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 instrumentboth 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.
Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge.Here, we report the first highly enantioselective metalcatalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples of the enantioisotopomer.
Increasing demand for deuterium‐labeled organic molecules has spurred a renewed interest in selective methods for deuterium installation. Catalytic transfer deuteration and transfer hydrodeuteration are emerging as powerful techniques for the selective incorporation of deuterium into small molecules. These reactions not only obviate the use of D2 gas and pressurized reaction setups but provide new opportunities for selectively installing deuterium into small molecules. Commercial or readily synthesized deuterium donors are typically employed as easy‐to‐handle reagents for transfer deuteration and hydrodeuteration reactions. In this minireview, recent advances in the catalytic transfer deuteration and hydrodeuteration of alkenes and alkynes for the selective synthesis of deuterated alkanes will be discussed.
A copper-catalyzed
reduction of alkynes to alkanes and deuterated
alkanes is described under transfer hydrogenation and transfer deuteration
conditions. Commercially available alcohols and silanes are used interchangeably
with their deuterated analogues as the hydrogen or deuterium sources.
Transfer deuteration of terminal and internal aryl alkynes occurs
with high levels of deuterium incorporation. Alkyne-containing complex
natural product analogues undergo transfer hydrogenation and transfer
deuteration selectively, in high yield. Mechanistic experiments support
the reaction occurring through a cis-alkene intermediate
and demonstrate the possibility for a regioselective alkyne transfer
hydrodeuteration reaction.
Catalytic transfer hydrodeuteration of unactivated alkenes is challenging because of the requirement that chemically similar hydrogen and deuterium undergo selective insertion across a π-bond. We now report a highly regioselective catalytic transfer hydrodeuteration of unactivated terminal alkenes across a variety of heteroatom-or hetero-[a] A.
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