Pyrroles Subject

Because the a-aminoketone is subject to self-condensation, the condensation with a P-dicarbonyl derivative (6) is usually carried out by generating the a-aminoketone in situ through reduction of an oximino derivative (7) 2iac ia glacial acetic acid is used as the reductant. For example, Knorr s pyrrole... 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Katritzky offers a general one-pot alternative approach to polysubstituted pyrroles utilizing disubstituted olefins of which a wider variety is commercially available compared to acetylenes . Thus, thioamides 32 were subjected to Mannich condensation with aldehydes and BtH to yield functionalized thioamides 33 which were then treated with base... 

Monocrotaline (170) has been the subject of extensive metabolic study with mammalian and microbiological systems. Pyrrolizidine alkaloids such as monocrotaline require metabolic activation to the corresponding pyrrole derivatives or dehydro alkaloids before they are capable of forming covalent bonds with critical macromolecules within the cell. The X-ray structure of dehydromonocrotaline has recently been determined (226), and the ability of dihydroretronicine derived from monocrotaline to react with deoxyguanosine has been demonstrated in vitro (225). 

The pyrrole-3-boronic acid 67 has been prepared from the 3-iodopyrrole by Muchowski and subjected to a range of Suzuki couplings to afford 2-arylpyrroles 68 [59]. Subsequent fluoride deblocking to give 69 occurs in excellent yield. 

Pyrrole 98 has been employed in Stille couplings with dibromobenzoquinone 99 [76]. The product 100 can be subjected to a second Stille coupling to afford unsymmetrical diheteroarylquinones. Similar couplings between 98 and 2,3-dibromo- 1,4-naphthoquinone were also described. 

Pyrrole 151 can be thallated [110] and subjected to Heck (and Sonogashira) conditions to afford the anticipated products 152 [111]. 

The methodology is useful for a variety of synthetic purposes. The cycloadditions are not subject to steric hindrance. Thus diyne cycloadditions to 2,5-disubstituted furans or pyrroles, followed by elimination of the oxygen or nitrogen bridges, provides an excellent, short route to peri-substituted arenes, as in the following examples 4 6 8... 

A new synthesis of arylmethylene- and arylmethine-pyrroles [25 R = CH2C6H4X and CH(C02H)CH2Y] uses 2,5-dimethoxytetrahydrofuran (26). The reaction is subject to acid-base catalysis, and is typically successful only in solvent mixtures of such character, e.g. acetic acid-pyridine. A mechanistic investigation has identified a number of iminium ion intermediates [e.g. tautomerism (27a) (27b)] to explain by-products in particular cases. 

Possibly, the most common protocols used in the generation of azomethine ylides are those based on the in situ, fluorine-mediated desilyation of cyanoami-nosilanes developed by Padwa et al. (2). Typically, treatment of precursor 1 with AgF, in the presence of dimethyl acetylenedicarboxylate (DMAD), led to the formation of the intermediate cycloadduct 2, which was subjected to immediate DDQ oxidation to give pyrrole 3. The mechanistic rationale invokes fluoride-mediated desilyation to form the intermediate anion 4, which then undergoes loss of cyanide furnishing the corresponding azomethine yhde (Scheme 3.1). 

Milkiewicz et al. <2003TL4257> prepared a series of novel tetrasubstituted furo[3,2-/ ]pyrroles from the methyl or ethyl 3-bromo-2-phenylfuro[3,2-3]pyrrole-5-carboxylate 336. The compounds 336 were subjected to a Suzuki coupling with 4-chlorophenylboronic acid to form 337, which was treated with a variety of alkylating agents to afford the corresponding esters 338. The esters were then saponified to acids 339 (Scheme 34). 

This synthetic route is based on ring closure by Dieckmann condensation of 1,2-bis-carbalkoxyalkylpyrrolidines. It has gained special importance during the last few years, after application to several total syntheses of naturally occurring pyrrol izidine bases. The usual starting compounds employed in this route are esters of a-pyrrolidineacetic acid, proline, and their homologues, which are converted into N-substituted dialkyl dicarboxylates. The esters of the dicarboxylic acids are subjected to Dieckmann condensation and subsequent ketonic hydrolysis the resultant ketones are used in further reactions. 

The relative importance of through-bond (hyperconjugative) and through-space (homoconjugative) interactions between the heteroatom and the double bond in 2,5-dihydro-furan, -thiophene and -pyrrole has been the subject of a CNDO/S study (76ZN(A)215). This analysis concluded that the proportion of through-space interaction increased from 19% in the dihydrofuran and 20% for dihydrothiophene to 83% for the dihydropyrrole (cf. Section 2.3.3.9). 

The conformational preferences of 2- and 3-monosubstituted derivatives of furans, thiophenes and pyrroles have been the subject of ab initio MO studies (77JCS(P2)160l, 78JA3981,79JA311). Of the systems considered, experimental information from microwave spectroscopy is available for 2- and 3-methyl... 

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