Preparation of new nitrogen-bridged heterocycles 67.1 syntheses of α,α′-bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and p-xylene derivatives and their conformational structures

Article abstract of DOI:10.1248/cpb.57.1385

The alkaline treatment and dehydrogenation of pyridinium salts, formed from the S-alkylations of 3-(1-pyridinio)thiophene-2-thiolates with α,α-dibromo-o-, m-, or p-xylene, provided the corresponding α,α′-bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and

Full text of DOI:10.1248/cpb.57.1385

December 2009
Chem. Pharm. Bull. 57(12) 1385—1390 (2009)
1385
Preparation of New Nitrogen-Bridged Heterocycles 67.1) Syntheses of
a aꢀ
, -Bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and p-xylene Derivatives
and Their Conformational Structures
Akikazu KAKEHI, ,a Hiroyuki SUGA,a Yukihisa OKUMURA,a Masatoshi SHINOHARA,a Tomonao KAKO,a
*
b
Takeshi SEKIGUCHI,a and Motoo SHIRO
a Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University; Wakasato, Nagano
b
380–8553, Japan: and Rigaku X-Ray Research Laboratory, Rigaku Corporation; Matsubara-cho, Akishima, Tokyo 196–
0003, Japan. Recieved July 21, 2009; accepted September 4, 2009; published online September 14, 2009
The alkaline treatment and dehydrogenation of pyridinium salts, formed from the S-alkylations of 3-(1-
pyridinio)thiophene-2-thiolates with a,a-dibromo-o-, m-, or p-xylene, provided the corresponding a,aꢀ-
1
bis[(thieno[3,4-b]indolizin-3-yl)thio]-o-, m-, and p-xylene derivatives in low to good yields. Both H-NMR and
UV–Vis spectra of these products supported distinctly the predominance of the gauche–gauche conformation in
relation to the two sulfide linkages as the spacer in these molecules. On the other hand, the X-ray analyses indi-
cated the expected gauche–gauche conformation for the m- and the p-xylene derivatives, but the anti–anti one for
the o-xylene derivative.
Key words cyclization; arene–arene interaction; thieno[3,4-b]indolizine; sulfide linkage; X-ray analysis
Intramolecular and intermolecular attractive interactions ring is interacted with it. In contrast, the increased steric hin-
such as arene–arene, arene–p, and cation–p interactions are drance between the central benzene ring and the two bulky
important means for the conformational control of many thieno[3,4-b]indolizine rings might make these molecules to
organic molecules and have been extensively investigated in take the more strain-free anti–anti conformation. In this paper
the fields of molecular recognition2—5) and in the stereoselec- we report the preparation of the title compounds and discuss
tive or asymmetric syntheses.2,6—8) Recently, we have reported their conformations by their spectral and X-ray analyses.
facile and effective syntheses of 3-(arylmethylthio)-,9—11) 3-
(allylthio)-,12) 3-(propargylthio)-12) and 3-(acylmethylthio)- Results and Discussion
thieno[3,4-b]indolizine derivatives13) and the presence of
Preparation of a,aꢀ-Bis[(thieno[3,4-b]indolizin-3-yl)thio]-
their intramolecular arene–arene or arene–p interaction. In o-, m-, and p-xylene Derivatives The S-alkylations of 5-
addition we disclosed that the gauche conformation in the re- arylcarbonyl-4-ethoxycarbonylmethyl-3-(1-pyridinio)- (1a—
lation of the sulfide linkage in these molecules is more stable c) and 3-[1-(4-methylpyridinio)]thiophene-2-thiolate (1d—
than the anti one, because the longer carbon–sulfur bond in f)9,10) with a half equivalent of a,aꢁ-dibromo-o-xylene (2a)
comparison with a carbon–carbon bond does not only dra- in the presence of a large excess of sodium iodide in acetone,
matically reduce the steric hindrance, but the favorable in- followed by the treatment of the resulting pyridinium salts
tramolecular arene–arene or arene–p interactions in their 3a—f with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
gauche forms are also possible. This was supported by their then chloranil at 0 °C in chloroform afforded the correspon-
molecular orbital calculations using MOPAC PM3,14) but the ding a,aꢁ-bis[(1-arylcarbonyl-9-(ethoxycarbonyl)thieno[3,4-
energy differences between the gauche and anti conforma- b]indolizin-3-yl)thio]-o-xylene (4a—f) in 28—79% yields.
tions were generally low (ꢀ1.5 kcal/mol).11—13) As an exten- Similarly, the dehydrohalogenation and dehydrogenation of
sion of this work we are interested in the syntheses and the the corresponding pyridinium salts 3g—i, obtained from the
structure of the title compounds in which the gauche–gauche, S-alkylations of 3-[1-(3,5-dimethylpyridinio)]thiophene-2-thio-
gauche–anti, and anti–anti comformations are possible as late (1g—i) with 2a in chloroform, gave a,aꢁ-bis[(1-arylcar-
shown in Fig. 1. For example, such molecules could be pres- bonyl-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-b]indolizin-
ent as a gauche–gauche conformation if both thieno[3,4-b]in- 3-yl)thio]-o-xylene (4g—i) in 69, 41, and 44% yields, re-
dolizine rings are attracted by the electron-rich benzene ring spectively. These results are shown in Chart 1.
