Diastereoselective addition of γ-substituted allylic nucleophiles to ketones: Highly stereoselective synthesis of tertiary homoallylic alcohols using an allylic tributylstannane/stannous chloride system

Article abstract of DOI:10.1021/ja0274047

The diastereoselective addition of γ-substituted allylic nucleophiles to ketones has been accomplished to give tertiary homoallylic alcohols. The reaction of tributylcinnamyltin 1a with simple ketones 2 in the presence of stannous chloride (SnCl₂

Full text of DOI:10.1021/ja0274047

Published on Web 10/19/2002
Diastereoselective Addition of γ-Substituted Allylic
Nucleophiles to Ketones: Highly Stereoselective Synthesis of
Tertiary Homoallylic Alcohols Using an Allylic
Tributylstannane/Stannous Chloride System
Makoto Yasuda, Kay Hirata, Mitsuyoshi Nishino, Akihiro Yamamoto, and Akio Baba*
Contribution from the Department of Molecular Chemistry and Handai Frontier Research
Center, Graduate School of Engineering, Osaka UniVersity,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Received June 21, 2002
Abstract: The diastereoselective addition of γ-substituted allylic nucleophiles to ketones has been
accomplished to give tertiary homoallylic alcohols. The reaction of tributylcinnamyltin 1a with simple ketones
2 in the presence of stannous chloride (SnCl2) gave the tertiary homoallylic alcohols 3, which include the
anti form (based on Ph and OH), with high diastereoselectivity. In the reaction course, transmetalation of
tributylcinnamyltin 1a with SnCl2 proceeds to form an active nucleophile which is tentatively considered to
be a cinnamyltin(II) species. A cyclic transition state A is favorable because the chlorinated tin(II) center is
highly capable of accepting ligands. The other diastereomers (syn form) 4 were obtained in the reaction of
tributylcinnamyltin 1a with ketones 2 by the use of BF3‚OEt2 instead of SnCl2. This reaction proceeds through
an acyclic transition state in which BF3 acts as a Lewis acid for activation of ketones. When 3-tributylstan-
nylcyclohexene 1b or 3-tributylstannylcyclopentene 1c was used with SnCl2, high diastereoselective
formation of the corresponding homoallylic alcohols 6 which have the syn form (based on ring chain and
OH) was observed. The selectivity was also explained by the cyclic transition state B. When tributylcrotyltin
1d or 1e was used, the stereochemistry of the products depends on the additives (SnCl2 or BF3‚OEt2),
substituents of ketones, and reaction temperature. It is interesting that those additives compensate for
each other in terms of diastereoselective alkylation. The alkylation of R-alkoxy, aryloxy, or hydroxyketones
16 was achieved in extremely high selectivity using an allylic tributyltin 1a-c/SnCl2 system. The chelation
by carbonyl and â-oxygens provides a rigid transition state (E or F) for selective reactions. It is noted that
the hydroxyketone can be used without protection in this reaction system. The relative stereochemistry of
the produced tertiary homoallylic alcohols was determined on the basis of X-ray analyses.
to the stereoselection, is smaller in ketones than in aldehydes.3
In fact, as far as we know, the stereoselective addition of a
Introduction
A stereoselective carbon-carbon bond formation is one of
the most important reactions to construct a carbon skeleton in
organic synthesis. A diastereoselective addition of γ-substituted
allylic metals to aldehydes is a powerful method for that purpose
and has been extensively studied,1 giving secondary homoallylic
alcohols bearing adjacent chiral centers with high selectivity.
