Reactions of β-alkoxyvinyl trifluoromethyl ketones. The synthesis of N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines and 4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines

Article abstract of DOI:10.1081/SCC-120013748

A series of five N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines 2 [CF₃COCH=C(R)NH-o-PhNH₂], where R=Ph, 4-MePh, 4-BrPh, 4-ClPh, 4-OMePh from the reaction of β-aryl-β-methoxyvinyl trifluoromethyl ketones 1 with o-ph

Full text of DOI:10.1081/SCC-120013748

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REACTIONS OF β-ALKOXYVINYL TRIFLUOROMETHYL
KETONES. THE SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-
TRIFLUORO-1-BUTEN-1-YL]-o-PHENYLENEDIAMINES AND
4-ARYL-2-TRIFLUOROMETHYL-3H-1,5-BENZODIAZEPINES
Helio Gauze Bonacorso a , Livete Magali Leão Marques a , Nilo Zanatta a & Marcos Antonio
Pinto Martins a
a Nucleo de Química de Heterociclos (NUQUIMHE) , Departamento de Química , Universidade
Federal de Santa Maria , Santa Maria, RS, 97.105-900, Brazil
Published online: 16 Aug 2006.
To cite this article: Helio Gauze Bonacorso , Livete Magali Leão Marques , Nilo Zanatta & Marcos Antonio Pinto Martins
(2002) REACTIONS OF β-ALKOXYVINYL TRIFLUOROMETHYL KETONES. THE SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-TRIFLUORO-1-
BUTEN-1-YL]-o-PHENYLENEDIAMINES AND 4-ARYL-2-TRIFLUOROMETHYL-3H-1,5-BENZODIAZEPINES, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:20, 3225-3232, DOI: 10.1081/
SCC-120013748
To link to this article: http://dx.doi.org/10.1081/SCC-120013748
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 20, pp. 3225–3232, 2002
REACTIONS OF b-ALKOXYVINYL
TRIFLUOROMETHYL KETONES. THE
SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-
TRIFLUORO-1-BUTEN-1-YL]-o-
PHENYLENEDIAMINES AND 4-ARYL-2-
TRIFLUOROMETHYL-3H-1,5-
BENZODIAZEPINES
*
Helio Gauze Bonacorso, Livete Magali Leao Marques,
Nilo Zanatta, and Marcos Antonio Pinto Martins
Nucleo de Quımica de Heterociclos (NUQUIMHE),
Departamento de Quımica, Universidade Federal de
Santa Maria, 97.105-900 Santa Maria, RS, Brazil
ABSTRACT
A series of five N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-
o-phenylenediamines
2
[CF3COCH¼C(R)NH-o-PhNH2],
where R¼Ph, 4-MePh, 4-BrPh, 4-ClPh, 4-OMePh from the
reaction of b-aryl-b-methoxyvinyl trifluoromethyl ketones
1 with o-phenylenediamine was prepared and isolated in
good yield (59–71%). Another series of five 4-aryl-2-trifluoro-
methyl-3H-1,5-benzodiazepines 3, where aryl¼Ph, 4-MePh,
*Corresponding author. E-mail: heliogb@base.ufsm.br
3225
DOI: 10.1081/SCC-120013748
Copyright & 2002 by Marcel Dekker, Inc.
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3226
BONACORSO ET AL.
4-BrPh, 4-ClPh, 4-OMePh was also obtained in an one-step
reaction from ketones 1 by an intramolecular cyclization reac-
tion with o-phenylenediamine under mild acid conditions in
good yields (60–77%).
Acetylated enol ethers and acetophenone acetals[1–11] with functiona-
lized acyl groups of the type CF3C(O), CCl3C(O) and CHCl2C(O) are of
general interest as precursors for a variety of substituted five-, six- and
seven-membered halomethylated heterocyclic compounds, e.g., isoxazoles
and dihydroisoxazoles, pyrazoles and pyrazolines,[7,12–17] pyrimidines, thio-
pyrimidines and pyrimidinones[18–22] and benzodiazepines.[23,24] More
specifically, the introduction of a trifluoromethyl group into many bioactive
molecules sometimes has resulted in significant enhancement of their
potency and duration of action because of the increased lipophilicity.[25]
In addition, we have observed in the literature that the condensation
of o-phenylenediamine with 1,3-dicarbonyl compounds has been the most
widely used method and the conventional procedure for the synthesis of
3H-1,5-benzodiazepines.[26,27] Recently, Venkataratnam and co-workers[28,29]
obtained trifluoromethylated 3H-1,5-benzodiazepines derived from 1,1,1-
trifluoromethyl-3-(isobutoxymethylene)-2-propanones in good yield, using
microwave irradiation. The conventional condensation of these propa-
nones, which have no aryl substituents at carbon-4, with o-arylenediamines
in refluxing xylene led to a complex mixture of products unsuitable for a
preparative method. This situation prompted us to investigate the poss-
ibility of the synthesis of trifluoromethylated 3H-1,5-benzodiazepines from
b-alkoxyvinyl trifluoromethyl ketones with the isolation of the acyclic
intermediates. These intermediates are very important and cannot be
isolated from conventional reactions between 1,3-dicarbonyl compounds
and o-phenylenediamine or using microwave irradiation. As an example,
the trichloromethylated intermediate N-[1-phenyl-3-oxo-4,4,4-trichloro-1-
buten-1-yl]-o-phenylenediamine, synthesized previously,[24] was submitted
to the National Cancer Institute for evaluation in vitro in 3-cell line anti-
cancer screen (NCS 715846). This compound showed a discreet anticancer
activity against lung, breast and CNS culture tumor cells.[31]
With continuing interest in new di- and trihalomethylated precursors,
intermediates and heterocyclic structures, the aim of the present work is to
report the results of reactions of 4 aryl-4-methoxyvinyl trifluoromethyl
ketones (1a–e) with o-phenylenediamine to isolate the intermediates
molecules (2a–e) and the application of these vinyl ketones (1a–e) to obtain
4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines (3a–e) by intramolecular
cyclo-condensation reaction with o-phenylenediamine in an one-step reaction
and without microwave procedures.

