Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with Quantitative Isotopomer Purity Analysis by Molecular Rotational Resonance Spectroscopy

Abstract

A copper-catalyzed alkene transfer hydrodeuteration reaction that selectively incorporates one hydrogen and one deuterium atom across an aryl alkene is described. The transfer hydrodeuteration protocol is selective across a variety of internal and terminal alkenes and is also demonstrated on an alkene-containing complex natural product analog. Beyond using 1H, 2H, and 13C NMR analysis to measure reaction selectivity, six transfer hydrodeuteration products were analyzed by molecular rotational resonance (MRR) spectroscopy. The application of MRR spectroscopy to the analysis of isotopic impurities in deuteration chemistry is further explored through a measurement methodology that is compatible with high-throughput sample analysis. In the first step, the MRR spectroscopy signatures of all isotopic variants accessible in the reaction chemistry are analyzed using a broadband chirped-pulse Fourier transform microwave spectrometer. With the signatures in hand, measurement scripts are created to quantitatively analyze the sample composition using a commercial cavity enhanced MRR spectrometer. The sample consumption is below 10 mg with analysis times on the order of 10 min using this instrumentboth representing order-of-magnitude reduction compared to broadband MRR spectroscopy. To date, these measurements represent the most precise spectroscopic determination of selectivity in a transfer hydrodeuteration reaction and confirm that product regioselectivity ratios of >140:1 are achievable under this mild protocol.

Catalytic Transfer Deuteration and Hydrodeuteration: Emerging Techniques to Selectively Transform Alkenes and Alkynes to Deuterated Alkanes

“…Building on their alkyne transfer deuteration reaction, the Clark group developed a Cu-catalyzed transfer hydrodeuteration of aryl alkenes (Scheme 27). [32] A broad scope of aryl alkenes was investigated which included both terminal and internal alkenes. Alkenes substituted with electron-rich, electron-neutral or electron-poor aryl groups all performed well under the optimized conditions.…”

Testing the Scalability of the HS-AUTOFIT Tool in a High-Performance Computing Environment

“…The comparison between the rotational transitions measured in the laboratory and those observed by radio telescopes allows a reliable identification of the molecules present in the interstellar medium. Moreover, very recently the technique has proved to be of fundamental use in the field of analytical chemistry as a support method for various scientific fields, for example in pharmaceutical research [27] such as in the analysis of isotopic impurities [28]. The ultimate goal in the field is to be able to create a technique that has the potential to directly analyze complex chemical mixtures and also perform chiral analyses without the need for chemical separation by chromatography [29,30].…”

Highly Regioselective Copper‐Catalyzed Transfer Hydrodeuteration of Unactivated Terminal Alkenes

“…[27] We recently reported a mild and general Cu-catalyzed transfer hydrodeuteration reaction that regioselectively incorporates one H and one D across both terminal and internal aryl alkene substrates to make [D 1 ]alkanes selectively deuterated at the benzylic position (Scheme 1c). [28] Encouragingly, this report included one example of an unactivated terminal alkene undergoing regioselective transfer hydrodeuteration, however it required that we change the deuterium source to [D 8 ]isopropanol and increase the catalyst loading to 3 mol%. While this single example was successful, we were intrigued that reactions of unactivated terminal alkenes generally did not reach full conversion and trace alkene isomerization by-product was forming under the standard conditions for promoting alkenyl arene transfer hydrodeuteration (Table 1, entry 1).…”

“…[29,30,33] Given the mild and general protocol we established for the transfer hydrodeuteration of alkenyl arene substrates, we were interested in exploring alternate reactions conditions to extend reactivity to unactivated terminal alkenes while retaining the high reaction selectivities found in our initial report. [28] The regioselectivity of the CuÀ H addition across a terminal unactivated alkene is likely influenced by the steric environment of the substrate, where Cu adds to the least sterically hindered alkene position. This has been elegantly demonstrated in several CuÀ H catalyzed terminal alkene hydrofunctionalization reactions.…”

“…Returning to the conditions previously reported by our research group for Cu-catalyzed aryl alkene transfer hydrodeuteration, we recognized the necessity to optimize the reaction for complete conversion of alkene 1 to precisely deuterated alkane 2 a without promoting the formation of byproduct 2 b (Table 1). [28] Unactivated terminal alkene 1 was chosen as the optimization substrate because the terminal alkene is distal from functionality. Compared to our previously reported conditions (entry 1), efforts to increase the yield of desired product 2 a were successful by increasing the reaction temperature to 60 °C, however this also led to a slightly higher yield of alkene isomerization by-product 2 b (entry 2).…”