A straightforward synthesis of novel 4H-thiazolo[3,2-d][1,5]benzodiazepine derivatives

Article abstract of DOI:10.1002/hc.20026

The novel 4H-thiazolo[3,2-d][1,5]benzodiazepinium salts have been synthesized in a single step by the reaction of the variously substituted 2,3,4,5-tetrahydro-1, 5-benzodiazepine-2(1 H)-thiones and bromoacetaldehyde diethyl acetal. Cyclization is obviously influenced by the nature of the substituents in the benzodiazepine system. Theoretical modeling and B3LYP DFT computational studies are presented. 2004 Wiley Periodicals, Inc.

Full text of DOI:10.1002/hc.20026

Heteroatom Chemistry
Volume 15, Number 5, 2004
A Straightforward Synthesis of Novel
4H-Thiazolo[3,2-d][1,5]benzodiazepine
Derivatives
Regina Janciene, Ausra Vektariene, Zita Stumbreviciute,
Lidija Kosychova, Algirdas Klimavicius,
and Benedikta D. Puodziunaite
Department of Bioorganic Compounds Chemistry, Institute of Biochemistry, Mokslininku str. 12,
LT-08662, Vilnius, Lithuania
Received 24 March 2004; revised 5 April 2004
derivatives have been characterized as a new class of
ABSTRACT: The novel 4H-thiazolo[3,2-d][1,5]ben-
anti-HIV agents [3]. In numerous previous publica-
zodiazepinium salts have been synthesized in a single
tions it has been described that adding another ring
step by the reaction of the variously substituted
to the 1,4-benzodiazepine or 1,5-benzothiazepine
2,3,4,5-tetrahydro-1,5-benzodiazepine-2(1H)-thiones
moiety leads to an enhancement of the heptatomic
and bromoacetaldehyde diethyl acetal. Cyclization is
ring mobility, meanwhile influencing the specific bi-
obviously influenced by the nature of the substituents
ological activity [4]. In connection with our inves-
in the benzodiazepine system. Theoretical modeling
tigations on the chemistry of peri-annelated imi-
and B3LYP DFT computational studies are pre-
dazo[1,5]benzodiazepines with the in vitro anti-HIV
ꢀ
C
sented. 2004 Wiley Periodicals, Inc. Heteroatom Chem
activity [5] we have been interested in the synthe-
sis of compounds containing an additional thiazole
nucleus fused at 1 and 2 positions of 1,5-benzodia-
15:363–368, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20026
zepine system.
INTRODUCTION
RESULTS AND DISCUSSION
Benzodiazepines and their annelated derivatives ex-
hibit a wide spectrum of biological activities and
have found applications in pharmaceutical chem-
istry [1]. More recently, considerable efforts have
been devoted to discover new biologically active
compounds in antitumor antibiotic group by the re-
placement of the pyrrole fused ring of pyrrolo[2,1-c]
[1,4]benzodiazepine system by thiazole moiety [2].
Moreover, a series of thiazolo[3,4-a]benzimidazole
In the present work we describe the synthesis of
novel tricyclic title compounds obtained by one-step
direct cyclofunctionalization of variously substi-
tuted tetrahydro-1,5-benzodiazepine-2-thiones with
bidentate reagent (Scheme 1). The reaction of eas-
ily accessible compounds 1–11 with an excess
of ꢀ-bromoacetaldehyde diethyl acetal in refluxing
butan-2-one and water mixture gave the expected
thiazolo[3,2-d][1,5]benzodiazepinium bromides 12–
22 in relatively good yields (Table 1). In order to
broaden the scope of this reaction we have em-
ployed the thiolactams which possess various func-
tional substituents on the benzodiazepine skeleton.
Correspondence to: Regina Janciene; e-mail: apalaima@bchi.lt.
