Ni-catalyzed regioselective three-component coupling of alkyl halides, arylalkynes, or enynes with R-M (M = MgX′, ZnX′)

Article abstract of DOI:10.1039/b918548h

A new method for the regioselective three-component cross-coupling of alkyl halides, alkynes, or enynes with organomagnesium or organozinc reagents in the presence of a nickel catalyst and a dppb ligand has been developed.

Full text of DOI:10.1039/b918548h

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Ni-catalyzed regioselective three-component coupling of alkyl halides,
arylalkynes, or enynes with R–M (M = MgX0, ZnX0)w
Jun Terao,*a Fumiaki Bandob and Nobuaki Kambe*b
Received (in Cambridge, UK) 8th September 2009, Accepted 22nd September 2009
First published as an Advance Article on the web 13th October 2009
DOI: 10.1039/b918548h
A new method for the regioselective three-component cross-
coupling of alkyl halides, alkynes, or enynes with organo-
magnesium or organozinc reagents in the presence of a nickel
catalyst and a dppb ligand has been developed.
Transition-metal-catalyzed C–C bond formation via the
reaction of organic halides with organometallic reagents or
unsaturated hydrocarbons has been extensively studied and
used in many applications in the field of organic chemistry.1
These reactions are generally initiated by the oxidative
addition of halides to low-valent metals such as Ni(0) and
Pd(0); however, the scope of halides as substrates is restricted,
partly because of the slow oxidative addition of alkyl halides
to metal complexes and the facile b-hydrogen elimination from
the alkyl metal intermediates. With the aim of increasing the
applicability of alkyl halides in transition-metal-catalyzed
reactions, we recently developed a new method for the
generation of alkyl radical species from a variety of alkyl
halides (Alkyl–X; Alkyl = primary, secondary, or tertiary
alkyl group; X = Cl, Br, or I) by single-electron transfer
from anionic Ti and Ni complexes and successfully used
this method for C–C bond formation among alkyl halides,
unsaturated hydrocarbons, and Grignard reagents.2 The
addition of a variety of alkyl halides containing Cl, Br, and
I to primary, secondary, and tertiary alkyl groups proceeds
smoothly. However, the unsaturated hydrocarbon substrates
that can be used in this reaction are restricted to styrenes
and 1,3-butadienes. As an extension of these studies, we
discuss herein the regioselective three-component coupling3
of alkyl halides, arylalkynes, or enynes with organomagnesium
Scheme 1
at the terminal carbon of the phenylacetylene unit, in 86% GC
yield with perfect regio- and stereoselectivity. The crude
product was purified by silica gel column chromatography
using pentane as the eluent to afford pure 1a in 73% yield.
Increase in the reaction time did not lead to isomerization of
the double bond in the product. When dppb was replaced with
PPh3, dppe, dppp, dppf, and Xantphos, 1a was isolated in
moderate yields (17%, 59%, 61%, 38%, and 56%, respectively).
Under identical reaction conditions, 2-naphthyl, 3-tolyl,
4-methoxyphenyl, 4-perfluoromethylphenyl, and 2-thienyl
substituted alkynes also gave the corresponding three-component
coupling products in good yields (runs 2, 6–8, 10). Tertiary
alkyl bromides and secondary alkyl iodides also gave the
corresponding addition products in good yields (runs 3 and 4),
whereas the desired coupling product was obtained in a poor
yield (7%) when n-butyl iodide was used (run 5). The use of a
benzyl Grignard reagent also afforded the corresponding
products in good yields (runs 9 and 10). The reaction also
proceeded readily when diorganozincs were employed instead
of Grignard reagents (run 11). This catalytic system was found
to tolerate unsaturated heteroatom functional groups such as
esters, nitriles, and ketones (runs 12–15).
or organozinc reagents by the combined use of
4
a
Alkyl Grignard reagents having a b-hydrogen are also
suitable for use in the proposed cross-coupling reaction
(Scheme 2). In this reaction, two different alkyl groups can
be introduced at adjacent alkynyl carbons with good regio- and
stereoselectivity. It is also noteworthy that the hydroalkylation
product 3 is selectively formed when sec- and tert-butyl
Grignard reagents are used. However, there is no evidence
for the formation of the three-component coupling product 2.
We carried out control experiments to elucidate the reaction
pathway. First, we examined the relative reactivities of alkyl
halides via competitive experiments. To a mixture of phenyl-
acetylene (0.5 mmol), Ni(acac)2 (8 mol%), dppb (10 mol%),
and equimolar amounts of n-, sec-, and tert-butyl iodides
(0.5 mmol) was added an ether solution of MeMgBr (1.0 mmol,
1 mL) (Scheme 3). After stirring for 10 min, 1a, 1o, and 1p
were formed in 55%, 3%, and o1% yields, respectively. This
result indicated the conversion of the alkyl groups into radical
or cationic species.
catalytic amount of Ni(acac)2 and a phosphine ligand,
bis(diphenylphosphino)butane (dppb) (Scheme 1).
