Direct halogenation of the C1–H bond in pyrrolo[1,2–a]quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2021.152879

Although pyrrolo[1,2–a]quinoxalines are important in pharmaceutical research and organic synthesis, diversification of these compounds is still limited. Herein we have developed a method for the selective chlorination of the C1–H bond in 4-aryl pyrrolo[1,

Full text of DOI:10.1016/j.tetlet.2021.152879

Tetrahedron Letters 67 (2021) 152879
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct halogenation of the C1AH bond in pyrrolo[1,2–a]quinoxalines
Huy X. Le a,b, Tran N.B. Hoang a,b, Thang H. Tran a,b, Cao T.D. Nguyen a,b, Linh N.T. Chiem a,b
,
Nam T.S. Phan a,b, Tung T. Nguyen a,b,
⇑
a Faculty of Chemical Engineering, Ho Chi Minh City University of Technology (HCMUT), 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
b Vietnam National University, Ho Chi Minh City, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
Although pyrrolo[1,2–a]quinoxalines are important in pharmaceutical research and organic synthesis,
diversification of these compounds is still limited. Herein we have developed a method for the selective
chlorination of the C1AH bond in 4-aryl pyrrolo[1,2–a]quinoxalines. The reactions proceeded in the pres-
ence of NCS as a chlorinating agent, a catalytic amount of DMSO, and CHCl3 as the solvent. Various func-
tional groups including fluoro, chloro, and methylthio were compatible with the reaction conditions.
Heterocycles located at the C4 positions of pyrrolo[1,2–a]quinoxalines such as furan, thiophene, or pyr-
idine were also compatible with the reaction conditions. The bromination of pyrrolo[1,2–a]quinoxalines
was successful in the presence of CuBr2 as a brominating agent, K2S2O8 as an oxidant, and toluene as the
solvent.
Received 15 October 2020
Revised 21 January 2021
Accepted 26 January 2021
Available online 4 February 2021
Keywords:
Pyrrolo[1,2–a]quinoxaline
Halogenation
Electrophilic
CAH functionalization
Ó 2021 Elsevier Ltd. All rights reserved.
Introduction
ers recently described a notable method for the chlorination of
arene CAH bonds at room temperature [5]. The reaction utilized
Pyrrolo[1,2–a]quinoxalines have found various uses in bio-
related studies (Fig. 1) [1]. Such [6,5]fused heterocycles have
attracted substantial attention [2]. Most of the known examples
utilize three-step synthetic sequences starting from commercially
available 2-nitroanilines. Meanwhile, a general method for the
direct monofunctionalization of CAH bonds in pyrroloquinoxalines
is unknown. 1-Halo-4-arylpyrroloquinoxalines have been obtained
via a sequence of dihalogenation/CAC cross coupling [2a]. One
example of the bromination of N-acetyl dihydropyrroloquinoxaline
was reported [1b]. Since the direct CAH functionalization of pyr-
rolo[1,2–a]quinoxalines would facilitate late-stage diversification,
the development of such methods is of interest.
The halogenation of aromatic CAH bonds is perhaps the most
typical and convenient transformation for the prefunctionalization
of substrates toward cross-coupling [3]. Although electrophilic
substitution of halogens is well-precedented, the toxic and corro-
sive reagents utilized represents a major drawback. Additionally,
using highly electrophilic reagents often results in the formation
of isomeric mixtures. Methods for the direct halogenation of sp2
CAH bonds under mild conditions have recently been reported
[4]. A novel reagent, namely chlorobis(methoxycarbonyl)guani-
dine, was developed by Baran and co-workers, allowing for the
functionalization of challenging substrates [4a]. Jiao and co-work-
an electrophilic chlorinating agent formed in situ from NCS and
DMSO. Herein, the synthesis of 1-chloro-4-arylpyrroloquinoxalines
directly from its precursors is reported. Bromination of the C1AH
bond in 4-aryl pyrrolo[1,2–a]quinoxalines was also feasible, thus
providing flexible routes to obtain halogenated [6,5]fused N,N-
heterocycles.
Results and discussion
Our study started with the chlorination of 4-phenyl pyrrolo
[1,2–a]quinoxaline 1a. Different conditions were investigated,
and the results are shown in Table 1. Using NCS as a chlorinating
source in the presence of a catalytic amount of DMSO and CHCl3
as the solvent, the C1-chlorinated product 2a was obtained in
59% yield (Entry 1) [6]. Cheeseman previously described a method
for the chlorination of pyrrolo[1,2–a]quinoxaline, using NCS in
aqueous sulfuric acid [7]. However, only one example, which was
obtained as the regioisomeric product, was reported. Omitting
DMSO only gave trace amounts of 2a (Entry 2) [5]. Attempts to
use hypervalent iodine reagents were examined, affording the
desired product in moderate yields (Entries 3 and 4). The chlorina-
tion was successful using Togni’s reagent (Entry 5). However, the
two-step synthesis of this chloro-benziodoxolone limits the conve-
nience of this method [4b]. Recently, a protocol for selective halo-
genation was developed using trihaloisocyanuric acids [4d]. Using
the reported conditions with pyrrolo[1,2–a]quinoxaline 1a
⇑
Corresponding author.
E-mail address: tungtn@hcmut.edu.vn (T.T. Nguyen).
https://doi.org/10.1016/j.tetlet.2021.152879
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H.X. Le, Tran N.B. Hoang, T.H. Tran et al.
Tetrahedron Letters 67 (2021) 152879
Fig. 1. Bio-related pyrrolo[1,2–a]quinoxalines.
afforded an isomeric, inseparable mixture of chlorinated products
(Entry 6). A selective bromination was also considered. In the first
attempt, replacing NCS with NBS gave heteroaryl bromide 2b in
47% yield (Entry 7). After extensive screening, the desired halide
2b was obtained in good yield (66%) using CuBr2 as a bromide
source, K2S2O8 as an oxidant, and toluene as the solvent (Entry
8). Notably, using CuCl2 for the chlorination under similar condi-
tions afforded a complex mixture of regioisomers.
The scope of the selective chlorination is presented in Scheme 1.
Benzylic CAH bonds were inert, thus methyl-substituted sub-
strates were obtainable (2b, 2f). Functionalities such as fluoro
(2c), chloro (2d), and methylthio (2h) groups were compatible
with the reaction conditions, affording the chlorinated heterocy-
cles in moderate yields. Nitro-substituted pyrrolo[1,2–a]quinoxa-
line could also be used; albeit giving the desired chloride 2e in
low yield. Naphthalene-derived pyrrolo[1,2–a]quinoxaline (2g)
was obtained in 82% yield. Substrates bearing heteroaryl rings at
the C4 positions are potential bidentate ligands. Thus, attempts
to chlorinate such pyrrolo[1,2–a]quinoxalines were examined.
The corresponding chlorides 2i-2k were obtained in moderate to
high yields (35–80%).
Control experiments were carried out to clarify the mechanism
of the chlorination (Scheme 2). The addition of radical quenchers
such as TEMPO or BHT did not significantly affect the yield of 2a.
This result somewhat eliminated the involvement of radical spe-
cies during the reaction course. Omitting NCS gave only trace
Scheme 1. Chlorination of pyrrolo[1,2–a]quinoxalines. Reagents and conditions:
pyrrolo[1,2–a]quinoxaline (0.1 mmol), NCS (0.12 mmol), DMSO (0.02 mmol), CHCl3
(1 mL), room temperature, 24 h. Isolated yields.
Table 1
Reaction optimization for the C1-halogenation of pyrroloquinoxaline 1a.a
Entry
X
‘‘X” source
Conditions
Yield 2a or 3a (%)b
1c
2d
3e
4f
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Cl
NCS
NCS
DMSO, CHCl3, rt
CHCl3, rt
PhI(OAc)2, DCE, 50 °C
PhI(OTFA)2, CH2Cl2, rt
DMF, rt
59
33
51
54
57
n.d.
47
66
n.d.
Bu4NCl
TMSCl
Togni’s reagent
TCICA
NBS
g
5
h
6
EtOH, rt
7i
8j
DMSO, CHCl3, rt
K2S2O8, toluene, 80 °C
K2S2O8, toluene, 80 °C
CuBr2
CuBr2
k
9
a
1a (0.1 mmol). bIsolated yields. cNCS (0.12 mmol), DMSO (0.02 mmol), CHCl3 (1 mL), room temperature, 24 h. dNCS (0.12 mmol), CHCl3 (1 mL), room temperature, 24 h.
eBu4NCl (0.5 mmol), PhI(OAc)2 (0.15 mmol), 1,2-dichloroethane (2 mL), 50 °C, 1 h. fTMSCl (0.2 mmol), PhI(OTFA)2 (0.1 mmol), CH2Cl2 (0.5 mL), room temperature, 18 h.
gTogni’s reagent (1-chloro-1,2-benziodoxol-3-one, 0.12 mmol), DMF (2 mL), room temperature, 12 h. hTrichloroisocyanuric acid (TCICA, 0.04 mmol), EtOH (1 mL), room
temperature, 1 h; a mixture of chlorinated products was obtained. iNBS (0.12 mmol) instead of NCS. jCuBr2 (0.1 mmol), K2S2O8 (0.2 mmol), toluene (1 mL), 80 °C, 24 h. kCuCl2
(0.1 mmol) instead of CuBr2. Abbreviation: n.d. = not determined.
2

H.X. Le, Tran N.B. Hoang, T.H. Tran et al.
Tetrahedron Letters 67 (2021) 152879
Conclusion
A novel method has been developed for the selective chlorina-
tion and bromination of sp [2] CAH bonds in 4-aryl pyrrolo[1,2–
a]quinoxalines. The conditions are mild and simple, and thus com-
patible with functionalities such as halogen, methylthio, nitro and
heterocyclic groups. Our approach represents a feasible route for
the late-stage functionalization of complex pyrrolo[1,2–a]
quinoxalines.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Scheme 2. Control experiments for the chlorination reaction.
Acknowledgments
We would like to thank the Vietnam National Foundation for
Science and Technology Development (NAFOSTED) for supporting
this research (under grant number 104.01-2019.44).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152879.
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3