A new facile approach to the synthesis of 3-methylthio-substituted furans, pyrroles, thiophenes, and related derivatives

Article abstract of DOI:10.1021/jo702585s

(Chemical Equation Presented) 2-(Methylthio)-1,4-diaryl-2-butene-1,4-dione (3) are prepared from readily available aryl methyl ketones in the presence of copper(II) oxide, iodine, and dimethyl sulfoxide. The success of the cross-coupling reaction of 4-chloroacetophenone with 2-acetylthiophene confirms a proposed self-sorting tandem reaction mechanism. Both Z- and E-isomers of compound 3 are readily converted into the corresponding 3-methylthio 2,5-diaryl furan 7 in good yield through a domino process involving the reduction of the double bond followed by the Paal-Knorr furan synthesis. Meanwhile, 4-bromo-3-methylthio 2,5-diaryl furan 10 is obtained either by the treatment of furan 7 with molecular bromine or by the treatment of diketone 3 with 30% hydrogen bromide in acetic acid solution in one pot. Removal of the methylthio group is accomplished by the treatment of 7 with Raney Ni in ethanol, which affords the diaryl-substituted furan 11 in excellent isolated yield. Selective reduction of the double bond of compound 3 leads to the formation of the saturated 1,4-diketone 13, which is easily converted to the corresponding 3-methylthio-2,5-diaryl-substituted pyrrole 14 and thiophene 15 via the Paal-Knorr cyclization reaction.

Full text of DOI:10.1021/jo702585s

A New Facile Approach to the Synthesis of 3-Methylthio-Substituted
Furans, Pyrroles, Thiophenes, and Related Derivatives
Guodong Yin,† Zihua Wang,† Aihua Chen,† Meng Gao,† Anxin Wu,*,† and
Yuanjiang Pan*,‡
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal
UniVersity, Wuhan 430079, People’s Republic of China, and Department of Chemistry, Zhejiang
UniVersity, Hangzhou 310027, People’s Republic of China
chwuax@mail.ccnu.edu.cn; panyuanjiang@zju.edu.cn
ReceiVed December 4, 2007
2-(Methylthio)-1,4-diaryl-2-butene-1,4-dione (3) are prepared from readily available aryl methyl ketones
in the presence of copper(II) oxide, iodine, and dimethyl sulfoxide. The success of the cross-coupling
reaction of 4-chloroacetophenone with 2-acetylthiophene confirms a proposed self-sorting tandem reaction
mechanism. Both Z- and E-isomers of compound 3 are readily converted into the corresponding
3-methylthio 2,5-diaryl furan 7 in good yield through a domino process involving the reduction of the
double bond followed by the Paal-Knorr furan synthesis. Meanwhile, 4-bromo-3-methylthio 2,5-diaryl
furan 10 is obtained either by the treatment of furan 7 with molecular bromine or by the treatment of
diketone 3 with 30% hydrogen bromide in acetic acid solution in one pot. Removal of the methylthio
group is accomplished by the treatment of 7 with Raney Ni in ethanol, which affords the diaryl-substituted
furan 11 in excellent isolated yield. Selective reduction of the double bond of compound 3 leads to the
formation of the saturated 1,4-diketone 13, which is easily converted to the corresponding 3-methylthio-
2,5-diaryl-substituted pyrrole 14 and thiophene 15 via the Paal-Knorr cyclization reaction.
Introduction
recent years to generate these substituted five-membered
heterocycles.8–11 Among the reported methods, the classical
Substituted furans, thiophenes, and pyrroles represent three
important classes of five-membered heterocycles that are found
as structural elements in many natural products, as well as
pharmaceutically important substrates.1–3 They also can be
employed as useful intermediates in synthetic organic chemis-
try,4 material science,5 nonlinear optics,6 and supramolecular
chemistry as molecular sensors and other devices.7 Therefore,
a large number of synthetic methods have been developed in
(2) (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans 1. 1999, 2849. (b) Boger,
D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
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J. C.; Young, P. J.; Adams, T. B. Food Chem. Toxicol. 2003, 41, 1761. (f)
Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664. and
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Dannhardt, G.; Kiefer, W.; Kramer, G.; Maehrlein, S.; Nowe, U.; Fiebich, B.
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* To whom correspondence should be addressed.
† Central China Normal University.
‡ Zhejiang University.
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ComprehensiVe Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.;
Pergamon: Oxford, UK, 2003; Vol. 15. (b) Jones, R. A. Pyrroles, Part II, the
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10.1021/jo702585s CCC: $40.75
Published on Web 03/20/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3377–3383 3377

Yin et al.
Paal-Knorr12 reaction (cyclocondensation of 1,4-dicarbonyl
compounds) is still the most frequently used for the synthesis
of these five-membered heterocycles.
