Novel rearrangements of a 8aH-pyrido[1,2-d]thieno[2',3'-b][1,4]thiazepine derivative

Article abstract of DOI:10.3987/COM-11-12398

The reaction of 5-ethoxycarbonyl-3-[1-(4-methylpyridinio)]-4-phenythiopene- 2-thiolate with dimethyl acetylenedicarboxylate in refluxing chloroform or tetrahydrofuran afforded the corresponding 10H-pyrrolo[1,2-d]-thieno[2',3'-b][1, 4]thiazocines or the 6,8-dithia-2-azatetracyclo[7.3.2.02,10.03,7]-tetradeca- Δ3,7,4,11,13-tetraene derivative. Also, the thermal conversion from the former product to dimethyl (Z)- and (E)-2-[thieno[2',3':2,3][1,4]thiazino-[4,5- a]pyrrol-8-ylidene]succinates was confirmed.

Full text of DOI:10.3987/COM-11-12398

HETEROCYCLES, Vol. 85, No. 2, 2012
305
HETEROCYCLES, Vol. 85, No. 2, 2012, pp. 305 - 312. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 24th November, 2011, Accepted, 15th December, 2011, Published online, 22nd December, 2011
DOI: 10.3987/COM-11-12398
NOVEL REARRANGEMENTS OF
A
8aH-PYRIDO[1,2-d]THIENO-
[2’,3’-b][1,4]THIAZEPINE DERIVATIVE 1
Akikazu Kakehi,* Kennosuke Itoh, Hiroyuki Suga, Yuuki Ohkubo, Ayaka
Kobayashi, and Takashi Nishi
Department of Chemistry and Material Engineering, Faculty of Engineering,
Shinshu University, Wakasato, Nagano, 380-855, Japan
E-Mail: xkakehi@shinshu-u.ac.jp
Abstract – The reaction of 5-ethoxycarbonyl-3-[1-(4-methylpyridinio)]-4-
phenythiopene-2-thiolate with dimethyl acetylenedicarboxylate in refluxing
chloroform or tetrahydrofuran afforded the corresponding 10H-pyrrolo[1,2-d]-
thieno[2’,3’-b][1,4]thiazocines or the 6,8-dithia-2-azatetracyclo[7.3.2.02,10.03,7]-
tetradeca-3,7,4,11,13-tetraene derivative. Also, the thermal conversion from the
former product to dimethyl (Z)- and (E)-2-[thieno[2’,3’:2,3][1,4]thiazino-
[4,5-a]pyrrol-8-ylidene]succinates was confirmed.
In our recent paper2 we reported the formation of an interesting byproduct, dimethyl
2-[thieno[2’,3’:2,3][1,4]thiazino[4,5-a]pyrrol-8-ylidene]succinate such as C (see Figure 1), in the one-pot
synthesis of thieno[3,2-d]thiazole derivatives by the reactions of some 3-(1-pyridinio)thiophene-
2-thiolates with dimethyl acetylenedicarboxylate (DMAD) in refluxing xylene. We were particularly
interested in the presence of the pyrrole ring in this byproduct because a ring contraction rearrangement
from the pyridine ring to the pyrrole one is involved in this reaction and we already observed the
formation of similar ring transformation products, e.g., 5-thia-2,3-diazatricyclo[4.3.2.02,7]undeca-
3,8,10-triene derivatives such as F in the reactions of pyridinium 1-(arylthiocarbonyl)aminides with
DMAD.3 From these observations we first assumed the following rough mechanistic sequence:
8aH-pyrido[1,2-d]thieno[2’,3’-b][1,4]thiazepine (A)
→
6,8-dithia-2-azatetracyclo[7.3.2.02,10.03,7]-
tetradeca-3,7,4,11,13-tetraene (B) → 8H-thieno[2’,3’:2,3][1,4]thiazino[4,5-a]pyrrole (C) and examined
the isolation or the detection of the intermediates such as B or its thiophene-free analogue in the reactions
of various pyridinium 1-(2-thioxo)ethylides and 3-(1-pyridinio)thiophene-2-thiolates with DMAD (2)
under milder conditions. Almost all reactions which we reinvestigated under this assumption afforded

