Phosphonium phosphonate intermediates

An interesting comparison has been made between the behaviour of (78)—(80) in their reaction with Cl2 and SOaCla.61 Compounds (78) and (79) react at -70 °C via phosphonium-like intermediates, with retention of configuration in the former case the product is the phosphonic chloride (81) whereas (79) yields the cyclic oxophos-phoranesulphenyl chloride (82). On the other hand, the benzodioxaphospholan (80)... 

In the reaction outlined in Section II.A.2.b, the desired cross-coupled product is sometimes contaminated with small amounts of symmetrical TTFs. The contaminants are believed [61] to arise because of the instability of the phosphonium salt intermediate (25). Lerstrup has reported an improved synthesis utilizing phosphonate reagents (27) that presumably circumvents this problem [62]. Dimethyltetrathiafulvalene can be synthesized in good yield with no contaminating TTF by products following the sequence in Scheme 10. 

Although other mechanisms are conceivable, the most likely scheme involves direct nucleophilic displacement by phosphite on carbon to furnish a trialkoxy phosphonium halide intermediate as in the Michaehs-Arbuzov reaction. Recently, we have developed an improved method for the preparation of Mannich bases of steroids and carried ouf reactions with their methiodides and trialkyl phosphite to obtain the first steroidal phosphonates to be reported (132). 

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

The condensation of an aldehyde, benzyl carbamate, and triphenyl phosphite, first described by Oleksyszyn et al., 25,26 affords a direct route to a-aminoalkylphosphonates 4 that are conveniently protected for subsequent reactions (Scheme 4). Since dealkylation of the quaternary phosphonium intermediate 3 is not possible in this case, formation of the pen-tavalent product 4 presumably involves activation of the solvent and formation of phenyl acetate. This method is useful for the synthesis of aliphatic and aromatic amino acid analogues. However, monomers with more elaborate side chains are often incompatible with the reaction conditions. The free amine can be liberated by treatment with HBr/AcOH or by hydrogenolysis after removal of the phenyl esters. The phosphonate moiety can be manipulated by ready exchange of the phenyl esters in alkaline MeOH and activation as described in Section 10.10.2.1.1. Related condensations with other trivalent phosphite derivatives have been reported. 27-30 ... 

Compounds containing phosphorus can be both valuable synthetic intermediates and target compounds of solid-phase synthesis. Important synthetic intermediates include phosphonium salts and phosphorus ylides, which are key intermediates in carbonyl olefinations. Their preparation is discussed in Section 5.2.2.1. The preparation of oligonucleotides, these being the most important phosphorus-containing target molecules in solid-phase synthesis, is considered in Section 16.2. In this chapter, the preparation of phosphines, phosphonic acid derivatives, and phosphinic acid derivatives is discussed. 

To obtain more information on the nature of the quasiphosphonium intermediates involved in these systems we have studied the reactions gf sterically hindered neopentyl esters by means of 1P nmr spectroscopy. Trineopentyl phosphite and a-bromoacetophenone gave rise to a peak at +41 ppm due to the ketophosphonium intermediate 3 (R = Me.CCH, R = Ph X = Br ) within half an hour of mixingJthe reactants in acetone-dfi at 27 °C ( p nmr shifts are relative to 85% H-PO. down-field positive). Peaks due to the ketophospnonate 4 +19 ppm and the vinyl phosphate 7 (-7 ppm) were also observed (compound 4 and 7 have satisfactory elemental analysis and spectroscopic data ). The concentration of the intermediate reached a maximum after about two hours when it was precipitated from acetone solution by the addition of anhydrous ether to give white crystals of trineopentyloxy (phenacyl)phosphonium bromide, identified by elemental analysis and nmr spectroscopy ( XP 6+41, in CDCl ). When redissolved in acetone-dg, deuterochloroform, acetic acid, or acetic acid-acetone mixtures, the intermediate decomposed to yield keto-phosphonate 4 but none of the vinyl phosphate 6 (Perkow product). Nor was the course of reaction affected by the addition of chloride ion or of a-chloro-acetophenone in acetonitrile. 

