A versatile catalyst for heck reactions of aryl chlorides and aryl bromides under mild conditions

Article abstract of DOI:10.1021/ja010988c

In the presence of Cy₂NMe, Pd/P(t-Bu)₃ serves as an exceptionally mild and versatile catalyst for Heck reactions of aryl chlorides and bromides. A sterically and electronically diverse array of aryl bromides, as well as activated aryl chlorides, couple with a range of mono- and disubstituted olefins at room temperature, furnishing the arylated product with high E/Z stereoselection. The corresponding reactions of a broad spectrum of electron-neutral and electron-rich aryl chlorides proceed at elevated temperature, also with high selectivity. In terms of scope and mildness, Pd/P(t-Bu)₃/Cy₂NMe represents an advance over previously reported catalysts for these Heck coupling processes.

Full text of DOI:10.1021/ja010988c

J. Am. Chem. Soc. 2001, 123, 6989-7000
6989
A Versatile Catalyst for Heck Reactions of Aryl Chlorides and Aryl
Bromides under Mild Conditions
Adam F. Littke and Gregory C. Fu*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed April 18, 2001
Abstract: In the presence of Cy2NMe, Pd/P(t-Bu)3 serves as an exceptionally mild and versatile catalyst for
Heck reactions of aryl chlorides and bromides. A sterically and electronically diverse array of aryl bromides,
as well as activated aryl chlorides, couple with a range of mono- and disubstituted olefins at room temperature,
furnishing the arylated product with high E/Z stereoselection. The corresponding reactions of a broad spectrum
of electron-neutral and electron-rich aryl chlorides proceed at elevated temperature, also with high selectivity.
In terms of scope and mildness, Pd/P(t-Bu)3/Cy2NMe represents an advance over previously reported catalysts
for these Heck coupling processes.
Introduction
utility of the Heck arylation. In contrast to many coupling
processes,9 for the Heck reaction, nickel-based catalysts are
generally ineffective.10
Since its discovery in the early 1970s, the palladium-catalyzed
arylation of olefins (Heck reaction, eq 1)1,2 has been applied to
a diverse array of fields, ranging from natural products
synthesis3,4 to materials science5 to bioorganic chemistry.6 This
powerful carbon-carbon bond-forming process has been prac-
ticed on an industrial scale for the production of compounds
such as naproxen7 and octyl methoxycinnamate.8
Aryl Chlorides as Substrates. Among aryl halides, aryl
chlorides are arguably the most attractive class of substrates
for coupling reactions, due to their lower price and higher
availability. However, until very recently, palladium-catalyzed
couplings of aryl chlorides were very uncommon.11 This low
reactivity has usually been attributed to the reluctance of the
aryl-chloride bond to oxidatively add to Pd(0) (Figure 1).
By 1999, however, several investigators, most notably Mil-
stein (bulky, electron-rich chelating bisphosphines),12 Herrmann
(palladacycles, N-heterocyclic carbenes),13 Reetz (tetraphenyl-
phosphonium salts),14 and Beller (phosphites),15 had established
the viability of Heck couplings of aryl chlorides using homo-
Functional group tolerance and the ready availability and low
cost of simple olefins, compared to the vinylmetal compounds
that are employed in the corresponding Suzuki, Stille, Kumada,
and other cross-coupling reactions, contribute to the exceptional
(5) For example, see: (a) Step-Growth Polymers for High-Performance
Materials; Hedrick, J. L., Labadie, J. W., Eds.; ACS Symposium Series
624; American Chemical Society: Washington, DC, 1996; Chapters 1, 2,
and 4. (b) DeVries, R. A.; Vosejpka, P. C.; Ash, M. L. Catalysis of Organic
Reactions; Herkes, F. E., Ed.; Marcel Dekker: New York, 1998; Chapter
37. (c) Tietze, L. F.; Kettschau, G.; Heuschert, U.; Nordmann, G. Chem.
Eur. J. 2001, 7, 368-373.
(6) For some recent examples, see: (a) Haberli, A.; Leumann, C. J. Org.
Lett. 2001, 3, 489-492. (b) Burke, T. R., Jr.; Liu, D.-G.; Gao, Y. J. Org.
Chem. 2000, 65, 6288-6292.
(7) Stinson, S. C. Chem. Eng. News 1999, January 18, 81.
(8) Octyl methoxycinnamate (OMC) is the most common UV-B sun-
screen that is on the market: Eisenstadt, A. In Catalysis of Organic
Reactions; Herkes, F. E., Ed.; Marcel Dekker: New York, 1998; Chapter
33.
(9) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley: New York, 1998.
(10) (a) Geissler, H. In Transition Metals for Organic Synthesis; Beller,
M., Bolm, C., Eds.; Wiley-VCH: New York, 1998; p 166. (b) Beller, M.;
Riermeier, T. H.; Stark, G. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: New York, 1998; p 214. (c)
Herrmann, W. A. In Applied Homogeneous Catalysis with Organometallic
Compounds. A ComprehensiVe Handbook; Cornils, B., Herrmann, W. A.,
Eds.; VCH: New York, 1996; p 713. (d) Heck, R. F. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 4,
p 834.
(11) (a) Grushin, V. V.; Alper, H. In ActiVation of UnreactiVe Bonds
and Organic Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin, 1999; pp
193-226. (b) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(12) (a) Ben-David, Y.; Portnoy, M.; Gozin, M.; Milstein, D. Organo-
metallics 1992, 11, 1995-1996. (b) Portnoy, M.; Ben-David, Y.; Milstein,
D. Organometallics 1993, 12, 4734-4735. (c) Portnoy, M.; Ben-David,
Y.; Rousso, I.; Milstein, D. Organometallics 1994, 13, 3465-3479.
(1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320-
2322.
(2) For reviews of the Heck reaction, see: (a) Bra¨se, S.; de Meijere, A.
In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley: New York, 1998; Chapter 3. (b) Beletskaya, I. P.; Cheprakov,
A. V. Chem. ReV. 2000, 100, 3009-3066. (c) Heck, R. F. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 4,
Chapter 4.3. (d) Heck R. F. Org. React. 1982, 27, 345-390. (e) Crisp, G.
T. Chem. Soc. ReV. 1998, 27, 427-436. (f) de Meijere, A.; Meyer, F. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (g) Jeffery, T. In
AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI: London,
1996; Vol. 5, pp 153-260. (h) Cabri, W.; Candiani, I. Acc. Chem. Res.
1995, 28, 2-7.
(3) For example, see the following. (a) Taxol: Danishefsky, S. J.;
Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.;
Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn,
C. A.; Di Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843-2859. (b)
Scopadulcic acid: Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem.
Soc. 1993, 115, 2042-2044.
(4) For overviews of applications of the Heck reaction in natural products
synthesis, see: (a) Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 1998; Chapter 6. (b) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New
York, 1998; Chapter 3.6. (c) Nicolaou, K. C.; Sorensen, E. J. Classics in
Total Synthesis; VCH: New York, 1996; Chapter 31. These authors refer
to the Heck reaction as “one of the true ‘power tools’ of contemporary
organic synthesis” (p 566).
10.1021/ja010988c CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/28/2001

6990 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Littke and Fu
serves as an active catalyst for Heck reactions. Thus, DeVries
described a coupling of an aryl bromide with a vinylsilane (95
°C),23 and Hartwig discovered that Pd/P(t-Bu)3 effects Heck
reactions of para-substituted aryl chlorides with n-butyl acrylate
(110 °C).24-27
While Pd/P(t-Bu)3/Cs2CO3 provided a comparatively mild and
general method for accomplishing Heck reactions of aryl
chlorides (eq 2), we felt that important challenges remained,
including demonstrating broader scope (particularly with respect
to the olefin component) and developing even milder conditions.
Aryl Bromides as Substrates. In contrast to the situation
with aryl chlorides, there are numerous examples of aryl
bromides with wide-ranging steric and electronic properties
undergoing Heck reactions with a variety of olefins.2 Despite
this more advanced state-of-the-art, there is still significant room
for improvement with regard to the same general issues of
versatility and mildness of conditions that were raised for aryl
chlorides.
With respect to versatility, although current catalyst systems
can, collectively, effect Heck reactions of a broad spectrum of
coupling partners, particular catalysts have not proved to be
widely applicable. Comments from recent reviews of the Heck
reaction have noted this shortcoming. For example, Overman
has observed that, “It is apparent in the examples highlighted
in this summary that no single catalyst recipe has emerged as
optimal. We have found it useful when conducting a Heck
cyclization for the first time to screen catalysts on the extreme
of reactivity and stability.” 28 In addition, de Meijere has referred
to “the diverse and sometimes mysterious compositions of
applicable catalyst ‘cocktails’ ” for the Heck reaction.29 Clearly,
the development of a versatile catalyst would greatly facilitate
applications of the Heck coupling reaction, particularly in areas
such as automated parallel synthesis.
Figure 1. Outline of the catalytic cycle for the Heck coupling reaction.
geneous catalysts.16,17 Unfortunately, the reaction temperatures
were somewhat high (120-160 °C), and the reaction scope was
somewhat narrow. With respect to the aryl chloride, just one
coupling of a sterically demanding substrate had been reported,18
and only two reactions of highly electron-rich aryl chlorides
(wless reactive) had been described;19 with respect to the olefin,
only reactive substrates (styrene and acrylic acid derivatives)
had been examined.
In 1999, we reported that Pd2(dba)3/P(t-Bu)3 catalyzes Heck
couplings of an array of aryl chlorides, including sterically
demanding and electron-rich aryl chlorides, at 100-120 °C (eq
2; Cs2CO3 as the base).20-22 Although we demonstrated that
Pd2(dba)3/P(t-Bu)3 provides broader scope than previous cata-
lysts with respect to the aryl chloride (under milder conditions),
we did not establish increased generality with respect to the
olefin.
The development of milder conditions (e.g., room tempera-
ture) for Heck couplings of aryl bromides would also be a
significant advance. From the standpoints of functional group
tolerance, substrate stability, and regio-/stereoselectivity issues,
the elevated temperatures that are required for most Heck
reactions are not ideal. Furthermore, as chemistry moves from
basic research laboratories into the industrial process/develop-
ment arena, the practical advantage of room-temperature reac-
tions can become increasingly important.
It is important to note that, around the time of our initial
publication, two other groups also reported that Pd/P(t-Bu)3
(13) (a) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 1844-1848. (b) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.;
Reirmeier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357-1364.
(c) Herrmann, W. A.; Elison, M.; Fischer, J.; Ko¨cher, C.; Artus, G. R. J.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2371-2374. (d) See also: Herrmann,
W. A.; Brossmer, C.; Ofele, K.; Beller, M.; Fischer, H. J. Mol. Catal. A
1995, 103, 133-146.
(14) Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed.
1998, 37, 481-483.
(23) DeVries, R. A.; Vosejpka, P. C.; Ash, M. L. In Catalysis of Organic
Reactions; Herkes, F. E., Ed.; Marcel Dekker: New York, 1998; Chapter
37.
(24) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123-2132.
(15) Beller, M.; Zapf, A. Synlett 1998, 792-793.
(16) See also: Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett 1996,
1091-1092.
(17) For very early work on Heck reactions of aryl chlorides, see: (a)
Davison, J. B.; Simon, N. M.; Sojka, S. A. J. Mol. Catal. 1984, 22, 349-
352. (b) Spencer, A. J. Organomet. Chem. 1984, 270, 115-120.
(18) Coupling of 2-chloro-5-nitrotoluene and n-butyl acrylate: Beller,
M.; Zapf, A. Synlett 1998, 792-793.
(19) (a) Coupling of 4-chloroanisole and styrene (49% yield; 3:1 cis:
trans): Portnoy, M.; Ben-David, Y.; Milstein, D. Organometallics 1993,
12, 4734-4735. (b) Coupling of 4-chloroanisole and n-butyl acrylate (48%
yield): Herrmann, W. A.; Brossmer, C.; Ofele, K.; Beller, M.; Fischer, H.
J. Mol. Catal. A 1995, 103, 133-146.
(20) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11.
(21) For our other studies of Pd/P(t-Bu)3-catalyzed coupling reactions,
see the following. (a) Suzuki cross-couplings: Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 1998, 37, 3387-3388. Littke, A. F.; Dai, C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028. (b) Stille cross-
couplings: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411-
2413. (c) Sonogashira cross-couplings: Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-1731. (d) Negishi
cross-couplings: Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-
2724.
(22) For pioneering studies of the use of P(t-Bu)3 in a palladium-catalyzed
process (amination), see: (a) Nishiyama, M.; Yamamoto, T.; Koie, Y.;
Tetrahedron Lett. 1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.;
Koie, Y. Tetrahedron Lett. 1998, 39, 2367-2370.
(25) Since our initial report, Herrmann has determined that Pd2(dba)3/
P(t-Bu)3 was the most effective catalyst, among those surveyed, for Heck
couplings of aryl chlorides in nonaqueous ionic liquids: Bohm, V. P. W.;
Herrmann, W. A. Chem. Eur. J. 2000, 6, 1017-1025.
(26) For recent examples of Heck couplings of activated aryl chlorides,
see: (a) McGuinness, D. S.; Cavell, K. J. Organometallics 2000, 19, 741-
748. (b) Iyer, S.; Ramesh, C. Tetrahedron Lett. 2000, 41, 8981-8984. (c)
Peris, E.; Loch, J. A.; Mata, J.; Crabtree, R. H. Chem. Commun. 2000,
201-202. (d) Calo, V.; Nacci, A.; Lopez, L.; Mannarini, N. Tetrahedron
Lett. 2000, 41, 8973-8976. (e) Gruber, A. S.; Zim, D.; Ebeling, G.;
Monteiro, A. L.; Dupont, J. Org. Lett. 2000, 2, 1287-1290.
(27) For recent examples of Heck couplings of unactivated aryl chlorides,
see: (a) Herrmann, W. A.; Bohm, V. P. W. J. Organomet. Chem. 1999,
572, 141-145. Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J.
Organomet. Chem. 1998, 557, 93-96. Bohm, V. P. W.; Herrmann, W. A.
Chem. Eur. J. 2000, 6, 1017-1025. (b) Morales-Morales, D.; Redon, R.;
Yung, C.; Jensen, C. M. Chem. Commun. 2000, 1619-1620. (c) Ehrentraut,
A.; Zapf, A.; Beller, M. Synlett 2000, 11, 1589-1592.
(28) Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
p 262.
(29) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New York, 1998; p 99,
see also Tables 3-5.

