N-Substituted hepta(methoxycarbonyl)-3a,7a-dihydroindazoles as new sources for the generation of nitrile imines

Article abstract of DOI:10.1007/s11172-010-0251-8

Thermal decomposition of N-substituted hepta(methoxycarbonyl)-3a,7a- dihydroindazoles proceeds through the elimination of hexamethyl benzenehexacarboxylate and results in the generation of l-aryl-3- methoxycarbonylnitrile imines, which are intercepted by both the electron-withdrawing and electron-releasing olefins, for example, methyl acrylate, cyclopentene, vinylcyclopropane, or ethyl vinyl ether, to form the corresponding pyrazolines and pyrazoles. In the presence of propan-2-ol, the main process proceeds through the addition of nitrile inline to the O-H bond to form methyl 2-isopropoxy-2-[2-(4-methoxyphenyl)hydrazono]acetate.

Full text of DOI:10.1007/s11172-010-0251-8

Russian Chemical Bulletin, International Edition, Vol. 59, No. 7, pp. 1387—1392, July, 2010
1387
NꢀSubstituted hepta(methoxycarbonyl)ꢀ3a,7aꢀdihydroindazoles
as new sources for the generation of nitrile imines
Yu. V. Tomilov, D. N. Platonov, G. P. Okonnishnikova, and O. M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6390. Eꢀmail: tom@ioc.ac.ru
Thermal decomposition of Nꢀsubstituted hepta(methoxycarbonyl)ꢀ3a,7aꢀdihydroindazoles
proceeds through the elimination of hexamethyl benzenehexacarboxylate and results in the
generation of 1ꢀarylꢀ3ꢀmethoxycarbonylnitrile imines, which are intercepted by both the elecꢀ
tronꢀwithdrawing and electronꢀreleasing olefins, for example, methyl acrylate, cyclopentene,
vinylcyclopropane, or ethyl vinyl ether, to form the corresponding pyrazolines and pyrazoles.
In the presence of propanꢀ2ꢀol, the main process proceeds through the addition of nitrile imine
to the O—H bond to form methyl 2ꢀisopropoxyꢀ2ꢀ[2ꢀ(4ꢀmethoxyphenyl)hydrazono]acetate.
Key words: 3a,7aꢀdihydroindazoles, nitrile imines, pyrazolines, pyrazoles, 1,3ꢀdipolar addiꢀ
tion, thermolysis.
Nitrile imines belong to the class of highly reactive
1,3ꢀdipoles and, like aliphatic diazo compounds, are widely
used in various 1,3ꢀdipolar cycloaddition reactions to unꢀ
saturated compounds, which lead to the formation of pyrꢀ
azolines, pyrazoles, and other heterocyclic compounds.1—5
The electron state of nitrile imines is represented by four
major resonance structures (propargylic, allenic, allylic,
and carbene), the contribution of each of which can sigꢀ
nificantly change depending on the electronic properties
of substituents.5—8
ble nitrile imines with bulky substituents in the moleꢀ
cule.4,5,10
In the present work, we found a new source of Nꢀsubꢀ
stituted 3ꢀ(methoxycarbonyl)nitrile imines 1, formed durꢀ
ing thermal decomposition of 1ꢀarylꢀ3,3a,4,5,6,7,7aꢀ
hepta(methoxycarbonyl)ꢀ3a,7aꢀdihydroindazoles (2) and
intercepted with unsaturated compounds or isopropyl
alcohol.
