Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors

Article abstract of DOI:10.1021/jo049264k

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diarylpyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.

Full text of DOI:10.1021/jo049264k

Syn th esis of 4,5-Dia r yl-1H-p yr a zole-3-ol Der iva tives a s P oten tia l
COX-2 In h ibitor s
Meena V. Patel,*,‡ Randy Bell, Sandra Majest, Rodger Henry, and Teodozyj Kolasa‡
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-3500
meena.v.patel@abbott.com
Received April 30, 2004
4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of
compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its
analogues 11a -c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized
with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-
pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the
O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large
scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily
synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representa-
tive compound from each class was confirmed by X-ray crystallography. Selected compounds tested
for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus
COX-1 enzyme.
In tr od u ction
for the COX-2 enzyme (Table 3). This compound, how-
ever, also showed high affinity for the COX-1 enzyme.
To improve the COX-2 enzyme selectivity of compound
2, we explored a series of conformationally restricted
N-acyl hydrazones such as compound 3. Acyl hydrazones
have been reported6 in the literature to exhibit antiin-
flammatory and analgesic activity. As we expected,
compound 3 showed a 100-fold selectivity for COX-2 over
COX-1 enzyme in the in vitro assay (Table 3). Cyclic aryl
hydrazones such as 4,5-diaryl-2H-pyridazine-3-one and
Pyrazole derivatives have a long history of application
in the agrochemical and the pharmaceutical industry1 as
herbicides and insecticides2 and as part of biologically
active pharmaceuticals.1,3 Celebrex3a (1), a currently
marketed selective COX-2 inhibitor, is a diaryl pyrazole
derivative. 3-Hydroxy pyrazoles and 3-amino pyrazoles
have been shown to be versatile intermediates to access
a variety of biologically active heterocycles.4
Our quest for a novel COX-2 inhibitor5 began with the
discovery that diaryl hydrazone 2 showed high affinity
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* Address correspondence to this author. Phone: +1-847-935-4846.
Fax: +1-847-935-5466.
‡ These authors contributed equally to this work.
(1) (a) Elguero, J . In Comprehensive Heterocyclic Chemistry II;
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10.1021/jo049264k CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/17/2004
7058
J . Org. Chem. 2004, 69, 7058-7065

Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol Derivatives
4, 5-diaryl-1H-pyrazol-3-one might provide even greater
selectivity. Since the six-membered hydrazones, pyridazi-
nones, had been elaborated by both Merck and Abbott,7
we focused our research effort on five-membered cyclic
acyl hydrazone, 4, 5-diaryl-1H-pyrazol-3-one.8 There are
several reports1,9 in the literature on the nature of the
tautomerism of unsubstituted 1H-pyrazol-3-ones and 4,5
mono or dialkyl 1H-pyrazol-3-ones showing the existence
of the keto as well as enol tautomers as a function of the
solvent and the mode of substitution. Therefore, we
decided to examine if 4,5-diaryl analogues such as the
intermediate 4-(4-fluorophenyl)-5-(4-methylsulfonyl)-1H
pyrazole-3-one, 4, would exist as a pyrazol-3-one or
pyrazole-3-ol. On the basis of the information in the
literature1,9 regarding the nature of the dipolar repulsion
between contiguous NH’s or lone pair repulsion between
contiguous imino nitrogens, compound 4 could potentially
F IGURE 1. Isomer A derivatives.
F IGURE 2. Isomer B derivatives.
exist mainly in the enolic form. In addition, the second
aryl group on the C4 position would be expected to
increase the acidity of the benzylic proton and promote
population of the enolic tautomeric form. Indeed, the
X-ray crystal structure of compound 4 demonstrated that
the molecule exists exclusively in the enolic form.
Two regioisomeric hydroxypyrazoles were possible
depending on the position of the sulfanylmethyl phar-
macophore (Figures 1 and 2). To determine which isomer
would show higher affinity and selectivity for the COX-2
enzyme, we synthesized both 4-(4-fluorophenyl)-5-(4-
methylsulfonyl)-1H pyrazole-3-ol (4) (isomer A) and 5-(4-
fluorophenyl)-4-(4-methylthio)-1H pyrazole-3-ol (12) (iso-
mer B). The presence of the hydroxy functionality in 4
could provide access to a 1,3 or 2,3 substitution pattern,
leading to several structurally diverse classes of com-
pounds such as 1,3-dialkyl pyrazoles 5 and 6, pyrazolo-
oxazines10 7, dihydro-oxa-1,8a-diaza-azulene 8, pyrazolo-
benzooxazines 9, and pyrazolo-oxazoles 10 and its
analogues 11a -c (Figures 1 and 2). The synthetic
methodology to prepare these various pyrazolo deriva-
tives and the biological activity of selected compounds is
described herein.
(6) (a) Matheus, M. E.; Oliveira, L. F.; Freitas, A. C. C.; Carvalho,
A. M. M. S. P.; Barreiro, E. J . Braz. J . Med. Biol. Res. 1991, 24, 1291-
1222. (b) Chem. Abstr. 1992, 116, 187490. (c) Sui, Z.; Guan, J .; Ferro,
M. P.; McCoy, K.; Wachter, M. P.; Murray, W. V.; Singer, M.; Steber,
M.; Ritchie, D. M.; Argentieri, D. C. Bioorg. Med. Chem. Lett. 2000,
10, 601-604. (d) Murineddu, G.; Loriga, G.; Gavini, E.; Peana, A. T.;
Mule, A. C.; Pinna, G. Arch. Pharm. Pharm. Med. Chem. 2001, 334,
393-398. (e) Reddy, E.; Reddy, M. V. patent WO 03/049698 A2.
(7) (a) Li, C. S.; Brideau, C.; Chan, C. C.; Savoie, C.; Claveau, D.;
Charleson, S.; Gordon, R.; Greig, G.; Gaunthier, J . Y.; Lau, C.;
Riendeau, D.; Therien, M.; Wong, E.; Prasit, P. Bioorg. Med. Chem.
Lett. 2003, 13, 597-600. (b) Black, L. A.; Basha, A.; Kolasa, T.; Kort,
M. E.; Liu, H.; McCarty, C. M.; Patel, M. V.; Rohde, J . J . WO9910331,
U.S. patent 6,307,047B1, 2001 (Abbott).
