Nucleophile Induced Elimination Reactions

Elimination reactions have been induced under phase transfer conditions by a variety of techniques [1, 2, 4, 5, 25—28]. Predominant among these is the dehydrohalogena-tion of alkyl halides or sulfonates [1, 2, 5] and the dehalogenation of vicinal dihalides [25]. In the former case, some elimination is observed as a side reaction of the intended Sn 2 halogen exchange reaction. The direct displacement of halide by halide (the 

Finkelstein reaction) is favored for primary alkyl halides and also by sulfonate leaving groups. For example, in the case of resin-bound fluoride ion in pentane solution, 2-bromooctane is transformed into a mixture of octenes and fluoride in a ratio of 73% 20%. In contrast, 2-octyl mesylate yields the same products in ratios which are essentially reversed (25% 70% see Eqs. 9.6 and 9.7) [5]. 

Likewise, 1-bromooctane is converted by 18-crown-6 complexed KF in acetonitrile solution into 1-fluorooctane (92%) and the by-product olefin in only 8% yield. Bro-mocyclohexane, on the other hand, is converted quantitatively into cyclohexene under the same conditions [2]. Although most of the systems which can give mixtures of E-2 and Sn 2 products, do so, the sulfonates seem to most favor substitution and the fluoride nucleophile/bromide nucleofuge pair tends to favor elimination. 

Vicinal dehalogenation has been reported under phase transfer conditions [25]. In this case, a series of vicinal dibromides was treated with an aqueous solution of sodium iodide and sodium thiosulfate in the presence of a quaternary ammonium catalyst. 1,2-Dibromooctane was thereby converted to 1-octene in 92% yield (see Eq. 9.8) [25]. It was found that the elimination reaction could be effected by sodium thiosulfate itself, but that this method was slower than when iodide ion was present. Only a catalytic amount of iodide ion was required in the reaction, it being continuously regenerated by reaction with thiosulfate. 

Another elimination technique which deserves mention is the deoxygenation of epoxides by trimethylsilylpotassium [26]. 18-Crown-6 apparently catalyzes the reaction of potassium methoxide with hexamethyldisilane in HMPT solvent. The trimethylsilylpotassium thus generated deoxygenates the epoxide with overall inversion of sterochemistry. The process is formulated in equation 9.9 and examples are recorded in Table 9.4. 

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Nucleophile Induced Elimination Reactions Table 9.2. Reactions of activated halides with J-chloro-a,/3-unsaturated esters (4]... 

The gas-phase base-induced elimination reaction of halonium ions was thoroughly investigated in radiolytic experiments22. Radiolytically generated acids C/JH5+ (n = 1,2) were allowed to react at 760 Torr with selected 2,3-dihalobutanes to form the halonium intermediates which, in the presence of trimethylamine, undergo base-induced bimolecu-lar elimination as shown in Scheme 6. This elimination reaction occurs in competition with unimolecular nucleophilic displacement to the cyclic halonium ion and subsequent rearrangement. Isolation and identification of the neutral haloalkenes formed and kinetic treatment of the experimental results indicated that 3-halo-1 -butene is formed preferentially with respect to the isomeric 2-halo-2-butenes and that the bimolecular elimination process occurs predominantly via a transition state with an anti configuration22. 

One of the key features in Scheme 27 is the intramolecular cycloaddition of an o-quinodimethane intermediate, and this reaction has featured in several other new approaches to steroidal and related polycyclic carbon skeletons (Scheme 28). The last example in Scheme 28 also illustrates a new route to the cyclization precursor (119) via a nucleophilic induced elimination-addition of an a-halogeno-... 

The reaction of an alkyl halide or tosylate with a nucleophile/base results either in substitution or in elimination. The resultant nucleophilic substitution and base-induced elimination reactions are two of the most widely occurring and versatile reaction types in organic chemistry, both in the laboratory and in biological pathways. 

The reaction of 3-methoxy-1,2,4-triazine 1-oxide 20 with the carbanion generated from chloromethyl phenyl sulfone proceeds as the vicarious nucleophilic substitution (VNS) of hydrogen (Scheme 1, path B) via addition of the carbanion at position 5 of the heterocycle. Following base-induced elimination of HCl and protonation, 3-methoxy-5-phenylsulfonyl-1,2,4-triazine 4-oxides 65 result (88LA627). 

Here too, a second alkylation can be made to take place yielding RC=CR or R C=CR. It should, however, be remembered that the above carbanions—particularly the acetylide anion (57)—are the anions of very weak acids, and are thus themselves strong bases, as well as powerful nucleophiles. They can thus induce elimination (p. 260) as well as displacement, and reaction with tertiary halides is often found to result in alkene formation to the exclusion of alkylation. 

Because sodium sulfide is a strong nucleophile, other non nucleophilic reagents such as Ca/Hg 144 or Bu3SnH145 are more suitable than Na2S in the synthesis of functionalized olefins (see Eq. 7.105). NaTeH is also effective to induce the elimination reaction presented in Eqs. 7.103 and 7.104.146... 

Although highly reactive, 2/7-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4//-l, 3-diazepines 86. Reaction of 80 with difluorocarbene in the presence of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines <06TL639>. 

