Synthesis of functionalized allylic sulfoxides and their use in the construction of 2,3,4-trisubstituted furans via a [3 + 2] annulation

Article abstract of DOI:10.1021/jo801406p

(Chemical Equation Presented) A route to 2,3,4-trisubstituted furan derivatives based on a [3 + 2] annulation of functionalized allylic sulfoxides and aldehydes is described. In this strategy, the precursors of allylic sulfoxides 4, allylic sulfides 3, were synthesized via a thiomethylation reaction of an α-EWG ketene-S,S-acetal 1 (EWG: electron-withdrawing group), formaldehyde, and a thiol 2 in high to excellent yields. Allylic sulfoxides 4 were prepared by a highly regioselective oxidation of 3, using m-chloroperoxybenzoic acid as oxidant. Thus, starting from these readily available sulfoxides 4, 2-alkylthio-3,4-disubstituted furans 6 were efficiently constructed via the [3 + 2] annulation reaction of 4 with aldehydes 5 under mild conditions. Further replacement of the 2-alkylthio group of 6 with amines led to the formation of 2-amino-3,4-disubstituted furan derivatives 7.

Full text of DOI:10.1021/jo801406p

Synthesis of Functionalized Allylic Sulfoxides and Their Use in the
Construction of 2,3,4-Trisubstituted Furans via a [3 + 2] Annulation
Zhenqian Fu, Mang Wang,* Yuhui Ma, Qun Liu,* and Jun Liu
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, People’s Republic of China
wangm452@nenu.edu.cn
ReceiVed June 27, 2008
A route to 2,3,4-trisubstituted furan derivatives based on a [3 + 2] annulation of functionalized allylic
sulfoxides and aldehydes is described. In this strategy, the precursors of allylic sulfoxides 4, allylic sulfides
3, were synthesized via a thiomethylation reaction of an R-EWG ketene-S,S-acetal 1 (EWG: electron-
withdrawing group), formaldehyde, and a thiol 2 in high to excellent yields. Allylic sulfoxides 4 were
prepared by a highly regioselective oxidation of 3, using m-chloroperoxybenzoic acid as oxidant. Thus,
starting from these readily available sulfoxides 4, 2-alkylthio-3,4-disubstituted furans 6 were efficiently
constructed via the [3 + 2] annulation reaction of 4 with aldehydes 5 under mild conditions. Further
replacement of the 2-alkylthio group of 6 with amines led to the formation of 2-amino-3,4-disubstituted
furan derivatives 7.
Introduction
Functionalized ketene-S,S-acetals are versatile intermediates
in organic synthesis (Figure 1).1-4 Among them, R-EWG
ketene-S,S-acetals (EWG: electron-withdrawing group) have
proven to be especially important in the construction of a diverse
FIGURE 1. Structure of functionalized ketene-S,S-acetals.
array of polysubstituted carbo-1,5 and heterocyclic compounds.1,6,7
Some recent research has revealed that the highly polarized push
(RS)-pull (EWG) interaction on the C-C double bond of
R-EWG ketene-S,S-acetals makes their R-carbon atom a po-
tential nucleophilic center and the coupling reaction at the
nucleophilic R-carbon atom of these ꢀ,ꢀ-dialkylthio activated
alkenes is reliable and incorporates a wide variety of carbon8,9
and heteroatom electrophiles.10 As a continuation of our interest
in the design and discovery of potentially synthetically useful
intermediates based on ketene-S,S-acetals,5,6,8,10 in the present
research, a thiomethylation of R-EWG ketene-S,S-acetals 1 with
formaldehyde and thiols 2, the first example of the thiomethy-
lation of activated alkenes as nucleophiles, was achieved to
furnish a set of allylic sulfides 3 bearing the structural feature
of ketene-S,S-acetals (Scheme 1). Thus, a route toward 2-alky-
lthio/2-amino-3,4-disubstituted furans 6/7 has been established
based on a [3 + 2] annulation strategy of allylic sulfoxides 4
(the oxidated products of 3) and aldehydes 5 (Scheme 1). In
(1) For reviews on R-oxo ketene-S,S-acetals, see: (a) Dieter, R. K. Tetra-
hedron 1986, 42, 3029–3096. (b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423–5506. (c) Elgemeie, G. H.; Sayed, S. H. Synthesis 2001, 1747–
1771.
(2) For synthesis and synthetic application of phosphonoketene-S,S-acetals,
see: (a) Minami, T.; Okauchi, T.; Matsuki, H.; Nakamura, M.; Ichikawa, J.;
Ishida, M. J. Org. Chem. 1996, 61, 8132–8140. (b) Kouno, R.; Okauchi, T.;
Nakamura, M.; Ichikawa, J.; Minami, T. J. Org. Chem. 1998, 63, 6239–6246.
(3) For synthesis and synthetic applications of fluorinated ketene-S,S-acetals,
see: (a) Muzard, M.; Portella, C. J. Org. Chem. 1993, 58, 29–31. (b) Pirrung,
M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683–5689. (c)
Sotoca, E.; Bouillon, J.-P.; Gil, S.; Parra, M.; Portella, C. Tetrahedron 2005,
61, 4395–4402, and references cited therein.
(4) For the reactions and applications of silylketene-S,S-acetals, see: (a)
Okauchi, T.; Tanaka, T.; Minami, T. J. Org. Chem. 2001, 66, 3924–3929. (b)
Yahiro, S.; Shibata, K.; Saito, T.; Okauchi, T.; Minami, T. J. Org. Chem. 2003,
68, 4947–4950.
