Synthesis of a novel functionalized tricyclic pyrimidine-fused 1,5-benzodiazepine library

Article abstract of DOI:10.1016/j.tet.2017.03.079

A series of novel tricyclic pyrimidine-fused 1,5-benzodiazepines (PFBZDs) was synthesized using an enaminone-based approach. The key step in the synthetic strategy involves the formation of the C[dbnd]C[sbnd]NMe₂ structure on vicinal carbonyl groups of the 1H-1,5-benzodiazepine-2,4(3H,5H)-dione (BZD). The synthesis of pyrimidine-fused 1,5-benzodiazepines was performed by a simple and efficient method in good to excellent yields under mild and green conditions. The β-enaminoamide intermediates were condensed with thiourea and guanidine derivatives to form the corresponding tricyclic PFBZDs. But reaction of aminoguanidine, thiosemicarbazide, 4-phenylthiosemicarbazide and ethane-1,2-diamine with β-enaminoamides didn't produce any desired product and led to recovery of the corresponding starting BZD.

Full text of DOI:10.1016/j.tet.2017.03.079

Accepted Manuscript
Synthesis of a novel functionalized tricyclic pyrimidine-fused 1,5-benzodiazepine
library
Hamid Reza Qomi, Azizollah Habibi
PII:
S0040-4020(17)30336-8
10.1016/j.tet.2017.03.079
TET 28585
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2017
Revised Date: 16 March 2017
Accepted Date: 27 March 2017
Please cite this article as: Qomi HR, Habibi A, Synthesis of a novel functionalized tricyclic pyrimidine-
fused 1,5-benzodiazepine library, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.079.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of a novel functionalized tricyclic pyrimidine-fused 1,5-benzodiazepine library
Hamid Reza Qomi, Azizollah Habibi*
Faculty of Chemistry, Kharazmi University, Tehran, P. Code 15719-14911, Iran
E-mail: habibi@khu.ac.ir; Tel-Fax: +98-2188820993
YH
N
O
H
N
R1
R2
NH2
NH2
R1
R2
N
NaOEt / EtOH
X
N
H
R1 = H, R2 = H
RHN
NH2
X = NH, R = H, CN, NO2
X = S, R = H
R1 = H, R2 = Me
R1 = Me, R2 = Me
R1 = H, R2 = Cl
R1 = H, R2 = Br
3a-q
Y = S, NH, N-CN, N-NO2
17 examples
Yields 70-94%

ACCEPTED MANUSCRIPT
Synthesis of a novel functionalized tricyclic pyrimidine-fused 1,5-benzodiazepine library
Hamid Reza Qomi, Azizollah Habibi*
Faculty of Chemistry, Kharazmi University, Tehran, P. Code 15719-14911, Iran
E-mail: habibi@khu.ac.ir; Tel-Fax: +98-21-88820893
Abstract
A series of novel tricyclic pyrimidine-fused 1,5-benzodiazepines (PFBZDs) was synthesized
using an enaminone-based approach. The key step in the synthetic strategy involves the
formation of the C=C-NMe2 structure on vicinal carbonyl groups of the 1H-1,5-benzodiazepine-
2,4(3H,5H)-dione (BZD). The synthesis of pyrimidine-fused 1,5-benzodiazepines was performed
by a simple and efficient method in good to excellent yields under mild and green conditions.
The β-enaminoamide intermediates were condensed with thiourea and guanidine derivatives to
form the corresponding tricyclic PFBZDs. But reaction of aminoguanidine, thiosemicarbazide, 4-
phenylthiosemicarbazide and ethane-1,2-diamine with β-enaminoamides didn’t produce any
desired product and led to recovery of the corresponding starting BZD.
Keywords: Pyrimidine-fused heterocycle, Pyrimidine-fused benzodiazepine, β-
enaminoamide, 2-Aminopyrimidine, Pyrimidine-2-thiol, Guanidine.
1. Introduction
The development of ‘privileged heterocyclic scaffolds’ is a rapidly emerging topic in
medicinal chemistry.1 Fused pyrimidine derivatives are an important class of potential bioactive
N-heterocyclic scaffolds in modern medicinal chemistry due to their affinity for various
biotargets. They display a broad spectrum of pharmaceutical applications such as anti-
inflammatory, antioxidant, anticancer, antimicrobial, and antiviral and constitute the backbones
of several marketed drugs.2-6
Benzodiazepines and their polycyclic derivatives are one of the most explored compound
classes as privileged scaffolds in drug discovery. They are used in pharmaceuticals as cytotoxic
agents against cancer cell lines7-10 and anti-HIV-1 agents.11 It is well documented that the
pharmacological activity increases when an additional heterocyclic ring is fused to the
heptatomic diazepine nucleus.12 Because of the biological importance of the polyheterocyclic
systems including the 1,5-benzodiazepine moiety13-15 considerable attention has been directed
towards the synthesis of polycyclic 1,5-benzodiazepines, in particular pyrimidine-fused
benzodiazepines, as well as the 1,4-isomers.16 Figure 1 shows some examples of pyrimidine-
fused benzodiazepines, which have shown interesting pharmacological properties, such as
antihypoxic and antipyretic (A); analgesic (B); gastric secretion inhibition (C); and
1

ACCEPTED MANUSCRIPT
immunosuppressive activity (D). Compound D showed two-fold higher activity than
cyclosporine A when it was tested in mice.17
NHR
N
H
N
H
N
N
N
N
Cl
NH
N
H
O
O
A
B
HO
N
N
N
OH
H
Ph
N
O
N
N
N
O
N
N
O
H
N
D
C
Figure 1. Examples of some bioactive pyrimidine-fused benzodiazepines.
A drug-like molecule could be considered as a congregation of small pieces of chemicals
which are linked together and the biological effect of such a complex molecule is due to the
contribution of these small fragments which are now working together as a unit. Considering the
biological activity of fused-pyrimidine and polycyclic benzodiazepine derivatives, substantial
attention has been paid to develop efficient new methodologies to synthesise and screen them
against various cancer cell lines.
Heretofore, several fused tricyclic and polycyclic pyrimido 1,5-benzodiazepine derivatives
have been reported in the literature, for which in many cases the starting material is a pyrimidine
derivative and then the benzodiazepine is created in moderate to good yields in the presence of a
catalyst. Among them, Panahi18-20 et al. synthesized the pyrimidine-fused heterocycles (PFHs)
via one-pot synthesis using three components of barbituric acid and amine with aldehyde or
glucose in the presence of an acidic catalyst. Długosz21 synthesized pyrimido[4,5-
b][1,5]benzodiazepine
derivatives
starting
with
6-methyl-2-oxo-4-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid and then in four steps the benzodiazepine ring was
created with diethyl aniline as catalyst. Bai22-24 and co-workers synthesized novel tricyclic and
tetracyclic pyrimidine-fused benzodiazepines from the reaction of 4,6-dichloro-5-nitropyrimidine
and/or 6-chloropyrimidine-4,5-diamine as a starting material with an aromatic amine and
aldehyde under transition-metal catalysis and or acid-catalyzed conditions. The group of Roma25
synthesized a number of 5H-pyrimido[4,5-b]-[1,5]benzodiazepin-5-ones from the reaction of 4-
(dimethylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-one with N,N-dimethylformamide (DMF)
in the presence of phosphorus pentachloride (PCl5) at room temperature and subsequently react
with amidines to form pyrimidines.
β-Enaminones are established as a versatile synthetic intermediate in the synthesis of
polyfunctionally substituted heterocycles.26,27 There are several reports of synthesis of
pyrimidine-fused heterocyclic compounds using an enaminone-based approach.28-30,31-33 In
solution, β-enaminones have been reported to condense with thiourea, amidines, and guanidines
2

