Facile Regioselective Synthesis of Functionalized Heterocycle-Tethered Spiro Compounds via an Intramolecular Electrophilic Ipso-Iodocyclization Process

Abstract

A general, regioselective, and efficient intramolecular electrophilic ipso-iodocyclization of a series of N-alkyl-N-aryl phenylpropiolamides in the presence of I₂ (molecular iodine) and NaHCO₃ via 5-endo-dig mode of cyclization has been developed for the synthesis of hitherto unreported coumarin, quinolone, and pyrimidine-annelated heterocyclic compounds in excellent yields (84-92%). The development of this methodology provides efficient and mild reaction conditions that allow for easy isolation of products. The synthesized spiro derivatives offer an attractive and useful scope for further functionalization and to synthesize new bioactive heterocycles.

Key words

azaspiro heterocycle - electrophilic ipso-iodocyclization - coumarin - quinolone - uracil

References and Notes

• 1a Carson MW. Kim G. Hentemann MF. Trauner D. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4450 
• 1b Carson MW. Kim G. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4453 
• 2 Trauner D. Schwarz JB. Danishefsky SJ. Angew. Chem. Int. Ed.  1999,  38:  3542 
• 3a Weinreb SM. Auerbach J. J. Am. Chem. Soc.  1975,  97:  2503 
• 3b Semmelhack MF. Chong BP. Stauffer RD. Rogenson TD. Chong A. Jones LD. J. Am. Chem. Soc.  1975,  97:  2507 
• 3c Isuno N. Mori M. J. Org. Chem.  1995,  60:  115 ; and references cited therein
• 3d Tietze LF. Schirok H. Woehrmann M. Schrader K. Eur. J. Org. Chem.  2000,  3:  2433 
• 4 Nieczypor P. Mol JC. Bespalova NB. Bubnov YN. Eur. J. Org. Chem.  2004,  812 
• For selected recent papers on the electrophilic iodocyclizations of arylalkynes, see:
• 5a Zhang X. Campo MA. Yao T. Larock RC. Org. Lett.  2005,  7:  763 
• 5b Yao T. Larock RC. J. Org. Chem.  2005,  70:  1432 
• 5c Yao T. Campo MA. Larock RC. J. Org. Chem.  2005,  70:  3511 
• 5d Yue D. Yao T. Larock RC. J. Org. Chem.  2005,  70:  10292 
• 5e Yue D. Yao T. Larock RC. J. Org. Chem.  2006,  71:  62 
• 5f Hu T. Liu K. Shen M. Yuan X. Tang Y. Li C. J. Org. Chem.  2007,  72:  8555 
• 5g Pattarozzi M. Zonta C. Broxterman QB. Kaptein B. De Zorzi R. Randaccio L. Scrimin P. Licini G. Org. Lett.  2007,  9:  2365 
• 5h Worlikar SA. Kesharwani T. Yao T. Larock RC. J. Org. Chem.  2007,  72:  1347 
• 5i Ciochina R. Grossman RB. Chem. Rev.  2006,  106:  3963 
• 5j Bi H.-P. Guo L.-N. Duan X.-H. Gou F.-R. Huang S.-H. Liu X.-Y. Liang Y.-M. Org. Lett.  2007,  9:  397 
• 5k Fischer D. Tomeba H. Pahadi NK. Patil NT. Yamamoto Y. Angew. Chem. Int. Ed.  2007,  46:  4764 
• 5l Barluenga J. Vazquez-Villa H. Ballesteros A. Gonzalez JM. J. Am. Chem. Soc.  2003,  125:  9028 
• 5m Barluenga J. Vazquez-Villa H. Ballesteros A. Gonzalez JM. Org. Lett.  2003,  5:  4121 
• 5n Barluenga J. Trincado M. Rubio E. Gonzalez JM. Angew. Chem. Int. Ed.  2003,  42:  2406 