SCHEME 1
Sulfur-containing aromatics are attractive candidates for
organic semiconductors13 and can act as unique coordination
compounds for electronic, magnetic, and optical materials.14
Many 3-thio-substituted furan derivatives (such as thioethers 1
and 2, Scheme 1) have been identified in coffee and cooked
beef.15 In addition, alkylthio-substituted heterocycles are par-
ticularly attractive intermediates that have found widespread
usage in organic synthesis. They can undergo a variety of
reactions16,17 including addition/elimination, nickel-catalyzed
Grignard coupling, Michael additions, ortho-metalation, acid
SCHEME 2
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hydrolysis to butenolides, [4 + 2]-cycloaddition reactions, and
the Liebeskind-Srogl reaction.18 Although many synthetic
procedures are available for their formation,19 most of the
existing methods often require harsh conditions and are fre-
quently based on the use of a preexisting heterocycle.
The formation of carbon-carbon bonds is central to organic
synthesis because it provides the carbon skeleton that defines
the structure and function of an organic compound. Although
many excellent methods have been published, the direct
carbon-carbon bond-forming reaction between two sp3 C-H
bonds is still a challenge.20 Recently, we reported a carbon-
carbon double-bond-forming reaction for the preparation of
2-methylthio-substituted 1,4-diketones from readily available
(hetero)aryl methyl ketones (Scheme 2),21 which is a novel
carbon-carbon double-bond-forming reaction between the sp3
C-H bonds of two methyl groups. This is also a simple,
effective, and interesting approach to the 1,4-diketones compared
with the previously reported methods22 and an attractive way
to introduce the methylthio group into these molecules from
inexpensive dimethyl sulfoxide. In this paper, the scope of the
substrates is extended to other heteroaryl methyl ketones and
the reaction mechanism is further confirmed via cross-coupling
reactions. In addition, the Paal-Knorr cyclization reactions of
these 1,4-diketones to give methylthio-substituted furans, pyr-
roles, and thiophenes and their derivatives have been investi-
gated. These have been found to proceed in good yield.
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Results and Discussion
Homocoupling of aryl methyl ketones in the presence of
iodine, copper(II) oxide, and dimethyl sulfoxide affords 2-me-
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3378 J. Org. Chem. Vol. 73, No. 9, 2008

Substituted Furans, Pyrroles, and Thiophenes
TABLE 1. Formation of 2-Methylthio 1,4-Diketones via
Homocoupling of (Hetero)aryl Methyl Ketones
SCHEME 3. The Cross-Coupling Reaction
yielda
yielda
entry
R
3
(%, Z/E) entry
R
3
(%, Z/E)
1
2
3
4
5
6
7
8
C6H5
3a 86 (86/14)
9
2-naph
3i 89 (63/37)
3j 81
3k 80 (93/7)
4-MeC6H4 3b 94 (81/19) 10b 2-furyl
4-MeOC6H4 3c 81 (86/14) 11 2-thienyl
4-EtOC6H4 3d 86 (93/7) 12 5-Br-2-thienyl 3l 74 (81/19)
4-ClC6H4
4-BrC6H4
3e 85 (70/30) 13 5-Cl-2-thienyl 3m 70 (84/16)
3f 92 (70/30) 14 3-thienyl 3n 77 (88/12)
4-NO2C6H4 3g 71 (57/43) 15b 2-benzofuryl 3o 65
1-naph
3h 88 (63/37)
a Isolated yield. b E-isomers are not isolated.
thylthio-substituted 1,4-diketones in good yield (Table 1, entries
1–9).21 Unsubstituted heteroaryl methyl ketone substrates also
give good results (Table 1, entries 10 and 11). Since the building
blocks for the synthesis of oligomers that are used in the material
sciences are often the mixed thiophene/furan/pyrrole units,23 we
first extended the scope of the reaction to the substituted (or
different position-substituted) heteroaryl methyl ketone sub-
strates. For example, heating a mixture of 5-bromo-2-acetyl-
thiophene, iodine, copper(II) oxide, and dimethyl sulfoxide at
60–65 °C for about 18 h produces the expected diketones 3l in
74% overall yield (Z/E ) 81/19) (Table 1, entry 12). Similarly,
substrates 5-chloro-2-acetylthiophene, 3-acetylthiophene, and
2-acetylbenzofuran also give the desired products 3m, 3n, and
3o in 70%, 77%, and 65% overall yields, respectively (Table
1, entries 13–15). Z-isomers are the major products due to their
better thermodynamic stability than E-isomers during the
dehydrating process of the intermediate.21 The Z/E-stereocon-
figuration determination for compounds 3 was accomplished
by means of one- and two-dimensional NMR experiments24
including 1H, 13C, gCOSY, gHSQC, gHMBC, and NOESY. The
1H NMR spectra show that the protons of the SCH3 appear as
a singlet at 2.45–2.52 and 2.16–2.29 ppm in E-isomers and
Z-isomers, respectively, while the vinyl hydrogen (H-2) of
E-isomers and Z-isomers presents a singlet in the range
6.69–6.96 and 6.89–7.03 ppm, respectively. In other words, the
methyl protons of Z-configuration in this system resonate at
higher field than those of E-configuration, but the vinyl hydrogen
of Z-configurational compounds exhibits resonance at lower field
than that of E-configurational compounds.
