Construction of diaminobenzoquinone imines via ferrocene-initiated radical reaction of benzoquinone with amines

Article abstract of DOI:10.1016/j.cclet.2019.09.026

A ferrocene-initiated radical reaction of benzoquinone with amines has been successfully developed for the direct access to diaminobenzoquinone imines in high yields, in which the commercially available and cheap ferrocene was employed as a radical initiator and TBHP was used as an oxidant. Moreover, this reaction could be achieved with low loading of ferrocene (0.5 mol%). This protocol is highly efficient with good substrate tolerance and provides a new approach for the construction of benzoquinone imines with potential pharmaceutical interest.

Full text of DOI:10.1016/j.cclet.2019.09.026

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CCLET 5232 No. of Pages 3
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Construction of diaminobenzoquinone imines via ferrocene-initiated
radical reaction of benzoquinone with amines
a
a
a
a
b,
Yadong Fenga,b, , Ying Liu , Qi Fu , Zhongai Zou , Jinhai Shen , Xiuling Cui
*
*
a
College of Environment and Public Health, Xiamen Huaxia University, Xiamen 361024, China
Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen
Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 24 July 2019
Received in revised form 9 September 2019
Accepted 12 September 2019
Available online xxx
A ferrocene-initiated radical reaction of benzoquinone with amines has been successfully developed for
the direct access to diaminobenzoquinone imines in high yields, in which the commercially available and
cheap ferrocene was employed as a radical initiator and TBHP was used as an oxidant. Moreover, this
reaction could be achieved with low loading of ferrocene (0.5 mol%). This protocol is highly efficient with
good substrate tolerance and provides a new approach for the construction of benzoquinone imines with
potential pharmaceutical interest.
Keywords:
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Benzoquinone imines
Ferrocene-initiated
Radical process
Benzoquinone
Amines
Substitutedbenzoquinonesarekeystructuralmotifs,existingina
broadspectrumofbiologicallyactivenaturalproductsandimportant
pharmaceuticals [1]. Among them, benzoquinone imines are
important synthons in organic synthesis, which are also widely
used in the dye industry and inhibitors against the photo-oxidation
ofpolymers[2]. Forexample, early in1983, Rajappagroup reported a
novel synthesis of 5-acylaminobenzimidazole-2-carbamates
through intramolecular regioselective addition of benzoquinone
imines [3]. In 2001, Nair group reported a dipolar cycloaddition of
carbonyl ylides to para-benzoquinone imines, which could be used
as a facile route to bicyclo[3.2.1] and [2.2.1] systems [4]. After that,
amination to synthesize carbazoles at room temperature [8]. In
2012,WhitegroupreportedanIron-catalyzedintramolecularallylic
C–H amination to synthesize sulfonamides [9]. Recently, our group
has developed a series of Ir-catalyzed direct C–H bond amination of
arylquinazolinones [10]. On the other hand, radical C–H bond
functionalization has emerged as a promising approach because of
their high reactivity with high atom- and step-economy [11]. For
example, Studer and co-workers have disclosed effective methods
of iron-initiated radical C–H functionalization for the direct
synthesis of phenanthridines, fluorenones, and xanthones starting
from commercially available aromatic aldehydes [12]. For this
direction, our group has developed a ferrocene-initiated oxidative
cyclization of benzaldehyde with alkyne as a new strategy to
substituted indenones [13]. In our continuing effort to demonstrate
the clean C–H functionalization [14], herein, we present a new
ferrocene-initiatedradicalreactionofbenzoquinonewithaminesto
synthesize diaminobenzoquinone imines (Scheme 1). This protocol
features easy operation, low loading of ferrocene (0.5 mol%), cheap
andeasilyavailablestartingmaterials,highefficiency, andtolerance
of a broad range of substrates.
Nair group reported
isocyanides, dimethyl acetylenedicarboxylate and benzoquinone
imines as a facile synthesis ofspiro-fused -iminolactams [5]. In
a three component reaction involving
g
addition, Parker group reported an annulation of enolizable vinyl
benzoquinone imines for the synthesis of dihydroquinolines,
quinolines and indoles [6]. Recently, catalytic transformation of
C–H bonds into valuable C–N bonds offers an efficient synthetic
approach to constructN-functionalized molecules [7]. Over the last
fewdecades, transition-metal catalysis provesas a powerful tool for
the direct C–H bonds amination reactions. For example, in 2008,
Gaunt group reported an oxidative Pd(II)-catalyzed C–H bond
Initially, the reaction of benzoquinone (BQ) (1a) with aniline
(2a) was chosen as
a model reaction to optimize various
reaction conditions (Table 1). The results revealed that (E)-2,5-
bis(phenylamino)-4-(phenylimino)cyclohexa-2,5-dienone
(3a)
was obtained as a main product in 78% yield in toluene at 80 ꢀC
when FeBr3 (0.5 mol%) was used as an initiator and t-BuOOH
(TBHP) (3.0 equiv.) was used as the oxidant (Table 1, entry 1). Only
* Corresponding authors at: College of Environment and Public Health, Xiamen
Huaxia University, Xiamen 361024, China.
E-mail addresses: fengyd@hxxy.edu.cn (Y. Feng), cuixl@hqu.edu.cn (X. Cui).
https://doi.org/10.1016/j.cclet.2019.09.026
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Y. Feng, et al., Construction of diaminobenzoquinone imines via ferrocene-initiated radical reaction of
benzoquinone with amines, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.09.026

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Table 2
Scope of substrates.a
Scheme 1. Ferrocene-initiated radical reaction of benzoquinone with amine.
Table 1
Optimization of the reaction conditions.a
Entry
R1
3
Yield (%)b
1
2
3
4
5
6
7
8
2a, R1 = Ph
3a
3b
3c
3d
3e
3f
3g
3 h
3i
3 j
3k
3l
3m
3n
3o
95
69
72
93
67
90
85
77
75
67
65
61
76
65
68
2b, R1 = 2-CH3C6H4
2c, R1 = 3-CH3C6H4
2d, R1 = 4-CH3C6H4
2e, R1 = 4-FC6H4
2f, R1 = 4-ClC6H4
2g, R1 = 4-BrC6H4
2h, R1 = 4-IC6H4
9
2i, R1 = 4-OCH3C6H4
2j, R1 = 4-CF3C6H4
2k, R1 = 2-OCH3C6H4
2l, R1 = 3-OCH3C6H4
2m, R1 = 2-ClC6H4
2n, R1 = 3-ClC6H4
2o, R1 = 2-BrC6H4
10
11
12
13
14
15
Entry
Initiator (mol%) TBHP (equiv.) Solvent
Temp (oC) Yield (%)b
1
2
3
4
5
6
7
8
FeBr3 (0.5)
–
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
–
Toluene 80
78
33
87
65
95
74
93
54
nd
90
21
92
trace
40
75
69
80
56
95
77
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
Toluene 80
a
Reaction conditions: 1 (0.20 mmol), 2 (1.0 mmol), Fc (0.5 mol%), TBHP (3.0
FeCl3 (0.5)
Fe2(SO4)3 (0.5)
Fc (0.5)
FeCl2 (0.5)
Fc (1.0)
Fc (0.2)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
equiv.), solvent (2.0 mL).
b
Isolated yields.
yields, which indicated that steric effect of substituted groups
slightly affected this transformation. Halogen groups, such as F, Cl,
Br, and I at the 4-position of aniline provided the corresponding
products 3e-3 h in 67%, 90%, 85%, and 77% yields, respectively.
Other groups, such as methoxyl and trifluoromethyl, were well
tolerated and gave the corresponding products in satisfactory
yields (3i and 3j) (75% and 67%). Compared to the yield of 3d, these
results indicated that the electron-withdrawing groups have
certain influence on the efficiency of this coupling reaction.
Moreover, methoxyl and halogen groups, such as Cl, and Br at the
2- or 3-position of aniline could also provide the corresponding
products 3k-3o in 65%, 61%, 76%, 65% and 68% yields,
respectively. However, other quinones, aliphatic amines, or
9
10
11
12
13
14
15
16
17
18
19c
20d
2.5
0.5
3.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
DMF
DMSO
NMP
80
80
80
Dioxane 80
Toluene 90
Toluene 70
Toluene 80
Toluene 80
a
Reaction conditions: 1a (0.20 mmol), 2a (1.0 mmol), TBHP (70% solution in ethyl
acetate), solvent (2.0 mL), 24 h.
b
amides,
such
as
2-methylcyclohexa-2,5-diene-1,4-dione,
benzylamine,
Isolated yields. nd = not detected.
26 h.
22 h.
c
2-(tert-butyl)cyclohexa-2,5-diene-1,4-dione,
propylamine, or benzamide, failed to give the desired products.
d
33% yield of the target 3a was achieved when the reaction was
carried out in the absence of an initiator (Table 1, entry 1 vs. 2). Iron
salts, such as FeCl3, Fe2(SO4)3, FeCl2 and ferrocene (Fc), were
screened. Ferrocene gave the highest yield (95%) (Table 1, entry
1 vs. entries 3–6). Better result was achieved with 0.5 mol% of
ferrocene (Table 1, entry 5 vs. entries 7–8). Moreover, 3.0 equiv. of
TBHP favor this reaction (Table 1, entry 5 vs. entries 9–12). Toluene
was demonstrated to be better than other solvents, such as DMF,
DMSO, NMP (N-methyl pyrrolidone) and dioxane (Table 1, entry
5 vs. entries 13–16). The yield of 3a decreased when the reaction
temperature and reaction time were changed (Table 1, entries
17–20). Based on the results, the optimal reaction conditions were
identified as follows: toluene as solvent, at 80 ꢀC, ferrocene
(0.5 mol%) as an initiator and t-BuOOH (TBHP) (3.0 equiv.) as an
oxidant (Table 1, entry 5).
With the optimized reaction conditions in hand, the scope of
the substrates was examined (Table 2). Benzoquinone (1a) reacted
smoothly with aniline (2a) and its derivatives (2b-1o) to give the
desired products (3a-3o) in moderate to good yields (61%–95%).
Methyl group at the ortho-, meta-, and para-position of aniline
provided the corresponding products 3b-3d in 69%, 72%, and 93%
Scheme 2. Control experiments.
Please cite this article in press as: Y. Feng, et al., Construction of diaminobenzoquinone imines via ferrocene-initiated radical reaction of
benzoquinone with amines, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.09.026

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CCLET 5232 No. of Pages 3
Y. Feng et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
3
Outstanding Youth Scientific Research Cultivation Plan in Fujian
Province University (No. 201808).
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.09.026.
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This work was supported by the National Natural Science
Foundation of China (No. 21572072), 111 Project (No. BC2018061)
and Y. Feng thanks the financial support of Scientific Research
Foundation of Xiamen Huaxia University (No. HX201807),
Please cite this article in press as: Y. Feng, et al., Construction of diaminobenzoquinone imines via ferrocene-initiated radical reaction of
benzoquinone with amines, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.09.026