2 (1 mol %), L51 (1 mol %),


(75) 51Cl

OO

130


P(t-Bu)3 (10 mol %),

LiHMDS (3 eq),

dioxane, 90°, 3 h

63

Br

(—)

SMe

O OTBSOTBS

O

SMe

45

Pd2(dba)3 (1 mol %), L17 (4 mol %),

K3PO4 (2.5 eq),

p-methoxyphenol (20 mol %),

toluene, 30–80°

Cl

OMe

(—)



dioxane, 90°, 3 h

63(—)



dioxane, 90°, 3 h

63(—)

ClO

O

OMe

O

CN

ClO OMe

OTBS

Br

OTBS

O

OMe

OTBS

Br

OTBS

O

CN

NO2NO2

Catalyst, Cs2CO3, DMF, 153°

Catalyst

Pd(OAc)2

Pd cat 11

(52)

(70)

54

Ligand

PPh3

none

Br

FF

O

OMe

131



Aryl Compound

C9

Catalyst, ligand, K3PO4, xylene,

153°, 22 h

56

(89)

(89)

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

Ligand

L36

L37

O

O

O

BrPd2(dba)3 (5 mol %), L23 (6 mol %),

NaOt-Bu (1.3 eq), THF, 70°16

Br

O

O

O

Ph

O

Ph

48Pd(OAc)2, L35, base, dioxane,

100°, 20 h

Base

K3PO4

Cs2CO3

(42)

(26)Cl

O O

(56) 13PdCl2[P(o-tol)3]2 (3 mol %),

Bu3SnF, benzene

(47) 13PdCl2[P(o-tol)3]2 (3 mol %),

Bu3SnF, benzene

Me3SiO

Br

O

OSiMe3 O

Br

(29) 13PdCl2[P(o-tol)3]2 (3 mol %),

Bu3SnF, benzene

Me3SiO O

Br

(84)

132

Pd2(dba)3 (2.5 mol %),

P(t-Bu)3 (6 mol %), Bu3SnF, benzene

151

R

2-Me

2-Me

4-O2N

4-O2N

2-Me

4-O2N

4-Me2N

4-MeO

4-MeO

4-MeO2C

H

2-MeO

3-MeO

4-O2N

4-MeO

X

Cl

Cl

Cl

Cl

Br

Br

Br

Br

Br

Br

I

I

I

I

I

Time (h)

3.5

20

5

20

21

8

9

9

19

20

21

21

20

8

19

(25)

(55)

(61)

(64)

(70)

(71)

(54)

(78)

(64)

(62)

(75)

(71)

(53)

(70)

(82)

O

X

OSiMe3

RR

(<15) 13PdCl2[P(o-tol)3]2 (3 mol %),

Bu3SnF, benzeneBr

O

133



Aryl Compound

C10

Pd(OAc)2 (1 mol %), L51 (1 mol %),


51

O

(20)

R1

R2

148

R1

H

Me

H

Me

X

Cl

Cl

Br

Br


dioxane, 80–100°

Catalyst

Pd cat 3

Pd cat 3

[Pd(cinnamyl)Cl]2

[Pd(cinnamyl)Cl]2

Ligand

none

none

L32

L32

(60)

(58)

(66)

(74)

R2

MeOCH2CH2O

MeO

MeOCH2CH2O

MeO

R1

R2

O

OH

O

O

OH

O

X

Cl

O

Br

Br

Pd(OAc)2, PPh3 (5 mol %),

Cs2CO3 (4 eq), DMF, 80°, 21 h

60

O

(62)

O

134

II

(23)

(78)

(19)

(81)

(64)

(50)

47Pd(OAc)2 (x mol %), phosphine,

Cs2CO3, xylene, 140°

II

R

H

H

H

H

F

Me

Time (h)

2

2

2

4.5

2

2

x

0.1

0.1

0.1

0.075

0.075

0.075

Phosphine

PPh3

P(o-tol)3

P(t-Bu)3

P(o-tol)3

P(o-tol)3

P(o-tol)3

I

(20)

(14)

(78)

(12)

(—)

(—)

+

I

Br

RR

Ph

O OPh

O

Ph

R

R

O R

X

Pd(dba)2, ligand, NaOt-Bu, rt to 70° 23

(82)

(92)

(78)

(87)

R

MeO

MeO

H

H

X

Cl

Cl

Br

Br

Ligand

L3

P(t-Bu)3

L3

P(t-Bu)3

R

O

Pd(dba)2 (2 mol %), L2 (15 mol %),

KHMDS (1.2 eq), THF, reflux, 5 h

(55) 40Br

O

135



Aryl Compound

C10

Catalyst (2 mol %),

ligand (2.5 mol %), NaOt-Bu,

THF, 50°40

Catalyst

Pd(dba)2

Pd(OAc)2

Ligand

L3

P(t-Bu)3

(87)

(92)

Br

O

Time (h)

6

12

(72) 43

Pd(OAc)2 (0.5 mol %),

L15 (0.2 mol %),

NaOt-Bu (1.3 eq), toluene, 80°, 1 h

OMeO

Br

MeO

O

53

Pd(OAc)2 (1 mol %),

PPh3 (8 mol %), Cs2CO3 (2.5 eq),

DMF, 150°, 0.5–1 h

(74)

53

Pd(OAc)2 (1 mol %),

PPh3 (8 mol %), Cs2CO3 (2.5 eq),

DMF, 150°, 0.5–1 h

(85)

Br

OMe

OMe

O

MeO

Br

O

O

OMe

OMe

O

OMe

OMe

136

55See table

(62)

(90)

(57)

(82)

(47)

(64)

(70)

(72)

(35)

(20)

(52)

(90)

(88)

(74)

R1

H

H

H

H

H

H

O2N

O2N

F

F

F

MeO

MeO

MeO

R2

H

H

H

MeO

MeO

MeO

H

H

H

H

H

MeO

MeO

MeO

Catalyst

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd cat 10

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd(OAc)2

Pd cat 10

Pd cat 11

Pd(OAc)2

Ligand

PPh3

none

none

none

none

PPh3

none

PPh3

none

none

PPh3

none

none

PPh3

Base

Cs2CO3

NaOt-Bu

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

NaOt-Bu

Cs2CO3

Cs2CO3

Solvent

DMF

THF

DMF

THF

DMF

DMF

DMF

DMF

THF

DMF

DMF

THF

DMF

DMF

Temp (°)

153

85

153

85

153

153

153

153

85

153

153

85

153

153

R2

Br

R1

O

OMe

OMe

R1

R2

R2

R1

137



Aryl Compound

C10

54Catalyst, ligand, Cs2CO3, DMF,

153°

R1

H

H

H

H

O2N

O2N

MeO

MeO

(62)

(90)

(57)

(82)

(35)

(20)

(47)

(64)

R2

R2

H

H

MeO

MeO

H

H

MeO

MeO

Catalyst

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Ligand

PPh3

none

PPh3

none

PPh3

none

PPh3

none

O

OMe

OMe

R1

R2

R1

R2

Br

R1

O

OMe

OMe

(91)Pd(OAc)2 (1 mol %), L19 (2 mol %),

NaOt-Bu, toluene, 80°43

O OMe

OMe

Br

OMe

O OMe

OMe

OMe

114

Br

Br

Pd(OAc)2 (4.9 mol %), L32 (2 eq),

Cs2CO3, toluene, 130°, 20 h

(17)

BrO

NH

MeO2C

O

NH

MeO2C

138

Pd(0), L23, NaOt-Bu, toluene, 100° (79), 70% ee 30

R

H

MeO

Me

(15)

(22)

(51)

153Pd(OAc)2, L19, NaOt-Bu,

toluene or THF, 60–80°

R2

H

H

Me

NC

CF3

MeO

H

R3

H

CF3

H

H

H

H

t-Bu

34

(77)

(70)

(79)

(84)

(69)

(78)

(84)

% ee

70

86

78

95

96

82

89

Catalyst, L22, NaOt-Bu (2 eq),

toluene

Catalyst

Pd(dba)2

Ni(cod)2

Pd(dba)2

Ni(cod)2

Ni(cod)2

Pd(dba)2

Pd(dba)2

Temp (°)

60

80

60

80

80

60

60

Br

OOO

O

O

O

OTf

R1

R2

R3

R1

R2

R3O

O

O

Br

R

O

OR

R1

H

H

H

H

H

MeO

t-Bu


toluene or THF, 60–80°(39)

Br O

O

OMeO OMe

O

139



Aryl Compound

C10

O

R

OMe

Me

(35)

(50)


THF

Temp (°)

70

60

50

Pd(OAc)2 (1 mol %), L51 (1 mol %),


(90) 51

Pd(OAc)2, ligand, NaOt-Bu,

toluene, 80°

(76)

(93)

Ligand

L17

L19

43

Time (h)

6

1

Time (h)

22

5

(21)

(35)

(50)


toluene or THF, 60–80°

R

H

MeO

Me

R

Br

R

O

OMe

OMe

O

RO

O OMe

OMe

Cl

Cl

Cl

RO

O

O

140

OSiMe3

PdCl2[P(o-tol)3]2 (3 mol %),

Bu3SnF, benzene

13

(85)

(65)

(22)

X

Br

Br

I

Time (h)

3

4

3.5

Pd(OAc)2, L19, base

Base

NaOt-Bu

K3PO4

(85)

(91)

43

Solvent

THF

toluene

Temp (°)

80

100

Time (h)

22

23

EtO2C

Br

EtO2C

OO

X

OOSiMe3

Pd(dba)2 (3 mol %),

P(Bu-t)3 (5.4 mol %), ZnF2 (1.4 eq),

MnF2 (1.4 eq), DMF, 90°

NO2

150

Cl

(77)O

NO2

Pd(OAc)2 (3 mol %),

P(t-Bu)3 (5.4 mol %), Bu3SnF (1.4 eq),

CsF (1.4 eq), toluene

150

R

O2N

Me(O)C

MeO2C

Temp (°)

85

90

90

(84)

(70)

(80)

Cl

RR

O

141



Aryl Compound

C10

150(85)

Pd(OAc)2 (3 mol %),

P(t-Bu)3 (5.4 mol %),

Bu3SnF (1.4 eq), CsF (1.4 eq), toluene

Pd(OAc)2 (3 mol %),

P(t-Bu)3 (5.4 mol %), Bu3SnF (1.4 eq),

CsF (1.4 eq), toluene

150(78)

Pd2(dba)3 (2.5 mol %),

P(t-Bu)3 (6 mol %), Bu3SnF,

benzene, 21 h

(58) 151

S

Br

Pd2(dba)3 (2.5 mol %),

P(t-Bu)3 (6 mol %), Bu3SnF,

benzene, 21 h

151(85)I

O

Br

Me3SiOOI

S

O

O

Ph

OSiMe3

C11

O

X

Cl

Br


dioxane, 80–100°

Catalyst

Pd cat 3

[Pd(allyl)Cl]2

Ligand

none

L32

148

MeO

X7

7

H

O

H

OMe

(58)

(70)

142


PPh3 (10 mol %),

Cs2CO3, DMF, 60°, 21 h

(58) 92

O

OBn

X

Cl

Br


dioxane, 80–100°

Catalyst

Pd cat 3

Pd(OAc)2

Ligand

none

L32

(57)

(73)

148Me2N

XH

Br

n-C5H11

O

OBnH

NMe2

O

n-C5H11

Ph

Pd(0), (S)-L23, NaOt-Bu, toluene, 100° 30

(66)

(74)

(73)

(40)

R

H

CN

t-Bu

O

O

% ee

73

84

88

61

Br

RR

OO

Pd(0), (S)-L23, NaOt-Bu, toluene, 100° (56), 77% ee 30

t-Bu

Br

t-BuO

143



Aryl Compound

R1

H

H

H

H

H

MeO

t-Bu

R2

H

Me

NC

CF3

t-Bu

MeO

H

R3

H

H

H

H

H

H

t-Bu

R1

34

(81)

(79)

(55)

(40)

(85)

(79)

(83)

% ee

90

92

97

98

92

91

95

Catalyst, L22, NaOt-Bu (2 eq),

toluene

Catalyst

Pd(dba)2

Pd(dba)2

Ni(cod)2

Ni(cod)2

Ni(cod)2

Pd(dba)2

Pd(dba)2

Temp (°)

60

60

100

100

60

60

60

OTf

R2

R1

R3R3

R2

O

OC11



dioxane, 90°, 3 h

63(—)

OTBS

Br

OTBS

O

O

OSiMe3


Bu3SnF, benzene

(35) 13Br

O

C12



dioxane, 90°, 3 h

63(—)

OOTBS

O

OTBS

Br

144



dioxane, 90°, 3 h

63(—)

OOTBS

OOTBS

Br

O


THF, 70°, 1 h

50

O

(35)Br

63(—)

OTBS

OPd2(dba)3 (5 mol %),


dioxane, 90°, 3 h

OTBS

Br

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %), NaOt-Bu (1.3 eq),

THF, 70°16(75)

Br

NC

n-C7H15

OSiMe3


Bu3SnF, benzene

13(65)

(62)Br

R R

n-C7H15

O

Fe

O FeO

NC

R

H

MeO

154

Pd(dba)2 (3 mol %),

P(t-Bu)3 (5.4 mol %), ZnF2 (1.4 eq),

MnF2 (1.4 eq), DMF, 90°(78)

OSiMe3

OMe

O

OMe

CN

Br

NC

145



Aryl Compound

C12

O

1. Pd(OAc)2, DMF, H2O

2. H3O+

X

1. Pd(OAc)2, DMF, H2O, 48 h

2. H3O+

X

Br

I

Temp (°)

100

80

154

R

4-PhCO

H

2-MeO

2-MeO

3-MeO

4-MeO

4-PhCO

X

Br

I

I

I

I

I

I

Temp (°)

80

70

70

80

70

70

100

Time (h)

24

68

24

30

18

18

24

(47)

(61)

(67)

(50)

(68)

(54)

(78)

% ee

97

94

98

94

93

93

94

(49)

(45)

% ee

91

90

R

X

O

NMe R

O

154

Br

O

PdCl2(Ph3P)2 (10 mol %),

CsCO3 (3 eq), THF, 100°, 16 h

(26) 20O

146

C13

I

N

CO2Me

Et3N, toluene, 110°, 24 h

N

CO2Me

O

155, 113

(29)

N

CO2Me

HO

(44)

O

+

1. CuCl (1 mol %), (S)-L25 (1 mol %),

NaOt-Bu (1 mol %),

Ph2SiH2 (0.51 eq), 0°2. Pd(OAc)2 (5 mol %), L15 (10 mol %),


44

Solvent

THF

toluene

THF

THF/pentane

toluene

R

H

MeO

t-Bu

t-Bu

t-Bu

% ee, dr

95, 98:2

95, 99:1

76, —

95, —

95, —

(75)

(55)

(80)

(75)

(—)

Br

R

R

Ph

OO

Ph

1. CuCl (1 mol %), (S)-L25 (1 mol %),

P(t-Bu)3 (1 mol %), Ph2SiH2 (0.51 eq),

THF/pentane, 0°2. Pd(OAc)2 (5 mol %), L15 (10 mol %),


R2

H

Me

R2

44

R1

EtO2C

Me

% ee, dr

95, 98.5:1.5

95, 99:1

(44)

(58)

R2

R1 Br

R1

O

Ph

147



Aryl Compound

C13

Catalyst, (S)-L23, base 30

Br

O

O

% ee

95

94

98

Catalyst

Pd(OAc)2

Pd2(dba)3

Pd(OAc)2

R R

R

3-Me

3-

4-t-Bu

Base

NaOt-Bu

NaHMDS

NaOt-Bu

(86)

(80)

(75)

Br

O

Ph

O

Ph

Br

34Pd(OAc)2, L22, NaOt-Bu (2 eq),

toluene, 100°(70), 95% ee

OTfPh

O

Ph

Pd(OAc)2 (3 mol %), P(t-Bu)3,

additive, toluene, 85°150

X

ROSiMe3

R

O

X

Cl

Cl

Br

Br

Br

Br

Br

Br

Br

R

CN

CO2Me

NO2

NMe2

OH

CF3

C(O)Me

t-Bu

t-Bu

Additive

Bu3SnF (1.4 eq), CsF (1.4 eq)







none

Me4NF (1.2 eq)

(80)

(89)

(84)

(96)

(55)

(91)

(97)

(0)

(0)

148

t-Bu

t-Bu

t-Bu

t-Bu

t-Bu

t-Bu

Br

Br

Br

Br

Br

Br

CsF (1.2 eq)

CsF (1.4 eq)

ZnF2 (1.2 eq)

Bu3SnF (1.2 eq)



(18)

(81)

(38)

(34)

(67)

(65)

(97)

(93)

150

Pd(OAc)2 (3 mol %), P(t-Bu)3,

Bu3SnF (1.4 eq), CsF (1.4 eq),

toluene, 85°

R1

H

Me

R2

OMe

Me

R1

Br

R2

O

Ph

R1 R2

IO

MeO2C

Pd(PPh3)4 (20 mol %), KOt-BuMeO2C

O

(6)

C14

148

X

Cl

Br


dioxane, 80–100°

Catalyst

Pd cat 3

Pd(OAc)2

Ligand

none

L20

(55)

(68)

58

Me2N

Xt-Bu

H

O

t-Bu

H

O

Me2N

149



Aryl Compound

C14

R1

H

MeO

R2

H

MeO

34

(80)

(70)

% ee

78

77

Pd(dba)2, L22, NaOt-Bu (2 eq),

toluene, 60°

R2

OTf

OR1

R2

R1

O

O

NMe

PhCatalyst (x mol %), (S)-L23,

NaOt-Bu, toluene, 100°41

Br

O

NMe

PhR

R

R

2-Me

2-Me

3-MeO

3-Me

3-

4-MeO

4-Me

4-CF3

4-t-Bu

4-t-Bu

O

O

Catalyst

Pd2(dba)3

Pd(OAc)2

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd(OAc)2

x

2.5

5

5

2.5

5

5

5

5

5

10

(45)

(52)

(87)

(70)

(96)

(74)

(65)

(93)

(65)

(70)

% ee

8

10

85

80

86

57

63

53

88

89

(S)

