Phosphorus acid derivatives electrophilic reactions

A review (91 references) on electrophilic and nucleophilic reactions of trivalent phosphorus acid derivatives, reactions of two-coordinate phosphorus compounds, and miscellaneous reactions has appeared.228 Earlier in this review we looked at the heavy-atom isotope effects on reactions of Co(III)-bound /vnitrophenyl phosphate,186 the uranyl ion hydrolysis of /vnitrophcnyl phosphodiesters (218)-(220),190 and the Th(IV) hydrolysis of these.191... 

Tervalent phosphorus acid derivatives (1) are compounds with three covalent bonds to phosphorus and at least one electronegative atom bound directly to the phosphorus atom. Such compounds are able to undergo a diversity of reactions since they are nucleophiles due to the lone pair on phosphorus and also electrophiles because of the presence of a leaving group X. They are generally reactive towards water and often easily oxidized. They are therefore mainly used as intermediates for the preparation of more stable phosphorus compounds, such as phosphine oxides, phosphates and phosphonates. 

Electrophilic substitution reactions (Scheme 4) in many cases convert one derivative of a tervalent phosphorus acid into another and numerous examples have been given in Section II. Therefore, the following discussion will be limited to electrophilic reactions which are not treated in Section II because they give products that are not tervalent phosphorus acid derivatives, or because the reactions are of limited preparative value. 

A general review (61 references) of the nucleophiUc and electrophilic reactions of tervalent phosphorus acid derivatives has appeared. The kinetics of the reaction of diisopropyl tetrazolylphosphonite (146 R = Mc2CH) with r-BuOH in dry THF have been studied in the presence of various acids, bases, and salts that catalyse the process. Ammonium azolide salts were found to be considerably more efficient catalysts than the corresponding azole acids or tertiary amine bases. For instance, the relative rates obtained with lV,lV-diisopropylethylammonium tetrazolide, N,N-diisopropylethylamine, and tetrazole were 104, 28 and 1, respectively. ... 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

In the case of diethyl chlorophosphate 1-ethylindole, the formation of which agrees with data on the alkylating ability of the derivatives of the phosphorus acids, was isolated [114]. In the transition to the dichlorides of P(IV) acids, where the electrophilicity of the phosphorus atom is increased in comparison with the monochlorides, the reaction takes place under milder conditions (at about 0°C) and is accompanied by an insignificant exothermic effect. In the reaction products (121) the phosphorus atom is bonded to the nitrogen atom of indole ... 

Considerable research effort has been focused on the preparation of compounds of biochemical interest, using electrophilic reactions of phosphoramidites and phosphorochloridites to prepare modified phosphates of nucleosides or lipids. Intense interest has been shown in the synthesis of myoinositol phosphates, and also of aminoalkylphosphonic acids and their derivatives and analogues. Away from the biological emphasis, however, the first (recorded) syntheses of acetylenic phosphates have been described, and so have the first 1-alkoxyphosphole, the first cis amino-iminophosphine, and the first dithiaphospholium ions ex Phosphorus semper aliquid novi The use of silyl phosphites for synthetic purposes seems to be an increasing trend, while the number of papers on metaphosphate seems to be in decline. 

The two terminal linkages of the triphosphate are phosphoric acid anhydrides i.e. they are activated phosphoric acid derivatives and nucleophilic attack at the electrophilic y OT P phosphorus is thermodynamically very favourable. The advantage of phosphoric anhydride derivatives over acyl derivatives is that the former are kineti-cally stable in neutral aqueous solution unless a suitable enzyme is present to catalyse its reactions. 

Acid-catalysed addition of primary, secondary, and tertiary alcohols to 3,4-dihy-dro-2//-pyran in dichloromethane at room temperature is the only general method currently in use for preparing THP ethers and the variations cited below concern the choice of acid. The reaction proceeds by protonation of the enol ether carbon to generate a highly electrophilic oxonium ion which is then attacked by the alcohol. Yields are generally good. Favoured acid catalysts include p-toluenesulfonic acid or camphorsulfonic acid. To protect tertiary allylic alcohols and sensitive functional groups such as epoxides, the milder acid pyridinium p-toluenesulfonate has been employed (Scheme 4.316]. A variety of other acid catalysts have been used such as phosphorus oxychloride, iodotrimethylsilane- and bis(trimethylsilyl)sulfate. but one cannot help but suspect that in all of these cases, the real catalyst is a proton derived from reaction of the putative catalysts with adventitious water. Scheme 4.317 illustrates the use of bis(trimethylsilyl)sulfate in circumstances where other traditional methods failed. - For the protection of tertiary benzylic alcohols, a transition metal catalyst, [Ru(MeCN)2(triphos)](OTf)2 (0.05 mol%) in dichloromethane at room temperature is effective. ... 

