Asymmetric 1,2-Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α-Keto Imines.

A carbonyl-assisted asymmetric 1,2-migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α-amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face-selective 1,2-allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram-scale synthesis, showcasing broad functional-group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.

Double 1,2-Carbon Migration at Mixed Heavier Sn=Ge Vinylidenes.

1,2-migration is one recurring isomerization reaction in organic chemistry. In contrast, double 1,2-migration remains rare and limited to transition-metal complexes. Herein, we describe the synthesis, characterization and reactivity of mixed heavier Sn=Ge vinylidenes. Double 1,2-carbon migration enables the isomerization of the stannagermenylidene (3) to the germastannenylidene (4). X-ray diffraction analysis and DFT calculations revealed that 3 and 4 feature a Sn=Ge double bond. The reaction of 3 with IMe4 (1,3,4,5-tetramethylimidazoline-2-ylidene) results in the electron redistribution in the Sn=Ge core to give the germylone-stannylene adduct (5). Moreover, treatment of 3 with 0.25 equiv. of (AlCp*)4 produces the heteronuclear aluminyl stannagermyne (6).

Catalyst- and Substrate-Controlled Regiodivergent Synthesis of Carbazoles through Gold-Catalyzed Cyclizations of Indole-Functionalized Alkynols.

A wide variety of regioselectively substituted carbazole derivatives can be synthesized by the gold-catalyzed cyclization of alkynols bearing an indol-3-yl and an additional group at the homopropargylic positions. The regioselectivity of the process can be controlled by both the oxidation state of the gold catalyst and the electronic nature of the substituents of the alkynol moiety. The 1,2-alkyl migration in the spiroindoleninium intermediate, generated after indole attack to the activated alkyne, is favored with gold(I) complexes and for electron-rich aromatic substituents at the homopropargylic position, whereas the 1,2-alkenyl shift is preferred when using gold(III) salts and for alkyl or non-electron-rich aromatic groups.

Application of bioorganometallic B12 in green organic synthesis.

Bioorganometallic structure found in coenzyme B12 is a key component in B12-dependent enzymatic reactions in natural enzymes. Cleavage of a cobalt-carbon bond in organometallic B12 compound provide reactive intermediate for molecular transformations. Application of the bioorganometallic B12 in organic synthesis have been developed using natural vitamin B12 as well as synthetic vitamin B12 derivatives as a bioinspired catalyst in organic solvent. Vitamin B12 derivatives composed of corrinoid structure should form stable organometallic compound having a cobalt-carbon bond. Using the unique property of the organometallic vitamin B12 derivatives, various catalytic reactions have been developed in synthetic organic chemistry. The dual catalytic system of vitamin B12 derivatives and photocatalyst, such as Ru(II) polypyridyl complex or titanium oxide, could construct light-driven molecular transformations. The B12-dependent enzymes mimic reactions, such as the dechlorination of organic halides and the radical mediated isomerization reactions, catalytically proceed in the dual catalyst system. Electroorganic syntheses mediated by the vitamin B12 derivatives have been developed as green molecular transformations. The redox active vitamin B12 derivatives shows a unique catalysis in the electroorganic synthesis, such as alkene and alkyne reductions.

Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S-Oxides with Boronic Esters.

Benzothiophenes are valuable heterocycles that are widely used in medicines, agrochemicals, and materials science. Herein, we report a general method for the synthesis of enantioenriched 2,3-disubstituted benzothiophenes via a transition-metal-free C2-alkylation of benzothiophenes with boronic esters. The reactions utilize benzothiophene S-oxides in lithiation-borylations to generate intermediate arylboronate complexes, and subsequent Tf2 O-promoted S-O bond cleavage to trigger a Pummerer-type 1,2-metalate shift, which gives the coupled products with complete enantiospecificity. Primary, secondary and tertiary alkyl boronic esters and aryl boronic esters are successfully coupled with a range of C3-substituted benzothiophenes. Importantly, this transformation does not require the use of C3 directing groups, therefore it overcomes a major limitation of previously developed transition-metal-mediated C2 alkylations of benzothiophenes.

α-Selective Ring-Opening Reactions of Bicyclo[1.1.0]butyl Boronic Ester with Nucleophiles.

