Dearomative Aminocarbonylation of Arenes via Bifunctional Coordination to Chromium

Abstract

Amides are ubiquitous in physical and life sciences. Given the significant abundance of arenes, dearomative aminocarbonylation of arenes would lead to a large and underexplored chemical space for amide discovery. However, such reactions are challenging due to the high degree of resonance stabilization and selectivity issues. Herein, we disclose an unprecedented dearomative trifluoromethylative aminocarbonylation of arenes via bifunctional coordination to chromium, providing a modular platform for the construction of amides possessing trifluoromethyl (CF 3 ) groups and three-dimensional rings. Its versatility further enabled a switchable difluoromethylation or trifluoromethylation aminocarbonylation of arene CÀ H bonds. A possible mechanism was proposed based on control experiments. Finally, the synthetic utility was well demonstrated by diverse applications in the total synthesis of CF 3 -functionalized amide-type drugs, including praziquantel, nateglinide, maraviroc and alloyohimbane.

Chemoselective 1,2‐Reduction and Regiodivergent Deuteration of Chromium‐Bound Arenes

“…The high chemoselectivity could be ascribed to the selective and efficient activation of the arene π-bonds via η 6 -coordination, as well as the appropriate selection of a mild hydride source Ph 3 SiH. A high level of tolerance was also observed to other mono-, disubstituted benzene derivatives possessing diverse functional groups, like acetal group, methoxyl, free hydroxyl, SiMe 3 , and medicinally relevant heterocycles (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The final ketone product 20 was generated from the corresponding unstable vinyl ether product via hydrolysis in situ after the reduction.…”

“…First, the possible isomerization from the 1,4‐reduction product (Birch‐type product) into our 1,2‐reduction product under the quenching conditions was excluded (Scheme 4A), which supported the 1,2‐reduction speculation. Based on our recent mechanistic studies on (η 6 ‐arene)Cr(CO) 3 reagents, [15] the η 5 ‐cyclohexadienyl tricarbonylchromium(0) intermediate formed through the nucleophilic addition of hydride to (η 6 ‐biphenyl)Cr(CO) 3 was successfully trapped by the addition of the Togni's reagent, giving the CF 3 ‐stabilized Cr II complex 57 in 58 % yield (Scheme 4B). X‐ray crystallographic analysis of complex 57 [17] indicated that the nucleophilic addition of hydride should attack the ortho position of the aryl substituent.…”

“…Generally speaking, the regioselectivity of deuteride (hydride) attack mainly depends on the partial charges at arene carbon atoms, but in fact is also influenced by many factors, including the nature and relative positions of the substituents on the arene ring, the conformation of the Cr(CO) 3 tripod, and other stereoelectronic effects. [11, 12a, 15] Based on further derivatizations and 1D NOESY experiments (see Supporting Information page [14][15][16][17][18][19][20], the relative configuration of the two deuterium atoms in 56 was determined to be trans, which implies the current method should be a trans-1,2-reduction.…”

“…[a] The total yield of the isomers is given. reagents, [15] the η 5 -cyclohexadienyl tricarbonylchromium(0) intermediate formed through the nucleophilic addition of hydride to (η 6 -biphenyl)Cr(CO) 3 was successfully trapped by the addition of the Togni's reagent, giving the CF 3 -stabilized Cr II complex 57 in 58 % yield (Scheme 4B). X-ray crystallographic analysis of complex 57 [17] indicated that the nucleophilic addition of hydride should attack the ortho position of the aryl substituent.…”

“…[13] It is worth mentioning that low valent chromium (0, +2, +3) compounds have much lower toxicity than chromium(VI) salts. [14] Inspired by these elegant works, [15] we assumed that if a regioselective 1,2-reduction of chromium-bound arenes could be realized via step-wise nucleophilic/electrophilic additions of one hydride and one proton, different combinations of the correspondingly deuterated and nondeuterated reagents would give rise to a diverse set of 1,3-cyclohexadiene isotopologues. We report herein a general strategy for chemo-and regioselective 1,2reduction of arenes and the related regiodivergent deuteration based on selective activation on arene π-bonds via η 6coordination (Scheme 1C).…”