Palladium carbanion alkylations

Table 5. Chemoselectivity with Palladium-Promoted Alkylation of Functionalized Cyclic Allyl Acetates with Soft Carbanions...

In general, allyl ethers are less reactive than esters and therefore rarely used as substrates in the palladium-assisted alkylation with soft nucleophiles. Phenyl a- or )5-D-eor//jro-hex-2-enopyra-nosides react with a variety of soft carbanions under neutral conditions to give the a- or t -C -g]ycopyranosides, respectively in good to excellent yields both stereoselectively and with complete regioselectivity88. Since the liberated phenoxide ion deprotonates the active methylene compounds, no external base has to be added. 

Alkenyl zirconium complexes derived from alkynes form C—C bonds when added to aHyUc palladium complexes. The stereochemistry differs from that found in reactions of corresponding carbanions with aHyl—Pd in a way that suggests the Cp2ZrRCl alkylates first at Pd, rather than by direct attack on the aUyl group (259). 

The use of organozirconium compounds as carbanion equivalents is greatly facilitated by trans metallations to the more reactive aluminum [11,100], copper [104—106], nickel [96—98], and palladium [99] derivatives. Copper-catalyzed carbon—carbon bond-forming reactions of alkyl- and alkenylzirconocene compounds have been particularly well studied, and have found considerable application in organic synthesis [107,108]. 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

Terminal monoalkenes were alkylated by stabilized carbanions (p a 10-18) in the presence of 1 equiv. of palladium chloride and 2 equiv. of triethylamine, at low temperatures (Scheme l).1 The resulting unstable hydride eliminate to give the alkene (path b), or treated with carbon monoxide and methanol to produce the ester (path c).2 As was the case with heteroatom nucleophiles, attack at the more substituted alkene position predominated, and internal alkenes underwent alkylation in much lower (=30%) yield. In the absence of triethylamine, the yields were very low (1-2%) and reduction of the metal by the carbanion became the major process. Presumably, the tertiary amine ligand prevented attack of the carbanion at the metal, directing it instead to the coordinated alkene. The regiochemistry (predominant attack at the more sub-... 

Considering the reductive elimination mechanism that takes place within the coordination sphere of the palladium, one might expect the nucleophilic addition of unstabilized nucleophiles to be more enantioselective than that of stabilized nucleophiles because the nucleophile can directly interact with the chiral ligand. However, there are only a few examples in the literature that give high enantioselectivity. In the case of the alkylation with unstabilized carbanions, nickel catalysts have been more frequently used (see next section). 

Chiral crown ether phosphine-palladium complexes have been used to catalyse the alkylation of carbanions derived from a-nitro ketones and a-nitro esters,63 and proline rubidium salts have been used to catalyse asymmetric Michael addition of nitroalkanes to prochiral acceptors 64 80% enantioselectivity can be achieved in each case. 

The palladium(O) catalysed allylic alkylation of soft carbon nucleophiles represents a very useful tool for organic synthesis. The reaction conditions often involve heating a mixture of stabilised carbanions together with the substrate and the catalyst mixture in THF. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Using this method, synthesis of functionalized substituted cyclopropanes can be achieved via nucleophilic alkylation of the monoacetates of but-2-ene-l,4-diols 18 with malonates (and similar stabilized) carbanions in the presence of a palladium(0) catalyst. Subsequent acylation of the second hydroxyl function and subsequent treatment with base in the presence of the palladium(0) catalyst leads to intramolecular nucleophilic alkylation. This method and similar conversions have been applied to numerous other cyclopropane ring constructions. - - ... 

This reaction type differs from die three-component reaction reported by Grigg et al. Thus, Grigg et al. [53] (Scheme 7) immobihzed 3-iodo-4-(N-acetyl-N-(2-methyl-2-propenyl)amino)benzoate (36) onto a sohd support. In the presence of suitable Pd salts, Pd substituted the iodide function of the aromatic. The proximal isopropyhdene group trapped the resulting metalated species in an intramolecular Heck reaction. The resulting alkyl palladium species (37) could then react with a suitable carbanion equivalent. The authors used vinylstaimanes or boronates for this purpose, which they obtained in situ from alkynes by hydroboration or hydro-starmylation. The latter procedure allowed them to attach the same vinylic species via its terminal carbon (boronate) (41) and its subterminal carbon (stannane) (39). 

