Electrophilic carbon moieties, allylations

It is very well known that jr-allyl palladium complex 1, which is a key intermediate for the Tsuji-Trost type allylation, has an electrophilic character and reacts with nucleophiles to afford the corresponding allylation products. We discovered that bis 7r-allyl palladium complex 2 is nucleophilic and reacts with electophiles such as aldehydes [27] and imines [28-32] (Scheme 2, Structure 2). We have also shown that bis 7r-allyl palladium complex 2 can act as an amphiphilic catalytic allylating agent it reacts with both nucleophilic and electrophilic carbons at once to produce double allylation products [33]. These complexes incorporate two allyl moieties that can bind with different hapticity to palladium (Scheme 3). The different complexes may interconvert by ligand coordination. The complexes 2a, 2b and 2c are called as r]3,r]3-bisallypalladium complex (also called bis-jr-allylpalladium complex), r)l,r)3-bis(allyl)palladium complex, -bis(allyl)palladium complex, respectively. Bis zr-allyl palladium complex 2 can easily be generated by reaction of mono-allylpalladium complex 1 and allylmetal species 3 (Scheme 4) [33-36]. Because of the unique catalytic activities of the bis zr-allyl palladium complex 2, a number of interesting cascade reactions appeared in the literature. The subject of the present chapter is to review some recent synthetic and mechanistic aspects of the interesting palladium catalyzed cascade reactions which in-... 

The coupling of an allyl or acyl moiety onto carbon atoms is achieved by anodic oxidation of a-heteroatom substituted organostannanes or Oj -acetals in the presence of allylsilanes or silyl enol ethers. The reaction probably involves carbocations as intermediates that undergo electrophilic addition to the double bond [245c]. 

Similar to the reaction course of the allylic substitution, which involves formation of tr-allyl moieties followed by subsequent nucleophilic addition across the Jt-bond, the mononitrosyl iron(—II) complex was expected to be active in transesterifications involving activation of carbonyl group and nucleophilic addition to the electrophilic carbon atom [100]. This assumption could be verified by experimental tests. Under neutral conditions without addition of a ligand co-catalyst, the iron complex 31 exhibited high activity in the transesterification of vinyl acetate. Good to excellent yields were obtained affording a new ester bond, as depicted in Scheme 39. 

When the electrophile contains two allyl halide moieties, two carbon—carbon bonds are formed, resulting in cyclized compounds 47 and 48, as shown in Eq. 2.34 [7f]. 

Cyclic epoxides such as 124 can react in two ways with strong bases (a) via abstraction of a /3-proton to form allylic alcoholates 125 or (b) by deprotonation at the epoxide carbon atom forming the intermediate 126 and, after electrophilic substitution, the epoxides 128. If there is a suitable C—H bond in the vicinity of the C-Li moiety, intramolecular carbenoid insertion reactions to 127 may take place (equation 27) ° . ... 

An example of a structural substituent that is often metabolized (bioactivated) to an electrophile is the allyl alcohol substituent (C=C—C—OH). Allyl alcohol moieties are found in many commercial chemical substances, either as the free alcohol or as an ester or ether. As illustrated in Scheme 4.1, allyl alcohols (and also as their esters or ethers) that contain at least one hydrogen atom on the alcoholic carbon can be oxidized in the liver by alcohol dehydrogenase (ALDH) to the corresponding a, 3-unsaturated carbonyl metabolite, which is toxic in many cases [29-31]. The hepatotoxicity of allyl alcohol (1), for example, is due to its oxidation by ALDH to acrolein (2), an a,(3-unsaturated aldehyde, which undergoes Michael addition with cellular nucleophiles in the liver [29] (Scheme 4.1). Cyclic allyl alcohols (Scheme 4.1) are expected to undergo similar enzymatic oxidation to yield a,(3-unsaturatcd carbonyl metabolites and are also likely to be toxic. 

When designing substances that contain oleftnic or acetylenic moieties, chemists should keep in mind the potential for these substituents to be bioactivated to electrophilic species and, whenever possible, incorporate other structural changes that lessen the likelihood for bioactivation. Terminal carbon-carbon double or triple bonds should be avoided or at least contain an alkyl substituent on the C-2 carbon (in the case of olefins) and alkyl substituents on the allylic or propargylic carbons. Halogens on terminal unsaturated carbons should be avoided. Aromatic substituents at the allylic or propargylic positions should also be avoided if allylic or propargylic hydrogens are present. 

All types of electrophiles have been used with 2-lithio-l,3-dithiane derivatives, including alkyl halides, sulfonates, sulfates, allylic alcohols, arene-metal complexes, epoxides, aziridines, carbonyl compounds, imines, Michael-acceptors, carbon dioxide, acyl chlorides, esters and lactones, amides, nitriles, isocyanates, disulfides and chlorotrialkylsilanes or stannanes. The final deprotection of the dithioacetal moiety can be carried out by means of different types of reagents in order to regenerate the carbonyl group by heavy metal coordination, alkylation and oxidation184 or it can be reduced to a methylene group with Raney-nickel, sodium or LiAIII4. 

The transfer of the allylic moieties from boron to the electrophilic carbonyl carbon proceeds via rearrangement to form intermediate boronic esters C and D (see below). The reaction is highly diastereoselective. The ( )-crotylboronate reacts to give the anfr-homoallylic alcohol and the (Z)-crotylboronate reacts to afford the syn-homoallylic alcohol.This behavior has been interpreted in terms of the Zimmerman-Traxler chair-type transition state model.Because of the double bond geometry, coordination of the (Ei-crotylboronic ester places the Me preferentially equatorial, whereas coordination of the (Z)-crotylboronic ester places the Me axial, as illustrated in the cyclohexane chair-form transition state conformations A and B, respectively. In both cases, the R moiety of the aldehyde must occupy a pseudo-equatorial position to avoid steric repulsion by one of the OR substituents on boron. 

Figure 4 Electrophilic aromatic substitution, constituting the most likely mechanism for DMAT synthase. The diphosphate moiety dissociates to generate the allylic carbocation, which then attacks the activated carbon-4 of the indole ring system. Approach of the aromatic C-4 is opposite the diphosphate leaving group, as indicated by experiments with specifically mono-tritiated (T) DMAPP (Shibuya et al., 1990). 

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