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Synlett 2011(11): 1547-1550  
DOI: 10.1055/s-0030-1260787
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient One-Pot, Three-Component Reaction: Synthesis of Complex-Annelated α-Carbolines via an Intramolecular [3+2]-Dipolar Cycloaddition Reaction

Swarup Majumder, Pulak J. Bhuyan*
Medicinal Chemistry Division, North East Institute of Science & Technology (CSIR), Jorhat 785006, Assam, India
Fax: +91(376)2370011; e-Mail: pulak_jyoti@yahoo.com;
Further Information

Publication History

Received 17 March 2011
Publication Date:
15 June 2011 (online)

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Abstract

Novel annelated α-carbolines have been synthesized from oxindole using three components in a one-pot procedure involving an intramolecular [3+2]-dipolar cycloaddition reaction of azides to nitriles.

Key words

α-carboline - oxindole - [3+2]-dipolar cycloaddition reaction - β-halo aldehyde - multicomponent reaction

    References and Notes

  • 1a Venkat RG, Qi L, Pierce M, Robbins PB, Sahasrabudhe SR, and Selliah R. inventors; WO  2007076085. 
  • 1b Arakawa H, Monden Y, Nakatsuru Y, and Kodera T. inventors; WO  2003080077. 
  • 1c Burstein HJ. Overmoyer B. Gelman R. Silverman P. Savoie J. Clarke K. Dumadag L. Younger J. Ivy P. Winer EP. Invest. New Drugs  2007,  25:  161 
    Google Scholar
  • 2a Li X. Vince R. Bioorg. Med. Chem.  2006,  14:  2942 
    Google Scholar
  • 2b Zhao G. Wang C. Liu C. Lou H. Mini-Rev. Med. Chem.  2007,  7:  707 
    Google Scholar
  • 3a Gelbard HA, Maggirwar SB, Dewhurst S, and Schifitto GP. inventors; WO  2007076372. 
  • 3b Mellman I, and Jiang A. inventors; WO  2007075911. 
  • 4a Paolini L. Sci. Rep. Ist. Super. Sanita  1961,  1:  86 
    Google Scholar
  • 4b Okamoto T, Akase T, Izumi S, Inaba S, and Yamamoto H. inventors; JP  7220196.  ; Chem. Abstr. 1972, 77, 152142
  • 4c Winter J, and Di Mola N. inventors; DE  2442513.  ; Chem. Abstr. 1975, 82, 156255
  • 5a Stubbs MC. Armstrong SA. Curr. Drug Targets  2007,  8:  703 
    Google Scholar
  • 5b Shenoy S. Vasania VS. Gopal M. Mehta A. Toxicol. Appl. Pharmacol.  2007,  222:  80 
    Google Scholar
  • 5c Seedhouse CH. Hunter HM. Lloyd-Lewis B. Massip A.-M. Pallis M. Carter GI. Grundy M. Shang S. Russel NH. Leukemia  2006,  20:  2130 
    Google Scholar
  • 6a Joseph J, Meijer L, and Liger F. inventors; FR  2876377. 
  • 6b Das S, Brown JW, Dong Q, Gong X, Kaldor SW, Liu Y, Paraselli BR, Scorah N, Stafford JA, and Wallace MB. inventors; WO  2007044779. 
  • 7 Fong TM, Erondu NE, Macneil DJ, Mcintyre JH, and Vander Pleog LHT. inventors; WO  2004110368. 
  • 8a Beccalli EM. Clerici F. Marchesini A. Tetrahedron  2001,  57:  4787 
    Google Scholar
  • 8b Erba E. Gelmi ML. Pocar D. Tetrahedron  2000,  56:  9991 
    Google Scholar
  • 8c Kaczmarek L. Peczynka-Czoch W. Osiadacz J. Mordarski M. Sokalski WA. Boratynski J. Marcinkovska E. Glazman-Kusnierczyk H. Radzikowski C. Bioorg. Med. Chem. Lett.  1999,  7:  22457 
    Google Scholar
  • 8d Tahri A. Buysens KJ. Van der Eycken EV. Vanderberghe DM. Hoornaert GJ. Tetrahedron  1998,  54:  13211 
    Google Scholar
  • 8e Molina P. Alajarín M. Vidal A. Sánchez-Aranda P. J. Org. Chem.  1992,  57:  929 
    Google Scholar
  • 8f Rocca P. Marsais F. Godard A. Queguiner G. Tetrahedron  1993,  49:  49 
    Google Scholar
