In Situ Generation of 1-Propyne: A Useful Introduction of 1-Propyne on Unsaturated Halogenated Compounds through the Sonogashira Reaction

Abstract

Reaction of (E/Z)-1-bromopropene with exactly 1.42 equivalents of nBuLi followed by addition of water produces in situ a THF solution of propyne. Addition of a vinylic or aromatic halogenated substrates, Pd(PPh₃)₂Cl₂, CuI and an amine to this solution give high yield of the corresponding coupling product bearing a propyne moiety. This practical procedure avoids the use of expensive and inflammable propyne gas which need a special apparatus for bubbling it into the reaction flask.

Key words

alkyne - palladium - catalysis - cross-coupling

References

• 1a Bleckmann W. Hanack M. Chem. Ber.  1984,  117:  3021 
• 1b Froehler BC. Wadwani S. Terhorst TJ. Gerrard SR. Tetrahedron Lett.  1992,  33:  5307 
• 1c Tanaka H. Baba M. Hayakawa H. Sakamaki T. Miyasaka T. Ubasawa M. Takashima H. Sekiya K. Nitta I. J. Med. Chem.  1991,  34:  349 
• 1d Makra F. Rohloff JC. Muehldorf AV. Link JO. Tetrahedron Lett.  1995,  36:  6815 
• 1e Awano H. Shuto S. Miyashita T. Ashida N. Machida H. Arch. Pharm.  1996,  329:  66 
• 1f Blough BE. Abraham P. Lewin AH. Kuhar MJ. Boja JW. Carroll FI. J. Med. Chem.  1996,  39:  4027 
• 1g Kuyper LF. Baccanari DP. Jones ML. Hunter RN. Tansik RL. Joyner SS. Boytos CM. Rudolph SK. Knick V. Wilson HR. Caddell JM. Friedman HS. Comley JCW. Stables JN. J. Med. Chem.  1996,  39:  892 
• 1h Cushman M. He H.-M. Katzenellenbogen JA. Varma RK. Hamel E. Lin CM. Ram S. Sachdeva YP. J. Med. Chem.  1997,  40:  2323 
• 1i Kloppenburg L. Song D. Bunz UHF. J. Am. Chem. Soc.  1998,  120:  7973 
• 1j Xu L. Lewis IR. Davidsen SK. Summers JB. Tetrahedron Lett.  1998,  39:  5159 
• 1k Ostrowski T. Wroblowski B. Busson R. Rozenski J. De Clercq E. Bennett MS. Champness JN. Summers WC. Sanderson MR. Herdewijn P. J. Med. Chem.  1998,  41:  4343 
• 1l Pschirer NG. Bunz UHF. Tetrahedron Lett.  1999,  40:  2481 
• 1m Froehler BC. Wadwani S. Terhorst TJ. Gerrard SR. Tetrahedron Lett.  1992,  33:  5307 
• 1n Sakamoto T. An-naka M. Kondo Y. Yamanaka H. Chem. Pharm. Bull.  1986,  34:  2754 
• 1o Al-Hassan MI. J. Organomet. Chem.  1990,  395:  227 
• 1p Bleckmann W. Hanack M. Chem. Ber.  1984,  117:  3021 
• 2 Jauch J. Schmalzing D. Schurig V. Emberger R. Hopp R. Köpsel M. Silberzahn W. Werkhoff P. Angew. Chem., Int. Ed. Engl.  1989,  28:  1022 
• 3a Suffert J. Toussaint D. J. Org. Chem.  1995,  60:  3550 
• 3b Toussaint D. Suffert J. Organic Synthesis  1999,  76:  214 
• 4a Fritsch P. Liebigs Ann. Chem.  1894,  272:  319 
• 4b Buttenberg WP. Liebigs Ann. Chem.  1894,  272:  324 
• 4c Wiechell H. Liebigs Ann. Chem.  1894,  272:  337 
• 5 Sonogashira K. Toha Y. Hagihara N. Tetrahedron Lett.  1975,  4467 

6

Representative Procedure (Table, Entry 2):
[2,2-Dimethyl-5-(2-pent-1-en-3-ynyl-phenyl)-[1,3]dioxolan -4-ylethynyl]-trimethyl-silane: A solution of nBuLi (1.8 mL, 1.54 M in hexane, 2.73 mmol, 2.2 equiv) was slowly added to a cooled solution of (Z/E)-1-bromopropene (0.233 g, 1.92 mmol, 1.55 equiv) in anhydrous THF (2.5 mL) under argon. This solution was stirred at -78 °C during 2 hours. H₂O (0.05 mL, 2.73 mmol, 2.2 equiv) was then added in one portion at -78 °C via syringe and the reaction mixture warmed to 0 °C. The halogenated substrate (0.470 g, 1.24 mmol, 1 equiv) dissolved in THF (2 mL) was added via syringe to the propyne solution, followed by Pd(Ph₃P)₂Cl₂ (43.5 mg, 0.062 mmol, 0.05 equiv), CuI (23.6 mg, 0.124 mmol, 0.1 equiv) and iPr₂NH (2.2 mL). The temperature was raised to 20 °C and the reaction followed by TLC. Then the reaction was quenched with 20 mL of a saturated NH₄Cl in water and extracted with the appropriate solvent (3 × 10 mL). The organic phase was dried over Na₂SO₄, decolored by charcoal, filtered and the solvent was removed under reduce pressure. The crude propynylated product was purified by flash chromatography (1:99, ether-hexane) on silica gel to give the desired compound (0.418 g 98%). ¹H NMR (200 MHz, CDCl₃) δ 0.21 (s, 9 H, Si(CH₃)₃); 1.61 (s, 3 H,); 1.62 (s, 3 H); 2.01 (d, 3 H, J = 2.4 Hz); 4.38 (d, 1 H, J = 7.9 Hz); 5.38 (d, 1 H, J = 7.9 Hz); 6.05 (dq, 1 H, J _trans = 16 Hz, ⁵ J = 2.4 Hz); 7.25-7.38 (m, 2 H, arom. H); 7.47 (d, 1 H, J _trans = 16 Hz); 7.43-7.57 (m, 2 H, arom. H). ¹³C NMR (50 MHz, CDCl₃): δ 0.44 [Si(CH₃)₃]; 4.5, 26.3, 26.8, 73.1, 79.2, 79.4, 88.5, 93.3, 100.8, 110.4, 111.5, 125.6, 126.2, 128.4, 128.5, 134.0, 135.6, 137.2. IR (CHCl₃, cm^-1) 3668 (w); 3026 (m, CH); 2991 (m, CH); 2962 (s); 2918 (m); 2217 (m); 2177 (m, C≡C); 1600 (m); 1453 (m); 1383 (w); 1255 (w); 1210 (w); 1163 (w); 1100 (w); 1052 (w); 990 (w); 956 (m).