New Carbohydrate‐Based Phosphite‐Oxazoline Ligands as Highly Versatile Ligands for Palladium‐Catalyzed Allylic Substitution Reactions

We have designed and synthesized a new family of readily available phosphite‐oxazoline ligands for Pd‐catalyzed asymmetric allylic substitution reactions. These ligands can be tuned in two regions to explore their effect on catalytic performance. By carefully selecting the ligand components, we obtained high enantioselectivities in the Pd‐catalyzed allylic substitution in substrates with different steric properties     

Kinetics of Bis-Allylic Hydroperoxide Synthesis in the Iron-Containing Lipoxygenase 2 from Cyanothece and the Effects of Manganese Substitution

Lipoxygenases (LOX) catalyze the regio‐ and stereospecific insertion of dioxygen into polyunsaturated fatty acids. While the catalytic metal of LOX is typically a non‐heme iron, some fungal LOX contain manganese as catalytic metal (MnLOX). In general, LOX insert dioxygen at C9 or C13 of linoleic acid leading to the formation of conjugated hydroperoxides. MnLOX (EC 1.13.11.45), however, catalyze the oxygen insertion also at C11, resulting in bis‐allylic hydroperoxides. Interestingly, the iron‐containing CspLOX2 (EC 1.13.11.B6) from Cyanothece PCC8801 also produces bis‐allylic hydroperoxides. What role the catalytic metal plays and how this unusual reaction is catalyzed by either MnLOX or CspLOX2 is not understood. Our findings suggest that only iron is the catalytically active metal in CspLOX2. The enzyme loses its catalytic activity almost completely when iron is substituted with manganese, suggesting that the catalytic metal is not interchangeable. Using kinetic and spectroscopic approaches, we further found that first a mixture of bis‐allylic and conjugated hydroperoxy products is formed. This is followed by the isomerization of the bis‐allylic product to conjugated products at a slower rate. These results suggest that MnLOX and CspLOX2 share a very similar reaction mechanism and that LOX with a Fe or Mn cofactor have the potential to form bis‐allylic products. Therefore, steric factors are probably responsible for this unusual specificity. As CspLOX2 is the LOX with the highest proportion of the bis‐allylic product known so far, it will be an ideal candidate for further structural analysis to understand the molecular basis of the formation of bis‐allylic hydroperoxides.     

Palladacycle‐Catalyzed Tandem Allylic Amination/Allylation Protocol for One‐Pot Synthesis of 2‐Allylanilines from Allylic Alcohols

An efficient methodology involving the predominant formation of C C bonds is described for the first direct synthesis of 2‐allylanilines from allylic alcohols via a one‐pot tandem allylic amination/allylation protocol catalyzed by a palladacycle under mild conditions without the requirement for additional activators.     

Tuning of Regioselectivity in Inorganic Iodide‐Catalyzed Alkylation of 2‐Methoxyfurans via Electronic and Steric Effects

In the presence of inorganic iodide, the methoxy C O bond in 2‐methoxyfurans may be cleaved to afford the corresponding lactonic anion. Due to the presence of an electron‐withdrawing group at the 3‐position, the alkylation with normal organic iodides occurred at the 3‐position highly regioselectively. However, when electron‐deficient allylic iodides with an electron‐withdrawing group at the 2‐position were used the 5‐alkylation products were formed as the major products with sodium iodide as the catalyst. With magnesium iodide as the catalyst, the 5‐allylation occurred highly regioselectively. As a whole, the 3‐ vs. 5‐alkylation selectivity may be determined by the relative steric hindrance at the 3‐ and 5‐positions and the electronic effect of the allylic iodides. A rationale was proposed.     

Pd-catalyzed allylic amination in supercritical carbon dioxide: Synthesis of carborane-containing terpenoids

Pd-catalyzed amination of allylic carbonates with N-(ortho-carboran-3-yl)-N-methylamine was carried out in supercritical CO₂. It has been demonstrated that complete conversion of allylic carbonates to the corresponding carborane amines with excellent regioselectivity may be achieved in scCO₂ (170 atm, 60 °C) using NaHCO₃ as the acceptor base. The reaction offers a selective method for the preparation of allylic amines and provides a useful approach to new terpenoids.     