Contract grant sponsor: Lithuanian State Science and Studies
Foundation.
c
ꢀ
2004 Wiley Periodicals, Inc.
363

364 Janciene et al.
lactam 11 (R2 = Me) has been transformed into tri-
cyclic derivative 22 just at the presence of the hydro-
bromic acid. This may be attributed to the different
nucleophility of N5 heterocyclic atom in the start-
ing thiolactam 11 compared to N5-acylated deriva-
tives 1–7. We assumed that protonation of the hete-
rocyclic amine group would promote this reaction.
Thus, using such approach thiolactam 11 was con-
verted to 22 in 61% yield. Surprisingly, treatment of
N5-unsubstituted thiolactams 8–10 (R2 = H) contain-
ing the bromine or nitro group at the aromatic ring
under the neutral reaction conditions or at the pres-
ence of hydrobromic acid gave the corresponding
products 19–21 in only 33% yield. Formation of the
tricyclic system has been proved by 1H NMR spectral
data. In the spectra of compounds 12–22 the pro-
tons of the CH CH group of the thiazole nucleus
are observed as two doublets between 8.23 and 8.99
SCHEME 1
Synthesis of 5,6-dihydro-4H-thiazolo[3,2-d]
[1,5]benzodiazepin-11-ium bromides.
1
ppm. The H NMR spectra of compounds 1–3 and
12–14 showed the existence of two forms exhibit-
ing double sets of signals, due to the presence of ro-
tational isomers of the exocyclic amide bond. New
compounds were all characterized by IR, H NMR
(Table 2), and CHN analysis.
Excess bidentate reagent was needed in this reac-
tion. When this reaction was repeated using less of
diethyl acetal (1.0 or 2.5 equiv), the cyclic thiolactam
1 was consumed slowly. However, after the addition
of 5.0 equivalents of this reagent to the reaction mix-
ture, the conversion of 1 was completed in 1 h. It
is important to note that N5-methylsubstituted thio-
1
Thiolactams 1, 2, 4, and 3 were obtained from
the N5-unsubstituted (R2 = H) the corresponding
TABLE 1 Characterization of Compounds 1–22 and Elemental Analysis Dataa
Found (Calcd.)
H
Molecular Formula
(Molecular Weight)
Yieldb (%)
mp ( ◦C)c
C
N
1
87
68
41
57
94
96
93
60
70
62
70
73
81
45
91
60
85
81
34
33
31
61
207–210
195–198
230–233
174–176
185–187
179–182
209–211
242–244
203–205
234–236
137–139d
236–238
222–224
>280 dec
253–256
232–234
190–193
181–183
>208 dec
>107 dec
>280
C10H10N2OS (206.27)
58.33 (58.23) 4.67 (4.89) 13.46 (13.58)
