Meta-Nitration Of Arenes Bearing Ortho/Para Directing Group(s) Via C–H Activation

Nitration is one of the important reactions for the synthesis of dyes,explosives,agrochemicals and pharmaceuticals.The nitro derivatives such as aniline and amine are fundamental building blocks that are found in a large number of medicines and materials.Generally,aromatic nitro compounds are prepared by the electrophilic aromatic nitration method that relies on the use of strong acids such as nitric acid.Moreover,the electrophilic nitration of aromatic compounds is controlled by electronic factors,always forming the mixture of isomers.Highly electron poor（hetero）arenes are too sluggish to undergo nitration.In additional to this,acid labile groups such as–COOt Bu,-OTBDMS,etc.are not stable under classical nitration conditions.The other nitration methods such as the ipso-nitration are limited by the substrate scope or the requirement of pre-functionalized starting materials（such as an aryl halide）.Hence,it is a long-standing challenge to access meta-nitro compounds of arenes bearing ortho/para directing group（s）.In this regard,the Ir-catalyzed C–H borylation method followed by nitration of the crude aryl boronate formed could overcome the regioselective problem and the other problems discussed above.Regioselective C–H functionalization plays an important role in modern organic synthesis.Among various C-H functionalization,the C–H borylation has emerged as a powerful platform for the functionalization of the C–H bond of arenes selectively at the least hindered site（usually at the meta position）.Steric factors rather than electronic factors mostly control this reaction.To this end,this reaction has been utilized to functionalize arenes selectively at the meta position with aryl,alkyl,azido,trifluoromethyl,halo,cyano groups etc.via the in situ generated aryl boronate in a one-pot fashion.Several groups had successfully transformed C–B bond to C–C,C–O,C–N,C–P and C–X（X=F,Cl,Br,I）bonds through this way.However,the C-H to C-NO2transformation was first described through this work.We have developed a strategy for meta-nitration of arenes bearing ortho/para directing group（s）in one-pot.In this method,we use iridium-catalyzed C-H borylation reaction followed by a newly developed copper（II）-catalyzed transformation of the crude aryl pinacol boronate esters into the corresponding nitroarenes.The success of this method was the discovery of optimal conditions to convert the aryl boronate to the nitroarene.This protocol allows the synthesis of meta nitrated arenes that are tedious to prepare or require multistep synthesis using the existing methods.The substrate scope of the array can be expanded to a wide of ortho/para-directing groups such as-F,-Cl,-Br,-CH₃,-Et,-i Pr-OCH₃ and-OCF₃.It also provides regioselective access to the nitro derivatives of electron poor heterocycles such as pyridines and quinolines.This methodology is also successful applied in the nitration of pyrene（nitrated selectively at the 2-position）,late-stage modification of（+）-α-tocopherol nicotinate.We have synthesized an intermediate en route to the FDA-approved drug Nilotinib in gram-scale.Lastly,we have directly converted the nitro product obtained by this method to the aniline or hindered amine via Baran’s amination protocol in a one-pot fashion.