Highly active, air-stable palladium catalysts for the C-C and C-S bond-forming reactions of vinyl and aryl chlorides: Use of commercially available [(t-Bu)2P(OH)]2PdCl2, [(t-Bu)2P(OH)PdCl2]2, and [[(t-Bu)2PO···H·· ·OP(t-B0. u)2]PdCl]2 as catalysts

Article abstract of DOI:10.1021/jo010983y

Air-stable palladium complexes [(t-Bu)₂P(OH)]₂PdCl₂, [(t-Bu)₂P(OH)PdCl₂]₂, and [[(t-Bu)₂PO···H··· OP(t-Bu)₂]PdCl]₂ serve as efficient catalysts for a variety of cross-coupling reactions of vinyl and aryl chlorides with arylboronic acids, arylzinc reagents, and thiols to yield the corresponding styrene derivatives, biaryls, and thioethers. ³¹P NMR and mechanistic studies argue that the phosphinous acid ligands in the complexes can be deprotonated in the presence of a base to yield an electron-rich anionic species, which is likely a catalyst intermediate, and dimeric [[(t-Bu)₂PO···H·· ·OP(t-Bu)₂]PdCl]₂ was isolated and cystallographically characterized. These anionic complexes are anticipated not only to accelerate the rate-determining oxidative addition of aryl chlorides but also to stabilize the palladium complexes in the catalytic cycle.

Full text of DOI:10.1021/jo010983y

J . Org. Chem. 2002, 67, 3643-3650
3643
High ly Active, Air -Sta ble P a lla d iu m Ca ta lysts for th e C-C a n d
C-S Bon d -F or m in g Rea ction s of Vin yl a n d Ar yl Ch lor id es: Use of
Com m er cia lly Ava ila ble [(t-Bu )2P (OH)]2P d Cl2,
[(t-Bu )2P (OH)P d Cl2]2, a n d [[(t-Bu )2P O‚‚‚H‚‚‚OP (t-Bu )2]P d Cl]2 a s
Ca ta lysts
George Y. Li*
DuPont Company, Central Research and Development Department, Experimental Station,
P.O. Box 80328, Wilmington, Delaware 19880-0328
george.y.li@combiphos.com
Received October 8, 2001
Air-stable palladium complexes [(t-Bu)2P(OH)]2PdCl2, [(t-Bu)2P(OH)PdCl2]2, and [[(t-Bu)2PO‚‚‚H‚‚‚
OP(t-Bu)2]PdCl]2 serve as efficient catalysts for a variety of cross-coupling reactions of vinyl and
aryl chlorides with arylboronic acids, arylzinc reagents, and thiols to yield the corresponding styrene
derivatives, biaryls, and thioethers. 31P NMR and mechanistic studies argue that the phosphinous
acid ligands in the complexes can be deprotonated in the presence of a base to yield an electron-
rich anionic species, which is likely a catalyst intermediate, and dimeric [[(t-Bu)2PO‚‚‚H‚‚‚OP(t-
Bu)2]PdCl]2 was isolated and cystallographically characterized. These anionic complexes are
anticipated not only to accelerate the rate-determining oxidative addition of aryl chlorides but also
to stabilize the palladium complexes in the catalytic cycle.
In tr od u ction
stable transition-metal complexes for the catalytic cross-
coupling of unactivated aryl chlorides with arylboronic
acids, organozinc reagents, and thiols.
In the course of our ongoing research on the discovery
and development of new materials and industrial cata-
lysts via combinatorial approaches, we reported the first
Carbon-carbon and carbon-sulfur bond-forming reac-
tions are important fundamental transformations in
synthetic chemistry. These reactions would be even more
useful and efficient if performed catalytically, rather than
stoichiometrically.1,2 The palladium-catalyzed cross-
coupling reactions of vinyl and aryl halides with arylbo-
ronic acids, organozinc reagents, and thiols are versatile
synthetic methods in the processes of C-C (Suzuki,3
Negishi4 cross-coupling), and C-S bond-forming trans-
formations.5 Moreover, promising catalytic systems for
less expensive and readily available unactivated aryl
chlorides have been studied extensively.3,4,6-8 However,
to the best of our knowledge, no air-stable phosphorus-
containing ligands have ever been used in generating air-
(3) For Suzuki cross-coupling reactions of aryl chlorides mediated
by palladium complexes, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J .
Am. Chem. Soc. 2000, 122, 4020-4028. (b) Zapf, A.; Ehrentraut, A.;
Beller, M. Angew. Chem. Int. Ed. 2000, 39, 4153-4155. (c) Suzuki, A.