and as a gauche–anti one if only one thieno[3,4-b]indolizine
Similar reactions of pyridinium salts 5a—i and 7a—i
which were prepared from the S-alkylations of 3-(1-pyri-
dinio)thiophene-2-thiolate (1a—i) and a,aꢁ-dibromo-m-
xylene (2b) or a,aꢁ-dibromo-p-xylene (2c) provided the
corresponding a,aꢁ-bis[(1-arylcarbonyl-9-(ethoxycarbonyl)-
thieno[3,4-b]indolizin-3-yl)thio]-m-xylenes (6a—i) in 16—
80% yields or a,aꢁ-bis[(1-arylcarbonyl-9-(ethoxycarbonyl)-
thieno[3,4-b]indolizin-3-yl)thio]-p-xylenes (8a—i) in 7—
97% yields, as seen in Charts 2 and 3. The low yields for
products 4d—f, h, i, 6a, c—f, h, and 8a, b, d—f are mainly
attributable to the sluggish S-alkylations of the 3-(1-pyri-
dinio)thiophene-2-thiolates (1a—i) and most of these reac-
tions did not complete even under more prolonged heating
Fig. 1. Possible Three Conformations of a,a-Bis(thieno[3,4-b]indolizin-
3-yl)-o-, m-, and p-Xylene Derivatives
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: xkakehi@ shinshu-u.ac.jp

1386
Vol. 57, No. 12
Chart 3
Chart 1
shifts (ca. d 0.10—0.36) for the phenylene protons were ob-
served in comparison with the chemical shifts (d 6.99—7.14)
of the aromatic protons in o-, m-, and p-xylene. In addition,
the interaction between the 5-proton on the thieno[3,4-b]in-
dolizine ring and the methine protons a to the methylene
groups in the a,a-disubstituted xylene moieties were indi-
cated in the differential nuclear Overhauser effect (NOE)
measurements for 4g, 6g, and 8g. For example, when the sig-
nal of the 5-proton in 4g was irradiated, the higher of the two
aromatic signals (d 6.87) survived, though its intensity was
not high. On the other hand, the 2-proton in the a,a-disubsti-
tuted m-xylene moiety of 6g and the all aromatic protons in
the a,a-disubstituted p-xylene moiety of 8g showed strong
differential NOE on the irradiation of the 5-proton. The
UV–Vis spectra of products 4a—i, 6a—i, and 8a—i each
showed absorption band (near 430 nm) characteristics of an
arene–arene interaction in this kind of system,9—13) though
the molar extinction coefficients of o-xylene derivatives 4a—
i were considerably lower than those of m- 6a—i and p-xy-
lene derivatives 8a—i. These facts strongly supported the hy-
pothesis that the structures of products 4a—i, 6a—i, and
8a—i must be the gauche–gauche conformations in the solu-
tion state.
Chart 2
conditions over 2 weeks.
The elemental analyses of products 4a—i, 6a—i, and 8a—
To obtain further information for the conformation of
i were in good accord with our proposed compositions and these molecules we next investigated their X-ray analyses.
the IR spectra showed a characteristic a,b-unsaturated ester Unfortunately parent 4a—c, 6a—c, and 8a—c and 7-methyl
carbonyl band (1663—1721 cmꢂ1) and an arylcarbonyl one derivatives 4d—f, 6d—f, and 8d—f showed very low solu-
(1599—1638 cmꢂ1). The 1H-NMR spectra of products 4a—i, bility for many solvents such as chloroform and ethanol and
6a—i, and 8a—i exhibited only one set of signals for the two we could not prepare suitable single crystals for them. How-
thieno[3,4-b]indolizine rings in these molecules, and this fact ever, the 6,8-dimethyl compounds 4g—i, 6g—i, and 8g—i
indicated the presence of a symmetric element in these mole- had considerable solubility in chloroform and we could ob-
cules. The chemical shifts for the protons and the methyl pro- tain single crystals for the three compounds 4i, 6g, and 8g.
tons at the 5- and 6-positions on the thieno[3,4-b]indolizine The ORTEP drawings16) for these molecules (4i, 6g, 8g) are
ring were significantly shifted to higher magnetic regions exhibited in Figs. 2—4. As seen in these figures, the confor-
(ca. d 0.12—0.26) in comparison with those of ethyl 3- mations of the m-6g and the p-derivative 8g were the gauche–
1
(methylthio)thieno[3,4-b]indolizine-9-carboxylates (9a—c),15) gauche ones as suggested in the H-NMR and the UV–Vis
and these values of the chemical shifts were almost compara- spectral analyses, but that of the o-derivative 4i was shown to
