Enantiopure 3-Amino-Substituted 1-Indanones, 1-Tetralones, and 1-Benzosuberones via Friedel–Crafts Cyclisation of ω-Aryl-β-benz­amido Acids

Dedicated to Peter Vollhardt on the occasion of his 69^th birthday

Abstract

Conjugate addition of enantiopure lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of ω-aryl-α,β-unsaturated esters gives the corresponding ω-aryl-β-amino esters as single diastereoisomers in high yields. Friedel–Crafts cyclisation of the pendant carbonyl group onto the ω-aryl ring then gives a range of 3-amino-substituted 1-indanones, 1-tetralones, and 1-benzosuberones, representing an efficient and short protocol for the preparation of these benzo-fused carbocycles in enantiopure form.

Key words

1-benzosuberone - conjugate addition - Friedel–Crafts - 1-indanone - 1-tetralone

• References and Notes

• 1a Davies SG, Price PD, Smith AD. Tetrahedron: Asymmetry 2005; 16: 2833
• 1b Davies SG, Fletcher AM, Roberts PM, Thomson JE. Tetrahedron: Asymmetry 2012; 23: 1111

For related examples, see:
• 2a Horton WJ, Thompson G. J Am. Chem. Soc. 1954; 76: 1909
• 2b Zymalkowski P, Dornhege E. Tetrahedron Lett. 1968; 55: 5743
• 2c Rault S, Dallemange P, Robba M. Bull. Soc. Chim. Fr. 1987; 6: 1079
• 2d Kimbara K, Katsumata Y, Saigo K. Chem. Lett. 2002; 266
• 3 For the preparation of 4 and 22, see: Davies SG, Garrido NM, Kruchinin D, Ichihara O, Kotchie LJ, Price PD, Price Mortimer AJ, Russell AJ, Smith AD. Tetrahedron: Asymmetry 2006; 17: 1793