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b-ALKOXYVINYL TRIFLUOROMETHYL KETONES
3227
The b-aryl-b-methoxyvinyl trifluoromethyl ketones (1a–e) were
synthesised from the respective acetophenone dimethyl acetals with trifluoro-
acetic anhydride.[8] When b-aryl-b-methoxyvinyl trifluoromethyl ketones
(1a–e) were treated with o-phenylenediamine in dichloromethane for 2 h at
room temperature, the new N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-
phenylenediamines (2a–e) were formed with 59–71% yield. Subsequently,
we have found that b-aryl-b-methoxyvinyl trifluoromethyl ketones (1a–e)
when treated with o-phenylenediamine in ethanol/acetic acid (4 : 1) for 2–3 h,
but at 60–65ꢀC, form 4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines
(3a–e) in one-step with 60–77% yields. The compounds 2a–e could be read-
ily converted into 3a–e by refluxing in dichloromethane for 1.5 h with yields
higher than 90% (Sch. 1). All compounds 2a–e are yellow solid and stable
for many days at room temperature or for months without deterioration, if
stored in the refrigerator. All new compounds 2a–e were fully characterised
by NMR and GC/MS spectral data, the purity of compounds 2a–e and 3a–e
was assigned on the basis of elemental analysis. Selected physical and NMR
spectral data are shown in Tables 1 and 2. Elemental analysis data are
shown in Table 3.
Our experiments show an efficient method for the synthesis of a series
of new N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines 2
Scheme 1.

