The first general method for palladium-catalyzed Negishi cross-coupling of aryl and vinyl chlorides: Use of commercially available Pd(P(t-Bu)3)2 as a catalyst

Article abstract of DOI:10.1021/ja003954y

With a single protocol, commercially available Pd(P(t-Bu)₃)₂ can effect the Negishi cross-coupling of a wide range of aryl and vinyl chlorides with aryl- and alkylzinc reagents. The process tolerates nitro groups, and it efficiently generates sterically hindered biaryls. In addition, a high turnover number (>3000) can be achieved.

Full text of DOI:10.1021/ja003954y

J. Am. Chem. Soc. 2001, 123, 2719-2724
2719
The First General Method for Palladium-Catalyzed Negishi
Cross-Coupling of Aryl and Vinyl Chlorides: Use of Commercially
Available Pd(P(t-Bu)3)2 as a Catalyst
Chaoyang Dai and Gregory C. Fu*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed NoVember 14, 2000
Abstract: With a single protocol, commercially available Pd(P(t-Bu)3)2 can effect the Negishi cross-coupling
of a wide range of aryl and vinyl chlorides with aryl- and alkylzinc reagents. The process tolerates nitro
groups, and it efficiently generates sterically hindered biaryls. In addition, a high turnover number (>3000)
can be achieved.
Introduction
however, there have been only isolated instances of palladium-
catalyzed Negishi reactions of aryl chlorides,15 although methods
for the corresponding nickel-catalyzed process have been
described.16,17 In this report, we establish that commercially
The palladium-catalyzed cross-coupling of aryl and vinyl
halides/triflates with organozinc reagents (Negishi reaction)1
represents a powerful method for generating aromatic com-
pounds such as styrene derivatives and biaryls, which are
important synthetic targets in disciplines ranging from materials
science2 to medicine.3 The ready availability and the functional-
group compatibility of organozinc reagents4 significantly en-
hance the utility of this cross-coupling process.
Among aryl halides, chlorides are arguably the most useful
class of substrates for coupling reactions, due to their lower
cost and the wider diversity of available compounds.5 Unfor-
tunately, although palladium-catalyzed reactions of aryl bro-
mides and aryl iodides have been commonplace for a number
of years,6 until quite recently the corresponding couplings of
aryl chlorides were generally unsuccessful.5,7
(9) For early examples, see: (a) Old, D. W.; Wolfe, J. P.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 9722-9723. Wolfe, J. P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561.
(b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1998, 37, 3387-
3388. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028. (c) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805. (d) Herrmann, W. A.; Reisinger, C.-P.; Spiegler,
M. J. Organomet. Chem. 1998, 557, 93-96. Weskamp, T.; Bohm, V. P.
W.; Herrmann, W. A. J. Organomet. Chem. 1999, 585, 348-352.
(10) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. (b)
Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
2123-2132.
(11) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411-
2413.
(12) For early examples, see: (a) Reddy, N. P.; Tanaka, M. Tetrahedron
Lett. 1997, 38, 4807-4810. (b) Nishiyama, M.; Yamamoto, T.; Koie, Y.
Tetrahedron Lett. 1998, 39, 617-620. (c) Hamann, B. C.; Hartwig, J. F. J.
Am. Chem. Soc. 1998, 120, 7369-7370. (d) Old, D. W.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. Wolfe, J. P.;
Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000,
65, 1158-1174.
(13) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2000, 122, 1360-1370. (b) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478.
(14) (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224-3225. (b) Aranyos, A.; Old, D. W.; Kiyomori,
A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 4369-4378. (c) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1999, 40, 8837-8840.
Since 1998, however, noteworthy strides have been made in
the development of palladium-based catalyst systems for reac-
tions of aryl chlorides.8 For example, versatile methods have
been reported for classic coupling processes such as the Suzuki,9
Heck,10 and Stille11 reactions, as well as for more recently
discovered amine,12 ketone,13 and alcohol14 arylations. To date,
(1) For a review, see: Negishi, E.-i. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
Chapter 1.
(2) For example, see: Step Growth Polymers for High-Performance
Materials; Hedrick, J. L., Labadie, J. W., Eds.; ACS Symp. Ser. 624;
American Chemical Society: Washington, D.C., 1996.
(3) For example, see: (a) A review of vancomycin antibiotics: Nicolaou,
K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2096-2152. (b) Reviews of sartans and Losartan: Birkenhager,
W. H.; de Leeuw, P. W. J. Hypertens. 1999, 17, 873-881. Goa, K. L.;
Wagstaff, A. J. Drugs 1996, 51, 820-845.
(15) We are aware of only one example of a palladium-catalyzed Negishi
cross-coupling of an unactivated aryl chloride: Herrmann, W. A.; Bohm,
V. P. W.; Reisinger, C.-P. J. Organomet. Chem. 1999, 576, 23-41 (coupling
of PhZnBr with chlorobenzene).
