An approach towards the synthesis of novel fused nitrogen tricyclic heterocyclic scaffolds: Via GBB reaction

Article abstract of DOI:10.1039/c7ob02933k

A concise and efficient one-pot synthesis of novel N-fused tricyclic derivatives has been developed by using the Groebke-Blackburn-Bienaymé (GBB) reaction, which involved the reaction of 3-amino-1H-indazoles, aldehydes and isonitriles to afford 2-aryl-5H-imidazo[1,2-b]indazol-3-amine derivatives via a formal [4 + 1] cycloaddition reaction. Furthermore, we describe an unprecedented reaction of chromone-3-carboxaldehydes with 3-amino-1H-indazoles to afford (2-hydroxyphenyl)(pyrimido[1,2-b]indazol-3-yl)methanones in one-pot at ambient temperature. This protocol features a robust method for the one-step construction of new tricyclic rings, column chromatography free methods with a clean reaction profile, high yields, operational simplicity and it tolerates a diverse collection of reactants.

Full text of DOI:10.1039/c7ob02933k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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An Approach towards the Synthesis of Novel Fused Nitrogen
Tricyclic Heterocyclic Scaffolds via GBB Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Sandip Gangadhar Balwe, Yeon Tae Jeong*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A concise and efficient one‐pot synthesis of novel N‐fused tricyclic derivatives has been developed by using Groebke‐
Blackburn‐Bienayme (GBB) reaction, which involved the reaction of 3‐amino‐1H‐indazoles, aldehydes and isonitriles to
afford 2‐aryl‐5H‐imidazo[1,2‐b]indazol‐3‐amine derivatives via [4+1] formal cycloaddition reaction. Furthermore, we
describe an unprecedented reaction of chromone‐3‐carboxaldehydes with 3‐amino‐1H‐indazoles to afford (2‐
hydroxyphenyl)(pyrimido[1,2‐b]indazol‐3‐yl)methanones in one‐pot at ambient temperature. This protocol features,
robust method for one‐step construction of new tricyclic rings, column chromatography free methods with clean reaction
profile, high yields, operational simplicity and tolerate a diverse collection of reactants.
poised for an ever increasing impact on the discovery and
development of new chemical entities (NCEs). The wide spectrum
of biological features of these frameworks, such as anticancer
activity by inhibition of topoisomerase IIα,7 antianxiety,8
neuropsychotic9 activities, and also used to treat hepatitis C virus
(HCV) infection.10 They are cognitive enhancers effective in the
treatment of several neurodegenerative diseases, including familial
Alzheimer's Disease and Down's syndrome11 (Scheme 1).
1. Introduction
In the family of heterocyclic compounds Nitrogen‐fused bi‐ and tri‐
cyclic scaffolds have received substantial attention in drug discovery
and development programs.1 The compounds containing nitrogen
prodigiously occur in natural products and synthetic drugs. Indeed
the synthetic drugs widely contain more number nitrogen atoms
than the natural products because nitrogen can bear a positive
charge, and act as a hydrogen bond donor and/or acceptor that
substantially influences the interaction between the drug with the
biochemical structure of the target.2 In addition, pKa values of
amines are in the span of physiological pH, an important factor that
influences the pharmacokinetics properties of the drugs.3
Therefore, the development of novel nitrogen‐rich heterocyclic
compounds is highly desirable. More specifically fused imidazo‐
indazole4 systems have shown promise in a majority of therapeutic
areas due to their pronounced biological activity.5 These
heterocycles are adaptable chemical building blocks for use in both
a ‘drug hunter’s probe to discover new lead molecules and a
biologists search for potent molecular tools. The recent drug
discovery and development process have authenticated the
discovery of new methodologies which rapidly have enabled access
to a broad spectrum of these basic chemo‐types. Such adamant
chemo‐types, all containing a bridgehead nitrogen atom,6 are thus
O
NH2
N
N
O
O
O
N
O
CF3
S
N
H
N
NH
N
N
N
N
N
H
N
H
N
N
N
H
O
O
N
O
O
Antianxiety agent
Anticancer agent
F
Hepatitis C virus infection
Cl
NH
O
N
O
N
N
N
N
N
N
N
H3C
N
H
N
H
H
O
Neuropsychotic agent
Anticancer agent
Neurodegenerative agent
Scheme 1. Pharmaceutically important imidazo[1,2‐b]indazole and
pyrimido[1,2‐b]indazole derivatives.
In addition, these scaffolds allow the efficient creation of
functionally diverse molecules for the further discovery of novel,
biologically interesting molecules.12 Therefore, the development of
efficient synthetic approaches toward such scaffolds is instrumental
in the rapid synthesis and evaluation of these compounds.
Unfortunately, owing to their importance and utility, no
Department of Image Science and Engineering, Pukyong National University, Busan
608‐737, Republic of Korea. E‐mail: ytjeong@pknu.ac.kr; Fax: +82‐51‐629‐6408; Tel:
+82‐51‐629‐6411
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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considerable attention has been paid to construct tricyclic 2‐aryl‐
5H‐imidazo[1,2‐b]indazole derivatives. The existing patent method
has their own drawbacks, including use of expensive reagents,
limited structural diversity of the product, harsh reaction
conditions, low yields and use of α‐halo carbonyl compounds which
have lachrymatory properties.11
2. Results and discussion
The reaction conditions were optimized using 3‐amino‐1H‐indazole
(1a, 1 mmol), 3,4,5‐trimethoxybenzaldehyde (2a, 1 mmol), and tert‐
butyl isocyanide (3a, 1 mmol), as the model substrates (Scheme 2).
At the outset, these three reactants were dissolved in EtOH and
allowed it to stir at room temperature in the absence of any
catalyst for 12 h. After 12 h (the reaction was monitored by TLC),
we could not observe any product formation (Table 1, entry 1).
Next, the same set of reaction was performed in the presence of p‐
TsOH, we were pleased to find that with 20 mol % p‐TsOH, this
reaction afforded the desired product 4a in 57% yield. (Table 1,
entry 2). The structure of 4a, was assigned with the help of 1H NMR,
13C NMR, and HRMS data. Encouraged by this result, we evaluated
the use of several different acids to further optimize the reaction
conditions. The other acids, including Sc(OTf)3, TFA, TfOH, HClO4,
and AcOH, were screened, and the results of these experiments are
summarized in Table 1 (entries 3‐7). Among all the screened
catalysts acetic acid was found superior with respect to reaction
time and product yield (Table 1, entry 7). Moreover, we found that
the yields were obviously affected by the amount of acetic acid
loaded. The yield of 4a, was increased appreciably, when 50 mol%,
of acetic acid was used (Table 1, entry 8). Furthermore, no
significant improvement in the reaction rate and product yield was
observed while increasing the amount of catalyst loading (Table 1,
entry 9). At this juncture, solvents representing other categories
such as polar aprotic (THF, CH3CN), nonpolar (toluene), polar protic
(MeOH, H2O), and halogenated (CHCl3), were screened (Table 1,
entries 10−15). Among the various solvent tested, a drop in the
yield was observed in the case of polar aprotic and nonpolar
solvents (Table 1, entries 11‐13). Notably, all the reactants
remained unconsumed when water is used as solvent (Table 1,
entry 15). The results revealed that ethanol is the optimal solvent
for this reaction (Table 1, entry 8). We were pleased to achieve
complete conversion of reactant and high yield of the 4a using 50
mol% of acetic acid in ethanol at ambient temperature for 2h.
