Cascade assembling of pyrazolin-5-ones and benzylidenemalononitriles: The facile and efficient approach to medicinally relevant spirocyclopropylpyrazolone scaffold

Article abstract of DOI:10.1515/hc-2015-0141

A new cascade reaction provides a direct transformation of pyrazolin-5-ones and benzylidene-malononitriles by the action of bromine into substituted spirocyclopropylpyrazolones in 60-88% yields. This process can be realized in two variants, namely, (1) by treatment with bromine in the presence of base and (2) by treatment with bromine only with heating. These facile and efficient one-step cascade processes lead to the spirocyclopropylpyrazolone framework, which is present in a perspective class of compounds with prominent pharmacological and physiological activity.

Full text of DOI:10.1515/hc-2015-0141

Heterocycl. Commun. 2015; 21(6): 355–360
Anatoly N. Vereshchagin, Michail N. Elinson*, Aleksander D. Korshunov, Victor A. Korolev
and Mikhail P. Egorov
Cascade assembling of pyrazolin-5-ones and
benzylidenemalononitriles: the facile and
efficient approach to medicinally relevant
spirocyclopropylpyrazolone scaffold
DOI 10.1515/hc-2015-0141
Received July 10, 2015; accepted July 29, 2015; previously published
online November 12, 2015
them, bis(spiro-2,4-dihydro-3H-pyrazol-3-one)cyclopropanes
2,3,8,9-tetraazadispiro[4.0.4.1]undeca-3,9-diene-1,7-dione
ring system) are effective agents against P. oryzae and
H.oryzaefungithatareresponsibleforricecropdiseases[7].
Recently, the corresponding 4,10-dimethyl-2,8,11-triphenyl-
(
Abstract: A new cascade reaction provides a direct
transformation of pyrazolin-5-ones and benzylidene-
malononitriles by the action of bromine into substituted
spirocyclopropylpyrazolones in 60–88% yields. This pro-
cess can be realized in two variants, namely, (1) by treat-
ment with bromine in the presence of base and (2) by
treatment with bromine only with heating. These facile
and efficient one-step cascade processes lead to the spiro-
cyclopropylpyrazolone framework, which is present in a
perspective class of compounds with prominent pharma-
cological and physiological activity.
2
,3,8,9-tetraazadispiro[4.0.4.1]undeca-3,9-diene-1,7-dione
was patented as advanced glycation end products (AGE)
formation inhibitor intended for treatment of human schiz-
ophrenia [8]. Thus, spirocyclopropylpyrazolones appear to
be of interest because they incorporate the spiro scaffold
containing cyclopropane and 2-pyrazolin-5-one groups [9].
These moieties are promising with the respect to biological
responses.
The discovery of novel and efficient synthetic meth-
odologies is one of the main points of research activity in
Keywords: activated olefins; cascade reaction; cyclization; the field of modern organic, medicinal and combinatorial
pyrazoline-5-one; spirocyclopropylpyrazolone.
chemistry [10–12]. One of the main approaches in this area
involves combination of two or more distinct reactions
into a single transformation, producing cascade reactions
as a sequential reaction process [13, 14]. Thereby, cascade
reactions have significant economical and ecological ben-
Introduction
The cyclopropyl group is an important structural unit efits [15, 16], especially for the design and construction of
in many synthetic and naturally occurring compounds elaborate heterocyclic frameworks possessing enhanced
which are characterized by a wide spectrum of biologic ‘drug-like’ properties [17–19]. Considering our experience
properties ranging from enzyme inhibition to herbicidal, in cascade synthesis of cyclopropane rings [20–22], as
antibiotic, antitumor and antiviral activities [1–4]. The well as certain biomedical applications of cyclopropylhet-
spirocyclopropyl moiety jointed with a heterocyclic frag- erocycles mentioned above, we were prompted to design
ment has also aroused a special interest because of the a convenient methodology for ‘one-pot’ transformation of
wide range of pharmacological applications of such com- pyrazolin-5-ones and activated olefins into a spirocyclo-
pounds. In particular, fused spirocyclopropyl heterocycles propylpyrazolone scaffold.
have been recognized as α-L-fucosidase [5], and HIV-1 non-
nucleoside reverse transcriptase inhibitors [6]. Among
Results and discussion
*
Corresponding author: Michail N. Elinson, N. D. Zelinsky Institute
of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow,
Russia, e-mail: elinson@ioc.ac.ru
We wish to report our results on the novel efficient cascade
assembling of pyrazoline-5ones 1a,b and activated olefins
Anatoly N. Vereshchagin, Aleksander D. Korshunov, Victor A.
