Unexpected aromatization of 2-acetoxy-3, 3-dichloro-4-(α-chloroalkyl) tetrahydrofurans to 3-alkyl-4-chlorofurans with NaI/DMF

Article abstract of DOI:10.1080/00397910801997678

An unexpected aromatization of 2-acetoxy-3,3-dichloro-4-(α- chloroalkyl)tetrahydrofurans to 3-alkyl-4-chlorofurans occurs on heating with sodium iodide in dimethylformamide (DMF) at 120°C. Copyright Taylor & Francis Group, LLC.

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Unexpected Aromatization of
2-Acetoxy-3, 3-dichloro-4-(α-
chloroalkyl)tetrahydrofurans
to 3-Alkyl-4-chlorofurans with
NaI/DMF
Ram N. Ram a & I. Charles a
a Department of Chemistry, Indian Institute of
Technology , New Delhi, India
Published online: 12 Jun 2008.
To cite this article: Ram N. Ram & I. Charles (2008) Unexpected Aromatization
of 2-Acetoxy-3, 3-dichloro-4-(α-chloroalkyl)tetrahydrofurans to 3-Alkyl-4-
chlorofurans with NaI/DMF, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:12, 1946-1951, DOI:
10.1080/00397910801997678
To link to this article: http://dx.doi.org/10.1080/00397910801997678
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Synthetic Communications1, 38: 1946–1951, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997678
Unexpected Aromatization of 2-Acetoxy-3,
3-dichloro-4-(a-chloroalkyl)tetrahydrofurans to
3-Alkyl-4-chlorofurans with NaI/DMF
Ram N. Ram and I. Charles
Department of Chemistry, Indian Institute of Technology,
New Delhi, India
Abstract: An unexpected aromatization of 2-acetoxy-3,3-dichloro-4-(a-chloro-
alkyl)tetrahydrofurans to 3-alkyl-4-chlorofurans occurs on heating with sodium
iodide in dimethylformamide (DMF) at 120 ꢀC.
Keywords: Aromatization; b-Chlorofurans; Dechloroacetoxylation; Dehydro-
chlorination; Sodium iodide; Tetrahydrofurans
Variously substituted furans are frequently found in many biologically
active natural products,[1] pharmaceuticals,[2] and flavor and fragrance
compounds.[3] Furthermore, they are also used as versatile intermediates
in many synthetic pathways leading to aromatic, alicyclic, and acyclic
compounds.[4] Because of the utilities of furans, a variety of methods
using cyclic and acyclic precursors have been devised for their syn-
thesis.[5,6] Among them, relatively few reports deal with the preparation
of b-mono-, di-, or trisubstituted furans with either or both the a-
positions unsubstituted. This is because these furans need to be prepared
from suitably substituted acyclic compounds, as direct electrophilic sub-
stitution or lithiation of furan ring occurs at the a-position(s). Because
many naturally occurring bioactive compounds have these substitution
patterns, the direct synthesis of such furans assumes considerable impor-
tance. In this respect, the synthesis of b-halo-substituted furans would be
more useful because direct replacement of the halo group would give a
Received July 31, 2006
Address correspondence to R. N. Ram, Department of Chemistry, Indian Institute
of Technology, Hauz Khas, New Delhi-110016, India. E-mail: rnram@chemistry.
iitd.ernet.in
1946

