Direct asymmetric bromination of aldehydes catalyzed by a binaphthyl-based secondary amine: Highly enantio- and diastereoselective one-pot synthesis of bromohydrins

Article abstract of DOI:10.1039/c0cc02739a

One-pot stereoselective synthesis of bromohydrins as a useful chiral building block was achieved by the reaction of Grignard reagents with optically active α-bromoaldehydes, which were in situ generated by direct asymmetric bromination of aldehydes cataly

Full text of DOI:10.1039/c0cc02739a

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COMMUNICATION
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Direct asymmetric bromination of aldehydes catalyzed by a
binaphthyl-based secondary amine: highly enantio- and
diastereoselective one-pot synthesis of bromohydrinsw
Taichi Kano, Fumitaka Shirozu and Keiji Maruoka*
Received 23rd July 2010, Accepted 18th August 2010
DOI: 10.1039/c0cc02739a
One-pot stereoselective synthesis of bromohydrins as a useful
chiral building block was achieved by the reaction of Grignard
reagents with optically active a-bromoaldehydes, which were
in situ generated by direct asymmetric bromination of aldehydes
catalyzed by a binaphthyl-based secondary amine (S)-3.
Asymmetric enamine catalysis is a powerful organocatalytic
strategy for the stereoselective a-functionalization of carbonyl
compounds.1,2 In this area, catalytic asymmetric a-halogenations
of carbonyl compounds have been investigated by several
research groups,3–5 since a-haloaldehydes and ketones can
serve as versatile synthetic intermediates in the formation of
carbon–carbon bonds as well as various carbon–heteroatom
We first investigated a-bromination of 3-phenylpropanal
bonds.6 However, optically active a-haloaldehydes except
a-chloroaldehydes need to be converted to the corresponding
alcohols prior to the isolation procedure due to their instability,
thereby losing the apparent advantage of carbonyl functionality.
Although a-bromo and a-iodoaldehydes would be useful
building blocks because of their size and leaving group ability
of bromine and iodine atoms, only a few in situ transformations
using such characteristic features have been reported to
date.5c,7,8 In addition, among the direct asymmetric
a-halogenations, the bromination of aldehydes requires a high
catalyst loading (B20 mol%), probably due to the deactivation
of the secondary amine catalyst by a brominating agent. In
this context, we have been interested in the development of a
general method for synthesis of optically active a-bromoaldehydes
and utilization of their carbonyl moiety by in situ transformation.
Herein we wish to report a direct asymmetric a-bromination
of aldehydes using a novel binaphthyl-based secondary
amine catalyst and highly stereoselective one-pot synthesis of
bromohydrins.
with various brominating agents 4 in CH2Cl2 in the presence
of 10 mol% of a secondary amine catalyst rac-1 at ꢀ20 1C, and
the results are shown in Table 1. Among the brominating
agents tested, 4d and 4f5a,b,9 gave the brominated product in
moderate yield (entries 4 and 6). We then examined an axially
Table 1 Direct asymmetric bromination of 3-phenylpropanal with
various brominating agentsa
Entry
4
Cat
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4d
4f
4d
4f
4f
4f
4f
4f
4f
4f
4f
rac-1
rac-1
rac-1
rac-1
rac-1
rac-1
rac-1
(S)-2
(S)-2
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
o5
o5
o5
40
—
—
—
—
—
—
—
87
96
91
97
97
92
3
o5
30
o5
17
10
69
94
76
97
64
9
10
11
12d
13e
14
15
16
17
18
Et2O
64
29
16
7
—
87
Toluene
Hexane
CF3C6H5
o5
79
a
Unless otherwise specified, the reaction between 3-phenylpropanal
(0.1 mmol) and brominating agent 4 (0.1 mmol) was carried out in a
solvent (2.0 mL) in the presence of a secondary amine catalyst
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81 75-753-4041;
Tel: +81 75-753-4041
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc02739a
b
c
(0.01 mmol) at ꢀ20 1C. Isolated yield. Enantiomeric excess
d
determined by HPLC analysis using chiral column. 5 mol% of (S)-3.
e
3 mol% of (S)-3 for 72 h.
c
7590 Chem. Commun., 2010, 46, 7590–7592
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chiral amino alcohol catalyst (S)-210 with the expectation
of activating the brominating agent through hydrogen
bonding with hydroxydiphenylmethyl groups at 3,30-positions.
Although excellent enantioselection was observed in the reaction
with 4f, the product yield was drastically decreased (entry 9).
