(Ethoxycarbonylmethylene)triphenylphosphorane1

Ph3P=CHCO2Et

[1099-45-2]  · C22H21O2P  · (Ethoxycarbonylmethylene)triphenylphosphorane  · (MW 348.38)

(stabilized phosphorane reagent useful for Wittig alkenation reactions to give a,b-unsaturated ethyl esters on reaction with carbonyl compounds;1 heterocyclic ring construction;2-4 synthesis of cyclopropanes from epoxides5)

Physical Data: mp 128-130 °C.

Solubility: sol EtOH (42 g 100 mL-1), THF (13 g 100 mL-1), and CHCl3 (29 g 100 mL-1); insol water (<0.5 g 100 mL-1).

Form Supplied in: white crystalline powder.

Handling, Storage, and Precautions: no special handling or storage requirements are necessary. The use of carefully dried reagents leads to a lower rate of Wittig alkenation reaction.6 The compound is stable in water (>3 h), and >99% stable in 0.5 N NaOH in MeOH-water (1:1) for at least 3 h.

Weakly Basic Phosphorus Ylide.

This phosphorane is readily prepared by deprotonation of (Ethoxycarbonylmethyl)triphenylphosphonium Bromide (pKa 8.95-9.2), typically with Sodium Ethoxide or Sodium Hydroxide.7 Deprotonation of the phosphonium bromide produces a phosphorane in which the negative charge on the a-carbon is stabilized by dp-pp bonding to the phosphorus and also by the adjacent ethoxycarbonyl group. Additionally, NMR studies have shown that this reagent exists as a ca. 3:1 mixture of cis:trans ylide/enolates as shown in eq 1, with a barrier to rotation estimated at ca. 10 kcal mol-1 for the methyl ester.6,8 The high proportion of negative charge on the oxygen is reflected in O-ethylation with Triethyloxonium Tetrafluoroborate at -78 °C to give a 3:1 mixture of cis:trans ethyl vinyl ethers.6 The presence of small amounts of water or other proton sources facilitate the reaction of the phosphorane, presumably by reversibly protonating the a-carbon and lowering the barrier to rotation, allowing for more reactive ylide forms with single bond character between the a- and b-carbons (viz. cis- and trans-ylide structures).6 For this reason, it is counterproductive to be overly concerned with removing traces of moisture in standard reactions involving this phosphorane.

Wittig Alkenation Reactions.

This reagent is among those typically referred to as stabilized Wittig reagents, because of the extra negative charge stabilization by the ester functionality (see also (Methoxycarbonylmethylene)triphenylphosphorane). As such, its basicity and reactivity is moderated relative to the nonstabilized alkylidenephosphoranes. If more reactive reagents are required, phosphonates such as (EtO)2P(O)CH2CO2Et can be employed in the Horner-Wadsworth-Emmons (HWE) alkenation procedure.1 The phosphonate reagents have the added advantage that the phosphates obtained as side-products are easier to remove than triphenylphosphine oxide, the phosphorus-containing product of the phosphorane reactions. Although intermediates have not been observed in reactions of stabilized phosphoranes by spectroscopic techniques, the reaction mechanism would be expected to include a four-membered oxaphosphetane immediately prior to elimination to the alkene and triphenylphosphine oxide.1a

(Ethoxycarbonylmethylene)triphenylphosphorane reacts with the carbonyl groups of aldehydes,9-26 ketones,27-34 ketenes,35-37 anhydrides,39 imides,40 and certain amides41a,42 and esters4,41 to insert the a,b-unsaturated ethyl ester (ethyl acrylate) functionality. The reaction has wide generality and has been extensively employed, especially en route to intermediates for further synthetic manipulation. Where the newly established double bond has stereochemistry, such as in reactions with aldehydes and unsymmetrical ketones, it is generally trans (E) in nature, although the (E:Z) ratio is influenced by a variety of factors, such as the nature of the aldehyde, solvent, and additives.

Reactions with Aldehydes.

