Synthesis of 1-Vinyl/Arylbenzotriazole 3-Oxides through a Copper-Mediated C–N Bond Coupling Reaction

Article abstract of DOI:10.1002/adsc.201700462

An efficient synthesis of 1-vinyl/arylbenzotriazole 3-oxides via the copper-promoted coupling of N-hydroxybenzotriazoles with alkenyl- or arylboronic acids is reported. This strategy features mild reaction conditions, good functional group tolerance, broad substrate scope and rapid introduction of benzotriazole N-oxide moieties into molecules. Density functional theory calculations revealed that the formation of the favored N-coupling product depends on the kinetically more favorable C–N bond formation pathway. (Figure presented.).

Full text of DOI:10.1002/adsc.201700462

Title: Synthesis of 1-Vinyl/Aryl Benzotriazole 3-Oxides through Copper-
Catalyzed C-N Bond Coupling Reaction
Authors: Wei-Min Shi, Feng-Ping Liu, Zhi-Xin Wang, Hong-Yan Bi, Cui
Liang, Li-Ping Xu, Gui-Fa Su, and Dong-Liang Mo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700462
Link to VoR: http://dx.doi.org/10.1002/adsc.201700462

Advanced Synthesis & Catalysis
10.1002/adsc.201700462
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of 1-Vinyl/Aryl Benzotriazole 3-Oxides through
Copper-Mediated C-N Bond Coupling Reaction
†
a
†a
a
a
a
Wei-Min Shi , Feng-Ping Liu , Zhi-Xin Wang , Hong-Yan Bi , Cui Liang , Li-Ping
b
a
a
Xu* , Gui-Fa Su* , and Dong-Liang Mo*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and
Technology of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road,
Guilin, 541004, China. E-mail: gfysglgx@163.com; moeastlight@mailbox.gxnu.edu.cn
School of Chemical Engineering, Shandong University of Technology, 266 West Xincun Road, Zibo, 255049, China.
E-mail: xulp@sdut.edu.cn
b
†
These authors contributed equally to this work
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An efficient synthesis of 1-vinyl/aryl (Scheme 1-B).[6] Consequently, the synthesis of 1-
benzotriazole 3-oxides via the copper-promoted coupling of vinyl benzotriazole 3-oxides remains challenging,
N-hydroxybenzotriazoles with alkenyl or aryl boronic acids and a general and practical strategy to access these
is reported. This strategy features mild reaction conditions, compounds is desirable.
good functional group tolerance, broad substrate scope and
rapid introduction of benzotriazole N-oxides moieties into
molecules. Density functional theory calculations revealed
that the formation of the favored N-coupling product
depends on the kinetically more favorable C−N bond
formation pathway.
A) Katritzky and coworkers, oxidation of 1-allylbezotriazole by DMD
O
O
O
N
N
N
N
N
(
DMD)
N
N
N
+
N
0 °C, 24 h
0 °C, 12 h
2
4
6%
O
28%
O
Keywords: copper-catalyzed; organoboronic acids; C−N
bond formation; benzotriazole oxides; N−O bond
compounds
B) Shi's group, N-vinylation of HOBt under metal-free conditions
N
HO2C
O
CF3
DMF, r.t, 24 h
61%
N
O N
+
N
O
N
N
Ph
OH
HOBt)
O
(
CF3
Ph
1
-Vinyl benzotriazole derivatives have a broad
[1]
C) This work, first copper-catalyzed N-vinylation of HOBt
range of biological activity
such as tubulin
R2
R1
inhibition[
1a]
[1b]
3
or anti-inflammatory properties , and
N
B(OH)2
R1
2
Cu(OAc) , pyridine
2
R
N
N 1
N
N
are extensively used as versatile synthetic
+
R2
dioxane, rt, in air
R
[2]
N
intermediates. Some studies show that N-oxide
OH
groups exhibit better bioactivity than their parent
O
[3]
heterocycles in pharmaceuticals. Thus, modification
of 1-vinyl benzotriazoles to 1-vinyl benzotriazole 3-
oxides is desirable for further applications in
pharmaceutical and medicinal chemistry. Traditional
syntheses of N-oxides involve direct oxidation of the
nitrogen with oxidants such as m-CPBA, oxone, or
Scheme 1. Strategies to prepare 1-vinyl benzotriazole 3-
oxides.
Oxidative cross-coupling has been identified as a
promising strategy for the construction of carbon-
[4]
H
2
O
2
,
but direct oxidation is not suitable for
[7]
benzotriazoles containing a vinyl bond. For example,
Katritzky and co-workers found that 1-
allylbenzotriazole was preferentially oxidized at the
C=C bond by dimethyldioxirane (DMD), giving a
heteroatom bonds. Direct N-functionalization of the
N−O bond can be used to synthesize N-oxide
derivatives, such as quinoline and pyridine N-
[8]
[9]
oxides,
and nitrones.
