Catalytic asymmetric rearrangement of allylic trichloroacetimidates. A practical method for preparing allylic amines and congeners of high enantiomeric purity

COP-Cl catalyzes the rearrangement of (E)-allylic trichloroacetimidates to provide transposed allylic trichloroacetamides of high enantiopurity, a transformation that underlies the first truly practical method for transforming prochiral allylic alcohols to enantioenriched allylic amines and congeners. The high functional group compatibility of this asymmetric rearrangement and the demonstrated broad utility in synthesis of the allylic trichloroacetimidate to allylic trichloroacetamide conversion are singular features of this new catalytic asymmetric reaction.     

Catalytic asymmetric rearrangement of allylic N-aryl trifluoroacetimidates. A useful method for transforming prochiral allylic alcohols to chiral allylic amines

[reaction: see text] A useful method for the conversion of prochiral allylic alcohols to chiral allylic amines of high enantiopurity is reported. N-(4-Methoxyphenyl)trifluoroacetimidates are excellent substrates for the palladium(II)-catalyzed allylic imidate rearrangement as the allylic trifluoroacetamide products can be deprotected in two steps to provide chiral nonracemic allylic amines. Di-mu-chlorobis[(eta(5)-(S)-(pR)-2-(2'-(4'-isopropyl))oxazolinylcyclopentadienyl,1-C,3'-N))(eta(4)-tetraphenylcyclobutadiene)cobalt]dipalladium (6a, COP-Cl) is a superior catalyst because it does not require activation with silver salts and provides rearranged allylic trifluoroacetamides in good yields and high enantiomeric purities.     

Kinetic and computational analysis of the palladium(II)-catalyzed asymmetric allylic trichloroacetimidate rearrangement: development of a model for enantioselectivity

The asymmetric rearrangement of allylic trichloroacetimidates catalyzed by palladium(II) complexes of the COP family is a powerful method for the preparation of enantioenriched chiral allylic amines from prochiral allylic alcohols. A detailed kinetic analysis of this reaction was performed to elucidate the rate- and enantiodetermining step of this important reaction. The results of these studies support a cyclization-induced rearrangement mechanism and prompted DFT studies (B3LYP/LACVP**+) of C-N bond formation, believed to be the enantiodetermining step of this catalytic cycle. On the basis of these calculations, a model for enantioinduction was developed, in which the planar chirality of the catalyst controls the enantioselectivity. These studies should allow the rational design of more enantioselective catalysts.     

Asymmetric lithiation-substitution sequences of substituted allylamines

[reaction: see text] (-)-Sparteine-mediated asymmetric lithiation-substitution sequences of 2- and 3-substituted N-(Boc)-N-(p-methoxyphenyl) allylic amines with electrophiles have been investigated. Asymmetric lithiation-substitutions of N-(Boc)-N-(p-methoxyphenyl) allylic amines 11, 12, 13, 14, and 15 provide highly enantioenriched enecarbamates in good yields. Further transformations to give aldehydes, acids, ketones, and a Diels-Alder adduct are reported. The 1,4-addition products from reactions of the lithiated allylic amines from 14 and 15 with conjugated activated alkenes gives enecarbamates with two and three stereogenic centers in good yields with high diastereomeric and enantiomeric ratios. Synthetic transformation of these products by acid hydrolysis and subsequent cyclization provide stereoselective access to bicyclic compounds containing four and five stereogenic centers with high diastereoselectivity and enantioselectivity. It is suggested that allyllithium complexes generated by asymmetric deprotonation react with most electrophiles with inversion of configuration.     

Palladacyclic imidazoline-naphthalene complexes: synthesis and catalytic performance in Pd(II)-catalyzed enantioselective reactions of allylic trichloroacetimidates

A new family of air- and moisture-stable enantiopure C,N-palladacycles (PIN-acac complexes) were prepared in good overall yield in three steps from 2-iodo-1-naphthoic acid and enantiopure β-amino alcohols. Three of these PIN complexes were characterized by single-crystal X-ray analysis. As anticipated, the naphthalene and imidazoline rings of PIN-acac complexes 18a and 18b were canted significantly from planarity and projected the imidazoline substituents R(1) and R(2) on opposite faces of the palladium square plane. Fifteen PIN complexes were evaluated as catalysts for the rearrangement of prochiral (E)-allylic trichloroacetimidate 19 (eq 2) and the S(N)2' allylic substitution of acetic acid with prochiral (Z)-allylic trichloroacetimidate 23. Although these complexes were kinetically poor catalysts for the Overman rearrangement, they were good catalysts for the allylic substitution reaction, providing branched allylic esters in high yield. However, enantioselectivities were low to moderate and significantly less than that realized with palladacyclic complexes of the COP family. Computational studies support an anti-acetoxypalladation/syn-deoxypalladation mechanism analogous to that observed with COP catalysts. The computational study further suggests that optimizing steric influence in the vicinity of the carbon ligand of a chiral C,N-palladacycle, rather than near the nitrogen heterocycle, is the direction to pursue in future development of improved enantioselective catalysts of this motif.     

