Ag⁺-Mediated Synthesis of Substituted Furo[2,3-b]pyrazines

Abstract

A highly efficient method for the preparation of trisubstituted furo[2,3-b]pyrazines has been developed. Sonogashira coupling reaction with the readily available 1-(4-methoxybenzyl)-3,5-dichloropyrazin-2(1H)-ones was followed by silver-catalyzed heteroannulation to provide the corresponding 2-chlorofuro[2,3-b]pyrazines in excellent yields. The latter were subjected to Suzuki or Buchwald-Hartwig coupling reaction for further decoration.

annulations - pyrazin-2(1H)-ones - catalysis - furo[2,3-b]pyrazines - cross-coupling

References and Notes

For representative illustrations, see the following reviews:

1a Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 

1b Zeni G. Larock RC. Chem. Rev.  2004,  104:  2285 

1c Alonso F. Beletskaya IP. Yus M. Chem. Rev.  2004,  104:  3079 

1d Vizer SA. Yerzhanov KB. Al Aziz Al Quntar A. Dembitsky VM. Tetrahedron  2004,  60:  5499 

2a Banwell MG. Flynn BL. Willis AC. Hamel E. Aust. J. Chem.  1999,  52:  767 

2b Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Moro L. Synlett  1999,  1432 

2c Hu Y. Zhang Y. Yang Z. Fathi R. J. Org. Chem.  2002,  67:  2365 

2d Colobert F. Castanet A.-S. Abillard O. Eur. J. Org. Chem.  2005,  3334 

2e Yue D. Yao T. Larock RC. J. Org. Chem.  2005,  70:  10292 

2f Liang Y. Tang S. Zhang X.-D. Mao L.-Q. Xie Y.-X. Li J.-H. Org. Lett.  2006,  8:  3017 

3a Arcadi A. Cacchi S. Di Giuseppe S. Fabrizi G. Marinelli F. Org. Lett.  2002,  4:  2409 

3b Aillaud I. Bossharth E. Conreaux D. Desbordes P. Monteiro N. Balme G. Org. Lett.  2006,  6:  1113 

4a Yue D. Larock RC. J. Org. Chem.  2002,  67:  1905 

4b Hessian KO. Flynn BL. Org. Lett.  2003,  5:  4377 

5a Rao MS. Esho N. Sergeant C. Roman D. J. Org. Chem.  2003,  68:  6788 

5b Liu Z. Li D. Li S. Bai D. He X. Hu Y. Tetrahedron  2007,  63:  1931 

6a Yue D. Larock RC. Org. Lett.  2004,  6:  1037 

6b Barluenga J. Trincado M. Rubio E. González JM. Angew. Chem. Int. Ed.  2003,  42:  2406 

6c Yao D. Yue D. Larock RC. J. Comb. Chem.  2005,  7:  809 

6d Lu BZ. Zhao W. Wei H.-X. Dufour M. Farino V. Senanayake CH. Org. Lett.  2006,  8:  3271 

6e Nakamura M. Ilies L. Otsubo S. Nakamura E. Org. Lett.  2006,  8:  2803 

7 McLaughlin M. Palucki M. Davies IW. Org. Lett.  2006,  8:  3307 

8 Yao T. Larock RC. J. Org. Chem.  2005,  70:  1432 

9 Ames DE. Mitchell JC. Takundwa CC. J. Chem. Res., Synop.  1985,  5:  144 

10 Huang Q. Hunter JA. Larock RC. J. Org. Chem.  2002,  67:  3437 

For the synthesis of furo[2,3-b]pyrazines, see:

11a Kruse CG. Timmermans PBMWM. Van der Laken C. Van der Gen A. Recl. Trav. Chim. Pays-Bas  1978,  97:  151 

11b Timmermans PBMWM. Kruse CG. Van der Gen A. Recl. Trav. Chim. Pays-Bas  1978,  97:  81 

11c Imbert T, Monse B, and Koek W. inventors; WO 03/037904  A1. 