60.34 (59.98) 5.27 (5.49) 12.61 (12.72)
49.61 (49.80) 4.36 (4.18) 15.53 (15.84)
61.85 (61.51) 6.09 (6.02) 12.21 (11.95)
64.81 (64.62) 5.17 (5.08) 14.44 (14.13)
65.31 (65.57) 5.63 (5.50) 13.57 (13.49)
65.26 (65.57) 5.65 (5.50) 13.25 (13.49)
2
C11 12
11H11N3O3S (265.29)
C12H14N2OS (234.32)
H N2OS (220.29)
3
C
4
5
C
C
16H15N3OS (297.38)
17H17N3OS (311.41)
H N3OS (311.41)
6
7
C17 17
C9H8Br2N2S (336.06)
C10H10Br2N2S (350.09)
8
32.02 (32.17) 2.56 (2.40)
34.64 (34.31) 2.94 (2.88)
8.72 (8.34)
8.11 (8.00)
9
10
11
12
13
14
15
16
17
18
19
20
21
22·HBr
C
10H11N3O2S (237.28)
–
50.47 (50.62) 4.45 (4.67) 17.56 (17.71)
–
–
–
C
C
12H11BrN2OS (311.21)
13H13BrN2OS (325.23)
46.24 (46.31) 3.62 (3.56)
48.12 (48.01) 4.06 (4.03)
8.70 (9.00)
8.57 (8.61)
C
13H12BrN3O3S (370.23)
C14H15BrN2OS (339.26)
18H16BrN3OS (402.32)
C19 18BrN3OS (416.35)
19H18BrN3OS (416.35)
C11H9Br3N2S (441.00)
42.26 (42.17) 3.19 (3.27) 11.33 (11.35)
49.41 (49.57) 4.37 (4.46) 8.19 (8.26)
53.62 (53.74) 4.22 (4.01) 10.48 (10.44)
54.73 (54.81) 4.49 (4.36) 10.36 (10.09)
54.93 (54.81) 4.48 (4.36) 10.11 (10.09)
C
H
C
30.32 (29.96) 2.27 (2.06)
31.57 (31.68) 2.69 (2.44)
6.41 (6.35)
5.89 (6.16)
C
12H11Br3N2S (455.02)
C
12H12Br1N3O2S (342.22)
41.93 (42.12) 3.78 (3.53) 12.19 (12.28)
6.27 (6.36)
175–177e C13H15BrN2S .HBr.1.5 CH3OH (440.23) 39.83 (39.56) 4.80 (5.04)
aSatisfactory microanalyses were obtained: C 0.36; H 0.25; N 0.38.
bYields of purified products.
cCrystallization solvent: 1–4 (EtOAc), 5–7, 10 (toluene), 8, 9 (i -PrOH).
dLit. [6] 137–139◦C (MeOH).
eSolvate with MeOH.

A Straightforward Synthesis of Novel 4H-Thiazolo[3,2-d ][1,5]benzodiazepine Derivatives 365
TABLE 2 Spectroscopic Data of Compounds 1–10 and 12–22
IRa,ν (cm−1
)
1H NMR δ (ppm), J (Hz)
1b
2b
1645, 3100, 3150
1640, 3100, 3150
Two rotamers in a ratio of 86:14c. 2.99 (m, 2H, CH2), 4.05 (m, 2H, CH2N), 7.37 (m, 4H,
arom), 8.22 (s, 1H, CHO), [8.41 (s, 1H, CHO)], [11.90 (s, 1H, NH)], 12.01 (s, 1H, NH)
Two rotamers in a ratio of 87:13c. 1.20 (d, 3H, CH3), 3.04 (m, 1H, CH), 3.58 (dd, 1H,
J = 4.8, 12.8, CH2), 4.06 (dd, 1H, J = 12.8, CH2), 7.38 (m, 4H, arom), 8.19 (s, 1H,
CHO), [8.36 (s, 1H, CHO)], [11.90 (s, 1H, NH)], 12.02 (s, 1H, NH)
3b
1338, 1505, 1660,
3195
Two rotamers in a ratio of 85:15c. 1.19 (d, 3H, CH3), [1.25 (d, 3H, CH3)], 2.55–3.30 (m, 2H,
