Enantioselective Henry reaction catalyzed by C2-symmetric chiral diamine-copper(II) complex

Article abstract of DOI:10.1039/b904254g

A copper(II) complex of C₂-symmetric diamine has been proved to be an efficient catalyst for the enantioselective Henry reaction between nitroalkanes and various aldehydes to provide β-hydroxy nitroalkanes in high yields (up to 97%), moderate diastereoselectivities (up to 71:29) and excellent enantiomeric excesses (up to 96%). The chiral nitroaldol adduct obtained has been further converted into chiral aziridine in few steps.

Full text of DOI:10.1039/b904254g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective Henry reaction catalyzed by C2-symmetric chiral
diamine–copper(II) complex†
Sermadurai Selvakumar,a Dhanasekaran Sivasankarana and Vinod K. Singh*a,b
Received 2nd March 2009, Accepted 13th May 2009
First published as an Advance Article on the web 11th June 2009
DOI: 10.1039/b904254g
A copper(II) complex of C2-symmetric diamine has been proved to be an efficient catalyst for the
enantioselective Henry reaction between nitroalkanes and various aldehydes to provide b-hydroxy
nitroalkanes in high yields (up to 97%), moderate diastereoselectivities (up to 71:29) and excellent
enantiomeric excesses (up to 96%). The chiral nitroaldol adduct obtained has been further converted
into chiral aziridine in few steps.
Introduction
Results and discussion
The Henry1 (nitroaldol) reaction remains one of the most
widely utilized transformations in synthetic organic chemistry.
The enantioselective version of this reaction can provide access
to important enantiomerically enriched b-nitroalkanols, which
are versatile precursors for a wide range of important organic
intermediates.2 The nitro group in the product can be converted
into amines (reduction), carbonyl compounds (Nef reaction),3c
azides (SN2 displacement),2d and other bifunctional compounds.3
However, despite its importance, the asymmetric Henry reaction
was not explored until 1992. Shibasaki et al. reported the first
example of asymmetric addition of nitromethane to aldehyde
using a BINOL derived heterobimetallic complex.4 Since this
pioneering work, the enantioselective Henry reaction has gained
much attention and various types of chiral metal catalyst and
organocatalyst5 have been extensively studied. Copper com-
plexes of chiral ligands such as bis(oxazoline),6 (-)-sparteine,7
bisimidazoline,8 diamine,9 sulfonyldiamine,10 aminopyridine,11
tetrahydrosalen,12a and N,N¢- dioxide12b have been developed for
this reaction. Although a reasonable number of catalysts having
metals other than copper, such as dinuclear zinc,13a zinc triflate-
amino alcohol,13b zinc-bisoxazolidine,13c zinc-fam catalyst,13d
cobalt-ketoimino complexes,14 nano-crystalline MgO,15 and salen-
chromium complex16 have also been developed. Some of these
methods have certain limitations such as high catalyst loading,
the use of activated silylnitronates, low substrate scope, expensive
starting materials, and long synthetic sequences for the ligand
synthesis and the use of additives such as molecular sieves.
Besides these, only a few catalytic systems have been tested for
the diastereoselective Henry reaction. In this paper, we address
some of these issues and delineate full details of our work in this
area.
The design, synthesis, and tuning of a suitable chiral ligand around
a metal center is an important task in asymmetric synthesis.17
As a part of our research programme towards the application of
versatile and fine tunable chiral non-racemic diamines in enantios-
elective reactions,18 we intended to evaluate similar kinds of amino
acid derived diamine ligands (Fig. 1) for the enantioselective Henry
reaction.
Fig. 1 Chiral diamine ligands.
