Palladium-catalyzed carbonylative reaction of 1-(2,2-Dibromovinyl)-2- alkenylbenzene and carbon monoxide, with phenol or alcohol

Article abstract of DOI:10.1021/ol202420j

A palladium-catalyzed carbonylative reaction of 1-(2,2-dibromovinyl)-2- alkenylbenzene and carbon monoxide, with phenol or alcohol, is reported, which affords 1-methylene-1H-indene-2-carboxylates in moderate to good yields. This cascade process, which inc

Full text of DOI:10.1021/ol202420j

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5980–5983
Palladium-Catalyzed Carbonylative
Reaction of 1-(2,2-Dibromovinyl)-2-
alkenylbenzene and Carbon Monoxide,
with Phenol or Alcohol
Shengqing Ye† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
jie_wu@fudan.edu.cn
Received September 7, 2011
ABSTRACT
A palladium-catalyzed carbonylative reaction of 1-(2,2-dibromovinyl)-2-alkenylbenzene and carbon monoxide, with phenol or alcohol, is reported,
which affords 1-methylene-1H-indene-2-carboxylates in moderate to good yields. This cascade process, which includes carbonylation and Heck
reaction, proceeds smoothly with good functional group tolerance and high selectivity.
Currently, palladium-catalyzed carbonylation reactions
have become a powerful device in synthetic organic
chemistry, which provide straightforward access to (hetero)-
aromatic carboxylic acid derivatives.1 The synthesis of
acids, amides, esters, ketones, and aldehydes has been well
established by using this method, starting from easily
available aryl halides.2 Recently, gem-dihaloolefins have
found broad applications in organic synthesis with good
stereoselectivity.3À5 For example, Lautens and co-workers
reported efficient pathways for the construction of carbo-
and heterocycles starting from gem-dihaloolefins.5 Wealso
† Fudan University.
‡ Chinese Academy of Sciences.
(1) For reviews on palladium-catalyzed carbonylations, see:
€
(a) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
€
2009, 48, 4114. (b) Brennfuhrer, A.; Neumann, H.; Beller, M. Chem-
CatChem 2009, 1, 28. (c) Barnard, C. F. J. Organometallics 2008, 27,
5402. (d) Beller, M. Carbonylation of Benzyl- and Aryl-X Compounds.
In Applied Homogeneous Catalysis with Organometallic Compounds, 2nd
ed.; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002; pp
€
ꢀ
145À156. (e) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6,
1097. (f) Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley: Chichester, 1995. (g) Colquhoun, H. M.; Thomp-
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Compounds; Plenum Press: New York, 1991.
(3) For reviews of gem-dihaloolefins, see: (a) Handbook of Organo-
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Chem. 2001, 21, 252.
(2) For selected examples of palladium-catalyzed carbonylations of
aryl halides, see: (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org.
Chem. 1974, 39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem.
1974, 39, 3327. (c) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974,
(4) For selected examples, see: (a) Zeng, X.; Qian, M.; Hu, Q.;
Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259. (b) Molander,
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9581 and references cited therein.
r
10.1021/ol202420j
Published on Web 10/20/2011
2011 American Chemical Society

