Carbonylation reaction pyrroles

Aldehydes and Ketones. Pyrrole aldehydes and ketones are somewhat less reactive than the corresponding benzenoid derivatives. The aldehydes do not undergo Cannizzaro or Perkin reactions but condense with a variety of compounds that contain active methylene groups. They also react with pyrroles under acidic conditions to form dipyrryhnethenes (26). The aldehydes can be reduced to the methyl or carbinol stmctures. The ketones undergo normal carbonyl reactions. 

There have been some studies of the diazo coupling and carbonyl reactions with imi-dazo[2,1 -b ]thiazol-3 (2//)-ones (67CHE706), 2,3 -dihydrothiazolo[4,3-c ]-s-triazol-5-ones (76ZN(B)853) and 2,3-dihydroimidazo[2,l-6]thiazol-3(2//)-ones (81ZN(B)50l). Oxidation of 2,3-dihydrothieno[3,2-fc]pyrrole with chloranil to thieno[3,2-fc]pyrrole has been reported (72CHE1428). 

The use of Pd/C to effect carbonylation reactions, which has long been known, is equally successful with pyrrole aldehydes, e.g. 276 277 [133]. 

Reaction of vinyl Wittig reagents with carbonyl-substituted pyrroles has been used to generate the pyrrolizine ring system, from which pyrrolizidines are available by reduction. In this way, Schweizer and Light prepared... 

Zamora, R., Alaiz, M., and Hidalgo, F.J. 2000. Contribution of pyrrole formation and polymerization to the nonenzymatic browning produced by amino-carbonyl reaction. Journal of Agricultural and Food Chemistry 48 3152-3158. 

Kato Hiromichi (1967) Chemical studies on amino carbonyl reactions. III. Formation of substituted pyrrole-2-aldehydes by reaction of aldoses with alkylamines, Agric. Biol Chem. 31, 1086-90. 

From 2-methylpyrrole and formaldehyde, orange-coloured pyrrolyl(pyrrol-2-ylidene)methane is formed, which is unsubstituted in the 5-position. In acid-catalysed reactions with carbonyl compounds, pyrroles behave similarly to phenols, which give diphenylmethanes via hydroxymethyl compounds. 

Early workers converted pyrrole into its a-homologues by reaction with an alcohol and zinc chloride at 270-280 and the complex products formed from pyrrole and aldehydes or ketones in the presence of zinc chloride give C-alkylpyrroles when distilled (see carbonyl reactions, p. 71). More clear-cut are the substituted alkylations brought about by some carbi-nols formed when pyrroles react with carbonyl compounds (p. 72). 

An especially important group of reactions is that with carbonyl compounds. Pyrrole reacts vigorously with formalin giving condensed products, presumbly of the type (15), which on pyrolysis produce some 2-methyl-pyrrole . 

Gabriele, B., Salerno, G. and Cassoni, S. (2005) Heteroqfdic derivative syntheses by palladium-catalyzed oxidative cyclization-alkoxycarbonylation of substituted y-oxoalkynes. The Journal of Organic Chemistry, 70, 4971 979. no Gabriele, B., Salerno, G., Fazio, A. and Campana, F.B. (2002) Unprecedented carbon dioxide effect on a Pd-catalysed oxidative carbonylation reaction a new synthesis of pyrrole-2-acetic esters. Journal of the Chemical Society, Chemical Communications, 1408-1409. m Gabriele, B., Salerno, G., Fazio, A. and Veltri, L (2006) Versatile synthesis of pyrrole-2-acetic esters and (pyridine-... 

Pd(II) salts promote the carbonylation of organomercury compounds. Reaction of phenylmercury chloride and PdCh under CO pressure affords benzophenone (429)[387]. Both esters and ketones are obtained by the carbonylation of furylmercury(Il) chloride in alcohol[388]. Although the yields are not satisfactory, esters are obtained by the carbonylation of aryl- and alkylmercuryfll) chlorides[389,390]. One-pot catalytic carbonylation of thiophene, furan, and pyrrole (430) takes place at the 2-position via mercuration and transmetallation by the use of PdCb, Hg(N03), and CuCl2[391]. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

Knorr Synthesis. Condensation of an a-aminoketone with a carbonyl compound was first reported by Knott (20). This reaction and its modifications are among the most important and widely used methods for the synthesis of pyrroles. 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of iV-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive... 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

Furans, thiophenes and pyrroles have all been obtained by addition of alkynic dienophiles to a variety of other five-membered heterocycles, as illustrated in Scheme 104. As the alkynic moiety provides carbons 3 and 4 of the resulting heterocycle, this synthetic approach provides an attractive way of introducing carbonyl containing substituents at these positions, especially as many of the heterocyclic substrates are readily generated. Such reactions do... 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

A one pot samarium-catalyzed three-component reaction of aldehydes, amines, and nitroal-kanes leads to pyrroles. The reaction proceeds via imines, generated from the amine and carbonyl compound, followed by the Michael addition of the nitro compound (Eq. 10.10).12a In... 

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