Dimethyl Methylphosphonate1

[756-79-6]  · C3H9O3P  · Dimethyl Methylphosphonate  · (MW 124.09)

(treatment with BuLi gives a carbanion that reacts with aldehydes,1 ketones,1,2 esters,1,3 acid chlorides,4 enol lactones5 and other electrophiles6-11)

Alternate Names: dimethyl methylphosphate; dimethyl methanephosphate.

Physical Data: bp 180-181 °C; d 1.145 g cm-3.

Solubility: sol common organic solvents.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: flammable; irritant; stench. Store under N2.

Reactions with Aldehydes and Ketones.

(MeO)2P(O)Me in THF (or less commonly Et2O, DME, DMF, or MeCN) is deprotonated by n-Butyllithium1 or Lithium Diisopropylamide,2,11 at -78 °C, to give (MeO)2P(O)CH2Li. Unlike the carbanions of phosphonate esters which possess a charge-stabilizing electron withdrawing group (see discussion on Triethyl Phosphonoacetate and Trimethyl Phosphonoacetate), (MeO)2P(O)CH2Li does not react directly with aldehydes or ketones to give an alkene.1 Rather, the reaction gives a b-hydroxyalkylphosphonate which has a low efficiency of cycloelimination (eq 1).1a,12,13 Cycloelimination, and hence alkene formation, is induced by treating the b-hydroxyalkylphosphonate with Cesium Fluoride in DMF (eq 1).12 Thioalkylated acetophenones react directly with (MeO)2P(O)CH2Li to give 2-aryl-1-thioalkyl-2-propenes (eq 2).14 a-Lithio derivatives of alkylphosphonothioates [(MeO)2P(S)Me] react directly with aldehydes and ketones to give 1,1-disubstituted, trisubstituted, and tetrasubstituted alkenes.1a,15 Ligand exchanged derivatives of (MeO)2P(O)Me such as alkylphosphonic diamides, alkylphosphonothioates, alkyldiphenylphosphine oxides, and alkyldiphenylphosphinothioic amides also form alkenes directly.12

b-Hydroxyalkylphosphonates are precursors to copper b-metalated alkylphosphonates (eq 3).16 These versatile d2 reagents react in excellent yields with a range of electrophiles such as acyl chlorides, aldehydes, enones, alkynic esters, allylic and alkynyl halides, trialkyltin halides and nitroalkenes (eq 3).16

Reactions with Esters.

The reaction of (MeO)2P(O)CH2Li with an ester3a,b (eq 4)3b or a lactone3c gives a b-ketophosphonate. The condensation has been carried out in the presence of a number of functional groups.3a For example, (MeO)2P(O)CH2Li reacts preferentially with a methyl ester in the presence of a phenylethyl ester (eq 5, entry 1)17a and a Weinreb amide in the presence of a methyl ester (eq 5, entry 2).17b Some problems were encountered with b-elimination and retro-aldol reactions.3a,17 The condensation of an ester or equivalent with (MeO)2P(O)CH2Li has also been carried out in the presence of an acid3a,b,18 (eq 5, entry 318 and 43a), ketone (eq 6),19 and an acetal.3c,20 An acid chloride reacts with (MeO)2P(O)CH2Li to give a b-ketophosphonate.4 Anhydrous Magnesium Bromide promotes the preferential reaction of (MeO)2P(O)CH2Li with an acid chloride in the presence of an ester (eq 7).4 b-Ketophosphonates have also been prepared by oxidation of a b-hydroxyphosphonate obtained from the reaction of (MeO)2P(O)CH2Li with an aldehyde.13

The b-ketophosphonates are versatile synthetic intermediates and react with aldehydes to give a,b-unsaturated esters under Roush-Masamune18,21 and other basic conditions13,18,22 (also see discussion on Horner-Emmons reactions of Triethyl Phosphonoacetate and Trimethyl Phosphonoacetate). b-Ketophosphonates also react intramolecularly with ketones to give cyclohexenones and cyclopentenones19,20,23 (eq 619). In some cases the ketone is protected as an acetal prior to the preparation of the b-ketophosphonate.20,23 Higher esters of phosphonic acids are prepared by a-alkylation of the Sodium Hydride-generated carbanion of b-ketophosphonates.20a,24 The corresponding dianion, generated by the sequential addition of NaH and BuLi to a b-ketophosphonate, undergoes g-alkylation.20a,25

Reactions with Enol Lactones.

An enol lactone reacts with (MeO)2P(O)CH2Li, at low temperatures, to give an a,b-unsaturated ketone5,10 (eq 85c). The reaction does not proceed with a-unsubstituted five-membered endocyclic enol lactones.20a Perhydroazulenones have also been prepared from a lactam and (MeO)2P(O)CH2Li in a related reaction (eq 9).26 The analogous Wittig reaction of enol lactones proceeds with nonstabilized ylides5a,27 but not readily with stabilized ylides.27,28

Reactions with 1,3-Diketones.

The reaction of 2,2-disubstituted 1,3-cyclohexanediones with (MeO)2P(O)CH2Li in the presence of Chlorotrimethylsilane gives 3-substituted 2-cyclohexanones in good yields (22-93%) (eq 10).2 The reaction proceeds by a retro-aldol cleavage followed by a Horner-Emmons reaction.2 The use of BuLi rather than LDA to generate (MeO)2P(O)CH2Li results in reduced yields.2

Other Reactions.

