New pyrrolidine-triazole-based C2 symmetric organocatalysts and their utility in the asymmetric Michael reaction of β-nitrostyrenes and the synthesis of nitrochromenes

Article abstract of DOI:10.1016/j.tetasy.2008.12.007

The synthesis of new C₂ symmetric bis(pyrrolidine-triazole)-based organocatalysts and their utility in the asymmetric Michael reaction of β-nitrostyrenes with very high diastereo- and enantioselectivity in water without any additives is reporte

Full text of DOI:10.1016/j.tetasy.2008.12.007

Tetrahedron: Asymmetry 19 (2008) 2741–2745
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New pyrrolidine-triazole-based C2 symmetric organocatalysts and their utility
in the asymmetric Michael reaction of b-nitrostyrenes and the synthesis
of nitrochromenes
*
Thandavamurthy Karthikeyan, Sethuraman Sankararaman
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new C2 symmetric bis(pyrrolidine-triazole)-based organocatalysts and their utility in the
asymmetric Michael reaction of b-nitrostyrenes with very high diastereo- and enantioselectivity in water
without any additives is reported. The asymmetric synthesis of nitrochromenes is also illustrated.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 November 2008
Accepted 5 December 2008
Available online 12 January 2009
1. Introduction
2. Results and discussion
Asymmetric synthesis using organocatalysts is at the forefront
of organic synthesis; the past decade has witnessed many
contributions in this area.1 The development of new organocata-
lysts and new synthetic methodologies are two major components
Organocatalysts 3a–c were synthesized by the Huisgen 1,3-
dipolar cycloaddition of N-Boc-protected proline azide 2 (derived
from L
-proline)11 to the corresponding alkynes 1a–c followed by
deprotection of the N-Boc group using TFA (Scheme 1).
of research in this area.2 Since the discovery of
L-proline-catalyzed
asymmetric transformations,3 a number of proline-based organo-
catalysts have been developed.4 Among these, pyrrolidine-
tetrazole,5 pyrrolidine-triazole,6 pyrrolidine-thiourea,7 and
pyrrolidine-imidazolium8 conjugates, to name a few, have been
successfully employed as catalysts for various asymmetric trans-
formations. Asymmetric Michael addition and aldol condensation
have been widely used to test the efficacy of new organocatalysts
because of the importance of these two C–C bond-forming reac-
tions in organic synthesis.9 Recent literature reveals the use of
excellent pyrrolidine-triazole conjugate-based organocatalysts
with a pyrrolidine unit as the catalytically active moiety and a tri-
azole unit as the face-shielding group for the above transforma-
tions.6 Pyrrolidine-triazole-based organocatalysts supported on
ionic liquids, polymers or silica gels have also been reported.10
Herein, the synthesis of three pyrrolidine-triazole conjugate cata-
lysts is reported. It is envisaged that the apparent C2 symmetry
in the bis(pyrrolidine-triazole) catalysts 3a–b might be beneficial
for asymmetric transformations. We anticipated that the pyridine
ring in 3a and 3c might provide additional hydrogen bonding sites
and improve the catalytic activity. The catalytic activity and effi-
ciency were tested using the well-known Michael addition of
cyclohexanone to b-nitrostyrene. In addition, the asymmetric syn-
thesis of nitrochromenes is reported using these catalysts.
N3
N
R
X
BOC
2
X
N
R
1) CuI
C
CH
CH
1a
1b
DMSO/H2O
CH
N
C
2)TFA,DCM
1c
H
N
N
N
X
N
R
H
N
N
N
65%
35%
61%
3a
3b
3c
X = N
R =
N
X = CH
H
X = N, R = H
Scheme 1. Synthesis of organocatalysts 3a–c.
Michael addition of cyclohexanone to b-nitrostyrene was used to
screen the catalysts (Scheme 2, Table 1). The reactions were per-
formed either in water or without any solvent under neat conditions.
In all the cases, the syn isomer was obtained as the predominant
product which was identified by spectroscopic and specific rotation
* Corresponding author. Tel.: +91 44 22574210; fax: +91 44 22570545.
E-mail address: sanka@iitm.ac.in (S. Sankararaman).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.007

2742
T. Karthikeyan, S. Sankararaman / Tetrahedron: Asymmetry 19 (2008) 2741–2745
Table 2
O
O
Ph
Michael addition to substituted b-nitrostyrenes catalyzed by 3a
cat
(10 mol%)
NO2
Ph
5 Ar
6 Yield (%)
dr (%)
ee (%)
NO2
rt
5a C6H5
6a 70
6b 53
6c 95
6d 90
6e 74
6f 83
6g 60
6h 66
97:3
95:5
94:6
92:8
94:6
94:6
90:10
86:14
99
94
86
93
93
93
90
80
5b 4-ClC6H4
5c 2-MeOC6H4
5d 2-NO2C6H4
5e 3-MeOC6H4
5f 4-MeC6H4
5g 3-NO2C6H4
5h 2-Furanyl
4
5a
6a
Scheme 2. Michael addition of cyclohexanone to nitrostyrene.
