A new technique for the ex situ generation of carbon monoxide (CO) and its efficient incorporation in palladium catalyzed carbonylation reactions was achieved using a simple sealed two-chamber system. The ex situ generation of CO was derived by a palladium catalyzed decarbonylation of tertiary acid chlorides using a catalyst originating from Pd(dba)2 and P(tBu)3. Preliminary studies using pivaloyl chloride as the CO-precursor provided an alternative approach for the aminocarbonylation of 2-pyridyl tosylate derivatives using only 1.5 equiv of CO. Further design of the acid chloride CO-precursor led to the development of a new solid, stable, and easy to handle source of CO for chemical transformations. The synthesis of this CO-precursor also provided an entry point for the late installment of an isotopically carbon-labeled acid chloride for the subsequent release of gaseous [13C]CO. In combination with studies aimed toward application of CO as the limiting reagent, this method provided highly efficient pall...

Ex situ generation of stoichiometric and substoichiometric 12CO and 13CO and its efficient incorporation in palladium catalyzed aminocarbonylations.

The Use of Gases in Flow Synthesis

Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh2SiCO2H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor. Finally, the synthesis of MePh2Si13CO2H and its application in carbonyl labeling of two bioactive compounds was demonstrated.

Silacarboxylic acids as efficient carbon monoxide releasing molecules: synthesis and application in palladium-catalyzed carbonylation reactions.

Recent advances in the transition metal catalyzed carbonylation of alkynes, arenes and aryl halides using CO surrogates

The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pKa, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

A simple and expedient process for the Heck aminocarbonylative synthesis of Weinreb and MAP amide acylating agents, from aryl halides, is reported. This methodology utilizes solid sources of CO making it readily accessible to chemists working in small-scale laboratory applications.

Microwave-Assisted Synthesis of Weinreb and MAP Aryl Amides via Pd-Catalyzed Heck Aminocarbonylation Using Mo(CO)6 or W(CO)6

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.

Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality.

Background
Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P1-7 (SP1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP1-7 and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice.

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The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system

A simple and an expedient process to prepare 5-aryl-1-benzyl-1H-imidazole-4-carboxamides by the aminocarbonylation of 5-aryl-4-iodo-1H-imidazoles using ex situ generation of CO from Mo(CO)6 with an amino acid amide nucleophile is reported. Furthermore, a microwave-assisted protocol for the direct C-5 arylation of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to acquire starting material for our aminocarbonylation are presented. The method can be used to prepare imidazole based peptidomimetics, herein exemplified by the synthesis of constrained H-Phe-Phe-NH2 analogues.

Rebecca Fransson

Papers

Microwave-Assisted Synthesis of Weinreb and MAP Aryl Amides via Pd-Catalyzed Heck Aminocarbonylation Using Mo(CO)6 or W(CO)6

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.

Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality.

The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system

Aminocarbonylation of 4-iodo-1H-imidazoles with an amino acid amide nucleophile: synthesis of constrained H-Phe-Phe-NH2 analogues.