Copper(I)/Ligand-Catalyzed 5- endo Radical Cyclization-Aromatization of 2,2,2-Trichloroethyl Vinyl Ethers: Synthesis of 2,3-Difunctionalized 4-Chlorofurans

Article abstract of DOI:10.1021/acs.joc.5b02830

Copper(I)/ligand-catalyzed one pot synthesis of highly substituted 2,3-difunctionalized-4-chlorofurans has been reported. The reaction proceeds via a Cu(I)-catalyzed regioselective 5-endo-trig radical cyclization of 2,2,2-trichloroethyl vinyl ethers follo

Full text of DOI:10.1021/acs.joc.5b02830

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Article
Copper(I)/Ligand-Catalyzed 5-endo Radical Cyclization-Aromatization of 2,2,2-
Trichloroethyl Vinyl Ethers: Synthesis of 2,3-Difunctionalized 4-Chlorofurans
Ram Nath Ram, Dharmendra Kumar Gupta, and Vineet Kumar Soni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02830 • Publication Date (Web): 21 Jan 2016
Downloaded from http://pubs.acs.org on January 22, 2016
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Copper(I)/Ligand−Catalyzed 5−endo Radical Cyclization−Aromatization of 2,2,2−Trichloroethyl
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Vinyl Ethers: Synthesis of 2,3−Difunctionalized 4−Chlorofurans
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Ram N. Ram, Dharmendra Kumar Gupta*† and Vineet Kumar Soni*‡
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Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi−110016, India
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Abstract: Copper(I)/ligand−catalyzed one pot synthesis of highly substituted 2,3−difunctionalized−4−chlorofurans
has been reported. The reaction proceeds via a Cu(I)−catalyzed regioselective 5−endo−trig radical cyclization of
2,2,2−trichloroethyl vinyl ethers followed by the base−promoted dehydrochlorination. The success of the kinetically
disfavored 5−endo cyclization was attributed to the formation of captodatively stabilized radical intermediate in the
cyclization step and relatively high reaction temperature. Synthetic application of this protocol was also
demonstrated in the preparation of alkyl and aryl substituted 4−chlorofuranonapthoquinones.
INTRODUCTION
5−Endo−trig radical cyclization is a kinetically ‘disfavored’ process according to the Baldwin−Beckwith set of
empirical rules but its product is thermodynamically stable due to less ring strain.1 Therefore, it has been observed in
good number of systems involving cyclization of radicals2 such as carbon−,2a-c sulphur−2d and silicon−,2e
nitrogen−centered2f,2g onto C=C bond and carbon−centered radicals3 onto heteroatom−containing double bonds such
as azo,3a-b imine3c-d and carbonyl3e-g groups etc. producing a variety of carbo− and heterocyclic compounds.
Haloenamides4 are most extensively investigated systems for 5−endo radical cyclization reactions and their products
have found applications in synthesis of natural products and drugs.4i On the contrary, 5−endo radical cyclization on
β−haloalkyl vinyl ether is scarcely investigated and is a methodological challenge.5 A tin hydride−promoted 5−endo
radical cyclization of β−iodovinyl ethers has been reported to yield a few tetrahydrofurans.5a However, the reaction
suffers from several disadvantages associated with this methodology such as non−regioselectivity, access of toxic tin
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reagent, low yields of the products, reductive dehalogenation of the starting material and tedious separation of the
products. On the other part, Copper(I)−catalyzed 5−endo−trig halogen atom transfer radical cyclization (HATRC) is
free of such limitations.4a A combination of copper(I) salt and tert−amine ligands4a,4e under different reaction
conditions4f in the 5−endo cyclization of structurally different α−haloacetaenamides is proven to be a highly flexible,
mild and efficient methodology. Moreover, the 5−endo cyclic product undergo Cu(II)−mediated radical
polar−crossover reaction and tert−amine ligand−mediated dehydrohalogenation to generate two olefinic bonds.4c
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Although, our laboratory previously demonstrated
a DBU−promoted double dehydrohalogenation of
trichlorotetrahydrofuran to yield chlorofurans.6 The potential of β−trihaloroethylvinyl ethers as viable system to
undergo 5−endo radical cyclization and spontaneous dehydrohalogenations of its 5−endo product in the presence of
Cu(I)/ligand to give an aromatic system (furan ring) in single step, has not been envisaged so far.
A furan core bearing ester, acid and keto functionalities is a key structural unit of many naturally occurring
compounds7 (pentacyclic polyketides,7b furanonapthoquinones,7c furanosesquiterpenes,7d furanosteroids,7e
pseudopterenes,7f furanocembranolides7g), drugs molecules7a,8 (Fig. 1), materials9 and useful synthetic
intermediates.10 A β−chlorine functionality6,11 in a furan ring enhances its synthetic utility further by influencing the
reactivity of its furan ring6b and providing a center for specific chemical reactions such as metal−catalyzed coupling
and nucleophilic substitution reactions.11a−c Such β−chlorofurans have been transformed into bioactive natural
products,12 pharmaceutically important furans and non−furanoid compounds.13 They are potential substrates for
studying ‘structure−activity relationships”14 and ‘halogen−effect” in Diels−Alder cycloaddition reaction.6b High
stability and low cost of chlorofurans among other halofurans make them suitable particularly for industrial
applications.6b,13,15 Despite their useful applications, a few methods are reported for the synthesis of functionalized
β−chlorofurans. Furthermore, these methods suffer from the limitations with regard to substrate specificity,11c,15 low
yield of the products,16 number of steps,17,14c accessibility of starting materials,14c,18 and nature of the
substituents.11c,15,19 Although, the reactions of activated alkenes and alkynes (or their derivatives) and has been
extensively explored.20 Recently, Antonchick and co-worker21 reported a highly efficient, mild and direct method for
the synthesis of polysubstituted furans by an intermolecular radical addition of carbonyl compounds to alkynes.
However, there is still a need for a method of general applicability to install the highly useful halogen atom
functionality.
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With consideration to achieve a Cu(I)−catalyzed regiospecific 5−endo−trig radical cyclization of β−haloethylvinyl
ethers, and develop a direct and efficient route for the synthesis of such chlorofurans, herein, we report one pot
cyclization−aromatization of β−haloethylvinyl ethers to access highly functionalized β−chlorofurans.
O
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O
O
H
O
O
O
CO2Me
O
O
O
2-Isopropenylnaphtho
[2,3-b]furan-4,9-dione
Tsugicoline F
(Furosesquiterpene)
Halenaquinone
(Furanonapthoquinone)
(Pentacyclic polyketide)
CO2Me
CO2Me
O
AcO
MeO
O
O
O
O
H
O
O
O
O
O
O
Pseudopterolide
Wortmannin
O
(Pseudopterane)
(Furanosteroid)
Pukalide
(Furanocembranolide)
MeO2C
O
O
Cl
OH
CO2H
O
O
O
RO
O
Toumefolin C (R = H)
Toumefolin B (R = Me)
Selective inhibitor of MetAP
Angelone
Fig. 1 Some Natural products and Drugs Molecules
RESULT AND DISCUSSION
First, an HATRC precursor (E)−dimethyl−2−(2,2,2−trichloro−1−phenylethoxy)maleate 2a (Table 1) was prepared
by Michael addition of 1−phenyl−2,2,2−trichloroethanol22 1a to DMAD.23 The reaction of vinyl ether 2a with
varying amounts of CuCl was performed in the presence of commercially available 2,2′−bipyridine (bpy),
tetramethylethylenediamine (TMEDA) and pentamethyldiethylenetriamine (PMDETA) ligands at reflux under a
nitrogen atmosphere. The data with minimum required amount of the catalyst to complete the reaction are shown in
Table 1. The reaction followed a regioselective 5−endo−trig radical cyclization pathway. Although, the reaction
required more than stoichiometric amount of the CuCl/bpy (120 mol%) for completion (Entry 1, Table 1).
