Synthesis and structure elucidation of new regioisomeric 2-alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones

Article abstract of DOI:10.1002/jhet.1778

Novel 2-Alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)- ones 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o were prepared regioselectively by the reaction of 2-alkylamino-5,6-diaminopyrimidin-4(3H)-ones 3a, 3b, 3c and dimethyl

Full text of DOI:10.1002/jhet.1778

Month 2013 Synthesis and Structure Elucidation of New Regioisomeric 2-Alkylamino-
6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones
a
b
a
a
c
c
*
*
Braulio Insuasty, Fabián Orozco, Jairo Quiroga, Rodrigo Abonía, Manuel Nogueras, and Justo Cobo
aHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A., 25360 Cali,
Colombia
bDepartment of Chemistry, Universidad Nacional de Colombia, AA 14490 Bogotá, DC, Colombia
cDepartment of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
*
E-mail: braulio.insuasty@correounivalle.edu.co or mmontiel@ujaen.es
Received January 24, 2012
DOI 10.1002/jhet.1778
Published online in Wiley Online Library (wileyonlinelibrary.com).
Novel 2-Alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones 5a–o were prepared
regioselectively by the reaction of 2-alkylamino-5,6-diaminopyrimidin-4(3H)-ones 3a–c and dimethylamino
propiophenones (Mannich bases) 4a–f. The combination of conventional heating and microwave irradiation
approaches provided the possibility of working with both stable and sensitive diaminopyrimidines by
controlling parameters such as reaction rates, temperature, and power of irradiation. All products were fully
characterized by detailed NMR measurements.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
There has been a growing interest in fused 1,4-diazepine
systems due mainly to their biological activity that
has been emphasized largely in several reports [1–4].
Pyrimido[4,5-b][1,4]diazepines are a remarkable example
of such fused diazepine systems mentioned because
they contain the biologically interesting moieties of both
a pyrimidine ring and a diazepine core. This fused
system has exhibited important and varied bioactivities
[3,4] and has been efficiently synthesized by different
methods [5–7]. Some of these compounds also proved
to be particularly active against different cancer types, as
described in some of our previous papers [8–10].
Another important feature consists in the combination
of conventional heating and the microwave irradiation
approach that has become a versatile synthetic tool in
the efficient preparation of a wide range of organic
compounds, simplifying the synthetic processes and pro-
viding the possibility of working under milder reaction
conditions with higher rates, giving rise to cleaner
products [11–17].
The synthetic procedure started with the preparation of
the 2-alkylamino-6-amino-5-nitrosopyrimidin-4(3H)-ones
2a–c, by the addition of acetic acid to an aqueous solution
of aminopyrimidines 1a,b and sodium nitrite (Scheme 1).
The obtained nitrosoderivatives were treated with the
corresponding amine through an aromatic nucleophilic
substitution to yield the functionalized nitrosoderivatives
2a–c. The reaction was controlled by mean of the evident
color change (bluish tones to purple), and also by the
release of methanethiol gas (Scheme 1). Compound 2b
has been reported previously by a slightly different method
performed by Melguizo and coworkers [18], involving the
substitution of –OMe instead of –SMe group but with a
lower yield (92% vs 86%).
The synthesis of the o-diaminopyrimidines was
carried out by the catalytic reduction of the nitrosoderiva-
tives 2a–c, using reported method involving methanol
as solvent, hydrazine hydrate, and Pd/C as catalyst [19].
The reaction proceeded quantitatively, but since the
products resulted very sensitive to oxidation, they were
isolated (but not characterized) and reacted directly
with the corresponding 3-dimethylaminopropiophenones,
via cyclocondensation reaction. Considering this, the
first series of pyrimidodiazepines 5a–f and 5m–o were
prepared by refluxing an ethanolic equimolar mixture of
In the present paper, we report the regioselective synthesis
and characterization of new 2-alkylamino-6-aryl-8,9-
dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones 5a–o.
All compounds were obtained by the combination of
conventional heating and microwave irradiation technology.
© 2013 HeteroCorporation

B. Insuasty, F. Orozco, J. Quiroga, R. Abonía, M. Nogueras, and J. Cobo
Vol 000
Scheme 1. Synthesis of 2-alkylamino-6-amino-5-nitrosopyrimidin-4(3H)-
ones 2a–c.
Scheme 2. Synthesis of 2-alkylamino-6-aryl-8,9-dihydropyrimido[4,5-b]
[1,4] diazepin-4(7H)-ones 5a–o.
5,6-diaminopyrimidin-4-ones 3b,c and the corresponding
Mannich bases 4a–f, in 1.5–20 h with yields of 45–73%
(Scheme 2 and Table 1).
When the same procedure was applied to 2-benzylamino-
5,6-diaminopyrimidin-4-one 3a with Mannich bases 4a–f, a
major degree of decomposition of the o-diaminopyrimidine
was observed even under controlled conditions (inert
atmosphere, absence of light, lower temperature, and
different solvents). Because we found major decomposition
with higher reaction times, the reaction mixture in ethanol
was subjected to microwave irradiation (100 W and 80 ꢀC)
under stirring, absence of light and inert atmosphere,
observing the formation of the expected pyrimidodiazepine
derivatives 5g–l in shorter reaction times (2–6.5 min) with
good yields (62–86%) (Scheme 2, Table 1).
The existence of non-equivalent amino groups at the
ortho-position of some studied analogs o-diaminopyrimidines
3 has been reported previously [20–23], where the amino on
C-5 exhibits a higher nucleophilicity. According to this, the
formation of regioisomers during the cyclocondensation
was a possibility, and it has been observed before in one of
our previous studies involving different types of o-diamines
and 1,3-dielectrophilic adducts (Mannich bases), as well as
in analog works reported in the literature where the use of
symmetric o-arylenediamines has been considered in order
to avoid mixtures of regioisomeric cyclocondensation
products [24,25]. Such mentioned studies explain the lack
of regioselectivity in terms of the competition between
nucleophilic addition of such amino group to the C═O
and the Michael addition of the same nucleophile to the
b-carbon, considering the Mannich base as a masked a,
b-unsaturated carbonyl functionality. In contrast, we found
that nucleophilic addition products were preferred to the
Michael addition ones, because the formation of such
regioisomers was not observed even under the reaction
conditions used in both methods (conventional heating
and MW induced approaches).
