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.