Possible rearrangements during the syntheses of Di- and trisubstituted pyrazoles

Article abstract of DOI:10.1007/PL00010144

The reaction of ethoxymethylene malononitrile and ethoxymethylene cyanoacetic acid ethylester with substituted hydrazines to substituted 5-aminopyrazoles is described. The influence of different substituents on possible migrations during the ring closure was studied.

Full text of DOI:10.1007/PL00010144

Monatshefte fuÈr Chemie 129, 1313±1318 (1998)
Possible Rearrangements During the Syntheses
of Di- and Trisubstituted Pyrazoles
Claudia Reidlinger1;Ã, Renate Dworczak1, Hans Junek1,
and Heinz Graubaum2
1
Institute of Organic Chemistry, Karl Franzens University Graz, A-8010 Graz, Austria
2
WITEGA Angewandte Werkstoff-Forschung GmbH, D-12489 Berlin, Germany
Summary. The reaction of ethoxymethylene malononitrile and ethoxymethylene cyanoacetic acid
ethylester with substituted hydrazines to substituted 5-aminopyrazoles is described. The in¯uence of
different substituents on possible migrations during the ring closure was studied.
Keywords. Ethoxymethylene malononitrile; Ethoxymethylene cyanoacetic acid ethylester; 1,4,5-
Trisubstituted pyrazoles; 4,5-Disubstituted pyrazoles; Acyl migration; Rearrangement.
È È
Mogliche Umlagerungen wahrend der Synthese von zwei- und dreifach substituierten
Pyrazolen
Zusammenfassung. Die Reaktion von Ethoxymethylenmalodinitril und Ethoxymethylencyanessig-
È
saureethylester mit substituierten Hydrazinen zu substituierten 5-Aminopyrazolen wird beschrieben.
È È
Der Ein¯uû unterschiedlicher Substituenten auf mogliche Wanderungen wahrend des Ringschlusses
wurde untersucht.
Introduction
Recently we have reported on the syntheses of di- and trisubstituted pyrazoles from
aminomethylene- and anilinomethylene derivatives of cyanoacetophenone and
various hydrazines [1]. No rearrangements have been observed during the ring
closure reactions. Reactions of ethoxymethylene malononitrile with semicarba-
zides and thiosemicarbazides have been performed earlier and have afforded
1-acyl-5-aminopyrazoles [2]. However, no 13C NMR data have been given, making it
hard to decide, if acyl migrations towards 1-acyl-3-aminopyrazoles have occured.
Rearrangements have been observed in N-carbamoyl pyrazoles, resulting in three
products: compounds A and B and substituted urea C arising from migration of
the carbamoyl residue to the amino group (Scheme 1, R1 ˆ carbamoyl, R2 ˆ H)
[3, 4].
In our experiments, N-substituted pyrazoles have been obtained directly by
condensation reactions of substituted hydrazines with ethoxymethylene malononi-
Ã
Corresponding author

1314
C. Reidlinger et al.
Scheme 1
trile (1) and ethoxymethylene cyanoacetic acid ethylester (2). Thus, we tried to ®nd
out if migrations of acyl or carbamoyl groups are possible also during the ring
closure reaction itself.
Results and Discussion
Reactions of 1 [5±8] and 2 generally gave the 1-substituted 5-amino-4-cyano-
pyrazoles 3a±e and 5-amino-4-ethoxycarbonyl pyrazoles 4a, b, (Scheme 2).
Condensations of 1 with hydrazinoformic acid methylester were performed in
ethanol or xylol at different temperatures. All syntheses gave 3a as the sole
product.
Hydrolysis of the nitrile groups of 3a, b under mild conditions gave carbamoyl
compounds 5a, b as expected [9]. However, migrations of the ester groups were not
observed.
Scheme 2

