Amino oxazolines as a new class of organocatalyst for the direct intermolecular asymmetric aldol reaction between acetone and aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.07.020

A series of chiral amino oxazolines were synthesized and screened as organocatalysts for asymmetric intermolecular aldol reactions between acetone and aromatic aldehydes. The reaction works well with a range of aromatic aldehydes showing good to high sele

Full text of DOI:10.1016/j.tetasy.2013.07.020

Tetrahedron: Asymmetry 24 (2013) 1035–1041
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Tetrahedron: Asymmetry
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Amino oxazolines as a new class of organocatalyst for the direct
intermolecular asymmetric aldol reaction between acetone and
aromatic aldehydes
⇑
Akeel S. Saiyed, Ashutosh V. Bedekar
Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Accepted 19 July 2013
A series of chiral amino oxazolines were synthesized and screened as organocatalysts for asymmetric
intermolecular aldol reactions between acetone and aromatic aldehydes. The reaction works well with
a range of aromatic aldehydes showing good to high selectivity. The present new system of the organo-
catalyst was effective for the asymmetric aldol reaction for a wide range of aromatic aldehydes and isatin
to carry out an asymmetric carbon–carbon bond forming reaction with a high enantioselectivity of up to
91%.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
organocatalytic reactions have been reported with various selectiv-
ities and mechanistic investigations. In addition to proline, other
The use of asymmetric catalysts for accessing enantiomerically
pure organic compounds is by far the most attractive and efficient
option. Developments in the field of asymmetric catalysis are in-
spired by the natural biochemical processes induced by biomole-
cules such as enzymes and antibodies. Although, we cannot
match Nature in terms of the efficiency of biological systems, it
has been an endeavour of many scientists to search for artificial
or semisynthetic molecules to serve as catalysts for enantioselec-
tive reactions. Most of the early developments were based on tran-
sition metal/chiral ligand based asymmetric catalysis. The
introduction of organic molecules capable of influencing basic or-
ganic reactions has ushered in the era of ‘organocatalysis’ in mod-
ern chemistry. The ability of organocatalysts to control asymmetric
transformations in the key step is attributed mainly to supramolec-
ular interactions, similar to enzymes in the biochemical reactions.
Elimination of the use of potentially toxic metal ion based catalysis
in the wake of this development goes well with the advent of green
chemistry and realization of the commitment of the scientists to-
wards environmental concerns.
chiral organic molecules based on thiourea,3 thiazolidine,4 cin-
chona alkaloids,5 peptides6 and cabohydrates7 have been screened
successfully as organocatalysts for asymmetric reactions. In addi-
tion, some chiral amines and diamines have also been employed
as organocatalysts for aldols and their variations with good enanti-
oinduction.8 Recently an elegant combination of amino oxazoline
and proline has been prepared and tested for inducing chirality
in intermolecular aldol reactions.9 These types of prolinamide-
oxazolines are amongst a series of modifications designed on the
basic amino acid unit of proline where a second chiral element
has been introduced. Such derivatives with two chiral units have
been more selective compared to some of the prolinamides pre-
pared with achiral amines.10 This series of prolinamide-oxazolines
are neutral molecules in nature, as the carboxylic acid of proline is
blocked by the amide group.
O
O
R
N
R
N
Developments in the area are mostly focused on carbon–carbon
bond forming asymmetric reactions such as the aldol condensation
and its variants, Michael reactions, Baylis–Hillman reactions and
Mannich reactions.1 The major thrust in this effort began with
the pioneering work by Barbas, List and others when they utilized
NH
COOH
N
H
NH
R'
H
N
O
L-proline
amino oxazoline
prolinamide-oxazoline
Herein we report our efforts to scan amino oxazolines, without
L
-proline to catalyse aldol reactions with excellent enantioselectiv-
ity.2 Since these reports, many applications of proline induced
the attachment of -proline, as organocatalysts to induce chirality
L
in intermolecular aldol reactions. It is widely accepted that organo-
catalysed aldol reactions follow either an acid assisted enamine
⇑
Corresponding author. Tel.: +91 02652795552.
E-mail address: avbedekar@yahoo.co.in (A.V. Bedekar).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.020

1036
A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
route (Eq. 1) or the base induced enol–enolate pathway (Eq. 2). For
the aldol reaction of unactivated ketones, the enamine mechanism
(assisted by proline) appears favourable, while the base induced
enol–enolate pathway is less likely due to the low acidity of the
HO
CHO
organocatalyst
acetone
O
a-protons.
NO2
NO2
N
H
O
N
OH
OH
O
O
Scheme 2. Application of amino oxazolines as organocatalysts for asymmetric aldol
reactions.
i.ArCHO
ii. H2O
ð1Þ
Ar
Ar
H2O
Since the chiral amino oxazoline is a weak base, we therefore
screened sufficiently activated enolate acceptors for the aldol reac-
tion. With this in mind, we used 4-nitro benzaldehyde as the stan-
dard aldehyde and scanned the conditions with a number of amino
oxazolines (Table 1).
-
O
O
i.ArCHO
ii. Base-H+
Base
ð2Þ
Base-H+
There are only few reports utilizing chiral amines functioning as
bases in organocatalysis for asymmetric aldol reactions, mostly for
activated ketones.5,8,11,12 Hence, we report our preliminary results
using chiral amino oxazolines as weakly basic entities to effect
asymmetric aldol reactions of unactivated ketones.
Table 1
Screening of amino oxazoline 10 (20 mol %) for standard reactions of 4-nitro
benzaldehyde and acetone (4 equiv except for entry 3)
No.
Solvent
Temp (°C)/time (h)
Yield (%)
% ee (R)
1
2
3
4
5
6
7
PEG-400
PEG-400
Acetone
Acetonitrile
Toluene
THF
30/24
5–8/24
5–8/24
5–8/24
5–8/24
5–8/24
5–8/72
79
61
71
33
16
33
48
16
51
40
75
91
75
71
2. Results and discussion
The amino oxazolines required were prepared by the Lewis acid
mediated reactions of isatoic anhydride 1 and a suitable amino
alcohol (Scheme 1).13
A series of chiral derivatives of 2 were prepared from suitably
N-alkylated isatoic anhydride and chiral amino alcohols (Fig. 1,
Scheme 2).
THF
Recently polyethylene glycol was used as a solvent for L-proline
mediated aldol reactions.14 In addition to this we have also used
other solvents (Table 1). The reaction proceeded with moderate re-
sults with PEG-400 and THF, while the configuration of the b-hy-
droxy compound was established as (R) by comparison of the
specific rotation.
