Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal under controlled microwave heating

The multicomponent reaction of 5-aminopyrazole derivatives with cyclic 1,3-dicarbonyl compounds and dimethylformamide dimethylacetal (DMFDMA) in DMF at 150 °C under controlled microwave heating afforded regioselectively 8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones 6 rather than the corresponding dihydropyrazolo[5,1-b]quinazolin-8(5H)-ones 4.


Introduction
Several naturally occurring and synthetic compounds containing quinazoline derivatives are of considerable interest in fields related to the organic and medicinal chemistry of natural products [1,2]. The quinazoline ring system represents the core skeleton of an important class of heterocyclic compounds possessing a wide range of biological activities [3,4]. Multicomponent reactions (MCR) occupy an interesting position in organic synthesis because of their atom economy, simple procedures and convergent character [5][6][7]. An unresolved issue in multicomponent reactions is whether their selectivity is chemo- or regioselectivity, or both, due to the several possible parallel reaction pathways, which result in the formation of different products [8][9][10]. Many factors modulate the selectivity of synthetic transformations, such as temperature, pressure, solvent, catalyst and type of reaction control, i.e., either kinetic or thermodynamic [11][12][13]. It has been reported that the use of microwave or ultrasound irradiation provides an additional parameter for synthetic selectivity [14][15][16][17].

Results and Discussion
The multicomponent reaction of 5-aminopyrazoles, dimedone and aromatic aldehydes was reported to afford several different tricyclic products. Thus, in an early report [18], the reaction of the three components in ethanol under conventional heating afforded mainly the corresponding pyrazolo [3,4-b]quinolin-5ones. This finding was later supported by other authors [19].
Recently, the results of an interesting study dealing with such reactions were described by Chebanov et al. [20] Specifically, these researchers performed the reaction at 150 °C in the presence of triethylamine by employing a sealed vessel under microwave or conventional heating, and which thus afforded pyrazoloquinolinones (Hantzsch-type dihydropyridines). On the other hand, the use of sonication at room temperature under neutral conditions favours the formation of isomeric pyrazolo[5,1-b]quinazolin-8(4H)-ones (Biginelli-type dihydropyrimidines) [9]. Employing more nucleophilic bases to catalyse the reaction afforded the corresponding pyrazolo [4,3c]quinazolin-9-ones [20]. It was concluded that, under ambient and neutral conditions, the reaction proceeds under kinetic control, and the Biginelli-type dihydropyrimidines are the predominant isomers. Increasing the reaction temperature in the presence of triethylamine as base produces the more thermodynamically stable dihydropyridine (Hantzsch-type product). In addition, the nature of the catalyst plays an important role [20].
A one-pot three component reaction of 5-amino-1H-pyrazole-4carbonitrile, dimedone and triethylorthoesters in toluene under reflux was recently reported to afford the corresponding pyrazolo[1,5-a]-quinazolin-6-one derivatives [21]. Although it is well established that 5-amino-pyrazoles have nonequivalent nucleophilic reaction centres in the aminopyrazole scaffold (N1, C4, NH 2 ), which can lead to the formation of several different tricyclic reaction products, no general basis on which to determine the preferred tautomeric form of the final product has been established.
In continuation of our studies in which we performed multicomponent reactions using controlled microwave heating [22][23][24], we report herein the results of our investigation concerning the regioselectivity in multicomponent reactions of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal (DMFDMA) under controlled microwave heating.
We began this study by treating 5-amino-3-methylpyrazole (1a) and dimedone (2a) with DMFDMA (3) in DMF under microwave heating at 150 °C for 15 min. After being cooled to room temperature, the precipitated solid product was isolated in 88% yield ( Table 1). The mass spectrum of the reaction product showed a molecular ion peak m/z = 229.12 (100%). The 1 H NMR revealed a singlet signal at δ = 6.70 ppm integrated for one proton, which was assigned to the pyrazoloquinazolone C 3 proton, and which indicates the lack of involvement of such a proton in the condensation leading to the tricyclic system. Although, it was previously reported [20] that, due to reduced steric hindrance, the multicomponent reaction of 5-amino-3methyl-pyrazole, aromatic aldehydes and dimedone under controlled microwave irradiation at 150 °C involves the participation of C 3 -H of the pyrazole ring in such a cyclocondensation reaction, this is not favoured in our case. In addition two Scheme 1: Microwave-assisted synthesis of 4 and 6.
signals were assigned to two CH 2 groups and three methyl functions, and a singlet at δ = 8.75 ppm corresponding to one proton at C 5 . The pyrazolo[1,5-a]-quinazolin-8(5H)-one 6a was established as the reaction product, and 13 C NMR was in agreement with the proposed structure, rather than with isomeric 4a, which was prepared by first reacting 1a with dimedone (2a) in DMF under microwave heating at 150 °C for 10 min to afford 5. Subsequently, treating compound 5 with DMFDMA (3), under the same experimental conditions, gave compound 6a in excellent yield (Scheme 1 and Table 1). Furthermore, the structures of compounds 5 and 6a were unambiguously confirmed by single-crystal X-ray diffraction [25,26] ( Figure 1, Figure 2 and Table 1, Table 2, Table 3).
With this result in hand, we went on to study the scope of such multicomponent reactions with several substituted 5-aminopyrazoles and cyclic 1,3-diketones. Thus, the reaction of 1b-f with 2a,b and 3, under the same experimental conditions, afforded the corresponding pyrazolo[5,1-b]quinazolin-8(5H)-ones 6b-g, respectively. The structures of 6b-g were deduced from their 1 H NMR, 13 C NMR, mass spectra and elemental analyses.

