The first synthesis of dihydro-3H-pyrido[2,3-b][1,4]diazepinols and a new alternative approach for diazepinone analogues

Article abstract of DOI:10.1016/j.tetlet.2007.05.072

The first synthesis of a series of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b][1,4]di azepin-4-ols, where aryl = C₆H₅, 4-FC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄

Full text of DOI:10.1016/j.tetlet.2007.05.072

Tetrahedron Letters 48 (2007) 4835–4838
The first synthesis of dihydro-3H-pyrido[2,3-b][1,4]diazepinols
and a new alternative approach for diazepinone analogues
Helio G. Bonacorso,* Rogerio V. Lourega, Everton D. Deon,
Nilo Zanatta and Marcos A. P. Martins
Nu´cleo de Quı´mica de Heterociclos, NUQUIMHE, Departamento de Quı´mica, Universidade Federal de Santa Maria,
97105-900 Santa Maria, RS, Brazil
Received 21 March 2007; revised 8 May 2007; accepted 11 May 2007
Available online 18 May 2007
Abstract—The first synthesis of a series of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ols,
where aryl = C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4,40-biphenyl, 1-naphthyl and heteroaryl = 2-thien-
yl, 2-furyl obtained from the direct cyclocondensation reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,3-diaminopyri-
dine in 54–71% yield, is reported. Another alternative and efficient route for the synthesis of a series of 2-aryl(heteroaryl)-3H-
pyrido[2,3-b][1,4]diazepin-4(5H)-ones from the reaction 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with 2,3-diaminopyridine, in
54–70% yield, is also reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Benzodiazepine compounds have been considered the
most extensively consumed psychoactive drugs world-
wide due to their anxiolytic and anticonvulsant activity.
However, many undesirable side effects have been asso-
ciate with the use of benzodiazepines. Modifications in
the structure of these heterocycles have been made,
and the anxiolytic effect of benzodiazepines (clobazam)
has been described. However, considerably less is known
about the effects of substituents on 1,5-benzodiazepines,
and few studies on the synthesis and pharmacological
effects of new 1,4-diazepines fused to six-membered het-
erocycles have been carried out.1 On the other hand, the
trihaloacetylation of enol ethers or acetals has produced
4-aryl(heteroaryl)-4-methoxy-1,1,1-trifluoro(chloro)-alk-
3-en-2-ones (1, 2) in one step and in good yields.
Compounds 1 and 2 proved to be useful building blocks
for the synthesis of five-, six- and seven-member-trihalo-
methylated heterocyclic compounds. Moreover, these
trihalomethyl vinyl ketones have been considered the
best method for attaching a trihalomethyl group to het-
erocyclic rings due to their chemical versatility and easy
obtainment.2
known3 but just a few references from the literature
report the use of the trichloromethyl substituent as a good
leaving group in heterocyclic syntheses involving cyclo-
condensation reactions with 4-methoxy-1,1,1-trichloro-
alk-3-en-2-ones (2).4
Recently, we reported the synthesis of 2-trifluoro- and 2-
trichloromethyl-3H-1,5-benzodiazepines from the reac-
tion of ketones (1, 2) with o-phenylenediamine in good
yields.5 Next, we demonstrated that 4-phenyl-2-tri-
chloromethyl-3H-1,5-benzodiazepine hydrogen sulfate
possessed anxiolytic activity and produced motor
uncoordination similar to that observed in mice with
diazepam.6 In the same year, we also reported that
the same trichloro-substituted benzodiazepines pre-
sented an inhibitory effect on acetylcholinesterase and
ATPDase activities from the cerebral cortex of adult
rats.7
In recent years, Savelli et al.8 described pyrido[2,3-b]-
[1,4]diazepinone structures, some of which revealed
interesting neuroleptic properties. However, because of
the failure of the reactions of simple b-diketones, that
is, pentan-2,3-dione or benzoylacetone with 2,3-diamino-
pyridine to yield 3H-pyrido[2,3-b][1,4]diazepine struc-
tures since 1964 acyclic and cyclic b-ketoesters have
only been used as precursor for a series of pyrido[2,3-b]-
[1,4]diazepin-2-ones and/or the respective pyridodiaze-
pin-4-one isomers.8a,9–11 Moreover, no publication has
The classical haloform reaction in which the trichloro-
