Regiospecific synthesis of 3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones via haloform reaction with the isolation of N3-[3-oxo-4,4,4-trichloroalk- 1-en-1-yl]-2,3-diaminopyridine intermediates

Article abstract of DOI:10.1002/jhet.89

(Chemical Equation Presented) The synthesis of a novel series of analogous intermediates N³-[1-alkyl(aryl/heteroaryl)-3-oxo-4,4,4-trichloroalk- 1-en-1-yl]-2,3-diaminopyridines and N²-(methanesulfonyl) [Cl ₃CC(O)CH=CRNH(C

Full text of DOI:10.1002/jhet.89

July 2009
Regiospecific Synthesis of 3H-Pyrido[2,3-b][1,4]diazepin-4(5H)-
ones via Haloform Reaction with the Isolation of N3-[3-Oxo-
4,4,4-trichloroalk-1-en-1-yl]-2,3-diaminopyridine Intermediates
603
´
Helio G. Bonacorso,* Rogerio V. Lourega, Liliane M. F. Porte,
Everton D. Deon, Nilo Zanatta, Alex F. C. Flores, and Marcos A. P. Martins
´
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica,
Universidade Federal de Santa Maria, 97105-900 Santa Maria, Rio Grande do Sul, Brasil
*E-mail: heliogb@base.ufsm.br
Received August 6, 2008
DOI 10.1002/jhet.89
Published online 30 June 2009 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of a novel series of analogous intermediates N3-[1-alkyl(aryl/heteroaryl)-3-oxo-4,4,4-tri-
chloroalk-1-en-1-yl]-2,3-diaminopyridines and N2-(methanesulfonyl) [Cl3CC(O)CH¼¼CRNH(C5H3N)
ANHY], where R ¼ H, Me, C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4,40-
biphenyl, 1-naphthyl, 2-thienyl, 2-furyl, and Y ¼ H, SO2Me, is reported. A new corresponding series of
2-aryl/heteroaryl-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones obtained from intramolecular cyclization
reaction of the first series of trichloroacetyl enamines or from the direct cyclocondensation reaction of
4-methoxy-1,1,1-trichloalk-3-en-2-ones with 2,3-diaminopyridine, under mild conditions, is also
demonstrated.
J. Heterocyclic Chem., 46, 603 (2009).
INTRODUCTION
boiling xylene, in an approximation of the incompletely
defined conditions given by Barchet and Merz [1] and
obtained and proved the isolation of the same pyridodia-
zepinone described firstly in 1964.
The reactions of 2,3-diaminopyridine with ethyl ben-
zoylacetate and ethyl nicotinoylacetate were first
reported in a communication in 1964 by Barchet and
Merz [1]. However, no evidence was given in support
of the first 2-phenyl-1,3-dihydro-4H-pyrido[2,3-b][1,4]
diazepin-4-one structure assignment.
In the 1960s, the determination of the correct struc-
ture for a given pyridodiazepinone product from the
reaction involving 2,3-diaminopyridine and b-ketoesters
was difficult and laborious, and, in some instances, an
impossible task. Contributing with the solution of this
problem, Israel and Jones [3,4] developed the thermal
conversion of pyridodiazepinones into imidazolones,
which permitted the assignment of the correct structures
to ambiguous products through the knowledge that the
N1AC2 bond of the pyridodiazepinone was not cleaved
during the course of the rearrangement reaction.
Three years later, Israel et al. [2] found that different
reaction conditions resulted in the preferential formation
of dihydropyrido[2,3-b][1,4]diazepin-2-one or the 4-one
isomer from the reaction of 2,3-diaminopyridine with
ethyl acetoacetate. This reaction when conducted in
boiling xylene for 8 h with azeotropic removal of water,
afforded 2-methylpyrido[2,3-b][1,4]diazepin-4-one as the
major product. However, 1,3-dihydro-1-isopropenyl-2H-
imidazo[4,5-b]pyridin-2-one was present in small yield.
In the absence of solvent, the mixture of 2,3-diamino-
pyridine with an excess of ethyl acetoacetate at 185ꢀC
for 15 min furnished 4-methylpyrido[2,3-b][1,4]diaze-
pin-2-one, which was obtained as an inseparable tauto-
meric mixture of 1,3- and 1,5-dihydro-4-methyl-2H-pyr-
ido[2,3-b][1,4]diazepin-2-one.
Recently, various diamine-ketoester condensations
involving reactions of ethyl 2-oxocyclohexanecarboxy-
late [5] or ethyl 2-oxocyclopentanecarboxylate [6]
(cyclic b-ketoesters) with nonsymmetrical diaminopyr-
idines have been studied, and the results compared in
a attempt to develop generalizations of predictive
value regarding the direction of ring closure to form
diazepinones, as well as, in search of novel tricyclic
ring systems which may be of interest in obtaining
Later, in 1969, Israel and Jones [3] studied the reac-
tion of 2,3-diaminopyridine with ethyl benzoylacetate in
C
V
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H. G. Bonacorso, R. V. Lourega, L. M. F. Porte, E. D. Deon, N. Zanatta, A. F. C. Flores,
and M. A. P. Martins
Vol 46
clozapine and pirenzapine analogues with psychotropic
properties.
nopyridine intermediates by the reaction of 4-alkoxy-
1,1,1-trichloroalk-3-en-2-ones with 2-aminopyridine
[13]. However, when these reactions were carried out in
dichloromethane as solvent, under mild conditions, the
respective trichloroacetyl enamines were isolated only in
very low yields (>10%). Surprisingly, when the same
reactions were carried out in a molar ratio of 1:1 in an-
hydrous ethanol as solvent under reflux for 5 h, 4-oxo-
4H-pyrido[1,2-a]pyrimidines were easily isolated in 45–
81% yields instead of N-[1-alkyl(aryl)-3-oxo-4,4,4-tri-
chloroalk-1-en-1-yl]-2-aminopyridine intermediates.
Surprisingly, since the first pyridodiazepinone was
reported in 1964 [1], no publications have been found
with the objective of carrying out a regiospecific and si-
multaneous introduction of trichloromethyl and substi-
tuted aryl groups at the pyrido[2,3-b][1,4]-diazepine
derivatives starting from trichloromethyl substituted 1,3-
diketones or 4-methoxy-1,1,1-trihaloalk-3-en-2-ones. In
addition, there is no data on reactions involving simple
1,3-diketones, such as acetylacetone or benzoylacetone,
with 2,3-diaminopyridine.
Finally, in 2001 Savelli et al. [7] studied the reaction
of 3-amino-2-(methylamino)pyridine with diethyl 1,3-
acetonedicarboxylate to develop pyridodiazepinone
derivatives. From the reaction mixture, Savelli separated
dipyrido[1,2-a:2,3-d]imidazole derivatives as well as two
isomeric pyrido[2,3-b]diazepinone derivatives in which
the complex structural differentiation was achieved
through NMR experiments and chemical evidence, but
attempts to obtain the cited pyrido[2,3-b][1,4]diazepinone
isomers as pure compounds have failed until now.