A Catalyst for Heck Reactions of Aryl Halides
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 6991
Table 1. Heck Couplings of Aryl and Vinyl Bromides at Room
Temperature
The only reasonably general room-temperature protocol for
the Heck reaction that has been reported is the Jeffery system
(Pd(OAc)2, HCO3-, R4NX), which can be applied to couplings
of aryl and vinyl iodides;30 in a recent review, this development
has been characterized as “a major achievement”.31 Jeffery has
documented how the mildness of this procedure provides
significant advantages over other catalyst systems with regard
to selectivity issues and reactions of thermally labile compounds.2g
To the best of our knowledge, however, until this year no
catalysts that effect room-temperature Heck couplings of aryl
bromides32 (or chlorides) had been described.
In summary, in view of the importance of the Heck reaction,
we felt that the development of a more versatile and milder
catalyst system would be a worthwhile achievement. In this
article we present our progress toward accomplishing this
objective.
Results and Discussion
Room-Temperature Heck Couplings of Aryl Bromides.
In our 1999 communication, we reported that Pd2(dba)3/P(t-
Bu)3/Cs2CO3 catalyzes the Heck coupling of a variety of aryl
chlorides with styrene and methyl acrylate (eq 2).20 We
employed this system as a starting point in our development of
a catalyst for room-temperature Heck reactions of aryl bromides.
In an initial study, we established that, although Pd2(dba)3/P(t-
Bu)3/Cs2CO3 does effect the room-temperature coupling of a
wide array of aryl bromides with styrene and methyl acrylate,
we observe little or no reaction with more challenging olefins
such as 1-hexene and methyl methacrylate. Since our objective
was an extremely versatile catalyst for room-temperature Heck
couplings of aryl bromides, we were forced to conclude that
our first-generation system was inadequate.
The choice of base can have a crucial effect on the rate and
the product distribution of Heck reactions.33 Prompted by a
recent report from the Buchwald laboratory that described the
unusual effectiveness of a bulky tertiary amine, Cy2NMe, in
Heck couplings of disubstituted olefins at 85-100 °C,34 we
investigated the replacement of Cs2CO3 with Cy2NMe. We were
pleased to observe that use of Cy2NMe leads to a significantly
more active catalyst, permitting the room-temperature coupling
of a wide array of aryl bromides with a broad spectrum of olefins
(Table 1).35,36
A 1:1 Pd:P(t-Bu)3 ratio appears to provide the most active
catalyst for these room-temperature Heck reactions, consistent
(30) Jeffery, T. In AdVances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; JAI: London, 1996; Vol. 5, pp 153-260.
(31) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New York, 1998; p
106.
(32) Very recently, Hartwig has reported that room-temperature Heck
arylation of reactive olefins (styrene and methyl acrylate) by a variety of
aryl bromides can be accomplished by using 1-adamantyl-di-tert-butyl
phosphine and a ferrocenyl-di-tert-butyl phosphine as ligands: Stambuli,
J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 2677-2678.
(33) For some recent examples, see: (a) Morales-Morales, D.; Grause,
C.; Kasaoka, K.; Redon, R.; Cramer, R. E.; Jensen, C. M. Inorg. Chim.
Acta 2000, 300-302, 958-963. (b) Hartung, C. G.; Ko¨hler, K.; Beller, M.
Org. Lett. 1999, 1, 709-711. (c) Beller, M.; Riermeier, T. H. Eur. J. Inorg.
Chem. 1998, 29-35. (d) Beller, M.; Riermeier, T. H. Tetrahedron Lett.
1996, 37, 6535-6538.
(34) Gu¨rtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107-3112.
(35) Notes: (a) A variety of other amines (tertiary, secondary, cyclic,
and aromatic) were surveyed, but all were inferior to Cy2NMe. (b) Toluene
and THF are also suitable solvents for these couplings. (c) Pd2(dba)3 is
superior to Pd(OAc)2 and Pd(MeCN)2Cl2. (d) No reaction is observed in
the absence of P(t-Bu)3.
a Isolated yield, average of two runs. b Unless otherwise indicated,
the E:Z ratio is >20:1, as determined by 1H NMR. c 16:1 ratio of
internal:terminal olefin. d 20:1 ratio of internal:terminal olefin. e 1.0%
Pd2(dba)3, 2.0% P(t-Bu)3 were used. f 1.5% Pd2(dba)3, 3.0% P(t-Bu)3
were used.
with our observations regarding room-temperature Suzuki cross-
couplings.21a As illustrated in entry 1 of Table 1, the usual
regioselectivity for Heck arylations of alkyl vinyl ethers is
observed; i.e., electron-rich aromatic rings preferentially add
(36) For all of the Heck reactions that are reported in this article, no
regio- or stereoisomers, except those that are described, are detected by 1H
or 13C NMR.

6992 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Littke and Fu
to the R carbon of the enol ether.37 Although the regioselection
is moderate (4:1), it compares favorably with that of other
catalysts38,39 and may be due to the lower reaction temperature.
groups disfavors â-hydride elimination to generate the trisub-
stituted olefin.46
As noted in a recent review, intermolecular Heck reactions
of 1,2-disubstituted olefins are relatively uncommon, due to their
low reactivity toward typical catalysts.47 Pd2(dba)3/P(t-Bu)3/
Cy2NMe couples 1,2-disubstituted olefins with aryl bromides
at room temperature (entries 9-11). The stereoselective genera-
tion of â,â-diarylacrylates, which are useful intermediates in
the synthesis of a variety of medicinally interesting compounds,
including angiotension II antagonists,48 can be difficult, as a
result of isomerization of the olefin at the elevated temperatures
typically employed for Heck reactions.49 Under our conditions,
we can couple 4-bromo-N,N-dimethylaniline with methyl trans-
cinnamate to furnish the desired â,â-diarylacrylate with >20:1
E:Z selectivity (entry 9).
Heck reactions of aryl halides with methyl methacrylate, a
1,1-disubstituted olefin, can furnish R-methylcinnamic acid
derivatives, an important family of compounds that both possess
biological activity (e.g., hypolipidemic40 and antiobiotic41) and
serve as intermediates in the synthesis of pharmaceuticals (e.g.,
Sulindac, a non-steroidal anti-inflammatory drug42). In Heck
reactions of methacrylates, there are two possible pathways for
â-hydride elimination, one leading to a 1,1-disubstituted olefin,
which is susceptible to further Heck arylation,43 and the other
leading to the desired trisubstituted olefin, for which there is
an E/Z stereochemical issue (eq 3).44
Pd2(dba)3/P(t-Bu)3/Cy2NMe can also be applied to the stereo-
selective construction of synthetically useful â-arylcrotonic
esters, which can be converted, for example, into biologically
important 2(5H)-furanones.50 Not only electronically deactivated
(entry 10) but also extremely sterically demanding (entry 11)
aryl bromides can be coupled with methyl crotonate at room
temperature (>20:1 E:Z). Significantly, we have established that
this catalyst system is not limited to Heck reactions of aryl
bromidessvinyl bromides are also efficiently coupled at room
temperature (entry 12).
Entries 2-7 of Table 1 establish that Pd2(dba)3/P(t-Bu)3/
Cy2NMe effects the Heck coupling of methyl methacrylate with
electronically and sterically diverse aryl bromides, at room
temperature, to produce R-methylcinnamates with very good
selectivity (>15:1 trisubstituted:disubstituted olefin; >20:1 E:Z,
except for entry 3). Methyl ketones (entry 2) and phenols (entry
3)45 are compatible with the reaction conditions. Even the Heck
coupling of deactivated, highly electron-rich 4-bromo-N,N-
dimethylaniline proceeds smoothly at room temperature, fur-
nishing the desired product in excellent yield (96%; entry 4).
An aryl bromide reacts selectively in the presence of either a
chloride (entry 5) or a triflate (entry 6).
In summary, both in terms of reaction scope and temperature,
Pd2(dba)3/P(t-Bu)3/Cy2NMe represents an unusually effective
catalyst for Heck reactions of bromides.
Room-Temperature Heck Couplings of Activated Aryl
Chlorides. We next turned our attention to reactions of
chlorides, and we were pleased to discover that Pd2(dba)3/P(t-
Bu)3/Cy2NMe also catalyzes the room-temperature Heck cou-
pling of a variety of activated aryl chlorides with an array of
olefins (Table 2). These results are particularly interesting in
view of the fact that Heck reactions of aryl chlorides using other
homogeneous catalysts require temperatures g100 °C, even for
couplings with highly reactive olefins.
Most catalysts for the Heck reaction do not effectively couple
hindered substrate pairs,2 but Pd2(dba)3/P(t-Bu)3/Cy2NMe aryl-
ates methyl methacrylate with 2-bromotoluene in good yield at
room temperature (entry 7). Interestingly, reaction of very bulky
2-bromo-m-xylene leads to preferential formation of the 1,1-
disubstituted olefin (entry 8); this coupling is the only example
that we have encountered in which this isomer is the major
product. Presumably, the steric demand of the two ortho methyl
As illustrated in Table 2, Heck coupling of 4′-chloroaceto-
phenone with styrene proceeds smoothly at room temperature,
affording the stilbene derivative with good E:Z stereoselection
(>20:1; entry 1). Heck reactions of unactivated, alkyl-substituted
terminal olefins can be plagued by modest regioselectivity and
by olefin isomerization;51 under our conditions, 4′-chloroaceto-
phenone couples with 1-hexene to provide the 1,2-disubstituted
olefin exclusively with E:Z selectivity that compares favorably
with that of other catalyst systems (6:1; entry 2).52 n-Butyl vinyl
(37) (a) Andersson, C.-M.; Hallberg, A.; Daves, G. D., Jr. J. Org. Chem.
1987, 52, 3529-3536. (b) Daves, G. D., Jr.; Hallberg, A. Chem. ReV. 1989,
89, 1433-1445.
(38) For example, see: (a) Reference 13b. (b) Bohm, V. P. W.;
Herrmann, W. A. Chem. Eur. J. 2000, 6, 1017-1025.
(39) The use of additives such as AgOTf or TlOAc (Cabri, W.; Candiani,
I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481-1486)
or of an ionic-liquid solvent (Xu, L.; Chen, W.; Ross, J.; Xiao, J. Org.
Lett. 2001, 3, 295-297) is generally required to obtain high R:â selectivity
in Heck reactions of aryl halides.
(40) For example, see: Watanabe, T.; Hayashi, K.; Yoshimatsu, S.; Sakai,
K.; Takeyama, S.; Takashima, K. J. Med. Chem. 1980, 23, 50-59.
(41) For example, see: Buchanan, J. G.; Hill, D. G.; Wightman, R. H.;
Boddy, I. K.; Hewitt, B. D. Tetrahedron 1995, 51, 6033-6050.
(42) Eisenstadt, A. In Catalysis of Organic Reactions; Herkes, F. E.,
Ed.; Marcel Dekker: New York, 1998; Chapter 33.
(43) For some recent examples, see: (a) Morales-Morales, D.; Grause,
C.; Kasaoka, K.; Redon, R.; Cramer, R. E.; Jensen, C. M. Inorg. Chim.
Acta 2000, 300-302, 958-963. (b) Beller, M.; Riermeier, T. H. Eur. J.
Inorg. Chem. 1998, 29-35. (c) Beller, M.; Riermeier, T. H. Tetrahedron
Lett. 1996, 37, 6535-6538.
(44) We do not intend to imply that product formation in these Heck
couplings must be under kinetic control. In fact, for one reaction we have
evidence that an appreciable quantity of disubstituted olefin is generated
initially, and that it is converted to the trisubstituted olefin under the coupling
conditions.
(45) Heck couplings of halophenols can be problematic. For example,
see: (a) Bates, R. W.; Gabel, C. J. Tetrahedron Lett. 1993, 34, 3547-
3550. (b) Ziegler, C. B., Jr.; Heck, R. F. J. Org. Chem. 1978, 43, 2941-
2946.
(46) We believe that the disubstituted olefin may be the kinetic product.
When we conduct this coupling at 120 °C with 0.5% Pd2(dba)3/2.0% P(t-
Bu)3, we obtain an 87% yield (by NMR, vs an internal standard) of the E
trisubstituted olefin, with no evidence of other isomers. Thus, by appropriate
choice of conditions, we can preferentially generate either a di- or a
trisubstituted olefin.
(47) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New York, 1998; p
102.
(48) For example, see: Almansa, C.; Gomez, L. A.; Cavalcanti, F. L.;
de Arriba, A. F.; Rodriguez, R.; Carcellar, E.; Garcia-Rafanell, J.; Forn, J.
J. Med. Chem. 1996, 39, 2197-2206.
(49) For example, see: (a) Moreno-Manas, M.; Perez, M.; Pleixats, R.
Tetrahedron Lett. 1996, 37, 7449-7452. (b) Reference 34.
(50) For example, see: Kagabu, S.; Shimizu, Y.; Ito, C.; Moriya, K.
Synthesis 1992, 830-832.
(51) (a) References 2d and 2h. (b) For recent examples, see: Mabic, S.;
Vaysse, L.; Benezra, C.; Lepoittevin, J.-P. Synthesis 1999, 7, 1127-1134.
Bra¨se, S.; Schroen, M. Angew. Chem., Int. Ed. 1999, 38, 1071-1073.
(52) With other catalysts, lower E:Z stereoselectivity is often observed.
For example, see: Brunner, H.; de Courcy, N. L. C.; Genet, J.-P.
Tetrahedron Lett. 1999, 40, 4815-4818.

