Lewis-acid Promoted Chemoselective Condensation of 2-Aminobenzimidazoles or 3-Aminoindazoles with 3-Ethoxycyclobutanones to Construct Fused Nitrogen heterocycles

Article abstract of DOI:10.1002/adsc.201701641

A Lewis-acid promoted chemoselective condensation of 2-aminobenzimidazoles or 3-aminoindazoles with 3-ethoxycyclobutanones is presented. Diverse fused heterocycles benzo[4,5]-imidazo[1,2-a]pyrimidine and pyrimido[1,2-b]-indazole derivatives were obtained in moderate to high yields under mild conditions, the reaction mechanism of which was in sharp contrast to previous [3+3] annulation reaction of 3-ethoxycyclobutanones. (Figure presented.).

Full text of DOI:10.1002/adsc.201701641

Title: Lewis-acid Promoted Chemoselective Condensation of
2-Aminobenzimidazoles or 3-Aminoindazoles with 3-
Ethoxycyclobutanones to Construct Fused Nitrogen Heterocycles
Authors: Weiguang Kong, Yao Zhou, and Qiuling Song
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701641
Link to VoR: http://dx.doi.org/10.1002/adsc.201701641

10.1002/adsc.201701641
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Lewis-acid Promoted Chemoselective Condensation of 2-
Aminobenzimidazoles
Ethoxycyclobutanones
heterocycles
or
to
3-Aminoindazoles
Construct Fused
with
3-
Nitrogen
Weiguang Kong,a,b Yao Zhou,a,b Qiuling Songa,*
a
Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei
Blvd, Xiamen, Fujian, 361021, P. R. China
W. Kong and Y. Zhou contributed equally to this work.
b
fax:(+86)-592-6162990; email: qsong@hqu.edu.cn
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))
analgesic/anti-inflammatory activities.[4] Compound
Abstract:
condensation
A
Lewis-acid promoted chemoselective
of 2-aminobenzimidazoles or
3- D is a commercial drug—Zaleplon, which has the
hypnotic and sedative effects for the therapy of
insomnia.[5] These important benzo[4,5]-imidazo[1,2-
aminoindazoles with 3-ethoxycyclobutanones is presented.
Diverse fused heterocycles benzo[4,5]-imidazo[1,2-
a]pyrimidine and pyrimido[1,2-b]-indazole derivatives
were obtained in moderate to high yields under mild
conditions, the reaction mechanism of which was in sharp
contrast to previous [3+3] annulation reaction of 3-
ethoxycyclobutanones.
a]pyrimidine
derivatives
and
could
pyrimido[1,2-b]-indazole7
be achieved from 2-
aminobenzimidazoles and 3-aminoindazoles, which
are two families of the most important classes of
heterocycles for drug and material development
purposes. In recent years, condensation of 2-
aminobenzimidazoles and 3-aminoindazoles with
carbonyl compounds is the frequent and effective
tactic for the construction of benzo[4,5]-imidazo[1,2-
Keywords: chemoselective condensation; benzo[4,5]-
imidazo[1,2-a]pyrimidine; pyrimido[1,2-b]-indazole; 3-
ethoxycyclobutanones; [3+3] annulation
a]pyrimidine[6]
and
pyrimido[1,2-b]-indazole
derivatives.[7] However, all the three adjacent
Due to the important biological activity and
therapeutic effect, fused nitrogen heterocyclic
skeletons are present in a broad range of natural
products and synthetic molecules.[1] Among them,
benzo[4,5]-imidazo[1,2-a]pyrimidine
and
pyrimido[1,2-b]-indazole derivatives have emerged
as two frequent scaffolds. As shown in Figure 1,
compound A (T808) can work as a specific PET
tracer for imaging of Tau Pathologies.[2] Compound B
displays good antiinflammatory activity against IL-6
Scheme 1. Chemoselective condensation of 2-
aminobenzimidazoles or 3-aminoindazoles
nucleophilic nitrogens in 2-aminobenzimidazoles and
3-aminoindazoles could attack and condense the
carbonyl group, leading to the inseparable
regioisomers, which might limit the application of 2-
Figure 1. Some representatively bioactive compounds.