ACCEPTED MANUSCRIPT
to give 2-mercapto-, 2-alkyl/aryl-, and 2-aminoalkyl/arylpyrimidines, respectively, in moderate
to good yields.34 Using a similar strategy, Farghaly35 et al. developed the synthesis of analogous
tetracyclic and pentacyclic PFHs with heterocyclic amines.
We were inspired by the biologically active PFHs, 2-amino pyrimidine,6,36-38 and pyrimidine-
2-thiol moiety.39,40 A new approach is proposed for the synthesis of a library of various new
tricyclic pyrimidine-fused derivatives with the 1,5-BZD core via an enaminone-based approach,
including 2-aminopyrimidine, pyrimidine-2-yl-cyanamide, N-nitro pyrimidine-2-amine, and
pyrimidine-2-thiol derivatives (3a-q) as precursors of bioactive compounds (Table 2). Unlike the
previous reports, in this method pyrimidine was not used as the starting material and instead
pyrimidine rings were formed on the BZD scaffold. Also the substituted pyrimidine-fused 1,5-
benzodiazepines (PFBZD) were obtained from cheaper and easier to access starting materials by
this simple enaminone-based strategy in good to excellent yields under mild conditions and
without catalyst.
2. Results and Discussion
In this project, a simple route for the synthesis of a series of novel tricyclic PFBZD
derivatives was reported. In the first step, the 1H-1,5-benzodiazepine-2,4(3H,5H)-dione (BZD)
derivatives (1a-e) were obtained by the reaction of benzene-1,2-diamines and 1,3-propanedioic
acid in the presence of two equivalents of HCl at 80 °C in good yields within 3 hours (Table 1).
In the following step, for the synthesis of key intermediates (2a-e), the BZDs 1a-e reacted
with N,N-dimethylformamide-dimethylacetal (DMF-DMA) in dry p-xylene and/or toluene or
under solvent-free condition at reflux for a short time and afforded the corresponding isolable
solid product benzodiazepinic β-enaminoamides (2a-e) in good yields (Table 1). The
intermediate 3-((dimethylamino)methylene)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (2a)
was synthesized from the reaction of 1a with DMF-DMA under reflux in a sealed tube (Scheme
1). The formamide acetal (DMF-DMA) enters into alkylation mostly via methoxide elimination
and generation of a methoxyiminium ion.41-43 Elemental analysis and spectral data were in
1
complete accordance with the assigned structure 2. For example, the H NMR spectrum of
compound 2a revealed two new singlet signals at δ 2.91 and 7.48 ppm characteristic for the N,N-
dimethylamino group and the exocyclic C=CH protons, respectively. A plausible mechanism for
the formation of the β-enaminoamides (2a-e) is proposed in Scheme 1. The β-enaminoamide
derivatives 2a-e were then used as intermediates for the synthesis of the tricyclic PFBZD
derivatives.
3

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Me
Me
OMe
N
N
OMe
O
OH
O
H
N
Me
Me
OMe
H
N
R1
R2
R1
R2
OMe
H
- MeOH
N
H
N
H
O
O
1f
1a-e
O
H
N
H
N
R1
R1
R2
OMe
OMe
NMe2
- MeOH
R2
NMe2
N
H
N
H
O
O
1g
1h
- MeOH
O
H
N
R1
R2
H
NMe2
N
H
O
2a-e
Scheme 1. A plausible mechanism for the formation of the benzodiazepinic β-enaminoamides.
Table 1. Synthesis of the BZDs 1a-e and the benzodiazepinic β-enaminoamides 2a-e.
Entry R1 R2 Product Yield (%)
1
2
3
4
5
6
7
8
9
H
Me
Me Me
Cl
Br
H
Me
Me Me
H
H
64
70
63
72
62
63
65
62
68
55
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
H
H
H
H
Cl
Br
H
H
10
The intermediates (2a-e) were condensed with thiourea and guanidine derivatives to form the
corresponding tricyclic PFBZD derivatives including 2-aminopyrimidine, pyrimidine-2-yl-
cyanamide, N-nitro pyrimidine-2-amine, and pyrimidine-2-thiol fused 1,5-benzodiazepine
derivatives (3a-q). The cyclization reaction of β-enaminoamide 2a with guanidine nitrate was
investigated under reflux in basic conditions which proceeded smoothly to give the desired
product 3a in high yield (Table 2). The scope of this cyclization was then explored with other
guanidine derivatives and thiourea which produced the desired 6,11-dihydro-5H-
benzo[b]pyrimido[4,5-e][1,4]diazepin-5-ones (3b-q) in good to excellent yields (Table 2). All
compounds were synthesized by a similar method. The structural confirmation of the initially
synthesized starting heterocycles (1a-e), benzodiazepinic β-enaminoamide intermediates (2a-e),
1
13
and the final products (3a-q) were corroborated using FT-IR, H NMR, C NMR spectroscopy,
and CHN (see Supplementary data). The synthetic route established here provides a basis to
obtain functionalized tricyclic PFBZD derivatives, as illustrated in Scheme 2. By investigation of
the products of the synthetic route we observed that:
4

ACCEPTED MANUSCRIPT
I) Six PFBZD products with non-substituted and symmetrically substituted benzene ring (3a,
3c, 3f, 3h, 3n, 3p) were obtained as a single isomeric product. The isolated yields of pure
products from reaction of the symmetric substituted β-enaminoamides 2a and 2c with guanidine
derivatives and thiourea were 70-94%, as depicted in Table 2 and Table 3.
II) Eight PFBZD products containing non-symmetrically substituted benzene rings (3b, 3d,
3e, 3g, 3i, 3j, 3o, 3q) were obtained as a mixture of two isomers from the reaction of the non-
symmetrically substituted β-enaminoamides 2b, 2d, and 2e with guanidine derivatives and
thiourea in good to excellent yield (72-94%). According to the structure of the β-enaminoamides
2b, 2d, and 2e, condensation and cyclization with the reagents can occur with each of two
carbonyl groups. Therefore, the two structures for each of the products containing non-
symmetrically substituted benzene rings are likely, as depicted in Table 2, Table 3 and Scheme 2.
1
The work-up of the reactions gave a solid crude product. H NMR spectra for each of the
13
products did not show separate chemical shifts for the various protons of the isomers, while C
NMR spectra easily showed the existence of two isomers due to the appearance of two sets of
signals especially in aromatic area (see Supplementary data). Since the two isomers of crude
1
product have similar H NMR spectra, calculation of the percent of each isomer in the mixture
by 1H NMR was not possible. These crude products decomposed within the range 270 to 350˚C.
Thin-layer chromatography (TLC) of the each crude product on silica gel revealed a single spot
in various solvent systems. All attempts to separate these isomers in the crude products by
preparative TLC and column chromatography failed.
Table 2. The synthesis of functionalized tricyclic pyrimidine-fused 1,5-benzodiazepine (PFBZD) derivatives
under optimized conditionsa
NHR
N
O
H
N
O
O
H
N
R1
R2
R1
R2
N
N
H
NaOEt / EtOH
NH
N
H
N
H
RHN
NH2
2a-e
R = H, CN, NO2
3a-m
13 examples
Yields 70-94%
I)
The products from the symmetrically substituted β-
enaminoamidesb
5

