Unexpected Side Products in the Large-Scale Preparation of 2,3-Dihydro-1,1,2,2,3,3-hexamethyl-1H-indene

Abstract

During the development of an optimized procedure for the synthesis of 2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene significant amounts of 5-tert-butyl-2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene were formed, along with 5-tert-hexyl-2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene under certain conditions. The structures of 5-tert-hexyl-2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene and 5-tert-butyl-2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene were established by spectroscopic means and confirmed by X-ray single-crystal structure determinations. The mechanism for the formation of 5-tert-butyl-2,3-dihydro-1,1,2,2,3,3-hexamethyl-1H-indene is discussed.

Key words

electrophilic aromatic substitution - highly crowded indenes - mechanisms - carbocation rearrangements - X-ray structural analysis

Publication History

Received: 29 November 2024

Accepted after revision: 20 December 2024

Article published online:
28 January 2025

• References and Notes

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• 5 General Protocol for the Preparation of 2,3-Dihydro-1,1,2,2,3,3-hexamethyl-1H-indene (3, [CAS Reg. No. 91324-94-6]): A solution of TiCl4 (2.5 mL) in CH2Cl2 (50 mL) was added dropwise to a solution of (2-chloroprop-2-yl)benzene (1, 77.3 g, 0.50 mol) and tetramethylethylene (2 [CAS Reg. No. 563-79-1], 90.0 g, 1.07 mol, Sigma-Aldrich, ≥99%) in 1.0 L anhydrous dichloromethane [>99.5%, Sigma-Aldrich, stabilizer 0.002% amylene] cooled to –78 °C with stirring under an N₂ atmosphere. When ca. 10 mL of the solution of TiCl₄ had been added, an exothermic reaction started, and the addition was interrupted until the temperature of the reaction mixture dropped to –78 °C. After complete addition of the TiCl₄, the reaction mixture was stirred for 30 min at –78 °C and poured with stirring into a mixture of concd HCl (300 mL) and water (600 mL). After vigorous stirring for 30 min, the organic phase was separated, washed with a mixture of concd HCl (100 mL) and water (200 mL), then with a mixture of concd (25%) aq. NH₃ (150 mL) and water (100 mL), and finally with brine (100 mL). After drying with Na₂SO₄, and filtration through a pad of Celite (Ø 60 mm, ca. 3 cm high), the filtrate was concentrated under reduced pressure on a rotary evaporator (bath temp. 50 °C), and the residue was then kept at r.t. in vacuo (0.6 mbar) until the weight stayed constant. The crude product was distilled over a MIsprint column (20 cm, vacuum sleeve, bath temp 120 °C, 0.6 mbar) to yield 97.1 g (0.48 mol, 96%) of the product 3, which was pure according to a GC analysis. ¹H NMR (200 MHz, CDCl₃): δ = 7.24–7.06 (m, 4 H, aromatics), 1.20 (s, 12 H, CH₃ at C1 and C3), 0.87 (s, 6 H, CH₃ at C2). ¹³C NMR (50.3MHz, CDCl₃): δ = 150.4 (C8, C9), 126.6 (C4, C7), 122.5 (C5, C6), 48.4 (C2), 47.6 (C1, C3), 27.4 (CH₃ at C1 and C3), 21.5 (CH₃ at C2).
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• 16 General Protocol for the Reaction of 2,3-Dihydro-1,1,2,2,3,3-hexamethyl-1H-indene (3) with Alkenes 2 or 18: A solution of 0.1 mL (0.9 mmol) of TiCl₄ in 0.9 mL of CH₂Cl₂ was added dropwise over 10 min to a solution of 3 (1.0 g, 5 mmol), and the alkene 2 or 18 (0.42 g, 5 mmol) in CH₂Cl₂ (5 mL), kept at –78 °C (dry ice/acetone bath). The reaction mixture was stirred at –78 °C for 30 min and poured with stirring into a mixture of concd HCl (30 mL) and water (60 mL). After vigorous stirring for an additional 30 min, the organic phase was separated, washed with a mixture of concd HCl (10 mL) and water (20 mL), then with a mixture of concd (25%) aq. NH₃ (15 mL) and water (10 mL), and finally with brine (10 mL). The solution was dried over Na₂SO₄, filtered through a pad of Celite and concentrated under reduced pressure in a rotary evaporator (bath temp. 50 °C), the residue was then kept at r.t. in vacuo (0.6 mbar) until the weight stayed constant. The product ratio was determined by GC analysis.
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• 18 General Protocol for the Direct Isomerization of tert-Hexyl Chloride (6, [CAS Reg. No. 594-57-0]): A solution of 6 (0.60 g, 5 mmol) in 5 mL of dichloromethane was treated with a solution of TiCl₄ (0.1 mL) in CH₂Cl₂ (0.9 mL) at –78 °C (dry ice/acetone bath). The reaction mixture was stirred at this temperature for 30 min, then poured into a mixture of concd hydrochloric acid (30 mL) and ice (60 mL). After vigorous stirring for 30 min, the organic phase was separated, washed with a mixture of concd HCl (10 mL) and water (20 mL), then with a mixture of concd (25%) aq. NH₃ (15 mL) and water (10 mL), finally with brine (10 mL). After drying with Na₂SO₄, the solution was filtered through a pad of Celite, concentrated under reduced pressure on a rotary evaporator (bath temp. 50 °C), and the residue was fractionally distilled under reduced pressure. The product ratio was established on the basis of a ¹H NMR spectrum