Functionalized pyrrolidines

An auxiliary controlled enantioselective route to generate seven-membered ring lactams 75 used the a-alkylation of cyclic hydrazide derivatives 74. Initially, 6-chloro hydrazides 73,bearing the chiral information in the M-amino-pyrrolidine function underwent amidocyclization in the presence of a base. A subse-... 

We reported the first example of such a compound, porphyrin-fullerene dyad 23, in 1994 [134, 135]. Since that paper, a number of examples of dyads consisting of fullerenes linked to porphyrins or phthalocyanines have been prepared [136, 137-159]. Some of these, such as 24, use amide linkages related to those employed in some porphyrin-quinone systems [137, 149, 152]. In dyad 25, the moieties are linked by an extended, rigid bridge, of the type that has been shown to facilitate rapid long-range electron transfer in other systems [146, 147]. A number of dyads feature pyrrolidine-functionalized fullerenes, as in 26 and 27 [90, 139, 145, 148]. 

Recently, Zhao et al. reported the use of 2-trimethylsilanyloxy-methyl-pyrrolidine functionalized chiral dendrimer catalysts (Figure 4.20) for catalytic enantio- and diastereoselective Michael addition of aldehydes to nitrostyrenes (Scheme 4.15)... 

Scheme 1.15 Pyrrolidine functionalization via Rh carbenoid mediated C—H bond insertion reported by Davies.

The synthesis of a bis-fullerene material 3, where two pyrrolidine functionalized carbon spheres are bridged together via a rigid TPhA unit was achieved in one step [146]. The reaction conditions followed were important in order to obtain bis-fullerene material 3 in good yield. Such optimized reaction parametres include the utility of (i) excess C60, (ii) small reaction volume and (iii) short reaction time. 

Pyrrolidine-functionalized IL covalently attached onto the surface of silica gel is an active catalyst for the asymmetric Michael addition to nitrostyrene. Scheme 2.27 [117]. Normally, >90% yields to the Michael addition products with >90% ee can be obtained when using cyclohexanone as nucleophile. The ee value was <50% when other ketones were used. In addition, the ee value was maintained at 98% when the catalyst was reused at the sixth run but the yield decreased slowly from 91% to 85%. 

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). 

Vinylogous amides, which have an enamine function in conjugation with a carbonyl group, constitute tridentate systems and thus open the possibility of alkylation on carbon, nitrogen, or oxygen. It has been found that the pyrrolidine enamine of acetylacetone gives rise to a carbon mcthylation but an oxygen ethylation product 41). The alkylation of cyclic 1,3-diketone-derived enamines has been studied 41,283). O Alkylation was found in alcohol solvents and predominant C alkylation in nonprotonic solvents. 

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

A,A-Diacetyl-2-trifluoromethylaniline, organic solvents, 3-24 h, rt or reflux, 54-99% yield. Acylation selectivity is a very sensitive function of steric effects this reagent selectively acylates pyrrolidine over piperidine (15 1). It is more selective than the diacetylaminoquinazolinones. ... 

In conclusion, the Hofmann-Loffler-Freytag reaction tends to give moderate and sometimes poor yields for the preparation pyrrolidines under the classic conditions. Nonetheless, the utility of this reaction to functionalize molecules via the aminyl radical mechanism plays an unique role in the tool box for the organic chemist, enabling transformations not easily achievable using other means. Furthermore, milder conditions and better yields can be achieved by taking advantages of the newer developments such as the Suarez modification. 

Synthesis of the densely functionalized heterocyclic system of antitumor antibiotics azinomycins AandB, azirino [l,2-<2]pyrrolidine derivatives 98SL1031. 

The (TMS)3Si radical addition to terminal alkenes or alkynes, followed by radical cyclization to oxime ethers, were also studied (Reaction 50). The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process. Yields of 79 and 63% are obtained for oxime ethers connected with an olefin or propargyl group, respectively. 

A common feature of the reactions in this section is that they serve to introduce functionality at a position remote from functional groups already present. As such, they have proved very useful in synthesizing many compounds, especially in the steroid field (see also 19-2 and 19-14). When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines or piperidines are formed, in a reaction known as the Hofmann-Loffier reaction... 

Michael additions of secondary allylamines to nitroalkenes followed by treatment with Me3SiCl and Et3N afford highly functionalized pyrrolidines via the stereoselective ISOC reaction (Eq. 8.86).137... 

Pyrrolidines are structural subunits found in many natural and unnatural products, which have important biological activity.102 Depending on the substitution pattern and functionalization, pyrrolidines have been shown to be effective antibacterials,103 neuroexcitatory agents,104 potent venom,105 and glyosidase inhibitors.106... 

In addition, the use of appropriate hydrophilic constituents on the aldehyde or glycine reactants can result in excellent water solubility of the (To derivative. Two such modification arms can be added simultaneously to the pyrrolidine ring, thus providing a functional group for further conjugation and a hydrophilic arm for increased water solubility. PEG derivatives have been formed in this manner, which create highly soluble fullerene derivatives. 

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