Carbon nucleophiles allylation

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

Formation of a Tr-allylpalladium complex 29 takes place by the oxidative addition of allylic compounds, typically allylic esters, to Pd(0). The rr-allylpal-ladium complex is a resonance form of ir-allylpalladium and a coordinated tt-bond. TT-Allylpalladium complex formation involves inversion of stereochemistry, and the attack of the soft carbon nucleophile on the 7r-allylpalladium complex is also inversion, resulting in overall retention of the stereochemistry. On the other hand, the attack of hard carbon nucleophiles is retention, and hence Overall inversion takes place by the reaction of the hard carbon nucleophiles. 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

The enamine 315 as a carbon nucleophile reacts with 7r-allylpalladium complexes to give allyl ketones after hydrolysis[265],... 

Hard carbon nucleophiles of organometallic compounds react with 7r-allyl-palladium complexes. A steroidal side-chain is introduced regio- and stereo-selectively by the reaction of the steroidal 7T-allylpalladium complex 319 with the alkenylzirconium compound 320[283]. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

In addition, a catalytic version of Tt-allylpalladium chemistry has been devel-oped[6,7]. Formation of the Tr-allylpalladium complexes by the oxidative addition of various allylic compounds to Pd(0) and subsequent reaction of the complex with soft carbon nucleophiles are the basis of catalytic allylation. After the reaction, Pd(0) is reformed, and undergoes oxidative addition to the allylic compounds again, making the reaction catalytic.-In addition to the soft carbon nucleophiles, hard carbon nucleophiles of organometallic compounds of main group metals are allylated with 7r-allylpalladium complexes. The reaction proceeds via transmetallation. These catalytic reactions are treated in this chapter. 

In addition to the catalytic allylation of carbon nucleophiles, several other catalytic transformations of allylic compounds are known as illustrated. Sometimes these reactions are competitive with each other, and the chemo-selectivity depends on reactants and reaction conditions. 

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]. 

Interestingly, the allylation of a stabilized carbon nucleophile has been found to be reversible. Complete isomerization of dimethyl methylmalonate, involving bis-allylic C—C bond cleavage, from a secondary carbon 38 to a primary carbon 39 was observed by treatment with a Pd catalyst for 24 h. The C—C bond cleavage of a monoaliylic system proceeds slowly[40]. 

The intramolecular allylation of soft carbon nucleophiles with allylic acetates as a good cyclization method has been extensively applied to syntheses of various three, four, five and six-membered rings, and medium and macrocyclic compounds[44]. Only a few typical examples of the cyclizations are treated among numerous applications. 

The allyl-substituted cyclopentadiene 122 was prepared by the reaction of cyclopentadiene anion with allylic acetates[83], Allyl chloride reacts with carbon nucleophiles without Pd catalyst, but sometimes Pd catalyst accelerates the reaction of allylic chlorides and gives higher selectivity. As an example, allylation of the anion of 6,6-dimethylfulvene 123 with allyl chloride proceeded regioselectively at the methyl group, yielding 124[84]. The uncatalyzed reaction was not selective. 

The allylic esters 189 and 191 conjugated with cyclopropane undergo regio-selective reactions without opening the cyclopropane ring. The soft carbon nucleophiles are introduced at the terminal carbon to give 190, and phenylation with phenylzinc chloride takes place on the cyclopropane ring to form 192[120]. 

Asymmetric allylation of carbon nucleophiles has been carried out extensively using Pd catalysts coordinated by various chiral phosphine ligands and even with nitrogen ligands, and ee > 90% has been achieved in several cases. However, in most cases, a high ee has been achieved only with the l,3-diaryl-substitiitcd allylic compounds 217, and the synthetic usefulness of the reaction is limited. Therefore, only references are cited[24,133]. 