Korolev and Mikhail P. Egorov: N. D. Zelinsky Institute of Organic
Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia
2
a-k into substituted spirocyclopropylpyrazolones 3a-o
(Scheme 1, Tables 1 and 2). First, the ‘one-pot’ cascade
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56ꢀꢀꢀꢀꢁꢀA.N. Vereshchagin et al.: Medicinally relevant spirocyclopropyl-pyrazolone scaffold
R2
R2
X
Method A or B
N
X
N
N
CN
N
O
O
R1
CN
R1
1
a,b
2a-k
3a-j
1
2
1
2
a: R = Ph
a: R = H; X = CN
a: R = Ph; R = H; X = CN
1
2
1
2
b: R = H
b: R = 4-Me; X = CN
b: R = Ph; R = Me; X = CN
2
t
1
2
t
c: R = 4- Bu; X = CN
c: R = Ph; R = 4- Bu; X = CN
2
1
2
d: R = 4-MeO; X = CN
d: R = Ph; R = 4-OMe; X = CN
2
1
2
e: R = 2-Cl; X = CN
e: R = Ph; R = 2-Cl; X = CN
2
1
2
f: R = 3-Cl; X = CN
f: R = Ph; R = 3-Cl; X = CN
2
1
2
g: R = 4-Cl; X = CN
g: R = Ph; R = 4-Cl; X = CN
2
1
2
h: R = 3-Br; X = CN
h: R = Ph; R = 3-Br; X = CN
2
1
2
i: R = 4-NO ; X = CN
i: R = Ph; R = 4-NO ; X = CN
2
2
2
1
2
j: R = H; X = CO Me
j: R = H; R = H; X = CN
2
2
1
2
t
k: R = 4-Cl; X = CO Me
k: R = H; R = 4- Bu; X = CN
2
1
2
l: R = H; R = 4-Cl; X = CN
1
2
m: R = H; R = 3-Br; X = CN
1
2
Method A: i, EtONa/EtOH; ii, Br , 3 h, rt
n: R = H; R = H; X = CO Me
2
2
1
2
Method B: 0.2 M Br in water, EtOH 1 h, 40°C
o: R = H; R = 4-Cl; X = CO Me
2
2
Scheme 1ꢀ
Table 1ꢀCascade transformation of pyrazoline-5-one 1a and
benzylidenemalononitrile 2a into substituted spirocyclopropylpyra-
zolone 3a.a
olefins 2a-k into substituted spirocyclopropylpyrazolo-
nes 3a-o by the use of bromine only (Method B, Scheme 2;
Table 2). The yields of spirocyclopropylpyrazolones 3a-o
under conditions of the method B are generally slightly
lower, in the range of 60–80%.
Entryꢁ
Quantity of EtONaꢁ
Yield of
b
(
equivalents)
ꢂa (%)
The structures of 3c-e and two diastereoisomers
of 3a,b,f-i were established by NOESY experiments
ꢂ
ꢆ
ꢈ
ꢉ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢂ.ꢄꢃ
ꢂ.ꢆꢃ
ꢂ.ꢉꢃ
ꢂ.ꢇꢃ
ꢆ.ꢄꢃ
ꢅꢆ
ꢇ8
ꢊꢇ
(
Figure 1). The NOESY spectrum of the major (2R*,3S*)
ꢇꢋ isomer shows interactions between the CH group and
3
ꢇꢈ ortho-H atoms of both phenyl rings, as well as interactions
between a proton in the cyclopropane ring and ortho-H
atoms of both phenyl rings. In the minor (2R*,3R*) isomer
a10 mmol of 1a, 10 mmol of 2a, 10 mmol of bromine, 30 mL of
ethanol, time of the reaction: 3 h.
b
of 3a,b,f-i the interactions are observed for the CH group
Isolated yield.
3
and the H proton of the cyclopropane ring as well as
transformation of pyrazoline-5-one 1a and benzylidenem- between the latter and ortho-H atoms of the phenyl sub-
alononitrile 2a into spirocyclopropylpyrazolone 3a was stituent. The NOESY results are fully consistent with the
studied by the action of bromine in ethanol in the presence (2R*,3S*) configuration for 3j,k and the major isomer of
of EtONa as base (Method A, Table 1). The best yield of 3l,m (Figure 2). The (1S*,2R*,3R*)-structures for 3n,o were
spirocyclopropylpyrazolone 3a (76%) was obtained when established earlier on the data of the X-ray diffraction
1
.4 equivalents of EtONa were used (Entry 3, Table 1). The study [23].
increase of the amount of EtONa (Entries 4 and 5, Table 1) With the results above taken into consideration and
resulted in a decrease of the cyclization yield. Under the the available literature data on mechanisms of the trans-
optimal conditions, pyrazoline-5-ones 1a,b and activated formation of carbonyl compounds and activated olefins
olefins 2a-k were transformed into spirocyclopropylpyra- into cyclic structures [20–22], the following mechanism
zolones 3a-o in 63–88% yields (Method A, Table 2).
for the cascade addition of pyrazolin-5-ones 1 to activated
Recently, we have found that the base can be excluded olefins 2 with further cyclization into substituted spirocy-
from this cascade synthesis [22]. Thus, we carried out clopropylpyrazolones 3 in the presence of EtONa is pro-
transformation of pyrazoline-5-ones 1a,b and activated posed (Method A, Scheme 2).
