New hydroxy-pyrazoline intermediates, subtle regio-selectivity and relative reaction rate variations observed during acid catalyzed and neutral pyrazole cyclization

Article abstract of DOI:10.1039/b500413f

Arylhydrazines 4 and 1,3-dicarbonyl compounds 5 react to form pyrazoles by loss of water via hydrazone isomer pairs 6 and 7 which give rise to two possible regio-isomers. Occasionally, 3-hydroxy-3,4-dihydropyrazoles or hydroxy-pyrazolines 8 and 9 are obse

Full text of DOI:10.1039/b500413f

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A R T I C L E
New hydroxy-pyrazoline intermediates, subtle regio-selectivity and
relative reaction rate variations observed during acid catalyzed and
neutral pyrazole cyclization†
Timothy Norris,* Roberto Colon-Cruz and David H. B. Ripin
Chemical Research & Development, Pfizer Inc Global Research & Development, Eastern Point
Road, Groton, CT-06340, USA. E-mail: timothy.norris@pfizer.com; Fax: +860 686 5340;
Tel: +860 441 4406
Received 11th January 2005, Accepted 11th April 2005
First published as an Advance Article on the web 20th April 2005
Arylhydrazines 4 and 1,3-dicarbonyl compounds 5 react to form pyrazoles by loss of water via hydrazone isomer
pairs 6 and 7 which give rise to two possible regio-isomers. Occasionally, 3-hydroxy-3,4-dihydropyrazoles or
hydroxy-pyrazolines 8 and 9 are observed as stable isolatable intermediates that can be fully characterized prior to
loss of the second molecule of water that gives rise to pyrazoles 10 and 11. Fully characterized examples of
intermediates of type 8 and 9 are relatively rare. We studied the reaction series where R = CH3, CHF2 and CF3 and
Ar = Ph and 5-methanesulfonylpyridin-2-yl, (Scheme 2), and observed differences in properties between kinetic
behavior and regio-isomerism depending on the degree of electron-withdrawing capability of the R and Ar
substituents. The reaction conditions that caused cyclization to pyrazoles varied from direct condensation of the
hydrazine and 1,3-dicarbonyl compounds, to reactions requiring catalytic quantities of sulfuric acid to sulfuric acid in
excess. Unexpected regio-selectivity was observed in the case of R = CF3 that depended upon the reaction conditions.
9 is much less common and only documented in more recent
Introduction
literature reports.6 Several new members of the class were fully
Pyrazoles were discovered in the 19th Century and in contrast
characterized and single crystal X-ray data was obtained. When
to the isomeric 1,3 diazole, imidazole they are quite rare
the Ar group is very strongly electron withdrawing such as
in nature and natural products. Recently they have become
2,4-dinitrophenyl the reaction is halted at the hydrazone stage.
interesting from a medicinal chemistry view point as HIV-
When R is switched to CF3 from CH3 in Scheme 2 the cyclic
hydroxy dihydropyrazole can sometimes be isolated. From the
perspective of a process chemist, control of the condensation of
1 reverse transcriptase inhibitors 1,1 sodium hydrogen ion
exchanger NHE-1 inhibitors 22 and cyclooxygenase-2, COX-2
inhibitors 33 (Scheme 1). In connection with this type of project
mono substituted hydrazines and 1,3-dicarbonyl compounds to
work we researched the formation of pyrazoles and studied
produce one of the two pyrazole products is desirable to avoid
formation and properties of the less well known intermediate
difficult purifications (Scheme 2).
hydroxy pyrazolines 8 and 9.4 Subtle differences that give quite
different results were noted, which allow flexibility in control of
the major product obtained.
Results and discussion
We conducted a series of experiments in refluxing 2-propanol
reacting 4 and 5 with a small, approximately 4% molar excess
of the hydrazine 4 using the two hydrazines and three 1,3-
dicarbonyl compounds (Table 1). Single crystal X-ray structures
were obtained for new hydroxy-pyrazolines 8b, 8c and 9a and
the pyrazoles 10a, 10b, and 10d. The regio-isomerism of the
diphenyl series of hydroxy dihydro pyrazoles and pyrazoles 8f,
9f, 10f and 11f was determined by preparation of an authentic
sample of 1,5-diphenyl-3-methylpyrazole.7
The hydroxy-pyrazolines 8b, 8c and 9a were obtained using
the neutral reaction conditions as described in Table 1 and
Scheme 1 Pyrazoles found in reverse transcriptase HIV-1, NHE-1 and
then purified by chromatography and/or recrystallization. The
pyrazoles 10a–f were obtained using acidic conditions (Table 2)
and similarly purified. The reactions were studied by HPLC
monitoring8 using authenticated reference samples as markers
for peak identification. Some minor peaks were characterized
by LC/MS techniques. All major products were individually
synthesized, purified and single crystal X-ray data and/or
satisfactory spectroscopic and/or elemental analysis data ob-
tained. Some minor products were isolated by chromatographic
techniques from mother liquors of the main reaction product.
