Enantioselective reactions of scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates

[reaction: see text] Scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates prepared from organostannanes via organolithium reagents react with vinyl iodides, propargyl mesylates, and alpha,beta-enones to afford coupled products with enantioselectivities ranging from 0 to 99% ee depending upon cuprate reagent, substrate structure, solvent, and temperature. In general, lithium cuprates give higher chemical yields and lower enantioselectivities, while the trends are reversed for the corresponding zinc cuprate reagents.     

Acylation of α-(N-carbamoyl)alkylcuprates and alkyl- or aryl(halo)cuprates

α-(N-Carbamoyl)alkylcuprates [R₂CuLi·LiX or RCuXLi (X=CN, Cl)] when prepared from THF soluble CuX·2LiCl (X=Cl, CN) undergo a reliable and generally high yield reaction with aroyl, alkanoyl, and alkenoyl chlorides to provide a rapid and efficient synthesis of α-carbamoyl ketones. Cuprates prepared from acyclic, cyclic, and a functionalized carbamate can be utilized. Although yields are a function of cuprate reagent and substrate structure, nearly quantitative yields can be obtained with reagents generated from 2RLi+CuCN·2LiCl. The use of reagents generated from CuCl·2LiCl are more efficient in the α-(N-carbamoyl)alkyl ligand, although yields are slightly lower. Acylation of alkyl(chloro)cuprates generated from one equivalent of CuCl·2LiCl and organolithium or Grignard reagents provides an efficient and high yield procedure for ketone synthesis.     

Regio- and enantioselective control in the reactions of alpha-(N-carbamoyl)alkylcuprates with allylic phosphates

Alpha-(N-carbamoyl)alkylcuprates (RCuCNLi or R2CuLi) react with allylic phosphates to afford homoallylic amines in good chemical yields. Regioselectivity is governed by steric factors in both the cuprate reagent and phosphate substrate and systems can be designed to give either the S(N)2' or S(N)2 substitution product cleanly. Excellent enantioselectivities can be achieved with either a scalemic alpha-di[(N-carbamoyl)alkyl]cuprate and an achiral phosphate or with a scalemic allylic phosphate and an achiral cuprate reagent. [reaction: see text]     

A Study of factors affecting alpha-(N-carbamoyl)alkylcuprate chemistry

The effect of Cu(I) salt (i.e., CuCN, CuCN.2LiCl, CuI), cuprate reagent, sec-butyllithium quality, solvent, and temperature upon the chemical yields obtained in the reactions of alpha-(N-carbamoyl)alkylcuprates [i.e., N-Boc-protected alpha-aminoalkylcuprates] with (E)1-iodo-1-hexene, 5,5-dimethyl-2-cyclohexenone, methylvinyl ketone, crotonate esters, and an acid chloride has been examined. Cuprate conjugate addition and vinylation reactions can succeed with low-quality sec-butyllithium, presumably containing insoluble lithium hydride and lithium alkoxide impurities, although yields are significantly lower than those obtained with high-quality s-BuLi. alpha-(N-Carbamoyl)alkylcuprates prepared from high-quality sec-butyllithium are thermally stable for 2-3 h at room temperature and are equally effective when prepared from either insoluble CuCN or THF-soluble CuCN.2LiCl. Use of the latter reagent permits rapid cuprate formation at -78 degrees C, thereby avoiding the higher temperatures required for cuprate formation from THF-insoluble CuCN that are problematic with solutions containing thermally unstable alpha-lithiocarbamates.     

Coupling reactions of alpha-(N-carbamoyl)alkylcuprates with enol triflates derived from cyclic beta-keto esters: A facile approach to gamma-carbamoyl-alpha,beta-enoates

alpha-(N-Carbamoylalkyl)cuprates couple with enol triflates derived from carbocyclic and heterocyclic (i.e., piperidinones) beta-keto esters. Product yields are higher with the alkyl(cyano)cuprates [i.e., RCu(CN)Li, 56-93%] than with the dialkylcuprate reagents (i.e., R(2)CuLi.LiCN). An enol nonaflate works as well as the corresponding enol triflate. A facile synthetic route to gamma-amino alpha,beta-enoates not readily prepared from gamma-keto-alpha,beta-enoates is thus established. The gamma-amino-alpha,beta-enoates, available via N-Boc deprotection, can be cyclized to annulated pyrrolin-2-ones.     

Reactivity and enantioselectivity in the reactions of scalemic stereogenic alpha-(N-carbamoyl)alkylcuprates

Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN.2LiCl react with vinyl iodides, vinyl triflates, beta-iodo-alpha,beta-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the alpha-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.     

Palladium‐Catalysed Direct Cross‐Coupling of Organolithium Reagents with Aryl and Vinyl Triflates

A palladium‐catalysed cross‐coupling of organolithium reagents with aryl and vinyl triflates is presented. The reaction proceeds at 50 or 70 °C with short reaction times, and the corresponding products are obtained with moderate to high yields, with a variety of alkyl and (hetero)aryl lithium reagents.     

