The Wittig reaction

The 17-ethylidene steroids are extremely useful intermediates for the preparation of 17-oxygenated, 20-oxygenated, or 17,20-bis-oxygenated pregnanes (Chart I) and their further conversion will be discussed in later sections 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for 

The solvated phosphorane adds to the polarized carbonyl with the incipient C-21 methyl group pointing away from the bulk of the steroid nucleus. The newly formed carbon-carbon bond must then rotate in order for the tri-phenylphosphine group and oxygen atom to have the proper orientation for the elimination of triphenylphosphine oxide. This places the C-21 methyl in the CIS configuration. 

3-Methoxy-cis-19-norpregna-l,3,5(10),17(20)-tetraene A solution of 31 g (109 mmolesi of estrone methyl ether in 600 ml of benzene is added rapidly to a solution of 469 mmoles of ethylidenetriphenylphosphorane in 1.2 liters of DMSO. After heating under nitrogen at 60° overnight, the reaction is cooled, poured into ice water, and extracted with three portions of hexane, backwashed with three portions of water and the hexane removed. The crude product, dissolved in petroleum ether (bp, 30-60°), is filtered through 225 g of alumina (activity I). The residue from the eluate consists of 95 % cis- and 5 % tran5-isomers, as determined by vpc analysis. After recrystallization from ether-methanol, 26.3 g (82%) of cw-isomer is obtained mp 76.5-77.5° [a]o 60°. 

The reaction of 17-keto steroids with hydrogen cyanide (or acetone cyanohydrin) to form a mixture of the 17-cyano-17-hydroxy compounds, followed by dehydration and reaction with methyl Grignard reagent, is one of the earliest methods for the conversion of androstanes to pregnanes. 

The phosphorus-stabilized carbanion is an ylide (pronounced ill -id )—a molecule that bears no overall charge but has a negatively charged carbon atom bonded to a positively charged heteroatom. Phosphorus ylides are prepared from triphenylphosphine and alkyl halides in a two-step process. The first step is nucleophilic attack by triphenylphosphine on an unhindered (usually primary) alkyl halide. The product is an alkyltriphenylphosphonium salt. The phosphonium salt is treated with a strong base (usually butyllithium) to abstract a proton from the carbon atom bonded to phosphorus. 

The phosphorus ylide has two resonance forms one with a double bond between carbon and phosphorus, and another with charges on carbon and phosphorus. The double-bonded resonance form requires ten electrons in the valence shell of phosphorus, using a d orbital. The pi bond between carbon and phosphorus is weak, and the charged structure is the major contributor. The carbon atom actually bears a partial negative charge, balanced by a corresponding positive charge on phosphorus. 

Trimethylphosphine is much less expensive than triphenylphosphine. Why is trimethylphos-phine unsuitable for making most phosphorus ylides  

The four-membered ring quickly collapses to give the alkene and triphenylphos-phine oxide. Triphenylphosphine oxide is exceptionally stable, and the conversion of triphenylphosphine to triphenylphosphine oxide provides the driving force for the Wit-tig reaction. 

The Wittig Reaction Step 1 The ylide attacks the carbonyl to form a betaine. 

Wittig reactions, and reactions related to it, are used for the regiospecific synthesis of alkenes from aldehydes and ketones. Their retrosynthetic analysis begins with disconnecting the double bond as shown and introduces a novel stmctural type called an yiide. 

Although second-row elements such as phosphorus can accommodate more than 8 electrons in their valence shell, the dipolar sttucture is believed to be the major contributing structure for Wittig reagents. 

Ylides are prepared by a two-step procedure. First, an alkyl halide is treated with a phosphine—typically triphenylphosphine—to give a phosphonium salt. The alkyl halide can be methyl, primary, or secondary. 

The phosphonium salt is isolated, then converted to an ylide by an acid-base reaction. The conjugate base of dimethyl sulfoxide is often used. 

An atkyltriphenyl- Conjugate base of phosphonium ion dimethyl sulfoxide 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

Stabilized ylides are those which bear a carbanion-stabilizing substituent on the negatively charged carbon of the ylide. Stabilized ylides such as (carboethoxy-methylidene)triphenylphosphorane (entries 6 and 7) react with aldehydes to give exclusively trans- alkenes. Stabilized ylides react sluggishly or not at all with ketones. 

Benzylidenetriphenylphosphorane (entries 8 and 9) occupies a borderline position between stabilized and nonstabilized ylides. It will react with both aldehydes and ketones. Mixtures of cis and trans-stilhene result from the reaction of benzyl-idenetriphenylphosphorane with benzaldehyde. 

