1.6- Dicarbonyl type compounds synthesis

This type of synthesis has been used extensively in the preparation of hydroxamic acids resembling aspergillic acid. a-Aminohj droxamic acids react with a-dicarbonyl compounds to yield pyrazine hydroxamic acids (18). Glyoxal and diacetyl react readily, but poor... 

Approaches that represent a type (ii) synthesis of 277-pyran-2-ones include the self-condensation of 1,3-dicarbonyl compounds, the reaction of cyclopropanones with pyridinium enolbetaines and the reaction of activated methylene groups with acetylenic esters <1984CHEC, 1996CHEC-II>. 4-Perfluoroalkyl-6-aryl-pyran-2-ones are formed by the reaction of the phosphonium salts 631 with 2-perfluoroalkynoates (Equation 254) <1999JFC(95)135, 1998JFC(91)99>. Dimedone reacts with dimethyl acetylenedicarboxylate to afford the pyran-2-one 632 in excellent yield (Equation 255) <2003PS2627>. 

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]. 

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... 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

Several significant pyrrole syntheses involve the formal tricomponent cyclization of type III ace (equation 126). The Hantzsch pyrrole synthesis involves a dicarbonyl compound, an a -halo ketone and ammonia or an amine. The mechanistic pattern is similar to that involved in the Knorr synthesis (Section 3.06.3.4.1). In addition to a-halo ketones and a-haloal-dehydes, compounds such as 1,2-dichloroethyl acetate, 1,2-dibromoethyl acetate and 1,2-dichloroethyl ethyl ether can serve as a -haloaldehyde equivalents (equation 127) (70CJC1689, 70JCS(C)285>. It is believed that the initial step in these reactions is the formation of a stabilized enamine from the amine and the /3 -dicarbonyl compound. A structural ambiguity... 

The intermediate 1,5-dicarbonyl compounds of type 24 (Scheme 1) can be constructed not only on the basis of meta-alkoxy-substituted benzyl ketones (C4 + Ci synthesis, Section II,C), but also under definite conditions starting from aryl ketones (C2 + C3 synthesis). Thus, in a molecule of acylveratrole derivatives of type 79, the excess of 7r-electron density due to the presence of two ortho-methoxy groups allows such compounds to be involved in electrophilic substitutions with benzoin (73URP2 74KGS1575). 

The use of aryl-A3-iodanes for C-heteroatom bond formation at the a-carbon atoms of ketones and / -dicarbonyl compounds, and related transformations of silyl enol ethers and silyl ketene acetals, has been exhaustively summarized in recent reviews (Scheme 27) [5,8]. Reactions of this type are especially useful for the introduction of oxygen ligands (e. g., L2 = OH, OR, OCOR, 0S02R, OPO(OR)2), and have been extensively utilized for the synthesis of a-sulfonyl-oxy ketones and a-hydroxy dimethyl ketals. 

Allylic C-H insertions have been used in key steps of the enantioselective synthesis of the pharmaceuticals (+)-ceitedil (26) [21] and (+)-indatraline (27) [22] (Scheme 11). The allylic C-H insertion reaction is an exciting alternative to the Claisen rearrangement as a rapid method for the synthesis of y,c>-unsaturated ester [23 ]. Similarly, the allylic C-H insertion with vinyl silyl ethers generates protected 1,5-dicarbonyl compounds, a complimentary reaction to the Michael addition [24]. Both types of C-H insertion can be achieved with high diastereoselectiv-ity and enantioselectivity [23, 24]. 

The time-proven approaches for the synthesis of pyrroles and more elaborate systems have been thoroughly reviewed in the literature. Our focus is drawn to the Knorr synthesis of pyrroles as the [3 + 2] component condensation-type approach which serves as the foundation for the methodology discussed in this chapter.3 The classic reaction entails the reaction of an a-aminoketone with a P-dicarbonyl compound (Eq. 1). The likely intermediate is a P-aminoenone, which undergoes an acid-catalyzed internal cyclization reaction leading to the pyrrole ring. A variation of this process involves the condensation of a-aminoesters and... 

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). 

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