For the preparation of 5, see:
• 4a Bunnage ME, Davies SG, Goodwin CJ. Synlett 1993; 731
• 4b Bunnage ME, Davies SG, Goodwin CJ, Ichihara O. Tetrahedron 1994; 50: 3975
• 5 Costello JF, Davies SG, Ichihara O. Tetrahedron: Asymmetry 1994; 5: 1999
• 6 Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1044396.
• 7 For the preparation of 22 and 24, see: Davies SG, Mulvaney AW, Russell AJ, Smith AD. Tetrahedron: Asymmetry 2007; 18: 1554
• 8a Coote SJ, Davies SG, Middlemiss D, Naylor A. J. Chem. Soc., Perkin Trans. 1 1989; 2223
• 8b Coote SJ, Davies SG, Fletcher AM, Roberts PM, Thomson JE. Chem. Asian J. 2010; 5: 589
• 9 General experimental procedure (ester hydrolysis/acid chloride formation/Friedel–Crafts cyclisation sequence). The requisite β-benzamido tert-butyl ester (1 mmol) was dissolved in TFA (2 mL) and the solution was stirred at r.t. for 30 min. After this time the TFA was removed in vacuo. The residue was co-evaporated with PhMe (3 × 4 mL), then dried under high vacuum. The residue was then dissolved in CH₂Cl₂ (2 mL) and one drop of DMF, then (COCl)₂ (1.1 mmol) was added drop-wise. The resultant solution was stirred until cessation of effervescence, then cooled to 0 °C. AlCl₃ (2.0 mmol) was added portion-wise, and the resultant solution was stirred for 16 h. The reaction was quenched with H₂O (0.5 mL) and the resultant mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed sequentially with 10% aq HCl (20 mL), sat. aq NaHCO₃ (20 mL) and brine (20 mL), then dried (MgSO₄), filtered and concentrated in vacuo.Data for 16: solid; mp 168–169 °C; [α]²¹ d +23.1 (c 1.1, CHCl₃); IR: ν_max 1679, 1642; ¹H NMR (400 MHz, CDCl₃): δ = 2.83 (1 H, dd, J = 16.9, 8.8 Hz), 3.05 (1 H, ddd, J = 16.9, 4.2, 0.9 Hz), 3.12 (1 H, dd, J = 16.1, 8.0 Hz), 3.43 (1 H, dd, J = 16.1, 4.5 Hz), 4.80–4.88 (1 H, m), 6.33 (1 H, d, J = 7.0 Hz), 7.27–7.72 (8 H, m), 8.05–8.08 (1 H, m); ¹³C NMR (100 MHz, CDCl₃): δ = 35.7, 44.6, 46.0, 126.9, 127.2, 128.6, 129.6, 131.7, 132.1, 134.3, 140.6, 167.2, 195.7; HRMS (ESI⁺): m/z calcd for C₁₇H₁₆NO₂ ⁺ ([M+H]⁺): 266.1181; found: 266.1185.Data for 17: oil; [α]²² d +19.8 (c 1.4, CHCl₃); IR: ν_max 1674, 1627; ¹H NMR (400 MHz, CDCl₃): δ = 1.74–1.82 (1 H, m), 2.46–2.55 (1 H, m), 2.83 (1 H, dd, J = 17.0, 1.6 Hz), 2.94 (1 H, dd, J = 14.0, 6.3 Hz), 3.18 (1 H, dt, J = 14.0, 4.2 Hz), 3.82 (1 H, ddd, J = 17.0, 11.9, 1.8 Hz), 4.57–4.66 (1 H, m), 6.80 (1 H, br s), 7.21–7.48 (5 H, m), 7.66–7.81 (3 H, m), 8.04 (1 H, d, J = 8.0 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 31.1, 32.9, 45.7, 47.0, 123.3, 126.8, 127.1, 127.3, 129.1, 130.2, 131.6, 133.1, 134.2, 137.5, 138.5, 142.2, 167.9, 201.6; HRMS (ESI⁺): m/z calcd for C₁₈H₁₇NNaO₂ ⁺ ([M+Na]⁺): 302.1156; found: 302.1151.Data for 30: solid; mp 80–81 °C; [α]²³ d +4.6 (c 0.7, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.58 (1 H, dd, J = 19.0, 3.3 Hz), 2.96 (1 H, dd, J = 19.0, 7.7 Hz), 3.88 (3 H, s), 5.86–5.90 (1 H, m), 6.78 (1 H, d, J = 8.3 Hz), 6.95 (1 H, dd, J = 8.6, 2.1 Hz), 7.08 (1 H, d, J = 2.1 Hz), 7.44–7.48 (2 H, m), 7.52–7.54 (1 H, m), 7.61 (1 H, d, J = 8.6 Hz), 7.84–7.86 (2 H, m); ¹³C NMR (100 MHz, CDCl₃): δ = 45.1, 47.7, 55.9, 109.0, 117.4, 125.1, 127.1, 128.7, 131.9, 133.5, 137.4, 157.1, 166.0, 167.4, 201.7; HRMS (ESI⁺): m/z calcd for C₁₇H₁₆NO₃ ⁺ ([M+H]⁺): 282.1130; found: 282.1130.Data for 31: solid; mp 83–85 °C; [α]²³ d +6.9 (c 0.5, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.56 (1 H, dd, J = 19.0, 3.3 Hz), 3.20 (1 H, dd, J = 19.0, 7.7 Hz), 3.84 (3 H, s), 5.82 (1 H, td, J = 8.1, 3.3 Hz), 6.89 (1 H, dd, J = 8.5, 2.2 Hz), 7.04 (1 H, d, J = 2.2 Hz), 7.09 (1 H, d, J = 8.5 Hz), 7.41–7.44 (2 H, m), 7.56–7.58 (2 H, m), 7.85 (2 H, d, J = 7.