G. D. Yadav, S. Singh / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 3
4. Experimental
Evaluation of aldol reaction in different prolinamidea
4.1. General
O
O
O
HO
O
Isatin derivatives and acetone were purchased from commer-
cial source and used as such. Proton and carbon nuclear mag-
netic resonance spectra (1H and 13C NMR, respectively) were
recorded on 400 MHz (operating frequencies: 1H, 400.13 MHz;
13C, 100.61 MHz) Jeol-FT-NMR spectrometers at ambient temper-
ature. The chemical shifts (d) for all compounds are listed in
parts per million (ppm) downfield from tetramethylsilane using
the NMR solvent as an internal reference. The reference values
used for deuterated chloroform (CDCl3) were 7.26 and
77.00 ppm for 1H and 13C NMR spectra, respectively. HRMS anal-
ysis was carried out using QSTAR XL Pro system microTOF-Q-II.
Infrared spectra were recorded on a Perkin–Elmer FT-IR spec-
trometer. Thin layer chromatography was carried out using
Merck Kieselgel 60 F254 silica gel plates. Column chromatogra-
phy separations were performed using silica gel 230–400 mesh.
The enantiomeric excess was determined on Shimadzu LC-
2010HT using chiralcel OD-H, chiralpak AD-H and IC columns.
Optical rotations were taken using Rudolph digipol polarimeter.
Organocatalysts 1–4 were synthesised according to our earlier
report and their data also similar to the reported in literature.22
All unknown compounds were characterized by 1H, 13C NMR and
HRMS and known compounds were characterized by 1H and 13C
NMR. Copy of 1H NMR, 13C NMR and HPLC chromatogram are
given in Supporting information.
O
prolinamide 1-6 (10 mol %)
N
H
THF, -35oC, 48h
N
H
8a
7a
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
1
2
3
4
5
6
43
79
65
42
20
33
74
74
59
16
38
36
a
Prolinamide (10 mol %), isatin (0.3 mmol), acetone (1 mL) stirred in THF (2 mL
for 48 h.
Isolated yield after purification by column chromatography.
The ee was determined by HPLC using Chiralpak AD-H column and the absolute
configuration of the product was found to be (S).
b
c
Table 4
Aldol reaction of derivatives of isatin with acetone catalyzed by prolinamide 2a
O
O
O
R1
HO
R1
O
O
prolinamide 2 (10 mol %)
N
R3
THF, -35oC
N
R3
R2
R2
4.2. Synthesis of catalysts 5 and 622
Entry
R1
R2
R3
Time
Yieldb (%)
eec (%)
4.2.1. (S)-N-Benzhydrylpyrrolidine-2-carboxamide 5
1
2
3
4
5
6
7
8
9
10
H
H
H
H
F
Cl
Br
NO2
OMe
Br
H
H
H
H
H
H
H
H
H
Br
H
48
36
36
30
26
26
24
24
36
48
79
91
72
72
97
97
97
99
79
92
74
54
46
66
58
70
80
52
24
51
Compound (S)-tert-butyl 2-(benzhydrylcarbamoyl)pyrrolidine-
1-carboxylate (1.60 g, 4.21 mmol) was taken in dry dichloro-
methane (2.28 mL) and TFA (2.28 mL) was slowly added to this
solution at 0 °C and stirred for 3 h at room temperature. The solu-
tion was then concentrated in vacuo, and dissolved in 10% NaOH
(10 ml). The product was then extracted with ethyl acetate
(3 Â 10 ml), dried over MgSO4 and concentrated in vacuo to yield
an oil, which was purified on silica gel in 10% MeOH/DCM, to give
Me
Bn
All
H
H
H
H
H
H
25 = À25.7 (c 0.605 in MeOH), IR
a
product 5 as an oil (1.04 g, 89%). [a]
Prolinamide 2 (10 mol %), isatin derivatives (0.3 mmol) and acetone (1 mL) in
D
(KBr): 3357, 2937, 1649, 1054 cmÀ1
.
1H NMR (400 MHz, CDCl3):
THF (2 mL) stirred at À35 °C for specified time.
b
Isolated yield after purification by column chromatography.
d = 8.44 (br s, 1H), 7.35–7.18 (m, 10H), 6.22–6.19 (m, 1H) 3.79–
3.76 (m, 1H), 3.02–2.86 (m, 2H), 2.16–1.89 (m, 2H), 1.75–1.66
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): d = 174.10, 141.86 (2C),
128.53 (2C), 128.47 (2C), 127.43 (2C), 127.25, 127.12, 127.00
(2C), 60.50, 55.92, 47.24, 30.70, 26.16 ppm. HRMS (ESI): m/z [M
+H]+ calcd for C18H21N2O: 281.1653; found: 281.1660.
c
The ee was determined by HPLC using Chiralpak AD-H and Chiralcel OD-H and
IC column and the absolute configuration of the products was found to be (S).6,21,23
groups (–NO2) at the 5-position of isatin were found to be more
reactive, but the ee was lower (Table 4, entries 1 and 8). Electron
donating groups (MeO–) in isatin afforded the product in 79% yield
and with poor ee after 36 h (Table 4, entry 9). The aldol reaction of
5,7-di-bromoisatin afforded (S)-convolutamydines alkaloid in 92%
yield and with 51% ee (Table 4, entry 10).
4.2.2. trans-4-Hydroxy-N-((S)-1-(naphthalen-1-yl)ethyl)pyrroli-
dine-2-carboxamide 6
Compound
trans-butyl
2-((S)-1-phenylethylcarbamoyl)-4-
hydroxypyrrolidine-1-carboxylate (0.412 g, 1.07 mmol) was taken
in dry dichloromethane (0.58 mL) with TFA (0.58 mL) using the
same method as prolinamide 5 to give an oil. The oil was purified
on silica gel using methanol:dichloromethane (10:90), yielding the
3. Conclusions
In conclusion we have developed an organocatalyst for direct
asymmetric aldol reactions between isatin derivatives and acetone.
trans-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide
2 (10 mol %) is sufficient to catalyse the reaction and afforded pro-
duct 8a in 79% yield and with 74% ee. An hydroxyl group on the
prolinamide enhanced the reactivity of the organocatalyst. The
organocatalyst can be applied to isatin derivatives and afforded
the corresponding (S)-3-hydroxy-3-(2-oxopropyl)indolin-2-one
derivatives in 72–99% yields with 24–80% ee. Alkaloid (S)-convolu-
tamydine was synthesised in excellent yields and with 51% ee.
product 6 as an oil (0.292 g, 96%). [
a]
25 = À24.0 (c 0.734 in MeOH),
D
IR (KBr): 3435, 2918, 1665, 1378 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 8.40 (br s, 1H), 7.81–7.78 (m, 1H), 7.58–7.35 (m, 2H), 7.26–7.17
(m, 5H), 5.55–5.54 (m, 1H), 5.07 (br s 1H), 4.19–4.06 (m, 2H),
2.92–2.79 (m, 2H) 2.10–2.08 (m, 1H), 1.63–1.55 (m, 1H), 1.41–
1.33 (m, 3H), ppm. 13C NMR (100 MHz, CDCl3): d 170.20, 138.38,
133.18, 130.19, 128.21, 127.33, 125.73, 125.14, 124.85, 122.57,
121.89, 70.84, 58.37, 54.08, 49.26, 44.11, 20.77 ppm. HRMS (ESI):
m/z [M+H]+ calcd for C17H21N2O2: 285.1603; found: 285.1610.