Purification of the crude product by column chromatography using neutral alumina afforded a colorless solid as the
major product 3a and a very small amount of the reduced starting material. The reduced starting material was
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formed probably due to hydrogen atom abstraction by the intermediate radical from the solvent DCE.24 The reaction
of the vinyl ether 2a in a poor hydrogen atom donor solvent benzene24 at reflux was heterogeneous but the reduction
of the starting material could be prevented (Entry 2, Table 1). TMEDA was found to be more effective. The
reaction was completed in 18 h to obtain 3a in 81% yield with lower catalyst loading (Entry 3, Table 1). However,
PMDETA was not as effective as TMEDA as a higher amount of the catalyst was required for reaction completion
with extended reaction time (Entry 4, Table 1). A possible explanation of relatively higher reactivity of
Cu(I)/TMEDA complex over Cu(I)/PMDETA could be the availability of more nitrogen sites for proton abstraction
in earlier case (Table 1, see molar concentration of ligands) in the base−promoted dehydrochlorination step. The
necessity of higher amount of the complex might be due to its deactivation by the liberated HCl produced during the
reaction by protonating the ligand. However, the reaction was incomplete with lower amount of the catalyst, for
example 10 mol% of CuCl provided <10% of 3a in all cases. No cyclization product formed when the reaction of 2a
was conducted at room temperature for 24 h even with the stoichiometric amount of CuCl/TMEDA and
CuCl/PMDETA in benzene.
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Table 1. CuCl/Ligand catalyzed 5−endo chlorine atom transfer radical cyclization−aromatization of 2aa
COOMe
CO2Me
CO2Me
Cl
Ph
CO2Me
CO2Me
CCl3
OH
CuCl/Ligand
K2CO3 (0.3 eq)
THF, reflux, 4 h
82%
CCl3
O
Ph
+
solvent, reflux, N2 atm
Ph
O
COOMe
3a
1a
2a
Entry
CuCl
Ligand
CuCl/Ligand
Solventb
Time (h)
3a (%)
(mol %)
(molar ratio)
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2
3
4
120
120
55
bpy
1:1
1:1
1:2
1:1
DCE
18
24
18
20
69
75
81
80
bpy
benzene
benzene
benzene
TMEDA
PMDETA
70
aAll he reactions were performed with 1 mmol of 2a under a N2 atmosphere at reflux.
bReaction mixture was heterogeneous in benzene.
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This methodology was further applied to 2,2,2−trichloroethyl vinyl ethers 2b−k under the optimized reaction
conditions to synthesize functionalized chlorofurans 3b−k in 67−82% yields with complete regioselectivity (Table
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2). The structures of chlorofurans 3 were established by H NMR, 13C NMR and IR spectroscopy and mass
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spectrometry. The formation of the chlorofurans 3 was further supported by single crystal X−ray diffraction data of
the p−tolyl derivative 3b (see supporting information). The reaction time required for the formation of chlorofurans
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3 was in accordance with the ease of dehydrochlorination of the cyclized product (p−O2NC4H4 < pyridyl < Ph <
alkyl). Several functional groups such as nitro, ester and halogen atoms were survived under such reaction
conditions.
Table 2. Synthesis of functionalized 4−chlorofurans 3a
Entry
1
R
Vinyl ether 2
4−Chlorofuran 3
Time (h) Yield (%)
Time (h) Yield (%)
1
2
3
a
Ph
4
4
5
82
80
70
18
18
24
81
71
67
b
c
d
e
f
4−MeC6H4
2−ClC6H4
3−ClC6H4
4−ClC6H4
4−BrC6H4
4−MeOC6H4
4−O2NC6H4
2−pyridyl
n−Et
4
5
4
4
4
4
4
4
4
4
78
80
82
80
79
80
78
75
18
16
18
16
12
16
24
24
73
75
71
75
76
75
80
82
6
7
g
h
i
8
9
10
11
j
k
i−Pr
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aIn first step, all the reactions were performed by taking 1 (10 mmol) and DMAD (10
mmol) and K2CO3 (3 mmol) in THF at reflux. In second step, vinyl ether (1 mmol), CuCl
(55 mol%) and TMEDA (110 mol%) were reacted in benzene at reflux under a nitrogen
atmosphere.
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Furanonapthoquinones are biologically important natural products and their cytotoxic activity varies with the type of
substituent on parent naphtho[2,3−b]−furan−4,9−dione.7c The synthetic application of this approach was
demonstrated by the treatment of vinyl ethers 5a and 5b (Scheme 1) with CuCl/TMEDA under the optimized
reaction conditions to obtain 4−chlorofuranonapthoquinones 6a (R = Ph) and 6b (R = Me) in 76% and 83% yields,
respectively.
Scheme 1
Furthermore, the synthesis of trisubstituted 4−chlorofurans could be realized with slight modifications in the
reaction conditions. The α−unsubstituted vinyl ether 2l (Scheme 2) did not undergo the expected 5−endo cyclization
to completion on treatment with CuCl/TMEDA catalyst even after prolonged heating for 24 h with large excess of
the catalyst (1 equiv) and only 23% of the product 3l along with 67% of starting material was obtained. In this case,
the ligand PMDETA was found to be more effective than TMEDA. Probably, a more effective ligand i.e. PMDETA
was required to promote the reaction of less activated vinyl ether 2l during the cyclization step. Thus, 2l was
refluxed 60 mol% of CuCl/PMDETA (1:1 mol ratio) in benzene at reflux for 18 h, followed by addition of 30 mol %
of PMDETA into the cooled reaction mixture and reflux for another 12 h. Usual work up of the reaction mixture and
purification by column chromatography gave 3l in 63% isolated yield. The vinyl ether 8 on a similar two stage
treatment with CuCl/PMDETA (60 mol%) for 18 h and with PMDETA (30 mol%) for 14 h furnished 9 in 58%
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yield. In these cases, the dehydrochlorination was not as facile as in the case of tetrasubstituted 4−chlorofurans due
to the absence of the substituent at C−5 position, thus requiring an additional amount of the basic ligand.
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Scheme 2
The functionalized 4−chlorofurans 3, 6 and 9 were stable at low temperatures unlike earlier reported alkyl and aryl
substituted 3−chlorofurans which were stable in hydrocarbon solvents.6b
MECHANISTIC STUDY
A plausible mechanism involving 5−endo−trig chlorine atom transfer radical cyclization of the trichloroethyl vinyl
ethers 10 (Scheme 3) to the α−chlorotetrahydrofuran 13 followed by ligand−promoted dehydrochlorination has been
proposed. Captodative radical center bearing electron donating alkoxy and electron withdrawing ester groups are
known to abstract halogen atom from halogen atom source easily.25 α−Chlorotetrahydrofuran 13 might undergo
successive dehydrochlorination to furan 15 in the presence of tertiary amine. Another possibility is the formation of
a carbocation 16 by losing one electron from the radical intermediate 12 to Cu(II), followed by proton abstraction to
give 14 first and then dehydrochlorination to 15. Such ligand promoted dehydrochlorination reaction in some
CuCl/bpy−catalyzed ATRC reactions has been observed earlier where bpy promoted the elimination.4d,4f
α−Chloroethers are known to undergo dehydrochlorination easily.26 Further, the dehydrochlorination of the
dihydrofuran 14 occurs easily due to the formation of the aromatic product 15.
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Scheme 3. Proposed mechanism for the formation of 4−chlorofurans
The formation of the dihydrofuran intermediate 14 (Scheme 3) was confirmed by quenching the reaction of the
vinyl ether 2a (Scheme 4) under optimized condition after 12 h instead of 18 h. Further purification of the crude
product gave the 4−chlorofuran 3a, a small amount of the dihydrofuran 19 and the starting material 2a.
