Silver-Catalyzed Three-Component Coupling Reaction of Amines, 2-Isocyanobenzaldehydes, and 2,2,2-Trifluorodiazoethane and Synthesis of Trifluoromethyl-Substituted Indolo[1,2-c]quinazolines

Article abstract of DOI:10.1002/adsc.202000957

A silver-catalyzed three-component coupling reaction of amines, 2-isocyanobenzaldehydes, and 2,2,2-trifluorodiazoethane has been developed. This reaction provides an efficient method for the construction of CF₃-containing dihydroquinazolines. On the basis of this reaction, using trifluorodiazoethyl-substituted dihydroquinazolines as synthons, trifluoromethyl-substituted indolo[1,2-c]quinazolines were prepared in high yields via a TBHP/KI-mediated sequential intramolecular cyclization and aromatization process. (Figure presented.).

Full text of DOI:10.1002/adsc.202000957

Title: Silver-Catalyzed Three-Component Coupling Reaction
of Amines, 2-Isocyanobenzaldehydes, and 2,2,2-
Trifluorodiazoethane and Synthesis of Tifluoromethyl-Substituted
Indolo[1,2-c]quinazolines
Authors: Xiang-He Meng, Ming Yang, Ju-Yin Peng, and Yu-Long Zhao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000957
Link to VoR: https://doi.org/10.1002/adsc.202000957

Advanced Synthesis & Catalysis
10.1002/adsc.202000957
VERY IMPORTANT PUBLICATION FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Silver-Catalyzed Three-Component Coupling Reaction of Amines, 2-
Isocyanobenzaldehydes, and 2,2,2-Trifluorodiazoethane and Synthesis of
Trifluoromethyl-Substituted Indolo[1,2-c]quinazolines
a
a
a
a,
Xiang-He Meng, Ming Yang, Ju-Yin Peng, and Yu-Long Zhao *
a
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of Chemistry, Northeast
Normal University, Changchun 130024, P.R. of China, E-mail: zhaoyl351@nenu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.202######.
Abstract. A silver-catalyzed three-component coupling reaction of amines, 2-isocyanobenzaldehydes, and 2,2,2-
trifluorodiazoethane has been developed. This reaction provides an efficient method for the construction of CF -containing
3
dihydroquinazolines. On the basis of this reaction, using trifluorodiazoethyl-substituted dihydroquinazolines as synthons,
trifluoromethyl-substituted indolo[1,2-c]quinazolines were prepared in high yields via a TBHP/KI-mediated sequential
intramolecular cyclization and aromatization process.
Keywords: Amines; 2-Isocyanobenzaldehydes; 2,2,2-Trifluorodiazoethane; Dihydroquinazolines; Indolo[1,2-c]quinazolines
been developed over the past few decades.[12,13]
Introduction
However, to the best of our knowledge, there are
no reports on the synthesis of CF -containing
dihydroquinazolines. Although several methods
are available for the construction of
3
Incorporation of fluorine atoms or fluorinated
moieties into organic molecules could significantly
alter their physical, biological, and chemical
tifluoromethyl-substituted
indolo[1,2-
properties.[
1,2]
These effects have led to wide
c]quinazolines, such as cyclocarbonylation of o-
application of organofluorine compounds in
pharmaceutical, agrochemical, and materials
alkynyltrifluoroacetanilides,[
cyclization of
14]
coupling-
N-(2-
sciences. Special attention has been paid to the
syntheses of trifluoromethyl-containing compounds,
especially trifluoromethyl-containing N-heterocycles,
due to their unique properties, such as the high
iodophenyl)trifluoroacetimidoyl chlorides and
indoles[ and intramolecular cyclization of 2-(2-
15]
amidoaryl)-1H-indoles,[
16]
transition
required.
