The Application of Vinamidinium Salt to the Synthesis of 3-Chloro-α-carbolines

Abstract

A convenient synthesis of 3-chloro-α-carbolines by the condensation of vinamidinium salt with 2-indolinones via two steps is reported. This protocol has the advantages of readily available starting materials, high yields and easy workup.

Key words

α-carboline - 3-chloro-α-carboline - synthesis - vinamidinium salt - 2-indolinone

• References and Notes

• 1 Peczynska-Czoch W. Pognan F. Kaczmarek L. Boratynski J. J. Med. Chem. 1994; 37: 3503
• 2 Okamoto T. Akase T. Izumi T. Inaba S. Yamamoto H. JP 7220196, 1972 ; Chem. Abstr. 1972, 77, 152142.
• 3 Winters G. Mola ND. DE 2442513, 1975 ; Chem. Abstr. 1975, 82, 156255
• 4 Zhang X. He Q. Xiang H. Song S. Miao Z. Yang C. Org. Biomol. Chem. 2014; 12: 355
• 5 Bolton D. Forbes IT. Hayward CJ. Piper DC. Thomas DR. Thompson M. Upton N. Bioorg. Med. Chem. Lett. 1993; 3: 1941
• 6 Jaromin A. Kozubek A. Suchoszek-Lukaniuk K. Malicka-Blaszkiewicz M. Peczynska-Czoch W. Kaczmarek L. Drug Delivery 2008; 15: 49
• 7a Lawson W. Perkin WH. Robinson R. J. Chem. Soc., Trans. 1924; 125: 626
• 7b Freak RH. Robinson R. J. Chem. Soc. 1938; 2013
• 7c Stephenson L. Warburton WK. J. Chem. Soc. C 1970; 1355
• 7d Mehta LK. Parrick J. Payne F. J. Chem. Soc., Perkin Trans. 1 1993; 1261
• 7e Peczyńska-Czoch W. Pognan F. Kaczmarek Ł. Boratyński J. J. Med. Chem. 1994; 37: 3503
• 7f Mohamed MB. Parrick J. J. Chem. Res., Miniprint 1980; 0577
• 8a Chavan NL. Nayak SK. Kusurkar RS. Tetrahedron 2010; 66: 1827
• 8b Ma Z. Ni F. Woo GH. C. Lo S. Philip MR. Schaus SE. Snyder JK. Beilstein J. Org. Chem. 2012; 8: 829
• 9 Basavaiah D. Reddy DM. Org. Biomol. Chem. 2012; 10: 8774
• 10a Kumar AS. Rao PV. A. Nagarajan R. Org. Biomol. Chem. 2012; 10: 5084
• 10b Markey SJ. Lewis W. Moody CJ. Org. Lett. 2013; 15: 6306
• 10c Kumar AS. Nagarajan R. Org. Lett. 2011; 13: 1398
• 11a Ghahremanzadeh R. Ahadi S. Bazgir A. Tetrahedron Lett. 2009; 50: 7379
• 11b Gupta S. Kumar B. Kundu B. J. Org. Chem. 2011; 76: 10154
• 11c Sharma SK. Gupta S. Saifuddin M. Mandadapu AK. Agarwal PK. Gauniyal HM. Kundu B. Tetrahedron Lett. 2011; 52: 65
• 12a Rocca P. Marsais F. Godard A. Queguiner G. Tetrahedron 1993; 49: 49
• 12b Aubriot S. Nicolle E. Lattier M. Morel C. Cao W. Daniel KW. Collins S. Leclerc G. Faure P. Bioorg. Med. Chem. Lett. 2002; 12: 209
• 12c Hung TQ. Dang TT. Janke J. Villinger A. Langer P. Org. Biomol. Chem. 2015; 13: 1375
• 12d Dhara S. Singha R. Ahmed A. Mandal H. Ghosh M. Nuree Y. Ray JK. RSC Adv. 2014; 4: 45163
• 12e Sera M. Mizufune H. Ueda T. Mineno M. Zanka A. Tetrahedron 2017; 73: 5946
• 13a Laha JK. Barolo SM. Rossi RA. Cuny GD. J. Org. Chem. 2011; 76: 6421
• 13b Schneider C. Gueyrard D. Popowycz F. Joseph B. Goekjian PG. Synlett 2007; 2237
• 14 Wadsworth AD. Naysmith BJ. Brimble MA. Eur. J. Med. Chem. 2015; 97: 816
• 15 Schneider C. Goyard D. Gueyrard D. Joseph B. Goekjian PG. Eur. J. Org. Chem. 2010; 6665
• 16 Routier J. Spangenberg T. WO 2014108168, 2014 ; Chem. Abstr. 2014, 161, 232181
• 17 Gambacorti Passerini C. Mologni L. Scapozza L. Ahmed S. Goekjian PG. Gueyrard D. Popowycz F. Joseph B. Schneider C. Garcia P. WO 2010025872, 2010; Chem. Abstr. 2010, 152, 335176
