Formal [4+1] annulation of cyclopropyl amides and water mediated by Lewis acid: A novel entry to γ-butyrolactones

Article abstract of DOI:10.1055/s-0031-1290971

An efficient one-pot synthesis of substituted -butyrolactones from cyclopropyl amides mediated by the Lewis acid SnClH is reported. A mechanism involving a tandem ring-opening reaction and intramolecular cyclization reaction is proposed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290971

PAPER
▌1679
paper
Formal [4+1] Annulation of Cyclopropyl Amides and Water Mediated by
Lewis Acid: A Novel Entry to γ-Butyrolactones
[4+1] Annulation to γ-Butyrolactones
Dingyuan Zhang, Rui Zhang,* Yongjiu Liang, Dewen Dong*
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. of China
Fax +86(431)85262676; E-mail: ariel@ciac.jl.cn; E-mail: dwdong@ciac.jl.cn
Received 10.02.2012; Accepted after revision: 28.03.2012
of γ-butyrolactones. Nevertheless, to match the increasing
scientific and practical demands, it is still of great impor-
tance to develop simple and efficient approaches to the
construction of γ-butyrolactone derivatives, especially
those with wide applicability to achieve more elaborate
and flexible substitution patterns.
Abstract: An efficient one-pot synthesis of substituted γ-butyrolac-
tones from cyclopropyl amides mediated by the Lewis acid
SnCl4·5H2O is reported. A mechanism involving a tandem ring-
opening reaction and intramolecular cyclization reaction is pro-
posed.
Key words: -lactones, cyclopropyl amides, Lewis acids, synthetic
methods, water
The utility of cyclopropanes in organic synthesis has been
recognized. This is, in part due to their ready accessibility
and good reactivity, which originates from the inherent
ring strain that can lead to a variety of ring-opening or
ring-enlargement reactions under the influence of a wide
range of chemicals including electrophiles, nucleophiles,
and radicals.11,12 Indeed, the groups of Reissig and Reiser
reported the synthesis of γ-butyrolactones from cyclopro-
panes.13,14 In a present paper, we investigated the reaction
of primary cyclopropyl amides, and provided an alterna-
tive synthesis of substituted γ-butyrolactones. Herein, we
wish to report our experimental results and present a plau-
sible mechanism for the ring-opening/recyclization.
The γ-butyrolactone motif makes up the core structure of
numerous bioactive compounds that display broad phar-
macological and biological profiles including antifungal,
antiinflammatory, antihelmitic, antitumor, antibiotic, anti-
viral, and cytostatic properties.1,2 A variety of synthetic
methods for γ-butyrolactones are available, including N-
heterocyclic carbene chemistry (path I, Scheme 1),3 direct
oxidative C–H lactonization (path II),4 SmI2-mediated re-
ductive coupling reaction (path III),5 radical addition cy-
clization reaction (path IV),6 formal [2+2+1]
cycloaddition (path V),7 epoxide carbonylation (path VI),8
cyclization of epoxides with 1,3-dicarbonyl compounds
(path VII),9 and Baeyer–Villiger oxidation (path VIII).10
Each of these approaches represents an important advance
toward the objective of a general method for the synthesis
In our recent work, we developed a one-pot synthesis of
halogenated pyridin-2(1H)-ones from 1-carbamoyl-1-
acyl cyclopropanes under Vilsmeier conditions,15a and the
divergent synthesis of fully substituted 1H-pyrazoles15b
O
O
O
path I
[3+2]
path V
X
+
CO
+
[2+2+1]
Y
R2
R1
OH
OH
O
path II
path VI
[4+1]
+
CO
O
R1
oxidative C–H
lactonization
O
O
O
O
R3
path III
[3+2]
path VII
[3+2]
+
O
O
O
R1
R2
OMe
+
R1
R3
R2
NOBn
path IV
path VIII
H2O2
+
radical
cyclization
Baeyer–Villiger
oxidation
O
O
Scheme 1 General synthetic strategies available to access γ-butyrolactones
SYNTHESIS 2012, 44, 1679–1685
Advanced online publication: 08.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290971; Art ID: SS-2012-H0134-OP
© Georg Thieme Verlag Stuttgart · New York

1680
D. Zhang et al.
PAPER
and pyrazolin-5-one N-oxides15c from the oximes of 1- In the case of the reaction of 1a and SnCl4·5H2O (2.0
acyl-1-carbamoyl cyclopropanes in the presence of equiv) in toluene at reflux, 2a could be obtained in 88%
Vilsmeier reagent (POCl3/DMF) and hypervalent iodine yield (Table 1, entry 5). It is worth noting that when the
reagent (PIFA), respectively.
reaction of 1a was conducted with a Lewis acid, such as
SnCl4, TiCl4, FeCl3 or BF3·OEt2, in anhydrous toluene, no
desired product 2a was detected (Table 1, entries 6–9).
