Pyrroline reduction

In contrast to ammonia, primary, secondary, and tertiary amines can add to aldehydes and ketones to give different kinds of products. Primary amines give imi-nes and secondary amines gives enamines (10-69). This section will focus on imines. Reduction of co-azido ketones leads to the amino-ketones, which cyclizes to form a 2-substituted pyrroline. Reduction of nitro-ketones in the presence... 

Ornithine-Derived Alkaloids. Ornithine (23) undergoes biological decarboxylation reductively to generate either putrescine [110-60-1] (36), or its biological equivalent, and subsequent oxidation and cyclization gives rise to the pyrroline [6724-81-2], (37), C H N. 

Catalysts. Silver and silver compounds are widely used in research and industry as catalysts for oxidation, reduction, and polymerization reactions. Silver nitrate has been reported as a catalyst for the preparation of propylene oxide (qv) from propylene (qv) (58), and silver acetate has been reported as being a suitable catalyst for the production of ethylene oxide (qv) from ethylene (qv) (59). The solubiUty of silver perchlorate in organic solvents makes it a possible catalyst for polymerization reactions, such as the production of butyl acrylate polymers in dimethylformamide (60) or the polymerization of methacrylamide (61). Similarly, the solubiUty of silver tetrafiuoroborate in organic solvents has enhanced its use in the synthesis of 3-pyrrolines by the cyclization of aHenic amines (62). 

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

Pyrroline-N-oxides (12) are sometimes isolated when using zinc-ammonium chloride (19,20), iron-sulfuric acid (14) or hydrazine-Raney nickel (21) as reducing agents. During the reduction, dimerization has been often observed (22). 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

Enamine salts react with many nucleophilic reagents. The reaction with the cyanide ion is noteworthy. l-Methyl-2-ethyl-2-cyanopyrrolidine (170) is formed on treatment of alkali cyanide with l-methyl-2-ethyl-.d -pyrrolin-ium perchlorate (242). The reduction of the tertiary nitrile (170) with... 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

Anionic/oxidative reaction sequences have been developed in addition to the domino anionic/reductive processes. For example, with regard to the synthesis of novel diaryl heterocycles as COX-2 inhibitors [500], including rofecoxib (Vioxx) 2-972 [501] (which has recently been withdrawn from the market) or the pyrrolin-2-one derivative 2-973 [494], Pal and coworkers reported on a so-far unique domino aldol condensation/oxidation sequence (Scheme 2.218) [503]. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

Additionally, it was found that the double reductive alkylation of the 2,5-diester 66 could be achieved under Birch conditions (Li/NH3) to produce the 3-pyrroline 67. On the basis of a mechanistic postulate that such reductions do not involve transfer of a proton from ammonia, the authors discovered that the same reduction could be performed in THF (no ammonia) with lithium metal and catalytic amounts of naphthalene as an electron shuttle, thereby making this reaction more practicable on a large scale <00TL1327>. 

Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-0 bond reduction. Addition of iV-acryloyl-(2/()-bomane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85 15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline A-oxide to chiral pentenoates using (-)-/rans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The... 

Intramolecular variations of a series of bifunctional derivatives lead to the formation of cyclic nitrones. Many pyrroline /V-oxide derivatives were obtained in the course of intramolecular interaction in situ between carbonyl and hydrox-ylamine groups, resulting from the reduction of a y-nitro group (Scheme 2.31) (Fig. 2.8) (238-253). 

Addition of lithium derivatives of acetylenides (Li—C=C-C02R) to chiral nitrones proceeds with high stereoselectivity, giving a-acetylene substituted hydroxylamines (410a,b) (656). This reaction has been successfully applied to the synthesis of y-hydroxyamino-a, 3-ethylene substituted acids (411a,b), formed in the reduction of (410) with Zn in the presence of acid (657, 658), and to chiral 5-substituted-3-pyrroline-2-ones (412a,b) (Scheme 2.184) (658). 

Each transformation shown in Scheme 3.104 involves consecutive reactions, for which optimal procedures were found. For example, path b involves four transformations successive reduction of the nitronate fragment to the oximino group and then to the imino group followed by keto imino condensation and dehydration of intermediate pyrroline. 

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

Phenyl-1-pyrroline is useful for various purposes.10 11 In particular, its reduction product, 2-phenylpyrrolidine, is important in the synthesis of pyrroloisoquinoline antidepressants,20 12 and can be a starting point in alkaloid synthesis.13 The overall reaction sequence described here has been used to prepare nicotine derivatives such as myosmine.2a b... 

According to the working potential, the medium, and the nature of substituents, the cathodic reduction of aliphatic y-nitroketones leads to pyrroline... 

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-... 

A recent adaptation of this type of approach involves the spontaneous intramolecular cyclization of imino ketones, formed by the reduction of nitro ketones through the action of tributylphosphine/diphenyl sulfide (Scheme 6.14). When the corresponding esters (R = OR) are used, pyrrolin-2-ones are formed (Scheme 6.15). 

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. 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

A new synthesis of pyrrolizidine, which is based on the reaction of bis-tertiary glycols with co-chloronitriles, was reported by Meyers and Libano.28 The method involves three steps (a) condensation of 2,5-dimethyl-2,5-hexanediol (48) with 4-chlorobutyronitrile in the presence of sulfuric acid to give a derivative of A 1-pyrroline (49), (6) reduction of 49 with sodium borohydride to give the corresponding pyrrolidine (50), and (c) intramolecular cyclization of the pyrrolidine in the presence of alkali to give the pyrrolizidine derivative 51. The three-step synthesis was performed without isolation of the intermediate products. 

Dialkylpyrrolidines. These compounds can be prepared by reductive amination of 1,4-diketones with sodium cyanoborohydride and ammonium acetate (4, 448-449). 1-Pyrrolines are usually formed also, but they can be reduced to pyrrolidines by NaBH4 in a second step.1... 

A3-Pyrrolines, e.g. (176), are formed on the reduction of pyrroles and simple alkylpyrroles with zinc and acid. These are derived from the corresponding a-protonated species (66JA1335). 

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