methyl substituent is a leaving group has long been
*
Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220
8031; e-mail: heliogb@base.ufsm.br
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.072

4836
H. G. Bonacorso et al. / Tetrahedron Letters 48 (2007) 4835–4838
been found with the objective of carrying out a regio-
specific and simultaneous introduction of a trifluoro-
methyl or a trichloromethyl and substituted aryl
groups at the pyrido[2,3-b][1,4]diazepine derivatives
starting from trihalomethyl substituted 1,3-diketones
or 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones. Thus, the inex-
istence of data about the reactions involving simple 1,3-
diketones and 2,3-diaminopyridine led us to try 1 and 2,
as possible cyclizing agents, especially in view of the
successful synthesis of 2-trifluoro- and 2-trichloro-
methyl-3H-1,5-benzodiazepines and in the search of
new heterocyclic structures with promising biological
activity. However, an extension of the reaction of 1
and 2 with 2,3-diaminopyridine, a non-symmetrical
heteroaromatic diamine, necessarily introduces the addi-
tional problem of two possible isomeric diazepine prod-
ucts. The formation of the pyridodiazepine system
presumably will depend on whether the initial reaction
at the more nucleophilic 3-amino function to occur at
the b-olefinic carbon of vinyl ketones 1 and 2 or at the
carbonyl carbon.
(1a–f, 1h–j) and 4-methoxy-1,1,1-trichloroalk-3-en-2-
ones (2a–j) with 2,3-diaminopyridine, respectively
(Scheme 1).
Ketones 1 and 2 are readily available CCC synthetic
blocks and were prepared from trifluoroacetylation or
trichloroacetylation reactions of enol ethers generated
in situ from the respective aryl- or heteroaryl methyl
ketone acetals with trifluoroacetic anhydride or with
trichloroacetyl chloride, respectively.12
In this study we found that trifluoromethylated ketones
1 when treated with 2,3-diaminopyridine at a molar
ratio of 1:1, respectively, in methanol as solvent for 24 h,
at 60–65 ꢁC, regiospecifically produced 2-aryl(hetero-
aryl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b][1,4]-
diazepin-4-ols (3a–f, 3h–i) in a one-step reaction and in
54–71% yield.13,14 Somewhat surprisingly, when these
reactions were carried out, employing ketones 2, also
at a molar ratio of 1:1, respectively, in anhydrous meth-
anol as solvent under reflux for 24 h, 2-aryl(heteroaryl)-
3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones (4a–j) were
easily isolated in 54–70% yields, as pure isomers.15,16
The above described conditions allowed us to regiospe-
cifically obtain diazepinones (4) instead of the analogues
2-aryl(heteroaryl)-4-trichloromethyl-4,5-dihydro-3H-pyr-
ido[2,3-b][1,4]diazepin-4-ol or the respective 2-keto-
pyridodiazepine isomer.
Striving for 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 trihalomethyl or carbonyl, aryl
and heteroaryl groups could be introduced as substitu-
ents on this promising triaza fused heterocyclic family.
Thus, as an extension of our research programme we
wish to report 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 (3a–f, 3h–i), as
well as a new alternative and efficient route to obtain
2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-
one (4a–j) analogues from the direct cyclocondensation
reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones
Although previously similar reaction conditions were
employed 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 towards the car-
bonyl group of the 4-aryl(heteroaryl)-4-methoxy-1,1,1-
trichloroalk-3-en-2-ones (2) promoting a efficient halo-
form reaction. Only compound 4a was synthesized
previously by Israel et al.10,11 and by Barchet and Merz9a
in 65% yield from the reaction of 2,3-diaminopyridine
with ethyl benzoylacetate, but under difficult reaction
conditions (boiling xylene for 4 h with azeotropic distilla-
tion of the formed water). Our procedure gives the same
compound under milder conditions (refluxing methanol
for 24 h) and in a similar yield (54%), as well as increas-
ing the scope of the reaction with the possibility of intro-
ducing other aryl and heteroaryl substituents on this
pyridodiazepinone system.
