Easy conjugations between molecules via copper-catalyzed reactions of ortho-aromatic diamines with ketones

Article abstract of DOI:10.1039/c3gc41585f

It is a great challenge to achieve a useful reaction under benign conditions. In this paper, a highly efficient method for copper-catalyzed conjugations of o-aromatic diamines with ketones has been developed using benign chemistry. Interestingly, the conjugation between the biological small molecules worked very well.

Full text of DOI:10.1039/c3gc41585f

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Easy conjugations between molecules via copper-
catalyzed reactions of ortho-aromatic diamines with
ketones†
Cite this: DOI: 10.1039/c3gc41585f
Received 4th August 2013,
Accepted 10th September 2013
Juyou Lu,a,b Haijun Yang,a Yunhe Jin,a Yuyang Jiangc and Hua Fu*a,c
DOI: 10.1039/c3gc41585f
www.rsc.org/greenchem
It is a great challenge to achieve a useful reaction under benign chemistry. Molecular oxygen is the ideal oxidant for its abund-
conditions. In this paper, a highly efficient method for copper- ance, low cost and lack of toxic by-products, and it has been
catalyzed conjugations of o-aromatic diamines with ketones has used in the selective transition metal-catalyzed aerobic oxi-
been developed using benign chemistry. Interestingly, the conju- dative formation of bonds.6 Recently, copper-catalyzed reac-
gation between the biological small molecules worked very well.
tions with inexpensive and low toxic copper-catalysts have
shown wide application with high tolerance of functional
groups.7 Herein, we report a highly efficient copper-catalyzed
conjugation of o-aromatic diamines with ketones under benign
conditions. It is worth noting that some biological small mole-
cules can be selectively conjugated via coupling of o-aromatic
diamines with ketones in aqueous medium.
Introduction
It is highly desirable to develop site-selective coupling or
conjugation between molecules, especially biomolecules for
chemists and biologists via a benign chemistry process. Benign
chemistry was defined as “click chemistry” by Sharpless et al.,
and it includes simple reaction conditions (insensitive to
oxygen and water), readily available starting materials and
reagents, wide scope of substrates, the use of no solvent or
environmentally friendly solvent, high selectivity, high yields,
Results and discussion
At first, copper-catalyzed conjugation of 1,2-phenylenediamine (1a)
with acetone (2a) under air leading to 2,2-dimethyl-2H-benzo[d]-
only inoffensive byproducts, and simple product isolation.1 imidazole (3a) was chosen as the model reaction to optimize
The conjugation between biomolecules was defined as
the conditions including the catalysts and solvents. As shown in
Table 1, various copper catalysts (5 mol%, relative to amount of
bioorthogonal chemistry by Bertozzi et al.2 However, it is a
great challenge to achieve a useful reaction under such benign 1a) were screened (entries 1–11) using ethanol as the solvent at
conditions. o-Aromatic diamines and ketones are common
room temperature (∼25 °C) under air, and Cu(OAc)2 showed the
chemicals, and their coupling can provide 2,2-disubstituted
highest catalytic activity (entry 7). The conjugation did not
2H-benzo[d]imidazole derivatives that have been used in work in the absence of copper-catalyst (entry 12). Various
materials3 and biological molecules.4 However, traditional
solvents were attempted, and ethanol provided the highest yield
methods for the synthesis of 2,2-disubstituted 2H-benzo[d]-
imidazole derivatives usually use large quantities of hazardous amount of product in the absence of air (entry 22). Therefore,
(compare entries 7, 13–21). The reaction provided a small
3
5
MnO2, K2MnO4 or Cu(ClO4)2 as oxidant, and a high
temperature is often required,3 so the reactions under the condi-
the copper-catalyzed optimum conditions are as follows: 5 mol%
Cu(OAc) as the catalyst, ethanol as the solvent under air at
tions are far from those of click chemistry and bioorthogonal room temperature (∼25 °C).
