Synthesis of 5-amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H- pyrazol-3-ones

Article abstract of DOI:10.1055/s-0028-1083183

The reaction 5-amino-2-phenyl-3,4-dihydro-3H-pyrazol-3-one with activated lactams (lactim ethers, lactam acetals, and methylthioalkylidene iminium salts) was investigated. It occurs on the active methylene group of 5-amino-2-phenyl-3,4-dihydro-3H-pyrazol-

Full text of DOI:10.1055/s-0028-1083183

PAPER
3497
Synthesis of 5-Amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-
pyrazol-3-ones
5
-Amino-4-(2-azac
o
ycloalkylide
n
ne)-2-pheny
s
l-2,4-dihy
t
dro-3
H
a
-pyrazol-3-
n
ones tin G. Nazarenko,*a Sergey I. Bova,b Vitaliy Polovinko,c Andrey A. Tolmachevc
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska st., Kyiv 02094, Ukraine
Fax +380(44)5732643; E-mail: nazarenko@ioch.kiev.ua
b
c
Chernigiv State Technological University, 95 Shevchenko st., Chernigiv 14027, Ukraine
Research and Development Center for Chemistry and Biology, National Taras Shevchenko University,
62 Volodymyrska st., Kyiv 01033, Ukraine
Received 24 June 2008; revised 7 July 2008
eral nucleophilic centers including an active methylene
and an amino group.10 The reaction in question proceeds
in two steps: compound 4 is first heated to 145 °C with an
excess of 2c to form a product, presumably the O-substi-
Abstract: The reaction 5-amino-2-phenyl-3,4-dihydro-3H-pyra-
zol-3-one with activated lactams (lactim ethers, lactam acetals, and
methylthioalkylidene iminium salts) was investigated. It occurs on
the active methylene group of 5-amino-2-phenyl-3,4-dihydro-3H-
pyrazol-3-one to furnish cyclic enamines, 5-amino-4-(2-azacy- tuted 3-aminopyrazole 5 (Figure 2), which, if heated fur-
cloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones and 5-
ther with 2c at 180 °C for 6 hours, furnishes compound 6
amino-4-(1-methyl-2-azacycloalkylidene)-2-phenyl-2,4-dihydro-
patented as a muscle relaxant. Structures 5 and 6 assigned
3H-pyrazol-3-ones.
to the products in the literature11 appear unsupported by
any evidence and hence doubtful. According to literature
data, the carbonyl oxygen atom of 4 can be electrophili-
Key words: lactams, pyrazolone, cyclic enamine, ring opening,
heterocycles
cally attacked only in acylation reactions (which provide
a mixture of N-acyl and N,O-diacyl derivatives),11 where-
Compounds 1 representing bridged 1,3-dicarbonyl het-
eroanalogues (Figure 1) are conveniently employed in the
synthesis of various heterocyclic w-aminoalkyl deriva-
tives, synthetic pharmaceuticals, unnatural a-amino acids,
etc.1 One of the synthetic routes to 1 involves the reaction
between lactim ethers 2 or lactam acetals 3 and 1,3-dinu-
cleophiles, with the latter mostly exemplified by 1,3-SCN
(thioamides) and 1,3-NCN (a-aminoazaheterocycles)
compounds. The resultant substituted amidines 1 (X = N,
Y = S, NR) have been widely used to prepare w-ami-
as reactions with amides and their activated forms (in
DMF-DMA)12 involve the methylene group. As com-
pound 2c is the activated form of caprolactam, one can as-
sume that its reaction with 4 begins with an attack on the
4-C atom of the pyrazolone ring. To verify this conjecture
and to obtain new pyrazole-based building blocks for the
synthesis of w-aminoalkyl-substituted heterocycles, we
have studied the reaction of 5-amino-2-phenyl-3,4-dihy-
dro-5H-pyrazol-3-one (4) with a number of activated lac-
tams, namely, lactim ethers 2a–d, lactam acetals 3, and
methylthioalkylidene iminium salts 9c–d.
noalkyl-functionalized
thiazoles,2
imida-
zoles,3isoxazoles,4 1,2,4-triazoles,5 1,2,4-thiadiazoles,6
and bicyclic heterocycles.7
( )3
( )3
HN
NH2
NH2
N
( )3
O
N
N
( )n
( )n
N
N
O
N
( )n
O
N
N
OMe
OMe
N
Ph
6
X
Y
N
Ph
N
Ph
OMe
N
R
R
4
5
1: R = H, Alk;
X = CR1, N;
Y = S, NR2
2 a–d
3
Figure 2 Pyrazoles 4–6
Figure 1 Amidines 1, lactim ethers 2, and lactam acetals 3
First of all, we reacted 4 with 2c under various conditions
including heating at 150 °C with 2c used as a solvent and
also in refluxing DMF, toluene, and dioxane. In all cases,
the same product was formed, its melting point coinciding
Much less attention has been given to the reaction of 2 or
3 with 1,3-CCN dinucleophiles represented, as a rule, by
cyanoacetamides8 and 2-hetarylacetonitriles.9 The litera-
ture reports a nontrivial example in which O-methylca-
prolactam (2c) is reacted with 5-amino-2-phenyl-3,4-
dihydro-5H-pyrazol-3-one (4), a compound bearing sev-
1
with that of compound 5.10 However, IR, H, and 13C
NMR spectra as well as the data of 2D NMR (NOESY and
HMBC) experiments suggest that the compound obtained
has the structure of 5-amino-4-(hexahydro-2H-azepin-2-
ylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(7c)
(see Figure 3) rather than 3-amino-1-phenyl-5-(3,4,5,6-
SYNTHESIS 2008, No. 21, pp 3497–3503
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083183; Art ID: P07008SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
tetrahydro-2H-azepin-7-yloxy)-1H-pyrazole (5). In par-
1
ticular, the H NMR signal of the perhydroazepine NH
group appears at 11.2 ppm as a triplet (J = 5.2 Hz) due to

