Microwave-Assisted Synthesis of a Library of Pyrrolo[1,2-c]quinazolines

EMILIAN GEORGESCU1, FLOREA DUMITRASCU2, FLORENTINA GEORGESCU3, CONSTANTIN DRAGHICI2, DENISA DUMITRESCU4* 1Chimcomplex Rm. Valcea, Research Center, 1 Uzinei Str., 240050, Ramnicu Valcea, Romania 2Center of Organic Chemistry C. D. Nenitzescu, Romanian Academy, 202B Splaiul Independentei, 060023, Bucharest, Romania 3Enpro Soctech Com srl, 31 Elefterie Str., 050524, Bucharest, Romania 4Ovidius University of Constanta, Faculty of Pharmacy, 6 Capitan Aviator Al. Serbanescu Str., 900470, Constanta, Romania

(2.2 mmole) in 18 mL 1,2-epoxybutane was placed into a sealed microwave reactor at 120 °C for 45 min. The reaction mixture was cooled to room temperature, partly of the solvent was removed in vacuum, 5 mL of MeOH was added under a gentle stirring and the reaction mixture was left overnight at 5-10 o C. The solid formed was filtered-off, washed on the filter with a mixture of diethyl ether-MeOH 2:1 and crystallized from CHCl 3 or CHCl 3 /Et 2 O.The melting points and yields for all synthesized pyrrolo [1,2c]quinazolines are shown in Table 2. The spectral data and elemental analysis are given below.

Results and discussions
The one-pot, three components microwave-assisted synthesis of a library of pyrrolo [1,2-c]quinazolines starts from various quinazolines, 2-bromoacetophenones and electron-deficient alkynes in the presence of 1,2epoxybutane which acts both as reaction medium and as acid scavenger. Halogen atoms are grafted on several starting quinazolines in order to improve specific properties of the potentially bioactive final products regarding drugtarget interactions, increasing of membrane permeability and, therefore, their bioavailability [33].
The experimental data proved that the microwave irradiation significantly reduces the reaction time compared to the usual heating conditions and simplify the work-up of the final reaction mixture. The best conditions were reached by the microwave irradiation of reaction mixture at 120 o C for 45 min.
The reaction pathway implies the in situ formation of the quinazolinium salt, the in situ generation of the corresponding quinazolinium N-ylide from quinazolinium salt in the presence of 1,2-epoxybutane, followed by the in situ1,3-dipolar cycloaddition of the quinazolinium N-ylide with electron-deficient alkyne and dehydrogenation of the primary cycloadduct to give directly the desired pyrrolo [1,2c]quinazoline [13,[15][16][17][18].
Any substituted quinazoline can be used in this reaction, except 2-substituted quinazolines bearing large substituents because of steric hindrance of the quaternization reactions. A large range of 2-bromoacetyl derivatives or other quaternizing agents which can stabilize the intermediate N-ylides can be used instead of 2bromoacetophenone and any available electron-deficient alkynes can be used as dipolarophiles.
The synthesized pyrrolo [1,2-c]quinazolines were structurally characterized by chemical and spectral data. The chemical shifts assignments for the protons and carbons respectively, were made based on the information obtained from bidimensional homo-and heteronuclear correlations, like COSY and HETCOR experiments.

Conclusions
A library of pyrrolo [1,2-c]quinazoline derivatives has been successfully synthesized by combining an one-pot, three-component procedure with microwave irradiation method to easy access a librar y of pyrrolo [1,2c]quinazoline derivatives, starting from readily obtainable and inexpensive materials. This synthetic pathway starts from quinazolines, 2-bromoacetophenones and electrondeficient nonsymmetrical substituted alkynes in 1,2epoxybutane via 1,3-dipolar cycloaddition of quinazolinium N-ylides.Microwave acceleration method offers valuable features such as considerable shorter reaction time, substantially reduced solvent spending, decreasing of the consumed energy and good yields. This one-pot, threecomponent microwave-assisted synthetic pathway provide a simple, clean and rapid access to a large range of pyrrolo [1,2-c]quinazoline derivatives.