A Rapid and Efficient Access to 4-Substituted 2-Amino-4H-chromenes Catalyzed by InCl₃

Abstract

A series of 4-substituted 2-amino-4H-chromenes was synthesized via a simple and efficient one-pot synthesis from salicylaldehyde, malononitrile, and a few cyclic nucleophiles using indium trichloride as a catalyst. The methodology affords high yields of products in short reaction times.

chromenes - salicylaldehyde - indium(III) chloride - ­malononitrile - three-component

References and Notes

1a Batt DG. inventors; WO  2010009069. 

1b Tjoeng FS, Carter J, Springer JR, and Zupec ME. inventors; WO  2006040676A1. 

1c Cain J. Nature (London)  1960,  188:  774 

1d Torregroza I. Evans T. Das CB. Chem. Biol. Drug Des.  2009,  3:  339 

1e Fatome M. Andrieu L. Laval DJ. Clavel MJ. Blanco L. Guillaumel J. Rene L. Royer R. Eur. J. Med. Chem.  1977,  383 

2a Ramón DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 

2b Zhu J. Eur. J. Org. Chem.  2003,  1133 

2c Ugi I. Domling A. Werner B. J. Heterocycl. Chem.  2000,  37:  647 

2d Bienayme H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J.  2000,  6:  3321 

2e Shinu VS. Sheeja B. Purushothaman E. Bahulayan D. Tetrahedron Lett.  2009,  50:  4838 

2f Arabanian A. Mohammadnejad M. Balalaie S. Gross JH. Bioorg. Med. Chem. Lett.  2009,  19:  887 

2g Chebanov VA. Muravyova EA. Desenko SM. Musatov VI. Knyazeva IV. Shishkina SV. Shishkin OV. Kappe CO. J. Comb. Chem.  2006,  8:  427 

2h Dondoni A. Massi A. Sabbatini S. Bertolasi V.
J. Org. Chem.  2002,  67:  6979 

2i Rashinkar G. Salunkhe R. J. Mol. Catal. A: Chem.  2010,  316:  146 

2j Srihari P. Singh VK. Bhunia DC. Yadav JS. Tetrahedron Lett.  2009,  50:  3763 

3 Hafez EA. Elnagdi MH. Elagamey AGA. El-Taweel FMAA. Heterocycles  1987,  26:  903 

4a Limsuwan S. Trip EN. Kouwen TRMH. Piersma S. Hiranrat A. Mahabusarakam W. Voravuthikkunchai SP. Maarten von Dijl J. Kayser O. Phytomedicine  2009,  16:  645 

4b Bowers WS. Ohta T. Cleere JS. Marsella PA. Science  1976,  193:  542 

5a Skommer J. Wlodkowic D. Mattö M. Eray M. Pelkonen J. Leukemia Res.  2006,  30:  322 

5b Rossi A. Di Paola R. Mazzon E. Genovese T. Caminiti R. Bramanti P. Pergola C. Koeberle A. Werz O. Sautebin L. Cuzzocrea S. J. Pharmacol.  2008,  329:  76 

6 Hiramoto J. Nasuhara A. Michiloshi K. Kato T. Kikugawa K. Mutat. Res.  1997,  395:  47 

7 Bianchi G. Tava A. Agric. Biol. Chem.  1987,  51:  20 

For reviews on indium Lewis acids, see:

8a Frost CG. Chauhan KK. J. Chem. Soc., Perkin Trans. 1  2000,  3015 

8b Fringuelli F. Piermatti O. Pizzo F. Vaccaro L. Curr. Org. Chem.  2003,  7:  1661 

8c Frost CG. Hartley JP. Mini-Rev. Org. Chem.  2004,  1:  1 

9a Jayashree P. Shanthi G. Perumal PT. Synlett  2009,  917 

9b Shanthi G. Perumal PT. Tetrahedron Lett.  2007,  48:  6785 

9c Babu TH. Perumal PT. Synlett  2011,  341 

9d Shanthi G. Perumal PT. Synlett  2008,  2791 

10a Thirumurugan P. Perumal PT. Tetrahedron Lett.  2009,  50:  4145 

10b Thirumurugan P. Nandakumar A. Muralidharan D. Perumal PT. J. Comb. Chem.  2010,  12:  161 

