Chiral Phosphoric Acid Dual‐Function Catalysis: Asymmetric Allylation with α‐Vinyl Allylboron Reagents

We report a dual function asymmetric catalysis by a chiral phosphoric acid catalyst that controls both enantioselective addition of an achiral α‐vinyl allylboronate to aldehydes and pseudo‐axial orientation of the α‐vinyl group in the transition state. The reaction produces dienyl homoallylic alcohols with high Z‐selectivities and enantioselectivities. Computational studies revealed that minimization of steric interactions between the alkyl groups of the diol on boron and the chiral phosphoric acid catalyst influence the orientation of α‐vinyl substituent of the allylboronate reagent to occupy a pseudo‐axial position in the transition state.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

Atom‐Efficient Gold(I)‐Chloride‐Catalyzed Synthesis of α‐Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation

Gold(I)‐chloride‐catalyzed synthesis of α‐sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated α‐sulfenylated aldehydes and ketones in 60–97 % yield. Secondary aliphatic propargylic alcohols generated α‐sulfenylated ketones in yields of 47–71 %. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3‐position, and that the hydride from the alcohol was transferred to the 2‐position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2‐position of propargylic alcohol was determined by a low‐energy, five‐membered cyclic protodeauration transition state instead of the strained, four‐membered cyclic transition state found for attack at the 3‐position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2‐hydride shift, generating the final product of the reaction.     

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N‐Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N‐carbamoyl imines has been developed. Both α‐imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N‐tert‐butoxycarbonyl (Boc) or N‐carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N‐carbamate‐protected imines are generated in situ from stable and easily handled α‐amido sulfones.     

The Kabachnik–Fields and Pudovik Reactions on the Basis of E,Z‐Citral and Its Imines and (R,S)‐Citronellal

The Kabachnik–Fields reaction of E,Z‐citral with diethyl phosphite in the presence of isobutylamine has been found to form α‐aminophosphonates. The Pudovik reactions of diethyl phosphite with prenyl imines prepared on the basis of E,Z‐citral with isobutylamine also allowed us to obtain the same α‐aminophosphonates. We have managed to synthesize α‐aminophosphonates by the reaction of O,O‐dialkyl trimethylsilyl phosphites with prenyl imines in the presence of water or diethylamine. α‐Aminophosphonates were also synthesized by the reaction of diethyl phosphite with (R,S)‐citronellal in the presence of alkylamines. α‐Aminophosphonates obtained showed bacteriostatic activity against Staphylococcus aureus and Bacillus cereus. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:36–42, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21060     

A 4‐Hydroxypyrrolidine‐Catalyzed Mannich Reaction of Aldehydes: Control of anti‐Selectivity by Hydrogen Bonding Assisted by Brønsted Acids

An anti‐selective Mannich reaction of aldehydes with N‐sulfonyl imines has been developed by using a 4‐hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the α‐substituent of the pyrrolidine, the 4‐hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde‐derived imines, which have rarely been employed in previously reported enamine‐based anti‐Mannich reactions. Additionally, both N‐tosyl and N‐nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N‐deprotection the corresponding β‐amino acids and β‐amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine‐based reactions.     

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α‐methylbenzyl amine for cis‐aziridines from α‐diazo esters and for trans‐aziridines from α‐diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis‐aziridines involved the (R)‐amine with the (S)‐ligand, but curiously, for trans‐aziridines the matched case involved the (R)‐amine with the (R)‐ligand for imines derived from benzaldehyde and n‐butanal, and the (R)‐amine with the (S)‐ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.     

Access to α‐Arylglycines by Umpolung Carboxylation of Aromatic Imines with Carbon Dioxide

A straightforward and transition‐metal‐free approach for the efficient synthesis of α‐arylglycine derivatives from aromatic imines and carbon dioxide was enabled by an umpolung carboxylation reaction. Various substituted diphenylmethimines underwent the carboxylation smoothly with carbon dioxide in the presence of potassium tert‐butoxide and 18‐crown‐6 to give the corresponding carboxylated products in good to high yields. Besides the enhancement of the solubility of potassium tert‐butoxide in THF, 18‐crown‐6 also plays key roles in suppressing the reverse protonation or 1, 3‐proton shift isomerization as well as by stabilizing the carboxylated intermediate.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C?C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.     