A Catalyst for Heck Reactions of Aryl Halides
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 6993
Table 2. Heck Couplings of Activated Aryl Chlorides at Room
Temperature
alcohol furnishes the aldehyde exclusively, due to regioselective
â-hydride elimination (entry 6).55,56
Even 1,2-disubstituted olefins are suitable substrates for room-
temperature arylation by this catalyst (entries 7-10). For Heck
reactions of 2,3-dihydrofuran, we obtain the 2-aryl-2,3-dihy-
drofuran, resulting from arylation of the olefin followed by
isomerization (entries 7-9);57 the only other product that we
observe is the diarylated furan, the formation of which we
discourage through the use of excess olefin (3 equiv). Acyclic
1,2-disubstituted olefins can also undergo Heck coupling at room
temperature, although in somewhat modest yield (entry 10).
Until now, only styrene and acrylic acid derivatives, as well
as cyclopentene (which furnished an undetermined mixture of
isomeric arylated products),27c have participated in Heck reac-
tions with aryl chlorides; all of these couplings have required
an elevated reaction temperature (g100 °C). The results
provided in Table 2 represent the first examples of room-
temperature Heck reactions of aryl chlorides, as well as the first
examples of couplings of aryl chlorides to form trisubstituted
olefins. The high levels of regio- and stereoselection, as well
as the functional group tolerance (nitriles, ketones, esters,
thiophenes, alcohols, etc.) of Pd2(dba)3/P(t-Bu)3/Cy2NMe, are
worthy of note.
Heck Couplings of Aryl Chlorides at Elevated Temper-
ature. Methyl trans-cinnamate is the only olefin that we have
examined that does not undergo Heck coupling at room
temperature with activated aryl chlorides in the presence of
Pd2(dba)3/P(t-Bu)3/Cy2NMe. However, the arylation does pro-
ceed at 70 °C, furnishing the E-â,â-diarylacrylate with excellent
stereoselection (>20:1 E:Z; Table 3, entry 1).58,59
Pd2(dba)3/P(t-Bu)3/Cy2NMe effectively catalyzes the Heck
reactions of deactivated, electron-rich 4-chloroanisole with
styrene (entry 2) and of chlorobenzene and 4-chloroanisole with
methyl methacrylate (entries 3 and 4), providing excellent
stereoselection (>20:1). Even hindered aryl chlorides can be
coupled in good yield (entries 5 and 6), including a di-ortho-
substituted substrate, the most hindered aryl chloride that has
undergone a Heck coupling. 3-Chloropyridine is also a suitable
substrate (entry 7).
However, this catalyst system does have some limitations.
For example, although 3-chloropyridine can be coupled, 2-
chloropyridine is unreactive under identical conditions.60 In
addition, Heck arylation of methyl methacrylate with extremely
electron-rich 4-chloroaniline furnishes only a moderate yield
of the desired product (47%), albeit with excellent stereoselec-
tivity (>20:1); simple dehalogenation to generate aniline is the
major side reaction. Finally, Heck couplings of 1,2-disubstituted
a Isolated yield, average of two runs. b Unless otherwise indicated,
1
the E:Z ratio is >20:1, as determined by H NMR. c Product includes
5% 4′-chloroacetophenone. d 0.5% Pd2(dba)3, 1.0% P(t-Bu)3 were used.
e 3 equiv of olefin was used. f A small amount of the diarylated product
was also generated, and it was removed by chromatography. g Product
includes 6% diarylated product. h 2 equiv of olefin was used. i Product
includes 2% P(t-Bu)3/OP(t-Bu)3.
ether reacts with 4′-chloroacetophenone to yield primarily the
â-arylated product (10:1; entry 3).53
(55) For precedent, see: (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem.
1976, 41, 265-272. (b) Chalk, A. J.; Magennis, S. A. J. Org. Chem. 1976,
41, 1206-1209.
Pd2(dba)3/P(t-Bu)3/Cy2NMe also effects Heck couplings of
1,1-disubstituted olefins at room temperature (entries 4-6).
Thus, methyl methacrylate reacts smoothly with activated aryl
chlorides, including ortho-substituted ones, to generate trisub-
stituted olefins (no 1,1-disubstituted olefin) in good yield and
with excellent E:Z stereoselectivity (>20:1; entries 4 and 5).54
The Heck reaction of p-chlorobenzonitrile with a primary allylic
(56) When we arylate a secondary allylic alcohol, 2-methyl-1-penten-
3-ol, with p-chlorobenzonitrile, we obtain 57% of the ketone and 37% of
the allylic alcohol, due to poor regioselectivity in the â-hydride elimination.
Others have also reported mixtures of products from Heck reactions of
secondary allylic alcohols. For example, see: Kang, S.-K.; Jung, K.-Y.;
Park, C.-H.; Namkoong, E.-Y.; Kim, T.-H. Tetrahedron Lett. 1995, 36,
6287-6290.
(57) For leading references to isomerization reactions during Heck
couplings of 2,3-dihydrofuran, see: Jeffery, T.; David, M. Tetrahedron Lett.
1998, 39, 5751-5754.
(53) Heck reactions of 4′-bromoacetophenone typically generate this
regioisomer preferentially, although the selectivity is often modest. For
example, see: (a) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.;
Reirmeier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357-1364.
(b) Bohm, V. P. W.; Herrmann, W. A. Chem. Eur. J. 2000, 6, 1017-1025.
(54) In contrast to reactions of aryl bromides with methyl methacrylate,
for which diarylation had to be discouraged through the use of excess olefin
(up to 2 equivalents; Table 1), diarylation is not a problem in the analogous
couplings of aryl chlorides, and 1.1 equiv of olefin may be employed (Tables
2-3).
(58) The major side product in this reaction is 4,4′-dicyanobiphenyl,
arising from reductive homocoupling of the aryl chloride. This undesired
pathway has been observed by others in Heck arylations of cinnamic acid
esters with electron-deficient aryl iodides. For example, see: Moreno-Manas,
M.; Perez, M.; Pleixats, R. Tetrahedron Lett. 1996, 37, 7449-7452.
(59) Heck couplings of electron-deficient aryl bromides and iodides with
cinnamic acid esters generally require unusually vigorous reaction conditions
and often afford modest yield and stereoselectivity. For example, see ref
49.

6994 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Table 3. Heck Couplings of Unactivated Aryl Chlorides
Littke and Fu
Thus, in a competition experiment between chlorobenzene and
1-chloro-4-tert-butyl-cyclohexene for styrene, the aryl chloride
couples preferentially (eq 5).
Heck Couplings with Low Catalyst Loadings. For the Heck
reactions described above, we employed moderate catalyst
loadings (1-3% Pd). Because our goal is to develop a general,
reliable protocol, we did not attempt to individually optimize
the catalyst loading for each coupling. However, because for
certain applications (e.g., industrial) turnover number can be
important, we have briefly examined Heck reactions of both
aryl chlorides and aryl bromides using a lower catalyst loading.
In our initial communication, we reported a turnover number
(TON) of 400 for the coupling of chlorobenzene with styrene,
based on an 80% isolated yield of stilbene and a 0.2% loading
of Pd.20 This is the highest TON that has been described for a
Heck reaction of an unactivated aryl chloride using a homoge-
neous catalyst,63 although it is worth noting that Buchmeiser
has obtained a TON of 23 600 for the coupling of chlorobenzene
with styrene by a heterogeneous catalyst.64
As noted earlier, prior to this study the only olefins that had
been employed in Heck reactions of aryl chlorides (including
electron-poor chlorides) were activated monosubstituted olefins
(styrene and acrylic acid derivatives), along with cyclopentene,
which provided an undefined mixture of isomeric arylation
products. We decided to determine if Pd2(dba)3/P(t-Bu)3/
Cy2NMe can furnish a high TON in the relatively challenging
coupling of an unactivated aryl chloride with a disubstituted
olefin. We were pleased to find that, for the Heck reaction of
chlorobenzene with methyl methacrylate, we obtain a TON
∼335 with Pd2(dba)3/P(t-Bu)3 as the catalyst (eq 6).65
a Isolated yield, average of two runs. b E:Z ratio is >20:1, as
determined by 1H NMR. c 3.6% P(t-Bu)3 was used. d Product includes
2.5% P(t-Bu)3/OP(t-Bu)3. e 2 equiv of olefin was used.
olefins have thus far provided either modest stereoselection or
modest yield (e.g., Table 3, entry 8). Despite these limitations,
the examples illustrated in Table 3 significantly expand the scope
of the Heck reaction of unactivated aryl chlorides.
Heck Coupling of an Unactivated Vinyl Chloride. To the
best of our knowledge, there are no examples of Heck couplings
of unactivated vinyl chlorides.61 We have determined that
Pd2(dba)3/P(t-Bu)3/Cy2NMe can accomplish this transformation
(eq 4).
When we instead employ Pd(P(t-Bu)3)2 as the catalyst, we
observe a TON that is comparable to that obtained with
Pd2(dba)3/P(t-Bu)3 (eq 6). Because Pd(P(t-Bu)3)2 is a com-
mercially available,66 air-stable, crystalline solid,67 it represents
a very user-friendly alternative to Pd2(dba)3/P(t-Bu)3 for this
process.68
In virtually all palladium-catalyzed coupling processes, vinyl
chlorides are markedly more reactive than aryl chlorides, with
the Pd2(dba)3/P(t-Bu)3-catalyzed Suzuki reaction being the lone
exception of which we are aware.21a,62 We have established that
this unusual reactivity profile applies not only to Pd2(dba)3/P(t-
Bu)3-catalyzed Suzuki couplings, but also to Heck reactions.
(62) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Tsuji, J. Palladium Reagents
and Catalysis; Wiley: New York, 1995. (c) Farina, V. In ComprehensiVe
Organometallic Chemistry 2; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: New York, 1995; Vol. 12, Chapter 3.4.
(63) A turnover number of 750 for the Heck coupling of chlorobenzene
and n-butyl acrylate has been claimed, but this is based on a yield of less
than 1.5%: Gruber, A. S.; Zim, D.; Ebeling, G.; Monteiro, A. L.; Dupont,
J. Org. Lett. 2000, 2, 1287-1290.
(64) Buchmeiser, M. R.; Wurst, K. J. Am. Chem. Soc. 1999, 121, 11101-
11107.
(65) An even higher turnover number can be achieved at the expense of
lower conversion: with 0.05% Pd2(dba)3/0.2% P(t-Bu)3 at 130 °C, we obtain
a 53% isolated yield, which corresponds to a TON of 530. In general, it
appears that higher reaction temperatures provide higher turnover numbers.
(66) Strem Chemicals (Newburyport, MA), catalog number 46-0252.
(60) 2-Halopyridines can be difficult substrates for Heck couplings,
perhaps due to the formation, after oxidative addition, of an unreactive
pyridyl-bridged palladium dimer (Nakatsu, K.; Kinoshita, K.; Kanda, H.;
Isobe, K.; Nakamura, Y.; Kawaguchi, S. Chem. Lett. 1980, 913-914). For
reports of problems effecting Heck reactions of 2-halopyridines, see: (a)
Frank, W. C.; Kim, Y. C.; Heck, R. F. J. Org. Chem. 1978, 43, 2947-
2949. (b) Bozell, J. J.; Vogt, C. E.; Gozum, J. J. Org. Chem. 1991, 56,
2584-2587. (c) Basu, B.; Frejd, T. Acta Chem. Scand. 1996, 50, 316-
322.
(61) For examples of Heck couplings of activated vinyl chlorides, see:
(a) Horino, H.; Inoue, N.; Asao, T. Tetrahedron Lett. 1981, 22, 741-744.
(b) Voigt, K.; Schick, U.; Meyer, F. E.; de Meijere, A. Synlett 1994, 189-
190.

