IBX-mediated synthesis of indazolone via oxidative N-N bond formation and unexpected formation of quinazolin-4-one: In situ generation of formaldehyde from dimethoxyethane

Article abstract of DOI:10.1007/s12272-016-0706-z

Synthesis of indazolone derivatives, which exhibit diverse biological and pharmaceutical activities, were achieved by hypervalent λ⁵ iodine reagents, such as iodoxybenzoic acid (IBX),-mediated oxidative N-N bond forming cyclization. In this study, the equivalence of IBX was optimized to promote the formation of N-N bond by oxidatively generated acylnitrenium ion. Dimethoxyethane and dichloroethane were discovered as alternative solvents and the reaction could be conducted in more concentrated condition. Some unprecedented substrates successfully afforded the corresponding indazolone in new condition discovered in this study. When the reactions were conducted in DME solvent, substrates with no electron-rich phenyl substituted amides afforded the unanticipated quinazolin-4-ones in moderate yields, which were not formed in DCE solvent. The formation of quinazolin-4-ones was attributed to the in situ generation of formaldehyde from DME. Therefore, the reaction might undergo different pathway in DME when the substrate aryl amides have phenyl rings without electron donating substituents.

Full text of DOI:10.1007/s12272-016-0706-z

Arch. Pharm. Res.
DOI 10.1007/s12272-016-0706-z
RESEARCH ARTICLE
IBX-mediated synthesis of indazolone via oxidative N–N bond
formation and unexpected formation of quinazolin-4-one: in situ
generation of formaldehyde from dimethoxyethane
Sang Won Park1 Hoon Choi1 Jung-hun Lee2 Yeon-Ju Lee3 Jin-Mo Ku2
•
•
•
•
•
Sang Yeul Lee1 Tae-gyu Nam1
•
Received: 15 December 2015 / Accepted: 10 January 2016
Ó The Pharmaceutical Society of Korea 2016
Abstract Synthesis of indazolone derivatives, which
exhibit diverse biological and pharmaceutical activities,
were achieved by hypervalent k5 iodine reagents, such as
iodoxybenzoic acid (IBX),-mediated oxidative N–N bond
forming cyclization. In this study, the equivalence of IBX
was optimized to promote the formation of N–N bond by
oxidatively generated acylnitrenium ion. Dimethoxyethane
and dichloroethane were discovered as alternative solvents
and the reaction could be conducted in more concentrated
condition. Some unprecedented substrates successfully
afforded the corresponding indazolone in new condition
discovered in this study. When the reactions were con-
ducted in DME solvent, substrates with no electron-rich
phenyl substituted amides afforded the unanticipated
quinazolin-4-ones in moderate yields, which were not
formed in DCE solvent. The formation of quinazolin-4-
ones was attributed to the in situ generation of formalde-
hyde from DME. Therefore, the reaction might undergo
different pathway in DME when the substrate aryl amides
have phenyl rings without electron donating substituents.
Keywords Hypervalent iodine Á Indazolone Á N–N bond
formation Á Iodoxybenzoic acid Á Quinazolin-4-one
Introduction
Heterocyclic 1H-indazol-3(2H)-one (indazolone) deriva-
tives are scarcely occurring structural motif in nature, yet
they are found in a variety of synthetic compounds which
exhibit a wide range of biological and pharmaceutical
properties such as analgesic (Fletcher et al. 2006), antitumor
(Wang et al. 2006), anti-inflammatory (Yu et al. 2010),
anticancer (Chen et al. 2012), antiviral (Mitchell et al.
2008), antidiabetic (Qian et al. 2013), antipsychotic (Nor-
man et al. 1994), and anti-hyperlipidemia (Kawanishi et al.
2006) activities. Due to their versatility in biological
implications, numerous efforts have been devoted to
develop efficient synthetic routes for indazolone frame.