The cyclization reaction between hydrazines 4a and 4b with
1,3-dicarbonyl compounds 5a–c to form pyrazoles were ob-
served to take several days under neutral conditions at 85 ◦C in 2-
propanol and the main product was a hydroxy-pyrazoline when
two electron-withdrawing groups were present. Thus when Ar =
5-methanesulfonylpyridin-2-yl and R = CF3 or CHF2 the main
COX-2 inhibitors.
In general pyrazoles are conveniently prepared by the con-
densation of hydrazines and 1,3-dicarbonyl compounds. The
overall reaction involves loss of two molecules of water as shown
in Scheme 2. Four possible intermediate hydrazone isomers
6 and/or 7 are formed by the initial condensation by loss
of one molecule of water. The regio-selectivity of the final
products is set at this stage and quite often the intermediate
hydrazones can be isolated and characterized.5 The existence
of isolatable cyclic hydroxy dihydropyrazoles isomers 8 and/or
† Electronic supplementary information (ESI) available: 13C NMR
spectrum of 10b and IR spectrum of compounds 8b and 9a. See http://
www.rsc.org/suppdata/ob/b5/b500413f/
1 8 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 2 Formation of pyrazole and intermediates from condensation of arylhydrazines with 1,3-diketones.
Table 1 Pyrazoles and hydroxy-pyrazolines formed under neutral conditions
Entry 4(a–b)
Ar
5(a–c)
R
Main product (%) Isolated yield Reaction conditions
Minor products(s) (%)
1
2
3
4
4a
4a
4a
4a
5a
CF3
9a (100%)
8b (87%)
8c (70%)
10c (95%)
48%
99%
66%
86%
5 d 85 ◦C i-PrOH
1 d 85 ◦C i-PrOH
2 h 85 ◦C i-PrOH
8 d 85 ◦C i-PrOH
none significant
10b (12%)
5b
5b
5c
CHF2
CH3
10c (10/%)
8c (5%)
CH3
5
6
7
4b
4b
4b
5a
5b
5c
CF3
10d (82%)
10e (72%)
10f (89%)
97%
6 d 85 ◦C i-PrOH
5 d 85 ◦C i-PrOH
5 d 85 ◦C i-PrOH
8d (8%), 11d (10%)
11e (25%)
CHF2
CH3
100%
100%
11f (11%)
Table 2 Pyrazoles formed under acidic conditions (hydroxy-pyrazolines transient)
Entry 4(a–f)
Ar
5(a–f)
R
Main product (%) Isolated yield Reaction conditions
Minor products(s) (%)
none significant
1
2
3
4a
4a
4a
5a
CF3
10a (100%)
10b (99%)
10c (96%)
65%
93%
83%
H2SO4 1.5 mole 1 h
85 ◦C i-PrOH
5b
5c
CHF2
CH3
cat. H2SO4 0.1 mole
11b (<1%)
11c (4/%)
1 h 85 ◦C i-PrOH
cat. H2SO4 0.1 mole
1 h 85 ◦C i-PrOH
4
5
6
4b
4b
4b
5a
5a
5c
CF3
CF2
CH3
10d (87%)
10e (97%)
10f (93%)
98%
98%
98%
H2SO4 1.5 mole 1 h
11d (13%)
11e (3%)
11f (7%)
85 ◦C i-PrOH
cat. H2SO4 0.1 mole
1 h 85 ◦C i-PrOH
cat. H2SO4 0.1 mole
1 h 85 ◦C i-PrOH
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9
1 8 4 5

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products under these conditions were 9a and 8b, respectively.
The difference between the regio-selectivity for CF3 and CHF2
is quite remarkable when Ar = 5-methanesulfonylpyridin-2-yl,
as in each case the main product predominates to the extent
of 100% and 87% for 9a and 8b respectively. In cases when
only one, or no strong electron-withdrawing groups are present
then the reaction proceeds to the pyrazole product, which has
always been observed as the regio-isomer from the series 10c–
f. However, with one strong electron-withdrawing group the
reaction conversion to the pyrazole is only 90% complete and
the hydroxy-pyrazolines 8c and 8d are observed. For cases where
Ar = Ph, the selectivity favoring the pyrazole regio-isomers 10d–
f is reduced measurably in most cases when compared to the
situation when Ar = 5-methanesulfonylpyridin-2-yl, but 10d–f
are still the predominant regio-isomers.
The cyclization reaction is much more rapid when carried
out in the presence of sulfuric acid. At 85 ◦C in 2-propanol
complete conversion occurs to pyrazoles in 1–2 hours, with
the regio-isomer 10a–f predominating. Even here though there
is a significant difference between 1,3-dicarbonyl compound
5a and 5b containing the CF3 and CHF2 groups, respectively.