  • 8g Vera-Luque P. Alajarin R. Alvarez-Builla J. Vaquero JJ. Org. Lett.  2006,  8:  415 
    Google Scholar
  • 9 Majumder S. Bhuyan PJ. Synlett  2011,  173 
    Article in Thieme ConnectGoogle Scholar
  • 10 Habib PM. Rama BR. Veerababurao K. Kuo C.-W. Yao C.-F. Tetrahedron  2009,  65:  5799 
    CrossrefGoogle Scholar
  • 11a Carini DJ. John VD. Paul EA. Andrew TC. Alexander LJ. Michael EP. William AP. Joseph BS. Gregory JW. J. Med. Chem.  1991,  34:  2525 
    Google Scholar
  • 11b Koyama M. Ohtani N. Kai F. Moriguchi I. Inouye S. J. Med. Chem.  1987,  30:  552 
    Google Scholar
  • 11c Maxwell JR. Wasdahl DA. Wolfson AC. J. Med. Chem.  1984,  27:  1565 
    Google Scholar
  • 12a Brown M. inventors; US  3,338,915.  ; Chem. Abstr. 1968, 87299
  • 12b Tarver CM. Goodale TC. Shaw R. Cowperthwaite M. Proc. Symp. Int. Detonation 6th  1967,  231 ; Chem. Abstr. 1980, 92, 8480
    Google Scholar
  • 12c Henry RA. inventors; US 3, 096,  312. 
  • 13a Carruthers W. In Cycloaddition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series   Vol. 8:  Pergamon Press; Oxford / UK: 1990. 
    Google Scholar
  • 13b Tietze LF. Chem. Rev.  1996,  96:  115 
    Google Scholar
  • 13c Carruthers W. Coldham I. In Modern Method of Organic Synthesis   Cambridge University Press; Cambridge / UK: 2004. 
    Google Scholar
  • 13d Coldham I. Hufton R. Chem. Rev.  2005,  105:  2765 
    Google Scholar
  • 14a Jung ME. Yuk-Sun LP. Mansuri MM. Speltz LM. J. Org. Chem.  1985,  50:  1087 
    Google Scholar
  • 14b Coldham L. Hufton R. Chem. Rev.  2005,  105:  2765 
    Google Scholar
  • 15a Himo F. Demko ZP. Noodleman L. J. Org. Chem.  2003,  68:  9076 
    Google Scholar
  • 15b Himo F. Demko ZP. Noodleman L. Sharpless KB. J. Am. Chem. Soc.  2002,  124:  12210 
    Google Scholar
  • 15c Sutherland DR. Tennant G. J. Chem. Soc., Perkin Trans. 1  1974,  534 
    Google Scholar
  • 15d Lauria A. Patella C. Diana P. Barraja P. Montalbano A. Cirrincione G. Dattolo G. Almerico AM. Tetrahedron Lett.  2006,  47:  2187 
    Google Scholar
  • 16a Weber L. Illegen K. Almstetter M. Synlett  1999,  366 
    Google Scholar
  • 16b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Rev.  1996,  29:  123 
    Google Scholar
  • 16c Tempest PA. Brown SD. Keating TA. Acc. Chem. Rev.  1996,  29:  123 
    Google Scholar
  • 17a Shestopalov AM. Emeliyanova YM. Shestiopolov AA. Rodinovskaya IA. Niazimbetova ZI. Evans DH. Org. Lett.  2002,  423 
    Google Scholar
  • 17b List B. Castello C. Synlett  2001,  1687 
    Google Scholar
  • 17c Nair V. Vinod AU. Rajesh C. J. Org. Chem.  2001,  66:  4427 
    Google Scholar
  • 17d Bagley MC. Cale JW. Bower J. Chem. Commun.  2002,  1682 
    Google Scholar
  • 17e Cheng JF. Chen M. Arthenius T. Nadzen A. Tetrahedron Lett.  2002,  43:  6293 
    Google Scholar
  • 17f Bertozzi F. Gustafsson M. Olsson R. Org. Lett.  2002,  4:  3309 
    Google Scholar
  • 17g Dallinger D. Gorobets NY. Kappe CO. Org. Lett.  2003,  5:  1205 
    Google Scholar
  • 18a Baruah B. Bhuyan PJ. Tetrahedron  2009,  65:  7099 
    Google Scholar
  • 18b Deb ML. Majumder S. Baruah B. Bhuyan PJ. Synthesis  2010,  929 
    Google Scholar
  • 18c Deb ML. Bhuyan PJ. Synlett  2008,  325 
    Google Scholar
  • 18d Deb ML. Bhuyan PJ. Synthesis  2008,  2891 
    Google Scholar
  • 23 Soledade M. Pedras C. Suchy M. Ahiahonu WK. Org. Biomol. Chem.  2006,  4:  691 
    CrossrefGoogle Scholar
19