A chiral C2-symmetric diamine 1a is known in the literature
and has been used for enantioselective alkylation of carbonyl
compounds,19a asymmetric benzoylation of 1,2-meso diols,19b and
enantioselective Baylis–Hillman reactions.19c,d At the outset, it
appeared logical to test this diamine in the Henry reaction. It was
synthesized according to the known literature procedure starting
from L-proline.19b In order to optimize the reaction conditions,
a series of reactions were carried out between nitromethane and
benzaldehyde in ethanol with 1a–Cu(OAc)2·H2O complex as the
catalyst. The reaction was complete in 28 h at room temperature
and the nitroaldol adduct was obtained in 74% ee (Table 1, entry 1).
However, on decreasing the reaction temperature from rt to 0 ◦C
and then to -20 ◦C, enantioselectivity increased remarkably with
a decrease in the rate of the reaction (Table 1, entries 2 and 3).
In order to improve the chemical yield of the reaction, without
affecting the enantioselectivity, base promoter7 such as Et3N
were added for the activation of nitromethane. Thus, the catalyst
aDepartment of Chemistry, Indian Institute of Technology, Kanpur, India
208 016. E-mail: vinodks@iitk.ac.in; Fax: +91-512-2597436; Tel: +91-512-
2597291
bIndian Institute of Science Education and Research Bhopal, ITI Campus
(Gas Rahat) Building, Govindpura, India 460 023
† Electronic supplementary information (ESI) available: Experimental
details, characterization data including 1H NMR spectra, 13C NMR
spectra for all compounds, and HPLC chromatograms for nitroaldol
adducts. See DOI: 10.1039/b904254g
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Table 1 Effect of the amount of Et3N on the enantioselective Henry
reactiona
Et3N
(mol%)
entry
temperature (◦C)
time (h)
yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
–
–
–
2
5
10
20
50
100
10
rt
28
62
48
62
72
36
36
24
24
96
86
28
24
32
46
70
98
97
98
75
74
86
90
90
86
88
86
75
65
92
0
-20
-20
-20
-20
-20
-20
-20
-40
10
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane in 2 mL of ethanol. b Determined by chiral HPLC using
Chiralcel OD-H column. The absolute configurations were established by
comparison with literature data.
1a–Cu(II) complex was activated towards the Henry reaction
under dual acid/base catalysis20 conditions. It was gratifying to
note that Et3N increased the rate of the reaction without having a
significant effect on the enantioselectivity. With 2 mol% of Et3N at
◦
-20 C, the reaction took longer and the corresponding product
was obtained in 32% yield and 90% ee (Table 1, entry 4). However,
on increasing the amount of Et3N from 5 mol% to 20 mol%, the
chemical yield of the reaction increased rapidly without affecting
the enantioselectivity (Table 1, entries 5–7). Further increases in
the amount of base resulted in the depletion of enantioselectivity
(Table 1, entries 8 and 9). It was also observed that the use of
10 mol% of Et3N and a reaction temperature of -40 ◦C are
optimum for achieving high enantioselectivity in the reaction
(Table 1, entries 6 and 10).
Scheme 1 Synthesis of chiral diamines.
Having achieved good results in the above reaction with the
ligand 1a, it was logical to evaluate similar kinds of chiral
piperazine derivative having mono- and bicyclic skeletons. With
this aim, a variety of chiral diamines were synthesized. The
generality of the synthesis was demonstrated in the preparation
of these diamines in four steps from commercially available a-
amino acids. The nature of the substituent at the stereocenter is
dictated by the selection of the starting amino acid (Scheme 1). The
coupling reaction of N-Boc amino acids with appropriate amino
esters was carried out in the presence of ethylchloroformate and
N-methylmorpholine. The Boc protecting group was then cleaved
using TFA in CH2Cl2, which on subsequent reflux with Et3N in 2-
butanol:toluene (3:1) afforded diketopiperazine21 derivatives 3a–b
and 7a–g. The diketopiperazines 3a–b and 7a–g obtained in this
way were reduced to diamines 4a–b and 8a–g by using LiAlH4.