The Michaelis-Arbuzov reaction is the most used and well-known method for the synthesis of phosphonates and their derivatives and may also be used to synthesize phosphinates and tertiary phosphine oxides. The simplest form of the Michaelis-Arbuzov reaction is the reaction of a trialkyl phosphite, 3, with an alkyl halide, 4, to yield a dialkyl alkylphosphonate, 6, and new alkyl halide, 7 (Scheme 2). During this transformation the phosphorus atom of a ter-valent phosphorus(III) species (3) acts as a nucleophile resulting in the formation of an intermediate alkoxy phosphonium salt 5, containing a new [P—C] bond. The precise structure of the intermediates 5 is a subject of debate—as reflected by common reference to them as pseudophosphonium salts —with a penta-coordinate species (containing a [P—X] bond) being proposed and detected in some cases.18 Decomposition (usually rapid under the reaction conditions) of the intermediate 5 by nucleophilic attack of X- on one of the alkyl groups R1, with concomitant formation of a [1 =0] bond yields the product pentavalent phosphorus(V) compound (6) and the new alkyl halide, 7. 

AUcoxyaminophosphines react with alkyl halides in an Arbuzov Michaelis type reaction to form phosphonic acid diamides via thermally unstable phosphonium intermediates (equation 5). ... 

The mechanism of phosphonate anion (135) addition to carbonyl derivatives is similar to the phosphonium ylide addition however, there are several notable features to these anion additions that distinguish the reactions fix)m those of the classical Wittig. The addition of the anion gives a mixture of the erythro (136 and 137) and threo (139 and 140) isomeric p-hydroxyphosphonates (Scheme 24). In the case of phosphine oxides, the initial oxyanion intermediates may be trapped. The anion intermediates decompose by a syn elimination of phosphate or phosphinate to give the alkene. The elinunation is stereospecific, with tile erythro isomer producing the ci.r-alkene (138), and the threo addition adduct producing the... 

Kawamoto, A.M., and Campbell, M.M., A new method for the synthesis of a phosphonic acid analogue of phosphoserine via a novel 1,1-difluorophosphonate intermediate, J. Fluorine Chem.. 81, 181, 1997. Burton, D.J., Naae. D.G., Flynn, R.M., Smart, B.E., and Brittelli, D.R.. Phosphine- and phosphite-mediated difluorocarbene exchange reactions of (bromodifluoromethyl)phosphonium salts. Evidence for facile dissociation of (difluoromethylene)triphenylphosphorane. J. Org. Chem.. 48. 3616, 1983. Li, A.-R., and Chen. Q.-Y., Diethyl iododifluoromethylphosphonate. A new synthetic method and its reaction with alkynes. Synthesis, 606, 1996. 

Hildebrand, R.L., The Role of Phosphonates in Living Systems, CRC Press, Boca Raton, 1983. Hildebrand, R.L., Curley-Joseph, J, Lubansky, H.J., and Henderson, T.O., Biology of alkylphosphonic acids. A review of the distribution, metabolism, and structure of naturally occurring alkylphosphonic acids, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 297-338. Hudson, H.R., Quasi-phosphonium intermediates and compounds, in Topics in Phosphorus Chemistry, Vol. 11, John Wiley Sons, New York, 1983, pp. 339-436. 

The construction of the alkenyl side chain and the control of the C9, CIO and Cll stereogenic centers was achieved from (5)-(+)-methyl 3-hydroxy-2-methylpropionate 1. (Scheme 21) This compound was transformed to aldehyde 99 in three steps. Bis(2,2,2)trifluoroethyl)[(methoxycabonyl)methyl]-phosphonate [23] was employed for the selective formation of the cA-a, 3-unsaturated ester 100. From this Z-unsaturated ester 100, the three consecutive asymmetric units were constructed via epoxide 101 (m-CPBA), which was selectively opened by lithium dimethylcuprate to produce 102. After deprotection-protection, the alcohol 102 was converted to the phosphonium iodide 103 via a tosylate intermediate(Scheme 21). 