• 5o Barluenga J. Trincado M. Rubio E. Gonzalez JM. Angew. Chem. Int. Ed.  2006,  45:  3140 
• 5p Barluenga J. Palomas D. Rubio E. Gonzalez JM. Org. Lett.  2007,  9:  2823 
• 6 Appel TR. Yehia NAM. Baumeister U. Hartung H. Kluge R. Ströhl D. Fanghänel E. Eur. J. Org. Chem.  2003,  47 
• 7a Yu Q.-F. Zhang Y.-H. Yin Q. Tang B.-X. Tang R.-Y. Zhong P. Li J.-H. J. Org. Chem.  2008,  73:  3658 
• 7b Tang B.-X. Tang D.-J. Tang S. Yu Q.-F. Zhang Y.-H. Liang Y. Zhong P. Li J.-H. Org. Lett.  2008,  10:  1063 
• For examples, see
• 8a Hurley PB. Dake GR. J. Org. Chem.  2008,  73:  4131 
• 8b Sy AA. Swenson DC. Gloer JB. Wicklow DT. J. Nat. Prod.  2008,  71:  415 
• 8c Reisman SE. Ready JM. Weiss MM. Hasuoka A. Hirata M. Tamaki K. Ovaska TV. Smith CJ. Wood JL. J. Am. Chem. Soc.  2008,  130:  2087 
• 8d Wang F. Fang Y. Zhu T. Zhang M. Lin A. Gu Q. Zhu W. Tetrahedron  2008,  64:  7986 
• 8e Wu H. Zhang H. Zhao G. Tetrahedron  2007,  63:  6454 
• 8f Sivappa R. Hernandez NM. He Y. Lovely CJ. Org. Lett.  2007,  9:  3861 
• 8g O’Connor PD. Brimble MA. Nat. Prod. Rep.  2007,  24:  869 
• 8h Bennett NJ. Prodger JC. Pattenden G. Tetrahedron  2007,  63:  6216 
• 8i Nair V. Suja TD. Tetrahedron  2007,  63:  12247 
• 8j Dake G. Tetrahedron  2006,  62:  3467 ; and references cited therein
• 8k Hill RA. Annu. Rep. Prog. Chem., Sect. B: Org. Chem.  2007,  103:  125 
• 8l Adams LA. Valentea MWN. Williams RM. Tetrahedron  2006,  62:  5195 
• 8m Vanecko JA. Wan H. West FG. Tetrahedron  2006,  62:  1043 
• 8n Pradhan R. Patra M. Behera AK. Mishra BK. Behera RK. Tetrahedron  2006,  62:  779 ; and references cited therein
• 8o Yang J. Song H. Xiao X. Wang J. Qin Y. Org. Lett.  2006,  8:  2187 
• 8p Takikawa H. Biosci. Biotechnol. Biochem.  2006,  70:  1082 
• 8q Chang M.-Y. Pai C.-L. Kung Y.-H. Tetrahedron Lett.  2005,  46:  8463 
• 8r Madin A. O’Donnell CJ. Oh T. Old DW. Overman LE. Sharp MJ. J. Am. Chem. Soc.  2005,  127:  18054 
• For examples, see:
• 9a Crosignani S. Page P. Missotten M. Colovray V. Cleva C. Arrighi J.-F. Atherall J. Macritchie J. Martin T. Humbert Y. Gaudet M. Pupowicz D. Maio M. Pittet P.-A. Golzio L. Giachetti C. Rocha C. Gérald B. Filinchuk Y. Scheer A. Schwarz MK. Chollet A. J. Med. Chem.  2008,  51:  2227 
• 9b Kumar RR. Perumal S. Senthilkumar P. Yogeeswari P. Sriram D. Tetrahedron  2008,  64:  2962 
• 9c Bursavich MG. Gilbert AM. Lombardi S. Georgiadis KE. Reifenberg E. Flannery CR. Morris EA. Bioorg. Med. Chem. Lett.  2007,  17:  5630 
• 9d Hadda SRTB. Rahima B. Kerbal A. Baba BF. Akkurt M. Demailly G. Benazza M. ARKIVOC  2007,  (xiv):  276 
• 9e Chande MS. Verma RS. Barve PA. Khanwelkar RR. Eur. J. Med. Chem.  2005,  1143 
• 9f Dandia A. Sati M. Arya K. Sharma R. Loupy A. Chem. Pharm. Bull.  2003,  51:  1137 
• 9g Joshi KC. Dandia A. Bhagat S.
  J. Ind. Chem. Soc.  1990,  67:  753 
• For examples, see:
• 10a Gaz SA. Condamine E. Bogdan N. Terec A. Bogdan E. Ramondenc Y. Grosu I. Tetrahedron  2008,  64:  7295 