CH2), 4.95 (m, 1H, CH), 7.45 (d, 1H, J = 8.8, H-9), 8.16 (s, 1H, CHO), 8.20–8.50 (m, 2H,
H-6, H-8), [8.51 (s, 1H, CHO)], 12.07 (s, 1H, NH)
4d
5d
6d
7d
8b
9b
10b
1665, 3190
1.19 (d, 3H, CH3), 1.76 (s, 3H, CH3CO), 2.60 (dd, 1H, J = 12.8, CH2), 3.04 (dd, 1H,
J = 4.8, 12.8, CH2), 5.39 (m, 1H, CH), 6.80–7.65 (m, 4H, arom), 10.61 (s, 1H, NH)
3.00 (m, 2H, CH2), 4.32 (m, 2H, CH2N), 6.21 (s, 1H, NHCO), 6.90–7.50 (m, 9H, arom),
10.48 (s, 1H, NH)
1660, 3155, 3290
1645, 3155, 3290,
3370
1655, 3150, 3310,
3415
1.26 (d, 3H, CH3), 2.89 (m, 1H, CH), 3.75 (dd, 1H, J = 5.6, 12.4, CH2), 4.39 (dd, 1H,
J = 12.4, CH2), 6.18 (s, 1H, NHCO), 6.80–7.55 (m, 9H, arom), 10.51 (s, 1H, NH)
1.26 (d, 3H, CH3), 2.53 (dd, 1H, J = 12.8, CH2), 3.05 (dd, 1H, J = 4.8, 12.8, CH2), 5.29
(m, 1H, CH), 5.95 (s, 1H, NHCO), 6.80–7.70 (m, 9H, arom), 10.27 (s, 1H, NH)
3.00 (m, 2H, CH2), 3.65 (m, 2H, CH2N), 5.57 (s, 1H, NH), 7.30 (d, 1H, J = 2.4, H-9), 7.53
(d, 1H, J = 2.4, H-7), 11.65 (s, 1H, NHCS)
3120, 3340
3150, 3330
1.11 (d, 3H, CH3), 2.80–3.70 (m, 3H, CH2CH), 5.61 (s, 1H, NH), 7.30 (d, 1H, J = 2.4, H-9),
7.54 (d, 1H, J = 2.4, H-7), 11.75 (s, 1H, NHCS)
1340, 1517, 3176,
3394
1.27 (d, 3H, CH3), 2.67–3.17 (m, 2H, CH2), 3.88 (m, 1H, CH), 6.33 (bs, 1H, NH), 7.22 (d,
1H, J = 8.8, H-9), 7.56 (dd, 1H, J = 2.4, 8.8, H-8), 7.81 (d, 1H, J = 2.4, H-6), 12.05 (bs,
1H, NHCS)
12b
13b
14b
1670
Two rotamers in a ratio of 82:18c. 3.71 (m, 2H, CH2), 4.24 (m, 2H, CH2N), [4.37 (m, 2H,
CH2N)], 7.50–8.00 (m, 4H, arom), 8.19 (s, 1H, CHO), [8.28 (s, 1H, CHO)], 8.43 (d, 1H,
J = 4.0, HCS), [8.46 (d, 1H, J = 4.0, HCS)], 8.80 (d, 1H, J = 4.0, HCN), [8.86 (d, 1H,
J = 4.0, HCN)]
1680
Two rotamers in a ratio of 79:21c. [1.54 (d, 3H, CH3)], 1.58 (d, 3H, CH3), 3.40–4.00 (m, 2H,
CH and CH2), 4.31–4.62 (m, 1H, CH2), 7.45–8.00 (m, 4H, arom), 8.18 (s, 1H, CHO),
[8.26 (s, 1H, CHO)], 8.53 (d, 1H, J = 4.0, HCS), [8.57 (d, 1H, J = 4.0, HCS)], 8.86 (d,
1H, J = 4.0, HCN), [8.92 (d, 1H, J = 4.0, HCN)]
1350, 1535, 1695
Two rotamers in a ratio of 80:20c. 1.29 (d, 3H, CH3), [1.33 (d, 3H, CH3)], 3.10 (dd, 1H,
J = 12.4, 14.8, CH2), 4.25 (dd, 1H, J = 5.6, 14.4, CH2), 5.09 (m, 1H, CH), 8.12 (s, 1H,
CHO), 8.23 (d, 1H, J = 8.8, H-10), [8.28 (d, 1H, J = 8.8, H-10)], [8.40 (s, 1H, CHO)],
8.47 (d, 1H, J = 4.0, HCS), [8.52 (d, 1H, J = 4.0, HCS)], 8.53–8.72 (m, 2H, H-7, H-9),
8.87 (d, 1H, J = 4.0, HCN), [8.99 (d, 1H, J = 4.0, HCN)]