ACCEPTED MANUSCRIPT
NH2
N
NH2
N
N
N
H
N
H
N
H3C
H3C
N
H
N
H
O
O
3a: 88%
3c: 94%
3h: 72%
3m: 75%
HN CN
N
HN CN
N
N
N
H
N
H
N
H3C
H3C
N
H
N
H
O
O
3f: 70%
HN NO2
N
HN NO2
N
N
N
H
N
H
N
H3C
H3C
N
H
N
H
O
O
3k: 85%
II)
The products from the non-symmetrically substituted β-
enaminoamidesc
6

ACCEPTED MANUSCRIPT
NH2
N
H
N
O
N
H
N
N
H3C
N
H
N
H3C
N
H
3b: 94%
3d: 92%
3e: 93%
O
NH2
NH2
H
N
O
N
H
N
N
N
Cl
N
H
N
Cl
N
H
O
NH2
NH2
H
N
O
N
H
N
N
N
Br
N
H
N
Br
N
H
O
NH2
HN CN
N
H
N
O
N
H
N
N
H3C
3g: 75%
N
H
N
H3C
N
H
O
HN CN
HN CN
N
H
N
O
N
H
N
N
Cl
N
H
N
Cl
N
H
3i: 84%
O
HN CN
HN CN
N
H
N
O
N
H
N
N
Br
N
H
N
Br
N
H
3j: 73%
O
HN CN
HN NO2
N
H
O
N
N
H
N
N
H3C
N
H
N
H3C
N
H
O
3l: 81%
HN NO2
a
Reaction conditions: β-enaminoamide (1 mmol), guanidine derivatives (1.1 mmol), sodium ethoxide (1.1 mmol) and absolute
ethanol (10 mL), reflux 3-4 h. b All yields are pure yields. c All yields are crude yields.
7

ACCEPTED MANUSCRIPT
To account for the formation of products 3a-m, it is suggested that the reaction started with
the Michael type addition of the amino group of guanidine derivatives to the activated double
bond in β-enaminoamide derivative (2a-e), followed by elimination of the dimethylamino group
to afford an intermediate adduct (2g). Then an intramolecular cyclization and subsequent
aromatization via loss of water molecule under the reaction conditions would give the desired
products 3a-q, as depicted in Scheme 2.
NHR
O
O
H
N
HN
R1
R2
O
H
N
N
H
NaOEt / EtOH
NH
R1
R2
NH
N
H
H
NMe2
RHN
NH2
N
H
O
2a-e
R = H, CN, NO2
2f
H
R
N
HN
O
O
H
N
R1
R2
NH
N
H
2g
NHR
N
R
H
H
N
N
N
H
HO
N
N
R1
R2
N
R1
R2
- HNMe2
- H2O
N
H
N
H
O
O
2h
3a-m
Scheme 2. A plausible reaction mechanism for the synthesis of tricyclic pyrimidine-fused 1,5-benzodiazepine
(PFBZD) derivatives 3a-m. Note: In the case of non-symmetrically substituted compounds on the benzene ring,
condensation and cyclization with the reagents can occur with each of two carbonyl groups. Therefore, two
structures for each of the products containing non-symmetrically substituted benzene rings are likely, as depicted in
Table 2 and Table 3.
III) In the reaction of thiourea with β-enaminoamides 2a, 2b, and 2d, if the sulfur acts
initially as a nucleophile the products 4n-q would be achieved. While with initial nucleophilic
attack by nitrogen, the products 3n-q could be obtained (Table 3). Although it appears that the
nucleophilicity of the sulfur atom is greater than nitrogen, spectral evidence indicates that the
expected derivatives 4n-q were not obtained and rather the novel pyrimidine-2-thiol derivatives
3n-q were formed, as depicted in Scheme 3.31,32,44-47 The formation of compounds 3n-q would
involve an initial Michael addition of the amino group of thiourea to the activated double bond in
β-enaminoamide derivative (2a-e), followed by the same mechanism as described in Scheme 2 to
give 3n-q. Aromatization as a driving force would lead to the formation of products 3n-q. The
structures of the latter products (3n-q) were deduced from their elemental analysis and spectral
data.
Table 3. The synthesis of tricyclic fused pyrimidine-2-thiol 1,5-benzodiazepine derivatives under optimized
conditionsa
8

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SH
S
N
O
H
N
O
O
H
N
R1
R2
R1
R2
N
H
N
H2N
NH2
NaOEt / EtOH
N
H
N
H
2a-d
3n-q
4 examples
Yields 72-94%
SH
SH
N
N
N
H
H
N
N
H3C
N
H3C
N
H
N
H
O
O
3n: 94% b
3p: 82% b
SH
O
H
N
N
H
N
N
N
SH
H3C
N
H
N
H3C
N
H
O
3o: 77% c
SH
O
H
N
N
H
N
N
N
Cl
N
H
N
Cl
N
H
3q: 72% c
O
SH
a Reaction conditions: β-enaminoamide (1 mmol), thiourea (1.1 mmol), sodium ethoxide (1.1 mmol) and absolute ethanol (10
mL), reflux 3-4 h. b The yield of isolated product. c The yield of crude product.
9

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O
O
H
N
R1
R2
N
H
N
H
2a-d
S
SH
H2N
H2N
NH2
HN
NH2
NaOEt / EtOH
NH
S
H2N
H
N
O
H
N
O
R1
R2
R1
R2
S
NH
N
H
N
H
O
O
2i
2l
S
NH
H2N
H2N
O
O
O
H
N
H
N
R1
R2
R1
R2
S
NH
N
H
N
H
O
2j
2m
H
H
S
N
NH
S
HO
N
HO
N
N
O
N
O
N
O
R1
R2
R1
H
R2
N
H
N
H
2k
2n
-H2O - HNMe2
-H2O - HNMe2
NH
S
SH
N
H
N
H
N
R1
R2
R1
R2
N
N
H
N
H
O
4n-q
3n-q
4 examples
Yields 72-94%
Scheme 3. A plausible mechanism for the synthesis of tricyclic fused pyrimidine-2-thiol 1,5-benzodiazepine
derivatives 3n-q.
IV) In order to produce new fused seven-membered 1,2,4-triazepine and 1,4-diazepine rings
on the BZD scaffold, the reaction of aminoguanidine bicarbonate (6), aminothiourea
(thiosemicarbazide) (7), 3-amino-1-phenylthiourea (4-phenylthiosemicarbazide) (8), and ethane-
1,2-diamine (9) with some β-enaminoamides (2a-e) was performed. Surprisingly, results of
spectroscopic studies showed that these reactions led to the corresponding starting BZD. The
proposed mechanism of these reactions contains a nucleophilic substitution in the first step and
in the following an interamolecular Michael addition is performed instead of ring closure and
formation of the seven-membered ring. As an example of the possible mechanism, the reaction
of β-enaminoamide derivatives with aminoguanidine bicarbonate (6) is shown in the Scheme 4,
that followed by hydrogen shift and aromatization of the triazole gives the corresponding starting
BZD and 2H-1,2,4-triazol-3-amine.
10

