ANRORC amination

In order to obtain evidence for the formation of adducts at position 2 of pyrimidines, which are of interest as possible intermediates in the ANRORC amination of 5-bromo-4-X-pyrimidines, attempts are reported9 with several substrates bearing unreactive bulky groups at positions 4 and 6, so that the amide ion could be forced to attack position 2. 4,6-Diphenylpyrimidine was indeed found to react in the KNH2-NH3 system and to yield the C-2 adduct 34 (Table XI). 

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. 

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). 

Percentages of Sn(ANRORC) Particiption in the Amination of 4-SuBSTrruTED-6-Halogenopyrimidines in Dependency of the Substituent Rat Position 4, the Leaving Group X at Position 6, and the Temperature... 

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. 

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. 

Percentages of Sn(ANRORC) Participation in the Amination of 2-Bromo-6-phenyl- and 4-Bromo-6-... 

Percentages of Sn(ANRORC) Participation IN THE Amination of 2-Substituted-4-phenylpyrimidine by Potassium Amide/Liouid Ammonia... 

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. 

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]. 

It has been reported (39JPJ18) that the Chichibabin amination of 4-methylpyrimidine, using sodium amide in boiling deealine, affords a mixture of 2-amino-4-methylpyrimidine and 2,6-diamino-4-methylpyrimidine. In light of the results mentioned in this section, it certainly eannot be excluded that in this aminodehydrogenation an Sn(ANRORC) meehanism is (partly) involved in the formation of these produets. 

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. 

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). 

The Chichibabin amination of phenylpyrazine with N-labeled potassium amide/liquid ammonia gave two products, 3-amino- and 5-amino-2-phenylpyrazine in both products the label is only present in the amino group, and no label was found to be incorporated into the pyrazine ring (82MI1). This result proves that in the aminodehydrogenation of phenylpyrazine, no Sn(ANRORC) mechanism is involved. This result is confirmed by the fact that amination of phenylpyrazine in the presence of the radical scavenger azobenzene, a compound that has been found to prevent the Sn(ANRORC) mechanism in the Chichibabin amination of 4-phenylpyrimidine, still yields both aminopyrazines. 

Comparison of this reactivity order with that found in the amination of 2-X-4-phenyl pyrimidines (SCH3 Br = Cl > F > SO2CH3 I > (013)3 > CN see Table 11.5 in Section ll,C,l,d) shows that these reactivity orders differ considerably. The fluoro substituent, especially, which has in the pyrimidine series about the same reactivity order as the chloro or bromo atom, shows in the 1,2,4-triazine series a low ANRORC activity. Comparison of both series of reactivities is, however, a delicate matter, mainly because the yields obtained for the amino compounds in the 1,2,4-triazine series are much lower than those obtained in the pyrimidine series, because of the occurrence of many side reactions, such as ring contraction, dehalogenation, ring transformations, and degenerate ring transformations... 

Yields Obtained in the Amination oe 3-Y-5-Phenyl-1,2,4-Triazines and the Percentages OE Sn(ANRORC) Mechanism Involved. 

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