A short synthesis of highly substituted furans from alkenyl aryl ketones with dichloromethyl phenyl sulfoxide

Article abstract of DOI:10.1016/j.tetlet.2007.05.049

Two-step synthesis of 2-aryl-5-(phenylsulfanyl)furans was achieved starting from alkenyl aryl ketones and dichloromethyl phenyl sulfoxide. The phenylsulfanyl group was successfully converted to other functional groups, via sulfinyl group, to give highly substituted 2-arylfurans in good overall yields.

Full text of DOI:10.1016/j.tetlet.2007.05.049

Tetrahedron Letters 48 (2007) 4849–4853
A short synthesis of highly substituted furans from alkenyl
aryl ketones with dichloromethyl phenyl sulfoxide
Toshifumi Miyagawa and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 23 April 2007; revised 2 May 2007; accepted 10 May 2007
Available online 16 May 2007
Abstract—Two-step synthesis of 2-aryl-5-(phenylsulfanyl)furans was achieved starting from alkenyl aryl ketones and dichloro-
methyl phenyl sulfoxide. The phenylsulfanyl group was successfully converted to other functional groups, via sulfinyl group, to give
highly substituted 2-arylfurans in good overall yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Furans are obviously one of the most important com-
pounds in organic and synthetic organic chemistry. Fur-
an moiety was frequently found as the skeletal structure
of natural products, such as furano-terpenes, in the
plant kingdom.1 Furan is a relatively highly reactive het-
eroaromatic compound and is frequently used as an
intermediate in organic synthesis.2 In view of the impor-
tance of furans in organic chemistry many procedures
for their synthesis have been reported;3 however, new
methods for their synthesis are still very much desired.
anion of dichloromethyl phenyl sulfoxide to alkenyl aryl
ketones 1 gave adduct 2 in high yield. The adduct was
treated with trifluoroacetic anhydride (TFAA) in the
presence of sodium iodide to give 2-aryl-5-(phenylsulfan-
yl)furan 3 in good yield. As the synthetic method for 2-
thio-substituted furans is quite limited,5 this is a good
procedure for the synthesis from alkenyl aryl ketones 1
in only two steps.
The phenylsulfanyl group was oxidized to give a sulfox-
ide, which was treated with isopropylmagnesium
chloride to afford 2-magnesiofuran via sulfoxide–
magnesium exchange reaction. Finally the 2-magne-
siofuran was treated with electrophiles to afford tri- or
tetra-substituted furans 4 in good overall yield.
Over this decade, we have been interested in the develop-
ment of new synthetic methods utilizing sulfoxides
having a chlorinated alkyl group as a ligand.4 As an
extension of this study, we recently investigated for
developing a new synthetic method using dichloro-
methyl phenyl sulfoxide, and a new procedure for a
short synthesis of highly substituted furans was achieved
(Scheme 1).
Details of this procedure are reported using 1-phenyl-2-
buten-1-one 5 as an example (Scheme 2). To a solution
of lithium carbanion of dichloromethyl phenyl sulf-
oxide6 in THF in the presence of HMPA at À78 °C was
added a solution of 5 in THF and the reaction mixture
was stirred for 2 h to give adduct 6 in quantitative yield
The essence of the procedure presented in this Letter is
as follows. Thus, conjugate addition of the lithium carb-
O
TFAA
NaI
O
R2
O
O
Ar
R1
SPh
R2
PhS(O)CHCl2
1) MCPBA
Ar
R1
E
S(O)Ph
Cl
Ar
R2
Ar
2)
i
-PrMgCl,
R2
R1
Cl
R1
Electrophile
3
4
2
1
Scheme 1.
Keywords: Furan; Dichloromethyl phenyl sulfoxide; Pummerer reaction: 2-(Phenylsulfanyl)furan; Sulfoxide–magnesium exchange reaction.
