Asymmetric synthesis of 4H-1,3-oxazines: Enantioselective reductive cyclization of N-acylated β-amino enones with trichlorosilane catalyzed by chiral Lewis bases

Article abstract of DOI:10.1039/b905102c

N-Acylated β-amino enones reductively cyclize by treatment with trichlorosilane and a chiral Lewis base catalyst to afford optically active 4H-1,3-oxazines, which can be transformed to other chiral compounds without racemization.

Full text of DOI:10.1039/b905102c

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Asymmetric synthesis of 4H-1,3-oxazines: enantioselective reductive
cyclization of N-acylated b-amino enones with trichlorosilane catalyzed
by chiral Lewis basesw
Masaharu Sugiura,* Mako Kumahara and Makoto Nakajima*
Received (in Cambridge, UK) 12th March 2009, Accepted 16th April 2009
First published as an Advance Article on the web 11th May 2009
DOI: 10.1039/b905102c
N-Acylated b-amino enones reductively cyclize by treatment
with trichlorosilane and a chiral Lewis base catalyst to afford
optically active 4H-1,3-oxazines, which can be transformed to
other chiral compounds without racemization.
Table 1 Enantioselective reductive cyclization of N-acylated b-amino
enones 1 catalyzed by BINAPOa
4H-1,3-Oxazines are a class of six-membered heterocyclic
compounds with one oxygen and one nitrogen in the ring
structure.1 These compounds have been synthesized via
cyclization of N-acylated b-amino ketones using dehydrating
agents,2 or via reactions between nitriles and b-chloro ketones
(or enones)3 or between alkynes and N-acyl imines (or their
equivalents).4 However, to the best of our knowledge, the
enantioselective synthesis of chiral 4H-1,3-oxazines possessing
a stereogenic centre at the 4-position, as well as their biological
activities, have yet to be studied.5 During our studies on the
asymmetric synthesis of N-acylated b-amino ketones, we
unexpectedly found that optically active 4H-1,3-oxazines
2 could be directly obtained via reductive cyclization of
N-acylated b-amino enones 1 using trichlorosilane and chiral
Lewis base catalysts (Scheme 1). Herein, we describe this
finding, as well as the potential utility of chiral 4H-1,3-oxazine
products as synthetic intermediates.
yield (%) (ee (%), config.)
Entry R1, R2 (1)
Time/h
2
3
1b
2
Me, Ph (1a)
1a
i-Pr, Ph (1b)
Ph, Ph (1c)
Me, p-NO2C6H4 (1d) 24
11
24
9
2a: 56 (71, R) 3a: 13 (4)
2a: 68 (74, R) 3b: 17 (7, S)
2b: 72 (47, R) 3b: 23 (42, S)
2c: 75 (53, S) 3c: 12 (51, S)
2d: 38 (50, R) 3d: 20 (28, S)
2e: 68 (81, R) 3e: 18 (14, S)
2f: 58 (26, R)f 3f: 27 (22, S)
3c
4d
5e
6
9
Me, p-MeOC6H4 (1e)
Me, Me (1f)
5
2
7b
a
Unless otherwise noted, reactions were carried out using an
N-acylated b-amino enone (0.25 mmol), trichlorosilane (3 equiv.),
and (S)-BINAPO (10 mol%) in dichloromethane (1 mL) at rt, and
b
c
quenched with water. With trichlorosilane (2 equiv.). N-(4-Methyl-
1-phenylpent-1-en-3-yl)benzamide was obtained in 2% yield with
d
55% ee. N-(1,3-Diphenylallyl)benzamide was obtained in 10% yield
e
f
with 4% ee. Enamide 1d was recovered in 37% yield. The yield and
selectivity were determined after hydrolysis to keto amide 3f (see text).
Scheme
1 Enantioselective reductive cyclization of N-acylated
b-amino enones for asymmetric synthesis of 4H-1,3-oxazines.
We have recently reported that Lewis bases such as
Ph3PQO and HMPA catalyze the conjugate reduction of
simple enones with trichlorosilane, and that a chiral Lewis
base can catalyze the reduction with a high enantioselectivity.6
Therefore, we envisaged that optically active b-amino carbonyl
compounds might be obtained via the enantioselective
conjugate reduction of N-acylated b-amino enones 1 utilizing
this method.7
First, (Z)-N-benzoyl enone 1a (Table 1, entry 1), derived via
the benzolylation of 3-amino-1-phenylbutane-1,3-dione,
was treated with trichlorosilane (2 equiv.) in the presence of
Faculty of Medical and Pharmaceutical Sciences, Kumamoto
University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Fig. 1 Screening of Lewis base catalysts.
