Preparation of new 2-amino- and 2,3-diamino-pyridine trifluoroacetyl enamine derivatives and their application to the synthesis of trifluoromethyl-containing 3H-pyrido[2,3-b][1,4] diazepinols

Article abstract of DOI:10.1002/jhet.5570450619

(Chemical Equation Presented) The synthesis of a novel series of the intermediates N²(N³)-[1-alkyl(aryl/heteroaryl)-3-oxo-4,4, 4-trifluoroalk-1-en-1-yl]-2-aminopyridines [F₃CC(O)CH=CR ¹(2-NH-C₅H₃

Full text of DOI:10.1002/jhet.5570450619

Nov-Dec 2008
1679
Preparation of New 2-Amino- and 2,3-Diamino-pyridine
Trifluoroacetyl Enamine Derivatives and
Their Application to the Synthesis of Trifluoromethyl-containing
3H-Pyrido[2,3-b][1,4] diazepinols
Helio G. Bonacorso,* Rogério V. Lourega, Fernando J. Righi, Everton D. Deon,
Nilo Zanatta and Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97.105-900 - Santa Maria, RS – Brazil, (Fax: +55 55 32208031, E-mail: heliogb@base.ufsm.br)
Received May 13, 2008
R1
N
N
O
OMe
R1
H
N
H
O
N
O
N
N
i.
ii.
F3C
NH2
F3C
R1
F3C
R1
N
OH
CF3
H
(i): 2-aminopyridine; (ii): 2,3-diaminopyridine
R1 = H, Alkyl, Aryl, Heteroaryl
The synthesis of a novel series of the intermediates N2(N3)-[1-alkyl(aryl/heteroaryl)-3-oxo-4,4,4-
trifluoroalk-1-en-1-yl]-2-aminopyridines [F3CC(O)CH=CR1(2-NH-C5H3N)] and 2,3-diaminopyridines
[F3CC(O)CH=CR1(2-NH2-3-NH-C5H3N)], where R1 = H, Me, C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-
CH3C6H4, 4-OCH3C6H4, 4,4'-biphenyl, 1-naphthyl, 2-thienyl, 2-furyl, is reported. The corresponding series
of 2-aryl(heteroaryl)-4-trifluoromethyl-3H-pyrido[2,3-b][1,4]diazepin-4-ols obtained from intramolecular
cyclization reaction of the respective trifluoroacetyl enamines or from the direct cyclocondensation
reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,3-diaminopyridine, under mild conditions, is
also reported.
J. Heterocyclic Chem., 45, 1679 (2008).
INTRODUCTION
L-amino acids in aqueous sodium hydroxide solution
[15].
Recently, we also reported an addition/elimination
The presence of trifluoromethyl groups directly
linked to acyclic and cyclic organic compounds confers
special chemical, physical and biological properties to
molecules, mostly due to the elevated electronegative
and lipophilic character of fluorine atoms [1-11]. Thus,
much attention has been given to the synthesis of
trifluorinated compounds, many of which have been
shown to be of notable pharmacologic value [12-13].
Although the reactions of 4-alkoxy-1,1,1-trifluoroalk-
3-en-2-ones with primary and secondary amines have
been well documented, there are few reports in the
literature dealing with ꢀ-alkoxyvinyl trifluoromethyl
ketones as electrophile precursors and 2-amino- or 2,3-
diaminopyridine as nucleophiles [14-19].
Gerus et al. reported the reactions of 4-alkoxy-1,1,1-
trifluorobut-3-en-2-ones with ammonia and primary
amines to afford ꢀ-aminovinyl trifluoromethyl ketones
[14]. Of particular importance, the synthesis of N2-[3-
oxo-4,4,4-trifluorobut-1-en-1-yl]-2-aminopyridine in a
very satisfactory yield was reported in the same
publication. The reaction of diamino compounds
(ethylenediamine or o-phenylenediamine) with two
equivalents of enones, giving the respective N,N-
diaminovinyl trifluoromethyl ketones, was also
described.
sequence leading to trifluoroacetyl- and trichloroacetyl-
enamines from the reaction of o-phenylenediamine [16],
o-aminophenol [17], 1-naphthylamine [18] and S,S-
dimethylsulfoximide [19] with 4-alkyl(aryl)-1,1,1-
trihalo-4-alkoxyalk-3-en-2-ones.
Considering the importance of developing new
anticancer agents, in the last several years we have
researched the possibility of using 4-alkoxy-1,1,1-
trihaloalk-3-en-2-ones (1) for the synthesis of new
structures with anti-cancer/chemotherapeutic potential.
Thus, some acyclic trihaloacetyl enamines, derived
from o-phenylenediamine and o-aminophenol, and
submitted to in vitro anti-tumor screens have shown
interesting results [17].
In 1989, Hojo et al. reported that 4-alkoxy-1,1,1-
trifluoroalk-3-en-2-ones readily undergo O-N exchange
reactions with various amines to give the corresponding
N-[4,4,4-trifluoro-3-oxo-1-alkenyl]amines in high yields
[20]. In 1992, the same author demonstrated that a
series of N-[4,4,4-trifluoro-3-oxo-1-butenyl]amino acid
esters, ꢀ-aminoacetophenones and aminacetonitriles
were easily obtained in excellent yields by the O-N
exchange reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-
2-ones with some amino acid esters, ꢀ-amino-
acetophenone and aminoacetonitrile [21].
In 1991, protected amino acids were prepared by the
reaction of ꢀ-ethoxyvinyl trifluoromethyl ketone with

1680
H. G. Bonacorso, R. V. Lourega, F. J. Righi, E. D. Deon, N. Zanatta, and M. A. P. Martins
Vol 45
Recently, we also reported attempts to obtain N-[1-
alkyl(aryl)-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-2-amino-
pyridine intermediates by the reaction of 4-alkoxy-1,1,1-
trichloroalk-3-en-2-ones with 2-aminopyridine [22].
When these reactions were carried out in
dichloromethane as solvent, under mild conditions, the
respective trichloroacetyl enamines were isolated in very
low yields (> 10%). Surprisingly, when the same
reactions were carried out in a molar ratio of 1:1
respectively, in anhydrous ethanol as solvent under
reflux for 5 hours, 4-oxo-4H-pyrido[1,2-a]pyrimidines
were easily isolated in 45 – 81% yield, instead of N-[1-
alkyl(aryl)-3-oxo-4,4,4-trichloroalk-1-en-1-yl]-2-amino-
pyridine intermediates.
A review of the literature showed that, except for the
synthesis of N2-[3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2-
aminopyridine (2a) [14], the preparation of trifluoroacetyl
enamines (2-amino- and 2,3-diaminopyridine derivatives)
(2b, 2h-m and 3b-k, 3o, 3q) as precursors to obtain
trifluoromethylated heterocycles has not been reported
yet.
On the other hand, the reactions of 2,3-diaminopyridine
with ethyl benzoylacetate and ethyl nicotinoylacetate were
first reported in a communication in 1964 by Barchet and
Merz [23]. However, no evidence was given to support
the first 2-phenyl-1,3-dihydro-4H-pyrido[2,3-b][1,4]di-
azepin-4-one structure assignment.
Later, Israel et al. [24] found that different reaction
conditions resulted in the preferential formation of
dihydro-pyrido[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 afforded 2-methyl-
pyrido[2,3-b][1,4]diazepin-4-one as the major product
when conducted in boiling xylene. In the absence of
solvent, the mixture of 2,3-diaminopyridine with an
excess of ethyl acetoacetate at 185 ºC furnished 4-methyl-
pyrido[2,3-b][1,4]diazepin-2-one, which was obtained as
an inseparable tautomeric mixture of 1,3- and 1,5-
dihydro-4-methyl-2H-pyrido[2,3-b][1,4]diazepin-2-one.
Moreover, since the 60's various diamino-ketoester
condensations [25-29] involving reactions of cyclic and
acyclic ꢀ-ketoesters with non-symmetrical diamino-
pyridines have been studied in an attempt to develop
generalized predictions regarding the direction of ring
closure to form diazepinones as well as to find novel
tricyclic ring systems which could be of interest in
obtaining clozapine and pirenzapine analogues with
psychotropic properties.