The reaction of nonstabilized ylides with aldehydes can be induced to yield trans 3 kenes with high stereoselectivity by a procedure known as the Schlosser modification of the Wittig reaction. In this procedure, the ylide is generated as a lithium halide complex and allowed to react with an aldehyde at low temperature, presumably forming a mixture of diastereomeric betaine-lithium halide complexes. At the temperatures under which the addition is carried out, fragmentation to an alkene and triphenylphosphine oxide does not occur. This complex is then treated 

SECTION 2.5. THE WITTIG AND RELATED CARBONYL OLEFINATION REACTIONS 

The Wittig reaction converts a ketone to an alkene. A phosphorous ylide (pronounced ill -id ) is used. An ylide is a neutral molecule with a negatively charged carbanion. 

The ketone behaves in its normal fashion, first undergoing nucleophilic addition from the ylide to form a betaine (pronounced bay -tuh-ene ). However, the betaine is unstable and quickly breaks down to a triphcnylphosphine oxide and the alkene. When possible, a mixture of both cis and trans isomers are formed by the Wittig reaction. 

Even mote strange is the ability of the (hcarbon to undergo nucleophilic addition directly. This is sometimes called conjugate addition. 

Of course, we know that aldehydes and ketones undergo nucleophilic addition at the carbonyl, and for many nucleophiles this carbonyl addition is still the major product in tire above reaction. 

What is the major product of the crossed aidol reaction shown below  

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

Wittig reactions may be carried out in a number of different solvents normally tet-rahydrofuran (THF) or dimethyl sulfoxide (DMSO) is used. 

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

Identify the alkene product in each of the following Wittig reactions  

Sample Solution (a) In a Wittig reaction the negatively charged substituent attached to phosphorus is transferred to the aldehyde or ketone, replacing the carbonyl oxygen. The reaction shown has been used to prepare the indicated alkene in 65% yield. 

The Wittig reaction is regiospecific. The double bond forms between the carbonyl carbon atom and the carbon atom bonded to the phosphorus atom of the ylide. However, the reaction is not stereospecific. Thus, if geometric isomers are possible, both isomers form. The Wittig reaction is carried out in polar aprotic solvents such as diethyl ether, tetrahydrofuran, or dimethyl sulfoxide. The Wittig reaction can be carried out in the presence of alkene, alkyne, halogen, ether, or ester functional groups. 

Enamines are used as reagents in synthetic organic chemistry and are involved in certain biochemical transformations. 

The mechanisms of the Wittig reaction have been reviewed (108 references), with the authors drawing a clear distinction between the well-established Li salt-free reaction (with an oxaphosphetane as its first-formed and indeed only intermediate) and the Li-product cases, where the precise mechanistic details are less clear.  

The Wittig reaction has been carried out under very mild green conditions weakly basic water, ambient temperature and overnight completion Employing silver carbonate to convert a phosphonium salt into an ylide, the reaction works for stabilized, semi-stabilized and non-stabilized ylides, using aromatic, heteroaromatic and aliphatic aldehydes (and an example of a ketone). 

The anomalous Z-selectivity observed in Wittig reactions of ortto-substituted ben-zaldehydes has previously been ascribed to phosphorous-heteroatom interactions in the addition TS, but a DFT study identifies the cause as being primarily steric.  

The Wittig reaction has been rendered catalytic (in phosphane), using diphenylsilane to chemoselectively reduce a phosphane oxide precatalyst and a simple base sodium carbonate or Hunig s. /Z-selectivity 95/5 is seen in many cases. 

Olefinations of P-stabilized C-nucleophiles have been reviewed.  

The stereochemistry of the salt-free Wittig reaction has been reviewed.  

The additi( ], an l all mo Kime w steps—nucleophilic attack followed by protonation. Other examples of nucleophilic addition in Chapter 21 are somewhat different. Although they still involve attack of a nucleophile, the initial addition adduct is converted to another product by one or more reactions. 

A Wittig reaction forms two new carbon-carbon bonds—one new a bond and one new n bond-as well as a phosphorus by-product, Ph3P=0 (triphenylphosphine oxide). 

Step [1 ] Sn2 reaction of triphenylphosphine with an alkyl halide forms a phosphonium salt. 

Because phosphorus Is located below nitrogen In the periodic table, a neutral phosphorus atom with three bonds also has a lone pair of electrons. 