*
Corresponding author. E-mail: tsatoh@rs.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.049

4850
T. Miyagawa, T. Satoh / Tetrahedron Letters 48 (2007) 4849–4853
PhS(O)CHCl2
LDA (1.2 eq)
O
O
Me
TFAA (5 eq)
NaI (5 eq)
O
HMPA (1.2 eq)
Ph
SPh
Me
S(O)Ph
Ph
Me
Ph
CH3CN, r.t., 89%
THF, -78 °C, 99%
H
H
Cl Cl
H
7
5
6
Scheme 2.
O
O
F3C
O
CF3
O
O
Me
O
S
O
Me
O
S
CF3
Ph
O
Me
S
Ph
Ph
Ph
Ph
Ph
H
H
Cl Cl
Cl
H
Cl Cl
I
B
A
6
Cl
O
Cl
O
O
Ph
SPh
Ph
SPh
Ph
SPh
Me
H
H
Me
O
CF3
Me
F3C
O
7
O
C
D
O
Scheme 3. A plausible mechanism for the reaction of 6 with TFAA–NaI giving furan 7.
as a mixture of two diastereomers.7,8 Adduct 6 was then
treated with 5 equiv of TFAA in acetonitrile in the pres-
ence of 5 equiv of NaI at room temperature overnight.
The starting material disappeared and from this rather
clean reaction mixture, 4-methyl-2-phenyl-5-(phen-
ylsulfanyl)furan 7 was obtained in 89% yield.9
ester and amide (entries 8 and 9). Treatment of adduct 9
with TFAA–NaI was carried out under the same condi-
tions as described above and the results are summarized
in Table 1. Interestingly, the adducts derived from alke-
nyl aryl ketones gave the desired furans 10 in good yields
except two examples (entries 1–6). When the adduct has
alkyl group (methyl group) as R, entry 7, the reaction
did not give the desired furan. The adducts derived from
a,b-unsaturated ester and amide (entries 8 and 9) also
did not give the expected furans but gave a complex mix-
ture. From these results, the enolizability of ketone 9
(the acidity of the hydrogen at the a-position)11 is
thought to be quite important in this furan synthesis.
The mechanism of this reaction is thought to be the
Pummerer-type reaction10 which is as follows (Scheme
3). At first, the reaction of sulfoxide 6 with TFAA gives
an acyloxysulfonium ion A. The iodide anion attacks the
chlorine atom to afford thionium ion B. The thionium
ion is attacked by the oxygen atom of the carbonyl
group5d to give cyclic oxonium ion C, from which the
hydrogen at the b-position is picked up by the trifluoro-
acetate anion to afford dihydrofuran derivative D. As
the elimination of HCl from intermediate D gives the
aromatic compound, it would take place easily to give
furan 7.
Table 2 shows the results for the synthesis of tri- and
tetra-substituted furans 13 starting from several alkenyl
phenyl ketones 11 via adducts 12. As shown in the table,
all adducts 12 were obtained under the same conditions
as described above in 62–99% yields. The formation of
furans 13 proceeded in good to excellent yields except
one example (entry 3). In this case, the starting material
did not disappear under the reaction conditions, and
58% yield of the starting material was recovered.
In order to investigate the generality of this reaction,
first, the conjugate addition of lithium a-sulfinyl carban-
ion of dichloromethyl phenyl sulfoxide and several a,b-
unsaturated carbonyl compounds was carried out, and
second, the adducts were treated with TFAA–NaI as
mentioned above. The results are summarized in Table
1.
The phenylsulfanyl group in the produced furans could
be used for further introducing functional groups. Thus,
sulfoxide–metal exchange reaction12 of the correspond-
ing 2-sulfinylfuran would afford the corresponding 2-
lithio- or 2-magnesiofuran, which could be trapped with
several electrophiles to afford new furan derivatives. We
investigated this idea and the preliminary results are
summarized in Table 3.