Aromatization of Tetrahydrofurans
1947
variety of b-substituted furans. Both iodo- and bromo-furans have been
well utilized for this purpose by replacing the halo group with a variety
of carbon groups such as alkyl, alkenyl, alkynyl, aryl, heteroaryl,
formyl, and acyl groups.[4,7–11] There is considerable current interest in
the chloro group replacement reactions of chloroarenes and chloroheter-
oarenes[12] because chloro compounds are, in general, less expensive and
more stable than their bromo and iodo counterparts. However, not only
are relatively few general methods known to prepare b-chlorofurans,
but also these methods have their own limitations with respect to the
yields, the nature of other substituents, and the substitution pat-
terns.[13–16] Recently, Karpov et al.[17] have reported an elegant one-pot
synthesis of 3-chloro- and 3-iodofurans by a modified Sonogashira
coupling of acid chlorides with tetrahydropyranyl (THP)-protected pro-
pargyl alcohols. The THP-protected c-hydroxy alkynones thus formed
undergo sequential acid-induced deprotection, addition of sodium halide,
and cyclocondensation to give the 2-substituted-4-halofurans or 2,5-dis-
ubstituted-4-halofurans in one step. These furans can be isolated or the
iodofurans can be made to undergo Suzuki coupling with boronic acid
in the same pot. However, this procedure gives furans that lack a sub-
stituent at the 3-position.
Recently, we reported[18] a new method to prepare 3-substituted- and
2,3-disubstituted-4-chlorofurans from easily accessible allylic alcohols
using CuCl=bipy-catalyzed chlorine atom transfer radical cyclization of
the protected hemiacetals (1) as the key step (Scheme 1).
However, during the dechloroacetoxylation with Zn=THF, the tetra-
hydrofurans with a tertiary or benzylic chloro substituent in the side
Scheme 1. Reagents and conditions: i. CCl3CHO, 2 h, then Ac2O, pyridine,
DMAP (30 mol%), rt, overnight; ii. CuCl=bpy (30 mol%, 1:1 mixture), 1,2-dichlo-
roethane, reflux, 2 h; iii. Zn, THF, reflux, 4 h; iv. t-BuOK=18-Crown-6, THF,
reflux, 10 h.

1948
R. N. Ram and I. Charles
Scheme 2. Aromatization of tetrahydrofurans 2.
chain at the 3-position, such as 2 (R ¼ Ph), gave the dihydrofurans 5 by
reductive dechlorination of the side chain, thus terminating the sequence
for further conversion to the chlorofurans 4. As a solution to this prob-
lem, we considered using some other reagents with low reducing ability.
Thus, sodium iodide with its known efficacy in dechlorotrifluoroacetox-
ylation[19] and related reactions[20] was chosen as an alternative reagent
for this purpose. We were gratified to observe that when the reaction
was done by heating the tetrahydrofurans 2 with NaI (5 equivalents) in
DMF at about 120 ꢀC for 4 h, it led not only to the expected dechloroa-
cetoxylation but also to an unexpected and much welcomed dehydro-
chlorination and aromatization by double bond shift, all in one step,
to give the desired b-chlorofurans 4 in 23–46% yields (Scheme 2,
Table 1). The low yields of b-chlorofurans could be reconciled by the
advantages offered by this method over the earlier method.[18] All the
1
products were characterized by IR and H NMR spectral analysis and
by comparison with the authentic samples including their Diels–Alder
reaction products with dimethyl acetylenedicarboxylate.[18] The chloro-
furans were found to be fairly stable in hydrocarbon solvents but tend
to deteriorate in chlorinated or oxygenated solvents even during the
course of recording their 13C NMR spectra.
Table 1. Aromatization of tetrahydrofurans 2 by NaI=DMF
4-Chlorofuran
4 yield (%)
S. no.
Tetrahydrofuran 2
R
R0
1
2
3
4
5
6
a
b
c
d
e
f
H
H
n-C3H7
CH3
Ph
Ph
41
38
23
39
46
43
n-C5H11
H
Ph
H
CH3
Ph

