Synthesis of 2-substituted 7-hydroxybenzofuran-4-carboxylates via addition of silyl enol ethers to o-benzoquinone esters

Article abstract of DOI:10.1021/ol900416x

Mukaiyama Michael addition of silyl enol ethers 13 to the 1,2-quinone-4-carboxylate 6 (formed in situ by oxidation of the catechol ester 8) afforded the 2-subsituted 7-hydroxybenzofuran-4-carboxylates 14 in fair to good yields. Alkyl and aryl systems work

Full text of DOI:10.1021/ol900416x

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2165-2167
Synthesis of 2-Substituted
7-Hydroxybenzofuran-4-carboxylates via
Addition of Silyl Enol Ethers to
o-Benzoquinone Esters
Michael E. Jung* and Felix Perez
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, 405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received February 28, 2009
ABSTRACT
Mukaiyama Michael addition of silyl enol ethers 13 to the 1,2-quinone-4-carboxylate 6 (formed in situ by oxidation of the catechol ester 8)
afforded the 2-subsituted 7-hydroxybenzofuran-4-carboxylates 14 in fair to good yields. Alkyl and aryl systems work well, but highly electron-
rich silyl enol ethers could not be used because of competing oxidation.
The benzofuran structural unit 1 is often found in natural
products and in biologically active materials.1 Several general
methods for its synthesis have been reported, many involving
an o-substituted phenol, e.g., o-halo 2 or o-acyl phenols 3
(Scheme 1).2 However the methods available for the
benzofurans that arose from our interest in a new approach
(Scheme 2) for the total synthesis of morphine 4.3 We were
Scheme 2
Scheme 1
interested in whether o-benzoquinone esters esters could be
used as dienophiles in the Diels-Alder reaction with very
synthesis of highly functionalized benzofurans are fewer in
number. In this paper we report a novel synthesis of
(2) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Cambridge, 2000; pp 380-391.
(1) (a) Zhang, J.; Zhang, Y.; Zhang, Y.; Herndon, J. W. Tetrahedron
2003, 59, 5609. (b) Dat, N. T.; Jin, X.; Lee, K.; Hong, Y.-S.; Kim, Y. H.;
Lee, J. J. J. Nat. Prod. 2009, 72, 39. (c) Chen, Y.; Wei, X.; Xie, H.; Deng,
H. J. Nat. Prod. 2008, 71, 929. (d) Lin, Y.-L.; Chang, Y.-Y.; Kuo, Y.-H.;
Shiao, M.-S. J. Nat. Prod. 2002, 65, 745. (e) Naya, K.; Takai, K.; Nakanishi,
M.; Omura, K. Chem. Lett. 1977, 1179.
(3) For recent syntheses of morphine, see: (a) Tanimotoa, H.; Saitoa,
R.; Chida, N. Tetrahedron Lett. 2008, 49, 358. (b) Parker, K. A.; Fokas, D.
J. Org. Chem. 2006, 71, 449. (c) Uchida, K.; Yokoshima, S.; Kan, T.;
Fukuyama, T. Org. Lett. 2006, 8, 5311. (d) Trost, B. M.; Tang, W. J. Am.
Chem. Soc. 2002, 124, 1454.
10.1021/ol900416x CCC: $40.75
Published on Web 04/16/2009
 2009 American Chemical Society

