Use of the α-amination reaction for the synthesis of pyrazole derivatives containing carbo- and heterocyclic substituents on the nitrogen atom

Article abstract of DOI:10.1007/s10593-012-0993-3

A method has been developed for the synthesis of pyrazoles with carbo- and heterocyclic substituents on the nitrogen atom based on the α-amination reaction of carbo- and heterocyclic ketones, using azodicarboxylate-L-proline system with subsequent interaction with malonodialdehyde tetramethylacetal. In the case of carbocyclic ketones and tetrahydro-γ-pyranone, the reaction occurs stereoselectively to give chiral hydrazines and pyrazoles. With derivatives of piperidin-4-one, α-amination is accompanied by racemization.

Full text of DOI:10.1007/s10593-012-0993-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 2, May, 2012 (Russian Original Vol. 48, No. 2, February, 2012)
USE OF THE α-AMINATION REACTION FOR THE SYNTHESIS
OF PYRAZOLE DERIVATIVES CONTAINING CARBO- AND
HETEROCYCLIC SUBSTITUENTS ON THE NITROGEN ATOM
A. A. Utkina1*, A. V. Kurkin1, and M. A. Yurovskaya1
A method has been developed for the synthesis of pyrazoles with carbo- and heterocyclic substituents on
the nitrogen atom based on the α-amination reaction of carbo- and heterocyclic ketones, using
azodicarboxylate–L-proline system with subsequent interaction with malonodialdehyde tetramethyl-
acetal. In the case of carbocyclic ketones and tetrahydro-γ-pyranone, the reaction occurs stereo-
selectively to give chiral hydrazines and pyrazoles. With derivatives of piperidin-4-one, α-amination is
accompanied by racemization.
Keywords: azodicarboxylate, cyclohexanone, cyclopentanone, N-substituted piperidones, pyrazoles,
L-proline, tetrahydro-γ-pyranone, stereoselective α-amination.
At present more and more attention is devoted to search of biologically active chiral non-racemic
compounds in connection with obtaining optimal ratios of activity and safety in such compounds. This is
particularly concerned with pyrazole derivatives with chiral substituent on the nitrogen atom because the
pyrazole unit is part of many medicinal agents [see, for example, 1, 2].
There are no references to methods of synthesis of such pyrazole compounds in the literature. Recently
we proposed [3] an original method for the synthesis of pyrazole derivatives with chiral substituent on the
nitrogen atom based on a stereoselective α-amination reaction of 3-phenylpropanal with the di-tert-butyl ester of
azodicarboxylic acid, catalyzed by L-proline [4]. Reaction of the synthesized chiral hydrazine with the
malonodialdehyde tetramethyl acetal led to the formation of pyrazole with a chiral substituent at the nitrogen
atom with a very high degree of optical purity (ee 99%) [3]. Considering the known biological activity of
pyrazole derivatives [1] and also of heterocyclic compounds containing carbo- and heterocyclic substituents [2]
we decided to extend this method to carbo- and heterocyclic ketones.
Boc
O
O
HN
N
O
OMe OMe
OMe
20 mol%
L-proline
N
Boc
N
N
N
MeO
Boc
+
H+
MeCN
20oC
X
Boc
X
X
2a–g
3a–g
1a–g
a,b X = (CH2)n, a n = 1, b n = 0; c–f X = NR, c R = Me, d R = Bn, e R = Ac, f R = Bz; g X = O
_______
*To whom correspondence should be addressed, e-mail: AnastasiaUtkina@mail.ru.
1M. V. Lomonosov Moscow State University, 1 Bld. 3 Leninskie Gory, Moscow 119991, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.2, 347-354, February, 2012. Original
article submitted September 13, 2011.
0009-3122/12/4802-0327©2012 Springer Science+Business Media, Inc.
327

We chose cyclohexanone (1a) and cyclopentanone (1b) as model carbocyclic ketones. The α-amination
of cyclohexanone (1a) leading to the hydrazine 2a, is known in the literature [5]. We replicated the described
method which included addition of 20 mol% L-proline to a previously prepared solution of a 1:1.5 mole ratio
mixture of the azodicarboxylate and the carbonyl compound at room temperature. The corresponding optically
active di-tert-butyl 1-(2-oxocyclohexyl)hydrazine-1,2-dicarboxylate (2a) was produced in 65% yield, the
specific rotation of which corresponded to the literature value [5]. However, investigation of the enantiomeric
purity of the obtained hydrazine by HPLC using a chiral stationary phase showed the presence of both
enantiomers, so the enantiomeric purity of the α-hydrazine ketone derivative did not exceed 56%.
