53-Dimethyl barbituric acid

Methyl 2-benzoylamino-3-dimethylaminopropenoate reacts with barbituric acid or its 1,3-dimethyl derivative to give a pyranopyrimidine 118 (89JHC1273). 

The Pd(0)-catalyzed transfer of the allyl moiety to dimedone [23], morpholine [22], or N,N -dimethyl barbituric acid [27] resulted in the completely selective cleavage of the Aloe group, whereas the numerous other protecting groups and the glycosidic bonds,... 

One of the most reactive 1,3-dicarbonyl compounds used in the domino-Knoevenagel-hetero-Diels-Alder reaction is N,N-dimethyl barbituric acid 2. It has been shown that the fairly stable products can easily been transformed into other compounds via a reduction of the urea moiety with DIBAL-H [20]. Thus, reaction of 30 with DIBAL-H at 78 °C led to 46, which can be hydrolyzed to give 47 (Scheme 5.9). In a similar way, 48 was transformed into 50 via 49 and 12 to 52 via 51. The obtained compounds containing a lactone and an amide moiety can again be further transformed using DIBAL-H followed by an elimination. In this way, dihydropyran 54 is obtained from 50 via 53 as one example. 

Scheme 5.9. Transformation of cycloadducts with N,N-dimethyl barbituric acid.

Fig. 5.4. Products of the domino-Knoevenagel-hetero-Diels-Alder-hydrogenation sequence of a-amino acids with N,N-dimethyl barbituric acid.

The necessary amino aldehydes are accessible from widely available amino acids and amino alcohols. In addition to N,N-dimethyl barbituric acid shown in Figure 5.3, other 1,3-dicarbonyl compounds can be employed, such as cydohexane-1,3-diones or coumarines (Figure 5.5). 

This reaction has been applied to a great number of carbonyl compounds, e.g., cyclopentanone,27 1,3-cyclohexanedione,36 5,5-dimethyl-l,3-cyclohexanedione,S5 1-acenaphthenone,24,25 1,3-indane-dione,35 1,3-phenalanedione,85 86 sodium salts of 3-aryl-3-oxo-propanals,39 2,3-dihydrobenzo[6]thiophen-3-one,40 sodium benzoyl-acetate,41 benzoylacetonitrile,29 30,88 ethyl cyanoacetate,30 35 cyano-acetanilide,30 barbituric acid,35 rhodanine,35 jV-phenylrhodanine,37 and iV-methylenebenzothiazoline.37... 

Alkylated barbituric acids, 6-chloro-a-methylcarbazole-2-aceticacid, 1-phenylethanol, 1-phenyl-1-propanol, dimethyl, 3,4,5,6-pentafluoro-benzyl alcohol, l-(2-naphthyl)-ethanol, 1 -(p-biphenyl)-ethanol Chirasil-Dex coated column, 0.15 pm... 

Barbituric acid, 1,3-dimethyl-, Vilsmeier formylation, 55, 190 Barbituric acids, 5-ethyl-5-phenyl-, nitration, 58, 256... 

In most cases convergent types of syntheses are the most cost effective and preferred for various reasons. However, that was not the case with ERH-1 as it will show in the following examples. In the convergent approach (see Scheme 3) it was assumed that barbituric acid would be a cheap source ( 4 per kg) for the pyrimidine portion since it was prepared from inexpensive materials such as ethyl malonate and urea with sodium ethoxide as a condensing agent. Numerous reports [4] have shown that barbituric acid is easily converted to 2,4,6-trichloropyrimidine by heating with phosphorus oxychloride and a trialkylamine. Our intent was to couple 2,4,6-trichloropyrimidine 10 to 2,2-dimethyl-1-indanone followed by various reactions that would lead to ERH-1 [5] as shown in Scheme 3. 

Reaction of 5,5-dimethyl-l,3-cyclohexanedione and arylidenemalononitrile gave 5, and of 1,3-diarylthiobarbituric acids with hippuric acid and triethyl orthoacetate or triethyl orthoformate and malononitrile or alkylnitriles gave pyranopyrimidines 6 or 7. Pyranopyrimidines 8 were obtained from reaction of arylidenemalononitriles or N-phenyl maleimides with barbituric acid . ... 

Raman spectra of barbituric acid could not be obtained because of its high luminescent backround,99,100 but Willis et al. gave interpretations of Raman spectra for eight barbiturates,89 and Barnes et al. reported a detailed analysis of IR and Raman spectra for the whole frequency range for 1-methyl-, 1,3-dimethyl-, and 5,5-diethylbarbituric acids.92-94 Similar IR and Raman spectra analyses were described for 5-ethyl-5-phenylbarbituric acid and its N-mono-and N,N-disubstituted derivatives.101 A detailed interpretation of IR spectra of the 1-acyl and l-(4 -aminobutynyl) derivatives was also reported.102,103... 

Deduce structures for the heterocyclic products from the following combinations (i) C11H7N3O2 from 2-aminobenzaldehyde and barbituric acid (ii) CmHuNOs from 4,5-methylenedioxy-2-aminobenzaldehyde and dimethyl acetylenedicarboxylate (iii) CmHuNS from 2-aminoacetophenone and 2-acetylthiophen (iv) C21H19NO from 2-aminobenzophenone and dimedone (v) C15H12N2O2S from 2-aminopyridine-3-aldehyde and 1-phenylsulfonylacetone (vi) C15HHN3 from 4-amino-pyrimidine-5-aldehyde and a-tetralone. 

The allylation reaction was extended to various carbonucleophiles [7, 10-12], It was observed that the selectivity in the formation of mono- and diallylated compounds was very sensitive to the nature of carbonucleophile and its p Ka. The acyclic carbonucleophiles such as ethyl acetoacetate, acetylacetone, dimethyl malo-nate, dicyanomethane, and bis(phenylsulfone)methane, gave predominantly the monoallylated product (Eq. 2), although the cyclic carbonucleophiles such as te-tronic acid, dimedone, and barbituric acid gave predominantly the diallylated product (Eq. 3). 

Malonomonoamides can be condensed with aldehydes to give acrylamides or cinnanamides, but condensation with malonodiamides is of only minor impjortance. In contrast to Meldrum s acid (58), Knoevenagel reactions of barbituric acid (56) and A A -dimethylbarbituric acid have been less explored. However, several aliphatic, aromatic and heteroaromatic aldehydes are known to react easily and with high yields in most cases. Reactions of 1,2-dimethyl-3,5-pyrazolidinedione (93) with several aliphatic and aromatic aldehydes using standard conditions yield Knoevenagel products in good yield. A similar reactivity is observed with 2-phenyl-3,5-dioxoisoxazolidine (94) and oxazepanediones (45 see Section 1.11.2.5). Recently, the oxidations of alcohols to carbonyl compxiunds and thiols to disulfides with 5-arylidene-l,3-dimethylbarbituric acids (95) have been described Mechanistically (95) mimics enzymic oxidation by flavin adenine dinucletide (FAD). ... 

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