Rh-Catalyzed Annulation of ortho-C?H Bonds of 2-Arylimidazoles with 1,4,2-Dioxazol-5-ones toward 5-Arylimidazo[1,2-c]quinazolines

Article abstract of DOI:10.1002/adsc.201701331

A Rh-catalyzed unique and direct approach for constructing a series of 5-arylimidazo[1,2-c]quinazolines in moderate to excellent yields from simple and readily available 2-arylimidazoles and 3-phenyl-1,4,2-dioxazol-5-ones was described. This procedure pro

Full text of DOI:10.1002/adsc.201701331

Title: Rh-Catalyzed Annulation of ortho- C-H Bonds of 2-Arylimidazoles
with 1,4,2-Dioxazol-5-ones toward 5-Arylimidazo[1,2-
c]quinazolines
Authors: Xiaopeng Wu, Song Sun, Shengbo Xu, and Jiang Cheng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701331
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10.1002/adsc.201701331
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial sttaff))
Rh-Catalyzed Annulation of ortho- C-H Bonds of 2-Arylimidazoles with
1,4,2-Dioxazol-5-ones toward 5-Arylimidazo[1,2-c]quinazolines
Xiaopeng Wu, Song Sun, Shengbo Xu, and Jiang Cheng*
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu
Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China.
Fax: (+86)519-8633-0257; E-mail: jiangcheng@cczu.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))
straightforward and halo-free methods starting from
series of 5-arylimidazo[1,2- readily available substrates kept highly desired goal
Abstract: A Rh-catalyzed unique and direct approach
for constructing
a
c]quinazolines in moderate to excellent yields from
simple and readily available 2-arylimidazoles and 3-
phenyl-1,4,2-dioxazol-5-ones was described. This
procedure proceeds with sequential ortho- C-H bond
amidation and cyclization, which represents a facile and
straightforward pathway to access such frameworks.
for organic chemists to access such frameworks.
Keywords: Rhodium catalysis; amidation; annulation;
dioxazolones; quinazolines
Imidazo[1,2-c]quinazolines
were
widely
recognized as antitumor, [1] antimicrobial, [2] antiviral,
antimicrobial[4] and anticonvulsants[5] agents. Thus,
[3]
the construction of such frameworks has drawn much
attention for organic chemists.
Recently, Fu developed copper-catalyzed reaction
between
2-(2-halophenyl)benzoimidazoles
and
amidines leading to imidazo[1,2-c]quinazolines
(Scheme 1, eq 1).[6] Afterwards, Zhang described
copper-catalyzed sequential Ullmann N-arylation and
aerobic oxidative C-H amination to access indolo[1,2-
c]quinazolines (Scheme 1, eq 2).[7] Meanwhile,
Korshin demonstrated a sequential procedure leading
[8]
Scheme 1. Pathways toward Imidazo[1,2-c]quinazolines.
to imidazo[1,2-c]quinazolines (Scheme 1, eq 3).
Very recently, Xi reported the CuI-catalyzed
intramolecular N-arylation toward such frameworks
(Scheme 1, eq 4).[9] Nevertheless, the aforementioned
procedures required the employment of ortho-
fuctionalized (Br, Cl and NH2, etc.) aromatic starting
material, which reduced the synthetical practibility
and the diversity of the final product. Thus, the
Meanwhile,
with
the
development
of
organometallic chemistry, 1,4,2-dioxazol-5-ones were
applied in C-H amidation reactions. [10] Moreover, in
combined with the sequential cyclization step, they
served as subunits to access polysubstituted 4-
aminooxazoles, [11] benzimidazoles, [12] quinazolines
1
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10.1002/adsc.201701331
Advanced Synthesis & Catalysis
and their derivatives, [13] functionalized oxazoles, [14] reaction. To our delight, the annulation yield
[15]
and azolopyrimidines.
These aforementioned dramatically increased to 66% in dioxane (2.5 mL)
elegant examples spurred us to test the feasibility of containing 0.4 mmol of HOAc (Table 1, entry 6).
the reaction between 2-arylimidazoles and 1,4,2- Among the tested combination, such as HOAc/MeCN
dioxazol-5-ones toward imidazo[1,2-c]quinazolines (33%, Table 1, entry 8) and HOAc/toluene (69%,
whereby the sequential C-H amidation and cyclization Table 1, entry 9), HOAc/DCE was the best (73%,
(Scheme 1, eq 5). Compared to the reported examples Table 1, entry 7). The catalytic system
leading to imidazo[1,2-c]quinazolines, this procedure [Cp*IrCl2]2/AgSbF6 provided the annulated product
is characterized by: 1) the readily available starting 3aa in 65% yield (Table 1, entry 10). [Cp*RhCl2]2
material; 2) free of halo functionalization handles. exhibited lower catalytic activity in the absence of Ag
Herein, we wish to report our study on it.
salt (23%, Table 1, entry 11). The reaction efficiency
decreased under N2 (67%) or O2 (71%), and so did the
reaction conducting under lower reaction temperature
(110 oC, 57%; 100 oC, 45%, Table 1, entry 12).
