Wittig–Horner Approach for the Synthesis of Tamoxifen

A stereoselective synthesis of Z‐tamoxifen, a tetra‐substituted alkene with antiestrogenic activity, is described. The Wittig–Horner reaction has been employed as the key step to establish the olefin stereochemistry.     

Synthesis of Some New Triphenylphosphanylidenes,Alkylphosphonates, and Heterocycles of Pyrazole Derivatives and Their Antimicrobial Activity

Abstract

The reaction of 5(4H)-pyrazolone with phosphorus ylides afforded new triphenylphosphanylidene alkanone derivatives. Moreover, its benzylidene derivative reacted with Wittig–Horner reagents to give the corresponding dialkoxyphosphoryl, alkyl phosphonate, and heterocyclic products. Treatment of pyrazole-4-carbaldehyde with Wittig–Horner reagents and trialkyl phosphites gave the respective alkyl phosphonate adducts. Mechanisms accounting for the formation of the new products are discussed. The biological activity of some of the newly synthesized compounds was also examined.     

A Concise Total Synthesis of Diospongins A and B

The total synthesis of the diarylheptanoids (?)‐diospongin A ( 1 ) and B ( 2 ) was achieved stereoselectively via the δ‐lactone intermediate 6 . The key reactions involved are a stereoselective reduction of β‐keto ester and the Horner–Wadsworth–Emmons and intramolecular oxy‐Michael reactions.     

Vinyl Triphenylphosphonium Salt–Mediated Synthesis of Functionalized Alkenes

Deoxybenzoin undergoes a smooth reaction with acetylenic esters in the presence of triphenylphosphine to produce phosphorus ylides. Only the tert-butyl phosphorus ylide undergoes an intramolecular Wittig reaction to produce highly strained cyclobutenes in boiling toluene, which spontaneously undergoes ring-opening reactions to produce highly functionalized 1,3-dienes. The unstable ylides undergo a 1,2-proton transfer and the loss of PPh₃ to produce functionalized alkenes.     

Catalytic Reactions with Hydrosilane and Carbon Monoxide [New synthetic methods (30)]

The reagent hydrosilane/carbon monoxide opens up new possibilities for organic synthesis. Four cases will be discussed: 1. The reaction of olefins with hydrosilane (trialkylsilane) and carbon monoxide in the presence of Co, Ru, and Rh complexes leads to enol silyl ethers having one more carbon atom that the olefins. 2. Cyclic ethers underto carbonylative ring opening to ω-siloxyaldehydes when reacted with hydrosilane and carbon monoxide in the presence of Co₂(CO)₈ as catalysts 3. Aldehydes are catalytically converted into the next higher α-siloxyaldehydes or 1,2-bis(siloxy)alkenes depending on the reaction conditions used. 4. The reaction of alkyl acetates proceeds in various ways depending on the nature of the alkyl group; enol silyl ethers or alkenes are optained.–Mechanisms of these Co₂(CO)₈ catalyzed reactions using hydrosilane and carbon monoxide are discussed in which HCo(CO)_n or R₃SiCo(CO)_nL function as catalytically active agents. With these species there are four types of catalytic cycles.–The synthetic possibilities of these catalytic reactions have still not been fully explored.     

Scope and Limitation of the Reactions of 3-Imino Derivatives of Pentane-2,4-Diones with Organophosphorus Reagents

Abstract

3-(Hydroxyimino)pentane-2,4-dione reacts with phosphonium ylides, Wittig–Horner reagents, trialkyl phosphites, and Lawesson's reagents to give the olefinic and cyclic products, the phosphonate adducts, the dialkyl phosphate products, the phosphinodithioic acid, and 2,4-dithione products, respectively. Furthermore, the reaction of 3-(phenylimino)pentane-2,4-dione with Wittig, Wittig–Horner reagents and trialkyl phosphite resulted in the formation of 2,5-diendioate, diethoxy phosphoryl hexanoate and the phosphate products. Possible reaction mechanisms are considered and the structural assignments are based on analytical and spectroscopic results. The antibacterial and antifungal activities for some of the new compounds are also reported.     