Since the removal of the tert-butoxycarbonyl protective group, which is necessary for the subsequent
cyclization into the pyrazoles, and the cyclization itself occur under analogous conditions (in acidic media) we
decided to combine these processes to decrease the number of steps in the reaction thus increasing the
effectiveness of the process. As a result of in situ cyclization, which allows the elimination of the stage of
chromatographic purification of the hydrazine, accompanied by partial loss of optical purity, we obtained from
the di-tert-butyl 1-(2-oxocyclohexyl)hydrazine-1,2-dicarboxylate (2a) the corresponding pyrazole 3a in 61%
yield with an enantiomeric purity of about 89%.
A quite different result was obtained in the case of cyclopentanone (1b). From the reaction of 1.5 mol of
the cyclic ketone 1b with di-tert-butyl diazodicarboxylate under the conditions described above the product of
α,α'-diamination was formed predominantly [6]. Further cyclization into the bispyrazolylcyclopentanone (5b)
occurred with formation of an optically inactive compound in low yield (20%).
Boc
Boc
Boc
Boc
OMe OMe
MeO
OMe
O
Boc
20mol%
L-proline
O
HN
N
N
N
NH
N
1b
Boc
+
N
N
N
N
MeCN
20°C
H+
4b
5b
We used the method developed to obtain the heterocyclic analogs 3c and 3d. N-Methyl- and
N-benzylpiperidin-4-ones (1c,d) were used as ketones. The result of the reaction of 1.5 mol of
N-methylpiperidin-4-one (1c) with 1 mol of di-tert-butyl azodicarboxylate was a mixture of products of
α-amination 2c and α,α'-diamination 4c in a ratio of about 1:2 (from LC/MC data). Compounds 2c and 4c
(optically inactive) after chromatographic separation of the reaction mixture were isolated in yields of 8% and
16%, respectively.
Boc
O
Boc
20 mol%
L-proline
N
N
Boc
HN
Boc
NH
Boc
N
N
2c–f
+
1с–f
+
MeCN
20°C
N
Boc
R
4c–f
c R = Me, d R = Bn, e R = Ac, f R = Bz
The main component of the reaction mixture appears to be the di-tert-butyl hydrazine-1,2-dicarboxy-
late, that may indicate the decomposition of the target products during the chromatographic isolation. Different
aminated ketones, including heterocyclic ketones, but excluding cyclohexanone, are known from the literature
to undergo partial racemization and decomposition even during preparative HPLC for their purification and
isolation [6].
We have assumed that yet another possible reason for racemization of the required compounds in the
case of N-methyl- and N-benzylpiperidin-4-ones (1c,d) may be the basic properties of a nitrogen atom of the
N-substituted piperidinone which facilitates keto-enol tautomerism in the substrates which leads to
racemization. We have used N-acetyl- and N-benzoylpiperidin-4-ones (1e,f) as carbonyl compounds without
328

such properties to determine the influence of the substrate nature on the process. As a result we observed that
the reaction of 1.5 mol of N-benzoylpiperidin-4-one (1f) with 1.0 mol of di-tert-butyl azodicarboxylate gave the
predominant formation of the α-amination product 2f (mono:bis, 21:1), but in the case of N-acetylpiperidin-
4-one (1e) the products of both α-amination 2e and α,α'-diamination 4e were formed in a ratio of ~5:1.
Compounds 2e and 4e, 2f and 4f were isolated in yields of 57% and 15%, 70% and 4%, respectively, after
chromatographic separation.
However none of these compounds possessed optical activity after chromatographic separation. The
results obtained confirm the suggestion that the stage of chromatographic separation plays the main role in the
racemization process.
Tetrahydro-4H-pyran-4-one (1g) was chosen as yet another heterocyclic substrate for the amination
process. Its reaction with di-tert-butyl azodicarboxylate gave only the product of mono-α-amination 2g
precipitated from the reaction mixture as the pure compound. The specific rotation of compound 2g was
measured to be [α]D = -18° (c = 1.0, MeOH). However chromatographic separation of the mother liquor by flash
chromatography on silica gel gave an additional amount of optically inactive di-tert-butyl 1-(oxotetrahydro-
2H-pyran-3-yl)hydrazine-1,2-dicarboxylate. This example illustrates well the undesirable use of chromato-
graphic isolation on silica gel of optically active products of the amination of heterocyclic ketones.