However, the stereoselective reaction of the γ-substituted allylic
metals with simple ketones instead of aldehydes has been rarely
reported. This is probably because the conditions achieving the
allylation of ketones would be too severe to control the selective
addition owing to the much lower reactivity of ketones than
that of aldehydes.2 Additionally, the difference in steric demand
between two substituents on the carbonyl carbon, which leads
cinnamyl nucleophile to ketones has not so far been reported
with determination of the stereochemistry of the products which
are tertiary homoallylic alcohols.3a,4-6 A cinnamyl Grignard
reagent, which is a common alkylating reagent, gave poor
(2) The striking difference in reactivity between aldehydes and ketones
sometimes presents a problem in the selective reaction using ketones. For
recent papers dealing with the reaction of ketones to overcome their different
reactivity from that of aldehydes, see: (a) Dosa, P. I.; Fu, G. C. J. Am.
Chem. Soc. 1998, 120, 445-446. (b) Yasuda, M.; Kitahara, N.; Fujibayashi,
T.; Baba, A. Chem. Lett. 1998, 743-744. (c) Casolari, S.; D’Addario, D.;
Tagliavini, E. Org. Lett. 1999, 1, 1061-1063.
(3) Although a few papers dealing with crotylation of ketones have appeared,
they usually afford moderate selectivities. (a) Maeda, H.; Shono, K.;
Ohmori, H. Chem. Pharm. Bull. 1994, 42, 1808-1812. (b) Sjo¨holm, R. E.
Acta Chem. Scand. 1990, 44, 82-89. (c) Reetz, M. T.; Steinbach, R.;
Westermann, J.; Peter, R.; Wenderoth, B. Chem. Ber. 1985, 118, 1441-
1454. (d) Katritzky, A. R.; Fali, C. N.; Qi, M. Tetrahedron Lett. 1998, 39,
363-366. (e) Rollin, Y.; Derien, S.; Dun˜ach, E.; Gebehenne, C.; Perichon,
J. Tetrahedron 1993, 49, 7723-7732. (f) Hebri, H.; Dun˜ach, E.; Pe´richon,
J. Tetrahedron Lett. 1993, 34, 1475-1478. (g) Seebach, D.; Wildler, L.
HelV. Chim. Acta 1982, 65, 1972-1981.
(4) Sjo¨holm, R.; Rairama, R.; Ahonen, M. J. Chem. Soc., Chem. Commun.
1994, 1217-1218.
(5) Araki, S.; Hatano, M.; Ito, H.; Butsugan, Y. J. Organomet. Chem. 1987,
333, 329-335.
* To whom correspondence should be addressed. E-mail: baba@
chem.eng.osaka-u.ac.jp.
(1) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243-249. (c) ComprehensiVe
Organic Syntheses; Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991;
Vol. 1. (d) ComprehensiVe Organic Syntheses; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 2.
9
13442
J. AM. CHEM. SOC. 2002, 124, 13442-13447
10.1021/ja0274047 CCC: $22.00 © 2002 American Chemical Society

Addition of Allylic Nucleophiles to Ketones
A R T I C L E S
Table 1. Diastereoselective Addition of 1a to 2
selectivity in the reaction with acetophenone (eq 1). This result
clearly shows that a highly nucleophilic species would give low
selectivity for the allylation and a nucleophile which has
appropriate reactivity is required.
entry
X
ketone
additive
yield/%
3:4
1a
2a
H
Cl
Br
Me
OMe
H
Cl
Br
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
SnCl2
SnCl2
SnCl2
SnCl2
82 (3a, 4a)
73 (3b, 4b)
84 (3c, 4c)
52 (3d, 4d)
56 (3e, 4e)
49 (3a, 4a)
67 (3b, 4b)
83 (3c, 4c)
29 (3d, 4d)
0
92:8
92:8
93:7
94:6
88:12
16:84
13:87
13:87
11:89
3a
4a
5a
SnCl2
The lack of information to determine the stereochemistry of
the products as well as the difficulty of finding a suitable
reaction system might have retarded the development of this
area of chemistry. In this paper, we report the following: (i)
Highly diastereoselective addition of γ-substituted allylic nu-
cleophiles toward simple ketones was achieved to form each
diastereomer of tertiary homoallylic alcohols by an allylic
tin(IV)-SnCl2 or -BF3 system. Those two systems mostly show
different diastereoselectivities (syn or anti). (ii) The stereo-
chemistry of the products was unambiguously determined on
the basis of X-ray analysis. (iii) The highly selective allylation
of R-alkoxy, aryloxy, or hydroxy ketones was controlled by
strong oxophilicity of the Sn(II) species that contributes to form
a rigid chelated cyclic transition state.