Examples of literature procedures for indazolone structures
include (a) a base-mediated intramolecular SNAr reaction of
2-halobenzohydrazides (Kawanishi et al. 2006), (b) PIFA
[phenyliodine bis(trifluoroacetate)]-mediated intramolecu-
lar oxidative N–N bond formation via trapping of the
intermediate N-acylnitrenium (Correa et al. 2006a, b),
(c) transition metals such as Ti(IV) (Dou and Shi 2009)- or
Zn(II) (Bruneau et al. 1991)-mediated reductive N–N bond-
forming cyclization of 2-nitrobenzamides, (d) Cu(I)-medi-
ated intramolecular C–N bond formation of 2-halobenzo-
hydrazides (Tanimori et al. 2008), (e) basic hydrolysis of
3-chloro-2H-indazoles (Fletcher et al. 2006), (f) mi-
crowave-assisted basic cyclization/nucleophilic substitution
of 2-azidobenzamides (Shaw et al. 2009), and (g) Davis
Electronic supplementary material The online version of this
article (doi:10.1007/s12272-016-0706-z) contains supplementary
material, which is available to authorized users.
& Jin-Mo Ku
medichem@gstep.re.kr
& Tae-gyu Nam
tnam@hanyang.ac.kr
1
Department of Pharmacy and Institute of Pharmaceutical
Science and Technology, Hanyang University, Ansan,
Gyeonggi-do 15588, Republic of Korea
2
Gyeonggi Institute of Science and Technology Promotion,
Suwon, Gyeonggi-do 16229, Republic of Korea
3
Marine Natural Product Chemistry Laboratory, Korea
Institute of Ocean Science and Technology, Ansan,
Gyeonggi-do 15627, Republic of Korea
123

S. W. Park et al.
Beirut reaction of 2-nitrobenzyl bromide (Conrad et al.
2011) (Scheme 1).
aryl ring and the amino-substituent should be an electron-
donating group (Scheme 2). Hence, we herein report our
efforts to develop an alternative protocol for the oxidative
N–N bond formation, including improved reaction condi-
tions, new oxidizing agents and the electronic and steric
requirements for the substrates.
Among the protocols listed above, PIFA-mediated
oxidative N–N bond forming method have several inter-
esting features (Correa et al. 2006a, b). First of all, a highly
reactive intermediate, acylnitrenium ion, which is stabi-
lized by an electron rich neighboring group, is generated.
Secondly, the heterocycle is constructed via an N–N bond
formation, a heteroatom–heteroatom bond formation,
which is relatively underdeveloped than carbon-heteroatom
bond formations. In addition, a hypervalent k3 iodine
reagent PIFA plays an important role as an oxidizing agent.
Although the chemistry of polyvalent iodine compounds
has experienced a great expansion during the last decades
owing to their low toxicity, functional group tolerance,
availability, easy handling, and reactivities similar to those
of heavy metals, their usages in the generation of an N-
acylnitrenium ion has not been very popular (Correa et al.
2006a, b). The scheme also has some limitations that it
requires excess equivalent of PIFA and that the reaction
has to be conducted in a diluted concentration (0.01 M).
Further, the amido-substituent has to be an electron-rich
Materials and methods
Typical procedure for the synthesis of indazolones
2a–2d
Synthesis of 1-methyl-2-(4-methoxyphenyl)-1,2-dihydro-
3H-indazol-3-one (2a)
A stirred solution of N-(4-methoxyphenyl)-2-(methy-
lamino)benzamide (50 mg, 0.20 mmol) in DME (4 mL)
was treated with IBX (137 mg, 0.22 mmol) and trifluo-
roacetic acid (TFA) (0.46 mL, 0.60 mmol). The reaction
mixture was stirred at rt for 18 h under Ar. The reaction
mixture was diluted with EtOAc (50 mL), washed with
saturated aqueous NaHCO3 (3 9 10 mL), water and satu-
rated aqueous NaCl, dried (MgSO4), and concentrated
under reduced pressure to provide the crude product. Flash
chromatography (SiO2, 40 % EtOAc-hexanes) afforded an
O
O
X
O
R
R
NH2
R
NHR1
NHR2
N
NHR1
NO2
1
R1
indazolone 2a as a gray solid (28 mg, 56 %): H NMR
(DMSO-d6, 400 MHz) d 7.78–7.61 (m, 3H), 7.42 (d,
J = 9.0 Hz, 2H), 7.29–7.25 (m, 1H), 7.10 (d, J = 9.0 Hz,
2H), 3.82 (s, 3H), 3.12 (s, 3H); CAS registry: 886974-91-0.