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A.N. Vereshchagin et al.: Medicinally relevant spirocyclopropyl-pyrazolone scaffoldꢌꢁꢀꢀꢀꢌ357
Table 2ꢀCascade transformation of pyrazoline-5-ones 1a,b and activated olefins 2a-k into substituted spirocyclopropylpyrazolone 3a-o.a
ꢄ
Rꢅ
Entry ꢁ
Pyrazoline-ꢁ
ꢃ-one
R ꢁ
Activatedꢁ
olefin
ꢁ
X
ꢁ
Spirocyclopropylpyrazolone,
method, yield, ratio of isomersb
ꢂ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
Phꢃ
H ꢃ
H ꢃ
H ꢃ
H ꢃ
H ꢃ
H ꢃ
ꢅa
ꢅb
ꢅc
ꢅd
ꢅe
ꢅf
ꢅg
ꢅh
ꢅi
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
H
ꢃ
ꢃ
ꢃ
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢂa, A ꢊꢇ (ꢉ:ꢂ); B ꢊꢄ (ꢉ:ꢂ)
ꢂb, A 8ꢇ (ꢈ:ꢂ); B ꢊꢅ (ꢈ:ꢂ)
ꢂc, A ꢊꢄ, B ꢇꢅ
ꢆ
ꢉ-Me
ꢉ-tBu
ꢈ
ꢉ
ꢉ-MeOꢃ
ꢂd, A ꢊꢆ; B ꢇꢈ
ꢅ
ꢆ-Cl
ꢈ-Cl
ꢉ-Cl
ꢈ-Br
ꢉ-NOꢆ
H
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢂe, A ꢊꢊ; B ꢊꢆ
ꢇ
ꢂf, A 8ꢆ (ꢅ:ꢆ); B ꢊꢅ (ꢈ:ꢂ)
ꢂg, A 88 (ꢈ:ꢂ); B 8ꢂ (ꢉ:ꢂ)
ꢂh, A ꢊ8 (ꢈ:ꢂ); B ꢇꢈ (ꢉ:ꢂ)
ꢂi, A ꢊꢂ (ꢉ:ꢈ); B ꢇꢅ (ꢆ:ꢂ)
ꢂj, A ꢊꢅ; B ꢊꢂ
ꢊ
8
ꢋ
ꢂꢄ
ꢂꢂ
ꢂꢆ
ꢂꢈ
ꢂꢉ
ꢂꢅ
ꢅa
ꢅc
ꢅg
ꢅh
ꢅj
ꢉ-tBu
ꢉ-Cl
ꢈ-Br
H
ꢂk, A ꢇꢇ, B ꢇꢂ
ꢂl, A ꢊꢈ (ꢉ:ꢂ); ꢂl, B ꢇꢇ (ꢉ:ꢂ)
ꢂm, A 8ꢂ (ꢈ:ꢂ); B ꢊꢅ (ꢉ:ꢂ)
ꢂn, A ꢇꢈ; B ꢇꢄ
CO Meꢃ
ꢆ
ꢅk
ꢉ-Cl
CO Meꢃ
ꢂo, A ꢇꢅ, B ꢇꢆ
ꢆ
a
Method A: 10 mmol of 1, 10 mmol of 2, 10 mmol of bromine, 14 mmol of EtONa, 30 mL of EtOH, ambient temperature, 3 h. Method B:
1
0 mmol of 1, 10 mmol of 2, 50 mL of 0.2 ꢍ bromine in water, 40 mL of EtOH, 40°C, 1 h.
b
Isolated yields.
R2
R2
R2
X
CN
EtO
X
EtO
X
N
N
R2
N
N
N
-EtOH
X
CN
CHNH
N
N
CN
O
N
OH
OH
R1
R1
O
R1
R1
1
2
4
A
B
R2
X
R2
R2
Br2
Br
Br
EtO
X
X
–
N
N
–
N
-Br
-Br
-EtOH
CN
CN
CN
N
N
N
O
O
O
R1
R1
R1
5
3
Scheme 2ꢀ
NOE
NOE
NOE
NOE
H
NOE
H
NOE
H
R2
H
Me
O
H
R2
Me
Me
Me
CN
CN
CN
CN
N
N
N
N
N
N
N
N
H
NOE
NOE
CN
CN
CN
CN
H
H
H
H
H
H
H
H
O
H
O
O
H
H
NOE
R2
NOE
NOE
2R*,3S*)
Major diastereoisomer
NOE
R2
(
(2R*,3R*)
Minor diastereoisomer
(
2R*,3S*)
Major diastereoisomer
(2R*,3R*)
Minor diastereoisomer
Figure 1ꢀNOESY interactions for spirocyclopropylpyrazolones 3a-i.
Figure 2ꢀNOESY interactions for 3j-m.
In the first step, Michael addition of pyrazolin-5-one equilibrium with anion B. Then, bromination leads to bro-
to activated olefin 2 catalyzed by ethoxide anion leads minated arylpropionitrile 5, which in the presence of eth-
1
to the adduct 4 which in the presence of another ethox- oxide anion is cyclized into spirocyclopropylpyrazolone
ide anion is transformed into anion A, which exists in 3. In the mechanism on Scheme 2, two moles of ethoxide
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58ꢀꢀꢀꢀꢁꢀA.N. Vereshchagin et al.: Medicinally relevant spirocyclopropyl-pyrazolone scaffold
Typical procedures for cascade synthesis of products 3
Br
Br2
N
N
N
-HBr
N
Method AꢀTo a 30 mL of ethanolic suspension of pyrazolin-5-one
1 (10 mmol) and activated olefin 2 (10 mmol) in a 50 mL beaker,
O
O
R1
R1
1
6
1
4 mmol of sodium ethoxide in 15 mL of ethanol was added during
1
min. Then 10 mmol of bromine was added during 1 min without
6
2
3
external cooling. The mixture was magnetically stirred at room tem-
perature for 3 h. Then the precipitate of 3 was filtered off, washed
with water and dried in a desiccator over P O .
