Synthesis of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-diones

Article abstract of DOI:10.1007/s11172-021-3099-1

A convenient method was developed for the combinatorial synthesis of substituted (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepine-5,10-diones. The structure and the most probable conformation of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione in solution was established by NMR spectroscopy and calculations using the Gaussian program.

Full text of DOI:10.1007/s11172-021-3099-1

394
Russian Chemical Bulletin, International Edition, Vol. 70, No. 2, pp. 394—405, February, 2021
Synthesis of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-
pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-diones
A. E. Fedorov,a L. A. Rodinovskaya, A. M. Shestopalov, and A. S. Sigeev
a
a
b
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: alf@server.ioc.ac.ru
b
A N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
8 ul. Vavilova, 119991 Moscow, Russian Federation
2
A convenient method was developed for the combinatorial synthesis of substituted
5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-
(
diazepine-5,10-diones. The structure and the most probable conformation of (5aS)-2-benzyl-
thio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-
dione in solution was established by NMR spectroscopy and calculations using the Gaussian
program.
Keywords: thieno[2,3-e][1,4]diazepinediones, domino reactions, Thorp—Ziegler cyclization,
combinatorial synthesis.
There are quite a number of published studies address-
4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e]-
[1,4]diazepine-5,10-diones substituted in the benzene ring
in order to compose libraries of derivatives for biological
screening (Scheme 1).
ing the anticancer activities of analogs of natural tetra-
hydropyrrolo[1,4]benzodiazepines (PBD): anthramycin,
1
tomaymycin, and sibiromycin; a PBD dimer designated
by SJG-136 (also known as SG2000, NSC 694501, or
BN2629) has passed phase II clinical trials in leukemia
and ovarian cancer patients.2
Therefore, it is of interest to develop approaches to the
synthesis of a hetero analogs of PBD in which the benzene
ring has been replaced by a heteroaromatic, in particular,
thiophene ring.
The method includes one-pot synthesis of a building
block, potassium salt 6 (as a solution in aqueous ethanol),
which is then used for combinatorial synthesis of the tar-
get compounds. The method can be easily adjusted for the
automated synthesis.
The sequence of reactions that are involved in the
building block preparation includes nucleophilic addition
of the active methylene group of malononitrile 1 to the
electron-deficient carbon atom of carbon disulfide 2 in
the presence of KOH to give vicinal mercaptonitrile salt
3, alkylation of salt 3 with 2-(chloroacetyl)proline 4, and
the Thorpe—Ziegler cyclization of the resulting thioester
5 to the corresponding thiophenethione salt 6. Then
nucleophilic replacement of the chlorine atom of benzyl
chlorides 7a—e by the exocyclic sulfur atom of thio-
phenethione salt 6 and cyclization of the resulting thio-
ethers 8 furnish diazepinediones 9a—e. We found that the
cyclization to diazepinedione takes place even at room
temperature under acid catalysis in water.
The directed synthesis of tetrahydropyrrolo[1,2-a]-
thieno[3,2-e]- and [2,3-e][1,4]diazepine-5,10(4H)-diones
3
possessing carcinolytic activity was first reported by
4
Jolivet-Fouchet et al. The synthetic procedure was tra-
ditional for PBD, using the thiophene analog of isatoic
anhydride. Drawbacks of this method are the necessity to
prepare the appropriately substituted 2,3-aminothiophen-
ecarboxylic acids, which are difficult to obtain, and to
convert them to the thiaisatoic anhydride using environ-
mentally hazardous phosgene.
Previously, it was proposed to synthesize pyrido-
3´,2´:4,5]thieno[2,3-e][1,4]diazepinediones by alkylation
[
of a vicinal mercaptonitrile, 3-cyanopyridine-2-(1H)-
thione, with 2-chloroacetamide of -amino acid and
subsequent construction of annulated thiophene and di-
azepine rings by successive domino reactions: Thorpe—
Ziegler cyclization and thermal cyclization to give diaz-
epinedione.5
Compounds 9a—e are high-melting colorless or slightly
colored solids. The IR spectra of products 9a—e exhibit
a broad band at 3200 cm– corresponding to the NH stretch-
ing mode, a narrow stretching band for the cyano group
at 2220 cm– , characteristic of this type of compounds,
and carbonyl absorption bands of two amide groups at
1700 and 1630 cm– . UV spectra show two broad absorp-
tion bands at 250—259 and 320—324 nm, which probably
1
1
,6
1
Relying on these data, in this study, we developed
a combinatorial synthesis of (5aS)-2-benzylthio-3-cyano-
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 394—405, February, 2021.
066-5285/21/7002-0394 © 2021 Springer Science+Business Media LLC
1

