Propargylamines, formation

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

The possible mechanisms of inhibition of flavin by (—)-deprenyl, as an irreversible acetylenic inhibitor, were studied by ab initio methods with the 6-31G basis set using simplified model compounds, 3-formyl-2-imino-l-hydroxypyrazine, and propargylamine. The formation of two energetically stable cyclic adducts, the 0,N adduct 286 and a C,N adduct, was shown <1999THA147>. 

The same type of bis-functionalization has been reported for the palladium-catalyzed borylstannylative carbocy-cyclization of 1,6-, 1,5-, 1,7-diynes, bis-propargylamine, and ether.377 It should be noted that even 1,2-dialkylidene cyclobutane can be obtained in reasonable yield. Ito has proposed the related silaborative reaction involving nickel(O) catalysis.378 This reaction has been performed in an intra- and intermolecular fashion. The intramolecular reaction allows the formation of cyclic dienes and the intermolecular process proceeds through a dimerization of alkynes to give acyclic dienes. 

The transition metal catalysed formation of five membered heterocycles through the insertion of a triple bond has also been explored. o-Halophenyl-alkynylamines, propargylamines and propargyl-ethers have been subjected to ring closure reactions. These processes, however also require the presence of a second, anionic reagent, which converts the palladium complex formed in the insertion step to the product. 

Pyrroles and fiirans were prepared by the intramolecular carbon-carbon bond formation between pendant acetylene and nitrile or carbonyl functions. The process, running in acetic acid, starts by the fraw-acetoxypalladation of the acetylene moiety, which initiates a series of further transformations. The nature of the ring formed is determined by heteroatom bridging the two reactive units. The propargylamine derivative in 3.88., for example gave a pyrrole ring.112... 

The reactions of propargylamines with carbon dioxide have been systematically examined in the presence of transition metals Pd(OAc)2 was the best catalyst for the formation of the corresponding oxazolidinone 212 <02JOC16>. 

Vinyl propargylamines work also very well (72-73) 120 -122) provided the longest straight chain has no more than five carbon atoms or it is sufficienlly ramified as to preclude the formation of aminohexatrienes. 

Even formation of an acetyhde which adds to ketones and aldehydes can be promoted by a catalytic amount of cesium hydroxide (Scheme 2.36). Propargylamine, which has an acidic proton, is deprotonated elFiciently to form an acetylide. This adds to aldehydes in good yield without forming an imine (Scheme 2.37) [52]. 

Diastereoselective carbon-carbon bond formation at the a-position to the amine nitrogen may be accomplished as shown in Scheme 37. Propargylamine is converted into the silylated amidine, which is metallated with n-butyllithium. After alkylation, the metallation and alkylation are repeated with a second alkyl halide to obtain the fully alkylated derivative. Thus, optically active a-substituted propargy-lamines and amino acids are obtained by hydrolysis of the amidine function and oxidative cleavage.- ... 

One class of mechanism-based MAO inhibitors includes the unsaturated alkylamines (propargylamine analogs) (Table II). Although the kinetics of enzyme inactivation for these compounds are consistent with a mechanism-based inhibitor, in only a few cases has the chemical mechanism and site of protein modification been determined. Pargyline (iV-benzyl-N-methyl-2-propynylamine) is a classic example. Pargyline reacts stoichiometrically and irreversibly with the MAO of bovine kidney, with protection from inactivation afforded by substrate benzylamine (91). Furthermore, the reaction involves bleaching of the FAD cofactor at 455 nm and the formation of a new absorbing species at 410 nm and a covalent adduct of inactivator with flavin cofactor (92). 

Information in support of this hypothesis has been obtained in detailed studies on the inactivation kinetics and mechanism of pig and beef liver MAO-A by A -cyclopropyl-A-arylalkylamines. The structures and some kinetic properties of this second group of MAO inhibitors are summarized in Table III. The inactivation characteristics of the A/-cyclopropylamines are generally similar to those of the propargylamines (1) time-dependent, first-order loss of enzyme activity, saturation kinetics, and protection from inactivation by substrate or product (2) pH-dependent rate of inactivation corresponding to the pH dependence of enzyme activity (3) little activity recovery after exhaustive dialysis (4) partitioning between normal product formation and inactivation and (5) time-dependent conversion of the covalently bound FAD cofactor from the oxidized to a reduced form, which is fairly resistant to reoxidation. An important differ-... 

Selegiline and rasagiline are propargylamine-type selective inhibitors of MAO-B, which inactivates dopamine in the brain. The MAO-B inhibitors extend the duration of response to levodopa by reducing metabolism of dopamine thus, the dose of levodopa can be reduced without loss of therapeutic benefit (3). It has been proposed that MAO-B inhibitors may prevent formation of neurotoxic oxidation products of dopamine and slow neurodegeneration in Parkinson s disease however, data from recent clinical studies do not support this attractive neuroprotective hypothesis (54,55). Nevertheless, MAO-B inhibitors have a beneficial effect on motor fluctuations because of their levodopa-sparing effect (56). 

Recently, well-defined AB2 dual (temperature and pH) sensitive miktoarm star copolymers of (PNIPAm)-(PLL)2 were synthesized through the combination of ATRP, ROP and click chemistry. " Propargylamine was used to initiate ROP of ZLL-NCA for the preparation of all nyl-terminated polypeptide. The use of a diazide-functional ATRP initiator afforded PNIPAm with two azide groups at the chain end. The subsequent click reaction led to the formation of a (PNIPAm)-(PZLL)2 star. The final double hydrophilic structure was obtained after deprotection of the polypeptide arms. 

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