Regioselective double alkylation of styrenes with alkyl halides using a titanocene catalyst [14]

Full text of DOI:10.1021/ja982732l

11822
J. Am. Chem. Soc. 1998, 120, 11822-11823
Table 1. Titanocene-Catalyzed Double Alkylation of Olefins with
Alkyl Bromides
Regioselective Double Alkylation of Styrenes with
Alkyl Halides Using a Titanocene Catalyst
Jun Terao, Koyu Saito, Shinsuke Nii, Nobuaki Kambe,* and
Noboru Sonoda†
Department of Applied Chemistry
Faculty of Engineering, Osaka UniVersity
Suita, Osaka 565-0871
ReceiVed August 3, 1998
Transition metal catalysts provide powerful tools for 1,2-
addition reactions to carbon-carbon double bonds, which enable
versatile and useful transformations of alkenes by means of
introducing a variety of functionalities at the olefinic carbons.
We wish to describe an unprecedented metal-catalyzed double
alkylation of alkenes with alkyl halides (eq 1). This reaction
n
proceeds via the use of Cp2TiCl2 in the presence of BuMgCl
and gives rise to Vic-dialkylated products regioselectively in high
yields under mild conditions.1
A typical example is as follows. To a mixture of styrene (1.03
mmol), 1-bromopentane (1.1 equiv), tert-butyl bromide (1.1
equiv), and titanocene dichloride (0.05 equiv) was added a THF
solution of nBuMgCl (2.2 equiv, 2.5 mL) at 0 °C, and the solution
was stirred for 1 h. The NMR analysis of the crude mixture
indicated the formation of the double alkylation product 1 in 94%
yield in which pentyl and tert-butyl groups are regioselectively
incorporated at the adjacent carbons (Table 1, run 1). The product
was obtained in pure form in 88% yield by a recycling preparative
HPLC using CHCl3 as the eluent. No evidence for the presence
of the regioisomer of 1 nor dialkylated products which contained
the same alkyl moiety was detected. The combined use of
secondary and primary bromides (runs 2, 3) or tertiary and
secondary bromides (run 4) afforded the corresponding dialkylated
products 2-4 in good yields with high regioselectivities. In run
2, only the exo-isomers were obtained in a diastereomer ratio of
ca. 1:1. Chloro substituents were not affected in this reaction
system and the desired product 5 was obtained in good yield (run
5). The same primary alkyl groups can be introduced at both
vicinal carbons by the use of 2.2 equiv of the corresponding alkyl
bromide (runs 6-8). Under the same conditions 1-iodooctane
gave 9-phenyloctadecane in 54% yield, whereas no dialkylated
product was obtained when 1-chlorooctane was used. Double
alkylation also occurred when sec-alkyl bromides were used as
shown in run 9, but tert-butyl bromide failed to give the
corresponding dialkylated product under the same conditions.
R-Substituted styrenes also efficiently underwent double alkylation
(runs 7, 8). The reaction was sluggish with respect to internal
alkenes, such as â-methyl styrene or stilbene, and to 1-alkenes
which contain no aryl group, such as 1-octene or 3-methyl-1-
pentene. This chemoselectivity allows the successful synthesis
of diene 10 in 82% yield, using 5-bromo-1-pentene (run 10).
Interestingly, when 1,4-dibromobutane was used as the alkylating
reagent, cyclohexylbenzene was obtained in moderate yield (run
a NMR yield. Isolated yield is in parentheses. b exo-2-Norbornyl
bromide was used in 1.5 equiv. As a by-product, 6 was formed in 7%
yield. c Besides, 6 and 9 were formed in 22% and 5% yields,
respectively. d A trace amount of the by-product having two iPr groups
was formed in <1% which was identified by GC-MS. e GC yield.
n
1,4-Dibromobutane (5 equiv), BuMgCl (5 equiv), and Cp2TiCl2 (10
mol %) were used.
Scheme 1
11). Vinyl ethers, sulfides, sulfoxides, and sulfones were not
alkylated under the same conditions.
A plausible reaction pathway is shown in Scheme 1.2 Alkyl
radicals, formed by the electron transfer to alkyl bromides from
† Present address: Department of Applied Chemistry, Faculty of Engineer-
ing, Kansai University, Suita, Osaka 564-8680, Japan.