used gem-dibromoolefins as substrates for the synthesis of
1-methyleneindenes through palladium-catalyzed tandem
reactions6 with arylboronic acids.4k,l
carbonylation tandem reaction of 1-(2,2-dibromovinyl)-2-
alkenylbenzene, carbon monoxide, and phenol or alcohol,
which affords 1-methylene-1H-indene-2-carboxylates. Al-
though several routes to the 1-methylene-1H-indene-2-
carboxylates were reported,9gÀi they usually suffered from
multiple steps, low yields, and high temperature. Addi-
tionally, the functional group tolerance is not satisfactory,
which limits its diversity-oriented synthesis.
Our proposed synthetic route is shown in Scheme 1,
which includes a cascade carbonylation and Heckreaction.
1-(2,2-Dibromovinyl)-2-alkenylbenzene 1 could be easily
accessed using a well-known method.4k We hypothesized
that, in this reaction process, an oxidative addition would
occur in the presence of Pd(0) to produce intermediate A.
Subsequently, a nucleophile (phenol or alcohol) and car-
bon monoxide were involved through a palladium-cata-
lyzed carbonylation reaction to afford compound B. Con-
currently the Pd(0) was released, which then underwent
oxidative addition of vinyl bromide B again to furnish
intermediate C. After intramolecular insertion and β-
hydrogen elimination, (Z)-1-methylene-1H-indene-2-car-
boxylate 3would be generated according to the Heck reaction
mechanism.11 In the meantime, the Pd(0) would re-enter
the catalytic cycle. We believed that this hypothesis was
feasible, although several competitive reactions seemed
inevitable.
Indene has been recognized as a privileged fragment, which
can be found in many natural products and drug can-
didates.7 Additionally, applications of indenes in materials
science have been discovered.8 So far, synthetic methodol-
ogies to this carbacycle (including 1-methyleneindene)
have been developed.9,10 Due to its importance, it is still
of high interest and great demand to develop novel
approaches for efficient generation of functionalized in-
denes, especially in the field of chemical biology. Prompted
by the achievement of palladium-catalyzed carbonylation
reactions and the versatility of gem-dihaloolefins, we con-
ceived that the combination of 1-(2,2-dibromovinyl)-
2-alkenylbenzene and carbon monoxide would provide a
novel and efficient pathway for the formation of indene
derivatives. Herein, we report a palladium-catalyzed
(5) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Yuen, J.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (c) Fayol, A.; Fang, Y.-
Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (d) Fang, Y.-Q.; Karisch, R.;
Lautens, M. J. Org. Chem. 2007, 72, 1341. (e) Nagamochi, M.; Fang, Y.-
Q.; Lautens, M. Org. Lett. 2007, 9, 2955. (f) Fang, Y.-Q.; Lautens, M. J.
Org. Chem. 2008, 73, 538. (g) Bryan, C. S.; Lautens, M. Org. Lett. 2008,
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2009, 48, 7064. (j) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M.
Chem. Commun. 2009, 5236. (k) Chai, D. I.; Lautens, M. J. Org. Chem.
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Int. Ed. 2004, 43, 3890. (b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.;
Liu, F. Chem. Rev. 1996, 96, 365. (c) Tietze, L. F. Chem. Rev. 1996, 96,
115. (d) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65.
(e) Miura, T.; Murakami, M. Chem. Commun. 2007, 217. (f) Malacria,
M. Chem. Rev. 1996, 96, 289. (g) Nicolaou, K. C.; Montagnon, T.;
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Scheme 1. Proposed Route for the Palladium-Catalyzed Car-
bonylative Reaction of 1-(2,2-Dibromovinyl)-2-alkenylben-
zene, Alcohol or Phenol, and Carbon Monoxide
€
Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(j) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
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man, D. C.; Scanlan, T. S. J. Med. Chem. 2005, 48, 5989. (b) Lautens, M.;
Marquardt, T. J. Org. Chem. 2004, 69, 4607. (c) Gao, H.; Katzenellen-
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Cava, M. P. J. Org. Chem. 2000, 65, 6739. (b) Barbera, J.; Rakitin, O. A.;
Ros, M. B.; Torroba, T. Angew. Chem., Int. Ed. 1998, 37, 296.
(c) Akbulut, U.; Khurshid, A.; Hacioglu, B.; Toppare, L. Polymer
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Larock, R. C. J. Org. Chem. 2007, 72, 251. (b) Xi, Z.; Guo, R.; Mito, S.;
Yan, H.; Kanno, K.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003,
68, 1252. (c) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 202. (d) Romines, K. R.; Lovasz, K. D.; Mizsak,
S. A.; Morris, J. K.; Seest, E. P.; Han, F.; Tulinsky, J.; Judge, T. M.;
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N.; Abu-Shqara, E. J. Org. Chem. 1994, 59, 6090.
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T.; Iinuma, M.; Fujii, S.; Tanaka, K.; Kan, T. Chem. Commun. 2006,
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T.; Marcos, C. F.; Miguel, D.; Barbera, J.; Ros, M. B.; de la Fuente,
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(f) Schmittel, M.; Vavilala, C. J. Org. Chem. 2005, 70, 4865. (g)
Schreiner, P. R.; Prall, M.; Lutz, V. Angew. Chem., Int. Ed. 2003, 42,
5757. (h) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun.
2009, 5406. (i) Gao, K.; Wu, J. Org. Lett. 2008, 10, 2251. (j) Qiu, G.;
Ding, Q.; Gao, K.; Peng, Y.; Wu, J. ACS Comb. Sci. 2011, 13, 13.
In an initial attempt, 1-(2,2-dibromovinyl)-2-alkenyl-
benzene 1a and n-butyl alcohol 2a were used as model
substrates for reaction development. At the outset, the
reaction was catalyzed by Pd(OAc)2 (5 mol %) and PPh3
(10 mol %) in the presence of K2CO3 (3.0 equiv) as a base
in toluene at 100 °C with a balloon of carbon monoxide
(Table 1, entry 1). However, only a trace amount of product
was observed. To our delight, the expected product 3aa
(50% yield) was formed when KHCO3 was employed as a
replacement of base in the reaction (Table 1, entry 2).
(11) Jutand, A. In The MizorokiÀHeck Reaction; Oestreich, M., Ed.;
John Wiley and Sons: Hoboken, NJ, 2009; p 1.
Org. Lett., Vol. 13, No. 22, 2011
5981

