Titanocene-catalyzed alkylative dimerization of vinyl Grignard reagent using alkyl halides

Article abstract of DOI:10.1039/b813596g

Dimerization of vinyl Grignard reagents and concomitant alkylation with alkyl halides have been achieved by using Cp₂TiCl₂ as a catalyst. The Royal Society of Chemistry.

Full text of DOI:10.1039/b813596g

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Titanocene-catalyzed alkylative dimerization of vinyl Grignard reagent
using alkyl halidesw
Yuuki Fujii,a Jun Terao,*b Yuichiro Katoa and Nobuaki Kambe*a
Received (in Cambridge, UK) 5th August 2008, Accepted 29th August 2008
First published as an Advance Article on the web 6th October 2008
DOI: 10.1039/b813596g
Dimerization of vinyl Grignard reagents and concomitant alky-
lation with alkyl halides have been achieved by using Cp2TiCl2
as a catalyst.
In the past decade, remarkable progress has been made in C–C
bond forming reactions using non-activated alkyl halides,
which had rarely been employed as carbon sources in conven-
tional transition-metal-catalyzed systems.1 We have recently
developed cross-coupling reactions2 and regioselective alkyla-
tion reactions of C–C unsaturated compounds3 using alkyl
Scheme 1
halides and shown that the ate complexes of transition metals
formed using Grignard reagents play an important role as
active catalytic species. During the course of these studies, we
have observed that Ni catalyzes regioselective 2 : 1 coupling of
vinyl Grignard reagents with alkyl halides or cyclic ethers to
afford alkylated homoallylic Grignard reagents 1 (Scheme 1).4
Here, we reveal that the alkylative dimerization of vinyl
Grignard reagents proceeds regioselectively in the presence
of a titanocene catalyst, resulting in allyl Grignard reagents 2,
possessing an alkyl group at the terminal carbon.
Scheme 2
When vinyl magnesium chloride (1.5 mmol, 1.4 M in THF)
was reacted with 2-bromo-2-methyloctane (0.5 mmol) in the
presence of Cp2TiCl2 (0.06 mmol) and hexane (0.22 ml) at
–20 1C under nitrogen, a mixture of coupling products 3 and 4
was obtained (Scheme 2). When the reaction mixture was
quenched with D2O, deuterated compounds 3-d1 (d-content
498%) and 4-d1 (d-content 498%) were formed in 72% and
20% yields, respectively. This result implies that the allyl
Grignard reagent 2 was formed in this reaction. The quenching
of the resulting mixture with CO2 or chlorosilane yielded the
single regioisomers. For example, CO2 reacted with the allylic
Scheme 3
Grignard reagents 2a via a six-membered cyclic transition state
to form 5. On the other hand, the silylation of the terminal
carbon of 2a (or its regioisomer 2a0) yielded 6, probably due to
the steric hindrance of the silyl group (Scheme 3).
alkyl bromides afforded corresponding products in moderate to
good yields (entries 2–5). Under similar conditions, alkyl io-
dides afforded corresponding alkylated products (entries 6–8);
however, no reaction occurred when we used alkyl chlorides
and fluorides. The present reaction was sluggish toward sub-
stituted vinyl Grignard reagents, such as MeCHQCHMgBr,
CH2QCMeMgBr, and PhCHQCHMgBr.
The results obtained using various alkyl halides, along with
3-pentanone as an electrophile, are summarized in Table 1. The
use of 2-bromo-2-methyloctane yielded tertiary alcohol 7a in
87% yield (Table 1, entry 1). Tertiary, secondary, and primary
a Department of Applied Chemistry Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.
E-mail: kambe@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-7390;
Tel: +81-6-6879-7388
A plausible reaction pathway is shown in Scheme 4. First,
titanocene dichloride reacts with two equivalents of vinyl
magnesium chloride to afford divinyl titanocene 8, which
undergoes reductive coupling to afford a titanocene–butadiene
complex 9.5,6 Then, 9 reacts with vinyl magnesium chloride to
afford a titanate complex 10.7 Subsequent one-electron trans-
fer from 10 to alkyl halides yields alkyl radicals along with a
titanocene(III) complex 11.8 Finally the addition of the alkyl
radicals to a coordinated butadiene ligand of 11, or to free
b Department of Energy and Hydrocarbon Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto, Japan 615-8510.
E-mail: terao@scl.kyoto-u.ac.jp; Fax: +81-75-383-2516;
Tel: +81-75-383-2514
w Electronic supplementary information (ESI) available: Typical ex-
perimental procedures and analytical data of products. See DOI:
10.1039/b813596g
ꢀc
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Table 1 Titanocene-catalyzed coupling reaction of vinyl Grignard
reagent with alkyl halides and quenching with 3-pentanonea
Scheme 5
alkyl bromides with more branched chains reacted faster than
those with less branched chains may suggest that alkyl groups
are introduced to the coupling products as alkyl radical
intermediates.