(16) For reports of nickel-catalyzed Negishi cross-couplings of unacti-
vated aryl chlorides, see: (a) House, H. O.; Ghali, N. I.; Haack, J. L.;
VanDerveer, D. J. Org. Chem. 1980, 45, 1807-1817. (b) Lebedev, S. A.;
Sorokina, R. S.; Berestova, S. S.; Petrov, E. S.; Beletskaya, I. P. Bull. Acad.
Sci. USSR, DiV. Chem. Sci. 1986, 35, 620-622. (c) Miller, J. A.; Farrell,
R. P. Tetrahedron Lett. 1998, 39, 6441-6444. (d) Lipshutz, B. H.;
Blomgren, P. A.; Kim, S.-K. Tetrahedron Lett. 1999, 40, 197-200. Lipshutz,
B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999, 121, 5819-5820.
(17) For discussions of the advantages of palladium over nickel, see:
(a) Negishi, E.-i. In Metal-catalyzed Cross-coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; p 38. (b) Negishi,
E.-i. In Organozinc Reagents, A Practical Approach; Knochel, P., Jones,
P., Eds.; Oxford: New York, 1999; pp 214-215 and Table 11.1.
(4) (a) Organozinc Reagents, A Practical Approach; Knochel, P., Jones,
P., Eds.; Oxford: New York, 1999. (b) Erdik, E. Organozinc Reagents in
Organic Synthesis; CRC Press: Boston, 1996.
(5) (a) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062. (b)
Grushin, V. V.; Alper, H. In ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin, 1999; pp 193-226.
(6) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: New York, 1998.
(7) The low reactivity of chlorides is usually attributed primarily to the
strength of the C-Cl bond (bond dissociation energies for Ar-X: Cl )
96 kcal/mol; Br ) 81 kcal/mol; I ) 65 kcal/mol). See ref 5.
(8) Stu¨rmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307-3308.
10.1021/ja003954y CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/22/2001

2720 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Dai and Fu
Table 1. Negishi Cross-Couplings of Aryl Chlorides to Generate
Biaryls
available Pd(P(t-Bu)3)2 serves as a versatile catalyst for the
Negishi cross-coupling of aryl- and alkylzinc reagents with aryl
and vinyl chlorides (eq 1).
Results and Discussion
In early studies, we determined that Pd2(dba)3/P(t-Bu)3
catalyzes the challenging Negishi coupling of electron-rich
4-chloroanisole with sterically demanding o-tolylzinc chloride
(100 °C, THF/NMP).18,19 On the basis of our observation that
a Pd:P(t-Bu)3 ratio of 1:2 appeared to be optimal, we decided
to examine the catalytic activity of Pd(P(t-Bu)3)2.20,21 We were
pleased to discover that this air-stable complex does indeed serve
as an effective catalyst for the Negishi cross-coupling of aryl
chlorides.
Using a standard set of reaction conditions (2% Pd(P(t-Bu)3)2,
THF/NMP, 100 °C), we can couple a diverse array of aryl
chlorides and organozinc reagents. Electronic variation in both
reaction partners is tolerated, as illustrated by entries 1-6 of
Table 1. Whereas coupling of a ketone-containing substrate is
accompanied by the generation of unidentified byproducts (entry
4), nitro groups (which interfere with nickel catalysts22) and
esters are compatible with the reaction conditions (entries 5 and
6). Heteroaromatic aryl chlorides are also suitable coupling
partners (entries 7 and 8), and with this protocol Negishi cross-
coupling proceeds in preference to Suzuki cross-coupling (entry
9).
With our standard reaction conditions, we can also efficiently
synthesize quite hindered biaryls (Table 2). For example, we
can generate 1,1′-dimethylbiphenyl in 96% yield from 2-chlo-
rotoluene and o-tolylzinc chloride (entry 1). Furthermore, we
can produce tri-ortho-substituted biaryls in excellent yield
(entries 2 and 3), and we can even synthesize tetra-ortho-
substituted biaryls (entry 4);23 to the best of our knowledge,
this is the first example of a Negishi coupling that furnishes a
tetra-ortho-substituted biaryl.
a Isolated yield, average of two runs. b (RO)2B ) pinacolboronate.
Table 2. Negishi Cross-Couplings of Aryl Chlorides to Generate
Hindered Biaryls
We have established that we can apply the same protocol to
the Negishi reaction of vinyl chlorides,24 thereby producing
styrene derivatives in very good yield (Table 3). Thus, 1-chlo-
rocyclopentene couples cleanly with a range of arylzinc reagents,
including very hindered ones (entries 1-3). A substituent cis
to chlorine is also tolerated, as illustrated in entries 4-6.
(18) Pd2(dba)3/PCy3 is also an effective catalyst.
(19) Pd2(dba)3/P(t-Bu)3 effects clean coupling of 4-bromoanisole and
o-tolylzinc chloride at room temperature.
(20) (a) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J. Am.
Chem. Soc. 1976, 98, 5850-5858. (b) Yoshida, T.; Otsuka, S. Inorg. Synth.