3498
K. G. Nazarenko et al.
PAPER
spin-spin coupling with the neighboring 7-CH2 group of At the same time, we failed to prepare any of pyrrolidine
the same ring. The amino group gives rise to a broad sin- derivatives 8 (m = 1). As O-methylbutyrolactim (2c)
glet at 4.96 ppm which disappears on adding D2O. The 13C needed to obtain the corresponding product is not suffi-
NMR spectrum exhibits a signal at 90.6 ppm assigned to ciently high-boiling, the reaction was run in a closed reac-
the pyrazolone 4-C atom. As seen from 1H-13C HMBC da- tor or, alternatively, with S-methylbutyrothiolactim
ta, this atom shows a cross-peak with the 3-CH2 group of having a higher boiling point. Nevertheless, complex mix-
the perhydroazepine ring at 2.87 ppm (Figure 3). Out of tures of products resulted in all cases; they contained com-
two theoretically possible isomers of such enamines,13 pounds with an open polymethylene chain, as evidenced
1
only the Z-isomer was always formed for 7c, with the NH by H NMR spectra. Products of this kind are probably
group and the carbonyl oxygen atom intramolecularly H- formed by an intramolecular reaction between the enam-
bonded. This relative disposition of the perhydroazepine ine and amidine moieties in compounds 8 at m = 1, which
1
and pyrazolone rings was determined from the H-1H should lead to the formation of the pyrazolo[3,4-d]pyrim-
NOESY correlation between the amino and perhy- idine nucleus12b and, accordingly, to the cleavage of one
droazepine 3-CH2 groups (Figure 3).
pyrrolidine ring.
2.81–2.86, m
( )n
( )m
HN
N
H
H
i
NOESY
NH2
7a–d
2b–d
+
HN
N
N
O
N
H
8a n = m = 2 (56%)
b n = m = 3 (78%)
c n = m = 4 (61%)
d n = 1, m = 3 (52%)
e n = 2, m = 3 (48%)
f n = 3, m = 4 (56%)
g n = 4, m = 2 (63%)
Ph
90.6
N
O
4.96, br s
N
Ph
HMBC correlations
Figure 3 NOESY and HMBC correlations for 7c
Scheme 2 Reagents and conditions: (i) oil bath, 160 °C, 6–8 h
Like 2c, the other lactim ethers 2a,b,d react with pyra-
zolone 4 via initial attack on its active methylene group
leading to the Z-isomers of enamines 7a,b,d (see
Scheme 1). Compounds 7 are most conveniently obtained
by boiling 4 with a slight excess of lactim ether 2 in tolu-
ene for 7–8 hours. On cooling the reaction mixture, the re-
sulting products precipitate in a fairly pure state and in
64–83% yields.
Compounds 8 were structurally determined by a combina-
tion of spectral methods. Unlike the starting enamines 7a–
d, which do not exhibit enamine-imine tautomerism,
products 8 exist as two tautomers, with the endo- and exo-
cyclic double bond, due to the N,N-prototropic shift in the
amidine moiety.14 As a result, two characteristic signal
sets are observed in their 1H and 13C NMR spectra.
Just as lactim ethers 2 react with pyrazolones 4 attacking
their active methylene group, so do lactam acetals 3. For
instance, boiling compound 4 in toluene with a 10% ex-
cess of the dimethyl acetal of N-methylcaprolactam 3
(R = Me) furnishes condensation product 10c in 65%
yield, along with a small amount of unreacted 4
(Scheme 3). As found, compounds 10 are prepared more
easily using methylthioalkylidene iminium salts 9 instead
of lactam acetals 3 in the reaction with pyrazolones 4.
Salts 9a–d, readily formed by the alkylation of the corre-
sponding thiolactams15 or thiolactim ethers,16 are stable in
storage and smoothly react with active methylene com-
pounds in the presence of bases.17 We have established
that their condensation with 4 occurs already at room tem-
perature, if conducted in DMF in the presence of excess
potassium carbonate. The reaction proceeds exclusively at
the active methylene group of 4 to afford products 10a–d
in yields up to 80–85%. Their 1H and 13C NMR spectra are
similar to those of compounds 7a–d, and the NOESY
cross-peaks between the amino group and the 3-CH2
group of the saturated ring suggest the Z-configuration, as
in 7.
( )n
NH2
HN
NH2
( )n
toluene, reflux, 8 h
+
N
O
OMe
N
N
N
O
N
Ph
Ph
2a–d
4
7a (64%)
b (76%)
c (83%)
d (84%)
a n = 1, b n = 2, c n = 3, d n = 4
Scheme 1 Reaction of lactim ethers 2a–d with 4
The second stage of the reaction involves the amino group
and requires more severe conditions than the condensa-
tion at the active methylene group. On boiling enamines
7a–d at 160–170 °C in a three-fold excess of an appropri-
ate lactim ether, the alkoxy group of the latter is replaced
by the amino group to give compounds 8a–g (Scheme 2).
Depending on the reagents used, products 8 contain two
saturated rings of the same (m = n) or different (m ≠ n)
sizes. In the former case, it is unnecessary to carry out the
reaction in two stages: initial pyrazolone 4 is merely
boiled in an excess of appropriate lactim ether 2 at 170 °C.
