Pd-catalyzed allylic alkylation

The starting illylic rutro compound is obtained by nitranon of 2-methylpropene with NO Subsequent Michael addition to methyl vinyl ketone followed by Pd-catalyzed allylic alkylation affords terpenoids... 

Pd-catalyzed allylic alkylation with soft nucleophiles1151 is probably the most important categoiy within the more general area of transition metal-catalyzed allylic substitution (Scheme 6).116,171... 

A mechanism for the asymmetric induction for Pd-catalyzed allylic alkylations using chiral ligands such as 23 was proposed on the basis of stereochemical results and the X-ray structure of the intermediate Pd complex 24 <2004T2155>. The enantioselectivity of the alkylations, an example of which is shown in Equation (8), was rationalized by a conformational equilibrium that favored one of two possible 7i-allylpalladium complexes due to steric interference between the aryl substituent on the sulfmyl group of 24 and the phenyl of the 7i-allyl system. 

An NOE study of the intermediate [Pd(ti -PhCHCHCHPh)(Binap)], 82, thought to be involved in the Pd-catalyzed allylic alkylation of a 1,3-diphenylpropene, revealed that two phenyl rings, one from the auxiliary, D, and one from the substrate, F, are forced to take up parallel positions, i.e, they are 7i-stacked, as shown in 83 [103]. Since the ti-stacking is repulsive, and thus selectively weakens one of the two Pd-C(allyl) bonds, the reaction becomes stereoselective. The D and F rings do not show inter-ligand NOEs. 

Chiral nonracemic bidentate 2-[o-(diphenylphosphino)phenyl]-5,6-dihydro-4//-l,3-oxazine derivatives proved to be effective P,N-ligands in Pd-catalyzed asymmetric transformations. When used in the Pd-catalyzed allylic alkylations of 1,3-diphenylallyl acetate with dimethyl malonate, phosphino-oxazines 147 and 148 and the... 

A reaction of sulfoximine 268 with ort o-substituted halobenzaldehydes 269 takes place in the presence of a catalytic amount of Pd(ii), 2,2 -bis(diphenylphosphanyl)-l,l -binaphthyl (BINAP), and caesium carbonate at 110°C to afford fully conjugated 2-phenyl-2,l-benzothiazine 2-oxides 270 with a S(vi) oxidation state (Scheme 38) <1999AGE2419>. Bis-benzothiazine 75 has been prepared from dibromo-dialdehyde 271 in a similar manner and investigated as a ligand for Pd-catalyzed allylic alkylation reactions (see Section 8.07.12.3) <20010L3321>. 

The chiral nonracemic bis-benzothiazine ligand 75 has been screened for activity in asymmetric Pd-catalyzed allylic alkylation reactions (Scheme 42) <20010L3321>. The test system chosen for this ligand was the reaction of 1,3-diphenylallyl acetate 301 with dimethyl malonate 302. A stochiometric amount of bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc were added to the reaction mixture. A catalytic amount of chiral ligand 75 along with a variety of Pd-sources afforded up to 90% yield and 82% ee s of diester 303. Since both enantiomers of the chiral ligand are available, both R- and -configurations of the alkylation product 303 can be obtained. The best results in terms of yield and stereoselectivity were obtained in nonpolar solvents, such as benzene. The allylic alkylation of racemic cyclohexenyl acetate with dimethyl malonate was performed but with lower yields (up to 53%) and only modest enantioselectivity (60% ee). 

The Pd-catalyzed allylic alkylation of thiocarboxylate ions was carried out with potassium thioacetate (KSAc) and potassium thiobenzoate (KSBz) and the racemic cyclic and acyclic carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, rac-lba, and rac-lca, respectively (Scheme 2.1.4.21). The carbonates rac-3aa, rac-3ba, rac-lda, rac-laa, and rac-lba were treated with KSAc (1.4 equiv) or KSBz (2.0 equiv) in the presence of Pd(0)/L (2 mol%) and BPA (8 mol%) in CH2CI2/H2O. Under these conditions the acyclic carbonates rac-3aa and rac-3ba gave the thioesters 18aa, 18ab and 18ba, respectively (Table 2.1.4.14, entries 1-3), with high enantioselec-tivities in high yields [26]. 

