Michaelis-Arbuzov Synthesis

Also known as Michaelis–Arbuzov. Synthesis of phosphonates 8 by heating of alkyl halides 5 with trialkyl phosphites. Ni catalyzed conversion of aryl halides 3 to aryl phosphonates 4 by reaction with phosphites 1, via phosphite-Ni complex 2.

The so-called Michaelis-Arbuzov reaction is frequently quoted in literature regarding phosphites.^56,295,296 The reaction was first described in 1898.^300–302 It outlines transitional steps of reaction of phosphite with either HCl or ZnCl₂ to obtain phosphonate and alkyl chloride:

Tertiary phosphine oxides are also obtained by the Michaelis–Arbuzov reaction, which involves the reaction of phosphinic acid esters with alkyl halides to give intermediate phosphonium salts, followed by rapid decomposition (Scheme 18) <55JA3526>.

Scheme 18.

An optically active phosphine oxide has been prepared by the Michaelis–Arbuzov reaction of asymmetric methyl ethylphenylphosphinite with methyl iodide, which proceeds with retention of configuration at phosphorus (Equation (114)) <75CC382>.

(114)

The oxazaphospholidine (41) undergoes a Michaelis–Arbuzov reaction to give the phosphine oxide (46). This reaction was completely stereospecific with retention of configuration 〈89CC805〉. Reaction of (41) with borane-THF gave a stable complex (47) which has been used as a catalyst in enantioselective borane reductions of ketones 〈92CC287〉. Base-catalyzed methanolysis of oxazaphospholidine oxides and sulfides (32) and (33) gave the corresponding ring-opened products (48) resulting from PO bond fission. This reaction proceeds with inversion of configuration at phosphorus 〈81TL477〉. Similarly, (32) and (33) react with Grignard reagents to give (49;R = alkyl, aryl) in almost quantitative yield 〈81TL571〉 (Scheme 1).

Scheme 1.

Finally, we note an important direct synthesis of β-ketophosphonates from aldehydes using the Gilbert–Seyferth reagent (454). Thus, Roskamp and coworker disclose that aldehydes are converted into HWE olefination ready phosphonates by treatment with dimethyl diazomethyl-phosphonate (454) in the presence of stannous chloride.²⁷¹ The illustrated synthesis of an advanced norhalichondrin B fragment (455) by Phillips and coworkers exemplifies the method (equation 96).²⁷² An enantioselective variant of the Roskamp phosphonate synthesis was recently reported.²⁷³

The oxazaphospholidine 72 can undergo an enantiospecific Michaelis–Arbuzov reaction with activated electrophiles, leading to phosphinamide 71 with complete retention of configuration at the phosphorus atom (Scheme 3) <1989CC805, 1997T11577>. Under the same reaction conditions, E-crotyl bromide led to the corresponding phosphinamide with retention of the double bound configuration. It is interesting to note that a Perkow reaction is observed with α-chloroacetophenone, leading to compounds 73 and 74 in a 7/3 diastereomeric ratio. The mechanism of this transformation has been discussed (Scheme 3).

Scheme 3.

The ring expansion of diazaphospholidine oxide 75 involves a stereospecific migration of phosphorus atom from N to a Csp² center (Equation 1). The overall retention of configuration at the phosphorus center has been explained by a sequential intramolecular apical addition, Berry pseudo-rotation and apical elimination pathway <1999AGE1479>. A P–O to P–C stereospecific rearrangement occurs when only 2 equiv of lithium diisopropylamide (LDA) are used for the deprotonation step, leading to diazaphospholidine oxide 78 from compound 77 (Equation 2) <1999EJO1099, 1998CEJ1061>.