150

Pd(dba)2 (10 mol %),

L35 (10 mol %),

base (2.2 eq), toluene, 20 hPh

Ph

O

R

2-F

4-MeO

4-Me

4-Me

Base

K3PO4

K3PO4

K3PO4

Cs2CO3

(72)

(76)

(90)

(99)

48R

PhPh

O

Cl

R

Catalyst, ligand, Cs2CO3,

toluene, 130°56

(78)

(84)

(95)

(96)

(88)

(96)

R

H

H

MeO

MeO

Me

Me

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

Ligand

L36

L37

L36

L37

L36

L37

Br

RR

Ph

O

Ph

Pd2(dba)3, ligand, NaOt-Bu,

toluene

(57)

(83)

(72)

Ligand

(R,Rp)-L27

(R,Sp)-L27

(R)-L28

31

% ee

5

10

58

Br

O

NMe

Ph(S)

151



Aryl Compound

46Catalyst (0.5 mol %), ligand, base

III

III

Base

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

+

+

Catalyst

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(PPh3)4

Pd(OAc)2

Pd(PPh3)4

Pd(PPh3)4

Pd(PPh3)4

Pd(PPh3)4

Ligand

PPh3

PPh3

PPh3

PPh3

none

P(o-tol)3

none

none

none

none

Solvent

xylene

xylene

DMF

DMF

xylene

xylene

xylene

xylene

xylene

xylene

R

H

H

H

H

H

H

H

3-Cl

3-CF3

4-Cl

Time (h)

5

22

2

22

20

22

24

20

44

20

I

(47)

(1)

(79)

(3)

(6)

(91)

(96)

(—)

(—)

(—)

II

(35)

(5)

(5)

(1)

(7)

(7)

(3)

(—)

(—)

(—)

III

(9)

(54)

(0)

(0)

(61)

(0)

(0)

(54)

(41)

(25)

Br

R

Ph

O

Ph R

Ph

O

R

R

Ph

O

R

R

R

53Pd(OAc)2 (1 mol %), PPh3 (8 mol %),

Cs2CO3 (2.5 eq), DMF, 150°, 0.5–1 h

R2

H

H

(80)

(73)

(70)

R1

Br

R2 R1

H

OMe

—OCH2O—

PhPh

O

C14

Ph

O

Ph

R1

R2

152

R2

R1

Br

Catalyst, ligand, Cs2CO3, DMF 55

R3

H

H

H

H

NO2

OMe

OMe

OMe

OMe

R2

H

H

OMe

OMe

H

H

H

—OCH2O—

—OCH2O—

OMe

OMe

R1

H

H

H

H

H

H

H

H

H

H

F

Catalyst

Pd(OAc)2

Pd cat 10

Pd(OAc)2

Pd cat 10

Pd(OAc)2

Pd(OAc)2

Pd cat 10

Pd(OAc)2

Pd cat 10

Pd cat 10

Pd(OAc)2

Ligand

PPh3

none

PPh3

none

PPh3

PPh3

none

PPh3

none

none

PPh3

Temp (°)

150

153

150

153

150

150

153

150

153

153

150

(80)

(57)

(73)

(54)

(54)

(71)

(60)

(70)

(45)

(37)

(57)

R3

R 2

R1R3

Ph

O

Ph

X

RR

Ph

O

Ph73PdCl2, Cs2CO3, DMF, 2 h

Temp (°)

130

100

100

100

(96)

(90)

(93)

(82)

R

H

H

MeO

Cl

X

Br

I

I

I



dioxane, 90°, 3 h

63

Br

(—)

OTBSOTBS

Ph

Ph

O

153



Aryl Compound

C14Br

Br

Pd(OAc)2 (0.5 mol %),

PPh3 (20 mol %), Cs2CO3 (2 eq),

xylene, 160°O

Ph

Ph

60

R

R

R

R

R

F

Me

(40)

(69)

Time (h)

2

4

I

PdCl2, PPh3, K2CO3, DMF,

100°, 2 h

(75) 73

PhPh

O

PhPh

O

Ph

O

Cl

Pd(PPh3)4 (0.5 mol %), Cs2CO3,

xylene, 160°47

Br

Time (h)

6

20

(59)

(40)

46Pd(PPh3)4 (0.5 mol %),

CsCO3 (3–5 eq), xylene

(59)

(30)

Time (h)

6

21

R

H

Ph

R

Br

O

Ph

Ph

Ph

Ph Cl

O

Ph

Ar

Ar

Ar Cl

Ar = 4-RC6H4

Br

Br

Pd(OAc)2 (0.5 mol %), PPh3 (0.2 eq),

Cs2CO3 (2 eq), xylene, 160°, 2 h O

Ph

Cl

(49) 60

154



dioxane, 90°, 3 hBr

(—)PhOPh

63

OTBSOTBS

OPh

O

Ph

O

OPd(OAc)2 (2.5 mol %),

PPh3 (10 mol %), Cs2CO3 (1 eq),

xylene, 160°, 5 h

47

Ph PhO

HO Ph

(47)Br

MeO2C

O

Pd(OAc)2, PPh3, additive, Et3N,

MeCN, 82°58

Additive

none

Bu4NCl

none

Time (h)

4

3

0.8

(22)

(23)

(24)

I

MeO2C

O

C15

O

Ph

Ph

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %),

NaOt-Bu (1.3 eq), THF, 70°O

O

16O

O

Br

O

Ph

Ph (72)

155



Aryl Compound

Pd2(dba)3 (1.5 mol %),

L25 (3.6 mol %),

NaOt-Bu (1.3 eq), THF, 70°16(69)

O

Et2N

Br

O

Et2N O

Ph

Ph

Ph

OBr

Br

Pd(OAc)2 (0.5 mol %),

PPh3 (20 mol %), Cs2CO3 (2 eq),

xylene, 160°, 2 h O

Ph

(74) 60

C15

O

Ph

Ph

Ph

O

OMe

Pd(OAc)2 (0.5 mol %),

PPh3 (20 mol %), Cs2CO3 (2 eq),

xylene, 160°, 2 h O

Ph

OMe

(75) 60

Ph

O

Ph

Br

Br

Pd(OAc)2 (0.5 mol %),

PPh3 (20 mol %), K2CO3 (2 eq),

xylene, 160°, 4 h

60(64)

Br

Br

O

Ph

Ph

PdCl2, LiCl (4 mol %), Cs2CO3 (48) 18

I

I

Ph

O

Ph

Ph Ph

73PdCl2, Cs2CO3, DMF, 100°, 2 h I (59)I

156

Br

Br

(0)

(0)

(0)

(0)

(76)

(72)

(86)

(61)

(0)

Catalyst, ligand, base 114

Catalyst

Pd(dba)2

Pd(dba)2

Pd(OAc)2

Pd2(dba)3

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Ligand

P(t-Bu)3

L1

PPh3

L23

L32

L32

L32

L32

L51

Base

K3PO4

NaOt-Bu

Cs2CO3

NaOt-Bu

K3PO4

K3PO4

Cs2CO3

Cs2CO3

NaOt-Bu

Solvent

toluene

THF

DMF

THF

toluene

toluene

toluene

THF

dioxane

Temp (°)

80

80

80

80

130

130

120

130

130

Time (h)

24

8

22

22

5

29

48

5

5

BrO

TsHN

O

TsHN

Bu3Sn

O149Catalyst, toluene, 100°, 5 h RR

Br

O

R

H

H

H

H

H

2-Cl

2-Me

3-Me

4-Me2N

4-MeO

Catalyst

Pd(PPh3)4

PdCl2(PPh3)2

PdCl2[P(o-tol)3]2

PdCl2[P(p-tol)3]2

PdCl2[P(2,4,6-Me3C6H2)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

(22)

(15)

(78)

(16)

(0)

(80)

(91)

(88)

(71)

(51)

157



Aryl Compound

C15

Bu3Sn

O149Catalyst, toluene, 100°, 5 h R

Catalyst

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

PdCl2[P(o-tol)3]2

(73)

(80)

(64)

(94)

R

4-Cl

4-Me

4-Ac

2,4,6-Me3

R

Br

O

Pd(PPh3)4 (10–12 mol %), base

MeO2C

O

Base

Et3N

K2CO3

(6)

(23)

58I

MeO2C

O

I

N

MeO2C

O

PdCl2(PPh3)2 (0.2 eq), Et3N 155, 113

N

CO2Me

HO

N

CO2Me

O

I II

+

Solvent

THF

toluene

Time (h)

65

24

I

(32)

(45)

II

(24)

(31)

Pd(OAc)2 (1 mol %), PPh3 (8 mol %),

Cs2CO3 (2.5 eq), DMF, 150°, 0.5–1 h

(74) 53, 55

I

Br

Ph

O

OMe

OMe

Ph

Ph

O

OMe

OMe

C16

158

55I (51)Pd cat 11, Cs2CO3, DMF, 153°, 0–8 hBr

Catalyst, ligand, Cs2CO3,

toluene, 130°, 75 min

56

I

(92)

(95)

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

Ligand

L36

L37BrI

47Ph

O

Pd(OAc)2 (1 mol %),

P(t-Bu)3 (4 mol %), Cs2CO3 (1 eq),

xylene, 160°, 2 h

O

Ph

Ph Ph

I (8) II (12)

OPh

III (34)

47

Pd(OAc)2 (1.7 mol %),

PPh3 (6.8 mol %), Cs2CO3 (1 eq),

xylene, 160°, 2 h

II (85)

++Ph

Br

Br

O

Ph

Ph Ph

Ph

Ph

Ph Ph

Ph

Ph

Pd2(dba)3 (1 mol %), (S)-L23 (2.5 mol %),

NaOt-Bu (2 eq), toluene

(74), 91% ee 41Br

O

NMe

Phn-Pr

O

NMe

Phn-Pr

Bu3Sn

O149PdCl2[P(o-tol)3]2 (10 mol %),

toluene, 100°, 5 h

(67)Br

O

159



Aryl Compound

Bu3Sn

O

149PdCl2[P(o-tol)3]2 (10 mol %),

toluene, 100°, 5 h

(60)

PdCl2(PPh3)2 (10 mol %),

Cs2CO3 (3 eq)O

H

HO

64

OO O

H

HO

I II

+

O

Br

C16

+

CHO

O OBr

Solvent

toluene

THF

Temp

reflux

100°

Time (h)

5

24 O O

CHO

H

III

I

(76)

(29)

II

(11)

(9)

III

—

(17)


Cs2CO3 (3 eq)

64

Solvent

toluene

THF

Temp

reflux

100°

Time (h)

6

22

I

(32)

(31)

II

(17)

(10)

III

(13)

(19)

I + II + III

Bu3Sn

O

149PdCl2[P(o-tol)3]2 (10 mol %),

toluene, 100°, 5 h

(87)

C17

Br

O

CHO

O OBr

160

64PdCl2(PPh3)2 (10 mol %),

Cs2CO3 (3 eq), 3 h

OHC OHC

OH

H

III

+

Solvent

toluene

THF

Temp

reflux

100°

I

(49)

(52)

II

(4)

(9)

III

(22)

(—)

64PdCl2(PPh3)2 (10 mol %),

Cs2CO3 (3 eq), 3 h

OH

HI + II +

Solvent

toluene

THF

Temp

reflux

100°

I

(52)

(48)

II

(22)

(6)

IV

(6)

(—)


Cs2CO3 (3 eq), toluene,

reflux, 1.5 hO O

HCHO

(32)

64

O O

(23)

O

II I

IV

+

O OO O

O O

O O

O O

CHOBr

O O

CHOBr

CHO

O OBr

H H

H H

H

+

161



Aryl Compound

C17


Cs2CO3 (3 eq), THF, 100°, 14 h

64

O

H

HO

(30)(23)

C18

Catalyst, ligand, Cs2CO3, toluene,

130°56

Catalyst

PdCl2(cod)

Pd(OCOCF3)2

PdCl2(cod)

Pd(OCOCF3)2

R

H

H

MeO

MeO

(93)

(92)

(95)

(91)

Ligand

L36

L37

L36

L37

RO

OMe

OMe

OMe

OMe

O OO

H

H O

O

OMe

OMe

OMe

OMe

Br

R

CHO

O OBr

+


(S)-L23 (2.5 mol %),

NaOt-Bu (2 eq), toluene

(75), 93% ee 41Br

O

n-C5H11NMe

Ph

O

NMe

Phn-C5H11

S

162

I

II

+R1

Br

R2

R3

R1

O

OMe

OMe

OMe

OMe

R3

R2

R1

O

OMe

OMe

OMe

OMe

R3

R2

R3

R2

R1

53See table

R1

H

H

H

H

H

H

H

H

H

H

H

—OCH2O—

MeO

R2

H

H

H

H

H

H

H

H

H

MeO

MeO

MeO

R3

H

H

H

H

H

H

H

O2N

MeO

H

MeO

H

MeO

Catalyst

PdCl2

PdCl2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Ligand

none

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

PPh3

Base

Cs2CO3

K2CO3

K2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Solvent

DMF

DMF

xylene

DMF

xylene

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

Temp (°)

100

170

170

170

150

150

170

150

150

150

150

150

150

I

(20)

(24)

(55)

(83)

(85)

(85)

(52)

(44)

(46)

(51)

(47)

(55)

(12)

II

(—)

(—)

(29)

(—)

(—)

(—)

(35)

(—)

(—)

(—)

(—)

(—)

(—)

163



Aryl Compound

R1

R2

Br

55See tableR3

O

O

OMe

OMe

OMe

OMe

III

R1

H

H

H

H

H

H

H

H

H

H

H

MeO

—OCH2O—

—OCH2O—

MeO

R2

H

H

H

H

H

H

H

H

MeO

MeO

MeO

MeO

MeO

R3

H

H

H

H

H

H

O2N

MeO

H

H

MeO

H

H

H

MeO

Catalyst

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Pd cat 11

Pd(OAc)2

Ligand

PPh3

PPh3

PPh3

PPh3

PPh3

PEt3

none

PPh3

none

PPh3

PPh3

none

PPh3

none

PPh3

Base

K2CO3

K2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Cs2CO3

Solvent

xylene

xylene

xylene

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

Temp (°)

150

170

170

150

170

150

150

150

150

153

150

150

153

150

153

I

(86)

(58)

(23)

(89)

(56)

(32)

(53)

(51)

(40)

(47)

(44)

(53)

(55)

(38)

(12)

II

(—)

(31)

(32)

(—)

(38)

(29)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

III

(—)

(6)

(25)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

I

II

+

Ar

O

OMe

OMe

OMe

OMe

Ar

O

OMe

OMe

OMe

OMe

ArAr =

R1R2

R3

O

OMe

OMe

OMe

OMe

C18

164

Bu3Sn

O149PdCl2[P(o-tol)3]2 (10 mol %),

toluene, 100°, 5 h

(64)

O


toluene, 100°, 5 h

149(54)

Br

Bu3Sn

O

O

Br

64

OHC

H

OHC

H


Cs2CO3 (3 eq), toluene,

reflux, 3.5 h

OMe

OH

HOMe

OH

HOMe

OMe

I (2) II (12)

III (34)

IV (10)

+ +

+

O

O

O

O

O O O O

CHO

O O

Br

OMe


Cs2CO3 (3 eq), THF, 100°, 14 h

I (12.5) + II (52.5) + III (11) + IV (6) 64

165



Aryl Compound

C18

I

N

Bn

PdCl2(PPh3)2 (0.2 eq),

Cs2CO3 (3 eq),

THF, 100–110°, 48 h

155, 113

N

Bn

O

(20)

N

Bn(9)

HO

+


Cs2CO3 (3 eq), THF, 100°, 14 h

CHOH

H(40) 64

OO

Pd(PPh3)4 (20 mol %),

Bu4NF (3 eq), THF, rt, 15 h

MeO2C

O

(68)

t-Bu

58

C20

46

O

Pd(PPh3)4 (0.5 mol %),

Cs CO32 (3–5 eq), xylene, 23 h

Br

(43)O

Ph

Ph

O O

Br

CHO

I

MeO2C

O

t-Bu

O3

O

166

MeO2C

O

(42)

Ph

Pd(PPh3)4, KOt-Bu, THF,

rt, 5 h

58

Bu3Sn

O

149PdCl2[P(o-tol)3]2 (10 mol %),

toluene, 100°, 5 h

(90)Br

O

C21

Bu3SnF (1.5 eq), PdCl2[P(o-tol)3]2

(0.045 eq), benzene, 3 h

AcO

13

(56)

Br

AcO

a The intermediate dimeric silyl enol ether was formed with 97% ee.b The intermediate dimeric silyl enol ether was formed with 84% ee.c These yields were determined by GC-MS.