Resu lts a n d Discu ssion
Schemes 1 and 2 depict the synthetic methodologies
utilized to obtain diaryl-1H-pyrazole-3-ols 4 and 12. The
starting â-keto ester, 2-(4-fluorophenyl)-3-(4-(methylsul-
fanyl)phenyl)-3-oxo-propionic acid ethyl ester (22), was
synthesized by two methods. In the first approach
(Method 1, Scheme 1), known methodology for the
(8) (a) Kolasa, T.; Patel, M. V. U.S. patent 6,472,416B1, 2002
(Abbott). (b) This work was presented in part at the 28th National
Medicinal Chemistry Symposium in San Diego, CA, on J une 8-12,
2002; Poster No. 70.
(9) Parchment, O. G.; Green, D. V. S.; Taylor, P. J .; Hillier, I. H. J .
Am. Chem. Soc. 1993, 115, 2352-2356 and the references therein.
(10) During preparation of this manuscript, a publication by Rana-
tunge et al. (Ranatunge, R.; Garvey, D. S.; J anero, D. R.; Letts, L. G.;
Martino, A. M.; Murty, M. G.; Richardson, S. K.; Young, D. V.;
Zemetseva, I. S. Bioorg. Med. Chem. 2004, 12, 1357-1366) appeared
that describes some compounds from this class.
J . Org. Chem, Vol. 69, No. 21, 2004 7059

Patel et al.
SCHEME 1a
SCHEME 3
23, and 24 in good yield. In the second approach (Method
2, Scheme 1), compound 22 was synthesized via a
Grignard reaction between 4-fluorobenzylmagnesium
bromide (25) and 4-methylsulfanyl-benzonitrile (26) to
give 2-(4-fluorophenyl)-1-(4-(methylsulfanyl)phenyl)etha-
none11 (27), which upon condensation with ethyl cyano
formate12 in the presence of LHMDS gave the desired
product 22 in good yield. Cyclocondensation of 23 with
hydrazine hydrate in the presence of acetic acid provided
the key intermediate 4 in essentially quantitative yield.
Similarly, cyclocondensation of the thiomethyl analogue
22 with hydrazine followed by oxidation of the thiomethyl
group to the methyl sulfone gave the desired compound
4 in 90% yield.
Compound 12 was synthesized similarly from com-
pounds 18 and 21 in excellent yield.
Alkylation of 4 could lead to the mono- or dialkylated
product. When 1 equiv of alkylating reagent, e.g., phen-
acyl bromides, benzyl bromides, or bromopinacolone, etc.,
was used, the 3-O-alkylated analogue was formed exclu-
sively in high yield. This product can then be alkylated
at the 1 position with a different alkyl group. When two
or more equivalents of the alkylating reagent mentioned
earlier was used, 1,3-dialkylated product was isolated as
the major product and not the 2,3-dialkylation product.
This was confirmed by X-ray crystal structure of the
dialkyl product (compound 5a ). A series of 1,3-dialkylated
derivatives of 4 were synthesized with an excess of alkyl
halide and K2CO3 in an aprotic solvent, such as DMF
(5a -d , Scheme 3, Table 1). Compounds 6a -e were
synthesized by alkylation of 4 with a stoichiometric
amount of one alkyl halide, R-X, to give the O-alkylation
product followed by reaction with a second alkylating
agent R′-X in acetone with K2CO3 (Scheme 4, Table 1).
The structure assignment of compound 6c was supported
by X-ray crystallography. In the case of dibromoalkyl
reagents where the O-alkylated product can undergo an
intramolecular alkylation, alkylation occurs on the ni-
trogen at position 2 and not on the nitrogen at position
1 (Scheme 4). For example, reaction of 4 with the
requisite dibromo alkyl group in DMF at 50 °C afforded
pyrazolo-oxazine compounds 7a -c (Scheme 4). For n )
0, the cyclization occurred in excellent yield and moderate
yields were obtained for larger ring sizes (n ) 1, 2).
Alkylation of 4 with commercially available 1,4-dibro-
mobutene (tech. grade) under the same reaction condi-
tions provided compound 8a in low yield presumably
because the commercially available 1,4-dibromobutene
was predominantly the trans isomer. On the other hand,
reaction of 4 with dibromo-o-xylene afforded 3-(4-fluo-
rophenyl)-2-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-c][1,3]-
benzooxazepine (8b) in high yield.
a
Reagents and conditions: (a) LHMDS, THF, -78 °C; (b) Et2O,
0 °C to room temperature, 14 h; (c) LHMDS, THF, -78 °C, ethyl
cyanoformate.
SCHEME 2a
a
Reagents and conditions: (a) NH2NH2‚H2O, CH3CO2H, diox-
ane/H2O, reflux, 24 h; (b) 32% CH3CO3H, 0 °C, 1.15h.
synthesis of monoaryl â-keto-esters11 was used to syn-
thesize the diaryl â-ketoesters. (4-Fluorophenyl)acetic
acid ethyl ester (17) or (4-(methylsulfanyl)phenyl)acetic
acid ethyl ester (18) undergo acylation with the benzoyl
chlorides 19, 20, and 21 to give diaryl â-ketoesters 22,
(11) (a) Logue, M. W. J . Org. Chem. 1974, 39, 3455-3456. (b)
Scheibler: Stein: J PCEAO J . Prakt. Chem. 1934, 139, 105-107. (c)
Demopoulos, V. J .; Rekka, E.; Retsas, S. Pharmazie 1990, 45, 403-
407.
(12) Otter, R. R.; Shriner, R. L. J . Am. Chem. Soc. 1951, 73, 887-
891.
7060 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol Derivatives
TABLE 1. 1-Alk yl-3-a lk oxy-4,5-d ia r yl P yr a zoles
C no.
