Heteroannulation through copper catalysis: A novel cyclisation leading to an unusual formation of 2-aroylquinoxalines

Article abstract of DOI:10.1016/S0040-4039(00)01766-4

N-[(3'-Aryl)prop-2'-ynyl]-N,N'-1,2-phenylene di-p-tosylamides, 15-22, underwent an unusual ring closure with potassium carbonate (2 equiv.) and copper(I) iodide (10 mol%) in DMF at 100°C for 24 h to yield 2-aroylquinoxalines (23-30) instead of the expecte

Full text of DOI:10.1016/S0040-4039(00)01766-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9927–9930
Heteroannulation through copper catalysis: a novel
cyclisation leading to an unusual formation of
2
-aroylquinoxalines
Rupa Mukhopadhyay and Nitya G. Kundu*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Calcutta 700032, India
Received 15 August 2000; revised 28 September 2000; accepted 4 October 2000
Abstract
N-[(3%-Aryl)prop-2%-ynyl]-N,N%-1,2-phenylene di-p-tosylamides, 15–22, underwent an unusual ring clo-
sure with potassium carbonate (2 equiv.) and copper(I) iodide (10 mol%) in DMF at 100°C for 24 h to
yield 2-aroylquinoxalines (23–30) instead of the expected 2-alkylidene-1,4-di-tosyl-1,2,3,4-tetra-
hydroquinoxalines (31). © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: copper catalysis; quinoxalines.
1
2
Palladium-catalysed reactions have been of great significance in carboannulation and
3
heteroannulation processes. Our own efforts in this area have been the use of terminal alkynes
4
under palladium–copper catalysis to generate a number of heterocyclic structures, e.g. benzo-
5
6
7
8
9
10
11
furans, phthalides, quinolines, isoindolinones, flavanones, benzodioxanes, benzoxazines,
1
2
12
benzodioxepines and benzoxazepines, which usually follow the expected cyclisation processes.
Recently, however, we reported some unusual reactions where 2-substituted benzothiazolines (3)
were formed from 3-(2-aminophenylthio)prop-1-yne (1) due to the use of excess copper(I) iodide
1
3
in the cyclisation step (Scheme 1a). Similarly the use of excess CuI in the arylation step of the
terminal alkynes (4) together with the palladium catalyst led to novel depropargylation and
14
S-arylation reactions leading to diaryl sulfides (5) (Scheme 1b).
In the present letter we report some unusual reactions during cyclisation of alkynes under
copper catalysis. The terminal alkyne (6) underwent the usual C-arylation reaction with aryl
iodides (7–14) in the presence of (PPh ) PdCl (3 mol%), CuI (8 mol%), triethylamine (5 mmol)
3
2
2
in acetonitrile at room temperature for 24 h to yield the disubstituted alkynes (15–22) in
moderate to good yields. These were then cyclised with CuI (10 mol%) in the presence of K CO3
2
*
Corresponding author. Tel: +91-33-4734971, ext: 240; fax:+91-33-4732805; e-mail: ocngk@mahendra.iacs.res.in
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01766-4

9928
Scheme 1.
in DMF by heating at 100°C for 24 h. But interestingly, instead of the expected 2-alkylidene-
,2,3,4-tetrahydroquinoxaline 31, the 2-aroylquinoxalines (23–30) were formed in good yields
Scheme 2, Table 1).
1
(
Scheme 2.

