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Synlett 2011(18): 2657-2662  
DOI: 10.1055/s-0031-1289526
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

K. C. Majumdar*, Tapas Ghosh, Pranab K. Shyam
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
e-Mail: kcm_ku@yahoo.co.in;
Further Information

Publication History

Received 19 July 2011
Publication Date:
19 October 2011 (online)

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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

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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.

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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.

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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.