Synthesis of trifluoromethyl-substituted pyrazoles and 1,2,4-triazines by ring transformation of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates with phenylhydrazine

Article abstract of DOI:10.1248/cpb.56.433

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates 1 were easily prepared by the cyclodehydration reaction of N-acyl-N-alkyl-α-amino acids with trifluoroacetic anhydride. Due to the presence of the trifluoromethyl ketone and the mesoionic five-membered oxazole, there are three reaction sites to be attacked by the nucleophiles at C-2, C-5 and the trifluoroacetyl group in 1. Based on this model, three modes of regioselective attack by phenylhydrazine were found to provide three different products, i.e., 6-trifluoromethyl-1,2,4- triazines 3, 3-trifluoromethyl-5-pyrazolones 5 and 5-trifluoromethyl-3- hydroxypyrazoles 4, in good yields, respectively, depending on the nature of the solvent and reaction temperature. These three types of different reactions may be explained by the polarity of the reaction solvent and the mesoionic oxazole-ketene tautomerism.

Full text of DOI:10.1248/cpb.56.433

April 2008
Chem. Pharm. Bull. 56(4) 433—438 (2008)
433
Synthesis of Trifluoromethyl-Substituted Pyrazoles and 1,2,4-Triazines by
Ring Transformation of Mesoionic 4-Trifluoroacetyl-1,3-oxazolium-
5-olates with Phenylhydrazine
b
Masami KAWASE ,a,b and Hiromi KOIWAI
*
a Faculty of Pharmaceutical Sciences, Matsuyama University; 4–2 Bunkyo-cho, Matsuyama, Ehime 790–8578, Japan: and
b Faculty of Pharmaceutical Sciences, Josai University; 1–1 Keyakidai, Sakado, Saitama 350–0295, Japan.
Received August 29, 2007; accepted December 7, 2007; published online January 15, 2008
Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates 1 were easily prepared by the cyclodehydration reaction
of N-acyl-N-alkyl-a-amino acids with trifluoroacetic anhydride. Due to the presence of the trifluoromethyl ke-
tone and the mesoionic five-membered oxazole, there are three reaction sites to be attacked by the nucleophiles at
C-2, C-5 and the trifluoroacetyl group in 1. Based on this model, three modes of regioselective attack by phenyl-
hydrazine were found to provide three different products, i.e., 6-trifluoromethyl-1,2,4-triazines 3, 3-trifluo-
romethyl-5-pyrazolones 5 and 5-trifluoromethyl-3-hydroxypyrazoles 4, in good yields, respectively, depending on
the nature of the solvent and reaction temperature. These three types of different reactions may be explained by
the polarity of the reaction solvent and the mesoionic oxazole-ketene tautomerism.
Key words 1,3-oxazolium-5-olate; trifluoromethyl; ring transformation; pyrazole; 1,2,4-triazine
Trifluoromethyl-substituted heterocyclic compounds have Results and Discussion
received much attention due to their potential biological ac-
The mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates 1
tivities and will continue to play a significant role in medi- were generally obtained as colored (yellow) solids by the re-
cine and agricultural chemistry as well as in material action of the N-acyl-N-alkyl-a-amino acids 2 with trifluo-
science.1—4) However, the facile introduction of the trifluo- roacetic anhydride (Chart 2). Compounds 1 are the subject of
romethyl group into heterocyclic rings is limited, and the de- a reaction with PH under a variety of reaction conditions.
velopment of new practical methods remains a formidable
Reaction of 1 with PH in N,N-dimethylformamide
task. Recently, such molecules have found outstanding appli- (DMF) We examined the reaction of 4-trifluoroacetyl-1,3-
cations in the pharmaceutical field, as illustrated by Cele- oxazolium-5-olates 1a—f with PH in DMF. The reaction was
coxib (antiarthritic) bearing a trifluoromethyl substituent on completed within 24 h at room temperature to afford the 6-
the pyrazole-ring, a recent drug used in the treatment of trifluoromethyl-1,2,4-triazines 3 in good yields (Table 1).
human diseases.5) Therefore, much attention has been paid to
In general, the terminal nitrogen (N-2) of PH is more nu-
the synthesis of trifluoromethyl-substituted pyrazoles due to cleophilic than the substituted nitrogen (N-1) in neutral
their biological activities in the medicinal and agrochemical media.20) Thus, PH would attack at the C-2 position of 1 to
fields.6—13) In contrast to the trifluoromethylated pyrazoles, produce an adduct 8 followed by the decarboxylation. Subse-
the 1,2,4-triazines, which possess trifluoromethyl groups, quently, the intramolecular cyclization of 9 leads to the prod-
seem to be less known in the literature, although some triflu- uct 3, as shown in Chart 3 (route A). The reaction appears to
oromethylated 1,2,4-triazines have been developed as agro- proceed via a mechanism similar to that described for the re-
chemicals.14,15)
action of 1 and ammonia.17) It is possible that in the highly
In previous papers, we reported that mesoionic 4-trifluo- polar DMF solvent, the mesoionic form of 1 is stabilized.
roacetyl-1,3-oxazolium-5-olates 1 are useful synthons for the This led to the attack mode by PH at C-2, which produced
synthesis of trifluoromethyl substituted imidazoles by the re- the product 3. These data are consistent with the previous
action with amidines16) or ammonia.17) These reactions occur molecular orbital (MO) study that N-nucleophiles attack at
via the initial attack of the nucleophiles on the C-2 position C-2 in the mesoionic oxazole 1 on the basis of the Hard and
of the ring. In line with this continuing interest,18) we have
undertaken an investigation of the reaction of 1 with the bis-
nucleophile such as phenylhydrazine (PH). Regioselective at-
tacks by PH on mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-
olates 1 are found to be a function of the solvent and the re-
action temperature. In principle, nucleophilic reagents can be
expected to add to one of the three electrophilic centers at C-
2, C-5 and COCF3 in 1 (Chart 1). On this occasion, all three
modes of attack leading to the addition products of type 2, 3
or 4 were found (Chart 1). We now present a full account of
the reactions of 1 with PH19) and the efficient synthesis of
new trifluoromethylated heterocycles in the 1,2,4-triazine, 3-
pyrazolone and 5-pyrazolone.
Chart 1
∗ To whom correspondence should be addressed. e-mail: kawase@cc.matsuyama-u.ac.jp
© 2008 Pharmaceutical Society of Japan

434
Vol. 56, No. 4
Table 2. Reactions of Compounds (1) with Hydrazine Derivativesa)
Starting
materials
Hydrazine
derivatives
Yields of
products
Run
1
2
3
4
5
6
1a
1a
1b
1a
1g
1f
NH2NH2
CH3NHNH2
4-CH3C6H4SO2NHNH2
NH2NHCO2CH3
NH2NHCO2CH3
NH2NHCONH2
3g (48)
3h (58)
3i (17)
3j (29)
3k (14)
6b (76)
a) The reaction was done at room temperature for 24 h in DMF.
Chart 2
Table 1. Reactions of Compounds (1) with Phenylhydrazine
Starting
materials
Reaction
Run
Yields of products
conditionsa)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1b
1c
1d
1e
1f
1a
1b
1c
1e
1f
1a
1a
1b
1c
1d
1e
A
A
A
A
A
A
B
B
B
B
B
Bb)
C
C
C
C
C
3a (74)
3b (40)
3c (68)
3d (64)
3e (88)
3f (83)
4a (63)
4a (73)
4a (46)
4b (95)
6a (24)ꢁ5d (25)
4c (74)
5a (62)
5b (70)
5c (48)
5d (14)ꢁ4b (55)
5e (41)
Chart 3
carbonyl of 10 and the subsequent intramolecular cyclization
of 11 led to 12, as shown in Chart 3 (route B). In this case,
the intermediates 12 and 13 were not isolated, thus showing
that the dehydration of 12 followed by hydrolysis of the re-
sulting amide 13 easily occurred under the adopted reaction
conditions. The driving force of the dehydration is probably
due to stabilization by the formation of an aromatic pyrazole
derivative.23,24) The reason why the reaction of 1f affords the
different products 5d and 6a is unclear. In the reaction of 1a
with 4-methoxyphenylhydrazine instead of PH, 4c was also
isolated in 74% yield.
