One-Pot Sequential Hydrogen Isotope Exchange/Reductive Deuteration for the Preparation of α,β-Deuterated Alcohols using Deuterium Oxide

Abstract

An efficient one-pot sequential hydrogen isotope exchange (HIE)/ reductive deuteration approach was developed for the preparation of α,β-deuterated alcohols using ketones as the precursors. The HIE step can also be used for the synthesis of α-deuterated ketones. This method has been applied in the synthesis of four deuterated drug and MS internal standards.Letter pubs.acs.org/OrgLett

Copper-Catalyzed Synthesis of Multideuterium-Labeled Alcohols from Styrenes with CO and D2 as the Source of the Hydroxymethyl Group

“…General conditions, general procedures, control experiments, failed examples, analytical data, and 1 H and 13 C spectra of products (PDF)…”

“…The number of isotopic atoms is also vital for analyzing and improving medicinal properties . Multideuterium labeled molecules facilitate MS analysis because they have sufficient mass to avoid the cross-signal overlap with natural isotopic molecules . Besides, D 2 gas has been widely utilized in various reactions to prepare deuterated compounds with high efficiency and regioselectivity, such as in the deuterogenation of an unsaturated C–C bond, dehalogenation, the deoxygenation of benzylic alcohols, and the ring-opening of epoxides…”

“…12 Multideuterium labeled molecules facilitate MS analysis because they have sufficient mass to avoid the cross-signal overlap with natural isotopic molecules. 13 Besides, D 2 gas has been widely utilized in various reactions to prepare deuterated compounds with high efficiency and regioselectivity, such as in the deuterogenation of an unsaturated C−C bond, dehalogenation, the deoxygenation of benzylic alcohols, and the ring-opening of epoxides. 14 Recently, our group developed several copper-catalyzed organic transformations with CO as the carbon or carbonyl source.…”

BaO‐Catalyzed α‐Deuteration of Ketones, Sulfones, Sulfoxides, and Nitriles

“…Early in 1981, Na 2 CO 3 promoted α‐deuteration of alkyl mesityl ketones have been reported [16] . Later, sodium methoxide, [11a] potassium tert‐butoxide, [11b] pyrrolidine, [11k] 1,8‐Diazabicyclo [5,4,0]undec‐7‐ene (DBU), [11d,i] 1,5,7‐Triazabicyclo [4.4.0]dec‐5‐ene (TBD), [11e] and triethylamine [11l] were reported as bases for the HIE step. Among these known methods to prepare α‐deuterated ketones, they mainly focus on aryl/alkyl methyl ketones and aryl alkyl ketones which led to the development of methods for synthesis of α‐deuterated various ketones of great importance.…”

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA

“…Whereas many advances have been made in recent years in HIE using transition metals, ,, the field of acid/base deuteration has been slower to develop due to its lower selectivity and harsher reaction conditions. , The main advances in acid-mediated HIE focused on the use of superelectrophilic acids for the perdeuteration of arenes, allowing the labeling of not only electronically activated aromatic and unsaturated molecules but also more recently nonactivated (halo)­arenes . However, the field of base-mediated HIE has remained limited to its application to relatively acidic C–H bonds (Figure b), as for example, terminal alkynes, the α-position to carbonyls, fluoroarenes, benzylic positions, or pyridines, often requiring high temperatures and extended reactions times. Due to this restricted reactivity and the limited mechanistic understanding, a general strategy for base-mediated deuteration of nonactivated arenes remains elusive.…”