A sulfoxide-promoted, catalytic method for the regioselective synthesis of allylic acetates from monosubstituted olefins via C-H oxidation

Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidation versus Wacker oxidation chemistry and to control the regioselectivity in the C-H oxidation products. A catalytic method for the direct C-H oxidation of monosubstituted olefins to linear (E)-allylic acetates in high regio- and stereoselectivities and preparatively useful yields is described. The method using benzoquinone as the stoichiometric oxidant and 10 mol % of Pd(OAc)2 or Pd(O2CCF3)2 as the catalyst in a DMSO/AcOH (1:1) solution was found to be compatible with a wide range of functionality (e.g., amides, carbamates, esters, and ethers, see Table 2). Addition of DMSO was found to be critical for promoting the C-H oxidation pathway, with AcOH alone or in combination with a diverse range of dielectric media, leading to mixtures favoring Wacker-type oxidation products (Tables 1, S3). To explore the role of DMSO as a ligand, the bis-sulfoxide Pd(OAc)2 complex 1 was formed and found to be an effective C-H oxidation catalyst in the absence of DMSO (eqs 2, 3). Moreover, catalyst 1 effects a reversal of regioselectivity, favoring the formation of branched allylic acetates.     

A new method for the selective oxidation of allylic and benzylic alcohols

A new method is described for the selective oxidation of allylic or benzylic alcohols, in the presence of saturated alcohols, using trimethylamine-N-oxide in the presence of an iron carbonyl.     

Regioselective palladium-catalyzed allylic alkylations

Palladium-catalyzed allylic alkylations on asymmetrical allylic carbonates using a variety of chiral ligands gave good to excellent ee’s and poor to excellent regioselectivity depending on the nucleophile used.     

Highly enantioselective copper-bisoxazoline-catalyzed allylic oxidation of cyclic olefins with tert-butyl p-nitroperbenzoate

Catalytic asymmetric allylic oxidation of cyclic olefins ocurrs for the first time in very high (94-99% ee) enantioselectivity using copper(I) complexes of malonyl derived bisoxazolines and tert-butyl p-nitroperbenzoate giving allyl benzoates in moderate yield. The copper complex, 15 mol %, was used in acetonitrile at -20 degrees C over an extended period, 5-12 d, with excess olefin together with one equivalent of perester. The S-esters were generated in accord with the model proposed previously for the (S,S)-bisoxazoline ligand. An eta2 intermediate was ruled out using low-temperature 13C NMR with the complex in the presence of olefin.     

Beta-alkyl-alpha-allylation of Michael acceptors through the palladium-catalyzed three-component coupling between allylic substrates, trialkylboranes, and activated olefins

The palladium-catalyzed three-component beta-alkyl-alpha-allylation reaction of activated olefins has been achieved. For example, in the presence of 5 mol % of Pd(PPh3)4, the reaction of benzylidenemalononitrile 1a with Et3B and allyl acetate 2a in THF proceeded smoothly at 40 degrees C to give the corresponding beta-ethyl-alpha-allylated product 3a in 81% yield.     

New spiro phosphinooxazolines for palladium-catalyzed asymmetric allylic amination

The new conformational rigid spiro phosphinooxazolines 1 were synthesized from 7-bromo-1-indanone. The asymmetric catalytic potential of them was demonstrated in the asymmetric palladium catalyzed allylic amination. High yields and enantioselectivities were obtained with alkylamines.     

Influences on the regioselectivity of palladium-catalyzed allylic alkylations

Chelated amino acid ester enolates are excellent nucleophiles for palladium-catalyzed allylic alkylations. These enolates react rapidly at -78 degrees C and in general without isomerization of pi-allyl palladium complexes. Therefore, they are good candidates for mechanistic studies and regioselective reactions. Terminal pi-allyl palladium complexes are preferentially attacked at the least hindered position giving rise to linear products, as illustrated with several (E)-configured allylic substrates. Under isomerization free conditions the branched products are formed preferentially from the corresponding (Z)-allyl substrates. An interesting behavior is observed in the reaction of secondary allylic substrates. Aryl-substituted substrates show a significant memory effect which can be explained by an asymmetric pi-allyl complex. For alkyl-substituted substrates a strong dependence of the regioselectivity on the leaving group is observed, which can be explained by different conformations in the ionization step. Under isomerization free conditions the product ratio gives important information about this step.     

