Nitrile solid-supported

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

Poly(ethylene glycol) supported liquid-phase syntheses by both the reaction of (polyethylene glycol (PEG))-supported imines with nitrile oxides, generated in situ from aldoximes, (300) and 1,3-dipolar cycloadditions of nitrile oxide, generated in situ on soluble polymers with a variety of imines (301, 302) have been described. The solid-phase synthesis of 1,2,4-oxadiazolines via cycloaddition of nitrile oxide generated in situ on solid support with imines has also been elaborated (303). These syntheses of 1,2,4-oxadiazolines provide a library of 1,2,4-oxadiazolines in good yields and purity. 

Baxendale IR, Ley SV Sneddon H (2002a) A clean conversion of aldehydes to nitriles using a solid-supported hydrazine. Synlett 775-777 Baxendale IR, Lee A-L, Ley SV (2002b) A concise synthesis of carpanone using solid-supported reagents and scavengers. J Chem Soc Perkin Trans 1 1850-1867... 

In addition, minor variation of the catalyst in combination with immobilization on a resin support gave an analogous recyclable solid-supported organocatalyst. Varying the derivatization method by trapping the a-amino nitrile intermediate with formic acid and acetic anhydride gives the crystalline formamides 19 in excellent yield and with high enantioselectivity. These features of this catalytic process have been demonstrated by results from the synthesis of r-tert-leucine (Scheme 14.8) [49]. 

The use of solid supported, recyclable catalysts, is a well-assessed technique in classic organic chemistry, and many exhaustive reviews dealing with this subject are available [105, 115]. The use of solid supported catalysts for library synthesis in solution has also been reported. Among others, Kobayashi et al. presented the use of a new supported scandium catalyst for 3CC reactions leading to solution libraries of amino ketones, esters, and nitriles (24-member model discrete library) [116], or to quinolines (15-member model discrete library) [117], and Jang [118] presented a polymer bound Pd-catalyzed Suzuki coupling of organoboron compounds with halides and triflates. This area was also briefly reviewed recently [119]. 

The Gewald synthesis can be performed on a solid support. Treatment of resin-bound nitrile 559 with carbonyl compounds and sulfur gives resin-bound aminothiophenes 560. Acylation and removal of the resin provide thiophenes 561 (Scheme 88) <2001TL7181>. The same resin-bound nitrile 559 reacts under MW irradiation to give 560 <2004S3055>. MW-assisted synthesis of 2-A -acylthiophenes 563 from 562 on a solid support has also been reported <2003SL63>. 

An efficient synthesis of amides by the Ritter reaction of alcohols and nitriles under MW irradiation was developed under solvent-free conditions (Scheme 8.36). This green protocol is catalyzed by solid-supported Nafion NR50 with improved efficiency and reduced waste production." ... 

McCarthy and co-workers [275] prepared nitrile imines in situ by exposing two hydrazonyl chlorides (210) to basic conditions, and these underwent [2 -i- 3]-cy-cloaddition reaction -with solid-supported-enamines derived from a Merrifield-based piperazine resin and the selected phenylacetaldehyde (209) (Scheme 46). Pyrazoles (212) were then obtained after cleavage from the resin under mildly acidic conditions, the resin functioning as a traceless linker. 

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. 

Asymmetric 1,3-dipolar cycloadditions employing diphenylnitrone and mesito-nitrile oxide were carried out by applying a tyrosine derived Evans auxiliary on solid support [13, 31]. Preparation of the chiral linker 56 started with esterification, protection of the amino functionality and subsequent reduction of commercially available L-tyrosine 54. The obtained alcohol 55 was then cyclized under thermal conditions and has been attached to Wang or Merrifield resin (Scheme 12.21). 

Another novel approach to labelling molecules with carbon-11 has been published by Somawardhana, Sajjad and Lambrecht . These workers have absorbed one of the reactants required for the synthesis on a solid support and the reaction has been done by adding the other reagents to the solid support and heating the mixture in a sealed vial. One example illustrating their methodology is the formation of [l- C]putrescine. The H CN is trapped on a potassium-hydroxide-coated silica gel. Then, acrylonitrile is added, and the reaction tube sealed at both ends. After the tube had been heated at 75 °C for 5 minutes, the Michael addition product was eluted from the solid support and the solvent evaporated. Finally, the nitrile groups were reduced with a borane-dimethylsulphide complex in THF (equation 77). The total reaction time was less than 40 minutes and the product was obtained in a 53% radiochemical yield. 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

In the same publication, a nitrile coupling followed by a subsequent cycloaddition, forming a tetrazole, was executed as a one-pot procedure on a TentaGel-support, as depicted in Scheme 15.52. Negligible decomposition of the solid support was reported. 

This reaction has been extended to the Michael Addition on a,)0-unsaturated nitrile by temporarily chelating the Grignard reagent to y-hydroxy unsaturated nitrile. An alternative route involving a free-radical )0-alkylation of nonactivated carbon atoms and subsequent anionic cyclization has been developed as a complementary route of the Robinson annulation. In addition, this reaction has been modified to occur under antibody catalysis" or with the combination of a lithium enolate with aluminum tris(2,6-diphenylphenoxide). Further modifications include the Robinson annulation in supercritical C02, the reaction promoted by K2CO3 under ultrasound,and the solid-supported reaction under microwave irradiation. ... 

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