Modular Furanoside Diphosphite Ligands for Pd‐Catalyzed Asymmetric Allylic Substitution Reactions: Scope and Limitations

We have synthesized a library of furanoside diphosphite ligands for the Pd‐catalyzed allylic substitution reactions of acyclic and cyclic allylic esters. The library has been designed to rapidly screen the ligands to uncover their important structural features and to determine the scope of diphosphite ligands in these catalytic reactions. After the systematic variation of the sugar backbone, the substituent at C‐5 and the phosphite moieties, the diphosphite ligand 4c was found to be optimal in the Pd‐catalyzed asymmetric allylic substitution of hindered ( S1 ) and unhindered ( S2 – S5 ) substrates, yielding high activities [TOFs up to >3000 mol×(mol×h)⁻¹] and enantioselectivities (ees up to 99%). In addition, the screening of the library enabled us to find other suitable ligands for hindered disubstituted linear substrate S1 (ligands 1b – d, g and 4b, d, g ) and for unhindered cyclic substrates S3 – S5 ( ligands 6c and 7c ).     

A General Approach to the Synthesis of β2‐Amino Acid Derivatives via Highly Efficient Catalytic Asymmetric Hydrogenation of α‐Aminomethylacrylates

A new strategy was developed for the synthesis of a valuable class of α‐aminomethylacrylates via the Baylis–Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′‐type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et‐Duphos) catalysts provided the corresponding β²‐amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)‐configurated substrates was studied for the synthesis of β²‐amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²‐amino acids and their derivatives under mild reaction conditions.     

Direct Copper‐Free Domino Conjugate Addition‐Cycloallylation using Organozinc Reagents

The Direct Approach: Enones possessing appendant allylic carbonates react directly with diorganozinc reagents in the presence of zinc diiodide [ZnI₂] to provide 5‐ and 6‐membered ring products of tandem or domino conjugate addition‐cycloallylation in good to excellent yield. In a related copper‐free transformation, allylic carbonates are found to engage in direct allylic substitution with diorganozinc reagents.     

Modular Furanoside Phosphite‐Phosphoroamidites,a Readily Available Ligand Library for Asymmetric Palladium‐Catalyzed Allylic Substitution Reactions. Origin of Enantioselectivity

A library of furanoside phosphite‐phosphoroamidite ligands has been synthesized and screened in the palladium‐catalyzed allylic substitution reactions of several substrate types. These series of ligands can be prepared efficiently from easily accessible D ‐xylose and D ‐glucose. Their modular nature enables the position of the phosphoroamidite group, configuration of C‐3 of the furanoside backbone and the substituents/configurations in the biaryl phosphite/phosphoroamidite moieties to be easily and systematically varied. By carefully selecting the ligand components, therefore, high regio‐ and enantioselectivities (ees up to 98%) and good activities have been achieved in a broad range of mono‐ and disubstituted hindered and unhindered linear and cyclic substrates. The NMR studies on the palladium‐π‐allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity. They also indicate that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphoroamidite moiety.     

An Engineered Cholesterol Oxidase Catalyses Enantioselective Oxidation of Non-steroidal Secondary Alcohols

The enantioselective oxidation of 2° alcohols to ketones is an important reaction in synthetic chemistry, especially if it can be achieved using O₂-driven alcohol oxidases under mild reaction conditions. However to date, oxidation of secondary alcohols using alcohol oxidases has focused on activated benzylic or allylic substrates, with unactivated secondary alcohols showing poor activity. Here we show that cholesterol oxidase (EC 1.1.3.6) could be engineered for activity towards a range of aliphatic, cyclic, acyclic, allylic and benzylic secondary alcohols. Additionally, since the variants demonstrated high (S)-selectivity, deracemisation reactions were performed in the presence of ammonia borane to obtain enantiopure (R)-alcohols.     

Reactions of Ring C in Glycyrrhetic Acid Derivatives

The chemistry of the relatively unreactive glycyrrhetic acid (1) ring C was investigated. The enone group in this ring was reduced by diborane to allylic alcohols (6, 7), which can be readily converted into the corresponding homoannular dienes (2, 5). These dienes were also prepared by NaBH₄ reduction of the enone group. The epoxidation of the diene 2 leads to the mono-( 12 ) and di-( 14 ) epoxides. A new ring C enone system ( 13 ) was also obtained. Treatment of the two different tosylhydrazones derivatives ( 16, 20 ) with methyllithium gave the conjugated methylene compounds ( 17, 21 ). The NMR spectrum of the latter compound was also studied with a shift reagent — Eu(FOD). The mass spectra of the homoannular dienes ( 2, 5 ), allylic alcohols ( 6, 7 ) and 11-methylene compounds ( 17, 21 ) were studied and some new types of fragmentation were suggested.     

