Dihydroquinazolino[3,2-a][1,5]benzodiazepines: Synthesis and computational study of reductive N-heterocyclization of N-(2-nitrobenzoyl)-1,5-benzodiazepin-2-ones

Article abstract of DOI:10.1002/jhet.2038

A number of 6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepin-13(5H)-ones were prepared utilizing the coupling of readily available 5-acyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-ones with 2-nitrobenzoyl chloride followed by a reductive N-heterocyclizatio

Full text of DOI:10.1002/jhet.2038

Month 2014 Dihydroquinazolino[3,2-a][1,5]benzodiazepines: Synthesis and Computa-
tional Study of Reductive N-Heterocyclization of N-(2-Nitrobenzoyl)-1,5-
benzodiazepin-2-ones
a
a
a
b
b
a
*
Regina Janciene, Gema Mikulskiene, Tomas Javorskis, Ausra Vektariene, Gytis Vektaris, and Lidija Kosychova
aVilnius University Institute of Biochemistry, Mokslininku 12, LT-08662 Vilnius, Lithuania
bVilnius University Institute of Theoretical Physics and Astronomy, A. Gostauto 12, LT-01108 Vilnius, Lithuania
*
E-mail: regina.janciene@bchi.vu.lt
Received February 8, 2013
DOI 10.1002/jhet.2038
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A number of 6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepin-13(5H)-ones were prepared utilizing the
coupling of readily available 5-acyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-ones with 2-nitrobenzoyl chlo-
ride followed by a reductive N-heterocyclization. 3-Methylsubstituted 1-(2-nitrobenzoyl)-1,5-benzodiazepinone
derivatives did not cyclize under the reductive N-heterocyclization conditions. The possible mechanism of this
heterocyclization was discussed, and it was demonstrated that the hydroxylamine intermediate was the initiator
of this reaction. To clarify the reasons of different reactivities of various 1,5-benzodiazepine derivatives, the
quantum-chemical reactivity descriptors of the hydroxylamine intermediates were calculated and evaluated.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
synthesis of such combined heterocyclic rings, where the
quinazoline nucleus is fused at different positions of the
1,5-benzodiazepine skeleton, have been reported [10,11]. It
concerns the reaction of 2-carbethoxymethyl-4H-3,1-
benzoxazin-4-one with primary aromatic amine (1,2-
phenylenediamine) followed by thermal cyclization of the
obtained product [10] or the reaction of 2-chloroquinoline-
3-carboxaldehyde with 1,2-phenylenediamine [11].
To extend our study, we present herein the synthesis of
novel dihydroquinazolino[3,2-a][1,5]benzodiazepine de-
rivatives with possible biological activity [12,13]. The in-
fluence of the substituents of the heptatomic nucleus of
Quinazolinones and their derivatives are of great interest
because of their pharmacological properties. The
quinazolin-4-one moiety fused with a benzodiazepine ring
system is a building block of naturally occurring alkaloids
[1] such as asperlicins [2,3], sclerotigenin [4], and
circumdatins [5,6], which are now known to have a wide
range of useful biological properties. For instance, the
asperlicin family has antagonist activity against cholecys-
tokinin, sclerotigenin has insecticidal properties, and
circumdatins have shown biological activity as inhibitors
of the mammalian mitochondrial chain. These alkaloids
incorporate quinazolino[3,2-a] or [3,2-d][1,4]benzodiaze-
pine systems, and the main synthetic routes to these
quinazolinone compounds are published in a broad range
of scientific journals including those mentioned earlier.
Following our previous studies on the construction of
polycyclic compounds containing different heterocyclic
rings annelated to the basic 1,5-benzodiazepine bicyclic sys-
tem ([1,3]thiazolo[3,2-a][1,5]benzodiazepines [7], [1,2,4]
oxadiazolo[4,3-a][1,5]benzodiazepines [8], [1,4]diazepino
[3,2,1-hi]pyrido[4,3,2-cd]indoles, and [1,4]diazepino[2,3-g]
quinolines [9]), we planned the preparation of some
quinazolino[1,5]benzodiazepines. Several examples of the
N-(2-nitrobenzoyl)-1,5-benzodiazepin-2-ones
on
the
course of the studied reductive N-heterocyclization was
also investigated; the possible mechanism of this cycliza-
tion reaction was suggested and confirmed by means of
quantum-chemical reactivity descriptors calculations.
RESULTS AND DISCUSSION
The cyclofunctionalization strategy of the 1,5-
benzodiazepine system was realized by employing the
overall sequence of acylation of tetrahydro-1,5-
benzodiazepin-2-ones with 2-nitrobenzoyl chloride
© 2014 HeteroCorporation

R. Janciene, G. Mikulskiene, T. Javorskis, A. Vektariene, G. Vektaris, and L. Kosychova
Vol 000
followed by reductive N-heterocyclization of the obtained
N-(2-nitrobenzoyl)amides (Scheme 1).
afforded quinazolino[1,5]benzodiazepines 3a, 3b, 3d, and 3e
with slightly higher yields (Table 1) than the experiments
performed using H2, Re/Ni. Although the use of catalytic hy-
drogenation conditions has become a common practice, in our
study, the N-heterocyclization process was accompanied by
the formation of by-products of unknown structure. Therefore,
the isolation and purification of the main polycyclic products 3
were complicated. Then, we turned our attention towards the
reductive cyclization of nitrobenzoylamides 2c and 2f–j
employing zinc dust in glacial acetic acid [4]. TLC monitoring
indicated that these reactions, in comparison with procedures i
and ii, proceeded without the formation of by-products. Com-
pounds 3g–j were isolated in acceptable 68–57% yields.
The structures of all synthesized compounds were char-
acterized by elemental analysis, IR, and 1H and 13C NMR
spectral data presented in Table 1 and the Experimental
section.
In the IR spectra of amides 2a–j, typical asymmetric and
symmetric absorption bands of nitro group at ~1530 and
~1346 cmꢀ1 and carbonyl group absorption bands in the
region of 1744–1663 cmꢀ1 were observed. The absence
of the nitro group and one of the carbonyl group absorption
bands and the rise of the C═N linkage absorption band at
~1610 cmꢀ1 in the IR spectra confirmed the structure of
quinazolinones 3.
5-Acyl(acetyl, formyl, trifluoroacetyl, ethoxycarbonyl)-
3-R1-4-R2-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-
ones 1a–j were used as starting compounds. Compounds
1a–c were described by us in [14], 1d–f in [15], and 1g
in [16]. Compounds 1h–j were synthesized by acylation
of the corresponding N5-unsubstituted 3-R1-4-R2-
tetrahydro-1,5-benzodiazepinones with trifluoroacetic acid
anhydride (1h) using the procedure described in [17] and
by treatment with ethyl chloroformate (1i and 1j).
