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.

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.