In another approach to the technical synthesis of the apocarotenoids 286, 287 and 292 [118] the C25-aldehyde 12 -apo-p-caroten-12 -al (293) is the key intermediate. Several ways to synthesize this compound have been developed, applying the Wittig reaction to couple the building blocks. By the reaction of the Cas-aldehyde 293 with the protected Cs-phosphonium salt 294 the Cao-aldehyde is obtained [119,120], and this can be transformed by a base-catalysed aldol condensation with acetone (295) to give the Css-ketone citranaxanthin (292) [121]. Alternatively the C2s-aldehyde 293 can be reacted in a Horner-Emmons reaction with the Cs-phosphonate 296 to give 292 [122] Scheme 61). 

Variations in the types of reactants have been noted which are a reminder of those variations described in the previous chapter for the basic Michaelis-Arbuzov reaction. In this case, a a-haloketone reacts with a phosphorous chloride the reaction is envisaged as proceeding through a phosphonium intermediate which, when decomposed through alcoholysis, yields a (2-oxoalkyl)phosphonic derivative (Scheme 50). The usual pattern of... 

Evidence for the formation of intermediate quasiphosphonium salts comes from the isolation of the ion 436 (A = B = EtO R = H, R = R = Me E = SPh) as the hexa-chloroantimonate and further evidence stems from reactions with cyclic esters of the (alka-l,2-dienyl)phosphonic acids. The reactions of the l,3,2-dioxaphosph(V)olanes 444, of known geometry, with CI2, Br2 and RSCl or RSeCl " are highly stereoselective and would be expected to proceed through the quasiphosphonium salts 445 such salts have been isolated from other reactions. The 1,2-oxaphosph(V)ol-3-enes 446 have been isolated (66-75%) when EY is RSCl or RSeCl, but in the former case, were accompanied by 449 (65-73%) Phosphonium salts 436 (A = B = alkyl) have been obtained from reactions of propadienyldialkylphosphineoxides. ... 

In the exceptional case of the reaction of / -anisoyl chloride with trimethyl phosphite in the presence of / -anisic acid, the product was an unusual monophosphorus compound (equation 20). The formation of this was also rationalized as proceeding through the common phosphonate phosphonium intermediate, the difference being merely in the mode... 

The scope of the Scheme can be extended to include (1,2-propadiene)-phosphonic dichlorides when an additional equilibrium between the dichloro-phosphonium chloride and a trichloro pentaco-ordinate compound can be considered. Thus, the chlorination of the 3-phosphylated-penta-l,2,4-triene compound (150 R == X = Cl) yields the linear (hexa-l,3,5-triene)-phosphonic dichloride (153 R = X = Cl) via the proposed intermediate equilibrium... 

Aldehydes were converted to predominately trans olefins with 1136 and 1137 although trans.ds ratios of up to 99 1 were obtained using 1137b. Both LDA and KH were effective bases in the reaction. As expected, the phosphonium salts were more reactive than the stabilized phosphonates. Examples of trons-4-aIkenylox-azoles 1141—1143 prepared as advanced intermediates for natural product synthesis are shown in Scheme 1.297. 

The Cs-phosphonium ester salts 95 + 99 and the Cs-phosphonate ester 100 (Scheme 11), as well as their corresponding methyl esters, are key building blocks for the manufacture of various polyenecarboxylic acid esters for use in the carotenoid field [34-36]. An efficient route uses as an intermediate 2-hydroxy-2-methylbut-3-enoic acid ethyl ester (101) [37,38], which can be prepared from methylvinyl ketone (102) by acidic ethanolysis of the cyanohydrin 103, prepared by reaction of 102 with HCN (104). Reaction of 101 with thionyl chloride under reflux conditions led to a 76% yield of distilled 4-chloro-2-methyl-but-2-enoic acid ethyl ester (105), from which the phosphonium chloride 98 was obtained in good yield [36]. 

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