Ketones alkoxy, synthesis

The precise nature of the carbonyl groups determines what happens next. If R is a leaving group (OR, Cl, etc.), the tetrahedral intermediate collapses to form a ketone and the product is a 1,3-di-ketone. The synthesis of dimedone (later in this chapter) is an example of this process where an alkoxy group is the leaving group. Alternatively, if R is an alkyl or aryl group, loss of R is not an option and the cyclization is an intramolecular aldol reaction, Dehydration produces an a,P-unsaturated ketone, which is a stable final product. 

Paterson I, Tillyer RD. High rr-face selectivity in anti aldol reactions of E-enol borinates from chiral alkoxy-methyl ketones stereocontrolled synthesis of a C24—C32 polyol subunit of rapamycin. J. Org. Chem. 1993 58 4182 184. 

The preference for the /3-silyl isomer product complements methods available for hydrostannation of alkynes, for which the a-stannyl regioisomer is formed preferentially.70 7011 70c In addition, the /3-silyl products serve as the platform for a tertiary alcohol synthesis (Scheme 15). Upon treatment of vinylsilanes such as B with tetrabutylam-monium fluoride (TBAF) in DMF at 0 °C, a 1,2 carbon-to-silicon migration occurs, affording the tertiary heterosilane E. Oxidation of the C-Si bond then provides the tertiary alcohol. Good 1,2-diastereocontrol has been demonstrated for y-alkoxy substrates, as in the example shown. The studies suggest that the oxidation of the sterically demanding silane intermediate is facilitated by the intramolecular formation of a silyl hemiketal or silyllactone for ketone or ester substrates, respectively.71... 

Two different methods have also been described for the synthesis of 4-alkoxy-5(2//)-oxazolones 50. In the first case, 4-(phenylthio)-5(277)-oxazolones 48 are oxidized to the 4-phenylsulfinyl derivatives that react with the alcohol present in the reaction medium to afford the corresponding 4-alkoxy derivatives. Alternatively, 4-alkoxy-5(2//)-oxazolones 50 have been obtained by condensation of iminooxalates and ketones in acidic medium. (Scheme 7.12 Table 7.7, Fig. 7.8 Table 7.8, Fig. 7.9). 

TABLE 7.8. SYNTHESIS OE 4-ALKOXY-5(2H)-OXAZOLONES FROM IMINOOXALATES AND KETONES OR ALDEHYDES ... 

A number of other useful modifications of the intramolecular Williamson synthesis have been developed. Reaction of a,a-dialkyl-/3-tosyloxy aldehydes and ketones with potassium cyanide or with sodium alkoxide gives the corresponding 2-cyano- or 2-alkoxy-oxetanes... 

Another example of the superiority of the alkoxy group as a directing group was reported by Johnson in his synthesis of enantiomericaUy pure cyclopropyl ketones after auxiliary cleavage (equation 56). In that case, the product resulting from a sulfoximine directed cyclopropanation was never observed. 

The (n,n excited state of a ketone has electrophilic character, similar to that associated with alkoxy radicals, and it is not surprising that these excited states readily attack carbon-carbon multiple bonds. The overall reaction that normally ensues is a cycloaddition, giving a four-membered oxygen heterocycle—an oxetane from an alkene addend (4.62), or an oxete from an alkyne addend (4.63). Some oxetanes are of interest in their own right, but many are useful intermediates in the synthesis of other compounds. 

It is known that 3-aminobenzo[6]furan can be prepared from o-cyanophenols and a-halogenocarbonyl compounds with subsequent Thorpe cyclization (73JPR779). The extension of this synthesis to heteroatom substituted benzo[6]furans is straightforward (76JPR313). The reaction of potassium salts of 3-cyano-2-pyridones (e.g. 27) with a-halogenocarbonyl compounds (esters, ketones) yields 2-alkoxy-3-cyanopyridines which can be cyclized in the presence of sodium ethoxide to give 3-aminofuro[2,3-6]pyridines (Scheme 6). 

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 final aldol reaction used in our synthesis of spongistatin 1 was one of the more remarkable reactions of this type our group has witnessed over the years. The aldol union of ketone 64 with ( )-4-chloro-2,4-pentadienal 65 required the creation of the (475) stereochemistry in the resultant alcohol 66. Formally, this would require 1,5-syn induction from the ketone 64, which is opposite to that observed previously for boron aldol reactions with simple [i-alkoxy methyl ketones. However, ketone 64 is densely packed with stereocentres, and predicting the influence of these remote centres on the reaction outcome was not possible with any degree of certainty. It was hoped that should 64 display undesirable 1,5-anti bias, this may be overturned by appropriate choice of Ipc ligands on boron. 

Organotin-zinc derivatives can be used as reagents in organic synthesis. Thus, the stannyl zincate complex Me3Sn(Et)2ZnLi reacts with alkoxy-unsaturated ketones to form five-membered ring heterocycles434. 

Similar to the synthesis of tetrahydrofuranols by the irradiation of [i-alkoxy ketones, Henning s group was the first to show that the photolysis of N-( 3-benzoylethyl)-N-... 

Some alkoxy-substituted dioxetanes yield a-peroxy ketones and esters via zwitterionic intermediates which are formed by heterolytic C-O bond cleavage as proven by trapping with acetaldehyde [135]. This behavior which has been fully explored by Jefford [135b], has been exploited for the total synthesis of the antimalarial (+)artemisinin [136a-c] and related analogs [136d-f]. One recent example is reported in Sch. 83 [136f ]. 

The most commonly used method for the preparation of fused thiazoles involves the reaction of a-mercapto N-heterocyclic compounds of type (138) with an a-halocarbonyl compound or ester to give S-alkylated intermediates (139) which can be dehydrated to (140). When R2 is alkoxy, thiazolones (141) are formed (Hantzsch synthesis). Strong dehydrating agents are necessary to cyclize aldehydes and ketones (139) to fused thiazoles. The method has been used to prepare (dihydro) imidazo[2,l-6]thiazoIes and thiazolo[3,2- ]-s-triazoles (80JHC1321, 78JHC401, 82IJC(B)243). 

Acylamino ketones also provide a convenient synthesis of thiazoles on treatment with phosphorus pentasulfide (Gabriels method). Substituents are usually restricted to alkyl, aryl, and alkoxy derivatives. Thus, the -acylamino ketone 234 with P4S10 gave the thiazole 240. Lawessons reagent (LR) can be effectively used as the source of sulfur in these cyclizations (e.g., Scheme 116) <1996JME957, 2006TL2361, CHEC-III(4.06.9.1.3)682>. 

In the second classical method (Bischler synthesis), an aromatic primary or secondary (arylalkyl, but not diaryl) amine is condensed with an obromo (or better, hydroxy) ketone to give a 2,3-dialkylindole. This in turn is alkylated directly to the 1,2,3,3-tetraalkylindoleninium salt. Use of acetoin gives 2,3-dimethylindole, which is easily isolated and purified. The Bischler synthesis from a substitued aniline, and especially from anilines bearing one or more alkoxy groups, is much preferred in practice for indoles substitued in the 4-7-positions, since the substituted aiylhy-drazines needed for the Fischer synthesis are costly, unstable, or unavailable. 

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