Experimental and theoretical investigation of substituent effects in a two-pathway reaction of tetrahydro-1,5-benzodiazepine-2-thiones with 4-substituted 2-bromoacetophenones

Article abstract of DOI:10.1007/s00706-011-0496-4

The interaction of 5-acetyl(or formyl)-3-R¹(CH₃, H)-4-R²(CH₃, Ph, H)-1,3,4,5-tetrahydro-2H-1,5- benzodiazepine-2-thiones with 2-bromo-4′-X(CH₃, OCH ₃, Br, H)-acetophenones leads to a mixture of products: 5,6-dihydro-4H-[1,3]thiazolo[3,2-a][1,5]benzodiazepinium salts and S-[2-oxo-2-(4-X-phenyl)ethyl] 3-(1H-benzimidazol-1-yl)propane(or butane-)thioate hydrobromides. The course of the concurrent reactions depends on the presence of substituents of the starting thiones and on the nature of the 4-substituent of the bromoacetophenones. Semiempirical Austin method 1 (AM1) and density functional theory (DFT) B3LYP computational studies for the interpretation of two concurrent reaction pathways are presented.

Full text of DOI:10.1007/s00706-011-0496-4

Monatsh Chem (2011) 142:609–618
DOI 10.1007/s00706-011-0496-4
ORIGINAL PAPER
Experimental and theoretical investigation of substituent effects
in a two-pathway reaction of tetrahydro-1,5-benzodiazepine-
2-thiones with 4-substituted 2-bromoacetophenones
Regina Janciene
Zita Stumbreviciute
•
Ausra Vektariene
Benedikta Puodziunaite
•
•
Received: 3 March 2011 / Accepted: 30 March 2011 / Published online: 4 May 2011
Ó Springer-Verlag 2011
1
Abstract The interaction of 5-acetyl(or formyl)-3-R -
In previous papers [2–4] we reported a cyclofunctional-
2
CH , H)-4-R (CH , Ph, H)-1,3,4,5-tetrahydro-2H-1,5-
(
ization strategy of the 1,5-benzodiazepine system, which
exploited the reactivity of the C=S bond of the heptatomic
nucleus by interaction with a-halogen carbonyl compounds.
Tricyclic thiazolo[1,5]benzodiazepines were obtained
from 1,3,4,5-tetrahydro-1,5-benzodiazepine-2-thiones by
treatment with bromoacetaldehyde diethylacetal [2],
3
3
0
benzodiazepine-2-thiones with 2-bromo-4 -X(CH , OCH ,
3
3
Br, H)-acetophenones leads to a mixture of products: 5,6-
dihydro-4H-[1,3]thiazolo[3,2-a][1,5]benzodiazepinium salts
and S-[2-oxo-2-(4-X-phenyl)ethyl] 3-(1H-benzimidazol-
1
-yl)propane(or butane-)thioate hydrobromides. The course
0
of the concurrent reactions depends on the presence of
substituents of the starting thiones and on the nature of the
chloroacetone [3], and 2-bromo(or 2,4 -dibromo)acetophe-
nones [4]. In a recent paper [4] we reported that treatment of
the aromatic bromoketones with thiolactams, carrying
N(5)-acetyl substituents, gives rise to two concurrent reac-
tions leading to the corresponding thiazolobenzodi-
azepinium bromides and N-substituted benzimidazole
derivatives as a result of hydrolysis of starting compounds
followed by rearrangement. The bromoacetophenone reac-
tion carried out on N(5)-formyl- or N(5)-anilinocarbonyl-
substituted 1,5-benzodiazepine-2-thiones afforded only
tricyclic thiazolobenzodiazepines.
4
-substituent of the bromoacetophenones. Semiempirical
Austin method 1 (AM1) and density functional theory
DFT) B3LYP computational studies for the interpretation
(
of two concurrent reaction pathways are presented.
Keywords 5-Acyl-1,3,4,5-tetrahydro-2H-1,
5
-benzodiazepine-2-thiones ꢀ Cyclizations ꢀ
Density functional theory ꢀ Structure–activity
relationships ꢀ Semiempirical calculations
To extend our study, we present herein a detailed
investigation of the interaction of 5-acyl-1,5-benzodiaze-
pine-2-thiones with 4-substituted aromatic bromoketones.
The influence of substituents in the heptatomic nucleus of
the starting thiolactams and of the nature of 4-substituents
of aromatic ketones on the course of the studied interaction
was also elaborated. The estimation of local structure–
reactivity descriptors was performed using DFT and AM1
computations.
Introduction
In recent years, great effort has been applied in the ben-
zodiazepine area to develop new members of this family.
Among the new compounds are those containing different
heterocyclic rings annulated to the basic 1,5-benzodiaze-
pine system [1].
Results and discussion
R. Janciene (&) ꢀ Z. Stumbreviciute ꢀ B. Puodziunaite
Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
e-mail: regina.janciene@bchi.vu.lt
1
-Acetyl(or formyl)-3-R -4-R -1,3,4,5-tetrahydro-2H-1,5-
2
5
benzodiazepine-2-thiones 1–6, previously described by us
in [2] (compounds 2, 5, 6), [3] (compound 1), and [4]
(compound 4), were used as starting compounds to prepare
A. Vektariene
Institute of Theoretical Physics and Astronomy,
Vilnius University, Vilnius, Lithuania
123

6
10
R. Janciene et al.
cyclocondensation derivatives. Thione 3 was synthesized
by acylation of 2,3,4,5-tetrahydro-4-phenyl-1H-1,5-ben-
zodiazepin-2-thione [5] using the procedure described in
derivatives 8a and 8b (31% and 40% yields). In this case,
two reactions are equally possible. Analogously, two
products were obtained by treatment of thiolactam 1 with
0
[
4]. The reaction of thiolactams 1–6 with slight excess of
the appropriate 4-substituted bromoacetophenone [X =
CH (a), OCH (b), H (c)] was performed in refluxing
2,4 -dibromoacetophenone [X = Br (d)] or 2-bromoaceto-
phenone [X = H (c)] [4]. The reaction of 5-acetyl-4-
methyl(or phenyl)benzodiazepine-2-thiones 2 and 3 with
4-substituted bromoacetophenones (X = OCH , CH ) and
3
3
butan-2-one according to the procedure previously descri-
bed by us [4]. The reaction sequence is illustrated in
Scheme 1.
3
3
2-bromoacetophenone (X = H) afforded only 2-methyl-
benzimidazole derivatives 9a–9c and 10a–10c in moderate
yields (25–66%), whereas tricyclic benzodiazepines were
not formed. Thus, one of the concurrent reactions domi-
nated, namely the rearrangement of the heptatomic
diazepine ring to five-membered imidazole. In our previous
papers [2, 3], we described synthesis of thiazolo[1,5]
benzodiazepines from 4-methyl-substituted thiolactam 2
Thus, the treatment of 5-acetyl-3-methylbenzodiaze-
0
pine-2-thione (1) with 2-bromo-4 -methylacetophenone
0
[
X = CH3 (a)] or 2-bromo-4 -methoxyacetophenone
X = OCH3 (b)] gave a mixture of products: tricyclic
[
thiazolobenzodiazepinium bromides 7a and 7b (60% and
7% yields) and N-substituted 2-methylbenzimidazole
3
Scheme 1
X
S
S
Br
O
NH
N
N
i
ii
.
R1
HBr
O
R1
S
from 3
N
N
R2
R2
R1
O
R3
-6
R3
N
R2
1
1
2
O
R3
Int1a, Int1b, Int2a-Int2c,
Int3a-Int3c, Int4a, Int4b
from 1,5
from 1-4,6
from 6
X
Br
.
HBr
R3
N
N
.
