Chiral amine-catalyzed α-benzylation of α-branched aldehydes

Full text of DOI:10.1002/bkcs.10547

Communication
DOI: 10.1002/bkcs.10547
BULLETIN OF THE
A. Lee
KOREAN CHEMICAL SOCIETY
Chiral Amine-catalyzed α-Benzylation of α-Branched Aldehydes
*
Anna Lee
Department of Chemistry, Myongji University, Yongin 449-728, Korea. *E-mail: annalee@mju.ac.kr
Received May 18, 2015, Accepted July 24, 2015, Published online October 4, 2015
Keywords: Homogeneous HCl scavenger, Imidazole, Asymmetric organocatalysis, α-Benzylation reaction
Chiral amine-catalyzed asymmetric SN2-type reaction of car-
bonyl compounds has emerged as a powerful strategy.1,2
Recently, noticeable α-alkylation reactions via organocataly-
sis have been reported.3,4 Common to these studies is the addi-
tionofadditivessuchasacidsand/orbasestoprovideactivated
reaction conditions. There have been a few pioneering studies
of this type of reaction; however, the development of efficient
methods has remained elusive. For example, in α-benzylation
studies reported by the List group, the mixed acid/base
buffer system has been employed.5 The first asymmetric
α-benzylation reaction of α-branched aldehydes with benzyl
bromides has been accomplished successfully under the
optimized reaction conditions. However, there are some lim-
itations of this study such as relatively high catalyst loading
(30 mol %) and long reaction times (for 144 h at 50 ꢀC). Also,
the addition of large excess of acids and bases (5 equiv each)
was necessary to afford the desired products.
The main reason of this limited reaction conditions might be
based on the buffer system5,6 which was crucial to provide the
proper reaction conditions using benzyl bromides as alkylat-
ing reagents.5 In our previous studies, it turned out that the
addition of imidazole was beneficial to remove in situ gener-
ated hydrogen chloride in N-heterocyclic carbenes (NHCs)-
catalyzed7 [4+2] annulation reactions.8 Both the yield and
enantioselectivity are improved in the presence of imidazole.
Based on this result, we envisioned that the ability of the imid-
azole as an efficient homogeneous HCl scavenger could be
applied to other reactions. After screening some reactions,
we found that the asymmetric α-benzylation reaction of
α-branched aldehydes5 would be a proper candidate reaction
to demonstrate this research concept (Scheme 1).
1). Indeed, imidazole was beneficial to improve the reactivity.
Significantly improved yields and enantioselectivities were
observed even at 23 ꢀC (entries 2–8). Improved reaction yield
and enantioselectivity were observed when we added 20 mol
% of imidazole (entry 2). Increasing the amount of imidazole
also improved the reaction yield (entry 3). In addition, we
could decrease the amount of acid and base additives in the
presence of imidazole (entries 4–9), only catalytic amounts
of additives have been used to afford the desired products
without loss of reactivity and enantioselectivity (entry 7).
To our delight, even catalyst loading could be decreased under
the reaction conditions. We were able to conduct the reaction
with only 10 mol % of catalyst to provide the desired products
in good yields and high enantioselectivities (entries 6–8). To
identify the effect of the benzyl halide, the reaction was carried
out with benzyl bromide instead of benzyl chloride. Interest-
ingly, decreased yield and enantioselectivity were observed in
this case (entry 10). This result indicates that imidazole reacts
with hydrogen chloride in a more effective way under the
reaction conditions. Optimal results were obtained in terms
of reactivity and enantioselectivity when we introduced
0.2 equiv of catalyst 3a and acid/base additives; the desired
product was obtained in 85% yield and 95:5 e.r. (entry 7).
With the optimized reaction conditions in hand, the scope of
this α-alkylation was explored (Table 2). The desired alkylat-
ing aldehydes were obtained in good yields (72–85%) with
high enantioselectivities (up to 95:5 e.r.).
α-Branched aldehydes that possess meta or para substitu-
ents on the aromatic structure furnished the desired products
in good yields and enantioselectivities (4b–4g). Also, 4-
bromobenzyl chloride and 4-iodobenzyl chloride were suita-
ble substrates under the reaction conditions (4h and 4i). The
absolute configuration of product 4a was determined to be
R by comparison of the optical rotation value.9
In conclusion, we have demonstrated that imidazole would
act as an efficient homogeneous HCl scavenger during the
reaction. This useful protocol has been applied to a catalytic
asymmetric α-benzylation reaction of α-branched aldehydes
successfully. The desired products were obtained in good
yields and high enantioselectivities. It is noteworthy that only
catalytic amounts of acid/base additives were employed and
we could decrease the catalyst loading (10–20 mol %) under
the mild reaction conditions. This useful methodology would
be of use in other challenging reaction system.
We set the model reaction using 2-phenylpropionaldehyde
1a and benzyl chloride 2a as the starting compounds (Table 1).