R'' R'
O
N
O
R''
R'
H2N
OH
O
N
The series of ligands synthesized were then scanned under the
optimized conditions of THF as the solvent for 72 h reaction time
using 4-nitro benzaldehyde and acetone. The results are summa-
rized in Table 2. In most cases, the yield and selectivity were mod-
erate to good. The ligands with a free –NH2 group 3 and –NHCOPh
group 5 were both ineffective in this reaction, while derivatives
prepared from tert-leucine showed good selectivity.
ZnCl2
heat
O
NH
R
R
1
, R = H
2, R = H
Scheme 1. Synthesis of amino oxazolines.
O
O
R''
R'
O
R''
R'
R''
O
R''
R'
R'
N
N
N
N
NH
NH
NH
R
NH
R'''
3
, R = H, R' = i-Pr, R'' = H
Br
4, R = COPh, R' = i-Pr, R'' = H
R'''
, R' = i-Pr, R'' = H, R''' = Br
10
, R' = i-Pr, R'' = H
11
, R' = CH2Ph, R'' = H
12, R' = i-Pr, R'' = H
5
, R = CH2Ph, R' = R'' = Me
13
14
6
, R = R' = CH2Ph, R'' = H
, R' = CH2Ph, R'' = H, R''' = Br
15, R' = i-Pr, R'' = H, R''' = Me
16
7, R = CH2Ph, R' = i-Pr, R'' = H
8
, R = CH2Ph, R' = Ph, R'' = H
, R' = CH2Ph, R'' = H, R''' = Me
17
9
, R = CH2Ph, R' = tert-Bu, R'' = H
, R' = i-Pr, R'' = H, R''' = Ph
18, R' = CH2Ph, R'' = H, R''' = Ph
Figure 1. List of amino oxazolines used herein.

A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
1037
Table 2
Screening of amino oxazolines (20 mol %) for standard reactions of 4-nitro benzaldehyde and acetone (4 equiv)
No.
Amino oxazoline
Yield (%)
ee (%)
No.
Amino oxazoline
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
3
4
6
7
8
9
10
11
NR
NR
68
66
65
52
48
51
—
—
9
12
13
14
15
16
17
18
59
57
59
60
56
60
62
39
63
71
76
75
75
76
10
11
12
13
14
15
76
76
63
86
79
71
For all reactions, the (R)-isomer was formed. Solvent = THF; reaction temp = 5-8 °C; time 72 h. NR = no reaction.
The amino oxazolines 9 and 10 showed consistent results with
both good conversion and enantioselectivity. As a result, these
were then investigated for a few aromatic aldehydes substituted
with electron withdrawing groups (Table 3).
The major advantage of amino oxazolines is their high solubility
in almost all routine organic solvents, unlike proline. Since the
reaction is assisted by a base and the conditions are neutral (no
acid additive is used) we propose that the reaction must follow
Table 3
Screening of amines 9 and 10 for selected examples
% Yield (% ee)
No.
1
RC6H4CHO
R = 4-NO2
b-Hydroxy ketone (R)
with 9
with 10
OH
O
54 (91)
48 (79)
19
O2N
OH
O
2
3
4
R = 2-NO2
R = 3-NO2
R = 4-CI
69 (91)
73 (74)
47 (66)
72 (84)
68 (70)
52 (61)
20
NO2
OH
O
O2N
21
OH
O
22
OH
Cl
Br
O
5
R = 4-Br
49 (84)
58 (57)
23
Many researchers have also studied isatin 24 as an acceptor of
enolates in asymmetric organocatalysed aldol reactions.6a,7b,15 To
test this system, we carried out the reaction of acetone with isatin
in the presence of amino oxazoline 9 and the aldol product was iso-
lated with moderate enantioselectivity (Scheme 3).
enol–enolate pathway. The enantioselectivity of the amino oxazo-
lines for aldol reaction is mainly controlled by the size and shape of
the chiral substituent on the oxazoline ring and is almost indepen-
dent of the group attached on the amino unit (Ar0). However, deriv-
ative 3 with a primary amino group as well as the benzoyl
derivative 4 failed to catalyse this reaction. It is possible that in
the former, the condensation of the aldehyde with a primary amine
is a competing reaction while the neutral nature of the benzoyl
derivative does not favour the enol formation in the latter case.
It is also noteworthy that the acid labile amino oxazoline re-
mains intact after the reaction is complete (TLC), although so far
we have not made any attempt to recover and recycle the catalyst.
O
O
HO
acetone
9
(20%)
O
O
THF, 5-8 °C.
72 h
N
N
H
H
3. Conclusion
25
24
46 % Y
61 % ee
Herein we have reported on the application of chiral amino
oxazolines as a new class of organocatalysts for the asymmetric
Scheme 3. Application of isatin with acetone for the aldol reaction.

1038
A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
intermolecular aldol reactions of acetone and aromatic aldehydes
and isatin. The reaction conditions are free from any additives
and are relatively mild and simple to follow in the laboratory.
30 min. Next, benzoyl chloride (0.075 g) was added at the same
temperature. The reaction mixture was then stirred overnight at
room temperature. The reaction was checked by TLC. After comple-
tion, the reaction mixture was washed with water (10 mL ꢀ 2). The
organic layer was dried over sodium sulfate and evaporated on a
rotary evaporator. The crude product was then purified by column
chromatography on silica gel (60–120 mesh) using ethylacetate
and petroleum ether as eluents. The pure product was isolated as
4. Experimental
4.1. General
a white solid. Yield: 82%; ½a D28
ꢁ
¼ þ82:8 (c 1.00, CHCl3). [lit.17
Reagents were purchased from Sigma–Aldrich Chemicals Lim-
ited, SD Fine, Sisco, Qualigens, Avara Chemicals Limited etc. Thin
Layer Chromatography was performed on Merck 60 F254 Alumin-
ium coated plates. The spots were visualized under UV light or
with iodine vapour. All compounds were purified by column chro-
matography using Sisco Research Laboratory silica gel (60–
120 mesh) and neutral alumina. All reactions were carried out un-
der an inert atmosphere (nitrogen) unless other conditions are
specified. NMR Spectra were recorded on 400 MHz Bruker Avance
400 Spectrometer (400 MHz for 1H NMR and 100 MHz for 13C
NMR) with CDCl3 or DMSO as solvents and TMS as internal stan-
dard. Signal multiplicity is denoted as singlet (s), doublet (d), dou-
blet of doublet (dd), triplet (t), quartet (q) and multiplet (m). Mass
spectra were recorded on Thermo-Fischer DSQ II GCMS instrument.
