Hydrogenation of pyrrole

C4H N. Almost colourless, ammonia-like liquid, b.p. 88-89 C, which fumes in air. Strong base. It occurs naturally in tobacco leaves, but is made industrially by hydrogenation of pyrrole. 

Partial hydrogenation of pyrrole derivatives and partial dehydrogenation of pyrrolidines afford /I -pyrrolines (80-82). However, because of the complex nature of the reaction, it is of little preparative value. The same is true for isomerization of /) -pyrrolines to /) -pyrrolines (83). A photodehydrogenation of 2,6-dimethylpiperidine (26) has been observed recently, affording 2,6-dimethyl-3,4,5,6-tetrahydropyridine (27) in a good yield (84)-... 

Approach C, direct asymmetric hydrogenation of pyrrole 4, had no precedent at the time, and was deemed to require extensive development. Only recently, the first successful cases of asymmetric hydrogenation of certain pyrroles have been reported by Kuwano (Scheme 8.7) [9]. 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

Although hydrogenation of pyrrole over a rhodium/alumina catalyst gives some 1-pyrroline (Scheme 6.18a), a better method is to dehydro-halogenate A-chloropyrrolidine by heating it with alcoholic potassium hydroxide (Scheme 6.18b). 2,5-Dihydro-1//-pyrrole, containing 15% pyrrolidine, is obtained by the zinc/hydrochloric acid reduction of pyrrole. 

The susceptibility of pyrroles to acid-catalyzed polymerization is a distinct disadvantage in the catalytic hydrogenation of pyrroles in acidic media and, similarly, the oligomerization of indoles by acids can also be a problem under such hydrogenation conditions. 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

Pyrrole is non-basic. The pyrrole ring is very sensitive to acid. Electrophilic attack on pyrrole is rapid and takes place predominantly at C-2. The N-H hydrogen of pyrrole is acidic and, in the presence of a strong base, pyrrole forms a powerful nucleophile. 

The catalytic hydrogenation of pyrroles to pyrrolidines (2,3,4,5-tetrahydropyrroles), although an old transformation (equation has not been heavily exploited as a preparative route to pyrrolidines. Nevertheless, sufficient examples exist so as to illustrate the importance of this method. As would be expected, the hydrogenation of 2,5-disubstituted pyrroles proceeds with cis stereoselectivity (equation 2). - ... 

The use of rhodium-amino acid complexes in catalytic hydrogenation has been reported by Rajca to be capable of reducing a wide variety of aromatic and heteroaromatic compounds under mild conditions (1 atm, 22 °C, DMF 1 atm = 101 kPa). Thus, the rhodium-anthranilic acid catalyzed hydrogenation of pyrrole under these mild conditions yields a 2 1 mixture of pyrrolidine and 2,5-dihydropyrrole (53% conversion after 8 h)." Recently, Lunn found that the hydrogenation of pyrrole can be carried out with a nickel-aluminum alloy, as generated with aqueous KOH, to give pyrrolidine in 58% yield, albeit relatively slowly (4 d, r.t.)."... 

Pyrrolidines are obtained by the hydrogenation of pyrroles in glacial acetic acid over platinum, rhodium or palladium catalysts at 25°-50°C and 3-4 atmospheres of hydrogen. S.He jjjg isomer is formed on hydrogenation of disubstituted pyrroles under these conditions (Eqn. 17.41). The N-substituted pyrroles are more easily hydrogenated than the N-unsubstituted compounds. 

The selectivity observed in the hydrogenation of pyrroles is strongly dependent on the catalyst and conditions used for the reactions. The pyrrole ring in nicotyrine, 42, was hydrogenated preferentially over palladium in acetic acid, 7 but over platinum the pyridine ring was saturated first (Eqn. 17.42), 48,149 K.eto and ester groups on an N-unsubstituted pyrrole were... 

The asymmetric hydrogenation of pyrroles is a useful method to optically active pyrrolidines that are building blocks of pyrroline based alkaloids and otlier biolog ically active compounds. It was not until very recently that the catalytic asymmetric hydrogenation of pyrroles has become the truth. 

The pyrrole nucleus is reduced to pyrolidine derivatives over Pt or Rh catalyst with stereochemical control as in hydrogenation of pyrrole 7 °. 

Hydrogenation. The Rh/Al203 catalyst is well suited for hydrogenation of pyrrole... 

Although the hydrogenation of pyrroles is an old method, it has not been extensively exploited as a preparative route to pyrrolidines, even though the hydrogenation proceeds with excellent cis diastereoselectivity. 

For the hydrogenation of pyrroles, palladium and rhodium catalysts can be used besides platinum, under 3 to 4 atm of hydrogen. Electron-deficient pyrroles can even be hydrogenated at atmospheric pressure. Multiply-substituted pyrroles are hydrogenated by use of platinum or rhodium catalysts to give the cis product only [34]. This method has, for example, been used in the synthesis of a pyrroli-dizine carboxylic acid derivative (Scheme 3), a possible agent of the angiotensinconverting enzyme [35], and in the synthesis of Anatoxin a [36]. 

Hydrogenation of pyrrole is very difficult. Platinum in glacial acetic acid,240 and rhodium or palladium on asbestos,241 should be considered. Andrews and McElvain used platinum oxide.69... 

A claim has been made in patents issued to Auzies (374) that nicotine can be prepared on an industrial scale from ammonia and butadiene. This process is reported to involve the production of pyrrole by the catalytic interaction of ammonia and butadiene, the methylation and hydrogenation of pyrrole, the conversion of ZV-methylpyrrolidine to 8-chloropyridine by heating over a thorium catalyst with chloroform, and the interaction of /8-chloropyridine with A-methylpyrrolidine over the same catalyst. The process, however, does not seem to have been put into practice and the reactions described have never been confirmed by a precise chemical investigation. 

Hydrogenation of pyrroles to pyrrolidines by Raney nickel proceeds only under pressure and at high temperatures. Autoxidation of pyrroles, as well as oxidation with hydrogen peroxide, can be considered addition reactions. Attack of O2 or H2O2 occurs first at the 2-position and then at the 5-position, resulting finally in the formation of maleimide or A-substitued maleimide ... 

Enantioselective hydrogenation of pyrroles has also been conducted, and is somewhat more complex than that of indoles. These reactions were conducted with N-Boc-substituted pyrroles and a ruthenium-TRAP catalyst. The pyrroles can be mono-, di-, or tri-substituted. For example, the asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave the product from addition of hydrogen to the same face of both olefin units to form products containing three stereocenters in high enantioselectivity. These reactions occur by initial reduction of the less-substituted carbon-carbon double bond. 

PROBLEM 15.68 The carbon-bound hydrogens of pyrrole appear at 8 6.05 and 6.62 ppm in the NMR spectrum, upheld of the typical aromatic signal region. Does this observahon mean that pyrrole is not aromatic ... 

---