The conjugate addition of all the investigated a,b-unsat-
urated carbonyl compounds gave adducts 9 in high to
quantitative yields. Sodium hydride was found to be a
better base for the addition reaction of a,b-unsaturated

T. Miyagawa, T. Satoh / Tetrahedron Letters 48 (2007) 4849–4853
Table 1. Synthesis of 2-(phenylsulfanyl)furans 10 from enones 8 through the adducts 9
4851
R2
O
O
NaI (5 eq)
PhS(O)CHCl2
O
R
SPh
R2
S(O)Ph
Cl Cl
Conditions
TFAA (5 eq)
Conditions
R
R2
R
R1
CH3CN, r.t.
R1
R1
THF
8
9
10
Entry
8
Yield (%)
R
R1
R2
9
10
1
2
3
4
5
6
7
8
9
Phenyl
1-Naphthyl
p-Methoxyphenyl
p-Tolyl
p-Fluorophenyl
2-Thienyl
Me
H
H
H
H
H
H
Me
H
H
Me
Me
Me
Me
Me
Me
Me
H
LDA, HMPA (1.2 equiv), À78 °C
99
70
99
94
99
92
90
94
99
89
83
25
51
71
36
Complex mixture
Complex mixture
Complex mixture
t-BuO
Me2N
NaH (2 equiv), 0 °C to rt
H
Table 2. Synthesis of 2-phenyl-5-(phenylsulfanyl)furans 13 from enones 11 through the adducts 12
PhS(O)CHCl2
LDA (1.2 eq)
O
O
R2
O
NaI (5 eq)
Ph
R1
SPh
R2
HMPA (1.2 eq)
TFAA (5 eq)
S(O)Ph
Ph
R2
Ph
CH3CN, r.t.,
overnight
THF, -78 °C
R1
R1
12
Cl Cl
13
11
Entry
11
Yield (%)
R1
R2
12
13
1
2
3
4
5
6
H
H
H
Me
Me
Me
n-Pr
i-Pr
Ph
H
Me
n-Pr
93
72
62
99
91
91
88
83
41a
61
72
99
a Starting material was recovered in 58%.
Table 3. Synthesis of tri- and tetra-substituted furans 16 from 2-phenyl-5-(phenylsulfanyl)furans 13 via 2-magnesiofurans 15 derived from sulfoxides
14 with i-PrMgCl
O
O
Ph
R1
S(O)Ph
Ph
SPh
R2
MCPBA (1.3 eq)
0 °C
R2
R1
a R1=H, R2=Me
b R1=Me, R2=Me
a (99%)
b (94%)
14
13
O
O
Ph
R1
MgCl
R2
Ph
R1
E
Electrophile
i
-PrMgCl
14
THF, -78 °C
-78 °C ~ r.t.
R2
15
16
Entry
R1
R2
i-PrMgCl (equiv)
Electrophile (equiv)
Yield (%) 16
1
2
3
4
5
H
H
H
Me
Me
Me
Me
Me
Me
Me
1.8
1.8
1.8
3.0
3.0
CH3OH
Excess
88
59
69
63
57
(E = H)
(E = COOEt)
(E = COPh)
(E = COOEt)
(E = COPh)
ClCOOEt
ClCOPh
ClCOOEt
ClCOPh
3.0
3.0
5.0
5.0
At first, furans 13a and 13b were oxidized to the corre-
sponding sulfoxides 14a and 14b, respectively, in almost
quantitative yields. Sulfoxide 14a was treated with
1.8 equiv of isopropylmagnesium chloride in THF at
À78 °C (2-magnesiofuran intermediate 15 was gener-
ated) and the reaction was quenched with methanol to
afford 4-methyl-2-phenylfuran (Table 3, entry 1) in
88% yield. The intermediate was treated with ethyl

4852
T. Miyagawa, T. Satoh / Tetrahedron Letters 48 (2007) 4849–4853
Recrystallized N-chlorosuccinimide (27.4 g; 0.205 mol)
was added to a solution of methyl phenyl sulfoxide
(14.0 g; 0.1 mol) in 200 mL of THF at 0 °C with stirring.