Other bases such as KOAc, K3PO4, and iPr2NEt were not
effective in the transformation (Table 1, entries 3À5). The
yields could not be improved when other ligands were
screened (Table 1, entries 6À9). The palladium source was
examined subsequently, which showed that the acetate
anion was crucial for the successful conversion (Table 1,
entries 10À15). Solvent effect was then explored, and no
better results were obtained (Table 1, entries 16À18). The
same outcome was obtained when the reaction was per-
formed at 90 °C (Table 1, entry 19). The yield was de-
creased when the reaction occurred at 70 °C (12% yield,
Table 1, entry 20). The reaction was retarded when a
catalytic amount of palladium acetate was reduced to
2.5 mol % (Table 1, entry 21). No improvement was ob-
served when the amount of palladium catalyst was increased
to 10 mol % (Table 1, entry 22).
Table 2. Palladium-Catalyzed Carbonylative Reaction of
1-(2,2-Dibromovinyl)-2-alkenylbenzene 1a, Alcohol or Phenol 2,
and Carbon Monoxide
Table 1. Initial Studies for the Palladium-Catalyzed Reaction of
1-(2,2-Dibromovinyl)-2-alkenylbenzene 1a, n-Butyl Alcohol 2a,
and Carbon Monoxide
yield
entry
[Pd]
ligand
base
solvent
(%)a
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
DPPF
DPPP
S-Phos
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
trace
50
2
KHCO3
KOAc
3
trace
trace
nr
4
K3PO4
5
iPr2NEt
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
6
30
7
26
8
24
9
20
10
11b
12
13b
14
15b
16
17
18
19c
20d
21c,e
22c,f
nr
24
nr
33
nr
33
trace
nr
DMSO
toluene
toluene
toluene
toluene
nr
50
12
trace
40
a Isolated yield based on 1-(2,2-dibromovinyl)-2-alkenylbenzene 1a.
˚
Molecular sieves (4 A) were added for the reactions of phenols.
a Isolated yield based on 1-(2,2-dibromovinyl)-2-alkenylbenzene 1a.
b In the presence of 10 mol % of AgOAc. c The reaction was performed at
90 °C. d The reaction was performed at 70 °C. e In the presence of 2.5 mol
% of Pd(OAc)2 and 5 mol % of PPh3. f In the presence of 10 mol % of
Pd(OAc)2 and 20 mol % of PPh3.
Tables 2 and 3. Various alcohols and phenols were exam-
ined for the reaction of 1-(2,2-dibromovinyl)-2-alkenyl-
benzene 1a with carbon monoxide. All reactions worked
well to give the desired product 3 in moderate to good
yields. For instance, when 2-phenylethanol 2b was used as
a nucleophile, the corresponding indene 3ab was afforded
in 46% yield (Table 2, entry 2). The conditions could be
Under the optimized conditions [Pd(OAc)2 (5 mol %),
PPh3 (10 mol %), KHCO3 (3.0 equiv), toluene, 90 °C], we
investigated the scope of this palladium-catalyzed carbo-
nylation tandem reaction. The results are summarized in
5982
Org. Lett., Vol. 13, No. 22, 2011

