J. M. Penney, J. A. Miller / Tetrahedron Letters 45 (2004) 4989–4992
4991
Table 1 (continued)
Entry ArCN
Reaction time (h)
Product yield (%)b
R
ZnBr
R
Ar
CN
CN
Ph
n-C4H9
Ph
n-C4H9
ZnBr
ZnBr
17
20
80
18
n-C4H9
20
65i
n-C4H9
Cl
Cl
a All reactions were carried out with stoichiometries, catalyst loadings, etc., as illustrated in the representative procedure6.
b Chemical yields are by GC analysis using an internal reference standard.
c Cl2Ni(PMe3)2 (5 mol %) was used.
d The reaction was carried out at 23 °C.
e Benzonitrile (10%) remained unreacted.
f Benzonitrile (4%) remained unreacted.
g Benzonitrile (12%) remained unreacted.
h p-Tolunitrile (5%) remained unreacted.
i 1,4-Bis(10-hexynyl)benzene (5%) was also present in the reaction mixture; no 4-(10-hexynyl)benzonitrile was detected.
a variety of aryl nitriles and terminal alkynes participate
efficiently in this alkynylation reaction. For example,
electron donating and withdrawing groups are accom-
modated on the aromatic ring of the nitrile substrate,
although the former substrates tend to lead to longer
reaction times. Heteroaromatic nitrile substrates, such
as cyanopyridines and cyanofurans also participate well
in this cross coupling reaction. Superior results are
obtained from accessing the alkynylzinc halide reagent
via transmetallation of the respective alkynyl lithium
intermediate with ZnX2 versus use of the alkynyl Grig-
nard reagent as a precursor to the alkynylzinc halide.
However, the nature of the halide ligand ‘X’ does not
appear to be critical in this cross coupling reaction; thus,
zinc chloride and zinc bromide may both be used to
prepare the alkynyl zinc halide reagent via transmetal-
lation of the respective alkynyl lithium. Use of the cor-
responding bis(alkynyl)zinc reagent (i.e., that derived
from use of 2 equiv of alkynyl lithium per mole of ZnX2)
also produces an effective alkynyl coupling partner for
this aryl nitrile alkynylation reaction.
bond toward the nickel catalyst is far greater than that
of the C–Cl bond.
With efficient reaction conditions now established for
the alkynylation of benzonitriles, the scope of useful
C–C and C–N bond forming reactions from these
substrates has been further expanded. This new alkynyl-
ation methodology should provide for increased
flexibility in designing a synthetic route utilizing an
aromatic alkynylation step since aryl nitriles can now be
considered as substrates along with the aryl halides
commonly employed in Negishi or Sonogashira alkynyl-
ation protocols.
Acknowledgements
We thank Prof. B. M. Trost (Stanford University) for
helpful discussions concerning this chemistry.
References and notes
The preformed nickel complex ‘Cl2Ni(PMe3)2’7 and the
species derived in situ from Ni(acac)2 and PMe3 serve as
efficient catalysts for this alkynylation reaction.
Depending upon the reactivity of the particular sub-
strates, it may be beneficial to employ excess PMe3
ligand with either the preformed complex or in situ
derived catalyst. The use of PMe3 as ligand in this
reaction is imperative; no other phosphine ligand sur-
veyed (e.g., Ph3P, Et3P, i-Pr3P, Me2PCH2CH2PMe2)
delivered the desired alkynylation products in more than
minor yields.
1. Miller, J. A. Tetrahedron Lett. 2001, 42, 6991.
2. Miller, J. A.; Dankwardt, J. W.; Penney, J. M. Synthesis
2003, 643.
3. Miller, J. A.; Dankwardt, J. W. Tetrahedron Lett. 2003, 44,
1907.
4. Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
5. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
6. Representative procedure: (1-Hexynylbenzene; entry 2).
A solution of 1-hexyne (0.450 mL, 0.329 g, 4.00 mmol)
in THF (2 mL) was treated at 0 °C with n-butyllithium
(1.6 mL, 4.0 mmol, 2.5 M in hexanes) and the resulting solu-
tion was allowed to warm to room temperature and stirred
for 15 min. The solution was cooled to 0 °C, then treated
with a solution of ZnBr2 (0.901 g, 4.00 mmol) in THF
(2 mL) and allowed to warm to room temperature and
stirred for 30 min. The solvent was removed in
vacuo, and the resulting residue was dissolved in
THF (2 mL). This solution was then added at room
The selectivity toward cross coupling at the nitrile
moiety in 4-chlorobenzonitrile (Table 1, entry 18) is
remarkable. Thus, cross coupling of this bifunctional
substrate with excess 1-hexynylzinc bromide afforded 1-
chloro-4-(10-hexynyl)benzene as the only mono-alkynyl-
ation product detected by GC analysis; none of the
corresponding monoalkynylation adduct derived from
cross coupling at the aryl chloride group was observed.
For at least this substrate, the reactivity of the C–CN
temperature to
a solution of benzonitrile (0.204 mL,
0.206 g, 2.00 mmol), dichlorobis(trimethylphosphine)nickel
(0.0564 g, 10 mol %), and tridecane (0.244 mL, 0.184 g,
1.00 mmol, internal GC standard) in THF (2 mL). The