Surprisingly, since the first pyridodiazepinone was
reported in 1964 [23], there have been no publications
whose objective was to carry out a regiospecific and
simultaneous introduction of a trifluoromethyl and
substituted aryl groups at the pyrido[2,3-b][1,4]-diazepine
derivatives starting from trifluoromethyl 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.
Recently, we communicated the first synthesis of 2-
aryl(heteroaryl)-4-trifluoromethyl-3H-pyrido[2,3-b][1,4]-
diazepin-4-ols from the direct cyclocondensation reaction
of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with 2,3-
diaminopyridine [30].
The purpose of this paper is to report the results of a
chemical behavior study of the reactions of 4-alkoxy-
1,1,1-trifluoroalk-3-en-2-ones (1) with 2-aminopyridine
and with 2,3-diaminopyridine to obtain two series of
trifluoroacetyl enamines and also to investigate the
possibility of using these enamino ketones for the
synthesis of new nitrogen-containg heterocycles with
conventional procedures.
RESULTS AND DISCUSSION
Initially, we report the synthesis of a new series of N2-
[1-alkyl(aryl)-3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2-amino-
pyridines (2) (Scheme I) and N3-[1-alkyl(aryl/
heteroaryl)-3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2,3-dia-
minopyridines (3) (Scheme II) from the reaction of
Scheme I
CF3
X
X
H
N
N
R1
O
OR
O
N
N
i
62-85%
CF3
R1
F3C
R1
1a-b, 1h-m
F3C
2a-b, 2h-m
N
N
R1
1,2
a
b
h
i
j
k
l
m
R
R1
Et
H
Me
Me
Me
Ph 4-MePh 4-OMePh 4-FPh 4-ClPh 4-BrPh
Me
Me
Me
Me
Me
(i): 2-Aminopyridine, EtOH, reflux, 2 h

Nov-Dec 2008
Preparation of New Trifluoromethyl-containing 3H-Pyrido[2,3-b][1,4] diazepinols
1681
4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with
2-aminopyridine and 2,3-diaminopyridine,
espectively. Second, we present the complete results
and data of the first regiospecific preparation of a
series of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-
dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ols (4) from
However, an extension of the reaction of ketones 1 with
2,3-diaminopyridine, a non-symmetrical heteroaromatic
diamine, necessarily introduces the additional problem of
two possible isomeric enaminones and subsequently
diazepine products. The formation of the pyridodiazepine
system presumably will depend on whether the initial
reaction of the more nucleophilic 3-amino function to
occur at the ꢀ-olefinic carbon of the vinyl ketones 1 or at
the carbonyl carbon.
Fortunately, the reactions of compounds 1 with 2,3-
aminopyridine, in methanol for 20 hours at 0ºC, led
exclusively to N3-[3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2,3-
aminopyridine intermediates (3b-k, 3o, 3q) in 65 to 96%
yields and its X-ray diffraction data is shown (Figure 1).
Crystallographic data for compound 3i, reported in this
paper, have been deposited with the Cambridge
Crystallographic Data Center (CCDC 687400) [33].
the
intramolecular
cyclization
reaction
of
trifluoroacetyl
enamines
[F3CC(O)CH=CR1(NH-
C5H3N-NH2] (3), or from the direct cyclocondensation
reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones
(1) with 2,3-diaminopyridine.
4-alkyl(aryl)-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones
(1) were synthesized from the acylation reaction of the
respective enolethers or ketone dimethyl acetals with
trifluoroacetic anhydride according to
developed previously [31].
a procedure
The reactions of compounds 1 with 2-aminopyridine, in
ethanol for 2 hours under reflux, led to N2-[3-oxo-4,4,4-
trifluoroalk-1-en-1-yl]-2-aminopyridines (2a-b, 2h-m) in
62 to 85% yields. Although, 4H-pyrido[1,2-a]pyrimidin-
4-one and 5H-thiazolo[3,2-a]pyrimidin-5-ones were
synthesized previously in our laboratories from the
reactions of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with
2-aminopyridine [22] and 2-aminothiazole [32],
respectively, the reactions of 1,1,1-trifluoroalk-3-en-2-
ones (1) with 2-aminopyridine or N-[3-oxo-4,4,4-trifluor-
oalk-1-en-1-yl]-2-aminopyridines (2) in refluxing ethanol,
n-butanol or an acidic media such as sulfuric acid or PPA
at reflux or using TiCl4 as catalyst at different
temperatures in an attempt to obtain any heterocyclic
structure, always resulted in the recovery of the
precursors or complex mixtures of non identified products
by 1H- and 13C-NMR spectroscopy.
Scheme II
H
N
i
O
N
3b-k, 3o, 3q
65-96%
NH2
F3C
R1
O
OMe
R1
1b-k, 1o, 1q
iii
50-73%
R1
F3C
N
ii
4h-n, 4p-q
54-71%
N
N
OH
CF3
H
(i): 2,3-Diaminopyridine, MeOH, 0 oC, 20 h; (ii): 2,3-Diaminopyridine,
MeOH, 50 oC, 24 h; (iii): MeOH, 50 oC, 20 h.
1,3-4
b
c
d
e
f
g
h
i
j
k
R1 Me n-Pr i-Pr i-Bu i-Pen n-Hex Ph 4-MePh 4-OMePh 4-FPh
1,3-4
l
m
n
o
p
q
R1 4-ClPh
4-BrPh
4,4'-BiPh 1-Naphthyl 2-Furyl 2-Thienyl
Subsequently, we found that trifluoromethylated
ketones 1h-n, 1p, 1q when treated with 2,3-
diaminopyridine at a molar ratio of 1:1 respectively, in
methanol as solvent for 24 hours, at 50 °C, produced
regiospecifically 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-
dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ols (4h-n, 4p,
4q) in a one-step reaction and in 54 to 71% yield. The
conditions described above allowed us to regiospecifically
obtain the diazepinols (4) instead of the isomer analogues.
As an extension of this study, compounds 3h-n, 3q were
readily also converted into 4h-n, 4q by heating in
methanol (50 ºC) for 20 hours in 50 to 73 % yields.
All reactions are presented in Scheme I and 2 and the
best results, NMR spectral data, selected physical and
analytical data are included in the experimental section.
In summary, it was observed that the reactions of 4-
alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with 2-amino-
Figure 1. Perspective view of compound 3i. Thermal ellipsoids
correspond to 50% probability.

1682
H. G. Bonacorso, R. V. Lourega, F. J. Righi, E. D. Deon, N. Zanatta, and M. A. P. Martins
Vol 45
2
2.60 (s, 3H, CH3). 13C NMR (CDCl3) ꢀ = 177.3 (C=O, JCF
=
34), 167.2 (PyC-2), 151.6 (C-1), 148.3 (PyC-6), 138.3 (PyC-4),
pyridine and 2,3-diaminopyridine are regiospecific and
when carried out in anhydrous ethanol under reflux or in
methanol at 0 ºC give the enamino ketone intermediates
N-[3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2-aminopyridines
(2) or N3-[3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2,3-amino-
pyridines (3), respectively. Moreover, we also developed
the first efficient and regiospecific preparation of 3H-
pyrido[2,3-b][1,4]diazepinol system (4) from intra-
molecular cyclization reaction of the respective
trifluoroacetyl enamines (3) or from the direct
cyclocondensation reaction of 4-methoxy-1,1,1-trifluoro-
alk-3-en-2-ones (1) with 2,3-diaminopyridine, under mild
conditions by a conventional procedure in a moderate to
good yields. A specific synthesis and the properties of
trifluoromethyl substituted 4,5-dihydro-3H-pyrido[2,3-b]-
[1,4]diazepin-4-ols are not yet known.
1
120.3 (C-2), 117.2 (CF3, JCF = 289), 115.8 (PyC-5), 93.4 (PyC-
3), 22.4 (CH3). GC/MS (EI, 70eV): m/z (%) = 230 (M+, 6), 161
(20), 133 (100), 78 (71), 51 (17). Anal. Calcd. for C10H9F3N2O
(230.19): C, 52.18; H, 3.94; N, 12.17%. Found: C, 52.49; H,
3.94; N, 12.24%.
