An unusual formal migrative cycloaddition of aurone-derived azadienes: synthesis of benzofuran-fused nitrogen heterocycles

Aurone-derived azadienes are well-known four-atom synthons for direct [4 + n] cycloadditions owing to their s-cis conformation as well as the thermodynamically favored aromatization nature of these processes. However, distinct from this common reactivity, herein we report an unusual formal migrative annulation with siloxy alkynes initiated by [2 + 2] cycloaddition. Unexpectedly, this process generates benzofuran-fused nitrogen heterocyclic products with formal substituent migration. This observation is rationalized by less common [2 + 2] cycloaddition followed by 4π and 6π electrocyclic events. DFT calculations provided support to the proposed mechanism.

A HNTf₂-catalyzed formal migrative cycloaddition of aurone-derived azadienes with siloxy alkynes has been developed to provide access to benzofuran-fused dihydropyridines.

Benzofuran is an important scaffold in biologically important natural molecules and therapeutic agents.¹ Among them, benzofuran-fused nitrogen heterocycles are particularly noteworthy owing to their broad spectrum of bioactivities for the treatment of various diseases (Fig. 1).² Consequently, the development of efficient methods for their assembly has been a topic receiving enthusiastic attention from synthetic chemists.³ Notably, aurone-derived azadienes (e.g., 1) have been extensively employed as precursors toward these skeletons owing to their easy availability and versatile reactivity (Scheme 1a).³ The polarized conjugation system, combined with the preexisting s-cis conformation, has enabled them to serve as ideal annulation partners for the synthesis of nitrogen heterocycles of variable ring sizes. Moreover, the aromatization nature of these processes by forming a benzofuran ring provides additional driving force for them to behave as a perfect four-atom synthon for [4 + n] cycloaddition.³ In contrast, the use of such species as a two-atom partner for [2 + n] cycloaddition has been less developed.^3c,k,4 Herein, we report a new migrative annulation leading to benzofuran-fused dihydropyridines of unexpected topology (Scheme 1b, with formal R² migration), which is initiated by the less common [2 + 2] cycloaddition.Open in a separate windowFig. 1Benzofuran-fused N-heterocyclic natural and bioactive molecules.Open in a separate windowScheme 1Synthesis of benzofuran-fused nitrogen heterocycles.Siloxy alkynes are another important family of building blocks in organic synthesis.^5–8 The presence of a highly polarized C–C triple bond enables such molecules to serve as versatile two-carbon cycloaddition partners in various annulation reactions.^5–7 In the above context and in continuation of our interest in the study of such electron-rich alkynes,⁷ we envisioned that the reaction between aurone-derived azadienes 1 and siloxy alkynes 2 should lead to facile electron-inversed [4 + 2] cycloaddition to form benzofuran-fused dihydropyridine products (Scheme 1b). Interestingly, the expected product 3′ from direct [4 + 2] cycloaddition was not observed. Instead, a dihydropyridine product 3 with formal R² migration was observed. Careful analysis of the mechanism suggested that a [2 + 2] cycloaddition followed by 4π and 6π electrocyclic steps might be responsible for this unexpected product topology (vide infra).We began our investigation with the model substrates 1a and 2a, which were easily prepared in one step from aurone and 1-hexyne, respectively.⁸ Various Lewis acids were initially examined as potential catalysts for this cycloaddition (Table 1). Unfortunately, common Lewis acids (e.g., TiCl₄, BF₃·OEt₂, Sc(OTf)₃, In(OTf)₃, and AgOTf) were all ineffective (entries 1–5). Substrate decomposition into an unidentifiable mixture was typically observed. However, further screening indicated that AgNTf₂ served as an effective catalyst, leading to benzofuran-fused dihydropyridine 3a in 44% yield (entry 6). Careful analysis by X-ray crystallography confirmed that it was not formed by simple [4 + 2] cycloaddition, as the positions of the phenyl and the siloxy groups were switched (vs. the expected topology). The distinct catalytic performance of AgNTf₂ (vs. AgOTf) suggested that the triflimide counter anion Tf₂N⁻ might be important. However, further screening of various metal triflimide salts did not improve the reaction efficiency (entry 7). Instead, we were delighted to find that the corresponding Brønsted acid HNTf₂ served as a better catalyst (57% yield, entry 8). However, triflic acid (TfOH) led to no desired product in spite of complete conversion (entry 9). After considerable efforts in the optimization of other reaction parameters, an improved yield of 75% was obtained with 2.5 mol% of HNTf₂ and 2.5 equivalents of 2a at 60 °C (entry 10). Solvent screening indicated that the reaction proceeded faster in DCE with comparable yield (entry 11). However, other solvents were all inferior (entries 12–15). Finally, with a reversed order of addition of the two reactants, the yield was slightly improved (entry 16). We believe that this might be related to the relative decomposition rates of the substrates.Reaction conditions^a

Regioselective B(3,4)–H arylation of o-carboranes by weak amide coordination at room temperature

Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.

B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides.

o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.¹ The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,² medicine,³ optoelectronics,⁴ nanomaterials,⁵ boron neutron capture therapy agents⁶ and organometallic/coordination chemistry.⁷ In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).⁸ Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),⁹ with major contributions by the groups of Xie,¹⁰ and Yan,¹¹ among others.¹² Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),¹³ and amide-assisted B(4,7,8)–H arylations¹⁴ (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.^15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.¹⁷ Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.¹⁸ In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.¹⁹ Within our program on sustainable C–H activation,²⁰ we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1^†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)₂ and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).²¹ Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag₂O, K₂HPO₄, and Na₂CO₃ failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI^†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag₂CO₃ resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditions^a

Rh(iii)-catalyzed tandem annulative redox-neutral arylation/amidation of aromatic tethered alkenes

Transition-metal-catalyzed directed C–H functionalization has emerged as a powerful and straightforward tool to construct C–C bonds and C–N bonds. Among these processes, the intramolecular annulative alkene hydroarylation reaction has received much attention because this intramolecular annulation can produce more complex and high value-added structural motifs found in numerous natural products and bioactive molecules. Despite remarkable progress, these annulative protocols developed to date remain limited to hydroarylation and functionalization of one side of alkenes, thus largely limiting the structural diversity and complexity. Herein, we developed a rhodium(iii)-catalyzed tandem annulative arylation/amidation reaction of aromatic tethered alkenes to deliver a variety of 2,3-dihydro-3-benzofuranmethanamine derivatives bearing an all-carbon quaternary stereo center by employing 3-substituted 1,4,2-dioxazol-5-ones as an amidating reagent to capture the transient C(sp³)–Rh intermediate. Notably, by simply changing the directing group, a second, unsymmetrical ortho C–H amidation/annulation can be achieved to provide tricyclic dihydrofuro[3,2-f]quinazolinones in good yields.

A rhodium(iii)-catalyzed tandem annulative arylation/amidation reaction of aromatic tethered alkenes was developed to deliver a variety of 2,3-dihydro-3-benzofuranmethanamine derivatives.

Transition-metal-catalyzed C–H functionalization for the direct conversion of C–H bonds to C–C bonds and C–N bonds has evolved into a widespread and effective strategy for fine chemical production.¹ Among these processes, the hydroarylation of C–C double bonds via a C–H addition has been well-established and become an effective strategy to access synthetically useful structural motifs.¹ Recently, this alkene hydroarylation reaction has received much attention in an intramolecular fashion² (Scheme 1a) because this intramolecular annulation can produce more complex and high value-added structural motifs found in numerous natural products and bioactive molecules (Fig. 1).³ Despite remarkable progress in this area, most of the annulative protocols developed to date remain limited to one-component intramolecular alkene hydroarylation and functionalization of one side of alkenes. More challenging C–H arylation of intramolecular alkenes followed by a tandem coupling with a different coupling partner have unfortunately proven elusive thus far, thus largely limiting the structural diversity and complexity.Open in a separate windowFig. 1Representative bioactive 2,3-dihydrobenzofurans.Open in a separate windowScheme 1Transition-metal-catalyzed C–H functionalization to construct the C–C and C–N bonds.On the other hand, nitrogen-containing molecules have gained great attention due to their widespread presence in natural products and widespread use in pharmaceutical science.⁴ During the last two decades, transition-metal-catalyzed direct C(sp²)–H amination/amidation assisted by chelating directing group is a well-established strategy.⁵ Recently, several examples of C(sp³)–H amination/amidation have also been reported for the efficient installation of C–N bonds.^6,7 Mechanistically, the reaction is initiated by a chelation-assisted C–H metalation to form a C(sp³)–M species, which is then coupled with amination reagents to construct the C–N bonds.In this context, we wondered if a catalytic annulative C–H arylation of a O-bearing olefin-tethered arenes might be possible, thus leading to a C(sp³)–M intermediate, which upon capture with a amidation reagent to construct a new C–N bond and provide bioactive 2,3-dihydro-3-benzofuranmethanamine derivatives. Inherently, the tandem annulative 1,2-arylation/amidation of alkenes has several challenges. First, the resulting C(alkyl)–M intermediate is liable to undergo protonation to provide the alkene hydroarylation products.^1,2 Moreover, a potential competing β-H elimination of the resulting C(alkyl)–M intermediate also required to be suppressed. In addition, compared with the C(sp²)–M species, the resulting C(alkyl)–M species is relatively unstable and also has a low reactivity.To address these challenges and with our continuing interest in the Rh(iii)-catalyzed C–H functionalization,⁸ we introduced a Weinreb amide as a directing group and 3-substituted 1,4,2-dioxazol-5-ones as the amide sources⁹ to trigger a new tandem annulative 1,2-arylation/amidation of alkenes via a Rh(iii)-catalyzed C–H activation,¹⁰ providing a variety of synthetically challenging 2,3-dihydro-3-benzofuranmethanamine derivatives bearing an all-carbon quaternary stereo center (Scheme 1b). More importantly, through simply changing the directing group, a second, unsymmetrical ortho C–H amidation/annulation could be realized to provide tricyclic dihydrofuro[3,2-f]quinazolinone derivatives. This protocol provides a good complement to previously reported carboamination reactions.¹¹To begin our studies, Weinreb amide 1a was reacted with methyl dioxazolone 3a in the presence of various catalyst and AgSbF₆ at 70 °C in DCE (Table 1, entries 1–4). The use of [Cp*RhCl₂]₂ as the catalyst was found to be crucial to give the desired tandem annulative product 4a, with other catalysts, such as [Ru(p-cymene)Cl₂]₂, [Cp*IrCl₂]₂, and Cp*Co(CO)I₂, resulting in no desired product. Attempt to increase or lower the reaction temperature led to a slightly low yield (entries 5 and 6). Interestingly, when employing a NH–OMe amide 2a as the substrate and using 3 equivalent of 3a, a second, unsymmetrical ortho C–H amidation/annulation was achieved to provide the tricyclic dihydrofuro[3,2-f]quinazolinone 5a in 50% yield (entry 7). A screen of additives (entries 8–10) identified LiOAc as the optimal additive, affording the desired product 5a in 93% yield (entry 10). The Rh(iii) catalyst was found to be crucial for this tandem annulative arylation/amidation reaction, with no reactivity in its absence (entries 11 and 12).Optimization of reaction conditions^a

S(vi) in three-component sulfonamide synthesis: use of sulfuric chloride as a linchpin in palladium-catalyzed Suzuki–Miyaura coupling

Sulfuric chloride is used as the source of the –SO₂– group in a palladium-catalyzed three-component synthesis of sulfonamides. Suzuki–Miyaura coupling between the in situ generated sulfamoyl chlorides and boronic acids gives rise to diverse sulfonamides in moderate to high yields with excellent reaction selectivity. Although this transformation is not workable for primary amines or anilines, the results show high functional group tolerance. With the solving of the desulfonylation problem and utilization of cheap and easily accessible sulfuric chloride as the source of sulfur dioxide, redox-neutral three-component synthesis of sulfonamides is first achieved.