IR spectra for nitrosoderivatives 2a–c show typical bands
between 3410 and 3164cmꢁ1 (NH and NH2 groups) and
1686–1498 cmꢁ1 (N═O, C═N, and C═O groups). On the
other hand, IR spectra for pyrimido[4,5-b][1,4]diazepines
5a–o exhibited bands between 3407 and 3233cmꢁ1
(heterocyclic NH group) and 1640–1523 cmꢁ1 (C═O, C═N
and C═C groups). Nitro derivatives (5a, 5g, and 5m) show
characteristic bands at 1336–1338 and 1523–1530 cmꢁ1
because of NO2 asymmetric and symmetric stretching
vibrations, respectively.
Structure elucidation of compounds 2a–c and 5a–o was
based on the spectral data (1H NMR, 13C NMR, and mass
spectrometry) summarized in the experimental section.
Additionally, nitrosoderivative 2c (and other analogs) was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Structure Elucidation of New Regioisomeric 2-Alkylamino-6-aryl-8,9-
dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones
Table 1
Yields and reaction times for the preparation of pyrimidodiazepines 5a-o.
5
R1
R2
R3
Yield (%)
Time
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Me
Me
Me
Me
Me
Me
H
H
H
H
H
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
–NHCH2C6H5
Morpholin-1-yl
Morpholin-1-yl
Morpholin-1-yl
NO2
Cl
Br
58
68
73
70
69
45
56
86
79
65
62
58
64
59
55
1.5 h
2 h
2 h
2.5 h
4.5 h
H
Me
OMe
NO2
Cl
Br
H
Me
OMe
NO2
Cl
5 h
2 mina
2 mina
3.5 mina
4 mina
5.5 mina
6.5 mina
2 h
H
Me
Me
Me
20 h
16 h
Br
aMicrowave-assisted reaction times
previously analyzed by X-ray diffraction, and the results
of the study have been reported by our research group
[26,27]. Because of the major complexity of the target
diazepinic derivatives, we will proceed with a short
aryl-8,9-dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones
5a–o. Interestingly, the microwave-assisted synthetic approach
resulted convenient in the case of o-diaminopyrimidines
sensitive to oxidation or thermal decomposition by shorten-
ing dramatically the reaction times in comparison with
conventional heating methodology. It is important to state
that both methods lead to the regioselective formation of
the desired products in similar yields, because the other
possible regioisomer was not observed in any case.
1
description of the H NMR spectra for all compounds,
focused on the diazepine ring. The methylenic protons on
C-7 appear as two doubled-doublets or a doublet and a
triplet (when poorly resolved) at 1.45–1.32 ppm and
3.93–3.10 ppm (2Jgem = 12.2–11.2 Hz), exhibiting a vicinal
coupling (3J = 7.9–6.0 Hz) with methylenic protons on
C-8 also as two doubled-doublets at 3.09 ppm and
3.54 ppm (2Jgem = 13.9–13.2 Hz). The diazepine NH proton
is usually observed as a triplet for all compounds at
d = 7.66–7.04 ppm because of coupling with protons
H-8 (3JH-NH = 7.4–7.0 Hz).
EXPERIMENTAL
Melting points were determined in a Buchi Melting Point
Apparatus (Buchi, Flawil, Switzerland) and are uncorrected. The
1H and 13C NMR spectra were run on a Bruker DPX 400 spectro-
meter (Bruker, Billerica, MA) operating at 400 and 100 MHz,
respectively, using dimethyl sulfoxide-d6 as solvent and tetra-
methylsilane as internal standard. Mass spectra were obtained on a
Hewlett Packard HP Engine-5989 spectrometer (equipped with a
direct inlet probe) operating at 70 eV (Hewlett Packard, Palo Alto,
CA). Elemental analyses have been obtained using a LECO
CHNS-900 elemental analyzer (LECO, St. Joseph, Michigan,
USA). Reactions under microwave irradiation were performed using
the CEM Discover LabMateW monomode system (CEM, Matthews,
North Carolina, USA) equipped with the IntelliVent™ Pressure
Control Device (IntelliVent Team, Ashland City, TN), in open
vessels under magnetic stirring and with maximum power of 300 W.
General procedure for synthesis of 2-alkylamino-6-amino-
Finally, 13C NMR, DEPT-135 and two dimensional
heteronuclear NMR spectra provided the final structural
elucidation of derivatives 2a–c and 5a–o. Mass spectra of
all compounds exhibit well defined molecular ions of
medium intensity, whereas the base pick use to correspond
to tropylium cation (M+, 91) due to the loss of benzyl radical
(in the particular case of derivatives including benzylamine
substituent). Other particular fragmentation patterns involve
the loss of CO (M+ꢂꢁ28), methyl, ethylene, and Ar–C ꢃ N.
The latter fragmentation occurs by scission on C–C bond in
b position to diazepine NH (type-B homolytic process)
followed by a C–N cleavage (type-A5 heterolytic process),
which generates a constant and stable radical with high
relative intensity [28].
5-nitrosopyrimidin-4(3H)-ones (2a–c).
The synthesis was
carried out by dissolving under reflux and stirring the
corresponding 6-aminopyrimidone 1a,b (100 mmol) in 800 mL
of distilled water. While the mixture still hot, a solution of 6.2 g
of NaNO2 (90 mmol) in 7 mL of water was added, and the
mixture was homogenized with the addition dropwise and under
stirring of glacial acetic acid (22.5 mL) to the formation of a
deep blue solid that was then filtered and washed with fractions
of water and ethanol (90% and 75% for nitrosoderivatives
CONCLUSION
In conclusion, we have achieved two efficient and
practical methods for the synthesis of new 2-alkylamino-6-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Insuasty, F. Orozco, J. Quiroga, R. Abonía, M. Nogueras, and J. Cobo
Vol 000
R1 = H and Me, respectively). The obtained nitrosoderivatives
(26.8 mmol) were then reacted with the corresponding alkylamine
(100mmol) in 80mL of methanol under stirring and at room
temperature, until the observation of a strong color change from
blue to violet and the liberation of methanethiol. The resulting
solid products were collected by filtration and washed with cold
ethanol (2a–c, 57–98%). Nitrosoderivative 2c was recrystallized
from dimethylformamide–water (3:1v/v) to give red–violet
crystals suitable for single-crystal X-ray diffraction [26,27]. For
derivative 2b, see also an alternative procedure described
previously by Melguizo and coworkers [18].