These results revealed that the presence of water in the re-
action system was necessary for the ring-opening/cycliza-
tion process, which was further demonstrated by other
reactions of 1a in the presence of either hydrated Lewis
acid, such as FeCl3·6H2O, FeCl2·4H2O, or CuCl2·2H2O
(Table 1, entries 10–12), or Lewis acid in a wet reaction
medium (Table 1, entry 13).
Very recently, we achieved a novel synthesis of cyclopro-
pyl amides through the application of the iodoform reac-
tion in water.16 In connection with these studies, and
because of our continued interest in the synthesis of car-
bo- and heterocycles,17 we synthesized a series of cyclo-
propyl amides to examine their behavior toward Lewis
acids. Thus, the reaction of N-phenylcyclopropane-1,1-di-
carboxamide (1a) and SnCl4·5H2O (1.0 equiv) was first
attempted in toluene at room temperature, but no reaction
occurred as indicated by TLC. When 1a and SnCl4·5H2O Having established the optimal conditions for the synthe-
(1.0 equiv) were heated in toluene at reflux for 12 hours, sis of γ-butyrolactones, we intended to determine its scope
the reaction proceeded and furnished a product (in 48% with respect to the amide motif. Thus, a series of cyclo-
yield) that was characterized as 2-oxo-N-phenyl-tetrahy- propyl amides 1b–h were subjected to SnCl4·5H2O under
drofuran-3-carboxamide (2a) on the basis of its spectro- identical conditions to those used with 2a (Table 1, entry
scopic and analytical data (Table 1, entry 1).
5); the results are summarized in Table 2. It was observed
that all the reactions proceeded smoothly to afford the cor-
responding γ-butyrolactones 2b–h in good yields (Table
2, entries 2–8).
Optimization of the reaction conditions, including reac-
tion temperature, solvent, and Lewis acid, was then under-
taken. When 1a was treated with SnCl4·5H2O (1.0 equiv)
in either acetonitrile at reflux or in DMF at 110 °C, no re- The versatility of this γ-butyrolactone synthesis was also
action was observed (Table 1, entries 2 and 3). Subjecting evaluated by using 1-benzoylcyclopropane-carboxamide
1a and SnCl4·5H2O (2.0 equiv) to acetic acid at 110 °C af- 1i (Table 2, entry 9). In the case of cyclopropyl amide 1j,
forded 2a in 82% yield (Table 1, entry 4).
which bears a 2-substituted methyl group (cis-1j was
used),18 the reaction proceeded to give γ-butyrolactone 2j
Table 1 Optimization of the Reaction Conditions for the Synthesis of 2a
O
O
O
O
conditions
H2N
NHPh
O
NHPh
1a
2a
Entry
Lewis acid
Equiv
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
2
SnCl4·5H2O
SnCl4·5H2O
SnCl4·5H2O
SnCl4·5H2O
SnCl4·5H2O
SnCl4
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
toluene
MeCN
DMF
reflux
reflux
110
12
12
12
3
48
n.r.
n.r.
82
3
4
AcOH
110
5
toluene
tolueneb
tolueneb
tolueneb
tolueneb
toluene
toluene
toluene
toluenec
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
2
88
6
12
12
12
12
5
n.r.
n.r.
n.r.
n.r.
81
7
TiCl4
8
FeCl3
9
BF3·Et2O
FeCl3·6H2O
FeCl2·4H2O
CuCl2·2H2O
BF3·Et2O
10
11
12
13
10
8
74
53
2
81
a Isolated yield of 2a.
b Anhydrous toluene was employed.
c H2O (2.0 equiv) was added.