Inspired by the successful synthesis of 1,4-diketones by the
homocoupling reaction, and to confirm further the proposed self-
sorting tandem reaction mechanism,21 we investigated the cross-
coupling reaction between two representative substrates 4-chlo-
roacetophenone and 2-acetylthiophene under the above-noted
standard conditions. As shown in Scheme 3, according to the
reaction mechanism, heating a mixture of equimolar 4-chloro-
acetophenone and 2-acetylthiophene should give eight 1,4-
diketones. This complex reaction process may proceed as
follows: First, R-iodoketones 4a and 4b, obtained by iodination
of the methyl ketones with copper(II) oxide and iodine, likely
are sequentially oxidized by dimethyl sulfoxide to 4d and 4e.
Thereafter, 4a and 4b react with dimethyl sulfide (DMS), which
is readily produced from dimethyl sulfoxide in high yield by
the presence of HI, which is formed in the first step. This leads
to the sulfur ylides 4c and 4f, respectively. Then 4d condenses
with 4c or 4f (4e with 4c or 4f) in aldol-type reactions to produce
intermediates which after the loss of MeI are then dehydrated
to yield 1,4-diketones 3e or 6 (5 or 3k). Fortunately, the eight
products could be identified by HPLC-MS analysis of the crude
isolated reaction mixture, as shown in Figure 1 [the peaks of
(Z)-5 and (Z)-6 overlapped, see the Supporting Information for
details). Furthermore, the heterocoupling products (Z)-5 and
(Z)-6 were also isolated by column chromatography in 24% and
6% yields, respectively. Furthermore, the structure of (Z)-5 is
confirmed by an X-ray crystal analyses (see the Supporting
Information).
Next, we attempted to synthesize 3-methylthio 2,5-diaryl
furans in one pot from the already synthesized unsaturated 1,4-
diketones through a domino process involving the reduction of
the double bond followed by a Paal-Knorr furan cyclization.
As shown in Scheme 4, reduction of (Z)-3a with stannous
chloride in the presence of concentrated hydrochloric acid in
acetic acid at reflux25 resulted in the formation of furan 7a in
85% isolated yield within 30 min (Table 2, entry 1). 7a was
also obtained in 87% yield starting from (E)-3a under the same
reaction conditions (Table 2, entry 2). When diketones (Z)-3
bearing electron-donating Me, OMe, and OEt groups or
moderately electron-withdrawing Cl or Br atoms at the C-4
position of the phenyl ring were heated in this way, furans 7b–f
were obtained in 83–89% yields (Table 2, entries 3 and 5–8).
The structure of 7b is unambiguously supported by an X-ray
crystal structure analysis (see the Supporting Information).
However, in the case of substrate 3g bearing an electron-
withdrawing NO2 group on the phenyl ring, the reaction gave
a complicated mixture and the expected furan 7g was not
observed, which accorded with the published results (Table 2,
(23) (a) Hucke, A.; Cava, M. P. J. Org. Chem. 1998, 63, 7413. (b) Kitamura,
C.; Tanaka, S.; Yamashita, Y. Chem. Mater. 1996, 8, 570.
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J. Org. Chem. Vol. 73, No. 9, 2008 3379

Yin et al.
FIGURE 1. HPLC-MS analysis of the crude isolated reaction mixture. Chromatography was performed on a Hypersil ODS2 column (4.6250 mm,
5 µm) with methanol–water (75%:25%) as the mobile phase. The detection wavelength was 280 nm (see the Supporting Information for details).
Homocoupling and heterocoupling products are marked with a circle (b) or a square (9), respectively.
TABLE 2. Synthesis of 3-Methylthio-2,5-diaryl Furans
entry
reactants
R
products
yielda (%)
entry
reactants
R
products
yielda (%)
1
2
3
4
5
6
7
8
9
(Z)-3a
(E)-3a
(Z)-3b
(E)-3b
(Z)-3c
(Z)-3d
(Z)-3e
(Z)-3f
(E)-3f
C6H5
C6H5
7a
7a
7b
7b
7c
7d
7e
7f
85
87
89
90
88
85
83
85
88
10
11
12
13
14
15
16
17
(Z)-3g
(Z)-3h
(E)-3h
(Z)-3i
(Z)-3j
(Z)-3k
(Z)-3n
(Z)-3o
4-NO2C6H4
1-naph
1-naph
2-naph
2-furyl
2-thienyl
3-Thienyl
2-benzofuryl
7g
7h
7h
7i
0
80
82
84
trace
78
75
69
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-EtOC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
7j
7k
7n
7o
7f
a Isolated yield.