J . Organomet. Chem. 1999, 576, 147-168 and references therein. (d)
Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem. 1999,
64, 3804-3805. Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed.
1999, 38, 2413-2416. (e) Wolfe, J . P.; Singer, R. A.; Yang, B. H.;
Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 9550-9561. (f) Bei, X.;
Guram, A. S.; Turner, H. W.; Weinberg, W. H. Tetrahedron Lett. 1999,
40, 3855-3858. (g) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram,
A. S. J . Org. Chem. 1999, 64, 6797-6803. (h) Firooznia, F.; Gude, C.;
Chan, K.; Satoh, y. Tetrahedron Lett. 1998, 39, 3985-3988. (i) Old, D.
W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722-
9723. (j) Littke, A. F.; Fu, G. C. Angew. Chem. 1998, 110, 3586-3587.
(k) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-
3388. (l) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120,
7369-7370. (m) Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew.
Chem., Int. Ed. 1998, 37, 481-483. (n) Shen, W. Tetrahedron Lett.
1997, 38, 5575-5578.
* Current address: CombiPhos Catalysts, Inc., P.O. Box 220,
Princeton, NJ 08542-220.
(1) For general references, see: (a) Grushin, V. V.; Alper, H. In
Topics in Organometallic Chemisty; 1999; Vol. 3, pp 193-226 and
references therein. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Chapter 2. (c) Beller, M.; Riermeier, T. H. In
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998; Vol. 1, pp 184-193. (d) Beller, M.;
Riermeier, T. H.; Stark, G. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 1, pp
208-236. (e) Negishi, E.-i.; Liu, F. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J ., Eds; Wiley-VCH: Weinheim,
1998; pp 1-48. (f) Herrmann W. A. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds;
Wiley-VCH: Weinheim, 1996; pp 764-765.
(2) For leading reviews, see: (a) Yang, B. H.; Buchwald, S. L. J .
Organomet. Chem. 1999, 576, 125-146. (b) Suzuki, A. J . Organomet.
Chem. 1999, 576, 147-168 and references therein. (c) Sturmer, R.
Angew. Chem. 1999, 111, 3509-3510; Angew. Chem., Int. Ed. 1999,
38, 3307-3308. (d) Belfield, A. J .; Brown, G. R.; Foubister, A. J .
Tetrahedron 1999, 55, 11399-11428 and references therein. (e) Wolfe,
J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805-818. (f) Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998, 37,
2046-2067. (g) Baranano, D.; Mann, G.; Hartwig, J . F. Curr. Org.
Chem. 1997, 1, 287-305. (h) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457-2483. (i) Kumada, M. Pure Appl. Chem. 1980, 52, 669-679.
(4) For Negishi cross-coupling reactions of aryl chlorides mediated
by palladium complexes, see: (a) Dai, C.; Fu, G. C. J . Am. Chem. Soc.
2001, 123, 2719-2724. (b) Reference 1e.
(5) For the cross-coupling reactions of C-S bond-forming processes
mediated by transition-metal complexes, see: (a) Kondo, T.; Mitsudo,
T-A. Chem. Rev. 2000, 100, 3205-3220. (b) Harr, M. S.; Presley, A.
L.; Thorarensen, A. Synlett 1999, 10, 1579-1581. (c) Zheng, N.;
McWilliams, J . C.; Fleitz, F. J .; Armstrong, J . D., III; Volante, R. P. J .
Org. Chem. 1998, 63, 9606-9607. (d) Still, I. W. J .; Toste, F. D. J .
Org. Chem. 1996, 61, 7677-7680. (e) Baranano, D.; Hartwig, J . F. J .
Am. Chem. Soc. 1995, 117, 2937-2938. (f) Takagi, K. Chem. Lett. 1987,
2221-2224. (g) Kosugi, M.; Ogata, T.; Terada, M.; Sano, H.; Migita,
T. Bull. Chem. Soc. J pn. 1985, 58, 3657-3658. (h) Migita, T.; Shimiza,
T.; Asami, Y.; Shiobara, J .; Kato, Y.; Kosugi, M. Bull. Chem. Soc. J pn.
1980, 53, 1385-1389. (i) Kosugi, M.; Shimizu, t.; Migita, T. Chem. Lett.
1978, 13-14.
(6) For Suzuki cross-coupling reactions of aryl chlorides mediated
by palladacycle complexes, see: Beller, M.; Fischer, H.; Herrmann, W.
A.; Ofele, K.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34,
1848-1849.