Rearrangements in Pyrazole Synthesis
1315
Table 1. Selected 13C NMR data of compounds 3a±e, 4a, b,
and 5a, b; for the numbering of the carbon atoms, see isomer A
in Scheme 1; 13C NMR spectra were recorded with a Varian
CFT-20 NMR spectrometer in DMSO-d6 (ppm relative to
internal TMS)
C-3
C-4
C-5
3a
b
144
143
144
142
157a
140
143
143
142
142
72
71
73
73
84a
72
93
93
95
95
150
154
156
154
129a
154
151
153
152
151
c
d
e
4a
b
5a
b
a
Signals of isomer B (Scheme 1)
Selected 13C NMR data of compounds 3a±e, 4a, b, and 5a, b are given in Table 1.
All 1-substituted 5-aminopyrazoles (isomer A in Scheme 1) showed the signal of
C-3 at 140 to 144 ppm. Atoms C-5 (those bearing the amino groups) displayed
signals at 150 to 156 ppm. The signals of C-4 were strongly substituents dependent.
4a, b with a 4-alkoxy-carbonyl group and 5a, b with a 4-carbamoyl group showed
the signals of C-4 at 95 or 93 ppm, respectively. A nitrile group at C-4 resulted in
an up®eld shift of the signal of C-4 to 73 to 71 ppm.
Interestingly, 3d was the only compound to show migration of R1: The reaction
of 1 and 4-phenylsemicarbazide gave two isomers (A and B, R1 ˆ N-phenyl-
carbamoyl, R2 ˆ nitrile in Scheme 1). The 13C NMR spectra of A and B were
signi®cantly different. Whereas the signal of C-3 resonated at 142 ppm in A, C-5
gave a signal at 129 ppm in isomer B, the up®eld shift being caused by the
carbamoyl group at N-1. Signals of C-4 occured at 73 (isomer A) or at 84 (isomer
B) ppm. No distinct difference was found for the signal of the carbon atom bearing
the amino group (C-5 in isomer A, 154 ppm; C-3 in isomer B, 157 ppm).
The ®rst 13C NMR spectrum of product 3d pointed at a mixture of 3.7 parts A
and 1 part B. Heating the sample to 100ꢀC for approximately one minute changed
this ratio to 2 parts A and 1 part B, indicating a thermal isomerization. However, if
3d was heated for prolonged time intervals or to higher temperatures (150ꢀC), the
signals of isomer A as well as of isomer B disappeared due to sample decom-
position.
Conclusion
Ring closure reactions of 1 and 2 with substituted hydrazines generally resulted in
the formation of 1-substituted 5-amino-pyrazoles with electron withdrawing
substituents in position 4. In only one case (3d), a second isomer was found; due to
a thermal equilibrium reaction, it could not be obtained in pure form. Thus it may

