Amination of 4-Phenylpyrimidine

It is interesting that the Sn(ANRORC) mechanism did not operate when 29 was aminated under heterogeneous conditions. When 29 was treated with potassium [ N] amide in m-xylene at 90°C, most of the label was present in the exocyclic amino group, thus proving that both products, 32 and 33, were formed by an Sn(AE) mechanism. 

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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. 

Even though it has been shown that the S fANRORC) mechanism did not operate in the amination of 4-phenylpyrimidine (29) in m-xylene (83RTC367), a ring-opening and ring-closure mechanism cannot be excluded in the pres-... 

Chichibabin amination of 4-phenylpyrimidine gives both the 2-amino- and 6-amino-derivatives, in 60 and 15% yields, respectively N-labelling showed that, in contrast to the 6-amino-derivative, the 2-amino-compound is formed by an ANRORC route. 

Breuker K, Van der Plas HC. Occurrence of an S m(ANRORC) mechanism in the chichibabin amination of 4-phenylpyrimidine. J Org Chem. 1979 44 4677-4680. Francis RF, Davis W, Wisener JT. Reaction intermediates in the alkylation of pyridine... 

Phenylpyrimidine. Amination of 5-phenylpyrimidine showed about the same results as obtained with 4-phenylpyrimidine (82MI1). Reaction with potassium amide/liquid ammonia for 20 hr at 33°C and quenching of the reaction mixture with ammonium chloride yielded both 2-amino-5-phenylpyrimidine (70/73, 20%) and 6-amino-5-phenylpyrimidine (72, 20%). Investigations by and NMR spectroscopy of solutions of 5-phenylpyrimidine in potassium amide/liquid ammonia clearly showed the presence of the 4(6)-amino adduct hardly any indication for the presence of the 2-amino adduct was observed (Scheme 11.34). 

Furthermore, it was pointed out that, whereas the formation of the amino adduct is fast and the formation of the product slow, it is possible that an equilibrium exists among the starting materials, their 1 1 a-amino adducts, and their open-chain amidines (Scheme 11.54). When this is the case, one may expect that, if the amination of phenyl-1,3,5-triazine is stopped before complete conversion, the retrieved starting material should be N-labeled. This has indeed been found. This behavior is in agreement with that observed with the Chichibabin amination of 4- and 5-phenylpyrimidine. 

Ethoxy-6-methylpyrimidine 1-oxide (499) reacts with phenyl isocyanate to eliminate carbon dioxide and give a mixture of 4-ethoxy-6-methyl-N-phenylpyrimidin-2-amine (SOO) and (the derived) 7V-(4-ethoxy-6-methylpyrimidin-2-yl)-7V,7V -diphenylurea (SOI) phenyl isothiocyanate reacts quite differently (79CPB2642). 

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). 

As already reported in Section II,A, the amination of 6-bromo-5-deuterio-4-phenylpyrimidine with potassium amide in liquid ammonia provides a produet in which deuterium is no longer present. Based on the work deseribed previously, it seems reasonable to conclude that this easily occurring deuterium-hydrogen exchange takes place in the intermediary imidoyl bromide (17a, X = Br) (Scheme 11.18) and not in the cyanoazadiene (17b). In the strong basie medium a fast equilibrium can be formulated between these open-ehain intermediates (17a, X = Br, 29, and 30) (Scheme 11.18). 

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-Substituted-4-phenylpyrimidine by Potassium Amide/Liouid Ammonia... 

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]. 

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. 

Thus, reaction of 6-bromo-4-phenylpyrimidine (316) with lithium isopropylamide in isopropylamine proceeds via 317 to the ring-opened product 318 to eventually give 6-isopropylamino-4-phenylpyrimidine (319) in 70% yield. Since these particular aminations have been reviewed (78ACR462), they will not be discussed further. Nor will nucleophilic aminations proceeding via aryne-type intermediates (65AG557, 65AHC121) be a topic of this review. 

There are cine- and fe/e-amination reactions which proceed via a special multi-step pathway, known as the ANRORC mechanism (Addition of a Aucleophile, Ring Opening, Ring Closure) (for reviews on this topics, see [11, 23,128]). For instance, 2-bromo-4-phenylpyrimidine reacts with KNH2 in liquid ammonia to afford 2-amino derivative 93 (Scheme 60). Thorough investigation of this reaction has shown that it proceeds via the formation of cr -adduct 91 followed by opening of the... 

It has been established by experimental data that the Chichibabin amination of pyrimidine proceeds either by an Sn(AE) or Sn(ANRORC) mechanism. Each mechanism is favored according to substituents, substitution pattern and reaction conditions. In turn, the region-chemical outcome for the reaction depends on the mechanism course the reaction follows. 2-bromo-4-phenylpyrimidine (21) reaction with KNH2-NH3... 

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