Nucleophiles solid-supported

Recently, the Bartoli indole synthesis was extended to solid supports. In contrast to the earlier reports in the liquid phase, o,o-unsubstituted nitro analogs (see 25) prove to be useful substrates. In addition, fluoro/chloro substituted nitro derivatives are well tolerated, which typically undergo nucleophilic substitution under Bartoli conditions in the liquid phase. 

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. 

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... 

As an extension to thep-carboxybenzenesulfonamide safety-catch linker [43,44], alkanesulfonamide handle 37 was developed [45]. This linker tethers carboxylic acids to the solid support to give an acylated sulfonamide which is stable to both basic and acidic conditions (Scheme 12). Products were released by treatment with iodoacetonitrile followed by the addition of a nucleophile. 

A versatile approach for the solid-phase synthesis of aminopyr-idazines used the anchoring of 3,6-dichloropyridazine to resin-bound thiophenol 59 (Scheme 28) [68]. Treatment with nucleophilic amines released the aminopyridazine products from the solid support without further oxidation. 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

Solid-supported co-chloroalkyl tetrazoles 205 were reacted with a variety of nucleophiles followed by acidic cleavage to give tetrazoles 206 <00JCC19>. 

Kaldor SW, Siegel MG, Dressman BA, Hahn PJ (1996) Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries. Tetrahedron Lett 37 7193-7196... 

With these solid supports in hand, we turned our attention to a new route to the synthesis of our target molecule 23 (Scheme 8). The tricky reductive amination should be replaced by an N-alkylation. To that end, bromoacetic acid is attached to 24c using DIC and Hiinig s base followed by the nucleophilic substitution with the corresponding benzy-lamine in DMSO/toluene (1 1), which can be easily monitored by the Beilstein test, followed by sulfonamide formation in DCM using N-methylmorpholine as base. For the final cleavage, 2% TFA in DCM is used and the resulting solution is filtered in a saturated NaHCC>3 solution to neutralise the acid before evaporation of the solvent. The crude product was then crystallised from ethyl acetate/heptane to yield the desired product in 27% yield overall and 99A% HPLC purity (see Table 4). 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman, P. J. Hahn, Use of Solid Supported Nucleophiles and Electrophiles for the Purification of Non-Peptide Small Molecule Libraries , Tetrahedron Lett. 1996,37,7193-7196. 

Most conventional scavenging is based on the concept of complementary reactivity. In the simplest cases, electrophilic and nucleophilic species are sequestered via a reciprocally functionalized support (Scheme 2.11 see also Tab. 2.1) likewise, acids and bases can be removed via salt formation with a solid-supported base or acid. 

Kaldor [49 i, 55] demonstrated the advantages of applying solid-supported scavengers to the preparation of parallel arrays in a multi-step fashion. In these studies he examined the clean-up of multiple amine alkylation and acylation reactions using a variety of immobilized electrophilic and nucleophilic scavenger reagents including an amine, isocyanate, aldehyde and acid chloride (Tab. 2.1). 

The successful assembly of organic compounds on a solid support represents only part of the challenge in SPOS. After completion of synthetic sequence, the compounds must be cleaved from linkers attached to polymer by a chemical or photochemical reaction, for example, treatment of a polymer-bound compound with acids, bases, nucleophiles, redox reagents, and even photons. Acid-labile linker and amine-cleavable Marshall linker are two major classes of hnkers used in combinatorial synthesis. 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

Many catalysts do not use metals in their pure reduced metallic forms. Anchored organometallic complexes are often analogs of homogenous catalysts fixed on a solid support. In particular, titanate complexes both in solution and in supported form have been found to be especially active in transesterifications of simple esters.It was proposed that titanates catalyze the transesterification reaction through a Lewis acid mechanism where the reactant ester and metal form a Lewis complex activating the carbonyl groups for a nucleophilic attack by the reactant alcohol. The tetrahedral intermediate that is formed breaks down into the product alcohol and an ester-metal Lewis... 

Johnson, C. R. Zhang, B. Fantauzzi, P. Hocker, M. Yager, K. M. Libraries of/V-Alkylaminoheterocycles from Nucleophilic Aromatic Substitution with Purification by Solid Supported Liquid Extraction, Tetrahedron 1998, 54, 4097. 

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