There are numerous instances in which this reaction has been carried out in organic synthesis, and only a few representative examples are given here. In the synthesis of rapamycin, the aldehyde group was converted to the expected (E) ester, without significant epimerization or elimination of the a-mesyloxy or b-benzyloxy substituents, respectively (eq 2).10a The relatively low basicity of the phosphorane allows for mild transformations of this type, without affecting base-sensitive groups.

There are occasions when these mild conditions are preferred to the more basic conditions attendant to the HWE phosphonate reagent (EtO)2P(O)CHCO2Et- Na+. For example, in the preparation of a substrate for a quinolizine synthesis, the phosphorane produced the desired acrylate ester, whereas use of the HWE reagent resulted in considerable amounts of premature ring closure to give a piperidine side product (eq 3).10b

The alkenation reaction can be carried out by the in-situ generation of the phosphorane reagent by the use of ethylene oxide (eq 4).11 The bromide counterion of the phosphonium salt opens the ethylene oxide, and the alkoxide which then forms deprotonates the a-carbon.

When the phenyl ligands on the phosphorus atom are replaced with alkyl groups, the relative proportion of (E) isomer increases.12 For example, in reactions with benzaldehyde under the same conditions, Ph3P=CHCO2Et and Bu3P=CHCO2Et gave (E:Z) ratios of 89:11 and 95:5, respectively.12 The placement of ferrocenyl ligands on the phosphorus also resulted in the same degree of (E) stereoselectivity,13 but 2-furyl ligands produced more of the (Z) isomer in ethanol.14 Rate studies on phosphoranes of type (p-XC6H4)3P=CHCO2Et gave ρ values in the area of +2.5-3.0.15 Bridged phosphorane species in which two of the phenyl ligands are attached via a divinyl spacer react slowly to give more (Z) isomer (24%) than use of the standard reagent (11%).16

Greater (E) selectivity is observed when the a-carbon is alkylated, such as in reactions of Ph3P=C(Me)CO2Et.1,17 However, a-halogenation of the phosphorane and its use to prepare vinyl halides is less (E) selective (eq 5).18

Generally, the formation of the (E) isomer is favored by the use of aprotic solvents in the absence of lithium salts,1a and the influence of solvent can often be remarkable. For example, reaction of the phosphorane with a sugar-derived aldehyde gave the corresponding acrylates with (E:Z) mixtures that varied from 86:14 (DMF) to 8:92 (MeOH; eq 6).19

The high amounts of the (Z)-acrylate observed in eq 6 under certain conditions is characteristic of the reactions of a-alkoxy aldehydes, particularly in the presence of an additional b-alkoxy group and in an anhydrous alcoholic solvent.1a For example, treatment of isopropylideneglyceraldehyde with the phosphorane reagent in methanol at 0 °C20 or 25 °C21 gave the expected acrylates with an (E:Z) ratio of ca. 10:90. This effect has been observed repeatedly in reactions with carbohydrate-based aldehydes, as they bear multiple oxygenated sites. In the reaction of a fucose-derived hemiacetal (reacting in the aldehyde form) a ca. 1:2 mixture of (E:Z) isomers formed (eq 7),22 whereas reaction of 2-deoxyribose derivatives (lacking an a-alkoxy group) gave solely (E) acrylates.23

The reaction of sugar-derived hemiacetals with stabilized phosphoranes has provided an important starting point for the synthesis of key natural products such as the leukotrienes.1c Additionally, the hydroxyl group that remains from the hemiacetal can attack the b-carbon of the acrylate in a Michael fashion to form C-glycosides, useful as important synthetic intermediates, such as in the reaction of diisopropylideneallofuranose shown in eq 8.24 The alkene product of the Wittig reaction can be isolated directly in some cases or the Michael closure can be so fast that only the C-glycoside products are detected. In certain circumstances, diene products formed by further elimination reactions are observed.25 The nature of the ester group and the presence of free or masked hydroxyls on the sugar substrate are important determinants in whether cyclized or open chain products are isolated in these systems.26

Reactions with Ketones.

