2,3-Disubstituted pyrrolo[2,3-b]quinoxalines via aminopalladation- reductive elimination

Article abstract of DOI:10.1016/j.tetlet.2004.01.058

2,3-Disubstituted pyrrolo[2,3-b]quinoxalines have been prepared in good to high yield through the reaction of 2-alkynyl-3-trifluoroacetamidoquinoxalines with aryl and vinyl halides or triflates in the presence of Pd(PPh ₃)₄ and K₂CO₃ in MeCN at 100°C.

Full text of DOI:10.1016/j.tetlet.2004.01.058

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2431–2434
2,3-Disubstituted pyrrolo[2,3-b]quinoxalines via aminopalladation–
reductive elimination
Antonio Arcadi,a Sandro Cacchi,b,* Giancarlo Fabrizib and Luca M. Parisib
aDipartimento di Chimica Ingegneria Chimica e Materiali della Facoltꢀa di Scienze, Universitꢀa di L’Aquila, Via Vetoio, Coppito Due,
I-67100 L’Aquila, Italy
bDipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universitꢀa degli Studi ÔLa SapienzaÕ
P. le A. Moro 5, 00185 Roma, Italy
Received 5 November 2003; revised 8 January 2004; accepted 14 January 2004
Abstract—2,3-Disubstituted pyrrolo[2,3-b]quinoxalines have been prepared in good to high yield through the reaction of 2-alkynyl-
3-trifluoroacetamidoquinoxalines with aryl and vinyl halides or triflates in the presence of Pd(PPh3)4 and K2CO3 in MeCN at
100 °C.
Ó 2004 Elsevier Ltd. All rights reserved.
The quinoxaline nucleus is present in many pharma-
ceutical agents exhibiting a broad spectrum of biological
activities such as antiviral,1 antiglucoma,2 and antican-
cer3 activity. Recently, novel pyrrolo[1,2-a]quinoxalines
have been proved to be potent and selective 5-HT3
receptor ligands.4 Because of this, a variety of conven-
tional methods have been developed for the preparation
of quinoxaline derivatives.5 A solid-phase synthesis of
quinoxalines has also been described.6 Rather surpris-
ingly, palladium catalysis, despite its remarkable versa-
tility and efficiency in the synthesis of heterocyclic
compounds,7 has very rarely been mentioned in this
area. To the best of our knowledge, Suzuki8 and Stille8;9
cross-coupling reactions have been applied to the syn-
thesis of quinoxaline derivatives from haloquinoxalines
and an intramolecular Heck reaction10 on aminoqui-
noxaline scaffolds has been used in the synthesis of
3-substituted pyrrolo[2,3-b]quinoxalines.
to drug-like products starting from the quinoxaline
skeleton, we decided to explore the extension of this
chemistry to the synthesis of pyrrolo[2,3-b]quinoxaline
derivatives.
Here we illustrate a direct entry to 2,3-disubstituted
pyrrolo[2,3-b]quinoxalines 3 through the reaction of
2-alkynyl-3-trifluoroacetamidoquinoxalines 1 with aryl
and vinyl halides or triflates 2 (Scheme 1).
The starting alkynes 1 were prepared from commercially
available phenylenediamine as shown in Scheme 2.
Treatment of phenylenediamine with diethyl oxalate
afforded 1,4-dihydroquinoxaline-2,3-dione.12 Treatment
of 1,4-dihydroquinoxaline-2,3-dione with PBr5 gave 2,3-
dibromoquinoxaline,13 which was converted into 414
(the procedure described in literature15 was slightly
As far as pyrrolo[2,3-b]quinoxalines are concerned, our
aminopalladation–reductive elimination procedure11
appeared particularly suited for the construction of the
functionalized pyrrole ring incorporated into the pyr-
roloquinoxaline system. Therefore, as part of a program
devoted to the development of new synthetic procedures
R1
R
N
N
N
N
Pd cat
R1X
R
N
H
NHCOCF3
1
2
3
R = Ph, 1a
R = CH3(CH2)4-, 1b
R = p-MeO-C6H4-, 1c
R = m-MeO-C6H4-, 1d
Keywords: Quinoxalines; Alkynes; Palladium; Cyclization; Aminopal-
ladation–reductive elimination.
* Corresponding author. Tel.: +39-06-49912795; fax: +39-06-499127-
80; e-mail: sandro.cacchi@uniroma1.it
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.058

