Formal group insertion into aryl C‒N bonds through an aromaticity destruction-reconstruction process

Given the abundance and the ready availability of anilines, the selective insertion of atoms into the aryl carbon–nitrogen bonds will be an appealing route for the synthesis of nitrogen-containing aromatic molecules. However, because aryl carbon–nitrogen bonds are particularly inert, anilines are normally activated by conversion to more reactive intermediates such as aryldiazonium salts to achieve functionalization of the aryl carbon–nitrogen bonds, but the nitrogen atom is usually not incorporated into products, instead being discarded. The selective insertion of groups into aryl carbon–nitrogen bonds remains an elusive challenge and an unmet need in reaction design. Here we show an aromaticity destruction-reconstruction process that selectively inserts a trimethylenemethane (TMM) group into the aromatic carbon–nitrogen bond of anilines concomitant with a benzylic carbon–hydrogen bond functionalization. This process provides a transformative mode for anilines, and the insertion products are versatile precursor to various nitrogen-containing aromatic molecules through simple conversions.

The manuscript by Fan and co-workers described a interesting aromaticity destructionreconstruction process for formal insertion of a trimethylenemethane group into the aromatic C -N bond and concomitant with bezylic C -H bond functionalization. By using this process, a wide range of Ts-substituted anilines could be efficiently converted into the corresponding nitrogen -containing molecules. The present manuscript not only provided a method to synthesis of functional molecules that other method can not be acce ssed, but also provided a new strategy for cleaving innert C -N bond. Thus, I believe the present manuscript is suitable to be published in Nature C ommunications after addressing the following points: (1)The manuscript is mainly relevant to C -N bond cleavage,thus, the introduction part should be revised and pay more attention to the movement of the C -N activation chemistry. Thus, some reference on the insertion of functional groups such C O, alkene, C arbenoid into C -N bond should be cited.
(2)The catalyst loading of Palladium used here is 10mol%, is it possible reduce the Pd -loading to 5 mol% or even to 1 mol%? (3) The functional group insertion into the C -N bond here is formal insertion, thus, the title should be revised as Formal insetion.....

Reviewer #2 (Remarks to the Author):
This manuscript by Fan and co-worker reported a selective insertion of a trimethylenemethane group into the aryl carbon-nitrogen bond in anilines by a palladium catalyzed aza -TMM cycloaddition of the dearomatized anilines and a subsequent rearrangement reaction. Under the developed conditions, the TMM insertion reactions proceeded well accompanied by the functionalization of the para-or the ortho-benzylic carbon-hydrogen bonds. The key design for the reaction is the realization of an unprecedented group insertion reaction through a simple aromaticity destruction and reconstruction process, which enabled a previously impossible transformation of anilines (the nitrogen atom kept in this reaction vs the nitrogen atom discarded in the previously reported in references 19-33). This reaction also provides a novel application of the dearomatization strategy and the TMM cycloaddition. Moreover, the authors further demonstrated the synthetic utility of the TMM insertion products, and pr oves that this reaction is not only a new transformative mode of anilines, but also highly useful for the easy conversion of anilines into a variety of nitrogen-containing molecules. Due to the importance of the reaction and products, this reviewer believ es that these results should be highly interesting for a broad range of the readership for Nature C ommunications. In addition, the manuscript is clearly written, and all the new compounds have been well characterized in the SI. Therefore, publication of this work in Nature C ommunications is highly recommended. However, there are some issues need to be addressed as follows: 1) How about the reaction involving substrates without an alkyl substituent at the para -or the ortho-position? 2) Why did the reaction of substrates bearing an ethynyl group fail to give product 20?

DEPARTMENT OF CHEMISTRY, FUDAN UNIVERSITY
Answers for reviewer 1:

Comment:
The manuscript is mainly relevant to C-N bond cleavage, thus, the introduction part should be revised and pay more attention to the movement of the C-N activation chemistry. Thus, some reference on the insertion of functional groups such CO, alkene, Carbenoid into C-N bond should be cited.