Synthesis of new 1-[4-methane(amino)sulfonylphenyl]-5-[4-(aminophenyl)]-3- trifluoromethyl-1H-pyrazoles

Article abstract of DOI:10.1002/jhet.5570450623

(Chemical Equation Presented) A regiospecific cyclization-dehydration reaction of a 1-[4-(N-alkyl-N-(tert-butyloxycarbonyl)amino)-phenyl]-4,4,4- trifluorobutane-1,3-done with a 4-aminosulfonyl-, or 4-methylsulfonyl-, phenylhydrazine hydrochloride in refluxing ethanol proceeded with simultaneous loss of the N-tert-butyloxycarbonyl protecting group to afford a group of 1-(4-methanesulfonylphenyl or 4-aminosulfonylphenyl)-5-[4-(N-alkylaminophenyl)]- 3-(trifluoromethyl)-1H-pyrazoles (6). Subsequent reaction of the pyrazole 6 (R¹ = R² = Me) with nitric oxide (40 psi) proceeded via a N-methylamino-N-diazen-1-ium-1,2-diolate intermediate that undergoes protonation of the more basic diazen-1-ium-1,2-diolate N²-nitrogen and then loss of a nitroxyl (HNO) species to furnish the N-nitroso product 7.

Full text of DOI:10.1002/jhet.5570450623

Nov-Dec 2008
1707
Synthesis of New 1-[4-Methane(amino)sulfonylphenyl)]-5-[4-
(aminophenyl)]-3-trifluoromethyl-1H-pyrazoles
Khaled R. A. Abdellatif, Morshed A. Chowdhury, Edward E. Knaus*
aFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada T6G 2N8
eknaus@pharmacy.ualberta.ca
Received June 9, 2008
O
R1
O
N
Me
Me
N
H
+ O
N
N
N
N
N
N
H
+
HNO
Nitric oxide, 40 psi
NaOMe/MeOH, 25°
O
S
O
O
S
N
R2
N
Me
N
S
Me
N
F3C
O
F3C
O
F3C
O
7
6, R1 = Me, Et; R2 = Me, NH2
A regiospecific cyclization-dehydration reaction of a 1-[4-(N-alkyl-N-(tert-butyloxycarbonyl)amino)-
phenyl]-4,4,4-trifluorobutane-1,3-done with a 4-aminosulfonyl-, or 4-methylsulfonyl-, phenylhydrazine
hydrochloride in refluxing ethanol proceeded with simultaneous loss of the N-tert-butyloxycarbonyl
protecting group to afford a group of 1-(4-methanesulfonylphenyl or 4-aminosulfonylphenyl)-5-[4-(N-
alkylaminophenyl)]-3-(trifluoromethyl)-1H-pyrazoles (6). Subsequent reaction of the pyrazole 6 (R1 = R2 =
Me) with nitric oxide (40 psi) proceeded via a N-methylamino-N-diazen-1-ium-1,2-diolate intermediate
that undergoes protonation of the more basic diazen-1-ium-1,2-diolate N2-nitrogen and then loss of a
nitroxyl (HNO) species to furnish the N-nitroso product 7.
J. Heterocyclic Chem., 45, 1707 (2008).
INTRODUCTION
O
R1
N
O
N
+
N
+
The original concept that an anti-inflammatory drug
which selectively inhibits the inducible cyclooxygenase-2
(COX-2) isozyme in the periphery would be devoid of
adverse ulcerogenic effects was confirmed with the
development of celecoxib [1], rofecoxib [2] and
valdecoxib [3]. It soon became evident that highly
selective COX-2 inhibitors alter the balance in the COX
pathway causing a decrease in the level of the favorable
vasodilatory and anti-aggregatory prostacyclin (PGI2)
together with a simultaneous increase in the level of the
unfavorable prothrombotic thromboxane A2 (TxA2).
These contraindicated biochemical changes culminated in
higher incidences of elevated blood pressure and
myocardial infarction which prompted the voluntary
withdrawal of rofecoxib and valdecoxib [4]. Nitric oxide
(NO) is an effective vasodilation agent that also inhibits
platelet aggregation and adhesion [5]. Accordingly,
attachment of a NO-donor moiety to highly selective
COX-2 inhibitors offers a potential drug design concept to
circumvent the adverse cardiovascular events associated
with their chronic clinical use. We now describe an
investigation directed toward the synthesis of model
hybrid NO donor selective COX-2 inhibitory anti-
inflammatory agents that would be devoid of adverse
cardiovascular effects (see structure 1 in Figure 1).