I

MeO2C

O

Ph

OSiMe3

OSiMe3

7

O

OSiMe3

7

167


TABLE 2. ARYLATION OF ESTERS, AMIDES, LACTONES, LACTAMS, NITRILES,

KETENE ACETALS, AND PREFORMED ENOLATES

Aryl Compound

CN

R

C2 R

Pd(OAc)2 (5 mol %), L23 (5 mol %),

NaHMDS (1.3 eq), toluene, 100°, 16 h

CH3CN

R R

H

Me

(62)

(60)Br

26

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1 mol %), L12 (1 mol %),

rt, 24 h

NMe2

O R

2-MeO

4-NC

4-MeO2C

(91)

(89)

(95)

68R R

Br NMe2

O

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

KHMDS (2 eq), dioxane, 100°X NMe2

O NMe2

O

67

I II

X

Br

Br

Br

Br

Br

I

I

(72)

(48)

(72)

(24)

(66)

(70)

II

(4)

(18)

(10)

(74)

(13)

(4)

Time (h)

1.5

4

1.5

1.5a

2

1

R

2-Me

4-MeO

4-Me

4-Me

4-Ph

4-Me

+R R

R

C4

R

168

Pd(OAc)2 (7.5 mol %),

ligand (9 mol %), base (1.2 eq),

85°, 2 hBr

t-Bu

NMe2

Ot-Bu t-Bu

Ligand

L1

L1

L1

L1

L23

I

(22)

(48)

(5)

(38)

(32)

I

II

(22)

(2)

(4)

(5)

(8)

Solvent

THF

dioxane

THF

dioxane

THF

Base

KHMDS

KHMDS

LTMP

LTMP

KHMDS

II

67+

(96)NMe2

O

Br68

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1 mol %), L12 (1 mol %),

rt, 24 h

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

KHMDS (2 eq), dioxane, 100°, 2 h

(70)

Br NMe2

O

(9)

NMe2

O

67+

Br

Pd2(dba)3•CHCl3 (1 mol %),

P(t-Bu)3 (2 mol %),

LiHMDS (2.2 eq), toluene, 70°, 6 h

CNCN

(69)Ph Ph

26

169



KETENE ACETALS, AND PREFORMED ENOLATES (Continued)

Aryl Compound

BrCN

C4

Pd(OAc)2 (x mol %), L23 (x mol %),

NaHMDS (1.3 eq), toluene, 100°

CN

R

2-Me

4-MeO

4-NC

4-t-Bu

(70)

(83)

(99)

(87)

x

1

1

0.5

1

Time (h)

6

8

1

2

RR 26

Catalyst (10 mol %)CO2EtX CO2Et

X

Cl

Cl

Br

Br

I

I

(0)

(65)

(15)

(67)

(47)

(55)

109BrZn

Catalyst

Pd(PPh3)4

Ni(PPh3)4

Pd(PPh3)4

Ni(PPh3)4

Pd(PPh3)4

Ni(PPh3)4

Solvent

CH2(OMe)2/HMPA (1:1)


benzene/HMPA (1:1)




Time (h)

3

3

7

3

6

3

Temp

reflux

reflux

reflux

reflux

reflux

rt

Pd(PPh3)4 (10 mol %),

CH2(OMe)2/HMPA (1:1), reflux, 3 hI CO2Et

HO2C

(85)HO2C

109

170

Catalyst (10 mol %),

CH2(OMe)2/HMPA (1:1), reflux, 3 h

X

Br

Br

I

(0)

(69)

(47)

Catalyst

Pd(PPh3)4

Ni(PPh3)4

Pd(PPh3)4

X CO2Et

109

C5

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), LiNCy2,

toluene, rt or Pd(dba)2, carbene,b

NaHMDS, toluene, rt

CO2Et(<5) 99

BrOMe

CO2Et

OMe

CO2Me

(0)

trace

(90)

(0)

trace

Temp

rt

60°100°

rt

100°

Base

NaHMDS

NaHMDS

NaHMDS

LiNCy2

LiNCy2

1. Base (1.3 eq), toluene, rt, 10 min

2. [PdP(t-Bu)3Br]2 (0.1 mol %), 4 hCl156CO2Me

171




Aryl Compound

1. NaHMDS (1.2 eq), toluene, rt,

10 min

2. Catalyst (x mol %),

ligand (y mol %), 100°, 4 h

Cl

R

H

H

3-MeO

3-MeO

3-F

3-F

3-CF3

3-CF3

4-MeO

4-MeO

4-F

4-F

4-CF3

4-CF3

4-Me

4-Me

(89)

(92)

(77)

(74)

(77)

(81)

(81)

(75)

(67)

(71)

(90)

(87)

(67)

(71)

(79)

(84)

Ligand

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

156CO2Me

Catalyst

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

x

0.2

0.1

0.4

0.2

0.4

0.2

0.4

0.2

0.4

0.2

0.4

0.2

0.4

0.2

0.4

0.2

y

0.2

—

0.4

—

0.4

—

0.4

—

0.4

—

0.4

—

0.4

—

0.4

—

C5

CO2Me

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.1–5.0 mol %),

LiNCy2 (1.3 eq), toluene, rtBr

75CO2Me

R R

R1

R2

R1

R2

172

R1

H

3-MeO

3-F

3-Cl

3-Me

3-CF3

4-Me2N

4-MeO

4-PhO

4-F

4-Cl

4-Me

4-CF3

4-t-Bu

4-Ph

4-PhCO

3-F

(87)

(97)

(93)

(71)

(97)

(89)

(88)

(90)

(95)

(90)

(72)

(90)

(86)

(91)

(96)

(73)

(91)

Time (h)

18

24

16

12

24

24

18

24

12

16

14

24

24

12

18

16

14

R2

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

4-Ph

x

0.1

0.1

0.1

0.1

0.1

0.1

0.05

0.1

0.1

0.1

0.1

0.1

0.1

0.1

0.05

3.0

0.2

1. LiNCy2 (1.3 eq), toluene, rt, 10 min

2. [PdP(t-Bu)3Br]2 (x mol %), rt, 4 h

R

3-MeO

3-F

4-Me2N

4-MeO

4-F

4-Cl

4-CF3

4-t-Bu

(88)

(72)

(88)

(85)

(85)

(89)

(60)

(72)

x

0.5

0.5

0.05

0.5

0.5

0.5

0.5

0.05

157Br

CO2MeR R

173




Aryl Compound

Pd(dba)2 (2.0 mol %),

P(t-Bu)3 (2.0 mol %),

LiNCy2 (1.3 eq), toluene, rt, 16 hBr

CO2MeO

O

O

O

(77) 75

C5

CO2Me

Pd(dba)2 (0.5 mol %),

P(t-Bu)3 (0.5 mol %),

LiHMDS (2.3 eq), rt, 12 h

(92) 77

t-Bu

Br

t-Bu

CO2Me

1. LiNCy2 (1.3 eq), toluene,

0°, 20 min

2. [PdP(t-Bu)3Br]2 (0.05 mol %), rt, 4 h

157

I

I (86)

Pd(dba)2 (0.1 mol %),

P(t-Bu)3 (0.1 mol %),

LiNCy2 (1.3 eq), toluene, rt, 20 hCO2Me (95)

Br

O

O

O

O75

1. NaHMDS (1.2 eq), toluene, rt, 10 min

2. Catalyst (x mol %), ligand (y mol %),

100°, 4 hBr

156CO2Me

Cl Cl

(69)

(82)

Ligand

P(t-Bu)3

none

Catalyst

Pd(dba)2

[PdP(t-Bu)3Br]2

x

0.4

0.2

y

0.4

—174

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.1–0.2 mol %),

LiNCy2 (1.3 eq), toluene, rtBrCO2Me

R

H

MeO

(94)

(93)

x

0.1

0.2

RR

Time (h)

8

24

75


2. [PdP(t-Bu)3Br]2 (0.5 mol %), rt, 4 hN156

Br

1. NaHMDS (1.2 eq), toluene,

rt, 10 min

2. Catalyst (x mol %),

ligand (y mol %), 100°, 4 h

ClN N156CO2Me

(66)

(71)

Ligand

P(t-Bu)3

none

Catalyst

Pd(dba)2

[PdP(t-Bu)3Br]2

x

0.4

0.2

y

0.4

—

Pd(dba)2 (5.0 mol %),

P(t-Bu)3 (5.0 mol %),

LiNCy2 (1.3 eq), toluene, rt, 12 hN N

(70) 75

BrCO2Me

Pd(dba)2 (5.0 mol %),

P(t-Bu)3 (5.0 mol %),

LiNCy2 (1.3 eq), toluene, rtN N

X

2-Br

3-Br

4-Br

(94)

(80)

(51)

Time (h)

7

12

16

XCO2Me

75

I

I (71)

175




Aryl Compound

Pd(dba)2 (5.0 mol %),

P(t-Bu)3 (5.0 mol %),

LiNCy2 (1.3 eq), toluene, rt

X

2-Br

3-Br

2-Br

3-Br

I

(72)

(71)

(48)

(71)

ITime (h)

7

9

9

9

Y

X

Y Y

IIII

(—)

(—)

(43)

(—)

75

Pd(dba)2 (5 mol %),

P(t-Bu)3 (7.5 mol %), KHMDS (2 eq),

dioxane, 100°, 3 h

(16)

NMe2

O

Br NMe2

O

(78)

n-Bun-Bun-Bu

67

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %),

ZnBr2 (15 mol %), NaHMDS (2.3 eq),

toluene/THF (3:1), 60°, 17–20 h

33

O O

O OR1

(86)

(81)

(86)

(67)

(76)

+

+

R2

Cl


2. [PdP(t-Bu)3Br]2 (0.5 mol %), rt, 4 hSS

156(75)

Br CO2Me

C5CO2Me

CO2Me CO2Me

% ee

>97

97

96

95

94

R1

H

Me2N

MeO

H

H

R2

H

H

H

TBSO

MeO

Y

O

O

S

S

R2

R1

176

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %),

NaHMDS (x eq), toluene,

60°, 17–20 h

33

(40)

(52)

x

1.3

2.3ClMeO

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %),


toluene/THF (3:1), 60°, 17–20 h

(58), 93% ee

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %),

NaHMDS (2.3 eq), toluene,

60°, 17–20 h

(29), 99% ee

33

33

Brt-BuO2C

BrMeO

O O

OMe

O O

CO2t-Bu

O O

OMe

Pd2(dba)3 (2.5 mol %),

(S)-L23 (15 mol %), NaHMDS,

toluene, 50°(31), 59% ee 33

Ni(cod)2 (5 mol %),

(S)-L20 (8.5 mol %),

ZnBr2 (15 mol %), NaHMDS (8 eq),

toluene/THF (3:1), 60°, 17–20 h

(73), 90% ee 33

Cl

EtO2C

O O

CO2Et

O O

OMe

% ee

95

95

BrMeO

177




Aryl Compound

Ni(cod)2 (5 mol %), (S)-L23 (8.5 mol %),

ZnBr2 (15 mol %),

NaHMDS (2.3 eq),

toluene/THF (3:1), 60°, 17–20 h

(57), 94% ee 33

t-Bu

BrO O

t-Bu

O O

C5

Cl

Br

Pd2(dba)3 (2.5 mol %), (S)-L23 (15 mol %),

NaHMDS, toluene, 50°(62), 60% ee

Ni(cod)2 (5 mol %), (S)-L23 (8.5 mol %),

ZnBr2 (15 mol %),

NaHMDS (2.3 eq),

toluene/THF (3:1), 60°, 17–20 h

(95), 94% ee

Ni(cod)2 (5 mol %), (S)-L23 (8.5 mol %),

NaHMDS (2.3 eq),

toluene, 60°, 17–20 h

I (33), 98% ee

33

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

KHMDS (2 eq), dioxane, 100°, 3 h

(49)OO

Ph Ph

(9)ON

Me

NMe N

Me

Ph

67Br

33

33Br

O O

+

O O

I

178

CN


ligand (x mol %), ZnF2 (0.5 eq),

DMF, 90°80

(83)

(69)

(71)

(68)

(83)

(64)

(79)

(81)

(84)

(78)

(78)

(87)

(92)

(78)

(84)

(74)

Time (h)

24

24

24

8

18

18

18

8

8

18

8

18

8

24

24

18

R2

H

H

H

H

H

H

H

H

H

H

H

H

H

4-Me

6-Me

5-Me

Ligand

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

L23

PPh(t-Bu)2

L23

L23

L23

L23

L23

L23

L23

L23

P(t-Bu)3

P(t-Bu)3

L23

R1

2-Me

2-i-Pr

2-Cy

4-O2N

4-Me2N

4-MeO

4-F

4-NC

4-EtO2C

4-CF3

4-MeCO

4-t-Bu

4-PhCO

2-Me

2-Me

3-Me

R2R2

(78)Pd2(dba)3 (2 mol %), L23 (2 mol %),

ZnF2 (0.5 eq), DMF, 90°, 18 h

(87)Pd2(dba)3 (2 mol %), L23 (2 mol %),

ZnF2 (0.5 eq), DMF, 90°, 18 h

80

80

R1R1

CNBr

x

4

4

4

2

4

2

2

2

2

2

2

2

2

4

4

2

Me3Si

CNBr

MeO MeO

CNBr

OOOO

179




Aryl Compound

C6

MeCO2t-Bu Pd(dba)2 (x mol %), L47 (x mol %),

LiHMDS (2.3 eq), rt, 12 hBr CO2t-Bu

R

H

2-MeO

3-MeO

4-MeO

4-t-Bu

4-Ph

(87)

(87)

(88)

(85)

(92)

(92)

x

1

2

0.5

1

0.5

0.5

77R R

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.2–1.0 mol %),

LiNCy2 (1.3 eq), toluene, rtBr CO2t-Bu

R1

H

2-F

2-CF3

3-MeO

3-F

3-CF3

4-MeO

4-F

4-CF3

4-t-Bu

4-Ph

3-F

(92)

(88)

(82)

(94)

(95)

(85)

(95)

(95)

(94)

(87)

(96)

(93)

Time (h)

24

15

15

24

15

24

24

15

10

8

15

15

R2

H

H

H

H

H

H

H

H

H

H

H

4-Ph

x

0.2

1.0

1.0

0.5

1.0

0.5

0.5

1.0

1.0

0.5

0.5

1.0

75R2

R1R1

R2

180

Pd(dba)2 (x mol %),

L47 (0.5–2 mol %), LiHMDS (2.3 eq),

toluene, rt

R1

H

2-MeO

3-MeO

3-F

3-CF3

4-MeO

4-F

4-t-Bu

4-Ph

3-F

(87)

(87)

(88)

(91)

(88)

(85)

(90)

(92)

(93)

(80)

Time (h)

12

12

12

12

12

12

12

12

15

12

R2

H

H

H

H

H

H

H

H

H

4-Ph

x

1.0

2.0

0.5

1.0

1.0

1.0

1.0

0.5

0.5

1.0

75

CO2t-BuR2

R1

Br

R1

R2

Pd(dba)2 (3 mol %), L17 (6.3 mol %),

LiHMDS (2.5 eq), tolueneBr CO2t-Bu

R

2-Me

4-F

4-Me

(78)

(71)

(81)

Time (h)

0.2

6

4

Temp

80°rt

rt

74R R


2. [PdP(t-Bu)3Br]2 (x mol %), rt, 4 hBr CO2t-Bu

R

MeO

F

CF3

t-Bu

(86)

(82)

(73)

(83)

x

0.2

0.4

0.4

0.2

157

RR

181




Aryl Compound

MeCO2t-Bu

C6

1. LiNCy2 (1.3 eq), toluene, 0°, 20 min

2. [PdP(t-Bu)3Br]2 (0.04 mol %), rt, 4 hBr

157CO2t-Bu

t-Bu t-Bu

(87)

Pd(dba)2 (0.5 mol %),

P(t-Bu)3 (0.5 mol %),

LiHMDS (2.3 eq), toluene, rt

I (98)

Pd(dba)2 (0.2 mol %),

P(t-Bu)3 (0.2 mol %),

LiNCy2 (1.3 eq), toluene, rt, 10 hBr CO2t-Bu

(97)

Pd(dba)2 (0.5 mol %), L47 (0.5 mol %),

LiHMDS (2.3 eq), rt, 12 hBr

CO2t-Bu

Br

(98) 77

I

75

75

Pd(dba)2 (3 mol %), L17 (6.3 mol %),

LiHMDS (2.5 eq), toluene, rtBr CO2t-Bu

R

H

MeO

(84)

(90)

ITime (h)

1

4

R R

Pd(dba)2 (0.5 mol %), L47 (0.5 mol %),

LiHMDS (2.3 eq), rt, 12 hBr CO2t-Bu(90) 77

74

182

Pd(dba)2 (x mol %),

L47 (0.5–1.0 mol %),

LiHMDS (2.3 eq), toluene, rt, 12 h

R

H

MeO

(90)

(60)

x

0.5

1.0

Pd(dba)2 (x mol %),

L47 (0.2–0.5 mol %),

LiNCy2 (1.3 eq), toluene, rt, 15 h

R

H

MeO

(93)

(96)

x

0.2

0.5

75

Pd(dba)2 (2 mol %),

P(t-Bu)3 (2 mol %),

K3PO4 (2.3 eq), 100°, 12 h

CO2Et

(84)

t-Bu

CO2Et

NMe2

t-Bu

BrNMe2

75

77

I

I

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.1–0.2 mol %),


CO2MeCO2Me

R1

3-MeO

3-F

3-Me

3-CF3

4-MeO

4-F

4-Me

4-CF3

4-Ph

3-F

(96)

(91)

(87)

(76)

(99)

(90)

(81)

(83)

(78)

(83)

Time (h)

16

12

18

10

10

12

14

10

10

10

R2

H

H

H

H

H

H

H

H

H

4-Ph

x

0.1

0.2

0.1

0.1

0.2

0.2

0.1

0.1

0.1

0.1

75

Br

R1

R2R2

R1

Br

R

Br

R

183

R

R

2-F

2-NC

4-Me2N

4-O2N

4-MeO

4-MeS

4-Cl

4-NC

4-CF3

4-MeO2C

4-MeCO

4-t-Bu

4-PhCO

(92)

(84)

(90)c

(90)

(93)

(91)

(94)

(98)

(90)

(97)

(92)

(93)

(92)

x

3

2

3

1

1

1

1

1

1

1

2

1

1




Aryl Compound

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.1–0.2 mol %),


CO2Me

R

H

MeO

(88)

(99)

x

0.1

0.2

R

Time (h)

12

10

R

75

CuBr (cat), NaH (2 eq), 0.5 hCO2Me

Br CO2Me

CO2HCO2H

(60)MeO2C CO2Me 101

CO2Me

C6

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (x mol %),

L12 (x mol %), rt, 24 h

68R

NEt2

O

BrNEt2

O

184

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. [PdP(t-Bu)3Br]2 (0.5 mol %),

KH (1.05 eq), rt, 24 h

R

H2N

HO

(80)

(91)

R

Br

R

NEt2

O68

1. Base, rt, 1 min

2. ZnCl2, rt, 5 min

3. Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, rt, 4 h

Base

LDA (2 eq)

LiNCy2 (1.2 eq)

(20)

(100)

68

Br

t-Bu t-Bu

NEt2

O

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1–5 mol %),

ligand (x mol %), 24 h

Ligand

P(t-Bu)3

P(t-Bu)3

PCy3

PCy3

L12

L12

L17

L17

L17

L17

L23

L23

(25)

(34)

(0)

(0)

(100)

(100)

(25)

(57)

(40)

(76)

(0)

(60)