N-Methyl ligands 5a–b and 9a–g were synthesized by reductive
amination21a of formaldehyde with the diamines 4a–b or 8a–g in
the presence of formic acid.
phenylalanine-based diamines (4a vs 5a) showed a significant effect
on the enantioselectivity (Table 2, entries 2 and 3). Furthermore,
only a trace amount of product was obtained in low enantioselec-
tivity with diamine 5b having different absolute stereochemistry
(Table 2, entry 4). This clearly indicated that the matched chirality
between the two amino acids is crucial for the high catalytic
efficiency.
In order to study the effect of cyclic structures of diamine
on enantioselectivity, diamines with bicyclic skeletons were then
screened (Table 2, entries 5–12). A similar trend in enantioselec-
tivity (vide supra) was observed after introducing a substituent on
the nitrogen atom (Table 2, entries 2–3 vs 5–6). Next, the effect
of variation in the substituents at the chiral centers of the bicyclic
diamine ligands on the Henry reaction was studied. When the
isobutyl group of the ligand 9a was replaced by methyl, isopropyl,
sec-butyl, benzyl or phenyl, the asymmetric induction in the
reaction was scarcely affected (Table 2, entries 6–11). The absence
of any asymmetric induction with ligand 9g (Table 2, entry 12)
indicated that both the stereogenic centers (S,S) of the diamine
skeleton were essential for the chirality transfer in the catalytic
After successful completion of ligand synthesis, the chiral
piperazines with monocyclic skeletons (Fig. 1) were first examined
in the enantioselective Henry reaction under optimized condi-
tions. Interestingly, the substituents on the nitrogen atoms of
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Table 4 Effect of solvent on the enantioselective Henry reactiona
Table 2 Enantioselective Henry reaction of benzaldehyde with ni-
tromethane in the presence of different ligandsa
entry
solvent
yield (%)
eeb (%)
entry
ligand
time (h)
yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
methanol
ethanol
59
75
83
92
66
39
41
94
24
63
92
89
90
83
83
71
27c
73
1
2
3
4
5
6
7
8
9
1a
4a
5a
5b
8a
9a
9b
9c
9d
9e
9f
96
96
102
120
98
102
96
96
75
22
47
36
21
61
58
63
86
53
79
44
92
40
77
rac
46
89
69
75
83
39
79
rac
n-propanol
2-propanol
n-butanol
THF
acetonitrile
nitromethane
dichloromethane
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane in 2 mL of solvent for 4 d. b Determined by chiral HPLC
using Chiralcel OD-H column. c Reaction was carried out at -20 ◦C.
96
10
11
12
144
102
144
9g
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane and 0.05 mmol of base in 2 mL of ethanol. b Determined
by chiral HPLC using Chiralcel OD-H column.
Table 5 Screening of Lewis acids for the enantioselective Henry reactiona
Table 3 Effect of different bases on the enantioselective Henry reactiona
entry
Lewis acid
yield (%)
eeb (%)
1
2
3
4
5
6
7
Cu(OAc)2·H2O
CuCl2
CuCl
Cu(OTf)2
Zn(OTf)2
Zn(OAc)2·2H2O
Pd(OAc)2
75
98
51
94
17
20
06
92
75
37
entry
base
time (h)
yield (%)
eeb (%)
75
rac
rac
16
1
2
3
4
5
6
7
8
Et3N
Et(iPr)2N
N-methylmorpholine
pyridine
DMAP
1-methyl-1H-imidazole
K2CO3
96
72
72
72
48
96
48
96
72
86
14
14
11
12
34
72
92
82
87
52
17
04
18
59
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of nitro-
methane in 2 mL of ethanol for 4 d. b Determined by chiral HPLC using
Chiralcel OD-H column.
DBU
The effect of solvent on the enantioselectivity in the Henry
reaction catalyzed by diamine 1a was also studied (Table 4).
Among the different solvents screened, protic solvents were found
to be superior to the aprotic ones, and of the different protic
solvents screened, ethanol was the solvent of a choice (Table 4,
entry 2).
