Dicarbonyl compounds, formation

In addition to formation from a ketone, the hydra2ones can be obtained from dicarbonyl compounds by a Japp-Klingemann reaction. This is especially useful for P-ketoesters and P-ketoacids, which undergo either deacylation or decarboxylation. 

It is customary to perform the condensation of 1,4-dicarbonyl compounds with hydrazines in the presence of mineral acid to avoid the formation of A-aminopyrroles. Contrary to early claims that 4,5-dihydropyridazines are formed <07CB4598), these compounds are now regarded as 1,4-dihydro derivatives 81CB564). 

Formation o( oleltns by coupling or cross coupling of ketones, mediated by low valent titanium Also coupling ol enol ethers of 1,3-dicarbonyl compounds. 

The chloride of triflic acid (trifluoromethanesulfonyl chloride) is an effective sulfonylating agent Like triflic anhydride, it usually reacts with alcohols and other nucleophiles with the formation of the corresponding derivatives of tnflic acid [69] However, in some reactions, it acts as a chlorinating reagent [98] The reactions of tnfluoromethanesulfonyl chloride with 1,3-dicarbonyl compounds or some carboxylic esters in the presence of a base result m the formation of chlonnated products in high yields (equation 49)... 

The formation of vinylogous amides from primary amines and -dicarbonyl compounds gives rise to hydrolyzable amine derivatives with greatly decreased nucleophilicity of the nitrogen function. Thus these derivatives have found some use as protecting groups in peptide syntheses 617-619). 

Because of the potential for the formation of two product isomers from the reactions of hydrazines with unsymmetrical dicarbonyl compounds and the resulting difficulty in separations, many efforts have been reported in the literature to enhance the selectivity of... 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

Reaction of substituted hydrazine analogue with protected 3-dicarbonyl compound 67 leads to a ring-forming two-site reaction and formation of the pyrazoline diuretic agent, muzolimine (68). ... 

Scheme 3b). It is instructive at this point to reiterate that the furan nucleus can be used in synthesis as a progenitor for a 1,4-dicarbonyl. Whereas the action of aqueous acid on a furan is known to provide direct access to a 1,4-dicarbonyl compound, exposure of a furan to an alcohol and an acid catalyst should result in the formation of a 1,4-diketal. Indeed, when a solution of intermediate 15 in benzene is treated with excess ethylene glycol, a catalytic amount of / ara-toluenesulfonic acid, and a trace of hydroquinone at reflux, bisethylene ketal 14 is formed in a yield of 71 %. The azeotropic removal of water provides a driving force for the ketalization reaction, and the presence of a trace of hydroquinone suppresses the formation of polymeric material. Through a Finkelstein reaction,14 the action of sodium iodide on primary bromide 14 results in the formation of primary iodide 23, a substance which is then treated, in crude form, with triphenylphosphine to give crystalline phosphonium iodide 24 in a yield of 93 % from 14.

Formation of C —C Bonds by Addition to Chiral Dicarbonyl Compounds Where One Carbonyl Group is Modified or Masked with a Chiral Auxiliary... 

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.)... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

It is assumed that the overall process is initiated by a Michael addition of the 1,3-dicarbonyl compound onto the ci,(5-uri saturated carbonyl derivative. There follows the formation of either an aminal and an iminium intermediate which is followed by the formation of two N.O-acetals. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The reaction, formally speaking a [3 + 2] cycloaddition between the aldehyde and a ketocarbene, resembles the dihydrofuran formation from 57 a or similar a-diazoketones and alkenes (see Sect. 2.3.1). For that reaction type, 2-diazo-l,3-dicarbonyl compounds and ethyl diazopyruvate 56 were found to be suited equally well. This similarity pertains also to the reactivity towards carbonyl functions 1,3-dioxole-4-carboxylates are also obtained by copper chelate catalyzed decomposition of 56 in the presence of aliphatic and aromatic aldehydes as well as enolizable ketones 276). No such products were reported for the catalyzed decomposition of ethyl diazoacetate in the presence of the same ketones 271,272). The reasons for the different reactivity of ethoxycarbonylcarbene and a-ketocarbenes (or the respective metal carbenes) have only been speculated upon so far 276). 

The reaction of dicarbonyl compounds, such as glyoxal or phenylglyoxal, with a guanidinyl group, such as that of an arginine residue, proceeds to yield a more stable linkage due to the formation of a cyclic derivative (Reaction 46). 

---