Method A.
A solution of ortho-diamines 3b,c (2.0 mmol)
and the proper 3-dimethylaminopropiophenone 4a–f (2.0 mmol) in
absolute ethanol (40mL) was heated under reflux during 1.5–20h
according to TLC control. The reaction proceeded with formation
of precipitate that was then filtered and washed with ethanol
yielding compounds 5a–f (45–73%). Diazepines 5m–o were
obtained and purified by liquid chromatography using
dichloromethane: acetone (98:2 and 96:4) as mobile phase (55–
64%).
Method B. A mixture of the ortho-diamine 3a (1.0 mmol)
and the corresponding 3-dimethylaminopropiophenone 4a–f
(1.0mmol) in absolute ethanol (10 mL) was subjected to
microwave irradiation at 100 W and 80ꢀC with stirring in sealed
tube, absence of light and under argon atmosphere. Under such
conditions, the reaction proceeded in short times (2–6.5 min),
giving rise to pyrimidodiazepine derivatives 5g–l as amorphous
solids that were filtered and washed with fractions of ethanol and
ethyl ether (62–86%).
6-Amino-2-(benzylamino)-5-nitrosopyrimidin-4(3H)-one (2a). This
compound was obtained as violet solid (98%); mp 238 ꢀC (d); FTIR
(KBr): 3410, 3253 (N–H); 2968, 2848 (C–H); 1649–1450 (N═O,
1
C═N, C═O) cmꢁ1; H NMR (DMSO-d6, 400 MHz): d 4.61 (d,
2H, CH2, J = 5.3Hz), 7.22 (t, 1H, H-p, J = 7.3Hz), 7.31 (t, 2H, H-
m, J = 7.3Hz), 7.38 (d, 2H, H-o, J = 7.3 Hz), 7.77 (t, 1H, NH,
J = 5.5Hz), 8.01 (s, 1H, NH2), 10.89 (s, 1H, NH2) ppm; 13C NMR
(DMSO-d6, 100MHz): d 44.6, 127.1, 127.8, 128.6, 139.7, 142.0,
153.0, 156.6, 161.7 ppm; Mass (m/z, %): 245 (Mꢂ+, 100), 243
(12), 168 (70), 154 (47), 139 (19), 106 (13), 93 (22), 42 (92).
Anal. Calcd for C11H11N5O2: C, 53.87; H, 4.52; N, 28.56. Found:
C, 54.01; H, 4.61; N, 28.52.
2-(Benzylamino)-8,9-dihydro-3-methyl-6-(4-nitrophenyl)-3H-
pyrimido[4,5-b][1,4]diazepin-4(7H)-one (5a). This compound
was obtained as red solid (58%); mp 230 ꢀC (d); FTIR (KBr):
3258 (N–H); 2925 (C–H); 1637 (C═O), 1527 (C═N, C═C),
1523, 1338 (NO2) cmꢁ1; H NMR (DMSO-d6, 400MHz): d 1.43
1
6-Amino-2-(benzylamino)-3-methyl-5-nitrosopyrimidin-4(3H)-
one (2b). This compound was obtained as pink solid (92%); mp
261 ꢀC (d); FTIR (KBr): 3396, 3273 (N–H); 2967, 2862 (C–H);
(t, 1H, H-7, J = 7.4 Hz), 3.15 (d, 1H, H-8, J = 13.6 Hz), 3.28
(s, 3H, N-Me), 3.52 (m, 1H, H-8), 3.90 (m, 1H, H-7), 4.61
(s, 2H, CH2), 7.23 (t, 2H, H-p (B), NH-9, J = 7.3 Hz), 7.32
(t, 2H, H-m (B), J = 7.3Hz), 7.37 (d, 2H, H-o (B), J = 7.3Hz),
7.78 (t, 1H, NH, J = 5.5 Hz), 8.06 (d, 2H, H-o (A), J = 8.5Hz),
8.15 (d, 2H, H-m (A), J = 8.5 Hz)ppm; 13C NMR (DMSO-d6,
100 MHz): d 25.2 (C-7), 27.0 (N-Me), 39.9 (C-8), 44.6 (CH2),
102.0 (C-4a), 123.0 (C-o, A), 126.2 (C-p, B), 126.7 (C-o, B),
126.8 (C-m, A), 127.6 (C-m, B), 144.7, 146.1, 147.0, 148.2,
153.1, 156.8, 161.0ppm; Mass (m/z, %): 404 (M+, 11), 387 (12),
368 (11), 338 (28), 321 (19), 255 (31), 191 (98), 177 (14), 91
(100). Anal. Calcd for C21H20N6O3: C, 62.37; H, 4.98; N, 20.78.
Found: C, 62.21; H, 4.85; N, 20.69.
1601–1498 (N═O, C═N, C═O) cmꢁ1 1H NMR (DMSO-d6,
;
400 MHz): d 3.31, (s, 3H, CH3), 4.56 (d, 2H, CH2, J =5.2Hz),
7.21 (t, 1H, H-p, J= 7.3 Hz), 7.31 (t, 2H, H-m, J = 7.3 Hz), 7.40 (d,
2H, H-o, J = 7.3 Hz), 7.58 (t, 1H, NH, J = 5.2 Hz), 8.06 (s, 1H,
NH2), 10.85 (s, 1H, NH2) ppm; 13C NMR (DMSO-d6, 100 MHz):
d 27.1, 44.4, 127.1, 127.8, 129.0, 140.1, 142.1, 152.8, 157.0,
161.3 ppm; Mass (m/z, %): 259 (M+, 89), 244 (18), 229 (7), 182
(100), 168 (32), 153 (12), 42 (90). Anal. Calcd for C12H13N5O2:
C, 55.59; H, 5.05; N, 27.01. Found: C, 55.48; H, 4.98; N, 26.87.
6-Amino-3-methyl-2-morpholino-5-nitrosopyrimidin-4(3H)-one
(2c). This compound was obtained as purple solid (57%); mp 235–
236 ꢀC (d); FTIR (KBr): 3396, 3318 (N–H); 3173–2721 (C–H);
2-(Benzylamino)-6-(4-chlorophenyl)-8,9-dihydro-3-methyl-3H-
pyrimido[4,5-b][1,4]diazepin-4(7H)-one (5b).