As shown in Scheme 1, the benzoylation of 1,5-
benzodiazepinones 1a–j with freshly prepared 2-nitrobenzoyl
chloride in the presence of 4-dimethylaminopyridine (DMAP)
and N,N-diisopropylethylamine (DIPEA) in dry dichloroethane
(DCE) at room temperature gave 2-nitrobenzoylamides
2a–j. The yields of these products ranged from 41 to
70%. The generation of better yields by increasing the re-
action temperature and the amount of catalyst and
chloranhydride was unsuccessful. The monitoring of the
crude reaction mixture by TLC indicated the incomplete
conversion of 1a–j to the corresponding nitro derivatives
2a–j within 24 h. Some products were isolated after chro-
matographic purification. Furthermore, we can point out
that in some cases after the purification of products 2b
and 2f by chromatography, starting compounds 1b and
1f were isolated (21 and 18%, respectively). On the
other hand, in [6], it is mentioned that aqueous work up
of the reaction mixture resulted in partial hydrolysis of
1-nitrobenzoylamides of 1,4-benzodiazepines to the
starting materials and 2-nitrobenzoic acid. As planned, the
process of the reduction of nitro compounds 2a, 2b, 2d,
2e, and 2g–j to the corresponding amines was accom-
plished by a simultaneous N-heterocyclization leading to
dihydroquinazolino[3,2-a][1,5]benzodiazepinones 3a, 3b,
3d, 3e, and 3g–j. The study of the reduction of nitroamides
2a–e was commenced under mild catalytic conditions
(i: H2, Re/Ni; ii: H2, 10% Pd/C) in methanol. It was observed
that the reduction reaction conducted with H2, 10% Pd/C
For the analysis of NMR spectra, we used the arbitrary
numbering of atoms as in Scheme 2 (A for compounds
2a–j and B for compounds 3a, 3b, 3d, 3e, and 3g–j).
1H NMR spectra of starting compounds 1h–j exhibited
the singlet at 8.4–8.7 ppm attributed to NH group analo-
gously to the spectral data of compounds 1a–g published
previously [15–18].
The formation of compounds 2a–j was evidenced by the
disappearance of NH singlet and the increase in the number
1
of aromatic protons (8H) in H NMR spectra. The most
deshielded proton (at ~8.3 ppm) in the aromatic region of
compounds 2a–j was assigned to H-C30 by means of
HMBC spectra. The characteristic signals of 13C NMR
spectra for the three CO groups of molecules 2a–j also
confirmed the predictable structure. The values of the
chemical shift of the resonances of CO-N1 group varied
about 1.0 ppm among compounds 2a–j in the range
166.5–167.5 ppm. The carbons of C2 and CO-N5 were
affected by CH3-C3, CH3-C4, and N5-substituents; there-
fore, their resonances were found in wider regions of
169.0–173.5 and 154.5–170.5 ppm, respectively. The car-
bons of C2 and C4 of heterocyclic moiety of compounds
2a–j were shielded at approximately 1.8 ppm, whereas
C3 was deshielded at ~2 ppm, compared with the respec-
tive carbons of 1a–j.
Scheme 1
The formation of the compounds of structure 3 was
confirmed by the appearance of resonance at ~153.4 ppm
attributed to C═N group carbon and the absence of the sig-
nal of CO group in 2-position compared with the respective
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DOI 10.1002/jhet

Month 2014
Dihydroquinazolino[3,2-a][1,5]benzodiazepines: Synthesis and Computational Study of
Reductive N-Heterocyclization of N-(2-Nitrobenzoyl)-1,5-benzodiazepin-2-ones
Table 1
Physicochemical properties of compounds 2a–j, 3a, 3b, 3d, 3e, and 3g–j.
Elemental analysis %
Calcd./Found
Compound
Yield (%)
mp (ꢁC)
199–201
205–207
263–265
202–204
200–202
224–226
186–188
199–201
154–156
169–171
216–218
193–195
270–273
204–205
236–239
199–201
120–122
130–132
Molecular formula
18H15N3O5
C
H
N
2a
2b
2c
2d
2e
2f
74
70
55
61
52
41
65
67
56
55
C
61.19
61.01
62.12
62.00
62.12
62.41
60.18
60.44
61.19
61.41
61.19
60.94
53.08
53.31
54.16
54.32
59.53
59.34
60.45
60.67
70.81
70.50
71.46
71.18
70.09
70.37
70.81
70.56
60.17
60.38
61.13
60.89
68.05
68.29
68.75
68.51
4.28
4.32
4.66
4.79
4.66
4.49
3.86
3.77
4.28
4.19
4.28
4.36
2.97
2.86
3.35
3.27
4.47
4.59
4.82
4.67
4.95
4.81
5.37
5.31
4.50
4.58
4.95
4.84
3.37
3.31
3.78
3.90
5.11
5.04
5.48
5.56
11.89
11.97
11.44
11.65
11.44
11.66
12.38
12.13
11.89
11.67
11.89
11.99
10.32
10.50
9.97
10.03
10.96
10.73
10.57
10.74
13.76
13.98
13.16
13.39
14.42
14.15
13.76
13.51
11.69
11.41
11.26
11.47
12.53
12.77
12.03
12.20
C19H17N3O5
C19H17N3O5
C17H13N3O5
C18H15N3O5
C18H15N3O5
C18H12F3N3O5
C19H14F3N3O5
C19H17N3O6
C20H19N3O6
C18H15N3O2
C19H17N3O2
C17H13N3O2
C18H15N3O2
C18H12F3N3O2
C19H14F3N3O2
C19H17N3O3
C20H19N3O3
2g
2h
2i
2j
3a
3b
3d
3e
3g
3h
3i
47 (i)
57 (ii)
45 (i)
55 (ii)
48 (i)
77 (ii)
48 (i)
61 (ii)
57 (iii)
42 (ii)
65 (iii)
62 (iii)
3j
68 (iii)
spectra of compounds 2a–j. The resonances of CO-N1
group were shifted up-field at approximately 7 ppm and
were observed in the range 160.1–160.8 ppm; the reso-
nances of C10 carbon were shifted up-field ~13.5 ppm and
those of C20 down-field ~2.3 ppm. The carbons of the C2
and C3 atoms of heterocyclic moiety of the compounds
of structure 3 were shielded ~16.8 and ~1 ppm, respec-
tively, whereas C4 was deshielded ~2.5 ppm compared
with the corresponding atoms of compounds 2a–j. In the
case of compounds 3, the most deshielded ArH (at
~8.3 ppm) in the aromatic region was assigned to H-C60
1
in H NMR spectra.
Scheme 2
The specific splitting of resonances of carbon atoms
(CF3 at about 115.9 ppm, ~1JC-F = 288.6 Hz and CO at
about 156.3 ppm, ~2JC-F = 36.5 Hz) of compounds 1h, 2g,
2h, 3g, and 3h possessing COCF3 group on 5-position
was observed in 13C NMR spectra.
The aforementioned procedures (i–iii) for the N-
heterocyclization of 2-nitrobenzoylamides 2c and 2f were
also explored. In all cases, the reduction of compounds
2c and 2f was not successful. Unchanged 2c and 2f
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R. Janciene, G. Mikulskiene, T. Javorskis, A. Vektariene, G. Vektaris, and L. Kosychova
Vol 000
(~60%) and starting benzodiazepinones 1c and 1f (~25%)
were isolated after chromatographic separation of the mix-
ture of the reaction products. Thus, we can point out that
the reaction of the reductive cyclization of compounds 2c
and 2f, carrying the methyl substituent in 3-position of
the diazepine nucleus, proceeded differently as compared
with the other studied 1,5-benzodiazepin-2-one derivatives.
