Efficient synthesis of substituted tetrahydrothiopyrano[2,3-b]thiopyran-4, 5-diones by a double annulation strategy from dialkenoylketene dithioacetals

Article abstract of DOI:10.1055/s-2007-983749

An efficient synthetic procedure for substituted 2,3,6,7- tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones by a double annulation strategy is described. The ring systems are made in good yields from readily available dialkenoylketene dithioacetals in the p

Full text of DOI:10.1055/s-2007-983749

PAPER
2115
Efficient Synthesis of Substituted Tetrahydrothiopyrano[2,3-b]thiopyran-4,5-
diones by a Double Annulation Strategy from Dialkenoylketene Dithioacetals
Efficient
S
ynthesis of Su
e
bstituted T
i
e
trahydrothio
P
pyrano[2, 3-
b
]
a
thiopyran-4n,5-diones ,a Dewen Dong,*a,b Yan Ouyang,a Rigenhada Wu,a Yang Yang,a Qun Liu*a
a
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. of China
Fax +86(431)85098635; E-mail: dongdw663@nenu.edu.cn
b
Received 30 March 2007; revised 2 May 2007
readily available alkenoylketene dithioacetals showed
promising structural features as novel organic intermedi-
ates in annulation reactions. Accordingly, new synthetic
strategies were developed for the construction of highly
Abstract: An efficient synthetic procedure for substituted 2,3,6,7-
tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones by a double annu-
lation strategy is described. The ring systems are made in good
yields from readily available dialkenoylketene dithioacetals in the
presence of either sodium sulfide nonahydrate/N,N-dimethylform- substituted phenols and six-membered aza- and thia-
amide (DMF) or a sodium hydride/DMF/amine system.
heterocycles, relying on the use of alkenoylketene dithio-
acetals as five-carbon 1,5-dielectrophilic species in for-
mal [5+1] annulations with various carbon, nitrogen, and
sulfur nucleophiles, respectively.13 Considering the im-
portant synthetic utility of alkenoylketene dithioacetals,
we recently investigated the aldol condensation reaction
of 3-(1,3-dithiolan-2-ylidene)pentane-2,4-dione with var-
ious selected aromatic aldehydes in water and successful-
ly obtained the symmetric and unsymmetrical double
condensed products, dialkenoylketene dithioacetals.14
Key words: amines, annulations, dialkenoylketene dithioacetals,
sodium hydride, sodium sulfide
Thiopyrones have emerged as key units in medicinal
chemistry and versatile intermediates in organic synthe-
sis.1 As representatives of this kind of sulfur-containing
heterocycle, 2,3-dihydrothiopyran-4-ones have been used
in the synthesis of tetrahydrodicranenone B,2 phero-
mones,3 thromboxanes,4 cyclopentanoids,5 and related
natural products. A variety of synthetic procedures are
readily available for the preparation of 2,3-dihydrothiopy-
ran-4-ones, including (i) cycloaddition of structurally ap-
propriate acetylenic/divinyl ketones with hydrogen
sulfide,3,6 (ii) intramolecular Michael addition of a thi-
olate to an a,b-unsaturated carbonyl group,7 (iii) Diels–
Alder cycloadditions involving thiophosgene and donor-
substituted thioaldehydes,8,9 (iv) conjugate additions to
thiopyran-4-ones or oxidation of tetrahydrothiopyran-4-
ones with N-chlorosuccinimide (NCS),2,5d and (v) dimsyl
anion (DMSO anion) mediated tandem fragmentation–cy-
clization reactions of alkenoyl cyclic ketene dithioace-
tals.10 Nevertheless, it is still of continued interest and
great importance to explore novel and efficient synthetic
approaches to six-membered thia-heterocycles, especially
methods with broad general applicability to achieve more
flexible substitution patterns.
To explore the synthetic potential of the easily available
intermediates, dialkenoylketene dithioacetals, in our on-
going research, efficient synthesis of substituted 2,3,6,7-
tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones
has
been achieved in good yields by treatment of dial-
kenoylketene dithioacetals 3 either with sodium sulfide
nonahydrate (Na2S·9H2O) in N,N-dimethylformamide
(DMF) or with sodium hydride in DMF followed by a pri-
mary amine. In the following paper, the experimental re-
sults are described in detail and the reaction mechanism
involved is proposed.
The substrates for the synthesis of the tetrahydrothiopyra-
no[2,3-b]thiopyran-4,5-diones, dialkenoylketene dithio-
acetals 3, were prepared in high yields via alkenoylketene
dithioacetals 2 by the aldol condensation reactions of 3-
(1,3-dithiolan-2-ylidene)pentane-2,4-dione (1) with vari-
ous selected aldehydes in water according to our previous
reported procedure (Scheme 1).14
During the course of our studies on the chemistry of a-
oxo-substituted ketene dithioacetals,11,12 we noted that the
O
S
O
S
O
O
O
O
S
R1CHO
R2CHO
NaOH (aq)
r.t.
