Nickel-catalyzed cross-coupling of primary alkyl halides with phenylethynyl- and trimethylsilyethynyllithium reagents

Article abstract of DOI:10.1016/j.jorganchem.2011.05.017

A highly efficient alkyl-alkynyl coupling system is described which is promoted by a well-defined and moisture-stable pincer complex [NiCl{C ₆H₃-2,6-(OPPh₂)₂}] (1). Non-activated alkyl halides could be efficient

Full text of DOI:10.1016/j.jorganchem.2011.05.017

Journal of Organometallic Chemistry 696 (2011) 3011e3014
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Nickel-catalyzed cross-coupling of primary alkyl halides with phenylethynyl- and
trimethylsilyethynyllithium reagents
*
Guoqiang Xu, Xiaoyan Li, Hongjian Sun
School of Chemistry and Chemical Engineering, Shandong University, Shanda Nanlu 27, 250100 Jinan, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient alkylealkynyl coupling system is described which is promoted by a well-defined and
moisture-stable pincer complex [NiCl{C6H3-2,6-(OPPh2)2}] (1). Non-activated alkyl halides could be
efficiently coupled with phenylethynyl- and trimethylsilylethynyllithium reagents at room temperature.
Compared to the alkylation of primary alkyl halides with alkynyllithium reagents in literatures, this
method requires milder conditions (room temperature) and proceeds quickly. This research will make
these readily available alkynyllithium reagents much more useful for organic synthesis.
Ó 2011 Elsevier B.V. All rights reserved.
Received 18 February 2011
Received in revised form
20 May 2011
Accepted 31 May 2011
Keywords:
Nickel
Cross-coupling
Alkynylation
Pincer complex
1. Introduction
reaction may be a reductive elimination-controlled process because
of the better performance of triphenylphosphine than that of tri-
Over the past few decades, the alkynylation of Csp2-halides,
conducted either with alkynylmetal reagents or directly with
terminal alkynes, has emerged as an extremely powerful method
for the synthesis of alkynes [1e3]. However, for a long time, the
corresponding application of non-activated alkyl halides has been
a challenge due to a more difficult oxidative addition step and the
tendency of alkylmetal intermediates to undergo side reactions like
alkylphosphine [11]. For the Sonogashira coupling reaction of such
substrates, in addition to only two prior examples using Pd-NHC
catalysts [22,23], Hu recently [24] demonstrated a Ni system with
a pincer amidobis(amine) ligand [24e28]. Nitrogen based tri-
dentate ligands are believed to stabilize alkylmetal intermediates
[21,24e28]. Very recently, Cahiez released a new general procedure
for coupling aliphatic and aromatic Grignard reagents with alkynyl
halides under copper catalysis [29].
b
-H elimination. Recently, much effort has been made to conduct
metal-catalyzed cross-coupling reactions with alkyl halides as
electrophilic couplings partners [4e8] and notable advances have
been described for the Kumada [9e17] and Negishi [18e20] type
coupling reactions. Early investigations showed the application of
Ni, Co, Fe and Pd complexes in the activation of alkyl halides, which
follow a radical pathway (single-electron transfer mechanism) [21],
and in some cases the radical may undergo a ring closure in the
presence of remote double bond [12,20]. To date, most of the
investigations have focused on the use of alkyl and aryl metal
nucleophiles. In contrast, reports of coupling reactions with alkynyl
nucleophiles are rare. Oshima reported that Co(acac)3 (acac: ace-
tylacetonate) promoted cross-coupling of alkyl halides with
2-trimethylsilylethynylmagnesium bromide [12]. Luh described
a Pd-catalyzed cross-coupling reaction of alkyl bromides and
iodides with substituted alkyllithium and suggested this coupling
In our investigation of the strong bond activation using first row
platinum group metals (Fe, Co, Ni) with phosphite PCP-pincer ligands
[30], we reasoned that the PCP-Ni complex might be able to promote
the coupling of alkyl halides with nucleophiles. We herein report our
initial studies on the coupling reactions between un-activated alkyl
halides and alkynyllithium reagents at room temperature. The (pre)
Ⅱ
catalyst is a well-defined PCP-Ni -Cl compound [NiCl{C6H3-2,6-
(OPPh2)2}] (1) [31]. Alkynyllithiums are easily prepared and at least
as reactive as the corresponding alkynylzinc reagents. However,
cross-coupling reactions using these nucleophiles were generally
unsatisfactory and few examples have been reported [1,11].
2. Experimental methods
2.1. General remarks
All reactions were carried out under N2 atmosphere and all
solvents were freshly distilled before use. Alkyl halides were
* Corresponding author. Tel.: þ86 531 88361350; fax: þ86 531 88564464.
E-mail address: hjsun@sdu.edu.cn (H. Sun).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.05.017