The Pd-catalyzed allylic alkylation of sulfinate ions, thiols, and thiocarboxylate ions with racemic cyclic and acyclic allylic esters in the presence of bisphosphane BPA generally provides for an efficient asymmetric synthesis of allylic sulfones, sulfides, and thioesters. The Pd-catalyzed rearrangements of allylic sulfinates and allylic O-thiocarbamates, both of which proceed very efficiently in the presence of BPA, are attractive alternative ways to the asymmetric synthesis of allylic sulfones and allyUc thioesters also starting from the corresponding racemic alcohols. 

The Pd-catalyzed rearrangements most probably follow an ionization-substitution pathway with the intermediate formation of a jc-allyl-Pd complex. The Pd-catalyzed allylic alkylation is generally accompanied by a highly selective kinetic and synthetically useful resolution of the racemic allylic acetates and carbonates. 

Optically active Cr-complexed arylphosphines 57 can be prepared in three steps from achiral arene-Cr(CO)3 precursors 56. A successful addition of PPh2Li to the complex 56a with concomitant carbamate displacement has been suggested, giving rise to the desired phosphine complex 57a as an air-stable crystalline solid in 96 % yield (R = H) (Scheme 26). Therefore, efficient C-P bond construction can be achieved by reacting, for example, the biaryl complex 56b with PPh2Li, providing the optically active monophosphine ligand 57b in 87 % yield, which has been used in Pd-catalyzed allylic alkylation reactions (Scheme 26) [42]. 

The stereochemistry of Pd -catalyzed allylic alkylation is net retention (equation 62). This arises from sequential inversion steps. Initially, the Pd approaches from the face of the C3 unit opposite the leaving group, to form the jt-allyl complex. Subsequently, the nucleophile adds to the face of the TT-allyl opposite palladium. If a bulky or umeactive nucleophile is used with allylic acetates, the acetoxy group can add again to the complex. Ultimately, this results in the production of a mixture of stereoisomers upon nucleophihc addition. As an example of the range of allylic substrates that react, nitrogen nucleophiles, in particular primary and secondary amines, undergo palladium-catalyzed substimtion with aUyhc alcohols, acetates, and ethers (equation 63). 

Scheme 25 Tandem Pd-catalyzed allylic alkylation-allylic amination sequence...

However, Pd-catalyzed allylic alkylations have found more applications in intra- rather than in inter-molecular substitution reactions. Many of these alkylations are highly regio- and stereo-selective and occur with allylic rearrangement and are applied to construct various carbo- and hetero-cyclic sys-tems. " Some illustrative examples are shown in equations... 

Less electron-rich ligands could be applied efficiently in olefin hydrogenation (28) [118-122], Pd-catalyzed allylic alkylation (29) (up to 60% ee) [123], and hydroformylation (up to 77 % ee) [124]. 

The enantiopure phosphinooxazolinidines (POZ)s were a type of N—P chiral ligand developed by Nakano and used for asymmetric Pd-catalyzed allylic alkylations [133] and Diels-Alder reactions [59]. A PS-supported version of this type of chiral hgand 210 was prepared and apphed to the asymmetric aUylic alkylation of acetate 201 with dialkyhnalonates [134], affording the product in exceUent yield (99%) with 99% ee, as shown in Scheme 3.69. 

Sawamura, M., Sudoh, M., and Ito, Y., An enantioselective two-component catalyst system. Rh-Pd-catalyzed allylic alkylation of activated nitriles, 7. Am. Chem. Soc., 118, 3309, 1996. 

Madec and Poli recently reported that sulfenate anions can also be used as nucleophiles in catalytic formation of C ryi-S bonds, generating sulfoxides [103]. The sulfenate anions are generated in situ by base-induced elimination of (3-sulfinyles-ters [136]. These groups subsequently developed an enantioselective variant, allowing the asymmetric synthesis of sulfoxides with up to 83% ee (16) [105]. Chiral sulfoxides are present in a variety of pharmaceuticals and are widely used in asymmetric catalysis [137-141]. Likewise, Madec and Poli found that sulfenate anions can be used to generate Csp -S bonds in Pd-catalyzed allylic alkylation [ 142]. o... 