2432
A. Arcadi et al. / Tetrahedron Letters 45 (2004) 2431–2434
lated in 59% yield. The hypothesis that 6a may be
formed through the base-catalyzed cyclization of 5a was
ruled out on the basis of the fact that 5a was recovered
essentially unchanged after treatment with K2CO3 in
MeCN at 100 °C for 2h (no evidence of 6a was
obtained). To check the role of the trifluoroacetamido
group in the cyclization step, 5a was reacted with
p-iodoanisole under the conditions described in Table 1,
entry 4. No 2,3-disubstituted pyrroloquinoxaline prod-
uct was observed and the starting material was recov-
ered in 82% yield thus emphasizing the role of the
trifluoroacetamido group in the cyclization step.
H
N
NH2
NH2
N
N
Br
Br
O
O
(COOEt)
PBr
5
2
N
H
NH OH
4
R
N
N
Br
NH2
N
N
R
(CF CO) O
3
2
1
NH2
4
5
Scheme 2.
N
modified). The reaction of 4 with 1-alkynes in the
presence of PdCl2(PPh3)2, CuI, and Et2NH in DMF at
40 °C16 afforded the corresponding coupling derivative 5
Ph
N
N
6a
H
ꢀ
(R ¼ Ph, 5a, 85% yield; R ¼ CH3(CH2)4 , 5b, 65%;
ꢀ
ꢀ
R ¼ p-MeO–C6H4 , 5c, 92%; R ¼ m-MeO–C6H4 , 5d,
96%). Treatment of 5 with 2equiv of trifluoroacetic
anhydride and 1 equiv of triethylamine in THF at room
temperature furnished the trifluoroacetamido products
1a–d in almost quantitative yield (compounds 1 were
used without further purification during the present
study).
The best conditions developed so far [1 equiv of 1a,
1.5 equiv of aryl halide, 3 equiv of K2CO3, 5 mol % of
Pd(PPh3)4 in MeCN at 100 °C] have been used when the
process was extended to include other aryl and vinyl
halides or triflates.17 K2CO3 was usually employed
instead of Cs2CO3 because of its lower cost.
The trifluoroacetamido group was used because it was
found by us to be the nitrogen derivative of choice for
favoring palladium-catalyzed cyclizations11 of o-alkynyl-
aniline derivatives involving g2-alkyne organopalladium
intermediates. In addition, it allows for the formation of
free N–H pyrrole nuclei (the amide bond is broken
during the reaction or/and the workup), avoiding
troublesome and time-consuming deprotecting steps.
As shown in Table 2, the nature of the aryl halide plays
a key role in controlling the reaction outcome, the best
results being obtained in the presence of electron-
donating or slightly electron-withdrawing substituents.
With aryl halides containing strongly electron-with-
drawing groups, byproducts 6 are isolated in significant
yields and, in some cases (Table 2, entry 10), as the main
reaction products.
The influence of temperature, bases, and solvents on the
reaction of 1 with 2 was briefly investigated using 1a
(R ¼ Ph) and p-iodoanisole as the model system in the
presence of Pd(PPh3)4. The results of this study are
shown in Table 1.
As to the mechanism of the cyclization reaction, we
believe that the reaction proceeds through the basic
steps of the aminopalladation–reductive elimination
reaction:11 (a) formation of an g2-alkyne–r-organopal-
ladium complex via the reaction of 1 with an organo-
palladium intermediate generated in situ through the
oxidative addition of the organic halide or triflate to
Pd(0), (b) intramolecular nucleophilic attack of the
nitrogen nucleophile across the carbon–carbon triple
bond, (c) reductive elimination of the resultant r-pyr-
rolyl-r-organopalladium intermediate that furnishes the
desired product 3 and regenerates the active palladium
catalyst. Very likely, the beneficial effect of the trifluoro-
acetyl group on the cyclization step is due to its ability to
favor the formation of a stronger anionic nitrogen
The best results in terms of yields and 1a to 6a ratio were
obtained in MeCN, at 100 °C using Cs2CO3 (Table 1,
entry 3) or K2CO3 (Table 1, entry 4) as the bases.
Compound 6a is most probably generated through a
base-catalyzed cyclization of 1a. Accordingly, 6a was
isolated in 21% yield when 1a was reacted under the
conditions described in Table 1, entry 4, omitting
p-iodoanisole and the palladium catalyst. The starting
material was recovered in 13% yield and the amino
product 5a, derived from the hydrolysis of 1a, was iso-
Table 1. Solvent, base, and temperature in the synthesis of 3a from 1aa
Entry
T (°C)
t (h)
Solvent
Base
2CO3
Yield (%)b of 3a
Yield (%)b of 6a
1
80
8
2MeCN
DMSO
2MeCN
2MeCN
K
K
67
––
70
70
10
––
4
280
3
2CO3
2CO3
2CO3
100
100
Cs
K
4
4
a Reactions were carried out on a 0.293 mmol scale in 3 mL of solvent using 1 equiv of 1a, 1.5 equiv of p-iodoanisole, 3 equiv of base, and 5 mol % of
Pd(PPh3)4.
b Yields are given for isolated products.

