Sterically bulky thioureas as air- and moisture-stable ligands for pd-catalyzed heck reactions of aryl halides

Article abstract of DOI:10.1021/ol049697+

We demonstrate that sterically bulky N,N′-disubstituted cyclic thiourea-Pd(0) complexes are air- and moisture-stable and highly active catalysts for palladium-catalyzed Heck reaction of aryl iodides and bromides with olefins (TONs up to 500 000 for the reaction of Phl and methyl acrylate). Even activated aryl chlorides can undergo complete conversion in Bu ₄NBr in the presence of 1 mol % Pd catalyst.

Full text of DOI:10.1021/ol049697+

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1577-1580
Sterically Bulky Thioureas as Air- and
Moisture-Stable Ligands for
Pd-Catalyzed Heck Reactions of Aryl
Halides
Dan Yang,* Ying-Chun Chen, and Nian-Yong Zhu
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, China
yangdan@hku.hk
Received February 20, 2004
ABSTRACT
We demonstrate that sterically bulky N,N′-disubstituted cyclic thiourea−Pd(0) complexes are air- and moisture-stable and highly active catalysts
for palladium-catalyzed Heck reaction of aryl iodides and bromides with olefins (TONs up to 500 000 for the reaction of PhI and methyl
acrylate). Even activated aryl chlorides can undergo complete conversion in Bu4NBr in the presence of 1 mol % Pd catalyst.
The palladium-catalyzed arylation of olefins (the Heck
reaction) is one of the most versatile tools for C-C bond
formation in organic synthesis.1 Phosphine ligands are
generally used to stabilize the reactive palladium intermedi-
ates, and excellent results have been reported for Pd-catalyzed
Heck reactions when sterically bulky monophosphines,2
diphosphines,3 cyclometalated phosphines, or phosphites are
used as the ligands.4,5 The air-sensitivity of phosphine
ligands, however, places significant limits on their synthetic
applications. Therefore, the development of phosphine-free
palladium catalysts is a topic of enormous interest.6-8
Thioureas are air- and moisture-stable solids and have
recently been employed as ligands in Ru-, Rh-, and Pd-
catalyzed reactions.9,10 Very recently, Z. Yang and co-
workers reported Heck and Suzuki reactions of highly active
(4) For recent reviews on palladacycles for Heck reactions, see: (a)
Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem. 2001, 1917. (b)
Benford, R. B. Chem. Commun. 2003, 1787.
(5) For the use of tetraphenylphosphonium salts in Heck reactions, see:
Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed. 1998,
37, 481.
(1) (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) De Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379. (c) Cabri, W.; Candiani,
I. Acc. Chem. Res. 1995, 28, 2. (d) Negishi, E.; Coperet, C.; Ma, S.; Liou,
S.; Liu, F. Chem. ReV. 1996, 96, 365. (e) Crisp, G. T. Chem. Soc. ReV.
1998, 27, 427. (f) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009. (g) Whitcombe, N. J.; Kuok Hii, K.; Gibson, S. E. Tetrahedron
2001, 57, 7449. (h) Dounay, A. B.; Overman, L. E. Chem ReV. 2003, 103,
2945.
(2) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (b) Littke,
A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (c) Shaughnessy, K.
H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123. (d) Stambuli,
J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2677. (e) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589.
(3) (a) Ben-David, Y.; Portnoy, M.; Gozin, M.; Milstein, D. Organo-
metallics 1992, 11, 1995. (b) Portnoy, M.; Milstein, D. Organometallics
1993, 12, 1655. (c) Portnoy, M.; Ben-David, Y.; Milstein, D. Organo-
metallics 1993, 12, 4734. (d) Portnoy, M.; Ben-Dvid, Y.; Rousso, I.;
Milstein, D. Organometallics 1994, 13, 3465. (e) Shaw, B. L.; Perera, S.
D. Chem. Commun. 1998, 1863.
(6) For phosphorus-free palladacycles as catalysts, see ref 4.
(7) For recent reviews on N-heterocyclic carbene-palladium catalysts,
see: (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b) Yong,
B. S.; Nolan, S. P. Chemtracts: Org. Chem. 2003, 205.
(8) For recent reports on Heck reactions using catalysts that are air- and
moisture-stable, see: (a) Buchmeiser, M. R.; Wurst, K. J. Am. Chem. Soc.
1999, 121, 11101. (b) Silberg, J.; Schareina, T.; Kempe, R.; Wurst, K.;
Buchmeiser, M. R. J. Organomet. Chem. 2001, 622, 6. (c) Masllorens, J.;
Moreno-Manas, M.; Pla-Quintana, A.; Roglans, A. Org. Lett. 2003, 5, 1559.
(9) (a) Touchard, F.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry
1997, 8, 3319. (b) Touchard, F.; Gamez, P.; Fache, F.; Lemaire, M.
Tetrahedron Lett. 1997, 38, 2275. (c) Touchard, F.; Bernard, M.; Fache,
F.; Delbecq, F.; Guiral, V.; Sautet, P.; Lemaire, M. J. Organomet. Chem.
1998, 567, 133. (d) Tommasino, M. L.; Casalta, M.; Breuzard, J. A. J.;
Lemaire, M. Tetrahedron: Asymmetry 2000, 11, 4835. (e) Breuzard, J. A.
J.; Tommasino, M. L.; Touchard, F.; Lemaire, M.; Bonnet, M. C. J. Mol.
Catal. A: Chem. 2000, 156, 223. (f) Touchard, F.; Bernard, M.; Fache, F.;
Lemaire, M. J. Mol. Catal. A: Chem. 1999, 140, 1.
10.1021/ol049697+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/10/2004

