Preparation of new nitrogen-bridged heterocycles. 60. Syntheses and conformational analyses of bis(indolizin-1-yl) disulfides

Article abstract of DOI:10.1248/cpb.55.1458

Some bis(indolizin-1-yl) disulfides, readily obtainable from the treatment of 1-(benzoylthio)indolizines with piperidine, were prepared and their conformations were investigated. In comparison with those of 1-(benzoylthio) indolizines, the ¹H-N

Full text of DOI:10.1248/cpb.55.1458

1458
Chem. Pharm. Bull. 55(10) 1458—1465 (2007)
Vol. 55, No. 10
Preparation of New Nitrogen-Bridged Heterocycles. 60.1) Syntheses and
Conformational Analyses of Bis(indolizin-1-yl) Disulfides
b
Akikazu KAKEHI, ,a Hiroyuki SUGA,a Hiroko OKUNO,a Masaki OKUHARA,a and Akira OHTA
*
a Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University; Wakasato, Nagano
380–8553, Japan: and b Faculty of Science, Shinshu University; 3–1–1 Asahi, Matsumoto 390–8621, Japan.
Received April 29, 2007; accepted July 18, 2007; published online July 25, 2007
Some bis(indolizin-1-yl) disulfides, readily obtainable from the treatment of 1-(benzoylthio)indolizines with
piperidine, were prepared and their conformations were investigated. In comparison with those of 1-(benzoyl-
thio)indolizines, the 1H-NMR spectra of these disulfides showed considerable high field shifts (d 0.13—0.82 ppm)
on each pyridine ring proton and the UV spectra exhibited significant bathochromic and hyperchromic shifts.
These results supported strongly the participation of an intramolecular p–p interaction between the two in-
dolizine rings in these molecules and, hence, of a particular gauche (cis) conformation. However, the conforma-
tional considerations and molecular calculations (Mopac PM3) for some bis(indolizin-1-yl) disulfides showed the
presence of four more stable gauche forms in which two are enantiomeric, resulting in three types of gauche
structures. These three types of gauche structures were confirmed by X-ray analyses.
Key words bis(indolizin-1-yl) disulfide; conformational stability; p–p interaction; gauche form; X-ray analysis
In our preceding papers we described that the conforma- Results and Discussion
tional stability of a sulfide linkage is inherently in the follow-
Conformational Analyses of Some Bis(indolizin-1-yl)
ing order: gauche formꢀanti formꢀeclipse form, irrespec- Disulfides by Molecular Calculations Considering the
tive of the presence of some attractive interaction between molecular structures of bis[2-(R-thio)indolizin-1-yl] disul-
the substituents on the terminal atoms, but the difference in fides (5) (see Chart 2), the 6 most probable conformations
the formation energies of the optimized gauche and anti con- were selected for calculation (Fig. 1): two anti forms A1 and
formation is not large.1,2) This order was also consistent with A2, and 4 gauche forms G1 with an intramolecular p–p in-
our experimental results observed for various 3-(R-thio)- teraction, G2, G3, and G4. Since the gauche forms G3 and
thieno[3,4-b]indolizine derivatives,1—5) and the extra pres- G4 are enantiomeric, however, the Mopac PM3 calcula-
ence of the intramolecular p–p interaction made one of the tions15) were performed for the A1, A2, G1, G2, and G3 of
gauche conformations more predominant than the other Compounds 5a—e, i. The relative formation energy and one
gauche and anti ones in the solution state. These molecules torsion angle (C–S–S–C) in the respective optimized confor-
can be novel candidates for investigating face selectivity or mations using the G3 form as a standard are listed in Table 1.
conformational control through a single bond. As an exten- As expected, all or the majority of the A1 or A2 forms were
sion of this work, we are interested in the conformation about changed to the G1 and G2 or G3 and G4 forms respectively
the disulfide linkage, since we previously found a similar during the optimized calculations. Though some of them
phenomenon in the X-ray analysis of bis[thieno[3,4-b]in- converged in the anti forms, their formation energies were
dolizin-3-yl] disulfide.6) According to the literature there are considerably high. These data suggest clearly that the gauche
several MO calculations in which a preference of the gauche forms (G1, G2, G3, G4) are fairly more stable than the anti
(cis) form over the anti (trans) form in relation to the disul- forms (A1, A2) and, though the energy differences between
fide linkage and an energy minimum in the dihedral angle G1, G2, G3, and G4 are small (below 0.6 kcal/mol), the G3
near 90° have been shown.7,8) Furthermore, some structural
data for comparatively simple disulfides such as dimethyl
disulfide,9,10) dibenzyl disulfide,11) and diphenyl disulfide12,13)
by other investigators were in agreement with this prediction.
However, there have not been many studies on the conforma-
tions of disulfide compounds and a more detailed investiga-
tion of their conformations is still valuable. We selected
bis(indolizin-1-yl) disulfide derivatives as the model com-
pound for the following reasons: 1) an effective method for
the preparation of these compounds has been already devel-
oped by us14); 2) their Mopac PM3 calculations15) supported
the appearance of exclusive or nearly exclusive gauche
forms; and 3) the participation of the intramolecular p–p in-
teraction between the two indolizin-1-yl groups can be ex-
pected. In this paper we report the facile syntheses and the
conformations of some bis(indolizin-1-yl) disulfide deriva-
tives.
Fig. 1. Main Conformations of Bis(indolizin-1-yl) Disulfides for Molecu-
lar Calculations
∗ To whom correspondence should be addressed. e-mail: akakehi@shinshu-u.ac.jp
© 2007 Pharmaceutical Society of Japan

October 2007
1459
Table 1. Relative Energy Differences and the Dihedral Angles of the Disulfide Linkages for Some Bis(indolizin-1-yl) Disulfides by MOPAC (PM3) Calcu-
lations
No.
5a
5b
5c
5d
5e
5i
A1
A2
G1
G2
G3 (G4)a)
5.3883
119.8b)
to G1 or G2
to G3 or G4
to G3 or G4
to G3 or G4
0.5392
76.8b)
0.0322
82.5b)
0 (188.4218)
85.3b)
0.5668
0.2520
0 (180.1620)
76.9b)
78.5b)
85.3b)
2.9647
130.0b)
to G1 or G2
0.5287
77.2b)
0.1744
79.0b)
0 (246.7626)
85.3b)
6.5588
148.3b)
to G3 or G4
0.1227
0.5588
0 (282.3521)
76.2b)
85.3b)
88.3b)
to G1 or G2
to G1 or G2
0.1043
75.1b)
0.5375
79.7b)
0 (ꢁ54.0164)
85.2b)
to G3 or G4
0.1492
0.1864
0 (104.9178)
70.3b)
78.8b)
85.8b)
a) The values (kcal/mol) in the parentheses are those obtained actually from the MOPAC calculations. b) The dihedral angle (°) about the disulfide linkage.
Chart 2
Chart 1
On the other hand, products 4i—l, u—x bearing a 3-benzoyl
or G4 form is the most stable conformation. On the other group exhibited a maximum at a higher region (384—
hand, the calculated torsion angles for the disulfide moiety in 389 nm) and were yellow crystals.
the G1, G2, and G3 forms are in the range of 70.3—85.8°
Syntheses and Their Structures of Bis(indolizin-1-yl)
and these values are slightly lower than those (83.9—96.6°) Disulfide Derivatives The treatment of 1-(benzoylthio)in-
in the MO calculations and structural data described dolizines (4a—x) with piperidine in ethanol at the reflux
above.7—13)
temperature afforded the corresponding bis[2-(R-thio)in-
Syntheses of 1-(Benzoylthio)indolizine Derivatives dolizin-1-yl] disulfides (5a—x) in moderate to good yields
According to the procedure described earlier by us14) these 1- (Chart 2).
benzoylthio-2-(R-thio)indolizine derivatives 4a—x were syn-
The elemental analyses for new products (5a—d, f—l, n—
thesized from the S-alkylation of pyridinium 1-[2-(R-thio)-2- p, r—x) were in good accord with our proposed structures.
thioxo]ethanides (1a—x) with phenacyl bromide (2), fol- Their IR spectra showed an cyano band near 2200 cmꢁ1
lowed by the treatment of the resulting pyridinium salts (5a—d, m—p), an ester carbonyl band at 1674—1688 cmꢁ1
(3a—x) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and (5e—h, q—t), and a benzoyl carbonyl band at 1596—
chloranil in chloroform at 0 °C. These results are summa- 1620 cmꢁ1 (5i—l, u—x). The UV spectra of 5a—h, m—t ex-
rized in Chart 1.
