Syntheses of 7-phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)one, 7-phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-c]-pyrrolo[1,2-a][1,4] diazepine and 7-phenyl-5H-thiazolo[5,4-e]-[1,3,4]triazolo[5,1-c]pyrrolo[1,2-a][1,4] diazepines [1]

Article abstract of DOI:10.1002/jhet.5570390130

Fused tricyclic 7-phenyl-5H-thizolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)one (10) was prepared by thermolysis of 2-phenyl-4-(1-pyrrolylmethyl)thiazole-5-carbonyl azide (9) in acetic acid. In addition, starting from 10, 7-phenyl-5H-thiazolo [5,4-e][1,3,4]triazolo[5,1-c]pyrrolo[1,2-a][1,4]diazepines (13) and 7-phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-c]pyrrolo[1,2-a][1,4] diazepine (14) were synthesized.

Full text of DOI:10.1002/jhet.5570390130

Jan-Feb 2002
Syntheses of 7-Phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-
10(9H)one, 7-Phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-c]-
pyrrolo[1,2-a][1,4]diazepine and 7-phenyl-5H-thiazolo[5,4-e]-
[1,3,4]triazolo[5,1-c]pyrrolo[1,2-a][1,4]diazepines [1]
A. Shafiee* and M.Shekarchi
213
Department of Chemistry, Faculty of Pharmacy, Tehran University, of Medical Sciences, Tehran, Iran
Received July 27, 2001
Fused tricyclic 7-phenyl-5H-thizolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)one (10) was prepared by
thermolysis of 2-phenyl-4-(1-pyrrolylmethyl)thiazole-5-carbonyl azide (9) in acetic acid. In addition, start-
ing from 10, 7-phenyl-5H-thiazolo [5,4-e][1,3,4]triazolo[5,1-c]pyrrolo[1,2-a][1,4]diazepines (13) and 7-
phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-c]pyrrolo[1,2-a][1,4]diazepine (14) were synthesized.
J. Heterocyclic Chem., 39, 213 (2002).
The pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibi-
otics(PBDs), such as anthramycin (1) and DC-81 (2) are a
well-known class of sequence-selective DNA-binding
agents derived from Streptomyces species [2-4]. The anti-
tumor activity of the PBDs is exterted through sequence-
selective covalent binding to a C2-NH group of guanine
2
within the minor groove of double stranded DNA via the
electrophilic N10-C11 carbinolamineimine functionality.
Although the N10-C11 carbinolamine moiety is respon-
sible for the covalent (binding) component of DNA inter-
action, other features of the molecule, including the overall
3-dimensional shape and the substituents in the A-and C-
rings, may also contribute to the non-covalent interaction
with duplex DNA. Furthermore, this non-covalent compo-
nent may constitue part of the DNA-recognition process,
leading to the preferred binding site of 5'-Pu-G-Pu.
A recent study showed for the first time that PBD dilac-
tam 3 could bind strongly to DNA as measured by thermal
denaturation studies[5].We present in this paper the prepa-
ration of title compounds, which are structurally similar to
PBDs, as possible effective drugs against cancer.
The product of this reaction depended on the reaction
condition. When to a suspension of potassium salt of pyr-
role in tetrahydrofuran at 0°, a solution of compound 5
was added and stirred for 3 hours compound 7 was
obtained as a major product.We could presume that ini-
tially the expected product 6 was formed. However, hydro-
gen of the methylene group in compound 6 under experi-
mental condition gave an anion, which in a nucleophilic
substitution reaction with compound 5 gave compound 7.
When the reagents were added at 25º and refluxed for 4
hours, compound 6 could be obtained in a good yield.
Alkaline hydrolysis of compound 6 afforded 2-phenyl-
4-(1-pyrrolylmethyl)thiazole-5-carboxylic acid (8). This
acid was treated successively with triethylamine,
ethylchloroformate and sodium azide [7] to give carbonyl
azide 9 in 75% yield. Heating the carbonyl azide 9 in a
large excess of acetic acid gave 7-phenyl-5H-thiazolo-
[5,4-e]pyrrolo[1,2-a][1,4] diazepin-10(9H)one (10) in
47% yield [8,9]. Reaction of 1 equivalent of compound 10
in the presence of 1.1 equivlent of Lawesson's reagent in
dioxane at 75º gave thiolactam 11 (Scheme 2) [10].