and TNF-α,[3] and compound C exhibits decent
biological properties, such as anticancer and
1
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10.1002/adsc.201701641
Advanced Synthesis & Catalysis
condense
the
2,2-dimethyl-3-
aminobenzimidazoles and 3-aminoindazoles to
construct fused N-heterocycles. Therefore, the
development of an efficient and facile method to
accomplish the chemoselective reaction of these three
nucleophilic nitrogens is highly desirable and poses a
significant challenge. In generally, when 2-
aminobenzimidazoles and 3-aminoindazoles were
used to access N-heterocycles, the free primary NH2
group condensed of the carbonyl compounds
preferentially and then other annulation reactions
occurred (Scheme 1a Path A). The publications in
which efficient cyclization reactions stem from the
N1 or N2 in 3-aminoindazoles and N1 or N3 in 2-
aminobenzimidazoles are relatively rare (Scheme 1a
Path B).[6k]
ethoxycyclobutanone (2a), which might ferment
different reaction pathways to render various
products (Scheme 2). The exact structure of the
product was confirmed by the X-ray
crystallographic analysis,[13] which revealed that
the product we obtained was 3a rather than 3aa
.
Having identified the product structure, we then
turned our attention to optimize the reaction
conditions for this chemoselective condensation
(Table 1). When the reaction was performed using
o
BF3Et2O as Lewis-acid in MeCN at 80 C, 89%
yield of 3a was gained (Table 1, entry 1).
Subsequently, we tested other Lewis-acids (Table 1,
entries 2-5). Among the Lewis-acids investigated,
BF3Et2O still demonstrated the optimal efficiency.
We also screened the solvent effects on this
transformation and it turned out DCM was the best
choice (Table 1, entry 6). The attempt to reduce the
reaction temperature slightly decreased the yield of
3a (Table 1 entries 12-13). Disappointingly, only
marginal improvements were acquired when we
changed the loading of BF3Et2O (Table 1, entries
14-15). To our delight, the yield of 3a has no distinct
influence when we shorten the reaction time to 6 h
(Table 1, entry 16).
In recent years, 3-ethoxycyclobutanones has
emerged as
a
fruitful synthon to build N-
heterocycles.[8] For example, Matsuo’s group
developed the [4+2] cycloaddition reactions[9] and
Rao’s group discovered the [3+3] annulation
reactions[10] by employing 3-ethoxycyclobutanones as
annulation partners. Very recently, our group also
demonstrated a [3+3] annulation reaction between 3-
ethoxycyclobutanones and enamines or amidines
towards substituted pyrimidine and pyridine
derivatives.[11] Although 3-ethoxycyclobutanones
have been used for preparation of various nitrogen
heterocycles, the 3-ethoxycyclobutanones have never
been employed to construct the important benzo[4,5]-
Table 1. Screening of the reaction conditions
imidazo[1,2-a]pyrimidine
and
pyrimido[1,2-b]-
indazole derivatives. As part of our ongoing interest
in activation of cyclobutanones,[11,12] we herein report
transition-metal free synthesis of benzo[4,5]-
imidazo[1,2-a]pyrimidine
and
pyrimido[1,2-b]-
indazole derivatives via chemoselective condensation
of 2-aminobenzimidazoles and 3-aminoindazoles
with 3-ethoxycyclobutanones, in which the
heteroatomic nitrogen rather than the free primary
NH2 of 2-aminobenzimidazoles or 3-aminoindazoles
condensed 3-ethoxycyclobutanones preferentially
(Scheme 1b).
At the outset of our investigation, commercial 1H-
indazol-3-amine
(1a)
and
2,2-dimethyl-3-
ethoxycyclobutanone (2a) condensed in the presence
of BF3Et2O in CH3CN at reflux temperature for 12 h.