HBr
R3
R1
S
N
N
N
R1
R1
X
R2
N
R2
R2
S
O
O
OH
5a
R3
O
O
1
8a, 8b, 9a-9c, 10a-10c,
3a, 13b, 16a
7
a, 7b, 14a
1
X = CH (a), OCH (b), H (c)
i: BrCH2COPh-X(p), C2H5COCH3, reflux, 2-3 h
ii: BrCH CH(OC H ) , C H COCH , reflux, 1 h
3
3
2
2
5 2
2
5
3
R1
R2
H
R3
1
2
3
4
5
6
, Int1a, Int1b, 7a, 7b, 8a, 8b
, Int2a-Int2c, 9a-9c
, Int3a-Int3c, 10a-10c, 11, 12
, Int4a, Int4b, 13a, 13b
, 14a
CH3
H
CH3
CH3 CH3
H
H
CH3
H
Ph
H
H
CH3
CH3
H
, 15a, 16a
H
H
1
23

Experimental and theoretical investigation of substituent effects in a two-pathway reaction
611
by treatment with a-bromoacetaldehyde diethylacetal or
chloroacetone. In those reactions, the corresponding benz-
imidazole derivatives were not separated. Analogously,
cyclocondensation of 4-phenyl-substituted thiolactam 3 with
bromoacetaldehyde diethylacetal afforded only tricyclic
thiazole 12.
Finally, the reaction of 5-formyl-substituted thiolactams
5, 6 [2, 7] with 4-substituted acetophenones also proceeded
differently. The treatment of 3-methylbenzodiazepine-2-
0
thione 5 with 2-bromo-4 -methylacetophenone [X = CH
3
(a)] gave the thiazolobenzodiazepine 14a. A trace of the
corresponding benzimidazole derivative was detected by
TLC analysis, but was not isolated. Reaction of thiolactam
6 with the same bromoacetophenone gave two benzimid-
azole derivatives 15a and 16a in 27% and 30% yields.
The structure of the studied compounds was investigated
The isolation of compounds 9a–9c and 10a–10c was
rather intricate due to the resinification of the reaction
mixtures. It is noteworthy that the conversion of the staring
thioamides into the corresponding amides was observed by
thin-layer chromatography (TLC) in all cases. Thus, in the
reaction of thiolactam 3 with the corresponding bromo-
acetophenones [X = CH (a), OCH (b), H (c)], 5-acetyl-
1
13
using infrared (IR) and H and C nuclear magnetic res-
onance (NMR) spectra. For the description of NMR
spectra, we used the arbitrary numbering of atoms as in
Scheme 2 (I for compounds 8a, 8b, 9a–9c, 13a, 13b, 15a,
and 16a; II for compounds 10a–10c).
3
3
1
,3,4,5-tetrahydro-4-phenyl-2H-1,5-benzodiazepin-2-one
1 [6] was isolated (in 11–15% yields) from the reaction
1
resin residue. Attempts to optimize the cyclization reaction
conditions were not successful. Synthesis of 9b performed
in acetone or benzene solutions proceeded slowly, and only
the S-alkyl intermediate Int1b was detected (TLC analysis).
The experiment performed in refluxing toluene (compound
Spectral signals were consistent with the analogous
structures previously proposed by us in [4]. The existence
1
of a singlet signal of the proton of 2-CH group in the H
NMR spectra of compounds 7a, 7b, and 14a (8.34, 8.50,
and 8.33 ppm) confirms the formation of the thiazole
nucleus. The signal of the aromatic H-10 proton of
compound 7b at 7.3 ppm is shifted upfield with respect to
the signals of the same proton of compound 12 (H-10,
8.44 ppm) and 1-methylthiazolobenzodiazepines [3],
probably due to the anisotropic effect of the benzene ring in
1
0b) led to replacement of sulfur by the oxygen atom in
starting compound 3, whereas the reaction in dichloroeth-
ane afforded the same result as in butan-2-one. The
formation of S-alkylated 1,5-benzodiazepine derivatives as
intermediates was observed in all experiments by TLC
monitoring of reaction progress. In our previous paper [4],
the structure of S-alkyl intermediates formed in the first step
of the condensation–cyclization reaction was confirmed.
Furthermore, we can point out that the reaction of thio-
lactam 4, carrying no substituents in the 3- and 4-positions
of the diazepine nucleus, proceeded differently as compared
0
1-position. The low-field-shifted H-2 proton signals at 9.55
1
(CD OD) and 10.09 ppm (CDCl ) in the H NMR spectra
3
3
of compounds 15a and 16a are characteristic of the benz-
imidazole ring.
Consequently, the presented study of the interaction of
1
2
5-acyl-3-R -4-R -1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-
2-thiones 1–6 with 4-substituted aromatic bromoketones
suggests that two concurrent reactions take place: the
cyclization reaction resulting in the formation of tricyclic
thiazolo[1,5]benzodiazepinium salts 7a, 7b, 14a and acidic
hydrolysis leading to rearrangement of the diazepine
heterocycle to five-membered imidazole derivatives 8a, 8b,
9a–9c, 10a–10c, 13a, 13b, 16a. The course of the studied
interaction (i.e., whether both reactions occur simulta-
neously or one of them dominates) depends on the presence
of substituents of the starting thiones 1–6 in 3- and
with that of thiolactam 1. By treating compound 4 with
0
2
-bromo-4 -methyl (or methoxy) acetophenones [X = CH
3
(
a), OCH (b)], benzimidazole derivatives 13a and 13b
3
were the only products of the reaction, while the reaction of
0
compound 4 with 2-bromo (or 2,4 -dibromo) acetophenones
[
X = H (c), Br (d)] yielded a mixture of the corresponding
tricyclic thiazolobenzodiazepine and benzimidazole deriv-
atives [4]. We can presume that these cycloaddition
reactions are also influenced by the nature of the 4-sub-
stituents of bromoacetophenones.
Scheme 2
3'
N
3
'
O
5 6 1'' 6''
2''
4
'
3a'
7'
N
R3
O
O
2'
3
4'
3a'
O
1
'
5
'
1
2
'
N
S
1
'
4
S
5
6
1'' 6''
7a'
2'''
5'
2
4
N
5''
4''
7
a'
6'
3
2
1
1
5
''
2
''
R
6'
1'''
7'
3''
R2
R1
4''
X
6
'''
3
'''
3
''
X
4
'''
5'''
I
II
123

6
12
R. Janciene et al.
1
-positions (R = CH , H, R = CH , Ph, H) and on the
2
4
calculation of the geometries and energies of benzofused
heterocycles. Nevertheless, analysis of aromatic com-
pounds and large bioorganic heterocyclic systems shows
that AM1 Hamiltonian approximations based Fukui func-
tions and other reactivity descriptors correctly determine
reactivity features in the active sites of molecules [15, 16].
It is worth noting that a molecular electrostatic potential
based on the molecular electron density surface is a good
indicator for the interpretation of chemical reactivity. It
gives a suitable description of molecular properties, such as
strong noncovalent interactions that are predominantly
electrostatic in nature. It has been shown [13, 14, 17] that
the shell close to the van der Waals surface gives physi-
cally reasonable molecular dimensions and reflects
molecular features, such as bond formation and electron
lone pairs. Therefore, we calculated atom-centered point
charges fitted to the electrostatic potential (ESP) on the
shell held near the surface of a molecule at the van der
Waals radii [17, 18].
3
3
nature of the 4-substituent of the bromoacetophenones.
Our earlier investigations [4] of the reaction mechanism
in terms of the reaction potential-energy surface calcula-
tions showed that the first step of the studied interaction is
common to both pathways and proceeds through the for-
mation of the intermediates (Int, Scheme 1). In this work,
with the aim of estimating the regiochemical outcome of
the pending interaction, we extended our computational
investigations to selected reaction intermediate structures
Int1a-Int1d, Int1x, Int2a-Int2c, Int3a-Int3c, Int4a-Int4d
[
X = CH (a), OCH (b), H (c), Br (d)]. The optimal
3 3
geometry structure of Int1b is presented in Fig. 1 as an
example.
It is evident that the intermediate structure consists of the
1
,5-benzodiazepine-2-thione skeleton and the 4-substituted
acetophenone moiety. Such molecular geometry allows us to
estimate the influence of all substituents on the regiochem-
ical outcomes of the studied cyclization processes. The
C(3)=O and C(2)-S carbon atoms and the N(1)-C(2) bond
are the most important molecular sites for initialization of
the two concurrent reaction pathways. We focused our
attention on the estimation of reactivity indexes for these
atoms. We calculated optimal geometries of reaction
intermediate structures Int1a-Int1d, Int1x, Int2a-Int2c,
Int3a-Int3c, Int4a-Int4d and their local reactivity indexes
at two different levels of theory: density functional theory
Moreover, the hard and soft acids and bases (HSAB)
principle has been very useful to predict the reactivity of
chemical systems. The HSAB principle has been used by
Parr and Yang [19] in terms of DFT concepts for expres-
sion of local reactivity indexes such as the Fukui function.
