Highly selective palladium-catalyzed Heck reactions of aryl bromides with cycloalkenes

Article abstract of DOI:10.1021/ol9901063

Formula presented The influence of palladium catalysts and reaction conditions on the selectivity of Heck reactions of aryl bromides with cyclohexene and cyclopentene has been investigated. It is shown that the addition of DMSO as a cosolvent leads to improved selectivities of nonconjugated aryl olefins. On the other hand, high selectivities for conjugated arylcyclopentenes have been obtained with the catalytic system DMA/Na₂-CO₃/Pd₂(dba) ₃·dba/PCy₃.

Full text of DOI:10.1021/ol9901063

ORGANIC
LETTERS
1999
Vol. 1, No. 5
709-711
Highly Selective Palladium-Catalyzed
Heck Reactions of Aryl Bromides with
Cycloalkenes
,†
,‡
Christian G. Hartung,† Klaus Ko1hler,* and Matthias Beller*
Anorganisch-chemisches Institut, Technische UniVersita¨t Mu¨nchen,
Lichtenbergstrasse 4, D-85747 Garching, Germany, and Institut fu¨r Organische
Katalyseforschung (IfOK) an der UniVersita¨t Rostock e.V., Buchbinderstrasse 5-6,
D-18055 Rostock, Germany
matthias.beller@ifok.uni-rostock.de
Received May 26, 1999
ABSTRACT
The influence of palladium catalysts and reaction conditions on the selectivity of Heck reactions of aryl bromides with cyclohexene and
cyclopentene has been investigated. It is shown that the addition of DMSO as a cosolvent leads to improved selectivities of nonconjugated
aryl olefins. On the other hand, high selectivities for conjugated arylcyclopentenes have been obtained with the catalytic system DMA/Na2-
CO /Pd2(dba)3‚dba/PCy3.
3
The palladium-catalyzed arylation and vinylation of alkenes
(Heck reaction) has become one of the most important and
powerful transition-metal-catalyzed transformations in or-
ganic synthesis for generating new carbon-carbon bonds.1
Nevertheless, the control of selectivity in Heck reactions still
causes problems; e.g., the coupling of aliphatic (e.g. 1-hex-
ene), 1,1-disubstituted, or cyclic olefins often generates a
mixture of double-bond regioisomers. As an example, the
intermolecular Heck reaction of cyclic alkenes with aryl
bromides does not yield one specific double-bond regioiso-
mer by using standard reaction conditions (125 °C, polar
aprotic solvent, NaOAc or NR3, PdX2/PAr3).2 In addition,
in most cases the Heck reaction of aryl halides and
cycloalkenes proceeds extremely slowly, and thus only low
yields of product are obtained.1c,3 Although aryl iodides or
triflates and aryl diazonium salts can be coupled with
cycloalkenes more efficiently,3,4 the reactions of economi-
cally more attractive aryl bromides with cycloalkenes require
elevated temperatures (>80 °C) and give isomeric mixtures.
In this paper a new procedure for the selective coupling of
(2) (a) Larock, R. C. Pure Appl. Chem. 1990, 62, 653. (b) Harrington,
O. J.; DiFiore, K. A. Tetrahedron Lett. 1987, 28, 495. (c) Andersson, C.-
M.; Hallberg, A.; Daves, G. D., Jr. J. Org. Chem. 1987, 52, 3529. (d) Lee,
T. D.; Daves, G. D., Jr. J. Org. Chem. 1983, 48, 399. (e) Arai, I.; Daves,
G. D., Jr. J. Org. Chem. 1979, 44, 21. (f) Tamaru, Y.; Yamada, Y.; Yoshida,
Z. Tetrahedron 1979, 35, 329. (g) Heck, R. F. Acc. Chem. Res. 1979, 12,
146. (h) Cortese, N. A.; Ziegler, C. B., Jr.; Hrnjez, B. J.; Heck, R. F. J.
Org. Chem. 1978, 43, 2953.
† Technische Universita¨t Mu¨nchen.
‡ Universita¨t Rostock e.V.
(1) (a) Beller, M.; Riermeier, T. H.; Stark, G. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; VCH: Weinheim, Germany,
1998; p 208. (b) Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, U.K., 1995. (c) de Meijere, A.; Meyer, F. Angew. Chem. 1994,
106, 2473; Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (d) Heck, R. F.
In ComprehensiVe Organic Synthesis; Trost, B. M., Flemming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 4, p 833.
(3) Larock, R. C.; Baker, B. E. U.S. Patent 4 879 426, 1988.
(4) (a) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338. (b) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron
Lett. 1989, 30, 2603. (c) Larock, R. C.; Gong, W. H. J. Org. Chem. 1989,
54, 2047. (d) Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905.
(e) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron 1981,
37, 31.
10.1021/ol9901063 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/12/1999