Further cyclization of the α-aminated ketones 2c-f and the α,α-diaminated ketones 4c,d with the
malonodialdehyde tetramethylacetal in ethanol with 2.5 equiv. of 6 N HCl at room temperature led to the
formation of the corresponding derivatives of pyrazoles 3c-f and 5c,d in yields of 17-50%.
OMe OMe
O
MeO
OMe
N
N
N
4c,d
N
N
R
5c,d
5 c R = Me, d R = Bn
On the basis of the data obtained the optimum conditions and the limits of applicability of the L-proline-
catalyzed α-amination reaction for the preparation of a new class of chiral N-substituted pyrazoles have been
determined.
EXPERIMENTAL
1H and 13C NMR spectra were recorded in CDCl3 solution with TMS as internal standard on a Bruker
AMX-400 spectrometer (400 and 100 MHz, respectively). Specific rotation was measured with a Jasco DIP-360
polarimeter (589 nm). Enantiomeric purity was determined by HPLC using a Chiralpak AD-RH 4.6×150 mm
chiral stationary phase, 5 μm, H2O + CF3COOH/CH3CN, 50/50 as eluent, flow rate 1.0 ml/min, ~20°C, 250 nm.
Mass spectra were recorded on a Finnigan MAT ITD PD-700 (EI, ionization energy 70 eV). Chromato-mass-
spectra investigations of reaction mixtures and isolated compounds were carried out on a Shimadzu Analytical
HPLC SCL10Avp and a PE SCIX API 150 mass spectrometer (electrospray, positive ionization). Monitoring of
the course of reactions and purity of the isolated compounds was carried out by TLC in systems of petroleum
ether–ethyl acetate and ether–methylene chloride in different proportions with visualization by iodine vapor or
potassium permanganate solution.
Commercially available compounds – di-tert-butyl azodicarboxylate, cyclohexanone (1a), cyclopenta-
none (1b), N-methylpiperidin-4-one (1c), N-benzylpiperidin-4-one (1d), and L-proline ([α]D = -84°, c = 2) –
were used without further purification. N-acetyl- and N-benzoylpiperidin-4-ones (1e,f) were synthesized by a
known method [7].
329

Di-tert-butyl 1-(2-Oxocyclohexyl)hydrazine-1,2-dicarboxylate (2a). A solution of di-tert-butyl
azodicarboxylate (1.0 g, 4.30 mmol) and L-proline (0.5 g, 0.43 mmol) in MeCN (43 ml) was cooled to 0° and
cyclohexanone (1a) (0.64 ml, 6.50 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 24 h,
and then warmed to room temperature for 1 h, evaporated to dryness, and the residue was purified by column
chromatography on silica gel (Et2O–CH2Cl2, 1:20). Yield 0.92 g (65%). [α]D = -14.8 (c =1.08, CHCl3). 1H NMR
spectrum, δ, ppm : 1.46 (18H, s, 2C(CH3)3); 1.51-1.67 (2H, m, CH2); 1.73-1.86 (2H, m, CH2); 1.93-2.13 (2H, m,
CH2); 2.28-2.53 (2H, m, CH2); 4.80-4.95 (1H, m, CH); 6.51 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 24.2;
24.9; 28.1; 28.3; 29.6; 32.5; 61.6; 69.3; 81.0; 81.8; 154.8; 156.0. The specific rotation and the NMR spectra
agree with those reported in [1].
Compounds 2c-g and 4b-f were prepared analogously.
Tetra-tert-butyl 1,1'-(2-Oxocyclopentane-1,3-diyl)di(hydrazine-1,2-dicarboxylate) (4b). Clear oil,
1
solidifying on standing. Yield 54%. H NMR spectrum, δ, ppm: 1.44 (36H, s, 4C(CH3)3); 1.74-2.07 (2H, m,
CH2); 2.13-2.52 (2H, m, CH2); 4.10 and 4.42 (2H, each br. s, 2CH); 6.14 and 6.44 (total 2H, each br. s, NH). 13C
NMR spectrum, δ, ppm: 28.0; 28.1; 40.2; 45.0; 54.6; 57.7; 58.2; 80.7; 81.6; 154.8; 155.3; 205.1. Mass spectrum
(ESI), m/z (Irel, %): 545 [M+H]+ (0.1), 450(5), 277 (27), 157 (100), 138 (14). Mass spectrum (EI), m/z (Irel, %):
276 (46), 157 (47), 102 (45), 57 (100). Found, %: C 55.28; H 8.20; N 10.07. C25H44N4O9. Calculated, %:
C 55.13; H 8.14; N 10.29.
