Advancement of Direct Catalytic Mannich-type Reactions ... · Reaction Mechanism O H H R H N R H N...

Advancement of Direct Catalytic Mannich-type Reactions with Esters

or Ester-equivalents as Donors

Yong GuanOct. 17, 2007

Michigan State University

Outline

• Background Information

• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates

• Conclusions

Background Information

Mannich, C. Arch. Pharm. 1917, 255, 261.http://www.dphg.de/images/dphg_ap_mannich.gif

O

CH3Ph

CH2O

NH4Cl

O

Ph N3

NN

O

Ph

CH3

antipyrine

CH2O

NH4Cl

NN

O

Ph

H3CCH3

CH3

N

3

Carl Mannich

Tollens and von Marle (1903)

Mannich (1917)

Mannich reaction

Tollens, B.; Marle, v. Ber. 1903, 36, 1351.Mannich, C. J. Chem. Soc., Abstracts 1917, 112, 634.

NHR

R O

HH R2

OR1

acid or baseR2

O

NR1

R

R

+ +

Reaction Mechanism

O

HH

RHN

R

H

HNR

R

OH H+

HNR

R

OH2

NR

R

Step 1. Formation of the Schiff base

Name Reactions – A Collection of Detailed Reaction Mechanisms. Jie Jack Li. Springer-Verlag, Berlin. 2002.

Step2. Amino alkylation of an acidic hydrogen containing compound

Basic conditions

Acidic conditions

R2

OR1

H

B:

enolateformation

R2

O-

R1

NR

R

R2

O

NR1

R

R

R2

OR1

H+

enolization R2

OR1

H

NR

R

R2

O

NR1

R

R


• Indirect-type Mannich Reaction

• Direct-type Mannich Reaction

Indirect-type Mannich Reaction

EtO2C

NTs

R

OSiMe3+

CuClO4-tolBINAP (2-10 mol%)

THF, 0 oC EtO2C

NH

R

OTs

8 examples65-92% Yield89-98% ee

Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.

Silyl enol ether

P(p-tolyl)2P(p-tolyl)2

tolBINAP

N

HO

OEt

TsCuP

P*

The First Direct Catalytic Asymmetric Mannich Reaction

Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 41, 307.

Direct-type Mannich Reaction

Ar

O MeOCH2NEt2ALB (30 mol%)

La(OTf)3 nH2O (30 mol%)toluene, 3 MS, 50 oC

Ar

O

NEt2

5 examples61-76% yield34-44% ee

.Å

OO

OO

Al

Li

(R)-ALB = AlLibis(binaphthoxide)

General Difficulties

• Many Lewis acids are deactivated or sometimes decomposed by the nitrogen atoms of starting materials or products ( t rapped by the n i t rogen atoms)

• Imine-chiral Lewis acid complexes are rather flexible and often have several stable conformers (including E/Z-isomers of imines). Multiple transition states would exist.

Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.


O

HR

O

R2R1

Imines IminesMannichAdducts

O

OR2R1

?

Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348.Shibasaki, M.; Matsunaga, S. J. Organomet. Chem. 2006, 691, 2089Córdova, A. Acc. Chem. Res. 2004, 37, 102

O

CH3H3C

pKa 20

O

CH3t-BuO

pKa 24.5

Outline



• Conclusions

Outline



• Conclusions

NOR'

OAr

Ar

Glycine Schiff-bases

• Cu(I) Catalyst

• Phase-Transfer Catalyst


Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.Ooi, T.; Takeuchi, M.; Kamede, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.

NOR1

O

R2

R3

MeO2C CO2Me

MeO2C CO2Me

NH

CO2R1R2

R3

1,3-dipolar cycloaddition

NuSubstitution aldol reaction

Michealreaction

NOR1

O

R2

R3

CN

CH2=CHCN

OHCO2R1

NH2

OHCO2R1

NH2

CO2R1H2N

R4R5


• Challenges(1) “Force” the Lewis acid stabilized imino glycine alkyl ester to act

as a nucleophile rather than a 1,3-dipolar species

(2) Develop a chiral catalyst that can catalyze both a diastereo- and enantioselective addition of imino glycine alkyl ester to imines.

Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.

