Solid acids Michael additions

Examples of commercially applied solid base catalysts are much fewer than for solid acids. Nevertheless, much attention is currently focused on the development of novel solid base catalysts for classical organic reactions such as aldol condensations, Michael additions, and Knoevenagel condensations, to name but a few. 

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

Michael addition of methylene imines with alkenes under solid Iiquid two-phase conditions provides a route to substituted a-amino acids [26, 27] (Scheme 6.22). When ethyl glycine is (V-protected with (S)-menthone, C-alkylation under soliddiquid... 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

A unique utilization of an activated methylene group to form a thiophene derivative is represented in the cyclization in acidic xylene of (95), formed by Michael addition of 2-mercapto diethyl acetal, to cyclohexenone. Compound (96), produced as a crystalline solid in better than 80% yield, was readily converted to the corresponding thiophene (97) or benzothiophene (98) by oxidation. Oxidation of (96) with chloranil gave (97) in 63% yield (70JHC393). 

The two most commonly used types of allyl alcohol linker are 4-hydroxycrotonic acid derivatives (Entry 1, Table 3.7) and (Z)- or ( )-2-butene-l, 4-diol derivatives (Entries 2 and 3, Table 3.7). The former are well suited for solid-phase peptide synthesis using Boc methodology, but give poor results when using the Fmoc technique, probably because of Michael addition of piperidine to the a, 3-unsaturated carbonyl compound [167]. Butene-l,4-diol derivatives, however, are tolerant to acids, bases, and weak nucleophiles, and are therefore suitable linkers for a broad range of solid-phase chemistry. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate (1.24 g 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°C and the insoluble yellow-brown solid was collected by filtration and washed with a little ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene. This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on the steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange solid. Recrystallisation of this solid from ethyl acetate gave the required product as fluffy orange needles, mp 187°-188°C. 

In contrast with the widespread application of zeolites as solid acid catalysts (see earlier), their use as solid base catalysts received scant attention until fairly recently [121]. This is probably because acid-catalyzed processes are much more common in the oil refining and petrochemical industries. Nonetheless, basic zeolites and related mesoporous molecular sieves can catalyze a variety of reactions, such as Knoevenagel condensations and Michael additions, which are key steps in the manufacture of flavors and fragrances, pharmaceuticals and other specialty chemicals [121]. Indeed, the Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate (Fig. 2.36) has become a standard test reaction for solid base catalysts [121]. 

Solid-phase synthesis has also been used to make peptoids, some examples of which are shown in Fig. 2.4. Compounds of general structure 2.8, where the amino acid side chain is on the nitrogen, have been prepared either by the corresponding Fmoc-protected N-aUcylated glycines (33) or, in an improved method, via treatment of a resin-bound secondary amine with bromoacetic acid to produce the first peptoid building block, which is then elaborated via iteration of the procedure (34). Other modified P-peptoid structures such as 2.9 with repeating P-amino propionic units have been prepared by acylation of a resin-bound amine with acriloyl chloride followed by Michael addition of a primary amine. The cycle is repeated to build up the polymer... 

In conclusion, in spite of the heterogeneous conditions, solid montmorillonite can facilitate the Michael additions of silyl ketene acetals and silyl enol ethers to enoates, enones, and ynoates. Montmorillonite proved to be an alternative to conventional, moisture-sensitive homogeneous acids which are frequently troublesome in manipulation and work-up. 

Acrylic acid was first attached to tlie hydroxy-modified solid support via an ester bond to yield 73. This was followed by a Michael addition to give the tertiary amine 74. Alkylation led to the quaternary ammonium salt 75, which is suitably predisposed for 3-eliniination induced by Huenig s base, thereby yielding the required tertiary amine. 

An approach to carbocyclic arenes by cyclative cleavage is presented in Scheme 37 [53]. Merrifield resin was etherified with 3-hydroxypyridine (140), and then the pyridine moiety was quaternized with bromoacetone to yield 141. Formation of an yhde 142 with NaOH/ethanol and subsequent reaction with a chalcone (143) produced the intermediates 144 after a Michael addition. A subsequent condensation reaction released the phenolates 145 from the solid phase with restoration of the pyridine moiety on the solid support. Acidic work-up and filtration furnished... 