A. Arcadi et al. / Tetrahedron Letters 45 (2004) 2431–2434
2433
Table 2. Palladium-catalysed synthesis of 2,3-disubstituted pyrrolo[2,3-b]quinoxalines 3 from 2-alkynyl-3-trifluoroacetanilides 1 and aryl/vinyl
halides or triflates 2a
Entry
2
1
t (h)
3 Yield (%)b
6 Yield (%)b
1
p-MeO–C6H4–I
p-MeO–C6H4–Brc
p-MeO–C6H4–I
m-CF3–C6H4–I
1a
1a
1b
1a
1c
1c
1d
1d
1d
1a
1a
1a
270
8
3a
66 3a
45 3b
75 3c
3d
4 6a
traces
18 6b
5 6a
2
3
4
4
4
5
m-CF3–C6H4–I
p-F–C6H4–I
270
275
15
15
15
3
20 6c
25 6c
27 6d
10 6d
14 6d
40 6a
30 6a
25 6a
6
3e
7
3,5-(CF3)2–C6H3–I
3,5-(Me)2–C6H3–I
2-NO2–4-Me–C6H3–I
p-PhCO–C6H4–OTfc
p-NO2–C6H4–I
70 3f
82 3g
70 3h
30d 3i
40 3j
48d 3j
8
9
10
11
12
3
p-NO2–C6H4–OTfc
3
13
14
1a
1a
0.3
0.5
80d 3k
10 6a
Ph
OTf
OAc
83d 3l
––
TfO
15
16
1a
1a
0.5
0.5
95d 3m
73d 3n
––
––
OTf
But
OTf
a Unless otherwise stated, reactions were carried out on a 0.293 mmol scale in 3 mL of MeCN at 100 °C by using 1 equiv of 1a, 1.5 equiv of aryl halide,
3 equiv of base, and 5 mol % of Pd(PPh3)4.
b Yields are given for isolated products.
c 120 °C.
d Carried out by using 1.1 equiv of organic triflate.
nucleophile or to promote the intramolecular nucleo-
philic attack by proton removal in the transition state
leading to the cyclization adduct.
References and notes
€
1. Harmenberg, J.; Akesson-Johansson, A.; Graslund, A.;
Malmfors, T.; Bergman, J.; Wahren, B.; Akerfeldt, S.;
Lundblad, L.; Cox, S. Antiviral Res. 1991, 15, 193.
2. David, R. Exp. Opin. Invest. Drug 1998, 7, 1063.
3. Naylor, M. A.; Stephen, M. A.; Nolan, J.; Sutton, B.;
Tochcer, J. H.; Fielden, E. M.; Adams, G. E.; Strafford, I.
J. Anticancer Drug Res. 1993, 8, 439.
4. (a) Campiani, G.; Cappelli, A.; Nacci, V.; Anzini, M.;
Vomero, S.; Hamon, M.; Cagnotto, A.; Fracasso, C.;
Uboldi, C.; Caccia, S.; Consolo, S.; Mennini, T. J. Med.
Chem. 1997, 40, 3670; (b) Campiani, G.; Morelli, E.;
Gemma, S.; Nacci, V.; Butini, S.; Hamon, M.; Novellino,
E.; Greco, G.; Cagnotto, A.; Goegan, M.; Cervo, L.; Dalla
Valle, F.; Fracasso, C.; Caccia, S.; Mennini, T. J. Med.
Chem. 1999, 42, 4362.
In conclusion, the chemistry outlined here provides a
simple, straightforward method for the synthesis of
functionalized pyrrolo[2,3-b]quinoxalines via the palla-
dium-catalyzed reaction of readily available 2-alkynyl-3-
trifluoroacetamidoquinoxalines with a variety of aryl
and vinyl halides or triflates. Although moderate yields
are obtained with strongly electron-poor aryl halides or
triflates, the process holds considerable promise for the
synthesis of pyrroloquinoxalines containing a highly
functionalized pyrrole ring.
5. See, for example: (a) Kreher, R.; Use, G. Tetrahedron Lett.
1978, 4671; (b) Ames, D. E.; Mitchell, J. C.; Takundwa, C.
C. J. Chem. Res. 1985, 144; (c) Sugita, M.; Mitsuhashi, K.
J. Heterocycl. Chem. 1992, 29, 771; (d) Zhang, X.-c.;
Huang, W.-y. Tetrahedron 1998, 54, 12465; (e) Kobayashi,
K.; Matoba, T.; Irisawa, S.; Matsumoto, T.; Morikawa,
O.; Konishi, H. Chem. Lett. 1998, 551; (f) Kobayashi, K.;
Matsumoto, T.; Irisawa, S.; Yoneda, K.; Morikawa, O.;
Konishi, H. Heterocycles 2001, 55, 973, Refs. 4a,b.
6. Wu, Z.; Ede, N. J. Tetrahedron Lett. 2001, 42, 8115.
Acknowledgements
Work carried out in the framework of the National
Project ÔStereoselezione in Sintesi Organica. Metodolo-
gie ed ApplicazioniÕ supported by MURST, Rome.
Financial support of this research by the University ÔLa
SapienzaÕ is also gratefully acknowledged.

