Jones Limberger

Recent Progress in the Use of Pd-Catalyzed C-C Cross-Coupling Reactions in the Synthesis of Pharmaceutical Compounds

The impressive ability of palladium to assemble C-C bonds between appropriately functionalized substrates has allowed synthetic organic chemists to perform transformations that were previously impossible or only possible using multi-step approaches. In this context, one of the most important and elegant applications of the Pd-catalyzed C-C coupling reactions currently is the synthesis of pharmaceuticals. This review is intended to give a picture of the applications of Pd-catalyzed C-C cross-coupling reactions for the synthesis of drug components or drug candidates regardless of the scale from 2011 through to the end of July, 2014.

Pd-catalyzed Heck reactions of aryl bromides with 1,2-diarylethenes

A catalytic system composed of Pd(OAc)2 and P(o-tol)3 was found to be effective for the Heck reaction of aryl bromides with diarylethylenes. Using K2CO3 as a base and DMF as a solvent, trisubstituted olefins were obtained in good to excellent yields. Aryl bromides containing an electron-withdrawing group in para position were less reactive for the Heck coupling reaction and gave substantial amount of homocoupling by-product suggesting that oxidative addition is not the rate-determining step. Electron withdrawing group substituent in the para position of stilbene affects the regioselectivity of the reaction. In this case, the phenyl group from the Ph-Pd complex migrates preferentially to the same carbon of the double bond to which the phenyl is bonded. Finally, a one pot sequential double Heck arylation of styrene was performed, giving trisubstituted olefin with an overall yield of 73%.

Synthesis of limonene β-amino alcohol derivatives in support of new antileishmanial therapies

A series of seven limonene beta-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene beta-amino alcohol derivatives.

Stereoselective synthesis of (E)-3,3-diaryl and (E)-3-aryl-3-aryloxy allylamines and allylalcohols from trans-cinnamyl chloride and alcohol

In this work we describe the regio and stereoselective synthesis of (E)-3,3-diaryl and (E)-3-aryl-3-aryloxy allylamines and allylalcohols. The starting materials are the non-expensive commercially available cinnamyl alcohol and chloride. The bromination/dehydrobromination sequence furnished the (E)-3-bromo-3-phenylallyl amines and alcohol as single regioisomers and with high stereoselectivity (>98%). These vinyl bromides were used as substrates in cross-coupling reactions furnishing the arylated products with good to excellent yields and total E-configuration retention. With this protocol, we were able to produce regio and stereospecifically trisubstituted olefins and vinyl ethers by Suzuki cross-coupling and Ullmann vinylation.

Synthesis, Photophysical and Electrochemical Properties of Novel D-π-D and D-π-A Triphenylamino-Chalcones and β-Arylchalcones

A series of triphenylamino (TPA)-chalcones and triphenylamino-β-arylchalcones, displaying either D-π-D or D-π-A architecture, were synthesized through aldol condensations and Heck reactions. The chalcone derivatives display intense absorption bands ranging from 389 to 432 nm and molar extinction coefficients of ca. 10 L mol cm corresponding to π-π* electronic transitions. The photoluminescence emissions are peaked between 470 and 563 nm with large Stokes shifts (80-131 nm), attributed to charge transfer in the excited state. The dyes present low fluorescence quantum yields, which is attributed to radiationless excited state deactivation related to aryl rings rotation. Spectroscopic and electrochemical methods were used to determine the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels. Both optical and electrochemical properties of the TPA-chalcone derivatives are considerably affected by the substitution pattern of the chalcones aryl rings and also by the β-arylation of the olefin moiety.