N-Hydroxybenzotriazole
[5]
mixture of oxidation products (Scheme 1-A). In
012, Shi and co-workers reported that 1-vinyl
benzotriazole 3-oxide could be prepared through
Michael addition of N-hydroxybenzotriazole to
oxetane under metal-free conditions at room
temperature, but only one example was reported
(HOBt) is a widely used N-O bond compound,
serving as an activating reagent in organic and
2
[10]
peptide syntheses.
In transition-metal catalyzed
reactions of N-hydroxybenzotriazole with diverse
coupling reagents, the O-atom has primarily acted as
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700462
a nucleophilic site, while the N-atom has rarely
18
19
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
1.0
1.0
1.0
dioxane Cs
dioxane Et
dioxane bipyr
2
CO
3
N
3
<5
73
59
[11]
served as a nucleophilic site. During studies on O-
[
12]
arylation of the N-O bond in our group,
we
20
3
[a]
surmised that direct coupling of the N atom in HOBt
with alkenyl boronic acids under a copper-mediated
reaction to provide N-vinyl benzotriazole oxides
would be possible (Scheme 1-C). Herein, we report
coupling strategy to synthesize 1-vinyl
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol, 3.0
equiv), Cu salts (1.0 equiv), base (10.0 equiv), solvent (2
mL), Na
Without Na SO ; Pyridine (5.0 equiv).
[
b]
[c]
2 4
SO (6 equiv), 40 °C, 18−24 h. Isolated yield;
[13]
[d]
2
4
a
benzotriazole 3-oxides in high yields and broad
substrate scope.
Initially, the direct N-vinylation by a copper
catalyst was optimized. When HOBt (1a) and alkenyl
boronic acid (2a) were added with 1.0 equiv of
Using the optimized conditions, we examined the
substrate scope of the reaction for alkenyl boronic
acids. As shown in Table 2, terminal linear and
branched alkyl-substituted, Z-disubstituted, and
cyclic alkenyl boronic acids could be converted to
products 3 in good to excellent yields. The geometry
of the alkenyl boronic acids was retained in the
products. Alkenyl boronic acids containing sensitive
chloro, ester, and ketal functional groups smoothly
underwent N-vinylation in high yields. The reaction
was compatible with cyclic alkenyl boronic acids
with five, six, and seven-membered rings, but a low
yield was obtained for the seven-membered ring
(Table 2, entries 9-14). Interestingly, 0.2 equiv of
copper also provided 3i in good yields (Table 2,
entries 1−3, 5−6, 9, and 13).The yield for some
products 3 was low because the substrate 1 could not
be consumed completely (Table 2, 3e, 3h and 3n). In
no case the O-arylation products was observed. The
structure of product 3 was confirmed by X-ray
CuSO
pyr) in 1,2-dichloroethane (DCE) at 40 °C under air,
the desired product 3a was obtained in 30% yield
Table 1, entry 1). The reaction did not occur with
CuCl or CuBr, but afforded 3a in 40% and 80%
yields with CuI and Cu O, respectively (Table 1,
entries 2-5). Product 3a was obtained 90% yield by
using Cu(OAc) as a catalyst (Table 1, entry 6). The
yield of 3a decreased to 82% without Na SO in DCE
Table 1, entry 7). Solvent screening showed that the
best result was obtained in dioxane (Table 1, entries
−13). However, the yield of 3a also dropped without
Na SO (Table 1, entry 14). The amount of Cu(OAc)
4
, Na
2
SO
4
(6.0 equiv) and 10 equiv of pyridine
(
(
2
2
2
2
4
(
8
2
4
2
and pyridine also affected the yields of 3a (Table 1,
entries 15−17). For example, the yield of 3a
decreased to 73% when the amount of Cu(OAc) was
2
[14]
reduced to 0.2 equiv. Using 5.0 equiv of pyridine
provided 3a in 82% yield. The nature of the base was
also important for the N-vinylation process (Table 1,
entries 18−20). No reaction took place when using
diffraction analysis of compound 3l (see Figure 1).
The broad scope of this coupling reaction of HOBt 1a
and alkenyl boronic acids 2 provides a good starting
point for the synthesis of other benzotriazole oxides.
Cs
2
CO , but organic bases did promote the reaction.