Temp

rt

rt

rt

rt

rt

rt

rt

70°rt

70°rt

70°

68

t-Bu

Br

x

1

2

1

2

1

2

1

1

7.5

7.5

1

2

I

I

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1 mol %),

L12 (1 mol %), rt, 24 h

(96)NEt2

O

Br68

185




Aryl Compound

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1 mol %),

L12 (1 mol %), rt, 24 h

NEt2

O(95)

MeO

Br

MeO

68

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (2 mol %), L12 (2 mol %),

70°, 24 h

N N

(91)

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (2 mol %), L12 (2 mol %),

70°, 24 h

(89)

SS

68

68

NEt2

O

C6

Br

Br NEt2

NEt2

O

O

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (x mol %), L12 (x mol %),

rt, 12 h

N

O

R

O2N

MeO

MeS

CF3S

NC

CF3

MeO2C

PhCO

(89)

(89)

(89)

(83)

(89)

(88)

(89)

(92)

O

x

2

2

1

1

2

3

2

2

R

Br

R

N

O

68

O

186

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. [PdP(t-Bu)3Br]2 (1 mol %),

KH (1.05 eq), 70°, 12 h

(92)

HO

Br

HOO

N

O

68

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (2 mol %), L12 (2 mol %),

rt, 12 h

(90) 68

1. Zn (1.5 eq), THF, rt, 0.5 h

2. Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, rt, 6 hNEt2

O

R

2-F

4-O2N

4-NC

4-MeO2C

4-t-Bu

(91)

(81)

(87)

(89)

(90)

Br N

O

O

Br 68

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), 12 hNMe2

O

BrR

3-F

4-Me2N

4-MeO

4-Cl

4-CF3

4-t-Bu

4-PhCO

(91)

(93)

(94)

(91)

(86)

(94)

(88)

Temp

rt

70°rt

70°70°rt

rt

R R

Br

O

NMe2

68

Br

Br

R RO

NEt2

O

NEt2

1. Zn (1.5 eq), THF, rt, 0.5 h

2. Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, rt, 6 h

(91) 68

187




Aryl Compound

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), 70°, 12 hN N(94) 68

Br NMe2

O

NMe2

O

Br

C6

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), rt, 12 h

(82)

SS

68

Br NMe2

O

Pd2(dba)3 (2 mol %), ligand,

ZnF2 (0.5 eq), DMF, 90°

CN

(98)Pd2(dba)3 (2 mol %), L23 (2 mol %),

ZnF2 (0.5 eq), DMF, 90°, 18 h

80

(71)

(60)

(64)

(71)

(82)

(84)

(77)

(87)

Time (h)

24

24

24

18

8

8

18

8

R

2-Me

2-i-Pr

2-Cy

4-MeO

4-NC

4-EtO2C

4-t-Bu

4-PhCO

Ligand

P(t-Bu)3 (4 mol %)

P(t-Bu)3 (4 mol %)

P(t-Bu)3 (4 mol %)

L23 (2 mol %)

L23 (2 mol %)

L23 (2 mol %)

L23 (2 mol %)

L23 (2 mol %)

RR

80

BrCN

Me3Si

MeO

CN

MeO

Br

188

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), TlOAc (1 eq)OMe

Me3SiO(56) 100

Br CO2Me

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), LiOAc (2 eq),

THF, reflux, 6 h

(40)

MeO

CO2Me

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), LiOAc (2 eq),

THF, reflux, 6 h

R

H

MeO

(53)

(50)

100

R R

CO2MeOTf

100

MeO

O

CO2t-Bu

ZnBr•THFCatalyst (x mol %), ligand (1 mol %),

THF, 70°, 12 h

R

H

H

O2N

NC

MeO2C

trace

(95)

(83)

(86)

(85)

Catalyst

[PdP(t-Bu)3Br]2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Cl CO2t-Bu156

R

Ligand

—

L12

L12

L12

L12

R

x

0.5

1

1

1

1

Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, rt, 4 hR

2-O2N

2-NC

4-O2N

4-EtCO

4-PhCO

(87)

(91)

(96)

(94)

(72)d

76R RBr CO2t-Bu

Tf

189




Aryl Compound

Pd(dba)2 (1–2 mol %), L12, THF, rt

R

2-O2N

2-HO

2-NC

4-H2N

4-O2N

4-HO

4-PhCO

(87)

(83)

(91)

(80)

(96)

(91)

(75)

22R RBr CO2t-Bu

CO2t-Bu

ZnBr•THF

C6

[PdP(t-Bu)3Br]2 (0.5 mol %),

KH (1.05 eq), THF, rt

R

2-HO

4-H2N

4-HO

(83)

(85)

(91)

Time (h)

4

24

4

R RBr CO2t-Bu

76

CN

CO2t-Bu76

CN

Br

[PdP(t-Bu)3Br]2 (0.5 mol %),

THF, rt, 4 h

(81)

PdCl2(PPh3)2 (20 mol %), DIBALH,

THF/HMPA (2:1), overnight

R

MeS

Cl

(50)

(55)CO2t-Bu

RR

OTf

22

PdCl2(PPh3)2 (20 mol %), DIBALH,

THF/HMPA (2:1), overnightOTf CO2t-Bu(60) 158

190

Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, 70°, 4 h

X

3-Br

4-Br

(90)

(79)

76, 22N

X

N

CO2t-Bu

Pd(dba)2 (2 mol %), L11 (2 mol %),

dioxane, rt, 6 hNEt2

O

ZnBr•THF

R

MeO

NC

CF3

EtO2C

t-Bu

(91)

(86)

(91)

(94)

(92)

76, 68

R

Br

R

NEt2

O

CO2t-BuPd(dba)2 (1.0 mol %), L47 (1.0 mol %),

NaHMDS (2.2 eq), toluene, rt, 12 h

CO2t-Bu (71) 75

C7

Cl

(100)

(60)

Base

NaHMDS

LiNCy2


2.[PdP(t-Bu)3Br]2 (0.2 mol %), rt

156

I

I

Pd(dba)2 (x mol %), L47 (x mol %),

NaHMDS (2.3 eq), rt, 12 hX

CO2t-Bu

X

Cl

Br

Br

(71)

(75)

(88)

x

1

0.5

0.5

R

H

H

Me

R R

77

191




Aryl Compound

1. NaHMDS (1.2 eq), toluene,

rt, 10 min


4 h

Cl

R

H

H

2-MeO

2-MeO

3-MeO

3-MeO

4-MeO

4-MeO

4-F

4-Br

4-Br

2,6-Me2

2,6-Me2

(91)

(94)

(62)

(77)

(41)

(75)

(69)

(88)

(73)

(84)

(81)

(42)

(81)

Ligand

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

P(t-Bu)3

none

none

P(t-Bu)3

none

P(t-Bu)3

none

156CO2t-Bu

Catalyst

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Pd(dba)2

[PdP(t-Bu)3Br]2

Temp

rt

rt

rt

rt

rt

rt

rt

rt

60°60°60°60°60°

x

0.4

0.2

1

0.4

1

0.4

1

0.4

0.15

0.3

0.15

0.4

0.2

y

0.4

—

1

—

1

—

1

—

—

0.3

—

0.4

—

R RCO2t-Bu

C7

Pd2(dba)3 (1.5 mol %), L14 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°

R

MeO

PhO

(56)

(54)

Time (h)

5

3

74

Cl

R R

CO2t-Bu

192

R1

H

2-Me

4-MeO

4-CF3

3-F

(75)

(88)

(82)

(74)

(66)

R2

H

H

H

H

4-Ph

x

0.5

1.0

1.0

5.0

2.0


rt, 10 min

2. [PdP(t-Bu)3Br]2 (x mol %), rt, 4 h

CO2t-Bu

R

2-MeO

3-MeO

3-F

4-MeO

4-F

4-Cl

(87)

(84)

(90)

(87)

(88)

(83)

x

0.25

0.25

0.2

0.25

0.2

0.2

157Br

RR

Pd(OAc)2 (3.0 mol %),

L17 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°

R1

2-Me

2-H2C=CH

2-i-Pr

3-CF3

4-PhO

4-Ph

2-Me

3-F

(82)

(77)

(88)

(81)

(71)

(86)

(68)

(86)

Time (h)

2

2

2

1

2

0.5

2

0.3

R2

H

H

H

H

H

H

6-Me

4-Ph

74I

Br

R1

R2


0°, 20 min

2. [PdP(t-Bu)3Br]2 (0.2 mol %), rt, 4 h

157

Br

t-Bu t-Bu

CO2t-Bu (79)

Pd(dba)2 (x mol %),

L47 (0.5–5 mol %),

NaHMDS (2.2 eq), toluene, rt, 12 hCO2t-Bu

75

Br

R1 R1

R2 R2

I

193




Aryl Compound



rt, 4 h

157

Base

NaHMDS

LiHMDS

LiNCy2

LiNCy2

LiNCy2

LiNCy2

LiNCy2

(100)

(20)

(100)

(80)

(75)

(91)

(60)

Ligand

none

none

none

none

P(t-Bu)3

P(t-Bu)3

[HP(t-Bu)3] BF4

Catalyst

[PdP(t-Bu)3Br]2

[PdP(t-Bu)3Br]2

[PdP(t-Bu)3Br]2

[PdP(t-Bu)3Br]2

Pd(dba)2

Pd(dba)2

Pd(dba)2

x

0.25

0.25

0.25

0.05

0.1

0.25

0.25

y

—

—

—

—

0.1

0.25

0.25

Br

t-Bu t-Bu

CO2t-BuCO2t-Bu

C7

Pd(dba)2 (1 mol %), L47 (1 mol %),

NaHMDS (2.2 eq), toluene, rt, 12 h

75

Pd(dba)2 (1 mol %), P(t-Bu)3 (1 mol %),

NaHMDS (2.3 eq), rt, 12 hBr

CO2t-Bu (74) 77

I (74)


2. [PdP(t-Bu)3Br]2 (0.05 mol %), rt, 4 h

157I (72)

Pd(OAc)2 (3 mol %), L17 (6.3 mol %),

LiHMDS (2.5 eq), tolueneBrCO2t-Bu

R

H

H

MeO

MeO

(84)

(92)

(79)

(74)

Temp

rt

80°rt

80°

R R

Time (h)

17

0.25

15

0.5

74

I

194

Pd(dba)2 (1 mol %), L47 (1 mol %),

NaHMDS (2.2 eq), toluene, rt, 12 hCO2t-Bu (83)

MeO

"

"

Br

MeO

Pd(dba)2 (1 mol %), L47 (1 mol %),

NaHMDS (2.3 eq), rt, 12 h

I

I (83)

75

77


2. [PdP(t-Bu)3Br]2 (0.2 mol %), rt, 4 h

157I (75)

Pd(OAc)2 (3.0 mol %), L26 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°, 0.5 h

CO2Et(48)

Pd(OAc)2 (3.0 mol %), L26 (6.3 mol %),


(54)

74CO2Et

Br

Br

CO2Et 74

Pd(dba)2 (5 mol %), L47 (5 mol %),


CO2Et

(95) 77

t-Bu

i-Pr

CO2Et

Br

t-Bu

i-Pr

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (x mol %), L12 (x mol %),

rt, 24 h

NEt2

O

68RR

Br

O

NEt2

R

2-MeO

2-F

2-Me

4-O2N

4-MeO

4-MeS

4-Cl

4-NC

4-CF3

x

3

3

3

3

1

1

1

3

1

(88)

(86)

(98)

(87)

(94)

(91)

(87)

(91)

(90)

195




Aryl Compound

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (3 mol %), L12 (3 mol %),

70°, 24 h

NN

(86)

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (1 mol %), L12 (1 mol %),

70°, 24 h

(92)

SS

68

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (4 mol %), L12 (4 mol %),

rt, 24 h

N

O R

2-F

2-Me

4-MeO

4-Cl

4-CF3

4-EtO2C

4-PhCO

(69)

(79)

(91)

(89)

(82)

(85)

(65)

O

RR

Br

O

N

O

68

68

Br

Br

NEt2

NEt2

O

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (2 mol %), L12 (2 mol %),

rt, 24 h

NEt2

O

(92)

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. [PdP(t-Bu)3Br]2 (1 mol %),

KH (1.05 eq), rt, 24 h

R

H2N

HO

(90)

(95)

MeO

Br

MeO

RO

NEt2Br

R

68

68

O

NEt2

OC7

196

1. Zn (1.5 eq), THF, rt, 0.5 h

2. Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, 6 hNEt2

O

R

Me2N

MeO2C

(89)

(87)

Br

Temp

70°rt

68

Ni(cod)2 (5 mol %), (S)-L23

(8.5 mol %), ZnBr2 (15 mol %),

NaHMDS (2.3 eq), toluene/THF (3:1),

60°, 17–20 h

(84), 98% ee

O O

n-Pr

Ph

(25), 83% ee

O O O O

(56), 95% ee

(80), 89% ee

33

R

Br

RO

NEt2

33

33

33

O

n-Pr

O

Cl

ClMeO

Cl

Cl

O O

MeO

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %), ZnBr2 (15 mol %),


60°, 17–20 h

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %), ZnBr2 (15 mol %),


60°, 17–20 h

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %), ZnBr2 (15 mol %),


60°, 17–20 h O O

197




Aryl Compound

Pd(OAc)2 (2 mol %),

P(t-Bu)3 (4 mol %), ZnCl2 (1.2 eq),

THF, rt

Pd(OAc)2 (2 mol %),

P(t-Bu)3 (4 mol %), ZnCl2 (1.2 eq),

THF, rt

(91)

Pd(OAc)2 (2 mol %),

P(t-Bu)3 (4 mol %), ZnCl2 (1.2 eq),

THF, rt

(81)

80

(87)

(82)

(72)

(71)

(63)

(85)

(75)

(91)

R2

H

H

H

H

H

H

H

5-t-Bu

R1

2-Me

4-Me2N

4-MeO

4-NC

4-EtO2C

4-t-Bu

4-PhCO

2-Me

R1

R1C7

80

80

R2

MeO

Br

MeO

Br

R2NC

NC

NC

Br

NC

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), TlOAc (1 eq)

100OMe

Me3SiO R

Br

R

CO2Me

R

H

O2N

MeO

(70)

(40)

(70)

198

[η3-C4H7Pd(OAc)]2 (x mol %),

ligand (y mol %), LiOAc (2 eq),

THF, reflux

Ligand

PPh3

dppe

dppp

dppb

L1

L1

L1

L1

(15)

trace

(10)

(24)

(13)

(73)

(72)

(70)

x

2

2

2

2

2

2

1

0.5

Time (h)

6

6

12

6

6

6

6

6

OTfCO2Me 100


L1 (y mol %), LiOAc (2 eq),

reflux, 6 h

R

O2N

MeO

(25)

(30)

x

2

5

Solvent

DME

THF

100

OTf

R R

CO2Me

y

6

4

4

4

2

4

4

4

y

8

20

[η3-C4H7Pd(OAc)]2 (5 mol %),


R

H

MeO

(80)

(80)

RR

BrCO2Me 100

199




Aryl Compound


L1 (y mol %), LiOAc (2 eq),

reflux, 6 h

R

H

H

MeO

trace

(70)

(40)

x

2

2

5

Solvent

THF

DME

THF

R

CO2Me 100

R

OTf

y

8

8

20

OMe

Me3SiOC7

CO2t-BuTHF•BrZn

BrCO2t-Bu

I

R RPd(dba)2 (1–2 mol %), L12, THF

R

2-HO

2-NC

4-H2N

4-MeO2C

4-PhCO

(95)

(85)

(67)

(87)

(89)

Temp

rt

rt

rt

rt

70°

22

Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, 4 h

R

2-NC

4-PhCO

4-MeO2C

(85)e

(89)

(87)

I

Temp

rt

70° rt

76Br

R

R

4-H2N

4-MeO2C

(70)

(81)

Time (h)

12

4

[PdP(t-Bu)3Br]2 (0.5 mol %), THF, rt 76IBr

R

200

[PdP(t-Bu)3Br]2 (0.5 mol %),

KH (1.05 eq), THF, rt

R

4-H2N

4-HO

(66)

(95)

Time (h)

24

4

76IBr

R

PdCl2, L1 (15 mol %), THF,

rt, overnightOTfCO2t-Bu (18) 159

Pd(dba)2 (1 mol %), L12 (1 mol %),

THF, 70°, 4 h

Pd(dba)2 (1–2 mol %), L12, THF, rt

NN

(91)

I (91)

I

76

22

Br

N

Br

CO2t-Bu

Pd(dba)2 (2 mol %), L12 (2 mol %),

dioxane, rt, 6 hNEt2

O R

3-MeO

4-O2N

4-EtO2C

4-CF3

4-t-Bu

(88)

(97)

(95)

(88)

(88)

THF•BrZn 68, 76RR

NEt2

O

Br

C8

Pd(OAc)2 (3.0 mol %), L17 (6.3 mol %),


CO2t-BuBr

CO2t-Bu (81) 74

201




Aryl Compound

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.1–0.5 mol %),


R1

3-MeO

3-F

3-Me

3-CF3

4-MeO

4-F

4-Me

4-CF3

4-Ph

3-F

(94)

(94)

(92)

(90)

(94)

(82)

(95)

(78)

(86)

(90)

Time (h)

20

24

24

8

12

24

24

10

18

18

R2

H

H

H

H

H

H

H

H

H

4-Ph

x

0.1

0.1

0.2

0.5

0.2

0.1

0.2

0.5

0.5

0.5

Pd(dba)2 (0.1 mol %),

P(t-Bu)3 (0.1 mol %),


R

H

MeO

(91)

(97)

R Time (h)

18

10

75

75

R

Br

R1

R2

R1

R2

MeO2C

MeO2C

MeO2C

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), 12 hN

O

Br

O

68

R

Br

R

N

O

O

R

Me2N

MeO

Cl

CF3

t-Bu

Temp

70°rt

rt

rt

rt

(88)

(97)

(91)

(85)

(93)

C8

202

Pd(dba)2 (5 mol %),


toluene, rt or Pd(dba)2, carbeneb,

NaHMDS, toluene, rt

(<5)O

O

O

OMe

MeO

O

O

O

OMe

MeO

Ph

99

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), 70°, 12 hNN (92)

1. Zn (1.5 eq), THF, rt, 0.5 h

2. [PdP(t-Bu)3Br]2 (2.5 mol %),

THF/toluene (2:8), rt, 12 h

(72)