Table 1
Screening of catalysts 3a–c using the reaction in Scheme 2
Entry
Catalyst
Solvent
Duration
Yield (%)a
dr (%)b
ee (%)c
1
2
3
4
5
3a
3a
H2O
Neat
H2O
H2O
H2O
16 h
16 h
4.5 d
16 h
65 h
70
100
42
80
71
97:3
96:4
96:4
92:8
95:5
99
91
85
88
83
pentanone 7 to 5a proceeded smoothly in toluene to yield the
corresponding Michael adduct, namely 2-(2-nitro-1-phenyl-
ethyl)cyclopentanone 8. However, only moderate diastereoselec-
tivity (75:25) and poor enantioselectivity (50% ee) were
observed. Our observations with cyclopentanone are in accordance
with previous reports.6,10
3ad
3b
3c
a
Reactions with 5a (0.67 mmol), 4 (3.3 mmol) in 1.5 mL water, isolated yield
after column purification, for entries 2 and 4 5a (0.33 mmol), 4 (1.6 mmol).
Determined by peak integration in the 1H NMR spectrum of the crude product.
Determined by chiral HPLC analysis.
With only 1 equiv of 4 and 5a (1.3 mmol).
b
Having succeeded in the Michael reaction of b-nitrostyrenes, our
attentionwasnextfocusedontheevaluationof thecatalysts3a–cfor
the asymmetric synthesis of nitrochromenes. Although the synthe-
sis of nitrochromene by the reaction of salicylaldehyde with b-nitro-
styrene is well documented,13 asymmetric version of the reaction
has not been reported so far.13c Formation of nitrochromene can be
explained by the Michael addition of phenolic hydroxyl to b-nitro-
styrene followed by an intramolecular Henry reaction and dehydra-
tion. Among the three catalysts 3a–c, 3a performed better than the
others. Enantioselectivitywas betterinDMFthanin tolueneorwater
as solvent for this reaction. Nevertheless, in all cases, only moderate
yield and poor enantioselectivity were observed (Scheme 4, Table 3).
The absolute stereochemistries of the major product formed are as-
signed on the basis of chiral HPLC retention times in comparison
with the literature data.13c
c
d
data in comparison with the literature.6b,8a,10,12 Catalyst 3c with a
single active site gave good diastereoselectivities and moderate
enantioselectivities. However, compared to 3a, the rate of the reac-
tion with 3c was much slower (Table 1, entries 1 and 5). Although
the yield was better with 3b than with 3c (Table 1, entries 4 and
5), the enantioselectivity was poorer with 3b than with 3a (Table
1, entries 1 and 4). Catalyst 3a gave excellent diastereo- and enanti-
oselectivities in water as well as under neat conditions. Although the
reaction was slower with only one equivalent of 4 (Table 1, entry 3),
it proceeded to completion without any additives. Therefore catalyst
3a was chosen for further studies, and reactions were carried out in
water. It is noteworthy that this is the highest enantioselectivity ob-
tained so far for this Michael reaction using any pyrrolidine-triazole-
based organocatalyst. Furthermore, unlike earlier reports6,10 on this
Michael reaction using pyrrolidine-based catalysts which required
additives such as TFA, PEG or CSA, with catalysts 3a–c, the reactions
proceeded smoothly without any additives. The reactions also pro-
ceeded with only 5 equiv of 4, whereas in all the earlier reports, 4
had been used in a large excess (>20 equiv or so as solvent).6,10 In
all these reactions, the diastereoselectivity was determined from
the peak integration in the 1H NMR spectrum of the crude product
and the enantioselectivity was determined by chiral HPLC analysis.
In order to establish substrate scope, Michael reaction was per-
formed with several substituted b-nitrostyrenes in water at rt
(Scheme 3, Table 2).
Scheme 4. Asymmetric synthesis of nitrochromenes.
Table 3
Asymmetric synthesis of nitrochromenes
9a/9b
Catalyst
Solvent
10 Yield (%)
ee (%)
9aa
9a
9a
9a
9a
9b
3a
3a
3a
3b
3c
3a
Toluene
DMF
H2O
DMF
DMF
DMF
10a 40
10a 30
10a 22
10a 23
10a 27
10b 22
15
24
19
12
11
7
O
O
Ar
cat 3a
(10 mol%)
a
NO2
With 1.0 equiv of triethylamine added.
Ar
NO2
5a-h
H2O, rt
Reduction of 6a using Pd/C in ethyl acetate yielded the corre-
sponding nitrone 11 in 38% with retention of enantiomeric purity
(Scheme 5).
4
6a-h
Scheme 3. Michael addition of cyclohexanone to substituted b-nitrostyrenes
catalyzed by 3a.
The Michael addition of cyclohexanone to various substituted b-
nitrostyrenes 5a–h catalyzed by 3a proceeded smoothly and
yielded the corresponding Michael adducts 6a–h in good to excel-
lent yields. The diastereoselectivity was excellent in all the cases in
favor of the syn isomer. The enantioselectivity was also excellent,
and in case of 6a recrystallization of the crude product yielded
enantiomerically pure Michael adduct. Michael addition of cyclo-
Scheme 5. Reduction of Michael adduct to nitrone.