Myoglobin‐Catalyzed Olefination of Aldehydes

The olefination of aldehydes constitutes a most valuable and widely adopted strategy for constructing carbon–carbon double bonds in organic chemistry. While various synthetic methods have been made available for this purpose, no biocatalysts are known to mediate this transformation. Reported herein is that engineered myoglobin variants can catalyze the olefination of aldehydes in the presence of α‐diazoesters with high catalytic efficiency (up to 4,900 turnovers) and excellent E diastereoselectivity (92–99.9 % de). This transformation could be applied to the olefination of a variety of substituted benzaldehydes and heteroaromatic aldehydes, also in combination with different alkyl α‐diazoacetate reagents. This work provides a first example of biocatalytic aldehyde olefination and extends the spectrum of synthetically valuable chemical transformations accessible using metalloprotein‐based catalysts.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C−C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.     

Asymmetric [3+2] Annulation Approach to 3‐Pyrrolines: Concise Total Syntheses of (−)‐Supinidine, (−)‐Isoretronecanol,and (+)‐Elacomine

An asymmetric [3+2] annulation reaction to form 3‐pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4‐bromocrotonate is deprotonated and trapped with Ellman imines selectively at the α‐position to yield enantiopure 3‐pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (?)‐supinidine, (?)‐isoretronecanol, and (+)‐elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5‐dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza‐Darzens reaction can be realized.     

Asymmetric [3+2] Annulation Approach to 3‐Pyrrolines: Concise Total Syntheses of (−)‐Supinidine, (−)‐Isoretronecanol,and (+)‐Elacomine

An asymmetric [3+2] annulation reaction to form 3‐pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4‐bromocrotonate is deprotonated and trapped with Ellman imines selectively at the α‐position to yield enantiopure 3‐pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (−)‐supinidine, (−)‐isoretronecanol, and (+)‐elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5‐dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza‐Darzens reaction can be realized.     

Thermally Induced Denitrogenative Annulation for the Synthesis of Dihydroquinolinimines and Chroman‐4‐imines

A rapid growth in synthetic methods for the preparation of diverse organic molecules using N‐sulfonyl‐1,2,3‐triazoles is of great interest in organic synthesis. Transition metals are generally used to activate the α‐imino diazo intermediates. Metal‐free methods have not been studied in detail, but can be a good complement to transition metal catalysis in the mild reaction conditions. We herein report a novel method for the preparation of 2,3‐dihydroquinolin‐4‐imine and chroman‐4‐imine analogs from their corresponding N‐sulfonyl‐1,2,3‐triazoles in the absence of metal catalysts. To achieve intramolecular annulation, the introduction of an electron‐donating group is required at the meta position of N‐sulfonyl‐1,2,3‐triazole methyl anilines. The inclusion of tailored substituents on the aniline moieties and nitrogen atoms enhances the nucleophilicity of the phenyl π‐electrons, thus allowing them to undergo a Friedel–Crafts‐type reaction with the highly electrophilic ketenimines. This metal‐free method was carefully optimized to generate a variety of dihydroquinolin‐4‐imines and chroman‐4‐imines in moderate‐to‐good yields.     

Destruction and Construction: Application of Dearomatization Strategy in Aromatic Carbon–Nitrogen Bond Functionalization

The formation of carbon–carbon bonds through the functionalization of aromatic carbon–nitrogen bonds is a highly attractive synthetic strategy in the synthesis of aromatic molecules. In this paper, we report a novel aromatic carbon–nitrogen bond functionalization reaction by using a simple dearomatization strategy. Through this process para‐substituted anilines serve as a potential aryl source in the construction of a range of functionalized aromatic molecules, such as quaternary carbon centers, α‐keto esters, and aldehydes.     

