Stereogenic-at-Cobalt(III) Complex Catalyzed Halocyclization of Alkynes: Enantioselective Access to Axially Chiral ortho-Halo-C2-indoles.

Here, we report an anionic stereogenic-at-cobalt(III) complex catalysis strategy for the enantioselective halocyclization of ortho-alkynylanilines using N-halosuccinimide (NXS) as the halogen source. This protocol provides a distinct atroposelective approach to access the axially chiral ortho-halo-C2-indole skeletons in excellent yields with good to high enantioselectivities (up to 99% yield, 99:1 er).

Enantioselective Ugi and Ugi-azide reactions catalyzed by anionic stereogenic-at-cobalt(III) complexes.

Ugi reactions and related variations are proven to be atom and step-economic strategies for construction of highly valuable peptide-like skeletons and nitrogenous heterocycles. The development of structurally diverse range of novel catalytic systems and the discovery of new approaches to accommodate a broader scope of terminating reagents for asymmetric Ugi four-component reaction is still in high demand. Here, we report a strategy that enables enantioselective Ugi four-component and Ugi-azide reactions employing anionic stereogenic-at-cobalt(III) complexes as catalysts. The key nitrilium intermediates, generated through the nucleophilic addition of isocyanides to the chiral ion-pair which consists of stereogenic-at-cobalt(III) complexes counteranion and a protonated iminium, are trapped by either carboxylic acids or in situ-generated hydrazoic acid, delivering α-acylamino amides and α-aminotetrazoles in good to excellent enantioselectivities (up to 99:1 e.r.).

tert-Butyl Nitrite: Organic Redox Cocatalyst for Aerobic Aldehyde-Selective Wacker-Tsuji Oxidation.

An aldehyde-selective aerobic Wacker-Tsuji oxidation is developed. Using tert-butyl nitrite as a simple organic redox cocatalyst instead of copper or silver salts, a variety of aldehydes were achieved as major products in up to 30/1 regioselectivity as well as good to high yields at room temperature.

Direct oxidative lactonization of alkenoic acids mediated solely by NaIO4: beyond a simple oxidant.

Triflic acid-catalyzed direct oxidative lactonization of alkenoic acids mediated solely by NaIO4 without halogen salts is described. Sodium periodate works not only as an oxidant, but also as an active reagent and directly mediates the lactonization. A new cheap, green, and practical oxidative lactonization approach has been developed using NaIO4 as the sole reagent.

Pharmaceutical-Oriented Selective Synthesis of Mononitriles and Dinitriles Directly from Methyl(hetero)arenes: Access to Chiral Nitriles and Citalopram.

A pharmaceutical-oriented, transition-metal-free, cyanide-free one-step direct transformation of methylarenes to aryl nitriles is described. For the dimethylarenes, the selectivity can be well-controlled to form mononitriles or dinitriles. Enantioenriched nitriles can also be synthesized by this method. As a pharmaceutically practical method, the antidepressant drug citalopram was synthesized from cheap and commercially abundant m-xylene on a gram scale in high yield, avoiding transition-metal residues and toxic cyanides.

Transition-Metal-Free Deacylative Cleavage of Unstrained C(sp(3))-C(sp(2)) Bonds: Cyanide-Free Access to Aryl and Aliphatic Nitriles from Ketones and Aldehydes.

A transition-metal-free deacylative C(sp(3))-C(sp(2)) bond cleavage for the synthetically practical oxidative amination of ketones and aldehydes to nitriles is first described, using cheap and commercially abundant NaNO2 as the oxidant and the nitrogen source. Various nitriles bearing aryl, heteroaryl, alkyl, and alkenyl groups could be smoothly obtained from ketones and aldehydes in high yields, avoiding highly toxic cyanides or transition metals.

Transition-Metal-Free Self-Hydrogen-Transferring Allylic Isomerization.

Phenanthroline and tert-butoxide have been established as powerful radical initiators in reactions such as the SRN1-type coupling reactions due to the cooperation of large heteroarenes and a special feature of tert-butoxide. The first phenanthroline-tert-butoxide-catalyzed transition-metal-free allylic isomerization is described. The resulting ketones are key intermediates for indenes. The control experiments rule out the base-promoted allylic anion pathway. The radical pathway is supported by experimental evidence that includes kinetic study, kinetic isotope effect, isotope-labeling experiments, trapping experiments, and EPR experiments.

Direct Alkylation of Amines with Alcohols Catalyzed by Base.

A base-catalyzed/promoted transition-metal-free direct alkylation of amines with alcohols has been developed, giving the desired amines in generally high yields from either aromatic or aliphatic alcohols. On the basis of the (1)H NMR and in situ IR (React-IR) monitoring experiments, isotope-labeling experiments, as well as control experiments, a novel "hemiaminal" model is proposed to understand the mechanism, which explains the formation of the "extra" aldehyde in the reaction.

(E)-Specific direct Julia-olefination of aryl alcohols without extra reducing agents promoted by bases.

An unprecedented base-promoted direct olefination of aryl alcohols with sulfones via a Julia-type reaction has been described. No extra reductants are needed for Julia reaction since alcohols work as double sources of aldehydes and the hydride. Generally high yields were given for both terminal and highly (E)-selective internal olefins.

Ruthenium-catalyzed asymmetric N-demethylative rearrangement of isoxazolidines and its application in the asymmetric total syntheses of (-)-(1R,3S)-HPA-12 and (+)-(1S,3R)-HPA-12.

An asymmetric N-demethylative rearrangement of 1,2-isoxazolidines catalyzed by ruthenium is described. Enantioenriched syn-1,3-aminoalcohols as well as cis-1,3-oxazinanes, which are useful building blocks, can be efficiently prepared stereospecifically by this reaction in good yields, via the isoxazolidine intermediates in situ generated from a nitrone bearing a chiral auxiliary and styrenes. This asymmetric reaction was also applied in the asymmetric total syntheses of both (-)-(1R,3S)-HPA-12 and (+)-(1S,3R)-HPA-12.

Synthesis of syn-1,3-aminoalcohols via a Ru-catalyzed N-demethylative rearrangement of isoxazolidines and its application in a three-step total synthesis of HPA-12.

A highly efficient ruthenium-catalyzed stereospecific N-demethylative rearrangement of isoxazolidines to synthetically useful N-H-1,3-oxazinanes is described. 1,3-Oxazinanes are useful building blocks, which can be further converted to N-H-1,3-aminoalcohols in one step. This new method was used in a three-step gram-scale total synthesis of HPA-12 in an overall 24% yield.

Ru-catalyzed rearrangement of N-methyl isoxazolidines to N-H 1,3-oxazinanes: a strategy of self-hydride transferring cleavage of N-O bonds.

A strategy of ruthenium-catalyzed self-hydride transferring cleavage of N-O bonds was designed and utilized in a cascade 1,3-dipolar cyclization of alkenes and N-methyl nitrones followed by an N-demethylative rearrangement, furnishing synthetically useful N-H 1,3-oxazinanes.