Synthesis of 3,7-disubstituted hexahydro- and tetrahydro-2H-indazoles from cross-conjugated dienones

Article abstract of DOI:10.1134/S1070428016030167

The oxidation of 3,7-disubstituted hexahydroindazoles with potassium hexacyanoferrate(III) afforded previously unknown tetrahydro-2H-indazole derivatives. A novel ring contraction reaction leading to 2,3-diazaspiro[4.4]non-3-en-1-one derivatives was discovered. The product structure was proved by NMR spectroscopy, mass spectrometry, and X-ray analysis.

Full text of DOI:10.1134/S1070428016030167

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 3, pp. 389–396. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.N. Nuriev, I.A. Vatsadze, N.V. Sviridenkova, S.Z. Vatsadze, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 3, pp. 409–416.
Synthesis of 3,7-Disubstituted Hexahydro-
and Tetrahydro-2H-indazoles from Cross-Conjugated Dienones
a
b
c
a
V. N. Nuriev , I. A. Vatsadze , N. V. Sviridenkova , and S. Z. Vatsadze
a
Faculty of Chemistry, Moscow State University, Leninskie gory 1-3, Moscow, 119991 Russia
e-mail: szv@org.chem.msu.ru
b
Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
c
MISiS National University of Science and Technology, Leninskii pr. 4, Moscow, 119049 Russia
Received December 4, 2015
Abstract—The oxidation of 3,7-disubstituted hexahydroindazoles with potassium hexacyanoferrate(III)
afforded previously unknown tetrahydro-2H-indazole derivatives. A novel ring contraction reaction leading to
2
,3-diazaspiro[4.4]non-3-en-1-one derivatives was discovered. The product structure was proved by NMR
spectroscopy, mass spectrometry, and X-ray analysis.
DOI: 10.1134/S1070428016030167
In recent years, organic and hybrid molecular
systems have attracted keen interest of researchers [1].
Development of rational approaches for the target-
oriented synthesis of organic molecules constitutes the
basis for the preparation of such systems [2]. A huge
number of successful strategic and tactical solutions, as
well as synthetic techniques, have firmly become
routine tools of organic chemists [3].
polymers [4–7], as well as of biologically active com-
pounds [8, 9].
Two pathways can be proposed for the synthesis of
tetrahydroindazoles from cross-conjugated dienones
(
Scheme 1). The first pathway (a) is based on the
addition of hydrazine or substituted hydrazines to the
enone fragment of cross-conjugated dienone, followed
by oxidation (dehydrogenation) of cyclohexane-fused
dihydropyrazole thus formed. The second path (b)
involves addition of hydrazine to the dienone adduct
with bromine, by analogy with the data of [10]. In
addition, syntheses of structurally related pyrazoles via
heterocyclization of epoxy ketones [11] and oxidative
heterocyclization of dienone hydrazones [12] have
been reported. Despite long-term extensive studies,
However, a synthetic scheme that seemed to be
faultless at the design step often appears to be inap-
propriate for the preparation of target compounds or
leads to unpredictable structures. We have encountered
with analogous problem while trying to synthesize
3
,7-disubstituted hexahydro- and tetrahydroindazoles
used as ligands for the preparation of coordination
Scheme 1.
R
N
N
RNHNH2
[O]
Ar
Ar
Ar
R
a
b
N
O
N
Ar
Ar
Ar
Ar
Br
O
Br2
RNHNH2
Ar
Br
3
89

3
90
NURIEV et al.
Scheme 2.
O
N
NH
N
NH
K [Fe(CN) ]
3
6
N H ·H O, EtOH
PhH–H
2
O, KOH
2
4
2
Ar
Ar
Ar
Ar
Ar
Ar
1
a, 1b
2a, 2b
3a, 3b
6 4
Ar = Ph (a), 4-MeOC H (b).
arylmethylidene-substituted tetrahydro-2H-indazoles
with no substituent on the nitrogen atom have not been
described so far (according to SciFinder).
The dihydropyrazole ring in N-phenyl-substituted
derivatives remained unchanged in the reaction with
potassium hexacyanoferrate(III) [13]. N-Substituted di-
hydropyrazoles are more resistant to oxidation. They
do not react with quinones and potassium hexacyano-
ferrate(III), and their oxidation may be achieved only
with the use of lead tetraacetate. Presumably, the
oxidation with K [Fe(CN) ] primarily involves the NH
group. This follows from the instability of 2a and 2b
on storage in air or in solution at room temperature, as
well as from the formation of complex mixtures of
oxidation products. However, crystalline compounds
While planning the synthesis, we presumed that the
corresponding reactions or their analogs have already
been reported in the literature. However, our experi-
ments showed that the results obtained according to
pathway b essentially differ from those expected. Path
a was explored using phenyl-substituted dienone 1a
and its p-methoxy derivative 1b (Scheme 2). The
reaction of substituted hydrazines with dienones was
described previously [13].
3
6
2
a and 2b can be stored for a fairly long time at 5°C.
Aromatization of fused heterocyclic systems struc-
turally related to 2 has been the subject of a number of
studies. For this purpose, oxidation with bromine
Compounds 2a and 2b show yellow–green lumi-
nescence.
Thus, pathway a (Scheme 1) leads to previously
unknown tetrahydroindazoles 3 which can be readily
subjected to further functionalization at the NH group
or double bond. It is known that the C=C double bond
in dienones readily takes up bromine on treatment with
[14, 15], heating with elemental sulfur [16], oxidation
with singlet oxygen [16], or oxidation with potassium
hexacyanoferrate(III) in alkaline medium [17] was
generally used. In some cases, aromatization of binu-
cleophile adducts occurred even during their purifica-
tion [16]. Potassium hexacyanoferrate(III) turned out
to be the most efficient oxidant [17–19].
1
equiv of Br in CHCl [20]. We have reproduced the
2 3
described procedure, and the spectral parameters of the
resulting dibromo derivatives coincided with published
data. Moreover, we succeeded in obtaining single crys-
tals of dibromide 4a and showed that the addition of
bromine is stereospecific (trans-1,2-addition). How-
ever, the quality of crystals of 4a did not allow satis-
factory estimation of bond lengths, bond angels, and
intermolecular interactions therein. The bromination of
p-methoxy derivative 1b was accompanied by electro-
philic substitution in the aromatic rings. Nevertheless,
the corresponding dibromide 4b was isolated in
We tried to accomplish aromatization of 2 with
2
2
,3,5,6-tetrachloro-1,4-benzoquinone, 5,6-dichloro-
,3-dicyano-1,4-benzoquinone, and potassium hexa-
cyanoferrate(III). The oxidation with quinones in boil-
ing benzene afforded no desired results. 5,6-Dichloro-
2
,3-dicyano-1,4-benzoquinone as stronger oxidant
induced decomposition of the dihydropyrazole system
to initial dienone, while the reaction with 2,3,5,6-tetra-
chloro-1,4-benzoquinone did not involve the dihydro-
pyrazole fragment.
3
8% yield.
We succeeded in oxidizing compounds 2a and 2b in
At first glance, the synthesis of tetrahydroindazoles
good yields only with potassium hexacyanoferrate(III)
according to pathway b should not involve difficulties.
Taking into account high reactivity of bromine in the
β-position with respect to the carbonyl group, the
major product of the reaction of hydrazine hydrate
with dibromides derived from dienones should be pyr-
azole 3a (Scheme 3). However, physical and spectral
properties of the product isolated in the reaction of 4a
with hydrazine hydrate differed from those of com-
1
in alkaline medium (Scheme 2). The H NMR spectra
of oxidation products 3a and 3b lacked doublet signal
typical of 3-H in initial compounds 2. In addition, the
NH singlet appeared in the spectra of 3a and 3b in
a considerably weaker field (δ 9.9‒10.1 ppm against
δ 5.58 and 7.22 ppm in the spectra of 2a and 2b,
respectively).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

SYNTHESIS OF 3,7-DISUBSTITUTED HEXAHYDRO- AND TETRAHYDRO-2H-INDAZOLES
391
Scheme 3.
Br
NH
O
N
N H ·H O, EtOH
Br , CHCl
2
Ph
2
4
2
Ph
3
1
a
Ph
Ph
Br
4
a
3a
pound 3a obtained by oxidation of 2a (Scheme 2). In
particular, it melted at 161°C against mp 85‒86°C of
pyrazole 3a.
A probable scheme of the reaction of 4a with hy-
drazine includes a step analogous to the Favorskii rear-
rangement (Scheme 4). Initial Michael-type nucleo-
According to the MS data, compound 5 obtained by
reaction of 4a with hydrazine contained no bromine,
1
0
C
1
1
+
C
but its molecular ion [M] , m/z 302 (Irel 36%) did not
1
12
match the composition of 3a (C H N ). The H NMR
C
20
18
2
9
C
6
spectrum of 5 in CDCl contained upfield multiplet
C
3
8
7
C
C
signals from six nonequivalent methylene protons
1
3
C
3
(
cycloalkane) and CH= group (δ 6.15 ppm, br.s,), un-
5
C
2
C
C
resolved signals from two nonequivalent phenyl sub-
4
C
1
2
stituents, and an acidic proton signal at δ 8.91 ppm
C
N
1
3
(
δ 11.5 ppm in DMSO-d ). In the C NMR spectrum
1
6
14
O
C
1
N
of 5 we observed four aliphatic carbon signals, signals
from two nonequivalent benzene rings and one C=C
bond in the aromatic region, and a separate signal at
δ 144.4 ppm; also, signals at δ 180.5 and 160.3 ppm
1
5
C
1
6
C
1
7
20
C
C
C
C
were present, which may be assigned to amide C=O
and C=N carbon atoms, respectively.
19
C
18
C
The following conclusions can be drawn on the
basis of the above data. First, there are no bromine
atoms in molecule 5. Second, the elemental composi-
tion of 5 corresponds to the formula C H N O.
Fig. 1. Structure of the molecule of 6-benzylidene-4-phenyl-
,3-diazaspiro[4.4]non-3-en-1-one (5) according to the X-ray
diffraction data. Non-hydrogen atoms are shown as thermal
vibration ellipsoids with a probability of 50%.
2
2
0
18
2
Third, molecule 5 contains a fairly acidic NH proton
–
1
(
δ 8.5 ppm in CDCl ; νN–H 3200 cm ) and an amide
3
–
1
carbonyl group (δ 180.5 ppm; νC=O 1700 cm ).
C
However, it became possible to unambiguously deter-
mine the structure of 5 only when its crystals suitable
for X-ray analysis were obtained. Transparent yellow
plates with mp 161°C were grown by crystallization of
c
0
b
5
from benzene and from methylene chloride. Better
single crystals were obtained from benzene.
The X-ray diffraction study showed that molecules
of 5 have bicyclic structure and are composed of spiro-
fused cyclopentane and pyrazole rings (Fig. 1). A unit
cell of 5 contains two crystallographically independent
molecules (see table) differing by the conformation of
the carbocycle. These molecules are linked to each
other by two hydrogen bonds formed between the NH
group of one molecule and carbonyl oxygen atom
of the other (Fig. 2), N · · · O 2.8638(16) and
a
2
.9056(16) Å, ∠NHO 167°. As shown by ESI MS, the
Fig. 2. Packing of H-bonded dimers of compound 5 in a unit
H-bonded dimers are also retained in solution.
cell.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

3
92
NURIEV et al.
Scheme 4.
Br
NH2
H N
2
Br
O
NH2
O
HN
O
Br
H NNH
2
2
Ph
Ph
Ph
Ph
+
–H , –Br–
Ph
Ph
Br
Br
4
a
Ph
Ph
H
N
O
O
H
O–
HN
Br
HN
HN
HN
Ph
–H , –Br–
+
–2H
Ph
N
Ph
Ph
5
philic attack by hydrazine molecule on the double
bond conjugated with the carbonyl group leads to the
corresponding enolate. Next follows intramolecular
substitution of the bromine atom attached to the endo-
cyclic carbon atom. The ring contraction step is likely
to involve heterocyclization through the primary amino
group and carbonyl group. The tetrahedral interme-
diate is stabilized via nucleophilic replacement of the
second bromine atom. Taking into account stereochem-
ical structure of the initial dibromide, this step may be
regarded as a concerted fragmentation as shown in
Scheme 4. Dehydrogenation of the intermediate prod-
uct may be achieved by the action of atmospheric
oxygen. However, the low yield of 5 does not rule out
disproportionation path.
progress of the reactions was monitored by TLC. The
reaction in toluene on heating was complete in 7 h.
Five products were detected in the reaction mixture by
TLC, one of which was compound 5. The reaction
mixture was treated with water and extracted with
an organic solvent, the extract was dried and evaporat-
ed, and the residue was analyzed by NMR. Apart from
signals belonging to 5, signals from a large number of
unidentified compounds were present.
The addition of hydrazine hydrate to a solution of
4
a in THF was accompanied by gas evolution, and the
reaction mixture turned bright yellow. The mixture was
treated with ice, and the precipitate was filtered off.
1
The H NMR spectrum of the product showed signals
of compound 5 together with unidentified compounds;
however, the number of impurities was lower than in
the preceding case.
The reaction of 4a with excess hydrazine hydrate as
reaction medium afforded compound 5 in a low yield.
In order to improve the yield and obtain an analyt-
ically pure sample 5 directly from the reaction mixture,
the reaction of 4a with hydrazine was carried out in
other solvents, such as DMF, toluene, and THF. The
Bond lengths and bond angles in two independent molecules (separated by a slash) of compound 5 according to the X-ray
diffraction data
Bond
d, Å
Bond angle
ω, deg
1
1
1
1
3
O ‒C
1.2360(16) / 1.2349(15)
1.3581(17) / 1.3592(17)
1.4022(15) / 1.4075(15)
1.3048(17) / 1.3060(17
1.5448(18) / 1.5423(18)
1.5233(17) / 1.5187(17)
1.5454(18) / 1.5428(17)
1.5733(17) / 1.5612(17)
1.5202(18) / 1.5221(17)
001.539(2) / 1.5449(18)
1.5492(19) / 1.5426(18)
N C C
106.07(10) / 105.77(10)
113.01(11) / 113.23(11)
99.54(10) / 99.93(10)
1
1
2
2
2
3
N ‒C
N C C
1
2
3
1
4
4
7
7
7
3
6
3
N ‒N
C C C
2
2
2
3
N ‒C
C C C
114.89(10) / 115.49(10)
108.94(10) / 111.25(10)
118.29(11) / 117.37(10)
110.36(10) / 108.41(10)
104.61(10) / 104.32(10)
107.19(11) / 108.70(10)
102.76(11) / 104.74(10)
105.91(11) / 103.43(10)
1
3
1
3
C ‒C
C C C
2
3
4
7
5
6
7
2
3
C ‒C
C C C
3
1
3
C ‒C
C C C
3
4
3
C ‒C
C C C
4
5
4
C ‒C
C C C
5
4
5
C ‒C
C C C
6
6
7
C ‒C
C C C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

SYNTHESIS OF 3,7-DISUBSTITUTED HEXAHYDRO- AND TETRAHYDRO-2H-INDAZOLES
393
Scheme 5.
Ph
O
Br
Br
Br
O
O
Ph
Br
N H ·H O, EtOH
N H
2 4
2
4
2
HN
N
Ph
Ph
Ph
Br
–Br2
Br
–2HBr, –2H
Ph
4
a
5
Scheme 6.
Br
Ph
O
Ph
NH
2
PhH, reflux, 8 h
Ph
NH
Br
+
N
N
O
4
a
6
The reaction of 4a with hydrazine hydrate in DMF on
heating was complete in 7 h. The product was precip-
itated by addition of ice. In this case, pure compound 5
was isolated in a satisfactory yield (39%). Compound
peared as a broadened singlet at δ 6.70 ppm. The
C NMR spectrum of 6 contained signals from the
1
3
amide carbonyl carbon atom (δ 184.7 ppm), aromatic
C
carbons of the benzene and pyridine rings, and two
pairs of double-bonded carbon atoms. Methylene
5
can also be obtained by treatment of tetrabromo
derivative of dienone 1a with excess hydrazine hydrate
Scheme 5). Presumably, the process involves inter-
carbon signals were located at δ 23.4 and 26.5 ppm.
C
+
(
A fairly intense molecular ion peak (m/z 276 [M] ,
mediate formation of dibromide 4a. No satisfactory
results were obtained in the reactions of hydrazine
hydrate with dibromides derived from five- or seven-
membered cyclic dienones.
Irel 25%) was present in the mass spectrum of 6. At
present, we cannot propose a satisfactory mechanism
to rationalize loss of Ph‒C fragment during the forma-
tion of compound 6.
We also examined reactions of dibromide 4a with
nitrogen nucleophiles, in particular with those capable
of simultaneously acting as bases. Compound 4a was
inactive toward aniline on heating in boiling DMF,
benzene, or ethanol. On heating in boiling pyridine,
compound 4a lost bromine molecule with formation of
dienone 1a; analogous results were obtained when
compound 4a was heated in triethylamine and pyridin-
Searching in the CAS database showed that the
closest structural analogs of compound 5 are cardio-
tonic agents [21] and SIRT1 inhibitors for nontoxic
oncotherapy [22]. These compounds are synthesized by
reaction of hydrazine with keto esters [23, 24] which
are prepared in turn by double alkylation (with cycliza-
tion) of benzoylacetic acid esters. We have discovered
a simple and cost-efficient synthetic route to such com-
pounds via ring contraction. The presence of an aryl-
methylidene group and an NH hydrazide fragment in
molecule 5 provides the possibility of its further func-
tionalization.
4
-amine. Partial debromination of 4a was observed in
the reaction with hydroxylamine in ethanol, and the
product was a mixture of dienone 1a and unreacted
dibromide 4a.
By heating dibromide 4a with pyridin-3-amine in
benzene we obtained 41% of a compound which was
assigned structure 6 on the basis of spectral data and
the results of the reaction of 4a with hydrazine
EXPERIMENTAL
The IR spectra were recorded on UR-20 and
1
(
Scheme 6). Compound 6 showed in the aliphatic
Specord 75 IR instruments. The H NMR spectra were
1
region of the H NMR spectrum two two-proton
signals at δ 3.07 and 2.52 ppm, which were assigned to
methylene protons in the five-membered carbocycle.
Protons on the double bonds resonated at δ 7.76 (exo-
cyclic) and 6.48 ppm (endocyclic). In the aromatic
region we observed signals from one phenyl ring and
one 3-substituted pyridine ring. The NH signal ap-
measured on a Bruker Avance 400AMX spectrometer
at 27°C. The mass spectra were obtained on an Agilent
1100 Series LC/MSD Tramp SL system. The melting
points were determined in open capillaries and are
uncorrected (as are boiling points too). The elemental
analyses were obtained using a Carlo Erba ER-20
CHN analyzer.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

3
94
NURIEV et al.
The X-ray analysis of compound 5 was performed
at 100 K on a Bruker SMART APEX2 CCD diffrac-
J = 8.4), 7.42 d (2H, m-H, J = 8.4). Mass spectrum
+
(EI, 70 eV), m/z (I , %): 349 (100) [M + 1] , 348 (87)
rel
+
tometer (MoK radiation, graphite monochromator,
[M] , 333 (56), 214 (57), 212 (34), 147 (78), 134 (39),
α
ω-scanning). The structure was solved by the direct
method and was refined against Fhkl by the least-
121 (72), 91 (67).
2
Aromatization of the heterocycle in compounds
squares procedure in full-matrix anisotropic approxi-
mation. The NH hydrogen atoms were localized from
the difference Fourier maps, and the other hydrogen
atoms were placed in geometrically calculated posi-
tions. The positions of all hydrogen atoms were refined
according to the riding model. All calculations were
performed using SHELXTL PLUS package [25].
2
0
a and 2b (general procedure). Compound 2a or 2b,
.001 mol, was dispersed in a mixture of 10 mL of
benzene and 10 mL of water, 0.002 mol (0.1 g) of
potassium hydroxide and 0.0021 mol (0.84 g) of
K [Fe(CN) ] were added, and the mixture was stirred
for 16 h at room temperature. The organic phase was
separated, and the aqueous phase was extracted with
benzene (2×10 mL). The extracts were combined with
the organic phase, washed with water until neutral
washings, dried over sodium sulfate, filtered, and
evaporated, and the residue was recrystallized from
appropriate solvent.
3
6
Initial dienones 1a and 1b were synthesized accord-
ing to the procedures described in [5].
Heterocyclization of dienones 1a and 1b with
hydrazine hydrate (general procedure). A mixture of
2
.5 mmol of dienone 1a or 1b and 10 mmol of hydra-
zine hydrate in 15 mL of ethanol was stirred for
several hours on heating. The progress of the reaction
was monitored by TLC. When the reaction was com-
plete, the mixture was cooled, and the precipitate was
filtered off and recrystallized from ethanol.
(7E)-7-Benzylidene-3-phenyl-4,5,6,7-tetrahydro-
2
H-indazole (3a) was obtained from 0.29 g of 2a.
1
Yield 0.23 g (82%), mp 85‒86°C (from THF). H NMR
spectrum (CDCl ), δ, ppm: 2.22‒2.29 m (2H, 5-H),
2
7
1
3
.54‒2.59 m (2H, 4-H), 3.01‒3.06 m (2H, 6-H), 7.11‒
.53 m (9H, Harom, CH=), 7.96 d (2H, o-H, J = 7.5 Hz),
0.04 s (1H, NH). Found, %: C 83.99; H 6.22; N 8.91.
(
7E)-7-Benzylidene-3-phenyl-3,3a,4,5,6,7-hexa-
hydro-2H-indazole (2a) was synthesized from 0.68 g
of (2E,6E)-2,6-dibenzylidenecyclohexan-1-one (1a)
and 0.5 mL of hydrazine hydrate. Yield 0.48 g (70%),
mp 119°C (from EtOH); published data [26]:
C H N . Calculated, %: C 83.88; H 6.34; N 8.78.
2
0
18
2
(
7E)-3-(4-Methoxyphenyl)-7-[(4-methoxyphe-
nyl)methylidene]-4,5,6,7-tetrahydro-2H-indazole
–
1
(
(
(
(
3b) was obtained from 0.35 g of 2b. Yield 0.15 g
43%), mp 79‒82°C (from THF). H NMR spectrum
CDCl ), δ, ppm: 1.62‒1.98 m (2H, 5-H), 2.10‒2.28 m
2H, 4-H), 2.73‒2.84 m (2H, 6-H), 3.83 br.s (6H,
mp 121°C. IR spectrum (mineral oil): ν 3225 cm
1
1
(
N–H). H NMR spectrum (CDCl ), δ, ppm (J, Hz):
3
1
1
2
6
.32–1.49 m (1H, 5-H), 1.54 d.d (1H, 4-H, J = 10.1,
2.1), 1.90–1.99 m (1H, 5-H), 2.08‒2.12 m (1H, 4-H),
.35–2.50 m (1H, 6-H), 2.77–2.87 m (1H, 3a-H, J =
.6, 2.1), 3.05 d (1H, 6-H, J = 15.5), 4.88 d (1H, 3-H,
3
OCH ); 6.77‒7.09 m, 7.21‒7.69 m, and 7.76‒8.15 m
3
(
8H, Harom); 7.86 s (1H, CH=), 9.91 s (1H, NH).
J = 13.9), 7.22 s (1H, NH), 7.31‒7.45 m (9H, Harom
,
Bromination of dienones 1a and 1b (general
CH=), 7.52 d (2H, o-H, J = 7.8). Mass spectrum
procedure). A solution of 5 mmol (0.8 g) of bromine in
5 mL of carbon tetrachloride was slowly added drop-
wise under vigorous stirring to a solution of 5 mmol of
dienone 1a or 1b in 30 mL of carbon tetrachloride.
When the bromine color disappeared, the mixture was
stirred for 15 min, the solvent was distilled off, and the
residue was recrystallized from ethanol.
+
(
EI, 70 eV), m/z (I , %): 287 (100) [M ‒ 1] , 182 (16),
rel
1
15 (13), 91 (12).
7E)-3-(4-Methoxyphenyl)-7-[(4-methoxyphenyl)-
methylidene]-3,3a,4,5,6,7-hexahydro-2H-indazole
(
(2b) was synthesized from 0.84 g of (2E,6E)-2,6-bis-
[(4-methoxyphenyl)methylidene]cyclohexan-1-one
(1b) and 0.5 mL of hydrazine hydrate. Yield 0.90 g,
(6E)-6-Benzylidene-2-bromo-2-[bromo(phenyl)-
methyl]cyclohexan-1-one (4a) was obtained from
1.36 g of 1a. Yield 1.66 g (77%), mp 122‒124°C [20].
mp 84‒86°C (from EtOH) [26]. IR spectrum (mineral
–
1
1
oil): ν 3320 cm (N–H). H NMR spectrum (CDCl ),
3
–
1
δ, ppm (J, Hz): 1.38‒1.60 m (2H, 4-H, 5-H), 1.89‒
IR spectrum (mineral oil): ν 1680 cm (C=O).
1
1
2
.98 m and 2.02‒2.11 m (1H each, 4-H, 5-H), 2.35‒
.48 m and 2.72‒2.84 m (1H each, 3a-H, 6-H), 3.05 d
H NMR spectrum (DMSO-d ), δ, ppm: 1.75‒1.90 m
6
and 1.94‒2.04 m (1H each, 5-H), 2.21‒2.29 m and
2.69‒2.81 m (1H each, 4-H), 2.96‒3.11 m (2H, 6-H),
6.10 br.s (1H, CHBr), 7.37‒7.79 m (11H, Harom, CH=).
(
1H, 6-H, J = 15.5), 3.85 br.s (6H, OCH ), 4.47 d (1H,
3
3
-H, J = 13.9), 5.58 s (1H, NH), 6.85‒7.00 m (4H,
1
3
o-H), 7.18 s (1H, CH=), 7.32 d and 7.47 d (2H, m-H,
C NMR spectrum, δ , ppm: 19.6, 27.8, 33.0, 57.2,
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 3 2016

SYNTHESIS OF 3,7-DISUBSTITUTED HEXAHYDRO- AND TETRAHYDRO-2H-INDAZOLES
395
7
1
1.0, 128.3, 129.1, 129.3, 129.9, 130.7, 131.1, 131.4,
33.5, 135.5, 140.2, 192.0.
(3.5 mmol) of compound 4a in 15 mL of anhydrous
benzene. The mixture was heated for 8 h under reflux
and cooled, and the precipitate was filtered off. The
filtrate was evaporated, and the residue was subjected
to column chromatography on silica gel using ethyl
(
6E)-2-Bromo-2-[bromo(4-methoxyphenyl)-
methyl]-6-[(4-methoxyphenyl)methylidene]cyclo-
hexan-1-one (4b) was synthesized from 1.30 g of 1b.
Yield 0.75 g (38%), mp 139‒143°C. IR spectrum
acetate–petroleum ether (1:3) as eluent. Yield 0.04 g
1
–
1
1
(
41%). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz):
(
(
mineral oil): ν 1680 cm (C=O). H NMR spectrum
DMSO-d ), δ, ppm (J, Hz): 1.82‒1.99 m (2H, 5-H),
6
2
6
.53 d.d (2H, 4-H, J = 6.2, 4.8), 3.07 t (2H, 5-H, J =
.2), 6.48 t (2H, 3-H, J = 4.8), 6.69 br.s (1H, NH),
6
2
4
.29 q.d (1H, 4-H, J = 6.0, 3.1), 2.64‒2.71 m (1H,
-H), 3.37‒3.42 m (2H, 6-H), 3.81 s and 3.84 s (3H
7.19‒7.47 m (7H, Ph, 4′-H, 5′-H), 7.76 br.s (1H, CH=),
8.20 d (1H, 2′-H, J = 4.7), 8.47 d (1H, 6′-H, J = 2.4).
each, OCH ), 5.21 s (1H, CHBr), 7.87 d (2H, o-H, J =
8
8
Found, %: C 57.14; H 4.63. C H Br O. Calculated,
%
3
1
3
.4), 6.92 d (2H, o-H, J = 8.6), 7.42 d (2H, m-H, J =
.4), 7.55 d (2H, m-H, J = 8.6), 7.79 s (1H, CH=).
C NMR spectrum, δ , ppm: 23.4, 26.5, 116.1, 123.7,
C
125.0, 128.5, 128.6, 129.8, 134.4, 135.6, 136.6, 136.7,
138.5, 141.2, 142.3, 184.7. Mass spectrum (EI, 70 eV),
22
22
2
+
: C 57.17; H 4.80.
-Benzylidene-4-phenyl-2,3-diazaspiro[4.4]non-
-en-1-one (5). Hydrazine hydrate, 0.31 g (6 mmol),
m/z (Irel, %): 367 (25) [M] , 247 (10), 155 (81), 115
(
61), 91 (44), 78 (77), 51 (88), 43 (100).
6
3
The authors thank Dr. Yu.V. Nelubina (Nesmeyanov
was added to a solution of 0.68 g (1.6 mmol) of com-
pound 4a in 15 mL of ethanol. The mixture was heated
for 6 h under reflux, cooled, and diluted with 10 mL of
water, and the precipitate was filtered off and recrys-
tallized from ethanol. Yield 0.23 g (48%), mp 159‒
Institute of Organometallic Compounds, Russian
Academy of Sciences) for performing X-ray analysis
and Prof. A.L. Maksimov (Faculty of Chemistry,
Moscow State University) for performing mass spec-
tral studies.
–
1
1
63°C. IR spectrum (mineral oil), ν, cm : 3200
This study was performed under financial support
by the Russian Science Foundation (project no. 14-
1
(N–H), 1700 (C=O). H NMR spectrum (CDCl ), δ,
3
ppm (J, Hz): 2.08‒2.19 m (1H, 4-H), 2.21‒2.29 m (2H,
5
0-00126).
4
3
7
2
-H, 5-H); 2.39‒2.51 m, 2.96‒3.08 m, and 3.08‒
.18 m (1H each, 5-H, 6-H); 6.15 s (1H, CH=), 7.19‒
.43 m (9H, Harom, CH=), 7.56 d.d (2H, o-H, J = 7.8,
.2), 7.76 d (1H, o-H, J = 7.8), 8.91 s (1H, NH).
C NMR spectrum (DMSO-d ), δ , ppm: 25.2, 32.3,
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(
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rel
Crystallographic data. Triclinic crystal system,
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2
0
18
2
1
8
0.393(2), b = 12.279(3), c = 13.182(3) Å; α =
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