NaOH (aq)
reflux
R2
R1
R1
S
S
S
3
1
2
Scheme 1 Synthesis of dialkenoylketene dithioacetals
SYNTHESIS 2007, No. 14, pp 2115–2120
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983749; Art ID: F05907SS
© Georg Thieme Verlag Stuttgart · New York

2116
W. Pan et al.
PAPER
The reaction of (1E,6E)-4-(1,3-dithiolan-2-ylidene)-1,7- lation reactions with respect to using both symmetrical
di(4-tolyl)hepta-1,6-diene-3,5-dione (3a) (2 mmol) with and unsymmetrical dialkenoylketene dithioacetals 3 bear-
Na2S·9H2O (6 mmol) was initially performed in DMF (6 ing various aromatic (Table 1, entries 1–5 and 8–11), het-
mL) at 80 °C. After the mixture was stirred for 20 min, the eroaromatic (Table 1, entry 6), and aliphatic (Table 1,
starting material 3a was consumed as indicated by thin- entry 7) groups. We, therefore, have demonstrated a facile
layer chromatography (TLC). Workup and column chro- and efficient protocol for the synthesis of substituted bicy-
matography of the resulting mixture gave a yellowish clic thia-heterocycles 4.
solid in 82% yield. The main product was characterized
as 2,7-di(4-tolyl)-2,3,6,7-tetrahydrothiopyrano[2,3-b]thio-
pyran-4,5-dione (4a) on the basis of its spectral and ana-
Recently, Samuel et al. found that cyclic ketene dithioace-
tals containing a 1,3-dithiolane moiety could undergo a
facile fragmentation reaction, in the presence of dimsyl
lytical data. The reaction was then carried out under
sodium, and subsequent intramolecular cyclizations to af-
various conditions to optimize its yield. The experiments
ford substituted 2,3-dihydrothiopyran-4-ones.10 With di-
revealed that the reaction could not even proceed at room
alkenoylketene dithioacetals 3 being readily available, we
designed an alternative route to synthesize thia-heterocy-
cles 4 from the reaction of 3 with sodium hydride through
fragmentation and double thia-Michael addition. Thus,
the reaction of di(4-tolyl) derivative 3a with sodium hy-
dride (3.0 equiv) was performed in DMF at room temper-
ature. After the mixture was stirred for 30 min, 3a was
temperature, based on TLC results, and that an excess
amount of Na2S·9H2O (e.g., 5 equiv) would result in a low
yield of 4a. It was observed that 2.2 equivalents of
Na2S·9H2O were sufficient for a complete conversion,
and that the yield of the di(4-tolyl) derivative 4a could
reach 93% (Table 1, entry 1).
consumed, but the desired compound 4a was not formed
(monitored by TLC). Workup and column chromatogra-
Table 1 Reactions of Substrates 3 with Na2S⋅9H2O in DMF
O
S
O
S
phy of the resulting mixture gave a yellow solid in 85%
yield. The product was characterized as (E)-2-(4-tolyl)-5-
[3-(4-tolyl)acryloyl]-6-(vinylsulfanyl)-2,3-dihydrothio-
pyran-4-one (5a) on the basis of its spectral and analytical
data (Table 2, entry 1). Similarly, substrates 3b–d under-
went the tandem ring-opening and recyclization reactions
to afford the substituted dihydrothiopyran-4-ones 5b–d in
good yields (Table 2, entries 2–4).
O
S
O
S
Na2S⋅9H2O, DMF
80°C
R1
R2
R1
R2
3
4
Entry 3 R1
R2
Time 4
(min)
Yielda
(%)
1
2
a
b
c
d
e
f
Tol
Ph
Tol
25
20
25
30
a
b
c
d
e
f
93
89
90
85
86
78
70
86
87
84
88
Table 2 Reactions of Substrates 3 with NaH in DMF
O
O
Ph
O
O
3
4-ClC6H4
4-ClC6H4
4-MeOC6H4
NaH, DMF
r.t.
R1
R1
S
S
4
4-MeOC6H4
R1
R1
S
S
5
3,4-OCH2OC6H3 3,4-OCH2OC6H3 25
3
5
6
3-pyridyl
t-Bu
3-pyridyl
t-Bu
15
35
20
30
20
20
Entry
3
R1
Time
(min)
5
Yielda
(%)
7
g
h
i
g
h
i
1
2
3
4
a
b
c
Tol
Ph
30
25
25
30
a
b
c
85
8
4-ClC6H4
4-ClC6H4
4-ClC6H4
Tol
Ph
82
9
Tol
4-ClC6H4
89
10
11
j
4-MeOC6H4
Ph
j
d
4-MeOC6H4
d
75
k
k
a Isolated yield after silica gel chromatography.
a Isolated yield after silica gel chromatography.