15e
1655
1.34 (d, 3H, CH3), 1.74 (s, 3H, CH3CO), 2.87 (dd, 1H, J = 12.0, 14.4, CH2), 4.02 (dd, 1H,
J = 5.6, 14.4, CH2), 5.39 (m, 1H, CH), 7.57–8.02 (m, 4H, arom), 8.35 (d, 1H, J = 4.0,
HCS), 8.79 (d, 1H, J = 4.0, HCN)
16e
17e
18e
1680, 3140, 3235
3.40–3.74 (m, 2H, CH2), 4.10–4.60 (m, 2H, CH2N), 6.85–7.35 and 7.60–7.90 (m, 9H,
arom), 8.34 (d, 1H, J = 4.0, HCS), 8.67 (d, 1H, J = 4.0, HCN)
1685, 3110, 3200,
3380
1670, 3110, 3235,
3410
1.64 (d, 3H, CH3), 3.58 (m, 1H, CH), 3.98–4.55 (m, 2H, CH2N), 6.90–8.14 (m, 9H, arom),
8.39 (d, 1H, J = 4.0, HCS), 8.70 (d, 1H, J = 4.0, HCN)
1.41 (d, 3H, CH3), 2.84 (dd, 1H, J = 12.4, 14.8, CH2), 4.01 (dd, 1H, J = 6.4, 14.8, CH2),
5.16 (m, 1H, CH), 6.84–7.34 and 7.55–8.04 (m, 9H, arom), 8.33 (d, 1H, J = 4.0, HCS),
8.67 (d, 1H, J = 4.0, HCN)
19b
3105, 3280
3.67 (m, 2H, CH2), 3.80 (m, 2H, CH2N), 5.71 (s, 1H, NH), 7.92 (d, 1H, J = 2.4, H-8 or
H-10), 8.09 (d, 1H, J = 2.4, H-10 or H-8), 8.34 (d, 1H, J = 4.0, HCS), 8.77 (d, 1H,
J = 4.0, HCN)
20e
21e
3127, 3410
1.61 (d, 3H, CH3), 3.55–4.13 (m, 3H, CH2 and CH), 7.91 (d, 1H, J = 2.4, H-8 or H-10), 8.01
(d, 1H, J = 2.4, H-10 or H-8), 8.30 (d, 1H, J = 4.0, HCS), 8.62 (d, 1H, J = 4.0, HCN)
1.39 (d, 3H, CH3), 3.20–4.60 (m, 3H, CH2 and CH), 7.80–8.20 (m, 3H, arom), 8.26 (d, 1H,
J = 4.0, HCS), 8.66 (d, 1H, J = 4.0, HCN)
1349, 1532, 3272,
3412
22e·HBr 2257 (NH+)
1.58 (d, 3H, CH3), 2.84 (s, 3H, H3CN), 3.30–3.90 (m, 3H, CH2 and CH), 7.20–7.80 (m, 4H,
arom), 8.30 (d, 1H, J = 4.8, HCS), 8.56 (d, 1H, J = 4.0, HCN)
aCompounds 1, 2, 4–9, 12–17 (nujol), 3, 10, 18–22 (KBr).
bRecorded in DMSO-d6.
c1H NMR peaks corresponding to the minor isomer of compounds 1–3 and 12–14 are given in square brackets.
dRecorded in CDCl3.
eRecorded in CD3OD.

366 Janciene et al.
3-R-4-R1 -2,3,4,5-tetrahydro-1,5-benzodiazepine-
2(1H)-thiones (23, R = R1 = H; 24, R = Me, R1 = H;
25, R = H, R1 = Me) [6] and 10 [7] by formylation or
acetylation according to the procedures previously
described [8,9]. Treatment of 23–25 with phenyliso-
cyanate resulted in the formation of carbamoylated
derivatives 5–7. Early described 4-methyl-7-nitro-
and 6,8-dibromo-3-R(H or Me)-2,3,4,5-tetrahydro-
1,5-benzodiazepin-2(1H)-ones [8,9] were trans-
formed into the corresponding thiolactams 10, 8,
9 by treatment with the phosphorous pentasulfide
according to literature [7,10] procedure.