Scheme 4
Although, the 4−exo−trig radical cyclization is kinetically favored according to Beckwith−Baldwin’s rule,1 no 4−exo
1
cyclization product 18 could be detected in H NMR of crude products. 5−Endo radical cyclizations are called
‘disfavored’ but lead to the formation of thermodynamically more stable products due to relatively less ring strain in
the 5−membered ring. Chatgilialoglu et al.1d have further elaborated the kinetics of 4-exo and 5-endo-trig radical
cyclizations by experimental and theoretical studies. 5−endo products are predominantly or exclusively formed
under equilibrium conditions.4g In the present case, the relatively high reaction temperature (refluxing benzene)
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might also have promoted reversibility of the 4−exo cyclization leading to the formation of the thermodynamically
more stable 5−endo cyclization product 12. The preference to the formation of 5−endo product at higher
temperatures has been observed earlier.4h Additionally, a carbonyl group on the radical acceptor alkenic bond at
α−position, has been observed earlier to provide assistance in attainment of a less strained transition state for the
generally unfavorable 5−endo cyclization.5a 5−Endo cyclization was expected to be further facilitated due to greater
stabilization of the radical intermediate 12 by captodative effect.1,25 These features might have contributed to the
formation of the 5−endo cyclization product exclusively in the present case. The effect of captodative stablization
was supported by the fact that the trichloroethyl vinyl ether mono−ester 20 (Scheme 5) did not undergo 5−endo
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cyclization in the absence of an ester or a keto group at α−position to stabilize the radical intermediate 22 initially
formed by 5−endo cyclization by the captodative effect. No 5−endo cyclization product 23 was isolated or detected.
Using PMDETA in the place of TMEDA under the same reaction conditions produced higher amount of the
elimination product 21 (20%), nearly 30% of the starting material 20 and an unidentifiable complex mixture. The
elimination product 21 could have arisen by fragmentation of 20 by C−O bond cleavge.5b-c
Scheme 5
CuCl/bpy−catalyzed cyclization reaction of O−homoallylic α−chloroglycolic esters occur preferentially via a similar
but acyclic captodative radical mechanism,27 the oxidation of captodative radical intermediate to carbocation by
CuCl2/bpy complex also occurred to some extent (<10%). Under the similar reaction conditions employed in the
present case, the captodative radical 12 might be expected to oxidize to the carbocation 16 (Scheme 3) by
CuCl2−complex formed during progress of the reaction. This carbocation may reversibly combine with the chloride
ion to produce the α−chlorotetrahydrfuran intermediate 13 and undergo dehydrochlorination or undergo fast
deprotonation4d,4f to give the dihydrofuran intermediate 14 directly. Attempts to trap the captodative radical 12
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intermolecularly4b,4c in the reaction of 2a by IBN radical (AIBN) and alkenes styrene and methyl acrylate under the
optimized reaction conditions met with failure and only chlorofuran 3a was isolated by column chromatography. An
attempt to trap the carbocation 16 or α-chlorotetrahydrofuran 13 with ethanol in the reaction of 2a in
benzene/ethanol (4:1 ratio) in the presence of 1 equivalent of CuCl and TMEDA failed. The vinyl ether 2a
decomposed under such reaction conditions. Therefore, the exact nature of these intermediates could not be
confirmed. Acyclic captodative radical center bearing an alkoxy and an ester groups is not known to be much
sensitive to oxidation (<10%) to carbocation in the presence of Cu(II) species.27 The retention of radical character of
cyclic captodative radical 12 under similar radical conditions is expected in the present case as well. Thus, a radical
mechanism appears to be more favorable. However, the oxidation of the captodative radical intermediate to a
carbocation by Cu(II) species followed by aromatization could not be ruled out.
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CONCLUSIONS
In conclusion, a novel copper(I)/ligand−catalyzed tandem 5−endo radical cyclization−aromatization of
2,2,2−trichloroethyl vinyl ethers has been reported for the synthesis of polysubstituted 4−chlorofurans in good
yields. The success of the kinetically disfavored 5−endo cyclization was attributed to the formation of the
captodatively stabilized radical intermediate in the cyclization step and relatively high reaction temperature. A
plausible mechanism has been proposed. Application of this methodology for the synthesis of biologically important
furanonapthoquinones has also been demonstrated. These furans could be potential synthetic intermediates for
various biologically important molecules and as substrates for studying ‘structure−activity relationships and
halogen−effect’.
EXPERIMENTAL SECTION
General Information
IR spectra were recorded on an FT−IR spectrometer by taking solid samples as KBr pellets and liquids as thin films
on KBr disks. NMR spectra were recorded on a 300 MHz FT NMR spectrometer in CDCl3 with TMS as internal
standard. Multiplicities are indicated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) and dd (doublet of doublet). 13C DEPT spectra were routinely recorded to identify different types of
carbons. Mass spectra were recorded on a high−resolution mass spectrometer (ESI−TOF) in positive−ion mode.
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Melting points were determined on an electrically heated apparatus by taking the samples in a glass capillary sealed
at one end and are uncorrected. The progress of the reaction was monitored by TLC using a glass plate coated with a
TLC grade silica gel. Iodine was used for visualizing the spots. For column chromatography, silica gel and neutral
alumina were used as the stationary phase, and n−hexane−ethyl acetate mixtures were used as the mobile phase.
Solvents were evaporated on a rotary evaporator under reduced pressure using an aspirator. Methyl acrylate, styrene,
AIBN, DBU and sodium trichloroacetate, sodium hydride, 2,2,2−trichloroethanol, DMAD, bpy, TMEDA,
PMDETA, ethyl propiolate, aliphatic and aromatic aldehydes, methanesulphonyl chloride, K2CO3, liquid ammonia
and DMF (dried) were commercially available and used as received. THF was dried over KOH pellets overnight,
distilled and stored over sodium wires. Benzene was distilled, and stored over sodium wires. DCE was dried by
distilling over anhydrous P2O5. The commercial nitrogen gas was used after passing successively through traps
containing solutions of alkaline anthraquinone−sodium dithionite, alkaline pyrogallol, conc. H2SO4 and KOH
pellets. Nitrogen atmosphere was created by Schlenk technique in all the experiments carried out under a nitrogen
atmosphere.
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All the trichloromethy carbinols 1a−k were prepared by the reaction of aldehydes with chloroform in the presence of
catalytic amounts of DBU22b or by reaction of aldehydes with trichloroacetic acid in DMSO as reported in the
literature.22a 2−Bromo−1,4−napthoquinone284 and ethyl 2−hydroxy−4−oxopent−2−enoate29 were prepared by known
procedures.
Preparation of 2,2,2−trichloroethyl vinyl ethers 2a−l: Acyclic precursors 2a−l prepared by Michael addition of
2,2,2−trichloroethanol22 1a−l to DMAD relying on the well known addition of alcohol to DMAD23 with slight
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modifications. The (E)−stereochemistry was assigned to them by comparing the values of the H NMR chemical
shifts (δ) of the olefinic protons with the ones reported in the literature23a for the olefinic protons of structurally
analogous dimethyl 2−alkoxymaleates.
General procedure: A suspension of the 2,2,2−trichloroethalnol 1a−l (10 mmol), DMAD (1.420 g, 10 mmol) and
K2CO3 (0.424 g, 3 mmol) in dry THF (40 mL) was heated at reflux. The progress of the reaction was monitored by
TLC, which indicated completion of the reaction by disappearance of the starting organic material after 3−5 h. After
completion of the reaction, the reaction mixture was cooled and evaporated under reduced pressure. The residual
mass was treated with diethyl ether or ethyl acetate (150 mL) and filtered. The filtrate was washed with water (2×20
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mL), dried (Na2SO4), filtered and evaporated under reduced pressure to obtain the crude adduct which on
purification by column chromatography on a small pad of neutral alumina using a n−hexane/ethylacetate mixture
(95:5−90:10, v:v) as solvent for elution afforded the trichloroethyl vinyl ethers 2a−l in (75−85%) high yields.
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Dimethyl 2−(2,2,2−trichloro−1−phenylethoxy)maleate 2a: White crystals, mp 120 ˚C (DCM−n−hexane), 3.013g,
82% yield; 1H NMR (CDCl3, 300 MHz): δ 3.63 (s, 3H), 3.91 (s, 3H), 5.07 (s, 1H), 5.42 (s, 1H), 7.43−7.47 (m, 3H),
7.57−7.60 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.6 , 53.0 , 89.0, 97.6, 98.0, 128.4, 129.3, 130.3, 130.8,
158.4, 162.8, 165.2 ppm; IR (KBr): vmax 2950(w), 1729(s), 1633(s), 1443(m), 1383(m), 1223(s), 1183(s), 1150(s),
1041(m), 832(m), 782(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H13Cl3O5Na 388.9721, found 388.9721.
