Ni-catalyzed alkylative dimerization of vinyl Grignard reagents using alkyl fluorides

Article abstract of DOI:10.1021/ja042565r

Alkyl halides underwent unique cross-coupling reaction with vinylmagnesium chloride in the presence of Ni catalyst to give 2-alkyl-3-butenyl Grignard reagent (1) in high yields. This reaction proceeded efficiently at 25 °C in THF using primary and seconda

Full text of DOI:10.1021/ja042565r

Published on Web 02/22/2005
Ni-Catalyzed Alkylative Dimerization of Vinyl Grignard Reagents Using Alkyl
Fluorides
Jun Terao, Hiroyasu Watabe, and Nobuaki Kambe*
Department of Molecular Chemistry & Science and Technology Center for Atoms, Molecules and Ions Control,
Graduate School of Engineering, Osaka UniVersity, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
Received December 10, 2004; E-mail: kambe@chem.eng.osaka-u.ac.jp
Due to the strong bonding energy of a carbon-fluorine bond,
organofluorides have been thought to be one of the most inert
classes of organic compounds. As for the aryl fluorides, both
catalytic and stoichiometric reactions have already been developed
1
to replace the fluorine atom with other atoms or groups. However,
synthetic application of alkyl fluorides still remains undeveloped.2
When a reaction of n-octyl fluoride with vinyl Grignard reagent
was quenched with D O, deuterated compound 5 (d-content > 93%)
was formed in 92% yield (eq 5). When CO was introduced after
the reaction, carboxylic acid 6 was obtained in 85% yield (eq 5).
These results imply that the butenyl Grignard reagent 7 is formed
in the present reaction.
We have recently developed a cross-coupling reaction of alkyl
fluorides with Grignard reagents with the aid of Ni or Cu catalyst
2
2
3
under mild conditions. Here, we disclose that Ni catalyzes the
alkylative dimerization reaction of vinyl Grignard reagents using
alkyl fluorides under mild conditions, giving rise to 2-alkyl-3-
butenyl Grignard reagent (1) (eq 1).
For example, when a reaction of n-octyl fluoride (1 mmol) with
vinylmagnesium chloride (3 mmol, 1 M in THF) was conducted
in the presence of NiCl
2
(0.03 mmol) at 25 °C for 7 h, 3-methyl-
1-undecene 2 was obtained after protonolysis in 94% yield based
on n-octyl fluoride as the sole product (eq 2, entry 1). It should be
noted that the present reaction proceeds exclusively in the case of
alkyl fluorides, whereas the corresponding chlorides, bromides, and
iodides undergo reduction, elimination, or cross-coupling with vinyl
Grignard reagent either concomitantly (entry 2) or predominantly
As a synthetic application of the thus-formed 7, we undertook
further alkylation by Ni-catalyzed cross-coupling reaction with alkyl
4
halides. Into a solution of 7 prepared in situ under conditions
similar to those of eq 2 were added stearyl bromide (3.0 mmol)
and 1,3-butadiene (1 mmol). After stirring at 25 °C for 14 h, the
desired coupling product 8 was obtained in 80% yield, where two
different alkyl groups are introduced regioselectively to the butenyl
skeleton derived from the vinyl Grignard reagent (eq 6).
(entries 3 and 4).
To elucidate the reaction pathway, we first tested the intermediary
of alkenes, which may be formed by cross-coupling of alkyl fluo-
rides with vinyl Grignard reagents, since it is known that Ni cata-
When cyclohexyl fluoride was employed, the corresponding
5
product 3 was formed in 75% yield, although a longer reaction
time was required, indicating that secondary alkyl groups can be
introduced by this reaction (eq 3).
lyzes carbomagnetization of alkenes. A reaction of n-octyl fluoride
with vinyl Grignard reagent was carried out in the presence of 1-un-
decene (1 mmol) at 25 °C for 2 h under conditions identical to those
of eq 2. Quenching the reaction mixture with 1 N HCl afforded 2
in 91% yield, and unreacted 1-undecene was recovered (eq 7). This
result clearly indicates that 1-alkenes are not involved as intermedi-
ates.
2
No reaction took place with either MeCHdCHMgBr or CH d
CMeMgBr under conditions identical to those of eq 2, and alkyl
fluorides were recovered. Interestingly, PhCHdCHMgBr gave
double alkylative vinyl coupling product 4 in 69% yield as the sole
product (E/Z ) 62/38) (eq 4). In comparison to alkyl fluorides,
reactions using alkyl chloride (40%) and bromide (18%) were less
efficient.
3656
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J. AM. CHEM. SOC. 2005, 127, 3656-3657
10.1021/ja042565r CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
When the reaction depicted in eq 8 was run employing 6-fluoro-
,1-diphenyl-1-hexene as an alkyl fluoride, diene 9 was obtained
reagents to generate divinylnickel complex 11, which readily forms
nickel-butadiene complex 12 via reductive coupling. Then, 12
8
1
as the sole coupling product in 71% yield, without formation of
any cyclopentane derivatives, which may arise from ring-closing
of the 6,6-diphenyl-5-hexenyl radical if generated. This result
reacts again with the vinyl Grignard reagent to give 14 via nickelate
complex 13. Subsequent transmetalation of 14 with vinyl Grignard
9
6
reagent regenerates 11 along with allylic Grignard reagent 10 or
15, which reacts with alkyl fluorides, giving rise to 1. Alternatively,
direct reaction of 13 with alkyl fluorides leading to 16 followed
by transmetalation with vinyl Grignard reagent also affords 1. In
this system, cationic magnesium would activate the C-F bond by
the eminent Mg-F interaction.3
would rule out a radical mechanism.
a
When PhCHdCHMgBr is used, the reaction follows a similar
pathway via metallacyclopentene intermediates 10′ and/or 13′,
which react with 2 equiv of alkyl halides at both benzylic positions
(eq 11).
It is known that alkyl iodides, bromides, or chlorides react with
(
2-butene-1,4-diyl)magnesium 10 at a γ-vinylic carbon to give
7
2
-alkyl-3-butenyl Grignard reagents 1. So we carried out the direct
reaction of n-octyl fluoride with 1.5 equiv of 10 in the presence
and absence of a catalytic amount of NiCl (PPh . The time course
2
3 2
)
of the formation of 2 was plotted in Figure 1 together with the
result of the catalytic reaction depicted in eq 10. At any stage of
the reaction, 2 was formed more efficiently in the catalytic system
than in the direct reactions. These results would suggest that a more
reactive intermediate in comparison to 10 might be formed in the
present catalytic system.
In conclusion, a novel dimerization coupling reaction of vinyl
Grignard reagents with alkyl fluorides has been developed with
the aid of Ni catalysts. The present study provides the first example
of a catalytic reaction that demonstrates the superiority of alkyl
fluorides as alkylating reagents over the corresponding bromides
and iodides as well as chlorides,2 which may undergo oxidative
addition toward Ni(0) such as 12 or electron transfer from 13 leading
to the formation of reduction or cross-coupling products. On the
other hand, alkyl fluorides are inert for such reactions, and this is
key to accomplishing this clean reaction.
,3a
Acknowledgment. This research was supported financially in
part by a grant from the Ministry of Education, Culture, Sports,
Science and Technology of Japan and by JSPS COE program.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(
1) For recent reviews on activation and functionalization of C-F bonds,
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Figure 1. Time course of the formation of 2 in eqs 9 and 10.
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3
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5
N
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3
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