In order to get more insight into the nature of the
studied cyclization process we investigated the situ-
ation by means of theoretical modeling. It is known
that cyclic thioamides in the reaction mixture dis-
play the tautomeric equilibrium between the thione
and thiol forms having a nucleophilic center either
on the nitrogen atom or on the sulfur atom, respec-
tively [7,11,12]. Moreover, the literature data show
that in some cases of substitution of a thioamide
moiety with various electrophilic reagents the sulfur
atom attack is favored [12,13].
In order to estimate relative acidities at N1-H and
S-H positions of molecules 1–11 the proton affini-
ties of the corresponding deprotonated tautomeric
forms were determined. The close proton affinity val-
ues of deprotonated pairs (Table 3) clearly point to
the corresponding neutral parent molecules having
very similar acidity at these positions.
The charge distribution of the neutral molecules
1–11 and their deprotonated forms was determined
by Lowdin population analysis. The computational
results (Table 3) indicate that in thioamides the elec-
tron density on the N1 nitrogen atom is slightly
higher than that on the sulfur atom. On the other
hand, deprotonation gives rise to a much larger in-
crease in the electron density on the sulfur atom
(∼0.2–0.3) relative to that in the neutral molecules.
Moreover, a considerable increase of the negative
charge is induced on the sulfur atom than that on
N1 nitrogen atom. Meanwhile, an interchange of the
electron density on the N5 nitrogen atom is negligi-
ble (data are not presented in Table). So, the nega-
tive charge in deprotonated form decrease in the fol-
lowing succession S > N1 > N5. Taking these charge
distribution into account in both neutral and de-
protonated form of the molecules it is possible that
S-alkylation could take place as the primary step in
the course of the cyclization. However, it is note-
worthy that the substituents in aromatic ring (com-
pounds 3, 8–10) decrease the negative charge on
the sulfur atom and simultaneously influence the
coupling with the bidentate reactant to a great ex-
tent. Thus, theoretical computational studies are in
agreement with the explanation of the preparative
experiments.
A
convenient way to understand different
reactivity of the variously substituted 2,3,4,5-
tetrahydro-1,5-benzodiazepine-2(1H)-thiones 1–11
is to examine the energetic parameters and the
charge distribution of these species via quantum
chemical calculations. The computations were per-
formed using GAMESS 98 programme package [14].
Geometry optimizations of the starting materials
and deprotonated forms were carried out in two
steps. After initial geometry optimization using AM1
method the final optimizations were executed using
DFT with the 6-31G basis set and the B3LYP method
[14].
Generally, we have described that the reaction of
N5-acylsubstituted 1,5-benzodiazepinethiones with
TABLE 3 Proton Affinity and Charge Distribution of 1–11
Proton Affinity
(kJ/mol) and Position
of Protonation
Charge Distribution
Neutral Molecule
Deprotonated Form
N1 S
N1
S
N1
S
1
2
962.5
966.7
911.6
965.9
956.2
955.1
955.8
955.2
957.9
929.3
963.5
958.3
950.2
922.7
961.4
951.9
953.0
975.0
977.0
975.9
917.4
964.4
−0.233
−0.240
−0.258
−0.232
−0.234
−0.231
−0.233
−0.233
−0.231
−0.250
−0.242
−0.221
−0.243
−0.143
−0.230
−0.217
−0.221
−0.222
−0.160
−0.192
−0.157
−0.228
−0.308
−0.285
−0.294
−0.302
−0.307
−0.300
−0.301
−0.310
−0.292
−0.292
−0.308
−0.557
−0.551
−0.413
−0.554
−0.547
−0.556
−0.552
−0.506
−0.504
−0.426
−0.491
3
4
5
6
7
8
9
10
11

A Straightforward Synthesis of Novel 4H-Thiazolo[3,2-d ][1,5]benzodiazepine Derivatives 367
5-Formyl-3-R-4-R1-2,3,4,5-tetrahydro-1,5-
bromoacetaldehyde diethyl acetal provided an effi-
cient method to prepare novel tricyclic thiazolo[3,2-
d][1,5]benzodiazepines. When electron-donating
methyl group was present at N5 atom in thione
precursor such compound could also be utilized
by modifying experimental conditions to construct
tricyclic system. These original derivatives are of
potential interest in biologic evaluation.
