ANRORC process

Amination of 3-bromoisoquinoline with potassium amide/liquid ammonia involves (in contrast to the amination of 2-bromopyridine, see Section an ANRORC process. When 3-bromo[ N]isoquinoline was used as substrate, the 3-aminoisoquinoline being obtained contains 55% of its enrichment on the exocyclic nitrogen, i.e., the formation of 3-[ N-aminoJisoquinoUne (14), and 45% inside the heterocyclic ring, i.e., formation of 3-amino[ N]isoquinoline (13) (74RTC198). 

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... 

The influence of the nature of the substituent at position 4. In order to determine the influence of substituents at position 4 on the Sn(ANRORC) process in the aminodehalogenation, the amide-induced amination was studied with 6-chloropyrimidines containing different substituents at position 4, i.e., the 4-Ubutyl-, 4-methoxy-, 4-piperidino-, 4-anilino-, and 4-methyl-groups (79RTC5). The results are summarized in Table ILl. 

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). 

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-... 

As one can see from Table IL5, the compounds with X = SCH3, SO2CH3, and SCN react with high percentages of participation of the Sn(ANRORC) process (73-90%) in the amide-induced aminolysis, while for X = CN,... 

There has been an attempt to correlate that fraction of the 2-substituted 4-phenylpyrimidines that takes part in the Sn(ANRORC) process (Xanrorc) and the inductive and resonance effects of the substituents, present in the substrate on position 2 (see Table II.6). (85T237). 

It was observed that the participation of the Sn(ANRORC) process in the aminodemethylthiolation is strongly dependent on the concentration of the amide ion (77H205). When 10 equiv. of potassium amide was used instead of 4 equiv. (in the same volume of liquid ammoiua, 25 ml), the per-... 

The reaction is one of the few examples of a degenerate ring transformation in pyrazine chemistry. Extensive investigations on the amination of 2-chloroquinoxaline have shown that in the formation of the 2-amino compound no Sn(ANRORC) process is involved (72RTC850). 

ANRORC process, i.e., adduct formation at C-5, is not prevented by these groups. This is a remarkable effect, certainly when taking into consideration the bulkiness of the r-butyl group, which could be expected to diminish the participation of the ANRORC process. It demonstrates that the... 

Fluoro-5-phenyl-l,2,4-triazine (109, X = F) reacts much faster than the 3-chloro-, 3-bromo-, or 3-iodo-compound. Moreover, the reaction mixture obtained is cleaner than that from the corresponding 3-chloro- or 3-bromo compounds 3-amino-5-phenyl-l,2,4-triazine (110) is formed in good yield. This conversion takes place to only a small extent (18%) via the ANRORC process the main part of the aminodefluorination seems to involve the Sn(AE) mechanism. This result is consistent with the observation that the aminodefluorination of 4,6-diphenyl-2-fluoropyrimidine follows the Sn(AE) process, whereas 2-fluoro-4-phenylpyrimidine (position 6 is vacant for addition of the nucleophile) reacts for the most part according to the Sn(ANRORC) mechanism (see Section II,C,l,c). 

As mentioned in Section II,D,l,a, the presence of a r-butyl or phenyl group at position 5 of the 1,2,4-triazine ring does not prevent addition of the amide ion to that position. Therefore, it becomes of interest to investigate whether in the amino-dehalogenation of two annelated 3-chloro-l,2,4-triazines, i.e., 3-chloro-l,2,4-benzotriazine (123) and 3-chlorophenanthro[9,10-e]l,2,4-triazine (125), using potassium amide/liquid ammonia, the Sn(ANRORC) process would be involved. Both compounds... 

The occurrence of this Sn(ANRORC) process has also been substantiated by N-labeUng experiments. Reaction of 3-aminocarbonyl-l-methylpyridinium salt (5, R = CONH2, Alkyl = CH3) with N-labeled liquid ammonia gives incorporation of the label into the pyridine ring (Scheme III.5) (84T433). 

The reaction of l,4-diaryl-2-methylthiopyrimidinium iodide (39) with hydrazine did not lead to the corresponding 2-hydrazino compound, as expected, but to the rearranged l-amino-2-arylaminopyrimidinium salt (40) (90JHC1441). This transformation also occurs via an Sn(ANRORC) process, involving the open-chain intermediate 41 (Scheme III.22). It cannot... 

It has been suggested (97JA7817) that the formation of 1,2-dihydro-l-hydroxy-2,3,l-benzodiazaborine (70) from its 2-(4-methylbenzenesulfonyl) derivative 68 with hydrazine may occur via a Sn(ANRORC) process. This degenerate transformation may involve as intermediate the benzene derivative 69 (Scheme III.38). 

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