Synthesis 2012, 44, 1679–1685
© Georg Thieme Verlag Stuttgart · New York

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[4+1] Annulation to γ-Butyrolactones
1681
Table 2 The Synthesis of γ-Butyrolactones 2a
thesis of γ-butyrolactone of type 2. Indeed, γ-butyrolac-
tones 2 have several interesting characteristics stemming
from the presence of the amide and ester moieties that
should render them very useful for further synthetic trans-
formations.
O
O
O
O
SnCl4•5H2O
R1
O
H2N
R2
R1
toluene
R2
To examine the scope and limitation of the γ-butyrolac-
tone synthetic protocol, 1-phenylcyclopropyl amide 1k
and cyclopropyl amide 1l were prepared. However, no re-
action was observed when 1k or 1l were subjected to the
identical condition used for synthesis of 2a (Scheme 2).
The results suggested that the activation by the second
carbonyl group adjacent to the cyclopropane ring of 1 is
crucial for its ring-opening/cyclization transformation.
1
2
Entry
1
R1
R2
2
Yield (%)b
1
2
1a
1b
1c
1d
1e
1f
PhNH
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
88
80
82
79
71
67
65
83
81
84d
4-MeC6H4NH
4-MeOC6H4NH
4-ClC6H4NH
2-MeC6H4NH
2-MeOC6H4NH
2-ClC6H4NH
2,4-Me2C6H3NH
Ph
3
4
O
O
5
SnCl4•5H2O, toluene
R
R
H2N
O
6
1k R = Ph
1l R = H
2
7
1g
1h
1i
2g
2h
2i
8
Scheme 2 Reaction of cyclopropyl amides 1k and 1l
9
1jc
PhNH
Me
2j
The ring-opening or ring-enlargement reactions of cyclo-
propanes in the presence of various Lewis acids has been
widely investigated.11–14,19 Based on these literature re-
ports and on the results presented above, a plausible
mechanism for the synthesis of γ-butyrolactones 2 was
proposed and is depicted in Scheme 3. Cyclopropyl amide
1 is activated by chelation to a Lewis acid with two car-
bonyl oxygen atoms.21 The reaction then follows two pos-
sible modes of ring-opening: (a) the chelated A is attacked
by H2O to give intermediate B through a regioselective
ring-opening process (path A), or (b) chelated A is at-
tacked by a chloride nucleophile to form A′, followed by
an SN2 process with H2O to afford intermediate B (path
B).13,14,22 Sequential intramolecular oxa-Michael addition
and elimination reaction of ammonium chloride (SNV re-
action) then generates intermediate C, which is finally
converted into γ-butyrolactones 2.
10
a Reaction conditions: 1 (1.0 mmol), SnCl4·5H2O (2.0 mmol), toluene
(10 mL), reflux, 1.0–4.5 h.
b Isolated yield.
c cis-1j was used.
d Overall yield for diastereoisomers 2j; dr = 3:2 (determined by 1H
NMR analysis).
in a highly regioselective manner and the γ-butyrolactone
product was exclusively obtained with the methyl group at
the γ-position (Table 2, entry 10). Such a high degree of
regioselective ring-opening could result from the push–
pull effect of the methyl group (the donor) and two car-
bonyl groups (the acceptor).19 In addition, 2j was obtained
as inseparable diastereoisomers with a ratio of 3:2 accord-
ing to 1H NMR spectroscopic analysis.20 In the 1H NMR
spectra of 2j, the cis-isomer displayed four peaks at δ =
2.36, 2.75, 3.70 and 4.68 ppm, and a singlet peak at δ = The formal [4C+1O] annulation encouraged us to explore
9.16 ppm, which were assigned to the β-H, β-H, α-H and the reaction of cyclopropyl amides 1 with other nucleo-
γ-H of the γ-butyrolactone ring, and the proton of its philes. Thus, cyclopropyl amide 1a was treated with sul-
amide group, respectively, whereas trans-2j displayed fur nucleophile, Na2S·9H2O (1.5 equiv), in the presence of
four peaks at δ = 2.16, 3.00, 3.70, 4.83 ppm, and a singlet SnCl4·5H2O (2.0 equiv) in toluene heated to reflux. After
peak at δ = 8.72 ppm, respectively.
