Palladium-catalyzed selective Heck-type diarylation of allylic esters with aryl halides involving a β-OAc elimination process

Article abstract of DOI:10.1021/ol1031552

Palladium-catalyzed selective Heck-type diarylation of allylic esters with aryl halides has been developed. Allylic esters are reacted with aryl iodides to provide the corresponding 1,3-diaryl propenes through a β-OAc elimination process. It is noteworthy that the methodology can be applied in constructing the indole and benzofuran skeletons.(Figure Presented)

Full text of DOI:10.1021/ol1031552

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1126–1129
Palladium-Catalyzed Selective Heck-Type
Diarylation of Allylic Esters with Aryl
Halides Involving a β-OAc Elimination
Process
Yan Liu, Bo Yao, Chen-Liang Deng,* Ri-Yuan Tang, Xing-Guo Zhang, and Jin-Heng Li*
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035,
China
jhli@hunnu.edu.cn; dengchenliang78@tom.com
Received December 28, 2010
ABSTRACT
Palladium-catalyzed selective Heck-type diarylation of allylic esters with aryl halides has been developed. Allylic esters are reacted with aryl
iodides to provide the corresponding 1,3-diaryl propenes through a β-OAc elimination process. It is noteworthy that the methodology can be
applied in constructing the indole and benzofuran skeletons.
The Heck reaction is one of the most important methods
in organic chemistry, and widely applies in organic synth-
esis, pharmaceutical, and material industries.1-6 Despite
important advances in the Heck reaction of halides, pseu-
dohalides, or arenes, the selective Heck reactions of allylic
esters processes are scarce.3-6 Until now, there are only
two monoarylation routes for the Heck reactions of allylic
esters, including (1) β-OAc elimination to terminal alkenes
(route a, Scheme 1)4,5 and (2) β-H elimination to internal
allylic esters (route b).6 For example, Lautens and co-
workers have developed an intermolecular Heck reaction
of allylic acetates with aryl iodides through a β-OAc
elimination process in good yields.4b-e They observed
some β-H elimination products during their procedures,
(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.
(2) For reviews, see: (a) Heck, R. F. Palladium in organic synthesis;
Academic Press: New York, 1985. (b) Diederich, F.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reaction; Wiley-VCH: Weinheim, Germany,
1998. (c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d)
Beletskaya, I. P.; Cheprakov., A. V. Chem. Rev. 2000, 100, 3009. (e)
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (f ) Dounay,
A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (g) Xie, Y.-X.; Li,
J.-H.; Yin, D.-L. Chin. J. Org. Chem. 2006, 26, 1155 and references
cited therein. (h) Oestreich, M. The Mizoroki-Heck Reaction; Wiley:
Chichester, UK, 2009. (i) Heravi, M. M.; Fazeli, A. Heterocycles 2010, 81,
1979. ( j) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.;
Esfahani, F. K.; Zamani, A. Synthesis 2010, 1399.
Scheme 1. The Heck Reactions of Allyl Acetates
(3) For a review, see: Pan, D.; Jiao, N. Synlett 2010, 1577.
(4) (a) Steinig, A. G.; de Meijere, A. Eur. J. Org. Chem. 1999, 1333.
(b) Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005, 127, 72.
(c) Mariampillai, B.; Herse, C.; Lautens, M. Org. Lett. 2005, 7, 4745. (d)
Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens, M. Org. Lett.
2006, 8, 4569. (e) Menard, F.; Perez, D.; Roman, D. S.; Chapman, T. M.;
Lautens, M. J. Org. Chem. 2010, 75, 4056.
(5) For papers on the other metal-catalyzed β-OAc elimination
ꢀ
reactions, see: (a) Gomes, P.; Gosmini, C.; Perichon, J. Org. Lett.
ꢀ
2003, 5, 1043. (b) Botella, L.; Najera, C. J. Organomet. Chem. 2002, 663,
46.
r
10.1021/ol1031552
Published on Web 02/09/2011
2011 American Chemical Society

