Pyrimidines relative reactivity

All these methods demonstrate that the 2-positions of pyridine, pyrimidine, and other azines are the most electron deficient in the ground state. However, considerably greater chemical reactivity toward nucleophiles at the 4-position is often observed in syntheses and is supported by kinetic studies. Electron deficiency in the ground state is related to the ability to stabilize the pair of electrons donated by the nucleophile in the transition state. However, it is not so directly related that it can explain the relative reactivity at different ring-positions. Certain factors which appear to affect positional selectivity are discussed in Section II, B. 

Intramolecular inverse electron-demand Diels-Alder reaction of iV-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170 °C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series. 

All the halo-diazines, apart from 5-halo-pyrimidines, react readily with soft nucleophiles, such as amines, thiolates and malonate anions, with substitution of the halide. Even 5-bromopyrimidine can be brought into reaction with nucleophiles using microwave heating. All cases are more reactive than 2-halo-pyridines the relative reactivities can be summarised ... 

In 9-substituted purines, the relative reactivity of halides is 8 > 6 > 2, but strongly influenced by the presence of other substituents. In 9H-purines this is modified to 6 > 8 > 2, the demotion of the 8-position being associated with anion formation in the five-membered ring. Conversely, in acidic media the reactivity to nucleophilic displacement at C-8 is enhanced protonation of the five-membered ring facilitates the nucleophilic addition step." The relative reactivities of the 2- and 6-positions are nicely illustrated by the conditions required for the reaction of the respective chlorides with hydrazine, a relatively good nucleophile." It is worth noting the parallelism between the relative positional reactivity here with that in halo-pyrimidines where it is 4 > 2. 

Since chloro substituents in the benzenoid pyrimidine 5-position will not normally react with a stannane, the reaction between 2,5-dichloropyrimidine and styryltributylstannane is specific for the activated 2-position 5-bromo-2-chloropyrimidine is coupled with selective substitution of bromine in the 5-position (108). The 2-chlorine can subsequently be substituted [89ACSA(B)62]. In reactions of 2,4-dichloropyrimidine with /3-styryl- or phenyltributylstannane the carbosubstituent is selectively introduced into the 4-position (110) [89ACSA(B)62]. The same regioselectiv-ity is observed for Ni-catalyzed coupling with organomagnesium reagents (see below), and the regioselectivity corresponds to the relative reactivity... 

Bromo-2-chloropyrimidine, however, is coupled selectively at the 5-position to form the product 207. Phenylation by phenylstannanes takes place in the same regioselective manner (yide supra). In reactions of 2,4-dichloropyrimidine with p-styryl- or phenyl(tri-n-butyl)stannane, the carbosubstituent goes selectively into the 4-position 209. A second carbosubstituent can subsequently be introduced into the 2-position. The regioselectivity corresponds to the relative reactivity of pyrimidine toward heteronucleophiles. In 2,4,6-trichloropyrimidine one chlorine in the 4/6-position is replaced selectively 210 under conditions for monocoupling. 

Aryloxy, hydroxy arylsulfonyloxy, and phosphoryloxy. The 4-toluenesulfonyloxy and 4-nitrophenyloxy groups approximate the chloro group in replaceability in benzene derivatives. The former appears to be less reactive than chloro toward hydroxide on quinoline and -phenoxy on pyrimidine is relatively unreactive toward sulfanilamide anion or ammonia. On cinnoline, quinazoline, or quinoline, a 4-phenoxy group is less reactive than a chloro group. 

The 0X0 group facilitates reaction relative to H, CH3, or NH2 substituents on pyrimidines in the displacement of mercapto, arylthio, or amino groups by amines. The 2-thioxo group is reactive toward... 

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