workup and purification by column chromatography, the
reaction furnished two products, one was γ-butyrolactone
2a, and the second was characterized as γ-thiolactone 3a
on the basis of its spectral and analytical data (Table 3, en-
try 1). In the same fashion, selected cyclopropyl amides 1
SnCl4·5H2O, and Na2S·9H2O were heated in toluene to re-
flux to afford the corresponding γ-thiolactones 3 in good
to moderate yields (Table 3 , entries 2–5). Thus, we have
provided a facile one-pot synthesis of substituted γ-thio-
lactone of type 3 via a formal [4C+1S] annulation reac-
tion. Actually, γ-thiolactone derivatives represent another
important class of thiaheterocycles that impart a diverse
range of useful bioactivities and are widely used as key in-
It is worth mentioning that the structure of 2d was eluci-
dated by means of an X-ray single crystal analysis (Figure
1) and confirmed by its spectroscopic and analytical data.
Therefore, we have provided a facile and convenient syn-
Figure 1 ORTEP drawing of 2d
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1679–1685

1682
D. Zhang et al.
PAPER
LA
O
OH
LA
O
O
O
O
H3N
SnCl4•5H2O
H3N
R2
R1
H2N
R2
Nu = Cl–
path B
Cl
R2
R1
A'
Lewis acid chelation
protonation
R1
1
A
Nu
••
O
SN2
Nu = H2O
path A
H
H
O
LA
O
OH
OH
O
O
Cl– H3N
HO
SNV
O
O
R1
R1
– NH4Cl
R1
R2
R2
R2
2
C
B
Scheme 3 Plausible mechanism for the synthesis of γ-butyrolactones 2 from cyclopropyl amides 1
termediates in the preparation of natural products and re- work on the utilization and extensions to the scope of the
lated structures.23
protocol are under investigation in our laboratory.
In summary, a novel and efficient synthesis of γ-butyro-
lactones 2 has been developed from readily available cy-
clopropyl amides 1 mediated by the Lewis acid
SnCl4·5H2O. The approach involves a formal [4C+1O]
annulation process, namely tandem regioselective ring-
opening and intramolecular cyclization reactions. The
high regioselectivity, simplicity of execution, ready avail-
ability of substrates, and, importantly, the potential of the
products, make this novel protocol very attractive. Further
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR spec-
tra were recorded at 300 or 400 MHz with TMS as internal standard
at 25 °C on a Varian Inova-400 (or Bruker-300) spectrometer, and
13C NMR spectra were recorded at 100 or 150 MHz at 25 °C on a
Varian Inova-400 (or Bruker-600) spectrometer. IR spectra (KBr)
were recorded on a Shimadzu FTIR-8400S spectrophotometer in
the range of 400–4000 cm–1. MALDI-TOF MS analysis was record-
ed on a Bruker Daltonics Autoflex III Smartbeam, and ESI MS anal-
ysis was recorded on an Acquity UPLC Quattro Premier XE.
Petroleum ether (PE) used was the fraction boiling in the range 60–
90 °C. Elemental analyses were carried out on a Perkin-Elmer PE-
2400 analyzer.
Table 3 Synthesis of γ-Thiolactones from Cyclopropyl Amidesa
O
O
O
Substituted γ-Butyrolactones 2; Typical Procedure
NHAr
To a 50 mL round-bottomed flask was added 1a (1.0 mmol),
SnCl4·5H2O (2.0 mmol), and toluene (10.0 mL). The mixture was
heated at reflux for 1 h, then cooled to r.t. The mixture was neutral-
ized with sat. aq NaHCO3 (2 × 20 mL), extracted with CH2Cl2
(3 × 20 mL) and dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the residue was purified by short
flash silica gel column chromatography (EtOAc–PE, 1:3) to give
compound 2a.
O
O
R
R
2
SnCl4•5H2O
Na2S•9H2O
H2N
NHAr
+
O
O
R
1
S
NHAr
2-Oxo-N-phenyl-tetrahydrofuran-3-carboxamide (2a)
Yield: 181 mg (88%); white solid; mp 140–141 °C.