The following subtle differences were noted depending on the
presence of CF3 or CHF2 substituent. When a CHF2 group is
present the cyclization is promoted by a catalytic quantity of
10% mole sulfuric acid, but in order for the reaction to proceed
in a similar time frame in the CF3 case 150% mole of sulfuric
acid is required. When acid is used to promote cyclization,
1-aryl-5-phenylpyrazoles 10a–f are always formed even in the
case where 4a and 5a are condensed. In this latter case under
neutral conditions 9a is formed, which on treatment with 150%
mole excess of sulfuric acid in 2-propanol slowly converts to the
pyrazole 11a over a period of a day.
The cyclization reaction though apparently simple probably
proceeds by a number of different mechanisms depending on
the reaction media and conditions. A single mechanism or
single intermediate types cannot explain reaction rate differences
noted between neutral and acidic conditions, such as 12 and
13, which have been proposed as key intermediates. During the
course of our studies we found no evidence of intermediates
analogous to 12 and 13, but did monitor the progress of the
reaction by HPLC. Dihydroxy-pyrazolidines though relatively
rare are isolable when two CF3 substituents are present as in 14.10
Under the conditions we examined it appeared that the process
proceeded by a stepwise path since we observed a high degree of
regio-selectivity. We saw an example of complete reversal of the
regio-selectivity in one case. Hydrazine 4a was condensed with
1,3-diketone 5a in 2-propanol in the presence of 150% mole of
sulfuric acid at 85 ◦C to yield exclusively 10a, but when reacted
under the same conditions without acid we observed formation
of the 3-hydroxy-pyrazoline 9a also exclusively (Scheme 4).
Compound 9a does react in the presence of 150% mole
sulfuric acid to yield pyrazole 11a. However, in this case
the dehydration reaction is much slower and requires 1 day
using the same conditions of solvent and temperature, com-
pared to the regio-isomers 8a–f, which dehydrate within 1–
2 hours sometimes with catalytic quantities of 10% sulfuric
acid (Scheme 5, Table 2). The general observations can be
explained by characterized 3-hydroxy-pyrazoline intermediates,
which are also observed in situ by HPLC in this series and
suggests a sequential loss of two molecules of water (Scheme 2).
We have isolated and characterized with single crystal X-
ray structure determination, examples of 2-aryl-5-fluoroalkyl-
3-hydroxy-3-phenyldihydropyrazoles 8b and 8c (Fig. 1a and
1b) and an example of a 2-aryl-3-fluoroalkyl-3-hydroxy-5-
phenyldihydropyrazole 9a (Fig. 2). Hydroxy-pyrazoline 8d was
isolated and characterized by spectroscopic methods and re-
crystallization from hexane provided pyrazole 10d. The 1,5-
diaryl pyrazole regio-isomerism was indicated by the facile
dehydration and confirmed for 8d by single crystal X-ray
structure determination of the pyrazole product 10d. Thus far
we have not been able to detect physical evidence of dihydroxy-
pyrazolidines corresponding to 12 and 13 (Scheme 3), and if
present must rapidly lose one molecule of water to provide the
stable intermediates hydroxy-pyrazolines of the class 8 and 9.
Elguero and coworkers8 in contrast report three examples
of 2,5-diaryl-3-trifluoromethyl-3-hydroxy-pyrazolines based on
NMR structural evidence, these compounds were made by
condensing the 1-arylhydrazine with the 1,3-dicarbonyl com-
pounds in slightly alkaline conditions in the presence of sodium
acetate. This corresponds to the 1,3-diaryl substitution pattern
we observed in 9a, but we largely observed a strong preference for
the diaryl substitution pattern observed in 8b–f under neutral or
acidic conditions of condensation. In summary, condensations
of arylhydrazines 4a–b with 1,3-dicarbonyl compounds 5a–c
under acid catalyzed or acid media favor overwhelming predom-
inance of pyrazole regio-isomers 10a–f derived from hydroxy-
pyrazolines 8a–f. Reaction time is extremely rapid taking
<2 hours at 85 ◦C. In contrast conversion to the pyrazoles under
neutral conditions is very slow taking several days to go to com-
pletion especially when electron-withdrawing substituents are
present. Hydroxy-pyrazolines could be crystallized and isolated
Other workers9 recently have studied the products formed
as a result of cyclization of hydrazines and 1,3-dicarbonyl
compounds under several conditions; mildly alkaline conditions
in the presence of sodium acetate in ethanol, acetic acid and
large molar excesses of sulfuric acid and ethanol and large
molar excesses of hydrochloric acid. They believe that experi-
mental observations concerning the regio-isomerism observed
are a result of the equilibrium between two isomeric 3,5-
dihydroxypyrazolidines that would correspond to 12 and 13 in
our study series (Scheme 3).
Scheme 3 Potential dihydroxy-pyrazolidine intermediates (not ob-
served to date) and known example 14.
We observed that there were significant differences between
the condensation of hydrazines substituted with electron-
withdrawing Ar groups such as 5-methanesulfonylpyridin-2-yl
and phenyl and when R was varied with increasing electron-
withdrawing power from methyl, difluoromethyl to trifluo-
romethyl in the 1,3-dicarbonyl compound 5. The outcome
of the reaction also depended on the reaction conditions.
