Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

The first example of enantioselective S?H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S?H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

Cross‐Coupling of α‐Carbonyl Sulfoxonium Ylides with C−H Bonds

The functionalization of carbon–hydrogen bonds in non‐nucleophilic substrates using α‐carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross‐coupling reactions of sulfoxonium ylides with C(sp²)−H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C−H activation, migratory insertion of the ylide into the carbon–metal bond, and protodemetalation, the last step being turnover‐limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium‐catalyzed dehydrative cyclization.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Retro‐Corey‐Chaykovsky Epoxidation: Converting Geminal Disubstituted Epoxides to Ketones

Corey‐Chaykovsky epoxidation has been widely applied in the conversion of aldehydes and ketones to epoxides with sulfonium and sulfoxonium ylides. The reverse transformation is realized for conversion of geminal disubstituted epoxides to ketones in the presence of DABCO in refluxing mesitylene. The method is a weak basic transformation from epoxides to ketones with loss of a methylene group and can be applied as an alternative strategy of the acid‐catalyzed Meinwald rearrangement or oxidation for conversion of epoxides to carbonyl compounds.     

Diastereoselective Nucleophilic Ring‐Opening Reactions of 2,6‐Diazasemibullvalenes for the Synthesis of Diverse Functionalized Δ1‐Bipyrroline Derivatives

Nucleophilic ring‐opening reactions of 2,6‐diazasemibullvalenes (NSBVs) were investigated. Different types of nucleophile (alcohols, phenols, thiols, carboxylic acids, water, enols, amines, indoles, metal‐halide salts, sodium azide, organozinc compounds, lithium alkynethiolate, and sulfoxonium ylides) were used to afford diverse functionalized Δ¹‐bipyrroline derivatives in good yields with high regio‐ and diastereoselectivity. Most of the reactions featured milder conditions and higher reactivity relative to those for common aziridine derivatives, probably because of the rigid ring system and substitution patterns of NSBVs.     

Ruthenium(II)‐Catalyzed C−H Activation of Imidamides and Divergent Couplings with Diazo Compounds: Substrate‐Controlled Synthesis of Indoles and 3H‐Indoles

Indoles are an important structural motif that is commonly found in biologically active molecules. In this work, conditions for divergent couplings between imidamides and acceptor–acceptor diazo compounds were developed that afforded NH indoles and 3H‐indoles under ruthenium catalysis. The coupling of α‐diazoketoesters afforded NH indoles by cleavage of the C(N₂)?C(acyl) bond whereas α‐diazomalonates gave 3H‐indoles by C?N bond cleavage. This reaction constitutes the first intermolecular coupling of diazo substrates with arenes by ruthenium‐catalyzed C?H activation.     

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.     

Catalytic Asymmetric Construction of Quaternary α‐Amino Acid Containing Pyrrolidines through 1,3‐Dipolar Cycloaddition of Azomethine Ylides to α‐Aminoacrylates

The first catalytic enantioselective 1,3‐dipolar cycloaddition of azomethine ylides to α‐aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo‐ and enantioselectivity (92–99 % ee). This process provides efficient access to useful 4‐aminopyrrolidine‐2,4‐dicarboxylic acid (APDC)‐like compounds containing a unique quaternary α‐amino acid unit.     

Synthesis of New Stable Phosphorus Ylides and 1,4‐Diionic Organophosphorus Compound from a Reaction between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of CH‐Acids

A simple and efficient one‐pot three‐component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH‐acids, such as acetylacetone, 1,3‐indandione, dibenzoylmethane, anthrone, and N,N‐dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N‐dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4‐diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21067     

Rhodium(II)‐Catalyzed Enantioselective Synthesis of Troponoids

We report a rhodium(II)‐catalyzed highly enantioselective 1,3‐dipolar cycloaddition reaction between the carbonyl moiety of tropone and carbonyl ylides to afford troponoids in good to high yields with excellent enantioselectivity. We demonstrate that α‐diazoketone‐derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity.     