3
Table 2. Substrate Scope of Alkenyl Boronic Acids. [a]
The optimal reaction conditions were 1.0 equiv of
Cu(OAc) and 10 equiv of pyridine in dioxane under
an air atmosphere (Table 1, entry 13).
2
R2
R1
R1
N
Cu(OAc) , pyr
(
HO) B
2
N
N
N +
2
Table 1. Optimization of the Reaction Conditions. [a]
N
R2
dioxane, Na SO4
N
OH
2
40 °C, in air
n-Pr
O
1a
2
3
N
entry
2
R1
R2
3
yield %[b]
96 (84)[c]
89 (78)[c]
80 (60)[c]
(
HO) B
Cu salts / base
N
N
N
+
2
N
n-Pr solvent, Na SO
1
2
3
2a
2b
2c
H
H
H
n-Pr
3a
3b
Cl 3c
N
OH
2
4
4
0 °C, in air
n-Bu
O
1a
2a
3a
Entry Cu salts
Equiv Solvent Base
3a %[b]
4
2d
H
CO2Me 3d
82
65 (55)[c]
73 (52)[c]
73
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
CuSO
CuCl
CuBr
CuI
4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.5
1.0
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
toluene pyr
THF
MeCN
DMF
dioxane pyr
dioxane pyr
dioxane pyr
dioxane pyr
dioxane pyr
pyr
pyr
pyr
pyr
pyr
pyr
pyr
pyr
30
0
0
41
80
90
82
71
85
65
84
86
96
84
73
85
82
5
6
7
8
2e
2f
H
H
4-MeOC H5
3e
3f
6
4-FC H5
2
6
2g
2h
Me
Ph
Me
3g
3h
Et
37
62 (70)[c]
9
2i
2j
3i
3j
2
Cu O
1
0
O
67
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
[
c]
O
O
Ph
1
1
2k
3k
58
66
0
1
2
3
4
5
6
7
pyr
pyr
pyr
1
2
2l
3l
2m
2n
3m
3n
73 (67)[c]
32
1
1
3
4
[
[
c]
d]
[a]
Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol, 3.0
equiv), Cu(OAc)
2
(0.3 mmol, 1.0 equiv), Na
2
SO
4
(6 equiv),
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700462
pyr (3.0 mmol, 10.0 equiv), dioxane (3 mL), 40 °C, 18−24
Substrates with electron-rich groups generally gave
better yields than those with electron-deficient groups
h. [ Isolated yield; 0.2 equiv Cu(OAc)
b]
[c]
.
2
(
Table 4, entries 2–6 vs 8–10). Heteroaryl boronic
acids such as 2-thienyl and 5-indolyl boronic acids
gave the corresponding products only in moderate
yields (Table 4, entries 14–15). Interestingly, good
yields of product 5 were still obtained using a
catalytic Cu(OAc)
2
for some arylboronic acids (Table
4
, entries 3, 6, 7, 9, and 14). Lam and co-workers
reported a copper-mediated coupling reaction of
HOBt and 4-methylphenyl boronic acids and the O-
coupling product was afforded in 44% yield.
However, there was no data characterizing the O-
coupling product and they did not mention the N-
[15]
coupling products.
When we repeated the
conditions used by Lam’s group, only the N-arylation
product was obtained and the structure was confirmed
by X-ray diffraction of compound 5h (see Figure
Figure 1. Crystal structure of compound 3l.
[16]
2).
This oxidative coupling reaction can also be
applied to other N-hydroxybenzotriazoles 1. N-
Vinylation was successful for compounds with
electron-donating and electron-withdrawing groups in
the 5- and 6-positions of the aryl ring. However,
when a chloro substituent was present in the 4-
position, the yield of 3ah was reduced to 23% with
recovery of 1h. This incomplete reaction might be a
consequence of the steric hindrance in the 4-position
Table 4. Substrate Scope of Arylboronic Acids.[a]
Ar
N
Cu(OAc) , pyr
N
2
R
N
+
(HO)2B Ar
N
dioxane,Na2SO4
40 °C, in air
N
N
OH
O
1
4
5
[
b]
Entry
1
2
3
4
5
6
7
1
Ar
Ph
4-MeOC
4-PhOC
4-MeSC
4-(Me)
4-MeC
4-(CH
4-FC
4-CF
4-CHOC H4
3-MeOC
3,5-Me C H
2-naphthyl
2-thienyl
5-indolyl
Ph
5
Yield (%)
3
close to the N atom (Table 3, entry 8). 7-Aza-3-
[c]
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1e
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
77(58)
95(82)
77(92)
hydroxybenzotriazole 1i gave the desired product 3ai
[c]
6
H
4
in 57% yield (Table 3, entry 9).
[c]
6
H
4
[
c]
6
H
4
85(66)
80(18)
80(85)
49(70)
73(73)
62(66)
43(46)
80(30)
79(75)
68(65)
35(66)
61(27)
60
Table 3. Substrate Scope of N-Hydroxybenzotriazoles 1.[a]
[c]
2
6 4
NC H
5
[
[
c]
c]
n-Pr
6
H
3
4
2
=CH)C
6
H
4
4
3
5
6
N
2
5
N
[c]
c]
Cu(OAc) , pyr
8
9
10
6
H
4
R
N + (HO) B
2
2
N
2
R
[
N1
OH
n-Pr
X
7
dioxane,Na2SO4
40 °C, in air
3
6 4
C H
6
N1
O
X
[c]
[c]
7
6
1
2a
3ab-3ai
1
1
1
1
1
1
1
1
2
3
4
5
6
7
6
H
6 3
4
X = C (1a-1h), N (1i)
[
[
c]
c]
Entry
1
R
3
Yield (%)[b]
2
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
3a
95
68
77
77
80
76
89
23
57
[c]
[c]
6-MeO
6-Me
6-Cl
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
Ph
71
6-CF
3
[
a]
Reaction conditions: 1 (0.3 mmol), 4 (0.9 mmol, 3.0
equiv), Cu(OAc) (0.3 mmol, 1.0 equiv), Na SO (6 equiv),
pyr (3.0 mmol, 10.0 equiv), dioxane (3 mL), 40 °C, 18−24
6-CN
5-Me
4-Cl
H
2
2
4
[
b]
[c]
2
h; Isolated yield; 0.2 equiv Cu(OAc) .
[
a]
Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol, 3.0
equiv), Cu(OAc) (0.3 mmol, 1.0 equiv), Na SO (6 equiv),
2
2
4
pyr (3.0 mmol, 10.0 equiv), dioxane (3 mL), 40 °C, 18−24
h. [ Isolated yield.
b]
The copper-mediated coupling reaction is not only
suitable for N-vinylation, but can also be used for N-
arylation with arylboronic acids 4. These results are
summarized in Table 4. Various electron-rich and
electron-deficient groups with ortho-, meta-, and
para-substituents were efficiently arylated to afford
Figure 2. Crystal structure of compound 5h.
The O- or N-arylation mechanism via the copper-
catalyzed coupling reaction has been studied by the
1-aryl benzotriazole 3-oxides 5 in high yields.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700462
Stahl,[17] Norrby,[18] and Das[19] groups by using
density functional theory (DFT) calculations. The
Me
Me
Me
Me
O
reaction
involves
transmetallation,
binding,
O
1
) HBBr2·SMe2
Me
1
)
O
Me
N
2)
1a, Cu(OAc)2, pyr
deprotonation, oxidation, and reductive elimination
steps. A Cu (III) species was proposed as the key
intermediate in these studies. In our case, the
coupling reaction was not affected by addition of
radical trapping reagents such as TEMPO or p-
benzoquinone.[
O
N
Na2SO4, dioxane, air
N
7
8
, 71% yield
O
O
Me
H
O
Me
H
H
H
1a
2
)
H
20]
N
H
Cu(OAc) , pyr
2
N
O
N
Na2SO4, dioxane, air
(
HO)2B
9
10, 61% yield
To understand the selective N-arylation over O-
arylation of N-hydrobenzotriazole, DFT calculations
were carried out on the model reaction of HOBt 1a
with phenylboronic acid 4a. It was shown previously
Scheme 2. Applications of the N-vinylation/arylation
process.
[21]
that compounds 1a and 1a' are in equilibrium. Cu
III) intermediates IN1-O and IN1-N were formed
(
In summary, we have developed a protocol for the
with the former only 0.2 kcal/mol lower in free
energy than the latter after transmetallation, binding,
direct
N-vinylation/arylation
of
N-hydroxy
benzotriazoles with alkenyl or arylboronic acids to
prepare 1-vinyl/aryl benzotriazole 3-oxides in good to
excellent yields via the copper-mediated coupling
reaction. This reaction can be used for rapid and
efficient introduction of benzotriazole oxide group
into molecules. The reaction provides a general and
practical method to access 1-vinyl/aryl benzotriazole
[22]
deprotonation, and oxidation processes.
The
selectivity-determining reductive elimination step
proceeds through transition states TS1-O and TS1-N
I
to release the Cu (OAc)(pyr) and form products 6a
and 5a. Figure 3 shows that TS1-O is 3.0 kcal/mol
less favorable than TS1-N, making the O–arylation
pathway less likely to occur. Moreover, the formation
of a more stable N–Ph product (5a: −39.8 kcal/mol)
with respect to the O–Ph product (6a: −33.9 kcal/mol)
is a large driving force for the N-arylation process.
3-oxides.
Experimental Section
General Procedure for Synthesis of 3a: A 25 mL flask
was charged with N-hydroxybenzotriazole 1a (0.041 g, 0.3
N
N
N
2
mmol), Cu(OAc) (0.30 mmol, 1.0 equiv), anhydrous
Pyr
O
CuIII
Na SO (400 mg, 6.0 equiv) and alkenyl boronic acids 2a
2
4
N
N
N
O
Ph
(
0.103 g, 0.9 mmol) in air atmosphere, dioxane (3.0 mL)
O
N
N
Pyr
O
TS1_O
N
N
and pyridine (0.25 mL, 10.0 equiv) was added via syringe.
The reaction mixture was capped with a septum pierced
with a ventilation needle and stirred vigorously at 40 °C
for 15−26 h until substrate 1a disappeared (monitored by
CuIII
N
1
6.8 kcal/mol
N
O
Ph
1
a
OH
PhB(OH)2
O
6
a
O
Ph
4
a
IN1_O
6.5 kcal/mol
I
-33.9 kcal/mol
CuII(OAc)2(Pyr)
Cu (OAc)(Pyr)
H
N
O
2
TLC). At this time, the reaction was quenched with H O
O
N
N
N
(10 mL) and extracted with DCM (3 × 10 mL). Then, the
N
N
N
O
N
O
Pyr
2 4
organic layers were combined and dried with Na SO and
CuIII
N
1a'
Ph
5a
N
filtered. The solvent was removed under reduced pressure
and the crude product was purified by flash
chromatography (the crude residue was dry loaded with
silica gel, 1/6 to 2/1, ethyl acetate/petroleum ether) to
O
Ph
Pyr
N
O
-39.8 kcal/mol
CuIII
O
IN1_N
.7 kcal/mol
O
Ph
6
TS1_N
3.8 kcal/mol
1
provide product 3a. A white solid (0.059 g, 96%). mp:
1
9
4−95 °C; H NMR (400 MHz, CDCl
3
): δ 7.94 (d, J = 6.8
Hz, 1H), 7.62 (t, J = 7.2 Hz, 2H), 7.39 (t, J = 6.0 Hz, 1H),
Figure 3. Energy profiles for the formation steps of the N–
6
.92 (d, J = 14.0 Hz, 1H), 6.38−6.31 (m, 1H), 2.22 (q, J =
.8 Hz, 2H), 1.54−1.49 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H);
[
23]
Ph and O–Ph products.
6
13
3
C NMR (100 MHz, CDCl ): δ 132.1, 130.7, 130.5, 124.6,
1
3
(
22.7, 120.3, 115.7, 110.5, 31.8, 22.3, 13.5; IR (thin film)
−1
073, 2956, 1601, 1496, 1424, 1378, 730 cm ; HRMS
Finally, we illustrated the utility of this new
protocol for rapid introduction of the benzotriazole
oxide group into more complex molecules. Treatment
+
14 3
ESI) m/z calcd for C11H N O(M+H) 204.1137, found
204.1127.
of alkyne 7 with HBBr
2
·SMe
2
and subsequent
Acknowledgements
reaction with 1a under copper-mediated conditions
afforded the N-vinylation product 8 in 71% yield
Financial support from the “Overseas 100 Talents Program” of
Guangxi Higher Education, National Natural Science
Foundation of China (21562005, 21602037, 21462008), and
Natural Science Foundation of Guangxi (2016GXNSFFA380005)
are greatly appreciated. L. Xu acknowledges PKUSZ for
computational resources and Prof. Xinhao Zhang and Prof. Olaf
Wiest for helpful discussions and manuscript proofreading.
(
Scheme 2-1). Estrone-derived boronic acid 9 reacted
with 1a to provide the desired product 10 in 61%
yield (Scheme 2-2). These results show that further
applications of this method in the synthesis of
bioactive compounds are feasible.
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4
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Advanced Synthesis & Catalysis
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5
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COMMUNICATION
Synthesis of 1-Vinyl/Aryl Benzotriazole 3-Oxides
though Copper-Catalyzed C-N Bond Coupling
Reaction
Adv. Synth. Catal. Year, Volume, Page – Page
†
a
†a
a
Wei-Min Shi , Feng-Ping Liu , Zhi-Xin Wang ,
a
a
b
Hong-Yan Bi , Cui Liang , Li-Ping Xu* , Gui-Fa
a
a
Su* , and Dong-Liang Mo*
6
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