Synthesis 2008, No. 21, 3497–3503 © Thieme Stuttgart · New York

PAPER
5-Amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones
3499
of 12c goes to completion within 2–2.5 h at room temper-
ature and 10–15 minutes at boiling in 10% aqueous alkali,
whereas 7c and 10c remain unchanged under the same
conditions. It is evident that the endocyclic C=N bond in
12c undergoes hydrolytic cleavage in alkaline medium, in
contrast to the alkali-resistant enamine moiety in 7c and
10c.
( )n
NH2
( )n
N
NH2
K2CO3, DMF, r.t.
Me
SMe
+
N+
N
O
N
N
O
Me
I–
N
Ph
Ph
9a–d
4
10a (85%)
b (67%)
c (87%)
d (65%)
In conclusion, we have established that lactim ethers 2,
lactam acetals 3, and methylthioalkylidene iminium salts
9 react with 5-amino-2-phenyl-3,4-dihydro-3H-pyrazol-
3-one (4) via initial attack on its active methylene group
to furnish enamines 7 and 10. Compounds 7 can be con-
verted to derivatives 8 by the reaction with the second
equivalent of the lactim ether under more severe condi-
tions. Treatment of 7 with methyl iodide leads to alkyla-
tion at the pyrazolone 1-N atom thus affording derivatives
12a–d. As a further research, newly obtained compounds
7a–d, 8a–d, 10a–d, and 12a–d will be used to prepare
fused pyrazoles and their w-aminoalkyl derivatives.
a n = 1, b n = 2, c n = 3, d n = 4
Scheme 3 Reaction of methylthioalkylidene iminium salts 9a–d
with 4
One of the main objectives of the present study was to ob-
tain the pyrazole derivatives, which could be further used
in the synthesis of heterocyclic w-aminoalkyl compounds.
In this context, the alkylation products of enamines 7 ap-
pear to be relevant intermediates. We have found that the
regioselective 1-N methylation of the pyrazolone ring is
achieved by boiling 7 with an excess of methyl iodide in
acetonitrile (Scheme 4). The resultant (unpurified) salts
11 were cautiously treated with triethylamine to provide
the corresponding bases 12a–d.
The starting lactim ethers 1a–d were prepared as reported.18 Ami-
nophenylpyrazol-3-one was commercially available. All solvents
were purified by standard methods. All melting points were deter-
mined in open capillary tubes in a Thiele apparatus and are uncor-
rected. IR spectra for KBr tablets were obtained on a Pye Unicam
SP 3-300 apparatus. 1H NMR (400 MHz) spectra were recorded on
a Varian Mercury-400 spectrometer in DMSO-d6 solution with
TMS as an internal standard. 13C NMR (125 MHz) spectra were re-
corded on a Bruker Avance DRX 500 spectrometer in DMSO-d6 so-
Unlike cyclic enamines 7 and 10, compounds 12 exist as
imines with the endocyclic double bond in the saturated
ring. The most essential indication of the imine form is
given by the spectral characteristics of 12 different from
those of 7 and 10. The 1H NMR spectra of 12 lack the NH
signal at 11.2 ppm, whereas the broad singlet of the amino
group is observed in the region 8.0–8.5 ppm. The 13C lution with TMS as an internal standard. LC/MS spectra were
recorded using chromatography/mass spectrometric system that
consists of high-performance liquid chromatograph ‘Agilent 1100
Series’ equipped with diode-matrix and mass-selective detector
NMR spectra of the products mainly differ by the reso-
nances of the pyrazolone ring: for compounds 12, the 5-C
signal is found in the region 163–165 ppm (cf. 152 ppm
‘Agilent LC/MSD SL’. The parameters of chromatography-mass
for 7 and 10) and the 4-C signal at 85 ppm (5 ppm upfield
analysis are: column: Zorbax SB-C18, 1.8 mm × 4.6 mm × 15 mm;
from the corresponding peak of 7 and 10).
solvents: A, MeCN–H2O (95:5), 0.1% TFA; B, H2O (0.1% of TFA);
eluent flow: 3 mL/sec; volume of injected sample: 1 mL; UV-detec-
tors at 215, 254, and 265 nm; ionization method: chemical ioniza-
tion under atmospheric pressure (APCI); ionization mode:
simultaneous scanning of positive and negative ions in the mass
range of 80–1000 m/z. Microanalyses were performed in the Mi-
croanalytical Laboratory of the Institute of Organic Chemistry, Na-
The presence of the imine function in compounds 12a–d
is also evidenced by their higher sensitivity to nucleo-
philes as compared to enamines 7 and 10. To exemplify,
treatment of compound 12c or the corresponding salt 11
with aqueous alkali yields 5-amino-4-(6-aminohexanoyl)-
1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (13) as tional Academy of Sciences of Ukraine.
a result of opening of the saturated ring. This conversion
( )n
( )n
( )n
NH2
HN
NH2
HN
NH2
N
MeI, MeCN, 80 °C
Et3N, DMF
I–
Me
N
N+
N
Me
O
O
O
N
N
N
Ph
Ph
Ph
7a–d
12a (58%)
b (69%)
c (75%)
d (68%)
11 n = 3
H2N
a n = 1, b n = 2, c n = 3, d n = 4
O
NH2
OH– , H2O
N
Me
13 (86%)
O
N
Ph
Scheme 4 Alkylation of enamines 7 with MeI
Synthesis 2008, No. 21, 3497–3503 © Thieme Stuttgart · New York

3500
K. G. Nazarenko et al.
PAPER
Compounds 7a–d; General Procedure
Anal. Calcd for C16H20N4O: C, 67.58; H, 7.09.71; N, 19.70. Found:
C, 67.61; H, 7.11; N, 19.74.