11d Chekmarev DS. Shorshnev SV. Stepanov AE. Kasatkin AN. Tetrahedron  2006,  62:  9919 

11e Tong YC. Kerlinger HO. J. Heterocycl. Chem.  1983,  20:  365 

11f Aoyagi Y. Fujiwara T. Ohta A. Heterocycles  1991,  32:  2407 

12 Topics in Heterocyclic Chemistry   Vol. 1:  Van der Eycken E. Kappe CO. Springer; Berlin / Germany: 2006.  p.267 

13 Kaval N. Bisztray K. Dehaen W. Kappe CO. Van der Eycken E. Mol. Diversity  2003,  7:  125 

14 Kaval N. Van der Eycken J. Caroen J. Kappe O. Dehaen W. Strohmeier GA. Van der Eycken E. J. Comb. Chem.  2003,  5:  560 

For the Ag-catalyzed cyclizations, see:

15a Aucagne V. Amblard F. Agrofoglio LA. Synlett  2004,  2406 

15b Marshall JA. Wolf MA. Wallace EM. J. Org. Chem.  1997,  62:  367 

16

Sonogashira Coupling Reaction on 1-(4-Methoxy-benzyl)-3,5-dichloropyrazin-2(1 H )-ones 1a-d; Typical Procedure
In a 50 mL microwave vial were successively dissolved, in DMF-Et₃N (1:1, 20 mL), pyrazinone 1 (5 mmol), acetylene 2 (6.25-7.5 mmol), Pd(PPh₃)Cl₂ (35 mg, 1 mol%), and CuI (28 mg, 3 mol%). The reaction tube was sealed, and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 80 °C at 80 W maximum power for 10 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH₂Cl₂ (2 × 150 mL) and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography (from 10% to 30% EtOAc in PE) to afford compounds 3a-m.
5-Chloro-1-(4-methoxybenzyl)-3-(phenylethynyl)pyr-azin-2(1 H )-one (3a)
Yield 86%; mp 119-120 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.33 (m, 5 H), 7.17 (s, 1 H), 6.93 (d, J = 8.2 Hz, 2 H), 5.04 (s, 2 H), 3.82 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 160.6, 155.2, 141.2, 133.1, 130.9, 130.4, 128.9, 127.1, 126.5, 126.2, 121.8, 115.2, 99.1, 85.9, 55.8, 53.0. HRMS (EI): m/z calcd for C₂₀H₁₅ClN₂O₂: 350.0822; found: 350.0831.

17

Typical Procedure for the Preparation of Furopyrazines 4a-m
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in anhyd CH₂Cl₂ (12 mL). Then, AgOTf (11 mg, 2 mol%) and TFA (0.8 mL, 10 mmol, 5 equiv) were added and the reaction mixture was stirred at r.t. for 5-20 min. After reaction completion the solvent was evaporated and the residue was subjected to silica gel column chromatography (from 20% to 50% CH₂Cl₂ in PE) to afford compounds 4a-m. 2-Chloro-6-phenylfuro[2,3- b ]pyrazine (4a)
Yield 91% yield; mp 174-176 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.21 (s, 1 H), 7.95 (d, J = 8.3 Hz, 2 H), 7.53 (m, 3 H), 7.17 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 162.3, 154.6, 146.0, 142.1, 136.6, 131.3, 129.6, 128.8, 126.2, 101.2. HRMS (EI): m/z calcd C₁₂H₇ClN₂O: 230.0247; found: 230.0246.

For reports of microwave-promoted Suzuki couplings in organic solvents or solvent-free, see:

18a Hallberg A. Larhed M. J. Org. Chem.  1996,  61:  9582 

18b Wang Y. Sauer DR. Org. Lett.  2004,  6:  2793 

18c Kabalka GW. Wang L. Pagni RM. Hair CM. Namboodiri V. Synthesis  2003,  217 

18d Kabalka GW. Pagni RM. Wang L. Namboodiri V. Hair CM. Green Chem.  2000,  2:  120 

18e Appukkuttan P. Orts AB. Chandran RP. Goeman JL. Van der Eycken J. Dehaen W. Van der Eycken E. Eur. J. Org. Chem.  2004,  15:  3277 

18f Appukkuttan P. Dehaen W. Van der Eycken E. Org. Lett.  2005,  7:  2723 

18g Appukkuttan P. Dehaen W. Van der Eycken E. Comb. Chem. High Throughput Screening  , , accepted