N-[1-Phenyl-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2-amino-
pyridine (2h). This compound was obtained as yellow solid,
yields 85%, Mp. 82-83°C. H NMR (CDCl3) ꢀ = 12.23 (s, 1H,
1
NH), 8.26 (d, J = 5, 1H, PyH-6), 7.39 (m, 6H, PyH-4, Ph), 6.98
(t, J = 7, 1H, PyH-5), 6.47 (d, J = 8, 1H, PyH-3), 5.74 (s, 1H, H-
2). 13C NMR (CDCl3) ꢀ = 178.3 (C=O, JCF = 34), 164.5 (C-1),
151.4 (PyC-2), 148.8 (PyC-6), 137.4 (PyC-4), 134.3 (Ph), 130.7
2
1
(Ph), 127.9 (Ph), 120.3 (C-2), 117.0 (CF3, JCF = 289), 115.6
(PyC-5), 94.3 (PyC-3), 22.4 (CH3). GC/MS (EI, 70eV): m/z (%)
= 292 (M+, 1), 223 (11), 195 (100), 78 (74), 51 (24). Anal.
Calcd. for C15H11F3N2O (292.26): C, 61.65; H, 3.79; N, 9.59%.
Found: C, 61.43; H, 3.91; N, 9.92%.
N-[1-(4-Methylphenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-
2-aminopyridine (2i). This compound was obtained as yellow
solid, yields 77%, Mp. 52-53°C. 1H NMR (CDCl3) ꢀ = 12.11 (s,
1H, NH), 8.21 (d, J = 5, 1H, PyH-6), 7.38 (t, J = 8, 1H, PyH-4),
7.17 (m, 2H, Ph), 6.90 (t, J = 7, 1H, PyH-5), 6.42 (d, J = 8, 1H,
PyH-3), 5.64 (s, 1H, H-2), 2.30 (s, 3H, CH3). 13C NMR (CDCl3)
EXPERIMENTAL
Unless otherwise indicated, all common reagents and solvents
were obtained from commercial suppliers without further
purification. All melting points were determined on an
Electrothermal Melt-Temp 3.0 apparatus and are uncorrected.
Mass spectra were registered in a HP 5973 MSD connected to a
HP 6890 GC and interfaced by a Pentium PC. The GC was
equipped with a split-splitless injector, auto sampler, cross-
linked HP-5 capillary column (30 m, 0.32 mm internal
2
ꢀ = 178.0 (C=O, JCF = 34), 164.6 (C-1), 151.5 (PyC-2), 148.7
(PyC-6), 141.4 (PyC-4), 137.3 (Ph), 131.2 (Ph), 129.5 (Ph),
127.8 (Ph), 120.2 (C-2), 117.0 (CF3, 1JCF = 289), 116.7 (PyC-5),
93.9 (PyC-3), 21.3 (CH3). GC/MS (EI, 70eV): m/z (%) = 305
(M+, 1), 237 (5), 209 (100), 78 (27), 51 (5). Anal. Calcd. for
C16H13F3N2O (306.29): C, 62.74; H, 4.28; N, 9.15%. Found: C,
62.91; H, 4.43; N, 9.12%.
diameter), and helium was used as the carrier gas. H and 13C
1
NMR spectra were acquired on a Bruker DPX 200 spectrometer
(1H at 200.13 MHz and 13C at 50.32 MHz), 5 mm 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 (São Paulo University – USP / Brazil).
N-[1-(4-Methoxyphenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-
yl]-2-aminopyridine (2j). This compound was obtained as
1
yellow solid, yields 69%, Mp. 68-69°C. H NMR (CDCl3) ꢀ =
12.18 (s, 1H, NH), 8.30 (d, J = 5, 1H, PyH-6), 7.45 (t, J = 8, 1H,
PyH-4), 7.31 (d, J = 8.7, 2H, Ph), 6.99 (t, J = 7, 1H, PyH-5),
6.86 (d, J = 8.5, 2H, Ph), 6.52 (d, J=8, 1H, PyH-3), 5.73 (s, 1H,
H-2), 3.84 (s, 3H, OCH3). 13C NMR (CDCl3) ꢀ = 177.8 (C=O,
2JCF = 34), 164.3 (C-1), 161.8 (Ph), 151.8 (PyC-2), 148.8 (PyC-
6), 137.3 (PyC-4), 129.7 (Ph), 126.2 (Ph), 120.2 (C-2), 117.1
Synthetic Procedures.
General procedure for the Preparation of Substituted N2-
[3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2-aminopyridines (2a-b,
2h-m). To a stirred solution of 4-alkoxy-1,1,1-trifluoroalk-3-en-
2-one 1a, 1b, 1h-m (5 mmoles) in 15 mL of anhydrous ethanol,
2-aminopyridine (0.470 g, 5 mmoles) was added at 20 – 25 °C.
The mixture was stirred for 5 hours at 80 – 85 °C (oil bath).
After the reaction time, the solvent was evaporated under
reduced pressure and the crude products 2a, 2b, 2h-m were
purified by recrystallization from ethyl acetate.
1
(CF3, JCF = 289), 116.8 (PyC-5), 93.7 (PyC-3), 55.3 (OCH3).
GC/MS (EI, 70eV): m/z (%) = 253 (M+, 5), 225 (100), 78 (46),
51 (10). Anal. Calcd. for C16H13F3N2O2 (322.29): C, 59.63; H,
4.07; N, 8.69%. Found: C, 59.26; H, 4.09; N, 8.02%.
N-[1-(4-Fluorophenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-
2-aminopyridine (2k). This compound was obtained as yellow
solid, yields 93%, Mp. 91-92°C. 1H NMR (CDCl3) ꢀ = 12.20 (s,
1H, NH), 8.26 (d, J = 5, 1H, PyH-6), 7.49 (d, J = 8, 1H, PyH-4),
N-[3-Oxo-4,4,4-trifluorobut-1-en-1-yl]-2-aminopyridine
(2a). This compound was obtained as orange solid, yields 78%,
1
7.38 (m, 3H, PyH-5, Ph), 7.02 (m, 3H, Ph), 6.58 (m, 1H, PyH-
3), 5.72 (s, 1H, H-2). 13C NMR (CDCl3) ꢀ = 178.4 (C=O, JCF
Mp. 71-72°C (lit. [14]; Mp. 78-79ºC). H NMR (CDCl3) ꢀ =
2
=
11.72 (s, 1H, NH), 8.45 (dd, J = 8, 1H, H-1), 8.35 (d, J = 5, 1H,
PyH-6), 7.68 (t, J = 8, 1H, PyH-4), 7.07 (t, J = 7, 1H, PyH-5),
6.89 (d, J = 8, 1H, PyH-3), 5.73 (d, J = 8, 1H, H-2). 13C NMR
34), 163.9 (d, 1J = 252, F-Ph), 163.4 (C-1), 151.3 (PyC-2), 148.8
(PyC-6), 137.7 (PyC-4), 130.5 (d, 4J=3.5, F-Ph), 130.1 (d, 3J = 9,
1
2
F-Ph), 120.4 (C-2), 117.0 (CF3, JCF = 289), 116.7 (PyC-5),
(CDCl3) ꢀ = 180.3 (C=O, JCF = 34), 150.17 (PyC-2), 148.7 (C-
115.8 (d, 2J = 23, F-Ph), 94.39 (PyC-3). GC/MS (EI, 70eV): m/z
(%) = 310 (M+, 1), 241 (11), 213 (100), 78 (70), 51 (14). Anal.
Calcd. for C15H10F4N2O (310.25): C, 58.07; H, 3.25; N, 9.03%.
Found: C, 58.11; H, 3.37; N, 8.96%.