Table 1. Heck Reaction of Cyclohexene with Aryl Bromides8
entry
R
solventa
base
catalyst
n-Bu4NBr (mol %)b conversn (%)c yield (%)c
4:5:6d
e
1
2
3
4
5f
6
7
8
9
10j
11j
12j
13j
14j
15j
4-COCH3 DMA
4-COCH3 DMA
4-COCH3 DMA
4-COCH3 DMA
4-COCH3 TMSOg
4-COCH3 DMSO
4-COCH3 DMSO/DMA NaOAc
4-COCH3 DMSO/DMA NaOAc
4-COCH3 DMA
NaOAc
NaOAc
NaOAc
Na2CO3
NaOAc
NaOAc
Pd(OAc)2/2 PPh3
96
>99
94
15
39
48
59
98
63i
67
56
64
73
30
48
78
89
75
12
31
36
49
82
48
59
48
54
67
27
46
4:17:79
7:15:78
6:16:78
7:24:69
2:9:89
2:11:87
2:8:90
3:9:88
1:33:66
15:16:69
1:9:90
6:18:76
1:12:87
2:20:78
1:12:87
palladacycle 3e
e
e
Pd2(dba)3‚dba/4 PCy3
Pd2(dba)3‚dba/4 PCy3
e
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
palladacycle 3e
palladacycle 3k
palladacycle 3e
palladacycle 3k
e
e
e
50
h
e
EtN(iPr)2
NaOAc
e
3-CF3
3-CF3
H
DMA
e
DMSO/DMA NaOAc
DMA NaOAc
DMSO/DMA NaOAc
DMA NaOAc
DMSO/DMA NaOAc
30
30
30
H
4-OCH3
4-OCH3
a DMSO/DMA ) 1:4. b mol % n-Bu4NBr refers to aryl bromide. c Conversions and yields were determined by GC with internal standard (diethylene
glycol di-n-butyl ether). d Selectivities were determined by GC on the basis of area percentage. e 0.1 mol % Pd. f 130 °C. g Tetramethylene sulfoxide. h 2
equiv of base. i Side product: 7% acetophenone. j 150 °C. k 1 mol % Pd.
aryl bromides with cyclic olefins via the Heck reaction is
presented. The coupling reaction of 4-bromoacetophenone
with cyclohexene 2 (known to be a “difficult” substrate for
Heck reactions) served as a model reaction to develop
improved catalysts. Under standard conditions (DMA (N,N-
dimethylacetamide), NaOAc, 0.1 mol % Pd(OAc)2/2 PPh3,
140 °C, 20 h) only a mixture of double-bond isomers 4-6
(4:17:79)5 was obtained with a conversion of 96% and a yield
of aryl olefins of 78%.6 The difference between the conver-
sion and yield is mainly due to the formation of double-
arylated products. In addition, 4,4’-diacetylbiphenyl and
acetophenone were observed as side products.
selectivity (Table 1, entries 1-3). Predominantly, by using
inorganic bases (e.g. NaOAc) the 4-(aryl)cyclohexene de-
rivative 6 was produced in high yields. By using dimethyl
sulfoxide or tetramethylene sulfoxide as solvents, product 6
could be obtained with increased selectivity up to 4:5:6 )
2:9:89 (entries 5 and 6). Unfortunately, the coordination of
the sulfoxide to the metal resulted in a lower reaction rate
compared to DMA as the solvent. However, the use of
DMSO as cosolvent in combination with DMA in the
presence of n-Bu4NBr leads to both high conversion and high
selectivity (entry 8). Due to the limited ability to solubilize
inorganic bases, nonpolar solvents such as toluene gave very
low yields of products. When soluble amines were used as
the bases, relatively high amounts of product 5 were observed
(entry 9). This observation is explained by a faster HX
elimination in the presence of amines.7 To investigate the
scope of the DMSO/DMA system, different aryl bromides
were reacted with cyclohexene (Scheme 1, Table 1). In all
cases, even for nonactivated or deactivated aryl bromides,
improved selectivities for the 4-(aryl)cyclohexene were
observed using a mixture of DMSO and DMA. Although
electron-donating substituents on the aryl bromide cause a
We assumed that the selectivity of the coupling reaction,
leading to 4-6, might be influenced by the added base.7
Indeed, experiments with isolated Heck products (mixture
of isomers 4-6) showed that double-bond migration is
catalyzed slowly by base and not by a HPdX complex. To
improve the selectivity of the arylation of cyclohexene,
various palladium catalysts as well as different bases and
solvents were applied to this reaction.8 As shown in Table
1, the choice of solvent and base has an important influence
on the extent of C-C double-bond migration; in con-
trast, different catalysts showed no significant changes in
Scheme 1
710
Org. Lett., Vol. 1, No. 5, 1999

