similar conditions. It is noteworthy that other forms of zinc
metal such as zinc powder (-100 mesh), granular zinc (-30
+ 100 mesh), and even zinc shot (1-2 mm) have been
successfully employed in this procedure (Table 1).
Conceptually, the iodine in this process can play a novel
dual role: (1) the relative redox potentials between “I2 +
2e f 2I-” and “Zn f Zn2+ + 2e” allows a reaction to occur
between iodine and zinc and thus delivers a clean, reactive
surface on the metal and (2) the I- generated can convert
the alkyl bromide into the corresponding alkyl iodide, which
is a more reactive substrate toward oxidative zinc insertion.
Indeed, the formation of small amounts of n-octyl iodide
was observed during the zinc insertion reaction.
Scheme 1
1-iodooctane in 91% yield, respectively (Scheme 1). The
n-octylzinc bromide thus formed readily participated in the
Ni-catalyzed cross-coupling6 with 4-chlorobenzonitrile (0.8
equiv) to give 4-octylbenzonitrile in 94% yield (Table 1).
Alkyl chlorides can also be used as substrates in this zinc
insertion reaction. The presence of a stoichiometric amount
of a bromide salt, as found by Knochel (e.g., LiBr4 or R4NBr,
etc.), is required in addition to the iodine catalyst (Scheme
2).
Table 1. Direct Zinc Insertion into n-Octyl Bromide under
Various Conditions
Scheme 2
I2
temp time conversion yield of 3a
Zn
dust
dust
dustc
dust
dust
dust
dust
(mol %) solvents (°C)
(h)
(%)a
(%)b
5
1
0
5
5
5
5
5
5
5
DMA
DMA
DMA
DMF
DMSO
DMPU
NMP
DMA
DMA
DMA
80
80
80
80
80
80
80
80
80
80
3
9
9
4.5
3
3
6
3
3
>99
>98
20
>99
>99
>99
>98
>99
>98
>98
94
89
88
92
96
95
92
94
88
powder
granule
shot
12
The scope of this zinc insertion reaction is very broad.
Not only can many forms of zinc be used but also a variety
of functional groups such as halides, ethers, esters, nitriles,
amides, acetals, and alkenes are tolerated under the reaction
conditions (Table 2). These in situ-generated zinc reagents
readily participate in the Ni- or Pd-catalyzed cross-coupling
reaction with aryl halides to produce various functionalized
alkylarenes in excellent yields.7 It is noteworthy that organo-
zincs derived from bromides containing a terminal double
bond (1f and 1g) produced significant amounts of isomer-
ization and other byproducts (10-20%) from their Ni-
catalyzed cross-coupling with 4-chlorobenzonitrile. However,
a switch from Ni to Pd led to formation of desired products
a Conversion of n-octyl bromide. b GC yield. c Activated with 1,2-
dibromoethane and TMSCl.
The iodine effect is remarkable. Even with the use of 1 mol
% I2, the zinc insertion proceeded smoothly and was
complete within 9 h. However, in the absence of I2, the
conversion was only 20% even though zinc dust was
activated with 1,2-dibromoethane and Me3SiCl (Table 1).
This zinc insertion can also be performed in other polar
aprotic solvents such as DMF, DMSO, DMPU, and NMP,
giving comparable results as shown in Table 1. The sub-
sequent Ni-catalyzed cross-coupling reactions with 4-chloro-
benzonitrile in these solvents also proceeded readily, with
little (<2%) or no formation of homocoupling byproduct
4,4′-dicyanobiphenyl. On the other hand, when less polar
solvents such as diethyl ether, THF, dioxane, DME, and
acetonitrile were used, virtually no zinc reagent formed under
(7) Typical Procedure. Preparation of Ethyl 4-(4-Cyanophenyl)-
butyrate (3j). In a dry 25 mL two-necked flask were charged under N2
dry DMA (10 mL), I2 (127 mg, 0.5 mmol), and zinc dust (0.98 g, 15 mmol).
The mixture was stirred at 23 °C until the red color of I2 disappeared (ca.
2 min). Ethyl 4-bromobutyrate (1j) (1.95 g, 10 mmol) was added, and the
mixture was stirred at 80 °C for 3 h. Completion of the zinc insertion
reaction was indicated by GC analysis of the hydrolyzed reaction mixture.
The mixture was cooled to 23 °C, and 1.1 g (8 mmol) of 4-chlorobenzonitrile
and 105 mg (0.16 mmol) of Cl2Ni(PPh3)2 were added successively at 23
°C. The coupling reaction was complete at room temperature after 1 h as
checked by GC analysis. The reaction was quenched with 1 N HCl, and
the mixture was extracted with ethyl acetate (4 × 20 mL). The combined
organic phases were washed with brine, dried over MgSO4, filtered, and
evaporated. Flash chromatography on silica gel (98:2 hexane/ethyl acetate)
gave the cross coupling product 3j as a clear, colorless oil (1.69 g, 97%).
(6) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821. (b) Negishi, E.; Matsushita, H.; Kobayashi, M.; Rand, C. L.
Tetrahedron Lett. 1983, 24, 3823. For recent reports on Negishi coupling
of alkylzincs with aryl chlorides, see: (c) Lipshutz, B. H.; Blomgren, P.
A.; Kim, S. K. Tetrahedron Lett. 1999, 40, 197. (d) Lipshutz, B. H.;
Blomgren, P. A. J. Am. Chem. Soc. 1999, 121, 5819. (e) Dai, C.; Fu, G. C.
J. Am. Chem. Soc. 2001, 123, 2719.
424
Org. Lett., Vol. 5, No. 4, 2003