1), 147.9 (PyC-6), 138.7 (PyC-4), 120.2 (C-2), 116.7 (CF3, 1JCF
=
289), 112.1 (PyC-5), 90.9 (PyC-3). GC/MS (EI, 70eV): m/z (%)
= 216 (M+, 59), 147 (74), 119 (100), 78 (98), 51 (44)
N-[4-Oxo-5,5,5-trifluoropent-2-en-2-yl]-2-aminopyridine
(2b). This compound was obtained as white solid, yields 62%,
Mp. 66-67°C. 1H NMR (CDCl3) ꢀ = 12.91 (s, 1H, NH), 8.39 (d,
J = 4.6, 1H, PyH-6), 7.71 (t, J = 7.7, 1H, PyH-4), 7.09 (t, J =
7.4, 1H, PyH-5), 7.01 (d, J = 7.9, 1H, PyH-3), 5.58 (s, 1H, H-2),
N-[1-(4-Chlorophenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-
2-aminopyridine (2l). This compound was obtained as yellow
solid, yields 85%, Mp. 96-97°C. 1H NMR (CDCl3) ꢀ = 12.19 (s,
1H, NH), 8.24 (d, J = 5, 1H, PyH-6), 7.51 (d, J = 8, 1H, PyH-4),

Nov-Dec 2008
Preparation of New Trifluoromethyl-containing 3H-Pyrido[2,3-b][1,4] diazepinols
1683
7.33 (m, 4H, Ph), 7.01 (t, J = 7, 1H, PyH-5), 6.60 (d, J = 8, 1H,
PyH-3), 5.72 (s, 1H, H-2). 13C NMR (CDCl3) ꢀ = 183.9 (C=O,
2JCF = 34), 168.7 (C-1), 156.7 (PyC-2), 154.3 (PyC-6), 143.2
(PyC-4), 142.4 (Ph), 138.5 (Ph), 134.8 (Ph), 134.5 (Ph), 126.0
21.3 (CH3). Anal. Calcd. for C12H14F3N3O (273.11): C, 52.75; H,
5.16; N, 15.38%. Found: C, 52.37; H, 5.15; N, 15.23%.
N3-[2-Methyl-6-oxo-7,7,7-trifluorohept-4-en-4-yl]-2,3-dia-
minopyridine (3e). This compound was obtained as yellow
1
1
(C-2), 122.4 (CF3, JCF = 289), 122.1 (PyC-5), 99.9 (PyC-3).
solid, yields 73%, Mp. 123-125°C. H NMR (CDCl3) ꢀ = 11.51
GC/MS (EI, 70eV): m/z (%) = 326 (M+, 1), 257 (9), 229 (100),
78 (14), 51 (6). Anal. Calcd. for C15H10F3N2OCl (326.71): C,
55.15; H, 3.09; N, 8.57%. Found: C, 55.43; H, 3.31; N, 8.43%.
N-[1-(4-Bromophenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-
2-aminopyridine (2m). This compound was obtained as yellow
(s, 1H, NH), 8.07 (d, 1H, J = 5, PyH-6), 7.28 (d, 1H, J = 7.5,
PyH-4), 6.72-6.66 (m, 1H, PyH-5), 5.92 (s, 1H, H-2), 5.37 (s,
2H, NH2), 2.20 (d, 2H, J = 8, CH2), 1.80 (sept, 1H, J = 7, CH),
0.87 (d, 6H, J = 6, 2CH3). 13C NMR (CDCl3) ꢀ = 176.8 (q, 2JCF
=
34, C=O), 173.2 (C-1), 155.0 (PyC-2), 147.8 (PyC-6), 135.7
1
1
solid, yields 84%, Mp. 107-108°C. H NMR (CDCl3) ꢀ = 12.18
(PyC-4), 117.2 (PyC-3), 117.0 (q, JCF = 288, CF3), 113.3 (PyC-
(s, 1H, NH), 8.24 (d, J = 5, 1H, PyH-6), 7.51 (m, 3H, PyH-4,
Ph), 7.24 (d, J = 8.7, 2H, Ph), 7.01 (t, J = 7, 1H, PyH-5), 6.61 (d,
J = 8, 1H, PyH-3), 5.71 (s, 1H, H-2). 13C NMR (CDCl3) ꢀ =
178.5 (C=O, 2JCF = 34), 163.2 (C-1), 151.1 (PyC-2), 148.7 (PyC-
6), 137.7 (PyC-4), 134.4 (Ph), 131.9 (Ph), 129.4 (Ph), 125.1
5), 90.4 (C-2), 40.9 (CH2), 27.4 (CH), 22.0 (2CH3). Anal. Calcd.
for C13H16F3N3O (287.12): C, 54.35; H, 5.61; N, 14.63%. Found:
C, 54.09; H, 5.42; N, 14.31%.
N3-[2-Methyl-7-oxo-8,8,8-trifluorooct-5-en-5-yl]-2,3-dia-
minopyridine (3f). This compound was obtained as yellow
1
1
(Ph), 120.4 (C-2), 116.9 (CF3, JCF = 289), 115.4 (PyC-5), 94.4
solid, yields 65%, Mp. 122-124°C. H NMR (CDCl3) ꢀ = 12.00
(PyC-3). GC/MS (EI, 70eV): m/z (%) = 371 (M+, 1), 302 (7),
273 (100), 78 (67), 51 (14). Anal. Calcd. for C15H10F3N2OBr
(371.16): C, 48.54; H, 2.72; N, 7.55%. Found: C, 48.89; H, 2.85;
N, 7.38%.
(s, 1H, NH), 8.07 (d, 1H, J = 5, PyH-6), 7.29 (d, 1H, J = 7.5,
PyH-4), 6.71 (m, 1H, PyH-5), 5.60 (s, 1H, H-2), 5.04 (s, 2H,
NH2), 2.23 (t, 2H, J = 8, CH2), 1.47 (m, 1H, CH), 1.37 (m, 2H,
CH2), 0.77 (d, 6H, J = 6, 2CH3). 13C NMR (CDCl3) ꢀ = 177.6 (q,
2JCF = 34, C=O), 174.7 (C-1), 155.0 (PyC-2), 147.9 (PyC-6),
General procedure for the Preparation of Substituted N3-
[3-oxo-4,4,4-trifluoroalk-1-en-1-yl]-2,3-aminopyridines (3b-k,
3o, 3q). To a stirred solution of 2,3-diaminopyridine (0.327 g, 3
mmol) in 10 mL of dry methanol, 4-alkoxy-4-aryl(alkyl)-1,1,1-
trifluoroalk-3-en-2-ones (1b-k, 1o, 1q) (3 mmol) were added at
0°C. The mixture was stirred for 24 hours at 0°C. After the
reaction time, the solvent was removed under reduced pressure
and the crude solid products (3b-k, 3o, 3q) were recrystallized
from hexane.
1
135.6 (PyC-4), 117.2 (PyC-3), 117.0 (q, JCF = 288, CF3), 113.4
(PyC-5), 89.8 (C-2), 36.7 (CH2), 30.2 (CH), 27.6 (CH2), 21.7
(2CH3). Anal. Calcd. for C14H18F3N3O (301.14): C, 55.81; H,
6.02; N, 13.95%. Found: C, 55.50; H, 5.87; N, 13.72%.
N3-[9-Oxo-10,10,10-trifluorodec-7-en-7-yl]-2,3-diamino-
pyridine (3g). This compound was obtained as yellow solid,
yields 96%, Mp. 122-124°C. 1H NMR (CDCl3) ꢀ = 12.01 (s, 1H,
NH), 8.06 (d, 1H, J = 5, PyH-6), 7.29 (d, 1H, J = 7.5, PyH-4),
6.71 (dd, 2H, J = 7.5, J = 7.5, PyH-5), 5.61 (s, 1H, H-2), 5.05 (s,
2H, NH2), 2.40 (t, 2H, J = 8, CH2), 1.48 (quint., 2H, J = 7.5,
CH2), 1.25-1.14 (m, 6H, 3CH2), 0.83 (t, 3H, J = 7, CH3). 13C
NMR (CDCl3) ꢀ = 177.4 (q, 2JCF = 34, C=O), 174.3 (C-1), 155.0
(PyC-2), 148.1 (PyC-6), 135.9 (PyC-4), 117.4 (PyC-3), 117.1 (q,
1JCF = 288, CF3), 113.8 (PyC-5), 90.0 (C-2), 32.4 (CH2), 31.2
(CH2), 28.8 (CH2), 27.7 (CH2), 22.3 (CH2), 13.9 (CH3). Anal.