10.1021/jo010983y CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/03/2002

3644 J . Org. Chem., Vol. 67, No. 11, 2002
Li
Sch em e 1
Sch em e 2. Str u ctu r es of P a lla d iu m (II)
Com p lexes Em p loyed in th e Exa m p les of
Ta bles 1-6
air-stable phosphine oxides [RR′P(H)O],8b which were
derived from the novel combinatorial technologies,9 served
as efficient ligand precursors for a variety of cross-
couplings of unactivated aryl chlorides. All these trans-
formations involving aryl chlorides (or halides) are
mediated by air-stable palladium(II) complexes bearing
novel phosphinous acids as ligands that are produced by
tautomerization of RR′P(O)H to less stable phosphinous
acids in the presence of transition metals (Scheme 1).10
Although in situ preparation of palladium catalysts has
been widely utilized in the C-C bond-forming processes
of aryl chlorides,1-3 the Pd(II) complexes as only catalyst
source without excess ligands in solution have been
scarcely developed, principally because excess free ligands
are essential to prevent transition-metal complexes from
degradation in the catalytic cycle and that active catalytic
species are derived from the in situ reduction of Pd(II)
by excess phosphine ligands to Pd(0),1,11 leading to
difficulties in separating and purifying these complexes.
Herein, we present the first investigation of cross-
coupling reactions of vinyl and aryl chlorides with aryl-
boronic acids (Suzuki reaction), organozinc reagents
(Negishi reaction), and thiols catalyzed by simple, readily
accessible, and air-stable palladium(II) complexes [(t-
Bu)2P(OH)]2PdCl2 (abbreviated as POPd), [(t-Bu)2P(OH)-
PdCl2]2 (abbreviated as POPd2), and [[(t-Bu)2PO‚‚‚H‚‚‚OP-
(t-Bu)2]PdCl]2 (abbreviated as POPd1) (Scheme 2).12
Resu lts a n d Discu ssion
The principal goal of this study was to explore the
possibility of cross-coupling reactions of unactivated vinyl
and aryl chlorides with a variety of arylboronic acids,
organozinc reagents, thiols mediated by air-stable pal-
ladium-phosphinous acids for the construction of biaryls
and aryl-heteroatom-containing frameworks (e.g., un-
symmetric biaryls, aryl ketones, arylthioether, and other
biaryls). This study capitalized upon our previous success
with in situ Pd/RR′P(O)H complexes-catalyzed carbon-
carbon and carbon-heteroatom bond formations and upon
well-characterized air-stable palladium(II) complexes-
mediated Suzuki cross-coupling and C-N and C-S bond-
forming transformations.8
In early studies, we reported that in situ Pd2(dba)3/(t-
Bu)2P(H)O catalysts are capable of catalyzing a variety
of cross-coupling reactions of unactivated aryl chlorides
with arylboronic acids, aryl Grignard reagents, amines,
and thiols. We observed that both 1:1 and 1:2 ratios of
Pd/(t-Bu)2P(H)O were effective components for these
cross-coupling reactions. Encouraged by these interesting
results, we decided to compare the catalytic activity of
Pd/(t-Bu)2P(H)O with ratios of 1:1 and 1:2 and discovered
that both Pd/(t-Bu)2P(H)O complexes could be isolated
in air. We employed these isolated air-stable complexes
as the only catalyst source in the absence of free (t-Bu)2P-
(H)O ligands and found that both complexes are effective
catalysts for the Suzuki, Negishi cross-couplings and C-S
bond formation of aryl and vinyl chlorides.
(7) For Suzuki cross-coupling reactions of aryl chlorides mediated
by palladium/N-heterocyclic carbene complexes, see: (a) Zhang, C.;
Trudell, M. L. Tetrahedron Lett. 2000, 41, 595-598. (b) Zhang, C.;
Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem. 1999, 64, 3804-
3805. (c) Weskamp, T.; Bohm, V. P. W.; Herrmann, W. A. J . Organomet.
Chem. 1999, 585, 348-352. (d) Herrmann, W. A.; Reisinger, C.-P.;
Spiegler, M. J . J . Organomet. Chem. 1998, 557, 93-96.
(8) For examples of cross-coupling of unactivated aryl chlorides
mediated by air-stable palladium-phosphinous acid complexes, see: (a)
Li, G. Y.; Zheng, G.; Noonan, A. F. J . Org. Chem. 2001, 66, 8677-
8681. (b) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516.
(9) For combinatorial approaches to the synthesis of phosphorus-
containing ligands, see: (a) Li, G. Y.; Fagan, P. J .; Watson, P. L. Angew.
Chem., Int. Ed. 2001, 40, 1106-1109. (b) Li, G. Y. (E. I. Du Pont de
Nemours and Company, USA). US Patent Application 60/197,031, Case
No.: BC 1048 US PRV, 2000. (c) Fagan, P. J .; Li, G. Y. PCT Int. Appl
WO 2000021663 A2 20000420, 169 pp. APPLICATION: WO 1999-
US23509 19991013.