6b
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
7b
8b
9b
Me
OMe
10b
a Reactions were carried out in acetonitrile with cinnamylstannane 1a
(1.0 mmol), ketone 2 (1.0 mmol), and SnCl2 (1.0 mmol) at room temperature
for 3 h. b Reactions were carried out in dichloromethane with 1a (1.0 mmol),
2 (1.0mmol), and BF3‚OEt2 (2.0 mmol) at 0 °C for 20 h.
Table 2. Diastereoselective Addition of 1b or 1c with 2
Results and Discussion
entry
allylic tin
X
ketone
additive
yield/%
5:6
1a
2a
3a
4a
5a
6a
7b
1b
1b
1b
1b
1b
1c
H
Cl
Br
Me
OMe
H
2a
2b
2c
2d
2e
2a
2a
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
BF3‚OEt2
79 (5a, 6a)
87 (5b, 6b)
96 (5c, 6c)
87 (5d, 6d)
92 (5e, 6e)
84 (5f, 6f)
52 (5a, 6a)
<1:99
<1:99
<1:99
<1:99
12:88
<1:99
19:81
Diastereoselective Alkylation of Aryl Methyl Ketones with
Allylic Stannanes. We have previously reported a system using
allyltributylstannane with SnCl2,7 which accomplished the
allylation of ketones as well as aldehydes. This system also
provided highly diastereoselective addition of γ-substituted
allylic stannanes to aldehydes. We then examined this system
for cinnamylation of acetophenone, which gave, gratifyingly, a
promising result: To a reaction mixture of SnCl2 (1 equiv) and
acetophenone 2a (1 equiv) in acetonitrile was added tributyl-
cinnamyltin 1a (1 equiv) to give homoallylic alcohol in 82%
yield with high diastereoselectivity (3a/4a (anti/syn) ) 92/8)
(Table 1, entry 1).8 Only a small amount of an R-adduct (<5%)
was detected in the NMR spectra.9 In the course of our
investigation of other solvents, it was found that the use of
dichloromethane, THF, benzene, or hexane resulted in almost
no reaction. Varying the substituents, which have an either
electron-withdrawing or -donating property on the phenyl ring
in acetophenone, did not affect the selectivities (entries 2-5).
We turned our attention to Lewis acid-promoted allylation. A
BF3‚OEt2-accelerated allylation, which is an established method
for allylation of aldehydes using allylic stannanes, showed a
particular contrast to the reactions using SnCl2. As shown in
entries 6-9, the syn-homoallylic alcohols 4a-d were preferably
formed, although the ketone 2e bearing an electron-donating
group was inert to this reaction system (entry 10). These results
show that a switch of diastereoselectivity can be accomplished
by the addition of accelerators, SnCl2 or BF3‚OEt2.
1b
H
a Reactions were carried out in acetonitrile with allylic stannane 1b or
1c (1.0 mmol), ketone 2 (1.0 mmol), and SnCl2 (1.0 mmol) at room
temperature for 3 h. b Reactions were carried out in dichloromethane with
1b or 1c (1.0 mmol), 2 (1.0 mmol), and BF3‚OEt2 (2.0 mmol) at 0 °C for
2 h.
The results are summarized in Table 2. The reaction of
3-stannylcyclohexene 1b with acetophenone 2a in the presence
of SnCl2 gave the syn product 6a in high yield with perfect
selectivity (Table 2, entry 1). The product has different
stereoconfiguration from that obtained in the reaction of 1a that
has trans geometry. The substituents on the aryl ring did not
affect the yield and selectivity. A five-membered cyclic allylic
stannane 1c also gave the syn product 6f exclusively (entry 6).
