Organocatalytic asymmetric synthesis of 1,2,4-trisubstituted azetidines by reductive cyclization of Aza-Michael adducts of enones

Article abstract of DOI:10.1055/s-0031-1290954

An efficient and highly enantioselective organocatalytic aza-Michael addition of N-substituted phosphoramidates to enones generates aza-Michael adducts which undergo intramolecular reductive cyclization with (R)-alpine borane to afford 1,2,4-trisubstituted azetidines in a one-pot procedure. These optically active products are obtained in good to high yields (67-93%) with excellent stereocontrol (78-96% ee) from a vast variety of enones. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290954

LETTER
▌1321
letter
Organocatalytic Asymmetric Synthesis of 1,2,4-Trisubstituted Azetidines by
Reductive Cyclization of Aza-Michael Adducts of Enones
Asymmetric Synthesis of 1,2,4-Trisubstituted Azetidines
Ritu Kapoor, Ruchi Chawla, Santosh Singh, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received: 22.12.2011; Accepted after revision: 23.03.2012
difficulties associated with the formation of the four-
Abstract: An efficient and highly enantioselective organocatalytic
membered ring from acyclic precursors. This is a disfa-
aza-Michael addition of N-substituted phosphoramidates to enones
vored process compared to the analogous construction of
generates aza-Michael adducts which undergo intramolecular re-
ductive cyclization with (R)-alpine borane to afford 1,2,4-trisubsti-
slightly larger and even smaller rings. Recently, an excel-
tuted azetidines in a one-pot procedure. These optically active lent review by Couty et al.1b covered the synthesis of en-
products are obtained in good to high yields (67–93%) with excel-
lent stereocontrol (78–96% ee) from a vast variety of enones.
antiopure azetidines.
R1
R2
(R2 = CO2R3 or CH2OH)
Key words: asymmetric organocatalysis, conjugate addition,
enones, reductive cyclization, chiral azetidines, phosphoramidates
N
R2
Figure 1 Optically active azetidine-2,4-dicarboxylic acid deriva-
tives
Over the years, functionalized aza-heterocycles, which
are at the heart of many essential pharmaceuticals and
physiologically active natural products, have attracted the
attention of organic chemists in order to develop novel,
synthetically useful, and elegant methodologies for the
synthesis of such type of compounds as targets for design
of new drugs and important intermediates in organic syn-
thesis. Amongst chiral nitrogen heterocycles, azetidines1,2
have received much attention during the last decade be-
cause of their utilization as ligands3 and their biological
and pharmaceutical activities.4,5 For example, they are no-
ticeably active against influenza A H2N2 virus6 and have
anti-HIV-I, anti-HSV-I, and HSV-2 potential.7 Recently,
2-substituted N-tosylazetidines have been utilized as
masked 1,4-dipoles for the construction of N-containing
six-membered heterocycles.8
The use of asymmetric aminocatalysis11 has become a
well-documented and powerful synthetic tool for the che-
mo- and enantioselective functionalization of carbonyl
compounds. Recently, Bartoli and Melchiorre have devel-
oped primary amine salt catalyst A12 which offers the ad-
vantages of both iminium ion catalysis and asymmetric
counteranion-directed catalysis (ACDC) phenomenon,13
and exhibits high reactivity and selectivity in the highly
enantioselective conjugate addition of a series of different
nucleophiles (C-, S-, O- and N-centered nucleophiles) to
enones as both the cation and anion in the salt are chiral.14
This led us to extend Melchiorre’s method for the enantio-
selective aza-Michael addition to enones. The salt A, con-
taining a chiral cation and anion, is obtained by
combination of 9-amino-(9-deoxy)-epi-hydroquinine15
and D-N-Boc-phenylglycine, which efficiently activates
enones through iminium ion formation coupled with syn-
ergistic benefits of ACDC in enantioselective syntheses.
However, in terms of synthetic approaches and applica-
tions, azetidines have been comparatively less studied
than their lower and higher homologous saturated aza-het-
erocycles, viz. aziridines, pyrrolidines, and piperidines.