various phenols were conducted under the standard con-
ditions. However, the yields were very low. We finally
˚
realized that the results could be improved after adding 4 A
Table 3. Palladium-Catalyzed Carbonylative Reaction of
1-(2,2-Dibromovinyl)-2-alkenylbenzene 1, Phenol 2e, and Car-
bon Monoxide
molecular sieves, which was not effective for the reaction of
alcohols. Thus, reaction of 1-(2,2-dibromovinyl)-2-alke-
nylbenzene 1a, 3- methylphenol 2e, and carbon monoxide
led to the desired product 3ae in 67% yield (Table 2, entry
5). Reaction of 2-methylphenol 2f showed similar reactiv-
ity (64% yield, Table 2, entry 6). 1-(2,2-Dibromovinyl)-
2-alkenylbenzene 1a reacted with 4-methoxyphenol 2g in the
presence of carbon monoxide, leading to the correspond-
ing product 3ag in 75% yield (Table 2, entry 7). Lower
yields were generated when benzo[d][1,3]dioxol-5-ol 2h,
4-phenylphenol 2i, 4-benzoxyphenol 2j, or 2-naphthalenol
2k was employed in the reaction (Table 2, entries 8À11).
Noticeably, phenols with chloro, nitro, ester, ketone, cyano,
and fluoro groups attached on the aromatic ring were all
compatible under the standard conditions (Table 2, entries
12À18).
Next, investigations with various 1-(2,2-dibromovinyl)-
2-alkenylbenzenes 1 were conducted in the reaction of
3-methylphenol 2e with carbon monoxide under the opti-
mized conditions (Table 3). Compound 1b displayed good
reactivity during the transformation (Table 3, entry 1).
Different functional groups in the aromatic ring of 1-(2,2-
dibromovinyl)-2-alkenylbenzenes 1 were all tolerated when
an ester group was located at the R2 position (Table 3,
entries 3À7). When R2 is a cyano group, the corresponding
product 3ie was generated in 40% yield (Table 3, entry 8).
However, only a trace amount of product was observed
when the R2 position was replaced by a ketone or phenyl
group (Table 3, entries 9 and 10). It is noteworthy that
thiophenyl incorporated substrate 1l was a good reactant
as well in this palladium-catalyzed carbonylation cascade
reaction, although the yield is low (30% yield, Table 3,
entry 11).
In conclusion, we have described a novel and efficient
approach for the synthesis of 1-methylene-1H-indene-2-
carboxylates via a palladium-catalyzed carbonylation cas-
cade reaction of 1-(2,2-dibromovinyl)-2-alkenylbenzene,
carbon monoxide, and phenol or alcohol. This cascade
process, which includes carbonylation and a Heck reac-
tion, proceeds smoothly with good functional group tol-
erance and high selectivity. Currently, application of gem-
dihaloolefins in other tandem processes is under investigation
in our laboratory, and the results will be reported in due
course.
Acknowledgment. Financial support from National
Natural Science Foundation of China (Nos. 21032007
and 21172038) is gratefully acknowledged.
a Isolated yield based on 1-(2,2-dibromovinyl)-2-alkenylbenzene 1.
applicable to the reaction of benzyl alcohol 2c or 2,2,2-
trifluoroethanol 2d as well, which gave rise to the expected
product 3ac or 3ad in 50% and 40% yield, respectively
(Table 2, entries 3 and 4). Further investigations with
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 22, 2011
5983