Synthesis of 3-substituted and 2,3-disubstituted 4-chlorofurans

Article abstract of DOI:10.1039/a907270e

A simple method for the synthesis of 3-substituted and 2,3-disubstituted 4-chlorofurans is described which involves CuCl/bipy-catalysed regioselective cyclisation of 1-acetoxy-2,2,2-trichloroethyl allyl ethers followed successively by dechloroacetoxylation with Zn dust and tandem dehydrohalogenation-aromatisation with Bu(t)OK/18-crown-6.

Full text of DOI:10.1039/a907270e

Synthesis of 3-substituted and 2,3-disubstituted 4-chlorofurans
Ram N. Ram* and I. Charles
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi - 110 016, India.
E-mail: rnram@chemistry.iitd.ernet.in
Received (in Cambridge, UK) 8th September 1999, Accepted 1st October 1999
A simple method for the synthesis of 3-substituted and
2,3-disubstituted 4-chlorofurans is described which involves
CuCl/bipy-catalysed regioselective cyclisation of 1-acetoxy-
2,2,2-trichloroethyl allyl ethers followed successively by
dechloroacetoxylation with Zn dust and tandem dehy-
drohalogenation–aromatisation with ButOK/18-crown-6.
The synthesis of variously substituted furans continues to be of
considerable interest1 due to the presence of the furan nucleus in
commercially important pharmaceuticals,2 flavors3 and a vari-
ety of naturally occurring biologically active compounds.4
Furans also serve as useful synthetic intermediates for the
synthesis of aromatic, alicyclic and acyclic molecules.5 Since
furans undergo electrophilic substitution and lithiation at the 2-
and 5-positions, bypassing any of these positions to substitute
the 3- and/or 4-positions is not straightforward. Therefore, b-
mono-, di- and tri-substituted furans having either or both of the
2- and 5-positions unsubstituted are generally synthesised via
acyclic routes. If the substituent happens to be a functional
group, particularly at the 3- and/or 4-position(s), a variety of
furans can be prepared by simple functional group transforma-
tions, thus widening the scope of the synthesis. In this respect,
bromo and iodo groups have served particularly well by
undergoing replacement with alkyl, alkenyl, alkynyl, aryl,
heteroaryl, formyl and acyl groups.5a,6 Since the chloro
compounds, in general, are less expensive and more stable,
there is considerable current interest in the replacement of the
chloro group of aryl and vinyl chlorides with carbon groups.7
However, there are very few reported methods for the
preparation of 3- and/or 4-chlorofurans.8 Furthermore, these
methods have their own limitations with regard to yields,8a the
nature of the other substituents8b,e and the substitution pat-
tern.8b–e,9 Therefore, herein we disclose a simple, new and
broader route to prepare 3-substituted and 2,3-disubstituted
4-chlorofurans, which also complements the few reported
methods for 3- and/or 4-chlorofuran synthesis.
Our interest in the chemistry of reactive aldehydes and metal-
ion-promoted reactions10 led us to use a reaction analogous to
the reported11 CuI-catalysed cyclisation of b-chloroethyl allyl
ethers as the key step for the present synthesis. Thus, chloral
hemiacetals, prepared by simply mixing chloral with readily
accessible allylic alcohols, after protection as acetates, under-
went regioselective cyclisation with CuCl/bipy, as expected, to
afford the tetrahydrofurans 1a–f. Dechloroacetoxylation of 1a–
d with Zn dust gave the 2,3-dihydrofurans 2a–d as stereo-
isomeric mixtures in 61–81% overall yields. Dehydrochlorina-
tion of 2a–d with KOH/EtOH followed by isomerisation of the
crude isofurans with catalytic amounts of conc. H2SO4 and
purification thereafter by column chromatography (silica gel, n-
hexane) furnished the 4-chlorofurans 3a–d in 31–65% overall
yields (starting from the allyl alcohols). When the dehydro-
chlorination was performed with ButOK/18-crown-6/THF,
tandem isomerisation of isofurans was observed, giving the
4-chlorofurans 3a–d in better overall yields (51–74%) (Scheme
1).
Scheme 1 Reagents and conditions: i, CCl3CHO, 2 h, then Ac2O, pyridine,
DMAP, room temp., overnight; ii, 30 mol% of CuCl/bipy (1+1 mixture),
1,2-dichloroethane, reflux, 2 h; iii, Zn, THF, reflux, 4 h; iv, ButOK,
18-crown-6, THF, reflux, 10 h.
cinnamyl ether by the reaction of trichloroethanol with
cinnamyl bromide, followed by CuCl/bipy cyclisation and
dehydrochlorination with DBU (Scheme 2).12
These chlorofurans are fairly stable in hydrocarbon solvents
but tend to deteriorate in chlorinated or oxygenated solvents.
The decomposition is faster when they are stored as neat
liquids.
All the compounds have been characterised by IR, NMR and
mass spectral studies. The chlorofurans 3 were also charac-
terised by their transformation into the Diels–Alder adducts 4
on reaction with dimethyl acetylenedicarboxylate. In the case of
3a, the reaction proceeded further to give the phenol 5a under
the reaction conditions used (neat, 100 °C, 10 h). The furan 3b
gave a mixture of the cycloadduct 4b and the phenol 5b, which
was completely converted into the phenol 5b on slight warming
with BF3·OEt2 (Scheme 3).
An additional advantage of the present method of furan
synthesis is that it can be used to prepare 2,3-dihydrofurans as
well, which, like furans, are also widely distributed in Nature13
and are useful synthetic intermediates.5c,14 This advantage is not
Scheme 2 Reagents and conditions: i, CCl3CH2OH, K2CO3, acetone,
reflux, 6 h; ii, 30 mol% of CuCl/bipy (1+1 mixture), 1,2-dichloroethane,
reflux, 2.5 h; iii, DBU, benzene, reflux, 3 h.
During dechloroacetoxylation, reduction of the benzylic
chloro group was observed in the case of 1e–f. The 4-chloro-
furan 3e was, however, prepared in 81% overall yield by a
simple modification involving preparation of trichloroethyl
Scheme 3 Reagents and conditions: i, DMAD, 100 °C, 10 h; ii, BF3·OEt2,
40–50 °C.
Chem. Commun., 1999, 2267–2268
This journal is © The Royal Society of Chemistry 1999
2267

