Tandem Synthesis of 2-Azaspiro[4.5]deca-1,6,9-trien-8-ones Based on Tf2O-Promoted Activation of N-(2-Propyn-1-yl) Amides.

Structurally novel 2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized from N-(2-propyn-1-yl) amides and 1,3,5-trimethoxybenzenes by a tandem method consisting of a Tf2O-promoted amide activation and a TfOH-promoted Friedel-Crafts ipso-cyclization. The method offered the first example of using N-(2-propyn-1-yl) amides as substrates in both Tf2O-promoted secondary amide activation and the synthesis of azaspiro[4.5]deca-6,9-diene-8-ones.

Bischler-Napieralski Synthesis of Polycyclic N-Heteroaromatics Based on Tf2O-Promoted Electrophilic Activation of N-Aryl-2-Propynamides.

2-Propynamides have been never used as substrates in classic and Tf2O-promoted Bischler-Napieralski reactions. In this article, a novel tandem synthesis of benzo[a]acridines is developed from N-aryl-2-propynamides and alkynes consisting of a Tf2O-promoted intermolecular Bischler-Napieralski reaction and a TfOH-promoted intramolecular Friedel-Crafts reaction.

Bischler-Napieralski Synthesis of 6-Alkynyl Phenanthridines Based on Tf2O-Promoted Electrophilic Activation of N-Aryl-2-propynamides.

An efficient method for the synthesis of 6-alkynyl phenanthridines was developed. The method offered the first example to use 2-propynamides as substrates in the Bischler-Napieralski reaction and to create alkynylnitrilium triflates as new active intermediates in organic synthesis.

Tandem Synthesis of 1,3-Disubstituted Naphthalenes via TfOH-Promoted Directed-Aldol and Friedel-Crafts Reactions.

A TfOH-promoted tandem synthesis of 1,3-disubstituted naphthalenes is developed via a directed-aldol reaction and a Friedel-Crafts reaction. Two new C-C bonds and one new benzene ring are created efficiently in one pot due to the discovery of a TfOH-promoted highly chemoselective directed-aldol reaction between two different ketones with α-hydrogens.

General Synthesis of Fully Substituted 4-Aminooxazoles from Amides and 1,4,2-Dioxazol-5-ones Based on Amide Activation and Umpolung Process.

A general and efficient synthesis of fully substituted 4-aminodixazoles was developed based on the strategies of amide activation and umpolung reaction. In this method, 1,4,2-dioxazol-5-ones were introduced as a rare type of umpolung reagent bearing a nucleophilic N-atom that could be used well together with the activating agent Tf2O. Because 1,4,2-dioxazol-5-ones played triple roles as an umpolung reagent, a substrate, and a weak base, the method proceeded smoothly under extremely convenient conditions.

Metal-Free Method for Direct Synthesis of Functionalized ß-Ketoenamines.

A new method for direct synthesis of ß-ketoenamines was developed by a BF3·OEt2-catalyzed cyclization of 1-iodoalkyne and α-keto acid followed by an amine-mediated ring-opening in one pot. Its metal-free conditions allowed the easy synthesis of those products bearing the transition metal-sensitive functional groups. Its three-component process achieved wide range of functionalized products.

In-situ Generated and Premade 1-Copper(I) Alkynes in Cycloadditions.