This compound
1646–1590 (N═O, C═N, C═O) cmꢁ1
;
1H NMR (DMSO-d6,
was obtained as beige solid (68%); mp 242ꢀC (d); FTIR (KBr):
400 MHz): d 3.35 (s, 3H, CH3), 3.50 (t, 4H, H-30 y H-50,
morpholino, J = 4.3 Hz), 3.68 (t, 4H, H-20 y H-60, morpholino,
J = 4.3 Hz), 8.50 (s, 1H, NH2), 10.84 (s, 1H, NH2) ppm; 13C
NMR (DMSO-d6, 100 MHz): d 34.5, 48.5, 65.7, 142.8, 148.0,
151.7, 161.7 ppm; Mass (m/z, %): 239 (M+, 97), 224 (3), 154
(8), 125 (21), 86 (24), 69 (84), 42 (100). Anal. Calcd for
C9H13N5O3: C, 45.18; H, 5.48; N, 29.27. Found: C, 45.13; H,
5.53; N, 29.35.
3390, 3265 (N–H); 2921 (C–H); 1640 (C═O), 1528
(C═N, C═C)cmꢁ1 1H NMR (DMSO-d6, 400 MHz): d 1.39
;
(t, 1H, H-7, J= 7.2 Hz), 3.10 (d, 1H, H-8, J= 13.9 Hz), 3.27
(s, 3H, N-Me), 3.54 (m, 1H, H-8), 3.87 (m, 1H, H-7), 4.65
(s, 2H, CH2), 7.20 (d, 2H, H-m (A), J = 8.7 Hz), 7.27 (t, 1H, H-p
(B), J = 7.2 Hz), 7.34 (t, 2H, H-m (B), J= 7.2 Hz), 7.38 (s, 1H,
NH-9), 7.42 (d, 2H, H-o (B), J = 7.4 Hz), 7.59 (s, 1H, NH), 7.96
(d, 2H, H-o (A), J = 8.7 Hz) ppm; 13C NMR (DMSO-d6,
100 MHz): d 25.3 (C-7), 27.6 (N-Me), 39.9 (C-8), 44.1 (CH2),
102.5 (C-4a), 126.8 (C-p, B), 127.2 (C-o, B), 127.7 (C-m, A),
127.9 (C-o, A), 128.3 (C-m, B), 132.3, 139.2, 139.6, 150.7, 152.3,
155.2, 161.2 ppm; Mass (m/z, %): 393 (M+, 20), 365 (2), 302 (2),
256 (5), 189 (5), 149 (5), 106 (12), 91 (100). Anal. Calcd
for C21H20ClN5O: C, 64.04; H, 5.12; N, 17.78. Found: C, 64.11;
H, 5.06; N, 17.73.
General procedure for the reduction of nitrosoderivatives 2a–c
and synthesis of new 2-alkylamino-6-aryl-8,9-dihydropyrimido
[4,5-b][1,4]diazepin-4-ones (5a–o).
The synthesis of
intermediate ortho-diamines 3a–c was carried out by catalytic
reduction of a methanolic suspension (80 mL of MeOH) of
nitrosopyrimidin-4-ones 2a–c (1 eq, 20.4 mmol), using an
excess (5 eq, 100 mmol) of hydrazine monohydrate as reducing
agent and Pd/C 10% (0.6 g) as catalyst. Reduction proceeded
quantitatively in every case, by heating the reaction mixture
under reflux during 30 min. When the reaction was completed,
the mixture was filtered to eliminate the suspension of catalyst,
and the resulting solution was evaporated under reduced
pressure below 34 ꢀC, obtaining a dry residue of ortho-
diamines 3a–c, available to perform in situ the subsequent
cyclocondensation reaction.
2-(Benzylamino)-6-(4-bromophenyl)-8,9-dihydro-3-methyl-3H-
pyrimido[4,5-b][1,4]diazepin-4(7H)-one (5c).
This compound
was obtained as yellow solid (73%); mp 218 ꢀC (d); FTIR (KBr):
3390, 3266 (N–H); 2921 (C–H); 1640 (C═O), 1528 (C═N,
1
C═C)cmꢁ1; H NMR (DMSO-d6, 400 MHz): d 1.39 (t, 1H, H-7,
J = 7.9 Hz), 3.10 (d, 1H, H-8, J= 13.2 Hz), 3.28 (s, 3H, N-Me),
3.54 (m, 1H, H-8), 3.86 (m, 1H, H-7), 4.65 (dd, 2H, CH2,
3J =5.8Hz, 2J = 9.3 Hz), 7.28 (t, 1H, H-p (B), J = 7.2 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Structure Elucidation of New Regioisomeric 2-Alkylamino-6-aryl-8,9-
dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones
7.34-7.44 (m, 7H, H-m (A), H-m (B), NH-9, H-o (B)), 7.59
(t, 1H, NH, J= 5.8 Hz), 7.90 (d, 2H, H-o (A), J = 8.9 Hz) ppm;
13C NMR (DMSO-d6, 100MHz): d 18.5 (C-7), 27.6 (N-Me), 39.9
(C-8), 44.1 (CH2), 102.5 (C-4a), 121.0, 126.9 (C-p, B), 127.3
(C-o, B), 128.2 (C-m, A), 128.3 (C-m, B), 130.6 (C-o, A), 139.5,
139.6, 150.6, 152.3, 155.2, 161.2 ppm; Mass (m/z, %): 437
(M+, 13), 411 (2), 346 (2), 282 (2), 256 (5), 189 (4), 149 (5), 106
(14), 91 (100). Anal. Calcd for C21H20BrN5O: C, 57.54; H, 4.60;
N, 15.98. Found: C, 57.48; H, 4.67; N, 16.07.
(4), 267 (3), 256 (8), 241 (8), 189 (4), 106 (8), 91 (100). Anal.
Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C,
68.00; H, 6.04; N, 17.87.
2-(Benzylamino)-8,9-dihydro-6-(4-nitrophenyl)-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5g).
