ANRORC mechanism

Addition of Nucleophiles, Ring Opening and Ring Closure. 

One carbon homologation of carboxylic acids using diazomethane. 

Matthews, J. L. Braun, C. Guibourdenche, C. Overhand, M. Seebach, D. Enantiose-lective Synthesis of/3-Amino Acids 1997, pp 105-126. 

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Reactions with strongly basic nucleophiles such as potassium amide in liquid ammonia may prove much more complex than direct substitution. 2-Chloro-4,6,7-triphenylpteridine reacts under these conditions via an S ANRORC mechanism to form 2-amino-4,6,7-triphenylpteridine and the dechlorinated analogue (78TL2021). The attack of the nucleophile exclusively at C-4 is thereby in good accord with the general observation that the presence of a chloro substituent on a carbon position adjacent to a ring nitrogen activates the position meta to the chlorine atom for amide attack. 

An ANRORC mechanism has also been proposed (besides an inverse cycloaddition reaction) in the conversion of 1-methylpyrimidinium iodide into 3-ethoxycarbonyl-2-methylpyridine on treatment with ethyl -amino-crotonate (95RCB1272) (Scheme 23a). The reaction starts by addition of the -carbon of the crotonate at the electron-deficient 4-position of the... 

In certain cases, the SrnI mechanism has been found (p. 856). When the substrate is a heterocyclic aromatic nitrogen compound, still a different mechanism [the Sn(ANRORC) mechanism], involving opening and reclosing of the aromatic ring, has been shown to take place. 

The amino-debromination of 6-bromo-4-phenylpyrimidine (Scheme 1.3). The reaction has been proved to occur by the formation of an initial ct-adduct at C-2, which subsequently rearranges into the 6-amino product [Sn(ANRORC) mechanism]. 

It became evident that the mechanism for the simple hydroxydechlorination replacement reaction decribed in Scheme II.7 occurs in a way very different from the aminodebromination of 2-bromopyridine, but very similar to that of 2-bromopyrimidine (see Section II,C,l,c). It is, however, good to stress the point that, although the aminodehydroxylation occurs according to an Sn(ANRORC) mechanism, it does not involve a degenerate ring transformation. 

In conclusion, the amination of 2-chloro-5-nitropyridine mainly occcurs according to the Sn(ANRORC) mechanism (about 75%) and to a smaller degree (about 25%) according to the Sn(AE) process. 

As we have seen in Section II,A, 6-bromo-4-phenylpyrimidine reacts on treatment with potassium amide in liquid ammonia at -75°C into the corresponding 6-amino compound nearly quantitatively according to the Sn(ANRORC) mechanism (71RTC1239). Extensive investigations have been carried out on the scope and limitations of this mechanism and on the several factors that influence the occurrence of the Sn(ANRORC) mechanism in the aminodehalogenation of 4-substituted-6-halogenopyrimidines. 

To establish which percentage of the label is present on the ring nitrogen and which on the amino group, the amino compound was converted by acid hydrolysis into 4-phenylpyrimidin-6(l//)-one, which was subsequently converted into 6-bromo-4-phenylpyrimidine (18a) by treatment with phosphoryl bromide (Scheme 11.12). If the content of the bromo compound 18a contains y%, the percentage of the 6-halogeno compound that reacts according to the Sn(ANRORC) mechanism can be calculated, i.e., (y X 100%. 

The iodo compound reacts for only a very low percentage (13%) accord ing to the Sn(ANRORC) mechanism. It may be due to the low electroneg-... 

The influence of the temperature. It has been established that the temperature has a dramatic effect on the occurrence of the Sn(ANRORC) process. Whereas participation of the Sn(ANRORC) mechanism in the amino-debromination of 4-t-butyl-6-bromopyrimidine at -75°C was found to occur for 77% according to the Sn(ANRORC) mechanism (79RTC5), it decreased to 33% when the amination was carried out at -33°C. Apparently at -75°C attack of the amide ion on C-2 is clearly favored over attack on C-6 (kinetic vs thermodynamic control) (78TL3841). Notice that 4-t-butyl-6-chloropyrimidine, when aminated at -33°C, reacts for nearly the... 

In order to clarify the possible existence of these intermediates, 6-chloro-5-cyano-4-phenyl[l(3)- N]pyrimidine (20) (the label is scrambled over both nitrogens) and the radioactive 6-chloro-5-[ " C-cyano]-4-phenylpyrimidine (23) were synthesized as substrates. Because of the presence of the cyano function at C-5, one can expect that 20 (and 23) would undergo amination involving an Sn(ANRORC) mechanism. This has indeed been found. When 20 was reacted with potassium amide in liquid ammonia, two products were obtained as main product, 6-amino-5-cyano-4-phenylpyrimidine (21, 75%), and as minor product, a-amino-jS,jS -dicyanostyrene (22, about 20%) (Scheme 11.15). 

An important consequence of these results is that the overall amination process (37 to 39 ), which at first sight seems to follow a classical Sn(AE) pathway, is thus in fact a meta telesubstitution. This aminodehalogenation is one of the few reactions known that has proved to involve an Sn (ANRORC) mechanism, but that cannot be described as a degenerate ring... 

It is evident that in cases where the amination has taken place 100% according to the ANRORC process, no enrichment in the M + 2 peak could be measured and that only enrichment of the M+1 peak in the chloro compound could be observed. Based on these mass spectrometric determinations it was established that the 2-halogenopyrimidines react for the greater part according the Sn(ANRORC) mechanism see Table II.3. 

As one can see from the table, the degree to which this ANRORC process occurs is nearly independent of the temperature applied during the amination. For example, the amination of 2-chloro-4-phenylpyrimidine, when carried out at -33°C instead of -75°C, still occurs 90% according to the ANRORC mechanism. 

Further substantive support for the participation of the Sn(ANRORC) mechanism can be taken from two important observations (1) and C NMR spectroscopy of solutions of 2-A-pyrimidines in liquid ammonia containing potassium amide firmly proves the presence of the anionic adduct 6-amino-l,6-dihydropyrimidinide (44) (74RTC325), the initial adduct in the ANRORC process and (2) the azadiene intermediate (41, which as mentioned above can be isolated) easily converts into 2-amino-4-phenylpyrim-idine on treatment with potassium amide in liquid ammonia. Both observa-... 

Percent Yields/IOO [A] and Percentage Sn(ANRORC) Mechanism/IOO [B] Obtained in the Amination oe 2-X-4-Phenylpyrimidines,Xanrorc [A x B], Nonresonance Constants F, AND Resonance Factors R oe Substituents X. 

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]. 

However, in 2-amino-5-phenylpyrimidine, the pyrimidine ring did contain the label. From the mass spectral data it was calculated that the ratio 70 73 is about 20 80, proving that about 80% of 5-phenylpyrimidine participates in the Sn(ANRORC) mechanism. Consequently, the ring-labeled 2-amino-5-phenylpyrimidine (73) must be formed via ring opening... 

The application of the Chichibabin amination to effect a direct amination of quinazoline has been reported. It gives 4-aminoquinazoline (60MII) as well as 2,4-diaminoquinazoline (59GEP958197). No mechanistic details were discussed, but it can be expected (based on the experience with the amination with 4-phenyl- and 5-phenylpyrimidine) that amination of quinazoline would also involve, at least partly, participation of the Sn(ANRORC) mechanism. Amination with N-labeled potassium amide/liquid ammonia will certainly shed some light on the mechanism operative in this Chichibabin amination. 

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