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 44.9, 47.6, 55.9, 109.0, 117.4, 124.9, 127.1, 128.7, 129.8, 131.9, 133.7, 157.1, 165.9, 167.5, 201.9; HRMS (ESI⁺): m/z calcd for C₁₇H₁₅NNaO₃ ⁺ ([M+Na]⁺): 304.0944; found: 304.0937.Data for 32: solid; mp 80–83 °C; [α]²³ d +10.6 (c 1.0, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.79 (1 H, dd, J = 16.9, 8.3 Hz), 2.97 (1 H, dd, J = 16.9, 4.1 Hz), 3.09 (1 H, dd, J = 15.9, 7.5 Hz), 3.28 (1 H, dd, J = 15.9, 6.1 Hz), 3.88 (3 H, s), 4.80–4.88 (1 H, m), 6.20 (1 H, d, J = 7.2 Hz), 6.76 (1 H, app s), 6.90 (1 H, dd, J = 8.8, 1.9 Hz), 7.23–7.52 (4 H, m), 7.70 (2 H, d, J = 8.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 31.9, 44.9, 46.2, 55.6, 112.6, 126.8, 128.3, 130.4, 131.6, 131.7, 132.8, 141.4, 142.7, 164.3, 166.4, 195.1; HRMS (ESI⁺): m/z calcd for C₁₈H₁₇NNaO₃ ⁺ ([M+Na]⁺): 318.1101; found: 318.1092.Data for 33: solid; mp 84–85 °C; [α]²² d +2.4 (c 1.2, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.77 (1 H, dd, J = 16.8, 8.1 Hz), 2.96 (1 H, dd, J = 16.8, 4.6 Hz), 3.07 (1 H, dd, J = 15.4, 6.5 Hz), 3.25 (1 H, dd, J = 15.4, 3.1 Hz), 3.86 (3 H, s), 4.78–4.85 (1 H, m), 6.40 (1 H, d, J = 7.5 Hz), 7.41–7.57 (5 H, m), 7.82 (2 H, d, J = 7.2 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 31.3, 42.4, 46.7, 55.9, 109.9, 122.6, 124.0, 126.8, 128.4, 131.6, 133.8, 134.9, 146.2, 161.2, 166.7, 195.0; HRMS (ESI⁺): m/z calcd for C₁₈H₁₇NNaO₃ ⁺ ([M+Na]⁺): 318.1106; found: 318.1105.Data for 36: solid; mp 79–81 °C; [α]²³ d +5.7 (c 0.5, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.63 (1 H, dd, J = 19.3, 3.1 Hz), 3.36 (1 H, dd, J = 19.3, 7.4 Hz), 3.86 (3 H, s), 5.86 (1 H, td, J = 7.8, 3.0 Hz), 6.51 (1 H, d, J = 8.0 Hz), 7.20 (1 H, d, J = 2.5 Hz), 7.26 (1 H, dd, J = 8.5, 2.5 Hz), 7.45 (2 H, t, J = 7.7 Hz), 7.54 (1 H, t, J = 7.3 Hz), 7.58 (1 H, d, J = 8.5 Hz), 7.80 (2 H, d, J = 7.5 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 45.8, 47.5, 55.7, 104.8, 124.7, 126.9, 127.0, 128.7, 131.9, 133.7, 138.3, 146.4, 160.9, 166.8, 203.2; HRMS (ESI⁺): m/z calcd for C₁₇H₁₅NNaO₃ ⁺ ([M+Na]⁺): 304.0944; found: 304.0934.Data for 37: solid; mp 86–87 °C; [α]²² d +7.2 (c 0.3, CHCl₃); IR: ν_max 1682; ¹H NMR (400 MHz, CDCl₃): δ = 2.78 (1 H, dd, J = 16.8, 9.3 Hz), 2.97 (1 H, dd, J = 16.8, 3.7 Hz), 3.02 (1 H, dd, J = 15.9, 8.5 Hz), 3.29 (1 H, dd, J = 16.8, 4.1 Hz), 3.79 (3 H, s), 4.70–4.79 (1 H, m), 6.78 (1 H, d, J = 7.6 Hz), 7.09 (1 H, dd, J = 8.4, 2.8 Hz), 7.17 (1 H, d, J = 8.4 Hz), 7.33–7.37 (2 H, m), 7.43–7.45 (1 H, m), 7.46 (1 H, d, J = 2.8 Hz), 7.71 (2 H, d, J = 7.3 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 34.9, 44.4, 46.2, 55.5, 109.2, 122.5, 127.1, 128.6, 130.7, 131.7, 132.8, 133.3, 134.1, 158.8, 167.4, 196.0; HRMS (ESI⁺):m/z calcd for C₁₈H₁₈NO₃ ⁺ ([M+H]⁺): 296.1287; found: 296.1286.