Na
O
S
N
R2
N
F3C
O
1, R1 = Alkyl; R2 = Me, NH2
Figure 1. Structure of putative hybrid nitric oxide donor N-diazen-1-
ium-1,2-diolate derivatives of selective COX-2 inhibitory 1-(4-methane-
(amino)sulfonylphenyl)-5-[4-(N-alkylaminophenyl)]-3-trifluoromethyl-
1H-pyrazoles.
RESULTS AND DISCUSSION
In earlier studies, we reported N-diazen-1-ium-1,2-
diolate derivatives of secondary dialkylamines covalently
attached to the non-steroidal anti-inflammatory drugs
(NSAIDs) aspirin (acetylsalicylic acid), ibuprofen [2-(4-
isobutylphenyl)propionic acid] and indomethacin [1-(4-
chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid].
Biological evaluation indicated that these hybrid NO-
donor / NSAID prodrugs i) released NO efficiently, ii)
unlike the parent NSAIDs were devoid of gastrointestinal
ulcerogenicity, and iii) exhibited in vivo antiinflam-
matory activities comparable to the parent NSAID [6-8].

1708
K. R. A. Abdellatif, M. Chowdhury, E. Knaus
Vol 45
The synthetic strategy employed to prepare putative
Scheme 1
model compounds of general structure 1 (see Figure 1) is
illustrated in Scheme 1. Thus, reaction of the 4-
alkylaminoacetophenones (2a and 2b) with di-tert-butyl
dicarbonate gave the respective 1-[4-(N-alkyl-N-(tert-
butyloxycarbonyl)amino)phenyl]ethanone 3a (R1 = Me,
84%) and 3b (R1 = Et, 73%). The subsequent base-
catalyzed Claisen condensation of 3a and 3b with ethyl
trifluoroacetate furnished the corresponding 1-[4-(N-
alkyl-N-(tert-butyloxycarbonyl)amino)phenyl]-4,4,4-tri-
fluorobutane-1,3-diones 4a (R1 = Me, 93%) and 4b (R1 =
Et, 87%). The subsequent cyclization-dehydration
reaction of the 1,3-diones 4a and 4b with either (4-sulf-
amoylphenyl)hydrazine hydrochloride (5a), or (4-methyl-
sulfonylphenyl)hydrazine hydrochloride (5b), proceeded
with a simultaneous loss of the N-tert-butyloxycarbonyl
protecting group to afford the respective 1,5-diaryl-3-
trifluoromethylpyrazole product 6a-d in good yield (81-
98%). It is well documented that this latter reaction occurs
in a regiospecific manor to yield the 1,5-diarylpyrazole
R1
R1
CO2Bu-t
H
N
N
a
O
O
Me
Me
2a, R1 = Me
2b, R1 = Et
3a, R1 = Me
3b, R1 = Et
b
R1
CO2Bu-t
NHNH2 HCl
N
+
O
O
S
R2
O
O
CF3
product when
a phenylhydrazine hydrochloride is
4a, R1 = Me
4b, R1 = Et
5a, R2 = NH2
5b, R2 = Me
employed and the reaction is carried out in ethanol at
reflux temperature [1]. Reaction of 1-(4-methanesulfonyl-
phenyl)-5-[4-(N-methylaminophenyl)]-3-trifluoromethyl-
1H-pyrazole (6b) with nitric oxide gas (40 psi) at 25° in
the presence of NaOMe yielded a product which exhibited
a molecular ion in the mass spectrum (m/z 446.93, M +
Na) and microanalytical data that was consistent with the
N-nitroso product 1-(4-methanesulfonylphenyl)-5-[4-(N-
methyl-N-nitrosoaminophenyl)]-3-trifluoromethyl-1H-
pyrazole (7) in 47% yield.
