Copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates with sulfonamides

A copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates has been developed which is suitable for the coupling of a wide variety of functionalized sulfonamide nucleophiles with acetate electrophiles. The methodology allows for the amidation of benzylic substrates which are not further activated by an additional adjacent alkene or alkyne, enabling simple allylic acetates and primary benzylic acetates to be used as reaction partners.     

E/Z Isomerization of 3,3-disubstituted allylic thioethers

Allylic thioethers of the general structure 1 underwent E/Z isomerization during both basic and acidic hydrolysis of the ester moiety at the remote end of the molecule. The isomerization was dependent on the substitution of the allylic moiety. The presence of a 5-membered heterocycle on the double bond supported the isomerization. However, analogous oxy-ethers were stable.     

Highly selective 1,3-isomerization of allylic alcohols via rhenium oxo catalysis

Two reaction strategies are developed to promote the highly selective 1,3-isomerization of a variety of allylic alcohols using O3ReOSiPh3 as a catalyst. The first strategy utilizes substrates whose 1,3-regioisomer contains a conjugated alkene, which relies on thermodynamics to obtain high selectivity. The second strategy employs N,O-bis(trimethylsilyl)acetamide as an additive to selectively and irreversibly remove the product from the reaction equilibrium and works well for the isomerization of tertiary allylic alcohols into primary allylic alcohols containing trisubstituted alkene components. High stereoselectivity is also observed in the 1,3-isomerization of enantioenriched allylic alcohols.     

Evidence for involvement of cationic intermediate in epoxidation of chiral allylic alcohols and unfunctionalised alkenes catalysed by MnIII(quinazolinone) complexes

A pair of Mn^III(quinazolinone) complexes was prepared and evaluated in the catalytic epoxidation of the chiral allylic alcohols and unfunctionalised alkenes with iodosylbenzene. Epoxidation of chiral allylic alcohols with 1,3-allylic strain proceeded chemo- and diastereoselectively to give threo-epoxy alcohol (up to 99% d.r). Epoxidation of unfunctionalised alkenes by the proposed catalyst system proceeded nonselectively, as evidenced by the formation of isomerization and rearrangement products in the epoxidation of (Z)-stilbene. A three-step pathway involving a cationic intermediate is proposed for the formation of isomerization and rearrangement products. The fact that only products resulting from the cationic intermediate were detected in the oxidation of a mechanistic probe, (2-methoxy-3-vinylcyclopropyl)benzene, with Mn^III(quinazolinone) and PhIO substantiated the cationic oxygen transfer mechanism.     

Synthesis of 2-bromo-1-aryl-1H-indenes via a Ag(I) promoted domino 2π-electrocyclic ring-opening/4π-electrocyclization reaction of 1,2-diaryl substituted gem-dibromocyclopropanes

2-Bromo-1-aryl substituted indenes can be synthesized from 1,2-diaryl substituted gem-dibromocyclopropanes via a domino reaction sequence. The cascade reaction involves silver(I) promoted ionization and 2π-disrotatory electrocyclic ring-opening, followed by a 4π-conrotatory electrocyclic ring closing reaction of the allylic carbocation intermediate. Reaction conditions utilize silver tetrafluoroborate (AgBF₄) in dichloroethane at 65 °C. Selectivity effects for the electrocyclization were also studied. The 2-bromoindenes can be further functionalized using cross-coupling reactions, such as the Suzuki–Miyaura protocol. The alkene π-bond of the indenes can also be isomerized to give the thermodynamically more stable 2-bromo-3-aryl-1H-indene isomers using triethylamine in dichloromethane at room temperature.     