The reaction of bicyclo[1.1.0]butyl pinacol boronic ester (BCB-Bpin) with nucleophiles has been studied. Unlike BCBs bearing electron-withdrawing groups, which react with nucleophiles at the ß-position, BCB-Bpin reacts with a diverse set of heteroatom (O, S, N)-centred nucleophiles exclusively at the α-position. Aliphatic alcohols, phenols, carboxylic acids, thiols and sulfonamides were found to be competent nucleophiles, providing ready access to α-heteroatom-substituted cyclobutyl boronic esters. In contrast, sterically hindered bis-sulfonamides and related nucleophiles reacted with BCB-Bpin at the ß'-position leading to cyclopropanes with high trans-selectivity. The origin of selectivity is discussed.

Synthesis of 1,3-Bis-(boryl)alkanes through Boronic Ester Induced Consecutive Double 1,2-Migration.

A general and efficient approach for the preparation of 1,3-bis-(boryl)alkanes is introduced. It is shown that readily generated vinylboron ate complexes react with commercially available ICH2 Bpin to valuable 1,3-bis-(boryl)alkanes. The introduced transformation, which is experimentally easy to conduct, shows broad substrate scope and high functional-group tolerance. Mechanistic studies reveal that the reaction does not proceed via radical intermediates. Instead, an unprecedented boronic ester induced sequential bis-1,2-migration cascade is suggested.

Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles.

The stereospecific 1,2-migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2-migration of boronate complexes is driven by displacement of an α-leaving group, oxidation of an α-boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile-induced stereospecific 1,2-migration of groups from boron to sp2 and sp3 carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2-migration of boronate complexes: stereospecific Zweifel-type reactions, catalytic conjunctive coupling reactions, and transition metal-free sp2 -sp3 couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.

Divergent, Stereospecific Mono- and Difluoromethylation of Boronic Esters.

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH2 F and CHF2 groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α-fluoro-boronic esters. These unique intermediates can be readily transformed into the corresponding mono- or difluoromethylated compounds through proto- or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2-migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.

Gold-Catalyzed Iminations of Terminal Propargyl Alcohols with Anthranils with Atypical Chemoselectivity for C(1)-Additions and 1,2-Carbon Migration.

This work reports gold-catalyzed iminations of terminal propargyl alcohols with anthranils or isoxazoles to yield E-configured α-amino-2-en-1-ones and -1-als with complete chemoselectivity. These catalytic iminations occur exclusively with C(1)-nucleophilic additions on terminal alkynes, in contrast to a typical C(2)-route. For 3,3-dialkylprop-1-yn-3-ols, a methyl substituent is superior to long alkyl chains as the 1,2-migration groups toward α-imino gold carbenes. For secondary prop-1-yn-3-ols, phenyl, vinyl, and cyclopropyl substituents are better than hydrogen as the migrating groups, obviating typical gold carbene reactions. DFT calculations have been performed to rationalize the observed C(1)-regioselectivity and the preferable cyclopropyl migration based on gold carbene pathways.

Transition-Metal-Free Synthesis of Heterobiaryls through 1,2-Migration of Boronate Complex.

The synthesis of a diverse range of heterobiaryls has been achieved by a transition-metal-free sp2 -sp2 cross-coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source. The construction of heterobiaryls was carried out through electrophilic activation of the aryl-heteroaryl boronate complex, which triggered 1,2-migration from boron to the carbon atom. Subsequent oxidation of the intermediate boronic ester afforded heterobiaryls in good yield. A comprehensive 11 B NMR study has been conducted to support the mechanism. The cross coupling between two nucleophilic cross coupling partners without transition metals reveals a reliable manifold to procure heterobiaryls in good yields. Various heterocycles like furan, thiophene, benzofuran, benzothiophene, and indole are well tolerated. Finally, we have successfully demonstrated the gram scale synthesis of the intermediates for an anticancer drug and OLED material using our methodology.

Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies.

Demonstrated herein is an AuI -catalyzed annulation of sulfonyl-protected ynamides with substituted 1,2-benzisoxazoles for the synthesis of E-benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold-activated ynamide, ring expansion of the benzisoxazole fragment to provide an α-imino vinylic gold intermediate, and 1,2-migration of the sulfonamide motif to the masked carbene center to deliver the respective ring-expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α-imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.

Learning from B12 enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis.

Cobalamins (B12) play various important roles in vivo. Most B12-dependent enzymes are divided into three main subfamilies: adenosylcobalamin-dependent isomerases, methylcobalamin-dependent methyltransferases, and dehalogenases. Mimicking these B12 enzyme functions under non-enzymatic conditions offers good understanding of their elaborate reaction mechanisms. Furthermore, bio-inspiration offers a new approach to catalytic design for green and eco-friendly molecular transformations. As part of a study based on vitamin B12 derivatives including heptamethyl cobyrinate perchlorate, we describe biomimetic and bioinspired catalytic reactions with B12 enzyme functions. The reactions are classified according to the corresponding three B12 enzyme subfamilies, with a focus on our recent development on electrochemical and photochemical catalytic systems. Other important reactions are also described, with a focus on radical-involved reactions in terms of organic synthesis.

Selective Boryl-Anion Migration in a Vinyl sp2 -sp3 Diborane Induced by Soft Borane Lewis Acids.

An intramolecular 1,2-boryl-anion migration from boron to carbon has been achieved by selective activation of the π system in [(vinyl)B2 Pin2 )]- using "soft" BR3 electrophiles (BR3 =BPh3 or 9-aryl-BBN). The soft character is key to ensure 1,2-migration proceeds instead of oxygen coordination/B-O activation. The BR3 -induced 1,2-boryl-anion migration represents a triple borylation of a vinyl Grignard reagent using only B2 Pin2 and BR3 and forms differentially protected 1,1,2-triborylated alkanes. Notably, by increasing the steric bulk at the ß position of the vinyl Grignard reagent used to activate B2 Pin2 , 1,2-boryl-anion migration can be suppressed in favor of intermolecular {BPin}- transfer to BPh3 , thus enabling simple access to unsymmetrical sp2 -sp3 diboranes.

Reprint of: Impact of the corrin framework of vitamin B12 on the electrochemical carbon-skeleton rearrangement in comparison to an imine/oxime planar ligand; tuning selectivity in 1,2-migration of a functional group by controlling electrolysis potential.

Among the coenzyme B12-dependent enzymes, methylmalonyl-CoA mutase (MMCM) catalyzes the carbon-skeleton rearrangement reaction between R-methylmalonyl-CoA and succinyl-CoA. Diethyl 2-bromomethyl-2-phenylmalonate, an alkyl bromide substrate having two different migrating groups (phenyl and carboxylic ester groups) on the ß-carbon, was applied to the electrolysis mediated by a hydrophobic vitamin B12 model complex, heptamethyl cobyrinate perchlorate in this study. The electrolysis of the substrate at -1.0V vs. Ag-AgCl by light irradiation afforded the simple reduced product (diethyl 2-methyl-2-phenylmalonate) and the phenyl migrated product (diethyl 2-benzyl-2-phenylmalonate), as well as the electrolysis of the substrate at -1.5V vs. Ag-AgCl in the dark. The electrolysis of the substrate at -2.0V vs. Ag-AgCl afforded the carboxylic ester migrated product (diethyl phenylsuccinate) as the major product. The selectivity for the migrating group was successfully tuned by controlling the electrolysis potential. We clarified that the cathodic chemistry of the Co(III) alkylated heptamethyl cobyrinate is critical for the selectivity of the migrating group through mechanistic investigations and comparisons to the simple vitamin B12 model complex, an imine/oxime-type cobalt complex.

Impact of the corrin framework of vitamin B12 on the electrochemical carbon-skeleton rearrangement in comparison to an imine/oxime planar ligand; tuning selectivity in 1,2-migration of a functional group by controlling electrolysis potential.

Among the coenzyme B12-dependent enzymes, methylmalonyl-CoA mutase (MMCM) catalyzes the carbon-skeleton rearrangement reaction between R-methylmalonyl-CoA and succinyl-CoA. Diethyl 2-bromomethyl-2-phenylmalonate, an alkyl bromide substrate having two different migrating groups (phenyl and carboxylic ester groups) on the ß-carbon, was applied to the electrolysis mediated by a hydrophobic vitamin B12 model complex, heptamethyl cobyrinate perchlorate in this study. The electrolysis of the substrate at -1.0V vs. Ag-AgCl by light irradiation afforded the simple reduced product (diethyl 2-methyl-2-phenylmalonate) and the phenyl migrated product (diethyl 2-benzyl-2-phenylmalonate), as well as the electrolysis of the substrate at -1.5V vs. Ag-AgCl in the dark. The electrolysis of the substrate at -2.0V vs. Ag-AgCl afforded the carboxylic ester migrated product (diethyl phenylsuccinate) as the major product. The selectivity for the migrating group was successfully tuned by controlling the electrolysis potential. We clarified that the cathodic chemistry of the Co(III) alkylated heptamethyl cobyrinate is critical for the selectivity of the migrating group through mechanistic investigations and comparisons to the simple vitamin B12 model complex, an imine/oxime-type cobalt complex.

Silver-Catalyzed Isocyanide-Isocyanide [3+2] Cross-Cycloaddition Involving 1,2-Group Migration: Efficient Synthesis of Trisubstituted lmidazoles.

Imidazole ring is an important five-membered aromatic heterocycle that is widely present in natural products and synthetic molecules. The isocyanide-isocyanide [3+2] cross-cycloaddition reaction constitutes a straightforward method to access imidazoles starting from the easily available chemicals. So far, only three successive reports are known and all lead to the formation of 1,4-disubstituted imidazoles. Here, we report the first isocyanide-isocyanide [3+2] cross-cycloaddition reaction allowing for the formation of 1,4,5-trisubstituted imidazoles under silver catalysis. An unexpected 1,2-migration of sulfonyl, alkoxycaybonyl, and carbamoyl groups took place during the cyclization process that is responsible for the formation of trisubstituted imidazoles. This report displayed a mechanistically novel synthetic method toward a variety of imidazole derivatives, which are otherwise difficult to access by conventional methods.

Mechanistic Understanding of the Divergent Cyclizations of o-Alkynylbenzaldehyde Acetals and Thioacetals Catalyzed by Metal Halides.

The mechanisms of regiodivergent cyclizations of o-alkynylbenzaldehyde acetals and thioacetals catalyzed by Pd and Pt halides are studied. DFT calculations found that both reactions are initiated by electrophilic activation of the acetylenic moiety instead of the previously proposed metal-triggered CX (X=O, S) cleavage. Both the regioselective cyclization of the π-alkyne complex and the chemoselective [1,2]-migration in the carbenoid intermediate were determined as key steps to achieving the observed divergence. For acetal derivatives containing an internal alkyne, the 6-endo-dig cyclization is more favorable and leads to the carbenoid intermediate easily through further steps of CX fragmentation and carbocation cyclization. Then, from the carbenoid intermediate, the [1,2]-migration of sulfur is easier than that of H, Me, and Ph; whereas, a reversed aptitude was predicted for the oxygen analogue, which is consistent with the greater ability of sulfur atoms to stabilize ß-carbocations. However, for precursors containing a terminal alkyne, the 5-exo-dig pathway is preferred and only the 1,2-disubstituted indene product is seen, irrespective of the nature of the acetal; thus, a different product from that reported in the literature is predicted for benzaldehyde acetal with a terminal alkyne at the ortho position. This prediction led us to reconsider some of the reported results and hidden realities were uncovered with solid new experimental evidence.

Unexpected 1,2-migration in metallasilabenzenes: theoretical evidence for reluctance of silicon to participate in π bonding.

Density functional theory (DFT) calculations were carried out to investigate the 1,2-migration in metallasilabenzenes. The results suggested that the chloride migration of metallabenzenes is unfavorable due to the loss of aromaticity in the nonaromatic analogues. In sharp contrast, such a migration in metallasilabenzenes is favorable due to the reluctance of silicon to participate in π bonding. The migration of hydride and methyl group from the metal center to the silicon atom in metallasilabenzenes is computed to be also feasible. In addition, the π donor ligand and the third row transition metal can stabilize metallasilabenzenes. Thus, such a migration becomes less favorable thermodynamically and kinetically. These findings could be very helpful for synthetic chemists to realize the first metallasilabenzene.

Gold(I)-catalyzed furan-yne cyclizations involving 1,2-rearrangement: efficient synthesis of functionalized 1-naphthols and its application to the synthesis of wailupemycin†G.

Gold-catalyzed cascade cyclization/1,2-rearrangement of 1-(2-furanyl)phenyl propargyl alcohols has been developed, which provides a rapid and efficient access to multisubstituted 1-naphthols bearing an enal or enone moiety with high stereoselectivity. The (Z)- or (E)-stereochemistry can be easily controlled by choosing protected- or non-protected substrates. The utility of the methodology has been illustrated in the first total synthesis of wailupemycin G.