Synthetic applications of lithiated N-Boc allylic amines as asymmetric homoenolate equivalents

Lithiation of N-(Boc)-N-(p-methoxyphenyl) allylic amines in the presence of (-)-sparteine provides asymmetric homoenolate equivalents which react with electrophiles to provide highly enantioenriched enecarbamates. Acidic hydrolysis of the enecarbamates can provide the corresponding beta-substituted aldehydes. A synthetic sequence that involves a stereocontrolled intramolecular nitrone-olefin dipolar cycloaddition has been developed for the preparation of enantioenriched 2-formyl-4-phenyl-1-aminocyclopentanes from one beta-allyl-substituted aldehyde. Further manipulations allow access to an enantioenriched beta-lactam. In another synthetic sequence, transmetalation of the lithiated intermediates and reactions with aldehyde electrophiles can be controlled to afford highly enantioenriched anti homoaldol products. Use of an anti aldehyde homoaldol product as the chiral electrophile in an iterative reaction provides a double homoaldol product containing four stereogenic centers with high diastereoselectivity and enantioselectivity. Reaction pathways are proposed to account for the observed products.     

Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols

[formula: see text] The kinetic resolution of racemic epoxides via catalytic enantioselective rearrangement to allylic alcohols was investigated. Using the Li-salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as catalyst allowed both epoxides and allylic alcohols to be obtained in an enantioenriched form.     

Synthesis of 1-arylmethyl-2-(cyanomethyl)aziridines and their ring transformation into methyl N-(2-cyanocyclopropyl)benzimidates

1-Arylmethyl-2-(cyanomethyl)aziridines were prepared in high yields from the corresponding 2-(bromomethyl)aziridines upon treatment with potassium cyanide in DMSO. Ring opening of the aziridine moiety with N-chlorosuccinimide in CCl4 and subsequent treatment of the thus formed 4-chloro-3-(N-chloro-N-(alpha,alpha-dichlorobenzyl)amino)butanenitriles with sodium methoxide in methanol resulted in novel methyl N-(2-chloro-1-(cyanomethyl)ethyl)benzimidates, although in low yields. The latter gamma-chloro nitriles were smoothly converted into methyl N-(2-cyanocyclopropyl)benzimidates as precursors of biologically relevant beta-ACC derivatives through a 1,3-cyclization protocol by reaction with potassium tert-butoxide in THF.     

Reactions with Stilbenes and Related Derivatives. Part I. Reactions of 1, 2-Dihalogeno-1, 2-bis-(4-methoxyphenyl)ethanes with Alcohols

The reaction of 1, 2-dibromo-1, 2-bis(4-methoxyphenyl)ethane with alcohols was associated with rearrangement to give the corresponding bis(4-methoxyphenyl)acetals. In boiling ethylene glycol 4,4′-dimethoxy-deoxybenzoin was also obtained due to an aldehyde-ketone rearrangement. 4,4′-Dimethoxybenzophenone was also formed being apparently derived from the acetals. The mechanism of formation of the acetals has been discussed.     

Catalytic asymmetric intramolecular aminopalladation: enantioselective synthesis of vinyl-substituted 2-oxazolidinones, 2-imidazolidinones, and 2-pyrrolidinones.

A new catalytic asymmetric synthesis of five-membered nitrogen heterocycles is reported. This synthesis employs ferrocenyloxazoline palladacycles (FOP trifluoroacetate catalysts) 2 and 4 and proceeds by a catalytic cycle involving Pd(II) intermediates. For example, prochiral (Z)-4-acetoxy-2-buten-1-ols are condensed with an arylsulfonyl isocyanate and the derived allylic N-arylsulfonylcarbamates cyclize in situ upon addition of 0.5-5 mol % of 2 or 4 to form 4-vinyloxazolidin-2-ones 6, 13, and 15 in high yield and 89-99% ee. The related 2-pyrrolidinone 19 and 2-imidazolidinone 18 are prepared in similar fashion. Pyrrolidinone 19 can be converted in two steps to the unnatural enantiomer of the GABA inhibitor vigabatrin 20.     

Scope and mechanism of formal S(N)2' substitution reactions of a monomeric imidozirconium complex with allylic electrophiles

The zirconium imido complex Cp2(THF)Zr=NSi(t-Bu)Me2 (1) reacts with allylic ethers, chlorides, and bromides to give exclusively the products of the SN2' reaction; i.e., attack at the allylic position remote from the leaving group with migration of the double bond. The primary amine products can be isolated in excellent yields, after in situ Cbz protection, in the presence of variety of functional groups. Good diastereoselectivity and complete stereoselectivity allowed the formation of enantioenriched allylic amines from enantioenriched allylic ethers. Regiospecific substitution with 1 has also been achieved with allylic fluorides, which are notoriously poor substrates in other substitution reactions. On the basis of rate and kinetic isotope effect studies, we propose a general mechanism for the allylic substitution reactions with 1 which involves dissociation of THF and binding of the substrate, followed by the substitution step. In a DFT study of the substitution reaction, we identified a six-membered closed transition state for the substitution step and other relevant stationary points along the reaction coordinate. This study shows that the substitution reaction can be described as a concerted asynchronous [3,3]-sigmatropic rearrangement. This detailed knowledge of the reaction mechanism provides a rationale for the origins of the observed regio-, diastereo-, and stereoselectivity and of the unusual reactivity profile observed in the reaction.     

