Phosphonate ylids

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

Ylids are usually prepared from triphenylphosphine, but other triarylpho-sphines, trialkylphosphines, and triphenylarsine " have also been used. The Wittig reaction has also been carried out with other types of ylids, the most important being prepared from phosphonates " ... 

Stereoselective alkenylation reactions have been achieved using chiral additives or auxiliaries. Ylids formed from phosphinoxides / jP—CHRR phosphonic... 

Derivatives of the general formula (7) in Table 6 have been successfully used as probases and their properties in this context are being further explored. In common with the azobenzenes and ethenetetracarboxylate esters, the fluoren-9-ylidene derivatives usually display two reversible one-electron peaks in cyclic voltammetric experiments. Although disproportionation is possible (cf. Scheme 12) it is the dianions which are the effective bases. It was shown early on that the radical-anions of such derivatives are long-lived in relatively acidic conditions (e.g. in DMF solution the first reduction peak of Ph C -.QCN) remains reversible in the presence of a 570-fold molar excess of acetic acid, at 0.1 V s ). Even the dianions are relatively weak bases, useful mainly for ylid formation from phosphonium and sulphonium salts (pKj s 11-15) they are not sufficiently basic to effect the Wittig-Homer reaction which involves deprotonation of phosphonate esters... 

There are many examples of Wittig-type reactions in the literature, in which the behavior of phosphonium ylids, phosphine oxide ylids, and phosphonate ylids is significantly different. 

This is particularly so with a-heterosubstituted derivatives, as shown by a number of recent examples in which oxide derived ylids have been found to give vinyl derivatives in circumstances where the corresponding phosphonate derived ylids do not (2-5). It was therefore decided to prepare the parent (unsubstituted) a-methoxy-allyl phosphorus compounds 1, 2 and 3, in order to investigate their Wittig-type chemistry. 

Unfortunately the phosphonate 2, and the salt 3, are very hygroscopic, and this led us to select the oxide 1 for scrutiny as precursor of unusual Wittig reagents. Thus a range of ylids have been prepared from 1 and its substituted derivatives using standard conditions (n-BuLi, i-Pr2NH, in dry THF at -78°C). In general, these ambident ylids can react at either the a-carbon or at the y-carbon with electrophiles, and examples of both types of behavior will be published elsewhere (11). 

In tetrachloride solution, these two species 8 and remained essentially unchanged. With dichloromethane solution, the evolution takes a few hours only NMR signals appear for J 0 (Z + E) whereas the intensity of 8 and 9 signals are decreasing. When the percentage of J 0 is 60% the relative ratio of ylid versus phosphorane remains unchanged(36%-64%>. In the end, two isomers (Z+E) corresponding to the phosphonate J 0 can be seen (3,P NMF). 

Since our initial attempts to direct Scheme I towards path B by changing the group on the central phosphorus of I failed, we simplified our system to determine what factors control elimination of a phosphonate or phosphinate phosphorus during carbonyl olefination with PO ylids containing two phosphorus atoms. The results for the condensation of a series of phosphonomethylphosphinates IV with aldehydes (Scheme II) are given in Table I. 

When the substituent becomes very anion-stabilising, as in 42, the ylid may not react with ketones and anions of phosphonate esters are usually preferred in the Homer-Wadsworth-Emmons (HWE) variant.11 The reagent triethyl phosphonoacetate 46 is made by combining a phosphite (EtO)3P instead of a phosphine, with ethyl bromoacetate. Displacement of bromide 44 gives a phosphonium ion that is dealkylated by bromide 45. 

As the ylid 51 is stabilised by the nitrile as well as the benzene ring, the phosphonate ester 54 is preferred in the manufacture and the reaction is strongly trans selective.13 The by-product is the anion of dimethyl phosphate 55 which is water-soluble and very easy to separate from the product 50. By contrast, triphenylphosphine oxide is insoluble in water and can be difficult to separate from the alkene. 

These stabilized ylids really are stable—this one, for example, can be recrystallized from water. This stability means though that they are not very reactive, and often it is better not to use the phos-phonium salt but a phosphonate instead. 

Further reports have appeared on the reaction of trivalent phosphorus compounds with acetylene dicarboxylates. In the first, alkyl diphenylphosphinites (e.g.57) are shown to react with dialkylacetylene dicarboxylates (e.g.58) in the presence of carbon dioxide to form 1,2-oxaphosphol-3-enes (e.g.59) which in the presence of excess phosphinite decompose via (60) to give di-ylids (e.g.61). On the other hand, the phosphoranes (62) from phosphonites and phosphites react with a further phosphorus component to give the ylids (63) which are readily converted by treatment with alcohol into phosphonates (65) apparently via ketene intermediates (64) as evidenced by and isotopic tracer studies. ... 