NOR1

O

R2

R3

MLn

NOR1

O

R2

R3

LnM

R3N

NOR1

O

R2

R3

LnM

NOR1

O

R2

R3

LnM

N

R

PG

NOR1

O

R2

R3

R NHPG

H2NOR1

O

R NHPG

Cu(I) Catalyst

Optimal conditionLigand -CuClO4 (10 mol%), Et3N (10 mol%), -20 oC, THF, 4 Å MS


NPh

PhOR1

O

Ph

NTs

+R3N

Lewis acidNPh

PhOR1

O

Ph NHTsLigand

PAr2PAr2

O

N N

O

t-Bu t-Bu

PAr2

O

N

PPh2

O

NPPh2

O

N PPh2

O

NR

Ar = 2,4,6-Me3-C6H2

Substrate Scope

R yield (%) syn/anti ee (%)

Ph 94 79:21 97

4-MeO-C6H4 90 82:18 97

2-Br-C6H4 99 61:39 96

2-furyl 88 54:46 90

iPr 73 >95:5 96

Cy 85 >95:5 92

nBu 61 >95:5 88


NPh

Ph

CO2Me

R

NTs Ligand-CuClO4 (10 mol%)

Et3N (10 mol%)

THF, 4 MS, -20 oCR

CO2MeNHTs

N

Ph

Ph+

Å

PAr2

O

N

Ar = 2,4,6-Me3-C6H4

Coordination Modes

PAr2

O

N

NPh

PhMeO

OCu

PAr2

O

N

NPh

PhMeO

OCu

PAr2

O

N

NPh

OMe

OCu

Ph

Semiempirical PM3 calculationBernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.

PAr2

O

N

NPh

OMe

OCu

Ph

Ar = PhΔHf

Ө = -10.9 kcal/mol14% ee

Ar = PhΔHf

Ө = -11.1 kcal/mol

Ar = 2,4,6-Me3-C6H2ΔHf

Ө = -39.2 kcal/mol97% ee

Ar = 2,4,6-Me3-C6H2ΔHf

Ө = -26.8 kcal/mol

Transition State

Approach of the imine (blue) to the Si face of the benzophenone imine glycine methyl ester anion


X-ray structure

Ph CO2EtNHTs

N

Ph

PhR

S

Phase-Transfer Catalyst

Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.

tartrate-derived diammonium salt (TaDiAS)

Crystal Structure (R = nPr)

O

O

N

N

C6H4-4-MeC6H4-4-MeC6H4-4-MeC6H4-4-Me

2BF4-R

R

Me

Me

Substrate Scope

NPh

Ph

CO2tBu+

N

R

Boc cat. (10 mol%)

Cs2CO3 (2 eq)PhF, -45 to -20 oC

19 to 72 h(1.1 eq)

HN

R

Boc

N

CO2tBu

Ph

Ph

O

O

N

N


2BF4-

Me

Mep-F-C6H4

p-F-C6H4

R yield (%) dr (syn/anti) ee (%)

Ph 98 99:1 70

4-MeO-C6H4 95 95:5 82

4-Me-C6H4 98 98:2 80

2-Me-C6H4 99 97:3 68

4-Cl-C6H4 87 98:2 58

2-thiophenyl 98 98:2 80

(E)-PhCH=CH2 86 98:2 66


Kinetic Study

• Initial rate kinetic studies:1) First-order dependency for the glycine Schiff base and Cs2CO3

2) Zero-order dependency for the imine and the catalyst


NPh

Ph

CO2tBu+

N

R

Boc cat. (10 mol%)

Cs2CO3 (2 eq)PhF, -45 to -20 oC

19 to 72 h(1.1 eq)

HN

R

Boc

N

CO2tBu

Ph

Ph

• Conclusions:1) The rate-determining step is deprotonation of the glycine Schiff base by

Cs2CO3

2) The catalyst is not involved in this step

Catalytic Cycle


N

R

Boc

N

CO2tBu

Ph

Ph

N

R

Boc

N

CO2tBu

Ph

Ph

NPh

Ph

CO2tBu

NPh

Ph

O

OtBu

Q Q+ +- Cs+

Cs2CO3

CsHCO3

NPh

Ph

O

OtBu

-Q Q+ +BF4-

CsBF4

-Cs+

N

R

Boc

TaDiAS

O

O

N

N


2BF4-R

R

Me

Me

-Q Q+ +

BF4-

Interfacialdeprotonation

counteranionexchange

Control of Diastereoselectivity

The reaction may proceed via the nonchelate, acyclic transition-state model

Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794

NPh

Ph

CO2tBu+

NBoc

cat. (10 mol%)

