Microwave Assisted Condensation Reactions of 2-Aryl Hydrazonopropanals with Nucleophilic Reagents and Dimethyl Acetylenedicarboxylate

The reaction of methyl ketones 1a-g with dimethylformamide dimethylacetal (DMFDMA) afforded the enaminones 2a-g, which were coupled with diazotized aromatic amines 3a,b to give the corresponding aryl hydrazones 6a-h. Condensation of compounds 6a-h with some aromatic heterocyclic amines afforded iminoarylhydrazones 9a-m. Enaminoazo compounds 12a,b could be obtained from condensation of 6c with secondary amines. The reaction of 6e,h with benzotriazolylacetone yielded 14a,b. Also, the reaction of 6a,b,d-f,h with glycine and hippuric acid in acetic anhydride afforded pyridazinone derivatives 17a-f. Synthesis of pyridazine carboxylic acid derivatives 22a,b from the reaction of 6b,e with dimethyl acetylenedicarboxylate (DMAD) in the presence of triphenylphosphine at room temperature is also reported. Most of these reactions were conducted under irradiation in a microwave oven in the absence of solvent in an attempt to improve the product yields and to reduce the reaction times.


Introduction
Over the last 100 years mankind has not paid much attention to the environmental impact of chemistry, but in the last decade this has changed radically and the need for "Green Chemistry" has become apparent. The utility of microwaves in heterocyclic synthesis is also receiving now considerable attention [1][2][3][4]. Enaminones has been recently extensively utilized as precursors for the synthesis of heteroaromatics [5][6][7][8]. We report herein on the synthesis of iminoarylhydrazonopropanone, azolopyrimidine and 3-oxaloalkanonitrile derivatives of potential interest as pharmaceuticals and photochromic dyes [9][10][11][12][13], starting from enaminones. It has been reported that methylalkyl ketones and methylaryl ketones condense readily with dimethylformamide dimethylacetal (DMFDMA) to yield enaminones, whose chemistry has recently attracted considerable interest [5,6,[12][13][14][15][16][17][18][19][20]. The chemistry of 2-arylhydrazonopropanals has also received considerable interest in the last few years [21][22][23][24][25]. As part of an ongoing project in our laboratory aimed at exploring potential utility of microwave irradiation as a source of heat for producing polyfunctionally substituted heteroaromatics and because of our recent interest in making our synthetic approaches environmentally attractive, we have decided to investigate here the possibility of conducting our reactions in two ways: (i) Classical conventional heating methods with solvents (Δ).
(ii) Microwave heating without solvent (μω) . The yield of products obtained with the microwave heating technique and the time taken to complete the reactions will be compared with those seen with conventional methods [8,26].