A series of Lewis acids were then screened in combination with
1a and Et3N in ethanol (Table 5). Cu(OAc)2·H2O turned out to be
the most suitable Lewis acid for the reaction. CuCl2 and Cu(OTf)2
also facilitated the reaction and afforded the nitroaldol adduct in
excellent yield and moderate enantioselectivity (Table 5, entries 2
and 4). With other metal salts such as Zn(OTf)2, Zn(OAc)2·2H2O
and Pd(OAc)2, reaction was sluggish and the product was almost
racemic (Table 5, entries 5–7).
The scope and limitations of the Henry reaction catalyzed
by 1a–Cu(II) complex were then examined. A wide range of
aldehydes including both aromatic and aliphatic aldehydes reacted
smoothly with nitromethane under the optimized conditions,
to give nitroaldol adduct in good yield and enantioselectivity22
(Table 6). The rate of the reaction with aromatic aldehydes
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane and 0.05 mmol of base in 2 mL of ethanol. b Determined
by chiral HPLC using Chiralcel OD-H column.
Henry reaction (vide supra). From these results (Table 2), it was
concluded that (S)-proline derived diamine 1a with a tricyclic
skeleton is superior in terms of yield and stereoinduction (Table 2,
entry 1) and was thus chosen for further studies.
The drastic effect of Et3N on the rate of the reaction prompted
us to examine the effect of other bases for this reaction. Among
the bases screened, Et3N gave the best result (Table 3, entry 1). The
use of bulky tertiary amines like iPr2NEt and N-methylmorpholine
gave lower enantioselectivity (Table 3, entries 2 and 3). Strong co-
ordinating bases viz pyridine, DMAP and 1-methyl-1H-imidazole
gave the product in poor chemical and optical yield (Table 3,
entries 4–6). An inorganic base, K2CO3, gave poor results (Table 3,
entry 7). Interestingly, the bulkier and more basic DBU gave
the nitroaldol adduct in moderate yield and enantioselectivity
(Table 3, entry 8).
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Table 6 Enantioselective Henry reaction of nitromethane with different
Table 7 Diastereoselective Henry reaction of nitroalkane with different
aldehydesa
aldehydesa
yield syn/ ee
antib (%)csyn/anti
entry
R
time (h)
product
yield (%) eeb (%)
entry
R
R¢ time (h) product (%)
1
2
3
4
5
6d
C6H5
2-MeC6H4
2-OMeC6H4 Me 72
4-ClC6H4
C6H5
Me 96
Me 76
11a
11b
11c
11d
11e
11f
78
70
86
73
64
45
38/62 80/79
29/71 79/66
32/68 86/73
48/52 64/64
40/60 85/82
54/46 90/95
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C6H5
96
78
78
72
88
94
94
116
90
98
94
98
96
106
96
120
144
144
10a
10b
10c
10d
10e
10f
10g
10h
10i
75
91
69
60
97
91
93
94
93
70
77
66
94
88
90
91
42
51
92
87c
78c
90c
89
84
85
87
88
80
87
84
84
87
83
87d
93d
96d
2-NO2C6H4
4-NO2C6H4
4-CF3C6H4
4-FC6H4
3-MeC6H4
4-ClC6H4
4-MeC6H4
2-OMeC6H4
1-naphthyl
2-MeC6H4
2-thienyl
Me 78
Et 144
PhCH2CH2 Me 144
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane and 0.05 mmol of base in 2 mL of ethanol, unless noted
other-wise. b Determined by 1H NMR analysis. c Determined by HPLC
using chiral column. d 10 mol% of catalyst was used at 0 ◦C and in the
absence of base.