Et2NH
route a)
PIFA, route b)
TiCl4/Fe, or Zn
route c)
O
X
O
R
R
1-Isopropyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-
3-one (2b)
NHR2
N
H
R1, R2 = H, alkyl or aryl
X = halogen
N
N
R2
R1
Cu(I),
route d)
35 % yield; mp 126–129 °C; 1H NMR (DMSO-d6,
400 MHz) d 7.76 (d, J = 7.6 Hz, 1H), 7.68–7.60 (m, 2H),
7.42 (d, J = 9.2 Hz, 2H), 7.27 (td, J = 6.8, 1.6 Hz, 1H),
7.07 (d, J = 9.2 Hz, 2H), 3.99–3.90 (m, 1H), 3.83 (s, 3H),
1.08 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d
163.2, 158.8, 149.4, 132.4, 129.1, 126.7 (2C), 125.0, 123.1,
120.4, 114.7 (2C), 114.0, 55.8, 54.4, 19.1 (2C); HRMS
(ESI) m/z calcd for C17H18N2O2 [M ? H]? 283.1447,
found 283.1444.
R1NH2, KOH
route g)
NaH route f)
KOH,
route e)
O
Cl
R
R
R
Br
NHR1
N3
N
R1
N
NO2
Scheme 1 Selected literature procedures for the preparation of
indazolone moiety
Scheme 2 General scheme of oxidative N–N bond formation
123

IBX-mediated synthesis of indazolone via oxidative N–N bond formation…
1-Benzyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-
one (2c)
Typical procedure for the synthesis for indazolones
3g–3i
40 % yield; 1H NMR (CDCl3, 400 MHz) d 7.85 (d,
J = 8.0 Hz, 1H), 7.56–7.51 (m, 1H), 7.44 (d, J = 9.0 Hz,
2H), 7.26–7.11 (m, 5H), 7.01 (d, J = 9.0 Hz, 2H),
6.89–6.87 (m, 2H), 4.71 (s, 2H), 3.84 (s, 3H); CAS registry:
886974-93-2.
Synthesis of 1-methyl-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one (3g)
A stirred solution of N-phenyl-2-(methylamino)benzamide
(45 mg, 0.20 mmol) in DME (4 mL) was treated with IBX
(137 mg, 0.22 mmol) and TFA (0.46 mL, 0.60 mmol). The
reaction mixture was stirred at rt for 16 h under Ar. The
reaction mixture was diluted with EtOAc (50 mL), washed
with saturated aqueous NaHCO3 (3 9 10 mL), water and
saturated aqueous NaCl, dried (MgSO4), and concentrated
under reduced pressure to provide the crude product. Flash
chromatography (SiO2, 20 % EtOAc-hexanes) afforded an
indazolone 3g as a gray solid (18 mg, 38 %): mp 113–
116 °C; 1H NMR (DMSO-d6, 400 MHz) d 7.82 (dd,
J = 8.0, 1.6 Hz, 1H), 7.49–7.36 (m, 5H), 7.24–7.29 (m,
1H), 6.94–6.87 (m, 2H), 4.89 (s, 2H), 2.93 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) d 162.6, 150.4, 141.2, 134.4,
129.2 (2C), 129.1, 126.5, 125.4, 118.9, 117.9, 113.2, 68.3,
35.9; HRMS (ESI) m/z calcd for C15H14N2O [M ? H]?
239.1184, found 239.1181.
1-Phenyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-
one (2d)
1
22 % yield; H NMR (DMSO-d6, 400 MHz) d 7.85 (d,
J = 7.6 Hz, 1H), 7.66–7.61 (m, 1H), 7.45 (d, J = 9.2 Hz,
2H), 7.42–7.25 (m, 7H), 6.95 (d, J = 9.2 Hz, 2H), 3.72 (s,
3H); CAS registry: 886974-94-3.
1-Acetyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-
one (2e)
42 % yield; mp 166–168 °C; 1H NMR (DMSO-d6,
400 MHz) d 8.10 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (td,
J = 8.0, 1.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.51 (td,
J = 8.0, 1.2 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.09 (d,
J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.13 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) d 161.5,159.3, 155.0, 147.3, 134.5,
130.4, 129.5 (2C), 126.6, 126.3, 120.5, 114.7 (2C), 55.4,
24.1; HRMS (ESI) m/z calcd for C16H14N2O3 [M ? H]?
283.1083, found 283.1080.