Sulfuric chloride is used as the source of the –SO₂– group in a palladium-catalyzed three-component synthesis of sulfonamides.

Since its development in the 1970s,¹ Suzuki–Miyaura coupling has become a widely used synthetic step in diverse areas. With two of the most widely sourced materials, organoborons and alkyl/aryl halides, a number of C–C coupling reactions are established and the Suzuki–Miyaura reaction has successfully acted as the key step in the synthesis of medicines and agrochemicals.²In addition to the well-known aryl halides and esters, various other substrates such as acid chlorides,³ anhydrides,⁴ diazonium salts⁵ and sulfonyl chlorides⁶ were also reported for the coupling in the past decades. As far as acid chlorides are concerned, carbamoyl chlorides were successfully transformed to the corresponding benzamides in the early years of the 21st century.⁷ However, the use of sulfamoyl chlorides as coupling partners is challenging due to the strong electron-withdrawing properties of the sulfonyl group, which cause the tendency of desulfonylation to form tertiary amines.Synthesis of sulfonyl-containing compounds, especially sulfones and sulfonamides, via the insertion of sulfur dioxide has been extensively studied during the last decade.⁸ A series of sulfur-containing surrogates have been developed as the source of the –SO₂– group. Willis and co-workers first reported the use of DABCO·(SO₂)₂, a bench-stable solid adduct of DABCO and gaseous SO₂ discovered by Santos and Mello,^9a as the source of sulfur dioxide in the synthesis of sulfonylhydrazines.^9b Soon after, alkali metal metabisulfites were found to provide sulfur dioxide for the formation of sulfonyl compounds.¹⁰ In the recent developments in this field, DABCO·(SO₂)₂ and metabisulfites have become the most popular SO₂ surrogates for the insertion of sulfur dioxide.⁸ However, the practical applications of sulfur dioxide insertion reactions are limited by atom-efficiency problems and the unique properties of reactants. For instance, the three-component synthesis of aryl sulfonylhydrazines using aryl halides, SO₂ surrogates and hydrazines by a SO₂-doped Buchward–Hartwig reaction was realized in the earliest developments in this field.¹⁰ However, similar transformations from aryl halides and amines to the corresponding sulfonamides still remain unresolved (Scheme 1a).^11,12Open in a separate windowScheme 1Synthetic approaches to sulfonamides.In order to provide a simple and efficient method for the three-component synthesis of aryl sulfonamides without the pre-synthesis of sulfonyl chlorides, many scientists have made various attempts. Interestingly, the use of arylboronic acids instead of aryl halides provided an alternative route. An oxidative reaction between boronic acids, DABCO·(SO₂)₂ and amines for the preparation of aryl sulfonamides at high temperature was realized,¹² while reductive couplings of boronic acids, SO₂ surrogates and nitroarenes were also reported (Scheme 1b).¹³ However, due to the reversed electronic properties of boronic acids from halides, additional additives and restrictions had to be considered. Extra oxidants and harsh conditions were usually used, and some of the transformations required “oxidative” substrates, such as nitroarenes and chloroamines.¹⁴Early in 2020, a reductive hydrosulfonamination of alkenes by sulfamoyl chlorides was reported,¹⁵ which gave us the inspiration to use in situ generated sulfamoyl chlorides as the electrophile for the synthesis of aryl sulfonamides by Suzuki–Miyaura coupling. In this way, sulfamoyl chlorides could be formed by nucleophilic substitution of an amine to sulfuric chloride, and the S(vi) central atom introduced into the reaction could reverse the electronic properties of the amine, which would eliminate the addition of oxidants (Scheme 1c). With the utilization of boronic acids as the coupling partner, a palladium-catalyzed Suzuki–Miyaura coupling could provide the sulfonamide products. Compared with traditional attempts, reversing the electronic properties of an amine from nucleophilic to electrophilic could reverse the whole reaction process, and two-step synthesis starting from the amine side could bypass the existing difficulty of S–N bond forming reductive elimination.¹² Instead, a C–S bond formation could be the key for success (Scheme 2). In this proposed route, the presence of a base would be essential to remove the acid generated in situ during the reaction process. Additionally, we expected that the addition of a ligand would improve the oxidative addition of Pd(0) to sulfamoyl chloride, thus leading to the desired sulfonamide product.Open in a separate windowScheme 2Comparison between the traditional route and designed work.As designed based on our assumption, we used a commercialized sulfamoyl chloride intermediate A, which would be generated from morpholine 1a and SO₂Cl₂, to start our early investigations. The results showed that the direct Suzuki–Miyaura coupling of sulfamoyl chloride intermediate A and 2-naphthaleneboronic acid 2a mostly led to the generation of byproduct 3a′ with traditional phosphine ligands added to the reaction, and the desired product 3a was obtained in poor yields (Table 1, entries 1 and 2). It is known that an electron-rich ligand would enhance the oxidative addition of Pd(0) to the electrophile, and the bulky factor would facilitate the reductive elimination process. As expected, the yield of product 3a was increased significantly when electron-rich and bulky tris-(2,6-dimethoxyphenyl)phosphine was used as the ligand (Table 1, entry 3). Moreover, the reaction could proceed more efficiently by using a mixture of THF and MeCN as the co-solvent (Table 1, entry 4).Early investigations using morpholine-4-sulfonyl chloride A as the starting material

Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.

Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.¹ Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).² Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).³ However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,⁴ substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.^5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.⁶ In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)^9,10 as well as the synthesis of chiral tetraarylmethanes,⁸ we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag₂O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)₃ (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO₂ gave only 60% conversion (entry 10).Evaluation of oxidants

Ruthenium-catalyzed formal sp3 C–H activation of allylsilanes/esters with olefins: efficient access to functionalized 1,3-dienes

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.

1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.^1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.¹⁵ Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.^16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.^25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,^28–31 acrylates/acrylamides,^32–36 enamides,³⁷ and enol esters/ethers.^38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,⁴⁰ and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.⁴¹ In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.⁴² The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.⁴³ A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp² C–H bond functionalization was described by Loh et al.⁴⁴ Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.⁴⁵ Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.⁴⁶ Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.⁴⁷ Innumerable methods are known for the preparation of both allyl and vinyl silanes^48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction⁵³ and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp³)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.^54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl₂(p-cymene)]₂ catalyst in the presence of AgSbF₆ as an additive and co-oxidant Cu(OAc)₂ in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.⁵⁶ Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.⁵⁷ The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization of reaction conditions^a

Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides

Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C–S bond coupling. The IMDN-SO₂R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N–S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.

Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C–S bond coupling.

The high frequency of sulfur-containing moieties in natural products,¹ bioactive molecules,² pharmaceuticals,³ organic materials,⁴ fragrances⁵ and asymmetric catalysis as chiral catalysts/ligands⁶ has triggered the best endeavours for the selective construction of C–S bonds. The conventional cross-coupling of thiols with aryl halides generally relies on the conversion of mercaptans to thiolates by means of transition-metal catalysis⁷ (such as Pd,⁸ Cu,⁹ and Ni¹⁰) and other metals,¹¹ although these efforts were plagued by several drawbacks. The strong coordination of thiolates to metals often leads to catalyst deactivation and displays low efficiencies. Therefore, high catalyst loading, specific ligands, excessive heating and strong bases are often required to facilitate this transformation (Scheme 1a, left). Recent development using photochemical¹² and electrochemical¹³ induced thiol radicals as a sulfur source could avoid the problem of catalyst poisoning, although restricted substrate scope was displayed (Scheme 1a, middle). Despite the progress made for C–S bond construction,¹⁴ the longstanding issues that exist in the above-mentioned strategies should not be overlooked.Open in a separate windowScheme 1Origin of the reaction design. (a) C–S formation from organic halides. (b) The preparation of the electrophilic thiolating reagent (R–S⁺). (c) This work: cationic active reagent for cross electrophilic coupling.Compared to classical cross-coupling processes, the nickel-catalyzed reductive cross-coupling of two electrophilic partners has emerged as a powerful tool for the replacement of air- and moisture-sensitive organometallic reagents.¹⁵ The cross electrophilic coupling for the construction of C–S bonds is more challenging due to the lack of sulfur sources and homo-coupling of organic halides (Scheme 1a, right). Several examples of reductive thiolation¹⁶ have been described using thiol derivatives as S⁺ sources (Scheme 1b). We speculated that readily accessible sulfonyl chloride as an electrophilic sulfur source could avoid the use of highly toxic thiols and significantly the substrate scope.¹⁷ However, the direct reduction of sulfonyl chloride inevitably resulted in dimerization to disulfide.^17b Putatively, activated by an electron-deficient heterocycle such as imidazole, sulfonyl chloride could be assembled into a bench-stable cationic reagent (Scheme 1b). Benzimidazolium sulfonamides would be better electron acceptors¹⁸ and easily reduced by PPh₃ to generate a highly reactive N–S⁺ species in situ. The positive charge of this intermediate is delocalized on both nitrogens of imidazole. Followed by the cleavage of the weak N–S bond (BDE ≈ 70 kcal mol⁻¹),¹⁹ the electrophilic sulfur species can be captured by metal catalysts for cross-coupling. Herein, we have described a redox-active benzimidazolium sulfonamide reagent (IMDN-SO₂R) for Ni-catalyzed reductive coupling of organic halides for a portfolio of C(sp)–S, C(sp²)–S and C(sp³)–S bond formations (Scheme 1c). This strategy avoids the formation of disulfide by-products and the use of organometallic reagents, which facilitates purification and enhances the functionality tolerance.To determine the suitable conditions for the reductive coupling of the cationic reagent with organic halides, we first studied the reductive thiolation of p-iodo-methoxybenzene (2a) and 1a (2 equiv.) with a survey of Ni catalysts in the presence of dtbbpy (20 mol%), PPh₃ (2.5 equiv.), Zn powder (3.0 equiv.) and MgCl₂ (2.0 equiv.) in DMA at 60 °C (Table 1). Ni(OTf)₂ as a catalyst was able to promote the reductive process to afford the desired aryl thioether product 3a in 92% isolated yield (entry 1). When using Ni(cod)₂, Ni(acac)₂, Ni(OAc)₂·4H₂O and Ni(PCy₃)₂Cl₂, lower yields were obtained (entries 2–5). Decreasing the 1a loading to 1.5 equiv., the yield of 3a reduced to 75% (entry 6). Switching 1a to a 2-phenyl substituted imidazolium sulfonamide reagent 1b, similar yields were achieved (entry 7). When decreasing both Ni(OTf)₂ and dtbbpy loading to 10 mol%, the yield reduced to 75%. In the absence of Ni(OTf)₂ or Zn powder, no desired product was observed (entries 9–10). Switching Zn powder to an organic reductant tetrakis-(dimethylamino)ethylene (TDAE), still a low conversion of the reaction was observed (entry 11). The results demonstrated that no organozinc reagents were generated. In the absence of the ligand, MgCl₂ or PPh₃, the reaction resulted in low yields, indicating that these ingredients were essential for this catalytic system (entries 12–14). Thus, the optimized conditions were selected for further investigation of the reaction scope.Optimization of the reaction conditions. Reaction condition: 2a (0.20 mmol), 1a (0.40 mmol, 2.0 equiv.), MgCl₂ (2.0 equiv.), PPh₃ (2.5 equiv.), Zn (3.0 equiv.), Ni(OTf)₂ (20 mol%) and dtbbpy (20 mol%) in DMA (2 mL) at 60 °C under Ar. ^aCrude yields determined by ¹H NMR spectroscopy using dibromomethane as an internal standard. ^bIsolated yield. dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. TDAE = tetrakis(dimethylamino)ethylene

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

A highly efficient desymmetrizing asymmetric bromination of bisphenol phosphine oxides was developed, providing a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with high yields and enantioselectivities.