IR Spectra were recorded on a Perkin–Elmer FTIR RXI spectrometer
as KBr pellets. Optical rotations were measured on Jasco P-2000
polarimeter. Melting points were recorded in Thiele’s tube using
paraffin oil and are uncorrected. For the HPLC analysis chiral Lux
½ ꢁ ¼ þ83 (c 1.00, CHCl3)]. Mp 88–90 °C; IR (KBr): 3176, 3041,
a D
2957, 2888, 2864, 1823, 1669, 1635, 1496, 1445, 1187, 1161,
1102, 1049, 977, 883, 802, 757, 703 cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d 13.11 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 7.2 Hz,
2H), 7.92 (d, J = 7.6 Hz, 1H), 7.54–7.47 (m, 4H), 7.15–7.12 (t,
J = 7.6 Hz, 1H), 4.46–4.42 (t, J = 8.4 Hz, 1H), 4.28–4.22 (m, 1H),
4.12–4.08 (t, J = 8 Hz, 1H), 1.86 (d, J = 5.6 Hz, 1H), 1.04 (d,
J = 6 Hz, 3H), 0.99 (d, J = 6 Hz, 3H). MS (EI): m/z (%) 307.99 (100),
264.70 (49), 230.88 (39), 145.76 (20), 104.48 (53), 76.84 (35).
4.5. N-Benzyl-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline 5
Yield: 72%; mp 80 °C (lit.18 80 °C); IR (KBr):
1918, 1811, 1628, 1384, 1089, 925, 840, 766 cmꢂ1
m
3262, 2963,
1H NMR
.
(CDCl3, 400 MHz): d 1.36 (s, 6 H), 4.01 (s, 2 H), 4.51 (s, 2 H),
6.59–6.62 (t, J = 14.2 Hz and 5.88 Hz, 2 H), 7.19–7.25 (m, 2H),
7.37–7.30 (m, 4H), 7.74–7.76 (d, J = 7.4 Hz, 1 H), 8.96 (br s, 1H).
13C NMR (100 MHz, CDCl3): d 162.33, 148.89, 139.55, 132.28,
129.68, 128.50, 126.81, 114.63, 110.80, 108.93, 76.74, 67.83,
46.87, 28.73. MS (EI): m/z (%) 280.42 (59), 278.99 (100), 222.73
(18), 193.70 (17), 104.64 (15), 90.92 (9), 76.80 (3). Anal. Calcd
for C18H20N2O C, 77.11; H, 7.18; N, 9.99. Found: C, 77.12; H,
7.36; N, 10.02.
5
l Amylase—2 and Chiralpak IC column were used on Shimadzu
LC-20AD with a UV–vis detector.
4.2. General procedure for the synthesis of amino oxazolines
In
a 100 mL two-necked flask, anhydrous zinc chloride
(10 mol %) was prepared by melting under high vacuum. After
cooling to room temperature under nitrogen, dry chlorobenzene
(10 mL), isatoic anhydride or N-alkyl isatoic anhydride (1 equiv)
4.6. N-Benzyl-2-(4–isopropyl-4,5-dihydrooxazol-2-yl)aniline 6
Yield: 76%; ½a 3D5
¼ ꢂ18:7 (c 0.41, CHCl3); mp 74–76 °C; IR (KBr):
ꢁ
and L-amino alcohol (1.2 equiv) were charged to this flask under
m
3235, 3067, 3030, 2963, 2894, 2869, 1637, 1581, 1518, 1457,
nitrogen. The mixture was then refluxed for 24 h. The solvent
was then removed under reduced pressure and the oily residue
was dissolved in dichloromethane (25–30 mL). The solution was
washed three times with water (3 ꢀ 20 mL) and the aqueous phase
was extracted again with dichloromethane (2 ꢀ 20 mL). The com-
bined organic phase was dried over anhydrous sodium sulfate
and the solvent was removed in vacuo. The resulting oil was puri-
fied by column chromatography on neutral alumina using light
petroleum ether as the eluent to afford a pure product.
1358, 1332, 1287, 1271, 1166, 1144, 1079, 1049, 747 cmꢂ1 1H
.
NMR (400 MHz, CDCl3): d 9.07 (br s, 1H), 7.77 (d, J = 8 Hz, 1H),
7.43–7.26 (m, 6H), 6.69–6.63 (m, 2H), 4.52 (s, 2H), 4.37–4.33 (t,
J = 8.8 Hz, 1H), 4.14–4.08 (q, J = 8.0 Hz, 1H), 4.04–4.00 (t, J = 8 Hz,
1H), 1.81–1.73 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3):
d 163.80, 148.95, 139.31,
132.36, 129.80, 128.56, 127.15, 126.97, 114.58, 110.66, 108.76,
72.88, 68.77, 47.11, 33.32, 18.85, 18.78. MS (EI): m/z (%) 294.48
(50), 293.05 (94), 207.69 (100), 194.23 (26), 90.85 (30), 76.71 (9).
Anal. Calcd for C19H22N2O C, 77.52; H, 7.53; N, 9.52. Found: C,
77.08; H, 7.21; N, 9.62.
4.3. 2-(4-Isoprolyl-4,5-dihydrooxazol-2-yl)aniline 3
Yield: 48%; ½a 3D0
ꢁ
¼ ꢂ1:4 (c 0.80, CHCl3). [lit.13
½ ꢁ ¼ ꢂ1:35 (c
a D
0.85, CHCl3)]. Mp 65–64 °C. (lit.16 64–65 °C). IR (KBr): 3381, 3275,
4.7. N-Benzyl-2-(4–benzyl-4,5-dihydrooxazol-2-yl)aniline 7
3066, 2945, 1668, 1629, 1591, 1450, 1170, 1082, 1041, 754 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d 7.71–7.68 (dd, J = 1.6 and 7.6 Hz,
1H), 7.24–7.20 (m, 1H), 6.73–6.65 (m, 2H), 4.36–4.32 (q,
J = 8.0 Hz, 1H), 4.14–4.10 (m, 1H), 4.04–4.00 (t, J = 8.0 Hz, 1H),
1.83–1.78 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 163.51, 148.59, 131.90, 129.56,
115.98, 115.63, 109.17, 72.91, 68.75, 33.22, 19.00, 18.62. MS (EI):
m/z (%) 203.80 (57), 160.79 (100), 132.80 (76), 118.44 (11),
105.81 (14), 92.10 (5).