metal
Thus,
catalysts are generally
electronegativity, electron density, steric hindrance,
development of efficient methods for the
and hydrophobicity.[
1,2]
Thus, various reagents and
synthesis
of
tifluoromethyl-substituted
protocols for the trifluoromethylation of organic
compounds have been developed over the past
decades.[ In this field, 2,2,2-trifluorodiazoethane
indolo[1,2-c]quinazolines in the absence of
transition metals is highly desired. As a
continuation of our studies on the applications of
3]
(
CF
versatile CF
CF -containing N-heterocycles such as pyrazolines,
pyrazoles, triazoles, tetrazoles, pyridazines,
3
CHN
2
) has emerged as particularly useful and
diazo compounds[
9,17]
and isocyanides,
[18]
herein
3
-source in the preparation of various
we report a silver-catalyzed three-component
reaction
isocyanobenzaldehydes,
trifluorodiazoethane. This reaction provides an
efficient method for the construction of CF -
[4]
3
coupling
of
amines,
and
2-
2,2,2-
[5]
[6]
[7]
[8]
[9]
and imidazoles. Obviously, it is of value to develop
new synthetic strategies for the preparation of various
new CF -containing N-heterocycles employing 2,2,2-
trifluorodiazoethane as CF
3
3
containing dihydroquinazolines in a single step
from readily available substrates under rather
mild conditions. On the basis of this reaction,
3
-source.
Dihydroquinazolines
and
indolo[1,2-
c]quinazolines are an important class of fused N-
using CF -containing dihydroquinazolines as
3
heterocycles that are widely found in natural
synthon, trifluoromethyl-substituted indolo[1,2-
c]quinazolines were prepared in high yields via a
TBHP/KI-mediated sequential intramolecular
cyclization and aromatization process.
products and synthetic compounds with a broad
10,11]
spectrum
of
biological
activities.[
Consequently, numerous powerful methods for
the synthesis of these valuable skeletons have
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000957
Table 2. Reaction scope of amines. [a,b]
Results and Discussion
Initially, the three-component reaction of 4-
methoxyaniline 1a, 2-isocyanobenzaldehyde 2a
,
and 2,2,2-trifluorodiazoethane
3 was investigated
to optimize the reaction conditions. No desired
product was observed when the reaction of 1a
(0.2 mmol), 2a (0.2 mmol) and 3a (0.4 mmol)
was performed in the absence of silver catalysts
in toluene at room temperature for 12 h (Table 1,
entry 1). Under catalysis of Ag
2
CO (10 mol%),
3
the three-component reaction proceeded smoothly
to give the trifluorodiazoethyl-substituted
dihydroquinazoline 4aa in 29% yield in the
absence of 4Ǻ molecular sieves (entry 2). To our
delight, the addition of 4Ǻ molecular sieves (100
mg) improved the yield of 4aa to 93% under
otherwise identical conditions (entry 4).
Decreasing the amount of Ag
2
CO and the ratio
3
of 1a/2a/3 led to lower yields (entries 3 and 5).
When AgF was employed as catalyst, the desired
product 4aa was obtained in 90% yield (entry 8).
Other silver catalysts, such as AgOAc, AgOTf,
AgO
2
C
2
F
3
and AgNO
3
were less effective than
Ag CO
2
3
(entries 7-10). Among the solvents
tested, toluene turned out to be the best choice.
Product 4aa was produced in 86% yield when the
reaction was performed in THF (entry 11). When
the reaction was carried out in CHCl
trace amount of 4aa was observed (TLC) (entry
2).
3
, only a
1
Table 1. Optimization of reaction conditions.[a]
Yield[b]
[%]
Catalyst
[a]
Reaction conditions:
1
3
(0.2 mmol), 2a (0.2 mmol),
(0.02 mmol), 4Ǻ MS (100
3
Entry
Solvent 1a/2a/3 T/h
toluene 1:1:2 12 ---
[
mol%]
(
0.4 mmol), Ag CO
2
1
2
3
4
5
6
7
8
9
-----
mg), toluene (2.0 mL), at room temperature for 8-12
h.
Isolated yield.
[
[
c]
d]
Ag
Ag
Ag
Ag
2
2
2
2
CO
CO
CO
CO
3
3
3
3
(10) toluene 1:1:2
(5)
toluene 1:1:2
(10) toluene 1:1:2
(10) toluene 1:1:1
8
8
8
8
8
8
8
8
8
8
29
79
93
45
90
51
47
77
37
86
[
b]
AgF (10)
AgOAc (10) toluene 1:1:2
AgOTf (10)
toluene 1:1:2
AgO (10) toluene 1:1:2
AgNO (10)
toluene 1:1:2
toluene 1:1:2
2
2 3
C F
1
0
3
1
1
Ag
Ag
2
CO
CO
3
(10) THF
(10) CHCl
1:1:2
1:1:2
Figure 1. X-ray crystal structure of 4ca.