• 10b Dabiri M. Azimi SC. Khavasi HR. Bazgir A. Tetrahedron  2008,  64:  7307 
• 10c Pfefferkorn JA. Choi C. Tetrahedron Lett.  2008,  49:  4372 
• 10d Nazarenko KG. Shtil NA. Buth SA. Chernega AN. Lozinskii MO. Tolmachev AA. Tetrahedron  2008,  64:  4478 
• 10e Shih H.-W. Cheng W.-C. Tetrahedron Lett.  2008,  49:  1008 
• 10f Suresh Babu AR. Raghunathan R. Synth. Commun.  2008,  38:  1433 
• 10g Dalai S. Es-Sayed M. Nötzel M. de Meijere A. Eur. J. Org. Chem.  2008,  3709 
• 10h Rouillard F. Roy J. Poirier D. Eur. J. Org. Chem.  2008,  2446 
• 10i Yavari I. Mirzaei A. Moradi L. Hosseini N. Tetrahedron Lett.  2008,  49:  2355 
• 10j Alonso F. Melendez J. Synlett  2008,  1627 
• 10k Krishnan KS. Kuthanappillil JM. John J. Suresh CH. Suresh E. Radhakrishnan KV. Synthesis  2008,  2134 
• 10l Kotha S. Deb AC. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2008,  47:  1120 
• 10m Li J.-Q. Liao R.-Z. Ding W.-J. Cheng Y. J. Org. Chem.  2007,  72:  6266 
• 10n Prusov E. Maier ME. Tetrahedron  2007,  63:  10486 
• 10o Kumar RS. Perumal S. Kagan HB. Guillot R. Tetrahedron: Asymmetry  2007,  18:  170 
• 10p Basavaiah D. Reddy KR. Org. Lett.  2007,  9:  57 
• 10q Schulz V. Davoust M. Lemarie M. Lohier J.-F. Sopkova de Oliveira Santos J. Metzner P. Briere J.-F. Org. Lett.  2007,  9:  1745 
• 10r Ramezanpour S. Hashtroudi MS. Singh V. Singh V. Batra S. Bijanzadeh HR. Balalaie S. Tetrahedron Lett.  2008,  49:  3980 
• 10s Hu X. Feng Y. Zhou W. Qiao K. J. Heterocycl. Chem.  2006,  43:  75 
• 10t Holzer W. Claramunt RM. Pérez-Torralba M. Guggi D. Brehmer TH. J. Org. Chem.  2003,  68:  7943 
• 11a Tverdokhlebov AV. Gorulya AP. Tolmachev AA. Kostyuk AN. Chernega AN. Rusanov EB. Tetrahedron  2006,  62:  9146 
• 11b Soleiman HA. Koraiem AIM. Mahmoud NY. J. Chin. Chem. Soc. (Taipei, Taiwan)  2004,  51:  553 
• 11c Hatano M. Mikami K. J. Am. Chem. Soc.  2003,  125:  4704 
• 11d Cossy J. Poitevin C. Pardo DG. Peglion J.-L. Dessinges A. Tetrahedron Lett.  1998,  39:  2965 
• 11e Coutts RT. El-Hawari A.-M. Can. J. Chem.  1977,  55:  2856 
• 12a Lunt E. In Comprehensive Organic Chemistry   Vol. 4:  Barton D. Ollis WD. Pergamon Press; Oxford: 1974.  p.493 
• 12b Sasaki T. Minamoto K. Sujuki T. Yamashita S. Tetrahedron  1980,  36:  865 ; and references cited therein
• 12c Bradshaw TK. Hutchinson DW. Chem. Soc. Rev.  1977,  6:  43 
• 13a Marumoto R. Furukawa Y. Chem. Pharm. Bull.  1977,  25:  2974 
• 13b Cheng CC. Roth B. Prog. Med. Chem.  1971,  8:  61 
• 13c Jones SA. Sayers JR. Walker RT. De Clercq E. J. Med. Chem.  1988,  31:  268 
• 14a Macllwain C. Nature (London)  1993,  365:  378 
• 14b Balzarini J. Pauwels R. Hardewijn P. De Clercq E. Cooney DA. Kanj GJ. Dalai M. Jones DG. Breder S. Biochem. Biophys. Res. Commun.  1986,  140:  735 
• 15a Miyasaka T. Tanaka H. Baba M. Hayasaka H. Walker RT. Balzarini J. De Clercq E. J. Med. Chem.  1989,  32:  2507 