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G. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 3011e3014
Table 1
phenylethynyl- or trimethylsilyethynyllithium reagent prepared
from the corresponding alkyne (13 mmol) and n-BuLi (13 mmol,
2.5 M in hexane solution). After reaction the mixture was quenched
with H2O, extracted with Et2O, and again washed with water to
remove NMP, finally dried with MgSO4. After filtration and evapo-
ration, the residue was chromatographed on silica gel (hexane or
petroleum ether:ethyl acetate ¼ 40:1).
Catalytic coupling of 1-bromobutane with phenylethynyllithium.a
3. Results and discussion
Entry Solvent
Cat (mol%) t (h) T (ꢀC) PhCCLi (equiv) Yields (%)b
1
2
3
4
5
6
7
8
THF
THF
THF
Toluene
TMEDA
DMF
2.0
2.0
2.0
2.0
2.0
2.0
1.5 r.t.
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.0
1.0
2.0
2.0
1.3
5
7
60
3
Initial tests were carried out for the coupling of 1-bromobutane
with phenylethynyllithium. Screening results are listed in Table 1.
We were delighted to find the cross-coupling occurred in good to
excellent yields in polar amide solvents NMP (1-methyl-2-
pyrrolidinone) and DMF (dimethylformamide) (Table 1, entries
6e8). Further examination revealed the effect of NMP to provide
good yields, similar to earlier reports [18,19,32e34]. The choice of
solvent had a significant impact on the yield (Table 1, entry 17). The
usage of the PCP-NiII-Cl catalyst (0.5 mol%) made the increment of
the yield from 50% to 99% (Table 1, from entry 17 to entry 9). This
control experiment proves that nickel-catalyzed coupling is the
dominent reaction pathway. Without the participation of the nickel
12
r.t.
1.5 60
1.5 r.t.
1.5 r.t.
1.5 r.t.
1.5 r.t.
1.5 r.t.
1.5 r.t.
0.75 r.t.
1.5 r.t.
8
97
90
96
99
90
94
72
88
78
90
50
50
THF-NMP (2:1) 2.0
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
2.0
0.5
0.5
0.1
0.5
0.5
0.5
0.5
0.5
0
9
10
11
12
13
14
15
16
17
12
r.t.
1.5 r.t.
12
r.t.
1.5 r.t.
catalyst the possible reaction would be
a carbometalation-
12
r.t.
1.5 r.t.
elimination sequence [35,36]. Other combinations of solvents and
additives, such as toluene, THF, TMEDA (N,N,N0,N0-tetramethyle-
thylenediamine) and KI, led to lower coupling yields (Table 1,
entries 1e5, and see supporting information). Only 0.1 mol -
a
Typical reaction conditions: 1-bromobutane (1 mmol), Ni catalyst and internal
standard (n-dodecane) were mixed in the solvent (4 ml), phenylethynyllithium in
THF (1 ml) was added dropwise within 1 min according to the conditions specified
in Table 1.
0.5 mol% catalyst loading and
a slight excess of phenyl-
b
GC yield relative to 1-bromobutane against internal standard.
ethynyllithium (1.3 equiv) were required to afford excellent yields
(Table 1, entries 9e11). Further addition of phenylethynyllithium up
to 2 equiv or prolonged the reaction times (12 h) gave lower yields
(Table 1, entries 12 and 15). As the addition of organometallics (RM)
to alkynes constitutes a known method for the preparation of
alkenylmetal reagents [37,38], it appears likely that some alky-
nyllithium adds to the alkyne coupling product in a competitive
pathway.
purchased from commercial sources or prepared from the corre-
sponding alcohol with HBr. PCP-Ni-Cl compound [NiCl{C6H3-2,6-
(OPPh2)2}] (1) was prepared according to literature procedure [31].
NMR spectra were recorded on a Bruker 300 AV spectrometer.
GCeMS was performed on Thermo Trace GC Ultra-DSQ.
To evaluate the scope of this cross-coupling system, phenyl-
ethynyllithium and trimethylsilylethynyllithium reagents were
reacted with alkyl halides under the optimized conditions with
slight modification of the reaction times. A variety of substrates
were coupled in good yields at room temperature (Table 2). Even
non-activated 1-chlorobutane gave 70% yield (Table 2, entry 1). For
secondary alkyl halides, the increasing steric hindrance makes
2.2. Representative procedure for the coupling reactions of alkyl
halides
Under N2 atmosphere at room temperature, to a NMP (30 ml)
solution of PCP-Ni-Cl compound 1 (0.5 mol%) and alkyl halides
(10 mmol) was added dropwise a THF solution (10 ml) of
Table 2
Catalytic cross-coupling of alkyl halides with alkynyllithium reagents.
O
PPh2
Cl
Ni
PPh2
O
0.5 mol% cat. 1
R'
Li
R
R'
R
X
+
NMP, r. t.
1.3 equiv
R'
Entry
1
t (h)
Yield (%)a
R
X
Li
R'
R
0.75
1.5
1.5
99 (X ¼ I)b
90 (X ¼ Br)
70 (X ¼ Cl)b
Li
Li
X
2
1.5
91
Br

G. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 3011e3014
3013
Table 2 (continued )
Entry
t (h)
2.0
Yield (%)a
74
R
X
R'
Li
R'
R
3
Br
Li
4
5
1.5
1.5
85
Br
Li
Li
30 (X ¼ Br)
X
trace (X ¼ Cl)
70 (X ¼ I)
61 (X ¼ Br)
40 (X ¼ Cl)
6
Si
Li
0.75
Si
Si
X
7
8
Si
Si
Li
Li
0.75
0.75
56
55
Br
Br
Si
9
Si
Si
Li
Li
0.75
0.75
60
Br
Si
38 (X ¼ Cl)c
57 (X ¼ Br)c
X
10
Si
Si
X
a
Isolated yield.
b
GC yield relative to alkyl halides against internal standard (n-dodacane).
2.5 equiv of 2-trimethylsilylethynyllithium were used.
c
metal-catalyzed processes much more difficult [8]. Even under
optimized conditions, secondary alkyl halides gave unsatisfactory
results. 2-Bromopropane could be coupled only in 30% yield
(Table 2, entry 5). The reaction of 2-chloropropane (Table 2, entry 5)
and cyclic alkyl halides (data not shown) resulted in failure, only
minor amounts of coupling products were observed by GCeMS.
Modification of the reaction conditions, including solvent, catalyst
loading and temperature had no significant impact (see supporting
information). Under the conditions (20 or 40 mol% Co(acac)3, 4
equiv 2-trimethylsilylethynylmagnesium bromides) previously
reported by Oshima, secondary alkyl bromides could be coupled in
good yields, but employing phenylethynyl Grignard reagent also
gave yields below 20% [12].
(see supporting information), but generally the reactions gave
yields 20e30% lower compared with phenylethynyllithium. Reac-
tions of dihalides with trimethylsilylethynyllithium were also
studied. Treatment of 1,4-dichlorobutane and 1,4-dibromobutane
with 2.5 equiv of 2-trimethylsilylethynyllithium in the presence
of complex 1 gave bis-alkynylation product in moderate yields
(Table 2, entry 10).
Similar to Kumada and Negishi type coupling reactions using
alkyl or arylmetal nucleophiles, we propose that in this system the
Ⅱ
PCP-Ni -Cl complex 1 reacts first to form an alkynyl nickel species 2
Ⅱ
(Scheme 1). Zargarian proved that a closely related PCP-Ni -alkynyl
complex could be prepared by reacting {(i-Pr2PCH2CH2)2CH}NiBr
with LiC^CPh [39], while it could not be isolated in pure form.
Oxidative addition of alkyl halides delivers a formal nickel(IV)
intermediate 3, which gives rise to the coupling product 4 via
reductive elimination. It was suggested that the coupling of aryl
halides with bis(1,5-cyclooctadiene)nickel(0) implicates a transient
bis(aryl)nickel(IV) dihalide [40e44]. It is considered that the pincer
PCP-ligand plays a role in the formation of nickel(IV) species [44].
The self-coupling of alkylnyllithiums to 1,3-diynes by reaction with
NiCl2(PPh3)2 in the presence of triphenylphosphine under stoi-
chiometric conditions indicates that the 1,3-diynes are produced by
reductive elimination from intermediate dialkynylnickel species
[45]. Lithium acetylenides react with 2-chloro-2-nitropropane to
form the cross-coupling product by a process which does not
involve a free radical chain mechanism [46].
For trimethylsilylethynyllithium, the coupling reactions pro-
ceeded faster and the yields did not improve at longer reaction time
PCP-Ni-X
1
alkynyl'-Li
alkyl-alkynyl'
4
alkyl
PCP Ni(IV) X
PCP-Ni-alkynyl'
2
3
alkynyl'
Alternative pathways (such as radical mechanism or direct
bimolecular reaction of an arylnickel halide with an aryl halide)
might exist and more detailed studies will be necessary.
4. Conclusions
We have demonstrated a highly efficient alkylealkynyl coupling
system promoted by PCP-NiII-Cl complex 1 with alkynyllithium
reagents. The usage of the PCP-NiII-Cl catalyst made the increment
alkyl-X
Scheme 1. Proposed mechanism for Ni-catalyzed alkylealkynyl coupling reaction.

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G. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 3011e3014
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alkyl halides with alkynyllithium reagents in THF in the presence
of 10% NaI or Bu4NI [47] and the Sonogashia protocols [24], this
method requires milder conditions (room temperature) and
proceeds quickly. And in comparison with the traditional ways in
preparing the corresponding substituted alkynes, which were
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remarkably expanded using alkynyl nucleophiles. This research will
make these readily available alkynyllithium reagents much more
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Acknowledgments
This work is supported by the NSFC 21072113/20872080.
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Supplementary data associated with this article can be found, in
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