Bicyclic pyrrolidines

Azaallyl anion cycloadditions. Imines bearing one or more aryl groups are converted by LDA into 2-azaallyl anions. These anions undergo cycloaddition not only with activated alkenes,2 but can also undergo intramolecular cycloaddition with a double bond to form as-fused bicyclic pyrrolidines.3... 

Deprotonation of t-amine oxides LDA (excess) converts trimethylamine oxide into a reactive ylide (a) that dimerizes to the dimethylpiperazine (2). If a is generated in the presence of an alkene, pyrrolidines (3) are formed via a 1,3-dipolar cycloaddition. The ylide reacts with cyclic alkenes to form bicyclic pyrrolidines in 40-90% yield.2... 

Unactivated dipolarophiles readily participate in intramolecular azomethine ylide cycloadditions with a more reactive azomethine ylide. Thus, flash vacuum pyrolysis of aziridine (113) afforded a 67% yield of the 5,5-fused bicyclic pyrrolidine (Scheme 34).59 A singly stabilized azomethine ylide was the apparent intermediate. Similarly, cyclization of the azomethine ylides derived from (114a-c) gave the corresponding cw-fused 6,6-bicyclic pyrrolidines in 69%, 26% and 16% yield, respectively the original double bond stereochemistry was retained in the latter two cases. 

Confalone and Earl have reported a series of intramolecular azomethine ylide cyclizations employing a-dithiolanyl aldehydes (Scheme 35).60 Thus, reaction of the aldehydes (115a-b) with ethyl sarcosinate at 140 C provided the 5,6-fused bicyclic pyrrolidines (116a-b), presumably via cyclization of the singly stabilized azomethine ylides. The dithiolanyl group could be removed by standard reactions this route then provides bicyclic pyrrolidines which cannot be prepared directly from enolizable aldehydes. 

The reduction of azetidin-2-one 302 containing a thioacetal moiety at C-4 to the corresponding acetal azetidine, followed by diethylaluminium chloride promoted C(2)-N(l) bond cleavage, afforded bicyclic pyrrolidines 303 and pyrroles 304 (Equation 98) <1999JOC9596, 1998TL467>. 

The fused 4/5/5 system has been obtained by ring closure forming the lactam ring on a bicyclic pyrrolidine (Equation 62) <1998JOC8170>. Michael addition to an unsaturated lactone was used to form the middle ring of compound 409 (Equation 63) <1999T3427>. 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

Pyrrolidines. Ethyl N,N-diallylcarbamates. when irradiated in the presence of CuOTf, undergo bicyclization to bicyclic pyrrolidines (equation 1). 

In 2001, Rai and co-workers (114) reported a silver-mediated aziridination of olefins in THF with Chloramine-T. In their case, aprotic solvents gave better yields versus protic solvents. Then, in 2003, Komatsu and co-workers (115) used similar conditions and found no reaction in THF (solvent) while they detected 70% conversion in CH2CI2. Silver nitrate (AgNOs) was required stoichiometrically in this transformation. Komatsu proposed a nitrene-radical mechanism based on the fact that the reaction shut down in the presence of oxygen. They designed a model reaction using 1,6-dienes, and as they expected, bicyclic pyrrolidines were isolated as products instead of aziridines. The role of silver in this reaction is not clear and most likely a free nitrene radical is released with the precipitation of silver(I) chloride (Fig. 18). 

In order to maximize yields and regioselectivity in the Friedlander synthesis of quinolines, the bicyclic pyrrolidine base l,3,3-trimethyl-6-azabicyclo[3.2.1]octane (TABO) was utilized to good effect. TTie reaction was carried out with unactivated methyl ketones <03JOC467>. The ratios of the two products were 86% 2-substituted and 14% 2,3-disubstituted. 

The efficient catalytic cyclization (aminocarbonylation) of A-(3-hydroxy-4-pentenyl)amides and carbamates in acetic acid gave m-fused bicyclic pyrrolidine lactone compounds54,56 (Table 2), in agreement with the observed ra-directing capability of the hydroxy group in analogous electrophile mediated additions (Section 7.2.6). In tetrahydrofuran the reaction rate is unacceptably low. In methanol a competitive allylic substitution leads to 1,2,5,6-tetrahydropyridines. Furthermore, lower yields were obtained in the cyclization of the corresponding ureas. 

When the related aziridine 195 was used containing one less carbon in the tether, an unusual cyclization occurred which corresponds to a formal [3+2] aziridine allylsilane cycloaddition to give the bicyclic pyrrolidine 196. This substrate was used for the preparation of other fused ring systems (Scheme 53) <1999T8025>. 

Fig. 20.16. Synthesis of highly substituted pyrrolidines on monodisperse Rapp Wang-PS resin (diameter 160 pm). Coupling of an Fmoc-protected amino acid onto the Wang resin (TBTU/HOBt, DMF, rt). a. cleavage of the protecting group (DMF/piperidine) b. formation of imines, addition of substituted ben-zaldehydes (THF/TMOF, 1/1, rt), cycloaddition to bicyclic pyrrolidines (toluene, 110°C) c. cleavage from the solid support (DCM/TFA 1/1)...

Reactions of enamine derivatives of auxiliary 1.64 [162, 252, 262] are often disappointing, except when R = CH20SiMe3 [162], However, the alkylation of enamines derived from 1.65 (R = Me) gives satisfactory results [253, 275], as do the Michael additions of enamines of bicyclic pyrrolidine 1.68 [294],... 

A strategy for the desymmetrization of cyclohexadienones via asymmetric aza-Michael reaction using cinchonine-derived thiourea 52 was developed by You s group (Scheme 11.33) [113]. A series of highly enantioenriched bicyclic pyrrolidine and morpholine derivatives were obtained in excellent yields and enantioselectivities. 

Reactivity was enhanced remarkably with the more electrophilic alkenyldichlorob-oranes [60]. Moreover, amination with azides gave the corresponding amines in good yields. With a halogen atom in the appropriate position, ring closure of intermediate (o-halogenoalkylamines can be realized by treatment with base to afford bicyclic pyrrolidines and piperidines with a trans jtmction (Scheme 9.27) [61]. 

The aza-Cope rearrangement of cyclopentane derivative 86 gives a bicyclic pyrrolidine 87 in which original ring is expanded by one carbon atom [63]. 

The reaction of the oxazolones 159 with the trifluoromethylated chloroalkenones 160 proceeded regioselectively via the intermediate bicyclic pyrrolidines 161,... 

The synthesis of bicyclic pyrrolidines has also been reported by the same group via the reaction of tethered iV-substituted cyclopentenyl amine with aryl bromide in the presence of the Pd2(dba)3 catalyst, phosphine ligand, and NaOf-Bu as the base (Scheme 40.6). " ... 

SCHEME 40.6. Synthesis of bicyclic pyrrolidine via carboamination reaction. 

Scheme 17.15 Bicyclic pyrrolidine catalysts and the corresponding enantiomeric excess computed using transition state modeling. The higher and lower ee s are indicated.

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