Copper-catalyzed multicomponent reaction: Synthesis of 4-arylsulfonylimino- 4,5-dihydrofuran derivatives

Article abstract of DOI:10.1021/jo1010075

A series of 4-arylsulfonylimino-4,5-dihydrofurans (14 examples) were efficiently synthesized in good to excellent yields by using the copper-catalyzed three-component reaction between sulfonyl azides, phenylacetylene, and β-ketoesters in tetrahydrofuran (THF) at 40 °C for 8 h in the presence of triethylamine (TEA). A plausible mechanism for this process is proposed.

Full text of DOI:10.1021/jo1010075

pubs.acs.org/joc
Diels-Alder reactions, condensations, and cross-coupling
Copper-Catalyzed Multicomponent Reaction:
Synthesis of 4-Arylsulfonylimino-4,5-dihydrofuran
Derivatives
reactions. Among those, the metal-catalyzed processes using
Pd,4 Cu,5 Ag,6 Au,7 and Ru8 metals have been widely used
for the synthesis of furan structure, which requires the tedious
preparation of alkynones and allenones. On the other hand, the
synthesis of highly functionalized dihydrofuran derivatives from
simple compounds by using multicomponent reactions (MCRs)
remains a challenge. And to the best of our knowledge, 4-aryl-
sulfonylimino-4,5-dihydrofuran has never been reported.
Many MCRs show advantages in atomic economy, environ-
mental friendliness, simplified steps, and efficient use of
resources.9 Among those, the Cu-catalyzed three-component
reactions have been extensively used in organic synthesis.
Recently, CuI-catalyzed10 MCRs concerning sulfonyl azides
and alkynes have drawn special interest. Chang et al.11 and
Wang’s group12 have used the Cu-catalyzed MCRs of sulfo-
nyl azides and terminal alkynes for the efficient generation
of N-sulfonylamidines, amides, N-sulfonylazetidin-2-imines,
iminocoumarins, and 5-arylidene-2-imino-3-pyrrolines, and
γ-nitro imidates by using the corresponding amines, water
alcohol, imines, salicylaldehyde, aziridine, and nitroolefin as
the third component, respectively.
Yongjia Shang,* Kai Ju, Xinwei He, Jinsong Hu,
Shuyan Yu, Min Zhang, Kaisheng Liao, Lifen Wang, and
Ping Zhang
Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Key Laboratory of
Molecule-Based Materials, College of Chemistry and
Materials Science, Anhui Normal University,
Wuhu 241000, People’s Republic of China
shyj@mail.ahnu.edu.cn
Received May 23, 2010
Previously, we have developed an efficient synthesis of
the benzoxazoline-amidine using a MCR of sulfonyl azides,
alkynes, and Schiffs’ base.13 Herein, we report a novel path-
way for the synthesis of highly substituted dihydrofuran
A series of 4-arylsulfonylimino-4,5-dihydrofurans (14 exam-
ples) were efficiently synthesized in good to excellent yields
by using the copper-catalyzed three-component reaction
between sulfonyl azides, phenylacetylene, and β-ketoesters
in tetrahydrofuran (THF) at 40 °C for 8 h in the presence of
triethylamine (TEA). A plausible mechanism for this process
is proposed.
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DOI: 10.1021/jo1010075
r
Published on Web 07/16/2010
J. Org. Chem. 2010, 75, 5743–5745 5743
2010 American Chemical Society