Dimethyl 2−(2,2,2−trichloro−1−p−tolylethoxy)maleate 2b: White crystals, mp 114 ˚C (DCM−n−hexane), 3.052g,
80% yield; 1H NMR (CDCl3, 300 MHz): δ 2.37 (s, 3H), 3.61 (s, 3H), 3.90 (s, 3H), 5.07 (s, 1H), 5.39 (s, 1H), 7.23
(d, 2H, J = 8.1 Hz), 7.46 (d, 2H, J = 8.1 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 21.3, 51.6, 53.1, 89.1, 97.5, 98.3,
127.9, 129.1, 129.2, 140.5, 158.5, 162.9, 165.4 ppm; IR (KBr): vmax 2948(w), 1729(s), 1636(s), 1438(w), 1213(s),
1155(s), 1026(m), 830(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C15H15Cl3O5Na 402.9865, found 402.9877.
Dimethyl 2−(2,2,2−trichloro−1−(2−chlorophenyl)ethoxy) maleate 2c: Colorless crystals, mp 94 ˚C
(DCM−n−hexane), 2.815g, 70% yield; 1H NMR (CDCl3, 300 MHz): δ 3.63 (s, 3H), 3.90 (s, 3H), 5.11 (s, 1H), 6.03
(s, 1H), 7.34−7.48 (m, 3H), 7.79 (dd, 1H, J = 7.2, 2.1 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.8, 53.2, 83.9,
97.3, 97.7, 127.4, 129.2, 129.7, 129.8, 131.7, 135.5, 158.1, 162.8, 165.3 ppm; IR (KBr): vmax 2956(w), 1750(s),
1721(s), 1633(s), 1438(m), 1376(m), 1327(m), 1211(s), 1150(s), 1034(m), 825(m), 784(m), 754(m) cm−1; HRMS
(ESI+): m/z [M+Na]+ calcd for C14H12Cl4O5Na 422.9331, found 422.9341.
Dimethyl2−(2,2,2−trichloro−1−(3−chlorophenyl)ethoxy) maleate 2d: Colorless crystals, mp 107 ˚C
(DCM−n−hexane), 3.135g, 78% yield; 1H NMR (CDCl3, 300 MHz): δ 3.64 (s, 3H), 3.90 (s, 3H), 5.09 (s, 1H), 5.39
(s, 1H), 7.34−7.49 (m, 3H), 7.58 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.7, 53.1, 88.2, 97.6, 98.0, 127.5,
129.3, 129.7, 130.6, 132.9, 134.4, 158.1, 162.6, 165.1 ppm; IR (KBr): vmax 3103(w), 1727(s), 1632(s), 1574(m),
1476(m), 1437(s), 1380(s), 1220(s), 1145(s), 1034(m), 820(m), 763(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C14H12Cl4O5Na 422.9331, found 422.9345.
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Dimethyl 2−(2,2,2−trichloro−1−(4−chlorophenyl)ethoxy) maleate 2e: Colorless crystals, mp 116 ˚C
(DCM−n−hexane), 3.216g, 80% yield; 1H NMR (CDCl3, 300 MHz): δ 3.63 (s, 3H), 3.90 (s, 3H), 5.07 (s, 1H), 5.41
(s, 1H), 7.41 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.8, 53.1, 88.3,
97.8, 98.0, 128.8, 129.5, 130.7, 136.6, 158.2, 162.7, 165.1 ppm; IR (KBr): vmax 2998(w), 1745(s), 1632(s), 1494(m),
1442(m), 1375(m), 1216(s), 1154(s), 1023(m), 830(s), 775(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C14H12Cl4O5 Na 422.9331, found 422.9346.
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Dimethyl 2−(1−(4−bromophenyl)−2,2,2−trichloroethoxy) maleate 2f: Colorless crystals, mp 117 ˚C
(DCM−n−hexane), 3.660g, 82% yield; 1H NMR (CDCl3, 300 MHz): δ 3.64 (s, 3H), 3.90 (s, 3H), 5.06 (s, 1H), 5.39
(s, 1H), 7.46 (d, 2H, J = 8.4 Hz), 7.59 (d, 2H, J = 8.4 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.8, 53.2, 88.4, 97.7,
98.0, 125.0, 130.0, 130.9, 131.8, 158.2, 162.7, 165.1 ppm; IR (KBr): vmax 3088(w), 1745(s), 1721(s), 1631(s),
1492(w), 1440(m), 1375(m), 1340(m), 1215(s), 1154(s), 1020(m), 865(w), 772(m) cm−1; HRMS (ESI+): m/z
[M+Na]+ calcd for C14H12BrCl3O5Na 466.8810, found 466.8826.
Dimethyl 2−(2,2,2−trichloro−1−(4−methoxyphenyl)ethoxy) maleate 2g: Colorless crystals, mp 104 ˚C
(DCM−n−hexane); 1H NMR (CDCl3, 300 MHz), 3.183g, 80% yield; δ 3.62 (s, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 5.07
(s, 1H), 5.38 (s, 1H), 6.94 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz) ppm; 13C NMR (CDCl3, 75 MHz):
δ 51.7, 53.1, 55.2, 88.9, 97.5, 98.6, 113.8, 122.7, 130.7, 158.5, 161.0, 162.9, 165.4 ppm; IR (KBr): vmax 3025(w),
1752(s), 1709(s), 1633(s), 1515(m), 1442(m), 1374(m), 1309(m), 1256(m), 1212(s), 1150 (s), 1027(m), 831(m),
752(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C15H15Cl3O6Na 418.9809, found 418.9826.
Dimethyl 2−(2,2,2−trichloro−1−(4−nitrophenyl)ethoxy) maleate 2h: Light yellow crystals, mp 144 ˚C
(DCM−n−hexane); 1H NMR (CDCl3, 300 MHz), 3.260g, 79% yield; δ 3.64 (s, 3H), 3.92 (s, 3H), 5.09 (s, 1H), 5.56
(s, 1H), 7.83 (d, 2H, J = 8.7 Hz), 8.31 (d, 2H, J = 8.7 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.9, 53.3, 87.8,
97.1, 98.7, 123.5, 130.6, 137.8, 149.1, 157.8, 162.5, 164.9 ppm; IR (KBr): vmax 2921(w), 1747(s), 1721(s), 1635(s),
1525(m), 1438(m), 1349(m), 1144(s), 1030(m), 957(m), 826(m), 779(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd
for C14H12Cl3NO7 Na 433.9565, found 433.9572.
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Dimethyl 2−(2,2,2−trichloro−1−(pyridin−2−yl)ethoxy)maleate 2i: Low melting solid, 2.950g, 80% yield; H NMR
(CDCl3, 300 MHz): δ 3.62 (s, 3H), 3.92 (s, 3H), 5.16 (s, 1H), 5.63 (s, 1H), 7.37 (dd, 1H, J = 7.2, 5.1 Hz),
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7.72−7.84 (m, 2H), 8.68 (d, 1H, J = 4.5 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 51.8, 53.2, 89.9, 96.9, 98.0, 123.4,
124.9, 137.1, 149.2, 151.7, 158.3, 162.8, 164.4 ppm; IR (KBr): vmax 3106(w), 1721(s), 1644(w), 1593(m), 1517(s),
1438(m), 1345(s), 1303(s), 1129(s), 1073(m), 859(m), 801(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C13H12Cl3NO5Na 389.9672, found 389.9673.