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
395
Scheme 1
R = Ph (a), 4-ClC H (b), 4-BrC H (c), 4-MeC H (d), 2,6-F C H (e)
6
4
6
4
6
4
2 6 3
result from superposition of the electronic absorption
bands of the benzene and thiophene systems.
This made it possible both to assign the NMR signals and
to identify the most probable conformation of compounds
9a—e in solution. Since compounds 9a—e differ only by
substituents in the aromatic ring and their NMR spectra
differ considerably only regarding the signals of aromatic
protons, which can be easily interpreted, the experi-
ments were carried out for (5aS)-2-benzylthio-3-cyano-
4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e]-
[1,4]diazepine-5,10-dione (9a) as an example (Fig. 1). The
signals of the other compounds were assigned by analogy.
A preliminary analysis of the chemical shifts and signal
Optically active chloroacetamide prepared from S-pro-
line was used in the synthesis. All of the synthesized
compounds were optically active, which attests to the
absence of racemization. It is noteworthy that the optical
rotation angles of compounds 9a—e, measured on an
automatic polarimeter, were considerably different. This
is not expected of compounds that differ in substituents
remote from the asymmetric center. Measurements of the
rotation angles with a manual polarimeter resulted in more
convergent values.
1
multiplicities and intensities in the H NMR spectrum of
1
The H NMR spectra of compounds 9a—e exhibit
compound 9a measured in DMSO-d suggests that the
6
signals at  1.7—4.5 and  7.2—7.5 and one signal with
signal at  11.13 belongs to the N(4)H proton; multiplets
H
H
H
1
H intensity in a very low field, at  11.09—11.25. The
number of carbon signals in the C NMR spectra cor-
responds to the structural formulas.
at H 7.43, 7.36, and 7.30 correspond to protons in the
ortho-, meta-, and para-positions of the benzene ring,
respectively; the signal at H 4.48 is due to the C(15)H2S
protons; and the doublet at H 4.26 corresponds to the
H(5) proton at the C(5a) carbon atom, common to the
fused dihydrodiazepine and pyrrolidine rings. The signals
for other pyrrolidine protons occur in the H 1.78—3.46
range and are partly or completely overlapped with the
H
1
3
The presence of the benzyl group and pyrrolidine ring
in the molecules of compounds 9a—e gives rise to the
possibility of existence of several conformers. The Camb-
ridge Crystallographic Data Centre (CCDC) describes two
dozens of examples of pyrrolodiazepines differing in the
position of the methylene group of the pyrrolidine ring,
signals of water ( 3.46) and residual signals of the solvent
H
7
—9
10,11
either below
or above the ring plane,
respectively.
(H 2.47) (Fig. 2).
The SCH Ph moiety can also occur in different positions
2
relative to the heterocyclic nucleus of the molecule. In
CCDC, there are nine compounds with the PhCH S—
2
1
2,13
thiophene moiety existing in three conformations.
However, the absence of signal doubling or broadening in
1
the H NMR spectra of compounds 9a—c indicates that
these compounds mainly exist in solution in a single con-
formation.
The full NMR signal assignment was done using a series
of homo- and heteronuclear resonance experiments and
comparison of the results with the data of studies of the
potential energy surface by computer modeling methods.
Fig. 1. Numbering of atoms in compound 9a used in the inter-
pretation of the NMR spectra.

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Fedorov et al.
H O
a
2
C(15)H2
5
HAr
2
C(6)H, 2 C(7)H, 2 C(8)H
NH
C(5a)H
Sol
b
Sol
C(15)H2
2
C(6)H, 2 C(7)H, 2 C(8)H
5
HAr
C(5a)H
NH
H O
2
c
C(15)H2
2
C(6)H, 2 C(7)H, 2 C(8)H
NH
C(5a)H
4.0
Sol
H O
2
1
1.0
10.0
9.0
8.0
7.0
6.0
5.0
3.0
2.0

1
Fig. 2. H NMR spectra (600 МHz) of compound 9a recorded in DMSO-d (a), acetone-d (b), and pyridine-d (c).
6
6
5
The overlap of the signals of compound 9a with the
the spectrum is recorded in pyridine-d (H 1.73 and
5
water and residual solvent signals was almost eliminated
1.86) (Fig. 3).
1
Recording of the 13C NMR spectra in the J-modulation
mode (Fig. 4) makes it possible to assign the signal of the
C(5a) methine carbon atom (C 58.12) and the C(19)
by recording the H NMR spectra in acetone-d and
6
pyridine-d . Some changes in the proton chemical shifts
5
of compounds 9a were observed in this case. For example,
in acetone-d , the N(4)H proton signal occurred at
carbon atom ( 128.42). It is noteworthy that the
6
C
1
3
H 9.96, the chemical shifts of aromatic protons changed
C NMR signal of the C(15) atom partly overlaps with
the solvent signal. This overlap can be avoided by using
acetone-d or pyridine-d as the solvent.
slightly (H 7.31—7.49), the chemical shift of the
C(15)H S group did not change, and the signals of the
2
6
5
pyrrolidine ring were located in the following order:
The carbon chemical shifts in these solvents differ
H 4.37 (H(5)), 3.60, 3.52, 2.68, 2.13, 1.99, and 1.93
little, by no more than 0.5 ppm. It is noteworthy that in
1
3
(
H(6)—H(8)). All pyrrolidine ring protons proved to be
the C NMR spectrum recorded in pyridine-d , the sig-
5
magnetically non-equivalent.
nals at  140—120 overlap somewhat with the signals of
C
In pyridine-d , the signals of residual pyridine protons
the residual protons of the solvent.
5
Further assignment of the H and 13C NMR signals
was based on analysis of 2D NOESY, HMQC, and HMBC
spectra. The cross-peaks caused by the through-space
1
do not overlap with the phenyl proton signals. Like in the
spectra in acetoneе-d , the chemical shifts considerably
6
changed. The N(4)H proton resonated at H 12.8, the
aromatic protons were manifested at H 7.22—7.46, the
coupling between the C(15)H S protons ( 4.48) and the
2
H
C(15)H S signal occurred at  4.40, and the pyrrolidine
proton resonating as a multiplet at  7.43 in the NOESY
2
H
H
proton signals were at H 4.23 (H(5)), 3.61, 3.56, 2.79,
spectrum (DMSO-d ) unambiguously indicate that
6
1
.93, 1.86, and 1.73 (H(6)—H(8). Note that judging by
the latter should be identified as the H(17) and H(21)
1
the multiplicity, two highest-field signals of the H NMR
ortho-protons of the aromatic ring (Fig. 5); hence, the
spectrum of 9a recorded in DMSO-d ( 1.78 and 1.89)
multiplet at  7.36 is assigned to the meta-protons, H(18)
6
H
H
or acetone-d ( 1.93 and 1.99) exchange places when
and H(20).
6
H