Ketones can be unreactive partners in condensations with stabilized phosphoranes. These reactions can be enhanced by reaction at 9 kbar.27 For example, alkenation with benzophenone gave an 82% yield of product at 50 °C after 35 h, whereas refluxing in xylene after 1 d at 1 bar resulted in only 10% product. In addition, the reaction with ketones can be facilitated by prolonged heating or mixing the two reactants together at high temperature without the use of solvent.28 In other cases, the addition of small amounts of an acid catalyst (e.g. benzoic acid) increases the yield of reactions with hindered carbonyls (eq 9).29 The acid may be acting by increasing the electrophilicity of the carbonyl or by enhancing the rate of exchange of the various ylide forms as discussed above.

Keto sugars typically react very nicely with the phosphorane, often producing unexpected stereochemical outcomes. For example, the choice of a silyloxy or benzyl ether protecting group led to dramatically different mixtures of acrylates as shown in eq 10.30 Alkoxy or hydroxy substituted ketones may actually react faster than their deoxy counterparts.31

The use of a chiral carboxylic acid in reaction of the phosphorane and 4-methylcyclohexanone resulted in the expected ethyl acrylate with an enantiomeric excess (ee) of <10%.32 However, the presence of a chiral host in the same sequence afforded the expected acrylate with an ee of 42% (eq 11).33 There are only a few reported enantioselective Wittig alkenations, such as the use of bicyclic phosphonamide reagents, in which case as much as 90% ee is observed.34

Reactions with Ketenes.

Reaction of an acyl halide with the phosphorane in the presence of 1 mol equiv of Triethylamine affords allenic esters via in-situ generation of a ketene from the acid halide, followed by a standard Wittig reaction (eq 12).35 In a similar fashion, carboxylic acids, activated by triethylamine and 2-Chloro-1-methylpyridinium Iodide, generate ketenes which can be reacted with the stabilized phosphoranes to afford allenic carboxylate esters.36 The reaction of silicon- and germanium-substituted ketenes (Me3MCH=C=O) with the phosphorane also gives allenic esters, which rearrange to the alkynes Me3MC&tbond;CCH2CO2Et upon distillation.37

Allenes are also formed by the use of Ph3P=C=C(OEt)2, produced by treatment of Ph3P=CHCO2Et with Triethyloxonium Tetrafluoroborate followed by base treatment.38 Reaction with fluorenone gave the expected allene product, which dimerized immediately to a spirofluorene adduct.38

Reactions with Anhydrides and Imides.

Stabilized phosphoranes condense with anhydrides to yield enol lactones (see (Methoxycarbonylmethylene)triphenylphosphorane).39 Both the (E) and (Z) isomers can be obtained depending on the substrate, and also regioisomers are produced if the anhydride is unsymmetrical. There is predominant reaction at a site with weak steric hindrance (e.g. a-methyl) which changes to the less hindered carbonyl with added hindrance (a,a-dimethyl).39 Imides also react to give N-vinyl amides in a similar manner.40

Reactions with Amides and Esters.

Certain reactive or suitably disposed esters4,41 also react in a Wittig fashion to yield vinyl ethers, and some amides41a,42 such as those in penicillin and clavulanic acid derivatives afford vinyl amines.

Alkylations, Acylations, and Related Processes.

Stabilized phosphoranes are sufficiently nucleophilic to be alkylated in order to construct more complicated reagents, particularly with reactive alkyl groups such as allyl, benzyl, and methyl.1,43 Halogenation of the phosphorane leads to the a-halo derivatives, which give vinyl halides upon standard Wittig alkenations.7c,44 The nucleophilic alkylation reaction of the phosphorane with a large variety of substrates has been investigated, such as in the ring opening of N-methoxypyridinium salts45 and the b-alkylation of alkyl propynoates.46 Treatment of the phosphorane in the absence of an added electrophile leads to phosphaketene Ph3P=C=C=O.47 The phosphorane coordinates with organometallics to form stable complexes, and can occasionally participate in subsequent reactions of the organometallic complex.48

Acylation of the phosphorane provides diacylphosphoranes, which are often so highly stabilized and unreactive that they do not perform Wittig alkenations well.1 However, flash vacuum pyrolysis (FVP) can afford either terminal alkynes or propargylic esters, depending on the conditions (eq 13).49

Heterocyclic Ring Formation.

