Synthesis of Benzofuran Derivatives on Solid Support via SmI2-Mediated Radical Cyclization

Full text of DOI:10.1021/jo970913k

5678
J . Org. Chem. 1997, 62, 5678-5679
Sch em e 1
Syn th esis of Ben zofu r a n Der iva tives on
Solid Su p p or t via Sm I2-Med ia ted Ra d ica l
Cycliza tion
Xiaohui Du and Robert W. Armstrong*
Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095
Received May 23, 1997
Recently, progress in combinatorial library synthesis
has focused on scope and limitations of reactions on solid
support.1 Few studies have been directed toward radical
reactions on solid support,2 although they have emerged
as a powerful synthetic strategy in solution in the past
decade.3 Balasubramanian et al. reported a study on
tributyltin hydride mediated radical cyclization on solid
support to generate benzofuran and furan rings.4 Herein,
we wish to report an alternative synthesis of various
benzofuran derivatives through SmI2-mediated5 aryl
radical cyclizations on solid support.6,7 The cyclization
is mild, rapid, and easy to carry out at room temperature.
It thus offers an advantage over the harsher conditions
used in tributyltin hydride-mediated synthesis of ben-
zofuran derivatives in which heating to 80-100 °C for
several hours to overnight is usually needed.4,8
followed by TFA cleavage generated products 5a -j (Table
1). The coupling between 3 and 4 generally went very
well as TFA cleavage of 4a , 4h , and 4i showed clean
conversion of the phenol to the corresponding allylic
ethers as the only products. For compounds 4c, 4e, and
4g, TFA cleavage yielded only the starting phenol due
to the sensitivity of the electron-rich ethers toward TFA.
However, the coupling proceeded well for 4b-e as
evidenced by the efficiency of the subsequent SmI2-
mediated cyclization. In fact, the NMR spectra of the
crude products show the predominance of the cyclized
products with a small percentage of the reduced prod-
ucts.12 This coupling method serves as an excellent
alternative to existing aryl ether formation reactions on
solid support.1c
After Rink resin 1 was coupled to acid 29 (Scheme 1),
the acetate group of the resin-bound 2 could be cleanly
deprotected by NaOMe in 1 M MeOH/THF solution.
Phenol 3 is readily coupled to a variety of allyl halides
by using the Schwesinger base10 P1-t-Bu to generate 4.
Subsequent cyclization of 4a -j by SmI2 and HMPA11
The reactions are run without any special precautions
(i.e. solvent degassing, reagent preparations) since the
oxygen in the solvent can be consumed by the excess
equivalents of SmI2 and are thus readily adaptable to
parallel synthesis. A typical procedure for the cyclization
of 4 is as follows: A flask with resin-bound 4 and stirrer
is dried under high vaccuum at 55 °C for 1-2 h. HMPA
(40 equiv) is first added followed by 0.1 M SmI2 solution
in THF13 (10 equiv). The resulting mixture is stirred for
1 h at room temperature. The resin is then filtered,
washed with methanol, THF, and CH2Cl2, before it is
cleaved with 20% TFA in CH2Cl2.
(1) For reviews, see: (a) Chem. Rev. 1997, 97, whole issue of No. 2,
pp 347-510. (b) Fruchtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17-42. (c) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996,
96, 555-600. (d) Acc. Chem. Res. 1996, 29, whole issue of No. 3, pp
112-170.
(2) For reduction of halide to alkyl, see: Worster, P. M.; McArthur,
C. R.; Leznoff, C. C. Angew. Chem., Int. Ed. Engl. 1979, 18, 221-222.
For addition of thiol radical to olefin, see (a) Gasparrini, F.; Misiti, D.;
Villani, C.; Borchardt, A.; Burger, M. T.; Still, W. C. J . Org. Chem.,
1995, 60, 4314-4315. (b) Hodge, P.; Khoshdel, E.; Waterhouse, J .;
Frechet, J . M. J . J . Chem. Soc., Perkin Trans. 1 1985, 2327-2331.
(3) For reviews in radical reactions in organic synthesis, see: (a)
Malacria, M. Chem. Rev. 1996, 96, 289-306. (b) Iqbal, J .; Bhatia, B.;
Nayyar, N. K. Chem. Rev. 1994, 94, 519-564. (c) J asperse, C. P.;
Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286. (d) Curran,
D. P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds. Pergamon: Oxford, 1991; Vol. 4, pp 715-831. (e) Curran, D. P.
Synthesis 1988, 417-439, and 489-513.
As the coupling between phenol 3 and various halides
generally is very clean as mentioned above, the combined
yield reported in Table 1 should reflect generally the
cyclization step. Several trends are apparent from the
table. Cyclizations with a substituent group at the
terminal alkene carbon are higher yielding than ex-
amples with substitution at the internal alkene carbon.
(b-f vs h -i). Aryl substituents react with excellent yield
and without any radical disproportionation products (b
and c). Methyl substitution (d ) at the terminal position
results in about 11% radical disproportionation product
which increases to 30% in the dimethyl case (e). The
benzofuran derivatives could be functionalized (f, j, and
i) and a fused heteroaromatic system could be generated
(g). However, when COOEt is substituted at the alkene
terminal carbon, there is no cyclization. The electron
from SmI2 might be transferred to the enoate14 because
(4) Routledge, A.; Abell, C.; Balasubramanian, S. Synlett 1997, 61-
62.
