Pyrrole activated methylene groups

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. 

A zinc-free alternative to the Knorr pyrrole synthesis employs catalytic hydrogenation, as for 17 + 18 to 19. Oximes such as 17 are readily prepared by nitrosation (NaNOa, HO Ac) of the active methylene group. 

The Knorr synthesis is generally suitable for the synthesis of a range of substituted pyrroles utilising a-aminoketones (or keto esters as illustrated above) with carbonyl compounds containing an active methylene group. 

Scheme 8.7 The formation of pyrroles from hydrogenation of an a-hydroxyimino ketone in the presence of a ketone with an active methylene group (X acyl, alkoxycarbonyl, or cyano).

From activated methylene compounds and 1,2-diaza-l,3-butadienes. The activated methylene group of pyrroles 189a,b,d, under basic conditions in tetrahydrofuran, attacked C-4 of 1,2-diaza-l, 3-butadienes 190a-d to give the hydrazones 191a-e as diastereomeric mixtures (02S1546) (Scheme 43). Cyclization of these derivatives in the presence... 

A -Acyl substitution of 2-amino-2-deoxyaldohexoses prevents their reaction with /3-dicarbonyl compounds from giving pyrrole derivatives. Instead, the products of the aldol reaction of the aldehydo form of the sugar with the active methylene group of the /3-dicarbonyl compound are formed. These substances have the structural features of higher-carbon, branched-chain carbohydrates. 

Apparently, aminobutenyne A, the intermediate of the pyrrole synthesis, is fixed in an advantageous configuration by coordination to the Cu" " cation, whereas the absence of catalyst may result in the formation of imine B having an active methylene group which attacks the acetylene bond to form dihydropyridine C and then pyridine 2 (by dehydrogenation). 

In accordance with the above principle the spiro[4-pyrrolyne-3,2 -quinoxalin]-3 (4 /f)-one 140 was synthesized. The 3-(a-aminobenzyl)quinoxalin-2(l/0-one 51 was considered to be the hetero analogue of a-aminocarbonyl compound according to the Knorr reaction (Knorr 1884 Castro et al. 1970 Mironov et al. 1973) (i.e., obtaining pyrroles by the condensation of a-aminoketones with ketones containing an activated methylene group). Thus, at position 2 of quinoxalinone 51 we have set up the necessary pyrrolydine system with the help of the reaction of the compound 51 with acetoacetic ester 138 in EtOH in the presence of KOH. The reaction... 

Knoevenagel reaction org chem The condensation of aldehydes with compounds containing an activated methylene (=Cff2) group. ka ne va.nag al re.ak shan ) Knorr synthesis orgchem Acondensation reaction carried out In either glacial acetic acid or an aqueous alkali in which an a-aminoketone combines with an a-carbonyl compound to form a pyrrole possibly the most versatile pyrrole synthesis. nor, sin-th3-s3s ... 

Compounds containing methylene groups activated by both a cationic ring and another electron-withdrawing group easily form stable anhydro-bases, e.g. (636) — (637), (638) — (639). Stabilization is also achieved by utilization of the aromatic character of the cyclopentadiene anion or the pyrrole anion compounds of type (640 Z = NR, O, S) and (643) readily lose protons to give the mesomeric anhydro-bases (as 641 <- 642) which are called pseudoazulenes. 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Knorr pyrrole synthesis. Formation of pyrrole derivatives by condensation of a-amino ketones as such or generated in situ from isonitrosoke-tones with carbonyl compounds containing active ot-methylene groups. 

Carboxylic ester and activated N-methylene groups react under strongly basic conditions at room temperature to form a pyrrole ring, but attempts to cyclize the V-tosyl analogue of (70.1) under Dieckmann reaction conditions were unsuccessful when the -acetyl amine (70.1) was treated with sodium hydride, cyclization was achieved in good yield. 

This widely used general approach to pyrroles, utilizes two components one, the a-aminocarbonyl component, supplies the nitrogen and C-2 and C-3, and the second component supplies C-4 and C-5 and must possess a methylene group a to carbonyl. The Knorr synthesis works well only if the methylene group of the second component is further activated (e.g. as in acetoacetic ester) to enable the desired condensation leading to pyrrole to compete effectively with the self-condensation of the a-aminocarbonyl component. The synthesis of 4-methylpyrrole-3-carboxylic acid and therefrom, 3-methylpyrrole illustrates the process. 

Fillipone reported a solid phase synthesis of pyrroles from 1,2-diaza-1,3-butadienes 43 and 3-ketoamides 44 in the presence of copper(II) dichloride <01T5855>. It is envisaged that Michael-type addition of the activated methylene on the 1,2-diazaheterodiene moiety is followed by an intramolecular addition of the nitrogen atom of the C=N group to the carbonyl in 5-position yielding the pyrroles 45. 

Tubereidin 6-amino-9-p-D-ribofuranosyl-7-deaza-purine, M, 266.25, m.p. 247-248 °C (d.), [a] j -67° (c = 1, 50% acetic acid), a purine antibiotic (see Nucleoside antibiotics) from Streptomyces tubercidicus, and one of the group of 7-deaza-adenine-nucleoside analogs. The N7 of adenine is replaced by a methylene group. T. is biosynthesized from adenosine (Fig.) the C-atoms of the pyrrole ring are derived from a ribose moiety, which is introduced from 5-phosphoribosyl 1-pyrophosphate. As an antimetabolite of adenosine, T. interferes with purine metabolism. T. can also be eonverted into nicotinamide-dea-za-adenine dinucleotide, which inhibits glycolysis. T. is particularly active against Mycobacterium tuberculosis and Candida albicans. 

---