To have more insight into the nature of the studied reductive
cyclization process and to explain the unexpected reactivity
pattern, the theoretical studies of the reactivity descriptors of
2-nitrobenzoylamides were carried out. It is worth mentioning
that the mechanism of the reductive N-heterocyclization of
benzodiazepines bearing nitrobenzoylamide moiety has
not been established yet. A possible mechanism for this
heterocyclization is proposed in Scheme 3.
We assumed that the studied reductive cyclization reaction
starts in a similar way to the reduction reaction of aromatic
nitro compounds to amines [19]. After the nitro group is
activated by metal-mediated electrons and two hydrogen
atoms, the elimination of water molecule occurs, leading to
nitroso intermediates Ia–j, which after the reductive addition
of two hydrogen atoms form hydroxylamine intermediates
IIa–j. The formation of hydroxylamine intermediates IIa–j
enables the nucleophilic attack of the N-C20 atom on the C2
atom of the protonated carbonyl group. After the reductive ad-
dition of a hydrogen atom, intermediates IIIa–j possessing the
weak interaction between the C2 and N-C20 atoms are formed.
The subsequent elimination of two water molecules afforded
the CN double bond and final products 3a, 3b, 3d, 3e, and
3g–j. The presented reaction mechanism (Scheme 3) demon-
strates that the initiation of heterocyclization reaction becomes
possible after intermediate III is formed. Thus, the insight into
the electronic structure of intermediate III can be of great im-
portance for the explanation of different reactivity patterns of
nitrobenzoylamides 2a–j in the reductive heterocyclization
reaction. To confirm our assumptions, the theoretical investi-
gation of intermediates IIIa–j was carried out by means of
quantum-chemical reactivity descriptors calculations. The
calculated reactivity descriptors: frontier orbital p electron
population and Fukui functions for nucleophilic and
electrophilic attack on the selected atoms allowed us to
estimate the outcome of the studied reaction.
The frontier orbital electron population on atoms
provides a useful tool for the detailed characterization of
donor–acceptor interactions that can strictly be used only
to describe the reactivity of different atoms in the same
molecule [20]. According to the frontier orbital electron
reactivity theory, the majority of chemical reactions take
place at the position and in the orientation where the over-
lap of the highest occupied molecular orbital (HOMO) and
the lowest unoccupied molecular orbital (LUMO) of the
respective reactants can reach a maximum [20–22].
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
electronic density to deform at a given position, that is, to
accept or donate electrons [7,23–26]. With the aim of
estimating the outcome of the reductive cyclization progress,
we calculated the condensed Fukui function [23–25] for
nucleophilic attack [f + (r)] and electrophilic attack [f – (r)],
and the frontier orbital p electron population on the particular
atoms C2 and N-C20 of intermediates IIIa–j (Table 2).
The results of our computation reveal that the presence
of substituents on the diazepine skeleton of intermediates
IIIa–j influence the values of all calculated reactivity de-
scriptors. HOMO and LUMO populations on particular
atoms illustrate the most favorable sites for electrophilic
or nucleophilic attack. A higher LUMO electron popula-
tion on the C2 atom in intermediates IIIa, IIIb, IIId, IIIe,
and IIIg–j (~0.41–0.51) as compared with the values of
IIIc and IIIf (~0.1) and a comparatively high HOMO elec-
tron population on the N-C20 atom support the idea that
with the first clash between reacting atoms, an intrinsic mo-
lecular rearrangement should start in places of enhanced
electron density, that is, between the N-C20 and C2 atoms.
This initial interaction could succeed the subsequent
rearrangements to final products 3a, 3b, 3d, 3e, and 3g–j.
Meanwhile, the comparably small values of LUMO electron
population on the C2 atom of IIIc and IIIf (0.095 and 0.104,
respectively) are compatible with the experimental fact that
cyclization of 3-methyl substituted compounds 2c and 2f
does not take place. In the case when the intermolecular
rearrangement of intermediates IIIa, IIIb, IIId, IIIe, and
IIIg–j occurs, the Fukui function values for nucleophilic
attack [f+ (r)] on the C2 atom are from 0.39 to 0.57, and
those for electrophilic attack [fꢀ (r)] of the N-C20 atom are
from 0.30 to 0.48. Comparatively small values of [f+ (r)]
on the C2 atom of IIIc and IIIf (0.104 and 0.082,
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Dihydroquinazolino[3,2-a][1,5]benzodiazepines: Synthesis and Computational Study of
Reductive N-Heterocyclization of N-(2-Nitrobenzoyl)-1,5-benzodiazepin-2-ones
Table 2
Calculated HOMO and LUMO electron populations and Fukui functions [f + (r)], [f ꢀ (r)] on N-C20 and C2 atoms of IIIa–j intermediates.
N-C20
C2
Intermediate
R1
R2
R3
Me
Me
Me
H
H
H
CF3
CF3
OEt
OEt
HOMO
[f ꢀ (r)]
LUMO
[f + (r)]
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
H
H
Me
H
H
Me
H
H
H
H
H
Me
H
H
Me
H
H
Me
H
0.349
0.292
0.283
0.276
0.265
0.215
0.245
0.261
0.337
0.270
0.480
0.414
0.392
0.421
0.414
0.298
0.399
0.401
0.362
0.395
0.510
0.444
0.095
0.456
0.406
0.104
0.428
0.416
0.476
0.407
0.390
0.566
0.104
0.386
0.566
0.082
0.552
0.524
0.555
0.567
IIIj
Me
HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital.
on a Merck precoated silica gel aluminum roll (60F254) with
chloroform–ethyl acetate–methanol (n/n, 14:7:1) as the eluent
and was visualized with UV light. Dry column vacuum chro-
matography [27] was performed with silica gel Chemapol L 5/
40 mesh. The first optimization of intermediate structures was
carried out with AM1 method. Consequently, the AM1 geom-
etry optimized structures were used as initial coordinates for
optimization at the DFT level using the B3LYP functional
and the 6-31G* basis sets using the program product [28].
The vibrational frequencies were computed for optimized in-
termediate structures and checked to present no imaginary vi-
brational frequency to ensure that they were local minima
points on potential energy profile [29]. The calculation of lo-
cal reactivity descriptors was implemented according to
[20,23–25,30].
respectively) suggest rather the reduced reactivity of these
intermediates.
Thus, our computational results reveal that the presence
of substituents on 3-position on the diazepine skeleton
causes changes in the electron population on the frontier
molecular orbitals. The presence of the electron donating
the 3-methyl substituent decreases the electrophilicity of
the C2 atom and evokes resistance to further intramolecu-
lar rearrangements. The computational results are in agree-
ment with experimental observations and support the
proposed reaction mechanism.
In conclusion, a series of new 6,7-dihydroquinazolino[3,
2-a][1,5]benzodiazepin-13(5H)-ones was successfully syn-
thesized using a metal-induced reductive N-heterocyclization
of 1-(2-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-
2-ones. It was established that the course of this
heterocyclization depended on the presence of substituents
in the heptatomic ring of the starting heterocycles. The pos-
sible mechanism of this heterocyclization was discussed,
and it was demonstrated that the hydroxylamine intermediate
was the initiator of this reaction. The suggested reaction
mechanism was supported by means of quantum-chemical
reactivity descriptors calculations and evaluation. The com-
putational studies reported herein are a powerful tool for
the interpretation of experimental results and for the design
of synthetic pathways to novel fused heterocycles.
