Copper(I)-catalyzed benzylic C(sp3)–H geminal difunctionalization: Successive oxidative intramolecular amidation and hydroxylation

Article abstract of DOI:10.1016/j.tet.2018.11.023

A selective copper(I)-catalyzed benzylic C(sp³)–H geminal difunctionalization reaction of a benzylic-type sp³ carbon was developed. This novel strategy allowed simultaneous introduction of amide and hydroxyl group in a highly selecti

Full text of DOI:10.1016/j.tet.2018.11.023

Accepted Manuscript
3
Copper(I)-catalyzed benzylic C(sp )–H geminal difunctionalization: Successive
oxidative intramolecular amidation and hydroxylation
Zhiguo Zhang, Songnan Wang, Chunfang Hu, Nana Ma, Guisheng Zhang, Qingfeng
Liu
PII:
S0040-4020(18)31363-2
https://doi.org/10.1016/j.tet.2018.11.023
TET 29934
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 July 2018
Revised Date: 8 November 2018
Accepted Date: 11 November 2018
Please cite this article as: Zhang Z, Wang S, Hu C, Ma N, Zhang G, Liu Q, Copper(I)-catalyzed benzylic
3
C(sp )–H geminal difunctionalization: Successive oxidative intramolecular amidation and hydroxylation,
Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.023.
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ACCEPTED MANUSCRIPT
Copper(I)-Catalyzed Benzylic C(sp3)–H Geminal Difunctionalization: Successive Oxidative
Intramolecular Amidation and Hydroxylation
Zhiguo Zhanga,*, Songnan Wanga, Chunfang Hua, Nana Maa, Guisheng Zhanga,*, Qingfeng Liua
a
Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan 453007, China. E-mail: zhangzg@htu.edu.cn and zgs6668@yahoo.com Fax: (+86)-373-332-5250.
Abstract: A selective copper(I)-catalyzed benzylic C(sp3)–H geminal difunctionalization reaction of a
benzylic-type sp3 carbon was developed. This novel strategy allowed simultaneous introduction of
amide and hydroxyl group in a highly selective and efficient way via successive oxidative
intramolecular amidation and hydroxylation. This method was also applied to the synthesis of 3-
hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalinones from readily available 3-methyl-N-substituted
quinoxaline-2-carboxamides in moderate to good yields. The five-membered cyclic hemiaminal
moiety of the pyrrolo[3,4-b]quinoxalinones can serve as an intermediates for subsequent
transformations into other useful functional groups.
Keywords: Copper-catalysis; Benzylic C(sp3)–H difunctionalization; Amidation; Hydroxylation;
Pyrrolo[3,4-b]quinoxalinone
1. Introduction
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In the last decade, much research has focused on the selective construction of C–A (A = C, N, O, S,
Se, and P) bonds through direct activation of C(sp3)–H bonds under oxidative conditions.1 Common to
these cross-coupling methodologies is the generation of reactive intermediates through activation of
C(sp3)–H bonds in close proximity to a heteroatom.2 This strategy provides a waste-minimized
synthetic alternative to classic coupling procedures, which rely on the use of prefunctionalized starting
materials, and has achieved remarkable versatility, selectivity, and efficiency.3 However, this strategy
remains less studied than C(sp2)–H functionalization reactions4 because of the higher bond energy of
C(sp3)–H bonds than C(sp2)–H ones.5 Furthermore, studies on these reactions have mostly focused on
monofunctionalization through single C(sp3)–H activation (Scheme 1a);6 highly selective
multifunctionalization through the simultaneous introduction of different functional groups at the
same sp3 carbon atom via double or triple C(sp3)–H activation has seldom been reported (Scheme
1c).7 In fact, some double C(sp3)–H functionalization reactions at the same sp3 carbon, such as
oxidation of an sp3 C–H bond to a ketone8 or the formation of C=C or C=N double bonds by cross-
coupling with a carbon/nitrogen source,9 are considered monofunctional reactions because only one O,
C, or N atom is introduced into the new molecule, despite two C(sp3)–H bonds at the same carbon
being activated in the process (Scheme 1b). Therefore, the development of efficient catalyst systems
to simultaneously activate and multifunctionalize multiple C(sp3)–H bonds at the same sp3 carbon,
especially by introducing different functional groups with high selectivity and controllability via
double C(sp3)–H difunctionalization, remains an interesting challenge (Scheme 1d).
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Scheme 1. C(sp3)–H functionalization at the same carbon.