In this subsection, we describe a couple of examples taken from the recent literature, in which the Baylis-Hillman reaction has been employed for the construction of new carbon-carbon bonds. The Baylis-Hillman reaction proceeds in a catalytic cycle propagated by a nucleophilic catalyst (584). The nucleophilic catalyst initiates the cycle by Michael addition to a double bond bearing an EWG (586 or 590). The carbon a to the EWG is acidic and may react with an electrophile. Finally, the nucleophilic catalyst is eliminated, completing the cycle (Scheme 122). The most frequently used catalysts are quinuclidine, DABCO, phosphines, thiopheno-lates, and selenophenolates. The reaction rate of a catalytic Baylis-Hillman reaction approaches a maximum at a certain temperature and declines upon further heating, as the equilibrium concentration of (587) becomes very small. In the first example, the electrophilic component of the reaction was immobilized on a solid phase and the nucleophile was in solution, while in the other example the situation was reversed (Scheme 122). 

In early 1998, a further class of peptoid oligomers appeared [25], when a solid-phase method was developed to synthesize N-substituted P-aminopropionic acid oligomers, termed P-peptoids. Treatment of Wang s resin with acryloyl chloride, followed by Michael addition of primary amines afforded N-substituted P-alanines. A combinatorial library of... 

Nafion resins have been used not only for the opening of epoxides but also for their isomerization to aldehydes or ketones [137]. Various other rearrangements and isomerizations are catalyzed by this solid acid, in some cases with selectivities higher than those obtained with other solid catalysts [138-140]. Other reactions that have been studied include the Peterson methylenation of carbonyl compounds [141], hetero-Michael additions to unsaturated ketones [142], the Koch-type carbon-ylation of alcohols to form carboxylic acids [143], dimerization of a-methylstyrene [144], addition of carboxylic acids to olefins [145] and Diels-Alder reactions [146]. Notably, in most cases, reutilization of the catalyst is considered but only after an appropriate washing protocol to regenerate its acidity/activity. 

Goff and Zuckermann [51] reported the synthesis of 2-oxopiperazine 16 by intramolecular Michael addition on the solid phase. The coupling of resin-bound unsaturated dipeptoids with a variety of Fmoc-L-amino acids, N,N -diisopropylcarbodiimide (DIPCDI), and 1-hydroxybenzotriazole (HOBt) affords tripeptoids, which after treatment with 20% piperidine in DMF, were acylated with benzoyl chloride-EtaN in 1,2-dichloroethane. Following treatment with 95% TFA in H2O, a diastereomeric ratio of monoketopiperazines 16 was obtained (Fig. 8). Rather than benzoyl chloride, phenylisocyanate or bromoacetic acid and an amine could be used. 

A solid-phase submonomer approach to A-substituted j8-aminopro-pionic acid oligomers or )8-peptoids has been developed by Hamper et al. [63]. It is based on a simple two-step acylation and Michael addition reaction sequence. Treatment of Wang resin with 2 equiv. of acryloyl chloride in the presence of triethylamine in excess afforded the corresponding acrylate resin 86 (Scheme 23) [63]. Michael addition of a 6- to 10-fold excess of a given primary amine in DMSO afforded polymer-bound A-substituted -alanines (87). Trimeric A-benzyl-j8-aminopropionic acid (88) was prepared in 67% overall yield by repetition of this two-step sequence. 

The use of nitromethane as a probe of basicity of zeolites (NaX, CsX, CsX 9Cs) and mixed oxides, Mg(Al)0, is discussed. Various species (physisorbed nitromethane, aci-anion nitromethane, and methazonate salt analogue) formed upon nitromethane adsorption were characterized by C MAS NMR spectroscopy. Heterogeneous base catalysis of the Michael addition of nitromethane on cyclohex-2-en-1-one was also studied. Low rates were obtained for catalysts showing only nitromethane physisorption. Formation of aci-anion nitromethane was observed for solids of medium efficiency correlation of the chemical shift with the initial rate was established. Finally, the decrease of Lewis acidity and concomitant increase of basicity led to methazonate formation and to the more efficient catalysts. 

---