SS

Br

68

68

Br

BrO

N

O

N

O

O

Pd(OAc)2 (2 mol %), L23 (2 mol %),

KOt-Bu (1.3 eq), toluene, 100°, 2 h

Ph CN

(95) 26

Br

t-But-Bu

Ph

CN

PdCl2 (5 mol %),

ligand (10–20 mol %),

Cs2CO3 (1.2 eq)

CNPh

Ph

(47)

(68)

(18)

Time (h)

6

2

2

X

Br

Br

I

Ligand

PPh3

PPh3

none

Temp (°)

100

130

100

73X

203




Aryl Compound

Pd(OAc)2 (2 mol %), L23 (2 mol %),

NaHMDS (1.3 eq), toluene, 100°, 4 hCN

CN

t-Bu (46)

Br

t-Bu

26

C8

OMe

Me3SiO Pd(dba)2 (1 mol %),

P(t-Bu)3 (2 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 h

X

Cl

Cl

Br

Br

Br

Br

Br

Br

Br

(95)e

(96)e

(91)

(98)

(88)

(95)

(94)

(78)

(99)

R

O2N

MeO2C

H

O2N

MeO

CF3

MeO2C

MeCO

PhCO

99

99

99, 76

99, 76

99, 76

76

99, 76, 22

99, 76, 22

99, 76, 22

R

X

R

CO2Me

99

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %),

additive (x eq), 80°, 12 hBrCO2Me

CN

t-Bu+

(23)

204

Additive

none

LiCl

ZnF2

ZnF2

ZnF2

ZnCl2

ZnCl2

ZnCl2

ZnBr2

(—)

(—)

(95)

(100)

(93)

(0)

(—)

(66)

(38)

Solvent

DMF

DMF

DMF/DME (1:1)

DMF

DMF

DME

DMF/DME (1:1)

DMF/DME (1:1)

DMF/DME (1:1)

x

—

1

0.5

0.5

0.25

0.5

0.5

0.25

0.25

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), additive,


Additive

none

ZnCl2

CuCl

(0) 99

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), LiOAc (2 eq),

THF, reflux, 6 h

(0) 100CO2MeOTf

t-Bu

Br

t-Bu

CO2Me

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 hOEt

Me3SiO R

MeO2C

t-Bu

(63)

(54)MeO

R

Br

R

CO2Et

OMe

99

Pd(dba)2 (5 mol %), L47 (5 mol %),


CO2Me

(98) 77

t-Bu

Br

t-Bu

CO2Me

C9

205




Aryl Compound

PdCl2 (5 mol %),

ligand (10–20 mol %),

Cs2CO3 (1.2 eq), additive

CO2MeCO2Me

(9)

(7)

(60)

Time (h)

4

50

2

X

Br

I

I

Ligand

PPh3

none

none

Temp (°)

130

100

100

Additive

4 Å MS

none

4 Å MS

73X

NEt2

NEt2O

O

R

2-MeO

4-MeO

4-NC

4-MeO2C

4-t-Bu

(78)

(87)

(97)

(88)

(85)

68

C9

R

RBr

1. s-BuLi (1.2 eq), THF, –78°, 1 h

2. ZnCl2 (2.4 eq), rt, 10 min

3. Pd(dba)2 (3 mol %), L12 (3 mol %),

rt, 24 h

NMe


PCy3 (3 mol %),


160

IPd(dba)2 (2 mol %),

ligand (3 mol %),

base (x eq), THF/toluene

160

NMe

O

Ph

BrI

Br(0)

Ligand

PCy3

P(t-Bu)3•HBF4

L1

Base

KHMDS

KHMDS

KHMDS

x

2.0

2.0

2.0

Temp

70°70°70°

Time (h)

3

3

3

(0)

(<2)

(0)

206

(20)

(44)

(81)

(0)

(95)

(90)

(90)

(91)

(0)

70°70°70°rt

70°70°70°70°70°

L20

L21

L21

L21

L21

L21

L21

L21

L23

2.0

1.1

1.1

1.1

1.1

1.1

1.1

2.0

2.0

KHMDS

NaH

NaHMDS

KHMDS

KHMDS

KHMDS

KHMDS

KHMDS

KHMDS

3

3

3

3

0.5

1

3

3

3

Pd(dba)2 (2 mol %), L21 (3 mol %),

KHMDS, THF/toluene, 70°160

NMe

OBr

MeO

(—)

OMe

Pd(PPh3)4 (5 mol %),

p-cresol (10 mol %), C6D6, 120°, 1 d

59CN

CN

(85)

OEt

Me3SiO

Et

[η3-C4H7Pd(OAc)]2 (5 mol %),

ligand (x mol %), TlOAc (1 eq)

Ligand

PPh3

dppe

dppb

L1

(10)

trace

(8)

(80)

100Br

Et

CO2Etx

15

20

20

20

207




Aryl Compound

OEt

Me3SiO

Et

[η3-C4H7Pd(OAc)]2 (2 mol %),

L1 (10 mol %), LiOAc (2 eq),

solvent, reflux, 6 h

R

H

O2N

Solvent

THF

DMEEt

CO2Et

RR

OTf

(80)

(30)

100

C9

Pd(OAc)2 (10 mol %),

PCy3 (10 mol %), NaOt-Bu (1.5 eq),

dioxane, 70°, 12 h

32

Br

NMe

NMe

O

(61)

(60)

(56)

(55)

R

H

2-MeO

2-Me

4-Me

NMe

O

(56) 32

RO

Cl

O

O Cl

R

O

O

Pd(OAc)2 (10 mol %),


dioxane, 70°, 12 h

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq), 2 h

67(60) (1)

I

Br

NMe

NMe

O+

NMe

OO

Pd(OAc)2 (5 mol %),

ligand (5 mol %),

NaOt-Bu (1.5 eq), dioxane

X

NMe

I 32

O

208

(68)

(9)

(62)

(62)

(33)

(29)

(39)

(10)

Time (h)

5

10

3

10

10

10

10

10

X

Cl

Br

Br

Br

Br

Br

Br

Br

Ligand

PCy3

P(t-Bu)3

PCy3

PCy3

L15

L18

L47

L51

Temp (°)

70

50

50

50

50

50

50

50

Pd(OAc)2 (3.0 mol %),

L17 (6.3 mol %), LiHMDS (2.5 eq),

toluene, 80°

CO2Et

R1

3-Cl

4-Me2N

4-Me

4-Et2NCO

4-t-BuO2C

2-Me

(79)

(49)

(85)

(88)

(75)

(71)

Time (h)

1

3

0.5

1

0.5

2

R2

H

H

H

H

H

6-Me

R2 R2

CO2Et

PhBr

Pd2(dba)3 (1.5 mol %),

L14 (6.3 mol %), LiHMDS (2.5 eq),

toluene, 80°

R

MeO

Me

(87)

(82)

Time (h)

1

2

74

R

Cl

R

CO2Et

PhPh

74

C10

R1R1

Pd2(dba)3 (1.5 mol %), L14 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°, 0.2 h

(90)

H2N

Br

H2N

CO2Et

Ph

74

209




Aryl Compound

Pd(OAc)2 (3 mol %), L17 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°, 3 hBr

CO2Et

Ph

(88) 74CO2Et

Ph

C10

CO2Me

R1

3-F

3-Me

4-F

4-Me

4-Ph

3-F

(82)

(89)

(84)

(87)

(93)

(97)

Time (h)

15

8

15

8

15

15

R2

H

H

H

H

H

4-Ph

x

1.0

0.5

1.0

0.5

0.5

1.0

Ph

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.5–1.0 mol %),

LiNCy2 (1.3 eq), toluene, rtCO2Me

Ph

Pd(dba)2 (x mol %),

P(t-Bu)3 (0.5–1.0 mol %),

LiNCy2 (1.3 eq), toluene, rt, 15 hBrCO2Me

R

H

MeO

(78)

(82)

x

0.5

1.0

R

Ph

75

R

Br

R1

R2 R2

R1

75

Pd(OAc)2, P(t-Bu)3, Cs2CO3, o-xylene (—)Br

NH

O

Ph NH

O

Ph

Ph

Ph

Ph

47

210

Pd(OAc) (5 mol %), L34 (5 mol %),

K3PO4 (3.3 eq), toluene, 80°, 14 h

79Br

R

H

3-CF3

4-MeO

(85)

(75)

(85)I

N

O PhO

Pd(dba)2 (5 mol %), L34 (10 mol %),

K2CO3 (3.3 eq), toluene, 100°, 14–36 h

R

H

2-Me

3-CF3

4-O2N

4-MeO

4-F

4-NC

4-H2C=CH

4-t-Bu

(77)

(80)

(66)

(62)

(75)

(75)

(58)

(75)

(83)

I

Pd(dba)2 (5 mol %), L34 (10 mol %),

K2CO3 (3.3 eq), toluene, 100°, 14–36 h

(83)

Br

79

79

R

Pd(dba)2 (5 mol %), L34 (10 mol %),

K2CO3 (3.3 eq), toluene, 100°, 14–36 hN

Br

(40) 79

Pd(OAc) (5 mol %), L34 (10 mol %),

K3PO4 (3.3 eq), toluene, 100°, 36 h

BrN

O t-BuO

i-Pr

(63) 79

N

O PhO

N

O PhO

N

O PhO

N

O t-BuO

i-Pr

Br

R

R

N

211




Aryl Compound

Cu(OAc)2 (0.1 eq) 133(18)Pb(OAc)3

NH

O

OMe NH

O

OMe

C10

Pd2(dba)3•CHCl3 (1 mol %),

P(t-Bu)3 (2 mol %),

LiHMDS (1.3 eq), toluene, 70°, 3 hCN CN(89)

Ph26

Ph Ph

Br

Pd(OAc)2 (2 mol %),

ligand (4 mol %),

ZnCl2 (1.2 eq), THF, rt

i-Pr80

(76)

(80)

(86)

(77)

(82)

R2

H

H

H

H

4-MeO

Ligand

P(t-Bu)3

L33

P(t-Bu)3

L33

P(t-Bu)3

R1

4-t-Bu

4-t-Bu

4-PhCO

4-PhCO

3-MeO

R1 R1

Pd2(dba)3 (2 mol %), L23 (2 mol %),

KF (1 eq), DMF, 90°, 24 h

Me3Si

CN

(68)

(77)

(84)

(62)

R

H

MeO

EtO2C

t-Bu

80

R2

R

Br

R

NC

Br

R2

CNi-PrO

OO

O

CN

212

Pd(dba)2 (1 mol %),

P(t-Bu)3 (2 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 h

Ot-Bu

Me3SiO

R

MeO2C

MeOC

(80)

(68)

CO2t-Bu

RR

Br

22

76, 99

Pd(dba)2 (1 mol %),

P(t-Bu)3 (2 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 h

R

2-NC

3-NC

4-O2N

4-MeO2C

4-MeCO

(75)

(67)

(76)

(80)

(68)

RR

CO2t-BuBr

Pd(OAc)2 (5 mol %), ligand (5 mol %),


32X

NMe

NMe

O

(8)

(3)

(10)

(6)

(10)

(14)

(29)

(11)

Time (h)

24

10

3

10

10

10

10

10

X

Cl

Br

Br

Br

Br

Br

Br

Br

Ligand

PCy3

P(t-Bu)3

PCy3

PCy3

L15

L18

L47

L51

Temp (°)

70

50

50

50

50

50

50

50

O

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq), 15 hNMe

BrO

NMe

O

I (52) (8) 67+

I

213




Aryl Compound

Pd(dba)2 (5 mol %), L23 (7.5 mol %),


100°, 0.5 h

Br

MeN

MeN OO

(5) (7)

NMe

O67+

C10

C11Pd(dba)2(1.0 mol %),

P(t-Bu)3 (1.0 mol %),

LiNCy2 (1.8 eq), toluene, rt, 12 h

CO2Bn

CO2Bn

R1

3-Me

3-CF3

4-MeO

4-F

4-Me

3-F

(93)

(80)

(83)

(82)

(90)

(90)

R2

H

H

H

H

H

4-Ph

Pd(dba)2 (1.0 mol %),

P(t-Bu)3 (1.0 mol %), LiNCy2 (1.8 eq),

toluene, rt, 12 hBrCO2Bn

MeO

(88)

75

MeO

Br

R1

R2 R2

R1

75

Pd(OAc)2 (3 mol %), L17 (6.3 mol %),

LiHMDS (2.5 eq), toluene, 80°, 0.5 hBr

CO2Et

4-MeOC6H4

(83)

CO2Et

744-MeOC6H4

Ni(cod)2 (10 mol %),

(S)-L23 (17 mol %),


toluene/THF (3:1), 80°, 17–20 h

O

33ClR

OO

Bn

RO

Bn R

Me2N

MeO

% ee

96

94

(58)

(63)

214

Ni(cod)2 (5 mol %),

(S)-L23 (8.5 mol %), ZnBr2 (15 mol %),


60°, 17–20 h

(91), 96% ee

Pd(OAc) (5 mol %), L35 (10 mol %),

K3PO4 (3.3 eq), toluene, 80°, 36 h

N

O t-BuO

N

O t-BuO

i-Bu

(82) 79

33Cl

OO

Bn

t-Bu

Br

i-Bu

Pd(OAc)2 (2 mol %),

ligand (4 mol %),


i-Pr80

(69)

(72)

(47)

(55)

(85)

(78)

(68)

(72)

R2

H

H

H

H

H

H

4-MeO

4-MeO

Ligand

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

L33

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

L33

R1

4-Me2N

4-MeO

4-EtO2C

4-EtO2C

4-t-Bu

4-PhCO

3-MeO

3-MeO

R1 R1

Pd(OAc)2 (2 mol %), L33 (4 mol %),


(81)

80

Br

MeOMeO

R2 R2

BrCNi-Pr

CNi-Pr

CN

t-Bu

215




Aryl Compound

C11

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2,

DMF, 80° or

Zn(Ot-Bu)2, DMF, rt

(67–73)O

O

Me3SiO

OMe

MeO

O

O

O

OMe

MeO

Ph99

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %),

zinc additive (x eq), DMF, 12 h

I

R

H

H

2-Cl

3-O2N

3-O2N

3-O2N

3-MeCO

4-MeO

4-MeO2C

4-MeO2C

I + II

(67)

(73)

(78)

(64)

(89)

(78)

(76)

(57)

(95)

(80)

Temp

80°rt

80°80°rt

rt

80°80°rt

rt

Zinc Additive

ZnF2

Zn(Ot-Bu)2

ZnF2

ZnF2

Zn(Ot-Bu)2

Zn(Ot-Bu)2

ZnF2

ZnF2

Zn(Ot-Bu)2

Zn(Ot-Bu)2

II

I:II

>50:1

>50:1

20:1

>26:1

>50:1

>50:1

25:1

>50:1

>50:1

>50:1

O

O

O

OMe

MeO

O

O

O

OMe

MeO

R

R R

Br99+

Br

x

0.5

0.25

1

1

0.5

0.25

1

0.5

0.5

0.25

216

PdCl2(PhCN)2, P(o-tol)3,

ZnCl2, DMF/DME (1:1), 80°OEt

Me3SiO

Ph

O

O(87)

OEt

O161

Ph

O OTf

O

X

1-Br

2-Br

I + II

(72)

(58)

x

1

0.5

I:II

>50:1

>50:1

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %),

LiHMDS (1.5–2 eq), THF, 68°, 1–4 hNMe

NMe

O (43)

(67)

(80)

R

Me

MeO

Me

69

X

Cl

Br

Br

RR

XO

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq), 3 h NMe

O 67

(75) (2)

Br

NMe

+NMe

OO

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (x eq),

DMF, 80°, 12 h

II

O

O

O

OMe

MeO

O

O

O

OMe

MeO

X

99+

I

217




Aryl Compound

Catalyst (5 mol %), ligand (5 mol %),


32

Catalyst

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

(62)

(62)

(82)

(41)

(42)

(53)

(21)

(99)

(67)

(11)

(99)

(99)

Time (h)

5

3

1

5

4

3

3

3

3

3

3

3

Ligand

P(t-Bu)3

PCy3

PCy3

L3

L4

L23

P(t-Bu)3

PCy3

L15

L18

L47

L51

Temp (°)

100

50

100

100

100

100

50

50

50

50

50

50

NMe

O

Br

NMe

OC11

C12


K3PO4 (3 eq), toluene, 20 hCO2Et

CO2EtN

X

Cl

Cl

Br

Br

Br

Br

Br

Br

(67)

(67)

(75)

(72)

(71)

(67)

(73)

(80)

R

H

4-CF3

H

2-Me

4-MeO

4-F

4-CF3

4-Ph

N4-MeOC6H4

4-MeOC6H4

Temp (°)

120

120

100

100

100

100

100

100

X77R

R

218


K3PO4 (3 eq), toluene, 100°, 20 h

CO2EtN X

1-Br

2-Br

(74)

(74)

77


K3PO4 (3 eq), toluene, 100°, 20 h

CO2EtN

BrO

O

OO

(71) 77

Pd(OAc) (5 mol %), L3 (10 mol %),

K3PO4 (3.3 eq), toluene, 80°, 14 hBr

N

O PhO

N

O PhO

i-Pr

(29) 79

1. LiHMDS (2.0 eq),

ZnCl2 (2.2 eq), –20°2. Pd(dba)2 (5 mol %),

L17 (7.5 mol %), THF, 65°

NBn

O

NBn

O

R1

H

2-Me

3-MeO

4-MeO

4-Me

2-MeO

2-Me

(98)

(46)

(50)

(77)

(52)

(84)

(0)

72

Br

R2

R1R1

R2

X

Phi-Pr

R2

H

H

H

H

H

4-MeO

4-Me

4-MeOC6H4

4-MeOC6H4

219




Aryl Compound

R1 R2R2

1. LiHMDS (2.5 eq),

ZnCl2 (2.2 eq), –20°2. Pd(OAc)2 (3 mol %), L17 (6.3 mol %),

toluene, 80°

NBn

O R1

H

Me

MeO

(86)

(35)

(16)