Enamines: efficient nucleophiles for the palladium-catalyzed asymmetric allylic alkylation

Enamines were tested to be efficient nucleophiles for palladium-catalyzed asymmetric allylic alkylation, avoiding the use of unstablilized ketone enolates formed by strong bases. The influence of the chiral metallocene-based ligands upon this reaction was studied in detail. It was shown that planar chirality played an important role in enantioselectivities. Meanwhile, different kinds of enamines and allylic acetate to the reactions were also investigated. High catalytic activity and excellent enantioselectivity (up to 99% ee) were obtained with pyrrolidine enamines of both aliphatic and aromatic ketone.     

Electronic differentiations in palladium-catalyzed allylic substitutions

The “trans rule” in Pd-catalyzed allylic substitutions predicts trans to phosphorus additions of nucleophiles to Pd-allyl intermediates, e.g., with P,N-ligands. This computational study reveals that not only the intrinsic electronic differentiation between P- (i.e., PH₃) and N-ligands (i.e., para-X-substituted pyridines), but also the “late” or “early” nature of the transition structures is crucial for strong cis vs. trans discriminations and hence for selectivity. Although para-nitro pyridine exhibits less intrinsic electronic differentiation than para-dimethylamino pyridine, the higher reactivity of the Pd-allyl-intermediate and the earlier nature of the transition structure yield a higher sensitivity for electronic differentiation for XNO₂ than XNMe₂.     

New oxazoline-containing phosphoramidite ligand for palladium-catalyzed asymmetric allylic sulfonylation

New chiral oxazoline-containing phosphoramidite was synthesized and its complex formation with rhodium(i) and palladium(ii) was examined. The new ligand is a highly efficient chiral inductor (ee up to 92%) in palladium-catalyzed asymmetric sulfonylation of 1,3-diphenylallyl acetate with sodium p-toluenesulfinate.     

Novel chiral biferrocene ligands for palladium-catalyzed allylic substitution reactions

Eleven novel aminophosphine ligands have been synthesized, all of which contain a chiral 2,2' '-bridged biferroceno unit as part of a biferrocenoazepine substructure. The efficiency of these compounds as chiral auxiliaries in palladium-mediated allylic substitution reactions has been investigated. Depending on the degree of (steric) fit between proper ligands and cyclic or noncyclic substrates, reactions with 46-87% ee were achieved. The molecular structure of a palladium dichloride complex of one of the ligands was determined by X-ray diffraction and compared to its binaphthyl analogue. In the solid state, the azepine substructure of these two complexes adopts totally different conformations with either local C(2) (binaphthyl) or local C(1) (biferrocene derivative) symmetry. These structural changes are well-reproduced by empirical force field calculations and are also reflected in significantly different behavior in asymmetric catalysis.     

Stereoselective palladium-catalyzed carbocyclization of allenic allylic carboxylates

Palladium(0)-catalyzed reaction of allene-substituted allylic carboxylates 3-8 employing 2-5 mol % of Pd(dba)(2) in refluxing toluene leads to the carbocyclization and elimination of carboxylic acid to give bicyclo[4.3.0]nonadiene and bicyclo[5.3.0]decadiene derivatives (12-17). The carbon-carbon bond formation is stereospecific, occurring syn with respect to the leaving group. Addition of maleic anhydride as a ligand to the above-mentioned procedures changed the outcome of the reaction, and under these conditions 3-5 afforded cycloisomerized products 21-23. The experimental results are consistent with a mechanism involving oxidative addition of the allylic carboxylate to Pd(0) to give an electron-deficient (pi-allyl)palladium intermediate, followed by nucleophilic attack by the allene on the face of the pi-allyl opposite to that of the palladium atom. Furthermore, it was found that the Pd(dba)(2)-catalyzed cyclization of the trans-cycloheptene derivative (trans-8) can be directed to give either the trans-fused (trans-17) or the cis-fused (cis-17) ring system by altering the solvent. The former reaction proceeds via a nucleophilic trans-allene attack on the (pi-allyl)palladium intermediate, whereas the latter involves a syn-allene insertion into the allyl-Pd bond of the same intermediate. The products from the carbocylization undergo stereoselective Diels-Alder reactions to give stereodefined polycyclic systems in high yields.     

