Pyrrole ketones, conjugation

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

Additions to conjugated triple bonds occur with facility. Thus, base-catalyzed addition of benzoin to dimethyl acetylenedicarboxylate provides a route to furans (186 187 X = 0), while pyrroles and thiophenes result from an analogous addition of -amino ketones (186 187 X = NH) and -mercapto ketones (186 187 X=S), respectively (Scheme 104) <1964JA107>. 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

Harman and coworkers have explored the reactivity of -osmium complexes of pyrroles. These complexes can react as nonaromatic species in which the Os has localized two of the Ji-electrons. For example, the complex of 1-methylpyrrole gives a conjugate addition product with methyl vinyl ketone in the presence of TBDMS triflate <93JOC4788>. Decomplexation by reaction with a base gives a 3-substituted pyrrole (Scheme 131). 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

---