1- Pyrrolines, 2-methyl

This enzyme [EC 1.4.1.12] catalyzes the reaction of 2,4-diaminopentanoate with NAD(P)+ and water to produce 2-amino-4-oxopentanoate, ammonia, and NAD(P)H. The enzyme can also utilize 2,5-diaminohexanoate as a substrate (although not as effectively as the substrate mentioned above) forming 2-amino-5-oxohexanoate, which then cyclizes nonenzymically to form 1-pyrroline-2-methyl-5-carboxylate. 

The chemical shift of the A-pyrroline methyl group in the cyclazine (17) was diagnostic, occurring at 51.67 instead of in the 52.2-2.6 range observed for pyrrole methyl groups... 

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). 

Finally a general approach to synthesize A -pyrrolines must be mentioned. This is tl acid-catalyzed (NH4CI or catalytic amounts of HBr) and thermally (150°C) induced tea rangement of cyclopropyl imines. These educts may be obtained from commercial cyan> acetate, cyclopropyl cyanide, or benzyl cyanide derivatives by the routes outlined below. Tl rearrangement is reminiscent of the rearrangement of 1-silyloxy-l-vinylcyclopropancs (p. 7 83) but since it is acid-catalyzed it occurs at much lower temperatures. A -Pyrrolines constitut reactive enamines and may be used in further addition reactions such as the Robinson anei lation with methyl vinyl ketone (R.V. Stevens, 1967, 1968, 1971). 

The alkylation of imines by an alkyl halide to give an iminium salt will be illustrated by selected reactions over a period of years. A more complete survey is available (88). Decker and Becker (89) prepared a number of iminium salts (91, for example) by mixing methyl iodide and aromatic imines in benzene. 2,5-Dimethyl-2-pyrroline (92) has been alkylated and the... 

It is interesting to note that 4-aminopent-3-en-2-one (85), which is held in a cisoid arrangement by hydrogen bonding, gives the product 86, which is stable in anhydrous solvent, but which cyclizes under the influence of water to give methyl 2-methyl-5-oxo-4-(2-oxopropylidene)-2-pyrroline-3-carboxylate (87). 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

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. 

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

The reactivity of the methylene group adjacent to the lactam group affords the possibility of a Claisen condensation. Thus, treatment of 2-pyrrolidone or 2-piperidone with ethyl oxalate leads to the J -pyrroline-carboxylic (70) and, d -piperideine-2-carboxylic acids (71), respectively. N-methyl lactams furnish N-methyl derivatives (72,73) (Scheme 3). 

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

C alkylation was used in the corydaline synthesis 194). LukeS and Dedek 195) obtained on methylation of l-methyl-2-ethylidenepyrrolidine a C-alkylation product, i.e., l-methyl-2-isopropyl-/l -pyrroline (106). Alkylation of the same enamine with ethyl bromoacetate was the first synthetic step in the preparation of D,L-pseudoheliotridane 196). 

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). 

An explanation of the exclusive N methylation of 1,2-dimethyl-J -piperi-deine by means of methyliodide is more difficult. Pyrrolines and piperideines which are not alkylated on the nitrogen atom afford only quaternary ammonium salts on alkylation (203-205), for example 119. 

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... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

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). 

Rolgamidine (14) is a dihydropyrrole derivative which has antidiarrheal activity It can be synthesized by alkylation of trans 2,5-dimethyl-3 pyrroline (12) with methyl bromoacefate to give 13 An amide-ester exchange reaction with guanidine hydrochloride completes the synthesis of rolgamidine (14) [3]... 

The Rh and Ir complexes 85-88 (Fig. 2.14) have been tested for the intramolecular hydroamination/cyclisation of 4-pentyn-l-amine to 2-methyl-1-pyrroline (n = 1). The reactions were carried out at 60°C (1-1.5 mol%) in THF or CDCI3 The analogous rhodium systems were more active. Furthermore, the activity of 87 is higher than 85 under the same conditions, which was attributed to the hemilabihty of the P donor in the former complex, or to differences in the trans-eSects of the phosphine and NHC ligands, which may increase the lability of the coordinated CO in the pre-catalyst [75,76]. 

Photoelimination of carbon dioxide from the 2-oxazolin-5-one 474 in the presence of methyl acrylate affords the cis- and frans-l-pyrrolines 475 and 476.394 A nitrile ylid is believed to be involved in this and other analogous transformations.395... 

DBPMPO, 5-(di-/ -butoxyphosphoryl)-5-methyl-l-pyrroline-yV-oxide DCFH, dichlorodihydrofluorescin DDC, diethyldithiocarbamate... 

C. 2-Methylmercapto-N-methyl-A 2-pyrroline. 2-MethyImer-capto-N-methyl-A -pyrrolinium iodide (662 g., 2.57 moles) is suspended in 1.25 1. of anhydrous ether in a 4-1. three-necked flask equipped with a mechanical stirrer and a reflux condenser with a segment-shaped paddle. Potassium f-butoxide (448 g., 4.0 moles) is added in one batch to this suspension with vigorous stirring. The mixture warms up a little, and later the solid becomes fine-grained and more mobile as a result of separation of potassium iodide. After being stirred for 1.5 hours at room temperature, the mixture is treated with 1.81. of anhydrous ether and boiled under reflux on a water bath for 5 hours. 

Methylmercapto-N-methyl-A2-pyrroline has been prepared by the present method only.11,12... 

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