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
397
a
b
C(15)H2
H O
2
2
C(6)H, 2 C(7)H
2
C(8)H
C(5a)H
Sol
C(15)H2
Sol
2
C(6)H, 2 C(7)H
2
C(8)H
C(5a)H
H O
2
c
C(15)H2
2
C(6)H, 2 C(7)H
C(5a)H
2
C(8)H
3.6
4
.6
4.4
4.2
4.0
3.8
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8

1
Fig. 3. Aliphatic proton region in the H NMR spectra (600 МHz) of compound 9a recorded in DMSO-d (a), acetone-d (b), and
6
6
pyridine-d (c).
5
C(15)H + DMSO
2
C(5a)
C(19)
C(17),
C(18),
C(20), C(21)
1
70
160
150
140
130
120
110
100
60
50
40
30

Fig. 4. 13C NMR spectrum (DMSO-d , 151 МHz) of compound 9a recorded in the J-modulation mode.
6
It is clearly seen in the HMQC spectrum (Fig. 6) that
there are through-one-bond coupling between the C(19)
meta-proton (H 7.36) and the C(18) and C(20) carbon
nuclei ( 129.17). The spectra recorded in acetone-d and
C
6
carbon nucleus ( 128.42) and the H(19) para-proton of
pyridine-d are similar and, although the chemical shifts
C
5
the benzene ring ( 7.30); between the H(17) and H(21)
differ, the arrangement of cross-peaks remains the same.
H
ortho-protons (H 7.43) and C(17) and C(21) carbon
In the HMQC spectrum (DMSO-d ) corresponding
6
nuclei (C 129.52); and between the H(18) and H(20)
to aliphatic proton range (Fig. 7), one can clearly see that

3
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Fedorov et al.

2
3
4
5
6
7
8
C(15)H /H
2
o
C(15)H /H
2
o
7
.8
7.4
7.0
6.6
6.2
5.8
5.4
5.0
4.6
4.0

Fig. 5. Fragment of the NOESY spectrum (DMSO-d ) of compound 9a.
6
the C(15)H S protons ( 4.48) are coupled with the C(15)
2
H
carbon atom ( 39.58), whose signal partly overlaps with
C
the solvent signal; the H(5) proton (H 4.26) is coupled
with the C(5a) carbon atom (C 58.12); and the H(8)
and H(8) protons, whose signals partly overlap with the

signal of water present in the solvent ( 3.43), are coupled
H
1
1
1
24
26
28
with the C(8) nucleus ( 47.25). The protons resonating at
C
H 2.48 (partly overlap with the solvent signal) and  1.96
H
(
multiplet) are coupled with one and the same carbon
atom ( 26.21). The remaining two protons ( 1.89 and 1.78)
C
H
C(19)/H(19)
are coupled with the carbon atom manifested at  23.86.
C
In the HMQC spectrum recorded in acetone-d , the
6
signal of H(8) and H(8) protons, which coincides with
the signal of water in DMSO-d , is manifested as two
6
multiplets at  3.52 and 3.60. These protons are coupled
H
C(18,20)/H(18,20) 130
with the carbon atom at C 46.82. The same pattern is
observed in the HMQC spectrum recorded in pyridine-d5.
The HМВC spectrum allows complete assignment of
the 13C NMR signals (Fig. 8). It can be seen that the
C(17,21)/H(17,21)
1
1
1
1
32
34
36
C(15)H S protons are coupled with both the already as-
2
signed C(17)—C(21) five carbon atoms of the benzene
ring and a carbon atom ( 135.95) that is, in turn, coupled
C
with aromatic protons. Hence, this is the signal of the sixth
carbon atom of the benzene ring, C(16), which is directly
linked to the C(15)H methylene group. The carbon signal
2
at  153.72 can be assigned in a similar way. This signal
C
belongs to the nucleus coupled with both the C(15)H2S
protons and the N(4)H protons. This condition is met
most closely by the C(2) carbon atom of the thiophene
ring, which is linked to two sulfur atoms. The carbon
38
7
.8
7.4
7.0
6.8

Fig. 6. Aromatic proton region in the HMQC spectrum
(DMSO-d ) of compound 9a.
signal at  137.56 can be assigned in a similar way. This
C
6

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
399

2
3
4
5
6
0
0
0
0
0
H(15)/C(15)
H(8)/C(8)
H(5)/C(5a)
4.0
4
.5
3.5
3.0
2.5
2.0
1.5

Fig. 7. Aliphatic proton region in the HMQC spectrum (DMSO-d ) of compound 9a.
6

1
3
5
7
9
1
1
1
1
0
0
0
0
0
10
30
50
70
HN/C(3)
H(15)/C(17—21)
H(15)/C(16)
H(8,)/C(10)
H(15)/C(2)
HN/C(2)
1
2.0
11.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0

