Chemoselective Alpha‐Deuteration of Amides via Retro‐ene Reaction

Abstract A synthetically convenient approach for the direct α‐deuteration of amides is reported. This mechanistically unusual process relies on a retro‐ene‐type process, triggered by the addition of deuterated dimethyl sulfoxide to a keteniminium intermediate, generated through electrophilic amide activation. The transformation displays broad functional‐group tolerance and high deuterium incorporation.

Abstract: As ynthetically convenient approach for the direct a-deuteration of amides is reported. This mechanistically unusual processr elies on ar etro-ene-type process, triggered by the addition of deuterated dimethyl sulfoxide to ak eteniminiumi ntermediate, generated through electrophilic amide activation. The transformation displays broad functional-group tolerance and high deuterium incorporation.
The elucidation of reactionm echanismsh as long been at the heart of organic synthesis. In particular, isotope labelling is a powerful tool that enablest he precise monitoring of specific atoms by using them as markers during chemical transformations. [1,2] Moreover, understanding the fate of ad rug candidate is of great importance to drug discovery,e specially when studying the absorption, distribution, metabolism and excretion (ADME) properties. [3] The introduction of isotopicl abels is also one of the most effectivea nd least invasive methods for monitoring bioactive substances. [4] While radioactive compounds containing Tor 14 Ca re frequently used for quantification of metabolites and ADME properties, [5,6] stable isotopes such as D, 13 C, 18 Oo r 15 Nc an also be used as internal standards for bioassays, [7] or for overcoming matrix effectsf rom sample analysisi nL C/MS studies. [8] Moreover,l ife sciences can exploit the deuterium kinetic isotope effect to slow down cytochrome P450 metabolism, optimize pharmacokinetic properties or reduce toxicity. [9][10][11] Expanding the toolboxt oe nable cheap, re-gioselectivea nd mild late-stage deuterium incorporation is therefore highly desirable. Ap rime example of such at ransformation was reported by MacMillan, who developed ap hotoredox-catalyzed deuteration and tritiationo fb ioactive compoundsu sing D 2 Oo rT 2 O, [12] while more recently Wasa et al. reportedafrustrated Lewisp air-catalyzed a-deuteration of carbonyl compounds. [13] Also, late-stage hydrogen isotope exchange, often mediated by an organometallic complex,h as been am ethod of choice to incorporate aDo rT . [14,15] While other methods for the a-deuteration of carbonyls are known,m any of these suffer from low selectivity,o wing to the fact that they are strongly pK a -dependent and therefore only allow for the deuteration of aldehydes, ketones or esters, using alarge excess of D 2 O. [16][17][18][19][20][21][22][23] a-Deuterated amides have occasionally been prepared during the course of mechanistic studies, [24][25][26][27][28][29] with only few reportso ft hese valuable compounds as the actual targets.T he a-deuterationo fa mides can be accomplished employing aM eO À /MeOD system at elevated temperatures. However, this requires several cycles to achieveh igh levels of labelling. [30,31] In addition to thwarting any possibility of chemoselective labelling in compounds carrying multiple carbonylf unctionalities, any base-sensitive functional groups, or those prone to solvolysis, can be potentially negatively impacted( Scheme 1A). Af urthers traightforward approach to adeuterated amides involves deprotonation with sec-BuLi and subsequentq uenching of the resultinga nion with D 2 O (Scheme 1B), [32] although the use of av ery strong base once more limits potentialf unctional-group tolerance. Recently,A tzrodt and Derdau described an iridium-catalyzed deuteration of aliphatic amides using gaseous D 2 that was even applicable to small peptides (Scheme 1C). [33] Our group has developed research programs centered on the chemoselective,e lectrophilic activation of amides, [34][35][36][37] as well as the sigmatropic rearrangement chemistry of aryl and vinyl sulfoxides. [38][39][40][41][42][43] During ongoing studies into the reactivity of keteniminiumi ons with various classes of sulfoxides,w en oticed that the reaction with the simplest sulfoxide, DMSO (dimethyl sulfoxide), led to recovery of seemingly unreacted starting material. Our interest having been sparkedb yt he unexpectedr esult,w ep erformed the reaction with deuteratedd imethyl sulfoxide ([D 6 ]DMSO) and, surprisingly,w eo bserved the a-incorporation of ad euterium atom (Scheme 1D). Eyeing the aforementioned potential benefits of am ild and chemoselective a-deuteration, we set out to find optimal reactionc onditions using the amide 1a as amodel substrate (Table 1).
Our investigationsc ommencedw ith abroad screening of reaction conditions (  entries 6a nd 7). Introduction of molecular sieves (4 MS) led to an increasei nd euterium incorporation, while variation of the stoichiometry of the base did not prove beneficial (Table 1, entries 8t o1 0). Apart from the potentials ynthetic practicability of this method, the mechanistic aspects are highlyi ntriguing. Ouri nitial hypothesis startedo ut with the textbook electrophilica ctivation of amides with trifluoromethanesulfonica nhydride (Tf 2 O) in the presence of 2-halopyridines to form ak eteniminium ion 4 and its stabilized adduct 3 (Scheme 2A). In analogy to the previously described methodologies, we then assumed that addition of [D 6 ]DMSO to the keteniminium intermediate 4 generates intermediate 5.A tt his point, we proposed the latter to undergo ar etro-ene fragmentation to yield the deuterated product 2 through simultaneous cleavage of the CÀDa nd the SÀOb onds. [44][45][46][47][48][49][50] In studies reported duringt he preparation of this manuscript, Movassaghi and co-workers proposed asimilar mechanistic pathway. [51] In this mechanistic proposal,t he oxygen atom is ultimately transferred from DMSO to the amide. In support of this assumption,w hen 1a wast reated with isotopically labelled [18O]DMSO (6)a fter amide activation, 18 Oi ncorporation into the product 1a-[18O] was observed (Scheme 2B). In af urther experiment, 18 O-labelled amide 1c-[18O] was treated with [D 6 ]DMSO following activation, and afforded the 16 O/D combination as the main product 2c (Scheme 2C). These results confirm unambiguously that the carbonyl oxygen of the deuterated products stemsf rom DMSO, lending strong support to our mechanistic hypothesis.
To furtherc orroborate the reaction mechanism, we undertook DFT analysis of the reaction system, which showedt he proposed pathway to be thermodynamically favorable by 51.0 kcal mol À1 (Scheme 3). Starting from 1a,t he amide follows ac lassical amide activation pathway [52] to yield ion pairs A (A E at 0.7 kcal mol À1 and A Z at À1.4 kcal mol À1 )a fter addition of dimethyl sulfoxide to the keteniminium ion 4 (see Scheme 2A). Deuterium transfer takes place in ac oncerted fashion through Scheme1.Differentapproaches to incorporate adeuterium atom in the aposition of an amide.  Havinge stablished optimized reaction conditions and with a better understandingo ft he mechanistic intricacies of this transformation, the applicability of this reactiont od ifferent amides was explored (Scheme 4). Initial focus was placed on the substitution patterns tolerated at the amide nitrogen with different carbon chains. Ab road range of tertiarya mides derived from dimethyl-(2b), diethyl-(2c), diallyl-( 2d)a nd dibenzylamine( 2e), as well as pyrrolidine (2a and 2i), piperidine (2f)a nd azepane (2g)w ere successfully deuterated. Notably, deuterated lactam 2h was also formed in excellent yield and with ah igh level of deuterium incorporation. We then turned our attention to the carbon chain and the tolerance of reactive functional groups.W ew erep leased to find that the reaction displayed good functional-group tolerance, leaving alkyne (2j), alkene (2k), ester (2l), methyl ketone (2m), nitrile (2n), halide (2o and 2p)a nd trifluoromethyl (2q)m oieties untouched. Satisfyingly, the amide obtained from the natural productd ehydrocholic acid (2r)a lso afforded the desired product with high levels of deuterium incorporation and no noticeable labelling aroundt he ketone functionalities. In terms of limitations,w e found that amides bearing bulkier substituents on either side of the central sp 2 carbon, such as 2s and 2t,w ere less amenable to this protocol.
Lastly,w ew ere eager to address the question, whether this approachi sc apable to similarly deliver a-bisdeuterated amides, as such compounds promise more wide-spread applicability in the study of biological andm edicinal systems. [10,11] To this end, monodeuterated amide 2e (97 %D )w as subjectedt o the reaction conditions, providing the desired product 7 in 61 %y ield with 78 %o fb isdeuteration (Eq. (1)). [53] While ap ronounced kinetici sotope effect is not uncommon for enolization, [54] this result must still be highlighted for its high selectivity.
In conclusion, we have presentedt he highly chemoselective a-deuteration of amides via ar etro-ene reaction triggered by the addition of [D 6 ]DMSO to activateda mides. Experimental mechanistic probing and DFT analysiss hed light on this intriguing process that is able to tolerate ab road range of functional groupsa nd tertiary amides. Good yields and high levels of deuterium incorporation were obtained throughout. The possibility to perform chemoselective bisdeuterationw as established, adding to the potential applicability of this method in the study of reaction mechanismsand in life sciences.