T. Karthikeyan, S. Sankararaman / Tetrahedron: Asymmetry 19 (2008) 2741–2745
2743
(t, J = 6.8 Hz, 4H), 3.55–3.59 (m, 2H), 4.17–4.22 (dd, J = 8.0,
13.4 Hz, 2H), 4.37–4.42 (dd, J = 4.4, 13.6 Hz, 2H), 7.77 (t, J = 8 Hz,
1H), 7.98 (d, J = 7.6 Hz, 2H), 8.29 (s, 2H), 13C NMR (100 MHz, CDCl3)
d 25.4, 29.1, 46.5, 55.5, 58.0, 119.0, 123.1, 137.6, 148.1, 150.1,
HRMS-ESI calcd for C19H26N9 380.2311; found 380.2311.
3. Conclusion
In conclusion, we have described the synthesis of new bis(pyr-
rolidine-triazole)-based organocatalysts 3a–c and their utility in
the asymmetric Michael reaction of b-nitrostyrenes. Organocata-
lyst 3a can able to mediate the Michael reaction without any addi-
tives and only with 5 equiv of cyclohexanone. The asymmetric
synthesis of nitrochromenes from salicylaldehyde and b-nitrosty-
rene is also reported, albeit in poor enantioselectivities.
4.3. Synthesis of 1,3-bis(1-((S)-pyrrolidin-2-ylmethyl)-1H-1,2,3-
triazol-4-yl)benzene 3b
Compound 1b (400 mg, 3.17 mmol) and 2 (1.43 g, 6.3mm) gave
N-Boc-protected 3b as a foamy white solid after column chroma-
tography over silica gel using ethyl acetate–hexane mixture (2:3
v/v) in 50% yield (920 mg, 1.6 mmol). mp 97–99 °C, 1H NMR
(400 MHz, CDCl3) d 1.51 (s, 18H), 1.78–2.04 (br, 8H), 3.18–3.42
(br m, 4H), 4.17 (s, 2H), 4.48–4.66 (br m, 4H), 7.49 (t, J = 8 Hz,
1H), 7.79–7.86 (br, 4H), 8.27 (s, 1H), HRMS-ESI calcd for
C30H42N8O4Na (M+Na+) 601.3227; found 601.3221. N-Boc-pro-
tected 3b (0.45 g, 0.77 mmol) was treated with TFA to yield 3b as
4. Experimental
4.1. General
All reactions were carried out in oven-dried glasswares. Com-
mercial reagents were used without purification. The reactions
were monitored by TLC using silica gel plates (Silica gel 60 F254
,
Merck) and visualized either with UV light or with phosphomolyb-
dic acid stain followed by heating. Column chromatography was
carried out with Acme Silica Gel (100–200 mesh). NMR spectra
were recorded in CDCl3 using TMS as internal standard at
400 MHz for 1H and 100 MHz for 13C using Bruker AV400 spec-
trometer. IR spectra were recorded on Thermo Nicolet 6700 FT-IR
in ATR mode. Mass spectrum was recorded either with Micromass
a
½
pale yellow semi solid (206 mg, 0.544 mmol, 70%),
¼ þ16:6 (c 1.0, CHCl3), IR (neat) 3317, 3127, 2954, 2868,
a 3D4
ꢀ
2359, 1616, 1449, 1223, 1085, 1047 cmꢁ1 1H NMR (400 MHz,
,
CDCl3) d 1.48–1.55 (m, 2H), 1.72–1.81 (m, 4H), 1.93–2.0 (m, 2H),
2.08 (br s, 2H), 2.94–2.97 (t, J = 6.8 Hz, 4H), 3.63–3.66 (m, 2H),
4.21–4.27 (dd, J = 8.0, 13.6 Hz, 2H), 4.43–4.48 (dd, J = 4.4, 13.6 Hz,
2H), 7.47 (t, J = 8Hz, 1H), 7.81–7.82 (d, J = 1.6 Hz, 1H), 7.831–
7.835 (d, J = 1.6 Hz, 1H), 8.04 (s, 2H), 8.27 (m, 1H), 13C NMR
(100 MHz, CDCl3) d 25.5, 29.1, 46.6, 55.4, 58.03, 121.04, 122.8,
125.2, 129.4, 131.2, 147.1; HRMS-ESI calcd for C20H27N8
379.2359; found 379.2351.
TM
Q-TOF Micro spectrometer or with Jeol GC mate spectrometer.
Enantiomeric excesses were determined with Waters HPLC con-
nected to a Waters 515 pump and Waters 2487 UV detector. Opti-
cal rotations were measured in AutopolÒ IV polarimeter supplied
by Rudolph research analytical. Melting point was determined by
melting point apparatus supplied by Cintex industrial corporation,
Mumbai. The N-BOC-protected proline azide 2 was prepared by lit-
erature procedure.11 2-Ethynlpyridine 1c was obtained from Al-
drich. 1,6-Diethynylpyridine 1a and 1,3-diethynyl benzene 1b
were prepared by literature procedures.14 b-Nitrostyrenes were
prepared by literature procedure.15 All Michael reactions were per-
formed in air in closed vessels. All Michael adducts are known
compounds.