H9
R
N
H8
H3
i
(X = F)
54-71%
H3
OH
CF3
H7
N
N
H
O
OMe
3a-f, 3h-i
X3C
R
1a-f, 1h-i (X = F)
H9
2a-j
(X = Cl)
R
In order to obtain other new pyridodiazepin-2-
ones bearing interesting aryl substituents and owning
10- and 12-p-electron systems at the 2-position of these
heterocycles, novel 4-aryl-1,1,1-trichloro-4-methoxybut-
3-en-2-ones (2g–h) were prepared from the reaction of 1-
acetonaphthone and 4,40-acetylbiphenyl, respectively,
with trimethyl orthoformate in the presence of p-tolue-
nosulfonic acid (Scheme 2).17 The subsequent acylation
reaction of the respective acetals using trichloroacetyl
chloride in pyridine and chloroform as solvent was car-
ried out at a molar ratio of 1:2:2 (acylating agent/pyri-
dine/acetal) to obtain 2g–h. The most satisfactory
reaction condition was found to be 16 h at a tempera-
ture ranging from 0 to 45 ꢁC for both trichloroacetyl-
ation reactions.
N
N
H8
H3
H3
ii
(X = Cl)
54-70%
H7
N
O
H
4a-j
1-4
R
a
Ph
b
c
d
e
4-MePh
4-OMePh
4-FPh
4-ClPh
1-4
R
f
g
h
i
j
4-BrPh
1-Naphtyl
4-4’-Biphenyl
2-Furyl
2-Thienyl
Scheme 1. Reagents and conditions: (i) 2,3-(NH2)2C5H3N, MeOH,
60–65 ꢁC, 24 h; (ii) 2,3-(NH2)2C5H3N, MeONa, MeOH, 60–65 ꢁC,
24 h.

H. G. Bonacorso et al. / Tetrahedron Letters 48 (2007) 4835–4838
4837
1. p-CH3PhSO3H, HC(OCH3)3,
MeOH, r. t., 24 hours.
2. Cl3CCOCl, pyridine, CHCl3,
0-45 °C, 16 hours.
Unless otherwise indicated all common reagents and sol-
vents were used as obtained from commercial suppliers
without further purification. All melting points were
determined on a Reichert Thermovar apparatus and
are uncorrected. 1H and 13C 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 DMSO-
d6 for 3a–f, 3h–i and 4a–j using TMS as internal refer-
ence. The CHN elemental analyses were performed on
O
O
OMe
R
CH3
Cl3C
R
74 - 86 %
2g-h
R
2
g
h
a Perkin Elmer 2400 CHN elemental analyzer (Sao
˜
Paulo University—USP/Brazil).
Scheme 2.
The unambiguous 1H and 13C NMR chemical shift
assignments of 4-trifluoromethylated pyridodiazepin-4-
ols (3a–f, 3h–i) and pyridodiazepin-4(5H)-ones (4a–j)
were obtained with the help of 1D- and DEPT 135-
NMR experiments, by comparison with NMR data of
other diazepinones formerly synthesized in our labora-
tory and by structural analyses by X-ray diffraction
performed on the N3-[1-(p-tolyl)-3-oxo-4,4,4-trifluoro-
(chloro)but-1-en-1-yl]-2,3-diaminopyridine intermediates,
which demonstrated clearly that the first reaction step
occurs when the N-3 of 2,3-diaminopyridine adds to
the b-olefinic carbon of the vinyl ketones 1b and 2b.
Acknowledgements
The authors thank the Conselho Nacional de Desen-
´
´
volvimento Cientıfico e Tecnologico—CNPq (Process
No. 303636/2002-5) for financial support and PIBIC-fel-
lowship (for E. D. Deon). Fellowship from Coor-
´
denac¸ao de Aperfeic¸oamento de Pessoal de Nıvel
˜
Superior—CAPES (for R.V.L.) is also acknowledged.