ble to those of ethyl 3-(benzylthio)thieno[3,4-b]indolizine-9- be the anti–anti conformation. The torsion angles about the
carboxylates (10a—c)10) (see Table 1). Similar high-field sulfide linkage for 4i, 6g, and 8g were 179.7(2)°, 85.1(2)°,

December 2009
1387
Table 1. Main 1H-NMR Spectral Data of 4a—i, 6a—i, 8a—i, and 9a—c and the Shielding Effect to the Pyridine Ring Protons
No.a,b)
C-5
C-6
C-7
C-8
CH2
Phenylene
d5-H
d6-H
d7-H
d8-H
9a
4a
4b
4c
6a
6b
6c
8a
8b
8c
8.96
8.79
8.80
8.80
8.77
8.78
8.78
8.79
8.80
8.79
8.79
6.73
6.52
6.55
6.56
6.55
6.58
6.58
6.56
6.59
6.59
6.51
7.31
7.21
7.23
7.24
7.23
7.26
7.26
7.24
7.27
7.26
7.23
8.20
8.11
8.10
8.11
8.12
8.12
8.12
8.15
8.14
8.13
8.13
2.68c)
4.18
4.20
4.20
3.93
3.94
3.94
4.00
4.02
4.01
4.12
0.00
0.17
0.16
0.16
0.19
0.18
0.18
0.17
0.16
0.17
0.17
0.00
0.21
0.18
0.17
0.18
0.15
0.15
0.17
0.14
0.14
0.22
0.00
0.10
0.08
0.07
0.08
0.05
0.05
0.07
0.04
0.05
0.08
0.00
0.09
0.10
0.09
0.08
0.08
0.08
0.05
0.06
0.07
0.07
6.84, 6.92
6.86, 6.94
6.87, 6.94
6.74, 6.89, 6.99
6.76, 6.91, 7.00
6.76, 6.91, 7.00
6.93
6.94
6.94
7.08, 7.11—7.18
10a
C-5
C-6
C-7
C-8
CH2
Phenylene
d5-H
d6-H
d7-Me
d8-H
9b
4d
4e
4f
6d
6e
6f
8d
8e
8f
10b
8.84
8.66
8.68
8.68
8.64
8.67
8.67
8.66
8.69
8.68
8.68
6.58
6.36
6.40
6.40
6.40
6.43
6.44
6.43
6.46
6.45
6.37
2.40
2.32
2.35
2.35
2.35
2.37
2.37
2.35
2.37
2.37
2.36
8.00
7.90
7.90
7.90
7.91
7.92
7.92
7.95
7.96
7.95
7.94
2.67c)
4.18
4.20
4.20
3.93
3.94
3.95
3.99
4.01
4.01
4.11
0.00
0.18
0.16
0.16
0.20
0.17
0.17
0.18
0.15
0.16
0.16
0.00
0.22
0.18
0.18
0.18
0.15
0.14
0.15
0.12
0.13
0.21
0.00
0.08
0.05
0.05
0.05
0.03
0.03
0.05
0.03
0.03
0.04
0.00
0.10
0.10
0.10
0.09
0.08
0.08
0.05
0.04
0.05
0.06
6.88, 6.94
6.90, 6.96
6.91, 6.96
6.77, 6.90, 7.00
6.79, 6.93, 7.02
6.79, 6.94, 7.02
6.94
6.96
6.95
7.09, 7.12—7.19
C-5
C-6
C-7
C-8
CH2
Phenylene
d5-H
d6-Me
d7-H
d8-Me
9c
4g
4h
4i
6g
6h
6i
8g
8h
8i
8.59
8.39
8.40
8.40
8.37
8.38
8.39
8.41
8.43
8.43
8.38
2.29
2.03
2.06
2.06
2.13
2.14
2.14
2.15
2.17
2.17
2.13
6.86
6.72
6.75
6.75
6.75
6.77
6.77
6.77
6.79
6.79
6.76
2.49
2.44
2.45
2.45
2.44
2.44
2.45
2.46
2.46
2.46
2.46
2.65c)
4.18
4.19
4.19
3.89
3.90
3.90
3.98
4.00
4.00
4.09
0.00
0.20
0.19
0.19
0.22
0.21
0.20
0.18
0.16
0.16
0.21
0.00
0.26
0.23
0.23
0.16
0.15
0.15
0.14
0.12
0.12
0.16
0.00
0.14
0.11
0.11
0.11
0.09
0.09
0.09
0.07
0.07
0.10
0.00
0.05
0.04
0.04
0.05
0.05
0.04
0.03
0.03
0.03
0.03
6.87, 6.97
6.88, 6.98
6.88, 6.99
6.64, 6.88, 7.00
6.62, 6.89, 7.01
6.63, 6.90, 7.01
6.94
6.96
6.96
7.08, 7.12—7.23
10c
a) The coupling constants are as follows: J5,6ꢃJ6,7ꢃ6.8—7.1 Hz, J7,8ꢃ9.0—9.2 Hz, J5,7ꢃ1.2—1.5 Hz, J6,8ꢃ1.0—1.3 Mz. b) The ethoxycarbonyl signals (d 0.93—1.20 (3H,
t, Jꢃ6.9—7.2 Hz) and 3.62—4.02 (2H, q, Jꢃ6.9—7.2 Hz) and the arylcarbonyl signals (d 7.20—8.00 (4H or 5H, m) were also appeared. c) Methyl group.
Fig. 3. ORTEP Drawing of m-Xylene Derivative 6g
and 75.5(3)°, respectively. In the crystal structure of 4i the
Fig. 2. ORTEP Drawing of the o-Xylene Derivative 4i
two pyridine rings were the closest and the distance between
them was in the range of 3.477—3.990 Å, while the distance
between the 5-carbon on the thieno[3,4-b]indolizine ring and
the aromatic carbons on the a,a-disubstituted m- (6g) or p-

1388
Vol. 57, No. 12
Jꢃ7.1 Hz, OCH2CH3), 2.60 (6H, s, 3,5-diMe), 3.72 (2H, s, CH2), 4.16 (2H,
q, Jꢃ7.1 Hz, OCH2CH3), 7.41 (2H, m, Ph-H), 7.78 (2H, m, Ph-H), 8.04 (1H,
br s, 4-H), 8.46 (2H, s, 2,6-H). Anal. Calcd for C22H20ClNO3S2: C, 59.25; H,
4.52; N, 3.14%; Found C, 59.44; H, 4.52; N, 2.95%.
5-(4-Bromobenzoyl-3-(3,5-dimethyl-1-pyridinio)-4-(ethoxycarbonyl-
methyl)thiophene-2-thiolate (1i): 55%; orange prisms (from ethanol); mp
174—175 °C. IR (KBr) cmꢂ1: 1730, 1624. 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jꢃ7.1 Hz, OCH2CH3), 2.60 (6H, s, 3,5-diMe), 3.72 (2H, s, CH2), 4.16 (2H,
q, Jꢃ7.1 Hz, OCH2CH3), 7.57 (2H, m, Ph-H), 7.71 (2H, m, Ph-H), 8.04 (1H,
br s, 4-H), 8.45 (2H, br s, 2,6-H). Anal. Calcd for C22H20BrNO3S2: C, 53.88;
H, 4.11; N, 2.86%; Found C, 54.11; H, 4.07; N, 2.67%.