Reaction of 1 with PH in 1,2-Dichloroethane Com-
pounds 1 were treated with PH at rt in a 1,2-dichloroethane
solution to give the 3-trifluoromethyl-5-pyrazolones 5. None
of the 1,2,4-triazine derivative 3 was obtained in the reaction.
The nucleophilic site in 1 was changed by the solvent polar-
a) A: the reaction was done at room temperature for 24 h in DMF. B: the reaction
mixture was refluxed for 2 h in benzene. C: the reaction was done at room temperature
for 24 h in DCE. b) 4-Methoxyphenylhydrazine was used instead of phenylhydrazine.
Soft Acids and Bases (HSAB) theory.21)
We have carried out, besides the reaction of 1 with PH, the ity. Thus, the first step of the reaction consists of an attack at
reaction of 1 with other hydrazine derivatives, such as hy- the trifluoromethyl ketone group by PH, as shown in Chart 3
drazine hydrate, methylhydrazine, hydrazine carbamate or (route C). The adduct 14 underwent intramolecular cycliza-
tosylhydrazine, leading to the 1,2,4-triazine derivatives 3 in tion that led to the product 5. The reaction of 1d afforded 5d
moderate yields, as shown in Table 2. On the other hand, the in only 14% yield and 4b was obtained as the main product
reaction of the semicarbazide with 1a afforded only the non- in 55% yield. It is difficult to obtain a definitive explanation
cyclized semicarbazone 6b in 76% yield.
for the transformation.
Reaction of 1 with PH in Benzene The reaction of
Structural Determination of 3, 4 and 5 The structural
1a—d with PH in refluxing benzene solution afforded the 5- determination of products 3, 4, and 5 were performed by
trifluoromethyl-3-hydroxyprazoles 4 in good yields. At ele- spectral and analytical analyses. The 1H-NMR spectrum of 3
vated temperature, the mesoionic 1 is in equilibrium with the exhibited the methylene signal of C-5 at around 3.4 ppm (d,
trifluoroacetylketenes 10. Similar ketene-type valence tau- Jꢀ13 Hz) and 3.8 ppm (d, Jꢀ13 Hz). In the 13C-NMR spec-
tomers are often encountered during the cycloaddition of tra, the C-5 carbon atom appears at around 52 ppm and the
these mesoionic systems.22) Thus, PH attacked at the ketene C-6 carbon atom at around 79 ppm (2JCFꢀ30 Hz). The carbon

April 2008
435
Chart 5. 13C-NMR Chemical Shifts of Representative Heterocycles Pre-
pared in This Work and Two Related Pyrazoles
materials by only selecting different reaction conditions is an
interesting research topic for chemists. We observed three
different types of ring-opening reactions followed by ring-
closure of the mesoionic oxazoles 1. The reaction of 1 with
PH affords a completely different product depending on the
reaction solvent and temperature. With the application of dif-
Chart 4
of CF3 and the C-2 appear at around 123 ppm (1JCFꢀ290 Hz) ferent reaction conditions, the highly selective formation of
and 147 ppm, respectively. These H- and 13C-NMR data are 6-trifluoromethyl-1,2,4-triazines 3, 5-trifluoromethyl-3-hy-
1
similar to the data for the 4-hydroxy-1-methyl-2-phenyl-4- droxypyrazoles 4 and 3-trifluoromethyl-5-pyrazolones 5 can
trifluoromethyl-4,5-dihydro-imidazole.16)
be realized. Regioselective attacks by PH on the mesoionic
The structure of 4a was determined by the X-ray crystal- 4-trifluoroacetyl-1,3-oxazolium-5-olates 1 are a function of
lography.25) Compound 4a was treated with benzoyl chloride the solvent and the reaction temperature. Due to the easy
in the presence of pyridine to yield 7a in 87% yield (Chart availability of the starting materials and synthetic potential of
4). When compound 5a reacted with benzoic anhydride the trifluoromethyl substituted heterocycles, this methodol-
under reflux in benzene, compound 7e was obtained in 59% ogy will show its utility in organic synthesis. Further studies
yield, which was formed by dehydration and benzoylation. in this area are being pursued in our laboratory.
Compound 7e was the regioisomer of 7a. Thus, these trans-
Experimental
formations confirmed the structure of 5a. The regioisomeric
General Methods All melting points were determined using a Yanagi-
pyrazoles 7a and 7e have significantly different 13C-NMR
moto hot-stage melting point apparatus and are uncorrected. 1H-NMR spec-
spectra as shown in Chart 5. The 13C-NMR spectral data of
tra were measured on either a JEOL JNM-PMX60SI or JNM-GSX500 spec-
trometer with tetramethylsilane (Me4Si) as an internal reference and CDCl3
7a were similar to those of the 5-trifluoromethy-3-hydroxyl-
as the solvent. 13C-NMR spectra were obtained on a JEOL JNM-GSX500
1-phenylpyrazole.26) The same was observed between 7e and
spectrometer (at 127 MHz). Both 1H- and 13C-NMR spectral data are re-
ported in parts per million (d) relative to Me4Si. Infrared (IR) spectra were
recorded on a JASCO IR810 spectrometer. Low- and high-resolution MS
3-trifluoromethy-5-hydroxyl-1-phenyl-pyrazole26) as shown
in Chart 5.
Compound 4a was reacted with 4-methoxybenzoyl chlo-
ride in the presence of pyridine to yield 7b in 95% yield. On
the other hand, the same reaction of 4a with 4-methoxyben-
zoyl chloride was done under Schotten–Baumann reaction
condition to give a mixture of 7b and 7c in 9% and 17%
yields, respectively. 4a and 5b were also treated with acetic
anhydride in the presence of pyridine to yield 7d and 7f in
88% and 61%, respectively (Chart 4).
were obtained with a JEOL JMS-DX300 spectrometer with a direct inlet
system at 70 eV. High-resolution (HR) ESI-MS of compound 6b was per-
formed with a microTOF-Q (Bruker Daltonics) mass spectrometer using
acetonitrile as a solvent. Elemental analyses were carried out in the microan-
alytical laboratory of Josai University. Standard work-up means that the or-
ganic layers were finally dried over Na2SO4, filtered, and concentrated in
vacuo below 45 °C using a rotary evaporator.
Materials The following compounds were prepared by reported proce-
dures:
N-Benzoyl-N-methylglycine (2a) mp 101—104 °C (mp17) 102—104 °C).
N-(4-Methoxybenzoyl)-N-methylglycine (2b) mp 101—104 °C (mp27)
102—104 °C).
Conclusion
The selective synthesis of different products from the same
N-(4-Bromobenzoyl)-N-methylglycine (2c) Yield 92%, mp 147—

436
Vol. 56, No. 4
150 °C (AcOEt–hexane), IR (Nujol) cmꢂ1: 1725, 2570 (br); 1H-NMR 365.1353. Found: 365.1352.