References and notes
1
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Diazepinols 3a–f, 3h–i, show H NMR chemical shifts,
in DMSO-d6, of the diastereotopic methylene protons
(H-3a and H-3b) as a characteristic AB system and as
a doublet in the range of 3.38–3.45 ppm and another
doublet in the range of 2.85–2.90 ppm, respectively, with
2
a geminal coupling constant in the range of J = 14.3–
19.4 Hz. Still show a signal characteristic of NH as a sin-
glet in the range of 6.07–6.45 ppm, and the hydrogenius
of hydroxyls shows a signal in the range 7.04–7.9 ppm.
The signals for the pyridine hydrogens H-7, H-8, H-9,
for compounds 3a–f, 3h–i and 4a–j, are in the range of
8.14–8.06 ppm, 7.13–7.09 ppm and 7.66–7.59 ppm,
respectively. Diazepinones 4a–j show the 1H NMR
chemical shifts of the methylene protons (H-3) as a sin-
glet in the range of 3.5–3.7 ppm. The trifluoromethyl-
ated heterocycles 3a–f, 3h–i present the 13C chemical
shifts of diazepine ring C-3 at the average of 34.1 ppm.
The C-3 for compounds 4a–j present a signal at the aver-
age of 40 ppm. Pyridodiazepines 3a–f, 3h–i and 4a–j
present the typical 13C chemical shifts of pyridine ring
carbons at the average of 146 ppm (C-7), 129 ppm
(C-8) and 117 ppm (C-9). The carbonyl carbon for
compounds 4a–j shows signals in the range of
166–168 ppm. The NMR signals of the furan (3i, 4i) and
thiophene (3j, 4j) derivatives were assignmented by
comparison with NMR data of other compounds
previously synthesized in our laboratory.18
3. March, J. In Advanced Organic Chemistry; Wiley Inter-
science: New York, 1992; p 632.
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1997, 34, 509; (b) Zanatta, N.; Madruga, C. C.; Marisco,
P. C.; Flores, D. C.; Bonacorso, H. G.; Martins, M. A. P.
J. Heterocycl. Chem. 2001, 37, 1213; (c) Flores, A. F. C.;
Zanatta, N.; Rosa, A.; Brondani, S.; Martins, M. A. P.
Tetrahedron Lett. 2002, 43, 5005; (d) Bonacorso, H. G.;
Lourega, R. V.; Wastowski, A. D.; Flores, A. F. C.;
Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2002, 43,
9315; (e) 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.
5. (a) Bonacorso, H. G.; Marques, L. M. L.; Zanatta, N.;
Martins, M. A. P. Synth. Commun. 2002, 32, 3225; (b)
Bonacorso, H. G.; Bittencourt, S. T.; Wastowski, A. D.;
Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Tetrahedron
Lett. 1996, 37, 9155; (c) Bonacorso, H. G.; Bittencourt, S.
T.; Wastowski, A. D.; Wentz, A. P.; Zanatta, N.; Martins,
M. A. P. J. Heterocycl. Chem. 1999, 36, 45.
6. 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.
7. 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.
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Heterocycl. Chem. 1987, 24, 1709; (b) Savelli, F.; Boido,
A.; Satta, M.; Peana, A.; Marzano, C. Il Farmaco 1994,
49, 259; (c) Savelli, F.; Boido, A.; Damonte, G. J.
Heterocycl. Chem. 1996, 33, 1737.
In summary, we developed the first efficient and regio-
specific preparation of 3H-pyrido[2,3-b][1,4]diazepinol
system 3, as well as, a useful and alternative approach
to obtaining regiospecific 3H-pyrido[2,3-b][1,4]diaze-
pin-4(5H)-one 4, under mild conditions by a conven-
tional 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.