18h Appukkuttan P. Dehaen W. Van der Eycken E. Chem. Eur. J.  2007,  13:  6452 

19

Typical Procedure for the Preparation of Furopyrazines 5a-g In a 15 mL microwave vial were successively dissolved, in DMF-H₂O (1:1, 6 mL), furopyrazine 4 (0.7 mmol), boronic acid 6 (0.86 mmol, 1.25 equiv), Pd(PPh₃)₄ (8 mg, 1 mol%), and Na₂CO₃ (150 mg, 2 equiv). The reaction tube was sealed and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 100 °C at 100 W maximum power for 10 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH₂Cl₂ (2 × 50 mL) and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was subjected to silica gel flash chromatography (from 10% to 50% CH₂Cl₂ in PE) to afford compounds 5a-g.
2-(4-Chlorophenyl)-6-propylfuro[2,3- b ]pyrazine (5a)
Yield 81%; mp 143-144 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.55 (s, 1 H), 8.94 (d, J = 8.3 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 6.65 (s, 1 H), 2.87 (d, J = 7.5 Hz, 2 H), 1.86 (m, 2 H), 1.06 (d, J = 7.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.2, 154.7, 148.6, 141.9, 135.7, 135.3, 134.1, 129.4, 129.1 (2×), 128.3 (2×), 103.8, 31.2, 20.6, 13.7. HRMS (EI): m/z calcd for C₁₅H₁₃ClN₂O: 272.0716; found: 272.0708.

For use of tetrabutylammonium bromide additive in Buchwald-Hartwig amination, see:

20a Mei X. Martin RM. Wolf C. J. Org. Chem.  2006,  71:  2854 

20b Mei X. Wolf C. Tetrahedron Lett.  2006,  47:  7901 

20c Mei X. Martin RM. Wolf C. J. Am. Chem. Soc.  2006,  128:  13326 

For reports of microwave-promoted amination, see:

21a Jonckers THM. Maes BUW. Lemière GLF. Dommisse R. Tetrahedron  2001,  57:  7027 

21b Sharifi A. Hosseinzadeh R. Mirzaei M. Monatsh. Chem.  2002,  133:  329 

21c Wan Y. Alterman M. Hallberg A. Synthesis  2002,  1597 

21d Wang T. Magnin DR. Hamann LG. Org. Lett.  2003,  6:  897 

21e Maes BUW. Loones KTJ. Hostyn S. Diels G. Rombouts R. Tetrahedron  2004,  60:  11559 

21f Loones KTJ. Maes BUW. Rombouts G. Hostyn S. Diels G. Tetrahedron  2005,  61:  10338 

22

Typical Procedure for the Preparation of Furopyrazines 5h-l In a 15 mL microwave vial were successively dissolved, in 1,4-dioxane (4 mL), furopyrazine 4 (0.5 mmol), amine 6 (0.63 mmol, 1.25 equiv), Pd(OAc)₂ (3.5 mg, 3 mol%), and (±)-BINAP (11 mg, 3.3 mol%), tetrabutylammonium bromide (1.0-1.2 equiv), and NaOt-Bu (1.5-1.7 equiv). The reaction tube was sealed and irradiated in the cavity of a Milestone-MYCROSYNTH multimode reactor at a ceiling temperature of 120 °C at 300 W maximum power for 15 min. After the reaction mixture was cooled with an airflow for 15 min, then it was extracted with CH₂Cl₂ (2 × 50 mL) and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was subjected to silica gel flash chromatography (from 10% to 30% EtOAc in PE) to afford compounds 5h-l. 2-Morpholin-4-yl-6-phenylfuro[2,3- b ]pyrazine (5h)
Yield 91%; mp 95-97 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.91 (d, J = 8.3 Hz, 2 H), 7.76 (s, 1 H), 7.46 (m, 3 H), 7.03 (s, 1 H), 3.89 (t, J = 4.6 Hz, 4 H), 3.57 (t, J = 4.6 Hz, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 159.9, 155.2, 151.1, 130.3, 129.9, 129.4 (2×), 125.8 (2×), 124.4, 101.3, 67.1, 46.7. HRMS (EI): m/z calcd for C₁₆H₁₅N₃O₂: 281.1164; found: 281.1174.