SCHEME 4
SCHEME 5
entry 10).26 To our satisfaction, when the R groups of the
Z-isomers are naphthyl, thienyl, or benzofuryl, the corresponding
furans (7h, 7i, 7k, 7n, and 7o) were obtained in 69–84% yields
(Table 2, entries 11, 13, and 15–17). Unfortunately, we failed
to obtain furan 7j due to the difficulty in the cyclization reaction
in the presence of the furyl group even when starting from the
saturated 1,4-diketone (Table 2, entry 14).27 It should be noted
that the E-isomers of 3b, 3f, and 3h also afford the correspond-
ing products 7b, 7f, and 7h in 82–90% yields (Table 2, entries
4, 9, and 12). Therefore, it is unnecessary to separate the Z/E
isomers before cyclization to the furans. It was interesting to
find that the reaction of the diketone (Z)-3l under the above-
noted standard conditions led to the undesired debrominated
furan 7k instead of 7l in 70% yield. This is likely due to the
known easy dehalogenation of 2-halogenated thiophenes in the
presence of stannous chloride under acid conditions (Scheme
5).28 In addition, the Z-isomers of the heterocoupling products
5 and 6 also afforded the desired products 8 and 9 in 82% and
80% yields, respectively (Scheme 6).
stituted furan. The latter can be readily converted into related
important derivatives via classic coupling reactions (Heck,
Suzuki, Sonogashira, Liebeskind-Srogl, et al.). As shown in
Scheme 7, treatment of 3-(methylthio)-2,5-diphenylfuran 7a with
bromine in chloroform at 0 °C within 5 min gave 3-bromo-4-
(methylthio)-2,5-diphenylfuran 10a in 92% yield (Table 3, entry
1). Bromo-furans 10b, 10e, and 10f were also obtained in good
yields from the corresponding furans (7) (Table 3, entries 4, 6,
and 8). We were pleased to find also that the (Z)-3a, (E)-3a,
(Z)-3b, (Z)-3e, and (Z)-3f could be converted directly into the
corresponding bromo-furans 10 by means of 30% hydrogen
bromide in chloroform (rather than in glacial acetic acid25b) at
0 °C in 58–64% yields (Table 3, entries 2, 3, 5, 7, and 9).
It has been reported that a number of 2,5-diaryl furans exhibit
excellent biological activity.29 Removal of the methylthio group
may be achieved by treating the newly synthesized furan 7 with
Raney Ni in ethanol.30 This affords the 2,5-diaryl furans (11)
in 85–91% isolated yields (Scheme 8 and Table 4).
We also attempted to introduce a bromine atom into the newly
synthesized trisubstituted furan ring 7, to obtain the tetrasub-
(29) (a) Lansiaux, A.; Dassonneville, L.; Facompré, M.; Kumar, A.; Stephens,
C. E.; Bajic, M.; Tanious, F.; Wilson, W. D.; Boykin, D. W.; Bailly, C J. Med.
Chem. 2002, 45, 1994. (b) Xiao, Ge.; Kumar, A.; Li, K.; Rigl, C. T.; Bajic, M.;
Davis, T. M.; Boykin, D. W.; Wilson, W. D. Bioorg. Med. Chem. 2001, 9, 1097.
(c) Perrier, H.; Bayly, C.; Laliberté, F.; Huang, Z.; Rasori, R.; Robichaud, A.;
Girard, Y.; Macdonald, D. Bioorg. Med. Chem. Lett. 1999, 9, 323.
(30) Herrera, A.; Martinez-Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J. J.
Org. Chem. 2006, 71, 3026.
(26) (a) Rao, H. S. P.; Jothilingam, S. J. Org. Chem. 2003, 68, 5392. (b)
Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301.
(27) Fajari, L.; Brillas, E.; Aleman, C.; Julia, L. J. Org. Chem. 1998, 63,
5324.
(28) (a) Mamardashvili, N. Z.; Golubchikov, O. A. Russ. J. Org. Chem. 1999,
35, 1056. (b) Hawksley, D.; Griffin, D. A.; Leeper, F. J. J. Chem. Soc., Perkin
Trans. 1 2001, 144.
