Synthesis of aminoalkylpyrazoles and-isoxazoles from cyclic β-(trifluoroacetyl) enamines

Article abstract of DOI:10.1007/s11172-007-0055-7

A method for the synthesis of cyclic β-(trifluoroacetyl) enamines was proposed. Reactions of the latter with hydrazine and hydroxylamine gave pyrazoles and isoxazoles, respectively, containing trifluoromethyl and ω-aminoalkyl fragments. Addition of hydraz

Full text of DOI:10.1007/s11172-007-0055-7

Russian Chemical Bulletin, International Edition, Vol. 56, No. 2, pp. 336—344, February, 2007
336
Synthesis of aminoalkylpyrazoles and ꢀisoxazoles
from cyclic βꢀ(trifluoroacetyl) enamines
V. G. Nenajdenko,ꢀ S. V. Pronin, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3181. Eꢀmail: nen@acylium.chem.msu.ru
A method for the synthesis of cyclic βꢀ(trifluoroacetyl) enamines was proposed. Reactions
of the latter with hydrazine and hydroxylamine gave pyrazoles and isoxazoles, respectively,
containing trifluoromethyl and ωꢀaminoalkyl fragments. Addition of hydrazine (hydroxylamine)
to the above amino enones was regiospecific, the regiochemistry of the heterocyclization of
trifluoromethyl ketones being different from that for nonfluorinated analogs.
Key words: α,βꢀenones, enamines, pyrazoles, isoxazoles, hydrazines, hydroxylamine,
organofluorine compounds, heterocyclization.
Scheme 1
βꢀAryl(hetaryl)alkylamines are important objects of
organic and medicinal chemistry because of their high
biological activities due to efficient interactions of such
compounds with serotoninergic, adrenergic, and other
types of receptors. Recently,1,2 it has been confirmed that
βꢀaryl(hetaryl)alkylamines take part in the operation of
the cardiovascular system and regulate some processes,
including the desynchronization of biological rhythms,
the disruption of the sleep cycles, and the formation of
mental disorders and depressive states.
α,βꢀUnsaturated trifluoromethyl ketones are suitable
building blocks for introduction of a trifluoromethyl group
into various classes of acyclic, carbocyclic, and heteroꢀ
cyclic compounds; however, their properties have not been
extensively studied hitherto.3—5 The goal of the present
work was to obtain βꢀaminosubstituted α,βꢀunsaturated
trifluoromethyl ketones of cyclic series and investigate
their reactions with polynucleophiles. These compounds
feature the simultaneous presence of two fragments of
synthetic interest: the trifluoroacetyl group and the cyclic
enamine fragment. The latter is incorporated in the conꢀ
jugated system of an α,βꢀunsaturated carbonyl compound
and can participate in heterocyclization, converting itself
to the ωꢀaminoalkyl group.6 Thus, reactions of such comꢀ
pounds with binucleophiles can open up a concise and
efficient route to heterocycles containing both trifluoroꢀ
methyl and ωꢀaminoalkyl fragments (Scheme 1).
Scheme 2
A. RLi; B. RCO2Alk/NaH
Comꢀ
n
R
PG
Method Yield
pound
(%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
3
Ph
CH=CH2
CH=CH2
CH=CH2
CH=CH2
CH=CH2
CH=CH2
CH(OEt)2
CH=CH2
A
A
A
A
B
B
A
A
67
66
59
50
67
38
83
59
4ꢀMe2NC6H4
4ꢀMeOC6H4
5ꢀMethylthienyl
But
Me
Ph
Ph
For the synthesis of the target trifluoroacetyl enamines,
we used cyclic imines 1—8, which were prepared in good
yields from protected lactams by addition of organolithium
compounds or by condensation with carboxylic acid esꢀ
ters followed by acid hydrolysis7,8 (Scheme 2).
Direct electrophilic trifluoroacetylation of alkenes is a
convenient method for the synthesis of α,βꢀunsaturated
trifluoromethyl ketones.9 We initially chose this approach
for trifluoroacetylation of cyclic imines. It is known10 that
Nꢀalkenylsulfonamides can be acylated with trifluoroꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 325—333, February, 2007.
1066ꢀ5285/07/5602ꢀ0336 © 2007 Springer Science+Business Media, Inc.

4ꢀAminoalkylꢀ3ꢀtrifluoromethylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
337
acetic anhydride in pyridine. Unexpectedly, treatment of
cyclic imines with two equivalents of trifluoroacetic anꢀ
hydride in pyridine gave Nꢀtrifluoroacetyl derivatives
only.11 Further Cꢀtrifluoroacetylation was probably preꢀ
vented by the strong CF3CO acceptor, which substanꢀ
tially lowers the nucleophilicity of the double bond. Variaꢀ
tions in the solvent (CHCl3, CH2Cl2, CH2ClCH2Cl,
MeCN, and DMF), the reaction temperature, and the
base, as well as conducting the reaction steps as separate
processes, were unsuccessful.
the reaction mixture was 0.2 mol L–1 (Scheme 4). The use
of higher dilution increased the yield of product 13 to 67%.
Scheme 4
Because of this, we employed an alternative oneꢀstep
approach based on trifluoroacetylation of enamides of
alkali metals. This approach has been once applied to the
synthesis of trifluoroacetyl derivatives of cyclic imines.12
Trifluoroacetylation of lithium enamide (prepared by
treatment of an imine with lithium diisopropylamide
(LDA) at 10 °C) gave a mixture of Cꢀ and Nꢀtrifluoroꢀ
acetylation products in the ratio 9 : 1 (Scheme 3). The
Nꢀtrifluoroacetyl derivative can be easily removed by
washing with benzene. We found it indispensable to use at
least two equivalents of a metalation agent; otherwise, the
yield of the product did not exceed 35—40%. This is due
to the protonation of the enamide by the resulting amino
enone, which has a higher acidity than that of the starting
imine, and elimination of the enamide from the reaction
zone. The second equivalent of LDA converts the triꢀ
fluoroacetylation product into the lithium salt, which
keeps the imine deprotonated. The use of N,Nꢀdimethylꢀ
trifluoroacetamide, as well as lithium hexamethyldisilazide
as a metalation agent, did not increase the yields.
Interestingly, the trifluoroacetylation of 5ꢀ(5ꢀmethylꢀ
2ꢀthienyl)ꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (4) occurred at the
methyl group of the thiophene ring and was accompanied
by migration of the double bonds to give compound 15 in
39% yield (Scheme 5).
Scheme 5
Scheme 3
The trifluoroacetylation of 5ꢀmethylꢀ3,4ꢀdihydroꢀ2Hꢀ
pyrrole (6) also involved the methyl group; the yield of the
resulting exocyclic amino enone 16 was 78% (Scheme 6).
Scheme 6
Compound
n
R
Yield (%)
9
1
1
1
1
2
3
Ph
4ꢀMe2NC6H4
4ꢀMeOC6H4
But
64
60
53
27
67
41
10
11
12
13
14
Ph
Ph
In the trifluoroacetylation of 6ꢀphenylꢀ2,3,4,5ꢀtetraꢀ
hydropyridine (7), the yield of the target amino enone 13
was only 35% because of the formation of 25% byꢀprodꢀ
uct 13´ when the concentration of the starting imine in
First attempts to carry out reactions of the amino
enones obtained with various binucleophiles (urea deꢀ
rivatives, semicarbazide, thiosemicarbazide, amidines, and
3ꢀaminopyrazoles) resulted only in their Cꢀdeacylation to

338
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
Nenajdenko et al.
the corresponding starting cyclic imines (1H and 13C NMR
data). Such a behavior can be explained by the lability of
these amino enones in the presence of bases. For inꢀ
stance, the roomꢀtemperature decomposition of comꢀ
pound 9 by sodium methoxide in methanol to imine 1 was
completed in 1 h (Scheme 7).
For compound 13 containing a sixꢀmembered ring,
~1ꢀh refluxing was required. Under analogous conditions,
a reaction with sevenꢀmembered amino enone 14 gave
the corresponding cyclic imine as the result of deacylation.
However, the reaction in boiling acetic acid in the presꢀ
ence of HCl afforded pyrazole 21 in 73% yield.
