A Ritter‐Type Reaction: Direct Electrophilic Trifluoromethylation at Nitrogen Atoms Using Hypervalent Iodine Reagents

Abstract

The unique features the trifluoromethyl group imparts to pharmaceuticals, crop-protection agents, and functional materials emphasize the necessity to design and develop new reagents and methods for the direct trifluoromethylation of a wide range of organic substrates. Electrophilic trifluoromethylation, that is, the reaction of a suitable reagent capable of formally transferring an intact CF 3 + unit, has been shown to be one of these methods.[1] However, despite the availability of several such effective reagents, the electrophilic trifluoromethylation of hard nucleophiles, for example, oxygen-or nitrogen-centered ones, remains challenging. In particular, the formation of a N À CF 3 bond by such a reaction is still extremely rare. In fact, the NCF 3 unit is usually constructed by the interconversion of suitable functional groups. Thus, fluorination of N-formylamines, [2] thiuram sulfides, [3] isocyanates, [4] and trichloromethylamines, [5] the reaction of secondary amines with CBr 2 F 2 and tetrakis(dimethylamino)ethylene, [6] and the electrochemical fluorination of alkylamines [7] constitute the still relatively modest set of methods. Of these, the most frequently used approach is the oxidative desulfurization-fluorination of dithiocarbamates first described for the generation of NCF 3 groups by Hiyama and Kuroboshi.[8]The single, still very recent report of a direct trifluoromethylation at nitrogen is due to Umemoto and co-workers.[9] They describe the direct N-trifluoromethylation of amines, anilines, and pyridines under very mild conditions achieved with in situ generated and thermally unstable O-(trifluoromethyl)dibenzofuranium salts (corresponding reactions of alcohols and phenols are also known). However, this type of reagent suffers from several shortcomings. The active CF 3 source is obtained by photochemical decomposition of diazonium salts at very low temperature, and the synthesis requires several steps including the construction of a CF 3 O-aryl moiety. It is therefore likely that this methodology will not replace the corresponding functional-group interconversions in the near future.We have shown that a new generation of readily accessible trifluoromethylation reagents based on hypervalent iodine, such as compounds 1 and 2 (Scheme 1), display the desired reactivity towards a number of C-, S-, P-, and O-centered nucleophiles. Despite their purported soft nature, reagents 1 and 2 do trifluoromethylate alcohols and sulfonic acids upon activation with Lewis [10] and Brønsted acids, [11] respectively, thus significantly expanding their application range.During a recent investigation of the direct electrophilic trifluoromethylation of heteroarenes [12] using reagent 1 and catalytic amounts of bis(trifluoromethanesulfonyl)imide (HNTf 2 ) in acetonitrile, we surprisingly found that benzotriazole (3) is converted to the corresponding N-substituted N-trifluoroimidoyl derivative 4, as shown in Scheme 2. The generation of compound 4 corresponds to a novel Rittertype [13] reaction during which a new NÀCF 3 bond...

S‐Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study

“…[1][2][3][4][5][6][7][8][9][10] Corresponding reagents for the trifluoromethylation of av ast array of substrates, as reported from our laboratory,f or example, 3,3-dimethyl-1-(trifluoromethyl)-1l 3 ,2-benziodoxol (1) [11][12][13][14][15][16] contributed to recent significant developments in organofluorine chemistry. [1][2][3][4][5][6][7][8][9][10] Corresponding reagents for the trifluoromethylation of av ast array of substrates, as reported from our laboratory,f or example, 3,3-dimethyl-1-(trifluoromethyl)-1l 3 ,2-benziodoxol (1) [11][12][13][14][15][16] contributed to recent significant developments in organofluorine chemistry.…”

“…[21][22][23][24][25][26][27][28][29][30] We previously investigatedt he electronica nd structural properties leadingt o the distinct reactivity of reagent 1 as well as polar mechanistic details in combination with N-a nd S-nucleophiles. [22] N-Trifluoromethylation of the solventa cetonitrile( MeCN) by protonated reagent 1,a st he key step in aR itter-type reaction, [14] likely proceeds by polar reductivee limination (RE), whereas Snucleophiles follow concomitantly RE and nucleophilic substitution( S N )p athways. [22] N-Trifluoromethylation of the solventa cetonitrile( MeCN) by protonated reagent 1,a st he key step in aR itter-type reaction, [14] likely proceeds by polar reductivee limination (RE), whereas Snucleophiles follow concomitantly RE and nucleophilic substitution( S N )p athways.…”

Dividing a complex reaction involving a hypervalent iodine reagent into three limiting mechanisms by ab initio molecular dynamics

“…The first step ( 1 → 2 ) in the formation of 9 represents the rate‐determining step. Therefore, the reactive intermediate 2 , which is essential in a newly discovered Ritter‐type reaction, is the species of interest …”

The solvent effect on two competing reaction mechanisms involving hypervalent iodine reagents (λ3‐iodanes): Facing the limit of the stationary quantum chemical approach

“…The reagent transfers the electrophilic trifluoromethyl‐group (CF 3 ) to a vast array of nucleophiles . A novel unexpected Ritter‐type reaction, in which N ‐trifluoromethyl amidines are obtained by N–CF 3 bond‐formation, has been discovered in our laboratories . The elucidation of the reaction mechanism in view of the optimization of the reagent and/or the reaction conditions is the main topic of this article.…”