3380 J. Org. Chem. Vol. 73, No. 9, 2008

Substituted Furans, Pyrroles, and Thiophenes
SCHEME 6
SCHEME 9
SCHEME 10
SCHEME 7
TABLE 5. Selective Reduction of the Double Bond in Diketones 3
entry
reactants
R
products
yielda (%)
1
2
3
4
5
6
7
(Z)-3a
(E)-3a
(Z)-3b
(Z)-3c
(Z)-3j
(Z)-3n
(Z)-3o
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
2-furyl
13a
13a
13b
13c
13j
13n
13o
71
70
69
73
75
72
80
3-thienyl
2-benzofuryl
a Isolated yield.
TABLE 3. Synthesis of 4-Bromo-3-(methylthio)-2,5-diaryl Furans
refluxing methanol led to a complicated mixture. Therefore an
attempt was made to reduce the double bond selectively then
isolate the saturated 1,4-diketone intermediate. Reaction of
compound (Z)-3a with zinc dust in acetic acid at 80 °C for 4 h
produced product 13a in 52% yield along with the desulfurized
product 12 in 42% yield (Scheme 9). Finally, stirring a solution
of the Z- or E-isomer of 3a in the presence of KI and
concentrated hydrochloric acid in acetone at room temperature32
gave saturated 1,4-diketone 13 in 71% and 70% yields,
respectively, whose structure was confirmed by NMR spectro-
scopic and HRMS data. Furthermore, the structure of 13c is
supported by an X-ray crystal structure analysis (see the
Supporting Information). Selective examples and yields are listed
in Scheme 10 and Table 5. To our satisfaction, treatment of the
saturated 1,4-diketones 13 with ammonium formate in refluxing
acetic acid afforded 3-methylthio 2,5-diaryl-substituted pyrroles
14 in 80–92% yields. Similarly, treatment of 13 with Lawesson’s
reagent in refluxing toluene affords 3-methylthio-substituted
thiophenes 15 in 75–88% yields along with desulfurized
products 16 in 2–3% yields (Scheme 11 and Table 6).
entry
reactants
R
method
products
yielda (%)
1
2
3
4
5
6
7
8
9
7a
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
A
B
B
A
B
A
B
A
B
10a
10a
10a
10b
10b
10e
10e
10f
10f
92
61
60
90
60
90
58
88
64
(Z)-3a
(E)-3a
7b
(Z)-3b
7e
(Z)-3e
7f
(Z)-3f
a Isolated yield.
TABLE 4. Reductive Desulfuration of 7 to 2,5-Diaryl Furan 11
entry
reactants
R
products
yielda (%)
1
2
3
4
5
6
7
7a
7b
7d
7e
7h
7i
C6H5
11a
11b
11d
11e
11h
11i
91
85
89
88
85
88
90
4-MeC6H4
4-EtOC6H4
4-ClC6H4
1-naph
2-naph
2-benzofuryl
7o
11o
a Isolated yield.
Conclusion
SCHEME 8
In summary, we have developed a concise and efficient
carbon-carbon bond-forming reaction from two sp3-hybridized
methyl groups. This is also a simple, effective, and interesting
method for the synthesis of the important 1,4-diketones inter-
mediates. Methylthio-substituted furans, pyrroles, and thiophenes
and their related derivatives can be obtained in good yields via
the Paal-Knorr cyclization of these 1,4-diketones. The cross-
coupling reaction further confirms of the proposed self-sorting
tandem reaction mechanism. This also offers the possibility of
synthesis of a number of 1,4-diketones in one pot.
With an efficient synthesis of substituted furan 7 in hand,
we turned our attention to the preparation of the 3-methylthio-
substituted pyrroles and thiophenes. We also expected to
synthesize the pyrrole 14 from 3 through domino processes
involving the reduction of the double bond followed by
amination-cyclization. Proceeding according to the method
reported by Rao and co-workers,31 treatment of substrate (Z)-
3a with ammonium formate (as a source of hydrogen and
ammonia) in the presence of palladium on carbon (10%) in
(31) Rao, H. S. P.; Jothilingam, S. Tetrahedron Lett. 2001, 42, 6595.
(32) D’auria, M.; Piancatelli, G.; Scettri, A. Synthesis 1980, 245.
J. Org. Chem. Vol. 73, No. 9, 2008 3381

Yin et al.
SCHEME 11
1H NMR (CDCl3, 400 MHz) δ (ppm) 8.02 (d, J ) 8.4 Hz, 2H),
7.73 (d, J ) 8.4 Hz, 2H), 7.47–7.40 (m, 4H), 7.32–7.30 (m, 2H),
6.79 (s, 1H), 2.48 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm)
152.2, 149.1, 130.5, 130.0, 128.7, 128.4, 127.7, 127.2, 125.3, 123.7,
116.9, 109.5, 18.1; HRMS m/z calcd for C17H14OS [M + H]+
267.0838, found 267.0826.