-
HBr
2
5
Scheme 3ꢀ
Method BꢀTo a 40 mL of ethanolic suspension of pyrazolin-5-one 1
10 mmol) and activated olefin 2 (10 mmol) in a 100 mL three-necked
flask, 50 mL of 0.2 ꢁ bromine in water (10 mmol) was added during
(
anion are needed for one mole of pyrazolin-5-one 1. Actu-
ally, under the optimized conditions, only 1.4 equiva-
lents of ethoxide are needed. This quantity is sufficient
to ensure 70% yield of spirocyclopropylpyrazolone 3. At
the same time, the best 88% yield was obtained in the
case of spirocyclopropylpyrazolone 3g. Thus, brominated
arylpropionitrile 5 is a reasonably strong acid which can
be ionized to the corresponding anion for further cycli-
zation. The cyclizations of brominated C-H acids of such
5
min. The mixture was magnetically stirred at 40°C for 1 h. Then the
precipitate of 3 was filtered off, washed with water and dried in a
desiccator over P O .
2
5
4
-Methyl-7-oxo-2,6-diphenyl-5,6-diazaspiro[2.4]hept-4-ene-
1
,1-dicarbonitrile (3a)ꢀWhite solid; yield 2.48 g (76%); diastere-
1
omeric ratio 4:1; mp 187–189°C (Lit. [23] mp 188–189°C); H NMR:
major diastereoisomer: δ 1.71 (s, 3H, CH ), 4.20 (s, 1H, CH), 7.38–7.52
H
3
(
m, 8H, Ar), 7.95 (d, J ꢂ=ꢂ 7.9 Hz, 2H, Ar); minor diastereoisomer: δ 2.35
H
type in ethanol without adding ethoxide anion have been (s, 3H, CH ), 4.94 (s, 1H, CH), 7.19–7.35 (m, 8H, Ar), 7.85 (d, J ꢂ=ꢂ 7.9 Hz,
3
reported [24].
In the absence of base (Method B), bromination of
pyrazolin-5-ones 1 affords bromo-substituted pyrazolin-
-one 6 (Scheme 3), which is a reasonably strong CH-acid
and can under heating provide a sufficient concentra-
2H, Ar).
4
-Methyl-2-(4-methylphenyl)-7- oxo -6-phenyl-5,6- di-
azaspiro[2.4]hept-4-ene-1,1-dicarbonit-rile (3b)ꢀWhite solid;
yield 2.93 g (86%); diastereomeric ratio 3:1; mp 175–178°C; IR for
5
a mixture: ν 3314, 2996, 2253, 1718, 1597, 1501, 1373, 1326, 1179,
tion of anion of bromo-substituted pyrazolin-5-one B in 758 cm ; MS for a mixture: m/z (%) 340 ([M ], 26), 276 (3), 221 (4),
max
-1
+
1
1
80 (18), 165 (17), 115 (12), 91 (28), 77 (100), 51 (49), 39 (22); H NMR:
ethanol to ensure further Michael addition and cyclization
into spirocyclopropylpyrazolone 3.
major diastereoisomer: δ 1.88 (s, 3H, CH ), 2.41 (s, 3H, CH ), 3.93 (s,
H
3
3
1
H, CH), 7.20–7.32 (5H, m, Ar), 7.43–7.51 (2H, m, Ar), 7.94–8.01 (2H, m,
Ar); minor diastereoisomer: δ 2.36 (s, 3H, CH ), 2.38 (s, 3H, CH ), 3.99
H
3
3
(
s, 1H, CH), 7.20–7.32 (5H, m, Ar), 7.38–7.43 (2H, m, Ar), 7.87–7.94 (2H,
1
3
m, Ar); C NMR: major diastereoisomer: δ 16.3, 19.9, 20.7, 42.7, 44.7,
C
Conclusion
The new cascade reaction of pyrazolin-5-ones and acti-
1
1
10.8, 111.3, 118.2 (2C), 124.6, 125.3, 129.0 (2C), 129.4 (2C), 129.7 (2C),
37.7, 139.0, 151.9, 165.0; minor diastereoisomer: δ 14.0, 20.0, 20.7, 40.7,
C
4
4.5, 109.3, 113.0, 118.2 (2C), 124.3, 125.2, 129.0 (2C), 129.5 (2C), 129.7
vated olefins in the presence of bromine results in the (2C), 138.1, 139.0, 153.8, 163.1. Anal. for a mixture. Calcd for C H N O:
2
1
16
4
C, 74.10; H, 4.74; N, 16.46. Found: C, 73.96; H, 4.68; N, 16.51.