In a reaction of amino enone 9 (R = Ph) with hydrꢀ
azine, intermediate hydroxypyrazoline was detected
(1H and 13C NMR data). This compound is sufficiently
stable at room temperature since the presence of the
trifluoromethyl substituent stabilizes amino alcohol and
gemꢀdiol fragments.4 However, we failed to isolate this
hydroxypyrazoline in the individual state because of the
presence of pyrazole 17.
Scheme 7
Reactions of ketones 9—11 with phenylhydrazine in
ethanol yielded mixtures of products. Acetic acid as a
solvent proved to ensure the best chemoselectivity of the
reaction. The presence of two electrophilic centers in
the amino enone molecule suggests that the reaction
with phenylhydrazine can produce two regioisomers
(Scheme 9). Nevertheless, only one of them was obtained
in each case (compounds 22, 29, and 30), via addition of
phenylhydrazine to the trifluoroacetyl fragment of amino
ketones 9—11. Variation of the aryl substituent in arylꢀ
hydrazine showed that the lowering of the nucleophilicity
B– is a base
We did manage to find the heterocyclization condiꢀ
tions. It turned out that the reaction pathway depends on
both the particular polynucleophile and the starting amino
enone. Reactions of compounds 9—11, 13, and 14 with
hydrazine gave the corresponding pyrazoles (Scheme 8).
The reaction conditions strongly depend on the ring size
in the starting amino enone. For instance, for fiveꢀmemꢀ
bered cycles, the reaction occurred in ethanol at room
temperature. Subsequent acid treatment of the reaction
mixture afforded the target pyrazoles in high yields as the
sole product.
Scheme 9
Scheme 8
Comꢀ
R
R´
Yield
pound
(%)
22
Ph
Ph
Ph
Ph
Ph
Ph
4ꢀBrC6H4
3ꢀClC6H4
3ꢀCF3C6H4
2,4ꢀF2C6H3
4ꢀMeOC6H4
Benzodioxanꢀ6ꢀyl
Ph
85
90
92
60
82
91
92
90
88
84
82
77
23•HCl
24•HCl
25•HCl
26•HCl
27•HCl
28•HCl
29•2HCl
30•HCl
31•HCl
32•2HCl
33•HCl
Ph
Ph
Compound
n
R
Yield (%)
17
1
1
1
2
3
Ph
4ꢀMe2NC6H4
4ꢀMeOC6H4
Ph
91
89
92
87
73
4ꢀMe2NC6H4
4ꢀMeOC6H4
Ph
4ꢀMe2NC6H4
4ꢀMeOC6H4
18•2HCl
19•HCl
20•HCl
21
Ph
Me
Me
Me
Ph

4ꢀAminoalkylꢀ3ꢀtrifluoromethylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
339
increases the reaction time and decreases the yield; howꢀ
ever, the reaction keeps regiospecific (see Scheme 9, comꢀ
pounds 23—28).
logs existing as the amino enone tautomer (1H and
13C NMR data).
Heterocyclization with methylhydrazine required still
more drastic conditions (CH3COOH + conc. HCl); unꢀ
der less acidic conditions, amino enones decomposed only
(two N atoms in methylhydrazine are known to differ in
nucleophilicity much less than those in arylhydrazines).
However, the reaction was also regiospecific (1H and
13C NMR data), giving the corresponding 1ꢀmethylꢀ3ꢀ
trifluoromethylpyrazoles 31—33 as the sole products.
Thus, the regiospecificity of heterocyclization of methylꢀ
and arylhydrazines with the amino enones under study is
of general character and allows one to obtain Nꢀsubstiꢀ
tuted pyrazoles containing the trifluoromethyl substituent
in position 3.
Scheme 11
Reactions of amino enones 9—11 with hydroxylamine
hydrochloride in ethanol gave hydroxyisoxazolines 38—40
(Scheme 12). In this case, the substrate is initially atꢀ
tacked by the oxygen center of hydroxylamine (the chemiꢀ
cal shift of the C(5) atom at δ 106—108). According to
1H NMR data, only one diastereomer of isoxazolines
38—40 was obtained. These products are highly resistant
to the action of dehydrating agents: the corresponding
isoxazoles were not obtained on refluxing in toluene with
pꢀtoluenesulfonic acid, or on heating at 80 °C with
conc. H2SO4, or in the presence of polyphosphoric
acid. However, prolonged heating of compound 38 in
conc. H2SO4 at 150 °C gave isoxazole derivative 41 in
high yield.
In the 13C NMR spectra of pyrazoles 22—33, the sigꢀ
nal for the C(3) atom appears at δ 139—140 as a quadruꢀ
2
plet with JC,F = 34—37 Hz, which agrees well with the
published data on the chemical shifts of the C(3) atom in
1ꢀarylꢀ3ꢀtrifluoromethylpyrazoles (δ 140—143).13—15
Note that the chemical shift of the C(3) atom in isomeric
1ꢀarylꢀ5ꢀtrifluoromethylpyrazoles (see Scheme 9) was
δ 129—134.16,17 This allows unambiguous determination
of the regiochemistry of heterocyclization from 13C NMR
spectra. An analogous pattern was observed for Nꢀmethylꢀ
pyrazoles.
Reactions of exocyclic amino enone 16 with phenylꢀ
and methylhydrazines gave pyrazoles 34 and 35 containing
the 3ꢀaminopropyl substituent in position 5 (Scheme 10).
Scheme 12
Scheme 10
The behavior of the trifluoromethyl derivatives in variꢀ
ous reactions can often differ radically from the behavior
of nonfluorinated analogs. For this reason, we compared
the site of initial nucleophilic attack for a fluorinated
compound and its nonfluorinated analog 36, which has
similar steric demands of the substituent4 and was preꢀ
pared analogously through lithium enamide. The reaction
of compound 36 with phenylhydrazine proved to be
regiospecific (Scheme 11), yielding pyrazole 37 with the
tertꢀbutyl group in position 5 (NOESY data). Therefore,
phenylhydrazine adds to the imine fragment rather than
the carbonyl group (i.e., the regiochemistry of the heteroꢀ
cyclization is inverse with respect to trifluoromethyl deꢀ
rivatives). It should be noted that compound 36 exists
as the oxo imine tautomer, in contrast to fluorinated anaꢀ
Compound
R
Yield (%)
38
39
40
Ph
97
95
95
4ꢀMe2NC6H4
4ꢀMeOC6H4
In conclusion, we discovered a route to cyclic βꢀ(triꢀ
fluoroacetyl) enamines via trifluoroacetylation of lithium
enamides prepared from the corresponding cyclic imiꢀ
nes. The reactions of βꢀ(trifluoroacetyl) enamines with

340
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
Nenajdenko et al.
6ꢀPhenylꢀ2,3,4,5ꢀtetrahydropyridine (7). The yield was 83%,
Rf 0.55 (hexane—ethyl acetate, 1 : 1). 1H NMR (CDCl3), δ:
7.73—7.77 (m, 2 H, H arom.); 7.34—7.37 (m, 3 H, H arom.);
3.82, 2.61, 1.82, 1.66 (all m, 2 H each, CH2). The 1H NMR
spectrum was identical with the earlier reported one.23
hydrazines and hydroxylamine were found to be regioꢀ
specific; the regiochemistry of the heterocyclization of
trifluoromethyl ketones differs from that for nonfluoriꢀ
nated analogs. We proved that the reaction proceeds
through intermediate hemiaminals and hemiacetals; such
isoxazole derivatives can be isolated in the individual state.
We developed the method for the synthesis of pyrazoles
and isoxazoles that simultaneously contain trifluoromethyl
and ωꢀaminoalkyl fragments.
7ꢀPhenylꢀ3,4,5,6ꢀtetrahydroꢀ2Hꢀazepine (8). The yield
20
was 59%, Rf 0.67 (hexane—ethyl acetate, 1 : 1), nD 1.5660
20
(cf. Ref. 24: b.p. 139—141 °C (9 Torr), nD 1.5650).
Acylation of cyclic imines (general procedure). A solution of
imine 1—8 (0.025 mol) in anhydrous THF (20 mL) was added in
one portion under argon at 0 °C to a stirred solution of LDA
prepared from diisopropylamine (5.05 g, 0.05 mol) and a 2.5 M
solution of BunLi (20 mL, 0.05 mol) in anhydrous THF
(100 mL). The reaction mixture was kept at 10 °C for 30 min
and cooled to –80 °C, whereupon ethyl trifluoroacetate
(0.0625 mol) was added in one portion. The solution was kept at
–30 °C for several hours (monitoring by TLC) and quenched
with a saturated solution of NH4Cl. The organic phase was
separated and the product was extracted from the aqueous phase
with ether (2×50 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated in a rotary evaporator.