Molybdenum-catalyzed asymmetric allylic alkylations

The highly regio- and enantioselective molybdenum-catalyzed allylic alkylation reaction has become a powerful synthetic tool during the past few years. This Account describes the achievements gained so far in the area, with special attention directed to the different chiral ligands that have been used for inducing chirality in the products, the range of allylic substrates and nucleophiles employed, mechanistic studies, and applications of the reaction in asymmetric syntheses.     

The reaction of low levels of nitrogen dioxide with methyl linoleate in the presence and absence of oxygen

The reaction of methyl linoleate with low levels of nitrogen dioxide in a carrier gas, such as helium or air, at nitrogen dioxide concentrations ranging from 2 to 228 ppm was studied and the products formed were monitored. In both aerobic and anaerobic conditions, low concentrations of nitrogen dioxide reacted with methyl linoleate predominately to form allylic products. When a 1∶1 mixture of methyl palmitate/methyl linoleate was layered over an aqueous buffer and a nitrogen dioxide stream was passed from underneath, so that the stream passed through the aqueous layer before contacting the organic layer, allylic products again predominated. In the absence of air, the allylic products consisted of allylic nitro and nitrite derivatives of linoleate, whereas in the presence of air, allylic hydroperoxides were the principal products. The findings suggest that fatty acids with doubly allylic hydrogen atoms react preferentially by a hydrogen atom abstraction reaction rather than by the addition of nitrogen dioxide to a double bond.     

Iridium‐Catalyzed Enantioselective Allylic Alkylation using Chiral Phosphoramidite Ligand Bearing an Amide Moiety

New chiral phosphoramidites with an amide moiety were used for iridium‐catalyzed asymmetric allylic alkylation reactions. The best results were obtained with a ligand bearing an oxazolidinone moiety. The reaction of cinnamyl acetate with diethyl sodiomalonate without the use of lithium chloride gave the branched product with 94% ee.     

Cycloaddition Reactions of Substituted Allenes with Triplet Excited Aromatic Thiones: Product Formation and Reaction Mechanism

The reactivity of substituted allenes H₂CCC(R)X towards three triplet aromatic thiones has been investigated. Product analysis reveal the formation of two (2+2)-cycloaddition products the thietanes 3, 4 (E + Z) and occasionally of one (4+2)-cycloaddition product, thiopyran derivative (Z)-5, generally in high overall yields. Steady state measurements show that electron donating substituents in the allenic system enhance the overall reaction rate. There is little effect of solvent polarity on the reaction rate. The correlation between the relative reaction rates and the first adiabatic ionization energy of the substituted allenes is in accordance with the formation of an exciplex between the excited thione and that π-bond of the allenic system which is conjugated with the substituent X. From this exciplex two isomeric allylic 1,4-biradicals (Z)-8 and (E)-8 are probably formed. After inter-system crossing, ring closure gives the thietanes 3 , (E)- 4 , (Z)- 4 and/or thiopyran derivative (Z)- 5 . The ratio in which 3 , (E)- 4 , (Z)- 4 and (Z)- 5 are formed is explained by considering electronic and steric factors in the proposed reaction mechanism. Experiments with an optically active allene (+)-PhC(H)CC(H)Me support the intermediacy of a non-chiral relatively stable allylic 1,4-biradical. At infinite allene concentration the quantum yield approaches 1, indicating no energy loss during the reaction. Thus no measurable disproportionation of the allylic biradicals (Z)- 8 and (E)- 8 occurs.     

Iron‐Catalyzed Nitrogen‐Directed Coupling of Arene and Aryl Bromides Mediated by Metallic Magnesium

2‐Arylpyridines, 2‐alkenylpyridine, and aromatic imines can be coupled with aryl bromides in the presence of an iron catalyst, metallic magnesium, a diamine ligand and an organic dihalide oxidant at 0 °C. The use of a 1:1 mixture of tetrahydrofuran and 1,4‐dioxane is essential for this C H bond activation reaction. The reaction has wider scope of the substrate compared with the reaction using a separately prepared Grignard reagent, and proceeds with lower catalyst loading (2.5 mol%).     