(500 MHz, CDCl3ꢁDMSO-d6) d: 3.11ꢁ3.03 (s, 3H), 3.92ꢁ4.22 (s, 2H),
3-(4-Bromophenyl)-6-trifluoromethyl-1,4,5,6-tetrahydro-4-methyl-1-
7.31ꢁ7.37 (d, 2H, Jꢀ8.2), 7.53ꢁ7.56 (d, 2H, Jꢀ8.2); MS m/z: 271 (1.8)ꢁ phenyl-1,2,4-triazin-6-ol (3c) Oil, IR (oil) cmꢂ1: 1610, 3250 (br); 1H-
273 (1.8) (Mꢁ, 1 : 1), 183 (100)ꢁ185 (98). Anal. Calcd for C10H10BrNO3: C,
44.14; H, 3.70; N, 5.15. Found: C, 44.22; H, 3.58; N, 4.86.
NMR (500 MHz, CDCl3) d: 2.89 (s, 3H), 3.52 (d, 1H, Jꢀ12.8), 3.76 (d, 1H,
Jꢀ12.8), 7.15 (t, 1H, Jꢀ7.8), 7.28 (t, 2H, Jꢀ7.8), 7.38 (d, 2H, Jꢀ8.5), 7.40
(d, 2H, Jꢀ7.8), 7.51 (d, 2H, Jꢀ8.5); 13C-NMR (125 MHz, CDCl3) d: 40.48
(CH3), 52.40 (CH2), 79.52 (C, 2JCFꢀ30), 123.38 (CF3, 1JCFꢀ290), 123.93
N-Acetyl-N-phenylglycine (2d) mp 196—198 °C (mp11) 193—195 °C).
N-Benzyl-N-(4-methoxybenzoyl)glycine (2e) Yield 84%, mp 149—
1
151 °C (AcOEt–hexane), IR (Nujol) cmꢂ1: 1590, 1740, 2700 (br); H-NMR (C), 125.59 (CH), 125.79 (CH), 128.68 (CH), 130.13 (CH), 131.63 (CH),
(500 MHz, CDCl3) d: 3.82 (s, 2H), 4.17 (s, 2H), 4.71 (s, 2H), 6.89 (d, 2H, 132.89 (C), 144.04 (C), 147.04 (C); MS m/z: 413 (100)ꢁ415 (100) (Mꢁ,
Jꢀ8.2), 7.19—7.42 (m, 5H), 7.47—7.56 (br, 2H); MS m/z: 299 (Mꢁ, 10), 1 : 1). HR-MS Calcd for C17H1579BrF3N3O (C17H1581BrF3N3O): 413.0323
135 (100). Anal. Calcd for C17H17NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, (415.0336). Found: 413.0337 (415.0333).
68.20; H, 5.91; N, 4.64.
6-Trifluoromethyl-1,4,5,6-tetrahydro-3-methyl-1,4-diphenyl-1,2,4-tri-
N-Phenyl-N-(4-methoxybenzoyl)glycine (2f) Yield 88%, mp 135—
azin-6-ol (3d) mp 139—141 °C (Et2O–hexane), IR (Nujol) cmꢂ1: 1630,
137 °C (AcOEt–hexane) (lit.27) mp 158—163 °C), IR (Nujol) cmꢂ1: 1660, 3000 (br); 1H-NMR (500 MHz, CDCl3) d: 1.86 (s, 3H), 3.46 (dq, 1H, Jꢀ1.5,
1
1730, 3070 (br); H-NMR (500 MHz, CDCl3) d: 3.74 (s, 3H), 4.62 (s, 2H),
6.66 (d, 2H, Jꢀ7.7), 7.25 (t, 2H, Jꢀ7.7), 7.31 (d, 2H, Jꢀ8.9).
11.9), 3.90 (d, 1H, Jꢀ11.9), 7.11 (d, 2H, Jꢀ7.7), 7.17 (t, 1H, Jꢀ7.7), 7.26
(t, 1H, Jꢀ7.7), 7.33 (t, 2H, Jꢀ7.7), 7.38 (t, 2H, Jꢀ7.7), 7.45 (d, 2H, Jꢀ7.7);
13C-NMR (125 MHz, CDCl3) d: 19.29 (CH3), 52.09 (CH2), 80.16 (C,
N-Methyl-N-pivaloylglycine (2g) mp 75—76 °C (mp17) 75—76 °C).
General Procedure for the Preparation of 1 TFAA (11 ml, 78 mmol) 2JCFꢀ30), 123.30 (CF3, 1JCFꢀ290), 125.47 (CH), 125.69 (CH), 125.98
was added to a stirred solution of N-acyl-N-alkylglycine (26 mmol) in (CH), 126.49 (CH), 128.68 (CH), 129.36 (CH), 141.49 (C), 143.64 (C),
CH2CH2 (50 ml) at 0 °C for 10 min. The mixture was stirred at 25 °C for 3 h
and then extracted with CH2Cl2 (80 mlꢃ2). The combined extracts were 60.89; H, 4.81; N, 12.53. Found: C, 60.67; H, 4.89; N, 12.46.
washed successively with 3% HCl, H2O, 1% Na2CO3, and H2O. After the
6-Trifluoromethyl-1,4,5,6-tetrahydro-3-(4-methoxyphenyl)-1-phenyl-
144.65 (C); MS m/z: 335 (Mꢁ, 100). Anal. Calcd for C17H16F3N3O: C,
standard workup, the residue was recrystallized from CH2Cl2–hexane to give 4-phenylmethy-1,2,4-triazin-6-ol (3e) Oil, IR (oil) cmꢂ1: 1610, 1740,
the 4-trifluoroacetyl-1,3-oxazolium-5-olates (1).
3300 (br); 1H-NMR (500 MHz, CDCl3) d: 3.45 (d, 1H, Jꢀ13.0), 3.69 (d, 1H,
Jꢀ13.0), 3.79 (s, 3H), 4.36 (d, 1H, Jꢀ16.0), 4.48 (d, 1H, Jꢀ16.0), 6.88
(d, 2H, Jꢀ8.8), 7.26—7.43 (m, 10H), 7.52 (d, 2H, Jꢀ8.8); 13C-NMR
(125 MHz, CDCl3) d: 49.59 (CH2), 55.33 (CH3), 55.64 (CH2), 79.61 (C,
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-oxazolium-5-olate (1a) mp
161—163 °C (mp17) 162—163 °C).
2-(4-Bromophenyl)-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-olate
(1b) mp 75—76 °C (mp17) 75—76 °C).
1
2JCFꢀ30), 114.06 (CH), 123.79 (CF3, JCFꢀ279), 126.15 (CH), 126.23 (C),
2-(4-Bromophenyl)-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-olate
127.25 (CH), 127.84 (CH), 128.57 (CH), 128.85 (CH), 128.97 (CH), 129.27
(1c) Yield 89%, mp 188—191 °C (CH2Cl2–hexane), IR (Nujol) cmꢂ1
:
(C), 129.82 (CH), 137.23 (C), 144.34 (C), 160.89 (C); MS m/z: 441 (Mꢁ,
1780; 1H-NMR (500 MHz, CDCl3) d: 4.14 (s, 3H), 7.62 (d, 2H, Jꢀ8.9), 7.80 47), 332 (100). HR-MS Calcd for C24H22F3N3O2: 441.1664. Found:
(d, 2H, Jꢀ8.9); MS m/z: 349 (23)ꢁ351 (22) (Mꢁ, 1 : 1), 183 (100)ꢁ185 441.1653.
(99). Anal. Calcd for C12H7BrF3NO3: C, 41.17; H, 2.02; N, 4.00. Found: C,
40.99; H, 2.10; N, 3.80.
