New thienoyl-substituted pyrrolo [ 1 , 2-c ] quinazoline derivatives

By the reaction of quinazoline with ω-bromo-2-acethylthiophene in methanol followed by treatment of the intermediate mixture of quaternary salts with unsymmetrical activated alkynes in propenoxide, 3-(2-thienoyl)pyrrolo[1,2-c]quinazoline derivatives were obtained. 3-(2-Thienoyl)pyrrolo[1,2-c]quinazolines were also obtained by an alternative one-pot procedure directly from quinazoline, ω-bromo-2-acetylthiophene and unsymmetrical activated alkynes in propenoxide, by one-pot, multi-step sequences of reactions. Heating the same mixture of quinazolinium salts in the presence of the strong base 1-(2-thienoyl)-2-(2-thienyl)pyrrolo[1,2-c]quinazoline, an interesting inactivation product of the intermediate quinazolinium-3-thienoylmethylide was obtained.


Results and Discussion
Synthetic procedure 1,3-Dipolar cycloaddition reaction of quinazolinium-ylide with activated alkynes was considered for the synthesis of thienoyl-substituted pyrrolo [1,2-c]quinazolines.This method involves quaternary salts of quinazoline as intermediates.
The IR spectra of compounds 5-7 exhibit the characteristic carbonyl absorption bands at about 1601-1609 cm -1 .The IR spectrum of the compound 8 reveals the carbonyl absorption band at 1632 cm -1 due to the nearby position of thienyl group. All

Theoretical study
The cycloaddition reactions of intermediate quinazolinium-3-(2-thienoyl)methylide 4 with 1-butyn-3-one, phenylethynyl ketone and ethyl propiolate have been studied theoretically by performing semiempirical calculations with full optimization of the molecules at the AM1 level using the HyperChem Program. 16,17tomic charges, energies and molecular frontier orbitals for all the reactive centers involved in these reactions are presented in Table 2.These calculations showed a small positive charge of the ylide nitrogen atom N3.It means that the positive charge is rather delocalized on all the atoms of the quinazoline ring.The ylide carbon atom C9 is negatively charged meaning that the formal negative charge for the ylidic carbanion is less delocalized and this demonstrate a nucleophilic character of ylidic carbon atom.The total atomic charges of cyclic carbon atoms C2 and C4, adjacent to the ylide nitrogen atom, have small negative charges and could be explained by the resonance interaction between the heterocycle and carbanion.
The ∆E of interaction HOMO ylide -LUMO dipolarophile and HOMO dipolarophile -LUMO ylide were calculated.The HOMO ylide -LUMO dipolarophile interactions show smaller energy gaps than the opposite HOMO ethyl propiolate -LUMO ylide interactions, which is consistent with ylide-HOMO controlled reactions.
In accordance with FMO postulates, 18,19 once the HOMO/LUMO pair closer in energy has been identified, the new bonds will be formed between centres with atomic orbital coefficients with the same sign, the relative sizes of the possible pairs of coefficients predicting the regioselectivity.In the presented reactions of the quinazolinium-thienoylmethylide with unsymmetrical substituted alkynes only one regioisomer was formed, the one in which the ylide carbanion makes the new bond with the most electrophilic carbon atom from alkyne.Thus, the regiochemistry predicted by the FMO analysis is in agreement with the experimental facts.

Conclusions
The quaternization reaction of the quinazoline with ω-bromo-2-acetylthiophene in methanol led to a mixture

3-(2-Thienoyl)pyrrolo[1,2-c]quinazolines (5-7)
General procedure (a).To the suspension of the obtained mixture of quinazolinium N-methylthienoyl salts 2 and 3 (1.835g, about 5 mmol) in propenoxide (50 mL) an unsymmetrical activated alkyne (7.5 mmol) was added.The reaction mixture was stirred at room temperature for 10-12 days, and then the solution was concentrated under reduced pressure.The residue was treated with methanol (10 mL) and kept overnight at cool.The solid was filtered and washed with cold methanol and then with diethyl ether.All crude products were recrystallized from chloroform / methanol.General procedure (b).To a solution of 1.3 g (10 mmol) quinazoline în 50 mL propenoxide was added 2.05g (10 mmol) ω-bromo-2-acetylthiophene and 15 mmol of alkyne.The mixture was stirred for 20 days at room temperature, then it was concentrated under reduced pressure and kept overnight at cool.The solid was filtered and washed with methanol and then diethyl ether.All crude products were recrystallised from chloroform-diethyl ether.The yields are shown in Table 1.The melting points and spectral data are given below.
1 H-NMR spectra of the compounds 5-8 show the signals of the qinazoline ring H-5, at δ 9.52-10.26,as characteristic singlets.The 1 H-NMR spectra of 3-(2-thienoyl)pyrrolo[1,2-c]quinazolines 5-7 exhibit the characteristic singlet signals of the pyrrolo ring H-2 at different chemical shifts according to the different nearby substituents and the signals for the protons of different substituents from position 1 of the pyrrolo ring appear at normal chemical shifts.The 13 C-NMR spectra of 5-8 show characteristic signals for the carbonyl carbon at δ 176.46-178.62 (CO from thienoyl group), δ 191.74 (CO from benzoyl group) and δ 163.7 (CO from carbethoxy group).