Cs2CO3 (2 eq)PhF, 4 oC

HNBoc

N

CO2tBu

Ph

PhMeO MeO

1h, 77% ee, d.r. = 95:5without cat. , 24h, d.r. = 94:6

N

R

HN

OO

Ph

Ph

O

O

/ NR

NH

Ph

Ph

O

O

/

O OtBu tBu

anti syn

_ _

tBu tBu

H H

Control of Enantioselectivity

• The benzyl moieties around one ammonium cation covers the Si face of the Z enolate of the glycine Schiff base

• The electrophiles approach from the less-hindered face (Re face) to afford the products with S configuration

Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794

NO

O

NMe

MeR'

R'

H HO ON

Ph PhtBu

NBoc

RH

Improvement

Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794

R yield (%) dr (syn/anti) ee (%)

Ph 66 99:1 79

4-MeO-C6H4 96 99:1 90

4-Me-C6H4 92 99:1 88

4-Cl-C6H4 88 98:2 70

nPr 95 >20:1 71

2-thiophenyl 89 98:2 83

(E)-PhCH=CH 89 >20:1 75

NPh

Ph

CO2tBu+

N

R

Boc cat. (10 mol%)

Cs2CO3 (2 eq)PhF/pentane (4:1)

-45 to -20 oC3 to 43 h

HNBoc

N

CO2tBu

Ph

PhR

O

O

N

N


2BF4-

Me

Me

Ph

Ph

Outline



• Conclusions

R1

O

OR2

O

R'O

O

OR'

O

β-Keto Esters or Malonates

• Cu(II) Catalysts

• Pd Catalysts

• Cinchona Alkaloid Catalysts

Cu(II) Catalysts

R yield (%) dr ee (%)

76 84:16 23

75 93:7 51

81 >95:5 53

43 >95:5 -66

33 >95:5 -88

Et

O

OR

O

Me

N

CO2Et

Ts Cu(OTf)2-(R)-Ph-BOX (10 mol%)

CH2Cl2, -20 oCEt

O HNTs

CO2EtMe CO2R

* *+

Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.

O

N N

OMeMe

Ph Ph

(R)-Ph-BOX

Me

Ph

Ph

MeMe

Me

Et

O HNTs

CO2EtCO2CHPh2

(R,R)from X-ray structure

Me

Cu(II) Catalysts

R1

O

OtBu

O

Me

N

CO2Et

Ts+

Cu(OTf)2-(S)-tBu-BOX(10 mol%)

CH2Cl2R1

O HNTs

CO2EtMe CO2tBu

* *

R1 T (oC) t (h) yield (%) dr ee (%)

Me -20 40 55 97:3

84:16

93:7

84:16

95

iPr -20 40 15 92

Me RT 16 87 88

iPr RT 16 55 91


O

N N

OMeMe

t-But-Bu

(S)-tBu-BOX

81% yield, 53% eedr = >95:5

33% yield, -68% eedr = >95:5

80% yield, 92% eedr = 98:2


Transition States

Et

O

OR

O

Me

N

CO2R'

Ts Cu(OTf)2-ligand (10 mol%)

CH2Cl2, -20 oCEt

O NHTs

CO2R'Me CO2R

* *+

NO

NO

Ph

Ph

Cu

Me

Me

Ph2HCO

MeO

O Et

N

EtO2C

HTs

NO

NO

Ph

Ph

Cu

Me

MeEtO

O

OtBuMe

NTs

H CO2Et

NO

NO

Cu

Me

Me

t-Bu

tBu

Me

O Et

O

t-BuO

NTs

HEtO2C

Pd Catalysts

a: Ar = C6H5: (R)-BINAPb: Ar = 4-Me-C6H4: (R)-TOL-BINAP

c: Ar = C6H5: (R)-SEGPHOSd: Ar = 3,5-Me2-C6H3: (R)-DM-SEGPHOS

Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.Int. Ed. 2005, 44, 1525.