Results and Discussion
Recently,11 while studying the reaction of hepta(methꢀ
oxycarbonyl)cycloheptatrienylpotassium with aryldiazoꢀ
nium salts we suggested a new method for the synthesis of
a number of substituted 3a,7aꢀdihydroindazoles 2. It turned
out that the latter undergo thermal decomposition at
130—140 °C with elimination of benzenehexacarboxylate
3 and generation of the intermediates, whose interception
with unsaturated substrates indicates that they are nitrile
imines 1 containing a methoxycarbonyl fragment at the
carbon atom (Scheme 1). The experiments were carried
out in sealed tubes under inert atmosphere by heating diꢀ
hydroindazoles 2 with a 10ꢀfold molar excess of an unsatꢀ
urated compound or propanꢀ2ꢀol. The unsaturated comꢀ
pounds were methyl acrylate, ethyl vinyl ether, cyclopenꢀ
tene, or vinylcyclopropane, and in all the cases, the reacꢀ
tion mixtures were diluted with a small amount of 1,4ꢀdiꢀ
oxane for complete dissolution of 2. For instance, therꢀ
molysis (135 °C, 10 h) of dihydroindazole 2a in the presꢀ
ence of methyl acrylate leads, together with benzenehexacꢀ
arboxylate 3, to 1ꢀ(4ꢀfluorophenyl)ꢀ2ꢀpyrazolineꢀ3,5ꢀdiꢀ
Due to the specificities of the electronic structure and,
as a rule, higher reactivity as compared to diazo comꢀ
pounds, which are their structural isomers, nitrile imines
can exhibit ambiphilic character, reacting with equal faꢀ
cility with multiple bonds of unsaturated compounds conꢀ
taining either electronꢀwithdrawing, or electronꢀreleasing
substituents at the multiple bond.2—4,9 Among various
methods for the generation of nitrile imines, the following
should be mentioned: 1,3ꢀdehydrochlorination of chloriꢀ
nated Nꢀarylhydrazones (YC(Cl)=N—NHAr, Y = Ar,
COOMe); thermolysis or photolysis of 2,5ꢀdisubstituted
tetrazoles, sidnones, or 1,3,4ꢀoxadiazolꢀ5ꢀones; oxidaꢀ
tion of aldehyde Nꢀacylꢀ or Nꢀhetarylꢀsubstituted hydrꢀ
azones,1—5,9 as well as addition of electrophiles at the
terminal nitrogen atom of metallated derivative of diꢀ
azo compound, mainly used for the preparation of staꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1357—1362, July, 2010.
1066ꢀ5285/10/5907ꢀ1387 © 2010 Springer Science+Business Media, Inc.

1388
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Tomilov et al.
Scheme 1
E = CO2Me; X = F (a), OMe (b)
carboxylate 4a in 80% yield (see Scheme 1), whose formaꢀ
tion is easily explained by the generation of nitrile imine
1a and its regioselective addition to the double bond of
methyl acrylate.
magnitude than on generation of methoxyphenylꢀsubstiꢀ
tuted intermediate 1b.
It should be noted that the lack of regiospecificity in
the 1,3ꢀdipolar cycloaddition reactions of nitrile imines to
the multiple bonds of unsaturated compounds is not surꢀ
prising. Thus, for example, if cycloaddition of diphenylꢀ
nitrile imine to alkenes with electronꢀreleasing substituꢀ
ents virtually entirely leads to 5ꢀsubstituted 2ꢀpyrazolines,
then in the case of conjugated and electronꢀdeficient diꢀ
polarophiles the fraction of 4ꢀsubstituted regioisomers sigꢀ
nificantly increases.2,13 The lack of regioselectivity is esꢀ
pecially noticeable in the case of acetylene dipolarophiles.
Thus, for example, cycloaddition of the same nitrile imiꢀ
nes 1a,b generated in situ by 1,3ꢀdehydrochlorination of
chlorinated Nꢀarylhydrazones MeO2C—CCl=N—NHAr
in the presence of methyl propiolate leads to isomeric pyrꢀ
azoleꢀ3,4ꢀ and pyrazoleꢀ3,5ꢀdicarboxylates in the ratio
close to 1 : 1 (see Ref. 12).
Further we studied the reactivity of nitrile imines 1a,b
with respect to electronꢀreleasing olefins. It turned out
that thermolysis of dihydroindazole 2b (130 °C, 10 h) in
the presence of cyclopentene, similar to the case of methyl
acrylate, leads to a predominant formation of bicyclic pyrꢀ
azoline 6 (the yield was 70%) and a small amount of pyrꢀ
azole 7 (Scheme 2) isolated in the individual state by colꢀ
umn chromatography on SiO2. It should be noted that the
presence of pyrazoles 5b and 7 was observed in the
1H NMR spectra of the reaction mixtures even when the
reaction was carried out under inert atmosphere. It cannot
be excluded that their formation is due to the easy deꢀ
hydrogenation of the corresponding 4ꢀsubstituted pyrazolꢀ
ines upon the action of nitrile imine 1b itself in the course
of the reaction; at least, no oxidation of pyrazolines 4a,b
Recently,9 an intermediate similar to 1a, viz., 1ꢀ(4ꢀchloꢀ
rophenyl)ꢀ3ꢀ(ethoxycarbonyl)nitrile imine, has been genꢀ
erated by photolytic dediazotization of 2ꢀ(4ꢀchlorophenyl)ꢀ
5ꢀethoxycarbonyltetrazole. It was trapped with methyl
methacrylate as a result of 1,3ꢀdipolar cycloaddition and
also gave 5ꢀsubstituted pyrazoline with high regioselectivity.
