Atyl halides

Despite its utility, the Friedel-Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (atyl) halides and vinylic halides do not react because aryl and vinylic carbocations are too high in energy to form under Friedel-Crafts conditions. 

The catalytic cycles for reduction of alkyl and atyl halides using Ni(o), Co(i) or Pd(o) species are interrupted by added carbon dioxide and reaction between the first formed carbon-metal bond and carbon dioxide yields an alkyl or aryl car-boxylate. These catalyses reactions have the advantage of occuriiig at lower cathode potentials than the direct processes summarised in Table 4.14. Mechanisms for the Ni(o) [240] and Pd(o) [241] catalysed processes have been established. Carbon dioxide inserts into the carbon-metal bond in an intermediate. Once the carboxy-late-metal species is formed, a further electron transfer step liberates the carboxy-late ion reforming the metallic complex catalyst. 

R-X = alkenyl and atyl halides and triflates R M = alkenyl and aryl zinc, aluminum, zirconium, or boron and tin... 

Table 9.4 Copper/ligand catalyzed coupling between atyl halides and N-heterocycles amines.

Table 9.11 Copper/ligand catalyzed coupling of atyl halides and aliphatic alcohols.

Reaction Procedure (Scheme 2.100) Catalyst (0.1 mmol), atyl halide (1.0 mmol), NaOH (1.0 mmol), allgme (1.2 mmol), (nBu)4NBr (0.2 mmol PTC), and water (2 mL) were added to a sealed tube. The reaction mixture was stirred at 100 °C for 24 h and then cooled to room temperature and extracted with ethyl acetate. The organic layer was then dried with anhydrous Na2S04, and the solvent was removed under reduced pressure. The product was finally obtained by column chromatography on silica gel. 

Reaction Procedure (Scheme 3.20a) A mixture of atyl halide (0.25 mmol), Pd(OAc)2 (2.8 mg, 0.0125 mmol), bis(diphenylphosphino)methane (4.8 mg, 0.0125 mmol), caesium pivalate (0.1170 g, 0.5 mmol), and the indicated amounts of alkene (if employed) in dry DMF (4 mL) was quickly flushed with argon and stirred at the indicated reaction temperature. The reaction was monitored by TLC and gas chromatographic analysis. After the reaction was complete, it was diluted with ethyl ether, washed with satd aq. NaHCOs, dried over Na2S04, concentrated, and purified by flash chromatography on silica gel. 

Microwave-assisted coupling of atyl halides with vinyl trialkoxysilanes has been performed using Pd(OAc)2-L112 in the presence of NaOH [117]. The coupling of aryl chlorides with K[B(OMe) ] is reported using Pd2(dba)3-L21 [118] (Scheme 20.42). 

The Heck reaction couples a vinylic or an atyl halide with an alkene in the presence of a base (such as triethylamine) and a palladium catalyst (PdL2). Like the Suzuki reaction, the Heck reaction is a substitution reaction the R group of the halide replaces a vinylic hydrogen of an alkene. If there is a substituent attached to the alkene (Z), the R group will be trans to that substituent in the product. Notice that the new C—C bond joins two sp carbons. 

After optimizing the reaction conditions (see foot note a of Table 17), the reaction scope was extended with various atyl halides and azoles. A variety of substituted chloro- and fluoroarenes possessing a wide range of functional groups are examined. As illustrated in Table 17, when o- and p-chloronitrobenzenes were used, the corresponding iV-aiylated products were obtained in excellent yields (entries 1 and 2). Cyano, nitre, and aldehyde groups are well tolerated. 2-Qiloropyridine and... 

Coupling o( organotin reagents (and Pd catalyst) with atyl or vinyl halides or triflates, acyl chlorides or iMyl acetates. 

Acylcahaltate complexes, [RCCo(SO)(CO)P(CJH[j)t) Li (2)> These ttrc prepared by reaction of Ri.i with 1 in TIIF, They are stable at - 40 but decompose at 25. The atyl group is transferred to a. nooes, tjuinoncs, and allylic halides. ... 

Scheme 13.20 Atyl-allq l coupling reactions between allq l halides and Grignard reagents under iron catalysis.

Cacchi, S., Fabrizi, G. and Goggiamani, A. (2003) Palladium-catalyzed hydroxycarbonylation of atyl and vinyl halides or triflates by acetic anhydride and formate anions. Organic Letters, 5, 4269-4272. 

The allqrl/aiyl zinc halides can also be made in situ from allqrl/atyl iodides (Scheme 18.10). Optimal yields were obtained when 2 equivalents of the desired allqrlating agent were used. Whilst both these methods are currently limited for in situ monomer preparation, they are valid methods to increase diversity of monomer sets. More useful methodology would allow in situ parallel formation of sulfones. 

In instanees where a functionalized aromatic moiely is desired in the target structure, the Heck reaction of an atyl/vinyl halide/triflate with an alkene in the presenee of a palladium catalyst and base is an obvious choice and, indeed, has found application in the macrocycle arena. The first demonstration of a Pd(0) process on the solid phase actually involved Heck chemistry and was directed toward the synthesis of small libraries containing 20- to 24-membered macrocycles (94, Scheme 11.10). Analogous procedures were employed for the assembly of macrocyclic RGD mimet-ics °° and p-turn mimics (97, Figure 11.12, site of reaction and palladium species employed indicated) on the solid phase. For these conversions, it was postulated that an intramolecular hydrogen bond in the precursor assisted in the formation of the cycle. 

A series of atyl-diphenylphosphine oxides was prepared by the [NiCl2(dppp)]-catalyzed cross-coupling of aiyl halides with diphenylphos-phine oxide (Scheme 32). ... 

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