Conversions of 2-(2-oxo cyclohexylcarbonyl)benzoic acid derivatives to pyrazolo[5,1-a]isoindole and pyrimidine rings

Article abstract of DOI:10.1080/104265090508127

Phtalic acid derivative of o-methylcarboxybenzoylchloride readily acylates N(1-cyclohexenyl) morpholine and is likely to acylate other enamines along the classic path to 1,3-diketones. It is a convenient route towards o-(1-(1,3-diketone)) derivatives of b

Full text of DOI:10.1080/104265090508127

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Conversions of 2-(2-Oxo
Cyclohexylcarbonyl)Benzoic
Acid Derivatives to
Pyrazolo[, , , , , , , , , , ]Isoindole
and Pyrimidine Rings
J. G. Wolf b , Z. V. Voitenko a , O. A. Pokholenko a ,
I. S. Kondratov a , V. O. Kovtunenko a & C. André b
a Kiev National Taras Shevchenko University, 64 Str
Volodymyrs'ka, Kiev, 01033, Ukraine
b Université Paul Sabatier, SPCMIB UMR CNRS no
5068, 118 route de Narbonne, Toulouse, 31062,
France
Version of record first published: 01 Feb 2007.
To cite this article: J. G. Wolf , Z. V. Voitenko , O. A. Pokholenko , I. S.
Kondratov , V. O. Kovtunenko & C. André (2005): Conversions of 2-(2-Oxo
Cyclohexylcarbonyl)Benzoic Acid Derivatives to Pyrazolo[, , , , , , , , , , ]Isoindole and
Pyrimidine Rings, Phosphorus, Sulfur, and Silicon and the Related Elements, 180:1,
163-177
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Phosphorus, Sulfur, and Silicon, 180:163–177, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508127
Conversions of 2-(2-Oxo Cyclohexylcarbonyl)Benzoic
Acid Derivatives to Pyrazolo[5,1-a]Isoindole
and Pyrimidine Rings
Z. V. Voitenko
O. A. Pokholenko
I. S. Kondratov
V. O. Kovtunenko
Kiev National Taras Shevchenko University, 64 Str Volodymyrs’ka,
01033 Kiev, Ukraine
´
C. Andre,
J. G. Wolf
Universite´ Paul Sabatier, SPCMIB UMR CNRS no 5068, 118 route de
Narbonne, 31062 Toulouse, France
Phtalic acid derivative of o-methylcarboxybenzoylchloride readily acylates N(1-
cyclohexenyl) morpholine and is likely to acylate other enamines along the classic
path to 1,3-diketones. It is a convenient route towards o-(1-(1,3-diketone)) deriva-
tives of benzoic acid, which are precursors of o-(heteroaryl)-benzoic acids. Further
conversions with hydrazines and amidines lead to pyrazolo[5,1-a]isoindole and
pyrimidine rings respectively. The structures of the obtained compounds were con-
firmed by X-ray structure determinations.
Keywords 1,3-Diketones; enamines; O-acylated enols; pyrazolo[5,1-a]isoindoles; pyrim-
idines; X ray diffraction analysis
INTRODUCTION
Properly functionalized β-diketones may lead to heterocyclic com-
pounds with desired functional groups. Their applications are numer-
ous, so we limited the examples to very recent results, i.e. the synthesis
of fluorescein derivatives,1 of UVA absorbers,2 and protein kinase in-
hibitors (balanol).3
Received June 1, 2004; accepted June 15, 2004.
Address correspondence to J. G. Wolf, Universite´ Paul Sabatier, SPCMIB UMR 5068,
118, route de Narbonne, Toulouse, Cedex, F-31062, France. E-mail: wolf@chimie.ups-
tlse.fr
163

164
Z. V. Voitenko et al.
The literature shows a few scattered examples of synthesis of such
β-diketones,4−8 but the reported yield is low. Thus, we decided to test
other approaches to obtain compounds possessing the sub-structure
presented below as a source of o-(heteroaryl)-benzoic acids, precursors
of nitrogen heterocycles.
Among the targeted series, pyrazolo[5,1-a]isoindole derivatives are
interesting, but not yet extensively covered in the literature in
spite of their described biological activity.9 Thus, reactions with
dienophiles seem not to be studied despite unusual results obtained
for other isoindole derivatives with bridged nitrogen and azine or
azole ring annelated at 1,2 positions. An earlier synthesis of 8-oxo-8H-
pyrazolo[5,1-a]isoindole-2,3-dicarboxylic acid dimethyl ester from N-
aminophtalimide(2-amino-isoindole-1,3-dione) and dimethylacetylene
dicarboxylate ester10 was reported. The obtained 2-aryl-1,3a-dihydro-
pyrazolo[5,1-a]isoindol-8-ones and their dehydrated derivatives 2-aryl-
pyrazolo[5,1-a]isoindol-8-ones showed herbicidal and plant growth reg-
ulating activity.11 The synthesis of 2-aryl-8H-pyrazolo[5,1-a]isoindoles
start from o-(ω-(β-diketone)) derivatives A which were obtained by con-
densation of phtalic anhydride and arylmethylketones. Chupp et al.8
suggested a Claisen condensation of aromatic ortho-diesters with
methylketones to generate derivatives of A, though this reaction was
reported to be limited to electron-deficient and aza-analogs of aro-
matic ortho-diesters. Additionally, such reactions normally lead to 2-
acylindanediones-1,312 and the desired compounds A are side products.
In contrast to “simple” β-diketones, such substrates are scarcely
studied due to the lack of efficient synthetic approaches. Thus, the aim
of this paper is to attempt to develop new synthetic methods for A and
use it as precursor for the synthesis of pyrazolo[5,1-a]isoindoles or to
other nitrogen heterocycles, like pyrimidines.
RESULTS AND DISCUSSION
Preparation of the β-Diketone
This study addressed the well-known reaction of acylchlorides (o-
methyl carboxybenzoylchloride I here) with enamines.

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
165
We prepared I and reacted it with N-(1-cyclohexenyl)morpholine II.
Along with the expected β-diketone III we isolated with a good yield
another compound which was attributed to IV (Scheme 2). The separa-
tion of the obtained compounds was achieved by crystallization because
III failed to be distilled in vacuum (at 0.005 torr it distilled with signifi-
cant decomposition). The structures of III and IV were established with
PMR, C13-NMR and X-ray structural analysis. The β-diketone III may
exist in the tautomeric forms of Scheme 1 as seen in CDCl3 solution in
PMR whereas it adopts the IIIa one in the crystal state.
SCHEME 1
The use of 50% excess of enamine did not prevent the formation of
IV and did not reduce its yield significantly. The formation of such com-
pounds during an enamine acylation seems to have not been described
earlier in the chemical literature. This is probably due to the distilla-
tion generally used in the final step of the previous synthetic method,
which leads to the loss of such side compounds.
SCHEME 2
We think that IV arise from Scheme 3, where V is one of the known
intermediates of the reaction above (Scheme 2).
If pyridine was used instead of triethylamine then only IV was iso-
lated, probably because of the weaker basicity of pyridine, which led
to the protonation and thus the deactivation of half of the enamine II.
This left 50% excess of chloroanhydride I in the reaction mixture, which
react with the intermediate V.
The compound III readily formed crystals of diketonates with Cu2+
and Fe3+ ions of green and red color respectively, but failed to react in

166
Z. V. Voitenko et al.
SCHEME 3
similar conditions with Ni2+ and Co2+, while reaction with Ni(OAc)2 in
presence of ammonia or triethylamine lead to a red solution, probably
due to a flat square coordinated Ni diketonate formation.
Reaction of III with Hydrazines
The compound III react easily with an equimolecular amount of hy-
drazine acetate in presence of acetate buffer in water/alcohol solution
to give the pyrazole ring VI (Scheme 4). But it did not react with
phenylhydrazine while boiling in isopropanol for 3 h. The reaction of
III with arylhydrazines would require harder conditions, thus it was
reacted with phenylhydrazine and p-chlorophenylhydrazine in boiling
isopropanol/acetic acid yielding then the pyrazoles VI. The esters VI
are easily hydrolyzed into acids VII. Moreover, in the case where R H,
the acid reacted with dehydrating agents to give the pyrazoloisoin-
dolone VIII which was also identified by X ray structure determination
(see below).
SCHEME 4

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
167
Reactions of VIII
Compound VIII, [5,6,7,8-tetrahydro-9,9a-diaza-indeno[1,2-a]inden-10-
one] is a representative of the isoindoloindazole topological system, but
its π-electronic system is similar to that of pyrazoloisoindolone, so we
treated it as a derivative of the latter. It could be also considered as
N-acylpyrazole, so it is expected to react with nucleophiles by a lactame
ring cleavage. It reacted with hot water, methanol, and amines giving
the corresponding derivatives of the acid VIIa, i.e. compounds VIa,
VIIa itself, and IX (Scheme 5) respectively.
SCHEME 5
We also reacted VIII with LiAlH4 in ether to obtain a mixture of two
products (Scheme 6). Their PMR-spectrum contain two singlets at 4.51
and 5.16 ppm with an intensity ratio near to 6:1. The mixture is treated
by TsCl in pyridine and after work-up a 8H-pyrazoloisoindole deriva-
tive like 1,3,4,7-tetrahydro-2H-isoindolo[2,1-b]indazole XI is obtained.
Its PMR-spectrum contains a unique singlet at 4.51 ppm. A probable
explanation is the formation of both isoindole XI and a benzyl alco-
hol derivative X corresponding to the singlet at 5.16 ppm. The hydroxy
group of X activated with TsCl become capable to attack the pyrazole
ring, thus forming XI.
These compounds are novel members of previously known biologi-
cally active series.13
Reaction of III with Amidines
We studied the reaction of III with formamidine and benzamidine which
lead to the formation of a pyrimidine ring. Unexpectedly, this formation

168
Z. V. Voitenko et al.
SCHEME 6
SCHEME 7
is accompanied by a spontaneous hydrolysis of the ester group. Finally,
the isolated compound is the acid XII (Scheme 7).
The hydrolysis of the intermediate can be explained by a base catal-
ysis by one nitrogen atom of the pyrimidine ring. But the pyrazole ring
also has a nitrogen with lone electron pair in similar position and no
spontaneous hydrolysis occurs in this case, despite similar reaction
conditions. The preparation of 2-pyridin-2-yl-benzoic acid ethyl ester
was also reported and the ester group appeared to be stable in similar
conditions.14 To have a better insight of this hydrolysis, we studied the
geometric features of the methyl ester of XIIa optimized by molecular
modeling, and compared it to the results obtained with VIa. The molec-
ular mechanics calculations were done with the Hyperchem 5.01 pro-
gram (1996) from Hypercube Inc. using the MM+ force field, the lowest
energy structures were obtained after a molecular dynamics research
and the final geometry was checked with a semi-empirical calculation
(AM1 hamiltonian). As shown in Figure 1, the most striking difference
˚
is the N/OMe distance, which is equal to 2.26 A for the methyl ester
˚
of XIIa, and 3.33 A for VIa. The former distance is somewhat shorter
(#0.6 A) than the sum of the Van der Waals radii (O = 1.4 and N = 1.5 A)
˚
˚

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
169
FIGURE 1 Calculated structures showing the greater distance N-O in VIa
˚
than in the methyl ester of XIIa (3.33 versus 2.26 A respectively).
indicating a large interaction which may explain in this case the base
assistance to the hydrolysis.
X Ray Structural Analysis of Compounds III, IV, and IX
General Features
Reflection data were collected at low temperature using an oil-coated
shock-cooled crystal on a Bruker-AXS CCD 1000 diffractometer. The

170
Z. V. Voitenko et al.
structures were solved by direct methods (SHELXS-97)15 and parame-
ters were refined using the least-squares method on F2.16
Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no.
221048, 221047, and 237640 for III, IV and VIII respectively. Copies
of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB21EZ, UK [fax:(+44)-1223-3360-33;
E-mail:deposit@ccdc.cam.ac.uk].
Crystal data for III: C15H16O4, M = 260.28, monoclinic, P21/n, a =
◦
˚
˚
˚
˚
8.511(2) A, b = 14.594(3) A, c = 10.489(2) A, β = 92.847 (4) , V =
1301.1(4)A , Z = 4, ρcalcd = 1.329 Mgm−3, F (000) = 552, λ = 0.71073 A,
T = 173(2)K, µ (MoKa) = 0.096 mm−1, crystal dimensions 0.3 × 0.4 ×
0.5 mm3, 7520 reflections (2671 independent, Rint = 0.0333) were col-
3
˚
lected, R (for I > 2σ(I)) = 0.0404 and wR2 (all data) = 0.1085 with
1
R = ꢀ|Fo| − |F |/ꢀ|Fo| and wR2 = w(ꢀw (F2 − F2)2/ꢀw(F2)2)0.5
.
1
c
o
c
o
The most interesting results on this structure (Figure 2) is that it
adopts the IIIa configuration in the solid state (see Scheme 1). Thus,
the enolic form on the cyclohexyl ring render the C12-C11-C10-C15
˚
moiety planar, the C10-C11 bond shorter (1.363 A as compared to C9-
˚
C11 = 1.437 A) meanwhile the C10-O4 bond correspond to a single one
˚
(1.331 A). The enolic H form a strong H-bond with O1 (distance O1-
˚
O4 only 2.497 A) with an angle of 153˚. Additionally, the C9-C11 bond
(1.437 A ) is intermediate between the double C10-C11 (1.363 A) and
˚
˚
˚
the single C9-C6 (1.505 A) ones.
FIGURE 2 ORTEP III for Windows17 drawing of the X Ray structure of III.

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
171
Crystal data for IV: C24H22O7, M = 422.42, monoclinic, P21/n, a =
◦
˚
˚
˚
˚
8.4305(5) A, b = 22.693(1) A, c = 11.0423(7) A, β = 101.032 (1) , V =
2073.5(2) A , Z = 4, ρcalcd = 1.353 Mgm−3, F (000) = 888, λ = 0.71073 A,
T = 173(2) K, µ (MoKa) = 0.100 mm−1, crystal dimensions 0.5 × 0.5 × 0.7
mm3, 12200 reflections (4246 independent) were collected, R (for I >
4σ(I)) = 0.0336 and wR2 = 0.0899 (all data) with R = ꢀ|Fo| − |1F |/ꢀ|F |
3
˚
1
c
o
and wR2 = (ꢀw (Fo2 − F2)2/ꢀw(Fo2)2)0.5
.
c
Concerning this structure, it is interesting to notice that its con-
figuration confirms the synthetic pathway whereas in the crystal the
compact arrangement is due to strong inter- and intramolecular in-
teractions. The intermolecular ones are mainly due in part to O1-H1
interactions (2.491 A, −0.23 A % sum VdW) and to O6-H11(2.517 A)
between different neighboring asymmetric units, creating a polymeric
network in the crystal. Other noticeable intermolecular interactions are
˚
˚
˚
˚
˚
observed with O4–H8 (2.625 A) and O6–H24B (2.521 A).
Concerning the intramolecular interactions and the geometrical
features of IV, one may consider that it is an enol ester of III with the or-
thomethylester benzoic acid. The position of the two terminal aromatic
methylester groups is interesting, one (C16-O3-C23) is nearly perpen-
dicular to the aromatic plane (dihedral angle C11-C9-C16-O3 = 92.8◦)
whereas the other lies in quite a plane (dihedral angle C15-C4-C7-O5 =
−15.9◦). This is due to the strong internal interaction between O4 and
˚
˚
C10 and C21, 2.787 and 2.713 A respectively, i.e. −0.43 and −0.51 A %
˚
˚
sum VdW, and also with O1-C16, 2.683 A, −0.53 A % sum VdW
(Figure 3).
FIGURE 3 ORTEP III for Windows drawing of the X Ray structure of IV.

172
Z. V. Voitenko et al.
FIGURE 4 ORTEP III for Windows drawing of the X Ray structure of VIII.
Crystal data for VIII: C14H12N2O, M = 224.26, monoclinic, P21/c, a =
◦
˚
˚
˚
10.90(2) A, b = 13.92(3) A, c = 7.37(1) A, β = 106.97 (5) , V = 1070(3)
A , Z = 4, ρcalcd = 1.392 Mgm−3, F(000) = 472, λ = 0.71073 A, T =
193(2)K, µ (MoKa) = 0.090 mm−1, crystal size 0.2 × 0.5 × 0.7 mm3,
6191 reflections (2156 independent) were collected., R (for I > 4σ(I)) =
0.0494 and wR2 = 0.1062 (all data) with R = ꢀ|Fo|1− |F |/ꢀ|Fo| and
3
˚
˚
1
c
wR2 = (ꢀw (Fo2 − F2)2/ꢀw(F2)2)0.5 (Figure 4).
The structure is entirely polanar with the exception of the cyclohexyl
ring which present a C7-C8-C9 flap. The C8 atom lies at 0.5 A over
c
˚
the mean plane formed by the 16 heavy atoms whereas the C9 one is
˚
under the plane (−0.265 A). The other atoms do not deviate for more
˚
˚
˚
than 0.09 A. The C4-C5 bond (1.367 A) and the C6-N2 one (1.334 A ) are
˚
slightly longer than expected for formal double bonds (1.34 and 1.32 A
respectively)18 whereas N1-N2 (1.374 A) is relatively short, this may be
˚
due to a delocalization over the five membered diaza cycle. This is also
˚
observable for C5-C6 (1.437 A) shorter than a formal C-C single bond
˚
(1.46 A) in this environment.
Concerning the intermolecular interactions, only a weak non clas-
˚
sical H bond between H11 and O1 is noticeable (2.70 A) and in the
packing, the planes of alternated molecules (with respect of the C O
˚
orientation) are separated by about 3.6 A.
CONCLUSIONS
The reaction of o-methylcarboxybenzoylchloride II with enamines
is a convenient route toward β-diketones like o-(ω-(β-diketone))
derivatives of benzoic acid, which might give rise to heterocycles
with o-carboxylphenyle radical in corresponding position. Prepared
in this manner 2-(2-oxocyclohexylcarbonyl)benzoic acid methyl ester

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
173
was studied and its reactions with hydrazines and amidines yielded
pyrazole and pyrimidine rings respectively. The obtained derivative
of o-pyrazolobenzoic acid was turned into pyrazolo[5,1-a]isoindole
derivatives.
Experimental
Preparation of 2-Chlorocarbonyl-benzoic Acid Methyl Ester I
90 g (0.5 m) of o-methylcarboxybenzoic acid were dissolved in 100 mL
of toluene and the obtained solution was filtered from traces of phtalic
acid. 50 mL (∼50% excess) of thionyl chloride and then one droplet of
DMFA were added to the toluene solution. Vigorous endothermic reac-
tion followed by intensive emission of gases started. When the emis-
sion almost stopped, reaction mixture was placed in a bath at 60◦C
for an hour. When reaction was completed, all the volatile part was
thoroughly removed with a rotary evaporator at 60–80◦C thus leaving
I as viscous yellow oil (100%) which was then used in reaction with
enamine.
Synthesis of 2-(2-Oxo-cyclohexanecarbonyl)-benzoic
Acid Methyl Ester III and Phthalic Acid 1-[2-(2-
Methoxycarbonylbenzoyl)-cyclohex-1-enyl]
Ester 2-Methyl Ester IV
Acylation of enamine with the chloranhydride19. Freshly distilled
enamine II (85 mL, slightly more than 0.5 mol) was placed in a round
flask, dry toluene (200 mL) and triethylamine (85 mL, 20% excess) were
added and the flask was placed in a bath at 35◦C with magnetic stirring.
A solution of freshly prepared chloranhydride in dry toluene (100 mL)
was placed in a dropper funnel and all the system was connected to at-
mosphere through a desiccating system. The chloranhydride solution
was added slowly with intensive stirring of the reaction mixture, which
first became yellow and then, when approximately 2/3 of chloranhy-
dride was added, sharply changed to red. A precipitate (triethylamine
hydrochloride) was formed during the addition. The reaction mixture
was stirred at 35◦C for an hour and then let to stand overnight at room
temperature. Then 100 mL of 10% aqueous solution of HCl was slowly
added to the red reaction mixture and all was refluxed for 30 min and
cooled. The red colored toluene layer was separated, and the aqueous
layer was extracted twice with toluene (100 mL), the last extraction
gave a clear toluene layer. All toluene fractions were gathered, washed
successively with water, 5% sodium bicarbonate, water and then dried
over Na2SO4. Toluene was removed with a rotary evaporator giving a

174
Z. V. Voitenko et al.
crude mixture of III, IV, and tracks of cyclohexanone in form of red
viscous oil.
Separation of III and IV by Column Chromatography
3 g of the crude mixture was passed through 100 mL of silica gel
40–100 mesh with chloroform as eluent. Fractions containing IV and
V were collected successively. After evaporation of chloroform pure III
and IV were obtained. III formed big white crystals of slight green
shade, IV formed big white crystals of slight yellow shade.
Separation of III and IV by Crystallization
Several crystals of III were added into a crude mixture of products,
which then was put in a refrigerator for a week. This lead to crystalliza-
tion of III. Remaining oil was decanted from crystals of III, which then
were washed with several small portions of toluene (this did not lead to
a noticeable dissolving). Remaining oil and toluene layer were joined,
toluene was removed with a rotary evaporator, seed crystals of IV were
added to the resulting oil and all was put again in a refrigerator for a
week. This, in turn, lead to crystallization of IV. Obtained crystals of
IV were separated from remaining small quantities of oil and, like III,
washed with several small portions of toluene. Obtained samples III
and IV were pure, according to TLC.
Reaction of III with Hydrazine: Preparation of
2-(4,5,6,7-Tetrahydro-1(2)H-indazol-3-yl)-benzoic
Acid Methyl Ester VI
Hydrazine sulfate (8 g, 0.06 mol) and sodium acetate trihydrate (32 g,
0.24 mol) were dissolved in 100 mL of hot water and the resulting
solution was added to a solution of III (10.4 g, 0.04 mol) in i-PrOH
(100 mL). The resulting mixture was refluxed for 2 hours, cooled and
carefully poured into 100 mL of water with 100 mL of saturated solution
of sodium bicarbonate. White precipitate was formed. It was filtered off,
carefully washed with several portions of saturated sodium bicarbon-
ate solution, water, small quantity of cooled methanol and crystallized
from methanol yielding white crystals of VIa–c (8.1 g, 78%).
Reaction of III with Phenylhydrazine
III and freshly distilled phenylhydrazine were heated in isopropanol
for 3 hours. Then, the reaction mixture was poured into water. Dark-
red oil was formed, separated, extensively washed with water, and then
triturated with MeOH to give XIb.

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
175
Reaction of III with p-Chlorphenylhydrazine:
Preparation of 2-[1-(4-Chloro-phenyl)-4,5,6,7-
tetrahydro-1H-indazol-3-yl]-benzoic Acid Methyl
Ester and 2-[1-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-
1H-indazol-3-yl]-benzoic Acid XIc
III and p-chlorphenylhydrazine were heated in 50 mL of i-PrOH and
20 mL of acetic acid for 2 hours. Then the reaction mixture was poured
into water and treated with an excess of NaHCO3 yielding a brownish
precipitate. The precipitate was collected and crystallized from MeOH
thus giving a white crystalline substance. The mother liquor after crys-
tallisation was evaporated giving an additional quantity of pyrazole
VI in form of brownish solid. This sample was heated with aqueous
solution of KOH for 30 minutes until dissolved and formed deep red
solution. The solution was treated with charcoal, filtered and acidified
giving light brown solid, which appeared to be VII.
Reaction of III with Formamidine Acetate
Formamidine acetate (1.7 g) was added to a solution prepared by
dissolving 0.4 g Na in 10 mL of MeOH. Solution of III (2.68 g) in
20 mL of i-PrOH was added and the resulting mixture was kept at room
temperature for a week. TCL showed the absence of the starting III.
Dark-colored reaction mixture was poured into water, a viscous dark oil
was separated and treated with MeOH. The resulting precipitate was
crystallised from MeOH, giving brownish crystals of XIa.
Reaction of III with Benzamidine Hydrochloride
Reaction III (2.2 g) was dissolved in 20 mL of warm MeOH, giving
a clear solution. Benzamidine hydrochloride (2 g m.p. 72–76◦C) was
dissolved in 15 mL of warm MeOH. The solution of benzamidine was
added to the solution of I. The resulting solution immediately became
dark-red. Dry triethylamine (1.2 mL) was added and the obtained reac-
tion mixture was refluxed for 2 hours, and then let to stand for 3 days.
White precipitate was formed and TLC showed absence of I in the
reaction mixture. Dilution of the reaction mixture with water led to
more white precipitate. Obtained precipitate was filtered, washed con-
sequently with water, MeOH and small quantities of EtOAc. Then the
precipitate was diluted in minimal quantities of DMFA and the ob-
tained solution was poured into excess of 5% water solution of KOH,
giving a suspension, which was filtered and the filtrate acidified with
HCl to pH ∼6, giving a white precipitate, which was filtered and dried.
m = 2.4 g. TLC showed that the obtained product was a pure individual
compound.

176
Z. V. Voitenko et al.
Hydrolysis of 2-(4,5,6,7-Tetrahydro-1(2)H-indazol-3-yl)-
benzoic Acid Methyl Eester VI to 2-(4,5,6,7-Tetrahydro-
1(2)H-indazol-3-yl)-benzoic Acid VII
Ester VI (7.69 g, 0.03 mol) was dissolved in 100 mL of methanol and
KOH (2.24 g, pellets) in 10 mL of water was added to the solution. The
mixture was heated under reflux for 30 min at 80◦C (oil bath tempera-
ture), then cooled and diluted with 200 mL of water. Obtained dark-red
solution was treated with charcoal, filtered and acidified, thus giving
a white precipitate of acid VIIa. The product was filtered off, carefully
washed with water and methanol and crystallized from methanol to
give a white solid. VIIa–c was almost insoluble in acetone and chloro-
form; but is easily dissolved in mineral acids and bases.
Cyclization of 2-(4,5,6,7-Tetrahydro-1(2)H-indazol-3-yl)-
benzoic Acid VII into 1,3,4,7-Tetrahydro-2H-isoindolo
[2,1-b]indazol-7-one VIII
Acid VIIa was stirred with SOCl2 in dioxane at room temperature
for one hour and then heated for 30 min and cooled. The acid substrate
gradually dissolved and after a short period, a yellow solid started to
precipitate. Finally, the reaction mixture was diluted with excess water,
which resulted in intensive precipitation of yellow solid, which was fil-
tered, washed with water, triturated with a diluted solution of NaHCO3,
washed with water again and dried. It moderately dissolved in chloro-
form, dioxane, DMFA, ethanol. Solution in ethanol turned from yellow
to colorless after standing for some hours. It did not dissolve in water
or diluted mineral acids.
Hydrolysis of 1,3,4,7-Tetrahydro-2H-isoindolo [2,1-b]indazol-
7-one VIII
A sample of VIII was boiled with an excess of water. The main part
was dissolved after 15 min. Cooling the reaction mixture gave a white
precipitate which, according to TLC was identical to VIIa.
Reaction of VIII with Methanol
A sample of VIII was dissolved in hot methanol, giving a yellow so-
lution, which was then heated to boiling till yellow colour disappeared.
TLC of the resulting solution showed only the presence of VIa.
Reaction of VIII with Amines
A sample of VIII was placed in a flask with 10 mL of dioxane. An
equimolecular amount of amine was added. The mixture was stirred till
all the solids dissolved and the yellow color disappeared. If reaction was
slow, the reaction mixture was heated till the yellow color disappeared.

Pyrazolo[5,1-a]isoindole and Pyrimidine Synthesis
177
When the reaction is completed, water was added to reaction mixture,
thus precipitating the amide IX, which was then filtered off, washed
with water, and recrystallized.
ACKNOWLEDGMENTS
This work was supported in the frame of a co-operation agreement be-
tween the Paul Sabatier University (Toulouse-France) and the Kiev
National Taras Shevchenko University (Ukraine).
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