(10) For examples of metal-phosphinous acid complexes, see: (a)
Cobley, C. J .; Heuvel, M. van den; Abbadi, A.; de Vries, J . G.
Tetrahedron Lett. 2000, 41, 2467-2470. (b) Ghaffar, T.; Parkins, A.
W. Tetrahedron Lett. 1995, 36, 8657-8660; UK Patent Application
9506389.7. (c) Goerlich, J . R.; Fischer, A.; J ones, P. G.; Schmutzler, R.
Z. Naturforsch., B: Chem. Sci. 1994, 49, 801-811. (d) Heuer, L.; J ones,
P. G.; Schmutzler, R. New J . Chem. 1990, 14, 891-900. (e) Arif, A.
M.; Bright, T. A.; J ones, R. A. J . Coord. Chem. 1987, 16, 45-50.
(11) Amatore, C.; J utand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009-3012.
(12) (a) Li, G. Y. (E. I. Du Pont de Nemours and Company, USA).
US Patent 6,291,722 B1, 2001. (a) Li, G. Y. (E. I. Du Pont de Nemours
and Company, USA). US Patent Application No: 60/274,530, Case
No.: BC1029 US NA PRV (2001). (b) Li, G. Y. (E. I. Du Pont de
Nemours and Company, USA). US Patent 6,124,462, 2000.
The POPd,13 POPd1,13 and POPd213 were prepared
according to our reported procedures.8,12 Well-character-
ized examples of this type of Pd(II) complexes are rare.10
POPd, POPd1, and POPd2 were isolated and character-
1
ized by 1-D, 2-D, H/13C, and 31P NMR spectroscopy, as
well as elemental analysis. The structure of POPd1 was
confirmed by X-ray crystallography (ORTEP view is
shown in Figure 1).14 As expected, the core structures of
the POPd1 are P-Pd coordination with phosphinous acid
ligands (RR′P-OH) and anionic ligand moieties forming
a six-membered chelating ring with strong hydrogen
bonding as part of the ring. Important features of the
(13) [(t-Bu)2POH]2PdCl2 (POPd), [[(t-Bu)2PO‚‚‚H‚‚‚OP(t-Bu)2]PdCl]2
(POPd1), and [(t-Bu)2P(OH)PdCl2]2 (POPd2) are available exclusively
from CombiPhos Catalysts, Inc. Web site: www.combiphos.com.
(14) X-ray data for POPd1 has been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no. CCDC
171240. Copies of the data may be obtained from CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: (+44)1223-336033. E-mail:
deposit@ccdc.cam.ac.uk).

C-C and C-S Bond-Forming Reactions of Vinyl and Aryl Chlorides
J . Org. Chem., Vol. 67, No. 11, 2002 3645
F igu r e 1. ORTEP view (50% probability) of dihydrogen di-µ-chlorotetrakis(di-tert-butylphosphinito-κ-P)dipalladate(2-) (P OP d 1).
Ta ble 1. Effect of F r ee Liga n d s on th e P a lla d iu m -Ca ta lyzed Su zu k i Cr oss-Cou p lin g Rea ction s of Ar yl Ch lor id esa
a
Reaction conditions (not optimized): (a) 1.0 equiv of aryl chloride, 1.5 equiv of boronic acid, 3.0 equiv of K2CO3, 2 h; (b) 1.0 equiv of
aryl chloride, 1.5 equiv of boronic acid, 3.0 equiv of K2CO3, 22 h.
structure of POPd1 include the O1-P1 (1.5478 Å) and
O2-P2 (1.5543 Å) and the P-Pd bonding distance of
2.2863(5) Å between P1 and Pd1. These O-P distances
are about 0.100 Å longer than a PdO double-bond
distance in RRP(O)H and to a first approximation can
be interpreted as a O-P single bond.
The palladium-phosphinous acid complexes POPd,
POPd1, and POPd2 efficiently and regiospecifically cata-
lyze the Suzuki cross-coupling of a variety of vinyl and
aryl chlorides with arylboronic acids to yield the corre-
sponding styrene derivatives and biaryls (Tables 1-4).