(1) For recent reviews on synthetic application of titanium complexes,
see: (a) Bochmann, M. In ComprehensiVe Organiometallic Chemistry II; Abel,
E. W., Ed.; Pergamon Press: Oxford, U.K., 1995; Vol. 4, Chapters 4 and 5.
(b) Houri, A. F.; Hoveyda, A. H. In Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley & Sons: Chichester, 1995; Vol. 3, pp 1663-1667.
(2) A similar pathway has been proposed for three-component coupling
reactions of alkyl iodides, electron-deficient olefins, and carbonyl compounds
using excess amounts of manganese or chromium salts. (a) Takai, K.; Ueda,
T.; Ikeda, N.; Moriwake, T. J. Org. Chem. 1996, 61, 7990-7991. (b) Takai,
K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem., Int. Ed. Engl.
1998, 37, 152-155.
10.1021/ja982732l CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 45, 1998 11823
some reduced titanocene complex3 (step 1), add to the terminal
carbon of styrene yielding benzyl radical intermediates (step 2).
Recombination of the benzyl radicals with a titanocene complex
gives rise to benzyl-Ti intermediates (step 3) which then undergo
transmetalation with nBuMgCl to afford benzylmagnesium chlo-
rides (step 4). The dialkylated products are formed by the reaction
of benzylmagnesium chlorides with the alkyl halides (step 5).
This pathway clearly explains the observed regioselectivity by
taking into account the features of the following reactions. The
rates of alkyl radical formation increase in the order of primary
< secondary < tertiary reflecting the stabilities of alkyl radicals.
The radical addition to carbon-carbon unsaturated bonds takes
place at the terminal carbons exclusively. The alkylation at the
benzylic carbon, probably via an SN2 mechanism, would be
favorable for less hindered alkyl halides in the order of primary
> secondary > tertiary.
formed in this reaction. While 14 could not be trapped efficiently
with 2-norbornyl bromide probably due to steric reasons, sterically
nonencumbered primary and secondary alkyl bromides react
smoothly with R-substituted benzylmagnesium chlorides under
the reaction conditions employed. For example, the reaction of
155 (0.36 M) with isopropyl bromide (1.5 equiv) in THF at 0 °C
afforded 9 in 62% yield after only 10 min.6
Interestingly, when iPrMgCl was used instead of nBuMgCl, the
reduction of the alkyl bromides3,7 predominated, and only a trace
amounts of dialkylated products (<2%) were obtained. It should
also be noted that the Ti-catalyzed hydromagnesiation of olefins,
which can proceed under similar conditions,8 is completely
suppressed in this reaction system. The fact that Cp2TiCl2 reacts
with Grignard reagents (RMgX) to form anionic Ti(III) ate
complexes Cp2TiR2 and that Cp2TiiPr2 is unstable at temper-
-
-
atures above -50 °C yielding hydride complexes, whereas
Cp2TiEt2 is stable at room temperature,8b,9 leads us to propose
-
To confirm the validity of the proposed pathway, we employed
(bromomethyl)cyclopropane as the alkylating reagent. As might
be expected, cyclopropylmethyl and 3-butenyl units were intro-
duced regioselectively giving rise to 12 as the sole dialkylation
product in 50% yield (eq 2). This result along with the evidence
-
that an ate complex Cp2TinBu2 may play an important role as
the active species for the electron transfer to alkyl halides. A
detailed study of the mechanism of this titanocene-catalyzed
double alkylation is currently under investigation.
In conclusion, we report that a titanocene complex catalyzes
the double alkylation of aryl alkenes with various alkyl halides
n
in the presence of BuMgCl.10 Although aryl, vinyl and allyl
halides have widely been used for a number of transformations
catalyzed by transition metals, the use of alkyl halides in transition
metal chemistry is very limited mainly due to the facile
â-elimination from the alkylmetal intermediates.11 The present
study outlines a novel methodology for overcoming this drawback
by the use of a titanocene catalyst and will provide a useful
synthetic method, especially for the construction of carbon
skeletons, with the concomitant formation of two carbon-carbon
bonds at the adjacent carbons.
that ring opening of cyclopropylmethyl radical to 3-butenyl radical
is a rapid process which is much faster than the addition of
primary radicals to styrene4 strongly supports the proposal that
the first alkylation step is a radical process but that the second
step is not.