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Dimethyl 2−(1,1,1−trichlorobutan−2−yloxy)maleate 2j: Colorless liquid, 2.495g, 78% yield; 1H NMR (CDCl3, 300
MHz): δ 1.11 (t, 3H, J = 7.5 Hz), 1.89−2.04 (m, 1H), 2.25−2.31 (m, 1H), 3.70 (s, 3H), 3.90 (s, 3H), 4.49 (dd, 1H, J
= 9.6, 2.1 Hz), 5.48 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 10.1, 24.6, 51.8, 53.0, 89.2, 96.5, 99.2, 161.1,
163.1, 165.9 ppm; IR (KBr): vmax 2983(m), 1753(s), 1716(s), 1632(s), 1440(m), 1368(m), 1273(m), 1152(s),
1036(m), 785(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C10H13Cl3O5Na 340.9709, found 340.9721
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Dimethyl 2−(1,1,1−trichloro−3−methylbutan−2−yloxy) maleate 2k: Colorless liquid, 2.503g, 75% yield;; H NMR
(CDCl3, 300 MHz): δ 1.00 (d, 3Η, J = 6.9 Hz), 1.08 (d, 3H, J = 6.9 Hz), 2.43−2.48 (m, 1H), 3.57 (s, 3H), 3.77 (s,
3H), 4.38 (d, 1H, J = 3.3 Hz), 5.37 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 16.7, 22.2, 30.9, 51.3, 52.6, 90.4,
95.9, 98.9, 161.0, 162.7, 165.4 ppm; IR (KBr): vmax 2959(m), 1752(s), 1722(s), 1633(s), 1440(w), 1366(s), 1205(m),
1146(s), 1039(m), 823(w), 764(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C11H15Cl3O5Na 354.9885, found
354.9877.
Dimethyl 2−(2,2,2−trichloroethoxy)maleate 2l: Colorless solid, mp 82−84 ˚C (DCM−n−hexane), 2.480g, 85%
yield; 1H NMR (CDCl3, 300 MHz): δ 3.73 (s, 3H), 3.93 (s, 3H), 4.43 (s, 2H), 5.33 (s, 1H) ppm; 13C NMR (CDCl3,
75 MHz): δ 51.9, 53.2, 79.4, 93.3, 96.4, 159.2, 162.7, 165.3 ppm; IR (KBr): vmax 3096(w), 2955(w), 1756(s),
1712(s), 1630(s), 1438(m), 1373(s), 1209(s), 1164(s), 1082(w), 1041(m), 852(m), 734(m) cm−1; HRMS (ESI+): m/z
[M+Na]+ calcd for C8H9Cl3O5Na 312.9409, found 312.9408.
Preparation of 2,2,2−trichloroethyl vinyl ethers 5a and 5b: Acyclic precursors 5a−b prepared by nucleophilic
substitution reaction of 2−bromo−1,4−napthoquinone 4 with sodium salt of 1−substituted 2,2,2−trichloroethanols 1a
and 1j using a method reported in the literature30 with slight modification.
General procedure: To a suspension of NaH (0.48 g, 0.01 mol, 60% dispersion in mineral oil) in dry THF/DMF
(25 mL, 4:1 v/v) was added a solution of the trichloroethanol 1a (2.254 g, 0.01 mol) or 1j (1.775 g, 0.01 mol) in dry
THF (10 mL) drop wise at 0˚C over 15 min duration. The mixture was stirred at 0 ˚C for another 30 min and then
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2−bromo−1,4−naphthoquinone 4 (2.370 g, 0.01 mol) was added into the suspension. The ice bath was then removed
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and the mixture was stirred at room temperature (25−30 ˚C). The progress of the reaction was monitored by TLC,
which indicated the completion of the reaction by disappearance of the starting material after 18 h (16 h in the case
of 1j). The volatiles were removed under reduced pressure and water (20 mL) was added to the residual mass. The
resulting suspension was extracted with ethylacetate (2×50 mL) and the combined solvent extract was washed with
brine (2×20 mL), dried (Na2SO4), filtered and evaporated under reduced pressure. Purification of the residual mass
by column chromatography on a small pad of neutral alumina using n−hexane/ethyl acetate mixture (98:1%, v/v)
afforded the pure trichloroethyl vinylic ethers 5a and 5b as yellow solids in high yields.
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2−(2,2,2−Trichloro−1−phenylethoxy)naphthalene−1,4−dione 5a: Yellow solid, mp 101 ˚C (DCM−n−hexane), 2.60
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g, 78% yield; H NMR (CDCl3, 300 MHz): δ 5.60 (s, 1H), 6.02 (s, 1H), 7.42−7.44 (m, 3H), 7.65 (d, 2H, J = 6 .0
Hz), 7.71−7.74 (m, 2H), 7.99−8.03 (m, 1H), 8.13−8.16 (m, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 88.3, 98.3,
113.1, 126.0, 126.5, 128.3, 129.3, 130.3, 130.8, 131.0, 131.4, 133.4, 134.1 , 157.0, 178.7, 184.2 ppm; IR (KBr): vmax
3061(w), 1689(m), 1656(s), 1609(s), 1330(w), 1243(m), 1210(m), 1064(w), 1036(m), 1006(m), 820(s), 775(s) cm−1;
HRMS (ESI+): m/z [M+Na]+ calcd for C18H11Cl3O3Na 402.9668, found 402.9666.
2−(1,1,1−Trichlorobutan−2−yloxy)naphthalene−1,4−dione 5b. Yellow crystals, mp 110 ˚C (DCM−n−hexane),
2.905g, 76% yield; 1H NMR (CDCl3, 300 MHz): δ 1.20 (t, 3H, J = 7.5 Hz), 2.11−2.22 (m, 1H), 2.33−2.39 (m, 1H),
4.82 (dd, 1H, J = 8.4, 2.1 Hz), 6.42 (s, 1H), 7.75−7.77 (m, 2H), 8.07−8.10 (m, 1H), 8.14−8.17 (m, 1H) ppm; 13C
NMR (CDCl3, 75 MHz): δ 10.4, 24.5, 88.7, 99.5, 112.6, 126.1, 126.8, 131.1, 131.6, 133.6, 134.3, 159.3, 179.1,
184.9 ppm: IR (KBr): vmax 3067(w), 1690(s), 1653(s), 1612(s), 1587(m), 1238(m), 1206(s), 1052(m), 1022(w),
819(m), 745(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H11Cl3O3 Na 354.9656, found 354.9666.
Preparation of (Z)−ethyl 2−(2,2,2−trichloroethoxy)−4−oxopent−2−enoate 8: The required starting material ethyl
2−(methylsulfonyloxy)−4−oxo−2−enoate 7 was obtained in 1.227 g, 52% yield as colorless liquid by reaction of
ethyl 2−hydroxy−4−oxopent−2−enoate29 (10 mmol) with methansulfonyl chloride following a procedure reported in
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the literature31; H NMR (CDCl3, 300 MHz): δ 1.29 (t, 3H, J = 7.1 Hz), 2.40 (s, 3H), 3.37 (s, 3H), 4.26 (q, 2H, J =
7.1 Hz), 6.75 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 13.8, 31.2, 40.2, 63.0, 126.3, 141.0, 161.7, 195.9 ppm. IR
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(KBr): vmax 2924(w), 1731(s), 1667(s), 1603(m), 1236(s), 1136(m), 1131(s), 1044 (m), 972(m), 823(m),
724(m)cm−1, m/z [M+Na]+ calcd for C8H12O6SNa 259.0252, found 259.0263.