3
Entry
1
Ar
R
H
3
Yield
(%)b
2
Yield
(%)b
IR (KBr, neat): 3251, 3089, 2933, 1755, 1645, 1608, 1554, 1448,
1382, 1151, 1010, 952, 759, 688 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.54–2.64 (m, 1 H), 2.76–2.88 (m,
1 H), 3.61 (t, J = 9.5 Hz, 1 H), 4.32–4.40 (m, 1 H), 4.45–4.52 (m,
1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.54 (d, J =
8.0 Hz, 2 H), 8.93 (s, 1 H).
1
2
3
4
5
1a
1b
1e
1g
1jc
PhNH
3a
3b
3e
3g
3j
64
52
74
70
63d
2a
2b
2e
2g
2j
27
41
23
24
28
4-MeC6H4NH
2-MeC6H4NH
2-ClC6H4NH
PhNH
H
H
13C NMR (100 MHz, CDCl3): δ = 24.5, 45.8, 67.6, 119.9 (2C),
124.7, 128.9 (2C), 137.2, 163.2, 175.7.
H
+
MS: m/z [M + 1]+ calcd for C11H12NO3 : 206.0; found 206.0.
Me
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83; Found: C,
64.26; H, 5.47; N, 6.88.
a Reaction conditions: 1 (1.0 mmol), SnCl4·5H2O (2.0 mmol),
Na2S·9H2O (1.5 mmol), in toluene (10 mL), 1.0–12.0 h, reflux.
b Isolated yield.
2-Oxo-N-(p-tolyl)tetrahydrofuran-3-carboxamide (2b)
Yield: 175 mg (80%); yellow solid; mp 125–126 °C.
c cis-1j was used.
d Overall yield for diastereoisomers 3j; dr = 5:3 (determined by 1H
IR (KBr, neat): 3247, 3044, 2918, 1760, 1670, 1546, 1377, 1157,
1012, 821 cm–1.
NMR analysis).
Synthesis 2012, 44, 1679–1685
© Georg Thieme Verlag Stuttgart · New York

PAPER
[4+1] Annulation to γ-Butyrolactones
1683
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H), 2.56–2.67 (m, 1 H),
2.76–2.89 (m, 1 H), 3.61 (t, J = 10.0 Hz, 1 H), 4.33–4.41 (m, 1 H),
4.45–4.53 (m, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.5 Hz,
2 H), 8.84 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.8, 24.5, 45.7, 67.6, 120.0 (2C),
129.5 (2C), 134.4, 134.7, 162.8, 175.8.
4.45–4.52 (m, 1 H), 6.88–6.98 (m, 2 H), 7.04–7.11 (m, 1 H), 8.28–
8.32 (m, 1 H), 9.38 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.6, 46.1, 55.8, 67.5, 110.2,
119.8, 120.8, 124.3, 127.1, 148.4, 162.8, 175.3.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95; Found: C,
61.48; H, 5.63; N, 5.79.
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39; Found: C,
65.57; H, 6.17; N, 6.35.
N-(2-Chlorophenyl)-2-oxotetrahydrofuran-3-carboxamide (2g)
Yield: 156 mg (65%); white solid; mp 111–112 °C.
N-(4-Methoxyphenyl)-2-oxotetrahydrofuran-3-carboxamide
(2c)
IR (KBr, neat): 3261, 2974, 1762, 1679, 1541, 1184, 1035, 752
cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.59–2.70 (m, 1 H), 2.77–2.90 (m,
1 H), 3.70 (t, J = 9.5 Hz, 1 H), 4.35–4.43 (m, 1 H), 4.47–4.54 (m,
1 H), 7.05–7.10 (m, 1 H), 7.25–7.31 (m, 1 H), 7.38–7.41 (m, 1 H),
8.30–8.33 (m, 1 H), 9.49 (s, 1 H).
Yield: 193 mg (82%); yellow solid; mp 108–109 °C.
IR (KBr, neat): 3234, 3049, 2921, 2837, 1757, 1645, 1510, 1384,
1242, 1155, 1012, 956, 800 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.55–2.67 (m, 1 H), 2.75–2.86 (m,
1 H), 3.60 (t, J = 9.0 Hz, 1 H), 3.80 (s, 3 H), 4.33–4.41 (m, 1 H),
4.46–4.52 (m, 1 H), 6.87 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 9.0 Hz,
2 H), 8.81 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.5, 45.9, 67.4, 121.7, 123.6,
125.1, 127.5, 129.3, 134.2, 163.2, 175.3.
Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84; Found: C,
55.06; H, 4.30; N, 5.89.