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3228
BONACORSO ET AL.
1
Table 1. Selected Physical and H/13C NMR Spectral Dataa of Compounds 2a–e
Yield
(%)b
1H NMR, ꢀ (ppm)/13C NMR,
ꢀ (ppm), JC-F (Hz)
Compd.
M.P. (ꢀC)c
106–108
2a
64
60
71
62
12.2 (s, 1H, N-H), 7.5–6.4 (m, 9H, aromatic-H),
5.8 (s, 1H, H2), 3.9(s, 2H, NH ).
2
177.8 (q, J ¼ 33.8,C¼O), 166.4 (C1), 137.0–114.1
(12C, aromatic-C), 117.3 (q, J ¼ 288.7, CF3),
92.9 (C2).
2b
2c
2d
2e
131–132
165–166
139–140
12.8 (s, 1H, N-H), 7.5–6.4 (m, 8H, aromatic-H),
5.8 (s, 1H, H2), 3.7 (s, 2H, NH2), 2.4 (s, 3H, CH3).
177.5 (q, J ¼ 35.2, C¼O), 166.2 (C1), 137.1–116.2
(12C, aromatic-C), 117.1 (q, J ¼ 288.0, CF3), 92.9
(C2), 21.3 ( p-CH3).
12.1 (s, 1H, N-H), 7.4–6.5 (m, 8H, aromatic-H),
5.7 (s, 1H, H2), 3.6 (s, 2H, NH2).
177.7 (q, J ¼ 33.6, C¼O), 167.7 (C1), 141.4–116.2
(12C, aromatic-C), 117.2 (q, J ¼ 288.4, CF3),
92.1 (C2).
12.1 (s, 1H, N-H), 7.3–6.4 (m, 8H, aromatic-H),
5.8 (s, 1H, H2), 3.7 (s, 2H, NH2).
178.2 (q, J ¼ 34.1, C¼O), 165.2 (C1), 137.4–114.2
(12C, aromatic-C), 117.0 (q, J ¼ 288.7, CF3),
93.7 (C2).
59142–143
12.1 (s, 1H, N-H), 7.3–6.5 (m, 8H, aromatic-H), 5.7
(s, 1H, H2), 3.9(s, 3H, p-OCH3), 3.8 (s, 2H, NH2).
177.8 (q, J ¼ 33.6, C¼O), 166.4 (C1), 132.8–114.1
(12C, aromatic-C), 117.3 (q, J ¼ 288.7, CF3),
92.9 (C2), 55.3 ( p-OCH3).
aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13 MHz and 13
at 50.32 MHz) in CDCl3/TMS; Yields of isolated compounds; The melting points
are uncorrected.
C
b
c
and 4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines 3 from b-trifluoro-
acetylated acetophenone acetals 1, which have been prepared previously
in analytically pure form and in moderate to good yields.
EXPERIMENTAL
1H- and 13C-NMR spectra, at 200.13 and 50.32 MHz respectively,
were recorded on a Bruker DPX-200 in a 5-mm probe in chloroform-D