The decomposition pathway of the N-amino-N-diazen-
1-ium-1,2-diolate moiety (see Figure 1) is dependent upon
the site of protonation. In this regard, protonation at the
amine nitrogen and then decomposition would produce
the amine and 2 molecules of NO as illustrated below.
c
R1
H
N
N
O
N
S
R2
F3C
O
6a, R1 = Me, R2 = NH2; 6b, R1 = R2 = Me
6c, R1 = Et, R2 = NH2; 6d, R1 = Et, R2 = Me
d (Compound 6b)
+
H
O
N
O
O
N
R2NH + 2NO
O
O
R1
O
N
O
+
+
R2N
N
R2N
N
N
N
R2N
N
H
Alternatively, protonation of the diazen-1-ium-1,2-
diolate N2-nitrogen and then decomposition would furnish
a nitrosamine (such as product 7 in Scheme 1) and a
nitroxyl species (HNO) as indicated below.
O
S
N
R2
N
F3C
O
7, R1 = R2 = Me
+
H
R2N N O
+
HNO
O
N
O
O
N
O
N
O
O
+
+
R2N
N
R2N
N
N
R2N
Reagents and conditions: a) di-tert-butyl dicarbonate, 4-
dimethylaminopyridine (DMAP), THF, reflux, 16 hours; b) NaOMe in
MeOH (25% w/v), methyl tert-butyl ether (MTBE), CF3CO2Et, 25°, 16
hours; c) EtOH, reflux, 20 hours, d) NaOMe in MeOH (25% w/v),
diethyl ether, nitric oxide (40 psi), 25°, 48 hours.
H
The formation of the N-nitroso product 7 indicates that
the intermediate N-amino-N-diazen-1-ium-1,2-diolate
product (see structure 1 in Figure 1) must undergo
protonation of the more basic diazen-1-ium-1,2-diolate
N2-nitrogen that is unstable undergoing subsequent
elimination of a HNO species [9].
The biological activity of the N-nitroso product 7 was
not investigated in view of the tumorigenic activity
frequently associated with the use of N-nitroso agents.

Nov-Dec 2008
Synthesis of 1,5-diaryl-3-trifluoromethyl-1H-pyrazoles
1709
3,74 (q, J = 6.9 Hz, 2H, CH2CH3), 7.33 (d, J = 8.6 Hz, 2H,
phenyl H-3, H-5), 7.94 (d, J = 8.6 Hz, 2H, phenyl H-2, H-6).
1-[4-(N-Methyl-N-(tert-butyloxycarbonyl)amino)phenyl]-
4,4,4-trifluorobutane-1,3-dione (4a). A solution of NaOMe in
MeOH (25% w/v, 4 mL, 17.7 mmoles) was added to a solution
of ethyl trifluoroacetate (2.35 g, 16.6 mmoles) in 7.5 mL of
methyl tert-butyl ether (MTBE) over a 2 minute period. A
solution of (3a) (3.74 g, 15 mmoles) in MTBE (4 mL) was then
added dropwise over 5 minutes, the reaction was stirred for 18
hours at 25°, and 3 N HCl (7 mL) was added. The organic layer
was collected, washed with brine (7.5 mL), dried over MgSO4,
filtered, and the solvent was removed in vacuo to give the dione
4a (4.8g, 93%) as a brown oil: IR (film) 2979 (C-H aromatic),
EXPERIMENTAL
Melting points were determined on
capillary apparatus and are uncorrected. Unless otherwise noted,
infrared (IR) spectra were recorded as films on NaCl plates
a
Thomas-Hoover
1
using a Nicolet 550 Series II Magna FT-IR spectrometer. H
NMR spectra were measured on a Bruker AM-300 spectrometer
in CDCl3 with TMS as the internal standard. Mass spectra (MS)
were recorded on a Water’s Micromass ZQ 4000 mass
spectrometer using the ESI ionization mode. Microanalyses
were performed for
C and H (MicroAnalytical Service
Laboratory, Department of Chemistry, University of Alberta)
and were within ± 0.4% of theoretical values unless otherwise
stated. Silica gel column chromatography was performed using
Merck silica gel 60 ASTM (70-230 mesh). 1-(4-
Methylaminophenyl)ethanone (2a) [10], (4-aminosulfonyl-
phenyl)hydrazine hydrochloride (5a) [11] and (4-methyl-
sulfonylphenyl)hydrazine hydrochloride (5b) [12] were prepared
according to literature procedures. All other reagents, purchased
from the Aldrich Chemical Company (Milwaukee, WI), were
used without further purification.