R
R′
R1
R2
methoda
yield (%)
5a
5b
5c
5d
6a
6b
6c
6d
6e
14a
14b
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
F
F
F
F
F
F
F
F
F
F
CH2COC(CH3)3
CH2(4-F-Ph)
CH2COC(CH3)3
CH2(4-F-Ph)
CH2CO(4-F-Ph)
CH2CO(2-thienyl)
ethyl
ethyl
ethyl
CH2CN
A
A
A
A
B
B
B
B
B
C
C
81
60
51
60
71
67
85
78
87
85
12
CH2CO(4-F-Ph)
CH2CO(2-thienyl)
CH2CO(4-F-Ph)
CH2CO(2-thienyl)
CH2COC(CH3)3
CH2COC(CH3)3
CH2COC(CH3)3
CH2CO(4-F-Ph)
CH2COC(CH3)3
CH2CHdC(Cl2)3
CH2CO(4-F-Ph)
ethyl
SO2CH3
SO2CH3
F
a
Method A: excess R1-X, K2CO3, DMF, 50 °C. Method B: (1) 1 equiv of R1-X, K2CO3, DMF; (2) 1 equiv of R2-X, acetone or DMF,
K2CO3, 50 °C. Method C: (1) 1equiv of R1-X, K2CO3, DMF; (2) 1 equiv of R2-X, acetone or DMF, K2CO3, 50 °C; (3) CH2Cl2, CH3CO3H, 0
°C, 2 h. Alkylating agents R1-X, R2-X: (5a ) bromopinacolone; (5b) 4-fluorobenzyl bromide; (5c) 4-fluorophenacylbromide; (5d ) bromomethyl-
2-thienyl-ketone; (6a ) (1) 4-fluorophenacyl bromide, (2) ethyl iodide, DMF; (6b) (1) bromomethyl-2-thienyl-ketone, (2) ethyl iodide, acetone;
(6c) (1) bromopinacolone; (2) ethyl iodide, acetone; 6d : (1) bromopinacolone; (2) bromoacetonitrile, acetone; (6e) (1) bromopinacolone, (2)
1,1,3-trichloroprop-1-ene, acetone; (14a ) (1) 4-fluorophenacyl bromide; (14b) (1) 4-fluorophenacyl bromide, (2) ethyl iodide, DMF.
SCHEME 4a
SCHEME 5a
a
Method A: alkylating agent, K2CO3, Cu, pyridine, rt. Method
B: alkylating agent, K2CO3, 50 °C then CuI, K2CO3, DMF, 150
°C. Alkylating agents: (9a ) 2-bromobenzylbromide, (9b) 2-chloro-
6-fluorobenzyl chloride, (9c) 1-(2-bromophenyl)-1-propylmesylate.
SCHEME 6
a
Reagents and conditions: (a) alkylating agent, K2CO3, DMF,
50 °C, 7 h. Alkylating agents: (7a ) 1,3-dibromoethane, (7b) 1,3-
dibromopropane, (7c) 1,4-dibromobutane, (8a ) 1,4-dibromo-2-
butene, (8b) R,R′-dibromo-o-xylene.
In the case of bromoalkyl-bromoaryl alkylating agents,
the first step, as seen in previous cases, leads to an
O-alkylated bromoaryl product. This bromoaryl com-
pound can then be cyclized on the nitrogen at the 2
position under Ullman coupling conditions to give com-
pounds such as 9a -c (Scheme 5). A stoichiometric
amount of 2-bromobenzyl bromide was reacted with 4 to
achieve complete O-alkylation. The reaction mixture was
then treated with Cu powder to afford the cyclization
product, pyrazolo-benzooxazines 9a , in 8% yield. When
CuI was used instead of Cu powder (Method B), a better
yield (60%) was obtained, therefore method B was used
to synthesize 9b in moderate yield (55%). Alkylation of
4 with the mesylate of 1-(2-bromophenyl)-1-propanol
followed by CuI-mediated cyclization at high temperature
yielded compound 9c in low yield (25%).
6, Table 2). The O-alkylated derivatives were formed by
alkylation of 4 and 12 with the appropriate R-halo
ketones. Cyclization of O-alkylated keto derivatives in
the presence of p-toluenesulfonic acid monohydrate in
toluene and acetic acid afforded pyrazolo[5,1-b]oxazole
compounds 10a -m . The structure of a representative
member of this series, compound 10m , was confirmed by
X-ray crystallography. Compounds 16a -c were obtained
by oxidation of the thiomethyl compounds to the sulfones
with peracetic acid in CH2Cl2. Scheme 7 depicts the
synthesis of substituted pyrazolo-oxazole derivatives
11a -c. Compound 11a was synthesized by O-alkylation
of 4 with 2-chlorocyclohexanone in DMF and K2CO3, as
described earlier. Cyclization with standard conditions
involving TsOH failed to give 11a ; however, under mildly
acidic conditions with pyridinium-p-toluenesulfonate com-
pound 11a was obtained in 70% yield. For the synthesis
In the case of R-halo ketones as alkylating agents, the
intramolecular cyclization of the O-alkylated keto com-
pound was accomplished under acidic condition (Scheme
J . Org. Chem, Vol. 69, No. 21, 2004 7061

Patel et al.
SCHEME 7a
TABLE 2. Dia r ylp yr a zolo[5,1-b]oxa zoles
yield
C no.
R
R′
R1
R2
methoda (%)
10a
SO2CH3
F
F
F
F
F
F
F
F
F
F
F
F
F
H
H
H
H
CH3
H
A
A
A
A
A
A
A
A
A
B
A
C
A
D
D
D
10
89
49
78
58
70
65
71
36
28
90
37
38
59
71
12
10b SO2CH3
10c SO2CH3
10d SO2CH3
10e
10f
10g SO2CH3
10h SO2CH3
10i
10j
10k SO2CH3
10l SO2CH3
10m SO2CH3
16a
16b
16c
4-F-Ph
Ph
Ph
C(CH3)3
CH2(C6H12
CH3
2-thienyl
CH3
H
CH3
CH3
CH2CH3
SO2CH3
SO2CH3
)
H
4-F-Ph
CH3
CH3
CF3
COOEt
CN
SO2CH3
SO2CH3
H
H
F
F
F
SO2CH3 4-F-Ph
SO2CH3 CH3
SO2CH3 CH2CH3
4-F-Ph
H
a
Method A: (1) alkylating agent, K2CO3, DMF, 50 °C; (2)
TsOH‚H2O, toluene/AcOH, reflux. Method B: (1) alkylating agent,
K2CO3, DMF, 50 °C; (2) PPA, toluene, reflux. Method C: (1)
alkylating agent, K2CO3, DMF, 50 °C; (2) TsOH‚H2O, toluene/
AcOH, reflux; (3) 1 N NaOH in dioxane/EtOH; (4) N-hydroxysuc-
cinimide, DCC, THF; (5) cyanuric chloride 50 °C. Method D: (1)
alkylating agent, K2CO3, DMF, 50 °C; (2) TsOH‚H2O, toluene/
CH3CO2H, reflux; (3) CH2Cl2, 32% CH3CO3H, 0 °C, 2 h. Alkylating
agents: (10a ) 2-bromomethyldioxolane; (10b) 4-fluorophenacyl
bromide; (10c) phenacyl bromide; (10d ) 2-bromopropiophenone;
(10e) 1-bromopinacolone; (10f) (a) bromomethyl cyclohexyl ketone;
(10g) 1-chloro-1-(4-fluorophenyl)acetone; (10h ) 2-chloropropio-2′-
thiophene; (10i) 2-bromo-3-butanone; (10j) 3-bromo-1,1,1-trifluo-
roacetone; (10k ) 2-chloro-3-ketobutyrate; (10l) 2-chloro-3-ketobu-
tyrate; (10m ) 1-bromo-2-butanone; (16a ) 4-fluorophenacyl bromide;
(16b) 3-chloro-3-(4-fluorophenyl)-2-propanone; (16c) 1-bromo-2-
butanone.
