A convenient reagent for aldehyde to alkyne homologation

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Tetrahedron Letters 49 (2008) 6904–6906 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet A convenient reagent for aldehyde to alkyne homologation Douglass F. Taber *, Sha Bai, Peng-fei Guo Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States a r t i c l e i n f o a b s t r a c t Article history: Received 10 September 2008 Accepted 17 September 2008 Available online 23 September 2008 A convenient reagent for the one-carbon homologation of an aldehyde to the corresponding alkyne is reported. This reagent allows this conversion to conveniently be carried out on a large scale under ambient conditions. Ó 2008 Elsevier Ltd. All rights reserved. transfer can be effected with the atom-economical methanesulfonyl azide.8 1. Introduction In 1989, Ohira1 reported a convenient procedure for the homologation of an aldehyde such as 1a (Eq. 1) to the corresponding alkyne 3a, by condensation with dimethyl diazomethyl phosphonate, generated in situ from the diazo phosphonate 2. Subsequently, Bestmann2 described a more detailed study of this transformation. O H CH3O 1a O 2 N 2 O P OCH3 OCH3 K2CO3 / CH3OH (CH3O)3P CH3SO2N3 NaH O O 4 Br 5 P O CH3O OCH 3 O N2 6 P O CH3O OCH ð2Þ 3 H ð1Þ CH3O 3a Although we3 and many others4 have found the Ohira–Bestmann reagent to be convenient, in recent years, its use has often been displaced by alternative protocols5 for effecting this homologation. Although the reagent 2 is convenient and easy to prepare from its precursor dimethyl 2-oxopropylphosphonate, the latter is sufficiently expensive ($2/mmol)6 that alternative reagents such as TMSCH@N2 are competitive. It occurred to us that as the acyl group is lost before the diazophosophonate reacts with the aldehyde, it might be possible to use a bulkier acyl group that would give intermediates that were less expensive and easier to handle. The phosphonate 5 (Eq. 2) immediately came to mind. Easy to prepare7 from the inexpensive 2-bromoacetophenone 4 (or potentially the even less expensive 2-chloroacetophenone), 5 is also easy to purify by extraction into aqueous base followed by distillation. We have found that the derived8,9 diazophosphonate 6 can be used directly,4c without any purification other than extraction. It is particularly noteworthy that in contrast to the preparation of the Ohira reagent, diazo * Corresponding author. Tel.: +1 302 831 2433; fax: +1 302 831 6335. E-mail address: [email protected] (D. F. Taber). 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.09.114 We were pleased to observe (Table 1) that the crude diazo phosphonate 6 efficiently converted a variety of aldehydes to the corresponding alkynes. The a,b-unsaturated aldehyde (entry 7) gave the methoxy-substituted alkyne. If desired, the methyl benzoate generated as a byproduct of the reaction could be removed by saponification during workup. The procedure described here for the homologation of an aldehyde to its corresponding alkyne is inexpensive, and can be conveniently carried out on a large scale. In particular, with a burgeoning interest of ‘click chemistry’,11 there is a need of the inexpensive preparation of terminal alkynes. We expect that the diazo phosphonate 6 will become a useful tool in the armamentarium of organic synthesis. 2. Experimental Safety note: Differential scanning calorimetry on the ethyl ester corresponding to 6, prepared at an early stage of this project, showed a substantial exotherm at 70 °C. The diazo phosphonate 6 should not be warmed past room temperature. The commonly used diazo phosphonate 2 showed a similar exotherm at about the same temperature, so it also must be handled with due caution. 