Fig. 8. HMBC spectrum (DMSO-d ) of compound 9a.
6

4
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Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
Fedorov et al.
carbon atom is coupled with both the N(4)H proton and
the H(5) methine proton of the pyrrolidine ring. This
condition is met for the C(10b) atom of the thiophene ring
linked to the N(4) atom. Then, the carbon signal at
C 123.65 should belong to the C(10a) carbon of the thio-
phene ring, because this atom is coupled with the N(4)H
and 3.47). A similar picture is observed in pyridine-d5.
This confirms the assignments of the methylene protons
1
13
made previously on the basis of H— C HMBC spectra;
however, the assignment of all magnetically nonequivalent
protons on the basis of spectral lines alone is impossible.
The calculation of the potential energy surface by the
1
4
proton and the C(8)H methylene protons of the pyrro-
Gaussian program using the Berny algorithm demon-
strated the possibility of existence of at least four conform-
2
lidine ring.
The signals of the other carbon atoms can also be as-
ers differing in both the position of the C(7)H methylene
2
signed without special difficulties. The signal at  169.03
group of the pyrrolidine ring either below or above the ring
C
belongs to the C(5) nucleus, which is linked to the
N(4) atom, since there is coupling with the N(4)H amide
proton, the H(5) proton, and two pyrrolidine ring protons
and the position of the SCH Ph moiety relative to the
2
heterocyclic system (K1—4) (Fig. 10).
1
The simulated H NMR spectra of conformations K2
(
H 2.48 and 1.96). According to the HMQC data, these
and K3 of compound 9a do not differ significantly from
the spectra of conformation K1; therefore, only conforma-
tions K1 and K4 are shown in Fig. 10.
protons are coupled with the carbon signal at C 26.21,
which implies that this carbon can be identified as C(6),
while the signals at H 1.96 and 2.48 can be assigned to
H(6) and H(6), respectively. Similarly, the carbon
signal at C 23.86 and the proton signals at H 1.89 and
According to the density functional theory simulation
1
3
13
of the C NMR spectra, the C chemical shifts of all
conformers differ quite little (Table 1).
1
1
.78 can be assigned to the C(7)H methylene group.
Meanwhile, the simulated H NMR spectra of con-
2
The carbon signal at  159.43 refers to C(10) bonded
formers 9a-K1 and 9a-K4 are considerably different
C
1
to N(9), because coupling with the H(5), H(8), and
(Table 2). As can be seen from Table 2, the H NMR
H(8) protons is observed. Out of the two remaining
spectrum of 9a-K1 and 9a-K4 differ in the position and
multiplicity of the H(5), H(8), and H(8) proton sig-
nals. In the case of conformer 9a-K1, the H(5) proton
signal is a doublet, since the spin—spin coupling constant
with H(6) is fairly low, the H(8) and H(8) signals are
located closely, with the lower-field multiplet for H(8)
having a simpler structure because of lower constant
carbon atoms, the atom at  104.49 is coupled with the
C
N(4)H amide proton and, hence, is coupled with the
C(3) atom of the thiophene ring, while the carbon atom
at  112.55, with no coupling with protons, is assigned
C
to the C(22)N carbon atom of the nitrile group.
The methylene protons of the pyrrolidine ring were
assigned on the basis of analysis of the cross-peaks in the
3
J7,8. In the case of conformer 9a-K4 where the constants
1
1
3
3
H— H NOESY spectra recorded in DMSO-d and
J5,6 and J
are nearly equal, the signal of the H(5)
6
5,6
pyridine-d (Fig. 9) and computer modeling data. The
proton is a distorted triplet, the H(8) and H(8) signals
are spaced apart by more than 1 ppm, and the H(8) signal
is thus located between signals of the H(5) and C(15)H2
protons; the signal multiplicity also changes due to low
5
cross-peaks between H(5) (H 4.26 in DMSO-d and
6
H 4.23 in pyridine-d ) and the protons resonating at
5
H 1.96 and 2.48 (DMSO-d ) confirm the HMBC-based
6
3
assignment of these protons to H(6) and H(6) at C(6).
The H(6) and H(6) protons also have cross-peaks
with the H(7) and H(7) protons (H 1.78 and 1.89),
J7,8. It is most likely that this considerable difference
1
in the H NMR spectra is due to the difference between
the O=C(10)—C(8)—H(8) and O=C(10)—C(8)—H(8)
dihedral angles (see Fig. 10, b and d and Table 3).
which are, in turn, coupled with H(8) and H(8) ( 3.41
H
Table 1. 13C NMR chemical shifts of the pyrrolodiazepine moiety of conformers 9a-K1—4 according
1
3
to B3LYP/6-31G** calculation and according to experimental C NMR spectrum of compound 9a
recorded in acetone-d6
Atom C
C
Calculation
Experiment
K1
K2
K3
K4
(
CH -down)
(CH -down)
(CH -down)
(CH -up)
2
2
2
2
C(5)
C(5a)
C(6)
C(7)
C(8)
C(10)
168.68
60.7
29.84
27.15
49.96
159.09
168.81
60.56
29.99
27.04
50.13
159.12
168.58
60.31
29.84
26.99
50.07
159.18
168.33
60.6
30.56
24.24
48.22
159.8
168.32
57.94
26.03
23.54
46.82
159.23

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
401
a

0
1
1
2
2
3
3
4
4
.5
.0
.5
.0
.5
.0
.5
.0
.5
H(5)/H(6)
H(6)/H(7)
H(5)/H(6)
H(7)/H(8)
H(7)/H(8)
4
.4
4.0
3.6
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
,
b

0
.5
.0
.5
.0
.5
1
1
2
2
H(7)/H(8)
H(8)/H(6)
H(7)/H(8)
3.0
H(5)/H(6)
H(5)/H(6)
3
.5
4
.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8

Fig. 9. Fragments of the NOESY spectra of compound 9a recorded in DMSO-d (a) and pyridine-d (b).
6
5
It can be seen in Fig. 10, a and b that the O=C—N—
C—H dihedral angles in conformer 9a-K1 account for the
virtually equal H(8)...O(11) and H(8)...O(11) distances,
which should lead to similar chemical shifts of these pro-
tons. In conformer 9a-K4, the H(8) proton is actually
located in the carbonyl group plane. This arrangement

