Rapid 1,4-Alkynylation of Acyclic Enones Using K[F₃BCCR]

Abstract

Conjugate alkynylation of acyclic enones using sp-hybridised potassium organotrifluoroborates in the presence of BF₃˙OEt₂ is rapidly attained. The simplicity of the processes is suitable for the preparation of small compound libraries.

conjugated alkynylation - enones - potassium organotrifluoroborates

References and Notes

1 For a recent review, see: Hall DG. In Boronic Acids - Preparation, Applications in Organic Synthesis and Medicine   Hall DG. Wiley-VCH; Weinheim: 2005.  p.1-99  

2a Darses S. Michaud G. Genet J.-P. Tetrahedron Lett.  1998,  39:  5045 

2b Molander GA. Rivero MR. Org. Lett.  2002,  4:  107 

3

Based on a survey of the SciFinder Scholar (ACS), CAPLUS and MEDLINE databases, September 2008.

4a Darses S. Michaud G. Genet J.-P. Eur. J. Org. Chem.  1999,  1875 

4b Molander GA. Katona BW. Machrouhi F. J. Org. Chem.  2002,  67:  8416 ; while presently relatively few K[F₃BCCR] are commercially available, this situation is changing rapidly

5a Kabalka GW. Venkataiah B. Dong G. Tetrahedron Lett.  2004,  45:  729 

5b Ochiai M. Miyamoto K. Yokota Y. Suefuji T. Shiro M. Angew. Chem. Int. Ed.  2005,  44:  75 

5c Vieira AS. Ferreira FP. Fiorante FP. Guadagnin FC. Stefani HA. Tetrahedron  2008,  64:  3306 

6 For a recent review on 1,4-alkynylations of enones, see: Shinji F. Knöpfel TF. Zarotti P. Ichikawa T. Boyall D. Carreira EM. Bull. Chem. Soc. Jpn.  2007,  80:  1635 

7a Knöpfel TF. Carreira EM. J. Am. Chem. Soc.  2003,  125:  6054 

7b Knöpfel TF. Zarotti P. Ichikawa T. Carreira EM. J. Am. Chem. Soc.  2005,  127:  9682 

7c Chang S. Na Y. Choi E. Kim S. Org. Lett.  2001,  3:  2089 

8 Nishimura T. Guo XX. Uchiyama N. Katoh T. Hayashi T. J. Am. Chem. Soc.  2008,  130:  1576 

9 Eriksson M. Iliefski T. Nilsson M. Olsson T. J. Org. Chem.  1997,  62:  182 

10 Kim S. Lee JM. Tetrahedron Lett.  1990,  31:  7627 

11 Kwak YS. Corey EJ. Org. Lett.  2004,  6:  3385 

12 Wu TR. Chong JM. J. Am. Chem. Soc.  2005,  127:  3244 

13 Fujishima H. Takada E. Hara S. Suzuki A. Chem. Lett.  1992,  658 

14 The nucleophile described in Equation 1 has been recently used by Tehrani and co-workers for the alkynylation of two imines. However, the corresponding products were obtained only in poor yields (17-31%). See: Stas S. Tehrani KA. Laus G. Tetrahedron  2008,  64:  3457 

15

α,β-Unsaturated esters were unreactive under the present conditions.

