Metal-Free Z-Selective Allylic C-H Nitrogenation, Oxygenation, and Carbonation of Alkenes by Thianthrenation

Selective functionalization of allylic C-H bonds into other chemical bonds with Z-selectivity are among the most straightforward and attractive, yet challenging transformations. Herein, a transition-metal-free protocol for direct allylic C-H nitrogenation, oxygenation, and carbonation of alkenes by thianthrenation was developed. This operationally simple protocol allows for the unified allylic C-H amination, esterification, etherification, and arylation of vinyl thiathrenium salts. Notably, the reaction preferably provides multialkyl substituted allylic amines, esters, and ethers with Z-selectivity. The reaction proceeds under mild conditions with excellent functional group tolerance and could be applied to late-stage allylation of natural products, drug molecules and peptides with excellent chemoselectivity. Methods for direct allylic C-H functionalizations are among the most attractive transformations to streamline organic synthesis as it maximizes the stepand atomeconomy to generate stereodefined allylic species amenable to further chemical transformations, thus minimizing the cost and waste.1-8 Traditional allylic C-H functionalization reactions generally require the catalysis of transition-metals such as Pd, Cu, and Ir, in which involve the formation of an allyl-metal complex via C-H activation followed by being attacked by an intraor intermolecular nucleometallation (Fig. 1a).9-28 Recently, the radical cleavage of an allylic C-H bond via hydrogen atom transfer is also developed to generate carbon-centered radical intermediates, which could be involved in following radical processes or transtion-metal catalysis.21,29-35 These two strategies proved to be powerful for organic synthesis and extensively investigated. The stereochemistry outcomes heavily rely on the property of transitionmetals and anchoring ligands and are mostly dominated by thermodynamic control, leading to the formation of C-H functionalizaiton products with more stable Eselectivity.9-24,36-44 On the contrast, the realization of Z-selective allylic C-H functionalizations is more challenging and remains elusive.45-47 On the other hands, organothiathrenium salts could be easily prepared from arenes and alkenes by thianthrenation using stoichiometric thianthrene S-oxide or phenoxathiine 10-oxide as the mediators, which could serve as the precousors for both cross-coupling reactions and radical precesses.48,49 This two-step strategy arises potential chemical space for

With the optimized conditions established, we turned to evaluate the scope of this reaction. It is found that the reaction conditions tolerate a variety of vinylthiathrenium salts and different nucleophiles with broad functional group and substitution pattern compatibility (Fig. 2). First, the scope for allylic C-H esterification was examined. A surprisingly wide range of carboxylic acids were tolerated (3a-3o). Aromatic and heteroaromatic carboxylic acids, such as quinoline carboxylic acid, thiophene carboxylic acid, indole carboxylic acid, furan carboxylic acid, pyrrole carboxylic acid, could be involved in the reaction to deliver the allylic C-H esterification products (3b-3f) in 72-83% yields. Aliphatic acids, including α-linear, α-branched and α-tertiary carboxylic acids, are good substrates for this metal-free C-H functionalization process, giving corresponding esters (3g-3k) in 64-89% yields. Formic acid could form allylic formic ester 3l in 74% yield. Benzoylformic acid could form corresponding ester 3m in 77% yield via allylic C-H functionalization. Propiolic acid was tolerated to give corresponding allylic ester 3n in 86% yield. Conjugated dienoic acid was converted to 3o in 90% yield, leaving the conjugated diene intact. Moreover, this protocol was applicable to late-stage functionalization of complex molecules. Naproxen was transformed to corresponding allylic ester 3p in 84% yield without erasing the stereogenic center. Oxaprozin, adapalene, lithocholic acid, telmisartan, D-biotin, and probenecid were all good substrates for this allylic C-H esterification reaction, furnishing corresponding esters (3q-3v) in 67-95% yields. Potassium benylpenicillin was compatible in the reaction, delivering the esterification product 3w in 92% yield in high chemoselectivity, without detecting the N-allylation product. Notably, the reaction tolerated a wide range of natural and unnatural amino acids and peptides. N-Boc protected L-proline was successfully converted to allylic ester 3x in 86% yield. Peptides, such as CBz-Gly-Gly and neotame underwent allylic C-H esterification selectively to leave free amide and amine unreactive, affording 3y and 3z in 79% and 84% yields, respectively. Next, the scope of vinylthiathrenium salts was investigated. Five, six, seven-membered cyclic alkenes could be involved to undergo allylic C-H oxygenation with benzoic acid to furnish cyclic allylic esters (4a-4c) in 56-74% yields. Cyclododecene was converted to corresponding allylic ester 4d in 58% yield with exclusive Z-selectivity. A mixture of isomers of alkene-derived thiathrenium salt delivered a single isomer of the corresponding allylic C-H oxygenation product 4e in 80% yield. It is noteworthy that 1-substituted alkene based thiathrenium salts were converted to allylic esterification products smoothly. Surprisingly, the reaction delivered 1,2-substituted alkenes favored Z-selectivity. Alkenes with pendant bromides, alkenes, alcohols, esters were all compatible in the reaction, delivering the esterification of allylic C-H bonds in 56-95% yields with 2.0:1-3.8:1 ratios of Z-selectivity (4f-4m). Notably, the Z-selectivity could be further improved up to 9.0:1 (4g, 4h, 4k, and 4m) using pentamethyldiethylenetriamine (PMDTA) as the base. The configuration of the major product was confirmed unambiguously by X-ray diffraction of 4m. Moreover, the reaction could be easily scaled up. The reaction on 4.0 mmol scale afforded 1.19 g of 4m in 83% yield. Next, the application of allylic C-H functionalization was extended to other nucleophiles was examined. Allylic C-H etherification was successful using both alcohols and phenols as the nucleophile, furnishing alkyl and phenyl allylic ethers (5a and 5b) in 45% and 66% yields. Thioesterification of allylic C-H bond was achieved in 97% yield (5c) using potassium thioacetate. Allylic C-H arylation was also accomplished in 62% yield (5d) with trimethoxybenzene as the nucleophile. Moreover, allylic C-H amination was also demonstrated. Primary anilines, aliphatic amines were all well tolerated, delivering allylic secondary amines (6a-6c) in 55-72% yields. Secondary amines with different substitution patterns were all good substrates for this reaction, giving diverse allylic tertiary amines (6d-6g) in 55-71% yields. Monosubstituted alkene based thiathrenium salts were converted to Z-selective 1,2disubstituted allylic amines in 47-75% yields with 1.9:1-4.9:1 ratio (6h-6j). The configuration of the major isomer of allylic amines was further confirmed by the X-ray diffraction of the salt of 6h. Impressively, tertiary amines were also compatible in allylic C-H amination reaction to afford allylic trialkyl ammonium salts in 70-76% yields (6k-6m). When 4-phenyl-1-butene derived thiathrenium salt was exposed in the reaction conditions with triethyl amine and quinuclidine, the desired allylic ammonium salts were obtained in 72% and 70% yields (6l and 6m), favoring Z-selectivity in 4.4:1.
Notably, allylic C-H sulfonyl amidation of vinyl thiathrenium salts were also successful, affording corresponding allylic sulfonyl amides in 73% and 75% yields (6n and 6o), respectively.   To demonstrate the practicality of this reaction, a one-pot operation from an alkene and thianthreneoxide, followed by a nucleophile was demonstrated (Fig. 3a). The one pot reaction from 3-phenyl-1-propene, followed by N-methylaniline could afford the desired allylic amine 6d in 63% yield without any workup or intermediate purification, which is comparable to previous result. Next, the reaction of 1a with 2a was conducted in the presence of a radical scavenger under otherwise identical to standard conditions (Fig. 3b). It is shown that the reaction proceeded smoothly in the presence of TEMPO, BHT or 9,10-dihydroanthracene, affording the desired product 3a without erasing the efficacy. These results exclude the involving of radical intermediates in this reaction. To further probe the mechanism of the reaction, a dithianthrenium salt 7 was submitted to the reaction with benzoic acid or N-methylaniline, corresponding allylic C-H esterification product 4g and amination product 6d were obtained in 72% and 71% yield, respectively (Fig. 3c). The yield and stereoselectivity are comparable to the results of using corresponding vinylthianthrenium. These results indicate dithianthrenium salt could serve as the reactive intermediate for this reaction.
Based on literature and the experimental results, a plausible mechanism is described in Fig. 4. First, intramolecular attack of sulfur on alkene moiety of vinylthianthrenium salt could deliver the dithianthrenium salt M1, which could further undergo site-selective ring-opening by intermolecular attack by a nucleophile to give an alkylthianthrenium salt intermediate M2.
In the presence of a base, M2 would undergo a syn-elimination via TS1 to give the final allylic C-H functionalization product in favor of Z-selectivity. In summary, a unified transition-metal-free protocol for diverse functionalizations of allylic C-H bonds of alkenes by thianthrenation under mild conditions has been demonstrated for the first time. Notably, the reaction features Z-selectivity to afford multi-alkyl substituted allylic esters, thioesters, ethers, primary, secondary, tertiary amines, amides, and arenes in good yields without incorporation of any transitionmetals. One-pot procedure proved efficient to access direct allylic C-H functionalizations from alkenes. The reaction tolerates a wide range of O-, Nnucleophiles with excellent functional group tolerance, and could be applied to latestage functionalizations of natural products, amino acids, and drug-like molecules with excellent chemoselectity.

TOC and Abstract
Selective functionalization of allylic C-H bonds into other chemical bonds with Zselectivity are among the most straightforward and attractive, yet challenging transformations. Herein, a transition-metal-free protocol for direct allylic C-H nitrogenation, oxygenation, and carbonation of alkenes by thianthrenation was developed. This operationally simple protocol allows for the unified allylic C-H amination, esterification, etherification, and arylation of vinyl thiathrenium salts. Notably, the reaction preferably provides multialkyl substituted allylic amines, esters, and ethers with Z-selectivity. The reaction proceeds under mild conditions with excellent functional group tolerance and could be applied to late-stage allylation of natural products, drug molecules and peptides with excellent chemoselectivity.