[20763-19-3]  · C20H19OP  · Methoxymethylenetriphenylphosphorane  · (MW 306.36)

(Wittig reagent for carbonyl homologation; vinyl ether synthesis1-8)

Physical Data: deep red in solution; unstable at 25 °C.1-3

Solubility: sol organic solvents; decomposes in protic solvents, aldehydes, and ketones.1

Analysis of Reagent Purity: unstable at 25 °C, decomposing completely in <24 h producing PPh3 (70%; 31P NMR d -5.1 ppm) and other unidentified species.2 The ylide gives a 31P NMR signal at d 7.9 ppm (-90 °C) which is shifted upfield to 5.8 ppm (2JP-H = 48 Hz; 3JP-H = 12 Hz) at ambient temperatures.

Preparative Methods: by the deprotonation of methoxymethyl(triphenyl)phosphonium chloride (from Triphenylphosphine/Chloromethyl Methyl Ether)4a,b with a number of bases (alkyllithiums, alkoxides, dimsylsodium, amides).4-8

Handling, Storage, and Precautions: should be generated in situ at low temperature (e.g. -90 °C) under a nitrogen atmosphere and used immediately.

Vinyl Ether Homologs from Carbonyl Compounds.

The Wittig alkenation of carbonyl compounds has evolved to occupy a preeminent position in the hierarchy of carbon-carbon bond-forming reactions.1 With a-alkoxy substitution, Wittig reagents convert carbonyl derivatives into their vinyl ether homologs, and methoxymethyltriphenylphosphorane (1) has enjoyed widespread use in this regard since its generation in 1958 by Levine (eq 1).4a In a more extensive study of a-substituted Wittig reagents (e.g. Ph3PCHX, X = OH, Cl, OMe, SMe, and OAr), it was determined that Phenyllithium is superior to n-Butyllithium for the deprotonation of the phosphonium salt and that X = OC6H4Me-p gives better yields of vinyl ether products than (1) in several cases.4b,c Moreover, the thermal instability of (1) has resulted in the reagent being commonly used in stoichiometric excess (2-4 equiv).2-8

While butylidene products have been observed on numerous occasions when n-BuLi has been used to generate (1),4b,o,s this base continues to be used for its preparation. Recently, it was discovered that n-BuLi, but not t-Butyllithium, displaces PhLi from (Ph3PCH2OMe)Cl, ultimately producing Ph2(MeOCH2)PCHPr, which accounts for the observed butylidene products when employing this base.2 Therefore, either PhLi4a,b or t-BuLi4s is superior to n-BuLi for the generation of (1). Alternatively, amide bases (e.g. Lithium Diisopropylamide),6 alkoxides (e.g. Potassium t-Butoxide)7 and Sodium Methylsulfinylmethylide8 are effective bases for the preparation of (1). As an example, (1) prepared from the t-BuKO method has been used for the effective conversion of conjugated enones to 1,3-dienyl ethers which function as useful Diels-Alder substrates (eq 2).7d

Insufficient comparative data exist for a definitive judgement on the best method to generate (1). However, the fact that (1) decomposes at 25 °C suggests that its generation and reaction with carbonyl substrates should be conducted at low temperatures (i.e. -70 to -90 °C). A survey of representative procedures suggests that t-BuLi, which can be used to generate (1) at -90 °C, may eliminate the need for using a large excess of (1) because this method avoids its exposure to higher temperatures which result in its partial decomposition.2 Moreover, even relatively hindered ketones are converted to the corresponding oxaphosphetanes at this temperature. Aliphatic carbonyl derivatives are likely to form these intermediates irreversibly, whereas their conjugated counterparts may well undergo complete or partial equilibration, ultimately giving rise to (E)-alkenes as the major vinyl ether products.1a With slow warming to 25 °C, the decomposition of the intermediate oxaphosphetane produces the corresponding vinyl ether very cleanly, at least in the systems examined (eq 3).2 The excellent yields which have been achieved for many substrates add support to this generality.

Both aldehydes and ketones undergo reaction with (1), leading to vinyl ethers. While the product stereochemistry is not always reported, sufficient data are currently available for representative systems to indicate that unsymmetrical carbonyl compounds normally lead to (Z/E) product mixtures under Li+-catalyzed conditions. A recent study employing the Levine-Wittig-Schlosser method (PhLi, Et2O) provides useful stereochemical information for aromatic aldehydes which give roughly equal amounts of both cis and trans vinyl ethers under these conditions (e.g. PhCHO, 40:60; p-MeOC6H4CHO, 54:46; o-CF3C6H4CHO, 45:55).5g With aliphatic derivatives, as mentioned above, kinetic control is operative and the process is more (Z) selective, as can be observed below for octanal5g and pentanoyltrimethylsilane2 where the silyl group reverses the stereochemical relationship of the alkyl group with respect to the methoxy group in the vinyl ether products (2) and (3).

