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Synlett 2002(8): 1356-1358
DOI: 10.1055/s-2002-32963
LETTER
© Georg Thieme Verlag Stuttgart · New York

Metallation and Functionalisation of Dihydrodipyridopyrazines

Stéphanie Blanchard, Ivan Rodriguez, Paul Caubère*, Gérald Guillaumet*
Institut de Chimie Organique et Analytique UMR-CNRS 6005, Université d’Orléans, rue de Chartres, BP 6759, 45067 Orléans cedex 2, France
Fax: +33(238)417078; e-Mail: gerald.guillaumet@univ-orleans.fr.;
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Publication History

Received 7 May 2002
Publication Date:
25 July 2002 (online)

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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

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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.