of compounds 11b and 11c, the O-alkylation product was
obtained in high yield, but the intramolecular cyclization
of the O-alkylated ketone under the same reaction
conditions as 11a failed. It can be argued that the
interaction of the pyrazole oxygen with the heteroatom
in the 4 position of the tetrahydropyran or thiopyran ring
put the carbonyl group away from the 2 position nitrogen
of the pyrazole. Therefore we decided to convert the
carbonyl carbon into a conformationally more flexible
ketal (sp3 carbon) and indeed, cyclization of the ketal in
the presence of pyridinium-p-toluenesulfonate gave the
desired products 11b and 11c.
a
Reagents and conditions: (11a ) (a) 2-chloro cyclohexanone,
K2CO3, DMF, (b) pyridinium-p-toluenesulfonate, 70%; (11b ) (c)
3-bromo-tetrahydro-4H-pyran-4-one, K2CO3, DMF; (11c) (c) 3-bromo-
tetrahydro-4H-thiopyran-4-one, K2CO3, DMF, (d) pyridinium-p-
toluenesulfonate, EtOH, reflux, 12 h.
SCHEME 8a
Since a sulfonamide group is present in CelebrexTM,
we decided to synthesize sulfonamide analogues of some
selected sulfones to evaluate the effect of this pharma-
cophore on COX-2 activity. An efficient synthesis was
developed starting with commercially available 4-sulfam-
oylbenzoic acid 31 (Scheme 8). Acid chloride formation
and protection of the sulfonamide was achieved in a
single step with use of oxalyl chloride and DMF in
dichloromethane. â-Keto ester formation followed by
condensation with hydrazine as described earlier gave
compound 31 in excellent yield. This intermediate was
then utilized to synthesize final sulfonamide analogues
such as 32, 33, 34, and 35 (Scheme 9) via the synthetic
methodology described earlier.
a
Reagents and conditions:: (a) 2 M oxalyl chloride, CH2Cl2,
DMF, 40 °C, 12 h; (b) 4-fluorophenylacetate, LHMDS, THF, -78
°C; (c) NH2NH2‚H2O, CH3CO2H, dioxane/H2O, reflux, 24 h.
All the compounds synthesized from 4 (isomer A) and
12 (isomer B) were tested for their inhibitory activity
against recombinant human COX-1 (r-hu COX-1) and
COX-2 (r-hu COX-2) enzymes as a primary screen as
described in ref 7a. The data on selected compounds are
shown in Table 3. In general, isomer A derivatives were
more potent and selective for the COX-2 enzyme than
for isomer B derivatives.
7062 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol Derivatives
SCHEME 9a
crystallography. Several compounds demonstrated in
vitro activity and selectivity for the COX-2 enzyme.
Compounds 6c, 6d , and 10l demonstrated single digit
nanomolar potency for the COX-2 enzyme.
Exp er im en ta l Section
2-(4-F lu or op h en yl)-2-(4-m eth ylsu lfon ylp h en yl)a cetic
Acid Meth yl Ester (23). To a solution of ethyl (4-fluoro)-
phenylacetate (17) (2.35 g, 14 mmol) in THF (15 mL) at -78
°C was added dropwise 1 N lithium bis(trimethylsilyl)amide
(14 mL, 14 mmol) and after 15 min a suspension of 4-meth-
ylsulfonylbenzoyl chloride (20) (3.3 g, 15 mmol) in THF (25
mL) was added in portions. The reaction was then continued
for the next 60 min at -78 °C and for 12 h at 0 to 5 °C. The
mixture was quenched with 10% citric acid, the THF was
removed in vacuom and the residue was triturated with
hexane to provide 3.4 g (69%) of solid product 23. 1H NMR
(300 MHz, DMSO-d6) δ 3.27 (s, 3 H), 3.69 (s, 3 H), 6.35 (s, 1
H), 7.21 (m, 2 H), 7.44 (m, 2 H), 8.06 (d, J ) 9 Hz, 2 H), 8.25
(d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 368 (M + H)+.
4-(4-F lu or op h en yl)-5-(4-m et h ylsu lfon ylp h en yl)-3-h y-
d r oxyp yr a zole (4). A mixture of 2-(4-fluorophenyl)-2-(4-
methylsulfonylphenyl)acetic acid methyl ester (23) (2.09 g, 5.74
mmol), hydrazine hydrate (0.36 mL, 6 mmol), and CH3CO2H
(0.36 mL, 6 mmol) in dioxane (100 mL) and H2O (10 mL) was
refluxed for 24 h. The dioxane was removed in vacuo, and the
residue was diluted with water (50 mL), then the solid was
filtered and dried in vacuo to provide 1.8 g (95%) of 4. 1H NMR
(300 MHz, DMSO-d6) δ 3.26 (s, 3 H), 7.17 (m, 2 H), 7.27 (m, 2
H), 7.57 (m, 2 H), 7.93 (d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z
333 (M + H)+, 350 (M + NH4)+. C16H13FN2O3S‚0.5 H2O: C,
57.51; H, 3.98; N, 8.38. Found: C, 57.71; H, 4.13; N, 7.85.
Eth yl 2-(4-Flu or oph en yl)-2-((4-m eth ylth io)ben zoyl)ace-
ta te (22). Meth od A: To a solution of 4-methylthiobenzoic acid
(3.36 g, 20 mmol) and a few drops of DMF in anhydrous CH2-
Cl2 (50 mL) at 0 °C was added dropwise oxalyl chloride (4.4
mL, 50 mmol) and the resulting mixture was stirred at 0 °C
for 6 h. The mixture was then concentrated in vacuo to obtain
3.7 g (∼100%) of crude 4-methylthiobenzoyl chloride (19).