1990, 28, 113-119. This report states that Pd(P(t-Bu)3)2 is “stable in air in
the solid state”. We have observed slight decomposition after extended (>1
month) exposure to air (A. F. Littke, unpublished results).
(21) Pd(P(t-Bu)3)2 is available from Strem Chemicals.
(22) In his original report of the Negishi cross-coupling process, Negishi
notes that “the nitro group...destroys the catalytic ability of the Ni
complexes”: Negishi, E.-i.; King, A. O.; Okukado, N. J. Org. Chem. 1977,
42, 1821-1823.
a Isolated yield, average of two runs.
(23) For Negishi reactions that generate tetra-ortho-substituted biaryls,
we have found homocoupling to be a significant side reaction.
(24) We are only aware of a few examples of palladium-catalyzed Negishi
reactions of vinyl chlorides: (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am.
Chem. Soc. 1987, 109, 1257-1258. Minato, A. J. Org. Chem. 1991, 56,
4052-4056. (b) Sinha, S. C.; Keinan, E.; Reymond, J.-L. J. Am. Chem.
Soc. 1993, 115, 4893-4594.
Finally, we have examined the Pd(P(t-Bu)3)2-catalyzed Negishi
cross-coupling of aryl and vinyl chlorides with alkylzinc reagents
(Table 4).25 The reaction of a primary alkylzinc reagent proceeds
uneventfully (entry 1). In the case of a branched alkylzinc, for
Negishi couplings catalyzed by other Pd/(monodentate phos-
phine) complexes, products derived from isomerization of the
(25) Under the same conditions, vinyl- and alkynylzinc reagents are not
suitable coupling partners.

Pd-Catalyzed Negishi Cross-Coupling of Aryl and Vinyl Chlorides
J. Am. Chem. Soc., Vol. 123, No. 12, 2001 2721
for the treatment of hypertension.27 We have produced this target
in 97% yield through a Negishi cross-coupling of o-chloroben-
zonitrile with p-tolylmagnesium bromide in the presence of
0.03% Pd(P(t-Bu)3)2 (eq 2). This corresponds to a turnover
number (TON) >3000, which is the highest TON that we are
aware of for a Negishi reaction of an aryl chloride.28,29
Table 3. Negishi Cross-Couplings of Vinyl Chlorides to Generate
Styrenes
Conclusions
For the Negishi reaction, we have developed a single protocol
that efficiently cross-couples a variety of aryl and vinyl chlorides
with organozinc reagents. Noteworthy features of this method
include the following: use of a commercially available, air-
stable catalyst, Pd(P(t-Bu)3)2; tolerance of nitro functionality;
synthesis of very hindered biaryls; coupling of sterically
demanding vinyl chlorides and arylzinc reagents; reaction of
alkylzincs, including secondary alkylzincs; and high turnover
number.
This represents the first general method for accomplishing
palladium-catalyzed Negishi reactions of aryl and vinyl chlo-
rides. Mechanistic investigations and the development of other
applications of Pd/P(t-Bu)3 in cross-coupling processes are
underway.
a Isolated yield, average of two runs.
Table 4. Negishi Cross-Couplings of Aryl and Vinyl Chlorides
with Alkylzincs
Experimental Section
General. THF was distilled from sodium-benzophenone ketyl.
1-Methyl-2-pyrrolidinone (NMP; Aldrich; anhydrous, in a Sure-Seal
bottle), Pd2(dba)3 (Aldrich), PdCl2 (Strem), and P(t-Bu)3 (Strem) were
used as received. 2-(4-Chlorophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxa-
borolane30 was prepared through the treatment of 4-chlorophenylboronic
acid with pinacol in toluene. 1-Chloro-4-tert-butylcyclohexene31 was
prepared according to a literature procedure. Other aryl and vinyl
chlorides were purchased from commercial sources (Aldrich, Alfa-
Aesar) and distilled or recrystallized prior to use. Zinc chloride (0.5 M
solution in THF) and all Grignard reagents were purchased from Aldrich
in Sure-Seal bottles.
All reactions were carried out under an atmosphere of argon in oven-
dried glassware with magnetic stirring, unless otherwise indicated.
Pd(P(t-Bu)3)2. Pd(P(t-Bu)3)2 is available from Strem Chemicals
(catalog no. 46-0252). Alternatively, it may be prepared according to
the following procedure: In a glovebox, Pd2(dba)3 (459 mg, 0.50 mmol),
P(t-Bu)3 (425 mg, 2.1 mmol), and DMF (anhydrous; 10 mL) were added
to a vial equipped with a stir bar. The vial was capped, and the reaction
mixture was stirred for 3 h at room temperature. The resulting precipitate
was collected by filtration, washed thoroughly with DMF, and then
dissolved in hexane. The hexane solution was filtered and concentrated,
yielding 422 mg (83%) of white crystals. 31P{1H} NMR (C6D6) 85.2;
1H NMR (C6D6) 1.53 (t, J ) 5.7) [Pd(P(t-Bu)3)2 is not stable in
CDCl3].32
General Procedure: 4-Nitro-2′-methylbiphenyl (Table 1, entry
5).33 Under argon, ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol)
was added by syringe to a Schlenk tube. o-Tolylmagnesium chloride
(1.0 M solution in THF; 1.5 mL, 1.5 mmol) was then added dropwise,
and the resulting mixture was stirred at room temperature for 20 min.
