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

antipyrine

H3CCH3

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.

acid or baseR2

Reaction Mechanism

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

enolateformation

enolization R2

• Indirect-type Mannich Reaction

• Direct-type Mannich Reaction

Indirect-type Mannich Reaction

OSiMe3+

CuClO4-tolBINAP (2-10 mol%)

THF, 0 oC EtO2C

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

The First Direct Catalytic Asymmetric Mannich Reaction

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

Direct-type Mannich Reaction

O MeOCH2NEt2ALB (30 mol%)

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

5 examples61-76% yield34-44% ee

(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.

Imines IminesMannichAdducts

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

CH3H3C

pKa 20

CH3t-BuO

pKa 24.5

Outline

• Conclusions

Outline

• Conclusions

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.

MeO2C CO2Me

CO2R1R2

1,3-dipolar cycloaddition

NuSubstitution aldol reaction

Michealreaction

CH2=CHCN

OHCO2R1

CO2R1H2N

• 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.

R NHPG

H2NOR1

R NHPG

Cu(I) Catalyst

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

Lewis acidNPh

Ph NHTsLigand

PAr2PAr2

t-Bu t-Bu

N PPh2

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

NTs Ligand-CuClO4 (10 mol%)

Et3N (10 mol%)

THF, 4 MS, -20 oCR

CO2MeNHTs

Ar = 2,4,6-Me3-C6H4

Coordination Modes

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

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

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)

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

2BF4-R

Substrate Scope

CO2tBu+

Boc cat. (10 mol%)

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

19 to 72 h(1.1 eq)

CO2tBu

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

CO2tBu+

Boc cat. (10 mol%)

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

19 to 72 h(1.1 eq)

CO2tBu

• 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

CO2tBu

Q Q+ +- Cs+

Cs2CO3

CsHCO3

-Q Q+ +BF4-

TaDiAS

2BF4-R

-Q Q+ +

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

CO2tBu+

cat. (10 mol%)

Cs2CO3 (2 eq)PhF, 4 oC

CO2tBu

PhMeO MeO

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

O OtBu tBu

anti syn

tBu tBu

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

H HO ON

Ph PhtBu

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

CO2tBu+

Boc cat. (10 mol%)

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

-45 to -20 oC3 to 43 h

CO2tBu

Outline

• Conclusions

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

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.

(R)-Ph-BOX

O HNTs

CO2EtCO2CHPh2

(R,R)from X-ray structure

Cu(II) Catalysts

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

iPr -20 40 15 92

Me RT 16 87 88

iPr RT 16 55 91

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

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

CH2Cl2, -20 oCEt

O NHTs

CO2R'Me CO2R

Ph2HCO

OtBuMe

H CO2Et

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.

POH2OH2

2TfO-2+

+ TfO-

R2OtBu

H2O, TfOH

PAr2PAr2

Pd Catalysts

OCO2tBu

R2 CO2tBuR3

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

THF, 1M+

(1.5 eq)

**PPh2PPh2

a: (R)-BINAP

PPh2PPh2

Oc: (R)-SEGPHOS

O HNCO2Et

CO2tBu

OCO2Et

CO2tBu

PMPO HN

CO2tBu

O HNBoc

CO2tBu

O HNTs

CO2tBu

CO2tBuH3C

O HNTs

CO2tBu

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

One-Pot Reactions

CO2EtH

THF, 1M, RT, 3 h

CO2tBu

HNCO2EtCO2tBu

+ + * *

CO2EtH

Pd cat.- a(2.5 mol%)

THF, 1M, -20 oC, 72 h

CO2tBu

HNCO2EtCO2tBu + + * *

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

CO2tBu

1) LiAlH42) Ac2O

59% (2 steps)

O HNPh

R SCO2tBu

CO2tBu

O H NHR3

CO2tBuR2

Re face

Cinchona Alkaloid Catalysts

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

R3O+catalyst

cinchonine

cinchonidine

quinine

quinidine

activate electrophile

activate nucleophile

Cinchona Alkaloid Catalysts

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

2) 5 mol% Pd(II)methyl acetoacetate

cinchonine

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

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

2) 5 mol% Pd(II)methyl acetoacetate

cinchonine

Substrate Scope

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.

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

98% yield, 98% de, 90% ee

Cinchona Alkaloid Derivatives

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

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

HCH2(COOMe)2 R

NHBoccat. (20 mol%)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

Ar = 3,5-bisCF3-C6H3

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

Outline

• Conclusions

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

M+base

enolate

haloformC-C cleavage

intermolecularreaction with E+

Favorskirearrangement

Substrate Scope

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

ClClHR

PPh Ph

Asymmetric Variant

S OO CCl3

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-)

(2.0 eq) Å

(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

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.

La(OAr)3

+LiOAr

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

Outline

• Conclusions

N-acylpyrroles

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

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

+ In(OiPr)3

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

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

5 MS, THF, RT89-111 h

syn anti(2 eq)

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

5 MS, THF, RT65-99 h

synanti(2 eq)

TS-1 TS-2

R = alkenyl,less hindered Ar

R = cyclopropyl,o-substituted Ar

Outline

• Conclusions

N-Boc-anilides

R yield (%)

4-MeO-C6H4 63

4-Cl-C6H4 81

1-naphthyl 95

2-furyl 78

2-thienyl 83

(E)-PhCH=CH 76

PPh2 O

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

p-MeOC6H4OH (11 mol%)

RT, DMSO, 0.2 M5 MS, 30 min

(1.2 eq)

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

N-Boc-anilides

PPh2 O

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

RT, DMSO, 0.2 M5 MS, 30 min

(1.2 eq)

R yield (%) syn/anti

Ph 86 14:86

1-naphthyl 76 8:92

2-furyl 81 9:91

2-thienyl 81 15:85

Catalytic Cycle

BocPh2PO

N N PMP

Ph2PArOBa O

BocPh2P

Ba(OAr)2

Outline

• Conclusions

CO2tBu

Tert-Butyl Diazoacetate

CO2HCO2H

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

CO2tBu

CO2tBuAr

NHBoccat. (5 mol%)

CH2Cl2, 4 MS, 0 oCÅ+

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

CCl3R'

CO2tBu

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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