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.

Key words

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

References and Notes

• Reviews:
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• 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 
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• For strontium reagents, see:
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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.

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.