2-Butanone arylation

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

REDUCTIVE ARYLATION OF ELECTRON-DEFICIENT OLEFINS 4- (4-CHLQROPHEHYL1 BirrAN-2-OHE (2-Butanone, 4-(4-ch1oropheny11-1... 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

Intramolecular cyclopropanation of 4-aryl-1 -diazo-2-butanones 240 allows construction of the bicyclo[5.3.0]decane framework 12). In a reaction sequence analogous to that described above for the intermolecular ketocarbenoid reaction, bicyclo-[5.3.0]deca-l,3,5-trien-8-ones 241 are formed. They rearrange to the conjugated isomers 242 at the high temperatures needed if the reaction is catalyzed by copper 2311 or CuCl 232), but can be isolated in excellent yield from the Rh2(OAc)4-promoted reaction which occurs at lower temperature 233... 

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

Migration of a benzyl group appears to occur in preference to hydrogen, alkyl, or aryl migration, as with 1,3-diphenyl-2-methyl-1,2- Toxypropane (Eq. 461), which yields 3,4-diphenyl-2-butanone -elusively.1024-102 Of some interest, incidentally, is the report that... 

Asymmetric reduction of ketones. Ipc BCl is somewhat superior to B-3-pin-anyl-9-borabicyclo[3.3.1]nonane (12, 397) for enantioselective reduction of alkyl aryl ketones at normal pressures to (S)-alcohols. In general, optical yields are 78-98%. It is also useful for asymmetric reduction of ketones in which one alkyl group is tertiary. Thus 3,3-dimethyl-2-butanone is reduced in 95% ee at 25°.1... 

The impact of a carbonyl group on the chemical shift of a CF3 group somewhat emulates the effect of other electronegative substituents. As indicated by the examples of aldehyde and ketones in Scheme 5.28, when the carbonyl carbon is directly attached to the CF3 group, it causes shielding of the CF3 fluorines. Note that aryl trifluoromethyl ketones are considerably less shielded than are alkyl trifluoromethyl ketones. The fluorine signal of trifluoromethyl ketones of course always appears as a sharp singlet. The spectrum of l,l,l-trifluoromethyl-2-butanone, as... 

Isomeric enolate ions can be formed from unsymmetric dialkyl ketones, and the distribution of the two possible arylation products is mainly determined by the equilibrium concentration of the various possible enolate ions. However, the selectivity also depends on the structure of the attacking radical. Reactions with the enolate ions from 2-butanone afford arylation preferentially at the more substituted a carbon to render about twice as much 3-phenyl-2-butanone as 1-phenyl-2-butanone [68,69] however, in the reaction with the anion derived from /-propyl methyl ketone, the 1-phenyl derivative is predominantly formed [68]. When there is a substituent ortho- to the leaving group, the attack at the primary a carbon is enhanced [69,70]. 

Butanone, conversion to a-ethyl-a-methylsuccinic acid, 44, 59 Butenolides from aryl aldehydes and y-keto adds, 43, 5 7-(-Butoxynorbornadifne, 44,12... 

It is reported that alkylation of quinazolin-4(3//)-ones 2 almost invariably leads to 3-alkyl derivatives (cf. p 164), and that only occasionally, for reasons that are not clear, alkylation on oxygen occurs with the formation of quinazolin-4-yl ethers. However, with the Claisen method" using alkyl or aryl halides, or dialkyl sulfates and potassium carbonate in acetone or butanone, 0-alkyl derivatives 3 are obtained in good yields. " Selective... 

Similar experiments with cis- and /rarti-2,3-epoxybutane and the corresponding bromohydrins all gave a single product, 2-butanone. Thus the unusual factors in the aryl-substituted materials failed to appear in the simpler aliphatic materials. Here the product can be rationalized simply by assuming that hydride migration occurs more readily than methyl migration. Of course, this may be true for both concerted and carbenium ion processes, and the existence of a dual mechanism may be hidden in this example. The cyclohexene oxide results cited above suggest that this is plausible, and perhaps probable. 

This ligand class is quite useful for the synthesis of unsymmetrical alkyl diaryl amines.39 Typically, a primary aliphatic amine is first arylated using the Pd/BINAP catalyst system. The second arylation is then carried out with L6, Xantphos, or PPF-OMe (with CS2CO3 if a base sensitive aryl bromide). Ligand choice for the second arylation depends upon the electronic nature of the N-alkylaniline and Ar2Br as outlined in the table. They were unable to couple 2-bromobenzaldehyde, 4-(4 -bromophenyl)-2-butanone, or 4 -bromoacetophenone with N-alkylanilines (alkyl > Me). 

---