The residue was triturated with a small amount of benzene. The
resulting crystals were filtered off and dried in vacuo.
Experimental
1
H and 13C NMR spectra were recorded on a Bruker
Avance 400 spectrometer (400 and 100 MHz, respectively) in
CDCl3 and DMSOꢀd6 with Me4Si as the internal standard.
IR spectra were recorded on a URꢀ20 spectrophotometer in thin
films for liquids and in Nujol for solids. TLC analysis was
carried out on Merck 60 F254 plates; spots were visualized
with an acidified solution of KMnO4 and the iodine vapor. For
preparative chromatography, Merck 63ꢀ200 mesh silica gel
was used.
5ꢀArylꢀ3,4ꢀdihydroꢀ2Hꢀpyrroles were prepared according to
known procedures.7,8
5ꢀPhenylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (1). The yield was 67%,
large reddish crystals, Rf 0.45 (hexane—ethyl acetate, 1 : 1),
m.p. 43 °C, b.p. 85—95 °C (2 Torr) (cf. Ref. 18: m.p. 44 °C, b.p.
116—118 °C (8 Torr)).
5ꢀ(4ꢀDimethylaminophenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (2). The
yield was 66%, colorless crystals, Rf 0.38 (MeCN—NH3, 50 : 1),
b.p. 130—145 °C (2 Torr), m.p. 140—141 °C. Found (%):
C, 76.21; H, 8.39. C12H16N2. Calculated (%): C, 76.55; H, 8.57.
IR, ν/cm–1: 1590 (C=N). 1H NMR (CDCl3), δ: 7.71 (d, 2 H,
H arom., J = 8.0 Hz); 6.67 (d, 2 H, H arom., J = 8.9 Hz); 3.99
(m, 2 H, CH2); 2.98 (s, 6 H, 2 Me); 2.87, 1.97 (both m, 2 H each,
CH2). 13C NMR (CDCl3), δ: 172.78 (CN); 151.63, 128.84,
122.56, 111.33 (C arom.); 60.99 (CH2); 40.12 (2 Me); 34.56,
22.65 (both CH2).
2,2,2ꢀTrifluoroꢀ1ꢀ(2ꢀphenylꢀ4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ3ꢀ
yl)ethanone (9). The yield was 64%, bright yellow crystals, Rf 0.42
(hexane—ethyl acetate, 1 : 1), m.p. 140—141 °C. Found (%):
C, 58.97; H, 4.14. C12H10F3NO. Calculated (%): C, 59.75;
H, 4.18. IR, ν/cm–1: 3210 (NH), 1600 (CO), 1300—1060 (CF3).
1H NMR (CDCl3), δ: 7.36—7.52 (m, 5 H, H arom.); 5.37 (br.s,
1 H, NH); 3.79, 3.19 (both t, 2 H each, CH2, J = 10.0 Hz).
13C NMR (CDCl3), δ: 171.90 (q, CO, J = 32.3 Hz); 169.81
(quaternary C); 130.70, 128.40, 127.89 (C arom.); 118.07 (q,
CF3, J = 292.9 Hz); 100.30 (quaternary C); 46.54 (CH2); 27.67
(q, CH2, J = 3.2 Hz).
1ꢀ[2ꢀ(4ꢀDimethylaminophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ3ꢀ
yl]ꢀ2,2,2ꢀtrifluoroethanone (10). The yield was 60%, bright yelꢀ
low crystals, Rf 0.75 (MeCN—NH3, 50 : 1), m.p. 181—182 °C.
Found (%): C, 58.57; H, 5.17. C14H15F3N2O. Calculated (%):
C, 59.15; H, 5.32. IR, ν/cm–1: 3200 (NH), 1610 (CO),
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.71 (br.s, 1 H,
NH); 7.49, 6.67 (both d, 2 H each, H arom., J = 8.9 Hz); 3.65
(t, 2 H, CH2, J = 9.5 Hz); 2.97 (s, 6 H, 2 Me); 2.97 (t, 2 H, CH2,
J = 9.5 Hz). 13C NMR (DMSOꢀd6), δ: 170.19 (quaternary C);
167.98 (q, CO, J = 30 Hz); 152.16, 130.78 (C arom.); 118.80 (q,
CF3, J = 293.0 Hz); 116.56, 110.20 (C arom.); 96.62 (quaterꢀ
nary C); 45.51 (CH2); 40.07 (2 Me); 27.35 (CH2).
2,2,2ꢀTrifluoroꢀ1ꢀ[2ꢀ(4ꢀmethoxyphenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀ
pyrrolꢀ3ꢀyl]ethanone (11). The yield was 53%, bright yellow
crystals, Rf 0.65 (hexane—ethyl acetate, 1 : 1), m.p. 161—162 °C.
Found (%): C, 57.13; H, 4.64. C13H12F3NO2. Calculated (%):
C, 57.57; H, 4.46. IR, ν/cm–1: 3180 (NH), 1590 (CO),
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 7.46, 6.83 (both d,
2 H each, H arom., J = 8.6 Hz); 6.00 (br.s, 1 H, NH); 3.80 (s,
3 H, Me); 3.67, 3.10 (both t, 2 H each, CH2, J = 9.6 Hz).
13C NMR (DMSOꢀd6), δ: 169.71 (quaternary C); 168.70 (q,
CO, J = 30.0 Hz); 161.27, 130.82, 122.55 (C arom.); 118.45 (q,
CF3, J = 292.6 Hz); 113.05 (C arom.); 97.81 (quaternary C);
55.34 (Me); 45.87, 27.18 (both CH2).
5ꢀ(4ꢀMethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (3). The yield
was 59%, Rf 0.47 (hexane—ethyl acetate, 1 : 1), b.p. 121—125 °C
(2 Torr), m.p. 75 °C (cf. Ref. 19: m.p. 74 °C).
5ꢀ(5ꢀMethylꢀ2ꢀthienyl)ꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (4). The
yield was 50%, Rf 0.52 (hexane—ethyl acetate, 1 : 1), b.p.
95—103 °C (2 Torr), m.p. 54—56 °C. Found (%): C, 64.92;
H, 6.91. C9H11NS. Calculated (%): C, 65.41; H, 6.71. IR,
ν/cm–1: 1590 (C=N). 1H NMR (CDCl3), δ: 7.07 (m, 1 H,
H of thiophene); 6.68 (d, 1 H, H of thiophene); 3.96, 2.85
(both m, 2 H each, CH2); 2.46 (s, 3 H, Me); 1.98 (m, 2 H,
CH2). 13C NMR (CDCl3), δ: 167.69 (CN); 143.84, 137.19,
129.18, 125.57 (C arom.); 61.00, 35.06, 22.81 (all CH2);
15.52 (Me).
5ꢀtertꢀButylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (5). The yield was 67%,
Rf 0.28 (hexane—ethyl acetate, 1 : 1), b.p. 53 °C (15 Torr).
1H NMR (CDCl3), δ: 3.73, 2.46 (both t, 2 H each, CH2, J =
7.4 Hz); 1.78 (m, 2 H, CH2); 1.10 (s, 9 H, 3 Me). The 1H NMR
spectrum was identical with the earlier reported one.20
5ꢀMethylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole (6). The yield was 38%,
Rf 0.25 (hexane—ethyl acetate, 1 : 1), b.p. 88—96 °C (760 Torr),
1ꢀ(2ꢀtertꢀButylꢀ4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ3ꢀyl)ꢀ2,2,2ꢀtrifluoroꢀ
ethanone (12). The yield was 27%, colorless crystals, Rf 0.8
(hexane—ethyl acetate, 1 : 1), m.p. 175—176 °C. Found (%):
20
nD 1.4307 (cf. Ref. 21: b.p. 94 °C (760 Torr); cf. Ref. 22:
20
nD 1.4296).

4ꢀAminoalkylꢀ3ꢀtrifluoromethylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
341
C, 54.11; H, 6.52. C10H14F3NO. Calculated (%): C, 54.29;
H, 6.38. IR, ν/cm–1: 3330 (NH), 1600 (CO), 1300—1060 (CF3).
