Barium Hydride Promoted Homocoupling and Cross-Coupling Reactions of Enones: An Alternative Entry to Diels-Alder Adducts

Abstract

Barium hydride promoted regioselective dimerization and cross-coupling reactions of 2-cycloalken-1-ones were achieved in the presence of HMPA or DMPU as a Lewis base. The cross-coupling reaction between 2-cyclopenten-1-one and chalcone derivatives followed by intramolecular cyclization provides bicyclic 1,5-diketones, which have a norbornane skeleton, regio- and stereo­specifically in moderate to high yields.

barium - cross-coupling - 1,5-diketones - dimerizations - enones

References and Notes

Reviews:

1a Greeves N. In Comprehensive Organic Synthesis   Vol. 8:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.1 

1b Gawley RE. Zhang X. In Encyclopedia of Reagents for Organic Synthesis   Vol. 6:  Paquette LA. John Wiley & Sons; Chichester: 1995.  p.4238 

1c Gawley RE. In Encyclopedia of Reagents for Organic Synthesis   Vol. 7:  Paquette LA. John Wiley & Sons; Chichester: 1995.  p.4568 

2a Tsuda T. Fujii T. Kawasaki K. Saegusa T. J. Chem. Soc., Chem. Commun.  1980,  1013 

2b Mahoney WS. Brestensky DM. Stryker JM. J. Am. Chem. Soc.  1988,  110:  291 

2c Lipshutz BH. Ung CS. Sengupta S. Synlett  1989,  64 

3 CaH₂ has been utilized as a reductive hydride source: Aida T. Kuboki N. Kato K. Uchikawa W. Matsuno C. Okamoto S. Tetrahedron Lett.  2005,  46:  1667 

For characteristic reactivity and/or selectivity shown by barium reagents, see:

4a Yanagisawa A. Takahashi H. Arai T. Chem. Commun.  2004,  580 

4b Yanagisawa A. Okitsu S. Arai T. Synlett  2005,  1679 

Reviews:

4c Yanagisawa A. In Science of Synthesis   Vol. 7:  Yamamoto H. Thieme; Stuttgart: 2004.  p.695 

4d Yanagisawa A. In Main Group Metals in Organic Synthesis   Vol. 1:  Yamamoto H. Oshima K. Wiley-VCH; Weinheim: 2004.  p.175 

For strontium reagents, see:

4e Miyoshi N. In Science of Synthesis   Vol. 7:  Yamamoto H. Thieme; Stuttgart: 2004.  p.685 

4f Miyoshi N. Ikehara D. Matsuo T. Kohno T. Matsui A. Wada M. J. Synth. Org. Chem. Jpn.  2006,  64:  845 

For recent examples of dimerization of α,β-enones:

5a Carreño MC. Ribagorda M. Org. Lett.  2003,  5:  2425 

5b Zhang F.-Y. Corey EJ. Org. Lett.  2004,  6:  3397 

6

Dimerization Reaction of Enones Promoted by BaH ₂ ; General Procedure: An oven-dried, 50 mL two-necked round-bottomed flask equipped with a Teflon^®-coated magnetic stirring bar was flushed with argon. BaH₂ (280 mg, 2 mmol) was put into the apparatus and covered with anhyd THF (10 mL) and the mixture was stirred for 10 min at r.t. To the heterogeneous solution were added cyclic α,β-unsat-urated ketone (2 mmol) and Lewis base (10 mmol) at 0 °C. After being stirred for 10-62 h under reflux conditions (bath temperature: 80 °C), the mixture was treated with an aq 1 N HCl solution (1.5 mL) at 0 °C and the aqueous layer was extracted with CHCl₃ (5 mL). The combined organic extracts were washed with sat. brine, dried over anhyd Na₂SO₄, and concentrated in vacuo after filtration. The residual crude product was purified by column chromatography on silica gel to give the homocoupling product.
2-(3-Oxocyclohexyl)cyclohex-2-enone (Table [1] and Scheme [1] ): ¹H NMR (400 MHz, CDCl₃): δ = 1.52-1.81 (m, 3 H), 1.85-2.08 (m, 3 H), 2.22-2.48 (m, 8 H), 3.00 (m, 1 H), 6.72 (t, J = 4.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.4, 24.8, 25.7, 30.3, 37.2, 38.4, 40.9, 46.1, 141.4, 144.2, 198.2, 211.1. IR (neat): 3015, 2941, 2868, 1710, 1672, 1388, 1256, 1224, 755 cm^-1.
5-(3-Oxocyclopentyl)cyclopent-2-enone (1:1 mixture, Scheme [2] ): ¹H NMR (400 MHz, CDCl₃): δ = 1.69-2.65 (m, 9 H), 2.87 (m, 1 H), 6.21 (m, 1 H), 7.72 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.1, 27.1, 32.8, 32.9, 37.8, 37.9, 38.0, 38.1, 41.0, 42.6, 47.1, 47.6, 134.3 (2 × C), 163.2, 163.4, 210.5, 210.6, 218.0, 218.3. IR (neat): 2960, 2931, 2902, 1740, 1700, 1589, 1405, 1347, 1161, 778 cm^-1.

7

Besides the dimer, a few by-products were obtained in addition to a significant amount of the starting material.

For reactions via a barium enolate, see:

8a Yamada YMA. Shibasaki M. Tetrahedron Lett.  1998,  39:  5561 

8b Yamada YMA. Uozumi Y. Org. Lett.  2006,  8:  1375 

8c Saito S. Kobayashi S. J. Am. Chem. Soc.  2006,  128:  8704 

8d Takahashi H. Arai T. Yanagisawa A. Synlett  2006,  2833 

For recent examples of Michael addition of enolates, see:

9a Harada S. Kumagai N. Kinoshita T. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2003,  125:  2582 

9b Gnaneshwar R. Wadgaonkar PP. Sivaram S. Tetrahedron Lett.  2003,  44:  6047 

9c Miura K. Nakagawa T. Hosomi A. Synlett  2003,  2068 

9d Miura K. Nakagawa T. Hosomi A. Synlett  2005,  1917 

9e Wang X. Adachi S. Iwai H. Takatsuki H. Fujita K. Kubo M. Oku A. Harada T. J. Org. Chem.  2003,  68:  10046 

9f Harada T. Adachi S. Wang X. Org. Lett.  2004,  6:  4877 

9g Harada T. Yamauchi T. Adachi S. Synlett  2005,  2151 

9h Jaber N. Assié M. Fiaud J.-C. Collin J. Tetrahedron  2004,  60:  3075 

9i Nakagawa T. Fujisawa H. Nagata Y. Mukaiyama T. Bull. Chem. Soc. Jpn.  2005,  78:  236 

9j Kumaraswamy G. Jena N. Sastry MNV. Padmaja M. Markondaiah B. Adv. Synth. Catal.  2005,  347:  867 

9k Wang W. Li H. Wang J. Org. Lett.  2005,  7:  1637 

10

In the catalytic reaction (Scheme [1] ), a second barium enolate such as 2 in Scheme [3] is considered to act as a base to deprotonate 2-cyclohexen-1-one at the 4-position.

11

Although an alternative Morita-Baylis-Hillman-type mechanism can also be considered for the reaction [13] when 2-cyclohexen-1-one was treated with HMPA (5 equiv) in the absence of BaH₂ under the standard reaction conditions, the dimerization reaction did not proceed at all.