Nickel-mediated decarbonylative cross-coupling of phthalimides with in situ generated diorganozinc reagents

The nickel-mediated cross-coupling of phthalimides with diorganozinc reagents proceeds via a decarbonylative process to produce ortho-substituted benzamides in high yields. In addition to tolerating diverse phthalimide functionality, including alkyl, aryl, and heteroatom containing substituents, this methodology proceeds smoothly with diorganozinc reagents prepared from aryl bromides and utilized without purification.     

Novel and Efficient Insertions of Carbons Carrying O-, S-, and N-Linked Substituents: Synthesis of alpha-Alkoxyalkyl, alpha-(Alkylthio)alkyl, and alpha-(Carbazol-9-yl)alkyl Ketones

A wide variety of benzotriazolyl-stabilized anions 2, obtained by the lithiation of 1-(alpha-alkoxyalkyl)-, 1-[alpha-(alkylthio)alkyl]-, and 1-[alpha-(carbazol-9-yl)alkyl]benzotriazoles 1, on reaction with aliphatic and aromatic aldehydes and ketones, followed by rearrangement induced by heating in the presence of zinc bromide, furnish one-carbon-homologated alpha-alkoxyalkyl, alpha-(alkylthio)alkyl, and alpha-(carbazol-9-yl)alkyl ketones 4 in simple one-pot operations in good yields with excellent regioselectivity. In several alkoxymethylene insertions, intermediate 2-alkoxyoxiranes were separated in good yields, demonstrating the epoxide mechanism for the rearrangements and providing a facile approach to polysubstituted 2-alkoxyoxiranes, another class of important compounds.     

Reaction of alpha-(N-carbamoyl)alkylcuprates with propargyl substrates: synthetic route to alpha-amino allenes and delta3-pyrrolines

[reaction: see text] Carbamate deprotonation followed by treatment with CuCN.2LiCl affords alpha-(N-carbamoyl)alkylcuprates which react with propargyl halides, mesylates, tosylates, phosphates, acetates, and epoxides to give alpha-(N-carbamoyl) allenes via an anti-S(N)2' substitution process. Propargyl halides, sulfonates, and phosphates give good yields of carbamoyl allenes, while the acetates afford low yields. Propargyl substrates undergo regiospecific S(N)2' substitution in the absence of severe steric hindrance. The alpha-(N-carbamoyl) allenes can be cyclized to 2-oxazolidinones or deprotected to afford the free amines which can be cyclized to Delta(3)-pyrrolines with either AgNO(3) or Ru(3)(CO)(12).     

(Chiral) lithium–(magnesium–)zinc and lithium–cobalt combinations as dual reagents for aromatic deproto-metalation and aryl transfer to aldehydes

The deprotonating ability of mixed lithium–zinc or lithium–magnesium–zinc combinations containing amido and alkyl ligands in tetrahydrofuran were compared using anisole as substrate and iodine to quantitatively trap the formed arylmetal species. The results showed that the deprotonating ability is hampered if a Grignard reagent is employed to introduce the alkyl ligand, and is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic chiral amido or alkyls. Concerning the interception of the generated lithium–zinc aryl species by aldehydes, the presence of amido ligands leads to side reactions/lower yields, and no clear improvement was observed if lithium–magnesium–zinc aryl species are used. Racemic mixtures to very low enantioselectivities were noted when chiral amido ligands were incorporated in the composition of the bases.Still with enantioselective aryl transfer to aldehyde as purpose, the deprotonating ability of mixed lithium–cobalt combinations containing amido and alkyl ligands were compared using anisole as substrate and anisaldehyde to trap the formed arylmetal species. As before, the deprotonating ability is reduced when 2,2,6,6-tetramethylpiperidino ligands are replaced by less hindered/basic alkyls or chiral amido. The trapping step using aldehydes being in this case more efficient, even in the presence of amido ligands, the alcohols were obtained in higher yields. With recourse to a lower interception temperature, and using only bis[(R)-1-phenylethyl]amino as ligands, 32 and 22% yield, and 69 and 65% ee were obtained using, respectively, anisaldehyde and 3,4,5-trimethoxybenzaldehyde to intercept the metalated anisole.     

Iron-catalyzed arylmagnesiation of aryl(alkyl)acetylenes in the presence of an N-heterocyclic carbene ligand

Addition of arylmagnesium bromides to aryl(alkyl)acetylenes proceeded in the presence of an iron catalyst and a N-heterocyclic carbene ligand to give high yields of the corresponding alkenylmagnesium reagents, which were transformed into tetrasubstituted alkenes by subsequent treatment with electrophiles. [reaction: see text]     

Preparation of α-silyl- or α,α-bis(silyl)-substituted alkylcopper reagents and their synthetic use

Treatment of chlorobis(methyldiphenylsilyl)methyllithium with various alkyl and aryl Grignard reagents and CuCN·2LiCl afforded 1,1-disilylalkylcopper species. The aerobic oxidation of the resulting copper reagents provided a variety of acylsilanes in good yields. Meanwhile, treatment of dichloro(methyldiphenylsilyl)methyllithum with Bu₂CuLi·LiCN provided 1-cyano-1-silylalkylcopper species via consecutive double 1,2-migration of alkyl and cyano groups.     