PdP

POH2OH2

2TfO-2+

* O

R1

R2

O

OtBu

PdPP

*

+ TfO-

R1

O

R2OtBu

O

H2O, TfOH

PAr2PAr2

PAr2PAr2

O

O

O

O

Pd Catalysts

R1

OCO2tBu

R2

N

R3

PG

R1

O

R2 CO2tBuR3

NHPGPd cat.- a or c(x mol%)

THF, 1M+

(1.5 eq)

**PPh2PPh2

a: (R)-BINAP

PPh2PPh2

O

O

O

Oc: (R)-SEGPHOS


O HNCO2Et

PMP

CO2tBu

OCO2Et

HN

CO2tBu

PMPO HN

Ph

Boc

CO2tBu

O HNBoc

CO2tBu

O

O HNTs

CO2tBu

ClHN

Boc

CO2tBuH3C

O

H3C

O HNTs

CO2tBu

Ph

c (5 mol%), 35 h63%, dr = 77:23, 99% ee

a (5 mol%), 42 h70%, dr = 74:26, 86% ee

c (2.5 mol%), 5 h93%, dr = 88:12, 99% ee

a (2.5 mol%), 2 h75%, dr >95:5, 86% ee

a (2.5 mol%), 3 h71%, dr = 82:18, 96% ee

c (5 mol%), 9 h99%, dr = 85:15, 97% ee

c (1 mol%), 24 h88%, dr = 90:10, 99% ee

O

One-Pot Reactions

O O

CO2EtH

OMe

NH2

THF, 1M, RT, 3 h

O

CO2tBu

HNCO2EtCO2tBu

PMP

+ + * *

O O

CO2EtH

NH2

Pd cat.- a(2.5 mol%)

THF, 1M, -20 oC, 72 h

O

CO2tBu

HNCO2EtCO2tBu + + * *

ClCl

61% yield, dr = 70:3096% ee (major), 96% ee (minor)

85% yield, dr = 95:598% ee (major), 88% ee (minor)

Pd cat.- a(2.5 mol%)


PPh2PPh2

a: (R)-BINAP

Transition-State Model


O

CO2tBu

HNPh

Boc

* *

1) LiAlH42) Ac2O

59% (2 steps)

O HNPh

Boc

PhOAc

R SCO2tBu

NMeAc

CO2tBu

P PdP

*

OO

O

R1 R2

NR3

H

H

PG

R1

O H NHR3

CO2tBuR2

PG

Re face

Cinchona Alkaloid Catalysts

Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.

R1

O

OR2O

N

H Ar

O

R3O+catalyst

R1

O

OR2O

Ar

HN

O

OR3

N

N

HOH

H

cinchonine

N

H

H

OH

N

cinchonidine

quinine

N

N

HOH

H

O

quinidine

activate electrophile

activate nucleophile

N

H

H

OH

N

O

Cinchona Alkaloid Catalysts

H3C

O

OO

N

H Ar

O

H3CO

1) cinchonine (10 mol%)CH2Cl2, 0.5 M, -35 oC, 16 h

2) 5 mol% Pd(II)methyl acetoacetate

+ H3C

O HN

Ar

OCH3

O

N

N

HOH

H

cinchonine

H3C

O HN

Ar

OCH3

O

OO


Ar yield (%) ee (%)

Ph 79 92

4-F-C6H4 95 93

3-CH3-C6H4 78 96

3,4-(OCH2O)C6H3 77 80

2-furyl 78 93

2-thienyl 69 92

2-naphthyl 80 95

H3C

O

OO

N

H Ar

O

H3CO

1) cinchonine (10 mol%)CH2Cl2, 0.5 M, -35 oC, 16 h

2) 5 mol% Pd(II)methyl acetoacetate

+ H3C

O HN

Ar

OCH3

O

N

N

HOH

H

cinchonine


Substrate Scope


N

OH

HN

O

O

OMe

HH

N

HO

MeO

Cinchonine/methyl 2-oxocyclopentanecarboxylate enol tautomer complex (MMFF) approaching the Re face of methyl benzylidenecarbamate

Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003.

O O

OMe

H

N

Ph

O

MeO

cinchonine (5 mol%)CH2Cl2, 0.5 M, -55 oC

O

Ph

HN

O

OMe

OMeO

RS+

98% yield, 98% de, 90% ee

Cinchona Alkaloid Derivatives

McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.

