Silver(I)-Catalyzed Regioselective Synthesis of Triazole Fused-1,5-Benzoxazocinones

Article abstract of DOI:10.1021/acs.orglett.7b00907

An efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained fro

Full text of DOI:10.1021/acs.orglett.7b00907

Letter
pubs.acs.org/OrgLett
Silver(I)-Catalyzed Regioselective Synthesis of Triazole Fused-1,5-
Benzoxazocinones
†
†
,†,§
Indrajeet J. Barve, Tushar Ulhas Thikekar, and Chung-Ming Sun*
†
Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan
§
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan first Road, Kaohsiung 807-08,
Taiwan
*
S Supporting Information
ABSTRACT: An efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones through intramolecular
cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was
obtained from substituted 2-azido benzoic acid esters in a single step through a Copper-Catalyzed Azide−Alkyne Cycloaddition
(
CuAAC) reaction using a CuI/NBS catalytic system. A carbon−carbon triple bond was installed through a Sonogashira coupling
reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were cyclized by a AgOTf-
mediated intramolecular cyclization to afford 8-endo-dig 1,2,3-triazole-fused-1,5-benzoxazocinones exclusively.
ecently, triazole-fused polycyclic heterocycles have gained
The regular CuAAC reactions are limited to the synthesis of
only 1,4-disubstituted 1,2,3-triazoles. In this regard, 5-iodo-1,-
2,3-triazole is a useful synthetic precursor since its iodine atom
can undergo further transformation into various functional
groups to give corresponding trisubstituted triazoles, thereby
diversification and functionalization of the 1,2,3-triazole
R
much attention owing to their broad spectrum of
1
bioactivities; 1,2,3-triazoles particularly fused with heterocycles
at the 1,5-positions such as triazolo 1,5-benzodiazepin-2-one A
2
were reported to inhibit serine protease. Triazolo-benzox-
azepine B exhibits promising anticancer activity against multiple
3
cancer cell lines, whereas [1,2,3]-triazolo[1,5-a][1,4]benzo-
11
pharmacophore can be achieved.
diazepine C shows antimicrobial effects as well as potent
Intramolecular addition reaction of carboxylic acids to
proximate carbon−carbon triple bonds offers an efficient
route to the construction of oxygen-containing functionalized
anticancer activity against the A549 lung adenocarcinoma
4
cancer cell line (Figure 1). In recent years, several synthetic
12
heterocycles (Figure 2). According to Baldwin’s rules, both
exo-dig and endo-dig cyclizations are possible. Hence, much
attention has been focused toward the selective cyclization of
13
an enyne carboxylic acid system. We herein report a
Figure 1. Biologically active 1,2,3-triazole-fused heterocycles.
strategies have been reported for the synthesis of annulated
1
tifs.
,2,3-triazoles at 1,5-positions with other heterocyclic mo-
5
−10
However, a synthetic approach to access 1,2,3-triazole-
1b,3
fused benzoxazocinones is less explored.
Therefore, the
Figure 2. Endo-dig and exo-dig cyclization mode of enyne carboxylic
acid system.
development of a new and efficient synthetic method is greatly
needed to construct novel triazole-fused heterocycles. The
biological significance of fused 1,2,3-triazoles prompted us to
develop a simple protocol comprising minimum steps for the
preparation of 1,2,3-triazole fused benzoxazocinones.
Received: March 27, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00907
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions for Intramolecular Cyclization of Acid 1
b
entry
catalyst (mol %)
base
additive
solvent
temp (°C)
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
PTSA (10)
pyridine
−
−
−
−
−
−
−
−
−
−
−
−
−
PPh3
PPh3
−
CHCl3
−
reflux
100
16
N.R.
N.R.
N.R.
2a
0
−
−
−
−
−
16
0
DBU (10)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
reflux
100
16
0
c
DBU (100)
AgOTf (10)
AgOTf (20)
AgOTf (50)
AgOTf (100)
AgOTf (10)
0.34
16
trace
10
30
50
reflux
reflux
reflux
100
2a
16
2a
K CO
2
16
2a
3
3
c
K CO
2
0.34
0.34
16
2a
85
NaOH
100
2a
32
0
10
11
12
13
14
15
16
AgSbF (10)
−
K CO
2
reflux
reflux
reflux
100
N.R.
N.R.
N.R.
2a
6
AuCl (10)
CH CN
16
0
3
3
3
3
AuCl (10)
K CO
2
CH CN
16
0
3
3
AgOTf (10)
K CO
2
CHCl3
CHCl3
CHCl3
toluene
0.34
0.34
0.34
0.25
48
trace
20
AuCl/AgOTf (5)
Ag CO (20)
−
−
K CO
2
100
2a
100
2a
2
3
c
AgOTf (10)
−
130
2a
87
3
a
b
c
Reaction conditions: 1 (0.27 mmol), AgOTf (10 mol %), K CO (2 equiv), solvent (2 mL). N.R. = No Reaction. Isolated yield. Microwave
2
3
irradiation.
regioselective synthesis of novel 1,2,3-triazole benzoxazoci-
nones from substituted anthranilic acids. The key step of this
strategy includes preparation of a crucial intermediate 5-iodo-
transannular nonbonded interactions within the ring. This
preliminary discovery motivated us to improve the yield of
cyclized compound 2a. Accordingly, an increase in the catalyst
loading of AgOTf up to 20 mol %, yielded 2a in only 30% yield
(Table 1, entry 6). When acid 1 was treated with AgOTf and
1
,2,3-triazole benzoate by the CuI/NBS catalytic system and
regioselective intramolecular cyclization under the influence of
Lewis acid (AgOTf), respectively.
K CO3 in refluxing chloroform, the isolated yield of the
2
The required precursor acids 1 were prepared by
modification of the reported procedure (see Supporting
Information). With the key intermediate acid 1 in hand, we
next studied the intramolecular cyclization using a variety of
catalysts, and the results are summarized in Table 1. Our
attempted cyclization of acid 1 under the influence of PTSA,
pyridine, or DBU was unsuccessful, and only starting material 1
was recovered (Table 1, entries 1−4). When acid 1 was
subjected for cyclization in the presence of 10 mol % of AgOTf
in refluxing chloroform for 16 h, a pale yellow solid was
obtained in 10% yield with the recovery of acid 1 (Table 1,
entry 5). The structure of the isolated solid was identified as
compound 2a increased up to 50% (Table 1, entry 7); a further
increase in the quantity of AgOTf and K CO up to 100 mol %
2
3
did not improve the yield. When the cyclization of 1 was carried
out with AgOTf (100 mol %) and K CO (2 equiv) in
2
3
chloroform under microwave irradiation at 100 °C for 20 min,
an 85% conversion of starting material 1 into 8-endo-dig
cyclized product 2a was achieved (Table 1, entry 8). Even
though desired compound 2a was obtained in an excellent
yield, a stoichiometric amount of AgOTf is required. Hence,
effort toward the conversion of acid 1 into cyclized compound
2a under the influence of a catalytic amount of silver or gold
salt was carried out. Employment of a combination of strong
base NaOH and AgOTf for cyclization of 1 under microwave
irradiation resulted in cyclized product 2a in only 32% yield
(
Z)-3,5-diphenyl-7H-benzo[c][1,2,3]triazolo[1,5-e][1,5]-
oxazocin-7-one 2a. Its structure was confirmed by X-ray
crystallographic analysis (Figure 3).
(
Table 1, entry 9). The use of AgSbF in chloroform under
6
The ORTEP diagram of 2a revealed that the double bond
reflux conditions resulted in zero conversion (Table 1, entry
0). Surprisingly, the excellent carbophilic gold salts such as
AuCl and AuCl with a combination of K CO in acetonitrile
2
and sp carbon atom of the carboxylic group forces the eight-
1
member ring to adopt a boat conformation having minimum
3
2
3
by either conventional heating or microwave irradiation failed
to yield compound 2a (Table 1, entries 11−12). Utilization of
PPh as an additive in combination with a catalytic amount of
3
AgOTf and K CO under microwave conditions afforded 2a in
2
3
moderate yield (Table 1, entry 13). Similarly, combining AuCl
with cocatalyst AgOTf and additive PPh yielded compound 2a
3
in a trace amount (Table 1, entry 14). Furthermore, only 20%
of product 2a was obtained when Ag CO was employed alone
2
3
(
Table 1, entry 15). Finally, the use of 10 mol % of AgOTf in
Figure 3. ORTEP diagram of compound 2a.
the presence of K CO (2 equiv) in toluene under microwave
2
3
B
DOI: 10.1021/acs.orglett.7b00907
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
irradiation afforded cyclized compound 2a in excellent yield
Subsequent anti-endo-dig intramolecular nucleophilic attack by
a carboxylate anion on Ag(I)-alkyne complex A forms B.
Consequent protonolysis of the C−Ag bond of B produces 8-
endo-dig product 2 with regeneration of AgOTf. The formation
of highly regioselective 8-endo-dig intermediate B can be
rationalized through the polarization effect exerted by the
electron-withdrawing moieties present at the carbon of the
(Table 1, entry 16).
To investigate the scope of this protocol, a variety of
substituted acids 1 were prepared from substituted anthranilic
acids S1 and alkynes S4. The corresponding 8-endo-dig
products 2 were obtained in excellent yields and the current
protocol works well with aliphatic alkynes as well as with
aromatic alkynes having electron-donating and -withdrawing
groups on the phenyl ring (Scheme 1).
14,15
alkyne (Figure 4).
In this case, electron-deficient triazole-
Scheme 1. Substrate Scope for the Synthesis of 1,2,3-
a
Triazole-Fused-1,5,-Benzoxazocinones 2
Figure 4. Endo-dig intramolecular nucleophilic addition via triazole-
mediated polarization of alkyne.
mediated polarization of the alkyne increases the electro-
philicity of the terminal carbon atom of the alkyne which
facilitates endo-dig nucleophilic addition of the carboxylate
anion to afford 8-endo-dig products 2.
In conclusion, we have developed a synthetic protocol for the
synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones 2
via a regioselective intramolecular cyclization of substituted
ethynyl triazoyl benzoic acids 1. The salient feature of this
protocol involves the one-pot synthesis of crucial precursor 5-
iodo-1,2,3-triazole benzoates S5 from substituted 2-azido
benzoic acid esters S3 using the CuI/NBS catalytic system.
The 5-iodo-1,2,3-triazole benzoates S5 were further function-
alized by a carbon−carbon triple bond through Sonogashira
coupling with various terminal alkynes. Finally, the 1,4,5-
substituted-1,2,3-triazole benzoic acids 1 were subjected to an
intramolecular cyclization using AgOTf/K CO to afford
a
Reaction conditions: 1 (0.27 mmol), AgOTf (10 mol %), K CO (2
2
3
equiv), solvent (2 mL).
2
3
exclusively 8-endo-dig 1,2,3-triazole fused benzoxazocinones 2
in excellent yields.
It is interesting to note that, in all cases, only 8-endo-dig
cyclized products 2 were obtained. The structures of the
products 2b−t were confirmed by the two signals at 6−6.5 and
ASSOCIATED CONTENT
Supporting Information
■
S
1
13
*
∼
100 ppm respectively in the H and C NMR spectra.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00907.
The results suggested that activation of a C−C triple bond
and the subsequent intramolecular addition of carboxylic acid
were highly regioselective. In order to rationalize the
regioselectivity in the cyclization of acid 1, we propose a
plausible mechanism in Scheme 2. In the first step, carbophilic
AgOTf coordinates with the triple bond of acid 1, which results
in the enhancement of the electrophilicity of the alkyne.
Experimental procedures, characterization data, spectral
data, and X-ray data for compound 2a (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*
Scheme 2. A Plausible Mechanism for AgOTf/K CO
Catalyzed Intramolecular Cyclization of Acid 1
2
3
E-mail: cmsun@mail.nctu.edu.tw.
ORCID
Chung-Ming Sun: 0000-0002-1804-1578
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Ministry of Science and Technology
MOST) of Taiwan for financial assistance and the authorities
■
(
of the National Chiao Tung University for providing the
laboratory facilities.
C
DOI: 10.1021/acs.orglett.7b00907
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.7b00907
Org. Lett. XXXX, XXX, XXX−XXX