Coupling reactions alkyl halides

The most frequently used organocuprates are those m which the alkyl group is pri mary Steric hindrance makes secondary and tertiary dialkylcuprates less reactive and they tend to decompose before they react with the alkyl halide The reaction of cuprate reagents with alkyl halides follows the usual 8 2 order CH3 > primary > secondary > tertiary and I > Br > Cl > F p Toluenesulfonates are somewhat more reactive than halides Because the alkyl halide and dialkylcuprate reagent should both be primary m order to produce satisfactory yields of coupled products the reaction is limited to the formation of RCH2—CH2R and RCH2—CH3 bonds m alkanes... 

Based on these results, conditions for alkyl-Sonogashira coupling reactions were developed. Primary alkyl halides reacted with terminal alkynes catalyzed by 5 mol% of complex 24a and Cul in the presence of substoichiometric amounts of Nal for bromides or Bu4NI for alkyl chlorides (entry 29) [73]. The latter serves to catalyze the in situ generation of more reactive alkyl iodides under the reaction conditions. The internal alkyne products were isolated in 57-89% yield. The Sonogashira coupling can also be combined to the Kumada reaction described above. a,o)-Chloroalkyl bromides underwent the Kumada coupling first selectively... 

Castle and Widdowson were first to disclose alkyl-alkyl Kumada coupling reactions catalyzed by Pd(dppf)Cl2 [195]. This report was later questioned and corrected by Scott [196]. Matsubara and colleagues established formal Stille-type coupling reactions of perfluoroalkyl halides with allyl, alkynyl, or vinyl stannanes catalyzed by 10 mol% of Pd(PPh3)4, which have to be considered, however, better as radical addition/elimination reactions rather than as coupling reactions (see Sect. 3.1) [184],... 

Preparation of symmetrical and unsymmetfical aliphatic ethers can be accomplished by coupling alkyl halides and sodium alkoxides (H illiamson). The formation of the alkoxide may be slow and incomplete because the slow-dissolving alkoxide coats the sodium. This difficulty can be overcome by using a large excess of alcohol. After the sodium has dissolved, the alkyl halide is added to form the ether which is finally removed by fractional distillation. Sodium f-butoxide is not only formed slowly but also reacts very slowly with alkyl halides. The reaction of the f-alkyl halide with the sodium alcoholate is not any better, for the chief products are olefins. Consequently, another method must be considered for preparing f-alkyl ethers (method 118). Even in the conversion of s-alkyl halides, olefin formation occurs. 

Nucleophilic aromatic substitution often requires metal catalysis, as described above. In contrast, alkyl halides undergo reactions with phosphines directly. Nevertheless, metal-catalyzed cross-couplings of these reactive electrophiles have been developed by activation of the nucleophile. 

Coupling reactions of alkyl boranes, formed by hydroboration of alkenes, with unsaturated halides (or triflates or phosphonates) is possible, and this reaction is finding increasing use in synthesis. For example, coupling of the alkyl borane derived from hydroboration (with 9-borobicyclo[3.3.1]nonane, 9-BBN) of the alkene 200 with the alkenyl iodide 201 gave the substituted cyclopentene 202, used in a synthesis of prostaglandin Ei (1.205). This type of B-alkyl Suzuki coupling reaction is very useful for the synthesis of substituted alkenes. 

The alkyl nucleophiles used in the reactions shown in Eq. (5.26) and Figure 5.12 are all prepared from primary alkyl halides. Similar reactions with secondary alkylzinc reagents are more difficult, not only because of the increased steric hindrance but also because of the possibility for a secondary metal-alkyl species to undergo isomerization. For the coupling of propargyUc electrophiles specifically. 

The coupling of alkynyl metals with tertiary alkyl halides without the occurrence of elimination or other side-reactions has been achieved with the organo-alanes, which are prepared from the alkynyl-lithium by reaction with anhydrous AlCl3. Thus, reaction of (Bu C3C— )3A1 with 1-bromoadamantane gave (735 96%) two of the three acetylene units are not utilized and can be recovered nearly quantitatively. It appears that starting material savings caimot be made by using alkynyldialkylalanes since elimination processes tend to occur with t-alkyl halides. The reaction mechanism is not clear. 

Of-Silylalkanenitriles couples with aryl halides to give a variety of cx-arylalkanenitriles (Scheme 3-169). On the other hand, alkyl cross-coupling reaction using alkylsilane reagents as nucleophiles is successful only with... 

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