Mechanochemical synthesis of novel 1-[( N -arylthiocarbamoyl)amidino]pyrazoles and their application in thiocarbamoylguanylations

Guanidines are important for a variety of reasons, including their use in medicinal and industrial applications. Mechanochemistry is being increasingly adopted as a green-chemistry technique for solvent-free organic synthesis. The synthesis of novel 1-[( N -arylthiocarbamoyl)amidino]pyrazoles and their use as guanylating agents for the conversion of amines to N -alkyl- and N,N -cycloalkyl- N '-( N -arylthiocarbamoyl)guanidines by solvent-based and solvent-free mechanochemical methods are described.


Introduction
Guanidines occupy a prominent position among organic compounds, including a variety of biologically-active compounds, due to the presence of the guanidino structural motif 1 .Interest in guanidines also stems from their applications as super bases 2 , as base catalysts in organic synthesis 3 and as sweeteners 4 .Consequently, investigations on guanidine synthesis remain ever-active 5 and related reviews have appeared recently 6 .Prominent methods available for the synthesis of guanidines broadly involve the reaction of amines with thiourea derivatives such as S-alkylsulfanylisothioureas 7 , aminoiminomethane sulfonic acids 8 , and Bocisothioureas [9][10][11] , the addition of amines to carbodiimides and cyanamides, and amidine group-transfer reactions.The amidine group-transfer agents used for the conversion of amines to guanidines include 1amidinopyrazole and 1-amidino-1,2,4-benzotriazole derivatives [12][13][14][15][16] .We have earlier reported the synthesis and use of 1-[(N-arylthiocarbamoyl)amidino]-3,5-dimethylpyrazoles 17,18 and 1-N-arylamidino-1,2,4benzotriazoles 19 for the conversion of amines to N-(N-arylthiocarbamoyl)-N'-substituted guanidines and N,N'substituted guanidines, respectively.We now report the synthesis of hitherto undescribed 1-[(Narylthiocarbamoyl)amidino]pyrazoles (2) and their use in the thiocarbamoylamidination of amines under mechanochemical, solid-state conditions.Mechanochemistry is now being increasingly adopted as a greenchemistry technique for solvent-free organic synthesis as attested by the appearance of recent reviews [20][21][22] .Mechanochemical methods, including grinding and ball milling, have successfully been applied to coupling, condensation, addition, substitution, oxidation, reduction and halogenation reactions, and to asymmetric synthesis 23 .In addition to their compatibility with green-chemistry principles, mechanochemical reactions are now known to permit synthesis of compounds and isolation of reaction intermediates arising from alternative chemical reactivity and selectivity that are inaccessible by thermal-solution chemistry methods 24,25 .