1
2
2
3
3
12 trace
[
a]
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol),
(0.2 or 0.4 mmol), catalyst (0.01-0.02 mmol), 4Ǻ
With the optimal reaction conditions in hand,
we investigated the substrate scope of the
reaction with respect to amines and the results
3
MS (100 mg), solvent (2.0 mL), at rt for 8-12 h.
1
[
[
[
b]
c]
d]
1
Estimated by H NMR spectroscopy using CH
2
Br
2
are summarized in Table 2. Satisfyingly, the
three-component reaction showed broad tolerance
as an internal standard.
The reaction was performed in the absence of 4Ǻ
to amines 1. Various aromatic primary amines
MS.
1a-r, such as arylamines with electron-rich,
Isolated yield.
electron-neutral, or electron-deficient groups on
the aromatic ring, biphenyl-4-ylamine,
- and -
naphthylamine, and heteroaromatic amine, could
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000957
react smoothly with 2-isocyanobenzaldehyde 2a indolo[1,2-c]quinazoline 5a could be obtained in
and 2,2,2-trifluorodiazoethane to produce the 85% yield from trifluorodiazoethyl-substituted
corresponding dihydroquinazolines 4a-ra in good dihydroquinazoline 4aa (0.2 mmol) in C OH
to excellent yields. The structure of 4ca was (2.0 mL) in the presence of TBHP (0.4 mmol), KI
confirmed by single-crystal X-ray crystallography (0.06 mmol) and C SO Na (0.2 mmol) at 60 °C
It is noteworthy that three- for 8 h (Table 4). In addition, we found that the
component reaction tolerates ortho-substituted reaction showed broad tolerance to various R
arylamines 1l and 1m, indicating that the substituents of . All selected substrates 4a ca
transformation exhibits good tolerance of steric 4e ga and 4ma bearing either electron-
3
2
H
5
6
H
5
2
[
19]
(
Figure 1).
4
- ,
-
,
hindrance. Besides to aromatic primary amines, a withdrawing or electron-donating R groups on the
range of aliphatic primary amines, such as
benzylamine 1s 2-phenylethan-1-amine 1t
aromatic rings, could efficiently undergo the
,
,
cyclization–aromatization reaction to give the
cyclohexanamine 1u, butan-1-amine 1v, hexan-1- corresponding trifluoromethylated indolo[1,2-
amine 1w, propan-2-amine 1x, and even c]quinazolines 5a
including the sterically hindered tert-butylamine case of 4na, the intramolecular cyclization also
-g
in good to high yields. In the
1
y
, also proved to be efficient partners, and the
proceeded
efficiently with moderate
desired dihydroquinazolines 4s-ya were obtained regioselectivity, resulting in the expected
'
in high to excellent yields. More importantly, products 5h and 5h in 49% and 24% yields,
even in the case of using 2,2,2-trifluoroethan-1- respectively. Obviously, the reaction provides a
'
amine 1z and ethyl glycinate 1z as nitrogen new strategy for highly efficient synthesis of
sources, the three-component reaction also
trifluoromethylated
indolo[1,2-c]quinazoline
worked well, yielding the desired products 4za derivatives from readily available substrates
'
and 4za in 83% and 80% yields, respectively. In
addition, a scale-up reaction of 1a (5.0 mmol), 2a
under transition metal-free conditions.
Table 4. Synthesis of trifluoromethylated indolo[1,2-
(
5.0 mmol) and
2 h under otherwise identical conditions as
above, furnishing 1.47 g of the desired product
3 (10 mmol) was carried out for
[a,b]
c]quinazolines 5.
1
4
aa in 85% isolated yield, showing the
practicality of the transformation.