A mixture of 4-fluorophenylacetic acid (10.8 g, 70 mmol) and
concentrated H2SO4 (1 mL) in ethanol (150 mL) was refluxed
for 8 h. The reaction mixture was then concentrated in vacuo
and the residue was dissolved in ethyl ether. The ether solution
was washed with 10% NaHCO3 and brine, dried with anhy-
drous MgSO4, and concentrated in vacuo to give 12.2 g (96%)
of ethyl (4-fluorophenyl)acetate, 17.
a
Reagents and conditions: (32) (a) 1-bromopinacolone, K2CO3,
DMF, 50 °C, (b) p-TsOH‚H2O, CH3CO2H, toluene, reflux, 4 h; (33)
(c) (1) 2-chloro-3-ketobutyrate, K2CO3, DMF, 50 °C, (2) TsOH‚H2O,
toluene/CH3CO2H, reflux, (d) (1) 1 N NaOH in dioxane/EtOH, (2)
N-hydroxysuccinimide, DCC, THF, (3) cyanuric chloride, 50 °C;
(34) (e) 1-bromopinacolone, K2CO3, DMF, 40 °C, 1 h, (f) ethyl
iodide, acetone, K2CO3, 50 °C; (35) (g) 2-bromo benzyl bromide,
K2CO3, DMF, 50 °C, 40 min, (h) CuI, K2CO3, 150 °C, 2 h.
TABLE 3. In Vitr o COX-1 a n d COX-2 Activity of
Selected Com p ou n d s
r-hu COX-1,
% inhib.
r-hu COX-2,
% inhib. or IC50
C no.
Lithium bis(trimethylsilyl)amide (1 N, 20 mL, 20 mmol) was
added dropwise to a solution of ethyl (4-flluorophenyl)acetate
(17) (3.84 g, 20 mmol) in THF (20 mL) at -78 °C. After 15
min a suspension of crude 4-methylthiobenzoyl chloride (19)
(3.7 g, 20 mmol) in THF (50 mL) was added dropwise to this
mixture and the resulting mixture was stirred at -78 °C for
60 min. The mixture was quenched with saturated NH4Cl and
extracted with EtOAc. The acetate layer was washed with
water and brine, dried with anhydrous MgSO4, and concen-
trated in vacuo. The residue was chromatographed (silica gel,
19:1 CH2Cl2-EtOAc) to provide 4.55 g (69%) of the title
compound 22. 1H NMR (300 MHz, CDCl3) δ 1.25 (m, 3 H), 2.50
(s, 3 H), 4.20 (m, 2 H), 5.53 (s, 1 H), 7.03 (t, J ) 9 Hz, 2 H),
7.22 (d, J ) 9 Hz, 2 H), 7.38 (m, 2 H), 7.85 (d, J ) 9 Hz, 2 H);
MS (DCI-NH3) m/z 333 (M + H)+, 350 (M + NH4)+.
Meth od B: To a suspension of Mg turnings (2.4 g, 100
mmol) in anhydrous Et2O (200 mL) was added a few drops of
p-fluorobenzyl bromide and the mixture was warmed to
initiate the reaction. The remaining amount of p-fluorobenzyl
bromide (6.4 mL, 50 mmol) in Et2O (50 mL) was added slowly
at such rate as to maintain gentle boiling. Upon completion
of addition the mixture was refluxed for the next 2 h and then
cooled to 0 °C. The mixture was then slowly cannulated to a
solution of 4-methylthiobenzonitrile (7.46 g, 50 mmol). The
reaction mixture was allowed to warm to room temperature
2
3
5b
6c
6c
6d
7b
8a
95% at 1 µM
84% at 1 µM
76 nM
90% at 100 nM
5 nM
31 nM
5 nM
72% at 100 µM
17% at 100 µM
0% at 100 µM
3% at 100 µM
0% at 100 µM
4% at 100 µM
20% at 100 µM
25% at 100 µM
51% at 100 µM
61% at 100 µM
38% at 100 µM
23% at 100 µM
4% at 100 µM
20% at 100 µM
99% at 100 µM
96% at 100 µM
720 nM
90% at 100 nM
82% at 100 nM
94% at 100 nM
12 nM
4 nM
75% at 10 nM
213 nM
55 nM
88% at 100 nM
69 nM
9a
10f
10k
10l
10m
11b
11c
32
33
In summary, we have demonstrated the use of a 4,5-
diaryl-1H-pyrazole-3-ol intermediate to synthesize sev-
eral novel classes of compounds in moderate to good
yields. In addition, the structures of representative
compounds from each class were confirmed by X-ray
J . Org. Chem, Vol. 69, No. 21, 2004 7063

Patel et al.
and was left at ambient temperature for 14 h. The mixture
was quenched with saturated NH4Cl, and the ethyl layer was
washed with water and brine, dried with anhydrous MgSO4,
and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 5:4:1 hexane-CH2Cl2-EtOAc) to
provide 2.8 g (22%) of 4-fluorobenzyl 4-methythiophenyl ketone
phenyl)pyrazole. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3
H), 5.64 (s, 2 H), 7.22 (m, 2 H), 7.39 (m, 4 H), 7.60 (d, J ) 9
Hz, 2 H), 7.95 (d, J ) 9 Hz, 2 H), 8.12 (m, 2 H), 12.60 (s, 1 H);
MS (APCI + Q1) m/z 469 (M + H)+, (APCI - Q1) m/z 467 (M
- H)+. Anal. Calcd for C24H18F2N2O4S‚0.25H2O: C, 60.95; H,
3.94; N, 5.92; Found: C, 61.28; H, 4.28; N, 5.45.
1
(27). H NMR (300 MHz, DMSO-d6) δ 2.55 (s, 3 H), 4.36 (s, 2
To a mixture of 3-(4-fluorophenacyloxy)-4-(4-fluorophenyl)-
5-(4-methylsulfonylphenyl)pyrazole (117 mg, 0.25 mmol) and
K2CO3 (41 mg, 0.3 mmol) in DMF (20 mL) was added dropwise
ethyl iodide (0.04 mL, 0.5 mmol) and the mixture was refluxed
for 8 h at 50 °C. The mixture was then poured into water and
extracted with EtOAc, The organic layer was washed with
water and brine, dried with anhydrous MgSO4, and concen-
trated in vacuo. The residue was chromatographed (silica gel,
1:1 hexanes-EtOAc) to provide 90 mg (72%) of the desired
product 6a . Mp 170-171 °C. 1H NMR (300 MHz, DMSO-d6) δ
1.15 (t, J ) 7 Hz, 3 H), 3.31 (s, 3 H), 3.78 (q, J ) 7 Hz, 2 H),
5.70 (s, 2 H), 7.11 (t, J ) 9 Hz, 2 H), 7.22 (m, 2 H), 7.42 (t, J
) 9 Hz, 2 H), 7.63 (d, J ) 9 Hz, 2 H), 8.01 (d, J ) 9 Hz, 2 H),
8.10 (m, 2 H); MS (APCI+) m/z 497 (M + H)+, (APCI-) m/z
495 (M - H)-, 531 (M + Cl)-. Anal. Calcd for C26H22F2N2O4S‚
0.5H2O: C, 61.77; H, 4.58; N, 5.54. Found: C, 61.90; H, 4.41;
N, 5.47.
