Pyrrolidinones formation

Recently, Akiyama et al. reported an enantiocontrolled [3+2] cycloaddition of chirally modified Fischer alkenylcarbene complexes 180 with aldimines 181 under Lewis-acid catalysis (Sn(OTf)2) to afford enantiomerically pure 1,2,5-trisubstituted 3-alkoxypyrrolines 182 (Scheme 40) [121]. The mode of formation of these products 182 was proposed to be a [4+2] cycloaddition, with the complexes 180 acting as a 1-metalla- 1,3-diene with subsequent reductive elimination. Upon hydrolysis under acidic conditions, the enol ethers give the enantiomerically pure 3-pyrrolidinones 183 (Table 9). 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

Metabolism of NHEX- C in the rat results in dose dependent formation of C02> with 45% exhaled after a dose of 8 mg/kg NHEX but only 4% after 576 mg/kg (17). Similar results were obtained for NPYR and nitrosoheptamethyleneimine. At doses of 8-12 mg/kg NHEX, 33-37% of the radioactivity was excreted in the urine (17, 52). Urinary metabolites of NHEX were e-caprolactam, e-amino-caproic acid, and 6-aminocaprohydroxamic acid (52). The formation of 6-caprolactam is analogous to results with NPYR and NNN, in which 2-pyrrolidinone and norcotinine were observed as urinary metabolites. Caprolactam did not originate from hexamethylene-imine, a product of denitrosation. 

Reaction of the 2-amino-substituted thiophene 244 with pyrrolidinone in the presence of phosphorus oxychloride led to efficient formation of the central six-membered ring of tricycle 245 in 57% yield (Equation 67)... 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

Scheme 3.40. Stereoselective reaction between a-aminoalkyl-cuprates and allenic esters, with formation of 4-all

Scheme 3.41. Reactions between a-aminoalkylcuprates and alkynyl ketones [163] or esters [161b], and formation of pyrroles and pyrrolidinones (Boc = t-butoxycarbonyl).

Decomposition of l-methyl-2-pyrrolidinone (67) was studied by vapor-phase photolysis (72JA8281). Irradiation (Hg sensitized) led, in addition to extensive polymer formation, to the following products carbon monoxide (31%), ethene (24%), water (24%), l,3,5-trimethyl-hexahydro-l,3,5-triazine (8%), 1-methylazetidine (6%), 1-methylpyrrole, and methane (<1%). The mechanism of formation of most of these products involves... 

The formation of oxazolidines 54 or oxazolidinones 55 is currently utilized to assign the absolute stereochemistry of diastereomers of 1,2-amino alcohols, based on H NMR analysis of the H4 and H5 protons of these heterocycles. In the case of y-amino-p-hydroxy acids, the internally cyclized pyrrolidinone 56 is also suitable for determination of the relative configurations of the y-amino and p-hydroxy groups (Scheme 23). 

Commercially available VP is usually over 99% pure but does contain several methyl-substituted homologues and 2-pyrrolidinone. The vinylation of 2-pyrrolidinonc is carried out under alkaline catalysis analogous to the vinylation of alcohols. 2-Pyrrolidinone is treated with ca 5% potassium hydroxide, then water and some pyrrolidinone are distilled at reduced pressure. A ca 1 1 mixture (by vol) of acetylene and nitrogen is heated at 150- L60°C and ca 2 MPa (22 atm). Fresh 2-pyrrulidiuone and catalyst are added continuously while product is withdrawn. Conversion is limited to ca 60% to avoid excessive formation of hy-products. The AI-vinyl-2-pynolidinone is distilled at 70-85°C at 670 Pa (5 mm Hg) and the yield is 70-80%. 

Lactams and some non-cyclic, secondary amides (RCONHR) can be alkylated with high regioselectivity either at nitrogen (Section 6.6) or at oxygen. N-Alkylations are generally conducted under basic reaction conditions whereas O-alkylations are often performed with trialkyloxonium salts, dialkyl sulfates, or alkyl halides/silver salts without addition of bases. Protonated imino ethers are formed these are usually not isolated but are converted into the free imino ethers with aqueous base during the work-up. Scheme 1.8 shows examples of the selective alkylation of lactams and of the formation of 2-pyrrolidinones or 2-iminotetrahydrofurans by cycli-zation of 4-bromobutyramides. 

Decarbonylation of aldoses.2 Although this rhodium complex has been known since 1968 to effect decarbonylation of aldehydes, it has been used for decarbonylation of sugars only recently, probably for lack of a compatible solvent. Actually, this reaction when carried out in N-methyl-2-pyrrolidinone (NMP) at 110-130° is extremely useful in the case of simple aldoses, which are converted to the lower alditol with formation of carbonylchlorobis(triphenylphosphine)rhodium(I). The yields are 75-95%. This method of degradation has the further advantage that protecting groups are not necessary. Deoxyaldoses, particularly 2-deoxyaldoses, are decar-bonylated in 75-99% yield. A disadvantage of this reaction is that a full equivalent of the complex is required. 

A three-component one-pot coupling of 2,6-dimethylphenyl isocyanide, methyl 2,4-dioxopentanoate and alkynoic esters leads to the isatin-like compounds (or fused pyrans) 20 (Scheme 5). The reaction proceeds by initial formation of the zwitterionic intermediate 21, which is protonated by methyl 2,4-dioxopentanoate. Attack of the newly generated nucleophile then forms the intermediate 22. The pyrrolidinone ring is formed upon loss of methanol and electrocyclization then occurs to afford the desired 2//-pyrans (Scheme 5) <2005S1049>. 

The fused azepine 29 was formed unexpectedly by the cyclisation of the Al-arylsulfonyl caprolactam 28 as a competing reaction for the formation of the alkcnylphosphonite 30 <07OBC3472>. The cyclisation was also specific for the seven-membered derivatives, with pyrrolidinone and piperidinone derivatives yielding the phosphonites as the only products. The mechanism is believed to be initial ortho-lithiation followed by nucleophilic addition to the lactam followed by dehydration. 

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