An NMR study revealed that the deactivation rate of catalyst
(S)-2 with 4f was faster than that of rac-1 despite the sterically
more congested secondary amine moiety of (S)-2. This
observation suggested that the hydroxy groups of (S)-2
accelerated the undesired reaction between (S)-2 and 4f. Thus,
a hydroxy-protected secondary amine catalyst (S)-311 having
bulky substituents at 3,30-positions was synthesized by the
introduction of trimethylsilyl groups into (S)-2 with the aim of
circumventing the catalyst deactivation. As a result of the
protection of hydroxyl group and the introduction of steric
bulkiness into the catalyst, the bromination catalyzed by (S)-3
proceeded smoothly in excellent yield and enantioselectivity
(entry 11). The catalyst loading could be reduced to 5 mol%
without loss of enantioselectivity (entry 12). Both yield and
enantioselectivity in the present bromination showed a strong
solvent dependence (entries 14–18), and consequently, CH2Cl2
was determined to be the solvent of choice.
Fig. 1 Plausible transition state model.
The optically enriched a-bromoaldehydes should be reduced
in situ with NaBH4 to the corresponding alcohol due to the
inherent instability of a-haloaldehydes. If a certain carbon
anion species could be used instead of the hydride anion under
the influence of the large bromine atom, an additional stereo-
center could be constructed stereoselectively through the
carbon–carbon bond formation (Scheme 1).4d,13 Hence, we
then examined the one-pot synthesis of bromohydrins using
Grignard reagents as one of the most versatile organometallic
reagents. The reaction of the in situ generated optically
enriched a-bromoaldehyde with methyl Grignard reagents in
THF at ꢀ78 1C proceeded to give the corresponding anti-
bromohydrin in good to excellent diastereoselectivity (Table 3,
entries 1–3), and the best result was attained with methyl-
magnesium chloride (entry 1). The observed diastereoselectivity
is well explained by the non-chelation control, which might be
attributable to the large bromine atom.14 The product yield
could be improved by addition of Et2O as cosolvent (entry 4)
With the axially chiral secondary amine catalyst (S)-3 in
hand, the direct asymmetric a-bromination of several other
aldehydes with 4f was examined, and selected results are
shown in Table 2. In most cases examined, the direct asym-
metric a-bromination of aldehydes proceeded to give the
corresponding a-bromoaldehydes in good to excellent yields
and enantioselectivities (entries 1–7), while the use of sterically
demanding 3,3-dimethylbutanal was unsatisfactory (entry 8).
The absolute configuration of the product in this reaction
catalyzed by (S)-3 was determined to be R by comparison of
the optical rotation with the literature data.5a Based on the
observed stereochemistry, a transition state model can be
proposed as shown in Fig. 1.12 One face of the enamine
intermediate is effectively shielded by the bulky substituent
of (S)-3, and consequently, the reaction of an aldehyde with 4f
catalyzed by (S)-3 provides the R isomer predominantly.
Scheme 1 One-pot synthesis of bromohydrins.
Table
3
Enantio- and diastereoselective one-pot synthesis of
bromohydrinsa
Table 2 Direct asymmetric bromination of various aldehydes with 4f
catalyzed by (S)-3a
Entry
R
R0MgX
Equiv. Yieldb (%) anti/sync eed (%)
Entry
R
Yieldb (%)
eec (%)
1
2
3
Bn
Bn
Bn
Bn
Bn
Bn
MeMgCl 3.0
MeMgBr 3.0
MeMgI
MeMgCl 3.0
MeMgCl 5.0
PhMgCl
55
26
53
69
82
83
73
>20/1
>20/1
10/1
97
77
91
97
96
99
99
1d
2
3
4
5
6
7
8
Bu
Hex
Bn
CH2Cy
CH2OBn
i-Pr
Cy
t-Bu
80
92
94
82
92
71
73
o5
93
92
97
96
99
96
99
—
3.0
4e
5e
6e
7e
16/1
>20/1
>20/1
>20/1
5.0
5.0
i-Pr PhMgCl
a
Unless otherwise specified, the reaction between an aldehyde
(0.1 mmol) and 4f (0.1 mmol) was carried out in a solvent (2.0 mL)
in the presence of (S)-3 (0.01 mmol) at ꢀ20 1C, and was followed by
a
Unless otherwise specified, the reaction between an aldehyde
(0.1 mmol) and 4f (0.1 mmol) was carried out in a solvent (2.0 mL)
b
addition of a THF solution of Grignard reagent at ꢀ78 1C. Isolated
yield. Determined by 1H NMR spectroscopy. Enantiomeric
b
c
d
in the presence of (S)-3 (0.01 mmol) at ꢀ20 1C. Isolated yield.
c
e
excess determined by HPLC analysis using chiral column. After
Enantiomeric excess determined by HPLC and GC analysis using
d
chiral column. 2 equiv. of 4f.
the bromination, Et2O (2.0 mL) was added.
c
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and increasing the amount of the Grignard reagent (entry 5). In
the reaction of phenylmagnesium chloride, the optical purity of
the obtained bromohydrin slightly exceeded that observed in the
standard bromination–reduction procedure (Table 3, entry 6 vs.
