Acid-promoted rearrangement of arylmethyl azides: applications toward the synthesis of N-arylmethyl arenes and polycyclic heteroaromatic compounds

An acid-promoted Aubé–Schmidt's rearrangement of arylmethyl azides provides a useful in situ iminium ion intermediate, which can be efficiently trapped by various nucleophiles. We report here the reaction of this iminium ion with aromatic nucleophiles to give N-arylmethyl arenes and the reaction with heteroaromatic compounds to give fused polycyclic heteroaromatic products in a formal [4+2] cycloaddition. The short synthesis of isocrytolepine, an antimalarial agent, further demonstrated the utility of this process.     

Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl‐Substituted Diarylprolinol Silyl Ether

The reactions of α,β‐unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michael‐type reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethyl‐substituted diarylprolinol silyl ethers, which are widely used proline‐type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl‐substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl‐substituted catalyst is more reactive in a type B reaction. The iminium ion from an α,β‐unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl‐substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate‐determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael‐type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl‐substituted diarylprolinol silyl ether catalyst is preferred for type B reactions.     

Ruthenium-catalyzed oxidative cyanation of tertiary amines with molecular oxygen or hydrogen peroxide and sodium cyanide: sp3 C-H bond activation and carbon-carbon bond formation

Ruthenium-catalyzed oxidative cyanation of tertiary amines with molecular oxygen in the presence of sodium cyanide and acetic acid gives the corresponding alpha-aminonitriles, which are highly useful intermediates for organic synthesis. The reaction is the first demonstration of direct sp(3) C-H bond activation alpha to nitrogen followed by carbon-carbon bond formation under aerobic oxidation conditions. The catalytic oxidation seems to proceed by (i) alpha-C-H activation of tertiary amines by the ruthenium catalyst to give an iminium ion/ruthenium hydride intermediate, (ii) reaction with molecular oxygen to give an iminium ion/ruthenium hydroperoxide, (iii) reaction with HCN to give the alpha-aminonitrile product, H2O2, and Ru species, (iv) generation of oxoruthenium species from the reaction of Ru species with H2O2, and (v) reaction of oxoruthenium species with tertiary amines to give alpha-aminonitriles. On the basis of the last two pathways, a new type of ruthenium-catalyzed oxidative cyanation of tertiary amines with H2O2 to give alpha-aminonitriles was established. The alpha-aminonitriles thus obtained can be readily converted to alpha-amino acids, diamines, and various nitrogen-containing heterocyclic compounds.     

9-氨基奎宁催化剂催化1-溴代硝基甲烷和亚苄基丙酮的共轭加成反应的理论研究

通过密度泛函理论(DFT) B3LYP, M062X和从头算方法MP2, 给出了9-氨基奎宁作为有机催化剂和苯甲酸作为辅助催化剂催化1-溴代硝基甲烷与亚苄基丙酮的不对称共轭加成反应的详细反应机理. 反应过程主要包括3个阶段: (1) 亚胺离子中间体的形成; (2) 亚胺离子与1-溴代硝基甲烷的亲核加成; (3) 水解并伴随催化剂的还原. 计算结果不仅解释了苯甲酸加合物在亚胺离子形成过程中所起的重要作用, 而且提供了一般反应模型以理解这个共轭加成反应的反应机理和对映选择性.     

Theoretical study of the imidazolidinone catalyzed 1,4-addition of N,N-dimethyl-3-anisidine with α,β-unsaturated butyric aldehyde

Friedel–Crasfts alkylation reactions of α,β-unsaturated butyric aldehydes with N,N-dimethyl-3-anisidine catalyzed by a (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one HCl salt have been carried out at the PCM(CH₂Cl₂)/B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level. Three reaction processes have been characterized: (I) the formation of an iminium ion intermediate; (II) the 1,4-iminium addition of the iminium ion; and (III) the hydrolysis of the addition product. Moreover, Path 1-1 is the favorable channel in the formation of the iminium ion. From the point of view of energy, the enantioselectivity is controlled by the carbon–carbon bond formation step that is involved in both the intermediate M4 and the transition state TS4. The highest energy barrier of the reaction is the H2 proton transfer from the O10 atom of a water molecule to the N1 atom of the catalyst in the hydrolysis process, which is 23.4 kcal/mol. The presented calculated results may be helpful in understanding the experimental product distribution for the title reaction, and provide a general model to help explain the mechanisms of similar reactions.     

Mechanistic studies on a Cu-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline: structure of intermediates and the role of methanol as a solvent

The mechanism of an aerobic copper-catalyzed oxidative coupling reaction with N-phenyl tetrahydroisoquinoline was investigated. The oxidized species formed from the reaction of the amine with the copper catalyst were analyzed by NMR-spectroscopy. An iminium dichlorocuprate was found to be the reactive intermediate and could be structurally characterized by X-ray crystallography. The effect of methanol to effectively stabilize the iminium ion was investigated and shown to be beneficial in an oxidative allylation reaction.     

