Pyrrolidine acylation

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

In their original communication on the alkylation and acylation of enamines, Stork et al. (3) had reported that the pyrrolidine enamine of cyclohexanone underwent monoacylation with acid chlorides. For example, the acylation with benzoyl chloride led to monobenzoylcyclohexanone. However, Hunig and Lendle (33) found that treatment of the morpholine enamine of cyclopentanone with 2 moles of propionyl chloride followed by acid hydrolysis gave the enol ester (56), which was proposed to have arisen from the intermediate (55). 

Hunig and Salzwedel (20) report that the acylation of the pyrrolidine enamine of 3-methylcyclohexanone with propionylchloride followed by the hydrolysis and the base cleavage of the resulting dione isomers (71) and (72) and subsequent reduction of the keto groups gave a 3 7 mixture of the carboxylic acids (73 and 74), respectively. Vig et al. (39), however, found o o o o... 

Lochte and Pitman (44) have reported the cyanoethylation of the pyrrolidine enamine of 3-methylcycIopentanone (84), the product being a mixture of C-2 and C-5 cyanoethylated ketones (85 and 86). Hunig and Salzwedel 20) have obtained a mixture of C2- and C5-acylated products from the reaction of morpholine enamine of 3-methylcyclopentanone with propionyl chloride. 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

The reaction of ketene with the enamine (113) is reported (88) to give l-morpholino-2-acetyl-l-cyclohexene i.e., the enamino ketone expected from acylation of (113). The pyrrolidine enamine (28), however, has been shown to react (73) with excess ketene to give the a-pyrone (124). On the... 

Acylation of the vinylogous pyrrolidine amide of dimedone with acetic anhydride or acetyl chloride led (possibly indirectly) to the carbon acylation product, whereas trichloroacetyl chloride gave rise to products derived from attack of chloride at the oxygenated double bond position in an initial 0-acylation product (401-404). 

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. ... 

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117) acylation with propionic anhydride gives the analgesic agent prolidine (118)... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

The preferred TS is a chair with the enolate oriented syn to the bulky pyrrolidine substituent. It was suggested that the syn acylation occurs through an envelope conformation of the pyrrolidine ring with the nitrogen electron pair oriented axially. 

Alkylation of piperazine with the amide formed by reaction of chloroacetyl chloride with pyrrolidine gives amide 133. Acylation with 3,4,5-trimethoxy-... 

More recently, Kaiser and coworkers reported enantiomeric specificity in the reaction of cyclohexaamylose with 3-carboxy-2,2,5,5-tetramethyl-pyrrolidin-l-oxy m-nitrophenyl ester (1), a spin label useful for identifying enzyme-substrate interactions (Flohr et al., 1971). In this case, the catalytic mechanism is identical to the scheme derived for the reactions of the cycloamyloses with phenyl acetates. In fact, the covalent intermediate, an acyl-cyclohexaamylose, was isolated. Maximal rate constants for appearance of m-nitrophenol at pH 8.62 (fc2), rate constants for hydrolysis of the covalent intermediate (fc3), and substrate binding constants (Kd) for the two enantiomers are presented in Table VIII. Significantly, specificity appears in the rates of acylation (fc2) rather than in either the strength of binding or the rate of deacylation. 

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. 

The structure of hypercratine was deduced from spectroscopic data, including 200 MHz H NMR and I3C NMR. The mass spectrum of the acylated derivative of 28 was dominated by fragments at m/z 70 and 112, explained by an a cleavage of the pyrrolidine ring. The complexity of the NMR spectra and the distance between the C-2 and C-2 stereo centers have not permitted establishing the configuration of these centers. The nature of the substituents on atoms C-6 or C-7 remains yet to be settled [alternative structures 28 and 28 ]. 

Tetraphenyl-2-aza-21-carbaporphyrin 220 was reacted with various acyl chlorides and excess triethylamine in refluxing dry benzene, and unexpected pyrrolidin-2-one-fused N-confused calix[4]phyrins 221 were isolated in 60-70% yield (Scheme 54) <20060L1137>. 

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