ANRORC Closure

When 23 reacts in this ANRORC process, in fact two intermediates, a cyanoimidoyl chloride (24) and a dicyanoazadiene (25), can be postulated (Scheme 11.16). When the dicyano compound 25 is the transient open-chain intermediate, scrambling of the radioactive carbon over both cyano groups takes place, and consequently after ring closure (route a), incorporation of the C-label into the pyrimidine ring should be expected (Scheme 11.16). 

This partition was determined by mass spectrometry, measuring the N-content of the 6-amino compound 57 and that of the 6-chloropyrimidine 58, formed from 57 on diazotation by action of sodium nitrite in cone, hydrochloric acid. The content in both the 6-amino and the 6-chloro compound is the same, providing clear evidence that in the amino demethoxy-lation under described conditions the Sn(ANRORC) mechanism is the sole operative process. It follows the same pattern as described in previous sections for the aminodehalogenation, i.e., initial addition of the amide ion on position 2 and subsequent ring opening and ring closure (Scheme 11.31). 

When amination-without-quenching is carried out with N-labeled potassium amide/liquid ammonia and the degree and position of labeling in both amino products are determined, it appears that the incorporation of the label in the pyrimidine ring of 2-amino-4-phenylpyrimidine 61 has decreased from 92 to 52% see Table II.8. Thus, not only the yield of the 2-amino product is lower, but also the fraction that is formed via a ring opening-ring closure sequence [Sn(ANRORC) mechanism]. 

With [ N2]hydrazinium hydrogen sulfate and potassium hydroxide, the 2, 3, 5 -tri-0-acetyl-l-( N-amino) (3- N) inosine 54 is obtained (Scheme III.29). The reaction follows the same reaction pathway as described in Scheme III.28 addition of the nucleophile at C-6, ring opening between C(6) and N(l), and ring closure with elimination of nitrous oxide and water. This Sn(ANRORC) reaction provides us with an good entry to N-ring-labeled purines. 

In mechanistic terms, the most important of these processes involve either a ring open-ing/ring closure sequence, most commonly of the ANRORC type, or a cycloaddition reaction followed by decomposition/rearrangement of the cycloadduct. 

One final reaction of the ANRORC type which is of some limited synthetic utility is the conversion of certain 6-substituted 2-bromopyridines into pyrimidines by treatment with sodamide in liquid ammonia (e.g. equation 192). Here, the postulated mechanism involves addition of amide ion at the 4-position, ring opening by cleavage of the C(3)—C(4) bond and loss of the 2-bromo substituent, and ring closure of the acyclic intermediate thus obtained. 

Dehydroheteroarenes like (10) and (11) have also been proposed as intermediates in nucleophilic substitution.23-25 Some of these reactions were evaluated uncritically and operation of other mechanisms like addition-elimination (AE) and ring opening-ring closure (ANRORC) can now be demonstrated in many such cases. Nevertheless, there is conclusive evidence for heteroaryne intermediacy in some reactions of heterocyclic halides. From the preparative point of view, nucleophilic coupling of such intermediates has found only limited applications.26-28 Reactive intermediates with an additional formal bond between nonadjacent atoms, like (12) and (13), have also been postulated but again hold little synthetic interest. 

The recyclization of monocyclic pyrylium salts % occurs in accordance with the addition of nucleophile-ring opening-ring closure (ANRORC) mechanism (78ACR462) which starts with the a-addition of the nucleophile2 (Scheme 4). 

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