Since allylation with allylic carbonates proceeds under mild neutral conditions, neutral allylation has a wide application to alkylation of labile compounds which are sensitive to acids or bases. As a typical example, successful C-allylation of the rather sensitive molecule of ascorbic acid (225) to give 226 is possible only with allyl carbonate[l 37]. Similarly, Meldrum s acid is allylated smoothly[138]. Pd-catalyzed reaction of carbon nucleophiles with isopropyl 2-methylene-3,5-dioxahexylcarbomite (227)[I39] followed by hydrolysis is a good method for acetonylation of carbon nucleophiles. 

Some nucleophiles other than carbon nucleophiles are allylated. Amines are good nucleophiles. Diethylamine is allylated with allyl alcohol[7]. Allylammes are formed by the reaction of allyl alcohol with ammonia by using dppb as a ligand. Di- and triallylamines are produced commercially from allyl alcohol and ammonia[l74]. 

Phenols arc highly reactive 0-nucleophiles and allylated easily with allylic carbonates under neutral conditions. EWGs on phenols favor the reac-tion[213]. Allylic acetates are used for the allylation of phenol in the presence of KF-alumina as a base[214]. 

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],... 

Cross-Couplinf of Allylic Groups with Hard Carbon Nucleophiles... 

Dienes and allylarcncs can be prepared by the Pd-catalyzcd coupling of allylic compounds with hard carbon nucleophiles derived from alkenyl and aryl compounds of main group metals. Allylic compounds with various leaving groups can be used. Some of them are unreactive with soft nucleophiles, but... 

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are structurally sim liar—both contain a double bond and a pyrophosphate ester unit—but the chemical reactivity expressed by each is different The principal site of reaction m dimethylallyl pyrophosphate is the carbon that bears the pyrophosphate group Pyrophosphate is a reasonably good leaving group m nucleophilic substitution reactions especially when as in dimethylallyl pyrophosphate it is located at an allylic carbon Isopentenyl pyrophosphate on the other hand does not have its leaving group attached to an allylic carbon and is far less reactive than dimethylallyl pyrophosphate toward nucleophilic reagents The principal site of reaction m isopentenyl pyrophosphate is the carbon-carbon double bond which like the double bonds of simple alkenes is reactive toward electrophiles... 

Addition of carbon nucleophiles to vinylepoxides is of particular importance, since a new carbon-carbon bond is formed. It is of considerable tactical value that conditions allowing for regiocontrolled opening of vinyloxiranes with this type of nucleophiles have been developed. Reactions that proceed through fonnation of a rr-allyl metal intermediate with subsequent external delivery of the nucleophile, or that make use of a soft carbon nucleophile, generally deliver the SN2 product. In contrast, the Sn2 variant is often the major reaction pathway when hard nucleophiles are employed. In some methods a nucleophile can be delivered selectively at either the Sn2 or SN2 positions by changing the reaction conditions. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Nucleophilic substitution at an allylic carbon takes place either by an SN2 mechanism or by an Sn2 mechanism. No allylic rearrangement takes place in the former case, but it does occur in the latter case. 

For trisubstituted olefins, the nucleophile attacks predominantly at the less substituted end of the allyl moiety, e.g. to afford a 78 22 mixture of 13 and 14 (equation 7). Both the oxidative addition of palladium(O) and the subsequent nucleophilic attack occur with inversion of configuration to give the product of net retention7. The synthesis of the sex pheromone 15 of the Monarch butterfly has been accomplished by using bis[bis(l,2-diphenylphosphinoethane)]palladium as a catalyst as outlined in equation 87. A substitution of an allyl sulfone 16 by a stabilized carbon nucleophile, such as an alkynyl or vinyl system, proceeds regioselectively in the presence of a Lewis acid (equation 9)8. The... 

Nucleophilic substitution at an allylic carbon can also take place by an Sn2 mechanism, in which case no allylic rearrangement usually takes place. However, allylic rearrangements can also take place under Sn2 conditions, by the following mechanism, in which the nucleophile attacks at the y carbon rather than the usual... 

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