Di-tert-butyl 1-(1-Methyl-4-oxopiperidin-3-yl)hydrazine-1,2-dicarboxylate (2c). White crystalline
1
solid, mp 125-128°C. Yield 16%. H NMR spectrum, δ, ppm: 1.37 and 1.39 (total 18H, each s, 2C(CH3)3);
2.21-2.40 (6H, m, CH2, CH3); 2.53-2.69 (1H, m, CH2); 2.93-3.07 (1H, m) and 3.13-3.49 (1H, m, 2CH); 4.71 and
4.97 (total 1H, each br. s, CH); 6.38 and 6.72 (total 1H, each br. s, NH). 13C NMR spectrum, δ, ppm: 28.0; 44.6;
57.1; 57.7; 81.1; 81.8; 154.6; 155.3; 202.3. Mass spectrum (ESI), m/z (Irel, %): 344 [M+H]+ (57), 362
[M+H+H2O]+ (100), 288 (16), 232 (10). Mass spectrum (EI), m/z (Irel, %): 112 (100), 57 (51). Found, %:
C 56.14; H 8.58; N 11.99. C16H29N3O5. Calculated, %: C 55.96; H 8.51; N 12.24.
Tetra-tert-butyl 1,1'-(1-Methyl-4-oxopiperidine-3,5-diyl)di(hydrazine-1,2-dicarboxylate) (4c).
White crystalline solid, mp 213-215°C. Yield 8%. 1H NMR spectrum, δ, ppm: 1.41 and 1.44 (total 36H, each s,
4C(CH3)3); 2.33-2.63 (5H, m, CH2, CH3); 3.13-3.45 (2H, m, CH2); 4.71-5.26 (2H, m, 2CH); 6.29-6.88 (2H,
br. s, 2NH). 13C NMR spectrum, δ, ppm: 28.0; 28.1; 44.6; 57.6; 57.7; 81.1; 81.8; 154.6; 155.3; 202.3. Mass
spectrum (ESI), m/z (Irel, %): 574 [M+H]+ (100); 125 (6). Mass spectrum (EI), m/z (Irel, %): 342 (25), 286 (36),
230 (100), 110 (30), 70 (47), 57 (41). Found, %: C 54.50; H 8.18; N 12.09. C26H47N5O9. Calculated, %:
C 54.44; H 8.26; N 12.21.
Di-tert-butyl 1-(1-Benzyl-4-oxopiperidin-3-yl)hydrazine-1,2-dicarboxylate (2d). Substance de-
composes during the chromatographic separation on a silica gel (eluent 2:1 petroleum ether–ethyl acetate).
Preparative thick layer chromatography on silica gel was carried out on glass plates and succeeded in separation
of a colorless substance which solidified on standing. Yield 7%. 1H NMR spectrum, δ, ppm: 1.36 and 1.43 (total
18H, each s, 2C(CH3)3); 2.20-2.24 (2H, m, CH2); 2.49-2.71 (2H, m, CH2); 2.96-3.20 (1H, m, CH2); 3.39-3.65
(2H, m, CH2); 3.73-3.89 (1H, m, CH2); 4.70-5.19 (1H, br. s, CH); 6.22-6.72 (1H, br. s, NH); 7.12-7.52 (5H, m,
H Ph). 13C NMR spectrum, δ, ppm: 28.1; 40.2; 51.3; 55.7; 61.3; 63.2; 80.8; 81.7; 127.3; 128.4; 128.9; 137.5;
155.0; 155.8; 205.5. Mass spectrum (ESI), m/z (Irel, %): 420 [M+H]+, 288, 232, 125. Mass spectrum (EI), m/z
(Irel, %): 419 [M]+ (1), 188 (79), 120 (10), 91 (81), 57 (100). Found, %: C 63.15; H 7.85; N 9.88. C22H33N3O5.
Calculated, %: C 62.99; H 7.93; N 10.02.
Tetra-tert-butyl 1,1'-(1-Benzyl-4-oxopiperidine-3,5-diyl)di(hydrazine-1,2-dicarboxylate) (4d).
