Scalable Synthesis of 6,6-Dimethylbicyclo[3.1.0]hexan-3-one

Abstract

A simple five-step process for the conversion of technical grade (+)-3-carene into 6,6-dimethylbicyclo[3.1.0]hexan-3-one was developed. A robust process was required that delivered the 6,6-dimethylbicyclo[3.1.0]hexan-3-one, minimized chromatography, reduced the excess of silver salts, and avoided toxic chromium oxidants. A simple and scalable process that relies on crystallization and distillation was developed and demonstrated to produce hundreds of grams of 6,6-dimethylbicyclo[3.1.0]hexan-3-one.

Key words

semipinacol - Dess–Martin - carene - bromohydrin - silver nitrate - Baeyer–Villiger

• References and Notes

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Synthesis of ketone from alcohol (post pinacol):
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• 8 Current costs from sigmaaldrich.com (Item: 94415-1ML at $54.10; Item: W382108-1KG at $97).
• 9 See Supporting Information for GC method details.
• 10 Unidentified impurity was present at a relative retention time (RRT) of 0.87 min by gas chromatography.
• 11 (1S,3R,4R,6R)-4-Bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (2) To a clean and dry 45 L glass reactor was charged 1,4-dioxane (8,000 mL, 8.0 V), water (4,000 mL, 4.0 V), (+)-3-carene (1,000 g, 7.3 mol), and CaCO₃ (977 g, 9.8 mol), and the suspension was cooled to 10 °C. NBS (1,698 g, 9.5 mol) was added in portions over 1 h while maintaining the internal temperature. At the end of addition, the resulting mixture was warmed to 20 °C and maintained for 3 h, and the progress of the reaction was monitored by GC until (+)-3-carene was not detected. The reaction mixture was then diluted with water (20,000 mL, 20 V) and extracted twice with PE (12,000 mL, 12 V). The combined organic extracts were washed twice with 5% w/w Na₂S₂O₃ solution (10,000 L, 10 V), dried over anhydrous Na₂CO₄, and concentrated under vacuum at 35 °C to get the crude product. The crude product was dissolved in hexane (4,000 mL, 4 V), cooled to –40 °C, and stirred for 30 min. The solid was filtered, washed with chilled hexane (1,000 mL, 1 V), and dried at 25 °C for 5 h to get 850 g of (1S,3R,4R,6R)-4-bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol as off-white solid as main crop with 95% GC purity. The mother liquor was cooled to –40 °C, stirred for 30 min, filtered, dried, and isolated another 100 g as off-white solid (second crop) with 94% purity by GC. Both the crops material were mixed and taken forward into the next step. TLC: PE/EtOAc (8:2); Stain solution: PMA (10% EtOH), yield 950 g (56%). ¹HNMR of first crop (300 MHz, CDCl₃): δ = 0.69 (t, J = 7.26 Hz, 1 H), 0.80–0.88 (m, 1 H), 0.99 and 1.02 (s, 6 H), 1.30 (s, 3 H), 1.41 (d, J = 4.92 Hz, 1 H), 2.20 (dd, J = 14.63 and 9.72 Hz, 1 H), 2.34–2.49 (m, 2 H), 4.06 (dd, J = 10.79 and 7.95 Hz, 1 H).
• 12 Current costs from sigmaaldrich.com of 99% purity silver salt: AgNO₃(S6506-500G at $1,071.20/0.5kg) costs $546/mol 3 using 1.5 equiv AgNO₃ and Ag₂O (item: 221163-1KG at $2,195.00/kg) costs $1,017/mol 3 using 2.0 equiv Ag₂O.
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• 17 Distillation conditions: batch temperature 85–105 °C, pressure 10–1 mbar, isolated yield 88% on 7 g scale. Equipment: Short path distillation head with a combined cold-coil and Liebig condenser and affixed with a three-port distribution adapter.
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