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Extended Abstract

The Reaction of 5-Amino-3-(cyanomethyl)-1H-pyrazol-4-carbonitrile with beta-Cycloketols †

by
Victor V. Dotsenko
1,2,3,*,
Aminat M. Semenova
1,4,
Elena A. Chigorina
5,
Nikolai A. Aksenov
3 and
Inna V. Aksenova
3
1
Department of Chemistry and High Technologies, Kuban State University, 149 Stavropolskaya str, Krasnodar 350040, Russia
2
ChemEx Lab, Vladimir Dal’ Lugansk National University, 20A/7 Molodezhny, Lugansk 91034, Russia
3
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., 355009 Stavropol, Russia
4
North Caucasus Humanitarian Technological Academy, Medical Institute, 36 Stavropolskaya str., 369000 Cherkessk, Russia
5
The Federal State Unitary Enterprise “Institute of Chemical Reagents and High Purity Chemical Substances” of National Research Centre “Kurchatov Institute”, 3 Bogorodsky Val, Moscow 107076, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 22nd International Electronic Conference on Synthetic Organic Chemistry, 15 November–15 December 2018; Available Online: https://sciforum.net/conference/ecsoc-22.
Proceedings 2019, 9(1), 25; https://doi.org/10.3390/ecsoc-22-05679
Published: 14 November 2018
(This article belongs to the Proceedings of 22nd International Electronic Conference on Synthetic Organic Chemistry)
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Abstract

:
The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-2,4-di(ethoxycarbonyl)-5-hydroxy-5-methylcyclohexanones in boiling acetic acid leads to the formation of new 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazolines. The mechanism is discussed. The structure of the products was confirmed by means of 1Н и 13С (DEPTQ) NMR, as well as 2D NMR (NOESY, 1Н–13С HSQC, HMBC).

β-Сycloketols (2,4-di-(RC(O))-3-aryl-5-hydroxy-5-methylcyclohexano-nes) 1 which are easily accessible by the reaction of aromatic aldehydes with 1,3-dicarbonyls RC(O)CH2C(O)CH3, were recognized as promising reagents for organic synthesis. According to the literature [1,2], β-cycloketols are good precursors of a variety of carbocycles, enamine ketones and esters, etc. However, the heterocyclization reactions of β-cycloketols are not well studied. Thus, the literature describes the preparation of isoquinolines 2 [3,4,5,6,7], indazoles 3 [8,9,10], benzo[c]isoxazoles 4 [9,10], [1,2,4]triazolo[3–b]quinazolines 5 [11] and pyrazolo[3-c]isoquinolines 6 [12] (Scheme 1) by reactions of beta-cycloketols with various 1,2- and 1,3-dinucleophilic agents. Despite the large attention paid to reactions of aminoazoles with 1,3-dielectrophilic agents (see reviews [13,14]), only a few examples of reactions involving β-cycloketols were found in the literature. Thus, the reaction of cycloketols with 5-amino-3-hydrazinopiazole was reported to give 6,7,8,8a-tetrahydropyrazolo[5,1-b]quinazolin-9(5H)-one 7 [15] (Scheme 1).
In continuation of our studies in the chemistry of the malononitrile dimer [16,17,18,19], herein we report the reaction of 3-aryl-5-hydroxy-5-methyl-2,4-di (ethoxycarbonyl)cyclohexanones 1a,b with 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile 7 (Scheme 2). Aminopyrazole 7 can be easily prepared by the reaction of malononitrile dimer 8 with hydrazine hydrate [20].
We found that cycloketols 1a,b react with 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile 7 in boiling AcOH to give previously not described 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazolines 9a,b in low yields (15–22%). The structure of compounds 9a,b was confirmed by means of IR spectrophotometry, 1H and 13C NMR (DEPTQ), and by the results of 2D NMR experiments (NOESY, 1H–13С HSQC, HMBC) for 9a (Figure 1, Figure 2 and Figure 3). Presumably, the reaction proceeds through the initial attack of pyrazole NH group at C-1 followed by intramolecular attack of the NH2 group to ester carbonyl.