selective formation of substituted spirocyclopropylpyra-
zolones in 60–88% yields. This is a perspective class of
compounds with prominent pharmacological and physi-
ological activity. The procedure utilizes inexpensive rea-
(
2R*,3S*)-2-(4- tert -Butylphenyl)-4-methyl-7-oxo-6-phenyl-5,6-
diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3c)ꢀWhite solid;
yield 3.01 g (78%); mp 190–192°C; IR: ν 2964, 2869, 2251, 1719, 1597,
max
-1
+
gents and is easily carried out. Compared to the previously 1502, 1374, 1328, 756 cm ; MS: m/z (%) 382 ([M ], 8), 318 (1), 207 (15),
1
described [24] electrochemical method, this process is 185 (6), 140 (5), 119 (6), 91 (26), 77 (100), 67 (39), 57 (57); H NMR: δH
1
.29 (c, 9H, CH ), 1.72 (s, 3H, CH ), 4.15 (s, 1H, CH), 7.35–7.55 (m, 5H,
much simpler experimentally.
3
3
1
3
Ar), 7.85 (d, J ꢂ=ꢂ 8.0 Hz, 2H, Ar), 7.95 (d, J ꢂ=ꢂ 8.0 Hz, 2H, Ar); C NMR:
δC 16.6, 20.2, 31.3 (3C), 34.8, 40.9, 44.8, 111.2, 111.7, 118.6, 120.2, 125.0,
1
25.9 (2C), 129.3 (2C), 129.8 (2C), 138.1 (2C), 151.5, 152.4, 165.4. Anal.
Experimental
Calcd for C H N O: C, 75.37; H, 5.80; N, 14.65. Found: C, 75.28; H, 5.68;
24
22
4
N, 14.71.
All melting points were measured with a Gallenkamp melting point
1
13
apparatus and are uncorrected. H NMR (300 MHz) and C-NMR (2R*,3S*)-2-(4-Methoxyphenyl)-4-methyl-7-oxo-6-phenyl-5,6-di-
(
75 MHz) spectra were recorded with a Bruker AM-300 at ambient azaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3d)ꢀWhite solid; 2.57 g
temperature in DMSO-d solutions. IR spectra were registered with (72%); mp 219–221°C; IR: ν 2984, 2254, 1715, 1595, 1518, 1493, 1326,
6
max
-1
+
a Bruker ALPHA-T FT-IR spectrometer in KBr pellets. Electron-impact 1257, 1181, 1025, 762 cm ; MS: m/z (%) 356 ([M ], 57), 292 (11), 251 (9), 196
mass spectra were obtained at 70 eV on a Finningan MAT INCOS 50 (61), 181 (28), 153 (39), 119 (11), 91 (25), 77 (100), 67 (25); 1H NMR: δ 1.73
H
spectrometer.
(c, 3H, CH ), 3.78 (c, 3H, CH ), 4.07 (c, 1H, CH), 7.03 (d, J ꢂ=ꢂ 8.1 Hz, 2H,
3
3
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A.N. Vereshchagin et al.: Medicinally relevant spirocyclopropyl-pyrazolone scaffoldꢌꢁꢀꢀꢀꢌ359
Ar), 7.35–7.55 (m, 5H, Ph), 7.91 (d, J ꢂ=ꢂ 8.1 Hz, 2H, Ar); 13C NMR: δ 16.6, 118.5 (2C), 122.1, 125.6, 129.2 (2C), 129.4, 130.7, 131.9, 132.6, 133.1, 151.5,
C
2
0.4, 40.8, 44.9, 55.4, 111.2, 111.7, 114.1 (2C), 118.5 (2C), 119.3, 125.5, 129.3 163.4, 165.2; minor diastereoisomer: δC 14.4, 21.2, 41.9, 44.9, 109.5,
(
2C), 131.6 (2C), 138.1, 152.2, 159.7, 165.4. Anal. Calcd for C H N O : C, 113.1, 118.4 (2C), 121.6, 125.3, 129.3 (2C), 129.5, 131.2, 132.2, 132.8, 134.3,
21 16 4 2
70.77; H, 4.53; N, 15.72. Found: C, 70.59; H, 4.58; N, 15.61.
154.0, 163.9, 165.9. Anal. for a mixture. Calcd for C H BrN O: C, 59.28;
20 13 4
H, 3.23; Br, 19.72; N, 13.83. Found: C, 59.09; H, 3.29; Br, 19.57; N, 13.95.