The BF3‚OEt2-mediated reaction of 1b with 2a gave preferably
the same isomer 6a in lower yield and selectivity than the
reaction using SnCl2 (entries 1 and 7).
These reactions using SnCl2 in Tables 1 and 2 are stereospe-
cific because the geometry on the allylic moiety relates to the
stereochemistry of the product; trans-allylic stannane gives an
anti product, and cis type gives a syn product. A mixture of
cinnamylstannane 1a with SnCl2 in acetonitrile without ketone
afforded 92% of Bu3SnCl, which was monitored by 119Sn NMR.
This result strongly suggests the transmetalation between 1a
and SnCl2 and the generation of a new species which could be
allylic tin(II).10 A color change of the suspended solution to
dark brown was found in this case without ketone. The addition
We next examined the reaction using cyclic allylic stannanes
1b and 1c, which have cis geometry at their olefinic moiety.
(6) The reaction of allylic silicon compounds with ketimine was reported:
Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Org. Chem. 2002, 67, 5359-
5364.
(7) Yasuda, M.; Sugawa, Y.; Yamamoto, A.; Shibata, I.; Baba, A. Tetrahedron
Lett. 1996, 37, 5951-5954.
(8) The terms anti and syn are used on the basis of the relationship between
OH and Ph as shown in the schemes.
(10) Unfortunately, an allylic tin species was not confirmed probably because
of broadening of its signal in 119Sn NMR.
(9) 2,5-Diphenyl-4-penten-2-ol was observed as a minor product.3f
9
J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002 13443

A R T I C L E S
Yasuda et al.
Table 3. Diastereoselective Addition of 1d or 1e with 2a
Scheme 1. Plausible Path in the Reaction of 1a or 1b
of acetophenone 2a to the stirred mixture of 1a and SnCl2 for
20 min in acetonitrile gave a lower yield (41%) than that in
Table 1. The active species generated by transmetalation might
be gradually decomposed or deactivated by oligomerization.
Interestingly, no color change was found during the general
reaction procedure in which 1a was added to the premixed
suspension of 2a and SnCl2. In this case, the active species is
immediately consumed and smoothly gives the product.11 On
the basis of the stereochemical outcome, plausible reaction paths
are proposed in Scheme 1. At first, transmetalation of 1a with
SnCl2 proceeds to form an active nucleophile which is tenta-
tively considered to be a cinnamyltin(II) species.7,12,13 A cyclic
transition state is favorable because the chlorinated tin(II) center
is highly capable of accepting ligands.13a,b,14 In this transition
state A, a methyl group in ketone 2 (R ) Me) occupies an axial
position owing to its less steric hindrance than that of the aryl
group (Ar), giving highly diastereoselective formation of
homoallylic alcohols 3 (anti product). The alkylation with allylic
stannanes 1b or 1c which have a cis olefinic site also proceeds
through cyclic transition state B to give 6 (syn product). When
cinnamyl Grignard was used instead of 1a as an alkyl source
for transmetalation with SnCl2, no reaction with acetophenone
was observed.15,16 This result shows tin reagents are indispen-
sable to generate an active species for the alkylation in which
Bu3SnCl probably plays a key role to form a monomeric active
tin(II) species.13a
a Allylic stannane 1 was added to the mixture of 2 and SnCl2 in
acetonitrile. b The ketone 2 was added to the mixture of 1 and SnCl2 in
acetonitrile. c All reactions were carried out in dichloromethane with 1 (1.0
mmol), 2 (1.0 mmol), and BF3‚OEt2 (2.0 mmol).
of the olefinic moiety in the starting allylstannanes. For the BF3‚
OEt2 reactions with ketones in Tables 1 and 2, in fact, syn-type
products were predominantly obtained.