substituted dienes to produce intermediates for the synthesis
of morphine. Therefore we examined the reaction of the two
o-benzoquinone esters, 5 and 6, with silyloxy dienes (Scheme
3). The required dienophiles 5 and 6 were each prepared by
compound exhibited a blue fluorescence as do many 7-hy-
droxybenzofurans.9 There are two possible mechanisms for
this process (Scheme 6), namely, an initial [4 + 2] cycload-
Scheme 6
Scheme 3
the in situ oxidation of the corresponding known catechols 74
and 8.5 These compounds are generally too reactive to be
isolated pure but rather were used in solution. Oxidation of 7
with iodosobenzene bis(trifluoroacetate)6 to give 5 in the
presence of the very hindered silyloxy diene 10, which was
prepared by silyl enol ether formation from the ketone 9,7
afforded the Diels-Alder adduct 11 as mainly the diastereomer
shown in 62% yield (Scheme 4).8 The stereochemistry of the
dition (concerted or stepwise) of the electron-rich silyl enol
ether A and the electron-deficient diene 6 to produce the
cycloadduct B,10 which could then open the ring via a retro-
aldol-type process to give, with protonation of the phenoxide,
the very stabilized cation C. This intermediate could also
be prepared via the direct Mukaiyama Michel addition of
the silyl enol ether A to the o-quinone ester 6 (or more likely
the protonated form 6′) to generate the same intermediate.
The cyclohexadienone of unit C would tautomerize and the
system would aromatize to give the catechol D. The cation
of D would be trapped by the o-phenol group to generate
the five-membered ring E, which would lose the silyloxy
group to afford the benzofuran F. Because we do not see
any evidence for intermediates such as B, we favor the
Mukaiyama Michael pathway. There is one similar process
reported in the literature, namely, a side product obtained in
only two cases when the silyl enol ether of dibenzyl ketone
was added to 4-methyl and 4-tert-butyl o-benzoquinone.11
In this publication several other Mukaiyama Michael reac-
tions occurred without benzofuran formation.11
Scheme 4
adduct 11 was assigned by extensive NOE analysis. This
compound has some structural similarity to morphine and might
prove to be a useful intermediate for its synthesis in the future.
However, when the regioisomeric o-benzoquinone ester
6 (prepared by in situ oxidation of 8) was reacted with the
diene 10, a different product was obtained in 25% yield
(Scheme 5). The structure of the 7-hydroxybenzofuran-4-
(4) Dallacker, F.; Thiemann, E.; Uddrich, P. Chem. Ber. 1971, 104, 2347.
(5) Rama Rao, A. V.; Deshmukh, M. N.; Sivadasan, L. Chem. Ind. 1981,
164.
(6) (a) Carlini, R.; Fang, C.-L.; Herrington, D.; Higgs, K.; Rodrigo, R.;
Taylor, N. Aust. J. Chem. 1997, 50, 271. (b) Sayre, L. M.; Nadkarni, D. V.
J. Am. Chem. Soc. 1994, 116, 3157.
Scheme 5
(7) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649.
(8) The Diels-Alder reaction of 5, or alkyl analogues, with much less
hindered dienes has been reported: (a) Forte, M.; Orsini, F.; Pelizzoni, F.;
Ricca, G. Gazz. Chim. Ital. 1985, 115, 41. (b) Weller, D. D.; Stirchak, E. P.
J. Org. Chem. 1983, 48, 4873.
(9) Hwu, J. R.; Chuang, K.-S.; Chuang, S. H.; Tsay, S.-C. Org. Lett.
2005, 7, 1545.
(10) Such [4 + 2] cycloadditions are known, as are the simple
dimerization of o-benzoquinones. (a) Al-Talib, M.; Gerstenberger, I.; Jones,
P. G.; Winterfeldt, E. Liebigs Ann./Recl. 1997, 893. (b) Nair, V.; Kumar,
S. J. Chem. Soc., Perkin Trans. 1 1996, 443. (c) Sinclair, I. W.; Proctor,
G. R. J. Chem. Soc., Perkin Trans. 1 1975, 2485. (d) Horner, L.; Spietschka,
W. Liebigs Ann. Chem. 1955, 591, 1.
carboxylate 12 was easily assigned on the basis of proton
and carbon NMR spectra and also by the fact that the
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Org. Lett., Vol. 11, No. 10, 2009