This well known reaction can deceive us into thinking that o-complexes of Pd are stable. They are not. All the steps between 86 and 89 are reversible and in the absence of hydrogen, the reaction runs backwards. Palladium readily does the oxidative insertion into an alkyl halide to give the o-complex 92, a carbanion complex of Pd(II), but this immediately loses hydrogen by p-elimination and the alkene 86 is formed with the loss of a PdHBr complex. Notice that this Pd(II) complex immediately reverts 93 to Pd(0). 

By far, the most widely used method is the alkylation of an a-sulfonyl carbanion followed by reductive removal of the sulfonyl group. Different electrophiles such as alkyl halides, sulfonates, sulfinates, acetates, oxiranes, and electron-deficient multiple bonds are employed for the formation of the new C-C bond. Palladium-catalyzed it-allylic alkylation with a-sulfonyl carbanions is also a commonly used method. After the C-C bond formation, the conditions for the final desulfonylation reaction with the appropriate reagent will depend on the structure of the sulfone intermediate. 

Synthesis of All-t/a/is-Geranylgeraniol. The type of alkylation described above for the synthesis of bacillariolide III is widely used in the synthesis of natural products due to the mild reaction conditions and high stereospecificity. The formation of the C-C bond takes place when activated a-sulfonyl car-banions derived from (3-ketosul tones, a-sulfonyl sulfones or, less often, allylic sulfones react with the H-allyl palladium complex. In the synthesis of all-trans-geranylgeraniol, the a-sulfonyl carbanion adds to the Ti-allylpalladium complex of 2-(prop-l-en-2-yl)oxirane. Final reductive desulfonylation affords the desired compound, as depicted in Eq. 147.254... 

Excellent nucleophiles in palladium(0)-eatalyzed allylic alkylations are soft carbanions, i.e.. metal salts of C — H acids with a pKa in the range of 10-20. These are activated methylene compounds which are substituted with at least two geminal electron-withdrawing groups [CO.R, S02R, — CN, —NC. COR, N02, (C6H5)2C = N]. As an exception, deprotonated simple nitroalkanes are sometimes also effective as nucleophiles. 

The palladium-mediated substitution of allylic substrates proceeds in two independent steps. For stabilized carbanions both oxidative addition and the nucleophilic displacement occur with inversion of configuration. Thus, overall retention results, in contrast to the corresponding reactions of nonstabilized carbanions as nucleophiles (see Section D.l. 5.6.3.). The steric course of the reaction is proved by the absence of racemization in Lhe conversion of chiral substrates into chiral alkylated products. Furthermore, chiral n-allylpalladium complexes formed with inversion from stoichiometric reactions of palladium(O) with allyl substrates have been isolated. Coupling of these stereodefined complexes with soft carbanions yields the chiral alkylated products, again with inversion of configuration. 

The solvent may determine the stereochemistry in the stoichiometric formation of 7r-allyl-palladium complexes from allyl halides. Strong donor solvents such as acetonitrile and dimethylsulfoxide lead to the expected m-ir-allyl complexes cis-16, whereas benzene, dichloro-methane or tetrahydrofuran give the. vva-addition product Irans-1639. Using soft carbanions in tetrahydrofuran. both complexes are converted to the corresponding alkylated products 17 with clean inversion of configuration. 

Table 11. Palladium(0)-Catalyzed Neutral Alkylation of Vinyl Epoxides with Soft Carbanions...

The influence of double stereodifferentiation on palladium(0)-assisted alkylation of soft car-banions has not yet been thoroughly investigated. Coupling of a chiral ally ligand, prepared from a- or //-phenyl-n-cn // ru-hcx-2-enopyranoside (see Section 1.5.6.1.2.1.)4 with a prostereogenic soft carbanion in the presence of Diop has not improved the simple diastereoselectivity. 

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