Table 1. Screening the optimized reaction condition.[a]
Scheme 2. Substrates scope of substituted 2-
phenylimidazoles. [a], [b]
3a(%)[b] 3aa(%)[b]
entry
cat.
additive
solvent
1
2
3
4
5
6
7
8
9
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*IrCl2]2
--
--
--
--
dioxane
DCE
12
63
52
17
--
--
--
MeCN
AcOH
EtOH
--
35
--
AcOH
AcOH dioxane
--
66
73
33
69
65
AcOH
AcOH
AcOH
AcOH
DCE
MeCN
toluene
DCE
--
--
--
10
--
11
[Cp*RhCl2]2
AcOH
DCE
--
23c
67d/71e/
57f/45g
12
[Cp*RhCl2]2
AcOH
DCE
--
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol),
catalyst (5 mol %), Cp* 1,2,3,4,5-
=
pentamethylcyclopenta-1,3-diene, AgSbF6 (20 mol %),
additive (0.4 mmol), solvent (2.5 mL), under air, at 120
oC for 24 h, in a sealed Schlenk tube, unless otherwise
noted. [b] Isolated yield. [c] Without AgSbF6. [d] Under N2.
[e] under O2. [f] 110 oC. [g] 100 oC.
[a] Reaction conditions: substituted 2-phenyl-1H-imidazoles
1 (0.2 mmol), 3-phenyl-1,4,2-dioxazol-5-one 2a (0.3
mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), HOAc
(0.4 mmol), DCE (2.5 mL), under air, at 120 oC for 24 h, in
a sealed Schlenk tube. [b] Isolated yield.
We initially tested the reaction of 2-
phenylimidazole 1a (0.2 mmol) and 3-phenyl-1,4,2-
dioxazol-5-ones 2a (0.3 mmol) in dioxane (2.5 mL)
After the establishment of optimized reaction
conditions, the scope and limitation of substituted 2-
phenylimidazoles were studied, as shown in Scheme
2. Generally, the reaction tolerated substrates bearing
both electron-donating (3ba, 76%; 3ca, 66%) and
electron-withdrawing groups (3da-3ga, 49-89%) on
aryl. Some functional groups, such as chloro (3da,
49%), trifluoromethyl (3fa, 53%), fluoro (3ea, 89%),
and bromo (3ga, 87%) kept untouched after the
reaction, serving as handles for potentially further
o
under 120 C in the presence of catalytic amount of
[Cp*RhCl2]2 (5 mol %) and AgSbF6 (20 mol %). The
ortho- C-H amidation product 3a was isolated in 12%
yield (Table 1, entry 1). Replacing dioxane with DCE
and MeCN increased the amidation yields to 63% and
52%, respectively (Table 1, entries 2 and 3). However,
in HOAc, the amidation product 3a (17%), along with
the further cyclization product 3aa was isolated in
35% yield (Table 1, entry 4). The combination of
HOAc (0.4 mmol) and EtOH (2.5 mL) resulted in no
2
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10.1002/adsc.201701331
Advanced Synthesis & Catalysis
functionalization. 2-Methylimidazole failed to work
under the standard procedure.
Next, the scope of 3-aryl-1,4,2-dioxazol-5-ones
were also tested, as shown in Scheme 3. This reaction
In the case of substrates with substituents on the allowed to efficiently introduce a series of ortho- (3ac,
imidazolyl ring, indolo[1,2-c]quinazolines 3ha, which 72%), meta- (3ad, 74%; 3ak, 78% and 3al, 54%) and
showed antimicrobial activity,[7b] was isolated in
para- (3ab, 76%; 3ae-ak, 60-77% and 3am, 62%)
substituted aryl to 5- position of imidazo[1,2-
c]quinazolines. Notably, methoxyl (3ae, 55%), fluoro
(3ah, 77%), halo (3ai, 74%; 3al, 54%),
trifluoromethyl (3aj, 60%; 3ak, 78%), and nitro (3am,
62%) groups on the aryl survived well under the
procedure. To our delight, 3-benzyl-1,4,2-dioxazol-5-
oneran smoothly with 2-phenylimidazole leading to
3an in 72% yield. However, 3-methyl-1,4,2-dioxazol-
5-one resulted in no reaction.
95% yield. Meanwhile, 4-phenyl and methyl
analogues ran smoothly under the procedure,
affording 3ia and 3ja in 62% and 72% yields,
respectively. The stucture of 3ja was further
supported by NOEXY (see supporting information for
details). We also tried ortho-, meta-subsituted 2-
arylimidazoles, but almost no reaction took place.