On the contrary, the reaction of crotylstannane showed
unexpected results as depicted in Table 3. Crotylstannane can
be prepared as the E-rich form 1d or Z-form 1e. The use of
E-rich crotylstannane 1d provided the corresponding homoallylic
alcohols 7a and 8a in syn selectivity (entry 1). The selectivity
was improved to 24/76 when the ketone was added to the
mixture of 1d and SnCl2 in acetonitrile (entry 2). Surprisingly,
the use of Z-crotylstannane 1e gave the same isomer 8a as a
major product in 70% selectivity (entry 3). Ketone 2b also gave
preferably syn product 8b using either 1d or 1e (entries 6 and
7). On the other hand, the reactions with 2a using either 1d or
1e at higher temperature after stirring at room temperature gave
anti product 7a as a major product (entries 4 and 5). These
results suggest that the intermediate nucleophiles are identical
in both cases using 1d and 1e and that the homoallylic alcohol
8a is a kinetic product and 7a is a thermodynamic product.
Interestingly, the BF3‚OEt2-accelerated alkylation showed op-
posite selectivity as compared with the reactions using SnCl2.
The reaction of 1d and/or 1e in the presence of BF3‚OEt2 gave
anti product 7a as the major product at -60 °C (entries 8 and
9) and syn alcohol 8a at higher temperature (entry 10).
The reaction course of crotylstannane with SnCl2 can be
explained as shown in Scheme 2. The transmetalation of either
1d or 1e gives a common intermediate 3-metallobut-1-enyl
species by rearrangement, which kinetically transforms to a
Z-crotyl species.19 The Z-crotyl species might then lead to 8Sn
preferably through cyclic transition state D. Under the reversible
reaction conditions, the product ratio was thermodynamically
controlled between 7Sn and 8Sn. Although the reaction mech-
anism using BF3‚OEt2 is not clear yet, it is quite interesting
that the Lewis acid-accelerated system has complementary
selectivity to the SnCl2-mediated system. The reported examples
Because there are many precedents of the reaction courses
of Lewis acid-accelerated allylation of aldehydes using allylic
stannanes,17 we assume that the reactions with ketones using
BF3‚OEt2 proceed through an acyclic transition state as proposed
by Yamamoto1b or Keck.18 In the reaction system, the stereo-
chemistry of the major products is independent of the geometry
(11) The mixture of 1a and SnCl2 in dichloromethane gave Bu3SnCl in 13%
even after 7 h. The SnCl2-mediated reaction of 1a with 2a in dichlo-
romethane gave no product as described above. Thus, the correlation
between transmetalation and yield was observed.
(12) Yasuda, M.; Matsukawa, Y.; Okamoto, K.; Sako, T.; Kitahara, N.; Baba,
A. Chem. Commun. 2000, 2149-2150.
(13) A referee suggested that the tin(II) species is unlikely to exist as a
monomeric structure. The result of stereoselectivity apparently shows the
cyclic transition state as illustrated in Scheme 1. The monomeric tin(II)
compounds coordinated by two appropriate ligands are reported, and the
tin center coordinates to Lewis acid. Therefore, in the transition state, the
actual species could be chlorinated allylic tin(II) coordinated by carbonyl
oxygen and acetonitrile and interacting with Bu3SnCl. (a) Drost, C.;
Hitchcock, P. B.; Lappert, M. F. Organometallics 1998, 17, 3838-3840.
(b) Barret, M. C.; Mahon, M. F.; Molloy, K. C.; Steed, J. W.; Wright, P.
Inorg. Chem. 2001, 40, 4384-4388.
(14) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-
1923.
(15) To a solution of cinnamyl Grignard reagent (2 equiv) and SnCl2 (2 equiv)
in Et2O was added acetophenone (1 equiv) at 0 °C, and the mixture was
stirred for 3 h.
(16) The color change from gray to red-brown was observed when mixing the
cinnamyl Grignard reagent and SnCl2. This system probably gives an
inactive species, for example, bis(cinnamyl)tin(II), by transmetalation.