The reaction mixture was stirred at room temperature
overnight. The precipitate was filtered off and the solvent
of the filtrate was evaporated to give a residue, which was
purified by silica gel column chromatography to give
dichloromethyl phenyl sulfoxide (19.8 g; 95%) as a color-
less oil.
chloroformate and benzoyl chloride to give ethoxycar-
bonylated and benzoylated furans, respectively (entries
2 and 3), in moderate to good yields.13 A similar treat-
ment of 14b gave tetra-substituted furans (entries 4
and 5) in about 60% yield.
In conclusion, we have developed a new synthetic meth-
od for 2-aryl-5-(phenylsulfanyl)furans from alkenyl aryl
ketones with dichloromethyl phenyl sulfoxide in only
two steps. By utilization of the sulfanyl group, the syn-
thesis of fully substituted 2-arylfurans was also
achieved. The procedure presented in this Letter will
contribute to the synthesis of highly substituted furans.
7. Mahidol, C.; Reutrakul, V.; Panyachotipun, C.; Turong-
somboon, G.; Prapansiri, V.; Bandara, B. M. R. Chem.
Lett. 1989, 163.
8. HMPA (1.86 mL; 10.4 mmol) was added to a solution of
LDA (10.4 mmol) in 39 mL of dry THF at À78 °C with
stirring. After the solution was stirred for 10 min, a
solution of dichloromethyl phenyl sulfoxide (1.81 g;
8.67 mmol) in 2 mL of dry THF was added and the
reaction mixture was stirred for 10 min. To this solution of
carbanion, a solution of 5 (1.65 g; 11.3 mmol) in 2 mL of
dry THF was added. The reaction mixture was stirred for
2 h, then the reaction was quenched by satd aq NH4Cl.
The whole was extracted with CHCl3. The product was
purified by silica gel column chromatography to give
4-benzenesulfinyl-4,4-dichloro-3-methyl-1-phenylbutan-1-
one 6 (3.05 g; 99%) as colorless crystals (about 1:1
diastereomeric mixture). IR (diastereomeric mixture;
KBr) 2980, 1685 (CO), 1447, 1354, 1277, 1091,
References and notes
1. (a) Studies in Natural Products Chemistry; Atta-ur-Rah-
man, Ed. Stereoselective Synthesis (Part D); Elsevier:
Amsterdam, 1990; Vol. 6, pp 107–132; (b) Jefford, C. W.;
Sledeski, A. W.; Rossier, J.-C.; Boukouvalas, J. Tetra-
hedron Lett. 1990, 31, 5741; (c) Marshall, J. A.; Robinson,
E. D. J. Org. Chem. 1990, 55, 3450; (d) Aso, M.; Ojida, A.;
Yang, G.; Cha, O.-J.; Osawa, E.; Kanematsu, K. J. Org.
Chem. 1993, 58, 3960.
2. Reviews and selected recent papers for furans as interme-
diates in organic synthesis: (a) Lipshutz, B. H. Chem. Rev.
1986, 86, 795; (b) Tsubuki, M. J. Syn. Org. Chem. Jpn.
1993, 51, 399; (c) Griffith, G. A.; Hillier, I. H.; Moralee, A.
C.; Percy, J. M.; Roig, R.; Vincent, M. A. J. Am. Chem.
Soc. 2006, 128, 13130; (d) Padwa, A.; Zhang, H. J. Org.
Chem. 2007, 72, 2570.
3. Recent reviews and papers for synthesis of furans: (a)
Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850; (b)
Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076; (c) Patil,
N. T.; Yamamoto, Y. ARKIVOC 2007, x, 121; (d) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7,
1769; (e) Tseng, J.-C.; Chen, J.-H.; Luh, T.-Y. Synlett
2006, 1209; (f) Sniady, A.; Durham, A.; Morreale, M. S.;
Wheele, K. A.; Dembinski, R. Org. Lett. 2007, 9,
1175.
