Heck reactions in the presence of P(t-Bu)3: Expanded scope and milder reaction conditions for the coupling of aryl chlorides

Full text of DOI:10.1021/jo9820059

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J . Org. Chem. 1999, 64, 10-11
Ta ble 1. Effect of th e Solven t on th e Ra te of th e
P d 2(d ba )3/P (t-Bu )3-Ca ta lyzed Heck Cou p lin g of
Ch lor oben zen e a n d Meth yl Acr yla te
Heck Rea ction s in th e P r esen ce of P (t-Bu )3:
Exp a n d ed Scop e a n d Mild er Rea ction
Con d ition s for th e Cou p lin g of Ar yl Ch lor id es
Adam F. Littke and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
entry
solvent
% yield (GC)
Received October 5, 1998
1
2
3
4
5
6
7
CH3CN
N-methylpyrrolidine
N,N-dimethylacetamide
DMF
toluene
THF
dioxane
14
14
16
19
27
30
39
Aryl chlorides are both more readily available and less
expensive than aryl bromides and aryl iodides. Unfortu-
nately, for many years, reports of palladium-catalyzed
coupling reactions of aryl chlorides were relatively rare.1
This situation has changed rapidly in the past few years.
For example, in the case of the Heck reaction,2 noteworthy
advances in the use of aryl chlorides have been described
by Milstein,3 Herrmann,4 Reetz,5 and Beller,6 although, with
the exception of an example by Milstein,3b highly electron-
rich or hindered aryl chlorides have not proved to be
synthetically useful substrates.7,8
Recent work by us and by others has established that
certain palladium-catalyzed coupling reactions of aryl chlo-
rides can be accomplished quite efficiently in the presence
of sterically hindered, electron-rich phosphines (e.g., P(t-
Bu)3).9,10 Perhaps the simplest explanation for this enhanced
reactivity is that oxidative addition of an aryl chloride is
more facile with a more electron-rich palladium complex;
however, in at least some instances, the true explanation is
probably not so straightforward.11 To the best of our
knowledge, the possibility that the Heck reaction might also
be susceptible to this P(t-Bu)3 effect has not been investi-
gated. In this paper, we establish that in the presence of
P(t-Bu)3 the Heck reaction can indeed be achieved with good
efficiency (eq 1).
(1) The low reactivity of aryl chlorides in cross-coupling reactions is
generally ascribed to their reluctance to oxidatively add to Pd(0). For a
discussion, see: Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047-1062.
(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) Cabri, W.; Candiani, I. Acc. Chem.
Res. 1995, 28, 2-7. (c) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2379-2411. (d) Heck, R. F. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 4, Chapter
4.3.
We have determined that P(t-Bu)3 is an unusually effec-
tive ligand for the Pd2(dba)3-catalyzed coupling of chloroben-
zene with methyl acrylate (eq 2; dba ) dibenzylideneace-
tone). Not only triarylphosphines, but also other trialkylphos-
(3) (a) Chlorobenzene and electron-poor aryl chlorides (150 °C): Ben-
David, Y.; Portnoy, M.; Gozin, M.; Milstein, D. Organometallics 1992, 11,
1995-1996. (b) Chloroanisole, chlorobenzene, and electron-poor aryl chlo-
rides (140 °C): 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.
(4) (a) 4-Chlorobenzaldehyde (150 °C): Herrmann, W. A.; Brossmer, C.;
Ofele, K.; Beller, M.; Fischer, H. J . Mol. Catal. A 1995, 103, 133-146. (b)
Electron-poor aryl chlorides (130 °C): 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. Herrmann, W. A.; Brossmer, C.;
Reisinger, C.-P.; Reirmeier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J . 1997,
3, 1357-1364. (c) Electron-poor aryl chlorides (130 °C): Herrmann, W. A.;
Elison, M.; Fischer, J .; Ko¨cher, C.; Artus, G. R. J . Angew. Chem., Int. Ed.
Engl. 1995, 34, 2371-2374.
(5) Chlorotoluene, chlorobenzene, and chlorobenzaldehyde (150 °C):
Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed. Engl.
1998, 37, 481-483.
phines (even PCy3), appear to be completely ineffective
ligands for this process. Especially noteworthy is the fact
that we observe essentially no coupling in the presence of
phosphine A (eq 2), which has steric and electronic proper-
ties that are quite similar to P(t-Bu)3 (cone angles: P(t-Bu)3,
182°; A, 184°) (pKa of conjugate acid: P(t-Bu)3, 11.40; A,
11.02).12
The rate of the coupling reaction is solvent-dependent,
with dioxane being the solvent of choice, although THF and
toluene are also suitable (Table 1). Cs2CO3 and K3PO4 are
the bases of choice among those that we have surveyed
(6) Electron-poor aryl chlorides (140-160 °C): Beller, M.; Zapf, A. Synlett
1998, 792-793.
(7) For an overview of Heck couplings of aryl chlorides, see: Riermeier,
T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-309.
(8) Electron-poor aryl halides oxidatively add to Pd(0) more readily than
do the corresponding electron-rich aryl halides. For a discussion, see refs 1
and 2.
(9) Suzuki cross-coupling: Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.,
in press.
(10) For example, see: (a) Carbonylation: Huser, M.; Youinou, M.-T.;
Osborn, J . A. Angew. Chem., Int. Ed. Engl. 1989, 28, 1386-1388. Ben-David,
Y.; Portnoy, M.; Milstein, D. J . Am. Chem. Soc. 1989, 111, 8742-8744. (b)
Dechlorination: Ben-David, Y.; Gozin, M.; Portnoy, M.; Milstein, D. J . Mol.
Catal. 1992, 73, 173-180. (c) Cross-coupling with vinylsilanes and arylsi-
lanes: Gouda, K.-i.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. J . Org. Chem.
1996, 61, 7232-7233. (d) Suzuki cross-coupling: Shen, W. Tetrahedron Lett.
1997, 38, 5575-5578. Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetra-
hedron Lett. 1998, 39, 3985-3988. Old, D. W.; Wolfe, J . P.; Buchwald, S. L.
J . Am. Chem. Soc. 1998, 120, 9722-9723. (e) Amination: Reddy, N. P.;
Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810. Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. Hamann, B.
C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120, 7369-7370. Old, D. W.;
Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722-9723.
(11) For example, see: (a) Portnoy, M.; Milstein, D. Organometallics
1993, 12, 1655-1664. Portnoy, M.; Milstein, D. Organometallics 1993, 12,
1665-1673. Reference 3. (b) Reference 4a. (c) Beller has shown that Heck
reactions of electron-poor aryl chlorides can be effected with electron-poor
phosphites as ligands: Reference 6.
(12) Wada, M.; Higashizaki, S. J . Chem. Soc., Chem. Commun. 1984,
482-483. For an extensive compilation of cone angles and pKa data for
phosphines, see: Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering,
W. P. Organometallics 1989, 8, 1-7.
10.1021/jo9820059 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