Results and Discussion
Based on the reported mechanochemical synthesis of thiourea derivatives by the reaction of amines with isothiocyanates 26,27 , and our recent success in the solvent-free, mechanochemical syntheses of heterocycles 28 , the reaction of 1-amidinopyrazole hydrochloride (1) with aryl isothiocyanates, in the presence of a base, was investigated using both thermal (Method A) and mechanochemical (Method B) conditions.The thermal reaction was done in N,N-dimethylformamide (DMF), using a modified version 17 of the one reported by Scott and Reilly 29 , by first stirring (1) with powdered potassium hydroxide at 0-4 ⁰C for 20 min, and then adding aryl isothiocyanates and continuing the stirring at 65-70⁰C for another 2 h.The mechanochemical method required a simple grinding of (1) and aryl isothiocyanates for 15-20 min in the presence of solid KOH (Scheme 1).The products obtained by both methods were found to be identical by m.p., mixed m.p., TLC, and FTIR.The 1 H NMR spectra of the products indicated that these compounds exist in solution as more than one conformertautomer.Based on NMR spectral studies, the existence of such preferred conformer-tautomer systems have recently been demonstrated 30 for N-Boc-N′-propyl-N"-pyridin-2-ylguanidines and related compounds due to conformational control induced by strong intramolecular hydrogen bonding in CDCl 3 solution.A freezing of C=N cis  trans configurational interconversion has also been reported by NMR studies in the case of Nbenzoyl-N'-pyridin-2-ylguanidines 31 .Thus, the product obtained from (1) and 4-methoxyphenyl isothiocyanate, taken as a typical example, was found to be homogeneous by TLC and HPLC analysis (data not shown), and the HRMS data were in good agreement with the proposed structure, 1-[(N-4methoxyphenylthiocarbamoyl)amidino]pyrazole (2c).In the 400 MHz 1 H NMR spectrum in CDCl 3 , the pyrazole ring hydrogen H-4 appeared as a pair of signals, i.e., one doublet of a doublet, and the other a broad, poorlyresolved signal, in the ratio 1.71:1 at  6.37 and 6.45 ppm, respectively.This assignment is based on a comparison with the 1 H NMR spectral data of 1-[N,N'-bis-(tert-butyloxycarbonyl)amidino]pyrazole 13 .The other two pyrazole hydrogens, H-3 and H-5, as well as the aryl hydrogens, also exhibited multiple broadened signals.
The 1 H NMR spectrum of the product (2c) in CD 3 OD was less complex, and clearly indicated the presence of at least two conformer-tautomer molecular species.Thus, in the spectrum, the three signals due to the pyrazolering hydrogen H-4 at  6.35 ppm and at  6.41 ppm, the two aryl hydrogens ortho to the CS-NH group at  7.17 ppm and  7.44 ppm, and the pyrazole ring hydrogen H-5 at  7.96 ppm and at  8.47 ppm appeared as pairs, and in the ratios 1.24:1, 1.28:1 and 1.33:1, respectively.These ratios seem to indicate that (2c) exists in CD 3 OD solution as 56% of one molecular species and 44% of another.The 1 H NMR spectrum of (2g) in DMSO-d 6 also clearly showed the existence of at least two conformer-tautomer species since the 1 H NMR signals of the pyrazole-ring hydrogen H-4, the two aryl hydrogens ortho to the CS-NH moiety, and the pyrazole ring hydrogen H-5 appeared as pairs in each case, and in the ratios 1.6:1, 1.48:1 and 1.43:1, respectively.A limited, variable-temperature, NMR study of (2c) in CDCl 3 indicated a temperature-dependent broadening of signals which is suggestive of a dynamic process in solution (data not shown).The FTIR spectrum of (2c) recorded from the KBr-pellet method was similar to that recorded in CHCl 3 , thus pointing to no significant difference in structure in solid and solution states.The HRMS spectrum of (2c) showed a [M+H] peak at 276.0915, which is in agreement with the calculated value of 276.0841, based on the molecular composition C 12 H 13 N 5 OS.To obtain further insight into the structure of these products, single-crystal X-ray diffraction analysis of crystals of (2a), obtained from ethyl acetate/petroleum ether by slow evaporation, was done.The solid-state structure (Fig. 1) revealed the preference for the amino-thione tautomer (2) with an anti-conformation along the C-N bond of the CS-NHPh moiety.An intramolecular hydrogen-bonding interaction between one hydrogen of the amino group and the thione sulfur, another weak intramolecular hydrogen-bonding interaction of the remaining hydrogen of the amino group with the sp 2 nitrogen of the pyrazole ring, and yet another weak intramolecular hydrogen-bonding interaction between the C5-H hydrogen of the pyrazole ring and the sp 2 -N atom of the amidine unit, lead to the conformationally-restricted conformer-tautomer (2), which seems to persist in solution along with another conformer-tautomer, presumably (2).The intramolecular distances, calculated based on the crystallographic data, show that the length of the C=S••••H-N hydrogen bond in (2) to be 2.414 Å, and the S••••H-N bond angle to be 132 o .The intramolecular distance between the pyrazole-ring nitrogen and the hydrogen of the amino group involved in the [sp 2 The intramolecular distance between the C5-H hydrogen of the pyrazole ring and the sp 2 -N atom of the amidine unit in (2) is seen to be 2.642 Å.Interestingly, Kelly et al. have reported a similar intramolecular hydrogen bond between the C3-H of a pyridine ring and the sp 2 -N atom of an attached guanidino group in N,N-di-Boc-N-pyridin-2-ylguanidine and N,N-di-Boc-N-phenylguanidine. 30lthough details of intermolecular hydrogen bonding between N-H hydrogen and the sulfur atom of a thione group C=S flanked by two nitrogen atoms, as in thioureas, are known 32,33 , the corresponding information regarding intramolecular hydrogen bonding seems sparse.The length of the thioureido C=S••••H-N intermolecular hydrogen bond has been reported to be 2.51 Å 32 .It is now suggested that the presence of the conformer-tautomers (2') and (2) in solution, with the latter predominating, could account for the appearance of more than one signal of the hydrogens of the pyrazole and aryl rings, and their broadening in the 1 H NMR spectra.Furthermore, the presence of the conformer (2) seems to account for the prominent deshielding of the pyrazole ring C5-H hydrogen, due to the influence of the juxtaposed phenyl ring, and the intramolecular hydrogen-bonding interaction between the C5-H hydrogen of the pyrazole ring and the sp 2 -N atom of the amidine unit.Such a remarkable deshielding effect, along with peak broadening, has been reported by Kelly et al. for the C3-H hydrogen of the pyridine ring in N,N-di-Boc-N-pyridin-2-ylguanidine due to intramolecular hydrogen bonding between the C3-H hydrogen of the pyridine ring and the sp 2 -N atom of the N,N-di-Boc-guanidino group. 30Similar deshielding and peak broadening due to a possible interaction between the C5-H hydrogen of the pyrazole ring and the sp 2 -N atom of the amidine unit, however, has not been reported in the 1 H NMR spectrum of 1-(N,N-di-Boc-amidino)pyrazole 13