Dithioacetals as an Entry to Titanium–Alkylidene Chemistry: A New and Efficient Carbonyl Olefination

Wittig, Horner–Wadsworth–Emmons , Julia–Lythgoe, Tebbe, Grubbs, and Petasis—when it comes to carbonyl olefinations, these names are familiar to all chemistry students. In the future, the name Takeda will probably have to be added to this list. His recent work on the formation of titanium–alkylidene species from dithioacetals has provided organic chemists with a remarkable method for carbonyl olefination that is generally applicable under neutral to Lewis acidic conditions.     

Synthesis and stereoselectivity of a new type of unsaturated phosphonates

A series of unsaturated phosphonates 2, 3, 4 with structures similar to that of abscisic acid (ABA) were synthesized by the Wittig‐Horner reactions of bisphosphonylmethane 1 with β‐substituted propenals, propargyl aldehydes or α,β‐unsaturated methyl ketones. Compounds 5 were prepared by the Michaelis‐Becker reactions of ω‐bromodienes 7 with sodium phosphites. Compounds 7 were obtained by the phase transfer Wittig reactions of ω‐bromobutylphosphonium salt 6 with β‐substituted propenals. The structures of all new compounds prepared were characterized by ¹H NMR, ³¹P NMR, IR spectra, and elemental analysis or MS. The stereochemistry of the Wittig reactions was studied. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:261–266, 2000     

Furanyl Alcohols as Alkylating Reagents in Friedel–Crafts Reaction of Arenes

Furanyl alcohols react with arenes by a variant of the Friedel–Crafts reaction to give benzyl furans with fairly satisfying yields. The reaction is mediated by Tf₂O and occurs with reduced times in the presence of Ph₃PO. Some prepared compounds exhibit a lignan‐like backbone.     

Phosphine‐Relayed Aldehyde‐Olefination and Aza‐Wittig Reaction with 2,2,2‐Trifluorodiazoethane

Phosphine‐relayed olefination and aza‐Wittig reactions of readily available aldehydes with 2,2,2‐trifluorodiazoethane (CF₃CHN₂) have been realized. This protocol enables the facile construction of a series of trifluoromethylated alkenes and hydrazones in good to high yield under mild conditions.     

Part I: The Development of the Catalytic Wittig Reaction

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1 . Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N‐diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di‐ and trisubstituted olefins in moderate‐to‐high yields (60–96 %) by using a precatalyst loading of 4–10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β‐unsaturated products was achieved through a phosphane‐mediated isomerization event. The CWR was applied to the synthesis of 54 , a known precursor to the anti‐Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition‐/heavy‐metal‐free catalytic olefination process, excluding proton‐catalyzed elimination reactions.     

The Wittig–Horner reaction for the synthesis of neratinib

The Wittig–Horner reaction is a classic method to get alkenes by reaction phosphonates with carbonyl compounds. In this study, it was used for the synthesis of the anticancer drug neratinib. In this method, ethyl diethoxyphosphinylacetate and dimethylaminoacetaldehyde diethylacetal, replacing (E)-4-(dimethylamino)but-2-enoyl acid hydrochloride and oxalyl chloride, were used to synthesize the 6-position side chain of neratinib.     

Synthesis and Rearrangement of P‐Nitroxyl‐Substituted PIII and PV Phosphanes: A Combined Experimental and Theoretical Case Study

Low‐temperature generation of P‐nitroxyl phosphane 2 (Ph₂POTEMP), which was obtained by the reaction of Ph₂PH ( 1 ) with two equivalents of TEMPO, is presented. Upon warming, phosphane 2 decomposed to give P‐nitroxyl phosphane P‐oxide 3 (Ph₂P(O)OTEMP) as one of the final products. This facile synthetic protocol also enabled access to P‐sulfide and P‐borane derivatives 7 and 13 , respectively, by using Ph₂P(S)H ( 6 ) or Ph₂P(BH₃)H ( 11 ) and TEMPO. Phosphane sulfide 7 revealed a rearrangement to phosphane oxide 8 (Ph₂P(O)STEMP) in CDCl₃ at ambient temperature, whereas in THF, thermal decomposition of sulfide 7 yielded salt 10 ([TEMP‐H₂][Ph₂P(S)O]). As well as EPR and detailed NMR kinetic studies, indepth theoretical studies provided an insight into the reaction pathways and spin‐density distributions of the reactive intermediates.     

