Copper-Catalyzed One-Pot Cascade Cyclization for the Synthesis of Isoindolo[2,1-a]quinoxalines

Article abstract of DOI:10.1002/adsc.202100643

A copper-catalyzed one-pot cascade cyclization of 2-(1-(acetyloxy)propargyl)benzaldehydes with o-phenylenediamines for an access to substituted isoindolo[2,1-a]quinoxalines has been developed. The reaction features readily available starting materials, simple operational procedure, and broad substrate scopes. Under optimal conditions, various isoindolo[2,1-a]quinoxalines were afforded in 41–88% yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202100643

UPDATES
doi.org/10.1002/adsc.202100643
Copper-Catalyzed One-Pot Cascade Cyclization for the Synthesis
of Isoindolo[2,1-a]quinoxalines
Ling Li,a, b Zhen-Ting Liu,a,* and Xiang-Ping Hua,*
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road,
Dalian 116023, People’s Republic of China
Fax: (+86)-411-84684746; Phone: (+86)-411-84379206
E-mail: liuzhenting@dicp.ac.cn; xiangping@dicp.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
b
Manuscript received: May 26, 2021; Revised manuscript received: July 13, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100643
two days, which generated a complex mixture with
Abstract: A copper-catalyzed one-pot cascade cyc-
lization of 2-(1-(acetyloxy)propargyl)benzaldehydes
with o-phenylenediamines for an access to substi-
tuted isoindolo[2,1-a]quinoxalines has been devel-
isoindolo[2,1-a] quinoxaline isolated in only low yield
(Scheme 1a). Diana’s[5a] and Potikha’s[6b] groups pro-
vided a similar synthetic approach that involved the
annulation of a quinoxaline ring on the isoindole
oped. The reaction features readily available starting
backbone via the 2-(2’-aminoaryl)-1-cyano-isoindole
materials, simple operational procedure, and broad
intermediates, which were formed from highly toxic
substrate scopes. Under optimal conditions, various
KCN
or
special
reagent
o-(bromomethyl)
isoindolo[2,1-a]quinoxalines were afforded in 41–
benzophenone respectively (Scheme 1b and c). Das
and co-workers utilized readily obtainable ninhydrin-
phenol adducts for the reaction with o-phenylenedi-
amine in refluxing ethylene glycol/Et3N, leading to the
fully unsaturated isoindolo[2,1-a]quinoxaline. How-
ever, the ninhydrin-phenol adducts were preferentially
transformed into intramolecular hemiketal form, which
was deleterious to the process (Scheme 1d).[6d]
88% yields.
Keywords: copper; cyclization; synthetic method;
nitrogen heterocycles; isoindolo[2,1-a]quinoxalines
Nitrogen heterocycles play a central role in drug Although these achievements, the synthesis of isoindo-
discovery and are present in ~85% of all biologically lo[2,1-a]quinoxalines remains a challenging task,
active chemical molecules.[1] A particularly important especially for those with substituents on the phenyl
subgroup of this class are quinoxalines[2] and ring of isoindole core. Therefore, the development of
isoindoles,[3] which occur widely in bioactive natural diverse synthesis for isoindolo[2,1-a]quinoxalines is
products and synthetic compounds. As an assembly of still in high demand.
quinoxaline and isoindole scaffolds, isoindolo[2,1-a]
In the past decade, many studies have disclosed that
quinoxalines have been demonstrated to possess propargylic compounds can serve as bis-electrophilic
remarkable antitumor and biological activities.[4] For synthons for the transition metal-catalyzed cycloaddi-
example, Diana’s group disclosed that isoindolo[2,1-a] tion with bis-nucleophiles, which represents a powerful
quinoxaline derivatives displayed the prominent anti- tool for the formation of structurally diverse
proliferative activity against a wide range of human heterocycles.[7,10] We envisaged this method should be
cancer cells as well as the inhibitory activity of tubulin a potential and efficient strategy for the synthesis of
polymerization and topoisomerase I.[5] The synthesis of isoindolo[2,1-a]quinoxalines by searching for suitable
isoindolo[2,1-a]quinoxaline framework has been propargylic compounds and diamines. As a result,
achieved by either constructing the isoindole unit onto herein we described a Cu-catalyzed one-pot cascade
the quinoxaline core or vice versa, normally requiring cyclization process of 2-(1-(acetyloxy)propargyl)
harsh reaction conditions or tedious procedure, yet benzaldehydes with o-phenylenediamines, providing
remains underdeveloped.[5,6] Dyker and co-workers[6a] various isoindolo[2,1-a]quinoxalines with substituents
reported the condensation of o-phenylenediamine with on both phenyl rings of the isoindole and quinoxaline
o-alkynylbenzaldehydes in refluxing nitrobenzene for core.