Reaction of the phosphorane with azides gives phosphazenes, whereas similar treatment of Ph3P=C(Me)CO2Et results in triazole formation via 1,3-dipolar cycloaddition of the azide to the enolate resonance form of the phosphorane (eq 14).50 A similar cyclocondensation occurs with hydrazonyl chlorides to give 5-alkoxy substituted pyrazoles.2

The combination of Wittig alkenation followed by further reaction of the a,b-unsaturated ester has resulted in the efficient preparation of several heterocyclic ring systems. In addition to the C-glycoside synthesis discussed earlier, pyrrolidines can be prepared in a similar Wittig/Michael sequence starting from a-hydroxypyrrolidine carbamates.51

Reaction of o-hydroxybenzaldehydes with the phosphorane is followed by condensation of the ester with the phenyl hydroxyl in a synthesis of coumarins (eq 15).3,43,52

Nucleophilic Epoxide Opening.

Under rigorous conditions, oxiranes react with the phosphorane to give ethoxycarbonylcyclopropanes (eq 16).5 The mechanism proceeds via nucleophilic opening of the epoxide, followed by attack of the alkoxide on the phosphorus, cleavage of the alkyl-phosphorus bond, and backside displacement of triphenylphosphine oxide. Normal Wittig alkenations of aldehydes with the phosphorane are sufficiently mild so as to not react with the epoxide functionality.

Oxidation.

Oxidation of the phosphorane yields symmetrical alkenes, or cyclic alkenes if bisylides are employed. This reaction was carried out originally using Triphenyl Phosphite-Ozone;53 however, a newer procedure using oxaziridines is a more general method.54

Formation of Thio- and Selenoaldehydes.

Treatment of the phosphorane with sulfur,55 episulfides,56 or selenium57 results in formation of Ph3P=S or Ph3P=Se and S=CHCO2Et or Se=CHCO2Et. These unstable thio- or selenoaldehydes can be trapped as their Diels-Alder adducts. In reaction with elemental sulfur or episulfides,55,56 the symmetrical alkene (EtO2CCH=CHCO2Et) was formed by decomposition of the thioaldehyde. Treatment of thioaldehyde S=CHCO2Et with amines (e.g. Morpholine) led to good yields of thioamides R1R2NC(=S)CO2Et.55a