Table 2, entry 3; Table 3, entry 7 vs. Table 2, entry 6). This
observation might indicate the partial degradation of the optical
purity during reduction of a-bromoaldehydes.
M. Bella, A. Prieto, J. Overgaard and K. A. Jorgensen, Chem.–Eur. J.,
2006, 12, 6039.
4 Chlorination: (a) M. P. Brochu, S. P. Brown and D. W. C.
MacMillan, J. Am. Chem. Soc., 2004, 126, 4108; (b) M. Marigo,
S. Bachmann, N. Halland, A. Braunton and K. A. Jorgensen,
Angew. Chem., Int. Ed., 2004, 43, 5507; (c) N. Halland,
A. Braunton, S. Bachmann, M. Marigo and K. A. Jørgensen,
J. Am. Chem. Soc., 2004, 126, 4790; (d) B. Kang and R. Britton,
Org. Lett., 2007, 9, 5083.
In summary, we have developed a direct asymmetric
bromination of aldehydes catalyzed by the binaphthyl-based
secondary amine (S)-3 and the one-pot procedure for the
highly stereoselective synthesis of bromohydrins. This method
represents a rare example of the organocatalytic asymmetric
bromination and the in situ transformation of the resulting
a-bromoaldehydes.
5 Bromination and iodination: (a) S. Bertelsen, N. Halland,
S. Bachmann, M. Marigo, A. Braunton and K. A. Jørgensen, Chem.
Commun., 2005, 4821; (b) J. Franzen, M. Marigo, D. Fielenbach,
T. C. Wabnitz, A. Kjœrsgaard and K. A. Jørgensen, J. Am. Chem.
Soc., 2005, 127, 18296; (c) T. Kano, M. Ueda and K. Maruoka,
J. Am. Chem. Soc., 2008, 130, 3728.
6 (a) R. C. Larock, Comprehensive Organic Transformations,
Wiley-VCH, New York, 2nd edn, 1999; (b) H. House, in Modern
Synthetic Reactions, W. A. Benjamin, New York, 2nd edn, 1972,
pp. 459–478; (c) N. De Kimpe and R. Verhe, The Chemistry of
a-Haloketones, a-Haloaldehydes, and a-Haloimines, John Wiley &
Sons, New York, 1988.
Notes and references
1 For reviews, see: (a) P. I. Dalko and L. Moisan, Angew. Chem., Int.
Ed., 2001, 40, 3726; (b) P. I. Dalko and L. Moisan, Angew. Chem.,
Int. Ed., 2004, 43, 5138; (c) A. Berkessel and H. Groger,
Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis, Wiley-VCH, Weinheim,
2005; (d) Enantioselective Organocatalysis, ed. P. I. Dalko,
Wiley-VCH, Weinheim, 2007.
2 For reviews, see: (a) M. Marigo and K. A. Jørgensen, Chem.
Commun., 2006, 2001; (b) S. Mukherjee, J. W. Yang,
S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471.
7 H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V. Marcos and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2009, 48, 6844.
8 In situ transformation of optically active a-fluoroaldehydes: H. Jiang,
A. Falcicchio, K. L. Jensen, M. W. Paixao, S. Bertelsen and
K. A. Jørgensen, J. Am. Chem. Soc., 2009, 131, 7153.
9 K. Omura, J. Org. Chem., 1996, 61, 2006.
10 T. Kano, M. Ueda, J. Takai and K. Maruoka, J. Am. Chem. Soc.,
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11 T. Kano, H. Mii and K. Maruoka, Angew. Chem., Int. Ed., 2010,
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3 Fluorination: (a) D. Enders and M. R. Huttl, Synlett, 2005, 991;
(b) M. Marigo, D. Fielenbach, A. Braunton, A. Kjœrsgaard and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 3703;
(c) D. D. Steiner, N. Mase and C. F. Barbas III, Angew. Chem.,
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c
7592 Chem. Commun., 2010, 46, 7590–7592
This journal is The Royal Society of Chemistry 2010