12

Cross-Coupling Reaction of Enones Promoted by BaH ₂ ; General Procedure: An oven-dried, 50 mL two-necked round-bottomed flask equipped with a Teflon^®-coated magnetic stirring bar was flushed with argon. BaH₂ (70 mg, 0.5 mmol) was put into the apparatus and covered with anhyd THF (10 mL) and the mixture was stirred for 10 min at r.t. To the heterogeneous solution were added cyclic α,β-unsaturated ketone (1 mmol), chalcone derivative (2 mmol), and DMPU (5 mmol) at 0 °C. After being stirred for 5-40 h under reflux conditions (bath temperature: 80 °C), the mixture was treated with an aq 1 N HCl solution (1.5 mL) at 0 °C and the aqueous layer was extracted with CHCl₃ (5 mL). The combined organic extracts were washed with sat. brine, dried over anhyd Na₂SO₄, and concentrated in vacuo after filtration. The residual crude product was purified by column chromatography on silica gel to give the cross-coupling product.
2-(3-Oxo-1,3-diphenylpropyl)cyclohex-2-enone (Scheme [4] ): ¹H NMR (400 MHz, CDCl₃): δ = 1.88-1.99 (m, 2 H), 2.32-2.43 (m, 4 H), 3.45 (dd, J = 7.7, 16.7 Hz, 1 H), 3.63 (dd, J = 7.2, 16.7 Hz, 1 H), 4.63 (t, J = 7.0 Hz, 1 H), 6.71 (t, J = 4.2 Hz, 1 H), 7.12-7.59 (m, 8 H), 7.89-7.98 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.3, 25.8, 38.3, 40.0, 42.6, 126.2, 127.4 (2 × C), 127.8 (2 × C), 128.2, 128.5 (3 × C), 132.7, 136.6, 141.3, 142.2, 145.5, 197.9, 199.7. IR (neat): 3028, 2946, 1722, 1680, 1598, 1495, 1448 cm^-1.
5-Benzoyl-6-phenylbicyclo[2.2.1]heptan-2-one (Table [2] , Entry 1): ¹H NMR (400 MHz, CDCl₃): δ = 1.87-2.00 (m, 3 H), 2.39 (d, J = 10.9 Hz, 1 H), 2.93 (s, 1 H), 3.12 (s, 1 H), 3.96 (d, J = 5.5 Hz, 1 H), 4.11 (t, J = 4.6 Hz, 1 H), 7.12-7.27 (m, 5 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.97 (d, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 37.7, 39.0, 41.0, 42.0, 55.9, 57.0, 126.3 (4 × C), 126.5, 128.5 (4 × C), 133.2, 136.2, 142.4, 198.5, 213.9. IR (neat): 3056, 2997, 1749, 1675, 1596, 1447, 758 cm^-1.
5-(4-Bromobenzoyl)-6-(4-bromophenyl)bicy-clo[2.2.1]heptan-2-one (Table [2] , Entry 2): ¹H NMR (400 MHz, CDCl₃): δ = 1.95 (m, 2 H), 2.00 (dd, J = 1.2, 10.7 Hz, 1 H), 2.35 (d, J = 10.7 Hz, 1 H), 2.92 (s, 1 H), 3.13 (s, 1 H), 3.89 (d, J = 5.5 Hz, 1 H), 3.95 (t, J = 5.0 Hz, 1 H), 7.09 (d, J = 8.9 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.83 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 38.0, 39.1, 41.2, 41.7, 55.8, 57.5, 120.5, 128.5 (3 × C), 128.8, 129.9, 131.9 (2 × C), 132.1 (2 × C), 135.1, 141.4, 197.5, 213.4. IR (neat): 2997, 2920, 1747, 1676, 1585, 1489, 1399, 1070, 1008, 841, 808 cm^-1.