Preparation of a,aꢀ-Bis(thieno[3,4-b]indolizin-3-yl)-o- (4a—i), m-
(6a—i), and p-xylene Derivatives (8a—i). General Method 1: An acetone
suspension (20 ml) of 3-(1-pyridinio)thiophene-2-thiolates (1a—f) (2.0
mmol), a,a-dibromo-o- (2a), m- (2b), or p-xylene (2c) (0.264 g, 1 mmol),
and sodium iodide (2 g, 13.3 mmol) was heated at 50 °C in a water bath until
the disappearance of 1 was confirmed by thin layer chromatographic (TLC)
monitoring (5—10 d). The reaction mixture was concentrated at reduced
pressure and the resulting residue was washed 3 times with ether (each
10 ml) to remove the unaltered halide. The residue was dissolved in chloro-
form (30 ml) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.364 g, 2.4 mmol)
was added at 0 °C in an ice bath. After 15 min, chloranil (0.492 g, 2 mmol)
was added at that temperature and stirred for a further 4 h. The reaction mix-
Fig. 4. ORTEP Drawing of p-Xylene Derivative 8g
xylene (8g) were in the range of 3.506—4.264 or 3.547—
3.824 Å, respectively.
In conclusion, we first prepared some compounds in which ture was filtered by suction, and the chloroform solution was concentrated at
reduced pressure. Chromatographic separation on alumina of the residues
using chloroform as an eluent followed by the recrystallization from chloro-
form gave the corresponding products 4a—f, 6a—f and 8a—f.
General Method 2: 3-(3,5-Dimethyl-1-pyridinio)thiophene-2-thiolates
two thieno[3,4-b]indolizine nuclei were combined with the
spacers involving an o-, m-, and p-phenylene moieties at the
3-position and investigated their conformations. All of the
compounds indicated the predominance of the gauche–
gauche conformation in the solution state as shown in their
NMR and UV–Vis spectral indications, but only the o-xylene
derivative 8g appeared as the anti–anti conformation in the
solid state.
(1g—i) (2.0 mmol) were allowed to react with a,a-dibromo-o-, m-, or p-
xylene (2) (0.264 g, 1 mmol) in chloroform (20 ml) at room temperature
until the disappearance of 1 was confirmed by tlc monitoring (12 h—3 d).
The reaction mixture was concentrated at reduced pressure and the resulting
residue was washed 3 times with ether (each 10 ml) to remove the unaltered
halide. Similar treatment of the residue as described above and the recrystal-
lization from chloroform–hexane afforded the corresponding products 4g—
i, 6g—i, and 8g—i.
Experimental
1H-NMR spectral data for 4a—i and 6a—i, and 8a—i are shown in Table
1 and some other data are described below.
Melting points were measured on a Yamagimoto micro melting point ap-
paratus and were not corrected. IR spectra were measured on a JASCO
FT/IR-5300 IR spectrophotometer from samples as KBr pellets and UV–Vis
spectra on a Shimadzu UV-2450 spectrophotometer. NMR spectra were
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonylthieno[3,4-b]indolizin-3-yl)thio]-o-
xylene (4a): From 1a and 2a; 48%; red prisms (from CHCl3); mp 142—
143 °C. IR (KBr) cmꢂ1: 1680, 1613. UV–Vis (nm (log e), CHCl3): 330
(shoulder), 432 (3.89), 497 (3.86). 13C-NMR (CDCl3) d: 14.3, 41.6, 59.0,
93.2, 110.6, 114.9, 119.8, 125.4, 126.4, 128.1, 128.2, 129.3, 130.0, 130.6,
132.4, 134.2, 134.5, 137.0, 138.7, 149.6, 163.7, 187.8. Anal. Calcd for
C48H36N2O6S4: C, 66.64; H, 4.19; N, 3.24%; Found C, 66.71; H, 4.15; N,
3.21%.
a,a3ꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-
3-yl)thio]-o-xylene (4b): From 1b and 2a; 54%; red prisms (from CHCl3);
mp 202—203 °C. IR (KBr) cmꢂ1: 1684, 1616. UV–Vis (nm (log e), CHCl3):
331 (shoulder), 432 (3.84), 498 (3.81). Anal. Calcd for C48H34Cl2N2O6S4: C,
61.73; H, 3.67; N, 3.00%; Found C, 61.97; H, 3.59; N, 2.84%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-3-
yl)thio]-o-xylene (4c): From 1c and 2a; 79%; red prisms (from CHCl3); mp
205—206 °C. IR (KBr) cmꢂ1: 1682, 1618. UV–Vis (nm (log e), CHCl3): 329
(shoulder), 432 (3.85), 499 (3.82). Anal. Calcd for C48H34Br2N2O6S4: C,
56.36; H, 3.35; N, 2.74%; Found C, 56.55; H, 3.30; N, 2.59%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-7-methylthieno[3,4-b]indolizin-3-
yl)thio]-o-xylene (4d): From 1d and 2a; 42%; red prisms (from CHCl3); mp
144—145 °C. IR (KBr) cmꢂ1: 1676, 1638. UV–Vis (nm (log e), CHCl3): 329
(shoulder), 441 (3.95), 488 (3.87). 13C-NMR (CDCl3) d: 14.3, 22.1, 41.6,
58.9, 92.2, 113.5, 114.9, 118.1, 124.9, 125.9, 128.3, 128.4, 129.4, 130.7,
132.5, 134.3, 135.0, 137.0, 138.9, 142.4, 150.5, 164.1, 188.1. Anal. Calcd
for C50H40N2O6S4: C, 67.24; H, 4.51; N, 3.14%; Found C, 67.52; H, 4.46; N,
2.87%.
1
measured on a JEOL JNM-GX400 (400 MHz for H and 67.8 MHz for 13C)
in deuteriochloroform solutions. Tetramethylsilane was used as the internal
standard and J values were given in Hz. Elemental analyses were performed
on a Perkin-Elmer 2400 elemental analyzer.
