A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

2,5‐Bis(methylthio)‐1,4‐benzo­quinone and 2‐methyl‐3‐(methylsulfonyl)benzo[b]thiophene

The structure of 2,5‐bis­(methyl­thio)‐1,4‐benzo­quinone, C₈H₈O₂S₂, is composed of an essentially planar centrosymmetric benzo­quinone substituted with two methyl­thio groups. The important bond distances are S—Csp³ 1.788 (2) and S—Csp² 1.724 (2) Å, and the two Csp²—Csp² distances are 1.447 (3) and 1.504 (3) Å, which differ significantly. There are short S?S interactions of 3.430 (1) Å and Csp²—H?O‐type contacts forming a dimeric motif with graph set R₂²(8). The structure of 2‐methyl‐3‐(methyl­sulfonyl)­benzo­[b]­thio­phene, C₁₀H₁₀O₂S₂, is composed of an essentially planar benzo­thio­phene moiety substituted with methyl and methyl­sulfonyl groups. The mean values of the important bond distances are endocyclic S—Csp² 1.734 (3), S=O 1.434 (4) and C—C_aromatic 1.389 (10) Å. The exocyclic S—Csp² and S—Csp³ distances are 1.759 (4) and 1.763 (5) Å, respectively.     

Chemoselective Amination of Propargylic C(sp3)H Bonds by Cobalt(II)‐Based Metalloradical Catalysis

Highly chemoselective intramolecular amination of propargylic C(sp³)? H bonds has been demonstrated for N‐bishomopropargylic sulfamoyl azides through cobalt(II)‐based metalloradical catalysis. Supported by D_2h‐symmetric amidoporphyrin ligand 3,5‐Di^tBu‐IbuPhyrin, the cobalt(II)‐catalyzed C? H amination proceeds effectively under neutral and nonoxidative conditions without the need of any additives, and generates N₂ as the only byproduct. The metalloradical amination is suitable for both secondary and tertiary propargylic C? H substrates with an unusually high degree of functional‐group tolerance, thus providing a direct method for high‐yielding synthesis of functionalized propargylamine derivatives.     

Modular Stereoselective Synthesis of (1→2)‐C‐Glycosides based on the sp2–sp3 Suzuki–Miyaura Reaction

This work reports a modular and rapid approach to the stereoselective synthesis of a variety of α‐ and β‐(1→2)‐linked C‐disaccharides. The key step is a Ni‐catalyzed cross‐coupling reaction of D ‐glucal pinacol boronate with alkyl halide glycoside easily prepared from commercially available D ‐glucal. The products of this sp²–sp³ cross‐coupling reaction can be converted to glucopyranosyl, mannopyranosyl, or 2‐deoxy‐glucopyranosyl C‐mannopyranosides by one‐ or two‐step stereoselective oxidative–reductive transformations. To the best of our knowledge, we demonstrated the first synthetic application of a challenging sp²–sp³ Suzuki‐Miyaura cross‐coupling reaction in carbohydrate chemistry.     

Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

Rhodium‐Catalyzed Defluorinative Vinylation of gem‐Difluoroalkenes for the Synthesis of 2‐Fluoro‐1,3‐dienes

Herein, we present a strategy for the formation of 2‐fluoro‐1,3‐diene derivatives via rhodium‐catalyzed direct C(sp²)—C(sp²) cross‐coupling of gem‐difluoroalkenes and acrylamides. By merging Rh(III)‐catalyzed C(sp²)–H bond activation and nucleophilic addition/F‐elimination of gem‐difluoroalkene, an efficient defluorinative vinylation reaction is uncovered, which leads to the generation of 2‐fluoro‐1,3‐dienes in moderate to good yields with excellent stereoselectivity under mild conditions. Preliminary mechanistic study suggests unique effects of fluorine substituents which allow the reactivity profile not observed with the congeners bearing heavier halides.     

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

A metal‐free C(sp²)–C(sp²) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp²) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp²)–C(sp²) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.     

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol,the oxygenated side chain of 22(S)‐hydroxycholestrol,and its synthetic precursor (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol, C₉H₂₀O₂, (I), was synthesized from the ketone (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one, C₁₉H₂₇NO₄, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C—H...O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp³...Csp² contact that represents a usually unrecognized type of intermolecular interaction.     

Synthesis of α‐Aryl Esters and Nitriles: Deaminative Coupling of α‐Aminoesters and α‐Aminoacetonitriles with Arylboronic Acids

Transition‐metal‐free synthesis of α‐aryl esters and nitriles using arylboronic acids with α‐aminoesters and α‐aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp³)? N bonds into C(sp³)? C(sp²) bonds. The reaction conditions are mild, demonstrate good functional‐group tolerance, and can be scaled up.     

Combination of sp2‐ and sp3‐Type Phosphorus Atoms for Gold Chemistry: Preparation,Structure, and Catalytic Activity of Gold Complexes That Bear Ligated 2‐Silyl‐1,3‐diphosphapropenes

Kinetically protected 2‐silyl‐1,3‐diphosphapropenes that bear both sp²‐ and sp³‐type phosphorus atoms were employed in the preparation of gold complexes. The structural properties of the 1,3‐diphosphapropene digold(I) complexes were characterized by spectroscopic and crystallographic analyses, which revealed unique aurophilic interactions and conformational properties of the ligand. The 2‐silyl‐1,3‐diphosphapropene‐bis(chlorogold) complexes catalyzed cycloisomerization reactions of 1,6‐enyne derivatives even in the absence of silver co‐catalyst, and were able to be recovered after the reaction. The catalytic activity of the digold complexes primarily depended on the sp²‐type phosphorus atom and the silyl group, and could be tuned by the sp³‐phosphino group. Additionally, results on the catalytic activity of the digold complex in the presence and absence of silver salts showed considerable differences.     

4,5‐Di­hydro‐3‐methyl‐5‐(4‐methyl­phenyl)‐1H‐pyrazole‐1‐carbox­amide

The reaction between 4‐(4‐methyl­phenyl)­but‐3‐en‐2‐one and amino­guanidine produced an unexpected product of formula C₁₂H₁₅N₃O, consisting of a carbox­amide moiety joined to a substituted pyrazoline ring at one of the N atoms. The pyrazoline ring adopts a flat‐envelope conformation and the substituted phenyl ring is oriented almost perpendicular to the heterocycle. The carbonyl O atom has partial anionic character as a result of the transfer of π density from the two adjacent sp² N atoms and is involved in an intermolecular hydrogen bond with the amide group.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

(1R,2S)‐2‐[N‐Methyl‐N‐(4‐toluene­sulfonyl)amino]‐1‐phenylpropan‐1‐ol

In the title compound, C₁₇H₂₁NO₃S, the S atom is in a distorted tetrahedral geometry and the N atom exhibits sp² character. The antiperiplanar conformation is observed for the N and hydroxyl‐O atoms and the torsion angle around the N—C linkage is ?136.3 (2)°. The mol­ecules are linked by O—H?O intermolecular hydrogen bonds to form an infinite one‐dimensional chains along the c axis.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

α‐Arylation/Heteroarylation of Chiral α‐Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross‐Coupling Catalysis

Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross‐coupling dual catalysis strategy has been developed. New C(sp³)? C(sp²) bonds are forged starting from abundant and inexpensive natural amino acids.     

A study of the planarity of the pyrrolone fragment in 2‐isopropyl‐2,3‐dihydro‐1H‐isoindol‐1‐one

Orthophthalaldehyde (o‐phthalaldehyde, OPA) is an aromatic dialdehyde bearing two electron‐withdrawing carbonyl groups. The reactions of OPA with primary amines are broadly applied for the synthesis of important heterocyclic compounds with biological relevance. A number of such reactions have been investigated recently and several structures of condensation products have been reported, however, the complex reaction mechanism is still not fully understood and comprises concurrent as well as consecutive reactions. The reaction products depend on the primary amine which reacts with OPA, the reaction environment (solvent) and the proportion of the reactants. The title molecule, C₁₁H₁₃NO, the product of the reaction of OPA with isopropylamine, contains a five‐membered pyrrole C₄N ring with a carbonyl substituent, which forms part of the isoindolinone unit. Though this pyrrole ring contains one C atom in the sp³‐hybridized state, it is fairly planar. The title molecule has been compared with similar structures retrieved from the Cambridge Structural Database in order to study this phenomenon. The planarity of this fragment has been explained by the presence of partially delocalized C—C, C—N and C—O bonds, and by an inner angle in the planar pentagonal ring (∼108°), which is close to the ideal tetrahedral value for the sp³‐hybridized state of the constituent C atom. Due to this propitious angle, this C atom can be present in states intermediate between sp³‐ and sp²‐hybridized in different structures, while still maintaining the planarity of the ring. There are only weak intermolecular C—H…O hydrogen bonds and C—H…π‐electron ring interactions in the structure. In particular, it is the pyrrole ring which is involved in these interactions.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Diastereoselective Total Syntheses of (±)‐Caseabalansin A and (±)‐18‐Epicaseabalansin A via Intramolecular Robinson‐type Annulation

Highly diastereoselective total syntheses of (±)‐caseabalansin A ( 1 ) and (±)‐18‐epicaseabalansin A ( 2 ) are described in this paper. We revealed that the intramolecular Robinson‐type annulation of an alkynone was effective in the stereocontrolled construction of the bicyclic skeleton of 1 and 2 . Further transformation of the resulting enone, including diastereoselective reduction by LiAlH(OtBu)₃, hydroxy‐group‐directed hydrogenation, cyclization to form the cyclic acetal moiety, and introduction of a side chain by a C(sp³)?C(sp³) Stille coupling reaction, resulted in the total syntheses of (±)‐ 1 and (±)‐ 2 .     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.