Effects of allylic and homoallylic substituents on the ring closing metathesis reaction used to synthesise simplified eleuthesides

During the course of our synthetic studies towards simplified eleuthesides, we have found that p-methoxyphenyl (PMP) protected allylic alcohols are compatible with the RCM reaction and can give better yields than the corresponding free allylic alcohols.     

A highly atom efficient, solvent promoted addition of tetraallylic, tetraallenic, and tetrapropargylic stannanes to carbonyl compounds.

Tetraallylic, tetraallenic, and tetrapropargylic stannanes (0.25 equiv) react with aldehydes in methanol to provide unsaturated alcohols in good to excellent yields (56-99%). These reactions proceed exclusively with allylic rearrangement for tetra(2-butenyl)tin 2b and tetra(1,2-butadienyl)tin 16c and predominantly with allylic rearrangement for tetrapropadienyltin 16a and tetra(2-butynyl)tin 6e. Allylation reactions also proceeded smoothly with reactive ketones such as ethyl pyruvate (9a) and cyclohexanone (9b). The corresponding TFA-catalyzed reactions of dimethyl acetals 4d and 4e are regiospecific with allylic rearrangement.     

Diastereoselective ireland-claisen rearrangement of allylic alcohols

The “chelation-controlled” Ireland-Claisen rearrangement of allylic glycolate esters is described in which the stereocontrol of the prochiral sp² sites is achieved by the allylic oxygen substitutent.     

Planar-chiral cyclopalladated ferrocenyl amines and imines as enantioselective catalysts for allylic imidate rearrangements

A series of enantiopure cyclopalladated ferrocenyl amines and imines were synthesized and evaluated as catalysts for the [3,3]-rearrangement of allylic benzimidates to allylic benzamides. Yields and extent of enantioselection were found to be highly dependent upon the counter-ion, with a high of 78% yield and 73% ee being realized under optimum conditions.     

Dechalcogenative allylic selenosulfide and disulfide rearrangements: complementary methods for the formation of allylic sulfides in the absence of electrophiles. Scope, limitations, and application to the functionalization of unprotected peptides in aqueous media

Primary allylic selenosulfates (seleno Bunte salts) and selenocyanates transfer the allylic selenide moiety to thiols giving primary allylic selenosulfides, which undergo rearrangement in the presence of PPh3 with the loss of selenium to give allylically rearranged allyl alkyl sulfides. This rearrangement may be conducted with prenyl-type selenosulfides to give isoprenyl alkyl sulfides. Alkyl secondary and tertiary allylic disulfides, formed by sulfide transfer from allylic heteroaryl disulfides to thiols, undergo desulfurative allylic rearrangement on treatment with PPh3 in methanolic acetonitrile at room temperature. With nerolidyl alkyl disulfides this rearrangement provides an electrophile-free method for the introduction of the farnesyl chain onto thiols. Both rearrangements are compatible with the full range of functionality found in the proteinogenic amino acids, and it is demonstrated that the desulfurative rearrangement functions in aqueous media, enabling the derivatization of unprotected peptides. It is also demonstrated that the allylic disulfide rearrangement can be induced in the absence of phosphine at room temperature by treatment with piperidine, or simply by refluxing in methanol. Under these latter conditions the reaction is also applicable to allyl aryl disulfides, providing allylically rearranged allyl aryl sulfides in good yields.     

Stereoselective ring opening of meso bicyclic hydrazines: a straightforward approach to hydrazino cyclopentenic cores

The diastereoselective synthesis of hydrazinocyclopentenes 6 or 7 can be achieved in a straightforward manner from Diels-Alder adduct 4 using an acid-catalyzed rearrangement or a palladium-catalyzed allylic substitution reaction. In the latter case, enantioenriched compounds with ee values up to 58% can be obtained when an appropriate chiral ligand is used. [reaction: see text]     

Sequential Ir‐Catalyzed Allylation/2‐aza‐Cope Rearrangement Strategy for the Construction of Chiral Homoallylic Amines†

Sequential Ir‐catalyzed asymmetric allylation/2‐aza‐Cope rearrangement of arylidene aminomalonates with allylic carbonates was successfully developed, and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent E/Z‐geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system established for this transformation, the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.     

Regio- and Enantioselective Substitution of Acyclic Allylic Sulfoximines with Butylcopper in the Presence of Lithium Iodide and Boron Trifluoride

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.     

Regiochemical control in the metal-catalyzed transposition of allylic silyl ethers

A novel mode of regiochemical control over the allylic [1,3]-transposition of silyloxy groups catalyzed by Re2O7 has been developed. This strategy relies on a cis-oriented vinyl boronate, generated from the Alder-ene reaction of homoallylic silyl ethers and alkynyl boronates, to trap out the allylic hydroxyl group. The resulting cyclic boronic acids are excellent partners for cross-coupling reactions. High chirality transfer is observed for the rearrangement of enantioenriched allylic silyl ethers.