t-BuOK mediated oxidative coupling amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines

Article abstract of DOI:10.1039/d1ra00193k

The transition-metal free amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with amines, such as various (hetero)aromatic amine and aliphatic aminevia t-BuOK-mediated oxidative coupling at room temperature has been developed. This react

Full text of DOI:10.1039/d1ra00193k

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t-BuOK mediated oxidative coupling amination of
1,4-naphthoquinone and related 3-
indolylnaphthoquinones with amines†
a
Cite this: RSC Adv., 2021, 11, 6776
Yu Dong,
Ting Mei,a Qi-Qi Luo,a Qiang Feng,a Bo Chang,a Fan Yang,a
c
a
Hong-wei Zhou,a Zhi-Chuan Shi,b Ji-Yu Wang
and Bing He
*
*
The transition-metal free amination of 1,4-naphthoquinone and related 3-indolylnaphthoquinones with
amines, such as various (hetero)aromatic amine and aliphatic amine via t-BuOK-mediated oxidative
coupling at room temperature has been developed. This reaction provides efficient access to the
biologically important and synthetically useful 2-amino-1,4-naphthoquinones and 2-amino-3-
indolylnaphthoquinones with good yields under mild conditions. The present protocol is simple, practical
and shows good functional group tolerance. In addition, the obtained 2-amino-3-
indolylnaphthoquinones were further transformed to synthesize polycyclic N-heterocycles.
Received 9th January 2021
Accepted 1st February 2021
DOI: 10.1039/d1ra00193k
rsc.li/rsc-advances
developed with two general methods. On the one hand, 2-
amino-1,4-naphthoquinones are prepared by oxidative addition
Introduction
coupling of amines to naphthoquinones in the presence of
catalysts such as CeCl3$7H2O,11 FeCl3,12 Cu(OAc)2,13 I2,14 Au15
and HClO4–SiO2.16 Wang reported that 2-amino-1,4-
naphthoquinones were obtained by combine the nitro reduc-
tion with the 1,4-nucleophilic addition of amines to 1,4-naph-
thoquinones.17 On the other hand, nucleophilic substitution
reactions of 2-halonaphthoquinones,18 or 2-methoxynaph-
thoquinone derivatives19 also can afford 2-amino-1,4-
naphthoquinones. The studies reported that the use of water
was benecial, resulting in nucleophilic substitution and
addition reactions with quinones.20 The use of a bentonitic clay
and ultrasonic irradiation were reported to give moderate to
excellent yields of 2-amino-1,4-naphthoquinones.21
The quinone scaffold can be found not only in various natural
products and pharmaceutical compounds1 but it is also well-
known as a versatile building block extensively applied in
organic synthesis and functional materials.2 Among the deriv-
atives of quinone, the 2-amino-1,4-napthoquinone (I) moiety is
found in a considerable number of natural product antibiotics
(Fig. 1).3 The representative compounds include the quinone-
fused polycyclic N-heterocycles calothrixin A (antiproliferative
and potent antimalarial)4 and hygrocins A, isolated during the
purication of the immunosuppressive agent rapamycin from
Streptomyces hygroscopicus ATC25293.5 Additionally, 2-amino-
1,4-napthoquinone is also important as an intermediate for
the synthesis of biologically active compounds.6
With the objective of studying concise routes into natural
products, their analogues, and polyheteroaromatic systems
2-Amino-1,4-napthoquinone has demonstrated that the
amino group in the naphthoquinone structure can change the
electron-accepting capacity and therefore result in increased
biological activities.7 What's more, this type of compound
possesses several interesting biological properties such as
antibacterial,8 antifungal,9 and anticancer activities.10 There-
fore, much effort has been devoted to developing synthetic
methods for the construction of 2-amino-1,4-napthoquinone
derivatives. The reaction of amines with 1,4-naphthoquinone
derivatives to give 2-amino-1,4-naphthoquinone have been
aCollege of Chemistry and Life Science, Institute of Functional Molecules, Chengdu
Normal University, Chengdu, 611130, P. R. China
bSouthwest Minzu University, Chengdu 610041, P. R. China
cChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra00193k
Fig. 1 Representative biological compounds containing 2-amino-
quinones skeleton.