TABLE 6. Synthesis of 3-Methylthio-Substituted Pyrroles and
Thiophenes
entry
reactants
R
products (isolated yield, %)
1
2
3
4
5
6
13a
13b
13c
13j
13n
13o
C6H5
14a (92)
15a (85)
15b (80)
16a (2)
4-MeC6H4
4-MeOC6H4
2-furyl
3-thienyl
2-benzofuryl
14b (82)
14c (88)
16b (3)
a
a
-
-
b
b
Furan 7a was also obtained in 87% yield starting from (E)-3a
under the same reaction conditions.
-
15j (75)
-
a
a
14n (85)
14o (80)
-
-
General Procedure for the Synthesis of 4-Bromo-3-(meth-
ylthio)-2,5-diarylfuran: 4-Bromo-3-(methylthio)-2,5-diphenyl-
furan (10a). Method A. To a solution of 1.33 g (5 mmol) of the
furan 7a in 15 mL of CHCl3 was added 0.30 mL of bromine. After
the reactant disappeared (TLC), the solvent was evaporated and
the residue was purified by column chromatography over silica gel
with petroleum ether as the eluent to give 10a (1.13 g, 92%) as a
white solid. Mp 79–80 °C; IR (KBr) 2916, 1483, 1443, 1121, 1069,
15o (88)
16o (2)
a Not examined. b The desulfurized product was not isolated.
Experimental Section
Home-Coupling Reaction. Reference 21 and Supporting Infor-
mation refer to the synthesis and characterization of 2-methylthio-
substituted 1,4-diketones 3 of Table 1.
1
1032, 938, 767, 690, 664 cm-1; H NMR (CDCl3, 400 MHz) δ
(ppm) 8.18 (d, J ) 7.6 Hz, 2H), 8.06 (d, J ) 7.6 Hz, 2H), 7.48–7.44
(m, 4H), 7.39–7.36 (m, 2H), 2.37 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ (ppm) 152.8, 147.6, 129.7, 129.3, 128.5, 128.2, 126.1,
125.5, 116.8, 105.7, 18.7; EI-MS (70 eV) m/z (%) 346 (51), 344
(55), 265 (30), 237 (32), 221 (24), 145 (26), 105 (97), 77 (100);
HRMS m/z calcd for C17H13BrOS [M + H]+ 344.9943, found
345.0250.
Method B. To a solution of (Z)-3a (282 mg, 1.0 mmol) in 8 mL
of chloroform was added 1.0 mL of 30% hydrogen bromide in acetic
acid at 0 °C. One drop of concentrated H2SO4 then was added to
the mixture and stirring was continued overnight. The solvent was
evaporated and the residue was purified by column chromatography
over silica gel with petroleum ether as the eluent to give 10a (210
mg, 61%). Furan 10a was also obtained in 60% yield starting from
(E)-3a under the same reaction conditions.
General Procedure for Reductive Removal of the Meth-
ylthio Group: 2,5-Bis(4-ethoxyphenyl)furan (11d). Compound
7d (177 mg, 0.25 mmol) was dissolved in anhydrous EtOH (15
mL). Raney nickel (900 mg, excess) in EtOH was added, and the
reaction mixture was refluxed for 1.5 h. The hot reaction mixture
was filtered then washed with hot EtOH (15 mL). The solvent was
removed under reduced pressure and the residue was purified by
column chromatography on silica gel with petroleum ether as the
eluent to give 11d (137 mg, 89%) as a white solid. Mp 174–176
°C; IR (KBr) 2977, 2930, 1589, 1504, 1491, 1249, 1117 cm-1; 1H
NMR (CDCl3, 400 MHz) δ (ppm) 7.62 (d, J ) 8.8 Hz, 4H), 6.92
(d, J ) 8.8 Hz, 4H), 6.54 (s, 2H), 4.08 (q, J ) 6.8 Hz, 4H), 1.43
(t, J ) 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 158.3,
152.8, 125.0, 124.0, 114.7, 105.5, 63.5, 14.8; HRMS m/z calcd for
C20H20O3 [M + H]+ 309.1485, found 309.1470.
Reduction of 2-Ene-1,4-diones to 1,4-Diones by Zn-AcOH.
A mixture of (Z)-3a (141 mg, 0.50 mmol) and zinc dust (780 mg,
6.0 mmol) in acetic acid (15 mL) was stirred at 80 °C for 4 h until
the reaction mixture became almost colorless. After filtration, the
reaction mixture was poured into 20 mL of water and extracted
with CHCl3 (3 × 15 mL). The organic layer then was washed with
saturated NaHCO3 solution and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by column chromatography on silica gel with EtOAc/
petroleum ether (v:v 1:10) as the eluent to give both the desulfurized
byproduct 12 (43 mg, 42%) and 13a (74 mg, 52%) as a white solid.
