Facile multi-decagram synthesis of methyl but-2-ynoate

Abstract

A high yielding and operationally simple protocol affords multi-decagram quantities of the synthetically useful methyl but-2-ynoate from commercially available starting materials and reagents.

---

Methyl but-2-ynoate (3) is the simplest internal alkyl alkynoate making it a molecule commonly used in numerous methodologies in order to demonstrate the scope of new reactions.¹ This compound has also been used in a number of natural product total syntheses² as well as in medicinal chemistry projects.³ In our recent efforts toward the synthesis of calyciphylline A-type Daphniphyllum alkaloids,⁴ multi-gram quantities of this specific methyl alkynoate were required. Although available in small quantities from various suppliers, the high price necessitated its straightforward synthesis from commercially available and inexpensive starting materials and reagents.

One of the current procedures to synthesize 3 involves a four-step protocol⁵ starting from the reaction of methyl bromoacetate and triphenylphosphine to give phosphane 4 after a deprotonation (Scheme 2). This is then acetylated and subsequently subjected to a technically challenging vacuum pyrolysis at 180 °C to promote an internal Wittig reaction giving 3 in a 60% overall yield. In another method, pyrazole 5 is oxidized to 3 either by using 2 equivalents of hypervalent iodine⁶ or 2 equivalents of the highly toxic thallium(III) nitrate⁷ giving 3 in 60% and 78% yield respectively (toxic Pb(OAc)₄ can also be used as an alternative for this oxidation however the product is only afforded in 35% yield).⁸ A simpler method involves the esterification of the relatively costly 2-butynoic acid (6) in methanol giving the desired molecule in 4 days with a 67% yield after an aqueous work up.⁹ Finally a two-step protocol starting with the bromination of propyne gas (7)¹⁰ followed by a palladium catalyzed carbonylation of the bromopropyne¹¹ product using CO gas (1 atm) in methanol affords the product in an overall 61% yield over two steps.¹² Iodopropyne can also be carbonylated using PdI₂, giving a higher 80% yield for the second step; however, iodopropyne is expensive and only available from a limited number of suppliers.

Scheme 1 Facile synthesis of methyl but-2-ynoate.

Scheme 2 Current methods for the synthesis of 3.

All the aforementioned procedures present certain drawbacks which would make the synthesis of this simple alkynoate challenging on a multi-gram scale. Our aim was to gain rapid access to large quantities of 3 which if possible, avoided the use of propyne and CO gas, long reaction periods, toxic reagents and by-products as well as the use of expensive starting materials. Furthermore, it was desirable to have a high yielding, operationally simple and reproducible experimental procedure. We therefore believed that it would be useful to devise a straightforward method to prepare large quantities of 3 efficiently, at a low-cost and with an improved yield.

Our efficient protocol (Scheme 1) is based on a method previously reported for the preparation of propargylic secondary alcohols and ketones.¹³ In our synthesis we make use of the cheap and commercially available mixture of Z and E isomers of 1-bromo-1-propene (1) by treating it with n-BuLi at −78 °C to generate the propynyllithium anion (2) in situ. This nucleophile is then reacted with methyl chloroformate to afford the desired molecule in 80% yield. The procedure is more atom-economic when compared to most of the existing methodologies and furthermore gives rise to LiCl and LiBr as side products which are environmentally benign and easy to remove via an aqueous work-up; 1-bromo-1-propene currently has no known severe health hazards. The facile method described below is safe and technically easy to perform. The high yield and reproducibility of this procedure make it a practical alternative to accessing multi-gram quantities of this important compound.

Procedure

An oven-dried 3 L round-bottom flask equipped with a magnetic stirring bar, a rubber septum, an electronic thermometer and flushed with nitrogen was charged with (Z/E)-1-bromo-1-propene (81.5 mL, 952 mmol),§ 1 L of anhydrous tetrahydrofuran (THF)¶ and maintained under a nitrogen atmosphere. The flask was cooled to −78 °C with a dry ice-acetone bath, and after 10 minutes n-butyllithium 2.5 M (800 mL, 2.00 mol)|| was added slowly to maintain the internal temperature below −60 °C. Following the end of the addition, the off-white mixture was stirred for 1.5 hours at −78 °C before methyl chloroformate (96.0 mL, 1.24 mol)** was added dropwise over 40 minutes in order to maintain the internal temperature between −70 °C and −60 °C. The mixture was stirred for 2 hours at −78 °C before the cooling bath was removed allowing the mixture to warm to room temperature over 1.5 hours. 500 mL of water were subsequently added and the organic layer was decanted. The aqueous fraction was extracted twice with 400 mL of diethyl ether and the combined organic fractions were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure (40 °C, 100 mbar)†† to afford an orange brown liquid.‡‡ After distillation through a 5 cm long vigreux column (Bp = 64–67 °C, 60 mbar)§§ methyl but-2-ynoate (74.7 g, 80%)¶¶ was obtained as a colourless oil.||||