Triphenylphosphine (Ph3P ), which contains a lone pair of electrons on P, is the nucleophile. Because the reaction follows an Sn2 mechanism, it works best with unhindered CH3X and 1° alkyl halides (RCH2X). Secondary alkyl halides (R2CHX) can also be used, although yields are often lower. 

Thiol and sulfide chemistry resembles alcohol and ether chemistry. There are differences, but many of the differences are quantitative, not fundamental. For example, we have learned that mercaptides (RS ) are much better nucleophiles than alkoxides (RO ), but even an alkoxide can undergo the Sn2 reaction given the right conditions and reagents. There are areas in which substantial differences do appear, for example, sulfur is far more prone to oxidation than oxygen. 

FIGURE 16.80 Displacement of iodide by the nucleophilic phosphorus atom of triphenylphosphine leads to ph osphonium ions. 

The phosphonium ion contains acidic hydrogens that can be removed by strong bases such as alkyllithium reagents. The product is an ylide (pronounced ill-id), a compound containing opposite charges on adjacent atoms (Fig. 16.81). 

FIGURE 16.81 Protons adjacent to the positively charged phosphoms atom can be removed in strong base to give yhdes. 

The carbon of the ylide is a nucleophile, and like other nucleophiles, adds to carbon-oxygen double bonds (Rg. 16.82). Intramolecular closure of the intermediate 

Quantum mechanical calculations in the gas phase and DMSO solution at different temperatures can highlight the hazards of standard 0 K gas-phase calculations.259 For the Wittig reaction, a small barrier in the potential energy curve is transformed into a significant entropic barrier in the free energy profile, and the formally neutral oxaphosphetane intermediate is displaced in favour of the zwitterionic betaine in the presence of DMSO. 

Stabilized ylides react with aldehydes in water to give Wittig products, sometimes with remarkable acceleration.260 For example, pentafluorobenzaldehyde reacts with ester-stabilized ylide, Ph3P=CHC02Me, at 20 °C in 5 min in 86% yield, with 99 1 E Z-selectivity. Water s ability to stabilize the polar transition state of the reaction, and its participation in the reaction (as determined by deuterium exchange), are discussed. 

2-Formylarylketones are readily isomerized in dimethyl sulfoxide (DMSO) to 3-substituted phthalides by photolysis or by a Cannizarro-Tishchenko-type nucleophilic catalysis by NaCN.  

A study of the addition of Me3SiCN to aldehydes catalysed by four Lewis bases (Et3N and Bu4N X, where X = CN, N3, or SCN) has revealed three different reaction mechanisms there was spectroscopic evidence of formation of a hypervalent silicon species by each of the ammonium salts. ° Asymmetric trifluoromethylation of aromatic aldehydes by Me3SiCF3 is catalysed cooperatively by (IPr)CuF and a quinidine-derived quaternary ammonium salt.  

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With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins. Seebach et al... 

An altematiye route to olefins is by an immediate disconnection of the double bond. This corresponds to the Wittig reaction ... 

If you are unfamihar with the Wittig reaction see Norman p.297-299 or Tedder, Paid 3, p.233-6. 

A good approach to 1,2-diols is hydroxylation of an olefin with reagents such as OSO4 or KMn04. The olefin can be made by the Wittig reaction so the discoimections arc ... 

Note that is must be the trans olefin as it is the trans epoxide we want. Tins is all right as the Wittig reaction can easily be controlled to give mostl the more stable trans olefin. 

Notice that sulphur ylids behave quite differently from phosphorus ylids, which would of course do the Wittig reaction (ftames 41-43). 

Analysis The carbene synthon is easy it can be ethyl diazoacetate NiCHCOiEt. The diene can be made by the Wittig reaction from a familiar aUylic bromide (TM 31). 

The phosphorus ylides of the Wittig reaction can be replaced by trimethylsilylmethyl-carbanions (Peterson reaction). These silylated carbanions add to carbonyl groups and can easily be eliminated with base to give olefins. The only by-products are volatile silanols. They are more easily removed than the phosphine oxides or phosphates of the more conventional Wittig or Homer reactions (D.J. Peterson, 1968). 

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 ... 

The Julia-Lythgoc olefination operates by addition of alkyl sulfone anions to carbonyl compounds and subsequent reductive deoxysulfonation (P. Kocienski, 1985). In comparison with the Wittig reaction, it has several advantages sulfones are often more readily available than phosphorus ylides, and it was often successful when the Wittig olefination failed. The elimination step yields exclusively or predominantly the more stable trans olefin stereoisomer. 