hibited an absorption band at 334—349 nm and those of 5i—
The structures of products 4a—x were determined by their l, u—x showed an absorption band at 393—400 nm. The
1
elemental analyses, IR, UV, and H-NMR spectral analyses bathochromic shifts of each absorption maximum in compar-
and by comparison with those of known compounds (4a, e, i, ison with those of 4a—x were not large (5 nm maximum) but
m, q, u). In particular, the IR spectra of 4a—x showed an un- the end absorption bands were spread largely to a higher re-
saturated carbonyl absorption band at 1663—1686 cmꢁ1, to- gion and, hence, even compounds (5a—h, m—t) having the
gether with an unsaturated cyano band (2199—2213 cmꢁ1) in 3-cyano or 3-ethoxycarbonyl group were pale yellow in
1
4a—d, m—p and a largely shifted carbonyl band (1591— color. In the H-NMR spectra of disulfides 5a—x the 2 sets
1609 cmꢁ1) due to the 3-benzoyl group in 4i—l, u—x. Com- of pyridine ring protons in the molecule completely over-
pounds 4a—h, m—t having a cyano or ethoxycarbonyl lapped each other suggesting the presence of a symmetric
group at the 3-position showed a absorption maximum at factor. In addition, all the pyridine ring protons of 5a—x
330—351 nm in the UV spectra and were colorless crystals. were shifted considerably at higher magnetic regions com-

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Vol. 55, No. 10
pared to those of 1-benzoylthio-2-(R-thio)indolizines (4a, e, analyses of bis(indolizin-1-yl) disulfides 5a, k, n, q showed
i, m, q, u) (see Table 2). These results indicated that the pre- the G2, G4, G1, and G1 forms respectively. Furthermore,
dominant conformation of 5a—x in the solution state must the crystal of the 2-benzylthio derivative (5k) had a gauche
be the G1 form with a C2 symmetry in which the intramolec- and an anti sulfide linkage and did not have any symmetric
ular p–p interaction is possible. Unexpectedly, the X-ray structure. The dihedral angles for the disulfide moiety in
5a, k, n, q are 68.4(2)°, 69.6(3)°, 96.4(2)°, and 68.4(5)° re-
spectively, and the values for 5a, k, q are significantly smaller
than those (78.5—85.3, 85.2—85.8, and 70.3—77.2°) calcu-
lated for G2, G4, and G1 respectively (see Table 1). The
larger angle (96.4(2)°) for 5n (G1 form) must be attributable
to the steric interaction between the two ethylthio moieties
facing inward. The ORTEP drawings16) of compounds (5a, k,
n, q) are shown in Figs. 2—5. From these results we could
deduce the predominance of the gauche forms over the anti
forms in our model compounds and a particular gauche form
(G1) having an intramolecular p–p interaction between the
two indolizine rings is the most stable conformation in the
solution state. However, the difference in the conformational
stability between the gauche forms is not so large and even
though such attractive interaction worked only on the G1
form, the other gauche forms (G2, and G3 or G4) also ap-
peared in the crystalline state.
Table 2. 1H-NMR Spectral Data for the Pyridine Ring Protons of Bis(in-
dolizin-1-yl) Disulfides (5a—x)
No.
C-5
C-6
C-7
C-8
dC-5 dC-6 dC-7 dC-8
4a
8.29
6.94
7.17
7.47
0.00
0.00
0.00
0.00
5a
5b
5c
5d
8.11
8.13
8.03
8.02
6.80
6.81
6.73
6.74
6.94
6.94
6.80
6.87
7.01
7.02
6.80
6.95
0.18
0.16
0.26
0.27
0.14
0.13
0.21
0.20
0.23
0.23
0.37
0.30
0.46
0.45
0.67
0.52
4e
9.55
6.90
7.15
7.51
0.00
0.00
0.00
0.00
5e
5f
6g
5h
9.29
9.30
9.29
9.28
6.65
6.66
6.66
6.66
6.73
6.71
6.72
6.74
6.90
6.91
6.89
6.93
0.26
0.25
0.26
0.27
0.25
0.24
0.24
0.24
0.42
0.44
0.43
0.41
0.61
0.60
0.62
0.58
In conclusion, we synthesized some bis[2-(R-thio)in-
dolizin-1-yl] disulfides and could confirm that the gauche
conformations predominate over the anti ones and also that
the p–p interaction is the main factor for the G1 conforma-
tion in the solution state.
4i
9.47
6.93
7.22
7.52
0.00
0.00
0.00
0.00
5i
9.28
9.29
9.25
9.24
6.79
6.79
6.78
6.80
6.97
6.98
6.98
7.01
7.18
7.21
7.23
7.15
0.19
0.18
0.22
0.23
0.14
0.14
0.15
0.13
0.25
0.24
0.24
0.21
0.34
0.31
0.29
0.37
5j
5k
5l
Experimental
4m
8.15
6.76
2.37
7.22
0.00
0.00
0.00
0.00
Melting points were measured with a Yanagimoto micromelting point ap-
paratus and were not corrected. Microanalyses were carried out on a Perkin-
Elmer 2400 elemental analyzer. The 1H-NMR spectra were determined with
a Hitachi R-600 spectrometer (60 MHz) or a JEOL JNM-LA400 (1H:
400 MHz) spectrometer in deuteriochloroform with tetramethylsilane used
as the internal standard; the chemical shifts are expressed in d values. The
IR and UV spectra were taken with JASCO FT/IR-5300 IR and SHI-
MADZU UV-2450 spectrophotometers, respectively.
5m
5n
5o
7.96
7.98
7.88
7.90
6.61
6.62
6.52
6.56
2.22
2.21
2.07
2.16
6.63
6.64
6.40
6.62
0.19
0.17
0.27
0.25
0.15
0.14
0.24
0.20
0.15
0.16
0.30
0.21
0.59
0.58
0.82
0.60
5p
4q
9.43
6.73
2.36
7.26
0.00
0.00
0.00
0.00
Preparation of Pyridinium 1-[2-(R-thio)-2-thioxo]ethanides These
pyridinium methylides were prepared according to the procedure described
by Tominaga et al.17) The results and some properties of new pyridinium
methylides (1b—d, f—h, j—l, n—p, r—t, v—x) are as follows:
Pyridinium 1-(1-Cyano-2-ethylthio-2-thioxo)ethanides (1b): 64% (from
1-(cyanomethyl)pyridinium chloride, carbon disulfide, and diethyl sulfate),
5q
5r
5s
5t
9.14
9.15
9.14
9.15
6.44
6.44
6.44
6.46
2.03
2.02
1.99
2.03
6.50
6.49
6.45
6.55
0.29
0.28
0.29
0.28
0.29
0.29
0.29
0.27
0.33
0.34
0.37
0.33
0.76
0.77
0.81
0.71
4u
9.42
6.78
2.39
7.28
0.00
0.00
0.00
0.00
pale yellow needles (from CHCl3–ether), mp 120—122 °C. IR (KBr) cmꢁ1
:
2170. 1H-NMR (60 MHz) d: 1.36 (3H, t, Jꢂ7.0 Hz), 3.38 (2H, q, Jꢂ7.0 Hz),
7.88 (2H, br t, Jꢂ7.0 Hz, 3-, 5-H), 8.26 (1H, br t, Jꢂ7.0 Hz, 4-H), 9.07 (2H,
br d, Jꢂ7.0 Hz, 2-, 6-H). Anal. Calcd for C10H10N2S2: C, 54.02; H, 4.53; N,
12.60. Found: C, 54.06; H, 4.52; N, 12.58.
5u
5v
5w
5x
9.24
9.26
9.19
9.20
6.59
6.60
6.57
6.62
2.16
2.16
2.11
2.18
6.78
6.80
6.76
6.91
0.18
0.16
0.23
0.22
0.19
0.18
0.21
0.16
0.23
0.23
0.28
0.21
0.50
0.48
0.52
0.37
Pyridinium 1-(2-Benzylthio-1-cyano-2-thioxo)ethanides (1c): 70% (from
1-(cyanomethyl)pyridinium chloride, carbon disulfide, and benzyl bromide),
The coupling constants are as follows:
7,8ꢂ8.8—9.0 Hz, J6,8ꢂ1.5—2.0 Hz.
J5,6ꢂ6.8—7.2 Hz, J6,7ꢂ6.8—7.2 Hz,
pale yellow needles (from CHCl3–ether), mp 151—156 °C. IR (KBr) cmꢁ1
:
J
Fig. 2. ORTEP Drawings of Bis[3-cyano-2-(methylthio)indolizin-1-yl] Disulfide (5a)

October 2007
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Fig. 3. ORTEP Drawings of Bis[3-benzoyl-2-(benzylthio)indolizin-1-yl] Disulfides (5k)
Fig. 4. ORTEP Drawings of Bis[3-cyano-2-(ethylthio)indolizin-1-yl] Disulfides (5n)
52% (from 1-(ethoxycarbonylmethyl)pyridinium chloride, carbon disulfide,
and benzyl bromide), pale yellow needles (from CHCl3–ether), mp 171—
173 °C. IR (KBr) cmꢁ1: 1658. 1H-NMR (60 MHz) d: 1.12 (3H, t, Jꢂ7.0 Hz),
4.11 (2H, q, Jꢂ7.0 Hz), 4.59 (2H, s), 6.9—7.5 (5H, m), 7.79 (2H, br t,
Jꢂ7.0 Hz), 8.27 (1H, br t, Jꢂ7.0 Hz), 8.48 (2H, br d, Jꢂ7.0 Hz). Anal. Calcd
for C17H17NO2S2: C, 61.60; H, 5.17; N, 4.23. Found: C, 61.80; H, 5.15; N,
4.05.