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Table 1. Optimization of the reaction conditions.[a]
Entry
[Cu]
L*
Base
Yield (%)[b]
1
2
3
4
5
6
7
8
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
CuCl
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
-
<5
36
<5
65
65
66
77
75
69
72
59
63
<5
77
62
8
9
CuOTf·(C6H6)0.5
CuI
10
11
12
13
14[c]
15[d]
16[c,e]
17[c,f]
18[c,g]
19[c,h]
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Et3N
K2CO3
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
20
80
80
Scheme 1. Synthetic methods for isoindolo[2,1-a]quinoxalines.
[a] Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), [Cu]
(0.01 mmol, 5 mol%), L (0.011 mmol, 5.5 mol%), base
(0.24 mmol, 1.2 equiv.), 8 mL of MeOH, rt, 12 h.
[b] Yield of isolated products.
The investigation was initiated by optimizing the
reaction conditions with 2-(1-(acetyloxy)propargyl)
benzaldehyde 1a and o-phenylenediamine 2a as model
[c] Base (0.1 mmol, 0.5 equiv.).
[d] Base (0.04 mmol, 0.2 equiv.).
substrates
(Table 1).
2-(1-(acetyloxy)propargyl)
[e] CH2Cl2 instead of MeOH.
benzaldehydes 1 could be readily prepared as previ-
ously reported (Scheme 2).[8] Disappointedly, no de-
sired product was detected when the reaction was
performed at room temperature in MeOH with a
combination of Cu(OAc)2 ·H2O and Binap L1 as the
[f] Toluene instead of MeOH.
[g]
°
60 C.
[h] 24 h.
i
catalyst and Pr2NEt as the base (Table 1, entry 1).
Gratifyingly, when P,N,N-ligand L2 was used instead
of L1, the reaction provided 6-methyl isoindolo[2,1-a]
quinoxaline 3aa in 36% yield (Table 1, entry 2). The
structure of 3aa was unambiguously confirmed by X-
ray crystallographic analysis (Table 2).[9] Extensive
screening of different ligands disclosed that pybox-
type ligands were promising as dramatically increased
yields of 3aa could be achieved by use of them
(Table 1, entries 4–7). Among them, Ph-pybox ligand
L7 proved to be optimal with a yield of 77% obtained
Scheme 2. A typical approach to the synthesis of 1.
(Table 1, entry 7). Copper precursors had little effect product was detected by employing K2CO3 (Table 1,
on the reaction (Table 1, entries 8–10). The reaction entry 13). Reducing the base to 0.5 equiv. had no
proceeded smoothly in the absence of base, which observable effect in the yield (Table 1, entry 14), but a
resulted in 59% yield (Table 1, entry 11). The use of further decrease to 0.2 equiv. proved to be deleterious
TEA as the base, a decreased yield of 63% was to the reaction (Table 1, entry 15). When the reaction
achieved (Table 1, entry 12). However, only trace was carried out in other solvents such as CH2Cl2 and
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heteroaromatic substrate 1n was also suitable for the
protocol, albeit with a moderate yield of 47%
(Table 2).
Table 2. Substrate scope for 2-(1-(acetyloxy)propargyl)
benzaldehydes 1.[a,b]
Subsequently, we evaluated the generality of the
approach in regard to o-phenylenediamines 2 (Table 3).
The reaction was carried out under slightly modified
conditions that the ratio of 1a:2 was changed to 1:2.
The substrates bearing either electron-withdrawing (F,
Cl) or electron-donating (Me) substituents on the
phenyl ring of o-phenylenediamines 2 could furnish
the corresponding products (3ab-3ah) in moderate to
good yields. Difluro-substituted substrate 2b delivered
3ab in 64% yield. Dichloro- and dibromo-substituted
substrates (2c and 2d) could also proceed well, leading
to similar isolated yields. The substrate 2e bearing Me-
substituents at both 4- and 5-positions of phenyl ring
displayed the decreased reactivity, providing the
corresponding product 3ae in 41% yield. Naphthyl-
substituted substrate 2f furnished the isoindolo[2,1-a]
quinoxaline 3af in 55% yield. Monosubstituted sub-
strates provided two isomers of isoindolo[2,1-a]
quinoxalines. Thus, Me-substituted substrate 2g deliv-
ered an inseparable mixture of isoindolo[2,1-a]
quinoxalines 3ag and 3 ag’ in a total yield of 80%
[a] Method A: 1 (0.24 mmol), 2a (0.2 mmol), Cu(OAc)2 ·H2O
(0.01 mmol, 5 mol%), L7 (0.011 mmol, 5.5 mol%), iPr2NEt
°
(0.1 mmol, 0.5 equiv.), 8 mL of MeOH, 60 C, 12 h.
[b] Yield of isolated products.
[c] The reaction was performed at room temperature.
toluene, the desired product was furnished in low yield with a ratio of 2:1 (Table 3). When 4-chloro-o-phenyl-
(Table 1, entries 16–17). Further investigation of the enediamine 2h was employed, two isomers were
°
reaction temperature revealed that 60 C was optimal, obtained in isolated yields of 36% (major) and 15%
at which the reaction displayed higher reactivity to (minor), respectively (Table 3). As for alkyl-diamine
give 3aa in 80% yield (Table 1, entry 18). Prolonging 2i, no desired product 3ai was obtained under standard
reaction time didn’t improve the yield (Table 1, conditions (Method B, Scheme 3). We also evaluated
entry 19).
other analogues, such as 2-aminophenol 6, which
With the optimized conditions in hand, we inves- proved to be not suitable for the process (Method B,
tigated the substrate scope of 2-(1-(acetyloxy) Scheme 3).
propargyl)benzaldehydes 1 (Table 2). The current
methodology exhibits good functional group compati-
bility, which offers a diverse synthesis of isoindolo
Table 3. Substrate scope for o-phenylenediamine 2.[a,b]
[2,1-a]quinoxalines containing substituents on isoin-
dole core. The substrates bearing electron-withdrawing
(F, Cl, CF3) and electron-donating (Me, OMe) sub-
stituents proceeded smoothly with o-phenylenediamine
2a, affording the corresponding products 3ba-3na in
42–88% yields (Table 2). These results revealed that
the reaction was sensitive to the electronic effect of
substituents on the phenyl ring of 2-(1-(acetyloxy)
propargyl)benzaldehydes 1. The electron-withdrawing
substituents (F, Cl, or CF3) were beneficial to the
reaction in comparison with the electron-donating
substituents (Me or OMe) (Table 2). The substrates
with a substituent at the 4-position of phenyl ring was
commonly superior to those with the same substituent
at the 5-position (3ba-3ka, Table 2). Under standard
conditions, dimethoxy-substituted substrate 1l resulted
[a] Method B: 1a (0.2 mmol), 2 (0.4 mmol), Cu(OAc)2 ·H2O
(0.01 mmol, 5 mol%), L7 (0.011 mmol, 5.5 mol%), iPr2NEt
in the product in 45% yield. By performing the
reaction at room temperature, the yield of 3la could be
promoted to 62% (Table 2). Naphthyl-substituted sub-
strate 1m underwent the reaction well and furnished
the desired product 3ma in 65% yield. Moreover,
°
(0.1 mmol, 0.5 equiv.), 8 mL of MeOH, 60 C, 12 h.
[b] Yield of isolated products.
[c] Not separable.
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ate E isomerizes to more stable 6-methylisoindolo[2,1-
a]quinoxaline 3aa.
In summary, we have demonstrated an operationally
simple one-pot procedure for the formation of sub-
stituted isoindolo[2,1-a]quinoxalines through copper-
catalyzed cascade cyclization between substituted 2-(1-
(acetyloxy)propargyl)benzaldehydes and o-phenylene-
diamines. The reaction features readily available
Scheme 3. Experiments for special substrates.
Some control experiments were carried out to starting materials, simple procedure and broad sub-
explore the reaction mechanism. When aldimine 4 was strate scopes. This strategy provides a concise access
employed, no 3aa was detected, suggesting that 4 may to various isoindolo[2,1-a]quinoxalines with different
not be an intermediate for the reaction (Scheme 4a, 1). substituents at the phenyl ring of isoindole core that
A copper-catalyzed propargylic substitution at the first hasn’t been reported previously. Further exploration of
step is therefore proposed as reported previously.[10] In new catalytic strategies for rapid access to various
order to capture the key intermediate, the reaction substituted isoindolo[2,1-a]quinoxalines is currently
°
temperature was lowered to À 20 C. A mixture of 3aa ongoing in our laboratory.
and 5 were obtained in 18% yield and 39% yield,
respectively. 5 should be the key intermediate for the
Experimental Section
reaction as 5 could be transformed to 3aa in 59% yield
Method A: A solution of Cu(OAc)2 ·H2O (2.0 mg, 0.010 mmol)
and pybox L7 (4.1 mg, 0.011 mmol) in 1 mL of anhydrous
methanol placed in an oven-dried 25 mL Schlenk flask was
under standard conditions (Scheme 4a, 2 and 3). By
considering all the experimental evidence, a plausible
mechanism was proposed as in Scheme 4b. Initially,
copper-allenylidene complex A is formed from 1a and
°
stirred at 35 C under a nitrogen atmosphere for 1 h. Then 2-(1-
i
(acetyloxy)propargyl)benzaldehydes 1 (0.24 mmol), o-phenyl-
enediamine 2a (0.2 mmol) and i-Pr2NEt (12.9 mg, 0.1 mmol) in
7 mL of anhydrous methanol was added. The mixture was
copper salt under the promotion of Pr2NEt, where the
copper-acetylide complex B bearing a cationic carbon
exists as a resonance structure of A. Then the amino
group of o-phenylenediamine attacks at the cationic
carbon of B and delivers the propargylic amination
product C, which is followed by the imine condensa-
tion to form isoindole skeleton 5. Then, the nucleo-
philic attack of another amino group of o-phenylenedi-
amine at alkynyl group produces intermediate E
bearing an exocyclic double bond. Finally, intermedi-
°
stirred at 60 C for 12 h, filtered through a pad of celite, and
concentrated in vacuum. The residue was purified by silica gel
chromatography (PE/EtOAc) to afford the 6-methylisoindolo
[2,1-a]quinoxalines 3aa-3na (Table 2).
Method B: A solution of Cu(OAc)2 ·H2O (2.0 mg, 0.010 mmol)
and pybox L7 (4.1 mg, 0.011 mmol) in 1 mL of anhydrous
methanol placed in an oven-dried 25 mL Schlenk flask was
°
stirred at 35 C under a nitrogen atmosphere for 1 h. Then 2-(1-
(acetyloxy)propargyl)benzaldehyde 1a (0.2 mmol), o-phenyl-
enediamines 2 (0.4 mmol) and i-Pr2NEt (12.9 mg, 0.1 mmol) in
7 mL of anhydrous methanol was added. The mixture was
°
stirred at 60 C for 12 h, filtered through a pad of celite, and
concentrated in vacuum. The residue was purified by silica gel
chromatography (PE/EtOAc) to afford the 6-methylisoindolo
[2,1-a]quinoxalines 3ab-3ai (Table 3).
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21772196, 22071240),
and the Dalian Institute of Chemical Physics (DICP I201911).
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Copper-Catalyzed One-Pot Cascade Cyclization for the
Synthesis of Isoindolo[2,1-a]quinoxalines
Adv. Synth. Catal. 2021, 363, 1–6
L. Li, Z.-T. Liu*, X.-P. Hu*