Reaction of compound 11 with hydrazine hydrate in
ethanol at room temperature for 48 hours gave poor yield
of 10-hydrazino-7-phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-
a][1,4] diazepine(12). Refluxing compound 11 with
hydrazine hydrate in ethanol resulted in decomposition of
the starting material. However, compound 12 could be
obtained in good yield, when compound 11 was reacted
The starting material, namely ethyl 2-phenyl-4-(1-
pyrrolylmethyl)thiazole-5-carboxylate (6) was prepared
from the reaction of ethyl 4-bromomethyl-2-phenylthia-
zole-5-carboxylate (5) [6] with potassium salt of pyrrole in
dry tetrahydrofuran (Scheme 1).

214
A. Shafiee and M. Shekarchi
Vol. 39
EXPERIMENTAL
Melting points were taken on a Kofler hot stage apparatus and
1
are uncorrected. H nmr spectra were recorded on a Brucker FT-
80 spectrometer. Tetramethylsilane was used as an internal stan-
dard. The infrared spectra were acquired on a Nicolet 550-FT
spectrometer. The mass spectra were run on Finigan TSQ 70
spectrometer at 70 eV. Elemental analyses were carried out with a
Perkin-Elmer Model 240-C apparatus. The results of elemental
analyses (C, H, N) were within ±0.4% of the calculated amounts.
Ethyl 4-methyl-2-phenylthiazole-5-carboxylate (4) and ethyl 4-
bromomethyl-2-phenylthiazole-5-carboxylate (5) were prepared
according to reported methods [5].
Ethyl 2-Phenyl-4-(1-pyrrolylmethyl)thiazole-5-carboxylate (6).
To a well stirred suspention of potassium salt of pyrrole [pre-
pared from pyrrole (1.79 g, 26 mmoles) and potassium metal
(1.04 g, 26 mg-atom)] in dry tetrahydrofuran, a solution of com-
pound 5 (7.85 g, 24 mmoles) in 32 ml THF was added dropwise
under argon atmosphere at 25°. The mixture was heated under
reflux for 4 hours. After cooling to room temperature, the solvent
was evaporated. The residue was treated with 50 ml of water and
the mixture was extracted with n-hexane (3×25 ml). The com-
bined organic layers were washed with brine, dried (anhydrous
sodium sulfate) and evaporated under reduced pressure to give
the crude product. The crude product was crystallized from
methanol/diethyl ether (7:3) to yield 4.5 g (60%) of compound 6
as white solid, mp 78- 79°; ir (potassium bromide): ν 3414, 2927,
with hydrazine hydrate in ethanol under ultrasonic irradia-
tion for 12 minutes. Treatment of hydrazine 12 with substi-
tuted triethyl orthoformates in the presence of p-toluene-
sulfonic acid gave substituted triazoles 13a-d [10]. The 7-
phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-
c]pyrrolo[1,2-a][1,4]diazepine (14) was obtained from the
reaction of hydrazine 12 with sodium nitrite in 10% acetic
acid (Scheme 3).
The structures of the designed fused diazepines10-14
were supported by their ir, nmr and mass spectra as well as
by their elemental analyses.The physical constants of tria-
zoles 13a-d are summarized in table 1.
-1
1
1710, 1525, 1269, 1092, 755, 717 cm ; H nmr (deuteriochloro-
form): δ 1.4 (t, J=7 Hz, 3H, OCH CH ), 4.39 (q, J=7 Hz, 2H,
2
3
OCH ), 5.5 (s, 2H, CH -N), 6.1 (t, J=2 Hz, 2H, H and H pyr-
2
2
3
4
role),6.92 (t, J=1 Hz, 2H, H and H pyrrole), 7.39-7.47 (m, 3H,
2
5
+
aromatic), 7.88-7.97 (m, 2H, aromatic); ms: m/z (%) 312 (M ,
100), 283 (48), 239 (84).
Anal. Calcd. for C H N O S: C, 65.36; H, 5.16; N, 8.97.
17 16
2 2
Found: C, 65.28; H, 5.21; N, 8.99.
'
'
Ethyl 2-Phenyl-4-[1-(pyrrolyl)-2-(2 -phenyl-5 -ethoxycarbonyl-
'
4-thiazolyl)ethyl]thiazole-5-carboxylate (7).