Entry
1
Alkyl-X
Time/h
3
Product
Yield (%)b
87
7a
Next, we employed cyclopropylmethyl iodide as an alkylat-
ing reagent. As expected, an acyclic product, 13, was obtained
via the ring opening of the cyclopropylmethyl radical to
3-butenyl radical (Scheme 6).11
2
3
tC4H9-Br
1
3
3
4
1
1
3
7b
7c
7d
7e
7f
77
64
63
50
56
48
69
sC4H9-Br
2-Norbornyl-Br
4
5c
6
nC4H9-Br
From a mechanistic viewpoint, it is interesting to examine
whether the alkyl radical attacks butadiene coordinated to the
Ti complex or that in the free state. In order to determine this
behavior of the alkyl radical, we reacted the vinyl Grignard
reagent with tert-butyl bromide in the presence of 2,3-di-
methylbutadiene at different concentrations, and the ratio of
15 to 14 was plotted against the amount of 2,3-dimethylbuta-
diene added (Scheme 7). Fig. 1 shows that the addition of
2,3-dimethylbutadiene causes a decrease in the ratio of 15 to
14; however, this ratio does not obey the first-order kinetics
equation on the concentration of 2,3-dimethylbutadiene, i.e.,
three times the concentration of the 2,3-dimethylbutadiene
leads to a 1.7 times increase in the ratio. This result may imply
that the alkyl radical attacks the coordinated form of
2,3-dimethylbutadiene and not free 2,3-dimethylbutadiene,
1-Adamantyl-I
nC8H17-I
7c
8
7g
7h
cC6H11-I
a
Cp2TiCl2 (0.06 mmol), hexane (0.22 ml), alkyl halide (0.5 mmol)
vinyl Grignard reagent (1.5 mmol), ꢁ20 1C, then 3-pentanone
b
c
(0.75 mmol) 25 1C, 1 h. Isolated yield. Vinyl Grignard reagent
(1.7 mmol) and Cp2TiCl2 (0.075 mmol) were used.
Scheme 6
Scheme 4
butadiene followed by recombination with Cp2Ti(vinyl), leads
to the formation of an Z1-allyltitanocene complex 12,9 which
undergoes transmetallation with vinyl magnesium chloride to
yield allyl Grignard reagent 2 and regenerate 8.10
We performed two control experiments to confirm the
radical mechanism of the alkylation step. We first carried
out a competitive reaction by using equimolar amounts of
n-butyl, sec-butyl, and tert-butyl bromides to obtain the
relative reactivities of alkyl halides (Scheme 5). The quenching
of the reaction with 3-pentanone afforded alcohols 7b, 7c and
7e in 44%, 9% and 4% yields, respectively. The evidence that
Scheme 7
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Notes and references
1 For recent reviews on transition-metal catalyzed cross-coupling
reactions using alkyl halides, see: (a) M. R. Netherton and G. C.
Fu, Adv. Synth. Catal., 2004, 346, 1525; (b) A. C. Frisch and M.
Beller, Angew. Chem., Int. Ed., 2005, 44, 674; Recent reports for
Mizoroki-Heck type reactions using alkyl halides, see: (c) Y. Ikeda,
T. Nakamura, H. Yorimitsu and K. Oshima, J. Am. Chem. Soc.,
2002, 124, 6514; (d) T. Fujioka, T. Nakamura, H. Yorimitsu and
K. Oshima, Org. Lett., 2002, 4, 2257; (e) W. Affo, H. Ohmiya, T.
Fujioka, Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, Y.
Imamura, T. Mizuta and K. Miyoshi, J. Am. Chem. Soc., 2006,
128, 8068; (f) L. Firmansjah and G. C. Fu, J. Am. Chem. Soc.,
2007, 129, 11340; For cobalt-catalyzed tandem radical cyclizations
and cross-coupling reactions using 6-halo-1-hexene derivatives,
see: (g) K. Wakabayashi, H. Yorimitsu and K. Oshima, J. Am.
Chem. Soc., 2001, 123, 5374; (h) H. Ohmiya, K. Wakabayashi, H.
Yorimitsu and K. Oshima, Tetrahedron, 2006, 62, 2207; (i) H.
Someya, H. Ohmiya, H. Yorimitsu and K. Oshima, Org. Lett.,
2007, 9, 1565; (j) K. Oshima, Bull. Chem. Soc. Jpn., 2008, 81, 1; For
cobalt-catalyzed three-component coupling reaction using diene,
Grignard reagents, and alkyl halides, see: (k) K. Mizutani, H.
Shinokubo and K. Oshima, Org. Lett., 2003, 5, 3959.
Fig. 1
2 (a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu and N. Kambe,
J. Am. Chem. Soc., 2002, 124, 4222; (b) J. Terao, A. Ikumi, H.
Kuniyasu and N. Kambe, J. Am. Chem. Soc., 2003, 125, 5646; (c) J.
Terao, Y. Naitoh, H. Kuniyasu and N. Kambe, Chem. Lett., 2003,
32, 890; (d) J. Terao, H. Todo, H. Watanabe, A. Ikumi and N.
Kambe, Angew. Chem., Int. Ed., 2004, 43, 6180; (e) J. Terao, Y.
