A Practical and User-Friendly Method for the Selenium-Free One-Step Preparation of 1,2-Diketones and their Monoxime Analogs

Abstract

Treatment of α-methylene ketones with excess sodium nitrite and aqueous HCl in THF at reduced temperatures provides an effective tool for the preparation of a variety of 1,2-diketones. The diastereoselective synthesis of the corresponding (Z)-1,2-dione monoximes could be accomplished under similar conditions, but by using only one equivalent of nitrosating reagent.

1,2-diketones - 1,2-dione monoximes - nitrosation - α-oximation - oxidations

References

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12

The ¹H NMR of 2 showed a significantly low field shifted singlet at δ = 8.53 ppm accounting for an OH group being part of a hydrogen bridge.

13

MS analysis provided evidence for the formation of a minor amount of a dehydrogenated form of 2, that was purified by silica gel chromatography, characterized and proved to be 2-nitroso-cyclododec-2-enone (1% yield), colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 6.91 (t, ³ J = 7.7 Hz, 1 H), 2.74 (t, ³ J = 6.7 Hz, 2 H), 2.46 (dt, ³ J = 7.7 Hz, ³ J = 6.2 Hz, 2 H), 1.80-1.66 (m, 2 H), 1.46 (quint., ³ J = 6.2 Hz, 2 H), 1.34-1.23 (m, 10 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 198.23 (s, C1), 140.99 (d, C3), 133.57 (s, C2), 37.53 (t), 29.07 (t), 26.55 (t), 25.66 (t), 24.79 (t), 24.75 (2 C, t), 24.72 (t), 23.95 (t)ppm. MS (EI): m/z (%) for C₁₂H₁₉NO₂ (209.29) = 209 (19) [M - NO]⁺ , 161 (16), 149 (10), 143 (23), 132 (27), 111 (32), 98 (100), 84 (67), 55 (71).

14

In a control experiment we could show that diketone 3 did not react further to give the corresponding 1,2,3-trione, even if large excess of sodium nitrite in combination with longer reaction times was used.

15

General Procedure for the Prearation of 1,2-Diketones and 1,2-Dione Monoximes.
A suspension of the starting ketone (50 mmol) and NaNO₂ (10.35 g, 150 mmol) in THF (100 mL) was cooled to 0 °C. To this mixture, concd HCl (65 mL) was added in such a way that the temperature did not exceed 10 °C. In order to avoid the evolution of nitrous gases the acid was added via cannula that was immerged into the reaction mixture. After the addition the cooling bath was removed and the suspension turned dark yellow. The progress of the reaction was monitored by GC. After the starting material had vanished (0.1-12 h) the reaction mixture containing the crude 1,2-diketone was poured into a separatory funnel containing crushed ice (200 g) and Et₂O (100 mL). The organic layer was separated, and the aqueous phase extracted with Et₂O (3 × 100 mL). The combined organic layers were washed with a sat. aq solution of NaHCO₃ (100 mL) and with brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by filtration over a pad of silica gel (5:1) using hexane-EtOAc (50:1) as eluent. The corresponding 1,2-dione monoximes were prepared accordingly by using only 3.45 g (50 mmol) of NaNO₂ and 25 mL of concd HCl. The crude product was purified either by filtration over a pad of silica gel (5:1) using hexane-EtOAc (50:1) as eluent or by crystallization from hexane-EtOAc.

