One-Pot Synthesis of Pyrrolo[1,2- a ]quinoxaline Derivatives via a Copper-Catalyzed Aerobic Oxidative Domino Reaction

Article abstract of DOI:10.1021/acs.orglett.5b01167

A copper-catalyzed process for the synthesis of pyrrolo[1,2-a]quinoxalines from readily available α-amino acids and 1-(2-halophenyl)-1H-pyrroles is described. Different functional groups were well tolerated to give the corresponding products.

Full text of DOI:10.1021/acs.orglett.5b01167

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of Pyrrolo[1,2‑a]quinoxaline Derivatives via a
Copper-Catalyzed Aerobic Oxidative Domino Reaction
Huanhuan Liu,† Tiantian Duan,† Zeyuan Zhang,† Caixia Xie,† and Chen Ma*,†,‡
†School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, P. R. China
S
* Supporting Information
ABSTRACT: A copper-catalyzed process for the synthesis of pyrrolo[1,2-
a]quinoxalines from readily available α-amino acids and 1-(2-halophenyl)-
1H-pyrroles is described. Different functional groups were well tolerated
to give the corresponding products.
Scheme 1. Different protocols for the syntheses of
pyrrolo[1,2-a] quinoxalines
he pyrrolo[1,2-a]quinoxaline skeleton is present in
Tvarious biologically active agents and plays an important
role in medicinal chemistry. For example, some substituted
(phenylamino) pyrrolo[1,2-a]quinoxaline-carboxylic acid de-
rivatives promised utilization for a novel class of potent
inhibitors of the human protein kinase CK2.1 Some 5,6-
dihydro-indolo[1,2-a]quinoxalines exhibit antifungal activities
in vitro against the phytopathogenic fungi and revealed their
potential role as novel promising lead candidates for further
design and synthesis of agricultural fungicides.2 2-(Amino-
methyl)-4-phenylpyrrolo[1,2-a]-quinoxalines have been found
to possess a central dopamine antagonist activity.3 Further-
more, many derivatives have been proven to possess other
biological activities, including in vitro antiparasitic activities,4
potential nonpeptide glucagon receptor antagonist activities,5 5-
HT3 receptors,6 antiproliferative activity,7 and antimycobacte-
rial agents.8 In addition, some of them are also used as
fluorescent probes for amyloid fibril.9
Due to their great value, the preparation of pyrrolo[1,2-
a]quinoxalines has gained much attention.10 Unsubstituted
pyrrolo[1,2-a]quinoxalines were first synthesized from 2-(1H-
pyrrol-1-yl)anilines and HCO2H by Cheeseman and Tuck in
1965.11 Two other traditional strategies have been followed.
One synthetic method utilized acyl chlorides with 2-(1H-
pyrrol-1-yl)anilines to access the acetamides, followed by
reaction with POCl3 to obtain the pyrrolo[1,2-a]quinoxalines
according to the Bischler−Napieralski reaction.12 The other
method involves the reaction between 2-(1H-pyrrol-1-yl)-
anilines and aldehydes to obtain the intermediates, followed
by an oxidation process to give the target compounds.13 In
those cases, volatile and toxic reagents such as aldehydes were
used, and multistep syntheses led to low atom economy.
Recently, the Thiery group reported an Fe(0)-catalyzed
strategy from nitroarenes and alcohols to assemble these
compounds,14 but this strategy needs excessive Fe catalyst and
volatile HCl (Scheme 1). The Senanayake group developed a
Cu-catalyzed strategy from 2-formylpyrroles and o-amino-
iodoarenes to construct pyrrolo[1,2-a]quinoxalines,15 but this
method involved an expensive ligand. Therefore, it is highly
desirable to develop an efficient, minimally toxic, and
convenient approach for the synthesis of those heterocycles.
