Allyl chloride nucleophilic addition

Nucleophilic addition reactions of allylic tin reagents to chiral 3-substituted 3,4-dihydroisoquinolines 89 activated by acyl chlorides afford trans 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines 90 stereoselectively <95CL1003>. 

If the side chain with the nucleophile is situated in the 1-position of the conjugated diene, a palladium-catalyzed spirocyclization occurs. In this case stereoselective oxa-spirocyclizations were obtained from the diene alcohols 59 and 60 (equation 23 -25)58. The reaction worked well for the formation of a tetrahydrofuran and tetrahydropyran in the spirocyclization. In the absence of chloride ions 59 gave high yields of the acetoxy oxaspirocyclic compound 61 via a 1,4-anti addition across the diene (equation 23). In the presence of stoichiometric amounts of LiCl a 1,4-syn oxychlorination took place and allylic chloride 62 was obtained (equation 24). Under chloride-free conditions, cyclohep-tadiene alcohol 60 afforded oxaspirocyclic acetate 63 (equation 25). 

The addition of sodium phenylsulfinate nucleophiles to stereodefined acyclic allylic chlorides was reported to proceed with complete overall retention of configuration, indicating that this nucleophile adds with inversion of configuration, i.e. via attack at the allyl ligand (equation 193).21S A cyclohexenyl acetate substrate also showed predominant ligand addition, but some isomeric product was also produced (equation 194).216 This loss could be due to acetate epimerization of starting material, ir-allyl epimeriza-tion by PdL2, or by attack of the sulfur at the metal, followed by reductive elimination. 

Pd(0)/phosphine complexes, or their precursors, in the presence of a suitable co-base, have also been shown to promote, in good yields (66-100%), the formation of allylic carbamates from various primary and secondary aliphatic amines, pressurized C02 and allylic chlorides, in THF, at ambient temperature [87a]. The choice of the added co-base (Base), used for generating the carbamate salt RR NC02 (BaseH)+, was found to be critical for high yields of O-allylic urethanes. The use of a guanidine (CyTMG) or amidine (DBU) base was optimal for this system (see also Section 6.3.1). ft is assumed that this chemistry passes catalytically through a mechanism similar to that illustrated in Scheme 6.19. This involves nucleophilic attack by carbamate anion on a (tt-allyl) palladium species, formed by the oxidative addition of the allylic chloride to a palladium(O) intermediate. 

Allylic amination of allyl halides can also be achieved using lithium and potassium bis(trimethylsilyl)amides [34] and potassium 1,1,3,3-tetramethyldisilazide [35] as the nucleophiles. It has been found that for the reaction of alkyl-substituted allyl chlorides using lithium bis(trimethylsilyl)amides as the nucleophile the allylic amination proceeds smoothly in a SN2 fashion to give /V,Af-disilylamines in high yields when silver(I) iodide was used as an additive. Other metal complexes such as copper ) iodide and other silver(I) salts can also be used as additives for the reaction. 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

The lithium derivative from the unsymmetrical allylic carbazole 141 reacts with the unsym-metrical allyl chloride 142 to give 143. The starting material was made from carbazole 132 and 142 so this allyl electrophile has reacted twice at its less substituted end, but the nucleophilic homoenolate from 141 has reacted at its more substituted end, because that is y-addition relative to the nitrogen atom.38,39 Hydrolysis of the resulting enamine ii-143 gives the aldehyde 144. 

In addition to steric effects, there are other important substituent effects that influence both the rate and mechanism of nucleophilic substitution reactions. As we discussed on p. 302, the benzylic and allylic cations are stabilized by electron delocalization. It is therefore easy to understand why substitution reactions of the ionization type proceed more rapidly in these systems than in alkyl systems. Direct displacement reactions also take place particularly rapidly in benzylic and allylic systems for example, allyl chloride is 33 times more reactive than ethyl chloride toward iodide ion in acetone." These enhanced rates reflect stabilization of the Sjv2 TS through overlap of the /2-type orbital that develops at carbon." The tt systems of the allylic and benzylic groups provide extended conjugation. This conjugation can stabilize the TS, whether the substitution site has carbocation character and is electron poor or is electron rich as a result of a concerted Sjv2 mechanism. 

The entire allyl palladium alkylation process discussed in Sections 12.6.A and 12.6.B can be made catalytic in palladium. The basis for this catalytic activity involves the use of an allylic substituted species (339, allylic acetate, allylic chloride, etc.) rather than an allylic hydrocarbon. A rerra/ /5-palladium(0) complex (L4Pd) reacts with the allylic substrate to form a jr-allyl palladium complex (369). Substitution with a nucleophile generates 370 with liberation of palladium species L4Pd, which is recycled to react with additional 339.223... 

Another way to make allylic chlorides is by treating dienes with HCl. Electrophiles attack conjugated dienes more readily than they do isolated alkenes. There was some discussion of this in Chapter 19, establishing the main point that the terminal carbon atoms are the most nucleophilic and that the initial attack produces an allylic cation. A simple example is the addition of HCl to cyclopentadiene. 

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