10j
10k
10l
2-ClC6H4
10m
10n
10o
10p
10q
10r
3,5-OMeC6H3
3,4,5-OMeC6H2
PhCH2CH2
cyclohexyl
3-pentyl
a Reactions were carried out on a 0.5 mmol scale with 5 mmol of
nitromethane and 0.05 mmol of base in 2 mL of ethanol, unless noted
otherwise. b Deter◦mined by HPLC using chiral column. c Reaction was
carried out at -20 C and in the absence of base. d 10 mol% of catalyst was
used at 0 ◦C and in the absence of base.
containing electron-withdrawing groups (Table 6, entries 2–5) was
faster in comparison to aldehydes having an electron-donating
group (Table 6, entries 6–15). Under these conditions, the rate of
the reaction was much slower for the aliphatic substrates. This was
Scheme 2
Conclusions
◦
overcome by carrying out the reaction at 0 C with 10 mol% of
the catalyst and in the absence of Et3N (Table 6, entries 16–18).
The catalytic activity of the 1a–Cu(II) complex was tested for the
diastereoselective Henry reaction, for which there are not many
reports in the literature.9d,10,11b,13c Under the optimized reaction
conditions, aromatic aldehydes reacted with nitroethane to give
nitroaldol product in moderate diastereoselectivity (up to 71: 29,
anti/syn) and the anti product was formed predominantly, with
an ee of 79% (Table 7, entry 1). On the other hand, reaction
of nitroethane with aliphatic aldehyde afforded the syn isomer
predominantly, with lower diastereoselectivity (54:46, syn/anti)
and higher ee than the reaction of aromatic aldehydes (Table 7,
entry 6).
In conclusion, the chiral Cu(II)–1a complex prepared from
Cu(OAc)2·H2O and the C2-symmetric diamine ligand 1a was
found to be an effective catalyst for the enantioselective Henry
reaction between nitroalkanes and aldehydes. The procedure is
operationally very simple and can provide a variety of b-hydroxy
nitroalkanes in good to excellent yields with excellent enantiose-
lectivities (up to 96% ee). In addition, the chiral nitroaldol adduct
has been derivatized to synthetically useful chiral aziridine in few
steps.
Experimental section
With the nitroaldol adduct 10a in hand, we found that it
could be further elaborated into chiral amino alcohol (S)-1223
through catalytic hydrogenation using 10% Pd/C in good yield
(Scheme 2). The chiral amino alcohol thus obtained was then
cyclised via sulfonylation followed by Mitsunobu reaction24 with
DIAD and PPh3 readily furnished the corresponding aziridine
(R)-13 without loss of optical purity.25 These aziridines constitute
the key structural feature of several N-containing natural products
and also serve in synthesis as chiral building blocks, auxiliaries,
and ligands.26 The chiral amino alcohol (S)-12 is also a key
intermediate in the synthesis of Levamisol (9S), an anthelmintic
agent.27
General Methods
1H and 13C NMR spectra were recorded on JEOL JNM-LA 400
and Jeol ECX 500 spectrometer. Chemical shifts are expressed
in ppm downfield from TMS as internal standard, and coupling
constants are reported in Hz. Mass spectrometric analyses were
done on Waters Q Tof Premier Micromass (ESI) spectrometer.
Routine monitoring of reactions was performed by TLC, using
0.2 mm Kieselgel 60 F254 precoated aluminium sheets, commer-
cially available from Merck. Visualization was done by fluores-
cence quenching at 254 nm, exposure to iodine vapor, and/or 2,4-
dinitrophenylhydrazine solution. All the column chromatographic
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separations were done by using silica gel (Acme’s, 60–120 mesh).
HPLC was done on a Daicel chiral column having 0.46 cm internal
diameter ¥ 25 cm length. Petroleum ether used was of boiling
range 60–80 ◦C. Reactions that needed anhydrous conditions
were run under an atmosphere of nitrogen or argon using flame-
dried glassware. The organic extracts were dried over anhydrous
sodium sulfate. Evaporation of solvents was performed at reduced
pressure. CH2Cl2, CHCl3 and triethylamine (Et3N) were distilled
from CaH2.
stirred for 10 min. The reaction mixture was warmed slowly to
room temperature and refluxed for 6–24 h. Reaction mixture was
then cooled slowly to 0 C and excess of LAH was destroyed by
the addition of few drops of EtOAc. Water (200 mL) was added,
followed by the same amount of 4N NaOH. After 5 min, 600 mL
of water was again added and the mixture stirred for 15 min. The
white precipitate formed was filtered off, the filtrate was dried,
and solvent was evaporated. The crude product was purified by
column chromatography using neutral alumina.