Yield: 69%; ½a 3D5
¼ þ20:3 (c 1.00, CHCl3); mp 80–82 °C; IR (KBr):
ꢁ
m
3258, 3061, 3027, 2896, 2851, 1631, 1588, 1525, 1451, 1363,
1330, 1273, 1234, 1164, 1142, 1071, 1050, 971, 749, 697 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d 9.01 (br s, 1H), 7.77 (d, J = 8 Hz, 1H),
7.41–7.23 (m, 11H), 6.66–6.63 (m, 2H), 4.63–4.58 (m, 1H), 4.54
(s, 2H), 4.34–4.30 (t, J = 8.4 Hz, 1H), 4.09–4.05 (t, J = 8.0 Hz, 1H),
3.14–3.09 (dd, J = 6.4 and 13.6 Hz, 1H), 2.84–2.78 (dd, J = 7.6 and
13.6 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 164.34, 149.02,
139.45, 138.32, 132.54, 129.90, 129.29, 128.61, 128.49, 126.96,
126.93, 126.45, 114.66, 110.84, 108.63, 70.12, 68.10, 46.92, 42.31.
MS (EI): m/z (%) 342.50 (57), 341.05 (100), 250.85 (67), 207.76
(85), 194.15 (23), 193.07 (24), 90.82 (6). Anal. Calcd for
4.4. N-(2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzam-
ide 4
To the solution of 0.100 g of 3 in dichloromethane (10 mL), N,N-
diisopropylethylamine (0.190 g) was added at 0 °C and stirred for
C
8.61.
23H22N2O C, 80.67; H, 6.48; N, 8.18. Found: C, 80.36; H, 6.24; N,

A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
1039
4.8. N-Benzyl-2-(4–phenyl–4,5-dihydrooxazol-2-yl)aniline 8
392.48 (100), 301.18 (43), 258.19 (83), 244.22 (31), 140.94 (56),
90.84 (16), 76.81 (7). Anal. Calcd for C27H24N2O C, 82.62; H, 6.16;
N, 7.14. Found: C, 82.43; H, 6.01; N, 7.42.
Yield: 71%; ½a 3D5
¼ þ137:8(c 0.40, CHCl3); mp 116–118 °C; IR
ꢁ
(KBr):
m 3248, 3062, 3026, 2966, 1632, 1584, 1521, 1493, 1269,
1168, 103, 897, 749, 730, 696 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d
4.12. N-(4-Bromobenzyl)-2-(4-isopropyl-4,5-dihydrooxazol-2-
9.13–9.10 (t, J = 5.6 Hz, 1H), 7.88–7.86 (m, 1H), 7.42–7.25 (m,
11H), 6.71–6.67 (m, 2H), 5.53–5.48 (dd, J = 8.4 and 10 Hz, 1H),
4.76–4.71 (dd, J = 8.4 and 9.6 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.2–
4.15 (t, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 165.33,
149.21, 142.79, 139.43, 132.75, 130.10, 128.72, 128.55, 127.54,
126.89, 126.92, 114.72, 111.01, 108.44, 72.92, 70.14, 46.88. MS
(EI): m/z (%) 328.41 (87), 327.05 (100), 223.24 (24), 208.24 (30),
179.03 (38), 146.76 (55), 105.03 (49), 90.88 (54), 76.61 (27). Anal.
Calcd for C22H20N2O C, 80.46; H, 6.14; N, 8.53. Found: C, 80.21; H,
5.79; N, 8.71.
yl)aniline 12
Yield: 81%; ½a 3D5
¼ ꢂ6:7 (c 0.70, CHCl3); mp 100–102 °C; IR
ꢁ
(KBr):
m 3243, 2958, 2864, 1632, 1488, 1455, 1239, 1308, 805,
748 cmꢂ1 1H NMR (400 MHz, CDCl3): d 9.08 (br s, 1H), 7.78–7.59
.
(dd, J = 1.6 and 7.6 Hz, 1H), 7.48–7.46 (m, 2H), 7.29–7.24 (m, 3H),
6.67–6.63 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H), 4.46 (d, J = 4.4 Hz, 2H),
4.37–4.33 (q, J = 8.0 Hz, 1H), 4.15–4.11 (m, 1H), 4.05–4.01 (t,
J = 7.6 Hz, 1H), 1.82–1.74 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.94 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 163.84, 148.71,
138.45, 132.47, 132.41, 131.62, 129.89, 128.82, 120.67, 114.91,
110.66, 108.90, 72.79, 68.77, 46.51, 33.27, 18.89, 18.70. MS (EI):
m/z (%) 373.62 (100), 371.82 (30), 331.18 (11), 328 (17), 287.10
(21), 285.54 (44), 272.05 (11), 270.83 (6). Anal. Calcd for C19H21-
BrN2O C, 61.13; H, 5.67; N, 7.50. Found: C, 60.67; H, 5.31; N, 7.99.
4.9. N-Benzyl-2-(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)aniline 9
Yield: 80%; ½a 3D0
ꢁ
¼ ꢂ20:7 (c 0.80, CHCl3); mp 96–98 °C; IR (KBr):
m
3255, 3063, 3031, 2968, 2954, 2887, 1632, 1578, 1574, 1515, 1497,
1470, 1452, 1361, 1328, 1287, 1263, 1240, 1167, 1143, 1091, 1076,
1050, 1028, 975, 906, 749, 700, 670 cmꢂ1
.
1H NMR (400 MHz,
4.13. N-(3,5-Dibromobenzyl)-2-(4-isopropyl-4,5-dihydrooxazol-
CDCl3): d 9.08 (br s, 1H), 7.77–7.75 (dd, J = 0.8 and 7.6 Hz, 1H),
7.42 (d, J = 7.2 Hz, 2H), 7.38–7.34 (t, J = 7.6 Hz, 2H), 7.30–7.27 (q,
J = 4.8 and 7.6 Hz, 2H), 6.70–6.63 (m, 2H), 4.51 (d, J = 4.8 Hz, 2H),
4.30–4.23 (m, 1H), 4.15–4.07 (m, 2H), 0.91 (s, 9H). 13C NMR
2-yl)aniline 13
Yield: 61%; ½a 3D5
¼ ꢂ17:15 (c 0.50, CHCl3); mp 118–120 °C; IR
ꢁ
(KBr):
m 3216, 3085, 2959, 2899, 2864, 1637, 1586, 1520, 1463,
(100 MHz, CDCl3):
d
163.74, 148.98, 139.25, 132.34, 129.78,
1357, 1328, 1080, 1049, 964, 849, 744, 682, 632, 588, 537 cmꢂ1
.
128.57, 127.27, 127.01, 114.53, 110.59, 108.72, 76.27, 66.80,
47.18, 33.86, 25.86. MS (EI): m/z (%) 307.83 (100), 250.79 (63),
207.77 (57), 194.14 (21), 90.85 (10). Anal. Calcd for C20H24N2O C,
77.89; H, 7.84; N, 9.08. Found: C, 77.64; H, 7.43; N, 9.44.
