Lewis base-catalyzed conjugate reduction and reductive aldol reaction of α,β-unsaturated ketones using trichlorosilane

Article abstract of DOI:10.1039/b807529h

Lewis bases such as Ph₃P=O and HMPA catalyze the 1,4-reduction of α,β-unsaturated ketones with trichlorosilane, and because the 1,2-reduction of aldehydes scarcely proceeded under the conditions, one-pot reductive aldol reactions with aldehydes were successfully achieved; preliminary studies using a chiral Lewis base revealed a high potential for enantioselective catalysis. The Royal Society of Chemistry.

Full text of DOI:10.1039/b807529h

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Lewis base-catalyzed conjugate reduction and reductive aldol reaction
of a,b-unsaturated ketones using trichlorosilanew
Masaharu Sugiura,* Norimasa Sato, Shunsuke Kotani and Makoto Nakajima*
Received (in Cambridge, UK) 2nd May 2008, Accepted 3rd June 2008
First published as an Advance Article on the web 17th July 2008
DOI: 10.1039/b807529h
Lewis bases such as Ph3PQO and HMPA catalyze the 1,4-
reduction of a,b-unsaturated ketones with trichlorosilane, and
because the 1,2-reduction of aldehydes scarcely proceeded under
the conditions, one-pot reductive aldol reactions with aldehydes
were successfully achieved; preliminary studies using a chiral
Lewis base revealed a high potential for enantioselective catalysis.
base-catalyst. N,N-Dimethylacetamide, isoquinoline N-oxide and
DMSO showed a negligible catalytic activity.
Thus, with effective catalysts in hand, conjugate reduction
of various a,b-unsaturated ketones was examined (Table 1).
The reactions were performed in the presence of HMPA
(20 mol%) at 0 1C or rt. Acyclic b-monosubstituted enones
Conjugate reduction of a,b-unsaturated carbonyl compounds
and subsequent one-pot reactions with electrophiles such as
aldehydes are efficient synthetic tactics in organic synthesis. In
these processes, transition metals are typically utilized as
catalysts with silane or borane reductants.1 Recently, organo-
catalytic variants of conjugate reduction (chiral secondary
amines as catalysts and Hantzsch esters as stoichiometric
reducing agents) have been reported,2 but subsequent reac-
tions with electrophiles have yet to be fully explored.3 Herein,
we report an alternative methodology for organocatalytic
conjugate reduction of enones and subsequent reactions with
aldehydes (reductive aldol reactions). The method employs
phosphorus oxide (PQO) compounds as Lewis base-catalysts
and trichlorosilane as a reductant.4–6
Table 1 HMPA-catalyzed conjugate reduction of various enonesa
Entry Enone R1, R2, R3, R4
Conditions
Yield (%)
1
2
3
4
1a
1b
1c
1d
Me, H, Ph, H
Ph, H, Ph, H
Ph, H, Me, H
0 1C, 30 min
0 1C, 30 min
0 1C, 30 min
0 1C, 60 min
87
91
72
80
We hypothesized that if a suitable Lewis base activates the
silane, the 1,4-reduction may proceed selectively via a six-mem-
bered transition state, and with the assistance of the same Lewis
base, the generated trichlorosilyl enolate should react with coex-
isting aldehyde electrophile.7 Therefore, we investigated the
reduction of benzalacetone (1a) with trichlorosilane in the pre-
sence of a catalytic amount of various Lewis bases (Scheme 1).8
Reduction was not observed in the absence of catalyst, but 1,2-
reduction mainly occurred upon the addition of DMF [2a (2%),
3a (43%)]. On the other hand, 1,4-reduction proceeded selec-
tively when DMPU [2a (11%), 3a (o1%)], Ph3PQO [2a (64%),
3a (0%)], or HMPA [2a (99%), 3a (0%)] was used as the Lewis
5
6
1e
1f
0 1C, 4 h then rt, 93
2 h
0 1C, 30 min
94
7
8
9
1g
1h
1i
Ph, H, Ph, Me
Ph, Me, H, H
0 1C, 5 h then rt, 74
19 h
0 1C, 9 h then rt, 60
17 h
0 1C, 30 min
89
10
1j
0 1C, 40 min
82
11
1k
0 1C, 4 h then rt, 84b
16 h
Scheme 1 Lewis base-catalyzed reduction of benzalacetone.
