Tetrahedron Letters
A facile synthesis of 2-(3-alkynyl-2,3-dihydrobenzofuran-3-yl)acetate
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Fengbin Song , Michael D. Gaul, William V. Murray
Janssen Research & Development LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Welsh & McKean Roads, Spring House, PA 19477-0776, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of 2-(3-alkynyl-2,3-dihydrobenzofuran-3-yl)acetate (1a, 1b), with a unique alkynyl-
benzylic quaternary center on a dihydrobenzofuran ring, was accomplished. The key step of the synthesis
is the aryl radical cyclization to the tethered enyne carboxylate to generate the unique alkynyl-benzylic
quaternary center. The synthesis started from simple building blocks with high flexibility and
constructed the complex template in a total of four steps. With several functional groups available,
compounds of structure 1a and 1b could be easily further derivatized.
Received 25 June 2015
Revised 30 July 2015
Accepted 5 August 2015
Available online 8 August 2015
Keywords:
Facile synthesis
Ó 2015 Elsevier Ltd. All rights reserved.
Radical cyclization
Alkynyl-benzylic quaternary center
Introduction
Results and discussion
In the course of one of our drug discovery research programs,
compounds of the structure 2-(3-alkynyl-2,3-dihydrobenzofuran-
3-yl)acetate (1a, b) (Scheme 1) were required. The structure
Starting from 2-bromo-5-((tetrahydro-2H-pyran-2-yl)oxy)phe-
nol (5), alkylation with 3-bromoprop-1-yne gave the phenol
propargyl ether 6 in 80% yield (Scheme 2). The alkyne was
extended to the alkynoate 7 in 72% yield by quenching the acety-
lide carbanion with chloroformate. Next, the alkynoate 7 was sub-
jected to the palladium catalyzed 1,4-conjugated addition of
ethynyltrimethylsilane to afford the requisite enyne carboxylate
8. It was observed that with low catalyst loading (0.0075 equiv),
the reaction did not go to completion and gave a lower yield
(25%) of the desired product 8 in addition to the recovered starting
material. With higher catalyst loading (0.03–0.05 equiv), the reac-
tion provided the requisite enyne carboxylate 8 in 51% yield.
Further increase in catalyst loading (0.1 equiv) resulted in a lower
yield of 8 (39%), with compound 5 isolated as the byproduct.
Presumably compound 5 was formed via the palladium catalyzed
cleavage of the propargyl phenol ether6 or the allyl phenol ether.
With the enyne carboxylate 8 in hand, the stage was set for the
key cyclization reaction. The presence of an alkynyl functional
group in 8 caused some concerns at the beginning. Fortunately,
under the radical cyclization conditions reported by Parker with
slight modifications:1c heating at reflux a mixture of compound 8
and 2 equiv of Bu3SnH in benzene in presence of 0.5 equiv of
AIBN, compound 8 cyclized to give product 9 in 60% yield, plus
some uncharacterized byproducts. Even though the 1H NMR of
the crude reaction mixture was relatively clean, the isolated yield
features
a unique alkynyl-benzylic quaternary center on a
dihydrobenzofuran ring. Establishment of the alkynyl-benzylic
quaternary center presented a major synthetic challenge. We
surmised that an aryl radical cyclization approach, developed to
construct the b,b-disubstituted dihydrobenzofuran fragment of
alkaloids,1 could be explored to quickly assemble the alkynyl-
benzylic quaternary center. Retrosynthetically, compound 1 could
be synthesized from the requisite enyne carboxylic ester 2 by
the radical cyclization of the phenyl bromide to the tethered
a,b-unsaturated ester (Scheme 1). We noticed that the alkynyl
function group in compound 2 may also participate in the radical
induced cyclization to form an undesired 6-exo cyclized product,2
but we reasoned that the 5-exo Michael type cyclization to the
a,b-unsaturated ester moiety yielding the desired benzofuran ring
should prevail due to the electronic and the kinetic effects.3
Further retrosynthetically, we recognized that the requisite enyne
carboxylic ester 2 could be quickly accessed through the Trost
pioneered palladium catalyzed 1,4-conjugated addition of terminal
alkyne to alkynoate 3.4 Finally, compound 3 could be prepared
straightforwardly from the mono-protected 4-bromobenzene-1,
3-diol 4.5 Herein we report a facile synthesis of 2-(3-alkynyl-2,
3-dihydrobenzofuran-3-yl)acetate.
of
9 was only moderate. Nonetheless, the unique structure
template 2-(3-alkynyl-2,3-dihydrobenzofuran-3-yl)acetate was
assembled from simple building blocks in only four steps with
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