2-Chloropyrimidines, reaction with

From the standpoint of geometrical considerations, the major difference is in the far greater steric requirements of the nitro group. This could result in either primary or secondary steric effects. Nevertheless, primary steric effects do not seem to be necessarily distinguishable by direct kinetic comparison. A classic example is the puzzling similarity of the activation parameters of 2-chloropyrimidine and 2,6-dinitrochlorobenzene (reaction with piperidine in ethanol), which has been described by Chapman and Rees as fortuitous. However, that nitro groups do cause (retarding) primary steric effects has been neatly shown at peri positions in the reaction with alkoxides (see Section IV,C, l,c). 

Addition of aqueous hydrogen peroxide significantly accelerates the substitution reactions with hydroxide. For example, treatment of 2-chloropyrimidine 166 with lithium hydroxide and hydrogen peroxide in water at 50 °C afforded 2-pyrimidinone 167 in 67% yield <2006TL4249>. 

Some of the ring expansion reactions discussed in Section 2.03.3.3.1 can be extended to five-membered heterocycles containing two or more heteroatoms. Reaction of imidazoles and pyrazoles with dichlorocarbene, for example, gives chloropyrimidines together with small amounts of chloro-pyrazines or -pyridazines, and oxidative ring expansion of 1-aminopyrazole with nickel peroxide gives 1,2,3-triazine (this, in fact, constitutes the only known synthesis of the unsubstituted triazine). There are, however, a number of interesting and useful transformations which are unique to five-membered polyheteroatom systems. 

The reaction of the cyanide ion with alkyl halides, using PTC, has been widely studied since the first example was reported by Starks.167 However, with unactivated aryl halides (e.g., chlorobenzene and dichlorobenzene) the reaction fails.229 On the other hand, chloropyrimidine reacts with tetra-ethylammonium cyanide in acetonitrile.230 Hermann and Simchen231 have described more generally the synthesis of cyano heterocycles, using tetra-ethylammonium cyanide. 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Acetylenic pyrimidines undergo hetero-Diels-Alder reactions yielding pyrido-fused lactams with recent reports of improved yields using microwave-assisted conditions <2005TL3423>. The use of alkynes as dieneophiles has also been reported in an intramolecular reaction with chloropyrimidine (Scheme 55) <2000SL625>, in this case toward the total synthesis of cerpegin via demethylation. 

Organotin reagents can be prepared 2-chloropyrimidine 901, for example, is stannylated by reaction with tributyl-, trimethyl-, or triphenylstannyllithium giving, e.g., 902. Stannanes can be obtained in the opposite sense too 4-iodo-2-methylthiopyrimidine can be stannylated by way of lithiation followed by quenching with a stannyl chloride. 

Bromo-2-chloropyrimidine is stannylated in the 5-position (195) (Scheme 42). The reaction of 2,4-dibromopyrimidine with trimethylstan-nylsodium results in regioselective substitution in the 2-position to furnish 4-bromo-2-trimethylstannylpyrimidine (196), whereas reactions with the corresponding stannyllithium reagent failed (94T275). 

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