Shang et al.
JOCNote
TABLE 1. The Optimal Reaction Conditions of CuI-Catalyzed
Three-Component Reactions of Sulfonyl Azides, Phenylacetylene,
and β-Ketoesters
TABLE 2. CuI-Catalyzed Three-Component Reaction for the
Formation of 4-Arylsulfonylimino-4,5-dihydrofuran Derivativesa
entry
R1
R2
R3
R4
yield (%) a
yield (%)a
1
2
3
4
5
6
7
8
9
C6H5 (1a)
C6H5
CH3 C2H5 (3a)
CH3 C2H5
4a, 80
4b, 82
4c, 85
4d, 82
4e, 87
4f, 78
4g, 75
4h, 80
entry
base
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
pyridine
K3PO4
K2CO3
TEA
TEA
TEA
solvent
temp (°C)
time (h)
p-ClC6H4 (1b) C6H5
C6H5 C6H5
p-CH3C6H4 (1c) C6H5
p-ClC6H4
C6H5
p-CH3C6H4
p-ClC6H4
C6H5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
THF
THF
THF
THF
CH2Cl2
CH3CN
toluene
DMF
THF
THF
THF
THF
THF
THF
r.t.
40
60
80
40
40
40
40
40
40
40
40
40
40
8
8
8
8
8
8
8
8
8
8
8
4
6
10
45
80
81
78
17
70
68
54
51
36
32
76
78
80
CH3 n-C4H9 (3b)
CH3 n-C4H9
CH3 n-C4H9
C6H5 C2H5 (3c)
C6H5 C2H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5 C2H5
CH3 C6H5CH2 (3d) 4i, 75
10 p-CH3C6H4
11 C6H5
12 p-ClC6H4
13 C6H5
14 p-CH3C6H4
15 C6H5
16 C6H5
CH3 n-C5H11 (3e)
CH3 n-C5H11
CH3 n-C5H11
CH3 n-C7H15 (3f)
CH3 n-C7H15
4j, 82
4k, 84
4l, 88
4m, 85
4n, 88
0
p-CH3C6H4 CH3 C2H5
p-CH3OC6H4 CH3 C2H5
0
aReaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), 3a (3.0 mmol),
CuI (0.1 mmol), and TEA (2.0 mmol), N2 atmosphere in a sealed tube.
17 C6H5
n-C5H11
CH3 C2H5
0
aReaction conditions: sulfonyl azide (1.1 mmol), phenylacetylene (1.0
mmol), β-ketoester (3.0 mmol), CuI (0.1 mmol), and TEA (2.0 mmol),
N2 atmosphere, 40 °C, 8 h in a sealed tube.
derivatives via CuI-catalyzed three-component reaction with
sulfonyl azide, phenylacetylene, and β-ketoester. To the best
of our knowledge, no synthetic routes aimed at 4-arylsulfo-
nylimino-4, 5-dihydrofuran derivatives have been reported.
The optimized reaction conditions for our CuI-catalyzed
three-component reaction of sulfonyl azide, phenylacety-
lene, and β-ketoester were obtained with benzenesulfonyl
azide 1a, phenylacetylene 2a, and ethyl acetoacetate 3a as the
starting materials as shown in Table 1.
SCHEME 1. Possible Mechanistic Pathway Leading to the
Highly Substituted Dihydrofurans 4
Solvent, base, and temperature were found to be able to
greatly affect this reaction. Among those, base was found to
be critical for this reaction. In the absence of an external base,
no reaction was observed. In comparison with K3PO4, K2CO3,
and pyridine, triethylamine (TEA) generally gave better yields.
In comparison with commonly used solvents, such as CH2Cl2,
CH3CN, DMF, and toluene, THF gave better yields (Table 1,
entries 5-11). The increase of the reaction temperature up to
40 °C also brought the increase of the yield (Table 1, entry 2).
However, the further increase of the reaction temperature
shows little effect on the yield (Table 1, entries 3 and 4).
In THF, at 40 °C for 8 h, ethyl 2-methyl-5-phenyl-4-(phenyl-
sulfonylimino)-4,5-dihydrofuran-3-carboxylate 4a was ob-
tained in 80% yield (Table 1, entry 2). Compound 4a14 was
unequivocally confirmed by single-crystal analysis as shown
in Figure S1 in the SI. Thus, THF was used as solvent, TEA
was used as base, and the reaction temperature was set at
40 °C for the rest of the studies.
sulfonyl azides 1, phenylacetylene 2, and β-ketoester 3 as
summarized in Table 2. Among various sulfonyl azides 1
investigated (Table 2, entries 1, 2, and 4), molecules with
either electron-withdrawing groups (-Cl) or electron-donating
groups (-CH3) attached all provided high yields. Among
various β-ketoester 3 investigated, when R3 was an alkyl group,
it often gave higher yields (Table 2, entries 5, 12, and 14). On
the other hand, when R3 was a phenyl group, it often gave
slightly lower yields (Table 2, entries 6-8). The reaction was
also limited to β-ketoesters. Use of β-dicarbonyl compounds
as substrates did not afford the desired products. In compari-
son with phenylacetylene, when the substituted phenylace-
tylene and aliphatic terminal alkyne, such as p-methylphenyl-
acetylene, p-methoxyphenylacetylene, and n-heptylacetylene,
To test the versatility of this reaction, this optimized
reaction condition was applied to the MCRs between various
˚
(14) Crystallographic data for 4a: space group P1, a=10.0868(8) A, b=
o
˚
˚
15.8235(13) A, c= 12.3174(10) A, R=90°, β =99.1310(10) , γ =90°, V=
1941.0(3) A , T=293(2) K, Z=4. Crystallographic data for compound 4a
3
˚
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC-751364.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/
retrieving.html.
5744 J. Org. Chem. Vol. 75, No. 16, 2010

