Synthesis and some reactions of 1-α-cyanoalkyl(aralkyl)-2-pyrazolines

Article abstract of DOI:10.1007/s10593-005-0317-y

1-α-Cyanoalkyl(aralkyl)-2-pyrazolines were obtained by the reaction of 1-alkylidene(arylidene)-2-pyrazolinium tetrafluoroborates with metal cyanides. Reduction of the products led to substituted β-aminoalkyl-2- pyrazolines. Hydrolysis of the nitrile group

Full text of DOI:10.1007/s10593-005-0317-y

Chemistry of Heterocyclic Compounds, Vol. 41, No. 10, 2005
SYNTHESIS AND SOME REACTIONS OF
1-α-CYANOALKYL(ARALKYL)-2-PYRAZOLINES
N. I. Vorozhtov and G. A. Golubeva
1-α-Cyanoalkyl(aralkyl)-2-pyrazolines were obtained by the reaction of 1-alkylidene(arylidene)-2-
pyrazolinium tetrafluoroborates with metal cyanides. Reduction of the products led to substituted
β-aminoalkyl-2-pyrazolines. Hydrolysis of the nitrile groups gave the corresponding substituted
acetamides.
Keywords: 1-alkylidene(arylidene)2-pyrazolinium tetrafluoroborates, β-(4,5-dihydropyrazol-1-yl)-
alkylamines, α-(4,5-dihydropyrazol-1-yl)acetamides, α-(4,5-dihydropyrazol-1-yl)acetonitriles.
We have shown [1,2] that 1-alkylidene(arylidene)2-pyrazolinium tetrafluoroborates 1 are prospective
synthons for the preparation of both 1-benzyl(hetarylmethyl)-2-pyrazolines and 1-benzyl(hetarylmethyl)-
pyrazolidines. The success of these syntheses depends on the us of C=N bonds with different reactivities in these
salts. We have shown previously the possibility in principle of the reaction of salt 1 with metal cyanides [2]. The
present paper is concerned with further study of this process and further reactions of the functional derivatives of
the 2-pyrazolines synthesized. Under inter-phase reaction conditions (ether-water) attack by the cyanide occurs
regioslectively only at the exocyclic C=N+ bond of the arylidenium salt at room temperature for 1-3 h to give 1-
α-cyanobenzyl-2-pyrazolines 2a-f, i, j, m, n.
R1
R1
O
R1
–
R2
R3
R2
R3
R4
HBF4
R5
CN
R2
R3
+
N
N
N
–
N
N
BF4
R5
N
N
H
–
R4
R4
R5
SCN
α
1a–n
2 a–n
1, 2 a−h, n R1 = Ph, i−m R1 = Me; a−l, n R2 = H, m R2 = Me; a−h R3 = H, i−l, n R3 = Ph,
m R3 = Me; a−f, i, j, m, n R4 = H; g, k R4 = Me, h, l R4+R5 = c-C6H10; a, j, m, n R5 = Ph,
b R5 = C6H4Cl-p, c R5 = C6H4OMe-p, d R5 = 1-ethyl-3-methyl-4-pyrazolyl, e, i R5 = Fur-2,
f R5 = Ind-3, g, k R5 = Me
The reaction is of a general nature. The yields of the desired products (85-95%) depend only slightly on
the substituents on either the pyrazoline nucleus or the arylidenium unit. It was determined chromatographically
that the reaction mixtures contained negligible amounts of 2-pyrazolines without substituents at N, formed by
hydrolytic scission of salt 1.
__________________________________________________________________________________________
Chemistry Faculty, M. V. Lomonosov Moscow State University, Moscow 199899, Russia; e-mail:
nvor@org.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, 10, 1558-1565, October
2005. Original article submitted May 13, 2005
0009-3122/05/4110-1307©2005 Springer Science+Business Media, Inc.
1307

1
In the H NMR spectra of compounds 2 the signals of the protons of the pyrazoline ring are shifted to
strong field in comparison with the arylidenium salts of 2-pyrazoline [1,2]. The α-H signal appears in the region
of 4.8-5.2 ppm. The C=N+ vibration (1640) is absent from the IR spectrum and the carbon-nitrogen triple bond
absorption appears in the 2320-2240 cm-1 region (Tables 1 and 2).