Results and Discussion
The enaminones required for this investigation were first synthesized via condensation of methyl aryl 1a or heteroaryl ketones 1b-g with DMFDMA in refluxing xylene. The desired compounds were obtained in low yield, consequently we have modified this synthetic approach by condensing the methyl ketones with slightly excess of DMFDMA in the absence of solvent [26] (Scheme 1). In this case the reaction products 2b-g were obtained in almost quantitative yields yield on cooling in a much more economical synthesis. Enaminones 2a-g coupled with diazotized methyl anthranilate 3a or diazotized anthranilonitrile 3b in the presence of ethanolic sodium acetate to yield the corresponding aryl hydrazone coupling products 6 a-h [17,27] (Scheme 2). When N,N-dimethylamino-3-buten-2-one (2a) and 3-N,N-dimethylamino-1-(4-chloro phenyl)-2propen-1-one (2g) were treated with excess diazotized anthranilonitrile 3b the bisazo compounds 7a and 7b was formed in a Japp-Klingmann type reaction which proceed via intermediate formation of 6a,b [28] (Scheme 3). The 1 H-NMR of the resulting product 7a showed a single absorption signal at δ 15.50 ppm, corresponding to the NH proton resonance. The 13  We also report herein on the reactivity of 6a-h towards a variety of nitrogen and carbon nucleophiles in the absence of solvent under irradiation (μω) in a domestic microwave oven. The yields of products obtained under the microwave heating technique μω and the time taken to complete the reactions are compared with those obtained by conventional heating (Δ) in Table 2 (see  Experimental). Thus, 6a-h were heated with a variety of heterocyclic amines such as 2-aminothiazole (8a), 2-aminopyridine (8b), 2-aminobenzimidazole (8c) and 2-amino-benzothiazole (8d) yielding the corresponding condensation products 9a-m. Several tautomeric forms (cf. 10, 11), seemed possible for the iminoaryl hydrazone condensation products 9a-m, whose structures were established based on spectral data. For example, the 1 H-NMR of the 9k showed two singlets, the first at δ 6.89 ppm, corresponding to the resonance of the olefin CH proton and the second at δ 14.46 ppm corresponding to the hydrazone NH proton. The 13 C-NMR has also showed the disappearance of the absorption signal of the carbon atom corresponding to the formyl carbonyl group and the appearance of a signal at δ 165.27 ppm for the carbon atom of the HC=N group. The IR of the 9l showed an absorption band at 3350 cm -1 of the NH group, as well as an absorption band at the rather low value of 1684 cm -1 for the carbonyl group. This indicates that there is a hydrogen bond between the hydrazone NH hydrogen and the oxygen of the carbonyl group. Treatment of 6c with secondary amines such as piperidine and morpholine afforded compounds 12a,b in good yield (Scheme 3).
Arylhydrazones 6e,h reacted with benzotriazolylacetone (13) in boiling ethanol in the presence of traces of pyridine as a catalyst to give 14a,b by loss of a water molecule (Scheme 4). The structure of this product is proposed based on its elemental analysis and spectral data. The IR showed an absorption band at 1674 cm -1 and another at 1646 cm -1 for the carbonyl groups, as well as an absorption band at 3308 cm -1 for the NH group. The 1 H-NMR showed two singlets at δ 1.99 and 7.20 ppm, corresponding to the resonances of the CH 3 protons and the olefin CH proton. Similar results were obtained when the reaction was performed under microwave irradiation. It was noted that the reaction of 3-arylhydrazono-4-butanals 6a,e and 2-arylhydrazono-3-propanals 6b,d,f,h with glycine or N-acetylglycine and with hippuric acid by boiling in acetic anhydride (Ac 2 O) gave similar compounds. The structural formulae 17a-g are proposed for the resulting products based on their elemental analysis and spectral data. Thus the 1 H-NMR of compound 17a showed a singlet at δ 2.23 ppm corresponding to the protons of the CH 3 attached to the amide group. Another singlet was seen at δ 8.61 ppm, corresponding to the resonance of the pyridazine ring (HC-4) proton. A third singlet seen at δ 10.21 ppm was assigned to the amide group NH proton. The 13 C-NMR showed a signal for the carbon atom of the methyl group attached to the amide group (NHCOCH 3 ) at δ 24.83 ppm and an absorption at δ 171.98 ppm corresponding to the carbon atom of the amide group carbonyl (NHCOCH 3 ). The same result was obtained when the reaction was performed by means of microwave irradiation in a microwave oven for 5-15 minutes, in yields of 35 %-50 % (Scheme 5). It is proposed that when Ac 2 O is present the glycine is acetylated to N-acetylglycine and then this compound cyclizes to form 2-methyloxazol-5-one (15a) and the latter in turn condensed with the arylhydrazone derivatives 6a,b,d-f,h to form the intermediate 16 which cannot be isolated, but then rearranges to form pyridazinone derivatives 17a-f. Similarly hippuric acid cyclized in the presence of Ac 2 O to give 5-phenyloxazol-5-one (15a) and then this compound condensed with arylhydrazone derivative 6a to gave pyridazinone derivative 17g [28,29].
Recently Elnagdi et al. [10,30,31] have described a synthesis of pyridazine-5,6-dicarbonates 22a,b via reaction of 6b,e with dimethyl acetylenedicarboxylate in the presence of diphenylphosphine. The exact mechanism has never been discussed. In our hands, a similar reaction took place affording dimethyl-1,6-dihydropyridazines-5,6-dicarboxylate. We believe that the initial step in this reaction is the addition of triphenylphosphine to the dimethyl acetylenedicarboxylate to yield 18, then this compound attacks the formyl carbonyl group yielding 19, which cyclizes to 20 and the latter is then converted into the final product via intermediate 21 (Scheme 6).

General
All melting points were measured on a Gallenkamp Electrothermal melting point apparatus and are uncorrected. The IR absorption spectra (KBr disks) were measured on a Nicolet Magna 520FT IR Spectrophotometer. 1 H-NMR and 13 C-NMR spectra were recorded in deuterated dimethylsulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ) at 200 MHz on a Varian Gemini NMR spectrometer or a Bruker DPX 400 MHz spectrometer using tetramethylsilane (TMS) as an internal reference and results are expressed as δ values (ppm). Mass spectra were recorded on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Microwave irradiation was carried out using a commercial microwave oven (SGO 390W). Elemental analyses were carried out at the Microanalytical Center of Cairo University, Egypt.