Scope, mechanism and diene inhibition of isomerization of allylic alcohols to saturated ketones catalyzed by ruthenium(II)-cyclopentadienyl complexes

The isomerization of 3-buten-2-ol to butanone catalyzed by Ru(II)Cp-complexes (Cp = η⁵-cyclopentadienyl) with phosphine and amine ligands is described. The reaction catalyzed by [RuCp(MeCN)₃](PF₆) and two equivalents of triphenylphospine is first order in substrate with a k_ini of 0.43 h⁻¹ and an initial TOF of 13,000 h⁻¹. The catalyst precursor complex [RuClCp(dppb)] (dppb = bis(diphenylphosphino)butane) has been characterized by X-ray diffraction. This compound features a seven-membered ring incorporating the ruthenium centre and the dppb ligand.Combination of two equivalents of primary, secondary or tertiary amines and [RuCp(MeCN)₃](PF₆) results in active catalyst precursors. Within each group, increasing the bulk of the ligand gives lower isomerization rates. The combined effects of optimal pK_a, nucleophilicity and steric bulk make RuCp-complexes with secondary amines the most active precursors. With di-n-butylamine, 745 turnovers can be reached after 1 h. ³¹P NMR spectra indicate that the resting state in the catalytic cycle is a complex in which 3-buten-2-ol is η²-coordinated through the alkene moiety. This implies that coordination of the oxygen moiety and concomitant β-hydrogen abstraction is the rate-limiting step. A counterintuitive result is that allylic alcohols bind stronger to RuCp complexes with phosphine ligands than dienes. Inhibition of the catalyst appears to be a result of interaction of the diene with a ruthenium-allyl alcohol complex, which is sufficiently strong to prevent coordination of the oxygen moiety of the allylic alcohol. This hinders orientation of the allylic alcohol substrate in a suitable way to undergo β-hydrogen abstraction, thereby blocking isomerization catalysis.     

Oxidation of acyclic alkenes and allyl and benzyl ethers with DIB/t-BuOOH/Mg(OAc)2

Oxidation of (11Z)-1′,2′-didehydrostemofoline with DIB/TBHP/Mg(OAc)₂·4H₂O resulted in oxidative cleavage of the C-11–C-12 double bond instead of the desired allylic oxidation of the 1-butenyl side chain. Stemofoline gave a similar result. The oxidation of more simple terminal alkenes was regioselective and gave vinyl ketones while allyl and benzyl ethers gave acrylate and benzoate esters, respectively. Allyl and benzyl ethers could be chemoselectively oxidized in the presence of a terminal alkene or benzyl group. Oxidation of an internal alkene was poorly regioselective, in contrast to the oxidation of 1-substituted cyclohexenes.     

Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.     

Peracid dependent stereoselectivity and functional group contribution to the stereocontrol of epoxidation of (E)-alkene dipeptide isosteres

Twelve Boc-protected phenylalanyl-phenylalanine and phenylalanyl-glycine trans-vinyl isosteres were epoxidised with magnesium monoperoxyphtalate hexahydrate (MMPP) and trifluoroperacetic acid, and the results have been compared with those from earlier studies on epoxidations with m-CPBA. The alkenes were synthesised in high yields with high E/Z-selectivities using either the Julia or Schlosser reactions. The formation of threo isomers was favoured in all epoxidation reactions except with CF₃CO₃H on substrates containing two allylic/homoallylic functional groups directing the peracid to opposite faces of the alkene. The switch to erythro selectivity observed with CF₃CO₃H is suggested to emanate from coordination to the allylic ester functionalities via hydrogen bond donation from the peracid. The other peracid reagents seem to be preferentially coordinated to the allylic carbamate function. The contribution of individual functional groups to the stereopreference was also investigated.     

Stereoselective synthesis of imidazolidin-2-ones via Pd-catalyzed alkene carboamination. Scope and limitations

A method for the synthesis of imidazolidin-2-ones from N-allylureas and aryl or alkenyl bromides via Pd-catalyzed carboamination reactions is described. The N-allylurea precursors are prepared in one step from readily available allylic amines and isocyanates, and the Pd-catalyzed reactions effect the formation of a C-C bond, a C-N bond, and up to two stereocenters in a single step. Good diastereoselectivities are obtained for the conversion of substrates bearing allylic substituents to 4,5-disubstituted imidazolidin-2-ones, and excellent selectivity for the generation of products resulting from syn-addition across the alkene is observed when substrates derived from cyclic alkenes or E-1,2-disubstituted alkenes are employed. A brief discussion of reaction mechanism and product stereochemistry is presented.     