Nitriles with pyrazole, indole, and furan nuclei in the arylidene unit of the molecule were prepared
analogously. The reaction of 1-alkylidene-2-pyrazolium tetrafluoroborate with potassium cyanide also occurred
selectively at the exocyclic C=N+ bond.
When sodium cyanide was used as the nucleophile in the reaction with compound 1j in the conditions
described above the only product was 1-nitrosopyrazoline-2 3, the melting point of which agreed with the
literature value [3]. The formation of the derivative 3 is evidently the result of the formation of pyrazoline with
no substituent on N and its subsequent nitrosation.
Me
Me
+
N
NaNO2
N
H
N
N
N
Ph
–
Ph
BF4
Ph
O
α
3
1j
The signals of one aromatic ring and α-H are absent from the 1H NMR spectrum of compound 3 and the
H-5 signal appears at a weaker field (5.63 ppm) than in alkyl-2-pyrazolines [1,2]. The synthesis of
1-nitrosopyrazolines is well known [3,4].
Salts 1 did not react with potassium thiocyanate under our reaction conditions.
TABLE 1. Characteristics of 2-Pyrazolines
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
2a
2b
2c
2d
2e
2f
C17H15N3
C17H14ClN3
C18H17N3O
C17H14N5
C15H13N3O
C19H16N4
C13H15N3
C16H19N3
C16H15N3O
C17H21N3
C14H17N3
C23H19N3
78.16
78.21
69.08
69.03
74.23
74.47
69.59
69.62
71.99
71.71
75.71
76.00
73.55
73.24
76.05
75.89
72.47
72.45
76.58
76.40
73.83
74.01
81.87
81.89
5.75
5.66
4.52
4.73
5.84
5.81
6.75
6.48
5.09
5.18
5.30
5.00
6.98
7.04
7.83
7.51
5.68
5.66
8.10
7.86
7.60
7.48
5.77
5.64
16.36
16.09
13.99
14.21
14.48
14.43
23.94
23.80
16.99
16.73
18.62
18.66
19.56
19.72
16.57
16.60
15.70
15.85
15.90
15.73
18.41
18.50
12.50
12.46
91-93
118-119
122-124
138-139
86-87
79
82
94
80
68
79
86
81
75
84
67
78
153-154
104-105
114-115
82-83
2g
2h
2i
2l
89-90
2k
2n
76-77
155-156
1308

TABLE 2. Spectroscopic Characteristics of Compounds 2
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
2a
2b
1575, 2242
1635, 2245
3.16 (4H, m, H-4,5); 5.90 ( 1H, s, CH); 7.30-7.70 (5H, m, HPh)
3.03 (1H, m, H-4); 3.18 (3H, m, H-4,5); 5.77 (1H, s, 1-CH);
7.38 (3H, m, HPh); 7.42 (2H, d, J = 8, HAr); 7.56 (2H, d, J = 8, HAr);
7.67 (2H, m, HPh)
2c
1265, 1620, 2240
1560, 2245
3.14 (4H, m, H-4,5); 3.85 (3H, s, OCH3); 5.88 (1H, s, 1-CH);
6.95 (2H, d, J = 8, HAr); 7.39-7.53 (5H, m, HPh); 7.69 (2H, d, J = 8, HAr)
2d
1.42 (3H, t, J = 7, CH3СН2); 2.28 (3H, s, CH3);
3.09 (4H, m, H-4,5); 4.04 (2H, q, J = 7, CH2СН3); 5.53 (1H, s, CH);
7.20 (1H, s, HPyr); 7.31 (3H, m, HPh); 7.61 (2H, m, HPh)
2e
2f
1570, 2250, 3160
1560, 2250, 3370
2.97 (1H, m, H-4); 3.19 (3H, m, H-4,5); 5.78 (1H, s, CH);
6.37 (1H, m, 5-HFur); 6.55 (1H, m, 4-HFur); 7.31 (3H, m, HPh);
7.42 (1H, m, 3-HFur); 7.62 (2H, m, HPh)
2.95 (1H, m, H-4); 3.23 (3H, m, H-4,5); 6.11 (1H, s, CH);
7.18 (1H, m, 5-Hind); 7.25 (1H, m, 6-HIind); 7.42 (5H, m, HPh);
7.75 (2H, m, 4-Hind, 7-Hind); 7.88 (1H, d, J = 8, 2-Hind);
8.40 (1H, s, NH)
2g
2h
1570, 2235
1570, 2230
1.72 (6H, s, CH3); 3.08 (2H, t, J = 9, H-4); 3.35 (2H, t, J = 9, H-5);
7.35-7.69 (5H, m, HPh)
1.41 (1H, m, с-С6Н10); 1.70 (3H, m, с-С6Н10);
1.87 (4H, m, с-С6Н10); 2.38 (2H, m, с-С6Н10); 3.06 (2H, t,