Scheme 2:
A proposed mechanism to account for the formation of products 6. The factors that determine the nature of the end product are, however, at present unclear.
From the data of the X-ray crystal structure it can be concluded that the bridged head nitrogen has bond angles closer to those of sp 3 nitrogen. One may thus conclude that the lone pair on this nitrogen atom does not contribute much to the actual state of the molecule and that charge-separated ions also do not contribute significantly; although, the pyrazolo[5,1-b]quinazolin ring is almost planar.

Conclusion
In summary, we can reveal that the reaction of substituted 5-aminopyrazoles, cyclic 1,3-diketones and dimethyformamide dimethylacetal (DMFDMA, 3) proceeds by initial attack of the exocyclic amino function. Although an attack by the ring nitrogen has been proposed for the reaction of 5-aminopyrazoles with acrylonitrile [29], here steric factors hinder such an attack and the reaction occurs exclusively, in every case studied, at the amino function.

Experimental
General information. All the reactions were carried out in a Milestone START Microwave Labstation (temperature control by IR sensor). 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were measured on a Bruker DPX instrument by using DMSO-d 6 as solvent and TMS as internal standard. Chemical shifts are expressed as δ in ppm. Coupling constants (J) are given in Hertz (Hz). The melting points were measured in a Gallenkamp melting-point apparatus and are not corrected. Mass spectra were measured by using VG Autospec Q MS 30 and MS 9 (AEI) spectrometer with the EI (70 eV) mode.

Synthesis of 4a:
A solution of 1a (1 mmol) and 2a (1 mmol) in DMF (10 mL) was heated under reflux in a Milestone Microwave Labstation at 150 °C for 10 min. After concentration and cooling to room temperature, the resulting solid product so formed was collected by filtration, washed well with EtOH, dried and recrystallized from EtOH to afford a pure sample of (Z)-3,3-dimethyl-5-(3-methyl-1H-pyrazol-5ylimino)cyclo-hexanone (5) as yellow crystals, 186 mg (85% yield); mp 233-235 °C. (1 mmol) in DMF (10 mL) was heated under reflux in a Milestone Microwave Labstation at 150 °C for 10 min. After evaporation to dryness under reduced pressure, the resulting solid product was collected by filtration, washed well with EtOH, dried and recrystallized from EtOH to give 4a.