Organocatalytic asymmetric direct phosphonylation of alpha,beta-unsaturated aldehydes: mechanism, scope, and application in synthesis

The first direct organocatalytic enantioselective phosphonylation of alpha,beta-unsaturated aldehydes with phosphite, in combination with a Br?nsted acid and a nucleophile, is presented. Mechanistic investigations have revealed that the first step in the catalytic process, after the formation of the iminium intermediate, is the addition of phosphite to the beta-carbon atom, leading to the phosphonium ion-enamine intermediate. The rate-determining step for the reaction is the transformation of P(III) to P(V), which occurs via a nucleophilic SN2-type dealkylation, and a screening of various nucleophiles shows that soft nucleophiles in combination with a Br?nsted acid improve the reaction rate and enantioselectivity. The reaction conditions developed show that the use of 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanoxymethyl]pyrrolidine as the catalyst and tri-iso-propyl phosphite as the phosphonylation reagent, in the presence of stoichiometric amount of benzoic acid and sodium iodide, gave the beta-phosphonylation of aromatic and aliphatic alpha,beta-unsaturated aldehydes in good yields and enantioselectivities. The products formed by this new reaction have been used for the synthesis of a number of biologically important compounds, such as optically active hydroxyl phosphonate esters, phosphonic acids, and especially glutamic acid and fosmidomycin precursors, of which the two latter are showing important properties for the treatment of central nervous system diseases and as anti-malarial compounds, respectively. DFT calculations have been applied to explain the approach of the phosphite to the reactive carbon atom in the iminium intermediate in order to account for the observed absolute enantioselectivity in the reaction.     

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

The effect of silyl substituents in diphenylprolinol silyl ether catalysts was investigated. Mechanistically, reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types: two that involve an iminium ion intermediate, such as for the Michael‐type reaction (type A) and the cycloaddition reaction (type B), and one that proceeds via an enamine intermediate (type C). In the Michael‐type reaction via iminium ions (type A), excellent enantioselectivity is realized when the catalyst with a bulky silyl moiety is employed, in which efficient shielding of a diastereotopic face of the iminium ion is directed by the bulky silyl moiety. In the cycloaddition reaction of iminium ions (type B) and reactions via enamines (type C), excellent enantioselectivity is obtained even when the silyl group is less bulky and, in this case, too much bulk reduces the reaction rate. In other cases, the yield increases when diphenylprolinol silyl ethers with bulky substituents are employed, presumably by suppressing side reactions between the nucleophilic catalyst and the reagent. The conformational behaviors of the iminium and enamine species have been determined by theoretical calculations. These data explain the effect of the bulkiness of the silyl substituent on the enantioselectivity and reactivity of the catalysts.     

Action comparée de l'eau oxygénée et d'un peracide sur un sel d'immonium pyrrolinique stéroïdique et sur l'énamine correspondante. Formation et propriétés d'un sel d'oxaziridinium

The reaction of a pyrrolinium salt with a peracid affords an oxaziridinium salt. The corresponding enamine reacts similarly to give products oxidized at the α-position to the nitrogen atom. These results are rationalized in terms of the formation of an intermediate oxaziridinium ion. The oxaziridinium salt reacts with nucleophiles to give either an carbinol iminium salt or products resulting from oxygen transfer.     

Aminocatalytic Cross‐Coupling Approach via Iminium Ions to Different CC Bonds

Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH₂ group is replaced by C?O was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium‐catalyzed or iminium‐equivalent pathway are apparently unavailable. Previously, tandem cross‐coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2‐addition to give a putative three‐component intermediate that abstracts a proton in situ and undergoes self‐deamination followed by unprecedented DMSO/aerobic oxidation to generate α‐ketoamides. However, later it was observed that iminium ions can generate valuable α‐ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2‐oxoaldehydes with secondary amines.     

Thermodynamic stability and reactivity of silylated bis(oxy)iminium ions

Silylation of various nitronates with trialkylsilyl triflates was investigated by applying NMR techniques. In several cases, a flexible nitronate-bis(oxy)iminium ion (as an ion pair with triflate as counterion) equlibrium was found, and its thermodynamic parameters were determined. Elevation of temperature or dilution shifts this equilibrium toward the reactants. Activation parameters for the C,C-coupling reaction of silylated bis(oxy)iminium ions with a series of reference nucleophiles were determined. Estimated electrophilicity of bis(oxy)iminium ions allows one to count on C,C-coupling when partner nucleophilicity is N > 4.     

Gold-Catalyzed Cyclisation by 1,4-Dioxidation

Amide-substituted diynes were cyclized in the presence of a cationic gold catalyst and an external nucleophile leading to 1-indenones and 1-iminoindenones. The electron-donating features of the nitrogen atom enable the formation of a reactive ketene iminium ion, which can be trapped by either diphenyl sulfoxide or anthranil as nucleophiles in a subsequent oxidation step, providing substituted inden-1-on-3-carboxamides.     