E-mail: msugiura@kumamoto-u.ac.jp, nakajima@gpo.kumamoto-u.ac.jp
w Electronic supplementary information (ESI) available: General
procedures and spectroscopic data and See DOI: 10.1039/b905102c
(S)-BINAPO (10 mol%, Fig. 1) in dichloromethane at rt. The
consumption of 1a was sluggish and incomplete. However,
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4H-1,3-oxazine 2a was unexpectedly generated as the major
product in moderate yield with good enantioselectivity
(71% ee), whereas the yield and selectivity of anticipated keto
amide 3a were low. The use of a Lewis base catalyst is
indispensable for the reaction, since no product was obtained
in the absence of a catalyst. The quenching method was
important; employing saturated aq. NaHCO3 instead of water
lowered the yield of 2a. Changing the solvent to propionitrile
also had a detrimental effect. Next, chiral Lewis bases other
than BINAPO were tested for the reaction of 1a (Fig. 1).
Although (R,R)-DIOPO significantly improved the yield,
the selectivity was disappointing. (S)-SEGPHOSO also
enhanced the yield of 2a, but with moderate enantioselectivity.
Other types of phosphine oxides, (S)-PhanePhosO and
(S,S)-DIOPO, could not improve both the activity and
selectivity as well. With a chiral bisquinoline N,N0-dioxide,
(R)-BQNO, the enantioselectivity for 2a decreased, but
that for 3a increased, and reduction of BQNO with
trichlorosilane was observed. Finally, the use of three
equivalents of trichlorosilane with BINAPO catalyst and an
extended reaction time proved to be the optimal conditions
(Table 1, entry 2).
the N-acyl imine generated via equilibration of enamide 1.7
This mechanistic picture may explain the difference of the
enantioselectivities between 2 and 3. Further investigations are
needed to clarify the detailed mechanism.
The synthetic utility of optically active 4H-1,3-oxazines 2
was preliminarily investigated. Treatment of 2e (81% ee) with
hydrobromic acid in ethanol gave b-amino ketone 3e (eqn (1)).
Pd/C-catalyzed hydrogenation of 2e caused cleavage of the
C–O bond of the oxazine to give saturated amide 4e
(eqn (2)).10 On the other hand, oxidation of 2e by bromine
and subsequent treatment with silica gel generated 4,5-dihydro-
oxazole 5e (eqn (3)).11 All these transformations proceeded
without losing optical purity. The absolute configuration of 2e
was R, which was determined by transforming hydrogenated
product 4e into the known primary amine, (R)-4-phenylbutan-
2-amine.9
In summary, we are the first to demonstrate that chiral
Lewis bases catalyze the enantioselective reductive cyclization
of N-acylated b-amino enones with trichlorosilane to afford
optically active 4H-1,3-oxazines. In this reaction, trichloro-
silane acts not only as a reductant, but also as a dehydrating
agent. 4H-1,3-Oxazines can be converted via a variety of
conditions to other chiral compounds without racemization.
Further investigations to elucidate the reaction mechanism,
synthetic utility and biological activity of chiral 4H-1,3-
oxazines are currently in progress.
Under the conditions using (S)-BINAPO and trichlorosilane
(3 equiv.), the reactions of N-benzoyl enones 1b (R1 = iPr) and
1c (R1 = Ph) proceeded smoothly to give products 2b and 2c
in good yields, and moderate enantioselectivities, respectively
(Table 1, entries 3 and 4). On the other hand, an electron-
donating R2 group enhanced the formation rate of 4H-1,3-
oxazines, as well as the enantioselectivity (entries 5 vs. 6). The
coordination of the amide carbonyl to trichlorosilane may
play an important role for both the rate- and enantio-
determining steps. The reaction of enone 1f, which has
a similar electron-donating N-acetyl group, also rapidly
afforded oxazine 2f and keto amide 3f, albeit with low
selectivities (Table 1, entry 7). However, oxazine 2f was
unstable and readily hydrolyzed to 3f during the workup.8
In almost all cases, the ee of 2 differed from that of 3. Even
the absolute configurations differed in many cases.9 These
observations imply that 2 is not generated from 3 via a simple
dehydration (or formation of 3 from 2 via hydrolysis). It is
plausible that 4H-1,3-oxazine 2 is generated via the conjugate
reduction of N-acylated b-amino enone 1, followed by cycliza-
tion of the resulting enolate and elimination of HOSiCl3,
whereas keto amide 3 originates from the 1,2-reduction of
This work partially supported by a Grant-in-Aid of
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
Notes and references
1 (a) M. Sainsbury, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, ch. 2.27,
1984; (b) M. Sainsbury, in Comprehensive Heterocyclic Chemistry
II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Pergamon, Oxford, ch. 6.05, 1996; (c) A. S. Fisyuk and