Thermolysis of dihydroindazole 2b under analogous
conditions in the presence of methyl acrylate, together
with expected pyrazoline 4b, additionally gave pyrazoleꢀ
3,4ꢀdicarboxylate 5b (the total yield was 78%, the ratio
was ~6 : 1) (see Scheme 1). The latter was identified* by
1
comparison of H and 13C NMR spectra obtained by us
with those given in the work.12 The side formation of pyrꢀ
azole 5b apparently occurs due to the fact that nitrile imine
1b reacts with methyl acrylate with lower regioselectivity
than 1a, whereas pyrazoline 4b´ resulted from this, in conꢀ
trast to regioisomeric pyrazoline 4b, undergoes rapid oxiꢀ
dation to pyrazole 5b. After obtaining such a result, we
studied in detail the composition of the products of the
reaction of 2a with methyl acrylate and made certain that, if
the corresponding 1ꢀ(4ꢀfluorophenyl)pyrazoleꢀ3,4ꢀdicarbꢀ
oxylate 5a is really present in the reaction mixture, then its
amount does not exceed 1.5%, i.e., is lower by an order of
* The 13C NMR spectrum obtained by us significantly differs
from that described in the work12 in position of the signal for the
methoxy group of the aryl fragment. Chemical shift δ 55.5 found
by us seems more reasonable than the value δ 44.1 given by the
authors.12

Aryl(methoxycarbonyl)nitrile imines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1389
Scheme 3
or 6 to pyrazoles was observed during chromatographic
separation of the reaction mixture and their isolation.
Scheme 2
X = F (a), OMe (b)
of pyrazoline 10 at 150 °C for 6 h leads to its entire converꢀ
sion to pyrazole 11.
Analogous transformations take place on the intercepꢀ
tion of nitrile imines with vinylcyclopropane. For instance,
thermolysis of dihydroindazoles 2a and 2b at 135—140 °C
in the presence of vinylcyclopropane leads, together with
pyrazolines 8a,b, to a significant amount of the correꢀ
sponding pyrazoles 9a,b (Scheme 3). In this case, NMR
spectroscopy with the use of homoꢀ and heteronuclear
twoꢀdimensional COSY, HMBC, and HSQC correlation
spectra unambiguously showed that the cyclopropyl subꢀ
stituent in both pyrazoline 8b and pyrazole 9b is located
on the C(5) atom of the heterocycle. The result obtained,
as it was mentioned above, is in agreement with the fact
that cycloaddition of nitrile imines to electronꢀsaturated
alkenes occurs with high regioselectivity, leading to the
formation of 5ꢀsubstituted 2ꢀpyrazolines. At the same
time, pyrazolines containing electronꢀreleasing subsꢀ
tituents apparently undergo much easier oxidation,
that results in significant formation of pyrazoles 9a,b
independent on the nature of substituents in the phenyl
fragment.
It is known14 that the reaction of butyl vinyl ether with
nitrile imine 1b, generated by elimination of HCl from
methyl [(4ꢀmethoxyphenyl)hydrazono]chloroacetate at
20 °C, gives a mixture of 5ꢀbutoxyꢀ3ꢀmethoxycarbonylꢀ1ꢀ
(4ꢀmethoxyphenyl)ꢀ2ꢀpyrazoline and 3ꢀmethoxycarbonꢀ
ylꢀ1ꢀ(4ꢀmethoxyphenyl)pyrazole in 27 and 28% yields,
respectively. During thermal decomposition (130 °C) of
dihydroindazole 2a in the presence of 50—60ꢀfold excess
of ethyl vinyl ether, the reaction also proceeds through the
1,3ꢀdipolar cycloaddition of generated nitrile imine 1a to
the double bond of the substrate. The yield of 5ꢀethoxyꢀ
pyrazoline 10 is only 15—18%, whereas the major reacꢀ
tion product is pyrazole 11, formed in ~60% yield from
pyrazoline 10 as a result of elimination of ethanol (Scheme 4).
In fact, an additional experiment showed that thermolysis
Scheme 4
i. 130 °C, 11 h
In addition to unsaturated substrates, alcohols also
proved active interceptors of nitrile imines.15,16 We showed
that heating a solution of dihydroindazole 2b in isopropyl
alcohol in a sealed tube at 130 °C for 10 h leads to the
formation of 2ꢀhydrazonoꢀ2ꢀisopropoxyacetate 12 in
~80% yield, the addition product of 1b at the O—H bond
of propanꢀ2ꢀol (Scheme 5).
Scheme 5
i. 130 °C, 10 h

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Tomilov et al.