1H NMR (DMSOꢀd6), δ: 8.53 (br.s, 1 H, NH); 3.56, 2.89 (both t,
2 H each, CH2, J = 9.5 Hz); 1.28 (s, 9 H, 3 Me). 13C NMR
(DMSOꢀd6), δ: 182.11 (quaternary C); 166.69 (q, CO, J =
30.0 Hz); 118.97 (q, CF3, J = 293.1 Hz); 97.03 (quaternary C);
45.66 (CH2); 34.60 (quaternary C); 26.55 (q, CH2, J = 4.3 Hz);
26.03 (3 Me).
2,2,2ꢀTrifluoroꢀ1ꢀ(2ꢀphenylꢀ1,4,5,6ꢀtetrahydropyridinꢀ3ꢀ
yl)ethanone (13). The reaction was carried out in anhydrous
THF (500 mL). The yield was 67%, yellow crystals, Rf 0.48
(hexane—ethyl acetate, 1 : 1), m.p. 189—190 °C. Found (%):
C, 61.47; H, 5.10. C13H12F3NO. Calculated (%): C, 61.17;
H, 4.74. IR, ν/cm–1: 3270 (NH), 1620 (CO), 1300—1060 (CF3).
1H NMR (CDCl3), δ: 7.40 (m, 3 H, H arom.); 7.27 (m, 2 H,
H arom.); 5.13 (br.s, 1 H, NH); 3.42 (m, 2 H, CH2); 2.68 (t,
2 H, CH2, J = 6.0 Hz); 1.97 (m, 2 H, CH2). 13C NMR (CDCl3),
δ: 173.30 (q, CO, J = 30.0 Hz); 163.80 (quaternary C); 138.76,
129.19, 128.44, 128.20 (C arom.); 118.56 (q, CF3, J = 293.0 Hz);
95.30 (quaternary C); 42.02 (CH2); 22.10 (q, CH2, J = 2.5 Hz);
21.16 (CH2).
(Z )ꢀ1,1,1ꢀTrifluoroꢀ3ꢀ(pyrrolidinꢀ2ꢀylidene)propanꢀ2ꢀone
(16). The yield was 78%, yellowish crystals, Rf 0.73 (hexꢀ
ane—ethyl acetate, 1 : 1), m.p. 90—92 °C. 1H NMR (CDCl3), δ:
10.18 (br.s, 1 H, NH); 5.43 (s, 1 H, H vinyl.); 3.70 (t, 2 H, CH2,
J = 7.1 Hz); 2.75 (t, 2 H, CH2, J = 7.8 Hz); 2.08 (m, 2 H, CH2)
1
(cf. Ref. 12: m.p. 88—90 °C, identical H NMR spectrum).
2,2ꢀDimethylꢀ1ꢀ(5ꢀphenylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolꢀ4ꢀ
yl)propanꢀ1ꢀone (36). The yield was 74%, brown crystals, Rf 0.68
(hexane—ethyl acetate, 1 : 1), m.p. 54—56 °C. Found (%):
C, 78.60; H, 8.22. C15H19NO. Calculated (%): C, 78.56; H, 8.35.
IR, ν/cm–1: 1690 (CO), 1620 (CN). 1H NMR (CDCl3), δ: 7.65
(m, 2 H, H arom.); 7.33 (m, 3 H, H arom.); 4.67 (m, 1 H, CH);
4.14, 4.04, 2.38, 1.97 (all m, 1 H each, CH2); 1.25 (s, 9 H,
3 Me). 13C NMR (CDCl3), δ: 213.50 (CO); 171.34 (CN); 134.06,
130.03, 128.25, 127.45 (C arom.); 60.42 (CH); 54.44 (CH2);
44.53 (quaternary C); 30.52 (CH2); 26.87 (3 Me).
Reactions of amino enones 9—11 and 13 with hydrazine (genꢀ
eral procedure). Hydrazine hydrate (0.05 g, 0.001 mol) was added
to a solution of an amino enone (0.001 mol) in ethanol (15 mL).
The reaction mixture was kept at ~20 °C for 30 min (monitoring
by TLC), treated with conc. HCl (0.3 mL), and evaporated to
dryness in vacuo. The residue was triturated with ether—EtOH
(5 : 1, 5 mL). The product was filtered off and dried in vacuo. To
isolate the free base, aminopyrazole hydrochloride was dissolved
in water (10 mL) and treated with 25% NH3 (1 mL). The preꢀ
cipitate that formed was filtered off, washed with a small amount
of water, and dried in vacuo.
2,2,2ꢀTrifluoroꢀ1ꢀ[2ꢀphenylꢀ2ꢀ(6ꢀphenylꢀ1ꢀtrifluoroacetylꢀ
1,2,3,4ꢀtetrahydropyridinꢀ5ꢀyl)piperidinꢀ3ꢀyl]ethanone (13´).
The reaction was carried out in anhydrous THF (100 mL). The
yield was 35%, yellow crystals, Rf 0.75 (hexane—ethyl acetate,
1 : 1), m.p. 191—192 °C. Found (%): C, 60.94; H, 4.86.
C
26H24F6N2O2. Calculated (%): C, 61.17; H, 4.74. IR, ν/cm–1
:
3390 (NH), 1690, 1650 (CO), 1300—1060 (CF3). 1H NMR
(CDCl3), δ: 7.25—7.43 (m, 8 H, H arom.); 7.02—7.04 (m, 2 H,
H arom.); 5.59 (br.s, 1 H, NH); 4.79, 3.72, 3.12 (all m, 1 H each,
H aliph.); 2.53 (m, 2 H, H aliph.); 2.34—2.40 (m, 1 H, H aliph.);
2.09—2.17 (m, 2 H, H aliph.); 1.92—1.67 (m, 5 H, H aliph.).
13C NMR (DMSOꢀd6), δ: 173.37 (q, CO, J = 30.0 Hz); 162.52;
157.07 (q, CO, J = 34.5 Hz); 138.34; 137.67; 128.85, 128.27,
128.05, 127.70, 127.38, 127.28 (C arom.); 117.72 (q, CF3, J =
293.5 Hz); 116.40 (q, CF3, J = 288.7 Hz); 96.12 (quaternary C);
70.96, 58.23, 43.41, 30.28, 23.56, 23.23, 21.23, 17.26 (C aliph.).
2,2,2ꢀTrifluoroꢀ1ꢀ(2ꢀphenylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀazepinꢀ
3ꢀyl)ethanone (14). The yield was 41%, bright yellow crystals,
Rf 0.31 (hexane—ethyl acetate, 1 : 1), m.p. 166—167 °C.
Found (%): C, 62.46; H, 5.21. C14H14F3NO. Calculated (%):
C, 62.45; H, 5.24. IR, ν/cm–1: 3280 (NH), 1610 (CO),
1300—1060 (CF3). 1H NMR (CDCl3), δ: 7.47 (m, 1 H,
H arom.); 7.37 (m, 4 H, H arom.); 5.25 (br.s, 1 H, NH); 3.63,
2.81 (both m, 2 H each, CH2); 1.89 (m, 4 H, 2 CH2). 13C NMR
(CDCl3), δ: 178.73 (q, CO, J = 31.0 Hz); 169.23 (quaternary C);
138.95, 130.80, 129.11, 128.60 (C arom.); 117.79 (q, CF3, J =
292.0 Hz); 103.39 (quaternary C); 46.89, 26.74, 26.60, 25.33
(all CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole
(17). The yield was 91%, gray crystals, Rf 0.55
(MeCN—EtOH—NH3, 80 : 12 : 8), m.p. 97—98 °C. Found (%):
C, 56.47; H, 4.92. C12H12F3N3. Calculated (%): C, 56.47;
H, 4.74. IR, ν/cm–1: 3370, 3310 (NH2), 1300—1060 (CF3).
1H NMR (DMSOꢀd6), δ: 7.59 (d, 2 H, H arom., J = 7.5 Hz);
7.49 (t, 2 H, H arom., J = 7.5 Hz); 7.45 (t, 1 H, H arom., J =
7.5 Hz); 2.65 (m, 4 H, 2 CH2) 13C NMR (DMSOꢀd6), δ: 142.18
(C of pyrazole); 139.65 (q, C of pyrazole, J = 35.0 Hz); 128.93,
128.85, 128.70, 127.84 (C arom.); 122.39 (q, CF3, J = 269.0 Hz);
113.94 (C of pyrazole); 42.91, 27.00 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀdimethylaminophenyl)ꢀ3ꢀtrifluoroꢀ
methylꢀ1Hꢀpyrazole dihydrochloride (18•2HCl). The yield was
89%, gray crystals, Rf 0.42 (MeCN—EtOH—NH3, 80 : 12 : 8),
m.p. 249—250 °C. Found (%): C, 45.57; H, 5.50.