16

Typical Procedure for the Conjugated Alkynylation of Acyclic Enones (Entry 4, Table 2)
Under an argon atmosphere, BF₃˙OEt₂ (0.45 mmol, 63.9 mg), was added at r.t. to a stirred suspension of potassium organotrifluoroborate 1b (0.6 mmol, 124.8 mg) in CH₂Cl₂ (3.0 mL). To the resulting mixture was added a solution of enone 2b (0.3 mmol, 62.6 mg), and the reaction was allowed to react for 25 min at r.t. The reaction was then quenched with brine (2.0 mL) and then diluted with CH₂Cl₂ (6 mL). Evaporation of the dried (MgSO₄) organic solution afforded a crude reaction mixture which was purified by silica gel column chromatography eluting with light petroleum-Et₂O (9:1) to give pure 1,3,5-triphenylpent-4-yn-1-one (4bb; 87%) as a white solid, mp 89-90 ˚C. IR (CHCl₃): ν = 3009, 1687, 1601, 1491, 1449, 1351, 1239 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.47 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.0 Hz), 3.71 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 8.0 Hz), 4.66-4.73 (m, 1 H), 7.28-7.32 (m, 4 H), 7.38-7.43 (m, 4 H), 7.48-7.52 (m, 2 H), 7.57-7.61 (m, 3 H), 7.98-8.04 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 33.8, 47.3, 83.4, 90.8, 123.4, 127.1, 127.6, 127.9, 128.2, 128.7, 128.8, 131.7, 133.3, 136.9, 141.3, 197.15. ESI-MS (+): m/z = 333.12 [M + Na]⁺.
5-Methyl-7-phenylhept-6-yn-3-one (4ab, Entry 1, Table 2)
Yield 70%. Yellow liquid. IR (CHCl₃): ν = 3011, 2979, 2937, 1713, 1599, 1489, 1459, 1410, 1359, 1239, 1116 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.12 (t, 3 H, J = 7.2 Hz), 1.30 (d, 3 H, J = 7.2 Hz), 2.48-2.55 (m, 2 H), 2.58 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 7.2 Hz), 2.76 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.8 Hz), 3.19-3.26 (m, 1 H), 7.27-7.32 (m, 3 H), 7.37-7.41 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 7.7, 21.0, 22.4, 36.7, 49.1, 80.9, 93.2, 123.6, 127.4, 128.2, 131.6, 209.4. ESI-MS (+): m/z = 223.11 [M + Na]⁺.
5,8-Dimethylnon-8-en-6-yn-3-one (4ac, Entry 2, Table 2)
Yield 57%; pale yellow liquid. ^¹H NMR (400 MHz, CDCl₃): δ = 1.09 (t, 3 H, J = 7.2 Hz), 1.22 (d, 3 H, J = 6.8 Hz), 1.89 (s, 3 H), 2.41-2.53 (m, 3 H), 2.69 (dd, 1 H, J ₁ = 16.0 Hz, J ₂ = 7.2 Hz), 3.08-3.14 (m, 1 H), 5.15-5.20 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 7.7, 20.9, 22.3, 23.8, 36.6, 49.1, 82.1, 92.2, 120.8, 127.0, 209.4.
1,3-Diphenyldec-4-yn-1-one (4ba, Entry 3, Table 2)
Yield 75%; colorless oil. IR (CHCl₃): ν = 3008, 2933, 2861, 1686, 1600, 1494, 1449, 1351, 1255, 1181, 1024, 977 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, 3 H, J = 6.0 Hz), 1.22-1.39 (m, 4 H), 1.41-1.50 (m, 2 H), 2.19 (dt, 2 H, J ₁ = 7.2 Hz, J ₂ = 2.4 Hz), 3.30 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 7.2 Hz), 3.57 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 8.0 Hz), 4.40-4.46 (m, 1 H), 7.23-7.30 (m, 1 H), 7.32-7.38 (m, 2 H), 7.43-7.51 (m, 4 H), 7.54-7.61 (m, 1 H), 7.95-8.00 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 18.8, 22.2, 28.6, 31.1, 33.4, 47.7, 81.0, 83.7, 126.9, 127.5, 128.2, 128.3, 128.6, 133.1, 137.0, 142.0, 197.6. ESI-MS (+): m/z = 327.17 [M + Na]⁺.
6-Methyl-1,3-diphenylhept-6-en-4-yn-1-one (4bc, Entry 5, Table 2)
Yield 77%; solid; mp 44-46 ˚C. IR (CHCl₃): ν = 3009, 1687, 1600, 1494, 1450, 1351, 1255, 1023, 976, 900 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.86 (m, 3 H), 3.38 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.4 Hz), 3.61 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 7.6 Hz), 4.57 (dd, 1 H, J ₁ = 7.6 Hz, J ₂ = 6.4 Hz), 5.17-5.23 (m, 2 H), 7.24-7.30 (m, 1 H), 7.33-7.39 (m, 2 H), 7.44-7.51 (m, 4 H), 7.57-7.62 (m, 1 H), 7.94-8.01 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.6, 33.6, 47.3, 84.6, 89.7, 121.2, 126.9, 127.1, 127.6, 128.2, 128.6, 128.7, 133.2, 136.9, 141.3, 197.2. ESI-MS (+): m/z = 297.12 [M + Na]⁺.