◦
(3S,8aS)-3-Isobutyloctahydropyrrolo[1,2-a]pyrazine
(8a).
Yield 74%; Colorless liquid; [a]D +12.8 (c 1.0, CHCl3); IR
max/cm-1 (film) 3286, 2953; 1H NMR (400 MHz, CDCl3): d 0.90
(m, 6H), 1.28 (m, 1H), 1.47 (m, 1H), 1.62–1.83 (m, 5H), 2.02 (m,
1H), 2.2–2.33 (m, 2H), 2.64–2.77 (m, 2H), 2.91–2.97 (m, 3H); 13
General procedure for the coupling of N-Boc amino acid with
amino esters
25
n
A solution of (S)-N-Boc amino acid (10 mmol) and N-
C
methylmorpholine (12 mmol) in CH2Cl2 (30 mL) was treated with
◦
NMR (125 MHz, CDCl3): d 20.7, 22.2, 23.1, 24.9, 26.7, 41.0, 45.6,
50.4, 54.6, 57.0, 63.2; HRMS (ES+) calc. for C11H22N2 183.1861,
[M + H]+ found 183. 1861.
ethyl chloroformate (12 mmol) at 0 C for 10 min. Amino ester
(12 mmol) was then added dropwise at the same temperature and
the mixture was stirred for 16 h (0 ◦C to rt). After completion
of the reaction (monitored by TLC), the reaction mixture was
diluted with CH2Cl2 (20 mL) and washed with water and brine.
The organic layer was dried, and the solvent was evaporated in
vacuo. Purification by column chromatography over silica gel gave
pure coupled product 2 or 6.
General procedure for the reductive amination of piperazines
To a solution of amine 4 or 8 (2.5 mmol) in water (2.5 mL)
was added formaldehyde (8.5 mmol, 39% in w/v) and formic
acid (27.5 mmol) at room temperature. The reaction mixture was
allowed to reflux for 16 h. It was cooled and then basified by
the addition of saturated NaHCO3 and 10N NaOH solution.
Aqueous layer was extracted with EtOAc and the organic layer
was then washed with brine and dried over anhydrous Na2SO4.
Solvent was removed in vacuum and the residue was purified by
column chromatography using neutral alumina.
(S)-Methyl-1-((S)-2-(tert-butoxycarbonylamino)-4-methyl-pen-
tanoyl)pyrrolidine-2-carboxylate (6a). Yield 80%; Yellow liquid;
25
[a]D -7.8 (c 1.0, CHCl3); TLC Rf 0.60 (40%, EtOAc/Pet ether);
IR nmax/cm-1 (film) 3313, 2956, 1748, 1709, 1650; 1H NMR
(500 MHz, CDCl3): d 0.96 (m, 6H), 1.27 (m, 1H), 1.45 (s, 9H),
1.96 (m, 1H), 2.04 (m, 3H), 2.22 (m, 1H), 3.60 (m, 1H), 3.72 (s,
3H), 3.77 (m, 1H), 4.52 (m, 2H), 5.12 (d, J = 9.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3): d 21.8, 23.4, 24.5, 24.9, 28.3, 28.9, 41.9,
46.7, 50.2, 52.2, 58.6, 79.5, 155.7, 171.9, 172.5. Anal. Calcd. for
C17H30N2O5: C, 59.63; H, 8.83; N, 8.18. Found: C, 59.79; H, 8.85;
N, 8.20.