The Fukui function is a local reactivity descriptor that
indicates the best way to change the number of electrons in
a molecule. Hence, it indicates the propensity of the elec-
tronic density to deform at a given position, i.e., to accept
or donate electrons [20]. We calculated the condensed
Fukui function [19, 21, 22] for nucleophilic attack [f?(r)]
on the particular atoms of intermediates [C(2) and C(3)] as
the most important for the interpretation of the outcome of
the reaction.
(
DFT) and the Hartree–Fock–Roothaan semiempirical
methodology using the Austin method 1 (AM1) approach.
From a theoretical point of view, there are some kinetic
and quantum mechanics studies of the reactivity of ben-
zofused heterocycles that qualitatively predict the reactive
sites of these compounds [8–10]. It was demonstrated
[
11–14] that DFT B3LYP is a reliable method for
In this work, based on the optimized geometries of
reaction intermediate structures Int1–Int4, we calculated
local reactivity descriptors: bond length (BL), bond order
(BO), ESP-derived charges, and f?(r). The calculations
were carried out using the semiempirical AM1 method and
DFT B3LYP functional with two different basis sets
(6-31G* and 6-31?G*). BL and BO values for the frag-
ment N(1)-C(2) are presented in Table 1, while ESP
charges and f?(r) for the fragment N(1)-C(2)-C(3) of
Int1a–Int1d, Int1x, Int2a–Int2c, Int3a–Int3c, Int4a–
Int4d are presented in Table 2.
The results of our computation of the intermediates
1
2
reveal that the presence of substituents (R and R ) on the
diazepine skeleton, as well as 4-substituents on the aro-
matic bromoketones, influences the values of all calculated
reactivity descriptors. The nature of the substituents
determines the electron density displacement on the
molecular surface of the intermediates. Hence, changes in
electron density displacement cause N(1)-C(2) bond
weakening or strengthening. This allows us to predict the
Fig. 1 Optimal geometry of Int1b
1
23

Experimental and theoretical investigation of substituent effects in a two-pathway reaction
613
further possible course of the pending reaction. In the case
of Int2a–Int2c and Int3a–Int3c, the weakening and
lengthening of the N(1)-C(2) bond compared with that in
Int1a–Int1d, Int1x suggest that the hydrolysis reaction
pathway could be more probable (Table 1). Otherwise, the
strengthening of the N(1)-C(2) bond in Int1a–Int1d, Int1x,
Int4c, Int4d compared with that in Int2a–Int2c, Int3a–
Int3c could be compatible with the reaction pathway cor-
responding to formation of tricyclic thiazoles. For example,
the BO value *1.93 for Int1x represents a strong double
bond and correlates well with synthesis results showing the
exceptional formation of the tricyclic thiazole derivative
Table 1 Calculated N(1)-C(2) bond length (BL) and bond order
(BO) values of Int1a–Int1d, Int1x, Int2a–Int2c, Int3a–Int3c,
Int4a–Int4d
Int AM1
B3LYP 6-31G*
˚
B3LYP 6-31?G*
˚
BL (A)
˚
BL (A)
BO
BL (A)
BO
BO
[
3], while Int2c with BO value *1.70 undergoes the
1
1
1
1
1
2
2
2
3
3
3
4
4
4
4
a
a
1.291
1.283
1.290
1.290
1.270
1.295
1.295
1.296
1.295
1.295
1.295
1.295
1.300
1.300
1.295
1.830
1.826
1.831
1.829
1.842
1.750
1.744
1.742
1.750
1.759
1.754
1.799
1.800
1.829
1.805
1.275
1.274
1.274
1.274
1.273
1.279
1.280
1.281
1.280
1.281
1.279
1.280
1.276
1.275
1.277
1.729
1.729
1.736
1.720
1.924
1.703
1.700
1.685
1.700
1.700
1.704
1.705
1.702
1.731
1.733
1.276
1.277
1.277
1.277
1.274
1.282
1.281
1.280
1.283
1.281
1.279
1.278
1.277
1.281
1.281
1.755
1.781
1.746
1.770
1.930
1.701
1.701
1.701
1.690
1.698
1.702
1.701
1.695
1.751
1.753
hydrolysis reaction leading to N(1)-C(2) bond cleavage.
The ESP charge distribution illustrates the most favor-
able sites for nucleophilic or electrophilic attack and
confirms the results described above with new evidence
b
a
c
a
d
b
x
(Table 2). A decrease of positive ESP charge on the C(3)
a
b
c
carbon atom and an increase of positive ESP charge on the
C(2) atom in Int2a–Int2c, Int3a–Int3c, Int4a, Int4b as
compared with the corresponding values in Int1x allow the
start of the hydrolysis reaction at the C(2) reacting site with
the formation of the rearrangement products, i.e., benz-
imidazole derivatives. An increased positive ESP charge on
the C(3) atom in Int1x is compatible with the enhanced
power of this atom for nucleophilic attack as compared with
the C(2) atom. This is in full accordance with the course of
the reaction of 1,5-benzodiazepinethiones with aliphatic
halogen ketones, which proceeds through Int1x and gives
only one product, the tricyclic thiazolobenzodiazepine
a
b
c
a
b
a
c
a
d
Synthesis presented in [4]
b
Int1x, intermediate of interaction of 5-acetyl-3-methyl-1,5-benzodia-
zepine-2-thione (1) with chloroacetone [3]
Table 2 Calculated ESP charges and Fukui functions [f?(r)] for fragment N(1)-C(2)-C(3) of Int1a–Int1d, Int1x, Int2a–Int2c, Int3a–Int3c,
Int4a–Int4d
Int
AM1
B3LYP 6-31G*
ESP charges
B3LYP 6-31?G*
ESP charges
N(1)
f?(r)
ESP charges
C(2)
C(3)
N(1)
C(2)
C(3)
C(2)
C(3)
N(1)
C(2)
C(3)
1
1
1
1
1
2
2
2
3
3
3
4
4
4
4
a
a
-0.53
-0.52
-0.52
-0.49
-0.56
-0.57
-0.49
-0.58
-0.60
-0.60
-0.57
-0.56
-0.47
-0.55
-0.57
?0.50
?0.54
?0.60
?0.44
?0.49
?0.58
?0.57
?0.59
?0.76
?0.75
?0.77
?0.64
?0.48
?0.58
?0.63
?0.48
?0.54
?0.61
?0.46
?0.61
?0.48
?0.50
?0.46
?0.43
?0.48
?0.43
?0.55
?0.34
?0.56
?0.64
-0.42
-0.29
-0.40
-0.42
-0.40
-0.51
-0.52
-0.48
-0.60
-0.60
-0.51
-0.50
-0.44
-0.46
-0.49
?0.41
?0.33
?0.39
?0.39
?0.33
?0.54
?0.51
?0.50
?0.76
?0.54
?0.51
?0.50
?0.50
?0.45
?0.47
?0.39
?0.35
?0.38
?0.38
?0.68
?0.41
?0.40
?0.40
?0.43
?0.41
?0.38
?0.41
?0.36
?0.43
?0.44
0.18
0.21
0.17
0.14
0.02
0.18
0.28
0.17
0.18
0.19
0.20
0.23
0.16
0.14
0.24
0.17
0.18
0.06
0.15
0.13
0.06
0.07
0.07
0.01
0.06
0.07
0.03
0.08
0.10
0.16
-0.43
-0.36
-0.37
-0.38
-0.41
-0.47
-0.45
-0.46
-0.61
-0.62
-0.52
-0.53
-0.46
-0.45
-0.50
?0.39
?0.34
?0.38
?0.39
?0.32
?0.54
?0.56
?0.52
?0.76
?0.56
?0.53
?0.51
?0.52
?0.51
?0.50
?0.38
?0.39
?0.41
?0.39
?0.75
?0.39
?0.40
?0.41
?0.43
?0.39
?0.38
?0.38
?0.37
?0.52
?0.48
b
a
c
a
d
b
x
a
b
c
a
b
c
a
b
a
c
a
d
Synthesis presented in [4]
b
Int1x, intermediate of interaction of 5-acetyl-3-methyl-1,5-benzodiazepine-2-thione (1) with chloroacetone [3]
123

6
14
R. Janciene et al.
derivative [3]. Moreover, for Int1x, the Fukui function
values for nucleophilic attack [f?(r)] on the C(2) and
C(3) atoms are 0.02 and 0.13 and show greater reactivity
of C(3). For Int2a–Int2c, Int3a–Int3c, Int4a, Int4b, the
f?(r) values on the C(2) atom are increased by ten or
more times compared with C(3). This fact indicates a
greater possibility for the formation of only one benz-
imidazole derivative. When f?(r) values on C(2) and C(3)
are similar (Int1a, Int1b, Int4c, Int4d), both reactions
proceed equally.