6-Trifluoromethyl-1,4,5,6-tetrahydro-3-(4-methoxyphenyl)-1,4-diphenyl-
1,2,4-triazin-6-ol (3f) mp 129—131 °C (Et2O–hexane), IR (Nujol) cmꢂ1
:
2-(4-Bromophenyl)-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-olate
1620, 3200 (br); 1H-NMR (500 MHz, CDCl3) d: 3.49 (dq, 1H, Jꢀ2.1, 12.8),
3.73 (s, 3H), 4.19 (d, 1H, Jꢀ12.8), 6.82—6.76 (m, 2H), 6.78 (d, 2H, Jꢀ7.6),
6.95—6.99 (m, 1H), 7.13—7.20 (m, 3H), 7.31—7.38 (m, 4H), 7.51 (d, 2H,
(1d) mp 75—76 °C (mp17) 75—76 °C).
3-Benzyl-4-trifluoroacetyl-2-(4-methoxyphenyl)-1,3-oxazolium-5-
olates (1e) mp 158—160 °C (AcOEt–hexane), IR (Nujol) cmꢂ1: 1780; 1H- Jꢀ7.6); 13C-NMR (125 MHz, CDCl3) d: 51.72 (CH2), 55.17 (CH3), 81.18
2
1
NMR (500 MHz, CDCl3) d: 3.89 (s, 3H), 5.78 (s, 2H), 7.02 (d, 2H, Jꢀ9.0),
(C, JCFꢀ30), 113.48 (CH), 123.07 (CH), 123.31 (CF3, JCFꢀ290), 123.66
7.18 (d, 2H, Jꢀ7.2), 7.37 (t, 1H, Jꢀ7.2), 7.41 (t, 2H, Jꢀ7.2), 7.65 (d, 2H, (CH), 124.25 (CH), 124.71 (CH), 125.56 (C), 128.71 (CH), 128.76 (CH),
Jꢀ9.0); MS m/z: 377 (Mꢁ, 4), 91 (100). Anal. Calcd for C19H14F3NO4: C,
60.48; H, 3.74; N, 3.71. Found: C, 60.20; H, 3.86; N, 3.64.
129.91 (CH), 142.20 (C), 144.11 (C), 144.61 (C), 160.09 (C); MS m/z: 427
(Mꢁ, 100). HR-MS Calcd for C23H20F3N3O2: 427.1507. Found: 427.1491.
6-Trifluoromethyl-1,4,5,6-tetrahydro-4-methyl-3-phenyl-1,2,4-triazin-
6-ol (3g) The procedure was the same as described above, except that
4-Trifluoroacetyl-2-(4-methoxyphenyl)-3-phenyl-1,3-oxazolium-5-
olates (1f) mp 182—185 °C (AcOEt–hexane), IR (Nujol) cmꢂ1: 1790; 1H-
NMR (60 MHz, CDCl3) d: 3.80 (s, 3H), 6.75 (d, 2H, Jꢀ9.0), 7.58 (d, 2H, phenylhydrazine was replaced with hydrazine: Yield 45%, mp 159—161 °C
Jꢀ9.0), 7.07—7.63 (m, 5H); MS m/z: 363 (Mꢁ, 19), 135 (100). Anal. Calcd (Et2O), IR (Nujol) cmꢂ1: 1620, 3000 (br), 3310; 1H-NMR (500 MHz,
for C18H12F3NO4: C, 59.51; H, 3.33; N, 3.86. Found: C, 59.38; H, 3.49; N, CDCl3ꢁDMSO-d6, 5 : 1) d: 2.76 (s, 3H), 3.35 (dd, 1H, Jꢀ2.5, 11.6), 3.60
4.02.
3-tert-Butyl-4-trifluoroacetyl-2-methyl-1,3-oxazolium-5-olate (1g) mp
120—121 °C (mp17) 120—121 °C).
(d, 1H, Jꢀ11.6), 5.53 (s, 1H), 6.63 (s, 1H), 7.36—7.37 (m, 3H), 7.42—7.44
(m, 2H); 13C-NMR (125 MHz, CDCl3ꢁDMSO-d6, 5 : 1) d: 40.28 (CH3),
51.55 (CH2), 77.42 (C, 2JCFꢀ30), 123.69 (CF3, 1JCFꢀ287), 128.11 (CH),
General Procedure for the Reaction of 1 with PH in DMF Phenylhy- 128.26 (CH), 128.76 (CH), 134.40 (C), 148.54 (C); MS m/z: 259 (Mꢁ, 25),
drazine (162 mg, 1.5 mmol) was added to a solution of 1 (1 mmol) in dry
DMF (5 ml) at 0 °C and the mixture was stirred at rt for 24 h. The mixture
was diluted with AcOEt (30 ml) and washed with 3% Na2CO3 (20 ml), fol-
241 (100). Anal. Calcd for C11H12F3N3O: C, 50.97; H, 4.67; N, 16.21.
Found: C, 51.01; H, 4.77; N, 16.13.
6-Trifluoromethyl-1,4,5,6-tetrahydro-1,4-dimethyl-3-phenyl-1,2,4-tri-
lowed by brine (20 ml). After the standard work-up, the residue was purified azin-6-ol (3h) The procedure was the same as described above, except that
by chromatography on silica gel with AcOEt–hexane (2 : 3).
phenylhydrazine was replaced with methylhydrazine: Yield 58%, mp 153—
6-Trifluoromethyl-1,4,5,6-tetrahydro-4-methyl-1,3-diphenyl-1,2,4-tri- 154 °C (Et2O–hexane), IR (Nujol) cmꢂ1
1610, 3000 (br); 1H-NMR
:
azin-6-ol (3a) Oil, IR (oil) cmꢂ1: 1640, 3250 (br); 1H-NMR (500 MHz,
(500 MHz, CDCl3) d: 2.76 (s, 3H), 2.87ꢁ2.88 (s, 3H), 3.27 (dd, 1H, Jꢀ1.3,
CDCl3) d: 2.88 (s, 3H), 3.48 (dq, 1H, Jꢀ2.1, 12.8), 3.73 (d, 1H, Jꢀ12.8), 11.9), 3.54 (d, 1H, Jꢀ11.9), 7.36—7.39 (m, 3H), 7.41—7.44 (m, 2H); 13C-
7.13—7.18 (m, 1H), 7.27—7.32 (m, 2H), 7.36—7.39 (m, 4H), 7.40—7.44 NMR (125 MHz, CDCl3) d: 38.32ꢁ38.33 (CH3), 39.94 (CH3), 53.52 (CH2),
(m, 1H), 7.48—7.51 (m, 2H); 13C-NMR (125 MHz, CDCl3) d: 40.47 (CH3),
79.67 (C, 2JCFꢀ30), 123.50 (CF3, 1JCFꢀ290), 128.44 (CH), 128.56 (CH),
52.41 (CH2), 79.27 (C, 2JCFꢀ30), 123.49 (CF3, 1JCFꢀ291), 125.56 (CH), 129.18 (CH), 133.63 (C), 148.23 (C); MS m/z: 273 (Mꢁ, 68), 255 (100).
125.69 (CH), 128.32 (CH), 128.57 (CH), 128.71 (CH), 129.16 (CH), 133.82 Anal. Calcd for C12H14F3N3O: C, 52.75; H, 5.16; N, 15.38. Found: C, 53.01;
(C), 144.58 (C), 147.11 (C); MS m/z: 335 (Mꢁ, 47), 77 (100). HR-MS Calcd
for C17H16F3N3O: 335.1245. Found: 335.1215.
6-Trifluoromethyl-1,4,5,6-tetrahydro-3-(4-methoxyphenyl)-4-methyl-
H, 5.25; N, 15.36.