Several authors have pointed out the scarcity of general
and efficient methods for the synthesis of enantiopure
azetidines.1b,2d,9 Most of the literature reports on optically
active symmetrically disubstituted azetidines10 are largely
restricted to 1,3-disubstituted azetidines and azetidine-
2,4-dicarboxylic acid derivatives and azetidine-2,4-di-
methanol analogues derived from them (Figure 1). Fur-
thermore, the low number of publications on optically
active 2,4-disubstituted azetidines also reflects the need of
new enantioselective approaches towards these heterocy-
cles.1b Marinetti et al.9b conjectured that the reasons for
the lack of progress in the development of the chemistry
of optically active azetidines could be related to synthetic
In our endeavors to synthesize enantiopure azetidines, we
advanced this organocatalytic activation strategy to docu-
ment an operationally trivial procedure for the aza-
Michael addition of N-arylphosphoramidates 2 to α,β-un-
saturated ketones 1 catalyzed by the chiral salt A to give
aza-Michael adducts 3 followed by the intramolecular re-
ductive cyclization via (R)-alpine borane to give 1,2,4-tri-
substituted azetidines 4 (in 67–93% yield with 85–95%
diastereoselectivity and 78–96% enantioselectivity) in a
one-pot procedure as outlined in Scheme 1. We herein re-
port the first organocatalytic addition of phosphorami-
dates (a weak nitrogen nucleophile) to enones using
catalyst salt A ultimately leading to azetidines 4.
SYNLETT 2012, 23, 1321–1326
Advanced online publication: 14.05.2012
DOI: 10.1055/s-0031-1290954; Art ID: ST-2011-D0799-L
© Georg Thieme Verlag Stuttgart · New York
The organocatalytic asymmetric aza-Michael addition is
an excellent way of forming C–N bonds and is of tremen-
dous significance in asymmetric synthesis.16 Specifically,
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1322
R. Kapoor et al.
LETTER
the asymmetric aza-Michael addition of enones by imini- stoichiometric amount of secondary amines (proline or
um ion catalysis has received considerable attention in re- imidazolidinone) was undertaken which furnished poor
cent years.14d,17 Michael adducts formed during the course results, most probably due to the inherent difficulties in
of reaction have potential for broad utility as synthetic generating covalent intermediates from enones and chiral
building blocks in the preparation of natural and biologi- secondary amines owing to steric constraints. The steric
cally active products. These aza-Michael adducts have constraints are reduced in primary amine catalysis using
been used for the synthesis of various aza-heterocyclic chiral salt A, the cornerstone for the present organo ami-
scaffolds including azetidines through heterocyclization nocatalytic protocol, which has already provided a plat-
in our laboratory on several occasions.18
form for the development of a large range of asymmetric
transformations involving α,β-unsaturated ketones21 via
the formation of iminium ion intermediates from enones
availing the benefits of ACDC strategy as well. Attracted
by the chemistry of primary amino catalysis we then per-
formed the reaction with chiral salt A (20 mol%) and α,β-
unsaturated ketones 1 in toluene at 60 °C to generate im-
inium ion intermediates in situ to which the aza-Michael
addition of N-arylphosphoramidates 2 took place effi-
ciently to afford the representative adducts 3h (R1 = R2 =
Et, R3 = o-tolyl, yield 85%, ee 80%) and 3j (R1 = Bn, R2
= Et, R3 = Ts, yield 92%, ee 82%).19 Diastereoselective re-
duction of these adducts with (R)-alpine borane furnished
the corresponding azetidines 4h (yield 69%, ee 82%) and
4j (yield 73%, ee 80%).20 In place of the primary amine
chiral salt A, TFA salts of primary amines B and C were
also able to promote the reaction but with lower levels of
yield and diastereo- and enantioselectivity. Lowering the
catalyst loading (20 mol% to 15 mol%) exhibited signifi-
cant decrease in the yield and enantioselectivity of
Michael adducts 3h,j. Moreover, increasing the catalyst
loading from 20 mol% to 25 mol% neither improved the
yield nor the enantioselectivity. On carrying out the reac-
tion at room temperature instead of at 60 °C, there was a
marginal increase in the enantiomeric excess but at the ex-
pense of a drastic reduction in the yield of 3h,j. In view of
the advantages of one-pot syntheses, we combined the
above two steps in a one-pot procedure, and it worked
well for the asymmetric synthesis of azetidines 4.
