The Arbuzov Reaction

Hypophosphorous acid is an important reducing agent, both in chemistry labs and in industry. Its best known use in organic chemistry is in the reduction of arenediazonium cations (ArN2 ) to arenes (ArH). In industry, its chief application is electroless plating where a metal such as nickel or copper is deposited on a surface by chemical reduction, as opposed to passing an electfic current (hence the name). 

Hypophosphorous acid can reduce elemental iodine to HI, which is the reducing agent of choice for reducing ephedrine or pseudoephedrine to methamphetamine. The relevant reactions are as follows  

The sale and use of hypophosphorous acid therefore is strictly controlled in the United States and a number of other countries. Suggest mechanisms for the above two reactions. 

Phosphorus reagents are an integral part of modern organic chemistry, so weTl devote the next few sections to discuss some of the most instructive aspects of organophosphoms chemistry. We ll begin with the Michaelis-Arbuzov reaction, which is a powerful means of creating a carbon-phosphorus bond and hence a key route to organophosphoms chemistry. The reaction involves the interaction of an alkyl halide and a trialkyl phosphite  

Here the phosphorus lone pair is a plausible nucleophile and the alkyl halide a plausible electrophile. An 8 2 reaction can thus be envisioned  

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The Arbuzov reaction,also called the Michaelis-Arbuzov reaction, allows for the synthesis of pentavalent alkyl phosphoric acid esters 4 from trivalent phosphoric acid esters 1 (Z,Z = R,OR) by treatment with alkyl halides 2. 

The phosphonates obtained by the Arbuzov reaction are starting materials for the Wittig-Homer reaction (Wittig reaction), for example, appropriate phosphonates have been used for the synthesis of vitamin A and its derivatives/... 

Important and widely used variants of the Wittig reaction are based on carbanionic organophosphorus reagents, and are known as the Wadsworth-Emmons reaction, Wittig-Horner reaction or Horner-Wadsworth-Emmons reaction. As first reported by Horner, carbanionic phosphine oxides can be used today carbanions from alkyl phosphonates 13 are most often used. The latter are easily prepared by application of the Arbuzov reaction. The reactive carbanionic species—e.g. 14 —is generated by treatment of the appropriate phosphonate with base, e.g. with sodium hydride ... 

In this context, the treatment of the AT-phosphinyl iminoethers 15 with methyl iodide furnish the P-methyl phosphonium iodides, which by heating experience an 0-dealkylation, reminiscent of the Arbuzov reaction, for yielding the iV-acylphosphazenes 16 [45] (Scheme 16). 

An adaptation of the Arbuzov reaction (Scheme 14) using the hydrazones of 1-chloroalkyl ketones provides a route to dialkyl (2-oxoalkyl)phosphonates (79 R =Me, C1CH2, Ph, EtOOCCH2, or (Et0)2P(0)CH2 R2=H, generally R3=MeO, EtO).73... 

Shokol, V.A. and Kozhushko, B.N., Phosphorohalidites and phospho-ropseudohalidites in the Arbuzov reaction with halogen-containing compounds, Russ. Chem. Rev., 54, 98, 1983. 

The Arbuzov reaction has been applied for the synthesis of fluorinated carbohydrates. 1,2 3,4-Di-O-isopropylidene-a-D-galactopyran-ose 6-(N,N-diethyl-P-methylphosphonamidite) was treated with ethyl fluoroacetate, to afford 6-deoxy-6-fluoro-l,2 3,4-di-O-isopropylidene-a-D-galactopyranose in 19% yield.241 The corresponding 6-deoxy-6-fluoride was obtained in 60% yield by treatment of l,2 3,4-di-0-isopropylidene-a-D-galactopyranose 6-(dipropylphosphinite) with hexafluoropropene.242 The mechanism of this reaction has been discussed.243,244 In contrast, treatment of 1,2 -.3,4-di-O-isopropylidene-a-D-galactopyranose 6-(tetraethylphosphorodiamidite) with benzoyl fluoride yielded the corresponding 6-benzoate, not the 6-deoxy-6-flu-oride expected.245... 

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or Wittig-Hor-ner reaction,658 has several advantages over the use of phosphoranes.659 These ylides are more reactive than the corresponding phosphoranes, and when R is an electron-withdrawing group, these compounds often react with ketones that are inert to phosphoranes. In addition, the phosphorus product is a phosphate ester and hence soluble in water, unlike PhjPO, which makes it easy to separate it from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction ... 

A kinetic study of the reaction of trialkylphosphites with mucochloric acid has established that this unusual variant of the Arbuzov reaction proceeds with elimination of both alkyl halide and HC1 at the second stage.87... 