J = 9, H-4); 3.35 (2H, t, J = 9, H-5); 7.35 (3H, m, HPh);
7.67 (2H, m, HPh)
2i
1520, 2250, 3150
2.03 (3H, s, CH3); 2.74 (1H, m, H-4); 3.04 (1H, m, H-4);
4.37 (1H, m, H-5); 4.87 (1H, s, CH); 6.39 (1H, m, 4-Hfur);
6.61 (1H, m, 3-Hfur); 7.18 (1H, m, 5-Hfur); 7.39 (3H, m, HPh);
7.51 (2H, m, HPh)
2k
2l
1630, 2235
1610, 2230
1590, 2245
1.04 (3H, s, 5-CH3); 1.72 (3H, s, 5-CH3); 1.94 (3H, s, 3-CH3);
2.54 (1H, m, H-4); 3.15 (1H, m, H-4); 4.37 (1H, m, H-5);
7.18-7.33 (5H, m, HPh)
1.10 (2H, m, с-С6Н10); 1.34-1.62 (6H, m, с-С6Н10);
1.78 (2H, m, с-С6Н10); 2.00 (3H, s, CH3); 2.58 (1H, m, H-4);
3.22 (1H, m, H-4); 4.47 (1H, m, H-5); 7.22-7.28 (5H, m, HPh)
2n
3.07 (1H, m, H-4); 3.74 (1H, m, H-4); 4.63 (1H, t, H-5);
5.01 (1H, s, CH); 7.32-7.72 (15H, m, HPh)
From the structures of the pyrazolines synthesized it is seen that the products of selective reduction of
the nitrile group should be derivatives of phenylethylamines which are known for their pharmacological activity
[5]. The conditions for the reduction of nitrile grous are determined in large measure by the nature of the
substituents [6-8], which frequently complicates the process. In fact reduction of compounds 2j,m with an excess
of either LiAlH4 or AlH3 in boiling ether gave a mixture which was difficult to separate. According to chromato-
mass spectrometry, the mixture contained the desired product together with products of exhaustive reduction
with elimination of the benzyl and methylimine groups. In order to avoid processes caused by the presence of the
acidic H-α proton*, conditions for selective reduction were developed using the 1-cyanoalkyl-2-pyrazolines
2h,g,k,l in which an α-H is absent. Reduction of these compounds with aluminum hydride at -4°C and an
increased reaction time of 4 h allowed us to obtain the corresponding amines 4, which were isolated as NHBoc
5o or their benzoyl derivatives 5g,h,k,l*2. In the 1H NMR spectra there are signals of non-equivalent protons of
the CH2 group at 3.44 and 3.73 pp. The nitrile group absorption is absent from the IR spectrum, but bands for the
amide carbonyl group appear in the 1640-1660 cm-1 region.
_______
* Formation of anions occurs even under weakly basic conditions with nitriles having a proton in the α-position
[9].
*2 The hydrochlorides of the amines formed are hygroscopic.
1309

R1
R1
R2
R3
R2
R3
AlH3, cold
O
NEt3, PhCOCl
N
N
N
N
2
NH2
0 oC
N
H
Ph
R4
R4
R5
R5
Boc2O
4
5 a–m
R1
Ph
15% NaOH, 3% H2O2
EtOH
N
R2
R3
N
O
N
NH2
N
R4
-t
N
H
OBu
R5
O
R4
6a, c
5o, p
6 a R4 = Ph; c R4=C6H4OМе-p
Lower reaction temperatures (from ~50 to ~80°C) were necessary for the reduction of 1-α-cyanobenzyl-
2-pyrazolines with a proton α to the nitrile group. The amines produced were also isolated as NHBoc 5p or as
the benzoyl derivatives 5a-f,i,j,m,n. In their 1H NMR spectra the signal of the α-H-1 was shifted to strong field
from ~5.5 to ~4.0 ppm comparison with the pyrazoline starting materials 2 and the signal was split into a
multiplet. Their IR spectra contained an amide carbonyl band at 1640-1660 cm-1, but the nitrile band was absent.
