The present strategy commenced with the aromatic nucleophilic substitution of pyrrole 2 carboxylate onto PEG immobilized benzimidazole linked o-fluoro nitrobenzene.
For incorporation the pyrrole 2-carboxylate moiety into the aromatic ring we have screend several reaction conditions. But we have observed the desired product 18 was finally obtained in 80 % yield in refluxing conditions of DMF with K2CO3 after 18 h and microwave irradiation at 135 °C in 10 min as shown in scheme 26. Furthermore, the use of Cs2CO3 in DMF solvent produces the polymer immobilized compound 18 with significantly improved yield up to 95 % in 16 h under refluxing conditions and 10 min under microwave irradiation at 135 °C. To confirm the product formation by proton NMR spectroscopy a small portion of the reaction mixture was pulled out, the compound was precipitated and washed with cold ether and dried to record the proton NMR spectrum to monitor the progression of reaction. Upon completion of the reaction, the polymer bound compound mixtures were purified by the same precipitation and washing protocol. The 1H NMR confirmed that the pyrrole-2-carboxylate moiety has been introduced into the aromatic system. The signal at 6.5 ppm, 6.9 ppm, 7.2 ppm corresponds to the three aromatic proton of pyrrole moiety attachéd to the polymer conjugates 18. After incorporation of pyrrole 2 carboxylate moiety into the aromatic system 18 we plannd to cyclise this product in Scheme 2.31. In the next step, the nitro functionality in polymer pyrrole carboxylate conjugate was partial reduced to N-hydroxy compound and which subsequently reduced to in situ cyclic amide 19 using 10 % Pd/C and ammonium formate in methanol under microwave irradiation at 60 oC.
Scheme 2.31. Novel Microwave-Assisted Polymeric Approach to Benzimidazole-Pyrrolo [1,2-a] quinoxalines.
Formation of the conjugates N-hydroxy cyclic amide 19 was confirmed from change of yellow to blue color upon spotting on the TLC plate and also confirmed by the proton NMR analysis. Upon completion of the reaction, reaction mixtures were filtered through celite bed fritted funnel to get rid of the Pd/C. The reaction mixtures were evaporated and dichloromethane was added to salt out the ammonium formate finally filtered through celite bed fritted funnel to get rid of ammonium formate to obtain the compound 19.
PEG
R N
Scheme 2.32. Partial Nitro reduction to Benzimidazole-N-hydroxypyrrolo[1,2-a]quinoxalineone 19
The exact mechanism regarding the formation of compound 19 was observed in Scheme 2.32. Here we have observed that the aromatic protons of the pyrrole moiety has been shifted to the downfield. No loss of yield was observed during this reductive transformation, suggesting that the polymer support remained intact throughout the reaction. In order to introduce the second point of structural diversity into the N-hydroxy cyclic amide polymer conjugates, we further reacted different alkyl bromides with N-hydroxy cyclic amide polymer conjugates. For this reaction we have tried different reaction conditions a) sodium hydride and dichloromethane solvent, b) sodium hydride in THF solvent, the reaction does not proceed at al . We have observed the SN2 reaction of N-hydroxy cyclic amide polymer conjugates with different alkyl bromide in presence of sodim hydride as base in polar DMF solvent proceded smoothly under the room-temperature conditions for 24 hrs. The formation of the target polymer conjugates were confirmed from the appearance of corresponding alkyl proton in the aliphatic region of the NMR spectrum as in Figure 2.15. After completion of the reaction, the DMF solvent was reduced inder reduce pressure and the reaction mixture was taken in DCM solvent.
The cold ether was added to the reaction mixture and stirrd for some times to undergo complete precipitation, filtered through the fritted funnel and dried to obtain the O-alkylated polymer conjugates. Finally, polymer support was cleaved in a potassium cyanide solution in methanol to provides benzoimidazole-alkoxy-pyrrolo [1,2-a]quinoxalineone in good yields (Table 2.3).
Figure 2.15. Stepwise Monitoring towards the Formation of Benzimidazole-alkoxy-pyrrolo[1,2-a]quinoxalineone on PEG Support in CDCl3 at 25oC
In most of the cases, a cleavage reaction was completed at room temperature within 24 h.
The crude mixture was concentrated; the polymer was precipitated out with excess of cold ether and removed by filtration. The filtrate was dried and subjected to HPLC analysis, which depicted high purity and excellent yield of all the compounds without further purification. The completion of cleavage from the polymer support was verified by observing the disappearance of characteristic set of peaks corresponding to polymer protons.
R1NH2 Isolated yieldb
Table 2.3. Synthesis of benzimidazole-pyrrolo[1,2-a]quinoxalinone derivatives (21a-21o).
aLRMS were detected with ESI ionization source. bDetermined based on the weight of crude samples (%).
cDetermined by HPLC analysis (UV detection at 254 nm of the crude product (%).
The structure of the final compounds was also unequivocally confirmed by the X-ray crystallographic study. The X-ray crystallographic data of 21K are in full agreement with its structure. The benzimidazole ring was situated in the perpendicular plan where as alkoxy-pyrrolo[1,2-a]quinoxalineone remains to the plane in Figure 2.16.
N N O
O N
N O O
21l
Figure 2.16. X-ray crystallographic structure of of the Benzimidazole-Pyrrolo[1,2-a]quinoxalineone 21l
2.19. Conclusion
We have successfully developed novel synthesis of biologically promising novel derivatives of benzimidazole-pyrrolo[1,2-a]quinoxaline and benzimidazole-Pyrrolo[1,2-a]quinoxalineone on soluble polymer support under microwave condition. Linear sequence of nucleophilic aromatic substitution, nitro reduction and Pictet-Spengler cyclization and partial nitro reduction on polymer support in conjugation with microwave
irradiation were effectively used to develop short synthesis of benzimidazole linked bi-heterocyclics