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HETEROCYCLES, Vol. 85, No. 2, 2012
only already established products such as thiazepines (A) or their intramolecular Diels-Alder type adducts
(D). However, the reaction of one substrate, 5-ethoxycarbonyl-3-[1-(4-methylpyridinio)]-4-
phenylthiophene-2-thiolate, with 2 gave unexpected 10H-pyrrolo[1,2-d]thieno[2’,3’-b][1,4]thiazocines
(E) together with the expected 6,8-dithia-2-azatetracyclo[7.3.2.02,10.03,7]tetradeca-3,7,4,11,13-tetraene
(B).
In this communication we report novel rearrangement reactions from the
8aH-pyrido[1,2-d]thieno[2’,3’-b][1,4]thiazepine derivative to the corresponding rearranged products B
and
E
and the thermal transformation from
E
to the corresponding dimethyl
8H-pyrrolo[2,1-c]thieno[2’,3’-b][1,4]thiazin-8-ylidenesuccinate (C).
MeO2C
CO2Me
CO2Me
R
N
H
CO2Me
R
S
S
R
S
R2
R1
N
N
S
S
S
MeO2C
CO2Me
R2
R2
C
R1
R1
A
B
R
R
N
R
CO2Me
CO2Me
N
R2
R1
N
N
S
R2
R1
Ar
S
S
H
S
MeO2C
MeO2C
CO2Me
CO2Me
S
D
F
E
Figure 1
As described above, the reactions of almost all pyridinium 1-(2-thioxo)ethylides and
3-(1-pyridinio)thiophen-2-thiolates with 2 under various reaction conditions afforded only the
corresponding type A and/or D adducts, but not the type B product. For example, the reactions of
3-(1-pyridinio)thiophene-2-thiolates (1a–c), which formed the corresponding type C products in refluxing
xylene,2 with 2 in refluxing chloroform or tetrahydrofuran (THF) afforded only intramolecular
Diels-Alder type adducts 3a–c4 and any other significant products could not be obtained (Scheme 1). So,
we focused our attention on some other substrates whose yields for adducts such as 3 in our previous
reactions which were carried out in refluxing chloroform were very low.5 After some elaboration we
found that one substrate among them, 5-ethoxycarbonyl-3-[1-(4-methylpyridinio)]-4-phenyl-
thiophene-2-thiolate (1d), smoothly reacted with 2 in refluxing chloroform for 10 h to produce the
unexpected 2-ethyl 9,10-dimethyl 7-methyl-3-phenyl-10H-pyrrolo[1,2-d]thieno[2’,3’-b][1,4]thiazocine-
2,9,10-tricarboxylates (4d+5d)6 as a diastereomeric mixture7 in a 85% yield, while similar reactions of 1d