Br

72

R1

NBn

OC12

1. LiHMDS (x eq),

ZnX2 (y eq), –20°2. Pd(OAc) (5 mol %), L17 (7.5 mol %),

THF, rt

72NTs

O

NTs

O

x

2.0

0.95

2.0

2.0

(22)

(48)

(48)

(0)

ZnX2

none

ZnCl2

ZnCl2

ZnBr2

1. LiHMDS (2.0 eq),

ZnX2 (2.2 eq), –20°2. Pd(dba)2 (5 mol %), L17 (7.5 mol %),

THF, 65°

R

NTs

O R

H

Me

(92)

(41)Br

Br

R

72

y

—

1.1

2.2

2.2

Ot-Bu

TBSOPdCl2[P(o-tol)3]2 (2–5 mol %),

Bu3SnF (2 eq), benzene, reflux

R

2-MeO

4-MeO

4-MeCO

4-MeO2C

(42)

(51)

(80)

(82)

I

98Br CO2t-BuR R

Time (h)

20

22

6

22

R2

H

H

MeO

220

PdCl2[P(o-tol)3]2 (2–5 mol %),

Bu3SnF (2 eq), THF, reflux

R

2-MeO

4-MeO

4-MeCO

4-MeO2C

(81)

(95)

(76)

(73)

I

Time (h)

22

28

9

22

98Br

R


CuF2 (2 eq), benzene, reflux, 6 h

(87) 98

Br CO2t-Bu


Bu3SnF (2 eq), THF, reflux, 16 h

(75)Br CO2t-Bu

98

[η3-C4H7Pd(OAc)]2 (5 mol %),

L1 (20 mol %), LiOAc (2 eq), THF,

reflux, 6 h

OMe

Me3SiO

Ph

[η3-C4H7Pd(OAc)]2 (5 mol %),


(20) 100Br

OTf

CO2Me

PhI

I (60) 100

Pd(dba)2, P(t-Bu)3, ZnF2, DMF, 80°O N

OSiMe3O

i-PrI II

76, 22

Pd(dba)2, P(t-Bu)3, Zn(Ot-Bu)2,

DMF, rt

I + II (70), I:II = 91:9

I + II (67), I:II = 88:12

22

+Br

O O

NO

O O

i-PrPh

NO

O O

i-PrPh

221




Aryl Compound

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %),

ZnF2 (0.5 eq), DMF, 80°, 12 h

R

H

H f

2-Me

3-MeCO

4-NC

4-t-Bu

I + II

(67)

(70)

(78)

(75)

(65)

(57)

I:II

87:13

91:9

92:8

84:16

77:23

83:17

99RO N

OSiMe3O

i-Pr

C12

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq)NMe

BrO

R

MeO

NCg

I

(80)

(83)

II

(2)

(1)

Time (h)

12

4

R

67NMe

O

I II

RR

NMe

O+

69

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %),

LiHMDS (1.5–2 eq), THF, 68°, 1–4 hNMe

BrO

NMe

O (82)OMe

OMe

Br

I II

+NO

O O

i-Pr R

NO

O O

i-Pr R

222

Pd(OAc)2 (5 mol %), PCy3 (5 mol %),

NaOt-Bu (1.5 eq),

dioxane, 50°, 24 h

32

Br

NMe N

Me

O (98)O

O

O

Pd(dba)2 (5 mol %),


toluene, rt or Pd(dba)2, carbeneb,

NaHMDS, toluene, rt

CO2t-Bu

(<20) 99

C13

CO2t-Bu

OBnBrOBn

Pd(OAc) (5 mol %), L35 (10 mol %),

K3PO4 (3.3 eq), toluene, 80°, 14 h

N

O PhO

N

O PhO

i-Bu

i-Bu (47) 79

Pd(dba)2 (2 mol %), L20 (3 mol %),

KHMDS (1.1 eq), THF/toluene,

70°, 30 min

160N

ONO

Br(60)

Ph

BocBoc

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (0.5 eq),

additive (0.25 eq), DMF, 12 h

I + II

(58)

(61)

Temp

80°rt

Additive

none

Zn(Ot-Bu)2

I:II

92:8

95:5

99

Pd(dba)2, P(t-Bu)3, Zn(Ot-Bu)2,

DMF, rt

I + II (61), I:II = 95:5 22

Br

Ph

O N

OSiMe3O

t-Bu I II

+NO

O O

t-BuPh

NO

O O

t-BuPh

Br

Br

223




Aryl Compound

Pd(OAc)2, PPh3, AgNO3, Et3N, rt 111(68)i

NR N

R

O

IC13

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 hOMe

OSiMe3

BnO (75) 99

C14

BrCO2Me

BnO

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq), 4 h

(1) 67

Br

NMe

NMe

O

I (82) + NMe

OO

C15

Pd(OAc) (5 mol %), L12 (5 mol %),

K3PO4 (3.3 eq), toluene, 80°, 14 h

R

H

3-CF3

4-MeO

(94)

(92)

(75)

I

79R

Br

O

N

O PhON

O PhO

Ph

Ph

R



32

X

NMe

(90)

(93)

I

Time (h)

4

1

X

Cl

Br

Temp (°)

70

50

O224

Pd(dba)2 (5 mol %), L35 (10 mol %),

K2CO3 (3.3 eq), toluene, 100°, 14 h

I 79

R

H

3-CF3

4-MeO

(55)

(55)

(30)

R

Br

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 30 min

160

NBn

O

(70)

(60)

(70)

(66)

(91)

(74)

(85)

(73)

(77)

(85)

(70)

(80)

(79)

(85)

(70)

NBn

OX

Cl

Cl

Cl

Cl

Br

Br

Br

Br

Br

Br

Br

Br

Br

OTf

OTf

RR

H

2-Me

4-MeO

4-CF3

H

2-Me

3-MeO

3-Cl

3-Me

4-MeO

4-Cl

4-CF3

4-t-Bu

H

4-Cl

X

R

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 30 min

160

Br

OMe

Cl

(77)

NBn

O

OMe

Cl

225




Aryl Compound

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 2.5 h

160

NBn

O

Br

(61)

OMeCl

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 2.5 h

160NBn

O

Br

(70)

OMeCl

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 1 h

160NBn

O

Br

(66)

OMe

Cl

C15

NBn

O

NBn

O

NBn

O

NBn

O

OMe

OMe

OMe

Cl

Cl

Cl

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 30 min

160

NBn

O

(80)

X i

226

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 hI II

I + II (35), I:II = 89:11

99Br



32

Cl

NBn

NBn

O(64)

Pd(dba)2 (5 mol %),

ligand (7.5 mol %),

base (1.5 eq), THFNBn

Br

Ligand

L1

L1

L1

L23

L23

I

trace

(56)

(53)

(65)

(57)

I

II

(14)

(13)

(9)

(2)

(2)

Time (h)

19

19

3

23

3

Base

KHMDS

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

67

II

I +NBn

O

O

O

Temp (°)

75

75

100

75

100

Pd(dba)2 (5 mol %),

ligand (7.5 mol %),


Ligand

P(o-tol)3

L1

L1

L23

L23

I

(6)

(10)

(43)

(50)

(64)

II

(—)

(1)

(10)

(1)

(1)

Time (h)

4

23

3

23

3

I + II 67

Temp (°)

100

75

100

75

100

O N t-Bu

O

i-Pr

+NO

OOTMS

t-Bu

O

i-PrPh

NO

O

t-Bu

O

i-PrPh

227




Aryl Compound

Pd(OAc)2 (5 mol %), ligand (5 mol %),


32

X

NMe

NMe

O

(35)

(64)

(34)

(43)

(45)

(36)

(31)

(77)

(75)

(56)

Time (h)

24

24

10

3

10

10

10

10

20

10

X

Cl

Cl

Br

Br

Br

Br

Br

Br

Br

Br

Ligand

PCy3

L31

P(t-Bu)3

PCy3

PCy3

L15

L18

L47

L47

L51

Temp (°)

70

70

50

50

50

50

50

50

50

50



(69)

(82)

I

Time (h)

24

1.5

X

Cl

Br

Temp (°)

70

50


NaOt-Bu (1.5 eq), dioxane, 3 hNMe N

Me

O

(89)

(92)

ITemp (°)

70

50

X

Cl

Br

32

32

X

O

O

Ph

Ph

C15

228

Pd(OAc)2, P(o-tol)3, Et3NNH

111

Br

NH

O (—)

Pd(dba)2 (5 mol %), L23 (7.5 mol %),

NaOt-Bu (1.5 eq), 10 hNMe

Br

NMe

O 67

(63) (2)

Pd(OAc) (5 mol %), L35 (5 mol %),

K3PO4 (3.3 eq), toluene, 80°, 14 h

R

H

3-CF3

(78)

(74)

N

O PhO

N

O PhO

Pd(dba)2 (5 mol %), L35 (10 mol %),

K2CO3 (3.3 eq), toluene, 100°, 14 h

N

O PhO

BnPh

(65) 79

C16

79

+

R

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 30 min

160

NBn

ONBn

O

Br

(76)

OMeMeO

MeO

NMe

O

O

Ph

Ph

Ph

O

Ph

Br

Br

Bn

Bn

Ph

R

OMe

Pd(dba)2 (5 mol %),

P(t-Bu)3 (10 mol %), ZnF2 (0.5 eq),

DMF, 80°, 12 hOt-Bu

OSiMe3R

H

O2N

MeO

(85)

(79)

(87)

BnO 99

R

Br

R

CO2t-Bu

OBn

229




Aryl Compound

Pd2(dba)3 (x mol %),

ligand (y mol %), LiOt-Bu (2 eq),

dioxane, 85°, 20 h

N

Br

CO2t-Bu

N

t-BuO2CN

CO2t-Bu

78

I

(55)

(62)

Ix

3.8

2.3

IIII

(8)

(—)

Ligand

PCy3

L17

+

y

8

2.5

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %), LiHMDS (1.5–2 eq),

THF, 68°, 1–4 hNBn

NBn

O (90)

(40)

R

H

F

69

Pd(OAc)2 (5 mol %),


dioxane, 50°32

NMe

O (83)

(66)

Time (h)

4

9

R

MeO

NC

R

R Br

NMe

BrR

RPh

Ph

O

O

Pd(OAc)2 (5 mol %),


dioxane, 50°, 14 h

Br

NMe

NMe

O

(64) 32

O

C16

Pd(dba)2 (x mol %), ligand, rt, 24 h 32

Br

NMe

(94)

(74)

x

10

5

I

Ligand

L49

L50NMePh

Ph

O

O % ee

34

57

230

Pd(OAc)2 (5 mol %),


dioxane, 50°, 14 h

I (99)

Pd(OAc)2 (5 mol %),


dioxane

Br

NMe N

Me

O (0)

32

32

PhO

OPh

O

C17


K3PO4 (3 eq), toluene, 20 h

CO2EtCO2EtN

X

Cl

Cl

Cl

Cl

Cl

Cl

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

(82)

(81)

(83)

(83)

(85)

(84)

(88)

(89)

(84)

(85)

(90)

(86)

(89)

(89)

(86)

(92)

R

H

2-Me

4-MeO

4-F

4-NC

4-CF3

H

2-MeO

2-Me

4-MeO

4-PhO

4-F

4-NC

4-MeO2C

4-CF3

4-Ph

N

Ph

PhPh

Ph

Temp (°)

120

120

120

120

120

120

100

100

100

100

100

100

100

100

100

100

77

R

R

X

231




Aryl Compound


K3PO4 (3 eq), toluene, 20 h

CO2EtNPh

Ph

Br

OO

O

O(87) 77

C17

CO2EtN

Ph

Ph

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %), K3PO4 (3 eq),

toluene, 100°, 20 h

CO2EtN X

1-Br

2-Br

(87)

(89)

Ph

Ph

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %), K3PO4 (3 eq),

toluene, 20 hN

X

Cl

Br

(80)

(85)N

Temp (º)

120

100

77

77

X

N

CO2Et

Ph

Ph

Pd2(dba)3 (2.3 mol %), L13 (2.5 mol %),

LiOt-Bu (2 eq), dioxane, 85°, 3 h

(75)

Br

MeN

t-BuO2CNMe

CO2t-Bu

MeO

MeO

MeO

MeO

78

Pd(dba)2 (2 mol %), L21 (3 mol %),


70°, 30 min

160

NBn

ONBn

O

Br

(67)

OMe

X

OMe

232

Pd2(dba)3 (3.8 mol %), L13 (8 mol %),


(51)

NMe

Br

i-Pr

CO2t-Bu

NMe

CO2t-Bui-Pr

NMe

i-Pr

CO2t-Bu

(8)

78+

Pd2(dba)3 (2.3 mol %),

ligand (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 20 h

N

Br

CO2t-Bu

N

t-BuO2C

(39)

(84)

Ligand

PCy3

L17

Pd2(dba)3 (2.3 mol %), L17 (2.5 mol %),


(74)

Br

NN

CO2t-Bu t-BuO2C

78

78



32

Cl

NBn

NBn

O (93)

O

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %), LiHMDS (1.5–2 eq),

THF, 68°, 1–4 hNBn

Br

NBn

O 69(83)

O

Pd(dba)2 (x mol %), ligand, rt, 24 h

Br

NMe

NMe

O

(97)

(95)

x

10

5

Ligand

L49

L50

32

O % ee

33

42

233




Aryl Compound

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %), LiHMDS (1.5–2 eq),

THF, 68°, 1–4 hNBn

BrO

NBn

O 69(62)

C18

Pd2(dba)3 (2.3 mol %),



N N

t-BuO2CCO2t-Bu

(81)

(66)

Ligand

L13

L17

Pd2(dba)3 (2.3 mol %),

L13 (2.5 mol %), LiOt-Bu (2 eq),


(66)

Br

MeN

t-BuO2CNMe

MeO

MeO

MeO

MeO

78

CO2t-Bu

C19

Pd2(dba)3 (2.3 mol %),

L17 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 1 h

(79)NPh

Br

NPh

CO2t-Bu

78

78CO2t-Bu

See tableNMe

BrO

NMe

O

(60), 11% ee

(<1)

(<1)

(50)

(<5)

Ligand

(R)-L23

P(t-Bu)3

L1

L23

L23

70

Catalyst

Pd(OAc)2

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

Pd2(dba)3

MeO MeO

OTBS

Base

LiHMDS

LiHMDS

LiHMDS

LiHMDS

KHMDS

Solvent

THF

THF

THF

THF

toluene

Temp (°)

68

68

68

68

70

OTBS

234

Pd2(dba)3 (2.3 mol %),

L13 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 8 h

(79)

Br

PhN CO2t-Bu

NPh

CO2t-Bu

78

C20

Pd2(dba)3 (2.3 mol %),

L17 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 24 h

(91)NPh

Br

CO2t-Bu

NPh

CO2t-Bu

Pd2(dba)3 (2.3 mol %),

PCy3 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 24 h

I

I (89)

78

78

Pd2(dba)3 (2.3 mol %),


dioxane

NMe

Br

Ph

CO2t-Bu

NMe

CO2t-BuPh

NMe

Ph

CO2t-Bu

78

I

(35)

(65)

(95)

(99)

ITime (h)

17

20

3.5

2

Temp (°)

90

50

70

90

Ligand

none

L13

L13

L13

IIII

(5)

(—)

(—)

(—)

+

Pd(dba)2 (10 mol %), ligand 32

Cl

NMe

NMe

O

(91)

(5)

Time (h)

26

48

Temp (°)

50

0

Ligand

L49

L50

O

% ee

69

58

235




Aryl Compound



32

Br

NMe

NMe

O

(74)

Pd(dba)2 (x mol %), ligand, rt

(73)

(87)

Time (h)

24

20

x

10

5

I

Ligand

L49

L50

I

32

i-Bu

i-Bu

O

Catalyst (5 mol %), L49 (5 mol %),

base (1.5 eq)

Br

NMe

(50)

(60)

(55)

(64)

(61)

(20)

(93)

(89)

(5)

(56)

(57)

Time (h)

14

14

14

14

14

36

14

16

36

14

16

Catalyst

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(OAc)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Pd(dba)2

Temp

50°50°50°50°50°50°rt

50°50°50°50°

Base

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

NaOt-Bu

LiOt-Bu

NaOt-Bu

NaOt-Bu

KOt-Bu

NaHMDS

KHMDS

Solvent

toluene

m-xylene

THF

DME

diglyme

DME

DME

DME

DME

DME

DME

32

O

C20

NMe

O

% ee

40

50

% ee

34

28

42

55

51

50

67

59

11

48

6

I

236

Pd(dba)2 (x mol %), ligand 32

(93)

(91)

(27)

Time (h)

8

26

40

Ligand

L49

L50

L50

Temp

50°rt

0°

x

10

1

10

I

Pd(OAc)2 (5 mol %),

ligand (5 mol %), NaOt-Bu (1.5 eq),

dioxane

(89)

(57)

(67)

(70)

(55)

(56)

(24)

(60)

(49)

(45)

(49)

(63)

(50)

(72)

(72)

(66)

(75)

(82)

(37)

(18)

(35)

(56)

Time (h)

12

24

24

24

6

24

14

12

3

3

24

3

24

24

12

24

9

24

36

36

20

12

Ligand

PCy3

L5

L6

L7

L8

L9

L10

L11

(R)-L23

(R)-L24

(R)-L29

(R)-L30

(R)-L31

L39

L40

L41

L42

L43

L44

L45

L48

L49

Temp (°)

50

70

70

100

100

100

100

100

100

100

100

50

100

70

100

100

70

50

100

100

70

50

32I

% ee

—

38 (+)

41 (+)

61 (+)

31 (–)

61 (+)

38 (+)

15 (–)

46 (–)

18 (–)

7 (+)

0

2 (–)

6 (–)

2 (–)

16 (+)

53 (+)

20 (–)

4 (+)

5 (–)

4

34

% ee

59

69

70

237




Aryl Compound

Pd(dba)2 (10 mol %), ligand 32

I

NMe

(75)

(30)

Time (h)

6

36

Ligand

L49

L50

Temp (°)

50

0

O

C20

Pd2(dba)3 (2.3 mol %),

L17 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 85°, 24 h

(89)NPh

Br

CO2t-Bu

NPh

CO2t-Bu

MeO

MeO

MeO

MeO

78

C21

Pd2(dba)3 (2.3 mol %),



PhN CO2t-Bu

NPh

PhN CO2t-Bu

I

(12)

(62)

(27)

ILigand

PPh3

L13

L18

II

(7)

(—)

(—)

IICO2t-Bu

78+

NMe

O

Pd2(dba)3 (2.3 mol %),

L17 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 90°, 24 h

(67)N

Br

CO2t-Bu

N Cbz

Cbz

78

CO2t-Bu

C22

% ee

0

40

238

Pd2(dba)3 (1.5–3 mol %),

L52 (3–6 mol %), LiHMDS (1.5–2 eq),

THF, 68°, 1–4 hNBn

BrO

NBn

O (47)OBn

OBn

70

C25

Pd(dba)2, dppe, KOt-Bu, dioxane, 100°

Br

MeN 71

MeO

MeO (54)

(81)

R

3-OBn

5-OBnNMe

4-MeOC6H4

4-MeOC6H4

R

R

O

O

C26

Pd(OAc)2 (5 mol %),


dioxane, 50°, 12 h

32

Br

NBn (97)

I

O

Pd(dba)2 (x mol %), ligand

(88)

(80)

(75)

Time (h)

24

24

40

Ligand

L49

L50

L50

Temp

rt

rt

10°

I

x

10

2

10

32

NBn

O

% ee

67

71

76

239




Aryl Compound

Pd2(dba)3 (2.3 mol %),

L13 (2.5 mol %), LiOt-Bu (2 eq),

dioxane, 90°, 2 h

(86)N

Br

CO2t-Bu

PhN Cbz

PhCO2t-Bu

Cbz

78

C27

a The amount of amide used was 0.5 eq.b The carbene was not identified.c The reaction was performed at 70°.d Pd(dba)2 (2 mol %) and L12 (2 mol %) were used.e The reaction was performed with 5 mol % of catalyst.f The reaction was performed at room temperature with Zn(Ot-Bu)2 (0.25 eq).

g The reaction was performed with 10 mol % of Pd(dba)2.h The R group was not defined.i The X group was not defined.

