recent advances in 1,3-dipolar .improved approach to the diastereocontrol of 1,3-dipolar...

RECENT ADVANCESIN 1,3-DIPOLAR CYCLOADDITIONS

OF AZOMETHINE YLIDES

Marina Tanasova

1,3-Dipolar Cycloadditions - the best and most convenient method for construction of five-member heterocycles.

BA

C

R2

R1

BA

C

R2

R1

+R3

R4

CB

AR2 R1

R4R3

Five-member heterocycles

Introduction

Five-member heterocycles - building blocks for a variety of biologically active molecules.

Possibility to construct different ring systems.

Formation of several contiguous stereocenters in one pot.

OH

MeON

O O

+TiCl4

4A MSDCE

ON

O O

H

O

O

NH

ON

O

H

HO

Endo Product

Tamura, O.; Okabe, T.; Yamaguchi, T.; Kotani, J.; Gotanda, K.; Sakamoto, M. Tetrahedron 1995, 51, 119-128.

Intramolecular 1,3-Dipolar Cycloaddition

o

O

O

H

Me

N COOMe

NH

O

CO2MeO

Me

Me

Me

AgOAc, Et3N

CH3CN, rt+

Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2090-2013.

Synthesis of Spiro-Pyrrolidine

Only endo diastereomer is formed

Spiro-core with at least one heterocyclic ring,is found in various biologically active molecules.

Dipole precursor

O

HN

NN

O

OMeO

MeO O

HN

OCO2Me

N

MeMeO

MeSpirotryprostatin B

Formation of spiro-system by 1,3-dipolar cycloaddition

Synthesis of Spirotryprostatin B by 1,3-DipolarCycloaddition

Sebahar, P.R.; Hiroyuki, O.; Usui, T.; Williams, R.M. Tetrahedron 2002, 58, 6311-6322.

OPh

Ph

O

CO2MeH

HN

NN

O

OMeO

MeO O

Improved approach to the diastereocontrol of 1,3-dipolarcycloaddition of azomethine ylides with electron deficient mono- and di-substituted olefins.

Investigation and application of some chiral catalysts in order to increase enantiocontrol of cycloaddition.

Introduction of chirality through chiral vinyl sulfinyloxides. Recent approach to functionalized 2,5-dihydropyrroles.

Outline

Formation of substituted pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides.

1,3-dipolar cycloaddition of azomethine ylides with substituted imines, resulting in formation of different imidazo-compounds.

R3

R2 N

R1

O

OR

R3

R2 N

R1

O

OR

R3

R2 N

R1

O

OR

R3

R2 N

R1

O

OR

H

M

MX / Base

Generation of Azomethine Ylides

Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1978, 101,109-112. Kanemasa, S.; Yamamoto, H. Tetrahedron 1990, 113, 3633-3636. Padwa, A.; Burgess, E.M.; Gingrich, H.L.; Roush, D.M.J. Org. Chem. 1982, 47, 786-791.

R2 R3

O

H2N R1

O OR

+

R3

R2 N

R1

O

OR

H

N

O

R1

R3O

HON R1

O

R3 O

Ac2O

R2

R2

N CO2MePh

N

MeO2C

Ph

+R3

R4

NPh CO2Me

R3R4

Pyrrolidines

HN CO2MeAr

H

H

azomethine ylide

1,3-dipole

(generation in situ)

1,3-Dipolar Cycloaddition of Azomethine Ylide

Simultaneous formation of both C-C bonds Concerted mechanism!

NH

Ph

X

HH

exo endo

Stereoselectivity

Regioselectivity

N

EDG

H

Ph N

H

Ph

EWGhead-to-head head-to-tail

General Approach to the Selectivityin 1,3-Dipolar Cycloadditions

N

H

Ph

X

H

HNH

Ph NH

Ph

X X

NH

Ph

EDG

NH

Ph

EWG

BnO

R

NOR1

N

ORBnO

O+

RO

O OAr

NH

RO2C

Ar CO2R1

NOR1

O

ArRO2C CO2R N

H

RO2C

Ar CO2R1

CO2R

+

+

Karlsson, S.; Hofberg, H.E. Tetrahedron: Asymmetry 2001, 123, 1977-1982.Chen, C.; Schreiberg, S.L. J. Am. Chem. Soc. 2003, 125, 10714-10715.Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.