Pyridinium 1-[1-Ethoxycarbonyl-2-(1-naphthylmethylthio)-2-thioxo]-
ethanides (1h): 54% (from 1-(ethoxycarbonylmethyl)pyridinium chloride,
carbon disulfide, and 1-(chloromethyl)naphthalene), pale yellow needles
1
(from CHCl3), mp 203—205 °C. IR (KBr) cmꢁ1: 1657. H-NMR (60 MHz)
d: 1.07 (3H, t, Jꢂ7.0 Hz), 4.09 (2H, q, Jꢂ7.0 Hz), 4.84 (2H, s), 7.0—8.4
(10H, m), 8.53 (2H, br d, Jꢂ7.0 Hz). Anal. Calcd for C21H19NO2S2: C,
66.11; H, 5.02; N, 3.67. Found: C, 66.28; H, 5.03; N, 3.47.
Fig. 5. ORTEP Drawings of Bis[3-ethoxycarbonyl-2-(methylthio)in-
dolizin-1-yl] Disulfides (5q)
Pyridinium 1-(1-Benzoyl-2-ethylthio-2-thioxo)ethanides (1j): 60% (from
1-phenacylpyridinium chloride, carbon disulfide, and diethyl sulfate), pale
yellow needles (from CHCl3–ether), mp 205—208 °C. IR (KBr) cmꢁ1: 1622.
1H-NMR (60 MHz) d: 1.31 (3H, t, Jꢂ7.0 Hz), 3.26 (2H, q, Jꢂ7.0 Hz), 7.27
(5H, s, COPh), 7.73 (2H, br t, Jꢂ7.0 Hz), 8.23 (1H, br t, Jꢂ7.0 Hz), 8.53
(2H, br d, Jꢂ7.0 Hz). Anal. Calcd for C16H15NOS2: C, 63.76; H, 5.02; N,
4.65. Found: C, 64.06; H, 5.02; N, 4.36.
2179. 1H-NMR (60 MHz) d: 4.65 (2H, s, SCH2), 7.0—7.5 (5H, m), 7.82
(2H, br t, Jꢂ7.0 Hz), 8.21 (1H, br t, Jꢂ7.0 Hz), 9.03 (2H, br d, Jꢂ7.0 Hz).
Anal. Calcd for C15H12N2S2: C, 63.35; H, 4.25; N, 9.85. Found: C, 63.49; H,
4.25; N, 9.68.
Pyridinium 1-[1-Cyano-2-(1-naphthylmethylthio)-2-thioxo]ethanides
(1d): 77% (from 1-(cyanomethyl)pyridinium chloride, carbon disulfide, and
1-(chloromethyl)naphthalene), pale yellow needles (from CHCl3), mp 132—
Pyridinium 1-(1-Benzoyl-2-benzylthio-2-thioxo)ethanides (1k): 56%
(from 1-phenacylpyridinium chloride, carbon disulfide, and benzyl bro-
mide), pale yellow needles (from CHCl3–ether), mp 198—200 °C. IR (KBr)
1
136 °C. IR (KBr) cmꢁ1: 2172. H-NMR (60 MHz) d: 5.10 (2H, s, SCH2),
1
cmꢁ1: 1622. H-NMR (60 MHz) d: 4.53 (2H, s, SCH2), 7.26 (10H, s), 7.73
7.1—8.4 (10H, m), 8.89 (2H, br d, Jꢂ7.0 Hz). Anal. Calcd for C19H14N2S2:
C, 68.23; H, 4.22; N, 8.58. Found: C, 68.44; H, 4.24; N, 8.35.
(2H, br t, Jꢂ7.0 Hz), 8.22 (1H, br t, Jꢂ7.0 Hz), 8.56 (2H, br d, Jꢂ7.0 Hz).
Anal. Calcd for C21H17NOS2: C, 69.39; H, 4.71; N, 3.85. Found: C, 69.60;
H, 4.81; N, 3.54.
Pyridinium 1-(1-Ethoxycarbonyl-2-ethylthio-2-thioxo)ethanides (1f): 50%
(from 1-(ethoxycarbonylmethyl)pyridinium chloride, carbon disulfide, and
diethyl sulfate), pale yellow needles (from CHCl3–ether), mp 180—181 °C.
Pyridinium 1-[1-Benzoyl-2-(1-naphthylmethylthio)-2-thioxo]ethanides
(1l): 68% (from 1-phenacylpyridinium chloride, carbon disulfide, and 1-
(chloromethyl)naphthalene), pale yellow needles (from CHCl3), mp 222—
1
IR (KBr) cmꢁ1: 1655. H-NMR (60 MHz) d: 1.17 (3H, t, Jꢂ7.0 Hz), 1.34
(3H, t, Jꢂ7.0 Hz), 3.31 (2H, q, Jꢂ7.0 Hz), 4.16 (2H, q, Jꢂ7.0 Hz), 7.87
(2H, br t, Jꢂ7.0 Hz), 8.23 (1H, br t, Jꢂ7.0 Hz), 8.51 (2H, br d, Jꢂ7.0 Hz).
Anal. Calcd for C12H15NO2S2: C, 53.51; H, 5.61; N, 5.20. Found: C, 53.77;
H, 5.69; N, 4.92.
1
225 °C. IR (KBr) cmꢁ1: 1620. H-NMR (60 MHz) d: 4.84 (2H, s, SCH2),
7.0—8.5 (15H, m), 8.59 (2H, br d, Jꢂ7.0 Hz). Anal. Calcd for C25H19NOS2:
C, 72.61; H, 4.63; N, 3.39. Found: C, 72.79; H, 4.64; N, 3.19.
4-Methylpyridinium 1-(1-Cyano-2-ethylthio-2-thioxo)ethanides (1n): 71%
Pyridinium 1-(2-Benzylthio-1-ethoxycarbonyl-2-thioxo)ethanides (1g):

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Vol. 55, No. 10
(from 1-cyanomethyl-4-methylpyridinium chloride, carbon disulfide, and di- that temperature and stirred for a further 4 h. The solution was concentrated
ethyl sulfate), pale yellow needles (from CHCl3–ether), mp 129—130 °C. IR
at reduced pressure and the residual oil was separated by column chromatog-
raphy on alumina using chloroform as an eluent. The collected fraction of 1-
(KBr) cmꢁ1: 2164. 1H-NMR (60 MHz) d: 1.36 (3H, t, Jꢂ7.0 Hz), 2.67 (3H,
s, 4-Me), 3.36 (2H, q, Jꢂ7.0 Hz), 7.66 (2H, br d, Jꢂ7.0 Hz), 8.79 (2H, br d, (benzoylthio)indolizine was concentrated at reduced pressure, and recrystal-
Jꢂ7.0 Hz). Anal. Calcd for C11H12N2S2: C, 55.90; H, 5.12; N, 11.85. Found: lization from ethanol gave the pure products (4a—x). Some data for the new
C, 55.95; H, 5.12; N, 11.80.
compounds (4b—d, f—l, n—p, r—x) are as follows:
4-Methylpyridinium 1-(2-Benzylthio-1-cyano-2-thioxo)ethanides (1o):
1-Benzoylthio-2-(ethylthio)indolizine-3-carbonitrile (4b): From 1b and
71% (from 1-cyanomethyl-4-methylpyridinium chloride, carbon disulfide, phenacyl bromide (2), colorless needles (from ethanol), mp 128—129 °C. IR
and benzyl bromide), pale yellow needles (from CHCl3–ether), mp 160—
(KBr) cmꢁ1: 1676, 2209. 1H-NMR (60 MHz) d: 1.29 (3H, t, Jꢂ7.0 Hz), 3.07
166 °C. IR (KBr) cmꢁ1: 2173. 1H-NMR (60 MHz) d: 2.59 (3H, s), 4.64 (2H, (2H, q, Jꢂ7.0 Hz), 7.0—8.3 (6H, m, 8-H, COPh), 6.93 (1H, dt, Jꢂ7.0, 7.0,
s), 7.0—7.6 (5H, m), 7.60 (2H, br d, Jꢂ7.0 Hz), 8.72 (2H, br d, Jꢂ7.0 Hz). 1.0 Hz, 6-H), 7.18 (1H, q, Jꢂ9.0, 7.0 Hz, 7-H), 8.29 (1H, d, Jꢂ7.0 Hz, 5-H).
Anal. Calcd for C16H14N2S2: C, 64.40; H, 4.73; N, 9.39. Found: C, 64.44; H, UV lmax (CHCl3) nm (log e): 259 (4.51), 330 (3.95). Anal. Calcd for
4.72; N, 9.37.
C18H14N2OS2: C, 63.88; H, 4.17; N, 8.28. Found: C, 63.90; H, 4.05; N, 8.38.
4-Methylpyridinium 1-[1-Cyano-2-(1-naphthylmethylthio)-2-thioxo)-
1-Benzoylthio-2-(benzylthio)indolizine-3-carbonitrile (4c): From 1c and
ethanides (1p): 63% (from 1-cyanomethyl-4-methylpyridinium chloride, car- 2, colorless needles (from ethanol), mp 142—145 °C. IR (KBr) cmꢁ1: 1676,
1
bon disulfide, and 1-(chloromethyl)naphthalene), pale yellow needles (from 2199. H-NMR (60 MHz) d: 4.16 (2H, s, SCH2), 6.89 (1H, dt, Jꢂ7.0, 7.0,
CHCl3), mp 185—187 °C. IR (KBr) cmꢁ1: 2166. 1H-NMR (60 MHz) d: 2.57 1.0 Hz), 7.0—8.2 (6H, m), 7.23 (5H, s), 7.45 (1H, d, Jꢂ9.0 Hz), 8.23 (1H, d,
(3H, s), 5.09 (2H, s), 7.0—8.0 (9H, m), 8.75 (2H, br d, Jꢂ7.0 Hz). Anal.
Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 261 (shoulder), 330 (3.88). Anal.
Calcd for C20H16N2S2: C, 68.93; H, 4.63; N, 8.04. Found: C, 68.76; H, 4.85; Calcd for C23H16N2OS2: C, 68.97; H, 4.03; N, 6.99. Found: C, 68.84; H,
N, 8.00.
4-Methylpyridinium 1-(1-Ethoxycarbonyl-2-ethylthio-2-thioxo)ethanides
3.90; N, 7.26.
1-Benzoylthio-2-(1-naphthylmethylthio)indolizine-3-carbonitrile (4d):
(1r): 50% (from 1-ethoxycarbonylmethyl-4-methylpyridinium chloride, car- From 1d and 2, colorless needles (from ethanol), mp 166—167 °C. IR (KBr)
bon disulfide, and diethyl sulfate), pale yellow needles (from CHCl3–ether), cmꢁ1: 1672, 2207. 1H-NMR (60 MHz) d: 4.62 (2H, s), 6.90 (1H, dt, Jꢂ7.0,
1
mp 185—188 °C. IR (KBr) cmꢁ1: 1615. H-NMR (60 MHz) d: 1.16 (3H, t, 7.0, 1.0 Hz), 7.0—8.2 (12H, m), 7.14 (1H, br q, Jꢂ9.0, 7.0 Hz), 8.22 (1H, d,
Jꢂ7.0 Hz), 1.35 (3H, t, Jꢂ7.0 Hz), 2.67 (3H, s), 3.30 (2H, q, Jꢂ7.0 Hz), Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 258 (4.50), 333 (shoulder). Anal.
4.15 (2H, q, Jꢂ7.0 Hz), 7.63 (2H, br d, Jꢂ7.0 Hz), 8.32 (2H, br d, Calcd for C27H18N2OS2: C, 71.97; H, 4.03; N, 6.22. Found: C, 71.89; H,
Jꢂ7.0 Hz). Anal. Calcd for C13H17NO2S2: C, 55.10; H, 6.05; N, 4.94. Found: 4.04; N, 6.01.
C, 55.33; H, 6.16; N, 4.65.
Ethyl 1-Benzoylthio-2-(ethylthio)indolizine-3-carboxylate (4f): From 1f
4-Methylpyridinium 1-(2-Benzylthio-1-ethoxycarbonyl-2-thioxo)- and 2, colorless needles (from ethanol), mp 100—102 °C. IR (KBr) cmꢁ1
:
ethanides (1s): 45% (from 1-ethoxycarbonylmethyl-4-methylpyridinium 1682. 1H-NMR (60 MHz) d: 1.18 (3H, t, Jꢂ7.0 Hz), 1.47 (3H, t, Jꢂ7.0 Hz),
chloride, carbon disulfide, and benzyl bromide), pale yellow needles (from 2.96 (2H, q, Jꢂ7.0 Hz), 4.48 (2H, q, Jꢂ7.0 Hz), 6.90 (1H, dt, Jꢂ7.0, 7.0,
CHCl3–ether), mp 182—183 °C. IR (KBr) cmꢁ1: 1661. H-NMR (60 MHz) 1.0 Hz), 7.0—8.3 (6H, m), 7.14 (1H, br q, Jꢂ9.0, 7.0 Hz), 9.55 (1H, d,
1
d: 1.14 (3H, t, Jꢂ7.0 Hz), 2.66 (3H, s), 4.12 (2H, q, Jꢂ7.0 Hz), 4.57 (2H, s),
7.0—7.5 (5H, m), 7.60 (2H, br d, Jꢂ7.0 Hz), 8.33 (1H, br d, Jꢂ7.0 Hz).
Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 263 (4.45), 339 (4.04), 350 (4.03).
Anal. Calcd for C20H19NO3S2: C, 62.31; H, 4.97; N, 3.63. Found: C, 62.11;
Anal. Calcd for C18H19NO2S2: C, 62.58; H, 5.54; N, 4.05. Found: C, 62.39; H, 5.06; N, 3.75.
H, 5.55; N, 3.78.
Ethyl 1-Benzoylthio-2-(benzylthio)indolizine-3-carboxylate (4g): From
4-Methylpyridinium 1-(1-Ethoxycarbonyl-2-(1-naphthylmethylthio)-2- 1g and 2, colorless needles (from ethanol), mp 96—97 °C. IR (KBr) cmꢁ1
:
thioxo)ethanides (1t): 40% (from 1-ethoxycarbonylmethyl-4-methylpyri- 1671. 1H-NMR (60 MHz) d: 1.46 (3H, t, Jꢂ7.0 Hz), 4.43 (2H, q, Jꢂ7.0 Hz),
dinium chloride, carbon disulfide, and 1-(chloromethyl)naphthalene), pale
4.12 (2H, s), 6.88 (1H, dt, Jꢂ7.0, 7.0, 1.0 Hz), 7.0—8.3 (12H, m), 9.54 (1H,
d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 262 (shoulder), 340 (4.06). Anal.
yellow needles (from CHCl3), mp 188—191 °C. IR (KBr) cmꢁ1: 1658. H-
1
NMR (60 MHz) d: 1.14 (3H, t, Jꢂ7.0 Hz), 2.64 (3H, s), 4.11 (2H, q, Calcd for C25H21NO3S2: C, 67.09; H, 4.73; N, 3.13. Found: C, 67.09; H,
Jꢂ7.0 Hz), 4.55 (2H, s), 7.0—7.6 (7H, m), 7.58 (2H, br d, Jꢂ7.0 Hz). 8.32
(2H, br d, Jꢂ7.0 Hz). Anal. Calcd for C22H21NO2S2: C, 66.80; H, 5.35; N,
3.54. Found: C, 66.77; H, 5.53; N, 3.40.
4.80; N, 3.11.
Ethyl 1-Benzoylthio-2-(1-naphthylmethylthio)indolizine-3-carboxylate
(4h): From 1h and 2, colorless needles (from ethanol), mp 174—177 °C. IR
(KBr) cmꢁ1: 1678. 1H-NMR (60 MHz) d: 1.34 (3H, t, Jꢂ7.0 Hz), 4.28 (2H,
4-Methylpyridinium 1-(1-Benzoyl-2-ethylthio-2-thioxo)ethanides (1v):
59% (from 4-methyl-1-phenacylpyridinium chloride, carbon disulfide, and q, Jꢂ7.0 Hz), 4.55 (2H, s), 6.89 (1H, dt, Jꢂ7.0, 7.0, 1.0 Hz), 7.0—8.4 (14H,
diethyl sulfate), pale yellow needles (from CHCl3–ether), mp 190—194 °C.
m), 9.54 (1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 261 (shoulder),
340 (4.02). Anal. Calcd for C29H23NO3S2: C, 72.32; H, 4.81; N, 2.91. Found:
C, 72.41; H, 4.74; N, 2.89.
3-Benzoyl-1-benzoylthio-2-(methylthio)indolizine (4i): From 1i and 2,
yellow needles (from ethanol), mp 113—116 °C. IR (KBr) cmꢁ1: 1622,
1678. 1H-NMR (60 MHz) d: 2.12 (3H, s), 6.93 (1H, dt, Jꢂ7.0, 7.0, 1.0 Hz),
1
IR (KBr) cmꢁ1: 1633. H-NMR (60 MHz) d: 1.31 (3H, t, Jꢂ7.0 Hz), 2.56
(3H, s), 3.26 (2H, q, Jꢂ7.0 Hz), 7.1—7.4 (5H, m), 7.49 (2H, br d,
Jꢂ7.0 Hz), 8.32 (1H, br d, Jꢂ7.0 Hz). Anal. Calcd for C17H17NOS2: C,
64.73; H, 5.43; N, 4.44. Found: C, 64.87; H, 5.45; N, 4.27.
4-Methylpyridinium 1-(1-Benzoyl-2-benzylthio-2-thioxo)ethanides (1w):
70% (from 4-methyl-1-phenacylpyridinium chloride, carbon disulfide, and 7.0—8.2 (10H, m), 7.22 (1H, br q, Jꢂ9.0, 7.0 Hz), 7.52 (1H, d, Jꢂ9.0 Hz),
benzyl bromide), pale yellow needles (from CHCl3–ether), mp 176—177 °C.
IR (KBr) cmꢁ1: 1630. 1H-NMR (60 MHz) d: 2.55 (3H, s), 4.59 (2H, s),
7.0—7.5 (10H, m), 7.49 (2H, br d, Jꢂ7.0 Hz), 8.37 (1H, br d, Jꢂ7.0 Hz).
Anal. Calcd for C22H19NOS2: C, 69.99; H, 5.07; N, 3.71. Found: C, 70.27;
H, 5.19; N, 3.39.
9.47 (1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 320 (3.89), 384 (4.08).
Anal. Calcd for C23H17NO2S2: C, 68.46; H, 4.25; N, 3.47. Found: C, 68.48;
H, 4.17; N, 3.53.