6-Trifluoromethyl-1,4,5,6-tetrahydro-3-(4-methoxyphenyl)-4-methyl-
1-(4-methylbenzenesulfonyl)-1,2,4-triazin-6-ol (3i) The procedure was
1-phenyl-1,2,4-triazin-6-ol (3b) Oil, IR (oil) cmꢂ1: 1610, 1670, 2900— the same as described above, except that phenylhydrazine was replaced with
3550; 1H-NMR (500 MHz, CDCl3) d: 2.86 (s, 3H), 3.34 (d, 1H, Jꢀ12.8), tosylhyrazine: Yield 17%, oil, IR (oil) cmꢂ1: 1610, 1670, 1740, 3450; H-
1
3.65 (d, 1H, Jꢀ12.8), 3.81 (s, 3H), 6.90 (d, 2H, Jꢀ8.9), 7.15 (t, 1H, Jꢀ7.8), NMR (500 MHz, CDCl3) d: 2.43 (s, 3H), 2.81 (s, 3H), 3.38 (dd, 1H, Jꢀ3.1,
7.30 (t, 2H, Jꢀ7.8), 7.41 (d, 2H, Jꢀ7.8), 7.45 (d, 2H, Jꢀ8.9); 13C-NMR
13.4), 3.66 (d, 1H, Jꢀ13.4), 3.82 (s, 3H), 6.87 (d, 2H, Jꢀ8.9), 7.29 (d, 2H,
(125 MHz, CDCl3) d: 40.45 (CH3), 52.41 (CH2), 55.29 (CH3), 79.42 (C, Jꢀ8.9), 7.31 (d, 2H, Jꢀ8.2), 7.91 (d, 2H, Jꢀ8.2); 13C-NMR (125 MHz,
2JCFꢀ30), 113.72 (CH), 123.50 (CF3, 1JCFꢀ291), 125.28 (CH), 125.47 CDCl3) d: 21.60 (CH3), 40.13 (CH3), 51.84 (CH2), 55.30 (CH3), 80.41 (C,
(CH), 126.07 (C), 128.62 (CH), 129.93 (CH), 144.70 (C), 147.13 (C), 2JCFꢀ33), 113.65 (CH), 123.10 (CF3, JCFꢀ291), 124.74 (C), 128.64 (CH),
1
160.38 (C); MS m/z: 365 (Mꢁ, 100). HR-MS Calcd for C18H18F3N3O2: 129.03 (CH), 130.25 (CH), 135.03 (C), 144.21 (C), 148.06 (C), 160.91 (C);

April 2008
437
MS m/z: 443 (Mꢁ, 4), 148 (100). HR-MS Calcd for C19H20F3N3O4S:
443.1126. Found: 443.1118.
in dry 1,2-dichloroethane (5 ml) at 0 °C and the mixture was stirred at rt for
24 h. The mixture was diluted with AcOEt (30 ml) and washed with 3%
6-Trifluoromethyl-1,4,5,6-tetrahydro-1-methoxycarbonyl-4-methyl-3- Na2CO3 (20 ml), followed by brine (20 ml). After the standard work-up, the
phenyl-1,2,4-triazin-6-ol (3j) The procedure was the same as described residue was purified by chromatography on silica gel with AcOEt–hexane
above, except that phenylhydrazine was replaced with methyl hydrazinocar- (2 : 3).
boxylate: mp 122—123 °C (Et2O–hexane), IR (Nujol) cmꢂ1: 1620, 1690,
N-(3-Trifluoromethyl-3-hydroxy-5-oxo-1-phenyl-4-pyrazolidinyl)-N-
3375; 1H-NMR (500 MHz, CDCl3) d: 2.85 (s, 3H), 3.54 (dq, 1H, Jꢀ2.7,
methylbenzamide (5a) Oil, IR (oil) cmꢂ1: 1635, 1720, 3200 (br); 1H-
13.4), 3.71 (d, 1H, Jꢀ13.4), 3.87 (s, 3H), 7.37—7.42 (m, 3H), 7.44—7.47 NMR (500 MHz, CDCl3) d: 3.21 (s, 3H), 4.28—4.48 (br, 1H, D2O change-
(m, 2H); 13C-NMR (125 MHz, CDCl3) d: 40.31 (CH3), 51.11 (CH3), 53.90 able), 5.16 (s, 1H, D2O changeable), 7.19 (t, 1H, Jꢀ7.6), 7.36 (t, 2H,
(CH2), 79.87 (C, 2JCFꢀ32), 123.83 (CF3, 1JCFꢀ292), 128.60 (CH), 128.90 Jꢀ7.6), 7.44 (t, 2H, Jꢀ7.6), 7.50 (t, 1H, Jꢀ7.6), 7.58 (d, 2H, Jꢀ7.6), 7.76
(CH), 130.02 (CH), 132.84 (C), 148.85 (C), 156.20 (C); MS m/z: 317 (Mꢁ,
(d, 2H, Jꢀ7.6); 13C-NMR (125 MHz, CDCl3) d: 41.10 (CH3), 65.00 (CH),
41), 228 (100). Anal. Calcd for C13H14F3N3O3: C, 49.21; H, 4.45; N, 13.24. 86.73 (C, 2JCFꢀ32), 118.92 (CH), 122.68 (CF3, 1JCFꢀ284), 125.70 (CH),
Found: C, 49.06; H, 4.44; N, 13.20.
3-tert-Butyl-6-trifluoromethyl-1,4,5,6-tetrahydro-1-methoxycarbonyl-
127.78 (CH), 128.60 (CH), 128.92 (CH), 131.26 (CH), 133.32 (C), 137.08
(C), 161.10 (C), 176.20 (C); MS m/z: 379 (Mꢁ, 3), 105 (100). HR-MS Calcd
4-methyl-1,2,4-triazin-6-ol (3k) The procedure was the same as described for C18H16F3N3O3: 379.1143. Found: 379.1151.
above, except that phenylhydrazine was replaced with methyl hydrazinocar-
N-(3-Trifluoromethyl-3-hydroxy-5-oxo-1-phenyl-4-pyrazolidinyl)-4-
boxylate: Yield 14%, mp 93—94 °C (Et2O–hexane), IR (Nujol) cmꢂ1: 1610, methoxy-N-methylbenzamide (5b) Oil, IR (oil) cmꢂ1: 1610, 1720, 3200;
1670, 3250 (br); 1H-NMR (500 MHz, CDCl3) d: 1.28ꢁ1.29 (s, 9H), 3.10 (s, 1H-NMR (500 MHz, CDCl3) d: 3.27 (s, 3H), 3.85 (s, 3H), 4.35 (br s, 1H,
3H), 3.28 (dq, 1H, Jꢀ2.8, 13.4), 3.45 (d, 1H, Jꢀ13.4), 3.85ꢁ3.86 (s, 3H);
D2O changeable), 5.13 (s, 1H, D2O changeable), 6.93 (d, 2H, Jꢀ8.9), 7.18
13C-NMR (125 MHz, CDCl3) d: 28.93 (CH3ꢃ3), 37.11 (C), 40.96 (CH3), (t, 1H, Jꢀ7.9), 7.36 (t, 2H, Jꢀ7.9), 7.59 (d, 2H, Jꢀ8.9), 7.76 (d, 2H,
52.96 (CH3), 53.63 (CH2), 79.75 (C, 2JCFꢀ32), 124.20 (CF3, 1JCFꢀ291),
152.86 (C), 156.11 (C); MS m/z: 297 (Mꢁ, 39), 208 (100). HR-MS Calcd
for C11H18F3N3O3: 297.1301. Found: 297.1297.
Jꢀ7.9); 13C-NMR (125 MHz, CDCl3) d: 41.33 (CH3), 55.41 (CH3), 65.34
(CH2), 86.76 (C, 2JCFꢀ32), 113.83 (CH), 118.89 (CH), 122.72 (CF3,
1JCFꢀ282), 125.01 (C), 125.65 (CH), 128.90 (CH), 130.39 (CH), 137.08
N-[2,2,2-Trifluoro-2-(semicarbazono)propyl]-N-methylbenzamide (6b) (C), 161.04 (C), 162.14 (C), 176.00 (C); MS m/z: 409 (Mꢁ, 3), 135 (100).