Several structures of the transition state have been proposed (I. D. Williams, 1984 K. A. Jorgensen, 1987 E.J. Corey, 1990 C S. Takano, 1991). They are compatible with most data, such as the observed stereoselectivity, NMR measuiements (M.O. Finn, 1983), and X-ray structures of titanium complexes with tartaric acid derivatives (I.D. Williams, 1984). The models, e. g., Jorgensen s and Corey s, are, however, not compatible with each other. One may predict that there is no single dominant Sharpless transition state (as has been found in the similar case of the Wittig reaction see p. 29f.). 

The methyl enol ether 37 is oxidized to the a,/3-unsaturated aldehyde 39 via hemiacetal 38. Unsaturated aldehyde 39, elongated one carbon from the aldehyde 36, is prepared by the Wittig reaction of 36 to give 37, and application of this reaction[ 88]. 

To understand the mechanism of the Wittig reaction we need to examine the struc... 

The Wittig reaction is one that IS still undergoing mech anistic investigation An other possibility is that the oxaphosphetane intermedi ate IS formed by a two step process rather than the one step process shown in Figure 17 13... 

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... 

Another very important reaction initially involving nucleophilic attack on an aldehyde carbonyl is the Wittig reaction. An yUd adds to the carbonyl forming a betaine intermediate which then decomposes to produce an olefin and a tertiary phosphine oxide. 

A useful apphcation of phosphines for replacing a carbonyl function with a carbon—carbon double bond is the Wittig reaction (91). A tertiary phosphine, usually triphenylphosphine, treated with the appropriate alkyl halide which must include at least one a-hydrogen, yields the quaternary salt [1779A9-3] which is then dehydrohalogenated to form the Wittig reagent, methylenetriphenylphosphorane [19943-09-5] an yhde. 

The Corey process is also useful for the synthesis of PGs of the 1 and 3 series. Catalytic hydrogenation of (34) (see Fig. 5) with 5% Pd/C at — 15-20°C results in selective reduction of the 5,6-double bond. Subsequent transformations analogous to those in Figure 5 lead to PGE (9) and PGF (10). The key step for synthesis of the PG series is the Wittig reaction of (29) with the appropriate unsaturated CO-chain yUde (170). 

Total Synthesis. Poor yields encountered duriag the manufacture of vitamin D stimulated early attempts to synthesize vitamin D. In 1959 Inhoffen synthesized vitamin from 3-methyl-2-(2-carboxyethyl)-2-cyclohexenone (40), uskig the Wittig reaction extensively (103). 

In an unusual application of the Wittig reaction, treatment of clavulanic acid derivatives and esters of penicillin V with methoxycarbonylmethylenetriphenylphosphorane afforded the corresponding exo-alkylideneazetidines. Thus penicillin V benzyl ester (104) gave (lOS) as a mixture of E and Z isomers. The /3-lactam could be regenerated by low-temperature ozonolysis (81CC929). 

Cyanohydrin trimethylsilyl ethers are generally useful as precursors of ctir-bonyl anion equivalents and as protected forms of aldehydes. Direct conversion of p-anisaldehyde into 0-TRIMETHYLSILYL-4-METH0XYMANDEL0-NITRILE employs a convenient in situ generation of trimethylsilyl cyanide from chlorotnmethylsilane A general synthesis of allemc esters is a variant of the Wittig reaction. Ethyl (triphenylphosphoranylidene)acetate converts pro-pionyl chloride into ETHYL 2,3-PENTADlENOATE. 

The double bond transposition could also be achieved by the conversion of an intermediate for PGA2 synthesis into a 1,3-diene iron tricarbonyl complex from which PGC2 was synthesized in four steps. The Fe(CO)3 diene complex which survived the Wittig reaction was cleanly removed by Collins reagent in the subsequent step (Ref. 10). 

The work of Hyatt on cyclotriveratrylene—derived octopus molecules contrasts with this. Of course, these species have the advantage of ligand directionality absent in the benzene-derived octopus molecules. Except for the shortest-armed of the species (i.e., n = 1), all of the complexing agents (i.e., n = 2—4) were capable of complexing alkali metal cations. Synthesis of these species was accomplished as indicated below in Eq. (7.7). These variations of the original octopus molecules were also shown to catalyze the reaction between benzyl chloride and potassium acetate in acetonitrile solution and to effect the Wittig reaction between benzaldehyde and benzyltriphenylphos-phonium chloride. 

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 12. Fluorinated Esters and Amides in the Wittig Reaction to Form Enol Ethers [47 and Enamines 48 ...

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