Stereoselective Synthesis of 1,2,2-Trisubstituted Indane Derivatives Using a Tandem S_N2-Michael Addition Sequence

Abstract

An efficient strategy is developed for the synthesis of 1,2,2-trisubstituted indane derivatives employing a tandem S_N2-Michael reaction sequence. The method is extended towards the synthesis of spiroindanes and indanopiperidines.

Key words

indane derivatives - tandem reactions - Michael additions - alkylation reactions - indanopiperidines

References and Notes

• For reviews of indane derivatives of biological interest, see:
• 1a Galatsis P. Ann. Rep. Med. Chem.  1998,  33:  327 
• 1b Ganellin CR. Adv. Drug Res.  1967,  4:  163 
• For reviews on benzoannelated fenestranes and centropolyindanes, see:
• 2a Kuck D. Chem. Rev.  2006,  106:  4885 
• 2b Kuck D. Advances in Theoretically Interesting Molecules   Vol. 4:  Thummel RP. JAI Press; Greenwich, London: 1998.  p.81-155  
• 2c Kuck D. Top. Curr. Chem.  1998,  196:  167 ; and references therein
• For some recent examples, see:
• 3a Davies IW. Senanayake CH. Larsen RD. Verhoeven TR. Reider PJ. Tetrahedron Lett.  1996,  37:  1725 
• 3b Liang G. Trauner D. J. Am. Chem. Soc.  2004,  126:  9544 
• 3c Kurosu M. Porter JR. Foley MA. Tetrahedron Lett.  2004,  45:  145 
• For reviews on the synthesis of indane derivatives, see:
• 4a Hong B.-C. Sarshar S. Org. Prep. Proced. Int.  1999,  31:  1 
• 4b Ferraz HMC. Aguilar AM. Silva LF. Craveiro MV. Quim. Nova  2005,  28:  703 
• 5a Bunce RA. Tetrahedron  1995,  51:  13103 
• 5b Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 
• 5c Nicolaou KC. Montagnon T. Snyder SA. Chem. Commun.  2003,  551 
• For some selected examples of tandem alkylation-Michael reaction sequence for the synthesis of heterocycles and carbocycles, see:
• 6a Bunce RA. Peeples CJ. Jones PB. J. Org. Chem.  1992,  57:  1727 
• 6b Bunce RA. Kotturi SV. Peeples CJ. Holt EM. J. Heterocycl. Chem.  2002,  39:  1049 
• 6c Bunce RA. Allison JC. Synth. Commun.  1999,  29:  2175 
• 6d Goff DA. Tetrahedron Lett.  1998,  39:  1473 
• 6e Watanabe H. Onoda T. Kitahara T. Tetrahedron Lett.  1999,  40:  2545 
• 6f Le Dreau M.-A. Desmaele D. Dumas F. d’Angelo J. J. Org. Chem.  1993,  58:  2933 
• 6g Desmaele D. Louvet J.-M. Tetrahedron Lett.  1994,  35:  2549 
• 6h Srikrishna A. Reddy TJ. Kumar PP. Synlett  1997,  663 
• 6i Prabhu KR. Sivanand PS. Chandrasekaran S. Angew. Chem. Int. Ed.  2000,  39:  4316 
• 6j Liu H.-J. Han Y. J. Chem. Soc., Chem. Commun.  1991,  1484 
• 7 Lindsell WE. Palmer DD. Preston PN. Rosair GM. Jones RVH. Whitton AJ. Organometallics  2005,  24:  1119 
• 11 Meyer MD. DeBernardis JF. Hancock AA. J. Med. Chem.  1994,  37:  105 