arenediazonium salts catalyzed by a chiral thiourea-Pd
complex.11 Here, we report that sterically bulky thiourea-
Pd(0) complexes are air- and moisture-stable, highly active
catalysts for Heck reactions of aryl halides.
Table 1. Screening of Thiourea Ligands for the Pd-Catalyzed
Heck Reaction of Iodobenzene with Methyl Acrylatea
We have synthesized the acyclic and cyclic thioureas 1a-j
(Figure 1)12 and tested the catalytic activity of their com-
entry
ligand
Pd (mol %)
time (h)
yieldb
TON
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18c
19d
20e
1a
1b
1c
1d
1e
1f
2
2
2
1
0.1
0.1
0.1
0.1
0.01
0.01
0.01
0.01
0.01
0.002
0.002
0.001
0.001
0.00033
0.0001
0.01
4
4
4
4
1
1
1
1
4
0
3
8
0
1.5
4
1
1
>99
>99
>99
>99
>99
>99
>99
>99
>99
18
>99
51
>99
88
50
>99
103
103
1j
103
1k
1e
1f
1g
1h
1i
103
104
4
2
2
104
104
104
1.5
12
12
20
10
30
48
2
104
Figure 1. Structures of thiourea ligands.
1f
9 × 103
5 × 104
5.1 × 104
105
1k
1k
1g
1g
1i
plexes with Pd(0) in the Heck reaction between iodobenzene
and methyl acrylate at 100 °C (Table 1). We stress that the
reactions were conducted in air and that all the reagents were
used directly as received. The structure of each thiourea
ligand has a great influence on the catalytic efficacy of its
palladium complex. Acyclic thioureas 1a-c were almost
completely inactive (entries 1-3), as was also the case for
the cyclic thiourea 1d featuring an NH moiety (entry 4).
Good activity was observed, however, when using N,N′-
disubstituted bulky cyclic thioureas 1e, 1f, 1j, and 1k of
different ring sizes as the ligands; indeed, quantitative yields
were achieved within 1 h when 0.1 mol % Pd was applied
(entries 5-8). The catalyst loading could be decreased even
further, to 0.001 and 0.002 mol %, when using ligands 1g
and 1k, respectively (entries 15-17). In general, the pal-
ladium complexes formed with relatively bulky thiourea
ligands (1g-i) exhibit the highest catalytic activities (cf.
entries 11-13 vs entries 9 and 10). Attempts to decrease
the catalyst loading even further, to 0.00033 mol % Pd,
resulted in the incomplete conversion of iodobenzene, but a
good yield could still be obtained after prolonged heating
(entry 18; TON ) 2.6 × 105). We performed a reaction using
our lowest catalyst loading (10-4 mol % Pd) at a higher
temperature (130 °C) using bulky 1i as the ligand and
obtained a moderate yield (50%) of product (entry 19; TON
) 5.0 × 105). It is noteworthy that the thiourea-Pd(0)
catalysts demonstrated excellent stability, and almost no
palladium black was formed throughout the reaction. More-
2.6 × 105
5 × 105
104
1g
a Reactions were conducted under aerobic conditions. Unless indicated
otherwise, reactions were conducted using 2.5 mmol of PhI, with PhI/
acrylate/NEt3 ) 1:1.2:1.2, and Pd(dba)2/thiourea ) 1:4. b Yield was
determined by 1H NMR spectroscopy using nitrobenzene as the internal
standard. c On a 7.5 mmol scale at 120 °C. d On a 25 mmol scale at 130
°C. e Using a stock solution of the catalyst in DMF that had been standing
in air for 2 months.
oVer, the DMF stock solution of Pd(0) complex of 1g retained
its actiVity eVen after standing in air at room temperature
for two months (cf. entry 11 vs entry 20).
The catalytic efficacy of the thiourea 1g-Pd(0) complex
in the Heck reaction was studied further with a number of
aryl iodides and olefins. Table 2 indicates that high yields
were obtained within 4 h using 0.01 mol % Pd catalyst for
olefins such as butyl acrylates and styrene (entries 1-3),
but not for methyl vinyl ketone due to a lower reactivity
(entry 4). Excellent yields were obtained for Heck reactions
between butyl acrylate and para-substituted aryl iodides
(entries 5-7). Olefins that are R- or â-subsituted are also
suitable substrates and give trisubstituted olefins,2b,13 but
higher catalyst loadings and reaction temperatures were
required (entries 8-10).
Aryl bromides and chlorides are cheaper and more readily
available substrates than the corresponding iodides, but they
are more reluctant to undergo the catalytic Heck reactions.1g,14
Therefore, we tested the catalytic efficacy of our thiourea
1g-palladium(0) complex using aryl bromides as the
substrates, and the results are summarized in Table 3. In
(10) (a) De Munno, G.; Gabriele, B.; Salerno, G. Inorg. Chim. Acta 1995,
234, 181. (b) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J.
Organomet. Chem. 1995, 503, 21. (c) Zhang, T. Y.; Allen, M. J. Tetrahedron
Lett. 1999, 40, 5813. (d) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2,
297. (e) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765. (f) Hu, Y.; Yang, Z.
Org. Lett. 2001, 3, 1387.
(11) Dai, M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Org. Lett. 2004,
6, 221.
(12) For the synthesis of the thiourea ligands, see Supporting Information.
(13) Gurtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107 and
references therein.
(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
1578
Org. Lett., Vol. 6, No. 10, 2004