Preparation of 5-Arylcarbonyl-3-(1-pyridinio)-4-(ethoxycarbonyl-
methyl)thiophene-2-thiolates (1a—i) The starting 5-arylcarbonyl-4-
(ethoxycarbonylmethyl)-3-(1-pyridinio)thiophene-2-thiolates 1a—c and 3-
(4-methyl-1-pyridinio)thiophene-2-thiolates 1d—f were prepared according
t
o the procedure described in our previous paper.10) However, the correspond
-
ing 3-(3,5-dimethyl-1-pyridinio)thiophene-2-thiolates (1g—i) could not be
obtained by this procedure. So, we prepared them by the following method.
General Method: A solution of 3,5-lutidine (1.284 g, 12 mmol) and ethyl
4-chloroacetoacetate (1.645 g, 10 mmol) in chloroform (60 ml) was stirred at
room temperature until the disappearance of ethyl 4-chloroacetoacetate was
confirmed by tlc monitoring (5—7 d). To the reaction solution, carbon disul-
fide (1.140 g, 15 mmol), phenacyl bromide (10 mmol), and triethylamine
(2.020 g, 20 mmol) were added under cooling, and the resulting mixture was
then stirred in an ice bath for 12 h. The solution was moved in a separatory
funnel and washed two times with cold water (each 50 ml) to remove triethyl-
amine hydrochloride. After the CHCl3 layer was dried over anhydrous
sodium sulfate, it was concentrated at reduced pressure. Recrystallization of
the residue from ethanol afforded the corresponding 3,5-dimethylpyridinium
betaines 1g—i. Some data for the new compounds 1g—i are shown below.
5-Benzoyl-3-(3,5-dimethyl-1-pyridinio)-4-(ethoxycarbonylmethyl)thio-
phene-2-thiolate (1g): 59%; orange prisms (from ethanol); mp 167—168 °C.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-o-xylene (4e): From 1e and 2a; 38%; red prisms (from
CHCl3); mp 142—143 °C. IR (KBr) cmꢂ1: 1680, 1638. UV–Vis (nm (log e),
CHCl3): 328 (shoulder), 440 (3.98), 495 (3.88). Anal. Calcd for
C50H36Cl2N2O6S4ꢄH2O: C, 61.28; H, 4.11; N, 2.86%; Found C, 61.28; H,
4.16; N, 2.81%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-o-xylene (4f): From 1f and 2a; 28%; red prisms (from
CHCl3); mp 138—139 °C. IR (KBr) cmꢂ1: 1680, 1638. UV–Vis (nm (log e),
CHCl3): 331 (shoulder), 441 (3.95), 496 (3.87). Anal. Calcd for
1
IR (KBr) cmꢂ1: 1715, 1628. H-NMR (CDCl3) d: 1.25 (3H, t, Jꢃ7.1 Hz,
OCH2CH3), 2.59 (6H, s, 3,5-diMe), 3.75 (2H, s, CH2), 4.15 (2H, q, Jꢃ7.1
Hz, OCH2CH3), 7.43 (2H, m, Ph-H), 7.51 (1H, m, Ph-H), 7.83 (2H, m, Ph-
H), 8.04 (1H, br s, 4-H), 8.47 (2H, br s, 2,6-H). Anal. Calcd for
C22H21NO3S2: C, 64.21; H, 5.14; N, 3.40%; Found C, 64.29; H, 5.07; N,
3.36%.
5-(4-Chlorobenzoyl-3-(3,5-dimethyl-1-pyridinio)-4-(ethoxycarbonyl-
methyl)thiophene-2-thiolate (1h): 42%; orange prisms (from ethanol); mp
177—178 °C. IR (KBr) cmꢂ1: 1728, 1624. 1H-NMR (CDCl3) d: 1.25 (3H, t,

December 2009
1389
C50H38Br2N2O6S4: C, 57.14; H, 3.64; N, 2.67%; Found C, 57.41; H, 3.53; N,
2.51%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-m-xylene (6i): From 1i and 2b; 63%; red prisms (from
CHCl3–hexane); mp 111—113 °C. IR (KBr) cmꢂ1: 1709, 1615. UV–Vis
(nm (log e), CHCl3): 335 (shoulder), 518 (4.10). Anal. Calcd for C52H42-
Br2N2O6S4: C, 57.88; H, 3.92; N, 2.60%; Found C, 57.87; H, 4.20; N,
2.34%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonylthieno[3,4-b]indolizin-3-yl)thio]-p-
xylene (8a): From 1a and 2c; 34%; red prisms (from CHCl3–EtOH); mp
207—209 °C. IR (KBr) cmꢂ1: 1678, 1628. UV–Vis (nm (log e), CHCl3): 326
(shoulder), 433 (4.13), 473 (4.03). 13C-NMR (CDCl3) d: 14.4, 44.1, 59.0,
93.3, 110.5, 116.0, 119.8, 124.9, 126.8, 128.2, 129.0, 129.3, 130.1, 132.4,
134.5, 135.8, 136.9, 138.9, 149.7, 163.8, 187.8. Anal. Calcd for C48H36N2-
O6S4ꢄEtOH: C, 65.91; H, 4.65; N, 3.07%; Found C, 65.97; H, 4.78; N,
2.89%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-3-
yl)thio]-p-xylene (8b): From 1b and 2c; 25%; red prisms (from CHCl3); mp
199—201 °C. IR (KBr) cmꢂ1: 1678, 1624. UV–Vis (nm (log e), CHCl3): 328
(shoulder), 434 (4.11), 476 (4.02). Anal. Calcd for C48H34Cl2N2O6S4: C,
61.73; H, 3.67; N, 3.00%; Found C, 61.84; H, 3.62; N, 2.92%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-3-
yl)thio]-p-xylene (8c): From 1c and 2c; 61%; red prisms (from CHCl3); mp
215—216 °C. IR (KBr) cmꢂ1: 1678, 1620. UV–Vis (nm (log e), CHCl3): 327
(shoulder), 435 (4.00), 477 (3.92). Anal. Calcd for C48H34Br2N2O6S4: C,
56.36; H, 3.35; N, 2.74%; Found C, 56.50; H, 3.42; N, 2.61%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-7-methylthieno[3,4-b]indolizin-3-
yl)thio]-p-xylene (8d): From 1d and 2c; 41%; red prisms (from CHCl3); mp