Next, NMP (2.2 mL) was added by syringe, followed after 5 min by
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol) and 1-chloro-4-nitrobenzene (158
mg, 1.0 mmol). The Schlenk tube was closed at the Teflon stopcock,
and the reaction mixture was stirred in a 100 °C oil bath for 2 h. It
a Isolated yield, average of two runs. b Includes 8% 2-n-butyltoluene.
c Includes 2% 4-tert-butyl-1-n-butylcyclohexene.
alkyl group (secondary f primary) can be predominant.26 With
Pd(P(t-Bu)3)2, we generate the desired compound with ∼10:1
selectivity (entry 2) for the coupling of an aryl chloride with
s-BuZnCl and with ∼40:1 selectivity (entry 3) for the reaction
of a vinyl chloride.
2-Cyano-4′-methylbiphenyl is a key intermediate in the
synthesis of angiotensin II receptor antagonists that are used
(26) For example, see: Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada,
M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163. See
also ref 1.
(27) For leading references, see: Goubet, D.; Meric, P.; Dormoy, J.-R.;
Moreau, P. J. Org. Chem. 1999, 64, 4516-4518.
(28) With 0.01% Pd(P(t-Bu)3)2, this Negishi cross-coupling does not
proceed to completion: we isolate a mixture of 76% of the desired product
(w 7600 turnovers), along with 10% of the unreacted aryl chloride.
(29) To date, we have conducted only preliminary mechanistic studies
of the Pd(P(t-Bu)3)2-catalyzed Negishi cross-coupling process. Two of our
observations may be of interest: (a) During the course of the reaction of
4-chloroanisole with o-tolylzinc chloride, Pd(P(t-Bu)3)2 is the only phosphorus-
containing species that can be seen in the 31P NMR spectrum. (b) Excess
P(t-Bu)3 inhibits cross-coupling (which likely implicates a role in the reaction
for a palladium/monophosphine complex).
(30) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2000, 65, 164-168.
(31) Lambert, J. B.; Wang, G.-t.; Finzel, R. B.; Teramura, D. H. J. Am.
Chem. Soc. 1987, 109, 7838-7845.
(32) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J. Am. Chem.
Soc. 1976, 98, 5850-5858.

2722 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Dai and Fu
was then allowed to cool to room temperature, and aqueous HCl was
added (1.0 M; 6 mL). The resulting mixture was extracted with Et2O
(4 × 8 mL), and the organic extracts were combined, washed with
water (5 × 10 mL), dried (MgSO4), and concentrated, affording a
yellow solid. Flash chromatography (3% Et2O in hexanes) furnished
200 mg (94%) of the title compound as a pale-yellow solid.
1H NMR (CDCl3, 300 MHz): 8.27 (d, J ) 8.8 Hz, 2H), 7.48 (d, J
) 8.8 Hz, 2H), 7.30-7.20 (m, 4H), 2.27 (s, 3H). 13C NMR (CDCl3,
75 MHz): 148.9, 139.7, 135.2, 130.8, 130.2, 129.5, 128.6, 126.3, 123.5,
20.6.
4-Methoxy-2′-methylbiphenyl (Table 1, entry 1).34 The general
procedure was followed with use of 4-chloroanisole (143 mg, 1.0
mmol), o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL,
1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd-
(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 24 h at
100 °C, workup and column chromatography (5% Et2O in hexanes)
yielded 190 mg (95%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.27-7.21 (m, 6H), 6.95 (d, J ) 9.0
Hz, 2H), 3.85 (s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3, 75 MHz): 158.6,
141.6, 135.6, 134.5, 130.4, 130.4, 130.0, 127.1, 125.9, 113.6, 55.5,
20.8.
4-Butyl-2′-methylbiphenyl (Table 1, entry 2). The general proce-
dure was followed with use of 1-(4′-chlorophenyl)butane (168 mg, 1.0
mmol), o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL,
1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd-
(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 3 h at
100 °C, workup and column chromatography (hexanes) yielded 209
mg (93%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.25-7.21 (m, 8H), 2.65 (t, J ) 7.7
Hz, 2H), 2.28 (s, 3H), 1.65 (quintet, J ) 7.7 Hz, 2H), 1.40 (sextet, J
) 7.7 Hz, 2H), 0.95 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
142.0, 141.5, 139.3, 135.5, 130.4, 130.0, 129.2, 128.2, 127.1, 125.8,
35.7, 33.9, 22.8, 20.9, 14.3. IR (neat, cm-1): 2955, 2928, 2857, 1483,
1456, 1007, 836, 759. HRMS (EI, m/z) calcd for C17H20 (M+) 224.1565,
found 224.1561.