• 15b De Clercq E. J. Med. Chem.  1986,  29:  1561 
• 15c De Clercq E. Anticancer Res.  1986,  6:  549 
• 16 Majumdar KC. Mukhopadhyay PP. Synthesis  2004,  1864 
• 17a Ingham RK. Rosenberg SD. Gilman H. Chem. Rev.  1960,  60:  459 
• 17b Boyer IJ. Toxicology  1989,  55:  253 
• 18a Majumdar KC. Basu PK. Mukhopadhyay PP. Sarkar S. Ghosh SK. Biswas P. Tetrahedron  2003,  59:  2151 
• 18b Majumdar KC. Mukhopadhyay PP. Synthesis  2003,  920 
• 18c Majumdar KC. Das U. Jana NK. J. Org. Chem.  1998,  63:  3550 
• 18d Majumdar KC. Maji PK. Ray K. Debnath P. Tetrahedron Lett.  2007,  48:  9124 
• 18e Majumdar KC. Sinha B. Chattopadhyay B. Ray K. Tetrahedron Lett.  2008,  49:  4405 
• 18f Majumdar KC. Chattopadhyay B. Synlett  2008,  979 
• 18g Majumdar KC. Sinha B. Maji PK. Chattopadhyay SK. Tetrahedron  2009,  65:  2751 
• 18h Majumdar KC. Mondal S. Ghosh D. Synthesis  2010,  1176 
• 18i Majumdar KC. Mondal S. Ghosh D. Tetrahedron Lett.  2010,  51:  5273 
• 22a Yu Q.-F. Zhang Y.-H. Yin Q. Tang B.-X. Tang R.-Y. Zhong P. Li J.-H. J. Org. Chem.  2008,  73:  3658 
• 22b Wang Z.-Q. Tang B.-X. Zhang H.-P. Wang F. Li J.-H. Synthesis  2009,  891 
• 22c Tang B.-X. Tang D.-J. Tang S. Yu Q.-F. Zhang Y.-H. Liang Y. Zhong P. Li J.-H. Org. Lett.  2008,  10:  1063 
• 22d Tang B.-X. Yin Q. Tang R.-Y. Li J.-H. J. Org. Chem.  2008,  73:  9008 
• 23 Okitsu T. Nakazawa D. Kobayashi A. Mizohata M. In Y. Ishida T. Wada A. Synlett  2010,  203 
• 24 Singh V. Singh V. Batra S. Eur. J. Org. Chem.  2008,  5446 
• 25 Zhang X. Larock RC. J. Am. Chem. Soc.  2005,  127:  12230 
• 26a Heathcock CH. Graham SL. Pirrung MC. Plavac F. White CT. The Total Synthesis of Natural Products   Vol. 5:  Apsimon J. Wiley-Interscience; New York: 1983.  p.264-313  
• 26b Hesse M. Alkaloide   Verlag Helvetica Chimica Acta; Zürich: 2000. 
• 26c Yoneda K. Yamagata E. Nakanishi T. Nagashima T. Kawasaki I. Yoshida T. Mori H. Miura I. Phytochemistry  1984,  23:  2068 
• 26d Sakamoto K. Tsujii E. Abe F. Nakanishi T. Yamashita M. Shigematsu N. Izumi S. Okuhara M. J. Antibiot.  1996,  49:  37 
• 26e Biard JF. Guyot S. Roussakis C. Verbist JF. Vercauteren J. Weber JF. Boukef K. Tetrahedron Lett.  1994,  35:  2691 
• 26f Blackman AJ. Li C. Hockless DCR. Skelton BW. White AH. Tetrahedron  1993,  49:  8645 
• 26g Du Y. Lu X. J. Org. Chem.  2003,  68:  6463 ; and references cited therein
• 26h Amagata T. Minoura K. Numata A. J. Nat. Prod.  2006,  69:  1384 
• 26i Greger H. Planta Med.  2006,  72:  99 
• 26j Zhao Y.-M. Gu P. Tu Y.-Q. Fan C.-A. Zhang Q. Org. Lett.  2008,  10:  1763 ; and references cited therein
• 27a Sanz R. Martinez A. Garcia-Garcia P. Fernandez-Rodriguez MA. Rashid MA. Rodriguez F. Chem. Commun.  2010,  46:  7427 
• 27b Pradal A. Nasr A. Toullec PY. Michelet V. Org. Lett.  2010,  12:  5222 
• 28a Crone B. Kirsch SF. Umland K.-D. Angew. Chem. Int. Ed.  2010,  49:  4661 
• 28b Chongmin L. Shesha RM. Seunghoon S. Synlett  2010,  368 

