Bromine reaction with pyrimidines

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

Chloro, 3-bromo, 3-iodo, and 3-nitro derivatives of 5,7-dimethyl-pyrazolo[l,5-a]pyrimidine derivatives were prepared by chlorination, bromination, iodination, and nitration of 3-unsubstituted 5,7-dimethyl-pyrazolo[l,5-a]pyrimidines. Reaction with bromine and potassium thiocyanate gave a 3-thiocyanato derivative, which was converted into the mercapto derivative upon saponification. Nitrosation gives the 3-nitroso derivative and acylation with trifluoroacetic anhydride affords the trifluoroacetyl derivative (74JMC645 77JMC386). 

Triadimefon is made by bromination of l-(4-chlorophenoxy)-3,3-dimethylbutanone, followed by displacement with 1,2,4-triazole. Fenarimol requires reaction of pyrimidin-5-yllithium with 2,4 -dichlorobenzophenone. Further examples are imazilil (41) (71GEP2063857), prochloraz (42) <75GEP2429523) and buthiobate (43) (73BRP1337359). 

Sulfur-containing pyrimidines are frequent intermediates in substitution reactions. Several methods exist for exchange of the thiol group with hydrogen, either by hydrogenolysis, especially by the use of Raney Nickel, or by oxidative desulfurization which involves a sulfinic acid intermediate. Oxidation may also lead to a sulfonic acid. The 2- and 4-/6-thiones are considerably more stable to air oxidation than 5-thiol derivatives. Disulfides are conveniently formed by oxidation with bromine. Oxidation with chlorine at low temperature can be used to prepare sulfonyl chlorides. These reactions have been summarized [Pg.187]

The most studied diazine derivatives are the oxy- and amino-pyrimidines since uracil, thymine, and cytosine are found as bases in DNA and RNA. It is the enamide-like character of the double bonds in diazines with two oxygen substituents which allows electrophilic substitution - uracil, for example, can be brominated. One amino substituent permits electrophilic ring substitution and two amino, or one amino and one oxy, substituent, permit reaction with even weakly electrophilic reactants. 

In a related and more recent study a variety of solid-supported acylating agents were synthesized and used for microwave-mediated transformation of amines, alcohols, phenols, and thiophenols [123]. In a microwave-mediated procedure, Mer-rifield resin was first modified by attaching 1,4-butanediol to introduce a spacer unit. Bromination and subsequent reaction with commercially available 6-methyl-2-thiouracil then treatment with corresponding acyl chloride afforded the desired polymer-bound pyrimidines (Scheme 16.81). The acylating ability of this supported reagent has been proven by reaction with benzylamine. 

Thiazolonaphthyridinium salts 331 can be produced either by bromination of the 2-alkenylpyridine precursor, or by thermal cyclization of the 2-(bromoacetyl)pyridine (Scheme 81) <1997CL1203>, and reaction of the pyrano-pyrimidine 332 with o-aminothiophenol gives the benzothiazole-fused pyridopyrimidinedione 333 (Equation 118) <2003JCCS887>. 

Nucleophilic displacement of Z-, 4-, and 6-halo substituents by alkoxy or aryloxy ions occurs readily except in the presence of strongly electron-releasing substituents in the ring <1994HC(52)1>. Stepwise reaction can be achieved with di- and trihalo-pyrimidines, with the more reactive 4-position being the first site of reaction. For example, even with the presence of a bulky ortho substituent such as a 5-bromine atom, selective methanolysis at the 4-position was still observed with 5-bromo-2,4-dichloropyrimidine 179 <2006TL4415>. 

A number of 3-(alditol-l-yl)-5-methyl-7-oxo-l,2,4-triazolo[4,3-a]pyrim-idines l,2,4-triazolo[4,3-a]pyrimidines acyclo C-nucleosides (30) were synthesized (95PHA784) by oxidative cyclization of the corresponding aldehydo-sugar pyrimidin-2-ylhydrazones 27 with bromine in water. The alternative structure 29 was eliminated based on finding that acetylation of 30 afforded the same acetylated acyclo C-nucleosides 31 as those obtained by oxidative cyclization of the (A3-acetyl-poly-0-acetyl)hydrazones 28. Compounds 31 were also obtained by one-pot oxidative cyclization and acetylation of 27. In contrast to the oxidation and concurrent bromination of 19 to 25, it was possible to avoid nuclear bromination of 27 and 28 by performing the reaction in the absence of light (Scheme 13). 

Electrophilic and nucleophilic reactions of 2-(2-thienyl)thieno[2,3-cf pyrimidine (346), prepared as shown in Scheme 99, permits a conclusion concerning the reactivity compared with that of thiophene bearing an electron deficient substituent in position 2. Both nitration and bromination primarily occur in the thiophene moiety whereas lithium organic reagents (methyllithium, butyllithium) add at carbon atom 4 (77BSF676). Bromination of (324) yields the 5- (or 6-) bromo derivative (68CR(C)(267)697). 

Condensation of 2-hydrazinopyrimidine (384) with an aromatic aldehyde formed the Schiff bases (386), which then cyclized with bromine to 6-bromo-l,2,4-triazolo[4,3-a]pyrimidine (383) and with carbon disulfide to 387 (92PS145). A similar cyclization was effected also on 384 to give 388 (68T2839 85FRP2549834), but the cyclization of 384 or 385 with carbon disulfide afforded 3-thiolo-l,2,4-triazolo[4,3-a]pyrimidin-7-ones 389 and 390, respectively. A small amount of the isomeric 3-thiolo-l, 2,4-triazolo[4,3-a]pyrimidin-5-one was isolated in the former case (68T2839). Reaction of 385 with benzaldehyde [67JCS(C)498] or p-chlorobenzaldehyde (90MI3) followed by oxidation with LTA in benzene afforded 391 (Scheme 73). 

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