Substance decomposes during the chromatographic isolation. Preparative thick layer chromatography on silica
gel was carried out on glass plates and succeeded in separation of a clear oil. Yield 30%. 1H NMR spectrum, δ,
ppm: 1.37 and 1.45 (total 36H, each s, 4C(CH3)3); 2.22-2.49 (2H, br. s, CH2); 2.97-3.34 (1H, m, CH2); 3.42-3.66
(2H, m, CH2); 3.69-3.89 (1H, m, CH2); 4.76 and 5.09 (total 2H, each s, 2CH); 6.24 and 6.57 (total 2H, each s,
13
2NH); 7.18-7.45 (5H, m, H Ph). C NMR spectrum, δ, ppm: 28.0; 28.1; 53.7; 54.4; 55.6; 61.3; 61.9; 62.4; 80.7;
81.1; 81.7; 81.9; 127.5; 128.4; 128.9; 137.0; 154.5; 155.6; 155.8; 202.6. Mass spectrum (EI), m/z (Irel, %):
330

418 [M-(NHBoc)2]+ (13), 362 [M-(NHBoc)2-t-Bu]+ (7), 186 (30), 91 (16), 57 (100). Found, %: C 57.48; H 8.16;
N 10.04. C32H51N5O9·H2O. Calculated, %: C 57.55; H 8.00; N 10.49.
Di-tert-butyl 1-(1-Acetyl-4-oxopiperidin-3-yl)hydrazine-1,2-dicarboxylate (2e). Colorless oil. Yield
57%. H NMR spectrum, δ, ppm: 1.31 (18H, s, 2C(CH3)3); 2.08 (3H, br. s, CH3); 2.29-2.54 (2H, m, CH2);
1
2.66-2.97 (1H, m) and 3.20-3.51 (1H, m, CH2); 3.82-4.24 (1H, m) and 4.29-5.01 (2H, m, CH2, CH); 6.37, 6.49,
6.61, and 6.77 (total 1H, four s, NH). 13C NMR spectrum, δ, ppm: 21.2; 27.9; 28.0; 40.3; 44.7; 47.7; 63.0; 81.2;
82.1; 154.6; 155.5; 169.7; 203.1. Mass spectrum (EI), m/z (Irel, %): 271 [M-Boc]+ (2), 171 (11), 143 (24), 112
(12), 57 (100). Found, %: C 54.88; H 7.73; N 11.06. C17H29N3O6. Calculated, %: C 54.97; H 7.87; N 11.31.
Tetra-tert-butyl
1,1'-(1-Acetyl-4-oxopiperidine-3,5-diyl)di(hydrazine-1,2-dicarboxylate)
(4e).
1
Colorless oil. Yield 15%. H NMR spectrum, δ, ppm: 1.40 (36H, br. s, 4C(CH3)3); 2.19 (3H, br. s, CH3),
2.72-2.98 (1H, m) and 3.18-3.56 (1H, m, CH2); 3.84-4.59 and 4.73-5.16 (4H, each m, CH2, 2CH), 6.45, 6.57,
6.68, 6.78, and 7.04 (total 2H, five s, NH). 13C NMR spectrum, δ, ppm: 21.3; 28.0; 28.1; 43.3; 47.7; 82.0; 82.2;
154.4; 154.5; 170.0; 200.6. Mass spectrum (EI), m/z (Irel,%): 379 [M-(NHBoc)2]+ (2), 333 (11), 289 (22), 214
(14), 57 (100). Found, %: C 53.81; H 7.57; N 11.71. C27H47N5O10. Calculated, %: C 53.90; H 7.87; N 11.64.
Di-tert-butyl 1-(1-Benzoyl-4-oxopiperidin-3-yl)hydrazine-1,2-dicarboxylate (2f). Colorless oil.
1
Yield 70%. H NMR spectrum, δ, ppm: 1.35 (18H, s, 2C(CH3)3); 2.29-2.74 (2H, m, CH2); 2.88-3.56 (2H, m,
CH2); 3.70-4.37 (2H, m, CH2); 4.47-5.17 (1H, m, CH); 6.34 and 6.61 (total 1H, each s, NH); 7.28-7.53 (5H, m,
13
H Ph). C NMR spectrum, δ, ppm: 28.0; 40.5; 41.2; 49.1; 63.3; 81.0; 82.1; 127.0; 128.6; 130.3; 134.7; 154.6;
155.1; 171.0; 203.3. Mass spectrum (EI), m/z (Irel, %): 433 [M]+ (0.1), 171 (11), 205 (12), 105 (59), 77 (30), 57
(100). Found, %: C 60.94; H 7.11; N 9.54. C22H31N3O6. Calculated, %: C 60.95; H 7.21; N 9.69.
