Nitrenium ions esters

Romero and coworkers employed FIFA, in the synthesis of PNU-95666E, a selective high-aflinity agonist at the dopamine D2 receptor, by successive nitrenium ion cycliza-tions (Scheme 14). Nitrenium ion cyclizations converted 62 to the lactam 63 which, after reductive demethoxylation to 64, protection as 65 and Af-functionaUzation, afforded the hydroxamic ester (66). A second cyclization with FIFA afforded the benzimidazolinone (67), which was readily reduced to the product 68 in overall yield of 26%. ... 

Silver or zinc salts could also effect intermolecular addition of A-acyl-A-alkoxy-nitrenium ions generated from Af-chlorohydroxamic esters to arenes . ... 

The reactions obeyed pseudo-first-order kinetics consistent with a rapid reversible protonation of the substrate, S, at the ester carbonyl followed by a rate-determining decomposition to acetic acid and nitrenium ion according to Scheme 19. In accordance with equation 13, the pseudo-first-order rate constant, k, was shown to be proportional to acid concentration and inversely proportional to the activity of the water/acetonitrile solvent . 

Most recent investigations aimed specifically at the study of nitrenium ions have employed the heterolytic cleavage of various esters of hydroxylamines 46 (Fig. 13.26). ° This method has the advantage of not requiring the introduction of acids to promote the reaction. Also, because the N—O bond is stronger than the N—Cl, it is less likely to result in homolysis. With sterically unhindered esters (such as acetylhydroxylamines), complications can arise from acyl-transfer reactions, which generate the corresponding A-hydroxylamine Por this... 

Figure 13.26. Nitrenium ions through heterolysis of A-hydroxylamine esters.

Davidse et al. " described the photolysis of A-chloroamine and hydroxylamine esters (55) to form nitrenium ions by heterolysis (Fig. 13.33). As noted above, these reactants also yield nitrenium ions through thermal chemistry, albeit more slowly. 

Boche and co-worker ° carried out detailed studies of the decomposition reactions of various A -hydroxylamine esters in the presence of DNA and deoxygua-nosine, and characterized the adducts that resulted from these reactions. Thus, the nitrenium ion derived from 0-acetyl-N-(2-aminofluorene) added to DNA to give an adduct joining the C8 position of the base with the nitrenium ion nitrogen. Similar experiments carried out with the precursor of 2-naphthylnitrenium ion gave N2-ortho 148 and C8-N adducts 149 as shown in Figure 13.72. ... 

Although 68e could not be prepared, the less reactive pivalic acid ester analogues 71a-d (Scheme 29) were synthesized. Hydrolysis rate constants at 40°C were pH independent from pH 1.0 to 7.0 and k i,s correlated with to give a of —6.0. The products derived from 71a-c are summarized in Scheme 29. These products are consistent with a nitrenium ion mechanism. In particular, the products and product ratios derived from the meta-hxomo ester 71b were consistent with those previously reported for 68e and the Bamberger rearrangement of N-(3-bromophenyl)hydroxylamine, with the exception of the rearrangement products. The rearrangement products 72 appear to be derived from intramolecular aminolysis of 73. These... 

The para-nitro ester 71d generated only 4-nitroaniline (70%) and 4,4 -dinitroazoxybenzene (10%) when it underwent decomposition (Scheme 29). These products could have been derived from either a triplet nitrene or a triplet nitrenium ion precursor. Homolysis of the N—O bond to generate radical intermediates was ruled out because of the nearly quantitative yield of pivalic acid derived from 71d. The pivaloxy radical would have undergone rapid decarboxylation to generate CO2 and the rert-butyl radical under these conditions. Since no rearrangement product was observed, it was tentatively concluded that this ester underwent direct decomposition to 4-nitrophenyl-nitrene without the intermediacy of a nitrenium ion. ... 

The esters 71a-d were susceptible to reduction to the corresponding amine by Fe ". The reduction did not proceed through a nitrenium ion intermediate because it was accompanied by rate accelerations as large as 10 in... 

Since differences were often reported in product yields from photochemical and thermal reactions, it was not clear that the same intermediate was generated in both cases. This issue was complicated by the fact that the temperatures under whieh the two experiments were run were usually quite different. The acid-base chemistry of nitrenium ions was largely unexplored so it was not known under what conditions these species could be protonated or deprotonated. It had also not been demonstrated that nitrenium ions played any role in the biological activity of mutagenic and carcinogenic esters of N-arylhydroxylamines or hydroxamic acids, particularly in their reactions with the DNA bases. Over the next decade these issues would be resolved but many questions about nitrenium ion chemistry would remain unanswered. 

The mechanism of Scheme 34 quantitatively explains the yields of rearrangement, solvent-derived and N3-derived products of hydrolysis of hydroxylamine or hydroxamic acid esters that yield selective nitrenium ions (log 5 One of the characteristics of these hydrolysis reactions is the... 

Fishbein and McClelland examined the roles of ion pairs in the decomposition of 0-aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines (90, Scheme 42). These esters give rise to a nitrenium ion that has an estimated lifetime of ca. 0.25-0.50 ns based on the lifetime of 75m (1.5 ns) and an assumed 3- to 6-fold decrease in that lifetime caused by substituting NAc... 

The mechanisms proposed by both of these groups to explain the details of the chemistry of esters that give rise to short-lived nitrenium ions are not the only mechanisms that could fit these data. Further developments in this area will require application of picosecond spectroscopic methods to ion pairs generated by laser flash photolysis. 

Shortly after Anderson and Falvey reported the first observation of a shortlived nitrenium ion in CH3CN by UV spectroscopy, Novak and McClelland and co-workers demonstrated that the nitrenium ions 75h and 75o could be observed in aqueous solution after LFP of the pivalic acid ester 76h, the sulfuric acid ester 76o, and its N-chloro analogue N-chloro-4-phenylacetanilide. The transients with A ax of ca. 450 nm were identified as singlet nitrenium ions, based on the kinetics of their decomposition in the presence of NJ, the equivalence of kaz/ks determined by the azide clock method and by direct observation, the lack of sensitivity of the transients to O2, product studies that showed similar products from solvolytic and photolytic decomposition of N-chloro-4-phenylacetanilide, and identical transient UV spectra for 75o derived either from 76o or its N-chloro analogue. A comparison of azide/solvent selectivity data obtained by azide clock and direct observation of 7Sh and 75o is presented in Table 1. 

Nitrenium ions can also be generated by solvolyzing esters of N,N-di-alkylhydroxylamines. 3,5-Dinitrobenzoates (129) were found to be the most useful hydroxylamine derivatives.171... 

---