Numerous synthetic applications have been found for (1) and several representative examples are shown in (4)-(7), which include the base and solvent employed for the generation of (1) as well as the yield and isomeric (Z/E) distribution of the vinyl ether products derived from their carbonyl precursors.4d,4s,7c,7e

It can be noted from the above that the (E) isomer is isolated as the major product in each case, a result which may be attributable to oxaphosphetane equilibration either through its formation (i.e. highly conjugated systems) or through the participation of proximate functionality (e.g. alkoxy).1a In certain cases, these substrate features can result in a highly (E)-selective process, e.g. (8) and (9).6g

Homologation of Carbonyl Compounds.

The vast majority of the synthetic applications of (1) involve the homologation of carbonyl compounds. Often the intermediate vinyl ether is converted directly to the aldehyde (or acetal) which itself is a required intermediate for the total synthesis of a target molecule which can be a natural product (e.g. (+)-pleuromutilin (eq 4))6e or compounds of theoretical interest, such as 2a,8a,8b,8c-tetrahydropentaleno[6,1,2-aji]azulene (eq 5).4p The intermediate vinyl ethers can also be oxidized to provide a,b-unsaturated aldehydes as an important extension of the methodology (eq 6).5i

The hydrolysis of the vinyl ethers normally occurs smoothly with dilute aqueous acid at 25 °C, mild conditions which make these derivatives especially attractive precursors to the desired aldehydes, particularly in systems where the aldehyde must be generated selectively in the presence of other protected carbonyl functionalities (eq 7).5f For certain applications, other alkoxymethylene ylides (Ph3PCHOR, R = (CH2)2SiMe3,7d THP,5j or Ph2P(O)CHLi(OMe),5k or Ph2PCHLi(OMe))9 provide alternative or superior choices to (1) for the alkenation process or other subsequent conversions. However, (1) is a proven reagent for the effective homologation of aldehydes, both saturated and unsaturated, as well as their ketone counterparts.