Molecular ions are absent from the mass spectra of these compounds 5, but the fragmentation corresponds to the
proposed structures. The reaction has a general nature, except for 1-cyanobenzyl-3,5-diphenylpyrazoline (2n)
which was recovered unchanged from the reduction reaction under our conditions. It should be noted that
TABLE 3. Characteristics of the Pyrazolines 5
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
5a
5b
5c
5d
5e
5f
C24H23N3O
77.89
78.05
71.42
71.37
74.99
75.19
71.56
71.82
73.21
73.53
76.80
76.47
74.48
74.76
76.88
76.45
73.80
73.99
78.09
78.32
75.50
75.22
76.65
76.80
6.50
6.23
5.64
5.45
6.16
6.26
6.50
6.73
5.85
6.23
5.84
5.88
7.21
7.16
7.36
7.47
6.08
6.17
6.47
6.53
7.29
7.46
7.64
7.73
11.36
11.38
10.30
10.41
10.53
10.53
17.28
17.46
11.96
11.69
13.57
13.72
12.98
13.08
11.41
11.63
11.43
11.26
11.15
10.96
12.28
12.54
11.00
11.20
128-129
154-155
159-160
106-107
94-95
62
72
84
54
62
59
68
71
47
43
52
64
69
C24H22ClN3O
C25H25N3O2
C24H27N5O
C22H21N3O2
C26H24N4O
C20H23N3O
C23H27N3O
C23H23N3O2
C25H25N3O
C24H25N3O
C24H29N3O
C21H25N3O
201-202
82-83
5g
5h
5i
122-123
157-158
98-99
5j
5k
5l
122-123
137-138
112-113
5m
75.52
75.22
7.75
7.46
12.27
12.54
1310

derivatives of 3-methyl-5-phenylpyrazoline were reduced in worse yields than pyrazolines which did not contain
a 5-phenyl substituent (Table 3), so it can be proposed that not only a proton α to the nitrile but also a phenyl
group at position 5 of the pyrazoline affects the reaction.
It is significant that the pyrazoline ring and other heterocyclic substituents at the α-position of nitriles 2
were retained under our reaction conditions.
Hydrolysis of 1-α-cyano derivatives of 2-pyrazolines 2a,c with aqueous-ethanolic NaOH in the presence
of hydrogen peroxide gave the corresponding amides 6a,c in ~40% yield. In their 1H NMR spectra the signal of
α-H-1 is shifted to strong field at ~5.5 to ~4.5 ppm in comparison with the pyrazoline starting materials 2 and
TABLE 4. Spectral Characteristics of Compounds 5
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
5a
5b
1570, 1655,
3310
2.95 (3H, m, Н-4,5); 3.35 (1H, m, H-5); 3.95 (1H, m, CH2);
4.12 (1H, m, CH); 4.27 (1H, m, CH2); 7.32-7.88 (15H, m, HPh)
1565, 1650,
3420
2.95 (3H, m, H-4,5); 3.20 (1H, m, H-5); 3.95 (1H, m, CH2);
4.08 (1H, m, CH); 4,18 (1H, m, CH2); 7.32-7.39 (8H, m, HPh);
7.42 (2H, d, J = 8, HAr); 7.66 (2H, m, HPh); 7.79 (2H, d, J = 8, HAr)
5c
5d
5e
1250, 1620,
1640, 1305
2.91 (3H, m, H-4,5); 3.22 (1H, m, H-5); 3.80 (3H, s, OCH3);
3.95 (1H, m, CH2); 4.06 (1H, m, CH); 4.18 (1H, m, CH2);
6.89 (2H, d, J = 8, HAr); 7.35 (8H, m, HPh); 7.64 (2H, m, HPh);
7.79 (2H, d, J = 8, HAr)
