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Copper-Catalyzed Multicomponent Domino Reaction of 2Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1H-[1,2,3]Triazolo[4,5-c]quinoline Derivatives Cheng Xu, Shi-Fen Jiang, Yan-Dong Wu, Feng-Cheng Jia, and An-Xin Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02476 • Publication Date (Web): 15 Nov 2018 Downloaded from http://pubs.acs.org on November 20, 2018
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The Journal of Organic Chemistry
Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1H-[1,2,3]Triazolo[4,5-c]quinoline Derivatives Cheng Xu,† Shi-Fen Jiang,† Yan-Dong Wu,† Feng-Cheng Jia,*‡and An-Xin Wu*† †Key
Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡School
of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P. R. China
*E-mail:
[email protected];
[email protected].
TOC Graphic: R O Br
O NaN3
CuBr2, L-proline, Cs2CO3 DMSO, 100 oC
Ar
25 examples up to 86% yield
R
HN N N N
Ar
Multifunction of the CuBr2 catalyst
NaN3 serves as a dual synthon
Formation of one C-C and four C-N bonds
Simple and mild conditions
Abstract: A practical copper-catalyzed multicomponent reaction has been developed for the synthesis of 1H-[1,2,3]triazolo[4,5-c]quinoline derivatives from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This protocol integrated consecutive base-promoted condensation, [3+2] cycloaddition, copper-catalyzed SNAr, and denitrogenation cyclization sequences. Preliminary mechanistic studies revealed that CuBr2 acted as a multifunctional catalyst to streamline this domino process. The mild catalytic system enabled effective construction of one C–C and four C–N bonds in one operation. The pursuit of concise synthetic methods that enable the rapid, straightforward construction of multifarious heterocyclic frameworks with structural novelty and complexity is the key focus of organic synthesis and drug discovery.1 In this context, catalytic multicomponent reactions2 have proven to be extremely powerful protocols
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that allow the convergent synthesis of complex molecules from relatively simple substrates through facile formation of multiple covalent bonds in a single operation. A large number of corresponding methodologies have been established for the construction of N-containing heterocycles.3 The 1,2,3-triazole nucleus is a privileged structural motif that has been widely applied in the materials,4 chemical,5 and biological sciences.6 In particular, triazole-fused polycyclic heterocycles7 are extremely attractive owing to their remarkable pharmaceutical and biological functionalities. They have been reported to show good serine protease inhibition activity,8a
antimicrobial
effects,8b,c
and
promising
anticancer
properties.8d
1H-[1,2,3]Triazolo[4,5-c]quinolines are a class of structurally novel triazole-fused heterocycles that contain both 1,2,3-triazole and quinoline frameworks. It is assumed that this novel hybrid skeleton may feature promising bioactivity for screening considering analogue fused 1,2,3-triazoles and their component units. However, only a few synthetic approaches toward this novel structure have been reported, involving preparative substrates and stoichiometric amounts of metal salts.9 Therefore, the design and assembly of this structurally novel fused N-heterocycle from simple materials via an elegant catalytic multicomponent strategy remains a fascinating and desirable challenge. Sodium azide (NaN3) has been extensively utilized as an inexpensive and versatile synthon in numerous organic transformations.10–13,15–18,21 Generally, synthetic procedures for incorporating an azide moiety into organic molecules mainly includes the following two types: (i) 1,3-Dipole cycloaddition reactions of NaN3 with electron-deficient olefins11 or alkynes;12 and (ii) copper-catalyzed coupling reactions of NaN3 with aryl halides13 involving concomitant N-atom transfer reaction14. Great achievements have been made in the field of employing NaN3 as a versatile building block based on the two typical reaction patterns.15,16 However, illustrations for the construction of N-containing heterocycles using NaN3 as a dual nitrogen source remain rare. In 2015, we developed an appealing copper-catalyzed domino protocol for the rapid synthesis of 5-phenyl-[1,2,3]triazolo[1,5-c]quinazoline derivatives from