This compound was
obtained as orange solid (56%); mp 244 ꢀC (d); FTIR (KBr):
3386, 3268 (N–H); 2928 (C–H); 1637 (C═O), 1528 (C═N,
C═C), 1530, 1336 (NO2) cmꢁ1
;
1H NMR (DMSO-d6,
400 MHz): d 1.44 (t, 1H, H-7, J = 7.4 Hz), 3.15 (d, 1H, H-8,
J = 13.8 Hz), 3.50 (m, 1H, H-8), 3.86 (m, 1H, H-7), 4.58 (t, 2H,
CH2, J = 5.6 Hz), 7.25 (t, 2H, H-p (B), NH-9, J = 7.1 Hz), 7.34
(t, 2H, H-m (B), J = 7.0 Hz), 7.38 (d, 2H, H-o (B), J = 7.1 Hz),
7.80 (t, 1H, NH, J = 5.5 Hz), 7.96 (d, 2H, H-o (A), J = 8.3 Hz),
8.18 (d, 2H, H-m (A), J = 8.3 Hz), 10.62 (s, 1H, NH-3) ppm;
13C NMR (DMSO-d6, 100 MHz): d 25.2 (C-7), 40.1 (C-8), 44.4
(CH2), 102.2 (C-4a), 122.8 (C-o, A), 126.0 (C-p, B), 126.7
(C-o, B), 127.0 (C-m, A), 127.5 (C-m, B), 144.4, 146.1, 147.1,
147.9, 153.3, 156.6, 161.4 ppm; Mass (m/z, %): 390 (Mꢂ+, 18),
376 (10), 362 (6), 299 (17), 268 (25), 242 (42), 106 (8), 91
(100). Anal. Calcd for C20H18N6O3: C, 61.53; H, 4.65; N,
21.53. Found: C, 61.58; H, 4.57; N, 21.65.
2-(Benzylamino)-8,9-dihydro-3-methyl-6-phenyl-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5d).
This compound was
obtained as beige solid (70%); mp 227 ꢀC (d); FTIR (KBr): 3407,
3260 (N–H); 2939 (C–H); 1637 (C═O), 1528 (C═N,
1
C═C)cmꢁ1; H NMR (DMSO-d6, 400MHz): 1.44 (t, 1H, H-7,
J = 7.9Hz), 3.10 (d, 1H, H-8, J = 13.2Hz), 3.29 (s, 3H, N-Me),
3.53 (m, 1H, H-8), 3.93 (m, 1H, H-7), 4.69 (d, 2H, CH2,
J = 8.3Hz), 7.07–7.42 (m, 9H, H-m (A), H-p (A), H-o (B), H-m
(B), H-p (B), NH-9), 7.56 (s, 1H, NH), 7.93 (d, 2H, H-o (A),
J = 7.2Hz) ppm; 13C NMR (DMSO-d6, 100 MHz): d 25.2 (C-7),
27.6 (N-Me), 40.0 (C-8), 43.9 (CH2), 102.5 (C-4a), 126.2, 126.7,
127.0, 127.5, 127.7, 128.2, 139.7, 140.4, 150.5, 153.9, 155.0,
161.2ppm; Mass (m/z, %): 359 (Mꢂ+, 40), 343 (4), 331 (3), 282
(3), 268 (5), 256 (5), 189 (5), 106 (11), 91 (100). Anal. Calcd for
C21H21N5O: C, 70.17; H, 5.89; N, 19.48. Found: C, 70.22; H,
5.81; N, 19.52.
2-(Benzylamino)-6-(4-chlorophenyl)-8,9-dihydro-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5h).
This compound was
obtained as white solid (86%); mp 212 ꢀC; FTIR (KBr): 3398,
3259 (N–H); 2926 (C–H); 1639 (C═O), 1532 (C═N,
C═C)cmꢁ1; 1H NMR (DMSO-d6, 400MHz): d 1.33 (t, 1H, H-7,
J = 7.9 Hz), 3.03 (d, 1H, H-8, J = 13.9 Hz), 3.48 (m, 1H, H-8),
3.81 (t, 1H, H-7, J = 11.2Hz), 4.59 (s, 2H, CH2), 7.13 (d, 2H,
H-m (A), J = 8.7 Hz), 7.20-7.36 (m, 6H, H-o (B), H-m (B), H-p
(B), NH-9), 7.53 (s, 1H, NH), 7.89 (d, 2H, H-o (A), J = 8.5 Hz),
7.93 (s, 1H, NH-3)ppm; 13C NMR (DMSO-d6, 100MHz): d 25.0
(C-7), 39.6 (C-8), 43.8 (CH2), 102.2 (C-4a), 126.5 (C-p, B), 126.9
(C-o, B), 127.3 (C-m, A), 127.6 (C-o, A), 128.0 (C-m, B), 131.9,
138.9, 139.2, 150.3, 151.9, 154.9, 160.9 ppm; Mass (m/z, %): 379
(M+, 40), 351 (5), 323 (8), 268 (4), 242 (8), 177 (6), 106 (10), 91
(100). Anal. Calcd for C20H18ClN5O: C, 63.24; H, 4.78; N, 18.44.
Found: C, 63.18; H, 4.81; N, 18.53.
2-(Benzylamino)-8,9-dihydro-3-methyl-6-p-tolyl-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5e).
This compound was
obtained as white solid (69%); mp 233 ꢀC (d); FTIR (KBr): 3407,
3256 (N–H); 2939 (C–H); 1638 (C═O), 1527 (C═N, C═C)
cmꢁ1 1H NMR (DMSO-d6, 400 MHz): d 1.44 (t, 1H, H-7,
;
J = 7.9Hz), 2.22 (p-Me), 3.09 (d, 1H, H-8, J = 13.6 Hz), 3.27
3
2
(s, 3H, N-Me), 3.54 (dd, 1H, H-8, J = 4.8Hz, J =13.6Hz), 3.92
(dd, 1H, H-7, 3J =7.2 Hz, 2J = 12.2Hz), 4.68 (t, 2H, CH2,
J = 5.2Hz), 6.97 (d, 2H, H-m (A), J = 8.3Hz), 7.27 (t, 2H, H-p
(B), NH-9, J = 7.4Hz), 7.34 (t, 2H, H-m (B), J =7.2 Hz), 7.43
(d, 2H, H-o (B), J = 7.2Hz), 7.49 (t, 1H, NH, J = 5.2 Hz), 7.85
(d, 2H, H-o (A), J = 8.3Hz) ppm; 13C NMR (DMSO-d6,
100 MHz): d 20.7 (p-Me), 25.3 (C-7), 27.6 (N-Me), 40.1 (C-8),
44.0 (CH2), 102.5 (C-4a), 126.3 (C-o, A), 126.7 (C-p, B), 127.2
(C-o, B), 128.2 (C-m, B), 128.3 (C-m, A), 136.8 (C-i, A), 137.9
(C-p, A), 139.7 (C-i, B), 150.4 (C-2), 154.2 (C-6), 154.8 (C-9a),
161.2 (C-4) ppm; Mass (m/z, %): 373 (Mꢂ+, 27), 357 (4), 345 (6),
282 (4), 267 (3), 256 (5), 189 (3), 106 (12), 91 (100). Anal. Calcd
for C22H23N5O: C, 70.76; H, 6.21; N, 18.75. Found: C, 70.68;
H, 6.39; N, 18.61.