Reich and R. E. Olson, J. Org. Chem., 1987, 52, 2315; L. N. Pridgen and
S. S. Jones, J. Org. Chem., 1982, 47, 1590.
available with the existing methods of b-chlorofuran synthesis.
We expect that in the present method of furan synthesis the
chloro group might provide a branching point in the synthetic
tree at the 2,3-dihydrofuran or furan stage or later during
synthetic applications, to give access to a variety of di-, tri- and
tetra-substituted furans and other interesting molecules.
Financial assistance by the DST, New Delhi, is gratefully
acknowledged.
7 C. Zhang, J. Huang, M. L. Trudell and S. P. Nolan, J. Org. Chem., 1999,
64, 3804; B. H. Lipshutz, P. A. Blomgren and S.-K. Kim, Tetrahedron
Lett., 1999, 40, 197; X. Bei, T. Crevier, A. S. Guram, B. Jandeleit, T. S.
Powers, H. W. Turner, T. Uno and W. H. Weinberg, Tetrahedron Lett.,
1999, 40. 3855; B. H. Lipshutz and P. A. Blomgren, J. Am. Chem. Soc.,
1999, 121, 5819; D. W. Old, J. P. Wolfe and S. L. Buchwald, J. Am.
Chem. Soc., 1998, 120, 9722; A. F. Littke and G. C. Fu, Angew. Chem.,
Int. Ed., 1998, 37, 3387; S. Saito, S. Oh-tani and N. Miyaura, J. Org.
Chem., 1997, 62, 8024.
8 (a) R. C. Larock and C.-L. Liu, J. Org. Chem., 1983, 48, 2151 (poor
yields); (b) Y. Tanabe, K.-i. Wakimura, Y. Nishii and Y. Muroya,
Synthesis, 1996, 388 (2,5-diaryl-3-chlorofurans); (c) D. Obrecht, Helv.
Chem. Acta., 1989, 72, 447 (2-substituted and 2,5-disubstituted
3-chlorofurans); (d) N. D. Ly and M. Schlosser, Helv. Chem. Acta.,
1977, 60, 2085 (2-prenyl-3-chlorofuran); (e) R. E. Lutz and M. G.
Reese, J. Am. Chem. Soc., 1959, 81, 127 (2,5-diaryl-3-chlorofurans).
9 In fact, we could find no report on 3-substituted 4-chlorofurans and only
one report on 2,3-disubstituted 4-chlorofurans in which the formation of
two 2,3-disubstituted 4-chlorofuran derivatives has been described.
These chlorofurans were obtained as a mixture in poor yields, one of
which was characterised only by GC-MS [ref. 8(a)].
10 L. Singh and R. N. Ram, J. Org. Chem., 1994, 59, 710; R. N. Ram and
I. Charles, Tetrahedron, 1997, 53, 7335; R. N. Ram and L. Singh,
Tetrahedron Lett., 1995, 36, 5401.
11 J. H. Udding, H. Hiemstra, M. N. A. Van Zanden and W. N. Speckamp,
Tetrahedron Lett., 1991, 32, 3123.
Notes and references
1 For a general review, see: X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L.
Kwan, T. H. Lo, S. Y. Tong and H. N. C. Wong, Tetrahedron, 1998, 54,
1955. For some recent examples, see: J. W. Herndon and H. Wang,
J. Org. Chem., 1998, 63, 4564; P. Wipf, L. T. Rahman and S. R. Rector,
J. Org. Chem., 1998, 63, 7132; E. Bures, J. A. Nieman, S. Yu, P. G.
