Herein we describe the dearomatization of aryl sulfoxides with difluoroenol silyl ether (DFESE) using a rearrangement/addition protocol. The selection of the sulfoxide activator determines whether one or two difluoroalkyl groups are incorporated into dearomatized products. Using TFAA can deliberately halt the reaction at the mono-difluoroalkylated dearomatized intermediate formed via a [3,3]-rearrangement, which can be further trapped by external nucleophiles to give mono-difluoroalkylated alicycles. In contrast, switching to Tf2O enhances the electrophilicity of dearomatized intermediates, thus allowing for the adoption of a second DFESE to produce dual-difluoroalkylated alicycles.

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Dearomatization of aryl sulfoxides: a switch between mono- and dual-difluoroalkylation

Efficient, mild and metal-free [3 + 2] annulation of N-phenoxy amides with gem-difluoroalkenes has been realized via a base-mediated tandem [3,3]-sigmatropic rearrangement, which gives direct access to 2-aminobenzofuran derivatives involved in the one-pot cleavage of multiple bonds including C–H, O–N and twofold C–F bonds. The subsequent success of the on-DNA compatible synthesis and the application of the obtained products as potential anticancer agents further demonstrates the versatility of this transformation.

Synthesis of 2-aminobenzofurans via base-mediated [3 + 2] annulation of N-phenoxy amides with gem-difluoroalkenes

The Morita-Baylis-Hillman (MBH) reaction and [3, 3]-sigmatropic rearrangement are two paradigms in organic synthesis. We have merged the two types of reactions to achieve [3,3]-rearrangement of aryl sulfoxides with α,β-unsaturated nitriles. The reaction was achieved by sequentially treating both coupling partners with electrophilic activator (Tf2 O) and base, offering an effective approach to prepare synthetically versatile α-aryl α,β-unsaturated nitriles with Z-selectivity through direct α-C-H arylation of unmodified α,β-unsaturated nitriles. The control experiments and DFT calculations support a four-stage reaction sequence, including the assembly of Tf2 O activated aryl sulfoxide with α,β-unsaturated nitrile, MBH-like Lewis base addition, [3,3]-rearrangement, and E1cB-elimination. Among these stages, the Lewis base addition is diastereoselective and E1cB-elimination is cis-selective, which could account for the remarkable Z-selectivity of the reaction.

Z‐Selective α‐Arylation of α,β‐Unsaturated Nitriles via [3,3]‐Sigmatropic Rearrangement

α-aryl α,β-unsaturated carbonyls represent an important class of derivatizable synthetic intermediates, however, the synthesis of such compounds still remains a challenge. Recently, we showcased a novel Z -selective α-arylation of α,β-unsaturated nitriles with aryl sulfoxides via [3,3]-rearrangement involving an Morita-Baylis-Hillman (MBH) process. In this Article, we demonstrate the feasibility of reversing the stereoselectivity of such MBH-type [3,3]-rearrangement by switching to a new pair of rearrangement partners consisting of aryl iodanes and α,β-unsaturated oxazolines. As a result, the two protocols complement each other in approaching E- or Z- α-aryl α,β-unsaturated carbonyl derivatives. Mechanistic studies reveal a possible reaction pathway and provide an explanation for the opposite stereoselectivities.

Morita-Baylis-Hillman-Type [3,3]-Rearrangement: Switching from Z- to E-Selective α-Arylation by New Rearrangement Partners.

ConspectusSince Ludwig Claisen's discovery of the sigmatropic rearrangement of allyl aryl ethers in 1912, aromatic Claisen rearrangement has continuously attracted the attention of both experimental and theoretical chemists. Over more than a century of growth, this protocol has proven to be a practical and powerful synthetic tool in many aspects. However, the reaction scope has long been limited to aryl ethers and their S or N analogs until the serendipitous discovery of aromatic iodonium-Claisen rearrangement by Oh et al. in 1988 and the development of aromatic sulfonium-Claisen rearrangement by Kita et al. in 2004. Unlike traditional Claisen rearrangements, these hypervalent-bonding-based Claisen-type rearrangements can be performed by simply mixing electrophilically activated aryl sulfoxides/iodanes with certain nucleophiles to directly deliver rearrangement products. In addition to the simple operation, remarkable features, such as readily available substrates, valuable products and intriguing rearrangement patterns, have led to a dramatic resurgence of this rearrangement chemistry.In this Account, we summarize our recent works on developing new aromatic rearrangement modes using sulfonium/iodonium reagents. Interestingly, the program started with an accidental discovery that aryl sulfoxides could be coupled with alkyl nitriles in the presence of Tf2O and base. Mechanistic studies reveal that the reaction proceeds in three major steps, including the Tf2O-triggered assembly of both coupling partners, base-promoted deprotonation of in situ-generated aryl sulfonium-imine species leading to a key rearrangement precursor called aryl sulfonium-ketenimine species, and subsequent facile and rapid [3,3]-rearrangement. On the basis of the mechanistic underpinning, we divided the one-step operation into two steps called the "assembly/deprotonation" protocol for constructing unstable rearrangement precursors. Most notably, the switch from the commonly used one-step to mechanism-based multiple-step manipulation, which can be termed "breaking up the whole into parts", not only enables the independent control of each step of the reaction, thus significantly expanding the accessible synthetic scope, but also raises opportunities for developing new rearrangement patterns. For example, the "assembly/deprotonation" protocol has also been applied to the development of [5,5]-rearrangement of aryl sulfoxides and the asymmetric rearrangement of aryl iodanes, thus enabling the unprecedented regio- and stereocontrol of the rearrangement process. Furthermore, the "breaking up the whole into parts" thinking triggered us to merge the Morita-Baylis-Hillman (MBH) reaction into the rearrangement process to accomplish Z-selective MBH-type [3,3]-rearrangement of α,β-unsaturated nitriles and E-selective MBH-type [3,3]-rearrangement of α,β-unsaturated 2-oxazolines, which expands the scope of rearrangement partners to include α,β-unsaturated carbonyls. In addition, the impressive rapidity of the rearrangement process found in our initial discovery has also been recognized as a congestion-acceleration effect, which was further utilized to forge the rapid ortho-cyanoalkylative rearrangement of aryl iodanes, and thus leading to the first dearomatization of aryl iodanes. We anticipate that our protocols and ideas behind the methods will be complementary to the traditional thinking of the aromatic Claisen rearrangement.

Revisiting Aromatic Claisen Rearrangement Using Unstable Aryl Sulfonium/Iodonium Species: The Strategy of Breaking Up the Whole into Parts.

[3,3]-Sigmatropic Rearrangement of Aryl Fluoroalkyl Sulfoxides with Alkyl Nitriles

Aromatic [5,5]-rearrangement can in principle be an ideal protocol to access dearomative compounds. However, the lack of competent [5,5]-rearrangement impedes the advance of the protocol. In this Article, we showcase the power of [5,5]-rearrangement recently developed in our laboratory for constructing an intriguing dearomative sulfonium specie which features versatile and unique reactivities to perform nucleophilic 1,2- and 1,4-addition and cyclization, thus achieving dearomative di- and trifunctionalization of easily accessible aryl sulfoxides. Impressively, the dearomatization products can be readily converted to sulfur-removed cyclohexenones, naphthalenones, bicyclic cyclohexadienones, and multi-substituted benzenes. Mechanistic studies shed light on the key intermediates and the remarkable chemo-, regio- and stereoselectivities of the reactions. 

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Dearomative di- and trifunctionalization of aryl sulfoxides via [5,5]-rearrangement

Isotope Exchange-Based 18F-Labeling Methods.

Radiochemical yields (RCYs) of isotope exchange-based 18F-fluorination of non-carbon-centered substrates in water are rationally enhanced by adding surfactants, which increases both the rate constant k and local reactant concentrations. Among 12 surfactants, the cationic surfactant cetrimonium bromide (CTAB) and two nonionic surfactants (Tween 20 and Tween 80) were selected for their superior catalytic effects, namely, electrostatic effects or solubilization effects. For a model substrate, bis(4-methoxyphenyl)phosphinic fluoride, the 18F-fluorination rate constant (k) increased up to 7-fold, while its saturation concentration rose up to 15-fold due to micelle formation, encapsulating 70-94% of the substrate. With 30.0 mmol/L CTAB, the required 18F-labeling temperature of a typical organofluorosilicon prosthesis ([18F]SiFA) decreased from 95 °C to room temperature, achieving an RCY of 22%. For an E[c(RGDyK)]2-derived peptide tracer with an organofluorophosphine prosthesis, the RCY in water at 90 °C achieved 25%, correspondingly increasing the molar activity (Am). After high-performance liquid chromatography (HPLC) or solid-phase purification, the residual selected surfactant concentrations in the tracer injections were well below the FDA DII (Inactive Ingredient Database) limits or the LD50 in mice.

Taotao Dong

Papers

Z‐Selective α‐Arylation of α,β‐Unsaturated Nitriles via [3,3]‐Sigmatropic Rearrangement

[3,3]-Sigmatropic Rearrangement of Aryl Fluoroalkyl Sulfoxides with Alkyl Nitriles

Dearomative di- and trifunctionalization of aryl sulfoxides via [5,5]-rearrangement

Isotope Exchange-Based 18F-Labeling Methods.

Surfactants Accelerate Isotope Exchange-Based 18F-Fluorination in Water.