Conjugate addition of chiral lithium methyl[o(cyclohexyldimethylaminomethyl)phenyl]cuprate to methyl 3-phenyl-2-propenoate and 4-phenyl-3-buten-2-o

Chiral lithium methyl[o-(cyclohexyldimethylaminomethyl)phenyl]cuprate reacts with methyl 3-phenyl-2-propenoate and 4-phenyl-3-buten-2-one to give the conjugate addition products, viz. methyl 3-phenylbutanoate and 4-phenylpentan-2-one respectively. The reaction rates and chemical yields (30–60%) are lower than in corresponding reactions with lithium dimethylcuprate and lithium methyl[2-(1-dimethylaminoethyl)phenyl]cuprate respectively. Lithium halides in the reaction favour the formation of one enantiomer. The highest asymmetric induction obtained is 4.4%.     

An unprecedented iron-catalyzed cross-coupling of primary and secondary alkyl Grignard reagents with non-activated aryl chlorides

The use of N-heterocyclic carbene ligands in the iron-catalyzed cross-coupling of alkyl Grignards has allowed, for the first time, coupling of non-activated, electron rich aryl chlorides. Surprisingly, the tetrahydrate of FeCl₂ was found to be a better pre-catalyst than anhydrous FeCl₂. Primary Grignard reagents coupled in excellent yields while secondary Grignard reagents coupled in modest yields. The use of acyclic secondary Grignard reagents resulted in the formation of isomers in addition to the desired product. These isomeric products were formed via reversible β-hydrogen elimination, indicating that the cross-coupling proceeds through an ionic pathway.     

Uncatalysed coupling of an activated aryl chloride with aryllithium and aryl Grignard reagents

Substitution of the chloro group in 2-(2-chlorophenyl)-4,4-dimethyl-2-oxazoline to afford biaryls occurs upon reaction with either aryllithium reagents or aryl Grignard reagents. The reactions with Grignard reagents occur under similar conditions to a previously reported manganese-catalysed procedure. The reactions with lithium reagents, whilst not always affording greater yields of product than the Grignard reagents, involve much shorter reaction times and afford yields, which are comparable with those obtained from the corresponding fluoro derivative.     

CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and Phenols for Diaryl Ether Formation

Couplings between (hetero)aryl chlorides and phenols can be effectively promoted by CuI in combination with an N‐aryl‐N′‐alkyl‐substituted oxalamide ligand to proceed smoothly at 120 °C. For this process, N‐aryl‐N′‐alkyl‐substituted oxalamides are more effective ligands than bis(N‐aryl)‐substituted oxalamides. A wide range of electron‐rich and electron‐poor aryl and heteroaryl chlorides gave the corresponding coupling products in good yields. Satisfactory conversions were achieved with electron‐rich phenols as well as a limited range of electron‐poor phenols. Catalyst and ligand loadings as low as 1.5 mol % are sufficient for the scaled‐up variants of some of these reactions.     

某些含芳碲基或烷碲基的1, 4-苯醌和1, 4-萘醌衍生物

四氯-1,4-苯醌(1)和2,3-二氯-1,4-萘醌(2)中的氯相当活泼,能和许多亲核试剂反应,如醇和酚;硫醇和硫酚;胺及许多含NH的杂环化合物。1和2与磷亲核试剂的反应也是已知的,本文报道1及2和芳碲基或烷碲基亲试剂的反应。     

One-pot synthesis of(Z)-4-(2-bromovinyl)benezenesulfonamides by microwave-induced simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-chlorosulfonylphenyl)propanoic acid

One-pot simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-chlorosulfonylphenyl)propa-noic acid in DMF (for alkyl amines) or DMF-pyridine (for aryl amines) using a diverse range of alkyl and aryl amines under microwave irradiation condition stereoselectively afforded (Z)-4-(2-bromovinyl)benzenesulfonamides in good yields.     

Pd2(dba)3/P(i-BuNCH2CH2)3N-catalyzed Stille cross-coupling of aryl chlorides

[reaction: see text] The Pd(2)(dba)(3)/P(i-BuNCH(2)CH(2))(3)N (1d) catalyst system is highly effective for the Stille cross-coupling of aryl chlorides with organotin compounds. This method represents only the second general method for the coupling of aryl chlorides. Other proazaphosphatranes possessing benzyl substituents also generate very active catalysts for Stille reactions. Noteworthy features of the method are: (a) commercial availability of ligand 1d, (b) the wide array of aryl chlorides that can be coupled, and (c) applicability to aryl, vinyl, and allyl tin reagents.