Electrophilic oxo-derivatives

Short chain aldehydes Cyclopentenone prostaglandins Electrophilic oxo-derivates Oxidized phospholipids Nitrated fatty-acids... 

The high electrophilic character of the 2- and 4-positions in quinazoline makes hydrolysis to oxo derivatives relatively easy, and both 2- and 4-chloro substituents can be hydrolyzed in either alkaline or acid solution. The significantly higher reactivity in the 4-position simplifies stepwise substitutions, and the synthesis of 2-chloro-4(3//)-quinazoli-nones 173 is readily performed from the dichloro compounds 172 with sodium or potassium hydroxide at room temperature <2003BMC2439, 20050PD80, 2006H(67)489, 20060PD391>. 

Alkoxy derivatives in the electrophilic positions are readily available by nucleophilic substitution reactions as discussed for the oxo derivatives above. 2,4-Dialkoxyquinazolines can be prepared by boiling 2,4-dichloroquinazolines with two equivalents of alkali alkoxide in the appropriate alcohol. Mixed ethers (137) are possible because of the great difference in positional reactivity the first substitution is in the 4-position (136). 4-Chloro- and 2,4-dichloro-quinazoline very readily suffer alcoholysis in the 4-position with acid catalysis, presumably via 4-adduct formation as in the facile hydrolysis discussed above. 

These systems uniformly have at least one pyrimidine ring, and they are readily formed from aminodiazines, incorporating the amidine moiety, with bifunctional electrophiles serving as three-carbon fragments. In this way, most frequently, 0x0 derivatives are obtained. Alkoxymethyl-enemalonates and 2-benzoylamino-3-dimethylaminopropenoate convert the amines into 4-oxo isomers via, sometimes isolable, intermediates 2-oxo and/or 4-oxo isomers may be formed with acetylenecarboxylic or acrylic acid derivatives or with ethyl acetoacetate. The decisive factors for the regiochemistry have not yet been fully explored. The base-induced rearrangement of ethyl 2-diazanyl-5-oxo-2,5-dihydroisoxazole-4-carboxylates is also a powerful approach to the bicyclic systems. It gives 3-ethoxycarbonyl-2-hydroxy-4-oxo derivatives which present a versatile substitution pattern for further functionalization. A further important aspect of the synthetic methods discussed above is their wide applicability for preparation of the benzo-fused derivatives. 

Theoretical calculations have predicted that imidazo[l,2-a]pyrimidine (160) should be attacked at C-3 by electrophiles, although reactivity will be lower than in the corresponding imidazo[l,2-a]pyridines (see D,l,e) (74JHC1013). The 3-bromo derivative of 160 was formed when the parent was treated with NBS in chloroform (66JOC809). The usual transformation of oxo to chloro was responsible for the preparation of 5-chloroimidazo[ 1,2-a]pyrimidine [66LA(699) 127]. 

As mentioned earlier, metal complexation not only allows isolation of the QM derivatives but can also dramatically modify their reactivity patterns.29o-QMs are important intermediates in numerous synthetic and biological processes, in which the exocyclic carbon exhibits an electrophilic character.30-33 In contrast, a metal-stabilized o-QM can react as a base or nucleophile (Scheme 3.16).29 For instance, protonation of the Ir-T 4-QM complex 24 by one equivalent of HBF4 gave the initial oxo-dienyl complex 25, while in the presence of an excess of acid the dicationic complex 26 was obtained. Reaction of 24 with I2 led to the formation of new oxo-dienyl complex 27, instead of the expected oxidation of the complex and elimination of the free o-QM. Such reactivity of the exocyclic methylene group can be compared with the reactivity of electron-rich enol acetates or enol silyl ethers, which undergo electrophilic iodination.34... 

An interesting chain elongation of 4-oxo-l-tributylstannylbutyl carbamate 83 by ethynyl A,A-diisopropyl carbamate (82) to the dicarbamate 84 and the subsequent intramolecular carbolithiation to form the alkenyllithium 86 has been reported very recently (equation 18). 86 was trapped by electrophiles to yield—as expected—both epimers 87 and 88 in essentially equal amounts. From an X-ray analysis of a derivative, the shown absolute configuration and the ( )-stereochemistiy at the double bond was concluded. Thus, the attack at the triple bond here took place in the anti fashion, which is quite unusual. We suggest that a lithium cation in 85, captured by the second carbamoyl group, catalyses the anti addition. ... 

The 3-oxo-l,5-cyclocholestane (158) rearranges with BF3 and with HCOjH to give the enone (159) electrophilic attack at the carbonyl oxygen is followed by cleavage of the 1,5-bond to produce an intermediate C-5 carbocation. A minor product (160) in the BFs-catalysed reaction is derived from cleavage of the 1,10-bond. " Addition of methanol or ethanol across the 1,5-bond is catalysed by FeCU.bHzO. 

Hydroxy, thiol, and amino groups in pyrimidine exist in tautomeric equilibria with their oxo, thioxo, and imino forms. An amino group in an electrophilic position exists predominantly as such, and the compound is named as an amine. Pyrimidines with a hydroxy or thiol group in an electrophilic position are dominated by the oxo or thioxo forms and are named as such, or with -one or -thione suffixes, if these are the principal groups. In the benzenoid 5-position, these derivatives are mainly present in the hydroxy, thiol, or amino forms and are named as such. Similar considerations apply to the nomenclature of quinazolines and perimidines <1996CHEC-II(6)93>. 

The synthesis of this ring system by condensation of 3,4,5-triamino-l,2,6-thiadiazine-l,1-dioxide with formic acid equivalents to give the fused imidazole ring dates back to the review by Montgomery and Secrist <1984GHEC(5)607>. This methodology was extended to cyclocondensation reactions of 3,4,5-triamino-l,2,6-thiadia-zine-1,1-dioxide with electrophiles such as methyl chloroformate and carbon disulfide to yield 6-oxo 98 and 6-thioxo 99 derivatives of 4-aminoimidazo[4,5-d-l,2,6-thiadiazine-2,2-dioxide respectively (Scheme 72) <1999BMC1617>. 

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