A Catalyst for Heck Reactions of Aryl Halides
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 6995
We were also interested in determining if a high TON can
be achieved in the Pd2(dba)3/P(t-Bu)3-catalyzed Heck reaction
of aryl bromides at room temperature. We decided to focus on
the coupling of 4-bromoanisole, a deactivated aryl bromide, and
2-ethylhexyl acrylate, which furnishes a cinnamate-derived
product that is the most common UV-B sunscreen on the market
(eq 7).8 With 0.1% Pd2(dba)3 (4.0 mg) and 0.2% P(t-Bu)3, we
obtain an 89% yield (1.1 g) of the desired compound, which
corresponds to a turnover number of ∼450. For experimental
convenience, we have established that a mixture of air-stable
Pd(P(t-Bu)3)2 and Pd2(dba)3 provides a catalyst comparable to
Pd2(dba)3/P(t-Bu)3 (eq 7; the percentages of Pd and Pd:P(t-Bu)3
are the same for the two reactions).68,69
During room-temperature Heck couplings of aryl chlorides,
Pd(P(t-Bu)3)2 is essentially the only P(t-Bu)3-containing species
that is detected by 31P NMR. Since a 1:1 Pd:phosphine ratio is
employed for all room-temperature reactions, half of the
palladium is in the form of Pd(P(t-Bu)3)2, and the other half is
in the form of phosphine-free palladium complexes.
For couplings at room temperature, we have established that
changing the Pd:phosphine ratio from 1:1 to 1:2 leads to a
marked decrease in the rate of the reaction (eq 9). This suggests
that, although Pd(P(t-Bu)3)2 is the resting state of the system, it
is not the catalytically active species in these Heck couplings.
We believe that a palladium monophosphine adduct is the active
catalyst and that the presence of phosphine-free palladium
complexes leads to a higher concentration of this adduct.70-74
Kinetic Control of E:Z Stereoselectivity in Heck Couplings
of Methyl trans-Cinnamate. Our observation that Heck aryl-
ations of methyl trans-cinnamate with 4-bromo-N,N-dimethyl-
aniline (Table 1, entry 9) and 4-chlorobenzonitrile (Table 3,
entry 1) exclusively generate the E-â,â-diarylacrylate strongly
suggests that these processes are under kinetic control, and the
data are consistent with a pathway that includes syn olefin
insertion and syn â-hydride elimination (Figure 1). By way of
contrast, Buchwald has recently shown through a study with
C6D5Br that the product distribution of Heck reactions using
his catalyst, which operates at elevated temperature (85-100
°C), is thermodynamic in origin.34
To gain insight into which step of the catalytic cycle is
turnover-limiting (Figure 1), we undertook a series of reactivity
and kinetics studies. For example, we determined the relative
rate of arylation of a diverse set of olefins with 4′-chloroaceto-
phenone (Table 4). We discovered that styrene, 1-hexene,
n-butyl vinyl ether, and methyl methacrylate all react at similar
rates, despite their disparate electronic and steric properties
(entries 1-4). For most Heck couplings, styrene is considerably
more reactive than the other three olefins.2
For the arylation of styrene with 4′-chloroacetophenone, a
preliminary kinetics study indicates that the reaction rate is first
order in aryl chloride and zero order in olefin, which is
consistent with oxidative addition being the turnover-limiting
step. In the coupling of 4′-chloroacetophenone with methyl
crotonate (Table 4, entry 5), it is likely that a step after oxidative
addition is turnover-limiting, presumably due to the steric
demand of the olefin.
To provide support for our hypothesis that the above
arylations catalyzed by Pd2(dba)3/P(t-Bu)3/Cy2NMe are under
kinetic control, we also coupled C6D5Br with methyl trans-
cinnamate. In contrast to the findings of Buchwald, who
obtained a 1:1 mixture of isomeric products, with our room-
temperature method the E trisubstituted olefin is generated
exclusively (eq 8). Interestingly, if we conduct the arylation at
120 °C, we observe a 1:1 mixture of isomers. Thus, through
appropriate choice of reaction conditions, we can obtain either
the kinetic (room temperature) or the thermodynamic (120 °C)
product(s), highlighting an advantage of being able to perform
Heck reactions under mild conditions.
(68) Generally, for Pd/P(t-Bu)3-catalyzed couplings that proceed at
elevated temperature, a 1:2 Pd:phosphine ratio is preferred; for these
applications, Pd(P(t-Bu)3)2 furnishes a user-friendly, one-component alterna-
tive to mixing Pd2(dba)3 and air-sensitive P(t-Bu)3. For Pd/P(t-Bu)3-catalyzed
reactions that occur at room temperature, a 1:1 Pd:phosphine ratio is usually
preferred; for these processes, a 2:1 mixture of Pd(P(t-Bu)3)2:Pd2(dba)3 (both
air-stable) provides the desired Pd:phosphine ratio and avoids the need to
handle P(t-Bu)3.
(69) Even at low catalyst loadings, Pd/P(t-Bu)3 is not highly sensitive
to impurities such as hydroquinone or monomethyl ether hydroquinone,
which are present in the 2-ethylhexyl acrylate as inhibitors.
(70) We arrived at the same conclusion as a result of our mechanistic
study of the Pd/P(t-Bu)3-catalyzed Suzuki reaction of aryl chlorides (ref
21a).
(71) (a) It has been proposed for other Heck catalysts that a palladium
monophosphine plays a key role in the catalytic cycle. For example, see:
Beller, M.; Riermeier, T. H. Eur. J. Inorg. Chem. 1998, 29-35. van
Strijdonck, G. P. F.; Boele, M. D. K.; Kamer, P. C. J.; de Vries, J. G.; van
Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 1999, 1073-1076. (b)
Typically, for Heck reactions of PPh3-based catalysts, a palladium bis-
phosphine adduct is invoked (ref 2).
(72) For a study of palladium complexes that contain one P(t-Bu)3 ligand,
see: Krause, J.; Cestaric, G.; Haack, K.-J.; Seevogel, K.; Storm, W.;
Po¨rschke, K.-R. J. Am. Chem. Soc. 1999, 121, 9807-9823.
(73) For a study of oxidative addition of an aryl bromide to a palladium
monophosphine complex, see: Hartwig, J. F.; Paul, F. J. Am. Chem. Soc.
1995, 117, 5373-5374.
(74) For a study of reductive elimination of aryl halides from palladium
phosphine complexes, including P(t-Bu)3 adducts, see: Roy, A. H.; Hartwig,
J. F. J. Am. Chem. Soc. 2001, 123, 1232-1233.
Mechanistic Observations on the Heck Coupling of 4′-
Chloroacetophenone. An outline of the commonly accepted
mechanism for the Heck reaction is illustrated in Figure 1.
Although we have not yet had the opportunity to pursue a
detailed mechanistic study of couplings catalyzed by Pd2(dba)3/
P(t-Bu)3/Cy2NMe, the preliminary observations that are de-
scribed below provide some insight into the reaction pathway.
(67) (a) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J. Am.
Chem. Soc. 1976, 98, 5850-5858. (b) Yoshida, T.; Otsuka, S. J. Am. Chem.
Soc. 1977, 99, 2134-2140. (c) 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 only slight decomposition after extended
(>1 month) exposure to air.

6996 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Littke and Fu
Table 4. Effect of Olefin Structure on the Rate of Heck Coupling
of 4′-Chloroacetophenone
fluoromethanesulfonate76 was prepared from 4-bromophenol, and
1-chloro-4-tert-butyl-cyclohexene was prepared according to a literature
procedure;77 all other chlorides and bromides were purchased (Aldrich,
Alfa-Aesar, and Lancaster) and degassed prior to use (if liquids) or
used as received (if solids). All olefins were purchased from Aldrich.
Methyl methacrylate, methyl crotonate, and n-butyl vinyl ether were
vacuum transferred. Styrene was distilled. 2,3-Dihydrofuran was
distilled from calcium hydride. 1-Hexene was distilled from sodium.
2-Methyl-2-propen-1-ol and 2-ethylhexyl acrylate were degassed.
Methyl trans-cinnamate was used as received.
All GC yields and conversions have been corrected for response
factors. E or Z olefin geometries were assigned on the basis of NOE
studies or by analogy with known compounds.
All reactions were assembled under an inert atmosphere either in a
screw-cap vial or a resealable Schlenk tube (oven-dried). Because the
yields that are reported in the Results and Discussion section are the
average of two runs (one with procedure A and one with procedure
B), the yields that are reported below for a specific experiment may
differ from those values.
Procedure A. In a glovebox, Pd2(dba)3, the aryl or vinyl halide,
Cy2NMe, a solution of P(t-Bu)3 in dioxane, dioxane, and the olefin
(olefins that are solids were added prior to the addition of the halide)
were added in turn to a reaction vessel equipped with a stir bar. The
mixture was stirred at the indicated temperature for the indicated amount
of time. At the conclusion of the reaction, the mixture was diluted with
Et2O or EtOAc, filtered through a pad of silica gel with copious
washings, concentrated, and purified by column chromatography.
Mechanistic Observations on the Heck Coupling of 4-
Bromoanisole.75 In contrast to the Heck reaction of styrene and
4′-chloroacetophenone, during the arylation of styrene by
4-bromoanisole, only a small amount of Pd(P(t-Bu)3)2 is evident
by 31P NMR. The major phosphorus-containing species reso-
nates at δ ∼64 (broad), accompanied by a minor compound at
δ 92.
For experiments in which an internal standard was used, the internal
standard was added prior to the addition of the aryl or vinyl halide.
When we treat Pd2(dba)3/P(t-Bu)3 with a stoichiometric
amount of 4-bromoanisole (1:2:2), we also observe a 31P NMR
Procedure B (No Glovebox). Pd2(dba)3 was added (along with the
aryl or vinyl halide and the olefin, if they are solids) to an oven-dried
Schlenk tube equipped with a stir bar. The Schlenk tube was fitted
with a rubber septum, evacuated, and then refilled with argon. The
halide, Cy2NMe, a solution of P(t-Bu)3 in dioxane, the olefin, and then
dioxane were added via syringe. The septum was replaced with a Teflon
stopcock, and the reaction mixture was stirred at the indicated
temperature for the indicated amount of time. At the conclusion of the
reaction, the mixture was diluted with Et2O or EtOAc, filtered through
a pad of silica gel with copious washings, concentrated, and purified
by column chromatography.
1
peak at δ 92, and in the H NMR we can identify a set of
resonances for a new compound derived from P(t-Bu)3 and
4-bromoanisole. On the basis of these results, we speculate that
the 31P resonance at δ 92 arises from oxidative addition of the
aryl bromide to a palladium monophosphine complex. Our initial
attempts to isolate and further characterize this adduct have not
been successful.
Conclusions
In summary, we have established that a second-generation
Pd/P(t-Bu)3-based catalyst, using Cy2NMe rather than Cs2CO3
as the base, effects Heck reactions of a wide array of aryl
chlorides and bromides under exceptionally mild conditions.
This new system provides the following:
(i) a versatile method for Heck reactions of aryl and vinyl
bromides at room temperature, including couplings of sterically
and electronically demanding partners;
(ii) the first examples of Heck reactions of aryl chlorides that
proceed at room temperature (electron-poor aryl chlorides);
(iii) the most general method for Heck couplings of unacti-
vated and deactivated aryl chlorides;
(iv) a highly stereoselective route to trisubstituted olefins
through reactions of aryl chlorides and bromides with disub-
stituted olefins; and
1-Butoxyethenyl-4-dimethylaminobenzene and (E)- and (Z)-(2-
Butoxyethenyl)-4-dimethylaminobenzene (Table 1, Entry 1). Pro-
cedure B was employed, using 4-dimethylaminobromobenzene (185
mg, 0.926 mmol), n-butyl vinyl ether (0.130 mL, 1.00 mmol), Cy2NMe
(0.220 mL, 1.03 mmol), Pd2(dba)3 (4.3 mg, 0.0047 mmol), P(t-Bu)3
(0.10 M solution; 0.096 mL, 0.0096 mmol), and dioxane (0.84 mL).
After 48 h at room temperature, workup and column chromatography
(4% NEt3/hexanes) yielded 202 mg (99%) of a slightly pale-yellow
liquid, which on the basis of 1H NMR analysis was determined to
consist of the terminal olefin and the E and Z disubstituted olefins in
a 13:3:1 ratio.
1H NMR (C6D6, 300 MHz), terminal olefin: δ 7.83 (d, J ) 9.0 Hz,
2H), 6.58 (d, J ) 9.0 Hz, 2H), 4.76 (d, J ) 2.4 Hz, 1H), 4.16 (d, J )
2.4 Hz, 1H), 3.72 (t, J ) 6.3 Hz, 2H), 2.48 (s, 6H), 1.18-1.81 (m,
1
4H), 0.86 (t, J ) 7.2 Hz, 3H). H NMR (C6D6, 300 MHz), E olefin:
δ 7.23 (d, J ) 8.7 Hz, 2H), 6.99 (d, J ) 12.9 Hz, 1H), 6.02 (d, J )
12.9 Hz, 1H), 3.54 (t, J ) 6.3 Hz, 2H), 2.54 (s, 6H); other resonances
are obscured by the resonances for the terminal olefin and the Z olefin.
1H NMR (C6D6, 300 MHz), Z olefin: δ 6.70 (d, J ) 9.0 Hz, 2H), 5.91
(d, J ) 7.2 Hz, 1H), 5.35 (d, J ) 7.2 Hz, 1H), 3.51 (t, J ) 6.3 Hz,
2H), 2.52 (s, 6H); other resonances are obscured by the resonances for
the terminal olefin and the E olefin. 13C NMR (C6D6, 75 MHz), terminal
olefin: δ 161.4, 151.2, 127.1, 126.1, 112.5, 79.5, 67.7, 40.5, 32.1, 20.4,
14.6. IR (neat, cm-1): 2933, 1666, 1600, 1520, 1446, 1367, 1279, 947,
819. HRMS (EI, m/z): calcd for C14H21NO (M+), 219.1623; found,
219.1619.
(v) the first Heck coupling of an unactivated vinyl chloride.
In view of the well-documented utility of the Heck reaction
in synthesis, we anticipate that this active new catalyst will find
wide applicability.
Experimental Section
General. 1,4-Dioxane (anhydrous; Sure-Seal; Aldrich), Pd2(dba)3
(Aldrich), Pd(P(t-Bu)3)2 (Strem), P(t-Bu)3 (Strem), and P(t-Bu)3 (10
wt % solution in hexane; Sure-Seal; Strem) were used as received.
Cy2NMe (Aldrich) was degassed prior to use. 4-Bromophenyltri-
(76) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-
5486.
(77) Lambert, J. B.; Wang, G.-T.; Finzel, R. B.; Teramura, D. H. J. Am.
Chem. Soc. 1987, 109, 7838-7845.
(75) For a recent mechanistic study of a Heck coupling of an aryl
bromide, see: Rosner, T.; Bars, J. L.; Pfaltz, A.; Blackmond, D. G. J. Am.
Chem. Soc. 2001, 123, 1848-1855 and references therein.