4. Some of our new recent synthetic methods utilizing
chloromethyl p-tolyl sulfoxide and 1-chloroalkyl aryl
sulfoxides: (a) Satoh, T.; Osawa, A.; Ohbayashi, T.;
Kondo, A. Tetrahedron 2006, 62, 7892; (b) Satoh, T.;
Hirano, M.; Kuroiwa, A.; Kaneko, Y. Tetrahedron 2006,
62, 9268; (c) Satoh, T.; Tanaka, S.; Asakawa, N. Tetra-
hedron Lett. 2006, 47, 6769; (d) Satoh, T.; Ogata, S.;
Wakasugi, D. Tetrahedron Lett. 2006, 47, 7249; (e) Satoh,
T.; Sugiyama, S. J. Syn. Org. Chem. Jpn. 2006, 64, 1049;
(f) Satoh, T.; Takahashi, Y.; Shirai, Y.; Yamada, Y.
Chem. Pharm. Bull. 2006, 54, 1734; (g) Sugiyama, S.;
Shimizu, H.; Satoh, T. Tetrahedron Lett. 2006, 47, 8771;
(h) Fukushima, I.; Gouda, Y.; Satoh, T. Tetrahedron Lett.
2007, 48, 1855; (i) Sakurada, J.; Satoh, T. Tetrahedron
2007, 63, 3806; (j) Kashima, H.; Kawashima, T.; Waka-
sugi, D.; Satoh, T. Tetrahedron 2007, 63, 3953.
752 cmÀ1 1H NMR (less polar product) d 1.40 (3H, d,
;
J = 6.5 Hz), 3.16 (1H, dd, J = 17.0, 10.0 Hz), 3.34–3.42
(1H, m), 3.80 (1H, dd, J = 17.0, 1.2 Hz), 7.49 (2H, t,
J = 7.3 Hz), 7.53–7.65 (4H, m) 7.86 (2H, t, J = 7.1 Hz),
8.02 (2H, d, J = 7.1 Hz); (more polar product) d 1.43 (3H,
d, J = 6.2 Hz), 3.16 (1H, dd, J = 17.0, 10 Hz), 3.48–3.56
(1H, m), 3.70 (1H, dd, J = 17.0, 1.8 Hz), 7.48 (2H, t,
J = 7.8 Hz), 7.53–7.64 (4H, m), 7.87 (2H, t, J = 7.1 Hz),
8.00 (2H, d, J = 7.0 Hz). MS (diastereomeric mixture) m/z
(%) 266 (M+, 100), 189 (8), 161 (18), 105 (43), 77 (22).
Anal. Calcd for C17H14OS: M, 266.0760. Found: m/z
266.0763.
9. TFAA (0.139 mL; 1.0 mmol) was added to a solution of 6
(71.1 mg; 0.2 mmol) and NaI (150 mg; 1.0 mmol) in
acetonitrile (2 mL) at room temperature with stirring.
The solution was stirred overnight, then the reaction was
quenched by satd aq NaHCO3 and satd aq Na2SO3. The
whole was extracted with CH2Cl2. The product was
purified by silica gel column chromatography to give 3-
methyl-5-phenyl-2-(phenylsulfanyl)furan 7 (47.3 mg; 89%)
as colorless crystals. Mp 36.0–36.5 °C (hexane). IR (KBr)
3061, 1581, 1487, 1024, 928, 761 cmÀ1 1H NMR d 2.16
;
(3H, s), 6.66 (1H, s), 7.11–7.15 (3H, m), 7.21–7.28 (3H, m),
7.36 (2H, t, J = 7.8 Hz), 7.67 (2H, d, J = 7.2 Hz). 13C
NMR d 156.40 (C), 138.55 (C), 137.14 (C), 131.59 (C),
130.26 (C), 129.05 (CH), 128.68 (CH), 127.95 (CH), 126.64
(CH), 125.86 (CH), 124.05 (CH), 108.97 (CH), 11.20
(CH3). MS m/z (%) 266 (M+, 100), 189 (8), 161 (18), 105
(43), 77 (22). Anal. Calcd for C17H14OS: M, 266.0760.