On the other hand, over the last few years, we have
reported the synthesis of 2-trifluoro- and 2-trichloro-
methyl-3H-1,5-benzodiazepines from the reaction of 4-
aryl-4-methoxy-1,1,1-haloalk-3-en-2-ones with o-phenyl-
enediamine in good yields [8]. Next, we demonstrated
that 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine
hydrogen sulfate possesses anxiolytic activity and pro-
duces motor in co-ordination similar to that observed in
mice given diazepam [9]. In the same year, we also
reported that some 4-substituted 2-trichloromethyl-3H-
1,5-benzodiazepines presented an inhibitory effect on
acetylcholinesterase and ATPDase activities from cere-
bral cortex of adult rats [10].
Only recently, we have communicated the first syn-
thesis of 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diaze-
pin-4(5H)-ones from the direct cyclocondensation reac-
tion of 4-methoxy-1,1,1-trichloroalk-3-en-2-ones (1)
with 2,3-diaminopyridine [14].
Recently, we have also reported an addition/elimina-
tion sequence leading to trichloroacetyl enamines from
the reaction of o-phenylenediamine [8c] and o-aminophe-
nol [11] with 4-alkyl(aryl)-1,1,1-trichloro-4-alkoxyalk-3-
en-2-ones. Particularly, considering the importance of the
development of new anticancer agents, in the last several
years we have researched the possibility of using 4-
alkoxy-1,1,1-trichloroalk-3-en-2-ones for the synthesis of
new structures with promising chemotherapeutic poten-
tial. Thus, some acyclic trichloroacetyl enamines, derived
from o-phenylenediamine and o-aminophenol, were sub-
mitted to in vitro antitumor screens and showed interest-
ing results [11]. The best activity was obtained when the
structure was derived from o-aminophenol and presented
a p-bromophenyl substituent linked to the carbon-1 of the
trichloromethylated enamino ketone.
Considering the biological importance of heterocyclic
fused diazepinones and their derivatives and the fact
that 2-aryl- and 2-heteroaryl-dihydropyridodiazepinone
analogues and trichloroacetyl enamine intermediates
have not yet been reported, it would be worthwhile to
demonstrate a new synthetic application of b-aryl(heter-
oaryl)-b-methoxyvinyl trichloromethyl ketones. In addi-
tion, with the intention of carrying out future biological
evaluations, it seemed desirable to develop a general
method for the synthesis of pyridodiazepine derivatives
(3H-1,5-benzodiazepine analogues), in which a trichlor-
omethyl, carbonyl, aryl, or heteroaryl group could be
introduced as substituent to this promising triaza fused
heterocyclic family.
In 2002, we showed the use of the trichloromethyl
group as a convenient leaving group for the synthesis of
6-methyl- and 7-alkyl(aryl)-5H-thiazolo[3,2-a]pyrimidin-
5-ones in 45–89% yields from the reaction of 4-alky-
l(aryl)-1,1,1-trichloro-4-alkoxyalk-3-en-2-ones with 2-
aminothiazole in refluxing ethanol [12]. In the
mentioned work, it was only possible to isolate the non-
substituted N-[3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2-ami-
nothiazole and all the other (1-substituted) enamino ke-
tone intermediates N-[1-alkyl(aryl)-3-oxo-4,4,4-trichlor-
oalk-1-en-1-yl]-2-aminothiazoles could be not isolated.
Recently, we have reported attempts to obtain N-[1-
alkyl(aryl)-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-2-ami-
RESULTS AND DISCUSSION
Herein, the synthesis and isolation of a novel series of
fifteen N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trichloroalk-1-
en-1-yl]-2,3-diaminopyridines and some N3-[1-(aryl)-3-
oxo-4,4,4-trichloroalk-1-en-1-yl]-N2-(methanesulfonyl)-
2,3-diaminopyridines and the regiospecific preparation
of
a series of 10 2-aryl(heteroaryl)-3H-pyrido[2,3-
b][1,4]diazepin-4(5H)-ones from the intramolecular cy-
clization reaction of trichloroacetyl enamines, or direct
cyclocondensation reaction of 4-substituted-4-methoxy-
1,1,1-trichloroalk-3-en-2-ones with 2,3-diaminopyridine,
is presented (Scheme 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Regiospecific Synthesis of 3H-Pyrido[2,3-b][1,4]diazepin-4(5H)-ones via Haloform Reaction
with the Isolation of N3-[3-Oxo-4,4,4-trichloroalk-1-en-1-yl]-2,3-diaminopyridine Intermediates
605
Scheme 1
A review of the literature has shown that 2-methyl-
Crystallographic data for compound 2g, reported in
and 2-phenyl-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones,
obtained under hard reaction conditions in boiling xy-
lene, would result from the interaction of the more
nucleophilic 3-amino group of the 2,3-diaminopyridine
with the keto carbonyl function of the b-keto-ester [2].
This direction of cyclization was also seen in the cyclo-
condensation reaction of 2,3-diaminopyridine with ethyl
benzoylacetate under similar conditions [3].
this article, have been given to the Cambridge Crystallo-
graphic Data Center (CCDC 687399) [16].
Initially, to obtain other new protected pyridino-sulfo-
namides bearing the similarly interesting aryl substitu-
ents at the enamino function, four examples of these
new aryl-enamino ketones 2 were employed to obtain
the respective N3-[1-aryl-3-oxo-4,4,4-trichloroalk-1-en-1-
yl]-N2-(methanesulfonyl)-2,3-diaminopyridines (3g-i, 3l).
Thus, the reactions of 2g-i, 2l with methanesulfonyl
chloride were carried out in dichlomethane as solvent at
An extension of the reaction of ketones 1 with 2,3-
diaminopyridine, a nonsymmetrical heteroaromatic dia-
mine, necessarily introduces the additional problem of
two possible isomeric diazepine products. The forma-
tion of the pyridodiazepine system presumably will
depend on whether the initial reaction of the more
nucleophilic 3-amino function occurs at the b-olefinic
carbon of the vinyl ketones 1 or at the carbonyl
carbon.
The ketones 1a [15b], 1b-f [12], 1g-j [15a], 1m-n
[14], and 1o-p [15g] are readily available CCC synthetic
blocks and were prepared from trichloroacetylation reac-
tions of enol ethers generated in situ from the respective
aryl- or heteroaryl methyl ketone acetals [15] with tri-
chloroacetyl chloride, respectively.
Subsequently, a novel series of 15 N3-[1-alkyl(aryl/
heteroaryl)-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-2,3-diami-
nopyridines 2a-m, 2o-p was obtained in 65–93%
yields by the methoxy-amino exchange reaction of 1
with 2,3-diaminopyridine and its X-ray diffraction data
is shown (Fig. 1). The best results were obtained
when the reactions of compounds 1a-p with 2,3-dia-
minopyridine were carried out in methanol at 0ꢀC for
20 h.
Figure 1. Perspective view of compound 2g. Thermal ellipsoids corre-
spond to 50% probability. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
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H. G. Bonacorso, R. V. Lourega, L. M. F. Porte, E. D. Deon, N. Zanatta, A. F. C. Flores,
and M. A. P. Martins
Vol 46
35ꢀC for 4 h. This procedure allowed for the easy
attainment of sulfonamides 3g-i, 3l in 53–66% yields.