An appropriate lactim ether 2a–d (60 mmol) was added to a stirred
suspension of 4 (8.75 g, 50 mmol) in toluene (300 mL) and the mix-
ture was refluxed for 8 h. After cooling to r.t., the precipitate was
filtered, washed with i-PrOH (2 × 25 mL), and recrystallized from
i-PrOH.
Compounds 8a–g; General Procedure
A mixture of compound 7a–d (10 mmol) and the appropriate lactim
ether 2b–d (30 mmol) was heated in an oil bath at 160 °C for 6–8 h.
After cooling, resulting solid was recrystallized from MeCN. The
5-Amino-2-phenyl-4-(2-pyrrolidinylidene)-2,4-dihydro-3H-
pyrazol-3-one (7a)
compounds were prepared as a mixture of two isomers. 1H and 13
NMR signals of major isomers are given.
C
Yield: 7.74 g (32 mmol, 64%); brown solid; mp 232 °C.
2-Phenyl-4-(2-piperidinylidene)-5-(2-piperidinylideneamino)-
2,4-dihydro-3H-pyrazol-3-one (8a)
Yield: 1.89 g (5.6 mmol, 56%); yellow solid; mp 178 °C.
IR (KBr): 2950, 2880, 1660, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.56–1.75 (m, 6 H, CH2),
2.49–2.58 (m, 6 H, CH2), 3.09–3.26 (m, 2 H, CH2), 3.31–3.46 (m, 2
H, CH2), 6.97 (t, J = 7.0 Hz, 1 H, Ar), 7.28 (t, J = 7.5 Hz, 2 H, Ar),
7.98 (d, J = 7.8 Hz, 2 H, Ar), 9.72 (br s, 1 H, NH), 11.28 (br s, 1 H,
NH).
IR (KBr): 3430, 3320, 3280, 3200, 2960, 1640, 1590 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.02 (quint, J = 7.6 Hz, 2 H,
CH2), 3.08 (t, J = 8.2 Hz, 2 H, CH2), 3.62 (t, J = 7.6 Hz, 2 H, CH2),
5.15 (s, 2 H, NH2), 6.96 (t, J = 7.2 Hz, 1 H, Ar), 7.29 (t, J = 8.0 Hz,
2 H, Ar), 7.97 (d, J = 7.6 Hz, 2 H, Ar), 9.85 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 20.7, 31.9, 48.3, 88.9, 117.3,
122.2, 128.9, 140.6, 152.5, 164.7, 167.3.
MS (APSI): m/z = 243 [M + 1]+.
13C NMR (125 MHz, DMSO-d6): d = 17.6, 19.6, 20.9, 21.6, 25.2,
30.6, 39.5, 41.3, 90.3, 117.5, 122.4, 128.3, 140.1, 155.2, 160.7,
162.8, 166.9.
Anal. Calcd for C13H14N4O: C, 64.25; H, 5.82; N, 23.13. Found: C,
64.41; H, 5.78; N, 23.21.
5-Amino-2-phenyl-4-(2-piperidinylidene)-2,4-dihydro-3H-
pyrazol-3-one (7b)
MS (APSI): m/z = 338 [M + 1]+.
Yield: 9.72 g (38 mmol, 76%); yellow solid; mp 179 °C.
IR (KBr): 3400, 3320, 3230, 3080, 2970, 1625, 1595 cm–1.
Anal. Calcd for C19H23N5O: C, 67.63; H, 6.87; N, 20.76. Found: C,
67.58; H, 6.79; N, 20.72.
1H NMR (400 MHz, DMSO-d6): d = 1.78–1.84 (m, 4 H, CH2),
2.89–2.93 (m, 2 H, CH2), 3.47–3.51 (m, 2 H, CH2), 4.94 (s, 2 H,
NH2), 6.96 (t, J = 7.2 Hz, 1 H, Ar), 7.29 (t, J = 8.1 Hz, 2 H, Ar), 7.32
(d, J = 7.8 Hz, 2 H, Ar), 11.14 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 18.7, 21.3, 28.1, 41.7, 90.0,
117.6, 122.5, 128.9, 140.4, 152.5, 164.7, 165.8.
4-Hexahydro-2H-azepin-2-ylidene-5-(hexahydro-2H-azepin-2-
ylideneamino)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (8b)
Yield: 2.85 g (7.8 mmol, 78%); yellow solid; mp 194 °C.
IR (KBr): 2940, 2860, 1650, 1620, 1590 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.62–1.79 (m, 12 H, CH2),
2.57–2.62 (m, 2 H, CH2), 3.43–3.56 (m, 6 H, CH2), 6.99 (t, J = 7.0
Hz, 1 H, Ar), 7.29 (t, J = 7.5 Hz, 2 H, Ar), 7.93 (d, J = 7.8 Hz, 2 H,
Ar), 9.87 (br s, 1 H, NH), 11.43 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 23.9, 24.1, 24.5, 25.1, 28.1,
29.2, 29.8, 30.0, 36.3, 43.4, 90.8, 117.7, 122.3, 128.2, 139.8, 155.7,
162.7, 167.1, 173.2.
MS (APSI): m/z = 257 [M + 1]+.
Anal. Calcd for C14H16N4O: C, 61.61; H, 6.29; N, 21.86. Found: C,
61.58; H, 6.34; N, 21.83.