Enantioselective, (−)-sparteine-mediated deprotonation of geranyl and neryl N,N-diisopropylcarbamate: configurational stability of the intermediate lithium compounds

(E)/(Z)-Isomeric allylic carbamate esters were deprotonated by n-butyllithium/(−)-sparteine in toluene. Trapping experiments with chlorotrimethylsilane afforded the α-substitution products, with (R)-configuration, revealing that the pro-S proton is removed predominantly to form the corresponding (S)-lithium·(−)-sparteine derivatives; k_S/k_R>15:1 and >7:1, respectively. A slow (S)→(R)-epimerization occurs at −78 °C (T_1/2>60 min). The allylic double bond is stable to (Z)-(E) isomerization under these conditions.     

First total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA

The first total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA, derived from docosahexaenoic acid (DHA), and its 16-epimer have been achieved. Two synthetic approaches are described for the synthesis of 16(R),17(S)-diHDHA. The first strategy started from DHA and used an enzymatic reaction, a vanadium catalyzed allylic epoxidation and a base-promoted epoxide isomerization. The second approach utilized a chiral pool strategy starting from 2-deoxy-d-ribose to establish the chiral centers; Wittig reactions, mild acetonide cleavage and ester hydrolysis were the key steps in the synthesis.     

Visible-Light-Enabled Stereodivergent Synthesis of E- and Z-Configured 1,4-Dienes by Photoredox/Nickel Dual Catalysis

A stereodivergent reductive coupling reaction between allylic carbonates and vinyl triflates to furnish both E- and Z-configured 1,4-dienes has been achieved by visible-light-induced photoredox/nickel dual catalysis. The mild reaction conditions allow good compatibility of both vinyl triflates and allylic carbonates. Notably, the stereoselectivity of this synergistic cross-electrophile coupling can be tuned by an appropriate photocatalyst with a suitable triplet-state energy, providing a practical and stereodivergent means to alkene synthesis. Preliminary mechanistic studies shed some light on the coupling step as well as the control of the stereoselectivity step.     

Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides

A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported. The redox-neutral intramolecular hydrofunctionalization is enabled by a dual catalyst system comprised of 9-mesityl-N-methyl acridinium tetrafluoroborate and phenyl disulphide and exhibits complete selectivity for the anti-Markovnikov regioisomeric products. The cyclization of allylic thioamides is postulated to operate via a modified mechanism in which oxidation of the thioamide, rather than the alkene, is responsible for the observed reactivity.     

Deciphering the Mechanism Involved in the Switch On/Off of Molecular Pistons

Manufacturing machines converting energy to mechanical work at the molecular level is a vital pathway to explore the microscopic world. A kind of operable molecular engines, composed of β‐cyclodextrin (β‐CD), aryl, alkene and amide moiety was investigated using molecular dynamics simulations combined with free‐energy calculations. To understand how the integrated alkene double bond controls the work performed on the engines, two alkene isomers of the prototype were considered as two molecular engines. The free‐energy profiles delineating the binding process of the amide (Z)‐ and (E)‐isomers for each alkene isomer with 1‐adamantanol indicate that for the alkene (E)‐isomer, the apparent work performed on the amide bond is 1.6 kcal/mol, while the alkene (Z)‐isomer is incapable to perform work. Direct switch on/off of engines caused by the isomerization of the alkene bond was, therefore, witnessed, in line with experimental measurements. Decomposition of the free‐energy profile into different components and structural analyses suggest that the isomerization of the alkene bond controls the position of the aryl unit relative to the cavity of the CD, resulting in the difference among the free‐energy profiles and the stark contrast of the work performed on engines.     

