One-pot synthesis of highly functionalised 1 H -pyrazoles from arylcarbohydrazides, cyclohexyl isocyanide, and acetylene diesters

A novel one-pot isocyanide-based cascade four-component reaction between arylcarbohydr-azides, dialkyl acetylenedicarboxylates, and cyclohexyl isocyanide lead to dialkyl 1-(1,2-bis-alkoxycarbonylvinyl)-5-cyclohexylamino-2-aroyl-2,3-dihydro-1 H -pyrazole-3,4-dicarboxylates in excellent yields.


Introduction
Multi-component reactions (MCRs) are important for generating high levels of diversity, as they allow more than two building blocks to be combined in a practical, time-saving, one-pot operation, giving rise to complex structures by simultaneous formation of two or more bonds. 1s a special subclass, the isocyanide-based MCRs (IMCRs) offer a number of advantages originating from the unique reactivity of an isocyanide, which acts as a nucleophile and an electrophile at the same time.MCRs contribute to the requirements of an environmentally friendly process by reducing the number of synthetic steps, energy consumption, and waste production. 2 MCRs, which lead to interesting heterocyclic scaffolds, are particularly useful for the construction of diverse chemical libraries of "drug-like" molecules.Furthermore, the discovery of novel MCRs can be considered as an interesting topic for academic research, which also satisfies a practical interest of applied science. 35][6][7][8] Moreover, pyrazolines and pyrazoles play a crucial role in the development of theory in heterocyclic chemistry and also are extensively used as useful synthons in organic synthesis. 9s part of our ongoing program to develop efficient and robust methods for the preparation of heterocyclic compounds, [10][11][12][13] herein we wish to report an efficient and simple approach to the synthesis of dialkyl 1-[1,2-bis(alkoxycarbonyl)vinyl]-5-cyclohexylamino-2-aroyl-2,3-dihydro-1H-pyrazole-3,4-dicarboxylates by reaction between arylcarbohydrazides, dialkyl acetylenedicarboxylates and cyclohexyl isocyanide in good yields.

Results and Discussion
Reaction between furyl-2-carbohydrazide (1a), dimethyl acetylenedicarboxylate (DMAD, 2a, 2 eq.) and cyclohexyl isocyanide after 24h stirring in dichloromethane at ambient temperature and column chromatography afforded dimethyl 1-[1,2-bis(methoxycarbonyl)vinyl]-5-cyclohexylamino-2-(furan-2-yl)-2,3-dihydro-1H-pyrazole-3,4-dicarboxylate (5a) in 98% yield (Scheme 1).The structures of the products were deduced from their IR, mass, 1 H NMR, and 13 C NMR spectra.The IR spectrum of compound 5a exhibited an absorption band at 3290 cm -1 for the NH group and three strong broad absorption bands at 1680, 1718, 1745 cm -1 for carbonyl groups.The mass spectrum of this compound displayed molecular ion peak at the appropriate m/z value.The 1 H NMR spectrum of compound 5a consisted of multiplet signals for the methylene groups of cyclohexyl ring at δ = 1.05-1.67ppm and a multiplet signal at δ = 3.98 ppm for the CH of cyclohexyl ring.Four singlet signals were observed for methoxy groups at δ = 3.61, 3.62, 3.68 and 3.70 ppm.A broad doublet at δ = 6.47 ppm was observed for the NH proton, disappeared by the addition of D2O to CDCl3 solution of 5a.The proton of the methine group and the olefinic proton were observed as two singlet signals at δ = 5.52 and 5.75 ppm, respectively.The protons of the furan ring showed signals at δ = 6.46, 7.30, and 7.53 ppm. 13C NMR spectrum of compound 5a showed 24 distinct resonances in agreement with the proposed structure, partial assignments of these resonances are given in the experimental section.The NMR data for compounds 5a-h shows the presence of only one isomer, but with the available NMR data we could not definitely establish the configuration.
To explore the scope and limitations of this reaction further, we extended our studies to the benzohydrazide and other dialkyl acetylenedicarboxylates such as diethyl-and di-t-butyl acetylenedicarboxylate.As indicated in Scheme 1, the reactions proceeded efficiently to produce compounds (5b-f).We also examined the one-pot reaction between two different dialkyl acetylenedicarboxylates with phenylcarbohydrazide and cyclohexyl isocyanide.Thus, diethyl acetylenedicarboxylate (DEAD, 3b) or di-t-butyl acetylenedicarboxylate (DTAD, 3c) and cyclohexyl isocyanide were successively added to a mixture of DMAD and phenylcarbohydrazide in dichloromethane.After stirring for 24h at room temperature and column chromatography, the desired products 5g and 5h were obtained in good yields, respectively.
A mechanistic rationalization for this reaction is provided in Scheme 2. The Michael addition of arylcarbohydrazide 1 to acetylene diester 2 affords the adduct 6.The zwitterion 7, produced by the addition of cyclohexyl isocyanide to acetylene diester 3, is porotonated by compound 6 to yield the nitrilium cation 8. Michael addition of the conjugate base of 6 (anion 9) to nitrilium cation 8 leads to ketenimine 10, which then cyclizes to product 5.

Conclusions
In summary, we report herein a new and efficient method for the synthesis of highly functionalized 1H-pyrazole derivatives by a four-component reaction between arylcarbohydrazides, dialkyl acetylenedicarboxylates, and cyclohexyl isocyanide.Due to the easy availability of the synthetic approach and the neutral ring closure conditions, this new synthetic approach discussed here has the potential in synthesis of various functionalized 1Hpyrazole derivatives.The reactions carry the advantages that the starting materials are simply available and may be used without any purification or modification under neutral conditions.

Experimental Section
General.All melting points are uncorrected.Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer.Mass spectra were recorded on a Finnigan-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV.IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1 H, and 13 C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer at 500.1 and 125.8 MHz, respectively. 1H, and 13 C NMR spectra were obtained on solution in CDCl3 using TMS as internal standard.Column chromatography was performed with Merck silica gel 60, 230-400 mesh.The chemicals used in this work purchased from Fluka (Buchs, Switzerland) and were used without further purification.