5-Amino-4-hexahydro-2H-azepin-2-ylidene-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (7c)
Yield: 11.20 g (41.4 mmol, 83%); yellow solid; mp 191 °C.
MS (APSI): m/z = 366 [M + 1]+.
Anal. Calcd for C19H23N5O: C, 68.35; H, 7.17; N, 19.93. Found: C,
68.38; H, 7.15; N, 19.92.
IR (KBr): 3370, 3320, 3230, 3080, 3050, 2940, 1620, 1595 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.59–1.78 (m, 6 H, CH2),
2.81–2.86 (m, 2 H, CH2), 3.56–3.61 (m, 2 H, CH2), 4.96 (s, 2 H,
NH2), 6.96 (t, J = 7.2 Hz, 1 H, Ar), 7.27 (t, J = 8.1 Hz, 2 H, Ar), 7.95
(d, J = 7.8 Hz, 2 H, Ar), 11.24 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 24.7, 28.4, 28.9, 30.1, 44.1,
90.6, 117.7, 122.7, 128.9, 140.1, 152.4, 164.9, 171.7.
4-Hexahydro-2(1H)-azocinylidene-5-[hexahydro-2(1H)-azoci-
nylideneamino]-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (8c)
Yield: 2.40 g (6.1 mmol, 61%); yellow solid; mp 174 °C.
IR (KBr): 2940, 2870, 1660, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.51–1.79 (m, 16 H, CH2),
2.53–2.57 (m, 2 H, CH2), 3.20–3.37 (m, 6 H, CH2), 7.03 (t, J = 7.2
Hz, 1 H, Ar), 7.32 (t, J = 8.2 Hz, 2 H, Ar), 7.93 (d, J = 7.8 Hz, 2 H,
Ar), 9.71 (br s, 1 H, NH), 11.40 (br s, 1 H, NH).
MS (APSI): m/z = 271 [M + 1]+.
Anal. Calcd for C15H18N4O: C, 66.64; H, 6.71; N, 20.73. Found: C,
66.58; H, 6.73; N, 20.76.
13C NMR (125 MHz, DMSO-d6): d = 24.0, 24.6, 24.7, 25.0, 25.6,
29.8, 30.0, 30.4, 32.2, 32.8, 39.5, 43.5, 91.1, 118.0, 123.3, 129.0,
140.4, 156.5, 163.0, 166.4, 172.1.
5-Amino-4-hexahydro-2(1H)-azocinylidene-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (7d)
Yield: 11.50 g (40.4 mmol, 81%); yellow solid; mp 165 °C.
IR (KBr): 3370, 3320, 3230, 3080, 3050, 2940, 1620, 1595 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.47–2.01 (m, 8 H, CH2),
2.84–2.87 (m, 2 H, CH2), 3.64–3.73 (m, 2 H, CH2), 4.97 (s, 2 H,
NH2), 6.94 (t, J = 7.2 Hz, 1 H, Ar), 7.25 (t, J = 8.1 Hz, 2 H, Ar), 7.94
(d, J = 7.8 Hz, 2 H, Ar), 11.20 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 25.1, 25.4, 25.6, 29.3, 32.4,
44.7, 90.2, 117.6, 122.7, 128.9, 140.2, 152.1, 165.1, 170.2.
MS (APSI): m/z = 394 [M + 1]+.
Anal. Calcd for C23H31N5O: C, 70.20; H, 7.97; N, 17.80. Found: C,
70.18; H, 7.95; N, 17.75.
5-(Hexahydro-2H-azepin-2-ylideneamino)-2-phenyl-4-(2-pyr-
rolidinylidene)-2,4-dihydro-3H-pyrazol-3-one (8d)
Yield: 1.75 g (5.2 mmol, 52%); yellow solid; mp 211 °C.
IR (KBr): 2940, 2880, 1660, 1620, 1600 cm–1.
MS (APSI): m/z = 286 [M + 1]+.
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5-Amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones
3501
1H NMR (400 MHz, CDCl3): d = 1.63–1.81 (m, 6 H, CH2), 2.12
(quint, J = 7.6 Hz, 2 H, CH2), 2.57 (t, J = 7.8 Hz, 2 H, CH2), 3.28–
3.44 (m, 4 H, CH2), 3.66 (t, J = 7.2 Hz, 2 H, CH2), 7.04 (t, J = 7.0
Hz, 1 H, Ar), 7.32 (t, J = 8.0 Hz, 2 H, Ar), 7.98 (d, J = 6.4 Hz, 2 H,
Ar), 9.76 (br s, 1 H, NH), 9.96 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 20.4, 24.7, 29.5, 31.1, 36.0,
39.5, 43.1, 47.8, 90.3, 117.3, 122.0, 128.3, 140.0, 155.8, 163.6,
167.2, 169.1.
Compounds 10a–d; General Procedure
A solution of compound 9a–d (10 mmol) in anhyd DMF (50 mL)
was added in one portion to a suspension of 4 (1.75 g, 10 mmol) and
K2CO3 (1.38 g, 10 mmol) in DMF (50 mL) at r.t. The resulting mix-
ture was stirred for 5 h. H2O (300 mL) was added and solid was iso-
lated by filtration, washed with H2O (1 × 50 mL), and recrystallized
from DMF.
5-Amino-4-(1-methyl-2-pyrrolidinylidene)-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (10 a)
MS (APSI): m/z = 338 [M + 1]+.
Yield: 2.18 g (8.5 mmol, 85%); yellow solid; mp 239 °C.