Naitoh, H. Kuniyasu and N. Kambe, Chem. Commun., 2007, 825;
(f) J. Terao, H. Todo, S. A. Begum, H. Kuniyasu and N. Kambe,
Angew. Chem., Int. Ed., 2007, 46, 2086.
Scheme 8
3 For titanocene-catalyzed regioselective alkylations of styrenes or
butadienes using alkyl halides, see: (a) J. Terao, K. Saito, S. Nii, N.
Kambe and N. Sonoda, J. Am. Chem. Soc., 1998, 120, 11822; (b) S.
Nii, J. Terao and N. Kambe, J. Org. Chem., 2000, 65, 5291; (c) J.
Terao, H. Watabe, M. Miyamoto and N. Kambe, Bull. Chem. Soc.
Jpn., 2003, 76, 2209; (d) S. Nii, J. Terao and N. Kambe, J. Org.
Chem., 2004, 69, 573; For nickel-catalyzed three-component cou-
pling reaction using butadienes, Grignard reagents, and alkyl
halides, see: (e) J. Terao, S. Nii, F. A. Chowdhury, A. Nakamura
and N. Kambe, Adv. Synth. Catal., 2004, 346, 905; (f) J. Terao, Y.
Kato and N. Kambe, Chem. Asian J., 2008, 3, 1472.
4 (a) J. Terao, H. Watabe and N. Kambe, J. Am. Chem. Soc., 2005,
127, 3656; (b) Y. Fujii, J. Terao, H. Watabe, H. Watanabe and N.
Kambe, Tetrahedron, 2007, 63, 6635.
5 For dimerization disilylation, see: H. Watabe, J. Terao and N.
Kambe, Org. Lett., 2001, 3, 1733.
Fig. 2
6 (a) It is known that Cp2TiCl2 reacts with vinyl lithium in the
presence of TMEDA to yield butadiene: R. Beckhaus and K.-H.
Thiele, J. Organomet. Chem., 1986, 317, 23; (b) R. Beckhaus, S.
Flatau, S. Trojanov and P. Hoffman, Chem. Ber., 1992, 125, 291;
(c) R. Beckhaus, Angew. Chem., Int. Ed. Engl., 1997, 36, 686; (d)
The formation of a zirconocene–butadiene complex from divinyl
zirconocene has been reported as follows: R. Beckhaus and K.-H.
Thiele, J. Organomet. Chem., 1984, 268, C7.
7 Titanate complexes prepared by reacting Cp2TiCl2 with Grignard
reagents have been reported as follows: H. H. Brintzinger, J. Am.
Chem. Soc., 1967, 89, 6871.
8 17-Electron titanium(III) complexes have been reported: G. A.
Luinstra, L. C. T. Cate, H. J. Heeres, J. W. Pattiasina, A. Meetsma
and J. H. Teuben, Organometallics, 1991, 10, 3227.
where the former 2,3-dimethylbutadiene is formed by ligand
exchange in the titanocene complex 11. Next, we carried out
similar competitive reactions in the presence of a constant
concentration of 2,3-dimethylbutadiene and varying amounts
of 1,3-butadiene (Scheme 8). Fig. 2 shows the ratio of 14 to 15
plotted against the amount of 1,3-butadiene used, revealing
that the concentration of 1,3-butadiene did not significantly
affect the ratio of the two products (the addition of 20 times
the amount of butadiene increased the ratio of 14 to 15 ratio
by only 1.5 times). This result clearly suggests that the alkyl
radical does not attack free 1,3-butadiene, which, however,
may inhibit ligand exchange in the titanocene complex 11.
In conclusion, we have shown that titanocene catalyzes the
alkylative dimerization of a vinyl Grignard reagent with alkyl
halides to afford allyl Grignard reagents possessing a carbon
chain at a terminal carbon. The Ti catalyst would play an
important role in the generation of alkyl radicals from alkyl
halides by electron transfer from Ti(III) ate complexes. It is
also proposed that alkyl radicals would preferentially attack
coordinated butadiene rather than free butadiene.
9 Cp2Ti(Z1-allyl)X complex has been reported: (a) F. Sato, K. Iida, S.
Iijima, H. Morita and M. Sato, J. Chem. Soc., Chem. Commun., 1981,
1140; (b) Y. Hanzawa, N. Kowase and T. Taguchi, Tetrahedron Lett.,
1998, 39, 583; (c) Y. Hanzawa, N. Kowase, S. Momose and T.
Taguchi, Tetrahedron, 1998, 54, 11387.
10 For the transmetallation of allyltitanocene with nBuMgCl, see:
(a) ref. 3b; (b) ref. 3d; (c) S. Nii, J. Terao and N. Kambe,
Tetrahedron Lett., 2004, 45, 1699. For the transmetallation of
allyltitanocene with CH2QCHMgBr, see: (d) ref. 5.
11 The rate constant k = 1.3 ꢂ 108 sꢁ1 at 25 1C for the isomerization
of cyclopropylmethyl radical to 3-butenyl radical has been derived
as follows: B. Maillard, D. Forrest and K. U. Ingold, J. Am. Chem.
Soc., 1976, 98, 7024.
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5838 | Chem. Commun., 2008, 5836–5838