Similarly, we also investigated the scope of L‐proline as a catalyst for
the same set reaction (Table 1, entries 14‐15). Interestingly, 20 mol
Scheme 2. One‐pot three‐component synthesis of 2‐aryl‐5H‐
imidazo[1,2‐b]indazol‐3‐amines (4).
Initially, to access the tricyclic 2‐aryl‐5H‐imidazo[1,2‐b]indazol‐3‐
amines,
the
inspiration
was
derived
from
the
Groebke−Blackburn−Bienayme three‐component reaction (GBB‐
3CR).13 The three‐component Ugi‐variant (Ugi‐3CR) GBB reaction
was discovered independently by three research groups, Katrin
13c
Groebke,13a Christopher Blackburn13b and Hugues Bienayme
in
1998. This reaction consists of a heterocyclic amine, an aldehyde
and an isocyanide that proceeds through imine formation and
subsequent formal [4+1] cycloaddition to form structurally diverse
and highly substituted, drug‐like heterocyclic libraries. Indeed, the
GBB reaction is a highly competent example of an isocyanide‐based
multicomponent reaction (IMCR).14 Therefore, the further
development of new GBB‐based eco‐friendly methodologies is
highly desirable.12c, 13e, 13g The IMCRs represent a family of versatile
organic molecules that bear unique electronic properties and have
been extensively applied in synthetic organic chemistry, particularly
in the synthesis of nitrogen‐containing molecules and drug‐like
products with potential bioactivities.15 Similarly, isocyanide‐based
[4+1] cycloaddition reactions16 have been widely used, owing to the
ability of isocyanides to act as electrophiles as well as nucleophiles.
Indeed, the formal [4+1] cycloaddition reactions are a powerful tool
for the rapid construction of diverse heterocycles which are found
in central core of many natural products and synthetic libraries.17
Given our interest in the development of novel MCRs18 and new
molecular diversity via subsequent product manipulation and
fascinated by the medicinal profile of these pharmacophores, we
envisioned a one‐pot IMCR to afford a suite of novel 2‐aryl‐5H‐
imidazo[1,2‐b]indazol‐3‐amine scaffolds via formal [4+1]
cycloaddition reaction. To the best of our knowledge, this is the first
example for the construction of tricyclic 2‐aryl‐5H‐imidazo[1,2‐
b]indazol‐3‐amine derivatives (Scheme 2).
% of ‐proline also catalyze the reaction and afforded the desired
L
product 4a in optimum yield with sparingly slower rates (Table 1,
entry 15). It is particularly advantageous; since the products were
solid and could be collected by simple filtration avoiding
conventional chromatographic purification.
Table 1 Optimization of Reaction Conditionsa
Entry
1
Catalyst (mol %)
‐
Solvent
EtOH
Time (h)
12
Yieldb (%)
c
‐
2
p‐TsOH (20)
EtOH
12
57
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3
Sc(OTf)3 (20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CHCl3
CH3CN
THF
12
12
12
12
4
48d
Having optimized reaction conditions, we proceeded to expand the
scope of the reaction with a broad array of aromatic aldehyde
substrates (Table 2). A series of aldehydes with electron‐donating
and electron‐withdrawing substituents on the phenyl ring (e.g. ‐Me,
‐OMe, ‐OEt, ‐Cl) underwent the desired transformation in a
regiospecific fashion to deliver the corresponding products
(4a−4ab) in good to excellent yields (85−96%). The electronic and
steric properties of the aromatic aldehyde substrate had very little
impact on the efficiency of this reaction. The phenyl ring was
replaced by a naphthalene moiety (4e) in good yield of the product
as expected. Similarly, trans‐cinnamaldehyde was also suitable for
this reaction (4s). We were delighted to find that the heteroaryl
aldehydes such as, thiophene‐2‐carboxaldehyde, and furan‐2‐
carboxaldehyde afforded the desired products in good yields
without affecting the heterocyclic moieties (4t, 4u, 4v). Next, we
investigated the scope of this reaction for aliphatic aldehydes such
as cyclohexanecarboxaldehyde and butyraldehyde; however
reaction did not proceed (4ac and 4ad). Further diversity in the
products was introduced by using other isocyanides substrates,
although no specific electronic effect on the reaction yield was
observed when tert‐butyl isocyanide and cyclohexyl isocyanide
were subjected to reaction, afforded the desired products in good
to excellent yields. However, aromatic isocyanide derivatives such
as 4‐methoxyphenyl isocyanide were unable to proceed with the
reaction. We also employed substituted 3‐amino‐1H‐indazoles such
as (–F and –Br), are tolerated well, and provided a corresponding
products in good to excellent yields under the optimized reaction
condition. Therefore, the present protocol has general applicability,
accommodating a variety of substitution patterns.
4
TFA (20)
42
49
63
87
96
92
83
76
63
56
85
5
TfOH (20)
HClO4 (20)
AcOH (20)
AcOH (50)
AcOH (100)
AcOH (50)
AcOH (50)
AcOH (50)
AcOH (50)
AcOH (50)
AcOH(50)
L‐proline (10)
L‐proline (20)
6
7
8
2
9
2
10
11
12
13
14
15
16
17
4
4
4
toluene
MeOH
H2O
4
4
4
c
‐
EtOH
EtOH
12
12
78d
81
aReaction Conditions: 1.0 mmol of 1a, 1.0 mmol of 2a, and 1.0 mmol 3a, in
presence of catalyst in 2.5 ml of solvent (including the other solvents
tested). Ambient temperature, bIsolated yield, cNo Reaction, dReactants
remained unconsumed.
Table 2 Substrate Scopea,b
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N
N
NH
N
H
4e (2 h; 90%)
Cl
N
N
NH
N
H
4g (2.5 h; 87%)
N
N
Br
NH
N
H
4o (1.5 h; 91%)
Cl
N
Br
N
NH
N
H
4p (3.2 h; 86%)
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F
N
N
S
NH
N
H
4v (4 h, 89%)
aReactions were performed with 1 (1 mmol), 2 (1 mmol) and 3 (1 mmol), in the presence of 50 mol % acetic acid in 2.5 mL ethanol at
ambient temperature, bIsolated yields.