The catalytic reactions in general proceed either under
inert atmosphere or in open-to-air conditions (typically
0.5-2.0 mol % Pd catalyst) to completion in refluxing
organic solvents (THF, dioxane, DME), in contrast to
recently reported highly active Pd/ArP(t-Bu)2 and Pd/P(t-
Bu)3 systems that are generated in situ for Suzuki cross-
coupling of aryl chlorides (note: isolated phosphine
complex Pd(P(t-Bu)3)2 does not appear to be the active
catalyst for Suzuki cross-coupling process3a). Our isolated,
air-stable POPd, POPd1, and POPd2 are all capable of
catalyzing Suzuki coupling reactions of vinyl and aryl

3646 J . Org. Chem., Vol. 67, No. 11, 2002
Li
Ta ble 2. Effect of Ba se on th e Air -Sta ble P a lla d iu m Com p lexes-Ca ta lyzed Su zu k i Cr oss-Cou p lin g Resu lts of
Ar yl Ch lor id esa
a
Reaction conditions (not optimized): 1.0 equiv of aryl chloride, 1.5 equiv of arylboronic acid.
chlorides (or halides) to yield the corresponding biaryls
in high yields (Tables 1-4).
Suzuki cross-coupling of vinyl chlorides under compa-
rable conditions of palladium concentration, temperature,
and reaction time (Table 4, entries 3 and 5). The result
of entry 4 (Table 4) reveals that POPd2 is also an efficient
catalyst for Suzuki cross-coupling of vinyl chlorides.
In regard to comparisons of catalytic effects of POPd,
POPd1, and POPd2, entries 4, 5, and 7 of Table 3 offer
data comparing these catalysts to those (Table 3, entries
1-3) which are generated in-situ. It can be seen that the
transformations are equally effective under comparable
conditions of catalyst, concentration, and temperature.
Interestingly, and in marked contrast to the typical
catalytic systems employing excess free ligands to pre-
vent catalysts from degradation in the catalytic processes,
the present results (Table 1) demonstrate that the air-
stable Pd-complex (POPd) for Suzuki cross-couplings of
aryl chlorides are the same efficiency as those catalytic
systems with excess ligands. More importantly, from the
standpoint of organic synthesis, the direct use of POPd,
POPd1, and POPd2 as catalysts would be more practical
owing to the difficulties in generating in situ catalysts
and in handling extremely air-sensitive phosphine ligands.
The required cross-coupling products of vinyl and aryl
chlorides with arylboronic acids are produced in the
presence of a variety of bases. Among the bases listed in
Table 2, it would likely appear that CsF and NaO-t-Bu
are the bases of choice (Table 2, entries 6 and 9); however,
from the standpoint of organic synthesis, nonhalogenated
reagents and mild bases would have a broad application.
Therefore, we examined several nonhalogenated bases
that were effected to mediate Suzuki cross-coupling of
aryl chlorides; a variety of bases (Na2CO3, K2CO3, Cs2-
CO3, and K3PO4) have proved to be effective for cross-
coupling of aryl chlorides (Table 2); of these, Na2CO3 and
K2CO3 would be more suitable for industrial applications.
The catalytic results of Suzuki cross-coupling reactions
of vinyl chlorides and arylboronic acids are summarized
in Table 4. It can be seen that our air-stable palladium
complexes mediate C-C bond formation efficiently to
generate styrene derivatives in good yields. Interestingly,
and in marked contrast to the Pd2(dba)3/P(t-Bu)3 catalyst
(Table 4, entry 2),3a using air-stable POPd as only
catalyst source provides higher catalytic efficiencies in
Based on the successful Kumada-Tamao-Corriu cross-
coupling of aryl chlorides with aryl Grignard reagents
mediated by POPd at room temperature,15 we also
examined the Negishi cross-coupling of aryl chlorides
with arylzinc reagents (Table 5). The reaction of aryl
chlorides with organozinc reagents proceeds with dimin-
ished efficiency without the catalyst (Table 5, entry 1);
however, a variety of biaryls are indeed produced ef-
ficiently in the presence of catalysts in refluxing THF/
NMP solvents. Our air-stable catalysts can couple not
only chlorobenzene (Table 5, entry 2) but also electron-
rich substrates 4-chloroanisole (Table 5, entries 3 and 7)
and 4-bromothioanisole (Table 5, entry 6). Entries 4 and
5 (Table 5) show that a ketone-containing substrate is
tolerated by our catalysts as demonstrated by 4-chloro-
acetophenone. Also noteworthy is that an organic sulfur
compound is tolerated and coupled with arylzinc reagents
to form a biaryl containing thioethers, as illustrated by
entry 6 (Table 5).
It has been known that organic sulfur compounds
strongly bind to the transition-metal centers through
M-S bonding, thus poisoning them and making catalytic
reactions ineffective.16 However, our air-stable palladium-
phosphinous acid complexes, as illustrated in Table 6,
can be employed catalytically for the C-S bond-forming
reactions of vinyl chlorides generating thioethers. For
example, thiophenols undergo coupling with 1-chloro-1-
(15) For examples of Kumada-Tamao-Corriu cross-coupling of
unactivated aryl chlorides with aryl Grignard reagents mediated by
air-stable palladium-phosphinous acid or nickel-phosphinothious acid
complexes, see: (a) Li, G. Y. J . Organomet. Chem. (Special Issue on
Cross-Coupling Reaction) 2002, in press. (b) Li, G. Y.; Marshall, W. J .
