Wittig-reaction

Wittig reactions employing microwave heating have been published several times both in solution and under solvent-free conditions. They have been performed using stable ylides27, as well as using the pre-formed phosphonium salts, which under basic conditions forms the ylides in situ1.  

One well-known drawback with the Wittig reaction in solution is the formation of 1 equiv. of triphenylphosphine oxide, which is inherently difficult to separate from the final product. Thus, Westman23 developed a one-pot multi-step microwave-assisted 

The Wittig reaction is very rapid under microwave conditions however, the efficiency of the reaction sequence can be further improved if the ylide can be synthesised with the same speed. 

The Wittig Reaction (3.111) represents another highlight in organophosphorns chemistry. It has important industrial application and has been snccessfully used in the synthesis of alkenes andnatn-ral products. 

In this reaction, a ketone or aldehyde reacts to give initially two isomeric betaines (3.112). The relative rates of formation and decomposition of the diastereoisomeric betaines control the stereochemistry of the olefin mixtnre eventually produced. The reaction usually proceeds under mild conditions and the carbonyl compound can contain a wide range of functional gronps. 

It is known that many factors can influence the stereochemical outcome of the Wittig reaction. Although this reaction frequently leads to mixtures of stereoisomers by suitable choice of reagants and reaction conditions, the reaction can be made stereoselective. 

In a case where betaine formation is reversible, the thermodynamically more stable isomer will be formed before elimination occurs. This is normally (3.112b), which leads to trans alkene. Generally trialkylphosphonium yUds, or those containing stabilising groups, give mainly trans alkenes. 

The amount of cis isomer can be increased by the use of protoic solvents, which presumably solvate (b) reducing the interaction between P and O and allowing (3.112a) to be formed. In some cases the intermediate betaine (3.113) can be trapped by protonation or complex formation with lithium salts (3.114), or the oxaphosphetanes may be isolated or detected in solution (3.115) 

The first step in the Wittig reaction is nucleophihc attack of the negatively charged carbon atom of the ylide on the carbonyl group to give an adduct called a betaine that rapidly converts to an oxaphosphetane. The exact course of the reaction may depend on the type of groups bonded to the carbonyl carbon atom and the type of ylide. Nevertheless, the direction of the addition of the yhde to the carbonyl atoms is the same as for other addition reactions studied in this chapter. The electrophilic carbon atom of the ylide forms a bond to the carbonyl carbon atom and the phosphorus bonds to the oxygen atom. 

The intermediate phosphorus compound, either the betaine or the oxaphosphetane, immediately decomposes to yield the alkene and a phosphine oxide. This step is concerted all bonds break and form simultaneously in the transition state. The driving force for this reaction is the formation of a very strong phosphorus—oxygen bond. (The P—O bond dissociation energy in triphenylphosphine oxide is approximately 550 kj mole. ) 

What combination of phosphorus ylide and a carbonyl compound could be used to prepare each of the following alkenes  

Outline two possible syntheses of the following compound. Would you predict any difficulties in obtaining a pure product  

As indicated vide supra), the classical mechanism for the Wittig reaction involves the initial nucleophilic addition of the ylide carbanion (resonance structures 1 and 2) to the electrophilic carbon of the carbonyl in 3 to afford betaine intermediate 4. Rotation about the central C-C bond provides for ring closure to 1,2-oxaphosphetane 5. These species are thermally unstable and readily decompose, via a concerted electrocyclic process, to generate the corresponding phosphine oxide 8 and the ( )-alkene 6 or (Z)-alkene 7. 

By this process, the alkene geometry is set during the initial 1,2-carbonyl addition and a rationalization for the observed stereochemistry could be made. Kinetic addition of ylide 1 to carbonyl compound 3 would 

It has been observed that the Wittig reaction is greatly influenced by the presence of soluble salts.The degree to which the erythro/threo adducts (9 and 10) are able to equilibrate via reversible formation of the 

Starting material, is significantly affected by the inclusion of, or protocols to exclude, soluble salts, in particular lithium. Coordination of lithium to the betaine (11 and 12)/oxaphosphetane (13 and 14) intermediates retards the rate of loss of phosphine oxide 8, thus allowing more time for equilibration. For example, consider the reaction of benzaldehyde 15 with the ylide 16 to generate alkene The addition of lithium salts had a dramatic effect on the overall yield of the reaction. Not only was the yield negatively impacted, the product distribution was affected. Under salt free conditions, the product distribution favored the cis over trans. However, the addition of various forms of lithium salts resulted in an erosion of the selectivity to 50 to 50. 

Stereochemistry could be rationalized by which mode this cycloaddition progressed. The two modes proposed included a c/s-selective, puckered 4-membered TS 24 and a /ra 5-selective, planar TS 25. 

The presence of both cis and trans double bonds in the polymer can be explained by looking closely at the mechanism of the Wittig 

Isomerization of the polymers to an eX[-trans configuration is possible either by heating to 200-300° C or by heating with iodine in an appropriate solvent. 

The Wittig reaction and other step-growth processes have also been extensively used for the formation of oligomers, because molecular weight can be controlled and end groups incorporated, allowing tailor-made oligomers to be obtained [6]. 

Smith Kline Beecham Pharmaceuticals in Harlow, UK, carried out Wittig reactions using a microchip reactor under electroosmotic flow conditions. 2-Nitrobenzyltri-phenylphosphonium bromide was reacted with methyl 4-formylbenzoate and four other aldehydes - 3-benzyloxybenzaldehyde, 2-naphthaldehyde, 5-nitrothiophene-2-carboxaldehyde, and 4-[3-dimethylamino)propoxy]benzaldehyde [23,24]. 