As expected, a white solid was obtained after column
Having established the optimal reaction conditions,
the substrate scope of this chemoselective
condensation of 3-aminoindazoles with 3-
ethoxycyclobutanones was examined firstly (Scheme
3). A series of 3-ethoxycyclobutanones (2a-2g)
proved to be efficient annulation partners and
Scheme 3. Substrate scope for the synthesis of various
pyrimido[1,2-b]-indazoles
Scheme 2. Condensation of 1H-indazol-3-amine 1a with
2,2-dimethyl-3-ethoxycyclobutanone (2a)
chromatography. However, the accurate structure
of the product was unambiguously for the fact
that the three adjacent nucleophilic nitrogens in
1H-indazol-3-amine
(1a
)
could attack and
2
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10.1002/adsc.201701641
Advanced Synthesis & Catalysis
Scheme 4. Proposed Reaction Mechanism
deliver the products. To understand the reaction
mechanism, we cultivated several crystals and the
X- ray crystallographic analysis of 3a, 3g and 3o
confirmed the accurate position of the isopropyl,
which was in sharp contrast to previous
documents. Based on the reaction mechanism of
previous reports,[10,11] when anilines, hydrazines,
enamine and amidines reacted with 3-
ethoxycyclobutanones, the free primary NH2
group condensed of the carbonyl group
preferentially and then other intramolecular
annulation reactions occurred. If so, the product
in this transformation should be 3aa in which the
isopropyl was adjacent to nitrogen-atom of the
free primary NH2 group (path b in Scheme 4).
However, the product we acquired was 3a, which
implied the presence of unique reaction
mechanism of this transformations and it might
undergo the path a in Scheme 4 to give the
delivered the desired products (3a-3g) in good to
excellent yields. Similarly smooth transformations
were also achieved for 3-aminoindazoles bearing
various groups at different positions of the phenyl
ring. For instance, electron-donating groups
substituted 3-aminoindazoles 1h and 1i were good
candidates in this transformation, delivering the
corresponding pyrimido[1,2-b]-indazoles in 79% and
83% yield, respectively. Electron-withdrawing
groups substituted 3-aminoindazoles 1j-1l were
amenable to this transformation as well, rendering the
expected products 3j-3l in good to high yields. To our
delight, heteroaromatic 3-aminoindazoles 1m and 1n
could work smoothly under standard conditions as
well, giving the desired products 3m and 3n in good
yields. In addition to 3-aminoindazoles, 3-
aminopyrazoles such as 1o-1q were also good
substrates in this transformation and produced the
targeted products 3o-3q in 77%, 90% and 87% yields,
respectively.
product 3a
cyclobutanone 2a
substituted C2–C3 bond to form the zwitterionic
intermediate A [8-11,14]
which further was attacked
by 3-aminoindazole 1a to generate the
intermediate . Elimination of Lewis-acids and
one molecule of EtOH from intermediate
provides intermediate Subsequently,
intramolecular attack the carbonyl group by the
N2 in 3-aminoindazoles renders intermediate
which undergoes elimination of one molecule of
H2O to furnish the product 3a
.
Firstly, BF3
Et2O activates
via cleaving the more
,
B
B
C.
E,
.
Inspired by the successful synthesis of various
pyrimido[1,2-b]-indazoles via chemoselective
condensation of 3-aminoindazoles and 3-
ethoxycyclobutanones. Next we focused on the
scope for the reaction of 2-aminobenzimidazoles
and 3-ethoxycyclobutanones. As summarized in
Scheme 5, a series of benzo[4,5]-imidazo[1,2-
a]pyrimidine derivatives were synthesized by the
As depicted in Scheme 4, when 3-aminoindazoles
reacted with 3-ethoxycyclobutanones, there are two
possible pathways for condensation and annulation to
3
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10.1002/adsc.201701641
Advanced Synthesis & Catalysis
Sheme 5. Substrate scope for the synthesis of various
Benzo[4,5]-imidazo[1,2-a]pyrimidines
We also explored the scalability of this
chemoselective condensation of 3-aminoindazoles
with 3-ethoxycyclobutanones. When current protocol
was performed with 5 mmol of 1a, the desired
product 3a was obtained in good yield without loss of
efficiency (eq 1).
Recently, our group disclosed an effective
palladium-catalyzed reduction of N-heterocyclic
compounds
via
diboron-assisted
transfer
hydrogenation of water.[15] We were inquisitive
whether the benzo[4,5]-imidazo[1,2-a]pyrimidine and
pyrimido[1,2-b]-indazole derivatives of current
protocol could be reduced. To our delight, when 4-
isopropylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine
3k was subjected to the hydrogenation reactions, the
selective reduction of this fused N-heterocycles did
occur and delivered the product 6k in good yield
(Scheme 6).