M. A. Vorontsova, Chem. Heterocycl. Compd., 1998, 34, 629–645.
2 Z. Eckstein and T. Urbansky, Adv. Heterocycl. Chem., 1978, 23, 1.
3 (a) M. Lora-Tamayo, R. Madronero, G. G. Munoz and
H. Leiprand, Chem. Ber., 1964, 97, 2234; (b) M. Lora-Tamayo,
R. Madronero and H. Leiprand, Chem. Ber., 1964, 97, 2244;
(c) C. Kashima, S. Imada and T. Nishio, Chem. Lett., 1978,
1391; (d) E. Ghera, R. Maurya and A. Hassner, Tetrahedron Lett.,
1989, 30, 4741.
4 (a) K. Burger, E. Huber, W. Schontag and R. Ottlinger, J. Chem.
¨
Soc., Chem. Commun., 1983, 945; (b) P. M. Scola and
S. M. Weinreb, J. Org. Chem., 1986, 51, 3248.
5 Kundig et al. have reported that optically active 4H-1,3-benzoxa-
¨
zines derived from chiral 2-(1-aminoalkyl)phenols serve as
effective chiral ligands for metal catalysts, see: (a) E. P. Kundig
¨
and P. Meier, Helv. Chim. Acta, 1999, 82, 1360;
(b) G. H. Bernardinelli, E. P. Kundig, P. Meier, A. Pfaltz,
¨
K. Radkowski, N. Zimmermann and M. Neuburger-Zehnder,
Helv. Chim. Acta, 2001, 84, 3233.
6 M. Sugiura, N. Sato, S. Kotani and M. Nakajima, Chem.
Commun., 2008, 4309.
7 Lewis base-catalyzed enantioselective reduction of b-amino
enoates with trichlorosilane to b-amino esters has been reported.
1,2-Reduction of imines generated in situ from b-amino enoates
has been postulated for the mechanism, see: (a) O. Onomura,
Y. Kouchi, F. Iwasaki and Y. Matsumura, Tetrahedron Lett.,
2006, 47, 3751; (b) A. V. Malkov, S. Stoncius, K. Vrankova
´
,
M. Arndt and P. Kocovsky, Chem.–Eur. J., 2008, 14, 8082;
´
(c) H.-J. Zheng, W.-B. Chen, Z.-J. Wu, J.-G. Deng, W.-Q. Lin,
W.-C. Yuan and X.-M. Zhang, Chem.–Eur. J., 2008, 14, 9864. For
a recent comprehensive review on Lewis base catalysis, see:
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(d) S. E. Denmark and G. L. Beutner, Angew. Chem., Int.
Ed., 2008, 47, 1560. For leading references on 1,2-reductions of
aldehydes, ketones, and imines with trichlorosilane, see:
(e) S. Kobayashi, M. Yasuda and I. Hachiya, Chem. Lett., 1996,
407; (f) F. Iwasaki, O. Onomura, K. Mishima, T. Maki and
Y. Matsumura, Tetrahedron Lett., 1999, 40, 7507; see also
ref. 7a.
8 The formation of oxazine 2f was confirmed by checking the acidic
aqueous extract by 1H NMR analysis. However, 2f was readily
hydrolyzed to 3f upon the addition of saturated aq. NaHCO3. For
details, see the ESIw.
9 The absolute configurations of 2c and 2e were assigned based on
their transformations to known compounds (see the ESIw). Those
of 2a, 2b, 2d and 2f were tentatively assigned by analogy. Because
oxazine 2 is readily hydrolyzed to corresponding keto amide 3
without racemization (see eqn (1)), their configurations can be
compared easily.
10 It has been reported that the PtO2-catalyzed hydrogenation of
racemic 4H-1,3-oxazines provides similar cleaved products, see:
ref. 3b.
11 Formation of the corresponding N-acylated a-bromo-b-amino
ketone followed by cyclization is assumed.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3585–3587 | 3587