Faculty of Medical and Pharmaceutical Sciences, Kumamoto
University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan. E-mail:
msugiura@kumamoto-u.ac.jp; nakajima@gpo.kumamoto-u.ac.jp
w Electronic supplementary information (ESI) available: General
procedures and spectroscopic data. See DOI: 10.1039/b807529h
a
All reactions were carried out by addition of trichlorosilane
(2.0 mmol) to a solution of an enone (1.0 mmol) and HMPA
b
(0.2 mmol) in CH2Cl2 (2 mL) at 0 1C or rt. trans : cis = 1.7 : 1.
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Table 2 Lewis base-catalyzed reductive aldol reactiona
Preliminary studies using a chiral Lewis base (BINAPO)11
revealed a high potential for enantioselective catalysis of the
reactions (Scheme 2). Although HMPA required an extended
reaction time at rt for the reduction of enone 1g (see Table 1,
entry 7), the asymmetric reduction using BINAPO proceeded
smoothly at 0 1C to give a high enantioselectivity. On the other
hand, the asymmetric reductive aldol reaction of b-ionone (1f)
with benzaldehyde at À78 1C provided both high diastereo-
and enantioselectivities. The syn-diastereoselectivity can be as-
cribed to the formation of the (Z)-trichlorosilyl enolate9
followed by Lewis base-catalyzed aldol reaction via a chair-like
transition state.11,12
Entry Enone R5
Catalyst Conditions Yieldb (%)
1
2
3
4
5
6
7
8
a
1b
1b
1b
1b
1b
1c
1f
Ph
Ph
HMPA
Ph3PQO 0 1C, 4 h
0 1C, 4 h
52
78
69
72
19
70
65
39
p-MeOC6H4 Ph3PQO 0 1C, 4 h
p-NO2C6H4
Ph(CH2)2
Ph
Ph
Ph
Ph3PQO 0 1C, 4 h
Ph3PQO rt, 24 h
Ph3PQO 0 1C, 4 h
Ph3PQO 0 1C, 5 h
In summary, we have demonstrated Lewis base-catalyzed
conjugate reduction of a,b-unsaturated ketones with trichloro-
silane and subsequent one-pot reactions with aldehydes.
Further studies on the enantioselective catalysis as well
as extension to other related reactions are currently in
progress.
1h
HMPA
rt, 24 h
All reactions were carried out by addition of trichlorosilane (1.0 mmol)
to a solution of an enone (0.5 mmol), an aldehyde (0.6 mmol) and a Lewis
b
base-catalyst (0.1 mmol) in CH2Cl2 (2 mL) at 0 1C or rt. Isolated as
diastereomeric mixtures except for entry 8.
Notes and references
1 For leading references on metal-catalyzed reductive aldol reac-
tions, see: (a) A. Revis and T. K. Hilty, Tetrahedron Lett., 1987, 28,
4809; (b) S. Isayama and T. Mukaiyama, Chem. Lett., 1989, 2005;
(c) S. Kiyooka, A. Shimizu and S. Torii, Tetrahedron Lett., 1998,
39, 5237; (d) T. Ooi, K. Doda, D. Sakai and K. Maruoka,
Tetrahedron Lett., 1999, 40, 2133; (e) C.-X. Zhao, M. O. Duffey,
S. J. Taylor and J. P. Morken, Org. Lett., 2001, 3, 1829; (f) H.-Y.
Jang, R. R. Huddleston and M. J. Krische, J. Am. Chem. Soc.,
2002, 124, 15156; (g) I. Shibata, H. Kato, T. Ishida, M. Yasuda
and A. Baba, Angew. Chem., Int. Ed., 2004, 43, 711.
2 (a) J. W. Yang, M. T. H. Fonseca and B. List, Angew. Chem., Int.
Ed., 2004, 43, 6660; (b) J. W. Yang, M. T. H. Fonseca, N. Vignola
and B. List, Angew. Chem., Int. Ed., 2005, 44, 108; (c) S. G. Ouellet,
J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 32; (d) N. J. A. Matrin and B. List, J. Am. Chem. Soc., 2006,
128, 13368; For related reactions based on non-metal-catalyzed
hydrostannation, see: (e) T. Kawakami, M. Miyatake, I. Shibata
and A. Baba, J. Org. Chem., 1996, 61, 376; (f) D. S. Hays, M.
Scholl and G. C. Fu, J. Org. Chem., 1996, 61, 6751.
Scheme 2 Enantioselective catalysis.
gave the 1,4-reduction products in high yields with exclusive
1,4-selectivity (entries 1–6), while b- and/or a-disubstituted
enones required extended reaction time (entries 7, 8 and 11).
