Z- and E-selective Horner–Wadsworth–Emmons reactions

In the present work, we determined and evaluated the stereochemical outcome of the Horner–Wadsworth–Emmons (HWE) reaction of 2-oxoalkylphosphonates with different ester functions (bis(2,2,2-trifluoroethyl), 2,2,2-trifluoroethyl methyl, dimethyl) and side chains (aliphatic, aromatic) with three different aldehydes (benzaldehyde, THP- and PPB-protected Corey aldehydes) under two reaction conditions. The “trans” protocol is generally used in the E-selective HWE reactions, while “cis” protocol promotes the Z-selectivity.     

First mechanosynthesis of piperlotines A,C, and derivatives through solvent-free Horner–Wadsworth–Emmons reaction

Piperlotines are natural products characterized by an α,β-unsaturated amide moiety. These compounds found wide applications in Medicinal Chemistry like antibacterials, cytotoxic agents, anticoagulants, among others. To date, diverse methods of synthesis have been reported for piperlotines, but involving the use of catalysts, hazard reagents, anhydrous media or coupling reagents. Thus, in this work, we developed a greener method of synthesis of piperlotines A, C, and derivatives, through mechanochemical activation under solvent-free conditions. The reaction of a β-amidophosphonate, K₂CO₃, and an aromatic aldehyde afforded target compounds in moderate to good yields (46–77%), in an open atmosphere by grinding. It is worth to mention that this mechanochemical process was under thermodynamic control because just E isomer was isolated for every reaction. Moreover, synthesized piperlotines have been predicted by means of chemoinformatic analysis as potential therapeutic agents for the treatment of arthritis or cancer.     

A rapid ultrasound-promoted Horner–Wadsworth–Emmons reaction for the preparation of ferrocene derivatives. Application to ferrocene-modified ITO electrodes

The Horner–Wadsworth–Emmons reaction of ferrocenecarboxaldehyde with various phosphonate-stabilized carbanions has been performed under ultrasound irradiation. The reaction time at ambient temperature was considerably shortened (5–15 min) compared to nonsonicated conditions requiring often refluxing for 6–24 h. Control of the reaction time can be achieved by tuning the base strength in different solvents. This method was successfully applied to the preparation of various 2-substituted vinylferrocenes. The as-prepared (E)-2-ferrocenylvinylphosphonic acid was used to modify ITO electrodes to form redox-active functionalized ITO electrodes which have been characterized by means of electrochemical techniques.     

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.     

Recent advances of intermolecular Diels–Alder reaction in bio-inspired synthesis of natural products

The Diels–Alder(D–A)reaction is one of the most powerful reactions in organic synthesis.The intermolecular D–A reaction attracts much less attentions than its intramolecular counterpart in natural product synthesis,possibly due to the issues of reactivity and selectivity.In the past decade,the intermolecular D–A reaction has been increasingly utilized in the total synthesis of structurally complex natural products.In this article,we present a few examples for the elegant applications of the intermolecular D–A reaction that are inspired by biosynthetic hypotheses of the target natural products.These examples demonstrate that D–A reaction is not only useful for preparing building blocks but also powerful for coupling structurally complicated and sterically demanding segments in a highly chemo-and stereo-controlled fashion,which may inspire further developments of intermolecular D–A reaction from both strategy and methodology perspectives.     

Preparation of natural isovaleraldehyde by the Maillard reaction

Isovaleraldehyde possesses malty,fruity,cocoa-like odor and is widely used in fruit,chocolate,coffee flavors.The preparation of natural isovaleraldehyde by the Maillard model reaction was studied in this paper.The effects of the ratio of D-glucose/L-leucine, reaction temperature and pH value on the yield of isovaleraldehyde were explored.The optimum conditions were as follows: n(D-glucose):n(L-leucine)=4,temperature 150℃,reaction time 3 h,pH 5.The highest yield of isovaleraldehyde obtained was about 32%.     

Task-Specific Ionic Liquid as Reagent and Reaction Medium for the One-Pot Horner–Wadsworth–Emmons–Type Reaction Under Microwave Irradiation

A task-specific imidazolium-based phosphinite ionic liquid (IL-OPPh₂) was used as the dual solvent–reagent for the synthesis of E-cinamates and coumarin derivatives via the one-pot Horner–Wadsworth–Emmons–type reaction. The ionic liquid containing its corresponding phosphinite moiety was reacted with α-chloro esters and benzaldehyde or salicylaldehyde derivatives in the presence of sodium methoxide under microwave irradiation to produce the related E-cinamates or coumarins, respectively. The satisfactory results were obtained with good yields, short reaction time, and simple experimental procedure.     

Electrochemical synthesis of α,β-(E)-unsaturated esters in undivided cell (Horner–Emmons reaction)

The known electrochemical synthesis of α,β-(E)-unsaturated esters (Horner–Emmons reaction) was modified in order to achieve the electrolysis in an undivided cell using magnesium as the sacrificial anode. The undivided cell procedure showed advantages over the traditional two-compartment cell methodology. The best yield using undivided cell methodology for the synthesis of aliphatic α,β-(E)-unsaturated esters was 85–86%, which is almost the yield obtained by means of the homogenous chemical reaction. This electrochemical methodology presented some limitations when aromatic aldehydes or base sensitive products were used.     

Total synthesis of the natural product (±)-dibromophakellin and analogues

(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.     