4.4. (S)-2-(1-(Pyrolidine-2-ylmethyl)-1H-1,2,3-triazol-4-
yl)pyridine 3c
Compound 1c (500 mg, 4.8 mmol) was treated with 2 (1.097 g,
4.8 mmol) and CuI (92 mg, 0.48 mmol) to afford N-Boc-protected
3c (1.2g, 75%). 3c (0.55 g, 1.74 mmol) was treated with TFA to yield
3c as
¼ þ13:2 (c 1.0, CHCl3), IR (neat) 3330, 2958,2871, 1600,
1467, 1420,1233, 1085 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.51–
a yellow oil (315 mg, 1.37 mm, 82%). Compound 3c
½ ꢀ
a 3D4
4.2. Synthesis of 2,6-bis(1-((S)-pyrrolidin-2-ylmethyl)-1H-1,2,3-
;
triazol-4-yl)pyridine 3a
1.54 (m, 1H), 1.72–1.84 (m, 2H), 1.91–2.0 (m, 1H), 2.17 (br s,
1H), 2.9–2.98 (m, 2H), 3.61–3.68 (m, 1H), 4.25–4.31 (dd, J = 13.6,
7.6 Hz,1H), 4.42–4.47 (dd, J = 13.6, 4.8 Hz, 1H), 7.2–7.23 (m, 1H),
7.74–7.79 (dt, J = 7.6, 1.6 Hz, 1H), 8.15–8.17 (d, J = 8 Hz, 1H), 8.29
(s, 1H), 8.56–8.58 (m, 1H); 13C NMR (100 MHz, CDCl3) d 25.5,
29.2, 46.6, 55.6, 58.0, 120.3, 122.8, 122.9, 136.9, 148.2, 149.4,
150.5; HRMS-ESI calcd for C12H16N5 230.1406; found 230.1408.
Compound 1a (300 mg, 2.36 mmol) was treated with 2 (1.1 g,
4.7 mmol) in degassed DMSO:H2O (30 mL, 9:1 v/v) containing
CuI (90 mg, 0.47 mmol) at rt. The reaction mixture was stirred
for 12 h. The entire reaction mixture was solidified at the end of
the reaction. The solid mass was diluted with water (100 mL)
and filtered to give the product. The product was dissolved in
CH2Cl2 (40 mL), washed with brine solution (20 mL), and dried
over sodium sulfate. Evaporation of the solvent gave N-Boc-pro-
tected 3a (1.1 g, 1.9 mmol) as a pale yellow solid in 78% yield,
4.5. Representative procedure for the asymmetric Michael
reaction
mp 150–153 °C, ½a D34
ꢀ
¼ þ32:3 (c 1, CHCl3), 1H NMR (400 MHz,
Compounds 3a (25 mg, 0.067 mmol) and 5a (100 mg,
0.67 mmol) were taken in a test tube, and 1.5 mL of water was
added. The mixture was stirred, and then 4 (0.36 mL, 3.3 mmol)
was added through a syringe at rt. The reaction was monitored
by TLC for complete consumption of 5a (16 h). The crude was ex-
tracted with ethyl acetate (15 mL), and the extract was filtered
through a small pad of silica to remove 3a. Removal of the solvent
from the filtrate yielded the crude product. The 1H NMR spectrum
of the crude product was recorded and diastereomeric ratio was
estimated from the peak integration. The crude product was puri-
fied by column chromatography on silica gel using a mixture of
hexane and ethyl acetate as eluant to afford 6a as a colorless solid
(116 mg, 0.469 mmol, 70%). The enantiomeric ratio was obtained
from chiral HPLC analysis of the purified product on Chiralpak
AD-H or AS-H column using a mixture of hexane and 2-propanol
as the eluant, as described in the individual cases. The Michael ad-
CDCl3) d 1.43 (s, 18 H), 1.71–1.95 (m, 8H), 3.13–3.35 (m, 4H),
4.1–4.58 (m, 6H), 7.7–8.1 (m, 3H), HRMS calcd for C29H42N9 O4
580.3360, found 580.3366.
To the N-Boc-protected 3a (1.25 g, 2.1 mmol) in CH2Cl2 (20 mL)
was added TFA (2.4 mL, 31.5 mmol) at 0 °C, and the mixture was
allowed to stir at rt for 9 h. The reaction mixture was added to
water (75 mL) and the CH2Cl2 layer was separated. The aqueous
layer was washed sequentially with hexane and ether (20 mL
each). The aqueous layer was basified with aq. ammonia and ex-
tracted with CH2Cl2 (50 mL). The extract was dried over sodium
sulfate, and the solvent was evaporated to give 3a as a pale yellow
solid in 83% yield (703 mg, 1.85 mmol), mp 192–195 °C,
½
a 3D4
ꢀ
¼ ꢁ18:3 (c 1.08, CHCl3), IR (CH2Cl2) 3323, 3141, 2957, 2872,
1607, 1574, 1432 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.44–1.47
(m, 2 H), 1.66–1.76 (m, 4H), 1.85–1.92 (m, 2H), 2.27 (s, 2H), 2.89
,

2744
T. Karthikeyan, S. Sankararaman / Tetrahedron: Asymmetry 19 (2008) 2741–2745
ducts were thoroughly characterized by NMR, MS, and HRMS data
and by comparison with the literature-reported spectroscopic
data.6,9,10
CDCl3) d 1.23–1.3(m, 1H), 1.52–1.81(m, 4H), 2.05–2.11(m, 1H),
2.34–2.5 (m, 2H), 2.63–2.67 (m, 1H), 3.70–3.75 (m, 1H), 3.79
(s, 3H), 4.58–4.64 (dd, J = 10, 12.4 Hz, 1H), 4.90–4.94
(dd, J = 4.4, 12.8 Hz, 1H), 6.71–6.81 (m, 3H), 7.21–7.25 (t,
J = 7.6 Hz, 1H), 13C NMR (100 MHz, CDCl3) d 25.1, 28.6, 33.3,
42.8, 44.1, 52.6, 55.3, 78.9, 112.8, 114.6, 120.4, 130.09, 139.5,
160.05, 211.9; HRMS-ESI calcd for C15H19NO4Na (M+Na+).