The procedure was the same as described above, except that phenylhy- HR-MS Calcd for C19H18F3N3O4: 409.1249. Found: 409.1243.
drazine was replaced with semicarbazide: Yield 76%, IR (Nujol) cmꢂ1
:
4-Bromo-N-(3-trifluoromethyl-3-hydroxy-5-oxo-1-phenyl-4-pyrazo-
lidinyl)-N-methylbenzamide (5c) Oil, IR (oil) cmꢂ1: 1645, 1685, 3200
(br); 1H-NMR (500 MHz, CDCl3) d: 3.19 (s, 3H), 4.38 (br s, 1H), 5.18
(s, 1H), 7.19 (t, 1H, Jꢀ7.7), 7.37 (t, 2H, Jꢀ7.7), 7.44 (d, 2H, Jꢀ8.3), 7.58
1
1640, 1700 (br), 3000—3600; H-NMR (500 MHz, CDCl3) d: 3.04 (s, 3H),
4.45 (s, 2H), 6.19 (s, 2H), 7.30—7.43 (m, 5H), 10.67 (s, 1H); 13C-NMR
(125 MHz, CDCl3) d: 38.44 (CH3), 41.54 (CH2), 121.04 (CF3, 1JCFꢀ273),
127.44 (CH), 128.53 (CH), 130.59 (CH), 130.73 (C, JCFꢀ35), 133.91 (C), (d, 2H, Jꢀ8.3), 7.74 (dd, 2H, Jꢀ1.2, 7.7); 13C-NMR (125 MHz, CDCl3)
2
156.59 (C), 172.87 (C); MS m/z: 302 (Mꢁ, 0.5), 105 (100). HR-MS Calcd
d: 40.93 (CH3), 65.07 (CH), 86.66 (C, 2JCFꢀ32), 118.92 (CH), 122.63
for C12H12F3N4O2 (M-H): 301.0912. Found: 301.0911.
(CF3, 1JCFꢀ282), 125.80 (CH), 125.91 (C), 128.96 (CH), 129.40 (CH),
General Procedure for the Reaction of 1 with PH in Benzene 131.93 (CH), 132.14 (C), 137.00 (C), 160.95 (C), 175.08 (C); MS m/z:
Phenylhydrazine (162 mg, 1.5 mmol) was added to a solution of 1 (1 mmol)
in dry benzene (5 ml) at 0 °C and the mixture was refluxed for 3 h. The mix-
ture was diluted with AcOEt (30 ml) and washed with 3% Na2CO3 (20 ml),
followed by brine (20 ml). After the standard work-up, the residue was puri-
fied by chromatography on silica gel with AcOEt–hexane (2 : 3).
457 (2.6)ꢁ459 (2.5) (Mꢁ, 1 : 1), 183 (100)ꢁ185 (99). HR-MS Calcd
for C18H1579BrF3N3O3 (C17H1581BrF3N3O3): 457.0212 (459.0189). Found:
457.0175 (459.0209).
N-(3-Trifluoromethyl-3-hydroxy-5-oxo-1-phenyl-4-pyrazolidinyl)-4-
methoxy-N-phenylbenzamide (5d) Oil, IR (oil) cmꢂ1: 1650, 1670, 3100
(br); 1H-NMR (500 MHz, CDCl3) d: 3.72 (s, 3H), 4.80 (s, 1H), 5.22 (s, 1H),
5-Trifluoromethyl-1,2-dihydro-4-(methylamino)-1-phenyl-3H-pyrazol-
3-one (4a) mp 117—119 °C (cyclohexane), IR (Nujol) cmꢂ1: 1600, 3000 6.64 (d, 2H, Jꢀ8.7), 7.16-7.40 (m, 10H), 7.81 (d, 2H, Jꢀ8.7); 13C-NMR
(br); 1H-NMR (500 MHz, CDCl3) d: 2.86 (s, 3H), 7.34—7.41 (m, 3H), (125 MHz, CDCl3) d: 55.23 (CH3), 68.09 (CH), 86.66 (C, 2JCFꢀ32), 113.20
7.42—7.46 (m, 2H); 13C-NMR (125 MHz, CDCl3) d: 34.91 (CH3), 119.38 (CH), 118.94 (CH), 122.59 (CF3, 1JCFꢀ284), 124.82 (CH), 125.20 (C),
(C, 2JCFꢀ38), 120.45 (CF3, 1JCFꢀ260), 121.93 (C), 125.33 (CH), 128.37 125.70 (CH), 127.95 (CH), 128.92 (CH), 129.65 (C), 129.77 (CH), 131.87
(CH), 129.09 (CH), 139.05 (C), 154.79 (C); MS m/z: 257 (Mꢁ, 100). Anal.
(CH), 137.15 (C), 143.99 (C), 161.87 (C), 174.38 (C); MS m/z: 471 (Mꢁ, 6),
Calcd for C11H10F3N3O: C, 51.37; H, 3.92; N, 16.34. Found: C, 51.98; H, 135 (100). HR-MS Calcd for C24H20F3N3O4: 471.1392. Found: 471.1399.
4.10; N, 16.23.
N-(3-Trifluoromethyl-3-hydroxy-5-oxo-1-phenyl-4-pyrazolidinyl)-4-
5-Trifluoromethyl-1,2-dihydro-1-phenyl-4-[(phenylmethyl)amino]-3H-
methoxy-N-(phenylmethyl)benzamide (5e) Oil, IR (oil) cmꢂ1: 1610,
1
pyrazol-3-one (4b) mp 99—105 °C (cyclohexane), IR (Nujol) cmꢂ1
:
1720, 3200; H-NMR (500 MHz, CDCl3) d: 3.81 (s, 3H), 4,32 (s, 1H, D2O
1605, 3000 (br); 1H-NMR (500 MHz, CDCl3) d: 4.30 (s, 2H), 7.23—7.32 changeable), 4.54 (d, 1H, Jꢀ17.1), 5.05 (s, 1H, D2O changeable), 5.12 (d,
(m, 5H), 7.33—7.37 (m, 3H), 7.38—7.45 (m, 2H); 13C-NMR (125 MHz,
1H, Jꢀ17.1), 6.88 (d, 2H, Jꢀ8.9), 7.18 (t, 1H, Jꢀ7.6), 7.35 (t, 2H, Jꢀ7.6),
7.37 (t, 1H, Jꢀ7.6), 7.45 (t, 2H, Jꢀ7.6), 7.56 (d, 2H, Jꢀ7.6), 7.64 (d, 2H,
CDCl3) d: 51.48 (CH2), 119.70 (C, 2JCFꢀ37), 120.43 (CF3, 1JCFꢀ269),
120.93 (C), 125.38 (CH), 127.32 (CH), 127.91 (CH), 128.44 (CH), 128.48 Jꢀ8.9), 7.76 (d, 2H, Jꢀ7.6); 13C-NMR (125 MHz, CDCl3) d: 55.23 (CH2),
2
(CH), 129.08 (CH), 138.91 (C), 139.61 (C), 154.70 (C); MS m/z: 333 (Mꢁ,
55.41 (CH3), 61.54 (CH), 87.12 (C, JCFꢀ32), 113.99 (CH), 118.93 (CH),
55), 91 (100). Anal. Calcd for C17H14F3N3O: C, 61.26; H, 4.23; N, 12.61. 122.58 (CF3, 1JCFꢀ282), 124.68 (C), 125.64 (CH), 126.95 (CH), 128.30
Found: C, 61.17; H, 4.32; N, 12.70.