HETEROCYCLES, Vol. 85, No. 2, 2012
307
R
N
R
12
R
R
13
CO2Me
7
11
10
6
in solvent
12
8
R1
4
14
+
11
1
9
1
10
2
3
5
CO2Me
CO2Me
R1
S
2
N
4 N
N
3
4
reflux for 10 h
COR2
13
+
+
CO2Me
2
R1
7
S
10
COR2
9
3a
8
R1
6
S
14
8
S
S
5
9
MeO2C
S
11
H
7
5
3
S
MeO2C
CO2Me
6
COR2
1a—d
CO2Me
6d
S
2
R2CO
1
3a—d
4d+5d
R1
R2
1,3
6
React.
Solvent
Products
(%)
R
H
H
a
b
c
CHCl3 or THF
CHCl3 or THF
CHCl3 or THF
CHCl3
1a+2
1b+2
1c+2
1d+2
1d+2
1d+2
1d+2
3a (65 or 48%)
Me
Me
Me
Ph
3b
3c
(74 or 61%)
(28 or 78%)
H
Ph
Ph
Me
4d+5d (85%)a
6d
d
Me
OEt
THF
(38%)
4d 5d
a
b
6d
(30%)
CH2Cl2
+
(60%) ,
a
b
C6H6
3d
4d 5d
+
6d
(56%) , (11%)
(13%),
a) The ratio of 4d : 5d was . 85:15. b) These yields were determined
ca
by the integral ratios of the proton signals in the 1H-NMR spectrum.
Scheme 1
in refluxing THF gave the expected adduct 6d8 in a 38% yield. On the other hand, the reactions of 1d
with 2 in refluxing methylene chloride or benzene afforded the mixtures of 4d+5d (60%) and 6d (30%) or
3d (13%), 4d+5d (56%) and 6d (11%) respectively. Our attempts to separate the mixture of 4d+5d by
column chromatography were unsuccessful. This and the fact that the mixtures of 4d+5d obtained under
different conditions had almost the same isomeric ratio (ca.
85:15) strongly suggests the presence of an equilibrium
between them. The structures of products 3a–d could be
determined by comparison with some data of known
compounds and an authentic sample (3d)5 and the structure
of 6d was also decided by the similarity of the chemical
shifts and the coupling constants for the skeletal protons in
O6
O4
O3
O5
N1
S2
1
the H-NMR spectrum with those of dimethyl 4-aryl-5-
S1
thia-2,3-diazatricyclo[4.3.2.02,7]undeca-3,8,10-triene-6,11-
dicarboxylate derivatives.3 On the other hand, we could
recognize that mixture 4d+5d is a 1:1 adduct between
pyridinium betaine (1d) and 2 from its elementary analysis
and has a trisubstituted aromatic pyrrole structure and each
O2
O1
Figure 2. ORTEP drawing of 4d

308
HETEROCYCLES, Vol. 85, No. 2, 2012
1
one uncoupled vinyl and methine proton from its H-NMR spectral analysis, but further information for
these structures was not obtained. Eventually, the X-ray analysis of the crystals obtained from the
recrystallization of 4d+5d made the structure for the major product 4d clear.9 The ORTEP drawing for
4d is shown in Figure 2.10
We next examined the formation of a dimethyl 8H-pyrrolo[2,1-c]thieno[2’,3’-b][1,4]thiazin-8-
ylidenesuccinate derivative such as C. Contrary to our first assumption, compound 6d did not give the
corresponding 1,4-thiazine derivative 7 in refluxing xylene for 2 d and also was not converted to
1,4-thiazocines 4d+5d in refluxing chloroform for 10 h. On the other hand, mixture 4d+5d in boiling
xylene for 2 d provided the expected products 711 in 12 and 20% yield respectively as the (Z)- and
(E)-isomers in relation to the 8-exo methylene group, together with pyrrolium betaine 8 (34%)12
(Scheme 2). Interestingly, product 8 gradually changed to (Z)-7 and (E)-7 during the separation and
purification processes. Furthermore, (Z)-7 was also unstable and isomerized to (E)-7 even while being
kept at room temperature.
Me
CO2Me
MeO2C
Me
8(1) CO2Me
3
MeO2C
Me
4
5
2 2(1)
Me
7
CO2Me
CO2Me
1
N
N
2(2)
in xylene
S9
CO2Me
8
S
+
Ph
6
+
2(3)
CO2Me
N
N
Ph
EtO2C
S
H
S1
reflux for 2 d
61%
4
5
S
S
S
2
EtO2C
S
3
Ph
4d+5d
CO2Et
Ph
s-Bu
in xylene
in CHCl3
reflux for 10 h
8 (34%)
heat or rt
(E)-7 (20%)
(Z)-7 (12%)
reflux for 2 d
Me
heat or rt
Ph
N
CO2Et
S
S
MeO2C
CO2Me
6d
Scheme 2
1
The structures of (Z)-7 and (E)-7 were determined by comparison of their H-NMR spectra with known
compounds,2 and the distinction between the Z- and E-isomers was assumed by considering their stability
and the presence of the geminal coupling constant of the methylene group attached at the 8(1)-position of
(Z)-7. This structural assumption for isomers was also confirmed by their X-ray analyses and the
ORTEP drawings10 for compound (Z)-7 and (E)-7 are shown in Figures 3 and 4.13 Similarly, the
structure of 8 was assigned by the presence of a trisubstituted pyrrole ring and the 2 vinyl protons in its
1H-NMR spectral analysis and by the intermediacy as a precursor to final products (Z)-7 and (E)-7.
Possible mechanisms for these reactions are shown in Scheme 3. In particular, the transformation from
[1,4]thiazocines 4d+5d to final products (Z)-7 and (E)-7 can be readily interpreted by adding another