F, 6.78. MS (EI), m/z (Irel (%)): 280 [M]+ (73), 249 [M – OMe]+
(17), 221 [M – CO2Me]+ (65), 189 (100), 177 (54), 135 (45), 122
(75), 109 (62), 95 (85), 75 (75), 59 (45). IR, ν/cm–1: 2952, 1752
and 1724 (2 COO), 1564, 1512, 1440. 1H NMR (CDCl3), δ: 3.34
(dd, 1 H, Ha(4), 2J = 18.5 Hz, 3J = 7.0 Hz); 3.56 (dd, 1 H, Hb(4),
2J = 18.5 Hz, 3J = 13.5 Hz); 3.76, 3.90 (both s, 3 H each,
2 OMe); 4.92 (dd, 1 H, H(5), J = 7.0 Hz, J = 13.5 Hz); 7.00 (dd,
In conclusion, decomposition of 1ꢀarylꢀ3,3a,4,5,6,7,7aꢀ
hepta(methoxycarbonyl)ꢀ3a,7aꢀdihydroindazoles 2 upon
heating above 130 °C through the elimination of benzeneꢀ
hexacarboxylate 3 leads to the generation of intermediates
corresponding to the structure of 1ꢀarylꢀ3ꢀmethoxycarbꢀ
onylnitrile imines 1. The latter, similarly to nitrile imines
generated by other methods, undergo the 1,3ꢀdipolar adꢀ
dition reaction with unsaturated compounds containing
either electronꢀwithdrawing, or electronꢀreleasing substitꢀ
uents at the double bond, as well as undergo addition at
the O—H bond of aliphatic alcohols. In the case of elecꢀ
tronꢀdeficient olefins, the addition agrees with the propꢀ
argylic or allenic form, whereas in the case of electronꢀ
enriched olefins, with the allylic form of nitrile imines.
3
3
2 H, Hm, JH,H = 9.5 Hz, JH,F = 8.5 Hz); 7.08 (dd, 2 H, CHo,
3
3JH,H = 9.5 Hz, JH,F = 4.5 Hz). 13C NMR (CDCl3), δ: 37.3
3
(C(4)); 52.4, 53.0 (2 OMe); 62.7 (C(5)); 115.4 (d, Co, JC,F
=
= 8.0 Hz); 116.0 (d, Cm, 2JC,F = 23.0 Hz); 138.3 (C(3)); 138.90
(d, Cipso, JC,F = 2.0 Hz); 158.4 (d, Cp, JC,F = 243 Hz); 162.4,
170.4 (2 COO). 19F NMR (CDCl3), δ: –122.8 (tt, J = 8.5 Hz,
4
3
4J = 4.5 Hz).
Dimethyl 1ꢀ(4ꢀmethoxyphenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ
3,5ꢀdicarboxylate (4b) and dimethyl 1ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ
pyrazoleꢀ3,5ꢀdicarboxylate (5b). Dihydroindazole 2b (0.25 g)
and methyl acrylate (0.34 g) gave a mixture of pyrazoline 4b
and pyrazole 5b (91 mg, ~78%, the ratio was ~6 : 1 according
to the 1H NMR spectrum) as slightly yellowish fusible crysꢀ
tals, m.p. 25—28 °C, which were unseparable under these conꢀ
ditions.
Compound 4b. GLCꢀMS (EI), m/z (Irel (%)): 292 [M]+ (78),
233 [M – CO2Me]+ (80), 201 (100), 189 (36), 174 (58), 134 (40),
107 (35). 1H NMR (CDCl3), δ: 3.31 (dd, 1 H, Ha(4), 2J = 18.5 Hz,
3J = 7.0 Hz); 3.53 (dd, 1 H, Hb(4), 2J = 18.5 Hz, 3J = 13.5 Hz);
3.73, 3.77, 3.87 (all s, 3 H each, 3 OMe); 4.92 (dd, 1 H, H(5),
J = 7.0 Hz, J = 13.5 Hz); 6.85, 7.08 (both d, 2 H each, Ho, Hm,
3J = 9.0 Hz). 13C NMR (CDCl3), δ: 37.1 (C(4)); 52.3, 52.9
(2 COOMe); 55.6 (OMe); 62.94 (C(5)); 114.6, 115.5 (Co, Cm);
136.4 (C(3)); 137.1 (Cipso); 155.12 (Cp); 162.6, 170.7 (2 COO).
Compound 5b (see Ref. 12). 13C NMR (CDCl3), δ: 52.3,
53.5, 55.5 (3 OMe); 113.8 (Cm); 114.7 (C(5)); 115.6 (C(4));
127.4 (Co); 131.6 (Cipso); 144.7 (C(3)); 157.5 (Cp); 161.8, 162.2
(2 COO).
