Reactivity of the Acridine Ring: One-Pot Regioselective Single and Double Bromomethylation of Acridine and Some Derivatives

Abstract

We report here a new efficient regioselective synthetic route to 4-bromomethylacridine and to 4,5-bis-(bromomethyl)acridine, two interesting starting materials for various 4-methyleneacridine and 4,5-bis-(methylene)acridine derivatives, in one step by direct bromomethylation of acridine with bromomethylmethylether (BMME). We also describe some biologically interesting diesters derivatives from the corresponding 4,5-bis(hydroxymethyl)acridine precursor.

Key words

acridines - bromomethylation - electrophilic aromatic substitution - regioselectivity - reactivity

References

• 1 Hess FK. Cullen E. Grozinger K. Tetrahedron Lett.  1971,  28:  2591 
• 2 Chiron J. Galy JP. Heterocycles  2003,  60:  1653 
• 3a Chiron J. Galy JP. Z. Kristallogr. NCS  2002,  217:  287 
• 3b Sourdon V. Mazoyer S. Pique V. Galy JP. Molecules  2001,  6:  673 
• 3c Filloux N. Galy J.-P. Synlett  2001,  1137 
• 4 Charmantray F. Duflos A. Lhomme J. Demeunynck M. J. Chem. Soc., Perkin Trans. 1  2001,  2962 
• 5 Taylor RC. In Electrophilic Aromatic Substitution   John Wiley and Sons; Chichester: 1990.  p.219 
• 7 Hess FK. Stewart PB. J. Med. Chem.  1975,  18:  320 
• 9a Georghiou PE. Ashram M. Li Z. Chaulk SG. J. Org. Chem.  1995,  60:  7284 
• 9b Smith JG. Dibble PW. Sandborn RE. J. Org. Chem.  1986,  51:  3762 
• 9c Grissom JW. Klingberg D. Meyenburg S. Stallman B. J. Org. Chem.  1994,  59:  7876 
• 11a Read M. Harrison RJ. Romagnoli B. Tanious FA. Gowan SH. Reszka AP. Wilson WD. Kelland LR. Neidle S. Proc. Natl. Acad. Sci. U. S. A.  2001,  98:  4844 
• 11b Di Giorgio C. Delmas F. Filloux N. Robin M. Seferian L. Azas N. Gasquet M. Costa M. Timon-David P. Galy JP. Antimicrob. Agents Chemother.  2003,  47:  174 

6

4-Bromomethylacridine 6: Acridine 1 (1 g, 5.58 mmol) was dissolved in H₂SO₄ (20 mL) at 20 °C under N₂ and BMME 5 (1.05 g, 7,71 mmol) was added in one portion. The mixture was maintained at 20 °C for 17 h then it was poured into ice and stirred for 1 h. The precipitated was filtered off and dissolved in CHCl₃. The organic layer was then dried with MgSO₄, the solvent was removed under vacuo and the resulting yellow solid was chromatographed (silica gel, CHCl₃/cyclohexane, 7/3, v:v) to give 6 as a bright yellow powder (466 mg, 31%). Mp 166 °C, lit. [3b] 165 °C.

8

4,5-Bis(bromomethyl)acridine 7: Acridine 1 (2 g, 11.16 mmol) was heated in H₂SO₄ (25 mL) to 50 °C under N₂ and BMME 5 (6.08 g, 44.64 mmol) was added in one portion. The mixture was maintained at 50 °C for 12 h then it was poured into ice and stirred for 1 h. The precipitated was filtered off and dissolved in CHCl₃. The organic layer was then dried with MgSO₄, the solvent was removed under vacuo and the resulting yellow solid was recrystallized from dry Et₂O to give 7 as a bright yellow powder (2.49 g, 64%). Mp 156 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.19 (s, 4 H), 7.95 (dd, 1 H, J = 8 Hz), 8.37 (d, 1 H, J = 8 Hz), 8.50 (d, 1 H, J = 8 Hz), 9.91 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 27.01, 126.94, 127.59, 128.81, 131.55, 137.83, 139.45, 151.22. Anal. Calcd for C₁₅H₁₁Br₂N: C, 49.35; H, 3.04; N, 3.84. Found: C, 49.49; H, 3,03; N, 3.83.

10

(5-{[(4-Chlorobenzoyl)oxy]methyl}-4-acridinyl)methyl 4-Chlorobenzoate 9b: A solution of 4-chlorobenzoyl chloride (471 mg, 2.75 mmol) in CH₂Cl₂ (10 mL) was added dropwise under N₂ to a stirred solution of 7 (300 mg, 1.25 mmol), Et₃N (0.44 mL, 3.17 mmol) and DMAP (383 mg, 3.14 mmol) in CH₂Cl₂ (20 mL) at 0 °C. After complete addition, the mixture was allowed to stand at r.t. for 6 h. The organic layer was then washed with NaOH 1 N (2 × 35 mL), dried with MgSO₄ and the solvent was removed under vacuo. The resulting solid was purified by column chromatography (silica gel, CH₂Cl₂/EtOAc, 99:1, v:v) to give 9b as a yellow powder (515 mg, 81%). Mp 170 °C. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 6,21 (s, 4 H), 7.35 (m, 4 H), 7.53 (dd, J = 8.5, 6.9 Hz, 2 H), 7.84 (dd, J = 6.9, 0.8 Hz, 2 H), 7.97 (dd, J = 8.5, 0.8 Hz, 2 H), 8.02 (m, 4 H), 8.77 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 63.67, 125.50, 126.33, 128.26, 128.67, 128.73, 128.85, 131.10, 134.46, 136.18, 139.31, 146.13, 165.61. Anal. Calcd for C₂₉H₁₉Cl₂NO₄: C, 67.58; H, 3.71; N, 2.71. Found: C, 67.45; H, 3.70; N, 2.70.