ACCEPTED MANUSCRIPT
NH
S
S
H2N
H2N
H2N
H2N
Ph
NH2
N
NH2
N
NH2
N
N
H
H
H
H
9
6
8
7
NH
NH
O
O
H
N
H
N
H2N
N
R1
NH2
R1
R2
H
N
NH
NH
N
H
R1
R2
H
H
N
NH2
NaOEt / EtOH
N
H
R2
NMe2
N
H
N
H
N
H
O
O
NH
O
O
O
2a-e
2o
5a-e
H
H
N
H
N
R1
R2
NH
R1
R2
NH2
NH
N
N
N
+
NH
N
H
N
H
N
H
O
O
1a-e
2q
2p
Scheme 4. A possible mechanism for formation of the corresponding starting BZD from the reaction of β-
enaminoamide derivatives with aminoguanidine bicarbonate.
V) A spectroscopic study of the three compounds 3k-m showed two products as major and
minor species. The major products have the same structure as illustrated in Scheme 2. Four
tautomers are possible. A plausible structure for the tautomeric minor product of 3k-m is
proposed in Scheme 5. In the 1H NMR spectra, the ratio of major/minor tautomer for 3k, 3l, and
3m was found to be 72.7/27.3=2.66, 68.5/31.5=2.17, and 59/41=1.44, respectively. Hydrogen of
pyrimidine ring in the major tautomer should be appeared in low-field, but it appears in high-
field in minor tautomer due to the loss of aromaticity of the pyrimidine ring.
Due to a longer conjugated system connected with the benzene ring, the tautomers (III) and
(IV) are more stable and hence more likely. The tautomer (IV) is cross-conjugate, but the isomer
(III) has a longer linear conjugated system connected to the benzene ring. Therefore, it is
possible that the isomer (III) might be the minor product. Furthermore, while each of the four
tautomers has a structure with intramolecular hydrogen bonding between the nitro group oxygen
and the N-hydrogen, each of them has a resonance form.
11

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O
H
O
O
O
H
HN
HN
HN
HN
N
R1
H
R1
R2
N
R1
R1
N
NH
O
N
N
N
N
N
N
N
N
N
N
H
N
N
NO2
R2
N
H
H
N
H
R2
H
R2
O
H
NO2
O
(IV) (3km-mm
)
O
(I) (3km-mm
)
O
H
HN
R1
R2
N
N
N
NO2
H
N
H
(3kM-mM
)
O
O
O
O
HN
HN
HN
HN
N
R1
R1
NH
R1
H
N
N
R1
O
NO2
N
N
H
NH
N
N
N
N
N
N
N
N
NO2
N
R2
N
H
R2
H
H
H
R2
N
R2
O
O
O
(II) (3km-mm
)
(III) (3km-mm)
Scheme 5. Plausible structures for the minor product tautomers (3k-m).
3. Conclusions
A simple and efficient method for the synthesis of the tricyclic pyrimidine-fused 1,5-
benzodiazepine (PFBZD) derivatives 3a-q with the 1,5-benzodiazepine-2,4-dione (BZD) core
has been developed. An enaminone-based approach has been found to be a useful route for the
construction of some fused heterocyclic systems including tricyclic pyrimidine-fused
heterocycles (PFHs). The scope and generality of this methodology have been successfully
demonstrated by synthesizing a variety of fused pyrimidine derivatives. The prominent
advantages of the described report are the novelty of synthesized compounds, operational
simplicity in terms of step count, mild conditions, absence of catalysts, isolable intermediate, and
good to excellent yields. Furthermore, this method proved to be versatile since the pyrimidine
system can be replaced by other N-heterocycles such as pyrazoles, isoxazoles, pyridazines,
pyridines, and triazole to obtain various ring-fused systems. This strategy provides an efficient
method to access a library of polycyclic PFHs from privileged C-H acidic carbonyl compounds
that are of great interest in drug discovery.
4. Experimental
4.1.General
Chemical Reagents and solvents were purchased from commercial suppliers (Merck, Aldrich,
and Fluka) and were used as received without further purification. 1H-NMR (300 MHz) and 13C-
NMR (75 MHz) spectra were recorded on a Bruker Advance spectrometer in deuterated
dimethylsulfoxide (DMSO-d6) solutions and chemical shifts (δ) are reported in ppm relative to
tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are reported in Hertz
(Hz). A Perkin-Elmer 843 spectrophotometer Fourier-transform infrared (FT-IR) spectrometer
was employed for characterization of the products in KBr disc form and is reported in
wavenumbers (cm-1). The melting points were determined in open capillary tubes using an
12

ACCEPTED MANUSCRIPT
Electrothermal 9100 apparatus and are uncorrected. Reaction monitoring was accomplished by
thin-layer chromatography (TLC) using aluminium sheets with silica gel 60 F254 (Merck) and the
spots were visualized with UV light. Elemental analysis was determined with a Perkin-Elmer
CHN analyzer (2400 series II).
4.2.General procedure for the synthesis of the BZDs (1a-e)
The starting material, 1H-1,5-benzodiazepine-2,4(3H,5H)-dione (BZD) (1a) was synthesized
on the basis of earlier published methods by condensing 1,3-propanedioic acid with benzene 1,2-
diamine in hydrochloric acid, with minor modifications as mentioned below.48-53 One equivalent
(eq) 1,3-propanedioic acid (2.08 g, 20 mmol) was first stirred with 2 eq HCl (4 N) and then
treated with 1 eq benzene-1,2-diamine (2.17 g, 20 mmol). The reaction was heated to 80 °C for 3
h. The progress of the reaction was monitored by TLC. After the completion of the reaction and
cooling of the mixture, the obtained suspension was filtered and washed with cold ethanol and
water. The other BZD derivatives (1b-e) were prepared by the same method in good yields (62-
72%).
1H-1,5-Benzodiazepine-2,4(3H,5H)-dione (1a). White solid (Yield: 2.25 g, 64%); m.p. 350
°C (d) [lit54,48 m.p. >350 °C (d)]. IR (KBr, cm-1): 3193, 3054, 2955, 2891, 1704, 1670, 1597,
1503, 1428, 1400, 1350, 822. 1H NMR (300 MHz, DMSO-d6): δ 3.16 (2H, s, CH2), 7.09-7.16
(4H, m, Ar), 10.39 (2H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 45.1, 122.2, 124.9, 129.7,
165.8. Anal. Calcd for C9H8N2O2 (176.17): C, 61.36; H, 4.58; N, 15.90. Found: C, 61.38; H,
4.38; N, 16.10.
7-Methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1b). Pale brown solid (Yield: 2.66 g,
70%); m.p. 337-339 °C (d) [lit48 m.p. >350 °C (d)]. IR (KBr, cm-1): 3188, 3082, 2950, 2869,
1
1696, 1670, 1596, 1499, 1427, 1344, 812. H NMR (300 MHz, DMSO-d6): δ 2.25 (3H, s, CH3),
3.13 (2H, s, CH2), 6.90 (1H, s, Ar), 6.97 (1H, d, J = 8.3 Hz, Ar), 6.98 (1H, d, J = 8.3 Hz, Ar),
10.27 (1H, s, NH), 10.31 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 20.3, 45.0, 122.1,
122.2, 125.6, 127.3, 129.4, 134.2, 165.6, 165.7. Anal. Calcd for C10H10N2O2 (190.20): C, 63.15;
H, 5.30; N, 14.73. Found: C, 63.00; H, 5.31; N, 14.62.
7,8-Dimethyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1c). Yellow solid (Yield: 2.60 g,
63%); m.p. >350 °C (d) [lit48 m.p. >350 °C (d)]. IR (KBr, cm-1): 3193, 3076, 2971, 2858, 1695,
1655, 1595, 1514, 1430, 1348, 821. 1H NMR (300 MHz, DMSO-d6): δ 2.15 (6H, s, 2 CH3), 3.10
(2H, s, CH2), 6.86 (2H, s, Ar), 10.21 (2H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 18.7, 45.0,
122.7, 127.3, 133.0, 165.6. Anal. Calcd for C11H12N2O2 (204.23): C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.88; H, 5.93; N, 13.51.
7-Chloro-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1d). Dark brown solid (Yield: 3.05 g,
72%); m.p. 336-339 °C (d) [lit48 m.p. >250 °C (d)]. IR (KBr, cm-1): 3194, 3056, 2948, 2854,
13