Organometallics 2002, 21, 590-591.
(16) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J . Am. Chem. Soc.
1999, 121, 5108-5114.

C-C and C-S Bond-Forming Reactions of Vinyl and Aryl Chlorides
J . Org. Chem., Vol. 67, No. 11, 2002 3647
Ta ble 3. Air -Sta ble P a lla d iu m Com p lex Ca ta lyzed Su zu k i Cr oss-Cou p lin g Resu ltsa
a
Reaction conditions (not optimized): 1.0 equiv of aryl chloride, 1.5 equiv of boronic acid, 3.0 equiv of base; (a) 1.5-3 mol % catalyst,
100 °C; (b) 0.50 mol % catalyst, 65 °C/2 h; (c) 0.05mol % catalyst, 1.0 equiv of bromobenzene, 1.2 equiv of boronic acid, 1.2 equiv of K2CO3,
room temperature; (d) 0.5 mol % catalyst, 1.0 equiv of aryl bromide, 1.5 equiv of boronic acid, 3.0 equiv of CsF, room temperature.
cyclopentene in the presence of palladium-phosphinous
acid complexes (Table 6, entries 2-4), and alkylthiol can
also be coupled with vinyl chlorides in generating thio-
ethers (Table 6, entry 5). It would thus appear that all
the substrate thiols and the product thioethers are
tolerated by these palladium complexes in the catalytic
cycle. The reasons likely reflect a combination of ligand
steric bulk, differing substrate and/or product molecule
coordination, less electrophilic metal centers (anionic
species) generated by the deprotonalysis of phosphinous
acid ligands in the presence of bases.
OD or D2O solution argue that the palladium(II) chloride
dimer (POPd2) is subject to cleavage and deprotonolysis
giving mononuclear species at room temperature in the
presence of bases,17-19 yielding an electron-rich phos-
phine-containing anionic complex that would be antici-
pated not only to accelerate the rate-determining oxida-
(17) A reaction of POPd2 (100 mg, 0.147 mmol, 31P NMR (CD3OD):
δ 148.0 (singlet) ppm) and CsF (50.0 mg, 0.329 mmol) in 1.0 mL of
CD3OD at room temperature for 5 min generates an insoluble mixture.
(18) Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th
ed.; J ohn Wiley & Sons: New York, 1988; pp 921-922.
(19) For an excellent paper on tricoordinated anionic complexes
Pd0L2Cl- as the real active catalysts, see: Amatore, C.; J utand, A. Acc.
Chem. Res. 2000, 33, 314-321.
With regard to a plausible mechanism, 1H and 31P
NMR studies of the reaction of POPd2 with CsF in CD3-

3648 J . Org. Chem., Vol. 67, No. 11, 2002
Ta ble 4. Air -Sta ble P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g Resu lts of Vin yl Ch lor id es
Li
Ta ble 5. Air -Sta ble P a lla d iu m -Ca ta lyzed Negish i Cr oss-Cou p lin g of Ar yl Ch lor id es
tive addition of aryl chlorides20 but also to stabilize the
Con clu sion s
transition-metal complexes in the catalytic cycle. Further
evidence for the proposed anionic species is derived from
the direct reaction of POPd with Et3N in organic solvent
at room temperature to yield an anionic palladium dimer
POPd1 (Scheme 3), which has been isolated and charac-
terized by single-crystal X-ray analysis.14
In summary, air-stable palladium (II) complexes (POPd,
POPd1, and POPd2) possessing phosphinous acid ligands
were found to be highly active catalysts in the cross-
coupling reactions of vinyl and aryl chlorides with aryl-
boronic acids, organozinc reagents, and thiols. The use
of phosphine oxide [R2P(H)O] as a ligand precursor
instead of phosphine ligand (R3P) is the key to generate
these air-stable complexes. Of note is the attraction of
generating catalytically active electron-rich anionic spe-
cies in the presence of bases, these anionic complexes can
(20) The low catalytic reactivity of aryl chlorides in cross-coupling
reactions is usually attributed to their reluctance toward oxidative
addition to Pd(0). For a discussion, see: (a) Grushin, V. V.; Alper, H.
