Synthesis of 2,4-disubstituted 3-chlorofurans and the effect of the chlorine substituent in furan Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2007.11.193

2,4-Disubstituted 3-chlorofurans were synthesized in 42-69% overall yields by CuCl/bpy-catalyzed halogen atom transfer radical cyclization of 1-substituted 2,2,2-trichloroethyl allyl ethers to 2-substituted 3,3-dichloro-4-(1-chloroalkyl)tetrahydrofurans f

Full text of DOI:10.1016/j.tetlet.2007.11.193

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 799–802
Synthesis of 2,4-disubstituted 3-chlorofurans and the effect of
the chlorine substituent in furan Diels–Alder reactions
Ram N. Ram *, Neeraj Kumar
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India
Received 20 October 2007; revised 19 November 2007; accepted 29 November 2007
Available online 4 December 2007
Abstract
2,4-Disubstituted 3-chlorofurans were synthesized in 42–69% overall yields by CuCl/bpy-catalyzed halogen atom transfer radical
cyclization of 1-substituted 2,2,2-trichloroethyl allyl ethers to 2-substituted 3,3-dichloro-4-(1-chloroalkyl)tetrahydrofurans followed by
base promoted dehydrochlorination. Diels–Alder reactions of 4-substituted 2-(2-furyl)-, 2-styryl-, and 2-crotyl-3-chlorofurans with
dimethyl acetylenedicarboxylate occurred exclusively on the chlorofurano diene moieties and not on the non-chlorinated furano diene
or the chlorinated exocyclic diene alternatives, demonstrating the predominance of the halogen effect in the furan Diels–Alder reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 3-Chlorofurans; 3,3-Dichlorotetrahydrofurans; Radical cyclization; Diels–Alder reaction; Dehydrochlorination; Chlorine effect
Halofurans are important building blocks for the synthe-
sis of more complex furans for various applications as the
halogen atom can be replaced easily with a variety of groups1
through halogen–metal exchange2,3 or transition metal-cata-
lyzed cross-coupling4 and amination5 reactions. They are in
great demand especially when a substituent is required to be
introduced regiospecifically, particularly at the 3- or 4-posi-
tion in the presence of unsubstituted 2- and/or 5-positions.
The synthesis of such furans is not straightforward because
other substitution methods, such as electrophilic aromatic
substitution and direct metallation generally occur at the
2- and/or 5-positions with the possibility of complications
arising due to the problem of regioselectivity. In such a situ-
ation, one has to take recourse mostly to ab initio furan syn-
thesis involving cyclization of acyclic and often non-trivial
precursors.1c,6 Other alternatives involving oxazole-Diels–
Alder–retro-Diels–Alder methodology,1c the substituent-
directed b-lithiation of silicon-protected furans1b and the
intramolecular Diels–Alder reaction of 2-substituted furans
(furan-transfer reaction)1c are also useful in special cases.
However, all these methods are less preferable when a broad
synthetic methodology is required, particularly to build a
library of variously substituted furans for studying struc-
ture–activity relationship.
Further, theoretical calculations and experimental
results show that a halogen substituent enhances the rate
and efficiency of the furan Diels–Alder reaction and
decreases its reversibility.7 This, the so-called ‘halogen
effect’ has been rationalized in terms of the high propensity
of the electronegative halogen atom to attach to a more
substituted and thus more electropositive carbon frame-
work. Thus, through a more efficient Diels–Alder reaction8
or other standard methodologies9 halofurans may be trans-
formed into a variety of heterocyclic, carbocyclic, acyclic,
or aromatic products with a halogen atom handle which
can be elaborated further or easily removed.
Bromo- and iodo-furans have served particularly well in
substitutions through halogen–metal exchange and cross-
coupling reactions and have been used for the synthesis
of furanoid and other naturally occurring as well as
synthetic bioactive and other potentially useful mole-
cules.1–5 However, chloro derivatives are more attractive
options for industrial applications due to their higher
*
Corresponding author. Tel.: +91 11 26591508; fax: +91 11 26582037.