1H NMR (400 MHz, CDCl3): d 9.15 (br s, 1H), 7.79–7.77 (dd,
J = 1.6 and 8.0 Hz, 1H), 7.58–7.57 (m, 1H), 7.48–7.47 (m, 2H),
7.29–7.25 (m, 1H), 6.71–6.67 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H),
4.51–4.41 (q, J = 15.6 Hz, 2H), 4.39–4.34 (m, 1H), 4.17–4.11 (m,
1H), 4.07–4.03 (t, J = 8.0 Hz, 1H), 1.84–1.77 (m, 1H), 1.02 (d,
J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 163.82, 148.44, 143.83, 132.70, 132.48, 129.94, 128.78, 123.19,
115.32, 110.59, 109.16, 76.74, 72.77, 68.78, 46.25, 18.97, 18.69.
MS (EI): m/z (%) 453.70 (74), 452.37 (48), 451.81 (31), 450.95
(100), 449.22 (91), 410.12 (17), 409.03 (28), 408.10 (31), 406.35
(33), 368.18 (26), 367.12 (30), 365.54 (99), 363.46 (53), 146.51
(39), 104.51 (36), 76.75 (18). Anal. Calcd for C19H20Br2N2O C,
50.47; H, 4.46; N, 6.20. Found: C, 50.05; H, 3.98; N, 6.45.
4.10. 2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-N-(naphthalen-2-
ylmethyl)aniline 10
Yield: 62%; ½a 3D0
¼ ꢂ24:3 (c 0.80, CHCl3); mp 128–130 °C; IR
ꢁ
(KBr):
m 3250, 3053, 2959, 2927, 2898, 2871, 1631, 1586, 1523,
1463, 1362, 1318, 1273, 1236, 1163, 1144, 1087, 1049, 967, 904,
853, 816, 748, 686 cmꢂ1 1H NMR (400 MHz, CDCl3): d 9.17–9.14
.
(t, J = 4.8 Hz, 1H), 7.83–7.78 (m, 4H), 7.76–7.74 (dd, J = 1.6 and
8.0 Hz, 1H), 7.51–7.49 (dd, J = 1.6 and 8.4 Hz, 1H), 7.48–7.42 (m,
2H), 7.25–7.20 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.64–6.60 (m,
1H), 4.69–4.60 (m, 2H), 4.35–4.28 (m, 1H), 4.13–4.09 (m, 1H),
4.03–3.99 (t, J = 7.6 Hz, 1H), 1.80–1.72 (m, 1H), 0.96 (d, J = 6.8 Hz,
3H), 0.91 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 163.83,
148.99, 136.87, 133.51, 132.67, 132.37, 129.80, 128.28, 127.77,
127.68, 126.03, 125.54, 125.52, 125.41, 114.67, 110.79, 108.85,
72.87, 68.72, 47.31, 33.30, 18.91, 18.72. MS (EI): m/z (%) 345.20
(60), 344.19 (100), 302.37 (39), 233.31 (23), 144.01 (15), 91.90
(10). Anal. Calcd for C23H24N2O C, 80.20; H, 7.02; N, 8.13. Found:
C, 79.94; H, 6.87; N, 8.47.
4.14. 2-(4-Benzyl-4,5-dihydrooxazol-2-yl)-N-(3,5-dibromobenzyl)
aniline 14
Yield: 59%; ½a 3D5
¼ þ4:4 (c 0.71, CHCl3); mp 112–114 °C; IR (KBr):
ꢁ
m
3210, 3067, 3027, 2844, 1636, 1553, 1526, 1468, 1365, 1238, 1028,
847, 750, 693, 571, 541 cmꢂ1. 1H NMR (400 MHz, CDCl3): d 9.01 (br s,
1H), 7.79–7.77 (dd, J = 1.6 and 7.6 Hz, 1H), 7.59–7.58 (t, J = 1.6 Hz,
1H), 7.48–7.47 (m, 2H), 7.34–7.24 (6H), 6.71–6.66 (m, 1H), 6.52 (d,
J = 8.0 Hz, 1H), 4.68–4.64 (m, 1H), 4.46 (d, J = 4.8 Hz, 2H), 4.36–
4.32 (t, J = 8.4 Hz, 1H), 4.11–4.08 (q, J = 7.2 Hz, 1H), 3.17–3.12 (dd,
J = 6.4 and 13.6 Hz, 1H), 2.87–2.82 (dd, J = 7.6 and 13.6 Hz, 1H). 13
C
4.11. 2-(4-Benzyl-4,5-dihydrooxazol-2-yl)-N-(naphthalen-2-yl-
methyl)aniline 11
NMR (100 MHz, CDCl3): d 164.93, 149.51, 139.83, 138.72, 138.50,
132.95, 130.21, 129.68, 129.02, 128.88, 126.95, 125.12, 114.93,
111.21, 108.92, 70.40, 68.62, 47.43, 43.10. MS (EI): m/z (%) 501.64
(57), 500.05 (70), 499.07 (50), 497.99 (52), 410.59 (66), 409.00
(71), 407.71 (100), 405.98 (51), 367.75 (31), 363.81 (19), 362.63
(26), 351.91 (30), 350.67 (25), 349.59 (16), 248.46 (12), 90.87 (8).
Anal. Calcd for C23H20Br2N2O C, 55.22; H, 4.03; N, 5.60. Found: C,
54.88; H, 3.71; N, 5.93.
Yield: 58%; ½a 3D5
ꢁ
¼ þ10:1 (c 0.70, CHCl3); mp 124 °C; IR (KBr):
m
3255, 3056, 3024, 2885, 2851, 1627, 1580, 1516, 1452, 1363, 1328,
1281, 1240, 1166, 1080, 1034, 983, 905, 867, 819, 750 cmꢂ1 1H
.