ACCEPTED MANUSCRIPT
1
1708, 1668, 1600, 1593, 1494, 1422, 1396, 814. H NMR (300 MHz, DMSO-d6): δ 3.20 (2H, s,
CH2), 7.12 (1H, d, J = 8.6 Hz, Ar), 7.14 (1H, d, J = 2.1 Hz, Ar), 7.22 (1H, dd, J = 8.6, 2.1 Hz,
Ar), 10.47 (2H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 45.1, 121.5, 123.9, 124.7, 128.4,
128.7, 130.9, 165.6, 165.8. Anal. Calcd for C9H7ClN2O2 (210.62): C, 51.32; H, 3.35; N, 13.30.
Found: C, 51.23; H, 3.17; N, 13.20.
7-Bromo-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1e). Brown solid (Yield: 3.16 g, 62%);
m.p. 336-338 °C (d). IR (KBr, cm-1): 3192, 3053, 2947, 2851, 1706, 1669, 1594, 1490, 1424,
1
1395, 813. H NMR (300 MHz, DMSO-d6): δ 3.20 (2H, s, CH2), 7.06 (1H, d, J = 8.5 Hz, Ar),
7.28 (1H, d, J = 2.0 Hz, Ar), 7.33 (1H, dd, J = 8.5, 2.0 Hz, Ar), 10.45 (2H, s, NH). 13C NMR (75
MHz, DMSO-d6): δ 45.1, 116.2, 124.0, 124.3, 127.4, 129.1, 131.1, 165.5, 165.6. Anal. Calcd for
C9H7BrN2O2 (255.07): C, 42.38; H, 2.77; N, 10.98. Found: C, 42.39; H, 2.71; N, 10.97.
4.3. General procedure for the synthesis of β-enaminonamide intermediates (2a-e)
1H-1,5-Benzodiazepine-2,4(3H,5H)-dione (BZDs) derivatives (1a-e) (2 mmol) and an excess
of N,N-dimethylformamide dimethylacetal (DMF-DMA, 2.5 mL) were heated under reflux (110
°C) either solvent free (for 2a, 2b,2c) or in 5-8 mL toluene or p-xylene as a medium (for 2d, 2e)
with less DMF-DMA (1 mL) for 4-6 h. Progress and completion of the reaction was monitored
by TLC then the reaction was left to cool to room temperature. The crude product that formed
upon cooling was filtered and washed with cold diethyl ether to give the corresponding β-
enaminoamide derivatives (2a-e). The benzodiazepinic β-enaminoamides were obtained in good
isolated yields (55-68%).
3-((Dimethylamino)methylene)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (2a). White
powder (Yield: 0.30 g, 63%); m.p. 219-222 (d) °C. IR (KBr, cm-1): 3159, 3031, 2900, 1653,
1
1616, 1576, 1503, 1381, 1127, 1094, 970, 783, 736, 661, 625, 534, 452. H NMR (300 MHz,
DMSO-d6): δ 2.92 (6H, broad, s, 2 CH3), 6.98 (4H, s, Ar), 7.48 (1H, s, =CH), 9.23 (1H, s, NH),
13
9.45 (1H, s, NH). C NMR (75 MHz, DMSO-d6): δ 47.2 (2 CH3), 95.5 (C=CH), 120.9, 121.9,
123.7, 123.9, 130.2, 131.5 (Ar), 155.9 (C=CH), 166.5 (CONH), 171.4 (CONH). Anal. Calcd for
C12H12BrN3O2 (231.25): C, 62.33; H, 5.67; N, 18.17. Found: C, 62.32; H, 5.48; N, 18.24.
3-((Dimethylamino)methylene)-7-methyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione
(2b). Brown powder (Yield: 0.32 g, 65%); m.p. 236-239 (d) °C. IR (KBr, cm-1): 3184, 3028,
1
2924, 1653, 1611, 1577, 1521, 1384, 1128, 1100, 966, 808, 770, 677, 627, 553, 435. H NMR
(300 MHz, DMSO-d6): δ 2.18 (3H, s, CH3), 2.90 (6H, s, broad, 2 CH3), 6.77-6.80 (2H, m, Ar),
13
6.86 (1H, d, J = 8.4 Hz, Ar), 7.45 (1H, s, =CH), 9.13 (1H, s, NH), 9.36 (1H, s, NH). C NMR
(75 MHz, DMSO-d6): δ 20.3 (CH3), 46.1 (2 CH3), 95.7 (C=CH), 121.0, 124.5, 127.7, 129.0,
131.3, 133.0 (Ar), 155.6 (C=CH), 166.5 (CONH), 171.3 (CONH). Anal. Calcd for C13H15N3O2
(245.28): C, 63.66; H, 6.16; N, 17.13. Found: C, 63.83; H, 6.32; N, 17.12.
14

ACCEPTED MANUSCRIPT
3-((Dimethylamino)methylene)-7,8-dimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-
dione (2c). Cream powder (Yield: 0.32 g, 62%); m.p. 286-288 (d) °C. IR (KBr, cm-1): 3139,
1
3027, 2932, 1668, 1612, 1597, 1512, 1388, 1348, 1116, 875, 790, 678, 643, 534, 456. H NMR
(300 MHz, DMSO-d6): δ 2.09 (6H, s, 2 CH3), 2.89 (6H, broad, s, 2 N-CH3), 6.73 (2H, s, Ar),
7.42 (1H, s, =CH), 9.06 (1H, s, NH), 9.30 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 18.7 (2
CH3), 54.4 (2 NCH3), 95.9 (C=CH), 121.7, 121.8, 127.7, 129.0, 131.4, 131.7 (Ar), 155.3
(C=CH), 166.6 (CONH), 171.4 (CONH). Anal. Calcd for C14H17N3O2 (259.3): C, 64.85; H, 6.61;
N, 16.20. Found: C, 64.61; H, 6.67; N, 15.94.
7-Chloro-3-((dimethylamino)methylene)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione
(2d). Creamy-yellow powder (Yield: 0.36 g, 68%); m.p. 226-229 (d) °C. IR (KBr, cm-1): 3170,
3023, 2940, 1658, 1619, 1576, 1501, 1430, 1378, 1125, 1096, 774, 673, 626, 500. 1H NMR (300
MHz, DMSO-d6): δ 2.79 (3H, broad, s, CH3), 3.08 (3H, s, CH3), 6.97-7.06 (3H, m, Ar), 7.54
(1H, s, =CH), 9.35 (1H, s, NH), 9.48 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 54.4 (2
CH3), 94.9 (C=CH), 120.2, 122.4, 123.4, 127.2 (Ar), 156.6 (C=CH), 166.1 (CONH). Anal. Calcd
for C12H12ClN3O2 (265.7): C, 54.25; H, 4.55; N, 15.82. Found: C, 54.13; H, 4.54; N, 15.64.
7-Bromo-3-((dimethylamino)methylene)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione
(2e). Purple powder (Yield: 0.34 g, 55%); m.p. 246-248 (d) °C. IR (KBr, cm-1): 3177, 3044,
1
2936, 1660, 1619, 1578, 1496, 1384, 1340, 1124, 810, 769, 736, 669, 624, 482. H NMR (300
MHz, DMSO-d6): δ 2.77 (3H, s, CH3), 3.06 (3H, s, CH3), 6.93 (1H, d, J = 8.9 Hz, Ar), 7.14-7.17
(2H, m, Ar), 7.54 (1H, s, =CH), 9.35 (1H, s, NH), 9.47 (1H, s, NH). 13C NMR (75 MHz, DMSO-
d6): δ 53.3 (2 CH3), 94.8 (C=CH), 115.1, 122.6, 123.0, 126.3, 139.1, 139.4 (Ar), 156.6 (C=CH),
166.6 (CONH). Anal. Calcd for C12H12BrN3O2 (310.15): C, 46.47; H, 3.90; N, 13.55. Found: C,
46.50; H, 3.82; N, 13.39.
4.4. General procedure for the synthesis of compound 3a-q
The compound 2a-e (1 mmol) was added to a mixture of guanidine nitrate, aminoguanidine
bicarbonate, cyanoguanidine, nitroguanidine, or thiourea (1.1 mmol) in a solution of sodium
ethoxide (1.1 mmol) and absolute ethanol (10 mL), and then mixture was stirred under reflux for
3-4 h. After completion of the reaction, the solvent was removed by distillation and the residue
was treated with glacial acetic acid (2 mL), just enough to dissolve the pyrimidine sodium salt
and then heated at reflux for 15 min. The resulting solid products were collected by filtration,
washed with ethanol and cold diethyl ether and dried to give the corresponding derivatives (3a-
q). The tricyclic pyrimidine-fused 1,5-benzodiazepine (PFBZD) derivatives were obtained in
good to excellent yields. Among these products, six PFBZD compounds with non-substituted
and symmetrically substituted benzene rings (3a, 3c, 3f, 3h, 3n, 3p) were synthesized as a single
isomer in 70-94% pure yield, and eight PFBZD products containing non-symmetrically
substituted benzene rings (3b, 3d, 3e, 3g, 3i, 3j, 3o, 3q) were obtained as a mixture of two
isomers in 72-94% yield.
15

