Pyrrolidines intramolecular cyclization

Ammonia treatment removes the TFA group, which then releases the phosphate and pyrrolidine through intramolecular cyclization. The analogous pentyl derivative was also prepared. ... 

The reaction can be done intramolecularly. N-Benzyl pent-4-ynamide reacted with tetrabutylammonium fluoride to an alkylidene lactam. Similar addition of a tosylamide-alkene, with a palladium catalyst, led to a vinyl Al-tosyl pyrrolidine. Similar cyclization reactions occur with tosylamide-alkynes. ... 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Some A -enecarboxylic acids undergo a rapid intramolecular cyclization reaction of the 5-exo-trig type prior to the radical coupling step. Substituted tetrahydro-furans [95] and pyrrolidines [96] can be prepared by this Kolbe route. It is preferable to protect the amine function in the pyrrolidine synthesis by N-formy ation in... 

In a similar manner, intramolecular cyclization of the O-stannyl ketyl derivatives 201 and 206, generated from the oxazolyl aldehydes 200 and 205, provides a facile method for the chiral synthesis of 3-hydroxy-2-(hydroxymethyl)-5-substimted-pyrrolidines 202 and 203 and the piperidine analogues 207 and 208 that can be successfully transformed into naturally occurring amino alcohols, (+)-bulgecinine 204 and (—)-desoxoprosopinine 209, respectively (Fig. 

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. 

Formation of five-membered heterocycles through radical methodologies has been investigated extensively. Inter-, intramolecular, and cascade reactions have been reported for the synthesis of heterocycles. In the case of intramolecular cyclizations, 5-exo pathway is the preferred mode of reactivity. Rate constant for the formation of pyrrolidine by radical ring closure has been reported [95AJC2047],... 

An intramolecular cyclization of vinylsilanes with acyl amines yields substituted piperidines (Equation 31) <2003SL143>. Pyrrolidines are produced as by-products and the ratio of formation was dependent on the acid used, and the time and temperature. 

Condensation of l-(3,6-dihydropyran-4-yl)pyrrolidine with l,4-diacetoxy-2-butanone affords l-(isochroman-6-yl)pyr-rolidine in moderate yield. The reaction proceeds via intramolecular cyclization and elimination of pyrrolidine from the zwitterion 618 to form the ketones 619 and 620, which yield the desired isochroman upon aromatization (Scheme 133) <20000L1773>. 

The asymmetric approaches leading to the construction of enantiomerically pure 9-azabicy-clo[4.2. IJnonane skeleton are mostly concerned with the intramolecular cyclization of a pyrrolidine iminium ion (46). They differ significantly in the preparation of cA-substituted pyrrolidine (45) precursors and in overall yield for the construction of this basic skeleton. See Fig. 7.2. 

Substituted piperidines are obtained by an intramolecular cyclization of vinylsilanes with acyl amines <03SL143>. Ratio of piperidine to pyrrolidine products depends on the acid used, time and temperature. The silyl group is easily converted to a hydroxyl group. 

Starting from 1-substituted 4-alkenylamines, pyrrolidines are directly obtained by intramolecular cyclization mediated by phenylselenenyl chloride or TV-phenylselenophthalimidc71,72. Treatment with phenylselenenyl chloride in dichloromethane at — 70 °C in the presence of trifluo-roacetic acid and silica gel, afforded 2,5-disubstituted pyrrolidines 1 in moderate yield through... 

A third procedure for building aza-steroidal systems proceeds by intramolecular cyclization of enamine esters derived from jS-tetralones and appropriately substituted pyrrolidines. This reaction is illustrated in the synthesis of the 14-aza-steroid (162) by reaction of the j -tetralone (160) with a 3-substituted pyrrolidine ester. 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

Another strategy for the formation of /V-acyliminium ions as substrates for 2-aza-Cope rearrangements consists of the intramolecular cyclization of carboxylic amides of type 17. The Cope products are cyclized to afford substituted pyrrolidines, e.g., 20 and 21964. 

Synthesis from o-isoascorbic acid Syntheses of 2 and its antipode 37 from the commercially available D-isoascorbic acid have been reported by conversion to the enantiomerically pure acetonide lactone 29 on a large scale in 75% yield (Scheme 5). Lactone 29 was treated with amino vinylsilane 30 to give the amide 31 in 82% yield, which was used in two different ways. Mitsunobu conditions were not successful to convert 31 to 32. However, the conversion has been achieved in 88% yield by mesylation and then subjection to intramolecular cyclization. Treatment of 32 with Lawesson s reagent afforded the respective thioamide, which was treated with BFj OEtj followed by direct reduction with LiBEtjH to provide the 2-(ethylthio)pyrrolidine 35. Cyclization of 35 afforded the single stereoisomeric tetrahydroindolizine 36. Catalytic hydrogenation of 36 followed by deprotection provided 2-cp/-lentiginosine (2). 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

Dieter and coworkers reported an enantioselective total synthesis of (R)-pyrrolam (48), which involved an intramolecular cyclization of a y-aminoester as a key step (2002JOC847,2004JOC6105 Scheme 8). Enantioselective metaUation of a Boc-pyrrolidine (78) mediated by (—)-sparteine, followed by transmetaUation to the cuprate, and cross-coupling with (Z)-3-iodopropenoate (79) gives the corresponding y-aminoester (80). The best conditions for the subsequent deprotection/cyclization to (R)-pyr-rolam (48) involve trimethylsilyl chloride and phenol. 

In 2004, Wolfe et al. used a carboamination reaction for the first time for the stereoselective synthesis of substituted pyrrolidine derivatives via a Pd-catalyzed intermolecular iV-arylation followed by intramolecular cyclization reaction sequences. The reaction proceeds via an innersphere mechanism with the formation of the Pd(Ar)(NRR ) complex. In this reaction, a -(A-arylamino) alkene was treated with an aryl or heteroaryl bromide in the presence of NaO Bu as the base and Pd catalyst the corresponding 2,3- or 2,5-disubstituted pyrrolidine derivatives (Scheme 40.4) were obtained in good yields and excellent diastereoselectivity. ... 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

Intramolecular inverse electron-demand Diels-Alder reaction of iV-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170 °C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series. 

New cyclizations via photochemically generated aminyl radicals have been reported, including further examples of the Hofmann-Loeffler-Freytag reaction.313 Intramolecular addition of an aminyl radical, generated by photochemically induced nitrogen chlorine bond homoysis, is also accompanied by cyclization as illustrated by the conversion of the unsaturated N-chloroamide 378 to the pyrrolidine 379.314 Piperidine formation can also... 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

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