A Catalyst for Heck Reactions of Aryl Halides
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 6997
(E)-3-(4-Acetylphenyl)-2-methyl Acrylic Acid Methyl Ester (Table
1, Entry 2). Procedure B was employed, using 4-bromoacetophenone
(185 mg, 0.927 mmol), methyl methacrylate (0.200 mL, 1.87 mmol),
Cy2NMe (0.220 mL, 1.03 mmol), Pd2(dba)3 (4.3 mg, 0.0047 mmol),
P(t-Bu)3 (0.10 M solution; 0.095 mL, 0.0095 mmol), and dioxane (0.84
mL). After 26 h at room temperature, workup and column chroma-
tography (30% Et2O/hexanes) yielded 155 mg (77%) of the title
compound as a pale-yellow solid.
1H NMR (CDCl3, 300 MHz): δ 7.65 (apparent s, 1H), 7.45 (d, J )
9.0 Hz, 2H), 7.30 (d, J ) 9.0 Hz, 2H), 3.83 (s, 3H), 2.10 (d, J ) 1.2
Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 168.6, 149.0, 136.7, 136.3,
131.4, 130.2, 121.5, 118.8 (q, J ) 318 Hz), 52.5, 14.3. IR (neat, cm-1):
2955, 1718, 1640, 1596, 1426, 1213. 1141, 888. HRMS (EI, m/z):
calcd for C12H11F3O5S (M+), 324.0279; found, 324.0271.
(E)-3-(2-Methylphenyl)-2-methyl Acrylic Acid Methyl Ester
(Table 1, Entry 7). Procedure B was employed, using 2-bromotoluene
(0.150 mL, 1.25 mmol), methyl methacrylate (0.270 mL, 2.52 mmol),
Cy2NMe (0.290 mL, 1.35 mmol), Pd2(dba)3 (5.7 mg, 0.0062 mmol),
P(t-Bu)3 (0.10 M solution; 0.12 mL, 0.012 mmol), and dioxane (1.10
mL). After 69 h at room temperature, workup and column chroma-
tography (5% Et2O/hexanes) yielded 205 mg (86%) of the title
compound as a slightly yellow liquid that contained 5% of the terminal
olefin (based on NMR).
1H NMR (CDCl3, 300 MHz): δ 7.74 (apparent s, 1H), 7.18-7.23
(m, 4H), 3.82 (s, 3H), 2.28 (s, 3H), 1.96 (d, J ) 1.8 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 169.0, 138.5, 137.0, 135.2, 130.2, 129.1,
128.9, 128.3, 125.6, 52.3, 20.2, 14.3. IR (neat, cm-1): 2950, 1714,
1637, 1435, 1257, 1120, 758, 742. HRMS (EI, m/z): calcd for C12H14O2
(M+), 190.0994; found, 190.0991.
2-(2,6-Dimethylphenylbenzyl)acrylic Acid Methyl Ester and (E)-
3-(2,6-Dimethylphenyl)-2-methyl Acrylic Acid Methyl Ester (Table
1, Entry 8). Procedure B was employed, using 2-bromo-m-xylene
(0.140 mL, 1.05 mmol), methyl methacrylate (0.125 mL, 1.17 mmol),
Cy2NMe (0.250 mL, 1.17 mmol), Pd2(dba)3 (4.9 mg, 0.0054 mmol),
P(t-Bu)3 (0.10 M solution; 0.11 mL, 0.011 mmol), and dioxane (0.94
mL). After 12 h at room temperature, workup and column chroma-
tography (5% Et2O/hexanes) yielded 208 mg (97%) of a colorless liquid
that was an 8:1 mixture of 2-(2,6-dimethylphenylbenzyl)acrylic acid
methyl ester and (E)-3-(2,6-dimethylphenyl)-2-methyl acrylic acid
methyl ester (based on NMR).
1H NMR (CDCl3, 300 MHz): δ 7.98 (d, J ) 8.4 Hz, 2H), 7.70
(apparent s, 1H), 7.48 (d, J ) 8.4 Hz, 2H), 3.84 (s, 3H), 2.62 (s, 3H),
2.13 (d, J ) 1.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 197.5, 168.7,
140.6, 137.7, 136.4, 130.5, 129.8, 128.4, 52.5, 26.9, 14.5. IR (CH2Cl2
solution, cm-1): 2951, 1712, 1684, 1603, 1435, 1260, 1120, 737.
HRMS (EI, m/z): calcd for C13H14O3 (M+), 218.0943; found, 218.0950.
(E)-and (Z)-3-(4-Hydroxyphenyl)-2-methyl Acrylic Acid Methyl
Ester (Table 1, Entry 3) [153773-39-8] [169237-15-4].41 Procedure
B was employed, using 4-bromophenol (157 mg, 0.910 mmol), methyl
methacrylate (0.195 mL, 1.82 mmol), Cy2NMe (0.21 mL, 0.98 mmol),
Pd2(dba)3 (4.2 mg, 0.0046 mmol), P(t-Bu)3 (0.10 M solution; 0.094
mL, 0.0094 mmol), and dioxane (0.82 mL). After 26 h at room
temperature, workup and column chromatography (50% Et2O/hexanes)
yielded two sets of fractions: 114 mg (65%) of a white solid which
1
based on H NMR analysis was the E isomer and 24 mg (14%) of a
yellow solid which based on 1H NMR analysis was a 1.1:1 mixture of
the E and Z isomers. Total yield: 79%. Overall E:Z ratio ) 11:1.
1H NMR (CDCl3, 300 MHz), E isomer: δ 7.64 (apparent s, 1H),
7.32 (d, J ) 9.0 Hz, 2H), 6.88 (d, J ) 9.0 Hz, 2H), 5.98 (broad s, 1H),
1
3.82 (s, 3H), 2.13 (d, J ) 1.5 Hz, 3H). H NMR (CDCl3, 300 MHz),
Z isomer: δ 7.12 (d, J ) 9.0 Hz, 2H), 6.74 (d, J ) 9.0 Hz, 2H), 6.65
(apparent s, 1H), 3.69 (s, 3H), 2.07 (s, J ) 1.5 Hz, 3H) (cannot detect
phenolic hydrogen). 13C NMR (CDCl3, 75 MHz), E isomer: δ 170.0,
156.3, 139.3, 131.8, 128.4, 125.8, 115.6, 52.5, 14.4. 13C NMR (CDCl3,
75 MHz), Z isomer: δ 170.9, 155.7, 135.3, 129.9, 128.5, 127.4, 115.3,
52.0, 21.8.
1H NMR (CDCl3, 300 MHz), 2-(2,6-dimethylphenylbenzyl)acrylic
acid methyl ester: δ 7.01-7.15 (m, 3H), 6.12 (dt, J ) 3.3, 1.5 Hz,
1H), 4.92 (dt, J ) 3.6, 1.5 Hz, 1H), 3.83 (s, 3H), 3.62 (apparent triplet,
2H), 2.21 (s, 6H). 13C NMR (CDCl3, 75 MHz): δ 167.8, 137.8, 137.1,
135.0, 128.1, 126.6, 124.4, 52.2, 31.5, 20.0. IR (neat, cm-1): 3067,
3020, 2950, 1720, 1631, 1436, 1279, 1255, 1135, 770. HRMS (EI,
(E)-3-(4-Dimethylaminophenyl)-2-methyl Acrylic Acid Methyl
Ester (Table 1, Entry 4) [50704-04-6].78 Procedure B was employed,
using 4-dimethylaminobromobenzene (191 mg, 0.956 mmol), methyl
methacrylate (0.205 mL, 1.92 mmol), Cy2NMe (0.230 mL, 1.07 mmol),
Pd2(dba)3 (4.4 mg, 0.0048 mmol), P(t-Bu)3 (0.10 M solution; 0.098
mL, 0.0098 mmol), and dioxane (0.86 mL). After 24 h at room
temperature, workup and column chromatography (20% Et2O/hexanes)
yielded 210 mg (100%) of the title compound as a yellow solid.
1H NMR (CDCl3, 300 MHz):δ 7.62 (apparent s, 1H), 7.38 (d, J )
9.0 Hz, 2H), 6.70 (d, J ) 9.0 Hz, 2H), 3.79 (s, 3H), 3.00 (s, 6H), 2.16
(d, J ) 1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.8, 150.3,
139.5, 131.7, 123.7, 123.1, 111.7, 52.0, 40.4, 14.5.
(E)-3-(4-Chlorophenyl)-2-methyl Acrylic Acid Methyl Ester
(Table 1, Entry 5) [53059-73-7].79 Procedure B was employed, using
4-bromochlorobenzene (173 mg, 0.905 mmol), methyl methacrylate
(0.195 mL, 1.82 mmol), Cy2NMe (0.21 mL, 0.98 mmol), Pd2(dba)3
(4.2 mg, 0.0046 mmol), P(t-Bu)3 (0.10 M solution; 0.094 mL, 0.0094
mmol), and dioxane (0.82 mL). After 10 h at room temperature, workup
and column chromatography (5% Et2O/hexanes) yielded 134 mg (70%)
of the title compound as a slightly yellow liquid that contained 8% of
the terminal olefin (based on NMR).
1H NMR (CDCl3, 300 MHz): δ 7.63 (m, 1H), 7.37 (d, J ) 9.0 Hz,
2H), 7.32 (d, J ) 9.0 Hz, 2H), 3.82 (s, 3H), 2.10 (d, J ) 1.5 Hz, 3H).
13C NMR (CDCl3, 75 MHz): δ 168.9, 137.7, 134.4, 134.3, 131.0, 129.0,
128.8, 52.4, 14.4.
1
m/z): calcd for C13H16O2, 204.1150 (M+); found, 204.1154. The H
and 13C NMR spectra for the minor component, (E)-2-methyl-3-(2,6-
dimethylphenyl)acrylic acid methyl ester, were the same as those
reported in Table 3, entry 6.
(E)-3-(4-Dimethyaminophenyl)-3-phenyl Acrylic Acid Methyl
Ester (Table 1, Entry 9) [255054-06-9].34 Procedure B was employed,
using 4-dimethylaminobromobenzene (196 mg, 0.978 mmol), methyl
trans-cinnamate (172 mg, 1.06 mmol), Cy2NMe (0.230 mL, 1.07
mmol), Pd2(dba)3 (9.1 mg, 0.010 mmol), P(t-Bu)3 (0.10 M solution;
0.20 mL, 0.020 mmol), and dioxane (0.78 mL). After 72 h at room
temperature, workup and column chromatography (70% CH2Cl2/
hexanes f 85% CH2Cl2/hexanes) yielded 200 mg (73%) of the title
compound as a yellow solid.
1H NMR (CDCl3, 300 MHz): δ 7.36-7.41 (m, 3H), 7.18-7.22 (m,
4H), 6.61 (d, J ) 9.3 Hz, 2H), 6.30 (s, 1H), 3.58 (s, 3H), 2.98 (s, 6H).
13C NMR (CDCl3, 75 MHz): δ 166.9, 157.7, 151.3, 139.6, 129.6, 129.1,
127.8, 127.7, 111.8, 111.5, 51.2, 40.4.
(E)-3-(4-Dimethylaminophenyl)-3-methyl Acrylic Acid Methyl
Ester (Table 1, Entry 10). Procedure B was employed, using 4-
dimethylaminobromobenzene (186 mg, 0.929 mmol), methyl crotonate
(0.200 mL, 1.88 mmol), Cy2NMe (0.220 mL, 1.03 mmol), Pd2(dba)3
(8.6 mg, 0.0094 mmol), P(t-Bu)3 (0.10 M solution; 0.19 mL, 0.019
mmol), and dioxane (0.74 mL). After 23 h at room temperature, workup
and column chromatography (20% Et2O/hexanes) yielded 134 mg (66%)
of the title compound as a yellow solid.
1H NMR (CDCl3, 300 MHz): δ 7.44 (d, J ) 9.0 Hz, 2H), 6.67 (d,
J ) 9.0 Hz, 2H), 6.11 (q, J ) 1.5 Hz, 1H), 3.73 (s, 3H), 2.99 (s, 6H),
2.57 (d, J ) 1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 167.9, 155.8,
151.2, 128.9, 127.5, 112.4, 111.8, 51.2, 40.5, 17.5. IR (CH2Cl2 solution,
cm-1): 3052, 2947, 1707, 1599, 1438, 1349, 1266, 1159, 817. HRMS
(EI, m/z): calcd for C13H17O2N (M+), 219.1259; found, 219.1265.
(E)-3-(2,6-Dimethylphenyl)-3-methyl Acrylic Acid Methyl Ester
(Table 1, Entry 11). Procedure B was employed, using 2-bromo-m-
(E)-3-(4-Trifluoromethylsulfonylphenyl)-2-methyl Acrylic Acid
Methyl Ester (Table 1, Entry 6). Procedure B was employed, using
4-bromophenyltrifluoromethanesulfonate (311 mg, 1.02 mmol), methyl
methacrylate (0.220 mL, 2.06 mmol), Cy2NMe (0.240 mL, 1.12 mmol),
Pd2(dba)3 (4.7 mg, 0.0051 mmol), P(t-Bu)3 (0.10 M solution; 0.10 mL,
0.010 mmol), and dioxane (0.92 mL). After 19 h at room temperature,
workup and column chromatography (20% Et2O/hexanes) yielded 210
mg (63%) of the title compound as a yellow liquid that contained 7%
of the terminal olefin (based on NMR).
(78) El-Abbady, A. M.; Doss, A. M.; Ahmed, M. S. J. Drug Res. 1972,
4, 123-134.
(79) Bottin-Strzalko, T. Tetrahedron 1973, 29, 4199-4204.