(3S,8aS)-3-Isobutyl-2-methyloctahydropyrrolo[1,2-a]pyrazine
25
(9a). Yield 46%; Colorless liquid; [a]D +26.3 (c 0.6, CHCl3);
TLC Rf 0.50 (100%, MeOH); IR nmax/cm-1 (film) 2954, 2794; 1H
NMR (400 MHz, CDCl3): d 0.89 (m, 6H), 1.25–1.84 (m, 7H),
2.10 (m, 2H), 2.27–2.38 (m, 5H), 2.61 (m, 2H), 2.81 (dd, J = 2.4,
10.8 Hz, 1H), 2.95 (m, 1H); 13C NMR (125 MHz, CDCl3): d 21.1,
22.0, 23.6, 26.3, 27.4, 32.9, 42.2, 53.9, 54.0, 54.9, 57.3, 62.2; HRMS
(ES+) calc. for C12H24N2 197.2018, [M + H]+ found 197.2018.
General procedure for the synthesis of diketopiperazines
A solution of amide 2 or 6 (2.0 mmol) in dry CH2Cl2 (6 mL) was
treated with TFA (800 mL) at rt for 3h. Solvent was then evaporated
and the reaction mixture was dissolved in 2-butanol:toluene
(4:2 mL) followed by addition of triethylamine (2 mmol). The
mixture was allowed to reflux for 16 h. After the evaporation of
solvent, diketopiperazines 3 or 7 precipitated as a white solid,
which was filtered off, washed with MeOH, and used for next step
without further purification.
General procedure for the enantioselective/diastereoselective
Henry reaction
A solution of ligand 1a (4.6 mg, 0.0275 mmol) and Cu(OAc)·H2O
(5 mg, 0.025 mmol) in dichloromethane (2 mL) was stirred
overnight at room temperature. Solvent was removed under
reduced pressure and the residue was dissolved in dry EtOH
(2 mL). To the resulting blue solution, nitroalkane (5 mmol), Et3N
(7 mL, 0.050 mmol) and aldehyde (0.5 mmol) were added at -40 ◦C.
The reaction mixture was stirred for appropriate time and the
progress of the reaction monitored by TLC. After completion of
the reaction, the volatile components were removed under reduced
pressure and the residue was purified by column chromatography
on silica gel (EtOAc/Petroleum ether) to afford the nitroaldol
product. The enantiomeric excess was determined by chiral HPLC
and diastereoselectivity was determined by 1H NMR spectroscopy.
(3S,8aS)-3-Isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
(7a). Yield 75%; White solid; mp 164 ◦C; [a]D25–137.2 (c 0.5,
DMSO); TLC Rf 0.50 (5%, MeOH/CH2Cl2); IR nmax/cm-1 (pellet)
3429, 2993, 1670, 1634; 1H NMR (400 MHz, CDCl3): d 0.99 (m,
6H), 1.54 (m, 1H), 1.78–2.15 (m, 5H), 2.35 (m, 1H), 3.57 (m, 2H),
4.02 (m, 1H), 4.12 (m, 1H), 6.30 (bs, 1H); 13C NMR (125 MHz,
CDCl3): d 21.3, 22.8, 23.3, 24.7, 28.1, 38.6, 45.5, 53.4, 59.0, 166.3,
170.3; HRMS (ES+) calc. for C11H18N2O2 211.1446, [M + H]+
found 211.1445.
Synthesis of (S)-2-amino-1-phenylethanol (12). b-Nitro alco-
hol 10a (0.4 mmol) in methanol (2 mL) was hydrogenated (H2,
1 atm) in the presence of 10% Pd/C (20 mg) for 24 h. The solution
was filtered over celite, and the methanol was removed under
General procedure for the synthesis of piperazine
To a solution of amide (2 mmol) 3 or 7 in dry THF (8 mL)
◦
was added LAH (10 mmol) in portions at 0 C and the reaction
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reduced pressure. The crude material was used without further
5 (a) E. J. Corey and F. -Y. Zhang, Angew. Chem., Int. Ed., 1999, 38, 1931;
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12392.