General procedure for the synthesis of 5-acyl-1-(2-
nitrobenzoyl)-3-R1-4-R2-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-
2-ones (2a–j).
To
a
stirred solution of appropriate
benzodiazepinones 1a–j (5 mmol) in dry DCE (40–60 mL)
containing DIPEA (1.05 mL, 6 mmol) and catalytic amount of
DMAP, a solution of freshly prepared o-nitrobenzoylchloride
(0.8 mL, 6 mmol) in dry DCE (6 mL) was added dropwise at
room temperature. The reaction mixture was stirred at room
temperature for 24 h. Then, the reaction mixture was diluted
with 60 mL DCE and washed with 1N HCl, 5% NaHCO3, and
water. After drying and removal of the solvent in vacuum, the
residues were subjected to purification to give 2a–j. The solid
residues were recrystallized from dichloromethane–diethyl
ether mixture. The oily residues were firstly subjected to dry
column vacuum chromatography (silicagel) using the benzene-
DCE system for gradient elution and then recrystallized from
dichloromethane–diethyl ether mixture. The yields, mp, and
elemental analysis data are presented in Table 1.
EXPERIMENTAL
Melting points were determined in open capillaries on a
MEL-TEMP 1202D apparatus and are uncorrected. The IR
spectra (potassium bromide) were taken on a Perkin Elmer
Spectrum GX FT-IR spectrometer. 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded in deuteriochloroform
on a Varian Unity Inova 300 spectrometer. The chemical
shifts are referenced to tetramethylsilane [d (1H) = 0] and the
solvent signal deuteriochloroform [d (13C) = 77.0 ppm]. The
reactions were controlled by the TLC method and performed
5-Acetyl-1-(2-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzo-
diazepin-2-one (2a). IR: n CO 1742, 1684, 1663, asNO2 1533,
sNO2 1357 cmꢀ1 1H NMR: d 2.00 (s, 3H, COCH3), 2.36 (dd,
;
1H, J= 3.9, 13.6 Hz, 3-CH2), 2.56 (dt, 1H, J= 7.1, 13.7 Hz, 3-
CH2), 3.35 (dd, 1H, J= 6.9, 12.9 Hz, 4-CH2), 4.87
(dt, 1H, J= 5.0, 13.4 Hz, 4-CH2), 7.27–7.74 (m, 7H, ArH), 8.25
(dd, 1H, J= 0.8, 8.3Hz, H-C30); 13C NMR: d 22.59 (COCH3),
35.23 (C3), 45.04 (C4), 124.25 (CH), 126. 56 (CH), 129.14 (CH),
129.41 (CH), 129.51 (CH), 129.73 (CH), 130.17 (CH), 134.53
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(C10), 134.60 (CH), 135.18 (C9a), 135.81 (C5a), 144.50 (C20),
167.52 (CO-N1), 170.50 (CO-N5), 170.80 ppm (C2).
5-Acetyl-4-methyl-1-(2-nitrobenzoyl)-1,3,4,5-tetrahydro-
J = 1.2, 5.1, 13.6Hz, 3-CH2), 2.64 (dt, 1H, J = 7.2, 13.6 Hz, 3-
CH2), 3.55 (dd, 1H, J = 7.1, 13.1Hz, 4-CH2), 4.80 (dt, 1H, J = 5.1,
13.4Hz, 4-CH2), 7.25–7.81 (m, 7H, ArH), 8.27 (dd, 1H, J = 1.1,
8.3 Hz, H-C30); 13C NMR: d 34.65 (3C), 47.11 (C4), 115.91
(1JC-F = 288.3 Hz, CF3), 124.23 (CH), 126.64 (CH), 128.92
(CH), 129.56 (CH), 129.83 (2CH), 130.53 (CH), 132.02 (C9a
or C5a), 134.43 (C10), 134.74 (CH), 135.02 (C5a or C9a),
144.40 (C20), 156.17 (2JC-F = 36.3 Hz, CO-N5), 166.64 (CO-N1),
169.80 ppm (C2).
2H-1,5-benzodiazepin-2-one (2b).
IR:
;
n CO 1743,
1686, 1666, asNO2 1531, NO2 1355 cmꢀ1
1H NMR: d 1.00
s
(d, 3H, J = 6.4 Hz, CH3-C4), 1.83 (s, 3H, COCH3), 2.07–2.24
(m, 2H, 3-CH2), 5.00–5.13 (m, 1H, 4-CH), 7.17–7.67 (m,
7H, ArH), 8.13 (dd, 1H, J = 1.1, 8.3 Hz, H-C30); 13C NMR: d
18.49 (CH3-C4), 22.57 (COCH3), 42.12 (C3), 51.27 (C4), 123.73
(CH), 125.93 (CH), 128.80 (CH), 128.96 (CH), 129.25 (CH),
129.39 (CH), 130.09 (CH), 133.36 (C9a or C5a), 134.17 (CH),
134.17 (C5a or C9a), 134.86 (C10), 143.86 (C20), 167.17
(CO-N1), 169.04 (C2), 170.07 ppm (CO-N5).
4-Methyl-1-(2-nitrobenzoyl)-5-(trifluoroacetyl)-1,3,4,5-
tetrahydro-2H-1,5-benzodiazepin-2-one (2h).
IR: n CO
1
1744, 1698, asNO21524, NO2 1346 cmꢀ1; H NMR: d 1.20 (d,
s
3H, J = 6.4 Hz, CH3-C4), 2.34 (ddd, 2H, J = 8.8, 13.4,
25.6 Hz, 3-CH2), 5.06–5.18 (m, 1H, 4-CH), 7.24–7.83 (m, 7H,
ArH), 8.27 (dd, 1H, J = 1.1, 8.3 Hz, H-C30); 13C NMR: d 18.01
(CH3-C4), 41.98 (C3), 54.24 (C4), 115.93 (1JC-F = 288.7 Hz,
CF3), 124.22 (CH), 126.64 (CH), 129.34 (CH), 129.43 (CH),
129.76 (CH), 129.94 (C9a or C5a), 130.27 (CH), 130.55
(CH), 134.51 (C10), 134.73 (CH), 135.30 (C5a or C9a), 144.36
(C20), 156.17 (2JC-F = 36.3 Hz, CO-N5), 166.70 (CO-N1),
169.49 ppm (C2).
5-Acetyl-3-methyl-1-(2-nitrobenzoyl)-1,3,4,5-tetrahydro-
2H-1,5-benzodiazepin-2-one (2c).
