Ketone Wittig reaction

The CIO methyl was installed using a sequence of steps, which included an asymmetric hydroboration reaction. This approach was developed by Tatsuda for the synthesis of herbimycin and later followed by Panek for macbecin. Other unsuccessful approaches to this difficult region of the molecule are outlined below. To ready the material for this event, the ester 6 was reduced to the aldehyde and trimethylaluminum was added to generate alcohol 24 (Scheme 8). Oxidation to the ketone, Wittig reaction, and TBS removal with HF provided allyl alcohol 25 in... 

As already mentioned, ketone Wittig reactions are complicated by low carbonyl reactivity and by enolization in the case of nonstabilized ylides. The level of difficulty increases with increasing steric hindrance in the reactants, but experimental solutions are available even for the most extreme cases (159, 168-171). A discussion of the key variables is included below, partly to dispel the notion that the Wittig approach is not practical for hindered, enolizable ketones and partly to guide future stereochemical studies of the ketone reactions. 

Enolization in ketone Wittig reactions can usually be attributed to the use of lithium-containing ylide solutions. Thus, 3-methyl-2-butanone reacts rapidly with Ph3P=CHCH3/LiBr to form a precipitate, and prolonged heating produces only traces of the alkene (Table 20, entry 2). When the same... 

If ET intermediates play any role in representative aldehyde or ketone Wittig reactions, they are too short-lived for detection by the fastest available radical or radical anion clocks. This is conceivable if the geometry of the radical ion pair resembles that of an oxaphosphetane with partially developed bonds (223c). Such a scenario fits within the broad definition of a four-center mechanism and allows little (if any) distinction between the geometry of stereochemistry-determining TS that invoke ET versus those that do not. More precise distinctions may have theoretical significance, but they will not influence the stereochemical issues that are of concern in this review. 

Synthesis We must be able to do a Wittig reaction on the aldehyde but not on the ketone, so we must protect the ketone therefore add the aldehyde as an ester (there are many other solutions). 

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

The Wittig reaction uses phosphorus ylides (called Wittig reagents) to convert aldehydes and ketones to alkenes... 

The most attractive feature of the Wittig reaction is its regiospecificity The location of the double bond is never m doubt The double bond connects the carbon of the ongi nal C=0 group of the aldehyde or ketone and the negatively charged carbon of the yhde... 

The Wittig reaction (Sections 17 12-17 13) Reaction of a phosphorus ylide with aldehydes and ketones leads to the formation of an alkene A versa tile method for the regiospecific prepa ration of alkenes... 

Wittig reaction (Section 17 12) Method for the synthesis of alkenes by the reaction of an aldehyde or a ketone with a phosphorus yhde... 

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

Much better known are the fluonnatedphosphoranes, which have been widely used m the Wittig reaction for the preparation of fluoroolefms Difluoromethylena tion reactions have been effected by using a variety of conditions Treatment of dibromodifluoromethane with two equivalents of tns(dimethylammo)phosphine m carefully dried tnglyme yields a solution of bromodifluoromethylphosphonium broomide, which very effectively converts ketones to difluoromethylene derivatives A more sensitive reagent is prepared by the addihon of two equivalents of the phosphine to the reaction mixture of fluorohalomethane and a carbonyl compound [39, 40] (equation 40) (Table 14)... 

Table 10. Wittig Reactions with Trifluoromethyl Ketones...

The Wittig reaction, for which George Wittig received the 1979 Nobel Prize in Chemistry, is an important synthetic procedure for converting aldehydes and ketones into alkenes. The active reagent is a phosphorous ylide which undergoes nucleophilic addition to the carbonyl carbon, e.g., for addition of triphenylphosphinemethylidene to acetone. 

The Peterson olefination can be viewed as a silicon variant of the Wittig reaction, the well-known method for the formation of carbon-carbon double bonds. A ketone or aldehyde 1 can react with an a-silyl organometallic compound 2—e.g. with M = Li or Mg—to yield an alkene 3. 

The reaction of an alkylidene phosphorane 1 (i.e. a phosphorus ylide) with an aldehyde or ketone 2 to yield an alkene 3 (i.e. an olefin) and a phosphine oxide 4, is called the Wittig reaction or Wittig olefination reaction. ... 

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

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