Expedient Protocols for the Installation of Pyrimidine Based Privileged Templates on 2-Position of Pyrrolo [ 2 , 1-c ] [ 1 , 4 ]-benzodiazepine Nucleus Linked Through a p-phenoxyl Spacer

Exceedingly facile single step expedient protocols based on the versatility and reactivity of corresponding intermediates : [2(dimethylaminomethylene) ketone] (5) and chalcone (6), derived from 2(p-acetyl phenoxyl) substituted analogue of pyrrolo[2,1-c][1,4]benzodiazepine (4), have been developed to provide an easy installation of the pyrimidine based privileged templates at 2-position of pyrrolo[2,1c][1,4]-benzodiazepine through a p-phenoxyl spacer, by utilizing the synthetic strategy depicted in schemes-1 and 2.


Introduction
The development of 'privileged heterocyclic scaffolds' 1 is a rapidly emerging subject in medicinal chemistry. 2a-d) A diarylpyrimidine-based NNRTIs the etravirine (TMC-125) 5 (A) has emerged as one of the highly active second generation drug, which has found FDA approval for the treatment of HIV infected patients with NNRTI-resistant viruses.Federal Drug Administration has allowed its application in the highly active antiretroviral therapy [HAART] 6 along with other antiretroviral agents, to adult patients showing multidrugresistant HIV infections.

Experimental Section
Melting points were determined on an open capillary and are uncorrected.The IR sprectra were recorded on Schimadzu FTIR-8400S. 1 HNMR spectra were recorded in CDCl 3 on Bruker DRX-400 MHz spectrometer using TMS as internal reference and values are expressesd in δ ppm.Mass spectra were taken on a Joel SX-102 (EI/CI/FAB) mass spectrometer at 70 eV.Purity of all the synthesized compounds were routinely checked by TLC on silica gel G in the solvent system (9:1, benzene:methanol).
Preparation of 2-chloro-pyrrolo [2,1-c][1,4]-benzodiazepin-5-one (3) A solution of 2 (10.80 g., 0.05 mol), N,N-dimethylaniline (6.25 ml, 0.02 mol), POCl 3 (4.5 ml, 0.05 mol) and benzene (100 ml) was refluxed for 7 h.and then allowed to cool overnight.The reaction mixture was washed with ether and then with petroleum ether to remove the soluble impurities.Cold water was then added to the reaction mixture and brought to the neutral point by addition of NaHCO 3 solution.It was then extracted three times with dichloromethane to give 3 (8.52

Results and Discussion
Ubiquity of pyrimidine nucleus in chemical literature is undoubtedly a consequence of multifarious biological response which they elicit in combating a variety of body ailments.
Recent demonstrations that some of their derivatives can be used as privileged templates in the development of potential agents for the treatment of AIDS 7 has stimulated further interest in this nucleus from yet another perspective.As a part of our endeavour to create novel heterocyclic scaffolds of anticipated biological activity from easily accessible starting materials, herein we report, the preliminary results of our studies on the synthesis of pyrimidine incorporated pyrrolo [2.1-c][1,4]-benzodiazepines linked to it through a 2-pphenoxyl spacer in 7-12.A perusal of literature 9(a-f) on the potential of 2-(dimethylaminomethylene) ketones and chalcones for their use as versatile precursors in synthesis, has demonstrated that these were readily formed from the base catalyzed reaction of carbonyl species containing an active methylene group with (i) DMF-DMA (ii) C 6 H 5 CHO respectively.Application of this strategy on 4 afforded the intermediates 5 and 6 respectively in moderate to good yield.The versatility of these novel precursors in the formation of pyrimidine nucleus was examined by allowing these to react with urea, thiourea, guanidine nitrate and acetamidine which resulted the corresponding pyrimidine incorporated analogues 7-12 in acceptable yields.Compound 4 was in turn obtained through a three step strategy on isatoic anhydride.In its first step it was reacted with L-proline based on the reported procedure 10 to give pyrrolo [2,1-c][1,4]-benzodiazepin-2,5-dione (2) which in the subsequent step was treated with POCl 3 in dimethylaniline (DMA) to afford the corresponding 2-chloro derivative (3), the reaction of which with p-hydroxyacetophenone yielded 4 in good yield.
All the synthesized compounds gave satisfactory results of their elemental analysis, IR, 1 HNMR and MS spectral data which were found to be consistent to the assigned structures.

Conclusion
In conclusion, two elegant protocols have been developed to provide an easy access of the biologically active novel pyrimidine incorporated analogues of pyrrolo [2,1-c][1,4]benzodiazepine derivatives linked to it by a 2-p-phenoxyl spacer, utilizing the potential of corresponding 2-(dimethylaminomethylene) ketones (5) and chalcone (6) respectively in high yield and purity.