IR: n CO 1738, 1702,
1
1667, asNO2 1523, NO2 1347 cmꢀ1; H NMR: d 0.98 (d, 3H,
s
J = 6.4 Hz, CH3-C3), 2.01 (s, 3H, COCH3), 2.61–2.74
(m, 1H, 3-CH), 3.31 (dd, 1H, J = 6.7, 12.6 Hz, 4-CH2), 4.50
(t, 1H, J = 12.6 Hz, 4-CH2), 7.26–7.78 (m, 7H, ArH), 8.27
(dd, 1H, J = 1.1, 8.3 Hz, H-C30); 13C NMR: d 12.15
(CH3-C3), 22.63 (COCH3), 37.80 (C3), 52.08 (C4), 124.30
(CH), 126.47 (CH), 128.81 (CH), 129.36 (CH), 129.56
(CH), 129.67 (CH), 130.10 (CH), 134.64 (CH), 134.74 (C10),
134.81 (C9a or C5a), 136.56 (C5a or C9a), 144.37 (C20), 167.72
(CO-N1), 170.31 (CO-N5), 173.50 ppm (C2).
5-(2-Nitrobenzoyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepine-1-carbaldehyde (2d). IR: n CO 1724, 1692, 1678,
asNO21526, sNO2 1346 cmꢀ1; 1H NMR: d 2.60 (br, 2H, 3-CH2),
3.56 (br, 1H, 4-CH2), 4.46 (br, 1H, 4-CH2), 7.29–7.80
(m, 7H, ArH), 8.26 (dd, 1H, J = 1.1, 8.2 Hz, H-C30),
8.45 (s, (0.02)1H, COH), 8.48 (s, (0.98)1H, COH); 13C
NMR: d 34.34 (C3), 43.85 (C4), 124.21 (CH), 126.66 (CH),
127.74 (CH), 129.06 (CH), 129.79 (CH), 129.88 (CH),
130.27 (CH), 133.75 (C9a or C5a), 133.92 (C5a or C9a),
134.42 (C10), 134.63 (CH), 144.56 (C20), 162.03 (CO-N5),
167.32 (CO-N1), 170.49 ppm (C2).
Ethyl 5-(2-nitrobenzoyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepine-1-carboxylate (2i).
IR: n CO 1723, 1703,
1
1663, asNO2 1529, NO2 1347 cmꢀ1; H NMR: d 1.23 (br, 3H,
s
OCH2CH3), 2.39 (br, 1H, 3-CH2), 2.56 (br, 1H, 3-CH2), 3.55
(br, 1H, 4-CH2), 4.23 (br q, 2H, J = 6.4 Hz, OCH2CH3), 4.54
(br, 1H, 4-CH2), 7.28–7.75 (m, 7H, ArH), 8.25 (dd, 1H, J = 0.7,
8.2 Hz, H-C30); 13C NMR: d 14.50 (OCH2CH3), 35.41 (C3), 46.93
(C4), 62.32 (OCH2CH3), 124.20 (CH), 126.60 (CH), 128.21 (CH),
128.84 (CH), 129.47 (CH), 129.54 (2CH), 129.54 (C9a or
C5a), 134.43 (CH), 134.66 (C10), 134.86 (C5a or C9a), 144.59
(C20), 155.13 (CO-N5), 167.02 (CO-N1), 171.18 ppm (C2).
Ethyl 2-methyl-5-(2-nitrobenzoyl)-4-oxo-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepine-1-carboxylate (2j).
IR: n CO 1731,
1703, asNO2 1527, NO2 1347cmꢀ1 1H NMR: d 1.14 (d, 3H,
;
s
J = 6.4Hz, CH3-C4), 1.18 (br t, 3H, OCH2CH3), 2.16–2.35
(m, 2H, 3-CH2), 4.19 (br q, 2H, J = 6.8 Hz, OCH2CH3), 4.90
(br, 1H, 4-CH), 7.26–7.75 (m, 7H, ArH), 8.24 (d, 1H, J = 8.3 Hz,
H-C30); 13C NMR: d 14.52 (OCH2CH3), 19.10 (CH3-C4), 42.58
(C3), 53.55 (C4), 62.10 (OCH2CH3), 124.20 (CH), 126.50 (CH),
128.41 (CH), 128.61 (CH), 129.17 (CH), 129.51 (CH), 129.51
(C9a or C5a), 130.79 (CH), 132.66 (C5a or C9a), 134.46 (CH),
134.90 (C10), 144.51 (C20), 154.54 (CO-N5), 167.20 (CO-N1),
170.76 ppm (C2).
2-Methyl-5-(2-nitrobenzoyl)-4-oxo-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine-1-carbaldehyde (2e).
IR: n CO 1725,
1704, 1663, asNO2 1524, NO2 1346 cmꢀ1
;
1H NMR: d 1.17
s
(d, 3H, J = 6.4 Hz, CH3-C4), 2.35–2.50 (m, 2H, 3-CH2), 4.99
(pd, 1H, J = 5.9, 12.0 Hz, 4-CH), 7.26–7.81 (m, 7H, ArH),
8.25 (dd, 1H, J = 0.8, 8.3 Hz, H-C30), 8.36 (s, (0.96)1H, COH),
8.44 (s, (0.04)1H, COH); 13C NMR: d 18.75 (CH3-C4), 41.93
(C3), 50.97 (C4), 124.20 (CH), 126.80 (CH), 129.35 (CH),
129.50 (2CH), 129.74 (CH), 129.93 (CH), 132.12 (C9a or
C5a), 134.56 (C10), 134.64 (CH), 135.07 (C5a or C9a), 144.41
(C20), 161.33 (CO-N5), 167.49 (CO-N1), 170.10 ppm (C2).
3-Methyl-5-(2-nitrobenzoyl)-4-oxo-2,3,4,5-tetrahydro-1H-
General procedure for the synthesis of 5-acyl-3-R1-4-R2-
6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepin-13(5H)-ones
(3a, 3b, 3d, 3e, and 3g–i).
i. In a hydrogenation apparatus equipped with a magnetic
stirrer, the Re/Ni catalyst was added to a solution of
appropriate nitrobenzoylamides 2a–e (2.5 mmol) in
methanol (150–200 mL), and the mixture was hydrogenated
at room temperature and atmospheric pressure. After the
reduction was complete, as observed by TLC monitoring,
the catalyst was filtered off. The filtrate was concentrated to
dryness in vacuum. In case when the residue obtained is a
solid, it was crystallized from methyl tert-butyl ether. The
oily residues were subjected to dry column vacuum
chromatography (silicagel) using the DCE-ethyl acetate
system for gradient elution. Thus, compounds 3a, 3b, 3d,
and 3e were obtained.
1,5-benzodiazepine-1-carbaldehyde (2f).
IR: n CO 1737,
;
1694, 1671, asNO2 1530, sNO2 1346 cmꢀ1
1H NMR: d
1.01 (d, 3H, J = 6.5 Hz, CH3-C3), 2.88 (tt, 1H, J = 6.4, 12.8 Hz,
3-CH), 3.43 (dd, 1H, J = 5.8, 12.7 Hz, 4-CH2), 4.22
(t, 1H, J = 13.1 Hz, 4-CH2), 7.27–7.78 (m, 7H, ArH), 8.26 (d,
1H, J = 8.2Hz, H-C30), 8.41 (s, (0.05)1H, COH), 8.45 (s, (0.95)
1H, COH); 13C NMR: d 12.33 (CH3-C3), 36.77 (C3), 50.65 (C4),
124.24 (CH), 126.58 (CH), 127.43 (CH), 129.02 (CH), 129.69
(CH), 129.86 (CH), 130.16 (CH), 133.71 (C9a or C5a), 134.47
(C10), 134.63 (CH), 134.73 (C5a or C9a), 144.41 (C20), 161.77
(CO-N5), 167.50 (CO-N1), 173.17 ppm (C2).