(1)

(2)

The ring opening of various phosphinamides occurs with inversion of the phosphorus configuration <1996TL39, 1996TL2853, 1998JP11027, 2005TL8677>, leading to interesting ligands such as 81 or 82 (Scheme 4). The chlorodiazaphosphole oxide 83 leads to phosphoramide 84 when treated with pinane 2,3-diol in the presence of NaH <2004TA47>. The same reaction with diamines has been reported <2001TA685, 2004TA1881>. A similar reactivity is observed with chlorodiazaphospholidines <2005ASC61, 2002ASC868>. Among various oxidation reactions described at the phosphorus center of diazaphospholidines <2002TL4025>, the sterospecific reaction of compound 85 with phenylazide leading to iminophosphorane 86 is noteworthy <1999JA5807>.

Scheme 4.

Title compounds 186 (Figure 5) were usually obtained by Michaelis–Arbuzov reaction of the carbamimidic chlorides with trimethyl phosphite (P(OMe)₃). Another method for preparation of 187 consists in the attack of alkali metal organoarsenides at N,N′-dialkyl carbodiimides followed by hydrolysis or alkylation of the intermediary formed (lithioamidino)arsines <1995COFGT(6)639>.

Figure 5.

Recently, the phospha(III)guanidine compounds of the general formula Ph₂PC(NR) (NHR);R = Prⁱ, cyclohexyl) have been prepared in good yields as described in Scheme 55. Lithium diphenylphosphide obtained by treatment of Ph₂PH with BuLi is allowed to react with suitable carbodiimide giving the corresponding lithium phospha(III)guanidinate. Quenching the reaction with triethylamine hydrochloride yields the neutral phospha(III)guanidines 188 <2002CC2794, 2003JCS(D)2573>.

Scheme 55.

Unexpectedly, two products were obtained during the reaction of the methylene bisphosphonate salts, [((RO)₂PO)₂CH]⁻M⁺ (M = Li, Na, K), with CF₃SCl. The expected sulfenyl derivative is obtained in a mixture with chloro(trifluoromethylthio)methylene bisphosphonate, which results from a chlorination process (Equation (22)). The use of aluminum trichloride reduces the proportion of chlorinated by-product (16%) with respect to the sulfonylated product (74%) <85JCS(P1)1935>. CClF₂SCl and CCl₂FSCl have also been used in analogous reactions.

(22)

The asymmetric synthesis of P-stereogenic phosphine oxides, involving a Michaelis–Arbuzov process, was also achieved starting from the cyclic phosphonite 64, prepared from the diol (XX) derived from tartaric acid.⁶⁴ After reaction with benzyl halides, the phosphonite 64 afforded the corresponding phosphinate by P–O bond cleavage. The diastereoselectivities ranged from 23 to 100% depending on the stereoelectronic nature of the benzyl halide used. The second P–O bond cleavage was then performed by addition of a Grignard reagent affording the corresponding tertiary phosphine oxides in good yield but with only low or moderate enantiomeric excesses (<45% ee).

The use of the diol (XXI), also derived from tartaric acid, was reported by Hoppe and Eggert for the preparation of enantiomerically pure cyclic H-phosphite 65, which is useful for the synthesis of α-aminophosphonic acid derivatives 68 and 71 (Scheme 16).⁶⁵ The BF₃-catalyzed addition of 65 to dihydrothiazole 66 afforded the phosphonates 67 in a diastereomeric ratio 2:1 favoring the (R)-diastereomer. After separation, the hydrolysis of 67 gave rise to enantiopure α-aminophosphonic acid 68 (Scheme 16(a)).

Scheme 16. Stereoselective synthesis of α-amino phosphonic acids using tartaric acid (XVIII).

In the late 1980s, Giordano's group published the first asymmetric synthesis of fosfomycin 74 (Scheme 17).⁶⁷ The first step is based on the use of various tartaric acid derivatives (XVIII) as chiral auxiliaries for the condensation with the (Z)-1-propenyl phosphonic dichloride 72. After hydrolysis, the phosphono monoester 73 was obtained in 70% yield. After epoxydation via a bromhydrin intermediate, which was purified by crystallization, the enantiopure (1R,2S)-1,2-epoxypropylphosphonic acid (fosfomycin) 74 was obtained in 35% yield after hydrolysis (Scheme 17).

Scheme 17. Stereoselective synthesis of fosfomycin 74 using tartaric acid (XVIII).