Experimental
Melting points were determined in open capillaries on a
MEL-TEMP 1202D apparatus. The IR spectra (potassium
bromide) were taken on a PerkinElmer Spectrum GX
1
Fourier-transform infrared (FTIR) spectrometer.
H
1
3
(300 MHz) and C (75 MHz) NMR spectra were recorded
on a Varian Unity Inova 300 spectrometer at 302 K.
Chemical shifts are referenced to tetramethylsilane
1
[d( H) = 0] and the solvent signal for deuteriochloroform
1
3
13
It is worth mentioning that the use of both the AM1
and DFT B3LYP methods in this study provides the
opportunity to compare the performance of these two
approaches for the interpretation of reactivity descriptors.
Both methods provide very similar results: BL, BO, and
ESP charge values, despite some numerical differences,
are qualitatively similar and in reasonable agreement with
the relevant experimental results. Hence, both of them
can be employed for prediction of reactivity tendencies of
the interaction of substituted 1,5-benzodiazepine-2-
thiones with 4-substituted aromatic bromoketones. The
advantage of the AM1 model is that it is less time con-
suming, but it gives a sufficiently high correlation with
experiment and seems adequate as a simple reactivity
screening tool. However, the DFT model allows the
calculation of more molecular quantum properties, offers
better accuracy in the estimation of reactivity descriptors,
ensures high reliability, and includes a broader diversity
of descriptors.
[d( C) = 77.0 ppm] and deuteriomethanol [d( C) =
49.0 ppm]. The NMR peaks corresponding to the minor
isomer of compounds 7a and 14a are given in square
brackets. The assignment of the resonances in the NMR
spectra was based on the chemical shift theory and signal
intensity arguments, multiplicities, and comparison with
structurally related compounds, as well as on attached
proton test (APT), nuclear Overhauser effect (NOE),
1
13
correlation spectroscopy (COSY), and H,
C two-
dimensional (2D) NMR experiments for some compounds.
The reactions were controlled by the TLC method per-
formed on a Merck precoated silica gel aluminum roll
(60F254) with chloroform–ethyl acetate–methanol (v/v,
14:7:1) as eluent and visualized with ultraviolet (UV) light.
Elemental analyses (C, H, N) were performed on an Ele-
mental Analyser CE-440, and results were found to be in
good agreement (± 0.25%) with calculated values.
The first optimization of intermediate structures was
carried out with AM1 [18]. Consequently, the AM1
geometry optimized structures were used as initial coor-
dinates for geometry optimization at the DFT level using
the B3LYP functional and the 6-31G* and 6-31?G* basis
sets using the GAMESS package [20]. The vibrational
frequencies were computed for optimized intermediate
structures and checked to present no imaginary vibrational
frequency to ensure that they were local minima points.
The optimized structures were minima on the potential-
energy surface profile, and their harmonic vibrational
frequencies were positive. On the basis of the obtained
coordinates, visualization of optimized geometries and
evaluation of local reactivity descriptors was performed
using SPARTAN’06 [18].
Conclusions
1
2
Investigation of the interaction of 5-acyl-3-R -4-R -
,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-thiones 1–6
1
with 4-substituted 2-bromoacetophenones shows that the
progress of two competitive transformations apparently
depend on the presence of substituents in 3- and 4-positions
of the starting thiones 1–6 and as well as on the nature of
the 4-substituent of the bromoacetophenones. The semi-
empirical AM1 and DFT B3LYP computational studies of
local reactivity descriptors of the optimal geometry of
intermediate structures Int1a–Int1d, Int1x, Int2a–Int2c,
Int3a–Int3c, Int4a–Int4d reveal that the substitution of
the diazepine skeleton and aromatic bromoketones affects
the electronic density on the molecular space. The changes
of electronic density are reflected by differences in bond
length, bond order, ESP charge, and Fukui function values
for intermediates and explain the features of the studied
interaction. Computational studies reported herein may be
a powerful tool for interpretation of experimental results
and a valuable additional tool in the design of synthetic
pathways to novel fused heterocycles.
General procedure for preparation of compounds 7a,
7b, 8a, 8b, 9a–9c, 10a–10c, 13a, 13b, 14a, 15a, 16a
To a stirred solution of an appropriate 1,5-benzodiazepine-
3
2-thione derivative 1–6 (5.0 mmol) in 50–80 cm butan-2-
0
one, 2-bromo-4 -methyl (or methoxy) acetophenone or
bromoacetophenone (7.5 mmol) was added. The mixture
was refluxed for 1–3 h; the optimal reaction time was
determined by TLC monitoring. Then, the mixture was
stored overnight in a refrigerator. The work-up of the
1
23

Experimental and theoretical investigation of substituent effects in a two-pathway reaction
615
reaction mixture and separation of products in each case
was performed distinctively.
(br dd, 1H, H-10), 7.38 (br dt, 1H, H-9), 7.49 (br dd, 1H,
H-7), 7.62 (br dt, 1H, H-8), 8.50 (s, 1H, H-2), [8.54 (br s,
1
3
1
H, H-2)] ppm; C NMR (CDCl ): d = 14.83 (4-CH ),
3
3
6
-Acetyl-5,6-dihydro-4-methyl-1-(4-methylphenyl)-4H-
1,3]thiazolo[3,2-a][1,5]benzodiazepin-11-ium
bromide (7a, C H BrN OS)
0
2
2.73 (6-CH ), 35.03 (C-4), 55.39 (4 -CH ), 57.28 (C-5),
3
3
[
0
0
1
14.58 (C-3 ,5 ), 118.73, 123.33 (C-2), 128.96 (C-10),
0
2
1
21
2
0
1
29.71 (C-9), 129.76 (C-7), 131.03 (C-2 ,6 ), 132.30 (C-8),
0
The precipitate formed was collected by filtration. Recrys-
1
32.78, 135.31, 147.64 (C-1), 161.36 (C-4 ), 169.46 (6-
-
tallization from methanol-diethyl ether afforded 1.29 g
1
1
CO), 178.13 (C-3a) ppm; IR: vꢀ = 1,676 cm
.
(
60%) 7a. M.p.: 272–274 °C; H NMR (CD OD, two
3
rotamers in a ratio of 70:30): d = 1.71 (d, J = 6.5 Hz, 3H,
S-[2-(4-Methoxyphenyl)-2-oxoethyl] 2-methyl-3-(2-methyl-
1H-benzimidazol-1-yl)propanethioate hydrobromide
(8b, C H BrN O S)
4
-CH ), 2.08 (s, 3H, 6-CH ), [2.32 (s, 3H, 6-CH ), 2.35 (s,
3
3
3
0
0
3
H, 4 -CH )], 2.38 (s, 3H, 4 -CH ), 3.56 (m, 1H, CH), 3.93
3
3
2
1
23
2 3
(
dd, J = 6.3, 12.5 Hz, 1H, CH ), [4.2–4.4 (m, 2H, CH )],
2 2
The compound was isolated by following the procedure
4
8
.70 (t, J = 12.6 Hz, 1H, CH ), 7.03–7.81 (m, 8H, arom),
2
described for 8a. Recrystallization from dichloromethane
1
1
3
.34 (s, 1H, H-2) ppm; C NMR (CD OD): d = 14.72 (4-
3
gave 0.93 g (40%) 8b. M.p.: 150–152 °C; H NMR
0
CH ), 21.37 (4 -CH ), 23.03 (6-CH ), 36.19 (C-4), 58.81
3
3
3
(
CDCl ): d = 1.47 (d, J = 7.0 Hz, 3H, 2-CH ), 3.01 (s,
3
3
(
C-5), 121.82 (C-2), 125.63, 129.13, 130.85 (4C), 130.99
0
-
72.24 (6-CO),181.09 (C-3a) ppm; IR: vꢀ = 1,671 cm
.
