Formation of COOH-Ylides, and Their Reactivities and Selectivities in Wittig Reactions

Abstract

Whereas two equivalents of base are typically required to prepare carboxylate (CO₂ ^–) ylides [Ph₃P⁺C^–(H)-alk-CO₂ ^–] (alk = alkanediyl) from carboxy (CO₂H) phosphonium salts [(Ph₃PCH₂-alk-CO₂H)⁺] X^–, we reveal, for the first time, that carboxy ylides [Ph₃P⁺C^–(H)-alk-CO₂H] can be generated with one equivalent of NaHMDS at 0 °C, and that the Wittig reaction of simple aliphatic aldehydes (1 equiv) with these carboxy ylides (1.5–2 equiv) in THF at –95 to –90 °C for one hour, then at warming temperatures to 0 °C over two hours affords (Z)-alkenoic acids. Phosphonium salts containing (CH₂) _n alkanediyl chains (n = 2–5) showed adequate reactivity and high Z-selectivity, whereas shorter or longer alkanediyl chains resulted in a low Z-selectivity and/or a low yield. On the basis of these results with different (CH₂) _n chains and that obtained with a rigid methylene group, we propose that a rapid equilibrium between Ph₃PCH ₂-alk-CO₂ ^– and Ph₃P⁺C^–(H)-alk-CO₂ H, through an intramolecular hydrogen exchange, accounts for the success of the Wittig reaction.

Key words

Wittig reaction - carboxy phosphonium salt - carboxy ylides - carboxylate ylides - alkenoic acids

• References and Notes

• 1 Nicolaou KC, Härter MW, Gunzner JL, Nadin A. Liebigs Ann. 1997; 1283

For example:
• 2a Perlmutter P, Selajerern W, Vounatsos F. Org. Biomol. Chem. 2004; 2: 2220
• 2b Han X, Crane SN, Corey EJ. Org. Lett. 2000; 2: 3437
• 2c Nicolaou KC, Prasad CV. C, Ogilvie WW. J. Am. Chem. Soc. 1990; 112: 4988
• 2d Delorme D, Girard Y, Rokach J. J. Org. Chem. 1989; 54: 3635

For example:
• 3a Baars H, Classen MJ, Aggarwal VK. Org. Lett. 2017; 19: 6008
• 3b Prévost S, Thai K, Schützenmeister N, Coulthard G, Erb W, Aggarwal VK. Org. Lett. 2015; 17: 504
• 3c Quan LG, Cha JK. J. Am. Chem. Soc. 2002; 124: 12424
• 3d Boulton LT, Brick D, Fox ME, Jackson M, Lennon IC, McCague R, Parkin N, Rhodes D, Ruecroft G. Org. Process Res. Dev. 2002; 6: 138
• 3e Grieco PA, Reap JJ. J. Org. Chem. 1973; 38: 3413

For examples, see:
• 4a Srinivas J, Namito Y, Matsubara R, Hayashi M. J. Org. Chem. 2017; 82: 5146
• 4b Ishigami K, Kobayashi M, Takagi M, Shin-ya K, Watanabe H. Tetrahedron 2015; 71: 8436
• 4c Critcher DJ, Connolly S, Wills M. J. Org. Chem. 1997; 62: 6638
• 4d Wang SS, Shi X.-X, Powell WS, Tieman T, Feinmark SJ, Rokach J. Tetrahedron Lett. 1995; 36: 513
• 4e Just G, Wang ZY. J. Org. Chem. 1986; 51: 4796

For examples, see:
• 5a Ortgies S, Rieger R, Rode K, Koszinowski K, Kind J, Thiele CM, Rehbein J, Breder A. ACS Catal. 2017; 7: 7578
• 5b Hao H.-D, Trauner D. J. Am. Chem. Soc. 2017; 139: 4117
• 5c Liu Y.-T, Chen J.-Q, Li L.-P, Shao X.-Y, Xie J.-H, Zhou Q.-L. Org. Lett. 2017; 19: 3231
• 5d Paull DH, Fang C, Donald JR, Pansick AD, Martin SF. J. Am. Chem. Soc. 2012; 134: 11128
• 5e Poth D, Wollenberg KC, Vences M, Schulz S. Angew. Chem. Int. Ed. 2012; 51: 2187 ; Angew. Chem. 2012, 124, 2229
• 5f Wube AA, Hüfner A, Thomaschitz C, Blunder M, Kollroser M, Bauer R, Bucar F. Bioorg. Med. Chem. 2011; 19: 567
• 5g Seike H, Ghosh I, Kishi Y. Org. Lett. 2006; 8: 3865
• 5h Mascitti V, Corey EJ. J. Am. Chem. Soc. 2006; 128: 3118
• 6 Maryanoff BE, Reitz AB, Duhl-Emswiler BA. J. Am. Chem. Soc. 1985; 107: 217

For pK _a values in DMSO of phosphonium salts (14–23), see:
• 7a Ling-Chung S, Sales KD, Utley JH. P. J. Chem. Soc., Chem. Commun. 1990; 662
• 7b Zhang X.-M, Bordwell FG. J. Am. Chem. Soc. 1994; 116: 968

For carboxylic acids (pK _a= 12–13) see:
• 7c Bordwell FG, Algrim D. J. Org. Chem. 1976; 41: 2507