Nowick and Danheiser have employed the Horner-Emmons reaction of a-phosphon-oacyl silanes to prepare a,/l-unsaturated acyl silanes in 54-97% yields116. The a-phosphonoacetyl silane intermediate (21), prepared from a-iodoacetyl t-butyldimethylsilane through the Arbuzov reaction, undergoes enolate alkylation, for example using potassium t-butoxide and methyl iodide the alkylated products also underwent Horner-Emmons reaction (Scheme 53). 

The aldehydes 3 were synthesized either by Vilsmeyer formyladon of 2 or by reaction of 4-fluorobenzaldehyde with a secondary amine (20). The stilbenes 4 were formed from the corresponding 4-dialkylamino-benzaldehydes either by the Homer-Emmons reaction with 4-nitrobenzyl-(diethyl)phosphonate (prepared by the Arbuzov reaction of a-bromo-4-nitrotoluene) or with 4-methylsulfonylbenzyl(diethyl)phosphonate (prepared in three steps from 4-methylthiobenzylaicohol) (21). A few nitrostilbene compounds were synthesized by heating aldehyde 3 with 4-nitrophenylacetic acid in the presence of piperidine. 

We saw in Chapter 2 that metal ions may exert control over Arbuzov reactions. The Arbuzov reaction involves attack by a nucleophile upon the carbon atom of the alkyl group in an alkoxyphosphine (Fig. 4-45). 

Figure 4-45. The Arbuzov reaction. The final products may be derived from further reactions of those indicated.

In another related process, aryl ethers have been shown to undergo a facile cleavage reaction upon treatment with copper salts in the presence of an amine (Fig. 8-8). The driving force for the reaction is primarily the stabilisation of the phenoxide by co-ordination to the metal. Simple azo complexes have been shown to undergo these reactions under very mild conditions. The process is somewhat reminiscent of the Arbuzov reactions discussed in Chapter 4. The pyridine probably functions as both a ligand and as a base in this reaction. Reactions of this type are the basis of a useful conversion of a methoxy-substi-tuted dye, 8.6, to the corresponding phenol, 8.7, in the presence of copper(n) salts and ammonia. 

Methylindoline and 1,3-dimethylindoline are phosphorylated by phosphorus trichloride at 100-120°C (3 h). Here 5-dichlorophosphinylindoline 36a,b is obtained from approximately half the indoline, while the other half is converted into the corresponding hydrochloride (indoline is regenerated from it by treatment with alkali) [34, 35]. With phosphorus trichloride 1,2,3,3-tetramethylindoline forms dichlorophosphine 36c with a quantitative yield [36]. The acid chlorides 36 undergo hydrolysis (37), amidation (38), and alcoholysis (39). Phosphonites 38 and 39 are converted into thiophosphonates and phosphonates 40, 41 and enter into the Arbuzov reaction (42) [160] ... 

Indolines 41, 42 are dehydrogenated by anhydrous copper chloride in pyridine to the corresponding indoles 41a, 42a [33, 35] with yields of up to 40%. The production of 5-(diethoxyphosphoryl)indoline (43) and 5-(dicthoxyphosphoryl[indole (43a) from 5-bromoindoline (5-bromoindole) and trialkyl phosphites by the Arbuzov reaction, catalyzed by nickel chloride has been described [35] ... 

In [62] the synthesis of phosphorus-containing derivatives of 2-indolinone was reported. Thus, in 5-bromoisatin one phosphorus-containing fragment was introduced by the Abramov reaction with the formation of compound 66 [233], and a second was then introduced by the Arbuzov reaction (compound 67) ... 

The first publication on the use of phosphites for the synthesis of indoles phosphorylated in the side chain relates to 1957. The authors [64, 65] showed that gramine methiodide reacts with trialkyl phosphites by the Arbuzov reaction with the formation of 3-indolylphosphonates 69 ... 

By means of the Arbuzov reaction the authors of [71] synthesized 2-(alkoxyphosphonyl)methyl-3-ethoxycarbonyl-5-methoxyindoles 74 ... 

Phosphorylated indoles 151 were synthesized from 3-indolylphosphonite 4a by the Arbuzov reaction [52,151] ... 

Chemistry of Organophosphorus Compounds, dedicated to the 80th Anniversary of the Arbuzov Reaction [in Russian], Kazan (1985), p. 9. 

The precursors for these Horner-Wadsworth-Emmons reagents are /f-ketophosphomc acid dialkyl esters or a-(alkoxycarbonyl)phosphonic acid dialkyl esters. The first type of compound, i.e., a /3-ketophosphonic acid dialkyl ester is available, for example, by acylation of a metalated phosphonic acid ester (Figure 6.48). The second type of compound, i.e., an a-(alkoxycarbonyl)phosphonic acid dialkyl ester, can be conveniently obtained via the Arbuzov reaction (Figure 11.12). 

Fig. 11.12. The Arbuzov reaction, which provides the most important access to Horner-Wadsworth-Em mons reagents a sequence of two Sn2 reactions (cf. Figure 2.32).

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