Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond

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Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond Forming at a High-Valent Palladium Center Guoyin Yin, Xin Mu, and Guosheng Liu*

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State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China CONSPECTUS: Difunctionalization of alkenes to incorporate two functional groups across a double bond has emerged as a powerful transformation to greatly increase molecular complexity in organic synthesis with improved efficiency. Historically, palladium-catalyzed difunctionalization of alkenes has suffered from difficulties with introducing a second functional group through reductive elimination of a Pd(II) intermediate and competing β-hydride elimination reactions. To overcome these challenges, one strategy involves utilizing a steric bulky ligand to promote the reductive elimination steps from the Pd(II) center and impeding the β-hydride elimination reactions, which are beyond the scope of this Account. Alternatively, strong oxidants have been utilized to generate high-valent palladium species, which are prone to undergo reductive elimination to form a second C−X bond. This new strategy has been extensively applied to explore the difunctionalization of alkenes with enriched functional group diversity over the past decade. In this Account, we discuss our exploration and application of a “high-valent palladium strategy” for the synthesis of fluorine-containing organic molecules that are typically inaccessible from other methods. These studies were focused on the difunctionalization of alkenes that was initiated by nucleopalladation to form the alkyl C− Pd(II) species in high exo/endo regioselectivity. In the presence of nucleophilic fluorine-containing reagents (e.g., AgF, TMSCF3, and AgOCF3) and strong oxidants (hypervalent iodine and electrophilic fluorinating reagents), the in situ generated fluorinecontaining high-valent Pd(IV) intermediates undergo reductive elimination to provide the corresponding alkyl C−F, C−CF3, and C−OCF3 bonds. Using these methods, we synthesized a variety of heterocycles containing fluorine, trifluoromethyl, and trifluoromethoxyl moieties from alkene substrates under mild reaction conditions. Besides hypervalent iodine reagents and electrophilic fluorinating reagents, our group has demonstrated that hydrogen peroxide, which is an environmentally friendly oxidant, can oxidize alkyl C−Pd(II) species to form high-valent alkyl C−Pd intermediates, and based on this observation, several catalytic difunctionalizations of alkenes, such as aminochlorination, aminoacetoxylation, and aminohydroxylation reactions, have been successfully developed. In addition, water was the only waste derived from the oxidant. All of these studies provide attractive methods for the stereoselective introduction of C−N and C−O bonds across double bonds via high-valent palladium intermediates. To gain a deeper understanding of this “high-valent palladium strategy”, systematic mechanistic studies were performed to illustrate the stereochemistry of aminopalladation and reductive elimination. These results are summarized in the final section and serve as a guide for further exploration of novel alkene transformation as well as in other areas, such as Pdcatalyzed C−H bond functionalization reactions. been reported and involved the Pd(0/II) catalytic cycles.3 However, the more general approaches for developing catalytic transformations are impeded by the inertness of the alkyl− Pd(II) intermediates toward reductive elimination to deliver C−X (X = heteroatom) bonds and suffer from unproductive βH elimination that yield Wacker or Heck type products (Scheme 1a).4 Therefore, a new catalytic system to achieve difunctionalization with broader functional group scope, especially fluorine-containing functional groups, is highly desirable due to their unique physical and biological activities.5 In addition to the Pd(0/II) system, seminal studies on the synthesis and mechanistic studies of high-valent palladium complexes were reported by Canty6 and Bäckvall2 and have laid

1. INTRODUCTION Functionalization of alkenes has been a long-standing research topic in synthetic organic chemistry for the conversion of versatile and readily available olefins into more structurally complex molecules.1 Among the reported efforts in this area, transition metal catalysis has played a crucial role in this field. However, in comparison with the abundant studies on the monofunctionalization of alkenes, the difunctionalization of alkenes remains an underdeveloped area. The pioneering studies provided by Bäc kvall and co-workers on the palladium-catalyzed amination of alkenes involved sequential aminopalladation of an alkene with a stoichiometric amount of a palladium reagent and oxidative cleavage in the presence of various oxidants to afford 1,2-functionalization products.2 In addition, several catalytic difunctionalization reactions, such as aminoarylation, oxyarylations, and aminocarbonylation, have © 2016 American Chemical Society

Received: June 29, 2016 Published: October 14, 2016 2413

DOI: 10.1021/acs.accounts.6b00328 Acc. Chem. Res. 2016, 49, 2413−2423

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Accounts of Chemical Research

envisioned the application of an environmentally benign oxidant (e.g., H2O2) in the Pd-catalyzed difunctionalization of alkenes. In this Account, we summarize our efforts to address these two issues in the next two sections (i.e., application of high-valent palladium chemistry in fluorine chemistry and green oxidations). In the fourth section, we summarize the results from our detailed mechanistic studies on the regioselectivity and stereochemistry of these cyclization reactions.