This compound was prepared as explained for compound 6,
but reagents were added at 0° and stirred for 3 hours. The sol-
vent was removed under reduced pressure and the residue was
treated with 50 ml of water. The mixture was extracted with
hexane (3×25 ml). The combined organic layers were washed
with brine, dried (anhydrous sodium sulfate) and evaporated
under reduced pressure to give the crude product. The crude
product was crystallized from diethyl ether to yield 7 g (49%)
of compound 7 as yellow solid, mp 158-160˚; ir (potassium bro-
-1
mide): ν 3429, 2925, 1706, 1527, 1420, 1275, 1082, 724 cm ;
Table 1
Physical data for 13a-d
Comp.
R
Mp [a]
Yield
Formula
Calc
Found
Calc
Found
Calc
Found
C%
H%
N%
13a
13b
13c
13d
H
Me
Et
215-217
272-274
238-239
295-296
72
65
71
68
C
C
C
C
H
N S
62.93
63.93
64.84
69.27
62.65
63.85
64.72
69.32
3.63
4.10
4.53
3.96
3.83
4.22
4.44
3.81
22.93
21.93
21.00
18.36
22.78
21.85
21.14
18.42
16 11
5
H N S
17 13 5
H
N S
5
18 15
Ph
H N S
22 15 5
[a] All compounds were crystallized from chloroform/ether.

Jan-Feb 2002
Syntheses of 7-Phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-10(9H)one
215
1
H nmr (deuteriochloroform):δ 1.36 (t, J=7.1 Hz, 6H, 2
d ):δ 5.39 (s, 2H, CH -N), 6.12-6.17 (m, 1H, H ), 6.71-6.82 (m,
6 2 2
OCH CH ), 4.13-4.45 (m, 6H, CH-CH and 2 OCH CH ), 6.05
1H, H ), 7.18-7.23 (m, 1H, H ), 7.41-7.48 (m, 3H, aromatic),
7.77-7.91 (m, 2H, aromatic); ms: m/z (%): 281 (M , 100), 252
(15), 219 (57), 121 (59).
2
3
2
2
3
3 1
+
( t, J=2 Hz, 2H, H and H pyrrole ), 6.8-7.01 (m, 3H, CH-CH ,
3
4
2
H and H pyrrole), 7.41-7.50 (m, 6H, aromatic), 7.81-8.17 (m,
2
5
+
4H, aromatic); ms: m/z (%) 557 (M , 30), 511 (14), 417 (18),
311(100), 265 (64).
Anal. Calcd. for C H N OS: C, 64.04; H, 3.94; N, 14.94.
15 11
3
Found: C, 64.14; H, 3.86; N, 14.87.
Anal. Calcd. for C H N O S: C, 64.61; H, 4.88; N, 7.53.
Found: C, 64.56; H, 4.76; N, 7.61.
The remaining ether solution was concentrated under reduced
pressure and crystallized from methanol/diethyl ether (7:3) to
yield 1.5 g (20%) of compound 6, mp 78-79°.
30 27
3 4
7-Phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-a][1,4]diazepine-
10(9H)thione (11).
A solution of compound 10 (8.99 g, 32 mmoles) and
Lawesson's reagent (14.25 g, 35 mmoles) in dioxane (80 ml)
was heated at 75° for 3 hours. The solvent was removed under
reduced pressure. The residue was suspended in 200 ml of
40% aqueous sodium hydroxide and stirred for 1 hour.The
mixture was extracted with ethyl acetate (3×20 ml) and the
aqueous layer was acidified with acetic acid. The precipitate
was collected, dried and crystallized from methanol to yield 6
g (63%) of compound 11 as yellow solid, mp 228- 230°; ir
(potassium bromide): ν 3438, 2929, 1701, 1639, 1402, 751
2-Phenyl-4-(1-pyrrolylmethyl)thiazole-5-carboxylic Acid (8).
A mixture of ester 6 (3.12 g, 10 mmoles) and potassium
hydroxide pellets (1.5 g, 30 mmoles) in a mixture of methanol
(20 ml) and water (5 ml) was refluxed for 3 hours. After cooling,
the reaction mixture was concentrated in reduced pressure,
diluted with 40 ml of water and extracted with ether (2x30 ml).
