Ketones formylation

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

Acetylenedimagnesium bromide, 66, 84, 137 Acyl-alkyl diradical disproportionations, 299 Acyl-alkyl diradical recombination, 296 Alkaline hydrogen peroxide, 10, 12, 20 Alkylation of formyl ketones, 93 Alkylation via enolate anions, 86 17a-Alkynyl steroids from 17-ketones, 67 2a-Al]yl-17jS-hydroxy-5a-androstan-3 -one, 9 5 Allylic acetoxylation, 242 Allylmagnesium bromide, 64 17 -Aminoandrost-5-en-3 -ol, 145 17 a-Aminomethy 1-5 a-androstane-3, 1718-diol, 387... 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

A diazo group can be introduced adjacent to a single carbonyl group indirectly by first converting the ketone to an a-formyl ketone (10-118), and then treating it with tosyl azide. As in the similar cases of 12-7 and 12-8, the formyl group is cleaved... 

Tetramethyl-1,3-diphenyl-2,4,6,8-tetraoxaadamantane (163, R = CH3) is made either by dimerization of an a-formyl ketone, such as a-formyl-isobutyrophenone, (164, R = CH3) with sulfuric acid186 or by dimerization of the aldehyde (165) with borontrifluoride etherate.187 The structure of the product was determined by PMR.186... 

The reaction was carried out with /3-keto esters, /3-diketones, malonate, a-formyl ketones, a-cyano and a-nitro esters, cyanoacetamide, and phen-ylsulfonylacetate. (PPh3)2PdCl2 was used with sodium phenoxide. Also, Pd(OAc)2 and PPh3 are good catalysts. When bidentate ligand was used, the 1 1 rather than 1 2 addition reaction took place (56). For example, bis(diphenylphosphino) 1,2-ethane (39) produced a mixture of the following 1,4- (59) and 1,2- (60) addition products ... 

The end test is performed with about 0.5 ml. of solution, which is neutralized with dilute hydrochloric acid and treated with 3-5 drops of 10% ethanolic ferric chloride. A reddish brown color denotes the presence of unhydrolyzed formyl ketone. 

Catalytic hydrogenation of the formyl derivative (36-4) proceeds as usual from the more open a face of the molecule to afford the axial 2 3 methyl derivative (37-1). Treatment with a strong base leads to epimerization to the more stable equatorial 2a methyl isomer. There is thus obtained the androgen, dromostanolone (37-2) [35]. The compound is used clinically as its 17-propionate ester. Direct reaction of the formyl ketone (36-4) with hydrazine leads to the formation of a fused pyrrazole ring [36] this product is the widely used androgenic and anabohc drug, stanazole (37-3). 

The classical method for preparing isoxazole involves the condensation of 1,3-dicarbonyl compounds with hydroxylamine, a reagent that contains the preformed N—O bond. The regiochemistry of the reactions can usually be rationalized by assuming that the first step involves imine bond formation at the more reactive carbonyl group. Thus, reaction of formyl ketone (44-1) with hydroxylamine gives... 

No benzofurans are obtained from substituted p-benzoquinones.389 The enamines of a-formyl ketones (AcOH, room temperature) with p-benzoquinone give 3-acyl-5-hydroxybenzofurans.390... 

Oxalic esters (for electronic reasons) and formic esters (because of their low steric hindrance) are reactive esters that can acylate ketone enolates formed with NaOR in equilibrium reactions. Formic esters acylate ketones to provide formyl ketones (for example, see Figure 13.61). It should be noted that under the reaction conditions the conjugate base of the active-methylene formyl ketone is formed. The neutral formyl ketone is regenerated upon acidic workup. 

Fig. 13.61. Acylation of a ketone enolate with a formic ester to generate a formyl ketone. The ketone enolate intermediate (not shown) is formed in an equilibrium reaction.

In general, the dehydrogenation of steroidal ketones is carried out in dry benzene or dioxane at reflux with 1.1 to 2 equiv. of the quinone. ) Similar conditions have also been used to prepare flavones, chromones" and spirodienones" in good yields (Table 6). Consistent with the apparent requirement that enolization is a prerequisite to dehyi genation with quinones,reactants such as a-formyl ketones, e.g. (37) and (38), that have a high enol content, dehydrogenate raindly at room temperature (Table6)."5- 6... 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

In the first step, formyl ketone 14a reacts via its enol form 14b with tosyl azide in a 1,3-dipolar cycloaddition yielding intermediate 15. Its triazoline ring resolves into the a-diazo ketone 4 and 7V-formyl tosyl amide. 

This reaction sequence establishes the fifth cyclobutane ring of the ladderane core and is analogous to the reaction from 3 to 5. First P-formyl ketone 26 is formed, which undergoes deformylative diazo transfer in the second step yielding a-diazo ketone 27. The desired pentacyclic carboxylic acid ester 11 is built up via a light-induced IFb rearrangement. 

Procedures have been developed for the phenylselenenylation and oxidative elimination of P-formyl ketones and aldehydes to form the corresponding a,p-unsaturated aldehydes (Schemes 29 and 30). Other P-dicarbonyl compounds have also been oxidized to the corresponding a,P-unsaturated compounds by phenylselenenylation and oxidative elimination including 3-(l-oxotrienyl)pyrrolidinones,... 

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