Table 2. Heck Reaction of Cyclopentene with Aryl Bromides8
entry
R
base
catalysta
conversn (%)b
yield (%)b
8:9:10c
1d
2e
4-COCH3
4-COCH3
4-COCH3
4-COCH3
4-COCH3
3-CF3
3-CF3
H
H
NaOAc
NaOAc
NaOAc
Na2CO3
Na2CO3
NaOAc
Na2CO3
NaOAc
Na2CO3
NaOAc
Na2CO3
Pd(OAc)2/2 PPh3
Pd(OAc)2/2 PPh3
Pd2(dba)3‚dba/4 PCy3
Pd(OAc)2/2 PPh3
Pd2(dba)3‚dba/4 PCy3
Pd(OAc)2/2 PPh3
Pd2(dba)3‚dba/4 PCy3
Pd(OAc)2/2 PPh3
Pd2(dba)3‚dba/4 PCy3
Pd(OAc)2/2 PPh3
>99
>99
>99
>99
>99
98
>99
92
>99
39
94
95
98
98
>99
92
99
90
>99
36
92
17:72:11
11:78:11
39:45:16
83:13:4
91:7:2
7:82:11
90:9:1
7:83:10
92:7:1
3d
4d
5d
6d
7d
8d
9d
10d
11d
4-OCH3
4-OCH3
7:80:13
92:7:1
Pd2(dba)3‚dba/4 PCy3
93
a 0.1 mol % Pd refers to the aryl bromide. b Conversions and yields were determined by GC with internal standard (diethylene glycol di-n-butyl ether).
c Selectivities were determined by GC on the basis of area percentage. d DMA was used as the solvent. e 4:1 DMA/DMSO was used as the solvent.
is the most stable isomer. Regarding arylcyclopentenes, the
three isomeric products do have approximately the same
thermodynamic stability.
decrease in reactivity, yields of 67% and 46% were obtained
using bromobenzene and 4-bromoanisole, respectively.
Next, we studied the reactions of aryl bromides with
cyclopentene 7 (Scheme 2). As demonstrated in Table 2,
In summary, we have shown for the first time that Heck
reactions of aryl bromides with cyclohexene and cyclopen-
tene can be performed in an efficient manner. The addition
of DMSO as a cosolvent enhances the selectivity for the
nonconjugated Heck products. When cyclopentene was
applied as the olefinic substrate, both 1-(aryl)- and 3-(aryl)-
cyclopentenes were obtained selectively. Worthy of note are
the low quantities of catalyst required (0.1 mol %) and the
possibility of determining the double-bond selectivity by
simply changing the nature of the catalyst system.
Scheme 2
Acknowledgment. We thank Dr. L. Djakovitch and Dipl.-
Chem. M. Wagner (TU Mu¨nchen) for performing the
molecular mechanics calculations and for helpful discussions.
Dr. T. H. Riermeier (Aventis R&D) is thanked for valuable
comments on the project. C.G.H. thanks the Studienstiftung
des Deutschen Volkes for support. This work has been
financed by the Deutsche Forschungsgemeinschaft (Be 1993/
3-1; Ko 1458/3-1).
1-(aryl)cyclopentenes 8 and 3-(aryl)cyclopentenes 9 were
produced as the major products. When the standard system
DMA/NaOAc/Pd(OAc)2/2 PPh3 was applied at 140 °C, 9
was obtained with 68% overall selectivity. Again using a
mixture of DMA and DMSO (4:1) the selectivity increased
(74%); however, the effect is not as pronounced compared
to that of cyclohexene. Interestingly, under more basic
conditions double-bond isomerization takes place easily to
yield 1-(aryl)cyclopentene 8 as the major isomer. After some
optimization the catalyst system Pd2(dba)3‚dba/4 PCy3/Na2-
CO3 turned out to be very useful for the preparation of
conjugated arylcyclopentenes 8. In all cases here yields and
product selectivities >90% were observed in the presence
of only 0.1 mol % of palladium!
OL9901063
(5) Selectivities were determined by GC on the basis of area percentage.
(6) Conversions and yields were determined by GC with internal standard
(diethylene glycol di-n-butyl ether).
(7) Beller, M.; Riermeier, T. H. Tetrahedron Lett. 1996, 37, 6535.
(8) General procedure: 5 mmol of aryl bromide, 25 mmol of cyclo-
alkene, 6 mmol of base, 0.005 mmol of Pd catalyst, and 0.01 mmol of
phosphine were dissolved in 5 mL of DMA/DMSO (4:1), and the mixture
was stirred under argon at 140 °C for 20 h in a pressure tube. (CAUTION!
The reactions were done under pressure. Take the necessary safety measures
against explosion.) After it was cooled, the reaction mixture was washed
with a mixture of dichloromethane and 5% aqueous HCl (three times). The
phases were separated and the combined organic phases neutralized with
10% aqueous NaHCO3 and dried over MgSO4. After removal of the solvent
the desired products were isolated as colorless oils by distillation in vacuo.
The different behavior of arylcyclohexenes and aryl-
cyclopentenes toward isomerization is explained to some
extent by molecular mechanics calculations, which indicate
that in the case of arylcyclohexenes the 4-(aryl)cyclohexene
1
All products were identified by H and 13C NMR and mass spectroscopy
and by comparison with authentic samples by GC.
Org. Lett., Vol. 1, No. 5, 1999
711