Shang et al.
JOCNote
were used for this reaction, no desired product was obtained
(Table 2, entries 15-17).
Ethyl 4-(phenylsulfonylimino)-2-methyl-5-phenyl-4,5-dihydro-
furan-3-carboxylate (4a): white solid (80%), mp 136 °C; 1H
NMR (CDCl3, 300 Hz) δ 7.93 (d, J = 7.5 Hz, 2H), 7.65 (d,
J=7.9 Hz, 2H), 7.45-7.50 (m, 1H), 7.28-7.37 (m, 5H), 6.90 (s,
1H), 3.96 (q, J=7.0 Hz, 2H), 2.47 (s, 3H), 1.20 ppm (t, J=7.0
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.0, 156.8, 147.5,
138.6, 132.8, 128.8, 128.5, 128.2, 127.8, 125.4, 117.0, 111.4, 60.4,
14.3, 14.1 ppm; IR (KBr) ν 3234, 2974, 2904, 1689, 1627, 1585,
1571, 1492, 1440, 1406, 1382, 1342, 1327, 1251, 1230, 1174, 1136,
1101, 1016, 910, 866, 785, 767, 746, 694 cm-1; HRMS (ESI)
calcd for [C20H19NO5S þ H]þ 386.1062, found 386.1061.
Ethyl 4-(4-chlorophenylsulfonylimino)-2-methyl-5-phenyl-4,5-
dihydrofuran-3-carboxylate (4b): white solid (82%), mp 147 °C;
1H NMR (CDCl3, 300 Hz) δ 7.87 (d, J=7.0 Hz, 2H), 7.57 (d, J=
8.5 Hz, 2H), 7.55-7.36 (m, 5H), 6.91 (s, 1H), 4.04 (q, J=7.1 Hz,
2H), 2.49 (s, 3H), 1.24 ppm (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 163.2, 156.9, 147.8, 139.4, 137.1, 129.4,
128.7, 128.6, 128.3, 128.2, 125.5, 116.8, 60.6, 14.4, 14.1 ppm; IR
(KBr) ν 3286, 3242, 2980, 2956, 2937, 2378, 2347, 1730, 1676,
1625, 1585, 1571, 1475, 1415, 1328, 1230, 1170, 1087, 1072, 831,
756, 696 cm-1; HRMS (ESI) calcd for [C20H18ClNO5S þ H]þ
420.0672, found 420.0675.
A plausible mechanism for this three-component domino-
like process is shown in Scheme 1. First, in the presence of CuI,
sulfonyl azide 1 reacts with the alkyne 2 to form the ketenimine
species A. Protonation of A leads to the formation of the highly
reactive ketenimine B, which is quickly attacked by nucleophile
D to generate the intermediate E. The subsequent intramole-
cular nucleophilic addition of dihydrofuran F followed by
deprotonation generates 4,5-dihydrofuran 4.
In conclusion, an efficient copper-catalyzed three-compo-
nent reaction for the generation of a series of highly substituted
dihydrofurans has been developed. The method provides an
alternative synthetic route for the synthesis of 4-arylsulfonyli-
mino-4,5-dihydrofuran derivatives in excellent yields.
Experimental Section
General Procedure for the Synthesis of 4-Arylsulfonylimino-
4,5-dihydrofuran Derivatives. To a stirred mixture of CuI (19.1 mg,
0.1 mmol), benzenesulfonyl azide (219 mg, 1.2 mmol), phenylace-
tylene (102 mg, 1 mmol), and ethyl acetoacetate (309 mg, 3.0 mmol)
in anhydrous THF (5 mL) was slowly added TEA (2 mL) via
syringe under an N2 atmosphere at 40 °C. The reaction mixture
was stirred for 8 h in a sealed tube. Solvent was reduced under
vacuum, then extracted with CH2Cl2 (3 ꢀ 10 mL). Organic layers
were combined, dried over anhydrous Na2SO4, filtered, and con-
centrated under vacuum. The residue was purified by flash column
chromatography on silica gel (200-300 mesh) with ethyl acetate
and petroleum ether (1:10-1:15) as eluting solvent to give the
desired product.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20872001) and the Anhui Educa-
tion Department (Grant No. TD200707).
Supporting Information Available: Detailed experimental
procedures, characterization data, copies of 1H and 13C NMR
spectra for all products, and crystallographic information files
for compound 4a. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 16, 2010 5745