(5) For selected examples, see: (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao,
L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578–4579. (b) Zhang, Q.; Sun, S.; Hu,
J.; Liu, Q.; Tan, J. J. Org. Chem. 2007, 72, 139–143. (c) Gill, S.; Kocienski, P.;
Kohler, A.; Pontiroli, A.; Liu, Q. Chem. Commun. 1996, 1743–1744.
10.1021/jo801406p CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7625–7630 7625

Fu et al.
TABLE 1. Optimization of Conditions for Thiomethylation of 1a
with Formaldehyde and Benzylthiol 2aa
SCHEME 1
entry
catalyst
solvent
1a:HCHO:2a
yield of 3a (%)b
1
2
3
4
5
HCl
HCl
HCl
THF
THF
EtOH
AcOH
THF
1:1:1
1:2:1
1:2:1
1:2:1
1:2:1
36
97
52
83
c
-
this paper, two reactions, the [3 + 2] annulation reaction of 4
and 5 to polysubstituted furans 6 and the thiomethylation
reaction of 1 to functionalized allylic sulfides 3, are described
in detail.
a 1a (1.0 mmol), HCHO (40% aqueous), 2a (1.0 mmol), HCl (2.0
mmol, 36% aqueous), solvent (2.0 mL), rt, 0.5 h. b Isolated yields. c 24
h, no reaction.
Results and Discussion
bromide,14e etc., have been developed, to our knowledge, none
of them12-14 involved a Mannich-type thiomethylation15 of
activated alkenes, a simple method leading directly to allylic
sulfides with water as the only byproduct. In fact, in the three-
component thiomethylation reaction involving a nucleophile,
formaldehyde, and a thiol, various carbon nucleophiles (such
as ketones, nitroalkanes, phenols, aromatic amines, electron-
rich heterocyclic compounds, or even ferrocene) and heteroatom
nucleophiles (including nitrogen, oxygen, sulfur, phosphorus,
or halogens) have been proven to be effective.15 However, the
investigation of taking activated alkenes as carbon nucleophiles
in thiomethylation has been scarce. Kirk16a and Cohen16b
reported that the formal thiomethylated products of activated
alkenes could be achieved, for example, by refluxing a mixture
of cyclopent-2-enone, formaldehyde, and thiophenol in the
presence of triethylamine for 4 days to afford 2-(phenylthiom-
ethyl)cyclopent-2-enone in 73% yield. But the reaction was
proved to proceed in a non-Mannich-type process in which the
corresponding thia-Michael adduct, 3-(phenylthio)cyclopen-
tanone, was obtained as the intermediate.16b
As part of our research to assess R-EWG ketene-S,S-acetals
1 as activated alkenes in the C-C bond forming reactions with
carbon electrophiles,8 we showed that the R-carbon atom of 1
has high nucleophilicity. Encouraged by these results and the
foreseeable possibility of the thiomethylation based on R-EWG
ketene-S,S-acetals, we decided to investigate the thiomethylation
reaction of these activated alkenes with formaldehyde and thiols
under acidic conditions. Thus, hydrochloric acid (2.0 mmol, 36%
aqueous) was initially evaluated in the model reaction of 1-(1,3-
dithiolan-2-ylidene)propan-2-one 1a (1.0 mmol) with benzylthiol
2a (1.0 mmol) and formaldehyde (1.0 mmol, 40% aqueous) in
THF (2.0 mL). As depicted in Table 1, the reaction could furnish
the thiomethylated product, 4-(benzylthio)-3-(1,3-dithiolan-2-
ylidene)butan-2-one 3a, as a white solid in 36% isolated yield
after reacting for 0.5 h (Table 1, entry 1). Notably, a 2-fold
excess of formaldehyde could dramatically increase the yield
of 3a to 97% under identical conditions (entry 2). Compara-
tively, ethanol was an unfavorable solvent for this process (entry
Preparation of Starting Materials. According to the pro-
cedure reported previously,11 R-EWG ketene-S,S-acetals 1a-h
were conveniently prepared by a two-step process involving the
preparation of R-EWG R-acetyl ketene-S,S-acetals starting from
the corresponding ꢀ-dicarbonyl compounds, carbon disulfide,
and alkyl halides in the presence of K2CO3 catalyzed by
tetrabutylammonium bromide (TBAB) in water and the sequen-
tial acid-promoted deacylation, respectively.
Synthesis of r-EWG-r′-alkyl/arylthiomethyl Ketene-S,S-
acetals 3 via Thiomethylation of r-EWG Ketene-S,S-acetals
1. For the preparation of synthetically useful allylic sulfides,12,13
although some elegant methods, such as transition metal
catalyzed alkylation of thiols,14a-c allylation of diorganodisul-
fides with allyl halides,14d or indium-promoted one-pot reaction
of Baylis-Hillman acetates, sodium thiosulfate, and allyl
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Commun. 2005, 3580–3582. (b) Bi, X.; Dong, D.; Li, Y.; Liu, Q. J. Org. Chem.
2005, 70, 10886–10889. (c) Zhao, L.; Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org.
Chem. 2006, 71, 1094–1098. (d) Hu, J.; Zhang, Q.; Yuan, H.; Liu, Q. J. Org.
Chem. 2008, 73, 2442–2445. (e) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org. Chem.
2006, 71, 8006–8010. (f) Bi, X.; Zhang, J.; Liu, Q.; Tan, J.; Li, B. AdV. Synth.
Catal. 2007, 349, 2301–2306. (g) Liang, F.; Li, D.; Zhang, L.; Gao, J.; Liu, Q.