NMR (400 MHz, CDCl3): d 9.11 (br s, 1H), 7.88–7.78 (m, 5H),
7.54–7.49 (m, 3H), 7.28–7.18 (m, 6H), 6.71–6.65 (m, 2H), 4.70–
4.64 (m, 3H), 4.34–4.31 (t, J = 8.4 Hz, 1H), 4.10–4.06 (t, J = 7.6 Hz,
1H), 3.15–3.10 (dd, J = 6.4 and 13.6 Hz, 1H), 2.85–2.79 (dd, J = 7.6
and 13.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 164.45, 149.05,
138.22, 136.90, 133.54, 132.71, 132.62, 129.93, 129.25, 128.44,
128.34, 127.81, 127.71, 126.43, 126.09, 125.59, 125.41, 114.80,
110.98, 108.62, 70.19, 67.97, 47.23, 42.26. MS (EI): m/z (%)
4.15. N-(3,5-Dimethylbenzyl)-2-(4-isopropyl-4,5-dihydro oxaz-
ol-2-yl)aniline 15
Yield: 55%; ½a 3D5
¼ ꢂ36:9(c 0.60, CHCl3); mp 102–104 °C; IR
ꢁ
(KBr):
m 3230, 2892, 1639, 1519, 1455, 1356, 1332, 1271, 1236,

1040
A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
1160, 1075, 1045, 967, 739, 682, 719, 682 cmꢂ1. 1H NMR (400 MHz,
CDCl3): d 8.99 (br s, 1H), 7.78–7.76 (dd, J = 1.6 and 7.6 Hz, 1H),
7.32–7.28 (m, 1H), 7.05 (s, 2H), 6.935 (s, 1H), 6.70 (d, J = 8.4 Hz,
1H), 6.67–6.63 (m, 1H), 4.45–4.39 (m, 2H), 4.37–4.33 (m, 1H),
4.14–4.08 (m, 1H), 4.04–4.00 (t, J = 8.0 Hz, 1H), 2.33 (s, 6H), 1.81–
1.73 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 163.81, 149.08, 139.19, 132.39, 129.76,
128.65, 125.01, 114.46, 110.63, 108.70, 72.92, 68.81, 47.21, 33.37,
21.34, 18.86, 18.83. MS (EI): m/z (%) 322.51 (51), 321.05 (89.91),
278.84 (21), 235.83 (100), 146.75 (15), 105.03 (9), 90.82 (9),
76.71 (7). Anal. Calcd for C21H26N2O C, 78.22; H, 8.13; N, 8.69.
Found: C, 77.87; H, 7.78; N, 8.81.
243.14 (22), 241.11 (14), 116.90 (9), 90.84 (9). Anal. Calcd for
C35H30N2O C, 84.99; H, 6.11; N, 5.66. Found: C, 84.61; H, 5.88; N,
5.81.
4.19. General procedure for the asymmetric aldol reactions
Amino oxazoline (20 mol %) and acetone (4 equiv) were stirred
in dry THF at 5–8 °C for 30 min. Aldehyde (1 equiv) was then added
to the resulting solution and stirred at the same temperature for
72 h. The solvent was evaporated under reduced pressure after
which 20 mL of water was added to the crude mixture and it
was extracted with ethylacetate (3 ꢀ 20 mL). The combined organ-
ic layer was dried over sodium sulfate and the solvent was evapo-
rated on a rotary evaporator. The crude material was purified by
column chromatography using 60–120 mesh silica gel and ethyl-
acetate: petroleum ether as eluent to afford the aldol product as
the (R)-isomer with 47–73% yields.
4.16. 2-(4-Benzyl-4,5-dihydrooxazol-2-yl)-N-(3,5-dimethyl benzyl)
aniline 16
Yield: 49%; colourless liquid; ½a D35
ꢁ
¼ þ18:4 (c 1.01, CHCl3). IR
(KBr):
m
3257, 3026, 1633, 1234, 1061, 841, 748 cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d 8.97–8.94 (t, J = 5.2 Hz, 1H), 7.77–7.75 (dd,
J = 1.6 and 7.6 Hz, 1H), 7.31–7.21 (m, 7H), 7.03 (s, 2H), 6.93 (s,
1H), 6.67–6.61 (m, 2H), 4.67–4.59 (m, 1H), 4.50–4.42 (m, 2H),
4.33–4.29 (t, J = 8.4 Hz, 1H), 4.08–4.04 (q, J = 7.2 Hz, 1H), 3.16–
3.11 (dd, J = 6.4 and 13.6 Hz, 1H), 2.83–2.78 (dd, J = 8 and
13.6 Hz, 1H), 2.33 (s, 6H). 13C NMR (100 MHz, CDCl3): d 164.36,
149.18, 139.45, 138.32, 138.10, 132.55, 129.83, 129.28, 128.62,
128.48, 126.45, 124.78, 114.53, 110.86, 108.55, 70.07, 68.12,
47.00, 42.27, 21.42. MS (EI): m/z (%) 370.64 (61), 369.05 (100),
178.98 (86), 236.44 (79), 221.02 (27), 118.82 (32), 90.94 (42),
76.75 (12). Anal. Calcd for C25H26N2O C, 81.05; H, 7.07; N, 7.56.
Found: C, 80.67; H, 6.72; N, 7.91.
4.20. (R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one 19
Yield: 54%; ½a 3D0
ꢁ
¼ þ35:3 (c 0.20, CHCl3). [lit.19
½
a 2D5
ꢁ
¼ þ35:2 (c
3438,
.
1H NMR (400 MHz,
0.2, CHCl3), 81% ee]; mp 58 °C (lit.20 59–61 °C). IR (KBr):
m
3082, 2905, 1708, 1604, 1520, 134 cmꢂ1
CDCl3): d 8.23–8.20 (m, 2H), 7.56–7.53 (dd, J = 2.0 and 6.4 Hz,
2H), 5.29–5.25 (m, 1H), 3.60 (d, J = 3.2 Hz, 1H), 2.92–2.80 (m,
2H), 2.23 (s, 3H). MS (EI): m/z (%) 208.73 (51), 190.85 (100),
173.70 (76), 152.05 (30), 104.47 (10), 90.81 (11), 76.83 (14),
57.84 (11). Enantiomeric excess 91% determined by HPLC [Column:
Lux 5
l Amylose-2; solvent system: hexane/iso-propanol (90:10);
flow rate: 1.0 mL/min; kmax = 254 nm; tR = 26.6 min (minor, (S)-iso-
mer), tR = 31.7 min (major, (R)-isomer)].
4.17. N-([1,10:30,100-Terphenyl]-50-ylmethyl)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)aniline 17
4.21. (R)-4-Hydroxy-4-(2-nitrophenyl)butan-2-one 20
Yield: 44%; ½a 3D5
ꢁ
¼ ꢂ37:35 (c 0.51, CHCl3); mp 126 °C IR (KBr):
m
Yield: 69%; ½a 2D7
ꢁ
¼ ꢂ157:6 (c 0.3, CHCl3). [lit.21
½
a 2D5
ꢁ
¼ ꢂ141:0 (c
3420,
.
3080, 2924, 1715, 1613, 1528, 1352 cmꢂ1 1H NMR (400 MHz,
3217, 3064, 2945, 1633, 1525, 1246, 1047, 765, 758, 698 cmꢂ1
.