Rhodium-catalyzed hydroformylation of C6 alkenes and alkene mixtures - a comparative study in homogeneous and aqueous-biphasic media using PPh3, TPPTS and TPPMS ligands

The complexes RhH(CO)L₃, where L = PPh₃, P(m-C₆H₄SO₃Na)₃ (TPPTS), and (C₆H₅)₂P(m-C₆H₄SO₃Na) (TPPMS) were used as catalyst precursors for a comparative study of the catalytic hydroformylation of several C6 alkenes and alkene mixtures under moderate reaction conditions in homogeneous (PPh₃) and aqueous-biphasic (TPPTS, TPPMS) media. The biphasic systems are efficient for the hydroformylation of hex-1-ene, 2,3-dimethyl-1-butene, styrene, cyclohexene, and mixtures thereof, in water/n-heptane at 80 °C. The main problem associated with these catalysts is their tendency to promote alkene isomerization if the effective syngas concentration in the liquid phases is low, but this side-reaction can be suppressed by using higher CO/H₂ pressures (54 atm). The selectivity of both water-soluble catalysts for linear products of hex-1-ene and for branched products of styrene is modest in comparison with the homogeneous system, which may limit their utility for classical oxo uses, but this is not a disadvantage for other interesting applications related to the hydroformylation of alkene mixtures and particularly to naphtha upgrading where linear and branched products are equally useful. The catalysts can be recycled without significant loss of activity and are resistant to the presence of benzothiophene in the mixture.     

Enantioselective Nickel‐Catalyzed Intramolecular Allylic Alkenylations Enabled by Reversible Alkenylnickel E/Z Isomerization

Enantioselective nickel‐catalyzed arylative cyclizations of substrates containing a Z ‐allylic phosphate tethered to an alkyne are described. These reactions give multisubstituted chiral aza‐ and carbocycles, and are initiated by the addition of an arylboronic acid to the alkyne, followed by cyclization of the resulting alkenylnickel species onto the allylic phosphate. The reversible E /Z isomerization of the alkenylnickel species is essential for the success of the reactions.     

C(1→4)-linked disaccharides through carbonylative Stille cross-coupling

A tinglucal tributyl[4,6-O-bis(t-butyl)silylidene-3-O-tris(isopropyl)silyl]tin 7 and a triflate derived from isolevoglucosenone (1R,4R,5R)-4-benzyloxy-6,8-dioxabicyclo[3.2.1]oct-2-en-2-yl trifluoromethanesulfonate 10 undergo the carbonylative Stille condensation under special conditions requiring AsPh₃, LiCl, and powdered charcoal as co-catalysts to give a cross-conjugated dienone 6 in which the bicyclic alkene moiety is more reactive than the glucal alkene moiety. This allows the regio- and stereoselective hydrogenation of the bicyclic alkene moiety giving an enone 21 that can be reduced stereoselectively to an allylic alcohol 22. Hydroboration of the glucal and bicyclic acetal opening generates a C(1→4) linked disaccharide 25 in which a protected form of β-d-glucopyranose is attached at position C(4) of a α-d-3-deoxy-ribo-hexopyranoside derivative via a (S)-hydroxymethano linker.     

Pseudo‐Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3‐Oxo‐Allylation/Cope Rearrangement

The catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo‐stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin‐based Morita–Baylis–Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3‐oxo‐allylation reaction between N‐allylic ylides and chiral π‐allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3‐Cope rearrangement process.     

Synthesis of complex carbobicyclic compounds from sugar allyltins: functionalization of the allylic position in bicyclo[4.3.0]nonene derivatives

Two approaches for the functionalization of the allylic position in 7,8,9-tri-O-benzyl-5-substituted bicyclo[4.3.0]non-2-ene derivative 12 were examined. The first method, which involves an epoxidation of the C2–C3 double bond followed by a base induced isomerization, was found to be inappropriate. Although the epoxides were formed in good yields, the base-induced isomerization of the latter performed under the harsh conditions (LDA, HMPA, 80 °C) did not lead to the desired allylic alcohol 13, but to the tricyclic derivative 15 resulting from the opening of the oxirane ring by the anion generated from the benzyl group at the C9-position. The other, more promising approach, consisted of the cis-hydroxylation of the C2–C3 double bond followed by selective protection of one of the hydroxyl groups (at the C2-position) using the dibutyltin methodology. The free hydroxyl group located at the C3 position can be eventually eliminated to give the desired olefin with the double bond between the C3 and C4 carbon atoms of the bicyclic system.