2-(Methylthio)-1,4-diphenylbut-1,4-dione (13a): mp 98–101 °C;
IR (KBr) 3428, 2919, 1665, 1637, 1594, 1325, 1216 cm-1; 1H NMR
(CDCl3, 400 MHz) δ (ppm) 8.09 (d, J ) 8.0 Hz, 2H), 7.98 (d, J )
8.0 Hz, 2H), 7.61–7.46 (m, 6H), 4.87 (dd, J1 ) 10.0 Hz, J2 ) 4.0
Cross-Coupling Reaction. A mixture of 4-chloroacetophenone
(770 mg, 5 mmol), 2-acetylthiphene (630 mg, 5 mmol), iodine (5.08
g, 20 mmol), and CuO (2.40 g, 30 mmol) in DMSO (60 mL) was
heated at 60–65 °C for 18 h. After filtration the reaction mixture
was then poured into brine (150 mL) and the aqueous layer was
extracted with CHCl3 (4 × 40 mL). The extract was washed with
10% Na2S2O3 then NaOH solution then dried over anhydrous
Na2SO4, and after filtration solvent was removed under reduced
pressure. The residue was purified by column chromatography on
silica gel with petroleum ether/EtOAc (v/v ) 12:1) as the eluent
to give the mixture of the products 3k, 5, 6, and 3e in 67% overall
yield. (Z)-1-(4-Chlorophenyl)-2-(methylthio)-4-(2-thienyl)-2-
butene-1,4-dione, (Z)-5: 387 mg, yield 24%, mp 148–149 °C; IR
1
(KBr) 3085, 1677, 1654, 1532, 1413, 1251, 1086, 1069 cm-1; H
NMR (CDCl3, 400 MHz) δ (ppm) 8.01 (d, J ) 8.8 Hz, 2H),
7.66–7.63 (m, 2H), 7.52 (d, J ) 8.8 Hz, 2H), 7.12 (dd, J1 ) 5.2
Hz, J2 ) 4.0 Hz, 1H), 6.90 (s, 1H), 2.15 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 190.4, 180.6, 159.2, 145.1, 141.5, 133.8, 133.1,
131.3, 131.1, 129.5, 128.2, 116.2, 15.4; EI-MS (70 eV) m/z (%)
308 (M - CH3, 23), 306 (60), 256 (46), 231 (19), 139 (27), 110
(100); HRMS m/z calcd for C15H11ClO2S2 [M + H]+ 322.9962,
found 322.9961. (Z)-4-(4-Chlorophenyl)-2-(methylthio)-1-(2-thie-
nyl)-2-butene-1,4-dione, (Z)-6: 97 mg, yield 6%, mp 102–103 °C;
IR (KBr) 3104, 1650, 1633, 1534, 1406, 1241, 1088, 1035, 1008
1
cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 7.89 (d, J ) 8.8 Hz,
2H), 7.85 (dd, J1 ) 4.8 Hz, J2 ) 1.2 Hz, 1H), 7.82 (dd, J1 ) 3.6
Hz, J2 ) 1.2 Hz, 1H), 7.43 (d, J ) 8.8 Hz, 2H), 7.20 (dd, J1 ) 3.6
Hz, J2 ) 4.8 Hz, 1H), 7.14 (s, 1H), 2.25 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ (ppm) 186.8, 183.7, 160.6, 141.9, 139.1, 137.1, 136.5,
136.1, 129.4, 128.9, 115.9, 15.5; EI-MS (70 eV) m/z (%) 308 (M
- CH3, 29), 306 (100), 227 (16), 139 (33), 111 (38); HRMS m/z
calcd for C15H11ClO2S2 [M + H]+ 322.9962, found 322.9763.
General Procedure for the Synthesis of 3-Methylthio-2,5-
diaryl Furans: 3-(Methylthio)-2,5-diphenylfuran (7a). A mixture
of concentrated hydrochloric acid (4 mL) and acetic acid (6 mL)
was heated to boiling, and stannous chloride (1.13 g, 5 mmol) was
added, followed by (Z)-3a (141 mg, 0.5 mmol) in 5 mL of acetic
acid. Heating was continued for 20 min then the reaction mixture
was poured into 30 mL of water and extracted with CHCl3 (3 ×
15 mL). The organic layer was washed successively with saturated
NaHCO3 solution, and then dried over anhydrous Na2SO4. The
solvent was evaporated and the residue was purified by column
chromatography over silica gel with petroleum ether as the eluent
to give 7a (113 mg, yield 85%) as a pale yellow solid. Mp 35–36
°C; IR (KBr) 3059, 2986, 2918, 1604, 1488, 1443, 1056, 969 cm-1
;
3382 J. Org. Chem. Vol. 73, No. 9, 2008

Substituted Furans, Pyrroles, and Thiophenes
Hz, 1H), 4.10 (dd, J1 ) 18.0 Hz, J2 ) 10.0 Hz, 1H), 3.44 (dd, J1
) 18.0 Hz, J2 ) 4.0 Hz, 1H), 2.02 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ (ppm) 197.6, 193.9, 136.1, 135.5, 133.5, 133.1, 128.6,
128.1, 40.8, 40.0, 11.8; HRMS m/z calcd for C17H16O2S [M + H]+
285.0944, found 285.0950.
