Online and In Situ Monitoring of the Exchange, Transmetalation, and Cross-Coupling of a Negishi Reaction

Abstract

We have developed a reaction monitoring method which provides quantitative information through exchange, transmetalation (TM), and cross-coupling for a Negishi reaction. Online HPLC and ReactIR were used as orthogonal techniques to corroborate time-course data through each step. Excellent agreement between the two techniques was observed through monitoring the magnesium/bromine exchange. Quantitative information regarding the TM was gathered via a novel, inline quenching technique facilitated by online HPLC. Quenching reaction aliquots with the electrophile 4-chlorobenzaldehyde allowed us to determine the extent of TM because of its selectivity for reacting with organomagnesiums. After TM, the Negishi reaction was performed and monitored using online LC. Titrating ZnCl 2 into a solution of arylmagnesium allowed us to gain insights into zinc speciation in situ. Less than 1 equiv of ZnCl 2 was needed to achieve complete TM, evidencing the presence of diorganozincs/arylzincates. Additionally, using substoichiometric quantities of ZnCl 2 resulted in higher rates of catalysis for the Negishi reaction.

Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry

“…Development of an in situ FTIR spectroscopic method was highly desirable in order to obtain more granular and quantitative insight into reaction kinetics and intermediate 2 stability. Large electronic differences between bromoquinazoline 1 and the corresponding organomagnesium 2 resulted in easily identifiable changes in the resulting IR spectra, but identifying an indicative shift to the organozinc product 3 proved challenging . With the help of DFT computationally calculated IR stretch predictions, we were able to identify a fingerprint shift from 932 to 945 cm –1 for the Br–Mg exchange step, and a subtle shift from 945 to 957 cm –1 for the Mg–Zn transmetalation step, allowing one to follow reaction progress with high sample frequency as shown in the waterfall plot below (Figure a).…”

“…13 C NMR spectra were recorded at 151 MHz, ad are reported relative to the residual solvent peak (δ 40.0 for DMSO-d 6 ). Data for 13 C NMR spectra are reported in terms of chemical shift (δ ppm). High Resolution Mass Spectroscopy (HRMS) data were obtained on an Agilent 6210 Time-of-Flight instrument, using electrospray ionization in positive or negative mode.…”

Rose‐Bengal‐Photocatalyzed Cross‐Dehydrogenative Coupling Reactions under Visible Light

“…[20] The environmental cost and the need for transmetallation steps that produce stoichiometric quantities of metal salt as waste are the primary problems with many metal-catalysed cross-coupling reactions. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] The 2010 Nobel Prize in Chemistry recognized the significant achievements and importance of the crosscoupling process. [35] Cross-coupling processes in organic synthesis have had a noteworthy and remarkable impact on their commendable contribution to pharmaceutical chemistry and drug development over the past two decades.…”

“…The efficiency of this pathway in terms of atom economy is due to the production of negligible quantities of side products [20] . The environmental cost and the need for transmetallation steps that produce stoichiometric quantities of metal salt as waste are the primary problems with many metal‐catalysed cross‐coupling reactions [21–34] . The 2010 Nobel Prize in Chemistry recognized the significant achievements and importance of the cross‐coupling process [35] …”

Precise Control of the Oxidation Reaction in a High-Purity Dexlansoprazole Synthesis Process Using In Situ Infrared

“…In this work, we introduce in situ infrared (IR) spectroscopy − to provide real-time information of reaction processes as a typical example of the process analytical technology. − At first, we optimized the reaction parameters of asymmetric sulfur oxidation in Kagan to obtain the appropriate raw material ratio and reaction conditions. Then, the concentration changes of starting materials, intermediates, and products are monitored by in situ IR spectroscopy in real time, and the end point of the asymmetric sulfur oxidation reaction in Kagan could be easily determined, and the byproducts are traceable.…”