3-Benzoyl-1-benzoylthio-2-(ethylthio)indolizine (4j): From 1j and 2, yel-
low needles (from ethanol), mp 113—116 °C. IR (KBr) cmꢁ1: 1609, 1663.
4-Methylpyridinium 1-[1-Benzoyl-2-(1-naphthylmethylthio)-2-thioxo)- 1H-NMR (60 MHz) d: 0.90 (3H, t, Jꢂ7.0 Hz), 2.55 (2H, q, Jꢂ7.0 Hz), 6.90
ethanides (1x): 88% (from 4-methyl-1-phenacylpyridinium chloride, carbon (1H, dt, Jꢂ7.0, 7.0, 1.0 Hz), 7.0—8.3 (12H, m), 9.47 (1H, d, Jꢂ7.0 Hz). UV
disulfide, and 1-(chloromethyl)naphthalene), pale yellow needles (from lmax (CHCl3) nm (log e): 262 (shoulder), 284 (shoulder), 323 (3.86), 384
CHCl3), mp 208—211 °C. IR (KBr) cmꢁ1: 1633. 1H-NMR (60 MHz) d: 2.62 (4.08). Anal. Calcd for C24H19NO2S2: C, 69.04; H, 4.59; N, 3.35. Found: C,
(3H, s), 5.00 (2H, s), 7.0—8.2 (14H, m), 8.38 (2H, br d, Jꢂ7.0 Hz). Anal.
Calcd for C26H21NOS2: C, 73.04; H, 4.95; N, 3.28. Found: C, 73.36; H, 4.88;
N, 3.03.
Preparation of 1-(Benzoylthio)indolizine Derivatives. General 1686. H-NMR (60 MHz) d: 3.69 (2H, s), 6.6—8.3 (16H, m), 6.93 (1H, dt,
Method A mixture of pyridinium 1-[R-thio(thiocarbonyl)]methylide (1,
69.29; H, 4.42; N, 3.27.
3-Benzoyl-1-benzoylthio-2-(benzylthio)indolizine (4k): From 1k and 2,
yellow needles (from ethanol), mp 117—118 °C. IR (KBr) cmꢁ1: 1591,
1
Jꢂ7.0, 7.0, 1.0 Hz), 7.22 (1H, br q, Jꢂ9.0, 7.0 Hz), 9.41 (1H, d, Jꢂ7.0 Hz).
2 mmol) and phenacyl bromide (2, 0.420 g, 2.1 mmol) was dissolved in chlo- UV lmax (CHCl3) nm (log e): 286 (shoulder), 385 (4.09). Anal. Calcd for
roform (15 ml) and the resulting solution was kept at room temperature for C29H21NO2S2: C, 72.63; H, 4.41; N, 2.92. Found: C, 72.58; H, 4.66; N, 2.72.
2 h. The solution was concentrated at reduced pressure and the residue was
3-Benzoyl-1-benzoylthio-2-(1-naphthylmethylthio)indolizine (4l): From
washed 3 times with ether to remove unaltered phenacyl bromide. Pyri- 1l and 2, yellow needles (from ethanol), mp 163—165 °C. IR (KBr) cmꢁ1
:
1
dinium salt was then dissolved in chloroform (30 ml) and allowed to react 1607, 1669. H-NMR (60 MHz) d: 4.10 (2H, s, SCH2), 6.7—8.3 (19H, m),
with DBU (0.302 g, 2 mmol) under stirring in an ice bath for 5 min. Chlo-
7.23 (5H, s), 6.93 (1H, dt, Jꢂ7.0, 7.0, 1.0 Hz), 9.40 (1H, d, Jꢂ7.0 Hz). UV
ranil (0.500 g, 2 mmol) was then added to the resulting reaction mixture at lmax (CHCl3) nm (log e): 288 (shoulder), 385 (4.05). Anal. Calcd for

October 2007
1463
C33H23NO2S2: C, 74.83; H, 4.38; N, 2.64. Found: C, 74.89; H, 4.45; N, 2.52.
cooled in a refrigerator for 12 h and the precipitates which separated were
1-Benzoylthio-2-ethylthio-7-methylindolizine-3-carbonitrile (4n): From collected by suction. Recrystallization from ethanol afforded the correspon-
1n and 2, colorless needles (from ethanol), mp 152—154 °C. IR (KBr)
ding bis(indolizin-1-yl) disulfides as pale yellow needles or prisms. The
chemical shifts for the protons and the methyl protons on the pyridine ring in
1
cmꢁ1: 1674, 2205. H-NMR (60 MHz) d: 1.28 (3H, t, Jꢂ7.0 Hz), 2.37 (3H,
s, 7-Me), 3.05 (2H, q, Jꢂ7.0 Hz), 6.76 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.0—8.2 the 1H-NMR spectra were listed in the Table 1. The results and other data of
(5H, m), 7.23 (1H, br s), 8.14 (1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm 5a—x are as follows:
(log e): 259 (4.52), 330 (4.01). Anal. Calcd for C19H16N2OS2: C, 64.75; H,
4.58; N, 7.95. Found: C, 64.48; H, 4.73; N, 7.87.
Bis[3-cyano-2-(methylthio)indolizin-1-yl] Disulfide (5a)9): 1H-NMR
(400 MHz) d: 2.63 (3H, s, SMe). UV lmax (CHCl3) nm (log e): 276 (4.59),
1-Benzoylthio-2-benzylthio-7-methylindolizine-3-carbonitrile (4o): From 334 (4.26), 374 (shoulder).
1o and 2, colorless needles (from ethanol), mp 131—132 °C. IR (KBr)
Bis[3-cyano-2-(ethylthio)indolizin-1-yl] Disulfide (5b): From 4b, pale
1
1
cmꢁ1: 1676, 2213. H-NMR (60 MHz) d: 2.37 (3H, s), 4.15 (2H, s), 6.75 yellow needles (from ethanol), mp 118—120 °C. IR (KBr) cmꢁ1: 2201. H-
(1H, dd, Jꢂ7.0, 1.0 Hz), 7.0—8.2 (6H, m), 7.15 (5H, s), 8.12 (1H, d, NMR (400 MHz) d: 1.28 (3H, t, Jꢂ7.6 Hz), 3.10 (2H, q, Jꢂ7.6 Hz). UV
Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 262 (shoulder), 330 (4.05). Anal.
lmax (CHCl3) nm (log e): 279 (4.55), 335 (4.15), 374 (shoulder). Anal. Calcd
Calcd for C24H18N2OS2: C, 69.54; H, 4.38; N, 6.76. Found: C, 69.64; H, for C22H8N4S4: C, 56.62; H, 3.89; N, 12.01. Found: C, 56.94; H, 3.84; N,
4.43; N, 6.59.
11.73.
1-Benzoylthio-7-methyl-2-(1-naphthylmethylthio)indolizine-3-carboni-
trile (4p): From 1p and 2, colorless needles (from ethanol), mp 198—
Bis(2-benzylthio-3-cyanoindolizin-1-yl) Disulfide (5c): From 4c, pale yel-
low needles (from ethanol), mp 176—177 °C. IR (KBr) cmꢁ1: 2199. 1H-
1
201 °C. IR (KBr) cmꢁ1: 1674, 2206. H-NMR (60 MHz) d: 2.37 (3H, s),
NMR (400 MHz) d: 4.26 (2H, s), 7.17—7.32 (5H, m). UV lmax (CHCl3) nm
4.61 (2H, s), 6.76 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.1—8.3 (13H, m), 8.14 (1H, d, (log e): 280 (4.52), 335 (4.18). Anal. Calcd for C32H22N4S4: C, 65.75; H,
Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 260 (shoulder), 333 (3.98). Anal.
Calcd for C28H20N2OS2: C, 72.39; H, 4.34; N, 6.03. Found: C, 72.65; H,
4.19; N, 5.91.
Ethyl 1-Benzoylthio-2-ethylthio-7-methylindolizine-3-carboxylate (4r):
From 1r and 2, colorless needles (from ethanol), mp 115—116 °C. IR (KBr)
cmꢁ1: 1672. 1H-NMR (60 MHz) d: 1.18 (3H, t, Jꢂ7.0 Hz), 1.46 (3H, t,
Jꢂ7.0 Hz), 2.36 (3H, s), 2.97 (2H, q, Jꢂ7.0 Hz), 4.48 (2H, q, Jꢂ7.0 Hz),
3.68; N, 9.29. Found: C, 65.72; H, 3.66; N, 9.34.
Bis[3-cyano-2-(1-naphthylmethylthio)indolizin-1-yl] Disulfide (5d): From
4d, pale yellow needles (from ethanol), mp 185—186 °C. IR (KBr) cmꢁ1
:
1
2199. H-NMR (400 MHz) d: 4.64 (2H, s), 7.24—7.34 (2H, m), 7.46 (1H,
ddd, Jꢂ7.0, 7.0, 1.0 Hz), 7.53 (1H, ddd, Jꢂ7.0, 7.0, 1.2 Hz), 7.73 (1H, d,
Jꢂ7.8 Hz), 7.81 (1H, d, Jꢂ8.1 Hz), 8.14 (1H, d, Jꢂ8.3 Hz). UV lmax
(CHCl3) nm (log e): 284 (4.61), 338 (shoulder), 378 (shoulder). Anal. Calcd
6.74 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.27 (1H, br s), 7.3—8.3 (5H, m), 9.45 (1H, d, for C40H26N4S4: C, 69.54; H, 3.79; N, 8.11. Found: C, 69.48; H, 3.79; N,
Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 264 (4.47), 342 (4.10). Anal. Calcd 8.17.