ACCEPTED MANUSCRIPT
2-Amino-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one
(3a).
Green
powder (Yield: 0.20 g, 88%); m.p. 325-327 (d) °C. IR (KBr, cm-1): 3461, 3322, 3197, 3121,
1
3052, 1677, 1625, 1601, 1541, 1472, 1441, 1420, 1333, 1269, 796, 744, 597. H NMR (300
MHz, DMSO-d6): δ 6.86-6.95 (4H, m, Ar), 6.91-6.98 (2H, m, NH2), 8.45 (1H, s, =CH), 8.90
(1H, s, NH), 9.48 (1H, s, NHCO). 13C NMR (75 MHz, DMSO-d6): δ 101.6 (C=CH), 121.0,
121.4, 124.7, 124.9, 128.4, 132.3 (Ar), 163.3 (C=CH), 164.0 (C=N), 164.3 (C-NH2), 166.0
(CONH). Anal. Calcd for C11H9N5O (227.22): C, 58.14; H, 3.99; N, 30.82. Found: C, 57.91; H,
4.03; N, 30.53.
2-Amino-8-methyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one
(3b).
Yellow powder (Crude yield: 0.23 g, 94%); m.p. 313-315 (d) °C. IR (KBr, cm-1): 3487, 3386,
1
3354, 3210, 1639, 1599, 1542, 1427, 1418, 1377, 1334, 1270, 800, 611. H NMR (300 MHz,
DMSO-d6): δ 2.13 (3H, s, CH3), 6.77-6.95 (2H, broad s, NH2), 6.80 (1H, d, J = 8.0 Hz, Ar), 6.86
(1H, s, Ar), 6.94 (1H, d, J = 8.0 Hz, Ar), 8.43 (1H, s, =CH), 8.79 (1H, s, NH,, 9.39 (1H, s,
NHCO). 13C NMR (75 MHz, DMSO-d6): δ 20.2 (CH3), 101.0 (C=CH), 124.4, 125.8, 128.0,
129.4, 131.8, 132.9 (Ar), 162.6 (C=CH), 163.5 (C=N), 164.1 (C-NH2), 165.4 (CONH). Anal.
Calcd for C12H11N5O (241.25): C, 59.74; H, 4.60; N, 29.03. Found: C, 59.51; H, 4.35; N, 28.80.
2-Amino-8,9-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one (3c).
Yellow powder (Yield: 0.24 g, 94%); m.p. 268-271 (d) °C. IR (KBr, cm-1): 3392, 3322, 3193,
1629, 1594, 1546, 1467, 1409, 795. 1H NMR (300 MHz, DMSO-d6): δ 2.04 (6H, s, 2 CH3), 6.68
(1H, s, Ar), 6.82 (1H, s, Ar), 6.83 (2H, broad s, NH2), 8.43 (1H, s, =CH), 8.71 (1H, s, NH), 9.31
(1H, s, NHCO). 13C NMR (75 MHz, DMSO-d6): δ 18.5, 18.6 (2 CH3), 100.9 (C=CH), 121.4,
121.6, 125.7, 129.3, 131.4, 131.5 (Ar), 162.6 (C=CH), 163.5 (C=N), 164.1 (C-NH2), 165.3
(CONH). Anal. Calcd for C13H13N5O (255.28): C, 61.17; H, 5.13; N, 27.43. Found: C, 60.82; H,
4.86; N, 27.13.
2-Amino-8-chloro-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one
(3d).
Cream powder (Crude yield: 0.24 g, 92%); m.p. 350-352 (d) °C. IR (KBr, cm-1): 3491, 3384,
1
3328, 3208, 1636, 1599, 1546, 1476, 1419, 1370, 1328, 1264, 795, 598. H NMR (300 MHz,
DMSO-d6): δ 6.94-7.16 (2H, br, NH2, overlap with aromatic protons), 6.97 (1H, dd, J = 10.2, 2.5
Hz, Ar), 7.08 (1H, d, J = 8.5 Hz, Ar), 7.16 (1H, s, Ar), 8.46 (1H, s, =CH), 9.03 (1H, s, NH), 9.57
(1H, s, NHCO). 13C NMR (75 MHz, DMSO-d6): δ 100.8 (C=CH), 119.8, 122.0, 123.3, 127.3,
129.6, 130.9 (Ar), 162.0 (C=CH), 163.7 (C=N), 164.2 (C-NH2), 164.9 (CONH). Anal. Calcd for
C11H8ClN5O (261.67): C, 50.49; H, 3.08; N, 26.76. Found: C, 50.24; H, 2.82; N, 26.57.
2-Amino-8-bromo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one
(3e).
Brown powder (Crude yield: 0.29 g, 93%); m.p. 331-335 (d) °C. IR (KBr, cm-1): 3399, 3340,
1
3214, 1638, 1597, 1545, 1476, 1419, 1368, 1328, 1259, 797, 601. H NMR (300 MHz, DMSO-
d6): δ 6.87 (1H, d, J = 8.4 Hz, Ar), 7.00-7.12 (2H, br, NH2), 7.12 (1H, s, Ar), 7.29 (1H, s, Ar),
8.46 (1H, s, =CH), 9.02 (1H, s, NH), 9.57 (1H, s, NHCO). 13C NMR (75 MHz, DMSO-d6): δ
100.81 (C=CH), 115.2, 122.3, 122.5, 126.2, 129.8, 133.5 (Ar), 162.0 (C=CH), 163.6 (C=N),
16