4
02
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
a
Fedorov et al.
b
c
d
Fig. 10. General view of the molecule (two projections) of compound 9a in conformations 9a-K1 (a, b) and 9a-K4 (c, d).
Table 2. Chemical shifts and spin-spin coupling constants in the pyrrolodiazepine moiety for conformers 9a-K1 and 9a-K4 according
1
to the B3LYP/6-311G* calculation and according to experimental H NMR spectra of compound 9a measured in acetone-d
6
Proton
H (J/ Hz)
Calculation
Experiment
9
a-K1
9a-K4
3
3.91 (3J5,6= 8.3, J
3
H(5)
H(6)
H(6)
H(7)
H(7)
H(8)
H(8)
C(15)H2
3.85 (3J5,6= 0.36, J
= 8.4)
= 7.2)
4.37 (J5,6 = 8.1)
5,6β
56β
2.63 (2J6,6= –12.8, J
3
= 11.3, J6,7= 6.4) 2.61(2J6,6= –13.6, J
3
3
= 6.5, J6,7= 11.8) 2.13 or 2.68
3
6,7
= 6.4, J
6,7
= 0.18, J
3
3
3
3
2.08 ( J
= 0.25)
2.09 ( J
= 6.4)
2.13 or 2.68
6
,7
6,7
6,7
6,7
1.91 (2J7,7= –12.6, J
3
= 7.2, J7,7= 10.5) 1.94 (2J7,7= –12.5, J
3
3
= 5.3, J7,7= 0.13) 1.93 or 1.99
3
7,8
7,8
3
3
3
3
1.93 ( J
= 0.11, J7,8= 5.8)
1.88 ( J
= 10.2, J7,8= 7.4)
1.93 or 1.99
3.52 or 3.60
3.52 or 3.60
4.40
7
,8
7,8
2
2
3.49 ( J8,8= –11.9)
3.06 ( J8,8= –12.2)
3.45
4.22
4.20
4.22
should induce a downfield shift of the H(8) signal, because
of the anisotropic effect of oxygen atom, while the signal
of the H(8) proton should shift upfield. The same effect
may account for the difference between the chemical shifts
of H(6) and H(6), since the dihedral angles in both
conformers are such that the H(6) proton is located ap-
proximately in the plane of the O(12) oxygen atom.
Table 3. Selected dihedral angles (deg.) in conformers 9a-K1 and
a-K4 according to B3LYP/6-31+G* calculations
9
Angle
9a-K1
9a-K4
O=C(10)—C(8)—H(8)
–54.1
53.9
–18.2
88.2
–29.5
–147.9
1
O=C(10)—C(8)—H(8)
Analysis of the simulated and experimental H NMR
H(H5)—C(5a)—C(6)—H(H6)
H(H5)—C(5a)—C(6)—H(H6)
25.1
spectra, together with the results of molecular modeling
enable one to make an unambiguous choice between the
–94.8

