Double Heck reaction of bridged o,o′-dibromobiaryls with ethyl acrylate

Article abstract of DOI:10.1016/S0040-4039(02)02090-7

An inter- followed by an intramolecular double Heck reaction of bridged o,o′-dibromobiaryls with ethyl acrylate is described. The nature of the bridging atom/group determined the outcome of the reaction. This double Heck reaction strategy afforded a safe and convenient synthesis of 9-(ethoxycarbonylmethylene)-9H-xanthene and a novel route to 9 and/or 10-substituted anthracene derivatives.

Full text of DOI:10.1016/S0040-4039(02)02090-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8559–8562
Double Heck reaction of bridged o,o%-dibromobiaryls with
ethyl acrylate
Mahavir Prashad,* Yugang Liu, Xiao Yin Mak,† Denis Har, Oljan Repicˇ and Thomas J. Blacklock
Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research,
One Health Plaza, East Hanover, NJ 07936, USA
Received 22 July 2002; accepted 17 September 2002
Abstract—An inter- followed by an intramolecular double Heck reaction of bridged o,o%-dibromobiaryls with ethyl acrylate is
described. The nature of the bridging atom/group determined the outcome of the reaction. This double Heck reaction strategy
afforded a safe and convenient synthesis of 9-(ethoxycarbonylmethylene)-9H-xanthene and a novel route to 9 and/or 10-substi-
tuted anthracene derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
9-(Ethoxycarbonylmethylene)-9H-xanthene (1) serves
as an important intermediate in the synthesis of biolog-
ically important molecules. Preparation of 1 by a reac-
tion of 9H-xanthene-9-thione with ethyl diazoacetate at
60°C was reported in 51% yield.1 The known explosive
nature of ethyl diazoacetate at elevated temperature
presented safety concerns and made this method
impractical for a large scale. Thus, our goal was to
develop a safer synthesis of 1. Another look at the
structure of 1 revealed a new approach to this molecule
that involved an inter- followed by an intramolecular
Heck reaction of 2-bromophenyl ether (2a) with ethyl
acrylate (Scheme 1).
reaction conditions had to be used for the intramolecu-
lar Heck reaction. We reasoned that two consecutive
Heck reactions, inter- followed by intramolecular,
could be carried out in one-pot under the same reaction
conditions. This paper describes our results on this
approach.
It is well known that the Heck reaction often requires
specific conditions for different substrates.4 Thus, we
investigated this reaction under a variety of conditions,
and the results are listed in Table 1. The reaction of
2-bromophenyl ether (2a) with ethyl acrylate under
standard Heck reaction conditions using palladium ace-
tate, triphenylphosphine, and triethylamine in refluxing
acetonitrile (entry 1, Table 1), disappointingly, gave no
desired product 1. Interestingly, eliminating the phos-
phine ligand and changing the solvent to 1-methyl-2-
pyrrolidinone (NMP), the reaction of 2a with ethyl
acrylate in the presence of triethylamine (5 equiv.) and
tetra-n-butyl ammonium bromide (1 equiv.) afforded a
mixture of the desired product 1 and its reduced deriva-
We had previously reported an intermolecular double
Heck reaction with cyclopentene.2 A domino process
involving an inter- followed by an intramolecular Heck
reaction between (Z)-(2-bromoethenyl)bromobenzene
and
a
hexahydro-1H-indene derivative is also
reported.3 However, the intermediate of the intermolec-
ular Heck reaction had to be isolated and different
Scheme 1.
* Corresponding author. E-mail: mahavir.prashad@pharma.novartis.com
† Undergraduate Summer Intern (2002) from the University of Rochester, NY.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02090-7

