Pyrroline intermediate

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

A synthesis of chiral -substituted pyrroles involved the condensation of 1,4-dichloro-2-butene with chiral amines in the presence of silica and under microwave irradiation <07T9746>. The mechanism includes an in situ oxidation of the 3-pyrroline intermediates. 

The carbapenems are mechanism-based inhibitors which involve acylation of the active-site residue and subsequent rearrangement to a more stable acyl-enzyme species. Knowles and co-workers [32, 33] have demonstrated that the progressive inhibition of the TEM S-lactamase by the olivanic acids is due to the rearrangement of the J -pyrroline intermediate (15) to the tautomeric and thermodynamically more stable zl -pyrroline (16) Scheme 6.3). The resultant acyl-enzyme complex is believed to be stable to subsequent hydrolytic breakdown, thereby disrupting the catalytic activity of the enzyme. 

This methodology was used as the key eyclization step in the stereo- and enan-tioselective synthesis of ( + )- and (-)-a-kainic acid 43, the prototype of a group of neuroexeitatory amino aeids that are important substrates in physiological and pharmacological studies of the central nervous system [22e-f], One of the major obstacles in the synthesis of kainic aeid is the establishment of the 3,4-c/5-stereochemistry. This was overcome by using on the pyrroline intermediate 42 a... 

Pyrrole can be reduced catalyticaHy to pyrroHdine over a variety of metal catalysts, ie, Pt, Pd, Rh, and Ni. Of these, rhodium on alumina is one of the most active. Less active reducing agents have been used to produce the intermediate 3-pyrroline (36). The 2-pyrrolines are ordinarily obtained by ring-closure reactions. Nonaromatic pyrrolines can be reduced easily with to pyrroHdines. 

Pyridazin-3(2H)-ones rearrange to l-amino-3-pyrrolin-2-ones (29) and (30) upon irradiation in neutral methanol (Scheme 10), while photolysis of 5-amino-4-chloro-2-phenylpyridazin-3(2H)-one gives the intermediate (31) which cyclizes readily to the bis-pyridazinopyrazine derivative (32 Scheme 11). 

Complex reactions occur on the autoxidation of pyrroles (see Section 3.05.1.4) predictably, susceptibility to autoxidation increases with increasing alkyl substitution, llie photosensitized reaction of pyrrole and oxygen yields 5-hydroxy-A -pyrrolin-2-one, probably by way of an intermediate cyclic peroxide (Scheme 28) (76JA802). 

By use of potassium phthalimide we can isolate the intermediate. a-Oxo-S-aminovaleric (9, = 1) and a-oxo-e-aminocaproic acids (9, = 2) readily yield 2l -pyrroline-2-carboxylic acid (10, =1) and. d -piperideine-2-carboxylic acids (10, n = 2), respectively (7-10). The equilibria of the acids with their cyclic forms was observed in water solutions (11,12). 

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). 

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. 

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). 

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 hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

Hydrogen shifts are often observed in thermal isomerizations of vinylaziridines. Heating of compounds 221 at 180 °C produced mixture of 3-pyrrolines 222 and hydrazones 223 (Scheme 2.54) [87]. The formation of 223 can be explained in terms either of a concerted hydrogen shift as depicted in 224 or of diradical intermediates 225, both of which would be followed by thermal isomerization of the (Z)-carbon-carbon double bonds to provide the ( ) isomers 223. 

In related work, the reactions of hydrogen peroxide with iron(II) complexes, including Feu(edta), were examined.3 Some experiments were carried out with added 5.5"-dimethyl-1-pyrroline-N-oxide (DMPO) as a trapping reagent fa so-called spin trap) for HO. These experiments were done to learn whether HO was truly as free as it is when generated photochemically. The hydroxyl radical adduct was indeed detected. but for some (not all) iron complexes evidence was obtained for an additional oxidizing intermediate, presumably an oxo-iron complex. 

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. 

A3-Pyrroline formation with carbonyl insertion also occurs during the reaction of /V-sulfinylarylamines with diphenylcyclopropenone in the presence of nickel carbonyl (Scheme 36).64 Phenyl isocyanate does not give a pyrroline product under these reaction conditions, hence the SO-CO exchange probably occurs within an intermediate metallocycle. The reaction... 

Microwave irradiation in solvent-free conditions induces the cleavage of the 2,3-bond of 2-aroyl-aziridines 135 to give an azomethine ylide intermediate, which subsequently undergoes cycloadditions to a multiple bond and leads to oxazolidine, imidazoline, naphthooxazole and pyrroline derivatives 136 in good yields (Scheme 9.41) [32b], Reactions were performed at atmospheric pressure in an Erlenmeyer flask placed in a commercial domestic oven. The reactions were complete in 10-15 min while the conventional method requires 18-20 h. 