8

All compounds exhibited spectral data consistent with their structures. Melting point, IR, NMR (¹H and ¹³C) and HRMS spectral data for some of the compounds follow.
Triester 10a: IR (neat): 2954, 1731, 1434, 1247, 1157, 1074, 756, 735 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.12-7.19 (m, 4 H), 4.45 (dd, J = 5.3, 9.2 Hz, 1 H), 3.74 (s, 3 H), 3.71 (s, 6 H), 3.71 (AB, J = 16.4 Hz, 1 H), 3.42 (AB, J = 16.4 Hz, 1 H), 2.74 (ABX, J = 5.3, 16.0 Hz, 1 H), 2.51 (ABX, J = 9.2, 16.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 172.19 (C), 171.44 (C), 170.34 (C), 142.88 (CH), 138.96 (C), 127.56 (CH), 127.21 (CH), 124.25 (CH), 123.79 (CH), 64.31 (C), 52.96 (Me), 52.63 (Me), 51.74 (Me), 46.42 (CH), 39.28 (CH₂), 36.24 (CH₂). HRMS (ESI): m/z [M + Na⁺] calcd for C₁₆H₁₈O₆Na: 329.1001; found: 329.0996.
Ketoester 11d: mp 114-117 °C. IR (neat): 2986, 1742, 1686, 1597, 1233, 750 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.05 (dd, J = 1.2, 8.4 Hz, 2 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.22-7.26 (m, 3 H), 7.12-7.15 (m, 1 H), 4.56 (t, J = 6.8 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 3.77 (AB, J = 16.0 Hz, 1 H), 3.71 (d, J = 6.8 Hz, 2 H), 3.58 (AB, J = 16.0 Hz, 1 H), 1.33 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 197.37 (C), 168.52 (C), 141.01 (C), 137.95 (C), 136.34 (C), 133.62 (CH), 128.77 (CH), 128.22 (CH), 128.19 (CH), 127.90 (CH), 124.58 (CH), 123.60 (CH), 118.90 (C), 63.18 (CH₂), 55.03 (C), 47.84 (CH), 42.92 (CH₂), 40.83 (CH₂), 13.96 (Me). HRMS (ESI): m/z [M + Na⁺] calcd for C₂₁H₁₉NO₃Na: 356.1263; found: 356.1258.
Sulfone 11e: mp 125-127 °C. IR (neat): 3067, 2952, 1733, 1684, 1596, 1581, 1447, 1308, 1145, 749, 689 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.84-7.89 (m, 4 H), 7.54-7.58 (m, 2 H), 7.42-7.47 (m, 4 H), 7.03-7.09 (m, 3 H), 6.94-6.97 (m, 1 H), 4.86 (dd, J = 2.8, 8.8 Hz, 1 H), 3.89 (AB, J = 17.0 Hz, 1 H), 3.78 (AB, J = 17.0 Hz, 1 H), 3.70 (s, 3 H), 3.47 (ABX, J = 2.8, 17.6 Hz, 1 H), 3.33 (ABX, J = 8.8, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 197.44 (C), 167.78 (C), 142.21 (C), 138.58 (C), 136.81 (C), 136.70 (C), 134.26 (CH), 133.48 (CH), 130.48 (CH), 128.78 (CH), 128.76 (CH), 128.18 (CH), 127.82 (CH), 127.42 (CH), 123.96 (CH), 82.49 (C), 53.30 (Me), 45.35 (CH), 41.18 (CH₂), 37.99 (CH₂). HRMS (ESI): m/z [M + Na⁺] calcd for C₂₅H₂₂O₅NaS: 457.1080; found: 457.1074.
Spirodione 13: mp 95-98 °C. IR (neat): 2923, 1734, 1704, 1595, 1277, 1238, 751, 732 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.02-8.06 (m, 1 H), 7.95-7.98 (m, 1 H), 7.82-7.89 (m, 2 H), 7.14-7.27 (m, 4 H), 4.22 (dd, J = 6.2, 9.3 Hz, 1 H), 3.35 (AB, J = 16.2 Hz, 1 H), 3.34 (s, 3 H), 3.28 (AB, J = 16.2 Hz, 1 H), 2.89-2.92 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 202.56 (C), 201.71 (C), 172.54 (C), 143.12 (CH), 141.86 (C), 141.73 (C), 139.58 (CH), 135.78 (CH), 135.65 (CH), 127.95 (CH), 127.60 (CH), 124.40 (CH), 123.60 (CH₂), 123.47 (CH), 123.32 (CH), 61.81 (C), 51.58 (CH), 47.24 (CH₂), 41.44 (CH₂), 35.18 (CH₂). HRMS (ESI): m/z [M + Na⁺] calcd for C₂₀H₁₆O₄Na: 343.0946; found: 343.0954.
Lactam 16: mp 117-120 °C. IR (neat): 3235, 2982, 1721, 1651, 1485, 1367, 1265, 1224, 1015, 860, 732, 701 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.15-7.27 (m, 4 H), 6.04 (br s, 1 H), 4.18-4.24 (m, 1 H), 4.21 (q, J = 6.8 Hz, 2 H), 3.74 (ABX, J = 4.8, 13.2 Hz, 1 H), 3.43 (AB, J = 17.0 Hz, 1 H), 3.24 (ABX, J = 3.2, 13.2 Hz, 1 H), 3.02 (AB, J = 17.0 Hz, 1 H), 2.94 (ABX, J = 7.8, 15.6 Hz, 1 H), 2.53 (ABX, J = 6.4, 15.6 Hz, 1 H), 1.27 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 174.97 (C), 173.55 (C), 143.72 (C), 139.52 (C), 127.58 (CH), 127.55 (CH), 124.46 (CH), 123.94 (CH), 61.53 (CH₂), 53.15 (C), 46.84 (CH₂), 45.54 (CH), 41.62 (CH₂), 36.00 (CH₂), 14.13 (Me). HRMS (ESI): m/z [M + Na⁺] calcd for C₁₅H₁₈NO₃: 256.1287; found: 260.1291.

9

Representative Experimental Procedure: To a stirred solution of chloroester 1 (100.0 mg, 0.475 mmol) in DMF, were added dimethyl malonate (9a; 125.4 mg, 0.950 mmol) and Cs₂CO₃ (464.3 mg, 1.425 mmol) and the mixture was allowed to stir at r.t. for 3 h (TLC control). The reaction mixture was then diluted with Et₂O, washed with H₂O followed by brine and dried over Na₂SO₄. Subsequent filtration, evaporation of the solvent and purification of the residue by silica gel column chromatography using EtOAc-hexane (1:19) as eluent yielded the triester 10a [8] (118.0 mg, 81%) as a viscous oil.

10

Crystal data for 11d: formula: C₂₁H₁₉NO₃; unit cell parameters: a = 7.2791 (2), b = 12.4566 (4), c = 18.9233 (6) Å, β = 95.4010 (10)°; space group P2(1)/c; CCDC number 638873. Crystal data for 11e: formula: C₂₅H₂₂O₅S; unit cell parameters: a = 12.8473 (3), b = 9.1054 (2), c = 18.5010 (4) Å, α = 90.00°, β = 95.8910 (10)°, γ = 90.00°; space group P2 (1)/c; CCDC number 638872. CCDC 638873 and CCDC 638872 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.