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readily available (E)-1-bromo-2-(2-nitrovinyl)benzenes, aldehydes, and NaN3 (Scheme 1a).17 Moreover, we have also disclosed an efficient Fe/Cu relay-catalyzed domino protocol for the synthesis of 2-phenyl-quinazolin-4-amines (Scheme 1b).18 In conjunction
with
our
ongoing
research
into
developing
copper-catalyzed
multicomponent reactions using NaN3 as a dual nitrogen source, herein, we report a facile
and
efficient
approach
for
the
1H-[1,2,3]triazolo[4,5-c]quinolines
construction
from
of
structurally
commercially
novel
available
2-bromobenzaldehydes, aryl methyl ketones, and NaN3 (Scheme 1c). Notably, one C–C and four C–N bonds were formed sequentially in this copper-catalyzed domino reaction. Scheme 1. Copper-Catalyzed Multicomponent Reactions Using Sodium Azide as a Dual Nitrogen Source R2
Our previous work: R1
NO2 Br
R
R2
NaN3
CuI, L-proline
Ar
O
CN NaN3
Ar
O
Br
R1
DMSO, 100 oC
CuI, FeCl3, L-proline
N
R
DMF, 110 oC
O
O NaN3
Ar
Br
CuBr2, L-proline, Cs2CO3
R
(a) Ar
NH2 N N
This work: R
N N
N
(b) Ar
HN N N
(c)
DMSO, 100 oC
N
Ar
Our initial investigation focused on the model reaction of 2-bromobenzaldehyde (1a), acetophenone (2a), and NaN3 in the presence of 10 mmol % CuI, 0.2 equiv. of L-proline, and 3.0 equiv. of K2CO3 in DMSO at 100 °C for 20 h. Gratifyingly, the reaction
proceeded
to
give
the
desired
product
4-phenyl-1H-[1,2,3]triazolo[4,5-c]quinoline (3a) in 26% isolated yield (Table 1, entry 1). Encouraged by this preliminary result, various reaction parameters were systematically evaluated to further improve the yield, the results are summarized in Table 1. A range of inorganic and organic bases were first screened in the reaction (Table 1, entries 2–7), with Cs2CO3 exhibiting the highest efficiency. Then, a series of copper salts were examined (Table 1, entries 8–14), and the results suggested that the use of CuBr2 as catalyst gave the best yield and provided the optimum result. This
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transformation was also attempted using several other solvents, such as DMF, 1,4-dioxane, toluene, and CH3CN (Table 1, entries 15–18). However, it proved that they possess less capacity for the reaction. Subsequent increases or decreases in the temperature did not enhance the outcome of the reaction any further (Table 1, entries 19–20). We also attempted the reaction under an argon atmosphere, but only a trace amount of 3a was observed (Table 1, entry 21). This result indicated that this transformation was assisted by oxygen. Further optimization of the reaction conditions showed that decrease in the equivalent of NaN3, Cs2CO3, or CuBr2 catalyst gave lower yields (see the Supporting Information). Eventually, the optimal reaction conditions were determined as 1a (0.4 mmol), 1.0 equiv of 2a, 4.0 equiv of NaN3, 10 mmol % of CuBr2, 20 mmol % of L-proline, and 3.0 equiv. of Cs2CO3 in 3 mL of DMSO at 100 °C in a sealed vessel under air. Table 1. Optimization of the Reaction Conditionsa HN N N
O O
Conditions
NaN3
Br
N 2a
1a
3a
yieldb
entry
catalyst
base
solvent
temp (°C)
1
CuI
K2CO3
DMSO
100
26
2
CuI
Na2CO3
DMSO
100
19
3
CuI
NaHCO3
DMSO
100
21
4
CuI
Cs2CO3
DMSO
100
67
5
CuI
K3PO4
DMSO
100
52
6
CuI
KOH
DMSO
100
trace
7
CuI
DBU
DMSO
100
18
8
CuCl
Cs2CO3
DMSO
100
58
9
CuBr
Cs2CO3
DMSO
100
69
10
Cu2O
Cs2CO3
DMSO
100
43
11
CuCl2
Cs2CO3
DMSO
100
81
12
CuBr2
Cs2CO3
DMSO
100
85
13
Cu(OAc)2
Cs2CO3
DMSO
100
72
14
Cu(OTf)2
Cs2CO3
DMSO
100
46
15
CuBr2
Cs2CO3
DMF
100
32
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(%)
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aReactions
16
CuBr2
Cs2CO3
17
CuBr2
Cs2CO3
18
CuBr2
19
1,4-diox
100
trace
toluene
100
trace
Cs2CO3
CH3CN
100
trace
CuBr2
Cs2CO3
DMSO
90
62
20
CuBr2
Cs2CO3
DMSO
110
75
21c
CuBr2
Cs2CO3
DMSO
100