(17) Nishigaichi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron 1993,
49, 7395-7426.
(18) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J. Org. Chem.
1994, 59, 7889-7896.
(19) Miyake, H.; Yamamura, K. Chem. Lett. 1992, 1369-1372. In a cinnamyl
case, the Z-form is too unstable to form, and then the E-form, which is a
thermodynamic product, acts as the active species.
9
13444 J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002

Addition of Allylic Nucleophiles to Ketones
A R T I C L E S
Scheme 2. Plausible Path in the Reaction of Crotylstannane 1d
or 1e
Table 4. Comparison of Selectivity among Alkylating Systems for
Alkoxyketone
a The alcohol 17a was obtained as a major product with its diastereomer.
Yields were given as the total amount of diastereomers.
for crotylation of acetophenone mostly give 7a as a major
product or nonselectivity.3 Only the crotyl Grignard is reported
to provide 8a as a major product, although the selectivity is
lower than that of our results.3b
conformation accounts for the low selectivity in eq 2. On the
contrary, the stability of transition state B (R ) Et or Bu) is
not sterically affected by the R group because ring methylenes
are positioned in trans conformation to R, leading to high
selectivity in the reaction of 1b or 1c in eqs 3 and 4.
In the reaction with dialkyl ketones, steric demand on the
carbonyl group was an important factor for diastereoselectivity.
In fact, while methyl n-propyl ketone 2i gave low selectivity
(59:41), high selectivity was obtained in the reaction with
isopropyl methyl ketone 2j to give 15 (eq 5).
When 2-acetonaphthone 2f was used as a substrate, both yield
and selectivity were high in the SnCl2-mediated reaction
employing either 1d or 1e to give anti 7f (entries 12 and 13 in
Table 3). Elevating the temperature up to 82 °C gave no change
in the stereochemistry (entries 14 and 15). The different
diastereoselectivity giving the anti form observed in this case
is not explainable at this stage. As can be seen, the crotylation
of ketones is a characteristic feature in synthetic organic
chemistry. There are more factors to control the diastereo-
selectivity as compared with the reaction with aldehydes.
The SnCl2-mediated allylation using cinnamyltin, cycloalk-
enyltin, or crotyltin gave high selectivity for allylation of
ketones. Especially for the reaction of cinnamyl and crotyltins,
SnCl2 and BF3 systems show the opposite selectivity. This point
greatly contributes to stereoselective synthetic organic synthesis.
SnCl2-Mediated Alkylation of Other Simple Ketones by
Allylic Stannanes. When propiophenone 2g was used for the
SnCl2-mediated reaction with 1a, homoallylic alcohol 10 (γ-
adduct) was obtained in poor diastereoselectivity accompanied
with a significant amount of R-adduct 9 (eq 2).20 The reaction
of cyclic allylic species 1b and 1c gave single isomers in high
yields and selectivities as shown in eqs 3 and 4. High selectivity
was observed even using butyl ketone 2h. In transition state A
(R ) Et), the steric hindrance between Ph and Et in gauche
Diastereoselective Addition to r-O-Substituted Ketones.
As shown in eq 5, methyl n-propyl ketone 2i gave poor
selectivity in the SnCl2-mediated reaction. However, a single
diastereomer 17a was obtained in the reaction with 1-methoxy-
2-propanone 16a, which has similar steric demand with 2i (Table
4, entry 1). The reaction using BF3‚OEt2 gave lower selectivity
and yield (entry 2). Other alkylating systems for the reaction
of cinnamyl nucleophiles were tried but showed poor selectivi-
ties; a zinc/halide system and a Grignard reagent gave 78:22
and 54:46 selectivities, respectively (entries 3 and 4).
