Methylene solvent-free

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. 

A solvent-free synthesis of substituted spiroindolinonaphth[2,l-fo][l,4]oxazines through condensation of 2-methylene-l,3,3-trimethylindoline derivatives with 1-nitroso-2-naphthol under microwave irradiation has been described by Fedorova and colleagues (Scheme 6.263) [453], In a typical reaction, an equimolar mixture of the two starting materials was irradiated at 65-110 °C for 15 min to produce the desired spiroindolinonaphth[2,l-fo][l,4]oxazines, which are useful as photochromic compounds. In a related procedure, addition of morpholine to the reaction mixture led to the formation of the corresponding 6 -amino-functionalized spiroindolino-naphth[2,l-fo][l,4]oxazines, which exhibit a strong hypsochromic color shift (not shown) [453]. 

A similar reaction is the methylenation of 3,4-dihydroxybenzaldehyde in the presence of a phase-transfer catalyst on a benign calcium carbonate surface [26]. Presumably, bonding of the vicinal hydroxyl groups is low thereby enhancing the reaction with the alkylating agent under the action of solvent-free microwave irradiation (Eq. 15). 

Functional groups were selectively introduced at the C-2 position of isophorone by epoxide ring-opening by several nucleophiles with active methylene groups. Different behavior was observed depending on the reaction conditions and the nature of the nucleophilic agents [57]. The best experimental systems involved PTC or KF-alumina under solvent-free conditions and MW irradiation (Eq. 37 and Tab. 5.15). 

Starting from glyoxal monohydrazones and active methylene compounds, N-anilino-pyrroles were prepared under solvent-free conditions by use of piperidine as catalyst [79] (Scheme 8.55). 

Azizian J, Mohammadizadeh MR, Zomorodbakhsh S et al (2007) Microwave-assisted one-pot synthesis of some dicyano-methylene derivatives of indenoquinoxaline and tryptanthrin under solvent free conditions. Arkivoc (xv) 24-30... 

Lee, J. C., Park, H.-J., Park, J. Y. Rapid microwave-promoted solvent-free oxidation of a-methylene ketones to a-diketones. Tetrahedron Lett. 2002, 43, 5661-5663. 

Type of reaction C-C bond formation Reaction condition solvent-free Keywords active methylene compound, ZnCl2, styrene... 

Addition to olefins. Depending upon the polarity of the solvent, bromine azide adds to olefins by ionic or free radical processes. Ionic additions are achieved in nitromethane-methylene chloride free radical addition predominates in pentane ... 

Amino-3-cyano-thiophenes or 2-amino-thiophene-3-esters result from this route, generally conducted as a one-pot process, involving a ketone that has an a-methylene, ethyl cyanoacetate or malononitrile, sulfur, and morpholine. Various improvements to the original procedure include using microwave irradiation on solid snpport, or with potassium fluoride on alumina as the base, or solvent-free,and using morpho-lininm acetate in excess morpholine for aryl alkyl ketones. 

Crystallizes solvent-free, unlike ergocristine which tends to retain the solvent of crystn. Long prisms from abs ale, mp 226 (dec). +366 (c — 0.68 in chloroform) +471 (c — 0.35 in pyridine), uv max (methanol/methylene chloride) 313 nm (log < 3.96). Much less sol than ergocristine. Does not seem to form salts. 

Cyclopropane derivatives can be obtained by reacting active methylene compounds and 1,2-dibromoethane using a solvent-free PTC + MW technique (Eq. 

Condensation of 140 with 3-methyl-l-phenyl-pyrazolin-5-(4//)-one was carried out on alumina support and under solvent-free conditions using MWI to give 3-methyl-4-[(chromon-3-yl)methylene]-l-phenyl-pyrazolin-5-(4//)-ones 142 in 59-87% yields within 2 min (Scheme 28). The same reaction in refluxing dioxane using a catalytic amount of triethylamine required 45 min to give lower yields (02SC497). 

Cycloaddition between electron-rich 6-[(dimethylamino)methylene]amino-1,3-dimethyl uracil 242 and various electron-deficient substrates such as quinones 243 and coumarins 244 was considered to take place by elimination of dimethyla-mine from the respective cycloadducts, followed by oxidative aromatization in a highly regiospecific manner to give pyrido[2,3-solvent-free conditions, the times were reduced to 6-7 min and the yields were increased from 70-80% to 85-94% (04SL1179). 

Polycyclic quinoline derivatives can be prepared in good yields by the Friedlander synthesis an acid- or base-catalyzed condensation, between 2-aminobenzaldehyde or 2-aminoarylketones 407 and ketones possessing an active methylene group followed by cyclodehydration. Thus, the condensation of 407 with A-carbethoxy-3-pyrroli-done (417) or 4-chromanone 418 catalyzed by montmorillonite KSF under MWI and solvent-free conditions gave quinolines 419 and 420, respectively (Scheme 83) (99SC4403). 

Methylene-1,3-dioxepane (28) has also found application in 1,3-dipolar and hetero-Diels-Alder cycloadditions in solvent-free conditions under microwave irradiation to give products (47), (48), and (49) (Scheme 7) <94JCS(Pl)3595>. Treatment with phenyl isocyanate gives Spiro compound (46)... 

In non-nucleophilic solvents, free from added nucleophiles, the reactive intermediates attack other substrate molecules. For example, in methylene chloride with BU4NBF4 as electrolyte, mesitylene is oxidised at 1.8 V vs, SCE to form coupling products of the biphenyl type bimesityl and some termesityl. 

Zhang T-H, Wang G-W, Lu P, Li Y-L, Peng R-F, Liu Y, Murata Y, Komatsu K. Solvent-free reactions of Cgg with active methylene compounds, either with or without carbon tetrabromide, in the presence of bases under high-speed vibration milling conditions. Org Biomol Chem 2004 2 1698-702. 

In the hypothetical case, following the procedure yields the short-term solution of substituting the solvent toluene for methylene chloride, for toluene has a similar solubility parameter, is inexpensive, and although still toxic has not been banned by environmental authorities. The longer-term solution that appears most desirable is to change the resin chemistry to make the ink solvent-free but water soluble through a chemical trigger. 

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