ACCEPTED MANUSCRIPT
164.1 (C-NH2), 164.9 (CONH). Anal. Calcd for C11H8BrN5O (306.12): C, 43.16; H, 2.63; N,
22.88. Found: C, 42.97; H, 2.46; N, 22.65.
N-(5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-yl)cyanamide
(3f).
Yellow powder (Yield: 0.19 g, 70%); m.p. >350 °C. IR (KBr, cm-1): 3271, 3207, 3122, 3059,
1
2157, 1676, 1602, 1549, 1465, 1404, 1306, 1269, 792, 737, 602. H NMR (300 MHz, DMSO-
d6): δ 6.82-7.13 (4H, m, Ar), 8.35 (1H, s, =CH), 8.64 (1H, s, NH), 9.26 (1H, s, NHCO), 10.39
(1H, s, NHCN). 13C NMR (75 MHz, DMSO-d6): δ 99.5 (C=CH), 120.3 (C≡N), 120.5, 122.0,
123.6, 125.0, 128.4, 132.7 (Ar), 162.5 (C=CH), 162.7 (C=N), 165.8 (C-NHCN), 171.3 (CONH).
Anal. Calcd for C12H8N6O (252.23): C, 57.14; H, 3.20; N, 33.32. Found: C, 56.92; H, 2.97; N,
32.94.
N-(8-methyl-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)cyanamide (3g). Yellow powder (Crude yield: 0.20 g, 75%); m.p. 335-337 (d) °C. IR (KBr,
1
cm-1): 3287, 3221, 3122, 2154, 1657, 1610, 1554, 1456, 1378, 1301, 1272, 789, 615. H NMR
(300 MHz, DMSO-d6): δ 2.12 (3H, s, CH3), 6.63-6.93 (3H, m, Ar), 8.35 (1H, s, =CH), 8.57 (1H,
s, NH), 9.19 (1H, s, NHCO), 10.38 (1H, s, NHCN). 13C NMR (75 MHz, DMSO-d6): δ 20.2
(CH3) 99.5 (C=CH), 120.2 (C≡N), 120.5, 122.0, 123.7, 124.2, 132.1, 132.6 (Ar), 162.5 (C=CH),
162.7 (C=N), 165.8 (C-NHCN), 170.6 (CONH). Anal. Calcd for C13H10N6O (266.26): C, 58.64;
H, 3.79; N, 31.56. Found: C, 58.32; H, 4.07; N, 31.74.
N-(8,9-dimethyl-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)cyanamide (3h). White powder (Yield: 0.20 g, 72%); m.p. 344-346 (d) °C. IR (KBr, cm-1):
1
3281, 3211, 3125, 2155, 1654, 1608, 1542, 1457, 1340, 1358, 1299, 1279, 789, 631. H NMR
(300 MHz, DMSO-d6): δ 2.04 (6H, s, 2CH3), 6.66 (1H, s, Ar), 6.79(1H, s, Ar), 8.33 (1H, s,
=CH), 8.46 (1H, s, NH), 9.11 (1H, s, NHCO), NHCN signal was not observed. 13C NMR (75
MHz, DMSO-d6): δ 18.5, 18.6 (CH3), 99.5 (C=CH), 121.2 (C≡N), 121.4, 122.0, 125.8, 130.0,
130.6, 131.2 (Ar), 162.6 (C=CH), 165.7 (C=N), 165.8 (C-NHCN), 170.6 (CONH). Anal. Calcd
for C14H12N6O (280.28): C, 59.99; H, 4.32; N, 29.98. Found: C, 60.17; H, 4.13; N, 29.63.
N-(8-chloro-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)cyanamide (3i). Milky powder (Crude yield: 0.24 g, 84%); m.p. 349-353 (d) °C. IR (KBr, cm-
1): 3635, 3304, 3200, 2151, 1682, 1596, 1544, 1457, 1410, 1372, 1261, 1102, 792, 629. 1H NMR
(300 MHz, DMSO-d6): δ 6.85-7.12 (3H, m, Ar), 8.37 (1H, s, =CH), 8.84 (1H, s, NH), 9.39 (1H,
s, NHCO), NHCN signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ 99.3 (C=CH),
119.6 (C≡N), 121.8, 123.1, 127.1, 129.7, 131.5, 134.0 (Ar), 161.9 (C=CH), 162.8 (C=N), 165.2
(C-NHCN), 170.7 (CONH). Anal. Calcd for C12H7ClN6O (286.68): C, 50.28; H, 2.46; N, 29.32.
Found: C, 49.92; H, 2.37; N, 29.12.
N-(8-bromo-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)cyanamide (3j). Brown powder (Crude yield: 0.25 g, 73%); m.p. 336-340 (d) °C. IR (KBr,
1
cm-1): 3284, 3208, 3100, 2151, 1658, 1594, 1546, 1454, 1406, 1368, 1260, 792. H NMR (300
MHz, DMSO-d6): δ 6.82-7.25 (3H, m, Ar), 8.36 (1H, s, =CH), 8.84 (1H, s, NH), 9.35 (1H, s,
17