The elemental analysis and the spectral analysis of the product are as follows: Anal. Calcd for C₅H₆O₂: C, 61.22; H, 6.16. Found: C, 61.12; H, 6.00%. ¹H NMR (CDCl₃, 500 MHz) δ_H 3.76 (s, 3H, CH₃–O), 1.99 (s, 3H, CH₃–C≡). ¹³C NMR (CDCl₃, 125 MHz) δ_C 154.2 (C–CO₂Me), 85.7 (CH₃–C≡), 72.1 (C≡C–CO₂Me), 52.5 (CH₃–O), 3.7 (CH₃–C≡). IR (film)/cm⁻¹ν_max 2957, 2247, 1714, 1436, 1263, 1075.

References

1. For recent uses of 3 see: (a) G. Liu, Y. Shen, Z. Zhou and X. Lu, Angew. Chem., Int. Ed., 2013, 52, 6033; (b) R. S. Foster, H. Adams, H. Jakobi and J. P. A. Harrity, J. Org. Chem., 2013, 78, 4049; (c) Y. Liu, G. Wu and Y. Cui, Appl. Organomet. Chem., 2013, 27, 206; (d) P. A. Wender, A. B. Lesser and L. E. Sirois, Angew. Chem., Int. Ed., 2012, 51, 2736; (e) M. Onoe, K. Baba, Y. Kim, Y. Kita, M. Tobisu and N. Chatani, J. Am. Chem. Soc., 2012, 134, 19477; (f) B. M. Trost, B. R. Taft, J. T. Masters and J.-P. Lumb, J. Am. Chem. Soc., 2011, 133, 8502; (g) I. N. Michaelides, B. Darses and D. J. Dixon, Org. Lett., 2011, 13, 664; (h) J. Burghart, A. Sorg and R. Brückner, Chem.–Eur. J., 2011, 17, 6469; (i) H.-S. Yeom, E. So and S. Shin, Chem.–Eur. J., 2011, 17, 1764; (j) P. A. Evans, J. R. Sawyer and P. A. Inglesby, Angew. Chem., Int. Ed., 2010, 49, 5746.
2. (a) J. Burghart and R. Brückner, Angew. Chem., Int. Ed., 2008, 47, 7664; (b) T. Olpp and R. Brückner, Angew. Chem., Int. Ed., 2006, 45, 4023; (c) M. A. Arnold, K. A. Day, S. G. Durón and D. Y. Gin, J. Am. Chem. Soc., 2006, 128, 13255; (d) C. T. Brain, A. Chen, A. Nelson, N. Tanikkul and E. J. Thomas, Tetrahedron Lett., 2001, 42, 1247; (e) G. B. Dudley, K. S. Takaki, D. D. Cha and R. L. Danheiser, Org. Lett., 2000, 2, 3407.
3. (a) Y. Qian, M. Hamilton, A. Sidduri, S. Gabriel, Y. Ren, R. Peng, R. Kondru, A. Narayanan, T. Truitt, R. Hamid, Y. Chen, L. Zhang, A. J. Fretland, R. A. Sanchez, K.-C. Chang, M. Lucas, R. C. Schoenfeld, D. Laine, M. E. Fuentes, C. S. Stevenson and D. C. Budd, J. Med. Chem., 2012, 55, 7920; (b) J. R. Walker, S. C. Rothman and C. D. Poulter, J. Org. Chem., 2008, 73, 726; (c) R. Lira, A. X. Xiang, T. Doundoulakis, W. T. Biller, K. A. Agrios, K. B. Simonsen, S. E. Webber, W. Sisson, R. M. Aust, A. M. Shah, R. E. Showalter, V. N. Banh, K. R. Steffy and J. R. Appleman, Bioorg. Med. Chem. Lett., 2007, 17, 6797; (d) B. Cimetière, T. Dubuffet, O. Muller, J.-J. Descombes, S. Simonet, M. Laubie, T. J. Verbeuren and G. Lavielle, Bioorg. Med. Chem. Lett., 1998, 8, 1375; (e) K. Tatsuta, T. Yoshimoto and H. Gunji, J. Antibiot., 1997, 50, 289; (f) J. W. Coe, C. R. Hawes and P. Towers, J. Labelled Compd. Radiopharm., 1995, 36, 587; (g) G. Johnson, J. T. Drummond, P. A. Boxer and R. F. Bruns, J. Med. Chem., 1992, 35, 233.
4. (a) B. Kang, P. Jakubec and D. J. Dixon, Nat. Prod. Rep. 10.1039/C3NP70115H; (b) B. Darses, I. N. Michaelides, F. Sladojevich, J. W. Ward, P. R. Rzepa and D. J. Dixon, Org. Lett., 2012, 14, 1684; (c) F. Sladojevich, I. N. Michaelides, B. Darses, J. W. Ward and D. J. Dixon, Org. Lett., 2011, 13, 5132.
5. R. B. Boers, Y. P. Randulfe, H. N. S. van der Haas, M. van Rossum-Baan and J. Lugtenburg, Eur. J. Org. Chem., 2002, 2094.
6. R. M. Moriarty, R. K. Vaid, V. T. Ravikumar, T. E. Hopkins and P. Farid, Tetrahedron, 1989, 45, 1605.
7. E. C. Taylor, R. L. Robey and A. McKillop, Angew. Chem., Int. Ed. Engl., 1972, 11, 48.
8. B. Myrboh, H. Ila and H. Junjappa, Synthesis, 1982, 1100.
9. A. Viale, D. Santelia, R. Napolitano, R. Gobetto, W. Dastrù and S. Aime, Eur. J. Inorg. Chem., 2008, 4348.
10. L. Brandsma and H. D. Verkruijsse, Synthesis, 1990, 984.
11. 1-Bromopropyne is oxygen sensitive and can spontaneously ignite upon exposure to air (see ref. 10).
12. (a) T. T. Zung, L. G. Bruk, O. N. Temkin and A. V. Malashkevich, Mendeleev Commun., 1995, 5, 3. For an earlier related synthesis of 3 from propyne using a PdCl₂–CuCl system see: (b) T. T. Zung, L. G. Bruk and O. N. Temkin, Mendeleev Commun., 1994, 4, 2. For a 19% yielding direct oxidative methoxycarbonylation of propyne using PdCl₂–CuCl₂ catalysis see: (c) A. G. Mal’kina, R. N. Kudyakova, V. V. Nosyreva, A. V. Afonin and B. A. Trofimov, Russ. J. Org. Chem., 2002, 38, 1088.
13. (a) D. Toussaint and J. Suffert, Org. Synth., 1999, 76, 214. For a single report of an ester synthesis using a similar method see: (b) A. Otaka, E. Mitsuyama, T. Kinoshita, H. Tamamura and N. Fujii, J. Org. Chem., 2000, 65, 4888.