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was discovered in 2002, which has become the most remarkable example for "click chemistry" to date. In CuAAC reaction, 1-copper(I) alkyne has been recognized to be a key intermediate. However, many contradictory experimental results for this intermediate were reported in literature. For example, only the in-situ generated 1-copper(I) alkyne was used, while the premade 1-copper(I) alkyne proved to be inefficient under the standard conditions. The kinetic studies indicated that CuAAC reaction had a strict second-order dependence on Cu(I) and the DFT studies demonstrated that 1-copper(I) alkyne intermediate should be a dinuclear copper(I) complex. But these results were inconsistent with the structure of the premade 1-copper(I) alkyne. Although hundreds of structurally different ligands were reported to significantly enhance the efficiency of CuAAC reaction, their functions were assigned to prevent the oxidation and the disproportionation of Cu(I) ion. Based on the investigation of the references and our works, we proposed that the in-situ generated 1-copper(I) alkyne in CuAAC reaction is not identical with the premade 1-copper(I) alkyne. The ligands may play dual roles to activate the 1-copper(I) alkyne by blocking the polymerization of the in-situ formed 1-copper(I) alkynes and dissociating the polymeric structures of the premade 1-copper(I) alkynes. As a result, we first disclosed that carboxylic acids can function as such activators and a novel carboxylic acid-catalyzed CuAAC strategy was developed, which has been proven to be the most convenient and highly efficient CuAAC method to date. Furthermore, highly efficient and regioselective methods for the syntheses of 1,4,5-trisubstituted 1,2,3-triazoles were developed by using the premade 1-copper(I) alkynes as substrates, in which the novel function of the premade 1-copper(I) alkynes as excellent dipolarophiles was first disclosed and applied. In this article, a series of works reported by our group for the in-situ generated and the premade 1-copper(I) alkynes in cycloadditions are reviewed.

Tandem Synthesis of α-Diazoketones from 1,3-Diketones.

A highly efficient synthesis of α-diazoketone was achieved by simply stirring the mixture of 1,3-diketone, TsN3, and MeNH2 in EtOH. It was a tandem reaction including a novel primary amine-catalyzed Regitz diazo transfer of 1,3-diketone and a novel primary amine-mediated C-C bond cleavage of 2-diazo-1,3-diketone.

Silver-catalyzed decarboxylative acylation of quinoxalin-2(1H)-ones with α-oxo-carboxylic acids.

A novel silver-catalyzed decarboxylative acylation of α-oxo-carboxylic acids was developed, by which various 3-acyl quinoxalin-2(1H)-ones were synthesized by direct C-H bond acylation of quinoxalin-2(1H)-ones. In this method, α-oxo-carboxylic acids served as efficient acylating reagents to in situ generate the required active acyl radical. Its excellent chemoselectivity allowed the molecular diversity of 3-acyl quinoxalin-2(1H)-ones to be achieved by convenient functionalizations of both N1- and C3-positions.

Tandem Synthesis of 3-chloro-4-iodoisoxazoles from 1-copper(I) alkynes, dichloroformaldoxime, and molecular iodine.

A tandem synthesis for structurally novel 3-chloro-4-iodoisoxazoles was developed by simply mixing 1-copper(I) alkynes, dichloroformaldoxime, and molecular iodine together. The combination of 1-copper(I) alkyne and molecular iodine was well used as a synthetic equivalent of 1-iodoalkyne without the need for tedious preparation, purification, and storage of 1-iodoalkyne.

Tandem reaction of 1-copper(I) alkynes for the synthesis of 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles.

A novel tandem reaction of 1-copper(I) alkynes with azides (cycloaddition) and then NCS (electrophilic substitution) was developed as an efficient method for the synthesis of 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles. The method offers a rare example that a tandem reaction of an organometallic substrate does not involve in the reactivity of the metal-carbon bond in the first step.

Chemospecific C3- and C2-Olefinations of Isatins by TfOH-Promoted Tandem Aldol-Grob and Semiacetalization-Grob Fragmentations.

A novel method for TfOH-promoted chemospecific C3- and C2-olefinations of isatins is developed, which offers the first examples of Grob fragmentation using isatins and amides as substrates.

Copper(I) acetate-catalyzed azide-alkyne cycloaddition for highly efficient preparation of 1-(pyridin-2-yl)-1,2,3-triazoles.

A highly efficient copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of 6-substituted tetrazolo[1,5-a]pyridines was developed for the preparation of 1-(pyridin-2-yl)-1,2,3-triazoles by simply using copper(I) acetate as a catalyst. The in situ formed HOAc played important dual roles and an activation of 2-azidopyridine-copper(I) complex was observed.

Mechanistic Insights into Tf2O-Promoted Electrophilic Activation of 2-Propynamides and a New Synthesis of 2,4-Disubstituted Quinolines.

Direct evidence explaining why 2-propynamides have never been used as substrates in Tf2O-promoted electrophilic activations was obtained. Furthermore, a new method for the synthesis of structurally special 2,4-disubstituted quinolines was developed, by which the substituent at position 2 of quinolines can be diversified easily.

Total synthesis of (+)-epilupinine via an intramolecular nitrile oxide-alkene cycloaddition.

Total synthesis of (+)-epilupinine was accomplished in nine steps and in 48% overall yield, in which INOC was used as the key step for the construction of the quinolizidine skeleton. We found that it was an extremely difficult task to prepare the key intermediates (R)-N-(3-nitropropyl)-2-vinylpiperidine or (R)-(2-vinylpiperid-1-yl)propanal by routine methods. Thus, by using Fukuyama's oxime synthesis, a general method was developed for highly efficient conversion of 3-(N,N-dialkylamino)propanols into 3-(N,N-dialkylamino)propanal oximes without using the corresponding aldehydes.

Total synthesis of (-)-cocaine and (-)-ferruginine.

Total synthesis of tropane alkaloids (-)-cocaine and (-)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H-benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (-)-cocaine and (-)-ferruginine.

Acid-base jointly promoted copper(I)-catalyzed azide-alkyne cycloaddition.

In this novel acid-base jointly promoted CuAAC, the combination of CuI/DIPEA/HOAc was developed as a highly efficient catalytic system. The functions of DIPEA and HOAc have been assigned, and HOAc was recognized to accelerate the conversions of the C-Cu bond-containing intermediates and buffer the basicity of DIPEA. As a result, all drawbacks occurring in the popular catalytic system CuI/NR(3) were overcome easily.

Preparation of enantiopure substituted piperidines containing 2-alkene or 2-alkyne chains: application to total syntheses of natural quinolizidine-alkaloids.

A general method for the preparation of enantiopure 2-alkene- or 2-alkyne-containing chain substituted piperidines was established by using nonracemic Betti base as a chiral auxiliary. The key step is that the auxiliary residue was removed by a novel base-catalyzed N-debenzylation via a formation of o-quinone methide mechanism in stead of the traditional hydrogenolysis, by which the alkene or alkyne groups survived. By this method, ten 2-alkene- or 2-alkyne-containing chain substituted piperidines were prepared on the gram scale within a few hours. To demonstrate the efficiency of the method and the versatility of the product, total syntheses of natural alkaloids (+)-pelletierine, (-)-lasubine II, and (+)-cermizine C were achieved by using (S)-2-allyl-N-Boc-piperidine as a versatile building block.

Carboxylic acid-promoted copper(I)-catalyzed azide-alkyne cycloaddition.

In this article, we proved that all three key steps in the catalytic cycle of CuAAC can proceed in the presence of carboxylic acids and the latter two steps can be promoted significantly by carboxylic acids. Benzoic acid showed the best promotion activity, and the acids with strong chelating ability to Cu(I) ion could not serve for this purpose. Thus, the first carboxylic acid-promoted highly efficient CuAAC was established.

Enantiopure 2,6-disubstituted piperidines bearing one alkene- or alkyne-containing substituent: preparation and application to total syntheses of indolizidine-alkaloids.

A general and efficient procedure for the preparation of 2,6-disubstituted piperidines bearing one alkene- or alkyne-containing substituent was developed by using non-racemic Betti base as a chiral auxiliary. Many chiral benzylamines are excellent auxiliaries, but they were rarely used for this purpose because of the inefficient removal of the N-benzyl auxiliary residue under non-hydrogenative conditions. We found that N,N-disubstituted Betti base derivative has a typical Mannich structure of o-naphthol. When it carried out a base-catalyzed formation of o-quinone methide, an efficient non-hydrogenative N-debenzylation was achieved, and the alkene and alkyne groups survived. To demonstrate the efficiency of the method and the versatility of the products, asymmetric total syntheses of indolizidine-alkaloids (-)-167B, (-)-195H, (-)-209D and (-)-223AB were accomplished.