Moreover, the catalyst loading could be decreased further,
to 0.02 mol % Pd, without significantly decreasing the yields
(entries 4 and 5). Bromobenzene was a suitable substrate at
a loading of 0.5 mol % Pd but not at 0.1 mol % (entries 6
and 7). 3-Bromopyridine was also efficiently coupled with
styrene in 90% yield in the presence of 0.1 mol % Pd (entry
8). On the other hand, we observed very poor conversions
when a deactivated bromide or an activated chloride was
applied as the substrate (entries 9 and 10).
Table 2. Heck Reaction of Aryl Iodides with Olefinsa
Recently, Beller16 reported that the Heck reactions of aryl
chlorides can be greatly improved when using Bu4NBr as
an ionic liquid solvent.17 In fact, we have found that this
system is also suitable for the thiourea 1g-Pd(0)-catalyzed
Heck reactions of deactivated bromides and activated
chlorides when the reaction temperature is elevated slightly.
As reported in Table 4, excellent yields were achieved for
Table 4. Heck Reactions of Deactivated Bromides and
Activated Chlorides with Olefinsa
a Pd(dba)2/1g ) 1:4; PhI/olefin/NEt3 ) 1:1.2:1.2. b Yield was determined
by 1H NMR spectroscopy using nitrobenzene as the internal standard. c (E)-
Configuration products. d Reaction was conducted at 120 °C.
general, higher catalyst loadings and temperatures15 were
required to force the completion of the reactions of the aryl
bromides compared to the case of aryl iodides. For activated
bromides, complete conversions of the substrates were
observed after 15 h in the presence of 0.1 mol % Pd using
NMP as the solvent and NaOAc as the base (entries 1-3).
Table 3. Heck Reaction of Aryl Bromides with Olefinsa
a Pd(dba)2/1g ) 1:4; PhI/olefin/NaOAc ) 1:1.2:1.2. b Yield was deter-
mined by 1H NMR spectroscopy using nitrobenzene as the internal standard.
deactivated bromides after their reaction for 24 h in the
presence of 0.5 mol % Pd (entries 1-3), but incomplete
conversion occurred when using 0.2 mol % Pd catalyst (entry
4). Under the same conditions, activated aryl chlorides were
coupled successfully with styrene within 24 h when using 1
(15) Almost no reaction occurred at 100 °C using ArBr as substrates.
(16) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031.
(17) For recent reviews on the use of ionic liquids as solvents, see: (a)
Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem. 2002, 182-
183, 419. (b) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. ReV.
2002, 102, 3667. (c) Davis, J. H., Jr.; Fox, P. A. Chem. Commun. 2003,
1209.
a Pd(dba)2/1g ) 1:4; ArX/olefin/NaOAc ) 1:1.5:1.5. b Yield was
determined by 1H NMR spectroscopy using nitrobenzene as the internal
standard.
Org. Lett., Vol. 6, No. 10, 2004
1579

