Highly stereoselective synthesis of homoallylic amines based on addition of allyltrichlorosilanes to benzoylhydrazones

Article abstract of DOI:10.1021/ja011125m

Allyltrichlorosilanes reacted with benzoylhydrazones in DMF without the use of any catalyst to afford the corresponding homoallylic benzoylhydrazines in good to high yields. The reactions proceeded at 0°C to room temperature under mild conditions. In addi

Full text of DOI:10.1021/ja011125m

VOLUME 123, NUMBER 39
OCTOBER 3, 2001
© Copyright 2001 by the
American Chemical Society
Highly Stereoselective Synthesis of Homoallylic Amines Based on
Addition of Allyltrichlorosilanes to Benzoylhydrazones
Ryoji Hirabayashi, Chikako Ogawa, Masaharu Sugiura, and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST,
Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed May 4, 2001
Abstract: Allyltrichlorosilanes reacted with benzoylhydrazones in DMF without the use of any catalyst to
afford the corresponding homoallylic benzoylhydrazines in good to high yields. The reactions proceeded at 0
°C to room temperature under mild conditions. In addition, it was found that the reactions tolerated well the
steric hindrance of hydrazones and allyltrichlorosilanes. Indeed, ketone-derived benzoylhydrazones reacted
with allyltrichlorosilane smoothly to afford the corresponding N′-tert-alkyl-N-benzoylhydrazines in high yields.
In crotylation with (E)- and (Z)-crotyltrichlorosilanes, syn- and anti-adducts were stereospecifically obtained,
respectively. These reactions are most likely to proceed via a cyclic chairlike transition state where the R
group takes an axial position. When R-heteroatom-substituted chiral benzoylhydrazones were used, high anti-
diastereoselectivities were observed. These adducts can be readily converted to homoallylic amines in high
yields without epimerization.
Introduction
stereoselectivities have been shown in the reactions of crotyl-
trialkylborons with some imines, the selectivities are strongly
dependent upon the imine structures, and it is not possible to
obtain both syn- and anti-adducts stereoselectively from one
specific imine.3a,b While crotyltins selectively give syn-homoal-
lylic amines, as in their reactions with aldehydes, anti-adducts
are not obtained preferentially.3c As for silicon nucleophiles,
allyltrimethylsilane is usually weakly nucleophilic toward imines
even in the presence of a Lewis acid. It was reported that
crotyltrifluorosilanes react with imines in the presence of a
stoichiometric amount of cesium fluoride, but that the diaste-
reoselectivities are not high.3d To date, there are no crotylmetals
available to give both syn- and anti-homoallylic amines stereo-
selectively, to the best of our knowledge. Another problem is
that the secondary amines produced in the reaction with imines
cannot routinely be deprotected to the corresponding primary
amines.
Nucleophilic addition of allylmetal reagents to imines or their
analogues has been widely utilized for the syntheses of nitrogen-
containing compounds, since the resulting homoallylic amines
are useful intermediates for further transformations.1,2 However,
unlike in the case of aldehydes, the results of the processes have
often been unsatisfactory due to the low electrophilicity of
imines. With typical strong nucleophiles such as allyllithium
or -magnesium, R-deprotonation takes place exclusively over
the addition reactions when nonbranched “enolizable” imines
are applied. Moreover, a synthetically useful level of diastereo-
and regioselectivities is not achieved in crotylation using these
metals. Among the allylmetals devised to address these issues,
boron and tin in the presence of a Lewis acid catalyst have been
shown to be effective to some extent. Although excellent dia-
(1) (a) Kleinmann, E. F.; Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Heathcock, C. H., Ed.; Pergamom: Oxford, 1990; Vol. 2, p 975.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold: U.
Tetrahedron: Asymmetry 1997, 8, 1895.
(3) (a) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Org. Chem. 1985,
50, 3115. (b) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1987,
215. (c) Keck, G. E.; Enholm, E. J. J. Org. Chem. 1985, 50, 146. (d) Kira,
M.; Hino, T.; Sakurai, H. Chem. Lett. 1991, 277.
(2) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
10.1021/ja011125m CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

9494 J. Am. Chem. Soc., Vol. 123, No. 39, 2001
Table 1. Effect of Solvents
Hirabayashi et al.