1-(2-Nitrobenzoyl)-5-(trifluoroacetyl)-1,3,4,5-tetrahydro-2H-
1,5-benzodiazepin-2-one (2g).
IR: n CO 1731, 1708, 1699,
ii. An analogous catalytic hydrogenation procedure was
asNO2 1530, sNO2 1348cmꢀ1
;
1H NMR: d, 2.44 (ddd, 1H,
performed for appropriate nitrobenzoylamides 2a–h
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Dihydroquinazolino[3,2-a][1,5]benzodiazepines: Synthesis and Computational Study of
Reductive N-Heterocyclization of N-(2-Nitrobenzoyl)-1,5-benzodiazepin-2-ones
(2.5 mmol) using 10% palladium on carbon catalyst (10% of the
weight of the starting 2a–h). Compounds 3a, 3b, 3d, 3e, and 3h
were obtained.
18.50 (CH3-C4), 41.00 (C3), 53.49 (C4), 120.97 (C10), 127.21
(CH), 127.27 (2CH), 129.01 (CH), 129.21 (CH), 129.39 (CH),
129.89 (CH), 131.88 (C9a or C5a), 133.87 (C5a or C9a), 134.98
(CH), 146.80 (C20), 153.05 (C2), 160.80 (CO-N1), 161.49 ppm
(CO-N5).
iii. To a solution of appropriate nitrobenzoylamides 2c, 2f–j
(2.5 mmol) in glacial acetic acid (20–30 mL), Zn dust
(1.63 g, 25 mmol) was added, and the reaction mixture
was stirred at room temperature for 2–3 h. After the
reduction was complete, as observed by TLC monitoring,
the reaction mixture was filtered. The filtrate was concen-
trated to dryness in vacuum. The residue was dissolved in
dichloromethane, and the solution was washed with 5%
NaHCO3 and water, dried, and evaporated to dryness in
vacuum. Compounds 3g–j were worked-up analogously
to procedure i.
The reduction of compounds 2c and 2f in all cases (i, ii, and iii)
did not occur. Unchanged 2c and 2f (61%, ii and 57%, iii, respec-
tively) and benzodiazepinones 1c and 1f (19%, ii and 26%, iii, re-
spectively) were isolated after chromatographic separation of the
reaction mixture. Mixed samples with authentic compounds did
not show depression of the melting point.
5-(Trifluoroacetyl)-6,7-dihydroquinazolino[3,2-a][1,5]
benzodiazepin-13(5H)-one (3g).
IR: n CO 1698, CN
1614 cmꢀ1; H NMR: d 2.82 (dt, 1H, J = 6.7, 13.5 Hz, 3-CH2),
3.08 (dd, 1H, J = 5.0, 14.0 Hz, 3-CH2), 3.66 (dd, 1H, J = 6.6,
12.7 Hz, 4-CH2), 4.89 (dt, 1H, J = 5.2, 13.0 Hz, 4-CH2), 7.36–
7.84 (m, 7H, ArH), 8.29 (ddd, 1H, J = 0.5, 1.5, 8.0 Hz, H-C60);
13C NMR: d 33.42 (C3), 49.34 (C4), 115.94 (1JC-F = 288.5 Hz,
CF3), 120.95 (C10), 127.29 (CH), 127.36 (2CH), 128.87 (CH),
128.96 (CH), 129.65 (CH), 130.20 (CH), 131.61 (C9a or C5a),
134.10 (C5a or C9a), 134.94 (CH), 146.73 (C20), 152.55(C2),
156.83 (2JC-F = 37.0 Hz, CO-N5), 160.14 ppm (C2).
1
6-Methyl-5-(trifluoroacetyl)-6,7-dihydroquinazolino[3,2-a]
[1,5]benzodiazepin-13(5H)-one (3h).
IR: n CO 1690, CN
1612 cmꢀ1; H NMR: d 1.29 (d, 3H, J = 6.4 Hz, CH3-C4), 2.46
(dd, 1H, J = 12.4, 13.8 Hz, 3-CH2), 3.02 (dd, 1H, J = 5.0,
13.8 Hz, 3-CH2), 5.13–5.25 (m, 1H, 4-CH), 7.32–7.82 (m, 7H,
ArH), 8.31 (dd, 1H, J = 1.0, 8.0 Hz, H-C60); 13C NMR: d 17.77
(CH3-C4), 40.84 (C3), 56.54 (C4), 115.79 (1JC-F = 288.7 Hz,
CF3), 120.97 (C10), 127.33 (CH), 127.40 (2CH), 128.92 (CH),
129.22 (CH), 129.62 (C9a or C5a), 130.25 (2CH), 134.40 (C5a
or C9a), 134.98 (CH), 146.78 (C20), 152.46 (C2), 156.23 (2JC-
F = 36.4 Hz, CO-N5), 160.17 ppm (C2).
1
The yields, mp, and elemental analysis data of compounds 3a,
3b, 3d, 3e, and 3g-j are presented in Table 1.
5-Acetyl-6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepin-
1
13(5H)-one (3a).
IR: n CO 1694, 1663, CN 1610 cmꢀ1; H
NMR: d 1.85 (s, 3H, COCH3), 2.74 (dt, 1H, J = 6.5, 13.6 Hz, 3-
CH2), 2.99 (dd, 1H, J = 4.5, 13.9 Hz, 3-CH2), 3.47 (dd, 1H,
J = 6.4, 12.7 Hz, 4-CH2), 4.92 (dt, 1H, J = 5.2, 13.2 Hz, 4-CH2),
7.32–7.81 (m, 7H, ArH), 8.28 (d, 1H, J = 7.8 Hz, H-C60); 13C
NMR: d 22.77 (COCH3), 34.04 (C3), 47.53 (C4), 120.92 (C10),
127.14 (CH), 127.18 (CH), 127.25 (CH), 129.09 (CH), 129.11
(CH), 129.15 (CH), 130.08 (CH), 133.99 (C9a), 134.97 (CH),
135.43 (C5a), 146.68 (C20), 153.91 (C2), 160.68 (CO-N1),
170.42 ppm (CO-N5).
Ethyl
diazepine-5(6H)-carboxylate (3i). IR: n CO 1705, 1663, CN
1612 cmꢀ1 1H NMR: d 1.13 (br s, (0.7)3H, OCH2CH3), 1.91
13-oxo-7,13-dihydroquinazolino[3,2-a][1,5]benzo-
;
(br s, (0.3)3H, OCH2CH3), 2.79 (dt, 1H, J = 6.4, 13.7 Hz, 3-
CH2), 3.01 (dd, 1H, J = 4.3, 13.9 Hz, 3-CH2), 3.69 (dd, 1H,
J = 6.2, 11.8 Hz, 4-CH2), 4.00 (br, (0.3)2H, OCH2CH3), 4.15
(qd, 1H, J = 7.2, 10.3 Hz, 4-CH2), 4.62 (br, (0.7)2H,
OCH2CH3), 7.40–7.83 (m, 7H, ArH), 8.33 (dd, 1H, J = 1.5,
8.0 Hz, H-C60); 13C NMR: d 14.32 (OCH2CH3), 34.34 (C3),
49.48 (C4), 62.13 (OCH2CH3), 121.20 (C10), 127.03 (CH),
127.10 (CH), 127.30 (CH), 127.82 (CH), 128.41 (CH), 129.46
(2CH), 133.26 (C9a or C5a), 134.34 (C5a or C9a), 134.72
(CH), 146.94 (C20), 154.16 (C2), 155.19 (CO-N5), 160.63 ppm
(CO-N1).