Tetra-tert-butyl 1,1'-(1-Benzoyl-4-oxopiperidine-3,5-diyl)di(hydrazine-1,2-dicarboxylate) (4f).
1
Colorless oil. Yield 4%. H NMR spectrum, δ, ppm: 1.46 (36H, s, 4C(CH3)3); 2.56-2.96 (2H, m, CH2);
4.89-5.34 (2H, m, CH2); 6.29 and 6.76 (total 2H, each m, CH); 7.37-7.69 (5H, m, H Ph); 8.06-8.18 (2H, m,
2NH). 13C NMR spectrum, δ, ppm: 28.0; 28.1; 53.7; 54.4, 55.6; 61.3; 61.9; 62.4; 80.7; 81.0; 81.1; 81.7; 81.9;
127.5; 128.4; 128.9; 137.0; 154.5; 154.6; 155.6; 155.8; 202.6. Mass spectrum (EI), m/z (Irel, %): 432
[M-(NHBoc)2]+ (0.4), 232 [(NHBoc)2]+ (5), 105 (78), 77 (22), 58 (100). Found, %: C 57.76; H 7.46; N 10.54.
C32H49N5O10. Calculated, %: C 57.90; H 7.44; N 10.55.
Di-tert-butyl
1-(4-Oxotetrahydro-2H-pyran-3-yl)hydrazine-1,2-dicarboxylate
(2g).
White
1
crystalline solid, mp 155-160°C. [α]D -18° (c = 1.0, methanol).Yield 87%. H NMR spectrum, δ, ppm: 1.44
(18H, s, 2C(CH3)3); 2.40-2.56 (1H, m) and 2.61-2.76 (1H, m, CH2); 3.52-3.73 (2H, m, CH2); 4.19-4.30 (1H, m)
and 4.31-4.58 (1H, m, CH2); 4.68 and 4.98 (total 1H, each br. s, CH); 6.35 and 6.56 (total 1H, each br. s, NH).
13C NMR spectrum, δ, ppm: 28.0; 42.5; 63.6; 67.4; 69.4; 81.1; 82.1; 154.8; 155.3; 203.3. Mass spectrum (EI)
m/z (Irel, %); 230 [BocN=NBoc]+ (6), 215 [M-2t-Bu]+ (0.5), 177 (88), 130 (65), 102 (27), 57 (100). Found, %:
C 54.64; H 7.80; N 8.06. C15H26N2O6. Calculated, %: C 54.53; H 7.93; N 8.48.
2-(1H-Pyrazol-1-yl)cyclohexanone (3a). The di-tert-butyl ester 2a (1 g, 3 mmol) was dissolved in
ethanol (20 ml), 6 N HCl (20 ml) was added, and stirred for 4 h. Then malonodialdehyde tetramethylacetal
(0.50 ml, 3 mmol) was added to the reaction mixture and refluxed for 3 h. The reaction mixture was cooled to
room temperature, poured into water (100 ml) and extracted with CH2Cl2 (350 ml). The organic layer was
separated, dried over Na2SO4, and the solvent was removed in vacuum to give white crystalline solid, mp 68-70°C.
1
[α]D = -10.4° (c = 1.35, CHCl3). Yield 0.3 g (61%). H NMR spectrum, δ, ppm: 1.75-1.92 (2H, m, CH2);
2.07-2.29 (3H, m), 2.43-2.58 (2H, m), and 2.59-2.66 (1H, m, 3CH2); 5.03-5.10 (1H, m, CH); 6.34-6.37 (1H, m,
H-4 pyrazole); 7.41-7.47 (1H, m, H-5 pyrazole); 7.54-7.58 (1H, m, H-3 pyrazole). 13C NMR spectrum, δ, ppm:
24.7; 27.2; 34.3; 41.2; 69.1; 105.9; 128.8; 139.1; 205.0. Mass spectrum (EI), m/z (Irel,%): 165 [M]+ (1), 68 (41),
55 (46), 41 (100). Found, %: C 65.73; H 7.39; N 17.18. C9H12N2O. Calculated, %: C 65.83; H 7.37; N 17.06.
Compounds 3a-g and 5b-f were obtained analogously.
2,5-Di(1H)-pyrazol-1yl)cyclopentanone (5b). Yellowish oil, solidifying on standing. Yield 15%.