0 00
H, 2 -CH ), 3.52 (m, 1H, H-2), 3.87 (s, 3H, 4 -CH ), 4.23
3 3
3
(
2C), 132.11, 133.82, 137.09, 143.07 (C-4 ), 150.55 (C-1),
and 4.28 (AB-q, J = 16.6 Hz, 2H, 5-CH ), 4.45 (dd,
2
1
1
J = 5.0, 14.8 Hz, 1H, 3-CH ), 4.65 (dd, J = 10.0,
2
00 00
4.8 Hz, 1H, 3-CH ), 6.93 (m, 2H, H-3 ,5 ), 7.44–7.54
2
1
S-[2-(4-Methylphenyl)-2-oxoethyl] 2-methyl-3-(2-methyl-
H-benzimidazol-1-yl)propanethioate hydrobromide
8a, C H BrN O S)
0 0 0 0
(
m, 2H, H-5 ,6 ), 7.64 (m, 1H, H-7 ), 7.86 (m, 1H, H-4 ),
1
0
0
00
13
7
.90 (m, 2H, H-2 ,6 ) ppm; C NMR (CDCl ): d = 12.00
(
3
2
1
23
2 2
0
(
2 -CH ), 16.26 (2-CH ), 36.76 (C-5), 46.66 (C-2), 47.22
To the cooled filtrate obtained after isolation of 7a from the
reaction mixture, diethyl ether was added. The precipitate
formed was collected by filtration. Recrystallization from
3
3
00 0 00 00
C-3), 55.55 (4 -CH ), 111.58 (C-4 ), 113.98 (C-3 ,5 ),
3
(
0 0 0
1
1
15.09 (C-7 ), 126.19 (C-6 ), 126.52 (C-5 ), 128.02, 129.84,
00
0
0
00
0
30.73 (C-2 ,6 ), 130.95, 150.58 (C-2 ), 164.09 (C-4 ),
dichloromethane-diethyl ether gave 0.69 g (31%) 8a. M.p.:
1
189.92 (C-6), 199.28 (C-1) ppm; IR: vꢀ = 2,800–2,636,
1
3
3
5
59–161 °C; H NMR (CDCl ): d = 1.47 (d, J = 7.0 Hz,
3
-
1
1,680, 1,667 cm .
00
0
H, 2-CH ), 2.42 (s, 3H, 4 -CH ), 3.03 (s, 3H, 2 -CH ),
3
3
3
.51 (m, 1H, 2-H), 4.25 and 4.33 (AB-q, J = 16.8 Hz, 2H,
-CH ), 4.39 (dd, J = 5.1, 14.7 Hz, 1H, 3-CH ), 4.65 (dd,
S-[2-(4-Methylphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)butanethioate hydrobromide
2
2
0
0
00
J = 9.8, 14.7 Hz, 1H, 3-CH ), 7.27 (m, 2H, H-3 ,5 ),
2
(
9a, C H BrN O S)
21 23 2 2
0
0
0
7.46–7.55 (m, 2H, H-5 ,6 ), 7.60 (m, 1H, H-7 ), 7.83 (m,
13
2H, H-2 ,6 ), 7.89 (m, 1H, H-4 ) ppm; C NMR (CDCl3):
Diethyl ether was added to a cooled reaction mixture until
it became turbid, and the solution was decanted from the
resin precipitated. Addition of diethyl ether to the cooled
solution and partition from the precipitated resin was
repeated until the formation of the solid precipitate, which
was collected by filtration. Recrystallization from dichlo-
0
0
00
0
0
00
d = 11.96 (2 -CH ), 16.31 (2-CH ), 21.69 (4 -CH ), 37.03
3
3
3
0
(
C-5), 46.70 (C-2), 47.19 (C-3), 111.44 (C-4 ), 115.30 (C-
0
0 0 00 00
), 126.27 (C-6 ), 126.63 (C-5 ), 128.48 (C-2 ,6 ), 129.52
7
0
0
00
00
(
C-3 ,5 ), 129.90, 130.95, 132.62, 145.07 (C-4 ), 150.56
0
(
C-2 ), 191.00 (C-6), 199.14 (C-1) ppm; IR: vꢀ =
1
romethane-diethyl ether afforded 0.69 g (31%) 9a. M.p.:
1
-
2
,800–2,614, 1,693, 1,678 cm
.
1
04–106 °C; H NMR (CDCl ): d = 1.80 (d, J = 7.0 Hz,
3
0
0
0
6
-Acetyl-5,6-dihydro-1-(4-methoxyphenyl)-4-methyl-4H-
1,3]thiazolo[3,2-a][1,5]benzodiazepin-11-ium
3H, 3-CH
3
), 2.35 (s, 3H, 4 -CH
3
), 3.06 (s, 3H, 2 -CH
), 3.70 (dd,
), 4.16 and 4.30 (AB-q,
), 5.22 (m, 1H, H-3), 7.20 (m, 2H,
2
3
),
[
bromide (7b, C H BrN O S)
The compound was isolated by following the procedure
3.30 (dd, J = 4.0, 16.7 Hz, 1H, 2-CH
J = 10.5, 16.7 Hz, 1-H, 2-CH
J = 16.8 Hz, 2H, 5-CH
2
2
1
21
2 2
2
00 00 0 0 0
described for 7a. Recrystallization from methanol-diethyl
1
ether yielded 0.82 g (37%) 7b. M.p.: 231–233 °C;
NMR (CDCl , two rotamers in a ratio of 78:22): d = 1.71
H-3 ,5 ), 7.41–7.51 (m, 2H, H-5 ,6 ), 7.71 (m, 1H, H-7 ),
13
7.74 (m, 2H, H-2 ,6 ), 7.89 (m, 1H, H-4 ) ppm; C NMR
00 00 0
H
0
00
0
(CDCl
CH
): d = 12.36 (2 -CH
), 19.29 (3-CH
), 21.53 (4 -
3
3
3
3
(
d, J = 6.6 Hz, 3H, 4-CH ), [1.82 (d, J = 6.4 Hz, 3H,
3
3
), 36.88 (C-5), 46.58 (C-2), 53.35 (C-3), 112.73 (C-4 ),
0 0 0
4
-CH )], 2.02 (s, 3H, 6-CH ), [2.35 (s, 3H, 6-CH )], 3.60
3
115.38 (C-7 ), 125.90 (C-6 ), 126.11 (C-5 ), 128.28 (C-
00 00 00 00
2 ,6 ), 128.95, 129.33 (C-3 ,5 ), 130.25, 132.38, 144.85
3
3
(
m, 1H, CH), 3.76–3.83 (m, 1H, CH ), 3.83 (s, 3H,
2
0
00 0
4
1
-CH ), [4.2–4.3 (br m, 2H, CH )], 4.67 (t, J = 12.8 Hz,
3
(C-4 ), 150.17 (C-2 ), 191.16 (C-6), 194.24 (C-1) ppm; IR:
-1
vꢀ = 2,800–2,518, 1,692, 1,669 cm
.
2
0
0
0
0
H, CH ), 6.89 (m, 2H, H-3 ,5 ), 7.17 (m, 2H, H-2 ,6 ), 7.30
2
123

6
16
R. Janciene et al.
S-[2-(4-Methoxyphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)butanethioate hydrobromide
The resin partitioned after isolation of 10a was kept in a
refrigerator. After long standing (for 7–10 days), crystals
were formed. The crystals were taken up with cold
acetone, collected by filtration, and recrystallized from
dioxane to yield 0.15 g (11%) 5-acetyl-1,3,4,5-tetrahydro-
4-phenyl-2H-1,5-benzodiazepin-2-one (11); m.p.: 198–
200 °C (Ref. [6] 200–202 °C). A mixed sample with
authentic compound 11 did not show depression of the
melting point.