Aromatization of Tetrahydrofurans
1949
It was not possible to detect or isolate the expected dechloroacetoxy-
lation product or any isofuran intermediate even when the reaction was
done for shorter duration, at lower temperatures, or both. When the
dihydrofuran 3d was heated with NaI (5 equivalents) in DMF, the aro-
matization occurred and took about the same time (4 h) for completion
as taken by the tetrahydrofurans 2 to give the chlorofuran 4d in better
yield (60%). No reaction occurred when the tetrahydrofuran 2d or the
dihydrofuran 3d was heated in DMF at 120 ꢀC in the absence of NaI,
though a few special types of chlorosteroidal compounds have been
reported to aromatize on heating in DMF at reflux.[21] Thus, an iodide
ion seems to be required for the dechloroacetoxylation and probably
also for replacement of the side-chain chloro group with iodo group to
facilitate the dehydrohalogenation.
EXPERIMENTAL
General Procedure
NaI (1.5 g, 10 mmol) was added to a solution of tetrahydrofuran 2
(2 mmol) in 10 ml of DMF. The reaction mixture was protected from
atmospheric moisture with a calcium chloride guard tube and heated to
120 ꢀC in an oil bath for 4 h. The solution was cooled, diluted with
50 ml of equivolume mixture of petroleum ether–diethyl ether, and
washed successively with water (2 ꢁ 50 ml), 5% sodium thiosulphate sol-
ution (10 ml), and brine (10 ml). The organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure. The
crude product thus obtained was chromatographed on an alumina
column using n-hexane as the eluent to obtain the 4-chlorofuran 4 as a
colorless oil.
Spectral Data
4-Chloro-3-methyl-2-phenylfuran (4a): IR: nmax3057 (m), 2922 (s), 2850
1
(m), 1482 (s), 1431 (m), 737 (s), 698 (s) cmꢂ1. H NMR: d 2.24 (s, 3H),
7.24–7.44 (m, 4H), 7.59–7.61 (m, 2H) ppm.
4-Chloro-3-methyl-2-pentylfuran (4b): IR: nmax2976 (s), 1644 (w),
1484 (m), 1396 (m), 1260 (w), 1148 (s), 1070 (s), 930 (m), 742
(m) cmꢂ1
.
1H NMR: d 0.90 (t, J ¼ 6.89 Hz, 3H), 1.13–1.37 (m, 4H),
1.58 (quintet, J ¼ 7.35 Hz, 2H), 1.9 (s, 3H), 2.51 (t, J ¼ 7.4 Hz, 2H),
7.21 (s, 1H) ppm.
3-Butyl-4-chlorofuran (4c): IR: nmax2925 (s), 1604 (s), 1509 (s),
1451( s), 1233 (s), 1214 (s), 1146 (s), 1015 (s), 917 (s), 726 (s) cmꢂ1
.

1950
R. N. Ram and I. Charles
1H NMR: d 0.93 (t, J ¼ 7.24 Hz, 3H), 1.38 (sextet, J ¼ 7.27 Hz, 2H), 1.55
(quintet, J ¼ 7.44 Hz, 2H), 2.39 (t, J ¼ 7.6 Hz, 2H), 7.16 (s, 1H), 7.37
(s, 1H) ppm.
4-Chloro-3-ethyl-2-phenylfuran (4d): IR: nmax3036 (s), 2924 (m), 1603
1
(s), 1508 (s), 1479 (s), 1146 (s), 1014 (s), 916 (s), 727 (s), 676 (s) cmꢂ1. H
NMR: d 1.37 (t, J ¼ 7.53 Hz, 3H), 2.80 (q, J ¼ 7.52 Hz, 2H), 7.38–7.54
(m, 2.1H), 7.69–7.72 (m, 1.3H) ppm.
3-Benzyl-4-chlorofuran (4e): IR: nmax3008 (m), 2880 (m), 1504 (s),
1
1060 (s), 920 (s), 730 (s), 706 (s) cmꢂ1. H NMR: d 3.66 (s, 2H), 6.99
(m, 1H), 7.10–7.24 (m, 5H), 7.31 (d, J ¼ 1.69 Hz, 1H) ppm.
3-Benzyl-4-chloro-2-methylfuran (4f): IR: nmax2957 (s), 2872 (s), 1663
1
(w), 1456 (s), 1377 (m), 1037 (s), 763 (m), 698 (s) cmꢂ1. H NMR: d 2.17
(s, 3H), 3.70 (s, 2H), 7.15–7.28 (m, 6H) ppm.
ACKNOWLEDGMENT
Financial assistance from the Department of Science and Technology
(DST), New Delhi, is gratefully acknowledged.
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