H), 7.14 (t, J ) 9 Hz, 2 H), 7.29 (m, 2 H), 7.38 (d, J ) 9 Hz, 2
H), 7.98 (d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 261 (M + H)+,
278 (M + NH4)+.
Lithium bis(trimethylsilyl)amide (1 N, 3.9 mL, 3.9 mmol)
in anhydrous THF (10 mL) at -78 °C was treated dropwise
with a solution of 4-fluorobenzyl 4-methythiophenyl ketone
(27) (1.03 g, 3.9 mmol) in THF (25 mL). The mixture was
stirred at -78 °C for 30 min and then ethyl cyanoformate (0.39
mL, 3.9 mmol) was added. The reaction mixture was stirred
at -78 °C for 3 h and then at room temperature for 3 h. After
the mixture was quenched with saturated NH4Cl and ex-
tracted with ethyl acetate, the acetate layer was washed with
water and brine, dried with anhydrous MgSO4, and concen-
trated in vacuo. The residue was purified by chromatography
(silica gel, 5:4:1 hexane-CH2Cl2-EtOAc) to provide 1.1 g (83%)
of ethyl 2-(4-fluorophenyl)-2-((4-methylthio)benzoyl)acetate
(22). 1H NMR (300 MHz, CDCl3) δ 1.25 (m, 3 H), 2.50 (s, 3 H),
4.20 (m, 2 H), 5.53 (s, 1 H), 7.03 (t, J ) 9 Hz, 2 H), 7.22 (d, J
) 9 Hz, 2 H), 7.38 (m, 2 H), 7.85 (d, J ) 9 Hz, 2 H); MS (DCI-
NH3) m/z 333 (M + H)+, 350 (M + NH4)+.
3-(4-F lu or op h en yl)-2-(4-(m eth a n esu lfon yl)p h en yl)-5H-
ben zo[d ]p yr a zolo[5,1-b][1,3]oxa zin e (9a ). Meth od A: To
a mixture of 4 (133 mg, 0.4 mmol) and anhydrous K2CO3 (69
mg, 0.5 mmol) in pyridine (25 mL) were added 2-bromobenzyl
bromide (100 mg, 0.4 mmol) and copper powder (20 mg) and
the resulting mixture was stirred at room temperature for 14
h. The mixture was then poured into 10% citric acid and
extracted with EtOAc. The acetate layer was washed with
water and brine, dried with anhydrous MgSO4, and concen-
trated in vacuo. The residue was chromatographed (silica gel,
3:2 hexanes-EtOAc) to afford 12 mg (8%) of the title product.
1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3 H), 5.51 (s, 2 H),
7.30 (m, 5 H), 7.43 (d, J ) 8 Hz, 1 H), 7.53 (m, 1 H), 7.74 (t, J
) 9 Hz, 3 H), 7.96 (d, J ) 9 Hz, 2 H); MS (APCI + Q1) m/z
421 (M + H)+, (APCI - Q1) m/z 420 (M)+. Anal. Calcd for
A mixture of ethyl 2-(4-fluorophenyl)-2-(4-methylthioben-
zoyl)acetate (22) (1.33 g, 4 mmol), hydrazine hydrate (0.25 mL,
4.2 mmol), and CH3CO2H (0.25 mL, 4.2 mmol) in dioxane (50
mL) and H2O (5 mL) was refluxed for 24 h and then
concentrated in vacuo. To the residue was added water and
the solid was filtered and dried in vacuo to afford 1.15 g (95%)
1
of crude product 28. H NMR (300 MHz, DMSO-d6) δ 2.47 (s,
3 H), 7.12 (t, J ) 9 Hz, 2 H), 7.26 (m, 6 H); MS (DCI-NH3) m/z
301 (M + H)+, 318 (M + NH4)+.
To a solution of 28 (200 mg, 0.48 mmol) in CH2Cl2 (20 mL)
at 0 °C was added 32% peracetic acid (0.22 mL) and the
mixture was stirred at 0 °C for 4 h. The mixture was then
washed with water, saturated NaHCO3, and brine, dried with
anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by chromatography (silica gel, EtOAc) to afford
C
23H17FN2O3S‚0.25H2O: C, 65.01; H, 4.15; N, 6.59. Found: C,
65.08; H, 3.99; N, 6.47.
Meth od B: To a solution of 4 (200 mg, 0.6 mmol) and K2-
CO3 (97 mg, 0.7 mmol) in DMF (25 mL) at 50 °C was added
dropwise a solution of 2-bromobenzyl bromide (175 mg, 0.7
mmol) in DMF (5 mL). The mixture was stirred until the
starting material disappeared (∼40 min). To this mixture was
added K2CO3 (200 mg, 1.5 mmol) and CuI (30 mg) and the
resulting mixture was heated at 150 °C until starting material
was gone (∼2 h). The reaction mixture was then cooled to room
temperature, poured into 10% citric acid, and extracted with
EtOAc. The EtOAc extract was concentrated in vacuo and the
residue was purified to provide 150 mg (60%) of the desired
product. 1H NMR (300 MHz, DMSO-d6) δ 3.26 (s, 3 H), 5.51
1
compound 4 (194 mg, 90%). H NMR (300 MHz, DMSO-d6) δ
3.26 (s, 3 H), 7.17 (m, 2 H), 7.27 (m, 2 H), 7.57 (m, 2 H), 7.93
(d, J ) 9 Hz, 2 H); MS (DCI-NH3) m/z 333 (M + H)+, 350 (M
+ NH4)+.
