Polymer-Supported Secondary Amines

Polymer-bound piperazine can also be used for the deprotection of phosphane-, phosphate- and phosphinite-borane complexes to give the corresponding free 

The Power of Functional Resins in Organic Synthesis. Judit Tulla-Puche and Fernando Albericio Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31936-7 

The application of secondary amines as organocatalysts in different processes makes use of the inherent nucleophilicity of these compounds, but in this case they function as catalysts rather than reagents, and are thus covered in Chapter 4 of this book. Polymer-bound tertiary amines have so far only found use as depro-tecting agents for phosphorus-borane complexes (see above) [9]. They are widely used as scavengers and linkers, however. 

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SCHEME 9.19 Cascade reaction combining two star polymer-supported secondary amine... 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

Polymer-supported permthenate has also been used in two convergent pathways for the synthesis of isoxazoUdines with each route employing different starting materials in order to create the maximum structural diversity [73]. In the first route secondary hydroxylamines, readily prepared from amines by in situ treatment with dimethyldioxirane, were oxidized directly to nitrones using polymer-supported permthenate (PSP). Alternatively, primary alcohols were used as the... 

The chemo- and regiospecific palladium-catalyzed four-component reaction of aryl iodides followed by incorporation of carbon monoxide, a polymer-supported allene, and a range of secondary cyclic amines has been reported as a short and high-yielding route to complex heterocycles with three points of diversity, such as 7 <2000CC2241>. 

In summary, ULTRA resins can be prepared with extremely high loading compared to standard resins in use today. Secondary amine groups of the resin were very accessible to various derivatizations and even larger product molecules could be assembled successfully in the resin interior. Thus, these resins allowed solid-supported chemistry that was greatly improved in atom economy and provide a significant contribution to the efficient scale-up of polymer-supported syntheses. 

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6) [24]. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 28] while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. 

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

An analogous procedure has been adopted for the formation of tertiary amines, which utilised a polymer supported acid chloride 12 to scavenge the excess secondary amine, (Table... 

As this area of polymer supported reagents continues to expand the complexity of the polymeric supported resins has increased [18]. Although electrophilic supported reagents like the isocyanate 5 and acid chloride 12 have been shown to be efficient reagents for the covalent capture for primary and secondary amines (Table 1), they are not without their difficulties. The isocyanate resin is particularly expensive and the loading is rather low (approximately 1 mmol NCO/gram). 

The same polymer-supported organotin reagent was also used in the Barton-type deoxygenation of steroid derivatives, sugar derivatives and diols160. Furthermore, the radical deamination of secondary and tertiary amines via the corresponding isocyanides was also reported160,169. 

However, early attempts at synthesising compound arrays using polymer-supported reagents and automation proved to be problematic. Our group used an ACT 496 automated synthesiser to produce a 96-membered array of compounds in a single automated step. In this array, 12 aromatic aldehydes were reacted with eight aliphatic amines in the presence of polymer-supported cyanoborohydride to produce the corresponding secondary amines 33 (Scheme 11). 

Chiral amino alcohols can be prepared by reaction of chiral epoxides with amines. Enantiopure (25, 3.R)-2,3-epoxy-3-phenylpropanol anchored to Merrifield resin has been used for ring-opening with secondary amines in the presence of lithium perchlorate to afford polymer-supported chiral amino alcohols 47 (Eq. 18) [56], By analogy, (2i ,35)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-l,2-propanediol has been anchored to a 2-chlorotrityl chloride resin (48). Although this polymer had high catalytic activity in the enantioselective addition of diethylzinc to aldehydes, the selectivity of the corresponding monomeric catalyst was higher (97 % ee) in the same reaction. 

Bis(phosphino)amines (208)-(211) were readily prepared by condensation of Ph2PCl and the appropriate secondary amine in diethyl ether, tetrahydrofuran, dichloromethane, or benzene, with triethylamine as base.454-457 Polymer-supported phosphine-phosphino(amines) (212) have also been reported.458 Hersh and co-workers have described a novel series of bis(p-toluenesulfonylamino) phosphines (213) and (214) from bis(dichlorophosphino) starting materials and A,vV -(ditoluenesul-fonyl)-l, 2-diaminoethane.459... 

Chiral secondary amines such as nonracemic imidazolidin-4-ones have been found to be effective asymmetric organocatalysts in the Diels-Alder cyclization of cyclopentadiene and a,p-unsaturated aldehydes [60]. A tyrosine-derived imidazoli-din-4-one was immobilized on PEG to provide a soluble, polymer-supported catalyst 110. In the presence of 110, Diels-Alder cycloaddition of acrolein 112 to 1,3-cyclohexadiene 111 proceeded smoothly to afford the corresponding cycloadduct 113 with high endo selectivity and enantioselectivity up to 92% ee (Scheme 3.31) [61]. 

Another example of a polymer-bound phenolic leaving group has been reported by Huang et al. [22]. Supported 8-acyloxyquinolines were shown to readily acylate primary and secondary amines and anilines at room temperature. Neighboring group participation was proposed for the quinoline nitrogen atom. 

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