but low yields and low selectivity hindered the β-H elim-
ination transformation. Recently, Jiao and co-workers
described a selective Heck reaction of aryl halides with
allylic esters by β-H elimination avoiding β-OAc
elimination.6 To the best of our knowledge, however,
examples of selective diarylation of allylic esters are not
explored. Here, we report a selective palladium-catalyzed
Heck-type diarylation of allylic esters with aryl iodides
protocol for one-step synthesizing 1,3-diaryl propenes
involving a β-OAc elimination process (route c).7,8 It is
noteworthy that the methodology can be applied in con-
structing the indole and benzofuran skeletons.9,10
NMR spectra. To our delight, n-Bu4NCl could improve
the reaction, enhancing the yield of 3 sharply to 89%
(entry 2).11 Prompted by these results, a series of solvents,
such as Et3N, n-PrCN, DMF, DMA (N,N-dimethyl-
acetamide), NMP (N,N-dimethylpyridin-4-amine), to-
luene, and THF, were investigated, and they were less
effective than MeCN (entries 3-9). The yield was reduced
to 23% when Et3N was used as the base and medium
(entry 3). It was found that n-PrCN, the higher boiling
point solvent, also decreased the activity of the reaction
slightly (entry 4). Notably, the yield of 3 was lowered to
57% at 5 mol % of Pd(OAc)2 even prolonging the reaction
time (entry 10). Although three other Pd catalysts, PdCl2,
PdCl2(MeCN)2, and Pd(PPh3)4, had activity for the reac-
tion, they were less effective than Pd(OAc)2 (entries
11-13). In light of the above results, the effect of bases
was evaluated (entries 14-16). The yield of 3 was reduced
when 4 equiv of Et3N was added (entry 14). We found that
both DABCO and KOAc displayed less efficiency for the
diarylation reaction (entries 15 and 16). Among the ad-
ditives examination, it turned out that the reaction gave the
best results in the presence of n-Bu4NCl (entries 2 and
17-19). It is noteworthy that the identical results are observed
under either air or nitrogen atmosphere (entries 2 and 20).
Consequently, the scope of both ally lactates and aryl
halides was explored for the diarylation reaction under the
standard conditions (Table 2). In the presence of Pd(OAc)2,
n-Bu4NCl, and Et3N, a variety of aryl halides 2b-k were
first examined by reacting with allyl acetate (1a) (entries
1-10). The results indicated that both electron-rich and
electron-deficient aryl iodides were suitable for the diaryla-
tion reaction, but aryl bromides had no activity. For
example, aryliodide 2b, bearing a 2-MeO group on the
arylring, wastreated with acetate1a, Pd(OAc)2, n-Bu4NCl,
and E3N smoothly to afford the desired product 4 in 80%
yield (entry 1). Gratifyingly, substrate 2g with a p-NH2
group was successfully diarylated with acetate 1a leading
Table 1. Palladium-Catalyzed Diarylation Reaction of Allyl
Acetate (1a) with 4-Iodoansole (2a)a
entry
[Pd]
additive
base
Et3N
solvent yield (%)b
1
2
Pd(OAc)2
Pd(OAc)2
MeCN
MeCN
40
89
23
81
73
67
61
69
57
57
75
71
17
71
62
27
61
82
32
90
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
3c Pd(OAc)2
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
n-PrCN
DMF
DMA
NMP
toluene
THF
10d Pd(OAc)2
11 PdCl2
MeCN
MeCN
MeCN
MeCN
MeCN
12 PdCl2(MeCN)2 n-Bu4NCl
13 Pd(PPh3)4
14e Pd(OAc)2
15 Pd(OAc)2
16 Pd(OAc)2
17 Pd(OAc)2
18 Pd(OAc)2
19 Pd(OAc)2
20f Pd(OAc)2
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NBr
n-Bu4NF
DABCO MeCN
K2CO3 MeCN
Et3N
Et3N
MeCN
MeCN
MeCN
MeCN
n-Bu4NOAc Et3N
n-Bu4NCl Et3N
(7) For selected papers on the use of allyl acetates in organic synth-
esis, see: (a) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34,
2589. (b) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester,
UK, 2004; p 543. (c) Trost, B. M.; Lee, C. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; p 593.
(d) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999;
Vol. 2, p 833.
a Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), [Pd] (10 mol %),
additive (1.5 equiv), base (8 equiv), and solvent (2 mL) at 120 °C under
air atmosphere for 12 h. b Isolated yield. c Et3N (2 mL). d Pd(OAc)2 (5
mol %) for 26 h. e Et3N (4 equiv). f Under N2 atmosphere.
As shown in Table 1, the reaction of allyl acetate 1a with
4-iodoansole 2a was carried out to determine the optimal
reaction conditions. Initially, treatment of substrate 1a
with iodide 2a, Pd(OAc)2 (10 mol %), and Et3N (8 equiv)
in MeCN at 120 °C for 12 h afforded the desired (E)-
4,40-(prop-1-ene-1,3-diyl)bis(methoxybenzene) (3) in 40%
yield together with some monoarylation β-OAc or β-H
elimination products (entry 1). It is noteworthy that the
configuration of the carbon-carbon double bond in pro-
(8) For selected papers on diarylation (Heck-type) reactions, see: (a)
Cacchi, S.; Palmieri, G. Synthesis 1984, 575. (b) Gurtler, C.; Buchwald,
S. L. Chem.;Eur. J. 1999, 5, 3107. (c) Bagnell, L.; Kreher, U.; Strauss,
C. R. Chem. Commun. 2001, 1, 29. (d) Andersson, C. M.; Larsson, J.;
Hallberg, A. J. Org. Chem. 1990, 55, 5757. (e) Buezo, N. D.; Alonso, I.;
Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129. (f ) Nilsson, P.;
Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217.
(9) (a) Wen, J. R.; Tsai, C. H.; Kulp, S. K.; Chen, C. S. Cancer Lett.
2008, 262, 153. (b) Shimazaki, Y.; Yajima, T.; Takani, M.; Yamauchi, O.
Coord. Chem. Rev. 2009, 253, 479.
(10) (a) Proksch, P.; Proksch, M.; Towers, G. H. N.; Rodriguez, E.
J. Nat. Prod. 1983, 46, 331. (b) Parodi, F. J.; Fischer, N. H.; Flores, H. E.
J. Nat. Prod. 1988, 51, 594. (c) Durani, N.; Jain, R.; Saeed, A.; Dikshit,
D. K.; Durani, S.; Kapil, R. S. J. Med. Chem. 1989, 32, 1700. (d)
Tomaszewski, Z.; Johnson, M. P.; Huang, X.; Nichols, D. E. J. Med.
Chem. 1992, 35, 2061. (e) Jia, Z.; Zhao, Y. J. Nat. Prod. 1994, 57, 146. (f )
Bakunova, S. M.; Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz,
K. A.; Brun, R.; Hall, J. E.; Tidwell, R. R. J. Med. Chem. 2007, 50, 5807.
(11) (a) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559. (b)
Liu, W.-J.; Xie, Y.-X.; Liang, Y.; Li, J.-H. Synthesis 2006, 860.
1
duct 3 is determined according to the authoritative H
(6) (a) Pan, D.; Chen, A.; Su, Y.; Zhou, W.; Li, S.; Jia, W.; Xiao, J.;
Liu, Q.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2008, 47, 4729. (b) Su,
Y. J.; Jiao, N. Org. Lett. 2009, 11, 2980. (c) Chen., W.; Yu, M.; Pan, D.;
Jiao, N. Chin. J. Org. Chem. 2010, 30, 469. (d) Arvela, R. K.; Pasquini,
S.; Larhed, M. J. Org. Chem. 2007, 72, 6390.
Org. Lett., Vol. 13, No. 5, 2011
1127