All the structure of synthesized compounds (4a‐4ab) have been one‐pot GBB reaction, we envisaged to examine the synthetic utility
ascertained on the basis of 1H NMR, 13C NMR and HRMS data.
of this reaction. Consequently, we have performed the reaction on
After having successfully developed one‐pot strategy for the a gram‐scale (10 mmol, 1.33g) under the standard conditions and
synthesis of diverse 2‐aryl‐5H‐imidazo[1,2‐b]indazol‐3‐amines via isolated the desired product 4a in 88% yield (Scheme 3).
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Scheme 3 Gram Scale Reaction.
Based on our experimental results and literature reports
13a, 13e
we
have proposed a possible mechanism for the formation of 2‐aryl‐
5H‐imidazo[1,2‐b]indazol‐3‐amines (4) in Scheme 4.
Scheme
5.
Unprecedented
formation
of
(2-
hydroxyphenyl)(pyrimido[1,2-b]indazol-3-yl)methanone (7).
Table 3 Substrate Scopea,b
NH2
N
R1
N
H
1
H+
R1
H
H
R2
R2
R2
N
N
AcOH, -H2O
O
N
N
N
N
2
H
C
H
N
3
R
Iminium ion intermediate (A)
formal [4+1]
cycloaddition
R2
R2
N
H
H
[1,3-H] shift
-H+
N
R1
N
R1
R
N
N
N
R
N
H
H
N
H
4
B
Scheme 4. Possible reaction mechanism for the synthesis of 2‐aryl‐
5H‐imidazo[1,2‐b]indazol‐3‐amines (4).
aReaction conditions: 1a (1 mmol), 5a (1mmol) and acetic acid (50
Initially, the reaction of 3‐amino‐1H‐indazole (1) and benzaldehyde mol %), in 3 mL ethanol at ambient temperature, bIsolated yields.
(2) occurs to give iminium ion intermediate A, which on formal [4 +
1] cycloaddition with tert‐butylisocyanide (3) yields nitrilium ion
3. Conclusion
intermediate B, which on rearomatization followed by 1,3‐H shift,
afforded the desired product (4) in good to excellent yields.
In summary, we have developed a highly efficient approach for the
synthesis of N‐rich novel tricyclic heterocycles via efficient use of
Groebke‐Blackburn‐Bienayme reaction. In addition, we successfully
achieved the synthesis of (2‐hydroxyphenyl) (pyrimido[1,2‐
b]indazol‐3‐yl) methanones in one‐pot with good yields. This
synthetic approach has various prominent features such as shorter
reaction times, simplicity in operation, skeletal diversity, and
scalability with excellent yields. This protocol obviates tedious
work‐up and purifications techniques such as column
chromatography for the isolation of the products which makes this
protocol cost‐effective and environmentally friendly. We believe
that, these features will facilitate this procedure to find extensive
applications in the field of organic and medicinal chemistry.
During the course of our investigations on the synthesis of densely
functionalized
2‐aryl‐5H‐imidazo[1,2‐b]indazol‐3‐amines,
the
reaction of 3‐amino‐1H‐indazole with chromone‐3‐carboxaldehyde
(5) and tert‐butylisocyanide which was expected to afford 3‐(3‐
(tert‐butylamino)‐5H‐imidazo[1,2‐b]indazol‐2‐yl)‐4H‐chromen‐4‐
one (6), surprisingly we observed an unprecedented product, (2‐
hydroxyphenyl) (pyrimido[1,2‐b]indazol‐3‐yl)methanone (7) under
identical reaction conditions (Scheme 5). The literature scan
revealed that, there are few reports described the successful
implantation of
a
GBB reaction using chromone‐3‐
carboxaldehyde.19 While this chromone‐3‐carboxaldehyde moiety
have three electrophilic centers in their structure could react by
different reactive modes with various nucleophiles leading to ring‐
opening/ring‐closure to afford novel heterocyclic scaffolds.20
Notably, the reaction of chromone‐3‐carboxaldehyde with electron‐
rich amino heterocycles such as 3‐amino‐1H‐indazole afforded
fused (2‐hydroxyphenyl) (pyrimido[1,2‐b]indazol‐3‐yl)methanones
4. Experimental
and
the
substrate
scope
is
given
in
Table
3.
4.1 Material and methods
Chemicals were purchased from Aldrich and Alfa Aesar Chemical
Companies and used without further purification. NMR spectra
were recorded in parts per million (ppm) in DMSO‐d6 on a Jeol JNM
ECP 600 NMR instrument using TMS as internal standard. Standard
abbreviations were used to denote signal multiplicities (s = singlet,
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d = doublet, t = triplet, q = quartet, m = multiplet). HRMS were found: 348.1946. Anal. Calcd: C, 72.39; H, 6.94; N, 16.08. Found: C,
obtained by EI on a double‐focusing mass analyzer, ESI (positive ion
mode) on TOF mass analyzer. All melting points were determined
using open capillaries on an Electrothermal‐9100 (Japan)
instrument and are uncorrected. The elemental analysis (C, H, and
N) was performed using an Elementar Analysensysteme GmbH.
71.94; H, 6.85; N, 16.31.
N‐(tert‐butyl)‐2‐(p‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐amine (4c).
o
1
Yield: 91 % (289.6 mg); Off White solid; Mp: 248‐250 C; H NMR
(600 MHz, DMSO‐d6) δ 12.31 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.72 (d,
J = 8.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 –
7.16 (m, 1H), 6.83 (t, J = 7.4 Hz, 1H), 4.39 (s, 1H), 2.34 (s, 3H), 1.13
(s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 151.49, 136.73, 131.39,
129.08, 128.09, 126.16, 124.89, 124.65, 121.18, 118.55, 115.42,
114.59, 103.52, 55.18, 30.30, 20.86.; HRMS (ESI, m/z): calcd for
C20H22N4 (M+H+) 318.1844, found: 318.1838. Anal. Calcd: C, 75.44;
H, 6.96; N, 17.60. Found: C, 75.03; H, 7.03; N, 17.85.
4.2 Typical experimental procedure for the Synthesis of 2‐aryl‐5H‐
imidazo[1,2‐b]indazol‐3‐amines.
To a mixture of 3‐amino‐1H‐indazoles (1, 1 mmol), aldehydes (2, 1
mmol) and isocyanides (3, 1 mmol), in 2.5 ml of ethanol was added
acetic acid (50 mol %) and the reaction mixture was stirred at
ambient temperature, the progress of the reaction was monitored
by TLC (7:3 EtOAc/Hexane; Rf = 0.28). After completion of the
reaction, solid products was filtered under vacuum, air dried,
triturated and washed with chloroform: ethanol (80:20, v/v) to
obtain the analytically pure products. The compounds 4a‐4ab were
also synthesized by adopting this procedure.
N‐(tert‐butyl)‐2‐(o‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐amine (4d).
4.3 Typical experimental procedure for the Synthesis of (2‐
hydroxyphenyl)(pyrimido[1,2‐b]indazol‐3‐yl)methanones.
o
1
Yield: 88 % (280.6 mg); White solid; Mp: 246‐248 C; H NMR (600
MHz, DMSO‐d6) δ 12.21 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (d, J =
7.2 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38 – 7.28 (m, 3H), 7.19 (t, J =
7.3 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 4.15 (s, 1H), 2.40 (s, 3H), 0.96 (s,
9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 151.74, 137.59, 132.01,
131.60, 130.90, 130.82, 129.08, 126.19, 125.32, 124.84, 122.25,
118.87, 115.78, 115.07, 104.12, 55.12, 30.48, 20.68.; HRMS (ESI,
m/z): calcd for C20H22N4 (M+H+) 318.1844, found: 318.1839. Anal.
Calcd: C, 75.44; H, 6.96; N, 17.60. Found: C, 74.98; H, 7.09; N, 17.71.
A mixture of 3‐amino‐1H‐indazoles (1, 1 mmol) and chromone‐3‐
carboxaldehydes (5, 1 mmol) in 3 ml of ethanol was added acetic
acid (50 mol %) and reaction mixture was stirred at room
temperature, the progress of the reaction was monitored by TLC.
After completion of the reaction, solid products was filtered under
vacuum and air dried to obtain the analytically pure products.
N‐(tert‐butyl)‐2‐(3,4,5‐trimethoxyphenyl)‐5H‐imidazo[1,2‐
b]indazol‐3‐amine (4a). Yield: 96 % (378.4 mg); White solid; Mp:
246‐248 oC; 1H NMR (600 MHz, DMSO‐d6) δ 12.34 (s, 1H), 7.74 (d, J =
8.1 Hz, 1H), 7.50 (s, 2H), 7.44 (d, J = 8.7 Hz, 1H), 7.23 – 7.15 (m, 1H),
6.85 (t, J = 7.4 Hz, 1H), 4.50 (s, 1H), 3.88 (s, 6H), 3.71 (s, 3H), 1.20 (s,
9H); 13C{1H} NMR (150 MHz, DMSO‐d6) δ 152.89, 151.57, 136.82,
131.35, 131.28, 126.32, 124.99, 124.47, 121.35, 118.46, 115.58,
114.67, 103.64, 103.42, 60.17, 56.04, 55.06, 30.45.; HRMS (ESI,
m/z): calcd for C22H26N4O3 (M+H+) 394.2005, found: 394.2007. Anal.
Calcd: C, 66.99; H, 6.64; N, 14.20. Found: C, 66.50; H, 6.75; N, 14.43.
N‐(tert‐butyl)‐2‐(naphthalen‐1‐yl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4e). Yield: 90 % (318.4 mg); White solid; Mp: 227‐229 oC; 1H
NMR (600 MHz, DMSO‐d6) δ 12.49 (s, 1H), 8.12 – 7.97 (m, 3H), 7.81
(d, J = 6.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H),
7.62 – 7.56 (m, 2H), 7.49 (d, J = 8.6 Hz, 1H), 7.26 – 7.19 (m, 1H),
6.91–6.80 (m, 1H), 4.20 (s, 1H), 0.89 (s, 9H); 13C{1H} NMR (150 MHz,
DMSO‐ d6) δ 133.38, 131.47, 129.35, 129.33, 128.92, 128.39,
126.72, 126.13, 125.87, 125.46, 124.96, 122.68, 119.92, 118.51,
115.39, 114.61, 79.22, 54.52, 29.86.; HRMS (ESI, m/z): calcd for
C23H22N4 (M+H+) 354.1844, found: 354.1847. Anal. Calcd: C, 77.94;
H, 6.26; N, 15.81. Found: C, 77.62; H, 6.39; N, 16.04.
N‐(tert‐butyl)‐2‐(4‐ethoxyphenyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4b). Yield: 94% (326.7 mg); White solid; Mp: 242‐244 oC; 1H
NMR (600 MHz, DMSO‐d6) δ 12.28 (s, 1H), 8.01 (d, J = 8.9 Hz, 2H),
7.72 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.22 – 7.14 (m, 1H),
7.03 (d, J = 8.7 Hz, 2H), 6.83 (t, J = 7.3 Hz, 1H), 4.34 (s, 1H), 4.06 (q, J
= 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.13 (s, 9H); 13C{1H} NMR (150
MHz, DMSO‐ d6) δ 157.87, 151.38, 131.20, 127.71, 124.75, 123.20,
120.60, 118.46, 115.38, 114.57, 114.35, 103.59, 63.07, 55.08, 30.29,
14.69; HRMS (ESI, m/z): calcd for C21H24N4O (M+H+) 348.1950,
N‐(tert‐butyl)‐2‐(4‐methoxyphenyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4f). Yield: 94 % (314.1 mg); Pale pink solid; Mp: 234‐236 oC;
1H NMR (600 MHz, DMSO‐d6) δ 12.58 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H),
7.82 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.4 Hz,
1H), 7.09 – 7.04 (m, 2H), 4.58 (s, 1H), 3.82 (s, 3H), 1.11 (s, 9H); 13
C
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{1H} NMR (150 MHz, DMSO‐ d6) δ 158.99, 145.51, 137.78, 131.67, (600 MHz, DMSO‐d6) δ 12.50 (s, 1H), 8.43 (s, 1H), 8.10 (d, J = 7.1 Hz,
128.15, 128.12, 126.15, 125.52, 122.48, 121.31, 119.07, 114.07, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.53 – 7.42 (m, 4H), 7.21 (s, 1H), 6.90 –
113.59, 105.38, 55.34, 55.24, 30.05.; HRMS (ESI, m/z): calcd for 6.79 (m, 1H), 4.59 (s, 1H), 1.17 (s, 9H); 13C{1H} NMR (150 MHz,
C20H22N4O (M+H+) 334.1794, found: 334.1791. Anal. Calcd: C, 71.83; DMSO‐ d6) δ 151.80, 133.20, 131.90, 130.67, 129.84, 128.42,
H, 6.63; N, 16.75. Found: C, 71.53; H, 6.74; N, 16.98.
125.29, 124.70, 122.87, 122.31, 121.92, 118.69, 115.70, 114.71,
103.36, 55.34, 30.31.; HRMS (ESI, m/z): calcd for C19H20N4 (M+H+)
304.1688, found: 304.1683. Anal. Calcd: C, 74.97; H, 6.62; N, 18.41.
Found: C, 74.67; H, 6.73; N, 18.69.