Thermisch initiierte Addition von Alkanen an Alkene. V. Addition von Cyclohexan an Oct-1-en in einer freien Radikalkettenreaktion unter überkritischen Bedingungen

Thermal Addition of Alkanes to Alkenes. V. Addition of Cyclohexane to 1-Octene in a Free Radical Chain Reaction at Supercritical Fluid Conditions Alkanes can be added to alkenes in a thermally initiated free radical chain reaction (“ane reaction”). Kinetic and mechanistic studies on the addition of cyclohexane ( 1 ) to 1-octene ( 2 ) (molar ratio = 100:1) at 330−450°C and pressures of up to 300 bar have been performed in a high pressure - high temperature flow apparatus (“HP-HT” apparatus). The free radical chain is initiated by comproportionation of 1 and 2 to give alkyl radicals 6 and 7 . Addition of cyclohexyl radical 6 to alkene 2 and competing abstraction of an allylic hydrogen atom from 2 give radicals 7a and 8 , respectively. Subsequent stabilization of the radicals 7a and 8 by hydrogen abstraction from 1 yields the addition product cyclohexyloctane ( 3 ) and isomerized octenes ( 4 ), respectively. The relative rate of addition and isomerization can be controlled by pressure and temperature. The regioselectivity of the addition reaction was also measured.     

Polymer Cocktail: A Multitask Supported Ionic Liquid‐Like Species to Facilitate Multiple and Consecutive C?C Coupling Reactions

Polymer‐supported ionic liquid‐like species (SILLPs) with different functionalities have been combined to obtain new catalytic systems (polymer cocktail) with improved properties towards their application for C C coupling reactions. The SILLPs have been synthesized in a simple way and combined to play different functions in the reaction medium. Those roles involve simultaneously (or consecutively) their actuation as supported reagents, precatalysts and scavengers of undesired reaction side‐products. The system has been tested by employing three different C C coupling reactions for 8 consecutive cycles. Moreover, different aryl bromides and iodides have proved to be efficiently transformed by the catalytic cocktail. Finally, the Heck reaction has been conducted in continuous‐flow conditions using a packed bed of this polymer cocktail and employing supercritical carbon dioxide (scCO₂) as a solvent, which cannot be carried out with the use of soluble bases as this would lead to the clogging of the reactor. Finally, the SILLPs cocktail enables one to combine different reaction steps and purification in a single vessel, which represents a significant improvement in terms of process intensification and green chemistry. This is particularly true in the case of the use of scCO₂ as this allows the direct production of crude materials not contaminated either by salts or by solvents.     

Stereochemical Control in Palladium-catalyzed Allylic Etherification

Two alternative approaches for increasing the stereospecificity of Pd(0)-catalyzed allylic etherification are presented, both of which also suppress product isomerization and elimination. One of them involves addition of chlorotrimethylsilane to a benzene reaction mixture. In the model reaction studied, it increases the ratio of the two stereoisomeric products, arising from either retention or inversion of configuration at the allylic carbon, from 3:1 to 9:1, respectively. The second approach involves the employment of both donor- and acceptor-chelating ligands. Essentially 100% stereospecificity (retention of configuration) was achieved when the reaction was carried out in benzene at 60°C in the presence of Pd₂(dba)₃ and bis-1,2-diphenylphosphinoethane.     

二价钯催化烯丙位重排反应的研究

近年来二价钯催化反应已成为研究热点,其催化的烯丙位重排反应则研究较少。本文深入研究了烯丙醇与对甲苯磺酰异氰酸酯反应制得的对甲苯磺酰胺基甲酸烯丙酯在二价钯催化下的重排反应,并讨论及优化了反应条件。试验表明,底物结构越复杂反应条件越苛刻;催化剂用量影响不大;卤盐必需且过量;碱对反应无影响;溶剂据温度要求的提高可逐级选用四氢呋喃、1,4-二氧六环及N,N-二甲基甲酰胺;反应温度随底物结构复杂程度逐渐升高。