It is well known that a-oxo ketene dithioacetals are liable
to undergo an addition–elimination sequence with prima-
ry and secondary amines to yield the corresponding nitro-
gen acetal derivatives.11,13b,15 Thus, we examined the
reaction of the 4-tolyl-substituted compound 5a with eth-
ylamine (3.0 equiv) in DMF at room temperature. Inter-
estingly, compound 4a was obtained in 77% yield
(Table 3, entry 1). The addition reaction of ethylamine to
5a and subsequent intramolecular aza-Michael addition to
afford 6a did not take place. When 5a was treated with bu-
Subsequently, a range of reactions with dialkenoylketene
dithioacetals 3 and Na2S·9H2O were carried out under the
optimal conditions, namely 2.2 equivalents of Na2S·9H2O
in DMF at 80 °C. Some of the results are summarized in
Table 1. All the reactions proceeded smoothly under the
mild conditions and within very short reaction times to af-
ford the corresponding substituted 2,3,6,7-tetrahydrothio-
pyrano[2,3-b]thiopyran-4,5-diones 4 in high yields (up to
93%). These results demonstrate the efficiency, wide
scope, and synthetic utility of the double [5C + 1S] annu-
Synthesis 2007, No. 14, 2115–2120 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Substituted Tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones
2117
tylamine (3.0 equiv), the same compound, 4a, was ob- mation of compounds 4. It is noteworthy that a similar
tained in 72% yield. The results suggested that the amine SNV-type reaction was observed in our recent studies;12f
played the role of an organic base in the reaction. When however, the reason why the amine attacks the a-carbon
subjected to identical conditions, compounds 5b–d react- of the vinylsulfanyl double bond instead of the b-carbon
ed with ethylamine to give the corresponding tetrahy- of the carbonyl moiety still remains undiscovered.
drothiopyrano[2,3-b]thiopyran-4,5-diones 4b–d in good
yields (Table 3, entries 2–4). Thus, the reaction provides
an alternative protocol for the synthesis of substituted bi-
O
O
3
cyclic thia-heterocycles 4.
R1
R1
S
S
Table 3 Reactions of Dihydrothiopyran-4-ones 5 with EtNH2 in
DMF
O
O
NaH, DMF
O
Path B
Path A
O
Na2S⋅9H2O, DMF
EtNH2
DMF
6
O
O
O
S
O
S
R1
S
N
R1
Et
R1
R1
R1
S
R1
S
S
S
O
O
S
R1
R1
5
9
EtNH2
7
4
SH
DMF
r.t.
R1
S
R1
Na2S⋅9H2O,
– HS(CH2)2SH
O
DMF
O
O
S
5
Entry
5
R1
Time (min)
4
Yielda (%)
O
1
2
3
4
a
Tol
20
15
20
25
a
b
c
77
79
83
71
R1
R1
S
R1
S
R1
S
b
c
Ph
8
4-ClC6H4
EtNH2
DMF
d
4-MeOC6H4
d
O
O
a Isolated yields after silica gel chromatography.
O
O
S
4
R1
S
S
R1
The efficient synthesis of compounds 4 has been achieved
by two different procedures. On the basis of the above ex-
perimental results, together with our previous stud-
ies,12e,f,13 the mechanisms of the two protocols are
proposed as shown in Scheme 2. In path A, the 1,3-dithi-
olane moiety of dialkenoylketene dithioacetals 3 under-
goes a facile fragmentation reaction in the presence of
sodium sulfide nonahydrate, leading to the formation of S-
(sulfanylethyl)-substituted thiolates 7.10,16 Subsequent in-
tramolecular thia-Michael addition of intermediates 7 to
form a 2,3-dihydrothiopyran-4-one ring and loss of
ethane-1,2-dithiol gives the intermediate thiolate anions
8. Further intramolecular thia-Michael addition of 8 estab-
lishes the second 2,3-dihydrothiopyran-4-one ring and
gives the final products 4. In path B, the ring opening of
the 1,3-dithiolane moiety of 3, in the presence of sodium
hydride in DMF, creates S-vinyl-substituted thiolates 9.
The intermediates 9 give compounds 5 via an intramolec-
ular thia-Michael addition reaction. In the second step, the
regiospecific attack of the ethylamine amino group at the
a-carbon of the vinylsulfanyl double bond in 5 triggers a
nucleophilic vinylic substitution (SNV) type reaction,12f,17
which involves the cleavage of a carbon–sulfur bond.18
An intramolecular thia-Michael addition results in the for-
R1
R1
S
Et NH2
Scheme 2 Possible mechanisms for the syntheses of bicyclic thia-
heterocycles 4 from dialkenoylketene dithioacetals 3
In summary, efficient synthesis of substituted 2,3,6,7-tet-
rahydrothiopyrano[2,3-b]thiopyran-4,5-diones 4 from the
readily available dialkenoylketene dithioacetals 3 has
been developed. In one method, one-pot synthesis of com-
pounds 4 in high yields was achieved via formal double
[5+1] annulations of 3 using sodium sulfide nonahydrate
in DMF. Alternatively, a two-step method to give com-
pounds 4 was possible using sodium hydride and an alkyl-
amine in DMF and involved [5+1] annulation at each step.
In particular, the former method (path A, Scheme 2) pro-
vides a one-pot approach for the synthesis of disubstituted
bicyclic thia-heterocycles 4 that is most attractive because
of its readily available starting materials, mild conditions,
simple execution, and high yields. Further research on the
mechanism and the potential applications of the protocols
is in progress in our laboratory.
