Palladium-Mediated Reductive Heck Cyclization for the Formation of Dibenzoazepinone Framework

Abstract

The dibenzoazepinone framework has been synthesized through a palladium-mediated Sonogashira cross-coupling followed by a reductive Heck cyclization. The reactions are simple, straightforward, and have been carried out under ligand-free conditions.

Key words

dibenzoazepinone - reductive Heck - Sonogashira cross coupling - Pd(PPh₃)₄

References and Notes

• 1a Link JT. Org. React. (N. Y.)  2002,  60:  157 
• 1b Dyker G. In Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 1:  Negishi E.-I. de Meijere A. Wiley; New York: 2002. 
• 2a Liu P. Huang L. Lu Y. Dilmeghani M. Baum J. Xiang T. Adams J. Tasker A. Larsen R. Faul MM. Tetrahedron Lett.  2007,  48:  2307 
• 2b Mangeney P. Pays C. Tetrahedron Lett.  2003,  44:  5719 
• 2c Higuchi K. Comins DL. Beilstein J. Org. Chem.  2007,  3:  1 
• 2d Majumdar KC. Sinha B. Maji PK. Chattopadhyay SK. Tetrahedron  2009,  65:  2751 
• 2e Majumdar KC. Chakravorty S. De N. Tetrahedron Lett.  2008,  49:  3419 
• 2f Majumdar KC. Chakravorty S. Shyam PK. Taher A. Synthesis  2009,  403 
• 2g Majumdar KC. Chakravorty S. Ray K. Synthesis  2008,  2991 
• 2h Majumdar KC. Sinha B. Chattopadhyay B. Ray K. Tetrahedron Lett.  2008,  49:  4405 
• 3a Di Fabio R. Micheli F. Baraldi D. Bertani B. Conti N. Dal Forno G. Feriani A. Donati D. Marcchioro C. Messeri T. Missio A. Pasquarello A. Pentassuglia G. Pizzi DA. Provera S. Quaglia AM. Sabbatini FM. Farmaco  2003,  58:  723 
• 3b Hayashi M. Sai H. Horikawa H. Heterocycles  1998,  48:  1331 
• 3c Majumdar KC. Chattopadhyay B. Ray K. Tetrahedron Lett.  2007,  48:  7633 
• 3d Majumdar KC. Chattopadhyay B. Samanta S. Tetrahedron Lett.  2009,  in press
• 3e Cropper EL. Andrew JP. White AF. Hii KK. J. Org. Chem.  2006,  71:  1732 
• 4a Arnold LA. Luo W. Guy RK. Org. Lett.  2004,  6:  3005 
• 4b Gibson SE. Jones JO. Kalindjinan SB. Knight JD. Steed JW. Tozer MJ. Chem. Commun.  2002,  1938 
• 4c Alcaide B. Polanco C. Sierra MA. Eur. J. Org. Chem.  1998,  2913 
• 4d Gibson SE. Middleton RJ. J. Chem. Soc., Chem. Commun.  1995,  1743 
• 4e Majumdar KC. Chattopadhyay B. Sinha B. Tetrahedron Lett.  2008,  49:  1319 
• 4f Majumdar KC. Chattopadhyay B. Synlett  2008,  979 
• 4g For a recent review on this topic, see: Majumdar KC. Chattopadhyay B. Curr. Org. Chem.  2009,  in press
• For example, see:
• 5a Santos LS. Pilli RA. Synthesis  2002,  87 
• 5b Tietze LF. Sommer KM. Schneider G. Tapolzsanyi P. Wolfling J. Muller P. Noltemeyer M. Terlau H. Synlett  2003,  1494 
• 6 Kaufmann D. Fünfschilling PC. Beutler U. Hoehn P. Lohse O. Zaugg W. Tetrahedron Lett.  2004,  45:  5275 
• 7 Fauq AH. Simpson K. Maharvi GM. Golde T. Das P. Bioorg. Med. Chem. Lett.  2007,  17:  6392 
• 8 Kling A. Backfisch G. Delzer J. Geneste H. Graef C. Holzenkamp U. Hornberger W. Lange UEW. Lauterbach A. Mack H. Seitz W. Subkowski T. Bioorg. Med. Chem. Lett.  2002,  12:  441 

9

CCDC 747690 contains supplementary crystallographic data for the structure 4f.