IR (KBr): 3320, 3200, 3080, 2970, 1640, 1590 cm–1.
Anal. Calcd for C19H23N5O: C, 67.63; H, 6.87; N, 20.76. Found: C,
67.59; H, 6.78; N, 20.74.
1H NMR (400 MHz, DMSO-d6): d = 2.02 (quint, J = 7.2 Hz, 2 H,
CH2), 3.18 (t, J = 8.2 Hz, 2 H, CH2), 3.40 (s, 3 H, CH3), 3.67 (t,
J = 7.6 Hz, 2 H, CH2), 4.99 (s, 2 H, NH2), 6.95 (t, J = 8.0 Hz, 1 H,
Ar), 7.26 (t, J = 7.0 Hz, 2 H, Ar), 7.95 (d, J = 7.0 Hz, 2 H, Ar).
13C NMR (125 MHz, DMSO-d6): d = 20.7, 35.6, 40.0, 58.1, 88.1,
117.6, 122.0, 128.7, 140.9, 153.4, 162.1, 168.6.
5-(Hexahydro-2H-azepin-2-ylideneamino)-2-phenyl-4-(2-pipe-
ridinylidene)-2,4-dihydro-3H-pyrazol-3-one (8e)
Yield: 1.68 g (4.8 mmol, 48%); yellow solid; mp 198 °C.
IR (KBr): 2950, 2870, 1670, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.67–1.77 (m, 8 H, CH2),
2.49–2.60 (m, 2 H, CH2), 3.09–3.19 (m, 4 H, CH2), 3.38–3.47 (m, 4
H, CH2), 6.97 (t, J = 7.2 Hz, 1 H, Ar), 7.28 (t, J = 8.1 Hz, 2 H, Ar),
7.94 (d, J = 7.8 Hz, 2 H, Ar), 9.86 (br s, 1 H, NH), 11.20 (br s, 1 H,
NH).
MS (APSI): m/z = 257 [M + 1]+.
Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C,
65.58; H, 6.35; N, 21.89.
13C NMR (125 MHz, DMSO-d6): d = 17.6, 20.9, 24.6, 25.2, 29.6,
29.8, 36.8, 41.11, 43.2, 90.5, 117.5, 122.7, 128.3, 139.9, 155.2,
162.7, 166.9, 167.1.
5-Amino-4-(1-methyl-2-piperidinylidene)-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (10b)
Yield: 1.80 g (6.7 mmol, 67%); yellow solid; mp 239 °C.
IR (KBr): 3330, 3200, 2960, 1630, 1595, 1560 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.69–1.80 (m, 4 H, CH2),
3.10–3.13 (m, 2 H, CH2), 3.35 (s, 3 H, CH3), 3.50–3.53 (m, 2 H,
CH2), 4.76 (s, 2 H, NH2), 6.88 (t, J = 7.5 Hz, 1 H, Ar), 7.24 (t,
J = 7.0 Hz, 2 H, Ar), 7.98 (d, J = 8.5 Hz, 2 H, Ar).
13C NMR (125 MHz, DMSO-d6): d = 18.0, 21.4, 29.1, 45.6, 51.9,
89.5, 116.8, 120.1, 128.1, 140.7, 152.0, 162.7, 169.2.
MS (APSI): m/z = 352 [M + 1]+.
Anal. Calcd for C19H23N5O: C, 68.35; H, 7.17; N, 19.93. Found: C,
68.38; H, 7.15; N, 19.92.
4-Hexahydro-2H-azepin-2-ylidene-5-[hexahydro-2(1H)-azoci-
nylideneamino]-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (8f)
Yield: 2.12 g (5.6 mmol, 56%); yellow solid; mp 145 °C.
IR (KBr): 2940, 2860, 1660, 1620, 1590 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.54–1.80 (m, 14 H, CH2),
2.57–2.68 (m, 2 H, CH2), 3.45–3.56 (m, 6 H, CH2), 7.04 (t, J = 7.2
Hz, 1 H, Ar), 7.32 (t, J = 8.2 Hz, 2 H, Ar), 7.95 (d, J = 7.8 Hz, 2 H,
Ar), 9.73 (br s, 1 H, NH), 11.51 (br s, 1 H, NH).
MS (APSI): m/z = 271 [M + 1]+.
Anal. Calcd for C15H18N4O: C, 66.64; H, 6.71; N, 20.73. Found: C,
66.58; H, 6.78; N, 20.69.
5-Amino-4-(1-methylhexahydro-2H-azepin-2-ylidene)-2-phe-
nyl-2,4-dihydro-3H-pyrazol-3-one (10c)
Yield: 2.47 g (8.7 mmol, 87%); yellow solid; mp 222 °C.
13C NMR (125 MHz, DMSO-d6): d = 24.1, 25.2, 27.9, 28.2, 29.6,
30.0, 31.7, 32.2, 39.9, 41.2, 43.6, 90.7, 117.6, 122.3, 128.3, 139.8,
156.0, 163.9, 165.9, 173.1.
IR (KBr): 3390, 3320, 3200, 3070, 3040, 2970, 2920, 1630, 1590,
1560 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.59–1.81 (m, 6 H, CH2),
3.12–3.15 (m, 2 H, CH2), 3.35 (s, 3 H, CH3), 3.53–3.68 (m, 2 H,
CH2), 4.76 (s, 2 H, NH2), 6.90 (t, J = 7.2 Hz, 1 H, Ar), 7.21 (t,
J = 8.0 Hz, 2 H, Ar), 7.93 (d, J = 8.2 Hz, 2 H, Ar).
