Yingdong Luo

Umpolung Reactivity of Indole through Gold Catalysis

The indole 3-position is highly electron-rich and typically functions as the primary nucleophilic site to react with a large array of electrophiles, leading to various functionalized indoles.[1] The reversal of this prime reactivity, i.e., making the indole 3-position electrophilic, would be of significant synthetic utility and provide a complementary strategy to access derivatives[2] otherwise difficult to prepare conventionally. This reactivity umpolung[3] of indole has, however, only been realized in limited cases.[4] For the past few years we have engaged in extensive studies of gold-catalyzed intra-[5] and intermolecular[6] alkyne oxidations using oxygen-delivering oxidants,[7] where reactive α-oxo gold carbene intermediates are presumably generated[8] and responsible for the diverse reaction outcomes. Lately we extended this strategy to the use of nitrene precursors as oxidants, providing access to reactive α-imino gold carbenes (Scheme 1A);[9] however, the chemistry has so far been limited to ynamides,[10] which are activated alkynes. In our effort to expand the scope of this type of gold-catalyzed nitrene transfer,[11] we decided to use an azido group as a nitrene precursor, which was inspired by previous studies of gold-[12] and platinum-catalyzed[13] pyrrole synthesis. We reasoned that closely and rigidly positioned C-C triple bonds in ortho-azidoarylalkynes might facilitate an intramolecular nitrene transfer from the azido group to the C-C triple bond. Importantly, the thus-formed gold carbene B would serve as an electrophilic indole equivalent, as depicted in its resonance form C, therefore realizing reactivity umpolung of the indole 3-position (Scheme 1B).[14] Scheme 1 Gold-catalyzed nitrene transfer: realizing reactivity umpolung at the indole 3-position. We started by using ortho-azidophenylalkyne 1a as the substrate and anisole as the nucleophile, and the initial reaction was run in toluene using Ph3PAuNTf2[15] as the catalyst. To our delight, the desired indole regioisomers 2a and 2a’ were indeed formed (entry 1), confirming that the azido group could function as a nitrene precursor and a gold carbene of type B might be indeed formed; moreover, this proposed reactive intermediate seemingly reacted mainly via its cationic resonance form C[16] as no Buchner reaction,[17] i.e., the formation of cycloheptatriene products, which is characteristic of carbene chemistry, occurred. The regioselectivity on the anisole ring is consistent with an electrophilic aromatic substitution mechanism. To our surprise, the majority of the putative gold intermediate B/C reacted with the solvent toluene, yielding a mixture of regioisomers (p-3/o-3/m-3 = 41%/11%/8%). Although the concentration of toluene is ~190 time of that of anisole, anisole is much more nucleophilic than toluene.[18] These results indicate that intermediate C is strongly electrophilic and hence less selective. This conclusion is consistent with the ratio of p-3 vs. m-3 (~5), lower than that in the case of nitration (>10),[19] suggesting that C might be even more electrophilic than NO2+. Since products of type 2a, 2a’, and 3 are also good nucleophiles, we anticipated that it is essential to use excess intended nucleophiles in order to minimizing their competing reactions with highly electrophilic C. Other solvents were screened in order to minimize solvent participation (entries 2–4). While benzene also interfered the desired reaction (entry 2), neither DCE (entry 3) nor chlorobenzene (entry 4) did; a better reaction yield was realized in DCE. Examining different gold catalysts (entries 5–10) at a beneficiary higher reaction temperature (comparing entries 3 and 5) revealed that IPrAuNTf2 (entry 6) gave the best yield and bulky t-BuXPhosAuNTf2 gave the best para/ortho ratio (entry 8). We also run the reaction using anisole as the solvent at a higher concentration (0.2 M). Somewhat to our surprise, the reaction became dramatically faster and finished in 5 min at 80 °C; moreover, the yield was excellent. Perhaps even more surprising is that the para/ortho ratio decreased as the reaction temperature got lower (comparing entries 11–13). This may suggest the involvement of another reaction mechanism. As shown in Scheme 2, at a higher temperature (e.g., 80 °C), the formation of B/C should be facilitated, but at a lower temperature (e.g., −20 °C) its precursor, i.e. A, may persist and play an increasing role in the reaction by reacting with nucleophiles via an SN2’ process; since the Au-C bond length in B/C should be shorter than the Au-C bond in A, one might expect that the more the reaction goes through B/C the more regioselective as the bulky ligand (i.e., t- BuXPhos) can be more sterically imposing.