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To a suspension of NaH (0.48 g, 0.01 mol, 60% dispersion in mineral oil) was added a solution of the
2,2,2−trichloroethanol 2l (1mL, 1.494 g, 0.01 mol) in dry THF (10 mL) drop wise at 0˚C over 15 min duration. The
mixture was stirred at 0 °C for another 30 min and then ethyl 2−(methylsulfonyloxy)−4−oxo−2−enoate 7 (2.360 g,
0.01 mol) was added in one lot and the reaction mixture was stirred at room temperature for 12 h. The crude product
obtained after work up (as described for vinyl ethers 5a−b) was further purified by column chromatography on a
small pad of neutral alumina using n−hexane/ethyl acetate mixture (95:5, v:v) as the solvent for elution to get the
vinyl ether 8 in (1.70 g, 60 % yield ) as a colorless liquid; The Z−configuration was assigned to 8 on the basis of the
chemical shift of δ 6.33 of the vinylic CH proton which was in the range of the chemical shifts assigned in the
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literature23a,32 to the vinylic protons of 2−alkoxyfumarates. H NMR (CDCl3, 300 MHz): δ 1.36 (t, 3H, J = 7.1 Hz),
2.53 (s, 3H), 4.33 (q, 2H, J = 7.1 Hz), 4.77 (s, 2H), 6.33 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 14.0,
32.0, 62.7, 82.3, 95.4, 118.2, 150.4, 162.6, 197.7 ppm. IR (KBr): vmax 2924(w), 1732(s), 1668(s), 1603(m), 1236(s),
1136(s), 1045m), 824(m), 724(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C9H11Cl3O4Na 310.9615, found
310.9615.
Preparation of (E)−ethyl 3−(2,2,2−trichloro−1−phenylethoxy)acrylate 20: It was prepared according to a
procedure (as described for vinyl ethers 2a−l) by taking 2,2,2−trichloro−1−phenylethanol 1a (2.255 g, 10 mmol),
ethyl propiolate (0.910 g, 1.01 mL, 10 mmol) and K2CO3 (0.424 g, 3 mmol) in THF (40 mL) and heating at reflux
for 3 h. The crude product obtained after work up was purified by column chromatography on a small pad of neutral
alumina using a n−hexane/ethyl acetate mixture (95:5, v:v) as the solvent for elution to get the vinyl ether 20 (2.750
g, 85%) as a white crystalline, mp 89 ˚C (DCM−n−hexane). 1H NMR (CDCl3, 300 MHz): δ 1.23 (t, 3Η, J = 7.2 Hz),
4.11 (q, 2H, J = 7.2 Hz), 5.32 (s, 1H), 5.35 (d, 1H, J = 12.9 Hz), 7.42−7.44 (m, 3H), 7.52−7.58 (m, 3H) ppm; 13C
NMR (CDCl3, 75 MHz): δ 14.2, 60.0, 91.4, 98.7, 100.5, 128.2, 129.5, 130.1, 132.1, 159.7, 166.9 ppm; IR (KBr):
vmax 2993(w), 1694(s), 1637(s), 1383(m), 1317(m), 1215(m), 1123(s), 1037(m), 974(m), 780(m), 744(m) cm−1;
HRMS (ESI+): m/z [M+Na]+ calcd for C13H13Cl3O3Na 344.9823, found 344.9822.
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Preparation of the functionalized 4−chlorofurans 3a−k and 6a−b: CuCl/TMEDA−catalyzed chlorine atom
transfer 5−endo radical cyclization−aromatization of 2,2,2−trichloroethyl vinyl ethers 2a−k and 5a−b: A
flame−dried two−neck round−bottom flask was charged with CuCl (0.055g, 0.55 mmol), TMEDA (0.2 mL, 0.128 g,
1.10 mmol) and degassed dry benzene (40 mL). An atmosphere of nitrogen was created inside the flask using
Schlenk technique. The suspension was stirred for 10 minutes at room temperature (25−30 ˚C) and trichloroethyl
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vinyl ether 2a−k or 5a−b (1 mmol) was added to it. The reaction mixture was degassed again by applying vacuum
and refilled with the N2 gas. The mixture was heated at reflux with stirring and the progress of the reaction was
monitored by TLC. After completion of the reaction as indicated by disappearance of the starting vinyl ether (10−24
h), the reaction mixture was cooled and diluted with ethyl acetate (100 mL). The resulting mixture was washed with
brine (2x50 mL), dried (Na2SO4), filtered and evaporated under reduced pressure. In case the organic extract was
dark in color, the organic extract was also washed with aqueous ammonia solution (20 mL) prior to drying and
evaporating. The solid thus obtained was recrystallized from DCM−n−hexane or diethyl ether−n−hexane at room
temperature (low temperature in case needed). In the cases where the crude product was a liquid or could not be
crystallized by the above process, it was purified by column chromatography on a small pad of neutral alumina
using n−hexane/ethyl acetate mixture (90:10 to 80:20%, v/v) as the solvent for elution. Thus, the tetrasusbtituted
4−chlorofurans were obtained as crystalline solids or liquids in good to high yields (67−83%).
Dimethyl 4−chloro−5−phenylfuran−2,3−dicarboxylate 3a: Colorless crystals, mp 58 ˚C (DCM−n−hexane), 0.238g,
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81% yield; H NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 3.99 (s, 3H), 7.43−7.52 (m, 3H), 7.99-8.03 (m, 2H) ppm;
13C NMR (CDCl3, 75 MHz): δ 52.6, 53.0, 111.8, 126.0, 126.3, 127.4, 129.1, 135.9, 140.0, 149.6, 157.4, 161.6 ppm;
IR (KBr): vmax 2954(w), 1737(s), 1640(w), 1599(w), 1538(w), 1484(w), 1444(m), 1315(s), 1272(m), 1233(s),
1170(s), 1069(m), 797(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H11ClO5Na 317.0187, found 317.0178.
Dimethyl 4−chloro−5−p−tolylfuran−2,3−dicarboxylate 3b: Colorless crystals, mp 46 ˚C (DCM−n−hexane), 0.220g,
71% yield; 1H NMR (CDCl3, 300 MHz): δ 2.31 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 7.18 (d, 2H, J = 7.8 Hz), 7.80 (d,
2H, J = 7.8 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 21.4, 52.5, 52.9, 110.7, 124.8, 126.1, 126.4, 129.4, 139.4,
140.2, 151.0, 157.5, 161.8 ppm; IR (KBr): vmax 2955(w), 1740(s), 1598(w), 1548(w), 1492(m), 1446(m), 1380(w),
1309(s), 1231(m), 1199(s), 1167(m), 1068(m), 989(m), 824(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C15H13ClO5Na 331.0339, found 331.0344.
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X−ray crystallography data of 3b: Formula: C15H13ClO5, Formula weight: 308.7 g/mol; Crystal system: triclinic;
Space group: P −1 (2); Unit cell dimensions: a = 7.170(3) Å b = 9.128(4) Å c = 11.218(5) Å α = 98.826(7)° β =
90.908(7)° γ = 92.801(7)°; Cell volume = 724.43(50) Å3, Z = 2; Density calculated = 1.41512 g/cm3; RAll = 0.0688.
Detailed X−ray crystallographic data is available from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK (CCDC 989265).
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Dimethyl 4−chloro−5−(2−chlorophenyl)furan−2,3−dicarboxylate 3c: Colorless crystals, mp 66 ˚C
(DCM−n−hexane) , 0.221g, 67% yield; 1H NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 4.0 (s, 3H), 7.35−7.47 (m, 2H),
7.50−7.55 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.7, 53.0, 114.6, 125.0, 126.0, 126.7, 130.3, 131.7, 131.9,
134.2, 141.2, 149.8, 157.4, 161.7 ppm; IR (KBr): vmax 2951(w), 1731(s), 1596(w), 1555(w), 1437(m), 1310(s),
1228(m), 1205(m), 1164(m), 1051(m), 763(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H10Cl2O5 Na
350.9797, found 350.9797.
Dimethyl 4−chloro−5−(3−chlorophenyl)furan−2,3−dicarboxylate 3d: Colorless crystals, mp 51 ˚C
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(DCM−n−hexane), 0.240g, 73% yield; H NMR (CDCl3, 300 MHz): δ 3.95 (s, 3H), 3.99 (s, 3H), 7.41 (d, 2H, J =
5.1 Hz), 7.91 (t, 1H, J = 3.8 Hz), 7.99 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.6, 53.0, 111.8, 124.2, 126.3,
126.4, 127.5, 130.1, 131.6, 132.0, 140.0, 149.6, 157.4, 161.5 ppm; IR (KBr): vmax 2956(w), 1746(s), 1643(m),
1595(w), 1440(m), 1313(s), 1209(m), 1072(m), 993(m), 780(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C14H10Cl2O5Na found 350.9797, found 350.9787.