4838
H. G. Bonacorso et al. / Tetrahedron Letters 48 (2007) 4835–4838
9. (a) Barchet, von R.; Merz, K. W. Tetrahedron Lett. 1964,
15. Synthesis of 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diaze-
pin-4(5H)-ones (4a–j). General procedure: To a stirred
solution of 2,3-diaminopyridine (2 mmol, 0.218 g), in
6 mL of dry methanol, was added 2 mmol of CH3ONa.
After 10 min was added 4-aryl(heteroaryl)-4-methoxy-
1,1,1-trichlorobut-3-en-2-ones (2a–j) (2 mmol) in one
portion and the solution was stirred at 60–65 ꢁC for
24 h. Thereafter the reaction time the solvent was
removed under reduced pressure and the crude solids
products were washed with water and then with chloro-
form, obtaining a dark solid (4a–j), as pure compounds
(yields 54–70%).
16. Compound 4a was obtained as a dark solid, yield 54%, mp
250–252 ꢁC. See lit.10 yield 65%, mp 258 ꢁC. Compounds
4a–j were characterized by 1H and 13C NMR. Spectral
NMR data of compound 4a: 1H NMR (DMSO) d = 10.98
(s, 1H, NH), 8.37–8.34 (dd, 1H, J = 1.5, J = 1.5, H7),
8.11–8.06 (m, 2H, aromatic-H), 7.88–7.85 (dd, 1H,
J = 1.5, J = 1.5, H9), 7.58–7.54 (m, 3H, aromatic-C),
7.35–7.31 (dd, 1H, J = 4.3, J = 4.3, H8), 3.61 (s, 2H,
CH2). 13C NMR (DMSO) d = 166.0 (C@O), 159.3 (C2),
146.0 (C7), 142.4 (C5a), 136.7 (aromatic-C), 136.3 (C9),
134.4 (aromatic-C), 131.2 (aromatic-C), 128.6 (aromatic-
C), 127.6 (C8), 120.0 (C9a), 40.1 (C3). Melting points and
yields of new compounds 4: Compd. [Mp (ꢁC), yield (%)]:
4a [(250–252), 54]; 4b [(257–259), 55]; 4c [(245–247), 57]; 4d
[(252–254), 60]; 4e [(262–264), 64]; 4f [(266–268), 53]; 4g
[(251–253), 59]; 4h [(248–250), 59]; 4i [(218–220), 62]; 4j
[(264–266), 70].
17. Synthesis of 4-methoxy-4-(1-naphthyl)-1,1,1-trichlorobut-
3-en-2-one (2g) and the 4-(4,40-biphenyl) analogue (2h).
General procedure: To an ice-cold stirred mixture of 1-
acetonaphthone and 4,40-acetylbiphenyl dimethyl acetals
(30 mmol), pyridine (60 mmol), and anhydrous chloro-
form (30 mL) is added dropwise pure trichloroacetyl
chloride (60 mmol) and after the end of the slow addition,
the mixture is stirred for more 16 h at 45 ꢁC. Then, the
mixture is washed with 0.1 M aqueous solution of hydro-
chloric acid (3 · 15 mL) and water (2 · 15 mL), and is
dried with magnesium sulfate. The solvent is evaporated to
give the practically pure products 2g (86% yield) or 2h
(74% yield). The pure compounds 2g–h are obtained by
recrystallization from methanol. Compounds 2g–h were
fully characterized by spectroscopic methods and gave
satisfactory analytical and spectral data. Compound 2g:
C8H11Cl3O2, mw 245.53; red oil; 1H NMR (CDCl3): d 5.97
(s, H3), 3.81 (s, OCH3), 2.77 (t, CH2), 1.58 (sext, CH2), 0.98
(t, CH3); 13C NMR (CDCl3): d 183.8 (C4), 179.8 (C2), 97.9
(CCl3), 89.7 (C3), 56.2 (OCH3), 35.2 (CH2), 20.5 (CH2),
13.8 (CH3). Compound 2h: C9H13Cl3O2, mw 259.56;
mp 88–90 ꢁC; 1H NMR (CDCl3): d 6.00 (s, H3), 3.80
(s, OCH3), 2.70 (d, CH2), 2.03 (m, CH), 0.96 (d, 2CH3);
13C NMR (CDCl3): d 183.2 (C4), 179.9 (C2), 98.0 (CCl3),
90.3 (C3), 56.1 (OCH3), 41.7 (CH2), 27.4 (CH), 22.3
(2CH3).