Boc NH
COO
Ph
Ph
NH2
NH2
2
OMe
N
Ph
H3N
NH2
NH2
N
H
B
C
catalyst salt A
B
O
catalyst salt A
R2
R2
O
R3
O
P
EtO
R1
N
EtO
NH
R3
P
1
EtO
R1
O
3
OEt
2
O
H
OEt
P
H
R2
OEt
R3
N
H
B
H
N
O
R3
R1
H
R1
4
Me
R2
yield 67–93%
ee 78–96%
boat-like favored transition structure,
larger substituent in equatorial position
Scheme 1 Enantioselective synthesis of azetidines 4
From among the investigated solvents (toluene, dichloro-
methane, and diethyl ether), toluene was the best solvent
in terms of yield as well as enantioselectivity (Table 1).
Initially, enantioselective conjugate addition of N-ar-
ylphosphoramidates 2 to α,β-unsaturated ketones 1 with a
Table 1 Optimization of Reaction Conditions for the Synthesis of 4a in a One-Pot Procedurea
H
O
O
P
H
EtO
EtO
(i) catalyst
Ph
NH
Ts
+
Ph
N
H
(ii) (R)-alpine borane
Ts
Ph
H
Ph
Entry
1
1a
2a
4a
Catalystb
A
Solventc
Time (h)d
Yield (%)e
trans/cisf
ee (%)g
toluene
CH2Cl2
Et2O
54
60
59
87
62
65
95:5
91:9
92:8
96
93
90
2
B
toluene
CH2Cl2
Et2O
62
66
64
49
40
44
81:19
80:20
84:14
62
62
65
Synlett 2012, 23, 1321–1326
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of 1,2,4-Trisubstituted Azetidines
1323
Table 1 Optimization of Reaction Conditions for the Synthesis of 4a in a One-Pot Procedurea
H
O
O
P
H
EtO
EtO
(i) catalyst
Ph
NH
Ts
+
Ph
N
H
(ii) (R)-alpine borane
Ts
Ph
H
Ph
Entry
3
1a
2a
4a
Catalystb
C
Solventc
Time (h)d
Yield (%)e
trans/cisf
ee (%)g
toluene
CH2Cl2
Et2O
60
66
64
57
50
46
90:10
85:15
87:13
72
65
68
a For the experimental procedure, see ref. 21.
b Catalyst load used was 20 mol%.
c The reaction was performed in toluene at 60 °C, whereas in CH2Cl2 and Et2O at reflux.
d Total time for the completion of steps (i) and (ii) as indicated by TLC.
e Yields of isolated and purified product.
f As determined by 1H NMR integration of trans and cis isomers in the crude product.
g The ee of the trans isomer 4a was checked by chiral HPLC with a 250 × 4.6 mm, 5 chiral Eurocel column. HPLC traces were compared to
racemic samples prepared by our previously reported method.18a
H
In order to investigate the substrate scope for the present
O
H
synthetic strategy, different α,β-unsaturated ketones were
reacted with differently substituted phosphoramidates un-
der the optimized reaction conditions, and it was found
that in all the cases azetidines 4 could be isolated in good
to excellent yields along with high optical purity by har-
monizing the catalyst loading and the reaction time (Table
2). Our aforementioned organocatalytic protocol is also
worthwhile in activating aromatic ketones such as (E)-
chalcone (1, R1 = R2 = Ph), a class of substrates which is
not generally suitable for iminium ion activation.21
R2
O–
(EtO)2P
N
H
R3
R1
H
+
N
H
4
R2
R2
R2
+
R1
5
N
H
O
O
EtO
EtO
R1
N
EtO
EtO
R1
–N
P
O
P
R3
EtO
EtO
R3
H2O
O
P NH
R3
R2
2
The synthesis of azetidines may be tentatively rational-
ized by the enantioselective formation of adducts through
iminium ion catalysis with chiral salt A as outlined in
Scheme 2. These adducts underwent intramolecular re-
ductive cyclization with (R)-alpine borane to give the de-
sired products 4 in high yields and with high diastereo-
and enantioselectivity. The high affinity of phosphorus for
oxygen is the main driving force for the present heterocy-
clization reaction. The crude isolates of 4 were found to be
diastereomeric mixtures containing 85–95% of the 2,4-
trans isomer (Table 2). The 1H NMR spectra of azetidines
4a–i and 4m,n show common signals for Hb and Hc reso-
nances, which is a direct proof for their 2,4-trans config-