1H
0.5, CHCl3), 91% ee]; mp 58–60 °C (lit.22 59–61 °C). IR (KBr):
m
NMR (400 MHz, CDCl3): d 9.18–9.15 (t, J = 4.8 Hz, 1H), 7.77 (d,
J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.67–7.63 (t, J = 7.6 Hz, 6H), 7.49–
7.45 (t, J = 7.6 Hz, 4H), 7.41–7.37 (m, 2H), 7.32–7.28 (m, 1H), 6.76
(d, J = 8.4 Hz, 1H), 6.68–6.65 (t, J = 7.6 Hz, 1H), 4.68–4.58 (m, 2H),
4.36–4.31 (m, 1H), 4.13–4.07 (m, 1H), 4.03–3.99 (t, J = 8.4 Hz,
1H), 1.77–1.68 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 7.6 Hz,
CDCl3): d 8.00–7.98 (dd, J = 1.2 and 8.4 Hz, 1H), 7.93–7.91 (dd,
J = 1.6 and 8.0 Hz, 1H), 7.71–7.67 (m, 1H), 7.48–7.44 (m, 1H),
5.71–5.68 (dd, J = 2.0 and 8.2 Hz, 1H), 3.73 (br s, 1H), 3.19–3.14
(m, 1H), 2.78–2.71 (m, 1H), 2.26 (s, 3H). MS (EI): m/z (%) 190.94
(M+-18, 5), 151.17 (34), 131.78 (77), 103.98 (100), 90.83 (26),
76.61 (40). Enantiomeric excess 91% determined by HPLC [Column:
3H). 13C NMR (100 MHz, CDCl3):
d 163.80, 148.98, 142.10,
141.12, 140.51, 132.43, 129.83, 128.77, 127.44, 127.33, 125.07,
124.96, 114.74, 110.70, 108.98, 72.80, 68.67, 47.37, 33.21, 18.76,
18.59. MS (EI): m/z (%) 446.14 (100), 444.53 (50), 360.33 (57),
358.73 (34), 347.45 (10), 346.63 (14), 104.82 (12), 90.90 (10),
76.80 (13). Anal. Calcd for C31H30N2O C, 83.37; H, 6.77; N, 6.27.
Found: C, 82.93; H, 6.51; N, 6.42.
Lux 5 l Amylose-2; solvent system: hexane/iso-propanol (90:10);
flow rate: 1.0 mL/min; kmax = 220 nm; tR = 36.7 min (minor, (S)-iso-
mer), tR = 40.4 min (major, (R)-isomer)].
4.22. (R)-4-Hydroxy-4-(3-nitrophenyl)butan-2-one 21
Yield: 73%; ½a 2D7
ꢁ
¼ þ63:1 (c 0.5, CHCl3). [lit.23
½
a 2D0
ꢁ
¼ þ62:1 (c
3419,
.
3087, 2920, 1710, 1620, 1534, 1354 cmꢂ1 1H NMR (400 MHz,
4.18. N-([1,10:30,100-Terphenyl]-50-ylmethyl)-2-(4-benzyl-4,5-dihy
drooxazol-2-yl)aniline 18
0.35, CHCl3), 87% ee] Mp 50 °C (lit.24 50–52 °C). IR (KBr):
m
CDCl3): d 8.25 (s, 1H), 8.15–8.13 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H),
7.56–7.52 (m, 1H), 5.28–5.25 (m, 1H), 3.71 (br s, 1H), 2.91–2.89
(m, 2H), 2.24 (s, 3H). MS (EI): m/z (%) 191.55 (M+-18, 100),
150.29 (77), 118.82 (28), 104.83 (74), 90.85 (39), 76.92 (89),
57.75 (66). Enantiomeric excess 74% determined by HPLC [Column:
Yield: 46%; colourless liquid; ½a D36
¼ þ19:5 (c 0.50, CHCl3); IR
ꢁ
(KBr):
m 3236, 3028, 2895, 1632, 1238, 1165, 1030, 972, 758,
698 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d 9.14 (br s, 1H), 7.80–7.75
(m, 2H), 7.71–7.64 (m, 6H), 7.50–7.46 (m, 4H), 7.41–7.37 (m,
2H), 7.32–7.19 (m, 6H), 6.75 (d, J = 8.4 Hz, 1H), 6.68–6.65 (t,
J = 7.6 Hz, 1H), 4.67–4.60 (m, 3H), 4.34–4.30 (t, J = 8.4 Hz, 1H),
4.09–4.05 (t, J = 8.0 Hz, 1H), 3.14–3.09 (dd, J = 6.0 and 13.6 Hz,
1H), 2.81–2.76 (dd, J = 8.0 and 13.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 164.38, 149.11, 142.12, 141.16, 140.69, 138.24, 132.60,
129.92, 129.22, 128.81, 128.45, 127.47, 127.34, 126.43, 124.94,
124.82, 114.84, 110.93, 108.79, 70.10, 68.13, 47.23, 42.27. MS
(EI): m/z (%) 494.74 (41), 493.66 (49), 492.53 (53), 403.43 (17),
402.33 (37), 360.11 (100), 358.73 (38), 346.82 (23), 344.91 (19),
Lux 5
l Amylose-2; solvent system: hexane/iso-propanol (90:10);
flow rate: 1.0 mL/min; kmax = 220 nm; tR = 28.7 min (major, (R)-iso-
mer), tR = 40.4 min (major, (S)-isomer)].
4.23. (R)-4-(4-Chlorophenyl)-4-hydroxybutan-2-one 22
Yield: 47%; ½a 2D6
ꢁ
¼ þ55:2 (c 0.5, CHCl3). [lit.23
½
a 1D8
ꢁ
¼ þ62:7 (c
3425,
.
1H NMR (400 MHz,
0.48, CHCl3), 93% ee]; mp 50 °C (lit.22 47–50 °C). IR (KBr):
m
3000, 2901, 1717, 1600, 1321, 571, 490 cmꢂ1

A. S. Saiyed, A. V. Bedekar / Tetrahedron: Asymmetry 24 (2013) 1035–1041
1041
CDCl3): d 7.35–7.29 (m, 4H), 5.16–5.13 (m, 1H), 3.42 (d, J = 2.8 Hz,
1H), 2.90–2.78 (m, 2H), 2.22 (s, 3H). MS (EI): m/z (%) 200 (8),
197.74 (39), 182.16 (10), 180.21 (14), 164.75 (13), 144.88 (31),
142.20 (15), 140.72 (100), 112.73 (26), 76.86 (57). Enantiomeric
Narmada Fertilizer Corporation (GNFC), Bharuch for the research
grant to support this work. We also thank Professor N.D. Kulkarni
and Professor B.V. Kamath for their keen interest and for providing
facilities.
excess 66% determined by HPLC [Column: Lux 5
l Amylose-2; sol-
vent system: hexane/iso-propanol (90:10); flow rate: 1.0 mL/min;
kmax = 220 nm; tR = 28.5 min (major, (R)-isomer), tR = 31.3 min
(major, (S)-isomer).]
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Bui, T.; Barbas, C. F, III J. Am. Chem. Soc. 2001, 123, 5260.
