Ioannis N. Houpis

Amination of aryl halides using copper catalysis

Bromopyridine 4 was converted into aminopyridine 5 under Cu2O catalysis with an ethylene glycol solution of ammonia in excellent yield (90%). The amination reaction features low (0.5 mol%) catalyst loading, mild reaction temperature (80°C) and low reaction pressure (50 psi). This protocol is further studied in the amination of a variety of aryl halides.

Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677

Abstract The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.

Synthesis of functionalized furo[2,3-b]pyridines via the Pd-catalyzed coupling of acetylenes to iodopyridones. Preparation of a key intermediate to a new HIV protease inhibitor L-754,394

Abstract The synthesis of 1 was accomplished in 55% overall yield via the Pd-catalyzed coupling of 3 and 4 followed by Cu-catalyzed cyclization of the resulting intermediate 2.

A practical synthesis of the 5-chloromethyl-furo[2,3-b]pyridine pharmacophore

Synthesis of the furopyridine 2 was accomplished in 52% overall yield from 6-hydroxynicotinic acid (3). The synthesis is highighted by a Heck coupling of 5 with ethylene followed by an NCS mediated oxidative cyclization and elimination sequence.

Ni-catalyzed nucleophilic conjugate additions of Grignard and organozincate reagents to substituted 4-vinylpyridines. General synthesis of phosphodiesterase IV inhibitors

Abstract Alkyl, aryl, and vinyl Grignard reagents were added to olefin II under Ni(acac) 2 or Cl 2 Ni(PPh 3 ) 2 catalysis to give products with the general formula I in 74–95% yield. Organozincates gave similar results with Ni(acac) 2 as the catalyst.

Nickel catalyzed addition of organozincates to optically pure vinylic sulfoxides. Synthesis of the phosphodiesterase IV inhibitor L-765,527 (CDP-840)

Abstract Ph3ZnMgCl was added to the optically pure sulfoxide 3 in the presence of Ni(acac)2 to give, after desulfurization, the phosphodiesterase IV inhibitor 1 in good yield and 92% enantiomeric excess.

Towards the synthesis of HIV-protease inhibitors. Synthesis optically pure 3-carboxyl-decahydroisoquinolines.

Abstract The synthesis of optically pure decahydroisoquinoline 1 , a component of HIV-protease inhibitors, was accomplished in 30–33% overall yield from the readily available optically pure monoacid 4 .

In situ NMR spectroscopic studies of aniline ortho acylation (“sugasawa reaction”): The nature of reaction intermediates and Lewis acid influence on yield

Abstract Ortho acylation of anilines by nitriles in the presence of BCl 3 and a second Lewis acid appear to proceed through an intermediate “supercomplex” including all four components. Yield improvements were obtained based on recognition that chloride affinity of the second Lewis acid governs supercomplex formation. Aniline protonation was found to be the cause of incomplete reaction.

Palladium(II)-catalyzed coupling of 2-carboxyethyl enol triflates with organostannanes.

Abstract Enol triflates 1–5 , derived from the corresponding dicarbonyl compound, were coupled with tin reagents 6–8 using Pd(OAc) 2 and PPh 3 as the catalyst, at 7 mole %, in 56–91% yield.

Synthesis of a new generation reverse transcriptase inhibitor via the BCl3/GaCl3-induced condensation of anilines with nitriles (sugasawa reaction)

Abstract The synthesis of 1 was achieved in high overall yield through a mechanism-based improvement of the preparation of o-acyl anilines.