• 18 Schneider C. Gueyrard D. Joseph B. Goekjian PG. Tetrahedron 2009; 65: 5427
• 19 Mizuno M. Mizufune H. Sera M. Mineno M. Ueda T. WO 2008016184, 2008 ; Chem. Abstr. 2008, 148, 239178
• 20 Vera-Luque P. Alajarín R. Alvarez-Builla J. Vaquero JJ. Org. Lett. 2006; 8: 415
• 21 Lloyd D. Hamish M. Angew. Chem., Int. Ed. Engl. 1976; 15: 459
• 22 Coverdale HA. Hsung RP. Chemtracts 2003; 16: 238
• 23 Mao Y. Tian S. Zhang W. Xu G. Chin. J. Org. Chem. 2016; 36: 700
• 24 D'Souza FP. Crasto AM. Gharpure M. Naykodi SB. WO 2011158250, 2011 ; Chem. Abstr. 2011, 156, 99155
• 25 Procedure for the Synthesis of 3-(3-Amino-2-chloropropylidene)-6-chloro-2-indolinone (4a) To a one-neck round-bottom flask equipped with magnetic stirring was added 6-chloro-2-indolinone (2a, 1.00 g, 6.0 mmol), vinamidinium salt 3 ²⁴ (2.02 g, 12.0 mmol), Et₃N (1.82 g, 18.0 mmol), and DMF (10 mL). The mixture was stirred for 20 h at r.t., after the reaction was complete (monitored by TLC, EtOAc/MeOH = 20:1), 30 mL EtOAc and 30 mL water was added, then the aqueous layer was extracted with 30 mL EtOAc. The combined EtOAc layer was washed with sat. NaCl solution (15 mL) and water (15 mL) then dried over Na₂SO₄. After filtering the desiccant, the solvent was concentrated under vacuum to a volume of about 5 mL. The mixture was titrated with 15 mL n-hexane to give a yellow precipitant, the solid was filtered, and dried under vacuum to give 4a (1.34 g, yield 88%), a yellow powder, which was used in the next step without further purification; mp > 250 °C. ¹H NMR (500 MHz, DMSO): δ = 10.34 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.75 (t, J = 11.0 Hz, 1 H), 7.44 (s, 2 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.78 (s, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 170.53, 151.17, 141.75, 138.14, 129.98, 125.26, 122.07, 120.20, 109.96, 109.14, 101.24. ESI-HRMS: m/z calcd for C₁₁H₉Cl₂N₂O⁺: 255.0086; found: 255.0078 [M + H]⁺.
• 26 Deng X. Roessler A. Brdar I. Faessler R. Wu J. Sales ZS. Mani NS. J. Org. Chem. 2011; 76: 8262
• 27 In a 25 mL three-necked flask compound 4a (1.28 g, 5.0 mmol) and 25 mL 1,4-dioxane were added, and POCl₃ (1.53 g, 10.0 mmol) was added to the mixture dropwise at 0 °C under continuous stirring. The reaction mixture was stirred for 2 h at r.t. then heated at reflux for 20 h. After the reaction was complete (monitored by TLC, PE/EtOAc = 3:1), the solvent and POCl₃ were evaporated under vacuum, then 60 mL EtOAc was added. The organic phase was successively washed with water (25 mL), 8% aq NaHCO₃ (25 mL) and water (25 mL), then dried with Na₂SO₄ and evaporated under vacuum to yield a brown solid which on flash chromatography (SiO₂, EtOAc/hexane = 1:6) elution yielded 3,7-dichloro-α-carboline (1a, 1.08 g, 93%) as a yellow solid; mp >250 °C. ¹H NMR (500 MHz, DMSO): δ = 12.27 (s, 1 H), 8.72 (s, 1 H), 8.43 (s, 1 H), 8.23 (d, J = 8.5 Hz, 1 H), 7.54 (s, 1 H), 7.27 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 150.81, 144.91, 140.72, 132.21, 128.72, 123.71, 122.68, 120.53, 118,89, 116.28, 111.60. ESI-HRMS: m/z calcd for C₁₁H₇Cl₂N₂ ⁺: 236.9981; found: 236.9973 [M + H]⁺.