Resin-bound aniline

The solid-phase version of the Madeiung indole synthesis was developed by D.A. Wacker et al. for the preparation of 2,3-disubstituted indoles.The ort/ o-substituted aniline substrate was first attached to the Bal resin using reductive amination. The resin-bound aniline was then acylated and the cyclization was brought about with a variety of bases to afford high yields of the disubstituted indoles. The products were quantitatively removed from the resin with TFAiEtsSiH (95 5). 

A solid-phase synthetic route for the quinoxalines, which proceeds via benzyne intermediate, has been reported by Dixon et al. [37]. N-Alloc-3-amino-3-(2,4-difluoro-5-nitrophenyl)propanoic acid was tethered to Rink resin via its carboxylic acid group (Scheme 15). The 4-arylfluorine was displaced with a primary amine, alcohol, or thiol to create, respectively, a resin-bound aniline, phenol, or thiophenol derivative with one diversity element and one single atom (e.g., N, S, or O) diversity point. 

Immobilized, highly reactive phenyl esters can be prepared by acylating resin-bound 4-acyl-2-nitrophenol (Entry 4, Table 3.13 [285-288]) or 4-(aminocarbonyl)-2,3,5,6-tetrafluorophenol (Entries 7 and 8, Table 3.13). These esters are similar to oxime esters (see Section 3.3.3.3), and even react with weak nucleophiles such as anilines or alcohols. This type of linker is not, therefore, well suited for long synthetic sequences on insoluble supports, but only for the preparation of simple acid derivatives. Because cleavage yields the unchanged phenol, these resins can be reused several times, which renders this strategy of preparing acid derivatives quite cost-effective. 

Resin-bound 1-hydroxybenzotriazole (HOBt) has also been prepared [312-314], and yields, upon O-acylation, highly reactive esters [312,315,316], These are even cleaved by weak nucleophiles, such as anilines or even N-hydroxysuccinimide (Entry 7, Table 3.14). The reactivity of resin-bound HOBt esters is greater than that of resin-bound 4-acyl-2-nitrophenyl esters [296], Similarly, resin-bound /V-hydroxysuccinimide has also been used for the preparation of polymeric acylating agents (Entry 6, Table 3.14 [317-319]). 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

The attachment of anilines to benzyl alcohol linkers as carbamates can be achieved either by reaction of aryl isocyanates with a resin-bound alcohol [498-500] or by treat-... 

Acrylic acid esterified with cross-linked hydroxymethyl polystyrene or Wang resin reacts smoothly with primary or secondary aliphatic amines at room temperature (Entries 1 and 2, Table 10.6). Only sterically demanding amines or amines of low nucleophilicity (anilines, a-amino acid esters) fail to add to polystyrene-bound acrylate. Support-bound acrylamides are less reactive than acrylic esters, and generally require heating to undergo addition with amines (Entries 4 and 5, Table 10.6). a, 3-Unsaturated esters with substituents in the 3-position (e.g. crotonates, Entry 3, Table 10.6) react significantly more slowly with nucleophiles than do acrylates. The examples in Table 10.6 also show that polystyrene-bound esters are rather stable towards aminolysis, and provide for robust attachment even in the presence of high concentrations of amines. Entry 10 in Table 10.6 is an example of the alkylation of a resin-bound amine with an electron-poor alkene to yield a fluorinated peptide mimetic. 

Wang resin bound 4-nitrophenyl carbonate is a convenient intermediate for the attachment of amines to polystyrene as carbamates (see Experimental Procedure 14.2). Aliphatic amines [82-87], ammonia [88], and amino acids [89] react exothermically with this support, whereas anilines generally require catalysis and/or long reaction times (Entry 3, Table 14.7). For the immobilization of anilines as carbamates, Wang resin derived chloroformate [90-92] generally leads to better results than resin-bound 4-nitrophenyl carbonates. Amidines also react with polystyrene-bound 4-nitrophenyl carbonates to yield /V-alkoxycarbonyl amidines (Section 3.9 [93-95]). Support-bound alkoxycarbonyl hydrazines can be prepared by treating polystyrene-bound phenyl carbonates with hydrazine [96-98]. 

The capture of 4,6-dichloro-2-(methylthio)pyrimidine (8) was performed in DMF with diisopropylethylamine (DIPEA, Huenig s base) as a base and tetrabutylammonium bromide as a catalyst at 90°. The substitution of the remaining chlorine atom on the polymer-bound scaffold requires harsher conditions. Thus the immobilized 6-chlorothiomethylpyrimidine (9) could be substituted with aliphatic amines in neat amine at 140°. The coupling with anilines could be afforded consistently only by using KO Bu as base and [18]crown-6. Also, the use of Pd catalysts gave positive results, but failures were observed occasionally. Finally, the substitution of the thiomethyl group in resin-bound 2-(methylthio)pyrimidine-4,6-diamines... 

Cobb et al.30 constructed 4-amino-2-carboxy-6-chloroquinazolin-4-one on a solid support using the 2-carboxylic ester linkage as the resin point of attachment. The quinazolinone (43) was converted to the resin-bound 4-chloroquinazoline (44) with SOCl2. The chloro group was then displaced even with anilines under acid-catalyzed conditions at room temperature. Finally, the resin-bound quinazoline-2-carboxylic ester (45) was cleaved from the resin and decarboxylated with TMSCl/Nal (Fig. 8) (yield 69%, purity 95%). 

The authors first considered the attachment of the aldehyde component to the SP using the AMEBA (acid-sensitive methoxy benzaldehyde) PS resin (100). 4-Carboxy-benzaldehyde and two different amines were reacted to produce the resin-bound intermediates 6.1 and 6.2 on a 100-g scale according to the reaction scheme shown in Pig. 6.9, with good yields resulting from an optimization of the reaction conditions. Resin-bound 6.1 was reacted with the standard olefin (cyclopentadiene, 6.3) and an aromatic amine (aniline, 6.9) and, after optimization of the reaction conditions, the desired tetrahydroquinoline 6.14 was obtained in good yield and purity after cleavage. 

Modification of the butyl linker moiety was then studied on SP, treating 9.26 with Ml (symmetrical anhydrides or diacids, 10 representatives. Fig. 9.19) to give the resin-bound acids 9.34, which were pooled, reduced to alcohols 9.35, and brominated to give the alkyl bromides 9.36. The resin was split into 60 portions and treated with M2 (the same 60 thiophenol and aniline nucleophiles as for L13) to give the 600-member pool library L14 made of 60 pools of 10 individuals (Fig. 9.19). The library quality... 

A large number of aniline derivatives have been synthesized using a combination of the procedures discussed above209,328-336. In addition, resin-bound triarylbismuth diacetates (80a-c) were used as multidirectional linkers to form arylation products in yields and conditions similar to those reported for the solution-phase A-arylations (Figure 18)337. 

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