and Et3N was carried out smoothly to afford the desired
(E)-4,40-(prop-1-ene-1,3-diyl)bis(methoxybenzene) (3) in
53% yield (entry 13). To our surprise, the bulky acetate
1e underwent the β-H elimination and deacetylation to
furnish the monoarylation product 15,6d not the β-OAc
elimination to the diarylation product 14 (entry 14). How-
ever, internal alkenes, (E)-but-2-enyl acetate (1f) or cinna-
myl acetate (1g), provided a mixture of products including
the β-OAc elimination monoarylated or diarylated pro-
ducts, β-H elimination products, and others (entries 15and
16). It was interesting to observe that the reaction between
cinnamyl acetate (1g) with iodide 2a could furnish the
target product 17 in 30% yield (entry 16).
Table 2. Palladium-Catalyzed Diarylation Reactions of Allylic
Esters (1) with Aryl Halides (2)a
Table 3. Applications in the Synthesis of Indoles and Benzo-
furansa
a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), Pd(OAc)2
(10 mol %), n-Bu4NCl (1.5 equiv), Et3N (8 equiv), and MeCN (2 mL)
at 120 °C under air. b Isolated yield. c Another monoarylation product
15, (E)-4-(4-methoxyphenyl)-2-methylbut-3-en-2-ol, was obtained in
98% yield.
to the target product 9 in 50% yield (entry 6). It was found
that some active functional groups, Cl, CH3CO, and CF3
groups, were tolerated well under the standard conditions
(entries 7-9). Notably, the reaction of heteroaryl iodide 2k
with acetate 1a was also successful in moderate yield (entry
10). The results showed that the standard conditions were
compatible with terminal alkenes 1b-e (entries 11-14),
but were less effective for internal alkenes 1f and 1g (entries
15 and 16). For example, the reaction of allyl ethyl car-
bonate (1d) with 4-iodoansole (2a), Pd(OAc)2, n-Bu4NCl,
a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), PdCl2 (10 mol %),
n-Bu4NCl (1.5 equiv), K2CO3 (2 equiv), and DMA (2 mL) at 100 °C
under air atmosphere. b Isolated yield.
To our delight, the present methodology could be
applied in indole and benzofuran preparation (Table 3).9,10
However, the above standard conditions were not effi-
cient for the reaction of allyl acetate (1a) with 2-iodo-N-
methylaniline (2l) (38% yield, Table S1 in the Supporting
Information). Screening revealed that the best results of
1128
Org. Lett., Vol. 13, No. 5, 2011