1. (a) Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863. (b) Gosney, I.; Rowley, A. G. In Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic: New York, 1979; p 17. (c) Schlosser, M. Top. Stereochem. 1970, 5, 1. (d) Johnson, A. W. Ylid Chemistry; Academic: New York, 1966. (e) Hudson, R. F. Structure and Mechanism in Organo-Phosphorus Chemistry; Academic: New York, 1965. (f) Maercker, A. OR 1965, 14, 270. (g) Trippett, S. QR 1963, 17, 406.
2. Padwa, A.; MacDonald, J. G. H 1987, 24, 1225.
3. Mali, R. S.; Yadav, V. J. S 1977, 464.
4. Hercouet, A.; Le Corre, M. TL 1979, 20, 2995.
5. Denney, D. B.; Vill, J. J.; Boskin, M. J. JACS 1962, 84, 3944.
6. (a) Kayser, M. M.; Hatt, K. L.; Hooper, D. L. CJC 1991, 69, 1929. (b) Kayser, M. M.; Hooper, D. L. CJC 1990, 68, 2123.
7. (a) Speziale, A. J.; Ratts, K. W. JACS 1963, 85, 2790. (b) Isler, O.; Gutmann, H.; Montavon, M.; Rüegg, R.; Ryser, G.; Zeller, P. HCA 1957, 40, 1242. (c) Denney, D. B.; Ross, S. T. JOC 1962, 27, 998.
8. Crews, P. JACS 1968, 90, 2961.
9. (a) Isler, O.; Gutmann, H.; Montavon, M.; Ruegg, R.; Ryser, G.; Zeller, P. HCA 1957, 89, 863. (b) Wittig, G.; Haag, W. CB 1955, 88, 1654.
10. (a) Chen, S.-H.; Horvath, R. F.; Joglar, J.; Fisher, M. J.; Danishefsky, S. J. JOC 1991, 56, 5834. (b) Ihara, M.; Kirihara, T.; Kawaguchi, A.; Tsuruta, M.; Fukumoto, K.; Kametani, T. JCS(P1) 1987, 1719.
11. Buddrus, J. CB 1974, 107, 2050.
12. (a) Bissing, D. E. JOC 1965, 30, 1296. (b) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Inners, R. R.; Almond, H. R., Jr.; Whittle, R. R.; Olofson, R. A. JACS 1986, 108, 7664.
13. McEwen, W. E.; Sullivan, C. E.; Day, R. O. OM 1983, 2, 420.
14. Allen, D. W.; Ward, H. ZN(B) 1980, 35b, 754.
15. (a) Giese, B.; Schoch, J.; Rüchardt, C. CB 1978, 111, 1395. (b) Ruchardt, C.; Panse, P.; Eichler, S. CB 1967, 100, 1144.
16. Hocking, M. B. CJC 1966, 44, 1581.
17. (a) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. T 1988, 44, 491. (b) Aparicio, F. J. L.; Cubero, I. I.; Olea, M. D. P. Carbohydr. Res. 1983, 115, 250. (c) Oikawa, Y.; Nishi, T.; Yonemitsu, O. JCS(P1), 1985, 7.
18. Elliott, M.; Janes, N. F.; Pulman, D. A. JCS(P1) 1974, 2470.
19. Tronchet, J. M. J.; Gentile, B. HCA 1979, 62, 2091.
20. (a) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. JOC 1982, 47, 1373. (b) Häfele, B.; Jäger, V. LA 1987, 85. (c) Mann, J.; Partlett, N. K.; Thomas, A. JCR(S) 1987, 369. (d) Kametani, T.; Suzuki, T.; Nishimura, M.; Sato, E.; Unno, K. H 1982, 19, 205.
21. Minami, N.; Ko, S. S.; Kishi, Y. JACS 1982, 104, 1109.
22. Franck, R. W.; Subramaniam, C. S.; John, T. V.; Blount, J. F. TL 1984, 25, 2439.
23. (a) Rokach, J.; Lau, C.-K.; Zamboni, R.; Guindon, Y. TL 1981, 22, 2763. (b) Leblanc, Y.; Fitzsimmons, B. J.; Zamboni, R.; Rokach, J. JOC 1988, 53, 265.
24. Ohrui, H.; Jones, G. H.; Moffatt, J. G.; Maddox, M. L.; Christensen, A. T.; Byram, S. K. JACS 1975, 97, 4602.
25. (a) Nicotra, F.; Ronchetti, F.; Russo, G.; Toma, L. TL 1984, 25, 5697. (b) Nicotra, F.; Russo, G.; Ronchetti, F.; Toma, L. Carbohydr. Res. 1983, 124, C5.
26. (a) Collins, P. M.; Overend, W. G.; Shing, T. S. CC 1982, 297. (b) Webb, T. H.; Thomasco, L. M.; Schlachter, S. T.; Gaudino, J. J.; Wilcox, C. S. TL 1988, 29, 6823.
