6942
J. Am. Chem. Soc. 1999, 121, 6942-6943
Table 1. Effect of Solvents
Highly Stereoselective Synthesis of Homoallylic
Amines Based on Addition of Allyltrichlorosilanes to
Benzoylhydrazones under Neutral Conditions
Shuj Kobayashi* and Ryoji Hirabayashi
run
solvent
time, h
yield, %
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo
CREST, Japan Science and Technology Corporation (JST)
Hongo, Bunkyo-ku, Tokyo, 113-0033
1
2
3
4
5
6
7
DMF
2
2
18
18
18
18
18
95
91
44
32
31
29
<1
HMPA
DMAa
THF
CH3CN
CH2Cl2
MeOH
ReceiVed February 16, 1999
Homoallylic amines are useful intermediates for the synthesis
of versatile nitrogen-containing compounds which are biologically
important.1 Although addition of allylmetals to imines or their
analogues potentially provides a direct and efficient way to these
compounds, the reactivity and selectivity are not satisfactory in
most cases. This is in contrast to the addition of allylmetals to
aldehydes which proceeds in high yields with high stereoselect-
ivities in some cases.2 Several major problems are pointed out in
the addition of allylmetals to imines for synthesis of homoallylic
amines:3 first, basic allylmetal reagents sometimes cause competi-
tive R-deprotonation of imines; second, regioisomers, which
correspond to different positions of the allyl units, are formed;
third, there is no crotylmetal that provides both syn and anti
diastereomers stereoselectively, to the best of our knowledge; and
finally, the secondary amines produced cannot routinely be
deprotected to give the corresponding primary amines.
On the other hand, we have recently reported that allyltrichlo-
rosilanes react with aldehydes in N,N-dimethylformamide (DMF)
without a catalyst to afford the corresponding homoallylic alcohols
in a highly regio- and stereoselective manner.4 In these reactions,
(Z)- and (E)-crotyltrichlorosilanes give syn- and anti-homoallylic
alcohols, respectively, under neutral conditions. In view of the
utility of these reactions, we undertook a study to apply them to
the synthesis of homoallylic amines by employing nitrogen
analogues of aldehydes. Herein we describe the first examples
of the addition of allyltrichlorosilanes to imine analogues where
the stereo- and regioselectivities are successfully controlled,
leading to the preparation of both syn- and anti-homoallylic
amines.
a N,N-Dimethylacetamide.
any catalyst) to afford the corresponding adduct in an excellent
yield. It should be noted that benzoylhydrazones have several
advantages over imines as substrates. They are readily prepared
from benzoylhydrazine and aldehydes including aliphatic and R,â-
unsaturated ones, and they are all stable and can be stored at room
temperature. Moreover, the adducts are easily converted to
primary amines (vide infra). The significant effect of solvents in
the reaction of 1a with 2a at 0 °C is shown in Table 1. Among
the solvents we examined, DMF and HMPA gave better yields,
and lower yield was obtained when N,N-dimethylacetamide
(DMA) was used. In CH3CN, CH2Cl2, and THF, yields were
around 30%. Addition proceeded sluggishly in MeOH, presum-
ably because 2a was decomposed.6,7 According to these results,
we decided on the following standard reaction conditions: to a
solution of 1 (0.3 mmol) in DMF (2.4 mL) was added allyl-
trichlorosilane (0.36 mmol) at room temperature or 0 °C. After
1-20 h (checked by TLC), diluted aqueous sodium hydroxide
(∼0.2 N) was added to the reaction mixture until the pH value
indicated ∼9. After filtration, the aqueous solution was extracted
with dichloromethane. The combined organic phase was dried
(Na2SO4) and filtered, and the solvents were removed under
reduced pressure. The residue was purified by preparative TLC
(hexane/ethyl acetate ) 3/2) to yield the target adduct.
We then undertook to carry out the addition reactions over a
range of benzoylhydrazones and allyltrichlorosilanes. The results
are summarized in Table 2. It was proved that allylation of
benzoylhydrazones derived from aromatic, R,â-unsaturated, and
aliphatic aldehydes also proceeded smoothly. Only 1,2-addition
of 2a to R,â-unsaturated hydrazone 1b occurred exclusively, and
no 1,4-addition adduct was obtained (run 4). Crotylation of 1a
or 1b with (Z)-crotyltrichlorosilane (2b)8 proceeded with excellent
anti-selectivity at 0 °C (runs 2 and 5), while the syn-adduct was
obtained predominantly from the (E)-isomer (2c) (runs 3 and 6).9
In crotylation of 1c, an initial experiment gave a mixture of the
desired adduct (branched adduct) and an unexpected linear adduct
(Scheme 1). Although the branched/linear formation mechanism
is not clear at this stage, exclusive formation of the branched
adduct was achieved when i-Pr2NEt (0.1 equiv) was added to
In our initial investigations, the reactions of allyltrichlorosilane
(2a) with several imines were studied. While the reaction did not
proceed at all in DMF, none of the donor additives such as
HMPA, tributylphosphine, urea, and 4-(dimethylamino)pyridine,
and so forth, catalyzed the addition. After searching for alternative
nitrogen-containing electrophiles, it was found that benzaldehyde
benzoylhydrazone5 (1a) reacted with 2a in DMF (without using
(1) (a) Kleinmann, E. F.; Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon: Oxford, 1990; Vol. 2, p 975.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold: U.
Tetrahedron: Asymmetry 1997, 8, 1895.
(2) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(3) (a) Keck, G. E.; Enholm, E. J. J. Org. Chem. 1985, 50, 146. (b)
Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Org. Chem. 1985, 50, 3115.
(c) Hoffmann, R. W.; Endesfelder, A. Liebigs. Ann. Chem. 1987, 215. (d)
Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415. (e) Kira, M.; Hino, T.;
Sakurai, H. Chem. Lett. 1991, 277.
(4) (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 5453. (b)
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620. See also, (c) Marshall,
J. A. Chemtracts: Org. Chem. 1998, 11, 697. (d) Denmark, S. E.; Coe, D.
M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161. (e) Kobayashi,
S.; Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392. (f) Iseki, K.; Kuroki, Y.;
Takahashi, M.; Kobayashi, Y. Tetrahedron Lett. 1996, 37, 5149. (g) Short, J.
D.; Attenoux, S.; Berrisford, D. J. Tetrahedron Lett. 1997, 38, 2351. (h)
Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998,
120, 6419.
(6) The addition of allyltrichlorosilane to benzoylhydrazone proceeded in
DMA, CH3CN, CH2Cl2, and THF, whereas no addition to aldehydes occurred
in these solvents. See refs 4a and b.
(7) It is noted that solubility in solvents other than DMF, HMPA, and DMA
was inadequate.
(8) Synthesis of (Z)-isomer, see: (a) Kira, M.; Kobayashi, M.; Sakurai, H.
Tetrahedron Lett. 1987, 28, 4081. (b) Kira, M.; Hino, T.; Sakurai, H.
Tetrahedron Lett. 1989, 30, 1099. (E)-isomer, see: (c) Furuya, N.; Sukawa,
T. J. Organomet. Chem. 1975, 96, C1.
(9) syn and anti configuration was determined after converting to the
corresponding amine. See Supporting Information.
(5) (a) Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (b) Kobayashi, S.;
Furuta, T.; Sugita, K.; Oyamada, H. Synlett 1998, 1019. Cf. (c) Burk, M. J.;
Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266.
10.1021/ja990497g CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999