2-dimethyl-1H-indole (18) synthesis were obtained using the
PdCl2/K2CO3/DMA system (entry 1). In light of the above
results, a variety of 2-iodoanilines 2m-p and 2-halophenols
2q,r were examined to construct indoles and benzofurans
(entries 2-11). While N-(2-iodophenyl)acetamide (2m) and
2-iodoaniline (2n) displayed low activities for the reaction
with substrate 1a, PdCl2, n-Bu4NCl and K2CO3 (entries 2
and 3), N-methyl substrates 2o and 2p, bearing a Me or CF3
group on the aryl ring, were consistent with the optimized
conditions leading to good yields (entries 4 and 5). The other
allyl acetates 1d, 1e, 1f, and 1h were also successful for
constructing nitrogen-containing heterocyles in moderate
yields (entries 6-9). Notably, a six-membered ring product
23, 1,2,2-trimethyl-1,2-dihydroquinoline, was obtained from
the reaction between 2-methylbut-3-en-2-yl acetate (1e) and
2-iodo-N-methylaniline (2l) (entry 7). To our delight, both
2-iodophenol (2q ) and 2-bromophenol (2r) are also suitable
substrates, providing the desired benzofuran 26 in satisfac-
tory yields (entries 10 and 11).
Scheme 2. Controlled Experiments and Possible Mechanism
Three controlled experiments were carried out to under-
stand the mechanism (Scheme 2). Treatment of acetate 1a
with substrate 2s afforded an internal alkene 27 in 55%
yield under the standard conditions, and no cyclized
product was observed by GC-MS analysis (eq 1). (2-
Iodophenyl)methanol (2t) only gave the β-H elimination
product 28 by reacting with acetate 1a, PdCl2, n-Bu4NCl,
and K2CO3 (eq 2). Substrate 29 was also cyclized to furnish
the desired benzofuran 26 in 70% yield (eq 3).
catalyst to improve the reaction11 and (2) stability of
intermediate B to inhibit the β-hydride elimination.
In summary, a palladium-catalyzed tandem Heck pro-
tocol has been described for selectively synthesizing 1,3-
diaryl propenes in moderate to good yields. Importantly,
this protocol could be applied in indole and benzofuran
preparation. Work to extend the reaction in organic
synthesis is currently underway.
Therefore, a possible mechanism was proposed on the
basis of the present results and the reported mechanism
(Scheme 2).2-6 Insertion of Pd(0) into ArI yields ArP(II)I,
followed by addition of ArP(II)I to the CdC bond of allyl
acetate affords intermediate B. Reductive β-OAc elimina-
tion of intermediate B gives intermediate C or C0: (1) the
Heck reaction of intermediate C takes place leading to 1,3-
diaryl propenes and (2) intramolecular nucleophilic cycli-
zation of intermediate C0 provides indoles and benzofur-
ans. We deduce that two roles of n-Bu4NCl are played in
the reaction including: (1) the use as the phase-transfer
Acknowledgment. We thank the Program of Science
and Technology of Wenzhou (Nos. Y20090243 and
G20090080), National Natural Science Foundation of
China (Nos. 20872112 and 21002070), and Zhejiang Pro-
vincial Natural Science Foundation of China (Nos. Y407116
and Y4080169) for financial support.
Supporting Information Available. Analytical data and
spectra (1H and 13C NMR) for all the products and
typical procedure. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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