19

General Procedure for the Synthesis of Phenyl Propiolamides 2a-j N -(1-Ethyl-2-oxo-1,2-dihydroquinolin-6-yl)- N -methyl-3-phenylpropiolamide (2e) A mixture of phenylpropiolic acid (500 mg, 3.42 mmol) and SOCl₂ was stirred at 100 ˚C for 1.5 h. After evaporation of the solvent, the residue was dissolved in CH₂Cl₂ (20 mL). A solution of amine 1e (691 mg, 3.42 mmol) in CH₂Cl₂ (20 mL) and TBAHS (cat. amount) was added to the stirred solution of acid chloride. To this reaction mixture an aq solution of K₂CO₃ (930 mg, 6.84 mmol) was added slowly. After stirring for 6 h at r.t., the solution was washed with 5% HCl (2 × 20 mL) and then with 5% aq NaOH (2 × 20 mL). The organic layer was dried (Na₂SO₄), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using EtOAc-PE (3:7) as an eluent to afford amide 2e. Other compounds 2a-d,f-j were also prepared accordingly.
White solid; mp 116-118 ˚C; yield 87%. IR (KBr): 2216, 1643, 1591 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.39 (t, 3 H, J = 7.2 Hz), 3.43 (s, 3 H), 4.36-4.43 (m, 2 H), 6.77 (d, 1 H, J = 9.2 Hz), 7.09 (d, 2 H, J = 7.2 Hz), 7.21 (t, 2 H, J = 7.6 Hz), 7.32 (t, 1 H, J = 7.2 Hz), 7.45 (d, 2 H, J = 8.4 Hz), 7.59 (s, 1 H), 7.68 (d, 1 H, J = 9.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 161.7, 154.3, 138.3, 138.2, 137.2, 132.3, 130.2, 129.7, 128.6, 128.4, 127.3, 123.0, 121.2, 120.1, 114.8, 91.4, 82.5, 37.6, 36.5, 12.7. HRMS (ESI⁺): m/z [M + H⁺] calcd for C₂₁H₁₈N₂O₂: 331.1441; found: 331.1440.

20

General Procedure for the Synthesis of Spiro Compounds 3a-jProcedure for the Synthesis of 1′-Ethyl-4-iodo-5′-methoxy-1-methyl-3-phenyl-1′ H -spiro[pyrrole-2,6′-quinoline]-2′,5 (1 H ,5′ H )-dione (3e)
Using the general procedure, compound 2e (150 mg, 0.45 mmol), NaHCO₃ (115 mg, 1.36 mmol), and molecular I₂ (346 mg, 1.36 mmol) were added in MeCN (5 mL) containing MeOH (1.5 equiv) and stirred at r.t. for 4.2 h. Then the reaction mixture was quenched similarly with 10% Na₂S₂O₃ solution, extracted with CH₂Cl₂ (3 × 15 mL), washed with H₂O (2 × 10 mL) followed by brine (10 mL), and dried over anhyd Na₂SO₄. The solvent was removed to give a crude mass which was purified by column chromatography over silica gel (230-400 mesh) using EtOAc-PE (1:1) as eluent to furnish the desired product 3e. Other compounds 3a-d,f-j were also prepared accordingly.
Yellow solid; mp 184-186 ˚C; yield: 90%. IR (KBr): 1695, 1652, 1621 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.28 (t, 3 H, J = 7.2 Hz), 2.91 (s, 3 H), 3.34 (s, 3 H), 4.13-4.19 (m, 2 H), 4.28 (s, 1 H), 6.01 (d, 1 H, J = 10.0 Hz), 6.45 (d, 1 H, J = 9.2 Hz), 6.92 (d, 1 H, J = 10.4 Hz), 7.22 (d, 1 H, J = 9.6 Hz), 7.37-7.42 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 167.0, 161.6, 161.4, 137.2, 136.6, 132.9, 130.4, 129.7, 128.7, 128.7, 123.5, 119.7, 114.0, 78.5, 72.4, 59.9, 38.3, 28.5, 14.5. HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₂₂H₂₁IN₂O₃: 511.0489; found: 511.0441.

21

CCDC-826706 contains the supplementary crystallographic data (for compound 3c) 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.