NN

N

NS

H

H

F3C CF3

*

OMeThiourea moiety-activate electrophiles-two coplanar protons for H-bond donation-rigid

Thiourea N-aryl group-relatively unhindered-substitution variable-CF3 gruops serve as non Lewis basic EWG

Cinchona Alkaloid Derivatives

R

NBoc

HCH2(COOMe)2 R

NHBoccat. (20 mol%)COOMe

COOMe

+

(1.5 eq)acetone, -60 oC, 36 h

R yield (%) ee (%)

2-Me-C6H4 98 99

4-Me-C6H4 92 97

4-Cl-C6H4 98 99

4-MeO-C6H4 98 97

2-furyl 99 97

2-thienyl 95 97

Et 63 89

nBu 64 92

N

MeO

HN

HN

SAr

N

H

Ar = 3,5-bisCF3-C6H3

Song, J.; Wang, Y.; Deng, L. J. Am.Chem. Soc. 2006, 128, 6048.

N

NH

N

H

NS

CF3

CF3

HH

O

OOMe

OMe

H

NBocR

O

H

Outline



• Conclusions

O

CCl3R'

Trichloromethylketones

• -CCl3 is a good leaving group

• Strong inductive effect of -CCl3

Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146

CCl3

O

R

CCl3

OR E

RCCl3

O

Nu

O

RR Cl

Cl

O

M+base

a

b

c

d

Nu-

E+

enolate

haloformC-C cleavage

intermolecularreaction with E+

Favorskirearrangement

Substrate Scope

R

NPPh2

O

CCl3

O

MeR

NH

Me

O

CCl3

Ph2PO

p-MeO-C6H4OLi(10 mol%)

THF/CH2Cl2 = 1:1-40 oC, 3 MSÅ

+

syn (rac)(2 eq)

R t (h) yield (%) syn/anti

Ph 3 96 >20:1

4-Cl-C6H4 4 93 >20:1

4-MeO-C6H4 5 68 >20:1

2-furyl 1 88 6:1

2-thienyl 2 89 8:1

(E)-PhCH=CH 1 81 7:1

Cy 2 78 >20:1

iPr 3 71 >20:1

nBu 3 73 >20:1


Catalytic Cycle


OR' Cl

ClCl

ArOH

ArOLi

OR' Cl

ClClH

Li

R

N

R'

O

CCl3

Ph2PO

Li

R

NH

R'

O

CCl3

Ph2PO

ArOH

+

O

Cl

ClClHR

N

PPh Ph

OLi

R'

H

R

NPPh2

O

Asymmetric Variant

R

N

H

S OO CCl3

O

CH3

+

La(OAr)3 (10 mol%)(S,S)-iPr-pybox (10 mol%)

LiOAr (5mol%)

THF/toluene (1:1, 1.0M)3 MS, -40 oC

( Ar= 4-MeO-C6H4-)

CCl3

O

CH3

R

NHSO

O

S S

(2.0 eq) Å

NO

N N

O

(S,S)-iPr-pybox

R t (h) yield (%) dr (syn/anti) ee (%)

Ph 9 96 21:1 96

4-Cl-C6H4 20 97 20:1 96

4-MeO-C6H4 21 96 22:1 95

2-furyl 4 98 8:1 96

2-thienyl 19 98 20:1 95

(E)-PhCH=CH 19 75 21:1 96

Cy 22 85 >30:1 96

iBu 25 72 30:1 98

Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc., 2007, 129, 9588

NO

N N

O

La(OAr)3

+LiOAr

Mechanism Study

• La-OAr moiety functions as a Brønsted base to form La-enolate

• Preliminary kinetic studies on the concentration of trichloromethyl ketone suggested that the enolateformation is the RDS in the absence of LiOAr.

• Two possibilities for the role of LiOAr: (a) Complexation with La(OAr)3/pybox to form more basic ate complex(b) LiOAr deprotonates trichloromethyl ketone to form Li-enolate, followed by rapid transmetallation to generate La-enolate.