benzodiazepine-2(1H)-thiones (1–3)
Formylation of thiolactams 23, 24 [6], and 10 [7]
with the mixture of 98% formic acid and acetic an-
hydride was conducted by using a general procedure
[8].
5-Acetyl-4-methyl-2,3,4,5-tetrahydro-1,5-
benzodiazepine-2(1H)-thione (4)
Acetylation of thiolactam 25 (R = H, R1 = Me) [6]
with acetic anhydride and work up were conducted
by using procedure [9].
EXPERIMENTAL
Melting points (uncorrected) were determined in
open capillaries using a PTP (Thermopribor) appara-
tus. IR spectra were recorded on a Specord 75 IR or
on a Spectrum BX FT-IR (Perkin-Elmer) spectrom-
5-Phenylcarbamoyl-3-R-4-R1-2,3,4,5-tetrahydro-
1,5-benzodiazepine-2(1H)-thiones (5–7)
1
eter. H NMR spectra were measured at 80 MHz on
a BS 587A (Tesla) spectrometer with TMS as an in-
ternal reference. Elemental analyses were obtained
on a Microelemental Analyzer (Labopribor). Ascend-
ing TLC was performed on Silufol UV254 silica gel
plates with chloroform/ethyl acetate (14:7) as the elu-
ent and were visualized with UV light and/or iodine
vapor. Compound 11 was synthesized following the
literature method [6].
General Procedure. A mixture of the appropri-
ate thiolactam 23–25 [6] (8.0 mmol) and phenyliso-
cyanate (0.92 ml, 8.5 mmol) in anhydrous toluene
(80 ml) was refluxed for 45 min. After cooling the
mixture to room temperature the precipitated prod-
uct was filtered and recrystallized from a suitable
solvent.
Preparation of thiolactams 8–10
Synthesis of 4-R-5-R1-6-R2-5,6-dihydro-4H-
thiazolo[3,2-d][1,5]benzodiazepin-11-ium
bromides (12–22)
Thionation of the corresponding lactams [8,9] was
performed by treatment with the P2S5 in reflux-
ing dry pyridine according to literature procedure
[10].
General Procedure. To a stirred solution of the
appropriate 1,5-benzodiazepine-2-thione derivative
1–10 (5.0 mmol) in butan-2-one (30–60 ml for
1, 2, 4–7 and 200 ml for 3, 8–10) an excess of
ꢀ-bromoacetaldehyde diethyl acetal (4.0 ml, 25.7
mmol) and water (0.5 ml) were added. The mixture
was refluxed for 30 min and precipitation of product
was observed. In each case the optimum reaction
time (ca 0.5–1 h) was determined by TLC monitor-
ing. Then the mixture was stored overnight in re-
frigerator and filtered. The crude products were re-
crystallized from anhydrous methanol/diethyl ether
mixture.
When thiolactam 11 (5.0 mmol) was used, to its
solution in butan-2-one (40 ml), an aqueous HBr
(40%, 1.0 ml) was added instead of water. Sub-
sequently diethyl acetal (4.0 ml) was added. Af-
ter that the preparation of 22 had been performed
according to the above procedure. Compound 22
was isolated as its hydrobromide. Thiazolobenzo-
diazepinium bromides 19–21 were also obtained
from thiolactams 8–10 under the same reaction
conditions.
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