Solvent-free catalytic process

Some 0,0-dia]kyl 1-hydroxyalkylphosphonates have been prepared by the addition of diaJkyl phosphonates to aldehydes under dilferent reaction conditions [2], which can be summarized as follows (1) non-catalytic thermal addition [3, 4], (2) base-catalysis addition [5], and (3) solvent-free catalytic process using potassium fluoride, calcium fluoride, aluminum oxide, or others, as a catalyst [6-8]. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

It is a misconception that most chemicals are manufactured in organic solvents. Most high-volume bulk chemicals are actually produced in solvent-free processes, or at least ones in which one of the reactants also acts as a solvent. Typical examples of such large-scale processes include the manufacture of benzene, methanol, MTBE, phenol and polypropylene. In addition, some heterogeneous gas-phase catalytic reactions, a class of solvent-free processes, are discussed in Chapter 4. 

In addition to solvent-free processing, phase-transfer catalytic conditions (PTC) have also been widely employed as a processing technique in MAOS [15]. In phase-transfer catalysis, the reactants are situated in two separate phases, for example liquid-... 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

Earlier, the group of Laporterie reported on another prototype CF microwave reactor [80]. Solvent-free Friedel-Crafts reactions have been successfully carried out employing only catalytic amounts of the FeCl3 catalyst (Scheme 19). At a flow rate of 20-22 mL min 1 the corresponding substrates have been circulated in a molar scale (2 1 ratio) in the apparatus. Thus, 150-250 g products could be isolated. Excess substrates have been recovered by evaporation and recycled in the process. 

A catalytic version of the Zn( 11)-mediated enantioselective addition of alkynylides to aldehydes was documented after the stoichiometric process [19]. Initially, the reaction was reported to proceed using 22 mol % N-methylephedrine, 20 mol % Zn(OTf)2, and 50 mol % Et3N to furnish the product alcohols in yields and enantioselectivity only marginally lower than in the original stoichiometric version (Eq. 15). The key difference between the stoichiometric and the catalytic procedures is the elevated temperature (60 °C) for the catalytic process. Because the reaction can also be conducted under solvent-free conditions, ensuring a process with a high atom economy and volumetric efficiency (Eq. 16). Under these conditions, the reactions can be conducted with substantially lower catalyst loading (Eq. 17) [13]. 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

Transition-metal-mediated C-O bond cleavage reactions are interesting in view of environmentally benign halogen-free chemical processes [59]. Zerovalent ruthenium complexes are also active toward C-O bond-deavage reactions, and a number of catalytic processes have been developed in this respect. For example, Ru(l,5-COD)(l,3,5-COT) catalyzes allylic alkylation of carbon nucleophiles with allylic carbonates in basic solvent (Scheme 14.24) [60]. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Nitroethene is sufficiently electrophilic to substitute indole without the need for acid catalysis. Despite this, it has been shown that siUca-gel-supported CeCl3.7H20/NaI brings about such reactions at room temperature under solvent-free conditions or, to take another solvent extreme, the reaction occurs in water with a catalytic amount of a heteropoly acid (H3PWi204o). The employment of 2-dimethylamino-l-nitroethene in trifluoroacetic acid leads to 2-(indol-3-yl)nitroethene - the reactive species is the protonated enamine and the process is similar to a Mannich condensation (20.1.1.9). The use of 3-trimethylsilyl-indoles, with tpxo-substitution of the silicon, is an alternative means for effecting alkylation, avoiding the need for acid catalysis. 

Recent examples, for instance, of the catalytic application of the commercially available macroporous Amberlyst-15 include the Michael addition of pyrroles to a,P-unsaturated ketones (Scheme 10.4) [48]. In this process, the acid ion exchange resin (dry, 10% w/w) allows on to obtain mono and dialkylated pyrroles 5 and 6 in reasonable yields. Similarly, this catalyst (dry, 30% w/w) can catalyze the aza-Michael reaction of amines with a,P-unsaturated ketones, esters and nitriles to afford 7 in 75-95% yields under solvent-free conditions. Interestingly, yields were significantly lower using typical solvents such as DCM (dichloromethane), CH3CN, THF, DMF or EtOH [49], Recycling the catalyst is possible in both cases, but a smooth decrease in the yield is observed for each new run. 

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