(5) For a recent review on SmI2-mediated reactions, see: Molander,
G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-338.
(6) For synthesis of indole and benzofuran analogs on solid support
via Pd-mediated Heck reaction, see: (a) Yun, W.; Mohan, R. Tetrahe-
dron Lett. 1996, 37, 7189-7192. (b) Zhang, H.; Maryanoff, B. E. J .
Org. Chem. 1997, 62, 1804-1809.
(7) For solution studies of SmI2-mediated cyclization to generate
benzofuran derivatives, see: (a) Inanaga, J .; Ujikawa, O.; Yamaguchi,
M. Tetrahedron Lett. 1991, 32, 1737-1740. (b) Molander, G. A.;
Harring, L. S. J . Org. Chem. 1990, 55, 6171-6176. (c) Curran, D. P.;
Totleben, M. J . J . Am. Chem. Soc. 1992, 114, 6050-6058.
(8) For studies of solution radical cyclizations on related systems
using tributyltin hydride, see: (a) Shankaran, K.; Sloan, C. P.;
Snieckus, V. Tetrahedron Lett. 1985, 26, 6001-6004. (b) Parker, K.
A.; Spero, D. M.; Inman, K. C. Tetrahedron Lett. 1986, 27, 2833-2836.
(c) Abeywickrema, A. N.; Beckwith, A. L. J .; Gerba, S. J . Org. Chem.
1987, 52, 4072-4078.
(9) Compound 2 was synthesized from 4-hydroxy-3-iodo-5-methoxy-
benzaldehyde in 98% yield as follows: (a) CH3COCl, Et3N, CH2Cl2;
(b) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, THF.
(10) (a) O’Donnell, M. J .; Zhou, C.; Scott, W. L. J . Am. Chem. Soc.
1996, 118, 6070-6071. (b) Schwesinger, R.; Willaredt, J .; Schlemper,
H.; Keller, M.; Schmidt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435-
2454.
(12) Due to the sensitivity of reduced products toward TFA, they
are cleaved into their phenol derivatives during removal from resin.
(11) HMPA is essential for the reaction on solid support.
(13) Used as supplied by commercial sources.
S0022-3263(97)00913-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 17, 1997 5679
Ta ble 1: Sm I2-Med ia ted Cycliza tion s of Resin -Bou n d
4a -j, Givin g 5a -j. Th e Yield s Rep or ted in Th is Ta ble
Ar e th e Com bin ed Yield s for Solid -Su p p or ted Syn th esis
of 5a -j Ba sed on th e In itia l Loa d in g of Rin k Resin 1 a s
Sh ow n in Sch em e 1
F igu r e 1. D2O quenching experiments.
the alkoxy substituent lowers its reduction potential and
the aryl ether is reductively cleaved as a result. Similar
observations have been reported by Zhou and Bennett
in attempts to cyclize alkyl iodides onto enoates.15
Reduction of the aryl iodide 4 is a minor side reaction
except in i, where it is the predominant reaction.
The cyclization works equally well when switching to
polyethylene glycol grafted resin.16 Gel phase NMR17
analysis of the cyclization of 4a in the presence of t-BuOH
indicated excellent conversion to 5a . One advantage of
this resin is that it swells well in aqueous solvents. As
a result, the Sm3+ impurities in the beads can be washed
away by saturated NaHCO3 solution which is more
difficult for ungrafted polystyrene resins.
Consistent with literature,2c cyclization of o-crotyl
2-iodophenol 6 with D2O added prior to SmI2 generated
the cyclized product 7 with 79% deuterium incorporation
without radical disproportionation (Figure 1). We then
investigated the relatively high degree of radical dispro-
portionation product observed in 4d . D2O quenching of
4d showed 21% deterium incorporation in 5d with about
13% radical disproportionation. When the parallel solu-
tion experiment was run18 on 8, 32% deuterium incor-
poration in 9 was observed with about 17% of the product
arising from radical disproportionation. Therefore, radi-
cal disproportionation of 4d appears to be substrate
specfic rather than a result of being on resin.
We have developed a mild and efficient synthesis of
benzofuran derivatives on solid support via radical cy-
clization. When this reaction is carried out on PEG-
grafted resins, products free of the samarium reagent are
formed under mild reaction conditions.
a
Bromide made from 2-methoxycinnamaldehyde by (1) DIBALH,
b
THF, (2) PPh3, NBS. t-BuOH is added during the cyclization.
(14) A possible intermediate is:
Bromide made from ethyl 4-bromocrotonate by (1) DIBALH,
CH2Cl2, (2) TMSOTf, Et3N, THF. c 3 was first reacted with bis-
chloride and then was heated in morpholine in DMF at 55 °C
overnight to generate 4i.
Ack n ow led gm en t. This work was supported by
NIH grant number 51095.
(15) Zhou, Z.; Bennett, S. M. Tetrahedron Lett. 1997, 38, 1153-1156.
(16) Purchased from Argonaut Technologies, Inc.
(17) Look, G. C.; Holmes, C. P.; Chinn, J . P.; Gallop, M. A. J . Org.
Chem. 1994, 59, 7588-7590.
(18) To preclude the amide proton as a possible proton source in
solution, we synthesized the ester 8 instead of the benzamide.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, compound characterization data, and copies of 1H
NMR spectra for 2, 3, 4a , 4i, 4h , 5a -j (21 pages).
J O970913K