Other interests in the area of phosphorus acids and their derivatives has centered on the following subjects synthesis of new ligands and catalysts for known reactions, synthesis of supramolecular logic gates, use of phosphates as electrophiles in palladium-catalyzed cross-coupling reactions, synthesis of phosphate based dendrimers and conjugates with oligosaccharides. 

Amino-2,1,3-benzothiadiazole (237) is convertible into its anthranilic acid derivative (238), which is cyclized by phosphorus oxychloride to 6-chloro-[l,2,5]thiadiazolo[3,4-c]acridine (239). Replacement of its 6-halogeno-substituent produces derivatives such as (240). An analogous series of reactions provides 7,8,9,10-tetrahydro-analogues. The condensation of (237) and alkyl 2-oxocyclopentanecarboxylate yields derivatives of the [1,2,5]-thiadiazolo[3,4-h]quinoline ring system such as (241)—(243). Electrophilic substitutions of naphtho[l,2-d][2,l,3]thiadiazole (244) have been studied in some detail. Nitration produces a mixture of the 6- and... 

The monomeric metaphosphate ion itself commands a fair amount of attention in discussions of metaphosphates. It is postulated as an intermediate of numerous hydrolysis reactions of phosphoric esters 52 S4,S5) and also of phosphorylation reactions S6> kinetic and mechanistic studies demonstrate the plausibility of such an assumption. In addition, the transient formation of ester derivatives of meta-phosphoric acid — in which the double-bonded oxygen can also be replaced by thio and imino — has also been observed they were detected mainly on the basis of the electrophilic nature of the phosphorus. 

In spite of the general ambiphilicity of phosphonio-substituted phosphoHde derivatives, the aromaticity of the phosphoHde ring [10, 11] tends to reduce their electrophilicity while the intramolecular compensation of the negative charge by the phosphonio-substituents lowers at the same time their nucle-ophilicity [15, 16]. Bis-phosphonio-benzophospholides and -1,2,4-diaza-phospholides are therefore less reactive towards electrophiles and nucleophiles than other types of phosphorus containing multiple-bond systems and lack the notorious hydrolytic instabihty of many of these species [15, 16, 24]. Reactions are observed, however, with sufficiently strong electrophiles such as triflic acid or methyl triflate, or nucleophiles such as OH" or lithium alkyls, respectively. 

The attachment of the strongly electronegative phosphinyl (P—O) group to an imine, usually via reaction of an oxime with a chlorophosphine, also gives highly electrophilic imines which are reduced by NaBFWTHF and various modified borohydride and LAH derivatives " under mild conditions. The product A-phosphinylamines are protected forms of primary amines since removal of the phosphorus substituent is accomplished under mild acidic conditions. Entries 12 and 13 (Table 16) present representative reductions and illustrate (entry 13) that highly diastereoselective reductions of cyclic systems to axial amine derivatives are accomplished with LiBHBu s. Enantioselective reductions of A-diphenylphosphinyl imines to optically active amine derivatives have also been reported (Chapter 1,7, this volume). ... 

Several routes to benz[c]acridines involve electrophilic aromatic substitution to form the heterocyclic ring. Thus, 9-nitrobenz[c]acridine results from the cyclisation of the 2-(l-naphtlylamino)benzaldehyde derived from 1-naphthylamine and 2-fluoro-5-nitrobenzaldehyde (J. Rosevear and J.F.K. Wilshire, Austral. J. Qiem., 1981, 34, 839). The reaction between a ff-aryl-l-naphthylamine and acetic anhydride has been used to synthesise 9- and ll-hydroxy-7-methylbenz[c]acridines and cyclisation of partially reduced 2-(l-naphtltylamino)benzoic acid by phosphorus oxychloride affords the 7-chloro-l,2,3,4-tetralydro derivative (B.V. Lap et ai,y J. heterocyclic Chem., 1983, 20, 281). 

Other procedures for the synthesis of P-ketophosphonates based on the use of a phosphorus electrophile have been explored. For example, the reaction of dialkyl chlorophosphates with the dilithium derivatives of a-bromo ketones has been described,but the yields of isolated products remain modest. The Lewis acid-catalyzed reaction of oc-hydroxy ketones with dialkyl chlorophosphites constitutes an efficient synthesis of P-ketophosphonates in high yields (92-96%, Scheme 7.42). This reaction is of special value for the preparation of oc-fully substituted P-keto-phosphonates. ... 

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