Search

The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.

P-Chiral [2.2.1] bicyclic phosphines (HypPhos catalysts) have been applied to reactions between α-alkylallenoates and imines, producing guvacine derivatives. These HypPhos catalysts were assembled from trans-4-hydroxyproline, with the modular nature of the synthesis allowing variations of the exocyclic P and N substituents. Among them, exo-( p-anisyl)-HypPhos was most efficacious for [4 + 2] annulations between ethyl α-methylallenoate and imines. Through this method, ( R)-aplexone was identified as being responsible for the decrease in the cellular levels of cholesterol.

Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis-Beirut reaction, inspired by new mechanistic insights, were defined.

The enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl- and alkylketimines. Synthetic transformations of homopropargylic products via enyne ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions proceed with high stereochemical fidelity. Both allenyl and propargyl borolane reagents can be used to obtain homopropargylic products, a distribution most consistent with a mechanism involving transmetalation of the silver catalyst with the borolane reagent.

Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures.

A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.

A catalytic asymmetric [3 + 2] cyclization of novel 4-isothiocyanato pyrazolones and isatin-derived ketimines was developed, delivering a wide range of intriguing dispirotriheterocyclic products in high yield with excellent diastereoselectivity and enantioselectivity. A chiral sulfoxide derivative of this dispirocyclic product was identified to be a promising hit of the human carboxylesterase 1 inhibitor, and the significant difference of the activity between two enantiomers emphasized the importance of this asymmetric process. [ABSTRACT FROM AUTHOR]

o-Phenylene tetramers have been coassembled with linkers into macrocycles through imine condensation. Variation of linker connectivity and length allows both [1 + 1] and [2 + 2] macrocycles to be obtained, complementing (previously reported) [3 + 3] macrocycles. For the [1 + 1] macrocycles, linker length has a clear effect on o-phenylene geometry and macrocycle stability. For the [2 + 2] macrocycles, both homo- and heterochiral configurations are observed, suggesting limited communication of helix handedness in these systems. [ABSTRACT FROM AUTHOR]

A palladium-catalyzed enantioselective [4 + 2] cycloaddition reaction of vinyl benzoxazinones with sulfamate-derived cyclic imines is described, affording the tetrahydroquinazolines bearing several functional rings in high yields (up to 99% yield) with good to excellent diastereoselectivities and excellent enantioselectivities (up to 96% ee). This reaction represents the first Pd-catalyzed asymmetric decarboxylative cycloaddition of vinyl benzoxazinones with imines. [ABSTRACT FROM AUTHOR]

A dual catalytic system, dirhodium tetrapivalate/ytterbium(III) triflate, enables the three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and N-benzylidenebenzylamine derivatives to afford the corresponding β-amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts, whereas no β-amino alcohols are obtained in the absence of ytterbium(III) triflate. A similar dual catalytic system, dirhodium tetraacetate/ytterbium(III) triflate, is found to be effective in accelerating the reactions of α-aryl-α-diazoesters in high yields. Furthermore, the reactions using dimethyl diazomalonate are described. [ABSTRACT FROM AUTHOR]

A highly diastereo- and enantioselective silver-catalyzed azomethine ylide-imine (AYI) cycloaddition reaction of glycine aldimino esters with imines was developed in which the Xing-Phos-controlled syn-selective or DTBM-Segphos-induced anti-selective AYI cycloaddition reaction could be applied to the synthesis of a variety of stereodivergent 1-alkyl-2,5-substituted imidazolidines with high yields and excellent enantioselectivities (up to 99% ee) as well as good diastereoselectivities (up to 99:1 dr) under mild reaction conditions. [ABSTRACT FROM AUTHOR]

A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D2O as an inexpensive deuterium source (≥95% D ratio). The mechanism of this unusual transformation is probed. [ABSTRACT FROM AUTHOR]

Prolinate salt is an efficient catalyst in the Mannich reaction of alkynyl imine and aldehyde, to afford synthetically useful chiral propargyl amine derivatives with excellent syn-selectivity and nearly perfect control of the absolute configuration. The counterion of the prolinate salt does not affect the enantioselectivity. This is a rare example, in which proline alkali metals, alkaline-earth metals, or ammonium salt show higher reactivity and better stereoselectivity than the parent proline. [ABSTRACT FROM AUTHOR]