Calcd. for C15H20F3N3O (315.16): C, 57.13; H, 6.39; N, 13.33%.
Found: C, 56.70; H, 6.28; N, 13.08%.
N3-[3-Oxo-4,4,4-trifluoropent-2-en-2-yl]-2,3-diamino-
pyridine (3b). This compound was obtained as yellow solid,
yields 88%, Mp. 106-107°C. 1H NMR (CDCl3) ꢀ = 11.93 (s, 1H,
NH), 8.04 (d, 1H, J = 5, PyH-6), 7.28 (d, 1H, J = 7.5, PyH-4),
6.69 (dd, 1H, J=7.5, J=7.5, PyH-5), 5.58 (s, 1H, H-2), 5.21 (s,
2H, NH2), 2.01 (s, 3H, CH3). 13C NMR (CDCl3) ꢀ = 177.0 (q,
2JCF = 34, C=O), 169.9 (C-1), 154.9 (PyC-2), 147.9 (PyC-6),
1
135.4 (PyC-4), 117.5 (PyC-3), 117.2 (q, JCF = 288, CF3), 113.7
(PyC-5), 91.0 (C-2), 19.7 (CH3). Anal. Calcd. for C10H10F3N3O
(245.08): C, 48.98; H, 4.11; N, 17.14%. Found: C, 49.15; H,
4.21; N, 17.14%.
N3-[1-Phenyl-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2,3-dia-
minopyridine (3h). This compound was obtained as yellow solid,
N3-[6-Oxo-7,7,7-trifluorohept-4-en-4-yl]-2,3-diamino-pyridine
(3c). This compound was obtained as yellow solid, yields 71%,
1
yields 77%, Mp. 152-154°C. H NMR (CDCl3) ꢀ = 12.01 (s,1H,
NH), 7.84 (d, 1H, J = 5, PyH-6), 7.39-7.29 (m, 5H, Ph), 6.73 (d,
1H, J = 7.5, PyH-4), 6.39-6.37 (dd, 1H, J = 7.5, J = 7.5, PyH-5),
5.79 (s,1H, H-2), 5.26 (s, 2H, NH2). 13C NMR (CDCl3) ꢀ = 178.1
1
Mp. 128-130°C. H NMR (CDCl3) ꢀ = 12.01 (s, 1H, NH), 8.05
(d, 1H, J = 5, PyH-6), 7.28 (d, 1H, J = 7.5, PyH-4), 6.69 (dd,
2H, J = 7.5, J = 7.5, PyH-5), 5.60 (s, 1H, H-2), 5.23 (s, 2H,
NH2), 2.21 (q, 2H, J = 7, CH2), 1.52 (sex, 2H, J = 8, CH2), 0.88
2
(q, JCF = 34, C=O), 168.7 (C-1), 153.8 (PyC-2), 146.2 (PyC-6),
134.9 (PyC-4), 133.2 (Ph), 130.9 (Ph), 128.7 (Ph), 127.8 (Ph),
119.4 (PyC-3), 117.5 (q, 1JCF = 288, CF3), 113.6 (PyC-5), 92.9 (C-
2). Anal. Calcd. for C15H12F3N3O (307.09): C, 58.63; H, 3.94; N,
13.68%. Found: C, 58.27; H, 3.52; N, 13.73%.
2
(t, 3H, J = 7, CH3). 13C NMR (CDCl3) ꢀ = 177.2 (q, JCF = 34,
C=O), 174.1 (C-1), 155.0 (PyC-2), 147.9 (PyC-6), 135.6 (PyC-
1
4), 117.2 (PyC-3), 117.1 (q, JCF = 288, CF3), 113.5 (PyC-5),
N3-[1-(4-Methylphenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-
yl]-2,3-diaminopyridine (3i). This compound was obtained as
yellow solid, yields 78%, Mp. 156-158°C. 1H NMR (CDCl3) ꢀ =
12.01 (s, 1H, NH), 7.83 (d, 1H, J = 5, PyH-6), 7.18 (d, 2H, J =
7.5, Ph), 7.10 (d, 2H, J = 7.5, Ph), 6.76 (d, 1H, J = 7.5, PyH-4),
6.40 (m, 1H, PyH-5), 5.78 (s, 1H, H-2), 5.31 (s, 2H, NH2), 2.32
89.7 (C-2), 34.1 (CH2), 20.9 (CH2), 13.6 (CH3). Anal. Calcd. for
C12H14F3N3O (273.11): C, 52.75; H, 5.16; N, 15.38%. Found: C,
52.77; H, 4.82; N, 15.30%.
N3-[2-Methyl-5-oxo-6,6,6-trifluorohex-3-en-3-yl]-2,3-dia-
minopyridine (3d). This compound was obtained as yellow
1
solid, yields 66%, Mp. 146-148°C. H NMR (CDCl3) ꢀ = 12.17
2
(s, 3H, CH3). 13C NMR (CDCl3) ꢀ = 177.9 (q, JCF = 34, C=O),
(s, 1H, NH), 8.07 (d, 1H, J = 5, PyH-6), 7.27 (d, 1H, J = 7.5,
PyH-4), 6.72-6.69 (m, 1H, PyH-5), 5.92 (s, 1H, H-2), 5.87 (s,
2H, NH2), 2.63 (sept, 1H, J = 7, CH), 1.14 (d, 6H, J = 6, 2CH3).
168.8 (C-1), 164.4 (Ph), 153.8 (PyC-2), 145.8 (PyC-6), 135.7
(PyC-4), 130.2 (Ph), 129.4 (Ph), 127.8 (Ph), 118.7 (PyC-3),
2
13C NMR (CDCl3) ꢀ = 180.4 (C-1), 177.6 (q, JCF = 34, C=O),
1
117.2 (q, JCF = 288, CF3), 115.8 (PyC-5), 92.7 (C-2), 21.3
1
155.1 (PyC-2), 148.2 (PyC-6), 135.8 (PyC-4), 117.3 (q, JCF
=
(CH3). Anal. Calcd. for C16H14F3N3O (321.11): C, 59.81; H,
4.39; N, 13.08%. Found: C, 60.06; H, 4.13; N, 13.37%.
288, CF3), 117.0 (PyC-3), 113.9 (PyC-5), 86.4 (C-2), 29.7 (CH),

1684
H. G. Bonacorso, R. V. Lourega, F. J. Righi, E. D. Deon, N. Zanatta, and M. A. P. Martins
Vol 45
N3-[1-(4-Methoxylphenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-
yl]-2,3-diaminopyridine (3j). This compound was obtained as
yellow solid, yields 91%, Mp. 127-129°C. 1H NMR (CDCl3) ꢀ =
12.02 (s, 1H, NH), 7.85 (d, 1H, J = 5, PyH-6), 7.24 (d, 2H, J =
9, Ph), 6.79 (m, 3H, Ph, PyH-4), 6.42-6.40 (dd, 1H, J = 7.5, J =
7.5, PyH-5), 5.77 (s, 1H, H-2), 5.25 (s, 2H, NH2), 3.78 (s, 3H,
Method B. From 4-Aryl(heteroaryl)-4-methoxy-1,1,1-
trifluorobut-3-en-2-ones [30]. A stirred solution of 2,3-diamino-
pyridine (0.218 g, 2 mmol) with 4-aryl(heteroaryl)-4-methoxy-
1,1,1-trifluorobut-3-en-2-ones (1h-n, 1p, 1q) (2 mmol) in 6 mL of
dry methanol was stirred at 50 °C during 24 h. After the reaction
time the solvent was removed under reduced pressure and the crude
solid products were washed with chloroform, obtaining pure dark
or gray solids (4h-n, 4p, 4q) (yields 54 – 71 %).