4,6-Diphenylhex-5-yn-2-one (4cb, Entry 6, Table 2)
Yield 65%; pale yellow liquid. IR (CHCl₃): ν = 3011, 1717, 1601, 1491, 1453, 1405, 1360, 1240, 1160, 1070, 1027 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.21 (s, 3 H), 2.93 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.0 Hz), 3.11 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 8.0 Hz), 4.44-4.48 (m, 1 H), 7.22-7.50 (m, 10 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 30.7, 33.6, 51.9, 83.3, 90.4, 123.3, 127.2, 127.5, 128.0, 128.3, 128.8, 131.7, 141.0, 205.8. ESI-MS (+): m/z = 271.10 [M + Na]⁺.
7-Methyl-4-phenyloct-7-en-5-yn-2-one (4cc, Entry 7, Table 2)
Yield 54%; pale yellow liquid. IR (CHCl₃): ν = 3011, 1715, 1602, 1494, 1453, 1359, 1240, 1160, 900 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.91 (s, 3 H), 2.18 (s, 3 H), 2.85 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.4 Hz), 3.01 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 8.0 Hz), 4.33 (dd, 1 H, J ₁ = 8.0 Hz, J ₂ = 6.4 Hz), 5.21-5.28 (m, 2 H), 7.25-7.43 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.7, 30.7, 33.5, 52.0, 84.5, 89.3, 121.3, 126.8, 127.1, 127.4, 128.7, 141.0, 205.8. ESI-MS (+): m/z = 235.11 [M + Na]⁺.
4-(Phenylethynyl)heptan-2-one (4db, Entry 8, Table 2)
Yield 55%; light yellow liquid.IR (CHCl₃): ν = 3010, 2961, 2933, 2874, 1713, 1600, 1490, 1442, 1362, 1239, 1163, 909 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.98 (t, 3 H, J = 6.0 Hz), 1.45-1.62 (m, 4 H), 2.25 (s, 3 H), 2.62 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.4 Hz), 2.78 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 7.6 Hz), 3.09-3.15 (m, 1 H), 7.28-7.31 (m, 3 H), 7.39-7.42 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 20.5, 27.6, 30.6, 37.0, 49.0, 81.9, 92.0, 123.6, 127.7, 128.2, 131.6, 207.0. ESI-MS (+): m/z = 237.12 [M + Na]⁺.
4-Pentylundec-5-yn-2-one (4ea, Entry 9, Table 2)
Yield 40% (conversion 75%); colorless liquid. IR (CHCl₃): ν = 3007, 2958, 2932, 2860, 1713, 1602, 1466, 1361, 1239, 1163 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.82-0.93 (m, 6 H), 1.18-1.55 (m, 14 H), 2.15 (dt, 2 H, J ₁ = 6.8 Hz, J ₂ = 2.4 Hz), 2.20 (s, 3 H), 2.48 (dd, 1 H, J ₁ = 16.0 Hz, J ₂ = 6.0 Hz), 2.61 (dd, 1 H, J ₁ = 16.0 Hz, J ₂ = 8.0 Hz), 2.78-2.90 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.0 (2 C), 18.7, 22.2, 22.6, 26.9, 27.5, 28.7, 30.6, 31.0, 31.5, 35.2, 49.5, 81.9, 82.1, 207.4.
4-Hexylundec-5-yn-2-one (4fa, Entry 10, Table 2)
Yield 57%; pale yellow liquid. IR (CHCl₃): ν = 3010, 2958, 2931, 2859, 1713, 1602, 1466, 1361, 1239, 1162 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.81-0.92 (m, 6 H), 1.21-1.52 (m, 16 H), 2.15 (dt, 2 H, J ₁ = 7.2 Hz, J ₂ = 2.0 Hz), 2.20 (s, 3 H), 2.48 (dd, 1 H, J ₁ = 15.6 Hz, J ₂ = 6.4 Hz), 2.61 (dd, 1 H, J ₁ = 15.6 Hz, J ₂ = 8.0 Hz), 2.78-2.87 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 14.1, 18.7, 22.2, 22.6, 27.2, 27.5, 28.8, 29.0, 30.6, 31.0, 31.8, 35.2, 49.5, 81.9, 82.1, 207.5. ESI-MS (+): m/z = 273.21 [M + Na]⁺.
4-(Phenylethynyl)decan-2-one (4fb, Entry 11, Table 2)
Yield 48%; light yellow liquid. IR (CHCl₃): 3011, 2930, 2858, 1714, 1601, 1490, 1466, 1362, 1161, 913 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.86-0.94 (m, 3 H), 1.25-1.41 (m, 6 H), 1.43-1.62 (m, 4 H), 2.20 (s, 3 H), 2.62 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 6.4 Hz), 2.78 (dd, 1 H, J ₁ = 16.4 Hz, J ₂ = 7.6 Hz), 3.06-3.13 (m, 1 H), 7.28-7.33 (m, 3 H), 7.39-7.43 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 22.7, 27.3, 27.9, 29.0, 30.6, 31.8, 34.9, 49.0, 81.9, 92.1, 123.7, 127.7, 128.2, 131.6, 206.9. ESI-MS (+): m/z = 279.17 [M + Na]⁺.