Pyrrolidine-based amines

Pyrrolidine-based thrombine inhibitors are prepared by condensation of the ylid derived from /V-benzyl-iV-(methoxymethyl)trimethylsilyl methyl amine, with methyl m-trifluoromethyl cinnamate.420... 

After converting A -Phth-protected amines into the corresponding 2-(pyrrolidinocarbon-yl)benzamide derivative, Dieckmann reactions, ester hydrolysis, and transesterfication can be carried out. This strategy of pyrrolidine-based deactivation of phthaloyl-protected anoines followed by reclosure of the phthaloyl group has successfully been applied in the synthesis of (3-lactam antibiotics.P l... 

Secondary amine encoding method was used in the synthesis of a library of pyrrolidine-based inhibitors of angiotensin converting enzyme (ACE) via 2 + 3 cycloaddition [29]. 

Figure 2.6 Some chiral pyrrolidine-based amines employed as catalysts in the enantioselective Michael addition of aldehydes to nitroalkenes.

In 2001, Yamamoto prepared various chiral diamines (pyrrolidine based secondary and tertiary amines) " and screened a range of protic acids to catalyse the aldol reaction. Catalyst la TfOH, had no catalytic activity alone. However, the combination of diamine la and la TfOH catalysed the aldol reaction of ketones with p-nitrobenzaldehyde. The aldol products were obtained with high chemical yields and reasonable to high enantio- and diastereoselectivities (Scheme 9.1). ... 

Alexakis et al. proposed in 2010 the use of aminals deriving from 4-hydroxyproline for the asymmetric addition of aliphatic aldehydes to vinyl sulfones." " The idea that a fluorine atom at the C4 position of these pyrrolidine-based organocatalysts could be used to favour one single reactive enamine conformation was further exploited by the same authors in 2011, designing a catalyst (28) able to afford excellent yields and enantioselec-tivities (Scheme 11.24). ... 

Doddi and Vankar have described efficient syntheses of two pyrrolidine-based imino sugars, 431 and 432, beginning from the MBH adduct of (R)-2, 3-0-isopropylideneglyceraldehydes. The key steps included regiospecific amination via successive S n2 --S n2 displacement reactions), RCM and diastereospecific dihydroxylations (Scheme 3.192). These azasugars were reported to be moderate inhibitors of glycosidase. ... 

Enders et al. developed an asymmetric synthesis of polyfiinctionalized pyrrolidines based on Mannich-Michael cascade strategy (Scheme 2.42). Under the promotion of 10mol% thiourea catalyst 140b, y-malonate-substituted a,P-unsaturated esters 149 and N-protected aryl aldimines 148 underwent Mannich reaction to afford chiral amine intermediates, which then underwent an intramolecular aza-Michael reaction to yield pyrrolidine derivatives 150 with moderate to good enantioselectivities [60]. 

Gartner M, Weihofen R, Helmchen G. Enantioselective syntheses of 2,5-disubstituted pyrrolidines based on iridium-catalyzed allylic aminations-total syntheses of alkaloids from amphibian skins. Chem. Eur. J. 2011 17(27) 7605-7622. 

Pyrrolidine-based catalysts possessing a tertiary amine functionality were usually employed in the presence of an acid additive. Protonation of the tertiary nitrogen atom can furnish the H-bond donor (Figure 24.24a). Pyrrolidine-based catalyst 56... 

Pseudo-first-order rate constants (k bs) for the nucleophilic cleavage of phthalim-ide in the presence of buffer solutions of pyrrolidine follow Eqnation 7.52." These observed data may be explained by a brief reaction mechanism as shown by Scheme 7.8, in which SH and S represent respective nonionized and ionized phthalimide and Am represents a secondary amine in base form. 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

Experiments designed to clarify the situation were carried out by Wittig and Mayer (40). It was shown that changing the molar ratio of amine (diethylamine, di- -butylamine, or diisobutylamine) to -butyraldehyde from 1 1 to 2 1 did not affect the yield of enamine (53- 64%, based on the aldehyde). Contrariwise, changing the ratio of amine (morpholine, piperidine, or pyrrolidine) to n-butyraldehyde from 1 1 to 2 1 boosted the yields from 52-57 % to 80-85 %. The authors interpret these data as indicating that the cyclic amines form aminals with n-butyraldehyde, while the open-chain do not. Infrared evidence is stated as having shown that the aminal originates not from attack of excess amine on the enamine, which is stable under the conditions of the reaction, but from the N-hemiacetal (17). 

The only kinetic data reported are in a Ph.D. thesis (41). Integral order kinetics were usually not obtained for the reaction of a number of ketones with piperidine and a number of secondary amines with cyclohexanone. A few of the combinations studied (cyclopentanone plus piperidine, pyrrolidine, and 4-methylpiperidine, and N-methylpiperazine plus cyclohexanone) gave reactions which were close to first-order in each reactant. Relative rates were based on the time at which a 50% yield of water was evolved. For the cyclohexanone-piperidine system the half-time (txn) for the 3 1 ratio was 124 min and for the 1 3 ratio 121 min. It appears that an... 

Isomerization of the epoxide (IV) with pyrrolidine was carried out as described by Sih (8) and consistently gave yields of 35-60% rather than the 73% reported. Changes in experimental conditions including longer reaction times at lower temperatures, use of freshly distilled pyrrolidine, use of NaOH dried pyrrolidine, and use of distilled epoxide (IV) had little effect on the yield. The only variation that improved the yield was to allow the reaction to proceed at ambient temperature for a longer period of time than the recommended 3 hours. Allowing the reaction to proceed for 40 hours provided a maximum 67.5% yield. Other bases such as sodium carbonate, tri ethyl amine, diethylamine l,5-diazabicyclo[4.3.0]non-5-ene(DBN), and sodium methoxide all gave lower yields of distilled product than pyrrolidine. It is important to use the hydroxyaldehyde (V) as soon as possible since it is a very unstable material. 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

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