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

K. C. Majumdar; Tapas Ghosh; Pranab K. Shyam

doi:10.1055/s-0031-1289526

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Synlett 2011(18): 2657-2662
DOI: 10.1055/s-0031-1289526

LETTER

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)

Abstract
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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

References and Notes

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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.