A rapid synthesis of 2-aryl-5-substituted-2,3-dihydrobenzofurans

Article abstract of DOI:10.1021/jo0500941

(Chemical Equation Presented) An effective strategy has been developed for the rapid and efficient one-pot synthesis of 2-aryl-5-substituted-2,3- dihydrobenzofurans from readily available o-nitrotoluenes and aromatic aldehydes. This strategy allows access to a structurally diverse array of products for further manipulation.

Full text of DOI:10.1021/jo0500941

SCHEME 1
A Rapid Synthesis of
2-Aryl-5-substituted-2,3-dihydrobenzofurans
Jeffrey T. Kuethe,* Audrey Wong, Michel Journet, and
Ian W. Davies
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
Received January 17, 2005
an equimolar amount of TBAF, the 5-cyano-2,3-dihydro-
2-phenylbenzofuran 2 was obtained in 70% yield (Scheme
1).11 In connection with our ongoing programs involving
the reactions of o-trimethylsilylmethylnitrobenzenes,12
we began to investigate the Bartoli methodology in
greater detail. On the basis of our own observations, it
was apparent that tetrabutylammonium fluoride (TBAF)
An effective strategy has been developed for the rapid and
efficient one-pot synthesis of 2-aryl-5-substituted-2,3-dihy-
drobenzofurans from readily available o-nitrotoluenes and
aromatic aldehydes. This strategy allows access to a struc-
turally diverse array of products for further manipulation.
The 2,3-dihydrobenzofuran ring system constitutes the
core skeleton of an increasing number of neolignan
natural products that have been identified possessing a
range of biological activity.1 In addition, 2,3-dihydroben-
zofurans have been developed for the treatment of
traumatic and ischemic central nervous system (CNS)
injury,2 and are reported to be useful in the treatment
of arteriosclerosis, hepatopathy, and cerebrovascular
disease.3 Common approaches to the 2,3-dihydrobenzo-
furan ring system involve biomimetic couplings of quino-
nes and phenylpropenyl moieties,4 anionic,5 benzyne,6
dehydrative,7 electrocyclic,8 radical,9 and transition metal-
mediated10 cyclizations. To fully define biological profiles,
strategies which provide rapid access to highly function-
alized 2,3-dihydrobenzofurans not accessible through
current techniques are important synthetic tools. Our
general approach to the 2,3-dihydrobenzofuran ring
system was guided by the work of Bartoli, who investi-
gated the reaction of 4-cyano-1-nitro-2-[(trimethylsilyl)-
methyl]benzene 1 with benzaldehyde. In the presence of
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10.1021/jo0500941 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/24/2005
J. Org. Chem. 2005, 70, 3727-3729
3727

