Amidines Michael reaction

The presence of the ortho-riiXro group allowed nucleophilic cleavage to liberate the desired amine [6]. An amidine linker [7,8] provided a resin bound amine that was stable to oxidative, reductive, and alkylative conditions. The use of 2-chlorotrityl resin proved to be useful for the preparation of a secondary amine library [9] as well as hydroxamic acids [10]. Tertiary amines were prepared by 1,4 addition to a resin bound acrylate followed quatemization and a retro-Michael reaction [11]. The p-nitrophenyl carbonate linker has been shown to be useful for the inunobilization of ben-zamidines [12] and for the synthesis of sulfonamides [13]. Sulfonamides and amides were also prepared using a halogenated Wang resin [14]. 

In their synthesis of spirocyclopropanated oxazolines (see Section 2.1), the de Meijere group obtained initially unexpected cyclobutene-annelated pyrimidones 2-569 by reaction of the cyclopropylidene derivative 2-567 with the amidines 2-568. In this fourfold anionic transformation a Michael addition takes place to furnish 2-570, which is followed by an isomerization affording cyclobutenecarboxylates 2-572 and a final lactamization (Scheme 2.128) [294]. 

In most of these reactions, it is nitrogen of a urea, thiourea, isothiourea, or an amidine which is the nucleophile for the addition to an appropriately situated electrophilic carbon. Conditions which enhance the electrophilic character of the carbon, or the nucleophilicity of the nitrogen, promote cyclization. Most commonly, this cyclization is affected by nitrogen addition to the electrophilic / -carbon of a Michael acceptor, and can be performed under acid or basic conditions. 

The quinoline-based tyrosine kinase inhibitor pelitinib (31-11) incorporates a Michael acceptor function in the side chain that can form a covalent bond with a nucleophile on the target enzyme. Such an interaction would result in the irreversible inhibition of the target kinase. Reaction of aniline (31-1) with DMF acetal leads to the addition of a carbon atom to aniline nitrogen in the form of an amidine (31-2). This intermediate is next reacted with nitric in acetic acid to form the nitrated... 

The reason for the lack of follow-up on this synthetic route may be attributed to literature reports of failures to isolate or even observe the expected dihydropyrimidines, particularly in the case of the simple a,/ -ethylenic aldehydes.143,146 Dihydropyrimidine formation from a,/ -unsat-urated carbonyl compounds and amidines occurs via nucleophilic attack by amidine at the activated double bond (Michael-type addition), followed by ring closure and dehydration (see Scheme 4). In the course of confirming this reaction scheme, the intermediacy of tetrahydropyrimidines and dihydropyrimidines was demonstrated. 

Conversion of 1,3-diketones 315 into 2-substituted 7,8-dihydroquinazolin-5(6//)-ones 569 by a reaction with substituted amidine hydrochloride and dimethylform-amide dimethyl acetal (DMF-DMA) was achieved under MWI and in aqueous media. The aqueous conditions led to an environmentally friendly work-up. Compounds 569 were obtained in 21-68% yields within 2 min (Scheme 112). The reaction is a tandem addition-elimination/cyclodehydration that took place via a Michael addition of the terminal amino group of the substituted amidine to form intermediate 568, followed by an intramolecular cyclodehydration to give dihydroquinazoli-none derivatives 569 (02S1669). 

Spirocyclic sugar isoxazolidinones such as (34) have been synthesized by tandem Michael addition - 1,3-dipolar cycloaddition reactions as shown in Scheme 5. Reduction of adduct (34) yielded the spirocyclic glycosylamine derivative (35). The syntheses of 8-

[Pg.127]

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