Wittig reaction synthesis with

Firstly, it was necessary to develop the reaction sequence of the Wittig reaction — synthesis of the phosphonium salt, formation of the ylide and reaction with a carbonyl compound to give the olefin — into an industrial process, under the stringent criteria of safety and cost-efficiency. 

Now to the great Z-selective alkene synthesis. The Wittig reaction. Along with the Diels-Alder and the aldol reactions this is one of the most important reactions of all time. You probably have an idea of the basic reaction ... 

Figure 118. Synthesis of conjugated porphyrin polymers via the Wittig reaction. Reprinted with permission from Jiang, B. Szu-Wei, Y. Jones Jr., W. E. Chem. Mater. 1997, 9, 2031. 1997 American Chemical Society.

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). 

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 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). 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

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. 

With a regioselectivity opposite to that of the Zaitsev rule, the Hofmann elimination is sometimes used in synthesis to prepare alkenes not accessible by dehydrohalo-genation of alkyl halides. This application decreased in importance once the Wittig reaction (Section 17.12) becfflrre established as a synthetic method. Similarly, most of the analytical applications of Hofmann elimination have been replaced by spectroscopic methods. 

The discovery of junipal focused the attention of Sorensen, who had been investigating the occurrence of polyacetylenes in Com-positae, on the possibility that these acetylenes were accompanied by thiophenes. From Coreopsis grandiflora Hogg ex sweet, 2-phenyl 5-(1-propynyl) thiophene (240) was isolated and its structure confirmed by synthesis of the tetrahydro compound, 2-phenyl-5-n-propyl-thiophene. From the root of tansy, the cis and trans isomers of methyl 5-(l-propynyl)-2-thienylacrylate (241) have been isolated. The total synthesis of trans (241) was achieved by reacting junipal with methylcarbethoxy triphenylphosphonium bromide (Wittig reaction) Several monosubstituted thiophenes, (242), (243), and... 

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. 

With respect to the carbonyl substrate, a variety of additional functional groups is tolerated, e.g. ester, ether, halogen. With compounds that contain an ester as well as a keto or aldehyde function, the latter usually reacts preferentially. Due to its mild reaction conditions the Wittig reaction is an important method for the synthesis of sensitive alkenes, as for example highly unsaturated compounds like the carotinoid 17 shown above. 

Scheme 1-21. Synthesis of a blue-emitting copolymer with isolated chromophore by Wittig reaction a) base.

Intermediates 18 and 19 are comparable in complexity and complementary in reactivity. Treatment of a solution of phosphonium iodide 19 in DMSO at 25 °C with several equivalents of sodium hydride produces a deep red phosphorous ylide which couples smoothly with aldehyde 18 to give cis alkene 17 accompanied by 20 % of the undesired trans olefin (see Scheme 6a). This reaction is an example of the familiar Wittig reaction,17 a most powerful carbon-carbon bond forming process in organic synthesis. 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Bromo-capped biphosphole (8b) is also the precursor of cychc derivatives, as illustrated by the synthesis of the fully unsaturated macrocycle (11), via a Wittig reaction involving the 5,5 -bis(carboxaldehyde) (10) (Scheme 2) [22]. An X-ray diffraction study revealed that macrocycle (11) is distorted, with an flZZ-trans-disposition of the four P-phenyl substituants. 

Disconnection (a2) leads to the industrial synthesis as the half aldehyde, hall ester (46) of fumarie acid (100% tpans) is available and the Wittig reaction with unstabilised ylid (45) gives 85% cis geometry in the new double bond. 

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