Recently, copper-catalyzed Ullmann coupling reactions have
made significant progress, and many N-heterocycles have been
synthesized by us16 and other groups.17 However, most of the
reactions were performed under a nitrogen or argon
atmosphere. In addition, most of the cyclization reactions
which occurred at the C-2 position of pyrroles or indoles
require acid to activate the pyrrole ring system. Furthermore,
reports regarding Cu-catalyzed construction of pyrrolo[1,2-
a]quinoxalines are still rare. Herein, we report an efficient,
Received: April 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
minimally toxic, and convenient Cu-catalyzed one-pot domino
reaction of α-amino acids and 1-(2-halophenyl)-1H-pyrroles for
the synthesis of pyrrolo[1,2-a]quinoxalines in air.
Table 2. Preparation of Compounds 3a−i
To identify the best reaction conditions, 1-(2-iodophenyl)-
1H-pyrrole (1a) and alanine (2a) were initially used as the
model substrates under different conditions (Table 1). The
b
entry
1
3
yield, %
a
Table 1. Optimization of Reaction Conditions
1
R1 = H, X = I, 1a
3a
3a
3b
3c
3d
3e
3f
67
54
78
81
71
78
83
59
62
47
38
2
R1 = H, X = Br, 1b
R1 = 4-Cl, X = I, 1c
R1 = 4-CF3, X = I, 1d
R1 = 4-F, X = I, 1e
R1 = 4-CN, X = I, 1f
R1 = 4-OCF3, X = Br, 1g
R1 = 5-F, X = Br, 1h
R1 = 5-Cl, X = Br, 1i
R1 = 4-Me, X = I, 1j
R1 = 4-Me, X = Br, 1k
3
4
5
6
b
entry
cat.
base
solvent
t, °C
yield, %
7
1
CuBr
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KTB
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
150
110
130
130
32
8
3g
3h
3i
2
13
9
3
CuCl
15
10
11
4
Cu(OAc)2
CuCl2·2H2O
CuBr2
52
3i
5
trace
trace
trace
46
a
Reaction conditions: 1 (0.3 mmol), 2a (1.2 mmol), Cu(OAc)2 (0.06
mmol), K3PO4 (1.5 mmol), DMSO (3 mL), 4 Å MS, under air, 3 h.
6
7
CuSO4·5H2O
Cu(CF3SO3)2
−
b
Isolated yield.
8
9
0
the yields were lower (entries 1, 2, 10, and 11). It is worth
mentioning that the substrates bearing an iodine group had
higher reactivity than those bearing a bromide group (entries 1,
2, 10, and 11).
Encouraged by these promising results, we further
investigated substituted α-amino acids as shown in Table 3.
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
trace
56
K3PO4
NaOH
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
16
48
12
DMF
49
dioxane
PhCl
trace
0
a
Table 3. Preparation of Compounds 3j−p
DMSO
DMSO
DMSO
DMSO
37
16
c
67
d
trace
b
entry
2
3
yield, %
a
Reaction conditions: 1-(2-iodophenyl)-1H-pyrrole (1a) (0.3 mmol),
2-aminoacetic acid (2a) (1.2 mmol), catalyst (0.06 mmol), base (1.5
1
2
3
4
5
6
7
8
R2 = Me, 2a
R2 = H, 2b
R2 = Et, 2c
R2 = Pr, 2d
R2 = i-Pr, 2e
R2 = i-Bu, 2f
R2 = Cy, 2g
R2 = Ph, 2h
3b
3j
78
72
75
69
46
67
35
12
b
c
mmol), solvent (3 mL), under air, 3 h. Isolated yield. Reaction with
4 Å molecular sieves (4 Å MS). Reaction was performed under
d
3k
3l
nitrogen.
3m
3n
3o
3p
efficiency of different Cu catalysts was tested using K2CO3 as
the base in DMSO under air at 130 °C (entries 1−8). We
found that the copper salts have a remarkable impact on the
reaction yield, and Cu(OAc)2 gave the best yield. Reaction
without a catalyst was also explored with no corresponding
product observed (entry 9). Different bases were screened
(entries 4 and 10−13), and K3PO4 showed the best activity.
