Dicarbonyl condensation products

Reaction of such compounds as ethyl acetoacetate or 2,4-pentanedione with D-fructose gives /3-substituted furan derivatives this is in contrast with the a-substituted compounds obtained from aldoses. The mechanism of reaction is identical in both cases, and the structure has been proved by degradation methods and by infrared and ultraviolet spectroscopy. With sucrose as the starting material, a mixture of a- and /8-substituted compounds was obtained in the ratio of 65 35. 

When added to Amadori products, the /3-substituted pyrrole derivatives are formed, as expected by theory. The 1-arylamino-l-deoxy-D-fructoses behave in the same manner, but the yield is decreased to 20-30%, whereas the simple Amadori compoimds were obtained in yields of 80-90%. On the other hand, D-fructosylamines give a-substituted pyrrole derivatives, 

034) F. Garcia Gonzdlez, A. G6mez Sanchez, and J. G. Gomez, Andies Real Soc. Espan. 

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Alternatively, hydrogen sulfide could be produced alongside ammonia and acetaldehyde by the breakdown of the mercaptoimino-enol intermediate of the decarboxylation reaction of the cysteine-dicarbonyl condensation product. Fisher also points out that hydrogen sulfide is forms many odiferous an hence intensely flavoured products.2 Cysteine is important as it is one of the major sources of sulfur. 

Since the structures of the Gabriel-Isay condensation products of 5,6-diaminopyrimidines with unsymmetrical 1,2-dicarbonyl or a-substituted monocarbonyl compounds are always ambiguous, the synthesis of 6- and 7-substituted pteridines by an unambiguous approach was and still is a necessity and an important challenge. 

A large proportion of the condensation products of sugars with dicarbonyl compounds have been obtained in the crystalline state however, some have not yet been crystallized. All are more soluble in hot than in cold water. Those resulting from the condensations with heptoses, hexoses, and pentoses are almost insoluble in benzene. Generally speaking, all are soluble in ethyl acetate. 

Acid treatment of (6) furnishes products (13) including minor quantities of tricyclic condensation products, which result from the reaction of (13) with excess (6). This side reaction may be extended to become a synthesis of double anellated pyridines when (6) is fused with cyclic 1,3-dicarbonyl compounds. As expected, the spatial requirement of the acyl substituent R affects the yield of (15) (87TH1). (See Fig. 7.) Dipyrrolo[3,4-b 3, 4 -e]-pyridinediones of type (15a) were synthesized by Snyder et al. starting... 

Rate and equilibrium constants have been measured for representative intramolecular aldol condensations of dicarbonyls.60a For the four substrates studied (32 n = 2, R = Me n = 3, R = H/Me/Ph), results have been obtained for both the aldol addition to give ketol (33), and the elimination to the enone (34). A rate-equilibrium mismatch for the overall process is examined in the context of Baldwin s rales. The data are also compared with Richard and co-workers study of 2-(2-oxopropyl)benzaldehyde (35), for which the enone condensation product tautomerizes to the dienol60b (i.e. /(-naphthol). In all cases, Marcus theory can be applied to these intramolecular aldol reactions, and it predicts essentially the same intrinsic barrier as for their intermolecular counterparts. 

In the advanced stage, subsequently the ARP opens, via 1,2- or 1,3-enollsation, depending on the pH of the medium, leaving dicarbonyl-compounds, the so called reductones (10) after elimination of the glycine residue. These highly functionalized compounds are very reactive towards nucleophiles, like the amino acids, or may give rise to the formation of condensation products. 

Saturated 1,4-dicarbonyl compounds give 1,4-dihydro-pyridazines or -pyridazinones, etc., which are easily oxidized. 1,2-Diketone monohydrazones 124 and esters 125 containing a reactive CH2 group give 3-pyridazinones 126 (Scheme 64) . A popular modification of this approach is the Ugi four-component condensation of diarylethane-l,2-dione monohydrazones 127 with isocyanides, aldehydes, and methylene active acids leading to the corresponding substituted pyridazin-3(2//)-ones 128 (Scheme 65) The intermediate Ugi condensation products have never been observed because of their tendency to cyclize <2003S691>. 

There is one example in which part of the amidine system is a C—N bond in a heterocyclic ring. The enamino ketone condensation products (42) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles. The driving force for this reaction is provided by the well-established, general attack of a nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme 23). 

The reaction sequence of Scheme 3 might well be classified as an imidazole synthesis from other heterocycles, but it seems more logical to treat this as a cyclization involving formation of the 1,5-bond. The enaminoketone condensation products (12) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds are cyclized by base to imidazoles (13) in 60-80% yields." Such a reaction makes use of the well-established general attack of a nucleophilic center in the side chain on N-2 of the oxadiazole ring. Benzamidine combines with 2-amino-3-phenacyl-l,3,4-oxadiazolium bromides to produce 1-acyl-amino-2-benzimidoylamino-4-arylimidazoles. ... 