The aqueous layer was cooled and acidified with hydrochloric
solution (1:1). The precipitate was filtered, washed with diethyl
ether and finally crystallized from methanol to yield 2.84 g
(70%) of compound 8 as white solid, mp 168-169˚; ir (potassium
1
1
cm ; H nmr (deuteriochloroform):δ 5.31 (s, 2H, CH -N),
2
6.23-6.36 (m, 1H, H ), 6.91-7.15 (m,1H, H ), 7.35-7.55 (m,
2
3
4H, H and aromatic), 7.62-8.13 (m, 2H, aromatic); ms: m/z
1
+
(%): 297 (M , 25), 238(10), 193 (17), 109 (48), 68 (50), 42
-1
bromide):ν 3439, 2925, 1666, 1527, 1414, 1295, 1085, 724cm ;
(100).
1
H nmr (deuteriochloroform):δ 5.56 (s, 2 H, CH -N), 6.15 (t,
2
Anal. Calcd. for C H N S : C, 60.58; H, 3.73; N, 14.13.
J=2 Hz, 2 H, H and H pyrrole), 6.93 (t, J=1 Hz, 2H, H and H
15 11 3 2
3
4
2
5
Found: C, 60.43; H, 3.82; N, 14.25.
pyrrole), 7.12-7.52 (m, 3H, aromatic), 7.9 -8.2 (m, 2H, aro-
+
matic); ms: m/z (%) 284 (M ,100), 266 (16), 239 (42), 219 (40)
10-Hydrazino-7-phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-
a][1,4]diazepine (12).
,135 (28),104 (50).
Anal. Calcd. For C H N O S: C, 63.36; H, 4.25; N, 9.85.
15 12
2 2
A solution of thiolactam 11 (1.1 g, 4 mmoles) and hydrazine
monohydrate (1.55 ml, 32 mmoles) in ethanol (30 ml) was stirred
under ultrasonic irradiation at room temperature for 12 minutes.
The solvent was removed under reduced pressure and the residue
was taken up in 50 ml of 20% aqueous hydrochloric acid and
stirred for 1 hour. The mixture was extracted with chloroform
(3×25 ml). The aqueous layer was neutralized with sodium
hydroxide. The precipitate was collected, washed with water and
crystallized from water to yield 540 mg (50%) of compound 12
as white solid, mp 144-145°; ir (potassium bromide):ν 3417,
Found: C, 63.41; H, 4.32; N, 9.79.
2-Phenyl-4-(1-pyrrolylmethyl)thiazole-5-cabonyl Azide (9).
To a well stirred and cooled solution of carboxylic acid 8 (9.8
g, 33 mmoles), dry acetone (98 ml) and dry triethylamine (3.55
g, 35 mmoles) was added under an atmosphere of argon, a solu-
tion of ethyl chloroformate (4.94 g, 45 mmoles) in dry acetone
(13 ml) over a period of 10 minutes. The stirring was continued
at 0-5° for 30 minutes and a solution of sodium azide (3.8 g, 59
mmoles) in 13 ml of cool water was added dropwise. After the
addition was completed the reaction mixture was stirred at 0°
for 1 hour. The mixture was poured on crushed ice and
extracted with carbon tetrachloride (3×50 ml). The combined
organic layers were washed with water, dried (anhydrous
sodium sulfate) and evaporated under reduced pressure to give
7.46 g (70%) of compound 9 as yellow oil. This oil was used for
the next reaction without further purification; ir (chloroform): ν
1
3312, 2918, 1575, 1523, 1453, 1244, 725 cm ; ms: m/z (%): 295
+
(M , 100), 277 (21), 235 (15), 200 (17), 187 (16), 92 (29).
Anal. Calcd. for C
H N S: C, 61.00; H, 4.44; N, 23.71.
15 13 5
Found: C, 60.84; H, 4.29; N, 23.66.
7-Phenyl-5H-thiazolo[5,4-e][1,3,4]triazolo[5,1-c]pyrrolo[1,2-a]-
[1,4] diazepine (13a).
-1
1
A solution of compound 12 (400 mg, 1.35 mmoles), triethyl
orthoformate (13 mmoles) and p-toluenesulfonic acid (0.5 g) in
ethyl acetate was refluxed for 30 minutes.The precipitate was iso-
lated by filtration and purified by flash chromatography on silica
gel using diethyl ether/methanol (9:1) as eluent; ir (potassium bro-
mide): ν 3427, 2929, 1738, 1648, 1570, 1454, 1376, 1076, 720
1700, 1275 cm ; H nmr (deuteriochloroform):δ 5.61 (s, 2 H,
CH -N), 7.31(t, J=2 Hz, 2H, H and H pyrrole), 7.31 (t, J=1
2
3
4
Hz, 2H, H and H pyrrole), 7.42-7.68 (m, 3H, aromatic), 8.1-
2
5
8.31 (m, 2H, aromatic).
