Palladium-catalyzed cross-coupling reactions of allylic halides and acetates with indium organometallics

The palladium(0)-catalyzed cross-coupling reaction of allylic halides and acetates with indium organometallics is reported. In this synthetic transformation, triorganoindium compounds and tetraorganoindates (aryl, alkenyl, and methyl) react with cinnamyl and geranyl halides and acetates to afford the S(N)2 product regioselectively and in good yield. The reaction proceeds with net inversion of the stereochemical configuration.     

Palladium-catalyzed cross-coupling reaction of triorganoindium reagents with propargylic esters

[reaction: see text] Triorganoindium reagents (R(3)In) react with propargylic esters under palladium catalysis via an S(N)2' rearrangement to afford allenes in good yields and with high regioselectivity. The reaction proceeds smoothly at room temperature with a variety of R(3)In (aryl, alkenyl, alkynyl, and methyl). When chiral, nonracemic propargylic esters are employed, the reaction takes place with high anti-stereoselectivity providing allenes with high enantiomeric excess.     

Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate

[reaction: see text] Because of the lack of potency binding to the receptors responsible for psychoactivity, cannabidiol has received much attention as a lead compound to develop a nonpsychotropic drug. Herein, we establish a method to access not only cannabidiol but also its analogues. The key reaction is nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate with a new reagent, (alkenyl)ZnCl/TMEDA, which gives a S(N)2-type product with 94% regioselectivity in good yield.     

Alkenylzirconocene-mediated preparation of alkenylphosphines

Alkenylphosphines with various substituents were prepared by the reaction of an alkenylzirconocene with a chlorophosphine. Reactions of (alpha-unsubstituted alkenyl)zirconocenes with Ph2PCl or PhPCl2 gave the corresponding alkenylphosphines in good yields. On the other hand, direct reactions of (alpha-unsubstituted alkenyl)zirconocenes with iPr2PCl did not proceed. Analogously, (alpha-substituted alkenyl)zirconocenes did not react with chlorophosphines directly. However, these reactions proceeded in the presence of CuCl affording the corresponding alkenylphosphines as CuCl complexes. Treatment of the copper complexes with Na2(dtc) (dtc = N,N-diethyldithiocarbamate) or Na4(edta) liberated free alkenylphosphines from the copper centers. The overall protocol could be applicable to preparation of a variety of alkenylphosphines from alkynes via alkenylzirconocene species.     

Asymmetric petasis reactions catalyzed by chiral biphenols

Chiral biphenols catalyze the enantioselective Petasis reaction of alkenyl boronates, secondary amines, and ethyl glyoxylate. The reaction requires the use of 15 mol % of (S)-VAPOL as the catalyst, alkenyl boronates as nucleophiles, ethyl glyoxylate as the aldehyde component, and 3 A molecular sieves as an additive. The chiral alpha-amino ester products are obtained in good yields (71-92%) and high enantiomeric ratios (89:11-98:2). Mechanistic investigations indicate single ligand exchange of acyclic boronate with VAPOL and tetracoordinate boronate intermediates.     

Dimeric aluminum-phosphorus compounds as masked frustrated Lewis pairs for small molecule activation

Hydroalumination of aryldialkynylphosphines RP(C≡C-(t)Bu)(2) (R = Ph, Mes) with equimolar quantities of diethylaluminum hydride afforded mixed alkenyl-alkynyl cyclic dimers in which the dative aluminum-phosphorus bonds are geminal to the exocyclic alkenyl groups. Addition of triethylaluminum to isolated 1 (R = Ph) or to the in situ generated species (R = Mes) caused diethylaluminum ethynide elimination to yield the arylethylphosphorus dimers 2 and 3. These possess a chair-like Al(2)C(2)P(2) heterocycle with intermolecular Al-P interactions. The boat conformation (4) was obtained by the reaction of (t)Bu-P(C≡C-(t)Bu)(2) with di(tert-butyl)aluminum hydride. Despite being dimeric, 2 behaves as a frustrated Lewis pair and activates small molecules. The reaction with carbon dioxide gave cis/trans isomeric AlPC(2)O heterocycles that differ only by the configuration of the exocyclic alkenyl unit. Four isomers resulted from the reaction with phenyl isocyanate. This is caused by cis/trans isomerization of the initial C=O adduct and subsequent rearrangement to the AlPC(2)N heterocycle, being the C=N adduct.     

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described_. The CCR generally requires dual Ni catalysis and MgBr₂ promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr₂ in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl₂ as a precatalyst and MgBr₂ with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh₃)₂Cl₂ as a precatalyst and ZnPh₂ does not require salt promotion and is stereoretentive. The reaction with Zn(CH₂SiMe₃)₂, however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh₃)₂Cl₂. Ni-Catalyzed and MgBr₂-promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh₂ and Zn(CH₂SiMe₃)₂ is stereoretentive with Ni(dppp)Cl₂ and Ni(PPh₃)₂Cl₂. CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.     