13C NMR (100 MHz, CDCl3): δ = 24.6, 45.6, 55.4, 67.6, 114.0 (2C),
121.7 (2C), 130.3, 156.5, 163.0, 175.8.
N-(2,4-Dimethylphenyl)-2-oxotetrahydrofuran-3-carboxamide
(2h)
Yield: 194 mg (83%); yellowish solid; mp 121–122 °C.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95; Found: C,
61.48; H, 5.53; N, 5.87.
N-(4-Chlorophenyl)-2-oxotetrahydrofuran-3-carboxamide(2d)
Yield: 189 mg (79%); white solid; mp 131–132 °C.
IR (KBr, neat): 3224, 3022, 2920, 1770, 1641, 1537, 1161, 1014,
956, 800, 680 cm–1.
IR (KBr, neat): 3344, 3130, 2916, 1747, 1693, 1606, 1544, 1494,
1379, 1159, 1012, 952, 837 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.57–2.69 (m, 1 H), 2.75–2.88 (m,
1 H), 3.62 (t, J = 9.5 Hz, 1 H), 4.34–4.42 (m, 1 H), 4.47–4.54 (m,
1 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.50 (d, J = 9.0 Hz, 1 H), 8.99 (s,
1 H).
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.29 (s, 3 H), 2.57–
2.69 (m, 1 H), 2.76–2.89 (m, 1 H), 3.65 (t, J = 9.5 Hz, 1 H), 4.33–
4.42 (m, 1 H), 4.46–4.52 (m, 1 H), 7.00 (s, 1 H), 7.01 (d, J = 6.0 Hz,
1 H), 7.74 (d, J = 8.5 Hz, 1 H), 8.81 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.5, 20.7, 24.5, 45.5, 67.5, 122.3,
127.1, 129.0, 131.1, 132.6, 134.9, 163.1, 176.0.
13C NMR (100 MHz, CDCl3): δ = 24.4, 45.8, 67.6, 121.1 (2C),
129.0 (2C), 129.7, 135.8, 163.1, 175.8.
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00; Found: C,
66.76; H, 6.53; N, 6.13.
Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84; Found: C,
55.26; H, 4.15; N, 5.77.
3-Benzoyldihydrofuran-2(3H)-one (2i)
Yield: 154 mg (81%); yellowish solid; mp 48–50 °C.
Crystal data for 2d: CCDC 823715; C11H10ClNO3; white; M =
239.66; orthorhombic; space group P2(1)2(1)2(1); a = 5.294 (3),
b = 10.197 (5), c = 19.812 (10) Å; V = 1069.5 (10) Å3; α = 90.00°,
β = 90.00°, γ = 90.00°; Z = 4; T = 300 K; F000 = 500.0; R1 = 0.0479;
wR2 = 0.1131. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44(1223)336033; or deposit@ccdc.cam.ac.uk.
IR (KBr, neat): 3446, 1772, 1680, 1450, 1257, 1153, 761 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.46–2.58 (m, 1 H), 2.82–2.94 (m,
1 H), 4.40–4.48 (m, 1 H), 4.50–4.60 (m, 2 H), 7.52 (t, J = 7.5 Hz,
2 H), 7.64 (t, J = 7.0 Hz, 1 H), 8.09 (d, J = 7.0 Hz, 2 H).
13C NMR (150 MHz, CDCl3): δ = 26.0, 48.0, 67.8, 128.8 (2C),
129.5 (2C), 134.1, 135.3, 172.8, 193.0.
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30; Found: C, 69.23; H,
5.44.
2-Oxo-N-(o-tolyl)tetrahydrofuran-3-carboxamide (2e)
Yield: 156 mg (71%); white solid; mp 125–126 °C.
5-Methyl-2-oxo-N-phenyl-tetrahydrofuran-3-carboxamide (2j-
IR (KBr, neat): 3298, 2991, 1762, 1654, 1541, 1172, 1016, 958,
761 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3 H), 2.59–2.70 (m, 1 H),
2.77–2.90 (m, 1 H), 3.67 (t, J = 9.5 Hz, 1 H), 4.34–4.43 (m, 1 H),
4.47–4.54 (m, 1 H), 7.08 (t, J = 7.0 Hz, 1 H), 7.21 (t, J = 8.0 Hz,
2 H), 7.93 (d, J = 8.0 Hz, 1 H), 8.93 (s, 1 H).
1)
Yield: 184 mg (84%); yellowish solid; mp 105–107 °C.