13C NMR (125 MHz, DMSO-d6): d = 24.0, 24.7, 28.2, 31.3, 46.1,
53.9, 91.8, 116.8, 121.4, 128.0, 140.5, 151.9, 161.5, 172.6.
MS (APSI): m/z = 285 [M + 1]+.
MS (APSI): m/z = 380 [M + 1]+.
Anal. Calcd for C22H29N5O: C, 69.63; H, 7.70; N, 18.45. Found: C,
69.58; H, 7.74; N, 18.43.
4-Hexahydro-2(1H)-azocinylidene-2-phenyl-5-(2-piperidi-
nylideneamino)-2,4-dihydro-3H-pyrazol-3-one (8g)
Yield: 2.29 g (6.3 mmol, 63%); yellow solid; mp 191 °C.
IR (KBr): 2950, 2870, 1660, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.51–1.80 (m, 12 H, CH2),
2.45–2.56 (m, 2 H, CH2), 3.18–3.49 (m, 6 H, CH2), 6.99 (t, J = 7.2
Hz, 1 H, Ar), 7.29 (t, J = 8.0 Hz, 2 H, Ar), 7.95 (d, J = 7.6 Hz, 2 H,
Ar), 9.64 (br s, 1 H, NH), 11.28 (br s, 1 H, NH).
Anal. Calcd for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C,
67.51; H, 7.12; N, 19.69.
5-Amino-4-[1-methylhexahydro-2(1H)-azocinylidene]-2-phe-
nyl-2,4-dihydro-3H-pyrazol-3-one (10d)
Yield: 1.94 g (6.5 mmol, 65%); yellow solid; mp 177 °C.
13C NMR (125 MHz, DMSO-d6): d = 19.6, 21.6, 23.5, 24.6, 25.1,
28.6, 30.7, 31.6, 41.1, 41.4, 90.5, 117.6, 122.2, 128.3, 139.4, 155.8,
159.5, 160.8, 171.4.
IR (KBr): 3410, 3280, 3230, 3070, 3050, 2940, 1630, 1590, 1540
cm–1.
MS (APSI): m/z = 366 [M + 1]+.
Anal. Calcd for C21H27N5O: C, 69.01; H, 7.45; N, 19.16. Found: C,
69.08; H, 7.51; N, 19.22.
1H NMR (400 MHz, DMSO-d6): d = 1.33–1.44 (m, 4 H, CH2),
1.72–1.76 (m, 4 H, CH2), 3.04–3.07 (m, 2 H, CH2), 3.38 (s, 3 H,
CH3), 3.75–3.83 (m, 2 H, CH2), 4.95 (s, 2 H, NH2), 6.90 (t, J = 7.0
Hz, 1 H, Ar), 7.25 (t, J = 7.5 Hz, 2 H, Ar), 7.96 (d, J = 8.2 Hz, 2 H,
Ar).
Synthesis 2008, No. 21, 3497–3503 © Thieme Stuttgart · New York

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K. G. Nazarenko et al.
PAPER
13C NMR (125 MHz, DMSO-d6): d = 20.9, 25.2, 28.5, 29.9, 31.3,
43.9, 51.2, 89.7, 116.7, 120.9, 128.1, 140.6, 151.9, 161.5, 173.5.
5-Amino-4-(3,4,5,6,7,8-hexahydro-2-azocinyl)-1-methyl-2-phe-
nyl-1,2-dihydro-3H-pyrazol-3-one (12d)
Yield: 4.05 g (13.6 mmol, 68%); white solid; mp 206 °C.
IR (KBr): 3380, 3200, 2930, 1610, 1590 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.34–1.35 (m, 4 H, CH2),
1.55–1.60 (m, 4 H, CH2), 2.91–2.93 (m, 2 H, CH2), 2.99 (s, 3 H,
CH3), 3.58–3.60 (m, 2 H, CH2), 7.17 (t, J = 7.0 Hz, 1 H, Ar), 7.29
(d, J = 7.5 Hz, 2 H, Ar), 7.39 (t, J = 7.5 Hz, 2 H, Ar), 8.21 (br s, 2
H, NH2).
13C NMR (125 MHz, DMSO-d6): d = 24.4, 24.7, 25.6, 28.1, 31.0,
36.3, 45.5, 84.7, 121.8, 124.5, 128.6, 138.0, 164.5, 165.7, 169.4.
MS (APSI): m/z = 299 [M + 1]+.
MS (APSI): m/z = 299 [M + 1]+.
Anal. Calcd for C16H20N4O: C, 68.43; H, 7.43; N, 18.78. Found: C,
68.45; H, 7.39; N, 18.73.
Compounds 12a–d; General Procedure
To a stirred solution of 7a–d (20 mmol) in MeCN (70 mL) was add-
ed a solution of MeI (3.12 g, 22 mmol) in MeCN (20 mL) in one
portion. The mixture was refluxed for 3 h whereupon a precipitate
was formed during the course of the reaction. Upon cooling, the
mixture was filtered and the solid was washed with Et2O (2 × 30
mL). The crude product was dissolved in DMF (10 mL) and Et3N (3
mL, 22 mmol) was added. After the exothermal reaction had ceased,
the mixture was diluted with H2O (80 mL) and the solid was isolated
by filtration and recrystallized from i-PrOH.
Anal. Calcd for C17H22N4O: C, 68.43; H, 7.43; N, 18.78. Found: C,
68.51; H, 7.46; N, 18.81.