Selective ruthenium-catalyzed transformations of enynes with diazoalkanes into alkenylbicyclo[3.1.0]hexanes

Reaction of a variety of CCH bond-containing 1,6-enynes with N2CHSiMe3 in the presence of RuCl(COD)Cp* as catalyst precursor leads, at room temperature, to the general formation of alkenylbicyclo[3.1.0]hexanes with high Z-stereoselectivity of the alkenyl group and cis arrangement of the alkenyl group and an initial double-bond substituent, for an E-configuration of this double bond. The stereochemistry is established by determining the X-ray structures of three bicyclic products. The same reaction with 1,6-enynes bearing an R substituent on the C1 carbon of the triple bond results in either cyclopropanation of the double bond with bulky R groups (SiMe3, Ph) or formation of alkylidene-alkenyl five-membered heterocycles, resulting from a beta elimination process, with less bulky R groups (R = Me, CH2CH=CH2). The reaction can be applied to in situ desilylation in methanol and direct formation of vinylbicyclo[3.1.0]hexanes and to the formation of some alkenylbicyclo[4.1.0]heptanes from 1,7-enynes. The catalytic formation of alkenylbicyclo[3.1.0]hexanes also takes place with enynes and N2CHCO2Et or N2CHPh. The reaction can be understood to proceed by an initial [2+2] addition of the Ru=CHSiMe3 bond with the enyne CCH bond, successively leading to an alkenylruthenium-carbene and a key alkenyl bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis, into bicyclo[3.1.0]hexanes. Density functional theory calculations performed starting from the model system Ru(HCCH)(CH2=CH2)Cl(C5H5) show that the transformation into a ruthenacyclobutane intermediate occurs with a temporary eta3-coordination of the cyclopentadienyl ligand. This step is followed by coordination of the alkenyl group, which leads to a mixed alkyl-allyl ligand. Because of the non-equivalence of the terminal allylic carbon atoms, their coupling favors cyclopropanation rather than the expected metathesis process. A direct comparison of the energy profiles with respect to those involving the Grubbs catalyst is presented, showing that cyclopropanation is favored with respect to enyne metathesis.     

Intramolecular carbostannation reaction of active methine compounds with an unactivated C-C pi-bond mediated by SnCl(4)-Et(3)N

In the presence of SnCl(4) and Et(3)N, intramolecular carbostannation reaction of various active methine compounds having an unactivated alkenyl, alkynyl, or allenyl group proceeds in good yields with complete regioselectivity. The subsequent reaction of the resulting Sn intermediates with some electrophiles provides functionalized cyclopentane and cyclohexane derivatives.     

Diastereo- and enantioselective cyclopropanation with chromium fischer carbene complexes: alkenyl oxazolines as useful achiral and chiral substrates.

The cyclopropanation reaction of chromium Fischer carbene complexes with alkenyl oxazolines has been studied in both racemic and enantioselective fashions. The oxazolinyl group acts as both electron-acceptor substituent and chiral auxiliary. Achiral (4,4-dimethyloxazolin-2-yl)alkenes derived from trans-crotonic and trans-cinnamic acids 2a,b undergo the cyclopropanation reaction to give 4a-d,g with excellent diastereoselectivity (trans/cis ratio between 93:7 and >97:3), while those derived from acrylic and metacrylic acids 2c,d give the cyclopropanes 4e,f,h with much lower selectivity (trans/cis ratio between 68:32 and 83:17). The homogeneous catalytic hydrogenolysis of 4 leads in a selective manner to 5 or 6, depending on the nature of the R3 substituent. The removal of the oxazoline moiety is achieved by carboxybenzylation/hydrolysis and ester reduction, yielding monoprotected 1,4- and 1,3-diols 9 and 11, respectively. The alkenes derived from enantiopure (S)-valinol and (S)-tert-leucinol 3 led to cyclopropanes trans-12 with high relative and absolute stereocontrol. Using tert-leucinol as the auxiliary permits attaining total facial stereoselectivity (>98% ee). Reductive cleavage of the cyclopropane ring and removal of the auxiliary afford the enriched alcohols (3S,4S)-9 and (S)-11. The stereochemical outcome of the cyclopropanation reaction is rationalized by a trans approach of the s-cis conformer of the alkenyl oxazoline to the carbene complex involving the less hindered face of the oxazoline auxiliary and the re-face of the carbene complex.     

Cascade alkenyl amination/Heck reaction promoted by a bifunctional palladium catalyst: a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides

A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.     

Geometry‐Retentive C‐Alkenylation of Lithiated α‐Aminonitriles: Quaternary α‐Alkenyl Amino Acids and Hydantoins

α‐Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C‐alkenylation on treatment with base by attack of the lithionitrile derivatives on the N′‐alkenyl group. A geometry‐retentive alkene shift affords stereospecifically the E or Z isomer of the 5‐alkenyl‐4‐iminohydantoin products from the corresponding starting E ‐ or Z ‐N ′‐alkenyl urea, each of which may be formed from the same N ‐allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp² carbon atom, allows the direct regioselective incorporation of mono‐, di‐, tri‐, and tetrasubstituted olefins at the α‐carbon of amino acid derivatives. The initially formed 5‐alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α‐quaternary amino acids.     