Methyl 1ꢀ(4ꢀmethoxyphenyl)ꢀ1,3a,4,5,6,6aꢀhexahydrocycloꢀ
penta[c]pyrazoleꢀ3ꢀcarboxylate (6) and methyl 1ꢀ(4ꢀmethoxypheꢀ
nyl)ꢀ1,4,5,6ꢀtetrahydrocyclopenta[c]pyrazoleꢀ3ꢀcarboxylate (7).
Dihydroindazole 2b (0.25 g) and cyclopentene (0.27 g) gave
pyrazoline 6 (76 mg, 70%) and pyrazole 7 (11 mg, 10%).
Compound 6, lemon crystals, m.p. 90—91 °C (from hexꢀ
ane—C6H6, 5 : 1). Found (%): C, 65.56; H, 5.76; N, 10.18.
C15H18N2O3. Calculated (%): C, 65.68; H, 6.61; N, 10.21. MS
(EI), m/z (Irel (%)): 274 [M]+ (100), 259 [M – Me]+ (20), 243
[M – OMe]+ (6), 215 [M – CO2Me]+(40). 1H NMR (CDCl3),
δ: 1.40, 1.20 (both m, 1 H each, H2C(5)); 1.82—2.14 (m, 4 H,
2 CH2); 3.77, 3.85 (both s, 3 H each, 2 OMe); 3.93, 4.78 (both m,
1 H each, H(3a), H(6a)); 6.84, 7.13 (both d, 2 H each, Ho, Hm,
3J = 8.9 Hz). 13C NMR (CDCl3), δ: 24.4 (C(5)); 33.2, 34.4
(C(4), C(6)); 49.4 (C(3a)); 51.9 (CO2Me); 55.6 (OMe); 67.2
(C(6a)); 114.5, 115.4 (Co, Cm); 135.9 (Cipso); 140.1 (C(3)); 154.6
(Cp); 163.5 (COO).
Experimental
1
H and 13C NMR spectra were recorded on a Bruker
AVANCE II 300 (300 and 75.5 MHz) and Bruker DRXꢀ500
(500 MHz and 125.3 MHz, respectively) spectrometers for soluꢀ
tions in CDCl3 containing 0.05% of Me4Si as an internal stanꢀ
dard; chemical shifts for 19F are given relative to CCl3F. Assignꢀ
ment of signals and determination of isomeric composition of
compounds formed were made using homoꢀ and heteronuclear
twoꢀdimensional COSY, HMBC, and HSQC correlation specꢀ
tra. GLCꢀMS spectra were obtained on a Finnigan MAT DSQII
instrument (EI, 70 eV, the temperature of the source of ions—trap
of ions system was 200 °C) and Trace GC Ultra chromatograph
equipped with a Thermo TRꢀ5ms SQC column, 15 m×0.25 mm.
IR spectra were recorded on a Specord Mꢀ80 spectrometer in
KBr pellets. Thinꢀlayer chromatography was performed on Siliꢀ
ca gel 60 plates (Merck) with visualization in a chamber with
iodine vapors. Column chromatography was used for preparaꢀ
tive separations (silica gel 60, 0.040—0.063 mm, Merck) at the
ratio substance—sorbent of ~1 : 100. Melting points were meaꢀ
sured on a Nagema PHMKꢀ05 apparatus.
1ꢀ(4ꢀFluorophenyl)ꢀ (2a) and 3,3a,4,5,6,7,7aꢀhepta(methꢀ
oxycarbonyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3a,7aꢀdihydroindazoles (2b)
with the purity no less than 98% were obtained according to the
described procedure.11 Unsaturated compounds were distilled
under inert atmosphere before use, solvents (chemically pure
grade, >99.5%) were used without additional purification.
Thermolysis of 3a,7aꢀdihydroindazoles 2a,b in the presence of
olefins (general procedure). A mixture of heptamethyl dihydroꢀ
indazoleheptacarboxylate 2a or 2b (0.4 mmol), an unsaturated
compound (4 mmol), and 1,4ꢀdioxane (0.3 mL) was heated in
a sealed tube under Ar at 130—140 °C for 10 h. The reaction
1
mixture was analyzed by TLC and H NMR spectroscopy. The
major reaction products were isolated by column chromatograꢀ
phy on SiO2 using the benzene—EtOAc mixture as an eluent
with the solvents gradient from 10 : 1 to 2 : 1. In all the cases,
benzenehexacarboxylate 3 was eluted after the corresponding
pyrazolines and pyrazoles.