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All new compounds were fully characterized. Selected data for novel compounds:
3-Methylcyclododecane-1,2-dione (6f): yellow oil (1.42 g). ¹H NMR (300 MHz, CDCl₃): δ = 3.52 (qdd, ³ J = 7.0 Hz, ³ J = 6.9 Hz, ³ J = 3.5 Hz, 1 H, H-C3), 3.36-3.27 (m, 1 H), 2.26-2.17 (m, 1 H), 1.82-1.68 (m, 3 H), 1.38-1.17 (m, 13 H), 1.10 (d, ³ J = 6.9 Hz, 3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 204.07 (s, C2), 201.93 (s, C1), 38.34 (d, C3), 36.47 (t, C12), 29.86 (t), 26.34 (t), 26.17 (t), 24.95 (t), 23.79 (t), 23.70 (t), 22.09 (t), 14.45 (q, CH₃) ppm. MS (EI): m/z (%) C₁₃H₂₂O₂ (210.32) = 210 (7) [M⁺ ], 192 (1), 167 (3), 153 (6), 139 (8), 125 (22), 112 (29), 98 (37), 83 (24), 69 (51), 55 (100). Anal. Calcd for C₁₃H₂₂O₂ (210.32): C, 74.24; H, 10.54. Found: C, 74.44; H, 10.60.
( Z )-3-Methylcyclododecane-1,2-dione-1-oxime (5f): colorless crystals (0.99 g); mp 97-98 °C (from hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = ca. 8 (s, 1 H, NOH), 3.62 (qdd, ³ J = 7.0 Hz, ³ J = 6.9 Hz, ³ J = 3.6 Hz, 1 H, H-C12), 2.89-2.80 (m, 1 H), 2.65-2.57 (m, 1 H), 1.84-1.76 (m, 1 H), 1.66-1.42 (m, 3 H), 1.37-1.16 (m, 12 H), 1.09 (d, ³ J = 6.9 Hz, 3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 203.15 (s, C1), 160.06 (s, C2), 39.64 (d, C12), 31.38 (t, C3), 26.09 (t, 2 C), 25.04 (t), 23.42 (t), 22.87 (t), 22.65 (t), 21.89 (t), 21.19 (t), 15.12 (q, CH₃) ppm. MS (EI): m/z (%) C₁₃H₂₃NO₂ (225.32) = 225 (4) [M⁺ ], 208 (26), 197 (5), 180 (42), 168 (11), 138 (18), 124 (26), 110 (28), 96 (34), 82 (37), 69 (45), 55 (100). Anal. Calcd for C₁₃H₂₃NO₂ (225.33): C, 69.29; H, 10.29; N, 6.22. Found: C, 69.18; H, 10.19; N, 6.11.
3-Methoxycyclododecane-1,2-dione (6g): yellow oil (1.23 g). ¹H NMR (300 MHz, CDCl₃): δ = 4.85 (t, ³ J = 4.4 Hz, 1 H, H-C3), 3.38 (s, 3 H, OCH₃), 2.23-2.14 (m, 1 H), 1.90-1.83 (m, 2 H), 1.73-1.66 (m, 2 H), 1.53-1.49 (m, 1 H), 1.39-1.02 (m, 12 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 202.10 (s), 199.00 (s), 81.14 (d, C3), 57.61 (q, OCH₃), 36.71 (t, C12), 27.30 (t), 26.21 (t), 26.17 (t), 24.33 (t), 23.29 (t), 22.03 (t), 21.83 (t), 19.48 (t) ppm. MS (EI): m/z (%) C₁₃H₂₂O₂ (210.32) = 226 (1) [M⁺ ], 198 (8), 148 (5), 138 (8), 127 (6), 109 (13), 96 (19), 82 (43), 71 (100), 55 (34). Anal. Calcd for C₁₃H₂₂O₃ (226.32): C, 68.99; H, 9.80. Found: C, 69.12; H, 9.85.
( Z )-3-Methoxycyclododecane-1,2-dione-1-oxime (5g): colorless crystals (1.86 g); mp 100-102 °C (from hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 7.50 (s, 1 H, NOH), 4.88-4.86 (m, 1 H, H-C12), 3.37 (s, 3 H, OCH₃), 2.94-2.84 (m, 1 H), 2.65-2.58 (m, 1 H), 1.97-1.86 (m, 2 H), 1.55-1.37 (m, 2 H), 1.36-1.02 (m, 12 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 198.16 [s, C(1)], 159.63 [s, C(2)], 82.52 [d, C(12)], 57.46 (q, OCH₃), 29.03 (t), 26.24 (t), 26.16 (t), 24.02 (t), 22.81 (t), 22.50 (t), 21.91 (t), 21.78 (t), 18.80 (t)ppm. MS (EI): m/z (%) C₁₃H₂₃NO₂ (225.33) = 241 (2) [M⁺ ], 224 (58), 196 (95), 182 (17), 166 (14), 120 (23), 110 (21), 96 (27), 71 (100), 55 (52). Anal. Calcd for C₁₃H₂₃NO₃ (241.33): C, 64.70; H, 9.61; N, 5.80. Found: C, 64.83; H, 9.70; N, 5.88.

17 Rüedi G. Nagel M. Hansen H.-J. Org. Lett.  2003,  5:  2691 

18

(+)- trans -2-(2,2,3-Trimethylcyclopentyl)-1-phenyl-ethanedione (13): bright yellow oil; [α]_D ²³ +39.2 (c 1.6, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.03 (dd, ³ J = 8.2 Hz, ⁴ J = 1.4 Hz, 2 H), 7.64-7.59 (m, 1 H), 7.52-7.47 (m, 2 H), 3.61 (dd, ³ J = 8.3, 6.4 Hz, 1 H), 2.10-1.24 (m, 5 H), 0.97 (s, 3 H), 0.95 (s, 3 H), 0.87 (d, ³ J = 6.9 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 205.83 (s), 192.16 (s), 135.10 (s), 134.17 (d), 130.40 (d), 128.70 (d), 55.64 (d), 45.75 (s), 44.27 (d), 31.74 (t), 24.92 (q), 24.81 (t), 24.22 (q), 14.44 (q) ppm. MS (EI): m/z (%) C₁₆H₂₀O₂ (244.33) = 244 (3) [M⁺ ], 139 (59) [M - COPh]⁺ , 111 (97), 105 (82) [COPh⁺ ], 77 (75), 69 (100), 55 (94).

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Several reactions were conducted on a 20 g scale.