Scheme 1. Palladium-Catalyzed Oxidative Transformation Reactions of Alkenes

2. PALLADIUM-CATALYZED OXIDATIVE DIFUNCTIONALIZATION OF ALKENES WITH NUCLEOPHILIC FLUORINE AND FLUORINE-CONTAINING REAGENTS Due to having the highest electronegativity and small atomic radius, the incorporation of unique fluorine atoms into drugs can significantly enhance their bioavailability, lipophilicity, and metabolic stability. Currently, more than 20% of pharmaceutical drugs and 30% of agrochemicals on the market contain one or more fluorine atoms, which generates interest in the development of methodologies for the construction of C−F and C−RF bonds. However, due to the weak nucleophilicity (deactivated by hydrogen-bonding with water) and strong basicity (under anhydrous condition) of fluoride and the poor stabilities and steric hindrances of trifluoromethanide and trifluoromethoxide, methods for the direct incorporation of fluorine and RF groups into organic compounds are limited. Pioneering studies provided by Grushin revealed that the reductive elimination of (L)ArPdII−F and (L)ArPdII−RF to afford ArF and ArRF are not facile processes.19 In 2006, Sanford reported a palladiumcatalyzed C−H fluorination reaction in which an electrophilic fluorinating reagent was employed as both the fluorine source and oxidant and a C−F bond was formed through reductive elimination from a high-valent Pd center (Scheme 2a).20 In addition, Vendernikov21 and our group22 reported that the formation of aryl and alkyl C−Cl bonds could be achieved using both an oxidant (H2O2) and an inorganic chloride source

the foundation for the development of catalytic transformations. Since early this century, transition metal-catalyzed C−H functionalization has been intensively explored to enable a variety of chemical bond formations. Among these methods, Catellani,7 Sanford,8 Yu,9 Daugulis,10 Ritter,11 and others have reported the involvement of high-valent palladium species, such as PdIV and PdIII (for convenience, PdIV was described as highvalent palladium species in this Account), in the construction of carbon−carbon and carbon−heteroatom bonds (Scheme 1b).12 Notably, reductive elimination from high-valent palladium was favored over β-hydride elimination. Inspired by these studies, Sorensen,13 Muñiz,14 Stahl,15 Sanford,16 and Michael17 have reported a series of highly efficient Pd(II)-catalyzed oxidative difunctionalization reactions of alkenes, including aminoacetoxylation, diamination, arylchlorination, and aminochlorination (Scheme 1c) since 2005. Over the past decade, this research field has greatly advanced, and increasingly more practical and powerful tools have been developed for organic synthesis. When we started our own research program in 2007, various strong oxidants, such as PhI(OAc)2, PhICl2, N-chlorosuccinimide (NCS), and N-fluorobenzenesulfonimide (NFSI), had been reported for Pd-catalyzed difunctionalization of alkenes to form the corresponding C−O, C−N, and C−Cl bonds. However, several issues, which have been embedded in our research goals, have not yet been addressed: (1) Due to limited types of electrophilic fluorinating (F+) and other electrophilic fluorine-containing (RF+) reagents, we sought to combine the commercially available nucleophilic counterparts and external oxidants to develop diverse oxidative systems to incorporate fluorine or fluorine-containing functional groups into an alkene CC bond via high-valent Pd intermediates. In addition, as a potential application, these methods could be used in the synthesis of nucleophilic [18F]-radiolabeling experiments to further expand the scope of PET-imaging samples.18 (2) To eliminate stoichiometric amounts of byproducts, such as iodobenzene and succinimide, from traditional oxidants, we

Scheme 2. Oxidative Process of Palladium Complex for C−F and C−RF Formation

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Accounts of Chemical Research (HCl, LiCl or CaCl2) rather than an electrophilic chlorinating reagent (for the latter, see Scheme 2b). Inspired by these studies, we surmised that the combination of an easily available nucleophilic F/RF reagent and a strong oxidant may be a potential oxidative process for the delivery of a C−F/RF bond. Guided by this idea, we successfully developed a series of palladium-catalyzed oxidative fluorination and related reactions to achieve the difunctionalization of alkenes (Scheme 2c).

Scheme 3. Pd(II)-Catalyzed Intramolecular Aminofluorination of Alkenes

2.1. Palladium-Catalyzed Oxidative Aminofluorination Reactions of Alkenes

In 2005, Sorensen13 and Muñiz14 reported pioneering studies on the intramolecular aminoacetoxylation and diamination reaction of alkenes, respectively. These reactions likely proceed through a Pd(II/IV) catalytic cycle to generate C−O and C−N bonds. Encouraged by these studies, the intramolecular aminopalladation of alkenes was used as a suitable model system to investigate oxidative fluorination with a strong oxidant and a nucleophilic fluorinating reagent. To our delight, the first Pd-catalyzed intramolecular aminofluorination of Ntosyl alkenes (1) proceeded with good yields and chemoselectivity under the optimized conditions (Scheme 3a).23 Notably, AgF was the only effective nucleophilic fluorinating reagent, and I(III) reagents were the oxidants for the reaction. Alkenes 1 bearing N-tosyl protecting groups underwent 6-endo cyclizations to yield various 3-fluoropiperidines (2a−2d) with excellent regioselectivity. Furthermore, the 3,6-cis-isomer (2d) was delivered with moderate diastereoselectivity (4:1). In addition, substrate 3 bearing a sulfonamide-protecting group afforded the endo-cyclization products (4) in moderate yield as well as excellent regio- and diastereoselectivity.24 However, under modified reaction conditions, when the N-tosyl group was replaced by a strong chelating aminocarbonyl group (substrates 5 and 7), exo-cyclization products 6 and 8 were exclusively obtained in moderate to good yields (Scheme 3b).25 Importantly, chiral substrate 9 can be successfully converted to enantiomeric 3-fluoropiperidine 10 with excellent regio- and diastereoselectivity, and this product acted as a key synthon for the total synthesis of 6-(R)-fluoroswainsonine and 5-(R)fluoroferifugine (Scheme 3c).26 The novel AgF/I(III) oxidative fluorination system was also applied for the intermolecular aminofluorination of styrenes in the presence of a palladium catalyst.27 In addition, Sanford and co-workers demonstrated that this oxidative system is also good for palladium-catalyzed C−H bond oxidative fluorination.28 During our studies on the aminonitroxylation of alkenes, we discovered that the silver ion plays an important role in promoting the formation of PhI(ONO2)2 from PhI(OAc)2 and AgNO3.29 To further test the possibility of using the newly formed electrophilic fluorinating reagent in the aminofluorination reaction, ArIF2 was synthesized and subjected to the standard reaction conditions, but no product was observed. However, the fluorinated product was obtained in the presence of a silver salt (Scheme 4). We reasoned that the silver ion could facilitate the fluoride transfer to the high-valent palladium center, but we were unable to rule out the involvement of ArIF2 as an in situ generated oxidant in the transformations.25

Scheme 4. Mechanistic Study with ArIF2 and the Silver Effect

2.2. Palladium-Catalyzed Oxidative Trifluoromethylation Reactions of Alkenes

Encouraged by our oxidative fluorination studies, we surmised that the combination of a hypervalent iodine reagent and the Ruppert−Prakash reagent (TMSCF3), which is a readily available nucleophilic trifluoromethylation reagent, may be 2415


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addition, the signal at −27.1 ppm in the 19F NMR spectrum was indicative of an alkyl−PdIV−CF3 complex. Based on these observations, the proposed reaction mechanism is provided in Scheme 5c. The final sp3 C−CF3 bond is derived from the reductive elimination of the Pd(IV) complex, and this process can be accelerated by adding a Lewis acid, which has also been demonstrated by Yu32 and Sanford.33

suitable for the oxidative trifluoromethylation of an organopalladium complex, which has been demonstrated in our previous studies on the C−H oxidative trifluoromethylation of indoles.30 In this reaction, PhI(OAc)2 was employed as the oxidant, and CF3 anion was released from TMSCF3 in the presence of CsF. Inspired by this study, a similar catalytic system was applied to survey the oxidative trifluoromethylation of alkenes. In fact, the oxidative aryltrifluoromethylation reaction of alkenes 11 proceeded efficiently to provide various trifluoromethylated oxindoles under mild conditions, and the addition of a catalytic amount of the Yb(OTf)3 Lewis acid is beneficial for furthering improvement of the yields (Scheme 5a).31 However, an enantioselective transformation has not yet

2.3. Palladium-Catalyzed Oxidative Aminotrifluoromethoxylation Reactions of Alkenes

In comparison to fluorination and trifluoromethylation reactions, direct trifluoromethoxylation is a more formidable challenge. Due to the instability of the OCF3 anion, only a limited number of inorganic trifluoromethoxide reagents, such as CsOCF3, AgOCF3, and R4NOCF3, can be used, and electrophilic trifluoromethoxylating reagents are rarely reported. In addition, the facile β-fluoride elimination of the CF3O-ligated transition-metal complex (MOCF3) further impedes the metal-catalyzed trifluoromethoxylation reaction.34 Based on our previous understanding of the properties of highvalent palladium species, we speculated that the lack of open coordination sites on a high-valent palladium center may impede the β-fluoride elimination, and facile reductive elimination could deliver the desired C−OCF3 bond. By use of substrate 1 in the aminofluorination along with a hypervalent iodine reagent and AgOCF3, the desired aminotrifluoromethoxylation products 13 can be observed in the presence of a palladium catalyst. However, byproducts including aminofluorination and fluoroformylation of sulfonylamides were also obtained. However, these side reactions were significantly suppressed at a lower temperature (−20 °C), and using SelectFluor rather than the I(III) reagents as an oxidant provided higher yields with better reproducibility. The reactions underwent 6-endo-cyclization to yield 3-CF3O substituted piperidines in good yields (Scheme 6a).35 It is important to note that this reaction is the first example of a catalytic reaction that incorporates a OCF3 group into organic molecules. In 2012, Sanford and co-workers elucidated the detailed mechanism of sp3 C−F bond-forming reductive eliminations from a Pd(IV) center.36 In this case, the oxidation of Pd(II) complex 14 by NFTPB (N-fluoro-2,4,6-trimethylpyridine triflate) afforded the high-valent palladium fluoride complex 15, which could undergo reductive elimination to form the sp3 C−F bond in excellent yields. Inspired by this work, complex 14 was also employed to address the sp3 C−OCF3 bondforming step. Similar to Sanford’s results, Pd(IV) fluoride complex 15 could be obtained quantitatively in the presence of SelectFluor and reacted rapidly with AgOCF3 to afford a new palladium complex at 0 °C. Upon warming the solution to room temperature, the sp3 C−OCF3 bond was formed. A Pd(IV) trifluoromethoxide complex 17 may have been formed, and the following reductive elimination resulted in the C− OCF3 bond formation (Scheme 6b).35 Notably, when the reaction was conducted in CH3CN, decomposition of trifluoromethoxide yielded a Pd(IV) fluoride complex, which afforded a small amount of C−F bond-forming palladium complex 16 at room temperature. Similar to the oxidative fluorination, only AgOCF3 yielded the desired trifluoromethoxylation products efficiently, and other OCF3 reagents exhibited low reactivity. Therefore, silver may play a role similar to that in oxidative fluorination to

Scheme 5. Pd-Catalyzed Oxidative Aryltrifluoromethylation of Alkenes

been achieved. Electrophilic [CF3+] reagents, such as Togni’s reagent and Umemoto’s reagent, are ineffective for the transformation. It is important to note that diene substrate 11e can be converted to a single diastereomer (12e) in 62% yield, which indicates the involvement of a C(sp3)−Pd intermediate generated via arylpalladation of an alkene (Scheme 5b). Further ESI-MS experiments observed fragment signals at m/z = 435, 678, and 668 that are consistent with the proposed fragment mass of Pd(II) complex I [I − OAc]+ and Pd(IV) complexes IV [IV − OAc]+ and [IV − CF3]+. In 2416


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Accounts of Chemical Research Scheme 6. Pd(II)-Catalyzed Aminotrifluoromethoxylation Reaction

3.1. Palladium-Catalyzed Oxidative Chlorination Reactions

promote faster OCF3 transfer to the high-valent palladium center (see part 2.1.).

In 2007, during our first project related to the Pd(II)-catalyzed oxidative cyclization of enynes, we were surprised to observe the formation of sp3 C−Cl bond formation product 21a under aerobic reaction conditions in low yield (10%).22 Because the C−Cl bond-forming reductive elimination from a Pd(II) complex is less likely, we speculated that the hydrogen peroxide generated in situ may acts as the oxidant to promote the oxidation of the Pd(II) species, and the as-formed high-valent palladium complex underwent reductive elimination to generate the desired sp3 C−Cl bond. When 30 wt % aqueous hydrogen peroxide was used as the oxidant rather than dioxygen, chlorination product 21a was obtained in good yield (Scheme 7a). With LiCl as the optimal chlorine source, a variety of chlorinated lactones or lactams were efficiently obtained (Scheme 7b). Notably, 2−3 equiv of H2O2 was sufficient for the transformation, and no significant hydrogen peroxide decomposition was observed at room temperature. With the established oxidative chlorination system in hand, Pd(II)-catalyzed oxidative aminochlorination was also investigated. Unfortunately, the H2O2/LiCl system afforded only a small amount of the desired product, and the alkene isomerization product was obtained as the major product. However, the modified H2O2/CaCl2 system underwent 6-endo cyclization to yield 3-chloropiperidines with excellent regio- and

3. PALLADIUM-CATALYZED OXIDATIVE DIFUNCTIONALIZATION OF ALKENES WITH HYDROGEN PEROXIDE In addition to the use of hypervalent iodine reagents, NXS, NFSI, etc, in the Pd-catalyzed difunctionalization of alkenes, we have also been searching for “green” oxidants to achieve similar transformations. In the past few decades, molecular oxygen (O2) has been widely recognized as an ideal oxidant that has been successfully applied in numerous important organic transformations. For example, in Pd(II)-catalyzed aerobic oxidative reactions, dioxygen has been applied to regenerate the reduced Pd(0) species to the Pd(II) catalyst in the presence or absence of cocatalysts. However, due to the higher oxidative potential of Pd(II/IV) compared to that of Pd(0/II), the use of dioxygen to achieve the oxidation of Pd(II) to Pd(IV) is much more difficult.37 In contrast, hydrogen peroxide (H2O2), which has a higher oxidation potential, can oxidize Pd(II) to Pd(IV).38 Nevertheless, palladium-catalyzed oxidative reactions utilizing H2O2 as the sole oxidant have proved less successful due to the disproportionation of H2O2 and the competing Wacker process in the Pd-catalyzed oxidation of alkenes that affords ketone or aldehyde side products.39 2417


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valent palladium center. Second, chloride served as a ligand to coordinate with palladium and impede the β-hydride elimination. In fact, when the reaction of 1a was conducted under similar reaction conditions but without the inorganic chloride salt, no aminocyclization product was observed. However, the reaction afforded ketone product 24a in 75% yield, which is most likely derived from the sequential exoaminopalladation, β-H elimination to generate enamine product 24a′, and subsequent hydrolysis process (Scheme 9a). Inspired by the studies of Lu,42 some bidentate nitrogen-

Scheme 7. Pd-Catalyzed Oxidative Cyclization and Chlorination of Enynes

Scheme 9. Pd(II)-Catalyzed Intramolecular Aminoacetoxylation Reaction

diastereoselectivity (Scheme 8a).40 Similar to previous aminofluorination, the regioselectivity could be tuned by changing the Scheme 8. Pd(II)-Catalyzed Intramolecular Aminochlorination Reactions with H2O2 as an Oxidant

containing ligands were applied to inhibit β-hydride elimination. Interestingly, electron-deficient ligands, such as 4,5diazafluoren-9-one (DFA) and dipyridylketone (dpk), significantly suppressed the side reaction and afforded aminoacetoxylation product 25a in good yield. In addition, the dpk ligand exhibited better chemo- and regioselectivity than DFA (Scheme 9a).43 In addition, a variety of 3-acetoxylated piperidines were synthesized under standard conditions with high yields and excellent regioselectivities. Notably, for the αsubstituted alkenylamine substrates, the reaction also proceeded with excellent diastereoselectivity (>20:1, Scheme 9b). Furthermore, using dpk as the ligand, the deuterium-labeled substrate trans-1a-d1 delivers the single isomer trans-25a-2-d1. However, a mixture of isomers was obtained when bpy was used as the ligand (Scheme 10a). These observations indicated that the dpk ligand plays an important role in accelerating the oxidative cleavage of the C−Pd bond to generate the C−OAc bond. The formation of a semiketal intermediate from the reversible nucleophilic addition of H2O2 to dpk may facilitate the Pd(II) oxidation.

protecting group on the nitrogen atom. When the tosyl group was replaced by an aminocarbonyl group (substrate 5), the reaction completely switched to a 5-exo cyclization to afford chlorination products 23 in good yields (Scheme 8b).41 3.2. Palladium-Catalyzed Oxidative Aminoacetoxylation Reactions

In these chlorination reactions, the application of chloride played two roles. First, chloride served as the nucleophile to form the C−Cl bond through reductive elimination at the high2418


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Accounts of Chemical Research Scheme 10. Effect of dpk Ligand on the Palladium Oxidation

Vedernikov and co-workers.46 Their results demonstrated that MePtIV(OH)2 is involved in this nucleophilic reaction via two nucleophiles (i.e., water and itself). Therefore, a similar pathway may also be involved in the aminohydroxylation reaction, and the palladium oxidation by hydrogen peroxide was confirmed to be the rate-determining step.

In 2010, Vedernikov and co-workers reported that the sp2 aryl-palladium complex 27 bearing a dpk ligand could be oxidized by hydrogen peroxide to provide high-valent palladium complex 28 at 0 °C, and the sequential reductive elimination could occur at room temperature to generate the sp2 C−O bond (Scheme 10b).21 Furthermore, the related aryl−PdIVX complexes (X = Cl, Br) were obtained with H2O2/HX, which led to the formation of the C−X bond. In addition, Sanford and co-workers reported that the alkyl−Cl bond can be readily formed from the PdIV compound via reductive elimination using PhICl2 as the oxidant.44

4. MECHANISTIC INVESTIGATIONS OF THE CATALYTIC CYCLES During our studies of the oxidative aminations of alkenes, such as aminochlorination, aminofluorination, and aminoacetoxylation as well as aminotrifluoromethoxylation reactions, we discovered that N-protecting groups can be used to tune the regioselectivities of all of the reactions. For N-tosyl protected substrates, endo-cyclization products were always obtained with high regioselectivity. However, the alkenyl substrates with an N-aminocarbonyl group typically generated only exo-cyclization products (Scheme 12a). A reversible aminopalladation has been proposed to form endo-cyclization intermediate 34 and exocyclization intermediate 35. Due to the rate-determining oxidation of alkyl−Pd(II) by oxidants, more electron-rich secondary alkyl−Pd intermediate 34 can be oxidized faster than primary alkyl−Pd intermediate 35, which may contribute to the highly selective formation of piperidine products (Scheme 12b).40 In addition, Stahl and co-workers demonstrated that the related exo-cyclization of intermediate 35 that was stabilized by the bidentate nitrogen ligand could be converted to the alkene in the presence of acid (Scheme 12c).47 However, in the case of N-aminocarbonyl groups, the reaction involves an irreversible aminopalladation to afford intermediate 38 due to the kinetically favored exo-cyclization and chelation of palladium by the carbonyl, which resulted in the exo-cyclization product.25 It is important to note that due to the lack of isolation and

3.3. Palladium-Catalyzed Oxidative Aminohydroxylation Reactions

During our studies of the aminoacetoxylation, N-Ts alkenyl carbamate 30a was converted to unexpected 5-exo aminohydroxylation product 31a in 32% yield, and the expected aminoacetoxylation product 32a (48% yield) was formed in the absence of a bidentate nitrogen-containing ligand. Control experiments indicated that 31a was not derived from the hydrolysis of 32a (Scheme 11a). Based on this observation, when the solvent was switched from HOAc to acetone or dioxane, the reaction provided aminohydroxylation product 31a with excellent yields. The addition of the LiO2CCF3 Lewis acid was beneficial for further improving the yield. A broad substrate scope derived from the allylic alcohols provided various aminohydroxylation products with excellent diastereoselectivity (Scheme 11b).45 Further isotope labeling experiments were conducted using H2O2 in H218O to analyze the origin of the hydroxyl group (Scheme 11c). The reaction provides a mixture with both 16O and 18O incorporation, suggesting H2O is the major source of the hydroxyl group, and this result is consistent with the observation in the Shilov’s reaction that was reported by 2419


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Accounts of Chemical Research Scheme 11. Pd(II)-Catalyzed Intramolecular Aminohydroxylation Reaction

Scheme 12. Proposed Mechanism Based on the Regioselectivity

characterization of endo-aminopalladation intermediate 34, further investigation is required to illustrate the detailed mechanism. Furthermore, when deuterium-labeled substrate trans-1a-d1 was used to investigate the stereochemistry of the oxidative transformations, only the trans-isomer was obtained with high diastereoselectivity (Scheme 13a). A sequential trans-aminopalladation to afford a secondary C−Pd complex and direct reductive elimination at the high-valent palladium center have been proposed to address the stereochemistry (Scheme 13b). Gagné and co-workers also reported that the configuration at the carbon center was retained in the oxidative fluorination of alkyl−Pd complexes using the NFSI as the electrophilic fluorinating reagent (Scheme 13c).48 In comparison to the previously mentioned secondary C−Pd complex, the primary C−Pd complex was involved in the oxidative aminohydroxylation. The reaction of trans-30a-d1 in dioxane yielded trans-31a-d1 as the major product along with a trace amount of E-40a-d1, indicating that the reaction undergoes cis-aminopalladation, and the final reductive elimination of primary C−Pd(IV) involves a predominantly SN2 type nucleophilic attack process. For the reaction in HOAc, although trans-aminopalladation is observed, the SN2 type reductive elimination also occurs at the high-valent palladium center (Scheme 14a).46 A similar S N2 type reductive elimination has also been reported at the primary alkyl− Pd(IV) center under room temperature by Muñiz.14b However, the intermolecular aminoacetoxylation of alkenes conducted at

70 °C resulted in both an SN2 nucleophilic attack and a direct reductive elimination pathway to form the C−O bond (Scheme 14b).15b Unfortunately, the related stereochemistry of the halogenation of primary alkyl−Pd(IV) species is currently unknown.

5. SUMMARY AND PERSPECTIVE The facile reductive elimination from high-valent palladium intermediates has been extensively studied over the past decade and determined to be an extremely effective strategy for the difunctionalization of alkenes. In general, a combination of nucleophilic fluorinating or fluorine-containing (RF) reagents and strong oxidants can effectively convert alkenes to various fluorine-containing heterocycles using a palladium catalyst. In addition, H2O2 can be used as a green oxidant to successfully perform alkene difunctionalization reactions. These discoveries provide insight for the development of future environmentally friendly processes. Detailed mechanistic studies were also discussed in terms of the regioselectivity of the cyclization and the bond-forming stereochemistry of the reductive elimination from high-valent palladium species. These reaction modes have illustrated the enormous opportunity to further develop asymmetric reactions. In fact, our preliminary studies on the palladium-catalyzed 2420


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intramolecular aminoacetoxylation and aminohydroxylation reactions demonstrated encouraging enantioselective induction in the presence of chiral bipyridine ligands (eqs 1 and 2). We

Scheme 13. Proposed Mechanism Based on the Stereoselectivity of the Secondary Alkyl−Pd Complex

are continuing our efforts in this field to develop new alkene difunctionalization reactions with higher efficiency and “greener” properties while gaining increased mechanistic knowledge that can further facilitate our study of the enantioselective difunctionalization of alkenes.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Webpage: http://guoshengliu. sioc.ac.cn/. Notes

The authors declare no competing financial interest. Scheme 14. Proposed Mechanism Based on the Stereoselectivity of Primary Alkyl−Pd Complex

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Accounts of Chemical Research Biographies

(6) (a) Canty, A. J. Organopalladium and platinum chemistry in oxidising milieu as models for organic synthesis involving the higher oxidation states of palladium. Dalton. Trans. 2009, 47, 10409−10417. (b) Canty, A. J. Development of organopalladium(IV) chemistry: fundamental aspects and systems for studies of mechanism in organometallic chemistry and catalysis. Acc. Chem. Res. 1992, 25, 83−90. For the similar studies on the Pt(IV), see: Fekl, U.; Kaminsky, W.; Goldberg, K. I. A stable Five-Coordinate Platinum(IV) Alkyl Complex. J. Am. Chem. Soc. 2001, 123, 6423−6424. (7) Catellani, E.; Motti, N.; Della Ca’, N. Catalytic Sequential Reactions Involving Palladacycle-Directed Aryl Coupling Steps. Acc. Chem. Res. 2008, 41, 1512−1522. (8) Neufeldt, S. R.; Sanford, M. S. Controlling Site Selectivity in Palladium-Catalyzed C-H Bond Functionalization. Acc. Chem. Res. 2012, 45, 936−946. (9) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Pd-Catalyzed Stereoselective Oxidation of Methyl Groups by Inexpensive Oxidants under Mild Conditions: A Dual Role for Carboxylic Anhydrides in Catalytic C-H Bond Oxidation. Angew. Chem., Int. Ed. 2005, 44, 7420− 7424. (10) (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds. Acc. Chem. Res. 2009, 42, 1074−1086. (b) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon−Hydrogen Bonds. Acc. Chem. Res. 2015, 48, 1053−1064. (11) Powers, D. C.; Ritter, T. Bimetallic Synergy in Oxidative Palladium Catalysis. Acc. Chem. Res. 2012, 45, 840−850. (12) (a) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Emergence of Palladium(IV) Chemistry in Synthesis and Catalysis. Chem. Rev. 2010, 110, 824−889. (b) Hickman, A. J.; Sanford, M. S. High-valent organometallic copper and palladium in catalysis. Nature 2012, 484, 177−185. (c) Muñiz, K. High-Oxidation-State Palladium Catalysis: New Reactivity for Organic Synthesis. Angew. Chem., Int. Ed. 2009, 48, 9412−9423. (d) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Bystanding F+ Oxidant Enable Selective Reductive Elimination from High-Valent Metal Centers in Catalysis. Angew. Chem., Int. Ed. 2011, 50, 1478−1491. (13) Alexanian, E. J.; Lee, C.; Sorensen, E. J. Palladium-Catalyzed Ring-Forming Aminoacetoxylation of Alkenes. J. Am. Chem. Soc. 2005, 127, 7690−7691. (14) (a) Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. Palladium(II)-Catalyzed Intramolecular Diamination of Unfunctionalized Alkenes. J. Am. Chem. Soc. 2005, 127, 14586−14587. (b) Muñiz, K.; Hövelmann, C. H.; Streuff, J. Oxidative Diamination of Alkenes with Ureas as Nitrogen Sources: Mechanistic Pathways in the Presence of a High Oxidation State Palladium Catalyst. J. Am. Chem. Soc. 2008, 130, 763−773. (c) Muñiz, K. Advancing Palladium-Catalyzed C−N Bond Formation: Bisindoline Construction from Successive Amide Transfer to Internal Alkenes. J. Am. Chem. Soc. 2007, 129, 14542− 14543. (d) Iglesias, Á .; Pérez, E. G.; Muñiz, K. An Intermolecular Palladium-Catalyzed Diamination of Unactivated Alkenes. Angew. Chem., Int. Ed. 2010, 49, 8109. (e) Martínez, C.; Muñiz, K. PalladiumCatalyzed Vicinal Difunctionalization of Internal Alkenes: Diastereoselective Synthesis of Diamines. Angew. Chem., Int. Ed. 2012, 51, 7031−7034. (15) (a) Liu, G.; Stahl, S. S. Highly Regioselective Pd-Catalyzed Intermolecular Aminoacetoxylation of Alkenes and Evidence for cisAminopalladation and SN2 C-O Bond Formation. J. Am. Chem. Soc. 2006, 128, 7179−7181. (b) Martínez, C.; Wu, Y.; Weinstein, A. B.; Stahl, S. S.; Liu, G.; Muñiz, K. Palladium-Catalyzed Intermolecular Aminoacetoxylation of Alkenes and the Influence of PhI(OAc)2 on Aminopalladation Stereoselectivity. J. Org. Chem. 2013, 78, 6309− 6315. (16) (a) Desai, L. V.; Sanford, M. S. Construction of Tetrahydrofurans by PdII/PdIV-Catalyzed Aminooxygenation of Alkenes. Angew. Chem., Int. Ed. 2007, 46, 5737−5740. (b) Kalyani, D.; Sanford, M. S. Oxidatively Intercepting Heck Intermediates: Pd-Catalyzed 1,2- and

Guoyin Yin received his B.S. degree in chemistry from Northeast Agriculture University (2006) and his Ph.D. degree from Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS, 2011), under the supervision of Professor Guosheng Liu. Since 2011, he conducted his postdoctoral research at Technical University of Munich with Professor Thorsten Bach, as an Alexander von Humboldt Postdoctoral Fellow at RWTH Aachen University with Professor Franziska Schoenebeck, and at the University of Delaware with Professor Donald A. Watson. Then, he joined Wuhan University as an associate professor to start his independent research career. Xin Mu obtained his B.S. degree in chemistry from Zhejiang University (2008) and his Ph.D. degree from SIOC, CAS (2013), under the supervision of Professor Guosheng Liu. His research included the discovery of novel metal-catalyzed fluorination and trifluoromethylation of alkenes and arenes. Since February 2014, he has been performing postdoctoral research in the laboratory of Professor Gregory C. Fu at the California Institute of Technology as a SIOC postdoctoral research fellow. Guosheng Liu is a Professor of Chemistry at SIOC, China. He studied chemistry at Nanjing University of Science and Technology (1995) and obtained his M.S. degree at Dalian Institute of Physical Chemistry, CAS, in China (1999), with Professor Zhuo Zheng. Then, he moved to the group led by Professor Xiyan Lu at SIOC, CAS, where he received his Ph.D. in 2002. From 2003 to 2007, he conducted postdoctoral research at Lehigh University with Professor Li Jia and University of WisconsinMadison with Professor Shannon S. Stahl. In 2007, he began his independent career at SIOC, CAS. His current research interests focus on the development of novel synthetic methodologies, such as difunctionalization of alkenes and C−H functionalization, including fluorination and related transformations using transition metals.

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ACKNOWLEDGMENTS We thank all the co-workers from the Liu group at Shanghai Institute of Organic Chemistry, particular these involved in the high-valent palladium chemistry toward the difunctionalization of alkenes, for their invaluable intellectual and experimental contributions. We are grateful for financial support from the National Basic Research Program of China (Grant 9732015CB856600) and the National Nature Science Foundation of China (Nos. 21225210, 21532009, 21421091, and 21472219).

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REFERENCES

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