Table 3. Reaction scope of 2-isocyanobenzaldehydes.[a,b]
[
[
a]
b]
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), 3 (0.4
mmol), Ag CO (0.02 mmol), 4Ǻ MS (100 mg), toluene
2.0 mL), at room temperature for 8-12 h.
Isolated yield.
2
3
(
Next, we turned to extend the scope of 2-
isocyanobenzaldehydes . As shown in Table 3,
various 2-isocyanobenzaldehydes 2b-e bearing
either electron-withdrawing or electron-donating
R groups on the aromatic ring could react
smoothly with 1a and 2,2,2-trifluorodiazoethane
[
[
a]
b]
Reaction conditions: 4 (0.2 mmol), TBHP (0.4 mmol),
PhSO Na (0.2 mmol), KI (0.06 mmol), C OH (2.0
mL), at 60 C for 8-12 h.
Isolated yield.
2
2
2 5
H
o
3
to give the corresponding CF
dihydroquinazolines 4ab-e in high yields (Table
). Based on the structural feature of
trifluorodiazoethyl-substituted
dihydroquinazolines together with the
consideration of the application of carbene
3
-containing
3
Scheme 1. One-pot synthesis of 5a.
4,
In addition, one-pot synthesis of 5a without
[
20]
reaction of diazo compounds, we reasoned that
trifluoromethylated indolo[1,2-c]quinazoline
purification of dihydroquinozolines 4aa was also
investigated. As a result, when the three-component
reaction of 1a (0.2 mmol), 2a (0.2 mmol), and 3 (0.4
mmol) was performed under the optimal reaction
conditions for 8 h, followed by treatment with TBHP
derivatives can be constructed via an
intramolecular C−H carbene insertion to the
neighboring aryl ring. Detailed examination of
the reaction conditions indicated that the
(0.4 mmol), KI (0.06 mmol), and C
H
6 5
2
SO Na (0.2
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000957
mmol) in ethanol (2.0 mL) at 60 °C for 8 h,
indolo[1,2-c]quinazoline 5a was obtained in 43%
yield (Scheme 1).
To further probe the mechanism for the formation
of 4, the reaction of aldimine 6 with 2,2,2-
trifluorodiazoethane 3 was also investigated (Scheme
2
). As expected, the desired product 4aa was obtained
in 84% yield under the optimal reaction conditions,
which indicates aldimine 6 may be the key
intermediate.
Scheme 2. Control experiment for mechanistic study.
Scheme 3. Proposed mechanism for the formation of
4
and 5.
Based on the experimental results and the relevant
literature,[
20-24]
a
possible mechanism for the
formation of 4 and 5 is proposed in Scheme 3.
Initially, in situ condensation of amines 1 and 2-
isocyanobenzaldehydes 2 generates aldimine 6,
which is converted into intermediate B via the
nucleophilic addition of silver trifluorodiazoethylide
A, generated by the reaction of 2,2,2-
Conclusion
In conclusion, we have developed a silver-catalyzed
three-component coupling reaction of amines, 2-
isocyanobenzaldehydes,
trifluorodiazoethane. This reaction provides a highly
efficient method for the construction of CF
and
2,2,2-
[21]
trifluorodiazoethane 3 with Ag
2
CO , to aldimine 6.
3
3
-
Subsequently, intermediate B undergoes insertion of
containing dihydroquinazolines in a single step from
readily available substrates in good to excellent yields
under mild conditions. More importantly, using
trifluorodiazoethyl-substituted dihydroquinazolines as
isonitrile into the N−Ag bond to form intermediate
C,[
22]
followed by protonation to produce the
corresponding dihydroquinazolines 4 (Scheme 3).
Under thermal conditions, the reactive
dihydroquinazolines 4 may undergo denitrogenation
to produce carbene D, which undergoes a concerted
C−H carbene insertion to the neighboring arene to
synthon,
c]quinazolines were prepared in high yields via a
TBHP/KI-mediated sequential intramolecular
tifluoromethyl-substituted
indolo[1,2-
cyclization and aromatization process. Further studies
on the application of trifluorodiazoethyl-substituted
dihydroquinazolines are ongoing.
give intermediate E. In addition, PhSO
2
Na is
t
t
oxidized by BuO• and BuOO• generated by the
[23]
decomposition of TBHP in the presence of KI, to
produce the sulfonyl radical, which abstracts the H
3
atom on the sp -carbon adjacent to the nitrogen atom
Experimental Section
[24]
of intermediate E to give intermediate F. Finally,
radical intermediate
abstraction by the sulfonyl radical to give
trifluoromethylated indolo[1,2-c]quinazoline
Scheme 3).