Found: m/z 266.0763.
10. (a) Padwa, A.; Gunn, D. E.; Osterhout, M. H. Synthesis
1997, 1353; (b) Satoh, T.; Sugiyama, S.; Ota, H. Tetrahe-
dron Lett. 2002, 43, 3033; (c) Feldman, K. S. Tetrahedron
2006, 62, 5003.
11. The value of pKa of the a-hydrogen of aryl ketones was
reported to be 24–26 (Bordwell, F. G.; Cornforth, F. J. J.
Org. Chem. 1978, 43, 1763). While that of alkyl ketones
and esters was reported to be 27–30 ((a) Zhang, X. M.;
Bordwell, F. G.; Puy, M. V. D.; Fried, H. E. J. Org. Chem.
1993, 58, 3060. (b) Bordwell, F. G. Acc. Chem. Res. 1988,
21, 456). Obviously, aryl ketones are prone to be enolized
easier than alkyl ketones.
5. (a) Nolan, S. M.; Cohen, T. J. Org. Chem. 1981, 46, 2473;
(b) Datta, A.; Pooranchand, D.; Ila, H.; Junjappa, H.
Tetrahedron 1989, 45, 7631; (c) Padwa, A.; Ginn, J. D.;
McClure, M. S. Org. Lett. 1999, 1, 1559; (d) Sarkar, T.;
Panda, N.; Basak, S. J. Org. Chem. 2003, 68, 6919.
6. Dichloromethyl phenyl sulfoxide was reported to be
synthesized from methyl phenyl sulfoxide in two steps in
60% overall yield by Durst (Tin, K.-C.; Durst, T.
Tetrahedron Lett. 1970, 4643). We reinvestigated the
synthesis of dichloromethyl phenyl sulfoxide as follows.

T. Miyagawa, T. Satoh / Tetrahedron Letters 48 (2007) 4849–4853
4853
12. (a) Furukawa, N.; Shibutani, T.; Matsumura, K.; Fuji-
hara, H.; Oae, S. Tetrahedron Lett. 1986, 27, 3899; (b)
Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S. Tetrahedron
2001, 57, 3891; (c) Akai, S.; Kawashita, N.; Satoh, H.;
Wada, Y.; Kakiguchi, K.; Kuriwaki, I.; Kita, Y. Org. Lett.
2004, 6, 3793.
13. To a solution of 14a (56.5 mg ; 0.2 mmol) in 2 mL of dry
THF at À78 °C was added i-PrMgCl (2.0 M solution in
THF, 0.18 mL; 0.36 mmol) dropwise to give instanta-
neously 2-magnesiofuran 15a. Ethyl chloroformate
(0.057 mL; 0.60 mmol) was added to the reaction mixture
and the mixture was gradually allowed to warm to room
temperature. The reaction was quenched by satd aq
NH4Cl and the whole was extracted with CHCl3. The
product was purified by silica gel column chromatography
to give methyl 3-methyl-5-phenylfuran-2-carboxylate 16a
(27.3 mg; 59%) as colorless crystals. Mp 73.0–73.5 °C
(hexane). IR (KBr) 2980, 1704 (CO), 1294, 1170, 930,
1
767 cmÀ1; H NMR d 1.41 (3H, t, J = 7.2 Hz), 2.39 (1H,
s), 4.38 (2H, q, J = 7.2 Hz), 6.60 (1H, s), 7.30 (1H, t,
J = 7.2 Hz), 7.40 (2H, t, J = 7.2 Hz), 7.75 (2H, d, J = 7.2
Hz). 13C NMR d 179.23, 175.09, 159.05, 152.30, 149.05,
148.19, 144.25, 129.64, 79.91, 33.90, 31.29. Anal. Calcd for
C14H14O3: C, 73.03; H, 6.13. Found: C, 73.12; H, 6.07.