Download PDF
Synlett 2004(2): 0287-0290  
DOI: 10.1055/s-2003-45004
LETTER
© Georg Thieme Verlag Stuttgart · New York

2-Aryl and 2-Heteroaryl Pyrrolo[2,3-b]quinoxalines via Copper-Catalyzed
Reaction of 1-Alkynes with 2-Bromo-3-trifluoroacetamidoquinoxaline

Sandro Cacchi*a, Giancarlo Fabrizia, Luca M. Parisia, Roberta Berninib
a Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Roma, Italy
b Dipartimento A.B.A.C., Università degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
Fax: +39(6)49912780; e-Mail: sandro.cacchi@uniroma1.it;
Further Information

Publication History

Received 27 October 2003
Publication Date:
18 December 2003 (online)

    Permissions and Reprints All articles of this category

Abstract

2-Aryl and 2-heteroaryl pyrrolo[2,3-b]quinoxalines have been prepared in good to high yield through the reaction of 1-alkynes with 2-bromo-3-trifluoroacetamidoquinoxaline in the presence of catalytic amounts of CuI, PPh3, and K2CO3 in dioxane at 110 °C. The reaction appears to tolerate a wide range of functionalized 1-alkynes, including those containing ether, alcohol, amide, ­aldehyde, ketone, ester, and nitro groups.

Key words

coupling - cyclization - copper - alkynes - heterocycles

15

Synthesis of 2-amino-3-bromoquinoxaline ( 5): To a solution of 2,3-dibromo-quinoxaline (2.00 g, 6.92 mmol) in DMSO/MeCN (8 mL/12 mL), NH4OH (1.8 mL, 13.84 mmol, solution 30%) and K2CO3 (0.96 g, 6.92 mmol) were added. The solution was stirred at 50 °C for 120 h. After cooling, the reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 130 g; n-hexane/EtOAc 75:25) to give 1.29 g of 5 (83% yield). Mp 163-164 °C. IR (KBr): 3290, 3137 cm-1. 1H NMR (CDCl3): δ = 7.86 (dd, J 1 = 8.0 Hz, J 2 = 1.0 Hz, 1 H), 7.72-7.55 (m, 2 H), 7.49-7.40 (m, 1 H), 5.55 (bs, 2 H). 13C NMR (CDCl3): δ = 149.8, 141.0, 138.2, 130.6, 130.3, 128.5, 125.9, 125.7. Anal. Calcd for C8H7BrN3: C, 42.88; H, 2.70; N, 18.75. Found: C, 42.80; H, 2.68; N, 18.73.

17

When we attempted the conversion of 2,3-dibromoquinoxaline into 5 under the conditions described in ref. [16b] (NH4CO3, DMF) at 60 °C - instead of r.t. - for 20 h, compound 5 was isolated in 30% yield and the starting 2,3-dibromoquinoxaline was recovered in 50% yield. Switching to DMSO as the solvent led to a higher conversion. However, compound 5 was isolated in only 25% yield, the main by-product being 2,3-diaminoquinoxaline. After some experimentation we arrived at the conditions described in ref. [15] that afforded the desired product in 83% yield.

18

Synthesis of 2-bromo-3-trifluoroacetamidoquinoxaline ( 1): To a solution of 5 (0.500 g, 2.23 mmol) and Et3N (310 mL, 2.23 mmol) in THF (10 mL) trifluoroacetic anhydride (630 mL, 4.46 mmol) was added at 0 °C dropwise. The solution was stirred at r.t. for 1 h. Then, the reaction mixture was diluted with EtOAc, washed with a sat. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. Compound 1 was obtained in quantitative yield: mp 215-217 °C. IR (KBr): 3423, 1632, 1603 cm-1. 1H NMR (DMSO-d 6): δ = 7.83 (d, J = 7.9 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.53 (t, J = 7.1 Hz, 1 H). 13C NMR (DMSO-d 6): δ = 157.8, 157.6 (q, J = 31.7 Hz), 141.8, 141.4, 138.6, 130.0, 127.8, 127.3, 126.7, 119.1 (q, J = 290.1 Hz). 19F NMR {H} (DMSO-d 6): δ = -73.2.

20

Typical Procedure for the Preparation of 2-Aryl and 2-Heteroaryl Pyrrolo[2,3- b ]quinoxalines (4, Table 1, entry 12): To a solution of 1 (0.100 g, 0.31 mmol) in 1,4-dioxane (2 mL), 3-ethynylquinoline (0.530 g, 0.344 mmol), CuI (0.009 g, 0.047 mmol), PPh3 (0.025 g, 0.090 mmol), and K2CO3 (0.087 g, 0.630 mmol) were added. The solution was stirred at 110 °C for 6 h. After cooling, the reaction mixture was suspended on silica gel and the solvent evaporated. The residue was purified by chromatography (silica gel, 40 g; CHCl3/CH2Cl2/MeOH 1:1:0.1) to give 0.070 g of 4l (76% yield): mp 365-367 °C. IR (KBr): 3422, 3090 cm-1. 1H NMR (DMSO-d 6): δ = 9.32 (s, 1 H), 9.03 (s, 1 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.65-7.56 (m, 3 H), 7.49-7.28 (m, 4 H), 7.10 (s, 1 H). 13C NMR (DMSO-d 6): δ = 149.2, 148.2, 147.0, 144.6, 143.9, 141.1, 139.6, 133.5, 131.3, 129.5, 129.3 (2 Caryl-H isochrone resonances, as established by inverse gated 1H-decoupling experiments), 128.5, 128.2, 128.1, 127.7, 127.1, 124.3, 98.8. Anal Calcd for C19H12N4: C, 77.01; H, 4.08; N, 18.91. Found: C, 76.95; H, 4.07; N, 18.89.