First, to prove our hypothesis, the reaction was carried out in
the absence of imidazole. The reaction was slow at 23 ꢀC,
therefore, the reaction was carried out at 50 ꢀC. The desired
product was obtained in 40% yield and 93:7 e.r. (Table 1, entry
Scheme 1. α-Benzylation reactions in the presence of imidazole.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2585–2586
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BULLETIN OF THE
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Table 1. Optimization of reaction conditions.a
Table 2. Substrate scope.a
3a
5
6
7
Yield
Entry (equiv)
(equiv) (equiv) (equiv) (%)b
e.r.c
1d
2
3
4
5
6
7
8
0.3
0.3
0.3
0.3
0.3
0.2
0.2
0.1
0.2
0.2
5.0
5.0
5.0
1.0
1.0
1.0
0.2
0.2
0.1
0.2
5.0
5.0
5.0
1.0
1.0
1.0
0.2
0.2
0.1
0.2
0
40
68
78
82
75
81
85
70
42
55
93:7
94:6
95:5
95:5
94:6
95:5
95:5
95:5
93:7
93:7
0.2
0.5
0.5
0.2
0.5
0.5
0.5
0.5
0.5
9
10e
a Conditions: 1a (0.1 mmol, 1.0 equiv), 2a (1.5 equiv), 3a, 5, 6, 7, and
4 Å M.S. (50 mg) in chloroform (0.5 mL) at 23 ꢀC for 72 h.
b Yields are of isolated product after column chromatography.
c Determined by GC analysis on a chiral stationary phase.
d Reaction was carried out at 50 ꢀC.
e Benzyl bromide has been used instead of benzyl chloride.
a Conditions: 1 (0.1 mmol, 1.0 equiv), 2 (1.5 equiv), 3a (0.2 equiv), 4 Å
M.S. (50 mg), 5 (0.2 equiv), 6 (0.2 equiv), imidazole (0.5 equiv) in
chloroform (0.5 mL) at 23 ꢀC for 72 h. Yields are of isolated product
after column chromatography. Enantiomeric ratio was determined by
GC and HPLCs analysis.
Acknowledgments. This work was supported by 2015
Research Fund of Myongji University.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
2009, 1, 437; (b) P. Melchiorre, Angew. Chem. Int. Ed. 2009,
48, 1360; (c) J. Vesely, R. Rios, ChemCatChem 2012, 4, 942.
4. Also see: (a) H.-W. Shih, M. N. V. Wal, R. L. Grange,
D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 13600;
(b) A. E. Allen, D. W. C. MacMillan, J. Am. Chem. Soc. 2011,
133, 4260.
5. B. List, I. Coric, O. O. Grygorenko, O. S. J. Kaib, I. Komarov,
A. Lee, M. Leutzsch, S. C. Pan, A. V. Tymtsunik,
M. Gemmeren, Angew. Chem. Int. Ed. 2014, 53, 282.
6. J. E. Hein, J. Burs, Y.-H. Lam, M. Hughes, K. N. Houk,
A. Armstrong, D. G. Blackmond, Org. Lett. 2011, 13, 5644.
7. For reviews on NHC catalysis, see: (a) D. Enders, O. Niemeier,
A. Henseler, Chem. Rev. 2007, 107, 5606; (b) E. M. Phillips,
M. Riedrich, K. A. Scheidt, Aldrichimica Acta 2009, 42, 55;
(c) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511;
(d) H. U. Vora, P. Sheeler, T. Rovis, Adv. Synth. Catal. 2012,
354, 1617.
References
1. (a) R. Schmierer, G. Grotemeier, G. Helmchen, A. Selim, Angew.
Chem. Int. Ed. 1981, 20, 207; (b) D. A. Evans, M. D. Ennis,
D. J. Mathre, J. Am. Chem. Soc. 1982, 104, 1737;
(c) D. Enders, H. Eichenauer, U. Baus, H. Schubert,
K. A. M. Kremer, Tetrahedron 1984, 40, 1345;
(d) W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett. 1989,
30, 5603; (e) M. Imai, A. Hagihara, H. Kawasaki, K. Manabe,
K. Koga, J. Am. Chem. Soc. 1994, 116, 8829; (f )
T. Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656.
2. (a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726;
(b) K. N. Houk, B. List, Acc. Chem. Res. 2004, 37, 487;
(c) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719;
(d) B. List, J. W. Yang, Science 2006, 313, 1584;
(e) A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 2008, 47,
4638; (f ) D. W. C. MacMillan, Nature 2008, 455, 304.
8. A. Lee, A. Younai, C. K. Price, J. Izquierdo, R. K. Mishra,
K. A. Scheidt, J. Am. Chem. Soc. 2014, 136, 10589.
9. L. A. Paquette, J. P. Gilday, J. Org. Chem. 1988, 53, 4972.
3. For reviews on organocatalytic asymmetric α-alkylation of alde-
hydes, see: (a) A.-N. Alba, M. Viciano, R. Rios, ChemCatChem
Bull. Korean Chem. Soc. 2015, Vol. 36, 2585–2586
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