Iridium-Catalyzed Csp³–H Activation for Mild and Selective Hydrogen Isotope Exchange

Abstract

The increasing demand for isotopically labeled compounds has provided appreciable impetus for the development of improved methods for the late stage introduction of isotopes of hydrogen (deuterium or tritium). Moreover, sp 3-rich molecules are becoming increasingly common in the exploration of chemical space for drug design. Herein, we report an efficient iridium(I) catalysed C-H activation method for the hydrogen isotope exchange of sp 3 C-H bonds. A wide range of substrates have been labeled, including active pharmaceutical ingredients, delivering excellent levels of isotope incorporation and predictable regiocontrol, with low catalyst loadings, in short reaction times, and under mild reaction conditions.

Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides

“…Under the general reaction conditions, ortho ‐directed deuteration of a variety of phenylacetic amides ( 14 – 23 ) was also achieved with high yields, good selectivity, and high to excellent deuterium incorporation of up to 99 % D (Scheme ). In nearly all reactions of the N ‐methyl amides 14 , 15 , 17 , 18 , 20 , and 21 , we observed additional deuteration at the N ‐methyl group with 13–33 % D ( 15 , 63 % D) as observed previously for alkylamines containing directing groups, for example, pyridine and pyrimidine . Interestingly, these aliphatic labeling side reactions could be completely avoided by the introduction of larger N‐substituents like in amides 16 , 19 , 22 , and 23 , indicating that excellent selectivity and deuterium incorporation can be achieved.…”

“…In nearly all reactions of the N-methyl amides 14, 15, 17, 18, 20, and 21,w eo bserved additional deuteration at the N-methyl group with 13-33 %D( 15,6 3% D) as observedp reviously for alkylamines containing directing groups,f or example, pyridine and pyrimidine. [22] Interestingly,t hese aliphatic labeling side reactions could be completely avoided by the introductiono f larger N-substituents like in amides 16, 19, 22,a nd 23,i ndicating that excellent selectivity and deuterium incorporation can Scheme3.HIE reaction with various phenylacetic amides;conditions:catalyst 1 (10 mol %), 1atm. D 2 ,chlorobenzene 1mL, rt, 2h;a ll reactions repeated at least twice.…”

Highlights of aliphatic C(sp3)‐H hydrogen isotope exchange reactions

“…Kerr et al described recently the HIE at aliphatic C(sp 3 )‐H bonds directed by several heterocyclic aromatics ( 71→72 ; Scheme 29) under mild reaction conditions . In a high number of examples, they succeeded to introduce deuterium selectively in the aliphatic positions of morpholines, piperazines, piperidines, azepine, pyrrolidine, and azetidine in up to 99% D. Finally, they demonstrated by labeling of the drugs mirtazapine, azaperone, and caffeine the high applicability of this method to more complex molecules.…”

Frustrated Lewis pairs: A real alternative to deuteride/tritide reductions

“…Then 1/10 of the crude mixture was used for qualitative analysis. The specific activity of pure 3methoxyphenyl-[ 3 H]-methanol (40) was established at 27.1 Ci/mmol following 1 H NMR (see Data S1).…”

“…22,23,[32][33][34] The quite inert molecule of hydrogen always needs to be activated before any intended application. [35][36][37][38] The HIE approach has recently reached a significant improvement in terms of achieved specific activity (S.A.), 21,39,40 however, still suffers from low site-specificity label incorporation and the requirement of vast numbers of trials to develop workable reaction conditions, using up time and often the precious compound. Tritiodehalogenation represents a golden standard for hydrogen-labeling of iodinated, brominated, chlorinated, and fluorinated synthetic precursors, providing regiospecifically labeled material possessing high S.A.…”