Alkynes solid support

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. 

Another example of a Pdn-driven domino process is the reaction of the alkyne 6/1-367 with CO on a solid support to give the benzo[b]furan 6/1-368 (Scheme 6/1.92). Ninety different benzo[fc]furans were prepared using this procedure, with >90% purity in most cases [176]. 

The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. 

The examples listed in Table 3.21 illustrate the synthetic possibilities of cross metathesis. In many of the procedures reported, advantage is taken of the fact that some alkenes (e.g. acrylonitrile, styrenes) undergo slow self metathesis only. Interestingly, it is also possible to realize cross metathesis between alkenes and alkynes (Table 3.21, Entries 11-13), both in solution and on solid supports [927,928]. 

Blechert reported a skillful method of cross-enyne metathesis. Solid-supported alkyne 139 is reacted with alkene in the presence of Ic to give 140. For cleavage of 1,3-diene from solid-supported product 140 having an allyl acetate moiety, palladium-catalyzed allylic substitution is used. Thus, 140 is treated with Pd(PPh3)4 in the presence of methyl malonate to afford three-component coupling product 141 in good yield ... 

Functionalized 1,2,3-triazoles 86 and 87 were prepared by [2 + 3] cycloadditions of resin-bound a-azido esters 85 with substituted alkynes <02TL4059>. Regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of resin-bound alkynes 88 with azides afforded solid-supported 1,2,3-triazoles 89, which were ligated further to give 1,4-substituted-1,2,3-triazole peptide compounds <02JOC3057>. 

Fukase and co-workers have developed two types of alkyne linkers (O Scheme 7) [13]. A propargyl glycoside-type linker between a sugar residue and a solid support was formed... 

We have transferred the in situ generation of anion capture agents/cyclization-anion capture processes to solid supports Thus 35, attached to Wang resin, was reacted with alkyne 36 in the presence of Pd(0) and Bus SnH in toluene initially at 0 °C for 1 h, then 110 °C for 16 h. The expected product 37 was cleaved from the resin by transesterification with MeOH in good yield (Scheme 5.6.9). 

As with the Negishi and Suzuki reactions, the same solid-support (vide supra) could be adapted to the Sonogashira reaction [62]. The solid-supported bromopyridine 178 could undergo cross-coupling reactions with a variety of alkynes and be released from the solid-support to allow isolation of 331. 

Another resin-capture approach has been pubhshed in relation to the synthesis of tetrasubstituted ethylenes via Suzuki coupling reactions (Scheme 20) [42, 53]. A 25-member hbrary was synthesized using five alkynes, five aryl halides, and a polymer-bound aryl iodide. The alkynes 55 were converted into bis(boryl)alkenes 56 in solution, and the crude intermediates were used in Suzuki reactions with an excess of aryl halide. When all of the bis(boryl)alkene 56 had been consumed, the aryl iodide resin 59 was added to the reaction mixture and the reaction continued on the solid support. Side products such as 58, arising from a double Suzuki reaction, remained in solution and could be washed away. Compounds 60 were cleaved from the polymer using trifluoroacetic acid and products 61 were obtained in > 90% purity. 

This strategy has been appHed to different solid-supported dipolarophiles such as alkynes [277] and 3-hromo-4,4,4-trifluorobutenoic acid [278], which gave rise to isoxazoles upon dehydrohalogenation. Solid-supported vinyl ethers (215) [279] are worth mentioning, because TFA treatment of the resulting isoxazolines intermediate afforded isoxazoles (218) with simultaneous release from the resin (Scheme 48). 

Solid-supported nitrile oxides have the main advantage over those prepared in solution that formation of dimers is avoided. Thus, a 96-member library of 3-hydroxymethyl isoxazoles (265) [298] has been prepared from nitroethanol on a modified tetrahydropyranyl linker (263) as nitrile oxide precursor. The cycloaddition step was then performed by generating the nitrile oxide under the Mukaiyama conditions in the presence of alkynes (Scheme 59). As expected, the presence of dimer furoxane was never detected. 

FIGURE 19 First example of the Nicholas reaction [434, 173] [313] on a solid support. Various propa-rgylic alcohols were immobilized on a Merrifield resin. After forming the cobalt-alkyne complex, Nicholas reaction was performed as a diversifying cleavage step. Trimethylallylsilane, anisole, and silyl enol ethers were used as the carbon nucleophiles. 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

Semihydrogenation of alkynes The surface of silica gel is covered with hydrosilane groups on reaction with trichlorosilane. The solid-supported silane effects hydrogenation of alkynes to (Z)-alkenes selectively. 

The importance of electron transfer in the mechanism of ozonolysis has been discussed <97JOC5934> and ozonolysis of 2-methylthio-3-methylbut-2-ene on polyethylene has allowed isolation of pure tetrarnethyl-l,2,4-trioxolane 123 <97MI543>. Solid-supported 1,2,4-trioxolanes have been prepared by ozonolysis and used for further transformations <97TL1043>. Ozonolysis of alkynes in the presence of carbonyl compounds affords access to... 

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