HETEROCYCLES, Vol. 85, No. 2, 2012
309
CO2Me
Me
H
N
CO2Me
10
S
Me
Me
path a
b
N
Ph
Ph
a
CO2Et
5
N
5,10-cycliz.
path c
S
MeO2C
CO2Et
S
S
MeO2C
MeO2C
S
Ph
9d
S
MeO2C
CO2Et
10d
3d
Me
path b
Me
1d + 2
CO2Me
CO2Me
N
Ph
Ph
N
CO2Et
S
H
S
S
S
MeO2C
CO2Me
6d
EtO2C
ring
opening
4d+5d
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
H
S
S
Ph
Ph
1,3-shift
cycliz.
S
S
N
N
S
S
S
S
EtO2C
EtO2C
Ph
8d
Ph
8d'
CO2Et
CO2Et
11d
(Z)-7, (E)-7
Scheme 3
intermediate, 8-[1,2-bis(methoxycarbonyl)vinyl-8H-pyrrolo[2,1-c]thieno[2’,3’-b][1,4]thiazine (11d),
which is formed from the cyclization in another resonance structure 8d’ of pyrrolium betaine 8d.
However, the reaction mechanism from thiazepine 9d14 to 4d+5d is unclear15 because the promising route
from 6d, which has a 1,4-dihydropyrrole ring in that skeleton, to 4d+5d was refused. The reason why
different products 3d, 4d+5d, and 6d are formed from the same substrate 1d and reagent 2 dependent
upon the conditions employed is unclear, but the temperature dependency for the formation of 3d in
benzene5 or type F compounds in chloroform3 strongly suggests larger contribution of the reaction
temperature than the solvent effect. The scope and limitation for these rearrangements are now in
progress.
REFERENCES AND NOTES
1. Preparation of new nitrogen-bridged heterocycles. 75. For 74 of this series, see A. Kakehi, K. Itoh,
H. Suga, N. Yamaguchi, T. Abe, Y. Yuda, and H. Katsumata, Heterocycles, 2012, 84, 753.
2. A. Kakehi, S. Ito, H. Suga, Y. Okumura, and T. Nishi, Heterocycles, 2010, 81, 175.
3. A. Kakehi, S. Ito, F. Ishida, and Y. Tominaga, J. Org. Chem., 1997, 62, 7788.