C14H19Cl2F3N4. Calculated (%): C, 45.30; H, 5.16. IR, ν/cm–1
:
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 13.70 (br.s, 1 H,
NH+); 8.32 (br.s, 3 H, NH3+); 7.43, 6.82 (both d, 2 H each,
H arom., J = 8.8 Hz); 2.92—2.99 (m, 2 H, CH2); 2.95 (s, 6 H,
2 Me); 2.79 (m, 2 H, CH2). 13C NMR (DMSOꢀd6), δ: 150.31
(C arom.); 142.99 (C of pyrazole); 139.76 (q, C of pyrazole, J =
36.7 Hz); 128.61 (C arom.); 122.32 (q, CF3, J = 269.6 Hz);
115.64, 112.47 (C arom.); 109.59 (C of pyrazole); 39.96 (2 Me);
39.03, 20.92 (both CH2).
2ꢀ(Pyrrolidinꢀ2ꢀylidene)ꢀ5ꢀtrifluoroacetylmethylideneꢀ2,5ꢀ
dihydrothiophene (15). The yield was 39%, bright red crystals,
Rf 0.18 (hexane—ethyl acetate, 1 : 1), m.p. 260—262 °C
(decomp.). Found (%): C, 49.97; H, 4.12. C11H10F3NOS. Calꢀ
culated (%): C, 50.57; H, 3.86. IR, ν/cm–1: 2500—2800 (NH),
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀtrifluoromethylꢀ
1Hꢀpyrazole hydrochloride (19•HCl). The yield was 92%, gray
crystals, Rf 0.60 (MeCN—EtOH—NH3, 80 : 12 : 8), m.p.
275—276 °C. Found (%): C, 40.88; H, 5.19. C13H15ClF3N3O•
1
1630 (CO), 1300—1060 (CF3). H NMR (DMSOꢀd6), δ: 10.63
(br.s, 1 H, NH); 7.75 (br.s, 1 H, H vinyl.); 6.77 (d, 1 H, H vinyl.,
J = 4.0 Hz); 6.16 (s, 1 H, H vinyl.); 3.75, 3.24 (both t, 2 H each,
CH2, J = 7.3 Hz); 2.12 (m, 2 H, CH2). 13C NMR (DMSOꢀd6),
δ: 167.28; 164.75 (q, CO, J = 26.4 Hz); 163.22; 140.82; 120.42;
119.45 (q, CF3, J = 288.8 Hz); 113.85; 90.18; 50.04, 33.24,
21.15 (all CH2).
•3H2O. Calculated (%): C, 41.55; H, 5.63. IR, ν/cm–1
:
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.37 (br.s, 3 H,
NH3+); 7.54, 7.05 (both d, 2 H each, H arom., J = 8.6 Hz); 3.79
(s, 3 H, Me); 2.95, 2.77 (both m, 2 H each, CH2). 13C NMR
(DMSOꢀd6), δ: 159.85 (C arom.); 142.55 (C of pyrazole); 139.77
(q, C of pyrazole, J = 35.1 Hz); 129.52 (C arom.); 122.33 (q, CF3,

342
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
Nenajdenko et al.
J = 268.6 Hz); 120.42, 114.63 (C arom.); 110.47 (C of pyrazole);
55.42 (Me); 40.17, 20.87 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀ(3ꢀchlorophenyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoroꢀ
methylꢀ1Hꢀpyrazole hydrochloride (24•HCl). The yield was 92%,
white crystals, Rf 0.49 (MeCN—EtOH—NH3, 80 : 12 : 8), m.p.
208—209 °C. Found (%): C, 49.84; H, 4.04. C18H16Cl2F3N3.
Calculated (%): C, 50.36; H, 4.46. IR, ν/cm–1: 1300—1060
(CF3). 1H NMR (DMSOꢀd6), δ: 8.26 (br.s, 3 H, NH3+);
7.52—7.33 (m, 8 H, H arom.); 7.20 (m, 1 H, H arom.); 2.82 (m,
4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 144.00 (C of pyrazole);
139.75 (q, C of pyrazole, J = 36.0 Hz); 139.63, 133.14, 130.70,
130.14, 129.65, 129.00, 128.54, 127.47, 125.19, 123.97 (C arom.);
121.68 (q, CF3, J = 269.5 Hz); 114.60 (C of pyrazole); 39.77,
20.83 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1ꢀ(3ꢀtrifluoroꢀ
methylphenyl)ꢀ1Hꢀpyrazole hydrochloride (25•HCl). The yield
was 60%, white crystals, Rf 0.55 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 138—140 °C (decomp.). Found (%): C, 50.03;
H, 3.85. C19H16ClF6N3. Calculated (%): C, 50.29; H, 4.00. IR,
ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.29 (br.s,
3 H, NH3+); 7.73 (m, 1 H, H arom.); 7.32—7.68 (m, 8 H,
H arom.); 2.83 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ:
144.16 (C of pyrazole); 140.16 (q, C of pyrazole, J = 36.4 Hz);
139.02, 130.55, 130.22, 129.72 (C arom.); 129.35 (q, C arom.,
J = 22.1 Hz); 129.09, 129.04, 127.45, 125.14 (C arom.); 123.33
(q, CF3, J = 272.3 Hz); 121.85 (q, C arom., J = 3.7 Hz); 121.69
(q, CF3, J = 270.0 Hz); 114.82 (C of pyrazole); 39.73, 20.84
(both CH2).
4ꢀ(3ꢀAminopropyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole
hydrochloride (20•HCl). The reaction mixture was refluxed
for 1 h. The yield was 87%, colorless crystals, Rf 0.56
(MeCN—EtOH—NH3, 80 : 12 : 8), m.p. 290—292 °C.
Found (%): C, 50.05; H, 5.26. C13H15ClF3N3•1/3H2O. Calcuꢀ
lated (%): C, 50.09; H, 5.07. IR, ν/cm–1: 1300—1060 (CF3).
1H NMR (DMSOꢀd6), δ: 8.00 (br.s, 3 H, NH3+); 7.52 (m, 5 H,
H arom.); 2.72 (m, 2 H, CH2); 2.65 (t, 2 H, CH2, J = 7.9 Hz);
1.75 (m, 2 H, CH2). 13C NMR (DMSOꢀd6), δ: 141.84
(C of pyrazole); 139.60 (q, C of pyrazole, J = 35.0 Hz); 128.93,
128.85, 128.70, 127.84 (C arom.); 122.37 (q, CF3, J = 269.0
Hz); 114.78 (C of pyrazole); 38.55, 28.57, 19.77 (all CH2).
Reactions of amino enone 14 with hydrazine and of amino
enones 9—11 and 36 with arylꢀ and methylhydrazines (general
procedure). A suspension of hydrazine hydrochloride in HCl was
added to a boiling solution of an amino enone (0.001 mol) in a
mixture of glacial acetic acid (10 mL) and conc. HCl (1 mL).
The reaction mixture was refluxed for 30 min and concentrated in
a rotary evaporator. The residue was triturated with ether—EtOH
(5 : 1, 5 mL). The product was filtered off and dissolved in water
(20 mL). The resulting solution was treated with 25% NH3
(1 mL). The crystals that formed were filtered off, washed with a
small amount of water, and dried in vacuo.
4ꢀ(4ꢀAminobutyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole
(21). The yield was 73%, grayish crystals, Rf 0.65
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀ(2,4ꢀdifluorophenyl)ꢀ5ꢀphenylꢀ3ꢀtriꢀ
fluoromethylꢀ1Hꢀpyrazole hydrochloride (26•HCl). The yield was
82%, white crystals, Rf 0.50 (MeCN—EtOH—NH3, 80 : 12 : 8),
m.p. 228—229 °C. Found (%): C, 48.94; H, 4.12.
(MeCN—EtOH—NH3, 80
: 12 : 8), m.p. 122—123 °C.