E-mail address: rnram@chemistry.iitd.ernet.in (R. N. Ram).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.193

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R. N. Ram, N. Kumar / Tetrahedron Letters 49 (2008) 799–802
stability and lower cost. Therefore, there is a significant
current interest in the replacement of the chlorine atom
of chloroarenes with carbon and other groups and consid-
erable success has been realized to bring chloroarenes and
chloroheteroarenes into the realm of cross-coupling reac-
tions during the past few years.10 However, electron-rich
chloroheteroarenes, particularly sensitive chlorofurans
have hardly been explored.11 This is partly due to the scar-
city of easy routes to chlorofurans, especially 3- or 4-chloro-
furans. The reported methods for the synthesis of 3- or
4-chlorofurans have limitations with regard to the yields,
general applicability, the number and the nature of the
other substituents and the substitution pattern.12 Most of
the methods for the synthesis of trisubstituted chlorofurans
are concerned with the synthesis of 2,5-diaryl-3-chloro-
furans and do not describe the synthesis of contiguously
trisubstituted furans with a chlorine atom at C-3. Recently,
we reported the synthesis of 3-substituted 4-chloro and 2,
3-disubstituted 4-chlorofurans using CuCl/bpy-catalyzed
halogen atom transfer radical cyclization (HATRC) of
acetylated chloral allyl hemiacetals as the key step.12e
Herein, we report an efficient and shorter route for the
synthesis of isomeric 2,4-disubstituted 3-chlorofurans,
another type of scarcely known b-chlorofurans for which
a general method of preparation is not available with only
a few examples reported in the literature.13,14 Some of these
compounds possess promising biological activities14 and
appear mostly in patented documents.
The synthesis of 2,4-disubstituted 3-chlorofurans 4 is
shown in Scheme 1. Allylation of trichloromethyl carbinols
with easily available allylic bromides gave the 1-substituted
2,2,2-trichloroethyl allyl ethers 1. The trichloromethyl car-
binols were easily accessible by reaction of aldehydes with
chloroform in the presence of catalytic amounts of DBU15
or with trichloroacetic acid in DMSO16 as reported in the
literature. Copper-catalyzed HATRC17 of 1 with CuCl/
bpy (1:1 molar mixture, 30 mol %) in refluxing DCE for
3 h occurred in a highly diastereoselective manner to yield
tetrahydrofurans 2, generally in high yields. A one-pot
double dehydrochlorination and isomerization of tetra-
hydrofurans 2 with DBU in refluxing benzene for 10–12 h
afforded 2,4-disubstituted 3-chlorofurans 4 in 42–77%
overall yields from the trichloroethyl allyl ethers 1
(Table 1).18 However, the volatile chlorofuran 4a (entry
1) could be isolated only in poor overall yield (15%) due
to loss of material during workup.
Monitoring the progress of the dehydrochlorination
reaction by TLC indicated the absence of the starting mate-
rial after 3 h, however, formation of the furans required
10–12 h at reflux. Plausibly, isofurans 3 are formed first
which isomerize to the furans slowly. In the case of 2-(4-
nitrophenyl)tetrahydrofuran 2j (entry 10), complete iso-
merization to the corresponding furan 4j required treat-
ment of the mixture of furan and isofuran with a few
drops of concd H2SO4 in diethyl ether at ambient temper-
ature for 2 h. The dehydrochlorination of the basic tetra-
hydrofurans 2f (entry 6) and 2k (entry 11) was effected
by t-BuOK/18-crown-6 in refluxing THF instead of DBU
to avoid complications in separating them from the excess
organic base DBU. This method of dehydrochlorination
was also found to give better results for the synthesis of
3-chloro-4-isopropyl-2-(3-tolyl)furan which was prepared
in 60% overall yield from the corresponding ether obtained
by prenylation of 1-(3-tolyl)-2,2,2-trichloroethanol.
The tetrahydrofurans and furans were purified by column
chromatography on silica gel and alumina columns, respec-
tively, with n-hexane as the solvent for elution. The solid
chlorofurans are fairly stable and the liquid chlorofurans
are stable for a few days when stored at low temperatures
under a nitrogen atmosphere in hydrocarbon solvents but
tend to deteriorate in chlorinated or oxygenated solvents.