(
2R*,3S*)-2-(2-Chlorophenyl)-4-methyl-7-oxo-6-phenyl-5,6-
diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3e)ꢀWhite solid;
yield 2.78 g (77%); mp: 155–157°C; IR: ν 3411, 2973, 2249, 1714, 1595,
4
-Methyl-2-(4-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]
max
hept-4-ene-1,1-dicarbonitrile (3i)ꢀWhite solid; yield 2.64 g (71%);
-1
+
+
1
493, 1329, 1119, 753, 692 cm ; MS: m/z (%) 362 ([M ], 6), 360 ([M ], 19),
diastereomeric ratio 4:3; mp 161–163°C; IR: ν 3434, 3116, 2232, 1722,
max
1
3
25 (12), 261 (4), 206 (5), 165 (21), 119 (14), 91 (19), 77 (100), 67 (41); H
-1
+
1
501, 1349, 1118, 1006, 760, 693 cm ; MS: m/z (%) 371 ([M ], 26), 324
NMR: δ 1.85 (s, 3H, CH ), 3.77 (s, 1H, CH), 7.27–7.32 (m, 1H, Ar), 7.42–
H
3
(6), 254(2), 199 (16), 153 (25), 119 (20), 91 (21), 77 (100), 67 (30), 51 (32);
13
7
.57 (m, 5H, Ar), 7.61–7.68 (m, 1H, Ar), 7.99 (m, 2H, Ar); C NMR: δ 15.9,
1
C
H NMR: major diastereoisomer: δ 1.70 (s, 3H, CH ), 4.33 (s, 1H, CH),
H
3
2
1
0.4, 41.2, 44.7, 110.6, 111.2, 118.3 (2C), 125.5, 126.0, 127.6, 129.1 (2C),
7.26–7.32 (m, 1H, Ar), 7.49–7.56 (m, 2H, Ar), 7.80 (d, J ꢂ=ꢂ 8.7 Hz, 2H, Ar),
29.8, 131.5, 131.6, 134.4, 137.5, 151.9, 164.8. Anal. Calcd for C H ClN O:
20 13 4
7.88–7.94 (m, 2H, Ar), 8.33 (d, J ꢂ=ꢂ 8.7 Hz, 2H, Ar); minor diastereoiso-
mer: δ 2.27 (s, 3H, CH ), 5.10 (s, 1H, CH), 7.21–7.26 (m, 1H, Ar), 7.42–7.49
C, 66.58; H, 3.63; Cl, 9.83; N, 15.53. Found: C, 66.63; H, 3.49; Cl, 9.67;
N, 15.45.
H
3
(
m, 2H, Ar), 7.76–7.85 (m, 2H, Ar), 7.80 (d, J ꢂ=ꢂ 8.7 Hz, 2H, Ar), 8.33 (d,
1
3
J ꢂ=ꢂ 8.7 Hz, 2H, Ar); C NMR: major diastereisomer: δ 16.3, 21.0, 39.7,
C
2
-(3-Chlorophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diaza-
4
1
4.6, 109.2, 112.8, 118.5 (2C), 123.4 (2C), 125.5, 129.1 (2C), 131.6 (2C),
35.1, 137.8, 147.7, 153.8, 163.2; minor diastereoisomer: δ 16.5, 20.1,
spiro[2.4]hept-4-ene-1,1-dicarbo-nitrile (3f)ꢀWhite solid; yield
C
2
2
(
.96 g (82%); diastereomeric ratio 5:2; mp 164–167°C; IR: ν 3435,
max
41.8, 44.8, 110.7, 111.3, 118.4 (2C), 123.9 (2C), 125.5, 129.2 (2C), 131.8 (2C),
35.2, 137.7, 148.1, 151.3, 164.9. Anal. for a mixture: Calcd for C H N O :
-1
995, 2249, 1727, 1596, 1500, 1331, 1118, 758, 578 cm ; MS: m/z (%) 362
1
2
0
13
5
3
+
+
[M ], 8), 360 ([M ], 27), 296 (2), 206 (5), 185 (26), 165 (30), 119 (22),
C, 64.69; H, 3.53; N, 18.86. Found: C, 64.51; H, 3.48; N, 18.69.
1
9
1 (20), 77 (100), 67 (32); H NMR: major diastereoisomer: δ 1.93 (s,
H
3
H, CH ), 3.94 (s, 1H, CH), 7.53–7.29 (m, 7H, Ar), 7.95–8.03 (m, 2H, Ar);
3
(
2R*,3S*)-4-Methyl-7-oxo-2-phenyl-5,6-diazaspiro[2.4]hept-
-ene-1,1-dicarbonitrile (3j)ꢀWhite solid; yield 1.88 g (75%); mp
minor diastereoisomer: δ 2.40 (s, 3H, CH ), 3.98 (s, 1H, CH), 7.53–7.29
H
3
4
13
(
m, 7H, Ar), 7.88–7.94 (m, 2H, Ar); C NMR: major diastereoisomer:
1
1
94–195°C; IR: ν 3427, 3244, 2976, 2243, 1724, 1579, 1498, 1449, 1388,
max
+
δC 16.3, 20.0, 41.6, 44.6, 110.6, 111.2, 118.2 (2C), 125.3, 128.7, 129.0 (2C),
-1
263 cm ; MS: m/z (%) 250 ([M] , 25), 195 (3), 185 (11), 166 (15), 148
1
29.4, 129.8, 130.0, 130.6, 133.4, 137.7, 151.3, 164.9; minor diastereoiso-
1
(
10), 144 (12), 119 (15), 109 (19), 92 (63), 91 (100); H NMR: δ 1.55 (s,
H
mer: δ 14.0, 20.9, 41.6, 44.4, 109.2, 112.8, 118.3 (2C), 125.3, 128.6, 129.0
C
13
3
H, CH ), 3.98 (s, 1H, CH), 7.43–7.49 (m, 5H, Ar), 11.96 (s, 1H, NH);
C
3
(
2C), 129.7, 129.8, 130.2, 130.6, 132.8, 137.7, 153.7, 163.1. Anal. for a mix-
NMR: δ 16.3, 18.6, 42.0, 42.7, 110.9, 111.4, 127.7, 129.0 (2C), 129.4, 129.7
C
ture: Calcd for C H ClN O: C, 66.58; H, 3.63; Cl, 9.83; N, 15.53. Found:
2
0
13
4
(
2C), 150.2, 168.6. Anal. Calcd for C H N O: C, 67.19, H, 4.03, N, 22.39.