131.8, 129.0, 128.7, 126.9, 126.7, 126.5, 123.7, 114.7, 110.9, 19.6;
HRMS m/z calcd for C17H15NS [M + H]+ 266.0998, found
266.1001.
GeneralProcedurefortheSynthesisof3-MethylthioThiophenes:
3-(Methylthio)-2,5-diphenylthiophene (15a). To a toluene solution
(15 mL) of 13a (142 mg, 0.50 mmol) was added Lawesson’s reagent
(242 mg, 0.60 mmol). The mixture was stirred at reflux for 2 h.
After being cooled to room temperature, the solvent was evaporated
under reduced pressure, then the residue was purified by column
chromatography on silica gel with petroleum ether as the eluent to
give 3-(methylthio)-2,5-diphenylthiophene 15a (120 mg, yield 85%)
as a yellow oil together with desulfurized product 16a (3 mg, 2%)
as a white solid. 15a: IR (KBr): 2920, 1597, 1484, 1451, 757, 691
Reduction of 2-Ene-1,4-diones to 1,4-Diones by KI-HCl.
Potassium iodide (2.49 g, 15.0 mmol) and concentrated hydrochloric
acid (15.0 mmol) were added to a stirred solution of diketone (Z)-
3a (282 mg, 1.0 mmol) in acetone (100 mL) at room temperature.
After 12 h the solvent was removed under reduced pressure, 10%
Na2S2O3 solution was added to the reddish residue, and the mixture
was extracted with CHCl3 (3 × 15 mL). The organic layers were
combined and dried over anhydrous Na2SO4. The solvent was
evaporated and the residue was purified by column chromatography
over silica gel with EtOAc/petroleum ether (v:v ) 1:10) as the
eluent to give 13a (202 mg, yield 71%). Compound 13a was also
obtained in 70% yield starting from (E)-3a under the same reaction
conditions.
1
cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 7.66 (d, J ) 7.6 Hz,
2H), 7.58 (d, J ) 7.6 Hz, 2H), 7.43–7.29 (m, 7H), 2.42 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ (ppm) 142.5, 138.6, 133.7, 133.6,
130.2, 128.9, 128.8, 128.4, 127.8, 127.7, 125.6, 125.5, 18.5; HRMS
m/z calcd for C17H14S2 [M + H]+ 283.0610, found 283.0599.
Acknowledgment. We thank Central China Normal Univer-
sity, the National Natural Science Foundation of China (Grant
Nos. 20472022 and 20672042), the Scientific Research Founda-
tion for Returned Overseas Chinese Scholars, and the State
Education Ministry (No. [2005]383) for generous financial
support. We also thank Zhejiang University for performing the
HRMS and LC-MS analyses.
General Procedure for the Synthesis of 3-Methylthio Pyr-
roles: 3-(Methylthio)-2,5-diphenylpyrrole (14a). A solution of
13a (142 mg, 0.50 mmol) in 12 mL of acetic acid was heated at
110 °C, then ammonium formate (945 mg, 15 mmol) was added.
Heating was continued for 2 h and the cooled mixture was poured
into 20 mL of water and extracted with CHCl3 (3 × 10 mL). The
organic layer then was washed with saturated NaHCO3 solution
and dried over anhydrous Na2SO4. After removal of the solvent
under reduced pressure, the residue was purified by column
chromatography on silica gel with petroleum ether as the eluent to
give 14a (122 mg, yield 92%) as a white solid. Mp 78–79 °C; IR
Supporting Information Available: The general experi-
mental methods and the characterizing data for all other
compounds, 1H, 13C NMR spectra for all new compounds, and
X-ray crystallography data for compounds (Z)-5, 7b, and 13c.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(KBr) 3313, 1485, 1464, 1068, 762, 693 cm-1; H NMR (CDCl3,
400 MHz) δ (ppm) 8.47 (s, 1H), 7.69 (d, J ) 8.0 Hz, 2H), 7.49–7.35
(m, 6H), 7.30–7.21 (m, 2H), 6.62 (d, J ) 2.8 Hz, 1H), 2.37 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 132.2 (2C), 132.0,
JO702585S
J. Org. Chem. Vol. 73, No. 9, 2008 3383