232 °C. IR (KBr) cmꢂ1: 1672, 1622. UV–Vis (nm (log e), CHCl3): 326
(shoulder), 441 (4.17), 475 (shoulder). 13C-NMR (CDCl3) d: 14.3, 22.2,
44.1, 58.9, 92.2, 113.5, 116.0, 118.1, 124.5, 126.1, 128.3, 129.1, 129.4,
132.5, 135.0, 136.0, 136.9, 139.0, 142.4, 150.5, 164.2, 188.1. Anal. Calcd
for C50H40N2O6S4: C, 67.24; H, 4.51; N, 3.14%; Found C, 67.26; H, 4.48; N,
3.15%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-p-xylene (8e): From 1e and 2c; 7%; red prisms (from
CHCl3); mp 251—252 °C. IR (KBr) cmꢂ1: 1663, 1636. UV–Vis (nm (log e),
CHCl3): 328 (shoulder), 439 (4.13), 478 (shoulder). Anal. Calcd for C50H36-
Cl2N2O6S4: C, 62.43; H, 3.98; N, 2.91%; Found C, 61.70; H, 3.86; N,
2.76%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-p-xylene (8f): From 1f and 2c; 10%; red prisms (from
CHCl3); mp 261—263 °C. IR (KBr) cmꢂ1: 1663, 1636. UV–Vis (nm (log e),
CHCl3): 326 (shoulder), 438 (4.15), 478 (shoulder). Anal. Calcd for C50H38-
Br2N2O6S4: C, 57.14; H, 3.64; N, 2.67%; Found C, 57.24; H, 3.62; N,
2.60%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-b]in-
dolizin-3-yl)thio]-p-xylene (8g): From 1g and 2c; 97%; red prisms (from
CHCl3–hexane); mp 206—207 °C. IR (KBr) cmꢂ1: 1712, 1620. UV–Vis
(nm (log e), CHCl3): 333 (shoulder), 441 (3.90), 512 (4.09). 13C-NMR
(CDCl3) d: 14.3, 18.0, 20.6, 44.2, 60.5, 96.4, 117.0, 118.8, 121.6, 121.8,
128.3, 128.4, 129.0, 129.0, 131.8, 132.1, 135.8, 136.1, 136.7, 145.3, 166.0,
186.0 (one carbon is overlapping). Anal. Calcd for C52H44N2O6S4: C, 67.80;
H, 4.81; N, 3.04%; Found C, 68.02; H, 4.82; N, 2.82%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-b]in-
dolizin-3-yl)thio]-o-xylene (4g): From 1g and 2a; 69%; red prisms (from
CHCl3–hexane); mp 206—208 °C. IR (KBr) cmꢂ1: 1703, 1612. UV–Vis
(nm (log e), CHCl3): 332 (shoulder), 439 (shoulder), 522 (4.00). 13C-NMR
(CDCl3) d: 14.3, 17.8, 20.6, 42.0, 60.4, 96.4, 115.8, 118.9, 121.2, 122.4,
128.3, 128.4, 129.0, 130.6, 131.9, 132.2, 134.2, 136.3, 136.7, 139.1, 145.3,
165.9, 186.0 (one carbon is overlapping). Anal. Calcd for C52H44N2O6S4: C,
67.80; H, 4.81; N, 3.04%; Found C, 68.08; H, 4.78; N, 2.80%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-o-xylene (4h): From 1h and 2a; 41%; red prisms
(from CHCl3–hexane); mp 198—199 °C. IR (KBr) cmꢂ1: 1701, 1616. UV–
Vis (nm (log e), CHCl3): 330 (shoulder), 431 (shoulder), 525 (4.07). Anal.
Calcd for C52H42Cl2N2O6S4: C, 63.08; H, 4.28; N, 2.83%; Found C, 63.22;
H, 4.24; N, 2.73%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-o-xylene (4i): From 1i and 2a; 44%; red prisms (from
CHCl3–hexane); mp 196—198 °C. IR (KBr) cmꢂ1: 1701, 1599. UV–Vis
(nm (log e), CHCl3): 335 (shoulder), 436 (shoulder), 528 (4.02). Anal. Calcd
for C52H42Br2N2O6S4: C, 57.88; H, 3.92; N, 2.60%; Found C, 57.85; H, 3.96;
N, 2.60%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonylthieno[3,4-b]indolizin-3-yl)thio]-
m-xylene (6a): From 1a and 2b; 40%; red prisms (from CHCl3); mp 181—
183 °C. IR (KBr) cmꢂ1: 1682, 1615. UV–Vis (nm (log e), CHCl3): 330
(shoulder), 437 (4.07), 474 (4.03). 13C-NMR (CDCl3) d: 14.3, 44.2, 59.0,
93.3, 110.5, 115.8, 119.8, 125.0, 126.8, 128.1, 128.2, 128.9, 129.0, 129.3,
130.1, 132.4, 134.5, 136.6, 137.0, 138.8, 149.7, 163.8, 187.8. Anal. Calcd
for C48H36N2O6S4: C, 66.64; H, 4.19; N, 3.24%; Found C, 66.55; H, 4.18; N,
3.04%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-3-
yl)thio]-m-xylene (6b): From 1b and 2b; 59%; red prisms (from CHCl3); mp
181—182 °C. IR (KBr) cmꢂ1: 1672, 1624. UV–Vis (nm (log e), CHCl3): 329
(shoulder), 438 (4.10), 472 (4.03). Anal. Calcd for C48H34Cl2N2O6S4: C,
61.73; H, 3.67; N, 3.00%; Found C, 61.74; H, 3.69; N, 2.97%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonylthieno[3,4-b]indolizin-3-
yl)thio]-m-xylene (6c): From 1c and 2b; 45%; red prisms (from CHCl3); mp
179—180 °C. IR (KBr) cmꢂ1: 1676, 1624. UV–Vis (nm (log e), CHCl3): 330
(shoulder), 437 (4.10), 475 (4.04). Anal. Calcd for C48H34Br2N2O6S4: C,
56.36; H, 3.35; N, 2.74%; Found C, 56.63; H, 3.26; N, 2.56%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-7-methylthieno[3,4-b]indolizin-3-
yl)thio]-m-xylene (6d): From 1d and 2b; 37%; red prisms (from CHCl3); mp
214—216 °C. IR (KBr) cmꢂ1: 1682, 1615. UV–Vis (nm (log e), CHCl3): 327
(shoulder), 439 (4.12), 475 (shoulder). 13C-NMR (CDCl3) d: 14.3, 22.1,
44.0, 58.8, 92.2, 113.4, 115.8, 118.0, 124.5, 126.2, 128.2, 128.3, 129.0,
129.1, 129.3, 132.4, 135.0, 136.7, 137.0, 139.0, 142.4, 150.5, 164.1, 188.0.