14 10 4
C, 66.45; H, 3.55; Cl, 9.73; N, 15.39.
Found: C, 67.08, H, 4.12, N, 22.21.
2
-(4-Chlorophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diaza-
spiro[2.4]hept-4-ene-1,1-dicarbo-nitrile (3g)ꢀWhite solid; yield
.18 g (88%); diastereomeric ratio 3:1; mp 169–172°C; IR: ν 3436,
(
2R*,3S*)-2-(4-tert-Butylphenyl)-4-methyl-7-oxo-5,6-diaza-
spiro[2.4]hept-4-ene-1,1-dicarbonitrile (3k)ꢀWhite solid; 2.02
3
max
g (66%); mp: 205–207°C; IR: ν 3459, 3104, 2966, 2254, 1717, 1589,
-1
max
2
964, 2252, 1725, 1596, 1495, 1328, 1089, 761, 693 cm ; MS: m/z (%) 362
+ +
-1
+
1
391, 1308, 1268, 1203 cm ; MS: m/z (%) 306 ([M] , 100), 291 (79), 263
(
[M ], 1), 360 ([M ], 4), 296 (1), 200 (3), 185 (8), 165 (17), 119 (13), 91
1
(
12), 242 (27), 227 (65), 207 (41), 185 (35), 152 (19), 118 (23); H NMR: δH
1
(
19), 77 (100), 67 (38); H NMR: major diastereoisomer: δ 1.89 (s, 3H,
H
1
.28 (s, 9H, t-Bu), 1.55 (s, 3H, CH ), 3.92 (s, 1H, CH), 7.38 (d, J ꢂ=ꢂ 8.2 Hz,
3
CH ), 3.91 (s, 1H, CH), 7.27–7.32 (m, 1H, Ar), 7.35 (d, J ꢂ=ꢂ 8.2 Hz, 2H, Ar),
3
2
H, Ar), 7.47 (d, J ꢂ=ꢂ 8.2 Hz, 2H, Ar), 11.95 (s, 1H, NH); 13C NMR: δ 16.3,
C
7
.42–7.54 (m, 4H, Ar), 7.96 (d, J ꢂ=ꢂ 8.2 Hz, 2H, Ar); minor diastereoiso-
1
8.5, 30.9 (3C), 34.4, 41.7, 56.0, 110.9, 111.5, 125.6 (2C), 129.3, 129.4 (2C),
50.3, 152.0, 168.6. Anal. Calcd for C H N O: C, 70.57, H, 5.92, N, 18.29.
mer: δ 2.39 (s, 3H, CH ), 3.96 (s, 1H, CH), 7.27–7.32 (m, 1H, Ar), 7.40 (d,
H
3
1
1
3
18 18
4
J ꢂ=ꢂ 8.2 Hz, 2H, Ar), 7.42–7.54 (m, 4H, Ar), 7.88 (d, J ꢂ=ꢂ 8.2 Hz, 2H, Ar); C
NMR: major diastereoisomer: δ 16.4, 20.0, 41.9, 44.7, 110.7, 111.2, 118.2
Found: C, 70.43, H, 6.03, N, 18.13.
C
(
2C), 125.3, 126.7, 128.4, 128.9 (3C), 131.9 (2C), 134.3, 137.7, 151.4, 164.9;
2
-(4-Chlorophenyl)-4-methyl-7-oxo-5,6-diazaspiro[2.4]hept-
minor diastereoisomer: δ 14.1, 20.9, 41.9, 44.5, 109.2, 112.8, 118.2 (2C),
C
4
-ene-1,1-dicarbonitrile (3l)ꢀWhite solid; yield 2.07 g (73%); dias-
1
25.3, 126.4, 128.4, 129.0 (3C), 131.7 (2C), 133.6, 137.7, 153.7, 163.0. Anal.
1
tereomeric ratio 4:1; mp 186–188°C; (Lit. mp 184–185°C [26]); H NMR:
for a mixture: Calcd for C H ClN O: C, 66.58; H, 3.63; Cl, 9.83; N,
2
0
13
4
major diastereoisomer: δ 1.57 (s, 3H, CH ), 3.95 (s, 1H, CH), 7.51–7.58
1
5.53. Found: C, 66.49; H, 3.51; Cl, 9.68; N, 15.35.
H
3
(
m, 4H, Ar), 11.96 (s, 1H, NH); minor diastereoisomer: δ 2.13 (s, 3H,
H
CH ), 4.75 (s, 1H, CH), 7.38–7.47 (m, 4H, Ar), 11.76 (s, 1H, NH).