4-Methoxy-2′-methylbiphenyl (Table 1, entry 3).34 The general
procedure was followed with use of 2-chlorotoluene (127 mg, 1.0
mmol), 4-methoxyphenylmagnesium bromide (0.5 M solution in THF;
3.0 mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol),
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 24 h
at 100 °C, workup and column chromatography (5% Et2O in hexanes)
yielded 175 mg (88%) of the title compound as a colorless liquid.
4-Acetyl-2′-methylbiphenyl (Table 1, entry 4).35 The general
procedure was followed with use of 4′-chloroacetophenone (155 mg,
1.0 mmol), o-tolylmagnesium chloride (1.0 M solution in THF; 1.5
mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol),
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 2 h at
100 °C, workup and column chromatography (10% Et2O in hexanes)
yielded 105 mg (50%) of the title compound as a pale-yellow liquid.
NMR (CDCl3, 75 MHz): 167.1, 146.8, 140.9, 135.3, 130.6, 129.6,
129.5, 129.4, 128.7, 127.9, 126.0, 52.4, 20.7.
2-o-Tolylpyridine (Table 1, entry 7).37 The general procedure was
followed with use of 2-chloropyridine (114 mg, 1.0 mmol), o-
tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2
mg, 0.020 mmol), and NMP (2.2 mL). After 2 h at 100 °C, workup
(water, rather than aqueous HCl, was used for the extraction) and
column chromatography (30% Et2O in hexanes) yielded 157 mg (93%)
of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 8.70 (ddd, J ) 4.8 Hz, 1.8 Hz, 0.9
Hz, 1H), 7.74 (apparent triplet of doublets, 1H), 7.42-7.38 (m, 2H),
7.31-7.22 (m, 4H), 2.36 (s, 3H). 13C NMR (CDCl3, 75 MHz): 160.1,
149.3, 140.5, 136.2, 135.9, 130.9, 129.7, 128.4, 126.0, 124.2, 121.8,
20.5.
3-o-Tolylthiophene (Table 1, entry 8).38 The general procedure was
followed with use of 3-chlorothiophene (119 mg, 1.0 mmol), o-
tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol)), Pd(P(t-Bu)3)2
(10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 20 h at 100 °C,
workup and column chromatography (pentane) yielded 161 mg (92%)
of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.34 (dd, J ) 4.7 Hz, 2.7 Hz, 1H),
7.31-7.28 (m, 1H), 7.26-7.18 (m, 4H), 7.14 (dd, J ) 4.9 Hz, 1.4 Hz,
1H), 2.34 (s, 3H). 13C NMR (CDCl3, 75 MHz): 142.3, 136.7, 135.8,
130.6, 129.9, 129.0, 127.4, 125.9, 125.0, 122.7, 21.1.
2-(2′-Methylbiphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(Table 1, entry 9). The general procedure was followed with use of
2-(4-chlorophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (238 mg, 1.0
mmol), o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL,
1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd-
(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 2 h at
100 °C, workup and column chromatography (10% Et2O in hexanes)
yielded 256 mg (87%) of the title compound as a white solid.
1H NMR (CDCl3, 300 MHz): 7.85 (d, J ) 8.2 Hz, 2H), 7.30 (d, J
) 8.2 Hz, 2H), 7.25-7.20 (m, 4H), 2.26 (s, 3H), 1.36 (s, 12H). 13C
NMR (CDCl3, 75 MHz): 145.0, 141.9, 135.4, 134.6, 130.5, 129.8,
128.7, 127.5, 125.9, 84.0, 25.2, 20.7. IR (neat, cm-1): 2977, 2928,
1611, 1397, 1360, 1145, 1091, 962, 860, 661. HRMS (EI, m/z) calcd
for C19H23BO2 (M+) 294.1786, found 294.1783.
2,2′-Dimethylbiphenyl (Table 2, entry 1). The general procedure
was followed with use of 2-chlorotoluene (127 mg, 1.0 mmol),
o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2
mg, 0.020 mmol), and NMP (2.2 mL). After 20 h at 100 °C, workup
and column chromatography (hexanes) yielded 170 mg (93%) of the
title compound as a colorless liquid that was identical to authentic
1
material (TCI) by H NMR, GC, and TLC.
2,6,2′-Trimethylbiphenyl (Table 2, entry 2).39 The general pro-
cedure was followed with use of 2-chlorotoluene (127 mg, 1.0 mmol),
2,6-dimethylphenylmagnesium bromide (1.0 M solution in THF; 1.5
mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol),
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 18 h
at 100 °C, workup and column chromatography (hexanes) yielded 196
mg (96%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 8.01 (d, J ) 8.7 Hz, 2H), 7.43 (d, J
) 8.7 Hz, 2H), 7.30-7.20 (m, 4H), 2.65 (s, 3H), 2.27 (s, 3H). 13C
NMR (CDCl3, 75 MHz): 198.0, 147.1, 140.8, 135.7, 135.3, 130.6,
129.6, 129.6, 128.4, 128.0, 126.1, 26.9, 20.7.