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Communications
J . Org. Chem., Vol. 64, No. 1, 1999 11
Ta ble 2. Effect of th e Ba se on th e Ra te of th e P d 2(d ba )3/
P (t-Bu )3-Ca ta lyzed Heck Cou p lin g of Ch lor oben zen e a n d
Meth yl Acr yla te
Ta ble 3. Scop e of th e P d 2(d ba )3/P (t-Bu )3-Ca ta lyzed Heck
Cou p lin g of Ar yl Ch lor id es
entry
base
none
K2CO3
NaOAc
NEt3
% yield (GC)
1
2
3
4
5
6
5
9
21
37
50
56
K3PO4
Cs2CO3
(Table 2). Finally, we have found that use of 2.0 equiv, rather
than 1.2, of P(t-Bu)3 per palladium leads to a longer lifetime
for the catalyst.
Under our optimized conditions (1.5% Pd2(dba)3, 6% P(t-
Bu)3, 1.1 equiv of Cs2CO3, dioxane, 100-120 °C), we can
effect the Heck reaction of a wide array of aryl chlorides with
methyl acrylate and styrene in good yield (Table 3).13,14 Thus,
chlorobenzene and p-chloroanisole couple efficiently with
methyl acrylate to selectively generate the trans olefin
1
product (entries 1 and 2; one isomer by H NMR). We have
also established that a range of electronically diverse aryl
chlorides react with styrene to form stilbene derivatives with
high stereoselection (entries 3-5; g25:1 trans/cis by 1H
NMR). Furthermore, even sterically hindered o-chlorotolu-
ene couples in good yield (entry 6), although a longer reaction
time is required.
We have begun to investigate the maximum number of
turnovers that is possible with this system. In preliminary
experiments, we have found that with a catalyst loading of
0.1% Pd2(dba)3, we obtain an 80% yield for the coupling of
chlorobenzene and styrene (120 h at 120 °C; turnover
number ∼400) (eq 3).
(dba)3, 6% P(t-Bu)3, 1.1 equiv of Cs2CO3, dioxane, 100-120
°C). The choice of ligand appears to be critical for activity,
and P(t-Bu)3 is uniquely effective among the phosphines that
we have examined. Under our reaction conditions, which
employ only commercially available reagents, we can ac-
complish the Heck reaction of an array of substrates,
including sterically hindered and electron-rich aryl chlorides.
In terms of both scope and reaction temperature, this
catalyst system compares quite favorably with those previ-
ously reported.
Ack n ow led gm en t. Support has been provided by the
Alfred P. Sloan Foundation, the American Cancer Society,
Bristol-Myers Squibb, the Camille and Henry Dreyfus
Foundation, Eli Lilly, Firmenich, Glaxo Wellcome, the
National Science Foundation (Young Investigator Award,
with funding from Merck, Pharmacia & Upjohn, DuPont,
Bayer, and Novartis), the Natural Sciences and Engineer-
ing Research Council of Canada (predoctoral fellowship to
A.F.L.), Pfizer, Procter & Gamble, and the Research
Corporation.
In summary, we have developed a useful new catalyst
system for the Heck coupling of aryl chlorides (1.5% Pd2-
(13) Sample experimental data (Table 1, entry 1): Under an atmosphere
of argon, a solution of chlorobenzene (104 mg, 0.924 mmol; in 0.5 mL of
dioxane) and a solution of P(t-Bu)3 (11.2 mg, 0.055 mmol; in 0.42 mL of
dioxane) were added in turn to a Schlenk tube charged with Pd2(dba)3 (12.5
mg, 0.014 mmol), Cs2CO3 (330 mg, 1.01 mmol), and a magnetic stir bar.
Methyl acrylate (158 mg, 1.83 mmol) was then added by syringe, and the
Schlenk tube was sealed and placed in a 100 °C oil bath and stirred for 42
h. The reaction mixture was then cooled to room temperature, diluted with
Et2O, filtered through a pad of Celite, concentrated, and purified by flash
chromatography (5% EtOAc/hexane), which yielded 118 mg (79%) of methyl
cinnamate.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, characterization data, and 1H NMR spectra (9 pages).
J O9820059
(14) (a) Use of Pd(OAc)2 leads to a slower reaction. (b) With 2.0 equiv of
P(t-Bu)3 per palladium, Cs2CO3, K3PO4, and NEt3 display comparable
effectiveness as bases.