Solvent-free reduction

Usually metal-free phthalocyanine (PcH2) can be prepared from phthalonitrile with or without a solvent. Hydrogen-donor solvents such as pentan-l-ol and 2-(dimethylamino)ethanol are most often used for the preparation.113,127 128 To increase the yield of the product, some basic catalyst can be added (e.g., DBU, anhyd NH3). When lithium or sodium alkoxides are used as a base the reaction leads to the respective alkali-metal phthalocyanine, which can easily be converted into the free base by treatment with acid and water.129 The solvent-free preparation is carried out in a melt of the phthalonitrile and the reductive agent hydroquinone at ca. 200 C.130 Besides these and various other conventional chemical synthetic methods, PcH2 can also be prepared electrochemically.79... 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

Based on the molecular design of precursor metal complexes, the solvent-free controlled thermolysis of metal complexes may cause the thermal reduction and simultaneous attachment of organic moiety on the growing metal nuclei and give us a solution of the defects of ordinary... 

During the last few years, miniaturization has become a dominant trend in the analysis of low-level contaminants in food and environmental samples. This has resulted in a significant reduction in the volume of hazardous and expensive solvents. Typical examples of miniaturization in sample preparation techniques are micro liquid/liquid extractions (in-vial) and solvent-free techniques such as solid-phase microextraction (SPME). Combined with state-of-the-art analytical instrumentation, this trend has resulted in faster analyses, higher sample throughputs and lower solvent consumption, whilst maintaining or even increasing assay sensitivity. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

Most of these publications describe important accelerations of a wide range of organic reactions especially when performed under solvent-free conditions. The combination of solvent-free reaction conditions and microwave irradiation leads to large reductions in reaction times, enhancement of yield, and, sometimes [3, 4] in selectivity with several advantages of an eco-friendly approach, termed green chemistry . 

The pioneering work of Posner, on the reduction of carbonyl compounds with isopropyl alcohol and alumina [116], has now been adapted to an expeditious solvent-free reduction procedure that utilizes aluminum alkoxides under microwave irradiation conditions (Scheme 6.37) [117]. 

Scheme 6.37 Solvent-free reduction of carbonyls using aluminum alkoxides.

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

There are distinct advantages of these solvent-free procedures in instances where catalytic amounts of reagents or supported agents are used since they provide reduction or elimination of solvents, thus preventing pollution at source . Although not delineated completely, the reaction rate enhancements achieved in these methods may be ascribable to nonthermal effects. The rationalization of microwave effects and mechanistic considerations are discussed in detail elsewhere in this book [25, 193]. A dramatic increase in the number of publications [23c], patents [194—203], a growing interest from pharmaceutical industry, with special emphasis on combinatorial chemistry, and development of newer microwave systems bodes well for micro-wave-enhanced chemical syntheses. 

Reductive Carbonylation of Methanol. The reductive carbonylation of methanol (solvent free) was studied at variable I/Co, PPh,/I, temperature, pressure, synthesis gas ratio and methanol conversion (gas uptake) in the batch reactor, A summary of the results is given in Table I. In general, the acetaldehyde rate and selectivity increase with increasing I/Co. The PPh /I ratio has little effect except in run //7 where the rate is drastically reduced at I/Co =3.5 and PPh /I r 2. A good set of conditions is I/Co =3 5 and PPh /I = 1,T where the acetaldehyde rate and selectivity is 7.6 M/nr and 765 at 170 °C and 5000 psig. The effect of methanol conversion at these conditions is obtained by compearing runs 13, 1, 14, and 15. The gas uptake was varied from 14000 to 4000 psi, which corresponds to observed methanol conversions of 68% to 38 te. 

As indicated in Table 3, reducing the excess methanol to only a 3 fold molar excess (rendering a nearly solvent free process) far exceeded expectations and allowed significant reductions in the catalyst levels. Under these conditions, catalyst turnover numbers exceeding 10,000 mol MPA/mol Pd were achieved with a turnover frequency of >3400 mol MPA/mol Pd/h. The reaction mixtures obtained from this process formed two liquid phases and the product spontaneously separated from the amine and amine hydrochloride. As a consequence of eliminating large methanol excesses, the methyl pivaloylacetate concentration in the product was raised to 26 wt. % without additional reaction time being required. This represents an additional ca. 2.5 fold improvement in reactor productivity. No attempt was made to reduce the methanol further. 

Fluorescein or Resorcinol Phtholein, C2oHi4Oq mw 334.32, colorl ess ndls (from AcOH), mp (for solvent-free) 253—54° insol in w sol in ale, eth, AcOH alkalies. Can be prepd by reduction, of fluorescein or by heating p tzhalic anhydride resorcinol. Used as a reagent... 

Varma reported a facile and rapid method for the reduction of aldehydes and ketones to the respective alcohols, using alumina-supported sodium borohydride and microwave irradiation under solvent-free conditions. Aldehydes tend to react at room temperature, while for the reduction of ketones, short microwave irradiation of 30-180 s was applied to produce the corresponding alcohols in 62-92% yield. With unsaturated carbonyl compounds, reduction at the conjugated C=C bond might occur as a side reaction under these conditions (Scheme 4.9)26. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

The Leuckart reductive animation of carbonyl compounds with ammonium formate or formamide was found to benefit strongly, when the reaction was carried out under solvent free conditions with microwave irradiation. Yields of N-alkylated formamides of up to 97% were produced in reaction times of about 30 min, as compared to thermal... 

Rapid reduction of aromatic nitro compounds into amines has been described using sodium hypophosphite and FeSC>4-7H20. The reactions showed best results in terms of yields and purity, when the substrates were pre-absorbed on alumina and irradiated by microwaves under solvent-free conditions. The reaction is chemoselective and does not affect functional groups such as CN, OH, COOH, CONH2 or halogens. In addition, oximes were not reduced under the given reaction conditions, but were dehydrated to the corresponding nitriles instead (Scheme 4.32)57. 

Reductive dehalogenation of chlorinated phenols to phenol, cyclohexanol and other chlorine-free compounds takes place rapidly with hydrogen gas and Pd/C in an aqueous system or under solvent-free conditions. Thus, pentachloro phenol was able to be completely dechlorinated within 20 min (Scheme 4.45). This methodology enables a facile route for rapid and complete detoxification of highly toxic polychlorinated aromatic hydrocarbons and environmental remediation71,72. 

Bolourtchian, M., Zadmard, R. and Saidi, M.R., Microwave promoted reductive coupling of carbonyl compounds to bis(trimethylsilyl) pinacols under solvent-free conditions, Synth. Commun., 1998,28, 2017-2020. 

Varma, R.S. and Dahiya, R., Sodium borohydride on wet clay solvent-free reductive amination of carbonyl compounds using microwaves, Tetrahedron, 1998, 54, 6293-6298. 

Vass, A., Dudas, J., T6th, J. and Varma, R.S., Solvent-free reduction of aromatic nitro compounds with alumina-supported hydrazine under microwave irradiation, Tetrahedron Lett., 2001, 42, 5347-5349. 

T pe of reaction reduction Reaction condition solvent-free... 

Solvent-Free Reduction under Microwave Irradiation... 

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