Table 2. Allylation of Aldehyde-Derived Benzoylhydrazones
entry
solvent
time/h
yield/%
entry
R
time/h
product
yield/%
1
2
2
4
5
6
7
DMF
HMPA
2
2
18
18
18
18
18
95
91
44
32
31
29
<1
1
2
3
4
5
6
7
Ph (1a)
1
1
15
13
1
15
7
3a
3b
3c
3d
3e
3f
96
90
77
76
73
74
77
(E)-PhCHdCH (1b)
Ph(CH2)2 (1c)
CH3(CH2)4 (1d)
i-Bu (1e)
c-C6H11 (1f)
t-Bu (1g)
N,N-dimethylacetamide (DMA)
THF
CH3CN
CH2Cl2
MeOH
3g
Table 3. Allylation of Ketone-Derived Benzoylhydrazones
On the other hand, we have previously reported that allyl-
trichlorosilanes reacted with aldehydes in N,N-dimethylforma-
mide (DMF) without a catalyst to afford the corresponding
homoallylic alcohols in a highly regio- and stereoselective
manner.4-6 The strict stereospecificity of the transfer of the
geometry of the silanes to the products suggested a six-
membered chairlike transition state. This reaction system seemed
to us to be quite attractive, because the reactions have realized
high yields and diastereoselectivities in a simple procedure under
mild conditions using environmentally less harmful reagents.
In view of the utility of these reactions, we undertook a study
to apply them to the stereoselective syntheses of homoallylic
amines by employing nitrogen analogues of aldehydes. Herein
we describe the full details of the studies.7
entry
R1
R2
time/h
product
yield/%
1
2
3
4
5
6
7
8
Ph
CH3 (1h)
CH3 (1i)
CH3 (1j)
CH3 (1k)
CH3 (1l)
CH3 (1m)
3
3
3
3
2
0.3
2
3h
3i
3j
3k
3l
3m
3n
3o
95
95
90
96
60
81
62
87
p-MeOPh
m-NO2Ph
2-naphthyl
CH3
Ph(CH2)2
-(CH2)5- (1n)
Ph
C3H7 (1o)
3
Results and Discussion
The resulting hydrazines can be converted to the corresponding
primary amines. To our delight, when benzaldehyde benzoyl-
hydrazone (1a) was treated with allyltrichlorosilane (2a) in
DMF, the reaction proceeded without the use of any catalyst to
give the corresponding adduct, homoallylic hydrazine, in
excellent yield. It is noted that the reaction proceeded at room
temperature under mild conditions. Moreover, benzoylhydra-
zones have advantages over imines. They are usually stable
crystals, including those derived from aliphatic, R,â-unsaturated,
and aromatic aldehydes, and the resulting adducts can be easily
converted to the corresponding primary amines (vide infra).
The effect of solvents was then surveyed using 1a as a
substrate (Table 1). As illustrated in the table, a significant effect
of solvents was observed in this reaction. The addition proceeded
cleanly in DMF or HMPA to afford the desired adducts in high
yields (entries 1 and 2), whereas the reaction mixture turned
somewhat messy and lower yields were obtained in other
solvents (entries 3-6). In methanol allyltrichlorosilane decom-
posed rapidly (entry 7). It is noteworthy that the reaction
proceeded in even lower yields in other solvents than DMF and
HMPA, while no reaction of aldehydes with allyltrichlorosilane
occurred in these solvents.4a,b This result is presumably due to
the coordination of the benzoyl carbonyl to allyltrichlorosilane,
since allyltrichlorosilane is known to be a very weak nucleophile
if not coordinated.9 The mechanism of these reactions will be
discussed later. It should be pointed out here that the solubility
of 1a in other solvents than DMF, HMPA, and DMA is
We first examined the reaction of allyltrichlorosilane with
imines prepared from benzaldehyde and benzhydrylamine, but
no addition proceeded in DMF. An attempt to increase the
electrophilicity of imines by using that derived from p-
chloroaniline also failed to give the desired adduct. Assuming
that the activation of allyltrichlorosilane by DMF might not be
sufficient to react with imines, other Lewis bases such as
HMPA, tributylphosphine, 4-(dimethylamino)pyridine, ureas,
and so forth were added to the reaction mixture. However, they
did not catalyze the addition either. We judged on the basis of
these results that imines were inert or very sluggish toward
allyltrichlorosilane. Thus, our attention was turned to using other
nitrogen-containing electrophiles as imine equivalents.