Scheme 4 Relative reaction rate and pathway using acidic and neutral conditions for pyrazole cyclization leading to different regio-isomeric products.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9
1 8 4 6

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Scheme 5 Relative rates of dehydration of specific 3-hydroxy-pyrazolines.
Fig. 2 X-Ray structure of 2-(5-methanesulfonylpyridin-2-yl)-5-phenyl-
3-trifluoromethyl-3,4,-dihydro-2H-pyrazol-3-ol, 9a.
only when an electron-withdrawing group is present. In all
cases except one the 1,5-diaryl regio-isomers were the main
product usually >90% of fully unsaturated cyclized pyrazole
products. The exception proved to be the regio-isomer 9a, which
was more difficult to dehydrate to 11a using the conditions
that had rapidly dehydrated the regio-isomer series 8a–f. The
difference in the regio-isomerism observed in 9a formation and
its subsequent slower dehydration rate may only be speculated
upon at this point. The formation of 9a could be accounted
for by proposing a significant concentration of the enol form
of 5a under the neutral reaction conditions, which would result
in initial hydrazone formation at the phenyl carbonyl group
and subsequent dehydration to 9a, (Scheme 5). The slower
dehydration of 9a relative to 8a–f may be connected with the
hydroxy group being adjacent to the CF3 group, which stabilizes
the hydroxy-pyrazoline structure.
Fig. 1 a X-Ray structure of 5-difluoromethyl-2-(5-methanesulfonyl-
X-Ray
structure of 2-[5-(methylsulfonyl)pyridin-2-yl]-5-methyl-3-phenyl-
pyridin-2-yl)-3-phenyl-3,4-dihydro-2H-pyrazol-3-ol, 8b.
b
3,4-dihydro-2H-pyrazol-3-ol, 8c.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9
1 8 4 7

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at room temperature to constant weight. Obtained 9a (1.7 g,
48%). HPLC purity was 100%. DSC: 175.8–175.0 ◦C, 101.9 J g−1
(4.6 mg); IR (KBr) cm−1m 3187, 3071, 3021, 3006, 2980, 2927,
2565, 2369, 2286, 1966, 1884, 1798, 1594, 1488, 1413, 1315, 1293,
Experimental
Proton and 13C spectra were collected at 298 K using a Varian
5 mm dual gradient probe on a Varian Unity Inova NMR
spectrometer operating at 400 MHz. 13C NMR spectra were
recorded at 100 MHz. Chemical shifts (d) are quoted in ppm, and
coupling constants (J) are given in Hz. IR spectra were recorded
using ThermoNicolet Magna 560 series. Combustion analyses
were performed by Schwarzkopf Microanalytical Laboratory
(Woodside, NY) or Quantitative Technologies, Inc. (White-
house, NJ). Mass spectral data was collected on a Micromass
QTOF mass spectrometer (electrospray ionization). DSC data
were collected using a Thermal Analysis Q1000 or a Mettler
Toledo 821.
1
1183, 1158, 1106, 1028; H NMR (400 MHz, CDCl3) d 8.7 (d,
1 H, J = 2.5 Hz), 8.02 (dd, 1 H, J = 2.5, 9.1 Hz), 7.74 (m,
2 H), 7.69 (s, 1 H), 7.61 (d, 1 H, 9.1 Hz), 7.46 (m, 3 H), 3.72
(dd, 2H, J = 18.5, 41.5 Hz), 3.1 (s, 3 H); 13C NMR (CDCl3)
d 158.8, 153.0, 147.0, 137.5, 131.1, 130.4, 129.2, 128.6, 126.7,
111.2, 45.4, 44.2; HRMS m/z (M+) C16H14F3N3O3SH+ requires
386.0786, obsd 386.0791.
2-(3-Difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl-
pyridine (10b)12
The structures of hydroxy pyrazolines and pyrazoles, 8b, 8c,
9a, 10a, 10b, and 10d were confirmed by single crystal X-ray
data.11 Compounds that are either new or synthesized in a new
way are noted below.
Ketone 5b, 26.4 g (133.2 mmol, 0.96 equiv.), hydrazine 4a 25.9 g
(138.5 mmol, 1.0 equiv.), and 2-propanol (800 ml) were stirred
for 30 minutes at 30 ◦C, conc. H2SO4 747 ll (13.32 mmol,
0.1 equiv.) was added and the mixture heated at 83 ◦C for
60 min. The reaction mixture was cooled <45 ◦C and water
(1000 ml) added to form a slurry, stirred at ambient temperature
for 2 h. Crude 10b was isolated, washed with the mother
liquor then water until filtrate pH was neutral, and dried at
room temperature to constant weight. Obtained (43.2 g, 92.9%).