Synthesis 2007, No. 14, 2115–2120 © Thieme Stuttgart · New York

2118
W. Pan et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 46.7 (2 C), 47.8 (2 C), 125.7,
129.2 (4 C), 129.8 (4 C), 134.3 (2 C), 135.5 (2 C), 175.7, 188.4 (2
C).
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography using silica gel. The 1H and 13
C
MS: m/z calcd for C20H14Cl2O2S2: 420.1; found: 421.0 [M + 1]+.
NMR spectra were recorded at 25 °C on a Varian Inova-500 spec-
trometer at 500 and 125 MHz, respectively, with TMS as an internal
standard; IR spectra (KBr) were recorded on a Magna-560 FTIR
spectrophotometer in the range of 400–4000 cm–1. Mass spectra
were recorded on an Agilent 1100 LCMSD mass spectrometer. Pe-
troleum ether (PE) used had boiling range 30–60 °C.
Anal. Calcd for C20H14Cl2O2S2: C, 57.01; H, 3.35. Found: C, 57.23;
H, 3.27.
2,7-Bis(4-methoxyphenyl)-2,3,6,7-tetrahydrothiopyrano[2,3-
b]thiopyran-4,5-dione (4d)
Yellow solid.
2,7-Disubstituted 2,3,6,7-Tetrahydrothiopyrano[2,3-b]thiopy-
ran-4,5-diones 4 (Path A); Typical Procedure
Mp 169–171 °C.
To a solution of 3a (0.81 g, 2.0 mmol) in DMF (5 mL) was added
Na2S·9H2O (1.06 g, 4.4 mmol) in one portion at r.t. After heating to
80 °C and stirring for about 25 min (for complete conversion as in-
dicated by TLC), the mixture was treated with H2O (20 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were washed with H2O (3 × 20 mL), dried (MgSO4), filtered, and
concentrated in vacuo to give a white solid. Further purification was
carried out using flash chromatography (silica gel, PE–Et2O, 2:1) to
give product 4a. Yield: 0.71 g (93%).
IR (KBr): 1683, 1510, 1452, 1386, 1250, 1175, 1024, 828 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.10 (dd, J = 2.5, 17.0 Hz, 2 H),
3.20 (dd, J = 14.0, 17.5 Hz, 2 H), 3.84 (s, 6 H), 4.70 (dd, J = 2.5,
14.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 4 H), 7.26 (d, J = 8.0 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 45.6 (2 C), 46.9 (2 C), 54.3 (2 C),
113.6 (4 C), 124.3, 126.9 (2 C), 127.8 (4 C), 159.1 (2 C), 175.7,
187.9 (2 C).
Anal. Calcd for C22H20O4S2: C, 64.05; H, 4.89. Found: C, 64.18; H,
4.77.
2,7-Di(4-tolyl)-2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopyran-
4,5-dione (4a)
White solid.
2,7-Di(1,3-benzodioxol)-5-yl-2,3,6,7-tetrahydrothiopyrano[2,3-
b]thiopyran-4,5-dione (4e)
Yellow solid.
Mp 165–167 °C.
IR (KBr): 1691, 1645, 1457, 1301, 1254, 815 cm–1.
Mp 170–172 °C.
1H NMR (500 MHz, CDCl3): d = 2.36 (s, 6 H), 3.12 (dd, J = 3.0,
17.0 Hz, 2 H), 3.30 (dd, J = 14.0, 17.0 Hz, 2 H), 4.70 (dd, J = 3.0,
14.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 4 H), 7.25 (d, J = 8.0 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 21.4, 47.2, 48.1, 125.6, 127.7 (4
C), 130.0 (4 C), 132.9 (2 C), 139.4 (2 C), 176.9, 189.2 (2 C).
IR (KBr): 1671, 1470, 1306, 1255, 1074, 821 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.10 (dd, J = 2.5, 17.0 Hz, 2 H),
3.24 (dd, J = 14.0, 17.0 Hz, 2 H), 4.65 (dd, J = 2.5, 14.0 Hz, 2 H),
5.99 (s, 4 H), 6.77–6.83 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 47.3 (2 C), 48.2 (2 C), 101.8 (2
C), 107.9 (2 C), 109.1 (2 C), 121.7 (2 C), 125.5, 129.4 (2 C), 148.5
(2 C), 148.6 (2 C), 176.8, 189.1 (2 C).
MS: m/z calcd for C22H20O2S2: 380.1; found 381.0 [M + 1]+.
Anal. Calcd for C22H20O2S2: C, 69.44; H, 5.30. Found: C, 69.57; H,
5.39.
Anal. Calcd for C22H16O6S2: C, 59.99; H, 3.66. Found: C, 59.85; H,
3.54.
2,7-Diphenyl-2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopyran-
4,5-dione (4b)
White solid.
2,7-Di(3-pyridyl)-2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopy-
ran-4,5-dione (4f)
Yellow solid.
Mp 115–117 °C.
IR (KBr): 1692, 1643, 1499, 1307, 1235, 807 cm–1.
Mp 151–153 °C.