Acylhydrazones, which are readily prepared from the corre-
sponding aldehydes, have been shown in our laboratory to serve
as electrophiles in Mannich-type, allylation, and cyanation
reactions in the presence of a catalytic amount of a Lewis acid.8
(4) (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 5453. (b)
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620. (c) Kobayashi,
S.; Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392.
(5) For examples for enantioselective synthesis of homoallylic alcohols
using a chiral Lewis base and related work, see: (a) Denmark, S. E.; Coe,
D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161. (b) Iseki,
K.; Kuroki, Y.; Takahashi, M.; Kobayashi, Y. Tetrahedron Lett. 1996, 37,
5149. (c) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron
1999, 50, 977. (d) Angell, R. M.; Barrett, A. G. M.; Braddock, D. C.;
Swallows, S.; Vickery, B. D. J. Chem. Soc., Chem. Commun. 1997, 919.
(e) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc.
1998, 120, 6419. (f) Chataigner, I.; Piarulli, U.; Gennari, C. Tetrahedron
Lett. 1999, 40, 3633. (g) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000,
122, 12021. For other related works, see: (h) Short, J. D.; Attenoux, S.;
Berrisford, D. J. Tetrahedron Lett. 1997, 38, 2351. (i) Fu¨rstner, A.;
Voigtlander, D. Synthesis 2000, 7, 959.
(8) (a) Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (b) Kobayashi,
S.; Hasegawa, Y.; Ishitani, H. Chem. Lett. 1998, 1131. (c) Kobayashi, S.;
Furuta, T.; Sugita, K.; Oyamada, H. Synlett 1998, 1019. (d) Kobayashi, S.;
Sugita, K.; Oyamada, H. Synlett 1999, 138. (e) Kobayashi, S.; Furuta, T.;
Sugita, K.; Okitsu, O.; Oyamada, H. Tetrahedron Lett. 1999, 40, 1341. (f)
Manabe, K.; Oyamada, H.; Sugita, K.; Kobayashi, S. J. Org. Chem. 1999,
64, 8054. (g) Okitsu, O.; Oyamada, H.; Furuta, T.; Kobayashi, S.
Heterocycles 2000, 52, 1143.
(6) For related reviews, see: (a) Nakajima, M. J. Synth. Org. Chem.
Jpn. 2000, 58, 839. (b) Marshall, J. A. Chemtracts: Org Chem. 1998, 11,
697.
(7) For a preliminary communication of this work, see: Kobayashi, S.;
Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942.
(9) Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954.

StereoselectiVe Synthesis of Homoallylic Amines
Table 4. Crotylation of Benzoylhydrazones (1)
J. Am. Chem. Soc., Vol. 123, No. 39, 2001 9495
entry
R1
crotylsilane
temp/°C
time/h
yield/%
syn/antia
1
2
3
4
5
6
7
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
(E)-PhCHdCH (1b)
(E)-PhCHdCH (1b)
2b
2b
2c
2c
2c
2b
2c
rt
0
0
1
18
18
1
51
18
18
68 (4a)
79 (4a)
59b (4a)
56 (4a)
41c (4a)
80 (4b)
82 (4b)
9/91
1/99
78/22
40/60
80/20
3/97
rt
-10
0
0
95/5
1
a Determined by H NMR analyses. b The amount of starting material recovered was 37%. c A 1.5 equiv sample of 2c was used.
inadequate.10 However, the solvent effect is not a mere
consequence of the difference in the solubility, because the
reaction of 3-phenylpropanal benzoylhydrazone (1c), which is
soluble in dichloromethane, also gave a low yield (23%) in the
solvent, while in DMF a good yield was obtained as subse-
quently shown.