Dimethyl (alkylthio)methylphosphonates, (MeO)2P(O)CH2SR, are prepared by sulfenylation of (MeO)2P(O)CH2Li with alkyl and aryl benzenethiosulfonates.6 Treatment of (MeO)2P(O)CH2Li with Copper(I) Iodide gives the corresponding 1-copper derivative, (MeO)2P(O)CH2Cu. Dimethyl 1-(trimethylsilyl)- and 1-(trimethylstannyl) methanephosphonates are prepared by subsequent reaction of (MeO)2P(O)CH2Cu with Me3SiCl (eq 11, entry 1)7a,c and Chlorotrimethylstannane (eq 11, entry 2),7a respectively. The reaction of (MeO)2P(O)CH2Cu with O-alkyl carbonochloridothioates gives a phosphorylthiocarbonyl compound (eq 11, entry 3), a precursor to a-unsubstituted thiono esters.7b,d,e

Treatment of (MeO)2P(O)Me with Triphenylphosphine Dichloride gives a single ester linkage replacement by a chloride (eq 12, entry 1).8a An analogous reaction with Phosphorus(V) Chloride gives the dichloride (eq 12, entry 2).8b (MeO)2P(O)CH2Li N-methylates purines,9 is alkylated by an alkyl iodide,10 and also undergoes a Michael addition with 4-chloro-b-nitrostyrenes.11

1. (a) Corey, E. J.; Kwiatkowski, G. T. JACS 1966, 88, 5654. (b) Wadsworth, W. S., Jr. OR 1977, 25, 73. (c) Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863.
2. (a) Yamamoto, Y.; Furuta, T. JOC 1990, 55, 3971. (b) Furuta, T.; Oshima, E.; Yamamoto, Y. HC 1992, 3, 471.
3. (a) Karanewsky, D. S.; Malley, M. F.; Gougoutas, J. Z. JOC 1991, 56, 3744 and references therein. (b) Roush, W. R.; Murphy, M. JOC 1992, 57, 6622. (c) House, H. O.; Haack, J. L.; McDaniel, W. C.; Vanderveer, D. JOC 1983, 48, 1643.
4. Burke, S. D.; Piscopio, A. D.; Buchanan, J. L. TL 1988, 29, 2757.
5. (a) Henrick, C. A.; Böhme, E.; Edwards, J. A.; Fried, J. H. JACS 1968, 90, 5926. (b) Aristoff, P. A. JOC 1985, 50, 1765. (c) Desmaele, D.; Pain, G.; d'Angelo, J. TA 1992, 3, 863. (d) Tanyeli, C.; Tarhan, O. SC 1989, 19, 2749.
6. Smith, J. G.; Finck, M. S.; Kontoleon, B. D.; Trecoske, M. A.; Giordano, L. A.; Renzulli, L. A. JOC 1983, 48, 1110.
7. (a) Savignac, P.; Mathey, F. S 1982, 725. (b) Hartke, K.; Kunze, O.; Hoederath, W. S 1985, 960. (c) Aboujaoude, E. E.; Lietje, S.; Collignon, N. S 1986, 934. (d) Hartke, K. PS 1991, 58, 223. (e) Metzner, P. S 1992, 1185.
8. (a) Quast, H.; Heuschmann, M.; Abdel-Rahman, M. O. S 1974, 490. (b) Ylagan, L.; Benjamin, A.; Gupta, A.; Engel, R. SC 1988, 18, 285.
9. Yamauchi, K.; Hayashi, M.; Kinoshita, M. JOC 1975, 40, 385.
10. Aristoff, P. A.; Johnson, P. D.; Harrison, A. W. JACS 1985, 107, 7967.
11. Hall, R. G. S 1989, 442.
12. Kawashima, T.; Ishii, T.; Inamoto, N. CL 1983, 1375.
13. Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. JOC 1979, 44, 4011.
14. Fox, M. A.; Triebel, C. A.; Rogers, R. SC 1982, 12, 1055.
15. Hoffmann, F. W.; Wadsworth, D. H.; Weiss, H. D. JACS 1958, 80, 3945.
16. Retherford, C.; Chou, T.-S.; Schelkun, R. M.; Knochel, P. TL 1990, 31, 1833.
17. (a) Heathcock, C. H.; Hadley, C. R.; Rosen, T.; Theisen, P. D.; Hecker, S. J. JMC 1987, 30, 1858. (b) Theisen, P. D.; Heathcock, C. H. JOC 1988, 53, 2374.
18. Blackwell, C. M.; Davidson, A. H.; Launchbury, S. B.; Lewis, C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.; Tipping, A. S.; Todd, R. S. JOC 1992, 57, 1935.
19. Halterman, R. L.; Vollhardt, K. P. C. OM 1988, 7, 883.
20. (a) Clark, R. D.; Kozar, L. G.; Heathcock, C. H. SC 1975, 5, 1. (b) Roush, W. R.; Coe, J. W. TL 1987, 28, 931. (c) Rao, Y. K.; Nagarajan, M. JOC 1989, 54, 5678. (d) Kanemasa, S.; Otsuka, T.; Doi, K.; Tsuge, O.; Wada, E. S 1990, 1167.
21. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. TL 1984, 25, 2183.
22. Rathke, M. W.; Nowak, M. JOC 1985, 50, 2624.
23. Becker, K. B. T 1980, 36, 1717.
24. Clark, R. D.; Kozar, L. G.; Heathcock, C. H. S 1975, 635.
25. (a) Grieco, P. A.; Pogonowski, C. S. S 1973, 425. (b) Grieco, P. A.; Finkelhor, R. S. JOC 1973, 38, 2909.
26. Roberts, M. R.; Schlessinger, R. H. JACS 1979, 101, 7626.
27. Murphy, P. J.; Brennan, J. CSR 1988, 17, 1.
28. Abell, A. D.; Massy-Westropp, R. A. AJC 1982, 35, 2077.

Andrew Abell

University of Canterbury, Christchurch, New Zealand

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