[20] Scheme 2 Rationale for the inversed relationship between regioselectivities and reaction temperatures. The scope of o-azidoarylalkynes was subsequently examined by first varying the alkyne substituent. Using anisole as the solvent, primary alkyl groups such as n-butyl (Table 2, entry 1) and phenethyl (Table 2, entry 2) reacted smoothly; a lower yield was obtained with 1d containing a benzyl ether (Table 2, entry 3); cyclic secondary alkyl groups (Table 2, entries 4–6) as well as a tert-butyl group (Table 2, entry 7) all led to good yields; interestingly, substrate 1i with a terminal alkyne also worked (Table 2, entry 8); aryl groups with either a p-MeO (Table 2, entry 10) or a p-methoxycarbonyl group (Table 2, entry 11) were readily tolerated, and the corresponding indoles were formed in good to excellent yields. In all the cases, the regioselectivities correlated well with the substituent steric size, and the best 2/2’ ratio was realized with the tert-butyl alkyne 1h. In addition, substrates with substituted benzene ring also reacted with good efficiencies, thus offering highly substituted indole products (entries 11 and 12). Table 2 The scope of o-azidoarylalkyne substrates.[a] The applicability of this chemistry to other nucleophiles was then probed using the conditions in Table 1, Entry 6, and the successful examples are shown in Table 3. As expected, p-xylene, when used as solvent, served as a suitable nucleophile for this chemistry (entry 1). In the case of naphthalene, the α-position is preferred due to its stronger nucleophilicity (entry 2). More activated benzene rings (entries 3 and 4) gave good yields of desired products, and a good selectivity (10:1) was observed with 1,3-dimethoxybenzene, reflecting the more congested nature of the 2-position. In the case of N-methylpyrrole, apparently the electronic and the steric factors were working against each other; consequently, no regioselectivity was observed (entry 5); nevertheless, the overall efficiency was excellent. Increasing the steric hindrance at the pyrrole 2-position by installing a TIPS group on the ring nitrogen indeed made the reaction occurred selectively at the 3-position (entry 6). When N-benzylindole was used as the nucleophile, to our surprise, at least three inseparable regioisomers were formed, suggesting that its benzene ring participated in this reaction as the nucleophilic site. To our delight, with strongly electron-withdrawing nitro group on the indole benzene ring, the substitution selectively occurred on the 3-position, affording nonsymmetrical 3,3’-biindoles with good yields (entries 7 and 8). The use of the more polar azidoalkyne substrate 1k facilitated purification of the products. With the indole 2-position substituted and its benzene ring again deactivated, the electrophilic substitution proceeded expectedly at the 3-position to yield hindered biindole 5i. Notably, the 3,3-biindole structure has been found in natural products[21] and compounds of medical interest,[22] and their syntheses often require multiple steps.[23] Dimedone methyl ether could react as a nucleophile as well albeit accompanied with in-situ hydrolysis and in a relatively low reaction yield (entry 10). Besides carbon nucleophiles, alcohols could react with intermediates of type C (entries 11 and 12). The moderate yields were to some extent due to (1) (2) the susceptibility of the products towards aerobic oxidation. Interestingly, with allyl alcohol as the nucleophile, the product underwent one-pot Claisen rearrangement, yielding indol-3-one 5m in a serviceable yield (entry 13). Notably, no desired product was observed when using N-methyltosylamide as the nucleophile. Table 1 Initial discovery and condition optimizations.[a] Table 3 The scope of different nucleophiles.[a] This reactivity umpolung of indole was briefly tested in intramolecular scenarios. With azidoalkyne 1c, in the absence of an external nucleophile such as anisole (e.g., in Table 2, entry 2), the tethered benzene ring reacted as the nucleophile, efficiently trapping the electrophilic indole 3-position and thereby forming tetracyclic product 6 in a good yield (Eq. 1). To our surprise, even a seven-membered ring could be readily formed via this intramolecular trapping (Eq. 2); moreover, this reaction appeared to be rather facile as the tetracyclic product 7 was formed in ca. 4% yield even when anisole was used as the solvent (Table 2, entry 3), again implicating the high electrophilicity of the intermediate B/C. In summary, we have developed a new approach to achieving reactivity umpolung of indole at the 3-position via gold catalysis. By using an ortho-azido group to deliver a nitrene intramolecularly, an arylalkyne can be converted into a gold carbene intermediate that contains the indole skeleton but highly electrophilic at the 3-position. The reaction of this electrophilic indole intermediate with variously nucleophiles provides a novel and expedient synthesis of a range of functional indoles.

Tempering the reactivities of postulated α-oxo gold carbenes using bidentate ligands: implication of tricoordinated gold intermediates and the development of an expedient bimolecular assembly of 2,4-disubstituted oxazoles.

2,4-Oxazole is an important structural motif in various natural products. An efficient modular synthesis of this structure has been achieved via a [3 + 2] annulation between a terminal alkyne and a carboxamide using a gold-catalyzed oxidation strategy. The postulated reactive intermediate, a terminal α-oxo gold carbene, previously known to be highly electrophilic and hence unlikely to be trapped by stoichiometric external nucleophiles, is coerced to react smoothly with the carboxamide en route to the oxazole ring by a P,N- or P,S-bidentate ligand such as Mor-DalPhos; in stark contrast, often-used ligands such as monodentate phosphines and N-heterocyclic carbenes are totally ineffective. The role of these bidentate phosphines in this reaction is attributed to the formation of a tricoordinated gold carbene intermediate, which is less electrophilic and hence more chemoselective when reacting with nucleophiles. The success in using bidentate phosphine ligands to temper the reactivities of in situ-generated gold carbenes is likely to open many new opportunities to apply oxidative gold catalysis to the development of novel methods, and the implication of tricoordinated gold intermediates in homogeneous gold catalysis should stimulate further advances in gold catalysis.

[3,3]-Sigmatropic Rearrangement versus Carbene Formation in Gold-Catalyzed Transformations of Alkynyl Aryl Sulfoxides: Mechanistic Studies and Expanded Reaction Scope

Gold-catalyzed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant is a reaction of high impact in gold chemistry, as it introduced to the field the highly valued concept of gold carbene generation via alkyne oxidation. The proposed intermediacy of α-oxo gold carbenes in these reactions, however, has never been substantiated. Detailed experimental studies suggest that the involvement of such reactive intermediates in the formation of dihydrobenzothiepinones is highly unlikely. Instead, a [3,3]-sigmatropic rearrangement of the initial cyclization intermediate offers a reaction path that can readily explain the high reaction efficiency and the lack of sulfonium formation. With internal alkyne substrates, however, the generation of a gold carbene species becomes competitive with the [3,3]-sigmatropic rearrangement. This reactive intermediate, nevertheless, does not proceed to afford the Friedel-Crafts-type cyclization product. Extensive density functional theory studies support the mechanistic conclusion that the cyclized product is formed via an intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel-Crafts-type cyclization. With the new mechanistic insight, the product scope of this versatile formation of mid-sized sulfur-containing cycloalkenones has been expanded readily to various dihydrobenzothiocinones, a tetrahydrobenzocyclononenone, and even those without the entanglement of a fused benzene ring. Besides gold, Hg(OTf)2 can be an effective catalyst, thereby offering a cheap alternative for this intramolecular redox reaction.

Mechanism of Gold(I)-Catalyzed Rearrangements of Acetylenic Amine-N-Oxides: Computational Investigations Lead to a New Mechanism Confirmed by Experiment

Quantum mechanical studies of the mechanism of gold-catalyzed rearrangements of acetylenic amine-N-oxides to piperidinones or azepanones have revealed a new mechanism involving a concerted heteroretroene reaction, formally a 1,5 hydrogen shift from the N-alkyl groups to the vinyl position of a gold-coordinated methyleneisoxazolidinium or methyleneoxazinanium. Density functional calculations (B3LYP, B3LYP-D3) on the heteroretroene mechanism reproduce experimental regioselectivities and provide an explanation as to why the hydrogen is transferred from the smaller amine substituent. In support of the proposed mechanism, new experimental investigations show that the hydrogen shift is concerted and that gold carbenes are not involved as reaction intermediates.

Chemoselective Radical Dehalogenation and C–C Bond Formation on Aryl Halide Substrates Using Organic Photoredox Catalysts

Despite the number of methods available for dehalogenation and carbon-carbon bond formation using aryl halides, strategies that provide chemoselectivity for systems bearing multiple carbon-halogen bonds are still needed. Herein, we report the ability to tune the reduction potential of metal-free phenothiazine-based photoredox catalysts and demonstrate the application of these catalysts for chemoselective carbon-halogen bond activation to achieve C-C cross-coupling reactions as well as reductive dehalogenations. This procedure works both for conjugated polyhalides as well as unconjugated substrates. We further illustrate the usefulness of this protocol by intramolecular cyclization of a pyrrole substrate, an advanced building block for a family of natural products known to exhibit biological activity.

Highly Ordered Nanoporous Films from Supramolecular Diblock Copolymers with Hydrogen‐Bonding Junctions

We designed efficient precursors that combine complementary associative groups with exceptional binding affinities and thiocarbonylthio moieties enabling precise RAFT polymerization. Well defined PS and PMMA supramolecular polymers with molecular weights up to 30 kg mol(-1) are synthesized and shown to form highly stable supramolecular diblock copolymers (BCPs) when mixed, in non-polar solvents or in the bulk. Hierarchical self-assembly of such supramolecular BCPs by thermal annealing affords morphologies with excellent lateral order, comparable to features expected from covalent diblock copolymer analogues. Simple washing of the resulting materials with protic solvents disrupts the supramolecular association and selectively dissolves one polymer, affording a straightforward process for preparing well-ordered nanoporous materials without resorting to crosslinking or invasive chemical degradations.

Gold-catalyzed regioselective oxidation of terminal allenes: formation of α-methanesulfonyloxy methyl ketones

Summary Synthetically useful α-methanesulfonyloxy methyl ketones are readily prepared in one-step from terminal allenes in fair to good yields. The chemistry relies on a gold-catalyzed intermolecular oxidation of the 1,2-diene unit using 3,5-dichloropyridine N-oxide as the oxidant. The reaction tolerates a range of functional groups and shows excellent regioselectivity.

Modular synthesis of asymmetric rylene derivatives

The modular synthesis of asymmetric rylenes from naphthalic anhydride derivatives is presented. Imidization, Suzuki–Miyaura coupling and cyclodehydrogenation reactions are utilized for the generation of novel functional rylenes with these three core transformations providing significant flexibility over the final structure. The combination of simple purification and high yields enables access to asymmetric rylenes with functional handles at the imide-position and site-specific incorporation of bay position substituents. The resulting library of perylenes and bisnapthalimide-anthracene derivatives showcase the presented methodology and the ability to tune optoelectronic and electrochemical properties.