By employing a simple open-chain chiral phosphite-olefin ligand, a highly enantioselective rhodium-catalyzed alkenylation of 1,2,5-thiadiazole 1,1-dioxide-type cyclic ketimines with diverse vinylboronic acids was achieved under mild conditions at room temperature. This protocol provides an efficient and practical access to multifunctional α,α-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields (up to 99%) with good to excellent ee's (up to 99%). [ABSTRACT FROM AUTHOR]

A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl(t-BuXPhos) precatalyst selectively coupled the Ar-Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl coupled the Ar-Cl site with secondary amines. [ABSTRACT FROM AUTHOR]

For the biosynthesis of Pip in Huperzia serrata, the mechanistic studies were evaluated. Through a series of biochemical analyses, Pip is biosynthesized through a two-step cascade reaction. Three intermediates possibly exist simultaneously as an equilibrium matter in the first-step reaction catalyzed by HsAld1, while HsSard4 performs as a ketimine reductase and chemoselectively and stereoselectively takes 1,2-dehydropipecolic acid as the preferred substrate in vitro. [ABSTRACT FROM AUTHOR]

A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,β-unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly valuable α,α-disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups. [ABSTRACT FROM AUTHOR]

An efficient Ag(I)-catalyzed p-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the method is demonstrated by a formal synthesis of (±)-lasubine II and in a short total synthesis of (±)-indolizidine 209D. [ABSTRACT FROM AUTHOR]

The N-heterocyclic carbene (NHC)-catalyzed umpolung of aldimines for the synthesis of 4-difluoromethylquinoline derivatives is reported. In the presence of NHCs, the intramolecular cyclization of aldimines bearing a moderately electron-poor double bond due to the presence of the -CF3 group likely proceeds via the intermediacy of the aza-Breslow intermediate. The key to the success of this aza-Stetter type transformation is the NHC generated from the bicyclic triazolium salt using DBU as the base. [ABSTRACT FROM AUTHOR]

A rice cultivation of a fish gastrointestinal tract-derived fungus, Trichoderma sp. CMB-F563, yielded natural products incorporating a rare hydrazine moiety, embedded within a Schiff base. Structures inclusive of absolute configurations were assigned to prolinimines A-D (1-4) on the basis of detailed spectroscopic and C3 Marfey's analysis, as well as biosynthetic considerations, biomimetic total synthesis, and chemical transformations. Of note, monomeric 1 proved to be acid labile and, during isolation, underwent quantitative transformation to dimeric 3 and trimeric 4. Prolinimines are only the second reported natural products incorporating an N-amino-Pro residue, the first to include l-Pro, the first to occur as Schiff bases, and the first to be isolated from a microorganism. [ABSTRACT FROM AUTHOR]

The first example of catalytic enantioselective tautomerization of structurally labile but isolable enamines for accessing their chiral imine-tautomers is described. Kinetically stable enamine-based dibenzo[b,d]azepines were tautomerized by a simple chiral BINOL-phosphoric acid, providing a variety of seven-membered imine products bearing both central and axial stereogenic elements in good yields (up to 96%) with excellent enantio- and diastereoselectivities (up to 97% ee, >20:1 dr). [ABSTRACT FROM AUTHOR]

The unprecedented development of asymmetric Rh-catalyzed 1,2-allylation of N-Ts- and N-Ns-aldimines is achieved. This protocol utilizes potassium allyltrifluoroborates and various aldimines to generate enantioenriched homoallylic amines in the presence of 3.0 mol % of Rh(I)/L1b catalyst with up to 90% yield, 98% ee (R = H), and 10:1 diastereoselectivity (R = Me or Ph), yielding the same major diastereomer when using potassium (E)- and (Z)-crotyltrifluoroborate. Its synthetic utility is also illustrated in the total synthesis of (-)-crispine A. [ABSTRACT FROM AUTHOR]

A silver(I) and base-mediated [3 + 3]-cycloaddition reaction of in situ generated C,N-cyclic azomethine imines with in situ formed aza-oxyallyl cations is reported. This one-pot cycloaddition process shows broad substrate scope an excellent functional group tolerance and provides the corresponding biologically important isoquinoline-fused triazines in good to excellent yields. [ABSTRACT FROM AUTHOR]

A first phosphine-catalyzed enantioselective umpolung γ-addition of ketimines to allenoates has been developed that provides efficient access to optically active γ,δ-unsaturated α-amino esters and δ-amino esters with a chiral tertiary stereocenter under mild conditions. The salient features of this reaction include general substrate scope, mild conditions, good yields, high enantioselectivity, ease of scale-up to gram scale, and further transformations. [ABSTRACT FROM AUTHOR]

A rhodium-catalyzed reaction between 3-diazoindolin-2-imines and 2H-azirines, followed by treatment with a base, furnishes 5H-pyrazino[2,3-b]indoles in excellent yields. A number of functional groups tolerate the reaction conditions, and the resulting 5H-pyrazino[2,3-b]indoles present strong photoluminecence in solutions, powders, and films. [ABSTRACT FROM AUTHOR]

An efficient asymmetric [2 + 3] annulation of simple aldehydes with N,N'-cyclic azomethine imines via oxidative N-heterocyclic carbene (NHC) catalysis is disclosed, affording bicyclic pyrazolidinones bearing two vicinal tertiary stereogenic centers with moderate to good yields (56-84% for 19 examples), good to excellent diastereoselectivities (>20:1 for 17 examples), and good to excellent enantioselectivities (66-98% for 19 examples). This direct α-carbon functionalization reaction of aldehyde can be readily performed on gram scale under mild conditions, and a five-membered transition state is proposed to rationalize the stereochemical outcome. [ABSTRACT FROM AUTHOR]

An efficient enantioselective formal [3 + 2]-cycloaddition of azomethine imines with azlactones has been realized by using a chiral bifunctional bisguanidinium hemisalt as the catalyst. Optically active bicyclic pyrazolidinone compounds were generated under mild reaction conditions in high yields (up to 99%) with good dr (up to 88:12) and excellent ee values (up to 99%). This simple and efficient strategy provides a method to construct biologically important chiral tetrahydropyrazolo[1,2-a]pyrazole-1,7-dione derivatives bearing vicinal aza-quaternary and tertiary carbon centers. [ABSTRACT FROM AUTHOR]

A highly enantio- and diastereoselective [4 + 1]-annulation reaction between α,β-unsaturated imines and allylic carbonates has been realized under the catalysis of a novel hybrid P-chiral phosphine oxide-phosphine, providing enantioenriched polysubstituted 2-pyrrolines in good to excellent yields and up to 99% ee. Based on Han's methods, the catalyst featuring a sole P(O)-chirality in the molecule is readily accessible and represents a class of new chiral phosphine organocatalysts. In the plausible catalytic mechanism, an intramolecular Coulombic interaction between the in situ generated phosphonium cation and polar chiral P═O moiety may play a positive role. [ABSTRACT FROM AUTHOR]

Rh(III)-catalyzed [3 + 2] annulation of cyclic N-sulfonyl or N-acyl ketimines with activated alkenes has been realized, leading to the synthesis of spirocycles with three continuous stereogenic centers. This atom-economic reaction proceeded efficiently under mild and redox-neutral conditions via a C--H activation pathway, and the coupling is diastereodivergent, with the diastereoselectivity being controlled by silver additives. [ABSTRACT FROM AUTHOR]

An eight-step stereodivergent synthesis of enantiomerically pure (--)-14-epi-pseudotabersonine and (+)-pseudotabersonine has been developed from a common N-tert-butanesulfinyl ketimine key intermediate. [ABSTRACT FROM AUTHOR]

A powerful sequential [1 + 4]- and [2 + 3]-annulation has been developed using prop-2-ynylsulfonium salts and sulfonyl-protected o-amino aromatic aldimines, affording a series of hexahydropyrrolo[3,2-b]indoles in high yields. Prop-2-ynylsulfonium salts act as C2 synthons in the reaction, and fused rings containing two five-membered azaheterocycles can be constructed in a single operation with readily accessible starting materials. [ABSTRACT FROM AUTHOR]