(CH), 128.90 (CH), 129.35 (CH), 129.97 (CH), 134.51 (C), 137.09 (C),
5-Trifluoromethyl-1,2-dihydro-1-(4-methoxyphenyl)-4-(methylamino)- 161.16 (C), 162.45 (C), 176.49 (C); MS m/z: 485 (Mꢁ, 8), 91 (100). HR-MS
3H-pyrazol-3-one (4c) mp 170—172 °C (cyclohexane), IR (Nujol) cmꢂ1
:
Calcd for C25H22F3N3O4: 485.1580. Found: 485.1571.
N-(3-Benzoyloxy-5-trifluoromethyl-1-phenyl-1H-pyrazol-4-yl)-N-
1615, 3000 (br), 3400; 1H-NMR (500 MHz, CDCl3) d: 2.84 (s, 3H), 3.84 (s,
3H), 6.93 (d, 2H, Jꢀ9.1), 7.27 (d, 2H, Jꢀ9.1); 13C-NMR (125 MHz, CDCl3) methylbenzamide (7a) Benzoyl chloride (0.3 ml, 2.6 mmol) was added to
d: 35.09 (CH3), 55.44 (CH3), 114.15 (CH), 120.00 (C, 2JCFꢀ37), 120.39 a stirred solution of 4a (230 mg, 0.89 mmol) and pyridine (1 ml, 12 mmol) in
(CF3, 1JCFꢀ269), 121.05 (C), 127.09 (CH), 131.88 (CH), 154.55 (C), 159.54 CH2Cl2 (2 ml) at 0 °C and the mixture was stirred at rt for 24 h. The mixture
(C); MS m/z: 287 (Mꢁ, 100). Anal. Calcd for C12H12F3N3O2: C, 50.18; H, was diluted with AcOEt (30 ml) and washed with 3% Na2CO3 (20 ml), fol-
4.21; N, 14.63. Found: C, 50.39; H, 4.27; N, 14.72.
N-[2,2,2-Trifluoro-2-(phenylhydrazono)propyl]-N-phenyl-4-methoxy-
lowed by brine (20 ml). After the standard work-up, the residue was purified
by column chromatography on silica gel with AcOEt : hexane (1 : 3): Yield
benzamide (6a) Oil, IR (oil) cmꢂ1: 1730, 3030 (br), 3240 (br); H-NMR 87%, mp 102—104 °C (Et2O–hexane), IR (Nujol) cmꢂ1: 1660, 1750, 3050;
(500 MHz, CDCl3) d: 3.71 (s, 3H), 4.91 (s, 2H), 6.64 (d, 2H, Jꢀ7.1), 6.91— 1H-NMR (500 MHz, CDCl3) d: 3.41 (s, 3H), 7.32 (d, 3H, Jꢀ7.6), 7.37—
7.02 (m, 3H), 7.18—7.34 (m, 7H), 7.28 (d, 2H, Jꢀ7.1); 13C-NMR 7.47 (m, 7H), 7.55 (t, 2H, Jꢀ7.6), 7.70 (t, 1H, Jꢀ7.6), 8.15 (d, 2H, Jꢀ7.6);
(125 MHz, CDCl3) d: 43.47 (CH2), 55.17 (CH3), 113.11 (CH), 113,71 (CH), 13C-NMR (125 MHz, CDCl3) d: 37.26 (CH3), 118.63 (CF3, 1JCFꢀ270),
121.71 (CF3, 1JCFꢀ272), 121.77 (CH), 124.46 (C, 2JCFꢀ34), 125.79 (C), 119.95 (C), 125.70 (CH), 127.32 (C), 127.75 (CH), 127.80 (C, 2JCFꢀ38),
127.78 (CH), 127.88 (CH), 129.29 (CH), 129.47 (CH), 131.28 (CH), 141.65 127.85 (CH), 128.82 (CH), 129.13 (CH), 129.81 (CH), 130.37 (CH), 130.57
(C), 143.69 (C), 161.25 (C), 171.56 (C); MS m/z: 427 (Mꢁ, 6), 135 (100). (CH), 134.60 (CH), 134.81 (C), 138.40 (C), 150.58 (C), 163.34 (C), 171.19
1
HR-MS Calcd for C23H20F3N3O2: 427.1508. Found: 427.1509.
General Procedure for the Reaction of 1 with PH in 1,2-Dichloroethane
Phenylhydrazine (162 mg, 1.5 mmol) was added to a solution of 1 (1 mmol)
(C); MS m/z: 465 (Mꢁ, 14), 105 (100). Anal. Calcd for C25H18F3N3O3: C,
64.52; H, 3.90; N, 9.03. Found: C, 64.63; H, 4.13; N, 9.01.
N-[5-Trifluoromethyl-3-(4-methoxyphenyl)carbonyloxy-1-phenyl-1H-

438
Vol. 56, No. 4
pyrazol-4-yl]-N-methyl-4-methoxybenzamide (7b) The procedure was 433.1249. Found: 433.1251.
the same as described above, except that benzoyl chloride was replaced with
1
4-methoxybenzoyl chloride: Yield 95%, oil, IR (oil) cmꢂ1: 1610, 1750; H- References and Notes
NMR (500 MHz, CDCl3) d: 3.35 (s, 3H), 3.79 (s, 3H), 3.87 (s, 3H), 6.79 (d,
2H, Jꢀ8.5), 6.97 (d, 2H, Jꢀ9.0), 7.31—7.45 (m, 5H), 7.38 (d, 2H, Jꢀ9.0),
8.07 (d, 2H, Jꢀ8.5); 13C-NMR (125 MHz, CDCl3) d: 37.44 (CH3), 55.24
(CH3), 55.53 (CH3), 113.13 (CH), 114.12 (CH), 118.73 (CF3, 1JCFꢀ271),
119.51 (C), 125.28 (C), 125.70 (CH), 126.89 (C), 127.47 (C, 2JCFꢀ37),
129.10 (CH), 129.69 (CH), 130.03 (CH), 132.83 (CH), 138.56 (C), 150.71
(C), 161.24 (C), 163.04 (C), 164.66 (C), 170.96 (C); MS m/z: 525 (Mꢁ, 4),
135 (100). HR-MS Calcd for C27H22F3N3O5: 525.1511. Found: 525.1487.
5-Trifluoromethyl-3-(4-methoxyphenyl)carbonyloxy-4-methylamino-
1-phenyl-1H-pyrazole (7c) and 7b 4-Methoxybenzoyl chloride (0.15 ml,
11 mmol) was added to a stirred solution of 4a (300 mg, 12 mmol) and 3%
Na2CO3 (5 ml) in AcOEt (5 ml) at 0 °C and the mixture was stirred at rt for
3.5 h. The mixture was diluted with AcOEt (30 ml) and washed with 3%
Na2CO3 (20 ml), followed by brine (20 ml). After the standard work-up, the
residue was purified by column chromatography on silica gel with AcOEt :
hexane (2 : 3) to give 7c (80 mg, 17%) and 7b (55 mg, 9%). 7c: the less polar
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R., Ramanujam R., Yeleswarapu K. R., Iqbal J., Bioorg. Med. Chem.
Lett., 16, 3921—3926 (2006).
6) Kees K. L., Fitzgerald J. J., Jr., Steiner K. E., Mattes J. F., Mihan B.,
Tosi T., Modoro D., McCaleb M. L., J. Med. Chem., 39, 3920—3928
(1996).
7) Kawase M., Hirabayashi M., Saito S., Yamamoto K., Tetrahedon Lett.,
40, 2541—2544 (1999).
8) Krishnaiah A., Narsaiah B., J. Fluorine Chem., 115, 9—11 (2002).