Many macrocyclic SBs have been prepared by condensation of different dicarbonyl precursors (head units (55), see Scheme 16) such as 2,6-diformylpyridine (56, R = H, 56a), 2,6-diacetylpyridine (56, R = CH3, 56b), 2,6-diformyl-4-Z-phenol (57, Z = C1- 57a, CH3-, 57b), 2,6-diacetyl-4-Z-phenol (57, Z = C1—, 57c, Z = CH3, 57d) thiophene-2,5-dicarbaldehyde (58), furan-2,5-dicarbalde-hyde (59), pyrrole-2,5-dicarbaldehyde (60), 2,6-diformyl-4Z-thiophenol (61, Z = CH3, 61a Z Bu1, 61b) or /3-triketones (62) with a wide range of different diamines (lateral chains). The majority of SB macrocycles are symmetrical and contain either phenol or pyridine as head units. Asymmetrical SB macrocycles have also been prepared. The SB macrocycles are designated [1 + 1] and [2 + 2] depending on the number of head and lateral units present (see Scheme 17). With certain precursors (i.e., 2,6-diacetylpyridine and l,3-diamino-2-hydroxypropane) [3 + 3] and [4 + 4] macrocyclic complexes have also been synthesized.177-179 The [2 + 3] condensation products have also... 

More often, unsymmetrical 1,4-dihydropyridines are produced by conducting the Hantzsch synthesis in two stages, i.e. by making the (presumed) aldol condensation product separately, then reacting with ammonia and a different 1,3-dicarbonyl component, or an enamino-ketone, in a second step. ... 

Orthoesters and carbonic acid derivatives can be employed in lieu of carbonyl compounds. For example, 2,2-diethoxy-2//-chromene (178) and mediyl cyanoacetate give the 2//-chromene derivative (179 Scheme 31). (Methylthio)alkylideniminium salts (180) react with active methylene compounds under basic conditions (K2CO3 or EtsN) to give the corresponding condensation products (181 Scheme 32) 240 jjjis method is an alternative to the Eschenmoser procedure for synthesizing vinylogous lactams and urethanes. A(-Alkyl and A(-acylpyridinium salts can also serve as electrophiles in the Knoevena-gel condensation with activated methylenes. " Suitably activated nitriles (R CN) such as trichloroacetonitrile or ethyl cyanoformate react with various 1,3-dicarbonyl compounds to afford (182) in the presence of catalytic amounts of metal acetylacetonates [M(acac)n]. In the presence of TiCU non-... 

The reaction of amidrazones with dicarbonyl compounds in acidic media may lead to the bis-condensation products which are very stable for alkyl groups in the position R2.111 These can be converted to the 1,2,4-triazines by acidic hydrolysis. When an a-oxoaldehyde is used as the 1,2-dicarbonyl compound, under these conditions the 6-substituted 1,2,4-triazines 4 are formed predominantly. This can, again, be explained by the higher reactivity of the aldehyde group.111... 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

Aldol reactions of this type, involving 2-acetamido-2-deoxyaldohexoses, have been studied in connection with the chemical synthesis of A -acetyl-neuraminic acid (50) and related substances, and, for this reason, the choice of the dicarbonyl compound has thus far been limited to oxalacetic acid and its esters. Oxalacetic acid condenses readily with 2-acetamido-2-deoxyaldohexoses in aqueous solution at pH 11. Under these conditions, acetamido sugars partially epimerize, and the aldol reaction takes place for both of the 2-acetamido-2-deoxyaldohexoses present. The complexity of the reaction is further increased by the formation of asymmetric centers at carbon atoms 3 and 4 of the condensation products, namely, diacids (45) and (48), and this can result in the formation of four diastereo-isomers from each sugar. The reaction using 2-acetamido-2-deoxy-o-rnannose (47) has been the one most extensively studied. In this... 

Aminoalkylquinoxalines (17) have been derived from a-amino acids (10) as shown in Scheme 2, the amino group is protected by formation of a phthalimide derivative (11). The intermediate chloromethyl ketone (12) is converted via a pyridinium salt (13) to a nitrone (14) which on hydrolysis yields the a-dicarbonyl compound (15) required for diamine condensation. Finally the phthalimide residue is removed from the condensation product (16) by hydrazine treatment. ... 

The very acidic (in the region of pK 10) 1,3-dicarbonyl compounds (—CO—CH— CO—), diketones, and ketoesters are readily converted into the enolates by reaction with alkali hydrides in polar as well as in apolar solvents [1]. Also some acidic mono-ketones, e.g., PhCH2COCH3, react smoothly with sodium hydride [4], Potassium hydride has been used to convert aldehydes into the enolates [2, compare 3]. A serious drawback of this method is the handling of the commercially available potassium hydride, which inter alia involves removal of the protecting mineral oil. Reaction of kinetically less acidic ketones and carboxylic esters with alkali hydrides, in general, gives rise to extensive formation of self-condensation products [3,6],... 

The intramolecular variant of this reaction producing carbo-cyclic derivatives has been reported. Copper(II) chloride catalyzes the Knoevenagel condensation of 2,4-pentanedione with aldehydes and tosylhydrazones (eq 13). The reagent also catalyzes the reaction of various 1,3-dicarbonyls with dithianes such as benzaldehyde diethyl dithioacetal to give the corresponding condensation products (eq 14). ... 

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