2
-(3-Bromophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diazaspiro[2.4]
hept-4-ene-1,1-dicarbo-nitrile (3h)ꢀWhite solid; yield 3.16 g (78%);
diastereomeric ratio 3:1; mp 198–200°C; IR: ν 3059, 3015, 2249, 1726, 2-(3-Bromophenyl)-4-methyl-7-oxo-5,6-diazaspiro[2.4]hept-
3
max
-1
+
1
595, 1499, 1372, 1330, 1325, 757 cm ; MS: m/z (%) 406 ([M ], 99), 404 4-ene-1,1-dicarbonitrile (3m)ꢀWhite solid; yield 2.67 g (81%); dia-
+
1
(
[M ], 100), 342 (50), 340 (61), 186 (21), 185 (34), 165 (23), 153 (29), 119 stereomeric ratio 3:1; mp 215–217°C (Lit. mp 213–214°C [23]); H NMR:
1
(
24), 91 (61), 77 (81); H NMR: major diastereoisomer: δ 1.74 (c, 3H, major diastereoisomer: δ 1.57 (s, 3H, CH ), 3.97 (s, 1H, CH), 7.39–7.44
H
H
3
CH ), 4.18 (c, 1H, CH), 7.39–7.62 (m, 5H, Ar), 7.83–7.93 (m, 3H, Ar), 8.03 (m, 1H, Ar), 7.52 (d, J ꢂ=ꢂ 7.7 Hz, 1H, Ar), 7.66 (d, J ꢂ=ꢂ 7.7 Hz, 1H, Ar), 7.87 (s,
3
(
c, 1H, Ar); minor diastereoisomer: δ 2.33 (c, 3H, CH ), 4.94 (c, 1H, 1H, Ar), 11.96 (s, 1H, NH); minor diastereoisomer: δ 2.13 (s, 3H, CH ),
H
3
H
3
CH), 7.20–7.42 (m, 6H, Ar), 7.68 (d, J ꢂ=ꢂ 7.5 Hz, 2H, Ar), 7.96 (c, 1H, Ar); 4.74 (s, 1H, CH), 7.32–7.38 (m, 2H, Ar), 7.49–7.51 (m, 1H, Ar), 7.58 (d, J ꢂ=ꢂ
1
3
C NMR: major diastereisomer: δ 16.6, 20.3, 41.8, 44.8, 110.9, 111.6, 7.5 Hz, 1H, Ar), 11.77 (s, 1H, NH).
C
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3
60ꢀꢀꢀꢀꢁꢀA.N. Vereshchagin et al.: Medicinally relevant spirocyclopropyl-pyrazolone scaffold
Methyl (1S*,2R*,3R*)-1-cyano-4-methyl-7-oxo-2-phenyl-5,6-diaza- [10] Gore, R. P.; Rajput, A. P. A review on recent progress in multi-
spiro[2.4]-hept-4-ene-1-carboxylate (3n)ꢀWhite solid; yield 1.78 g
component reactions of pyrimidine synthesis. Drug Invention
Today 2013, 5, 14ꢎ–152.
1
(
63%); mp 170–172°C (Lit. [23] mp 170–171°C); H NMR: δ 1.51 (s, 3H,
H
CH ), 3.81 (s, 3H, OCH ), 3.93 (s, 1H, CH), 7.42–7.46 (m, 5H, Ar), 11.87 [11] Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small hetero-
3
3
(
s, 1H, NH).
cycles in multicomponent reactions. Chem. Rev. 2014, 114,
ꢎ323–ꢎ359.
Methyl (1S*,2R*,3R*)-2-(4-chlorophenyl)-1-cyano-4-methyl-7-oxo- [12] Dömling, A.; AlQahtani, A. D. General introduction to MCRs:
5
,6-diazaspiro[2.4]-hept-4-ene-1-carboxylate (3o)ꢀWhite solid;
Past, Present, and Future. In Multicomponent reactions in
organic synthesis. Zhu, J.; Wang, Q.; Wang, M. Eds. Wiley-VCH
Verlag GmbH & Co. KgaA: Weinheim, Germany, 2015; pp 1–12.
[13] Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade reactions
in total synthesis. Angew. Chem. 2006, 45, 7134–71ꢎ6.
1
yield 2.07 g (65%); mp 148–149°C (Lit. [23] mp 148–149°C); H NMR:
δ 1.90 (s, 3H, CH ), 3.88 (s, 3H, OCH ), 4.44 (s, 1H, CH), 7.34 (d, J ꢂ=ꢂ 8.4
H
3
3
Hz, 2H, Ar), 7.44 (d, J ꢂ=ꢂ 8.4 Hz, 2H, Ar), 11.70 (s, 1H, NH).
[
[
[
[
14] Padwa, A. Application of cascade processes toward hetero-
cyclic synthesis. Pure Appl. Chem. 2003, 75, 47–62.
15] Weber, L. Multi-component reactions and evolutionary
chemistry. Drug Disc. Today 2002, 7, 143–147.
16] Dömling, A. Recent advances in isocyanide-based multicom-
ponent chemistry. Curr. Opin. Chem. Biol. 2002, 6, 306–313.
17] Gerencsér, J.; Dormán, G.; Darvas, F. Meldrum’s acid in
multicomponent reactions: applications to combinatorial
and diversity-oriented synthesis. QSAR Comb. Sci. 2006, 25,
439–44ꢎ.
Acknowledgments: The authors gratefully acknowledge
the financial support of the Russian Foundation for Basic
Research (Project No. 15-33-20168).
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