33, 2239; (b) Israel, M.; Jones, L. C.; Modest, E. J. J.
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11. Synthesis of 2-phenyl-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-
ones (4a).10 Procedure: A mixture of 0.01 mol (1.09 g)
of 2,3-diaminopyridine and 0.015 mol (2.88 g) of ethyl
benzoylacetate in 80 mL of xylene was brought to a
boil. The water, which was formed during the reaction,
was separated by azeotropic distillation. Tan crystals
began to form after 1 hour and the mixture was heated for
an additional 3 h to complete the reaction. After being
cooled, product 4a was separated by filtration and was
recrystallized twice from xylene to give pale yellow
needles, 1.5 g (65%), mp 258 ꢁC.
12. (a) Martins, M. A. P.; Siqueira, G. M.; Flores, A. F. C.;
Clar, G.; Zanatta, N. Quı´mica Nova 1994, 17, 24; Chem.
Abstr. 1995, 122, 187063a; (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, 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, 1013; (f) Martins, M. A. P.;
Bastos, G. P.; Bonacorso, H. G.; Zanatta, N.; Flores, A.
F. C.; Siqueira, G. M. Tetrahedron Lett. 1999, 40, 4309.
13. Synthesis of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-dihy-
dro-3H-pyrido[2,3-b][1,4]diazepin-4-ols (3a–f, 3h–j). Gen-
eral procedure: A stirred solution of 2,3-diaminepyridine
(2 mmol, 0.218 g) with 4-aryl(heteroaryl)-4-methoxy-1,1,1-
trifluorobut-3-en-2-ones (1a–f, 1h–j) (2 mmol) in 6 mL of dry
methanol was stirred at 60–65 ꢁC for 24 h. After the reaction
time the solvent was removed under reduced pressure and
the crude solids products were washed with chloroform,
obtaining a pure dark solid (3a–g) (yields 54–71%).
14. Compound 3a was obtained as a dark solid, yield 56%, mp
141–143 ꢁC. Compounds 3a–f, 3h–i were characterized by
1H and 13C NMR. Spectral NMR data of compound 3a:
1H NMR (DMSO) d = 8.14–8.13 (dd, 1H, J = 1.5,
J = 1.5, H7), 8.06–8.03 (m, 2H, J = 8.8, J = 8.8, aro-
matic-H), 7.67–7.63 (dd, 1H, J = 1.5, J = 1.5, H9), 7.52–
7.49 (m, 3H, aromatic-H, 1H, OH), 7.12-7.09 (dd, 1H,
J = 4.7, J = 4.7, H8), 6.45 (s, 1H, NH), 3.45–2.91 (dd, 2H,
J = 14.0, J = 14.0, CH2). 13C NMR (DMSO) d = 154.88
(C2), 153.02 (C5a), 145.70 (C7), 144.03 (aromatic-C),
129.22 (C9), 128.83 (aromatic-C), 128.27 (aromatic-C),
126.93 (aromatic-C), 124.15 (CF3, J = 288.2), 119.70 (C8),
118.36 (C9a), 91.54 (C4, J = 31.0), 26.78 (C3). Melting
points and yields of new compounds 3: Compd. [Mp (ꢁC),
yield (%)]: 3a[(141–143), 54]; 3b [(140–142), 57]; 3c [(137–
139), 67]; 3d [(160–162), 69]; 3e [(148–150), 70]; 3f [(145–
147), 66]; 3h [(134–136), 71]; 3i [(151–153), 64]; 3j [(129–
131), 67].
18. Bonacorso, H. G.; Costa, M. B.; Silva, L. B.; Zanatta, N.;
Martins, M. A. P.; Flores, A. F. C. J. Braz. Chem. Soc.
2005, 16, 868.