IR (KBr): 1674, 1630, 1495, 1290, 1231, 861 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.16 (dd, J = 3.0, 17.0 Hz, 2 H),
3.32 (dd, J = 15.0, 17.0 Hz, 2 H), 4.74 (dd, J = 3.0, 15.0 Hz, 2 H),
7.36 (d, J = 7.5 Hz, 4 H), 7.39–7.40 (m, 2 H), 7.42 (d, J = 6.5 Hz, 4
H).
13C NMR (125 MHz, CDCl3): d = 47.4 (2 C), 47.9 (2 C), 125.6,
127.8 (4 C), 129.4 (2 C), 129.5 (4 C), 135.9 (2 C), 176.8, 189.1 (2
C).
1H NMR (500 MHz, CDCl3): d = 3.17 (dd, J = 2.5, 17.5 Hz, 2 H),
3.33 (dd, J = 14.0, 17.5 Hz, 2 H), 4.80 (dd, J = 2.5, 14.0 Hz, 2 H),
7.33–7.39 (m, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 8.59–8.65 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 43.7 (2 C), 46.2 (2 C), 123.0 (2
C), 124.6, 130.5 (2 C), 133.9 (2 C), 148.2 (2 C), 149.6 (2 C), 186.6
(2 C).
Anal. Calcd for C20H16O2S2: C, 68.15; H, 4.58. Found: C, 68.38; H,
4.65.
Anal. Calcd for C18H14N2O2S2: C, 60.99; H, 3.98; N, 7.90. Found:
C, 60.84; H, 3.82; N, 7.79.
2,7-Bis(4-chlorophenyl)-2,3,6,7-tetrahydrothiopyrano[2,3-
b]thiopyran-4,5-dione (4c)
Yellowish solid.
2,7-Di(tert-butyl)-2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopy-
ran-4,5-dione (4g)
White solid.
Mp 192–194 °C.
IR (KBr): 1692, 1640, 1492, 1456, 1311, 1091, 1014, 822 cm–1.
Mp 99–101 °C.
IR (KBr): 1723, 1658, 1500, 1307, 1101, 1014, 829 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.12 (dd, J = 3.0, 17.5 Hz, 2 H),
3.27 (dd, J = 14.0, 17.5 Hz, 2 H), 4.72 (dd, J = 3.0, 14.0 Hz, 2 H),
7.30 (d, J = 8.5 Hz, 4 H), 7.38 (d, J = 8.5 Hz, 4 H).
1H NMR (500 MHz, CDCl3): d = 1.50 (s, 18 H), 2.74 (dd, J = 2.5,
17.0 Hz, 2 H), 2.94 (dd, J = 15.0, 17.0 Hz, 2 H), 3.39 (dd, J = 2.5,
15.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 27.8, 33.8, 43.7, 54.9, 110.0,
178.2, 190.2.
Synthesis 2007, No. 14, 2115–2120 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Substituted Tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones
2119
Anal. Calcd for C16H24O2S2: C, 61.50; H, 7.74. Found: C, 61.51; H,
7.75.
13C NMR (125 MHz, CDCl3): d = 20.2, 45.9, 46.1, 46.7, 46.8, 124.4,
126.5, 127.8, 128.2, 128.7, 128.9, 131.6, 134.7, 138.2, 175.6, 187.8,
187.9.
2-(4-Chlorophenyl)-7-phenyl-2,3,6,7-tetrahydrothio-
pyrano[2,3-b]thiopyran-4,5-dione (4h)
Light yellow solid.
Anal. Calcd for C21H18O2S2: C, 68.82; H, 4.95. Found: C, 68.68; H,
4.84.
Mp 157–159 °C.
IR (KBr): 1683, 1445, 1297, 1090, 821, 698 cm–1.
2-Substituted 5-Alkenoyl-6-(vinylsulfanyl)-2,3-dihydrothiopy-
ran-4-ones 5; Typical Procedure
To a solution of 3a (0.81 g, 2.0 mmol) in DMF (5 mL) was added
NaH (0.14 g, 6.0 mmol) in three portions at r.t. The mixture was
stirred at r.t. for about 30 min (for complete conversion as indicated
by TLC). The resulting mixture was carefully treated with 10% aq
HCl (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with H2O (3 × 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give a yellow solid.
Purification was carried out by flash chromatography (silica gel,
acetone–EtOAc, 1:4) to give product 5a. Yield: 0.69 g (85%).
1H NMR (500 MHz, CDCl3): d = 3.10 (dd, J = 2.5, 17.5 Hz, 2 H),
3.24 (dd, J = 14.0, 17.5 Hz, 2 H), 4.72 (dd, J = 2.5, 14.0 Hz, 2 H),
7.29–7.31 (m, 4 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.36–7.41 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 45.4, 46.2, 46.5, 46.7, 124.4,
126.5 (2 C), 127.8 (2 C), 128.2 (2 C), 128.4 (2 C), 128.6, 133.0,
133.1, 134.2, 174.8, 187.2, 187.7.
Anal. Calcd for C20H15ClO2S2: C, 62.08; H, 3.91. Found: C, 62.19;
H, 3.85.