Using optimized reaction conditions, the Wittig reactions with four of the five aldehydes indeed resulted in improvement of their yields. The ratio of ( )- and (Z)-alkenes could be changed by simply adjusting the voltages in the electroosmotic flow-driven chip [25]. For a 1 1 ratio of the reactants, the Z/E ratio changed from 2.35-3.0 (premixed) to 0.82-1.09 (not premixed, separate movement) [24]. 

Organic superbases effectively generate carbonyl-stabilized ylides to promote Wittig reactions. In the synthesis of (-)-mycalolide A (68) by Panek and Liu, construction of 

The total synthesis of amaryllidaceae alkaloid buflavin was achieved in the laboratory of A. Couture by utilizing a Horner-Wittig reaction between a biaryl aldehyde and a metalated carbamate. The diphenyl phosphine oxide carbamate was deprotonated with n-BuLi. To the resulting metalated carbamate was added the solution of the biaryl aldehyde in THF. The reaction afforded the corresponding (Z)- and ( )-enecarbamates in good yield and with high -selectivity. 

Reproduced with permission from Balema VP, Wiench JW, Pruski M, Pecharsky VK. Mechanically induced solid-state generation of phosphorus ylides and the solvent-free wittig reaction. 

120 CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

A variant of the Williamson ether synthesis uses thallium alkoxides. The higher reactivity of these can be of advantage in the synthesis of ethers from diols, triols and hydroxy carboxylic acids, as well as from secondary and tertiary alcohols on the other hand however thallium compounds are highly toxic. 

A variant for the synthesis of diaryl ethers—e.g. diphenyl ether 9, where an aryl halide and a phenoxide are reacted in the presence of copper or a copper-(I) salt, is called the Ullmann ether synthesis.  

Krebserzeugende Stoffe, Wissenschaftliche Verlagsgesellschaft, Stuttgai t, 1983, pp. 49,54. 

Alkenes (olefins) from reaction of phosphonium ylides with aldehydes or ketones 

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.  

Angew Int 3 250 (1964) (unsaturated fatty acids) 16 423 (1977) (industrial practice) 21 545 (1982) (synthesis of R RJC=PPh3) 

Pure Appl Chem 9 255 (general), 271 (stereochemistry) (1964) 51 515 (1979) (polyenes) 

Johnson, Ylld Chemistry, Academic Press, New York (1966) 

Gosney, A. G. Rowley in Organophosphorus Reagents in Organic Synthesis, Ed. J. I. G. Cadogan, Academic Press, New York (1979), Chpt 2 JCS Perkin I 1 (1979) (polymer-supported reagents) 

Syn Conunun 11 125 (1981) (phase transfer) 12 107 (phase transfer), 469 (preparation of ylid via decarboxylation) (1982) 

Olefination of carbonyls using phosphorus ylides, typically the Z-olefin is obtained. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 269, Springer-Verlag Berlin Heidelberg 2009 

Wittig, G. Schollkopf, U. Ber. 1954, 87, 1318-1330. Georg Wittig (Germany, 1897-1987), bom in Berlin, Germany, received his Ph.D. from K. von Auwers. He shared the Nobel Prize in Chemistry in 1981 with Herbert C. Brown (USA, 1912-2004) for their development of organic boron and phosphorous compounds. 

Wittig reaction in. In Name Reactions for Homologations-Part I Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 588-612. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 288, Springer International Publishing Switzerland 2014 

Kajjout, M. Smietana, M. Leroy, J. Rolando, C. Tetrahedron Lett. 2013, 38, 1658-1660. 

The mechanism involves addition of the carbanion nucleophile to the electrophilic carbon of the carbonyl, followed by a breakdown of the resulting oxa-phosphetane intermediate. A molecule of triphenylphosphine oxide (Ph3P=0) is generated along with the alkene product. 

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Wittig reaction The reaction between an alkyl-idene phosphorane, C = PR3 and an... 

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

Aromatic Substitution (Carey Sundberg, Chapter 11) Intramolecular Wittig Reaction Sigmatropic Rearrangements... 

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 ... 

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). 

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). 

First the normal Wittig reaction, and then a second mol of Wittig reagent must be behaving as a carbene equivalent, just as we hoped the sulphur yhd would. 

The synthesis of vitamin Dj from a sensitive dienone was another etu-ly success of phosphorus ylide synthesis (H.H. Inhoffen, 1958 A). This Wittig reaction could be carried out without any isomerization of the diene. An excess of the ylide was needed presumably because the alkoxides formed from the hydroxy group in the educt removed some of the ylide. 

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. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

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.). 

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). 

Enantiomerically pure tetroses, pentoses, and hexoses have been synthesized by the following reaction sequence (A.W.M. Lee, 1982 S.Y. Ko, 1983), which is useful as a repetitive two-carbon hotnologi-.ation in total syntheses of higher monosaccharides and other polyhydroxy compounds (1) Wittig reaction of a protected hydroxy aldehyde with (triphenylphosphor-... 

The synthesis of 11-oxaprostaglandlns from o-glucose uses the typical reactions of gl cofuranose diacetonide outlined on p. 267. Reduction of the hemiacetal group is achieved a thioacetal. The carbon chains are introduced by Wittig reactions on the aldehyde grou] which are liberated by periodate oxidation and laaone reduction (S. Hanessian, 1979 G Lourens, 1975). 

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]. 

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

Wittig reactions may be carried out m a number of different solvents normally tetrahydrofuran (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 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... 

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 sample solution to Problem 17 16(a) showed the prepara tion of 3 methyl 3 heptene by a Wittig reaction involving the ylide shown Write equations showing the formation of this ylide beginning with 2 bromobutane... 

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... 

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