4-Carbomethoxy-2′-methylbiphenyl (Table 1, entry 6).36 The
general procedure was followed with use of methyl 4-chlorobenzoate
(171 mg, 1.0 mmol), o-tolylmagnesium chloride (1.0 M solution in
THF; 1.5 mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6
mmol), Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After
2 h at 100 °C, workup and column chromatography (10% Et2O in
hexanes) yielded 221 mg (98%) of the title compound as a white solid.
1H NMR (CDCl3, 300 MHz): 7.31-7.09 (m, 6H), 7.03-6.99 (m,
1H), 1.97 (s, 3H), 1.94 (s, 6H). 13C NMR (CDCl3, 75 MHz): 141.2,
140.7, 136.0, 135.8, 130.1, 129.0, 127.4, 127.1, 127.1, 126.2, 20.6,
19.7.
2,6,2′-Trimethylbiphenyl (Table 2, entry 3).39 The general pro-
cedure was followed with use of 2-chloro-m-xylene (141 mg, 1.0 mmol),
o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2
mg, 0.020 mmol), and NMP (2.2 mL). After 24 h at 100 °C, workup
and column chromatography (hexanes) yielded 186 mg (91%) of the
title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 8.07 (d, J ) 8.5 Hz, 2H), 7.39 (d, J
) 8.5 Hz, 2H), 7.30-7.18 (m, 4H), 3.94 (s, 3H), 2.26 (s, 3H). 13C
(33) Hecht, S. S.; El-Bayoumy, K.; Tulley, L.; LaVoie, E. J. Med. Chem.
1979, 22, 981-987.
(34) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem.
1993, 58, 5434-5444.
(37) Terashima, M.; Seki, K.-I.; Yoshida, C.; Ohkura, K.; Kanaoka, Y.
Chem. Pharm. Bull. 1985, 33, 1009-1015.
(35) Wirth, H. O.; Kern, W.; Schmitz, E. Makromol. Chem. 1963, 68,
69-99.
(38) Hartman, G. D.; Halczenko, W.; Phillips, B. T. J. Org. Chem. 1986,
51, 142-148.
(36) Ananthakrishnanadar, P.; Kannan, N. J. Chem. Soc., Perkin Trans.
2 1984, 35-37.
(39) Kamikawa, T.; Hayashi, T. Synlett, 1997, 163-164.

Pd-Catalyzed Negishi Cross-Coupling of Aryl and Vinyl Chlorides
J. Am. Chem. Soc., Vol. 123, No. 12, 2001 2723
2,3-Dimethoxy-6-cyano-2′,6′-dimethylbiphenyl (Table 2, entry 4).
The general procedure was followed with use of 2-chloro-3,4-
dimethoxybenzonitrile (198 mg, 1.0 mmol), 2,6-dimethylphenylmag-
nesium bromide (1.0 M solution in THF; 1.5 mL, 1.5 mmol), ZnCl2
(0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2 mg,
0.020 mmol), and NMP (2.2 mL). After 18 h at 100 °C, workup and
column chromatography (1:2 EtOAc/hexanes) yielded 207 mg (77%)
of the title compound as a pale-yellow solid.
1H NMR (CDCl3, 300 MHz): 7.50 (d, J ) 8.5 Hz, 1H), 7.25-7.11
(m, 3H), 6.97 (d, J ) 8.5 Hz, 1H), 3.96 (s, 3H), 3.54 (s, 3H), 2.06 (s,
6H). 13C NMR (CDCl3, 75 MHz): 156.8, 146.5, 138.9, 136.1, 133.9,
129.9, 128.5, 127.6, 117.9, 111.6, 105.6, 60.5, 56.2, 20.5. IR (neat,
cm-1): 2222 (CN), 1589, 1480, 1277, 1125, 1045, 1012. HRMS (EI,
m/z) calcd for C17H17NO2 (M+) 267.1259, found 267.1253.
1-(4′-Methoxy)cyclopentene (Table 3, entry 1).40 The general
procedure was followed with use of 1-chlorocyclopentene (103 mg,
1.0 mmol), 4-methoxyphenylmagnesium bromide (1.0 M solution in
THF; 1.5 mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6
mmol), Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After
8 h at 100 °C, workup and column chromatography (2.5% Et2O in
pentane) yielded 145 mg (83%) of the title compound as a white solid.
1H NMR (CDCl3, 300 MHz): 7.36 (d, J ) 8.6 Hz, 2H), 6.84 (d, J
) 8.5 Hz, 2H), 5.48 (apparent triplet, 1H), 3.80 (s, 3H), 2.70-2.63
(m, 2H), 2.52-2.46 (m, 2H), 2.05 (apparent quintet, 2H). 13C NMR
(CDCl3, 75 MHz): 158.6, 141.9, 129.8, 126.8, 124.1, 113.8, 55.5, 33.6,
33.5, 23.7.