Chem. Rev. 1994, 94, 1047-1062, and reference therein. (b) Grushin,
V. V. Organometallics 2000, 19, 1888-1900.

C-C and C-S Bond-Forming Reactions of Vinyl and Aryl Chlorides
J . Org. Chem., Vol. 67, No. 11, 2002 3649
Ta ble 6. Air -Sta ble P a lla d iu m -Ca ta lyzed C-S Bon d F or m a tion of Vin yl Ch lor id es
(121 MHz, CDCl3): δ 124.9 (s) ppm. Anal. Calcd for C32H74O4-
Cl2P4Pd2: C, 41.30; H, 8.02; P, 13.31; Cl, 7.62. Found: C, 41.21;
H, 8.66; P, 13.28; Cl, 7.54. The crystallographic sample was
obtained by slow recrystallization from a mixture of dichlo-
romethane and hexane.14
Sch em e 3
Gen er a l P r oced u r e for th e Rea ction of Vin yl a n d Ar yl
Ch lor id es w ith Ar ylbor on ic Acid s (En tr y 1, Ta ble 1).
POPd (25.0 mg, 0.05 mmol, 0.5 mol %), chlorobenzene (1.13 g,
10.0 mmol), Me-C6H4B(OH)2 (2.04 g, 15.0 mmol), and K2CO3
(4.15 g, 30.0 mmol) were weighed in air and transferred to a
50 mL reactor equipped with a magnetic stir bar and 20 mL
of THF. The reaction mixture was refluxed under N2 for 2 h.
The reaction was transferred to a separatory funnel and
diluted with 300 mL of hexane and 100 mL of H2O. The layers
were separated, the organic layer was washed with H2O (100
mL) and brine (100 mL), dried over MgSO4, and filtered, and
solvents were removed from the filtrate by rotary evaporation.
The resulting residue was chromatographed on silica gel using
hexane as eluant. The eluate was concentrated by rotary
evaporation followed by high vacuum to give 1.31 g (78% yield)
of the final product.
be incorporated into catalytic processes for cross-coupling
reactions of vinyl and aryl halides by not only facilitating
the rate-limiting oxidative addition of unactivated aryl
chlorides with palladium complexes, but also stabilizing
transition-metal complexes in the catalytic cycle. Also
noteworthy are the high efficiency for vinyl and aryl
chlorides; simplicity of use, low cost, air-stability, and
ready accessibility of these separable complexes. Ad-
ditional applications are currently under investigation.
Exp er im en ta l Section
Syn th esis of 4-P h en yla n isole8b (En tr y 2, Ta ble 3). In
the drybox, 110 mg (0.609 mmol) of (Me3C)2P-Cl, 67 mg (0.299
mmol) of Pd(OAc)2, and 3.0 mL of CH2Cl2 were loaded into a
reactor (10 mL) equipped with a magnetic stir bar. The
resulting mixture was stirred at room temperature for 4 h
before 60 mg (3.3 mmol) of H2O was added. The mixture above
was stirred at room temperature for 12 h. After removal of
solvent and excess H2O, the residue was dissolved in 15.0 mL
of 1,4-dioxane and transferred into a reactor (100 mL). Next,
1.43 g (10.0 mm) of 4-chloroanisole, 1.83 g (15.0 mm) of PhB-
(OH)2, and 4.56 g (30.0 mm) of CsF were added into the
mixture above. The resulting mixture was then taken out from
the drybox and refluxed for 18 h. The reaction mixture was
then cooled to room temperature, quenched with 50 mL of H2O,
and extracted with 300 mL of diethyl ether. The organic
extracts were washed with H2O (2 × 80 mL) and brine (80
mL), dried over MgSO4, and filtered, and the ether and dioxane
were removed from the filtrate by rotary evaporation. The
resulting residue was chromatographed on silica gel using
hexane as eluant. The eluate was concentrated by rotary
POPd, POPd1, and POPd2 are available from CombiPhos
Catalysts, Inc. Alternatively, they may be prepared according
to our reported procedures.12
P r ep a r a tion of Dih yd r ogen Di-µ-ch lor otetr a k is(d i-
ter t-bu tylp h osp h in ito-K-P )d ip a lla d a te(2-) (P OP d 1).13
A
solution of dichloro[bis(di-tert-butylphosphinous acid)]palla-
dium(II) (POPd) (7.40 g, 14.77 mmol) in 40 mL of CH2Cl2 was
treated with Et3N (7.4 g, 73.1 mmol) at room temperature
under open-to-air conditions over a period of 3 min. The
resulting yellowish solution was stirred at room temperature
for 4 h before the solvent and excess Et3N were removed by
rotary evaporation. The residue was washed with H2O (3 ×
50 mL) and hexane (2 × 50 mL). The crude product was
purified by column chromatography on silica gel with CH2Cl2/
hexane to afford 6.0 g (87% yield) of [[(t-Bu)2PO‚‚‚H‚‚‚OP(t-
Bu)2]PdCl]2. It was >95% pure by 1H NMR and GC/MS. 1H
NMR (300 MHz, CDCl3): δ 1.37 (d, J ) 14.6 Hz) ppm. 13C NMR
(76 MHz, CDCl3): δ 41.9 (t, J ) 14.4 Hz), 29.48 (s) ppm. 31P
1
NMR (121 MHz, CDCl3): δ 124.0 ppm. H-coupled 31P NMR

3650 J . Org. Chem., Vol. 67, No. 11, 2002
Li
evaporation followed by high vacuum to yield 1.58 g (86% yield)
of 4-phenylanisole.