---

Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00072a

‡ Current address: Institut de Chimie des Substances Naturelles, CNRS UPR2301, Centre de Recherche de Gif, Bâtiment 27, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.

§ 1-Bromo-1-propene (cis and trans, 98%) (CAS 590-14-7) was purchased from Sigma-Aldrich Chemical Company, Inc. (Cat. no. B78203) and used as received.

¶ Anhydrous tetrahydrofuran was obtained by filtration through activated alumina (powder ∼150 mesh, pore size 58 Å, basic, Sigma-Aldrich) columns.

|| n-Butyllithium, 2.5 M solution in hexanes, AcroSeal was purchased from Acros Organics and used as received.

** Methyl chloroformate (99%) (CAS 79-22-1) was purchased from Sigma-Aldrich Chemical Company, Inc. (Cat. no. M35304) and used as received.

†† Employing these conditions for concentrating in vacuo minimized product loss on the rotary evaporator.

‡‡ Depending on the scale, the colour of the crude product may change from pale yellow to brown; however, this has no significant effect on the yield.

§§ Towards the end of the distillation, the residue was transferred to a smaller flask and the distillation was continued to recover the maximum amount of product.

¶¶ Similar results were obtained starting with 40 mL and 10 mL of 1-bromo-1-propene; methyl but-2-ynoate was afforded in 84% and 77% yields respectively.

|||| The product is stable at −20 °C for at least three months.

---