Scheme 1. Crotylation of Benzoylhydrazones Derived from
3-Phenylpropanal without a Base
We then applied the allylation reaction over a range of
benzoylhydrazones in DMF (Table 2). A reaction of an R,â-
unsaturated aldehyde (cinnamaldehyde) benzoylhydrazone (1b)
proceeded to afford a 1,2-adduct exclusively over a 1,4-adduct
in high yield (entry 2). Hydrazones derived from aliphatic
aldehydes including bulky ones such as cyclohexanecarboxal-
dehyde (1f) and pivalaldehyde (1g) reacted smoothly to give
the products in good yields (entries 3-7). Note that the
difference in the reaction time does not signify a difference in
the reactivity.11
In addition, it was found that hydrazones derived from ketones
also reacted with allyltrichlorosilane smoothly to afford the
corresponding adducts in high yields (Table 3). The adducts,
N′-tert-alkyl-N-benzoylhydrazines, provide an interesting class
of compounds, but their synthesis is known to be difficult.1a,12
While the addition of Grignard reagents to aldimines for
preparation of R-substituted secondary amines has been reported,
the addition to ketimines for synthesis of R,R-disubstituted
tertiary amines is not well precedented, because ketimines are
sterically hindered, and competing enolization of ketimines
causes serious side reactions.13 Moreover, even aldimines are
less reactive, and activation by Lewis acids is often needed to
complete the reactions. It is noteworthy in the present system
that ketone-derived acylhydrazones smoothly reacted with
allyltrichlorosilane without the use of any catalyst under mild
conditions (0 °C to room temperature) to afford the desired
adducts in high yields.
diastereoselection changed to yield the anti-adduct as the slightly
major product (entry 4), suggesting that other transition states,
which gave the anti-product, competed here. A trial to obtain
better syn-selectivity by lowering the reaction temperature to
-10 °C met with lower reactivity and yield (entry 5). Similarly,
in the reaction of cinnamaldehyde benzoylhydrazone with (Z)-
and (E)-crotyltrichlorosilane, 1,2-addition proceeded exclusively
again to afford stereoselectively anti- and syn-adducts, respec-
tively (entries 6 and 7). It is remarkable that the correlations
between the geometry of crotylsilanes and the stereochemistry
of products in these cases (from Z to anti; from E to syn) are
found to be the reverse of those observed in reactions of
aldehydes with crotylsilanes.4a,b
In crotylation of 3-phenylpropanal benzoylhydrazone, initial
experiments gave a mixture of a branched and an unexpected
linear adduct (Scheme 1). The linear product was found to be
a single isomer irrespective of the geometry of the starting
crotylsilane, and the branched/linear ratio was not constant. That
the diastereomeric ratio of the branched product was high led
us to investigate the method of obtaining the branched isomer
selectively. Since it is well-known that nucleophilic attack of
allylsilanes occurs selectively at the γ positions of the silicon
atoms, the linear adduct was assumed to be formed via
isomerization of crotyltrichlorosilane before the addition15 or
isomerization of the product after the addition.16 Nevertheless,
the possibility of the former appeared to be low because the
reactions with benzaldehyde and cinnamaldehyde benzoylhy-
Next, we examined the crotylation reactions (Table 4). In
the reaction of benzaldehyde benzoylhydrazone with (Z)-
crotyltrichlorosilane,14a,b high anti-selectivity up to 99/1 was
obtained (entries 1 and 2). In contrast, the reaction of (E)-
crotyltrichlorosilane14c gave syn-adduct predominantly at 0 °C
(entry 3). These results suggest that the reactions proceed via a
cyclic transition state. When the reaction with (E)-crotyltrichlo-
rosilane was performed at room temperature, the course of
(14) For synthesis of the 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. For synthesis of the E-isomer,
see: (c) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1.
(15) For an example of iomerization of allylic silanes, see: Hosomi, A.;
Shibahara, A.; Sakurai, H. Chem. Lett. 1978, 901.
(10) Product 3a is soluble in all the solvents shown in Table 1.
(11) The reaction time of each allylation is not optimized.
(12) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1997, 62, 5537.
(13) Wang, D.-K.; Dai, L.-X.; Hou, X.-L.; Zhang, Y. Tetrahedron Lett.
1996, 37, 4187.

9496 J. Am. Chem. Soc., Vol. 123, No. 39, 2001
Table 5. Crotylation of Benzoylhdrazones (2)
Hirabayashi et al.
