Isonitrile support-bound

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Pyrrolidines and pyrrolidinones can be synthesized on insoluble supports by intramolecular carbometallation of alkenes (Entry 1, Table 15.4) and by Ugi reaction of support-bound isonitriles with amines and 4-oxo acids (Entry 4, Table 15.4). In Entry 5 in Table 15.4, the pyrrolidinone ring is formed by intramolecular Diels-Alder reaction of a furan with a fumaric acid derivative. 2-Pyrrolidinones have also been prepared by treatment of resin-bound O-mesitylenesulfonyl cyclobutanone oximes with... 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Very common Cl fragments bound to a polymeric support are carbenoids. The simplest carbenoid is CO itself, which can be used in transition metal-catalyzed insertions between benzofuran-3yl palladium and a nucleophile such as trifluoroethanol [161]. One of the most common carbenoids is isonitrile, which is used in a large number of multicomponent reactions. Diazoalkanes have often been used as carbene precursors, since they can be readily obtained from support-bound anions and sulfonyl azides [252]. Commonly, diazoalkanes are converted transi-... 

Reaction of isonitrile with support-bound electron-rich alkenes (Scheme 47)... 

Thus a support-bound benzylpiperazine (282) was allowed to undergo a Man-nich reaction with formaldehyde and a-keto-aldehyde hydrazones. Upon addition of 1,2-dibromo-ethane (388) the support-bound piperazine tether is N, N -dialky-lated to give a quinuclidinium species (389). Subsequent Hoffmann elimination released a diazaalkadiene (390) from the polymeric support, allowing it to react with isonitriles to give pyrazoles (395). With electron-rich dienophiles, HDA reactions were also reported to have been performed to yield compound (393) (Scheme 80). 

General procedure for Ugi reaction with support-bound isonitrile [346] A 1.2 m solution of 2-chlorobenzylamine (0.133 mL, 1.1 mmol) and 2-phenylpropio-naldehyde (0.146 mb, 1.1 mmol) in trimethylorthoformate (TMOF) was allowed to react for 30 min. (]3-Isocyano-ethyl)-alkyl-carbonate resin (126 mg, 110 pmol, 0.87 mmol g ) was suspended in 1,2-dichloroethane (1.75 mL) in a 5-mL Bohdan fritted reaction tube and allowed to stand for 15 min. The 1.2 M solution ofimine in trimethylorthoformate was added to the resin, and... 

Good yields and purities were obtained for the two examples shown. Ugi reaction using solid-supported benzenesulfonamide, prepared by coupHng 4-carbox-ybenzenesulfonamide onto Rink resin, has also been described. The sulfonamide took the place of the amino component in the classical Ugi MCR. An extension of this Ugi reaction involving a support-bound amine, furfural, and an isonitrile and an acrylic acid was used by Schreiber [307] to generate support-bound dipeptides capable of performing intramolecular Diels-Alder reactions (see Section 4.5.9). 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

More recently, a novel resin-bound isonitrile has been reported to be suitable for synthesizing libraries of l,4-benzodiazepine-2,5-diones through Ugi multicomponent reactions [25]. The method produces solid-supported Ugi products, which are cleaved by base activation to form N-acyloxazolidone intermediates that can be further elaborated. The flexibility of the approach was demonstrated by an analogous preparation of 2,5-diketopiperazines by simply replacing the 2-aminobenzoyl building blocks with a-amino acids. 

We have developed a Lewis acid-catalyzed three-component condensation [299] between a 2-aminoazine, an aldehyde, and an isonitrile that affords 3-aminoimidazo[l,2-fl]pyridines and related compounds. This reaction was adapted to the solid phase [300] by anchoring any one of the three reactants to RAM resin 7c. Thus, 6-aminonicotinic and 3-formylbenzoic acids could be anchored to support 7c in the presence of HATU and subjected to the 3CC reaction. Alternatively, a resin-bound isonitrile was obtained by coupling 7-aminobutyric acid (GABA) to 7c, followed by for-mylation of the amino group and dehydration (Scheme 11). After the 3CC reaction, cleavage was effected using TFA-CH2CI2 (1 1). 

Very recently, a polymer-supported construct for quantifying the reactivity of monomers involving multicomponent Ugi strategies was reported [53]. The authors investigated the Ugi four-component condensation of a set of aldehydes, acids, and isonitriles. The amine compound used was bound to a specially modified Rink amide polystyrene resin bearing an ionization leveler and bromine functionality as a mass splitter for accurate analysis by positive electrospray ionization mass spectrometry. The microwave-assisted experiment was performed with a set of ten carboxylic acids, hydrocinnamaldehyde, and cyclohexyl isonitrile in DCM-... 

Microwave-assisted heterocycle synthesis has also been used to prepare a small set of pharmaceutically important imidazole derivatives [54]. The procedure utilized an initially prepared polymer-bound 3-N,N-(dimethylamino) isocyanoacrylate. The best results in imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the corresponding amines (Scheme 16.31). Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

In related work, solid-phase-mediated synthesis of isonitriles from formamides was achieved by using polystyrene-bound sulfonyl chloride as a suitable supported reagent [115]. The sulfonyl chloride resin could be quantitatively regenerated by treatment of the sulfonic acid resin formed with phosphorus pentachloride (PCI5) in N,N-dimethy]formamide at room temperature. 

Ionic hquid-bound pyrrolo-[l,2-fl]-benzimidazoles have been synthesized by Sun et al. by reacting IL-supported 2-(cyanomethyl)benzimidazole with aldehydes and isonitriles under microwave irradiation at high temperature [95], After precipitation and cleavage from the IL support, the desired products could be obtained in good yields and moderate to high purity without chromatographic purification. 

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