Spinazzé, J.-L. J. Bontront, I. R. Hunt, A. Rauk and B. A. Keay, J. Org.
Chem., 1997, 62, 8750; Y. R. Lee, N. S. Kim and B. S. Kim,
Tetrahedron Lett., 1997, 38, 5671.
2 K. Nakanishi, Natural Products Chemistry, Kodansha, Tokyo, 1974.
3 The Chemistry of Heterocyclic Flavouring and Aroma Compounds, ed.
G. Vernin, Ellis Horwood, Chichester, 1982.
4 For review, see: P. Bosshard and C. H. Eugster, Adv. Heterocycl. Chem.,
1966, 7, 378; F. M. Dean, Adv. Heterocycl. Chem., 1982, 30, 167;
D. M. X. Donnelly and M. J. Meegan, Comp. Heterocycl. Chem., 1984,
4, 657. For recent examples, see: K.-S. Chen and Y.-C. Wu,
Tetrahedron, 1999, 55, 1353; A. Arnone, C. D. Gregorio, G. Nasini and
O. V. De Pava, Tetrahedron, 1998, 54, 10199.
5 For review, see: (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795. For some
recent examples, see: (b) D. Meng and S. J. Danishefsky, Angew. Chem.,
Int. Ed., 1999, 38, 1485; (c) R. H. Mitchell, T. R. Ward, Y. Wang and
P. W. Dibble, J. Am. Chem. Soc., 1999, 121, 2601; (d) W. E. Noland and
B. L. Kedrowski, J. Org. Chem., 1999, 64, 596; (e) J. M. Harris, M. D.
Keranen and G. A. O’Doherty, J. Org. Chem., 1999, 64, 2982; (f) A.
Padwa, M. A. Brodney, B. Liu, K. Satake and T. Wu, J. Org. Chem.,
1999, 64, 3595; (g) A. Frustner and H. Weintritt, J. Am. Chem. Soc.,
1998, 120, 2817; (h) M. Kurosu, L. R. Marcin, T. J. Grinsteiner and Y.
Kishi, J. Am. Chem. Soc., 1998, 120, 6627.
12 Although this scheme seems to be more attractive than Scheme 1, both
in the number of steps and overall yields, we were not successful in
preparing other trichloroethyl ethers by condensing trichloroethanol
with secondary allylic halides.
13 P. F. Schuda, Top. Curr. Chem., 1980, 91, 75.
14 T. Saito, M. M. Suzuki, T. C. Akiyama, T. Takeuchi, T. Matsumoto and
K. Suzuki, J. Am. Chem. Soc., 1998, 120, 11 633; S. Wadman, R.
Whitby, C. Yeates, P. Kocienski and K. Cooper, J. Chem. Soc., Chem.
Commun., 1987, 241; A. I. Meyers, C. J. Andres, J. E. Resek, Maureen
A. Melaughlin, Charlotte C. Woodall and P. H. Lee, J. Org. Chem.,
1996, 61, 2586; G. Vidari, G. Lanfranchi, P. Sartori and S. Serra,
Tetrahedron: Asymmetry, 1995, 6, 2977; H. Kawakami, T. Ebata, K.
Okano, K. Matsumoto, K. Koseki and H. Matsushita, Patent; Chem.
Abstr., 1994, 120, 107640g.
6 T. Bach and L. Krüger, Tetrahedron Lett., 1998, 39, 1729; M. K. Wong,
C. Y. Leung and H. N. C. Wong, Tetrahedron, 1997, 53, 3497; C.
Alvarez-Ibarra, M. L. Quiroga and E. Toledano, Tetrahedron, 1996, 52,
4065; S. P. Bew and D. W. Knight, Chem. Commun., 1996, 1007; H. J.
Communication 9/07270E
2268
Chem. Commun., 1999, 2267–2268