11 Lakshmi NV. Thirumurugan P. Perumal PT. Tetrahedron Lett.  2010,  51:  1064 

12 Lakshmi NV. Thirumurugan P. Jayakumar C. Perumal PT. Synlett  2010,  955 

13a Thirumurugan P. Perumal PT. Tetrahedron  2009,  65:  7620 

13b Praveen C. Karthikeyan K. Perumal PT. Tetrahedron  2009,  65:  9244 

14 Lakshmi NV. Thirumurugan P. Norrulla KM. Perumal PT. Bioorg. Med. Chem. Lett.  2010,  20:  5054 

15a Babu G. Perumal PT. Aldrichimica Acta  2000,  33:  16 

15b Babu G. Perumal PT. Tetrahedron Lett.  1997,  38:  5025 

15c Babu G. Perumal PT. Tetrahedron  1998,  54:  1627 

15d Babu G. Nagarajan R. Natarajan R. Perumal PT. Synthesis  2000,  661 

15e Shanthi G. Subbulakshmi G. Perumal PT. Tetrahedron  2007,  63:  2057 

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Experimental Procedure for the Synthesis of 2-Amino-4 H -chromene 4a (Table 2, Entry 1)
To a stirred mixture of salicylaldehyde 1 (1 mmol) and malononitrile (2, 1 mmol) in EtOH, 3-methyl-1-phenyl-1H-pyrazol-5 (4H)-one (3, 1 mmol) and InCl₃ (20 mol%) were added. The reaction mixture was stirred until complete conversion of the product as indicated by TLC (Table  [²] ). The solid formed was filtered, dried, and recrystallized from EtOH to obtain the pure product in good yield (85%) 4a. 2-Amino-4-(5-hydroxy-3-methyl-1-phenyl-1 H -pyrazol-4-yl)-4 H -chromene-3-carbonitrile (4a, Table 2, Entry 1) White solid; mp 150-152 ˚C. IR (KBr): ν_max = 3418, 3328, 3072, 2185, 1587 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.94 (s, 3 H), 2.04 (s, 1 H, OH, D₂O exchangeable), 4.78 (s, 1 H), 6.78 (s, 2 H, NH₂, D₂O exchangeable), 6.96 (d, 1 H, J = 8.4 Hz), 7.01-7.06 (m, 2 H), 7.14-7.17 (m, 2 H), 7.38 (t, 2 H, J = 8.0 Hz), 7.68 (d, 2 H, J = 8.4 Hz). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 29.2, 31.2, 54.6, 115.8, 116.1, 119.1, 119.5, 121.2, 121.4, 123.2, 125.2, 125.5, 128.5, 129.4, 147.5, 149.1, 160.9. MS: m/z = 344.5 [M⁺]. Anal. Calcd (%) for C₂₀H₁₆N₄O₂: C, 69.76; H, 4.68; N, 16.27. Found: C, 69.70; H, 4.72; N, 16.23.

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2-Amino-8-ethoxy-4-(2-oxo indolin-3-yl)-4 H -chromene-3-carbonitrile (6b, Table 3, Entry 2) White solid; mp 178-180 ˚C. IR (KBr): ν_max = 3614, 3189, 2183, 1698, 1583, 1476, 1422, 1334, 1269, 1217, 1076, 751 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.20 (t, 3 H, 6.9Hz), 3.58 (d, 1 H, 3.1 Hz), 3.86-3.93 (m, 2 H), 4.19 (d, 1 H, J = 3.1 Hz), 6.58 (d, 1 H, J = 7.7 Hz), 6.66 (d, 1 H, J = 7.7 Hz), 6.76 (d, 1 H, J = 8.4 Hz), 6.81 (t, 1 H, J = 6.9 Hz), 6.86 (t, 1 H, J = 7.7 Hz), 7.01 (t, 1 H, J = 7.7 Hz), 7.06 (s, 2 H, NH₂, D₂O exchangeable), 7.13 (d, 1 H, J = 7.7 Hz), 10.39 (s, 1 H, NH, D₂O exchangeable). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 15.03, 37.8, 52.9, 53.3, 64.7, 109.65, 113.3, 119.5, 121.2, 121.7, 124.2, 127.2, 128.6, 139.8, 143.5, 146.3, 162.4, 177.2. MS: m/z = 347.2 [M⁺]. Anal. Calcd (%) for C₂₀H₁₇N₃O₃: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.13; H, 4.90; N, 12.08.

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2-Amino-8-methoxy-4-(4,4-dimethyl-2,6-dioxocyclo-hexyl)-4 H -chromene-3-carbonitrile (8h, Table 4, Entry 8) White solid; mp 150-152 ˚C. IR (KBr): ν_max = 3336, 3162, 2209, 1704, 1635, 1508, 1390, 1028 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.05 (s, 3 H), 1.06 (s, 3 H), 2.48 (s, 2 H), 2.52 (s, 2 H), 3.72 (s, 3 H), 3.95 (d, 1 H, J = 3.1 Hz), 4.50 (d, 1 H, J = 3.1 Hz), 6.70-6.73 (m, 2 H), 7.17-7.19 (m, 1 H), 7.61 (s, 2 H, NH₂, D₂O exchangeable). ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 26.6, 27.0, 32.3, 55.9, 101.9, 109.2, 111.8, 112.2, 113.8, 117.5, 130.6, 151.6, 152.0, 160.3, 165.6, 168.4, 197.0. MS: m/z = 340.1 [M⁺]. Anal. Calcd (%) for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.03; H, 5.86; N, 8.27.