Mechanistic studies on the catalytic asymmetric Mannich-type reaction with dihydroisoquinolines and development of oxidative Mannich-type reactions starting from tetrahydroisoquinolines

Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that an N,O-acetal was generated in situ by the reaction of DHIQ with (Boc)2O, and cooperative action of the Pd(II) complex as an acid-base catalyst allowed the formation of a chiral Pd enolate and a reactive iminium ion via alpha-fragmentation. The iminium ion was also accessible via oxidation with DDQ as an oxidant, and a catalytic asymmetric oxidative Mannich-type reaction was achieved with tetrahydroisoquinolines (THIQs) as starting materials. This oxidation protocol was applicable to N-acryloyl-protected THIQs, allowing the efficient synthesis of optically active tetrahydrobenzo[a]quinolizidine derivatives via intramolecular Michael reaction.     

Bidentate NHC-based chiral ligands for efficient Cu-catalyzed enantioselective allylic alkylations: structure and activity of an air-stable chiral Cu complex

Cu-catalyzed addition of alkylzinc reagents to a range of allylic phosphates is promoted efficiently and with high enantioselectivity to afford tertiary as well as quaternary carbon centers (up to 98% ee). Reactions proceed to completion with 0.5-5 mol % catalyst loading and are best promoted by commercially available CuCl2.2H2O. The X-ray structure of the chiral NHC-Ag(I) complex used in the study as well as that of a catalytically active NHC-Cu(II) complex are also reported; both complexes are air-stable and are formed in >/=95% isolated yield. The isolated Cu complex, which can be handled in air, is catalytically active. The present report provides the first precedent for efficient Cu-catalyzed allylic alkylations with chiral NHC ligands.     

Organocatalytic Enantioselective Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes.     

Novel tetrahydroisoquinoline based organocatalysts for asymmetric Diels–Alder reactions: insight into the catalytic mode using ROESY NMR and DFT studies

For the first time an organocatalyst bearing a secondary nitrogen within a cyclohexane ring has been evaluated in the asymmetric Diels–Alder reaction. This organocatalyst is also the first of its kind based on a (1R,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline backbone. These catalysts were tested over a range of dienes and dienophiles and displayed promising chemical conversions of up to 100% with up to 64% ee with triflic acid as the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy were used to determine the structure of the intermediate iminium ion formed between the most efficient catalyst and cinnamaldehyde. The reaction profile for each of the four possibilities in this reaction were calculated and it was found that the iminium intermediate leading to the major product is higher in energy but kinetically preferred. The activation energies of all possible reaction paths were calculated and the results correlated with the observed products. These experiments revealed that the presence of both (E)- and (Z)-isomers of the cinnamaldehyde were contributing factors for the low enantioselectivity of the reaction products.     

Synthesis of γ-amino alcohols from aldehydes, enamines, and trichlorosilane using Lewis base catalysts

The reaction of aldehydes, enamines, and trichlorosilane in the presence of a Lewis base catalyst, particularly N-methylpyrrolidinone and DMF, affords γ-amino alcohols with a high diastereoselectivity. The method consists of C-C bond formation between an aldehyde and an enamine, and a subsequent intramolecular reduction of the resulting iminium ion intermediate. In most cases, one diastereomer is exclusively generated, and we propose a transition state model for the intramolecular reduction of the iminium ion intermediate. Enamines, prepared beforehand from the corresponding ketone and amine, can be used in the reaction without purification. Furthermore, enantioselective catalysis using a chiral Lewis base catalyst is possible, although the enantioselectivity is modest. The current tandem method offers the first, concise synthetic method of γ-amino alcohols from aldehydes and enamines.     

Reversal of the Stereochemical Course of 1‐Methyl‐1H‐indole Addition to Cinnamaldehyde with cis‐5‐Benzyl‐(2‐fluoromethyl)‐2,3‐dimethylimidazolidin‐4‐ones as Catalysts – a Puzzling ‘Fluorine Effect’

Replacement of the cis‐Me group by CH₂F in the imidazolidinone organocatalyst specified in the title (so‐called McMillan generation‐I catalyst) leads to reversal of the product configuration in the title reaction. The topicity reversal in the nucleophilic addition step must arise either from cis‐addition with respect to the benzylic substituent of an (E)‐iminium ion intermediate or from trans‐addition to the corresponding (Z)‐iminium ion. Mechanistic investigations have not provided evidence for either one of these two possibilities, so far.     

Nucleophilic addition to iminium ethers in the preparation of functionalized N-alkyl heterocycles

Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.     

Regioselective and Enantioselective Synthesis of β‐Indolyl Cyclopentenamides by Chiral Anion Catalysis

The regioselective and enantioselective synthesis of β‐indolyl cyclopentenamides, a versatile chiral building block, by asymmetric addition of indoles to α,β‐unsaturated iminium intermediates has been achieved through chiral anion catalysis. Key to the success of this methodology is the generation of a chiral anion‐paired ketone‐type α,β‐unsaturated iminium intermediate from α‐hydroxy enamides. Preliminary mechanistic studies and DFT calculations are consistent with a mechanism involving multiple, concurrent pathways for isomerization of the initially formed azaallylcation into the key α,β‐unsaturated iminium intermediate, all mediated by the phosphoric acid catalyst.