240


TABLE 3. ARYLATION OF 1,3-DICARBONYLS AND CYANOACETATES

Aryl Compound


KOt-Bu (2.2 eq),

monoglyme, 70°, 6 h

CO2Me

CNI

(88)


KOt-Bu (2.2 eq),


CO2MeCO2Me

CNCN

I(83) 88

88

C4

CuBr (cat), NaH (2 eq),

16 hBr

COMe

COMe

OO

(0)

CO2HCO2H

101COMe

Br

COMe (91)

(0)

(40)

(91)

(82)

(73)

(77)

(59)

(84)

Time (h)

1

5

38

0.5

0.8

6

6.5

3

7

COMe

COMe

CO2HCO2H

R

H

3-O2N

3-HO2C

4-O2N

4-Me

5-H2N

5-HO

4,5-(MeO)2

3,4,5-(MeO)3

101R

R

C5

Cu (6 mol %), NaOEt,

EtOHBr

COMe

COMe

CO2HCO2H

101(34)

CuBr (cat), NaH (2 eq),

neat

241

COMe

COMe

HO2C CO2H

R


TABLE 3. ARYLATION OF 1,3-DICARBONYLS AND CYANOACETATES (Continued)

Aryl Compound

CuBr (cat), NaH (2 eq)Br

COMe (72)

(25)

(—)

Time (h)

18

24

32COMe

R

H

4,5-(MeO)2

4,6-Br2

CO2HCO2H

CuBr (cat), NaH (3 eq)

Br

COMe (0)

Time (h)

24

24

30COMe

R

H

4,5-(MeO)2

4,6-Br2

CO2HCO2H

101

101

RR

RR

COMe

COMe

C5

CuBr (cat), NaH (2 eq), 16 h

Br

COMe

COMe

CO2HCO2H

(0)


Br

(0)

R

H

4,6-Br2

CO2H

CO2H

Time (h)

32

30

101

101R

CuBr (cat), NaH, 5 min

BrNN

(—)

CO2HCO2H

COMe

COMe

CuBr (cat), NaH, 10 min (78)

CO2H Br CO2HCOMe

COMe

101

101

242

Pd(OAc)2 (1 mol %),

L16 (2.2 mol %),

K3PO4 (2.3 eq)

R

OSolvent

dioxane

THF

(96)

(96)

Temp (°)

100

80

R

3-MeO2C

4-t-Bu

Time (h)

19

23

O

O

43

Catalyst (20 mol %),

NaH or NaOMe (2 eq),

80°, 4–6 dOH

R1

H

H

Br

Br

H

Br

H

H

(79)

(27)

(85)

(36)

(60)

(48)

(33)

(8)

103

R2

H

H

H

H

Me

F

H

H

X

Br

Br

Br

Br

Br

Br

I

I

Catalyst

CuBr

CuI

CuBr

CuBr•SMe2

CuBr

CuBr

CuBr

CuI

R2

R1

X

OO

CO2MeR2

R1

CO2Me

CO2Me

CO2Me

COMe

CuI (10 mol %),

L-proline (20 mol %),

Cs2CO3 (4 eq), DMSO,

50°, 12 h

NHCOCF3

162

O2N

(78)

I

NH

CF3

CO2MeO2N

Pd2(dba)3, P(t-Bu)3,

K3PO4, tolueneBr

t-BuO2Ct-BuO2C

163CO2Me

CO2Me

(—)

R

Br

O

243



Aryl Compound

CuI (5 mol %),

2-picolinic acid (10 mol %),

Cs2CO3 (3 eq), dioxane,

70°, 25 h

I106CO2Me

CO2Me

(82)CO2Me

CO2Me

C5

CO2Et

CN

[Pd(allyl)Cl]2 (1 mol %),

P(t-Bu)3 (4 mol %),

Na3PO4 (3 eq), toluene,

100°, 12 h

R

H

MeO

F

(86)

(90)

(82)

82CO2Et

CN

RR

Cl


ligand (4 mol %),

Na3PO4 (3 eq), toluene, 100°XCN

CO2Et

(86)

(90)

(83)

(89)

(85)

Time (h)

12

12

8

7

7

R

H

4-MeO

2-MeO

4-MeO

4-MeO

Ligand

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

P(t-Bu)3

L33

X

Cl

Cl

Br

Br

Br

90RR


P(t-Bu)3 (4 mol %),


100°, 12 h

(87)Cl

CO2Et

CN

82, 90


L12 (4 mol %),


100°, 12 h

(81)CO2Et

CNOMeOMe

Cl 82

244


L12 (4 mol %),


100°, 12 h

(86) 82Cl

O

OCO2Et

CN

O

O

[Pd(allyl)Cl]2 (0.05 mol %),

P(t-Bu)3 (4 mol %),


100°, 7 h

BrCN

CO2Et (89)

Pd(dba)2 (2 mol %),

ligand (4 mol %),

Na3PO4 (3 eq), toluene, 4 hBrCN

CO2Et

(87)

(87)

(91)

R

H

H

F

Ligand

P(t-Bu)3

L33

P(t-Bu)3

RR

Temp

70°rt

70°

Pd(dba)2 (4 mol %),

P(t-Bu)3 (8 mol %),


70°, 12 h

(90)Ph

PhCN

CO2Et

90

90

90

Pd(OAc)2 (1 mol %),

L1 (4 mol %),

KOt-Bu (2.5 eq), dioxane,

70°, 1–4 h

BrCN

CO2Et (90)

(—)

(90)

(—)

(—)

R

H

2-MeO

2-Me

4-F

4-Cl

164RR

Br

245



Aryl Compound


KOt-Bu (2.2 eq),

monoglyme, 70°X

CO2Et

R1

H

H

2-MeO

2-F

2-Me

4-MeO

4-F

4-Cl

4-Me

3-Cl

(8)

(73)

(44)

(36)

(45)

(71)

(46)

(45)

(78)

(42)

CNR2

H

H

H

H

H

H

H

H

H

4-Cl

X

Br

I

I

I

I

I

I

I

I

I

Time (h)

6

5

24

6

8

6

10

9

5

10

R2R2

88

R1

R1

CO2Et

CN

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

Na3PO4 (3 eq),

toluene, 70°, 6 h

R

2-Me

3-CF3

4-PhO

(85)

(87)

(90)

CO2Et

CNBr

RR

82

CuBr (cat), NaH

Br

(36)

CO2HNH

CO2Et

OH

O

101

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

Na3PO4 (3 eq),

toluene, 70°, 4 h

(81) 90O

O

CO2Et

CN

BrO

O

C5

246


L12 (4 mol %),


100°, 12 h

R

CF3

Ph

(87)

(91)

82

Pd(dba)2 (4 mol %),

P(t-Bu)3 (8 mol %),


70°, 16 h

R

MeO

CF3

(93)

(95)CO2Et

CN

R

82

RBr

R

Br

R

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 4 h

(84)

O

O 90CO2Et

CN

O

O Br

(83)

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 4 hCO2EtNC


L12 (4 mol %),


100°, 12 h

(91) 82Br

CO2Et

CN

Br

90


KOt-Bu (2.2 eq),

monoglyme, 70°

CO2Et (47)

(85)CN

X

1-I

2-I

Time (h)

12

6X88

CN

CO2Et

R

247



Aryl Compound

Pd(OAc)2 (1 mol %),

L1 (4 mol %),


70°, 1–4 h

N N

(84)

(85)

X

2-Br

3-Br

164XCO2Et

CN

Pd(OAc)2 (1 mol %),

L1 (4 mol %),


70°, 1–4 h

N

N

N

N

(85) 164

BrCN

CO2Et

C5CO2Et

CN

Pd(OAc)2 (1 mol %),

L16 (2.2 mol %),

K3PO4 (2.3 eq), THF,

80°, 15 hBrO

O O

O

(84) 43

CO2Et

COMe

Pd(OAc)2 (2 mol %),

L16 (4 mol %),

K3PO4 (2.8 eq), toluene,

90°, 16 h

CO2Et(93) 87

Cl

C6

See table

X

CO2Et

COMe

CO2HCO2H

101R

R

X

Cl

Br

Br

Br

Br

Br

R

H

H

H

3-O2N

4-O2N

4-Me

Catalyst

CuBr

Cu (6 mol %)

CuBr

CuBr

CuBr

CuBr

Base

NaH (2 eq)

NaOEt

NaH (2 eq)

NaH (2 eq)

NaH (2 eq)

NaH (2 eq)

Solvent

none

EtOH

none

none

none

none

Time (h)

0.8

—

0.3

2.5

0.7

1

(91)

(56)

(96)

(51)

(98)

(99)

248

Br

Br

Br

(98)

(90)

(99)

CuBr

CuBr

CuBr

none

none

none

2

2.5

7

NaH (2 eq)

NaH (2 eq)

NaH (2 eq)

5-MeO

4,5-(MeO)2

3,4,5-(MeO)3

Pd(OAc)2 (1 mol %),

P(t-Bu)3•HBF4 (2 mol %),


90°, 16 h(30)

CO2Et

(40)

Ph

OO

Ph

Cl

O

Ph 87+

Pd(OAc)2 (0.5 mol %),

L16 (1 mol %),


90°, 40 h

(75)CO2Et

MeO

Cl

MeO

87

Catalyst, ligand,


90°, 16 hCO2Et

87Br

Catalyst

Pd(dba)2 (1 mol %)

Pd(OAc)2 (1 mol %)

Pd(OAc)2 (5 mol %)

Pd(dba)2 (1 mol %)

Pd(OAc)2 (1 mol %)

Pd(OAc)2 (1 mol %)

Pd(OAc)2 (2 mol %)

Pd(OAc)2 (2 mol %)

Ligand

P(t-Bu)3 (2 mol %)

P(t-Bu)3 (2 mol %)

PPh3 (20 mol %)

PCy3 (2 mol %)

L15 (2 mol %)

L16 (2 mol %)

L15 (4 mol %)

L16 (4 mol %)

(45)

(48)

(0)

(0)

(56)

(89)

(68)

(93)

249



Aryl Compound

CO2Et

COMe

C6CuI (20 mol %),

K2CO3 (7.5 eq), DMSO,

80°, 20 hX CO2Et

X

Br

Br

Br

Br

I

I

I

I

I

(2)

(0)

(6)

(48)

(19)

(93)

(53)

(63)

165CO2Et+

I II COMe

II

(—)

(0)

(13)

(22)

(41)

(7)

(41)

(35)

R RR

R

H

4-MeO

4-NC

4-MeCO

2-Me

4-MeO

4-EtO2C

4-MeCO

(—)CuBr (cat), NaH (2 eq), 16 hBr

CO2Et

COMe

CO2HCO2H

101

Pd(OAc)2 (1 mol %),



90°, 16 h (40)

CO2Et

MeO

(35)

MeO

Br

MeO

87+

Copper catalyst (x mol %),

K2CO3 (y eq), DMSO, 80°I CO2Et

Copper Catalyst

CuBr

CuI

CuI

I

(56)

(85)

(85)

165CO2Et+

I II COMe

II

(—)

(11)

(9)

Time (h)

20

24

20

y

4

5

7.5

x

20

5

10

250

CuI (20 mol %),

ligand (40 mol %),

K2CO3 (4 eq), 80°, 20 hI

Ligand

none

none

none

none

ethylenediamine

ethylenediamine

ethylenediamine

N,N'-dimethylethylenediamine

N,N'-dimethylethylenediamine

1,8-diaminonaphthalene

1,1'-bipyridine

1,10-phenanthroline

2-phenylphenol

2-phenylphenol

proline

phenylalanine

phenylalanine

tryptophan

ornithine

2,4-diaminobutyric acid

I

(54)

(12)

(42)

(43)

(29)

(48)

(38)

(26)

(23)

(47)

(54)

(41)

(41)

(5)

(45)

(48)

(42)

(37)

(17)

(18)

Solvent

DMSO

dioxane

NMP

DMF

DMSO

dioxane

toluene

dioxane

toluene

DMSO

DMSO

DMSO

DMSO

dioxane

DMSO

DMSO

dioxane

DMSO

DMSO

dioxane

165I + II

II

(18)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(—)

(22)

(20)

(17)

(—)

(—)

(8)

(6)

(8)

(11)

(7)

(6)

CuI (5 mol %),



70°, 25 h

106II (78)I

251



Aryl Compound

CO2Et

COMeCuI (20 mol %),

ligand (40 mol %), base (x eq)I CO2Et

Ligand

none

none

none

none

none

none

none

none

none

none

ethylenediamine

ethylenediamine

I

(20)

(7)

(16)

(53)

(38)

(54)

(17)

(37)

(86)

(58)

(72)

(15)

Solvent

DMSO

DMSO

DMSO

DMSO

DMSO

DMSO

DMSO

DMSO

DMSO

dioxane

dioxane

toluene

165

C6

CO2Et+

I IICOMe

II

(26)

(17)

(34)

(16)

(38)

(18)

(65)

(56)

(4)

(7)

(3)

(0)

Temp (°)

80

80

80

80

40

80

40

40

80

80

80

80

Time (h)

20

20

7

20

40

20

20

40

20

44

40

44

Base

K3PO4

Cs2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K3PO4

x

1

4

1

2

4

4

7.5

7.5

7.5

7.5

7.5

5

CuI (10 mol %),


Cs2CO3 (4 eq), DMSONHCOCF3

R1

H

O2N

I

(27)

(85)

(78)

162

I

NH

CF3

Temp (°)

80

50

40

Time (h)

15

12

12

R2

H

H

MeO2C

CO2Et

R2

R1R1

R2

CuI (5 mol %),

ligand (10 mol %),

K2CO3 (1.5 eq)ICO2Et

104

Br Br

252

Ligand

none

none

none

none

none

L-proline

L-proline

(57)

(19)

(25)

(83)

(28)

(9)

(0)

Solvent

dioxane

DMSO

toluene

THF

THF

THF

DMSO

Temp (°)

100

100

100

100

70

70

40

CuI (5 mol %),

K2CO3 (1.5 eq),

THF, 100°, 24 hI CO2Et104CO2Et+

COMe

MeO MeOMeO

(45) (29)

CuI (5 mol %),

K2CO3 (1.5 eq), 100°Br

R

Cl

Me

CF3

HOCH2

TBSOCH2

MeCO

MeO2C

(75)

(88)

(82)

(32)

(75)

(78)

(79)

104

I

O

Time (h)

24

24

26

26

26

30

26

RR

CO2Et

CuI (5 mol %),

K2CO3 (1.5 eq), 100°Br

R

O2N

MeO

F

(52)

(78)

(80)

104

I

O

Time (h)

30

26

24

RR

CO2Et

253



Aryl Compound

CuI (5 mol %),

K2CO3 (1.5 eq),

THF, 100°, 26 hI104(70)

O

O

Br

O

O O

CO2Et

CuI (20 mol %),

K2CO3 (1.5 eq),

THF, 100°, 24 hI104+

I

(44) (28)

Br

BrBr

OO

O

EtO2C

CO2EtCO2Et

Pd(OAc)2 (1 mol %),



90°, 16 h

(15) (58) 87

CuBr (cat), NaH, 5 min (81)

CO2H BrCO2H CO2Et

COMe

CO2EtBr

101

+

CO2Et

COMe

C6


KOt-Bu (2.2 eq),


CO2i-PrCO2i-Pr

CNCN

I(74) 88

(BzO)2Pb, L38,

Hg(OAc)2 (cat),

pyridine (3 eq)

133CO2Me

O

CO2Me

O

PhPhB(OH)2 (69), 10% ee

C7

254

CO2Me

COi-Pr

CuI (10 mol %),


Cs2CO3 (4 eq), DMSONHCOCF3

R1

H

5-MeO

5-MeCO

H

H

H

6-Cl

5-Me

(80)

(70)

(65)

(84)

(63)

(93)

(77)

(79)

162

I

NH

CF3

Temp (°)

80

75

70

50

70

60

60

75

Time (h)

15

15

15

12

18

12

12

15

R1R1

R2

H

H

H

O2N

Me

MeCO

I

I

CO2Me

CuI (20 mol %),



80°, 18 h

NHCOCF3

162

Br

NH

CF3

CO2MeMeOMeO

(55)

