Pyrrole-2-carboxylic acid reduction

A Sml2-induced reductive cyclization of (V-(alkylketo)pyrroles provided an entry into medium ring 1,2-annelated pyrroles <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to a-(pyrrol-2-yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <060L2007>. 

The Reimer-Tiemann reaction is not an effective route to formyl-pyrroles or -indoles (see Section 3.05.1.6) and the oxidation of alkyl and hydroxyalkyl derivatives of the heterocycles and the reduction of carboxylic acid derivatives are discussed in Sections 3.05.2.2 and 3.05.2.4, respectively. 

Halogenomethylpyrroles have been oxidized with lead(IV) salts or by chromium trioxide to yield the formylpyrroles, whilst catalytic hydrogenolysis or zinc-acetic acid reduction produces the 2-methylpyrroles (B-77MI30504). The methyl derivatives are also obtained by hydride reduction of trifluoromethyl-pyrroles and -indoles, and trifluoromethylindoles are converted into the carboxylic esters by ethanol under basic conditions (74JOC1836). 

Curtius rearrangement of the heteroaroyl azides, obtained from the reaction of the carboxylic acid chlorides with sodium azide, provides a route to the amino-pyrroles and -indoles (e.g. B-70MI30504, B-77MI30506, 78CPB1054), which, because of the ease of synthesis of the carboxylic acids, is frequently preferable to reduction of the nitro compounds. 

Aminomethyl)pyrrole-2-carboxylic acid (85) was prepared from methyl 5-formylpyrrole-2-carboxylate by conversion to the oxime and subsequent reduction, Boc protection, and saponificationJ74 ... 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

The synthesis of )-A -BOC-2-hydroxymethyl-2,5-dihydropyrrole )-923 with ee up to 98% was achieved by its irreversible acetylation catalyzed by Pseudomonas fluorescens lipase (Scheme 179) <1998TA403>. Precursor ( )-922 for compound 923 can be easily prepared from commercially available pyrrole-2-carboxylic acid 921 by Birch reduction, followed by esterification and reduction according to literature procedure <1996JOC7664>. 

Apart from catalytic hydrogenation and dissolving metal methods, very few other techniques exist for the reduction of the pyrrole ring. However, one example is the improved use of hypophosphorus acid that has been described by Scott and coworkers in a reduction of pyrrole-2-carboxylic acid to the prolyl hydroxylase inhibitor (5)-3,4-dehydroproline (after resolution) (equation 10). r,—A i, HI, AcOH, H3PO2... 

Birch reduction of pyrrole carboxylic esters and tertiary amides gives dihydro-derivatives the presence of an electron-withdrawing gronp on the nitrogen serves both to remove the acidic iV-hydrogen and also to rednce the electron density on the ring. Quenching the immediate reduced species - an enolate - with an alkyl halide produces alkylated dihydropyrroles. ... 

Extension166-166 to pyrrole- and selenophene-2-carboxylic acids gives a sequence of sensitivity in the order pyrrole, furan, selenophene, thiophene, benzene, the same order as that observed by Tirouflet et al.ul in the polaro-graphic reduction of nitro derivatives of these rings. A different sequence, however, which correlates better with ground state aromatic character , viz., furan, pyrrole, thiophene, benzene, has been observed in the gas-phase ionization process,168 but results for electrophilic substitution appear to be anomalous.169... 

Pyrrole aldehydes and ketones are important sources of alkylpyrroles, formed from them by WolfF-Kishner reduction 232 -3, 33i, More recently, lithium aluminium hydride has been used for this purpose32 233, 332 -5 Direct addition of the carbonyl compound to the reagent gives the alkyl-pyrrole, whilst inverse addition allows preparation of the carbinol. Carboxylic acids and their esters are also reduced by lithium aluminium hydride to alkylpyrroles. In contrast to pyrrole aldehydes unsubstituted at nitrogen, 2-and 3-formyl-1-methylpyrroles are reduced by lithium aluminium hydride only to the carbinol stage sa. The difference is explained by the mechanism... 

A method for the synthesis of the derivative of A-(2-nitrophenyl) pyrrolidine-2-carboxylic acid 171b involves alcoholysis of 1-(5-chloro-2-nitrophenyl)-2-trichloroacetyl-l//-pyrrole 175, which is in mm obtained as a result of a two-stage process from 5-chloro-2-nitroaniline 173 (Silvestri et al. 2000). In this case, reductive cyclization is realized successfully with iron powder in acetic acid (60 °C, 3 h) (Scheme 3.51). 

In 1988, Ono and Maruyama reported a very simple synthesis of octaethylporphyrin (OEP) from 3,4-diethylpyrrole-2-carboxylate, as shown in Eq. 10.44 49 Reduction of this pyrrole with LiAlH4 gives 2-hydroxyethylpyrrole, which is converted into OEP on treatment with acid and an oxidizing agent. This route is very convenient for synthesis of porphyrins. This method is now used extensively for synthesis of P-substituted porphyrins.50 For example, a highly conjugated porphyrin, shown in Eq. 10.45, has been prepared by this route.51 The requisite pyrroles are prepared from nitro compounds or sulfones thus, various substituents are readily introduced into porphyrins. 

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