Pyrrolidine amides, 2- addition reactions

Asymmetric Michael addition reaction represents one of the most extensively explored organoctalytic transformations. Chiral secondary amines such as pyrrolidines have been proved to very effective catalysts for the reactions of Michael donors such as cyclohexanone and aldehydes [31]. Ala-Ala dipeptide 57 [32] was firstly found to be viable catalyst for the reaction of cyclohexanone and nitrosty-rene. Later, some primary amine-amide type catalysts such as 55 [33a], 56 [33b-c] and 58 [33d] have also been indentilied for the same reactions (Scheme 5.16) with slightly lower activity compared with typical chiral pyrrolidine catalysis. 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

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. 

Rapopoit found that 5-(2-pyridyl) thioates such as (28) did not function as selective acylating agents, and substantial amounts of tertiary alcohol were formed through overaddition (equation 16). Presumably, the tetrahedral intermediate, derived from nucleophilic addition to the S-(2-pyridyl) thioate, was not a stable entity in the reaction mixture. As will be discussed shortly, the lability of these intermediates had been recognized previously. The novel dimethylpyrazolide moiety of substrate (29) also did not confer any additional stability to the tetrahedral intermediate and tertiary alcohol was the major product (equation 16). Tertiary amides, such as those derived from pyrrolidine or dimethylamine, were reactive towards lithium adkynides in the presence of BF3, but analysis of the product indicated that it had undergone substantial racemization. ... 

An intramolecular carbenoid addition onto a carbon-carbon double bond provides a possible synthetic route to the pyrrolidine ring. The rho-dium(II) acetate-catalyzed reaction of diazo amide 106 leads to a mixture of diastereomers 107 and 108 (6 1) in 43% yield (88TL1181). The decomposition of AjA-diallyl-a-diazoacetamide catalyzed by Rh2(55-MEPY)4 forms product 109 from an enantioselective intramolecular cyclopropanation (50% yield, 72% e.e.) (94T1665). Spiro-fused ring systems were produced by this route from quinonediazides 110 and 111 under irradiation (83TL4773 86TL2687). 

The products are versatile auxiliaries not only for enantioselective deprotonation and elimination (Section C.), but are also valuable chiral ligands for complex hydrides in the enantioselective reduction of ketones (Section D.1.4.5.)- They are also applied in enolate reactions (Section D.l.5.2.1., D.1.5.2.4.). transition-metal-catalyzed Michael additions (Section D.l.5.8.), 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), and additions ofGrignard reagents (Section D.l.3.1.4.2.5.). (5 )-2-(Phenylaminomethyl)pyrrolidine has found most application and is also commercially available. Several methods exist for the preparation of such compounds. Two typical procedures for the synthesis of (.S)-2-(l-pyrrolidinylmcthyl)pyrrolidine are presented here. The methodology can be readily extended to other amides and alkylamino derivatives of proline. 

---