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
403
conformations 9a-K1 and 9a-K4. The proton chemical
shifts in the experimental spectrum of 9a coincide most
closely with the calculated values for 9a-K1. The presence
of two cross-peaks between H(5) (H 4.26 (DMSO-d6)
4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e]-
[1,4]diazepine-5,10-dione (9a) was carried out and the
most probable conformation of 9a in solution was deter-
mined by means of special heteronuclear magnetic reso-
nance and computer simulation experiments.
and H 4.23 (pyridine-d )) and H(6), H(6) (H 1.96,
5
2
.48 (DMSO-d ) and H 1.93, 2.79 (pyridine-d )) in the
6
5
NOESY spectrum of compound 9a (see Fig. 9) attests in
favor of conformer 9a-K1, since the arrangement of atoms
brings about through-space interaction between the H(5),
H(6) and H(5), H(6) protons. In the spectrum of
Experimental
NMR spectra were recorded in DMSO-d , acetone-d , and
6
6
1
pyridine-d using Bruker AM300 (300.11 ( H) and 75.46 MHz
5
1
3
1
13
9
a-K4, a cross-peak may arise between the H(5) and
( C)) and Bruker AM600 (600.22 ( H) and 150.93 MHz ( C))
H(6) protons, but the contact between H(5) and H(6)
is completely ruled out, since these protons are located on
different sides of the plane that passes through the C(5a),
C(6), C(8), and C(9) atoms. The absence of cross-peaks
between the H(5) and H(7, H(7) protons (H 1.78,
instruments at room temperature. The chemical shifts were re-
ferred to the residual signals of the corresponding deuterated
solvent (acetone-d :  2.05, C 29.92; DMSO-d :  2.51,
6
H
6
H
C 39.50; pyridine-d :  8.74, C 150.53), which were used as
5
H
internal standards. IR spectra were measured on a Bruker Alpha-Т
instrument for KBr pellets. UV spectra were obtained on
a Specord M80-2 instrument. The optical rotation angles were
measured on a Jasco P2000 automatic and an SM-2 manual
polarimeter. Melting points were determined on a Koefler hot
stage and were not corrected. Commercially available chemicals
were used. 2-Chloroacetamide of S-proline was synthesized
1
.89 (DMSO-d ) and H 1.73, 1.86 (pyridine-d )) also
6
5
attest in favor of conformer 9a-K1, since the contact be-
tween H(5) and H(7) is possible in 9a-K4 and ruled out
in 9a-K1.
All proton signals can be assigned by joint consideration
of molecular modeling data and the NOESY spectra.
5
by a known procedure. The solvents were purified by simple
distillation.
Evidently, the proton signal at  2.48 (DMSO-d ) belongs
H
6
Combinatorial synthesis of (5aS)-2-benzylthio-3-cyano-
,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-
to H(6), while the proton signal at H 1.96 corresponds
to H(6). The presence of cross-peak between H(6) and
the proton resonating at H 1.78 gives grounds to identify
the latter proton as H(7), while the signal at H 1.89
should be assigned to H(7). The assignment of H(8)
and H(8) signals presents certain difficulties as they
overlap with the signal of water in the solvent; neverthe-
less, thorough analysis of the NOESY spectrum reveals
4
diazepine-5,10-diones 9a—e (general procedure). Malononitrile
(1) (1.65 g, 25 mmol) was added with stirring to a solution of
KOH (2.8 g, 50 mmol) in 95% ethanol (100 mL). After dissolu-
tion, carbon disulfide (2) (3.8 g, 25 mmol) was added in one
portion. The mixture was stirred for 10 min at room temperature
(if a precipitate formed, water was added dropwise until the
precipitate completely dissolved). Solutions of compound 4 (4.8 g,
2
5 mmol) in ethanol (25 mL) and KOH (1.4 g, 25 mmol) in
two cross-peaks, one correlates the H(7) proton ( 1.78)
H
ethanol (50 mL) were added to the resulting solution. The mix-
ture was stirred for 15 min at room temperature and then refluxed
for 40 min. After cooling, the solution was diluted to a 200 mL
volume with 95% ethanol and separated into five 40-mL portions.
The specified benzyl chloride 7a—e (5 mmol) was added to each
portion with magnetic stirring. The mixture was stirred for 20 min
at room temperature, then acidified with concentrated HCl to
pH 1. Stirring was continued for an additional 1 h, the precipitate
that formed was collected on a filter, and washed successively
with a higher-field proton, evidently, H(8), while the
other correlates H(7) ( 1.89) with the low-field H(8)
C
proton, the signal of which fully overlaps with the signal
of water. The absence of cross-peaks between H(6) and
H(8, H(8) and the presence of a cross-peak between
H(6) and H(8) also attest for conformation 9a-K1.
The NOESY spectrum (pyridine-d ) of compound 9a
5
also exhibits a cross-peak between H(6) (H 1.93) and
with a saturated solution of NaHCO , water, ethanol, and hex-
ane. The products were recrystallized from propan-2-ol.
3
H(8) ( 3.64), which supports the previous assignment.
H
In this respect, it is of interest to compare the NOESY
(
5aS)-2-Benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-
spectra recorded in DMSO-d and pyridine-d (see Fig. 9).
6
5
pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione (9a). Yield
It can be plainly seen that cross-peaks between the H(8),
H(8) and H(7), H(7) protons exchange places, which
supports the assumption that the signals of the H(7) and
H(7) protons in the spectra recorded in pyridine-d5
exchange places. This phenomenon is probably attributable
to the specific solvation of molecule 9a by pyridine.
Thus, we developed a convenient method for the
synthesis of a relatively complex heterocyclic system,
1
.6 g (80%). Yellowish powder, m.p. 124 C (propan-2-ol).
1
H NMR (300 MHz, DMSO-d ), : 1.84 (m, 3 H); 2.41 (m, 1 H,
6
partly overlaps with the solvent signal); 3.42 (m, 2 H, overlaps
with the water signal), 4.23 (m, 1 H); 4.46 (s, 2 H); 7.37 (m, 5 H);
1
1
1.12 (s, 1 H, NH). H NMR (600 MHz, DMSO-d ), : 1.78
6
(
m, 1 H, H(7)); 1.89 (m, 1 H, H(7)); 1.96 (m, 1 H, H(6));
2
.48 (m, 1 H, H(6)); 3.41 (m, 1 H, H(8)); 3.47 (m, 1 H,
3
H(8)); 4.26 (d, 1 H, H(5), J5,6= 8.1 Hz); 4.48 (s, 2 H,
C(15)H ); 7.30 (m, 1 H, H(19)); 7.36 (m, 2 H, H(18), H(20));
7
2
4
,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e]-
1,4]diazepine-5,10-diones, from simple and readily ac-
cessible starting compounds. Full assignment for the
1
.43 (m, 2 H, H(17), H(21)); 11.13 (1 H, NH). H NMR
[
(
600 MHz, acetone-d ),: 1.93 (m, 1 H, H(7)); 1.99 (m, 1 H,
6
H(7)); 2.13 (m, 1 H, H(6)); 2.68 (m, 1 H, H(6)); 3.52
(m, 1 H, H(8)); 3.60 (m, 1 H, H(8β)); 4.37 (d, 1 H, H(5),
1
13
H and C NMR signals of (5aS)-2-benzylthio-3-cyano-

4
04
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
Fedorov et al.
3J5,6 = 8.1 Hz); 4.48 (s, 2 H, C(15)H ); 7.33 (m, 1 H, H(19));
(15230), 324 (11950). IR, /cm–1: 3210 (NH), 3134, 2979, 2226
(CN); 1685 (CO), 1631 (CO), 1550, 1510, 1487, 1425, 1340,
1306, 1294, 1269, 1251, 1217,1178, 1158, 1103, 1092, 1071, 1044,
2
7
.38 (m, 2 H, H(18), H(20)); 7.47 (m, 2 H, H(17), H(21)); 9.96
1
(
1 H, NH). H NMR (600 MHz, pyridine-d ),: 1.73 (m, 1 H,
5
2
0
H(7)); 1.86 (m, 1 H, H(7)); 1.93 (m, 1 H, H(6)); 2.79
1012. []D +81 (+36) (с 0.45, DMSO). Found (%): C, 48.15;
H, 3.21; N, 9.47. C18H14BrN O S . Calculated (%): C, 48.22;
(
4
7
m, 1 H, H(6)) 3.56 (m, 1 H, H(8)); 3.61 (m, 1 H, H(8));
3
2 2
3
.23 (d, 1 H, H(5), J
= 8.1 Hz); 4.40 (s, 2 H, C(15)H );
H, 3.15; N, 9.37.
5
,6
2
.24 (m, 1 H, H(19)); 7.30 (m, 2 H, H(18), H(20)); 7.43 (m, 2 H,
(5aS)-2-3-Cyano-[(4-methylbenzyl)thio]-4,5a,6,7,8,10-hexa-
hydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione
(9d). Yield 1.51 g (79%). Yellowish powder, m.p. 192 C (propan-
13
H(17), H(21)); 8.70 (1 H, NH). C NMR (600 MHz, DMSO-d ),
6