1-[1-(3,3-Dim et h yl-2-oxo-b u t yl)-4-(4-flu or op h en yl)-5-
(4-(m eth a n esu lfon yl)p h en yl)-1H-p yr a zol-3-yloxy]-3,3-d i-
m eth ylbu ta n -2-on e (5a ). A mixture of 4 (90 mg, 0.3 mmol),
bromopinacolone (0.21 mL, 0.6 mmol), and anhydrous K2CO3
(1.1 g, 0.8 mmol) in DMF (40 mL) was refluxed at 50 °C for 7
h. The mixture was poured into water and extracted with
EtOAc. The organic solvent was removed in vacuo and the
residue was purified by chromatography (silica gel, EtOAc) to
provide 250 mg (81%) of product 5a . Mp 180-182 °C. 1H NMR
(300 MHz, DMSO-d6) δ 0.95 (s, 9 H), 1.14 (s, 9 H), 3.23 (s, 3
H), 5.00 (s, 2 H), 5.22 (s, 2 H), 7.10 (m, 2 H), 7.22 (m, 2 H),
7.49 (d, J ) 9 Hz, 2 H), 7.97 (d, J ) 9 Hz, 2 H); MS (APCI+)
m/z 529 (M + H)+, (APCI-) m/z 527 (M - H)-, 563 (M + Cl)-.
Anal. Calcd for C28H33FN2O5S‚0.25H2O: C, 63.08; H, 6.33; N,
5.25. Found: C, 62.95; H, 6.39; N, 5.14.
2-[1-Eth yl-4-(4-flu or op h en yl)-5-(4-(m eth a n esu lfon yl)-
p h e n yl)-1H -p yr a zol-3-yloxy]-1-(4-flu or op h e n yl)e t h a -
n on e (6a ). To a mixture of 4 (200 mg, 0.6 mmol) and K2CO3
(83 mg, 0.6 mmol) in DMF (30 mL) at 50 °C was added
dropwise a solution of p-fluorophenacyl bromide (130 mg, 0.6
mmol) in DMF (10 mL) and the resulting mixture was stirred
at 50 °C for 50 min. The mixture was then poured into water
and extracted with ethyl acetate. The acetate layer was
washed with water and brine, dried with anhydrous MgSO4,
and concentrated in vacuo to provide 280 mg (99%) of
3-(4-fluorophenacyloxy)-4-(4-fluorophenyl)-5-(4-methylsulfonyl-
(s, 2 H), 7.30 (m, 5 H), 7.43 (d, J ) 8 Hz, 1 H), 7.53 (m, 1 H),
+
7.74 (t, J ) 9 Hz, 3 H), 7.95 (d, J ) 9 Hz, 2 H); MS (APCI
)
m/z 421 (M + H)+, (APCI-) m/z 420 (M)+. Anal. Calcd for
23H17FN2O3S‚0.5H2O: C, 64.32; H, 4.22; N, 6.59. Found: C,
C
64.25; H, 4.26; N, 6.25.
3,7-Bis(4-flu or oph en yl)-6-(4-(m eth an esu lfon yl)ph en yl)-
p yr a zolo[5,1-b]oxa zole (10b). A mixture of the O-alkylated
derivative from compound 5b (47 mg, 0.1 mmol), p-TsOH ×
H2O (19 mg, 0.1 mmol) in toluene (20 mL), and CH3CO2H (7
mL) was refluxed for 4 h with use of a Dean-Stark trap. The
mixture was then concentrated in vacuo and the residue was
dissolved in EtOAc. The acetate solution was washed with 10%
bicarbonate and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed (silica gel, 1:1
hexanes-EtOAc) to provide 40 mg (89%) of the desired
product. Mp 200-202 °C. 1H NMR (300 MHz, DMSO-d6) δ 3.25
(s, 3 H), 7.26 (t, J ) 9 Hz, 2 H), 7.45 (m, 4 H), 7.80 (d, J ) 9
Hz, 2 H), 8.00 (d, J ) 9 Hz, 2 H), 8.30 (m, 2 H), 8.83 (s, 1 H);
MS (APCI+) m/z 451 (M + H)+, (APCI-) m/z 449 (M - H)-,
7064 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol Derivatives
485 (M + Cl)-. Anal. Calcd for C24H16F2N2O3S‚0.6H2O: C,
62.49; H, 3.76; N, 6.07. Found: C, 62.62; H, 3.62; N, 5.68.
1-(4-F lu or op h en yl)-2-(4-(m eth a n esu lfon yl)p h en yl)-4,7-
dihydro-5H-6,8-dioxa-3,3a-diaza-cyclopenta[a ]indene (11b).
To a solution of 4-(4-fluorophenyl)-5-(4-methylsulfonyl)-3-
(tetrahydro-4H-pyran-4-on-3-yloxy)pyrazole, prepared accord-
ing to the procedure for compound 6a substituting 3-bromo-
tetrahydro-4H-pyran-4-one for p-fluorophenacyl bromide (340
mg, 0.8 mmol), in ethanol (120 mL) was added pyridinium
p-toluenesulfonate (30 mg) and the resulting mixture was
refluxed at 75 °C for 12 h. The mixture was then concentrated
in vacuo and the residue was chromatographed (silica gel, 1:2
hexanes-EtOAc) to provide 230 mg of cyclic ketal intermedi-
ate.
of ethyl 2-(4-(N′,N′-dimethylaminomethyleneaminosulfonyl)-
benzoyl)(4-fluorophenyl) acetate (30). 1H NMR (300 MHz,
DMSO-d6) δ 1.15 (t, J ) 7 Hz, 3 H), 2.90 (s, 3 H), 3.14 (s, 3 H),
4.14 (q, J ) 7 Hz, 2 H), 6.25 (s, 1 H), 7.20 (t, J ) 9 Hz, 2 H),
7.43 (m, 2 H), 7.90 (d, J ) 9 Hz, 2 H), 8.14 (d, J ) 9 Hz, 2 H),
8.23 (s, 1 H); MS (APCI+) m/z 421 (M + H)+, (APCI-) m/z 419
(M - H)-, 455 (M + Cl)-. A mixture of the keto ester 30,
hydrazine hydrate (1.5 mL, 25 mmol), and acetic acid (1.8 mL,
30 mmol) in dioxane (120 mL) was refluxed for 4 h. The
mixture was then concentrated; the residue was dissolved in
EtOAc, and washed with water and brine. Removal of acetate
in vacuo and purification of the residue by chromatography
(silica gel, CH2Cl2-EtOH 4:1) gave 3.4 g (∼85%) of 5-(4-
aminosulfonylphenyl)-4-(4-fluorophenyl)-3-hydroxypyrazole (31).