2.1. Dimethyl 2-oxo-2-phenylethylphosphonate (5) Following the published procedure,7 to a solution of 2-bromoacetophenone (98%, 12.2 g, 60.0 mmol) in THF (6.0 mL) was added trimethylphosphite (97%, 8.8 mL, 72.4 mmol) dropwise over 5 min. Author's personal copy D. F. Taber et al. / Tetrahedron Letters 49 (2008) 6904–6906 Table 1 Homologation of aldehydes with 6 Entry Aldehyde Alkyne Yield (%) OCH3 H 1 OCH3 H 77a O 2a 1a OCH3 OCH3 OCH3 OCH3 2 79b O H 1b H 2b CH3O CH3O 72c O 3 H 1c O O 4 H 2c 73d O H 1d BnO BnO 81 2e 1e O BnO 6 H H O BnO 7 1g a b c d e Ref. Ref. Ref. Ref. Ref. BnO 92 2f 1f H 2.2. Dimethyl 1-diazo-2-oxo-2-phenylethylphosphonate (6) To a solution of dimethyl-2-oxo-2-phenylphosphonate 5 (99%, 1% CH2Cl2 by 1H NMR , 4.7 g, 20.4 mmol) in MeCN (20 mL) was added NaH (60% in mineral oil, 0.99 g, 24.8 mmol) portionwise over 2 min at 0 °C. Mesyl azide8c (99%, 3.2 g, 26.2 mmol) was then added in one portion. The mixture was stirred for 3 h at 0 °C, and then partitioned between CH2Cl2 and, sequentially, 1 M aqueous NaOH (200 mL) at 0 °C and saturated aqueous NaHCO3 at 0 °C. The combined organic extracts were dried (Na2SO4) and concentrated. The crude diazo compound was received as a thick orange oil (5.3 g). A portion of the crude diazo compound (94.6 mg) was chromatographed to yield an analytical sample of the known9 diazo phosphonate 6 (87.1 mg) as a thick yellow oil. The isolated yield was 94% based on 5. TLC Rf = 0.41 (MTBE/CH2Cl2, 2:8); 1H NMR (400 MHz, CDCl3) d 7.64 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 3.81 (d, J = 11.8, 6H); 13C NMR (100 MHz, CDCl3), d d 53.9 (d, J = 5.8 Hz), 127.2, 128.5, 132.4; u 29.5, 136.6 (d, J = 3.2 Hz), 187.2 (d, J = 9.0 Hz). Diazo phosphonate 6 was stable in the freezer (20 °C). 2.3. Procedure A: (2S)-1-O-benzyl-2-methoxypent-4-yn-1-ol (2g) H H 7.48 (t, J = 7.6 Hz, 2H), 3.78 (d, J = 11.0 Hz, 6H), 3.64 (d, J = 22.6 Hz, 2H); 13C NMR12 (100 MHz, CDCl3) d d 52.7 (d, J = 6.6 Hz), 128.3, 128.6, 133.4; u 36.4, 37.7, 136.0 (d, J = 2.5 Hz), 191.4 (d, J = 6.6 Hz). H 2d O 5 6905 CH3O BnO H 75e 2g 10a. 10b. 10c. 10d. 10e. The resulting mixture was heated to reflux overnight, then concentrated. The product was a 7:3 mixture of dimethyl-2oxophenylphosphonate and dimethyl 1-phenylethenyl ester by 1 H NMR. The mixture was diluted with H2O (200 mL) and CH2Cl2/petroleum ether (PE) (1:19) (10 mL), and was then stirred with solid NaOH pellets (9.6 g, 240.0 mmol) at 0 °C for 2 h (NaOH dissolved). The mixture was diluted with 700 mL of H2O, and washed with 4  900 mL of CH2Cl2/PE (1:19). The aqueous phase was acidified with concentrated aqueous HCl (11 M, 22 mL) at 0 °C. The reaction mixture was partitioned between CH2Cl2 and, sequentially, H2O and saturated aqueous NaHCO3. The combined organic extracts were dried (Na2SO4) and concentrated. The crude phosphonate was received as a dark orange oil. Distillation (0.5 torr (pot) = 180–190 °C) delivered the known7b keto phosphonate as a pale yellow oil (7.7 g, 33.8 mmol, 55% yield). The phosphonate 5 was used in the diazo transfer reaction without further purification. TLC Rf = 0.26 (MTBE/CH2Cl2, 2:8); 1H NMR (400 MHz, CDCl3) d 8.01 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), To a mixture of the aldehyde 1 g (116 mg, 0.7 mmol) and K2CO3 (395 mg, 2.9 mmol) in MeOH (3 mL) were added the crude diazo 6 (85.8% pure, 301 mg, 1.0 mmol) and MeOH (7 mL) in one portion at 0 °C. The resulting mixture was stirred at 0 °C–rt overnight. The reaction mixture was chromatographed to yield the known alkyne 2g10d (101 mg, 0.5 mmol, 75% yield) as a pale yellow oil. TLC Rf = 0.24 (MTBE/PE, 1:9); 1H NMR (400 MHz, CDCl3) d 7.25–7.34 (m, 5H), 4.57 (s, 2H), 3.51–3.57 (m, 1H), 3.60–3.64 (m, 2H), 3.44 (s, 3H), 2.48–2.51 (m, 2H), 1.98 (t, 1H, J = 2.7 Hz); 13C NMR (100 MHz, CDCl3) d d 57.6, 78.3, 127.5, 127.6, 128.3; u 20.8, 69.9, 70.6, 73.4, 80.5, 138.0. 2.4. Procedure B (saponification of methyl benzoate): (1S,2S)(2-ethynylcyclopropyl)methyl benzyl ether (2f) To a mixture of the aldehyde 1f (103 mg, 0.5 mmol) and K2CO3 (312 mg, 2.3 mmol) in MeOH (2 mL) were added the crude diazo 6 (92% pure, 226 mg, 0.8 mmol) and MeOH (3.4 mL) in one portion at 0 °C. The resulting mixture was stirred at 0 °C–rt overnight. Then, solid NaOH pellets (256 mg, 6.4 mmol) were added, and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to rt, concentrated, and chromatographed to yield alkyne 2f (92 mg, 0.5 mmol, 92% yield) as a colorless oil. TLC Rf = 0.42 (MTBE/PE, 1:9); 1H NMR (400 MHz, CDCl3) d 7.24–7.38 (m, 5H), 4.56 (s, 2H), 3.55–3.64 (m, 2H), 1.81 (d, 1H, J = 2.0 Hz), 1.46–1.52 (m, 1H), 1.32–1.38 (m, 1H), 0.97–1.02 (m, 1H), 0.53– 0.58 (q, 1H, J = 5.5 Hz); 13C NMR (400 MHz, CDCl3) d d 4.7, 17.5, 127.4, 127.7, 128.2; u 12.4, 66.2, 70.6, 72.8, 83.8, 138.3; IR (film): 3294, 3028, 2860, 2360, 2117 cm1; MS 185 (M+1 19), 155 (31), 141 (65), 129 (61), 105 (100); HRMS calcd for C13H13O 185.0966, obsd 185.0966. Acknowledgments We thank John Dykins for high resolution mass spectra (supported by NSF0541775), and the National Institutes of Health (GM060287) for financial support. Author's personal copy 6906 D. F. Taber et al. / Tetrahedron Letters 49 (2008) 6904–6906 Supplementary data Experimental procedures and 1H NMR and 13C NMR spectra for all new compounds. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet. 2008.09.114. References and notes 1. 2. 3. 4. Ohira, S. Synth. Commun. 1989, 19, 561. Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522. Taber, D. F.; Wang, Y. J. Am. Chem. Soc. 1997, 119, 22. For the use of 2 by others see: (a) Kramer, C. S.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2000, 2, 3723; (b) Pietruszka, J.; Witt, A.; Frey, W. Eur. J. Org. Chem. 2003, 16, 3219; (c) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 1, 59; (d) Lepage, O.; Kattnig, E.; Furstner, A. J. Am. Chem. Soc. 2004, 126, 15970; (e) Dickson, H. D.; Smith, S. C.; Hinkle, K. W. Tetrahedron Lett. 2004, 45, 5597; (f) Dirat, O.; Clipson, A.; Elliott, J. M.; Garrett, S.; Jones, A. B.; Reader, M.; Shaw, D. Tetrahedron Lett. 2006, 47, 1729; (g) Quesada, E.; Raw, S. A.; Reid, M.; Roman, E.; Taylor, R. J. K. Tetrahedron 2006, 62, 6673; (h) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007, 72, 4246; (i) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2007, 9, 1125; (j) Vinntonyak, V. V.; Maier, M. E. Angew. Chem., Int. Ed. 2007, 46, 5209; (k) Shangguan, N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093; (l) Furstner, A.; Bouchez, L. C.; Funel, J.; Liepins, V.; Poree, F.; Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265; (m) Negru, M.; Schollmeyer, D.; Kunz, H. Angew. Chem., Int. Ed. 2007, 46, 9339. 5. (a) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2007, 129, 14556; (b) Barth, R.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 5791; (c) Monti, C.; Sharon, O.; Gennari, C. Chem. Commun. 2007, 4271; (d) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 2722. 6. For 2-oxopropylphosponate preparation see: (a) Cotton, F. A.; Schunn, R. A. J. Am. Chem. Soc. 1963, 85, 2394; (b) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931; (c) Pietruszka, J.; Witt, A. Synthesis 2006, 4266. 7. (a) Fang, F. G.; Feigelson, G. B.; Danishefsky, S. J. Tet. Lett. 1989, 30, 2743; (b) Moorhoff, C. M. Synth. Commun. 2003, 12, 2069. 8. For diazo transfer with methanesulfonyl azide see: (a) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077. For the preparation of methanesulfonyl azide see: (b) Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R., Jr. J. Org. Chem. 1958, 23, 1051; (c) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959. Note that it is convenient to carry out this preparation in acetone. We remove the acetone on high vacuum at room temperature, and do not further purify the methanesulfonyl azide. 9. Regitz, M.; Martin, R. Tetrahedron 1985, 41, 819. 10. (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204; (b) Marti, T.; Peterson, B. R.; Furer, A.; Mordasini-Denti, T.; Zarske, J.; Jaun, B.; Diederich, F. Helv. Chim. Acta 1998, 81, 109; (c) Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 17, 4044; (d) Stiles, M.; Burckhardt, U.; Haag, A. J. Org. Chem. 1962, 27, 4715; (e) Schuppan, J.; Wehlan, H.; Keiper, S.; Koert, U. Chem. Eur. J. 2006, 12, 7364. 11. For early references to click chemistry see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004; (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596; (c) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057; (d) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686. For more recent references see: (e) Ye, C.; Gard, G. L.; Inter, R. W.; Syvret, R. G.; Twamley, B.; Shreeve, J. M. Org. Lett. 2007, 9, 3841; (f) Turner, R. A.; Oliver, A. G.; Lokey, R. S. Org. Lett. 2007, 9, 5011; (g) Zhang, Q.; Takacs, J. M. Org. Lett. 2008, 10, 545. 12. 13C multiplicities were determined with the aid of a JVERT pulse sequence, differentiating the signals for methyl and methine carbons as ‘d’ from methylene and quaternary carbons as ‘u’.