Enolizable Carbonyls and N,O‐Acetals: A Rational Approach for Room‐Temperature Lewis Superacid‐Catalyzed Direct α‐Amidoalkylation of Ketones and Aldehydes

An efficient catalytic room‐temperature direct α‐amidoalkylation of carbonyl donors, that is, ketones and aldehydes with unbiased N,O‐acetals, is described. Sn(NTf₂)₄ is an optimal catalyst to promote this challenging transformation at low loading and the reaction shows promising scope. A comprehensive and rational evaluation of this reaction has led to the establishment of an empirical scale of nucleophilic reactivity for a broad set of ketones that should be helpful in the synthetic design and development of carbonyl α‐functionalization methods.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Reactions of o‐quinones with α‐methyl‐ (or methylene) substituted phosphorus ylides. Synthesis of benzo[b]furan derivatives

In Wittig reaction of some α‐methyl‐ and α‐methylene‐substituted phosphorus ylides with o‐quinones, benzo[b]furan derivatives were obtained via the cyclization of the o‐vinylphenols, initially formed from the tautomerization of the corresponding intermediate o‐quinone methides.     

Palladium‐Catalyzed Direct C2 Arylation of N‐Substituted Indoles with 1‐Aryltriazenes

A novel and efficient palladium‐catalyzed C2 arylation of N‐substituted indoles with 1‐aryltriazenes for the synthesis of 2‐arylindoles was developed. In the presence of BF₃ ? OEt₂ and palladium(II) acetate (Pd(OAc)₂), N‐substituted indoles reacted with 1‐aryltriazenes in N,N‐dimethylacetamide (DMAC) to afford the corresponding aryl–indole‐type products in good to excellent yields.     

Synthesis of 2-substituted indoles by iridium (III)-catalyzed CH functionalization of N-phenylpyridin-2-amines

A highly regioselective synthesis of 2-substituted indoles was realized through Ir(III)-catalyzed CH functionalization of N-phenylpyridin-2-amines followed by the reaction with sulfoxonium ylides and intramolecular cyclization under mild conditions. The reaction completed with broad range of substrate scopes and gave various 2-substituted indoles in up to 98% yields.     

N‐(tert‐Butoxycarbonyl)‐α‐aminoisobutyryl‐α‐aminoisobutyric acid methyl ester: two polymorphic forms in the space group P21/n

The title compound (systematic name: methyl 2‐{2‐[(tert‐butoxycarbonyl)amino]‐2‐methylpropanamido}‐2‐methylpropanoate), C₁₄H₂₆N₂O₅, (I), crystallizes in the monoclinic space group P2₁/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α‐aminoisobutyric acid (Aib) residues adopting ϕ and ψ values characteristic of α‐helical and mixed 3₁₀‐ and α‐helical conformations. The helical handedness of the C‐terminal residue (Aib2) is opposite to that of the N‐terminal residue (Aib1). In contrast to (I), the closely related peptide Boc‐Aib‐Aib‐OBn (Boc is tert‐butoxycarbonyl and Bn is benzyl) adopts an α_L‐P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen‐bonded parallel β‐sheet‐like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen‐bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α‐disubstituted residue.     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides

Described here is the first organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C–N bond formation is rate-determining.

An organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides has been developed to provide efficient access to α-amino esters without involving a metal carbenoid intermediate.     

Rh(III)-catalyzed [4 + 1]-annulation of azobenzenes with α- carbonyl sulfoxonium ylides toward 3-acyl-(2H)-indazoles

A Rh(III)-catalyzed [4?+?1]-annulation of azobenzenes with α- carbonyl sulfoxonium ylides was developed to access 2H-indazoles in moderate to excellent yields with good functional group compatibilities. It proceeded with the sequential insertion of the Rh(III) carbene to the C?H bond and cyclization steps, where sulfoxonium ylides served as efficient and stable carbene precursor.