1
for C21H21NO3S2: C, 63.13; H, 5.30; N, 3.51. Found: C, 63.46; H, 5.15; N,
3.33.
Bis[3-ethoxycarbonyl-2-(methylthio)indolizin-1-yl] Disulfide (5e)9): H-
NMR (400 MHz) d: 1.47 (3H, t, Jꢂ7.2 Hz), 2.67 (3H, s), 4.45 (2H, q,
Jꢂ7.1 Hz). UV lmax (CHCl3) nm (log e): 284 (4.53), 354 (4.26).
Ethyl 1-Benzoylthio-2-benzylthio-7-methylindolizine-3-carboxylate (4s):
From 1s and 2, colorless needles (from ethanol), mp 136—137 °C. IR (KBr)
cmꢁ1: 1671. 1H-NMR (60 MHz) d: 1.41 (3H, t, Jꢂ7.0 Hz), 2.34 (3H, s),
4.37 (2H, s), 4.55 (2H, q, Jꢂ7.0 Hz), 6.74 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.30
(5H, s), 7.0—8.3 (5H, m), 9.44 (1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (2H, q, Jꢂ7.5 Hz), 4.46 (2H, q, Jꢂ7.1 Hz). UV lmax (CHCl3) nm (log e):
(log e): 262 (shoulder), 344 (4.10). Anal. Calcd for C26H23NO3S2: C, 67.65; 284 (4.44), 353 (4.27). Anal. Calcd for C26H28N2O4S4: C, 55.69; H, 5.03; N,
Bis[3-ethoxycarbonyl-2-(ethylthio)indolizin-1-yl] Disulfide (5f): From 4f,
pale yellow needles (from ethanol), mp 118—120 °C. IR (KBr) cmꢁ1: 1687.
1H-NMR (400 MHz) d: 1.21 (3H, t, Jꢂ7.4 Hz), 1.47 (3H, t, Jꢂ7.0 Hz), 3.07
H, 5.02; N, 3.03. Found: C, 67.63; H, 5.14; N, 2.94.
5.00. Found: C, 55.74; H, 4.76; N, 5.22.
Ethyl 1-Benzoylthio-2-(1-naphthylmethylthio)-7-methylindolizine-3-car-
boxylate (4t): From 1t and 2, colorless needles (from ethanol), mp 183—
184 °C. IR (KBr) cmꢁ1: 1680. 1H-NMR (60 MHz) d: 1.35 (3H, t, Jꢂ7.0 Hz),
Bis[2-benzylthio-3-(ethoxycarbonyl)indolizin-1-yl] Disulfide (5g) From
4g, pale yellow needles (from ethanol), mp 126 °C. IR (KBr) cmꢁ1: 1686.
1H-NMR (400 MHz) d: 1.44 (3H, t, Jꢂ7.2 Hz), 4.23 (2H, s), 4.41 (2H, q,
2.36 (3H, s), 4.30 (2H, q, Jꢂ7.0 Hz), 4.57 (2H, s), 6.74 (1H, dd, Jꢂ7.0, Jꢂ7.2 Hz), 7.13—7.26 (5H, m). UV lmax (CHCl3) nm (log e): 284 (4.44),
1.0 Hz), 7.0—8.3 (13H, m), 9.46 (1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm 351 (4.26). Anal. Calcd for C36H32N2O4S4: C, 63.13; H, 4.71; N, 4.09.
(log e): 264 (shoulder), 344 (4.11). Anal. Calcd for C30H25NO3S2: C, 70.42; Found: C, 63.17; H, 4.74; N, 4.03.
H, 4.93; N, 2.74. Found: C, 70.71; H, 4.94; N, 2.66.
Bis[3-ethoxycarbonyl-2-(1-naphthylmethylthio)indolizin-1-yl] Disulfide
3-Benzoyl-1-benzoylthio-2-methylthio-7-methylindolizine (4u): From 1u (5h): From 4h, yellow needles (from ethanol), mp 111—114 °C. IR (KBr)
1
and 2, yellow needles (from ethanol), mp 150—155 °C. IR (KBr) cmꢁ1
:
cmꢁ1: 1691. H-NMR (400 MHz) d: 1.28 (3H, t, Jꢂ7.2 Hz), 4.24 (2H, q,
1604, 1678. 1H-NMR (400 MHz) d: 2.11 (3H, s), 2.56 (3H, s), 2.39 (3H, s), Jꢂ7.2 Hz), 4.63 (2H, s), 7.18—7.26 (2H, m), 7.40—7.55 (2H, m), 7.68 (1H,
6.78 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.4—8.2 (10H, m), 7.28 (1H, br s), 9.42 (1H,
d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 319 (3.86), 388 (4.13). Anal.
d, Jꢂ7.6 Hz), 7.79 (1H, d, Jꢂ8.6 Hz), 8.21 (1H, d, Jꢂ8.3 Hz). UV lmax
(CHCl3) nm (log e): 290 (4.58), 349 (4.25). Anal. Calcd for C40H26N2O4S4:
Calcd for C24H19NO2S2: C, 69.04; H, 4.59; N, 3.35. Found: C, 69.26; H, C, 67.32; H, 4.62; N, 3.57. Found: C, 67.38; H, 4.65; N, 3.48.
4.51; N, 3.20.
Bis[3-benzoyl-2-(methylthio)indolizin-1-yl] Disulfide (5i): From 4i, yel-
1
3-Benzoyl-1-benzoylthio-2-ethylthio-7-methylindolizine (4v): From 1v low needles (from ethanol), mp 73—75 °C. IR (KBr) cmꢁ1: 1608. H-NMR
and 2, yellow needles (from ethanol), mp 154—156 °C. IR (KBr) cmꢁ1
:
(400 MHz) d: 2.20 (3H, s), 7.43 (2H, t, Jꢂ7.5, 7.5 Hz), 7.56 (1H, br t,
1599, 1667. 1H-NMR (60 MHz) d: 0.89 (3H, t, Jꢂ7.0 Hz), 2.38 (3H, s), 2.53 Jꢂ7.5, 7.5 Hz), 7.66 (2H, br d, Jꢂ7.5 Hz). UV lmax (CHCl3) nm (log e): 293
(2H, q, Jꢂ7.0 Hz), 6.78 (1H, dd, Jꢂ7.0, 1.0 Hz), 7.0—8.3 (11H, m), 9.42 (shoulder), 394 (4.35). Anal. Calcd for C32H24N2O2S4: C, 64.40; H, 4.05; N,
(1H, d, Jꢂ7.0 Hz). UV lmax (CHCl3) nm (log e): 262 (shoulder), 322 (3.87),
388 (4.17). Anal. Calcd for C25H21NO2S2: C, 69.58; H, 4.90; N, 3.25. Found:
C, 69.63; H, 4.95; N, 3.15.
4.69. Found: C, 64.58; H, 4.09; N, 4.45.
Bis[3-benzoyl-2-(ethylthio)indolizin-1-yl] Disulfide (5j): From 4j, yellow
needles (from ethanol), mp 118—120 °C. IR (KBr) cmꢁ1: 1616. H-NMR
1
3-Benzoyl-1-benzoylthio-2-benzylthio-7-methylindolizine (4w): From 1w
(400 MHz) d: 0.90 (3H, t, Jꢂ7.4 Hz), 2.66 (2H, q, Jꢂ7.3 Hz), 7.41 (2H, t,
Jꢂ7.6, 7.6 Hz), 7.54 (1H, br t, Jꢂ7.4, 7.4 Hz), 7.62 (2H, br d, Jꢂ7.6 Hz).
and 2, yellow needles (from ethanol), mp 137—138 °C. IR (KBr) cmꢁ1
:
1
1604, 1678. H-NMR (60 MHz) d: 2.37 (3H, s), 3.67 (2H, s), 6.75 (1H, dd, UV lmax (CHCl3) nm (log e): 293 (shoulder), 394 (4.35). Anal. Calcd for
Jꢂ7.0, 1.0 Hz), 6.7—8.3 (11H, m), 9.39 (1H, d, Jꢂ7.0 Hz). UV lmax
C34H28N2O2S4: C, 65.36; H, 4.52; N, 4.48. Found: C, 65.46; H, 4.56; N,
(CHCl3) nm (log e): 266 (shoulder), 388 (4.16). Anal. Calcd for 4.34.
C30H23NO2S2: C, 72.99; H, 4.70; N, 2.84. Found: C, 73.03; H, 4.82; N, 2.68.
Bis[3-benzoyl-2-(benzylthio)indolizin-1-yl] Disulfide (5k): From 4k, yel-
3-Benzoyl-1-benzoylthio-2-(1-naphthylmethylthio)-7-methylindolizine low needles (from ethanol), mp 72—75 °C. IR (KBr) cmꢁ1: 1606. H-NMR
1
(4x): From 1x and 2, yellow needles (from ethanol), mp 139—141 °C. IR (400 MHz) d: 3.82 (2H, s), 6.84 (2H, br d, Jꢂ7.6 Hz), 7.06—7.15 (3H, m),
1
(KBr) cmꢁ1: 1597, 1672. H-NMR (60 MHz) d: 2.39 (3H, s), 4.09 (2H, s),
7.34 (2H, t, Jꢂ7.6 Hz), 7.46—7.56 (3H, m). UV lmax (CHCl3) nm (log e):
293 (shoulder), 394 (4.34). Anal. Calcd for C44H32N2O2S4: C, 70.56; H,
6.78 (1H, dd, Jꢂ7.0, 1.0 Hz), 6.8—8.3 (18H, m), 9.35 (1H, d, Jꢂ7.0 Hz).