Found (%): C, 58.45; H, 5.51. C14H16F3N3•1/3H2O. Calcuꢀ
lated (%): C, 58.12; H, 5.81. IR, ν/cm–1: 3340, 3280 (NH2),
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 7.44 (m, 3 H,
H arom.); 7.32 (m, 2 H, H arom.); 2.61 (t, 2 H, CH2, J =
8.0 Hz); 2.59 (t, 2 H, CH2, J = 7.0 Hz); 1.48, 1.35 (both m,
2 H each, CH2). 13C NMR (DMSOꢀd6), δ: 141.84 (C of pyrꢀ
azole); 139.40 (q, C of pyrazole, J = 34 Hz); 129.06, 129.01,
128.72, 127.76 (C arom.); 122.50 (q, CF3, J = 269.0 Hz); 116.22
(C of pyrazole); 41.20, 33.02, 28.16, 22.25 (all CH2).
4ꢀ(2ꢀAminoethyl)ꢀ1,5ꢀdiphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrꢀ
azole (22). The yield was 85%, a colorless oil, Rf 0.53
(MeCN—EtOH—NH3, 80 : 12 : 8). Found (%): C, 65.80;
H, 5.31. C18H16F3N3. Calculated (%): C, 65.25; H, 4.87. IR,
ν/cm–1: 3400—3300 (NH2), 1300—1060 (CF3). 1H NMR
(CDCl3), δ: 7.18—7.42 (m, 10 H, H arom.); 2.81, 2.71 (both t,
2 H each, CH2, J = 7.4 Hz); 1.19 (br.s, 2 H, NH2). 13C NMR
(CDCl3), δ: 142.86 (C of pyrazole); 140.13 (q, C of pyrazole,
J = 36.0 Hz); 138.99, 129.84, 129.01, 128.89, 128.67, 128.65,
127.70, 124.78 (C arom.); 121.87 (q, CF3, J = 269.0 Hz); 116.97
(C of pyrazole); 42.78, 27.38 (both CH2).
C18H15ClF5N3• •2H2O. Calculated (%): C, 49.16; H, 4.35. IR,
ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.27 (br.s,
3 H, NH3+); 7.69 (m, 1 H, H arom.); 7.37—7.45 (m, 4 H,
H arom.); 7.31 (m, 2 H, H arom.); 7.21 (m, 1 H, H arom.);
2.73—2.93 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 162.46
(dd, C arom., J = 250.2 Hz, J = 11.5 Hz); 156.45 (dd, C arom.,
J = 252.3 Hz, J = 12.6 Hz); 145.65 (C of pyrazole); 140.40 (q,
C of pyrazole, J = 35.8 Hz); 131.17 (d, C arom., J = 10.2 Hz);
129.68, 129.61, 128.86, 126.96 (C arom.); 123.04 (d, C arom.,
J = 16.9 Hz); 121.62 (q, CF3, J = 269.5 Hz); 113.69
(C of pyrazole); 112.40 (d, C arom., J = 23.3 Hz); 105.10 (t,
C arom., J = 23.5 Hz); 39.45, 20.68 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀphenylꢀ3ꢀtriꢀ
fluoromethylꢀ1Hꢀpyrazole hydrochloride (27•HCl). The yield
was 91%, grayish crystals, Rf 0.48 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 224—226 °C. Found (%): C, 57.30; H, 4.61.
C
19H19ClF3N3O. Calculated (%): C, 57.36; H, 4.81. IR, ν/cm–1
:
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.24 (br.s, 3 H,
NH3+); 7.42 (m, 3 H, H arom.); 7.31 (m, 2 H, H arom.); 7.17,
6.89 (both d, 2 H each, H arom., J = 8.7 Hz); 3.72 (s, 3 H, Me);
2.81 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 159.00
(C arom.); 143.85 (C of pyrazole); 139.15 (q, C of pyrazole, J =
36.0 Hz); 131.65, 130.16, 129.38, 128.89, 127.94, 126.90
(C arom.); 121.93 (q, CF3, J = 270.5 Hz); 114.12 (C arom.);
113.96 (C of pyrazole); 39.93, 21.01 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoroꢀ
methylꢀ1Hꢀpyrazole hydrochloride (23•HCl). The yield was
90%, white crystals, Rf 0.55 (MeCN—EtOH—NH3, 80 : 12 : 8),
m.p. 205—206 °C. Found (%): C, 45.96; H, 3.38.
C
18H16BrClF3N3•H2O. Calculated (%): C, 46.52; H, 3.90. IR,
ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.29 (br.s,
3 H, NH3+); 7.58 (d, 2 H, H arom., J = 8.3 Hz); 7.44 (m, 3 H,
H arom.); 7.34 (m, 2 H, H arom.); 7.19 (d, 2 H, H arom., J =
8.3 Hz); 2.81 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 143.88
(C of pyrazole); 139.88 (q, C of pyrazole, J = 35.8 Hz); 137.82,
132.08, 130.16, 129.61, 129.04, 127.57, 127.28 (C arom.); 121.75
(q, CF3, J = 269.7 Hz); 121.55 (C arom.); 114.63 (C of pyrazole);
39.71, 20.89 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀ(2,3ꢀdihydroꢀ1,4ꢀbenzodioxanꢀ6ꢀyl)ꢀ5ꢀ
phenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole hydrochloride (28•HCl).
The
yield
was
92%,
gray
12
crystals,
8), m.p. 331—332 °C.
Rf
0.52
(MeCN—EtOH—NH3, 80
:
:
Found (%): C, 56.12; H, 4.44. C20H19ClF3N3O2. Calcuꢀ
lated (%): C, 56.41; H, 4.50. IR, ν/cm–1: 1300—1060 (CF3).

4ꢀAminoalkylꢀ3ꢀtrifluoromethylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
343
1H NMR (DMSOꢀd6), δ: 8.25 (br.s, 3 H, NH3+); 7.51—7.28
(m, 5 H, H arom.); 6.80 (m, 2 H, H arom.); 6.68 (m, 1 H,
H arom.); 4.20, 2.80 (both br.s, 4 H each, CH2). 13C NMR
(DMSOꢀd6), δ: 143.79; 143.48; 143.05; 139.17 (q, C of pyrazole,
J = 35.0 Hz); 131.97, 130.13, 129.47, 128.93, 127.93 (C arom.);
121.89 (q, CF3, J = 269.3 Hz); 118.48, 117.08, 114.47 (C arom.);
114.05 (C of pyrazole); 64.05 (2 CH2); 40.15, 20.98 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀdimethylaminophenyl)ꢀ1ꢀphenylꢀ3ꢀ
trifluoromethylꢀ1Hꢀpyrazole dihydrochloride (29•2HCl). The
yield was 90%, gray crystals, Rf 0.31 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 247—249 °C (decomp.). Found (%): C, 49.95;
H, 5.34. C20H23Cl2F3N4•2H2O. Calculated (%): C, 49.70;
H, 5.63. IR, ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6),
δ: 8.19 (br.s, 3 H, NH3+); 7.35—7.41 (m, 3 H, H arom.); 7.25,
7.19 (both d, 2 H each, H arom., J = 8.3 Hz); 6.98 (m, 2 H,
H arom.); 2.95 (s, 6 H, 2 Me); 2.81 (m, 4 H, 2 CH2). 13C NMR
(DMSOꢀd6), δ: 172.04, 146.86 (C arom.); 143.42 (C of pyrazole);
139.62 (q, C of pyrazole, J = 36.1 Hz); 138.72, 131.49, 129.20,
128.66, 125.47 (C arom.); 121.92 (q, CF3, J = 269.2 Hz); 117.55
(C arom.); 114.51 (C of pyrazole); 42.94 (2 Me); 39.09, 20.98
(both CH2).
was 77%, gray crystals, Rf 0.55 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 155—156 °C. Found (%): C, 47.13; H, 5.32.
C
14H17ClF3N3O• •H2O. Calculated (%): C, 47.53; H, 5.41.
IR, ν/cm–1: 1300—1060 (CF3). H NMR (DMSOꢀd6), δ: 8.23
(br.s, 3 H, NH3+); 7.41, 7.26 (both d, 2 H each, H arom., J =
8.3 Hz); 3.82, 3.68 (both s, 3 H each, Me); 2.64—2.77 (m, 4 H,
2 CH2). 13C NMR (DMSOꢀd6), δ: 159.93 (C arom.); 143.51
(C of pyrazole); 137.27 (q, C of pyrazole, J = 35.2 Hz); 131.25
(C arom.); 121.90 (q, CF3, J = 269.3 Hz); 119.55, 114.46
(C arom.); 112.79 (C of pyrazole); 55.27 (Me); 38.95 (CH2);
37.64 (Me); 20.94 (CH2).
