synthesis of pyrrolidin-3-one type compounds via reductive amination

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DFT/B3LYP COMPUTATIONAL STUDY ON THE REACTION MECHANISM ... type compounds 1 via reductive amination of carbonyl compounds. Paola Borrego ...
SYNTHESIS OF PYRROLIDIN-3-ONE TYPE COMPOUNDS VIA REDUCTIVE AMINATION OF CARBONYL COMPOUNDS: A DFT/B3LYP COMPUTATIONAL STUDY ON THE REACTION MECHANISM Paola Borrego, Lili Becerra, Diego Quiroga & Ericsson Coy-Barrera Universidad Militar Nueva Granada (UMNG), Facultad de Ciencias Básicas y Aplicadas, Departamento de Química

INTRODUCTION N-heterocyclic compounds are widely known as an important family of biologically active compounds. Pyrrolidines are among the most bioactive compounds. Moreover, pyrrolidines are present in several natural products, being considered as important pieces for the synthesis of pharmaceuticals and biologically active compounds. Derivatives such as 3-substituted pyrrolidines are an important subclass of compounds, whose have been reported important pharmacological activities. In this paper, we proposed the synthesis of pyrrolidin-3-one type compounds 1 via reductive amination of carbonyl compounds. RESULTS R R

1

1

COOMe

O HN

NaBH4

COOMe

+

H2N

R

3

R

2 a-d

R2OH, 40 °C, 1-30 h

O

R

4

3

O R

3 a-c

1

3

a R =CH2Ph

60-75% yield

4

a R =R =CH3

1

4

3

4a-i

4

b R =CH2-4-PhOH

b R =CH3, R =OEt

c R1=CH2-3-(1H-indole)

c R3-R4=-(CH2)3-

Scheme 1. Reductive amination of carbonyl compounds 3 R

1

O COOMe

HN

R

O

O

R

4

O

O

R

t-BuOK, THF 0 °C, 6 h

3

R

O R

1

N H

4

R

3

+ R

1

O

+ R

R

1

R

N H

(2S, 4S, 5R)

(2S, 4R, 5R)

4a-i

N H

R

3

4

O 4

O

+

3

R

(2S, 4R, 5S)

R

1

R

N H

4

3

(2S, 4S, 5S)

Diasteromer ratio 3: 1: 3: 2.5 32-44% diastereomeric mixture yield 1

Scheme 2. General cyclization reaction of compounds 4

Ph CH3

O

CH3

O

HN

COOMe

-

CH3

O Ph

Ph

Ecalculated (kCal/mol)

H2N

H3C

B H

H3C

O COOMe

NH CH

H

H3C

O

-

O

H H

O

2.3 kCal/mol

20.5 kCal/mol

H3C

Ph

CH3

H3C H

O

-

CH3

N H

COOMe HN

Ph

O

(2S, 4S, 5R)

t-Bu

COOMe HN

H3C

NaBH4

H3C

O H3C

41.6-43.3 kCal/mol

O

28.3 kCal/mol

H3C Ph

Typical enamine formation

COOMe HN

Ph

31.2-37.6 kCal/mol

COOMe O

O H3C

t-BuOK

O

O

CH3

HN

HN

H3C

O H3C

-

O

O

H3C

CH3 O

-

N H

CH3

(2S, 4R, 5R)

H3C

O

CH3

+ H3C

H3C H3C

O

COOMe

COOMe H3C

HN

< 1.0 kCal/mol

Ph

Ph

N H

CH3

(2S, 4R, 5S)

+

H3C

CH3

N H

CH3

(2S, 4S, 5S)

Figure 1. B3LYP 6-31G(d, p) calculated reaction coordinate diagram

CONCLUSIONS Under reflux conditions, (2S, 4R, 5R), (2S, 4S, 5R) and (2S, 4S, 5S)-stereoisomers are thermodynamically favored (-28.3 kCal/mol). The (2S, 4S, 5R)stereoisomer formation is kinetically favored only by +2.3 kCal/mol. Consequently, compounds 1 could be obtained as diastereomeric mixtures in the reaction conditions tested. ACKNOWLEDGEMENTS Product derived from the project IMP-CIAS-2294 funded by Vicerrectoría de Investigaciones at UMNG - Validity 2018. REFERENCES [1] Alinezhad, H. et al. (2008). Synthetic Communications, 39(16), 2907-2916. [2] Heydari, A. et al. (2007). Tetrahedron Letters, 48(7),1135-1138.