Aromatic iodonium/sulfonium rearrangement using difluoroenol silyl ethers

Abstract Difluoroenol silyl ethers are a unique class of enol silyl ethers that are widely used as a powerful difluoroalkylating reagent to incorporate difluoromethylene groups into organic molecules. In this context, we revealed a fluorine effect that the difluoroenol silyl ethers exhibit the oxygen nucleophilicity in lieu of traditional α-carbon nucleophilicity toward the aromatic iodonium/sulfonium species, thus allowing us to develop difluoroalkylative [3,3]-rearrangement of aryl iodanes and aryl sulfoxides and the difluoroalkylative dearomatization of aryl sulfoxides. In this article, we summarize these works and illustrate the logic of our design. GRAPHICAL ABSTRACT


Introduction
Since the pioneering development of difluoroenol silyl ethers (DFSEs) by Ishihara in 1983, [1] DFSEs have attracted much attention from the synthetic chemistry community. [2] Due to their easy accessibility and diverse reactivities, these difluoroalkylating reagents have been widely used for various difluoroalkylation reactions including Mukaiyama aldol reaction, [3] Mannich reaction, [4] conjugated addition, [5] arylation, [6] allylation, [7] and others. [8] Recently, we serendipitously discovered an unprecedented rearrangement of aryl iodanes with such reagents in our study of the umpolung of DFSEs with aryl iodanes. [9] Remarkably, this study revealed a unique fluorine effect that DFSEs exhibit their oxygen nucleophilicity in lieu of the traditional a-carbon nucleophilicity toward iodonium species. Furthermore, we applied the newly discovered fluorine effect for the development of difluoroalkylative rearrangement of aryl sulfoxides and the rearrangement induced dearomatization of aryl sulfoxides. [10] This article summarizes our initial discovery and the development of these rearrangement reactions.

Results and discussion
Hypervalent iodine compounds are commonly available, flexible, and ecologically friendly oxidants that are widely used in organic synthesis. [11] In context, the iodine(III) mediated oxidative couplings of enol silyl ethers (ESEs) with different kinds of nucleophiles have constructed a diverse family of a-functionalized carbonyl compounds. [12] The umpolung of ESEs by aryl iodanes is recognized as a key step in these processes. Recently, Szpilman and coworkers revealed that aryl iodane-umpoled ESEs could be trapped by allylsilane to yield a-allyl carbonyls. [12b] Inspired by their protocol, we assumed that sequentially dealing with highly electrophilic PhI(OTf) 2 (in situ generated from PhI(OAc) 2 / TMSOTf) [13] with DFSE and allylsilane could offer a-allylica,a-difluorinated ketone 3. To our surprise, in lieu of the expected product, the reaction produced ortho-difluoroalkylated aryl iodide 4 in 52% yield. Simple optimization of the reaction improved the chemical yield from 52% to 83%. Remarkably, the low reaction temperature and short reaction time enable the procedure to tolerate a diverse array of functionalities. A wide range of aryliodanes bearing electron-donating groups or electron-withdrawing could be successfully adopted by the process. Impressively, the sterically hindered 1f gave the desired product (4f) smoothly in a good yield. Both naphthalene (1 g) and thiophene (1 h) derivatives were all tolerated in the reaction (see Ref. [9] for more examples). Therefore, we achieved [3,3]-sigmatropic rearrangement of highly electrophilic aryl iodanes [14] with difluoroenol silyl ethers (Scheme 1). In addition, our mechanistic studies unraveled an intriguing effect of fluorine associated with DFSEs that switches their nucleophilicity from traditional a-carbon to the oxygen, thus allowing the assembly of the rearrangement precursor via the attack of oxygen of DFSEs to electrophilic aryl iodanes.
Encouraged by the success of the initial discovery, we envisaged that this unique fluorine effect could also be applied for developing [3,3]-rearrangement of aryl sulfoxides. [15][16][17][18][19] Not surprisingly, DFSEs readily undergo [3,3]-rearrangement with a wide variety of aryl sulfoxides to give ortho-difluoromethylated aryl sulfides (Scheme 2). The reaction features its simple operation and excellent functional group compatibility. It should be noted that during our studies, Wang and coworkers reported a similar [3,3]-rearrangement of aryl sulfoxides with DFSEs. [20] They demonstrated a broad substrate scope and practicality of the reaction.
The remarkably low reaction temperature and short reaction time indicate a strong driving force for the rearrangement. As such, we envisaged the dearomatization of ortho, ortho'-disubstituted aryl sulfoxides via their rearrangement with DFSEs and the nucleophilic trap of in situ generated dearomatized sulfonium species.
(Schemes 3-5). Interestingly, one or two difluoroalkyl groups can be incorporated into products on demand by the choice of different electrophilic activation reagents. The TFAA activated aryl sulfoxides could undergo [3,3]-rearrangement leading to a relatively stable dearomatized intermediate which could be captured by external nucleophiles to produce mono-difluoroalkylated alicycles (Scheme 3). In contrast, switching the activation reagent from TFAA to Tf 2 O could result in more electrophilic dearomatized intermediates which adopt a second DFSE to generate dual-difluoroalkylated alicycles (Scheme 4). Impressively, both the mono-and dual-difluroalkylative dearomatization showcased excellent functional group compatibility and regioselectivity. In case of mono-  difluoroalkylative dearomatization, a wide variety of nucleophilies including silyl hydride, electron rich alkenes and arenes, zinc reagents and heteroatoms are all smoothly introduced to dearomatization products. It's worthy to note that the in situ NMR studies revealed the formation of a dearomatized bicyclic intermediate IM1 in lieu of originally proposed dearomative sulfonium species via rearrangement. The different counter ions in dearomatization intermediates IM1 and IM2 also account for their different electrophilicity toward a second nucleophilie.

Conclusions
In conclusion, we have developed [3,3]-rearrangement of aryl iodanes and aryl sulfoxides using difluoroenol silyl ethers and achieved the dearomatization of aryl sulfoxides. The key to the success of these reactions is an intriguing fluorine effect that difluoroenol silyl ethers exhibit the oxygen nucleophilicity in lieu of the traditional a-carbon nucleophilicity toward highly electrophilic aryl iodonium/ sulfonium species thus enabling the construction of proper rearrangement precursors. Further development of difluoroenol silyl ethers mediated rearrangement reactions are ongoing in our laboratory.

Funding
This work was supported by National Natural Science Foundation of China (NSFC-21901232).