R2R2

CO2Et

CO2Et

Na2PdCl4 (2 mol %),

Ba(OH)2 (2 eq),

DMA

CO2Et

CO2Et

X

Cl

Br

I

(93)

(99)

(100)

84X

Pd(dba)2 (2 mol %),

L33 (4 mol %),

K3PO4 (3 eq), toluene,

100°, 16–21 h

82Cl

RR

CO2Et

CO2Et

R

H

MeO

CF3

(85)

(90)

(86)

255



Aryl Compound

CO2Et

CO2Et

C7

Pd(dba)2 (2 mol %),

L12 (4 mol %),


100°, 16–21 h

R1

R1 R1

H

MeO

H

H

(81)

(87)

(86)

(89)

R2

Cl

R2

CO2Et

CO2Et

82

CuBr (cat), NaH (2 eq), neat

X

CO2Et

X

Cl

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

(80)

(92)

(70)

(85)

(88)

(90)

(70)

(27)

(92)

(83)

(84)

Time (h)

20

1.7

2

25

0.8

2

6

12

4

4.5

3

CO2Et

CO2HCO2H

R

H

H

3-O2N

3-HO2C

4-O2N

4-Me

5-H2N

5-HO

4,5-(MeO)2

4,6-Br2

3,4,5-(MeO)3

101R

R

Pd(dba)2 (2 mol %),

L12 (4 mol %),


100°, 16–21 h

(91)Cl

CO2Et

CO2Et

82

R2

H

H

MeO

CF3

256

Pd(dba)2 (2 mol %),

L12 (4 mol %),


100°, 16–21 h

(85)Cl

O

O

O

O CO2Et

CO2Et

82

CuBr (20 mol %),

NaH (1.1 eq),

dioxane, reflux, 5 h

Br

CO2Et

CO2Et

Pd(OAc)2 (2 mol %),

P(t-Bu)3 (2.5 mol %),


70°, 3 h

(80)

[Pd(allyl)Cl]2 (0.05 mol %),

L3 (0.1 mol %),


100°, 12 h

82

I

I (28)

I (91)

40

124

CuI (10 mol %),



110°, 32 h

106I (79)

Na2PdCl4 (2 mol %),

base (2 eq), DMA

84Br

I

Base

Li2CO3

Na2CO3

K2CO3

Ca(OH)2

Ba(OH)2

MgO

MgO/CaO

MgO/Al2O3

MgO/Ga2O3

% Conv. by GC

14.3

41.7

93.1

96.1

99.0

6.0

6.5

16.5

8.3

Time (h)

24

24

24

20

14

24

24

24

24

Br

Br

Br

257



Aryl Compound

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

K3PO4 (3 eq), toluene, 70°

R

H

MeCO

PhCO

(88)

(89)

(90)

Time (h)

5

14

14

82CO2Et

CO2Et

R

Br

R

Catalyst (1 mol %),

NaOt-Bu (2 eq),

THF, 110°, 20 h

R

H

H

O2N

O2N

MeO

MeO

F

F

Me

Me

MeCO

MeCO

(41)

(50)

(84)

(78)

(45)

(48)

(50)

(60)

(38)

(56)

(62)

(64)

Catalyst

Pd(OAc)2–NaY zeolite

Pd(OAc)2, PPh3 (4 mol %)











83

Br

R

CO2Et

CO2Et

C7

I

I

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq), THF, 70°82

R1

R1

Br

R2 R2

CO2Et

CO2EtR1

H

MeO

Me

H

H

H

R2

H

H

H

Me2N

MeO

PhO

Time (h)

1

8

8

6

3

8

(89)

(89)

(84)

(87)

(89)

(85)

258

(82)

(91)

(91)

(91)

H

H

H

H

F

CF3

MeO2C

Ph

3

3

3

4


Br

CO2Et

CO2Et

OO

(—)

CO2HCO2H

101

Cu(OAc)2 (4 mol %),

NaOEt, EtOHBr

CO2Et

CO2Et

CO2HCO2H

101(34)


Br

CO2Et (—)

(—)CO2Et

R

H

4,6-Br2

CO2HCO2H


Br

CO2Et

CO2Et

CO2HCO2H

(—)

101

101

RR

CuBr (cat), NaH (2 eq)Br

CO2Et (41)

(95)

(—)

Time (h)

24

7

32CO2Et

R

H

4,5-(MeO)2

4,6-Br2

CO2HCO2H

101RR

259



Aryl Compound

CO2Et

CO2Et

C7

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 6 h

(87)Br 82O

O

O

O

CO2Et

CO2Et

Catalyst (1 mol %),

ligand (4 mol %),

NaOt-Bu (2 eq), THF,

110°, 20 h

83CO2Et

CO2Et

Catalyst

Pd(0)–NaY zeolite

Pd(II)–NaY zeolite

Pd(NH3)4–NaY zeolite


Pd(OAc)2

(21)

(32)

(38)

(29)

(56)

Ligand

none

none

none

none

PPh3

Br

Catalyst (1 mol %),

base (2 eq), 110°, 20 h

CO2Et

CO2Et

83Br


Br

(0)

(0)

R

H

4,6-Br2

CO2H

CO2H

Time (h)

32

30

101R

CO2HHO2C

CO2Et

CO2Et

R

260

Base

NaOt-Bu

NaOt-Bu

KOt-Bu

KOt-Bu

K2CO3

K2CO3

NaOt-Bu

NaOt-Bu

KOt-Bu

KOt-Bu

K2CO3

K2CO3

(41)

(45)

(39)

(46)

(6)

(24)

(65)

(67)

(40)

(60)

(8)

(32)

Catalyst







Pd(OAc)2 (1 mol %), PPh3 (4 mol %)






Solvent

THF

DMF

THF

DMF

THF

DMF

THF

DMF

THF

DMF

THF

DMF

Pd(OAc)2 (1 mol %),

L16 (2.2 mol %),

K3PO4 (2.3 eq), THF,

70°, 10 h

(92)

Br

t-Bu

CO2Et

CO2Et

t-Bu

43

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq),

THF, 70°, 6 h

(83)CO2Et

CO2Et

O

O

O

O Br

82

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

K3PO4 (3 eq),

toluene, 70°, 12 h

(89)

Br82

Ph

CO2Et

CO2Et

F

Ph

F

261



Aryl Compound

CuI (5 mol %),

ligand (x mol %),

Cs2CO3 (3 eq), dioxane, 20 hI

CO2Et

Ligand

phenol

2-dioxolanephenol

2-t-butylphenol

2-phenylphenol

2-phenylphenol

2-phenylphenol

2,4-dimethylphenol

2,6-di-t-butylphenol

benzoic acid

thiophene-2-carboxylic acid

indole-2-carboxylic acid

2-picolinic acid

2-picolinic acid

2-picolinic acid

2-picolinic acid

(2)

(15)

(9)

(83)

(48)

(90)

(4)

(<1)

(79)

(60)

(66)

(92)

(99)

(93)a

(90)b

106

Temp

70°70°70°70°rt

70°70°70°70°70°70°rt

70°70°70°

x

10

10

10

10

20

20

10

10

10

10

10

10

10

10

10

CO2Et

CO2Et

CO2Et

C7

CuI (5 mol %),

2-phenylphenol (10 mol %),

Cs2CO3 (1.5 eq), THF, 70°105

I

CO2Et

CO2Et

RR

R

H

3-O2N

3-F

3-NC

Time (h I)

24

24

24

24

(91)

(84)

(87)

(61)

262

3-EtO2C

4-H2N

4-Cl

4-MeCO

(86)

(70)

(94)

(86)

24

29

3-CF2 (89)24

24

24

CuI (10 mol %),


Cs2CO3 (1.5 eq), THF,

70°, 31 h

i-Pri-Pr

(84)

I

CO2Et

CO2Et

105

CuI (5 mol %),


Cs2CO3 (3 eq), dioxane

(92)

(84)c

(79)

(96)

(80)

(73)

(82)

(88)

(88)

(81)

106

Temp

rt

70°rt

rt

rt

rt

rt

70°rt

rt

R

2-MeO

2-Me

3-MeO

3-EtO2C

4-MeO

4-F

4-NC

2,4-(MeO)2

3,5-Me2

3,4,5-(MeO)3

Time (h)

20

20

20

20

20

20

20

25

28

28

II

R

CuI (10 mol %),



70°, 29 h

(75)

I

NN

CO2Et

CO2Et

105

MeOMeO

263



Aryl Compound

CuI (10 mol %),



70°, 29 h

(80)

I

HO

CO2Et

CO2Et

HO

105CO2Et

CO2Et

C7

CuI (5 mol %),


Cs2CO3 (1.5 eq), THF, 70°

R1

2-MeO

3-Me

(90)

(95)

Time (h)

30

27

R2 R2105

I

CO2Et

CO2Et

CuI (10 mol %),



50°, 12 h

NHCOCF3

162

O2N

(64)

IO2N

NHCOCF3

CO2Et

CO2Et

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq),

THF, 70°, 6 h

(83)

Br EtO2C CO2Et

82

R2

4-MeO

5-Me

R1

R1

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq),

THF, 70°, 6 h

(89)Br

CO2Et

CO2Et 82

CO2H

CuBr (cat), NaH, 50 min (84) 101

CO2H BrCO2Et

CO2Et

264

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 12 h

(92)

Br

MeOMeO

CO2Et

CO2Et 82

CuI (10 mol %),



rt, 20 h

106(95)

EtO2C CO2EtI

CuI (5 mol %),



70°, 30 h

105

I

I (98)

CuI (5 mol %),



110°, 32 h

NN 106

Br

CO2Et

CO2Et

(88)

CuBr (cat), NaH, 30 min

BrNN

(77)

CO2HCO2H

CO2Et

CO2Et

101

CuI (5 mol %),



rt, 20 h

N N

(90)

(77)

106

X

2-I

3-I

XCO2Et

CO2Et

I

265



Aryl Compound

I CuI (5 mol %),



70°, 26.5 h

NN

(73) 105CO2Et

CO2EtCO2Et

CO2Et

C7

CuI (5 mol %),



rt, 20 h

106(68)S I S

CO2Et

CO2Et

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq), THF, 70°, 6 h

F CO2Et R

H

MeO

MeO2C

t-Bu

(84)

(88)

(89)

(86)

CO2Et

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq), THF, 70°, 6 h

(79)

82

R

Br

R

CO2Et

CO2Et

Br

CO2Et

CO2Et

F

F82

CuBr (cat), NaH

Br

CO2HO

OO

O

O

(63) 166

C8

Pd(dba)2 (1 mol %),

P(t-Bu)3 (2 mol %),


90°, 16 h

(55)CO2t-Bu

87Br CO2t-BuCOMe

266

CuI (10 mol %),



50°, 12 h

NHCOCF3

162

O2N

(81)

I

NH

CF3

CO2t-BuO2N

CO2Et

COi-Pr

CuI (20 mol %),



70°, 15 h

NH162

Br

NH

CF3

CO2EtMeO2C

MeO2C

(72)

CuI (10 mol %),



70°, 15 h

NHCOCF3

162

I

NH

CF3

CO2Et

(81)

Cl Cl

CuI (5 mol %),

K2CO3 (1.5 eq), THF,

100°, 26 hBr

104

I

Oi-Pr

CO2Et

(48)

OO

CuBr (cat), NaH, 80°, 6 h

Br

Solvent

noned

benzene

I

(38)

(87)

I

CO2HCO2H

CO2Et

EtO2C

O

II

O

O

II

(37)

(0)

166+

O

CuBr (cat), NaHCO2Et

Br

CO2EtCO2Et

CO2H

CO2Et

CO2H

(83) 166

COCF3

267



Aryl Compound

COi-Pr

CuI (10 mol %),



70°, 15 h

NH162

I

NH

CF3(72)

MeO2C

MeO2C

CuBr (cat), NaH, 80°, 6 h

Br

Solvent

noned

benzene

(72)

(58)

CO2HCO2H

O

EtO2C

O

166EtO2C

CuI (5 mol %),

K2CO3 (1.5 eq), THF, 100°Br104

I

O

CO2Et

EtO2C

RR R

H

MeO

(75)

(74)

Time (h)

24

26

O

OO

O

O

C9

Cu (6 mol %), NaOEt, EtOHCOPh

Br

COPhCOMe

COMe

CO2HCO2H

(78) 101

CONHPh

COMe

CuI (10 mol %),



50°, 12 h

I

162(78)

NHCOCF3NHCOCF3

O2NO2N

COMe

CONHPh

C10

CO2c-C6H11

COMe

CuI (10 mol %),



50°, 12 h

NHCOCF3

162

O2N

(80)

I

NH

CF3

CO2c-C6H11O2N

COCF3

268


BrCO2Et

i-Pr

CO2Et

CO2H

CO2Et

i-Pr

CO2H

(0) 166

CO2Me

COPh

CuI (5 mol %),

K2CO3 (1.5 eq),

THF, 100°, 24 hBr104(0)

I

OPh

CO2Me

CuBr (cat), NaH (2 eq), 1 hCO2Et

Br

CO2EtCOPh

COPh

CO2HCO2H

(98) 101

CO2Bn

COMe

CuI (5 mol %),

K2CO3 (1.5 eq),

THF, 100°, 26 hBr104(71)

I

O

CO2Bn

CuI (10 mol %),



50°, 12 h

NHCOCF3

162

O2N

(83)

I

NH

CF3

CO2BnO2N

Pd(dba)2 (2 mol %),

L3 (2.5 mol %),


100°, 12 h

CO2t-BuCO2t-Bu

CO2t-BuCO2t-Bu

(78)Cl

40

CuI (10 mol %),



50°, 12 h

NHCOCF3

162

O2N

(78)

I

NH

CF3

CO2EtO2N

C11

269



Aryl Compound

C11[Pd(allyl)Cl]2 (1 mol %),

P(t-Bu)3 (4 mol %),


100°, 12 h

R

H

MeO

CF3

(88)

(84)

(86)

82

R

Cl

R

CO2t-Bu

CO2t-BuCO2t-Bu

CO2t-Bu


P(t-Bu)3 (4 mol %),


100°, 12 h

(87)


P(t-Bu)3 (4 mol %),


100°, 12 h

(90)Cl

Cl

O

OCO2t-Bu

CO2t-Bu

O

O

CO2t-Bu

CO2t-Bu

82

82

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq), THF, 70°

R1

R1

(89)

(86)

(85)

(90)

(90)

(88)


P(t-Bu)3 (4 mol %),


45°, 8 h

R

H

CF3

(91)

(90)

82

R

Br

Br

R2R2

R

CO2t-Bu

CO2t-Bu

CO2t-Bu

CO2t-Bu

82

R1

H

MeO

Me

H

H

H

R2

H

H

H

Me2N

MeO

CF3

Time (h)

6

12

12

6

6

6

270

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

NaH (1.1 eq), THF, 70°, 6 hBr

O

O82(87)

Ph CO2Et

CN

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


100°, 16 h

R

H

MeO

(89)

(91)

82

Cl

RR

CO2Et

CNPhI

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 16 h

R

MeO

F

CF3

MeO2C

MeCO

Ph

PhCO

(93)

(89)

(91)

(92)

(92)

(90)

(93)

I

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 16 h

(94)

Br

Br

R

O

OCO2Et

CN

O

O

Ph

82

82

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 12 h

90

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

Na3PO4Br

CO2Et

CNPh

(93)

I

I (93) 90

CO2t-Bu

CO2t-Bu

O

O

Br

271



Aryl Compound

C12

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),

Na3PO4 (3 eq), toluene, 70°

4-MeOC6H4 CO2EtR

R

MeO

CF3

(94)

(90)CN

Time (h)

20

16

Pd(dba)2 (2 mol %),

P(t-Bu)3 (4 mol %),


70°, 20 h

(91)

82

Pd(PPh3)4, NaH, DMF,

130–140°

I

(54)

NCCN


130–140°85

I

(0)

CO2Me CO2Me

OO

CO2Et

CN4-MeOC6H4

Br

CO2Et

CN4-MeOC6H4

R

Br

82

85

C11

Ph

CuI (5 mol %),

K2CO3 (1.5 eq), THF,

100°, 26 hBr104

I

O

CO2Et

Ph

Cl

(78)

Cl

CO2Bn

COi-Pr

CuI (10 mol %),



80°, 15 h

NHCOCF3

162

I

NH

CF3

CO2Bn

(67)OH OH

EtO2C

O

CN

CN

C13

272


BrCO2Et

Ph

CO2Et

CO2H

CO2EtPh

CO2H

(45) 166


130–140°85(53)

MeO2CCO2Me


130–140°(38)

NCCO2Et

C

85

14


130–140°

I (49)

CN

CO2Et

NC CO2Et


130–140°85

SO2

(37)

OO

85

I

CO2Me

CO2Me

I

CN

CO2Et

I

SO2

O

O


130–140°

EtO2CCO2Et

(48) 85

(62)

X

Br

I

C15X

CO2Et

CO2Et


130–140° NMe

(31)

EtO2C

ON

85

Me

IO

CO2Et

273



Aryl Compound

C16


130–140°85I (41)

CO2Et

CO2Et

EtO2C CO2Et


130–140°

I

(75)

EtO2CCO2Et

Catalyst

Br

BocNBocN

NN

(—)N

N

C17

I

85

90

CO2Et

CO2Et

CN

O

O NMe

NMe2

SO2CN

O

O NMe

NMe2

SO2

Pd(PPh3)4 (10 mol %),

NaH, DMF, 130°, 6 h

15(68)

O

O

O

O

I

274

Pd(PPh3)4, NaH, DMF, 135° 85(76)Et2N

Et2N

O

OI

O

O

C25

Pd(OAc)2 (0.3 eq),

P(t-Bu)3 (0.6 eq),

KOt-Bu (2 eq), toluene, 70°86(74)

NMe

NMe

MeO2CO O

Br

HMeO2C

C20

OOMOM

O OMOM

a The reaction was performed in 2 hours.b CuI (1 mol %) was used.c CuI (10 mol %) was used.d The ester reactant was used as the solvent .

Br

BocN

NN

1Pd catalyst, ligand I (—)

Ligand

P(t-Bu)3

L33

L34

275


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Organic Reactions || Transition-Metal-Catalyzed α-Arylation of Enolates

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