Direct alkyl and aryl amination of heteroaromatic nitrogen compounds

Abstract

5672size and charge distribution. This is supported by measurements of KI for the benzene-p-xylene system over a temperature range of 50" which indicate that AGO and AH" for the equilibrium are essentially the same, suggesting negligible contribution from differences in the entropy effects of solvation. The importance of solvation and ion pairing is, however, being explored more fully despite experimental difficulties attendant on the variation of solvent and cation due to the inherent susceptibility of these radical ions to destructive side reactions.Perhaps the most surprising aspect of our experimental results is the range of more than three orders of magnitude in the values of Kl for the monoalkyl-and p-dialkylbenzenes. The perturbing effect of an alkyl substituent on the electron affinity of benzene may be estimated using molecular orbital theory in a manner such as has been employed successfully for predicting the relative ionization potentials of the alkylbenzenes. l 3 This simple method leads to the prediction that each of the mono-and p-dialkylbenzenes should have the same electron affinity as benzene. This prediction arises simply because the perturbing substituents cannot, to first order, change the energy of the highest filled molecular orbital of the benzene radical anion. l4 Furthermore, this is true for both inductive and hyperconjugative mechanisms of interaction between the alkyl substituent and the aromatic ring. l 4It should also be pointed out that although the apparent relative strengths of the "electron-donating" effects of alkyl groups inferred from our data are in accord with other chemical substituent effects (vide supra), they are opposite the order suggested by the esr hyperfine splittings of the radical anions. For example, of the groups studied, the t-butyl group produces the largest decrease in stability of the benzene radical anion but gives rise to the smallest perturbation of the spin density in the aromatic ring.I5 The esr data and our relative stabilities taken together constitute a significant goal for more refined theoretical treatments of the interaction between saturated and unsaturated groups.Acknowledgments. We wish to thank the National Science Foundation for partial financial support and Professor P. H. Rieger for the generous use of his esr spectrometer. Sir :There are relatively few methods available for the direct substitution of hydrogen in six-membered heteroaromatic nitrogen compounds. Some of the best known are the Tschitschibabin reaction which leads to primary amines and the alkylations and arylations using organolithium compounds.' We now wish to report a new and apparently general method of alkyl and aryl amination of five-and six-membered heteroaromatic nitrogen compounds which complements the Tschitschibabin reaction very nicely.A suitable N-oxide is heated with an imidoyl chloride (or with the corresponding nitrilium salt) in a polar nonprotic solvent. For example, pyridine N-oxide (I, X = Y = H) and N-phenylbenzimidoyl chloride (11, R = R ' = Ph) in boilin...

Amide activation: an emerging tool for chemoselective synthesis

“…Apart from functional group interconversion and the formation of heterocycles, heteroatom nucleophiles have also been employed to mediate C-C-and (on exception) C-N-bond-forming rearrangements. In the context of secondary amides, early work dates back to 1969, when Abramovitch and Singer reported the N-pyridinylation of imidoyl chlorides with pyridine N-oxide 90 -a method that was optimised, generalised and mechanistically elucidated by Movassaghi et al some 40 years later (Scheme 22). 91 The products of heteroatom addition to keteniminium ions, taking the form of functionalised or substituted enol ethers, can be readily employed for [3,3]-sigmatropic rearrangements.…”

2-Aminopyridines via Reaction of Pyridine N-Oxides and Activated Isocyanides

“…It has been previously shown that pyridine N -oxides are capable of yielding amides of 2-aminopyridines by reaction with imidoyl chlorides 4 or triflates 5 and 2-aminopyridines by reaction with isocyanates (Scheme 1). 6 Pyridine N -oxides activated with a phosphonium coupling reagent were shown to react with amines to give 2-aminopyridines by a Reissert− Henze-type reaction.…”

“…9 We were interested in investigating the unexplored interaction of pyridine N -oxides and isocyanides, whose unique dual nature of reactivity, their tendency to react both as nucleophilic carbanions and electrophilic carbenes, has resulted in a rich chemical history. 10 Given that some pyridine N -oxide derivatives have shown poor or zero reactivity in prior methods, 4a,11 or were not reported in another, 7 we sought to expand the synthetic arsenal for the synthesis of 2-amino-pyridines. Also, some previously reported methods yield 2-aminopyridine amides as products that require harsh conditions to cleave the amide bond and isolate the desired 2-aminopyridine derivatives.…”

“…Also, some previously reported methods yield 2-aminopyridine amides as products that require harsh conditions to cleave the amide bond and isolate the desired 2-aminopyridine derivatives. 4,5 Thus, we report here a new method for the synthesis of 2-aminopyridines by reaction of activated isocyanides with pyridine N -oxides followed by mild hydrolysis of the incipient N -formyl-2-aminopyridines.…”

“…It should be noted that pyridine N -oxides with electron-withdrawing cyano or nitro substituents, as in 1h (Table 3), 1c (Table 2, entry 3), and 1k (Table 3, entry 9), have shown no reactivity in previously published methods involving isocyanates and imidoyl chlorides as dipolarophiles. 4a,11 …”