General Procedure for Three-Component Reaction To a mixture of 1-Boc-2-chloro-3-formylindole (3a, 279 mg, 1 mmol), ethyl cyanoacetate (4a, 170 mg, 1.5 mmol), and NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) were added 2 drops of H2O. A catalytic amount (1-2 drops) of Et3N was then added, and the reaction mixture allowed to stir for 3 h at 50-60 ˚C. After completion of the reaction, the mixture was cooled to r.t. and poured into H2O with continuous stirring. A yellow-brownish solid product was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7).
Compound 6a
Yield 270 mg (71%); mp 221-223 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 7.07 Hz, 3 H), 1.72 (s, 9 H), 4.17-4.23 (m, 2 H), 7.20-7.86 (m, 3 H), 8.18 (s, 1 H), 8.57-8.63 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.23, 28.08, 62.20, 86.81, 105.09, 113.52, 115.22, 115.66, 121.09, 124.08, 124.40, 125.77, 130.83, 135.66, 146.37, 147.89, 162.57. MS (EI): m/z = 382.4 [M + H]+. Anal. Calcd (%) for C19H19N5O4: C, 59.84; H, 4.98; N, 18.37. Found: C, 59.65; H, 4.93; N, 18.42. IR (CHCl3): νmax = 2983.00, 2856.50, 1751.90, 1728.10 cm-¹. Similar compounds 6b-i were synthesized and characterized.

20

Synthesis of Compound 3a
Equimolar amounts of 2-chloro-3-formyl indole (2, 10 mmol, 1.79 g) and Boc-anhydride (10 mmol, 2.18 g) were stirred in the presence of catalytic amount of DMAP (0.12 g) and Et3N (0.10 g) at 0-5 ˚C for 1 h using CH2Cl2 as solvent. The solvent was evaporated under reduced pressure, and the solid compound obtained was purified by column chromatography using PE-EtOAc (9:1) as eluent. The product 3 was obtained in 70% yield (1.20 g) as white crystalline compound; mp 89-90 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.72 (s, 9 H), 7.26-7.40 (m, 2 H), 8.02-8.06 (m, 1 H), 8.27-8.30 (m, 1 H), 10.29 (s, 1 H).
Synthesis of Compound 3b
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was taken in a round-bottom flask in DMF (10 mL) on magnetic stirrer. NaH (0.48 g, 20 mmol) was added into the mixture. When the temperature reached 0 ˚C, MeI (1.42 g, 10 mmol) was added gradually, and the reaction mixture allowed to stir for 1.5 h. An off-white solid formed which was almost pure product. Yield 1.59 g (82%); mp 79-80 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H), 7.20-8.30 (m, 4 H), 10.12 (s, 1 H).
Synthesis of Compound 3c
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was refluxed with allyl bromide(10 mmol) in the presence of K2CO3 (10 mmol) using acetone (10 mL) as solvent for 10 h to afford 3c, 1.69 g (76%) as a colorless solid, mp 148-149 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 4.80 (d, J = 11.4 Hz, 2 H), 5.10-5.27 (d, J = 10.2 Hz, 2 H), 5.95-6.07 (m, 1 H), 7.20-8.26 (m, 4 H), 10.16 (s, 1 H).

21

Synthesis of Compound [A] 1-Boc-2-chloro-3-formylindole (3a, 558 mg, 2 mmol) was treated with ethyl cyanoacetate (4a, 283 mg, 2.5 mmol) in EtOH (8 mL). One drop of piperidine was added, and the reaction mixture was allowed to stir at r.t. for 30 min. The reaction mixture was kept inside the freezer overnight. The yellow solid which appeared in the reaction mixture was filtered, washed with cold EtOH and dried. Yield 508 mg (75%); mp 87-88 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.43 (t, J = 3.6 Hz, 2 H), 1.72 (s, 9 H), 4.36-4.44 (m, 2 H), 7.20-8.10 (m, 4 H), 8.49 (s, 1 H).

22

Synthesis of α-Carboline 6a from [A] The condensed product [A] (339 mg, 1 mmol) was mixed with NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) and 2 drops of H2O were added. A catalytic amount (1-2 drops) of Et3N was then added to the reaction mixture, and the whole was stirred for 3 h at 50-60 ˚C After completion of reaction, the mixture was cooled to r.t. and poured into H2O with stirring. A yellow-brownish solid was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7); yield 251 mg (66%); mp 221-223 ˚C.