9929
Table 1
Synthesis of 2-aroyl quinoxalines (23–30) through copper-catalysed reactions (Scheme 2)
a
b
Entry
Aryl iodides (Ar)
Disubstituted alkynes (%)
2-Aroyl quinoxalines (%)
1
2
3
4
5
6
7
8
Phenyl (7)
15 (43)
16 (59)
17 (60)
18 (60)
19 (55)
20 (41)
21 (52)
22 (65)
23 (46)
24 (44)
25 (60)
26 (53)
27 (50)
28 (40)
29 (49)
30 (45)
1-Naphthyl (8)
C H Cl-m (9)
6
4
C H Me-p (10)
6
4
C H Me-o (11)
6
4
C H OMe-p (12)
6
4
C H OMe-o (13)
6
4
2-Thienyl (14)
a
Yields are based on 6.
Yields are based on the corresponding disubstituted alkynes.
b
The palladium-catalysed reactions of the terminal alkyne 6 leading to the disubstituted
alkynes (15–22) needed both bistriphenylphosphine palladium(II) chloride as the catalyst and
CuI as the co-catalyst. The absence of either of them did not lead to the products. However, in
the cyclisation process yielding the 2-aroylquinoxalines (23–30), only CuI was needed and was
found to be essential. The absence of CuI did not give any cyclic product. Similarly, K CO was
2
3
found to be essential for the reaction. Its replacement with Et N failed to yield the cyclic
3
products (23–30). All the products were characterised by C,H,N analysis, and IR, UV and
1
5,16
NMR data.
Typical experimental condition are as follows: ArI (1.5 mmol), (PPh ) PdCl (3
3
2
2
mol%), CuI (8 mol%) and Et N (5 mmol) were stirred in acetonitrile (5 ml) for 1 h, compound
3
6
(1 mmol) was added and the mixture was stirred at rt for 24 h. After removal of solvent at
low pressure, the residue was extracted with chloroform (3×50 ml), washed with water (3×50 ml)
and dried over Na SO . After removal of the solvent and chromatographic purification on
2
4
neutral alumina (25% ethyl acetate in light petroleum, bp 60–80°C as the eluent), the disubsti-
tuted alkynes (15–22) were obtained as solids.
Synthesis of 2-aroylquinoxalines (23–30): The disubstituted alkynes (15–22) (1 mmol) were
dissolved in DMF (5 ml) and stirred with anhydrous K CO (2 mmol) for 3–4 h to form the
2
3
salts. CuI (10 mol%) was then added and the mixture was further stirred at rt for 1 h and then
heated at 100°C for 24 h. DMF was removed under low pressure and the residue in CHCl3
(
3×50 ml) was washed with H O (3×50 ml), dried over Na SO and solvent removed. The crude
2
2
4
product was purified by column chromatography on neutral alumina (10% ethylacetate in light
petroleum, bp 60–80°C as the eluent) to yield the 2-aroylquinoxalines (23–30) as solids, which
were further purified by crystallisation from ethanol.
In conclusion, we describe a novel cyclisation procedure under copper catalysis where instead
of the expected 2-alkylidene-1,2,3,4-tetrahydroquinoxalines a number of 2-aroylquinoxalines
17
were formed in good to excellent yields. Although a number of classical methods are available
for the synthesis of quinoxalines, we believe ours is the first successful and efficient copper-
catalysed procedure for the synthesis of 2-substituted quinoxalines under relatively mild condi-
18
tions. Also, since the quinoxalines are of immense biological significance, the procedure
described here could be of great value to many investigators active in this area.

9930
Acknowledgements
Grateful acknowledgement is made of the award of a CSIR fellowship to R.M.
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1
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1
5. For compound 17: H NMR (CDCl , 300 MHz): l 2.37 (3H, s, ArꢀCH ), 2.39 (3H, s, ArꢀCH ), 3.48 (1H, d,
3
3
3
13
J=18 Hz, H of CH ), 4.58 (1H, d, J=18 Hz, H of CH ), 6.84–7.88 (17H, m, ArꢀH and NH); C NMR
CDCl , 75.5 MHz): l 21.94, 22.01, 42.46, 84.44, 85.07, 122.96, 137.26, 144.32,145.02; DEPT-135: l 42.18
inverted-CH ); IR (KBr): w
a
2
b
2
(
(
3
3273, 1598, 1500; UV (chloroform) umax 244 nm (log m=4.468). Anal calcd for
max
2
C H N S O Cl: C, 61.65; H, 4.42; N, 4.96. Found: C, 61.47; H 4.61; N, 4.76%.
29
25
2
2
4
1
13
For compound 25: H NMR (CDCl , 300 MHz): l 7.26–8.26 (8H, m, ArꢀH), 9.51 (1H, s, ArꢀC ꢀH); C NMR
3
3
+
(
CDCl 75.5 MHz): l 129.81–148.3, 191.32; DEPT-135: absence of 191.32; mass spectra: m/z 270, 268 (M ), 240,
3
2
33, 205, 139, 111, 102, 75, 51; IR (KBr) wmax 1670, 1590, 1567; UV (ethanol): umax 253 (log m=4.385), 309
(
log m=4.442) nm; anal calcd for C H N OCl: C, 67.03; H, 3.35; N, 10.42. Found: C, 67.26; H, 3.53; N, 10.38%.
15
9
2
1
1
6. 2-Benzoylquinoxaline 23, mp 82°C (lit., mp 80–81°C), ref: Dahn, H.; Moll, H. Helv. Chim. Acta 1966, 49, 2426.
7. (a) Porter, A. E. A. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds. Pyrazine and
their benzo derivatives; 1984; Vol. 3, Part 2B, pp. 157–197. (b) Some recent references: Kornberg, B. E.; Nikam,
S. S.; Rafferty, M. F. J. Heterocycl. Chem. 1999, 36, 1271; Katoh, A.; Yoshida, J.; Ohkanda, J. Heterocycles
2
000, 52, 911; Elwahy, A. H. M. Tetrahedron 2000, 56, 897.
1
8. Echinomycin, levomycin and actinoleutin are antibiotics containing the quinoxaline ring (Sato, K.; Shiratory, O.;
Katagiri K. J. Antibiot. 1967, A20, 270. Dell, A.; Williams, D. H.; Morris, H. R.; Smith, G. A.; Feeney, J.;
Roberts, G. C. K. J. Am. Chem. Soc. 1975, 97, 2497). For other biological activities of quinoxaline derivatives,
see Kessler, M.; Baudry, M.; Lynch, G. Brain Res. 1989, 489, 377; Kher, S. M.; Cai, S. X.; Weber, E.; Keana,
J. F. W. J. Org. Chem. 1995, 60, 5838.
.