1. (a) Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863. (b) Murphy, P. J.; Brennen, J. CSR 1988, 17, 1. (c) Maryanoff, B. E.; Reitz, A. B. PS 1986, 27, 167. (d) Bestmann, H. J.; Vostrowsky, O. Top. Curr. Chem. 1983, 109, 85. (e) Schlosser, M. Top. Stereochem. 1970, 5, 13. (f) Maercker, A. OR 1965, 14, 270.
2. Anderson, C. L.; Soderquist, J. A.; Kabalka, G. W. TL 1992, 33, 6915.
3. Yamamoto, Y.; Kanda, Z. BCJ 1980, 53, 3436.
4. Alkyllithiums: (a) Levine, S. G. JACS 1958, 80, 6150. (b) Wittig, G.; Schlosser, M. CB 1961, 94, 1373. (c) Wittig, G.; Böll, W.; Krück, K.-H. CB 1962, 95, 2514. (d) Brewer, J. D.; Elix, J. A. AJC 1972, 25, 545. (e) Schlude, H. T 1975, 31, 89. (f) Field, D. J.; Jones, D. W.; Kneen, G. JCS(P1) 1978, 1050. (g) Bishop, R.; Parker, W.; Stevenson, J. R. JCS(P1) 1981, 565. (h) Oppolzer, W.; Grayson, J. I.; Wegmann, H.; Urrea, M. T 1983, 39, 3695. (i) Johnson, W. S.; Chen, Y-Q.; Kellogg, M. S. JACS 1983, 105, 6653. (j) Gibson, K. J.; d'Alarcao, M.; Leonard, N. J. JOC 1985, 50, 2462. (k) Brillon, D. SC 1986, 16, 291. (l) Shizuri, Y.; Okuno, Y.; Shigemori, H.; Yamamura, S. TL 1987, 28, 6661. (m) Johnson, W. S.; Telfer, S. J.; Cheng, S.; Schubert, U. JACS 1987, 109, 2517. (n) Nakamura, N.; Fujisaka, T.; Nojima, M.; Kusabayashi, S.; McCullough, K. J. JACS 1989, 111, 1799. (o) Pettit, G. R.; Green, B.; Dunn, G. L.; Sunder-Plassmann, P. JOC 1970, 35, 1385. (p) Trost, B. M.; Herde, W. B. JACS 1976, 98, 1988. (q) Weber, G. F.; Hall, S. S. JOC 1979, 44, 364. (r) Kozikowski, A. P.; Ishida, H.; Chen, Y-Y. JOC 1980, 45, 3350. (s) Trost, B. M.; Verhoeven, T. R. JACS 1980, 102, 4743. (t) Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S. JOC 1981, 46, 3856. (u) Miyashita, M.; Makino, N.; Singh, M.; Yoshikoshi, A. JCS(P1) 1982, 1303. (v) Kumar, K.; Wang, S-S.; Sukenik, C. N. JOC 1984, 49, 665. (x) Abarca, B.; Ballestros, R.; Jones, G. J. JHC 1984, 21, 1585. (y) Thompson, A.; Canella, K. A.; Lever, J. R.; Miura, K.; Posner, G. H.; Seliger, H. H. JACS 1986, 108, 4498. (z) Beautement, K.; Clough, J. M. TL 1987, 28, 475.
5. Alkyllithiums (continued): (a) Nagaoka, H.; Kobayashi, K.; Matsui, T.; Yamada, Y. TL 1987, 28, 2021. (b) Parkes, K. E. B.; Pattenden, G. JCS(P1) 1988, 1119. (c) Soderquist, J. A.; Anderson, C. L. TL 1988, 29, 2425. (d) Rigby, J. H.; Kierkus, P. C. JACS 1989, 111, 4125. (e) Nakamura, N.; Fujisaka, T.; Nojima, M.; Kusabayashi, S.; McCullough, K. J. JACS 1989, 111, 1799. (f) Taber, D. F.; Mack, J. F.; Rheingold, A. L.; Geib, S. J. JOC 1989, 54, 3831. (g) Griesbaum, K.; Kim, W.-S.; Nakamura, N.; Mori, M.; Nojima, M.; Kusabayashi, S. JOC 1990, 55, 6153. (h) Schreck, V. A.; Serelis, A. K.; Solomon, D. H. AJC 1989, 42, 375. (i) Takayama, H.; Koike, T.; Aimi, N.; Sakai, S.-I. JOC 1992, 57, 2173. (j) Boger, D. L.; Palanki, M. S. S. JACS 1992, 114, 9318. (k) Srikrishna, A.; Krishnan, K. JCS(P1) 1993, 667. (l) Harrison, P. J. TL 1989, 30, 7125.
6. Amides: (a) Mandai, T.; Osaka, K.; Wada, T.; Kawada, M.; Otera, J. TL 1983, 24, 1171. (b) Brillon, D. SC 1986, 16, 291. (c) Evans, E. H.; Hewson, A. T.; March, L. A.; Nowell, I. W.; Wadsworth, A. H. JCS(P1) 1987, 137. (c) Paquette, L. A.; Schaefer, A. G.; Springer, J. P. T 1987, 43, 5567. (d) Larock, R. C.; Hsu, M. H.; Narayanan, K. T 1987, 43, 2891. (e) Paquette, L. A.; Bulman-Page, P. C.; Pansegrau, P. D.; Wiedeman, P. E. JOC 1988, 53, 1450. (f) Majetich, G.; Defwauw, J. T 1988, 44, 3833. (g) Gallucci, J. C.; Ha, D.-C.; Hart, D. J. T 1989, 45, 1283.
7. Alkoxides: (a) Ireland, R. E.; Schiess, P. W. JOC 1963, 28, 6. (b) Casagrande, C.; Canonica, L.; Severini-Ricca, G. JCS(P1) 1975, 1652. (c) Schow, S. R.; McMorris, T. C. JOC 1979, 44, 3760. (d) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. JACS 1982, 104, 5719. (e) Newton, R. F.; Wadsworth, A. H. JCS(P1) 1982, 823. (f) Hamada, Y.; Kawai, A.; Shioiri, T. TL 1984, 25, 5409. (g) Dharanipragada, R.; Fodor, G. JCS(P1) 1986, 545. (h) Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T. TL 1988, 29, 6331. (i) Hutchings, M. G.; Chippendale, A. M.; Ferguson, I. T 1988, 44, 3727. (j) Mehta, G.; Reddy, K. R. TL 1988, 29, 3607. (k) Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T. TL 1984, 25, 5409.
8. Dimsyl: (a) Hayakawa, Y.; Yokoyama, K.; Noyori, R. JACS 1978, 100, 1799. (b) Danishefsky, S.; Harvey, D. F. JACS 1985, 107, 6647.
9. Burke, S. D.; Cobb, J. E.; Takeuchi, K. JOC 1990, 55, 2138.

John A. Soderquist & Jorge Ramos-Veguilla

University of Puerto Rico, Rio Piedras, Puerto Rico

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