Aryl C-H amination initiated by laccase-mediated oxidation of 4-phenylurazole

Article abstract of DOI:10.1039/c9cy00968j

A mild amination of aryl C-H has been developed using laccase as a green and sustainable catalyst, aerial O₂ as the oxidant, with water being the only by-product. Various aromatic compounds including anilines, naphthols, quinolines and substituted benzenes can be aminated with 4-phenylurazole in yields up to 93%.

Full text of DOI:10.1039/c9cy00968j

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CP al et aa lsy es i ds oS c ni eo nt c ae d &j uTs et c mh na or gl oi ng sy
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DOI: 10.1039/C9CY00968J
COMMUNICATION
Aryl C-H amination initiated by laccase-mediated oxidation of 4-
phenylurazole
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Jue Chen, Guo-Yan Zhang, Yan-Hong He*, Zhi Guan*
DOI: 10.1039/x0xx00000x
A mild amination of aryl C-H has been developed using laccase as active compounds and crucial intermediates in synthetic
9
a green and sustainable catalyst, aerial O
2
as the oxidant, with chemistry. The amination reaction initiated by laccase
water being the only by-product. Various aromatic compounds oxidation has always been the focus of chemists, and these
1
0
including anilines, naphthols, quinolines and substituted benzenes substrates are currently almost benzenediols.
can be aminated with 4-phenylurazole in yields up to 93%. 4-phenylurazole is a valuable moiety in agromedical and
1
1
pharmaceutical chemistry, and can be found in a wide range
As an important class of biocatalysts, enzymes can catalyze of biologically active substances, such as antibacterial and
1
1a
11b
different organic reactions to construct carbon-carbon bonds antifungal agents, insecticide for Spodoptera frugiperda,
1
11c
or carbon-hetero bonds under mild reaction conditions.
Laccases (EC 1.10.3.2) belong to blue multi-copper oxidases, and Semliki Forest virus,
which are widely distributed in nature, found in many plants, (Figure 1). Thus, 4-phenylurazole moiety has attracted
hepatitis C virus (HCV) inhibitor, inhibitor of Sindbis virus
1
1d
and antineoplastic agent11e etc.
2
12
fungi, and microorganisms. The typical reaction of laccases is increasing attention from medicinal and synthetic chemists.
the oxidation of phenols and similar aromatic compounds by In view of the advantages of laccase catalysis, we envisaged to
one-electron oxidation with the concurrent reduction of O
2
to use laccase as a clean and mild oxidant to oxidize 4-
3
water (using O
2
as the oxidant to regenerate laccases). Thus, phenylurazole to an electrophilic nitrogen compound, resulting
water is the only by-product of the entire laccase-catalytic in polarity reversal of the N atoms at the 1- and 2-positions.
process. Laccases are generally stable and inexpensive, and are The electrophilic substitution of an electron-rich aromatic ring
widely used in various fields of industry, such as the paper, with N accomplishes one-pot amination of the aromatic C-H
textile and bio-energy industries, as green polyphenol bond. To our delight, the reaction can be achieved as
4
oxidases. Due to these fascinating properties of laccases, the expected, and in this way, the C-H bonds of various aromatic
5
study of their catalytic mechanism has never been stopped. In compounds can be aminated with 4-phenylurazole. Herein, we
recent years, the range of substrates for laccase oxidation has report this novel aryl C-H amination initiated by laccase-
6
not been limited to phenols and similar aromatic compounds.
Functionalization of aromatic C-H bonds is an important tool
for the construction of drugs and natural products, and is of
mediated oxidation of 4-phenylurazole.
O
Cl
7
HN
N
N
great significance in the field of organic synthesis. Therefore,
O
F3C
S
N
8
there are many reports on this aspect. Nevertheless, there are
O
still many problems to be solved in practical applications, such
as noble metal catalysts, complex ligands and heavy metal
residues. It is extremely difficult to remove metal
contaminants in pharmaceutical production. Therefore, green
method for functionalization of aromatic C-H bonds remains a
challenge and is imperative for research and application. On
the other hand, by introducing nitrogen atom, the C-H
amination reaction can construct some elegant biologically
F
N
O
O
insecticide for Spodoptera frugiperda
N
O
N
N
O
HO
AcO
O
N
H
H
hepatitis C virus (HCV) inhibitor
O
N
O
N
H
O
N
N
HN
AcO
inhibitor of Sindbis virus and Semliki Forest virus
O
antineoplastic agent
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China
Figure 1. Bioactive molecules containing 4-phenyl-1,2,4-triazolidine-3,5-dione moiety
E-mails: heyh@swu.edu.cn (for Y.-H. He); guanzhi@swu.edu.cn (for Z. Guan)
Electronic Supplementary Information (ESI) available: [details of any
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Journal Name
A commercially available laccase (Novozym 51003) was used
in this study. This enzyme was purified from Myceliophthora
which is produced by genetically modified Aspergillus oryzae.
Initially, the reaction between an equimolar amount of N,N-
dimethylaniline (1a) and 4-phenylurazole (2) was selected as
the model reaction, which was catalyzed by laccase in 1:1 (v/v)
of EtOH/PBS (phosphate buffer saline solution, 0.2 M, pH 5.02)
under air (air balloon) for 10 h. Excitingly, it was found that the
reaction proceeded smoothly to afford products 3a and 4a
with yields of 34% and 12%, respectively (Scheme 1). In order
to explore the reaction mechanism, some control experiments
were conducted. In the absence of laccase, no reaction was
observed (Scheme 2), demonstrating that laccase is essential
for the reaction. Furthermore, we found that 3a can react with
O2
H2O
View Article Online
DOI: 10.1039/C9CY00968J
N
N
Laccase(red)
O
O
Laccase(ox)
O
HN
HN
N
1a
N
N
O
N
N
HN
N
O
O
3a
2
I
O2
Laccase(ox)
Laccase(red)
H2O
N
N
O
O
N
N
N
N
N
N
1
a
O
O
N
N
II
4a
1
a in the presence of laccase to give product 4a, indicating
Scheme 3. Plausible mechanism
that 4a is derived from further reaction of laccase-catalyzed 3a
and 1a (Scheme 2).
Based on the proposed mechanism, we investigated
whether the molar ratio of the substances can affect the
selectivity of the reaction. From Table 1, we can see that the
reaction between an equimolar amount of 1a and 2 gave the
products 3a and 4a in yields of 34% and 12%, respectively
O
N
O
O
N
O
N
O
HN
HN
laccase, air
N
+
N
N
+
N
NH
EtOH/PBS (pH 5.02) = 1:1 (2 mL)
O
(Table 1, entry 1). When 1a was excessive, two products were
N
N
N
also obtained at the same time. (Table 1, entry 2). However,
when 2 was excessive (molar ratio 1a:2 = 1:2), only product 3a
was isolated in 48% yield, and the product 4a was only
observed on TLC (Table 1, entry 3). We speculate that this may
be because excess substrate 2 can competitively inhibit the
oxidation of product 3a (3a can also be oxidized by laccase and
further reacts with 1a to form 4a), thereby avoiding further
reaction of 3a. Thus, by adjusting the molar ratio of substrates,
we can successfully regulate the selectivity of the reaction.
Therefore, 1a:2 = 1:2 was selected as the optimal molar ratio
of substrates for the reaction.
1
a
2
3a
4a
0
.3 mmol
0.3 mmol
34%
12%
Scheme 1. Preliminary experiment of model reaction
O
N
without laccase, air
EtOH/PBS (pH 5.02) = 1:1 (2 mL)
HN
HN
+
N
NR
O
1a
2
0.2 mmol
0.2 mmol
N
N
N
O
N
O
O
N
laccase, air
EtOH/PBS (pH 5.02) = 1:1 (2 mL)
N
N
N
+
N
HN
a
Table 1. Screening of substrate molar ratio
O
1a
3a
4a
0.2 mmol
0.2 mmol
23%
O
N
O
O
O
O
Scheme 2. Control experiments
N
HN
N
N
HN
HN
PBS/EtOH = 1:1 (2 mL)
laccase, air
N
+
N
+
O
Since 1a and 2 can be used as nucleophiles in many
reactions, we performed cyclic voltammetry (CV) experiments
on these two substrates to find out which one could be first
oxidized by laccase. The results showed that 1a is more
difficult to be oxidized than 2 (the potential difference
between the two substances is 0.13 V, see the Supporting
Information (SI), Figure S1 and Figure S2). In addition, we also
conducted a CV experiment on product 3a and found that 3a
has a lower oxidation potential (SI, Figure S3) than 1a,
indicating that 3a is more susceptible to oxidation than 1a.
This result can explain the generation of 4a in the control
experiment (3a can be oxidized by laccase and further reacts
with 1a to form 4a) (Scheme 2).
N
N
N
1a
2
3a
4a
Yield 3a (%) b
Yield 4a (%) b
Entry
1a (mmol)
0.3
2 (mmol)
0.3
0.3
1
2
3
34
44
48
12
26
0.6
0.3
0.6
Trace
a
Reaction conditions: 1a, 2, PBS (0.2 M, pH 5.02)/EtOH (1:1, 2.0 mL),
laccase (1 mL, 1123.5 LAMU, One LAMU (Laccase unit) is defined as the
amount of enzyme which oxidizes 1 mmol syringaldazine per minute at pH
o
o
b
7
.5 at 30 C), air balloon, 30 C, 6 h. Isolated yield.
Next, the effect of solvent on the yield of 3a was
On the basis of previous literatures and control experiments,
a possible mechanism was proposed (Scheme 3). In the
presence of oxygen, 2 is oxidized by laccase to intermediate I,
which acts as an electrophile to undergo aromatic electrophilic
substitution with 1a to afford the corresponding product 3a.
Next, a portion of 3a continues to be oxidized by laccase to
intermediate II, which can further react with 1a to give
another product 4a.
investigated. From the data listed in Table 2, it can be seen
that the reaction did not proceed smoothly when DMF, DMSO,
MeCN, and HFIP (Hexafluoroisopropanol) were used (Table 2,
entries 1-4). The reaction can afford moderate yields when
deionized water, PBS (0.2 M, pH = 5.02) and acetic acid buffer
solution (pH = 5.5) were respectively used as reaction solvents
(Table 2, entries 6-8). It was exciting to found that using 3 mL
2
| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
of laccase solution without adding additional solvent can give
a in 78% yield (Table 2, entry 10).
Laccase
solution (mL)
Activity of
laccase (LAMU)
1123.5
Yield 3a
DOI: 10.1039/(C%9)CY00968J
View Article Online
Entry
pH
b
3
1
2
3
4
1
2
3
4
1
5.98
54
60
78
93
31
Table 2. Solvent screening a
2247.0
3370.5
4494.0
1123.5
6.15
6.32
6.80
5.98
c
5
O
N
O
O
N
HN
a
o
HN
laccase, air
solvent
N
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Laccase, air balloon, 30 C, 6
+
N
HN
h. b Isolated yield. C 12 h.
O
N
1
a
2
3a
With the optimized conditions in hand, the substrate scope
of the reaction was explored and the results are listed in Table
4. A variety of aromatic compounds 1 could react smoothly
with urazole 2 under the standard conditions to furnish the
corresponding amination products in yields from 11% to 93%
although a few substrates required a small amount of ethanol
to increase solubility. It was found that the bromo, methyl and
methoxyl-substituted N,N-dimethylanilines exhibited good
compatibility to the reaction (Table 4, 3b-d). N,N-disubstituted
anilines bearing other substituents on N atom (such as ethyl,
benzyl and phenyl) could also participate in the reaction to
give the corresponding amination products (Table 4, 3e-h).
Among them, N-methyl-N-phenylaniline gave the product only
in a low yield of 14% (Table 4, 3h), probably due to the
conjugation effect of the substituted phenyl group, which
Laccase
Yield
3a (%)
Entry
Solvent (2 mL)
b
solution (mL)
1
2
3
4
5
6
7
8
9
MeCN
HFIP
DMSO
DMF
1
1
1
1
1
1
1
1
-
-
-
-
18
58
55
41
48
78
EtOH
H
2
O
PBS (pH = 5.02)
Acetate buffer (pH = 5.5)
PBS (pH = 5.02):EtOH = 1:1
--
1
1
0
3 (pH = 6.32)
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), solvent, laccase, air
o
b
balloon, 30 C, 6 h. Isolated yield.
The influence of laccase loading on the reaction was then weakens the nucleophilicity of the benzene ring. Then, various
examined (Table 3). The experimental results showed that the substituted naphthols were tested and it was found that their
yield of 3a increased significantly as the laccase loading compatibility with the reaction were very good. The
increased from 1 mL to 4 mL. When the laccase loading was unsubstituted 2-naphthol showed good reactivity, giving 3i in
increased to 4 mL (4494.0 LAMU), the yield of 3a reached 93% an excellent yield of 92% (Table 4, 3i). The reactions of series
within 6 h (Table 3, entry 4). We tried to improve the reaction of 6- or 7-substituted 2-naphthols also produced
by using less amount of enzyme and extending the reaction corresponding products in moderate to satisfactory yields
time, but the results showed that when 1 mL of laccase was (Table 4, 3j-n). However, 7-hydroxyquinolin exhibited poor
used, prolonging the reaction time from 6 h to 12 h resulted in reactivity giving 3o in a low yield of 11%, probably due to the
a decreased yield of 3a from 54% to 31% (Table 3, entry 5). weak nucleophilicity of the quinoline ring. Finally, the reaction
This may be due to the increase in oxidation of product 3a by was also applicable to electron-rich 1,3,5-trimethoxybenzene,
laccase over time (some complicated by-products were giving 3p in 29% yield. All products obtained, except 3a, 3i and
observed). Therefore, 4 mL of laccase was chosen as the 3p, are new compounds.
optimal enzyme loading to obtain a good yield within a
relatively short reaction time. Besides, we measured the pH of
the reactions with different laccase loading. The results
showed that as the laccase loading increases, the pH of the
reaction system is closer to neutral. When the amount of
laccase was increased from 1 mL to 4 mL, the pH of the
reaction system increased by 0.82 (Table 3, entries 1-4). The
pH of the laccase solution we used was 7.5, so we speculated
that the acidity of the reaction systems was caused by the
acidity of the substrate 2.
Table 3. Influence of laccase loading on the model reaction a
O
N
O
O
N
HN
N
HN
HN
laccase, air
+
N
O
N
1a
2
3a
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J. Name., 2013, 00, 1-3 | 3
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Table 4. Substrate scope a
Experimental section
View Article Online
DOI: 10.1039/C9CY00968J
General procedure for the synthesis of compound 3
R1
O
R2
O
X
A round-bottom flask was charged with the laccase solution (4
mL, 4494 LAMU), an aromatic compound 1 (0.3 mmol) and 4-
phenyl-1,2,4-triazolidine-3,5-dione 2 (0.6 mmol). The resultant
N
X = C, N
R1
R2
HN
HN
laccase, air
HN
O
or
+
N
X
N
O
X = C, N
1
2
3
o
mixture was stirred at 30 C under air (with an air balloon). The
N
N
N
N
N
reaction was monitored by TLC and terminated by extraction
with ethyl acetate. The organic layer was concentrated in
vacuo. The residue was purified by flash column
chromatography (ethyl acetate : petroleum ether = 1:1) to give
the product 3.
HN
N
HN
O
N
Br
HN
N
HN
N
O
HN
N
O
O
O
O
O
O
N
N
O
N
O
N
O
N
3bb 68%, 24 h
3cb 40%, 24 h
3db 79%, 18 h
3a 93%, 6h
3e 43%, 24 h
N
N
Br
N
Conflicts of interest
There are no conflicts to declare.
HO
HO
N
O
HN
N
HN
N
N
O
HN
HN
N
HN
O
O
N
O
N
O
N
O
N
O
N
O
O
Acknowledgements
jb 71%, 6 h
3f 23%, 24 h
3g 47%, 25 h
3h 14%, 25 h
3i 92%, 5.5 h
3
This work was financially supported by the National Natural
Science Foundation of China (No. 21672174).
COOMe
CN
HO
Br
HO
O
HO
HO
N
N
N
N
N
O
O
O
O
HN
O
HN
HN
O
HN
O
N
N
N
O
Notes and references
3
kb 75%, 5.5 h
3l 81%, 5 h
3m 88%, 6 h
3n 38%, 24 h
1
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MeO
MeO
OMe
NH
HO
N
O
1
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HN
O
N
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N
O
N
O
3o 11%, 24 h
3pc 29%, 23 h
a
Unless otherwise noted, reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol) and
laccase solution (4 mL, 4494 LAMU) under air conditions at 30 C. Yield refers to
the isolated yield. Addition of EtOH (0.7 mL). Addition of EtOH (0.3 mL).
o
b
c
2
3
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laccase-induced oxidation of 4-phenylurazole. Laccase
selectively oxidizes inexpensive and readily available 4-phenyl-
2
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,2,4-triazolidine-3,5-dione (2) rather than anilines into the 10
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and 2-positions. Electrophilic substitution of an aromatic ring
with N as an electrophile achieves the one-pot amination of
the aromatic C-H bond. By this method, the C-H bond of
various aromatic compounds such as anilines, naphthols,
quinolines and substituted benzenes can be directly aminated
with yields of up to 93%. The reaction is mild, environmentally
friendly, simple to operate, and free of any additives. We
believe that this novel approach provides a green alternative
to amination of aromatic C-H bonds. Laccase has been a focus
of extensive research for many years, and this work adds a
novel example to laccase-mediated organic reactions.
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| J. Name., 2012, 00, 1-3
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Catalysis Science & Technology
Page 6 of 6
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DOI: 10.1039/C9CY00968J
R1
O
R2
O
X
N
X = C, N
R1
R2
HN
HN
Laccase
air
HN
O
or
+
N
X
N
X = C, N
O
·
transition-metal free, additive free · O
2
as only sacrificial reagent
· 17 examples, up to 93% yield
A mild amination of aryl C-H initiated by laccase-mediated oxidation of
-phenylurazole is described.
4