5-Acetyl-6-methyl-6,7-dihydroquinazolino[3,2-a][1,5]benzo-
diazepin-13(5H)-one (3b).
IR: n CO 1690, 1655, CN
1610 cmꢀ1; H NMR: d 1.12 (d, 3H, J = 6.3 Hz, CH3-C4), 1.72
(s, 3H, COCH3), 2.31 (dd, 1H, J = 12.5, 13.6 Hz, 3-CH2), 2.89
(dd, 1H, J = 5.0, 13.7 Hz, 3-CH2), 5.11–5.23 (m, 1H, 4-CH),
7.19–7.73 (m, 7H, ArH), 8.22 (dd, 1H, J = 1.1, 8.0 Hz, H-C60);
13C NMR: d 18.49 (CH3-C4), 22.96 (COCH3), 41.32 (C3), 54.00
(C4), 120.83 (C10), 127.10 (2CH), 127.20 (CH), 128.95 (CH),
129.06 (CH), 129.62 (CH), 130.37 (CH), 133.47 (C9a or C5a),
134.23 (C5a or C9a), 134.88 (CH), 146.87 (C20), 153.50 (C2),
160.73 (CO-N1), 169.68 ppm (CO-N5).
1
Ethyl 6-methyl-13-oxo-7,13-dihydroquinazolino[3,2-a][1,5]
benzodiazepine-5(6H)-carboxylate (3j).
IR: n CO 1697,
CN 1610 cmꢀ1 1H NMR: d 1.05 (br t, 3H, OCH2CH3), 1.22
;
(d, 3H, J = 6.3 Hz, CH3-C4), 2.41 (t, 1H, J = 13.0Hz, 3-CH2),
2.95 (dd, 1H, J = 4.9, 13.7 Hz, 3-CH2), 3.87–4.13 (br m, 2H,
OCH2CH3), 4.95 (tt, 1H, J = 6.3, 12.4 Hz, 4-CH), 7.02–7.79
(m, 7H, ArH), 8.29 (dd, 1H, J = 1.4, 8.0 Hz, H-C60); 13C NMR:
d 14.25 (OCH2CH3), 18.67 (CH3-C4), 41.55 (C3), 56.03 (C4),
61.83 (OCH2CH3), 121.20 (C10), 126.92 (CH), 127.10 (CH),
127.17 (CH), 127.88 (CH), 128.22 (CH), 128.99 (CH), 130.77
(CH), 132.36 (C9a or C5a), 133.60 (C5a or C9a), 134.63
(CH), 146.89 (C20), 153.84 (C2), 154.50 (CO-N5), 160.57 ppm
(CO-N1).
13-Oxo-7,13-dihydroquinazolino[3,2-a][1,5]benzodiazepine-
5(6H)-carbaldehyde (3d).
IR: n CO 1699, 1668, CN
1610 cmꢀ1; H NMR: d 2.95 (dt, 1H, J = 5.8, 13.9 Hz, 3-CH2),
3.10–3.18 (m, 1H, 3-CH2), 3.58–3.66 (m, 1H, 4-CH2), 4.68 (dt,
1H, J = 4.9, 13.4 Hz, 4-CH2), 7.28–7.84 (m, 7H, ArH), 8.31 (ddd,
1H, J = 0.5, 1.1, 8.0 Hz, H-C60), 8.32 (br q, 1H, J = 0.9 Hz, COH);
13C NMR: d 33.29 (C3), 46.48 (C4), 120.98(C10), 127.06 (CH),
127.36 (CH), 127.45 (CH), 128.10 (CH), 128.87 (CH), 129.43
(CH), 130.28 (CH), 133.09 (C9a or C5a), 133.46 (C5a or C9a),
135.12 (CH), 146.53 (C20), 153.63 (C2), 160.79 (CO-N1),
162.19 ppm (CO-N5).
1
4-Methyl-5-trifluoroacetyl-1,3,4,5-tetrahydro-2H-1,5-
benzodiazepin-2-one (1h).
This compound was obtained
6-Methyl-13-oxo-7,13-dihydroquinazolino[3,2-a][1,5]benzo-
diazepine-5(6H)-carbaldehyde (3e). IR: n CO 1679, 1668, CN
according to procedure [17] from 4-methyl-1,3,4,5-tetrahydro-
2H-1,5-benzodiazepin-2-one [14] (3.6 g, 20 mmol) and
trifluoroacetic acid anhydride (4.2 mL, 30 mmol) in dry
dichloromethane (50 mL). Isolation and crystallization from
ethyl acetate–diethyl ether mixture gave 3.9 g (72%) of 1h; mp:
1
1610 cmꢀ1; H NMR: d 1.25 (d, (0.95)3H, J = 6.4 Hz, CH3-C4),
1.33 (d, (0.05)3H, J=6.4Hz, CH3-C4), 2.61 (dd, 1H, J= 12.6,
13.8 Hz, 3-CH2), 3.04 (ddd, 1H, J= 1.0, 4.6, 13.7 Hz, 3-CH2), 5.07
(tt, 1H, J= 6.0, 12.0 Hz, 4-CH), 7.24–7.82 (m, 7H, ArH), 8.21 (br t,
1H, COH), 8.32 (dd, 1H, J=0.9, 7.9Hz, H-C60); 13C NMR: d
1
195–198ꢁC; IR: n CO 1675, 1698, NH 3170 cmꢀ1; H NMR: d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Janciene, G. Mikulskiene, T. Javorskis, A. Vektariene, G. Vektaris, and L. Kosychova
Vol 000
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M.; Calcina, F.; Barocelli, E. Eur J Med Chem 2002, 37, 12, 933.
[13] Di Braccio, M.; Grossi, G.; Ceruti, M.; Rocco, F.; Loddo, R.;
Sanna, G.; Busonera, B.; Murreddu, M.; Marongiu, M. E. Il Farmaco
2005, 60, 2, 113.
[14] Puodzhunaite, B. A.; Yanchiene, R. A.; Talaikite, Z. A.; Zaks,
A. C.; Rabotnikov, Y. M.; Uzachev, E. A. Khim-Farm Zh 1985, 19, 1195;
Chem Abstr 1986, 105, 133861g.
[15] Puodzhyunaite, B. A.; Yanchene, R. A.; Stumbryavichyute, Z.