1.42 (3H, t, J = 7, CH3СН2 ); 2.30 (3H, s, CH3); 2.95 (2H, m, H-4);
3.07 (1H, m, H-5); 3.16 (1H, m, H-5); 3.90 (1H, m, CH2);
4.05 (3H, m, CH2, CH); 4.24 (2H, q, J = 7, CH2СН3);
7.25 (1H, s, HPyr); 7.37-7.81 (10H, m, HPh)
1580, 1635,
3350
1570, 1630,
3320
2.98 (2H, m, H-4); 3.22 (2H, m, H-5), 4.09 (1H, m, CH2);
4.24 (1H, m, CH2); 4.47 (1H, m, CH); 6.30 (1H, m, 5-HFur);
6.35 (1H, m, 4-HFur); 7.38-7.50 (8H, m, HPh); 7.65 (1H, m, 3-HFur);
7.81 (2H, m, HPh)
5g
5h
1590, 1650,
3300
1.24 (6H, s, CH3); 2.09 (2H, t, J = 9, H-4); 3.33 (2H, t, J = 9, H-5);
3.75 (2H, d, J = 5.2, CH2); 7.36-7.86 (10H, m, HPh)
1570, 1665,
3430
1.45-1.71 (8H, m, с-С6Н10); 1.85 (2H, m, с-С6Н10); 3.02 (2H, t, J = 9,
H-4); 3.36 (2H, t, J = 9, H-5); 3.71 (2H, d, J = 5, CH2);
7.29-7.45 (6H, m, HPh); 7.63 (2H, m, HPh); 7.75 (2H, m, HPh)
5f
5i
1580, 1630,
3280, 3365
2.86 (2H, m, H-4); 3.04 ( 1H, m, H-5); 3.23 (1H, m, H-5);
4.10 (1H, m, CH2); 4.21 (1H, m, CH2); 4.54 (1H, m, CH);
7.06 (1H, m, 5-Hind); 7.11 (2H, m, 6-Hind, HPh); 7.31 (6H, m, HPh);
7.40 (1H, m, 2-Hind); 7.66 (2H, m, HPh);
7.82 (4H, m, 4-Hind, 7-Hind, HPh); 8.46 (1H, s, NH)
1520, 1650,
3400
2.00 (3Н, s, СН3); 2.89 (1Н, m, Н-4); 3.00 (1Н, m, Н-4);
4.10 (1H, m, CH2); 4.35 (1H, m, CH2); 4.52 (1H, m, CH);
6.30 (1H, m, 5-H Fur); 6.35 (1H, m, 4-HFur); 7.38-7.50 (8H, m, HPh);
7.65 (1H, m, 3-HFur); 7.81 (2H, m, HPh)
5j
1570, 1765,
3420
1.95 (3H, s, CH3); 2.62 (1H, m, H-4); 2.98 (1H, m, H-4);
3.68 (1H, m, CH2); 3.88 (1H, m, CH2); 4.19 (1H, m, H-5);
4.21 (1H, m, СН); 7.19-7.49 (8H, m, HPh); 7.74 (2H, m, HPh)
5k
1580, 1640,
3310
0.89 (3H, s, CH3); 1.12 (3H, s, CH3); 1.97 (3H, s, CH3);
2.57 (1H, m, H-4); 3.15 (1H, m, H-4); 3.44 (1H, m, CH2);
3.74 (1H, m, CH2); 4.48 (1H, m, H-5); 7.30 (3H, m, HPh);
7.38-7.48 (5H, m, HPh); 7.73 (2H, m, HPh)
5l
1530, 1560,
3450
1.10 (1H, m, с-С6Н10); 1.25 (1H, m, с-С6Н10);
1.36-1.60 (8H, m, с-С6Н10); 1.95 (3H, s, CH3); 2.54 (1H, m, H-4);
3.18 (1H, m, H-4); 3.70 (1H, m, CH2); 3.88 (1H, m, CH2);
4.63 (1H, t, J = 11, H-5); 7.19-7.49 (8H, m, HPh); 7.74 (2H, m, HPh)
5m
1540, 1630,
3320
0.78 (3H, s, 5-CH3); 1.17 (3H, s, 5-CH3); 2.00 (3H, s, 3-CH3);
2.45 (2H, dd, J = 14, J = 6, H-4); 3.79 (1H, m, CH2);
3.96 (1H, m, CH2); 4.21 (1H, m, CH); 7.30 (3H, m, HPh);
7.40-7.49 (5H, m, HPh); 7.74 (2H, m, HPh)
1311

signals occur for the NH2 group at 7.08 and 7.49 ppm. Absorption bands corresponding to the amide carbonyl
group occur in the IR spectrum at 1640-1660 cm-1. When the hydrolysis was carried out on an aluminum oxide
surface without solvent but with microwave irradiation according to [10] the nitrile starting materials was only
25% hydrolyzed according to 1H NMR data.