(E)-2-(4-Tolyl)-5-[3-(4-tolyl)acryloyl]-6-(vinylsulfanyl)-2,3-di-
hydrothiopyran-4-one (5a)
Yellow solid.
2-(4-Chlorophenyl)-7-(4-tolyl)-2,3,6,7-tetrahydrothio-
pyrano[2,3-b]thiopyran-4,5-dione (4i)
Yellow solid.
Mp 135–137 °C.
Mp 181–183 °C.
IR (KBr): 3045, 2918, 1657, 1641, 1596, 1471, 1255, 1126, 816
cm–1.
IR (KBr): 2922, 1690, 1491, 1456, 1304, 1256, 1091, 1014, 817
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 3.14 (dd, J = 2.5,
17.5 Hz, 2 H), 3.30 (dd, J = 14.0, 17.5 Hz, 2 H), 4.70 (dd, J = 2.5,
14.0 Hz, 2 H), 7.16 (d, J = 8.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H),
7.38 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 20.1, 45.3, 45.9, 46.5, 46.8, 124.3,
124.4, 126.4, 128.3, 128.9, 131.5, 133.1, 134.1, 138.2, 174.9, 187.0,
187.8.
1H NMR (500 MHz, CDCl3): d = 2.37 (s, 3 H), 2.38 (s, 3 H), 3.04
(dd, J = 3.0, 17.0 Hz, 1 H), 3.24 (dd, J = 14.5, 17.0 Hz, 1 H), 4.71
(dd, J = 3.0, 14.5 Hz, 1 H), 5.64 (d, J = 9.0 Hz, 1 H), 5.73 (d, J =
16.5 Hz, 1 H), 6.73 (dd, J = 9.0, 16.5 Hz, 1 H), 7.08 (d, J = 16.0 Hz,
1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.30 (d,
J = 8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 16.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 21.5, 21.8, 45.1, 47.2, 114.2,
125.5, 126.0, 126.8, 127.8, 128.9, 129.8, 130.2, 132.4, 133.5, 139.4,
141.1, 143.7, 168.2, 190.5, 191.0.
Anal. Calcd for C21H17ClO2S2: C, 62.91; H, 4.27. Found: C, 62.79;
H, 4.15.
MS: m/z calcd for C24H22O2S2: 406.6; found: 407.5 [M + 1]+.
Anal. Calcd for C24H22O2S2: C, 70.90; H, 5.4. Found: C, 71.24; H,
5.32.
2-(4-Chlorophenyl)-7-(4-methoxyphenyl)-2,3,6,7-tetrahydro-
thiopyrano[2,3-b]thiopyran-4,5-dione (4j)
Yellow solid.
(E)-5-Cinnamoyl-2-phenyl-6-(vinylsulfanyl)-2,3-dihydrothio-
pyran-4-one (5b)
Mp 195–197 °C.
IR (KBr): 2931, 1682, 1514, 1438, 1299, 1260, 1179, 1089, 823
cm–1.
1H NMR (500 MHz, CDCl3): d = 3.13 (dd, J = 2.5, 17.0 Hz, 2 H),
3.29 (dd, J = 14.0, 17.0 Hz, 2 H), 3.82 (s, 3 H), 4.70 (dd, J = 2.5,
14.0 Hz, 2 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 9.0 Hz, 2 H),
7.30 (d, J = 9.0 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 46.6, 46.8, 47.0, 48.1, 55.6, 114.8,
125.6, 127.6, 128.9, 129.1, 129.8, 134.4, 135.4, 160.4, 176.4, 188.6,
189.1.
Yellow solid.
Mp 121–123 °C
IR (KBr): 3056, 1641, 1503, 1406, 1251, 1123, 985, 768 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.07 (dd, J = 3.0, 16.0 Hz, 1 H),
3.26 (dd, J = 14.0, 16.0 Hz, 1 H), 4.74 (dd, J = 3.0, 14.0 Hz, 1 H),
5.68 (d, J = 9.0 Hz, 1 H), 5.76 (d, J = 17.0 Hz, 1 H), 6.74 (dd, J =
9.0, 17.0 Hz, 1 H), 7.14 (d, J = 16.0 Hz, 1 H), 7.37–7.41 (m, 4 H),
7.42–7.45 (m, 4 H), 7.58–7.63 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 44.9, 47.3, 125.8, 126.7, 126.9,
127.9, 128.7, 129.0, 129.3, 129.5, 129.8, 130.5, 135.1, 136.4, 143.3,
168.9, 190.2, 190.8.
Anal. Calcd for C21H17ClO3S2: C, 60.49; H, 4.11. Found: C, 60.58;
H, 4.19.
Anal. Calcd for C22H18O2S2: C, 69.81; H, 4.79. Found: C, 69.98; H,
4.83.
2-Phenyl-7-(4-tolyl)-2,3,6,7-tetrahydrothiopyrano[2,3-b]thio-
pyran-4,5-dione (4k)
Yellow solid.