(0.54 mmol) of POPd, 1.89 g (18.47 mmol) of 1-chloro-1-
cyclopentene, 1.98 g (18.0 mmol) of PhSH, and 3.46 g (36.0
mmol) of NaO-t-Bu in 10.0 mL of toluene. The resulting
mixture was heated to 120 °C for 18 h before the mixture was
cooled to room temperature and quenched with 100 mL of H2O.
The mixture was transferred to a separatory funnel and
extracted with EtOAc (2 × 200 mL). The layers were sepa-
rated, the organic layer was washed with H2O (2 × 100 mL)
and brine (150 mL), dried over MgSO4, and filtered, and the
solvents were removed from the filtrate by rotary evaporation.
The final product was chromatographed on silicon gel using
tert-butylmethyl ether/hexane (1% volume ratio) as eluant. The
eluate was concentrated by rotary evaporation followed by high
vacuum to yield 2.8 g (88% yield) of 1-phenylthio-1-cyclopen-
tene.
1-(1-Cyclopen ten -1-yl)-4-m eth ylben zen e (En tr y 3, Table
4).3a The general procedure was followed with use of POPd
(47 mg, 0.10 mmol, 0.94% mol), 1-chloro-1-cyclopentene (1.03
g, 10.0 mmol), 4-Me-C6H4B(OH)2 (2.04 g, 15.0 mmol), and K2-
CO3 (4.16 g, 30.0 mmol) in 15 mL of THF. The reaction mixture
was refluxed for 15 h until the starting material was com-
pletely consumed as judged by TLC. Workup and column
chromatography (hexane) yielded 1.45 g (92% yield) of the final
product.
Gen er a l P r oced u r e for th e Rea ction of Ar yl Ch lor id es
w ith Ar ylzin c Rea gen ts (En tr y 3, Ta ble 5).8 In the drybox,
15 mL of o-tolylmagnesium chloride (15 mmol, 1.0 M solution
in THF) was treated with 32.0 mL of ZnCl2 (16 mmol, 0.5 M
solution in THF) dropwise over a period of 5 min. The resulting
mixture was stirred at room temperature for 20 min before
1-methyl-2-pyrrolidinone (NMP, 22 mL) was added. After the
mixture was stirred for an additional 5 min, 250.0 mg (0.50
mm) of POPd and 1.43 g (10.0 mm) of 4-chloroanisol were
added into the mixture above. The resulting mixture was
refluxed for 14 h before it was allowed to cool to room
temperature, and aqueous HCl was added (1.0 M; 60 mL). The
resulting mixture was extracted with Et2O (4 × 100 mL), and
the extracts were washed with H2O (5 × 100 mL) and 100 mL
of brine, dried over MgSO4, filtered, and concentrated by rotary
evaporation. The crude product was purified by column chro-
matography on silica gel (95:5 hexane/diethyl ether) to afford
1.12 g (57% yield) of 4-(2-tolyl)anisole.
Ack n ow led gm en t. I thank Dr. Patrick Y. S. Lam
and Dr. Rafael Shapiro for helpful discussions and
suggestions. I also thank Mr. William J . Marshall for
expert assistance with X-ray crystallographic work and
Mr. Gang Zheng for excellent technical assistance.
Su p p or tin g In for m a tion Ava ila ble: X-ray data of dihy-
drogen di-µ-chlorotetrakis(di-tert-butylphosphinito-κ-P)dipal-
ladate(2-) (POPd1), experimental procedures for all reactions,
as well as characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O010983Y
Gen er a l P r oced u r e for th e Rea ction of Vin yl Ch lo-
r id es w ith Th iols (En tr y 2, Ta ble 6).21 A 50 mL of reactor
equipped with magnetic stir bar was charged with 270 mg
(21) Martinez, A. G.; Barcina, J . O.; de Fresno C. A.; Subramanian,
L. R. Synlett 1994, (7), 561-562.