Palladium-catalyzed allylic oxidation of olefins by t-butyl hydroperoxide and tellurium(IV) oxide

Treatment of several cyclic olefins, β-pinene, allylbenzene, and estragole with palladium(II) salt in acetic acid in the presence of t-butyl hydroperoxide and tellurium(IV) oxide afforded mainly the corresponding allylic acetates. The reaction proceeded catalytically with palladium(II) salt, t-BuOOH working as a reoxidizing agent.     

Regioselective synthesis of allylic sulfones by palladium-catalyzed denitro-sulfonylation of allylic nitro compounds

Allylic nitro compounds undergo denitro-sulfonylation catalyzed by Pd(PPh₃)₄ or Pd(PPh₃)₄ +NaNO₂ with PhSO₂Na·2H₂O to afford allylic sulfones regioselectively.     

New insights into the mechanism of palladium-catalyzed allylic amination

A comparative investigation into palladium-catalyzed allylic amination of unsubstituted aziridines and secondary amines has been carried out. The use of NH aziridines as nucleophiles favors formation of valuable branched products in the case of aliphatic allyl acetates. The regioselectivity of this reaction is opposite to that observed when other amines are used as nucleophiles. Our study provides evidence for the palladium-catalyzed isomerization of the branched (kinetic) product formed with common secondary amines into the thermodynamic (linear) product. In contrast, the branched allyl products obtained from unsubstituted aziridines do not undergo the isomerization process. Crossover experiments indicate that the isomerization of branched allylamines is bimolecular and is catalyzed by Pd(0). The reaction has significant solvent effect, giving the highest branched-to-linear ratios in THF. This finding can be explained by invoking the intermediacy of sigma-complexes, which is consistent with NMR data. The apparent stability of branched allyl aziridines towards palladium-catalyzed isomerization is attributed to a combination of factors that stem from a higher degree of s-character of the aziridine nitrogen compared to other amines. The reaction allows for regio- and enantioselective incorporation of aziridine rings into appropriately functionalized building blocks. The resulting methodology addresses an important issue of forming quaternary carbon centers next to nitrogen. The new insights into the mechanism of palladium-catalyzed allylic amination obtained in this study should facilitate synthesis of complex heterocycles, design of new ligands to control branched-to-linear ratio, as well as absolute stereochemistry of allylamines.     

Regioselective synthesis of trifluoromethyl group substituted allylic amines via palladium-catalyzed allylic amination

The palladium-catalyzed regioselective allylic amination of α-trifluoromethylated allyl acetate occurred using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF. The selective formation of the γ-product was attained by Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF.     

Isotope effects and the mechanism of palladium-catalyzed allylic alkylation

The palladium-catalyzed allylic alkylation reaction of 1,1-dimethylallyl acetate with dimethyl malonate is studied by a combination of isotope effects and theoretical calculations. A large ¹³C isotope effect of ≈1.037 is observed at the tertiary carbon, while small isotope effects are observed at the olefinic carbons. These results support rate-limiting ionization of a η²-Pd complex. The observed isotope effects are compared with predictions from calculational models employing either solvent models or ionization of an amidinium ion. The calculated transition structures are notably η² in character, and the implications of this observation are discussed.     

Aziridine-derived iminophosphine ligands in palladium-catalyzed allylic substitution

New iminophosphines have been synthesized from (R,R)-1-amino-2-diphenylphosphino cyclohexane (R.R)-1 in good to excellent yields. The catalysts obtained from iminophosphines 3a-g and [Pd(C₃H₅)Cl]₂ promote the enantioselective allylic substitution of 1,3-diphenyl-2-propenyl acetate (6) with diethyl malonate with good enantioselectivity. The air-stable complex PdCl₂[κ²-P,N-(R,R)-2-Ph₂PC₆H₁₀NCHPh] (4) has been prepared and structurally characterized by X-ray crystallography.     

Regioselective palladium-catalyzed formate reduction of N-heterocyclic allylic acetates

The regioselective palladium-catalyzed formate reduction of allylic acetates in five- to eight-membered heterocycles is reported. Reduction of allylic acetates under mild conditions using allylpalladium chloride dimer, phosphines, and formic acid/triethylamine in DMF gives the exo-cyclic olefins in good regioselectivities and high yields. Synthetic application in preparing N-tosyl-3-oxo-piperidine is also reported.