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.

A novel ruthenium-catalyzed intramolecular cyclization of a nitrile and an azetidine was developed to achieve a one-step synthesis of the fused tricyclic 1H-2,3-dihydropyrimido[1,2-a]quinoline, which is the core skeleton for more than 100 natural pyoverdines and is also responsible for their fluorescence.

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.

•A tandem method for synthesis of 3,4,5-trisubstituted pyrazoles was developed.•It was performed by simply stirring the mixture of all reactants together.•Two bases were used, but each of them has its specific duties and responsibilities.•A novel four-step tandem pathway was proposed.A novel four-step tandem procedure was developed for efficient synthesis of 3,5-diaroyl-4-arylpyrazoles by simply stirring the mixture of 1,3-diarylpropane-1,3-diketones, TsN3, aqueous MeNH2 and Na2CO3 in DMF at 85 °C for 3 h.Download high-res image (52KB)Download full-size image

By simply heating the mixture of an arylaldehyde and a sulfonylisocyanate in a solvent or in neat form under catalyst- and additive-free conditions, the desired N-sulfonylimine was produced with the release of carbon dioxide. The method is characterized by its unique clean efficiency, convenience, and scalability, but it was reported to fail half a century ago.

A Lewis acid-catalyzed three-step tandem synthesis of 9-arylfluorene was developed by simply heating a mixture of 2-formyl biphenyl, TsNCO and an arene. In the absence of arene, a two-step tandem synthesis of 9-sulfonylaminofluorene was achieved. These advances were mainly attributed to the discovery of an anhydrous synthesis of N-tosyl arylaldimines from TsNCO and arylaldehydes.

A Cu(OTf)2-catalyzed and TsNCO-mediated three-step tandem synthesis of 9-arylfluorenes were developed from biphenyls and aryl aldehydes, by which the electron-poor 9-aryl substituted fluorenes were synthesized smoothly. Its success is mainly attributed to use an anhydrous synthesis of N-tosyl arylaldimines as a key step, which was achieved in situ from the reaction of TsNCO and aryl aldehydes.

Copper(I)-catalyzed cycloaddition of 1-iodoalkyne and azide has proven to be the most efficient method for the synthesis of 1,4,5-trisubstituted 5-iodo-1,2,3-triazoles, but pre-made 1-iodoalkyne is required. We find that the combination of 1-copper(I) alkyne and molecular iodine can serve as a synthetic equivalent of 1-iodoalkyne. Thus, the desired 5-iodo-1,2,3-triazole can be synthesized by simply mixing this combination and an azide together without the tedious synthesis of the corresponding 1-iodoalkyne.

Since palladium-catalysts have strong abilities for both hydrogenation of nitro-group and hydrogenolysis of benzylamine, they have a much lower chemoselectivity for the hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes. In this article, component stable Pd–Ni bimetallic nanoparticles were prepared by simply heating RANEY®-Ni and Na2PdCl4 together in water. They demonstrated novel synergistic effects when they were used as a bimetallic catalyst, by which a highly efficient and chemoselective hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines was achieved.

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.

A highly efficient and chemoselective hydrogenation of nitrobenzyl ethers to aminobenzyl ethers was developed by using a novel palladium–nickel bimetallic nanocatalyst. Since the catalytic selectivity was resulted from the synergistic effects between two metals rather than the traditional catalyst poisons, the hydrogenation proceeded smoothly under additive-free conditions. Thus, the work-up procedure was as simple as to recover the catalyst by a magnetic separation and then to evaporate the solvent.

A tandem synthesis of 3-halo-5-substituted isoxazoles has been developed from 1-copper(I) alkynes and dihaloformaldoximes under base-free conditions. Thus, 1,3-dipolar cycloaddition and all its drawbacks can now be avoided completely.

A novel copper(I)-catalyzed tandem reaction of N- and O-arylations of 2-[N-(2-chlorophenyl)amino]phenols was developed, by which a series of structurally novel N-aryl phenoxazines were synthesized efficiently. This success owes much to the discovery of highly efficient homogeneous copper(I)-catalyzed intramolecular O-arylation of chlorobenzenes under ligand-free-like conditions. Since 2-[N-(2-chlorophenyl)amino]phenols were prepared also by copper(I)-catalyzed N-arylation of 2-aminophenols, thus a general route for efficient synthesis of N-aryl phenoxazines was established via copper(I)-catalyzed N-, N-, and O-arylations of 2-aminophenols in two steps.

We found that alkoxalyl chloride (ClCOCO2R) did not carry out an acylation on 1-copper(I) alkyne in solvent without additives, but chemoselectively on 5-copper(I) 1,2,3-triazole (an intermediate in cycloaddition of 1-copper(I) alkyne and azide). Thus, a one-pot preparation of 1,4,5-trisubstituted 5-(2-alkoxy-1,2-dioxoethyl)-1,2,3-triazole was achieved by simply stirring the mixture of 1-copper(I) alkyne, azide, and alkoxalyl chloride at room temperature for 4 h.

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.