N‐(tert‐butyl)‐2‐(4‐chlorophenyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4g). Yield: 87 % (295.7 mg); Off white solid; Mp: 216‐218 oC;
1H NMR (600 MHz, DMSO‐d6) δ 12.88 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H),
7.79 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.51 – 7.47 (m, 1H), 8‐Bromo‐N‐(tert‐butyl)‐2‐(2,5‐dimethoxyphenyl)‐5H‐imidazo[1,2‐
7.30 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 4.61 (s, 1H), 1.13 (s, b]indazol‐3‐amine (4k). Yield: 94 % (416.7 mg); off White solid; Mp:
o
1
9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 145.55, 137.77, 132.37, 244‐246 C; H NMR (600 MHz, DMSO‐d6) δ 11.98 (s, 1H), 7.93 (s,
132.10, 129.63, 128.64, 128.14, 128.12, 126.47, 126.46, 125.52, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.12
124.87, 122.37, 119.02, 113.95, 55.52, 30.11.; HRMS (ESI, m/z): (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.15 (s, 1H), 3.86 (s, 3H),
calcd for C19H19ClN4 (M+H+) 338.1298, found: 338.1295. Anal. Calcd: 3.78 (s, 3H), 1.04 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐d6) δ
C, 67.35; H, 5.65; N, 16.54. Found: C, 66.98; H, 5.79; N, 16.26.
153.11, 150.12, 149.74, 141.08, 130.79, 127.56, 122.41, 120.84,
119.64, 116.62, 115.66, 114.71, 113.17, 56.32, 55.58, 54.86, 29.96.;
HRMS (ESI, m/z): calcd for C21H23BrN4O2 (M+H+) 442.1004, found:
442.1008. Anal. Calcd: C, 56.89; H, 5.23; N, 12.64. Found: C, 57.09;
H, 5.47; N, 12.41.
N‐(tert‐butyl)‐2‐(2‐chlorophenyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4h). Yield: 85 % (287.2 mg); White solid; Mp: 215‐217 oC; 1H
NMR (600 MHz, DMSO‐d6) δ 13.00 (s, 1H), 8.19 (s, 1H), 8.00 (d, J =
7.7 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.40 – 7.28
(m, 2H), 7.07 – 6.98 (m, 1H), 4.69 (s, 1H), 1.10 (s, 9H); 13C{1H} NMR 8‐bromo‐N‐(tert‐butyl)‐2‐(3,4,5‐trimethoxyphenyl)‐5H‐
(150 MHz, DMSO‐ d6) δ 146.05, 138.27, 132.87, 132.60, 130.13, imidazo[1,2‐b]indazol‐3‐amine (4l). Yield: 95 % (448.3 mg); White
129.14, 128.63, 128.62, 126.98, 126.02, 122.87, 119.51, 114.45, solid; Mp: 240‐242 oC; 1H NMR (600 MHz, DMSO‐d6) δ 12.57 – 10.79
56.01, 30.60.; HRMS (ESI, m/z): calcd for C19H19ClN4 (M+H+) (m, 1H), 7.87 (s, 1H), 7.47 (s, 2H), 7.41 (d, J = 8.9 Hz, 1H), 7.26 (d, J =
338.1298, found: 338.1296. Anal. Calcd: C, 67.35; H, 5.65; N, 16.54. 8.9 Hz, 1H), 4.54 (s, 1H), 3.88 (s, 6H), 3.71 (s, 3H), 1.18 (s, 9H);
Found: C, 67.03; H, 5.85; N, 16.31.
13C{1H} NMR (150 MHz, DMSO‐ d6) δ 161.32, 153.19, 152.91,
149.77, 140.20, 136.99, 130.53, 129.30, 127.65, 126.09, 121.44,
120.50, 116.76, 106.84, 105.58, 103.78, 60.18, 56.06, 55.95, 55.02,
30.41.; HRMS (ESI, m/z): calcd for C22H25BrN4O3 (M+H+) 472.1110,
found: 472.1116. Anal. Calcd: C, 55.82; H, 5.32; N, 11.84. Found: C,
55.91; H, 5.38; N, 12.04.
N‐(tert‐butyl)‐2‐(3‐methoxyphenyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4i). Yield: 93 % (310.8 mg); Pale pink solid; Mp: 221‐224 oC;
1H NMR (600 MHz, DMSO‐d6) δ 12.37 (s, 1H), 7.77 – 7.72 (m, 2H),
7.68 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.9 Hz,
1H), 7.19 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.0 Hz, 1H), 6.84 (t, J = 7.3
Hz, 1H), 4.47 (s, 1H), 3.84 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR (150 8‐bromo‐N‐(tert‐butyl)‐2‐(4‐ethoxyphenyl)‐5H‐imidazo[1,2‐
MHz, DMSO‐d6) δ 159.30, 151.64, 139.19, 132.19, 131.55, 129.62, b]indazol‐3‐amine (4m). Yield: 88 % (374.9 mg); White solid; Mp:
125.07, 124.29, 121.74, 119.85, 119.63, 118.63, 118.43, 115.52, 215‐217 oC; 1H NMR (600 MHz, DMSO‐ d6) δ 12.54 (s, 1H), 7.96 (d, J
114.64, 113.15, 111.50, 103.44, 57.73, 55.21, 30.35.;HRMS (ESI, = 7.3 Hz, 2H), 7.85 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.0 Hz,
m/z): calcd for C20H22N4O (M+H+) 334.1794, found: 334.1789. Anal. 1H), 7.04 (d, J = 7.8 Hz, 2H), 4.44 (s, 1H), 4.07 (q, 2H), 1.34 (t, J = 6.5
Calcd: C, 71.83; H, 6.63; N, 16.75. Found: C, 71.51; H, 6.91; N, 17.04. Hz, 3H), 1.10 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 158.16,
148.96, 130.41, 127.94, 125.80, 122.65, 120.90, 120.52, 116.46,
N‐(tert‐butyl)‐2‐phenyl‐5H‐imidazo[1,2‐b]indazol‐3‐amine
(4j).
114.44, 107.40, 105.33, 63.12, 55.13, 30.19, 14.68.; HRMS (ESI,
m/z): calcd for C21H23BrN4O (M+H+) 426.1055, found: 426.1057.
Yield: 96 % (291.9 mg); Pale pink solid; Mp: 240‐242 oC; H NMR
1
8 | J. Name., 2012, 00, 1‐3
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Anal. Calcd: C, 59.02; H, 5.43; N, 13.11. Found: C, 58.94; H, 5.68; N, 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 155.64, 153.99, 153.12,
13.19.
150.31, 141.27, 129.38, 125.22, 125.16, 122.83, 119.83, 116.48,
114.90, 113.11, 110.79, 109.77, 56.32, 55.59, 54.72, 29.86.; HRMS
(ESI, m/z): calcd for C21H23FN4O2 (M+H+) 382.1805, found: 382.1809.
8‐bromo‐N‐(tert‐butyl)‐2‐(o‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
amine (4n). Yield: 86 % (341.0 mg); White solid; Mp: 230‐232 oC; 1H Anal. Calcd: C, 65.95; H, 6.06; N, 14.65. Found: C, 66.05; H, 6.26; N,
NMR (600 MHz, DMSO‐ d6) δ 12.32 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 14.73.
7.3 Hz, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.36 (d, J = 3.3 Hz, 2H), 7.34 – N‐(tert‐butyl)‐9‐fluoro‐2‐(o‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
7.29 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 4.21 (s, 1H), 2.38 (s, 3H), 0.95 amine (4r). Yield: 90 % (303.0 mg); White solid; Mp: 238‐240 oC; 1H
(s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 149.51, 137.13, 131.09, NMR (600 MHz, DMSO‐ d6) δ 13.05 (s, 1H), 7.56 – 7.46 (m, 1H), 7.36
130.64, 130.36, 130.09, 128.76, 127.50, 125.73, 125.09, 121.92, – 7.24 (m, 5H), 6.77 – 6.63 (m, 1H), 4.40 (s, 1H), 2.34 (s, 3H), 0.91 (s,
120.33, 116.74, 106.54, 104.85, 54.59, 29.96, 20.12.. HRMS (ESI, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 160.41, 160.00, 155.52,
m/z): calcd for C20H21BrN4 (M+H+) 396.0950, found: 396.0954. Anal. 153.86, 151.22, 151.19, 142.16, 137.54, 131.40, 130.30, 129.34,
Calcd: C, 60.46; H, 5.33; N, 14.10. Found: C, 60.58; H, 5.47; N, 14.34. 129.11, 129.01, 127.11, 126.23, 125.69, 122.57, 109.98, 101.39,
101.29, 95.36, 95.23, 54.78, 29.79, 20.04.; HRMS (ESI, m/z): calcd
8‐bromo‐N‐(tert‐butyl)‐2‐(p‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐
for C20H21FN4(M+H+) 336.1750, found: 336.1754. Anal. Calcd: C,
amine (4o). Yield: 91 % (360.2 mg); Off White solid; Mp: 244‐245 oC; 71.41; H, 6.29; N, 16.65. Found: C, 71.12; H, 6.38; N, 16.43.
1H NMR (600 MHz, DMSO‐ d6) δ 12.56 (s, 1H), 7.95 (d, J = 6.7 Hz,
2H), 7.86 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.32 – 7.27 (m, 3H), 4.48 (s, (E)‐N‐(tert‐butyl)‐2‐styryl‐5H‐imidazo[1,2‐b]indazol‐3‐amine (4s).
1H), 2.34 (s, 3H), 1.11 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ Yield: 95 % (314.1 mg); Brown solid; Mp: 235‐237 oC; 1H NMR (600
149.23, 137.17, 130.64, 129.26, 127.96, 127.67, 126.34, 125.65, MHz, DMSO‐ d6) δ 12.32 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.56 (d, J =
121.43, 120.58, 116.55, 107.37, 105.20, 55.22, 30.21, 20.88..; HRMS 7.4 Hz, 2H), 7.44 – 7.38 (m, 3H), 7.32 – 7.25 (m, 2H), 7.18 (t, J = 7.4
(ESI, m/z): calcd for C20H21BrN4 (M+H+) 396.0950, found: 396.0954. Hz, 1H), 7.08 (d, J = 16.5 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 4.72 (s, 1H),
Anal. Calcd: C, 60.46; H, 5.33; N, 14.10. Found: C, 60.38; H, 5.51; N, 1.25 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐d6) δ 151.96, 136.99,
14.36.
132.64, 129.17, 128.97, 128.13, 127.47, 125.96, 125.27, 125.11,
124.40, 123.86, 118.59, 116.40, 115.64, 114.73, 102.99, 79.21,
54.78, 30.07.;HRMS (ESI, m/z): calcd for C21H22N4 (M+H+) 330.1844,
8‐bromo‐N‐(tert‐butyl)‐2‐(2‐chlorophenyl)‐5H‐imidazo[1,2‐
b]indazol‐3‐amine (4p). Yield: 86 % (358.1 mg); White solid; Mp: found: 330.1846. Anal. Calcd: C, 76.33; H, 6.71; N, 16.96. Found: C,
o
1
223‐225 C; H NMR (600 MHz, DMSO‐ d6) δ 12.32 (s, 1H), 7.85 (s, 75.93; H, 6.78; N, 17.04.
1H), 7.74 (d, J = 7.1 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.51 – 7.47 (m,
2H), 7.44 (d, J = 10.0 Hz, 1H), 7.28 (d, J = 9.1 Hz, 1H), 4.16 (s, 1H), N‐(tert‐butyl)‐9‐fluoro‐2‐(furan‐2‐yl)‐5H‐imidazo[1,2‐b]indazol‐3‐
0.97 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ 158.33, 149.71, amine (4t). Yield: 88 % (275.0 mg); Off White solid; Mp: 233‐235 oC;
134.72, 133.24, 133.19, 133.06, 130.63, 130.52, 130.20, 129.80, 1H NMR (600 MHz, DMSO‐d6) δ 12.51 (s, 1H), 7.82 (s, 1H), 7.23 (d, J
128.21, 127.78, 127.75, 127.27, 122.74, 120.51, 116.76, 106.72, = 8.6 Hz, 1H), 7.14 (m, 1H), 7.02 (s, 1H), 6.66 (m, 1H), 6.59 – 6.53
54.57, 29.83.; HRMS (ESI, m/z): calcd for C19H18BrClN4 (M+H+) (m, 1H), 4.48 (s, 1H), 1.22 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐d6)
416.0403, found: 416.0407. Anal. Calcd: C, 54.63; H, 4.34; N, 13.41. δ 155.63, 153.99, 144.80, 142.42, 125.54, 125.53, 125.49, 125.48,
Found: C, 54.38; H, 4.43; N, 13.46.
121.67, 111.78, 110.82, 110.80, 110.79, 107.48, 79.21, 54.94,
30.22.; HRMS (ESI, m/z): calcd for C17H17FN4O (M+H+) 312.1386,
found: 312.1389. Anal. Calcd: C, 65.37; H, 5.49; N, 17.94. Found: C,
N‐(tert‐butyl)‐2‐(2,5‐dimethoxyphenyl)‐9‐fluoro‐5H‐imidazo[1,2‐
b]indazol‐3‐amine (4q). Yield: 92 % (351.5 mg); Off white solid; Mp: 65.03; H, 5.63; N, 18.04.
243‐245 oC; 1H NMR (600 MHz, DMSO‐ d6) δ 12.35 (s, 1H), 7.24 (d, J
= 7.4 Hz, 2H), 7.17 – 7.08 (m, 2H), 7.00 (d, J = 8.9 Hz, 1H), 6.54 (t, J = 7‐bromo‐N‐(tert‐butyl)‐2‐(furan‐2‐yl)‐5H‐imidazo[1,2‐b]indazol‐3‐
8.8 Hz, 1H), 3.99 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 1.00 (s, 9H); amine (4u). Yield: 85 % (316.0 mg); White solid; Mp: 241‐243 oC; 1H
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NMR (600 MHz, DMSO‐ d6) δ 12.21 (s, 1H), 7.92 (d, J = 7.4 Hz, 2H), m/z): calcd for C23H26N4O2 (M+H+) 390.2056, found: 390.2051. Anal.
7.48 (s, 2H), 7.10 (d, J = 2.7 Hz, 1H), 6.71 (dd, J = 3.3, 1.7 Hz, 1H), Calcd: C, 70.75; H, 6.71; N, 14.35. Found: C, 70.45; H, 6.93; N, 14.46.
4.71 (s, 1H), 1.22 (s, 9H); 13C{1H} NMR (150 MHz, DMSO‐ d6) δ
157.23, 143.71, 142.99, 131.42, 127.40, 121.87, 121.21, 115.80, 2‐(4‐chlorophenyl)‐N‐cyclohexyl‐5H‐imidazo[1,2‐b]indazol‐3‐
115.78, 112.16, 108.28, 99.51, 55.65, 30.07.; HRMS (ESI, m/z): calcd amine (4y). Yield: 91 % (331.3 mg); Off White solid; Mp: 228‐230 oC;
for C17H17BrN4O (M+H+) 372.0586, found: 372.0588. Anal. Calcd: C, 1H NMR (600 MHz, DMSO‐ d6) δ 12.38 (s, 1H), 8.06 (d, J = 8.5 Hz,
54.59; H, 4.63; N, 15.01. Found: C, 54.70; H, 4.59; N, 15.29.
2H), 7.73 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.6
Hz, 1H), 7.23 – 7.18 (m, 1H), 6.85 (t, J = 7.4 Hz, 1H), 4.81 (d, J = 5.3
N‐(tert‐butyl)‐9‐fluoro‐2‐(thiophen‐2‐yl)‐5H‐imidazo[1,2‐b]indazol‐ Hz, 1H), 3.59 – 3.50 (m, 1H), 1.82 – 1.76 (m, 2H), 1.66 – 1.62 (m,
o
3‐amine (4v). Yield: 89 % (292.0 mg); White solid; Mp: 225‐227 C; 2H), 1.54 – 1.47 (m, 1H), 1.29 – 1.22 (m, 2H), 1.20 – 1.11 (m, 3H);
1H NMR (600 MHz, DMSO‐ d6) δ 12.26 (s, 1H), δ 7.75 (d, J = 3.3 Hz, 13C{1H} NMR (150 MHz, DMSO‐d6) δ 152.07, 131.81, 131.33, 129.48,
1H), 7.56 (d, J = 4.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.17 – 7.11 (m, 128.76, 127.01, 125.32, 123.75, 123.41, 120.00, 118.70, 115.70,
2H), 6.62 – 6.55 (m, 1H), 4.50 (s, 1H), 1.28 (s, 9H); 13C{1H} NMR (150 114.62, 103.37, 53.98, 33.14, 25.54, 24.26; HRMS (ESI, m/z): calcd
MHz, DMSO‐ d6) δ 155.88, 155.63, 153.99, 138.44, 133.86, 131.04, for C21H21ClN4 (M+H+) 364.1455, found: 364.1461. Anal. Calcd: C,
128.32, 126.73, 126.35, 125.44, 125.39, 124.71, 120.79, 110.91, 69.13; H, 5.80; N, 15.36. Found: C, 68.94; H, 5.91; N, 15.63.
54.66, 30.46.; HRMS (ESI, m/z): calcd for C17H17FN4S (M+H+)
328.1158, found: 328.1161. Anal. Calcd: C, 62.17; H, 5.22; N, 17.06. N‐cyclohexyl‐2‐(p‐tolyl)‐5H‐imidazo[1,2‐b]indazol‐3‐amine
(4z).
o
1
Found: C, 62.03; H, 5.41; N, 17.36.
Yield: 88 % (303.0 mg); White solid; Mp: 216‐218 C; H NMR (600
MHz, DMSO‐ d6) δ 12.26 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.73 (d, J =
8.1 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 –
N‐cyclohexyl‐2‐(3,4,5‐trimethoxyphenyl)‐5H‐imidazo[1,2‐
b]indazol‐3‐amine (4w). Yield: 94 % (394.8 mg); Off White solid; 7.17 (m, 1H), 6.83 (t, J = 7.4 Hz, 1H), 4.65 (d, J = 5.4 Hz, 1H), 3.56 –
Mp: 217‐219 oC; 1H NMR (600 MHz, DMSO‐ d6) δ 12.30 (s, 1H), 7.74 3.46 (m, 1H), 2.34 (s, 3H), 1.81 – 1.76 (m, 2H), 1.68 – 1.62 (m, 2H),
(d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.9 Hz, 3H), 7.23 – 7.18 (m, 1H), 6.85 1.53 – 1.46 (m, 1H), 1.29 – 1.20 (m, 2H), 1.19 – 1.10 (m, 3H); 13C{1H}
(t, J = 7.4 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H), 3.89 (s, 6H), 3.71 (s, 3H), NMR (150 MHz, DMSO‐d6) δ 151.84, 136.35, 131.40, 129.27,
3.62 – 3.49 (m, 1H), 1.85 – 1.78 (m, 2H), 1.71 – 1.65 (m, 2H), 1.54 – 127.73, 125.38, 125.04, 122.61, 121.21, 118.61, 115.49, 114.50,
1.49 (m, 1H), 1.35 – 1.27 (m, 2H), 1.22 – 1.13 (m, 3H); 13C{1H} NMR 103.49, 54.04, 33.17, 25.57, 24.26, 20.82; HRMS (ESI, m/z): calcd for
(150 MHz, DMSO‐ d6) δ 153.07, 151.94, 136.53, 131.27, 126.04, C22H24N4 (M+H+) 344.2001, found: 344.2006. Anal. Calcd: C, 76.71;
125.17, 122.77, 121.08, 118.53, 115.69, 114.60, 103.44, 102.80, H, 7.02; N, 16.27. Found: C, 76.83; H, 7.16; N, 16.29.
60.17, 55.98, 53.91, 51.03, 33.30, 25.61, 24.20.; HRMS (ESI, m/z):
calcd for C24H28N4O3 (M+H+) 420.2161, found: 420.2167. Anal. 8‐bromo‐N‐cyclohexyl‐2‐(3,4,5‐trimethoxyphenyl)‐5H‐imidazo[1,2‐
Calcd: C, 68.55; H, 6.71; N, 13.32. Found: C, 68.39; H, 6.78; N, 13.43. b]indazol‐3‐amine (4aa). Yield: 92 % (458.5 mg); White solid; Mp:
o
1
238‐240 C; H NMR (600 MHz, DMSO‐ d6) δ 12.37 (s, 1H), 7.85 (s,
1H), 7.44 (d, J = 9.1 Hz, 1H), 7.40 (s, 2H), 7.28 (dd, J = 9.1, 2.0 Hz,
N‐cyclohexyl‐2‐(2,5‐dimethoxyphenyl)‐5H‐imidazo[1,2‐b]indazol‐
3‐amine (4x). Yield: 89 % (347.0 mg); Off White solid; Mp: 214‐216 1H), 4.83 (d, J = 5.6 Hz, 1H), 3.89 (s, 6H), 3.71 (s, 3H), 3.58 – 3.50 (m,
oC; 1H NMR (600 MHz, DMSO‐ d6) δ 11.92 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 1.83 – 1.77 (m, 2H), 1.71 – 1.64 (m, 2H), 1.54 – 1.48 (m, 1H),
1H), 7.45 – 7.40 (m, 2H), 7.21 – 7.17 (m, 1H), 7.11 (d, J = 9.1 Hz, 1H), 1.34 – 1.25 (m, 2H), 1.22 – 1.13 (m, 3H); 13C{1H} NMR (150 MHz,
6.96 – 6.93 (m, 1H), 6.83 – 6.79 (m, 1H), 4.47 (d, J = 8.0 Hz, 1H), 3.85 DMSO‐d6) δ 153.08, 150.18, 136.76, 130.39, 127.77, 125.66, 122.87,
(s, 3H), 3.78 (s, 3H), 3.66 – 3.57 (m, 1H), 1.81 – 1.73 (m, 2H), 1.62 – 121.57, 120.45, 116.74, 106.89, 104.67, 102.98, 60.16, 55.97, 53.90,
1.55 (m, 2H), 1.51 – 1.42 (m, 1H), 1.19 – 1.10 (m, 5H); 13C{1H} NMR 33.27, 25.57, 24.16.; HRMS (ESI, m/z): calcd for C24H27BrN4O3
(150 MHz, DMSO‐ d6) δ 153.24, 151.96, 149.79, 131.81, 125.10, (M+H+) 498.1267, found: 498.1271. Anal. Calcd: C, 57.72; H, 5.45; N,
124.04, 119.75, 118.95, 115.29, 115.19, 114.98, 114.34, 113.96, 11.22. Found: C, 57.58; H, 5.61; N, 11.28.
113.25, 103.39, 56.29, 55.52, 52.76, 33.22, 25.49, 24.21; HRMS (ESI,
10 | J. Name., 2012, 00, 1‐3
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Journal Name
ARTICLE
8‐bromo‐N‐cyclohexyl‐2‐(2,5‐dimethoxyphenyl)‐5H‐imidazo[1,2‐
154.41, 154.38, 147.63, 142.34, 142.30, 138.02, 137.19, 133.28,
b]indazol‐3‐amine (4ab). Yield: 90 % (422.0 mg); White solid; Mp: 131.80, 131.74, 126.56, 123.43, 120.02, 113.18, 111.13, 105.66,
o
1
233‐235 C; H NMR (600 MHz, DMSO‐ d6) δ 11.96 (s, 1H), 7.95 (s, 105.54, 103.60, 103.48.; HRMS (ESI, m/z): calcd for C17H9BrFN3O2
1H), 7.50 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.26 (dd, J = 9.1, 2.0 Hz, (M+H+) 384.9862, found: 384.9866. Anal. Calcd: C, 52.87; H, 2.35; N,
1H), 7.11 (d, J = 9.1 Hz, 1H), 6.95 (dd, J = 9.0, 3.1 Hz, 1H), 4.55 (d, J = 10.88. Found: C, 52.68; H, 2.48; N, 10.94.
7.5 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.62 – 3.51 (m, 1H), 1.80 –
1.71 (m, 2H), 1.64 – 1.55 (m, 2H), 1.50 – 1.43 (m, 1H), 1.19 – 1.09 (5‐bromo‐2‐hydroxyphenyl)(pyrimido[1,2‐b]indazol‐3‐
(m, 5H); 13C{1H} NMR (150 MHz, DMSO‐d6) δ 153.21, 150.22, yl)methanone (7d). Yield: 97 % (357.2 mg); Yellow solid; Mp: 188‐
149.85, 130.75, 127.72, 124.03, 120.99, 119.28, 116.44, 116.26, 190 oC; 1H NMR (600 MHz, DMSO‐ d6) δ 10.75 (s, 1H), 9.63 (s, 1H),
114.83, 114.20, 113.22, 106.44, 104.69, 56.27, 55.51, 52.99, 33.19, 8.97 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.72 –
25.46, 24.18.; HRMS (ESI, m/z): calcd for C23H25BrN4O2 (M+H+) 7.64 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H); 13C{1H}
468.1161, found: 468.1158. Anal. Calcd: C, 58.85; H, 5.37; N, 11.94. NMR (150 MHz, DMSO‐ d6) δ 190.65, 155.79, 152.38, 145.86,
Found: C, 58.68; H, 5.43; N, 11.98.
143.37, 137.47, 136.48, 132.68, 130.77, 126.27, 122.52, 121.69,
120.76, 119.44, 116.35, 112.53, 110.61.; HRMS (ESI, m/z): calcd for
(2‐hydroxyphenyl)(pyrimido[1,2‐b]indazol‐3‐yl)methanone (7a). C17H10BrN3O2 (M+H+) 366.9956, found: 366.9958. Anal. Calcd: C,
Yield: 97 % (280.3 mg); Yellow solid; Mp: 160‐162 oC; 1H NMR (600 55.46; H, 2.74; N, 11.41. Found: C, 55.06; H, 2.83; N, 11.38.
MHz, DMSO‐ d6) δ 10.54 (s, 1H), 9.54 (s, 1H), 8.92 (s, 1H), 8.24 (d, J =
8.2 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.58 –
Conflicts of interest
7.48 (m, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.00 (m, 2H); 13C{1H} NMR (150
There are no conflicts of interest to declare.
MHz, DMSO‐ d6) δ 192.32, 157.09, 152.27, 145.97, 143.30, 137.06,
134.64, 131.17, 130.70, 123.83, 123.00, 121.63, 120.76, 119.67,
References
117.14, 116.33, 112.53.; HRMS (ESI, m/z): calcd for C17H11N3O2
(M+H+) 289.0851, found: 289.0854. Anal. Calcd: C, 70.58; H, 3.83; N,
14.53. Found: C, 70.43; H, 3.98; N, 14.48.
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DOI: 10.1039/C7OB02933K
An Approach towards the Synthesis of Novel Fused Nitrogen
Tricyclic Heterocyclic Scaffolds via GBB Reaction
Sandip Gangadhar Balwe, Yeon Tae Jeong*
Department of Image Science and Engineering,
Pukyong National University,
Busan 608-737, Republic of Korea
fax: +82 51 629 6408;
*Corresponding author E-mail: ytjeong@pknu.ac.kr