Anal. Calcd for C50H40N2O6S4: C, 67.24; H, 4.51; N, 3.14%; Found C,
67.53; H, 4.40; N, 2.96%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-m-xylene (6e): From 1e and 2b; 36%; red prisms
(from CHCl3); mp 227—228 °C. IR (KBr) cmꢂ1: 1665, 1616. UV–Vis (nm
(log e), CHCl3): 330 (shoulder), 4410 (4.16), 475 (shoulder). Anal. Calcd for
C50H36Cl2N2O6S4: C, 62.43; H, 3.98; N, 2.91%; Found C, 62.68; H, 3.87; N,
2.77%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-p-xylene (8h): From 1h and 2c; 66%; red prisms
(from CHCl3–hexane); mp 240—242 °C. IR (KBr) cmꢂ1: 1701, 1614.
UV–Vis (nm (log e), CHCl3): 334 (shoulder), 436 (shoulder), 516 (4.04).
Anal. Calcd for C52H42Cl2N2O6S4: C, 63.08; H, 4.28; N, 2.83%; Found C,
63.07; H, 4.32; N, 2.80%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-p-xylene (8i): From 1i and 2c; 55%; red prisms (from
CHCl3–hexane); mp 238—240 °C. IR (KBr) cmꢂ1: 1701, 1616. UV–Vis
(nm (log e), CHCl3): 336 (shoulder), 435 (shoulder), 517 (4.00). Anal. Calcd
for C52H42Br2N2O6S4: C, 57.88; H, 3.92; N, 2.60%; Found C, 57.87; H, 3.97;
N, 2.56%.
a,aꢁ-Bis[(1-(4-bromobenzoyl)-9-ethoxycarbonyl-7-methylthieno[3,4-
b]indolizin-3-yl)thio]-m-xylene (6f): From 1f and 2b; 16%; red prisms (from
CHCl3); mp 232—233 °C; IR (KBr) cmꢂ1: 1663, 1613. UV–Vis (nm (log e),
CHCl3): 331 (shoulder), 441 (4.10), 475 (shoulder). Anal. Calcd for
C50H38Br2N2O6S4: C, 57.14; H, 3.64; N, 2.67%; Found C, 57.29; H, 3.52; N,
2.49%.
a,aꢁ-Bis[(1-benzoyl-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-b]in-
dolizin-3-yl)thio]-m-xylene (6g): From 1g and 2b; 80%; red prisms (from
CHCl3–hexane); mp 206—208 °C. IR (KBr) cmꢂ1: 1711, 1620. UV–Vis
(nm (log e), CHCl3): 330 (shoulder), 447 (shoulder), 515 (4.05). 13C- NMR
(CDCl3) d: 14.3, 18.0, 20.6, 44.3, 60.5, 96.4, 107.6, 117.0, 118.7, 121.6,
121.8, 128.3, 128.4, 129.0, 129.0, 131.8, 132.1, 135.8, 136.1, 136.7, 139.3,
145.3, 166.0, 186.0 (one carbon is overlapping). Anal. Calcd for C52H44-
N2O6S4: C, 67.80; H, 4.81; N, 3.04%; Found C, 67.83; H, 4.85; N, 2.98%.
a,aꢁ-Bis[(1-(4-chlorobenzoyl)-9-ethoxycarbonyl-6,8-dimethylthieno[3,4-
b]indolizin-3-yl)thio]-m-xylene (6h): From 1h and 2b; 41%; red prisms
(from CHCl3–hexane); mp 108—111 °C. IR (KBr) cmꢂ1: 1721, 1620. UV–
Vis (nm (log e), CHCl3): 333 (shoulder), 441 (shoulder), 519 (3.99). Anal.
Calcd for C52H42Cl2N2O6S4: C, 63.08; H, 4.28; N, 2.83%; Found C, 63.24;
H, 4.24; N, 2.71%.
