Propargylamine compounds

Monoamine Oxidases and their Inhibitors. Figure 2 Structures of MAO inhibitors. In the top row, the structural similarity between selegiline/L-deprenyl and methamphetamine is shown. Below are the aminoindan series of propargylamine compounds such as rasagiline. Next, the bifunctional MAO and cholinesterase inhibitors (ladostigil) and lastly, the iron chelator-MAO inhibitors. 

Using propargyl alcohols and propargylamine derivatives as acetylenic compounds, the silylformylation reaction affords, in the presence of a base, a-silylmethylene-P-lactones, I, and P-lactams, II, respectively (Scheme 3) [13]. 

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>. 

Figure 17.10 Propargylamine can be used to add an alkyne group to amine-reactive reagents, such as the NHS ester group on the biotin-PEGj compound.

The silylated tin compound 199, obtained from tributyltin hydride and N-bis(trimethylsilyl)propargylamine (198) in the presence of a trace of AIBN (2,2/-azobisisobutyronitrile), is a versatile reagent for the preparation of allylic amines. Treatment with aryl bromides ArBr (Ar = Ph, 4-MeOCgH4, 4-O2NC6H4 etc.) under Pd(PPh3)4 catalysis yields the silylated amines 200, which are hydrolysed by acids to the free amines 201. 199 is converted into the lithium compound 202, which is transformed into 203 by aqueous ammonium chloride and into 204 by the action of alkyl halides RX (R = Me, Et or allyl) (equation 76)204. 

An alternative route to tertiary allyl- and propargylamines 145 and 146 is the reaction of Grignard compounds with iminium triflates 147 and 148 (equations 77 and 78). The intermediate iminium triflates 147 and 148 are obtained from the corresponding ami-nals by reaction with Tf20. Primary propargylamines can be prepared from tetraallylated aminals °. 

Van der Eycken and co-workers [179] have reported a microwave-assisted A -MCR of an aniline, an alkyne and biaryl aldehyde to generate a small library of propargylamines 126 using CuBr as the catalyst. The resulting compounds 126 were isolated in good to excellent yields except when n-butylamine was used as amine counterpart and were further converted into Steganacin aza-analogs (Scheme 98). 

Copper complexes of chiral Pybox (pyridine-2,6-bis(oxazoline))-type ligands have been found to catalyze the enantioselective alkynylation of imines [26]. Moreover, the resultant optically active propargylamines are important intermediates for the synthesis of a variety of nitrogen compounds [27], as well as being a common structural feature of many biologically active compounds and natural products. Portnoy prepared PS-supported chiral Pybox-copper complex 35 via a five-step solid-phase synthetic sequence [28]. Cu(l) complexes of the polymeric Pybox ligands were then used as catalysts for the asymmetric addition of phenylacetylene to imine 36, as shown in Scheme 3.11. tBu-Pybox gave the best enantioselectivity of 83% ee in the synthesis of 37. 

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). 

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