(
9b, C H BrN O S)
21 23 2 3
The compound was isolated by following the procedure
described for 9a. Recrystallization from dichloromethane
1
afforded 1.53 g (66%) 9b. M.p.: 118–120 °C; H NMR
(
CDCl ): d = 1.83 (d, J = 7.1 Hz, 3H, 3-CH ), 3.10 (s,
3
3
0
H, 2 -CH ), 3.28 (dd, J = 4.0, 16.6 Hz, 1H, 2-CH ), 3.71
3 2
3
00
dd, J = 10.5, 16.6 Hz, 1H, 2-CH ), 3.88 (s, 3H, 4 -CH ),
2 3
(
4
1
.18 and 4.36 (AB-q, J = 16.7 Hz, 2H, 5-CH ), 5.22 (m,
2
00
00
S-[2-(4-Methoxyphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)-3-phenylpropanethioate
hydrobromide (10b, C H BrN O S)
H, H-3), 6.94 (m, 2H, H-3 ,5 ), 7.48–7.55 (m, 2H,
00 00
0
0
0
H-5 ,6 ), 7.69 (m, 1H, H-7 ), 7.90 (m, 2H, H-2 ,6 ), 8.02
13
0
(
m, 1H, H-4 ) ppm;
0
C NMR (CDCl ): d = 12.35
26 25
2 3
3
The compound was isolated by following the procedure
(
2 -CH ), 19.38 (3-CH ), 36.87 (C-5), 46.69 (C-2), 50.38
3
3
00 0 00 00
C-3), 55.58 (4 -CH ), 112.55 (C-7 ), 114.04 (C-3 ,5 ),
3
described for 9a. Recrystallization from ethyl acetate
1
(
0 0 0
afforded 0.81 g (31%) 10b. M.p.: 106–108 °C; H NMR
1
1
1
1
15.89 (C-4 ), 126.06 (C-6 ), 126.35 (C-5 ), 128.00, 129.00,
00
0 00
CDCl ): d = 3.16 (s, 3H, 2 -CH ), 3.88 (s, 3H, 4 -CH ),
00
00
0
(
30.53, 130.77 (C-2 ,6 ), 150.26 (C-2 ), 164.18 (C-4 ),
3
3
3
3.88 (dd, J = 4.6, 16.3 Hz, 1H, 2-CH ), 4.00 (dd,
2
89.97 (C-6), 194.31 (C-1) ppm; IR: vꢀ = 2,800–2,522,
-
1
J = 10.5, 16.3 Hz, 1H, 2-CH ), 4.23 and 4.38 (AB-q,
2
,688, 1,672 cm
.
J = 16.7 Hz, 2H, 5-CH ), 6.33 (dd, J = 4.6, 10.5 Hz, 1H,
2
S-[2-Oxo-2-phenylethyl)] 3-(2-methyl-1H-benzimidazol-1-
yl)butanethioate hydrobromide (9c, C H BrN O S)
The compound was isolated by following the procedure
0
0
00
H-3), 6.94 (m, 2H, H-3 ,5 ), 7.18–7.22 (m, 2H, arom), 7.28
2
0
21
2 2
(
m, 1H, arom), 7.34–7.50 (m, 5H, arom), 7.92 (m, 2H,
0
0
00
0
13
H-2 ,6 ), 8.00 (m, 1H, H-4 ) ppm; C NMR (CDCl3):
described for 9a. Recrystallization from dichloromethane
1
afforded 0.67 g (31%) 9c. M.p.: 77–79 °C; H NMR
0
d = 12.40 (2 -CH ), 37.02 (C-5), 44.18 (C-2), 55.55 (C-3),
5
3
00 0 00 00
5.76 (4 -CH ), 112.85 (C-7 ), 114.03 (C-3 ,5 ), 115.68
3
(
CDCl ): d = 1.83 (d, J = 7.1 Hz, 3H, 3-CH ), 3.09 (s,
3
3
0 000 000 0 0
(
C-4 ), 125.94 (C-2 ,6 ), 126.11 (C-5 ), 126.42 (C-6 ),
0
H, 2 -CH ), 3.31 (dd, J = 4.1, 16.6 Hz, 1H, 2-CH ), 3.72
3 2
3
0 000 000
27.95 (C-4 ), 129.45, 129.53 (C-4), 129.66 (C-3 ,5 ),
1
1
(
dd, J = 10.5, 16.6 Hz, 1H, 2-CH ), 4.22 and 4.38 (AB-q,
2
00 00
0
30.37, 130.77 (C-2 ,6 ), 133.71, 150.91 (C-2 ), 164.17
00
-1
J = 16.9 Hz, 2H, 5-CH ), 5.23 (m, 1H, H-3), 7.43–7.53 (m,
2
(
C-4 ), 189.81 (C-6), 194.32 (C-1) ppm; IR: vꢀ =
0
0
00 00
0
00 00
4
H, H-5 ,6 ,3 ,5 ), 7.70 (m, 1H, H-7 ), 7.90 (m, 2H, H-2 ,6 ),
13
2
,800–2,518, 1,679, 1,662 cm
.
Analogously, compound 11 was isolated from the par-
0
7
.97 (m, 1H, H-4 ) ppm; C NMR (CDCl ): d = 12.42
2 -CH ), 19.37 (3-CH ), 37.11 (C-5), 46.70 (C-2), 50.42
3
3
0
(
(
(
(
(
3
titioned resin by following the procedure described for 10a
in 0.18 g (13%) yield.
0
0
0
C-3), 112.61 (C-7 ), 115.77 (C-4 ), 126.03 (C-6 ), 126.30
0
C-5 ), 128.31 (2C), 128.82 (2C), 129.03, 130.50, 133.99
0
0
0
C-4 ), 134.98 (C), 150.27 (C-2 ), 191.61 (C-6), 194.21
-
S-(2-Oxo-2-phenylethyl) 3-(2-methyl-1H-benzimidazol-
1-yl)-3-phenylpropanethioate hydrobromide
1
C-1) ppm; IR: vꢀ = 2,800–2,525, 1,697, 1,681 cm
.
S-[2-(4-Methylphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)-3-phenylpropanethioate
hydrobromide (10a, C H BrN O S)
(10c, C25 23BrN S)
H
O
2 2
The compound was isolated by following the procedure
described for 9a. Recrystallization from acetone afforded
1
2
6
25
2 2
The compound was isolated by following the procedure
0.62 g (25%) 10c. M.p.: 147–150 °C; H NMR (CDCl
):
3
0
described for 9a. Recrystallization from ethyl acetate
1
d = 3.15 (s, 3H, 2 -CH
3
), 3.87 (dd, J = 4.5, 16.2 Hz, 1H,
), 4.27 and
), 6.25 (dd, J = 4.6,
afforded 0.89 g (35%) 10a. M.p.: 127–129 °C; H NMR
2-CH
4.44 (AB-q, J = 17.0 Hz, 2H, 5-CH
2
2
), 3.99 (dd, J = 10.5, 16.3 Hz, 1H, 2-CH
2
00
0
(
CDCl ): d = 2.41 (s, 3H, 4 -CH ), 3.15 (s, 3H, 2 -CH ),
3
3
3
0
0
00
3
5
.82–4.02 (m, 2H, 2-CH ), 4.23 and 4.41 (br AB-q, 2H,
2
10.5 Hz, 1H, H-3), 6.94 (m, 2H, H-3 ,5 ), 7.26 (m, 1H,
-CH ), 6.31 (m, 1H, H-3), 7.17–7.47 (m, 8H, arom), 7.83
2
arom), 7.36 (m, 1H, arom), 7.36–7.51 (m, 5H, arom), 7.62
00 00
0
0
00
0
13
m, 2H, H-2 ,6 ), 8.00 (m, 1H, H-4 ) ppm; C NMR
(
(m, 1H, arom), 7.94 (m, 2H, H-2 ,6 ), 8.01 (m, 1H,
0
0
00
0
13
H-4 ) ppm; C NMR (CDCl
(
CDCl ): d = 13.14 (2 -CH ), 21.74 (4 -CH ), 37.56 (C-5),
3
): d = 12.44 (2 -CH
3
), 37.37
3
3
3
0
0
0
0
4
4.47 (C-2), 55.81 (C-3), 112.90 (C-7 ), 115.99 (C-4 ),
0
(C-5), 44.24 (C-2), 55.70 (C-3), 112.79 (C-7 ), 115.87
0
00 000
0
0
0
1
26.08 (C-2 ,6 ), 126.20 (C-6 ), 126.50 (C-5 ), 128.57
(C-4 ), 125.91 (2C), 126.10 (C-5 ), 126.41 (C-6 ), 128.38
(2C), 128.88 (2C), 129.51 (C), 129.58 (CH), 129.71 (2C),
00 00 00 00
(
C-2 ,6 ), 129.50, 129.58 (C-3 ,5 ), 129.68, 129.80
00
0
00 000
0
(
C-3 ,5 ), 130.60, 132.47, 133.72, 145.16 (C-4 ), 150.93
130.64 (C), 133.74 (C), 134.08 (CH), 134.97, 150.91 (C-2 ),
0
(
C-2 ), 190.92 (C-6), 194.26 (C-1) ppm; IR: vꢀ =
-
191.35 (C-6), 194.18 (C-1) ppm; IR: vꢀ = 2,800–2,512,
-1
1,698, 1,677 cm .
