Pyrrolines, preparation, from

Pyridyl)hydrazine (Aldrich), 4-acetylpyridine (Acros), N,N,N -trimethylethylenediamine (Aldrich), methylrhenium trioxide (Aldrich), InQj (Aldrich), Cu(N0j)2-3H20 (Merck), Ni(N03)2-6Il20 (Merck), Yb(OTf)3(Fluka), Sc(OTf)3 (Fluka), 2-(aminomethyl)pyridine (Acros), benzylideneacetone (Aldrich), and chalcone (Aldrich) were of the highest purity available. Borane dimethyl sulfide (2M solution in THE) was obtained from Aldrich. Methyl vinyl ketone was distilled prior to use. Cyclopentadiene was prepared from its dimer immediately before use. (R)-l-acetyl-5-isopropoxy-3-pyrrolin-2-one (4.15) has been kindly provided by Prof H. Hiemstra (University of Amsterdam). 

Pyrrolines and pyrroles can be readily prepared from the rearrangement of a-aminoallenes. Optically enriched a-aminoallene 137 is rearranged to pyrroline 138 by catalytic silver nitrate (Eq. 13.45) [53], The yield of the reaction is high and the cyclization occurs with high levels of asymmetry transfer. Annulated 3-pyrroline 140 is the product of rearrangement of allenyl pyrrolidine 139 (Eq. 13.46) [53]. 

Similarly, pyrroline N-oxides (12), pyrrolines, or pyrrolidines can be prepared from y-nitro ketones (13) in aqueous organic media at low temperatures the pyrroline N-oxide is obtained66 [Eq. (26)]. 

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... 

The dicyclopropyl ketimine 198 prepared from the 0,N-cyclopropanone hemiacetal 194 (vide supra, Sect. 4.9, Eq. (62)), heated in xylene with ammonium chloride for 4 hr underwent ring expansion exclusively to the enamine 399 followed by isomerization to the cyclopropyl pyrroline 400. Although further ring expansion was not observed on prolonged heating, 400 was converted to the hydrobromide 401 with anhydrous HBr 2091 which upon heating to 140 °C for 10 min experienced a second cyclopropyl imine rearrangement to provide the pyrrolizidone 403 in 51 % yield, most probably via the HBr adduct 401 by cyclization to the pyrroline 402 followed by acid-induced hydrolysis, Eq. (95) 129). 

Another synthetic route to ( )-retronecine (27) has been developed by Vedejs and Martinez.11 The protected hydroxy-lactam (22) was prepared from 2-methoxy-1-pyrroline by known methods. The key ylide intermediate (24) was then generated from the salt (23) by desilylation with caesium fluoride (Scheme 6). This ylide (24) reacted with methyl acrylate in a 1,3-dipolar cycloaddition to afford the unsaturated pyrrolizidine (25) in 57% yield from the lactam (22). Catalytic hydrogenation of the ester (25) gave an unstable endo-product, which epimerized to the exo-form (26). Introduction of the 1,2-double-bond into (26) was carried out by insertion and thermal elimination of a phenylseleno-group.12 Reduction then yielded ( )-retronecine (27). 

Recently, Brown has shown the feasibility of a one-carbon homologation procedure using a chiral non-racemic boronate derived from the hydroboration of 3-pyrroline. Pyrrole-containing nucleosides have been prepared from the pyrroline nucleoside by photodehydrogenation.9... 

Pyridazine 7V-ethoxycarbonylylides, prepared from pyridazines by N-amination and subsequent treatment with ethyl chloroformate, are transformed photochemically into 1-ethoxycarbony 1-pyrroles (80CPB2676) or 3-pyrrolin-2-one derivatives (85CPB3540). On the other hand, 1,2-bis(carbethoxy)pyridazines are transformed photochemically into 1-ethoxycarbonylpyrrolin-3-ones (87CB1597). 

Cyclic imines, such as 1-pyrroline (6) and A -piperidine (32), which are prone to trimerization, can be prepared from iV-halopyirolidine and iV-halopiperidine respectively and treated in situ with organoli-thium reagents to provide 2-alkylated and 2-aiylated pyrrolidines and piperidines in modest yield. Corey et al. treated substituted piperidine (17) generated in this fashion with iV-pentyllithium to establish die stereochemistry of the remote pentyl side chain of perhydrohistrionicotoxin (33), as condensation occurred from the more accessible re-face of the imine ir-system of (17). 

Oxaziridinium salts are the quartemized analogues of oxaziridines, and as a result of being more electrophilic, transfer oxygen more efficiently to nucleophilic substrates. The first oxaziridinium salt, described by Lusinchi in 1976 [1-3], was based on a steroidal pyrrolinic skeleton. Through peracid oxidation of the steroidal imine and quatemization using methylfluorosulphonate, it was shown that an oxaziridinium species could be formed (Scheme 5.1). This new species was rather unstable, and upon decomposition reverted to an iminium salt, which could be directly prepared from the imine. However, it was not until some 11 years later that the potential of this type of system to transfer oxygen was realized [4,5]. 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated by LDA in THF, by NaH in THF, by thallium(I) ethoxide in refluxing THF, or by electrochemical technique to oc,P-unsaturated esters provides a preparation of substituted 2-(alkoxycarbonyl)cyclopropylphosphonates in moderate to good yields via a tandem Michael addition-cyclization sequence (Scheme 8.47). The cyclopropanation has also been achieved via oxidation with iodine in the presence of KF-AI2O3. Nitrile ylides prepared from acyl chlorides and diethyl isocyanomethylphosphonate in the presence of Et3N react with methyl acrylates by a 1,3-dipolar cycloaddition to give phosphoryl pyrrolines or pyrroles. ... 

