Heterocyclic Synthesis Via Enaminonitriles: One-Pot Synthesis of Some New Pyrazole, Pyrimidine, Pyrazolo[1,5-A]Pyrimidine and Pyrido[2,3-D]Pyrimidine Derivatives

A simple route for the synthesis of 5-aminopyrazole derivatives (9) was described through the readily accessible acrylamide derivative (7). Reaction of the aminopyrazole with different reagents such as ,-unsaturated nitriles affo rded pyrazol[1,5-a]pyrimid ine (13,15,18). The structure of the enaminonitrile (6) was studied with different reagents such as thiourea and 2-thioxo-(1H)-pyrimid ine-4-one (36) afforded pyrimid inethione derivative (35) and the pyrido[2,3-d]pyrimidi ne derivative (41), respectively.

Also, almost high percentage of adults between ages 40-70 suffer fro m insomn ia at least one time during their lives. The drug Zaleplon (4) [10][11][12][13] has been found to be efficient in the treatment of sleep disorder where difficulty in falling asleep is the primary issue. Unlike many other hypnotic drugs, this substance does not interfere with sleep architecture and can be administered for up to five weeks without the risk o f dependence o r rebound insomn ia upo n discontinuation. Indiplon (5) [10,14] has recently been released for use for the same purpose while the developments of Ocinaplon (6) [15], wh ich is an an xiolyt ic drug in the pyrazo lopyrimidine family of d rugs, has been discontinued owing to liver comp lications observed in clin ical trials. As a result, a need exists for the development of analogs of (1-6). (figure 1).
The behavior of the enaminonitrile (6) toward some N-nucleophiles to attain polyfunctionally substituted azoles, azines and related fused systems linked to pyrazole mo iety through a carbo xamide linkage of potential pharmaceutical interest, has been investigated.
Reflu xing of the acry lamide derivative (7) with stirring in ethanol gave the cyanopyrazole (8). The structure of the later has been assigned as a reaction product on the basis of analytical and spectral data. The IR spectrum d isplayed absorption bands at 3270 cm -1 , 3164 cm -1 due to the (2NH) functions, 2228 cm-1 due to cyano function. The 1H NMR spectrum of (8) exh ibited three singlet signals at  8.34 pp m,  13.04 pp m and  9.61 pp m assignable to 2NH and pyrazole-CH protons, respectively. The mass spectrum showed a molecular ion peak at m/ z = 426, co rresponding to mo lecular formu la C22H18N8S. (scheme 3).
When the acrylamide (7) reflu xed in pyridine solution, cyclization gradually took place via addition of amino of hydrazine to the cyano function afforded 5-aminopyrazo le derivative (9) which achieved as a sole product. The structure of (9) has been assigned as a reaction product on the basis of analytical and spectral data. The IR s pectrum displayed absorption bands at 3430 cm -1 , 3354 cm -1 due to NH2 function, 3275 cm -1 , 3129 cm -1 due to the NH function, 1659 cm -1 due to the amid ic carbonyl function. Inspection of 1H NM R spectrum enabled establishing structure (9) for this pyrazole derivative since the pyrazole H-3 appeared as a singlet signal at  8.19 ppm. We could not trace in the 1H NMR spectrum any signals for the tautomeric 3-amino-pyrazole (10) as this could reveal pyrazo le-H5 as a doublet. The mass spectrum showed a mo lecular ion peak at m/ z = 444, corresponding to molecular formu la C22H20N8OS. (scheme 3).
Reaction of (9) with tetracyanoethylene (16) in reflu xing dio xane in the presence of catalytic amount of p iperidine afforded the 5-aminopyrazo lo[1,5-a]pyrimidine derivative (18). The mo lecular structure of compound (18) was confirmed on the basis of its elemental and spectral data. Its IR spectrum showed the characteristic absorption bands at 3411 cm -1 , 3318 cm -1 , 3252 cm -1 fo r (NH and NH2), 2203 cm-1 for CN group and 1648 cm -1 for C=O. The mass spectrum showed a molecular ion peak at m/ z = 545, corresponding to molecular formu la C27H19N11OS. Formation of pyrazolopyrimid ine (18) take place as depicted in (scheme 4), v ia an in itial Michael addition of the endocyclic NH in (9) to yield the non-isolable intermediate (17) followed by intramolecular cyclization to afford th e corresponding (18).
Pyrazo le (9) reacted smoothly with enaminones (19) to yield the acyclic product (20) that underwent cyclizat ion to generate (21) upon reflu xing in DMF/AcONa. It should be noted that the pyrazolo[1,5-a]pyrimidine (21) could be prepared directly fro m (9) and (19) in reflu xing pyrid ine. Attempts to synthesis pyrazolo[3,4-d]-pyrimidine (23) by the reaction of (9) with DMF-DMA failed and only the amid ines (22) were formed wh ich did not cyclize to generate the corresponding (23). All analys is of compounds (21,22,24) are consistent with the proposed structures. The site selectivity in cycloaddition of some nitrogen amb ident nucleophiles with enaminonitrile (6) was also investigate, Thus, reaction of (6) with thiourea in reflu xing ethanol containing catalytic amount of piperid ine afforded a single product for which five isomeric cycloadducts (27), (29),(31),(33) and (35) seemed possible. However, the pyrimidinethione (35) was assigned for the react ion product on its analysis. The IR spectrum lacked an absorption band due to a CN function and showed bands at 3386, 3161, 1673, 1635 and 1276cm -1 characteristic to 3NH, t wo amidic CO and CS functions., respectively. The 1H NM R spectrum exhibited no signal due to NH2 protons which was attributed to either structures (29), (31) or (33) and displayed doublet signal at  8.24pp m assignable to pyrimid ine-H6 proton, three broad singlet signals at  9.01pp m,  11.07pp m and  11.73pp m, specific for three NH protons, in addit ion to an aromat ic mu ltip let in the reg ion  7.21-7.93pp m.
Also, reaction between enaminonitrile (6) and 6-amino-2-thio xo -(1H)-pyrimidine-4-one (36) in ethanol containing catalytic amount of piperidine afforded a single product (as examined by TLC) for wh ich three iso meric cycloadducts (38), (40) and (41) seemed possible. However, the pyrido[2,3-d]pyrimidine derivative (41) was assigned for the reaction product on the basis of its elemental and spectral data. The IR spectrum lacked an absorption band due to a nitrile function and reaveled absorption bands at 3465 cm -1 , 3242 cm-1, 3216 cm -1 assigned to (NH and NH2), 1675 cm -1 , 1635 cm-1 characteristic to 2C=O functions., respectively. The 1H NMR spectrum exhib ited singlet signal at  4.88 ppm due to NH2 protons which was attributed to (41) which is consistent isomeric structure (41)  specific for three NH protons, in addition to an aro mat ic mu ltip let in the region  7.21-7.83 ppm. In addit ion, according to literature the reaction of hetercyclic amines to the double bond of the enaminonitrile occurs with concurrent elimination of dimethylamine rather than condensation of water mo lecule [45][46][47][48][49][50][51][52][53][54][55][56][57] but in our studying herein elimination of dimethylamine rather than addition on cyano group followed by aro mat ization. On the basis of these finding, structure of (38 and 40) was discarded and the product isolated fro m the studied reaction was assigned structure (41).