3. Kim, H. Y.; Oh, K. Org. Lett. 2011, 13, 1306.
4. Rambo, R. S.; Schneider, P. H. Tetrahedron: Asymmetry 2010, 21, 2254.
4.24. (R)-4-(4-Bromophenyl)-4-hydroxybutan-2-one 23
Yield: 49%; ½a 2D7
ꢁ
¼ þ26:6 (c 0.51, CHCl3) [lit.25
½
a 2D0
ꢁ
¼ þ47 (c 0.5,
m 3247, 3067,
CHCl3), 95% ee] Mp 58 °C (lit.24 58–60 °C). IR (KBr):
3027, 2844, 1718, 1605, 1322, 1077, 1051, 1028, 749, 687, 572,
544 cmꢂ1 1H NMR (400 MHz, CDCl3): d 7.50–7.48 (dd, J = 1.6 and
.
6.4 Hz, 2H), 7.27–7.24 (m, 2H), 5.15–5.12 (m, 1H), 3.40 (d,
J = 3.2 Hz, 1H), 2.90–2.78 (m, 2H), 2.22 (s, 3H). MS (EI): m/z (%)
244 (34), 242.04 (33), 226.11 (25), 225.21 (19), 186.98 (73),
185.00 (100), 158.99 (17), 156.96 (31), 76.84 (87). Enantiomeric
excess 84% determined by HPLC [Column: Chiralpak IC; solvent
system: hexane/iso-propanol (90:10); flow rate: 1.0 mL/min;
kmax = 254 nm; tR = 31.4 min (minor, (S)-isomer), tR = 32.4 min
(major, (R)-isomer)].
´
5. (a) Paradowska, J.; Rogozinnska, M.; Mlynarski, J. Tetrahedron Lett. 2009, 50,
1639; (b) Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 12248.
6. (a) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini,
C. J. Org. Chem. 2005, 70, 7418; (b) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller,
S. J. Chem. Rev. 2007, 107, 5759.
7. (a) Dwivedi, N.; Bisht, S. S.; Tripathi, R. P. Carbohydr. Res. 2006, 341, 2737; (b)
Shen, C.; Shen, F.; Xia, H.; Zhang, P.; Chen, X. Tetrahedron: Asymmetry 2011, 22,
708.
4.25. Procedure for the aldol reaction of isatin with acetone
8. (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun.
2004, 1808; (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983; (c) Davies, S. G.; Sheppard, R. L.; Smith, A.
D.; Thomson, J. E. Chem. Commun. 2005, 3802; (d) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84; (e)
Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611; (f) Davies, S. G.;
Russell, A. J.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2007, 5, 3190; (g) Luo, S.; Zhou, P.; Li, J.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 4457;
(h) Nugent, T. C.; Naveed Umar, M.; Bibi, A. Org. Biomol. Chem. 2010, 8, 4085.
9. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org.
Chem. 2008, 1759.
10. Sathapornvajana, S.; Vilaivan, T. Tetrahedron 2007, 63, 10253.
11. Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed. 2010, 49, 9460.
12. (a) Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am. Chem. Soc. 2007,
129, 7258; (b) Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc. 2010, 132,
6286.
Amino oxazoline 9 (20 mol %) and acetone (4 eq) were mixed in
dry THF at 5–8 °C and then stirred for 30 min. To this clear solution,
isatin (1 equiv) was added and stirred at the same temperature for
72 h. The solvent was then evaporated under reduced pressure after
which 20 mL of water was added to the crude mixture and extracted
with ethylacetate (3 ꢀ 20 mL). The combined organic layer was
dried over sodium sulfate and the solvent was evaporated on a ro-
tary evaporator. The crude material was purified by column chroma-
tography using 60–120 mesh silica gel and a mixture of ethylacetate
and petroleum ether as eluent to afford the aldol product.
4.26. (S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one 25
13. (a) Coppola, G. M. Synthesis 1980, 505; (b) Gajare, A. S.; Shaikh, N. S.;
Jnaneshwara, G. K.; Deshpande, V. H.; Ravindranathan, T.; Bedekar, A. V J. Chem.
Soc., Perkin Trans. 1 2000, 999.
14. Chandrasekhar, S.; Ramakrishna Reddy, N.; Shameem Sultana, S.; Narsihmulu
Venkatram Reddy, K. Tetrahedron 2006, 62, 338.
Yield 46%; ½a 3D2
ꢁ
¼ ꢂ21:1 (c 0.03, CH3OH) [lit.11
½
a 1D8
ꢁ
¼ ꢂ20:0 (c
0.03, CH3OH), 61% ee]; mp 166–168 °C (lit.15 169–170 °C). IR
(KBr):
m
3362, 3260, 2358, 1718, 1621, 1472, 1365, 1077,
752 cmꢂ1
.
1H NMR (400 MHz, DMSO): d 10.09 (s, 1H), 7.16 (d,
15. Kinsella, M.; Duggan, P. G.; Lennon, C. M. Tetrahedron: Asymmetry 2011, 22,
1423.
J = 7.2 Hz, 1H), 7.12–7.08 (t, J = 7.6 Hz, 1H), 6.87–6.83 (t,
J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 1.6 Hz, 1H),
3.16 (d, J = 16.4 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 1.99 (s, 3H). MS
(EI): m/z (%) 204.80 (100), 161.47 (80), 147.81 (92), 120.01 (43),
91.74 (19). Enantiomeric excess 62% determined by HPLC [Column:
Chiralcel OD-H; solvent system: hexane/iso-propanol (70:30); flow
rate: 1.0 mL/min; kmax = 254 nm; tR = 14.7 min (minor, (R)-isomer),
tR = 20.9 min (major, (S)-isomer).
16. McManus, H. A.; Guiry, P. J. J. Org. Chem. 2002, 67, 8566.
17. Binda, P. I.; Abbina, S.; Du, G. Synthesis 2011, 2609.
18. Saiyed, A. S.; Joshi, R. S.; Bedekar, A. V. J. Chem. Res. 2011, 408.
19. Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Chem. Commun. 2011, 224.
20. Lei, M.; Shi, L.; Li, G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron
2007, 63, 7892.
21. Tong, S.-T.; Harris, P. W. R.; Barker, D.; Brimble, M. A. Eur. J. Org. Chem. 2008,
164.
22. Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019.
23. Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
J. Am. Chem. Soc. 2003, 125, 5262.
24. Zhou, Y.; Shan, Z. Tetrahedron: Asymmetry 2006, 17, 1671.
25. Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N. J. Org. Chem. 2009, 74,
2541.
Acknowledgments
We are grateful to the University Grants Commission (UGC) for
the Maulana Azad Fellowship to A.S.S. We acknowledge the Gujarat