Cyclic Ketones in Spiroannulation

Conversion of a cyclic carbonyl carbon into a quaternary carbon has been effected by a Wittig–Horner reaction with diethyl (N-benzyliden)aminomethylphosphonate and a subsequent alkylation with a protected vinyl ketone. The product was a substrate for spiroannulation after initial hydrolysis. The reaction sequence was carried out as a one-pot reaction.     

Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate,a synthetic approach to new conformationally constrained prolines

Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several phosphoranes and the Horner–Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their utility in the synthesis of β-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has provided proline–amino acid chimeras [combinations of proline with other α-amino acids, such as l-norvaline, l-norleucine, l-α-(3-phenylpropyl)glycine or l-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure form.     

The Mechanism and Stereochemistry of Wittig Reactions of Phosphonium Ylide-Anions

Abstract

Schmidbaur's group have extensively investigated¹ the coordination properties of phosphonium 1,3-ylide-anions (1) in organometallic chemistry and more recently Cristau² has reported the potential usefulness of these compounds in synthetic organic chemistry. There have been a few studies³ of specific phosphonium 1,1-ylide-anions (2), however their only use in the Wittig reaction appears to be that of (2a).⁴ We have set out to study the stereochemistry and mechanism of Wittig reactions of (1) and (2) and to carry out some preliminary investigations on the arsenic analogues (3).     

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

An efficient and concise synthesis of the biologically interesting (+)‐machaeriol B ( 2 ) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine ( 7 ) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C ( 3 ) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6 , the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.     

Bifunctional Heterogeneous Catalysis of Silica–Alumina‐Supported Tertiary Amines with Controlled Acid–Base Interactions for Efficient 1,4‐Addition Reactions

We report the first tunable bifunctional surface of silica–alumina‐supported tertiary amines (SA–NEt₂) active for catalytic 1,4‐addition reactions of nitroalkanes and thiols to electron‐deficient alkenes. The 1,4‐addition reaction of nitroalkanes to electron‐deficient alkenes is one of the most useful carbon–carbon bond‐forming reactions and applicable toward a wide range of organic syntheses. The reaction between nitroethane and methyl vinyl ketone scarcely proceeded with either SA or homogeneous amines, and a mixture of SA and amines showed very low catalytic activity. In addition, undesirable side reactions occurred in the case of a strong base like sodium ethoxide employed as a catalytic reagent. Only the present SA‐supported amine (SA–NEt₂) catalyst enabled selective formation of a double‐alkylated product without promotions of side reactions such as an intramolecular cyclization reaction. The heterogeneous SA–NEt₂ catalyst was easily recovered from the reaction mixture by simple filtration and reusable with retention of its catalytic activity and selectivity. Furthermore, the SA–NEt₂ catalyst system was applicable to the addition reaction of other nitroalkanes and thiols to various electron‐deficient alkenes. The solid‐state magic‐angle spinning (MAS) NMR spectroscopic analyses, including variable‐contact‐time ¹³C cross‐polarization (CP)/MAS NMR spectroscopy, revealed that acid–base interactions between surface acid sites and immobilized amines can be controlled by pretreatment of SA at different temperatures. The catalytic activities for these addition reactions were strongly affected by the surface acid–base interactions.     

Reactions of group IV organometallic compounds : XXVII. Some reactions of [(trimethylsilyl)imino]phosphorane

The reaction of [(trimethylsilyl)imino]methyldiphenylphosphorane: Ph₂MePNSiMe₃ (I) with several acid anhydrides or alkyl isocyanates took place by the simple cleavage of silicon-nitrogen bond. In contrast the interaction of (I) with phenyl isocyanate, isothiocyanate or carbon disulphide led to addition-elimination reactions of the Wittig type. Detailed investigation in the case of phenyl isocyanate indicated the usual elimination of Ph₂MePO is suppressed by the strong affinity of the trimethylsilyl group for anionic oxygen atom.     

Synthesis of E-homoallylic alcohols, γ-hydroxyketones,and cyclopropyl ketones from 3-diphenylphosphinoyl (Ph2PO) propanols by acyl transfer

Carboxyl transfer (O→C) on 3-Ph₂PO propyl esters (9) gives an intermediate (10) from which the Ph₂PO group may be removed by the Horner-Wittig reaction or by Ph₂PO transfer (C→O) to give the title compounds.