P-Stereogenic compounds are a class of privileged structures, which have been widely present in natural products, drugs and biologically active molecules (Fig. 1a).^1–4 In addition, they are also important chiral materials for the development of chiral catalysts and ligands (Fig. 1b), because the chirality of the phosphorus atom is closer to the catalytic center which can cause remarkable stereo-induction.^5,6 Thus, the development of efficient methods for the synthesis of P-stereogenic compounds with novel structures and functional groups is very meaningful.^5a Conventional syntheses of P-stereogenic compounds mainly depended on the resolution of diastereomeric mixtures and chiral-auxiliary-based approaches, in which stoichiometric amounts of chiral reagents are usually needed.⁷ By comparison, asymmetric catalytic strategies, including asymmetric desymmetric reactions of dialkynyl, dialkenyl, diaryl and bisphenol phosphine oxides,^8–14 (dynamic) kinetic resolution of tertiary phosphine oxides,¹⁵ and asymmetric reactions of secondary phosphine oxides,¹⁶ can effectively solve the above-mentioned problems and have been considered as the most direct and efficient synthesis methods for constructing P-chiral phosphine oxides (Fig. 1c). Among them, organocatalytic asymmetric desymmetrization methods have been sporadic, in which the reaction sites were mainly limited to the hydroxyl group of bisphenol phosphine oxides that hindered their further transformation.^8–11 It is worth mentioning that asymmetric desymmetrization methods, especially organocatalytic desymmetrization reactions, due to their unique advantages of mild reaction conditions and wide substrate scope, have become an important strategy for asymmetric synthesis. Accordingly, the development of efficient organocatalytic desymmetrization strategy for the synthesis of important functionalized P-stereogenic compounds which contain multiple conversion groups is very meaningful and highly desirable.Open in a separate windowFig. 1(a) Examples of natural products containing P-stereogenic centers. (b) P-Stereogenic compound type ligand and catalyst. (c) Typical P-stereogenic compounds'' synthetic strategies.On the other hand, asymmetric bromination has been demonstrated to be one of the most attractive approaches for chiral compound syntheses.¹⁷ Since the pioneering work on peptide catalyzed asymmetric bromination for the construction of biaryl atropisomers,^18a the reports on constructing axially biaryl atropisomers,¹⁸ C–N axially chiral compounds,¹⁹ atropisomeric benzamides,²⁰ axially chiral isoquinoline N-oxides,²¹ and axially chiral N-aryl quinoids²² by electrophilic aromatic bromination have been well developed (Scheme 1a). In comparison, the desymmetrization of phenol through asymmetric bromination to construct central chirality remains a daunting task. Miller discovered a series of tailor made peptide catalyzed enantioselective desymmetrizations of diarylmethylamide through ortho-bromination (Scheme 1b).²³ Recently, Yeung realized amino-urea catalyzed desymmetrizing asymmetric ortho-selective mono-bromination of phenol derivatives to fix a new class of potent privileged bisphenol catalyst cores with excellent yields and enantioselectivities (Scheme 1b).²⁴ Despite this elegant work, there is no report on the synthesis of P-centered chiral compounds using the desymmetrizing asymmetric bromination strategy.Open in a separate windowScheme 1(a) Constructing axially chiral compounds by asymmetric bromination. (b) Known synthesis of central chiral compounds via asymmetric bromination. (c) This work: access to P-stereogenic compounds via desymmetrizing enantioselective bromination.Taking into account the above-mentioned consideration, we speculated that bisphenol phosphine oxides and bisphenol phosphinates are potential substrate candidates for desymmetrizing asymmetric bromination to construct P-stereogenic centers. The advantages of using bisphenol phosphine oxides and bisphenol phosphinates as substrates are shown in two aspects. First, the ortho-position of electron rich phenol is easy to take place electrophilic bromination reaction. Second, the corresponding bromination product structure contains abundant synthetic conversion groups, including bromine, hydroxyl group, alkoxy group and phosphoryl group. To achieve this goal, two challenges need to be overcome: (i) finding a suitable chiral catalyst for the desymmetrization process to induce enantiomeric control is troublesome, due to the remote distance between the prochiral phosphorus center and the enantiotopic site; (ii) selectively brominating one phenol to inhibit the formation of an achiral by-product is difficult. Herein, we report a chiral squaramide catalyzed asymmetric ortho-bromination strategy to construct a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with good to excellent yields and enantioselectivities (Scheme 1c). It is worth mentioning that the obtained P-stereogenic compounds can be further transformed at multiple sites.Our initial investigation was carried out with bis(2-hydroxyphenyl)phosphine oxide 1a and N-bromosuccinimide (NBS) 2a as the model substrates, 10 mol% chiral amino-thiourea 4a as the catalyst, and toluene as the solvent, which were stirred at −78 °C for 12 h. As a result, the reaction gave the desired desymmetrization product 3a in 65% yield with 56 : 44 e.r. (Table 1, entry 1). Then, thiourea 4b was tested, in which a little better result was obtained (Table 1, entry 2). To our delight, using the chiral squaramides 4c–4f as the catalysts, the enantiomeric ratios of the desymmetrization products had been significantly improved (Table 1, entries 3–6). Especially, when chiral squaramide catalyst 4c was applied to this reaction, the enantiomeric ratio of 3a was increased to 95 : 5 (Table 1, entry 3). To further improve the yield and enantioselectivity, we next optimized the reaction conditions by varying reaction media and additives. As shown in Table 1, the reaction was affected by the solvent dramatically. Product 3a was obtained with low yield and enantioselectivity in DCM (Table 1, entry 7). Also, when Et₂O was used as the solvent, the yield and e.r. value of product 3a were all decreased (Table 1, entry 8). As a result, the initial used toluene was the optimal solvent. We also inspected the effect of different bromine sources, and found that the initially used NBS was the optimal one (Table 1, entries 3, 11 and 12). Fortunately, by adjusting the amount of bisphenol phosphine oxides to 1.5 equiv., the yield and the enantiomeric ratio of 3a were increased to 80% and 96.5 : 3.5, respectively (Table 1, entries 3, 13 and 14). Further increasing the amount of bisphenol phosphine oxides to 2.0 equiv. resulted in a reduced enantioselectivity (Table 1, entry 15).Optimization of the reaction conditions^a

Catalytic asymmetric hydrogenation of (Z)-α-dehydroamido boronate esters: direct route to alkyl-substituted α-amidoboronic esters

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized. Using this approach, a class of therapeutically relevant alkyl-substituted α-amidoboronic esters was easily synthesized in high yields with generally excellent enantioselectivities (up to 99% yield and 99% ee). The utility of the products has been demonstrated by transformation to their corresponding boronic acid derivatives by a Pd-catalyzed borylation reaction and an efficient synthesis of a potential intermediate of bortezomib. The clean, atom-economic and environment friendly nature of this catalytic asymmetric hydrogenation process would make this approach a new alternative for the production of alkyl-substituted α-amidoboronic esters of great potential in the area of organic synthesis and medicinal chemistry.

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized.

Since FDA approval of bortezomib¹ for the treatment of multiple myeloma, chiral α-aminoboronic acids have been recognized as key pharmacophores for the design of proteasome inhibitors.² The incorporation of chiral α-aminoboronic acid motifs at the C-terminal position of a peptide³ to develop potential clinical drug candidates has drawn increasing interest⁴ (Fig. 1). Meanwhile, chiral α-amidoboronic acids and their derivatives are useful synthetic building blocks for the stereospecific construction of chiral amine compounds.⁵ The biological and synthetic value of α-amidoboronates has led to considerable efforts for the development of efficient synthetic methods. However, up to now, limited transition-metal-catalyzed asymmetric approaches have been reported. The widely used strategies to synthesize these compounds are stepwise Matteson homologation/N-nucleophilic replacement,⁶ borylation of imines,⁷ and alkene functionalization.⁸ Recently, two other elegant approaches, Ni-catalyzed decarboxylative borylation of α-amino acid derivatives⁹ and enantiospecific borylation of lithiated α-N-Boc species,¹⁰ were reported by the Baran and Negishi groups, respectively. To the best of our knowledge, the majority of the methods relied on either stoichiometric amounts of chiral auxiliaries^6,7a,b or substrate-control strategies⁹ and most of these methods enable the construction of aryl-substituted α-aminoboronates. Enantioselective methods to access unfunctionalized alkyl-substituted α-aminoboronic esters are still rarely developed and so far only two examples have been realized by the Miura^8a and Scheidt^7f groups, respectively. Considering that most therapeutically relevant α-amidoboronic acid fragments contain an alkyl subunit and the fact that the options for the synthesis of alkyl-substituted α-amidoboronic esters in an enantioselective manner are still rare, the development of other distinct approaches would be highly desirable. Herein, we report a new alternative to access these compounds by catalytic asymmetric hydrogenation of (Z)-α-dehydroamidoboronate esters. With this approach, the desired chiral alkyl-substituted α-amidoboronic esters could be obtained in high yields and generally excellent enantioselectivities (up to 99% yield and 99% ee) with simple purification.Open in a separate windowFig. 1Selected inhibitors containing chiral alkyl-substituted α-amidoboronic acids.Catalytic asymmetric hydrogenation of olefins is an atom-economic, environmentally friendly and clean process for the synthesis of valuable pharmaceuticals, agricultural compounds and feedstock chemicals.¹¹ Recently, hydrogenation of vinylboronic compounds has emerged for the preparation of chiral boronic compounds in a regiodefined manner.^12,13 However, surprisingly α-dehydroamido boronate esters and their derivatives, as elegant precursors to access alkyl-substituted α-amidoboronic compounds, have never been used as substrates in asymmetric hydrogenation and remain a challenging project. To our knowledge, only one efficient hydrogenation approach to (1-halo-1-alkenyl) boronic esters was reported for indirect synthesis of alkyl-substituted α-aminoboronic esters but it was accompanied by inevitable de-halogenated by-products¹⁴ (Scheme 1). Given the catalytic efficiency and atom economy of the hydrogenation method, the development of a new direct hydrogenation approach to construct these important chiral alkyl-substituted α-amidoboronic esters would be very appealing.Open in a separate windowScheme 1Approaches towards the synthesis of chiral alkyl-substituted α-aminoboronic esters.The inspiration for our approach to the hydrogenation of α-dehydroamido boronates came from the molecular structures of relevant biologically active inhibitors containing alkyl-substituted α-amidoboronic acid fragments. Due to the limited stability of free α-aminoboronic acids, an electron-withdrawing carboxylic N-substituent is often required.¹⁵ Thus, we envisaged that N-carboxyl protected α-dehydroamido boronate esters could serve as a potential precursor for the synthesis of alkyl-substituted α-amidoboronates through Rh-catalyzed asymmetric hydrogenation of the C C bond¹⁶ (Fig. 1), a strategically distinct approach to the construction of unfunctionalized alkyl-substituted α-amidoboronic esters. However, challenges still remain, including: (1) how to synthesize α-dehydroamido boronates; (2) the facile transmetalation process of the starting materials leading to deboronated by-products in the hydrogenation process;¹⁷ (3) the unknown stability of α-amidoboronic compounds in the presence of a transition-metal catalyst and hydrogen molecules. As part of our continuous efforts to develop efficient hydrogenation approaches to construct valuable motifs,¹⁸ here we present the results of the investigation to address the aforementioned challenges.The desired aryl-substituted (Z)-α-dehydroamido boronates could be obtained by Cu-catalyzed regioselective hydroborylation of ynamide according to a previous report.¹⁹ However, different α/β-regioselectivity was observed for the preparation of alkyl-substituted (Z)-α-dehydroamido boronate esters and a new synthetic route was developed (Scheme 2, see the ESI^† for details). Of note, (Z)-α-dehydroamido boronate esters should be purified with deactivated silica gel,^7c or else protodeborylation would occur readily with flash chromatography.Open in a separate windowScheme 2Synthetic route to (Z)-α-dehydroamino boronates.In order to check the feasibility of our hypothesis, three substrates were prepared with Rh(NBD)₂BF₄ and examined and our group prepared (Rc,Sp)-DuanPhos under 50 atm hydrogen pressure (Table 1). Gratifyingly, substrate 1b reacted smoothly to provide the desired product 2b in high yield and enantioselectivity (>99% conv., 98% ee, entry 2) whilst the reaction with substrate 1a yielded a mixture of deborylation products and 1c did not work at all (entries 1 and 3). Of note, we did not observe deborylation products with 1b under the current reaction conditions and we did not select (Z)-α-dehydroamido boronic acid 1a as the model substrate because of its poor solubility in most solvents. Then, a variety of chiral diphosphine ligands were investigated along with Rh(NBD)₂BF₄ and the results are shown in Table 1. In most cases, the reaction proceeded smoothly to furnish the desired products and the best results were obtained when (Rc,Sp)-DuanPhos was used as the ligand (entries 2 and 4–12). Poor results were obtained with axially bidentate phosphine ligands (entries 5, 6 and 9). (R,R)-QuinoxP* and (R,R)-Ph-BPE also gave good conversion with a slightly decreased ee whilst (R,R)-ⁱPr-DuPhos exhibited poor results (entries 4, 7 and 10). Subsequent solvent screening revealed that the desired products could be obtained in most of the solvents and 1,2-DCE was the best solvent. (Entry 13, see the ESI^†).Condition optimization for catalytic asymmetric hydrogenation of 1^a

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a

Benzannulation of isobenzopyryliums with electron-rich alkynes: a modular access to β-functionalized naphthalenes

Described here is a modular strategy for the rapid synthesis of β-functionalized electron-rich naphthalenes, a family of valuable molecules lacking general access previously. Our approach employs an intermolecular benzannulation of in situ generated isobenzopyrylium ions with various electron-rich alkynes, which were not well utilized for this type of reaction before. These reactions not only feature a broad scope, complete regioselectivity, and mild conditions, but also exhibit unusual product divergence depending on the substrate substitution pattern. This divergence allows further expansion of the product diversity. Control experiments provided preliminary insights into the reaction mechanism.

A substituent-controlled divergent benzannulation provides rapid access to various β-functionalized naphthalenes from electron-rich alkynes.

Functionalized naphthalenes are important structural motifs widely present in bioactive natural products, pharmaceuticals and functional materials.^1,2 They also serve as valuable intermediates in organic synthesis.³ Among them, naphthalenes bearing an electron-donating group (EDG) at the β-position (e.g., β-naphthols, β-naphthylamines, and β-naphthyl thioethers) are particularly versatile (Fig. 1).^2,3 For example, BINOL, which is derived from β-naphthol, is an extensively utilized synthetic precursor toward a wide range of privileged chiral ligands and catalysts.³ While various approaches have been developed for the synthesis of naphthalenes, efficient and selective de novo strategies toward these β-functionalized ones still remain in high demand. Moreover, to the best of our knowledge, a general and modular approach for rapid access to all these electron-rich β-functionalized naphthalenes remains unknown.⁴Open in a separate windowFig. 1Useful β-naphthol, β-naphthylamine, and β-naphthyl thioether units.Isobenzopyrylium ions are readily accessible and versatile intermediates in organic synthesis (Scheme 1).⁵ They are known to participate in cycloaddition reactions with diverse carbon–carbon double bonds or triple bonds for the synthesis of naphthalenes.^5,6 While extensive progress has been achieved in this topic, challenges still remain to be addressed. For example, the majority of these benzannulations with alkynes have to be executed at high temperature, except those intramolecular cases or with stoichiometric activators. Moreover, electron-rich alkynes have not been well explored as reaction partners for the benzannulations with isobenzopyrylium ions. Nevertheless, such reactions would provide expedient access to the valuable β-naphthol and β-napthylamine derivatives with diverse substitution patterns (Scheme 1). In this context, here we report our effort in achieving a general and modular strategy toward these electron-rich naphthalenes with high efficiency and regioselectivity under mild conditions. We also observed interesting selectivity divergence controlled by the substituent of the isobenzopyrylium substrates, giving rise to different types of naphthalene products (e.g., 2-hydroxy-1-naphthaldehydes, Scheme 1).Open in a separate windowScheme 1Benzannulation of isobenzopyryliums with electron-rich alkynes.We began our study with isochromene 1a as the isobenzopyrylium precursor. Siloxy alkyne 2a was first employed as the model electron-rich alkyne in view of the extraordinary versatility of this type of alkyne in various cyclization reactions, including benzannulation.^7–9 Various Brønsted and Lewis acids were evaluated as catalysts for this reaction. Unfortunately, most of them did not show obvious catalytic activity toward the formation of a naphthalene product (Table 1). These reactions either had little conversion or resulted in a mixture of undesired products. Nevertheless, further screening led to the identification of AgOTf and BF₃·OEt₂ as capable catalysts (entries 5–6), with the latter being superior, leading to the formation of naphthalene 3a as the major product (75% yield, entry 6). Increasing the catalyst loading to 20 mol% further improved the product yield to 85% (with an isolated yield of 81%, entry 7). Further increasing the catalyst loading proved to be not beneficial (entry 8). Notably, the use of substrate 1a′ bearing an ethoxy leaving group also provided an equally good result. Other solvents, such as toluene and MeCN, were also evaluated, but all gave lower product yields. Finally, it is worth noting that the mild conditions used here are in sharp contrast to the typical high temperature required for the previously known catalytic intermolecular benzannulations involving isobenzopyryliums and alkynes.^5dEvaluation of reaction conditions

Reductive radical-initiated 1,2-C migration assisted by an azidyl group

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. The reaction tolerates diverse migrating groups, such as alkyl, alkenyl, and aryl groups, allowing access to n+1 ring expansion of small to large rings. The possibility of directly using propargyl alcohols in one-pot is also described. Mechanistic studies indicated that an azidyl group is a good leaving group and provides a driving force for the 1,2-C migration.

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group.

Since the groups of Ryu and Sonoda described the reductive radical-polar crossover (RRPCO) concept in the 1990s,¹ it has attracted considerable attention in modern organic synthesis.² By using this concept, a variety of complex molecules could be assembled in a fast step-economic fashion which is not possible using either radical or polar chemistry alone. However, only two RRPCO reaction modes are known to date: nucleophilic addition and nucleophilic substitution (Fig. 1A). The first RRPCO reaction is the nucleophilic addition of organometallic species, which is generated in situ from the reduction of a strong reducing metal with a carbon-centered radical intermediate and cations (E⁺ = H⁺, I⁺, Br⁺, path 1).³ However, the necessity for a large amount of harmful and strong reducing metals has greatly limited the scope and functional group tolerance of the reaction. Recently, photoredox catalysis has not only successfully overcome the shortcomings of using toxic strong reducing metals in the RRPCO reaction,⁴ but also enabled the development of several new RRPCO reaction types, including the nucleophilic addition with carbonyl compounds or carbon dioxide (path 2),⁵ the cyclization of alkyl halides/tosylates (path 3),⁶ and β-fluorine elimination (path 4).⁷ Although the RRPCO reaction has been greatly advanced by photoredox catalysis, it is still in its infancy, and the development of a novel RRPCO reaction is of great importance.Open in a separate windowFig. 1(A) Reductive radical-polar crossover reactions; (B) this work: reductive radical-initiated 1,2-C migration assisted by an azidyl group.Herein, we wish to report a new type of reductive radical-polar crossover cascade reaction that is the reductive radical-initiated 1,2-C migration under metal-free conditions (Fig. 1B). The development of this approach is not only to further expand the application of the RRPCO reaction, but also to solve the problems associated with the oxidative radical-initiated 1,2-C migration, such as the necessity for an oxidant and/or transition metal for the oxidative termination of the radicals, and also required sufficient ring strain to avoid the generation of epoxy byproducts.⁸ To realize this reaction, a driving force is needed to drive the 1,2-C migration after reductive termination, to avoid the otherwise inevitable protonation of the generated anion.⁹ Inspired by the leaving group-induced semipinacol rearrangement,¹⁰ we envisaged that 2-azidoallyl alcohols¹¹ might be the ideal substrates for the reductive radical-initiated 1,2-C migration because these compounds contain both an allylic alcohol motif, which is vital for the radical-initiated 1,2-C migration, and an azidyl group, a good leaving group,¹² which may facilitate the 1,2-C migration after the reductive termination of the radicals.With the optimal conditions established (ESI, Table S1^†), we then explored the scope of this radical-initiated 1,2-migration. As shown in Table 1, a series of naphthenic allylic alcohols could undergo n+1 ring expansion with minimal impact on the product yield (Table 1, 3aa–aq). Notably, only the alkyl groups were migrated when using benzonaphthenic allylic alcohols in the reaction. These results might be attributed to the aryl group possessing greater steric resistance. The structure of 3an was further verified by single-crystal diffraction. Interestingly, the vinyl azide derived from a pharmaceutical ethisterone was also a viable substrate, affording the migration product 3aq in 57% yield, which highlighted the applicability of this strategy in the late-stage modification of pharmaceuticals. Moreover, the acyclic allylic alcohol with an alkyl chain also successfully delivered the migration product 3ar in 64% yield.Substrate scope of 2-azidoallyl alcohols^ab

Formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloaddition reactions of donor–acceptor cyclobutenes,cyclopropenes and siloxyalkynes induced by Brønsted acid catalysis

Brønsted acid catalyzed formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropenes, and siloxyalkynes with benzopyrylium ions are reported. [4 + 2]-cyclization/deMayo-type ring-extension cascade processes produce highly functionalized benzocyclooctatrienes, benzocycloheptatrienes, and 2-naphthols in good to excellent yields and selectivities. Moreover, the optical purity of reactant donor–acceptor cyclobutenes is fully retained during the cascade. The 1,3-dicarbonyl product framework of the reaction products provides opportunities for salen-type ligand syntheses and the construction of fused pyrazoles and isoxazoles that reveal a novel rotamer-diastereoisomerism.

Brønsted acid catalysis realizes formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropanes, and siloxyalkynes with benzopyrylium ions.

Medium-sized rings are the core skeletons of many natural products and bioactive molecules,¹ and a growing number of strategies have been developed for their synthesis.² Because of their enthalpic and entropic advantages, ring expansion is a highly efficient methodology for these constructions.^3–6 For example, Sun and co-workers have developed acid promoted ring extensions of oxetenium and azetidinium species formed from siloxyalkynes with cyclic acetals and hemiaminals (Scheme 1a).⁴ Takasu and co-workers have reported an elegant ring expansion with a palladium(ii) catalyzed 4π-electrocyclic ring-opening/Heck arylation cascade with fused cyclobutenes (Scheme 1b).⁵ Each transformation is initiated by the formation of fused bicyclic units followed by ring expansion or rearrangement to give medium-sized rings.Open in a separate windowScheme 1Cycloaddition/ring expansion background and this work.Strategies for the formation of fused bicyclic compounds rely on cycloaddition of dienes or dipoles with unsaturated cyclic compounds⁷ and, if the reactant cyclic compound is strained and chiral, the resulting bicyclic compound is activated toward ring opening that results in retention of chirality. We have recently reported access to donor–acceptor cycloalkenes by [3 + n] cycloaddition that have the prerequisites of unsaturated cyclic compounds suitable for cycloaddition.⁸ Donor–acceptor (D–A) cyclopropenes⁹ and cyclobutenes¹⁰ have sufficient strain in the resulting bicyclic compounds to undergo ring opening. We envision that the selection of a diene or dipolar reactant and suitable reaction conditions could realize cycloaddition and subsequent ring expansion. Benzopyrylium species,^11,12 which are generated by metal or acid catalysis, have attracted our attention. We anticipated that their high reactivity would overcome the conventional unfavorable kinetic and/or thermodynamic factors that typically impede medium-sized ring formation. From a mechanistic perspective, benzopyrylium species are often formed by transition metal catalyzed reactions with 2-alkynylbenzaldehydes.¹¹ Recently, the reaction between 1H-isochromene acetal and Brønsted acid catalyst forms the 2-benzopyrylium salts that could react with functional alkenes to give same cycloaddition products.¹² Consequently, we believed that the [4 + 2]-cyclization between benzopyrylium species and donor–acceptor cyclobutenes, cyclopropenes, or siloxyalkynes would give bridged oxetenium intermediates, which contain high strain energy that should provide the driving force for ring expansion. The “push and pull” electronic effect of donor–acceptor functional groups facilitates deMayo-type ring-opening of the cyclobutane or cyclopropane skeletons (Scheme 1c).¹³Here we report bis(trifluoromethanesulfonyl)imide (HNTf₂) catalyzed formal [4 + 4]-, [4 + 3]- and [4 + 2]-cycloaddition reactions of D–A cyclobutenes, cyclopropenes, and siloxyalkynes with benzopyrylium salts. Polysubstituted benzo-cyclooctatrienes, benzocycloheptatrienes and 2-naphthols, are produced in good to excellent yields and selectivities. Complete retention of configuration occurs using chiral cyclobutenes, and opportunities for further functionalization are built into these constructions.Initially, we conducted transition metal catalyzed reactions with 2-alkynylbenzaldehyde intending to produce the corresponding benzopyrylium ion and explore the possibility of cycloaddition/ring opening with donor–acceptor cyclobutene 2a. Use of Ph₃PAuCl/AgSbF₆, Pd(OAc)₂ and Cu(OTf)₂, which were efficient catalysts in previous transformations,¹¹ gave only a trace amount of cycloaddition product (Fig. 1). Spectral analysis showed that mostly starting material remained (Fig. 1-i and ii). Increasing the reaction temperature led only to decomposition of 2-alkynylbenzaldehyde (Fig. 1-iv) or donor–acceptor cyclobutene 2a (Fig. 1-iv).Open in a separate windowFig. 1Reaction of 2-alkynylbenzaldehyde with donor–acceptor cyclobutene 2a.From these disappointments we turned our attention to 1H-isochromene acetal 1a as the benzopyrylium ion precursor. Various Lewis acid catalysts were employed with limited success, but we were pleased to observe the formation of the desired formal [4 + 4]-cycloaddition benzocyclooctatriene product 3aa, albeit in low yields (Table 1, entries 1–6). Selection of the Brønsted super acid HNTf₂ (ref. 14) proved to be the most promising, producing 3aa in 40% yield (Table 1, entry 7). Increasing the amount of D–A cyclobutene 2a by 30% gave a much higher yield of 3aa (Table 1, entry 8 vs. 7). Optimization of the stoichiometric reaction between 1a and 2a by increasing the reaction temperature from rt to 35 °C led to the formation of the desired product in 76% isolated yield (Table 1, entry 9 vs. 8). However, a further increase in the reaction temperature (Table 1, entry 10) or reducing the catalyst loading to 5 mol% did not improve the yield of 3aa (Table 1, entry 11).Optimization of reaction conditions^a

Electrophilic fluoroalkylthiolation induced diastereoselective and stereospecific 1,2-metalate migration of alkenylboronate complexes

A transition metal free process for conjunctive functionalization of alkenylboron ate-complexes with electrophilic fluoroalkylthiolating reagents is described, affording β-trifluoroalkylthiolated and difluoroalkylthiolated boronic esters in good yield and excellent diastereoselectivity. The potential applicability of the method was demonstrated by the preparation of a difluoromethylthiolated mimic 12 of a potential drug molecule PF-4191834 for the treatment of asthma.

A transition metal free process for conjunctive functionalization of alkenylboron ate-complexes with electrophilic fluoroalkylthiolating reagents affords β-tri- and difluoroalkylthiolated boronic esters in good yield and diastereoselectivity.

An electrophile-induced 1,2-metalate migration of an alkenylboron “ate” complex and subsequent base-promoted β-elimination to form a functionalized cis-alkene, now the so-called Zweifel reaction, was first reported by Zweifel and co-workers in 1967 (Fig. 1A).^1–3 The reaction was proposed to proceed via an initial attack of the π electron of the alkene moiety to iodine to generate a zwitterionic iodonium ion, which then undergoes a stereospecific 1,2-metalate to afford a β-iodoboronic ester, followed by anti-elimination upon treatment with a base to afford a cis-olefin. Thus, if the iodine is replaced by an alternative electrophilic reagent and the use of a base is omitted, an interrupted-Zweifel reaction for the preparation of a stereospecific β-functionalized boronic ester could be realized. Toward this end, Aggarwal reported the first example of such a reaction by employing PhSeCl as the electrophilic reagent.⁴ It was proposed that PhSeCl first reacts with an alkenylboronate complex to form a zwitterionic seleniranium ion. Subsequent diastereospecific 1,2-metalate migration affords the stereospecific β-seleno-alkylboronate (Fig. 1B). Likewise, shortly after, Denmark and co-workers reported an analogous Lewis-base catalysed enantioselective and diastereoselective carbosulfenylation of an alkenylboronate complex using N-arylthiosaccharin as the electrophile (Fig. 1C).⁵Open in a separate windowFig. 1The interrupted Zweifel reaction.In light of these discoveries and our recent success in the development of a toolbox of electrophilic fluoroalkylthiolating reagents including three trifluoromethylthiolating reagents α-cumyltrifluoromethane sulfenate,⁶N-trifluoromethylthio-saccharin⁷ and N-trifluoromethylthiodibenzenesulfonimide,⁸ and two difluoromethylthiolating reagents N-difluoromethylthiophthalimide⁹ and S-(difluoromethyl)benzenesulfonothioate,¹⁰ we wondered whether these electrophilic fluoroalkylthiolating reagents could also trigger the proposed stereospecific 1,2-metalatation of the alkenylboronate complex to afford β-fluoroalkylthiolated borane derivatives (Fig. 1D). The trifluoromethylthio (–SCF₃) and the difluoromethylthio (–SCF₂H) groups have gained great attention recently, partially because of their high and tuneable lipophilicity¹¹ that might improve the drug candidate''s cell membrane permeability and consequently, its overall pharmacokinetics.¹² Thus, the development of new efficient reactions for the incorporation of the trifluoromethylthio¹³ or difluoromethylthio groups¹⁴ would be of vital importance in facilitating medicinal chemists'' endeavours in new drug discovery. Herein, we report that by employing electrophilic difluoromethylthiolating reagent PhSO₂SCF₂H 2a as the electrophile, the proposed difluoromethylthiolating induced stereospecific 1,2-metalate migration of alkenyl boronate complexes occurred smoothly to afford β-difluoromethylthiolated boronic esters in good yields and excellent diastereoselectivity. Likewise, when electrophilic trifluoromethylthiolating reagent N-trifluoromethylthiosaccharin 7 was used, an analogous reaction for the diastereoselective formation of β-trifluoromethylthiolated boronic esters was successfully achieved.We began our study by examining the reaction of the electrophilic difluoromethylthiolating reagent 2a with the alkenylboronate complex which was generated in situ by mixing 1a and PhLi in diethyl ether. It was found that the reaction in CH₃CN occurred in full conversion after 12 hours at room temperature, affording the corresponding product 3a in 53% yield (Table 1, entry 1). When the amount of PhLi was increased to 1.3 equivalents, the yield was increased to 76%, while the yield decreased to 66% when 2.0 equivalents of PhLi were used, likely due to the decomposition of the product under strong basic conditions (Table 1, entries 1–5). We then further investigated the effect of the reaction temperature and the solvent. It was found that the temperature did not affect the reaction significantly since the yields of the desired products were decreased slightly to 72% and 70%, respectively, when the reactions were conducted at 0 °C or −15 °C (Table 1, entries 6 and 7). Likewise, the reaction was not sensitive to the polarity of the solvent since reactions conducted in less polar solvents such as THF or CH₂Cl₂ or nonpolar solvents like toluene occurred in slightly lower 60–73% yields (Table 1, entries 9–11). We also found that reaction using N-difluoromethylthiophthalimide as the electrophilic difluoromethylthiolating reagent gave the same product in a slightly lower yield (Table 1, entry 8).Optimization of conditions for the reaction of the alkenyl boronate complex with PhSO₂SCF₂H^a

Pd/Cu-Catalyzed amide-enabled selectivity-reversed borocarbonylation of unactivated alkenes

The addition reaction between CuBpin and alkenes to give a terminal boron substituted intermediate is usually fast and facile. In this communication, a selectivity-reversed procedure has been designed and established. This selectivity-reversed borocarbonylation reaction is enabled by a cooperative action between palladium and copper catalysts and proceeds with complete regioselectivity. The key to the success of this transformation is the coordination of the amide group and slower CuBpin formation by using KHCO₃ as the base. A wide range of β-boryl ketones were produced from terminal unactivated aliphatic alkenes and aryl iodides. Further synthetic transformations of the obtained β-boryl ketones have been developed as well.

A selectivity-reversed borocarbonylation reaction has been developed with complete regioselectivity.

The catalytic borocarbonylation of alkenes represents a novel synthetic tool for the simultaneous installation of boron and carbonyl groups across alkenes, enabling rapid construction of molecules with high complexity from abundant alkenes. In particular, the obtained organoboron compounds are versatile synthetic intermediates that can be readily converted into a wide range of functional groups with complete stereospecificity.¹ Consequently, several catalytic systems have been developed to diversify the molecular frameworks through carbonylative borofunctionalization.² In general, carbonylative borofunctionalization of alkenes proceeds via an alkyl-copper intermediate, which was produced by the addition of CuBpin to the terminal position of the alkene starting material,³ followed by CO insertion and other related steps. A new C–B bond is formed at the terminal position of the alkene and a carbonyl group has been installed at the β-position simultaneously (Scheme 1a). However, in contrast to the progress in the borocarbonylation, a selectivity-reversed procedure (the boryl group is installed at the internal position) to give β-boryl ketone products is still unprecedented.Open in a separate windowScheme 1Strategies for borocarbonylation of activated alkenes.Recently, several attractive strategies have emerged for the borofunctionalization of unactivated alkenes to give β-boryl products.^4–7 In 2015, Fu, Xiao and their co-workers established a copper-catalyzed regiodivergent alkylboration of alkenes.^4a In the same year, Miura and Hirano''s group reported a copper-catalyzed aminoboration of terminal alkenes.^4b In these two attractive procedures, the regioselectivity was controlled by the ligand applied. More recently, an intermolecular 1,2-alkylborylation of alkenes was described by Ito''s research group.⁵ A radical-relay strategy was used to achieve the targeted regioselective addition. Furthermore, Engle and co-workers explored a palladium-catalyzed 1,2-carboboration and -silylation reaction of alkenes.⁶ Stereocontrol can be achieved in this new procedure with the assistance of a chiral auxiliary which is a coordinating group in this case.Inspired by these pioneering studies, we assumed that if the reaction could be initiated by the insertion of an acylpalladium complex into alkenes, followed by transmetalation with CuBpin before reductive elimination, β-boryl ketones can finally be produced (Scheme 1b). However, due to the inherent reactivity of the palladium species toward alkenes, olefin substrates were usually restricted to styrenes and a large excess of them is typically required (>6 equivalents).^8,9 Therefore, the critical part of the reaction design is to promote the reaction of the acylpalladium intermediate with alkenes faster than the insertion of CuBpin into olefins. One of the ideas is taking advantage of the coordinating group to transform the reaction from intermolecular to intramolecular. Among the developed directing groups,¹⁰ 8-aminoquinoline (AQ) is interesting and has been relatively well studied by various groups in a number of novel transformations.^11–13 Although the AQ directing group contains a NH group which can participate in intramolecular C–N bond formation,¹⁴ we believe that the selectivity-reversed borocarbonylation of alkenes can potentially be achieved through cooperative Pd/Cu catalysis. Then, valuable β-boryl ketones can be produced from readily available substrates directly and effectively.To test the viability of our design on selectivity-reversed borocarbonylation of alkenes, N-(quinolin-8-yl)pent-4-enamide (1a), iodobenzene (2a), and bis(pinacolato)diboron (B₂pin₂) were chosen as model substrates for systematic studies. As shown in 15 In the testing of palladium precursors, allylpalladium chloride dimer proved to be the best palladium catalyst for this reaction, affording 3a in 41% yield (†) and tend to generate the by-product β-aminoketone. Xantphos was found to be superior to the other tested bidentate ligands ( Entry[Pd]LigandCuBaseYield of 3a (%)1Pd(TFA)₂ L1 IMesCuClK₂CO₃292Pd(OAc)₂ L1 IMesCuClK₂CO₃343[Pd(η³-C₃H₅)Cl]₂ L1 IMesCuClK₂CO₃414[Pd(cinnamyl)Cl]₂ L1 IMesCuClK₂CO₃365[Pd(η³-C₃H₅)Cl]₂ L1 IPrCuClK₂CO₃06[Pd(η³-C₃H₅)Cl]₂ L1 CuClK₂CO₃337[Pd(η³-C₃H₅)Cl]₂ L1 CuBrK₂CO₃418[Pd(η³-C₃H₅)Cl]₂ L1 CuIK₂CO₃509[Pd(η³-C₃H₅)Cl]₂ L2 CuIK₂CO₃3810[Pd(η³-C₃H₅)Cl]₂ L3 CuIK₂CO₃4711[Pd(η³-C₃H₅)Cl]₂ L4 CuIK₂CO₃012[Pd(η³-C₃H₅)Cl]₂ L5 CuIK₂CO₃013[Pd(η³-C₃H₅)Cl]₂ L6 CuIK₂CO₃<214[Pd(η³-C₃H₅)Cl]₂ L7 CuIK₂CO₃1015[Pd(η³-C₃H₅)Cl]₂ L8 CuIK₂CO₃1216[Pd(η³-C₃H₅)Cl]₂ L1 CuIKHCO₃58 (51)^b17[Pd(η³-C₃H₅)Cl]₂ L1 CuIK₂HPO₄2618[Pd(η³-C₃H₅)Cl]₂ L1 CuINaHCO₃019[Pd(η³-C₃H₅)Cl]₂ L1 CuINaO^tBu1120^c[Pd(η³-C₃H₅)Cl]₂ L1 CuIKHCO₃<521[Pd(η³-C₃H₅)Cl]₂ L7 CuIKHCO₃40 Open in a separate window^aAll reactions were carried out on a 0.1 mmol scale with alkene (0.1 mmol) and aryl iodide (2.0 equiv.). Yields were determined by ¹H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard.^bIsolated yield.^cXantphos (10 mol%).With the optimized reaction conditions in hand, we examined the scope of this selectivity-reversed borocarbonylation with various unactivated alkenes and aryl iodides toward the synthesis of β-boryl ketones ( C bond even when there are two C C bonds in the amide substrates (4i and 4j). In addition, sterically hindered 4-pentenoic amide was subjected to the optimized reaction conditions, and the corresponding product was formed in 42% yield (4k). Furthermore, mono-substitution at the β-position of 4-pentenoic amides could also be employed, affording the corresponding products in moderate yields (4l and 4m). Iodoarenes containing more complex substrates such as L-menthol, L-borneol, vitamin E, diacetonfructose and nerol were also competent substrates and gave moderate to good yields of the corresponding products. Finally, no desired product could be detected when 3-butenoic amide, 2-vinylbenzamide or internal alkene was tested under our standard conditions.Substrate scope for the synthesis of β-boryl ketones^aOpen in a separate window^aAll reactions were carried out on a 0.1 mmol scale. Alkenes (0.1 mmol), aryl iodides (2.0 equiv.), B₂pin₂ (1.5 equiv.), CuI (10 mol%), [Pd(η³-C₃H₅)Cl]₂ (2.5 mol%), xantphos (5 mol%), KHCO₃ (2.0 equiv.), CO (10 bar), and DMSO (0.2 M) were stirred at 70 °C for 18 h. The dr value given was determined by ¹H NMR.To demonstrate the synthetic utilities of the obtained borocarbonylation products, a series of further synthetic transformations of the β-boryl ketones were performed (Scheme 2). From a practical point of view, the reaction can be easily performed on the gram-scale and gave the target product 3m in 67% yield. β-Hydroxyl ketone 6a (CCDC: 2079475;^† determined by X-ray crystallography and the ORTEP drawing with 50% thermal ellipsoids) was produced in 95% yield by oxidation of the parent β-boryl ketone 3a. Furthermore, the C–B bond can be easily converted into a C–N bond, affording β-aminoketone 6b in 60% yield. Upon the reduction reaction of 3m with NaBH₄, the corresponding reduced oxaborole amide 6c could be isolated in 70% yield. Finally, a two-step transamination process was performed to remove the AQ group.¹⁶Open in a separate windowScheme 2Diversification of β-boryl ketones.To gain some insight into the mechanism of this selectivity-reversed borocarbonylation of alkenes, several control experiments were performed. The target product 3a was not formed, instead byproduct 6b was obtained in 40% yield, in the case without xantphos. Possible explanations for this result are: (i) the bidentate directing group AQ increases the stability of Pd(ii) species and promotes the carbonylation step; (ii) the role of xantphos is to coordinate to C(sp³)–Pd(ii) species after its formation and inhibit the formation of the C–N bond to give byproduct 6b (Scheme 3a). In addition, copper and B₂pin₂ were proven to be important, and KHCO₃ was essential for the carbonylation step (Scheme 3b). Analysis of the copper system in the absence of palladium and iodobenzene revealed that alkenes failed to undergo CuBpin insertion under this condition and no hydroboration products could be detected after work-up (Scheme 3c). Additionally, alkenes without the directing group were also tested under our standard conditions, and no reaction occurred.Open in a separate windowScheme 3Control experiments.Although we did not observe compound 7a during our optimization and substrate scope processes, even after stopping the reaction after 8 hours, we tested the possibility that 7a might act as an intermediate. When 7a was subjected to this transformation, the product 3a was delivered in 24% yield and 6b was generated in 37% (Scheme 3d). No significant difference in the yield outcome was observed when xantphos was added. Additionally, in our deuterated substrate testing, the amount of the deuterated product obtained is lower than the theoretical value (Scheme 3e). Thus, a pathway of β-H elimination followed by hydroboration could be involved as well. However, we believe the direct reaction between palladium and copper intermediates is the main one for this procedure due to the proven importance of the AQ group and the known achievements of copper-catalyzed hydroboration of enones, even with enantioselective versions.¹⁷On the basis of the above results and related literature studies,^7,11–14 a possible reaction pathway is proposed (Scheme 4). Initially, the AQ directing group coordinates with Pd⁰, which produces the active AQ-Pd⁰ catalyst I. This is followed by oxidative addition to aryl iodides to generate Pd^II species II, and then by base promoted iodine dissociation to form complex III. After the CO insertion step, the acyl-Pd^II species IV coordinates with the alkene and undergoes migratory insertion to generate C(sp³)–Pd^II intermediate V, which is stabilized by the xantphos ligand and AQ directing group. Subsequently, C(sp³)–Pd^II complex V reacts especially with CuBpin to give the desired product β-boryl ketone and regenerate the Pd(0) complex. Finally, ligand exchange of Pd⁰Ln regenerates AQ-Pd⁰I for the next catalytic cycle. Additionally, another minor pathway that involves the carbonylative Heck reaction to give an enone derivative, followed by its hydroboration to give the final product could be included as well.Open in a separate windowScheme 4Proposed catalytic cycle.In summary, a novel Pd/Cu catalyzed amide-directed selectivity-reversed borocarbonylation for the selective synthesis of β-boryl ketones from terminal alkenes has been developed. Various aryl iodides and aliphatic alkenes were transformed into the desired β-boryl ketones in moderate to excellent yields. In this catalyst system, the assistance from the AQ directing group is essential for successful reaction design.     

Aluminum-catalyzed tunable halodefluorination of trifluoromethyl- and difluoroalkyl-substituted olefins

Herein, we report unprecedented aluminum-catalyzed halodefluorination reactions of trifluoromethyl- and difluoroalkyl-substituted olefins with bromo- or chlorotrimethylsilane. The interesting feature of these reactions is that one, two, or three fluorine atoms can be selectively replaced with bromine or chlorine atoms by modification of the reaction conditions. The generated products can undergo a variety of subsequent transformations, thus constituting a valuable stock of building blocks for installing fluorine-containing olefin motifs in other molecules.

Aluminum-catalyzed halodefluorination reactions of fluoroalkyl-substituted olefins are developed. The reactions can selectively deliver mono-, di-, or trisubstituted products.

Combined with the use of fluorine-18 for positron emission tomography, the discovery that incorporating fluorine atoms into drug molecules can improve their bioavailability, metabolic stability, and target specificity has driven the rapid development of new methods for generating C–F bonds and forming bond connections with fluorine-containing structural motifs over the past decade.¹ However, synthesis of compounds bearing fluorovinyl (F–C C) and gem-difluoroallyl (F₂C–C C) groups remains a challenge, despite the presence of these structural motifs in numerous drugs, such as tezacitabine,² seletracetam,³ and tafluprost⁴ (Scheme 1a). We envisioned that synthesis of fluorovinyls containing an allylic bromine atom (F–C C–C–Br) would facilitate the preparation of such compounds because the bromine atom would serve as a handle for a wide variety of substitution and cross-coupling reactions. The existing methods for their preparation generally rely on reactions of fluorovinyls containing an allylic hydroxyl group or gem-difluorinated vinyloxiranes with brominating reagents.⁵ Direct methods for their synthesis from readily accessible substrates are lacking.Open in a separate windowScheme 1Synthesis of fluorovinyls via Lewis acid activation of trifluoromethylalkenes.Elegant work from the groups of Maruoka,⁶ Oshima,⁷ Ozerov,⁸ Müller,⁹ Stephan,¹⁰ Oestreich,¹¹ Chen,¹² and Young¹³ on C–F bond activation reactions has proven that Lewis acid-promoted abstraction of fluoride from alkyl fluorides is a powerful tool for generating carbocations that can be trapped by nucleophiles. When trifluoromethylalkenes were studied as substrates, Ichikawa et al. reported that aryldefluorination of trifluoromethylalkenes can be accomplished with a stoichiometric amount of EtAlCl₂via fluoride abstraction and subsequent Friedel–Crafts reactions between the resulting allylic carbocation and arenes (Scheme 1b).¹⁴ In addition, Braun and Kemnitz and colleagues carried out hydrodefluorination reactions of trifluoromethylalkenes with hydrosilanes catalyzed by Lewis acidic nanoscopic aluminum chlorofluoride (Scheme 1b).¹⁵ In light of these reports and our experiences in developing Lewis acid-catalyzed reactions,¹⁶ we speculated that 3,3-difluoroallyl bromides (F₂C C–C–Br) could be directly prepared from trifluoromethylalkenes and a suitable bromide source via Lewis acid activation of the C–F bonds and subsequent nucleophilic attack of the bromide anion at the distal olefinic carbon of the resulting allylic carbocation, a process that has no precedent in the literature.Herein, we report our discovery that by using an aluminum-based Lewis acid catalyst and bromotrimethylsilane (TMSBr) or chlorotrimethylsilane (TMSCl) as a halide source, we were able to achieve the proposed C–F bond activation/substitution reaction (Scheme 1c). Furthermore, simply by adjusting the stoichiometry of the reactants and the reaction temperature, we could selectively obtain mono-, di-, or trisubstituted products. Mechanistic studies indicated the multi-substitution reaction was achieved by thermally promoted 1,3-halogen migration of the initially formed product, followed by further halodefluorination. Notably, the previously reported defluorination reactions of trifluoromethylalkenes, either Lewis acid-catalyzed^14,15 or promoted via other methods,^17–19 usually provide monosubstitution products; that is, our finding that we could selectively generate multiply substituted products is also unprecedented.To test various reaction conditions, we chose α-aryl-substituted trifluoromethylalkene 1a as a model substrate (Table 1). TMSBr was selected as the bromide source because we expected the generated silyl cation to be an excellent scavenger for the displaced fluoride anion. We began by evaluating several Lewis acid catalysts and found that no reaction occurred when 1a was treated with B(C₆F₅)₃, Zn(OTf)₂, Sc(OTf)₃, Al(OTf)₃, or ZrCl₄ (5 mol%) and 3 equiv. of TMSBr in DCE at 80 °C for 24 h (entries 1–5). However, we were encouraged to find that AlCl₃ would catalyze the proposed bromodefluorination reaction, giving monobrominated product 2a and dibrominated product 3a (ref. 20) in 17% and 2% yields, respectively (entry 6). Investigation of additional aluminum-based Lewis acids showed that AlEtCl₂ and Al(C₆F₅)₃(tol)_0.5 (ref. 21) had higher activities: AlEtCl₂ gave 2a and 3a in 5% and 38% yields, respectively (entry 7), and Al(C₆F₅)₃(tol)_0.5 gave 16% and 32% yields, respectively (entry 8). Because Al(C₆F₅)₃(tol)_0.5 is a solid and therefore easier to store and handle than AlEtCl₂ (a liquid), we chose Al(C₆F₅)₃(tol)_0.5 for further investigation. Changing the solvent to toluene inhibited the formation of 3a, but failed to improve the yield of 2a (entry 9). Coordinative solvents (acetonitrile and dioxane) shut down the reaction entirely (entries 10 and 11). When the reaction temperature was increased to 120 °C, 2a and 3a were obtained in 13% and 68% yields, respectively (entry 13). Gratifyingly, when 4 equiv. of TMSBr relative to 1a was used, 3a was generated as the sole reaction product in 90% yield (Z/E = 55 : 45, entry 14). Next, we tried using TMSBr as the limiting reagent to determine whether we could obtain the monobrominated product (2a) as the major product. Indeed, when 3 equiv. of 1a was treated with 1 equiv. of TMSBr at 80 °C, 2a was obtained as the sole product, although the yield was only 30% (entry 15). Further screening of reaction conditions revealed that using 9.0 mol% of Al(C₆F₅)₃(tol)_0.5 and running the reaction at 60 °C for 48 h (entry 16) gave the highest yield of 2a (76%; the yield of 3a was 8%).Optimization of reaction conditions^a

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented.

Alkenes are important and versatile building blocks in organic synthesis. 1,2-Difunctionalization of alkenes offers a highly valuable synthetic strategy to access 1,2-difunctionalized alkanes by sequentially forming two vicinal σ-bonds.^1a–h Among these vicinal difunctionalizations, the 1,2-carboamination of alkenes, in which a C–N and a C–C bond are formed, provides an attractive route for the straightforward preparation of structurally diverse amine derivatives (Scheme 1a).^2a–c Along these lines, transition-metal-catalyzed or radical 1,2-carboaminations of activated and unactivated alkenes have been reported.^3a–p However, the 1,2-carboamination of vinylboron reagents, a privileged class of olefins,^4a–h to form valuable 1,2-aminoboron compounds which can be readily used in diverse downstream functionalizations,^{5a–c,6a–d} has been rarely investigated. To the best of our knowledge, there are only two reported examples, as shown in Schemes 1b and c. In 2013, Molander disclosed a Rh-catalyzed 1,2-aminoarylation of potassium vinyltrifluoroborate with benzhydroxamates via C–H activation (Scheme 1b).⁷ Thus, the 1,2-carboamination of vinylboron reagents is still underexplored but highly desirable.Open in a separate windowScheme 1Intermolecular 1,2-carboamination of alkenes.1,2-Alkyl/aryl migrations induced by β-addition to vinylboron ate complexes have been shown to be highly reliable for 1,2-difunctionalization of vinylboron reagents (Scheme 1c).^4d–h In 1967, Zweifel''s group developed 1,2-alkyl/aryl migrations of vinylboron ate complexes induced by an electrophilic halogenation.⁸ In 2016, the Morken group reported the electrophilic palladation-induced 1,2-alkyl/aryl migration of vinylboron ate complexes.^9a–k Shortly thereafter, we,^10a–c Aggarwal,^11a–c and Renaud¹² developed alkyl radical induced 1,2-alkyl/aryl migrations of vinylboron ate complexes. In these recent examples, the migration is induced by a C-based radical/electrophile, halogen and chalcogen electrophiles.^13a,bIn contrast, N-reagent-induced migration of vinylboron ate complexes proceeding via β-amination is not well investigated. To our knowledge, as the only example the Aggarwal laboratory described the reaction of a vinylboron ate complex with an aryldiazonium salt as the electrophile, but the desired β-aminated rearrangement product was formed in only 9% NMR yield (Scheme 1c).^13a No doubt, β-amino alkylboronic esters would be valuable intermediates in organic synthesis. Encouraged by our continuous work on amidyl radicals^14a–i and 1,2-migrations of boron ate complexes,^{10a–c,15a–f} we therefore decided to study the amidyl radical-induced carboamination of vinyl boronic esters for the preparation of 1,2-aminoboronic esters. N-chloroamides were chosen as N-radical precursors,^16a–c as these N-chloro compounds can be easily prepared from the corresponding N–H analogues.¹⁷ Herein, we present a catalyst-free three-component 1,2-carboamination of vinyl boronic esters with N-chloroamides and readily available alkyl/aryl lithium reagents (Scheme 1d).We commenced our study by exploring the reaction of the vinylboron ate complex 2a with tert-butyl chloro(methyl)carbamate 3a applying photoredox catalysis. Complex 2a was generated in situ by addition of n-butyllithium to the boronic ester 1a in diethyl ether at 0 °C. After solvent removal, the photocatalyst fac-Ir(ppy)₃ (1 mol%) and THF were added followed by the addition of 3a. Upon blue LED light irradiation, the mixture was stirred at room temperature for 16 hours. To our delight, the desired 1,2-aminoboronic ester 4a was obtained, albeit with low yield (26%, EntryPhotocatalystSolventT (°C)Yield^b (%)1 fac-Ir(ppy)₃THFrt262 fac-Ir(ppy)₃DMSOrt23 fac-Ir(ppy)₃MeCNrt564Ru(bpy)₃Cl₂·6H₂OMeCNrt695Na₂Eosin YMeCNrt696^cNa₂Eosin YMeCNrt707^cNoneMeCNrt458^cNoneMeCN0789^cNoneMeCN−2088 (85)10^c,dNoneMeCN−202Open in a separate window^aReaction conditions: 1a (0.20 mmol), ⁿBuLi (0.22 mmol), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar. After vinylboron ate complex formation, solvent exchange to the selected solvent (2 mL) was performed.^bGC yield using n-C₁₄H₃₀ as an internal standard; yield of isolated product is given in parentheses.^c4 mL MeCN was used.^dReaction carried out in the dark.With optimal conditions in hand, we then investigated the scope of this new 1,2-carboamination protocol keeping 2a as the N-radical acceptor (Scheme 2). This transformation turned out to be compatible with various primary amine reaction partners bearing carbamate (4a, 4b and 4d–4g) or acyl protecting groups (4c) (20–85%). Notably, N-chlorolactams can be used as N-radical precursors, as shown by the successful preparation of 4h (71%). Moreover, Boc-protected ammonia was also tolerated, delivering 4i in an acceptable yield (55%).Open in a separate windowScheme 21,2-Carboamination of 1a with various amidyl radical precursors. Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), ⁿBuLi (0.22 mmol, 1.1 equiv.), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar; then [N]-Cl (0.24 mmol, 1.2 equiv.), −20 °C, 16 h, in MeCN (4 mL). Yields given correspond to yields of isolated products. ^aA solution of [N]-Cl (0.30 mmol, 1.5 equiv.) in MeCN (1 mL) was used. See the ESI^† for experimental details.We continued the studies by testing a range of vinylboron ate complexes (Scheme 3). To this end, various vinylboron ate complexes were generated by reacting the vinyl boronic ester 1a with methyllithium, n-hexyllithium, isopropyllithium and tert-butyllithium. For the n-alkyl-substituted vinylboron ate complexes, the 1,2-carboamination worked smoothly to afford 4j and 4k in good yields. However, the vinylboron ate complex derived from isopropyllithium addition provided the desired products in much lower yield (4l, 18% yield). When tert-butyllithium was employed, only a trace of the targeted product was detected (see ESI^†). As expected, cascades comprising a 1,2-aryl migration from boron to carbon worked well. Thus, by using PhLi for vinylboron ate complex formation, the 1,2-aminoboronic esters 4m–4o were obtained in 69–73% yields with the Boc (t-BuOCONClMe), ethoxycarbonyl-(EtOCONClMe) and methoxycarbonyl (Moc)-(MeOCONClMe) protected N-chloromethylamines (for the structures of 3, see ESI^†) as radical amination reagents. Keeping 3b as the N-donor, other aryllithiums bearing various functional groups at the para position of the aryl moiety, such as methoxy (4p), trimethylsilyl (4q), methyl (4r), phenyl (4s), trifluoromethoxy (4t), trifluoromethyl (4u), and halides (4v–4x) all reacted well in this transformation. Aryl groups bearing meta substituents are also tolerated, as documented by the preparation of 4y (81%). To our delight, a boron ate complex generated with a 3-pyridyl lithium reagent engaged in the cascade and the carboamination product 4z was isolated in high yield (82%).Open in a separate windowScheme 3Scope of vinylboron ate complexes. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), R_MLi (0.22 mmol, 1.1 or 1.3 equiv.), Et₂O or THF, under Ar; then [N]-Cl (0.30 mmol, 1.5 equiv.), −20 °C, 16 h, in MeCN. Yields given correspond to yields for isolated products. See the ESI^† for experimental details.The reason for the dramatic reduction in yield when α-branched alkyllithium or electron-rich aryllithium reagents were used might be that the corresponding vinylboron ate complexes could be oxidized by N-chloroamides via a single-electron oxidation process.^18a–e Furthermore, the α-unsubstituted vinyl boronic ester and vinyl boronic ester bearing various α-substituents are suitable N-radical acceptors and the corresponding products 4aa–4ac were obtained in 48–70% yield.To gain insights into the mechanism of this 1,2-carboamination, a control experiment was conducted. The reaction could be nearly fully suppressed when the reaction was carried out in the presence of a typical radical scavenger (2,2-6,6-tetramethyl piperidine-N-oxyl, TEMPO), indicating a radical mechanism (Scheme 4a). Further, considering an ionic process, the N-chloroamides would react as Cl⁺-donors that would lead to Zweifel-type products, which were not observed under the applied conditions. The proposed mechanism is shown in Scheme 4b. As chloroamides have been recently proposed to undergo homolysis under visible light irradiation,^19a,b we propose that initiation proceeds via homolytic N–Cl cleavage generating the electrophilic amidyl radical A, which then adds to the electron-rich vinylboron ate complex 2a to give the adduct boronate radical B. The radical anion B then undergoes single electron transfer (SET) oxidation with 3a in an electron-catalyzed process^20a,b or chloride atom transfer with 3a to provide C or D along with the amidyl radical A, thereby sustaining the radical chain. Intermediates C or D can then react via a boronate 1,2-migration^10c,11c,21 to eventually give the isolated product 4a.Open in a separate windowScheme 4Control experiment and proposed mechanism.To document the synthetic utility of the method, a larger-scale reaction and various follow-up transformations were conducted. Gram-scale reaction of 2a with 3a afforded the desired product 4a in good yield, demonstrating the practicality of this transformation (Scheme 5a). Oxidation of 4a with NaBO₃ provided the β-amino alcohol 5 in 89% yield (Scheme 5b). The N-Boc homoallylic amine 6 was obtained by Zweifel-olefination with a commercially available vinyl Grignard reagent and elemental iodine in good yield (79%).²² Heteroarylation of the C–B bond in 4a was realized by oxidative coupling of 4a with 2-thienyl lithium to provide 7.²³Open in a separate windowScheme 5Gram-scale reaction and follow-up chemistry.In summary, we have described an efficient method for the preparation of 1,2-aminoboronic esters from vinyl boronic esters via catalyst-free three-component radical 1,2-carboamination. Readily available N-chloro-carbamates/carboxamides, which are used as the N-radical precursors, react efficiently with in situ generated vinylboron ate complexes to afford the corresponding valuable 1,2-aminoboronic esters in good yields. The reaction features broad substrate scope and high functional group tolerance. The value of the introduced method was documented by Gram-scale reaction and successful follow-up transformations.     

Nickel catalysis enables convergent paired electrolysis for direct arylation of benzylic C–H bonds

Convergent paired electrosynthesis is an energy-efficient approach in organic synthesis; however, it is limited by the difficulty to match the innate redox properties of reaction partners. Here we use nickel catalysis to cross-couple the two intermediates generated at the two opposite electrodes of an electrochemical cell, achieving direct arylation of benzylic C–H bonds. This method yields a diverse set of diarylmethanes, which are important structural motifs in medicinal and materials chemistry. Preliminary mechanistic study suggests oxidation of a benzylic C–H bond, Ni-catalyzed C–C coupling, and reduction of a Ni intermediate as key elements of the catalytic cycle.

A direct arylation of benzylic C–H bonds is achieved by integrating Ni-catalyzed benzyl–aryl coupling into convergent paired electrolysis.

Electrochemical organic synthesis has drawn much attention in recent years.¹ Compared to processes using stoichiometric redox agents, electrosynthesis can potentially be more selective and safe, generate less waste, and operate under milder conditions.^1b In the majority of examples, the reaction of interest occurs at one electrode (anode for oxidation or cathode for reduction), while a sacrificial reaction occurs at the counter electrode to fulfil electron neutrality.^1a,2 Paired electrolysis uses both anodic and cathodic reactions for the target synthesis, thereby maximizing energy efficiency.^1a,3 However, there are comparatively few examples of paired electrolysis for organic synthesis.^1a,3,4Paired electrolysis might be classified into three types: parallel, sequential, and convergent (Fig. 1).^1a,3a In parallel paired electrolysis (Fig. 1a), the two half reactions are simultaneous but non-interfering. In sequential paired electrolysis (Fig. 1b), a substrate is oxidized and reduced (or vice versa) sequentially. In convergent paired electrolysis (Fig. 1c), intermediates generated by the anodic and cathodic processes react with one another to yield the product.^1a,3a,4b,c,5 The activation mode of all three types of paired electrolysis is based on the innate redox reactivity of substrates. As a result, the types of reactions that could be conducted by paired electrolysis remain limited. We proposed a catalytic version of convergent paired electrolysis, where a catalyst is used to cross-couple the two intermediates generated at the two separated electrodes (Fig. 1d). Although mediators have been used in paired electrosynthesis,^3a,4c,6 catalytic coupling of anodic and cathodic intermediates remains largely undeveloped. This mode of action will leverage the power of cross-coupling to electrosynthesis, opening up a wide substrate and product space. Here we report the development of such a process, where cooperative nickel catalysis and paired electrolysis enable direct arylation of benzylic C–H bonds (Fig. 1e).Open in a separate windowFig. 1Different types of paired electrolysis: (a) parallel paired electrolysis, (b) sequential paired electrolysis, (c) convergent paired electrolysis, (d) catalytic convergent paired electrolysis and (e) this work.Our method can be used to synthesize diarylmethanes, which are important structural motifs in bioactive compounds,⁷ natural products⁸ and materials.⁹ Direct arylation of benzylic C–H bonds has been recognized as an efficient strategy to synthesize diarylmethanes, and methods using metal catalysis¹⁰ and in particular combined photoredox and transition-metal catalysis have been reported.¹¹ Electrosynthesis provides a complementary approach to these methods, with the potential advantages outlined above. The groups of Yoshida¹² and Waldvogel¹³ previously developed synthesis of diarylmethanes via a Friedel–Crafts-type reaction of a benzylic cation and a nucleophile. The benzylic cations were generated by anodic oxidation of benzylic C–H bonds.¹⁴ To avoid the overoxidation of products and to stabilize the very reactive benzylic cations, the reactions had to be conducted in two steps, where the benzylic cations generated in the anodic oxidation step had to be trapped by a reagent. We thought a Ni catalyst could be used to trap the benzyl radical to form an organonickel intermediate, which is then prone to a Ni-catalyzed C–C cross-coupling reaction. Although such a coupling scheme was unprecedented, Ni-catalyzed electrochemical reductive coupling of aryl halides was well established.¹⁵ We were also encouraged by a few recent reports of combined Ni catalysis and electrosynthesis for C–N,¹⁶ C–S,¹⁷ and C–P¹⁸ coupling reactions.We started our investigations using the reaction between 4-methylanisole 1a and 4-bromoacetophenone 2a as a test reaction (Table 1). Direct arylation of benzylic C–H bonds was challenging and was typically conducted using toluene derivatives in large excess, e.g., as a solvent.^{11a,b,11d–f} To improve the reaction efficiency, we decided to use only 3 equivalents of 4-methylanisole 1a relative to 2a. After some initial trials, we decided to conduct the reaction in an undivided cell using a constant current of 3 mA. These conditions are straightforward from a practical point of view. After screening various reaction parameters, we found that a combination of 4,4′-dimethoxy-2-2′-bipyridine (L1) and (DME)NiBr₂ as a catalyst, THF/CH₃CN (4 : 1) as a solvent, fluorine-doped tin oxide (FTO) coated glass as an anode and carbon fibre as a cathode gave a 50% GC yield of 1-(4-(4-methoxybenzyl)phenyl)ethanone 3a after 18 h (Table 1, entry 1). Extending the reaction time to 36 h improved the yield to 76% (isolated yield) (entry 2). The target products were formed in a diminished yield with other bipyridine type ligands (entries 3–5). Solvents commonly used in Ni-catalyzed cross-coupling reactions, such as DMA and DMF, were less effective (entries 7–8). Replacing carbon fibre by nickel foam or platinum foil as the cathode was detrimental to the coupling, but substantial yields were still obtained (entries 9–10). On the other hand, FTO could not be replaced as the anode. Using carbon fibre as the anode shut down the reaction (entry 11). Likewise, using Pt foil as the anode gave only a 7% GC yield (entry 12). The sensitivity of the reaction outcomes to the electrodes originates from the electrode-dependent redox properties of reaction components (see below). Additional data showing the influence of other reaction parameters such as nickel sources, current, concentration, and electrolytes are provided in the ESI (Table S1, ESI^†).Summary of the influence of key reaction parameters^a