Their structures were established by IR, 1H, 13C, and DEPT
NMR spectroscopy.
Next, we briefly investigated the halogen effect on the
furan Diels–Alder reaction. This effect appears to be a gen-
eral effect applicable to other halogen substituted dienes as
well as dienophiles.7a,19 According to a recent theoretical
Table 1
Yields of tetrahydrofurans 2a–o and chlorofurans 4a–o
Entry
Ether 1
R1
R2
Yield (%)
2a
4b
4c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
a
b
c
d
e
f
n-Pr
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
60
93
85
87
85
83
86
87
89
90
84
83
70
66
88
25d
74
65
76
71
73d
68
76
72
85
70d
69
60
65
65
15
69
55
66
60
61
59
66
64
77
59
57
42
43
57
2-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
4-Me2NC6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
4-O2NC6H4
2-Pyridyl
2-Furyl
g
h
i
R2
R2
CuCl/bpy
CCl3
HO R1
NaH
CCl3
R1
+
DCE
reflux, 3 h
j
THF-DMF
( 4:1 v/v)
0-25 oC
O
Br
k
l
1
m
n
o
E-PhCH@CH
MeCH@CH (major E)
3-MeC6H4
R2
R2
Cl
R2
Cl
R1
Cl
Cl
R1
Cl
DBU
One-step (1?2).
One-step (2?4).
Two-steps (1?4).
R1
benzene
b
c
O
O
O
reflux
10-12 h
2
3
4
d
Dehydrochlorination of 2 was achieved with t-BuOK/18-crown-6 in
refluxing THF for 10 h.
Scheme 1. Synthesis of 2,4-disubstituted 3-chlorofurans 4a–o.

R. N. Ram, N. Kumar / Tetrahedron Letters 49 (2008) 799–802
801
calculation,7a the halogen effect is more important in the
Acknowledgment
Diels–Alder reaction of halofurans than with halo-substi-
tuted cyclic or acyclic hydrocarbon dienes, the maximum
effect occurring when the halogen atom is linked to one of
the termini of the diene. Accordingly, 2-halofurans have
been found to be more reactive than 3-halofurans. However,
experimental support for the theoretical predictions through
an intramolecular competition between a halofuran diene
and a non-halogenated furano diene or a non-furano halod-
iene has not been reported. The fortuitous availability of the
‘twin’ dienes 4(l–n) led us to investigate the Diels–Alder
reaction of these compounds. Thus, chlorobifuryl 4l having
a chlorofuran ring and a non-halogenated furan ring, on
heating with dimethyl acetylenedicarboxylate (DMAD) at
100 °C for 10 h gave exclusively furylchlorophenol 5l
(Scheme 2) in 74% yield by cycloaddition to the chlorofuran
ring. The structure of 5l was also supported by X-ray crys-
tallography.20 Similarly, 2-styryl-3-chlorofuran 4m and 2-
crotyl-3-chlorofuran 4n (predominantly as the E isomer)
having a chlorofurano diene and a chloro-substituted exo-
cyclic diene moiety, under similar conditions, yielded exclu-
sively styrylchlorophenol 5m and crotylchlorophenol 5n,
in 65% and 62% yields, respectively,21 showing the specific
participation of the chlorofurano diene in the Diels–Alder
reaction.22
One of us (N.K.) is thankful to the Council of Scientific
and Industrial Research, New Delhi for a research
fellowship.
References and notes
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In conclusion, the present method for the synthesis of
2,4-disubstituted 3-chlorofurans uses readily available
starting materials. It is quite general for the synthesis of a
variety of 2,4-disubstituted 3-chlorofurans with an alkyl,
alkenyl, aryl or heteroaryl substituent at C-2 and a primary
or secondary alkyl or benzylic substituent at C-4. In partic-
ular, this method would be well suited to a diversity
oriented synthesis of 2,3-disubstituted furans with a methyl
group at C-4, a structural feature of many natural and
bioactive synthetic furans.1c,6a–d,14d,23 These chlorofurans
possessing a chlorine atom in a sterically encumbered
position offer a formidable challenge to those interested in
cross-coupling reactions. While our results show the pre-
dominance of the halogen effect in furan Diels–Alder reac-
tions, conformational and steric effects might also be
contributing factors. Further studies with more suitable
substrates are required for a more precise conclusion.