Meanwhile,
some
alkyl-substituted
nitrogen
heterocycle such as 2-ethylimidazole (1k), 2-
(piperidin-4-yl)-1H-benzo[d]imidazole (1l) and 2-
benzyl-1H-benzimidazole (1m) failed to work under
standard condition.
The practibility of this procedure was increased
since it was applicable to a 2 mmol scale reaction,
providing 3aa in a comparable 71% yield (0.35g).
Scheme 4. Mechanism Study
Scheme 3. Scope of 3-aryl-1,4,2-dioxazol-5-ones.
Some experiments were conducted to get insights
into this transformation. The presumed intermediate
carbamate 3a was subjected to the reaction and 3aa
was isolated in a comparable 84% yield without any
metal catalyst, indicating the possibility of 3a serving
as intermediate (Scheme 4, eq 1). The intra- and inter-
molecular KIEs were found to be 2.1 and 3.3,
respectively (Scheme 4, eqs 2 and 3). Thus, the
cleavage of the ortho- C-H bond may be the rate-
determining step during the transformation.
A proposed mechanism was outlined in Scheme 5.
In the presence of Rh(III) and Ag(I), the chelation-
assisted cleavage of ortho- C-H bond produces
intermediate A. [16] Then, the reaction of intermediate
A with 1,4,2-dioxazol-5-one affords rhodium carbene
[a]
Reaction conditions: 2-phenyl-1H-imidazole 1a (0.2
mmol), 3-aryl-1,4,2-dioxazol-5-ones
2
(0.3 mmol),
,
,
[12] [13]
species B, along with the extrusion of CO2.[10]
[Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), HOAc (0.4
After that, the migratory insertion of rhodium carbene
species B takes place to afford intermediate C. Finally,
the Rh(III) species is released to fulfill the catalytic
cycle. Meanwhile, as confirmed in eq 1 of Scheme 4,
a cyclization reaction takes place for the formed
o
mmol), DCE (2.5 mL), under air, at 120 C for 24 h, in a
sealed Schlenk tube. [b] Isolated yield.
3
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10.1002/adsc.201701331
Advanced Synthesis & Catalysis
ortho-
amidation
product
leading
to
5- Foundation of Jiangsu Province (BK20171193), the Key
University Science Research Project of Jiangsu Province
(15KJA150001), Jiangsu Key Laboratory of Advanced Catalytic
Materials &Technology (BM2012110) and Advanced Catalysis
and Green Manufacturing Collaborative Innovation Center for
arylimidazo[1,2-c]quinazoline.
In conclusion, we have developed a rhodium-
catalyzed annulation of 2-arylimidazole and 5-aryl-
1,4,2-dioxazol-5-ones
toward
imidazo[1,2-
financial support. Sun thanks the National Natural Science
Foundation of China (no. 21602019) and Young Natural Science
Foundation of Jiangsu Province (BK20150263) for financial
support. We also thank Mr. Nai-Wen Zhang, who helped in the
isolation of 2-aryl-1H-imidazoles.
c]quinazolines whereby the cleavage of ortho- C-H
bonds. It represents an efficient methodology toward
such heterocycles. This procedure is characterized by:
1) the readily available starting material; 2) free of
halo functionalization handles.
Scheme 5. Proposed Mechanism
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Annulation toward 5-Arylimidazo[1,2-c]quinazolines:
3894. For
a
three-step synthesis of indolo[1,2-
whereby the annulation of
c]quinazolines
A 20 mL of Schlenk tube equipped with a stir bar was
charged with substituted 2-phenyl-1H-imidazoles (0.2
mmol, 1.0 equiv.), 3-aryl-1,4,2-dioxazol-5-one (0.3 mmol,
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mg, 20 mol %), HOAc (0.4 mmol, 2.0 equiv.) and DCE
(2.5 mL). The tube was sealed with a PTFE cap. The
reaction mixture was stirred at 120 °C for 24 h under air in
an oil bath. After the completion of the reaction, the
mixture was then allowed to warm to room temperature
and a saturated solution of NaHCO3 (2 mL) was added.
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washed with brine (5 mL) and dried over MgSO4, and the
residue was purified by flash column chromatography on
silica gel with petroleum ether-EtOAc (V1/V2, 5:1) as the
eluent to give the desired products.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701331
Advanced Synthesis & Catalysis
COMMUNICATION
Rh-Catalyzed Annulation of ortho- C-H Bonds of
2-Arylimidazoles
with 1,4,2-Dioxazol-5-ones
toward 5-Arylimidazo[1,2-c]quinazolines
Adv. Synth. Catal. 2017, XX, Page – Page
Xiaopeng Wu, Song Sun, Shengbo Xu, and Jiang
Cheng *
6
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