300.1212; found 300.1215, HPLC: Chiralpak AS-H, hexane/2-pro-
panol = 90/10, 1 mL/min, Rt = 13.8 (minor) and 31.1 (major), 93%
ee. syn/anti = 94/6.
4.6. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 6a12
Colourless solid, mp 128–130 °C, ½a D34
ꢀ
¼ ꢁ27:5 (c 1.2, CHCl3); IR
1H NMR
3024, 2955, 2865, 1698, 1549, 1444, 1382 cmꢁ1
;
(400 MHz, CDCl3): d 1.22–1.25 (m, 1H), 1.54–1.76 (m, 4H), 2.05
(m, 1H), 2.37–2.45 (m, 2H), 2.68–2.69 (m, 1H), 3.74–3.76 (m,
1H), 4.60–4.66 (dd, J = 10.4, 12.4 Hz, 1H), 4.91–4.95 (dd, J = 4.4
and 12.4 Hz, 1H), 7.15–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 25.1, 28.6, 33.3, 42.8, 44.1, 52.7, 79.03, 127.9, 128.3, 129.07,
137.9, 211.9; HRMS-ESI calcd for C14H17NO3Na (M+Na+)
270.1106; found 270.1101, HPLC: Chiralpak AS-H, hexane/2-pro-
panol = 80/20, 0.5 mL/min, Rt = 16.6 (minor) and 22.3 (major),
99.0% ee. syn/anti = 97/3.
4.11. (S)-2-((R)-2-Nitro-1-p-tolylethyl)cyclohexanone 6f8a
Colorless solid, mp 128–129 °C, IR: 2934, 2862, 1705, 1549,
1437, 1377 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.21–1.24 (m, 1H),
,
1.53–1.8 (m, 4H), 2.02–2.11 (m, 1H), 2.3 (s, 3H), 2.33–2.49 (m,
2H), 2.63–2.69 (m, 1H), 3.68–3.74 (dt, J = 10, 4.4 Hz, 1H), 4.57–
4.63 (dd, J = 9.6 and 12.0 Hz, 1H), 4.89–4.93 (dd, J = 4.8, 12.4 Hz,
1H), 7.03 and 7.11 (AA’BB’, J = 8.0 Hz, 4H); 13C NMR (100 MHz,
CDCl3) d 21.1, 25.1, 28.6, 33.3, 42.8, 43.7, 52.7, 79.1, 128.1, 129.7,
134.7, 137.5, 212.1; HRMS-ESI calcd for C15H19NO3Na (M+Na+)
284.1263; found 284.1269; HPLC: Chiralpak AS-H, hexane/2-pro-
panol = 95/5, 1 mL/min, Rt = 11.3 (minor) and 18.5 (major), 93%
ee. syn/anti = 94/6.
4.7. (S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone
6b6b
Colorless solid, 1H NMR (400 MHz, CDCl3) d 1.18–1.27 (m, 1H),
1.5–1.8 (m, 4H), 2.07–2.1 (m, 1H), 2.2–2.48 (m, 2H), 2.61–2.68
(m, 1H), 3.73–3.79 (m, 1H), 4.57–4.63 (m, 1H), 4.9–4.94 (m, 1H),
7.10–7.12 (m, 2H), 7.26–7.3 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 25.2, 28.5, 33.2, 42.8, 43.5, 52.6, 78.7, 129.3, 129.7, 133.8,
136.5, 211.5; HRMS-ESI calcd for C14H16NO3Cl Na (M+Na+)
304.0716; found 304.0711, HPLC: Chiralpak AD-H, hexane/2-pro-
panol = 90/10, 0.5 mL/min, Rt = 21.7 (minor) and 36.3 (major),
94.0% ee. syn/anti = 95/5.