Vinyl carbocations: solution studies of alkenyl(aryl)iodonium triflate fragmentations

Generation of vinyl cations is facile by fragmentation of alkenyl(aryl)iodonium trifluoromethanesulfonates. Kinetics and electronic effects were probed by (1)H NMR spectroscopy in CDCl(3). Products of fragmentation include six enol triflate isomers in addition to iodoarenes. The enol triflates arise from direct reaction of a triflate anion with the starting iodonium salts as well as triflate reaction with rearranged secondary cations derived from those salts. G2 calculations of the theoretical isodesmic hydride-transfer reaction between secondary vinyl cation 7 and primary vinyl cation 6 reveal that cation 6 is 17.8 kcal/mol higher in energy. Activation parameters for fragmentation of (Z)-2-ethyl-1-hexenyl(3,5-bis-trifluoromethylphenyl)iodonium triflate, 17e, were calculated using the Arrhenius equation: E(a) = 26.8 kcal/mol, Delta H(++) = 26.2 kcal/mol, and Delta S(++) = 11.9 cal/mol x K. Added triflate increases the rate of fragmentation slightly, and it is likely that for most beta,beta-dialkyl- substituted vinylic iodonium triflates enol triflate fragmentation products are derived from three competing mechanisms: (a) vinylic S(N)()2 substitution; (b) ligand coupling (LC); and (c) concerted aryliodonio departure and 1,2-alkyl shift leading to secondary rather than primary vinyl cations.     

A new cine-substitution of alkenyl sulfones with aryltitanium reagents catalyzed by rhodium: mechanistic studies and catalytic asymmetric synthesis of allylarenes

The reaction of alkenyl sulfones with aryltitanium triisopropoxide (ArTi(OPr-i )3) in the presence of 3 mol % of [Rh(OH)((S)-binap)]2 in THF at 40 degrees C gave high yield of cine-substitution products. The catalytic cycle was established by deuterium-labeling studies, and it was applied to catalytic asymmetric synthesis of allylarenes which proceeds with over 99% enantioselectivity.     

Chiral alpha-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates

A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having alpha-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the "alkylation" of sec- and tert-alkyl and aryl groups.     

syn-selective direct catalytic asymmetric Mannich-type reactions of hydroxyketones using Y{N(SiMe3)2}3/linked-BINOL complexes

[reaction, structure: see text] Chiral Y{N(SiMe3)2}3/linked-BINOL catalyst generated Y-enolate in situ from various hydroxyketones (R2 = aryl, heteroaryl). Beta-amino-alpha-hydroxy ketones (R1 = aryl, heteroaryl, alkenyl) were obtained syn-selectively (up to 96/4) in high ee (up to 98%) and good yield (up to 98% yield).     

Direct Access to MIDA Acylboronates through Mild Oxidation of MIDA Vinylboronates

Acylboronate esters/trifluoroborates represent an elusive class of boronates that are of increasing interest for both fundamental study as well as applications at the interface of chemistry and biology. Their preparation has been limited by the use of strongly basic anions, often introduced in multistep reactions. Herein, we demonstrate the facile preparation of acylboronate N‐methyliminodiacetyl (MIDA) esters from alkenyl‐2‐boronate esters through mild dihydroxylation and meta ‐periodate cleavage. Given the well‐known functional‐group tolerance of this mild reaction sequence and the availability of alkenyl‐2‐boronates, this method should greatly increase access to acylboronate MIDA esters.     

Synthesis of 2H-chromenes and 1,2-dihydroquinolines from aryl aldehydes, amines, and alkenylboron compounds

The one-step reaction of salicylaldehydes with amines and alkenyl boronic acids or alkenyl trifluoroborates to form 2H-chromenes (2H-1-benzopyrans) has been investigated in more detail and new suitable conditions have been identified, including the use of tertiary amines and protic solvents including water. This process was applied to a concise synthesis of a tocopherol analog. The analogous condensation reaction between 2-sulfamidobenzaldehydes and alkenyl trifluoroborates provides an efficient synthesis of 1,2-dihydroquinoline derivatives.     

Carbon monoxide free aminocarbonylation of aryl and alkenyl iodides using DMF as an amide source

[reaction: see text] Palladium-catalyzed coupling reaction of N,N-dimethylformamide with aryl or alkenyl halides successfully proceeded in the presence of phosphoryl chloride to afford the corresponding tertiary amides in good yields.     

半稳定磷叶立德和亚胺高选择性合成卤代烯烃

半稳定磷叶立德分别和合适的磺酰基活化的亚胺在温和的反应条件下得到高选择性的卤代烯烃产物,对于芳香族、杂芳环、α,β-不饱和以及脂肪族亚胺产物都可以得到良好的收率.除此之外,我们还以良好的收率选择性合成了单一构型的一系列的氯代和碘代烯烃产物.该反应机理和Wittig反应类似,反应通过[2+2]环加成生成中间体然后消除得到...