310
HETEROCYCLES, Vol. 85, No. 2, 2012
o
4. 3a, colorless needles, mp195−196 C. IR (KBr): 1628, 1713, 1730 cm-1. 1H-NMR (CDCl3):
2.40 (3H, s, 3-Me), 2.45 (3H, s, Ac), 2.77 (1H, ddd, J = 7.1, 5.9, 2.2 Hz, 11-H), 3.56 (1H, dd, J = 7.1,
1.4 (W-shaped coupling with the 10-H) Hz, 11-H), 3.72 and 3.74 (each 3H, s, CO2Me), 4.16 (1H, dd,
J = 6.6, 1.4 (W-shaped coupling with the 14-H), 1.2 Hz, 7-H), 6.09 (1H, ddd, J = 8.3, 6.6, 2.2 Hz,
13-H), 6.29 (1H, ddd, J = 8.3, 5.9, 1.2 Hz, 12-H). Anal. Calcd for C18H17NO5S2: Calcd C, 55.23; H,
o
4.38; N, 3.58. Found C, 55.18; H, 4.41; N, 3.50. 3b, colorless needles, mp 152−154 C. IR
(KBr): 1630, 1721, 1742 cm-1. Anal. Calcd for C23H19NO5S2: Calcd C, 60.91; H, 4.22; N, 3.09.
o
Found C, 60.81; H, 4.36; N, 3.05. 3c, colorless needles, mp178−181 C. IR (KBr): 1636, 1725,
1742 cm-1. Anal. Calcd for C23H19NO5S2: Calcd C, 60.91; H, 4.22; N, 3.09. Found C, 60.96; H,
4.26; N, 3.00.
5. A. Kakehi, S. Ito, M. Mitani, and M. Kanaoka, Bull. Chem. Soc. Jpn., 1994, 67, 1646.
o
6. 4d+5d, pale yellow prisms, mp 129−132 C. IR (KBr): 1653, 1699, 1734 cm-1. Anal. Calcd for
C25H23NO6S2: Calcd C, 60.35; H, 4.66; N, 2.82. Found C, 60.29; H, 4.75; N, 2.78. 1H-NMR
(CDCl3) 4d: 1.16 (3H, t, J = 7.1 Hz, OCH2CH3), 2.07 (3H, s, 7-Me), 3.75 and 3.80 (each 3H, s,
CO2Me), 4.10−4.20 (2H, m, OCH2CH3), 5.35 (1H, s, 10-H), 5.78 (1H, d, J = 2.8 Hz, 6-H), 6.14 (1H,
d, J = 2.8 Hz, 5-H), 6.88−6.94 (2H, m, Ph-H), 7.15−7.22 (2H, m, Ph-H), 7.23−7.28 (1H, m, Ph-H),
7.92 (1H, s, 8-H). 5d: 1.16 (3H, t, J = 7.1 Hz), 1.98 (3H, s, 7-Me), 3.49 and 3.86 (each 3H, s,
CO2Me), 4.10−4.20 (2H, m, OCH2CH3), 5.21 (1H, s, 10-H), 5.61 (1H, d, J = 2.8 Hz, 6-H), 6.07 (1H,
d, J = 2.8 Hz, 5-H), 6.88−6.94 (2H, m, Ph-H), 7.15−7.22 (2H, m, Ph-H), 7.23−7.28 (1H, m, Ph-H),
7.87 (1H, s, 8-H).
7. This molecule has only one asymmetric carbon (C(10)) and usually exists as a pair of enantiomers.
However, this rigid tricyclic structure, which is further promoted by the 3-phenyl group, strongly
prevents the rotation of the C(3a)-N(4) bond and leads to an additional asymmetry.
8. 6d, colorless needles, mp 156−158 oC. IR (KBr): 1437, 1719 cm-1. 1H-NMR (CDCl3): 1.14 (3H, t,
J = 7.1 Hz, OCH2CH3), 1.68 (3H, s, 12-Me), 3.21 (1H, d, J = 4.6 Hz, 1-H), 3.69 and 3.79 (each 3H, s,
CO2Me), 4.12 and 4.14 (each 1H, q, J = 7.1 Hz, OCH2CH3), 4.23 (1H, d, J = 2.0 Hz, 10-H), 5.64
(1H, br s, 11-H), 7.33−7.42 (5H, m, Ph-H), 7.44 (1H, d, J = 4.6 Hz, 13-H). 13C-NMR (CDCl3):
14.10, 15.05, 47.01, 52.00, 53.27, 60.75, 64.82, 66.64, 122.24, 125.53, 126.88, 127.76, 127.91,
128.24, 129.41, 134.14, 139.24, 142.49, 145.36, 151.44, 161.23, 164.16, 168.61. Anal. Calcd for
C25H23NO6S2: Calcd C, 60.35; H, 4.66; N, 2.82. Found C, 60.28; H, 4.81; N, 2.73.
9. Crystal data of 4d: C25H23NO6S2; M = 497.58; monoclinic, space group P21/n (#14), Z = 4 with a =
12.02 (2) Å, b=12.38 (3) Å, c=16.42 (2) Å, =95.99o (13); V=2430.1 (72) Å3, and Dcalc. = 1.360
g/cm3. All calculations were performed using CrystalStructure.16
The structure was solved by a