HPLC purity was 99.1% contained 0.85%, 11b. Crude 10b
was dissolved in 2-propanol (912 ml) and stirred at reflux
for 30 min, filtered hot solution, washed with hot 2-propanol
(200 ml). Combined filtrate and wash were concentrated to
740 ml, cooled <45 ◦C and initiated crystallization. Isolated and
washed residue with the mother liquor and 2-propanol (200 ml),
dried at room temperature to constant weight. Obtained 10b
(38.7 g, 83.2%). HPLC purity was 99.4% along with 0.59% 11b.
Overall yield 77.3%. Differential Scanning Spectroscopy: 125.2–
127.0 ◦C 95.23 J g−1 (4.8 mg); Calc. for C16H13F2N3O2S: C, 55.01;
H, 3.75; F, 10.88; N, 12.03; O, 9.16; S, 9.18. Found: C, 55.22; H,
3.65; F, 10.79; N, 11.99; S, 9.13%; 1H NMR (CDCl3) d 8.77 (d,
1 H, J = 1.5 Hz), 8.27 (dd, 1 H, J = 2.5, 6.2 Hz), 7.29 (m, 5 H),
6.78 (t, 1 H, J = 54.6 Hz), 6.74 (s, 1 H), 3.09 (s, 1 H); 13C
NMR (CDCl3) d 147.9, 147.7, 147.3, 144.9, 139.7, 129.9, 129.3,
128.8, 128.4, 125.6, 119.9, 111.6, 109.3, 105.0; HRMS m/z (M+)
C16H13F2N3O2SH+ requires 350.0775, obsd 350.0780.
5-Difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)-3-phenyl-
3,4-dihydro-2H-pyrazol-3-ol (8b)
Ketone 5b, 5.9 g (30 mmol, 1.0 equiv.), hydrazine 4a, 5.8 g
(31.2 mmol, 1.04 equiv.), and 2-propanol (100 ml), were stirred
for 3.0 hours at 83 ◦C. The reaction mixture was cooled to room
temperature and water (230 ml) added to form a slurry. Stirred
at ambient temperature for 24 h. Isolated solid, washed with 2-
propanol (50 ml) and water (50 ml), re-dissolved in 2-propanol
(100 ml) and stirred at reflux for 30 min., filtered while hot,
followed by 2-propanol (500 ml). The resultant solution was
cooled to <45 ◦C to initiate crystallization. The product was
isolated and washed with 2-propanol (50 ml), and dried, yielding
8b (4.6 g, 43%). HPLC purity was 99.9%. DSC: 142.1–143.4 ◦C,
110.1 J g−1 (3.2 mg). Calc. for C16H15F2N3O3S: C, 52.31; H, 4.12;
F, 10.34; N, 11.44; O, 13.07; S, 8.73. Found: C, 52.38; H, 3.94;
F, 10.29; N, 11.24; S, 8.69%; IR (KBr) m cm−1 3458, 3086, 3058,
1937, 1878, 1792, 1592, 1160, 1127, 1105, 1076, 1022; 1H NMR
(400 MHz, CDCl3) d 8.40 (d, 1 H, J = 2.3 Hz), 8.02 (dd, 1 H,
J = 2.3, 6.8 Hz), 7.37 (m, 5 H), 6.49 (t, 1 H, J = 54.1 Hz),
5.78 (bs, 1 H), 3.42 (dd, 2 H, J = 1.54, 2.48, 117.17 Hz), 3.00
(s, 1 H); 13C NMR (CDCl3) d 157.5, 147.7, 143.4, 137.4, 129.1,
128.7, 128.3, 124.5, 111.1, 95.9, 47.7, 45.3; HRMS m/z (M+)
C16H15F2N3O3SH+ requires 368.0880, obsd 368.0872.
5-Methanesulfonyl-2-(3-methyl-5-phenyl-pyrazol-1-yl)-pyridine
(10c)
2-[5-(Methylsulfonyl)pyridin-2-yl]-5-methyl-3-phenyl-3,4-
Ketone 5c 2.0 g (12.4 mmol, 0.96 equiv.), hydrazine 4a, 2.4 g
(12.8 mmol, 1.0 equiv.), and 2-propanol (74 ml) were stirred
for 30 min. at 30 ◦C, then for 8 days at 83 ◦C. The reaction
mixture was cooled to room temperature and a slurry formed.
Isolated and washed with 2-propanol (50 ml), dried at room
temperature until constant weight. Obtained, 10c (3.3 g, 86%).
HPLC purity, 95.0%. Regio-isomer r◦atio 99/1. Differential
Scanning Spectroscopy: 145.62–147.23 C 65.72 J g−1 (1.7 mg);
IR (KBr) cm−1 m 3065, 3011, 1960, 1892, 1767, 1693, 1582, 1155,
1103,; 1H NMR (400 MHz, CDCl3) d 8.74 (d, 1 H, J = 2.5 Hz),
8.18 (dd, 1 H, J = 2.5, 6.2 Hz), 7.76 (d, 1 H, J = 8.7 Hz), 7.32 (m,
5 H), 6.34 (S, 1 H), 3.07 (s, 3 H), 2.34 (s, 1 H); 13C NMR (CDCl3)
d 155.81, 152.32, 147.98, 145.71, 137.58, 134.02, 131.44, 128.98,
128.76, 128.52, 126.24, 116.97, 111.71, 45.18, 13.97; HRMS m/z
(M+) C16H15N3O2SH+ required 314.0978, obsd 314.0963.