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Toussaint and A. Pfaltz, Eur. J. Org. Chem., 2008, 4591.
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Yanagisawa, Angew. Chem., Int. Ed., 2006, 45, 5978; (b) M. Bandini,
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Commun., 2007, 616; (c) M. Bandini, M. Benaglia, R. Sinisi, S. Tommasi
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Watanabe and A. Yanagisawa, Org. Lett., 2007, 9, 3595.
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J. Org. Chem., 2008, 73, 4903.
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Feng, J. Org. Chem., 2007, 72, 9323.
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861; (b) C. Palomo, M. Oiarbide and A. Laso, Angew. Chem., Int.
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7373.
◦
25
purification. Yield 92%; white solid; mp 54–56 C; [a]D +9.1 (c
1.68, EtOH); [lit.23 (S) ee = 100%; [a]D +47.9 (c 2.4, EtOH)]; IR
20
n
max/cm-1 (film) 3384, 2925, 2855; 1H NMR (500 MHz, CDCl3): d
2.79 (m, 1H), 3.0 (m, 1H), 3.46 (bs, 1H), 4.63 (m, 1H), 7.25–7.36
(m, 5H); 13C NMR (125 MHz, CDCl3): d 49.3, 74.4, 125.9, 127.6,
128.5, 128.6, 142.6; HRMS (ES+) calc. for C8H11NO 138.0920,
[M + H]+ found 138.0919.
Synthesis of (R)-2-phenyl-1-tosylaziridine (13). p-Toluene sul-
fonyl chloride (1.2 mmol) was added in portions to a solution of
amino alcohol 12 (1 mmol) and diisopropylethylamine (2 mmol)
◦
in CH2Cl2 (4 mL) at 0 C. The ice bath was then removed, and
the reaction was allowed to warm to rt and further stirred for
6 h. The reaction mixture was then washed with water, brine
and dried over anhydrous Na2SO4. The organic layer was then
concentrated and the crude product was purified by column
chromatography on silica gel to afford the sulfonylated amino
alcohol. To this N-sulfonyl-substituted amino alcohol in dry THF
(4 mL) was added triphenylphosphine (1.2 mmol) in one portion
◦
at rt. The reaction mixture was then cooled to 0 C, and treated
slowly with diisopropylazodicarboxylate (1.2 mmol). The ice bath
was removed and the yellow solution was stirred at rt for 6 h.
THF was evaporated, and the residue was purified by column
chromatography to yield the chiral aziridine 13. Yield 85%; white
solid, mp 82–84 ◦C; TLC Rf 0.8 (40% EA in petroleum ether);
25
1
[a]D -86.4 (c 1.0, CHCl3); IR nmax/cm-1 (pellet) 3038, 1385; H
NMR (500 MHz, CDCl3): d 2.38 (m, 1H), 2.42 (s, 3H), 2.98 (m,
1H), 3.77 (m, 1H), 7.2–7.33 (m, 7H), 7.87 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 21.8, 36.1, 41.1, 126.7, 128.0, 128.4, 128.7,
129.9, 135.0, 135.1, 144.8; HRMS (ES+) calc. for C15H15NO2S
274.0902, [M + H]+ found 274. 0903.; Enantiomeric excess was
determined by HPLC with a Chiralcel OJ-H column (n-hexane/2-
propanol 90:10, l = 254 nm); flow rate 0.8 mL/min; tR(minor)
=
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Acknowledgements
16 (a) R. Kowalcyzk, P. Kwiatkowski, J. Skarzewski and J. Jurczak, J. Org.
Chem., 2009, 74, 753; (b) A. Zulauf, M. Mellah and E. Schulz, J. Org.
Chem., 2009, DOI: 10.1021/jo802769y.
V.K.S. thanks the Department of Science and Technology, India
for a research grant through J.C.Bose fellowship. S.S. and D.S.
thank the Council of Scientific and Industrial Research, New Delhi
for research fellowships.
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