Org. Lett. 2007, 9, 4845–4848. (h) Chen, L.; Zhao, Y.-L.; Liu, Q.; Cheng, C.;
Piao, C.-R. J. Org. Chem. 2007, 72, 9259–9263. (i) Liang, F.; Zhang, J.; Tan,
J.; Liu, Q. AdV. Synth. Catal. 2006, 348, 1986–1990. (j) Liu, J.; Wang, M.; Li,
B.; Liu, Q.; Zhao, Y. J. Org. Chem. 2007, 72, 4401–4405. (k) Sun, S.; Wang,
M.; Deng, H.; Liu, Q. Synthesis 2008, 573–583.
(7) (a) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org. Chem.
2005, 70, 10030–10035. (b) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J.
Org. Chem. 2003, 68, 3498–3506.
(8) (a) Yin, Y.; Wang, M.; Liu, Q.; Hu, J.; Sun, S.; Kang, J. Tetrahedron
Lett. 2005, 46, 4399–4402. (b) Sun, S.; Zhang, Q.; Liu, Q.; Kang, J.; Yin, Y.;
Li, D.; Dong, D. Tetrahedron Lett. 2005, 46, 6271–6274. (c) Pan, W.; Dong,
D.; Sun, S; Liu, Q. Synlett 2006, 1090–1094. (d) Zhang, Q.; Liu, Y.; Wang, M.;
Liu, Q; Hu, J.; Yin, Y. Synthesis 2006, 3009–3014. (e) Yin, Y.; Zhang, Q.; Li,
J.; Sun, S.; Liu, Q. Tetrahedron Lett. 2006, 47, 6071–6074.
(9) (a) Rao, H. S. P.; Sivakumar, S. J. Org. Chem. 2006, 71, 8715–8723. (b)
Anabha, E. R.; Asokan, C. V. A. Synthesis 2006, 151–155.
(10) (a) Wang, M.; Xu, X. X.; Liu, Q.; Xiong, L.; Yang, B.; Gao, L. Synth.
Commun. 2002, 32, 3437–3443. (b) Zhao, Y.-L.; Liu, Q.; Sun, R.; Zhang, Q.;
Xu, X. X. Synth. Commun. 2004, 34, 463–469.
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Org. Chem. 2005, 2, 755–759.
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ReV. 1997, 97, 2341–2372. (b) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–
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S.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 1999, 121, 8657–8658. (c) Gais,
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¨
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7626 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of Functionalized Allylic Sulfoxides
TABLE 2. Acid-Catalyzed Thiomethylation of 1 with
Formaldehyde and Thiols 2a
TABLE 3. Acid-Catalyzed Thiomethylation of 1 with
Formaldehydea
entry
1
EWG
R
3
time (h)
yield (%)b
time yield of
(h)
1
2
3
4
5
6
1c
1d
1e
1f
1g
1h
MeCO
MeCO
MeCO
PhCO
PhCO
CO2Et
Me
Et
Bn
Me
Et
3n
3i
3e
3o
3p
3q
2.0
4.5
12.0
12.0
13.0
12.0
85
97
66
86
85
91
entry
1
EWG R or R, R
2
R′
3
3 (%)b
1
2
3
4
5
6
7
8
1a MeCO
1b MeCO
1c MeCO
1d MeCO
1e MeCO
1f PhCO
1g PhCO
1h CO2Et
1d MeCO
1d MeCO
1d MeCO
1d MeCO
1d MeCO
(CH2)2
(CH2)3
Me
Et
Bn
Me
Et
Me
Et
Et
Et
Et
2a Bn
2a Bn
2a Bn
2a Bn
2a Bn
2a Bn
2a Bn
2a Bn
2b Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
0.5
0.5
0.5
0.5
0.5
4.0
4.0
6.0
0.5
0.5
8.0
8.0
97
72
93
97
78
92
98
83
98
71
72
83
97
Me
a 1 (1.0 mmol), HCHO (2.0 mmol, 40% aqueous), HCl (1.2 mmol,
36% aqueous), THF (2.0 mL), rt. b Isolated yields.
TABLE 4. Regioselective Oxidation of Allylic Sulfides 3a
9
10
11
12
13
2c n-C12H25
2d Ph
2e 4-MeC6H4 3l
3j
3k
Et
2f 4-ClC6H4 3m 8.0
a 1 (1.0 mmol), HCHO (2.0 mmol, 40% aqueous), 2 (1.0 mmol), HCl
(2.0 mmol, 36% aqueous), THF (2.0 mL), rt. b Isolated yields.
entry
3
EWG
R
R′
4
yield (%)b
3). In the case of the reaction performed in neat acetic acid
(without HCl, entry 4) for 0.5 h, 3a was also obtained in 83%
yield. But no reaction was detected when the reaction was
carried out without HCl in THF (entry 5).
1
2
3
4
5
6
7
8
3a
3d
3k
3l
3n
3o
3p
3q
MeCO
MeCO
MeCO
MeCO
MeCO
PhCO
PhCO
CO2Et
(CH2)2
Bn
Et
Bn
Bn
Ph
4a
4d
4k
4l
4n
4o
4p
4q
84
86
72
79
84
88
86
85
Et
4-MeC6H4
Me
Me
Et
Me
Me
Et
Under the optimized conditions (Table 1, entry 2), a range
of reactions were carried out with selected substrates 1 and thiols
2. As described in Table 2, all of the reactions between
formaldehyde, thiols 2 (including substituted thiophenols) and
R-EWG ketene-S,S-acetals 1 proceeded smoothly in acidic
aqueous media to afford R-EWG-R′-alkyl/arylthiomethyl ketene-
S,S-acetals 3a-m in one pot, and the yield reached up to 98%.