We decided to examine the generality and scope of this
new benzofuran synthesis by varying the silyl enol ether
starting material. Therefore a variety of silyl enol ethers of
ketones 13a-i were prepared by either deprotonation of the
ketone and trapping with trimethylsilyl chloride or by
treatment of the ketone with trimethylsilyl triflate and base.
The o-benzoquinone ester 6 was prepared by oxidation of the
catechol 8 in the presence of these silyl enol ethers and the
mixtures stirred for 24 h. Workup and careful column
chromatography12 provided the expected benzofurans 14a-i
in fair to good yields (Scheme 7). Some of the trends in
generally well tolerated with 4-methyl and 4-nitroacetophe-
nones, 13b and 13c, respectively, giving good yields of the
products 14b and 14c (each 74%). However, 4-methoxyac-
etophenone 13d gave only a 29% yield of the desired product
14d. Here the major side reaction is direct oxidation of the
silyl enol ether to give the R-oxygenated acetophenone. Such
R-oxidations of silyl enol ethers with oxidants such as
iodosobenzene diacetate are well-known.13 We believe that
is the reason that the 3-methoxy analogue 13g also gave a
relatively poor yield (33%) of 14g. The 4-bromo analogue
13e gave a moderate yield of 14e due to decomposition of
the starting silyl enol ether. Other aromatic systems worked
well, e.g., the silyl enol ether from 2-acetylnaphthalene 13f
gave an excellent 79% yield of the 2-naphthyl analogue 14f,
and the silyl enol ether of 2-acetylfuran 13h also gave the
desired 2-furyl analogue 14h in 60% yield. Finally nonaro-
matic ketones could be used, e.g., the silyl enol ether of
cyclohexanone 13i afforded a 34% yield of the tetrahydro
dibenzofuran analogue 14i. Here again direct oxidation of
the silyl enol ether was the major side reaction.14
Scheme 7
In conclusion, we have developed a new method for the
synthesis of functionalized benzofurans via the Mukaiyama
Michael addition of silyl enol ethers of ketones to the
o-benzoquinone-4-carboxylate followed by cyclization and
aromatization. Further work on the use of this process in
synthesis is underway in our laboratories and will be reported
in due course.
Acknowledgment. We thank the National Science Foun-
dation (CHE 0614591) for generous support of this work.
F.P. thanks the NIH Chemistry Biology Interface Training
program at UCLA for support.
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900416X
(13) Moriarty, R. M.; Prakash, O. Org. React. 1999, 54, 273.
(14) General Procedure for the Oxidation-Cyclization. To a solution
of methyl 3,4-dihydroxybenzoate 8 (1.0 mmol) and the silyl enol ether 13
(4 mmol) in 8 mL of THF at 0 °C was added 2 mL (1.1 mmol) of
bis(trifluoroacetoxy) iodobenzene (0.55 M solution in THF) dropwise over
10 min, forming a green solution initially. The reaction was allowed to stir
at 0 °C (unless specified otherwise) for 4 h, the solution becoming a dark
yellow. To the solution was added 0.5 mL of HCl (4 M solution in dioxane)
and 1.0 mL of methanol. The mixture was refluxed for 1 h, and the solution
lightened in color. The solution was extracted with 30 mL of diethyl ether,
washed with 2 × 10 mL saturated NaHCO3 and 1 × 10 mL brine, dried
over MgSO4, filtered, and concentrated in vacuo to yield an oily residue.
The residue was purified by flash column chromatography over silica gel
(ether and hexanes) to yield the benzofuran product 14. The products were
often recrystallized to give purer material.
reactivity deserve comment. The simple acetophenone silyl
enol ether 13a afforded the expected product, 2-phenyl-7-
hydroxybenzofuran-4-carboxylate 14a, in 73% yield. Sub-
stituents in the para position of the phenyl ring were
(11) Sagawa, Y.; Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1988, 1105.
For a different mode of 1,4-addition, see: Nair, V.; Rajesh, C.; Dhanya, R.;
Rath, N. P. Tetrahedron Lett. 2002, 43, 5349.
(12) These compounds were quite difficult to separate and purify by
normal silica gel chromatography because of their tendency to adhere to
the column, which made elution difficult at times.
Org. Lett., Vol. 11, No. 10, 2009
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