2-(Benzylamino)-6-(4-bromophenyl)-8,9-dihydro-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5i).
This compound was
obtained as yellow solid (79%); mp 226ꢀC (d); FTIR (KBr):
3405, 3263 (N–H); 2930 (C–H); 1638 (C═O), 1529 (C═N,
C═C)cmꢁ1; 1H NMR (DMSO-d6, 400MHz): d 1.32 (t, 1H, H-7,
J = 7.9 Hz), 3.04 (d, 1H, H-8, J = 13.6 Hz), 3.47 (m, 1H, H-8),
3
2
3.80 (m, 1 H, H-7), 4.57 (dd, 2H, CH2, J = 5.8 Hz, J = 9.3Hz),
7.20–7.37 (m, 8H, H-m (A), H-o (B), H-m (B), H-p (B), NH-9),
7.53 (t, 1H, NH, J = 5.8 Hz), 7.69 (s, 1H, NH-3), 7.83 (d, 2H, H-o
(A), J = 8.7Hz)ppm; 13C NMR (DMSO-d6, 100MHz): d 25.1
(C-7), 39.7 (C-8), 43.8 (CH2), 102.2 (C-4a), 120.7, 126.6, 127.0,
128.0, 130.3, 131.9, 139.2, 150.4, 152.0 (C-6 and C-9a), 154.9,
160.9 ppm; Mass (m/z, %): 423 (M+, 20), 395 (8), 344 (4), 268
(4), 242 (11), 177 (8), 106 (10), 91 (100). Anal. Calcd for
C20H18BrN5O: C, 56.62; H, 4.28; N, 16.51. Found: C, 56.71; H,
4.22; N, 16.59.
2-(Benzylamino)-8,9-dihydro-6-(4-methoxyphenyl)-3-methyl-
3H-pyrimido[4,5-b][1,4]diazepin-4(7H)-one
(5f).
This
compound was obtained as yellow solid (45%); mp 211 ꢀC (d);
FTIR (KBr): 3395, 3262 (N–H); 2936 (C–H); 1639 (C═O),
1528 (C═N, C═C) cmꢁ1 1H NMR (DMSO-d6, 400 MHz):
;
d 1.45 (t, 1H, H-7, J = 7.2 Hz), 3.10 (d, 1H, H-8, J = 13.2 Hz),
3.26 (s, 3H, N-Me), 3.52 (m, 1H, H-8), 3.71 (p-OMe), 3.91
(m, 1H, H-7), 4.56 (dd, 1H, CH2, 3J = 5.8 Hz, 2J = 15.1 Hz),
3
2
4.76 (dd, 1H, CH2, J = 5.8 Hz, J = 15.1 Hz), 6.78 (d, 2H, H-m
(A), J = 8.9 Hz), 7.25 (t, 2H, H-p (B), NH-9, J = 7.0 Hz), 7.33
(t, 2H, H-m (B), J = 7.4 Hz), 7.42 (d, 2H, H-o (B), J = 7.2 Hz),
7.50 (t, 1H, NH, J = 5.6 Hz), 7.91 (d, 2H, H-o (A), J = 8.9 Hz)
ppm; 13C NMR (DMSO-d6, 100 MHz): d 25.1 (C-7), 27.6
(N-Me), 40.3 (C-8), 44.1 (CH2), 55.0 (p-OMe), 102.5 (C-4a),
113.0 (C-p, A), 126.7 (C-o, A), 127.3 (C-o, B), 127.8 (C-m, A),
128.2 (C-m, B), 133.5, 139.7, 150.3, 154.3, 154.5, 159.1,
161.2 ppm; Mass (m/z, %): 389 (Mꢂ+, 38), 373 (7), 361 (4), 282
2-(Benzylamino)-8,9-dihydro-6-phenyl-3H-pyrimido[4,5-b][1,4]
diazepin-4(7H)-one (5j). This compound was obtained as beige
solid (65%); mp 263 ꢀC (d); FTIR (KBr): 3403, 3256 (N–H); 2939
(C–H); 1640 (C═O), 1528 (C═N, C═C) cmꢁ1; 1H NMR (DMSO-
d6, 400 MHz): d 1.44 (t, 1H, H-7, J= 7.9 Hz), 3.06 (d, 1H, H-8,
J= 13.8 Hz), 3.55 (m, 1H, H-8), 3.93 (m, 1H, H-7), 4.66
(s, 2H, CH2), 7.04-7.39 (m, 9H, H-m (A), H-p (A), H-o (B), H-m
(B), H-p (B), NH-9), 7.50 (t, 1H, NH, J= 5.9 Hz), 7.93 (d, 2H, H-o
(A), J= 7.2 Hz), 10.80 (s, 1H, NH-3) ppm; 13C NMR (DMSO-d6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Insuasty, F. Orozco, J. Quiroga, R. Abonía, M. Nogueras, and J. Cobo
Vol 000
100 MHz): d 25.0 (C-7), 39.7 (C-8), 44.1 (CH2), 102.5 (C-4a), 123.9,
126.6, 127.0, 127.3, 128.0, 128.2, 139.4, 140.2, 150.4, 152.8, 155.0,
161.6 ppm; Mass (m/z, %): 345 (M+, 21), 331 (6), 317 (12), 268 (8),
254 (10), 242 (4), 239 (13), 162 (5), 106 (12), 91 (100). Anal. Calcd
for C20H19N5O: C, 69.55; H, 5.54; N, 20.28. Found: C, 69.62; H,
5.47; N, 20.20.
N-Me), 7.74 (d, 2H, H-m, J =8.5 Hz), 7.75 (d, 2H, H-o,
J = 8.5 Hz) ppm; 13C NMR (DMSO-d6, 100 MHz): d 20.6 (N-Me),
25.5 (C-7), 33.2 (C-8), 53.4 (C-30 y C-50), 54.7 (C-20 y C-60),
102.5, 127.4, 127.9, 128.8, 129.0, 130.4, 135.2, 135.3, 148.1,
153.1, 161.3ppm; Mass (m/z, %): 373 (Mꢂ+, 11), 359 (4), 345
(11), 262 (35), 236 (12), 138 (100), 86 (62). Anal. Calcd for
C18H20ClN5O2: C, 57.83; H, 5.39; N, 18.73. Found: C, 57.78; H,
5.43; N, 18.80.