Dimethyl 4−chloro−5−(4−chlorophenyl)furan−2,3−dicarboxylate 3e:
Colorless crystals, mp 58 ˚C
(DCM−n−hexane) , 0.247g, 75% yield; 1H NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 3.98 (s, 3H), 7.42 (d, 2H, J =
8.4 Hz), 7.92 (d, 2H, J = 8.4 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.6, 53.0, 111.8, 126.0, 126.3, 127.4, 129.1,
135.9, 140.0, 149.6, 157.4, 161.6 ppm; IR (KBr): vmax 3011(w), 1738(s), 1659(w), 1591(m), 1478(m), 1440(m),
1312(s), 1238(m), 1206(m), 1176(m), 1070(m), 830(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H10Cl2O5
Na found 350.9797, found 350.9807.
Dimethyl 5−(4−bromophenyl)−4−chlorofuran−2,3−dicarboxylate 3f: Colorless crystals, mp 57 ˚C
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(DCM−n−hexane); H NMR (CDCl3, 300 MHz), 0.265g, 71% yield; δ 3.91 (s, 3H), 3.95 (s, 3H), 7.57 (d, 2H, J =
8.7 Hz), 7.85 (d, 2H, J = 8.7 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.6, 53.0, 111.8, 124.1, 126.25, 126.33,
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127.4, 132.0, 140.0, 149.5, 157.3, 161.5 ppm; IR (KBr): vmax 2957(w), 1728(s), 1643(w), 1590(w), 1478(m),
1437(m), 1300(s), 1232(m), 1197(m), 1068(m), 1006(m), 821(m) cm.−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C14H10BrClO5Na 394.9292, found 394.9298.
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Dimethyl 4−chloro−5−(4−methoxyphenyl)furan−2,3−dicarboxylate 3g: White solid, mp 56 ˚C (DCM−n−hexane),
0.244g, 75% yield; 1H NMR (CDCl3, 300 MHz): δ 3.86 (s, 3H), 3.92 (s, 3H), 3.97 (s, 3H), 6.98 (d, 2H, J = 8.7 Hz),
7.95 (d, 2H, J = 8.7 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.5, 52.9, 55.4, 109.8, 114.2, 120.3, 126.5, 127.9,
139.1, 151.0, 157.6, 160.8, 161.9 ppm; IR (KBr): vmax 3001(w), 1731(s), 1603(m), 1546(w), 1493(m), 1446(m),
1300(s), 1266(s), 1235(s), 1169(m), 1075(m), 1009(m), 829(m), 795(w) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd
for C15H13ClO6Na 347.0303, found 347.0293.
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Dimethyl 4−chloro−5−(4−nitrophenyl)furan−2,3−dicarboxylate 3h: Yellow crystals, mp 105 ˚C (DCM−n−hexane),
0.258g, 76% yield; 1H NMR (CDCl3, 300 MHz): δ 3.89 (s, 3H), 3.92 (s, 3H), 8.14 (d, 2H, J = 8.4 Hz), 8.26 (d, 2H,
J = 8.4 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.8, 53.1, 114.3, 124.0, 126.2, 126.5, 133.0, 141.2, 147.7, 147.8,
157.0, 161.0 ppm; IR (KBr): vmax 3111(w), 1727(s), 1595(w), 1518(m), 1445(w), 1347(m), 1316(s), 1242(w),
1205(w), 1074(m), 859(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H10ClNO7Na 362.0056, found 362.0038.
Dimethyl 4−chloro−5−(pyridin−2−yl)furan−2,3−dicarboxylate 3i: Colorless crystals, mp 81 ˚C (DCM−n−hexane),
0.222g, 75% yield; 1H NMR (CDCl3, 300 MHz): δ 3.88 (s, 3H), 3.92 (s, 3H), 7.26 (t, 1H, J = 6.0 Hz), 7.75 (t, 1H, J
= 6.0 Hz), 7.94 ( d, 1H, J = 7.8 Hz), 8.70 (d, 1H, J = 3.6 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.7, 53.1, 114.2,
121.8, 123.9, 126.4, 136.8, 140.8, 146.8, 149.1, 150.1, 157.4, 161.5 ppm; IR (KBr): vmax 3110 (w), 1727(s),
1643(w), 1598(w), 1520(m), 1349(m), 1316(m), 1205(m), 1174(m), 1073(m), 1024(w), 859(w) cm−1; HRMS
(ESI+): m/z [M+H]+ calcd for C13H10ClNO5H 296.0324, found 296.0320.
Dimethyl 4−chloro−5−ethylfuran−2,3−dicarboxylate 3j: Colorless liquid, 0.197g, 80% yield; 1H NMR (CDCl3, 300
MHz): δ 1.26 (t, 3H, J = 7.5 Hz), 2.74 (q, 2H, J = 7.5 Hz), 3.89 (s, 3H), 3.93 (s, 3H) ppm; 13C NMR (CDCl3, 75
MHz): δ 11.4, 19.1, 52.3, 52.8, 111.2, 124.6, 139.7, 156.6, 157.4, 161.9 ppm; IR (KBr): vmax 2953(m), 1734(s),
1648(w), 1603(w), 1551(m), 1442(m), 1314(s), 1252(m), 1206(m), 1167(m), 1086(m), 1023(m), 796(m) cm−1;
HRMS (ESI+): m/z [M+Na]+ calcd for C10H11ClO5Na 269.0195, found 269.0187.
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Dimethyl 4−chloro−5−isopropylfuran−2,3−dicarboxylate 3k: Colorless liquid, 0.213g, 82% yield; 1H NMR (CDCl3,
300 MHz): δ 1.31 (d, 6H, J = 6.9 Hz), 3.20 (sept, 1H, J = 6.9 Hz), 3.89 (s, 3H), 3.95 (s, 3H) ppm; 13C NMR (CDCl3,
75 MHz): δ 19.9, 26.3, 52.4, 52.8, 110.1, 124.8, 139.4, 157.5, 159.6, 162.1 ppm; IR (KBr): vmax 2970(m), 1733(s),
1603(w), 1547(m), 1414(m), 1377(w), 1314(s), 1227(m), 1201(m), 1166(m), 1075(m), 1022(m), 796(w) cm−1;
HRMS (ESI+): m/z [M+Na]+ calcd for C11H13ClO5 Na 283.0346, found 283.0344
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3−Chloro−2−phenylnaphtho[2,3−b]furan−4,9−dione 6a:. Yellow crystals, mp 127 ˚C (DCM−n−hexane), 0.235g,
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76% yield; H NMR (CDCl3, 300 MHz): δ 7.48−7.55 (m, 3Η), 7.71−7.75 (m, 2H), 8.10−8.16 (m, 4H) ppm; 13C
NMR (CDCl3, 75 MHz): δ 110.6, 126.6, 126.8, 127.0, 127.2, 127.7, 128.9, 130.5, 132.2, 133.1, 133.9, 134.0, 149.8,
153.9, 172.6, 179.4 ppm; IR (KBr): vmax 3067(w), 1679(s), 1587(m), 1531(w), 1480(m), 1360(m), 1216(m),
1038(w), 941(m), 766(w), cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C18H9ClO3Na 331.0121, found 331.0132.
3−Chloro−2−ethylnaphtho[2,3−b]furan−4,9−dione 6b: Yellow crystals, mp 112 ˚C (DCM−n−hexane), 0.216g, 82%
yield; 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, 3H, J = 7.5 Hz), 2.87 (q, 2H, J = 7.5 Hz), 7.68−6.70 (m, 2H, J = 3.0
Hz), 8.09 (d, 2H, J = 3.0 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 11.4, 19.3, 110.4, 126.6, 126.7, 126.8, 131.9,
132.8, 133.78, 133.83, 150.0, 160.7, 172.4, 179.3 ppm; IR (KBr): vmax 2930(m), 1679(s), 1587(m), 1536(m),
1458(w), 1199(m), 1063(w), 995(m), 718(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H9ClO3Na 283.0122,
found 283.0132.