SCHEME 2
might be basic enough to promote the direct formation
of the expected tetrabutylammonium alkoxide intermedi-
ate 3 from unfunctionalized o-nitrotoluenes 4. The direct
use of simple and often commercially available o-nitro-
toluenes for the preparation of highly functionalized 2,3-
dihydrobenzofurans of type 5 would greatly simplify the
Bartoli two-step sequence and promote wider application
in the synthesis of dihydrobenzofurans. In this Note, we
document the realization of this approach with a practi-
cal, high-yielding, one-pot procedure for the preparation
of 2-aryl-5-substituted-2,3-dihydrobenzofurans.
Investigations began with trimethylsilymethylnitroben-
zene 6.13 Reaction of a mixture of 6 and aldehyde 714 with
a catalytic amount of TBAF afforded the expected alcohol
8 in 79% yield together with a trace amount of dihy-
drobenzofuran 9 (Scheme 2).15 Treatment of alcohol 8
with TBAF (1.5 equiv) at room temperature gave a
mixture of aldehyde 7 (20%), dihydrobenzofuran 9 (40%),
and nitrotoluene 11 (20%). This product distribution
suggested that a reversible carbonyl addition process may
be occurring leading to the possibility that reaction of
nitrotoluene 11 with 7 in the presence of TBAF may
provide 9 directly. In a simple validation of this hypoth-
esis, reaction of 11 and 7 with 1.5 equiv of TBAF in
refluxing THF for 3 h furnished 9 in 57% yield. However,
when the reaction was conducted in the presence of 2
equiv of Hu¨nig’s base, which effectively removed the
liberated HF from the reaction mixture, the yield of 10
increased to 69%. The major byproduct observed was
hydrolysis of the methyl ester of 11 to give the corre-
sponding benzoic acid.16 There was no significant amount
of ester hydrolysis of 9 observed under the reaction
conditions even after prolonged reaction times. Reaction
of 3-methyl-4-nitrobenzonitrile 12 with aldehyde 7 fur-
nished dihydrobenzofuran 10 in 81% yield. The overall
sequence was general and gave access to a structurally
diverse array of substituted 2,3-dihydrobenzofurans in
good to excellent yields in a one-pot operation from
commercially available nitrotoluenes 11 and 12 (Table
1). Other bases and conditions were also examined. For
example, reaction of 12 with aldehyde 33 in the presence
of benzyltrimethylammonium hydroxide (Triton B)17 gave
34 in similar yield and reaction profile as when TBAF
was employed (Table 1, entry 12). While reaction of 12
and 33 in the presence of NaOMe in DMSO18-20 furnished
34 in low yield (<60%), cyclization of the alcohol inter-
mediate remained incomplete and the formation of
numerous byproducts was observed. The use of Hu¨nig’s
base, CsCO3/MeOH,21 NaOMe, or KOt-Bu in refluxing
THF, NH4OH, Bu4NCl, and DBU/DMSO resulted in no
reaction (CsCO3/MeOH, NH4OH, and Hu¨nig’s base),
formation of multiple reaction products (NaOMe or KOt-
Bu in refluxing THF), or stalling at the alcohol interme-
(16) Reaction of 11 under the reaction conditions (1.5 equiv of TBAF,
THF, reflux) in the absence of any aldehyde gave nearly quantitative
conversion to 3-methyl-4-nitrobenzoic acid.
(17) For the reaction of nitrotoluenes with aldehydes in the presence
of Triton B, see: Tsuji, Y.; Kotachi, S.; Huh, K.-T.; Watanabe, Y. J.
Org. Chem. 1990, 55, 580.
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of NaOMe/DMSO, see: (a) Bakke, J. Acta Chem. Scand. 1967, 21, 1967.
(b) Izumi, T.; Yokota, T. J. Heterocycl. Chem. 1992, 29, 1085.
(19) For the reaction of nitrotoluenes with aldehydes in the presence
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Lett. 1997, 38, 4033. (b) Williams, R. M.; Rollins, S. B.; Judd, T. C.
Tetrahedron 2000, 56, 521. (c) Judd, T. C.; Williams, R. M. Org. Lett.
2002, 4, 3711.
(12) (a) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5,
3721. (b) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3975.
(c) Wong, A.; Kuethe, J. T.; Davies, I. W.; Hughes, D. L. J. Org. Chem.
2004, 69, 7761.
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1986, 51, 3694.
(14) Wai, J. S.; Williams, T. M.; Bamberger, D. L.; Fisher, T. E.;
Hoffman, J. M.; Hudcosky, R. J.; MacTough, S. C.; Rooney, C. S.; Saari,
W. S.; Thomas, C. M.; Goldman, M. E.; O’Brien, J. A.; Emini, E. A.;
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Chem. 1993, 36, 249.
(15) 2,4,6-Trinitrotoluene (TNT) has been reported to undergo a
stepwise conversion to 2,3-dihydrobenzofurans, see: Rozhkov, V. V.;
Kuvshinov, A. M.; Shevelev, S. A. Synth. Commun. 2002, 32, 1465.
(20) For the reaction of a nitrotoluene with formaldehyde in the
presence of KOH/DMSO, see: Yasuda, N.; Williams, R. M. Tetrahedron
Lett. 1989, 30, 3397.
(21) Masubuchi, K.; Taniguchi, M.; Umeda, I.; Hattori, K.; Suda,
H.; Kohchi, Y.; Isshiki, Y.; Sakai, T.; Kohchi, M.; Shirai, M.; Okabe,
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2000, 10, 1459.
3728 J. Org. Chem., Vol. 70, No. 9, 2005

TABLE 1. Preparation of 2,3-Dihydrobenzofurans
SCHEME 3
A range of electron-withdrawing substituents in the
4-position of the nitrotoluene ring was examined (Scheme
3). For example, reaction of nitrotoluene 35 with aldehyde
14 furnished 36 in 47% yield.22 In similar fashion, the
trifluoromethyl-substituted nitrotoluene 3723 gave dihy-
drobenzofuran 38 in 33% unoptimized yield when allowed
to react with aldehyde 33.24 While the reaction of nitro-
toluenes 11 or 12 with aldehydes and ketones bearing
acidic protons only resulted in enolization,11 reaction of
12 with 2,2,2-trifluoroacetophenone 40 gave the interest-
ing trifluoromethylated derivative 41 in 97% isolated
yield. Reaction of 39 with 40 under the identical reaction
conditions gave 42 in 86%, which also demonstrates that
the reaction proceeds with amides in the 4-position of the
nitrotoluene ring.
In conclusion, we have outlined an efficient one-pot
procedure for the preparation of highly functionalized
2-aryl-5-substituted-2,3-dihydrobenzofurans from readily
available o-nitrotoluenes. The dihydrobenzofuran prod-
ucts may serve as a platform for further manipulation
leading to structurally unique benzofurans and other
pharmaceutically intriguing compounds. In addition,
there may be multiple applications to parallel and
diversity oriented syntheses.
Acknowledgment. We thank Dr. Jacqueline Smitro-
vich and Mr. Jimmy Qu of Merck & Co., Inc. for helpful
experimental assistance.
Supporting Information Available: Experimental de-
tails and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0500941
(22) Unidentified reaction byproducts, most likely arrising from
deprotonation of the methyl sulfone, account for the mass balance.
(23) Zumstein sen, F.; Assmann, E.; Koenigsferger, R.; Holzbauer,
R.; Zumstein jun, F. German Patent DE2750170, 1978.
(24) Significant amounts of starting materials, in addition to some
decomposition, account for the mass balance.
diate to give incomplete conversion to dihydrobenzofuran
products (Bu4NCl and DBU/DMSO).
J. Org. Chem, Vol. 70, No. 9, 2005 3729