Resin-Supported Halide

The process has also been adapted using resin supported catalysts [e.g. 23-28]. Generally, the reactivity of the alkyl halides follows the normal pattern of I>Br>Cl, but secondary alkyl halides are less reactive and require high reaction temperatures and tertiary alkyl halides fail to react. 

Tetraethylammonium borohydride reduces diphenyl diselenide to phenylselenolate anion. When an acyl halide is added to the toluene solution of phenylselenolate anion, the corresponding acylation product is isolated in good yield (equation 4). Resin-supported phenyl selenide anion underwent acylation with acetyl chloride under mild reaction conditions. ... 

The selective reduction of the primary halides can also be accomplished with NaCNBH3 in HMPA or DMSO or even by NaBH4 in warm DMSO. Epoxides, nitriles, amides, ketones, and esters are not affected under these conditions [HKl, LI], as illustrated in Figure 2.4. n-Bu4NCNBH3 or resin-supported cya-noborohydride is even more selective, since each reduces only the primary iodides and bromides, leaving the chlorides unchanged [HN3]. 

Cross-coupling reactions have also been examined in water using amphiphilic PS-PEG resin-supported palladium complexes. Palladium-catalyzed coupling of aryl halides with aryl(or alkenyl)boronic acids (the so-called Suzuki-Miyaura coupling) took place in aqueous alkaline solution in the presence of polymeric catalyst 59 at 25 °C to give the biaryls in excellent yields [90,... 

Several heterogeneous catalysts have been shown to effect related multicomponent couplings. These include cross-linked polymeric ionic liquid material-supported copper (Cu-CPSIL), silica-dispersed CuO (CuO/Si02), and imidazolium-loaded Merrifield resin-supported copper (Cu-PSIL), all of which can be used in water at room temperature to arrive at 1,4-disubstituted-1,2,3-triazoles from alkyl halides, NaNs, and terminal alkynes. Each can be filtered and reused several times with minimal loss of efficacy. Multistep flow synthesis, specifically including generation of underused vinyl azides and their subsequent click conversions to vinyl triazoles, has also been reported. ... 

Uozumi, Y. and Watanabe, T. (1999) Green catalysis Hydroxycarbonylation of aryl halides in water catalyzed by an amphiphilic resin-supported phosphine-paUadium complex. J. Org. Chem., 64, 6921-3. 

Suzuki couplings of aryl halides (eight varieties) and aryl- or vinylboronic adds (12 varieties) have been reported in water in the presence of a palladitmi complex of an amphiphilic polystyrene-poly(ethylene glycol) copolymer resin-supported N-an-chored 2-aza-l,3-bis(diphenylphosphino)propane ligand and potassium carbonate to give uniform and quantitative yields of the corresponding biaryls products (96 combinations) (Equation 75) [104]. 

Uozumi, Y., Danjo, H. and Hayashi, T., Cross-coupling of aryl halides and allyl acetates with arylboron reagents in water using an amphiphilic resin-supported palladium-catalyst, /. Org. Chem., 1999,64, 3384-... 

The following section deals with comparison study between the three immobilized copper catalysts, cross-linked polymeric material and ionic liquid-supported copper (Cu-CPSIL), imidazolium-loaded Merrifield resin-supported copper (Cu-PSIL), and silica-dispersed CuO (Cu0/Si02) and their application in the one-pot synthesis of l,4-disubstituted-l,2,3-triazoles by the reaction of alkyl halides with sodium azide and terminal alkynes in water at room temperature [36]. 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

The reactions were carried out in sealed Pyrex tubes employing a prototype single-mode microwave cavity. The reagents were added to the resin-bound aryl halide under a nitrogen atmosphere and irradiated for the time periods indicated (Scheme 7.14). Rather short reaction times provided almost quantitative conversions, with minimal degradation of the solid support. 

In a related study, Srivastava and Collibee employed polymer-supported triphenyl-phosphine in palladium-catalyzed cyanations [142]. Commercially available resin-bound triphenylphosphine was admixed with palladium(II) acetate in N,N-dimethyl-formamide in order to generate the heterogeneous catalytic system. The mixture was stirred for 2 h under nitrogen atmosphere in a sealed microwave reaction vessel, to achieve complete formation of the active palladium-phosphine complex. The septum was then removed and equimolar amounts of zinc(II) cyanide and the requisite aryl halide were added. After purging with nitrogen and resealing, the vessel was transferred to the microwave reactor and irradiated at 140 °C for 30-50 min... 

The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase. 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

Two methods are used for the SPPS of peptoids and peptoid-peptide hybrids (Scheme 41). The first method 122,215 (Scheme 41, route A) called the premade monomer method involves the preparation of a Fmoc-protected monomer in solution (see Section 10.1.1.4.1 and Table 8) and its incorporation into the peptoid or the peptoid-peptide hybrid using Fmoc/SPPS. The second method1216217 (Scheme 41, route B) called the submonomer method involves the formation of the peptoid monomer on the solid support by first forming a bromoacetylated peptide-resin and then substituting the alkyl halide with the appropriate alkyl- or side-chain protected co-functionalized alkylamine. 

Support-bound /V-sulfonyl carbamates, which can be prepared by N-sulfonylation of resin-bound carbamates, are susceptible to nucleophilic cleavage. These intermediates enable the solid-phase preparation of A-ary I- or /V-alkylsulfonamides using inexpensive hydroxymethyl polystyrene (Entries 8 and 9, Table 3.15). Polystyrene-bound carbamates can also be cleaved by treatment with acyl halides in the presence of Lewis acids (Entry 4, Table 3.16). 

Resin-bound triazenes with a free NH group can be acylated by treatment with acyl halides, or carbamoylated by treatment with isocyanates [342]. The resulting triazene derivatives are stable towards strong bases, but undergo acidolysis when treated with TFA or TMSC1, yielding amides and ureas, respectively (Entries 1 and 2, Table 3.16). Polystyrene-bound triazenes devoid of a free NH group or carbamates can be cleaved from the support by treatment with acyl halides to yield amides (Entries 3 and 4, Table 3.16). 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

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