For HN(TMS)₂ (pK _a= 26), see:
• 7d Grimm DT, Bartmess JE. J. Am. Chem. Soc. 1992; 114: 1227

For HN(TMS)₂ in THF (pK _a= 25.8), see:
• 7e Fraser RR, Mansour TS, Savard S. J. Org. Chem. 1985; 50: 3232

For t-BuOH (pK _a= 32) and ROH (R = Me, Et) (pK _a= 29–30), see;
• 7f Olmstead WN, Margolin Z, Bordwell FG. J. Org. Chem. 1980; 45: 3295

For DBU·H⁺ (pK _a= 14), see:
• 7g Hulla M, Chamam SM. A, Laurenczy G, Das S, Dyson PJ. Angew. Chem. Int. Ed. 2017; 56: 10559

Angew. Chem. 2017, 129, 10695. For PhOH (pK _a= 16–18), see:
• 7h Bordwell FG, McCallum RJ, Olmstead WN. J. Org. Chem. 1984; 49: 1424 ; and also ref. 7c
• 8a pK _a Values in THF for most of compounds shown in ref. 7 are not available, except for that of HN(TMS)₂, which is almost the same in THF as in DMSO.^7d,e Therefore, values of other compounds in DMSO are quoted for discussion of the relative acidity.
• 8b For a collection of pK _a values of compounds, see: Bordwell FG. Acc. Chem. Res. 1988; 21: 456
• 9 The ¹H NMR spectrum of 3 was superimposed with that of the (E)-isomer, which was synthesized by a method described in the Supplementary Information.
• 10 Signal-to-noise ratios of the ¹H and ¹³C NMR spectra were ~95% and ~97%, respectively.
• 11 Alkenoic acid 7 was previously synthesized by using 2c and t-BuOK (1:2); the ¹³C NMR spectrum provided in the Supporting Information of ref. 5a (page S97) allowed us to calculate the Z-selectivity to be 90%, by using the peak heights.
• 12 Hands AR, Mercer AJ. H. J. Chem. Soc. C 1968; 2448

For examples, see:
• 13a Zeng X, Miao C, Wang S, Xia C, Sun W. Chem. Commun. 2013; 49: 2418
• 13b Meyers AI, Collington EW. Tetrahedron 1971; 27: 5979
• 14 Phosphonium salt 2a and NaHMDS were mixed in a ratio of 0.8:1 or 2.1:1 then quenched with D₂O (10 equiv). However, the recovered material showed complicated ¹H NMR spectra, which prevented calculation of the incorporation of deuterium into 2a.
• 15a Byrne PA, Gilheany DG. Chem. Soc. Rev. 2013; 42: 6670
• 15b Maryanoff BE, Reitz AB. Chem. Rev. 1989; 89: 863
• 15c Maryanoff BE, Reitz AB, Mutter MS, Inners RR, Almond HR. Jr, Whittle RR, Olofson RA. J. Am. Chem. Soc. 1986; 108: 7664
• 16 A molecular model of the (E)-5-carboxypent-3-en-1-ylphosphonium salt, the trans-olefin analogue of 22, showed easy access to E.
• 17 (4Z)-7-Phenylhept-4-enoic acid (3; Table [1], Entry 1); Typical Procedure A 1.0 M solution of NaHMDS in THF (1.0 mL, 1.0 mmol, 2 equiv) was added to an ice-cold suspension of 2a (432 mg, 1.01 mmol, 2 equiv) in THF (5 mL). The mixture was stirred at 0 °C for 1 h and then the resulting reddish-orange mixture was cooled to −95 to –90 °C in a slushy mixture of hexane and liquid N₂. A solution of aldehyde 1 (67 mg, 0.50 mmol, 1 equiv) in THF (1.5 mL) was added dropwise to the mixture. After 1 h, the mixture was warmed to 0 °C over 2 h then sat. aq NH₄Cl was added. The resulting mixture was extracted with Et₂O (×3). The extracts were combined, dried (MgSO₄), and concentrated to afford a residue that was purified by chromatography (silica gel, hexane–EtOAc) to give a colorless liquid; yield: 66 mg (63%, Z / E = 90:10); R_f  = 0.13 (hexane–EtOAc, 4:1). IR (neat): 2924, 1710, 699 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.5–3.0 (br s, 1 H), 2.24–2.44 (m, 6 H), 2.66 (t, J = 7.5 Hz, 2 H), 5.30–5.42 (m, 1 H), 5.42–5.53 (m, 1 H), 7.14–7.32 (m, 5 H). ¹³C-APT NMR (75 MHz, CDCl₃): δ = 22.5 (–), 29.2 (–), 34.0 (–), 35.8 (–), 125.9 (+), 127.9 (+), 128.3 (+), 128.5 (+), 130.5 (+), 141.9 (–), 179.8 (–). HRMS (FAB⁺): m/z [M + Na]⁺ calcd for C₁₃H₁₆NaO₂: 227.1048; found. 227.1045. Note that candy-like phosphonium salts, such as 2f, or longer-chain methylene salts were heated to form a viscous mass that was transferred quickly to the reaction flask. After the addition of THF and a solution of NaHMDS, the mixture was sonicated at 0 °C until the candy-like phosphonium salt that caked in the flask was sufficiently dissolved to allow smooth stirring. The mixture was stirred at 0 °C for a total of 1 h after the addition of NaHMDS, then cooled to –90 °C before addition of aldehyde 1.