Crystallography of a,aꢀ-Bis[(1-(4-benzoyl)-9-ethoxycarbonylthieno[3,4-
b]indolizin-3-yl)thio]-o-xylene (4i) A single crystal (0.20ꢅ0.10ꢅ0.10
mm) grown from CHCl3–hexane was used for the unit-cell determinations
and the data collection by a Rigaku RAXIS RAPID imaging plate area de-
tector with graphite-monochromated CuKa radiation (lꢃ1.54187 Å). Crystal
data of these compounds are as follows: 4i: C52H42Br2N2O6S4; Mꢃ1078.96;
monoclinic, space group C2/c (#15), Zꢃ4 with aꢃ11.5689(2) Å, bꢃ
23.6937(4) Å, cꢃ17.0393(3) Å, bꢃ102.7864° (7); Vꢃ4554.83(14) Å3, and
D
calc.ꢃ1.573 g/cm3. All calculations were performed using CrystalStruc-
ture.17) The structure was solved by a direct method (SIR).18) The non-hydro-

1390
Vol. 57, No. 12
gen atoms were refined anisotropically, and the hydrogen atoms were at- References and Notes
tached at the idealized position and not refined. The final R- and Rw2-factors
after full-matrix least-squares refinements were 0.0496 for (Iꢆ2.00s(I)) and
0.1338 for all observed reflections (4147).
1) For part 66 of this series, see Abe T., Okumura Y., Suga H., Kakehi A.,
Heterocycles, in press.
2) Jones G. B., Tetrahedron, 57, 7999—8016 (2001).
3) Meyer E. A., Castellano R. K., Diederich F., Angew. Chem. Int. Ed.,
42, 1210—1250 (2003).
4) Yamada S., Yuki Gosei Kagaku Kyokaishi, 63, 339—350 (2003).
5) Carroll W. R., Pellechia P., Shimizu K. D., Org. Lett., 10, 3547—3550
(2008).
6) Kishikawa K., Naruse M., Kohmoto S., Yamamoto M., Yamaguchi K.,
J. Chem. Soc., Perkin Trans 1, 2001, 462—468 (2001).
7) Yamada S., Imoue M., Org. Lett., 9, 1477—1480 (2007).
8) Yamada S., Yamamoto J., Ohta E., Tetrahedron Lett., 48, 855—858
(2007).
Crystallography of a,aꢀ-Bis[(1-benzoyl-9-ethoxycarbonylthieno[3,4-
b]indolizin-3-yl)thio]-m-xylene (6a) A single crystal (0.88ꢅ0.42ꢅ1.00
mm) grown from CHCl3–hexane was used for the unit-cell determinations
and the data collection by a Rigaku AFC5S four-circle diffractometer with
graphite-monochromated MoKa radiation (lꢃ0.71069 Å). Crystal data of
these compounds are as follows: 6a: C52H44N2O6S4; Mꢃ921.17; monoclinic,
space group C2/c (#15), Zꢃ4 with aꢃ17.093(13) Å, bꢃ14.05(2) Å, cꢃ
19.623(13) Å, bꢃ102.33(6)°; Vꢃ4602.5 (80) Å3, and Dcalc.ꢃ1.329 g/cm3.
All calculations were performed using CrystalStructure.17) The structure was
solved by a direct method (SIR).18) The non-hydrogen atoms were refined
anisotropically, and the hydrogen atoms were attached at the idealized posi-
tion and not refined. The final R- and Rw-factors after full-matrix least-squares
9) Kakehi A., Ito S., Suga H., Miwa T., Mori T., Kobayashi T., Heterocy-
cles, 57, 17—20 (2002).
refinements were 0.068 and 0.055 respectively for 3152 (Iꢆ2.00s(I)) ob- 10) Kakehi A., Ito S., Suga H., Miwa T., Mori T., Fujii T., Tanaka N.,
served reflections. Kobayashi T., Chem. Pharm. Bull., 51, 75—84 (2003).
Crystallography of a,aꢀ-Bis[(1-benzoyl-9-ethoxycarbonylthieno[3,4- 11) Kakehi A., Suga H., Kako T., Fujii T., Tanaka N., Kobayashi T., Chem.
b]indolizin-3-yl)thio]-p-xylene (8a) A single crystal (0.88ꢅ0.42ꢅ0.18 Pharm. Bull., 51, 1246—1252 (2003).
mm) grown from CHCl3–hexane was used for the unit-cell determinations 12) Kakehi A., Suga H., Kaneko Y., Fujii T., Tanaka N., Chem. Pharm.
and the data collections by Rigaku AFC5S four-circle diffractometer with
graphite-monochromated MoKa radiation (lꢃ0.71069 Å). Crystal data of
8a: C52H44N2O6S4; Mꢃ921.17; triclinic, space group P-1 (#2), Zꢃ2 with aꢃ
Bull., 53, 1430—1238 (2005).
13) Kakehi A., Suga H., Isogai H., Chem. Pharm. Bull., 55, 95—101
(2007).
10.66(3) Å, bꢃ13.32(4) Å, cꢃ9.71(2) Å, aꢃ104.9° (3), bꢃ113.1° (2), gꢃ 14) “WinMOPAC (Version 2.0),” Fujitsu Corporation.
66.7° (2); Vꢃ1155.8(53) Å3, and Dcalc.ꢃ1.323 g/cm3. All calculations were 15) Kakehi A., Ito S., Suga H., Yasuraoka K., Heterocycles, 54, 185—200
performed using the CrystalStructure.17) The structure was solved by a direct
(2001).
method (SIR).18) The non-hydrogen atoms were refined anisotropically, and 16) Johnson C. K., “ORTEO II, Report ORNL-5138,” Oak Ridge National
the hydrogen atoms were attached at the idealized position and not refined. Laboratory, Oak Ridge, Tennessee, 1976.
The final R- and Rw-factors after full-matrix least-squares refinements were 17) “CrystalStructure 3.8,” Crystal Structure Analysis Package, Regaku
0.063 and 0.040 for 2386 (Iꢆ2.00s(I)) observed reflections, respectively.
and Regaku/Molecular Structure Corporation (2000—2005), 9009
New Trails Dr., The Woodlands, TX 77381, U.S.A.
18) Altomare A., Cascarano G., Giacovazzo C., Guagliardi A., J. Appl.
Cryst., 26, 343—350 (1993).