10c was also prepared by heating 8c in 2-propanol for 8 days.
The transformation was monitored by HPLC.
dihydro-2H-pyrazol-3-ol (8c)
Ketone 5c, 15.0 g (92.5 mmol, 0.96 equiv.), hydrazine 4a, 18 g
(96.2 mmol, 1.0 equiv.), and 2-propanol (555 ml) were stirred for
30 min at room temperature, then 2.0 h. at 75 ◦C. The reaction
mixture was then cooled down to <45 ◦C and water (1000 ml)
added, to form a slurry, stirred at ambient temperature for 24 h,
isolated solid, washed with water (50 ml) and 2-propanol (50 ml)
and dried at room temperature to constant weight. Obtained◦8c
(20.2 g, 66%). HPLC purity was 90.4%. DSC: 133.3–135.9 C
1
102.9, J g−1 (3.9 mg); H NMR (400 MHz, CDCl3) d 8.34 (d,
1 H, J = 2.5 Hz), 7.92 (dd, 1 H, J = 2.5, 6.6 Hz), 7.42–7.26
(m, 7 H), 5.96 (s, 1 H, OH), 3.22 (dd, 2 H, J = 18.7, 125.7),
2.99 (s, 3 H) 2.12 (s, 3 H); 13C NMR (CDCl3) d 154.06, 147.95,
144.50, 136.69, 128.9, 128.1, 126.3, 124.6, 109.6, 94.9, 55.0, 45.4,
16.4; HRMS m/z (M+) C16H17N3O3SH+ requires 332.1069, obsd
332.1071.
2-(5-Methanesulfonylpyridin-2-yl)-5-phenyl-3-trifluoromethyl-
1,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (10d)
3,4-dihydro-2H-pyrazol-3-ol (9a)
Ketone 5a, 2.0 g (9.3 mmol, 0.96 equiv.), hydrazine 4b, 1.8 g
(9.62 mmol, 1.0 equiv.), and 2-propanol (50 ml) were stirred for
30 minutes at 30 ◦C, conc. H2SO4 779 lL (13.9 mmol, 1.5 equiv.)
Ketone 5a 2.0 g (9.3 mmol, 0.96 equiv.), hydrazine 4a,1.8 g
(9.6 mmol, 1.0 equiv.), and 2-propanol (55 ml) were stirred for
30 min at room temperature then heated for 6 d at 83 ◦C. Cooled
and 2-propanol (50 ml) added, stirred at ambient temperature for
24 h. Isolated solid and washed with 2-propanol (30 ml), dried
◦
was added and the mixture heated at reflux 83 C for 90 min.
The reaction mixture was cooled <45 ◦C and water (93 ml)
added to form a slurry, stirred at ambient temperature for 2 h,
1 8 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9

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isolated and washed with mother liquor, then with water until
filtrate pH is neutral, dried at room temperature to constant
weight. Obtained, 10d (2.2 g, 65.3%). HPLC purity was 100%.
IR (KBr) cm−1 m 3132, 3066, 1595, 1495, 1472, 1446, 1375, 1236,
structures in this article. We also thank our colleagues, Henry
Cheng, David Koss, Jin Li, and Subas Sakya, who independently
observed the same un-dehydrated intermediate 9a and provided
useful discussion on the topic of this work.
1
1154, 1136; H NMR (400 MHz, CDCl3) d 6.76 (s, 5 H), 7.25
(m, 5 H); 13C NMR (CDCl3) d 129.6, 129.4, 129.4, 129.2, 129.1,
129.0, 128.9, 128.7, 126.1, 126.0, 125.7, 105.8; HRMS m/z (M+)
C16H11F3N2H+required 289.0952, obsd 289.0950.
References
1 M. J. Genin, C. Biles, B. J. Keiser, S. M. Poppe, S. M. Swaney, W. G.
Tarpley, Y. Yagi and D. L. Romero, J. Med. Chem., 2000, 43, 1034.
2 A. Guzman-Perez, R. T. Webster, M. C. Allen, J. A. Brown, A. R.
Buchholz, E. R. Cook, W. W. Day, E. S. Hamanaka, S. P. Kennedy,
D. R. Knight, P. J. Kowalczyk, R. B. Marala, C. J. Mularski, W. A.
Novomisle, R. B. Ruggeri, W. R. Tracy and R. J. Hill, Bioorg. Med.
Chem. Lett., 2001, 11(6), 803.