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M. Prashad et al. / Tetrahedron Letters 43 (2002) 8559–8562
Table 1. Double Heck reaction of 2-bromophenyl ether (2a) with ethyl acrylate (1.2 equiv.)10
tive 3 in a 7.2:2.8 ratio (entry 2), from which 1 was
isolated in 42% yield. The formation of the reduced
product 3 was unusual in that such a reduction has not
been previously reported in the Heck reaction. Allow-
ing the reaction to proceed for a longer period did not
increase the formation of 3. Also, pure 1 did not
undergo reduction when it was subjected to identical
conditions. Suspecting that triethylamine may be the
cause of the formation of reduced product 3, we
decided to change the base to well-known bases for this
reaction: potassium acetate or sodium acetate. The
desired product 1 was obtained in 67% yield with
potassium acetate as the base (entry 3) and in 76% yield
with sodium acetate (entry 4). The reduced by-product
3 was formed in only trace amounts in both cases.
Surprisingly, the use of DMF as the solvent (entry 5)
gave a complicated mixture, suggesting that NMP is the
best solvent for this reaction. Use of Herrmann’s pal-
ladacycle trans-di(m-acetato)bis[o-(di-o-tolylphophino)-
benzyl]dipalladium(II)5 afforded 1 in 65% yield. Thus,
the best conditions for an inter- followed by
intramolecular double Heck reaction of 2a with ethyl
acrylate involved palladium acetate, sodium acetate in
the presence of tetra-n-butylammonium bromide in
NMP at 120°C (entry 4).
Such a reduction of aryl halides, as the formation of 5,
has been reported in the literature.6 When the linker
was an ethylene group, as in dibromo compound 2c,
the desired product 6 was produced in only 49% yield
(entry 2). A by-product 7 was generated in significant
amounts by a double intermolecular Heck reaction. In
this case, however, use of Herrmann’s palladacycle
afforded the desired 6 in higher yield (71%, entry 3).
Interestingly, the reaction of 2d and 2e, with
methoxymethylene and methylene groups as linkers,
afforded anthracene derivatives 8 and 9, respectively
(entries 4 and 5) in excellent yields, representing a novel
route to this class of compounds. The expected double
Heck reaction product (A) aromatized spontaneously to
the anthracene skeleton (Scheme 2). This novel method
would allow an easy access to 9 and/or 10-substituted
anthracene derivatives.
No double Heck reaction was observed when the linker
was an N-methyl (2f)7 or a carbonyl group (2g).8
Instead, the dibromides underwent an intramolecular
homocoupling reaction to afford compounds 10 and 11,
respectively (entries 6 and 7), in excellent yields. Palla-
dium-catalyzed intermolecular homocoupling of aryl
halides has been reported.9
To test the general synthetic utility, we next studied the
double Heck reaction of a variety of bridged o,o%-
dibromo biaryls (2b–2g) with ethyl acrylate. The results
are summarized in Table 2. Reaction of 2,2%-dibromo-
biphenyl 2b with ethyl acrylate (entry 1) under the
above established conditions for 2a afforded a 8.7:1.3
mixture of the desired double Heck product 4 and the
acyclic debrominated Heck product 5. The desired
product 4 was isolated in 71% yield from this mixture.
Thus, the nature of the bridging atom/group in o,o%-
dibromobiaryls (2a–2g) determined the outcome of the
Heck reaction. The inter- followed by an intramolecular
double Heck reaction was favored when the bridge was
a hydrocarbon chain, an oxygen atom, or no bridging
atom; the intramolecular homocoupling of the substrate
was favored when the bridge was a carbonyl or an
N-methyl group.

M. Prashad et al. / Tetrahedron Letters 43 (2002) 8559–8562
Table 2. Double Heck reaction of bridged o,o%-dibromobiaryls10
8561
Scheme 2.
In summary, an inter- followed by an intramolecular
double Heck reaction of bridged o,o%-dibromobiaryls
with ethyl acrylate is described. The nature of the
bridging atom/group determined the outcome of the
reaction. This double Heck reaction strategy afforded a
safe and convenient synthesis of 9-(ethoxycarbonyl-
methylene)-9H-xanthene and a novel route to 9 and/or
10-substituted anthracene derivatives.

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M. Prashad et al. / Tetrahedron Letters 43 (2002) 8559–8562
mg, 1.83 mmol) and 1-methyl-2-pyrrolidinone (5 mL) was
Acknowledgements
flushed with nitrogen for 15 s, and the mixture was
heated to 140°C over a period of 20 min. The reaction
mixture was stirred at this temperature for an additional
12 h, cooled to 25°C, and t-butyl methyl ether (10 mL)
was added. The mixture was washed with water (10 mL),
and the organic layer was concentrated under reduced
pressure to afford a residue which was purified by silica
gel chromatography using heptane/EtOAc (20:1 to 5:1) as
the eluant to furnish the desired product 1 (310 mg, 76%
yield). The exact conditions for other substrates (2b–2g)
are listed in Table 2, but the procedure was essentially the
same.
We thank Dr. Bin Hu for a helpful discussion.
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1
Data for selected compounds: 1: H NMR (CDCl3, 300
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J=8.0 Hz, 1.5 Hz), 7.43–7.33 (m, 2H), 7.23–7.15 (m, 4H),
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(MH+). 6: H NMR (CDCl3, 300 MHz): l 7.30–6.97 (m,
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1
14.6; MS (ESI): m/z 279.0 (MH+). 8: H NMR (CDCl3,
300 MHz): l 8.36–8.26 (m, 4H), 7.56–7.46 (m, 4H), 4.56
(s, 2H), 4.12 (q, 2H, J=7.2 Hz), 4.11 (s, 3H), 1.19 (t, 3H,
J=7.2 Hz); 13C NMR (CDCl3, 75 MHz): l 171.5, 152.4,
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(CDCl3, 300 MHz): l 8.37 (s, 1H), 8.28–8.25 (m, 2H),
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1
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10. Typical procedure: A mixture of o-bromophenyl ether
(500 mg, 1.52 mmol), Pd(OAc)2 (8.6 mg, 0.038 mmol),
tetrabutylammonium bromide (491 mg, 1.52 mmol),
sodium acetate (625 mg, 7.62 mmol), ethyl acrylate (183