Allylation Pd -catalyzed

The stereochemistry of the Pd-catalyzed allylation of nucleophiles has been studied extensively[5,l8-20]. In the first step, 7r-allylpalladium complex formation by the attack of Pd(0) on an allylic part proceeds by inversion (anti attack). Then subsequent reaction of soft carbon nucleophiles, N- and 0-nucleophiles proceeds by inversion to give 1. Thus overall retention is observed. On the other hand, the reaction of hard carbon nucleophiles of organometallic compounds proceeds via transmetallation, which affords 2 by retention, and reductive elimination affords the final product 3. Thus the overall inversion is observed in this case[21,22]. 

Allylation under basic conditions. Allylation can be carried out under basic conditions with allylic acetates and phosphates, and under neutral conditions with carbonates and vinyloxiranes. The allylations under neutral conditions are treated separately in Section 2.2.2.1 from those under basic conditions. However, in some cases, allylations of the same substrates are carried out under both basic and neutral conditions to give similar results. These reactions are treated together in this section for convenience. Allylic acetates are widely used for Pd-catalyzed allylation in the presence of bases tertiary amines or NaH are commonly used[6,7,4l]. As a base, basic alumina or ICF on alumina is conveniently used, because it is easy to remove by filtration after the reaction[42]. Allyl phosphates are more reactive than acetates. The allylation with 40 proceeds stepwise. At first allylic phosphate reacts with malonate and then allylic acetate reacts with amine to give 41(43]. 

Various S-nucleophiles are allylated. Allylic acetates or carbonates react with thiols or trimethylsilyl sulfide (353) to give the allylic sulfide 354[222], Allyl sulfides are prepared by Pd-catalyzed allylic rearrangement of the dithio-carbonate 355 with elimination of COS under mild conditions. The benzyl alkyl sulfide 357 can be prepared from the dithiocarbonate 356 at 65 C[223,224], The allyl aryl sufide 359 is prepared by the reaction of an allylic carbonate with the aromatic thiol 358 by use of dppb under neutral condi-tions[225]. The O-allyl phosphoro- or phosphonothionate 360 undergoes the thiono thiolo allylic rearrangement (from 0-allyl to S -allyl rearrangement) to afford 361 and 362 at 130 C[226],... 

Carboxylic acids react with butadiene as alkali metal carboxylates. A mixture of isomeric 1- and 3-acetoxyoctadienes (39 and 40) is formed by the reaction of acetic acid[13]. The reaction is very slow in acetic acid alone. It is accelerated by forming acetate by the addition of a base[40]. Addition of an equal amount of triethylamine achieved complete conversion at 80 C after 2 h. AcONa or AcOK also can be used as a base. Trimethylolpropane phosphite (TMPP) completely eliminates the formation of 1,3,7-octatriene, and the acetoxyocta-dienes 39 and 40 are obtained in 81% and 9% yields by using N.N.N M -tetramethyl-l,3-diaminobutane at 50 in a 2 h reaction. These two isomers undergo Pd-catalyzed allylic rearrangement with each other. 

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... 

Scheme 6 The catalytic cycle for Pd-catalyzed allylic substitution.

In general, Pd-catalyzed allylic substitutions with soft nucleophiles involve nudeophilic attack directly on the allyl unit, on the opposite face to that occupied by the metal. This is contrasted with the situation for hard nucleophiles where the initial attack occurs at the metal, with subsequent migration of the nudeo-phile to the allyl moiety - the addition to the allyl unit therefore occurring from the same face as the metal. Obviously, this has profound implications on the stereochemical outcome. 

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. 

Scheme 5. Regioselectivity in the Pd-catalyzed allylation of carbonyl compounds in the presence of Zn salts...

An extension of these dendritic phosphine ligands for Pd-catalyzed allylic ami-nation was recently described using a thermomorphic system for separation [72]. 

The Pd-catalyzed allylic subshtution with soft nucleophiles proceeds via two substitutions with inversion-that is, with a net retention of configuration. By using standard tests, the same steric course was found for the Ir-catalyzed alkylation... 

Hydroxylamine derivatives are ambident nucleophiles. For example, N-benzylhy-droxylamine functions as an N-nucleophile in the Ir-catalyzed allylic substitution, while N-Boc-hydroxylamine yields mixtures of the N- and O-substituted products in Ir- as well as Pd-catalyzed allylic substitutions. Accordingly, either O- or N,0-protected hydroxylamine derivatives need to be used as nucleophiles [63]. 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

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. 

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