1
2
,800–2,513, 1,691, 1,676 cm
.
1
23

Experimental and theoretical investigation of substituent effects in a two-pathway reaction
617
Analogously, compound 11 was isolated from the par-
titioned resin by following the procedure described for 10a
in 0.21 g (15%) yield.
a ratio of 60:40): d = [14.33 (4-CH
3
)], 14.81 (4-CH
), 36.47 (C-4), [36.52 (C-4)], 56.95 (C-5),
[59.75 (C-5)], 121.58, [121.66, 125.72], 125.77, [128.73],
3
),
0
21.43 (4 -CH
3
1
1
1
29.34, 130.43, 130.62, 130.82 (2C), 130.86, 130.95 (3C),
S-[2-(4-Methylphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)propanethioate hydrobromide
31.94, [132.49], 133.53, 133.85, 134.01, [134.89, 135.26],
0
0
35.70, [142.82 (C-4 )], 142.85 (C-4 ), 150.91 (C-1),
(
13a, C H BrN O S)
20 21 2 2
[
150.99 (C-1)], 164.22 (C-6), [165.10 (C-6), 180.14 (C-
-
The compound was isolated by following the procedure
1
3
a)], 180.99 (C-3a) ppm; IR: vꢀ = 1,682 cm
.
described for 9a. Recrystallization from chloroform affor-
1
ded 1.10 g (51%) 13a. M.p.: 98–100 °C; H NMR
3-(1H-Benzimidazol-1-yl)propanoic acid hydrobromide
(15a, C10 11BrN
The compound was isolated by following the procedure
00
0
(
CDCl ): d = 2.42 (s, 3H, 4 -CH ), 3.08 (s, 3H, 2 -CH ),
H
O )
2 2
3
3
3
3
3
.37 (br t, 2H, 2-CH ), 4.35 (s, 3H, 5-CH ), 4.73 (br t, 2H,
2
2
00
00
0
-CH ), 7.28 (m, 2H, H-3 ,5 ), 7.49 (m, 1H, H-5 ), 7.52
2
described for 7a. Recrystallization from methanol-diethyl
1
ether afforded 0.34 g (27%) 15a. M.p.: 212–214 °C; H
NMR (CD OD): d = 3.11 (t, J = 6.3 Hz, 2H, 2-CH
4.86 (t, J = 6.3 Hz, 2H, 3-CH ), 7.68–7.75 (m, 2H,
2
H-5 ,6 ), 7.90 (m, 1H, arom), 8.05 (m, 1H, arom), 9.55
0
0
00 00
(
m, 1H, H-6 ), 7.63 (m, 1H, H-7 ), 7.84 (m, 2H, H-2 ,6 ),
13
0
00
7
.89 (m, 1H, H-4 ) ppm; C NMR (CDCl ): d = 12.05
3
2
),
3
0
(
2 -CH ), 21.69 (4 -CH ), 37.04 (C-5), 40.66 (C-2), 41.15
3
3
0 0 0
0
0
(
C-3), 111.42 (C-7 ), 115.23 (C-4 ), 126.29 (C-6 ), 126.63
0
00 00
00 00
0
(s, 1H, H-2 ) ppm; C NMR (CD OD): d = 33.67, 44.10,
3
13
(
C-5 ), 128.49 (C-2 ,6 ), 129.54 (C-3 ,5 ), 129.93, 130.71,
0
00
1
32.65, 145.11 (C-4 ), 150.69 (C-2 ), 191.33 (C-6), 194.64
-
114.26, 115.85, 127.98, 128.30, 132.19, 132.35, 142.85 (C-
0
1
(
C-1) ppm; IR: vꢀ = 2,800–2,556, 1,698, 1,686 cm
.
2 ), 173.58 (C-1) ppm.
S-[2-(4-Methoxyphenyl)-2-oxoethyl] 3-(2-methyl-1H-
benzimidazol-1-yl)propanethioate hydrobromide
S-[2-(4-Methylphenyl)-2-oxoethyl] 3-(1H-benzimidazol-1-
yl)propanethioate hydrobromide (16a, C19H19BrN O S)
2 2
(
13b, C H BrN O S)
2
The compound was isolated by following the procedure
described for 8a. Recrystallization from dichloroethane-
diethyl ether afforded 0.63 g (30%) 16a. M.p.: 90–92 °C;
0
21
2 3
The compound was isolated by following the procedure
described for 9a. Recrystallization from chloroform affor-
1
1
00
ded 1.11 g (49%) 13b. M.p.: 179–181 °C; H NMR
H NMR (CDCl
3
): d = 2.39 (s, 3H, 4 -CH
3
), 3.52 (br t,
0
(
CDCl ): d = 3.08 (s, 3H, 2 -CH ), 3.36 (br t, 2H,
2H, 2-CH
2
), 4.34 (s, 3H, 5-CH
2
), 4.99 (br t, 2H, 3-CH ),
2
3
3
00
00 00 0 0
2
-CH ), 3.89 (s, 3H, 4 -CH ), 4.34 (s, 3H, 5-CH ), 4.71
2
7.23 (m, 2H, H-3 ,5 ), 7.48–7.57 (m, 2H, H-5 ,6 ), 7.71 (m,
3
2
00
00
0 00 00 0
1H, H-7 ), 7.80 (m, 1H, H-2 ,6 ), 8.00 (m, 1H, H-4 ), 10.09
(
br t, 2H, 3-CH ), 6.96 (m, 2H, H-3 ,5 ), 7.47–7.56 (m, 2H,
2
0
0
0
0
0 00
(s, 1H, H-2 ) ppm; C NMR (CDCl ): d = = 21.67 (4 -
3
13
H-5 ,6 ), 7.61 (m, 1H, H-7 ), 7.91 (m, 1H, H-4 ), 7.93 (m,
13
2
0
0
00
0
H, H-2 ,6 ) ppm; C NMR (CDCl ): d = 12.01 (2 -
CH
3
), 36.92 (5-CH
0
2
), 42.38 (2-CH
0
2
), 42.55 (3-CH ),
2
3
0
0
0
CH ), 36.87 (C-5), 40.57 (CH ), 41.06 (CH ), 55.60 (4 -
3
112.15 (C-7 ), 115.82 (C-4 ), 126.71 (C-6 ), 126.94 (C-
0 00 00 00 00
2
2
0
00 00
0
CH ), 111.27 (C-7 ), 114.08 (C-3 ,5 ), 115.39 (C-4 ),
3
5 ), 128.50 (C-2 ,6 ), 129.44 (C-3 ,5 ), 130.44, 130.66,
0 00
132.66, 140.78 (C-2 ), 144.90 (C-4 ), 191.81 (C-6), 195.04
0
0
1
1
26.33 (C-6 ), 126.69 (C-5 ), 128.08, 129.98, 130.64,
00
0
0
00
0
-1
30.82 (C-2 ,6 ), 150.66 (C-2 ), 164.23 (C-4 ), 190.11
(C-1) ppm; IR: vꢀ = 2,800–2,608, 1,692, 1,676 cm
-Acetyl-5,6-dihydro-5-phenyl-4H-[1,3]thiazolo
3,2-d][1,5]benzodiazepin-11-ium
bromide (12, C19 17BrN OS)
.