3-(Difluoromethyl)-1,5-diphenyl-1H-pyrazole (10e)
Ketone 5b, 1.5 g (7.6 mmol, 0.96 equiv.), hydrazine 4b, 800 lL
(7.9 mmol, 1.04 equiv.), and 2-propanol (45 ml) were stirred
for 30 min at 30 ◦C, added conc. H2SO4 43 ll (0.8 mmol, 0.1
equiv.) heated at 83 ◦C for 60 min. The reaction mixture was
cooled <45 ◦C and water (50 ml) added, extracted with ethyl
acetate (3 × 20 ml). The combined organic phase was dried over
Na2SO4. Concentrated to obtain 10e (2.01 g, 98%). HPLC purity
was 92%; 97/3 regio-isomer ratio. 1H NMR (300 MHz, CDCl3)
d 6.77 (dd, 1 H, J = 20.53, 54.95 Hz), 7.28–7.38 (m, 10 H);
13C NMR (CDCl3) d 139.7, 129.9, 129.3, 129.3, 129.0, 129.0,
128.9, 128.8, 128.4, 125.6, 113.9 (CHF2), 111.6 (CHF2), 109.3
(CHF2), 105.0; HRMS m/z (M+) C16H12F2N2H+ 271.1047, obsd
271.1048.
3 T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter and P. W.
Collins, J. Med. Chem., 1997, 40, 1347.
4 J. Li, K. M. L. DeMello, H. Cheng, S. M. Sakya, B. S. Bronk, R. J.
Rafka, B. H. Jaynes, C. B. Ziegler, C. Kilroy, D. W. Mann, E. L.
Nimz, M. P. Lynch, M. L. Haven, N. L. Kolosko, M. L. Minich, C.
Li, J. K. Dutra, B. Rast, R. M. Crosson, B. J. Morton, G. W. Kirk,
K. M. Callaghan, D. A. Koss, A. Shavnya, L. A. Lund, S. B. Seibel,
C. F. Petras and A. Silvia, Bioorg. Med. Chem. Lett., 2004, 14, 95.
5 K. von Auwers and W. Schmidt, Chem. Ber., 1925, 58, 528.
6 K. N. Zetenin, V. V. Alekseyev, A. R. Tygysheva and S. I. Yaki-
movitch, Tetrahedron, 1995, 51(41), 11251.
7 (10f) is prepared as the exclusive (>99%) pyrazole isomer by con-
densing phenylhydrazine (4b) with benzoylacetone (5c) in ethanol–
water 2 : 1 in the presence of sodium acetate at reflux, see reference
3, page 1036. This compound has been used to prepare other 1,5-
diphenylpyrazoles that have known regio-isomerism.
5-(Methylsulfonyl)-2-[3-phenyl-5-(trifluoromethyl)-pyrazol-1-
yl]pyridine (11a)
8 Main and minor products were estimated by normalized chro-
matograms using authentic reference samples to confirm correct
identification by retention time. Column; Kromasil C8. 5 mm
spherical particles 150 mm × 4.6 mm, mobile phase; 55% 20 mM
potassium phosphate buffer, pH 3.0, 45% acetonitrile, flow rate;
1.0 mL g−1, injection vol., 10 lL wavelength of detection; 250 nm,
temperature; 35 ◦C, instrument; HP 1100 series.
9 S. P. Singh, D. Kumar, H. Batra, R. Nathani, I. Rozas and Jose
Elguero, Can. J. Chem., 2000, 78, 1109.