7-Phenyl-5H-thiazolo[5,4-e]pyrrolo[1,2-a][1,4]diazepin-
10(9H)one ( 10).
1
1
cm ; H nmr (deuteriochloroform): δ 5.34 (s, 2 H, CH -N), 6.21 -
2
6.35 (m, 1H, H ), 6.85-6.92 (m, 1H, H ), 7.08-7.23 (m, 1H, H ),
A solution of carbonyl azide 9 (1 g, 3.24 mmoles) in 50 ml
glacial acetic acid was refluxed vigorously for 2 hours. The sol-
vent was removed under reduced pressure. The residue after trit-
uration with diethyl ether was filtered and crystallized from ethyl
acetate/diethyl ether (8:2) to yield 550 mg (47%) of compound
10 as white solid, mp 235-237°; ir (potassium bromide):ν 3423,
2
3
1
7.35-7.52 (m, 3H, aromatic), 7.62-7.89 (m, 2H, aromatic), 8.39 (s,
+
1H, triazole); ms: m/z (%) 305 (M , 100), 277 (10), 251 (11), 202
(13),174 (18),147 (20), 121 (25), 103 (62), 70 (75).
Anal. Calcd. for C H N S: C, 62.93; H, 3.63; N, 22.93.
16 11
5
Found: C, 62.65; H, 3.83; N, 22.78.
Compounds 13b to 13d were prepared similarly (see Table 1).
1
1
2925, 1639, 1281, 1089, 724 cm ; H nmr (dimethyl sulfoxide-

216
A. Shafiee and M. Shekarchi
Vol. 39
REFERENCES AND NOTE
7-Phenyl-5H-thiazolo[5,4-e][1,2,3,4]tetrazolo[5,1-c]pyrrolo-
[1,2-a][1,4]diazepine (14).
[1] This work was partially presented in the Sixth
International Conference of Heteroatom Chemistry, Lodz´, Poland, p.
104 (2001).
[2] W. A. Remers, M. Mabilia and A. J. Hopfinger, J. Med.
Chem., 29, 2492 (1986).
[3] L. H. Hurley and R. L. Petrusek, Nature, 282, 529 (1979).
[4] D. E. Thurston and D. S. Bose, Chem. Rev., 94, 433
(1994).
To a solution of compound 12 (1.18 g, 4 mmoles) in 10%
acetic acid (40 ml) was added sodium nitrite (0.4 g, 6 mmoles)
and stirred at room temperature for 1 hour .The precipitate was
isolated by filtration, washed with water and purified by flash
chromatography on silica gel using n-hexane to yield 310 mg
1
(74%) of compound 14 as pink crystals, mp 263-265°;
H
nmr(deuteriochloroform): δ 5.45 (s, 2 H, CH -N), 6.31-6.42 (m,
2
1H, H ), 6.93-7.13 (m, 1H, H ), 7.18-7.26 (m, 1H, H ), 7.46-
[5] G. B. Jones, C. L. Davey and T. C. Jenkins, Anticancer
Drug Design, 5, 249 (1990).
[6] A. Shafiee, G. Kiaey and M. Vosoghi, J. Heterocyclic
Chem., 18, 789 (1981).
2
3
1
7.53 (m, 3H, aromatic), 7.91-8.01 (m, 2H, aromatic); ms: m/z
+
(%) 306 (M , 10), 278 (31), 252 (10), 187(17), 148(9), 121 (25),
103 (78), 70 (100).
[7] J. Weinstock, J. Org. Chem. 29, 3511 (1961).
[8] F. Povazanec, B. Decroix and J. Morel, J. Heterocyclic
Chem., 29, 1507 (1992).
Anal. Calcd. for C
Found: C, 58.73; H, 3.17; N, 27.32.
H N S: C, 58.81; H, 3.29; N, 27.43.
15 10 6
[9] C. Chedru, B. Decroix, J. Morel and F. Povazanec, J.
Heterocyclic Chem., 31, 1027 (1994).
Acknowledgements.
This work was partially supported by the International
Organization for Chemical Sciences in Development (IOCD).
[10] T. Flynn and A. Walser, J. Heterocyclic Chem., 29, 1477
(1992).