1
2934 (C-H aliphatic), 1707 (CO2), 1682 (CO) cm-1; H NMR
(CDCl3) ꢀ 1.51 [s, 9H, C(CH3)3], 3.34 (s, 3H, NCH3), 6.55 (s,
1H, H-2), 7.44 (d, J = 8.7 Hz, 2H, phenyl H-3, H-5), 7.93 (d, J =
8.7 Hz, 2H, phenyl H-2, H-6).
1-[4-(N-Ethyl-N-(tert-butyloxycarbonyl)amino)phenyl]-4,
4,4-trifluorobutane-1,3-dione (4b). The title compound 4b was
prepared starting from 3b, using a procedure similar to that
described to prepare 4a, as a brown oil in 87% yield: IR (film)
2978 (C-H aromatic), 2935 (C-H aliphatic), 1701 (CO2), 1684
(CO) cm-1; 1H NMR (CDCl3) ꢀ 1.24 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.51 [s, 9H, C(CH3)3], 3.78 (q, J = 7.2 Hz, 2H,
CH2CH3), 6.56 (s, 1H, H-2), 7.42 (d, J = 8.7 Hz, 2H, phenyl H-
3, H-5), 7.93 (d, J = 8.7 Hz, 2H, phenyl H-2, H-6).
General method for preparation of pyrazoles (6a-d). 4-
Aminosulfonylphenylhydrazine hydrochloride (5a, 0.982 g, 4.4
mmoles), or 4-methylsulfonylphenylhydrazine hydrochloride
(5b, 0.979 g, 4.4 mmoles) was added to a stirred solution of the
dione 4a or 4b (4.0 mmoles) in EtOH (50 mL) and the reaction
mixture was heated at reflux with stirring for 20 hours. After
cooling to 25°, the reaction mixture was concentrated in vacuo.
The residue was dissolved in EtOAc, washed with water and
brine, dried over MgSO4, filtered, and the solvent was removed
in vacuo to give the respective product 6a-d for which the
physical and spectral data are listed below.
1-(4-Ethylaminophenyl)ethanone (2b).
A
solution of
ethylamine (70% w/v in H2O, 23.3 mL, 362 mmoles) was added
to a solution of 4'-fluoroacetophenone (5.0 g, 36.2 mmoles) in
DMSO (10 mL), the reaction flask was fitted with a reflux
condenser, and the mixture was heated at 90° for 20 hours. The
reaction mixture was cooled to 25°, H2O (100 mL) was added,
the solid was filtered, dried, and then purified by silica gel
column chromatography (gradient elution: 10–60% EtOAc–
hexanes) to furnish 2b (2.1g, 36%) as a yellow solid: mp 101-
102° (lit [13] mp 103°); IR (film) 3325 (NH), 2935 (C-H
aromatic), 2904 (C-H aliphatic), 1652 (CO) cm-1; 1H NMR
(CDCl3) ꢀ 1.29 (t, J = 7.3 Hz, 3H, CH2CH3), 2.51 (s, 3H,
COCH3), 3.24 (q, J = 7.3 Hz, 2H, CH2CH3), 4.15 (br s, 1H, NH,
D2O exchangeable), 6.56 (dd, J = 7.0, 1.8 Hz, 2H, phenyl H-3,
H-5), 7.84 (dd, J = 7.0, 1.8 Hz, 2H, phenyl H-2, H-6).