UV lmax (CHCl3) nm (log e): 284 (shoulder), 389 (4.16). Anal. Calcd for 4.31; N, 3.74. Found: C, 70.82; H, 4.27; N, 3.52.
C34H25NO2S2: C, 75.11; H, 4.63; N, 2.58. Found: C, 75.27; H, 4.60; N, 2.46.
Bis[3-benzoyl-2-(1-naphthylmethylthio)indolizin-1-yl] Disulfide (5l):
Preparation of Bis(indolizin-1-yl) Disulfide Derivatives. General From 4l, yellow needles (from ethanol), mp 163—165 °C. IR (KBr) cmꢁ1
:
1
Method An ethanolic solution (30 ml) of 1-(benzoylthio)indolizine (4, 1620. H-NMR (400 MHz) d: 4.21 (2H, s), 6.84 (1H, d, Jꢂ6.4 Hz), 7.07—
0.5 mmol) and piperidine (0.200 g, 2.4 mmol) was heated under reflux condi-
tions in a water bath for 12 h—1 d. The resulting reaction solution was then
7.17 (3H, m), 7.23—7.29 (3H, m), 7.35—7.44 (2H, m), 7.63 (1H, d,
Jꢂ8.4 Hz), 7.74 (1H, d, Jꢂ8.4 Hz). UV lmax (CHCl3) nm (log e): 291 (4.55),

1464
Vol. 55, No. 10
lmax (CHCl3) nm (log e): 289 (4.54), 399 (4.38). Anal. Calcd for
C54H40N2O2S4+1/2H2O: C, 73.19; H, 4.66; N, 3.16. Found: C, 73.37; H,
4.88; N, 2.87.
393 (4.36). Anal. Calcd for C52H36N2O2S4: C, 73.56; H, 4.27; N, 3.30.
Found: C, 73.37; H, 4.11; N, 3.07.
1
Bis[3-cyano-7-methyl-2-(methylthio)indolizin-1-yl] Disulfide (5m)9): H-
Crystallography of Bis[3-cyano-2-(methylthio)indolizin-1-yl] Disulfide
(5a) A pale yellow prismatic single crystal (0.48ꢃ0.62ꢃ1.00 mm) grown
from ethanol was used for the unit-cell determinations and data collection by
a Rigaku AFC5S four-circle diffractometer with graphite-monochromated
MoKa radiation (lꢂ0.71069 Å). The crystal data of these compounds are
as follows: 5a: C20H14N4S4; Mꢂ438.60; monoclinic, space group C2/c
(#15), Zꢂ4 with aꢂ12.594(2) Å, bꢂ12.889(2) Å, cꢂ12.314(3) Å, bꢂ
100.00(2)°; Vꢂ1968.5(6) Å3 and Dcalc.ꢂ1.480 g/cm3. All calculations were
performed using the CrystalStructure crystallographic software package.18)
The structure was solved by a direct method (SIR92).19) The non-hydrogen
atoms were refined anisotropically, and the hydrogen atoms were attached at
the idealized position and not refined. The final R- and Rw-factors after full-
matrix least-squares refinements were 0.048 and 0.045 respectively for 1643
(Iꢀ2.00s(I)) observed reflections.
Crystallography of Bis[3-benzoyl-2-(benzylthio)indolizin-1-yl] Disul-
fide (5k) A yellow prismatic single crystal (0.28ꢃ0.28ꢃ0.72 mm) grown
from ethanol was used for the unit-cell determinations and data collection by
a Rigaku AFC5S four-circle diffractometer with graphite-monochromated
MoKa radiation (lꢂ0.71069 Å). Crystal data of these compounds are as
follows: 5k: C44H32N2O2S4; Mꢂ788.99; monoclinic, space group P21/n
(#14), Zꢂ4 with aꢂ9.741(3) Å, bꢂ18.209(3) Å, cꢂ21.419(3) Å, bꢂ
99.51(2)°; Vꢂ3747(1) Å3 and Dcalc.ꢂ1.328 g/cm3. All calculations were per-
formed using the CrystalStructure crystallographic software package.18) The
structure was solved by a direct method (SIR92).19) The non-hydrogen atoms
were refined anisotropically, and the hydrogen atoms were attached at the
idealized position and not refined. The final R- and Rw-factors after full-ma-
trix least-squares refinements were 0.063 and 0.047 respectively for 2695
(Iꢀ2.00s(I)) observed reflections.
NMR (400 MHz) d: 2.65 (3H, s). UV lmax (CHCl3) nm (log e): 279 (4.53),
332 (4.13), 376 (shoulder).
Bis[3-cyano-2-ethylthio-7-methylindolizin-1-yl] Disulfide (5n): From 4n,
pale yellow prisms (from ethanol), mp 234—246 °C. IR (KBr) cmꢁ1: 2207.
1H-NMR (400 MHz) d: 1.30 (3H, t, Jꢂ7.4 Hz), 3.11 (2H, q, Jꢂ7.3 Hz). UV
l
max (CHCl3) nm (log e): 276 (4.69), 333 (4.35), 376 (shoulder). Anal. Calcd
for C24H22N4S4: C, 58.27; H, 4.48; N, 11.33. Found: C, 58.44; H, 4.46; N,
11.17.
Bis(2-benzylthio-3-cyano-7-methylindolizin-1-yl) Disulfide (5o): From
4o, pale yellow needles (from ethanol), mp 172—173 °C. IR (KBr) cmꢁ1
:
2201. 1H-NMR (400 MHz) d: 4.30 (2H, s), 7.17—7.30 (3H, m), 7.35 (2H, d,
Jꢂ7.6 Hz). UV lmax (CHCl3) nm (log e): 279 (4.51), 331 (4.27). Anal. Calcd
for C34H26N4S4: C, 65.99; H, 4.23; N, 9.05. Found: C, 65.99; H, 4.15; N,
9.13.
Bis[3-cyano-7-methyl-2-(1-naphthylmethylthio)indolizin-1-yl] Disulfide
(5p): From 4p, pale yellow needles (from ethanol), mp 146—149 °C. IR
(KBr) cmꢁ1: 2199. 1H-NMR (400 MHz) d: 4.67 (2H, s), 7.29 (1H, q, Jꢂ8.1,
6.8 Hz), 7.35 (1H, d, Jꢂ6.3 Hz), 7.46 (1H, br t, Jꢂ7.4 Hz), 7.53 (1H, br t,
Jꢂ7.6 Hz), 7.73 (1H, d, Jꢂ8.0 Hz), 7.81 (1H, d, Jꢂ7.6 Hz), 8.18 (1H, d,
Jꢂ8.3 Hz). UV lmax (CHCl3) nm (log e): 283 (4.60), 338 (shoulder), 383
(shoulder). Anal. Calcd for C42H30N4S4: C, 70.16; H, 4.21; N, 7.79. Found:
C, 70.15; H, 4.33; N, 7.68.
Bis[3-ethoxycarbonyl-7-methyl-2-(methylthio)indolizin-1-yl] Disulfide
1
(5q)9): H-NMR (400 MHz) d: 1.47 (3H, t, Jꢂ7.2 Hz), 2.59 (3H, s), 4.46
(2H, q, Jꢂ7.1 Hz). UV lmax (CHCl3) nm (log e): 283 (4.52), 344 (4.30).
Bis[3-ethoxycarbonyl-2-ethylthio-7-methylindolizin-1-yl] Disulfide (5r):
From 4r, pale yellow needles (from ethanol), mp 257—259 °C. IR (KBr)
cmꢁ1: 1674. 1H-NMR (400 MHz) d: 1.26 (3H, t, Jꢂ7.4 Hz), 1.47 (3H, t,
Jꢂ7.2 Hz), 3.15 (2H, q, Jꢂ7.3 Hz), 4.44 (2H, q, Jꢂ7.2 Hz). UV lmax
(CHCl3) nm (log e): 282 (4.47), 347 (4.30). Anal. Calcd for C28H32N2O4S4:
C, 57.12; H, 5.48; N, 4.76. Found: C, 57.16; H, 5.58; N, 4.61.
Crystallography of Bis[3-cyano-2-ethylthio-7-methylindolizin-1-yl]
Disulfide (5n) A yellow prismatic single crystal (0.84ꢃ0.58ꢃ0.32 mm)
grown from ethanol was used for the unit-cell determinations and data col-
lection by a Rigaku AFC5S four-circle diffractometer with graphite-mono-
chromated MoKa radiation (lꢂ0.71069 Å). Crystal data of these com-
pounds are as follows: 5n: C24H22N4S4; Mꢂ494.70; monoclinic, space group
C2/c (#15), Zꢂ4 with aꢂ18.289(3) Å, bꢂ9.359(3) Å, cꢂ14.355(3) Å, bꢂ
97.42(2)°; Vꢂ2436.5(10) Å3 and Dcalc.ꢂ1.348 g/cm3. All calculations were
performed using the CrystalStructure crystallographic software package.18)
The structure was solved by a direct method (SIR).19) The non-hydrogen
atoms were refined anisotropically, and the hydrogen atoms were attached at
the idealized position and not refined. The final R- and Rw-factors after full-
matrix least-squares refinements were 0.076 and 0.061 respectively for 1612
(Iꢀ2.00s(I)) observed reflections.