Compound 7, a yellowish waxꢀlike mass. MS (EI), m/z
(Irel (%)): 272 [M]+ (100), 257 [M – Me]+ (20), 241 [M – OMe]+
1
(20), 229 (20), 213 [M – CO2Me]+(32). H NMR (CDCl3), δ:
Dimethyl 1ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ3,5ꢀ
dicarboxylate (4a) was obtained from dihydroindazole 2a (0.24 g)
and methyl acrylate (0.34 g). The yield of compound 4a was 90 mg
(80%), colorless crystals, m.p. 124—125 °C (from C6H6—AcOEt,
10 : 1). Found (%): C, 55.74; H, 4.60; N, 10.08; F, 6.74.
C13H13FN2O4. Calculated (%): C, 55.71; H, 4.68; N, 10.00;
2.65 (m, 2 H, H2C(5)); 2.86, 2.96 (both br.t, 2 H each, 2 CH2,
3J = 7.3 Hz); 3.84, 3.93 (both s, 3 H each, 2 OMe); 6.95 (d, 2 H,
2 Hm, 3J = 8.9 Hz); 7.59 (d, 2 H, 2 Ho, 3J = 8.9 Hz). 13C NMR
(CDCl3), δ: 19.5, 23.9 (C(4), C(6)); 30.9 (C(5)); 52.0 (CO2Me);
55.6 (OMe); 114.5 (Cm); 121.9 (Co); 131.3 (C(3a)); 132.2 (Cipso);
132.4 (C(3)); 150.1 (C(6a)); 158.6 (Cp); 163.6 (COO).

Aryl(methoxycarbonyl)nitrile imines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1391
Methyl 5ꢀcyclopropylꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀ
pyrazoleꢀ3ꢀcarboxylate (8a) and methyl 5ꢀcyclopropylꢀ1ꢀ(4ꢀ
fluorophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate (9a). Dihydroindꢀ
azole 2a (0.24 g) and vinylcyclopropane (0.27 g) gave pyrazoline
8a (53 mg, ~50%) and pyrazole 9a (23 mg, 22%), each of which
is enriched with the major substance by 93—95%.
(C(4)); 114.2 (Cm); 126.9 (Co); 132.6 (Cipso); 143.2 (C(3)); 147.9
(C(5)); 159.7 (Cp); 163.4 (COO).
Methyl 5ꢀethoxyꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrꢀ
azoleꢀ3ꢀcarboxylate (10) and methyl 1ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀpyrꢀ
azoleꢀ3ꢀcarboxylate (11). Dihydroindazole 2a (0.24 g, 0.4 mmol)
and ethyl vinyl ether (1.73 g, 24 mmol) after separation by colꢀ
umn chromatography on SiO2 (benzene—EtOAc, 8 : 1) gave
a mixture of 10 and 11 (30 mg, molar ratio 1 : 0.7) and pyrazole
11 (41 mg), the total yield of which was ~60%.
Compound 8a. IR, ν/cm–1: 2958, 1700 (COO), 1508. MS
(EI), m/z (Irel (%)): 262 [M]+ (10), 221 (5), 189 (16), 177 (10),
122 (12), 109 (100). 1H NMR (CDCl3), δ: 0.26, 0.41, 0.52, 0.65
(all m, 1 H each, CH2CH2); 1.07 (m, 1 H, CH in cycloꢀC3H5);
3.03 (dd, 1 H, Ha(4), 2J = 17.9 Hz, 3J = 6.0 Hz); 3.31 (dd, 1 H,
Hb(4), 2J = 17.9 Hz, 3J = 12.0 Hz); 3.90 (s, 3 H, OMe); 4.09
(ddd, 1 H, H(5), 3J = 6.0 Hz, 7.9 Hz, J = 12.0 Hz); 7.00 (dd, 2 H,
Compound 10. GLCꢀMS (EI), m/z (Irel (%)): 266 [M]+ (50),
235 [M – OMe]+ (10), 221 [M – OEt]+ (70), 190 (60), 177 (30),
109 (100). 1H NMR (CDCl3), δ: 1.12 (t, 3 H, Me, 3J = 7.0 Hz);
3.18—3.39 (m, 4 H, H2C(4), OCH2); 3.89 (s, 3 H, OMe); 5.83
(dd, 1 H, H(5), 3J = 3.5 Hz, 3J = 8.7 Hz); 7.01 (dd, 2 H, Hm,
3JH,H = 8.9 Hz, 3JH,F = 8.2 Hz); 7.30 (dd, 2 H, Ho, 3JH,H = 8.9
Hm, 3JH,H = 9.1 Hz, 3JH,F = 8.6 Hz); 7.24 (dd, 2 H, Ho, 3JH,H
=
4
= 9.1 Hz, JH,F = 4.5 Hz). 13C NMR (CDCl3), δ: 1.9, 6.3
4
(CH2CH2); 15.3 (CH in cycloꢀC3H5); 37.9 (C(4)); 52.2 (OMe);
Hz, JH,F = 4.8 Hz). 13C NMR (CDCl3), δ: 15.0 (Me); 37.0
66.2 (C(5)); 115.7 (d, Cm, 2JC,F = 22.5 Hz); 117.8 (d, Co, 3JC,F
=
(C(4)); 52.3 (OMe); 59.1 (OCH2); 88.8 (C(5)); 115.8 (d, Cm,
4
3
= 8.0 Hz); 137.8 (d, Cipso, JC,F = 2.2 Hz); 138.5 (C(3)); 160.0
2JC,F = 22.5 Hz); 116.2 (Co, JC,F = 8.0 Hz); 138.0 (d, Cipso
,
1
1
(COO); 160.1 (d, Cp, JC,F = 242 Hz). 19F NMR (CDCl3), δ:
4JC,F = 2.3 Hz); 139.0 (C(3)); 158.1 (d, Cp, JC,F = 243 Hz);
–122.8 (tt, 3J = 8.6 Hz, 4J = 4.5 Hz).
162.7 (COO).
Compound 9a. IR, ν/cm–1: 2958, 1724 (COO), 1516. MS
(EI), m/z (Irel (%)): 260 [M]+ (10), 229 [M – OMe]+ (90), 213
(10), 201 [M – COOMe]+ (12), 161 (12), 134 (15), 105 (50), 95
(100). 1H NMR (CDCl3), δ: 0.81, 1.01 (both m, 2 H each,
Compound 11, colorless crystals, m.p. 101—102 °C (from
C6H6). Found (%): C, 60.24; H, 4.08; N, 12.51. C11H9FN2O2.
Calculated (%): C, 60.00; H, 4.12; N, 12.72. MS (EI), m/z
(Irel (%)): 220 [M]+ (50), 189 [M – OMe]+ (71), 162 (25), 134
(45), 107 (40), 95 (100). IR, ν/cm–1: 2960, 1724 (COO), 1522,
1504. 1H NMR (CDCl3), δ: 3.99 (s, 3 H, OMe); 5.83 (dd, 1 H,
H(5), 3J = 3.5 Hz, 3J = 8.7 Hz); 7.00 (d, 1 H, H(4), 3J = 2.4 Hz);
7.17 (dd, 2 H, Hm, 3JH,H = 8.9 Hz, 3JH,F = 8.1 Hz); 7.71 (dd, 2 H,
Ho, 3JH,H = 8.9 Hz, 4JH,F = 4.9 Hz); 7.88 (d, 1 H, H(5), 3J= 2.4 Hz).
CH2CH2); 1.74 (tt, 1 H, CH in cycloꢀC3H5, Jcis = 8.5 Hz, Jtrans
=
= 5.2 Hz); 3.95 (s, 3 H, OMe); 6.50 (s, 1 H, H(4)); 7.18 (dd, 2 H,
Hm, 3JH,H = 9.0 Hz, 3JH,F = 8.3 Hz); 7.60 (dd, 2 H, Ho, 3JH,H
=
4
= 9.0 Hz, JH,F = 4.8 Hz). 13C NMR (CDCl3), δ: 7.5 (CH in
cycloꢀC3H5); 9.1 (CH2CH2); 52.1 (OMe); 105.3 (C(4)); 116.1
2
3
(d, Cm, JC,F = 22.7 Hz); 127.3 (d, Co, JC,F = 8.3 Hz); 135.6
13C NMR (CDCl3), δ: 52.2 (OMe); 110.6 (C(4)); 116.4 (d, Cm,
3
(d, Cipso
,
4JC,F = 2.2 Hz); 143.6 (C(3)); 147.9 (C(5)); 162.4
2JC,F = 22.7 Hz); 122.1 (Co, JC,F = 8.5 Hz); 136.0 (d, Cipso
,
1
(d, Cp, JC,F = 248 Hz); 162.9 (COO). 19F NMR (CDCl3), δ:
4JC,F = 2.2 Hz); 144.9 (C(3)); 147.9 (C(5)); 161.8 (d, Cp, 1JC,F
=
= 244 Hz); 162.6 (COO). 19F NMR (CDCl3), δ: –114.7 (tt, 3J =
–113.3 (tt, 3J = 8.3 Hz, 4J = 4.8 Hz).
Methyl 5ꢀcyclopropylꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀ
pyrazoleꢀ3ꢀcarboxylate (8b) and methyl 5ꢀcyclopropylꢀ1ꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate (9b). Dihydroindazole 2b
(0.25 g) and vinylcyclopropane (0.27 g) gave pyrazoline 8b
(53 mg, 48%) and pyrazole 9b (26 mg, 24%).
