Copper-Catalyzed Synthesis of Alkyl-Substituted Pyrrolo[1,2- a ]quinoxalines from 2-(1 H -Pyrrol-1-yl)anilines and Alkylboronic Acids

Article abstract of DOI:10.1055/s-0037-1610743

A radical pathway for the construction of pyrrolo[1,2- a ]quinoxalines by using 2-(1 H -pyrrol-1-yl)anilines and alkylboronic acids has been developed. Features of this process include Cu catalysis, readily accessible starting materials, and simple operat

Full text of DOI:10.1055/s-0037-1610743

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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X. Guan, R. Yan
Letter
Synlett
Copper-Catalyzed Synthesis of Alkyl-Substituted Pyrrolo[1,2-a]-
quinoxalines from 2-(1H-Pyrrol-1-yl)anilines and Alkylboronic
Acids
Xin Guan -02-3420-7937
Rulong Yan*
X
N
X
N
N
Cu(OPiv)2 (10 mol%)
R1
R2B(OH)2
R2 = alkyl
R1
PivOH, DCM, 80 °C, O2
R2
NH2
State Key Laboratory of Applied Organic Chemistry, Key Laboratory
of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Department of Chemistry, Lanzhou University, Lanzhou,
730000, Gansu, P. R. of China
X = C, N
21 examples, up to 77% yield
yanrl@lzu.edu.cn
Received: 03.12.2019
Accepted after revision: 02.01.2020
Published online: 17.01.2020
group previously developed protocols for the synthesis the
pyrrolo[1,2-a]quinoxalines containing hydroxyalkyl or cya-
noalkyl groups through a tandem ring-opening/cyclization
reaction (Scheme 1).10
DOI: 10.1055/s-0037-1610743; Art ID: st-2019-l0648-l
Abstract A radical pathway for the construction of pyrrolo[1,2-a]qui-
noxalines by using 2-(1H-pyrrol-1-yl)anilines and alkylboronic acids has
been developed. Features of this process include Cu catalysis, readily ac-
cessible starting materials, and simple operations. Alkylboronic acids
are used for the construction of pyrrolo[1,2-a]quinoxaline derivatives,
and the desired products are obtained in moderate yields.
a) Our group's previous work
FeCl3, 70% TBHP
Y
N
N
Y
N
X
F3CSO3H, t-BuOH, rt
R
R
XH
n
NH2
Key words pyrrolylanilines, alkylboronic acids, pyrroloquinoxalines,
radical reaction
X = O, S
Y = C, N
b) This work
The pyrrolo[1,2-a]quinoxaline skeleton is an important
scaffold in various compounds and in synthetic intermedi-
ates with biological activities.1 Some pyrrolo[1,2-a]quinox-
aline derivatives have been found to have potential
pharmacologically activities, such as anticancer activity,2
affinity toward 5-hydroxytyrosine receptors,3 and in vitro
antiparasitic activity.4 Because of their wide range of appli-
cations, pyrrolo[1,2-a]quinoxaline derivatives have attract-
ed considerable attention, and various novel synthetic
methods have been developed to build this framework. In
1965, Cheeseman and Tuck reported a related method for
synthesizing pyrrolo[1,2-a]quinoxalines from (1H-pyrrol-
1-yl)anilines.5 Recently, Ma and co-workers proposed a
convenient synthesis of pyrrolo[1,2-a]quinoxaline deriva-
tives from simple substrates.6 Jiang and co-workers de-
scribed a cyclization of (1H-pyrrol-1-yl)anilines with alkyl
alcohols to give pyrrolo[1,2-a]quinoxalines in good yields.7
In 2014, Jamison and co-workers reported a one-pot reac-
tion of 1-(2-isocyanophenyl)-1H-pyrrole with visible-light
photoredox catalysis for the synthesis of pyrrolo[1,2-a]qui-
noxalines.8 de Fatima Periera and Thiéry also reported a
synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-nitro-
phenyl)-1H-pyrrole in the presence of Fe(0) and HCl.9 Our
X
N
X
N
N
Cu(OPiv)2 (10 mol%)
R1
R2 B(OH)2
R1
R2
PivOH, DCM, 80 °C, O2
NH2
X = C, N
X = C, N
Scheme 1 Syntheses of pyrrolo[1,2-a]quinoxaline derivatives
Alkylboronic acids, as useful substrates in coupling re-
actions, have been widely studied. However, compared with
trialkylboranes or organotrifluoroborates, organoboronic
acids are rarely used as radical precursors to construct C–C
bonds.11 Although several transition-metal-catalyzed radi-
cal cascade reaction of boronic acids through radical path-
ways have been developed, the use of organoboronic acids
as radical precursors to construct heterocyclic scaffolds is
rare and challenging.12 We therefore hypothesized that al-
kyl moieties might be introduced into pyrrolo[1,2-a]qui-
noxalines by starting from alkylboronic acids and 2-(1H-
pyrrol-1-yl)anilines. Here we report the development of a
method for building alkyl-substituted pyrrolo[1,2-a]qui-
noxalines from 2-(1H-pyrrol-1-yl)anilines and alkylboronic
acids through a copper-catalyzed cyclization reaction
(Scheme 1).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
X. Guan, R. Yan
Letter
Synlett
To test our hypothesis, we attempted to react 2-(1H-
pyrrol-1-yl)aniline (1a) and butylboronic acid (2a) as model
substrates in the presence of Cu(OPiv)2 (10 mol %) and Piv-
OH (1 equiv) with stirring at 70 °C for 12 hours in NMP un-
der an O2 atmosphere (Table 1). The desired product 3aa
was obtained in 43% yield. Then, several solvents were ex-
amined (Table 1, entries 2–5), among which dichlorometh-
ane was found to be the most effective (entry 4). Subse-
quently, a screening of transition-metal catalysts was per-
formed and Cu(OPiv)2 was found to be more effective than
CuI, CuCl2, FeCl3, or Pd(OAc)2 in this reaction (entries 4 and
6–9). Furthermore, when the temperature was changed, an
enhancement in the product yield was observed at 80 °C
(entries 4 and 12–14). No significant increase in yield was
observed when other acids were used instead of PivOH (en-
tries 14–17). Finally, the optimal outcome was obtained by
using the conditions shown in entry 13.
ble 2. Substrates 1b–e with electron-donating groups af-
forded the desired products 3ba–ea in good yields. More-
over, substrates 1f–m bearing electron-withdrawing groups
such as F, Cl, Br on the phenyl ring of the N-heterocycle re-
acted smoothly with butylboronic acid to give the desired
products in yields of 55–77%. To our delight, the substituted
2-(1H-pyrrol-1-yl)pyridin-3-amines 1n–p reacted smooth-
ly with 2a to give the corresponding products 3na–pa in
yields of 22–29 %.
Table 2 Scope of the Substituted 2-(1H-Pyrrol-1-yl)aniline or 2-(1H-
Pyrrol-1-yl)pyridin-3-aminea
Cu(OPiv)2 (10 mol%)
PivOH (1.0 equiv)
X
N
X
N
R1
R1
B(OH)2
2a
DCM, O2, 80 °C
NH2
N
1
3
With the optimized reaction conditions in hand, we
started to investigate the scope of the 2-(1H-pyrrol-1-yl)an-
iline in this reaction, and the results are summarized in Ta-
N
N
N
N
N
N
3aa (73%)
3ba (70%)
3ca (72%)
Table 1 Optimization of the Reaction Conditionsa
O
N
N
N
catalyst
oxidant
N
N
tBu
F
N
N
F
N
B(OH)2
base
solvent
NH2
N
3da (53%)
3ea (69%)
3fa (53%)
1a
2a
3aa
N
F
F
N
N
Entry Catalyst
Oxidant
(equiv)
Solvent
Temp Acid
(°C)
Yieldb
(%)
N
N
Cl
Cl
N
1
2
Cu(OPiv)2
O2
O2
NMP
70
70
PivOH
3ga (58%)
3ha (69%)
3ia (59%)
43
Cu(OPiv)2
AcOH
PivOH
13
0
Cl
Cl
N
Cl
N
N
3
4
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
CuI
O2
DMSO
DCM
PhCl
70
70
70
80
80
80
80
80
80
40
80
90
80
80
80
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
TFA
N
N
N
O2
71
64
67
39
3
3ka (77%)
3ja (65%)
3la (55%)
5
O2
6
O2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
N
N
N
N
N
7
CuCl2
O2
Br
Cl
N
N
N
8
FeCl3
O2
3ma (63%)
3na (28%)
3oa (22%)
9
Pd(OAc)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
O2
7
10
11
12
13
14
15
16
17
TBHPc (2)
37
28
22
73
44
0
N
N
N
N
N
PIDAd (2)
O2
O2
O2
O2
O2
O2
N
N
3qa (trace)
3pa (29%)
a Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Cu(OPiv)2 (10 mol%),
PivOH (0.3 mmol), DCM (1.5 mL), 80 °C, under O2 (balloon) for 12 h.
TfOH
0
AcOH
7
Next, the substrate scope of the alkylboronic acid 2 was
investigated under the optimized conditions. As shown in
Table 3, the reaction of 1a with various alkylboronic acids 2
proceeded smoothly and gave the desired products 3ab–ae
in moderate yields. Cyclopropylboronic acid was also inves-
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), catalyst (10 mol%), acid
(0.3 mmol), solvent (1.5 mL), 80 °C, O2 (balloon), >12 h (monitored by TLC).
b Yield of the isolated product.
c 5.5 M TBHP in decane under argon.
d Phenyliodine diacetate.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
X. Guan, R. Yan
Letter
Synlett
tigated, but unfortunately only a trace of the desired prod-
uct 3af was obtained.
Table 3 Scope of the Alkylboronic Acida
To probe the mechanism of this transformation, we car-
ried out some control experiments (Scheme 2). When 2.0
equivalents of TEMPO were added to the reaction system,
none of the desired product was obtained and the alkylated
TEMPO 4 was isolated in 63% yield. As expected, on adding
2,6-di-tert-butyl-4-methylphenol (BHT) under the standard
conditions, 3aa was obtained in only 10% yield. These re-
sults indicate that an alkyl radical formed from substrate 2
is involved in this transformation. When 2a was added
without 1a under the standard conditions, no butanal (5)
was detected, proving that the alkyl radical does not react
with O2 to produce butanal.
N
N
Cu(OPiv)2 (10 mol%)
RB(OH)2
PivOH, DCM, 80 °C, O2
NH2
1a
N
R
2
3a
N
N
N
N
N
N
3ab (65%)
3ac (68%)
3ad (63%)
N
N
In light of these experimental results and reports in the
literature,13–15 a possible mechanism is proposed, as shown
in Scheme 3. First, the alkyl radical B is formed through
cleavage of butylboronic acid (2a) in the presence of Cun.
Radical B then reacts with 1a to produce intermediate C.
Subsequently, the peroxide intermediate D, formed from
NH
N
3af (trace)
3ae (62%)
a Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol), Cu(OPiv)2 (10 mol%),
PivOH (0.3 mmol), DCM (1.5 mL), 80 °C, O2 (balloon), 12 h.
TEMPO (3.5 equiv)
Cu(OPiv)2 (10 mol%)
N
N
N
O
B(OH)2
PivOH (1.0 equiv)
DCM, O2, 80 °C
NH2
N
1a
2a
4 (63%)
3aa (0%)
BHT (3.5 equiv)
Cu(OPiv)2 (10 mol%)
N
N
B(OH)2
PivOH (1.0 equiv)
DCM, O2, 80 °C
NH2
N
1a
2a
3aa (10%)
Cu(OPiv)2 (10 mol%)
CHO
B(OH)2
PivOH (1.0 equiv)
DCM, O2, 80 °C
2a
5 (0%)
Scheme 2 Control experiments
N
N
B(OH)2
+
NH2
NH2
B
C
2a
1a
Cun+1
X
CunX
PivO–
PivOH
[Cu]/O2
N
HOO
NH2
D
– H2O
N
N
– H2O
N
O
NH2
3aa
E
Scheme 3 Proposed mechanism
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
X. Guan, R. Yan
Letter
Synlett
compound C by Cu-promoted oxidation, decomposes to
give intermediate E. Finally, intramolecular nucleophilic at-
tack in intermediate E leads to the product 3aa.
In summary, we have developed an effective strategy for
synthesizing alkyl-substituted pyrrolo[1,2-a]quinoxalines
from 2-(1H-pyrrol-1-yl)anilines and arylboronic acids.16
This transformation shows broad functional-group toler-
ance, and a series of alkyl-substituted pyrrolo[1,2-a]qui-
noxalines can be obtained in moderate to good yields.
(7) Li, J.; Zhang, J.; Yang, H.; Gao, Z.; Jiang, G. J. Org. Chem. 2017, 82,
765.
(8) He, Z.; Bae, M.; Wu, J.; Jamison, T. F. Angew. Chem. Int. Ed. 2014,
53, 14451.
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(10) (a) An, Z.; Zhao, L.; Wu, M.; Ni, J.; Qi, Z.; Yu, G.; Yan, R. Chem.
Commun. 2017, 53, 11572. (b) An, Z.; Jiang, Y.; Guan, X.; Yan, R.
Chem. Commun. 2018, 54, 10738.
(11) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(b) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(c) Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13,
1852. (d) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.;
Molander, G. A. Acc. Chem. Res. 2016, 49, 1429. (e) Sorin, G.;
Martinez Mallorquin, R.; Contie, Y.; Baralle, A.; Malacria, M.;
Goddard, J.-P.; Fensterbank, L. Angew. Chem. Int. Ed. 2010, 49,
8721. (f) Zhang, L.; Liu, Z.-Q. Org. Lett. 2017, 19, 6594.
(12) (a) Demir, A. S.; Reis, Ö.; Emrullahoglu, M. J. Org. Chem. 2003,
68, 578. (b) Uchiyama, N.; Shirakawa, E.; Nishikawa, R.; Hayashi,
T. Chem. Commun. 2011, 47, 11671. (c) Lv, W.-X.; Zeng, Y.-F.;
Zhang, S.-S.; Li, Q.; Wang, H. Org. Lett. 2015, 17, 2972. (d) Seiple,
I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel,
A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194. (e) Fujiwara,
Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Del Bel, M.; Baran,
P. S. J. Am. Chem. Soc. 2011, 133, 3292. (f) Tobisu, M.; Koh, K.;
Furukawa, T.; Chatani, N. Angew. Chem. Int. Ed. 2012, 51, 11363.
(g) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem. Int. Ed. 2013, 52,
4453. (h) Bering, L.; Antonchick, A. P. Org. Lett. 2015, 17, 3134.
(i) Castro, S.; Fernández, J.; Fañanás, F. J.; Vicente, R.; Rodríguez,
F. Chem. Eur. J. 2016, 22, 9068. (j) Li, G.-X.; Morales-Rivera, C. A.;
Wang, Y.; Gao, F.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2016, 7,
6407.
Funding Information
This work was supported by the National Natural Science Foundation
of China (21672086) and by the Fundamental Research Funds for the
Central Universities (lzujbky-2018-81).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610743.
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References and Notes
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Pigm. 2015, 113, 581. (e) Carta, A.; Loriga, M.; Paglietti, G.;
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(16) 4-Propylpyrrolo[1,2-a]quinoxaline (3aa):2 Typical Procedure
A mixture of 2-(1H-pyrrol-1-yl)aniline (1a; 1 equiv, 0.3 mmol),
BuB(OH)2 (2a; 3 equiv, 0.9 mmol), PivOH (1 equiv, 0.3 mmol),
Cu(OPiv)2 (10 mol%, 0.03 mmol), and DCM (1 mL) was stirred at
80 °C under O2 (balloon) for 8 h. Upon completion of the reac-
tion (TLC), the mixture was concentrated in vacuo, and the
crude product was purified by column chromatography [silica,
gel, PE–EtOAc (10:1)] to give a light-yellow solid; yield: (40.3
mg, 73%); mp 45–46 °C.
1H NMR (400 MHz, CDCl3):  = 7.94–7.90 (m, 1 H), 7.90–7.89 (m,
1 H), 7.84–7.80 (m, 1 H), 7.49–7.44 (m, 1 H), 7.44–7.39 (m, 1 H),
6.92–6.89 (m, 1 H), 6.85–6.83 (m, 1 H), 3.02–2.97 (m, 2 H),
1.99–1.89 (m, 2 H), 1.10–1.05 (m, 3 H). 13C NMR (100 MHz,
CDCl3):  = 157.4, 136.0, 129.4, 127.3, 126.8, 126.1, 125.0, 114.1,
113.6, 113.4, 106.3, 37.8, 22.0, 14.3. HRMS (ESI): m/z [M + H]+
calcd for C14H15N2: 211.1230; found: 211.1227.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D