We then investigated the generality of the SnCl2-stannane
system for R-O-substituted ketones 16, and the results are
summarized in Table 5. Phenoxyacetone 16b and methoxy-
acetophenone 16c afforded the products in high yields with
perfect selectivities (entries 2 and 3). It is surprising that
hydroxyketones 16d and 16e can be directly used without
protection of the OH group and afford the product 17d and 17e,
respectively, as single isomers (entries 4 and 5).
Because a tin(II) species is reported to accept two ligands
and has oxophilicity, we expected a rigid transition state
especially for oxo-functionalized substrates.13a,b,21 The stereo-
(20) The steric effect causes a formation of R-product because γ-alkylation
product, which would be kinetically formed, is unstable under these
conditions and transforms to R-adduct by thermodynamic control. An
example for the transformation from γ-adduct to R-adduct: Sumida, S.;
Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310-
1313.
(21) (a) Yasuda, M.; Okamoto, K.; Sako, T.; Baba, A. Chem. Commun. 2001,
157-158. (b) Yasuda, M.; Tsuchida, M.; Baba, A. Chem. Commun. 1998,
563-564.
9
J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002 13445

A R T I C L E S
Yasuda et al.
Table 5. Diastereoselective Addition of 1a to 16a
Table 6. Competitive Reaction between R-Alkoxy and Alkyl
ketones
a The alcohol 17a was obtained as a major product with its diastereomer.
Yields were given as the total amount of diastereomers. b The exact
stereochemistry of the diastereomers was not determined. Yields were given
as the total amount of diastereomers.
Table 7. Diastereoselective Addition of 1b or 1c to 16a
a All reactions were carried out in acetonitrile with cinnamylstannane
1a (1.0 mmol), ketone 16 (1.0 mmol), and SnCl2 (1.0 mmol) at room
temperature for 3 h.
Scheme 3. Plausible Mechanism through Chelated Cyclic
Transition State
chemical outcome using SnCl2 in Table 5 suggests the cyclic
transition state with oxygen-coordinated mechanism as shown
in Scheme 3. The generated cinnamyl tin(II) species and alkoxy,
aryloxy, or hydroxy ketone gave the chelated cyclic transition
state E.22 The oxyalkyl group (CH2OR) occupies an axial
position even when R′ has less bulkiness than CH2OR. The high
affinity of the tin center with oxygen strongly causes axial
preference of the oxyalkyl group. Sakurai and Kira reported
the same type of bicyclic transition state model for highly
selective allylation of hydroxyketones using allylic silanes.23
Their reaction requires an equimolar amount of a base to form
a covalent O-metal bond for a rigid transition state. On the
contrary, the present allylation system can be applied to alkoxy
ketones and gives a transition state with coordinative interaction
between O and the metal center. It is noted that hydroxyketones
can be directly utilized without any base and form a rigid
bicyclic transition state with coordination of the hydroxy group
to the tin center.
The effect of chelation on the acceleration of reaction rate
was clearly shown by the competitive reaction between alkoxy-
ketone 16a and dialkyl ketone 2i (Table 6). A cinnamylstannane/
SnCl2 system gave only 17a with high diastereoselectivity (entry
1). Although the BF3-mediated allylic stannane system resulted
in selective alkylation of alkoxyketone, the yield and diaste-
reoselectivity were low (entry 2). Neither a zinc/halide system
nor a Grignard reagent showed selective reactions (entries 3
and 4). These results in Tables 5 and 6 describe that the SnCl2-
a All reactions were carried out in acetonitrile with allylic stannane 1b
or 1c (1.0 mmol), ketone 16 (1.0 mmol), and SnCl2 (1.0 mmol) at room
temperature for 3 h. b The reaction was performed at 0 °C for 3 h.
mediated system is the best choice for the selective alkylation
of R-O-substituted ketones.
The cyclic stannanes 1b or 1c were also applied to selective
alkylation to R-O-substituted ketones 16 (Table 7). The products
18 were obtained through the transition state F. Highly selective
alkylations were accomplished in most cases, although phen-
oxyketone gave slightly lower selectivities (entries 2, 3, and
8).