A New Method for the Synthesis of Symmetrical Disubstituted Pyrazines

Through the self‐condensation of α‐amino aldehydes, the synthesis of symmetrical disubstituted pyrazines was achieved in a three‐step one‐pot reaction. The α‐amino aldehydes were easily obtained by treating methyl esters of natural α‐amino acids with diisobutylaluminium hydride.     

One‐Pot Synthesis of N‐Substituted β‐Amino Alcohols from Aldehydes and Isocyanides

A practical two‐stage one‐pot synthesis of N‐substituted β‐amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon–carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α‐halo ketones, β‐halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.     

Ruthenium‐catalyzed carbonylative cycloaddition reactions involving carbonyl and imino groups as assembling units

This paper describes carbonylative cycloaddition reactions catalyzed by Ru₃(CO)₁₂. Ru₃(CO)₁₂ was found to catalyze an intramolecular Pauson–Khand‐type reaction. Carbonylative cycloaddition reactions involving a carbonyl group in aldehydes, ketones, and esters as a two‐atom assembling unit were also achieved in the presence of Ru₃(CO)₁₂ as the catalyst. The reaction of 5‐hexyn‐1‐al and 6‐heptyn‐1‐al derivatives with CO in the presence of Ru₃(CO)₁₂ resulted in cyclocarbonylation from which bicyclic α, β‐unsaturated lactones were obtained. Intermolecular [2 + 2 + 1] carbonylative cycloaddition of alkenes, ketones, and CO was also catalyzed by Ru₃(CO)₁₂ as the catalyst to give saturated γ‐lactone derivatives. Simple ketones were not applicable, but ketones having a C?O or C?N group at the α‐position served as a good substrate. These reactions could be extended to carbonylative cycloaddition of the corresponding imines leading to γ‐butyrolactam derivatives. The [4 + 1] carbonylative addition of α,β‐unsaturated imines leading to unsaturated γ‐lactams was achieved with Ru₃(CO)₁₂. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 201–212; 2008: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20149     

Transition metal-catalyzed cyclocarbonylation in organic synthesis

Cyclocarbonylation reactions proceed mainly by the coupling reactions of carbonylation components with cyclization components having an unsaturated π-electron bond, in the presence of transition metal compounds. The representative reactions are cyclocarbonylation of alkynes by carbon monoxide such as Pauson–Khand reactions, hetero Pauson–Khand reactions, cyclocarbonylation of alkynyl alcohols, cyclocarbonylation of alkynyl amines, cyclocarbonylative alkyne–alkyne coupling reactions, and reductive cyclocarbonylation of alkynes. The other reactions are cyclocarbonylation of alkenes by carbon monoxide such as alkene–alkene coupling reactions, cyclocarbonylation with aldehydes, ketones, amines or imines, cyclocarbonylation of alkenyl alcohols. Carbonylation via cyclometalation, carbonylative ring expansion reactions, cyclocarbonylation by aldehydes, carboxylic acids or carboxylic acid esters are also cyclocarbonylation reactions. These reactions are conveniently used for organic syntheses, especially, for the syntheses of pharmaceutical intermediates.     

Umpolung Reactivity of Aldehydes toward Carbon Dioxide

Carbon dioxide is an intrinsically stable molecule. Therefore, its activation requires extra energy input in the form of reactive reagents and/or activated catalysts and, often, harsh reaction conditions. Reported here is a direct carboxylation reaction of aromatic aldehydes with carbon dioxide to afford α‐keto acids as added‐value products. In situ generation of a reactive cyanohydrin was the key to the successful carboxylation reaction under operationally mild reaction conditions (25–40 °C, 1 atm CO₂). The resulting α‐keto acids served as a platform for α‐amino acid synthesis by reductive amination reactions, illustrating the chemical synthesis of essential bioactive molecules from carbon dioxide.