Methylene active

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. 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

A related pyranopyrimidine 63 has been prepared by the irradiation of 1,3-dimethylbarbituric acid 61, a methylene active nitrile 47a and N,N-di-methylformamide dimethylacetal 45 [77]. After initial formation of the enam-... 

Fig. 3 Tentative mechanism for the formation of substituted 2-pyridones in the reaction between enaminones and methylene-activated nitriles...

Quinoneimines can also be used, but in this case iminolactams 9-93 are the final products because the aromatization process cannot take place [59]. A completely different mechanism is proposed when methylene active compounds such as 4-hy-... 

This chapter reports on the reactivity of organic carbonates as alkylating agents, with emphasis on the lightest term of the series, DMC. Under both CF and batch conditions, DMC can react with a number of nucleophilic substrates such as phenols, primary amines, sulfones, thiols, and methylene-active derivatives of aryl and aroxy-acetic acids. The mechanistic and synthetic aspects of these processes will be elucidated. 

In analogous fashion, the basicity of the azole ring affects the ring closure to azolo-triazines 182 of the hydrazones 181 obtained from the coupling reaction of diazoazoles and methylene active compounds (76JMC517). 

The phosphonic group can be introduced in position 4 of a pyran ring (66) by utilization of phosphorus-containing UN 67 in a reaction with methylene-active ketones 35 or 36 on continuous heating in ethanol (00PS(165)17) (Scheme 15). 

There are some examples of pyran synthesis by Method 2, which involves the reactions of unsaturated ketones with methylene-active nitriles. In a typical case of Method 2, the Michael reaction of a,j5-unsaturated carbonyl compounds 26 (77TL1835, 78JHC57,... 

Method 2, which involves the reaction of imsaturated carbonyls with methylene-active nitriles, can be illustrated with pulegone 129 and MN 27a (3 equiv.) in the presence of KF as a mild base (70CJC3064) (Scheme 44). 

However, all the broad spectrum of products formed via the reaction of salicylic aldehydes with methylene-active nitriles cannot be shown on a one simple scheme. In the presence of ammonium acetate different chromenes 165 and 166 can be isolated, depending on the order of addition of reagents, the amount of catalyst, and temperature (77S871) (Scheme 60). 

Heterocyclic methylene-active carbonyl compounds (or their tautomers) with arylidenemalononitriles yield 2-amino-4H-pyrans condensed with... 

Because a base-catalyzed reaction involves the abstraction of a proton by the catalyst, one approach to measurement of the total number of basic sites and also the base strength distribution is to use the reactions of molecules with various values (96-100). For instance, the basic site distribution in calcined MgAl hy-drotalcites was determined by Corma et al. (99), who used the Knoevenagel condensation (Scheme 7) between benzaldehyde and methylene active compounds with various pKa values, i.e., ethyl cyanoacetate (pKa = 9), diethyl malonate (pKa = 13.3), and ethyl bromoacetate (pKa = 16.5). The authors found that this material has basic sites with pKa values up to 16.5, although most of the basic sites... 

Selective monomethylation reactions of methylene-active compounds with dimethylcarbonate. An example of clean synthesis... 

The Gewald synthesis provides a convenient synthetic pathway to substituted 2-aminothiophenes (Section 3.15.3.1.5), and has been widely applied. Condensation of a carbonyl compound with a methylene activated acetonitrile, followed by heating with sulfur in the presence of base, gives the 2-aminothiophene in yields ranging up to 90% (equation 47). Arylpropynthioanilides react with acidic bromomethylene compounds, BrCH2X, where... 

As shown in Scheme 4.21, in the reaction between methylene-active ketones and nonsymmetrical ortho-diamines, regioisomeric dihydrodiazepines can form. The interaction of nonsymmetrical substituted o-PDAs 88 with methyl aryl ketones 89, which may lead to the formation of the isomeric products 90A and 90B, was studied in [54, 65, 95, 97] (Scheme 4.28). It was shown that the... 

Thieno[3,2-i]pyridines 162 and 163 were prepared starting from o-aminonitrile 160 and methylene-active compounds 161 (1996M955). 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

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