Allylic alkylation catalyzed by Pd(dba)2 and ( PrO)3P has been used for incorporation of nucleobases (pyrimidines and purines) into carbocyclic nucleoside analogs. In certain cases, unstabilized nucleophiles have been found to participate in allylic alkylation reactions. For example, an aUenic double bond is sufficiently nucleophilic to react with the r-aUyl complex generated upon heating Pd(dba)2 and 1 in toluene (eq 15). Formation of the trans-fused product (2) was interpreted to arise via the double inversion pathway commonly observed in conventional Pd-catalyzed allylic alkylation reactions. Interestingly, changing to a coordinating solvent (CH3CN) resulted in allene insertion into the r-allyl complex to form the isomeric c/s-fused product (3). 

ProIine-derived phosphines bearing various sulfenyl substituents have been developed Use of 21a-g as chiral ligands provided (5)-2, except 21e [(/ )-2], with 31-88% ee in the Pd-catalyzed allylic alkylation of 1 with dimethyl malonate using [Pd(7r-allylX l]2, BSA, and AcONa in dichloromethane at room temperature. Increasing the steric bulk of the substituents of the sulfenyl groups results in enhanced enantiocontrol (21g. provides 88% ee). The thiophene ligand 22 provides (R)-2 with 30% ee (Scheme 12). 

Proline-derived phosphines 27a,b bearing chiral sulfinyl groups were used as chiral ligands in Pd-catalyzed allylic alkylations of 1 with dimethyl malonate using [Pd(7T-allyl)Cl]2, BSA, and AcONa, affording (5)-2 with 60% and 33% ee, respectively (Scheme 15). 

The Pd-catalyzed allylic alkylation or amination of 1 with dimethyl sodiomalonate or benzylamine using [Pd(7r-allyl)Cl]2 provided (S)-2 or (/ )-40 with 82% or 85% ee, respectively. 

Sulfinyl functionality serves as a slightly weaker coordinating element compared with sulfenyl function. Chiral sulfoxide ligands provide rather good enantioselectivity in Pd-catalyzed allylic alkylations. (/ )-o-(Diphenylphosphinoamino)phenyl 2-methoxy-l-naphthyl sulfoxide provided the highest enantioselectivity (97%) among known chiral sulfoxide ligands. 

The synthesis of P-chiral diarylphosphinocarboxylic acids 120 was achieved with excellent enantiopurity starting from the oxazaphospholidine boranes 82. Amido- and amino-diphosphine ligands 121, containing an L-proline backbone, were also derived from 82. The catalytic activities of the ligands 121 were evaluated in the Pd-catalyzed allylic alkylation reaction of 1,3-diphenylpropenyl acetate (Scheme 36) [66]. 

In 2010, Hoshi, Hagiwara, and co-workers designed and synthesized various (/ )-sulfur-MOP ligands with aryl and alkyl substituents on sulfur. These ligands were applied in the Pd-catalyzed allylic alkylation of indoles. The allylation products from substituted indoles were obtained with up to 95% ee (Scheme 6.79). 

V. G. Albano, M. Bandini, M. Melucci, M. Monari, F. PiccineUi, S. Tommasi and A. Umani-Ronchi, Novel chiral diamino-oligothiophenes as valuable ligands in Pd-catalyzed allylic alkylations. On the primary role of secondary interactions in asymmetric catalysis, Adv. Synth. Ceded., 347, 1507-1512 (2005). 

Another interesting application of allyl halides in Pd-catalyzed allylic alkylations utilizes substituted 1-alkenylcyclopropyl chlorides (Scheme 12.38). These allylic chlorides, as well as the more reactive, analogous tosylates, react with soft nucleophiles, such as malonates, in a highly regioselective manner [17d,e, 72]. The attack at the ii-allylpalladium intermediate takes place preferentially at the allylic position distal to the cyclopropyl substituent, providing access to a variety of synthetically useful methylenecydopropane derivatives. 

Nucleophiles have also been activated by other mild procedures (Scheme 10). Basic alumina and KF-alumina have been nsed to activate a range of pronucleophiles including the nitro ester 48 and sulfone Titanium tetraisopropoxide has also been nsed to promote Pd-catalyzed allylic alkylations, as exemplified by the reaction of cinnamyl acetate 50 with the bis-sulfone 51. ... 

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