uration. If 1,2,4-trisubstituted azetidines 4a–i and 4m,n
would have 2,4-cis stereochemistry, the Hb and Hc reso-
nances should appear as inequivalent signals. The stereo-
chemistry of 1,2,4-trisubstituted azetidines 4 was further
confirmed by NOE measurements between the He and Hf
protons (Figure 2). The absolute configurations of azeti-
dines 4d–f and 4i–n are known and were elucidated by
comparison of the measured specific rotations with those
reported in the literature.2a,9b The absolute configurations
of 4a–c and 4g,h were assumed by analogy based on the
uniform reaction mechanism and elution order in the chi-
ral HPLC.2a,9b
R2
O
catalyst A
O
–O
R1
N
O
P
P
R3
EtO
EtO
R1
EtO
EtO
N
R3
R2
3
–O
O
P
EtO
EtO
R1
N
B
R3
Scheme 2 A tentative reaction pathway leading to azetidines 4
Hb
Hb
Hc
Hc
Ph
Hf
N
Ph
Ph
N
He
Ts
Ts
He
Ph
Hf
12.5%
cis
trans
NOE
Figure 2 NOE observation in azetidine 4a
The protocol features an efficient and highly enantioselec-
tive organocatalytic aza-Michael addition of N-substitut-
ed phosphoramidates to enones followed by
intramolecular reductive cyclization with (R)-alpine bo-
rane to afford 1,2,4-trisubstituted azetidines in a one-pot
procedure. Operational simplicity, good to excellent
In summary we have developed a highly enantio- and dia-
stereoselective synthesis of 1,2,4-trisubstituted azetidines.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1321–1326

1324
R. Kapoor et al.
LETTER
Table 2 One-Pot Organocatalytic Asymmetric Synthesis of Azetidines 4a
H
O
O
P
H
EtO
EtO
(i) catalyst salt A
R2
R2
N
R3
4
NH
R3
+
H
(ii) (R)-alpine borane
R1
H
R1
60 °C
1
2
R1
R2
R3
Time (h)b Yield (%)c,d trans/cise
ee (%)f
Entry
Azetidine 4
1
4a
4b
4c
4d
4e
4f
Ph
Ph
Ts
Ph
54
56
55
66
57
62
58
70
68
67
61
64
68
67
87
90
93
75
84
71
92
67
75
70
73
76
72
76
95:5
96
93
94
82
80
92
94
81
85
78
85
79
84
83
2
Ph
Ph
94:6
3
Ph
Ph
4-MeOC6H4
95:5
4
Me
Me
Bn
Me
Me
Bn
Ph
90:10
89:11
94:6
5
o-tolyl
Bn
6
7
4g
4h
4i
4-ClC6H4
Et
4-ClC6H4
Et
Ph
93:7
8
o-tolyl
Bn
85:15
91:9
9
Et
Et
10
11
12
13
14
4j
Bn
Et
Ts
89:11
91:9
4k
4l
Ph
Et
Ts
Ph
n-Pr
Me
Ts
87:13
88:12
85:15
4m
4n
Me
Me
2-BrC6H4
Bn
Me
a For the experimental procedure, see ref. 21.
b Total time for the completion of steps (i) and (ii) as indicated by TLC.
c Yields of pure isolated products 4 after column chromatography.
d All compounds gave C, H, N analyses within ±0.36% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
e As determined by 1H NMR integration of trans and cis isomers in the crude products.
f The ee of the trans isomers 4 was checked by chiral HPLC with a 250 × 4.6 mm, 5 chiral Eurocel column. HPLC traces were compared to
racemic samples prepared by our previously reported method.18a
(2) For asymmetric synthesis of azetidines, see for example:
(a) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett.
2007, 48, 2471. (b) Pedrosa, R.; Andres, C.; Nieto, J.; del
Pozo, S. J. Org. Chem. 2005, 70, 1408. (c) Mangelinckx, S.;
Boeykens, M.; Vliegen, M.; Van der Eycken, J.; De Kimpe,
N. Tetrahedron Lett. 2005, 46, 525. (d) Enders, D.; Gries, J.;
Kim, Z.-S. Eur. J. Org. Chem. 2004, 4471. (e) Burtoloso, A.
C. B.; Correia, C. R. D. Tetrahedron Lett. 2004, 45, 3355.
(3) For azetidines used as ligands, see for example:
(a) Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J. M. M.; Zwanenburg, B. Tetrahedron
1998, 54, 4991. (b) Shi, M.; Jiang, J.-K. Tetrahedron:
Asymmetry 1999, 10, 1673. (c) Hermsen, P. J.; Cremers, J.
G. O.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 2001, 42,
4243. (d) Wilken, J.; Erny, S.; Wassmann, S.; Martens, J.