IR (KBr, neat): 3273, 3138, 1666, 1553, 1447, 1367, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 6.0 Hz, 3 H), 2.28–
2.39 (m, 1 H), 2.71–2.81 (m, 1 H), 3.67–3.74 (m, 1 H), 4.63–4.74
(m, 1 H), 7.13 (t, J = 7.0 Hz, 1 H), 7.33 (t, J = 7.0 Hz, 2 H), 7.52–
7.57 (m, 2 H), 9.16 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.6, 24.5, 45.6, 67.6, 122.0,
125.1, 126.7, 128.7, 130.5, 135.3, 162.9, 176.1.
13C NMR (100 MHz, DMSO-d6): δ = 20.6, 32.9, 49.1, 75.7, 119.2
(2C), 123.7, 128.8 (2C), 138.5, 165.7, 173.8.
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39; Found: C,
65.59; H, 6.03; N, 6.56.
5-Methyl-2-oxo-N-phenyl-tetrahydrofuran-3-carboxamide (2j-
N-(2-Methoxyphenyl)-2-oxotetrahydrofuran-3-carboxamide
(2f)
2)
Yield: 184 mg (84%); yellowish solid; mp 105–107 °C.
Yield: 158 mg (67%); yellowish solid; mp 123–124 °C.
1H NMR (400 MHz, CDCl3): δ = 1.46 (d, J = 6.0 Hz, 3 H), 2.11–
2.21 (m, 1 H), 2.97–3.06 (m, 1 H), 3.67–3.74 (m, 1 H), 4.76–4.86
(m, 1 H), 7.13 (t, J = 7.0 Hz, 1 H), 7.33 (t, J = 7.0 Hz, 2 H), 7.52–
7.57 (m, 2 H), 8.72 (s, 1 H).
IR (KBr, neat): 3319, 2979, 2881, 1772, 1677, 1529, 1251, 1180,
1020, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.54–2.66 (m, 1 H), 2.78–2.91 (m,
1 H), 3.64 (t, J = 9.0 Hz, 1 H), 3.91 (s, 3 H), 4.33–4.41 (m, 1 H),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1679–1685

1684
D. Zhang et al.
PAPER
13C NMR (100 MHz, DMSO-d6): δ = 20.9, 33.3, 48.1, 76.5, 119.2
(2C), 123.7, 128.8 (2C), 138.6, 165.7, 173.8.
5-Methyl-2-oxo-N-phenyl-tetrahydrothiophene-3-carbox-
amide (3j-1)
Yield: 148 mg (63%); yellowish solid; mp 124–126 °C.
Substituted γ-Thiolactones 3; Typical Procedure
IR (KBr, neat): 3404, 3157, 1693, 1656, 1404, 1313, 812, 582 cm–1.
To a 50 mL round-bottomed flask was added 1a (1.0 mmol),
SnCl4·5H2O (2.0 mmol), Na2S·9H2O (1.5 mmol), and toluene (10.0
mL). The mixture was heated at reflux for 2 h, then cooled to r.t. The
mixture was neutralized with sat. aq NaHCO3, then extracted with
CH2Cl2 (3 × 20 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the residue was purified
by short flash silica gel column chromatography (EtOAc–petroleum
ether, 1:4) to give compound 3a.
1H NMR (400 MHz, CDCl3): δ = 1.54 (d, J = 9.5 Hz, 3 H), 2.12–
2.19 (m, 1 H), 2.95–3.01 (m, 1 H), 3.63–3.69 (m, 1 H), 4.10–4.15
(m, 1 H), 7.10 (t, J = 6.0 Hz, 1 H), 7.32 (t, J = 8.5 Hz, 2 H), 7.52 (d,
J = 8.5 Hz, 2 H), 8.34 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.7, 36.4, 43.8, 58.8, 119.9,
124.5, 128.9, 137.3, 162.8, 207.4.
5-Methyl-2-oxo-N-phenyl-tetrahydrothiophene-3-carbox-
amide (3j-2)
Yield: 148 mg (63%); yellowish solid; mp 124–126 °C.
2-Oxo-N-phenyl-tetrahydrothiophene-3-carboxamide (3a)
Yield: 142 mg (64%); yellowish solid; mp 141–142 °C.