We initially investigated the addition of phenylacetylene
(0.5 mmol) to tert-butyl iodide (1 mmol) and an ether solution
of methylmagnesium bromide (MeMgBr; 1.0 mmol, 1.0 mL)
in the presence of Ni(acac)2 (0.08 mmol) and dppb (0.10 mmol)
(Table 1). The reaction was completed within 1 h (at 25 1C)
and afforded the coupling product 1a, which possessed a
methyl group at the benzylic carbon and a tert-butyl group
a Department of Energy and Hydrocarbon Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
E-mail: terao@scl.kyoto-u.ac.jp; Fax: +81-75-383-2516;
Tel: +81-75-383-2514
b 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; Tel: +81-6-6879-7388
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See
DOI: 10.1039/b918548h
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Table 1 Ni-catalyzed regioselective three-component coupling of alkyl halides, arylalkynes, and R–M (M = MgX0, ZnX0)a
Run
Ar
R–M
Alkyl–X
Yield (%)b
[E/Z]c
1
2
3
4
5
6
7
8
Ph
Me–MgBr
Me–MgBr
Me–MgBr
Me–MgBr
Me–MgBr
Me–MgBr
Me–MgBr
Me–MgBr
PhCH2–MgCl
PhCH2–MgCl
Ph2Zn
tBu–I
tBu–I
tBu–Br
sBu–I
nBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
tBu–I
1a
1b
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
73
79
60
54
7
77
78
68
64
80
82
68
56
40
47
[0/100]
[0/100]
[0/100]
[3/97]
[15/85]
[0/100]
[0/100]
[0/100]
[0/100]
[0/100]
—
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
3-MeC6H4
4-MeOC6H4
4-CF3C6H4
Ph
2-Thienyl
Ph
3-MeO2CC6H4
3-NCC6H4
3-MeOCC6H4
Ph
9
10
11
12
13
14
15
Ph2Zn
Ph2Zn
[2/98]
[4/96]
[3/97]
[0/100]
Ph2Zn
4-EtO2CC6H4ZnCH2TMS
a
Ni(acac)2 (0.08 mmol), dppb (0.10 mmol), arylalkyne (0.5 mmol), Grignard reagent (1.0 mmol, 1 M in Et2O) or organozinc reagent (1.0 mmol,
b
c
1 M in THF), and alkyl halide (1.0 mmol), 25 1C, 1 h. Isolated yield. Determined by GC.
Scheme 4
subsequent coordination with the dppb ligand. Since under
the present catalytic conditions, oxidative addition of alkyl
halides to Ni(0) could proceed via a radical pathway,6 we
investigated the reaction of (dppb)Ni(0), which was formed by
the in situ reaction of Ni(acac)2 with 2 eq. MeMgBr in the
presence of dppb, with tert-butyl iodide and phenylacetylene
(Scheme 5). After stirring for 1 h at 25 1C, the reaction was
quenched with 1 N aqueous HCl. GC and NMR analysis of
the resulting mixture confirmed that no alkylation products
were formed, and tert-butyl iodide was recovered intact. On
the other hand, when the same reaction was carried out
employing 3 eq. of MeMgBr (with respect to Ni(acac)2), 1a
was obtained in 38% yield, indicating that the addition of
excess MeMgBr facilitated the C–I bond cleavage.
Scheme 2
Taking into account these results, we propose a possible
reaction pathway for the proposed reaction, as shown
in Scheme 6. Accordingly, Ni(acac)2 reacts with R–M
Scheme 3
In order to examine the possibility of the coupling reaction
proceeding via a radical mechanism, the reaction of 6-iodo-1-
phenyl-1-hexyne 4 with a tert-butyl Grignard reagent was
carried out. This reaction afforded cyclopentylidenemethyl-
benzene 5 in 72% yield (Scheme 4). The formation of 5 strongly
suggested the possibility of a radical mechanism, i.e., 5-exo
cyclization of the 6-hexynyl radical to afford the cyclopentyl-
idenemethyl radical in the C–C bond forming step.5
In this reaction system, (dppb)Ni(0) was assumed to
be formed in situ by the reductive coupling of NiR2 and
Scheme 5
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Table
2
Ni-catalyzed regioselective three component coupling
reaction of alkyl halides, enynes, and R2Zna
Run
R0
R
Alkyl–X
Yield (%)b
1c
2c
3d
4d
5e
6c
7c
8c
Ph
Me
Me
Me
Me
tBu–I
sBu–I
nBu–I
tBu–Br
sBu–Br
tBu–I
tBu–I
tBu–I
11a
11b
11c
11d
11b
11e
11f
11g
77
78
50
70
60
54
56
66
nHex
nHex
nHex
nHex
nHex
nHex
nHex
Me
PhCH2
CH2QCHCH2
nBu
a
Scheme 6
Ni(acac)2 (0.08 mmol), dppb (0.10 mmol), diorganozinc reagent
b
(1.0 mmol, 1 M in THF), and alkyl halide (1.0 mmol). Isolated yield.