The 1,3-dipolar intermediate obtained in the ring opening reaction of 3H-azirines via cleavage of the C—C bond has been trapped to give oxa-zolines 355) (3.36) and pyrrolines (3.37) 356). 

Katritzky developed a facile synthesis of l,2-diaryl(heteroaryl)pyrroles in a two-step procedure from A-allylbenzotriazoles via intramolecular oxidative cyclization in the presence of a Pd(II) catalyst <00JOC8074>. Thus, treating A-allylbenzotriazole (21) with n-butyllithium followed by addition of a diarylimine yielded the (2-benzotriazolyl-l-arylbut-3-en)anilines 22 which were subsequently heated in the presence of the system Pd(OAc)2-PPh3-CUCI2-K2CO3 to undergo intermolecular amination with simultaneous oxidation of the intermediate 3-pyrroline to the pyrroles 23. 

Pyrroline-A-oxide (258) is isomerized into y-lactam (259) in the presence of lithium diisopropylamine (LDA) (470) and sodium trityl (471). In these reactions, deprotonation at C3 occurs, leading to carbanion (260). Then oxygen migration from Ni to C2 takes place via intermediate formation of oxaziridine... 

Dipolar cycloadditions of 2-tert-butoxycarbonyl-1 -pyrroline A -oxide (627) with several chiral acrylamides (634a-f) (Scheme 2.276) followed by hydrogenolysis of cycloadducts (635) and (636) has been used in the synthesis of enantiopure tert-butyl (2RJ R)- and (2.S. 7a.S )-2-hydroxy-3-oxo-tetrahydro-l II -pyrrolizine-7a(5// )-carboxylates, useful intermediates for the synthesis of Gly-(s-cis)Pro dipeptide mimetic (790). 

For example, the reaction of nitronates (123) with a zinc copper pair in ethanol followed by treatment of the intermediate with aqueous ammonium chloride a to give an equilibrium mixture of ketoximes (124) and their cyclic esters 125. Heating of this mixture b affords pyocoles (126). Successive treatment of nitronates (123) with boron trifluoride etherate and water c affords 1,4-diketones (127). Catalytic hydrogenation of acyl nitronates (123) over platinum dioxide d or 5% rhodium on aluminum oxide e gives a-hydroxypyrrolidines (128) or pyrrolidines 129, respectively. Finally, smooth dehydration of a-hydroxypyrrolidines (128) into pyrrolines (130f) can be performed. 

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. 

Special spin-trapping techniques are also available for the detection of short-lived radicals in both homogeneous and heterogeneous systems. For instance, a-phenyl A-ferf-butyl nitrone (PBN), ferf-nitrosobutanc (f-NB), -(4-pyridyl A-oxidc) A-ferf-butyl nitrone (4-POBN), or 5,5-dimethyl-l-pyrroline A-oxidc (DMPO) can be made to react with catalytic intermediates to form stable paramagnetic adducts detectable by ESR [135], Radicals evolving into the gas phase can also be trapped directly by condensation or by using matrix isolation techniques [139],... 

In a study of the flash vacuum pyrolysis of chiral isopropylidene N-isopropyl-N-(a-methylbenzyl)aminomethylenemalonates, (/ )- and (S)-(1239), McNab and Monahan demonstrated the existence of another intermediate (1242) in the reaction pathway from the methyleneketene (1240) to the pyrrolinone (1243) [87CC138 88JCS(P 1)869]. Pyrolysis of the enantiomers (R) and (S) of compound 1239 resulted in the formation of an enantiomeric mixture of l-isopropyl-5-methyl-5-phenyl-2-pyrrolin-5-one (1243), where incomplete chirality loss was observed (see Scheme 50). 

This method for preparing 2-phenyl-1-pyrroline, and assorted 2-substituted 1-pyrrolines, is one of the best currently available, particularly because it reproducibly affords clean materials. Generally, the procedure is amenable to various aromatic esters 2 it has also been applied successfully to aliphatic esters (Table I).3 An advantage of this method is the use of readily available, inexpensive N-vinyl-pyrrolidin-2-one as a key starting material. This compound serves effectively as a 3-aminopropyl carbanion equivalent. The method illustrated in this procedure has been extended to include the synthesis of 2,3-disubstituted pyrrolines. Thus, alkylation of the enolate of the intermediate keto lactam, followed by hydrolysis, leads to various disubstituted pyrrolines in good yields (see Table II).3... 

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