EXPERIMENTAL
The course of reactions was monitored by TLC on Silufol UV-254 strips with 4:1 benzene-ethyl acetate
as eluant and with iodine vapor as developing agent. IR spectra of nujol mulls were recorded with a UR-20
1
machine. H NMR spectra of CDCl3 (3,5,6a) or DMSO-d6 (6c) solutions with TMS as internal standard were
recorded with Varian VXR-400 (400 MHz) and Bruker Avance 400 (400 MHz) machines.
Arylidenium Salts of 2-Pyrazolines 1a-n (General Method) [1, 2]. 50% HBF4 (10 ml) was added
slowly to a solution of 2-pyrazoline (0.1 mol) in methylene chloride (15 ml). An aldehyde or ketone (0.1 mol) in
methylene chloride (5 ml) was added with vigorous stirring and stirring was continued for 2-6 h. The crystals*
which formed were filtered off, washed with water until neutral and then several times with ether. The residue
was recrystallized from ethanol.
1-α-Cyanobenzyl-2-pyrazolines 2a-n (General Method). A solution of a metal cyanide (0.3 mol) in
water (50 ml) was added to a suspension of an arylidenium salt of 2-pyrazoline 1a-n (15 mmol) in ether
(100 ml). The reaction mixture was stirred until the pyrazolinium salt had dissolved completely. The ether layer
was separated, the aqueous layer was extracted with ether, the combined ether extracts were dried over sodium
sulfate and evaporated. The residue was recrystallized from ethanol or ethyl acetate (Tables 1 and 2).
3-Methyl-1-nitroso-5-phenyl-2-pyrazoline (3). Sodium nitrite (4.8 g, 700 mmol) in water (50 ml) was
added to a suspension of the arylidenium salt 1j (2 g, 7 mmol) in ether (100 ml). The reaction mixture was
stirred until the pyrazolinium salt had dissolved completely. The ether layer was separated, the aqueous layer
was extracted with ether, the combined ether extracts were dried over sodium sulfate and evaporated. The yield
of compound 3 was 0.6 g (50%); mp 96-97°C (mp 96.5-97.5°C [7]). IR spectrum, ν, cm-1: 1420 (NO), 1630
(C=N). 1H NMR spectrum, δ, ppm: 2.26 (3H, s, CH3); 2.75 (1H, m, H-4); 3.42 (1H, m, H-4); 5.63 (1H,m, H-5);
7.10-7.32 (5H, m, H Ph).
[β-(4,5-Dihydropyrazol-1-yl)ethyl]benzamides 5a-n (General Method). Pyrazoline 2a-n (5.7 mmol)
was added to a cooled*2 suspension of aluminum hydride (23 mmol), made by the usual method [11], in ether,
the mixture was stirred for 4 h. Water (92 mmol) was added to the mixture at the same temperature, the inorganic
residue was filtered off and washed with THF, the combined organic liquids were dried over potassium
carbonate, and the solvents were evaporated. The residue was dissolved in methylene chloride, cooled to 0°C,
triethylamine (5 mmol) was added followed by benzoyl chloride (5 mmol) which was added dropwise with
vigorous stirring. The reaction mixture was stirred, poured into water, and extracted 4 times with chloroform.
The organic layers were combined, washed with water and soda solution, dried over sodium sulfate, and
evaporated. The residue was recrystallized from ethanol (an oil was chromatographed on a dry column with
benzene).
tert-Butyl 1-(3-Methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)cyclohexyl-1-methylcarbamate (5o).
