Competitive enolization

Different competitive processes are dependent on the diazo compound, on the unsaturated system, and on the solvent. With 1,1,1-trifluorobutan-2-one and diazomethane, the corresponding oxirane is formed almost exclusively. While methyl trifluoropyruvatc reacts with diazomethane to provide a mixture of the oxiranes, reaction of the pyruvate with ethyl diazoacetate provides a stable [3-1-2] cycloadduct.Chiral fluoroalkyl-substituted /i-oxo sulfoxide (e.g., 1) readily react with diazomethane to provide the corresponding chiral epoxides. Use of methanol as solvent favors oxirane formation over the competitive enol ether formation. 

The addition of organometallic agents to aldimines and ketimines provides a useful route to substituted amines, although this reaction is sensitive to imine/organometallic substitution. Along with addition, competitive enolization, reduction and bimolecular reduction (coupling) reactions are also possible. 

Attempts to extend the organometallic addition reaction to A -trialkylsilylimines derived from enoliz-able ketones have been frustrated by difficulties encountered in the preparation of these silylimines (due to competitive enolization), in addition to the existence of a tautomeric equilibrium between desired silylimines and the corresponding enamines. As a result, addition products (formed in low yield) are accompanied by significant amounts of starting materials (presumably generated via enamine hydrolysis).However, silylimines derived from enolizable aldehydes reportedly can be generated and trapped in situ with ester enolates to form 3-lactams (18-60% yield). 

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

A very convenient hydroxymethylation process has been developed based on the Sml2-mediated Bar-bier-type reaction. Treatment of aldehydes or ketones with benzyl chloromethyl ether in the presence of Smh provides the alkoxymethylated products in good to excellent yields. Subsequent reductive cleavage of the benzyl ether provides hydroxymethylated products. Even ketones with a high propensity for enolization can be alkylated by this process in reasonable yields. The method was utilized by White and Somers as a key step in the synthesis of ( )-deoxystemodinone (equation 27). This particular ketone substrate resisted attack by many other nucleophilic reagents (such as methyllithium) owing to competitive enolate formation. 

Analogously, it has been observed that treatment of dimethyl homophthalate with dimethyl 1-lithiomethylphosphonate provides only very low yields of the desired P-ketophosphonate. Competitive enolization of the acidic benzylic methylene appears to be the dominant reaction under these conditions. The unwanted enolization is partially suppressed when the monomethyl ester is used as substrate. ... 

Methyl substituent on the benzoyl group in the ortho position leads to competitive enolization in eompounds like 2,4,6-trimethylbenzoylphosphonic acid. This, however, is not observed in compounds like 2,4,6-2-trimethyl-... 

Interestingly the yields are much lower under the same conditions with n-BuLi, due to competitive enolization. Sec-BuLi-Cel. EtLi-Cel, MeLi-Cel and PhLi-Cel also react smoothly at - 65°C to give high yields of addition products. 

The 6-hydroxy compounds 3 (R=saturated or unsaturatcd C.. or chains) became of interest when they were identified as the major componi ts of tal exudates of immature lace bugs of the genus Corythucha (12) We recently completed the first synthesis of this class of compounds QQ) this work will be discussed in more detail elsewhere in this volume, but one of its key features included converting die easily available 2 to its dihydrobenzisoxazolone derivative 8. This procedure tied up two of the three oxygens of 2, circumventing competitive enolizations and insuring regioselectivity in the hydroxylation to 9, which was in turn converted, via 10, to 3. (Scheme 1). 

Aldol Additions to Ketones. Traditionally, cerium enolates or the Reformatsky-type reaction have been employed to achieve high-yielding aldol additions to enolizable ketones. In this regard, methyl trichlorosilyl ketene acetal provides a reliable alternative for the synthesis of tertiary -hydroxy esters. In the absence of a Lewis base promoter, the aldol additions of 1 to ketones are too slow to be synthetically useful. On the contrary, with pyridine A-oxide as catalyst, methyl trichlorosilyl ketene acetal reacts smoothly with nearly all classes of ketones (7) (Scheme 1). Good yields of the tertiary alcohol products (8) are obtained (eq 4), table 2 from aromatic (entries 1-2 and 4—6), hetereoaromatic (entry 3), olefinic (entries 7-8), acetylenic (entries 9-10), and aliphatic (entries 11-14) ketones. The only poorly performing substrate is 2-tetralone (7o), which affords a 45% yield of the addition product and returns 45% of unreacted starting material, most likely from competitive enolization. 

Another serious problem that can be encountered when reacting an a-sulfonyl anion with an aldehyde is competitive enolization of the carbonyl derivative, which can sometimes lead to large amounts of recovered starting material. It has been shown that judicious choice of the appropriate solvent may be a key factor for success [51]. As indicated in Table 3.1, using DME instead of THF suppresses the undesirable enolization almost completely. Whilst DME appears to be especially effective in the case of linear, aliphatic aldehydes (entries 1 and 2), THF seems to be preferred when a-substituted aldehydes are employed as coupling partners (entry 3). 

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