Palladium-Catalyzed β-C–H Arylation of Alkyl Carboxamides with Sterically Hindered Aryl Iodides Using ortho-Sulfinyl Aniline Auxiliaries

Abstract

We disclose a pair of ortho-sulfinylaniline auxiliaries for palladium-catalyzed β–C-H arylation of alkyl carboxamides. Together, these auxiliaries offer a means to effect efficient β-methyl and methylene C–H bond arylation with sterically hindered aryl iodides. ortho-Methylsulfinylaniline (MSOA) enables efficient β-methyl C–H arylation of propanamide substrates with aryl iodides bearing various ortho-substituents including alkyl groups. ortho-Tosylsulfinylaniline (TSOA) enables β-methylene C–H arylation with ortho-substituted aryl iodides. Both amide-linked MSOA and TSOA auxiliaries can be easily removed to give ester products under relatively mild conditions.

Stereoselective Sulfinyl Aniline‐Promoted Pd‐Catalyzed C−H Arylation and Acetoxylation of Aliphatic Amides

“…Based on this pioneering work and targeting a new asymmetric approach towards direct functionalization of linear alkanes, we report herein a diastereoselective C−H arylation of aliphatic substrates using ( S )‐2‐( p ‐tolylsulfinyl)aniline (APS) as a chiral auxiliary and precursor of a bicoordinating directing group. During the preparation of this manuscript, a closely related bicoordinating DG has been employed for direct arylation of aliphatic substrates, however, the stereoselective outcome of such transformation was just mentioned in one example …”

“…Regrettably, replacement of the silver salt by potassium or cesium carbonate resulted in an inhibition of the reaction (Table , entries 9, 10). Likewise, significantly inferior results in terms of either efficiency or stereoselectivity were obtained using pivalic acid or potassium fluoride additives, respectively (Table , entries 11, 12), reaction conditions inspired from the recent work of Chen and He . Although this aim of this optimization study was to establish a protocol allowing high reactivity for such a challenging C(sp 3 )−H activation at methylene position, it also clearly shows that regardless of the conditions used, only modest diastereoselectivity (typically 3:2) could be achieved.…”

“…Such a two‐step C−H activation would be particularly appealing as it allows in situ construction of a variety of 3‐arylpropionic acid derived substrates. In particular, use of the ortho ‐substituted iodoarenes in the first step seems challenging as ortho ‐substituted iodoarenes have only rarely been used with success in the context of direct arylation . However, a targeted coupling between 1 o and ortho ‐substituted iodoarenes would deliver straightforwardly a new class of non‐commercially available saturated cinnamic acid derivatives.…”

“…In order to showcase the synthetic value of our transformation, we next focused on a cleavage of the chiral auxiliary APS (Scheme ). Initially, inspired by the literature, a hydrolysis of 3 iH under acidic conditions was tested. Deceivingly, using a rather harsh protocol (1 m HCl in EtOH at 100 °C; 12 h), a degradation of the auxiliary was observed, yet preventing its recovery and reuse.…”

Palladium‐Catalyzed ortho C−H Arylation of Benzaldehydes Using ortho‐Sulfinyl Aniline as Transient Auxiliary

“…Interestingly, ortho ‐tolylsulfinyl aniline (TSOA, TA8 ) showed much lower reactivity. In our previous study, we have shown that these two ortho ‐sulfinyl aniline auxiliary group are particularly effective at facilitating Pd‐catalyzed β‐C(sp 3 )‐H arylation of the corresponding alkyl carboxamides with sterically hindered aryl iodides …”