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b-ALKOXYVINYL TRIFLUOROMETHYL KETONES
3229
1
Table 2. Selected Physical and H/13C NMR Spectral Dataa of Compounds 3a–e
Yield
(%)b
1H NMR, ꢀ (ppm)/13C NMR,
ꢀ (ppm), JC-F (Hz)
Compd.
M.P. (ꢀC)c
3a
64
82–84
81d
8.1–7.4 (2m, 9H, aromatic-H), 3.6 (s, 2H, H3).
153.4 (C4), 144.4 (q, J ¼ 35.7, C2), 141.2–125.8
(10s, 12C, aromatic-C), 119.0 (q, J ¼ 277.2,
CF3), 31.9(C3).
3b
65
118–120
7.9–7.2 (2d/m, 8H, aromatic-H), 3.4 (s, 2H, H3),
2.4 (s, 3H, p-CH3).
153.5 (C4), 144.6 (q, J ¼ 35.5, C2), 142.0–125.8
(10s, 12C, aromatic-C), 119.2 (q, J ¼ 277.0,
CF3), 32.0 (C3), 21.5 ( p-CH3).
3c
3d
3e
77
63
60
116–118
98–100
78–80
7.9–7.2 (d/m, 8H, aromatic-H), 3.4 (s, 2H, H3).
152.8 (C4), 144.3 (q, J ¼ 34.8 , C2), 141.1–125.7
(10s, 12C, aromatic-C), 118.8 (q, J ¼ 277.1,
CF3), 31.8 (C3).
8.0–7.2 (d/m, 8H, aromatic-H), 3.4 (s, 2H, H3).
151.9(C4), 143.7 (q, J ¼ 35.6, C2), 140.9–126.7
(10s, 12C, aromatic-C), 118.9(q, J ¼ 277.0,
CF3), 31.7 (C3).
8.1–7.0 (2d/m, 8H, aromatic-H), 3.8 (s, 3H,
p-OCH3), 3.6 (s, 2H, H3).
153.0 (C4), 144.3 (q, J ¼ 35.5, C2), 141.5–125.5
(10s, 12C, aromatic-C), 118.9(q, J ¼ 277.2,
CF3), 55.4 ( p-OCH3), 31.7 (C3).
aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13 MHz and
c
13C at 50.32 MHz) in CDCl3/TMS; bYields of isolated compounds; The melting
d
points are uncorrected; See Ref. [30].
with TMS as the internal reference. The melting points were taken on a
Reichert-Thermovar melting point microscope and are uncorrected. The
elemental analyses were performed on a CHN-Elementar Analysensysteme
Vario EL.
Synthesis of N-[1-Aryl-2-alkyl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-
o-phenylenediamines (2a–e)
General procedure: To a stirred solution of o-phenylenediamine
(20 mmol) in 80 mL of dry dichloromethane, a solution of the 4-methoxy-4-
aryl-1,1,1-trifluoro-3-buten-2-one (1a–e) (20 mmol) in dry dichloromethane

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3230
BONACORSO ET AL.
Table 3. Elemental Analysis Data of Compounds 2a–e and 3a–e
Elemental Analysis (%)
Calculated Found
Molecular Formula
Compound
Weight (g/mol)
C
H
N
C
H
N
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
C16H13F3N2O (306.28)
C17H15F3N2O (320.31)
C16H12BrF3N2O (385.18) 49.89 3.14 7.27 49.70 3.09 7.18
C16H12ClF3N2O (340.73) 56.40 3.55 8.22 56.20 3.30 8.17
C17H15F3N2O2 (336.31)
C16H11F3N2 (288.27)
C17H13F3N2 (302.29)
C16H10BrF3N2 (367.16)
C16H10ClF3N2 (322.71)
C17H13F3N2 (318.29)
62.74 4.28 9.16 62.45 4.23 9.10
63.75 4.72 8.75 63.60 4.398.50
60.71 4.50 8.33 60.61 4.22 8.29
66.66 3.85 9.72 66.66 4.06 9.71
67.54 4.33 9.27 67.58 4.55 9.29
52.34 2.75 7.03 52.21 2.81 7.06
59.55 3.12 8.68 59.50 3.26 8.72
64.15 4.12 8.80 64.02 4.28 8.87
was added for 1 h at 20–25ꢀC. The mixture was stirred for 1 h at 20–25ꢀC.
The solvent was evaporated and the solid or crude oily products 2a–e were
recrystallized from diethylether (yields 59–71%, Table 1).
Synthesis of 4-Aryl-2-trifluoromethyl-3H-
1,5-benzodiazepines (3a–e)
General procedure: To a stirred solution o-phenylenediamine (6 mmol)
in 4 mL of dry ethanol and 1 mL acetic acid, 4-alkoxy-4-aryl(alkyl)-1,1,1-
trifluoro-3-buten-2-ones (1a–e) (6 mmol) was added in small portions at
60ꢀC. The mixture was stirred for 2–3 h at 60ꢀC. The solvent was removed
and the crude solid products 3a–e were recrystallized from methanol (yields
60–77%, Table 2).
ACKNOWLEDGMENTS
The authors thank the financial support from the Conselho Nacional
de Desenvolvimento Cientıfico de Tecnologico (CNPq/PADCT III-Proj.
62.0228/97-0-QEQ).

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b-ALKOXYVINYL TRIFLUOROMETHYL KETONES
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Received in the USA September 14, 2001