10

General Procedure for the Formation of Amide 3f
A mixture of 2-iodobenzoic acid^¹² (500 mg, 2.01 mmol) and SOCl₂ was stirred at 100 ˚C for 3 h. After evaporation of the solvent, the residue was dissolved in CH₂Cl₂ (20 mL). A solution of amine 2f (583 mg, 2.01 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 (556 mg, 4.03 mmol) was added slowly. After stirring for 5 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 evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using PE-EtOAc (7:3) as an eluent.
Compound 3f: white solid, yield 78%, mp 176-178 ˚C. IR (KBr): ν_max = 2212, 1738, 1651, 1565 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.08 (t, 3 H, J = 7.2 Hz), 3.56-3.68 (m, 1 H), 4.49-4.61 (m, 1 H), 6.48 (d, 1 H, J = 9.6 Hz), 6.82-6.83 (m, 1 H), 7.03-7.11 (m, 1 H), 7.21-7.26 (m, 2 H), 7.45-7.47 (m, 3 H), 7.56-7.70 (m, 4 H), 8.15 (d, 1 H, J = 9.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 12.8, 43.7, 82.1, 93.6, 117.0, 117.6, 121.5, 126.7, 127.0, 127.6, 128.7, 128.8, 129.9, 130.1, 131.7, 131.9, 132.6, 139.8, 141.3, 141.9, 153.0, 159.6, 169.7. HRMS: m/z found for C₂₆H₁₈INO₃: 542.1890 [M⁺ + Na]. Anal. Calcd for C₂₆H₁₈INO₃: C, 60.13; H, 3.49; N, 2.70. Found: C, 60.33; H, 3.29; N, 2.93.

11

General Procedure for Reductive Heck Cyclization of Compound 3f A mixture of compound 3f ^¹² (100 mg, 0.19 mmol), HCOONa (19.6 mg, 0.29 mmol), Pd(PPh₃)₄ (6.6 mg,
5.710^-³ mmol) in DMF-H₂O (10 mL, 7:3) was heated with continuous stirring at 120 ˚C for 4.2 h. After completion of the reaction as monitored by TLC, the reaction mixture was cooled and H₂O (5 ml) was added. This was then extracted with CH₂Cl₂ (3 × 10 mL). The CH₂Cl₂ extract was washed with H₂O (3 × 10 mL) followed by brine (10 mL). The organic layer was dried (Na₂SO₄). Evaporation of CH₂Cl₂ furnished a crude mass, which was purified by column chromatography over silica gel. Elution of the column with PE-EtOAc (3:1) afforded product 4f.
Compound 4f: white solid, yield 85%, mp 198-200 ˚C. IR (KBr): ν_max = 1724, 1633 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.19-1.27 (m, 3 H), 3.74-3.81 (m, 1 H), 4.69-4.76 (m, 1 H), 6.18 (d, 1 H, J = 9.8 Hz), 6.98 (s, 1 H), 7.08-7.09 (m, 2 H), 7.19-7.20 (m, 3 H), 7.28-7.31 (m, 2 H), 7.38-7.41 (m, 1 H), 7.45-7.49 (m, 1 H), 7.57 (d, 1 H, J = 9.0 Hz), 7.63 (d, 1 H, J = 9.8 Hz), 7.89 (dd, 1 H, J = 0.8, 7.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 44.3, 114.3, 116.9, 117.3, 124.9, 127.8, 128.4, 128.5, 128.8, 128.9, 130.9, 131.7, 131.9, 132.2, 132.4, 132.8, 134.6, 135.4, 136.4, 140.5, 145.04, 152.2, 159.9, 167.6. HRMS: m/z calcd for C₂₆H₁₉NO₃: 394.1438 [M⁺ + H]; found: 394.1406 [M⁺ + H]. Anal. Calcd for C₂₆H₁₉NO₃: C, 79.37; H, 4.87; N, 3.56. Found: C, 79.58; H, 5.04; N, 3.75.

12

2-Bromobenzoic acid can also be used to give the corrosponding 2-bromo derivative 3 which also undergoes reductive Heck cyclization to afford 4f (yield 80%).