Birch reduction pyrroles

Donohoe reports a novel and unprecedented reductive aldol process involving the Birch reduction of furans and pyrroles (e.g., 62) which presumably generates a dianion 63 and subsequently (after protonation at C-5 by ammonia) an enolate 64. After quenching excess... 

Pyrroles are not reduced by sodium in liquid ammonia, but the Birch reduction of 2-furoic acid with lithium in liquid ammonia gives the 2,5-dihydro derivative in 90% yield (780PP94). Sodium-liquid ammonia-methanol reduction of thiophene gives a mixture of A2- and A3- dihydrothiophenes together with butenethiols. Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cis- 1,3-dihydro derivative (Scheme 36) (80JOC3982). 

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. 

Nonalkylated 3,4-dehydroprolines 914 were obtained in 76-81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the A -BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88-90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at —30°C). The diastereoselectivity of the reaction was detected by HPLC. 

The use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(l//)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with l-chloro-3-iodopropane or 1-chloro -iodobu-tane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178). 

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>. 

Although the Birch reduction (alkali metals in liquid NH3) of the pyrrole ring is apparently unknown (c/. equation 8), the partial reduction of pyrroles to 2,5-dihydropyrroles using Zn/HCl has been of considerable utility. For example, pyrrole gives 2,5-dihydropynole as the major product upon treatment with Zn dust/20% aq. HCl (equation 9), and Lemal and McGregor observed that 2,5-dimethylpyrrole gives a mixture of trans- (78%) and c/5-2,5-dimethyl-2,5-dihydropyrrole (22%) under similar conditions (47% yield). In one of these studies, Hudson and Robertson demonstrated that 2,5-dihydropyrrole is not reduced to pyrrolidine under these reaction conditions. Using these same conditions, Schumacher and Hall reported the reduction of 2-benzylpyrrole to the 2,5-dihydro derivative (67%) in a synthesis of the antibiotic anisomycin. ... 

Schafer, A., Schafer, B. Diastereoselective protonation after the Birch reduction of pyrroles. Tetrahedron 1999, 55, 12309-12312. 

Selective Birch reductions were investigated with a number of electron-rich fused pyrrole substrates <05JOC2054>. Deprotonation of phenol 79 followed by treatment of phenoxide 80 with sodium metal in ammonia gave 81. The same reaction with the corresponding 7-methoxy derivative gave a mixture that contained over-reduced products. 

Phenylmenthol is the auxiliary in an asymmetric Birch reduction of pyrroles by Donohoe37 Lithium in ammonia does the reduction and the enolate is trapped with various alkyl halides. Hydrolysis of the esters 227 releases the enantiomerically enriched (78-90% ee) dihydropyrroles 228 in good yield. Furans give similar products with a C2 symmetric amine as auxiliary. This should become a general route to a variety of heterocycles. 

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. ... 

Birch reductions. Derivatives of pyrrole and furan are reduced to the dihydro level opening up many synthetic possibilities. 

Syntheses from Non-Carbohydrate Sources. The Birch reduction of an iV-protected 2-carboxymethyl substituted pyrrole and subsequent quench with an appropriate electrophile e.g. methyl 2,3,4-tri-0-benzyl-6-deoxy-6-iodo-a-D-glucopyranoside) affords a simple route to N-protected 2,2-disubstituted dihydropyrroles 81. These can be further elaborated into the corresponding 4-sub-stituted imino-ribitols 82 in good overall yield by a simple strategy of reduction, acetylation, syn-dihydroxylation and deprotection. ... 

Birch reaction is the dearomatization of aromatic rings to unconjugated cyclohexadienes in the presence of alkali metals (Li, Na, K) in liquid ammonia, using alcohol as proton source. Compared to other heterocyclic compounds, including pyridines, furans, and pyrroles, the Birch reduction of thiophenes and their derivatives has been scarcely investigated. 

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