(22) Examples for interaction of two donors with the tin(II) center: refs 13a
and 13b. The carbonyl and â-oxygens in 16 now act as donors.
(23) Sato, K.; Kira, M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111, 6429-6431.
Determination of Relative Stereochemistry of Tertiary
Homoallylic Alcohols. Determining the relative stereochemistry
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13446 J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002

Addition of Allylic Nucleophiles to Ketones
A R T I C L E S
(1.0 mmol) in dry acetonitrile (2 mL) was added allylic stannane 1
(1.0 mmol) under nitrogen. The reaction mixture was stirred under the
reaction conditions noted in the text. Diethyl ether (30 mL) and an
aqueous NH4F (15%; 15 mL) were added, and the resulting Bu3SnF
was filtered off. The filtrate was washed with water (30 mL × 2), dried
(MgSO4), and evaporated. Column chromatography of the resultant
residue on silica gel followed by distillation or recrystallization gave
pure products.
of the products bearing a quaternary carbon is an essential step
to discuss the reaction mechanism. The relative stereochemistry
of the products was determined by X-ray analyses of the
products or their derivatives. Details are shown in the Supporting
Information.
Conclusions
We have demonstrated a highly diastereoselective alkylation
of ketones by γ-substituted allylic reagents to form tertiary
homoallylic alcohols. For the reaction of simple ketones with
cinnamyl nucleophiles, the 1a/SnCl2 system gave the anti
product 3 with high diastereoselectivity, while the opposite
isomer 4 was preferably obtained by the 1a/BF3‚OEt2 system.
The cyclic allylic reagents 1b or 1c gave syn alcohol 6
selectively by either SnCl2 or the BF3‚OEt2-mediated reaction.
In this case, higher selectivity was obtained by the SnCl2-
mediated reaction. The allylic stannane/SnCl2 system provides
a tin(II) reagent as an active species by transmetalation and
proceeds through the cyclic transition state. In the reaction with
crotyltins 1d or 1e, SnCl2- and BF3‚OEt2-mediated reactions
always give different selectivity and compensate for each other.
The selectivity depends on the additives (SnCl2 or BF3‚OEt2),
substituents of ketones, and temperature. A highly selective
alkylation was observed in the SnCl2-mediated reaction of allylic
stannane with R-alkoxy, aryloxy, or hydroxy ketones. The
chelation by carbonyl and â-oxygens provides a rigid transition
state for selective reactions. The stereochemistry of the products
obtained as tertiary homoallylic alcohols was unambiguously
determined on the basis of X-ray analyses.
General Procedure (II) for Synthesis of Homoallylic Alcohols
Using BF3‚OEt2. To a mixture of BF3‚OEt2 (2.0 mmol) and ketone 2
or 16 (1.0 mmol) in dry dichloromethane (1 mL) was added allylic
tributylstannane 1 (1.0 mmol) under nitrogen. The reaction mixture
was stirred under the reaction conditions noted in the text. Diethyl ether
(30 mL) and aqueous NH4F (15%; 15 mL) were added, and the resulting
Bu3SnF was filtered off. The filtrate was washed with water (30 mL ×
2), dried (MgSO4), and evaporated. Column chromatography of the
resultant residue on silica gel followed by distillation or recrystallization
gave pure products.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese
Government. Thanks are due to Mr. H. Moriguchi, Faculty of
Engineering, Osaka University, for assistance in obtaining MS
spectra.
Supporting Information Available: Experimental procedures
and spectral data; determination of relative stereochemistry of
the products; details and tables for X-ray crystal structures of
3aE, 6bE, 8bE, 7fE, 17dE, 17e, and 19 (PDF); X-ray
crystallographic files (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental Section
General Procedure (I) for Synthesis of Homoallylic Alcohols
Using SnCl2. To a mixture of SnCl2 (1.0 mmol) and ketone 2 or 16
JA0274047
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