= 8.1 Hz, 4J = 4.9 Hz).
Methyl 2ꢀisopropoxyꢀ2ꢀ(4ꢀmethoxyphenyl)hydrazonoacetate
(12). A mixture of dihydroindazole 2b (0.18 g, 0.3 mmol) and
PriOH (3 mL) was heated for 10 h in a sealed tube under Ar at
130 °C. After evaporation of propanꢀ2ꢀol, the target product was
isolated by column chromatography on SiO2 (benzene—EtOAc,
2 : 1). Hydrazone 12 (76 mg) was obtained with admixture of
benzenehexacarboxylate 3 (9—10%) as a colorless oil. MS (EI),
m/z (Irel (%)): 266 [M]+ (10), 224 (15), 164 (60), 149 (15),
137 (18), 122 (100), 84 (60). 1H NMR (CDCl3), δ: 1.35 (d, 6 H,
Compound 8b, colorless crystals, m.p. 112—113 °C (from
C6H6—AcOEt, 10 : 1). Found (%): C, 65.31; H, 6.50; N, 10.01.
C15H18N2O3. Calculated (%): C, 65.68; H, 6.61; N, 10.21. MS
(EI), m/z (Irel (%)): 274 [M]+ (100), 259 [M – Me]+ (10), 243
[M – OMe]+ (8), 233 (15), 215 [M – CO2Me]+ (5), 201 (50),
189 (12), 174 (20), 160 (15), 146 (17), 134 (20), 122 (90). 1H NMR
(CDCl3), δ: 0.24, 0.38, 0.50, 0.62 (all m, 1 H each, CH2CH2);
1.07 (m, 1 H, CH in cycloꢀC3H5); 3.01 (dd, 1 H, Ha(4), 2J= 18.0 Hz,
3J = 6.1 Hz); 3.29 (dd, 1 H, Hb(4), 2J = 18.0 Hz, 3J = 12.0 Hz);
3.80, 3.87 (both s, 3 H each, 2 OMe); 4.06 (ddd, 1 H, H(5),
3J = 6.1 Hz, 3J = 8.0 Hz, 3J = 12.0 Hz); 6.86 (d, 2 H, Hm,
3J = 9.0 Hz); 7.23 (d, 2 H, Ho, 3J = 9.0 Hz). 13C NMR (CDCl3),
δ: 1.8, 6.3 (CH2CH2); 15.2 (CH in cycloꢀC3H5); 37.5 (C(4));
52.1 (CO2Me); 55.6 (OMe); 66.8 (C(5)); 114.3 (Cm); 118.3 (Co);
137.0 (C(3)); 137.4 (Cipso); 155.2 (Cp); 163.6 (COO).
Compound 9b. MS (EI), m/z (Irel (%)): 272 [M]+ (100), 257
[M – Me]+ (20), 241 [M – OMe]+ (35), 225 (45), 213 [M –
– CO2Me]+ (25), 197 (22), 121 (33), 108 (25), 92 (37). 1H NMR
(CDCl3), δ: 0.78, 0.98 (both m, 2 H each, CH2CH2); 1.73
(tt, 1 H, CH in cycloꢀC3H5, Jcis = 8.5 Hz, Jtrans = 5.1 Hz); 3.87
and 3.91 (both s, 3 H each, 2 OMe); 6.98 (d, 2 H, Hm, 3J = 8.9 Hz);
7.50 (d, 2 H, Ho, 3J = 8.9 Hz). 13C NMR (CDCl3), δ: 7.6 (CH in
cycloꢀC3H5); 9.0 (CH2CH2); 52.1 (CO2Me); 55.6 (OMe); 104.9
3
2 Me, J = 7.0 Hz); 3.78, 3.87 (both s, 3 H each, 2 OMe); 4.88
(sept, 1 H, OCH, 3J = 7.0 Hz); 6.85 (m, 2 H, Hm, 3J = 9.0 Hz);
7.08 (m, 2 H, Ho, 3J = 9.0 Hz). 13C NMR (CDCl3), δ: 23.0
(2 Me); 52.5 (CO2Me); 55.7 (OMe); 74.7 (OCH); 114.7 and
114.8 (Co and Cm); 135.5 (Cipso); 137.0 (C=N); 154.6 (Cp);
160.7 (COO).
The authors are grateful to Yu. A. Strelenko (IOCh
RAS) for the methodical help in recording 1H and
13C NMR spectra on a Bruker DRXꢀ500 spectrometer.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00636).
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Received December 24, 2009;
in revised form February 24, 2010