1
5ꢀ(3ꢀAminopropyl)ꢀ1ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole
hydrochloride (34•HCl). The yield was 83%, gray crystals, Rf 0.41
(MeCN—EtOH—NH3, 80 : 12 : 8), m.p. 228—229 °C.
Found (%): C, 47.91; H, 4.94. C13H15ClF3N3. Calculated (%):
C, 48.23; H, 5.29. IR, ν/cm–1: 1300—1060 (CF3). 1H NMR
(DMSOꢀd6), δ: 8.18 (br.s, 3 H, NH3+); 7.55 (m, 5 H, H arom.);
6.85 (s, 1 H, H of pyrazole); 2.77 (m, 4 H, 2 CH2); 1.91 (m, 2 H,
CH2). 13C NMR (DMSOꢀd6), δ: 145.08 (C of pyrazole); 141.10
(q, C of pyrazole, J = 37.5 Hz); 138.36, 129.53, 129.12, 125.54
(C arom.); 121.59 (q, CF3, J = 268.3 Hz); 103.71 (C of pyrazole);
37.91, 22.69, 18.59 (all CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylꢀ3ꢀtriꢀ
fluoromethylꢀ1Hꢀpyrazole hydrochloride (30•HCl). The yield
was 88%, gray crystals, Rf 0.53 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 182—183 °C. Found (%): C, 57.11; H, 4.88.
5ꢀ(3ꢀAminopropyl)ꢀ1ꢀmethylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole
hydrochloride (35•HCl). The yield was 71%, gray crystals, Rf 0.57
(MeCN—EtOH—NH3, 80
: 12 : 8), m.p. 178—179 °C.
C19H19ClF3N3O. Calculated (%): C, 57.36; H, 4.81. IR, ν/cm–1
:
Found (%): C, 39.41; H, 5.11. C8H13ClF3N3. Calculated (%):
C, 39.43; H, 5.38. IR, ν/cm–1: 1300—1060 (CF3). 1H NMR
(DMSOꢀd6), δ: 8.27 (br.s, 3 H, NH3+); 6.56 (s, 1 H, H of
pyrazole); 3.81 (s, 3 H, Me); 2.78 (m, 4 H, 2 CH2); 1.92 (m,
2 H, CH2). 13C NMR (DMSOꢀd6), δ: 144.07 (C of pyrazole);
138.96 (q, C of pyrazole, J = 37.4 Hz); 121.65 (q, CF3, J =
267.6 Hz); 102.62 (C of pyrazole); 37.91 (CH2); 36.84 (Me);
21.65, 18.55 (both CH2).
1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 8.23 (br.s, 3 H,
NH3+); 7.35—7.40 (m, 3 H, H arom.); 7.25 (m, 4 H, H arom.);
6.97 (d, 2 H, H arom., J = 8.8 Hz); 3.75 (s, 3 H, Me); 2.74—2.86
(m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 159.83 (C arom.);
143.79 (C of pyrazole); 139.47 (q, C of pyrazole, J = 35.9 Hz);
138.73, 131.59, 129.11, 128.51, 125.35 (C arom.); 121.92 (q, CF3,
J = 269.9 Hz); 119.78, 114.38 (C arom.); 114.22 (C of pyrazole);
55.22 (Me); 38.98, 20.99 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀtertꢀbutylꢀ1,3ꢀdiphenylꢀ1Hꢀpyrazole
(37). The yield was 85%, grayish crystals, Rf 0.46 (MeCN—NH3,
50 : 1), m.p. 110—112 °C. Found (%): C, 75.01; H, 7.87.
4ꢀ(2ꢀAminoethyl)ꢀ1ꢀmethylꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀ
pyrazole hydrochloride (31•HCl). The yield was 84%, gray
crystals, Rf 0.62 (MeCN—EtOH—NH3, 80
:
12
:
8),
C
21H25N3. Calculated (%): C, 74.74; H, 8.06. IR, ν/cm–1: 3360,
m.p. 113—115 °C. Found (%): C, 49.98; H, 5.33.
C13H15ClF3N3•0.5H2O. Calculated (%): C, 49.61; H, 5.12. IR,
ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 7.54—7.60
(m, 3 H, H arom.); 7.46—7.51 (m, 2 H, H arom.); 3.70 (s, 3 H,
Me); 2.64—2.79 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ:
143.72 (C of pyrazole); 137.62 (q, C of pyrazole, J = 36.0 Hz);
129.92, 129.64, 129.18, 127.74 (C arom.); 122.01 (q, CF3, J =
269.0 Hz); 113.09 (C of pyrazole); 39.48 (CH2); 37.87 (Me);
21.01 (CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀdimethylaminophenyl)ꢀ1ꢀmethylꢀ3ꢀ
trifluoromethylꢀ1Hꢀpyrazole dihydrochloride (32•2HCl). The
yield was 82%, gray crystals, Rf 0.60 (MeCN—EtOH—NH3,
80 : 12 : 8), m.p. 281—282 °C (decomp.). Found (%): C, 45.57;
H, 5.93. C15H21Cl2F3N4•0.5H2O. Calculated (%): C, 45.70;
H, 5.62. IR, ν/cm–1: 1300—1060 (CF3). 1H NMR (DMSOꢀd6),
δ: 8.17 (br.s, 3 H, NH3+); 7.42 (d, 2 H, H arom., J = 8.2 Hz);
7.26 (br.s, 2 H, H arom.); 3.69 (s, 3 H, Me); 3.04 (s, 6 H, 2 Me);
2.64—2.78 (m, 4 H, 2 CH2). 13C NMR (DMSOꢀd6), δ: 147.60
(C arom.); 143.36 (C of pyrazole); 137.47 (q, C of pyrazole, J =
35.7 Hz); 131.16 (C arom.); 121.99 (q, CF3, J = 269.6 Hz);
117.18 (C arom.); 113.07 (C of pyrazole); 42.62 (2 Me); 39.05
(CH2); 37.82 (Me); 21.02 (CH2).
3300 (NH2). 1H NMR (DMSOꢀd6), δ: 7.30—7.57 (m, 10 H,
H arom.); 2.80, 2.64 (both m, 2 H each, CH2); 1.22 (s, 9 H,
3 Me). 13C NMR (DMSOꢀd6), δ: 150.40; 148.20; 143.37; 134.24;
128.71; 128.50; 128.43; 128.22; 128.05; 127.28; 113.69 (C of
pyrazole); 43.60 (CH2); 33.17 (quaternary C); 31.36 (3 Me);
29.29 (CH2).
Reactions of amino enones 9—11 with hydroxylamine (general
procedure). Hydroxylamine hydrochloride (0.1 g, 0.0014 mol)
was added to a solution of an amino enone (0.001 mol) in ethaꢀ
nol (15 mL). The reaction mixture was refluxed for 1 h. The
solvent was removed in a rotary evaporator. The residue was
dissolved in water (5 mL) and treated with 25% NH3 (0.2 mL).
The precipitate that formed was filtered off, washed with a small
amount of water, and dried in vacuo.
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀhydroxyꢀ3ꢀphenylꢀ5ꢀtrifluoromethylꢀ
4,5ꢀdihydroisoxazole (38). The yield was 97%, white crystals,
Rf 0.57 (MeCN—EtOH—NH3, 80 : 12 : 8), m.p. 174—175 °C.
Found (%): C, 52.52; H, 4.78. C12H13F3N2O2. Calculated (%):
C, 52.56; H, 4.78. IR, ν/cm–1: 3500—3260 (NH2, OH), 1620
(C=N), 1300—1060 (CF3). 1H NMR (DMSOꢀd6), δ: 7.70—7.74
(m, 2 H, H arom.); 7.44—7.47 (m, 3 H, H arom.); 4.17 (dd, 1 H,
CH, J = 6.6 Hz, J = 2.6 Hz); 2.59 (ddd, 1 H, CH2, J = 13.1 Hz,
J = 5.5 Hz, J = 2.0 Hz); 1.94—2.10 (m, 2 H, CH2); 1.77 (ddt,
1 H, CH2, J = 15.5 Hz, J = 11.2 Hz, J = 2.4 Hz). 13C NMR
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ3ꢀtriꢀ
fluoromethylꢀ1Hꢀpyrazole hydrochloride (33•HCl). The yield

344
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 2, February, 2007
Nenajdenko et al.