6998 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Littke and Fu
xylene (0.115 mL, 0.863 mmol), methyl crotonate (0.100 mL, 0.943
mmol), Cy2NMe (0.200 mL, 0.934 mmol), Pd2(dba)3 (11.9 mg, 0.013
mmol), P(t-Bu)3 (0.10 M solution; 0.26 mL, 0.026 mmol), and dioxane
(0.60 mL). After 49 h at room temperature, workup and column
chromatography (5% Et2O/hexanes) yielded 150 mg (85%) of the title
compound as a clear, colorless liquid.
P(t-Bu)3 (0.15 M stock solution; 0.17 mL, 0.025 mmol), and dioxane
(0.68 mL). After 33 h at room temperature, workup and column
chromatography (7% NEt3/hexanes) yielded 155 mg (84%) of a yellow
liquid that was comprised of a mixture of the E, Z, and terminal olefin
1
isomers in a ratio of 8.2:1.6:1.0 (according to H NMR). The olefin
1
mixture was contaminated with 4% of 4′-chloroacetophenone (by H
1H NMR (CDCl3, 300 MHz): δ 7.01-7.12 (m, 3H), 5.70 (q, J )
1.5 Hz, 1H), 3.76 (s, 3H), 2.39 (d, J ) 1.5 Hz, 3H), 2.20 (s, 6H). 13C
NMR (CDCl3, 75 MHz): δ 167.1, 158.4, 143.2, 133.7, 127.6, 127.2,
119.2, 51.3, 20.3, 19.9. IR (neat, cm-1): 3062, 3017, 2949, 2922, 1719,
1643, 1434, 1265, 1170, 1036, 771. HRMS (EI, m/z): calcd for
C13H16O2 (M+), 204.1145; found, 204.1144.
(E,Z)- and (E,E)-3-Methyl-1-phenylpenta-1,3-diene (Table 1,
Entry 12) [104722-44-3] [20414-99-7].80 Procedure B was employed,
using 2-bromo-trans-2-butene (0.0800 mL, 0.789 mmol), styrene (0.100
mL, 0.873 mmol), Cy2NMe (0.190 mL, 0.887 mmol), Pd2(dba)3 (11.1
mg, 0.012 mmol), P(t-Bu)3 (0.10 M solution; 0.25 mL, 0.025 mmol),
and dioxane (0.54 mL). After 77 h at room temperature, workup and
column chromatography (pentane) yielded 116 mg (93%) of the title
compound as a yellow liquid, which by 1H NMR analysis consisted of
an 8:1 mixture of the (E,Z) and (E,E) isomers.
NMR).
1H NMR (C6D6, 300 MHz), E isomer: δ 7.80 (d, J ) 8.4 Hz, 2H),
7.02 (d, J ) 8.4 Hz, 2H), 6.93 (d, J ) 12.9 Hz, 1H), 5.75 (d, J ) 12.9
Hz, 1H), 3.44 (t, J ) 6.3 Hz, 2H), 2.15 (s, 3H), 1.16-1.50 (m, 4H),
1
0.81 (t, J ) 7.2 Hz, 3H). H NMR (C6D6, 300 MHz), Z isomer: δ
7.90 (d, J ) 8.4 Hz, 2H), 7.71 (d, J ) 8.4 Hz, 2H), 5.88 (d, J ) 7.2
Hz, 1H), 5.15 (d, J ) 7.2 Hz, 1H), 2.12 (s, 3H). Other resonances are
obscured by the resonances for the E and terminal olefins. Terminal
olefin: 4.70 (d, J ) 2.7 Hz, 1H), 4.16 (d, J ) 2.7 Hz, 1H), 3.56 (t, J
) 6.6 Hz, 2H), 2.09 (s, 3H). Other resonances are obscured by the
resonances for the E and Z isomers. 13C NMR (C6D6, 75 MHz), E
isomer: δ 196.0, 150.9, 142.3, 135.3, 129.6, 125.3, 105.7, 70.3, 32.0,
26.6, 19.9, 14.4.
(E)-3-(4-Acetylphenyl)-2-methyl Acrylic Acid Methyl Ester (Table
2, Entry 4). Procedure B was employed, using 4′-chloroacetophenone
(0.180 mL, 1.39 mmol), methyl methacrylate (0.165 mL, 1.54 mmol),
Cy2NMe (0.330 mL, 1.54 mmol), Pd2(dba)3 (19.0 mg, 0.021 mmol),
P(t-Bu)3 (0.15 M stock solution; 0.28 mL, 0.042 mmol), and dioxane
(1.10 mL). After 36 h at room temperature, workup and column
chromatography (30% Et2O/hexanes) yielded 240 mg (79%) of the title
compound as a slightly yellow solid. Spectral data were the same as
those reported in Table 1, entry 2.
1H NMR (CDCl3, 300 MHz), (E,Z) isomer: δ 7.42-7.47 (m, 2H),
7.28-7.35 (m, 2H), 7.18-7.26 (m, 2H), 6.55 (d, J ) 16.2 Hz, 1H),
5.54 (qq, J ) 7.2, 1.5 Hz, 1H), 1.93 (apparent quintet, 3H), 1.82-1.87
1
(m, 3H). H NMR (CDCl3, 300 MHz), (E,E) isomer: δ 6.81 (d, J )
15.9 Hz, 1H), 6.44 (d, J ) 15.9 Hz, 1H), 5.67-5.75 (m, 1H), 1.77-
1.81 (m, 3H); other resonances are obscured by the major (E,Z) isomer.
13C NMR (CDCl3, 75 MHz), (E,Z) isomer: δ 138.1, 132.9, 128.7, 128.1,
127.3, 126.5, 126.2, 125.9, 20.8, 13.6.
(E)-3-(2-Carbomethoxyphenyl)-2-methyl Acrylic Acid Methyl
Ester (Table 2, Entry 5). Procedure B was employed, using methyl
2-chlorobenzoate (0.125 mL, 0.873 mmol), methyl methacrylate (0.105
mL, 0.982 mmol), Cy2NMe (0.21 mL, 0.980 mmol), Pd2(dba)3 (12.0
mg, 0.013 mmol), P(t-Bu)3 (0.10 M solution; 0.26 mL, 0.026 mmol),
and dioxane (0.62 mL). After 24 h at room temperature, workup and
column chromatography (25% Et2O/hexanes) yielded 186 mg (91%)
of the title compound as a clear yellow liquid.
trans-4-Acetylstilbene (Table 2, Entry 1) [20488-42-0].81 Procedure
B was employed, using 4′-chloroacetophenone (0.115 mL, 0.887 mmol),
styrene (0.110 mL, 0.960 mmol), Cy2NMe (0.210 mL, 0.980 mmol),
Pd2(dba)3 (12.3 mg, 0.013 mmol), P(t-Bu)3 (10 wt % solution in hexane;
0.080 mL, 0.029 mmol), and dioxane (0.80 mL). After 32 h at room
temperature, workup and column chromatography (15% Et2O/hexanes)
yielded 149 mg (76%) of the title compound as a pale-yellow solid.
1H NMR (CDCl3, 300 MHz): δ 7.94 (d, J ) 8.7 Hz, 2H), 7.57 (d,
J ) 8.7 Hz, 2H), 7.53 (d, J ) 7.2 Hz, 2H), 7.24-7.40 (m, 3H), 7.22
(d, J ) 16.5 Hz, 1H), 7.11 (d, J ) 16.5 Hz, 1H), 2.60 (s, 3H). 13C
NMR (CDCl3, 75 MHz): δ 197.5, 142.1, 136.8, 136.0, 131.5, 129.0,
128.9, 128.4, 127.5, 126.9, 126.6, 26.9.
(E)- and (Z)-1-[4-(Hex-1-enyl)phenyl]ethanone (Table 2, Entry
2) [137365-00-5].82 Procedure B was employed, using 4′-chloroaceto-
phenone (0.125 mL, 0.964 mmol), 1-hexene (0.135 mL, 1.08 mmol),
Cy2NMe (0.230 mL, 1.07 mmol), Pd2(dba)3 (13.4 mg, 0.015 mmol),
P(t-Bu)3 (0.15 M stock solution; 0.20 mL, 0.030 mmol), and dioxane
(0.76 mL). After 47 h at room temperature, workup and column
chromatography (8% Et2O/hexanes) yielded 136 mg (70%) of a slightly
pale-yellow liquid.
1H NMR (CDCl3, 300 MHz), E isomer: δ 7.88 (d, J ) 8.4 Hz,
2H), 7.40 (d, J ) 8.4 Hz, 2H), 6.37-6.45 (m, 2H), 2.58 (s, 3H), 2.19-
2.28 (m, 2H), 1.30-1.60 (m, 4H), 0.90-1.00 (m, 3H). 1H NMR (CDCl3,
300 MHz), Z isomer: δ 7.45 (d, J ) 8.7 Hz, 2H), 5.85-5.98 (m, 2H),
2.59 (s, 3H); other resonances for the Z isomer are obscured by the
resonances for the E isomer. 13C NMR (CDCl3, 75 MHz), E isomer:
δ 197.6, 142.8, 135.4, 134.6, 129.0, 128.8, 126.0, 33.1, 31.5, 26.8, 22.6,
14.2. IR (neat, cm-1): 2958, 2927, 1682, 1602, 1357, 1267, 1181, 856.
HRMS (EI, m/z): calcd for C14H18O (M+), 202.1358; found, 202.1361.
The E:Z ratio was determined by GC.
(E)- and (Z)-(2-Butoxyethenyl)-4-acetylbenzene and 1-Butoxy-
ethenyl-4-acetylbenzene (Table 2, Entry 3) [153390-96-6] [153390-
95-5].83 Procedure B was employed, using 4′-chloroacetophenone (0.110
mL, 0.848 mmol), n-butyl vinyl ether (0.120 mL, 0.927 mmol),
Cy2NMe (0.200 mL, 0.934 mmol), Pd2(dba)3 (11.6 mg, 0.013 mmol),
1H NMR (CDCl3, 300 MHz): δ 8.11 (apparent s, 1H), 8.04 (dd, J
) 7.8, 1.2 Hz, 1H), 7.52-7.57 (m, 1H), 7.37-7.43 (m, 1H), 7.27-
7.30 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 1.91 (d, J ) 1.5 Hz, 3H). 13
C
NMR (CDCl3, 75 MHz): δ 168.8, 166.9, 139.8, 137.9, 132.1, 130.8,
130.3, 129.1, 128.0, 127.9, 52.4, 52.3, 14.1. IR (neat, cm-1): 3065,
2994, 2951, 1715, 1639, 1598, 1434, 1270, 1203, 1080, 763. HRMS
(EI, m/z): calcd for C13H14O4 (M+), 234.0887; found, 234.0879.
3-(4-Cyanophenyl)-2-methylpropanal (Table 2, Entry 6) [57918-
88-4].84 Procedure B was employed, using 4-chlorobenzonitrile (142
mg, 1.03 mmol), 2-methyl-2-propen-1-ol (0.0950 mL, 1.13 mmol),
Cy2NMe (0.240 mL, 1.12 mmol), Pd2(dba)3 (14.3 mg, 0.016 mmol),
P(t-Bu)3 (10 wt % solution in hexane; 0.090 mL, 0.033 mmol), and
dioxane (0.94 mL). After 48 h at room temperature, workup and column
chromatography (50% Et2O/hexanes) yielded 127 mg (71%) of the title
compound as a clear, slightly yellow liquid.
1H NMR (CDCl3, 300 MHz): δ 9.70 (d, J ) 1.2 Hz, 1H), 7.58 (d,
J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1 Hz, 2H), 3.10-3.21 (m, 1H), 2.62-
2.79 (m, 2H), 1.12 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
δ 203.2, 144.8, 132.4, 129.9, 118.9, 110.4, 47.8, 36.6, 13.6.
2-(4-Acetylphenyl)-2,3-dihydrofuran (Table 2, Entry 7) [131516-
06-8].57 Procedure B was employed, using 4′-chloroacetophenone (0.145
mL, 1.12 mmol), 2,3-dihydrofuran (0.250 mL, 3.31 mmol), Cy2NMe
(0.260 mL, 1.21 mmol), Pd2(dba)3 (5.1 mg, 0.0060 mmol), P(t-Bu)3
(0.10 M solution; 0.115 mL, 0.012 mmol), and dioxane (1.00 mL).
After 24 h at room temperature, workup and column chromatography
(20% Et2O/hexanes) yielded 144 mg (68%) of the title compound as a
pale-yellow liquid.
1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J ) 8.1 Hz, 2H), 7.43 (d,
J ) 8.1 Hz, 2H), 6.46 (q, J ) 2.4 Hz, 1H), 5.56 (dd, J ) 8.4, 11.1 Hz,
1H), 4.96 (q, J ) 2.7 Hz, 1H), 3.14 (ddt, J ) 15.3, 10.8, 2.4 Hz, 1H),
2.60 (s, 3H), 2.57 (ddt, J ) 15.3, 8.1, 2.4 Hz, 1H). 13C NMR (CDCl3,
75 MHz): δ 197.7, 148.5, 145.4, 136.5, 128.8, 125.7, 99.2, 81.7, 38.2,
26.9.
(80) Uriac, P.; Bonnic, J.; Huet, J. Tetrahedron 1985, 41, 5051-5060.
(81) Bezou, P.; Hilberer, A.; Hadziioannou, G. Synthesis 1996, 449-
451.
(82) Kauffmann, T.; Laarmann, B.; Menges, D.; Neiteler, G. Chem. Ber.
1992, 125, 163-169.
(83) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1993,
58, 7421-7426.
(84) Sunjic, V.; Majeric, M.; Hamersak, Z. Croat. Chem. Acta 1996,
69, 643-660.