4.12. (S)-2-((R)-2-Nitro-1-(3-nitrophenyl)ethyl) cyclohexanone
6g12
Pale yellow oil, IR: 2941, 2864, 2361, 1706, 1538, 1349 cmꢁ1, 1H
NMR (400 MHz, CDCl3) d 1.26–1.30 (m, 1H), 1.59–1.85 (m, 4H),
2.04–2.17 (m, 1H), 2.27–2.47 (m, 2H), 2.71–2.79 (m, 1H), 3.91–
3.97 (dt, J = 9.6 and 4.4 Hz, 1H), 4.68–4.74 (dd, J = 10.2, 13 Hz,
1H), 4.98–5.02 (dd, J = 12.96, 4.48 Hz, 1H), 7.5–7.58 (m, 2H), 8.08
(t, J = 2 Hz, 1H), 8.13–8.16 (m, 1H); 13C NMR (100 MHz, CDCl3) d
25.2, 28.4, 33.3, 42.8, 43.8, 52.4, 78.2, 123.06, 130.09, 134.9,
140.3, 148.7, 210.9; HRMS-ESI calcd for C14H16N2O5Na (M+Na+)
315.0957; found 315.0953, HPLC: Chiralpak AD-H, hexane/2-pro-
panol = 90/10, 1 mL/min, Rt = 18.9 (minor) and 23.0 (major), 90%
ee. syn/anti = 90/10.
4.8. (S)-2-((R)-1-(2-Methoxyphenyl)-2-nitroethyl)
cyclohexanone 6c8a
Colorless oil, IR (neat) 2938, 2859, 1703, 1593, 1546, 1492,
1436, 1376, 1241 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.18–1.21
;
(m, 1H), 1.58–1.75 (m, 4H), 2.03–2.09 (m, 1H), 2.33–2.49 (m,
2H), 2.97 (m, 1H), 3.83 (s, 3H), 3.92–3.98 (m, 1H), 4.78–4.87 (m,
2H), 6.86–6.91 (m, 2H), 7.07–7.09 (m, 1H), 7.18–7.27 (m, 1H);
13C NMR (100 MHz, CDCl3): d 25.2, 28.6, 33.3, 41.3, 42.7, 50.7,
55.4, 77.6, 111.1, 120.9, 125.5, 129.0, 131.06, 157.7, 212.5;
HRMS-ESI calcd for C15H19NO4 Na (M+Na+) 300.1212; found
300.1216, HPLC: Chiralpak AS-H, hexane/2-propanol = 90/10,
0.5 mL/min, Rt = 21.5 (minor) and 25.3 (major), 86.0% ee. syn/
anti = 94/6.
4.13. (S)-2-((S)-1-(Furan-2-yl)-2-nitroethyl) cyclohexanone 6h12
Pale yellow oil, IR: 2940, 2864, 1706, 1551, 1376 cmꢁ1, 1H NMR
(400 MHz, CDCl3) d 1.27–1.3 (m,1H), 1.61–1.83 (m, 4H), 2.08–2.09
(m, 1H), 2.35–2.43 (m, 2H), 2.71–2.82 (m, 1H), 3.94–4.0 (m, 1H),
4.64–4.69 (dd, J = 12.2, 9.3 Hz, 1H), 4.76–4.8 (dd, J = 12.68,
4.88 Hz, 1H), 6.17 (m, 1H), 6.28 (m, 1H), 7.3 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 25.1, 28.2, 32.5, 37.6, 42.6, 51.2, 75.2, 109.01,
110.4, 142.3, 151.09, 210.95; HRMS-ESI calcd for C12H15NO4Na
(M+Na+) 260.0899; found 260.0899, HPLC: Chiralpak AD-H, hex-
ane/2-propanol = 95/5, 0.5 mL/min, Rt = 26.8 (major) and 33.6
(minor), 80% ee. syn /anti = 86/14.
4.9. (S)-2-((R)-2-Nitro-1-(2-nitrophenyl)ethyl) cyclohexanone
6d8a
Yellow oil, IR (neat) 2943, 2865, 1705, 1524, 1437, 1352 cmꢁ1
,
1H NMR (400 MHz, CDCl3) d 1.44–1.53 (m, 1H), 1.58–1.74 (m,
2H), 1.78–1.85 (m, 2H), 2.1–2.14 (m, 1H), 2.35–2.49 (m, 2H),
2.89–2.96 (m, 1H), 4.36–4.39 (dt, J = 8.8, 4.4 Hz, 1H), 4.85–
4.96(m, 2H), 7.41–7.48 (m, 2H), 7.56–7.62 (t, J = 7.6 Hz, 1H), 7.82
(d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 25.4, 28.4, 33.3,
38.8, 42.9, 52.3, 77.7, 125.06, 128.7, 129.4, 132.9, 133.2, 150.9,
211.1; HRMS-ESI calcd for C14H16N2O5Na (M+Na+) 315.0957; found
315.0958, HPLC: Chiralpak AD-H, hexane/2-propanol = 90/10,
1 mL/min, Rt = 20.86 (minor) and 34.5 (major), 93% ee. syn/
anti = 92/8.