Bis[2-benzylthio-3-ethoxycarbonyl-7-methylindolizin-1-yl] Disulfide (5s):
From 4s, pale yellow needles (from ethanol), mp 96—98 °C. IR (KBr) cmꢁ1
:
1688. 1H-NMR (400 MHz) d: 1.41 (3H, t, Jꢂ7.1 Hz), 4.31 (2H, s), 4.40
(2H, q, Jꢂ7.1 Hz), 7.03—7.30 (5H, m). UV lmax (CHCl3) nm (log e): 288
(shoulder), 345 (4.29). Anal. Calcd for C38H36N2O4S4: C, 64.02; H, 5.09; N,
3.93. Found: C, 64.08; H, 5.09; N, 3.87.
Bis[3-ethoxycarbonyl-7-methyl-2-(1-naphthylmethylthio)indolizin-1-yl]
Disulfide (5t): From 4t, pale yellow needles (from ethanol), mp 139—
140 °C. IR (KBr) cmꢁ1: 1674. 1H-NMR (400 MHz) d: 1.28 (3H, t,
Jꢂ7.1 Hz), 4.22 (2H, q, Jꢂ7.2 Hz), 4.72 (2H, s), 7.22—7.28 (2H, m), 7.44
(1H, ddd, Jꢂ8.0, 7.1, 1.2 Hz), 7.50 (1H, ddd, Jꢂ8.3, 6.8, 1.5 Hz), 7.69 (1H,
dd, Jꢂ6.6, 2.4 Hz), 7.80 (1H, d, Jꢂ7.8 Hz), 8.28 (1H, d, Jꢂ8.3 Hz). UV lmax
(CHCl3) nm (log e): 290 (4.59), 352 (shoulder). Anal. Calcd for
C46H40N2O4S4: C, 67.95; H, 4.96; N, 3.45. Found: C, 68.13; H, 4.93; N,
3.30.
Crystallography of Bis[3-ethoxycarbonyl-7-methyl-2-(methylthio)in-
dolizin-1-yl] Disulfide (5q)
A pale yellow prismatic single crystal
(0.20ꢃ0.32ꢃ1.00 mm) grown from ethanol was used for the unit-cell deter-
minations and data collection by a Rigaku AFC5S four-circle diffractometer
with graphite-monochromated MoKa radiation (lꢂ0.71069 Å). The crystal
data of these compounds are as follows: 5q: C26H28N2O4S4; Mꢂ560.76;
orthorhombic, space group P21/a (#14), Zꢂ4 with aꢂ13.222(4) Å,
bꢂ8.895(5) Å, cꢂ23.768(5) Å, bꢂ95.91(2)°; Vꢂ2780(2) Å3 and Dcalc.ꢂ
1.340 g/cm3. All calculations were performed using the CrystalStructure
crystallographic software package.18) The structure was solved by a direct
method (SIR).19) The non-hydrogen atoms were refined anisotropically, and
the hydrogen atoms were attached at the idealized position and not refined.
The final R- and Rw-factors after full-matrix least-squares refinements were
0.070 and 0.050 respectively for 1591 (Iꢀ2.00s(I)) observed reflections.
Bis[3-benzoyl-7-methyl-2-(methylthio)indolizin-1-yl] Disulfide (5u):
From 4u, pale yellow needles (from ethanol), mp 158—160 °C. IR (KBr)
1
cmꢁ1: 1602. H-NMR (400 MHz) d: 2.23 (3H, s), 7.43 (2H, t, Jꢂ7.7 Hz),
7.55 (1H, br t, Jꢂ7.4 Hz), 7.65 (2H, br d, Jꢂ7.7 Hz). UV lmax (CHCl3) nm
(log e): 264 (shoulder), 293 (shoulder), 400 (4.38). Anal. Calcd for
C34H28N2O2S4: C, 65.36; H, 4.52; N, 4.48. Found: C, 65.46; H, 5.56; N,
4.34.
Bis[3-benzoyl-2-ethylthio-7-methylindolizin-1-yl] Disulfide (5v): From
4v, pale yellow needles (from ethanol), mp 148—150 °C. IR (KBr) cmꢁ1
:
1596. 1H-NMR (400 MHz) d: 0.94 (3H, t, Jꢂ7.4 Hz), 2.71 (2H, q,
Jꢂ7.3 Hz), 7.42 (2H, t, Jꢂ7.7 Hz), 7.54 (1H, br t, Jꢂ7.4 Hz), 7.62 (2H, br d,
Jꢂ7.7 Hz). UV lmax (CHCl3) nm (log e): 291 (shoulder), 400 (4.41). Anal.
Calcd for C36H32N2O2S4: C, 66.23; H, 4.94; N, 4.29. Found: C, 66.44; H,
5.00; N, 4.02.
References and Notes
1) For part 59 of this series, see Kakehi A., Suga H., Isogai H., Chem.
Pharm. Bull., 55, 95—101 (2007).
2) Kakehi A., Suga H., Kako T., Fujii T., Tanaka N., Kobayashi T., Chem.
Pharm. Bull., 51, 1246—1252 (2003).
3) Kakehi A., Ito S., Suga H., Miwa T., Mori T., Kobayashi T., Heterocy-
cles, 57, 17—20 (2002).
4) Kakehi A., Ito S., Suga H., Miwa T., Mori T., Fujii T., Tanaka N.,
Kobayashi T., Chem. Pharm. Bull., 51, 75—84 (2003).
5) Kakehi A., Suga H., Kaneko Y., Fujii T., Tanaka N., Chem. Pharm.
Bull., 53, 1430—1438 (2005).
6) Kakehi A., Ito S., Hirata K., Zuo P., Chem. Pharm. Bull., 48, 865—
869 (2000).
Bis[3-benzoyl-2-benzylthio-7-methylindolizin-1-yl] Disulfide (5w): From
4w, pale yellow needles (from ethanol), mp 73—75 °C. IR (KBr) cmꢁ1
:
1
1602. H-NMR (400 MHz) d: 3.89 (2H, s), 6.91 (2H, m), 7.07—7.15 (3H,
m), 7.37 (2H, t, Jꢂ7.7 Hz), 7.47—7.56 (3H, m). UV lmax (CHCl3) nm
(log e): 290 (shoulder), 399 (4.38). Anal. Calcd for C46H36N2O2S4: C, 71.10;
H, 4.67; N, 3.61. Found: C, 71.30; H, 4.62; N, 3.46.
Bis[3-benzoyl-7-methyl-2-(1-naphthylmethylthio)indolizin-1-yl] Disulfide
(5x): From 4x, pale yellow needles (from ethanol), mp 145—150 °C. IR
(KBr) cmꢁ1: 1608. 1H-NMR (400 MHz) d: 4.28 (2H, s), 6.90 (1H, d,
Jꢂ6.1 Hz), 7.10—7.20 (3H, m), 7.24—7.34 (3H, m), 7.36—7.45 (2H, m),
7.65 (1H, d, Jꢂ8.0 Hz), 7.69 (1H, d, Jꢂ8.6 Hz), 7.76 (1H, d, Jꢂ8.0 Hz). UV
7) Boyd R. J., Perkyns J. S., Ramani R., Can. J. Chem., 61, 1082—1085

October 2007
1465
(1983).
Adachi K., Bull. Chem. Soc. Jpn., 60, 1867—1879 (1987).
8) Riga J., Verbist J. J., J. Chem. Soc. Perkin Trans. II, 1983, 1545—1551.
15) “WinMOPAC (Version 3.0),” Fujitsu Corporation.
9) Beagley B., McAloon K. T., Trans. Faraday Soc., 67, 3216—3222 16) Johnson C. K., “ORTEP II, Report ORNL-5138,” Oak Ridge National
(1971). Laboratory, Oak Ridge, Tennessee, 1976.
10) Lee J. D., Bryant M. W. R., Acta Crystallogr., B25, 2497—2504 17) Tominaga Y., Miyake Y., Fujito H., Matsuda Y., Kobayashi G., Yaku-
(1969).
gaku Zasshi, 97, 927—932 (1977).
11) Yokozeki A., Bauer S. H., J. Phys. Chem., 80, 618—625 (1976).
12) Lee J. D., Bryant M. W. R., Acta Crystallogr., B25, 2094—2101
(1969).
18) CrystalStructure 3.8: Crystal Structure Analysis Package, Rigaku and
Rigaku/MSC (2000—2006). 9009 New Trails Dr. The Woodlands TX
77381 U.S.A.
13) Sacerdotti M., Gilli G., Domiano P., Acta Crystallogr., B31, 327—332
(1975).
19) SIR92: Altomare A., Cascarano G., Giacovazzo C., Guagliardi A., J.
Appl. Cryst., 26, 343—350 (1993).
14) Kakehi A., Ito S., Yonezu S., Maruta K., Yuito K., Shiohara M.,