Experimental
All organic solvents were purchased fro m co mmercial sources and used as received or dried using standard procedures, unless otherwise stated. All chemical were purchased from Aldrich or Across and used without purification. Melting points were measured on a Gallen kamp apparatus and are uncorrected. IR spectra were recorded on Shimad zu FT-IR 8101 PC infrared spectrophotometer. The 1H NM R spectra were determined in DM SO-d6 at 300 M Hz on a Varian Mercury VX 300 NM R spectrometer using TMS as an internal standard. Mass spectra were measured on a GCM S-QP1000 EX spectrometer at 70Ev. Elemental analyses were carried out at the Microanalytical Center of Cairo University. A mixture of the enaminonitrile (7) (10 mmol) and hydrazine hydrate (80%. 0.65 ml) in ethanol (40 ml) stirred at reflu x for 4h., then concentrated in vacuo to one third of its volume, cooled to roo m temperature, poured onto ice/water. The solid product which formed was collected by filtrat ion, washed with water several times and recrystallized fro m dio xan to give (76%, yield) of (8) Method (A). Co mpound (6) (10 mmo l) in ethanol (25ml) was treated with hydrazine hydrate (80%. 0.65 ml) stirred at 50-60°C for 5h. Cooling to room temperature afforded a precipitate which was separated by filtration, washed with ethanol and recrystallized fro m DMF/ EtOH (2:1) as pale yellow crystals.
A mixture of (9) (10 mmol) and enaminone (19) (10 mmo l) in pyrid ine (20 ml) were stirred at reflu x for 5h., cooled to room temperature and poured onto ice/water acid ified with hydrochloric acid, forming a solid that was collected by filtration, washed with water several times and recrystallized fro m d imethylformamide as yellow crystals to give (71%, yield) of (20) Reflu xing of (20) (10 mmo l) in DMF (20 ml) containing anhydrous sodium acetate (1g) for 6h. The reaction mixtu re was cooled to room temperature and poured onto ice. The aqueous solution was acidified with hydrochloric acid, forming a solid that was collected by filtration, washed with water several times and recrystallized fro m DM F as pale buff crystals to give (73%, yield) of (21) (24).
A mixture of (9) (5 mmo l) and DMFDMA (5 mmo l) in case of (22) or (11 mmo l) in case of (24) in dimethylformamide (25 ml) was stirred at reflu x for 5h., cooled to room temperature and poured onto ice/water. The formed crude solid was collected by filtration, washed with water several times and recrystallized fro m the appropriate solvent.
A mixture o f enaminonitrile (6) (10 mmol) and thiourea (10 mmo l) in mixture of dimethylformamide and ethanol (1:1) (25 ml) containing a catalytic amount of piperidine (0.1 ml) was reflu xed fo r 6-8h (TLC control) and then left overnight at room temperature. The solid product so formed was filtered off, washed with ethanol and dried well and recrystallized fro m d imethylformamide as a pale yellow powder (81%, yield) of (35) A mixture of enaminonitrile (6) (10 mmo l) and 6-amino-2-thio xopyrimidine-4(1H)-one (36) (10 mmo l) in dio xan (25 ml) containing a catalytic amount of p iperidine (0.1 ml) was reflu xed fo r 6-8h (TLC control) and then cooled to room temperature and poured onto ice/water. The fo rmed crude solid was collected by filt ration, washed with ethanol several times and recrystallized fro m DMF as a yellow crystals (61%, y ield) o f (41)