Table 6. Crotylation of a Benzoylhydrazone Derived from
Pivalaldehyde
syn/antia
entry
R1
crotylsilane product yield/% syn/antia
entry
crotylsilane
temp/°C
time/h
yield/%
1
2
3
4
Ph(CH2)2 (1c)
Ph(CH2)2 (1c)
CH3(CH2)4 (1d)
CH3(CH2)4 (1d)
i-Bu (1e)
i-Bu (1e)
c-C6H11 (1f)
c-C6H11 (1f)
2b
2c
2b
2c
2b
2c
2b
2c
4c
4c
4d
4d
4e
4e
4f
65
66
65
67
65
68
61
48
9/91
92/8
7/93
93/7
7/93
94/6
5/95
55/45
1
2
3
4
2b
2b
2b
2c
0
rt
40
rt
18
18
7
16
60
49
49
77/23
81/19
87/13
3/97
18
5
a Determined by H NMR analyses.
1
6
7b
8b
Chart 1. Chemical Shift Values of syn- and anti-Isomers
4f
1
a Determined by H NMR analyses. b The reaction time was 20 h.
drazones gave only the branched adducts. Actually, during the
course of the investigation, we found that the ratio of the linear
to the branched isomer gradually increased in CDCl3 after
isolation of the product. On the basis of a conjecture that the
isomerization was brought about by the acid originated from
CDCl3, we assumed that the acid produced in the reaction of
crotyltrichlorosilane with water, which would inevitably be
present in DMF despite careful manipulation, promoted the
isomerization during the reaction. As expected, exclusive
formation of the branched adduct was achieved when 0.1 equiv
of N,N-diisopropylethylamine was added to the reaction mixture
as a neutralizing agent, though the mechanism of the isomer-
ization is still unclear.
Table 7. Prenylation of Benzoylhydrazones
Thus, crotylation of other benzoylhydrazones was performed
in the presence of N,N-diisopropylethylamine, and the results
are summarized in Table 5. Again in these cases anti-products
were uniformly obtained selectively with (Z)-crotyltrichlorosi-
lane (entries 1, 3, 5, and 7), while (E)-crotyltrichlorosilane gave
syn-products selectively (entries 2, 4, and 6) except in the case
of bulky cyclohexanecarboxaldehyde benzoylhydrazone (entry
8). Interestingly, when these reactions were carried out in the
absence of a base, no linear adduct was obtained from hexanal
benzoylhydrazone, while almost all the products were linear
isomers in the case of isobutyraldehyde and cyclohexanecar-
boxaldehyde benzoylhydrazones.
In crotylation of pivalaldehyde benzoylhydrazone (1g), yields
were acceptable at room temperature and good diastereoselec-
tivities were shown (Table 6). Especially, when (E)-crotylsilane
was used, excellent diastereoselectivity was obtained (entry 4).
No linear adduct was formed in these reactions even without
an amine. As for the relative configuration of these products,
we assigned it in this case assuming that syn- and anti-adducts
were preferentially obtained from (Z)- and (E)-crotylsilane,
respectively. That is, the correlation of crotylsilane geometry
and the product stereochemistry was the reverse of that in other
substrates (1a-f). This assignment was made on the basis of
the observed tendency that a higher temperature gave a better
diastereomeric ratio and that (E)-crotylsilane was more diaste-
reoselective. As already shown in the case of bulky benzalde-
hyde benzoylhydrazone (Table 4, entry 4), (E)-crotylsilane was
entry
R1
product
yield/%
1
2
3
Ph (1a)
5a
5b
5c
44
48
55
(E)-PhCHdCH (1b)
Ph(CH2)2 (1c)
slightly anti-selective at room temperature, and it would be more
anti-selective at higher temperature. This assignment was also
supported by 1H and 13C NMR analyses (Chart 1). The chemical
shift values of the R-nitrogen methyne proton of syn-isomers
and the methyl carbon of the anti-isomers have invariably
appeared at lower field than those of the corresponding anti-
and syn-isomers, respectively.
Next, prenylation was investigated (Table 7). Although the
reaction rate was slower, prenylation also proceeded to afford
the desired products in moderate yields. It can be concluded
from these results that the present allylation reactions tolerate
well the steric hindrance of hydrazones and allyltrichlorosilanes.
The stereoselectivities in these reactions are most likely
accounted for by assuming a chairlike transition structure in
which the nitrogen atom and a benzoyl carbonyl group coor-
dinate to the silicon atom (Figure 1). The E-geometry of hy-
drazone puts the R group at an axial direction; consequently,
syn- and anti-homoallylic hydrazines are stereospecifically
obtained from (E)- and (Z)-crotyltrichlorosilanes, respectively.