1316
C. Reidlinger et al.
be derived that electron withdrawing groups in position 4 of 5-aminopyrazoles
lower their tendency for rearrangements of the substituents at N-1.
Experimental
All melting points are uncorrected (BuÈchi 500). IR and 1H NMR spectra data were recorded with the
following instruments: Perkin-Elmer Spectrophotometer 500 (KBr), Varian Gemini 200 (spectra are
referenced to internal tetramethylsilane). Elemental analyses were performed on a C,H,N-Automat
Carlo Erba 1106; the results were in accordance with the calculated values.
Ethoxymethylene cyanoacetic acid ethylester (2; C8H11NO3)
A mixture of 28.25 g (0.25 mol) cyanoacetic acid ethylester, 36.00 g (0.24 mol) triethylorthoformate,
and 51.00 g (0.50 mol) acetic acid anhydride was re¯uxed for 5.5 h. The solvent was removed under
reduced pressure, and the precipitate was allowed to crystallize in the refrigerator overnight.
Colourless needles were ®ltered and washed with a small amount of cold ethanol.
Yield: 15.08 g (37%); m.p.: 50ꢀC; IR (KBr): ꢀ ˆ 3020, 2990, 2940, 2230, 1710, 1620 cmꢁ1; 1H
NMR (200 MHz, ꢁ, DMSO-d6): 1.22±1.32 (t, 3H, CH3), 1.32±1.38 (t, 3H, CH3), 4.17±4.28( q, 2H,
CH2), 4.43±4.53 (q, 2H, CH2), 8.42 (s, 1H, CH) ppm.
5-Amino-4-cyano-1-methoxycarbonylpyrazole (3a; C6H6N4O2)
3.66 g (30 mmol) 1 were re¯uxed with 2.70 g (30 mmol) hydrazinoformic acid methylester in 20 ml
ethanol for 6 h. Compound 3a precipitated from the hot solution. After cooling to room temperature,
the product was ®ltered by suction and washed with ethanol, giving 1.10 g yellowish platelets (22%).
M.p.: 180±182ꢀC (acetonitrile); IR (KBr): ꢀ ˆ 3460, 3380, 3205, 3115, 2210, 1750, 1630 cmꢁ1
;
1H NMR (200 MHz, ꢁ, DMSO-d6): 3.95 (s, 3H, OCH3), 7.78 (s, 2H, NH2), 7.85 (s, 1H, CH) ppm.
5-Amino-4-cyano-1-ethoxycarbonylpyrazole (3b; C7H8N4O2)
A mixture of 3.66 g (30 mmol) 1, 3.12 g (30 mmol) hydrazinoformic acid ethylester, and 20 ml
ethanol was re¯uxed for 5 h. The precipitate was ®ltered after cooling to room temperature and
washed with cold ethanol to give 3.20 g yellow platelets (60%).
M.p.: 164±168ꢀC (acetonitrile); IR (KBr): ꢀ ˆ 3500, 3280, 3220, 3160±3120, 2220, 1770,
1630 cmꢁ1; 1H NMR (200 MHz, ꢁ, DMSO-d6): 1.28±1.36 (t, 3H, CH3), 4.35±4.45 (q, 2H, CH2), 7.72
(s, 2H, NH2), 7.82 (s, 1H, CH) ppm.
5-Amino-1-benzoyl-4-cyanopyrazole (3c; C11H8N4O)
A mixture of 2.24 g (18 mmol) 1, 2.52 g (18 mmol) benzoylhydrazine, and 20 ml ethanol was
re¯uxed for 1 h. Compound 3c precipitated from the hot solution. After cooling to room temperature,
the mixture was ®ltered to yield 2.76 g colourless needles (72%).
1
M.p.: 176ꢀC (acetonitrile); IR (KBr): ꢀ ˆ 3430, 3300, 3240, 2230, 1690, 1650 cmꢁ1; H NMR
(200 MHz, ꢁ, DMSO-d6): 7.50±7.58 (t, 2H, aromatic protons (m)), 7.65±7.73 (t, 1H, aromatic protons
(p)), 7.91±7.95 (d, 3H, aromatic protons (o), CH), 8.07±8.11 (s, 2H, NH2) ppm.
5-Amino-4-cyano-N-phenyl-1-pyrazole-carboxamide (3d; C11H9N5O)
4.24 g (35 mmol) 1 and 5.00 g (33 mmol) 4-phenylsemicarbazide were stirred in 90 ml ethanol at
room temperature for 20 h. The precipitate was ®ltered and washed with ethanol to yield 1.60 g
colourless needles (21%).