2-Phenyl-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b]-
diazepin-4-ol (4h). This compound was obtained as gray solid,
yields 54%, Mp. 141-143°C. 1H NMR (DMSO-d6) ꢀ = 8.12 (d, J
= 5, 1H, H-7), 8.04-8.0 (m, 2H, Ph), 7.66 (s, 1H, OH), 7.63 (d, J
= 7.5, H-9), 7.52-7.49 (m, 3H, Ph), 7.13-7.09 (dd, J = 7.5, J =
7.5, 1H, H-8), 6.42 (s, 1H, NH), 3.45 (d, J = 14.5, 1H, H-3a),
2.91 (d, J = 14.5, 1H, H-3b). 13C NMR (DMSO-d6) ꢀ = 162.7
2
OCH3). 13C NMR (CDCl3) ꢀ = 177.5 (q, JCF = 34, C=O), 168.5
(C-1), 161.7 (Ph), 153.9 (PyC-2), 146.1 (PyC-6), 134.8 (PyC-4),
1
129.7 (Ph), 125.1 (Ph), 119.7 (PyC-3), 117.2 (q, JCF = 288,
CF3), 114.1 (Ph), 113.7 (PyC-5), 92.4 (C-2), 55.2 (OCH3). Anal.
Calcd. for C16H14F3N3O2 (337.1): C, 56.97; H, 4.18; N, 12.46%.
Found: C, 57.26; H, 3.99; N, 11.94%.
N3-[1-(4-Fluorophenyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-
2,3-diaminopyridine (3k). This compound was obtained as
yellow solid, yields 82%, Mp. 152-154°C. 1H NMR (CDCl3) ꢀ =
11.96 (s,1H, NH), 7.89 (d, 1H, J = 5, PyH-6), 7.32 (d, 2H, J = 9,
Ph), 7.01 (t, 2H, J = 8.5, Ph), 6.77 (d, 1H, J = 7.5, PyH-4), 6.44-
6.42 (dd, 1H, J = 7.5, J = 7.5, PyH-5), 5.76 (s, 1H, H-2), 5.31 (s,
(C-2), 147.3 (C-5a), 145.5 (C-7), 138.2 (Ph), 136.8 (C-9a), 131.9
1
(C-9), 130.5 (Ph), 128.4 (Ph), 127.3 (Ph), 123.6 (q, CF3, JCF
=
2
288), 117.6 (C-8), 92.4 (q, C-4, JCF = 29), 34.2 (C-3). Anal.
Calcd. for C15H12F3N3O (307.09): C, 58.63; H, 3.94; N, 13.68%.
Found: C, 58.18; H, 3.53; N, 14.15%.
2
2H, NH2). 13C NMR (CDCl3) ꢀ = 178.1 (q, JCF = 34, C=O),
1
167.6 (C-1), 165.2-162.7 (d, J = 252, F-Ph), 153.9 (PyC-2),
146.5 (PyC-6), 135.1 (PyC-4), 130.1-130.0 (2J = 29, F-Ph),
2-(4-Methylphenyl)-4-trifluoromethyl-4,5-dihydro-3H-
pyrido[2,3-b]diazepin-4-ol (4i). This compound was obtained as
gray solid, yields 57%, Mp. 140-142°C. 1H NMR (DMSO-d6) ꢀ =
8.11 (d, J = 5, 1H, H-7), 8.03 (d, J = 8, 2H, Ph), 7.67 (m, 2H, OH,
H-9), 7.55 (d, J = 8, 2H, Ph), 7.11 (m, 1H, H-8), 6.44 (s, 1H, NH),
3.40 (d, J = 14.5, 1H, H-3a), 2.91 (d, J = 14.5, 1H, H-3b), 2.13 (s,
3H, CH3). 13C NMR (DMSO-d6) ꢀ = 161.6 (C-2), 147.3 (C-5a),
145.7 (C-7), 136.9 (Ph), 136.8 (C-9a), 135.4 (C-9), 128.6 (Ph),
1
129.3 (Ph), 119.2 (PyC-3), 116.6 (q, JCF = 288, CF3), 116.1-
3
115.9 (d, J = 9, F-Ph), 115.3 (PyC-5), 92.8 (C-2). Anal. Calcd.
for C15H11F4N3O (325.08): C, 55.38; H, 3.41; N, 12.92%. Found:
C, 55.34; H, 3.23; N, 13.13%.
N3-[1-(1-Naphthyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2,3-
diaminopyridine (3o). This compound was obtained as yellow
1
solid, yields 73%, Mp. 161-163°C. H NMR (CDCl3) ꢀ = 12.48
1
(s, 1H, NH), 7.91 (d, J = 5, 1H, PyH-6), 7.80 (m, 2H, nf), 7.67
(m, 1H, nf), 7.46 (m, 2H, naph), 7.38 (m, 2H, naph), 6.55 (d, J =
7.5, J = 7.5, 1H, PyH-4), 6.08-6.06 (dd, J = 7.5, J = 7.5, 1H,
PyH-5) 5.85 (s, 1H, H-2), 5.19 (s, 2H, NH2). 13C NMR (CDCl3)
ꢀ = 177.9 (q, 2JCF = 34, C=O),167.9 (C-1), 153.1 (PyC-2), 146.4
(PyC-6), 133.2 (naph), 132.6 (PyC-4), 130.8-124.1 (naph), 118.8
128.4 (Ph), 123.5 (q, CF3, JCF = 288), 117.8 (C-8), 92.3 (q, C-4,
2JCF = 29), 33.9 (C-3). Anal. Calcd. for C16H14F3N3O (321.11): C,
59.81; H, 4.39; N, 13.08%. Found: C, 59.71; H, 4.37; N, 13.20%.
2-(4-Methoxyphenyl)-4-trifluoromethyl-4,5-dihydro-3H-
pyrido[2,3-b]diazepin-4-ol (4j). This compound was obtained
as gray solid, yields 67%, Mp. 137-139°C. 1H NMR (DMSO-d6)
ꢀ = 8.07 (d, J = 5, 1H, H-7), 7.97 (d, 2H, J = 9, Ph), 7.59 (d, J =
7.5, H-9), 7.48 (s, 1H, NH), 7.09-7.07 (dd, 1H, J = 7.5, J = 7.5,
H-8), 7.03 (d, 2H, J = 9, Ph), 6.07 (s, 1H, NH), 3.83 (s, 3H,
OCH3), 3.39 (d, 1H, J = 14.5, H-3a), 2.85 (d, 1H, J = 14.5, H-
3b). 13C NMR (DMSO-d6) ꢀ = 161.9 (Ph), 161.2 (C-2), 147.3
(C5a), 144.9 (C-7), 136.3 (Ph), 132.3 (C-9a), 130.7 (C-9), 129.0
(Ph), 129.6 (q, 1JCF = 288, CF3), 117.7 (C-8), 113.6 (Ph), 92.4 (q,
2JCF = 29, C-4), 55.2 (OCH3), 33.9 (C-3). Anal. Calcd. for
C16H14F3N3O2 (337.1): C, 56.97; H, 4.18; N, 12.46%. Found: C,
56.66; H, 3.82; N, 12.15%.
2
(PyC-3), 115.3 (q, JCF = 288, CF3), 114.9 (PyC-5), 94.7 (C2).