Similar transition structures where the R group is located at an
axial position have already been proposed in reactions of other
allylmetals (Li, Mg, and B) with imines.3a Another possibility
(16) Isomerization of homoallylic alcohols under Lewis acidic conditions
has been reported: (a) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida,
S. J. Am. Chem. Soc. 1998, 120, 6609. (b) Sumida, S.; Ohga, M.; Mitani,
J.; Nokami, J. J. Am. Chem. Soc. 2000, 120, 1310.

StereoselectiVe Synthesis of Homoallylic Amines
J. Am. Chem. Soc., Vol. 123, No. 39, 2001 9497
Figure 4.
Figure 1. Assumed transition states.
Figure 2.
Figure 3.
is formation of a transition structure in which a cationic
siliconate species is involved when a coordinating solvent such
as DMF or HMPA is used (Figure 2). Similar intermediates
have been suggested in the Lewis base catalyzed addition of
allyltrichlrosilanes to aldehydes.4b,5g,h Coordination of a Lewis
base to the silicon atom would enhance the nucleophilicity of
allyltrichlorosilane, while the Lewis acidic silicon activates the
hydrazone. Both factors would be essential for the reaction to
take place. Accordingly, coordination of the benzoyl carbonyl
group to the silicon atom must be essential, because benzoyl-
hydrazones reacted with allyltrichlorosilane even in noncoor-
dinating solvents where external coordination is absent (see
Table 1). The coordination is also likely to serve for stabilization
of the transition structures.
As already shown, in the crotylation of moderately bulky
benzaldehyde and cyclohexanecarboxaldehyde benzoylhydra-
zones, the diastereoselectivities deteriorated when (E)-crotyl-
trichlorosillane was used (Table 3, entry 4, and Table 4, entry
8), while even bulkier pivalaldehyde benzoylhydrazone (1g)
gave the reverse correlation between the crotylsilane geometry
and the product stereochemistry (from Z to syn; from E to anti).
Since the reactions should proceed via cyclic transition states,
these results indicate the presence of another competing cyclic
transition structure. It seems that a boatlike (Figure 3) or a
chairlike structure with the R group at an equatorial direction
after E f Z isomerization of hydrazone (Figure 4) is worth
considering.3a,b The stereochemical outcome of the possible
transition structures is summarized in Figure 5. The coordination
of the benzoyl carbonyl group is omitted for clarity.
Figure 5. Possible reaction pathway.
The following reaction courses are considered to rationalize
the change in diastereoselectivity in those substrates. As already
illustrated in Figure 1 (or Figure 2), when R is not so bulky (R
is not t-Bu, Ph, and c-Hex), TS1 is the most favorable and the
“normal” correlation is given as a consequence. On the other
hand, since the 1,3-diaxial interaction of R with the substituents
on the silicon atom increases with the steric bulk of R, TS1 is
no longer favorable when R is considerably bulky (R ) t-Bu).
Therefore, the reaction mainly proceeds via TS2 and/or TS3,
leading to the reverse correlation. The tendency that better
diastereoselectivity was given at higher reaction temperatures
would be explained by taking TS3 into account. The contribu-
tion from TS3 would be larger at higher temperature, because
the E/Z isomerization of benzoylhydrazone should be easier.
When the bulkiness of R is moderate (R ) c-Hex, Ph), a
distinct difference between (E)-and (Z)-crotylsilanes arises.
While large 1,3-diaxial interaction is present in both TS1-c and
-t, TS2-c is also unfavorable due to repulsion between R and
the methyl group of (Z)-crotylsilane. On the other hand, no such
repulsion is present in TS2-t. As a result, the reaction proceeds
selectively via TS1-c with (Z)-crotylsilane, leading to high
diastereoselectivity, whereas TS2-t competes against TS1-t,
resulting in low diastereoselectivity when (E)-crotylsilane is
used. TS3 would not be dominant in these cases.

9498 J. Am. Chem. Soc., Vol. 123, No. 39, 2001
Hirabayashi et al.
Scheme 2. Allylation of an R-Chiral Benzoylhydrazone
Table 8. Allylation of R-Alkoxy Benzoylhydrazones
Figure 6.
yield/%
entry
R
time/h
additive
(3/6) syn/antib
1
Bn
3
4
3
12
4
none
none
9/56
32/35
32/38
8/92
3/97
3/97
3/97
3/97
2a
3a
4
TBS
TBS
TBS
TBS
Figure 7.
i-Pr2EtN (0.2 equiv)
(Me3SiOCH2)2 (2.0 equiv) 66/8
(MeOCH2)2 (2.0 equiv) 26/39
Scheme 4. Effect of TMS Ether
5
a The opposite enantiomer was used in the reaction. b Estimated by
13C NMR analyses. The diastereomer ratios of 3 were identical with
those of 6.
Scheme 3. Mechanism for the Cleavage of Ether
Diastereoselective Allylation of Chiral Benzoylhydrazones.
Next, we investigated allylation of R-chiral benzoylhydrazones.
In the reaction of phenylalaninal derivative 1p, an expected anti-
adduct was obtained in 92% yield with high selectivity (syn/
anti ) 2/98) (Scheme 2). Although anti-adducts were also
selectively obtained from R-alkoxy benzoylhydrazones, the
reactions were accompanied by partial cleavage of the ethers
(Table 8). While addition of an amine did not suppress the
generation of the alcohol (entry 3), it was found that the
trimethylsilyl (TMS) ether ((Me3SiOCH2)2 as an additive)
significantly reduced the alcohol product (entry 4). On the other
hand, dimethoxyethane provided no such effect (entry 5). We
presently assume the mechanism of the cleavage of ether as
follows (Scheme 3): The silicon atom of the initial product A
coordinates to the neighboring ether oxygen, and successive
formation of the O-Si bond affords C. Intermediate C gives
rise to the alcohol on quenching. Therefore, the effect of the
external TMS ether should stem from its action to inhibit the
intramolecular formation of the O-Si bond as shown in Scheme
4. The high anti-diastereoselectivity observed can be explained
by considering the Cram (Felkin-Anh) transition structure
(Figure 6).17 The anti-Cram (anti-Felkin-Anh) structure is
further destabilized by additional repulsion between the side
chain of the hydrazone and the substituents on the silicon atom.
Scheme 5. Allylation of an R-Chiral Benzoylhydrazone
without a Heteroatom Substituent
Another possibility that an electron-withdrawing effect of the
heteroatom moiety is a major determinant for the stereochem-
istry should be taken into consideration (Figure 7), because the
substrate without a heteroatom substituent furnished a lower
diastereomeric ratio (Scheme 5).
Conversion of the Products to Homoallylic Amines. Using
SmI2, the homoallylic hydrazines produced can be converted
to the corresponding primary amines in high yields without
epimerization as exemplified in Scheme 6.18 Thus, the hydrazine
was treated with SmI2 in THF-MeOH at room temperature for
10 min. That the dark-blue color of SmI2 turned yellow showed
completion of the cleavage of the N-N bond, and this facile
deprotection process should be noted because tedious procedures
are often required for deprotection of secondary amines in many
other cases. Moreover, the reductive cleavage of the N-N bond
would also be possible with Raney nickel/H2,19 though in this
case transformation of the double bond moiety beforehand may
be required.
(17) (a) Che´rest, H.; Felkin, H. Tetrahedron Lett. 1968, 2205. (b) Anh,
N. T. Top. Stereochem. 1980, 88, 145. High 1,2-asymmetric induction in
the reaction of an allylic boron reagent with chiral imines is explained by
a similar transition state. (c) Yamamoto, Y.; Nishii, S.; Maruyama, K.;
Komatsu, T.; Itoh, W. J. Am. Chem. Soc. 1986, 108, 7778.
(18) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266.

StereoselectiVe Synthesis of Homoallylic Amines
J. Am. Chem. Soc., Vol. 123, No. 39, 2001 9499
Scheme 6. Reductive Cleavage of the N-N Bond Using
trichlorosilanes to benzoylhydrazones. The addition reactions
proceeded smoothly in DMF without the use of any catalyst to
afford the corresponding homoallylic benzoylhydrazines in good
to high yields. While the reactions proceeded under mild
conditions (0 °C to room temperature), even sterically bulky
hydrazones and allyltrichlorosilanes reacted smoothly. It should
be noted that benzoylhydrazones derived from ketones reacted
smoothly to afford the N′-tert-alkyl-N-benzoylhydrazines in high
yields at room temperature within 3 h. In crotylation, syn- and
anti-adducts were stereospecifically obtained from (E)- and (Z)-
crotyltrichlorosilanes, respectively. These reactions most likely
proceed via a cyclic chairlike transition state where the R group
takes an axial position. This is the first example to show high
selectivities (both syn- and anti-adducts) in the reaction of
crotylmetals with imines or their analogues. When R-heteroa-
tom-substituted chiral benzoylhydrazones were used, high anti-
diastereoselectivities were observed. The adducts can be readily
converted to homoallylic amines in high yields without epimer-
ization. Further investigations to apply the present reactions to
asymmetric catalysis are in progress.