4.14. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclo-pentanone 812
Colorless solid, mp 101 °C, IR: 2967, 2360, 1731, 1595, 1550,
1377 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.49–1.55 (m, 1H) 1.6–
,
1.75 (m, 2H), 1.85–1.95 (m, 2H), 2.10–2.19 (m, 1H), 2.33–2.42
(m, 2H), 3.66–3.72 (dt, J = 9.2, 5.6 Hz, 1H), 4.68–4.74 (dd,
J = 12.8, 9.6 Hz, 1H), 5.30–5.34 (dd, J = 12.8, 5.6 Hz, 1H), 7.12–
7.19(m, 2H), 7.24–7.33 (m, 3H), 13C NMR (100 MHz, CDCl3): d
20.3, 28.4, 38.7, 44.3, 50.6, 78.4, 128.0, 128.1, 129.02, 137.8,
218.5; HRMS calcd for C13H15NO3Na (M + Na+) 256.0950; found
256.0957, HPLC: Chiralpak AS-H, hexane/2-propanol = 80/20,
0.5 mL/min, Rt = 20.1 (minor) and 29.6 (major), 50% ee (syn) syn/
anti = 75/25.
4.10. (S)-2-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)
cyclohexanone 6e8a
Colorless solid, mp 133–134 °C, IR 2940, 1699, 1603, 1583,
1549, 1488, 1448, 1433, 1382, 1291 cmꢁ1 1H NMR(400 MHz,
,

T. Karthikeyan, S. Sankararaman / Tetrahedron: Asymmetry 19 (2008) 2741–2745
2745
4.15. (3R,3aS)-3-Phenyl-3,3a,4,5,6,7-hexahydro-2H-indole 1-
oxide 117
References
1. For reviews: (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–
4660; (b) List, B. Chem. Commun. 2006, 819–824; (c) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719–724; (d) Lelais, G.; MacMillan, D. W. C. Aldrichim.
Acta 2006, 39, 79–87.
2. For reviews: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–
5175; (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007,
46, 2988–3000; (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495; (d)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543; (e)
Guillena, G.; Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465–1492; (f)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418–5427.
3. (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971.; (b) Eder, U.;
Sauer, G.; Wiechert, R. German Patent DE 2014757, 1971.; (c) Eder, U.; Sauer,
G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496–497; (d) Hajos, Z. G.;
Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
4. (a) List, B. Tetrahedron 2002, 58, 5573–5590; (b) Barbas, C. F., III Angew. Chem.,
Int. Ed. 2008, 47, 42–47; (c) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975–
978.
5. (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun.
2004, 1808–1809; (b) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84–96.
6. (a) Yan, Z.-Y.; Niu, Y.-N.; Wei, H. _l.; Wu, L.-Y.; Zhao, Y.-B.; Liang, Y.-M.
Tetrahedron: Asymmetry 2006, 17, 3288–3293; (b) Luo, S.; Xu, H.; Mi, X.; Li, J.;
Zheng, X.; Cheng, J.-P. J. Org. Chem. 2006, 71, 9244–9247; (c) Chandrasekar, S.;
Tiwari, B.; Parida, B. B.; Reddy, Ch. R. Tetrahedron: Asymmetry 2008, 19, 495–
499.
7. (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451–1453; (b) Cao, Y.-J.; Lai,
Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21–24; (c) Wei,
S.; Yalaov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121, 151–157;
(d) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904.
8. (a) Xu, D. Q.; Luo, S. P.; Wang, Y. F.; Xia, A. B.; Yue, H. D.; Wang, L. P.; Xu, Z. Y.
Chem. Commun. 2007, 4393–4395; (b) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P.
Chem. Commun. 2006, 3687–3689; (c) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093–3097.
9. (a) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123–3135; (b) List, B.;
Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396; (c) List, B.;
Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–2425; (d) Cordova, A.; Zou,
W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383–5397;
(e) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J. 2006, 12,
4321–4332; (f) Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron: Asymmetry 2007,
18, 1443–1447; (g) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–
9625; (h) Vishnumaya; Singh, V. K. Org. Lett. 2007, 9, 1117–1119; Xu, Y.;
Cordova, A. Chem. Commun. 2006, 460–462; (i) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701–1716; (j) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299–365.
Michael adduct 6a (83 mg, 0.336 mmol) was dissolved in ethyl
acetate (5 mL) in a single-necked flask and Pd/C (20 mg) was
added. The flask was evacuated and a balloon filled with hydrogen
was connected to the flask, and the contents of the flask was stirred
at rt for 24 h. The reaction mixture was filtered through Celite and
was concentrated. The crude product was subjected to silica gel
chromatography (MeOH/CH2Cl2 = 1/99 by vol) to isolate the prod-
uct. The product was dissolved in CH2Cl2 and washed with 0.1 M
HCl to obtain pure 11 in 38% yield (11 mg, 0.051 mmol) (based
on recovered starting material, 50 mg, 0.202 mmol), 1H NMR
(400 MHz, CDCl3) d 1.42–1.21 (m, 3H), 1.83 (m, 1H), 2.1–1.97 (m,
3H), 3.25–3.19 (m, 2H), 4.31–4.14 (m, 2H), 7.4–7.23 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 23.7, 23.9, 24.4, 32.5, 46.1, 50.8, 68.4,
127.4, 127.6, 129.1, 140.0, 148.8, IR: 3060, 2934, 2858, 1630,
1447, 1222, 1177 cmꢁ1. Enantiomeric excess was determined by
HPLC using chiralpak AD-H column using 2-propanol/hexane (10/
90 v/v), 0.6 mL/min, Rt = 23.8 (major) and 30.6 (minor).
4.16. (R)-3-Nitro-2-phenyl-2H-chromene 10a13c
General procedure: b-nitrostyrene 5a (25 mg, 0.16 mmol) and
3a (12.7 mg, 0.033 mmol) were dissolved in DMF (1 mL) and al-
lowed to stir at rt. Salicyaldehyde (9a, 0.025 mL, 0.25 mmol) was
then added followed by powdered 4 Å molecular sieves (50 mg).
The reaction was allowed to stir at rt for 24 h. The reaction mixture
was diluted with 30 mL water and the product was extracted with
CH2Cl2 (10 mL ꢂ 2). The CH2Cl2 layer was washed with ice cold
0.1 M NaOH solution, dried over sodium sulfate, filtered, and was
evaporated. The crude product was subjected to silica gel column
chromatography (0.5 mL ethyl acetate:99.5 mL hexane) to give
product 10a as a yellow solid in 30% yield (13 mg, 0.05 mmol).
mp 94 °C, ½a 3D4
ꢀ
¼ 10:4 (c 1, CHCl3), IR (CH2Cl2) 3063, 1647, 1604,
1509, 1455, 1322 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 6.5 (s,1H),
10. For ionic liquid support: (a) Wu, L.-Y.; Yan, Z.-Y.; Xie, Y.-X.; Niu, Y.-N.; Liang,
Y.-M. Tetrahedron: Asymmetry 2007, 18, 2086–2090; (b) Ni, B.; Zhang, Q.;
Headley, A. D. Tetrahedron Lett. 2008, 49, 1249–1252; (c) Yacob, Z.; Shah, J.;
Leistner, J.; Liebscher, J. Synlett 2008, 2342–2344; For polymer support: (d)
Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericas, M. A. Org. Lett. 2007, 9,
3717–3720; (e) Miao, T.; Wang, L. Tetrahedron Lett. 2008, 49, 2173–2176;
For silica gel support: (f) Zhao, Y.-B.; Zhang, L.-W.; Wu, L.-Y.; Zhong, X.;
Li, R.; Ma, J.-T. Tetrahedron: Asymmetry 2008, 19, 1352–1355.
11. (a) Kurokawa, M.; Shindo, T.; Suzuki, M.; Nakajima, N.; Ishihara, K.; Sugai, T.
Tetrahedron: Asymmetry 2003, 14, 1323–1333; (b) Dahlin, N.; Bøgevig, A.;
Adolfsson, H. Adv. Synth. Catal. 2004, 346, 1101–1105.
6.8 (d, J = 8.4 Hz, 1H), 6.9 (t, J = 7.6 Hz, 1H), 7.29–7.38 (m, 7H),
8.04 (s, 1H); 13C NMR (100MHz, CDCl3) d 74.4, 117.4, 118.08,
122.6, 127.1, 128.9, 129.3, 129.6, 130.5, 134.4, 136.9, 153.7; Mass
(EI): 253, 236, 207, 178. HPLC: Chiralpak AS-H, hexane/2-propa-
nol = 98/2, 0.5 mL/min, Rt = 22.1(major) and 34.6 (minor), 24% ee.
4.17. (S)-7-Methoxy-2-methyl-3-nitro-2H-chromene 10b13c
Yellow solid, mp: 135 °C, IR 2937, 2840, 1608, 1557, 1496,
12. Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, K.; Barbas, C. F., III J. Am.
Chem. Soc. 2006, 128, 4966–4967.
1325 cmꢁ1 1H NMR (400 MHz, CDCl3): d 3.7 (s,1H), 6.39 (d,
,
13. (a) Yan, M.-C.; Jang, Y.-J.; Yao, C.-F. Tetrahedron Lett. 2001, 42, 2717–2721; b
Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Green Chem. 2005, 7, 825–827.
During the preparation of this manuscript a report describing organocatalytic
nitrochromene synthesis has been reported.; c D.-Q. Xu, Y.-F. Wang, S.-P. Luo, S.
Zhang, A.-G. Zhong, H. Chen, Z.-Y. Xu, Adv. Synth. Catal. doi:10.1002/
adsc.200800535.
14. (a) Srinivasan, M. Ph.D. Thesis, Indian Institute of Technology, Madras, 2002.;
(b) Shiohara, K. I.; Aoki, T.; Kaneko, T.; Uikawa, E. Polymer 2001, 42, 351–355.
15. Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559–2561.
J = 2.4 Hz, 1H), 6.55 (m, 2H) 7.22 (d, J = 8.4 Hz, 1H), 7.31–7.38 (m,
5H), 8.04 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
55.7, 74.7,
102.4,109.9, 111.3, 127.1, 128.9, 129.5, 129.8, 131.8, 137.2, 155.8,
165.2; mass (ESI): 284 (M+1), 306 (M+Na+), 322 (M+K+), HPLC:
Chiralpak AS-H, hexane/2-propanol = 90/10, 0.5 mL/min, Rt = 25.1
(minor) and 36.5 (major), 7% ee.