1.3- Diketones Mannich reaction

In a modified approach, the carbolinyl acetate 393 underwent a Mannich reaction with formaldehyde and acetone to give the keto ester 396 which, with base, cyclized to the diketone 397. This diketone (397) has recently been used to prepare a number of interesting pentacyclic compounds. 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

The unsymmetrical diketones 47 were needed for photochemical experiments. The better 1,5-diCO disconnection 47a is at the branchpoint. The enone 49 can be made by the Mannich reaction (chapter 20). 

The 1,3 relationship between C-N and C-O suggests a Mannich reaction to add the imidazole ling (Chapter 27), and that disconnection reveals an indole with an unsymmetrical right-hand side, having an extra ketone group. Fischer disconnection will reveal a diketone as partner for phenylhy-drazine. We shall leave aside for the moment when to add the methyl group to the indole nitrogen. 

Ohashi. M., Takahashi. T.. Inoue, S and Sato. K., The Mannich reaction of alicyclic a-diketones. A novel synthesis of 2-hydroxy-.3-methyl-2-cyclohexcn-l-one, Bull. Chem. StK-. Jpn.. 48, 1892, 1975. 

Metal /3-diketonates, particularly acetylacetonates, will undergo electrophilic substitution at the central methine carbon atom in a similar way to aromatic compounds. Known reactions of this sort include bromination, nitration, acylation, and the Mannich reaction. 

The mixed diketone required is a 1,5-dicarbonyl compound and can be specifically mai conjugate addition. We can use the Mannich reaction for the enone as in Problem 11 and we you to choose the specific enolate. 

Mannich reaction of the various diketones 78 with acyl amines generated in situ from the a-amidosulfones 79 (Scheme 8.26) [36]. 

The reaction of enamines with iminium ions provides access to substituted j3 amino aldehydes and ketones (Scheme 61). In a similar manner the Mannich reaction gives access to oc,) -unsaturated aldehydes or -amino ketones (Scheme 62). Enamines undergo the Vilsmeier reaction to give a-formyl ketones Solvolysis of the Vilsmeier salt with aqueous or alcoholic sodium hydrogen sulphide produces an enamino thioaldehyde. The use of A-dichloromethylene-A,A -dimethylammonium chloride gives tertiary /5-ketoamides (Scheme 63). Iminoalkylation of enamines with nitrilium salts provides access to enamino ketones and j3-diketones (Scheme 64). 

Aldol and Mannich reactions. Formation of cyclopentenones is readily achieved by a twofold Mukaiyama aldol reaction between l,3-bis(trimethylsiloxy)-1,3-dienes and 1,2-diketones. ... 

Rueping et al. reported a similar study on the Mannich reaction of aldimines 138 with cyclic 1,3-diketones 142. By the use of the calcium phosphate catalyst 140b, they obtained the corresponding products 143 in moderate yields and enantioselectivities (Scheme 3.44). 

A simple gold(I) NHC, l,3-bis(diisopropylphenyl)itnidazol-2-ylidene]AuNTf2, catalyses Mannich reactions of A-protected imines with 1,3-dicarbonyls under mild conditions (DCM/ambient). Using A-sulfonylimines, R" -CH=N-PG, the reaction 0 works in good yields for both -ketoesters and -diketones, affording protected / -amino-dicarbonyls, Ri-CO-CR C-CHR -NH-PGl-CO-R, in up to 62% de. 

Some methods for the synthesis of thiophene-substituted 1,4-diketones begin with the transformation of acetylthiophene. 2-Acetylthiophene 61 is reacted in a Mannich reaction with formaldehyde and dimethylamine to yield the corresponding Maimich base 62 in 70% yield. The Mannich base 62 is then subjected to a Stetter reaction [109] which results in l,4-di-(2 -thienyl)-l,4-butanedione 63 in 70% yield via the cyanhydrine of 2-thiophenecarbaldehyde [110]. Reaction of Mannich base 62 with the isomeric 3-thiophenecarbaldehyde under the same conditions results in l-(2 -thienyl)-4-(3 -thienyl)-l,4-butanedione 64 in lower (35%) yield [Eq. (27)] [110]. 

Following the cinchonine-catalyzed results, Schaus et al. [46] reported the use of cyclic 1,3-dicarbonyl donors to access adjacent quaternary-tertiary stereogenic centers. Under similar reaction conditions cyclic (l-ketoester and 1,3-diketones afforded the corresponding Mannich adducts in excellent yields and stereoselectivities (Scheme 7). The methodology was also applicable to aryl propenyl imines (32) - a class of novel aliphatic imines. 

As explained in chapter 21, vinyl ketones such as 57 are unstable and we often prefer to use the Mannich base instead. This example works spectacularly well. Heating the Mannich base 58 with cyclohexanone gives the 1,5-diketone 55 that combines with hydroxylamine to give the pyridine 54 both reactions giving excellent yield.10... 

The example below shows how these 1,5-diketones may be quickly made by the Mannich (Chapter 27) and Michael (Chapter 29) reactions. Our pyridine has a phenyl substituent and a fused saturated ring. First we must disconnect to the 1,5-diketone. 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

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