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