N

H

H

H

Substitution Pattern on Resulting Pyrrolidines

3

4

4

2

3

5

23

4 5

2

3 4

5

H

4 3

4

2

3

5

Formation through the concerted mechanism

NH

EtO2C

Ph

endo: 65%

NH

EtO2C

Ph

Ph N CO2Et

Me

+

+

Michael adduct: 10%

exo: 25%

Ph N CO2 Pr

Me

CO2Et

LiX / Base

1,3-Dipolar Cycloaddition of Azomethine Ylidewith Ethyl Acrylate

Ph N CO2 Pr

Me

M

i i

CO2 Pri CO2 Pri

CO2 Pri

Possible mechanism?

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

NH

O

H

H

LiSingle Favorable Conformation

for Metal Complexed Azomethine Ylide

Computational and Mechanistic Studiesof Azomethine Ylide Cycloadditions

NH

H

H

O

LiX

H2C CH2 NH

O

NO

H

Li

+

Orientation Complex Concerted Interaction

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

Concerted Mechanism for the Cycloaddition ofAzomethine Ylide with Ethylene

LiX / Base

34

Pyrrolidine

2534

25

O2NN

H

O

N

Li O

HN

Li O

H

O2NO2N

endo exo

+ +

Substitution Effect in 1,3-DipolarCycloaddition Reactions

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

LiX / Base

A

O2NN

H

O

N

Li O

HN

Li O

H

O2NO2N

endo exo

+ +

2

3

4

Substitution Effect in 1,3-DipolarCycloaddition Reactions

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

5

LiX / Base

C2 - C3 bond formationB

2

3

2

34

5

A

O2NN

H

O

N

Li O

HN

Li O

H

O2NO2N

endo exo

+ +

2

3

4

Substitution Effect in 1,3-DipolarCycloaddition Reactions

Li

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

5

LiX / Base

C

4

5

2

34

5

C2 - C3 bond formationB

2

3

A

O2NN

H

O

N

Li O

HN

Li O

H

O2NO2N

endo exo

+ +

2

3

4

Substitution Effect in 1,3-DipolarCycloaddition Reactions

Li

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.

5

LiX / Base

C

4

5

2

34

5

C2 - C3 bond formation

B

2

3

Aendo

N

O

OR

EWG

N

O

OR

EWG

M

N

EWG

O

OR

M

NH

EWG

O

OR

R3N

Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122,6078-6092.

ORN

OM

Stepwise Mechanism in Cycloadditions

N

O

OR

MXM

H

No change in mechanism was detected with N-protonated azomethine ylides.Equimolar endo/exo - 1:1 amounts of products were observed.Presence of metal in 1,3-dipolar cycloaddition reactions causes improvement of endo-exo selectivity and changes the mechanism to stepwise.!

N CO2MePh

NH

CO2MePh

MeO2C

+NH

CO2MePh

MeO2C

+

endo exo

CO2Me

Kanemasa, S.; Uchida, O.; Wada, E. J. Org. Chem. 1990, 55, 4411-4417.Barr, D.A.; Dorrity, M.J; Grigg, R.; Hargreaves, S.; Malone, J.F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Tornton-Pett, M. Tetrahedron 1995, 51, 273-294.

Search for the Best Metal for Cycloaddition

+ MX / Base

LiBr / NEt3 - 81% yield for cyclized products; endo: exo - 3:1

N-protonated ylide - 41% yield, only cyclized products; endo : exo - 1:1

MgCl2, ZnCl2, MnCl2, NiCl2 and CoCl2 - gave the Michael adduct as the major product

Michael adduct

iN CO2 PrPh

Me

NH CO2

iPrPh

EtO2C

+

NH CO2iPr

Ph

EtO2C

+

Ph N CO2Et

CO2iPr

endo exo Michael adduct

Solvents

Bases

AgOAc

20-25 oC

CO2Et

THF; Toluene; MeCN; CH2Cl2; MeOH

KOH; NaOH; K2CO3; LiOH; Et3N; DBU

Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.

Application of Silver to the Cycloadditions

+

N CO2 PrPh

Me

NH CO2

iPrPh

EtO2C

+

NH CO2

iPrPh

EtO2C

+Ph N CO2Et

CO2iPr

endo exo Michael adduct

CO2Et

Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.

Investigation of Better Conditions for Cycloadditions

+AgOAc -10 mol%KOH - 10 mol%

Toluene, CH2Cl2, THF - 100% conversion, but 75 - 80h, 88 - 92% yield of endo product

MeCN - 68% conversion, 90% - endo, 10% -