With the optimum reaction conditions in hand, we investi-
gated the scope of copper-catalyzed conjugations of o-aromatic
diamines with ketones. As shown in Table 2, the examined
substrates provided good to excellent yields. For ketones,
their reactivity depended on their electronic effect and steric
hindrance, the substrates with higher charge density on the
carbon of the carbonyl and bigger steric hindrance provided lower
yields. For example, 5-nonanone (3g), cyclopentadecanone (3q)
and 1-(4-nitrophenyl)-ethanone (3r) showed lower reactivity
aKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084,
P. R. China. E-mail: fuhua@mail.tsinghua.edu.cn; Fax: (+86) 10-62781695
bXi’an Modern Chemistry Research Institute, Xi’an 710065, P. R. China
cKey Laboratory of Chemical Biology (Guangdong Province), Graduate School of
Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
†Electronic supplementary information (ESI) available: Full experimental
details, characterization and NMR spectra of the target products are provided.
See DOI: 10.1039/c3gc41585f
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Table 1 Copper-catalyzed conjugation of 1,2-phenylenediamine (1a) with
acetone (2a) under air leading to 2,2-dimethyl-2H-benzo[d]imidazole (3a):
optimization of conditionsa
Table 2 Copper-catalyzed conjugations of o-aromatic diamines with ketonesa
3 (Time, yieldb)
Entry
Cat.
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
Cu2O
CuO
CuCl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
n-PrOH
i-PrOH
DMF
55
58
63
Trace
Trace
49
91
77
72
Trace
85
0
90
90
89
Cu(OAc)2
Cu(O2CCF3)2
Cu(OTf)2
Copper acetylacetonate
Copper 2-ethylhexanoate
—
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Trace
Trace
Trace
Trace
Trace
13
DMSO
THF
CH3CN
Toluene
Acetone
EtOH
15c
a Reaction conditions: under air (1 atm.), 1,2-phenylenediamine (1a)
(1 mmol), acetone (2a) (1.2 mmol), catalyst (0.05 mmol), solvent
(2 mL), reaction temperature (rt, ∼25 °C), reaction time (3 h). b Isolated
yield. c Under nitrogen atmosphere.
than other ketones. For o-aromatic diamines, the substrates
containing electron-donating groups exhibited higher reactiv-
ity than the others. The copper-catalyzed conjugations could
tolerate some functional groups including esters (3m, 3v,
3c′–e′), nitro (3r), ethers (3x–z, 3a′, 3c′–e′), C–Br bond (3b′).
Inspired by the excellent results above, we applied this
copper-catalyzed method to direct conjugation of biological
small molecules. As shown in Scheme 1, conjugation of 1,2-
phenylenediamine (1a) with ketone (4) containing a nucleo-
side provided 3f′ in 74% yield under the standard conditions.
In order to develop further application of the present
method, we prepared a new o-aromatic diamine (10) with
dipeptide. As shown in Scheme 2, reaction of 4-amino-3-nitro-
phenol with ethyl 2-bromoacetate in the presence of base
(K2CO3) provided 6 in 98% yield, and hydrolysis of 6 gave 7
(96% yield). Coupling of 7 with dipeptide (8) afforded 9 (95%
yield), and reduction of 9 led to 10 (93% yield). We attempted
conjugation of 10 with acetone (2a) in aqueous medium, and
2,2-dimethyl 2H-benzo[d]imidazole derivative (3g′) containing
dipeptide was obtained in 80% yield. Finally, treatment of the
o-aromatic diamine (10) containing a dipeptide with ketone
(4) containing a nucleoside was performed in aqueous
medium (Scheme 3), and we were very happy to get the
desired target product (3h′) containing a dipeptide and
a Reaction conditions: under air (1 atm.), o-aromatic diamine (1)
(1.0 mmol), ketone (2) (1.2 mmol), Cu(OAc)2 (0.05 mmol), EtOH
(2 mL), reaction temperature (rt, ∼25 °C), reaction time (1–48 h).
b Isolated yield.
Scheme 1 Conjugation of 1,2-phenylenediamine (1a) with ketone (4) contain-
nucleoside. The reaction showed wide tolerance of functional ing nucleoside under the standard conditions.
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Scheme 2 Synthesis of 2,2-methyl 2H-benzo[d]imidazole derivative (3g’)
containing dipeptide in aqueous medium (DIEA = N,N-diisopropylethylamine,
EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HOBt =
N-hydroxybenzotriazole).
Scheme 5 Possible mechanism for copper-catalyzed conjugations of
o-aromatic diamines with ketones.
and intramolecular addition of the ortho-amino group to
the imine in III in the presence of 1 affords IV leaving I.
Copper-catalyzed aerobic oxidation of IV provides the target
product (3).
Conclusions
In conclusion, we have developed a highly efficient copper-
catalyzed method for the conjugation of o-aromatic diamines
with ketones leading to 2,2-disubstituted 2H-benzo[d]imida-
zole derivatives. Interestingly, the conjugation between the bio-
logical small molecules worked very well. The method is of the
following advantages: (a) inexpensive Cu(OAc)2 as the catalyst;
(b) economical and environmentally friendly air as the term-
inal oxidant; (c) environmentally friendly ethanol or water as
the solvent; (d) without the addition of any acid, base or addi-
tive; (e) high reaction yields; (f) high selectivity; (g) all the reac-
tions were performed at room temperature; (h) water was the
only byproduct; (i) outstanding tolerance of functional groups;
( j) easy workup procedure. All these results meet the require-
ments of benign chemistry, so the present method will be of
widely practical application in various fields. Further investi-
gation on application of this method is in progress.
Scheme 3 Conjugation of o-aromatic diamine (10) containing dipeptide with
ketone (4) containing nucleoside in aqueous medium.
Scheme 4 Treatment of 1,2-phenylenediamine (1a) with cyclohexanone in the
absence of the copper-catalyst.
groups in biological small molecules, so the present
method that was carried out under the benign conditions
should provide a novel strategy for conjugation of biological
molecules.
In order to explore the mechanism of the copper-catalyzed
conjugation of o-aromatic diamines with ketones, a control
experiment was performed as shown in Scheme 4. Treatment
of 1,2-phenylenediamine (1a) with cyclohexanone in the
Experimental section
General procedure for copper-catalyzed conjugations of ortho-
aromatic diamines with ketones
A 25 mL flask was charged with a magnetic stirrer and ethanol
absence of copper catalyst was carried out at room temperature (2.0 mL) or water–ethanol (v/v = 10 : 1) (3.3 mL) (for 3g′ and
under air for 12 h, and no reaction occurred (3′ and 3i were
3h′), o-aromatic diamine (1) (1.0 mmol), ketone (2) (1.2 mmol)
not observed). The result showed that the copper catalyst was
and Cu(OAc)2 (0.05 mmol, 9.1 mg) were added to the flask.
involved in the formation of the intermediate 3′ under the The mixture was stirred at room temperature (∼25 °C) under
standard conditions. Therefore, a possible mechanism for
air. After the conjugation was completed (TLC determination),
the copper-catalyzed conjugation is proposed in Scheme 5.
the resulting solution was concentrated by a rotary evaporator,
First, coordination of the o-aromatic diamine with Cu(OAc)2 and the residue was purified by column chromatography on
provides complex I, and treatment of I with ketone leads
to II. Nucleophilic attack of the amino group to the carbonyl
silica gel using an eluent (petroleum ether–ethyl acetate, ethyl
acetate–methanol, ethyl acetate–ethanol or diethyl ether) to
in II and dehydration gives the imine-copper complex III, provide the desired target product (3a–h′).
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B. H. Lee, Y. Jin, S. H. Park, I. Kim, K. Lee and H. Suh,
Synth. Met., 2012, 162, 988–994.
Acknowledgements
The authors wish to thank the National Natural Science Foun- 4 (a) M. Boiani, L. Boiani, A. Denicola, S. T. de Ortiz, E. Serna,
dation of China (grant no. 21172128, 21105054, 21372139 and
21221062), and the Ministry of Science and Technology of
China (grant no. 2012CB722605) for financial support.
N. V. de Bilbao, L. Sanabria, G. Yaluff, H. Nakayama,
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