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NHCO), NHCN signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ 99.0 (C=CH), 114.1
(C≡N), 122.3, 125.9, 127.8, 130.0, 132.0, 134.3 (Ar), 161.8 (C=CH), 162.7 (C=N), 165.3 (C-
NHCN), 170.7 (CONH). Anal. Calcd for C12H7BrN6O (331.13): C, 43.53; H, 2.13; N, 25.38.
Found: C, 43.22; H, 2.46; N, 25.61.
N-(5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-yl)nitramide
(3k).
Yellow powder (Crude yield: 0.23 g, 85%); m.p. 290-292 (d) °C. IR (KBr, cm-1): 3497, 3210,
1
3069, 1663, 1596, 1529, 1473, 1321, 1266, 1054, 980, 779, 596. Major isomer: H NMR (300
MHz, DMSO-d6): δ 6.86-6.94 (3H, m, Ar), 7.05-7.08 (1H, m, Ar), 8.55 (1H, s, =CH), 9.07 (1H,
s, NH), 9.53 (1H, s, NHCO), NHNO2 signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ
101.0 (C=CH), 120.4, 120.8, 123.6, 124.0, 128.1, 132.5 (Ar), 162.4 (C=CH), 163.5 (C=N), 165.3
1
(C-NHNO2), 167.7 (CONH). Minor isomer: H NMR (300 MHz, DMSO-d6): δ 6.86-6.94 (3H,
m, Ar), 7.05-7.08 (1H, m, Ar), 8.45 (1H, s, =CH), 8.89 (1H, s, NH), 9.46 (1H, s, NHCO),
NHNO2. 13C NMR (75 MHz, DMSO-d6): δ 103.1 (C=CH), 120.4, 120.8, 123.6, 124.0, 128.1,
132.5 (Ar), 162.6 (C=CH), 164.1 (C=N), 165.2 (C-NHNO2), 167.7 (CONH). Anal. Calcd for
C11H8N6O3 (272.22): C, 48.53; H, 2.96; N, 30.87. Found: C, 48.82; H, 2.77; N, 30.64.
N-(8-methyl-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)nitramide (3l). Yellow powder (Crude yield: 0.23 g, 81%); m.p. 293-296 (d) °C. IR (KBr,
cm-1): 3492, 3390, 3214, 1666, 1598, 1528, 1471, 1321, 1360, 1051, 981, 796, 609. Major
isomer: 1H NMR (300 MHz, DMSO-d6) δ 2.13 (3H, s, CH3), 6.70 (1H, m, Ar), 6.84 (1H, m, Ar),
6.95 (1H, d, J = 7.9 Hz, Ar), 8.54 (1H, s, =CH), 9.01 (1H, s, NH), 9.47 (1H, s, NHCO), NHNO2
signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ 20.2 (CH3), 103.2 (C=CH), 120.8,
124.1, 124.5, 125.7, 132.6, 133.1 (Ar), 162.4 (C=CH), 163.4 (C=N), 165.2 (C-NHNO2), 167.7
(CONH). Minor isomer: δ 2.13 (3H, s, CH3), 6.70 (1H, m, Ar), 6.84 (1H, m, Ar), 6.95 (1H, d, J =
7.9 Hz, Ar), 8.44 (1H, s, =CH), 8.79 (1H, s, NH), 9.40 (1H, s, NHCO), NHNO2 signal was not
observed. 13C NMR (75 MHz, DMSO-d6): δ 20.2 (CH3), 109.5 (C=CH), 120.4, 120.7, 124.3,
130.1, 132.4, 132.9 (Ar), 162.7 (C=CH), 164.1 (C=N), 165.1 (C-NHNO2), 167.7 (CONH). Anal.
Calcd for C12H10N6O3 (286.25): C, 50.35; H, 3.52; N, 29.36. Found: C, 50.78; H, 3.77; N, 29.04.
N-(8,9-dimethyl-5-oxo-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-2-
yl)nitramide (3m). Yellow-orange powder (Crude yield: 0.23 g, 75%); m.p. 326-327 (d) °C. IR
(KBr, cm-1): 3400, 3322, 3213, 1665, 1636, 1599, 1551, 1374, 1357, 1051, 867, 799, 778, 635.
Major isomer: 1H NMR (300 MHz, DMSO-d6) δ 2.04 (6H, s, 2CH3), 6.68 (1H, s, Ar), 6.82 (1H,
s, Ar), 8.52 (1H, s, =CH), 8.92 (1H, s, NH), 9.38 (1H, s, NHCO), NHNO2 signal was not
observed. 13C NMR (75 MHz, DMSO-d6): δ 18.5 (CH3), 18.6 (CH3), 103.2 (C=CH), 121.3,
121.7, 125.6, 129.9, 131.2, 131.6 (Ar), 162.4 (C=CH), 163.4 (C=N), 165.3 (C-NHNO2), 167.6
(CONH). Minor isomer: 1H NMR (300 MHz, DMSO-d6) δ 2.04 (6H, s, 2CH3), 6.68 (1H, s, Ar),
6.82 (1H, s, Ar), 8.42 (1H, s, =CH), 8.70 (1H, s, NH), 9.32 (1H, s, NHCO), NHNO2 signal was
13
not observed. C NMR (75 MHz, DMSO-d6): δ 18.5 (CH3), 18.6 (CH3), 109.5 (C=CH), 121.4,
121.5, 125.6, 129.3, 131.4, 131.5 (Ar), 162.5 (C=CH), 162.7 (C=N), 165.3 (C-NHNO2), 167.6
18

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(CONH). Anal. Calcd for C13H12N6O3 (300.27): C, 52.00; H, 4.03; N, 27.99. Found: C, 52.17; H,
4.29; N, 28.12.
2-Mercapto-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one (3n). Yellow
powder (Yield: 0.23 g, 94%); m.p. 285-287 (d) °C. IR (KBr, cm-1): 3343, 3202, 3105, 1652,
1614, 1591, 1529, 1380, 1335, 1185, 1095, 979, 782, 748, 604. 1H NMR (300 MHz, DMSO-d6):
δ 6.79-6.91 (3H, m, Ar), 7.01 (1H, dd, J = 7.0, 2.2 Hz, Ar), 7.12 (1H, broad s, SH), 8.17 (1H, s,
=CH), 8.76 (1H, s, NH), 9.30 (1H, s, NHCO). 13C NMR (75 MHz, DMSO-d6): δ 101.3 (C=CH),
120.1, 120.5, 123.0, 123.6, 128.3, 132.9 (Ar), 158.0 (C=CH), 159.2(C=N), 166.0 (C-SH), 183.8
(CONH). Anal. Calcd for C11H8N4OS (244.27): C, 54.09; H, 3.30; N, 22.94. Found: C, 53.82; H,
2.98; N, 22.66.
2-Mercapto-8-methyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one (3o).
Yellow powder (Crude yield: 0.20 g, 77%); m.p. 336-339 (d) °C. IR (KBr, cm-1): 3297, 3192,
1
3087, 1647, 1585, 1527, 1370, 1175, 1090, 786, 614. H NMR (300 MHz, DMSO-d6): δ 2.12
(3H, s, CH3), 6.61-6.89 (3H, m, Ar), 8.16 (1H, s, =CH), 8.56 (1H, s, NH), 9.18 (1H, s, NHCO),
SH signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ 20.2 (CH3), 101.3 (C=CH),
120.5, 124.2, 125.9, 128.1, 131.9, 132.7 (Ar), 158.4 (C=CH), 159.3 (C=N), 166.4 (C-SH), 190.2
(CONH). Anal. Calcd for C12H10N4OS (258.30): C, 55.80; H, 3.90; N, 21.69. Found: C, 55.62;
H, 3.62; N, 21.84.
2-Mercapto-8,9-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one
(3p). Yellow powder (Yield: 0.22 g, 82%); m.p. 350 (d) °C. IR (KBr, cm-1): 3291, 3195, 3102,
1
1642, 1578, 1518, 1370, 1318, 1175, 1126, 871, 780. H NMR (300 MHz, DMSO-d6): δ 2.03
(6H, s, 2CH3), 6.65 (1H, s, Ar), 6.74 (1H, s, Ar), 8.15 (1H, s, =CH), 8.43 (1H, s, NH), 9.09 (1H,
s, NHCO), SH signal was not observed. 13C NMR (75 MHz, DMSO-d6): δ 18.5 (CH3), 18.6
(CH3), 101.3 (C=CH), 121.0, 121.4, 125.8, 130.4, 131.2, 133.9 (Ar), 158.5 (C=CH), 159.4
(C=N), 166.3 (C-SH), 190.2 (CONH). Anal. Calcd for C13H12N4OS (272.33): C, 57.34; H, 4.44;
N, 20.57. Found: C, 57.24; H, 4.36; N, 20.35.
8-Chloro-2-mercapto-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepin-5-one (3q).
Yellow powder (Crude yield: 0.22 g, 72%); m.p. >350 °C. IR (KBr, cm-1): 3283, 3189, 3100,
1
1650, 1604, 1581, 1522, 1366, 1226, 1176, 1090, 988, 785, 604. H NMR (300 MHz, DMSO-
d6): δ 6.83-7.02 (3H, m, Ar), 8.18 (1H, s, =CH), 8.86 (1H, s, NH), 9.38 (1H, s, NHCO), SH
13
signal was not observed. C NMR (75 MHz, DMSO-d6): δ 101.1 (C=CH), 119.6, 121.8, 122.3,
123.1, 126.1, 127.4 (Ar), 158.5 (C=CH), 165.8 (C=N), 165.9 (C-SH), 192.6 (CONH). Anal.
Calcd for C12H10N4OS (278.72): C, 47.40; H, 2.53; N, 20.10. Found: C, 47.84; H, 2.37; N, 19.87.
Supplementary data
Supplementary data related to this article can be found in the online version, at doi: … . These
data include FT-IR, 1H-NMR and 13C-NMR spectra for all the synthesized compounds.
19

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Acknowledgements
We would like to thank the partial financial support of the Deputy of Research and
Technology of Kharazmi University.
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