A novel preparation of N-substituted pyrrole-2-carboxylates has been developed based upon 1,3-dipolar cycloaddition and a conventional hydrogenolysis. By using this method as the key step, total syntheses of natural alkaloids (−)-hanishin, (−)-longmide B, and (−)-longmide B methyl ester were accomplished in the highest overall yields, respectively.

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.

A simple combination of Cu2O and PhCO2H ‘on H2O’ has been developed as a highly practical and efficient catalytic system for copper(I)–catalyzed azide–alkyne cycloaddition (CuAAC). It not only provides a further evidence for the strategy of carboxylic acids-promoted CuAAC, but also offers significant advantages to CuAAC because Cu2O is one of the most stable and cheapest Cu(I) sources; PhCO2H is one of the structurally simplest bidentate ligands; and water is the most ‘green’ solvent.

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/NR3 were overcome easily.

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.

A general and efficient procedure for the preparation of phenols was developed by copper-catalyzed oxidative hydroxylation of arylboronic acids at room temperature in water.

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.

A novel three-step synthesis of 3-aryl β-carbolin-1-ones from non-indole starting materials has been developed. The two nitrogen atoms in β-carbolin-1-one were introduced efficiently by Michael addition of ethyl acetamidocyanoacetate to chalcone. The desired pyridone and indole rings were assembled by an intramolecular ketone–nitrile annulation mediated by aqueous HCl–HOAc and a Cu(I)-catalyzed intramolecular N-arylation of the amide, respectively. The target compounds were found to possess significant activity against tumor cell proliferaton.

An expedient synthetic route for 3-aryl β-carbolin-1-ones was developed starting from ethyl acetamidocyanoacetate and chalcone derivatives. The five- and six-membered nitrogen-containing rings in the β-carbolin-1-ones were elaborated efficiently by an intramolecular ketone-nitrile annulation and an intramolecular N-arylation of amide respectively.

A novel one-pot preparation of chiral N-methyl-N-alkyl Betti bases has been developed involving a highly regioselective N-alkylation of (S)-(+)-Betti base. The strategy involved formation-cleavage of the oxazine ring and N-methylation with BtCH2OH under neutral conditions.GraphicC21H21NO2-Propyl-4-phenyl-naphtho[1,2-e][1,3]oxazineEe = 100%[α]D25=−19.8 (c 0.50, CHCl3)Source of chirality:(S)-Betti baseAbsolute configuration:SC18H15NO4-Phenyl-naphtho[1,2-e][1,3]oxazineEe = 100%[α]D25=−36.3 (c 0.50, CHCl3)Source of chirality:(S)-Betti baseAbsolute configuration:SC28H26N4ON-Benzotriazolylmethyl-4-phenylnaphtho[1,2-e][1,3]oxazineEe = 100%[α]D20=+65.0 (c 0.3, CHCl3)Source of chirality:(S)-Betti baseAbsolute configuration:R,SC25H20N4ON-Benzotriazolylmethyl-4-phenyl-naphtho[1,2-e][1,3]oxazineEe =>99%[α]D20=+70.2 (c 0.35, CHCl3)Source of chirality:(S)-Betti baseAbsolute configuration:SC22H25NO(S)-1-[α-(N-Methyl-N-butylamino)benzyl]-2-naphtholEe =>99%[α]D20=+198.4 (c 0.31, CHCl3)Source of chirality:(S)-Betti baseAbsolute configuration:SC19H19NO(S)-1-[α-(N,N-Dimethylamino)benzyl]-2-naphtholEe =>99%[α]D20=+228.0 (c 0.5, EtOH)Source of chirality: (S)-Betti baseAbsolute configuration: SC20H21NO(S)-1-[α-(N-Methyl-N-ethylamino)benzyl]-2-naphtholEe =>99%[α]D20=+187.9 (c 2.0, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC21H23NO(S)-1-[α-(N-Methyl-N-propylamino)benzyl]-2-naphtholEe =>99%[α]D20=+206.5 (c 0.3, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC25H31NO(S)-1-[α-(N-Methyl-N-hexylamino)benzyl]-2-naphtholEe =>99%[α]D20=+167.9 (c 0.36, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC28H37NO(S)-1-[α-(N-Methyl-N-nonylamino)benzyl]-2-naphtholEe =>99%[α]D20=+142.6 (c 0.3, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC23H27NO(S)-1-[α-(N-Methyl-N-(3-methylbutyl)amino)benzyl]-2-naphtholEe =>99%[α]D20=+167.9 (c 0.36, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC24H29NO(S)-1-[α-(N-Methyl-N-(2-ethylbutyl)amino)benzyl]-2-naphtholEe =>99%[α]D20=+148.6 (c 0.36, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC26H25NO(S)-1-[α-(N-Methyl-N-benzylamino)benzyl]-2-naphtholEe =>99%[α]D20=+143.4 (c 0.3, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC25H29NO(S)-1-[α-(N-Methyl-N-cyclohexylamino)benzyl]-2-naphtholEe =>99%[α]D20=+152.0 (c 0.35, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC25H23NO(S)-1-[α-(N-Methyl-N-phenylamino)benzyl]-2-naphtholEe =>99%[α]D20=+149.8 (c 0.30, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: SC29H31NO3(S)-1-[α-(N-Methyl-N-(3,4-diethoxyphenyl)amino)benzyl]-2-naphtholEe =>99%[α]D20=+217.2 (c 0.30, CHCl3)Source of chirality: (S)-Betti baseAbsolute configuration: S

An improved synthesis of homochiral 1-[α-(1-azacycloalkyl)benzyl]-2-naphthols and 1-[α-(2-arylpiperidyl)benzyl]-2-naphthols has been achieved by employing diastereomerically pure α-benzotriazolyl 1-azacycloalka[2,1-b][1,3]oxazines as homochiral precursors, which were obtained by condensation between nonracemic Betti base and dialdehydes in the presence of benzotriazole.Graphic(7aR,10R,12S)-10-(1-Benzotriazolyl)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazineC27H22N4OEe = 100%[α]D25=+101.6 (c 1.25, CHCl3)Source of chirality: S-Betti baseAbsolute configuration: 7aR,10R,12S(7aR,11R,13S)-11-(1-Benzotriazolyl)-13-phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazineC28H24N4OEe = 100%[α]D25=+152.6 (c 1.6, CHCl3)Source of chirality: S-Betti baseAbsolute configuration: 7aR,11R,13S(7aR,12R,14S)-12-(1-Benzotriazolyl)-14-phenyl-7a,8,9,10,11,12-hexahydro-14H-naphtho[1′,2′:5,6][1,3]oxazino[2,1-b]azepineC29H26N4OEe = 100%[α]D25=+146.2 (c 0.9, CHCl3)Source of chirality: S-Betti baseAbsolute configuration: 7aR,12R,14S(7aR,11R,13S)-11,13-Diphenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazineC28H25NOEe > 99%[α]D25=+110.1 (c 0.21, CHCl3)Source of chirality: synthesizedAbsolute configuration: 7aR,11R,13S (assigned by NMR spectroscopic and single crystal X-ray diffraction analysis)(7aR,11R,13S)-11-(4-Methylphenyl)-13-phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazineC29H27NOEe > 99%[α]D25=+97.1 (c 0.3, CHCl3)Source of chirality: synthesizedAbsolute configuration: 7aR,11R,13S (assigned by NMR spectroscopic and single crystal X-ray diffraction analysis)(7aR,11R,13S)-11-(4-Chlorophenyl)-13-phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazineC28H24ClNOEe > 99%[α]D25=+124 (c 0.1, CHCl3)Source of chirality: synthesizedAbsolute configuration: 7aR,11R,13S (assigned by NMR spectroscopic and single crystal X-ray diffraction analysis)(7aR,11R,13S)-11-(4-Phenylphenyl)-13-phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazineC34H29NOEe > 99%[α]D25=+95.4 (c 0.2, CHCl3)Source of chirality: synthesizedAbsolute configuration: 7aR,11R,13S (assigned by NMR spectroscopic and single crystal X-ray diffraction analysis)(7aR,11R,13S)-11-(1-Naphthyl)-13-phenyl-8,9,10,11-tetrahydro-7aH,13H-naphtho[1,2-e]pyrido[2,1-b][1, 3]oxazineC32H27NOEe > 99%[α]D25=+290.5 (c 0.3, CHCl3)Source of chirality: synthesizedAbsolute configuration: 7aR,11R,13S (assigned by NMR spectroscopic and single crystal X-ray diffraction analysis)(S)-1-[α-[(R)-2-Phenylpiperidyl]benzyl]-2-naphtholC28H27NOEe > 99%[α]D25=+46.8 (c 0.3, CHCl3)Source of chirality: synthesizedAbsolute configuration: S,R (assigned by NMR spectroscopic)(S)-1-[α-[(R)-2-(4-Methylphenyl)piperidyl]benzyl]-2-naphtholC29H29NOEe > 99%[α]D25=+28.9 (c 0.2, CHCl3)Source of chirality: synthesizedAbsolute configuration: S,R (assignedby NMR spectroscopic)(S)-1-[α-[(R)-2-(4-Chlorophenyl)piperidyl]benzyl]-2-naphtholC28H26ClNOEe > 99%[α]D25=+54.6 (c 0.2, CHCl3)Source of chirality: synthesizedAbsolute configuration: S,R (assigned by NMR spectroscopic)(S)-1-[α-[(R)-2-(4-Phenylphenyl)piperidinyl]benzyl]-2-naphtholC34H31NOEe > 99%[α]D25=+64.6 (c 0.1, CHCl3)Source of chirality: synthesizedAbsolute configuration: S,R (assigned by NMR spectroscopic)(S)-1-[α-[(R)-2-(1-Naphthyl)piperidyl]benzyl]-2-naphtholC32H29NOEe > 99%[α]D25=+194.5 (c 0.3, CHCl3)Source of chirality: synthesizedAbsolute configuration: S,R (assigned by NMR spectroscopic)

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.

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.