A. Chem Heterocycl Compd 1988, 24, 7, 786.
1.27 (d, 3H, J = 6.4 Hz, CH3-C4), 2.33–2.51 (m, 2H, 3-CH2),
5.21–5.33 (m, 1H, 4-CH), 7.18–7.50 (m, 4H, ArH), 8.69 (s, 1H,
NH); 13C NMR: d 18.41 (CH3-C4), 39.86 (C3), 56.69 (C4),
115.84 (1JC-F = 288.9 Hz, CF3), 123.01 (C9), 126.20 (C7), 128.31
(C5a), 130.59 (C6), 130.75 (C8), 136.57 (C9a), 156.30 (2JC-
F = 36.3Hz, CO-N5), 172.19 ppm (C2). Anal. Calcd. for
C12H11F3N2O2: C, 52.94; H, 4.07; N, 10.29. Found: C, 52.77; H,
4.21; N, 10.51.
Ethyl 4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-
carboxylate (1i).
To a stirred solution of 1,3,4,5-tetrahydro-
2H-1,5-benzodiazepin-2-one [14] (3.2 g, 20 mmol) and
triethylamine (2.8 mL, 20 mmol) in dry THF (100 mL), a
solution of ethyl chloroformate (2.1 mL, 22 mmol) in dry THF
(10 mL) was added dropwise at room temperature. The reaction
mixture was refluxed for 8 h with stirring. After quenching, the
formed precipitate was filtered off and the filtrate concentrated
to dryness. The residue was dissolved in chloroform, the
solution was washed with 1N HCl, 5% NaHCO3, and water,
and dried, and the solvent was removed in vacuum. The solid
residue was crystallized from ethyl acetate to give 3.1 g (69%) of
1
1i; mp: 120–122ꢁC; IR: n CO 1704, 1657, NH 3203cmꢀ1; H
[16] Puodꢀziūnaitė, B. Synth Commun 1998, 28, 24, 4537.
[17] Janciene, R.; Vektariene, A.; Stumbreviciute, Z.; Kosychova,
L.; Konstantinavicius, K.; Puodziunaite, B. D. Monatsh Chem 2003,
134, 1629.
NMR: d 1.18 (br, 3H, OCH2CH3), 2.63 (t, 2H, J =6.7 Hz, 3-
CH2), 4.12 (br, 4H, 4-CH2 + OCH2CH3), 7.05–7.29 (m, 4H,
ArH), 8.38 (br, 1H, NH). 13C NMR: d 14.43 (OCH2CH3), 33.59
(C3), 48.12 (C4), 62.11 (OCH2CH3), 122.28 (C9), 125.50 (C7),
127.97 (C8), 129.97 (C6), 132.58 (C5a), 134.75 (C9a), 154.99
(CO-N5), 173.11 ppm (C2). Anal. Calcd. for C12H14N2O3: C,
61.53; H, 6.02; N, 11.96. Found: C, 61.24; H, 6.17; N, 11.81.
ꢀ
ꢀ
[18] Puodziūnaitė, B. D.; Mikulskienė, G.; Jancienė, R.;
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Stumbreviciūtė, Z. Magn Reson Chem 1996, 34, 4, 324.
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1996, 96, 1027.
[21] Vektariene, A.; Vektaris, G. ARKIVOC 2006, xvi, 23.
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Chem 2007, 18, 7, 695.
[23] Parr, R. G.; Yang, W. J Am Chem Soc 1984, 106, 4049.
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A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J Comput
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[25] Ayres, P. W.; Parr, R. G. J Am Chem Soc 2000, 122, 2010.
[26] Vektariene, A.; Vektaris, G.; Svoboda, J. ARKIVOC 2009, vii, 311.
[27] Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 16, 2431.
[28] Wavefunction Inc, Irvine, CA. Spartan’06, In: Shao, Y.;
Molnar, L.F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S.T.;
Gilbert, A.T.B.; Slipchenko, L.V.; Levchenko, S.V.; O’Neill, D.P.;
DiStasio, Jr. R.A.; Lochan, R.C.; Wang, T.; Beran, G.J.O.; Besley, N.
A.; Herbert, J.M.; Lin,C.Y.; Van Voorhis, T.; Chien, S.H.; Sodt, A.;
Steele, R.P.; Rassolov, V.A.; Maslen, P.E.; Korambath, P.P.; Adamson,
R.D.; Austin, B.; Baker, J.; Byrd, E.F.C.; Dachsel, H.; Doerksen, R.J.;
Dreuw, A.; Dunietz, B.D.;Dutoi, A.D.; Furlani, T.R.; Gwaltney, S.R.;
Heyden, A.; Hirata, S.; Hsu,C.P.; Kedziora, G.; Khalliulin, R.Z.;
Klunzinger, P.; Lee, A.M.; Lee, M.S.; Liang, W.Z.; Lotan, I.; Nair, N.;
Peters, B.; Proynov, E.I.; Pieniazek, P.A.;Rhee, Y.M.; Ritchie, J.; Rosta,
E.; Sherrill, C.D.; Simmonett, A.C.; Subotnik,J.E.; Woodcock, H.L.;
Zhang, W.; Bell, A.T.; Chakraborty, A.K.; Chipman, D.M.; Keil, F.J.;
Warshel, A.; Hehre, W.J.; Schaefer, H.F.; Kong, J.; Krylov, A.I.; Gill,
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Heteroatom Chem 2008 19, 1, 72.
Ethyl
diazepine-1-carboxylate (1j).
according to the procedure described for 1i from 4-methyl-
1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one [14] (3.6g,
2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzo-
Compound 1j was obtained
20mmol). Crystallization from ethyl acetate–diethyl ether mixture
gave 3.35 g (71%) of 1j; mp: 193–196ꢁC; IR: n CO 1703, 1667,
1
NH 3176cmꢀ1; H NMR: d 1.09 (br, (0.7)3H, OCH2CH3), 1.21
(d, 3H, J = 6.3Hz, CH3-C4), 1.31 (br, (0.3)3H, OCH2CH3), 2.28–
2.44 (m, 2H, 3-CH2), 3.98 (br, (0.3)2H, OCH2CH3), 4.14 (br m,
(0.7)2H, OCH2CH3), 5.03 (br, 1H, 4-CH), 7.08–7.34 (m, 4H,
ArH), 8.49 (br, (0.3)1H, NH), 8.72 (br, (0.7)1H, NH); 13C NMR:
d 14.14 and 14.43 (OCH2CH3), 19.56 and 20.12 (CH3-C4),
40.42 (C3), 56.00 (C4), 61.74 and 62.01 (OCH2CH3), 122.61
(C9), 125.65 and 125.99 (C7), 128.34 (C8), 130.92 (C5a), 131.40
(C6), 135.82 (C9a), 154.51 (CO-N5), 173.16 ppm (C2). Anal.
Calcd. for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C,
63.06; H, 6.49; N, 11.02.
REFERENCES AND NOTES
[1] Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
[2] Taher, D.; Ishtaiwi, Z. N.; Al-Said, N. H. ARKIVOC 2008,
xvi, 154.
[3] Al-Said, N. H.; Al-Qaisi, L. S. Tetrahedron Lett 2006, 47, 693.
[4] Zhang, W.; Williams, J. P.; Lu, Y.; Nagashima, T.; Chu, Q.
Tetrahedron Lett 2007, 48, 563.
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Maran, U.; Strandberg, M.; Tamm, T. Mutat Res 1991, 247, 97.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet