Synthetic investigations on N-Substituted 4-and-5-Nitro-1H- Imidazotes

Abstract

The thesis entitled “SYNTHETIC INVESTIGATIONS ON N?SUBSTITUTED 4? AND 5?NITRO?1H?IMIDAZOLES” consists of seven chapters.

CHAPTER I : Synthesis and Biological Significance of Nitro?Imidazoles – A Review The introductory chapter reviews the biological importance of 1?alkyl?5?nitro? and 4?nitro?1H?imidazoles and their syntheses.

CHAPTER II : N?Alkylation Studies on 4(5)?Nitroimidazoles Alkylations of 4(5)?nitroimidazoles (1) have been studied in acidic and basic media to synthesise either of the two possible isomers 2 and 3 with high regioselectivity. In acidic media, the composition of the isomer mixture depends greatly on temperature and the nature of the alkylating agent. Reactive alkylating agents predominantly form the 5?nitro isomers (2) at lower temperatures, and the 4?nitro isomers (3) at higher temperatures. With unreactive alkyl halides such as EtBr, only 5?nitro isomers were produced irrespective of temperature. The mechanism involves quaternisation of the initially formed N?alkyl?5?nitroimidazoles (2), followed by preferential dealkylation to yield the thermodynamically more stable 4?nitroimidazoles (3) (SCHEME I). Reaction of 1 with alkyl halides in DMF/K?CO? was found to be the best method for carrying out regio?specific alkylations to obtain excellent yields of N?alkyl?4?nitroimidazoles (4) (SCHEME II). Alkylation of 1 with propargyl bromide in DMF/K?CO? resulted in the formation of N?propanedienyl?4?nitroimidazoles (6), while in acetone medium N?propynyl?4?nitroimidazoles (5) were obtained exclusively. Under other reaction conditions mixtures of 5 and 6 were produced (SCHEME III).

CHAPTER III : Studies on the Michael Addition of 4(5)?Nitroimidazoles The regiochemistry of the addition of 1 to standard Michael acceptors (7) has been studied under a variety of conditions using acidic and basic catalysts (SCHEME IV). Only 4?nitro isomers were produced under all conditions. The best yields of N?alkyl?4?nitroimidazoles (8) were obtained in DMSO/pyridine at 135–140°C. This method provides a high?yielding route to functionalised N?substituted 4?nitroimidazoles.

CHAPTER IV : Rearrangements of N?Alkyl?5?Nitroimidazoles A group of N?alkyl?5?nitroimidazoles (9) were found to undergo base?catalysed rearrangement to the corresponding 4?nitroimidazoles (10) (SCHEME V). The rearrangement was studied with respect to the nature of the side chain on N?1, base strength, base concentration and temperature. The mechanism involves cleavage of the side chain on N?1 and realkylation at the more nucleophilic N?3 to give the thermodynamically more stable 4?nitro isomers. The anion 11 of 4(5)?nitroimidazoles and the alkoxide compete for the generated Michael acceptors, producing 10 and 12 (SCHEME VI).

CHAPTER V : Synthesis and Reactivity of N?Acyl?2?Methyl?4?Nitroimidazoles The synthesis and isolation of a class of reactive N?acyl?2?methyl?4?nitroimidazoles (14) and their potential applications as facile acyl?transfer agents have been studied. These nitroimidazolides (14) could be synthesised from 13 and acid chlorides (SCHEME VII), and were found to be much better acyl?transfer agents than simple imidazolides.

CHAPTER VI : Applications of Fluoride Ion as Base in the Chemistry of Nitroimidazoles The base?catalysed Michael additions and rearrangements described earlier (SCHEMES III, IV and V) were studied using potassium fluoride both in free form and supported on alumina (KF–Al?O?). The reactions were several?fold faster and the work?up was much simpler. Alkylations of 1 under basic conditions were also investigated with KF and KF–Al?O?.

CHAPTER VII : Halogenation Studies on 4?Nitroimidazoles and Synthetic Utility of 1?Alkyl?4?Nitro?5?Haloimidazoles Bromination A new brominating system, Br?–DMF–KHCO?, has been used for preparing biologically important 2?alkyl?4(5)?nitro?5(4)?bromo and 1,2?dialkyl?4?nitro?5?bromoimidazoles (16) from the corresponding 4?nitroimidazoles (15) (SCHEME VIII). The mild conditions allow bromination in the presence of acid? and base?sensitive functionalities with nearly quantitative yields. With conventional brominating agents, yields were only moderate for compounds bearing ester, nitrile, or ketone functions. Iodination Direct iodination of 4?nitroimidazoles to obtain 4(5)?nitro?5(4)?iodoimidazoles has not been reported previously. A method for nuclear iodination of 2?methyl?4?nitroimidazoles (17a) has been developed using KI/HNO?/AcOH (SCHEME IX). The yields of iodinated products (18a) were in the range of 80–90%. The 4?nitroimidazoles (17b) lacking a substituent at C?2 yielded 2,5?diiodo?4?nitroimidazoles (18b) in good yields. The 4?nitro?5?haloimidazoles 19(a,b), having cyanoethyl and sulfonylethyl groups on N?1, were used for synthesising 4(5)?nitro?5(4)?amino?substituted imidazoles (21) via intermediates 20 (SCHEME X). The yields of 20 were excellent with 19a. The compounds 21 could not be prepared directly from the corresponding halo analogues.