2434
A. Arcadi et al. / Tetrahedron Letters 45 (2004) 2431–2434
7. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic
15. (a) Tanaka, K.; Takahashi, H.; Takimoto, K.; Sugita, M.;
Mitsuhashi, K. J. Heterocycl. Chem. 1992, 29, 771; (b)
Iwata, S.; Sakajyo, M.; Tanaka, K. J. Heterocycl. Chem.
1994, 31, 1433.
16. (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-WCH:
Weinheim, 1998; p 203; (b) Sonogashira, K. In Handbook
of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley: New York, 2002; Vol. 1,
p 493.
17. Typical procedure for the synthesis of pyrrolo[2,3-b]quin-
oxalines 3: To a solution of 1d (0.100 g, 0.29 mmol) in
MeCN (3 mL), 5-iodo-m-xylene (0.047 mL, 0.44 mmol),
Pd(PPh3)4 (0.017 g, 0.015 mmol) and K2CO3 (0.202 g,
1.47 mmol) were added. The solution was stirred at
100 °C for 15 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 v/v/v) to give 0.091 g of 3g
(82% yield): mp 243–245 °C; IR(KBr): 3345, 3004, 1466,
1297 cmꢀ1; 1H NMR (DMSO-d6) d 12.45 (s, 1H), 8.08 (dt,
J1 ¼ 9:3 Hz, J2 ¼ 1:1 Hz, 2H), 7.72–7.65 (m, 2H), 7.35 (t,
J ¼ 7:9 Hz, 1H), 7.26 (t, J ¼ 1:7 Hz, 1H), 7.21 (d,
J ¼ 7:9 Hz, 1H), 7.15 (s, 2H), 7.03–7.01 (m, 2H), 3.71 (s,
3H), 2.28 (s, 6H); 13C NMR (DMSO-d6) d 159.7, 145.2,
143.0, 140.9, 139.7, 137.8, 133.2, 132.7, 130.3, 129.4, 129.0,
128.7, 128.4, 128.0, 126.9, 121.6, 116.1, 114.4, 112.0, 55.6,
21.6. Anal. Calcd for C25H21N3O: C, 79.13; H, 5.58; N,
11.07. Found: C, 78.80; H, 5.56; N, 11.03.
Chemistry. A Guide for Synthetic Chemists; Baldwin, J. E.,
Williams, R. M., Eds.; Pergamon: Amsterdam, 2000.
8. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507.
9. Dinsmore, A.; Garner, C. D.; Joule, J. A. Tetrahedron
1998, 54, 3291.
10. Li, J. J. J. Org. Chem. 1999, 64, 8425.
11. For a review, see: Battistuzzi, G.; Cacchi, S.; Fabrizi, G.
Eur. J. Org. Chem. 2002, 2671.
12. Sarges, R.; Howard, H. R.; Browne, R. G.; Lebel, L. A.;
Seymour, K.; Koe, B. K. J. Med. Chem. 1990, 33, 2240.
13. Usherwood, E. H.; Whiteley, M. A. J. Chem. Soc. 1923,
1069.
14. Synthesis of 2-amino-3-bromoquinoxaline 4: To a solution
of 2,3-dibromoquinoxaline (2.00 g, 6.92 mmol) in DMSO/
MeCN (8 mL/12mL), NH 4OH (1.8 mL, 13.84 mmol, solu-
tion 30%) and K2CO3 (0.96 g, 6.92mmol) were added. The
solution was stirred at 50 °C for 120 h. After cooling, the
reaction mixture was diluted with ethyl acetate, washed
with water, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by chromato-
graphy (silica gel, 130 g; n-hexane/EtOAc 75/25 v/v) to give
1.29 g of 5 (83% yield): mp 163–164 °C; IR (KBr): 3290,
3137; 1H NMR (CDCl3)
d
7.86 (dd, J1 ¼ 8:0 Hz,
J2 ¼ 1:0 Hz, 1H), 7.72–7.55 (m, 2H), 7.49–7.40 (m, 1H),
5.55 (br s, 2H); 13C NMR (CDCl3) d 149.8, 141.0, 138.2,
130.6, 130.3, 128.5, 125.9, 125.7. Anal. Calcd for
C8H6BrN3: C, 42.88; H, 2.70; N, 18.75. Found: C, 42.74;
H, 2.67; N, 18.88.