2-(Benzylamino)-8,9-dihydro-6-p-tolyl-3H-pyrimido[4,5-b][1,4]
diazepin-4(7H)-one (5k). This compound was obtained as beige
solid (62%); mp 224 ꢀC (d); FTIR (KBr): 3400, 3262 (N–H); 2940
6-(4-Bromophenyl)-8,9-dihydro-3-methyl-2-morpholino-3H-
pyrimido[4,5-b][1,4]diazepin-4(7H)-one (5o). This compound
was obtained as beige solid (55%); mp 208 ꢀC (d); FTIR (KBr):
3395, 3260 (N–H); 2960–2728 (C–H); 1640 (C═O), 1528
(C–H); 1640 (C═O), 1523 (C═N, C═C)cmꢁ1
;
1H NMR
(DMSO-d6, 400 MHz): d 1.44 (t, 1H, H-7, J= 7.9 Hz), 2.24 (p-
Me), 3.06 (d, 1H, H-8, J = 13.8 Hz), 3.54 (m, 1H, H-8), 3.92 (m,
1H, H-7), 4.68 (s, 2H, CH2), 7.00 (d, 2H, H-m (A), J =8.5Hz),
7.26 (t, 2H, H-p (B), NH-9, J = 7.2 Hz), 7.35 (t, 2H, H-m (B),
J = 7.2Hz), 7.40 (d, 2H, H-o (B), J = 7.2Hz), 7.44 (t, 1H, NH,
J = 5.2Hz), 7.82 (d, 2H, H-o (A), J = 8.5 Hz), 8.96 (s, 1H, NH-
3)ppm; 13C NMR (DMSO-d6, 100MHz): d 20.2 (p-Me), 25.1 (C-
7), 40.4 (C-8), 44.4 (CH2), 102.5 (C-4a), 126.0, 126.6, 127.0,
127.9, 128.1, 137.0, 137.7, 139.5, 150.4, 154.4, 155.1, 161.3ppm;
Mass (m/z, %): 359 (Mꢂ+, 21), 345 (4), 331 (6), 268 (4), 253 (7),
242 (12), 106 (18), 91 (100). Anal. Calcd for C21H21N5O: C,
70.17; H, 5.89; N, 19.48. Found: C, 70.09; H, 5.81; N, 19.47.
2-(Benzylamino)-8,9-dihydro-6-(4-methoxyphenyl)-3H-pyrimido
(C═N, C═C) cmꢁ1 1H NMR (DMSO-d6, 400 MHz): d 3.02
;
(t, 4H, H-30 y H-50, morpholino, J = 4.4 Hz), 3.10 (t, 2H, H-7,
J = 6.8 Hz), 3.20-3.26 (m, 9H, H-8, H-20 y H-60, morpholino,
N-Me), 7.78 (d, 2H, H-m, J = 8.3 Hz), 7.82 (d, 2H, H-o,
J = 8.3 Hz), (signal for NH-9 was not obseved) ppm; 13C NMR
(DMSO-d6, 100 MHz): d 20.4 (N-Me), 25.5 (C-7), 33.1 (C-8),
53.2 (C-30 y C-50), 55.0 (C-20 y C-60), 102.4, 127.2, 128.0,
128.7, 129.2, 130.6, 135.0, 135.4, 148.1, 153.1, 161.4 ppm;
Mass (m/z, %): 417 (M+, 28), 403 (6), 389 (12), 338 (20), 332
(8), 262 (31), 236 (10), 183 (100), 156 (21), 86 (42). Anal.
Calcd for C18H20BrN5O2: C, 51.69; H, 4.82; N, 16.74. Found:
C, 51.76; H, 4.78; N, 16.80.
[4,5-b][1,4]diazepin-4(7H)-one (5l).
This compound was
obtained as yellow solid (58%); mp 205ꢀC (d); FTIR (KBr):
3402, 3233 (N–H); 2940 (C–H); 1633 (C═O), 1530 (C═N,
C═C) cmꢁ1; H NMR (DMSO-d6, 400 MHz): d 1.44 (t, 2H, H-
1
Acknowledgments. This work was financially supported by
7, J = 7.8 Hz), 3.08 (d, 2H, H-8, J = 13.4 Hz), 3.52 (m, 1H, H-8),
3.70 (p-OMe), 3.90 (m, 1H, H-7), 4.62 (d, 1H, CH2, J = 5.9 Hz),
6.80 (d, 2H, H-m (A), J = 8.8 Hz), 7.25 (t, 2H, H-p (B), NH-9,
J = 7.2 Hz), 7.32 (t, 2H, H-m (B), J = 7.2 Hz), 7.45 (d, 2H, H-o
(B), J = 7.3 Hz), 7.47 (t, 1H, NH, J = 5.8 Hz), 7.89 (d, 2H, H-o
(A), J = 8.8 Hz) ppm; 13C NMR (DMSO-d6, 100 MHz): d 25.5
(C-7), 40.4 (C-8), 44.0 (CH2), 55.1 (p-OMe), 102.2 (C-4a),
112.9 (C-p, A), 126.6 (C-o, A), 127.0 (C-o, B), 127.7 (C-m, A),
128.1 (C-m, B), 133.2, 140.1, 150.2, 154.2, 154.7, 160.0,
161.5 ppm; Mass (m/z, %): 375 (M+, 16), 361 (11), 347 (18),
344 (8), 284 (4), 268 (6), 253 (4), 242 (9), 106 (12), 91 (100).
Anal. Calcd for C21H21N5O2: C, 67.18; H, 5.64; N, 18.65.
Found: C, 67.23; H, 5.58; N, 18.60.
Colciencias, Universidad del Valle, Consejería de Innovación,
Ciencia
y Empresa (Junta de Andalucía, Spain), and
Universidad de Jaén. The authors thank "Servicios Técnicos de
Investigación of Universidad de Jaén" and the staff for data
collection. Fabián Orozco thanks Colciencias for his fellowship.
REFERENCES AND NOTES
[1] Landquist, J. K. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; p. 166.