Tetrahedron: Asymmetry 2000, 11, 2143. (e) Couty, F.;
Prim, D. Tetrahedron: Asymmetry 2002, 13, 2619.
chemical yields, and the first application of organocataly-
sis via iminium ion formation coupled with synergistic
benefits of ACDC to enantioselective aza-Michael addi-
tion of phosphoramidates (weak nitrogen nucleophiles) to
enones are additional interesting aspects of the present
methodology.
Acknowledgment
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalyses and spectra. R. Kapoor and R. Chawla are
grateful to the Department of the Science and Technology, New
Delhi, for the award of a Fast Track Young Scientist Scheme [refer-
ence no. SR/FT/CS-039/2011] and a Junior Research Fellowship
[reference no. SR/S1/OC-22/2010], respectively.
(f) Keller, L.; Sanchez, M. V.; Prim, D.; Couty, F.; Evano,
G.; Marrot, J. J. Organomet. Chem. 2005, 690, 2306.
(4) (a) Fowden, L. Nature (London) 1995, 176, 347. (b) Ohfune,
Y.; Tomita, M.; Nomoto, K. J. Am. Chem. Soc. 1981, 103,
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Biotechnol. Biochem. 1993, 57, 1107. (d) Liu, D.-G.; Lin,
G.-Q. Tetrahedron Lett. 1999, 40, 337. (e) Yoda, H.;
References and Notes
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Synlett 2012, 23, 1321–1326
© Georg Thieme Verlag Stuttgart · New York

LETTER
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Asymmetric Synthesis of 1,2,4-Trisubstituted Azetidines
1325
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(19) General Procedure for the Synthesis of Representative
Diethyl N,N-Disubstituted Phosphoramidates 3h,j
Reactions were carried out in undistilled toluene without any
precaution to exclude water. The aforementioned catalytic
salt A (0.04 mmol) was prepared from 9-amino-(9-deoxy)-
epi-hydroquinine (0.04 mmol, 13.0 mg) and 0.08 mmol (20
mg) of D-N-Boc-phenylglycine in toluene (2 mL) as reported
in the literature.14a After addition of α,β-unsaturated ketone
1 (0.2 mmol) to it, the mixture was stirred at 60 °C for 10
min. Then a solution of phosphoramidate 2 (0.2 mmol) was
added to the reaction mixture slowly with stirring at 60 °C,
and stirring was continued for 12–24 h which resulted in the
formation of aza-Michael adduct 3h,j as monitored by TLC.
The resulting mixture was diluted with toluene and filtered
on neutral Al2O3. The solvent was evaporated under reduced
pressure, and the product was purified by flash chroma-
tography on neutral Al2O3 (PE–CH2Cl2 = 6:4) to obtain pure
phosphoramidates 3h,j as white solids. Enantiomeric purity
of adducts were checked by chiral HPLC with a 250 × 4.6
mm, 5 chiral Eurocel column.
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Characterization Data of Representative Compounds
Compound 3h (R1 = R2 = Et, R3 = o-tolyl): white solid; yield
85%; mp 195–197 °C. IR (KBr): νmax = 3060, 2889, 1690,
1609, 1565, 1455, 1353, 1272, 1115, 742 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.83 (t, J = 7.4 Hz, 3 H), 1.14 (q, J =
7.4 Hz, 2 H), 1.20 (t, J = 7.5 Hz, 6 H), 1.52 (m, 2 H), 2.35 (s,
3 H), 2.50 (t, J = 7.2 Hz, 3 H), 2.96 (dd, J = 12.9, 8.5 Hz, 1
H), 3.16 (dd, J = 12.9, 3.5 Hz, 1 H), 4.06 (q, J = 7.5 Hz, 4 H),
4.09 (m, 1 H), 6.61 (d, J = 8.1 Hz, 1 Hortho), 6.68–7.06 (m,
3 Harom). 13C NMR (100 MHz, CDCl3): δ = 9.4, 10.4, 14.5,
16.0, 30.0, 40.1, 46.2, 54.0, 62.6, 113.4, 117.5, 126.9, 127.8,
130.5, 144.0, 219.5 ppm. MS (EI): m/z = 355 [M+]. Anal.
Calcd for C18H30NO4P: C, 60.83; H, 8.51; N, 3.94. Found: C,
60.57; H, 8.63; N, 4.27. [α]D25 –115 (c 1, CHCl3). The ee was
determined to be 80% by HPLC on a chiral Eurocel column
[(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90),
1 mL/min]; tR (minor) = 12.4 min, tR (major) = 14.2 min.