HETEROCYCLES, Vol. 85, No. 2, 2012
311
direct method (SIR92).17 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 0.063 and 0.045 for 3175 (I>2.00s(I)) observed
reflections, respectively.
10. C. K. Johnson, "ORTEO II, Report ORNL-5138," Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
11. (Z)-7 (this compound could not be obtained in a pure state because of the ready transformation to
(E)-7 isomer), pale yellow prisms. 1H-NMR (CDCl3): 1.15 (3H, t, J = 7.1 Hz, OCH2CH3), 1.96
(3H, s, 7-Me), 3.51 (1H, br d, J = 18.8 Hz), 3.69 (1H, br d, J = 18.8 Hz), 3.69 and 3.87 (each 3H, s,
CO2Me), 4.14 and 4.16 (each 1H, q, J = 7.1 Hz, OCH2CH3), 5.94 (1H, d, J = 2.9 Hz, 6-H), 6.11 (1H,
o
d, J = 2.9 Hz, 5-H), 7.41−7.50 (5H, m, Ph-H). (E)-7, pale yellow prisms, mp 181−182 C. IR
(KBr): 1414, 1688, 1746 cm-1. 1H-NMR (CDCl3): 1.14 (3H, t, J = 7.1 Hz, OCH2CH3), 1.92 (3H,
s, 7-Me), 3.71 and 3.76 (each 3H, s, CO2Me), 3.76 (2H, s, CH2), 4.15 (2H, q, J = 7.1 Hz, OCH2CH3),
5.89 (1H, d, J = 2.9 Hz, 6-H), 6.07 (1H, d, J = 2.9 Hz, 5-H), 7.31−7.49 (5H, m, Ph-H).
12. 8 (this compound could not be obtained in a pure state because of the transformation to (Z)-7 and
(E)-7 isomers), colorless powder. 1H-NMR (CDCl3): 1.12 (3H, t, J = 7.1 Hz, OCH2CH3), 1.95
(3H, s, 3-Me), 3.60 and 3.73 (each 3H, s, CO2Me), 4.12 and 4.13 (each 1H, q, J =7.1 Hz, OCH2CH3),
5.74 (1H, d, J = 2.9 Hz, 4-H), 5.97 (1H, d, J = 2.9 Hz, 5-H), 6.45 and 6.50 (each 1H, s, vinyl-H),
7.35−7.53 (5H, br s, Ph-H).
13. Crystal data of (Z)-7: C25H23NO6S2; M = 497.58; monoclinic, space group P21/c (#14), Z = 4 with a
= 9.83 (3) Å, b = 10.22 (4) Å, c = 24.60 (2) Å, = 96.03o
(16); V = 2455.9 (126) Å3, and Dcalc.= 1.346 g/cm3. All
O3
calculations were performed using CrystalStructure.16
O5
O4
The structure was solved by a direct method (SIR92).17
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 0.118 and
0.090 for 2704 (I>2.00s(I)) observed reflections,
respectively. Crystal data of (E)-7: C25H23NO6S2; M =
497.58; triclinic, space group P-1 (#2), Z = 2 with a =
10.26 (3) Å, b=12.64 (2) Å, c=10.113 (18) Å, =113.26
(12); = 98.6o (2); = 85.21 (19); V = 1190.9 (40) Å3,
O6
S2
N1
S1
O2
O1
Figure 3. ORTEP drawing of (Z)-7

312
HETEROCYCLES, Vol. 85, No. 2, 2012
and Dcalc.= 1.388 g/cm3. All calculations were performed using CrystalStructure.16 The structure
was solved by a direct method (SIR92).17 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 0.063 and 0.041 for 2632 (I>2.00s(I))
observed reflections, respectively.
O5
O3
14. A. Kakehi, S. Ito, and J. Hakui, Bull. Chem. Soc. Jpn.,
1993, 66, 3475.
O4
15. The transformation from thiazepine 9d to the
corresponding thiazocines 4d+5d was confirmed in CDCl3
O6
o
at 50−55 C for 5 h, while that from adduct 3d to
S2
thiazepine 9d could not be detected under the same
conditions even for 3 d.
N1
S1
O2
16. CrystalStructure 3.8: Crystal Structure Analysis Package,
Rigaku and Rigaku/MSC (2000−2006). 9009 New Trails
Dr. The Woodlands TX 77381 USA.
O1
17. SIR92: A. Altmare, G. Cascarano, C. Giacovazzo, A.
Guagliardi, M. Burla, G. Polridori, and M. Camalli, J. Appl.
Cryst., 1994, 27, 435.
Figure 4. ORTEP drawing of (E)-7