1-(o-Tolyl)cyclopentene (Table 3, entry 2).41 The general procedure
was followed with use of 1-chlorocyclopentene (103 mg, 1.0 mmol),
o-tolylmagnesium chloride (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2
mg, 0.020 mmol), and NMP (2.2 mL). After 2 h at 100 °C, workup
and column chromatography (pentane) yielded 153 mg (97%) of the
title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.19-7.10 (m, 4H), 5.75 (apparent
triplet, 1H), 2.70-2.62 (m, 2H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.98
(apparent quintet, 2H). 13C NMR (CDCl3, 75 MHz): 143.4, 138.3,
135.6, 130.6, 129.5, 128.1, 126.7, 125.6, 36.9, 33.9, 24.1, 21.5.
2-Methyl-1-o-tolylpropene (Table 3, entry 5).43 The general
procedure was followed with use of 1-chloro-2-methylpropene (91 mg,
1.0 mmol), o-tolylmagnesium chloride (1.0 M solution in THF; 1.5
mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol),
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 2 h at
100 °C, workup and column chromatography (pentane) yielded 132
mg (90%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.14-7.12 (m, 4H), 6.21 (broad s,
1H), 2.23 (s, 3H), 1.91 (d, J ) 1.5 Hz, 3H), 1.70 (d, J ) 1.0 Hz, 3H).
13C NMR (75 MHz, CDCl3): 138.0, 136.5, 135.2, 129.7, 129.5, 126.3,
125,4, 124.2, 26.4, 20.2, 19.6.
2-Methyl-1-mesitylpropene (Table 3, entry 6).44 The general
procedure was followed with use of 1-chloro-2-methylpropene (91 mg,
1.0 mmol), mesitylmagnesium bromide (1.0 M solution in THF; 1.5
mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol),
Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 3 h at
100 °C, workup and column chromatography (pentane) yielded 160
mg (92%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 6.84 (s, 2H), 6.00 (broad s, 1H), 2.26
(s, 3H), 2.13 (s, 6H), 1.88 (d, J ) 1.4 Hz, 3H), 1.42 (d, J ) 1.1 Hz,
3H). 13C NMR (75 MHz, CDCl3): 136.5, 135.6, 135.1, 135.0, 127.8,
123.2, 25.4, 21.3, 20.5, 19.4.
2-Methylbutylbenzene (Table 4, Entry 1).45 The general procedure
was followed with use of 2-chlorotoluene (127 mg, 1.0 mmol),
n-butylmagnesium chloride (2.0 M solution in THF; 0.75 mL, 1.5
mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-
Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 20 h at 100
°C, workup and column chromatography (pentane) yielded 120 mg
(83%) of the title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.15-7.02 (m, 4H), 2.59 (t, J ) 7.8
Hz, 2H), 2.30 (s, 3H), 1.55 (quintet, J ) 7.2 Hz, 2H), 1.41 (sextet, J
) 7.2 Hz, 2H), 0.94 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
141.2, 135.9, 130.2, 128.9, 125.9, 125.8, 33.3, 32.8, 23.1, 19.6, 14.4.
2-Methyl-s-butylbenzene (Table 4, entry 2).45 The general proce-
dure was followed with use of 2-chlorotoluene (127 mg, 1.0 mmol),
s-butylmagnesium chloride (2.0 M solution in Et2O; 0.75 mL, 1.5
mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-
Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL). After 24 h at 100
°C, workup and column chromatography (pentane) yielded 105 mg
(71%) of the title compound as a colorless liquid that contained ∼8%
1-Mesitylcyclopentene (Table 3, entry 3). The general procedure
was followed with use of 1-chlorocyclopentene (103 mg, 1.0 mmol),
mesitylmagnesium bromide (1.0 M solution in THF; 1.5 mL, 1.5 mmol),
ZnCl2 (0.5 M solution in THF; 3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2
mg, 0.020 mmol), and NMP (2.2 mL). After 3 h at 100 °C, workup
and column chromatography (pentane) yielded 170 mg (91%) of the
title compound as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 6.85 (s, 2H), 5.48 (apparent triplet,
1H), 2.57-2.40 (m, 4H), 2.26 (s, 3H), 2.18 (s, 6H), 2.03 (apparent
quintet, 2H). 13C NMR (CDCl3, 75 MHz): 143.0, 136.2, 136.1, 136.0,
128.6, 128.0, 36.8, 33.6, 24.4, 21.3, 20.2. IR (neat, cm-1): 2936, 2919,
1612, 1480, 1444, 1041, 849. HRMS (EI, m/z) calcd for C14H18 (M+)
186.1409, found 186.1405.