Compound 3j (R1 = Bn, R2 = Et, R3 = Ts): white solid; yield
92%; mp 178–179 °C. IR (KBr): νmax = 3054, 2992, 1692,
(11) (a) Barbas, C. F . III, Angew. Chem. Int. Ed. 2008, 47, 42.
(b) List, B. Chem. Commun. 2006, 819. (c) Marigo, M.;
Jørgensen, K. A. Chem. Commun. 2006, 2001.
(12) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759.
(13) (a) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193.
(b) Lacour, J.; Hebbe-Viton, V. Chem. Soc. Rev. 2003, 32,
373. (c) Llewellyn, D. B.; Arndtsen, B. A. Tetrahedron:
Asymmetry 2005, 16, 1789. (d) Dorta, R.; Shimon, L.;
Milstein, D. J. Organomet. Chem. 2004, 689, 751.
(e) Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron:
Asymmetry 2003, 14, 1995. (f) Martin, N. J. A.; List, B.
J. Am. Chem. Soc. 2006, 128, 13368. (g) Zhou, J.; List, B.
J. Am. Chem. Soc. 2007, 129, 7498. (h) Wang, X.; List, B.
Angew. Chem. Int. Ed. 2008, 47, 1119.
(14) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403.
(b) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci,
P.; Sambri, L.; Melchiorre, P. Eur. J. Org. Chem. 2007,
5492. (c) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.;
Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49.
(d) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.;
Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P.
Angew. Chem. Int. Ed. 2008, 47, 8703.
(15) Brunner, H.; Bügler, J.; Nuber, B. Tetrahedron: Asymmetry
1995, 6, 1699.
(16) For a review on organocatalytic aza-Michael addition, see:
Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15,
11058.
(17) (a) Lu, X.; Deng, L. Angew. Chem. Int. Ed. 2008, 47, 7710.
(b) Luo, G.; Zhang, S.; Duan, W.; Wang, W. Synthesis 2009,
5641. (c) Sanjib, G.; Zhao, C.-G.; Ding, D. Org. Lett. 2009,
11, 2249.
(18) (a) Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A.
Tetrahedron Lett. 2007, 48, 8037. (b) Yadav, L. D. S.; Patel,
R.; Srivastava, V. P. Synlett 2008, 583. (c) Yadav, L. D. S.;
Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 5652.
1605, 1580, 1455, 1372, 1337, 1263, 1154, 1130, 855 cm—1
.
1H NMR (400 MHz, CDCl3): δ = 0.78 (t, J = 7.4 Hz, 3 H),
1.23 (t, J = 7.5 Hz, 6 H), 2.37 (s, 3 H), 2.05 (q, J = 7.4 Hz, 2
H), 2.49 (dd, J = 12.9, 8.5 Hz, 1 H), 2.58 (dd, J = 12.9, 3.5
Hz, 1 H), 2.75 (dd, J = 13.4, 10.5 Hz, 1 H), 2.83 (dd, J = 13.4,
3.9 Hz, 1 H), 3.24 (m, 1 H), 4.16 (q, J = 7.5 Hz, 4 H), 7.08–
7.43 (m, 9 Harom). 13C NMR (100 MHz, CDCl3): δ = 8.4,
15.6, 23.3, 28.4, 35.8, 42.6, 44.7, 62.9, 124.4, 126.3, 128.2,
129.0, 129.9, 136.7, 138.0, 143.9, 218.9 ppm. MS (EI):
m/z = 481 [M+]. Anal. Calcd for C23H32NO6PS: C, 57.37; H,
6.70; N, 2.91. Found: C, 57.57; H, 6.97; N, 3.25. [a]D25 –120
(c 1, CHCl3). The ee was determined to be 82% by HPLC on
a chiral Eurocel column [(250 × 4.6 mm, 5μ), λ = 225 nm, (i-
PrOH–hexane = 10:90), 1 mL/min]; tR (minor) = 10.9 min,
tR (major) = 13.4 min.