Scheme 6. Selective reduction of 3k
In summary, a facile and one-pot method has been
developed for the synthesis of benzo[4,5]-
imidazo[1,2-a]pyrimidine
and
pyrimido[1,2-b]-
indazole derivatives in moderate to high yields. The
desired fused nitrogen heterocycles were obtained via
Lewis-acid promoted chemoselective condensation of
2-aminobenzimidazoles or 3-aminoindazoles with 3-
ethoxycyclobutanones, the reaction mechanism of
which was in sharp contrast to previous [3+3]
annulation reaction of 3-ethoxycyclobutanones. It is
noteworthy that the current protocol could be readily
scaled up without loss of the efficiency.
reaction
aminobenzimidazoles
ethoxycyclobutanones
benzo[d]imidazol-2-amines such as fluorine,
chlorine and bromine were well compatible in
this transformation, affording the desired
benzo[4,5]-imidazo[1,2-a]pyrimidines (5b
moderate yields. Although the isomers were
observed when mono-substituted 2-
aminobenzimidazoles (4b 4d) were employed, a
of
differently
substituted
and
2-
3-
4
2
.
Halo-substituted 1H-
-5d) in
-
single configuration was obtained when electron-
donating groups were installed on 2-
aminobenzimidazoles. For instance, 5-methyl-
1H-benzo[d]imidazol-2-amine 4e produced the
corresponding product 5e in 69% yield and no
Experimental Section
General process for the synthesis of 3:
BF3Et2O (42.6 mg, 0.3 mmol, 1.0 equiv) was added to a
mixture of 1H-indazol-3-amine 1 (0.3 mmol, 1 equiv),
cyclobutanones 2 (0.3 mmol, 1.5 equiv) in DCM or
CH3CN (1 mL). Then the sealed tube was stirred at 80 °C
for 6~12 h. Upon completion of the reaction, the solvent
was evaporated under reduced pressure and the residue
was purified by flash column chromatograph (silica gel,
petroleum ether:EtOAc = 20:1, v/v) to give the desired
product 3.
1
isomer was detected from H-NMR. In addtion to
the mono-substituted 2-aminobenzimidazoles, the
bis-substituted 2-aminobenzimidazole 4f was also
good candidate for this [3+3] annulation and
delivered the targeted product 5f in 71% yield.
Subsequently,
a
variety
of
3-
ethoxycyclobutanones were investigated under
standard conditions, which turned out that they
were both amenable to this transformation and
General process for the synthesis of 5:
BF3Et2O (42.6 mg, 0.3 mmol, 1.0 equiv) was added to a
mixture of 1H-benzo[d]imidazol-2-amine 4 (0.3 mmol, 1
equiv), cyclobutanones 2 (0.3 mmol, 1.5 equiv) in CH3CN
(1 mL). Then the sealed tube was stirred at 80 °C for 18 h.
Upon completion of the reaction, the solvent was
evaporated under reduced pressure and the residue was
purified by flash column chromatograph (silica gel,
MeOH:EtOAc = 1:100, v/v) to give the desired product 5.
provided
the
corresponding
benzo[4,5]-
imidazo[1,2-a]pyrimidines (5g
-
5l) in moderate to
good yields.
4
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10.1002/adsc.201701641
Advanced Synthesis & Catalysis
Acknowledgements
Ho, P. D. Q. Dao, C. S. Cho, Synlett 2017, 28, 1811; c)
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Financial supported by Recruitment Program of Global Experts
(1000 Talents Plan), the Natural Science Foundation of Fujian
Province (2016J01064), Fujian Hundred Talents Plan, Program
of Innovative Research Team of Huaqiao University (Z14X0047)
and Subsidized Project for Cultivating Postgraduates ’
Innovative Ability in Scientific Research of Huaqiao University
(for Y. Z.) are gratefully acknowledged. We also thank the
Instrumental Analysis Center of Huaqiao University for analysis
support.
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5
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10.1002/adsc.201701641
Advanced Synthesis & Catalysis
COMMUNICATION
Lewis-acid Promoted Chemoselective
Condensation of 2-Aminobenzimidazoles or 3-
Aminoindazoles with 3-Ethoxycyclobutanones to
Construct Fused Nitrogen heterocycles
Adv. Synth. Catal. Year, Volume, Page – Page
Weiguang Kong,a,b Yao Zhou,a,b Qiuling Songa,*
6
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