Cobalt-Catalyzed Cycloamination: Synthesis and Photophysical Properties of Polycyclic N-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c01753

The first earth-abundant cobalt-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amine under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. The process allows facile access to polycyclic N-heterocycles with tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (up to 89percent). In addition, The photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence properties, which is promising for fluorescent probes.

Full text of DOI:10.1021/acs.orglett.0c01753

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Letter
Cobalt-Catalyzed Cycloamination: Synthesis and Photophysical
Properties of Polycyclic N‑Heterocycles
Yu Dong, Jian Yang, Hua Zhang, Xiao-Yu Zhan, Shuai He, Zhi-Chuan Shi, Xiao-Mei Zhang,
and Ji-Yu Wang*
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ABSTRACT: The first earth-abundant cobalt-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amine
under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. The process allows facile access to
polycyclic N-heterocycles with tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (up to 89%). In
addition, The photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence
properties, which is promising for fluorescent probes.
Scheme 1. Representative Polycyclic N-Heterocycles
Complex
N-Heterocycles are the key structural element of natural
products, drugs, and functional materials.1 Among the different
classes of nitrogen heterocycles, polycyclic N-heterocycles,
which are complex molecules, are widespread in nature and
possess several interesting biological activities.2 The represen-
tative compounds include the indole-fused carbazole gran-
ulatimide (checkpoint kinase 1 inhibitor),3 staurosporine
(kinase inhibitor),4 rebeccamycin (topoisomerase I inhibitor),5
Clausamine D (Epstein−Barr virus (EBV) inhibitor),6 and the
quinone-fused polycyclic N-heterocycles calothrixin A (anti-
proliferative and potent antimalarial) (Scheme 1).7 Besides
remarkable biological activities, polycyclic N-heterocycles
exhibit a wide band gap, outstanding luminescence efficiency,
and photophysical properties, displaying widespread use in
organic optoelectronic materials8 and fluorescent probes.9
Annellated polycyclic complexes bearing a quinone skeleton
are electron acceptor groups that, electronically connected
with recognition sites, have proven to be suitable receptors for
the colorimetric sensing of certain anions and have also been
used for metal ion recognition.10 These compounds are very
promising for applications in various areas, due to the
combination of the two sensing effects, color and fluorescence.
Therefore, much effort has been devoted to developing
synthetic methods for the construction of annellated polycyclic
complex bearing a quinone skeleton. The representative
approaches have usually involved the classical Friedel−Crafts
reactions,11 introduction of the 9,10-carbonyl functions by
oxidation of the corresponding hydrocarbon,12 Lewis acid
catalyzed intramolecular cyclization by Lewis acid as catalyst,13
thermal or Lewis acid catalyzed Diels−Alder reaction followed
by aromatization,14 and transition-metal-catalyzed oxidative
cyclization.15 Despite their merits, many existing synthetic
Received: May 25, 2020
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© XXXX American Chemical Society
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approaches have several shortcomings, such as the preparation
of the prerequisite functional groups, multiple reaction steps,
harsh reaction conditions, expensive catalysts, and low product
yields.
in other solvents such as NMP, DMSO, HFIP, DCE, or PhCF3
(Table 1, entries 10−12; see SI). It should be noted that
increasing or decreasing the reaction temperature gave slightly
inferior results, indicating that the transformation was sensitive
to temperature (see SI).
With the optimized reaction conditions in hand, sub-
sequently, a series of substituted indolylnaphthoquinones were
tested for the annulation sequence (Scheme 2). As summarized
Transition-metal-catalyzed C−H amination has emerged as
a straightforward and step-economical synthetic methodology
to form aromatic C−N bonds.16 In particular, transition-metal-
catalyzed cross-dehydrogenative coupling (CDC) amination is
highly desirable, in which aromatic amines were directly
utilized as reactants.17 Among these, a cobalt catalyst is a viable
alternative and may be a promising catalyst for the synthesis of
the derivatives because of its low-toxicity, low-cost, earth-
abundant base metals. This paper describes a novel and
efficient synthesis of polycyclic N-heterocycle complexes by
cobalt-catalyzed cycloamination reaction between indolylqui-
nones and aromatic amines.
a
Scheme 2. Scope for Indolylquinones
Our investigation to explore CDC aromatic amination began
with the reaction of indolylnaphthoquinone (1a) and aniline
(2a) (see Table 1, as well as Tables S1−S5 in the Supporting
a
Table 1. Optimization Studies
b
Entry
[Cat.]
CoCl2
Co(acac)2
CoBr2·6H2O
Co(OAc)2·4H2O
FeCl3
CuCl2
CoCl2
CoCl2
CoCl2
Base
Solven
Yield
1
2
3
4
5
6
7
8
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
K2CO3
CH3ONa
Et3N
t-BuOK
t-BuOK
t-BuOK
t-BuOK
No
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
HFIP
DMF
DMF
89
53
58
69
23
31
50
42
NR
NR
35
NR
16
0
9
10
11
12
13
14
CoCl2
CoCl2
CoCl2
No
a
Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), CoCl2 (3 mol
%), t-BuOK (1.5 equiv), DMF (2.0 mL), 24 h, air, 120 °C. Isolated
yield. N.R. = no reaction.
CoCl2
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol, 1.5 equiv),
[Cat.] (3 mol %), Base (0.45 mmol, 1.5 equiv), Solvent (2.0 mL), 24
b
h, air, 120 °C. Isolated yield. DMF = N,N-Dimethylformamide;
NMP = N-Methylpyrrolidone; DMSO = Dimethyl sulfoxide; HFIP =
1,1,1,3,3,3-Hexafluoroisopropanol; N.R. = no reaction.
in Scheme 2, the reaction was compatible with a variety of
indole moieties (1a−1n) bearing electron-donating and
electron-withdrawing substituents to produce the desired
polycyclic N-heterocycle products (3aa−3na) in moderate to
good yields (61−89%). The structure of the polycyclic N-
heterocycle 3aa was confirmed by X-ray analysis. Notably, the
gram-scale synthesis afforded 1.29 g of 3aa in 86% yield. To
our delight, the reaction also showed good compatibility with a
wide range of valuable functional groups such as allyl (3ea),
fluoro (3la), chloro (3ga, 3ia, and 3ma), and bromo (3ja).
Tolerance to the halogen atoms was noteworthy since they
have been frequently used for further modification. N-
Alkylindoles and N-benzylindole naphthoquinone can
smoothly proceed to give the corresponding products in
good yields (3aa−3ca). Unfortunately, no desired product can
be obtained when 1d were used as the substrate. Significantly,
the annulation reaction strategy was also applicable to allyl
substituents (1e) which led to the corresponding product 3ea
Information (SI)). The reaction of CoCl2 (3 mol %), t-BuOK
(1.5 equiv), and DMF (2 mL), at 120 °C, for 24 h (Table 1,
entry 1), afforded the desired product 3aa in 89% isolated
yield. Other metal salts did not provide better results including
Co(acac)2, CoBr2·6H2O, Co(OAc)2·4H2O, CoCO3, FeCl3,
and CuCl2 which were also tested for the cycloamination
(entries 2−6; see SI). Subsequently, variation of t-BuOK to
K2CO3, KOH, Cs2CO3, CH3ONa, Et3N, or pyridine did not
show any improvement (entries 7−9; see SI). The reaction
performed under an air atmosphere in the absence of catalyst
or base afforded a very low yield of the products or no product
(entry 13 or 14), which showed that the catalyst or base played
a pivotal role in obtaining the desired product. The use of
DMF as a solvent was crucial, as the reaction gave poor results
B
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in 65% yield. Moreover, we were pleased to find that the
position of the substituent on the indole moiety showed no
obvious influence on the reaction outcome, and substitutions
at the C4-(3fa and 3ga), C5-(3ha−3ja), C6-(3ka−3ma), or
C7-(3na) were all well tolerated in the reaction. 1,4-
Anthraquinone-substituted indole 1o was also employed,
affording corresponding product 3oa in 82% yield.
amenable under our reaction conditions and provided the
expected cyclization products 3at and 3au. Even heteroanilines
are well tolerated in this reaction. The use of aminopyridines
provides moderate yields of the desired products (3av−3aw).
The strongly coordinating groups (pyridine), which were
employed as reagents for direct C−H functionalization, were
fully tolerated with high chemoselectivity and regioselectivity.
Unfortunately, only a trace amount of the desired product was
detected when aliphatic amines were used.
Subsequently, the scope of the anilines was investigated
(Scheme 3). A variety of substituted anilines were compatible
The large conjugated systems give the potential for these
synthetic new compounds to possess good fluorescence
properties. With these diverse polycyclic N-heterocycles
molecules in hand, we next turned our attention to the
photophysical properties of some chosen molecules 3 by
recording UV−vis and emission spectra in DCM at a low
concentration (3 × 10−5 M) as shown in Table 2 and Figure 1.
a
Scheme 3. Scope for Anilines
a b
,
Table 2. Photophysical Properties of Compounds 3
Entry
Compound
λmax (nm) [ε (M)−1 cm−1
]
λem (nm)
ΦF
1
2
3
4
5
6
7
8
3aa
3ac
3as
3at
3au
3av
3ba
3ca
3ea
3fa
505 [2800]
505 [7900]
505 [9100]
500 [6600]
505 [13900]
505 [14900]
505 [4800]
500 [9700]
500 [6800]
510 [8000]
510 [8100]
490 [2000]
495 [7100]
629
629
629
629
629
639
629
620
629
620
615
615
615
620
0.49
0.50
0.45
0.50
0.38
0.40
0.52
0.71
0.69
0.53
0.55
0.82
0.91
0.81
9
10
11
12
13
14
3ia
3ka
3la
3ma
495 [5400]
a
b
Concentration of 3 × 10−5 M in DCM. Excited at 500 nm.
a
Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), CoCl2 (3 mol
%), t-BuOK (1.5 equiv), DMF (2.0 mL), 24 h, air, 120 °C. Isolated
yield.
Figure 1. Fluorescence spectra of compounds 3 recorded in DCM.
with the Co-catalyzed amination, regardless of the electronic
properties of the substrates (3ab−3ai). It is noteworthy that
the valuable groups (F, Cl, Br, NH2, SH) could be readily
tolerated, which provides an opportunity for further elabo-
ration. Although ortho monosubstituted aromatic amines are
sterically challenging even for cyclization, the ortho-substituted
anilines underwent reactions successfully to give the
corresponding aminated products (3aj−3an). For disubsti-
tuted anilines, the reaction was also found to proceed smoothly
(3ao−3as). Especially, naphthylamine and aminopyrene were
They emit between 615 and 639 nm in DCM with moderate to
good quantum yields (ranging from 0.38 to 0.91). The
properties of substituents as well as their position on the
peripheral ring of polycyclic N-heterocycles molecules play the
same important role in their photophysical properties. The
presence of an electron-donating group at the C-3 position of
the polycyclic N-heterocycles ring increases the fluorescence
quantum yield (see 3aa vs 3ka) due to enhanced intra-
molecular charge transfer (ICT) throughout the molecule
C
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during excitation. On the other hand, the presence of −OMe
and −Cl group at C-1 and C-2 does not significantly change
their quantum yields (see 3fa vs 3ia). Interestingly, fluoro- or
chloro-substituted at the C-3 position highly conjugated
compound 3la or 3ma show a dramatic increase in its
quantum yield versus that of nonsubstituted compound 3aa.
Such changes can be understood by evoking the enhanced
ICT. In addition, compounds having n-butyl, benzyl, and allyl
substituents on the indolyl N-atom give higher fluorescence
quantum yields as compared to the methyl substituent (see
3aa, 3ba, 3ca, and 3ea). The photophysical properties are not
affected by the presence of substituted phenyl, naphthyl,
pyrenyl, or pyridine groups on the N-atom (compounds 3ac,
3as, 3at, 3au, and 3av). Furthermore, a fluorosolvatochromic
study was also carried out on the compound 3aa (see SI).
Compound 3aa exhibits a moderate fluorescence quantum
yield from 0.12 in toluene to 0.49 in DCM.
Scheme 4. Plausible Reaction Mechanism
To examine the selectivity, a fluorescence screening of
various acids has been carried out (Figure 2). Hence, 3aa as
2a generated the coupling product 4a without CoCl2 in a yield
of 53% (Scheme 4c). The studies revealed that the Michael
addition process of the aniline to the quinone in the presence
of base at first. Under the standard conditions, the reaction of
compound 4a generated the product 3aa in a yield of 82%
(Scheme 4d). We surmised that the coupling product 4a
should be a key intermediate in this reaction. Without CoCl2,
the reaction of compound 4a generated the product 3aa in just
15% yield (Scheme 4e). And the reaction of compound 4a
under N2 delivered only a trace amount of the product
(Scheme 4f). The studies demonstrated the importance of
CoCl2 and O2.
Figure 2. Changes of the fluorescence spectra of the 3aa (3 × 10−5
M) with acid.
the model compound (3.0 × 10−5 M) in dichloromethane
(DCM) interacted with 1000 equiv of different acid such as
TsOH, HF, H2CO3, AcOH, HCl, HBr, HNO3, H2SO3, and
H3PO4. While strong emission enhancement was observed for
the majority of acids tested, surprisingly nearly no fluorescence
was observed due to fluorescence quenching with the
CH3SO3H added into the solution, confirming its suitability
for the selective sensing of CH3SO3H. Furthermore, using this,
one can detect CH3SO3H selectively as it changes to a
distinctly different color (red to blue). The quantitative
analysis was carried out by fluorescence spectral titration of
3aa with the varying concentration of CH3SO3H (0−1000
equiv) in DCM (Figure 2; see SI). After our investigation of
other compounds, each compound showed a colorimetric
response upon addition of CH3SO3H in contrast to other acids
(Figure 1; see SI). The colorimetric sensors are even better, as
the signaling event can be detected by the naked eye itself.
Control experiments were conducted to clarify the cyclo-
amination reaction pathway (Scheme 4). The studies revealed
that the radical scavenger TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) did not inhibit the reaction under standard
conditions, ruling out the radical mechanism (Scheme 4a). At
room temperature for 6 h, the reaction of model compounds
1a and 2a generated the coupling product 4a in a yield of 51%
(Scheme 4b). And the reaction of model compounds 1a and
On the basis of this and previous reports,18 a possible
reaction mechanism was proposed (Scheme 4). Initially, the
Michael addition of indolylnaphthoquinone (1a) and aniline
(2a) in the presence of base gave the intermediate A, which
was immediately oxidized to intermediate 4a by O2 or the
oxidative naphthoquinone.18a On the other hand, a cobalt salt
was oxidized to a Co(III) species in the presence of O2, which
then reacted with intermediate 4a giving the Co(III) species B.
Finally, the intermediate B underwent reductive elimination
producing the desired product 3aa and regenerating Co(III)
by the oxidant (O2). Although the above-mentioned
mechanism suggests a Co(III)/Co(I) cycle, the Co(IV)/
Co(II) cycle could not be excluded.18b,c,d
In conclusion, we have successfully demonstrated Co(II)-
catalyzed cycloamination reaction between indolylquinones
and various (hetero)aromatic amines to accomplish the
polycyclic N-heterocycle molecules. The significant aspects of
our work with tolerance of chloride, bromide, amino, thio, etc.
D
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groups, including electron-donating and electron-withdrawing
groups, were compatible under the current methodology. The
synthetic compounds exhibit interesting fluorescence proper-
ties, and the selective sensing of CH3SO3H experiments was
conducted to show the application in fluorescent probes.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
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Full experimental procedures, characterization data,
photophysical properties, crystallographic data, and
NMR spectra data (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Ji-Yu Wang − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China;
orcid.org/0000-0002-0681-4836; Email: Jiyuwang@
cioc.ac.cn
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Authors
Yu Dong − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Jian Yang − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Hua Zhang − Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Xiao-Yu Zhan − Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. China;
University of Chinese Academy of Sciences, Beijing 100049, P.
R. China
Shuai He − Southwest Minzu University, Chengdu 610041, P. R.
China
Zhi-Chuan Shi − Southwest Minzu University, Chengdu
610041, P. R. China
Xiao-Mei Zhang − Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. China
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from CAS “Light of
West China” Program, Technological Innovation Program of
Chengdu, Sichuan province, China (No. 2018-YF05-00244-S)
and the Applied Basic Research Programs of Sichuan province,
China (No. 20YYJC0492).
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