the thiourea 1g-PdCl2 complex shows, however, that only
two of these thiourea molecules and two chloride ions are
coordinated with the Pd(II) center, which has a square-planar
geometry in which the two sulfur atoms are positioned in
either cis or trans form with respect to one another (Figure
2). While attempts to isolate the thiourea 1g-Pd(0) complex
failed, the ESI-MS study of the DMF solution of thiourea
1g and Pd(dba)2 (4:1) revealed one peak at m/z ) 783.2,
which corresponds to the [Pd(0)‚(1g)2 + H]+ ion, in addition
to the peak of free ligand 1g. Therefore, we believe it is
likely that the sterically bulky thiourea ligands form a 2:1
complex with palladium that is the catalytically active
species, although the detailed mechanism awaits further
investigation.18
In summary, we have demonstrated that sterically bulky
N,N′-disubstituted cyclic thiourea-palladium complexes are
highly active catalysts for Heck reactions of aryl halides with
olefins (TONs up to 500 000 for the reaction of PhI and
methyl acrylate). These novel thiourea ligands are air- and
moisture-stable, and the reactions can be readily conducted
in open air. Work is in progress in our laboratory to extend
the applications of thiourea ligands in asymmetric catalysis
as well as in other palladium-catalyzed transformations.
Acknowledgment. This work was supported by The
University of Hong Kong. We thank Nga-Wai Chung for
help in ESI-MS analysis. D.Y. acknowledges the Bristol-
Myers Squibb Foundation for an Unrestricted Grant in
Synthetic Organic Chemistry and the Croucher Foundation
for a Croucher Senior Research Fellowship Award.
Figure 2. Structures of cis- and trans-PdCl2‚(1g)2. Hydrogen atoms
have been omitted for clarity. Thermal ellipsoids are shown at 30%
probability.
Supporting Information Available: Synthetic schemes
and characterization data of compounds 1b, 1c, and 1f-k;
1H NMR data of coupling products; general procedures for
the Heck reactions of aryl halides with olefins catalyzed by
Pd-thiourea complexes; and X-ray structural analysis of
PdCl2‚(1g)2, containing tables of atomic coordinates, thermal
parameters, bond lengths, and angles. This material is
available free of charge via the Internet at http://pubs.acs.org.
mol % of the Pd catalyst (entries 5-7). n-Butyl acrylate
displayed reactivity that was slightly lower than that of
styrene, but good yields were also obtained (entries 8-10).
Chlorobenzene itself, however, was completely inert, even
when we used a higher loading of the Pd catalyst (2 mol %)
(entry 11).
Having established that thiourea-Pd(0) complexes pre-
pared in situ are active catalysts for Heck reactions of aryl
halides with olefins, we investigated the nature of the
thiourea-Pd(0) complexes to gain further insight with regard
to the possible reaction mechanism. It is known that four
molecules of unsubstituted thiourea 1a can coordinate
simultaneously to Pd(II) centers.10a,b An X-ray structure of
OL049697+
(18) When the Heck reactions of aryl halides were performed using a
1:2 ratio of Pd(dba)2 and thiourea 1g, both the yield and reaction rate were
quite similar to those obtained when using a 1:4 ratio. Generally, however,
almost no palladium black was formed when using Pd-thiourea in a 1:4
ratio, whereas trace amounts of Pd black could be observed when using
the 1:2 ratio, especially after heating for an extended period of time.
1580
Org. Lett., Vol. 6, No. 10, 2004