Outstanding progress has been achieved in copper-catalyzed intermolecular and intramolecular
direct C(sp3)–H amidation reactions in recent years.10 We developed two reliable and efficient
amidation and successive oxidations of a benzylic C(sp3)–H bond in the presence of CuI as a catalyst
and Oxone as an oxidant, respectively, to synthesize 1H-pyrrolo[3,4-b]quinoline-1,3(2H)-diones7b and
pyrrolo[3,4-d]pyrimidinones7c at 130 °C. A deeper mechanistic understanding of these triple C(sp3)–H
activation difunctionalization reactions showed that the pyrroledione moiety was derived from an
important Cu(III)-containing six-membered cyclic transition state A7b, 7c and subsequent five-
membered cyclic hemiaminal intermediate B (Scheme 2).11 The hemiaminal moiety is a versatile
building block in synthetic organic chemistry that can be transformed into many useful functional
groups including ketones, ethers, amines, and esters under different reaction conditions.12 Accordingly,
in this study, we synthesize hemiaminal-containing multifunctional organic molecules using a new
C(sp3)–H geminal difunctionalization strategy, which is highly desirable for production of electronic
materials and in synthetic organic chemistry.
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Scheme 2. Our recent work on triple C(sp3)–H difunctionalization.
3-Hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxa-linones are important functional small organic
molecules that can be used to synthesize triboluminescent materials.13 Furthermore, their analogues
often contain various azaporphyrins14 and azaphthalocyanines,15 which further regulate their
intramolecular charge transfer behavior. Traditionally, these analogues are prepared via a stepwise
synthetic route; for example, through initial construction of the quinoxaline moiety, then formation of
the pyrrole part via sequential condensation/hydrolysis/amidation reactions starting from the
corresponding diones (bearing electron-rich or neutral substituents), diamines, and amines.13a, 16
However, rapid access to these structurally diverse multifused heterocyclic systems via new and
simple synthetic methods is largely unexplored despite being highly desirable. Herein, we report a
copper(I)-catalyzed selective C(sp3)–H geminal difunctionalization reaction at benzylic-type sp3
carbons. The reaction allows amide and hydroxyl groups to be added simultaneously through a highly
selective and efficient process.17 This strategy is used to synthesize 3-hydroxy-2,3-dihydro-1H-
pyrrolo[3,4-b]quinoxalinones starting from readily available 3-methyl-N-substituted quinoxaline-2-
carboxamides (1, Scheme 3).18
Scheme 3. Double C(sp3)–H activation difunctionalization reaction.
2. Results and discussion
Our investigation began using 3-methyl-N-phenylquinoxaline-2-carboxamide (1a)18 as the model
substrate; important results are summarized in Table 1. After many attempts, 3-hydroxy-2-phenyl-2,3-
dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2a) was obtained in 82% yield by treating 1a with CuI
(0.1 equiv) and Oxone (1.2 equiv) in dimethyl sulfoxide (DMSO) at 80 °C for 1.5 h (Table 1, entry 1).
The amount of CuI catalyst could be further decreased to 0.05 equiv, although this extended the
reaction time to 2.5 h (entry 2). However, the control experiment in the absence of CuI catalyst did not
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afford target product 2a; instead, 91% of 1a was recovered (entry 3). Furthermore, decreasing or
increasing the reaction temperature led to a slightly lower yield of target compound 2a. The reaction
still gave the target product 2a without the formation of excessive oxidation products even when the
reaction was performed at 140 °C (entries 4–6). Other Cu salts, such as CuBr, CuCl, Cu2O, CuBr2,
and CuCl2, were also shown to be effective catalysts for this intramolecular benzylic-type C(sp3)–H
amidation reaction (entries 7–10), although the yields were inferior to that obtained using CuI. In
contrast, Cu(OAc)2 was not an effective catalyst (entry 11). Various oxidants, including K2S2O8, 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), Na2S2O8, 3-chloroperbenzoic acid (m-CPBA),
(NH4)2S2O8, Dess–Martin periodinane (DMP), di-tert-butyl peroxide (DTBP), tert-butyl
hydroperoxide (TBHP), and (diacetoxyiodo)benzene (PIDA), were screened (entries 12–20). Only
K2S2O8 and DDQ afforded product 2a in yields comparable to the reaction using Oxone (entries 12
and 13). Other solvents, such as N,N-dimethylformamide (DMF), toluene, dichloroethane (DCE), and
dioxane, resulted in lower yields of 2a compared with DMSO (entries 21–24). Notably, the
hemiaminal moiety of 2 was not excessively oxidized to the corresponding diimide in any of the
1
attempts, as confirmed by H nuclear magnetic resonance (NMR) spectroscopy and high-resolution
mass spectrometry (HRMS) analysis.
Table 1
Survey of the reaction conditions for the conversion of 1a to 2a.a
O
O
N
N
Condition
N
N
Ph
N
N
Ph
H
OH
1a
2a
Ent. Cat./equiv
[O]/equiv
T /h 2a/% Rec. 1a/%
1
2
3
CuI (0.1)
CuI (0.05)
CuI (0)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
1.5
2.5
2.5
4
82
83
0
0
0
91
0
4b CuI (0.05)
74
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5c CuI (0.05)
6d CuI (0.05)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
1.5
80
72
32
27
53
0
0
2
7
8
9
CuBr (0.05)
CuCl (0.05)
2.5
2.5
2.5
38
36
40
CuBr2 (0.05) Oxone (1.2)
10 CuCl2 (0.05) Oxone (1.2)
2.5
21
41
11 Cu(OAc)2 (0.05) Oxone (1.2) 2.5
0
80
77
73
60
61
47
0
76
0
12 CuI (0.05)
13 CuI (0.05)
14 CuI (0.05)
15 CuI (0.05)
K2S2O8 (1.2) 2.5
DDQ (1.2) 2.5
0
Na2S2O8 (1.2) 2.5
0
m-CPBA (1.2) 2.5
25
23
16
81
76
79
0
16 CuI (0.05) (NH4)2S2O8 (1.2) 2.5
17 CuI (0.05)
18 CuI (0.05)
19 CuI (0.05)
20 CuI (0.05)
21e CuI (0.05)
22f CuI (0.05)
23g CuI (0.05)
DMP (1.2)
DTBP (1.2)
TBHP (1.2)
PIDA (1.2)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0
0
71
0
85
86
84
0
24h CuI (0.05)
0
a
Unless otherwise indicated, all reactions were carried out
with 1 (0.5 mmol), CuI (0.05 equiv), and Oxone (1.2 equiv)
in dry DMSO (1.5 mL) at 80 °C. Ent. = Entry, Rec. =
Recovered.
b Reaction performed at 60 °C.
c Reaction performed at 100 °C.
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d Reaction performed at 140 °C.
e Reaction performed in DMF.
f Reaction performed in toluene.
g Reaction performed in DCE.
h Reaction performed in dioxane.
With optimized conditions in hand (Table 1, entry 2), the scope of the intramolecular
dehydrogenative amidation reaction of benzylic C(sp3)–H bond was then explored using various
quinoxaline derivatives (1). Initially, various R1 substituents were investigated. The experiments
showed that an unsubstituted phenyl group (1a) and various functional aryl groups bearing –MeO
(1b–d), –Cl (1e–g), and –CO2Et (1h) groups at the ortho, meta, and para positions reacted smoothly,
providing corresponding multi-fused heterocyclic products 2a–h in isolated yields of67%–86%. To
our delight, aliphatic substituents, including benzyl (1i), p-methoxybenzyl (PBM) (1j), and tert-butyl
(1k) groups, were also well tolerated under the optimized conditions, affording target products 2i, 2j,
and 2k in 81%, 60%, and 74% yields, respectively. For alkoxy groups (1l: –OMe),19 the reactivity was
dramatically decreased; only 36% of 2l was obtained. Notably, initial attempts starting from 3-ethyl-
N-phenylquinoxaline-2-carboxamide (1m) showed that it was not tolerated; instead, the major product
(68%) was 3-methylfuro[3,4-b]quinoxalin-1(3H)-one (2m’). Therefore, no additional experiments
were conducted with substrates further substituted at this position.
Next, variation of the R2 substituent was investigated. Different starting materials bearing electron-
donating groups (1n: –OMe, 1o: –Me) and electron-withdrawing groups (1p: –Cl, 1q: –NO2) at the 7-
position on the phenyl ring were used in the reaction, affording corresponding products 2n–q in yields
of 69%–78%. Starting materials 1r and 1s, in which the benzene moiety was replaced with pyridine
and thiophene rings, respectively, were confirmed to be suitable for the amidation reaction, affording
novel pyrrolo-fused heterocycles 2r and 2s in yields of 70% and 75%, respectively. These compounds
may be of great interest for the synthesis of optoelectronic materials. However, substrates 1t–x were not
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tolerated in this reaction; desired products 2t–x were not formed. Starting material 1y gave a complex
mixture after 1.5 h rather than the desired product 2y.
Table 2
Reaction extension.a
O
O
O
R
N
N
N
N
N
N
N Ph
OH
N Ph
N R
OH
OH
2u: 3 h, 0%d
2n: R = MeO, 2.5 h, 78%
2o: R = Me, 2 h, 74%
2p: R = Cl, 3 h, 71%
2q: R = NO2, 2 h, 69%
2a: R = Ph, 2.5 h, 83%
O
2b: R = 2ꢀMeOC6H4, 2.5 h, 73%
2c: R = 3ꢀMeOC6H4, 2 h, 67%
2d: R = 4ꢀMeOC6H4, 2.5 h, 71%
2e: R = 2ꢀClC6H4, 2 h, 80%
2f: R = 3ꢀClC6H4, 2 h, 86%
2g: R = 4ꢀClC6H4, 1.5 h, 81%
2h: R = 4ꢀEtO2CC6H4, 1.5 h, 79%
2i: R = Bn, 1.5 h, 81%
N Ph
OH
2v: 2 h, 0%e
O
N
O
N
N Ph
N Ph
N
N
N
OH
OH
2r: 2 h, 70%
2w: 2 h, 0%f
O
N
O
2j: R = PMB, 1.5 h, 60%
S
N Ph
N
N
2k: R = tBu, 1.5 h, 74%
N
OH
H
OH
2x: 2 h, 0%g
2s: 2 h, 75%
2l: R = MeO, 1 h, 36%
O
N
O
N
O
N
N Ph
OH
2t: 2 h, 0%c
O
NH
N
N
N
OH
2m': 1 h, 68%b
2y: 1.5 h, Complex mixture
a Unless otherwise indicated, all reactions were carried out with 1 (0.5 mmol), CuI (0.05
equiv), and oxone (1.2 equiv) in dry DMSO (1.5 mL) at 80 oC.
O
b The starting material was
NHPh
N
N
Et
c A complex mixture was observed.
d 71% of 1u was recovered.
e 86% of 1v was recovered.
f 90% of 1w was recovered.
g 81% of 1x was recovered.
To highlight the synthetic utility of this transformation, diverse transformations of representative
products 2a, 2i, 2j, and 2k were performed, as shown in Scheme 4. We first focused on the synthesis
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of 1H-pyrrolo[3,4-b]quinoxaline-1,3(2H)-diones 3, which have rigid coplanar molecular structures and
are of great interest in porphyrin chemistry, phthalocyanine chemistry, and luminescent materials
applications. This derivatization showed that oxidation of compounds 2i and 2k bearing secondary
OH groups with Jones’ reagent afforded 1H-pyrrolo[3,4-b]quinoxaline-1,3(2H)-diones 3i and 3k in
yields of 65% and 87%, respectively.20 It should be emphasized that in addition to the -OH group at
the 3-position being oxidized to a carbonyl group, the PMB protecting group at the 2-position was
removed simultaneously when compound 2j was employed in this transformation, affording N-
unprotected cyclic imide 3j, which would be useful for further synthetic transformations. These
observations highlighted the utility of this type of heterocycle in constructing dicarboximide-
containing functional molecules or their analogues. Furthermore, when 2a and styrene were treated
with BF3•Et2O (2.0 equiv) in DCM under N2 atmosphere at ambient temperature,21 multi-fused
heterocyclic compound 5-phenyl-6,6a-dihydrobenzo[5,6]indolizino[1,2-b]quinoxalin-13(5H)-one (4a)
was obtained in 59% isolated yield as a white solid. Overall, these results showed that 3-hydroxy-2,3-
dihydro-1H-pyrrolo[3,4-b]quinoxalinones 2 are versatile organic building blocks in organic synthesis.
O
Styrene
CrO3 (3.0 equiv)
H2SO4/H2O (7:3)
O
O
N
N
.
BF3 Et2O (2.0 equiv)
N
N
N
N
N
N
R
N R
DCM, N2, rt, 24 h
acetone, r.t.
OH
O
Ph
2a: R = Ph, 4a: 59%
3i: R = Bn, 1 h, 65%;
3j: R = H, 1 h, 83%;
3k: R = tBu, 0.5 h, 87%.
2i: R = Bn
2j: R = PMB
2k: R = tBu
Scheme 4. Applications of compound 2.
3. Conclusion
In summary, a new strategy for copper(I)-catalyzed selective C(sp3)–H geminal difunctionalization
was developed. This process allows the introduction of amide and hydroxyl groups on the same sp3
carbon of a benzylic-type group in a facile, selective, and efficient successive process. This valuable
and practical route was used to construct thefive-membered cyclic hemiaminal unit found in
structurally diverse 3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalinones, which can subsequently
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be transformed into other functional groups useful in electronic materials and synthetic organic
chemistry. Further applications of this chemistry are being investigated in our laboratory.
4. Experimental section
4.1. General methods
All reactions were carried out in air, unless otherwise indicated. All organic solvents were dried
and freshly distilled before use bystandard methods. Starting materials 1a–u,22 1v,23 1w,24 and 1x25
were synthesized by reported procedures. The petroleum ether (PE) used refers to the fraction of
1
13
petroleum with a boiling point of 60–90 °C. Ethyl acetate is abbreviated as EA. H and C NMR
13
spectra were recorded on a Bruker Avance/600 (1H: 600 MHz, C: 150 MHz at 25 °C) or Bruker
Avance/400 (1H: 400 MHz, 13C: 100 MHz at 25 °C) spectrometer using TMS as an internal standard.
Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d =
doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz).
HRMS analysis was performed on a mass spectrometer using electrospray ionization (ESI-oa-TOF),
1
and the purity of all samples used for HRMS (>95%) was confirmed by H and 13C NMR
spectroscopic analyses. Melting points were measured on a melting point apparatus equipped with a
thermometer and were uncorrected. All reactions were monitored by thin layer chromatography with
GF254 silica gel coated plates. Flash chromatography was carried out on silica gel (200–300 mesh).
4.2. Typical procedure for the preparation of starting material 1a-u (1a as an example)22
To a round-bottom flask (250 mL) were added 3-oxo-N-phenylbutanamide (5.3 g, 30 mmol) and
bis-(trifluoroacetoxy)iodo]benzene (PIFA) (19.3 g, 45 mmol), and the mixture was stirred well in a
CH3CN/H2O solvent (198 mL) at 40 °C (the whole process was closely monitored by TLC). Then
added benzene-1,2-diamine in the presence of 4-methylbenzenesulfonic acid at 40 °C in one pot. After
2 h, the residue was purified by flash silica gel column chromatography (eluent: PE/EA = 15/1) to
give 3-methyl-N-phenylquinoxaline-2-carboxamide (1a) as a red solid.
4.3. Typical experimental procedure for 2 (2a as an example)
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To an oven-dried round-bottom flask (25 mL) equipped with a drying tube was added 1a (131 mg,
0.5 mmol), CuI (5 mg, 0.025 mmol), Oxone (369 mg, 0.6 mmol), the mixture was well stirred for 2.5
o
h in DMSO (1.5 mL) at 80 C (the whole process was closely monitored by TLC). After cooling,
water (10 mL) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (20
mL × 3). The combined organic layer was dried over sodium sulfate. The solvent was evaporated, and
the residue was purified by a short flash silica gel column chromatography (eluent: PE/EA = 2/1) to
give 2a as a yellow solid (114 mg, 83%).
4.3.1. 3-hydroxy-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2a)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (114 mg,
83%). mp: 207-209 oC; 1H NMR (400 MHz, DMSO-d6) δ8.39-8.34 (m, 1H), 8.33-8.27 (m, 1H), 8.09 -
8.00 (m, 2H), 7.88 (dd, J = 8.6, J = 0.9 Hz, 2H), 7.56-7.50 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.23 (d, J
13
= 10.2 Hz, 1H), 6.68 (d, J = 10.2 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ 162.1, 156.1,144.9,
143.1, 142.9, 136.9, 132.3, 131.3, 130.3, 129.4, 130.0, 126.0, 122.9, 80.8. HRMS (ESI), m/z calcd. for
C16H11NaN3O2 ([M+Na]+) 300.0743, found: 300.0736.
4.3.2. 3-hydroxy-2-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2b)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (112 mg,
73%). mp: 207-208 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.2 Hz, 1H), 8.29 (d, J = 7.6 Hz,
1H), 8.04 (m, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 10.0 Hz, 1H), 7.11 (t,
13
J = 7.4 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 3.82 (s, 3H). C NMR (150 MHz, DMSO-d6) δ 162.1,
156.6, 155.0, 144.6, 142.9, 142.7, 132.3, 131.3, 130.3, 129.88, 129.56, 129.4, 123.9, 120.5, 112.5,
81.1, 55.8. HRMS (ESI), m/z calcd. for C17H14N3O3 ([M+H]+) 308.1030, found: 308.1030.
4.3.3. 3-hydroxy-2-(3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2c)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (102 mg,
67%). mp: 193-195 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 7.6 Hz,
1H), 8.08-7.98 (m, 2H), 7.52 (s, 1H), 7.45 (m, 2H), 7.29 (d, J = 10.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
6.68 (d, J = 10.0 Hz, 1H), 3.82 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 162.0, 159.6, 156.0, 144.6,
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143.1, 142.9, 138.0, 132.3, 131.2, 130.3, 129.7, 129.4, 115.0, 111.1, 108.8, 80.8, 55.3. HRMS (ESI),
m/z calcd. for C17H13NaN3O3 ([M+Na]+) 330.0849, found: 330.0844.
4.3.4. 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2d)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a red solid (109 mg,
71%). mp: 229-231 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.26 (m, 2H), 8.08-7.97 (m, 2H), 7.77-
7.71 (m, 2H), 7.18 (d, J = 10.4 Hz, 1H), 7.12-7.05 (m, 2H), 6.56 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H). 13C
NMR (150 MHz, DMSO-d6) δ 161.8, 157.4, 156.2, 144.9, 143.0, 142.8, 132.1, 131.2, 130.2, 129.6,
129.4, 124.9, 114.1, 81.0, 55.4. HRMS (ESI), m/z calcd. for C17H13NaN3O3([M+Na]+) 330.0849,
found: 330.0849.
4.3.5. 2-(2-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2e)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (124 mg,
80%). mp: 221-222 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 7.6 Hz,
1H), 8.12-7.99 (m, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.55 (m, 2H), 7.41 (d, J =
13
9.2 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H). C NMR (150 MHz, DMSO-d6) δ 161.8, 156.4, 144.2, 142.9,
142.8, 133.4, 132.5, 131.5, 130.8, 130.3, 130.2, 130.0, 129.4, 128.1, 81.9. HRMS (ESI), m/z calcd. for
C16H10ClNaN3O2 ([M+Na]+) 334.0354, found: 334.0354.
4.3.6. 2-(3-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2f)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (134 mg,
86%). mp: 217-219 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.0 Hz,
1H), 8.08-8.03 (m, 3H), 7.89 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.41-7.33 (m, 2H), 6.72 (d,
J = 10.4 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 162.2, 155.8, 144.3, 143.1, 143.0, 138.3, 133.3,
132.5, 131.4, 130.6, 130.3, 129.4, 125.5, 121.9, 120.9, 80.7. HRMS (ESI), m/z calcd. for
C16H10ClNaN3O2 ([M+Na]+) 334.0354, found: 334.0355.
4.3.7. 2-(4-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2g)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (126 mg,
81%). mp: 229-231 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 7.6 Hz,
12

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1H), 8.10-7.99 (m, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 10.4 Hz, 1H),
6.68 (d, J = 10.4 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 162.8, 156.2, 144.8, 143.6, 143.5, 135.9,
133.2, 132.1, 130.9, 130.8, 129.9, 129.6, 125.3, 81.2. HRMS (ESI), m/z calcd. for C16H10ClNaN3O2
([M+Na]+) 334.0354, found: 334.0354.
4.3.8. ethyl 4-(1-hydroxy-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-b]quinoxalin-2-yl)benzoate (2h)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (137 mg,
79%). mp: 229-233 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.34 (dd, J = 28.8, 7.8 Hz, 2H), 8.12 (dd, J
= 20.7, 8.1 Hz, 4H), 8.09-8.02 (m, 2H), 7.33 (d, J = 10.2 Hz, 1H), 6.78 (d, J = 10.8 Hz, 1H), 4.35 (d, J
= 6.6 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 165.7, 162.8, 156.2, 144.6,
143.6, 143.5, 141.7, 133.0, 131.9, 130.8, 130.5, 129.9, 126.8, 121.8, 81.0, 61.2, 14.7. HRMS (ESI),
m/z calcd. for C19H16N3O4 ([M+H]+) 350.1135, found: 350.1135.
4.3.9. 2-benzyl-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2i)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (118 mg,
81%). mp: 216-220 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 7.6 Hz,
1H), 8.06-7.95 (m, 2H), 7.43 (d, J = 7.2 Hz, 3H), 7.36 (t, J = 7.4 Hz, 3H), 7.29 (d, J = 6.8 Hz, 1H),
7.16 (d, J = 8.8 Hz, 1H), 5.88 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 15.2 Hz, 1H), 4.59 (d, J = 15.2 Hz, 1H).
13C NMR (150 MHz, DMSO-d6) δ 162.9, 156.6, 145.0, 142.7, 142.5, 136.7, 132.0, 131.1, 130.2, 129.3,
128.5, 127.9, 127.3, 79.2, 42.9. HRMS (ESI), m/z calcd. for C17H13NaN3O2 ([M+Na]+) 314.0900,
found: 314.0896.
4.3.10. 2-benzyl-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2j)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (96 mg,
60%). mp: 256-257 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.1 Hz, 1H), 8.25 (d, J = 7.8 Hz,
1H), 8.00 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 9.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 5.83 (d,
J = 9.6 Hz, 1H), 5.00 (d, J = 15.0 Hz, 1H), 4.48 (d, J = 15.0 Hz, 1H), 3.73 (s, 3H). 13C NMR (150
MHz, DMSO-d6) δ163.16 (s), 159.1, 157.0, 145.6, 143.2, 142.9, 132.4, 131.5, 130.7, 129.9, 129.8,
13

ACCEPTED MANUSCRIPT
129.1, 114.4, 79.5, 55.6, 42.7. HRMS (ESI), m/z calcd. for C18H15NaN3O3 ([M+Na]+) 344.1006,
found: 344.1006.
4.3.11. 2-(tert-butyl)-3-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2k)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (95 mg,
74%). mp: 209-211 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.34-8.18 (m, 2H), 8.05-7.91 (m, 2H), 6.78
(d, J = 10.4 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H), 1.62 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 164.0,
156.8, 146.0, 143.3, 143.0, 132.4, 131.5, 130.6, 129.7, 80.2, 55.7, 28.3. HRMS (ESI), m/z calcd. for
C14H16N3O2 ([M+H]+) 258.1237, found: 258.1233.
4.3.12. 3-hydroxy-2-methoxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2l)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a brown solid (41 mg,
36%). mp: 195-197 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.29 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 5.2 Hz,
13
1H), 7.98-8.03 (m, 2H), 7.47 (d, J = 9.0 Hz, 1H), 6.19 (d, J = 9.0 Hz, 1H), 4.03 (s, 3H). C NMR
(150 MHz, DMSO-d6) δ 158.7, 154.4, 144.1, 142.7, 132.1, 131.2, 130.2, 129.3, 80.0, 64.5. HRMS
(ESI), m/z calcd. for C11H9NaN3O3 ([M+Na]+) 254.0536, found: 254.0544.
4.3.13. 3-methylfuro[3,4-b]quinoxalin-1(3H)-one (2m’)
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a gray solid (68 mg,
68%). mp: 165-167 oC; 1H NMR (600 MHz, Chloroform-d) δ 8.40 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4
Hz, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.95 (t, J = 7.2 Hz, 1H), 5.81 (q, J = 6.8 Hz, 1H), 1.86 (d, J = 6.6 Hz,
13
3H). C NMR (150 MHz, Chloroform-d) δ 165.9, 160.0, 144.2, 144.2, 138.5, 133.5, 131.4, 131.3,
129.4, 19.1. HRMS (ESI), m/z calcd. for C11H8NaN2O2 ([M+Na]+) 223.0478, found: 223.0476.
4.3.14. 3-hydroxy-7-methoxy-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2n)26
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (119 mg,
78%). mp: 230-233 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 7.6 Hz,
2H), 7.73-7.67 (m, 2H), 7.52 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 10.4 Hz, 1H),
6.65 (d, J = 10.0 Hz, 1H), 4.02 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 161.1, 153.7, 145.1,
14

ACCEPTED MANUSCRIPT
144.3, 139.1, 136.9, 130.3, 128.9, 125.8, 125.2, 122.8, 108.0, 80.6, 56.2. HRMS (ESI), m/z calcd. for
C17H13NaN3O3 ([M+Na]+) 330.0849, found: 330.0841.
4.3.15. 3-hydroxy-7-methyl-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2o)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (107 mg,
74%). mp: 248-250 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.21 (dd, J = 24.0, 8.4 Hz, 1H), 8.11 (d, J =
24.6 Hz, 1H), 7.90 (dd, J = 8.4, 1.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.32 (t,
J = 7.2 Hz, 1H), 7.20 (dd, J = 10.2, 6.0 Hz, 1H), 6.66 (dd, J = 10.5, 2.1 Hz, 1H), 2.65 (d, J = 4.2 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) δ 162.2, 155.3, 144.5, 143.2, 141.8, 141.5, 136.9, 134.5, 129.0,
128.9, 125.9, 122.9, 122.9, 80.7, 21.4. HRMS (ESI), m/z calcd. for C17H13NaN3O2 ([M+Na]+)
314.0900, found: 314.0897.
4.3.16. 7-chloro-3-hydroxy-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2p)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (110 mg,
71%). mp: 250-252 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.43 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 8.4 Hz,
1H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 8.1 Hz, 2H), 7.33 (t, J = 7.5
13
Hz, 1H), 7.27 (d, J = 10.2 Hz, 1H), 6.68 (d, J = 10.2 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ
161.7, 156.5, 145.7, 143.4, 141.6, 136.7, 135.6, 132.8, 131.2, 128.99, 128.97, 126.1, 122.9, 80.7.
HRMS (ESI), m/z calcd. for C16H10ClNaN3O2 ([M+Na]+) 334.0354, found: 334.0353.
4.3.17. 3-hydroxy-7-nitro-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2q)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (111 mg,
o
1
69%). mp: 263-265 C; H NMR (600 MHz, DMSO-d6) δ 9.13 (dd, J = 40.2, 2.4 Hz, 1H), 8.71 (m,
1H), 8.56 (dd, J = 33.0, 9.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.35 (m, 2H),
6.73 (dd, J = 10.2, 8.4 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 161.7, 159.4, 148.7, 147.6, 145.8,
142.5, 137.0, 131.8, 129.5, 126.7, 126.6, 125.8, 123.4, 81.3. HRMS (ESI), m/z calcd. for
C16H10NaN4O4 ([M+Na]+) 345.0594, found: 345.0598.
4.3.18. 8-hydroxy-7-phenyl-7,8-dihydro-6H-pyrido[2,3-b]pyrrolo[3,4-e]pyrazin-6-one (2r)
15

ACCEPTED MANUSCRIPT
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (97 mg,
70%). mp: 234-235 oC; 1H NMR (600 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 8.09-
8.03 (m, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 6.73 (d, J =
13
10.2 Hz, 1H). C NMR (150 MHz, DMSO-d6) δ 161.8, 159.5, 156.5, 151.6, 146.1, 139.9, 139.2,
137.2, 129.4, 127.1, 126.5, 123.3, 81.1. HRMS (ESI), m/z calcd. for C15H11N4O2 ([M+H]+) 279.0877,
found: 279.0875.
4.3.19. 7-hydroxy-6-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]thieno[3,4-e]pyrazin-5-one (2s)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (106 mg,
o
1
75%). mp: 310 C; H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 3.6 Hz, 1H), 8.55 (d, J = 3.6 Hz,
1H), 7.86 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 10.4 Hz,
13
1H), 6.54 (d, J = 10.4 Hz, 1H). C NMR (100 MHz, DMSO-d6) δ 161.9, 155.0, 144.7, 143.0, 142.2,
136.9, 128.9, 126.0, 122.8, 122.0, 119.3, 80.4. HRMS (ESI), m/z calcd. for C14H9NaN3O2S ([M+Na]+)
306.0308, found: 306.0306.
4.4. Typical experimental procedure for 3.
A solution of Jones’ reagent (45 mg of chromium trioxide dissolved in 3 mL of sulfuric acid-water
5:2 v/v) was added slowly to a solution of 2 (77.1 mg, 0.3 mmol) in acetone (2 mL). The reaction
mixture was stirred at room temperature for 1 h, then the mixture was quenched with saturated
NaHCO3 until pH = 7 and extracted with EA. The combined organic layer was dried over sodium
sulfate. The solvent was evaporated, and the residue was purified by a short flash silica gel column
chromatography (eluent: PE/EA = 5/1) to give the target compound 3.
4.4.1. 2-benzyl-1H-pyrrolo[3,4-b]quinoxaline-1,3(2H)-dione (3i)
The product was isolated by flash chromatography (eluent: PE/EA = 5/1) as a white solid (94 mg,
o
1
65%). mp: 242-244 C; H NMR (600 MHz, Chloroform-d) δ 8.39 (s, 2H), 8.11 (s, 2H), 7.45 (d, J =
13
7.2 Hz, 2H), 7.35 (t, J = 6.9 Hz, 2H), 7.30 (d, J = 6.6 Hz, 1H), 4.96 (s, 2H). C NMR (150 MHz,
Chloroform-d) δ 164.7, 146.9, 143.3, 136.4, 133.4, 131.1, 128.9, 128.2, 127.9, 41.9. HRMS (ESI), m/z
calcd. for C17H11NaN3O2 ([M+Na]+) 306.0743, found: 306.0738.
16

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4.4.2. 1H-pyrrolo[3,4-b]quinoxaline-1,3(2H)-dione (3j)27
The product was isolated by flash chromatography (eluent: PE/EA = 5/1) as a white solid (82.5 mg,
83%). mp: 208-210 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.39 (s, 2H), 8.11 (s, 2H). 13C
NMR (100 MHz, DMSO-d6) δ 165.4, 147.2, 142.9, 132.8, 130.6. HRMS (ESI), m/z calcd. for
C10H6N3O2 ([M+H]+) 200.0455, found: 200.0455.
4.4.3. 2-(tert-butyl)-1H-pyrrolo[3,4-b]quinoxaline-1,3(2H)-dione (3k)
The product was isolated by flash chromatography (eluent: PE/EA = 5/1) as a white solid (125 mg,
o
1
87%). mp: 168-170 C; H NMR (600 MHz, Chloroform-d) δ 8.49-8.30 (m, 2H), 8.10-7.87 (m, 2H),
13
1.80 (s, 9H). C NMR (100 MHz, Chloroform-d) δ 165.2, 144.8, 144.6, 133.1, 131.3, 60.2, 29.2.
HRMS (ESI), m/z calcd. for C14H13NaN3O2 ([M+Na]+) 278.0900, found: 278.0897.
4.5. Typical experimental procedure for 4.
To a solution of 3-hydroxy-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-one (2a) (1.0
mmol) and the styrene (1.2 mmol) in anhydrous CH2Cl2 (2 mL) was added BF3·OEt2 (2.1 mmol) in
one portion. The reaction mixture was stirred at room temperature for 24 h, then the mixture was
quenched with Na2CO3 (aq. 0.1 M, 20 mL). The combined organic layer was dried over sodium
sulfate. The solvent was removed under reduced pressure and the residue was purified either by
column chromatography (eluent: PE/EA = 6/1) to give the target compound 4a.
4.5.1. 5-phenyl-6,6a-dihydrobenzo[5,6]indolizino[1,2-b]quinoxalin-13(5H)-one (4a)21
The product was isolated by flash chromatography (eluent: PE/EA = 6/1) as a yellow solid (109 mg,
59%). mp: 242-245 oC; 1H NMR (600 MHz, DMSO-d6) δ 8.64 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 7.8 Hz,
1H), 8.24 (d, J = 7.8 Hz, 1H), 8.07–7.94 (m, 2H), 7.39–7.33 (m, 3H), 7.31–7.23 (m, 3H), 7.11 (t, J =
7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 5.39 (dd, J = 12.6, 2.4 Hz, 1H), 4.64 (dd, J = 12.0, 6.0 Hz, 1H),
2.95–2.79 (m, 1H), 2.21 (q, J = 12.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 162.0, 156.7, 145.4,
145.2, 143.4, 143.2, 136.3, 132.6, 131.3, 131.0, 130.7, 130.4, 129.5, 129.2, 129.1, 127.4, 127.3, 125.2,
120.5, 58.1, 43.7, 35.0. HRMS (ESI), m/z calcd. for C24H17N3O ([M+Na]+) 386.1264, found: 386.1261.
Acknowledgments
17

ACCEPTED MANUSCRIPT
We thank the NSFC (21272057, 21772032, 21702051 and U1604285), PCSIRT (IRT1061), the 111
Project (D17007), Henan Provincial Natural Science Foundation (162300410180), Science &
Technology Innovation Talents in Universities of Henan Province (17HASTIT002), Outstanding
Young Talent Cultivation Project Funding of Henan Normal University (14YR002). We thank Natasha
Lundin, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the
English text of a draft of this manuscript.
Appendix A. Supplementary data
Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.****.**.***.
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