1-[4-(N-Methyl-N-(tert-butyloxycarbonyl)amino)phenyl]-
ethanone (3a). A solution of 2a (1.86 g, 12.5 mmoles), di-tert-
butyl dicarbonate (4.1 g, 18.8 mmoles) and DMAP (0.14 g, 1.3
mmoles) in THF (50 mL) was heated at reflux temperature for
16 hours. The solution was cooled to 20° and the solvent was
removed under reduced pressure. The residue was partitioned
between EtOAc (50 mL) and a saturated aqueous NaHCO3
solution (50 mL), and the aqueous fraction was extracted with
EtOAc (2 ꢁ 25 mL). The combined organic fractions were
washed with water (2 ꢁ 25 mL) and then brine (25 mL), the
organic fractions were dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue was purified by
silica gel column chromatography using EtOAc-hexane (1:3,
v/v) as eluent to give 3a (2.6 g, 84%) as a pale yellow oil: IR
(film) 2978 (C-H aromatic), 2930 (C-H aliphatic), 1704 (CO2),
1681 (CO) cm-1; 1H NMR (CDCl3) ꢀ 1.49 [s, 9H, C(CH3)3], 2.59
(s, 3H, COCH3), 3.31 (s, 3H, NCH3), 7.37 (d, J = 8.8 Hz, 2H,
phenyl H-3, H-5), 7.94 (d, J = 8.8 Hz, 2H, phenyl H-2, H-6).
1-[4-(N-Ethyl-N-(tert-butyloxycarbonyl)amino)phenyl]eth-
anone (3b). The title compound was synthesized starting from
1-(4-ethylaminophenyl)ethanone (2b), using the same procedure
described for the preparation of 3a, as a pale yellow oil in 73%
yield: IR (film) 2977 (C-H aromatic), 2935 (C-H aliphatic),
1701 (CO2), 1684 (CO) cm-1; 1H NMR (CDCl3) ꢀ 1.27 (t, J = 6.9
Hz, 3H, CH2CH3), 1.44 [s, 9H, C(CH3)3], 2.60 (s, 3H, COCH3),
4-[5-(4-N-Methylaminophenyl)-3-(trifluoromethyl)-1H-py-
razol-1-yl]benzenesulfonamide (6a). 98% yield; pale yellow
powder; mp 148-150°; IR (film) 3438 (NH), 3319, 3174 (NH2),
2961 (C-H aromatic), 2928 (C-H aliphatic), 1333, 1163 (SO2)
1
cm-1; H NMR (CDCl3) ꢀ 2.76 (s, 3H, NCH3), 3.00 (br s, 1H,
NH, D2O exchangeable), 6.51 (d,
J = 8.5 Hz, 2H,
methylaminophenyl H-3, H-5), 6.59 (s, 1H, pyrazole H-4), 6.84
(br s, 2H, NH2, D2O exchangeable), 6.94 (d, J = 8.5 Hz, 2H,
sulfonamidophenyl H-2, H-6), 7.40 (d, J = 8.5 Hz, 2H,
methylaminophenyl H-2, H-6), 7.86 (d, J = 8.5 Hz, 2H,
sulfonamidophenyl H-3, H-5), MS 397.04 (M + 1). Anal. Calcd.
for C17H15F3N4O2S: C, 51.51; H, 3.81. Found: C, 51.55; H, 3.95.
1-(4-Methanesulfonylphenyl)-5-[4-(N-methylaminophen-
yl)]-3-(trifluoromethyl)-1H-pyrazole (6b). 93% yield; yellow
crystals; mp 65-67°, IR (film) 3413 (NH), 3024 (C-H aromatic),
1
2927 (C-H aliphatic), 1318, 1151 (SO2) cm-1; H NMR (CDCl3)
ꢀ 2.88 (s, 3H, NCH3), 3.09 (s, 3H, SO2CH3), 4.50 (br s, 1H,
NH, D2O exchangeable), 6.61 (d,
J = 8.6 Hz, 2H,
methylaminophenyl H-3, H-5), 6.69 (s, 1H, pyrazole H-4), 7.04
(dd, J = 6.8, 1.8 Hz, 2H, methanesulfonylphenyl H-2, H-6), 7.58
(d, J = 8.6 Hz, 2H, methylaminophenyl H-2, H-6), 7.95 (dd, J =
6.8, 1.8 Hz, 2H, methanesulfonylphenyl H-3, H-5); MS 396.08
(M + 1). Anal. Calcd. for C18H16F3N3O2S.1/5H2O: C, 54.19; H,
4.11. Found: C, 54.56; H, 4.50.

1710
K. R. A. Abdellatif, M. Chowdhury, E. Knaus
Vol 45
4-[5-(4-N-Ethylaminophenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide (6c). 86% yield; white crystals;
Acknowledgement. We are grateful to the Canadian
Institutes of Health Research (CIHR) for financial support
(MOP-14712) of this research.