(
C-6), 194.65 (C-1) ppm; IR: vꢀ = 2,800–2,526, 1,691,
6
-
1
1
,677 cm
.
[
6
-Formyl-5,6-dihydro-4-methyl-1-(4-methylphenyl)-4H-
1,3]thiazolo[3,2-a][1,5]benzodiazepin-11-ium
H
2
[
bromide (14a, C H BrN OS)
The compound was isolated by following the procedure
The reaction of 2.96 g benzodiazepine-2-thione 3 (10
3
mmol) with 5 cm a-bromoacetaldehyde diethylacetal
(32 mmol) was performed according to the general proce-
2
0
19
2
described for 7a. Recrystallization from methanol-diethyl
1
dure described in [2] and yielded 2.56 g (64%) 12. M.p.:
1
ether afforded 0.69 g (33%) 14a. M.p.: 243–245 °C; H
245–248 °C (methanol-diethyl ether); H NMR (CD
OD):
3
NMR (CD OD, two rotamers in a ratio of 60:40): d =
d = 1.79 (s, 3H, 6-CH
CH ), 4.31 (dd, J = 5.4, 14.9 Hz, 1H, CH
2
3
), 3.57 (dd, J = 13.0, 14.9 Hz, 1H,
3
[
1.72 (d, J = 5.6 Hz, 3H, 4-CH )], 1.74 (d, J = 6.4 Hz,
3
2
), 6.48 (dd,
0
0
3
H, 4-CH ), [2.39 (s, 3H, 4 -CH )], 2.40 (s, 3H, 4 -CH ),
3
J = 5.3, 13.0 Hz, 1H, CH), 7.36–7.61 (m, 5H, arom), 7.60
(dd, J = 1.6, 7.7 Hz, 1H, H-7), 7.85 (dt, J = 1.6, 7.7 Hz,
1H, H-8), 7.92 (dt, J = 1.6, 7.7 Hz, 1H, H-9), 8.04 (dd,
J = 1.6, 7.9 Hz, 1H, H-10), 8.44 (d, J = 4.0 Hz, 1H, H-2),
3
3
[
3.70 (m, 1H, H-4)], 3.77 (m, 1H, H-4), 3.95 (dd, J = 5.8,
2.4 Hz, 1H, 5-CH ), [4.30 (dd, J = 7.2, 12.2 Hz, 1H,
1
2
5
-CH )], [4.38 (t, J = 12.1 Hz, 1H, 5-CH )], 4.56
2
2
1
3
(
t, J = 12.1 Hz, 1H, 5-CH ), 7.07–7.78 (m, 8H, arom),
2
8.87 (d, J = 4.0 Hz, 1H, H-1) ppm; C NMR (CD OD):
3
8
8
.33 (s, 1H, H-2), [8.34 (s, 1H, H-2)], [8.39 (s, 1H, H-6)],
d = 23.14 (C-6), 33.61 (C-4), 66.28 (C-5), 126.04, 127.14,
128.14 (2C), 129.83, 129.97 (2C), 132.43, 133.93, 134.10,
1
.53 (s, 1H, H-6) ppm; C NMR (CD OD, two rotamers in
3
3
123

6
18
R. Janciene et al.
1
34,65, 135.49, 137.99, 139.61, 172.29, 172.54 ppm; IR:
-
6. For reviews see: Krapcho J, Turk CF (1967) US Patent 3321468;
(1968) Chem Abstr 68:21970
1
vꢀ = 1,668, 1,660 cm
.
7
. Puodzhyunaite BA, Yanchene RA, Stumbryavichyute ZA (1988)
Chem Heterocycl Compd 24:786
5-Acetyl-1,3,4,5-tetrahydro-4-phenyl-2H-1,5-
benzodiazepine-2-thione (3, C H N OS)
Acetylation of 2.54 g 2,3,4,5-tetrahydro-4-phenyl-2H-1,5-
8
9
. Okujama T, Kunugiza KT (1974) Bull Chem Soc Jpn 47:1267
. Jursic BS (1998) J Mol Struct (Theochem) 427:165
1
7 16 2
1
0. Jursic BS (1996) Can J Chem 74:114
11. Nathaniel R, Mineva T, Nikolova R, Bojilova A (2006) Int J
Quantum Chem 106:1357
2. Jursic BS, Zdravskovski Z (1995) Int J Quantum Chem 54:161
3. Ehresmann B, Martin B, Horn AHC, Clark T (2003) J Mol Model
9:342
3
benzodiazepine-2-thione (10 mmol) [5] with 1.5 cm ace-
tic anhydride (15 mmol) and work-up were conducted
1
1
using a procedure from [4]. Yield 2.1 g (71%) 3. M.p.:
1
2
26–228 °C (ethyl acetate); H NMR (CDCl ): d = 1.78
3
(s, 3H, CH ), 3.20 (t, J = 13.0 Hz, 1H, CH ), 3.29 (ddd,
J = 1.3, 4.9, 12.9 Hz, 1H, CH ), 6.33 (dd, J = 5.0,
14. Vektariene A, Vektaris G, Svoboda J (2009) Arkivoc vii:311
3
2
1
5. Fayet G, Rotureau P, Joubert L, Adamo C (2010) J Mol Model
6:805
6. Khandogin J, York DM (2004) Proteins: Struct, Funct, Bioinf
6:724
17. Chirlian LE, Francl MM (1987) J Comput Chem 8:894
2
1
1
3.0 Hz, 1H, CH ), 7.18 (dd, J = 1.3, 7.8 Hz, 1H, arom),
2
1
7.28–7.32 (m, 6H, arom), 7.36 (dd, J = 1.5, 7.8 Hz, 1H,
arom), 7.49 (dt, J = 1.4, 7.7 Hz, 1H, arom), 10.45 (br s,
5
1
3
1
8. Spartan’06, Wavefunction Inc, Irvine, CA. In: Shao Y, Molnar
LF, Jung Y, Kussmann J, Ochsenfeld C, Brown ST, Gilbert ATB,
Slipchenko LV, Levchenko SV, O’Neill DP, DiStasio Jr RA,
Lochan RC, Wang T, Beran GJO, Besley NA, Herbert JM, Lin
CY, Van Voorhis T, Chien SH, Sodt A, Steele RP, Rassolov VA,
Maslen PE, Korambath PP, Adamson RD, Austin B, Baker J,
Byrd EFC, Dachsel H, Doerksen RJ, Dreuw A, Dunietz BD,
Dutoi AD, Furlani TR, Gwaltney SR, Heyden A, Hirata S, Hsu
C-P, Kedziora G, Khalliulin RZ, Klunzinger P, Lee AM, Lee MS,
Liang WZ, Lotan I, Nair N, Peters B, Proynov EI, Pieniazek PA,
Rhee YM, Ritchie J, Rosta E, Sherrill CD, Simmonett AC, Su-
botnik JE, Woodcock III HL, Zhang W, Bell AT, Chakraborty
AK, Chipman DM, Keil FJ, Warshel A, Hehre WJ, Schaefer HF,
Kong J, Krylov AI, Gill PMW, Head-Gordon M (2006) Phys
Chem Chem Phys 8:3172
1
H, NH) ppm; C NMR (CDCl ): d = 23.15 (CH ), 47.78
3
3
00 00
CH ), 63.74 (CH), 122.62, 126.63 (C-2 ,6 ), 127.68,
2
(
00
00
1
1
3
28.00, 128.59 (C-3 ,5 ), 129.60, 131.55, 133.63, 136.37,
39.87, 170.09 (CO), 203.36 (CS) ppm; IR: vꢀ = 3,300,
-
1
,149, 1,658 cm
.
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1
23