NO

N N

O

La(OAr)3

+LiOAr

Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc., 2007, 129, 9588

Outline



• Conclusions

O

NOH

N-acylpyrroles

Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,Int. Ed. 2005, 44, 4365

OHOH

O

HOHO

a: X= H: (S, S)-linked-binolb: X= TMS: (S, S)-6,6',6'',6'''-TMS-linked-binol

X X

X X

+ In(OiPr)3

O

OH

O

NOH

Y

aromaticketone

N-acylpyrrole

aromaticity of pyrrolesame coordination mode as ketoneactivated carboxylic acid derivative

Substrate Scope

R yield (%) dr (syn/anti) ee (%) (syn, anti)

(E)-PhCH=CH 94 91:9 96, 83

Ph 98 61:39 91, 81

4-Cl-C6H4 97 59:41 96, 94


R yield (%) dr (anti/syn) ee (%) (anti, syn)

2-naphthyl 87 77:23 94, 89

2-MeO-C6H4 74 77:23 92, 86

Cyclopropyl 86 75:25 98, 90

NO

NOH

In(OiPr)3 (20 mol%)Ligand a (10 mol%)

5 MS, THF, RT89-111 h

Å

O

NOH

NH

R

o-Ts

SR

O

NOH

NH

R

o-Ts

SS+

syn anti(2 eq)

+R

o-Ts

O

NOH

In(OiPr)3 (20 mol%)Ligand a or b (10 mol%)

5 MS, THF, RT65-99 h

Å

O

NOH

NH

R

o-Ts

SR

O

NOH

NH

R

o-Ts

SS +

synanti(2 eq)

+N

R

o-Ts


RH

NO H

o-Ts

O N

In RH

NH O

o-Ts

N OIn

O

NOH

NH

R

o-Ts

SR

syn

TS-1 TS-2

R = alkenyl,less hindered Ar

O

NOH

NH

R

o-Ts

SS

anti

R = cyclopropyl,o-substituted Ar


Outline



• Conclusions

O

NR

OMe

Boc

N-Boc-anilides

R yield (%)

Ph 91

4-MeO-C6H4 63

4-Cl-C6H4 81

1-naphthyl 95

2-furyl 78

2-thienyl 83

(E)-PhCH=CH 76

N

HR

PPh2 O

N

OMe

Boc

O

NH

OMeN

R

BocPh2PBa(Ot-Bu)2 (5 mol%)

p-MeOC6H4OH (11 mol%)

RT, DMSO, 0.2 M5 MS, 30 min

(1.2 eq)

+

O O

Å

Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.

N-Boc-anilides

N

HR

PPh2 O

N

OMe

Boc

O

NH

OMeN

R

BocPh2PBa(Ot-Bu)2 (5 mol%)Ligand (11 mol%)

RT, DMSO, 0.2 M5 MS, 30 min

(1.2 eq)

+

O O

Å

R yield (%) syn/anti

Ph 86 14:86

1-naphthyl 76 8:92

2-furyl 81 9:91

2-thienyl 81 15:85

OMeOH


Catalytic Cycle


N

O

OtBu

O

PMP

N

O

OtBu

O

PMP

BaOAr

N

HR

PPh2

O

O

NH

PMPN

R

BocPh2PO

R O

N N PMP

t-BuO

Ph2PArOBa O

O

O

NPMP

N

R

BocPh2P

Ba(OAr)2

ArOH

BaOAr

O

Outline



• Conclusions

N2

CO2tBu

Tert-Butyl Diazoacetate

CO2HCO2H

t-Bu

t-Bu

Ar t (h) yield (%) ee (%)

Ph 24 80 95

2-Me-C6H4 72 53 90

4-Me-C6H4 18 79 95

4-Cl-C6H4 26 89 96

4-MeO-C6H4 20 72 95

2-naphthyl 17 77 94

2-furyl 5 84 85

Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc., 2007, 129, 10054

N

Ar N2

CO2tBu

N2

CO2tBuAr

NHBoccat. (5 mol%)

CH2Cl2, 4 MS, 0 oCÅ+

Boc

Outline



• Conclusions

Conclusions

• Future challenges1) Expansion on esters or ester-equivalents2) Development of catalytic versions of the racemic reactions3) Improvement on the unsatisfactory reactions (new ligands, new

metal sources, etc.)4) One-pot cascades reactions

N OR'

OAr

Ar

R1

O

OR2

O

R'O

O

OR'

O

or

O

CCl3R'

N

O

OH

O

NR'

OMe

Boc

N2

CO2tBu

R

NH

R1R2

OPG

Acknowledgement

Dr. WulffDr. Walker, Dr. Staples

Li, Zhenjie, Aman, Munmun, Zhensheng, Anil, Nilanjana, Dima, Victor, Alex, Kostas

All those attended the seminar

Advancement of Direct Catalytic Mannich-type Reactions ... · Reaction Mechanism O H H R H N R H N...

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