Ex SituGeneration of Stoichiometric and Substoichiometric¹²CO and¹³CO and Its Efficient Incorporation in Palladium Catalyzed Aminocarbonylations

Abstract

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 [(13)C]CO. In combination with studies aimed toward application of CO as the limiting reagent, this method provided highly efficient palladium catalyzed aminocarbonylations with CO-incorporations up to 96%. The ex situ generated CO and the two-chamber system were tested in the synthesis of several compounds of pharmaceutical interest and all of them were labeled as their [(13)C]carbonyl counterparts in good to excellent yields based on limiting CO. Finally, palladium catalyzed decarbonylation at room temperature also allowed for a successful double carbonylation. This new protocol provides a facile and clean source of gaseous CO, which is safely handled and stored. Furthermore, since the CO is generated ex situ, excellent functional group tolerance is secured in the carbonylation chamber. Finally, CO is only generated and released in minute amounts, hence, eliminating the need for specialized equipment such as CO-detectors and equipment for running high pressure reactions.

Creation of Novel Toxic Gas Surrogates and the Development of Safe and Facile Catalytic Reactions

“…At the time of this important discovery of CO generation from 20a, various CO surrogates were known, including formic acid, [48][49][50] paraformaldehyde, 50) N,N-dimethylformamide (DMF), 51) chloroform, 52) aldehydes, [53][54][55][56] metal carbonyl complexes, 57) acid chlorides, 58) and silacarboxylic acids. 59) Alkyl formates 60) had been also reported to act as CO surrogates.…”

The Development and Application of Sulfur Dioxide Surrogates in Synthetic Organic Chemistry

“…Using a two chamber system, COgen is chemically "decomposed" releasing CO ex situ, which diffuses into the second chamber where the desired carbonylation reaction takes place. [20,21] However, whilst COgen satisfies the first and third roles of a surrogate described above, a specially adapted, pressure-resistant chamber reactor is still required as CO gas is explicitly released into the headspace.…”

Title Pages

“…A two-chamber process has also been devised for safe, laboratory-scale carbonylations based on in situ-generation of carbon monoxide from a solid source: 9-chlorocarbonyl-9-methylfluorene. This is converted to CO under palladium catalysis in the first chamber and passes to a second for the desired carbonylation in the presence of another catalyst, as illustrated by the palladium-catalyzed carbonylation of aryl halides 20 .…”