2-Methyl-1-(4′-methoxyphenyl)propene (Table 3, entry 4).42 The
general procedure was followed with use of 1-chloro-2-methylpropene
(91 mg, 1.0 mmol), 4-methoxyphenylmagnesium bromide (1.0 M
solution in THF; 1.5 mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF;
3.15 mL, 1.6 mmol), Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP
(2.2 mL). After 8 h at 100 °C, workup and column chromatography
(2.5% Et2O in pentane) yielded 131 mg (81%) of the title compound
as a colorless liquid.
1H NMR (CDCl3, 300 MHz): 7.15 (d, J ) 8.5 Hz, 2H), 6.84 (d, J
) 8.5 Hz, 2H), 6.20 (broad s, 1H), 3.80 (s, 3H), 1.88 (d, J ) 1.1 Hz,
3H), 1.84 (d, J ) 1.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): 157.7,
134.1, 131.4, 129.9, 124.6, 113.6, 55.5, 27.1, 19.6.
1
of 2-n-butyltoluene (determined by GC and by H NMR).
1H NMR (CDCl3, 300 MHz): 7.15-7.02 (m, 4H), 2.87 (sextet, J )
6.9 Hz, 1H), 2.32 (s, 3H), 1.59 (dq, J ) 7.2 Hz, 7.0 Hz, 2H), 1.19 (d,
J ) 7.8 Hz, 3H), 0.85 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3, 75
MHz): 145.9, 135.6, 130.2, 126.2, 125.5, 125.3, 36.4, 30.8, 21.5, 19.9,
12.6.
4-t-Butyl-1-s-butyl-1-cyclohexene (Table 4, entry 3). The general
procedure was followed with use of 4-tert-butyl-1-chlorocyclohexene
(173 mg, 1.0 mmol), s-butylmagnesium chloride (2.0 M solution in
Et2O; 0.75 mL, 1.5 mmol), ZnCl2 (0.5 M solution in THF; 3.15 mL,
1.6 mmol), Pd(P(t-Bu)3)2 (10.2 mg, 0.020 mmol), and NMP (2.2 mL).
After 5 h at 100 °C, workup and column chromatography (pentane)
yielded 169 mg (87%) of the title compound as a colorless liquid that
contained ∼2% 4-tert-butyl-1-n-butylcyclohexene (determined by GC).
1H NMR (CDCl3, 300 MHz): 5.38 (broad s, 0.5H), 5.37 (broad s,
0.5H), 2.05-1.70 (m, 6H), 1.41-1.05 (m, 4H), 0.96 (d, J ) 6.9 Hz,
1.5H), 0.95 (d, J ) 6.9 Hz, 1.5H), 0.86 (s, 9H), 0.81 (t, J ) 7.3 Hz,
1.5H), 0.78 (t, J ) 7.3 Hz, 1.5H). 13C NMR (CDCl3, 75 MHz) (two
diastereomers): 141.8, 141.6, 120.47, 120.45, 44.79, 44.76, 42.86,
42.76, 32.52, 28.15, 27.97, 27.5, 27.1, 26.8, 26.4, 24.71, 24.68, 19.96,
19.34, 12.54, 12.33. IR (neat, cm-1): 2960, 2865, 1458, 1435, 1362.
HRMS (EI, m/z) calcd for C14H26 (M+) 194.2035, found 194.2037.
Negishi Cross-Coupling of o-Chlorobenzonitrile and 4-Meth-
ylphenylzinc Chloride with 0.03% Pd(P(t-Bu)3)2 (eq 2). The general
procedure was followed with use of 2-chlorobenzonitrile (137 mg, 1.0
mmol), p-tolylmagnesium bromide (1.2 mL, 1.0 M solution in THF,
(40) Caldwell, R. A.; Cao, C. V. J. Am. Chem. Soc. 1982, 104, 6174-
6180.
(41) Baddeley, G.; Chadwick, J.; Taylor, H. T. J. Chem. Soc. 1956, 451-
456.
(44) Maxwell, R. W.; Adam, R. J. Am. Chem. Soc. 1930, 52, 2959-
2972.
(45) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163.
(42) Arrastia, I.; Cossio, F. P. Tetrahedron Lett, 1996, 37, 7143-7146.
(43) Rottendorf, H.; Sternhell, S.; Wilmshurst, J. R. Aust. J. Chem. 1965,
18, 1759-1773.

2724 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Dai and Fu
1.2 mmol), ZnCl2 (0.5 M solution in THF; 2.52 mL, 1.26 mmol), Pd-
(P(t-Bu)3)2 (0.0010 M stock solution in THF; 0.30 mL, 0.00030 mmol),
and NMP (2.2 mL). After 24 h at 100 °C, workup and column
chromatography (10% Et2O in hexane) yielded 185 mg (97%) of
2-cyano-4′-methylbiphenyl as a white solid that was identical to
Acknowledgment. Support has been provided by Bristol-
Myers Squibb, Merck, the Natural Sciences and Engineering
Research Council of Canada (postdoctoral fellowship to C.D.),
Novartis, and Pfizer.
1
authentic material (Alfa-Aesar) by H NMR, GC, and TLC.
JA003954Y