c
d
e
(M = MgX0, ZnX0) and dppb to generate the zero valent
complex 6, which further reacts with R–M to afford the
nickelate complex 7.7 This nickelate complex acts as an active
electron-transfer reagent. Electron transfer from 7 to the alkyl
halide results in the formation of an alkyl radical, along with
the concomitant generation of the nickel(I) complex 8, the
resulting alkyl radical adds to the terminal carbon of
the arylalkynes to yield the vinyl radical intermediate 9. The
combination of 8 with 9 affords the vinyl-NiR intermediate 10,
which then undergoes reductive elimination to afford the
three-component coupling product along with 6 to complete
the catalytic cycle. The intriguing result shown in Scheme 2
that different products are obtained when using Grignard
reagents containing sec- and tert-alkyl groups can be explained
as follows. In the presence of the aforementioned Grignard
reagents, 10 preferentially undergoes b-hydrogen elimination
to afford a hydroalkylation product rather than reductive
elimination to afford the three-component coupling product.
We found that enynes efficiently underwent the proposed
three-component coupling reaction as well.8 For example, the
reaction of 4-phenyl-1-buten-3-yne (0.5 mmol) with dimethyl-
zinc (1.0 mmol, 1 M in THF) and tert-butyl iodide (0.6 mmol)
at 25 1C for 12 h afforded the three-component coupling
product 11a, which had a methyl group at the benzylic carbon
and a tert-butyl group at the terminal olefinic carbon, in 77%
yield (Table 2, run 1). Alkyl substituted enynes also afforded
the desired product in good yields (runs 2–8). This reaction
also proceeded satisfactorily when sec-alkyliodides, n-alkyl-
iodides, tert-alkylbromides, and sec-alkylbromides were used
(runs 2–5). The use of benzyl, allyl, and n-butyl zinc reagents
also afforded the corresponding products in good yields
(runs 6–8).
At 25 1C for 12 h. At 50 1C for 20 h. Refluxing in THF for 12 h.
new method for the generation of alkyl radical species and is
expected to act as a scaffold for the development of novel
transition-metal-catalyzed radical reactions.
Notes and references
1 For reviews of transition metal-catalyzed cross-coupling
reactions, see: International Symposium on 30 years of the
Cross-coupling Reaction, J. Organomet. Chem., 2002, 653(1);
Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, New York, 2004; Transition Metals
for Organic Synthesis, ed. M. Beller and C. Bolm, Wiley-VCH,
Weinheim, 2004; Handbook of Organopalladium Chemistry for
Organic Synthesis, ed. E. Negishi, Wiley-Interscience, New York,
2002.
2 For Ti-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; (e) Y. Fujii, J. Terao, Y. Kato and N. Kambe, Chem.
Commun., 2008, 5836; (f) J. Terao, Y. Kato and N. Kambe,
Chem.–Asian J., 2008, 3, 1472. For Ni three-component coupling
reactions using butadienes, Grignard reagents, and alkyl halides,
see: (g) J. Terao, S. Nii, F. A. Chowdhury, A. Nakamura and
N. Kambe, Adv. Synth. Catal., 2004, 346, 905.
3 For Co-catalyzed three-component coupling reactions using dienes,
Grignard reagents, and alkyl halides via the generation of alkyl
radical species from alkyl halides by single-electron transfer from
anionic Co complexes, see: K. Mizutani, H. Shinokubo and
K. Oshima, Org. Lett., 2003, 5, 3959.
4 For recent reviews of Ni-catalyzed multiple-component coupling
reactions, see: (a) J. Montgomery, Acc. Chem. Res., 2000, 33, 467;
(b) S. Ikeda, Acc. Chem. Res., 2000, 33, 511; (c) M. Kimura,
J. Synth. Org. Chem., 2006, 64, 130; (d) M. Jeganmohan and
C.-H. Cheng, Chem. Commun., 2008, 3101.
We have developed a nickel-catalyzed regioselective three-
component reaction for the one-pot coupling of alkyl halides,
arylacetylenes, or enynes with organomagnesium or organo-
zinc reagents. In this reaction, alkyl radical species are
generated in situ from a variety of alkyl halides by single
electron transfer from a nickelate complex. The present
reaction involves two different C–C forming steps: (1) the
addition of alkyl radicals to unsaturated C–C bonds and (2)
reductive elimination of Ni(II) intermediates. This reaction is a
5 A. L. J. Beckwith and C. H. Schiesser, Tetrahedron, 1985, 41, 3925.
6 It is suggested that the oxidative addition of alkyl halides to Ni(0)
may proceed via
a radical pathway, see: C. W. Weston,
A. W. Verstuyft, J. H. Nelson and H. B. Jonassen, Inorg. Chem.,
1977, 16, 1313.
7 For magnesium nickelate complexes, see: W. Kaschube,
K. R. Porschke, K. Angermund, C. Kruger and G. Wilke, Chem.
¨
Ber., 1988, 121, 1921.
¨
8 For addition of alkyl radical to enynes, see: E. Ghera and S. Shoua,
Tetrahedron Lett., 1974, 15, 3843.
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This journal is The Royal Society of Chemistry 2009
7338 | Chem. Commun., 2009, 7336–7338