alkylation with 1c in moderate yields (entries 7-10).
Increasing the amount of AIBN and 1c was effective in
improving the yield. Functionalized unactivated haloalkanes
2k,l were also available for the present alkylation (entries
11 and 12). Instead of haloalkanes, phenylsulfide 2m and
thiocarbonates 2n,o14 could be alkylated with 1c. In the
absence of AIBN, the reactions shown in Table 2 did not
proceed to a significant extent except for the alkylation of
2d and 2f, in which 3cd and 3cf were obtained in 22% and
52% yields, respectively (entries 4 and 6).
(path b). A similar type of radical-based coupling reaction
using allylstannanes has been reported to provide a powerful
synthetic tool.16 Encouraged by the above result that stannyl
enolates serve as good radical alkylating agents, we next
directed our efforts to the three-component coupling reaction
among stannyl enolates, haloalkanes, and alkenes. For a
successful coupling, the radical intermediate R• should be
more reactive to 4 than to 1; therefore, simple iodoalkanes
2g,h,j and electron-deficient alkenes 4a-d were selected as
the substrates.17 Additionally, stannyl enolates 1c-e were
used in view of their high reactivities to secondary alkyl
radicals conjugated with an electron-withdrawing group.17
The results with 1c are shown in Table 3. As expected,
Stannyl enolates 1d and 1e, which exist as enol forms,
exhibited high reactivity to activated haloalkanes as did 1c,
while they were less reactive to simple haloalkanes than 1c
(Scheme 3). The low reactivity is attributable to the sterically
Table 3. Three-Component Coupling Reactiona
Scheme 3
iodoalkane
R
alkene
entry
E
E′
product
yield (%)b
68
1
2
3
4
5
6
7
8
9
Et
i-Pr
2g MeO2C
2h MeO2C
H
H
H
H
H
H
4a
4a
4a
4b
4b
4b
5a
5b
5c
5d
5e
5f
5g
5h
5i
78, 62c
t-Bu 2j
MeO2C
2g NC
2h NC
73
88
90
85
Et
i-Pr
t-Bu 2j
NC
Et
2g MeO2C CO2Me 4cd
95 (74:26)
quant (81:19)
85 (>99:1)
93 (81:19)
crowded reaction site in the enolates, which would retard
the homolytic substitution step in the chain process.
The present homolytic â-ketoalkylation would involve the
following propagation step (path a in Scheme 4): a tribu-
i-Pr
2h MeO2C CO2Me 4c
t-Bu 2j
MeO2C CO2Me 4c
10
i-Pr
2h MeO2C CO2Me 4d e
5h
a Unless otherwise noted, all reactions were performed with 1c (1.00
mmol), 2 (0.50 mmol), and 4 (1.00 mmol) in benzene (2.5 mL) at 80 °C
for 4 h. b Isomeric ratios are shown in parentheses. c With 1c (0.50 mmol)
and 4a (0.50 mmol). d Dimethyl fumarate. e Dimethyl maleate.
Scheme 4
the AIBN-initiated reaction among 1c, simple iodoalkanes,
and 4 gave the desired coupling products 5a-i in good to
high yields. The yields are correlated with the radical-
accepting ability of the alkenes except for the case with
dimethyl maleate (4d).18 The use of dimethyl fumarate (4c)
led to high efficiency of the coupling reaction with moderate
to high diastereoselectivity (entries 7-9). The stereoselec-
tivity was independent of the geometry of the alkene (entries
8 and 10). Judging from the report by Giese et al.,19 the
radical intermediate generated by radical addition to 4c,d
tylstannyl radical abstracts an atom or a group from 2 to
generate an alkyl radical (R•) and the radical reacts with 1
by the SH2′ mechanism to give 3 and regenerate the stannyl
radical. The high reactivity of haloalkanes activated by an
electron-withdrawing group can be rationalized by a polar
effect in the latter homolytic substitution step: Electron-
deficient radicals show high reactivity to electron-rich alkenes
such as stannyl enolates.2b,15 In this reaction system, the
coexistence of alkene 4 able to trap the alkyl radical is
expected to give the three-component coupling product 5
(16) (a) Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc.
1988, 110, 1288. (b) Keck, G. E.; Kordik, C. P. Tetrahedron Lett. 1993,
34, 6875. (c) Sibi, M. P.; Ji, J. J. Org. Chem. 1996, 61, 6090 and references
therein.
(17) Indeed, the reaction among 1c, 2a, and 4a gave only 3ca. The use
of 1a failed in the three-component coupling reaction.
(18) The relative rate constants in the addition of cyclohexyl radical to
4 are 1.0 (4a, standard), 3.6 (4b), 5.0 (4c), and 0.5 (4d). Giese, B. Angew.
Chem., Int. Ed. Engl. 1983, 22, 753. Thus, the reactivity of 4d is not as
high as that of other alkenes, but the present reaction with 4d shows higher
efficiency than that with 4a or 4b. This observation is probably due to the
stannyl radical-mediated isomerization of 4d to 4c.
(14) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983,
105, 4059.
(15) Giese, B.; He, J.; Mehl, W. Chem. Ber. 1988, 121, 2063.
(19) Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron Lett.
1992, 33, 1863.
Org. Lett., Vol. 3, No. 16, 2001
2593