27. Isaacs, N. S.; El-Din, G. N. TL 1987, 28, 2191.
28. (a) Roberts, D. L.; Heckman, R. A.; Hege, B. P.; Bellin, S. A. JOC 1968, 33, 3566. (b) Openshaw, H. T.; Whittaker, N. Proc. Chem. Soc. 1961, 454.
29. (a) Ruchardt, C.; Panse, P.; Eichler, S. CB 1967, 100, 1144. (b) Rüchardt, C.; Eichler, S.; Panse, P. AG(E) 1963, 2, 619. (c) Bose, A. K.; Manhas, M. S.; Ramer, R. M. JCS(C) 1969, 2728. (d) Mulzer, J.; Kappert, M. AG(E) 1983, 22, 63.
30. (a) Fraser-Reid, B.; Tsang, R.; Tulshian, D. B.; Sun, K. M. JOC 1981, 46, 3764. (b) Tulshian, D. B.; Tsang, R.; Fraser-Reid, B. JOC 1984, 49, 2347.
31. Garner, P.; Ramakanth, S. JOC 1987, 52, 2629.
32. Bestmann, H. J.; Lienert, J. CZ 1970, 94, 487.
33. Toda, F.; Akai, H. JOC 1990, 55, 3446.
34. Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. JACS 1984, 106, 5754.
35. (a) Lang, R. W.; Hansen, H.-J. HCA 1980, 63, 438. (b) Lang, R. W.; Hansen, H. J. OS 1984, 62, 202.
36. Kohl-Mines, E.; Hansen, H.-J. HCA 1985, 68, 2244.
37. Orlov, V. Y.; Lebedev, S. A.; Ponomarev, S. V.; Lutsenko, I. F. ZOB 1975, 45, 708.
38. Bestmann, H. J.; Saalfrank, R. W.; Snyder, J. P. CB 1973, 106, 2601.
39. Kayser, M. M.; Breau, L. CJC 1989, 67, 1401; and references cited therein.
40. (a) Flitsch, W.; Peters, H. TL 1969, 1161. (b) For reactions of the methyl ester with thioimides, see: Bishop, J. E.; O'Connell, J. F.; Rapaport, H. JOC 1991, 56, 5079.
41. (a) Murphy, P. J.; Brennan, J. CSR 1988, 17, 1. (b) Subramanyam, V.; Silver, E. H.; Soloway, A. H. JOC 1976, 41, 1272. (c) Le Corre, M.; Normant, H. CR(C) 1973, 276, 963.
42. Gilpin, M. L.; Harbridge, J. B.; Howarth, T. T. JCS(P1) 1987, 1369 (methyl ester).
43. For allylation, see: Mali, R. S.; Tilve, S. G.; Yeola, S. N.; Manekar, A. R. H 1987, 26, 121.
44. Speziale, A. J.; Ratts, K. W. JACS 1962, 84, 854.
45. Schnekenburger, J.; Heber, D.; Heber-Brunschweiger, E. T 1977, 33, 457.
46. Barluenga, J.; Lopez, F.; Palacios, F.; Sanchez-Ferrando, F. TL 1988, 29, 381.
47. Appel, R.; Winkhaus, V.; Knoch, F. CB 1986, 119, 2466; and references cited therein.
48. Hegedus, L. S.; McGuire, M. A. OM 1982, 1, 1175.
49. Märkl, G. CB 1961, 94, 3005.
50. L'abbé, G.; Ykman, P.; Smets, G. T 1969, 25, 5421.
51. Nagasaka, T.; Yamamoto, H.; Hayashi, H.; Watanabe, M.; Hamaguchi, F. H 1989, 29, 155.
52. Brubaker, A. N.; DeRuiter, J.; Whitmer, W. L. JMC 1986, 29, 1094.
53. Bestmann, H. J.; Kisielowski, L.; Distler, W. AG(E) 1976, 15, 298.
54. Davis, F. A.; Chen, B. JOC 1990, 55, 360.
55. (a) Okuma, K.; Komiya, Y.; Ohta, H. BCJ 1991, 64, 2402. (b) Sato, R.; Satoh, S.-I. S 1991, 785. (c) Okuma, K.; Tachibana, Y.; Sakata, J.-I.; Komiya, T.; Kaneko, I.; Komiya, Y.; Yamasaki, Y.; Yamamoto, S.-I.; Ohta, H. BCJ 1988, 61, 4323.
56. Okuma, K.; Yamasaki, Y.; Komiya, T.; Kodera, Y.; Ohta, H. CL 1987, 357.
57. (a) Okuma, K.; Kaneko, I.; Ohta, H.; Yokomori, Y. H 1990, 31, 2107. (b) Okuma, K.; Komiya, Y.; Kaneko, I.; Tachibana, Y.; Iwata, E.; Ohta, H. BCJ 1990, 63, 1653. (c) Okuma, K.; Sakata, J.-I.; Tachibana, Y.; Honda, T.; Ohta, H. TL 1987, 28, 6649.

Allen B. Reitz & Mark E. McDonnell

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.