Subsequently, the evaluation of solvents reveals that DMSO
was superior to NMP, DMF, dioxane, and PhCl (entries 11 and
14−17). Only 37% and 16% isolated yields were obtained when
the reaction temperature was varied (entries 18 and 19). The
yield was further improved by using 4 Å molecular sieves (entry
20). Finally, we attempted the reaction under a N2 atmosphere
(entry 21), and only a trace amount of product was observed.
Under the optimal conditions, the scope of 1-(2-
halophenyl)-1H-pyrroles was investigated. As shown in Table
2, most of the tested substrates provided moderate to good
yields. Reactions with 1-(2-halophenyl)-1H-pyrroles containing
electron-withdrawing groups proceeded smoothly to give the
target products (entries 3−9). Other representatives with
electron-neutral (H) and electron-donating (4-Me) groups
were also found to be suitable for this transformation, although
a
Reaction conditions: 1c (0.3 mmol), 2 (1.2 mmol), Cu(OAc)2 (0.06
mmol), K3PO4 (1.5 mmol), DMSO (3 mL), 4 Å MS, under air, 3 h.
b
Isolated yield.
Diverse α-amino acids that underwent the reaction with 1-(4-
chloro-2-iodophenyl)-1H-pyrrole 1c worked well to give the
corresponding products. Notably, the α-amino acids with a Cy
group and a Ph group showed lower reactivity, with only 35%
and 12% yields, respectively. Conversion rates of the raw
materials are low. One possible reason is that the steric
hindrance caused by the R2 group made the pyrrole ring system
less reactive.
To expand the applicability of this method, we next
examined the substituted 1-(2-halophenyl)-1H-indoles as
shown in Table 4. Different functional groups at different
positions of 1l−1q were tolerated in the reaction to afford the
target products in 48% to 84% yields. Moreover, the
attachments of a 3-Me group to the indole ring afford a higher
yield than those without it (entries 1−4). It is obvious that the
B
DOI: 10.1021/acs.orglett.5b01167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
The UV−vis absorption and emission spectra of 3q, 3r, 3s,
and 3t in highly dilute solution were collected (in ESI).
In conclusion, we have developed an efficient and convenient
Cu-catalyzed one-pot domino reaction from 1-(2-halophenyl)-
1H-pyrroles and readily available α-amino acids for the
synthesis of pyrrolo[1,2-a]quinoxalines in air. The domino
process includes Ullmann-type N-arylation, aerobic oxidation,
intramolecular addition, and decarboxylation. It is interesting
that the intramolecular addition step was achieved under
conditions with a base rather than an acid. By further
elaboration and diversification of the various functional groups,
a wide range of N-heterocycles can be produced. This Cu-
catalyzed one-pot process has potential applications in the
synthesis of biologically and medicinally relevant compounds.
Table 4. Preparation of Compounds 3q−t
b
entry
1
3
yield, %
1
2
3
4
5
6
R3 = H, R4 = H, X = I, 1l
3q
3q
3r
3r
3s
3t
74
63
84
65
56
48
R3 = H, R4 = H, X = Br, 1m
R3 = H, R4 = 3-Me, X = I, 1n
R3 = H, R4 = 3-Me, X = Br, 1o
R3 = H, R4 = 6-Cl, X = I, 1p
R3 = 4-Me, R4 = H, X = Br, 1q
a
Reaction conditions: 1 (0.3 mmol), 2a (1.2 mmol), Cu(OAc)2 (0.06
ASSOCIATED CONTENT
■
mmol), K3PO4 (1.5 mmol), DMSO (3 mL), 4 Å MS, under air, 3 h.
S
* Supporting Information
b
Isolated yield.
Experiment details, spectra data, UV−vis absorption and
emission spectra, and 1H and 13C NMR spectra. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01167.
3-Me group increased the nucleophilicity of the ring system,
which facilitates intramolecular attack of the C-2 position of the
indole to afford the cyclized products.
