New Alkynyl Amides by Negishi Coupling

Abstract

Negishi coupling of terminal alkynyl amides with ­(hetero)aryl iodides in the presence of Pd₂dba₃ and triphenyl­phosphine affords new alkynyl amides in yields of up to 90%.

alkynes - Negishi reaction - ynamides

References

1a For a recent review of ynamides and ynamines, see: Zificsak CA. Mulder JA. Hsung RP. Rameshkumar C. Wei L.-L. Tetrahedron  2001,  57:  7575 

1b See also: Mulder JA. Kurtz KCM. Hsung RP. Synlett  2003,  1379 

1c Viehe HG. Chemistry of Acetylenes   Marcel Dekker; New York: 1969.  Chap. 12. p.861-912  

1d Viehe HG. Angew. Chem., Int. Ed. Engl.  1967,  6:  767 

1e Himbert G. In Methoden der Organischen Chemie (Houben-Weyl)   Kropf H. Schaumann E. Georg Thieme Verlag; Stuttgart: 1993.  p.3267-3443  

2a Witulski B. Stengel T. Angew. Chem. Int. Ed.  1998,  37:  489 

2b Brückner D. Synlett  2000,  1402 

2c Stang PJ. J. Org. Chem.  2003,  68:  2997 

2d Frederick MO. Mulder JA. Tracey MR. Hsung RP. Huang J. Kurtz KCM. Shen L. Douglas CJ. J. Am. Chem. Soc.  2003,  125:  2368 

2e Dunetz JR. Danheiser RL. Org. Lett.  2003,  5:  4011 

3a Witulski B. Lumtscher J. Bergsträsser U. Synlett  2003,  708 

3b For a related reaction, see: Löffler A. Himbert G. Synthesis  1994,  383 

Selected publications:

4a Rodríguez D. Navarro A. Castedo L. Domínguez D. Saá C. J. Am. Chem. Soc.  2001,  123:  9178 

4b Rodríguez D. Navarro A. Castedo L. Domínguez D. Saá C. J. Org. Chem.  2003,  68:  1938 

4c Rodríguez D. Castedo L. Domínguez D. Saá C. Org. Lett.  2003,  5:  3119 

5 For a comprehensive review of the palladium-catalyzed cross-coupling, see: Negishi E. Handbook of Organopalladium Chemistry for Organic Synthesis   Part 3, Vol. 1:  Wiley-Interscience; New York: 2002.  p.215-1119  

6 As far as we know, there has been a report of Sonogashira coupling of an ynamine but not of any amide. Whether or not an ynamine dimer analogous to 8 was also produced in Liao et al’s reaction is not known, because they used a solid support for their aryl iodide and washed away all components of the reaction mixture other than the cross-coupled product. See: Liao Y. Fathi R. Reitman M. Zhang Y. Yang Z. Tetrahedron Lett.  2001,  42:  1815 

7 For homocoupling of 1-alkynyl tosylamides, see: Rodríguez D. Castedo L. Saá C. Synlett  2004,  377 

8

Typical Procedure for the Negishi Coupling of Zinc Acetylides with Aromatic Iodides: N-phenyl-N-(pyrimidin-2-ylethynyl) tosylamide (13i): n-BuLi (0.56 mL, 1.6 M in hexanes) was slowly added to a solution of 9 (0.15 g, 0.43 mmol) in dry THF (8 mL) cooled at -78 °C and the mixture was stirred for 5 min. Then, a solution of ZnBr₂ (0.31 mL, 1.5 M in THF) was added via syringe and the stirring continued for 20 min at r.t. The whole mixture was transferred via cannula to a solution of Pd₂dba₃ (22 mg, 0.02 mmol), PPh₃ (22 mg, 0.09 mmol) and 2-iodopyrimidine (0.11 g, 0.51 mmol) in dry THF (4 mL). After 3 h TLC showed complete consumption of the intermediate acetylide. The volatiles were removed and the residue was solved in EtOAc (20 mL) and washed with brine (2 × 20 mL). The organic layer was dried over anhyd Na₂SO₄ and evaporated to dryness. The crude residue was purified by column chromatography on silica gel using hexane/EtOAc 1:2 as eluent to yield 13i (0.12 g, 81%) as colorless prisms; mp 107-109 °C. ¹H NMR (250 MHz, CDCl₃): δ = 8.68-8.63 (m, 2 H, ArH), 7.75-7.67 (m, 2 H, ArH), 7.38-7.24 (m, 7 H, ArH), 7.19-7.12 (m, 1 H, ArH), 2.43 (s, 3 H, CH₃). ¹³C NMR + DEPT (62.83 MHz, CDCl₃): δ = 157.0 (2 × CH), 153.2 (C), 145.3 (C), 137.7 (C), 132.8 (C), 129.6 (2 × CH), 129.2 (2 × CH), 128.7 (CH), 128.2 (2 × CH), 126.5 (2 × CH), 119.0 (CH), 82.3 (C), 71.4 (C), 21.6 (CH₃). EM: m/z (%) = 349 (2) [M⁺], 284 (50), 91 (37), 77 (100). Elem. anal. calcd (%) for C₁₉H₁₅N₃O₂S (349.41): C, 65.31; H, 4.33; N, 12.03; S, 9.18. Found: C, 65.62; H, 4.21; N, 11.90; S, 9.38.
N-phenyl-N-(4-nitrophenylethynyl) tosylamide (13g): pale brown needles; mp 129-131 °C. ¹H NMR (250 MHz, CDCl₃): δ = 8.17 (d, J = 8.7 Hz, 2 H, ArH), 7.62 (d, J = 8.2 Hz, 2 H, ArH), 7.48 (d, J = 8.7 Hz, 2 H, ArH), 7.39-7.26 (m, 7 H, ArH), 2.45 (s, 3 H, CH₃). ¹³C NMR + DEPT (62.83 MHz, CDCl₃): δ = 146.3 (C), 145.4 (C), 138.1 (C), 132.7 (C), 131.0 (2 × CH), 130.0 (C), 129.7 (2 × CH), 129.3 (2 × CH), 128.7 (CH), 128.1 (2 × CH), 126.3 (2 × CH), 123.5 (2 × CH), 89.7 (C), 69.8 (C), 21.7 (CH₃); EM: m/z (%) = 392 (14) [M⁺], 237 (74), 91 (100).
N-(4-nitrophenylethynyl)-N-propyl tosylamide (14g): clear oil. ¹H NMR (250 MHz, CDCl₃): δ = 8.15 (d, J = 8.7 Hz, 2 H, ArH), 7.83 (d, J = 8.0 Hz, 2 H, ArH), 7.40 (d, J = 8.7 Hz, 2 H, ArH), 7.37 (d, J = 8.0 Hz, 2 H, ArH), 3.41 (t, J = 7.2 Hz, 2 H, CH₂N), 2.46 (s, 3 H, CH₃), 1.78-1.70 (m, 2 H, CH₂), 0.96 (t, J = 7.4 Hz, 2 H, CH₃). ¹³C NMR + DEPT (62.83 MHz, CDCl₃): δ = 146.1 (C), 145.0 (C), 134.3 (C), 130.7 (2 × CH), 130.3 (C), 129.9 (2 × CH), 127.4 (2 × CH), 123.5 (2 × CH), 88.4 (C), 70.4 (C), 53.0 (CH₂), 21.6 (CH₃), 21.3 (CH₂), 10.7 (CH₃). EM: m/z (%): 358 (7) [M⁺], 150 (37), 91 (100)