mp 64-66°, IR (film) 3395 (NH), 3357, 3263 (NH2), 2972 (C-H
1
aromatic), 2932 (C-H aliphatic), 1332, 1153 (SO2) cm-1, H
NMR (CDCl3) ꢀ 1.29 (t, J = 7.1 Hz, 3H, CH2CH3), 1.50 (br s,
1H, NH, D2O exchangeable), 3.19 (q, J = 7.1 Hz, 2H,
CH2CH3), 4.94 (br s, 2H, NH2, D2O exchangeable), 6.60 (d, J =
7.2 Hz, 2H, ethylaminophenyl H-3, H-5), 6.68 (s, 1H,
pyrazole H-4), 7.03 (d, J = 8.6 Hz, 2H, sulfonamidophenyl H-
2, H-6), 7.53 (d, J = 7.2 Hz, 2H, ethylaminophenyl H-2, H-6),
7.92 (d, J = 8.6 Hz, 2H, sulfonamidophenyl H-3, H-5); MS
411.05 (M + 1). Anal. Calcd. for C18H17F3N4O2S.2/5H2O: C,
51.77; H, 4.20. Found: C, 52.07; H, 4.23.
1-(4-Methanesulfonylphenyl)-5-[4-(N-ethylaminophenyl)]-
3-(trifluoromethyl)-1H-pyrazole (6d). 81% yield; white crystals;
mp 54-56°, IR (film) 3395 (NH), 2971 (C-H aromatic), 2876 (C-H
aliphatic), 1321, 1154 (SO2) cm-1; 1H NMR (CDCl3) ꢀ 1.29 (t, J =
7.2 Hz, 3H, CH2CH3), 1.61 (br s, 1H, NH, D2O exchangeable),
3.07 (s, 3H, SO2CH3), 3.19 (q, J = 7.2 Hz, 2H, CH2CH3), 6.59 (d,
J = 7.9 Hz, 2H, ethylaminophenyl H-3, H-5), 6.68 (s, 1H, pyrazole
H-4), 7.02 (d, J = 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6),
7.59 (d, J = 7.9 Hz, 2H, ethylaminophenyl H-2, H-6), 7.95 (d, J
8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5), MS 410.09 (M +
1), Anal. Calcd for C19H18F3N3O2S: C, 55.74; H, 4.43. Found: C,
56.12; H, 4.81.
1-(4-Methanesulfonylphenyl)-5-[4-(N-methyl-N-nitroso-
aminophenyl)]-3-(trifluoromethyl)-1H-pyrazole (7). A solution
of 6b (0.791g, 2 mmoles) in a 1:1 mixture of acetonitrile/diethyl
ether (25 mL) was mixed with a solution of NaOMe (0.2 mmoles,
0.43 mL of a 25% w/v solution in MeOH) with stirring at 25°.
This mixture was purged with dry nitrogen gas for 5 min, and then
the reaction was allowed to proceed under an atmosphere of nitric
oxide (40 psi internal pressure) with stirring at 25° for 48 hours.
The reaction mixture was concentrated in vacuo, and the residue
was purified by silica gel column chromatography using EtOAc
/hexane (1:1, v/v) as eluent to give 7 (0.399g, 47%) as a pale
yellow powder: mp 141-143°; IR (film) 3021 (C-H aromatic),
2930 (C-H aliphatic), 1317, 1153 (SO2) cm-1; 1H NMR (CDCl3) ꢀ
3.09 (s, 3H, SO2CH3), 3.47 (s, 3H, NCH3), 6.86 (s, 1H, pyrazole
H-4), 7.37 (dd, J = 6.7, 1.8 Hz, 2H, methanesulfonylphenyl H-2,
H-6), 7.61 (m, 4H, methylaminophenyl), 7.99 (dd, J = 6.7, 1.7 Hz,
2H, methanesulfonylphenyl H-3, H-5); MS 446.93 (M + Na).
Anal. Calcd. for C18H15F3N4O3S: C, 50.94; H, 3.56. Found: C,
51.34; H, 3.94.
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