1H NMR spectrum, δ, ppm (J, Hz): 2.22-2.32 (2H, m, CH2); 2.34-2.45 (2H, m, CH2); 5.31 (2H, m, 2CH);
6.36-6.42 (2H, m, H-4 pyrazole); 7.65-7.73 (2H, m, H-5 pyrazole); 7.86-9.92 (2H, m, H-3 pyrazole). 13C NMR
331

spectrum, δ, ppm: 29.7 (2C); 61.2 (2C); 109.2; 125.6; 133.5; 208.1. Mass spectrum (ESI), m/z (Irel, %): 217
[M+H]+ (1), 149 (100). Found, %: C 60.98; H 5.47; N 25.82. C11H12N4O. Calculated, %: C 61.10; H 5.59;
N 25.91.
1-Methyl-3-(1H-pyrazol-1-yl)piperidin-4-one (3c). Yellow oil, solidifying on standing. Yield 30%. 1H
NMR spectrum, δ, ppm: 2.42-2.65 and 2.50 (total 5H, each m, CH3, CH2); 2.74-2.89 (1H, m) and 2.91-3.04 (1H,
m. CH2); 3.13-3.23 (1H, m) and 3.44-3.53 (1H, m, CH2); 5.18-5.27 (1H, m, CH); 6.35 (1H, br. s, H-4 pyrazole);
7.47 (1H, br. s, H-5 pyrazole); 7.58 (1H, br. s, H-3 pyrazole). 13C NMR spectrum, δ, ppm: 38.0; 45.3; 56.4;
59.8; 63.7; 65.2; 105.5; 130.5; 139.2; 198.1. Mass spectrum (EI), m/z (Irel, %): 179 [M]+ (0.2), 108 (100), 94
(58), 68 (69), 55 (28), 41(56). Found, %: C 60.68; H 7.70; N 23.64. C9H13N3O. Calculated, %: C 60.32; H 7.31;
N 23.45.
1-Methyl-3,5-di(1H-pyrazol-1-yl)piperidin-4-one (5c). Yellow oil, solidifying on standing. Yield
32%. H NMR spectrum, δ, ppm: 2.55 (3H, br. s, CH3); 3.08-3.19 (2H, m, CH2); 3.51-3.59 (2H, m, CH2);
1
5.37-5.46 (2H, m, 2CH); 6.32 (2H, m, H-4 pyrazole); 7.45 (2H, m, H-5 pyrazole); 7.55 (2H, m, H-3 pyrazole).
13C NMR spectrum, δ, ppm: 44.7; 60.5; 66.0; 106.2; 130.0; 139.7; 197.8. Mass spectrum (ESI), m/z (Irel, %):
246 [M+H]+ (100), 203 (36), 178 (87), 135 (27). Mass spectrum (EI), m/z (Irel, %): 176 (20), 109 (100), 94 (49),
81 (47), 68 (57), 53 (27), 42 (69). Found, %: C 58.81; H 6.18; N 28.35. C12H15N5O. Calculated, %: C 58.76; H 6.16;
N 28.55.
1-Benzyl-3-(1H-pyrazol-1-yl)piperidin-4-one (3d). Clear oil, solidifying on standing. Yield 19%.
1H NMR spectrum, δ, ppm: 2.52-2.67 (2H, m, CH2); 2.72-2.85 (1H, m) and 2.92-3.02 (1H, m, CH2); 3.17-3.28
(1H, m) and 3.47-3.56 (1H, m, CH2); 3.68-3.81 (2H, m, CH2Ph); 5.16-5.28 (1H, m, CH); 6.31-6.37 (1H, m,
pyrazole), 7.27-7.42 (5H, m, H Ph); 7.42-7.49 (1H, m, H pyrazole); 7.53-7.60 (1H, m, H pyrazole). 13C NMR
spectrum, δ, ppm): 40.4; 52.9; 58.2; 61.6; 67.1; 105.9; 127.6; 128.6; 128.9; 129.7; 137.5; 139.5; 202.8. Mass
spectrum (EI), m/z (Irel, %): 255 [M]+ (0.3), 111(42), 96 (19), 91 (100). Found, %: C 70.64; H 6.83; N 16.28.
C15H17N3O. Calculated, %: C 70.56; H 6.71; N 16.46.
1-Benzyl-3,5-di(1H-pyrazol-1-yl)piperidin-4-one (5d). Clear oil, solidifying on standing. Yield 21%.
