Angewandte
Communications
Chemie
Heterocycles
Copper/P(tBu)3-Mediated Regiospecific Synthesis of Fused Furans and
Naphthofurans
Togati Naveen, Arghya Deb, and Debabrata Maiti*
Abstract: A novel [3+2] cycloaddition between a variety of
cyclic ketones and diverse olefins or alkynes can be effectively
promoted by copper in combination with the tri-tert-butyl-
phosphine [P(tBu)3] ligand. This protocol exhibits excellent
selectivity and provides an exemplary set of fused heterocycles
in good to excellent yields. Present strategy also represents an
extremely simple and atom-economic way to construct sub-
stituted fused furans and naphthofurans from readily available
starting materials under mild reaction conditions. The utility of
the method is further demonstrated by the synthesis of chiral
furans from (R)-(À)-carvone and (S)-(+)-carvone. A plausible
mechanism involving the oxidative radical cyclization has been
suggested based on experimental observations.
icals as reactants is a great challenge. Inspired by our recent
success in the synthesis of various heterocycles from olefins as
starting materials,[11] we herein report a new method joining
simple and readily available cyclic ketones and olefins or
alkynes to construct fused heterocycles in one step under mild
reaction conditions (Scheme 1).
Scheme 1. Synthesis of fused furans and naphthofurans.
F
used furans are an important class of heteroaromatic
molecules which are invaluable components in a variety of
biologically active natural products and important pharma-
ceuticals.[1] They are also extensively utilized as synthetic
intermediates for acyclic, carbocyclic, and heterocyclic com-
pounds in organic synthesis.[2] Consequently, the development
of efficient methods for the synthesis of fused furans has
attracted considerable interest from synthetic chemists.
Research interest in this area has also been encouraged by
the occurrence of a number of furano-sesquiterpene natural
products having interesting structural skeletons. For example,
pallescensin A, furodysinin, marginatafuran, and echino-
furan.[3] To date, a variety of inter- and intramolecular
strategies have been developed for constructing furan scaf-
folds. The two traditional methods include Feist–Benary
cyclocondensation of 1, 3-dicarbonyl compounds with halo-
ketones[4] and Paal–Knor cyclocondensation of 1,4-dicarbonyl
compounds.[5] Other approaches involve the transition-metal-
catalyzed cycloisomerizations of alkynyl[6] and allenyl[7]
ketones, the palladium-catalyzed decarboxylative cyclization
of propargyl b-ketoesters,[8] cycloisomerization of propargylic
oxiranes,[9] and the cycloaddition of a-diazocarbonyl com-
pounds with alkynes.[10] However, most of these approaches
require either prefunctionalized substrates or multistep
procedures. To the best of our knowledge there is no
method reported in the literature for the synthesis of fused
furans by reacting the cyclic ketones with olefins.
Our initial efforts were focused on the reaction of styrene
with cyclohexanone. A combination of copper salts and silver
salts, gave the furan A exclusively, albeit in low yield
(Table 1). Among various solvents and oxidants, a DCE and
Ag2CO3 combination were found to be most effective. We
also tested different additives in this system and observed that
1-adamantane carbonyl chloride was most efficient. Among
various ligands, P(tBu)3.HBF4 (Fu salt)[12] was found to be
most effective for producing A. Optimization studies and
control experiments confirmed that the transformation does
not occur in the absence of either copper or silver salts
(entries 1 and 2). However, 1-tetralone produced naphtho-
furan in 22% yield under these optimized reaction conditions
(entry 14). After re-optimization, use of 2 equivalents of
Cu(OAc)2 and trifluoroethanol (TFE), as the solvent, was
found to be the best for producing naphthofuran in excellent
yield (entry 15). External additives were found to be ineffec-
tive in increasing the yield of naphthofuran.
At the outset of our study, various cyclic ketones were
employed (Table 2). In particular, ketones having electron-
donating groups such as tert-butyl and tert-pentyl gave
corresponding fused furans in good to excellent yields (2b–
f). It was noteworthy that ether-linkage-containing cyclo-
hexanones were suitable substrates and produced the corre-
sponding furans (2g–j). Interestingly when we tested this
reaction with a natural-product-derived complex molecule,
5a-cholestan-3-one, the desired furan was produced in good
yield (2k). Moreover, the naturally occurring chiral substrates
(R)-(À)-carvone and (S)-(+)-carvone also reacted smoothly
with electronically different styrenes and provided the
corresponding furans in synthetically useful yields (2m–r).
Note that phenyl-substituted cyclohexanones produced a mix-
ture of furan and benzofuran (2a and 2l).
In general direct regiospecific synthesis of substituted
fused heterocycles from readily available and cheap chem-
[*] Dr. T. Naveen, A. Deb, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076 (India)
E-mail: dmaiti@chem.iitb.ac.in
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Naveen, Togati