(E)-2-(4-Chlorophenyl)-5-[3-(4-chlorophenyl)acryloyl]-
6-(vinylsulfanyl)-2,3-dihydrothiopyran-4-one (5c)
Yellow solid.
Mp 139–141 °C.
IR (KBr): 2927, 1692, 1573, 1343, 1259, 1047, 831 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 3.12 (dd, J = 2.5,
17.5 Hz, 2 H), 3.35 (dd, J = 14.0, 17.5 Hz, 2 H), 4.72 (dd, J = 2.5,
14.0 Hz, 2 H), 7.20 (d, J = 7.5 Hz, 2 H), 7.24 (d, J = 9.0 Hz, 2 H),
7.35 (d, J = 7.5 Hz, 2 H), 7.39–7.42 (m, 3 H).
Mp 146–148 °C.
IR (KBr): 3056, 1641, 1503, 1406, 1251, 1123, 985, 768, 741 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.05 (dd, J = 3.0, 16.0 Hz, 1 H),
3.24 (dd, J = 14.0, 16.0 Hz, 1 H), 4.71 (dd, J = 3.0, 14.0 Hz, 1 H),
5.70 (d, J = 9.5 Hz, 1 H), 5.78 (d, J = 16.5 Hz, 1 H), 6.72 (dd, J =
Synthesis 2007, No. 14, 2115–2120 © Thieme Stuttgart · New York

2120
W. Pan et al.
PAPER
9.0, 16.5 Hz, 1 H), 7.10 (d, J = 16.5 Hz, 1 H), 7.34–7.39 (m, 4 H),
7.41–7.49 (m, 2 H), 7.50–7.55 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 44.5, 46.3, 114.5, 126.0, 126.2,
126.8, 128.9, 129.0, 129.2, 129.4, 129.5, 133.4, 134.6, 135.0, 136.0,
141.3, 168.8, 189.2, 190.1.
(4) (a) McDonald, B. P.; Steele, R. W.; Sutherland, J. K.; Leslie,
B. W.; Brewster, A. J. Chem. Soc., Perkin Trans. 1 1988,
675. (b) Lawson, K. R.; McDonald, B. P.; Mills, O. S.;
Steele, R. W.; Sutherland, J. K.; Wear, T. J.; Brewster, A.;
Marsham, P. R. J. Chem. Soc., Perkin Trans. 1 1988, 663.
(5) (a) McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett.
2001, 42, 1197. (b) Taylor, R. J. K. Chem. Commun. 1999,
217. (c) Matsuyama, H.; Miyazawa, Y.; Takei, Y.;
Kobayashi, M. J. Org. Chem. 1987, 52, 1703.
(d) Matsuyama, H.; Fujii, S.; Kamigata, N. Heterocycles
1991, 32, 1875.
(6) Chen, C. H.; Doney, J. J.; Reynolds, G. A. J. Org. Chem.
1981, 46, 4604.
(7) Augustin, M.; Jahreis, G.; Rudorf, W. D. Synthesis 1977,
472.
(8) (a) Ward, D. E.; Gai, Y. Z. Tetrahedron Lett. 1992, 33,
1851. (b) Ward, D. E.; Nixey, T. E. Tetrahedron Lett. 1993,
34, 947. (c) Ward, D. E.; Zoghaib, W. M.; Rhee, C. K.; Gai,
Y. Z. Tetrahedron Lett. 1990, 31, 845.
(9) (a) Barluenga, J.; Aznar, F.; Valdes, C. Synlett 1991, 487.
(b) Vedejs, E.; Eberlein, T. H.; Mazur, D. J.; McClure, C. K.;
Perry, D. A.; Ruggeri, R.; Schwartz, E.; Stults, J. S.; Varie,
D. L.; Wilde, R. G.; Wittenberger, S. J. Org. Chem. 1986,
51, 1556.
(10) Samuel, R.; Nair, S. K.; Asokan, C. V. Synlett 2000, 1804.
(11) For reviews on the synthesis and application of a-oxo ketene
dithioacetals, see: (a) Dieter, R. K. Tetrahedron 1986, 42,
3029. (b) Tominaga, Y. J. Heterocycl. Chem. 1989, 26,
1167. (c) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (d) Kolb, M. Synthesis 1990, 171.
(e) Junjappa, H.; Ila, H. Phosphorous, Sulfur Silicon Relat.
Elem. 1994, 95, 35. (f) Junjappa, H.; Ila, H.; Mohanta, P. K.
In Progress in Heterocyclic Chemistry, Vol. 13; Gribble, G.
H.; Gilchrist, L. T., Eds.; Pergamon: Oxford, 2001, Chap. 1,
1–24.
(12) For selected examples of our recent work on a-oxo ketene
dithioacetals, see: (a) Ouyang, Y.; Dong, D.; Yu, H.; Liang,
Y.; Liu, Q. Adv. Synth. Catal. 2006, 348, 206. (b) Dong, D.;
Ouyang, Y.; Yu, H.; Liu, Q.; Liu, J.; Wang, M.; Zhu, J. J.