[2] Schutz, H. Benzodiazepines; Springer: Heidelberg, 1982.
[3] Costanzo, A.; Bruni, F.; Auzzi, G.; Selleri, S.; Vettori, L. P. J
Heterocycl Chem 1990, 27, 695.
[4] Kelly, T. A.; McNeil, D. W.; Rose, J. M.; David, E.; Shih, C. K.;
Grob, P. M. J Med Chem 1997, 40, 2430 and references therein.
[5] Insuasty, B.; Ramos, M.; Moreno, R.; Quiroga, J.; Sánchez,
A.; Nogueras, M.; Hanold, N.; Meier, H. J Heterocycl Chem 1995, 32,
1229.
[6] Insuasty, B.; Perez, A.; Valencia, J.; Quiroga, J. J Heterocycl
Chem 1997, 34, 1555.
[7] Insuasty, B.; Orozco, F.; García, A.; Quiroga, J.; Abonía, R.;
Nogueras, M.; Cobo, J. J Heterocycl Chem 2008, 45, 1659.
[8] Insuasty, B.; Orozco, F.; Quiroga, J.; Abonia, R.; Nogueras,
M.; Cobo, J. Eur J Med Chem 2008, 43, 1955.
[9] Insuasty, B.; Orozco, F.; Lizarazo, C.; Quiroga, J.; Abonia, R.;
Hursthouse, M.; Nogueras, M.; Cobo, J. Bioorg Med Chem 2008, 16,
8492.
[10] Insuasty, B.; García, A.; Quiroga, J.; Abonia, R.; Nogueras,
M.; Cobo, J. Eur J Med Chem 2010, 45, 2841.
[11] Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault,
P.; Mathé, D. Synthesis 1998, 9, 1213.
[12] Varma, R. S. Green Chem 1999, 1, 43.
[13] Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A.
Tetrahedron 1999, 55, 10851.
8,9-Dihydro-3-methyl-2-morpholino-6-(4-nitrophenyl)-3H-pyrimido
[4,5-b][1,4]diazepin-4(7H)-one (5m).
This compound was
obtained as orange solid (64%); mp 198 ꢀC (d); FTIR (KBr):
3400, 3263 (N–H); 2970–2748 (C–H); 1638 (C═O), 1530 (C═N,
1
C═C)cmꢁ1; H NMR (DMSO-d6, 400MHz): d 3.08 (t, 4H, H-30
y H-50, morpholino, J = 4.4Hz), 3.21 (t, 2H, H-7, J = 6.0 Hz),
3.27–3.31 (m, 9H, H-8, H-20 y H-60, morpholino, N-Me), 7.66
(s, 1H, NH-9), 8.25 (d, 2H, H-o, J = 8.5 Hz), 8.26 (d, 2H, H-m,
J = 8.5Hz) ppm; 13C NMR (DMSO-d6, 100MHz): d 20.6 (N-Me),
25.4 (C-7), 32.9 (C-8), 52.8 (C-30 y C-50), 54.8 (C-20 y C-60),
103.7 (C-4a), 123.9, 126.8, 137.8, 129.0, 142.8, 146.4, 147.9,
148.0, 151.8, 161.4 ppm; Mass (m/z, %): 384 (Mꢂ+, 28), 368 (10),
356 (6), 298 (8), 262 (10), 236 (5), 179 (4), 149 (100), 122 (80),
86 (30). Anal. Calcd for C18H20N6O4: C, 56.24; H, 5.24; N,
21.86. Found: C, 56.23; H, 5.18; N, 21.80.
6-(4-Chlorophenyl)-8,9-dihydro-3-methyl-2-morpholino-3H-
pyrimido[4,5-b][1,4]diazepin-4(7H)-one (5n). This compound
was obtained as white solid (59%); mp 203 ꢀC (d); FTIR (KBr):
3395, 3261 (N–H); 2963–2733 (C–H); 1638 (C═O), 1527
(C═N, C═C) cmꢁ1 1H NMR (DMSO-d6, 400 MHz): d 3.00
;
(t, 4H, H-30 y H-50, morpholino, J = 4.5 Hz), 3.10 (t, 2H, H-7,
J = 6.3Hz), 3.17–3.22 (m, 9H, H-8, H-20 y H-60, morpholino,
[14] Tanaka, K.; Toda, F. Chem Rev 2000, 100, 1025.
[15] Varma, R. S. Clean Prod Processes 1999, 1, 132.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Structure Elucidation of New Regioisomeric 2-Alkylamino-6-aryl-8,9-
dihydropyrimido[4,5-b][1,4]diazepin-4(7H)-ones
[16] Varma, R. S. Pure Appl Chem 2001, 73, 193.
[17] Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Chem Rev 2009, 109, 4140.
[18] Melguizo, M.; Marchal, A.; Nogueras, M.; Sánchez, A.; Low,
J. N. J Heterocycl Chem 2002, 39, 97.
[19] Grandberg, I. I.; Klyuchko, G. V. Zh Obshch Khim 1962, 32,
1898; Chem Abstr 1963, 58, 4537f.
[20] Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.; Mohammadi, A.
A.; Mohammadizadeh, M. R. J Org Chem 2005, 70, 1471.
[21] Kidwai, M.; Mothsra, P. Synth Commun 2006, 36, 817.
[22] Yanovskaya, L. A.; Krishtal, G. V.; Kulganek, V. V. Usp
Khim 1984, 53, 1280; Chem Abstr 1984, 101, 190667x.
[23] Orlov, V. D.; Papiashvili, I. Z.; Grigorov, P. A. Khim Geterotsikl
Soedin 1983, 5, 671; Chem Abstr 1983, 99, 53717q.
[24] Insuasty, B.; Insuasty, H.; Quiroga, J.; Saitz, C.; Jullian, C. J
Heterocycl Chem 1999, 36, 635.
[25] Roman, G.; Comaniţă, E.; Comaniţă, B. Acta Chim Slov 2002,
49, 575.
[26] Orozco, F.; Insuasty, B.; Low, J. N.; Cobo, J.; Glidewell, C.
Acta Cryst 2008, C64, o220.
[27] Orozco, F.; Insuasty, B.; Cobo, J.; Glidewell, C. Acta Cryst
2009, C65, o549.
[28] Quiroga, J.; Insuasty, B.; Gallo, G. Bol Soc Chil Quím 1996,
41, 415.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet