An intramolecular nitro-Mannich route to functionalised tetrahydroquinolines

A simple protocol for the diastereoselective synthesis of 3-nitrotetrahydroquinolines has been developed using an intramolecular nitro-Mannich reaction. In situ formation of an imine generated from treatment of 2-(2-nitroethyl)phenylamine with an aldehyde, in EtOH at room temperature, and subsequent addition of NH₄OH, led to the formation of trans-products in high yield and diastereoselectivity for 15 representative examples.     

Room temperature palladium-catalyzed intramolecular hydroamination of unactivated alkenes

A mild and facile Pd-catalyzed intramolecular hydroamination of unactivated alkenes is described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. The formation of hydroamination products rather than oxidative amination products is due to the use of a tridentate ligand on Pd which effectively inhibits beta-hydride elimination.     

Gold-catalyzed intramolecular hydroamination of α-amino allenamides as a route to enantiopure 2-vinylimidazolidinones

An efficient gold-catalyzed procedure for the preparation of 2-vinylimidazolidinones has been developed. The starting materials for the synthesis of these compounds are α-amino allenamides which undergo heterocyclization by means of nucleophilic attack of the amino group on the inside double bond of the 1,2-diene moiety. This is the first example of a gold-catalyzed cyclization on allene substrates bearing an amido group which, however, resulted inactive.     

Fluoradenes via palladium-catalyzed intramolecular arylation

A novel approach towards 7b-aryl-indeno[1,2,3-jk]fluorene based on a nitrogen-containing core is reported. The acid-promoted Friedel-Crafts reaction of 9-(2-bromophenyl)-9-fluorenol with carbazole, triphenylamine or triindole afforded 9-(2-bromophenyl)fluorenyl-carbazole, -triphenylamine and -triindole derivatives, which were subsequently converted to 7b-aryl-fluoradenes via palladium-catalyzed intramolecular C-H direct arylation as a key step.     

A new entry to polycyclic indole skeletons via palladium-catalyzed intramolecular heteroannulation

[reaction: see text] A one-step method was developed for elaboration of a variety of polycyclic indole skeletons via a novel palladium-catalyzed intramolecular indolization of 2-chloroanilines bearing tethered acetylenes. This novel intramolecular indolization method unveils an unusual syn amidopalladation pathway of a tethered alkyne.     

A novel synthesis of 2-aryl-2H-indazoles via a palladium-catalyzed intramolecular amination reaction

[reaction: see text] A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N(o-bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2/dppf/tBuONa gave the best results. This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.     

Tropene derivatives by sequential intermolecular and transannular, intramolecular palladium-catalyzed hydroamination of cycloheptatriene

A consecutive inter- and intramolecular hydroamination of cycloheptatriene with primary aromatic amines, benzylic amines, and beta-phenethylamines occurs to produce pharmaceutically relevant tropene (8-azabicyclo[3.2.1]octene) frameworks in good to excellent yields. This reaction occurs in the presence of a catalyst generated from palladium trifluoroacetate, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and a mild acid. Mechanistic studies reveal that the overall process has some reversible steps, but that the rate of these reverse reactions are far slower than the rates of the forward catalytic process.     

A redox-enabled strategy for intramolecular hydroamination

Metal- or acid-catalyzed intramolecular hydroamination and Cope-type intramolecular hydroamination, a distinct concerted approach using hydroxylamines, typically suffer from significant synthetic limitations. Herein we report a process for intramolecular hydroamination that uses a redox-enabled strategy relying on efficient in situ generation of hydroxylamines by oxidation, followed by Cope-type hydroamination, then reduction of the resulting pyrrolidine N-oxide. The steps are performed sequentially in a single pot, no catalyst is required, the conditions are mild, the process is highly functional group tolerant, and no chromatography is generally required for isolation. A robustness screen and a gram-scale example further support the practicality of this approach.

A redox strategy enables hydroaminations: mild conditions allows efficient hydroxylamine formation & cyclization, then B₂(OH)₄ as reductant also facilitates isolation!     

A concise route to indoloazocines via a sequential Ugi-gold-catalyzed intramolecular hydroarylation

A diversity oriented approach for the synthesis of indoloazocines is reported employing an Ugi reaction followed by a gold-catalyzed intramolecular hydroarylation.     

Enantioselective synthesis of P-stereogenic benzophospholanes via palladium-catalyzed intramolecular cyclization

Enantioselective or diastereoselective intramolecular cyclization of functionalized secondary phosphines or their borane adducts catalyzed by chiral Pd(diphosphine) complexes gave P-stereogenic benzophospholanes in up to 70% ee. These results provide a new method for the synthesis of chiral phospholanes, which are valuable ligands in asymmetric catalysis. [reaction: see text]     

A novel base-mediated intramolecular hydroamination to build fused heteroaryl pyrazinones

Functionalized fused heteroaryl pyrazinones were built up through a novel DBU-catalyzed intramolecular hydroamination reaction of aryl(prop-2-yn-1-yl)-1H-heteroaryl-2-carboxamides. The nucleophilic addition afforded three isomers; two with an exo-cyclic double bond [cis (Z), trans (E)], and a third one with an endo-cyclic double bond. After the carboxamide deprotection, isomerization of the mixture under acidic conditions resulted in a unique isomer.     

Synthesis of 2-substituted indoles via a palladium-catalyzed domino Heck reaction and dealkylation

A palladium-catalyzed domino Heck reaction and dealkylation for the preparation of 2-substituted indoles is described. This novel transformation is based on an intramolecular Heck reaction followed by dealkylation.     

Copper-catalyzed intramolecular hydroamination of allenylamines to 3-pyrrolines or 2-alkenylpyrrolidines

Copper salts, such as CuCl, CuI, CuCl₂ and Cu(OTf)₂, were used to catalyze the intramolecular hydroamination of allenylamines to provide the corresponding 3-pyrrolines or 2-alkenylpyrrolidines.     

Ligand-dependent,palladium-catalyzed stereodivergent synthesis of chiral tetrahydroquinolines

The most fundamental tasks in asymmetric synthesis are the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. Although great progress has been made in the past few decades, developing general and practical strategies that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through switching distinct chiral catalysts is a significant challenge. Here, attaining precise switching of the product stereochemistry, we develop a novel P-chirogenic ligand, i.e.YuePhos, which can be easily derived from inexpensive and commercially available starting materials in four chemical operations. Through switching of three chiral ligands, an unprecedented ligand-dependent diastereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-arylidene succinimides was developed. This novel method provides an efficient route for the stereodivergent synthesis of six stereoisomers of pyrrolidines bearing up to three adjacent stereocenters (one quaternary center). Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to 98% ee. In addition, the synthetic utilities of optically active hexahydrocarbazoles are also shown.

An unprecedented ligand-dependent stereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-aryliene succinimides was developed.

The chirality of a biologically active molecule can alter its physiological properties. Therefore, highly efficient access to and fully characterizing all possible stereoisomers of a chiral molecule is one of the fundamental challenges in organic synthesis, drug discovery and development processes. However, most asymmetric catalytic transformations afford products enantioselectively and diastereoselectively and only form one of the stereoisomers containing multiple stereocenters. Stereodivergent access to all possible stereoisomers of the products is incredibly difficult because diastereochemical preference is largely dominated by the inherent structural and stereoelectronic characteristics of substrates, while absolute conformation can be dictated by the choice of the chiral catalyst.¹ In 2013, Carreira and co-workers addressed this limitation by introducing the concept of stereodivergent dual-catalytic synthesis, reporting the allylation of aldehydes in a diastereodivergent fashion by the synergistic reactivity of iridium and amine catalysts under acidic conditions.² Soon after, Carreira,³ Zhang,⁴ Hartwig,⁵ Dong,⁶ Wang,⁷ Zi,⁸ Lee,⁹ and other groups¹⁰ reported using an appropriate combination of dual chiral catalysts in a series of elegant studies (Scheme 1A). Recently, chemists found, in some cases, that tuning non-chiral parameters, including solvents or additives, also controlled the stereochemical outcomes through subtle perturbation of the key diastereomeric transition states.¹¹ In 2018, You and co-workers reported a solvent-controlled palladium-catalyzed enantioselective dearomative formal [3 + 2] cycloaddition, affording stereodivergent synthesis of two diastereomeric tetrahydrofuroindoles.¹² However, a rapid and predictable way to access complete stereoisomers of products bearing multiple stereocentres (for example, three contiguous stereocentres) remains an unsolved challenge through switching of ligands. To the best of our knowledge, only two successful examples were reported by Buchwald and Zhang, in which eight stereoisomers were obtained through tuning catalysts and reactive substrates (Scheme 1B).^4a,13Open in a separate windowScheme 1Strategy for stereodivergent synthesis of different stereoisomers.In metal-catalyzed reactions, ligands can manipulate the reactivity and selectivity by affecting the steric and electronic properties of metal catalysts. Therefore, the design and development of new ligands to improve the utility, activity and selectivity of their related metal catalysts are greatly desired by organic chemists. Recently, our groups have synthesized a new and promising class of P-chiral ligands ZD-Phos (including Ganphos and Jiaphos), and their conformational rigidity and chemical robustness have endowed the structure and its variants with outstanding activity and selectivity as well as excellent stereocontrol features essential to asymmetric cycloaddition reactions.¹⁴ Inspired by these advances, we are interested in continuing the development of P-chiral ligands with new structural motifs in the search for new reactivity and selectivity to tackle current synthetic challenges. More recently, Sadphos has emerged as another superior chiral skeleton, owing to the pioneering contributions by Zhang.¹⁵ Thus its aminophosphine scaffold is envisaged to be introduced into our 1-phosphanorbornene framework (ZD-Phos).¹⁶ We aim to combine the advantages of the aforementioned two types of chiral motifs, thus developing a novel P,P-bidentate ligand. Thus the novel P-chiral ligands, called Yuephos, may show unique stereoselectivity in a metal-catalyzed asymmetric cycloaddition reaction (Fig. 1).Open in a separate windowFig. 1Design of the Yuephos framework.Tetrahydroquinolines are important molecular skeletons that widely occur in natural molecules, pharmaceuticals, and functional materials. For this reason, realizing stereodivergent synthesis of all stereoisomers of fully substituted tetrahydroquinolines has been an important and challenging task in organic synthesis. However, to date, full control of absolute and relative stereochemical configuration of these molecules has remained an unmet synthetic challenge. Considering the potentiality of fully substituted chiral tetrahydroquinolines in drug discovery and stereodivergent synthesis,¹⁷ we envisioned that using our new palladium/ZD-Phos catalytic system may offer an efficient strategy for overcoming the challenges related to regio-, enantio-, and diastereo-selectivity. Herein, we report our studies on the unexplored stereodivergent synthesis of fully substituted tetrahydroquinolines through ligand-controlled, metal-catalyzed asymmetric annulation. Six possible stereoisomers bearing two tertiary and one quaternary stereocenters were easily synthesized in good yields with high enantio- and diastereo-selectivities from the same starting materials (Scheme 1C).The new bisphosphorus ligands we report herein can be easily synthesized by a two-pot method with good yields (Scheme 2). Starting from the corresponding aldehyde¹⁸ and commercially available chiral amine, one-pot sequential reaction gave diastereomers Y1 and Y1′ with 1 : 1 dr, which could be straightforwardly separated by column chromatography. The subsequent reduction using Raney Ni produced the final Yuephos in good yields. The absolute configuration of Yue-1′ was established by single crystal X-ray diffraction.¹⁹ Importantly, the ligands Yuephos can remain stable in air and moisture for more than one year.Open in a separate windowScheme 2Synthesis of Yuephos ligands.With new Yuephos ligands in hand, we began our study by choosing vinyl benzoxazinanone 1a with α-phenylidene succinimide 2a as the model substrate, combined with the Pd₂dba₃·CHCl₃/L complex as the catalyst. Details of [Pd] source and solvent screening can be found in the ESI (Table S1 and S2^†). Notably, using Pd₂dba₃·CHCl₃/Yuephos as the catalyst in ethyl acetate, the reaction proceeded smoothly, affording the desired product 3a in 69% yield with 96% ee and >20 : 1 dr (entry 1). It should be noted that Yuephos ligands were found to be efficient for this reaction, and the product 3a was obtained in good enantioselectivity with seemingly irregular yields and diastereoselectivities (entries 2–6). Trost''s ligand (L1) and chiral diphosphine ligand (L2) promoted the reaction with good diastereoselectivity but in a low yield and poor enantioselectivity (entries 7–8). However, (R)-SegPhos (L3) failed to afford the desired product (entry 9). To our surprise, when the phosphoramidite ligand (L4) was used, the diastereoselectivity was reversed compared to that in Yuephos (entry 10). Thus, a diastereodivergent phenomenon induced by the chiral ligand was discovered. To further improve the yield and selectivity, various solvents and [Pd] sources were screened (Table S3 and S4 in the ESI^†), and an obvious improvement in the enantioselectivity and diastereoselectivity was observed when using DCM as the solvent (entries 10 vs. 11). The reaction enantioselectivity was further increased to 92% with good yield (85%) when the reaction temperature was reduced to −20 °C (entries 12–14).With the optimal conditions established for (S, R, S)-3a (20Optimization of reaction conditions^a

An intramolecular [2 + 2] cycloaddition of ketenimines via palladium-catalyzed rearrangements of N-allyl-ynamides

A cascade of Pd-catalyzed N-to-C allyl transfer-intramolecular ketenimine-[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.     

A novel palladium-catalyzed intramolecular redox reaction

[reaction: see text] A new type of palladium-catalyzed redox reaction is described, forming enones from 2-(2-bromobenzyl)-ketones with an overall loss of HBr. The scope and limitations of the reaction are demonstrated by a series of cyclic and acyclic substrates. The mechanism most probably involves the formation of an intramolecular arylpalladium enolate and is related to the oxidation of silyl enol ethers with palladium acetate.     

A route to a wide range of cyclopentanecarboxylic acids via 4-substituted camphors

4-Carboxycamphor, easily obtainable starting from camphor, is used as a versatile precursor in high-yielding syntheses of a wide range of cyclopentanecarboxylic acids using just a few steps. Regioselective bromination of 4-carboxy- and 4-methoxycarbonyl-3-bromocamphors leads to 10-bromomethyl derivatives in good yields. Grob-type fragmentation reactions proceed smoothly for 10-bromocamphor-4-carboxylic acid, 10-bromocamphorquinone-4-carboxylic acid and 3,4-dibromocamphor with the formation of unsaturated cyclopentanecarboxylic acids. Detailed studies of bromination and rearrangement reactions of brominated camphor-4-carboxylic acid and its derivatives, reported herein, highlight the unique chemistry of substituted camphor and offer easy access to a wide range of 2,2-dimethyl-3-methylenecyclopentanecarboxylic acid derivatives.     

A route to annulated indoles via a palladium-catalyzed tandem alkylation/direct arylation reaction

A norbornene-mediated palladium-catalyzed tandem alkylation/C-H functionalization sequence is described, in which an alkyl-aryl bond and a heteroaryl-aryl bond are formed in one pot. A variety of highly substituted six- and seven-membered ring annulated indoles were synthesized in good yields from bromoalkyl indoles and aryl iodides.     

A palladium-catalyzed route to mono- and diprotected cis-2-cyclopentene-1,4-diols

The π-allylpalladium complex arising from cyclopentadiene monoepoxide has been shown to react with carboxylic acids and derivatives both as a nucleophile and an electrophile. This reaction represents an attractive synthetic route to protected versions of $\text{cis}$-2-cyclopentene-1,4-diol.