In this study, we also found that aryl- and heteroaryl-
substituted trichloromethylated ketones 1g-p, when
treated directly with 2,3-diaminopyridine at a molar ra-
tio of 1:1, respectively, in anhydrous methanol as sol-
vent and in the presence of sodium methoxide under
reflux for 24 h, regiospecifically produced 2-aryl(heter-
oaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones (4g-p),
which were easily isolated in 52–70% yields, as pure
isomers. The above described conditions allowed us to
regiospecifically obtain the diazepinones (4) instead of
the analogous 2-aryl(heteroaryl)-4-trichloromethyl-4,5-
dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ol or the re-
spective 2-keto-pyridodiazepine isomers.
NMR spectra were acquired on a Bruker DPX 200 spectrometer
(1H at 200.13 MHz and 13C at 50.32 MHz), 5mm sample tubes,
298 K, digital resolution ꢁ0.01 ppm, in chloroform-d1 (for 2, 3)
or DMSO-d6 (for 4) using TMS as internal reference. The CHN
elemental analyses were performed on a Perkin Elmer 2400
CHN elemental analyzer (Sa˜o Paulo University–USP/Brazil).
General procedure for the preparation of substituted N3-
[3-oxo-4,4,4-trichloroalk-1-en-1-yl]-2,3-aminopyridines (2a-
m, 2o-p). To a stirred solutions of 2,3-diaminopyridine (0.327
g, 3 mmol) in 10 mL of dry methanol, 4-alkoxy-4-aryl(alkyl)-
1,1,1-trichloroalk-3-en-2-ones (1a-m, 1o-p) (3 mmol) were
added at 0ꢀC. The mixtures were stirred for 20 h at 0ꢀC. After
the reaction time, yellow solids (2a-m, 2o-p) were filtered,
washed with cold methanol and recrystallized from hexane
(yields 65–93%).
N3-[4-Oxo-5,5,5-trichloropent-2-en-2-yl]-2,3-diaminopyridine
1
(2a). Yield 86%; mp 120–122ꢀC; H NMR, d (ppm) ¼ 11.5 (s,
1H, NH), 8.0 (d, 1H, J ¼ 5, PyH6), 7.3 (d, 1H, J ¼ 7.5, PyH4),
6.70 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 5.9 (s, 1H, H2), 4.8 (s, 2H,
NH2), 2.1 (s, 3H, Me); 13C NMR, d (ppm) ¼ 181.7 (C¼¼O),
161.6 (C1), 154.9 (PyC2), 147.6 (PyC6), 135.6 (PyC4), 118
(PyC3), 113.9 (PyC5), 96.7 (CCl3), 88.9 (C2), 20.2 (Me). Anal.
Calcd. for C10H10Cl3N3O (mw 294.57): C, 40.77; H, 3.42;
N,14.26%. Found: C, 40.56; H, 3.33; N, 14.17%.
Although similar reaction conditions have been
employed previously to synthesize 5H-thiazolo[2,3-
a]pyrimidin-5-ones and 4H-pyrido[1,2-a]pyrimidin-4-
ones, we found in this case an unexpected reactivity of
the 2-amino group of the p-deficient pyridine ring toward
the carbonyl group of the 4-aryl(heteroaryl)-4-methoxy-
1,1,1-trichloroalk-3-en-2-ones (2), promoting an efficient
haloform reaction. Compound 4g had only been synthe-
sized previously by Israel et al. [3] and by Barchet and
Merz [1] in 65% yield from the reaction of 2,3-diamino-
pyridine with ethyl benzoylacetate, but under difficult
reaction conditions (boiling xylene for 4 h with azeo-
tropic distillation of the formed water). Our procedure
not only gave the same compound under milder condi-
tions (refluxing methanol for 24 h) and in a similar yield
(52%) but also increased the scope of the reaction with
the possibility of introducing other aryl and heteroaryl
substituents to this pyridodiazepinone system.
N3-[6-Oxo-7,7,7-trichlorohept-4-en-4-yl]-2,3-diaminopyridine
(2b). Yield 65%; mp 147–149ꢀC; 1H NMR, d (ppm) ¼ 11.6
(s, 1H, NH), 8.0 (d, 1H, J ¼ 5, PyH6), 7.3 (d, 1H, J ¼ 7.5,
PyH4), 6.72 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.0 (s, 1H, H2),
4.8 (s, 2H, NH2), 2.2 (t, 2H, J ¼ 8, CH2), 1,1 (qui., 2H, J ¼
7, CH2), 0.8 (t, 3H, J ¼ 7, Me) ; 13C NMR, d (ppm) ¼ 181.8
(CAO), 172.7 (C1), 155 (PyC2), 147.7 (PyC6), 135.8 (PyC4),
117.7 (PyC3), 113.8 (PyC5), 96.8 (CCl3), 87.7 (C2), 34.5
(CH2), 21.1 (CH2), 13.6 (Me). Anal. Calcd. for C12H14Cl3N3O
(mw 322.62): C, 44.60; H, 4.37; N, 13.02%. Found: C, 44.72;
H, 4.41; N, 12.87%.
N3-[2-Methyl-5-oxo-6,6,6-trichlorohex-3-en-3-yl]-2,3-diami-
nopyridine (2c). Yield 90%; mp 160–162 ꢀC; 1H NMR, d
(ppm) ¼ 11.4 (s, 1H,NH), 7.9 (d, 1H, J ¼ 5, PyH6), 7.4 (d,
1H, J ¼ 7.5, PyH4), 6.71 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1
(s, 2H, NH2), 5.9 (s, 1H, H-2), 2.6 (qui., 1H, CH), 1.1 (d, 6H,
J ¼ 7, 2Me); 13C NMR, d (ppm) ¼ 182.3 (C¼¼O), 179.1 (C1),
155.3 (PyC2), 147.5 (PyC6), 136 (PyC4), 117.5 (PyC3), 113.8
(PyC5), 96.7 (CCl3), 84.3 (C2), 29.9 (CH), 21.6 (2Me). Anal.
Calcd. for C12H14Cl3N3O (mw 322.62): C, 44.60; H, 4.37; N,
13.02%. Found: C, 44.37; H, 4.17; N, 13.10%.
Complementarily, examples of enamino ketones (2g-
m, 2o-p) were readily converted into 4g-m, 4g-p by
refluxing in methanol in the presence of sodium methox-
ide for 24 h with yields higher than 70% (Scheme 1).
We consider the one-pot reaction presented to be a
useful and convenient alternative to obtain regiospecifi-
cally pyridodiazepinone system and, in summary, the
use of this methodology allowed also the isolation of
two new series of N3-[1-alkyl(aryl/heteroaryl)-3-oxo-
N3-[2-Methyl-6-oxo-7,7,7-trichlorohept-4-en-4-yl]-2,3-diamino-
pyridine (2d). Yield 79%; mp 154–156ꢀC; 1H NMR, d (ppm)
¼ 11.5 (s, 1H, NH), 8.0 (d, 1H, J ¼ 5, PyH6), 7.3 (d, 1H, J ¼
7.5, PyH4), 6.6 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 5.9 (s, 1H, H-
2), 5.0 (s, 2H, NH2), 2.2 (d, 4H, J ¼ 8, CH2), 1.8 (sex, 1H,
CH), 0.8 (d, 6H, J ¼ 7, 2Me); 13C NMR, d (ppm) ¼ 181.3
(C¼¼O), 171.7 (C1), 155.1 (PyC2), 147.2 (PyC6), 135.9
(PyC4), 117.6 (PyC3), 113.3 (PyC5), 96.7 (CCl3), 88.4 (C2),
41.2 (CH2), 27.4 (CH), 22.1 (Me). Anal. Calcd. for
C13H16Cl3N3O (mw 336.65): C, 46.38; H, 4.79; N, 12.48%.