Clearly, the above results show the wide scope of the thiom-
ethylation reaction with respect to a range of R-EWG ketene-
S,S-acetals 1 and thiols 2. We therefore present here a facile
and efficient protocol for the synthesis of functionalized allylic
sulfides 3 based on ketene-S,S-acetals.
In the next study, the thiomethylations of R-EWG ketene-
S,S-acetals 1, in which compounds 1 were not only used as an
activated alkenes but also served as thiol sources, were
performed to extend the synthetic application of 1 as the odorless
thiol equivalents.17 As expected, the thiomethylation of 1c
readily occurred to afford the desired allylic sulfide 3n in 85%
yield (Table 3, entry 1) when 1c (1.0 mmol) was treated with
formaldehyde in the presence of 1.2 equiv of HCl (36%
aqueous) in THF. Similarly, the selected acyclic ketene-S,S-
acetals 1d, 1e, 1f, 1g, and 1h could also give the corresponding
3i, 3e, 3o, 3p, and 3q in good to excellent yields (entries 2-6)
under identical reaction conditions. Notably, this simple and
efficient alternative procedure can avoid the use of foul-smelling
thiols, especially the volatile methanethiol and ethanethiol.
Me
Me
a 3 (1.0 mmol), m-CPBA (1.0 mmol), CH2Cl2 (5.0 mL), 0 °C, 0.5 h.
b Isolated yields.
Regioselective Oxidation of Allylic Sulfides 3 with m-
CPBA to Afford Allylic Sulfoxides 4. In some cases, oxidations
of allylic sulfides with electrophilic oxidants have problems in
selectivity.12,18 In contrast, the oxidation of R-EWG-R′-alkyl/
arylthiomethyl ketene-S,S-acetals 3 with m-chloroperoxybenzoic
acid (m-CPBA) as oxidant has perfect regioselectivity in our
experiments. As described in Table 4, treatment of selected 3
(1.0 mmol) with m-CPBA (1.0 mmol) in dichloromethane (5.0
mL) at 0 °C for 0.5 h can furnish R-EWG-R′-alkyl/arylsulfi-
nylmethyl ketene-S,S-acetals 4 in 72-88% isolated yields,
respectively. It is clear that the oxidations of 3, including aryl
sulfides 3k and 3l (entries 3 and 4), occur selectively at the
allylic sulfide moiety with the dithioacetal residue intact.
Synthesis of Furans 6 by a Novel [3 + 2] Annulation of
Allylic Sulfoxides 4 with Aldehydes 5. Furans are important
five-membered heterocycles which are frequently occurring
structural subunits in numerous natural products with interesting
biological activities,19 and are also versatile building blocks in
organic synthesis.20 Most known methods for the construction
of furan scaffold proceed via various types of cyclization or
(15) For a review, see: (a) Massy, D. J. R. Synthesis 1987, 589–603. For
selected examples for thiomethylation, see: (b) Torisawa, Y.; Satoh, A.; Ikegami,
S. Tetrahedron Lett. 1988, 29, 1729-1732. (c) Konishi, H.; Yamaguchi, H.;
Miyashiro, M.; Kobayashi, K.; Morikawa, O. Tetrahedron Lett. 1996, 37, 8547–
8548. (d) Morikawa, O.; Nakanishi, K.; Miyashiro, M.; Kobayashi, K.; Konishi,
H. Synthesis 2000, 233–236. (e) Akhmetova, V. R.; Nadyrgulova, G. R.;
Tyumkina, T. V.; Starikova, Z. A.; Antipin, M. Y.; Kunakova, R. V.; Dzhemilev,
U. M. Russ. J. Org. Chem. 2007, 43, 918–925.
(16) (a) Kirk, D. N.; Petrow, V. J. Chem. Soc. 1962, 1091–1096. (b) Cohen,
T.; Kosarych, Z.; Suzuki, K.; Yu, L.-C. J. Org. Chem. 1985, 50, 2965–2968.
(17) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong, D.
J. Org. Chem. 2003, 68, 9148–9150. (b) Dong, D.; Ouyang, Y.; Yu, H.; Liu,
Q.; Liu, J.; Wang, M.; Zhu, J. J. Org. Chem. 2005, 70, 4535–4537.
(18) (a) Choi, S.; Yang, J.-D.; Ji, M.; Choi, H.; Kee, M.; Ahn, K.-H.; Byeon,
S.-H.; Baik, W.; Koo, S. J. Org. Chem. 2001, 66, 8192–8198. (b) Linde´n, A. A.;
Kru¨ger, L.; Ba¨ckvall, J.-E. J. Org. Chem. 2003, 68, 5890–5896.
(19) For selected reviews, see: (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In
Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.;
Pergamon: Oxford, UK, 2003; Vol. 15, pp 167. (b) Keay, B. A.; Dibble, P. W.
In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.: Elsevier: Oxford, UK, 1997; Vol. 2, pp 395.
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Lipshutz, B. H. Chem. ReV. 1986, 86, 795–819.
J. Org. Chem. Vol. 73, No. 19, 2008 7627

Fu et al.
cycloisomerization of acyclic precursors,21 for example, the
cyclocondensation of 1,4-dicarbonyl compounds or equivalents
(Paal-Knorr synthesis),22 the condensation of simple ꢀ-dicar-
bonyl compounds with R-haloketones (Feist-Benary synthe-
sis),23 and the cycloisomerization of alkyne- and allene-
containing compounds.21b,24 Recently, some new strategies for
furan synthesis, such as the annulation of ketimines with
aldehydes,25a fluoropropargyl chloride with carbonyl
compounds,25b R,ꢀ-acetylenic ketones with R-diazo esters,25c
ynolates with R-acyloxyketones,25d and 2,3-bis(trimethylsi-
lyl)buta-1,3-diene with acyl chlorides,25e have been well
developed.
In the present research, the reactions of the functionalized
allylic sulfides/sulfoxides 3/4 with aldehydes were attempted
under the consideration that a [3 + 2] annulation strategy26
would be realized for the construction of substituted furans
(Scheme 1). However, several initial efforts were unsuccessful
in the reactions of allylic sulfide 3o and 4-nitrobenzaldehyde
5a in the presence of either NaOH in EtOH, or t-BuOK in THF,
or NaH in THF, or NaH in DMSO.
TABLE 5. Optimization of Conditions for [3 + 2] Annulation
Reaction of 4o with 5aa
entry
base (equiv)
solvent (V/mL)
time (h)
yield (%)b
1
2
3
4
5
6
7
NaOH (2.0)
NaOH (2.0)
t-BuOK (2.0)
NaH (2.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
EtOH (2.0)
MeOH (2.0)
THF (2.0)
DMSO (2.0)
EtOH (2.0)
EtOH (5.0)
EtOH (10.0)
4.0
76
43
74
64
88
82
73
14.0
14.0
1.0
1.5
5.0
7.0
a 4o (1.0 mmol), 5a (1.1 mmol), rt, then quenched by dilute HCl at 0
°C. b Isolated yields.
TABLE 6. [3 + 2] Annulation Reaction of 4 with 5a
Then, we turned to the more reactive allylic sulfoxides 4 as
the three carbon components and the reaction of 4o with 5a
using 2.0 equiv of NaOH as base in EtOH was carried out. To
our delight, 2-methylthio-3-benzoyl-5-(4-nitrophenyl)furan 6a
was obtained in 76% isolated yield by reacting for 4.0 h at room
temperature (Table 5, entry 1). Thus, compound 4o was used
as model substrate to optimize the reaction conditions. As
described in Table 5, various bases, such as NaOH/MeOH,
t-BuOK/THF, and NaH/DMSO, were selected for this annula-
tion. It was observed that the annulated product 6a could be
obtained in all cases (entries 2-4). Among them, NaOH/EtOH
was proved to be more effective regarding the yields and
reaction times. In addition, the amount of NaOH and solvent
were also examined. By comparison (entries 5-7), the best
entry
4
EWG
R
5
R′
time (h)
6
yield (%)b
1
2
3
4
5
6
7
8
9
4o PhCO Me 5a 4-NO2C6H4
4o PhCO Me 5b 3-NO2C6H4
4o PhCO Me 5c 2-ClC6H4
4o PhCO Me 5d 4-ClC6H4
4o PhCO Me 5e 4-FC6H4
4o PhCO Me 5f 4-pyridinyl
4o PhCO Me 5g Ph
1.5
1.5
2.0
2.0
2.0
1.5
3.0
5.0
6a
88
73
60
61
61
85
59
55
54
61
46
85
32
6b
6c
6d
6e
6f
6g
6h
6i
4o PhCO Me 5h 4-CH3C6H4
4o PhCO Me 5i 3,4-O2CH2C6H3 4.0
10 4o PhCO Me 5j 2-furyl
2.0
2.0
1.5
6j
6k
6l
11 4o PhCO Me 5k 2-thienyl
12 4p PhCO Me 5a 4-NO2C6H4
13 4n MeCO Me 5d 4-ClC6H4
14 4q CO2Et Me 5a 4-NO2C6H4
10.0 6m′c
d
5.0
-
(21) For selected reviews of furan synthesis, see: (a) Kirsch, S. F. Org.
Biomol. Chem. 2006, 4, 2076–2080. (b) Brown, R. C. D. Angew. Chem., Int.
Ed. 2005, 44, 850–852. (c) Keay, B. A. Chem. Soc. ReV. 1999, 28, 209–215. (d)
Cacchi, S. J. Organomet. Chem. 1999, 576, 42–64. (e) Hou, X. L.; Cheung,
H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955–2020.
a 4 (1.0 mmol), 5 (1.1 mmol), NaOH (4.0 mmol), EtOH (2.0 mL), rt,
then quenched by aq HCl at 0 °C. b Isolated yields. c 6m’:
(22) For selected examples of Paal-Knorr synthesis, see: (a) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277–5288, and
references cited therein. (b) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett.
2004, 6, 389–392. (c) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng,
J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992–4993.
d Complex mixture was obtained.
(23) For selected examples of the Feist-Benary synthesis, see: (a) Mross,
G.; Holtz, E.; Langer, P. J. Org. Chem. 2006, 71, 8045–8049. (b) Holtz, E.;
Langer, P. Synlett 2004, 1805–1807. (c) Calter, M. A.; Zhu, C.; Lachicotte, R. J.
Org. Lett. 2002, 4, 209–212.
(24) For selected examples of cycloisomerization of alkyne- and allene-
containing compounds, see: (a) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim,
J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452.
(b) Kim, S.; Lee, P. H. AdV. Synth. Catal. 2008, 350, 547–551. (c) Peng, L.;
Zhang, X.; Ma, M.; Wang, J. Angew. Chem., Int. Ed. 2007, 46, 1905–1908. (d)
Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2007, 129, 9868–9878. (e) Zhang, J.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. 2006, 45, 6704–6707.
(25) For selected examples of recent advances in annulation strategies, see:
(a) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem. Soc. 2006,
128, 12376–12377. (b) Xu, B.; Hammond, G. B. J. Org. Chem. 2006, 71, 3518–
3521. (c) Zhao, L.-B.; Guan, Z.-H.; Han, Y.; Xie, Y.-X.; He, S.; Liang, Y.-M.
J. Org. Chem. 2007, 72, 10276–10278. (d) Shindo, M.; Yoshimura, Y.; Hayashi,
M.; Soejima, H.; Yoshikawa, Y.; Matsumoto, K.; Shishido, K. Org. Lett. 2007,
9, 1963–1966. (e) Babudri, F.; Cicco, S. R.; Farinola, G. M.; Lopez, L. C.; Naso,
F.; Pinto, V. Chem. Commun. 2007, 3756–3758.
(26) One example of a [3 + 2] annulation reaction toward tetrahydrofuran
skeleton was reported by Junjappa and co-workers in 1988, in which a
tetrasubstituted furan could be obtained in 25% overall yield by treating
2-benzoyl-3-cyano-1,1-bis(methy1thio)propenide anion with 4-chlorobenzalde-
hyde to yield a cyclic hemiacetal, which was further treated with BF3 · OEt2 and
methanol. Singh, L. W.; Ila, H.; Junjappa, H. J. Chem. Soc., Perkin Trans. I
1988, 2365-2368.
results were obtained when 4o (1.0 mmol) was treated with 5a
(1.1 mmol) in EtOH (2.0 mL) in the presence of NaOH (4.0
mmol) at room temperature for 1.5 h, thus providing 6a in 88%
isolated yield (entry 5).
For a more general understanding of the scope of this [3 +
2] annulation strategy, a variety of aldehydes 5 were selected
to react with 4o under the optimized conditions and the
experimental results are given in Table 6. It was found that all
arylaldehydes tested, including benzaldehyde (entry 7), aryla-
ldehydes with both electron-withdrawing (entries 1-6) and
electron-donating groups (entries 8 and 9), and heteroaromatic
aldehydes (entries 10 and 11), could readily react with 4o to
afford 2-alkylthio-3,4-disubstituted furans 6a-k in good to high
yields. For comparison, the reactions of electron-rich arylalde-
hydes give slightly lower yields (entries 8-11). However, the
reactions of aliphatic aldehydes (acetaldehyde, cyclohexanecar-
baldehyde, or pivalaldehyde) with 4o led to a complex mixture
in which no type 6 could be detected. The tolerance of substrate
4 was then investigated. It was found that the variation of the
7628 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of Functionalized Allylic Sulfoxides
SCHEME 2
SCHEME 3. Proposed Mechanism for the [3 + 2]
Annulation of 4 and 5
EWG and ketene-S,S-acetal moieties of 4 had influence on the
annulation. The reaction of 4p with 5a could give the desired
furan 6l in high yield (entry 12). In the case of 4n and 5d, furan
6m′ was afforded by a [3 + 2] annulation along with an aldol
condensation (entry 13). However, a complex mixture was
obtained when 4q was selected as substrate under identical
conditions (entry 14). All furans 6 obtained were characterized
by their spectra and elemental analysis and the structure of 6
was further established by X-ray diffraction studies of 6a.27
As described above, we have provided an efficient and
convenient procedure for the synthesis of 2-alkylthio-3,4-
disubstituted furans 6. It is obvious that these 2-alkylthio furans
can be further utilized in the synthesis of various 2-substituted
furans via the direct replacement of the alkylthio group by a
nucleophile. For further investigation of the application of these
useful functionalized furans 6, we explored the substitution
reactions of 6a with amines. As described in Scheme 2,
2-aminofurans 7, which are evaluated as either a scaffold in
natural product synthesis or useful building blocks in organic
synthesis,28 could be obtained in excellent yields. For example,
when a mixture of 6a (1.0 mmol) and ethylamine (3.0 mmol)
was stirred in ethanol (5.0 mL) at reflux for 24 h, 2-aminofuran
7a was produced as a white solid (98% yield). Similarly, when
6a and piperidine or 6a and benzylamine were subjected to the
identical conditions, the desired products 7b and 7c were
obtained in 99% and 90% isolated yields, respectively. However,
when aniline was taken as the nucleophile, no reaction occurred
after reacting for 48 h under identical reaction conditions and
6a was recovered in quantitative yield.
an R-EWG ketene-S,S-acetal 1, formaldehyde, and a thiol 2, is
the first example of the Mannich-type thiomethylation of
activated alkenes. Allylic sulfoxides 4 are readily obtained by
a highly regioselective oxidation of the corresponding allylic
sulfides 3 with use of m-CPBA as oxidant. Both allylic sulfides
3 and allylic sulfoxides 4 might have potential in organic
synthesis due to their diverse functionalities. Thus, we explored
the applications of sulfoxides 4 in the construction of poly-
functionalized furans. As a result, a [3 + 2] annulation reaction
of allylic sulfoxides 4 and aldehydes 5 was uncovered. The key
features of this furan synthesis are that the combination of the
properties of sulfoxide (the alkylsulfinyl group is either an
activating group of the adjacent methylene or a good leaving
group) and ketene-S,S-acetal (substitution reaction of alkylthio
group) contributes to the formation of furan scaffold and that
the resulting furan derivatives, bearing a wide range of functional
groups such as alkylthio, alkylamino, or carbonyl, etc., can be
taken as valuable synthons for the preparation of various
synthetically useful compounds. It is also of great interest to
note that the presented [3 + 2] annulation gives furans in good
to high yields from readily available starting materials under
mild conditions. Future studies focused on the development of
related transformations via the [3 + 2] annulation methodology
are in progress.
Experimental Section
Proposed Mechanism for the [3 + 2] Annulation. On the
basis of all of the above experimental results, a possible
mechanism for the [3 + 2] annulation of 4 with 5 is proposed
as shown in Scheme 3. This pathway begins with an aldol
condensation of functionalized sulfoxide 4 with aldehyde 5 in
the presence of base to give intermediate I. Subsequently, an
intramolecular addition-elimination reaction of I involving an
attack of alkoxyl on ketene-S,S-acetal moiety affords dihydro-
furan II, of which elimination of a sulfenic acid gives the target
product of type 6.
General Procedure for the Preparation of 3a-m via the
Thiomethylation of 1 with Formaldehyde and Thiols (with
3d as an example). To a solution of 4,4-bis(ethylthio)but-3-en-2-
one (1d) (190 mg, 1.0 mmol), formaldehyde (0.17 mL, 40%
aqueous, 2.0 mmol), and benzylthiol (0.12 mL, 1.0 mmol) in THF
(2.0 mL) was added HCl (0.17 mL, 36% aqueous, 2.0 mmol). The
resulting mixture was stirred for 0.5 h at room temperature. After
completion of the reaction as indicated by TLC (petrolum ether:
diethyl ether ) 3:1), the reaction mixture was poured into saturated
aqueous NaCl (20 mL). The mixture was neutralized with aqueous
Na2CO3 and extracted with CH2Cl2 (3 × 20 mL). The combined
organic phase was washed with water (3 × 20 mL), dried over
MgSO4, and concentrated in vacuo. The crude product was purified
by flash chromatography (silica gel, petroleum ether:diethyl ether
) 20:1) to give 3d (317 mg, 97%) as a yellow oil.
Conclusion
In summary, a set of functionalized allylic sulfides 3 have
been synthesized by a thiomethylation reaction based on R-EWG
ketene-S,S-acetals 1. This three-component reaction, involving
3-(Benzylthiomethyl)-4,4-bis(ethylthio)but-3-en-2-one (3d). 1H
NMR (CDCl3, 500 MHz) δ 1.21 (t, J ) 7.5 Hz, 3H), 1.27 (t, J )
7.5 Hz, 3H), 2.46 (s, 3H), 2.77-2.83 (m, 4H), 3.73 (s, 2H), 3.74
(s, 2H), 7.24-7.25 (m, 1H), 7.29-7.33 (m, 4H). 13C NMR (CDCl3,
125 MHz) δ 203.9, 147.6, 138.1, 135.8, 129.2 (2C), 128.8 (2C),
127.4, 37.0, 34.6, 31.8, 28.3, 28.2, 15.2, 14.9. IR (KBr, cm-1) 3027,
2967, 2923, 1689, 1497, 1255, 1079, 886, 704. ES-MS calcd m/z
326.1, found 365.0 [(M + 39)]+. Anal. Calcd for C16H22OS3: C,
58.85; H, 6.79. Found: C, 58.99; H, 6.70.
(27) Crystal data for 6a: C18H13NO4S, yellow, M ) 339.35, monoclinic, space
group P 21/c, a ) 16.312(4) Å, b ) 13.323(3) Å, c ) 7.362(2) Å, V ) 1599.7(7)
Å3, R ) 90.00°, ꢀ ) 90.00°, γ ) 90.00°, Z ) 4, T ) 293 K, F000 ) 704, R1 )
0.0563, wR2 ) 0.0803.
(28) Selected examples for applications and synthesis of 2-amino furans, see:
(a) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org. Chem. 1999,
64, 4617–4626. (b) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019–1020.
(c) Alizadeh, A.; Rostamnia, S.; Hu, M.-L. Synlett 2006, 1592–1594. (d) Alizadeh,
A.; Rostamnia, S.; Zoreh, N.; Oskueyan, Q. Synlett 2007, 1610–1612.
J. Org. Chem. Vol. 73, No. 19, 2008 7629

Fu et al.
Typical Procedure for the Preparation of 3e, 3i, and 3n-q via
the Thiomethylation of 1, in Which 1 by Themselves Served As
Thiol Sources (with 3i as an example). To a solution of 4,4-
bis(ethylthio)but-3-en-2-one (1d) (190 mg, 1.0 mmol) and form-
aldehyde (0.17 mL, 40% aqueous, 2.0 mmol) in THF (2.0 mL)
was added HCl (0.10 mL, 36% aqueous, 1.2 mmol). The resulting
mixture was stirred for 4.5 h at room temperature. After completion
of the reaction as indicated by TLC (petroleum ether:diethyl ether
) 3:1), the reaction mixture was poured into saturated aqueous
NaCl (20 mL). The mixture was neutralized with aqueous Na2CO3,
and extracted with CH2Cl2 (3 × 20 mL). The combined organic
phase was washed with water (3 × 20 mL), dried over MgSO4,
and concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether:diethyl ether ) 30:1)
to give 3i (128 mg, 97%) as a yellow oil.
General Procedure for the Preparation of 4a, 4d, 4k, 4l, and
4n-q (with 4o as an example). To a solution of 3,3-bis(methylthio)-
2-(methylthiomethyl)-1-phenylprop-2-en-1-one (3o) (284 mg, 1.0
mmol) in 5.0 mL of CH2Cl2 was added m-CPBA (204 mg, 1.0
mmol). The resulting mixture was stirred for 0.5 h at 0 °C. After
completion of the reaction as indicated by TLC (pure diethyl ether),
the reaction mixture was poured into saturated aqueous NaCl (30
mL). The mixture was neutralized with aqueous Na2CO3 and
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase
was washed with water (3 × 20 mL), dried over MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, pure diethyl ether) to give 4o (263 mg,
88%) as a yellow oil.