On the stereochemistry of the Horner—Emmons reaction between 3-functionally substituted 2-methyl-2-propenylphosphonates and aliphatic aldehydes

The reaction of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate (1a) with 3-methylbutanal (2) in heterogeneous MOH (solid)-benzene systems in the presence of 5–10 mol.% of benzyltriethylammonium chloride (BTEAC) gives the reaction product (3) with a higher, for M=K, or lower, for M=Li, ratio of 2E,4E and 2Z,4E-stereoisomers than that observed in the absence of BTEAC. Tetrabutylammonium bromide (TBAB) as a catalyst of the reaction1a + 2 3 in the system KOH (solid)-wet benzene leads to a higher [2E,4E-3][2Z,4E-3] ratio than BTEAC; this ratio grows from 4456 without TBAB to 8020 at 100 mol.% of TBAB. In the latter case the stereochemical outcome of the reaction is similar to that obtained when tetrabutylammonium hydroxide in dry benzene is used as the deprotonating agent. The corresponding diisopropyl phosphonate (1b) and 3,7-dimethyloctanal (4a) interact in the system KOH (solid)-wet benzene-TBAB to give hydroprene (5) containing 88 % of the 2E,4E-isomer (5a) while in the case of 1 equiv. of [(n-Bu₄)N]OH in dry benzene the content of5a is 92 %. Diisopropyl 3-isopropoxycarbonyl-2-methyl-2-propenylphosphonate (1c) and 7-methoxy-3,7-dimethyloctanal (4b) under either of these conditions afford methoprene (6) containing 93 % of the 2E,4E-isomer.Part 6, see ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1094–1098, June, 1993.     

On the stereochemistry of the Horner—Emmons reaction between 3-functionally substituted 2-methyl-2-propenylphosphonates and aliphatic aldehydes

The reaction of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate (1) with 3-methylbutanal (2) in the system solid MOH (M=K, Na, Li)-benzene without phase transfer catalysts affords ethyl 3,7-dimethyl-2,4-octadienoate with the ratios of 2E,4E stereoisomer (3a) to 2Z,4E-stereoisomer (3b) of 4456, 4654, and 6040 for KOH, NaOH, and LiOH, respectively. The similar tendency is observed when DMSO is substituted for benzene, although the proportion of3a in this case is 65% with any MOH used. The reaction of1 with2 in the presence of a stoichiometric amount of a quaternary ammonium hydroxide QOH (Q=NMe₄, BnNMe₃, (n-Bu)₄N) in benzene gives higher3a3b ratios than those obtained with LiOH in the former reaction system. The increase in the content of 2E,4E-isomer3a is possibly due to the growth of the population of solvent-separated ion pairs or, generally, to the increase in the distance between the charge centers in the ionic intermediates on passing from KOH to LiOH and from [Me₄N]OH to [(n-Bu)₄N]OH. The position of the equilibrium betweenE- and Z-isomers of phosphonate1 under the reaction conditions (E-1Z-13565) is almost unaffected by the nature of the cation of the base.Part 5, see ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1089–1094, June, 1993.     

Convenient synthesis of α-bromo ketones by the Meerwein reaction

A simple and convenient procedure was proposed for the synthesis of 4-aryl-3-bromobutan-2-ones from methyl vinyl ketone and arenediazonium bromides under Meerwein reaction conditions.     

Total synthesis of specionin - natural product or artifact ?

The iridoid insect antifeedant specionin has been synthesised from endo-cis-bicyclo[3.3.0]oct-7-en-2-ol. When the bis acetal ring is cyclised at a late stage the correct stereochemistry is generated selectively.     

Development of the radical C–O coupling reaction of phenols toward the synthesis of natural products comprising a diaryl ether skeleton

Compounds comprising a diaryl ether skeleton exist among natural phenols. The diaryl ether skeleton is thought to be biosynthesized through the coupling of two or more phenols. It is an important structural feature in medicines and agrochemicals, and it is imperative to develop methods for constructing such skeletons in organic synthesis. However, by the synthesis method through the coupling of phenols, coupling occurs preferentially at the ortho-substituted carbon atom of phenols. In this study, various radical-generating reagents and conditions were investigated with the aim of developing a short-step construction method of the diaryl ether skeleton by the radical homo-coupling of two phenol molecules. In addition, cross-coupling reactions between radicals of 2,4,6-tri-tert-butylphenol and p-substituted phenol were conducted to synthesize eight C (ortho)–O coupling products. Based on the results, a computational chemical approach was employed to verify the cause of C (ortho)–O bond formation.     

Modification of the Pictet–Spengler reaction in the synthesis of fused 2,3-benzodiazocines

A new strategy for the synthesis of the eight-membered heterocyclic skeleton of tetrahydro-quinazolino[3,2-c][2,3]benzodiazocin-15-ones, based on the Pictet–Spengler reaction of 3-amino-2-[2-(3,4-dimethoxyphenyl)ethyl]quinazolin-4(3H)-one with carbonyl compounds in acidic media, is proposed.     

An efficient access to (Z)-β-fluoroallyl alcohols based on the two carbon homologation of aromatic aldehydes by Horner–Wadsworth–Emmons reaction with 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid,S-ethyl ester followed by reduction with sodium borohydride

We describe a biomimetic approach to (Z)-β-fluoroallyl alcohols based on the two carbon homologation of aromatic aldehydes to α-fluorocinnamic thioesters by Horner–Wadsworth–Emmons reaction with 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid, S-ethyl ester, followed by reduction with sodium borohydride in mild conditions. The α-fluorothioesters were obtained in a good yield by condensing the aldehydes with the lithium anion of 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid, S-ethyl ester in THF at ?78 °C. The (E,Z)-α-fluorocinnamic thioester mixtures were then cleanly reduced with double bond isomerisation to the corresponding (Z)-β-fluoroallyl alcohols by NaBH₄ at room temperature. This methodology may be applied to highly functionalized aldehydes as exemplified by the straightforward access to (Z)-β-fluoroconiferin, a strong inhibitor of lignin polymerization from O-glucosylated vanillin.