5
1
1
1
2
: 23.86 (C(7)), 26.21 (C(6)), 39.58 (C(15)), 47.25 (C(8)),
8.12 (C(5a)), 104.49 (C(3)), 112.55 (C(22)), 123.65 (C(10a)),
28.42 (C(19)), 129.17 (C(18), C(20)), 129.52 (C(17), C(21)),
36.25 (C(16)), 137.56 (C(10b)), 153.72 (C(2)), 159.43 (C(10)),
1
2-ol). H NMR (DMSO-d ), : 1.88 (m, 3 H, H(7), H(7),
6
H(6)); 2.28 (s, 3 H, CH ); 2.45 (m, 1 H, H(6), partly overlaps
3
with the solvent signal); 3.42 (m, 2 H, H(8), H(8), partly
69.03 (C(5)). 13C NMR (600 MHz, acetone-d ), : 23.54 (C(7)),
overlaps with the water signal); 4.24 (m, 1 H, H(5)); 4.43 (s, 2 H,
6
3
6.03 (C(6)), 39. 92 (C(15)), 46.82 (C(8)), 57.94 (C(5a)), 105.20
C(15)H ); 7.36 (d, 2 H, H , J = 7.6 Hz); 7.53 (d, 2 H, HAr,
2
Ar
2,3
3
13
(
(
(
(
(
(
C(3)), 111.59 (C(22)), 124.06 (C(10a)), 128.04 (C(19)), 128.76
C(18), C(20)), 129.15 (C(17), C(21)), 135.58 (C(16)), 137.05
J2,3 = 7.6 Hz); 11.09 (s, 1 H, NH). C NMR (DMSO-d ), :
6
20.76, (CH ) 23.42 (C(7)), 25.78 (C(6)), 39.00 (C(15)), 46.80
3
13
C(10b)), 152.77 (C(2)), 159.23 (C(10)), 168.32 (C(5)). C NMR
(C(8)), 57.67 (C(5a)), 104.09 (C(3)), 112.12 (C(22)), 123.09
(C(10a)), 129.00 (CAr), 129.29 (CAr), 130.58 (CAr), 132.37 (CAr),
137.30 (C(10b)), 153.49 (C(2)), 158.98 (C(10)), 168.58 (C(5)).
600 MHz, pyridine-d ), : 23.84 (C(7)), 26.39 (C(6)), 40.44
C(15)), 47.16 (C(8)), 58.25 (C(5a)), 105.26 (C(3)), 112.79
C(22)), 124.16 (C(10a)), 128.24 (C(19)), 128.98 (C(18), C(20)),
5
UV (MeOH), /nm (): 256 (9960), 322 (7400). IR, /cm–1
:
1
29.32 (C(17), C(21)), 135.61 (C(16)), 137.95 (C(10b)), 153.58
3207 (NH), 3132, 2981, 2226 (CN); 1687 (CO), 1627 (CO),
1548, 1510, 1427, 1398, 1360, 1341, 1317, 1307, 1294, 1268,
(
C(2)), 159.61 (C(10)), 168.97 (C(5)). UV (MeOH), /nm ():
58 (20700), 321 (16200). IR, /cm– : 3212 (NH), 3134, 2984,
1
1253, 1218,1182, 1159, 1042, 1022. []D +93 (+60) (с 0.45,
20
2
2
1
220 (CN); 1699 (CO), 1627 (CO), 1542, 1508, 1498, 1425,
DMSO). Found (%): C, 59.48; H, 4.51; N, 10.87. C H N O S .
19 17 3 2 2
2
0
383, 1289, 1254, 1216, 1188, 1157, 1041. []D +93 (+105)*
Calculated (%): C, 59.51; H, 4.47; N, 10.96.
(
с 0.45, DMSO). Found (%): C, 58.46; H, 4.11; N, 11.47.
(5aS)-3-Cyano-2-[(2,6-difluorobenzyl)thio]-4,5a,6,7,8,10-
hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-
dione (9e). Yield 1.4 g (69%). Yellowish powder, m.p. 118 C
C18H15N O S . Calculated (%): C, 58.52; H, 4.09; N, 11.37.
3
2 2
(
5aS)-2-[(4-Chlorobenzyl)thio]-3-cyano-4,5a,6,7,8,10-hexa-
1
hydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione
(propan-2-ol). H NMR (DMSO-d ), : 1.89 (m, 3 H, H(7),
6
(
2
9b). Yield 1.74 g (86%). Yellowish powder, m.p. 176 C (propan-
H(7), H(6)); 2.42 (m, 1 H, H(6), partly overlaps with the
1
-ol). H NMR (DMSO-d ), : 1.88 (m, 3 H, H(7), H(7),
solvent signal); 3.44 (m, 2 H, H(8), H(8), partly overlaps with
6
H(6)); 2.43 (m, 1 H, H(6), partly overlaps with the solvent
signal); 3.43 (m, 2 H, H(8), H(8), partly overlaps with the
the water signal); 4.24 (m, 1 H, H(5)); 4.38 (s, 2 H, C(15)H );
2
7.11 (m, 2 H, HAr); 7.43 (m, 1 H, HAr); 11.16 (s, 1 H, NH).
1
3
water signal); 4.25 (m, 1 H, H(5)); 4.46 (s, 2 H, C(15)H ); 7.41
C NMR (DMSO-d ), : 23.40 (C(7)), 25.81 (C(6)), 28.39
2
6
1
3
(
m, 4 H, HAr); 11.10 (s, 1 H, NH). C NMR (DMSO-d ),
: 23.43 (C(7)), 25.80 (C(6)), 38.48 (C(15)), 46.83 (C(8)), 57.67
(C(15)), 46.87 (C(8)), 57.67 (C(5a)), 108.55 (C(3)), 111.68—
6
2
4