Treatment of the triflate 9 with the sodio derivative of r-butyl dimethoxphosphorylacetate in dimethylformamide (DMF), at room temperature for 20 h in the presence of a crown ether, gives the epimeric phosphonates 10 in 81% yield [9]. Cleavage of the glycosidic bond by hydrogenolysis then affords the hemiacetals 11 which, with sodium hydride in tetra-hydrofuran (THF), give the C-6 phosphonium ylid, which reacts with C-1 in the aldehydo form to afford the alkene 12 in 73% (from the glycoside 10 Scheme 2). The cyclization... 

CostiseUa, B., and Gross, H., a-Subsliluted phosphonates. Part 40. 1-Trimethylammonium-l-dieth-ylphosphono-l-cyanomethylid, a stable A-ylid, J. Prakt. Chem., 324, 545, 1982. 

More general methods depend on Wittig reactions with functionalised ylids. The ylid24 from 116 and the lithium derivatives of 117-120 all react with aldehydes and ketones to give enol ethers that can be hydrolysed to chain-extended aldehydes. Yields with the ylid from 116 are not always wonderful and the phosphonate ester 120a with a chelating substituent generally does better.25... 

The extra stabilisation makes the ylid rather unreactive and phosphonate esters 91 are often used instead of phosphonium salts in these reactions. Treatment with a base (NaH or RO is often used, BuLi will certainly not do) gives an inherently more reactive enolate anion 92 rather than an ylid. These Horner-Wadsworth-Emmons reagents (H WE as we shall call them, though they go under many other names) react with ketones as well as aldehydes and the product is normally the E-alkcnc16 93. 

Monocyclic Phosphoranes. - Further studies of the reaction of P-fluoro-ylids (53) with carbonyl compounds (54) reveals formation of P-fluoro-oxaphosphetans (55) as the initial addition products. These may decompose in a conventional Wittig reaction to form alkenes (56)21 ajgo lose HF to form alkyl phosphonates (57).22... 

The ylid is stabilised by CN as well as by aryl so the phosphonate ester (18) is used instead and the reaction is strongly irons selective. 

The reaction of triethyl phosphite with maleic anhydride has been re-investi-gated. The product is not the dimeric phosphorane (11), but the ylid (12). Reactions of alkyl or aryl diphenylphosphinites with 1-nitro-l-alkenes have been studied in detail. Radical ion-pairs are involved as shown by e.s.r. and P CIDNP experiments. Allene may be hydrophosphorylated in a radical-initiated process to give allyl- and isopropenyl-phosphonates. A phosphorane (14) has been observed during the reaction of ethyl diethylthiophosphinite (13) with methacrylic acid. ... 

The reaction of trialkylphosphines, especially triphenylphosphine, with alkyl halides is particularly useful since the resultant phosphonium salts are easily converted to the phosphonium ylid on treatment with a suitable base (sec. 8.8r kk Ylids are, of course, the reactive species in the well-known Wittig olefination reaction, which will be discussed in section 8.8.A.i. A related Sn2 process involves reaction of a trialkylphosphite with an alkyl halide, the Arbuzov reaction (sometimes called the Michaelis-Arbuzov reaction). Triethylphos-phite (70) reacts with iodomethane to give the phosphonium salt, 71. Heating generates the monoalkyl phos-phonic ester (72). This type of phosphonic ester can be converted to an ylid and used in the well-known Horner-Wadsworth-Emmons oiefination (sec. 8.8.A.iii). 

A.iu. Phosphine Oxides and Phosphonate Esters. Many extensions of the Wittig reaction have been introduced that improve or modify the reactivity and/or stereoselectivity of the ylid. Horner et al. showed that a-lithiophosphine oxides such as that derived from 552 react with aldehydes or ketones to give a p-hydroxy phosphine oxide (553) as an isolable species. Subsequent treatment with base liberates the alkene, (554). Wadsworth and Emmons modified the Horner reaction to use phosphonate ester derivatives such as... 

The major product of olefination with phosphonate carbanions is usually the ( )-isomer.304 However, a (Z)-selective reaction has recently been developed that uses sodium iodide and DBU as the base.305 Speziale and Ratts suggested that increased amounts of (Z) alkene were obtained by increasing the steric bulk of the L and l1 groups in 557 and 560, formed by reaction of the phosphonate ester ylid with a carbonyl compound. This equilibrium favors the anti conformation(557 over 560 and elimination gives more of the (Z) product, 559.306 jjjjg model assumes that steric encumbrance is more important in 557 and 560 than in oxaphos-phetanes 558 and 561, respectively, that are required for syn elimination to the alkene. This equilibrium generally favors 559 over 562 due to the stereochemical preferences in the initially formed ylid products. 

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