SmI2
Scheme 7. Synthesis of an Authentic Sample of the
anti-Primary Amine
Scheme 8. Relative Configuration Assignment for 3p
Experimental Section
A General Experimental Procedure for the Reaction of Ben-
zoylhydrazone with Allyltrichlorosilane. Allyltrichlorosilane (0.36
mmol) was added dropwise to a solution of benzoylhydrazone (0.3
mmol) in DMF (2.4 mL) at a temperature according to the reaction
conditions shown in the text. The mixture was stirred at the same
temperature, and then aqueous NaOH (ca. 0.2 N) was added to the
reaction mixture until the pH value of the solution was about 9. The
solution was filtered through a pad of Celite (if necessary) and washed
with dichloromethane, and the aqueous layer was further extracted with
the same solvent. The combined organic phase was dried over Na2SO4
and filtered, and then solvents were removed under reduced pressure.
The residue was purified by preparative TLC (hexane/ethyl acetate )
∼3/1 to ∼2/1) to yield the adduct.
Relative Configuration Assignment. Assignment of the
relative configuration of the crotylation products was made after
their conversion to the corresponding primary amines. The
determination was actually made on the products 4a20 and 4c,
and the others are assigned by analogy. An authentic sample of
the primary amine corresponding to anti-4c was synthesized
according to the unambiguous method shown in Scheme 7. The
relative configuration of the product 3r was also determined
after conversion to the corresponding primary amine,21 and
desilylation of anti-3r established the stereochemistry of 6. Since
the diastereomeric ratio of 3q was the same as that of 6, we
judged the major isomer in 3q was anti. The product from the
phenylalaninal derivative (3p) was converted to cyclic urea via
scission of the N-N bond followed by cyclization. The larger
H4-H5 coupling constant in the urea derived from the major
isomer suggests that the original adduct was the anti-isomer
(Scheme 8), because it is known in an analogous oxazolidinone
system that the H4-H5 coupling constant of the cis-isomer is
larger than that of the trans-isomer.
A Typical Experimental Procedure for the Reductive Cleavage
of the Hydrazine to the Corresponding Amine. 2-Methyl-1-phenyl-
3-butenylamine.3b 4a (syn/anti ) 1/99) (28.2 mg, 0.10 mmol) was
dissolved in MeOH (0.2 mL), and to this solution was added SmI2 in
THF (0.1 M, 3.0 mL, 0.3 mmol). Upon addition, the dark blue color
of SmI2 turned yellow. The mixture was stirred for 10 min, and then
solvents were removed under reduced pressure. The residue was purified
by preparative TLC (hexane/i-PrNH2 ) 10/1) to afford 2-methyl-1-
1
phenyl-3-butenylamine (syn/anti ) 1/99) (13.6 mg, 84%). H NMR
(CDCl3) (anti): δ ) 0.82 (d, 3H, J ) 6.8 Hz), 1.43 (br, 2H), 2.32-
2.41 (m, 1H), 3.64 (d, 1H, J ) 8.5 Hz), 5.11 (dd, 1H, J ) 2.0, 10.2
Hz), 5.17 (ddd, 1H, J ) 0.9, 1.7, 17.1 Hz), 5.74 (ddd, 1H, J ) 8.5,
10.2, 17.2 Hz), 7.22-7.35 (m, 5H).
Conclusion
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
We have developed a novel method for the stereoselective
synthesis of homoallylic amines based on addition of allyl-
Supporting Information Available: Experimental details
and characterization of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Gilchrist, T. L. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 388-389.
(20) Both syn- and anti-isomers of the primary amine corresponding to
4a are known compounds. See ref 3b.
(21) Cainelli, G.; Giacomini, D., Mezzina, E.; Panunzio, M.; Zarantonello,
P. Tetrahedron Lett. 1991, 32, 2967.
JA011125M