General Procedure for the preparation of enaminones 2a-g
Method I (Δ): Dimethylformamide dimethylacetal (DMFDMA) (0.1 mol) was added to solution of methyl ketone (0.1 mol) in dry xylene (30 mL) or dry toluene (30 mL), and the reaction mixture was refluxed for 8 hours. Removal of the solvent under reduced pressure yielded the crude product, which was recrystallized from xylene.
Method II (Δ without solvent): A mixture of dimethylformamide dimethylacetal (DMFDMA, 0.1 mol) and the corresponding methyl ketone (0.1 mol) was refluxed for 9 hours and was allowed to cool. The solid product formed was collected and recrystallized from xylene.
Method III (μω): Dimethylformamide dimethylacetal (DMFDMA, 0.1 mol) and methyl ketone (0.1 mol) were placed in the microwave oven and irradiated at full power for 1-5 min., left to cool to room temperature and the solid formed was collected and recrystallized from xylene.
Yields and properties of the products are summarized in Table 1.

Preparation of 2-arylhydrazono-3-oxo-3-substituted-propanals 6a-h [15]
A cold solution of aryldiazonium salt (10 mmol) was prepared by adding a solution of sodium nitrite (1 g in 10 mL H 2 O) to a cold solution of aryl amine hydrochloride (10 mmol of aryl amine in 5 mL concentrated HCl) with stirring as described earlier [15]. The resulting solution of the aryldiazonium salt was then added to a cold solution of enaminone in EtOH (50 mL) containing sodium acetate (1g in 10 mL H 2 O).The mixture was stirred at room temperature for 1h and the solid product thus formed was collected by filtration and crystallized from the appropriate solvent.

General procedure for the preparation of bisazo compounds 7a,b
A cold solution of aryldiazonium salt (10 mmol, a slight excess) was prepared by adding a solution of sodium nitrite (1g in 10 mL H 2 O) with stirring to a cold solution of arylamine hydrochloride (10 mmol of arylamine in 5 mL concentrated HCl) as described earlier. The resulting solution of the aryldiazonium salt was then added to a cold solution of enaminone in EtOH (50 mL) containing sodium acetate (1g in 10 mL H 2 O). The mixture was stirred at room temperature for 1 h and the solid product thus formed was collected by filtration and crystallized from the appropriate solvent.

Reaction of 2-Arylhydrazones with heterocyclic amines:
Method I (Δ): A mixture of compounds 6a-h (0.1 mol) and amine (0.1 mol) was refluxed in ethanol (30 mL) for 2 hours, then left to cool to room temperature and the solid was collected and crystallized from the appropriate solvent.
Method II (μω): A mixture of compounds 6a-h (0.1 mol) and amine (0.1 mol) and a few drops of ethanol was placed in the microwave oven and irradiated at 390 w for 5 min., then left to cool to room temperature and the solid was collected and crystallized from the appropriate solvent.         Each of compounds 6a,b,d,e,f,h (0.1 mol) and glycine or N-acetylglycine or hippuric acid (0.1 mol) was refluxed in acetic anhydride (20 mL) for 1 hour, then left to cool at room temperature and poured into ice-cold water. The solid product so formed was collected by filtration and crystallized from the appropriate solvent.

2-{N′-[1-(Benzothiazol-2-yliminomethyl)-2-oxo-propylidene]-hydrazino}-benzonitrile
Method II (μω): Each of compounds 6a,b,d,e,f,h (0.1 mol) and glycine or N-acetylglycine or hippuric acid (0.1 mol) and drops from acetic anhydride (20 mL) was placed in the microwave oven and irradiated at 390 W for 5-15 min., then left to cool to room temperature and the solid was collected and crystallized from the appropriate solvent.   Method I (Δ): To stirred solution of triphenylphosphine (0.1 mol) and each of compound 6b,e (0.1 mol) in dichloroethane (10 mL) was added a few drops of DMAD solution (0.1 mol) in dichloroethane (10 mL) then left at room temperature overnight. The solvent was removed and the residue cooled to deposit a solid, which was crystallized from the appropriate solvent. Method II (μω): Each of compounds 6b,e (0.1 mol) and triphenylphosphine (0.1 mol) and a few drops of DMAD solution (0.1 mol), was placed in the microwave oven and irradiated at 390 W for 10-30 min., then left to cool to room temperature and the solid was collected and crystallized from the appropriate solvent.