A Catalyst for Heck Reactions of Aryl Halides
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 6999
2-(4-Trifluoromethylphenyl)-2,3-dihydrofuran (Table 2, Entry
8). Procedure B was employed, using 4-chlorobenzotrifluoride (0.130
mL, 0.974 mmol), 2,3-dihydrofuran (0.220 mL, 2.91 mmol), Cy2NMe
(0.230 mL, 1.07 mmol), Pd2(dba)3 (13.3 mg, 0.014 mmol), P(t-Bu)3
(0.15 M stock solution; 0.20 mL, 0.030 mmol), and dioxane (0.78 mL).
After 26 h at room temperature, workup and column chromatography
(2% Et2O/hexanes) yielded 163 mg (78%) of the title compound as a
clear, colorless liquid.
1H NMR (CDCl3, 300 MHz): δ 7.61 (d, J ) 7.8 Hz, 2H), 7.46 (d,
J ) 7.8 Hz, 2H), 6.46 (q, J ) 2.7 Hz, 1H), 5.56 (dd, J ) 10.8, 8.1 Hz,
1H), 4.96 (q, J ) 2.7 Hz, 1H), 3.14 (ddt, J ) 15.6, 10.5, 2.4 Hz, 1H),
2.56 (ddt, J ) 15.6, 7.8, 2.4 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ
147.2, 145.4, 130.1, 129.7, 125.9, 125.6, 99.2, 81.6, 38.2. IR (neat,
cm-1): 3106, 2936, 2864, 1619, 1418, 1326, 1125, 843. HRMS (EI,
m/z): calcd for C11H9F3O (M+), 214.0600; found, 214.0604.
2-(2-Carbomethoxythiophene)-2,3-dihydrofuran (Table 2, Entry
9). Procedure B was employed, using 2-carbomethoxy-3-chloro-
thiophene (167 mg, 0.946 mmol), 2,3-dihydrofuran (0.215 mL, 2.84
mmol), Cy2NMe (0.220 mL, 1.03 mmol), Pd2(dba)3 (13.2 mg, 0.014
mmol), P(t-Bu)3 (0.15 M stock solution; 0.20 mL, 0.030 mmol), and
dioxane (0.76 mL). After 23 h at room temperature, workup and column
chromatography (7% Et2O/hexanes) yielded 172 mg (86%) of the title
compound as a clear, colorless liquid.
1H NMR (CDCl3, 300 MHz): δ 7.44 (d, J ) 5.1 Hz, 1H), 7.18 (d,
J ) 5.1 Hz, 1H), 6.45 (q, J ) 2.7 Hz, 1H), 6.23 (dd, J ) 10.8, 7.5 Hz,
1H), 4.94 (q, J ) 2.7 Hz, 1H), 3.87 (s, 3H), 3.26 (ddt, J ) 15.3, 10.8,
2.7 Hz, 1H), 2.41 (ddt, J ) 15.3, 7.5, 2.7 Hz, 1H). 13C NMR (CDCl3,
75 MHz): δ 162.6, 152.8, 145.1, 131.0, 127.4, 125.5, 99.5, 78.2, 52.2,
37.7. IR (cm-1): 3104, 2994, 2950, 1711, 1620, 1532, 1436, 1256,
778. HRMS (EI, m/z): calcd for C10H10O3S (M+), 210.0351; found,
210.0354.
(E)-3-(4-Cyanophenyl)-3-methyl Acrylic Acid Methyl Ester (Table
2, Entry 10) [255054-11-6].34 Procedure B was employed, using
4-chlorobenzonitrile (115 mg, 0.838 mmol), methyl crotonate (0.180
mL, 1.70 mmol), Cy2NMe (0.200 mL, 0.934 mmol), Pd2(dba)3 (11.8
mg, 0.013 mmol), P(t-Bu)3 (0.15 M stock solution; 0.18 mL, 0.026
mmol), and dioxane (0.66 mL). After 60 h at room temperature, workup
and column chromatography (25% Et2O/hexanes) yielded 88.4 mg
(52%) of the title compound as a pale-yellow solid.
Cy2NMe (0.245 mL, 1.14 mmol), Pd2(dba)3 (14.1 mg, 0.015 mmol),
P(t-Bu)3 (0.14 M stock solution; 0.43 mL, 0.060 mmol), and dioxane
(0.60 mL). After 60 h at 100 °C, workup and column chromatography
(5% Et2O/hexanes) yielded 158 mg (87%) of the title compound as a
slightly red solid.
1H NMR (CDCl3, 300 MHz): δ 7.70 (q, J ) 1.5 Hz, 1H), 7.29-
7.40 (m, 5H), 3.82 (s, 3H), 2.12 (d, J ) 1.5 Hz, 3H). 13C NMR (CDCl3,
75 MHz): δ 169.2, 139.0, 135.9, 129.7, 128.4, 128.4, 128.3, 52.3, 14.3.
(E)-3-(4-Methoxyphenyl)-2-methyl Acrylic Acid Methyl Ester
(Table 3, Entry 4) [126356-04-5].86 Procedure B was employed, using
4-chloroanisole (0.110 mL, 0.898 mmol), methyl methacrylate (0.105
mL, 0.982 mmol), Cy2NMe (0.210 mL, 0.980 mmol), Pd2(dba)3 (12.2
mg, 0.013 mmol), P(t-Bu)3 (0.14 M stock solution; 0.37 mL, 0.052
mmol), and dioxane (0.52 mL). After 53 h at 120 °C, workup and
column chromatography (20% Et2O/hexanes) yielded 123 mg (66%)
of the title compound as a clear, yellow liquid.
1H NMR (CDCl3, 300 MHz): δ 7.64 (apparent s, 1H), 7.38 (d, J )
9.0 Hz, 2H), 6.92 (d, J ) 9.0 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.13
(d, J ) 1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.5, 159.7,
138.8, 131.5, 128.5, 126.1, 114.0, 55.5, 52.2, 14.4.
(E)-3-(2-Methylphenyl)-2-methyl Acrylic Acid Methyl Ester
(Table 3, Entry 5). Procedure B was employed, using 2-chlorotoluene
(0.110 mL, 0.941 mmol), methyl methacrylate (0.110 mL, 1.03 mmol),
Cy2NMe (0.220 mL, 1.03 mmol), Pd2(dba)3 (12.9 mg, 0.014 mmol),
P(t-Bu)3 (0.15 M stock solution; 0.38 mL, 0.057 mmol), and dioxane
(0.56 mL). After 24 h at 110 °C, workup and column chromatography
(5% Et2O/hexanes) yielded 158 mg (88%) of the title compound as a
clear, colorless liquid. Spectral data were the same as those reported
in Table 1, entry 7.
(E)-3-(2,6-Dimethylphenyl)-2-methyl Acrylic Acid Methyl Ester
(Table 3, Entry 6) [124317-09-5].87 Procedure B was employed, using
2-chloro-m-xylene (0.120 mL, 0.905 mmol), methyl methacrylate (0.110
mL, 1.03 mmol), Cy2NMe (0.210 mL, 0.980 mmol), Pd2(dba)3 (12.3
mg, 0.013 mmol), P(t-Bu)3 (0.15 M stock solution; 0.36 mL, 0.054
mmol), and dioxane (0.54 mL). After 39 h at 120 °C, workup and
column chromatography (5% Et2O/hexanes) yielded 134 mg (72%) of
the title compound as a clear, colorless liquid.
1H NMR (CDCl3, 300 MHz): δ 7.62 (apparent s, 1H), 7.03-7.15
(m, 3H), 3.83 (s, 3H), 2.16 (s, 6H), 1.68 (d, J ) 1.2 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 168.4, 139.2, 135.5, 135.2, 130.5, 127.5,
127.4, 52.2, 20.4, 14.1.
(E)-3-(3-Pyridyl)-2-methyl Acrylic Acid Methyl Ester (Table 3,
Entry 7). Procedure B was employed, using 3-chloropyridine (0.0950
mL, 0.999 mmol), methyl methacrylate (0.120 mL, 1.12 mmol),
Cy2NMe (0.240 mL, 1.12 mmol), Pd2(dba)3 (13.6 mg, 0.015 mmol),
P(t-Bu)3 (0.15 M stock solution; 0.41 mL, 0.061 mmol), and dioxane
(0.58 mL). After 26 h at 100 °C, workup and column chromatography
(60% Et2O/hexanes) yielded 140 mg (79%) of the title compound as a
clear, yellow liquid.
1H NMR (CDCl3, 300 MHz): δ 8.65 (apparent s, 1H), 8.55-8.56
(m, 1H), 7.71 (apparent dt, 1H), 7.64 (s, 1H), 7.32-7.36 (m, 1H), 3.84
(s, 3H), 2.13 (d, J ) 1.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ
168.5, 150.6, 149.1, 136.5, 135.2, 131.8, 130.7, 123.4, 52.5, 14.4. IR
(neat, cm-1): 3027, 2994, 2951, 1709, 1638, 1566, 1435, 1260, 1192,
1118, 1024, 800. HRMS (EI, m/z): calcd for C10H11O2N (M+),
177.0790; found, 177.0787.
1H NMR (CDCl3, 300 MHz): δ 7.67 (d, J ) 8.4 Hz, 2H), 7.55 (d,
J ) 8.4 Hz, 2H), 6.15 (q, J ) 1.2 Hz, 1H), 3.77 (s, 3H), 2.57 (d, J )
1.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 166.6, 153.5, 146.6, 132.5,
127.1, 119.3, 118.6, 112.6, 51.6, 18.1.
(E)-3-(4-Cyanophenyl)-3-phenyl Acrylic Acid Methyl Ester (Table
3, Entry 1). Procedure B was employed, using 4-chlorobenzonitrile
(140 mg, 1.01 mmol), methyl trans-cinnamate (186 mg, 1.15 mmol),
Cy2NMe (0.240 mL, 1.12 mmol), Pd2(dba)3 (14.0 mg, 0.015 mmol),
P(t-Bu)3 (0.15 M stock solution; 0.25 mL, 0.037 mmol), and dioxane
(0.76 mL). After 70 h at 70 °C, workup and column chromatography
(30% Et2O/hexanes) yielded 190 mg (71%) of the title compound as a
pale-yellow solid.
1H NMR (CDCl3, 300 MHz): δ 7.61 (d, J ) 8.1 Hz, 2H), 7.36-
7.43 (m, 5H), 7.15-7.20 (m, 2H), 6.39 (s, 1H), 3.63 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ 165.9, 154.7, 145.3, 137.6, 132.3, 129.1, 129.0,
128.9, 128.3, 119.6, 118.6, 113.0, 51.8. IR (CH2Cl2 solution, cm-1):
3056, 2950, 2229, 1725, 1622, 1434, 1265, 1169, 841, 738. HRMS
(EI, m/z): calcd for C17H13O2N (M+), 263.0941; found, 263.0930.
trans-4-Methoxystilbene (Table 3, Entry 2). Procedure B was
employed, using 4-chloroanisole (0.145 mL, 1.18 mmol), styrene (0.150
mL, 1.31 mmol), Cy2NMe (0.280 mL, 1.31 mmol), Pd2(dba)3 (16.2
mg, 0.018 mmol), P(t-Bu)3 (0.15 M stock solution; 0.49 mL, 0.073
mmol), and dioxane (0.70 mL). After 26 h at 120 °C, workup and
column chromatography (1% Et2O/hexanes) yielded 171 mg (69%) of
the title compound as a white solid that was identical to authentic
(E)-3-Phenyl-3-methyl Acrylic Acid Methyl Ester (Table 3, Entry
8) [3461-50-5].85 Procedure B was employed, using chlorobenzene
(0.100 mL, 0.983 mmol), methyl crotonate (0.210 mL, 1.98 mmol),
Cy2NMe (0.230 mL, 1.07 mmol), Pd2(dba)3 (13.8 mg, 0.015 mmol),
P(t-Bu)3 (0.14 M stock solution; 0.42 mL, 0.059 mmol), and dioxane
(0.56 mL). After 49 h at 120 °C, workup and column chromatography
(5% Et2O/hexanes) yielded 86.7 mg (50%) of the title compound as a
slightly pale-yellow liquid.
1
material (Alfa-Aesar) by GC, TLC, and H NMR.
1H NMR (CDCl3, 300 MHz): δ 7.44-7.49 (m, 2H), 7.34-7.39 (m,
3H), 6.13 (q, J ) 1.5 Hz, 1H), 3.75 (s, 3H), 2.58 (d, J ) 1.5 Hz, 3H).
(E)-3-Phenyl-2-methyl Acrylic Acid Methyl Ester (Table 3, Entry
3) [22946-43-6].85 Procedure B was employed, using chlorobenzene
(0.105 mL, 1.03 mmol), methyl methacrylate (0.120 mL, 1.12 mmol),
(86) Mitra, J.; Mitra, A. K. Indian J. Chem. 1992, 31B, 613-616.
(87) Moormann, A. E.; Pitzele, B. S.; Jones, P. H.; Gullikson, G. W.;
Albin, D.; Yu, S. S.; Bianchi, R. G.; Sanguinetti, E. L.; Rubin, B.; Grebner,
M.; Monroy, M.; Kellar, P.; Casler, J. J. Med. Chem. 1990, 33, 614-626.
(85) van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetra-
hedron 1996, 52, 12313-12322.