1-Methyl-3-(4-bromophenyl)-2,3-dihydroquinazolin-
4(1H)-one (3h)
30 % yield; mp 152–154 °C; 1H NMR (CDCl3, 400 MHz)
d 8.08 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H),
7.51–7.49 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.02–6.96
(m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.81 (s, 2H), 2.98 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 163.1, 149.5, 139.9,
134.2, 132.2 (2C), 129.7, 126.6 (2C), 119.81, 119.75,
118.2, 112.8, 69.0, 36.5; HRMS (ESI) m/z calcd for C15-
H13BrN2O [M ? H]? 317.0290, found 317.0281.
1-Methyl-2-(p-tolyl)-1,2-dihydro-3H-indazol-3-one (2f)
42 % yield in DCE; mp 90–93 °C; 1H NMR (CDCl3,
400 MHz) d 8.02 (d, J = 8.4 Hz, 1H), 7.60 (td, J = 7.6,
1.2 Hz, 1H), 7.43 (J = 8.4 Hz, 2H), 7.30–7.21 (m, 4H),
3.15 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
161.8, 151.3, 137.1, 133.1, 132.2, 130.1 (2C), 125.1, 124.4
(2C), 123.3, 118.6, 112.3, 39.3, 21.3; HRMS (ESI) m/z
calcd for C15H14N2O [M ? H]? 239.1184, found
239.1181.
1-Methyl-3-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-
one (3i)
32 % yield; mp 175–177 °C; 1H NMR (DMSO-d6, 400 MHz)
d 8.27 (d, J = 9.2 Hz, 2H), 7.89–7.84 (m, 1H), 7.68 (d,
J = 9.2 Hz, 2H), 7.53–7.47 (m, 1H), 6.95–6.89 (m, 2H), 5.01
(s, 2H),2.96(s,3H);13CNMR(DMSO-d6,100 MHz)d162.2,
149.9, 146.1, 143.9, 134.4, 128.9, 124.3 (2C), 123.9 (2C),
118.6, 116.8, 112.9, 67.2, 35.5; HRMS (ESI) m/z calcd for
C15H13N3O3 [M ? H]? 284.1035, found 284.1030.
1-Methyl-2-phenyl-1,2-dihydro-3H-indazol-3-one (2g)
1
32 % yield in DCE; H NMR (CDCl3, 400 MHz) d 7.94-
7.92 (m, 1H), 7.64–7.56 (m, 3H), 7.51–7.45 (m, 2H),
7.31–7.22 (m, 2H), 3.14 (s, 3H); CAS registry: 92148-68-0.
1-Methyl-2-(3-bromophenyl)-1,2-dihydro-3H-indazol-3-
one (2h)
Results and discussions
23 % yield in DCE; 1H NMR (CDCl3, 400 MHz) d
7.92–7.88 (m, 1H), 7.64–7.57 (m, 3H), 7.51–7.46 (m, 2H),
7.29–7.22 (m, 2H), 3.13 (s, 3H); CAS registry: 886974-97-6.
First, several oxidizing agents such as 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ), NaOCl, potassium
peroxymonosulfate (Oxone) and I2 were applied in place of
123

S. W. Park et al.
Table 1 Optimization of hypervalent iodine mediated N–N bond formation
Entry
Oxidizer (eq.)
Acid (eq.)
Solvent
Temp.
Rxn Conc. (M)
Yields (%)
1
DMP (2.0)
DMP (2.0)
DMP (2.0)
IBX (2.0)
IBX (2.0)
DMP (1.1)
IBX (1.1)
DMP (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
IBX (1.1)
TFA (3.0)
TFA (3.0)
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMSO
THF
rt
0.01
0.05
0.05
0.01
0.05
0.05
0.05
0.1
17
2
rt
20
N. R.a
3
rt
4
TFA (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
HCl (3.0)
TsOH (3.0)
CSA (3.0)
BF3 (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
TFA (3.0)
None
rt
22
5
rt
25
6
rt
37
7
rt
43
8
rt
32
9
rt
0.1
41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
rt
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
Decomp.b
Trace
21
rt
rt
rt
Trace
47
rt
rt
5
rt
16
EtOAc
toluene
TFE
rt
8
rt
18
rt
10
TFA (3.0)
TFA (3.0)
TFA (3.0)
CSA (3.0)
DME
rt
56
DME
50 °C
rt
51
DCE
53
DME
rt
60
No reaction (SM recovered)
b
SM decomposed
PIFA to substrate 1a in CH2Cl2 (0.01 M reaction concen-
tration) (Scheme 2) (Correa et al. 2006a, b). DDQ and
Oxone caused the complete decomposition of 1a. NaOCl
also led to the decomposition of 1a but very small amount
of desired product 2a was formed. A mild oxidizing agent,
I2, did not result in decomposition but afforded complete
recovery of 1a (data not shown), which led us to further test
higher valent iodine reagents. In fact, hypervalent k5 iodine
(V) reagents, Dess-Martin periodinane (DMP) and 2-io-
doxybenzoic acid (IBX), afforded substantial level of
conversion of 1a into 2a. Both reagents showed similar
patterns in many aspects of the reactions (entries 1–9,
Table 1). It was found that 1.1 eq. of oxidizers gave the
decent yields whereas 2.0 equivalents significantly
decreased the yields in both oxidizers (entries 6–9 vs. 1–5).
Running the reaction in more concentrated conditions, in
general, provided improved results (entries 6 and 7).
However, too high reaction concentration seems to
decrease yield (entries 8 and 9). Overall, IBX afforded not
only higher yields but also cleaner reaction profile than
DMP, which led us to conduct further optimization using
IBX.
In search of an optimal solvent, several solvents were
tested in the oxidation of N-PMP-2-(methylamino)benza-
mide (1a) to indazolone (2a) (entries 14–23). 1,2-Dime-
thoxyethane (DME) gave the best yields (entries 20, 21 and
23) followed by 1,2-dichloroethane (DCE), which gave
quite promising yield (entry 22), and halogenated CH2Cl2
and CHCl3 (entries 7 and 14). All the other solvents
resulted in poor yields. Various acids were also tested in
the presence of PIFA to identify alternative candidates.
Lewis acids, such as CuO, resulted in the decomposition of
1a along with the formation of trace amount of 2a. AgNO3
and ZnBr2 did not cause the decomposition but they
123

IBX-mediated synthesis of indazolone via oxidative N–N bond formation…
Table 2 Scope of amino substituents (R1) in IBX-mediated reaction
not shown). Trifluoroethanol (TFE), which is known as an
alternative to TFA/CH2Cl2 system (Correa et al. 2006a, b),
also produced a poor outcome (entry 19). Thus, TFA was
chosen as an optimal acid (entry 14). Running the reaction
in elevated temperatures increased the reaction rate, but the
yield decreased to some extent (entries 20 and 21). Taken
together, 1.1 eq. IBX and 3.0 eq. TFA in 0.05 M DME was
chosen as the optimal condition.
Entry
R1
Yields (%)
Then, we investigated the effect of the amino substituent
on the oxidative cyclization. A series of 2-amino-p-
methoxyphenylbenzamides with varying R1 group in
amino moiety were synthesized (Correa et al. 2006a, b),
and subjected to the IBX-mediated reaction (Table 2).
Alkyl and benzyl R1 groups afforded medium yields
(40–56 %), while showing some level of steric effect. The
yields are slightly lower than literatures where trivalent k3
iodine PIFA was used as an oxidizing agent (entries 1–4).
Interestingly, the acetyl substituent, an electron withdraw-
ing group, afforded higher yield than alkyl substituents
(entry 5). Because it has been believed that electron rich
substituents should be positioned on R1 position in order to
promote indazolone formation by stabilizing the interme-
diate N-acylnitrenium ions (Correa et al. 2006a, b), it might
be possible that the acetyl group undergoes some kind of
coordination with N-acylnitrenium intermediate to give the
unexpected yield in IBX-mediated cyclization. Substrates
with hydrogen, carbamate or tosylate on R1 position did not
produce desired indazolones (entries 6–9).
1
2
3
4
5
6
7
8
9
a
Methyl
Isopropyl
Benzyl
Phenyl
Acetyl
Boc
2a
2b
2c
2d
2e
56 (68a)
35
40 (67a)
22 (61a)
42
0
Cbz
0
Tosyl
H
0 (0a)
0 (0a)
Taken from reference 9 where PIFA was an oxidizing agent
produced little amount of 2a (data not shown). With DMP
as an oxidizer, reaction did not proceed without trifluo-
roacetic acid (TFA) (entry 3). With IBX as an oxidizer,
anhydrous HCl led to the complete decomposition of 1a
(entry 10), but TsOH and BF3ÁEt2O produced a trace
amount of 2a (entries 11 and 13). Camphorsulfonic acid
(CSA), having pKa value similar to TFA, afforded the best
result in this system (60 %, entry 23), but it gave poor
outcomes in other substrates shown in Tables 2 and 3 (data
The effect of the amido substituent on the oxidative
cyclization was also investigated (Table 3). With R1 group
Table 3 Scope of amide substituents (R2) in IBX-mediated reaction
Entry
R2
Yields (%) (product (solvent))
2 (DME/DCE)
3 (DME/DCE)
1
2
3
4
5
6
7
8
9
p-Methoxyphenyl
p-Tolyl
2a (56/53)
0
2f (37/42)
0
Phenyl
2g (trace/32)
2h (0/23)
3g (38/0)
3h (30/0)
3i (32/0)
p-Bromophenyl
p-Nitrophenyl
Benzyl
2i (0/0)
SM decomposed
SM decomposed
SM decomposed
SM decomposed
n-Butyl
OMe
Allyl
123

S. W. Park et al.
Fig. 1 Formation of formaldehyde from DME in the presence of IBX and TFA. Line 1 0.3 mM TFA; line 2 0.1 mM IBX; line 3 0.1 mM IBX,
0.3 mM TFA; line 4 0.2 mM IBX, 0.3 mM TFA; line 5 0.3 mM IBX, 0.3 mM TFA. Formaldehyde peak is indicated with an arrow
Scheme 3 Proposed reaction pathways for the formation of 2g and 3g
being methyl based on the above study, a series of
2-methylaminobenzamide derivatives with various R2
group were prepared (Correa et al. 2006a, b) and subjected
to the IBX-mediated reaction in DCE and DME solvents.
In DCE solvent, our results were generally parallel to the
PIFA-mediated reactions, suggesting that corresponding N-
acylnitrenium ions formation which resulted in indazolone
products (entries 1–6). That is, electron donating phenyl
substituents on R2 group favored the formation of the
indazolones and electron withdrawing substituents pro-
duced virtually disfavored indazolone formation. It was
also confirmed that R2 group should have a phenyl moiety.
Otherwise, starting materials were almost completely
decomposed. When the reactions were conducted in DME
solvent, however, two different products were obtained:
desired indazolones (2) and unexpected by-products (3).
Formation of the unexpected by-products (3) was depen-
dent on the electronic environment of the phenyl ring
(entries 1 and 2 vs 3–5). When R2 substituents were phenyl
ring with electron donating group, only desired indazolones
(2) were obtained (entries 1 and 2). However, phenyl
substituents without electron donating group resulted in
only the by-products (entries 3–5). Both phenyl and
4-bromophenyl substituents barely afforded desired inda-
zolones (2g and 2h). Instead, by-products (3g and 3h) were
obtained in moderate yields (entries 3 and 4). Further, the
electron withdrawing 4-nitrophenyl substituent gave no
indazolone (2i) but moderate level of by-product (3i) in
DME solvent (entry 5). It is noteworthy that 4-nitrophenyl
substituent failed to give indazolone product in DCE
123

IBX-mediated synthesis of indazolone via oxidative N–N bond formation…
solvent as well. All the substrates having alkyl or alkoxy R2
substituents were unsuccessful in formation of desired
indazolones, only giving complex mixtures on TLC (en-
tries 6–9). Because the by-products were observed only
when DME was solvent, it is likely that DME is involved in
generation of the unexpected by-product when R2 group is
a phenyl ring without electron donating groups (entries
3–5), in which the formation of indazolone products is
supposed to be suppressed.
on solvent, when the substrate aryl amides have phenyl
rings without electron donating substituents.
Acknowledgments This work was supported by Research Fund of
Hanyang University (HY-2012-N).
Compliance with ethical standards
Conflict of Interest Authors declare no conflict of interest.
All the by-products (3) showed an CH2 peak at about
1
4.5 ppm in H-NMR and at 69 ppm in 13C-NMR (Fig. 1),
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