F
undergoes hydrogen
General Procedure for the Preparation of 4 (4aa as
Example)
5
To a solution of An oven-dried vial equipped with a
magnetic stir bar was charged with p-anisidine 1a (24.6
mg, 0.2 mmol), 2-isocyanobenzaldehyde 2a (26.3 mg,
(
0
.2 mmol), Ag
2
CO (5.6 mg, 10 mol%), 4Å MS (100
3
mg), then a fresh solution of CF
3
CHN 3 in toluene (0.2
2
M, 2.0 mL) was added. The resulting suspension was
stirred at 25 °C for 8 h until 2a disappeared. After the
reaction was complete, the resulting mixture was
filtered (Celite/DCM) and concentrated under a reduced
pressure. The crude residue was purified by silica gel
column chromatography (eluent: petroleum ether/ethyl
acetate = 5/1, V/V) to afford pure product 4aa (64.4 mg,
1
9
7
7
9
3%) as a yellow liquid. H NMR (600 MHz, CDCl
3
) δ:
.37 (s, 1H), 7.35 – 7.31 (m, 1H), 7.27 – 7.23 (m, 3H),
.23 – 7.19 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.99 (dd, J =
13
.6, 2.7 Hz, 2H), 5.87 (s, 1H), 3.84 (s, 3H). C NMR (151
MHz, CDCl
3
) δ: 158.91, 147.26, 140.82, 135.01, 129.64,
1
1
26.35, 126.31, 126.10, 125.39, 125.27 (q, JCF = 269.1 Hz),
19
3
19.25, 115.22, 56.70, 55.56. F NMR (470 MHz, CDCl )
+
δ: -56.95. HRMS (ESI-TOF): [M + H] calculated for
+
17 14 3 4
C H F N O : 347.1114, found: 347.1117.
General Procedure for the Preparation of 5 (5a as
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000957
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6
via a syringe pump at room temperature. After completion
of the addition, the reaction mixture was stirred at 60 °C
for an additional 8 h, until complete consumption of 4aa as
monitored by TLC analysis. After completion of the
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by column chromatography on silica gel (eluent, petroleum
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ether/ethyl acetate = 5:1, V/V) to afford the product 5a
1
(
53.8 mg, 85%) as a white solid. m.p. 143 – 145 °C; H
3
NMR (600 MHz, CDCl ) δ: 9.00 (s, 1H), 8.40 (d, J = 8.1
Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H),
7
1
.65 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.39 (s,
13
H), 7.06 (dd, J = 9.0, 2.3 Hz, 1H), 3.91 (s, 3H). C NMR
) δ: 157.96, 140.59, 135.81, 132.36 (q,
CF = 4.4 Hz), 130.38, 128.74, 128.33, 127.39 (d, JCF = 1.5
(
151 MHz, CDCl
3
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1
9
23.87, 118.89, 114.05, 110.58, 101.56 (q, JCF = 4.1 Hz),
19
9.26 (q, JCF = 37.0 Hz), 55.71. F NMR (470 MHz,
+
CDCl
3
) δ: -52.90. HRMS (ESI-TOF): [M + H] calculated
+
12 3 2
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Acknowledgements
Financial support of this research by the National Natural
Sciences Foundation of China (21871044 and 21472017) and
Natural Sciences Foundation of Jilin Province (20190201073JC)
are greatly acknowledged.
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FULL PAPER
Silver-Catalyzed Three-Component
Coupling
Reaction of Amines, 2-Isocyanobenzaldehydes, and
2
,2,2-Trifluorodiazoethane and Synthesis of
Tifluoromethyl-Substituted
zolines
Indolo[1,2-c]quina-
Adv. Synth. Catal. Year, Volume, Page – Page
Xiang-He Meng, Ming Yang, Ju-Yin Peng, and Yu-
Long Zhao*
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