1H NMR (400 MHz, CDCl3): δ = 1.54 (d, J = 9.5 Hz, 3 H), 2.30–
2.33 (m, 1 H), 2.81–2.85 (m, 1 H), 3.63–3.69 (m, 1 H), 3.84–3.87
(m, 1 H), 7.01 (t, J = 6.0 Hz, 1 H), 7.32 (t, J = 8.5 Hz, 2 H), 7.52 (d,
J = 8.5 Hz, 2 H), 8.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.8, 37.3, 41.7, 59.0, 120.1,
124.6, 128.9, 137.3, 163.6, 207.4.
IR (KBr, neat): 3225, 3040, 1681, 1664, 1639, 1541, 1363, 1310,
1041, 816 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.63–2.86 (m, 2 H), 3.33–3.42 (m,
1 H), 3.45–3.56 (m, 2 H), 7.13 (t, J =7.5 Hz, 1 H), 7.33 (t, J =
7.0 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 2 H), 8.62 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.4, 30.8, 57.4, 119.9 (2C),
124.6, 128.9 (2C), 137.3, 163.2, 207.7.
Anal. Calcd for C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; Found: C,
59.58; H, 5.06; N, 6.38.
Acknowledgment
Financial support of this research by the National Natural Science
Foundation of China (51073150 and 21172211) and ‘Hundred
Talents Program’ of the Chinese Academy of Sciences is greatly
acknowledged.
2-Oxo-N-p-tolyl-tetrahydrothiophene-3-carboxamide (3b)
Yield: 122 mg (52%); yellowish solid; mp 160–161 °C.
IR (KBr, neat): 3285, 1697, 1653, 1541, 1356, 1047, 926, 758 cm–1.
1H NMR (600 MHz, CDCl3): δ = 2.31 (s, 3 H), 2.64–2.68 (m, 1 H),
2.76–2.80 (m, 1 H), 3.35–3.38 (m, 1 H), 3.46–3.53 (m, 2 H), 7.12
(d, J = 7.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 8.49 (s, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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r
itmnatr
13C NMR (150 MHz, CDCl3): δ = 20.9, 28.5, 30.8, 57.3, 120.1 (2C),
129.5 (2C), 134.3, 134.8, 162.8, 207.9.
Primary Data for this article are available online at
Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; Found: C,
61.51; H, 5.49; N, 5.89.
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI: mPirDyramPiartDyar
1
at 0.4125/pd0028th.mPiryarDaZatahenl01
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hemyrst
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2-Oxo-N-o-tolyl-tetrahydrothiophene-3-carboxamide (3e)
Yield: 174 mg (74%); yellowish solid; mp 149–151 °C.
IR (KBr, neat): 3306, 1695, 1662, 1591, 1541, 1443, 746 cm–1.
References
1H NMR (600 MHz, CDCl3): δ = 2.31 (s, 3 H), 2.70–2.71 (m, 1 H),
2.79–2.81 (m, 1 H), 3.38–3.40 (m, 1 H), 3.46–3.49 (m, 1 H), 3.56–
3.60 (m, 1 H), 7.07 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 2 H),
7.90 (d, J = 8.0 Hz, 1 H), 8.58 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 17.7, 28.5, 30.8, 57.3, 122.1,
125.1, 126.7, 128.7, 130.5, 135.4, 163.0, 208.2.
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Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; Found: C,
61.53; H, 5.52; N, 5.91.
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IR (KBr, neat): 3229, 3034, 1691, 1641, 1543, 1360, 1034, 866,
754 cm–1.
1H NMR (600 MHz, CDCl3): δ = 2.68–2.72 (m, 1 H), 2.80–2.82 (m,
1 H), 3.36–3.41 (m, 1 H), 3.47–3.50 (m, 1 H), 3.59–3.62 (m, 1 H),
7.06 (t, J = 7.0 Hz, 1 H), 7.26 (t, J = 7.0 Hz, 1 H), 7.38 (d, J =
7.0 Hz, 1 H), 8.31 (d, J = 7.0 Hz, 1 H), 9.15 (s, 1 H).
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C, 51.48; H, 4.02; N, 5.43.
Synthesis 2012, 44, 1679–1685
© Georg Thieme Verlag Stuttgart · New York

PAPER
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1679–1685