(DMSOꢀd6), δ: 150.05 (C of isoxazoline); 130.21, 128.96, 128.90,
126.76 (C arom.); 123.73 (q, CF3, J = 287.2 Hz); 107.50 (q, C of
isoxazoline, J = 31.0 Hz); 48.57 (C of isoxazoline); 34.41 (Me);
26.68 (CH2).
2. P. Depreux, D. Lesieur, H. Mansour, P. Morgan, H. E.
Howell, P. Renard, D. Caignard, B. Pfeiffer, P. Delagrange,
B. Guardiola, S. Yous, A. Demarque, G. Adam, and
J. Andrieux, J. Med. Chem., 1994, 37, 3231.
3. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova,
Molecules, 1997, 2, 186.
4. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova, Usp.
Khim., 1999, 6, 483 [Russ. Chem. Rev., 1999, 6 (Engl.
Transl.)].
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀ(4ꢀdimethylaminophenyl)ꢀ5ꢀhydroxyꢀ5ꢀ
trifluoromethylꢀ4,5ꢀdihydroisoxazole (39). The yield was 95%,
white crystals, Rf 0.42 (MeCN—EtOH—NH3, 80 : 12 : 8), m.p.
180—181 °C. Found (%): C, 50.50; H, 5.91. C14H18F3N3O2•
•H2O. Calculated (%): C, 50.15; H, 6.01. IR, ν/cm–1
:
3620—3300 (NH2, OH), 1600 (C=N), 1300—1060 (CF3).
1H NMR (DMSOꢀd6), δ: 7.51, 6.72 (both d, 2 H each, H arom.,
J = 9.0 Hz); 4.08 (m, 1 H, CH); 2.94 (s, 6 H, 2 Me); 2.54—2.61
(m, 1 H, CH2); 2.07, 1.96, 1.74 (all m, 1 H each, CH2).
13C NMR (DMSOꢀd6), δ: 158.90 (C of isoxazoline); 151.34,
127.89 (C arom.); 123.85 (q, CF3, J = 287.2 Hz); 115.67, 111.83
(C arom.); 106.30 (q, C of isoxazoline, J = 31.0 Hz); 48.88 (C of
isoxazoline); 39.73 (CH2); 34.36 (2 Me); 27.19 (CH2).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀhydroxyꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀtriꢀ
fluoromethylꢀ4,5ꢀdihydroisoxazole (40). The yield was 95%, white
crystals, Rf 0.55 (MeCN—EtOH—NH3, 80 : 12 : 8), m.p.
194—195 °C. Found (%): C, 50.93; H, 5.14. C12H13F3N2O2.
Calculated (%): C, 51.32; H, 4.97. IR, ν/cm–1: 3600—3280
(NH2, OH), 1610 (C=N), 1300—1060 (CF3). 1H NMR
(DMSOꢀd6), δ: 7.66, 7.00 (both d, 2 H each, H arom., J =
8.6 Hz); 4.15 (m, 1 H, CH); 3.78 (s, 3 H, Me); 2.56—2.61 (m,
1 H, CH2); 2.06 (t, 1 H, CH2, J = 11.9 Hz); 1.93—2.00 (m, 1 H,
CH2); 1.75 (d, 1 H, CH2, J = 13.2 Hz). 13C NMR (DMSOꢀd6),
δ: 160.74 (C arom.); 158.64 (C of isoxazoline); 128.42 (C arom.);
123.80 (q, CF3, J = 287.2 Hz); 121.19, 114.44 (C arom.); 106.98
(q, C of isoxazoline, J = 30.9 Hz); 55.31 (Me); 48.74 (C of
isoxazoline); 34.34, 26.87 (both CH2).
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀphenylꢀ5ꢀtrifluoromethylisoxazole (41).
A solution of hydroxyisoxazoline 38 (0.137 g, 0.0005 mol) in
conc. H2SO4 (0.5 mL) was heated at 150 °C for 2 h. The reacꢀ
tion mixture was cooled, diluted with water (5 mL), and treated
with 25% NH3 (3 mL). The product was extracted from the
resulting solution with CH2Cl2 (3×5 mL). The combined exꢀ
tracts were dried over Na2SO4, the solvent was removed, and the
residue was dried in vacuo. The yield of compound 41 was 93%,
a colorless oil, Rf 0.87 (MeCN—EtOH—NH3, 80 : 12 : 8).
Found (%): C, 56.01; H, 4.44. C12H11F3N2O. Calculated (%):
C, 56.25; H, 4.33. IR, ν/cm–1: 3400—3200 (NH2), 1300—1060
(CF3). 1H NMR (CDCl3), δ: 7.54—7.58 (m, 2 H, H arom.);
7.44—7.48 (m, 3 H, H arom.); 2.75 (s, 4 H, 2 CH2); 1.52 (br.s,
2 H, NH2). 13C NMR (CDCl3), δ: 163.59 (C of isoxazole);
154.90 (q, C of isoxazole, J = 40.4 Hz); 130.14, 128.96, 128.25,
127.64 (C arom.); 118.66 (q, CF3, J = 270.9 Hz); 117.09 (C of
isoxazole); 41.74, 25.79 (both CH2).
5. S. V. Druzhinin, E. S. Balenkova, and V. G. Nenajdenko,
Tetrahedron, 2007, 63.
6. M. Kawase, M. Hyrabayashi, S. Saito, and K. Yamamoto,
Tetrahedron Lett., 1999, 40, 2541.
7. V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, and E. S.
Balenkova, Tetrahedron, 2004, 60, 11719.
8. V. G. Nenajdenko, A. M. Gololobov, E. P. Zakurdaev, and
E. S. Balenkova, Izv. Akad. Nauk, Ser. Khim., 2003, 2338
[Russ. Chem. Bull., Int. Ed., 2003, 52, 2473].
9. V. G. Nenajdenko, I. D. Gridnev, and E. S. Balenkova,
Tetrahedron, 1994, 50, 11023.
10. M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, and S. Matsuo,
Chem. Lett., 1976, 499.
11. H. Brunner, A. Kuerzinger, S. Mahboobi, and W. Wiegrebe,
Arch. Pharm., 1988, 321, 73.
12. S. Fustero, M. G. de la Torre, B. Pina, and A. S. Fuentes,
J. Org. Chem., 1999, 64, 5551.
13. J. Diab, A. Laurent, and I. Le Drean, J. Fluor. Chem., 1997,
84, 145.
14. J. C. Sloop, C. L. Bumgardner, and W. D. Loehle, J. Fluor.
Chem., 2002, 118, 135.
15. M. A. P. Martins, G. P. Bastos, A. P. Sinhorin, N. E. K.
Zimmermann, A. Rosa, S. Brondani, D. Emmerich, H. G.
Bonacorso, and N. Zanatta, J. Fluor. Chem., 2003, 123, 249.
16. H.ꢀB. Yu and W.ꢀY. Huang, Synlett, 1997, 679.
17. H. G. Bonacorso, M. A. P. Martins, S. R. T. Bittencourt,
R. V. Lourega, N. Zanatta, and A. F. C. Flores, J. Fluor.
Chem., 1999, 99, 177.
18. F. M. Korte and H.ꢀJ. SchulzeꢀSteinen, Chem. Ber., 1962,
95, 2444.
19. W. Koller and P. Schlack, Chem. Ber., 1963, 96, 93.
20. S. Edwards and F.ꢀH. Marquardt, J. Org. Chem., 1963,
39, 1963.
21. D. Bacos, J.ꢀP. Celerier, and G. Lhommet, Tetrahedron
Lett., 1987, 21, 2353.
22. S. Burckhalter, J. Org. Chem., 1958, 23, 1281.
23. B. Sezen and D. Sames, J. Am. Chem. Soc., 2004,
126, 13244.W
24. D. Kvano, Collect. Czech. Chem. Commun., 1965, 30, 2472.
References
Received November 10, 2006;
in revised form February 2, 2007
1. R. A. Glennon, J. Med. Chem., 1987, 30, 1.