Anal. Calcd. for C19H14F3N3O (357.11): C, 63.86; H, 3.95; N,
11.76%. Found: C, 63.55; H, 3.87; N, 11.53%
N3-[1-(2-Thienyl)-3-oxo-4,4,4-trifluorobut-1-en-1-yl]-2,3-
diaminopyridine (3q). This compound was obtained as
1
yellow solid, yields 76%, Mp. 158-160°C. H NMR (CDCl3)
ꢀ = 12.18 (s, 1H, NH), 8.05 (d, J = 5, 1H, PyH-6), 7.48 (d, J =
5.0, 1H, tn), 7.29 (d, J = 3.0, 1H, tn), 7.15 (d, J = 7.0, 1H, tn),
7.00 (dd, J = 7.5, J = 7.5, 1H, PyH-4), 6.64-6.62 (dd, J = 5.0,
J = 5.0, 1H, PyH-5) 6.02 (s, 1H, H-2), 4.79 (s, 2H, NH2). 13C
2
NMR (CDCl3) ꢀ = 176.6 (q, JCF = 34, C=O), 161.3 (C-1),
2-(4-Fluorophenyl)-4-trifluoromethyl-4,5-dihydro-3H-
pyrido[2,3-b]diazepin-4-ol (4k). This compound was obtained
as gray solid, yields 69%, Mp. 160-162°C. 1H NMR (DMSO-d6)
ꢀ = 8.11 (d, J = 5, 1H, H-7), 8.07-8.05 (d, 2H, J = 6, Ph), 7.63
(d, J = 7.5, H-9), 7.53 (s, 1H, OH), 7.30 (t, 2H, J = 9, Ph), 7.10-
7.09 (dd, 1H, J = 7.5, J = 7.5, H-8), 6.21 (s, 1H, NH), 3.38 (d,
1H, J = 14.5, H-3a), 2.92 (d, 1H, J = 14.5, H-3b). 13C NMR
(DMSO-d6) ꢀ = 164.8 (Ph), 162.4 (C-2), 161.7 (C-5a), 147.3 (C-
7), 145.5 (C-9), 136.7 (Ph), 134.8 (Ph), 131.8 (C-9a), 129.8 (d,
154.7 (PyC-2), 147.7 (tn), 136.1 (PyC-6), 133.6 (PyC-3),
131.7 (tn), 131.6 (tn), 127.7 (PyC-4), 118.7 (tn), 117.3 (q, 1JCF
= 288, CF3), 114.1 (PyC-5), 91.1 (C-2). Anal. Calcd. for
C13H10F3N3OS (313.05): C, 49.84; H, 3.22; N, 13.41%.
Found: C, 49.73; H, 2.96; N, 12.69%.
General Procedures for the Preparation of 2-aryl(hetero-
aryl)-4-trifluoromethyl-3H-pyrido[2,3-b][1,4]diazepin-4-ols
(4).
1
3J = 9, F-Ph), 124.1 (q, JCF = 288, CF3), 117.7 (C-8), 115.2 (d,
Method A. From N3-[1-Aryl(heteroaryl)-3-oxo-4,4,4-
trifluorobut-1-en-1-yl]-2,3-diaminopyridine (3). A stirred
solution of N3-[1-aryl(heteroaryl)-3-oxo-4,4,4-trifluorobut-1-en-
1-yl]-2,3-diaminopyridines (3h-n, 3q) (3 mmol) in 5 mL of dry
ethanol was stirred at 50 °C during 16 h. After the reaction time
the solvent was removed under reduced pressure and the crude
solid products were washed with chloroform, obtaining pure
dark or gray solids (4h-n, 4q) (yields 50 - 73 %).
2
2J = 21, F-Ph), 92.3 (q, JCF = 29, C-4), 34.2 (C-3). Anal. Calcd.
for C15H11F4N3O (325.08): C, 55.39; H, 3.41; N, 12.92%. Found:
C, 55.72; H, 3.76; N, 12.60%.
2-(4-Chlorophenyl)-4-trifluoromethyl-4,5-dihydro-3H-
pyrido[2,3-b]diazepin-4-ol (4l). This compound was obtained
as gray solid, yields 70%, Mp. 148-150°C. 1H NMR (DMSO-d6)
ꢀ = 8.13 (d, J = 5, 1H, H-7), 7.96 (d, 2H, J = 9, Ph), 7.70 (d, 2H,
J = 9, Ph, 1H, OH), 7.65 (d, J = 7.5, H-9), 7.11-7.10 (dd, 1H, J =

Nov-Dec 2008
Preparation of New Trifluoromethyl-containing 3H-Pyrido[2,3-b][1,4] diazepinols
1685
7.5, J = 7.5, H-8), 6.45 (s, 1H, NH), 3.40 (d, 1H, J = 14.5, H-3a),
2.91 (d, 1H, J = 14.5, H-3b). 13C NMR (DMSO-d6) ꢀ = 161.6
(C-2), 147.2 (C-5a), 145.7 (C-7), 137.0 (Ph), 136.8 (Ph), 135.4
- CAPES (R. V. Lourega and F. J. Righi) and CNPq (E. D.
Deon), are also acknowledged.
1
(C-9a), 131.1 (Ph), 129.1 (Ph), 128.4 (C-9), 123.5 (q, J = 288,
REFERENCES AND NOTES
2
CF3), 117.7 (C-8), 92.3 (q, J = 29, C-4), 34.1 (C-3). Anal.
Calcd. for C15H11ClF3N3O (341.05): C, 52.72; H, 3.24; N,
12.30%. Found: C, 52.34; H, 2.89; N, 12.25%.
[1] Song, L.; Chu, Q.; Zhu, S. J. Fluorine Chem. 2001, 107, 107.
[2] Zhu, S.; Qin, C.; Wang, Y.; Chu, Q. J. Fluorine Chem. 1999,
99, 183.
[3] Zhu, S.; Qin, C.; Xu, G.; Chu, Q.; Huang, Q. J. Fluorine
Chem. 1999, 99, 141.
[4] Kruchok, I. S.; Gerus, I. I.; Kukhar, V. P. Tetrahedron, 2000,
56, 6533.
[5] Andrew, R. J.; Mellor, J. M.; Reid, G. Tetrahedron, 2000, 56,
7255.
[6] Andrew, R. J.; Mellor, J. M. Tetrahedron, 2000, 56, 7267.
[7] Coles, J. S.; Mellor, J. M.; El-Sagheer, A. F.; Salem, E. E.;
Metwally, R. N. Tetrahedron, 2000, 56, 10057.
[8] Chi, K.; Furin, G. G.; Gatilov, Y. V.; Bagryanskay, I. Y.;
Zhuzhgov, E. L. J. Fluorine Chem. 2000, 103, 105.
[9] Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron, 2001, 57, 201.
2-(4-Bromophenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido-
[2,3-b]diazepin-4-ol (4m). This compound was obtained as gray
1
solid, yields 66%, Mp. 145-147°C. H NMR (DMSO-d6) ꢀ =
8.13 (d, J = 5, 1H, H-7), 7.96 (d, 2H, J = 9, Ph), 7.70 (d, 2H, J =
9, Ph, 1H, OH), 7.65 (d, J = 7.5, H-9), 7.12-7.10 (dd, 1H, J =
7.5, J = 7.5, H-8), 6.43 (s, 1H, NH), 3.40 (d, 1H, J = 14.5, H-3a),
2.92 (d, 1H, J = 14.5, H-3b). 13C NMR (DMSO-d6) ꢀ = 161.7
(C-2), 147.2 (C-7), 145.7 (C-5a), 137.4 (Ph), 136.9 (C-9a), 131.7
1
(Ph), 131.3 (Ph), 129.3 (C-9), 124.4 (Ph), 123.6 (q, JCF = 288,
2
CF3), 117.7 (C-8), 92.3 (q, JCF = 29, C-4), 34.1 (C-3). Anal.
Calcd. for C15H11BrF3N3O (385.0): C, 46.65; H, 2.87; N,
10.88%. Found: C, 46.70; H, 2.54; N, 11.18%.
2-(4,4'-Biphenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido-
[2,3-b]diazepin-4-ol (4n). This compound was obtained as gray
[10] Nenajdenko, V. G.; Statsuk, A. V.; Balenkova, E. S.
Tetrahedron, 2000, 56, 6549.
1
solid, yields 71%, Mp. 134-136°C. H NMR (DMSO-d6) ꢀ =
8.14 (d, J = 5, 1H, H-7), 8,10 (Ph), 7.81 (d, J = 8, 3H, Ph), 7.76
(d, J = 8, 2H, Ph), 7.68 (m, 1H, Ph, 1H, OH), 7.50 (m, 3H, Ph),
7.42 (d, J = 7.5, H-9), 7.14-7.10 (dd, J = 7.5, J = 7.5, 1H, H-8),
6.45 (s, 1H, NH), 3.48 (d, J = 14, 1H, H-3a), 2.94 (d, J = 14, 1H,
H-3b). 13C NMR (DMSO-d6) ꢀ = 168.1 (Ph), 162.1 (C-2), 154.9
(Ph), 147.3 (C-5a), 145.4 (C-7), 141.9 (Ph), 139.3 (Ph), 137.1
(Ph), 136.7 (C-9a), 131.9 (C-9), 128.8 (Ph), 127.9 (Ph), 126.6
[11] Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S.