Org. Chem. 2005, 70, 4535. (c) Liu, Q.; Che, G.; Yu, H.;
Liu, Y.; Zhang, J.; Zhang, Q.; Dong, D. J. Org. Chem. 2003,
68, 9148. (d) Zhao, Y.; Liu, Q.; Zhang, J.; Liu, Z. J. Org.
Chem. 2005, 70, 6913. (e) Li, Y.; Liang, F.; Bi, X.; Liu, Q.
J. Org. Chem. 2006, 71, 8006. (f) Liang, Y.; Liu, Q. Adv.
Synth. Catal. 2006, 348, 1986.
(13) Formal [5+1] annulations of alkenoylketene dithioacetals
see: (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B.
J. Am. Chem. Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.;
Liu, Q.; Cong, F. Chem. Commun. 2005, 3580. (c) Bi, X.;
Dong, D.; Li, Y.; Liu, Q.; Zhang, Q. J. Org. Chem. 2005, 70,
10886. (d) Zhao, L.; Liang, F.; Bi, X.; Sun, S.; Liu, Q. J.
Org. Chem. 2006, 71, 1094.
Anal. Calcd for C22H16Cl2O2S2: C, 59.06; H, 3.60. Found: C, 59.30;
H, 3.47.
(E)-2-(4-Methoxyphenyl)-5-[3-(4-methoxyphenyl)acryloyl]-6-
(vinylsulfanyl)-2,3-dihydrothiopyran-4-one (5d)
Yellow solid.
Mp 119–121 °C.
IR (KBr): 1643, 1562, 1511, 1398, 1249, 1175, 1131, 1021, 830
cm–1.
1H NMR (500 MHz, CDCl3): d = 3.03 (dd, J = 3.0, 17.0 Hz, 1 H),
3.23 (dd, J = 14.5, 17.0 Hz, 1 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 4.69
(dd, J = 3.0, 14.0 Hz, 1 H), 5.64 (d, J = 9.5 Hz, 1 H), 5.73 (d, J =
17.0 Hz, 1 H), 6.73 (dd, J = 9.5, 17.0 Hz, 1 H), 6.89 (d, J = 9.0 Hz,
2 H), 6.93 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 16.0 Hz, 1 H), 7.33 (d,
J = 9.0 Hz, 2 H), 7.52–7.57 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 45.1, 46.9, 55.6 (2 C), 114.5,
114.8, 124.7, 125.3, 126.8, 127.8, 128.3, 129.1, 130.2, 130.5, 143.5,
160.2, 161.7, 167.6, 190.5, 190.9.
Anal. Calcd for C24H22O4S2: C, 65.73; H, 5.06. Found: C, 65.91; H,
5.19.
2,7-Disubstituted 2,3,6,7-Tetrahydrothiopyrano[2,3-b]thio-
pyran-4,5-diones 4 (Path B); Typical Procedure
To a solution of 5a (0.81 g, 2.0 mmol) in DMF (5 mL) was added
EtNH2 (0.30 g, 6.0 mmol) in one portion at r.t. After stirring for
about 20 min, the mixture was treated with 10% aq HCl (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were washed with H2O (3 × 20 mL), dried (MgSO4), filtered, and
concentrated in vacuo to give a white solid. Further purification was
carried out by flash chromatography (silica gel, PE–Et2O, 3:1) to
give product 4a. Yield: 0.59 g (77%).
Acknowledgment
Financial support of this research by the National Natural Science
Foundation of China (20572013), the Ministry of Education of
China (105061 and 10412), and the Department of Science and
Technology of Jilin Province (20050392) is greatly acknowledged.
References
(1) (a) Ingall, A. H. In Comprehensive Heterocyclic Chemistry
II, Vol. 5; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. W.,
Eds.; Pergamon: Oxford, 1996, 501. (b) Vedejs, E.; Krafft,
G. A. Tetrahedron 1982, 38, 2857. (c) Hollick, J. J.;
Golding, B. T.; Hardcastle, I. R.; Martin, N.; Richardson, C.;
Rigoreau, L. J. M.; Smith, G. C. M.; Griffin, R. J. Bioorg.
Med. Chem. Lett. 2003, 13, 3083.
(2) Casy, G.; Taylor, R. J. K. Tetrahedron 1989, 45, 455.
(3) Fujisawa, T.; Mobele, B. I.; Shimizu, M. Tetrahedron Lett.
1992, 33, 5567.
(14) Ouyang, Y.; Dong, D.; Pan, W.; Zhang, J.; Liu, Q.
Tetrahedron 2006, 62, 10111.
(15) Ja Augustin, M.; Groth, Ch. J. Prakt. Chem. 1979, 321, 215.
(16) Nair, S. K.; Samuel, R.; Asokan, C. V. Synthesis 2001, 573.
(17) Bernasconi, C. F. Tetrahedron 1989, 45, 4017.
(18) Ogurtsov, V. A.; Rakitin, O. A.; Rees, C. W.; Smolentsev, A.
A.; Belyyakov, P. A.; Golovanov, D. G.; Lyssenko, K. A.
Org. Lett. 2005, 7, 791.
Synthesis 2007, No. 14, 2115–2120 © Thieme Stuttgart · New York