The 1,4-reduction of one enone moiety proceeded regioselec-
tively even when substrates had an additional olefin moiety
(entries 4, 5, 6 and 10). Exocyclic enones gave 1,4-reduction
products smoothly (entries 9, 10 and 11), whereas an endo-
cyclic enone, 3-phenyl-2-cyclohexenone, showed low reactiv-
ity. These observations strongly suggest the importance of the
s-cis configuration in the transition state.9
3 A catalytic asymmetric reductive Michael cyclization has been
reported, see: J. W. Yang, M. T. H. Fonseca and B. List, J. Am.
Chem. Soc., 2005, 127, 15036.
4 Trichlorosilane has been utilized for (asymmetric) 1,2-reduction of
aldehydes, ketones, aldimines and ketimines in combination with
(chiral) Lewis base-catalysts. For leading references, see: (a) S.
Kobayashi, M. Yasuda and I. Hachiya, Chem. Lett., 1996, 407;
(b) F. Iwasaki, O. Onomura, K. Mishima, T. Maki and Y.
Matsumura, Tetrahedron Lett., 1999, 40, 7507; (c) Y. Matsumura,
K. Ogura, Y. Kouchi, F. Iwasaki and O. Onomura, Org. Lett.,
2006, 8, 3789; (d) A. V. Malkov, A. Mariani, K. N. MacDougall
and P. Kocovsky
P. Stewart Liddon, P. Ramı
P. Kocovsky, Angew. Chem., Int. Ed., 2006, 45, 1432; (f) L. Zhou,
´
, Org. Lett., 2004, 6, 2253; (e) A. V. Malkov, A. J.
HMPA or Ph3PQO scarcely promoted the 1,2-reduction of
benzaldehyde under these conditions. Thus, three-component
reactions of enones, aldehydes and trichlorosilane (reductive
aldol reactions) proceeded smoothly in the presence of a Lewis
base-catalyst to afford the corresponding aldol products in
good yield (Table 2).10 For the reaction of chalcone (1b) with
benzaldehyde, Ph3PQO catalyst showed better activity than
HMPA (entries 1 and 2). Reactions of 1b with electron-
donating and -withdrawing benzaldehyde derivatives also
afforded good yields, but reaction with an aliphatic aldehyde
gave a low yield (entries 3–5). Reactive enones 1c and 1f
provided good results (entries 6 and 7), but enone 1h having
low reduction activity resulted in a low yield (entry 8).
´
rez-Lopez, L. Bendova, D. Haigh and
´
´
´
Z. Wang, S. Wei and J. Sun, Chem. Commun., 2007, 2977.
5 Cobalt(II) chloride-catalyzed 1,4-reduction of enones or acryl esters
with trichlorosilane has been reported, see: M. Chauhan and P.
Boudjouk, Can. J. Chem., 2000, 78, 1396. For a palladium-
catalyzed reductive aldol reaction with trichlorosilane, see ref. 1c.
6 A patent that describes a formamide-catalyzed conjugate reduction
of enones with the silane has been reported, see: Y. Matsumira and
F. Iwasaki, Jpn. Pat., JP 2003171334 A. However, this patent does
not describe the effect of Lewis bases other than formamides.
Formamides are generally effective in the reduction of aldehydes
with trichlorosilane, see ref. 4.
7 For a pioneering study on aldol reaction of trichlorosilyl enolates,
see: S. E. Denmark, K.-T. Wong and R. A. Stavenger, J. Am.
Chem. Soc., 1997, 119, 2333.
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8 Yields were determined by 1H NMR analysis of the crude reaction
mixture using dibenzyl ether as an internal standard.
A similar mechanism has been suggested for borane reduction,
see: G. P. Boldrini, M. Bortolotti, F. Mancini, E. Tagliavini,
C. Trombini and A. Umani-Ronchi, J. Org. Chem., 1991, 56
5820.
9
1H NMR study of the reaction of benzalacetone with trichlorosi-
lane in deuterated dichloromethane confirmed the formation of the
corresponding (Z)-trichlorosilyl enolate (assigned by a NOESY
experiment), which supports a six-membered cyclic transition state
with the s-cis conformation of enones (Figure).
10 Low diastereoselectivities (dr = 50 : 50 to 78 : 22) were observed in
each case probably due to contributions of both catalyzed and
non-catalyzed aldol processes, see ref. 7.
11 We have employed BINAPO as a chiral Lewis base catalyst for
enantioselective allylation, aldol reaction and epoxide ring-opening
reaction, see: S. Kotani, S. Hashimoto and M. Nakajima, Tetra-
hedron, 2007, 63, 3122.
12 The minor anti-isomer is racemic, which is consistent with the fact
that the non-catalyzed aldol process favors the anti-product in a
similar system, see ref. 7.
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Chem. Commun., 2008, 4309–4311 | 4311