Found: C, 46.49; H, 4.75; N, 12.37%.
4,4,4-trichloroalk-1-en-1-yl]-2,3-diaminopyridines
and
N3-[1-aryl-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-N2-(metha-
nesulfonyl)-2,3-diaminopyridines, which have been pre-
pared in an analytically pure form and in good yields,
for future chemical and biological studies.
EXPERIMENTAL
N3-[2-Methyl-7-oxo-8,8,8-trichlorooct-5-en-5-yl]-2,3-diamino-
1
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without fur-
ther purification. All melting points were determined on a cali-
brated Electrothermal Melt-Temp 3.0 apparatus. 1H and 13C
pyridine (2e). Yield 93%; mp 132–135ꢀC; H NMR, d (ppm) ¼
11.4 (s, 1H, NH), 8.0 (d, 1H, J ¼ 5, PyH6), 7.4 (d, 1H, J ¼
7.5, PyH4), 6.72 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 5.9 (s, 1H,
H2), 5.4 (s, 2H, NH2), 2.2 (t, 2H, J ¼ 7, CH2), 1.5 (t, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Regiospecific Synthesis of 3H-Pyrido[2,3-b][1,4]diazepin-4(5H)-ones via Haloform Reaction
with the Isolation of N3-[3-Oxo-4,4,4-trichloroalk-1-en-1-yl]-2,3-diaminopyridine Intermediates
607
J ¼ 6, CH), 1.46–134 (m, 3H, CH2 and CH), 0.8 (t, 3H, J ¼
7, 2Me); 13C NMR, d (ppm) ¼ 181.8 (C¼¼O), 173.4 (C1),
154.9 (PyC2), 147.6 (PyC6), 135.9 (PyC4), 117.7
(PyC3),113.8 (PyC5), 96.8 (CCl3), 87.8 (C2), 36.9 (CH2), 30.8
(CH), 27.8 (CH2), 21.9 (Me). Anal. Calcd. for C14H18Cl3N3O
(mw 350.68): C, 47.95; H, 5.17; N 11.98%. Found: C,48.13;
H, 5.26; N, 12.22%.
374.63): C, 48.09; H, 2.96; N, 11.22%. Found: C, 48.21; H,
3.03; N, 11.15%.
N3-[1-(4-Chlorophenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
2,3-diaminopyridine (2k). Yield 67%; mp 180–182ꢀC; 1H
NMR, d (ppm) ¼ 11.4 (s, 1H, NH), 7.9 (d, 1H, J ¼ 5, PyH6),
7.4 (d, 2H, 3J ¼ 8, Ph), 7.2 (d, 2H, 3J ¼ 8, Ph), 6.7 (d, 1H,
J ¼ 7.5, PyH4), 6.46 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1 (s,
1H, H2), 4.8 (s, 2H, NH2); 13C NMR, d (ppm) ¼ 182.5
(C¼¼O), 165.9 (C1), 153.3 (PyC2), 142.9 (PyC6), 137.2 (Ph),
135.9 (PyC4), 132.1, 129.3, 129.2 (3C, Ph), 120.8 (PyC3),
113.5 (PyC5), 96.4 (CCl3), 92.3 (C2). Anal. Calcd. for
C15H11Cl4N3O (mw 391.08): C, 46.07; H, 2.84; N 10.74%.
Found: C, 45.88; H, 2.87; N, 10.68%.
N3-[9-Oxo-10,10,10-trichlorodec-7-en-7-il]-2,3-diaminopyri-
dine (2f). Yield 81%; mp 121–123ꢀC; 1H NMR, d (ppm) ¼
11.4 (s, 1H, NH), 8.0 (d, 1H, J ¼ 5, PyH6), 7.3 (d, 1H, J ¼
7.5, PyH4), 6.74 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 5.9 (s, 1H,
H2), 5.0 (s, 2H, NH2), 2.2 (t, J ¼ 8, 2H, CH2), 1.50–1.46 (m,
2H, CH2), 1.24–1.19 (m, 6H, 3CH2), 0.8 (t, J ¼ 7, 3H, Me);
13C NMR, d (ppm) ¼ 181.9 (C¼¼O), 172.9 (C1), 154.8
(PyC2), 147 (PyC6), 136.2 (PyC4), 118 (PyC3), 113.8 (PyC5),
96.8 (CCl3), 87.9 (C2), 32.6 (CH2), 31.1 (CH2), 28.7 (CH2),
27.7 (CH2), 22.3 (CH2), 13.9 (Me). Anal. Calcd. for
C15H20Cl3N3O (mw 364.70): C, 49.40; H, 5.53; N, 11.52%.
Found: C, 49.63; H, 5.47; N, 11.57%.
N3-[1-(4-Bromophenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
2,3-diaminopyridine (2l). Yield 93%; mp 182–184ꢀC; 1H
NMR, d (ppm) ¼ 11.4 (s, 1H, NH), 7.9 (d, 1H, J ¼ 5, PyH6),
7.4 (d, 2H, 3J ¼ 8, Ph), 7.2 (d, 2H, 3J ¼ 8, Ph), 6.7 (d, 1H,
J ¼ 7.5, PyH4), 6.47 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1 (s,
1H, H2), 4.8 (s, 2H, NH2); 13C NMR, d (ppm) ¼ 179.9
(C¼¼O), 165.9 (C1), 154.3 (PyC2), 143.1 (PyC6), 136.4
(PyC4), 133.6, 131.8, 129.9, 124.2 (4C, Ph), 120.2 (PyC3),
112.2 (PyC5), 96.6 (CCl3), 90.2 (C2). Anal. Calcd. for
C15H11Cl3BrN3O (mw 435.53): C, 41.37; H, 2.55; N 9.65%.
Found: C, 41.50; H, 2.47; N, 9.94%.
N3-[1-(4,40-Biphenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2,3-
diaminopyridine (2m). Yield 71%; mp 171–173ꢀC; 1H NMR,
d (ppm) ¼ 11.5 (s, 1H, NH), 7.9 (d, 1H, J ¼ 5, PyH6), 7.6–
7.4 (m, 9H, Ph), 6.8 (d, 1H, J ¼ 7.5, PyH4), 6.5 (dd, 1H, J ¼
5, J ¼ 5, PyH5), 6.2 (s, 1H, H2), 4.9 (s, 2H, NH2); 13C NMR,
d (ppm) ¼ 182.2 (C¼¼O), 167.3 (C1), 153.8 (PyC2), 146.2
(PyC6), 143.5, 139.4, 132.6, 128.9, 128.5, 128.1, 127.2, 126.9
(8C, Ph), 134.6 (PyC4), 119.8 (PyC3), 113.9 (PyC5),96.7
(CCl3), 91.3 (C2). Anal. Calcd. for C13H10Cl3N3O2 (mw
346.60): C, 45.05; H, 2.91; N, 12.12%. Found: C, 45.17; H,
3.13; N, 12. 25%.
N3-[1-Phenyl-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2,3-diamino-
1
pyridine (2g). Yield 90%; mp 149–150ꢀC; H NMR, d (ppm) ¼
11.4 (s, 1H, NH), 7.8 (d, 1H, J ¼ 5, PyH6), 7.41–7.32 (m, 5H,
Ph), 6.7 (d, 1H, J ¼ 7.5, PyH4), 6.40 (dd, 1H, J ¼ 5, J ¼ 5,
PyH5), 6.1 (s,1H, H2), 5.1 (s, 2H, NH2); 13C NMR, d (ppm)
¼ 182.3 (C¼¼O), 167.6 (C1), 153.8 (PyC2), 144.8 (PyC6),
135.1 (PyC4), 133.9, 130.7, 128.7, 127.8 (4C, Ph), 119.9
(PyC3), 113.6 (PyC5), 96.6 (CCl3), 91.3 (C2). Anal. Calcd. for
C15H12Cl3N3O (mw 356.64): C, 50.52; H, 3.39; N, 11.78%.
Found: C, 50.32; H, 3.31; N, 11.83%.
N3-[1-(4-Methylphenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
2,3-diaminopyridine (2h). Yield 73%; mp 174–175ꢀC; 1H
NMR, d (ppm) ¼ 12.0 (s, 1H, NH), 7.8 (d, 1H, J ¼5, PyH6),
3
3
7.2 (d, 2H, J ¼ 8, Ph), 6.8 (d, 1H, J ¼ 8, Ph), 6.7 (d, 1H, J
¼ 7.5, PyH4), 6.44 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 5.8 (s, 1H,
H2), 5.3 (s, 2H, NH2), 2.3 (s, 3H, Me); 13C NMR, d (ppm) ¼
168.0 (C¼¼O), 153.8 (C1), 146.1 (PyC6), 145.2 (PyC2), 134.9
(PyC4), 129.4, 129.2, 128.8, 127.8 (4C, Ph), 119.9 (PyC3),
113.6 (PyC6), 92.7 (C2), 91.1 (CCl3), 21.3 (Me). Anal. Calcd.
for C16H14Cl3N3O (mw 370.67): C, 51.85; H, 3.81; N,
11.34%. Found: C, 51.70; H, 3.75; N, 11.13%.
N3-[1-(2-Furyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2,3-dia-
minopyridine (2o). Yield 75%; mp 167–169ꢀC; 1H NMR, d
(ppm) ¼11.4 (s, 1H, NH), 7.8 (bs, 1H, PyH6), 7.2 (d, 1H, J ¼
4, fr), 7.1 (t, 1H, J ¼ 4, fr), 7.0 (d, 1H, J ¼ 4, fr), 6.9 (d, 1H,
J ¼ 7.5, PyH4), 6.41 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1 (s,
1H, H2), 4.8 (s, 2H, NH2); 13C NMR, d (ppm) ¼ 182.3
(C¼¼O), 167.3 (C1), 153.7 (PyC2),146 (PyC6), 139.5 (fr),
132.6 (PyC4), 128.9, 128.1, 127.3 (3C, fr), 119.9 (PyC3),
114.1 (PyC5), 96.7 (CCl3), 91.4 (C2). Anal. Calcd. for
C19H14Cl3N3O (mw 406.70): C, 56.11; H, 3.47; N, 10.33%.
Found: C, 56.37; H, 3.46; N, 10.40%.
N3-[1-(4-Methoxyphenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
2,3-diaminopyridine (2i). Yield 78%; mp 174–175ꢀC; 1H
NMR, d (ppm) ¼ 11.5 (s, 1H, NH), 7.8 (d, 1H, J ¼ 5, PyH6),
7.2 (d, 2H, 3J ¼ 9, Ph), 6.8 (d, 1H, 3J ¼ 9, Ph), 6.7 (d, 1H,
J ¼ 7.5, PyH4), 6.45 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1 (s,
1H, H2), 4.9 (s, 2H, NH2), 3.8 (s, 3H, OMe); 13C NMR, d
(ppm) ¼ 181.3 (C¼¼O), 167.4 (C1), 161.5 (Ph), 153.7 (PyC2),
145.7 (PyC6), 134.6 (PyC4), 129.7, 125.8, 114.1 (3C, Ph), 120.1
(PyC3), 113.8 (PyC5), 96.8 (CCl3), 90.8 (C2), 55.3 (OMe).
Anal. Calcd. for C16H14Cl3N3O2 (mw 386.67): C, 49.70; H,
3.65; N, 10.87%. Found: C, 49.95; H, 3.72; N, 10.60%.
N3-[1-(2-Thienyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-2,3-
1
diaminopyridine (2p). Yield 79%; mp 175–177ꢀC; H NMR, d
(ppm) ¼11.4 (s, 1H, NH), 7.9 (d, 1H, J ¼ 5, PyH6), 7.3 (d,
1H, J ¼ 5, tn), 7.1 (d, 1H, J ¼ 3, tn), 7.0 (d, 1H, J ¼ 7, tn),
6.5 (d, 1H, J ¼ 7.5, PyH4), 6.4 (dd, 1H, J ¼ 5, J ¼ 5, PyH5),
6.1 (s, 1H, H2), 5.2 (s, 2H, NH2); 13C NMR, d (ppm) ¼ 182.1
(C¼¼O), 160.3 (C1), 154.6 (PyC2), 147.2 (PyC6), 135.8
(PyC4), 130.2, 127.7, 127.3 (3C, tn), 119.3 (PyC3), 114.1
(PyC5), 103.7 (CCl3), 89.3 (C2). Anal. Calcd. for
C21H16Cl3N3O (mw 432.74): C, 58.29; H, 3.73; N, 9.71%.
Found: C, 58.32; H, 3.76; N, 9.66%.
N3-[1-(4-Fluorophenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
2,3-diaminopyridine (2j). Yield 80%; mp 146–148ꢀC; 1H
NMR, d (ppm) ¼ 11.1 (s, 1H, NH), 7.8 (d, 1H, J ¼ 5, PyH6),
7.3 (d, 2H, 3J ¼ 9, Ph), 7.0 (d, 2H, 3J ¼ 9, Ph), 6.8 (d, 1H,
J ¼ 7.5, PyH4), 6.4–6.3 (m, 1H, PyH5 and 2H, NH2), 6.1 (s,
1H, H2); 13C NMR, d (ppm) ¼ 182.2 (C¼¼O), 166.5 (C1),
1
163.8 (d, JCF ¼ 249.2, Ph), 153.8 (PyC2), 146.1 (PyC6),
General procedure for the preparation of substituted N3-
[1-alkyl(aryl/heteroaryl)-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-
N2-(methanesulfonyl)-2,3-diaminopyridines (3g-i, 3l). To
3
134.8 (PyC4), 130.1 (d, JCF ¼ 9, Ph), 129.9 (PyC3), 119.6 (d,
4
2JCF ¼ 22, Ph), 116.0 (d, JCF ¼ 3, Ph), 113.9 (PyC5), 96.6
(CCl3), 91.3 (C2). Anal. Calcd. for C15H11Cl3FN3O (mw
a
stirred solutions of N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

608
H. G. Bonacorso, R. V. Lourega, L. M. F. Porte, E. D. Deon, N. Zanatta, A. F. C. Flores,
and M. A. P. Martins
Vol 46
trichlorobut-1-en-1-yl]-2,3-diaminopyridines (2g-i, 2l) (1 mmol)
in 5 mL of dry dichloromethane, pure methanesulfonyl chloride
(0.15 mL, 2 mmol) was added at room temperature. The mix-
tures were stirred for 4 more hours at 35ꢀC. After the reaction
time, the reactions were filtered and the organic solvent was
removed under reduced pressure. The crude yellow solids (3g-i,
3l) were recrystallized from hexane (yields 53–66%).
carried out under reflux during 24 h. After the reaction time
the solvent was removed under reduced pressure and the crude
solid products were washed with water and then with chloro-
form, obtaining dark solids (4g-p), as pure compounds (yields
70–85%).
Method B: From 4-aryl(heteroaryl)-4-methoxy-1,1,1-tri-
chlorobut-3-en-2-ones (1g-p). To a stirred solutions of 2,3-dia-
minopyridine (2 mmol, 0.218 g), in 6 mL of dry methanol,
was added CH3ONa (2 mmol). After 10 min, the respective 4-
aryl(heteroaryl)-4-methoxy-1,1,1-trichlorobut-3-en-2-ones (1g-
p) were added (2 mmol) in one portion and the solutions were
stirred at 60–65ꢀC during 24 h. After the reaction time the sol-
vent was removed under reduced pressure and the crude solid
products were washed with water and then with chloroform,
obtaining dark solids (4g-p), as pure compounds (yields 52–
70%).
2-Phenyl-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-one (4g).
Yield 52%; mp 250–252ꢀC. See ref. [3] yield 65%; mp 258ꢀC;
1H NMR, d (ppm) ¼ 10.9 (s, 1H, NH), 8.3 (d, 1H, J ¼ 5,
H7), 8.0 (bs, 2H, Ph), 7.8 (bs, 1H, H9), 7.5 (bs, 3H, Ph), 7.3
(bs, 1H, H8), 3.6 (s, 2H, H3); 13C NMR, d (ppm) ¼ 166.1
(C¼¼O), 159.3 (C2), 146 (C7), 142.4 (C5a), 136.7 (Ph), 136.3
(C9a), 134.4 (C9), 131.2 (Ph), 128.7 (Ph), 127.6 (Ph), 120
(C8), 40.2 (C3).
N3-[1-Phenyl-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-N2-(meth-
anesulfonyl)-2,3-diamino-pyridine (3g). Yield 63%; mp 168–
170ꢀC; 1H NMR, d (ppm) ¼10.9 (s, 1H, NH), 8.3 (s, 1H,
NH), 7.6 (d, 1H, J ¼ 5, PyH6), 7.42–7.28 (m, 5H, Ph), 7.0 (d,
1H, J ¼ 7.5, PyH4), 6.5 (dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.1 (s,
1H, H2), 2.8 (s, 3H, Me); 13C NMR, d (ppm) ¼ 182.6 (C¼¼O),
164.5 (C1), 145.1 (PyC6), 140.9 (PyC2), 135.1 (Ph), 133.9
(PyC4), 131.1 (PyC3), 129.2, 128.3, 124.8 (3C, Ph), 111.7
(PyC5), 96.3 (CCl3), 93.8 (C2), 43.5 (Me). Anal. Calcd. for
C22H18Cl3N3O3S (mw 510.82): C, 51.73; H, 3.55; N, 8.23%.
Found: C, 52.01; H, 3.60; N, 8.33%.
N3-[1-(4-Methylphenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
N2-(methanesulfonyl)-2,3-diaminopyridine (3h). Yield 53%;
1
mp 174–176ꢀC; H NMR, d (ppm) ¼11.0 (s, 1H, NH), 8.2 (s,
1H, NH), 7.61 (d, 1H, J ¼ 5, PyH6), 7.28–7.20 (m, 4H, Ph),
7.0 (d, 1H, J ¼ 7.5, PyH4), 6.52 (dd, 1H, J ¼ 5, J ¼ 5,
PyH5), 6.2 (s, 1H, H2), 2.8 (s, 3H, Me), 3.3 (s, 3H, Me); 13C
NMR, d (ppm) ¼ 181.2 (C¼¼O), 162.7 (C1), 155.1 (Ph), 145.9
(PyC2), 144.5 (PyC6), 129.6, 129, 127.2 (3C, Ph), 128.2
(PyC4), 122.4 (PyC3), 113.8 (PyC5), 95.1 (CCl3), 89 (C2),
39.5 (Me), 21.7 (Me). Anal. Calcd. for C23H20Cl3N3O4S (mw
540.85): C 51.08% H 3.73% N 7.77%. Found: C, 50.92; H,
3.58; N, 7.69%.
2-(4-Methylphenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-
one (4h). Yield 55%; mp 257–259ꢀC; 1H NMR, d (ppm) ¼
3
10.8 (s, 1H, NH), 8.3 (d, 1H, J ¼ 5, H7), 7.9 (d, J ¼ 7, 2H,
Ph), 7.8 (d, J ¼ 7, 1H, H9), 7.35–7.33 (m, 3H, Ph and H8),
3.5 (s, 2H, H3), 2.3 (s, 3H, Me); 13C NMR, d (ppm) ¼ 165.7
(C¼¼O), 158.9 (C2), 145.4 (C7), 142.1 (C5a), 140.9 (Ph),
135.2 (C9), 134.2 (C9a), 133.9 (Ph), 128.9 (Ph), 127.3 (Ph),
119.5 (C8), 20.4 (Me). Anal. Calcd. for C15H13N3O (mw
251.29): C, 71.70; H 5.21; N 16.72%. Found: C, 71.83; H,
5.31; N, 16.75%.
N3-[1-(4-Methoxyphenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-
yl]-N2-(methanesulfonyl)-2,3-diaminopyridine (3i). Yield
1
66%; mp 180–182ꢀC; H NMR, d (ppm) ¼ 11.0 (s, 1H, NH),
3
8.1 (s, 1H, NH), 7.5 (d, 1H, J ¼ 5, PyH6), 7.29 (d, 2H, J ¼ 7,
3
Ph), 7.0 (s, 1H, J ¼ 7.5, PyH4), 6.69 (d, 2H, J ¼ 7, Ph), 6.55
2-(4-Methoxyphenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-
one (4i). Yield 57%; mp 245–247ꢀC; 1H NMR, d (ppm) ¼
(dd, 1H, J ¼ 5, J ¼ 5, PyH5), 6.2 (s, 1H, H2), 3.8 (s, 1H,
OMe), 2.8 (s, 3H, Me); 13C NMR, d (ppm) ¼ 182.5 (C¼¼O),
164.8 (C1), 152.1 (PyC6), 138.6 (PyC4), 134.9 (PyC2), 134.8,
132.9, 129.4, 128.5, 125.9 (5C, Ph), 124.2 (PyC3), 112.2
(PyC5), 96.3 (CCl3), 93.9 (C2), 53.4 (OMe), 39.4 (Me). Anal.
Calcd. for C22H17Cl3FN3O3S (mw 528.81): C, 49.97; H, 3.24;
N, 7.95%. Found: C, 50.12; H, 3.27; N, 8.01%.
3
11.0 (s, 1H, NH), 8.4 (d, 1H, J ¼ 5, H7), 8.1 (d, J ¼ 8.5, 2H,
3
Ph), 7.9 (d, J ¼ 7, 1H, H9), 7.4 (bs, 1H, H8), 7.1 (d, 2H, J ¼
8.5, Ph), 3.9 (s, 2H, OMe), 3.6 (s, 2H, H3); 13C NMR, d
(ppm) ¼ 166.0 (C¼¼O), 161.8 (C2), 158.6 (Ph), 145.4 (C7),
142.4 (C5a), 136.1 (Ph), 134.6 (C9a), 129.6 (Ph), 129,1 (C9),
119.9 (C8), 114 (Ph), 55.3 (OMe), 40.6 (C3). Anal. Calcd. for
C15H13N3O2 (mw 267.29): C, 67.41; H, 4.90; N, 15.72%.
Found: C, 67.20; H,4.95; N, 15.83%.
N3-[1-(4-Bromophenyl)-3-oxo-4,4,4-trichlorobut-1-en-1-yl]-
N2-(methanesulfonyl)-2,3-diaminopyridine (3l). Yield 61%;
1
mp 177–179ꢀC; H NMR, d (ppm) ¼ 11.0 (s, 1H, NH), 7.8 (s,
2-(4-Fluorophenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-
one (4j). Yield 60%; mp 252–254ꢀC; 1H NMR, d (ppm) ¼
10.9 (d, 1H, NH), 8.3 (d, 1H, J ¼ 5, H7), 8.1 (bs, 2H, Ph), 7.8
(bs, 1H, H9), 7.40–7.31 (m, 3H, Ph and H8), 3.6 (s, 2H, H3);
1H, NH), 7.7 (bs, 1H, PyH6), 7.5 (bs, 2H, Ph), 7.2 (bs, 2H,
Ph), 6.9 (bs, 1H, PyH4), 6.5 (bs, 1H, PyH5), 6.1 (s, 1H, H2),
2.8 (s, 3H, Me); 13C NMR, d (ppm) ¼ 182.5 (C¼¼O), 165.2
(C1), 153.1 (PyC6), 141.7 (PyC2), 136.3 (PyC4), 132.5, 132.2,
129.4, 125.6 (4C, Ph), 121.3 (PyC3), 113.3 (PyC5), 96.4
(CCl3), 92.5 (C2), 52.5 (Me). Anal. Calcd. for
C22H17BrCl3N3O3S (mw 589.72): C, 44.81; H, 2.91; N,
7.13%. Found: C, 44.99; H, 3.01; N, 7.19%.
13C NMR, d (ppm) ¼ 165.6 (C¼¼O), 157.9 (C2), 156.5 (d,
4
1JCF ¼ 250, Ph), 145.7 (C7), 142.1 (C5a), 135.8 (d, JCF
¼
3
22, Ph), 134.1 (C9a), 133.2 (C9), 129.9 (d, JCF ¼ 9, Ph),
2
119.7 (C8), 115.3 (d, JCF ¼ 22), 33.9 (C3). Anal. Calcd. for
C14H10FN3O (mw 255.25): C, 65.88; H, 3.95; N 16.46%.
Found: C, 66.02; H, 3.80; N, 16.37%.
2-(4-Chlorophenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-
General procedure for the preparation of substituted
2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones
(4g-p).
one (4k). Yield 64%; mp 262–264ꢀC; 1H NMR, d (ppm)
Method A: From N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-tri-
chlorobut-1-en-1-yl]-2,3-diaminopyridines (2g-p). To a stirred
solutions of N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trichlorobut-1-
en-1-yl]-2,3-diaminopyridines (2g-p) (3 mmol) in 5 mL of dry
ethanol, were added CH3ONa (3 mmol). The reactions were
¼10.8 (s, 1H, NH), 8.3 (d, 1H, J ¼ 5, H7), 8.0 (d, J ¼ 8, 2H,
3
3
Ph), 7.8 (d, J ¼ 7, 1H, H9), 7.7 (d, J ¼ 8, 2H, Ph), 7.3 (bs,
1H, H8), 3.5 (s, 2H, H3); 13C NMR, d (ppm) ¼ 165.9 (C¼¼O),
158 (C2), 145.8 (C7), 143 (C5a), 138.3 (C9a), 135.9 (C9),
133.9 (Ph), 131.3 (Ph), 129.2 (Ph), 119.9 (C8). Anal. Calcd.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Regiospecific Synthesis of 3H-Pyrido[2,3-b][1,4]diazepin-4(5H)-ones via Haloform Reaction
with the Isolation of N3-[3-Oxo-4,4,4-trichloroalk-1-en-1-yl]-2,3-diaminopyridine Intermediates
609
´
de Pessoal de Nıvel Superior—CAPES (R. V. Lourega) is also
acknowledged.
for C14H10ClN3O (mw 271.71): C, 61.89; H, 3.71; N, 15.47%.
Found: C, 61.94; H, 3.68; N, 15.32%.
2-(4-Bromophenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4(5H)-one
1
(4l). Yield 53%; mp 266–268ꢀC; H NMR, d (ppm) ¼10.6 (s,
1H, NH), 8.3 (d, 1H, J ¼ 5, H7), 8.0 (bs, 2H, Ph), 7.8 (bs,
1H, H9), 7.7 (bs, 2H, Ph), 7.3 (bs, 1H, H8), 3.5 (s, 2H, H3);
13C NMR, d (ppm) ¼ 165.5 (C¼¼O), 158 (C2), 145.8 (C7),
142.1 (C5a), 135.9 (C9), 135.8 (C9a), 133.9, 131.3, 129.1,
124.7 (4C, Ph), 119.6 (C8). Anal. Calcd. for C14H10BrN3O
(mw 316.16): C, 53.19; H, 3.19; N, 13.29%. Found: C, 53.02;
H, 3.10; N, 13.17%.
REFERENCES AND NOTES
[1] Barchet, R.; Merz, K. W. Tetrahedron Lett 1964, 33, 2239.
[2] Israel, M.; Jones, L. C.; Modest, E. J. J Heterocycl Chem
1967, 4, 659.
[3] Israel, M.; Jones, L. C. J Heterocycl Chem 1969, 6, 735.
[4] Israel, M.; Jones, L. C.; Modest, E. J. Tetrahedron Lett
1968, 9, 4811.
2-(4,40-Biphenyl)-3H-pyrido[2,3-b][1,4]-diazepin-4-one (4m).
1
Yield 59%; mp 248–250ꢀC; H NMR, d (ppm) ¼11.0 (s, 1H,
3
NH), 8.3 (d, J ¼ 5, 1H, H7), 8.0 (bs, J ¼ 8, 2H, Ph), 7.9–7.8
[5] Israel, M.; Jones, L. C. J Heterocycl Chem 1973, 10, 201.
[6] Savelli, F.; Boido, A.; Vazanna, I.; Sparatore, F. J Hetero-
cycl Chem 1987, 24, 1709.
3
(m, 2H, Ph and 1H, H9), 7.7 (d, J ¼ 8, 2H, Ph), 7.5 (t, 2H,
3J ¼ 8, Ph), 7.4 (t, 1H, 3J ¼ 8, Ph), 7.3 (dd, J ¼ 5, J ¼ 5,
1H, H8), 3.6 (s, 2H, H3); 13C NMR, d (ppm) ¼ 165.7 (C¼¼O),
158.6 (C2), 145.6 (C7), 142.5 (C5a), 142.1 (Ph), 138.7 (C9a),
135.9 (C9), 135.5, 134.2, 128.5, 127.9, 127.6, 126.5, 126.4
(7C, Ph), 119.6 (C8). Anal. Calcd. for C20H15N3O (mw
313.36): C, 76.66; H, 4.82; N 13.41%. Found: C, 76.45; H,
4.71; N, 13.20%.
[7] Savelli, F.; Boido, A.; Piacente, S. J Heterocycl Chem
2001, 38, 659.
[8] (a) Bonacorso, H. G.; Marques, L. M. L.; Zanatta, N.; Mar-
tins, M. A. P. Synth Commun 2002, 32, 3225; (b) Bonacorso, H. G.;
Bittencourt, S. T.; Wastowski, A. D.; Wentz, A. P.; Zanatta, N.; Mar-
tins, M. A. P. Tetrahedron Lett 1996, 37, 9155; (c) Bonacorso, H. G.;
Bittencourt, S. R. T.; Wastowski, A. D.; Wentz, A. P.; Zanatta, N.;
Martins, M. A. P. J Heterocycl Chem 1999, 36, 45.
2-(1-Naphthyl)-3H-pyrido[2,3-b][1,4]-diazepin-4-one (4n).
Yield 67%; mp 251–253ꢀC; 1H NMR, d (ppm) ¼ 8.5 (s, 1H,
NH), 8.3 (d, 1H, J ¼ 5, H7), 7.9 (bs, 2H, Ph), 7.8 (bs, 2H,
Ph), 7.7–7.5 (m, 2H, OH and H9 and 2H, Ph), 7.2 (bs, 1H,
Ph), 6.7 (bs, 1H, Ph), 6.3 (bs, 1H, H8), 3.6 (s, 2H, H3); 13C
NMR, d (ppm) ¼ 170.8 (Ph), 166.9 (C¼¼O), 161.2 (C2), 148.5
(C7), 136.1 (C5a), 134.9 (C9), 132.8 (C9a), 131.2 (Ph), 127.7–
124.9 (Ph), 113.8 (C8). Anal. Calcd. for C18H13N3O (mw
287.32): C, 75.25; H, 4.56; N, 14.62%. Found: C, 75.48; H,
4.85; N, 14.83%.
[9] Rubin, M. A.; Albach, C. A.; Berlese, D. B.; Bonacorso, H.
G.; Bittencourt, S. R. T.; Queiroz, C. M. T.; Maixner, A. E.; Mello, C.
F. Braz J Med Biol Res 2000, 33, 1069.
[10] Schetinger, M. R. C.; Porto, N. M.; Moretto, M. B.; Morsch,
V. M.; Rocha, J. B. T.; Vieira, V.; Moro, F.; Neis, R. T.; Bittencourt,
S.; Bonacorso, H. G.; Zanatta, N. Neurochem Res 2000, 25, 949.
[11] Bonacorso, H. G.; Wentz, A. P.; Bittencourt, S. R. T.; Mar-
ques, L. M. L.; Zanatta, N.; Martins, M. A. P. Synth Commun 2002,
32, 335.
2-(2-Furyl)-3H-pyrido[2,3-b][1,4]-diazepin-4-one (4o).
1
[12] Bonacorso, H. G.; Lourega, R. V.; Wastowski, A. D.;
Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett 2002,
43, 9315.
Yield 62%; mp 218–220ꢀC; H NMR, d (ppm) ¼11.0 (s, 1H,
NH), 8.3 (d, 1H, J ¼ 5, H7), 8.20–8.18 (m, OH, 1H, fr), 7.8
(bs, 1H, H9), 7.7 (bs, 1H, fr), 7.5 (bs, 1H, fr), 7.4 (bs, 1H,
H8), 3.6 (s, 2H, H3); 13C NMR, d (ppm) ¼ 165.8 (C¼¼O),
154.2 (C2), 145.8 (C7), 143.0 (fr), 136.1 (C9a), 134.1 (C9),
133.2 (fr), 131.6 (fr), 128.4 (fr), 120.1 (C8), 40.3 (C3). Anal.
Calcd. for C12H9N3O2 (mw 227.22): C, 63.43; H, 3.99; N,
18.49%. Found: C, 63.57; H, 4.03; N, 18.55%.
[13] Bonacorso, H. G.; Righi, F. J.; Rodrigues, I. R.; Cechinel,
C. A.; Costa, M. B.; Wastowski, A. D.; Martins, M. A. P.; Zanatta, N.
J Heterocycl Chem 2006, 43, 229.
[14] Bonacorso, H. G.; Lourega, R. V.; Deon, E. D.; Zanatta,
N.; Martins, M. A. P. Tetrahedron Lett 2007, 48, 4835.
[15] (a) Siqueira, G. M.; Flores, A. F. C.; Clar, G.; Zanatta, N.;
Martins, M. A. P. Quim Nova 1994, 17, 24; (b) Colla, A.; Martins, M.
A. P.; Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991, 483; (c) Hojo,
M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem Lett 1976,
5, 499; (d) Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Kobuchi,
T.; Nishigaki, T. Synthesis, 1986, 340; (e) Hojo, M.; Masuda, R.;
Okada, E. Tetrahedron Lett 1986, 27, 1013; (f) Martins, M. A. P.; Bas-
tos, G. P.; Bonacorso, H. G.; Zanatta, N.; Flores, A. F. C.; Siqueira, G.
M. Tetrahedron Lett 1999, 40, 4309; (g) Flores, A. F. C.; Brondani, S.;
Zanatta, N.; Rosa, A.; Martins, M. A. P. Tetrahedron Lett 2002, 43,
8701.
2-(2-Thienyl)-3H-pyrido[2,3-b][1,4]-diazepin-4-one (4p).
1
Yield 70%; mp 264–266ꢀC; H NMR, d (ppm) ¼10.9 (s, 1H,
NH), 8.3 (d, 1H, J ¼ 5, H7), 7.9 (bs, 1H, H9), 7.6 (bs, 1H,
tn), 7.4 (bs, 1H, tn), 7.0 (bs, 1H, H8), 6.9 (bs, 1H, tn), 3.6 (s,
2H, H3); 13C NMR, d (ppm) ¼ 165.8 (C¼¼O), 154.8 (C2),
145.8 (C7), 143 (tn), 142.5 (tn), 136.1 (C9), 134.1 (C9a),
133.2, 131.6, 128.4 (3C, tn), 120.1 (C8). Anal. Calcd. for
C12H9N3OS (mw 243.28): C, 59.24; H, 3.73; N, 17.27%.
Found: C, 59.37; H, 3.80; N, 17.32%.
[16] Crystallographic data for compound 2g, reported in this arti-
cle, have been deposited with the Cambridge Crystallographic Data
Center (CCDC 687399). Copies of the data can be obtained, free of
charge, on application to CCDC 12 Union Road, Cambridge CB2
1EZ, UK (Fax: þ44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments. The authors thank the Conselho Nacional de
´
´
Desenvolvimento Cientıfico e Tecnologico—CNPq (Process No.
303636/2002-5) for financial support and the PIBIC-fellowship
(E. D. Deon). Fellowship from Coordenac¸a˜o de Aperfeic¸oamento
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet