Fused‐Ring Formation by an Intramolecular “Cut‐and‐Sew” Reaction between Cyclobutanones and Alkynes

The development of a catalytic intramolecular “cut‐and‐sew” transformation between cyclobutanones and alkynes to construct cyclohexenone‐fused rings is described herein. The challenge arises from the need for selective coupling at the more sterically hindered proximal position, and can be addressed by using an electron‐rich, but less bulky, phosphine ligand. The control experiment and ¹³C‐labelling study suggest that the reaction may start with cleavage of the less hindered distal C?C bond of cyclobutanones, followed by decarbonylation and CO reinsertion to enable Rh insertion at the more hindered proximal position.     

Palladium‐Catalyzed Defluorinative Coupling of 1‐Aryl‐2,2‐Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes

The palladium‐catalyzed defluorinative coupling of 1‐aryl‐2,2‐difluoroalkenes with boronic acids is described. Broad functional‐group tolerance arises from a redox‐neutral process by a palladium(II) active species which is proposed to undergo a β‐fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional‐group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.     

Base‐Promoted Tandem Reaction Involving Insertion into Carbon–Carbon σ‐Bonds: Synthesis of Xanthone and Chromone Derivatives

Tandem reactions using base‐promoted processes have been developed for the synthesis of xanthone and chromone derivatives. The first examples of base‐promoted insertion reactions of isolated carbon–carbon triple bonds into carbon–carbon σ‐bonds have been reported. Using these approaches, polycyclic structures can be prepared. This reaction has the potential to become a general synthetic protocol for the preparation of multi‐substituted xanthones and chromones due to the abundance of easily accessible starting materials possessing diverse substituent groups.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.     

Cross‐Electrophile Coupling of Vinyl Halides with Alkyl Halides

An improved method for the reductive coupling of aryl and vinyl bromides with alkyl halides that gave high yields for a variety of substrates at room temperature with a low (2.5 to 0.5 mol %) catalyst loading is presented. Under the optimized conditions, difficult substrates, such as unhindered alkenyl bromides, can be coupled to give the desired olefins with minimal diene formation and good stereoretention. These improved conditions also worked well for aryl bromides. For example, a gram‐scale reaction was demonstrated with 0.5 mol % catalyst loading, whereas reactions at 10 mol % catalyst loading completed in as little as 20 minutes. Finally, a low‐cost single‐component pre‐catalyst, (bpy)NiI₂ (bpy=2,2′‐bipyridine) that is both air‐ and moisture‐stable over a period of months was introduced.     

Rhodium(III)‐Catalyzed Redox‐Neutral Coupling of α‐Trifluoromethylacrylic Acid with Benzamides through Directed C−H Bond Cleavage

A rhodium(III)‐catalyzed redox‐neutral coupling of α‐trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide‐directed C?H bond cleavage to produce β‐[2‐(aminocarbonyl)phenyl]‐α‐trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox‐neutral coupling of α‐trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen‐containing directing group can also be conducted under similar conditions.     

The Ene Reaction

The ene reaction is defined as the indirect substituting addition of a compound with a double bond (enophile) to an olefin with an allylic hydrogen (ene). For a long time the reaction has been neglected and has remained overshadowed by the related Diels-Alder addition. It is shown that the ene reaction possesses wide scope and applicability ranging from industrial to biosynthetic processes. Preparative aspects are summarized and current views on the mechanism are discussed.     

Recent Advances in Ring‐Opening Functionalization of Cycloalkanols by C–C σ‐Bond Cleavage

Cycloalkanols prove to be privileged precursors for the synthesis of distally substituted alkyl ketones and polycyclic aromatic hydrocarbons (PAHs) by virtue of cleavage of their cyclic C−C bonds. Direct functionalization of cyclobutanols to build up other chemical bonds (e. g., C−F, C−Cl, C−Br, C−N, C−S, C−Se, C−C, etc.) has been achieved by using the ring‐opening strategy. Mechanistically, the C−C cleavage of cyclobutanols can be involved in two pathways: (a) transition‐metal catalyzed β‐carbon elimination; (b) radical‐mediated ‘radical clock’‐type ring opening. The recent advances of our group for the ring‐opening functionalization of tertiary cycloalkanols are described in this account.     

Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Alkenylation and Application to Alkaloid Synthesis

A variety of strained α‐alkylidene‐γ‐lactams were synthesized by palladium(0)‐catalyzed intramolecular C(sp³)?H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for accessing various classes of mono‐ and bicylic alkaloids containing a pyrrolidine ring, as illustrated with the synthesis of an advanced model of the marine natural product plakoridine A and of the indolizidine alkaloid δ‐coniceine.     

Transition‐Metal‐Free Reaction of Aryltrimethylammonium Iodides with Arylzinc Reagents

Reaction of aryltrimethylammonium iodides with arylzinc chlorides in the absence of a transition‐metal catalyst to form biaryl compounds was performed under mild conditions. The reaction was suitable for a broad scope of substrates and exhibited good compatibility of functional groups. The Mg²⁺ ion was demonstrated to markedly promote the reaction.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Variable Reactivity of a N‐Heterocyclic Phosphenium Complex: P−C Bond Activation or “Abnormal” Deprotonation

The reaction of an N‐heterocyclic phosphenium complex of manganese with MeLi/Et₃NHCl under formal addition of CH₄ to the Mn=P double bond can be reversed upon UV photolysis, providing a rare example for selective P−C(alkyl) bond activation. Action of LDA on the phosphenium complex does not proceed via attack at phosphorus but rather via C4‐deprotonation to yield a unique P‐analogue of an “abnormal” carbene. A transmetalation product of the original complex was fully characterized. The C‐metalation is also applicable to bis‐phosphenium complexes of other metals.     

A Surprising Solid-Phase Effect: Development of a Recyclable “Traceless” Linker System for Reactions on Solid Support

Triazenes as “traceless” linkers for solid-phase synthesis have been utilized for the attachment of arenes to a solid support and yield the corresponding products after various organometallic reactions (Heck reaction and asymmetric dihydroxylation, see the reaction scheme) and cycloadditions (Diels–Alder reaction). The triazene linker is distinguished by its accessibility, thermal robustness, and capability to undergo regeneration.     

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

A new iron‐facilitated silver‐mediated radical 1,2‐alkylarylation of styrenes with α‐carbonyl alkyl bromides and indoles is described, and two new C?C bonds were generated in a single step through a sequence of intermolecular C(sp³)?Br functionalization and C(sp²)?H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.     

NH‐Heterocyclic Aryliodonium Salts and their Selective Conversion into N1‐Aryl‐5‐iodoimidazoles

The synthesis of N‐arylimidazoles substituted at the sterically encumbered 5‐position is a challenge for modern synthetic approaches. A new family of imidazolyl aryliodonium salts is reported, which serve as a stepping stone on the way to selective formation of N1‐aryl‐5‐iodoimidazoles. Iodine acts as a “universal” placeholder poised for replacement by aryl substituents. These new λ³‐iodanes are produced by treating the NH‐imidazole with ArI(OAc)₂, and are converted to N1‐aryl‐5‐iodoimidazoles by a selective copper‐catalyzed aryl migration. The method tolerates a variety of aryl fragments and is also applicable to substituted imidazoles.     

Palladium(II)‐Catalyzed ortho‐Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

A palladium(II)‐catalyzed C?H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline‐based hemiacetal scaffold that can direct the selective C?H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.     

Reactivity of Dialumane and “Dialumene” Compounds toward Alkenes

The reactions of dialumane [L(thf)Al? Al(thf)L] ( 1 , L=[{(2,6‐iPr₂C₆H₃)NC(Me)}₂]^2?) with stilbene and styrene afforded the oxidation/insertion products [L(thf)Al(CH(Ph)? CH(Ph))AlL] ( 2 ) and [L(thf)Al(CH(Ph)? CH₂)Al(thf)L] ( 3 ), respectively. In the presence of Na metal, precursor 1 reacted with butadienes, possibly through the reduced “dialumene” or the “carbene‐like” :AlL species, to yield aluminacyclopentenes [LAl(CH₂C(Me)?C(Me)CH₂)Na]_n ( 4 a ) and [Na(dme)₃][LAl(CH₂C(Me)?CHCH₂)] ( 4 b , dme=dimethoxyethane) as [1+4] cycloaddition products, as well as the [2+4] cycloaddition product 1,6‐dialumina‐3,8‐cyclodecadiene, [{Na(dme)}₂][LAl(CH₂C(Me)?C(Me)CH₂)₂AlL] ( 5 ). The possible mechanisms of the cycloaddition reactions were studied by using DFT computations.     

Palladium‐Assisted “Aromatic Metamorphosis” of Dibenzothiophenes into Triphenylenes

Two new palladium‐catalyzed reactions of aromatic sulfur compounds enabled the conversion of dibenzothiophenes into triphenylenes in four steps. This transformation of one aromatic framework into another consists of 1) 4‐chlorobutylation of the dibenzothiophene to form the corresponding sulfonium salt, 2) palladium‐catalyzed arylative ring opening of the sulfonium salt with a sodium tetraarylborate, 3) an intramolecular S_N2 reaction to form a teraryl sulfonium salt, and 4) palladium‐catalyzed intramolecular C? S/C? H coupling through electrophilic palladation. Symmetrical as well as unsymmetrical triphenylenes of interest were synthesized in a tailor‐made fashion in satisfactory overall yields.     

Regio‐ and Stereoselective Aliphatic–Aromatic Cross‐Benzoin Reaction: Enzymatic Divergent Catalysis

The catalytic asymmetric synthesis of chiral 2‐hydroxy ketones by using different thiamine diphosphate dependent enzymes, namely benzaldehyde lyase from Pseudomonas fluorescens (PfBAL), a variant of benzoylformate decarboxylase from Pseudomonas putida (PpBFD‐L461A), branched‐chain 2‐keto acid decarboxylase from Lactococcus lactis (LlKdcA) and a variant of pyruvate decarboxylase from Acetobacter pasteurianus (ApPDC‐E469G), was studied. Starting with the same set of substrates, substituted benzaldehydes in combination with different aliphatic aldehydes, PfBAL and PpBFD‐L461A selectively deliver the (R)‐ and (S)‐2‐hydroxy‐propiophenone derivatives, respectively. The (R)‐ and (S)‐phenylacetylcarbinol (1‐hydroxy‐1‐phenylacetone) derivatives are accessible in a similar way using LlKdcA and ApPDC‐E469G, respectively. In many cases excellent stereochemical purities (>98 % enantiomeric excess) could be achieved. Hence, the regio‐ and stereochemistry of the product in the asymmetric aliphatic–aromatic cross‐benzoin reaction can be controlled solely by choice of the appropriate enzyme or enzyme variant.