7000 J. Am. Chem. Soc., Vol. 123, No. 29, 2001
Littke and Fu
13C NMR (CDCl3, 75 MHz): δ 167.3, 156.0, 142.2, 129.2, 128.6, 126.4,
116.8, 51.4, 18.3.
1H NMR (CDCl3, 300 MHz): δ 7.35-7.40 (m, 3H), 7.18-7.22 (m,
2H), 6.36 (s, 1H), 3.61 (s, 3H).
2-(4-tert-Butyl-1-cyclohexenyl)styrene (Eq 4) [96575-67-6].88 Pro-
cedure B was employed, using 1-chloro-4-tert-butyl-cyclohexene (202
mg, 1.17 mmol), styrene (0.145 mL, 1.26 mmol), Cy2NMe (0.280 mL,
1.31 mmol), Pd2(dba)3 (16.5 mg, 0.018 mmol), P(t-Bu)3 (0.15 M stock
solution; 0.50 mL, 0.075 mmol), and dioxane (0.66 mL). After 46 h at
110 °C, workup and column chromatography (hexanes) yielded 188
mg (67%) of the title compound as a white solid.
31P NMR Study of the Heck Coupling of 4′-Chloroacetophenone
with Styrene. Procedure A was employed, using 4′-chloroacetophenone
(0.130 mL, 1.00 mmol), styrene (0.125 mL, 1.09 mmol), Cy2NMe
(0.240 mL, 1.12 mmol), Pd2(dba)3 (14.0 mg, 0.015 mmol), P(t-Bu)3
(0.20 M stock solution; 0.15 mL, 0.030 mmol), and dioxane (0.84 mL).
The reaction was stirred for 10 min at room temperature, and then it
was transferred via pipet to an NMR tube equipped with a Teflon
screwcap. The tube was sealed and removed from the glovebox, and
then the reaction was monitored by 31P NMR. Essentially the only
phosphorus-containing species observed during the course of the
reaction was Pd(P(t-Bu)3)2 at δ 86 (a trace of free P(t-Bu)3 was also
present).
1H NMR (CDCl3, 300 MHz): δ 7.38-7.40 (m, 2H), 7.24-7.31 (m,
2H), 7.14-7.20 (m, 1H), 6.78 (d, J ) 16.2 Hz, 1H), 6.41 (d, J ) 16.2
Hz, 1H), 5.88-5.90 (m, 1H), 2.43-2.50 (m, 1H), 2.10-2.30 (m, 2H),
1.88-2.04 (m, 2H), 1.14-1.38 (m, 2H), 0.89 (s, 9H). 13C NMR (CDCl3,
75 MHz): δ 138.1, 135.8, 132.2, 131.2, 128.6, 126.9, 126.2, 124.9,
44.5, 32.5, 28.0, 27.5, 26.2, 24.1.
Heck Coupling of 4′-Chloroacetophenone with Styrene as a
Function of Pd:Phosphine Ratio (Eq 9; Typical Procedure). In a
glovebox, Pd2(dba)3 (6.6 mg, 0.0070 mmol), Pd(P(t-Bu)3)2 (7.1 mg,
0.014 mmol), n-tridecane (internal standard; 38.7 mg, 0.206 mmol),
4′-chloroacetophenone (149 mg, 0.962 mmol), Cy2NMe (0.230 mL,
1.07 mmol), dioxane (0.96 mL), and styrene (0.120 mL, 1.05 mmol)
were added in turn to a 4-mL vial equipped with a stir bar. The reaction
mixture was stirred at room temperature; after 3 h, GC revealed 29%
conversion.
Competition Experiment between an Aryl Chloride and a Vinyl
Chloride (Eq 5). Procedure A was employed, using chlorobenzene
(0.0750 mL, 0.738 mmol), 1-chloro-4-tert-butylcyclohexene (125 mg,
0.723 mmol), styrene (0.0850 mL, 0.742 mmol), Cy2NMe (0.170 mL,
0.794 mmol), Pd2(dba)3 (10.0 mg, 0.011 mmol), P(t-Bu)3 (0.10 M
solution; 0.43 mL, 0.043 mmol), and dioxane (0.30 mL). After 26 h at
110 °C, workup and column chromatography (hexanes) yielded 76.6
mg (58%) of a white solid that consisted of a 37:1 mixture of stilbene:
diene and 68.1 mg (39%) of a white solid that consisted of a 32:1
mixture of diene:stilbene (ratios determined by 1H NMR). The “diene”
includes ∼10% of an isomer of the expected diene in which both double
bonds are part of the six-membered ring.
Rate of Heck Coupling of 4′-Chloroacetophenone as a Function
of Olefin (Table 4; Typical Procedure). Procedure A was employed,
using 4′-chloroacetophenone (149 mg, 0.964 mmol), styrene (0.120 mL,
1.05 mmol), Cy2NMe (0.230 mL, 1.07 mmol), Pd2(dba)3 (13.0 mg,
0.014 mmol), P(t-Bu)3 (0.20 M stock solution; 0.14 mL, 0.028 mmol),
dioxane (0.82 mL), and n-tridecane (internal standard; 42.5 mg, 0.230
mmol). After 3 h at room temperature, GC revealed 30% conversion.
31P NMR Study of the Heck Coupling of 4-Bromoanisole with
Styrene. Procedure A was employed, using 4-bromoanisole (0.0950
mL, 0.759 mmol), styrene (0.0950 mL, 0.829 mmol), Cy2NMe (0.180
mL, 0.840 mmol), Pd2(dba)3 (10.6 mg, 0.012 mmol), P(t-Bu)3 (0.20 M
stock solution; 0.12 mL, 0.024 mmol), and dioxane (0.65 mL). The
reaction was stirred for 2-3 min at room temperature, and then it was
transferred via pipet to an NMR tube equipped with a Teflon screwcap.
The tube was sealed and removed from the glovebox. The reaction
was then monitored by 31P NMR, which showed the major phosphorus-
containing species to be a broad peak at δ ∼64. In addition, resonances
at δ 86 (Pd(P(t-Bu)3)2) and δ 92 (small) were observed.
31P NMR Study of the Stoichiometric Reaction of 4-Bromoanisole
with Pd2(dba)3/P(t-Bu)3. In a glovebox, Pd2(dba)3 (17.3 mg, 0.019
mmol), 4-bromoanisole (0.0050 mL, 0.040 mmol), P(t-Bu)3 (0.20 M
stock solution; 0.19 mL, 0.038 mmol), and dioxane-d8 (0.54 mL) were
added successively to an NMR tube equipped with a Teflon screwcap.
The tube was sealed and removed from the glovebox. The initial 31P
NMR spectrum showed an ∼1:1 ratio of two species at δ 86 (Pd(P(t-
Bu)3)2) and δ 93. The initial 1H NMR spectrum revealed a new doublet
at δ 1.12 (J ) 11.7 Hz; P(t-Bu)3 group), a new singlet at δ 3.65 (MeO
group), and a new doublet at δ 6.52 (J ) 8.4 Hz; aromatic group); in
addition, unreacted 4-bromoanisole and Pd(P(t-Bu)3)2 were present.
Heck Coupling of Chlorobenzene with Methyl Methacrylate at
Low Catalyst Loading (Eq 6; Typical Procedure). Pd(P(t-Bu)3)2 (3.1
mg, 0.0060 mmol) was added to an oven-dried Schlenk tube equipped
with a stir bar. A rubber septum was then attached to the reaction vessel,
which was evacuated and refilled with argon. Next, chlorobenzene
(0.310 mL, 3.05 mmol), Cy2NMe (0.720 mL, 3.36 mmol), methyl
methacrylate (0.360 mL, 3.37 mmol), and dioxane (1.50 mL) were
added successively via syringe through the rubber septum. The rubber
septum was removed, and the Schlenk tube was sealed with a Teflon
stopcock. After the mixture was stirred for 48 h at 120 °C, workup
and column chromatography (5% Et2O/hexanes) yielded 339 mg (63%)
of the title compound as a colorless liquid that solidified on standing.
Spectral data were the same as those reported in Table 3, entry 3.
Room-Temperature Heck Coupling of 4-Bromoanisole with
2-Ethylhexyl Acrylate Catalyzed at Low Catalyst Loading (Eq 7;
Typical Procedure). Pd(P(t-Bu)3)2 (3.2 mg, 0.0060 mmol) and
Pd2(dba)3 (3.0 mg, 0.0030 mmol) were added to an oven-dried Schlenk
tube equipped with a stir bar. A rubber septum was then attached to
the reaction vessel, which was evacuated and refilled with argon. Next,
4-bromoanisole (0.800 mL, 6.39 mmol), Cy2NMe (1.50 mL, 7.00
mmol), 2-ethylhexyl acrylate (1.45 mL, 6.96 mmol), and dioxane (2.05
mL) were added successively via syringe through the rubber septum.
The rubber septum was removed, and the Schlenk tube was sealed with
a Teflon stopcock. After the mixture was stirred for 148 h at room
temperature, workup and column chromatography (15% Et2O/hexanes)
yielded 1.54 g (83%) of the title compound as a colorless liquid that
was identical to authentic material (Aldrich) by GC, TLC, and 1H NMR.
Heck Coupling of Bromobenzene-d5 with Methyl trans-Cin-
namate at Room Temperature (Eq 8). Procedure A was employed,
using bromobenzene-d5 (148 mg, 0.914 mmol), methyl trans-cinnamate
(161 mg, 0.993 mmol), Cy2NMe (0.220 mL, 1.03 mmol), Pd2(dba)3
(12.7 mg, 0.014 mmol), P(t-Bu)3 (0.20 M stock solution; 0.14 mL, 0.028
mmol), and dioxane (0.78 mL). After 14 h at room temperature, workup
and column chromatography (5% Et2O/hexanes) yielded 209 mg (94%)
of (E)-3-(phenyl-d5)-3-phenyl acrylic acid methyl ester as a pale-yellow
liquid.
Acknowledgment. Support has been provided by Boeh-
ringer-Ingelheim, Bristol-Myers Squibb, Merck, the Natural
Sciences and Engineering Research Council of Canada (pre-
doctoral fellowship to A.F.L.), the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
Novartis, Pfizer, and Pharmacia. We thank Ivory D. Hills for
assistance with NOE studies.
(88) Scott, W. J.; Pena, M. R.; Sward, K.; Stoessel, S. J.; Stille, J. K. J.
Org. Chem. 1985, 50, 2302-2308.
JA010988C