(2-(Methylthio)-5-(4-nitrophenyl)furan-3-yl)(phenyl)metha-
none (6a). Mp 166-168 °C. H NMR (500 MHz, CDCl3) δ 2.81
1
(s, 3H), 7.25 (s, 1H), 7.59 (t, J ) 7.5 Hz, 2H), 7.67 (t, J ) 7.5 Hz,
1H), 7.82 (d, J ) 8.0 Hz, 2H), 7.90 (d, J ) 7.5 Hz, 2H), 8.34 (d,
J ) 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 188.7, 160.8,
151.4, 146.4, 138.3, 135.0, 132.2, 128.5 (2C), 128.4 (2C), 124.4
(2C), 123.4 (2C), 122.6, 111.0, 13.7. IR (KBr, cm-1) 2927, 1627,
1592, 1382, 1100, 889. ES-MS calcd m/z 339.1, found 340.1 [(M
+ 1)]+. Anal. Calcd for C18H13NO4S: C, 63.71; H, 3.86; N, 4.13.
Found: C, 63.63; H, 3.91; N, 4.08.
General Procedure for the Synthesis of 7 (with 7a as an
example). To a solution of (2-(methylthio)-5-(4-nitrophenyl)furan-
3-yl)(phenyl)methanone (6a) (339 mg, 1.0 mmol) in 5.0 mL of
ethanol was added ethanamine (0.20 mL, 3.0 mmol). The resulting
mixture was stirred at refluxing temperature. After completion of
the reaction as indicated by TLC (petroleum ether:diethyl ether )
1:1), the reaction mixture was poured into saturated aqueous NaCl
(20 mL). The mixture was neutralized with aqueous NaHCO3 and
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase
was washed with water (3 × 20 mL), dried over MgSO4, and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether:diethyl ether ) 3:1)
to give 7a (329 mg, 98%) as a red solid.
(2-(Ethylamino)-5-(4-nitrophenyl)furan-3-yl)(phenyl)metha-
1
none (7a). Mp 172-174 °C. H NMR (500 MHz, CDCl3) δ 1.43
(t, J ) 7.5 Hz, 3H), 3.65-3.70 (m, 2H), 7.09 (s, 1H), 7.49-7.56
(m, 3H), 7.60 (d, J ) 8.5 Hz, 2H), 7.76 (d, J ) 7.0 Hz, 2H), 8.21
(d, J ) 8.5 Hz, 2H), 8.48 (br s, 1H). 13C NMR (125 MHz, CDCl3)
δ 188.3, 165.1, 145.5, 141.3, 140.0, 136.1, 131.4, 128.7 (2C), 128.1
(2C), 124.8 (2C), 122.3 (2C), 111.1, 100.3, 37.5, 15.5. IR (KBr,
cm-1) 3304, 2966, 2926, 1650, 1550, 1323, 1181, 1102, 739. ES-
MS calcd m/z 336.1, found 337.1 [(M + 1)]+. Anal. Calcd for
C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.69; H, 4.71;
N, 8.25.
2-(Methylsulfinylmethyl)-3,3-bis(methylthio)-1-phenylprop-2-en-
1
1-one (4o). H NMR (CDCl3, 500 MHz) δ 2.05 (s, 3H), 2.34 (s,
3H), 2.60 (s, 3H), 4.02 (d, J ) 13.0 Hz, 1H), 4.24 (d, J ) 13.0 Hz,
1H), 7.43 (t, J ) 7.5 Hz, 2H), 7.51 (t, J ) 7.5 Hz, 1H), 7.87 (d, J
) 7.5 Hz, 2H). 13C NMR (CDCl3 125 MHz) δ 195.8, 147.7, 137.0,
134.1, 133.1, 129.0 (2C), 128.6 (2C), 59.4, 39.0, 17.3, 16.9. IR
(KBr, cm-1) 3058, 2996, 2921, 1654, 1419, 1276, 1051, 963, 797.
ES-MS calcd m/z 300.0, found 323.0 [(M + 23)]+. Anal. Calcd
for C13H16O2S3: C, 51.97; H, 5.37. Found: C, 51.79; H, 5.25.
Representative Procedure for the Preparation of Furans 6 via
[3 + 2] Annulation of 4 with Aldehydes 5 (with 6a as an example).
To a well-stirred suspension of the corresponding 2-(methylsulfi-
nylmethyl)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one (4o) (300
mg, 1.0 mmol) and 4-nitrobenzaldehyde (5a) (166 mg, 1.1 mmol)
in ethanol (2.0 mL) was added NaOH (160 mg, 4.0 mmol) at room
temperature. After consumption of the starting material 4o (TLC),
the mixture was poured into saturated aqueous NaCl (20 mL). The
mixture was neutralized with dilute aqueous HCl and extracted with
CH2Cl2 (3 × 20 mL). The combined organic phase was washed
with water (3 × 20 mL), dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
(silica gel, petroleum ether:diethyl ether ) 3:1) to give 6a (298
mg, 88%) as a yellow solid.
Acknowledgment. Financial supports of this research by the
Ministry of Education of China (108044), the National Natural
Science Foundation of China (20672019), the Department of
Science and Technology of Jilin Province (20070549), and
Science Foundation for Young Teacher of Northeast Normal
University (20070308) are greatly acknowledged.
Supporting Information Available: Experimental details,
spectral and analytical data for compounds 3, 4, 6, and 7, copies
of 1H NMR and 13C NMR spectra of 3, 4, 6, and 7, and
crystallographic data for 6a (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO801406P
7630 J. Org. Chem. Vol. 73, No. 19, 2008