1H NMR spectrum, δ, ppm: 3.11-3.24 (2H, m, CH2); 3.60-3.73 (2H, m, CH2); 3.74 and 3.84 (total 2H, each s,
CH2Ph); 5.16-5.22 and 5.35-5.49 (total 2H, each m, 2CH); 6.28-6.39 (2H, m, H pyrazole); 7.23-7.49 (7H, m, H Ph,
H pyrazole); 7.53-7.61 (2H, m, pyrazole). 13C NMR spectrum, δ, ppm: 58.1; 61.2; 66.5; 127.9; 128.7; 128.9;
130.0; 137.6; 139.7; 198.0. Mass spectrum (EI), m/z (Irel,%): 231 [M]+ (0.2), 252 (21), 185 (72), 157 (14), 130
(12), 91 (100). Found, %: C 67.50; H 6.00; N 21.59. C18H19N5O. Calculated, %: C 67.27; H 5.96; N 21.79.
1-Acetyl-3-(1H-pyrazol-1-yl)piperidin-4-one (3e). Colorless glassy oil. Yield 28%. 1H NMR
spectrum, δ, ppm: 2.18 and 2.19 (total 3H, each s, CH3); 2.55-2.68 (2H, m, CH2); 3.14-3.26 (0.5H, m),
3.54-3.77 (1H, m), 3.34-4.12 (1H, m), 4.30-4.40 (0.5H, m), 4.64-4.75 (0.5H, m), and 4.84-5.06 (1.5H, m, 2CH2,
CH); 6.29 and 6.32 (total 1H, each s, H pyrazole); 7.41 and 7.45 (total 1H, each s, H pyrazole); 7.54 (1H, s,
H pyrazole). 13C NMR spectrum, δ, ppm: 21.3; 28.1; 40.1; 40.5; 41.0; 45.3; 45.5; 50.2; 65.8; 66.2; 106.0; 106.3;
130.2; 140.0; 140.1; 169.5; 201.0; 201.1. Mass spectrum (EI), m/z (Irel, %): 207 [M]+ (2), 139 (62), 97 (54), 81
(25), 69 (44), 43 (100). Found, %: C 55.67; H 6.53; N 19.43. C10H13N3O2·0.5H2O. Calculated, %: C 55.54;
H 6.53; N 19.43.
1-Benzoyl-3-(1H-pyrazol-1-yl)piperidin-4-one (3f). Colorless glassy oil. Yield 69%. 1H NMR
spectrum, δ, ppm: 2.37-2.91 (2H, m, CH2); 3.24-3.72 (1H, m) and 3.83-4.09 (1H, m, CH2); 4.21-5.22 (3H, m,
CH2, CH); 6.28 (1H, s, H-4 pyrazole); 7.28-7.49 (6H, m, H Ph, H-5 pyrazole); 7.53 (1H, s, H-3 pyrazole). 13C
NMR spectrum, δ, ppm: 40.4; 46.4; 66.0; 106.1; 127.0; 128.8; 130.3; 130.6; 134.5; 140.0; 171.1; 201.2. Mass
spectrum (EI) m/z (Irel, %): 269 [M]+ (2), 201 (33), 105 (100), 77 (49), 51 (13). Found, %: C 66.70; H 5.61;
N 15.27. C15H15N3O2. Calculated, %: C 66.90; H 5.61; N 15.60.
1
3-(1H-Pyrazol-1-yl)tetrahydro-4H-pyran-4-one (3g). Colorless solidified substance. Yield 25%. H
NMR spectrum, δ, ppm: 2.58-2.60 and 2.63-2.67 (total 1H, each m) and 2.75-2.86 (1H, m, CH2); 3.81-3.90 (1H,
m); 4.08-4.16 (1H, m), 4.28-4.36 (1H, m), and 4.46-4.53 (1H, m, 2CH2); 5.07-5.14 (1H, m CH); 6.31-6.36 (1H,
332

m, H-4 pyrazole); 7.44-7.49 (1H, m, H-5 pyrazole); 7.55-7.59 (1H, m, H-3 pyrazole). 13C NMR spectrum, δ,
ppm: 40.1; 67.2; 68.2; 71.4; 106.1; 130.0; 139.8; 200.7. Mass spectrum (EI) m/z (Irel, %): 166 [M]+ (11), 138
(8), 94 (100), 81 (28), 68 (78), 53 (25), 41 (30). Found, %: C 57.72; H 5.98; N 16.87. C8H10N2O2. Calculated,
%: C 57.82; H 6.07; N 16.86.
This work was carried with financial support of the Russian Foundation for Basic Research (grant 11-
03-00444a).
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