Experimental

IR spectra were recorded on a Bruker Vertex 70 spectrometer. NMR spectra were recorded on a Bruker Avance III HD (400 MHz) in DMSO-d6 using TMS as an internal standard. Selected experimental procedures are given.
Ethyl 3-cyano-2- (cyanomethyl)-8-hydroxy-6-(4-methoxyphenyl)-8-methyl-5-oxo-4,5,6,7,8,9- hexahydropyrazolo[1,5-a]quinazolin-7-carboxylate (9a). A mixture of 380 mg (1 mmol) of diethyl 5-hydroxy-5-methyl-3- (4-methoxyphenyl)cyclohexanone-2,4-dicarboxylate (1a), 5 ml of glacial AcOH and 150 mg (1 mmol) of pyrazole 7 was heated under reflux for 4 h (TLC control). The precipitate was filtered off and washed with EtOH. Yield 22%, beige amorphous powder.
IR spectrum, ν, cm−1: 3476 (O–H), 3182, 3076 (N–H), 2262, 2226 (2 C≡N), 1720 (C=O ester), 1688 (C=О amide), 1649, 1593 (С=С).
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.09 t (3Н, СН3СН2О, 3J 7.1 Hz), 1.28 s (3Н, С8СН3), 2.65–2.71 two d overlapped (2Н, Н9 and Н7), 3.22 d (1Н, Н9, 2J 17.1 Hz), 3.69 s (3Н, СН3О), 3.94–4.15 m (АВХ3) (2Н, СН3СН2О), 4.27 d (1Н, Н6, 3J 10.2 Hz), 4.34 s (2Н, CH2CN), 4.86 br.s (1Н, ОН), 6.76 d (2H, H3 and H5 Ar, 3J 8.4 Hz), 7.04 d (2H, H2 and H6 Ar, 3J 8.4 Hz), 13.29 br.s (1Н, NH). NMR 13С DEPTQ (101 МHz, DMSO-d6), δC, ppm.: 14.5* (СН3СН2О), 16.7 (CH2CN), 27.6* (C8CH3), 40.2* (C6), 41.5 (C9), 54.9* (СН3О), 58.6* (C7), 59.8 (СН3СН2О), 68.2 (C8), 73.2 (C3), 108.5 (C5a), 111.9 (CN), 113.3* (C3, C5 Ar), 116.2 (CH2CN), 128.7* (C2, C6 Ar), 135.6 (C1 Ar), 148.0 (C9a), 148.1 (С3а), 153.7 (С2), 153.8 (C5), 157.5 (C4 Ar), 171.4 (СО2Et). *Opposite signals.

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Proceedings 09 00025 sch001
Scheme 1. Heterocyclization reactions of β-cycloketols
Scheme 1. Heterocyclization reactions of β-cycloketols
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Scheme 2. The reaction of cycloketols 1a,b with 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile 7.
Scheme 2. The reaction of cycloketols 1a,b with 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile 7.
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Figure 1. HSQC 1H–13C NMR (400/101 MHz, DMSO-d6) spectrum of 9а.
Figure 1. HSQC 1H–13C NMR (400/101 MHz, DMSO-d6) spectrum of 9а.
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Figure 2. HMBC 1H–13C NMR (400/101 MHz, DMSO-d6) spectrum of 9а.
Figure 2. HMBC 1H–13C NMR (400/101 MHz, DMSO-d6) spectrum of 9а.
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Figure 3. The chemical shifts in the 1H NMR (left) and 13C NMR (right) spectra of 9а.
Figure 3. The chemical shifts in the 1H NMR (left) and 13C NMR (right) spectra of 9а.
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MDPI and ACS Style

Dotsenko, V.V.; Semenova, A.M.; Chigorina, E.A.; Aksenov, N.A.; Aksenova, I.V. The Reaction of 5-Amino-3-(cyanomethyl)-1H-pyrazol-4-carbonitrile with beta-Cycloketols. Proceedings 2019, 9, 25. https://doi.org/10.3390/ecsoc-22-05679

AMA Style

Dotsenko VV, Semenova AM, Chigorina EA, Aksenov NA, Aksenova IV. The Reaction of 5-Amino-3-(cyanomethyl)-1H-pyrazol-4-carbonitrile with beta-Cycloketols. Proceedings. 2019; 9(1):25. https://doi.org/10.3390/ecsoc-22-05679

Chicago/Turabian Style

Dotsenko, Victor V., Aminat M. Semenova, Elena A. Chigorina, Nikolai A. Aksenov, and Inna V. Aksenova. 2019. "The Reaction of 5-Amino-3-(cyanomethyl)-1H-pyrazol-4-carbonitrile with beta-Cycloketols" Proceedings 9, no. 1: 25. https://doi.org/10.3390/ecsoc-22-05679

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