(20) General Procedure for the Synthesis of Azetidines 4h,j
To a solution of adduct 3h or 3j (0.2 mmol) in THF was
added (R)-alpine borane (0.2 mmol), and the reaction
mixture was stirred at 60 °C for 42–48 h. A sat. aq NH4Cl
solution (4 mL) was added, and the resulting mixture was
extracted once with Et2O (5 mL) and then with CH2Cl2 (2 ×
5 mL), dried over anhyd MgSO4, filtered, and evaporated to
dryness. The crude product thus obtained was purified by
flash chromatography using a gradient mixture of EtOAc–
hexane as eluent to afford an analytically pure sample of 4h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1321–1326

1326
R. Kapoor et al.
LETTER
(yield 69%) or 4j (yield 73%). Characterization data were in
good agreement with those given in ref. 21.
(21) General Procedure for the One-Pot Synthesis of
Azetidines 4
CDCl3): δ = 0.83 (t, J = 7.4 Hz, 6 H), 1.33–1.52 (m, 4 H),
2.02 (t, J = 6.1 Hz, 2 H), 2.12 (s, 3 H), 4.07 (m, 2 H), 6.62 (d,
J = 8.1 Hz, 1 Hortho), 6.76–7.11 (m, 3 Harom). 13C NMR (100
MHz, CDCl3): δ = 9.0, 19.2, 26.0, 27.8, 61.8, 114.0, 119.4,
126.1, 130.8 ppm. MS (EI): m/z = 203 [M+]. Anal. Calcd for
C14H21N: C, 82.70; H, 10.41; N, 6.89. Found: C, 83.06; H,
10.49; N, 6.82. [α]D25 –193 (c 1, CHCl3). The ee was
determined to be 81% by HPLC on a chiral Eurocel column
[(250 × 4.6 mm, 5μ), λ = 225 nm, (i-PrOH–hexane = 10:90),
1 mL/min]; tR (minor) = 19.4 min, tR (major) = 20.5 min.
Compound 4j: colorless oil; yield 70%. 1H NMR (400 MHz,
CDCl3): δ = 0.67 (t, J = 7.6 Hz, 3 H), 1.35–1.43 (m, 1 H),
1.66–1.72 (m, 1 H), 1.86–1.97 (m, 2 H), 2.35 (s, 3 H), 2.70
(dd, J = 13.4, 10.5 Hz, 1 H), 3.29 (dd, J = 13.4, 3.9 Hz, 1 H),
4.04–4.08 (m, 1 H), 4.30–4.33 (m, 1 H), 7.06–7.25 (m, 7 H),
7.69 (d, J = 8.3 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ =
8.3, 21.5, 26.5, 27.2, 40.2, 62.8, 63.6, 126.6, 127.4, 128.5,
129.3, 129.6, 136.7, 137.9, 143.1 ppm. MS (EI): m/z = 329
[M+]. Anal. Calcd for C19H23NO2S: C, 69.27; H, 7.04; N,
4.25. Found: C, 69.35; H, 7.40; N, 4.50. [α]D25 +79 (c 1,
CHCl3). The ee was determined to be 78% by HPLC on a
chiral Eurocel column [(250 × 4.6 mm, 5μ),
Reactions were carried out in undistilled toluene without any
precaution to exclude water. The catalytic salt A (0.04
mmol) was prepared as described above (ref. 19) following
the literature method.14a After addition of α,β-unsaturated
ketone 1 (0.2 mmol) to it, the mixture was stirred at 60 °C for
10 min. Then a solution of phosphoramidate 2 (0.2 mmol)
was added to the reaction mixture slowly with stirring at 60
°C, and stirring was continued for next 12–24 h which
resulted in the formation of aza-Michael adduct 3 as
monitored by TLC. The reaction mixture was cooled to r.t.
followed by addition of (R)-alpine borane (0.2 mmol), and
stirring at r.t. for another 42–48 h. A sat. aq NH4Cl solution
(4 mL) was added, and the resulting mixture was extracted
once with Et2O (5 mL) and then with CH2Cl2 (2 × 5 mL),
dried over anhyd MgSO4, filtered, and evaporated to
dryness. The crude product thus obtained was purified by
flash chromatography using a gradient mixture of EtOAc–
hexane as eluent to afford an analytically pure sample of 4.
Characterization Data for Representative Compounds
Compound 4h: colorless oil; yield 67%. 1H NMR (400 MHz,
λ = 225 nm, (i-PrOH–hexane = 10:90), 1 mL/min];
tR (minor) = 21.3 min, tR (major) = 22.4 min.
Synlett 2012, 23, 1321–1326
© Georg Thieme Verlag Stuttgart · New York

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