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R2
O
R2
Cl
Cl
DMAD
R1
R1
100 oC, 10 h
O
MeO2C CO2Me
4(l-n)
, R2 = H
O
l: R1
=
Ph
R2 Cl
R1
, R2 = H
m: R1 =
n: R1 =
HO
CO2Me
CO2Me
Me
, R2 = Ph
5(l-n)
Scheme 2. Diels–Alder reaction of chlorofurans 4(l–n).

802
R. N. Ram, N. Kumar / Tetrahedron Letters 49 (2008) 799–802
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18. General procedure for the synthesis of 2,4-disubstituted 3,3-di-
chlorotetrahydrofurans 2: In a flame dried two necked round bottom
flask were placed the substituted 2,2,2-trichloroethyl allyl ether 1
(10 mmol), CuCl (0.3 g, 3 mmol) and degassed DCE (40 mL) under a
N2 atm. To this suspension was added bpy (0.47 g, 3 mmol) and the
mixture was heated at reflux with stirring for 3 h. The mixture was
then cooled and filtered. The filtrate was evaporated under reduced
pressure and the residual material was purified by column chroma-
tography (silica gel, n-hexane/EtOAc = 95:5 v/v) to give a diastereo-
meric mixture of 2,4-disubstituted 3,3-dichlorotetrahydrofuran 2.
General procedure for the synthesis of 2,4-disubstituted 3-chlorofurans
4: In a flame dried two necked round bottom flask was placed the 2,4-
disubstituted 3,3-dichlorotetrahydrofuran 2 (10 mmol). Dry benzene
(10 mL) was injected into the flask followed by the addition of DBU
(4.6 g, 30 mmol) under a N2 atm. The reaction mixture was heated at
reflux for 10–12 h. During this time some precipitation occurred. The
mixture was filtered and the solid was washed with benzene. The
filtrate was washed successively with 5% HCl (5 mL) and water
(5 mL), dried over Na2SO4, filtered, evaporated under reduced
pressure, and purified by short path column chromatography
(alumina, n-hexane) to give chlorofuran 4.
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¨
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21. General procedure for the Diels–Alder reaction of chlorofurans 4(l–n)
with dimethyl acetylenedicarboxylate: Chlorofurans 4(l–n) (2 mmol)
and DMAD (0.28 g, 2 mmol) were taken in a 25 mL round bottom
flask fitted with a two-way stopcock adapter. The flask was evacuated
and filled with nitrogen and again evacuated then placed in an oil bath
maintained at 100 °C, for 10 h. The flask was then cooled and the
crude product was chromatographed on a silica gel column using a
mixture of n-hexane and ethyl acetate (9:1 v/v) as the eluting solvent
to give chlorophenols 5(l–n).
22. For Diels–Alder reactions of 2-alkenylfurans as exocyclic dienes, see
Ref. 8a. For an ultrasound-promoted Diels–Alder reaction of 2-
alkenylfurans as furanodienes, see: Wei, K.; Gao, H.-T.; Li, W.-D. Z.
J. Org. Chem. 2004, 69, 5763–5765.
23. Recent references: (a) Manzo, E.; Ciavatta, M. L.; Gresa, M. P. L.;
Gavagnin, M.; Villani, G.; Naik, C. G.; Cimino, G. Tetrahedron Lett.
2007, 48, 2569–2571; (b) Jenkins, T. J.; Guan, B.; Dai, M.; Li, G.;
Lightburn, T. E.; Huang, S.; Freeze, B. S.; Burdi, D. F.; Jacutin-
Porte, S.; Bennett, R.; Chen, W.; Minor, C.; Ghosh, S.; Blackburn,
C.; Gigstad, K. M.; Jones, M.; Kolbeck, R.; Yin, W.; Smith, S.;
Cardillo, D.; Ocain, T. D.; Harriman, G. C. J. Med. Chem. 2007, 50,
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15. Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65, 7211–7212.