10 J. Elguero and G. I. Yranzo, J. Chem. Res. Synop., 1990, 120.
11 Single crystal X-ray data. Compound 8b: C16H15N3O3SF2; (M),
Pyrazoline 9a 130 mg (0.34 mmol, 1.0 equiv.), 2-propanol (20 ml)
and conc. H2SO4 72 ll (0.8 mmol, 1.5 equiv.) were heated at
83 ◦C for 24 h. A second portion of conc. H2SO4 was added
(57 lL, 1.0 mmol, 3.0 equiv.) and heating continued for 48 h. The
reaction mixture was cooled and stirred at ambient temperature
for 1 h. Isolated precipitated solid, washed with water until
neutral pH filtrate was obtained, dried at room temperature
1
to constant weight. Obtained pyrazole 11a (104 mg, 83%). H
NMR (400 MHz, CDCl3) d 9.03 (d, 1 H, J = 2.5 Hz), 8.27
(dd, 1 H, J = 8.7, 60.6 Hz), 7.73 (m, 1 H, 3 H), 7.42–7.52 (m,
5 H), 7.26 (s, 1 H), 3.2 (s, 3 H); 13C (100 MHz, d6-DMSO) d
153.7, 153.1, 147.8, 139.6, 136.6, 133.5 (q, J = 40.8 Hz), 130.9,
130.2, 129.6, 127.3, 126.6, 116.3, 111.8, 44.3; HRMS m/z (M+)
C16H12F3N3O2SH+ found: 368.0680, calc: 368.0681
367.37; unit cell dimensions (A, ◦) a = 10.5772(4), b = 17.2951(7),
˚
3
˚
c = 9.3940(4), a = 90, b = 109.7810(10), c = 90; vol. 1617.08(11) A ;
space group, P2(1)/c; (Z), 4; (l), 2.188 mm−1; independent reflections
1285[R(int) = 0.1021]; final R indices [I > 2r(I)], R1 = 0.0505,
wR2 = 0.1276. Compound 8c: C16H17N3O3S; (M), 331.39; unit cell
dimensions (A, ◦) a = 15.9809(10), b = 9.4557(6), c = 10.5313(7),
˚
3
˚
a = 90, b = 90.4710(10), c = 90; vol. 1591.34(18) A ; space
group, P2(1)/c; (Z), 4; (l), 0.222 mm−1; independent reflections
1663 [R(int) = 0.0592]; final R indices [I > 2r(I)], R1 = 0.0370,
wR2 = 0.0928. Compound 9a: C16H14F3N3O3S; (M), 385.36; unit cell
2-(5-Difluoromethyl-3-phenylpyrazol-1-yl)-5-methanesulfonyl-
pyridine (11b)
dimensions (A, ◦) a = 8.3741(5), b = 19.8459(13), c = 10.4665(7),
˚
The source of 11b was from a mixture of previous mother liquors
obtained from the synthesis of 10b. 11b was purified by column
chromatography using silica gel as stationary phase (Biotage
System, 75 L) and dichloromethane as the mobile phase. This
separation yielded 11b (3.5 g). HPLC purity of 99.0%. 1H NMR
(400 MHz, CDCl3) 8.97 (d, 1 H, J = 1.7 Hz), 8.15 (dd, 1 H, J =
2.1, 6.6 Hz), 7.9 (d, J = 6.64 Hz, 1 H) 7.76 (t, 1 H, J = 54.8 Hz),
7.46 (m, 3 H), 7.19 (s, 1 H), 3.15 (s, 1 H); 13C NMR (CDCl3) d
147.88, 138.48, 134.47, 129.62, 129.15, 126.37, 114.57, 109.13,
108.32, 45.31; Anal. Cald. for C16H13F2N3O2S: C, 55.01; H, 3.75;
F, 10.88; N, 12.03; O, 9.16; S, 9.18. Found: C, 54.97; H, 3.58; F,
10.83; N, 11.90; S, 9.34%. HRMS m/z (M+) C16H13F2N3O2SH+
requires 350.0775, obsd. 350.0779.
3
˚
a = 90, b = 108.8450(10), c = 90; vol. 1646.20(18) A ; space
group, P2(1)/n; (Z), 4; (l), 0.252 mm−1; independent reflections
1721[R(int) = 0.0542]; final R indices [I > 2r(I)], R1 = 0.0295, wR2 =
0.0767. Compound 10a: C16H12F3N3O3S; (M), 367.35; unit cell
dimensions (A, ◦) a = 31.208(4), b = 5.0510(10), c = 21.756(2), a =
˚
3
˚
90, b = 110.080(10), c = 90; vol. 3221.0(8) A ; space group, C2/c; (Z),
8; (l), 2.245 mm−1; independent reflections 1639 [R(int) = 0.0130];
final R indices [I > 2r(I)], R1 = 0.0445, wR2 = 0.1021. Compound
10b: C16H13F2N3O2S; (M), 349.35; unit cell dimensions (A, ◦) a =
˚
10.614(2), b = 7.4840(10), c = 20.523(3), a = 90, b = 96.250(10), c =
3
−1
˚
90; vol. 1620.6(4) A ; space group, P2(1)/c; (Z), 4; (l), 2.108 mm
;
independent reflections 1674 [R(int) = 0.0181]; final R indices
[I>2r(I)], R1 = 0.0419, wR2 = 0.1017. Compound 10d: C16H11F3N2;
◦
˚
(M), 288.27; unit cell dimensions (A, ) a = 8.4600(10), b = 16.282(2),
c = 10.7060(10), a = 90, b = 107.520(10), c = 90; vol. 1406.3(3)
3
A ; space group, P2(1)/n; (Z), 4; (l), 0.935 mm−1; independent
˚
Acknowledgements
reflections 1449 [R(int) = 0.0306]; final R indices [I > 2r(I)], R1 =
0.0461, wR2 = 0.1104. CCDC reference numbers 263085–263090.
See http://www.rsc.org/suppdata/ob/b5/b500413f/ for crystallo-
graphic data in CIF or other electronic format.
The authors thank colleagues Michael J. Castaldi and Dennis
E. Bourassa for invaluable experimental assistance, Professor
Steven Ley (Cambridge) for helpful discussions and Jon Bordner
and Ivan Samardjiev for solving the single crystal X-ray
12 D. E. Bourassa, M. J. Castaldi and D. H. B. Ripin, US Patent
6646128, 11 November 2003.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 4 4 – 1 8 4 9
1 8 4 9