Metallation and Functionalisation of Dihydrodipyridopyrazines

Abstract

We describe the lithiation of the recently prepared 5,10-dimethyl-5,10-dihydrodipyrido[2,3-b:3,2-e] and [2,3-b:2,3-e]pyrazines 1 (R = CH₃) and 2 (R = CH₃), respectively. Interestingly while 1 was metallated at the pyridine ring, 2 was lithiated at the methyl groups. Reactions with electrophiles led to new functionalised dihydrodipyridopyrazines.

Key words

dihydrodipyridopyrazines - lithiation - functionalisation

References

• 1a Pratt WB. Ruddon RW. Ensminger WD. Maybaum J. The Anticancer Drugs   2nd ed.:  Oxford University Press; Oxford: 1994. 
• 1b Denny WA. Cancer Chemother. Agents  1995,  218 
• 1c Graham SL. Williams TM. Exp. Op. Ther. Pat.  1996,  6:  1295 
• 1d Singh SB. Lingham RB. Exp. Op. Ther. Pat.  1996,  5:  1589 
• 1e Boger DL. Johnson DS. Angew. Chem., Int. Ed. Engl.  1996,  35:  1438 
• 1f Leonard DM. J. Med. Chem.  1997,  40:  2981 
• 1g Lerner EC. Hamilton AD. Sebti SM. Anti-Cancer Drug. Des.  1997,  12:  229 
• 1h Pierré A. Atassi G. Devissaguet M. Bisagni E. Drugs of the Future  1997,  22:  53 
• 1i Boger DL. Boyce CW. Garbaccio RM. Goldberg JA. Chem. Rev.  1997,  97:  787 
• 1j Takemura Y. Jackman AL. Anti-Cancer Drugs  1997,  8:  3 
• 2a Delfourne E. Darro F. Bontemps-Subielos N. Decaestecker C. Bastide J. Frydman A. Kiss R. J. Med. Chem.  2001,  44:  3275 
• 2b Vicker N. Burgess L. Chuckowree SI. Dodd R. Folkes AJ. Hardick DJ. Hancox TC. Miller W. Milton J. Sohal S. Wang S. Wren SP. Charlton PA. Dangerfield W. Liddle C. Mistry P. Stewart AJ. Denny WA. J. Med. Chem.  2002,  45:  721 
• 2c Gamage SA. Spicer JA. Rewcastle GW. Milton J. Sohal S. Dangerfield W. Mistry P. Vicker N. Charlton PA. Denny WA. J. Med. Chem.  2002,  45:  740 
• 2d Antonini I. Polucci P. Magnano A. Gatto B. Palumbo M. Menta E. Pescalli N. Martelli S. J. Med. Chem.  2002,  45:  696 
• 3 Rodriguez I. Kuehm-Caubère C. Vinter-Pasquier K. Renard P. Pfeiffer B. Caubère P. Tetrahedron Lett.  1998,  39:  7283 
• 4 Blanchard S. Rodriguez I. Kuehm-Caubere C. Renard P. Pfeiffer B. Guillaumet G. Caubère P. Tetrahedron  2002,  58:  3513 
• 5a Caubère P. Acc. Chem. Res.  1974,  7:  301 
• 5b Caubère P. Top. Curr. Chem.  1978,  73:  50 
• 5c Caubère P. Rev. Heteroat. Chem.  1991,  4:  78 
• 5d Caubère P. Chem. Rev.  1993,  93:  2317 
• 5e Caubère P. J. Chin. Chem. Soc.  1998,  45:  451 ; and references cited in these reviews
• 6 Caubère P, Guillaumet G, Rodriguez I, Vinter-Pasquier K, Kuehm-Caubère C, Blanchard S, Atassi G, Pierre A, Pfeiffer B, and Renard P. inventors; Eur. Pat. Appl. EP  96986.  ; Chem. Abstr. 2000, 132, 22978
• 7a Mongin F. Quequiner G. Tetrahedron  2001,  57:  4059 ; and references cited therein
• 7b Turck A. Plé N. Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4489 ; and references cited therein

8

Experimental Procedure: The following procedure for the synthesis of 5,10-dimethyl-5,10-dihydrodipyrido[2,3-b;3,2-e]pyrazin-4-carbaldehyde 4k is representative. Under inert atmosphere, to a solution of n-butyllithium (0.59 mL, 0.94 mmol, 1.6 M in hexane) in THF (2 mL), was added, at
-10 °C, 5,10-dimethyl 5,10-dihydrodipyrido[2,3-b;3,2-e] pyrazine 1 (100 mg, 0.47 mmol). After stirring at the same temperature for 1.0 h, N,N-dimethylformamide (146 µL, 1.88 mmol) was added. The mixture was allowed to warm at r.t., quenched with water and extracted with CH₂Cl₂. The combined extracts were dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent EtOAc/hexane: 10/90) to afford the desired compound 4k. Mp 184-185 °C. IR (KBr): 1683 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 3.13 (s, 3 H, CH₃), 3.37 (s, 3 H, CH₃), 6.62 (m, 2 H, H₆ and H₇), 6.78 (d, 1 H, H₃, J = 5.3 Hz), 7.52 (d, 1 H, H₂, J = 5.3 Hz), 7.67 (dd, 1 H, H₈, J = 4.4, 1.9 Hz), 9.86 (s, 1 H, CHO).
¹³C NMR (62.5 MHz, CDCl₃): δ = 28.2, 43.9, 116.2, 117.1, 119.9, 124.2, 132.4, 134.4, 138.0, 141.0, 148.2, 151.5, 188.5. MS: m/z = 241 (M + H)⁺.

9

Experimental Procedure : The following procedure for the synthesis of 2-[10-(2-oxo-ethyl)dipyrido[2,3-b;2,3-e]pyrazin-5(10H)-yl] acetaldehyde 6e is representative. Under insert atmosphere, to a solution of n-butyllithium (1.2 mL, 1.88 mmol, 1.6 M in hexane) in THF (2mL) was added, at -10 °C, 5,10-dimethyl-5,10-dihydrodipyrido[2,3-b;2,3-e]pyrazine 2. After stirring at the same temperature for 5 h, N,N-dimethylformamide (146 µL, 1.88 mmol) was added. The mixture was allowed to warm at r.t., quenched with water and extracted with CH₂Cl₂. The combined extracts were dried over MgSO₄, filtered and concentrated in vacuo. The crude solid was washed with pentane and dried to give 6e. Mp 179-180 °C. IR (KBr): 1729 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 4.59 (s, 4 H, CH₂), 6.48 (dd, 2 H, H₃ and H₈, J = 7.8, 4.9 Hz), 6.55 (dd, 2 H, H₄ and H₉, J = 7.8, 1.5 Hz), 7.29 (dd, 2 H, H₂ and H₇, J = 4.9, 1.5 Hz), 9.62 (s, 2 H, CHO). ¹³C NMR (62.5 MHz, CDCl₃): δ = 51.4, 117.1, 117.8, 130.7, 138.6, 146.2, 198.8. MS: m/z = 315 (M + H + HCOOH)⁺.

10

All new compounds were fully characterised by ¹H NMR, ¹³C NMR, MS and IR spectra.