111.95 (dd, C(18), C(20), J
= 23.25 Hz, J
= 1.5 Hz),
C—F
C—F
2
(
(
1

C(5a)), 104.76 (C(3)), 112.04 (C(22)), 123.64 (C(10a)), 128.71
CAr), 130.90 (CAr), 132.61 (CAr), 134.84 (CAr), 137.13 (C(10b)),
111.74 (C(22)), 112.00 (t, C(16), JC—F = 9.2 Hz), 126.00
4
(C(10a)), 130.90 (т, C(19), J
= 9.8 Hz), 137.25 (C(10b)),
C—F
52.49 (C(2)), 158.95 (C(10)), 168.58 (C(5)). UV (MeOH),
149.20 (C(2)), 158.78 (C(10)), 158.88—162.87 (dd, C(17)—C(21),
/nm (): 256 (16160), 320 (11090). IR, /cm– : 3209 (NH),
1
1
JC—F = 248.76 Hz, J
3
= 7.5 Hz); 168.58 (C(5)). UV (MeOH),
C—F
–
1
3
1
1
131, 2975, 2227 (CN); 1686 (CO), 1631 (CO), 1551, 1509,
491, 1425, 1359, 1341, 1307, 1294, 1270, 1251, 1217,1177, 1158,
043, 1016. []D2 +86 (+102) (с 0.45, DMSO). Found (%):
/nm (): 250 (9970), 322 (6210). IR, /cm : 3230 (NH), 3112,
2977, 2978, 2223 (CN); 1706 (CO), 1625 (CO), 1591, 1544,
1506, 1432, 1375, 1273, 1238, 1213, 1157, 1105, 1042, 999.
0
2
0
C, 53.56; H, 3.51; N, 10.29. C18H14ClN O S . Calculated (%):
[]D +106 (+131) (с 0.45, DMSO). Found (%): C, 53.29;
H, 3.32; N, 10.44. C18H13F N O S . Calculated (%): C, 53.32;
3
2 2
C, 53.53; H, 3.49; N, 10.40.
5aS)-2-[(4-Bromobenzyl)thio]-3-cyano-4,5a,6,7,8,10-hexa-
hydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione
2
3
2 2
(
H, 3.23; N, 10.36.
Calculation procedure. The calculations were carried out
1
5
(
2
9c). Yield 1.97 g (88%). Yellowish powder, m.p. 181 C (propan-
using the Gaussian 09 program and the B3LYP hybrid poten-
1
15
-ol). H NMR (DMSO-d ), : 1.88 (m, 3 H, H(7), H(7),
tial. For all stationary points, frequencies were found to confirm
6
H(6)); 2.45 (m, 1 H, H(6), partly overlaps with the solvent
signal); 3.42 (m, 2 H, H(8), H(8), partly overlaps with the
the correspondence of the optimized geometry to the energy
minimum on the potential energy surface. The ratio of conform-
ers in solution was found by calculating frequencies using the
water signal); 4.25 (m, 1 H, H(5)); 4.44 (s, 2 H, C(15)H ); 7.36
2
3
3
16
(
d, 2 H, HAr, J = 9.0 Hz); 7.53 (d, 2 H, H , J = 9.0 Hz);
PCM solvation model in the specified solvent. The chemical
2,3
Ar
2,3
1
3
17,18
1
2
1.10 (s, 1 H, NH). C NMR (DMSO-d ), : 23.43 (C(7)),
shifts in Me CO were calculated in the GIAO approximation
6
2
1
6
5.80 (C(6)), 38.53 (C(15)), 46.83 (C(8)), 57.67 (C(5a)), 104.70
in the PCM model. To compare the theoretical and experi-
mental values, the calculated chemical shifts were converted to
the -scale by the formula
(
C(3)), 112.04 (C(22)), 121.15, 123.61 (C(10a)), 131.22 (CAr),
1
1
31.62 (CAr), 135.27 (CAr), 137.13 (C(10b)), 152.52 (C(2)),
58.95 (C(10)), 168.58 (C(5)). UV (MeOH), /nm (): 259
com = st – calc +0st
,
*
Here and below, the angles measured with the automatic
where com is the chemical shift of the test compound in the
-scale; calc is the calculated chemical shift of the test compound,
polarimeter are given in parentheses.

Pyrrolothienodiazepinediones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 2, February, 2021
405
st is the calculated chemical shift of the compound used as the
internal standard, 0st is the chemical shift of the internal standard
13. F. S. Teplyakov, T. G. Vasileva, M. L. Petrov, D. A. Androsov,
Org. Lett., 2013, 15, 4038.
in the -scale. Me Si served as the internal standard. The results
14. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin,
V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi,
N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zak-
rzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapp-
rich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,
J. Cioslowski, D. J. Fox, Gaussian 09, Revision A.1, Gaussian
Inc., Wallingford (CT), 2009.
4
1
9,20
were visualized using the Jmol 12.2.27 program package.
The authors are deeply grateful to V. P. Kislyi for inap-
preciable contribution to molecular modeling and inter-
pretation of the results.
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Received March 24, 2020;
in revised form July 29, 2020;
accepted October 23, 2020
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