An assumed pathway for the formation of pyrrolo[1,2-
a]quinoxaline derivatives is illustrated in Scheme 2 according to
AUTHOR INFORMATION
■
Scheme 2. Proposed Reaction Mechanism
Corresponding Author
*E-mail: chenma@sdu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation of China
(No. 21172131) and the State Key Laboratory of Natural and
Biomimetic Drugs of Peking University (No. K20140208) for
financial support of this research.
REFERENCES
■
(1) Guillon, J.; Le Borgne, M.; Rimbault, C.; Moreau, S.;
Savrimoutou, S.; Pinaud, N.; Baratin, S.; Marchivie, M.; Roche, S.;
Bollacke, A.; Pecci, A.; Alvarez, L.; Desplat, V.; Jose, J. Eur. J. Med.
Chem. 2013, 65, 205−222.
(2) Xu, H.; Fan, L.-l. Eur. J. Med. Chem. 2011, 46, 1919−1925.
(3) Guillon, J.; Boulouard, M.; Lisowski, V.; Stiebing, S.; Lelong, V.;
Dallemagne, P.; Rault, S. J. Pharm. Pharmacol. 2000, 52, 1369−1375.
(4) (a) Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Leger, J.-M.;
Deprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaitre, N.;
Pehourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. J. Med. Chem.
2004, 47, 1997−2009. (b) Guillon, J.; Mouray, E.; Moreau, S.; Mullie,
C.; Forfar, I.; Desplat, V.; Belisle-Fabre, S.; Pinaud, N.; Ravanello, F.;
Le-Naour, A.; Leger, J.-M.; Gosmann, G.; Jarry, C.; Deleris, G.;
Sonnet, P.; Grellier, P. Eur. J. Med. Chem. 2011, 46, 2310−2326.
(c) Guillon, J.; Moreau, S.; Mouray, E.; Sinou, V.; Forfar, I.; Fabre, S.
B.; Desplat, V.; Millet, P.; Parzy, D.; Jarry, C.; Grellier, P. Bioorg. Med.
Chem. 2008, 16, 9133−9144. (d) Guillon, J.; Forfar, I.; Mamani-
Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.;
Tabourier, A.; Leger, J.-M.; Dufaure, B.; Haumont, G.; Jarry, C.;
Mossalayi, D. Bioorg. Med. Chem. 2007, 15, 194−210.
(5) Guillon, J.; Dallemagne, P.; Pfeiffer, B.; Renard, P.; Manechez, D.;
Kervran, A.; Rault, S. Eur. J. Med. Chem. 1998, 33, 293−308.
(6) (a) Prunier, H.; Rault, S.; Lancelot, J.-C.; Robba, M.; Renard, P.;
Delagrange, P.; Pfeiffer, B.; Caignard, D.-H.; Misslin, R.; Guardiola-
Lemaitre, B.; Hamon, M. J. Med. Chem. 1997, 40, 1808−1819.
(b) Butini, S.; Budriesi, R.; Hamon, M.; Morelli, E.; Gemma, S.;
Brindisi, M.; Borrelli, G.; Novellino, E.; Fiorini, I.; Ioan, P.; Chiarini,
the results above and previous research.18 First, the Cu-
catalyzed Ullmann-type coupling reaction occurs between
substrates 1 and 2 to afford intermediate I. Next, I can
undergo two pathways (route A and route B). Through route
A, aerobic oxidation of I leads to II, then intramolecular
addition of II affords III, and decarboxylation of III gives final
product 3. Through route B, decarboxylation of I gives IV.
Subsequently intramolecular addition of IV yields V. Finally,
aerobic oxidation of V provides 3.
C
DOI: 10.1021/acs.orglett.5b01167
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A.; Cagnotto, A.; Mennini, T.; Fracasso, C.; Caccia, S.; Campiani, G. J.
Med. Chem. 2009, 52, 6946−6950.
(7) (a) Desplat, V.; Geneste, A.; Begorre, M.-A.; Fabre, S. B.; Brajot,
S.; Massip, S.; Thiolat, D.; Mossalayi, D.; Jarry, C.; Guillon, J. J.
Enzyme Inhib. Med. Chem. 2008, 23, 648−658. (b) Desplat, V.;
Moreau, S.; Gay, A.; Fabre, S. B.; Thiolat, D.; Massip, S.; Macky, G.;
Godde, F.; Mossalayi, D.; Jarry, C.; Guillon, J. J. Enzyme Inhib. Med.
Chem. 2010, 25, 204−215.
(8) Guillon, J.; Reynolds, R. C.; Leger, J.-M.; Guie, M.-A.; Massip, S.;
Dallemagne, P.; Jarry, C. J. Enzyme Inhib. Med. Chem. 2004, 19, 489−
495.
(9) Gemma, S.; Colombo, L.; Forloni, G.; Savini, L.; Fracasso, C.;
Caccia, S.; Salmona, M.; Brindisi, M.; Joshi, B. P.; Tripaldi, P.; Giorgi,
G.; Taglialatela-Scafati, O.; Novellino, E.; Fiorini, I.; Campiani, G.;
Butini, S. Org. Biomol. Chem. 2011, 9, 5137−5148.
(10) (a) He, Z.; Bae, M.; Wu, J.; Jamison, T. F. Angew. Chem., Int. Ed.
2014, 53, 14451−14455. (b) Verma, A. K.; Jha, R. R.; Sankar, V. K.;
Aggarwal, T.; Singh, R. P.; Chandra, R. Eur. J. Org. Chem. 2011, 6998−
7010. (c) Agarwal, P. K.; Sawant, D.; Sharma, S.; Kundu, B. Eur. J. Org.
Chem. 2009, 292−303. (d) Biswas, S.; Batra, S. Eur. J. Org. Chem.
2013, 4895−4902. (e) Mishra, A.; Batra, S. Eur. J. Org. Chem. 2010,
4832−4840.
(11) Cheeseman, G. W. H.; Tuck, B. Chem. Ind. (London, U. K.)
1965, 1382.
(12) Cheeseman, G. W. H.; Tuck, B. J. Chem. Soc. C 1966, 852−5.
(13) Kaminskii, V. A.; Moskovkina, T. V.; Borodina, S. V. Chem.
Heterocycl. Compd. 1992, 28, 97−100.
(14) Pereira, M. d. F.; Thiery, V. Org. Lett. 2012, 14, 4754−4757.
(15) Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.; Yee,
N. K.; Senanayake, C. H. J. Org. Chem. 2010, 75, 992−994.
(16) (a) Huang, A.; Chen, Y.; Zhou, Y.; Guo, W.; Wu, X.; Ma, C.
Org. Lett. 2013, 15, 5480−5483. (b) Huang, A.; Liu, H.; Ma, C. RSC
Adv. 2013, 3, 13976−13982. (c) Huang, A.; Feng, L.; Qiao, Z.; Yu, W.;
Zheng, Q.; Ma, C. Tetrahedron. 2013, 69, 642−646.
(17) (a) Nandwana, N. K.; Pericherla, K.; Kaswan, P.; Kumar, A. Org.
Biomol. Chem. 2015, 13, 2947−2950. (b) Yang, B.; Mao, Z.; Zhu, X.;
Wan, Y. Catal. Commun. 2015, 60, 92−95. (c) Kong, L.; Zhou, Y.;
Huang, H.; Yang, Y.; Liu, Y.; Li, Y. J. Org. Chem. 2015, 80, 1275−1278.
(d) Jia, F.-C.; Xu, C.; Cai, Q.; Wu, A.-X. Chem. Commun. 2014, 50,
9914−9916. (e) Yang, D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv.
Synth. Catal. 2012, 354, 477−482. (f) Ma, D.; Cai, Q.; Zhang, H. Org.
Lett. 2003, 5, 2453−2455.
(18) (a) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13,
1274−1277. (b) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Org. Lett. 2012,
14, 3894−3897. (c) Wang, L.-X.; Xiang, J.-F.; Tang, Y.-L. Eur. J. Org.
Chem. 2014, 2014, 2682−2685.
D
DOI: 10.1021/acs.orglett.5b01167
Org. Lett. XXXX, XXX, XXX−XXX