5-Amino-4-(6-aminohexanoyl)-1-methyl-2-phenyl-1,2-dihydro-
3H-pyrazol-3-one (13)
A suspension of 11 (2.56 g, 10 mmol) in aq 1 M NaOH (100 mL)
was stirred for 3 h. The mixture was filtered and the residue crystal-
lized from EtOH–H2O; yield: 2.59 g (8.6 mmol, 86%); white solid;
mp 180 °C.
5-Amino-4-(3,4-dihydro-2H-pyrrol-5-yl)-1-methyl-2-phenyl-
1,2-dihydro-3H-pyrazol-3-one (12a)
Yield: 2.97 g (11.5 mmol, 58%); white solid; mp 258 °C.
IR (KBr): 3250, 3120, 2980, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.75 (quint, J = 7.2 Hz, 2 H,
CH2), 2.81 (t, J = 8.2 Hz, 2 H, CH2), 3.06 (s, 3 H, CH3), 3.73 (t,
J = 7.6 Hz, 2 H, CH2), 7.20 (t, J = 7.6 Hz, 1 H, Ar), 7.29 (d, J = 7.5
Hz, 2 H, Ar), 7.73 (t, J = 7.6 Hz, 2 H, Ar), 8.23 (br s, 2 H, NH2).
13C NMR (125 MHz, DMSO-d6): d = 21.4, 35.4, 36.3, 58.5, 83.1,
121.9, 124.8, 128.8, 137.7, 163.0, 165.8, 168.9.
IR (KBr): 3370, 3280, 3200, 3120, 2940, 2870, 1620 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.31 (m, 4 H, CH2), 1.51 (m, 2
H, CH2), 2.51 (m, 2 H, CH2), 2.71 (m, 2 H, CH2), 3.10 (s, 3 H, CH3),
4.25 (br s, 4 H, 2 × NH2), 7.25 (t, J = 7.5 Hz, 1 H, Ar), 7.28 (d,
J = 8.0 Hz, 2 H, Ar), 7.44 (t, J = 7.5 Hz, 2 H, Ar).
13C NMR (125 MHz, DMSO-d6): d = 24.6, 26.8, 32.9, 35.8, 39.4,
41.7, 89.9, 123.3, 126.0, 129.3, 137.6, 163.6, 165.8, 195.9.
MS (APSI): m/z = 257 [M + 1]+.
Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C,
65.67; H, 6.31; N, 21.90.
MS (APSI): m/z = 303 [M + 1]+.
Anal. Calcd for C16H22N4O2: C, 63.55; H, 7.33; N, 18.53. Found: C,
63.61; H, 7.35; N, 18.56.
5-Amino-1-methyl-2-phenyl-4-(3,4,5,6-tetrahydro-2-pyridi-
nyl)-1,2-dihydro-3H-pyrazol-3-one (12b)
Yield: 3.72 g (13.8 mmol, 69%); white solid; mp 236 °C.
Acknowledgment
IR (KBr): 3360, 3200, 3120, 2950, 1620, 1600 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.55–1.66 (m, 4 H, CH2),
2.63–2.66 (m, 2 H, CH2), 2.99 (s, 3 H, CH3), 3.56–3.57 (m, 2 H,
CH2), 7.13 (t, J = 7.0 Hz, 1 H, Ar), 7.26 (d, J = 8.5 Hz, 2 H, Ar),
7.37 (t, J = 7.0 Hz, 2 H, Ar), 8.09 (br s, 2 H, NH2).
13C NMR (125 MHz, DMSO-d6): d = 18.8, 21.9, 27.3, 36.3, 46.9,
85.3, 121.9, 124.6, 128.6, 137.9, 163.5, 164.7, 165.9.
We thank Enamine Co, Ukraine for the financial support of this
work.
References
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MS (APSI): m/z = 271 [M + 1]+.
Anal. Calcd for C15H18N4O: C, 66.64; H, 6.71; N, 20.73. Found: C,
66.70; H, 6.75; N, 20.69.
5-Amino-1-methyl-2-phenyl-4-(3,4,5,6-tetrahydro-2H-azepin-
7-yl)-1,2-dihydro-3H-pyrazol-3-one (12c)
Yield: 4.26 g (15.0 mmol, 75%); white solid; mp 194 °C.
IR (KBr): 3380, 3200, 2920, 1610, 1580 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.46–1.53 (m, 4 H, CH2),
1.76–1.77 (m, 2 H, CH2), 2.98 (s, 3 H, CH3), 3.12–3.17 (m, 2 H,
CH2), 3.56–3.62 (m, 2 H, CH2), 7.15 (t, J = 7.5 Hz, 1 H, Ar), 7.29
(d, J = 8.0 Hz, 2 H, Ar), 7.37 (t, J = 7.5 Hz, 2 H, Ar), 8.16 (br s, 2
H, NH2).
13C NMR (125 MHz, DMSO-d6): d = 23.7, 20.9, 27.5, 30.73, 36.4,
47.7, 85.0, 121.9, 124.6, 128.6, 138.0, 164.5, 165.8, 165.9.
MS (APSI): m/z = 285 [M + 1]+.
Anal. Calcd for C16H20N4O: C, 67.58; H, 7.07; N, 19.70. Found: C,
67.61; H, 7.12; N, 19.76.
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Synthesis 2008, No. 21, 3497–3503 © Thieme Stuttgart · New York

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5-Amino-4-(2-azacycloalkylidene)-2-phenyl-2,4-dihydro-3H-pyrazol-3-ones
3503
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Synthesis 2008, No. 21, 3497–3503 © Thieme Stuttgart · New York