Synthesis of trisubstituted 4−chlorofurans 3l and 9: A flame−dried two−necked round−bottom flask was charged
with CuCl (0.06 g, 0.6 mmol), PMDETA (0.12 mL, 0.103 g, 0.6 mmol) and degassed dry benzene (40 mL). An
atmosphere of nitrogen was created using Schlenk technique. The suspension was stirred for 10 minutes at room
temperature (25−30 ˚C) and trichloroethyl vinyl ether 2l (0.292 g, 1 mmol) or 8 (0.290 g, 1 mmol) was added to it.
The reaction mixture was degassed again by applying vacuum and refilled with the N2 gas. The mixture was heated
at reflux with stirring for 18 h. The heating was stopped and the reaction mixture was cooled to 5−10 ˚C. An
additional amount of PMDETA (0.06 mL, 0.052 g, 0.3 mmol) was added and the reaction mixture was stirred for 10
min at the same temperature. The heating at reflux temperature was then resumed for an additional 12 h (in the case
of 2l) or 14 h (in the case of 8). The reaction mixture was worked up (as described for 4−chlorofurans 3a−k and
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6a−b). The crude products were purified by column chromatography on a small pad of neutral alumina using
n−hexane/EtOAc mixture (90:10 to 80:20, v/v) as the solvent for elution to obtain 3l and 9.
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Dimethyl 4−chlorofuran−2,3−dicarboxylate 3l: Colorless crystals, mp 45 ˚C (DCM−n−hexane), 0.138 g, 63% yield;
1H NMR (CDCl3, 300 MHz): δ 3.93 (s, 3H), 3.96 (s, 3H), 7.57 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz):
δ 52.7, 53.0, 116.7, 123.9, 141.7, 142.6, 157.3, 161.5 ppm; IR (KBr): vmax 3147(w), 1737(s), 1594(w), 1508(m),
1442(s), 1312(m), 1279(m), 1218(m), 1170(w), 1066(m), 794(w) cm−1. HRMS (ESI+): m/z [M+Na]+ calcd for
C8H7ClO5Na 240.9871, found 240.9874.
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Ethyl 3−acetyl−4−chlorofuran−2−carboxylate 9: Colorless liquid, 0.126 g, 58% yield; 1H NMR (CDCl3, 300 MHz):
δ 1.35 (t, 3H, J = 7.1 Hz), 2.57 (s, 3H), 4.36 (q, 2H, J = 7.1 Hz), 7.52 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz):
δ 14.0, 31.7, 62.0, 115.7, 131.6, 141.0, 141.7, 157.2, 195.0 ppm; IR (KBr): vmax 3146(w), 1722(s), 1586(m),
1503(m), 1389(m), 1293(s), 1182(s), 1118(m), 1018(m), 782(s) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for
C9H9ClO5 Na 239.0081, found 239.0082.
Dimethyl 4,4-dichloro-5-phenyl-4,5-dihydrofuran-2,3-dicarboxylate 19: It was obtained in trace amount by
quenching the reaction of 2a after 12 h (before completion of the reaction, which required 18 h) followed by usual
work up and purification (as described for 4−chlorofurans 3a−k and 6a−b). Colorless solid, mp 40 ˚C
(DCM−n−hexane); 1H NMR (CDCl3, 300 MHz): δ 3.82 (s, 3H), 3.84 (s, 3H), 5.80 (s, 1H), 7.39−7.41 (m, 3H), 7.56
(d, 2H, J = 6.3 Hz) ppm; 13C NMR (CDCl3, 75 MHz): δ 52.5, 52.8, 90.7, 95.7, 125.8, 128.4, 128.6, 129.5, 136.1,
142.8, 161.9, 168.7 ppm; IR (KBr): vmax 2940(m), 1728(s), 1638(m), 1582(s), 1538(s), 1486(m), 1363(m), 1266(m),
1097(m), 968(m), 817(m), 761(m) cm−1; HRMS (ESI+): m/z [M+Na]+ calcd for C14H12Cl2O5Na 352.9954, found
352.9954.
Attempted CuCl/PMDETA−catalyzed chlorine atom transfer radical cyclization of the
2,2,2−trichloro−1−phenylethyl vinyl ether 20: The experiment was performed by the same procedure (as
described for 4−chlorofurans 3a−k and 6a−b) for the synthesis of the tetrasubstituted 4−chlorofurans using 1 equiv
of CuCl/PMDETA (1:1 mol ratio). Purification of the crude product by column chromatography on neutral alumina
column using n−hexane/ethyl acetate mixture (99:01−80:20, v:v ) as the solvent for elution gave a small amount of
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the known (2,2−dichlorovinyl)benzene 2122b (0.035 g, 20%) and the starting material 20 (0.100 g, 30%). Other
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(a) Attempted trapping of captodative radical intermediate 12 with alkenes and AIBN: This experiment was
performed by the same procedure (as mentioned for 4−chlorofurans 3a−k and 6a−b) for the synthesis of the
tetrasubstituted 4−chlorofurans. Excess amount of CuCl/TMEDA (1:2 mol ratio) (60 mol%) was used to ensure
complete disappearance of the starting material 2a. Large excess of alkenes were deliberately taken to promote the
trapping of the possible radical intermediate 12. Similarly, an excess of AIBN (1 equiv) was chosen due to possible
involvement of IBN radical in the reduction of Cu(II) to Cu(I)−complex.
General Procedure: A flame−dried two−neck round−bottom flask was charged with CuCl (0.060 g, 0.6 mmol) and
degassed benzene (40 mL) under a N2 atmosphere using Schlenk technique. TMEDA (0.18 mL, 0.139 g, 1.2 mmol)
was injected to this suspension and the suspension stirred for 10 minutes. Next, the vinyl ether 2a (0.367 g, 1 mmol)
and AIBN (0.137 g, 1 mmol) or styrene (0.58 mL, 0.52 g, 5 mmol) or methyl acrylate (0.45 mL, 0.43 g, 5 mmol)
were added and the mixture was heated at reflux. In the case of alkenes, the formation of the polymeric material
along the wall of the round bottom flask was observed. After the disappearance of the starting material (20−24 h) as
indicated by TLC, the reaction mixture was cooled and ethyl acetate (100 mL) was added. The resulting solution
was washed with brine (3x25 mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate was
concentrated under reduced pressure. The purification of the residual mass by column chromatography on a small
pad of neutral alumina column using n−hexane/ethyl acetate mixture (90:10 to 80:20, v:v) as the solvent for elution
gave the chlorofuran 3a 0.240 g (76%) in the case of AIBN), 0.215 g (68%) in the case of methyl acrylate and 0.221
g (70%) in the case of styrene.
(b) Attempted trapping of the carbocationic intermediate 16 with ethanol: This experiment was performed by
the same procedure as mentioned for 4−chlorofurans 3a−k and 6a−b using benzene/ethanol (40 mL, 4:1, v:v) as
solvent system. Excess catalyst (1 equiv. CuCl/TMEDA in 1:2 mol ratio) was taken to ensure complete
disappearance of the starting material 2a. However, most of the vinyl ether 2a decomposed into unidentifiable
complex mixture in 6 h as indicated by TLC and 1H NMR of the crude product.
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Supporting Information
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Copies of H and 13C NMR spectra of 2, 3, 5-9, 19 and 20, and X-ray data of 3b. CIF file of 3b. This material is
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available free of charge via the internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Authors
E−mail: dkgiitd@gmail.com, soni.1@iitj.ac.in
Present Address
†Dharmendra Kumar Gupta, Micro labs Ltd., Plot No. 43−45, KIADB, Jigni−Bommasandra Link Road, Bangalore
560105, India.
‡Vineet Kumar Soni, Department of Chemistry, Indian Institute of Technology Jodhpur, Ratanada,
Jodhpur−342011, India.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to Council of Scientific and Industrial Research, New Delhi, for a research fellowship to D.K.G. and
University Grant Commission, New Delhi, for a research fellowship to V.K.S.
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