Molecules, 1997, 2, 186.
[12] Pierce, M. E.; Parsons, R. L.; Radesca, L. A.; Lo, Y. S.;
Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M.
D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N.;
Chen, C.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson,
A. S.; Corley, E. G.; Grobowski, E. J. J.; Reamer, R.; Reider, P. J., J.
Org. Chem. 1998, 63, 8536.
1
(Ph), 126.5 (Ph), 126.4 (Ph), 123.6 (q, CF3, JCF = 288), 117.6
[13] Welch, J. T. Tetrahedron, 1987, 43, 3123.
2
(C-8), 92.3 (q, C-4, JCF = 29), 34.1 (C-3). Anal. Calcd. for
[14] Gerus,I. I.;
Gorbunova, M. G.;
Vdovenko, S. I.;
C21H16F3N3O (383.12): C, 65.79; H, 4.21; N, 10.96%. Found: C,
65.45; H, 3.88; N, 11.13%.
Yagupol'skii, Yu. L.; Kukhar, V. P. J. Org. Chem. USSR (Engl. Trans.)
1990, 26, 1623.
[15] Gorbunova, M.G.; Gerus, I. I.; Galushko, S.V.; Kukhar,V.
2-(2-Furyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b]-
diazepin-4-ol (4p). This compound was obtained as gray solid,
P. Synthesis 1991, 207.
1
[16] 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.
[17] Bonacorso, H. G.; Wentz, A. P.; Bittencourt, S. R. T.;
Marques, L. M. L.; Zanatta, N.; Martins, M. A. P. Synth. Comm. 2002,
32, 335.
[18] [a] Bonacorso, H. G.; Duarte, S. H. G.; Zanatta, N.;
Martins, M. A. P. Synthesis 2002, 1037. [b] Bonacorso, H. G.;
Drekener, R. L.; Rodrigues, I. R.; Vezzosi, R. P.; Costa, M. B.;
Martins, M. A. P.; Zanatta, N. J. Fluorine Chem. 2005, 126, 1384.
[19] Bonacorso, H. G.; Bittencourt, S. R. T.; Lourega, R. V.;
Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Synthesis 2000, 1431.
[20] Hojo, M.; Masuda, R.; Okada, E.; Sakaguchi, S.; Narumiya,
H.; Morimoto, K.; Tetrahedron Lett. 1989, 30, 6173.
[21] Okada, E.; Masuda, R.; Hojo, M.; Inoue, R. Synthesis 1992,
533.
yields 64%, Mp. 151-153°C. H NMR (DMSO-d6) ꢀ = 8.08 (m,
1H, H-7), 7.90 (s, 1H, fr), 7.71 (s, 1H, H-9), 7,58 (d, J = 7.5, 1H,
fr), 7.21 (m, 1H, H-6), 7.09 (dd, J= 7.5, J= 7.5, 1H, H-8), 6.68
(s, 1H, fr), 6.35 (s, 1H, fr), 3.37 (d, J = 14.5, 1H, H-3a), 2.87 (d,
J = 14.5, 1H, H-3b). 13C NMR (DMSO-d6) ꢀ = 152.8 (C-2),
147.3 (C-5a), 146.0 (C-7), 145.3 (fr), 136.6 (C-9a), 131.7 (C-
1
9a), 123.7 (q, CF3, JCF = 288), 117.7 (C-8), 113.9 (fr), 112.5
2
(fr), 92.0 (q, CF3, JCF = 29), 34.6 (C-3). Anal. Calcd. for
C13H10F3N3O2 (297.07): C, 52.53; H, 3.39; N, 14.14%. Found: C,
52.21; H, 3.17; N, 13.97%.
2-(2-Thienyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido-
[2,3-b]diazepin-4-ol (4q). This compound was obtained as gray
1
solid, yields 67%, Mp. 129-131°C. H NMR (DMSO-d6) ꢀ =
8.10 (d, J = 5, 1H, H-7), 7.75 (d, J = 5, 1H, tn), 7.68 (m, 2H,
OH, tn), 7.57 (d, J = 7.5, H-9), 7.17 (t, J = 4.5, 1H, tn), 7.09-
7.07 (dd, J = 7.5, J = 7.5, 1H, H-8), 3.50 (d, J = 14.5, 1H, H-3a),
2.90 (d, J = 14.5, 1H, H-3b). 13C NMR (DMSO-d6) ꢀ = 157.4
[22] 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.
(C-2), 147.4 (C-5a), 145.3 (C-7), 145.1 (tn), 136.4 (C-9a), 131.6
1
[23] Barchet, R.; Merz, K. W. Tetrahedron Lett. 1964, 2239.
[24] Israel, M.; Jones, L. C.; Modest, E. J. J. Heterocycl. Chem.
1967, 4, 659.
[25] Israel, M.; Jones, L. C. J. Heterocycl. Chem. 1969, 6, 735.
[26] Israel, M.; Jones, L. C.; Modest, E. J. Tetrahedron Lett.
1968, 4811.
(C-9), 131.3 (tn), 129.9 (tn), 128.1 (tn), 123.6 (q, CF3, JCF
=
2
288), 117.6 (C-8), 91.8 (q, C-4, JCF = 29), 35.2 (C-3). Anal.
Calcd. for C13H10F3N3OS (313.05): C, 49.84; H, 3.22; N,
13.41%. Found: C, 49.60; H, 2.96; N, 13.07%.
Acknowledgement. The authors are grateful for financial
support from Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq/ Proj. 473864/2006-1). Fellowships from
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
[27] Israel, M.; Jones, L. C.; J. Heterocycl. Chem. 1973, 10,
201.
[28] Savelli, F.; Boido, A.; Vazanna, I.; Sparatore, F. J.
Heterocycl. Chem. 1987, 24, 1709.

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H. G. Bonacorso, R. V. Lourega, F. J. Righi, E. D. Deon, N. Zanatta, and M. A. P. Martins
Vol 45
[29] Savelli, F.; Boido, A.; Piacente, S. J. Heterocycl. Chem.
2001, 38, 659.
[30] Bonacorso, H. G.; Lourega, R. V.; Deon, E. D.; Zanatta, N.;
Oliveira, M. R.; Costa, M. B.; Martins, M. A. P.; Zanatta, N.; Flores,
A. F. C. J. Heterocycl. Chem. 2005, 42, 1055; [f] Flores, A. F. C.;
Brondani, S.; Zanatta, N.; Rosa, A.; Martins, M. A. P. Tetrahedron Lett.
2002, 43, 8701.
Martins, M. A. P. Tetrahedron Lett. 2007, 48, 4835.
[32] Bonacorso, H. G.; Lourega, R. V.; Wastowski, A. D.;
Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2002,
43, 9315.
[33] Crystallographic data for compound 3i, reported in this paper,
have been deposited with the Cambridge Crystallographic Data Center
(CCDC 687400). Copies of the data can be obtained, free of charge, on
application to CCDC 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
[31] [a] Bonacorso, H. G.; Lopes, I. S.; Wastowski, A. D.;
Zanatta, N.; Martins, M. A. P. J. Fluorine Chem. 2003, 120, 29; [b]
Martins, M. A. P.; Colla, A.; Clar, G.; Fischer, P.; Krimmer, S.
Synthesis 1991, 483; [c] Siqueira, G. M.; Flores, A. F. C.; Clar, G.;
Zanatta, N.; Martins, M. A. P. Quim. Nova 1994, 17, 24. Chem Abstr.
1995, 122, 187063; [d] Bonacorso, H. G.; Martins, M. A. P.;
Bittencourt, S. R. T.; Lourega, R. V.; Zanatta, N.; Flores, A. F. C. J.
Fluorine Chem. 1999, 99, 177; [e] Bonacorso, H. G.; Cechinel, C. A.;