Rearrangements in Pyrazole Synthesis
1317
M.p.: 172ꢀC (ethanol) Ref. [2]: 171±173ꢀC; IR (KBr): ꢀ ˆ 3440, 3360, 3300, 2240, 1730,
1
1630 cm-1; H NMR (200 MHz, ꢁ, DMSO-d6): 7.11±7.20 (t, 1H, aromatic protons (p)), 7.31±7.40
(t, 2H, aromatic protons (m)), 7.63±7.70 (d, 2H, aromatic protons (o)), 7.78±7.81 (s, 2H, NH2), 7.96
(s, 1H, CH), 10.25 (s, 1H, NH) ppm.
5-Amino-4-cyanopyrazole (3e; C4H4N4)
2.44 g (20 mmol) 1, 1.00 g (20 mmol) hydrazine hydrate, and 50 ml ethanol were re¯uxed for 6 h. The
mixture was ®ltered, and the ®ltrate was evaporated to yield 0.77 g 3e (36%).
M.p.: 173ꢀC (acetonitrile) (Ref. [10]: 172±173ꢀC); IR (KBr): ꢀ ˆ 1645, 2240, 2830, 2950, 3140,
3340, 3420 cmꢁ1; 1H NMR (200 MHz, ꢁ, DMSO-d6): 6.15 (s, 2H, NH2), 7.70 (s, 1H, CH), 12.08 (s,
1H, NH) ppm.
5-Amino-4-ethoxycarbonyl-1-methoxycarbonyl-pyrazole (4a; C8H11N3O4)
3.38 g (20 mmol) 2 were re¯uxed with 1.80 g (20 mmol) hydrazinoformic acid methylester in 20 ml
ethanol for 22 h. After cooling to room temperature, the solid was ®ltered and washed with ice cold
ethanol to yield 2.10 g colourless crystals (49%).
1
M.p.: 134±136ꢀC; IR (KBr): ꢀ ˆ 3460, 3280, 3210, 2980, 1750, 1680, 1620 cmꢁ1; H NMR
(200 MHz, ꢁ, DMSO-d6): 1.28±1.32 (t, 3H, CH3), 3.98 (s, 3H, OCH3), 4.18±4.28 (q, 2H, CH2), 7.21
(s, 2H, NH2), 7.75 (s, 1H, CH) ppm.
5-Amino-1,4-diethoxycarbonylpyrazole (4b; C9H13N3O4)
5.07 g (30 mmol) 2, 3.12 g (30 mmol) hydrazinoformic acid ethylester, and 25 ml ethanol were
re¯uxed for 22 h. From the clear solution the product crystallized upon cooling to room temperature.
The precipitate was ®ltered and washed with cold ethanol to give 3.82 g colourless crystals (84%).
M.p.: 86ꢀC; IR (KBr): ꢀ ˆ 3480, 3280, 3120, 2980, 1750, 1690, 1620 cmꢁ1
;
1H NMR
(200 MHz, ꢁ, DMSO-d6): 1.22±1.29 (t, 3H, CH3), 1.30±1.38 (t, 3H, CH3), 4.13±4.25 (q, 2H, CH2),
4.35±4.45 (q, 2H, CH2), 7.15 (s, 2H, NH2), 7.72 (s, 1H, CH) ppm.
5-Amino-1-methoxycarbonylpyrazole-4-carboxamide (5a; C6H8N4O3)
To 0.80 g (5 mmol) 3a, 10 ml of cold conc. H2SO4 were added, and the mixture was stirred in an ice
bath for 10 min. The ice bath was removed, and stirring was continued at room temperature for 20 h.
Upon pouring carefully onto ice chips, 0.35 g (38%) yellow needles were obtained.
M.p.: 182ꢀC; IR (KBr): ꢀ ˆ 3440, 3340, 3170, 1725, 1670, 1600 cmꢁ1; 1H NMR (200 MHz, ꢁ,
DMSO-d6): 3.95 (s, 3H, OCH3), 6.90±7.50 (m, 4H, NH2), 7.92 (s, 1H, CH) ppm.
5-Amino-1-ethoxycarbonylpyrazole-4-carboxamide (5b; C7H10N4O3)
To 30 ml conc. H2SO4, 6.80 g (38 mmol) 3b were added at 0ꢀC and stirred at room temperature for
22 h. The solution was carefully poured onto ice chips, and the precipitate was ®ltered and washed
with cold ethanol.
Yield: 3.72 g yellow crystals (51%); m.p.: 200ꢀC; IR (KBr): ꢀ ˆ 3460, 3360, 3160, 2990, 1750,
1
1670, 1630 cmꢁ1; H NMR (200 MHz, ꢁ, DMSO-d6): 1.29±1.38 (t, 3H, CH3), 4.35±4.45 (q, 2H,
CH2), 6.90±7.45 (m, 4H, NH2), 7.93 (s, 1H, CH) ppm.

1318
C. Reidlinger et al.: Rearrangements in Pyrazole Synthesis
References
[1] Reidlinger C, Dworczak R, Junek H (1998) Monatsh Chem 129: 1207±1211
[2] Howe RK, Bolluyt SC (1969) J Org Chem 34: 1713
[3] Graubaum H (1993) J prakt Chem 335: 1
[4] Graubaum H (1993) J prakt Chem 335: 585
[5] Passalacqua T (1913) Gazz Chim Ital 43 (2): 566
È
[6] Diels O, Gartner H, Kaak R (1922) Ber Dtsch Chem Ges 55: 3441
[7] Jones RG (1952) J Am Chem Soc 74: 4889
[8] Schmidt HW, Junek H (1977) Monatsh Chem 108: 895
[9] Peet NP (1986) J Heterocyclic Chem 23: 193
[10] Takagi K, Nagahara K, Ueda T (1970) Chem Pharm Bull 18 (11): 2353
Received July 17, 1998. Accepted (revised) August 10, 1998