Nitrile 2l was reduced by the method given above. The oily residue was dissolved in ether, Boc2O (0.7 g,
3.5 mmol) was added with cooling, the mixture was stirred for 6h, evaporated, chromatographed on a dry
_______
* If crystals did not separate, the aqueous layer was separated, the organic layer was washed with water to pH 7,
evaporated, and the residue used in reactions without further purification.
*2 A temperature from -50 to -70°C was used for 1-α-cyanobenzylpyrazolines and a temperature of -4°C for
1-α-cyanobenzyl-2-pyrazolines.
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column, eluted with benzene and then 4:1 benzene–ethyl acetate to give compound 5o, yield 0.8 g (58%);
1
mp 86-87°C. IR spectrum, ν, cm-1: 1635 (C=N), 1715 (C=O), 3440 (NH). H NMR spectrum, δ, ppm (J, Hz):
1.30 (4H, m, c-C6H10); 1.41 (9H, s, CH3); 1.46 (6H, m, c-C6H10); 1.91 (3H, s, 3-CH3); 2.48 (1H, m, H-4); 3.15
(1H, m H-4); 3.44 (2H, d, J = 5.6, CH2); 4.59 (1H, m, H-5); 5.25 (1H, s, NH); 7.27-7.36 (5H, m, HPh). Found, %:
C 71.09; H 8.75; N 11.50. C22H33N3O2. Calculated, %: C 71.15; H 8.89; N 11.32.
tert-Butyl 1-(3,5,5-Trimethyl-4,5-dihydro-1H-pyrazol-1yl)-2-phenylethylcarbamate (5p) was
prepared analogously to 5o. Yield 0.9 g (78%); mp 55-56°C. IR spectrum, ν, cm-1: 1625 (C=N), 1710 (CO),
3290 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 0.74 (3H, s, 5-CH3); 1.17 (3H, s, 5-CH3); 1.41 (9H, s, CH3); 1.93
(3H, s, 3-CH3); 1.84 (2H, s, H-4); 3.49 (1H, m, CH2); 3.56 (1H, m, CH2); 4.07 (1H, m, CH); 5.18 (1H, m, NH);
7.22-7.43 (5H, m, HPh). Found, %: C 69.10; H 8.99; N 12.44. C19H29N3O2. Calculated, %: C 69.88; H 8.76;
N 12.68.
1-(3-Phenyl-4,5-dihydropyrazol-1-yl)phenylacetamide (6a). A solution of 3% hydrogen peroxide
(15 ml) and 15% aqueous sodium hydroxide (0.125 ml) was added dropwise to a hot solution of nitrile 2a (1g,
3 mmol) in ethanol (20 ml). The reaction mixture was boiled until the initial nitrile 2a disappeared (monitored by
TLC). The solvent was evaporated and the residue was recrystallized from ethanol to give amide 6a, 0.5 g,
1
(47%); mp 165-166°C. IR spectrum, ν, cm-1: 1660 (CO), 3455 (NH). H NMR spectrum, δ, ppm: 3.00 (3H, m,
H-4,5); 3.27 (1H, m, H-5); 4.59 (1H, s, CH); 5.74 (1H, s, NH2); 7.11 (1H, s, NH2) 7.22-7.67 (1oH, m, H Ph).
Found, %: C 73.21; H 6.23. C17H17N3O. Calculated, %: C 73.12; H 6.09.
1-(3-Phenyl-4,5-dihydropyrazol-1-yl)(4-methoxyphenyl)acetamide (6c) was made analogously to
amide 6a. Yield 0.7 g (66%); mp 256-257°C. IR spectrum, ν, cm-1: 1260 (CH3O), 1610 (C=N), 1660 (C=O),
1
3420 (NH). H NMR spectrum, δ, ppm (J, Hz): 2.88 (3H, m, H-4,5); 3.17 (1H, m, H-5); 3.74 (3H, s, CH3O);
4.43 (1H, s, CH); 6.89 (2H, d, J = 8, H Ar); 7.08 (1H, s, NH2); 7.37 (5H, m, H Ph); 7.49 (1H, s, NH2); 7.59 (2H, d,
J = 8, H Ar). Found, %: C 69.57; H 5.93; N 13.31. C18H19N3O2. Calculated, %: C 69.90; H 6.15; N 13.59.
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