1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, J ) 9 Hz, 2 H), 7.35
(m, 2 H), 7.40 (s, 2 H), 7.49 (d, J ) 9 Hz, 2 H), 7.80 (d, J ) 9
Hz, 2 H); MS (APCI+) m/z 334 (M + H)+, (APCI-) m/z 332 (M
- H)-, 368 (M + Cl)-.
2-(4-Am in osu lfon ylph en yl)-6-ter t-bu tyl-3-(4-flu or oph en -
yl)p yr a zolo[5,1-b]oxa zole (32). To a solution of 31 (666 mg,
2 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (25 mL) at 50
°C was added dropwise bromopinacolone (0.28 mL, 2 mmol)
in DMF (5 mL). The mixture was stirred at 50 °C for 30 min
and then poured into 10% citric acid and extracted with EtOAc.
The extract was concentrated in vacuo to provide 758 mg of
crude 5-(4-aminosulfonylphenyl)-4-(4-fluorophenyl)-3-pivaloyl
methoxypyrazole, MS (APCI+) m/z 432 (M + H)+, (APCI-) m/z
430 (M - H)-, 466 (M + Cl). A mixture of the above
O-alkylated derivative (216 mg, 0.5 mmol), p-TsOH‚H2O (30
mg) in CH3CO2H (20 mL), and toluene (80 mL) was refluxed
with use of a Dean-Stark trap for 4 h. The mixture was then
concentrated in vacuo, The residue was dissolved in EtOAc
and washed with water and brine, dried with MgSO4, and
concentrated in vacuo. The residue was chromatographed
(silica gel, 1:1 hexanes-EtOAc) to provide 32 (168 mg, 80%).
Mp 196-200 °C. 1H NMR (300 MHz, DMSO-d6) δ 1.50 (s, 9
H), 7.25 (t, J ) 9 Hz, 2 H), 7.33 (m, 2 H), 7.43 (s, 2 H), 7.65 (d,
J ) 9 Hz, 2 H), 7.83 (d, J ) 9 Hz, 2 H), 7.95 (s, 1 H); MS
(APCI+) m/z 414 (M + H)+, (APCI-) m/z 412 (M - H)-, 448 (M
+ Cl)-. Anal. Calcd for C21H20FN3O3S‚0.25H2O: C, 60.34; H,
4.94; N, 10.05. Found: C, 60.47; H, 5.14; N, 9.45.
This ketal intermediate was dissolved in toluene (30 mL)
and AcOH (5 mL) and treated with pyridinium p-toluene-
sulfonate (10 mg) at reflux for 6 h. The mixture was then
concentrated in vacuo and purified by chromatography (silica
gel, 1:2 hexanes-EtOAc) to provide 100 mg (31%) of the title
1
compound. Mp 200-201 °C. H NMR (300 MHz, DMSO-d6) δ
2.98 (m, 2 H), 3.25 (s, 3 H), 4.03 (t, J ) 6 Hz, 2 H), 4.75 (s, 2
H), 7.26 (t, J ) 9 Hz, 2 H), 7.37 (m, 2 H), 7.74 (d, J ) 9 Hz, 2
H), 7.95 (d, J ) 9 Hz, 2H); MS (APCI+) m/z 413 (M + H)+,
(APCI-) m/z 447 (M + Cl)-. Anal. Calcd for C21H17FN2O4S‚
0.5H2O: C, 59.84; H, 4.30; N, 6.64. Found: C, 60.02; H, 4.22;
N, 6.53.
3-Eth yl-7-(4-flu or oph en yl)-6-(4-(m eth an esu lfon yl)ph en -
yl)p yr a zolo[5,1-b]oxa zole (10m ). The title compound was
prepared according to the procedure of compound 10b, sub-
stituting 1-bromo-2-butanone for phenacyl bromide. Mp 177-
1
179 °C. H NMR (300 MHz, DMSO-d6) δ 1.35 (t, J ) 7 Hz, 3
H), 2.85 (q, J ) 7 Hz, 2 H), 3.25 (s, 3 H), 7.25 (m, 2 H), 7.35
(m, 2 H), 7.73 (d, J ) 9 Hz, 2 H), 7.95 (d, J ) 9 Hz, 2 H), 8.9
(s, 1 H); MS (DCI-NH3) m/z 357 (M + H)+, m/z 374 (M + NH4)+.
Anal. Calcd for C20H17FN2O3S: C, 62.49; H, 4.46; N, 7.29.
Found C, 62.28; H, 4.36; N, 6.95.
4-[4-(4-F lu or op h en yl)-5-h yd r oxy-2H-p yr a zol-3-yl]ben -
zen esu lfon a m id e (31). To a suspension of 4-aminosulfonyl-
benzoic acid (29) (5.03 g, 25 mmol) in 2 M oxalyl chloride in
CH2Cl2 (30 mL, 60 mmol) at room temperature was added
dropwise DMF (2.1 mL, 26 mmol) and the resulting mixture
was refluxed at 40 °C for 12 h. The mixture was then
concentrated in vacuo to provide crude 4-(N′,N′-dimethyl-
aminomethyleneaminosulfonyl)benzoyl chloride, which was
used directly in the next step. To a solution of commercially
available ethyl 4-fluorophenylacetate (4.5 g, 25 mmol) in THF
(50 mL) at -78 °C was added 1 N LHMDS (26 mL, 26 mmol).
After 20 min the 4-(N′,N′-dimethylaminomethyleneamino-
sulfonyl)benzoyl chloride was added in portions and the
reaction mixture was stirred at this temperature for the next
3 h. The mixture was then concentrated in vacuo, 10% citric
acid was added, and the solution was extracted with EtOAc.
The acetate layer was washed with water and brine, dried with
anhydrous MgSO4, and concentrated in vacuo. Purification by
column chromatography (silica gel, EtOAc) afforded 5 g (50%)
Ack n ow led gm en t. The authors wish to thank Dr.
Kathleen Mortell for kindly reviewing this manuscript
and providing helpful suggestions.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and procedures for the preparation of compounds 5b-d ,
6b-e, 14a ,b, 7a -c, 8a ,b, 9b,c, 10a , 10c-m , 16a -c, 11a , 11c,
33, 34, 35 and CIF files containing complete details supporting
the X-ray crystallographic determination of compounds 4, 5a ,
6b, 6c, and 10m . This material is available free of charge via
the Internet at http://pubs.acs.org.
J O049264K
J . Org. Chem, Vol. 69, No. 21, 2004 7065