Pyrroles with imines

The condensation of 2,5-diunsubstituted pyrroles with formic acid20 is a viable method to produce porphyrins. However, the most common procedure21 22 involves the heating of the corresponding pyrroles 1 with aldehydes and aldehyde derivatives like imines or a Mannich reagent in the presence of acid. The reaction is initiated by electrophilic attack of the aldehyde (or aldehyde derivative) to the pyrrole 1. The formed (hydroxyalkyl)pyrrole 3 then undergoes electrophilic substitution with another pyrrole to form a dipyrrylmethane 4. Repeated addition of aldehyde and pyrrole finally forms a tetrameric (hydroxyalkyl)bilane 5. 

Titanium-acetylene complexes 29 generated in situ from acetylenes, Ti(0-i-Pr)4 and /-PrMgX react with imines to form azatitanacyclopentenes 30 which then react with carbon monoxide under atmospheric pressure to provide pyrroles 31 <96TL7787>. This reaction, which utilizes commercially available reagents is an improvement over a related procedure via the corresponding zirconium complexes under 1500 psi CO <89JA776>. 

In the absence of the iV-oxide, the reaction of 3-aminopyridazino[3,4-i/ pyrimidinediones 33 with imines takes a different course (Equation 17), and cyclization of the intermediate occurs to form a pyrrole ring <2005JHC375>. The reaction with cyclohexylamine in this instance results in the formation of highly fused dimeric products <2003T7669, 2006T652>. 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

The imine and iminium functional groupings are, of course, the nitrogen equivalents of carbonyl and O-protonated carbonyl groups, and their reactivity is analogous. The Mannich reaction of pyrrole produces dialkylaminomethyl derivatives, the iminium electrophile being generated in situ from formaldehyde, dialkylamine and acetic acid. There are only a few examples of the reactions of imines themselves with pyrroles the condensation of 1-pyrroline with pyrrole as reactant and solvent is one such example. N-Tosyl-imines react with pyrrole with Cu(OTf>2 as catalyst. ... 

A titanium-promoted cyclization of 1,3-diketones with imines or oximes led to highly substituted pyrroles <04SL2239>. A nitroso group served as a novel source of nitrogen in a pyrrole synthesis. Treatment of l,4-bis(bromomagnesium)butadiene derivatives with nitrosobenzene (PhNO) gave A-phenylpyrroles <04CEJ3444>. 

Different heterocycles, e.g. furan, pyrrole, N-ben2ylpyrrole, indole, and pyrazole react with methyl a-acetamidoacrylate to give a-amino acid precursors under irradiation with silica-supported Lewis acids as catalysts [135]. Inhomogeneous catalysis, long reaction times were required. The reaction of vmylpyrazoles with imines has also been realized [136]. 

Besides indole, the AFC reaction of other electron-rich arenes such as furan, pyrrole, naphthol, 4,7-dihydroindole, and substituted benzene with imines have been also well developed over the past years. Some examples are given in this section. Terada and co-workers reported that in the presence of 2 mol% of CPA (R)-13f, the AFC reaction of 2-methoxyfuran with iV-Boc aldi-mines underwent smoothly at -35 °C to afford furan-2-ylamine derivatives in 80-96% yields with 86-97% ee (Scheme 6.16). ... 

The azomethine ylide represents one of the most reactive and versatile classes of 1,3-dipoles and is trapped readily by a range of dipolarophiles, forming substituted pyrroles or pyrrolidines (Coldham and Hufton 2005). Synthesis of aziridines by reaction of a fluorocarbene with imines under ultrasonic irradiation was described previously (Konev et al. 2005). This reaction proceeds by the formation of an azomethine ylide (9), which can be trapped with dimethyl maleate (13) to produce pyrrolidines (14) or pyrrole rings (15) in moderate yields (Scheme 8.5). 

A novel coupling cyclization reaction of 1,3-diketones with imines was applied for the synthesis of polyaryl substituted 3-trifluoromethylpyrroles. The reaction was promoted by a low-valent titanium reagent and afforded the pyrroles 295 in high to quantitative yields. A number of 1,3-diketones 293 and imines 294 provided a variety of pyrroles 295, bearing different combinations of electron-donating, as well as electron-withdrawing substituents in aromatic rings [100]. 

Besides being useful precursors to pyrroles pyridine-2-ones -4-ones, -4-thiones. and -4-imines 4-alkylidene-dihydropyridines thiophenes 1,2,4-triazoles thiapyrane-2-thiones, isoquinoline-3-ones isoben-zothiophenes and 4-mercaptoimidazolium hydroxide inner salts, mesoionic thiazoles are potentially useful in the construction of molecules with herbicidic (39). central nerve stimulating, and antiinflammatory properties (40,41). Application in dye synthesis has likewise been reported (42). 

The most generally useful method for acylation or formyl a ti on of pyrroles is the Vil smeier-Ha ack reaction (32,33). The pyrrole is treated with the phosphoryl complex of A/ A -dialkjlamide and the intermediate imine salt is hydroly2ed. 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

A mechanism has been formulated, starting with a condensation to give the imine 4, that can tautomerize to the corresponding enamine 5. The latter can be isolated in some cases, thus supporting the formulated mechanism. A cyclization and subsequent dehydration leads to the imine 6, which tautomerizes to yield the aromatic pyrrole 3 ... 

An analogous cyclization to eventually form five-membered rings has also been observed for l-metalla-l,3,5-hexatrienes with an additional heteroatom within the chain, such as in the complexes 157. These are obtained by Michael additions of imines to alkynylcarbene complexes in good to excellent yields (reaction type F in Scheme 4), and their configurations were determined to be Z (>91%) in all cases. Upon warming in THF solution, complexes 157 underwent cyclization with reductive elimination to furnish 2Ff-pyrroles 158 in up to 97% yield (Scheme 34). With two cyclopropyl substituents at the terminus in... 

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