5-(4-Bromobenzoyl)-6-phenylbicyclo[2.2.1]heptan-2-one (Table [2] , Entry 3): ¹H NMR (400 MHz, CDCl₃): δ = 1.96-2.02 (m, 3 H), 2.41 (d, J = 10.9 Hz, 1 H), 2.98 (s, 1 H), 3.11 (s, 1 H), 3.93 (d, J = 5.6 Hz, 1 H), 4.02 (dd, J = 4.1, 5.6 Hz, 1 H), 7.20-7.33 (m, 5 H), 7.62 (d, J = 8.7 Hz, 2 H), 7.84 (d, J = 8.7 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 37.9, 39.2, 41.1, 42.2, 56.0, 57.3, 126.7 (3 × C), 128.6, 128.8 (2 × C), 129.8 (2 × C), 132.0 (2 × C), 135.2, 142.4, 197.8, 213.9. IR (neat): 2985, 2926, 1746, 1674, 1583, 1400, 1218, 1072, 1004, 770, 698 cm^-1.
5-Benzoyl-6-(4-bromophenyl)bicyclo[2.2.1]heptan-2-one (Table [2] , Entry 4): ¹H NMR (400 MHz, CDCl₃): δ = 1.96-2.05 (m, 3 H), 2.36 (d, J = 10.6 Hz, 1 H), 2.93 (s, 1 H), 3.16 (s, 1 H), 3.92 (d, J = 5.6 Hz, 1 H), 4.02 (t, J = 4.8 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 7.98 (d, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 37.8, 39.0, 41.1, 41.5, 55.7, 57.3, 120.2, 128.2 (2 × C), 128.3 (2 × C), 128.6 (2 × C), 131.6 (2 × C), 133.4, 136.1, 141.5, 198.3, 213.6. IR (neat): 2998, 2956, 2920, 1748, 1673, 1598, 1490, 1250, 1008, 810, 757, 693 cm^-1.
5-(4-Bromobenzoyl)-6-(4-methoxyphenyl)bicy-clo[2.2.1]heptan-2-one (Table [2] , Entry 5): ¹H NMR (400 MHz, CDCl₃): δ = 1.95-2.05 (m, 3 H), 2.40 (d, J = 10.9 Hz, 1 H), 2.91 (s, 1 H), 3.11 (s, 1 H), 3.78 (s, 3 H), 3.86 (d, J = 5.3 Hz, 1 H), 3.98 (t, J = 4.8 Hz, 1 H), 6.84 (d, J = 8.9 Hz, 2 H), 7.14 (d, J = 8.7 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.83 (d, J = 8.7 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 37.9, 39.1, 41.1, 41.7, 55.3, 56.5, 57.5, 114.2 (2 × C), 127.8 (2 × C), 128.6, 129.9 (2 × C), 132.0 (2 × C), 134.4, 135.3, 158.3, 197.9, 213.9. IR (neat): 2963, 2937, 1749, 1668, 1582, 1514, 1251, 809 cm^-1.
5-(4-Bromobenzoyl)-6-(4-methoxyphenyl)-8,8-dimethyl-bicyclo[2.2.2]octan-2-one (Scheme [6] ): ¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 3 H), 1.45 (s, 3 H), 1.58 (d, J = 14.0 Hz, 1 H), 1.92 (d, J = 14.0 Hz, 1 H), 2.02 (s, 1 H), 2.34 (s, 2 H), 2.55 (s, 1 H), 3.76 (s, 3 H), 4.02 (d, J = 8.2 Hz, 1 H), 4.31 (d, J = 8.2 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 2 H), 7.17 (d, J = 7.7 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.87 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.1 (2 × C), 32.8, 35.2, 35.9, 36.7, 44.2, 46.1, 50.2, 55.2, 114.1 (2 × C), 128.4 (2 × C), 128.5, 129.8 (2 × C), 132.2 (2 × C), 132.3, 134.7, 158.3, 199.2, 214.9.

For dimerization reactions of 2-cyclohexen-1-one through the Morita-Baylis-Hillman-type mechanism, see:

13a Risinger GE. Haag WG. J. Org. Chem.  1973,  38:  3646 

13b Hwu JR. Hakimelahi GH. Chou C.-T. Tetrahedron Lett.  1992,  33:  6469 

13c Jenner G. Tetrahedron Lett.  2000,  41:  3091 

13d Reingold ID. Bowerman C. John M. Walters RS. Daglen BC. Butterfield AM. Gembicky M. Tetrahedron Lett.  2006,  47:  1653