Analysis on Microwave Based N-Chlorination of Amides

N-Haloamides are used as photoinitiators for radical polymerization and in room temperature vulcanization for the preparation of adhesives, caulks and sealants. They are also versatile reagents in organic synthesis as oxidizing agents in aqueous and non-aqueous media; Photolysis of N-haloamidcs gives amidy radicals and halogen atom intermediates. The amidy radicals so produced undergo efficient intramolecular addition to olefinic bonds. Olefinic amidyl radicals can ring-close to lactams or N-heterocvclic amides. N-chloroamides undergo the Hofmann reaction and Orton rearrangements. [1] Many literature methods are reported for the synthesis of primary N-chloroamides. Routes to synthesize secondary N-chloroamides include chlorination of secondary amides with NaCI in the presence of oxone, t-butyl hypochlorite, sodium hypochlorite, and N-chlorosuccinimide these methods for the synthesis of secondary N-chloroamides have their own limitations. t-Butyl hypochlorite is unstable and hazardous, reaction with NaCI in presence of oxone can require 2-5 hours Microwave heating has emerged as an environmental friendly technique to accelerate a variety of chemical reactions Automated and focused microwave flash heating has recently been demonstrated to improve the preparative efficacy and to dramatically reduce reaction times for many different types of organic transformations. We now report that by applying microwave heating, the N-chlorination of cyclic and acyclic secondary amides can be done in 15-20 minutes using N-chlorobenzotriazole as the chlorinating agent.

The reaction of N-methylbenzamide (la) with N- chlorobenzotriazole was attempted in the absence of microwave irradiation. After refluxing N-methylbenzamide (1a) with N-chlorobenzotriazole in acctonitrilc for 16 h. a yield of 60 % of the product was obtained. In contrast, the reaction was completed (as monitored by TLC) in 20 minutes in the case of microwave heating. Literature reports have characterized secondary N-chloroamides by IR. UV and NMR spectroscopy, chlorine estimation, iodometric assay and CHN analysis." The NMR data showed the absence of N-H protons. In H and C NMR, the N(Cl)-CH2 protons showed a downfield shift as compared to the ,YH-CH2 protons. In our experiments, the completion of the reaction was confirmed by the disappearance of the amide on TLC followed by the disappearance of NH proton in NMR, which was further confirmed by CHN analysis. The NMR data of chloro-2-azcpanonc was in close agreement with the literature data. The requires 12 hour reaction conditions are mild and the reaction can be finished in 15 minutes time. The same methodology converted cyclic secondary amides into the corresponding N-chloro amides in good to excellent yields in 15 minutes. The benzotriazole formed in the reactions was removed by washing with a saturated solution of sodium carbonate to give pure products. Scheme: Synthesis of N-chloro cyclic secondary amides [1]

It has been observed that the TiCl4-NR3 system reacts with 1-alkynes to give the corresponding diynes, through the intermediacy of the alkynyltitanium species. [2] Also, the alkynyltitanium species can be readily functionalised using certain electrophiles (Scheme 23). [2] Such direct metalation is an interesting observation, as previously alkynyl titanium reagents were prepared via metalation of 1-alkynes with alkyllithium reagents followed by exchange reaction with titanium complexes. [3] Interesting oxidative coupling reactions have been observed using N, N-dialkylaniline derivatives. [4] The corresponding benzidine derivatives are the products. Again, this transformation can be rationalized considering the intermediacy of the corresponding aryltitanium species. [4] The aryltitanium species prepared in this way can be readily functionalized using certain electrophiles (Scheme 24). [4] In 1955, it was reported that the TiCl4 oxidises tertiary amines. Presumably, the corresponding iminium ions would be the organic product and the reaction can be rationalized by the intermediates shown in Scheme 25 [5].

The N-chlorination of N-methyl benzamide by hypochlorite was studied in depth by Hardy et al. in 1967 [7], who found the reaction to be reversible. Figure 1 shows an adapted version of Hardy’s hypochlorite was reversible in alkaline media and proposed a transition state based on a six-membered ring. Values of 2.5 ± 0 and 13.7 ± 1.1 L mol-1 min-1 for the second order rate constant were calculated in his study at 293 K for the N-chlorination and the basic hydrolysis for the N-chloro N-methyl benzamide, respectively. Furthermore, a raise in the temperature to 303 K increases the rate constant for the hydrolysis to a value of 47.5 ± 4.8 L mol-1 min-1.

In this analysis we found that synthesis of 5d and 5e comprises exposing a solution of lactam in an organic solvent to chlorine gas in the presence of UV light which also promotes polymerization to some extent. However, in our reactions we didn't observe any polymerization and the reagents used are non-hazardous with minimal solvent and short reaction time. The preparation of N-chloro secondary amides: microwave irradiation leads to reaction rate enhancement, improved yields and safe conditions.

1. Alan R, Suman Mazuder, Ritu jain “Microwave Assisted N-Chlorination of Amides” 2. Bharathi, P.; Periasamy, M. Organometallics 2000, 19, 5511. 3. Krause, N.; Seebach, D. Chem. Ber. 1987, 120, 1845. 4. Periasamy, M.; Jayakumar, K. N.; Bharathi, P. J. Org. Chem. 2000, 65, 3548. 5. Antler, M.; Laubengayer, A. W. J. Am. Chem. Soc. 1955, 77, 5250. (b) Fowles, G. W. A.; Hoodless, R. A.; J. Chem. Soc. 1963, 33. 6. Mariappan Periasamy, “New synthetic methods using the TiCl4-NR3 reagent system” Issue in Honor of Prof. S. V. Kessar ARKIVOC 2002 ,151-166 ISSN 1424-6376 7. Hardy FE, Robson P (1967) Formation and Hydrolysis of Substituted N-ChloroN-Methylbenzamides in Aqueous Alkali. J Chem Soc B 1151-1154. 8. Giancarlo Barassi* and Thomas Borrmann , “N-chlorination and Orton Rearrangement of Aromatic Polyamides, Revisited” Barassi and Borrmann, J Memb Sci Technol 2012, 2:2