The intermediacy of benzylmagnesium chlorides in the second
alkylation step is supported by the following results. The reaction
of styrene with 1.5 equiv of 2-norbornyl bromide was conducted
at 0 °C for 1 h using 2.2 equiv of nBuMgCl in the presence of 5
mol % of Cp2TiCl2. Quenching the reaction with D2O afforded
the monoalkylated compound 13 which contained a deuterium at
the benzylic position (d-content > 95%) in 59% yield (eq 3).
Acknowledgment. This work was supported, in part, by a Grant-in-
Aid from the Ministry of Education, Science, Sports and Culture, Japan.
Thanks are due to the Instrumental Analysis Center, Faculty of Engineer-
ing, Osaka University.
Supporting Information Available: Experimental details and char-
acterization for all new compounds (9 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
JA982732L
(5) Prepared following a literature description: Harvey, S.; Junk, P. C.;
Raston, C. L.; Salem, G. J. Org. Chem. 1988, 53, 3134-3140.
(6) Reactivities of Grignard reagents toward alkyl bromides largely depend
on the structures of the Grignard reagents. For example, PhCH2MgCl (1.09
i
M) reacted with PrBr (1.5 equiv) more slowly, giving isobutylbenzene in
n
i
only 8% at 0 °C for 1 h, and BuMgCl was not alkylated by PrBr under the
same conditions.
(7) Colomer, E.; Corriu, R. J. Organomet. Chem. 1974, 82, 367-373.
(8) (a) Sato, F.; Ishikawa, H.; Sato, M. Tetrahedron Lett. 1980, 21, 365-
368. (b) Ashby, E. C.; Ainsle, R. D. J. Organomet. Chem. 1983, 250, 1-12.
(c) Gao, Y.; Sato, F. J. Chem. Soc., Chem. Commun. 1995, 659-660. (d) For
a review of hydromagnesiation, see: Sato, F. J. Organomet. Chem. 1985,
285, 53-64.
This result suggests that a benzylmagnesium chloride 14 was
(3) It is known that alkyl radicals are formed in the titanocene-catalyzed
reduction of alkyl bromides with iPrMgBr. Rilatt, J. A.; Kitching, W.
Organometallics 1982, 1, 1089-1093.
(9) (a) Brintzinger, H. H. J. Am. Chem. Soc. 1967, 89, 6871-6877. (b)
Troyanov, S. I.; Varga, V.; Mach, K. J. Organomet. Chem. 1993, 461, 85-
90.
(4) (a) The rate constant k ) 1.3 × 108 s-1 (at 25 °C) for the isomerization
of cyclopropylmethyl radical to 3-butenyl radical has been reported: Maillard,
B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 7024-7026. (b)
The rate constant k ) 5.4 × 104 M-1 s-1 (at 25 °C) for the addition of
5-hexenyl radical to styrene has been reported: Citterio, A.; Minisci, F. J.
Org. Chem. 1979, 44, 2674-2682. (c) Although cyclopropylmethylmagnesium
bromide is known to rearrange to CH2dCHCH2CH2MgBr, it is not likely that
these species are the intermediates, since the rearrangement is too slow (t1/2
) 30 h in THF at 27 °C): Silver, M. S.; Shafer, P. R.; Nordlander, J. E.;
Ruchardt, C.; Roberts, J. D. J. Am. Chem. Soc. 1960, 82, 2646-2647.
(10) The dialkylation of alkenes with alkyl halides proceeds by the use of
Li metal or by an electrochemical procedure; however, these reactions are
inefficient, and regioselective dialkylation has never been reported, see: (a)
Davis, A.; Morgan, M. H.; Richards, D. H.; Scilly, N. F. J. Chem. Soc., Perkin
Trans. 1 1972, 52, 286-288. (b) Satoh, S.; Taguchi, T.; Itoh, M.; Tokuda,
M. Bull. Chem. Soc. Jpn. 1979, 52, 951-952.
(11) See, for example: Tsuji, J. Palladium Reagents and Catalysts; John
Wiley & Sons: Chichester, 1995.