1.3- Dicarbonyl compounds. See

Vitamin C, also known as L-ascorbic acid, clearly appears to be of carbohydrate nature. Its most obvious functional group is the lactone ring system, and, although termed ascorbic acid, it is certainly not a carboxylic acid. Nevertheless, it shows acidic properties, since it is an enol, in fact an enediol. It is easy to predict which enol hydroxyl group is going to ionize more readily. It must be the one P to the carbonyl, ionization of which produces a conjugate base that is nicely resonance stabilized (see Section 4.3.5). Indeed, note that these resonance forms correspond to those of an enolate anion derived from a 1,3-dicarbonyl compound (see Section 10.1). Ionization of the a-hydroxyl provides less favourable resonance, and the remaining hydroxyls are typical non-acidic alcohols (see Section 4.3.3). Thus, the of vitamin C is 4.0, and is comparable to that of a carboxylic acid. 

In agreement with this, the enol content also depends strongly on the initial concentration of the 1,3-dicarbonyl compound see Fig. 4-3 [50],... 

Synthesis of furans by base catalyzed condensation of an a-halocarbonyl compound with an enol, derived from a 1,3-dicarbonyl compound (see 1st edition). 

The asymmetric 1,4-addition of nucleophiles to a,p-unsaturated carbonyl and related compounds is also an important and valuable method for preparation of highly functionalized aUcyl chains. While chiral Brpnsted base-catalyzed asymmetric transformation has been intensively explored (for reviews of asymmetric 1,4-addition reactions of 1,3-dicarbonyl compounds, see [26-33] for reviews of asymmetric 1,4-addition reactions of glycine Schiff bases, see [34—37] for reviews of asymmetric [3-1-2] cycloaddition reactions, see [38-41]), chiral alkaline-earth metal catalysts have been also successfully employed in this reaction. 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

In the oxidation of anionized 1,3-dicarbonyl compounds (Table 8, numbers 1-7) at potentials between 0.6 and 1.4 V (see) and in the presence of butadiene, mainly the additive dimer (24) is obtained in the presence of ethyl vinyl ether chiefly the disubstituted monomers (28) or (29) arise. 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

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... 

Aromatic aldehydes react very easily with tetramic acid under acidic conditions to give 3-benzylidene compounds (41). The yields are moderate, because often there are subsequent reactions. As a,/3-unsaturated carbonyl compounds, (41) react in a Michael addition with excess tetramic acid to form (67), but it can also react with other acyclic and cyclic 1,3-dicarbonyl compounds. In these reactions the aryl substituents may vary over a wide range. Thus, (67) and (68) can be cyclized with ammonium acetate to afford pharmacologically interesting compounds (70) and (71) (90TH1). The latter are dihydropyridines. Curiously, (69) does not cyclize under these conditions. (See Fig. 32.)... 

Reaction of 201 with 1,3-dicarbonyl compounds, or with aliphatic and cyclic ketones 203 in the presence of dilute sulfuric acid, gave the 3//-l,2,3-triazolo[4,5-6]pyridines 204 (79CPB2861). The mechanism of transformation involves ring fission to 202, followed by reaction with 203 to give 204, a type of Friedlaender synthesis (see Scheme 42). 

Open-chain 1,3-dicarbonyl compounds are observed in the tran -enolic form only in rare cases [41] (for examples, see references [44, 45]). When the trans -enolic form is excluded, the keto/enol equilibrium constant Ki is given by Eq. (4-23). 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone,72 butane-one,73 and butyric acid74 with elemental fluorine resulted in the formation of complex mixtures, with only low yields of a-monofluorinated carbonyl compounds formed. However, more recently, methyl 3-phenylpyruvate.75,7<1 and other pyruvate derivatives, e.g. I,77 are reported to be selectively monofluorinated with dilute elemental fluorine at — 10"C in moderate yield. The success of this reaction is attributed to the fact that the substrate predominantly exists in the enol form and not the keto form.77 Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-1,3-dicarbonyl compounds in good to excellent yield.78,79 Although in these systems the keto form predominates, there are significant concentrations of the enol form which undergoes fluorination (Table 5).78,79 The fluorination of 1,3-dicarbonyl compounds with acetyl hypo-fluorite is only successful when there are significant concentrations of the enol form compounds which have low concentrations of the enol form are successfully fluorinated by preparation of their metal cnolates followed by fluorination with acetyl hypofluorite (see Section 1.1.2.5.).95... 

Acylainino-4-acylimidazoles have been made from 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl reagents (see Section 2.2.1 and Scheme 2.2.5). 4(5)-Acylimidazoles can be derived from 4-acylaininoisoxazoles (see Section 6.1.2 and Scheme 6.1.3). (See also the discussion in Section 2.2.1 on 4-acylimidazole synthesis.) 5-Acyl-l-arylimidazoles can be made from or-oxoketene-SJV-acetals and nitrosoaromatics (see Section 3.2 and Scheme 3.2.5), and 4-acyl-imidazoles by nitration of 1,3-dicarbonyl compounds in their enolic forms, reduction to iV-alkenylformamides and subsequent cyclization (see Section 3.2 and Scheme 3.2.4). Examples have also been isolated from reactions of 2-oximino-l,2,3-tricarbonyls and amines (see Section 4.1 and Scheme 4.1.7), from compounds such as 3-chloro-4,4-dimethoxy-2-butanone and 3,4-disubstituted 3-buten-2-ones (see Section 4.3 and Scheme 4.3.5), and by ultraviolet irradiation of 1-alkenyltetrazoles which bear an acyl group conjugated with the exocyclic double bond (see Section 6.1.2.3). 

Aryl-l,4-dihydropyridines, which are easily convertible to 4-arylpyridines, are usually prepared accorchng to the method of Hantzsch starting from arylaldehyde, 1,3-dicarbonyl compound and ammonia in a one-step reaction A variation of the Hantzsch synthesis uses enaminones instead of -dicarbonyl derivatives (for another variant, see Section ILA.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14). Various dihydropyridines have been synthesized by this rnethod ". Enaminonitriles can be cyclocondensed in the same manner (equation 15). 

The Knoevenagel condensation is the method of choice for the preparation of a,p-unsaturated dicarbonyl compounds and related compounds and only a few alternative methods have been developed. However, with the traditional Knoevenagel condensation there are problems with the reactivity of ketones, with the competitive Michael addition occuring in the reaction of some active methylene compounds. There is also a problem with steieocontrol in the synthesis of Knoevenagel products from unsymmetrical 1,3-dicarbonyl compounds. An alternative method is the addition of Grignard reagents to vinylogous carbamates (see Section 11.2.6). Another possibility is the reaction of a metal ketimate with malonodini-trile to yield ylidenemalonodinitriles (see Section 11.3.1.7). ... 

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