Experimental Section
General.Melting points were uncorrected and determined by open capillary method.The thin-layer chromatographic (TLC) analyses were performed using silica gel 60 F 254 TLC aluminium sheets purchased from E. Merck, Mumbai, India.The FTIR spectra were recorded on Thermo Nicolet Avatar 370 and Agilent

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Technologies spectrophotometers.The 1 H and 13 C NMR spectra were recorded in CDCl 3 , DMSO-d 6 and CD 3 OD on a Bruker DPX 400 MHZ NMR spectrometer at room temperature using TMS as the internal-reference standard.Chemical shifts are given in ppm and the coupling constants in Hz.The HRMS-ESI analyses were performed on an Agilent 6520 QTOF-MS/MS system.The crystal structure of (2a) was determined using a Bruker Kappa Apex II Single-Crystal X-ray Diffractometer and the supplementary crystallographic data can be obtained free of charge from Cambridge Crystallographic Data Centre under the deposition number CCDC 1573139.All chemicals used were from Sigma Aldrich and E. Merck, India.
General experimental procedure for the preparation of 1-[(N-arylthiocarbamoyl)amidino]pyrazoles (2a-i) by method A (thermal method).Powdered potassium hydroxide (112 mg, 2 mmol) was added to DMF (5 mL) at 0 ⁰C, followed by 1-amidinopyrazole hydrochloride (1) (292 mg, 2 mmol).The mixture was stirred in ice for 20 min to obtain a clear solution.To this solution, aryl isothiocyanate (2 mmol) was added with stirring.The ice bath was replaced by a hot-water bath at 65-70 ⁰C and the stirring was continued for another 2 h.The mixture was poured into ice-water (50 mL), kept for coagulation of the precipitate which was then collected, washed with petroleum ether, and crystallized from an ethanol-water (1: 1) mixture.

General experimental procedure for the preparation of 1-[(N-arylthiocarbamoyl)amidino]pyrazoles (2a-g) by method B (mechanochemical method).
Powdered potassium hydroxide (112 mg, 2 mmol) was added to 1amidinopyrazole hydrochloride (1) (292 mg, 2 mmol) in an agate mortar and the mixture was ground with an agate pestle for 1-3 min.To this mixture, aryl isothiocyante (2 mmol) was added and the grinding continued at room temperature for 15-20 min.The oily emulsion first formed subsequently solidified and the solid was worked up by triturating with petroleum ether, followed by water.The product was collected by filtration and purified by crystallization from an ethanol-water mixture (1:1).