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Table 1 Optimization of the reaction conditionsa
Table 2 Scopes with respect to 3-arylnaphthoquinones with aminesa
Entry
Base (equiv.)
Solvent (2 mL)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
t-BuOK (1.5)
K2CO3 (1.5)
NaOH (1.5)
CH3ONa (1.5)
Cs2CO3 (1.5)
Et3N (1.5)
DMAP (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
No
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAC
HFIP
Dioxane
DMSO
DMF
DMF
DMF
DMF
6
6
6
6
6
6
6
6
6
6
6
6
6
6
2
53
NR
33
NR
NR
NR
NR
41
NR
NR
35
9
10
11
12
13
14c
15c
NR
71
78
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
86
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol, 1.5 equiv.), base
(1.5–2.0 mmol), solvent (2.0 mL), 2–6 h, air, at room temperature.
b
c
Isolated yield.
2a (0.6 mmol,
2
equiv.), DMF
¼
N,N-
¼
dimethylformamide; DMAP
¼
4-dimethylaminopyridine; DMSO
dimethyl sulfoxide; HFIP ¼ 1,1,1,3,3,3-hexauoroisopropanol; NR ¼
no reaction.
with the 2-amino-1,4-naphthoquinone moiety, we initially
investigated a synthetic protocol. To the best of our knowledge,
an efficient synthesis of 2-amino-1,4-naphthoquinones via a t-
BuOK mediated direct amination has not yet been reported. As
always, we have been interested in the synthesis of indo-
lylnaphthoquinones and related derivatives. In consideration of
the important pharmaceutical applications of the unique 2-
amino-1,4-naphthoquinones structural motif, we report herein
a simple and practical method for the synthesis of 2-amino-1,4-
naphthoquinones and 2-amino-3-indolylnaphthoquinones by
the t-BuOK mediated oxidative coupling amination of 1,4-
naphthoquinone and related 3-indolylnaphthoquinones with
amines.
a
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), t-BuOK (2.0 equiv.),
b
DMF (2.0 mL), 2 h, air, rt. Isolated yield. In a 5 mmol scale.
as DMAC, HFIP, dioxane, DCE, PhCF3 or DMSO, (entries 8–11;
see ESI†). The reaction performed under an air atmosphere in
the absence of base afforded no product (entry 12), which
showed that the base played a pivotal role in obtaining the
desired product. Aerward, the amount of t-BuOK or 2a were
further screened (entries 13–14; see ESI†). It was found that the
Results and discussion
Our investigation to explore amination began with the reaction yields of the product increased with the improved in the
of indolylnaphthoquinone (1a) and aniline (2a) (see Table 1, as amount of t-BuOK or 2a. Therefore, the optimal conditions for
well as Tables S1–S4 in the ESI†). The reaction of t-BuOK (1.5 the preparation of 2-amino-1,4-naphthoquinones and 2-amino-
equiv.), and DMF (2 mL), at room temperature under air 3-indolylnaphthoquinones were obtained: 2a (2 equiv.), t-BuOK
atmosphere, for 6 h (Table 1, entry 1), afforded the desired (2 equiv.), in DMF (2 mL) at room temperature for 2 h (Table 1,
product 3a in 53% isolated yield. Encouraged by this result, entry 15).
subsequently, variation of K2CO3 to NaHCO3, KOH, NaOH,
With the optimized reaction conditions in hand, subse-
CH3ONa, Cs2CO3, Et3N, or DMAP did not show any improve- quently, a series of substituted indolylnaphthoquinones and
ment (entries 2–7; see ESI†). The use of DMF as a solvent was amines were tested for the amination (Table 2). To nd the
crucial, as the reaction gave poor results in other solvents such
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Table 3 Scopes with respect to 1,4-naphthoquinone with aminesa
Scheme 1 R1 and R2 ¼ H unless otherwise stated. 6a R1 and R2 ¼ H,
81%; 6b R1 ¼ Cl, 62%; 6c R2 ¼ F, 56%.
Scheme 2 Plausible reaction mechanism.
2a under the optimized reaction conditions for the synthesis of
3m with moderate yields.
The reaction scope was next examined by using different
substituted anilines with 1,4-naphthoquinone 4a as a model
substrate (Table 3). Various anilines with different electronic
and steric nature were tolerated under the reaction conditions
to afford 2-amino-1,4-naphthoquinones 5a–5h in moderate to
high yields. In a 5 mmol scale reaction, 5a could be obtained in
89% yield, which indicates this transformation could be con-
ducted in a larger scale. Naphthylamine and disubstituted
aniline were also suitable reaction partners to give corre-
sponding products 5i and 5j. Especially, heteroanilines and
aliphatic amine were amenable under our reaction conditions
and provided the expected coupling product 5k and 5l.
Polycyclic N-heterocycles are the key structural element of
natural products, drugs and functional materials.22 Therefore,
a Co-catalyzed intramolecular cyclization reaction of some of
the 2-amino-3-indolylnaphthoquinones derivatives 3 allowed
the generation of polycyclic N-heterocycles derivatives 6 in
moderate yields (Scheme 1).
a
Reaction conditions: 1,4-naphthoquinone (0.3 mmol), 2 (0.6 mmol), t-
BuOK (2.0 equiv.), DMF (2.0 mL), 2 h, air, rt. Isolated yield. b In a 5 mmol
scale.
substrate scope leading to 3, a variety of substituted anilines
were sequentially coupled with 3-indolylnaphthoquinone (1a)
afforded the corresponding products 3 in good yields in spite of
the electronic nature of aniline (3a–h, Table 2). In a 5 mmol
scale reaction, 3a could be obtained in 83% yield, which indi-
cates this transformation could be conducted in a larger scale. It
is noteworthy that the valuable groups (F, Cl, Br) could be
readily tolerated, which provides an opportunity for further
elaboration. Even heteroanilines are well tolerated in this
reaction. The use of aminopyridine provides moderate yields of
the desired products (3i). The strongly coordinating groups
(pyridine), which were employed as reagents for direct C–H
functionalization, were fully tolerated with high chemo-
selectivity and regioselectivity. Next, a variety of indolylnaph-
thoquinones were also examined as substrates for the reaction
strategy. The reaction conditions are mild and notably
compatible with chloro, uoro, and methyl on the aryl ring (3j–l,
Table 2). In addition, phenylnaphthoquinone was treated with
On the basis of our and previous reports,23 a possible reac-
tion mechanism was proposed (Scheme 2). Initially, the Michael
addition of indolylnaphthoquinone (1a) and aniline (2a) in the
presence of base gave the intermediate A, which was immedi-
ately oxidized to the product 3a by O2 or the oxidative
naphthoquinone.
Conclusions
In conclusion, we have developed a practical and efficient
strategy for t-BuOK-mediated oxidative coupling amination of
1,4-naphthoquinone and related 3-indolylnaphthoquinones
with amines at room temperature. A series of 2-amino-1,4-
naphthoquinones and 2-amino-3-indolylnaphthoquinones
were conveniently synthesized in good yields under air
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conditions. The reaction took place under mild conditions,
displayed excellent functional group compatibility, and did not
use metals. In addition, the obtained 2-amino-3-
indolylnaphthoquinones derivatives were conducted further
transformation to synthesize polycyclic N-heterocycles.
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Conflicts of interest
There are no conicts to declare.
9 A. P. Neves, C. C. Barbosa, S. J. Greco, M. D. Vargas,
L. C. Visentin, C. B. Pinheiro, A. S. Mangrich, J. P. Barbosa
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Acknowledgements
We are grateful for the nancial support from the Foundation of
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