In a paper published along with that of Stevens and Wentland20 and in agreement with these authors, Keely and Tahk23 reported the independent synthesis of dl-mesembrine, also from I-methyl-3-(3,4-dimethoxyphenyl)-2-pyrroline and methyl vinyl ketone. In their work the cyclopropyl derivative 3b was prepared from the reaction of the anion of 3,4-dimethoxyphenylacetonitrile (lc) with ethylene dibromide in dimethyl sulfoxide and its sodium salt as solvent and base. Reduction with ethereal diisobutylaluminum hydride gave the aldehyde, which was condensed with excess methylamine in benzene-ether solution with calcium oxide as the dehydrating agent. 

V-Chloropyrrole, prepared from pyrrole and aqueous sodium hypochlorite, rearranges in methanol to a mixture of 2- and 3-chloropyrroles 2,5-dichloropyrrole is also formed/ Anodic oxidation of 1,2,5-trimethylpyrrole in the presence of cyanide ions yields the pyrroline (110) as the primary... 

The most important general method for preparing isopyrroles is by reaction of electrophiles with 1//-pyrroles. Other methods include cyclization of open-chain compounds, 1,3-dipolar cycloadditions using nitrile ylides, and preparations from pyrrolines. 

Pyrroles can be synthesized from 3-pyrrolines 39 which can be prepared from a Crabbe reaction of propargyl sulfonamides 38 and selective cycloisomerization of the resulting allene intermediate. Subsequent oxidation of 3-pyrrohnes with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) lead to 2-alkyl and aryl pyrroles 40 in this domino process (14EJO2305). 

Pyrrole oxidizes in air to red or black pigments of uncertain composition. More usehil is the preparation of 2-oxo-A -pyrrolines, which is best carried out by oxidation of the appropriate pyrrole with in pyridine (37), eg, 3,5-dimethyl-ethyl-3-pyrrolin-2-one [4030-24-4] from... 

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 original compound, maleimide (2,5-dioxo-A -pyrroline), is synthesized by the cyclo-condensation of ammonia and maleic acid. Similarly, primary amine is added to maleic anhydride, followed by cyclocondensation, to form N-substituted maleimide (Fig. 2). This reaction is applied to the preparation of bis-maleimides (BMl) [1]. At first, BMI was used as a crosslinking agent for natural rubber (NR). An o-dichlorobenzene solution of NR was crosslinked by BMI at I08-150°C in the presence of peroxides. The radicals generated from peroxides react with the double bonds of both BMI and NR [ 1 ]. 

Zl -Pyrrolines have been isolated from the hydrogenation products of y-ketonitriles (23-26) and in a large number of reactions during which enamino ketones are formed as intermediates. The preparation of pyrrolines from anhydro-5-hydroxyoxazolinium hydroxides (13, R, R" = Ph, R = Me) is also important (27). By the reaction of 13 with styrene, l-methyl-2,3,5-triphenyl-/l -pyrroline (14) is formed. 

Quaternary ammonium salts of pyrrolines 106) can be prepared only indirectly 197). Addition of bromine to l-dimethylamino-4-pentene followed by removal of hydrogen bromide afforded, depending upon the dehydrohalogenation conditions, quaternary bromides derived from either l,2-dimethyl-/f -pyrroline (107) or l-methyl-2-methylenepyrrolidine (108) (Scheme 7). 

Norhygrine has been prepared by Schopf from. d -pyrroline. Goldschmidt (308) synthesized l-carbethoxy-2,3-dioxopyrrolizidine (193) by condensation of d -pyrroline with diethylester of oxosuccinic acid. 

The reaction of alkenylcarbene complexes and imines in the presence of a Lewis acid generates pyrroline derivatives as a result of a [3C+2S] cyclisation process [76]. This reaction has been extended to an asymmetric version by the use of chiral alkenylcarbene complexes derived from several chiral alcohols. However, the best results are found when (-)-8-phenylmenthol-derived complexes are used and catalytic amounts of Sn(OTf)2 are added to the reaction. In these conditions high levels of trans/cis selectivity are achieved and the hydrolysis of the major tram diastereoisomers allows the preparation of optically pure 2,5-disubstituted-3-pyrrolidinone derivatives (Scheme 29). 

Starting from readily available substrates, a new one-pot procedure has been devised to prepare polycyclic lactams and sultams. 2-Pyrrolines 48 were obtained... 

This study has demonstrated that a cyclic pyrroline polymer could be prepared by a free radical initiation of the corresponding exocyclic diene monomer. The polymerization was shown to proceed predominantly by 1,4-addition as expected from a free radical initiator with diene monomers. 

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