The vicarious nucleophilic substimtion of carbo- and hetero-cyclic nitroarene hydrogen by a hydroxyl group, on reaction with silylhydroperoxide anions, has been shown to proceed via nucleophilic addition of ROO followed by base induced elimination of ROH by an ii2-type mechanism the required orientation of the hydroxylation can be controlled by the conditions selected. ... 

Nucleophilic displacement reactions are often competitive with other processes promoted by a nucleophile, such as addition-elimination, or proton abstraction and base-induced elimination in which the nucleophile acts as a strong base. This particular situation is especially true in reactions that also involve attack at an unsaturated carbon centre. The delicate interplay between these different mechanisms is in itself a matter of great interest, and as yet it has defied attempts to rationalize it on a quantitative basis. 

A convenient one-step conversion of moderately activated nitroarenes to phenols was achieved in DMSO via nucleophilic nitrite displacement by the anion of an aldoxime.153 TTie resulting O-arylaldox-ime is rapidly cleaved to the phenol derivative under the reaction conditions. The reaction is also applicable to activated fluorides and even to 2-chloropyridine which, at 110 °C, is converted to 2-pyridone in 72% yield.153 A somewhat related process concerns the synthesis, in 82-92% yield, of 4-alkoxybenzoni-triles (45 R = Me, CH2-oxirane, CHrfh, CHMeCTfcMe from O-alkyl-4-nitrobenzaldoximes (44) via hydride-induced elimination of the alkoxide followed by alkoxy denitration (Scheme 17).154... 

The competition between nucleophilic substitution and base-induced elimination in the gas phase has been studied using deuterium kinetic isotope effects (KIE).6 The overall reaction rate constants and KIE have been measured for the reactions of RC1 + CIO- (R = Me, Et, t -Pr, and r-Bu). As the extent of substitution in the alkyl chloride increases, the KIE effects become increasingly more normal. These results indicated that the E2 pathway becomes the dominant channel as the alkyl group becomes more sterically hindered. 

In spite of its unusual structural outcome, the N-fusion reaction is a very general process. It was observed in a number of other N-confused macrocycles. For instance, an N-fused intermediate forms in the synthesis of trans doubly N-confused porphyrin 96 [238], N-fusion was also induced by the reaction with PhBCl2, in which case the reaction was promoted by the small radius of the coordinating boron(III) center [251], The resulting boron complexes were also aromatic, even though in some cases further chemical modification of the macrocycle took place (as in 110). The fusion process, which appears to be a nucleophilic addition-elimination, is reversible, and N-fused macrocycles can often be reopened when treated with nucleophiles such as alkoxides [248, 249],... 

An efficient procedure for the nucleophilic displacement of the A, A -dimethylamino group of 1-triisopropylsilyl-gramines via the fluoride ion-induced elimination-addition reaction has been devised. 1-Triisopropylsilylgramine methiodide 1371 reacted smoothly with a variety of nucleophiles in the presence of tetrabutylammonium fluoride (TBAF) to give 3-substituted indoles 1372 (Scheme 262) <1995TL5929>. 

Nucleophile-coordinated SiCl2 can be regarded as one common intermediate of these reactions. The divaient silicon species is formed by nucleophile-induced a-elimination at the Si atoms of MejGeSiCls or EtsGeSiCls, and SiCli can be intercepted by re-insertion into Ge-Cl bonds of MejGeCl or EtjGeCl. 

The overall reaction amounts to a transposition of the initial alkene double bond. In contrast to ring opening of epoxides by nucleophiles, the base-induced elimination requires a non-nucleophilic strong base, such as a lithium dialkylamide (e.g., LDA). The reaction is believed to proceed via a yn-elimination involving a boatlike transition state. ... 

These two reactions—nucleophilic substitution and base-induced elimination—are two of the most widely occurring and versatile reactions in organic chemistry. We ll take a close look at both in this chapter to see how they occur, what their characteristics are, and how they can be used to synthesize new molecules. 

The generation of an alkene by the reaction of a v/c-disulfonate ester with iodide (the Tipson-Cohen reaction) has been known since 1943 and in some cases it has proved useful where other methods have failed, as in the preparation of the spirocyclic triene (54 Scheme 22). The mechanism probably involves an initial nucleophilic displacement to give an iodohydrin sulfonate, which then undergoes iodide-induced elimination to the alkene. Methanesulfonates can be used as well as arenesulfonates. 

Occasionally, gew-dichlorocyclopropanes with phenyl or alkoxy substituents are transformed by strong base in aprotic or (rarely) protic solvents to allylic substitution products that do not obey at all the rules for cyclopropyl to allyl rearrangements with regard to their constitution and configuration. "These reactions are mechanistically distinct. They are usually initiated by base-induced elimination of hydrogen chloride to form phenyl- or alkoxy-substituted cyclopropenes, which are then intercepted by nucleophiles. ° These reactions are discussed in Section 2.B.2.I. Small structural differences can divert the reaction into one or the other reaction channel. Cyclopropane 25 on treatment at — 50°C with 2 equivalents of potassium /er/-butoxide in tetrahydrofuran in the presence of catalytic dicyclohexano-18-crown-6... 

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