9) Schlosser M., Volle J.-N., Leroux F., Schenk K., Eur. J. Org. Chem.,
2002, 2913—2920 (2002).
fraction, Yield 17%, mp 129—130 °C (Et2O–hexane), IR (Nujol) cmꢂ1
:
10) Touzot A., Soufyane M., Berber H., Toupet L., Mirand C., J. Fluorine
Chem., 125, 1299—1304 (2004).
1
1735, 3400 (br); H-NMR (500 MHz, CDCl3) d: 2.85 (s, 3H), 3.89 (s, 3H),
6.99 (d, 2H, Jꢀ8.9), 7.38—7.48 (m, 5H), 8.17 (d, 2H, Jꢀ8.9); 13C-NMR 11) Peat A. J., Townsend C., McKay M. C., Garrido D., Terry C. M., Wil-
(125 MHz, CDCl3) d: 34.03 (CH3), 55.57 (CH3), 114.07 (CH), 118.84 (C,
son J. L. R., Thomson S. A., Bioorg. Med. Chem. Lett., 14, 813—816
(2004).
2JCFꢀ38), 120.35 (C), 120.52 (CF3, 1JCFꢀ267), 125.54 (CH), 126.44 (C),
128.76 (CH), 128.98 (CH), 132.79 (CH), 139.51 (C), 146.72 (C), 163.98 12) Bonacorso H. G., Oliveira M. R., Costa M. B., da Silva L. B.,
(C), 164.42 (C); MS m/z: 391 (Mꢁ, 4), 135 (100). Anal. Calcd for
C19H16F3N3O3: C, 58.31; H, 4.12; N, 10.74. Found: C, 58.30; H, 4.23; N,
10.67.
N-(3-Acetoxy-5-trifluoromethyl-1-phenyl-1H-pyrazol-4-yl)-N-methyl-
acetamide (7d) The procedure was the same as described for 7a, except
Wastowski A. D., Zanatta N., Martins M. A. P., J. Heterocyclic Chem.,
42, 631—637 (2005).
13) Bonacorsa H. G., Wentz A. P., Lourega R. V., Cechinel C. A., Moraes
T. S., Coelho H. S., Zanatta N., Martins M. A. P., Hoener M., Alves S.
H., J. Fluorine Chem., 127, 1066—1072 (2006).
that benzoyl chloride was replaced with acetic anhydride: Yield 88%, 14) Katagiri N., Watanabe H., Kaneko C., Chem. Pharm. Bull., 36, 3354—
mp 127—129 °C (cyclohexane), IR (Nujol) cmꢂ1: 1680, 1780; 1H-NMR
3372 (1988).
(500 MHz, CDCl3) d: 2.00 (s, 3H), 2.34 (s, 3H), 3.17 (s, 3H), 7.47—7.53 15) Kamitori Y., Hojo M., Masuda R., Sukegawa M., Hayashi K., Kouzeki
(m, 5H); 13C-NMR (125 MHz, CDCl3) d: 20.26 (CH3), 21.47 (CH3), 36.22
K., Heterocycles, 39, 155—162 (1994).
(CH3), 118.66 (CF3, 1JCFꢀ271), 118.94 (C), 125.63 (CH), 128.49 (C, 16) Kawase M., Saito S., Chem. Pharm. Bull., 48, 410—414 (2000).
2JCFꢀ35), 129.24 (CH), 129.92 (CH), 138.44 (C), 151.00 (C), 167.65 (C), 17) Kawase M., Saito S., Kurihara T., Chem. Pharm. Bull., 49, 461—464
171.17 (C); MS m/z: 341 (Mꢁ, 6), 257 (100). Anal. Calcd for C15H14F3N3O3:
C, 52.79; H, 4.13; N, 12.31. Found: C, 52.68; H, 4.19; N, 12.37.
N-(5-Benzoyloxy-3-trifluoromethyl-1-phenyl-1H-pyrazol-4-yl)-N-
(2001).
18) Kawase M., Koiwai H., Tanaka T., Tani S., Miyamae H., Heterocycles,
55, 1919—1926 (2001).
methylbenzamide (7e) The procedure was the same as described for 7a: 19) Kawase M., Koiwai H., Yamato A., Miyamae H., Tetrahedron Lett.,
1
Yield 59%, oil, IR (oil) cmꢂ1: 1765, 1770; H-NMR (500 MHz, CDCl3) d:
3.41 (s, 3H), 7.27—7.37 (m, 10H), 7.52 (t, 2H, Jꢀ7.7), 7.49 (t, 1H, Jꢀ7.7), 20) Elguero J., “Comprehensive Heterocyclic Chemistry,” Vol. 5, ed. by
7.94 (d, 2H, Jꢀ7.7); 13C-NMR (125 MHz, CDCl3) d: 37.02 (CH3), 115.76
Potts K. T., Pergamon Press, Oxford, 1984, pp. 167—303.
(C), 120.45 (CF3, 1JCFꢀ270), 123.20 (CH), 126.03 (C), 127.53 (CH), 127.80 21) Kawase M., Koiwai H., Saito S., Kurihara T., Tetrahedron Lett., 39,
(CH), 129.00 (CH), 129.04 (CH), 129.41 (CH), 130.22 (CH), 130.68 (CH), 6189—6190 (1998).
39, 663—666 (1998).
135.11 (C), 135.24 (CH), 136.57 (C), 137.24 (C, 2JCFꢀ39), 140.19 (C), 22) Potts K. T., “1,3-Dipolar Cycloaddition Chemistry,” Vol. 2, ed. by
161.56 (C), 171.23 (C); MS m/z: 465 (Mꢁ, 2), 105 (100). HR-MS Calcd for
C25H18F3N3O3: 465.1316. Found: 465.1308.
Padwa A., Wiley-Interscience, New York, 1984, pp. 1—82.
23) Bravo P., Diliddo D., Resnati G., Tetrahedron, 50, 8827—8836 (1994).
24) Shawali A. S., Hassaneen H. M., Tetrahedron, 29, 121—124 (1973).
N-(5-Acetoxy-3-trifluoromethyl-1-phenyl-1H-pyrazol-4-yl)-N-methyl-
4-methoxybenzamide (7f) The procedure was the same as described for 25) The X-ray structure of 4a was previously reported and the crystal data
7a, except that benzoyl chloride was replaced with acetic anhydride: Yield have been deposited at the Cambridge Crystallographic Data Centre.
61%, oil, IR (oil) cmꢂ1: 1610, 1790; 1H-NMR (500 MHz, CDCl3) d: 2.22 (s, 26) 13C-NMR chemical shifts of 3-trifluoromethyl-5-hydroxy- and 5-triflu-
3H), 3.32 (s, 3H), 3.78 (s, 3H), 6.78 (d, 2H, Jꢀ8.5), 7.32—7.46 (m, 5H),
7.39 (d, 2H, Jꢀ8.5); 13C-NMR (125 MHz, CDCl3) d: 20.03 (CH3), 37.38
(CH3), 55.29 (CH3), 113.28 (CH), 116.14 (C), 120.44 (CF3, 1JCFꢀ270),
oromethyl-3-hydroxypyrazoles are described in the following refer-
ence: Lee L. F., Schleppnik F. M., Schneider R. W., Campbell D. H., J.
Heterocycl. Chem., 27, 243—245 (1990).
123.40 (CH), 127.18 (C), 129.12 (CH), 129.49 (CH), 129.63 (CH), 136.73 27) DeRuiter J., Swearinen B. E., Wandreker V., Mayfield C. A., J. Med.
2
(C), 137.17 (C, JCFꢀ38), 140.19 (C), 161.21 (C), 165.78 (C), 171.07 (C);
Chem., 34, 2120—2126 (1991).
MS m/z: 433 (Mꢁ, 0.8), 135 (100). HR-MS Calcd for C21H18F3N3O4: