Synthesis of 1,2,4-Benzotriazines via Copper(I) Iodide/1 H -Pyrrole-2-carboxylic Acid Catalyzed Coupling of o -Haloacetanilides and N -Boc Hydrazine

Article abstract of DOI:10.1055/s-0034-1378708

Coupling of o-haloacetanilides and N-Boc hydrazine proceeded at room temperature under the catalysis of CuI/1H-pyrrole-2-carboxylic acid. The coupling products underwent oxidation to afford the azo compounds, which were subjected to deprotection with TFA

Full text of DOI:10.1055/s-0034-1378708

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1586–1590
letter
1586
Y. Zhou et al.
Letter
Synlett
Synthesis of 1,2,4-Benzotriazines via Copper(I) Iodide/1H-Pyrrole-
2-carboxylic Acid Catalyzed Coupling of o-Haloacetanilides and
N-Boc Hydrazine
Yijun Zhoua
H
NH2NHBoc
CuI, ligand
NHCOR
N
R
N
R
Zhigao Zhangb
Yongwen Jiangb
Xianhua Pan*a
Dawei Ma*b
TFA
then O2
20–86%
CH2Cl2
86–95%
N
O
Y
X
Y
N
Y
N
NBoc
X = I, Br
a School of Perfume and Aroma Technology, Shanghai Institute of
Technology, No. 120 Cao Bao Road, Shanghai 200235, P. R. of China
b State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
madw@mail.sioc.ac.cn
O–
N+
N
Received: 06.03.2015
Accepted after revision: 07.05.2015
Published online: 08.06.2015
DOI: 10.1055/s-0034-1378708; Art ID: st-2015-b0153-l
Et
N+
O–
N
Abstract Coupling of o-haloacetanilides and N-Boc hydrazine pro-
ceeded at room temperature under the catalysis of CuI/1H-pyrrole-2-
carboxylic acid. The coupling products underwent oxidation to afford
the azo compounds, which were subjected to deprotection with TFA
and in situ cyclization to give 1,2,4-benzotriazines.
H
Cl
1
N
O
N
N
Cl
N
N
H
Key words coupling, cyclization, copper, catalysis, 1,2,4-benzotri-
azine
2
CONH2
NMe2
NH2
N
The 1,2,4-benzotriazine and its analogues are an im-
portant class of pharmaceutical heterocycles that display a
wide range of biological properties. Recent examples in-
clude 1,2,4-benzotriazine 1,4-dioxide 1 that acts as hypoxia
selective cytotoxin,1 3-amino-substituted 1,2,4-benzotri-
azine 2 that possesses significant antitumor activity by in-
hibiting Src kinase,2 PARP inhibitor 3,3 microbiocide 4,4 so-
dium-glucose co-transporter 2 (SGLT2) inhibitor 5 that has
been used for prevention and treatment of metabolic disor-
ders,5 as well as selective A3 adenosine receptor antagonist
6 (Figure 1).6 In addition, compounds with 1,2,4-benzotri-
azine core structure have been utilized as fluorescent
brighteners,7 herbicides,8 and dyes.9
N
N
O
N
N
3
N
4
OH
OH
OH
O
OMe
N
O
N
N
OH
Me
N
Cl
N
NH
5
O
N
The typical method for preparing 1,2,4-benzotriazines
involves the initial formation of 1,2-dihydro-1,2,4 benzotri-
azines precursors through an acylation–reduction–cycliza-
tion process from 2-nitrophenylhydrazine.10 Another meth-
od starts with o-nitroanilines and requires a four-step se-
quence to afford the core structures.11 These methods suffer
from a limited number of available starting materials for di-
versity synthesis. Recently, a copper-catalyzed coupling of
2-haloanilines and hydrazides was found to give 1,2,4-ben-
zotriazines, but only 3-aryl-substituted products could be
6
Figure 1 Representative compounds
obtained.12 As such, development of an alternative route to
construct 1,2,4-benzotriazines and related heterocycles
would be highly valuable.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1586–1590

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Based on the copper (I)–amino acid promoted Ullmann-
type coupling reactions, we have developed a series of cas-
cade and one-pot processes for assembling heterocycles13
such as benzofurans, indoles, benzimidazoles, benzothi-
azoles, and phenothiazines. As an extension of this study,
we tried the coupling reaction of o-haloacetanilides and N-
Boc hydrazine, and found that N′-arylated products 8
formed selectively, which easily underwent oxidation to de-
liver azo compounds 9 (Scheme 1).14 Interestingly, treat-
ment of 9 with TFA provided 1,2,4-benzotriazines in excel-
lent yields. Herein, we wish to report our result.
DMSO as the solvent, and promoting the oxidation by addi-
tion of oxygen.
Table 1 Optimization of Reaction Conditionsa
H
N
H
N
H
N
O
n-Pr
NH2NHBoc
n-Pr
+
n-Pr
O
O
conditions
I
NH
N
NBoc
NHBoc
8a
7a
9a
HO
O
O
O
NHCOR
I
NH2NHBoc
CuI, ligand
NHCOR
N
N
OH
N
H
[Cu], O2
OH
H
OH
L2
coupling
L1
Y
Y
L3
Y
NH NHBoc
7
8
N
N
N
R
deprotection &
cyclization
NHCOR
N
OH
N
L4
L5
N
Y
N
N
Boc
Entry
Ligand Solvent
Additive Yield of 8a (%)b Yield of 9a (%)b
10
9
1
2
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
DMSO
DMSO
DMSO
DMSO
DMSO
PhMe
NMP
–
–
–
–
–
–
–
–
–
–
O2
22
51
18
40
10
–
10
16
7
Scheme 1 A new route for syntheses of 1,2,4-benzotriazines
3
As summarized in Table 1, we began our investigation
with conducting the coupling reaction of the N-(2-iodophe-
nyl)butyramide (7a) and N-Boc hydrazine. Our previous
study indicated the o-amide functional group may facilitate
the coupling reactions,13 and therefore initial reaction con-
ditions could be set at 35 °C. Firstly, a number of ligands
were tested. To our delight, most of the tested ligands could
directly deliver simple coupling product 8a and azo com-
pound 9a, while 1H-pyrrole-2-carboxylic acid (L2) was our
best ligand (Table 1, entries 1–5). This result indicated that
the C–N coupling took place selectively on the N′-position
of N-Boc hydrazine, which is different with the coupling re-
action of simple aryl halides with N-Boc hydrazine.15,16 Dif-
ferent solvents were then compared (Table 1, entries 6–8).
Although NMP gave a similar result (Table 1, entry 7), tolu-
ene and acetonitrile almost produced no desired coupling
or cyclization products but the deiodonation compound
and unreacted starting material. Moreover, it was proved
that addition of NaI could dramatically increase the reac-
tion rate, resulting in that comparable efficiency could also
be obtained even with lower catalyst and ligand loading
(Table 1, entries 9 and 10).17 As we observed, the coupling
product could be partially converted into the corresponding
azo compound in situ, which might result from copper-cat-
alyzed oxidation with air.14 To further promote the oxida-
tion, we decided to introduce oxygen into the reaction mix-
ture after consumption of o-iodoanilide 7a, and found that
the yield of 9a could be increased to 83% (Table 1, entry 11).
Taking together, we conclude that the optimal conditions
were using 1H-pyrrole-2-carboxylic acid as the ligand,
4
16
7
5
6c
7c
8c
9d
10e
11f
–
30
–
7
MeCN
DMSO
DMSO
DSMO
–
56
55
–
–
17
83
a Reaction conditions: 7a (0.5 mmol), N-Boc hydrazine (0.53 mmol), CuI (10
mol%), ligand (20 mol%), K2CO3 (1.0 mmol), solvent (1.5 mL), 35 °C, 36 h.
b Isolated yield.
c Reaction conditions: 25 °C, 36 h.
d Reaction conditions: CuI (5 mol%), L2 (15 mol%), NaI (0.5 mmol), 25 °C,
10 h.
e Reaction conditions: CuI (5 mol%), L2 (15 mol%), NaI (0.1 mmol), 25 °C,
24 h.
f Oxygen was added into the reaction mixture after coupling reaction, 25 °C,
3 h.
With the optimized conditions in hand, we then ex-
plored the scope and limitations of this novel transforma-
tion, and the results are summarized in Table 2.17 Our con-
ditions complied well with different steric hindered sub-
stituents, such as i-propyl, t-butyl, cyclopropyl groups
(Table 2, entries 2–5). A pyran-derived substrate and two
other substrates with additional functional groups could
also afford the desired azo products in 58–74% yields (Table
2, entries 6–8). Aromatic substitution (phenyl and thio-
phene) was also tested while only moderate yields could be
achieved (Table 2, entries 9, 10). The relatively low yields in
these cases might be caused by deiodination because the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1586–1590

1588
Y. Zhou et al.
Letter
Synlett
Table 2 (continued)
corresponding side products were determined, and further
study is needed to fix this problem. Furthermore, the elec-
tronic effect on the phenyl ring was investigated (Table 2,
entries 11–15). It was found that the substrates with elec-
tron-donating groups could deliver the azo compounds in
excellent yields (Table 2, entries 11 and 12), while those
with electron-withdrawing functional groups gave the de-
sired azo products in only moderate yields (Table 2, entries
13–15). Additionally, we found that o-bromoacetanilide
coupling partners were less reactive coupling partners than
o-iodoacetanilides, giving the corresponding products in
only 20–28% yields (Table 2, entries 16–19).
Entry
X
Product
Yield (%)b
O
H
N
6
I
69
O
N
NBoc
9g
OBn
H
N
7
8
I
I
74
58
O
N
NBoc
9h
9i
Table 2 Syntheses of Aromatic Azo Compounds via CuI/L2-Catalyzed
Coupling/Oxidation Processa
H
N
H
NH2NHBoc
CuI (5 mol%), L2 (15 mol%)
H
N
N
R
R
O
N
NBoc
O
O
NaI (0.2 equiv), K2CO3,
DMSO, r.t.;
Y
N
Y
X
NBoc
then, O2, r.t.
7
9
H
N
Entry
X
Product
Yield (%)b
9
I
I
42
42
O
H
N
N
Me
NBoc
9j
1
2
I
I
67
O
N
S
NBoc
H
N
9b
10
O
H
N
N
NBoc
9k
9l
78
72
78
O
N
H
N
NBoc
Me
9c
11
12
13
14
I
I
I
I
86
81
49
57
O
N
H
N
NBoc
3
4
I
I
O
H
N
N
Me
NBoc
9d
9e
O
MeO
N
H
N
NBoc
9m
O
H
N
N
Me
NBoc
O
MeO2C
N
NBoc
H
N
9n
H
N
5
I
78
Me
O
N
NBoc
O
9f
F
N
NBoc
9o
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1586–1590

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Letter
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Entry
Table 3 (continued)
Entry
X
Product
Yield (%)b
Product
Yield (%)b
H
N
Me
15
I
51
O
N
N
N
Br
9p
9a
9f
5
6
7
8
96
NBoc
N
N
16c
17c
18c
19c
Br
Br
Br
Br
24
20
28
23
10e
10f
O
9l
N
N
88
92
91
9m
a Reaction conditions: 7 (0.5 mmol), N-Boc hydrazine (0.53 mmol), CuI (5
mol%), ligand (15 mol%), K2CO3 (1 mmol), solvent (1.5 mL), 25 °C, 24–30
h; then oxygen was added at r.t. for 3–5 h.
b Isolated yield.
c Time for coupling step was 48 h.
N
N
N
N
Upon deprotection of the Boc group in the azo com-
pounds 9 with TFA in dichloromethane, exclusive formation
of 1,2,4-benzotriazines were observed. The mechanism for
this transformation is still unclear, and further studies are
required to address this issue. As shown in Table 3, a num-
ber of 1,2,4-benzotriazines could be obtained in excellent
yields. It is notable that this novel reaction was proved to be
compatible with a variety of functional groups, including
alkyl groups (Table 3, entries 1–6), aromatic substituents
(Table 3, entries 7 and 8), and electron-rich/poor substrates
(Table 3, entries 9 and 10).18
10g
S
N
N
10h
10i
N
N
Me
9
93
86
N
N
N
Me
Table 3 Syntheses of 1,2,4-Benzotriazinesa
10
N
MeO2C
H
10j
N
R
N
R
a Reaction conditions: 9 (0.2 mmol), TFA (0.5 mL), CH2Cl2 (2 mL), r.t., 2 h.
TFA
b Isolated yields.
O
N
CH2Cl2, r.t.
Y
N
Y
N
NBoc
10
9
In conclusion, we have developed a novel method for as-
sembling 1,2,4-benzotriazines, which relies on a one-pot
CuI–1H-pyrrole-2-carboxylic acid catalyzed coupling of o-
iodoacetanlides and N-Boc hydrazine and subsequent aero-
bic oxidation. Noteworthy is that a considerable number of
o-iodoacetanlides with different functionalized groups
worked well under the present conditions, and thereby al-
lowing diverse synthesis of these special heterocycles.
Entry
Product
Yield (%)b
91
N
Me
1
2
N
N
N
N
10a
10b
Me
90
95
N
Acknowledgment
The authors are grateful to Chinese Academy of Sciences and the Na-
tional Natural Science Foundation of China (grant 21132008 &
21372240) for their financial support.
N
N
3
4
N
N
10c
10d
Supporting Information
N
N
89
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378708.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1586–1590

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Letter
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References and Notes
pyrrole-2-carboxylic acid (9 mg, 0.08 mmol), NaI (15 mg, 0.1
mmol), and K2CO3 (138 mg, 1.0 mmol), evacuated, and back-
filled with argon. DMSO (1.5 mL) was successively added. The
reaction mixture was stirred at 25 °C for 24–30 h before oxygen
was introduced. After the reaction mixture was stirred at 25 °C
for 3–5 h, it was extracted with EtOAc. The combined organic
phase was washed with brine and dried over Na2SO4. After con-
centration in vacuo, the residue was purified by column chro-
matography on silica gel to provide 9.
(1) Hay, M. P.; Hicks, K. O.; Pchalek, K.; Lee, H. H.; Blaser, A.; Pruijn,
F. B.; Anderson, R. F.; Shinde, S. S.; Wilson, W. R.; Denny, W. A. J.
Med. Chem. 2008, 51, 6853.
(2) Noronha, G.; Barrett, K.; Cao, J.; Dneprovskaia, E.; Fine, R.; Gong,
X.; Gritzen, C.; Hood, J.; Kang, X.; Klebansky, B.; Li, G.; Lose, D.;
Mark, C.; McPherson, A.; Palanki, M.; Pathak, V.; Renick, J.; Soll,
R.; Splittgerber, U.; Wrasidlo, W.; Zeng, B.; Zhao, N.; Zhou, Y.
Bioorg. Med. Chem. Lett. 2006, 16, 5546.
Compound 9a: 1H NMR (500 MHz, CDCl3): δ = 9.54 (s, 1 H), 8.70
(dd, J = 8.5, 1.1 Hz, 1 H), 7.74 (dd, J = 8.2, 1.5 Hz, 1 H), 7.54 (ddd,
J = 8.6, 7.5, 1.5 Hz, 1 H), 7.09 (ddd, J = 8.4, 7.3, 1.3 Hz, 2 H), 2.41
(t, J = 7.4 Hz, 2 H) 1.80–1.72 (m, 2 H), 1.65 (s, 9 H), 1.00 (t, J = 7.4
Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 171.66, 160.23, 138.25,
138.05, 136.01, 123.11, 120.55, 119.36, 84.97, 40.16, 27.85 (3C),
18.75, 13.68. ESI-MS: m/z = 314.2 [M + Na]+. ESI-HRMS:m/z
calcd for C15H22N3O3+ [M + H]+: 292.1656; found: 292.1653.
Compound 9k: 1H NMR (500 MHz, CDCl3): δ = 11.10 (s, 1 H),
8.83 (dd, J = 8.5, 1.1 Hz, 1 H), 7.95 (dd, J = 8.1, 1.6 Hz, 1 H), 7.71
(dd, J = 3.8, 1.1 Hz, 1 H), 7.62 (dd, J = 7.3, 1.4 Hz, 1 H), 7.59 (dd,
J = 5.0, 1.0 Hz, 1 H), 7.22 (ddd, J = 8.3, 7.4, 1.2 Hz, 1 H), 7.14 (dd,
J = 5.0, 3.8 Hz, 1 H), 1.71 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ =
160.30, 159.14, 139.74, 138.01, 136.45, 136.30, 131.71, 128.83,
127.88, 125.30, 123.50, 120.31, 84.95, 27.88 (3 C). ESI-MS: m/z =
354.2 [M + Na]+. ESI-HRMS:m/z calcd for C16H18N3O3S+ [M + H]+:
332.1063; found: 332.1061.
(3) Boyle, R. G.; Travers, S. WO 2008015429, 2008.
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C.; Simorini, F.; Salerno, S.; Sergianni, V.; Tuccinardi, T.;
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1979, 16, 1005. (b) Reich, M.; Fabio, P.; Lee, V.; Kuck, N.; Testa, R.
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Madauss, K. P.; Marr, H. B.; McFadyen, R. B.; Miller, A. B.; Mills,
W. Y.; Navas, F. III.; Parks, D. J.; Smalley, T. L. Jr.; Spearing, P. K.;
Todd, D.; Williams, S. P.; Wisely, G. B. Bioorg. Med. Chem. Lett.
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(13) (a) Chen, Y.; Ma, D. Org. Lett. 2006, 8, 6115. (b) Chen, Y.; Xie, X.;
Ma, D. J. Org. Chem. 2007, 72, 9329. (c) Lu, B.; Wang, B.; Zhang,
Y.; Ma, D. J. Org. Chem. 2007, 72, 5337. (d) Zou, B.; Yuan, Q.; Ma,
D. Angew. Chem. Int. Ed. 2007, 46, 2598. (e) Ma, D.; Xie, S.; Xue,
P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem. Int. Ed. 2009, 48,
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(18) Typical Procedure for the Prepration of 10
To a solution of 9 (0.2 mmol) in CH2Cl2 (2.0 mL) was added TFA
(0.5 mL). The solution was stirred at r.t. for 2 h before aq
NaHCO3 (5 mL) was added. The mixture was extracted with
CH2Cl2. The organic phase was dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by
column chromatography on silica gel to provide 10.
Compound 10a: 1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 8.4
Hz, 1 H), 7.99 (d, J = 7.9 Hz, 1 H), 7.96–7.90 (m, 1 H), 7.83–7.77
(m, 1 H), 3.35 (t, J = 9.6 Hz, 2 H), 2.08–1.97 (m, 2 H), 1.06 (t, J =
7.4 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 166.45, 146.18,
140.85, 135.25, 129.82, 129.53, 128.51, 39.69, 22.28, 13.92. ESI-
+
MS: m/z = 174.1 [M + H]+. ESI-HRMS:m/z calcd for C10H12N3
[M + H]+: 174.1026; found: 174.1025.
Compound 10h: 1H NMR (500 MHz, CDCl3): δ = 8.46 (dd, J = 8.4,
0.7 Hz, 1 H), 8.35 (dd, J = 3.7, 1.1 Hz, 1 H), 8.02–7.97 (m, 1 H),
7.92 (ddd, J = 8.4, 6.8, 1.3 Hz, 1 H), 7.76 (ddd, J = 8.2, 6.8, 1.3 Hz,
1 H), 7.61 (dd, J = 5.0, 1.1 Hz, 1 H), 7.24 (dd, J = 4.9, 3.7 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 157.36, 146.00, 140.87, 140.72,
135.72, 131.31, 130.61, 129.75, 129.70, 128.65, 128.61. ESI-MS:
m/z = 214.1 [M + H]+. ESI-HRMS:m/z calcd for C11H8N3S+ [M +
H]+: 214.0433; found: 214.0432.
(14) For copper-catalyzed oxidation of aryl hydrazines to azo com-
pounds, see: Zhang, C.; Jiao, N. Angew. Chem. Int. Ed. 2010, 49,
6174.
(15) (a) Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009,
74, 4542. (b) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552.
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3803. (b) Lam, M. S.; Lee, H. W.; Chan, A. C.; Kwong, F. Y. Tetra-
hedron Lett. 2008, 49, 6192.
(17) General Procedure for the Preparation of 9
A Schlenk tube was charged with iodide 7 (0.5 mmol), N-Boc
hydrazine (70 mg, 0.53 mmol), CuI (5 mg, 0.025 mmol), 1H-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1586–1590