Facile Synthesis of Azaarene-Substituted Hydroxycoumarins Possessing High Biological Activities via Three-Component C(sp3)-H Functionalization

Article abstract of DOI:10.1021/acscombsci.6b00082

An unprecedented three-component C(sp³)-H functionalization of 2-alkylazaarenes with aryl aldehydes and 4-hydroxycoumarins was realized, providing azaarene-substituted 3-benzyl-4-hydroxycoumarins in good to excellent yields. These new target compounds displayed broad-spectrum antibacterial activities, providing a new type of antibacterial skeleton.

Full text of DOI:10.1021/acscombsci.6b00082

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Article
Facile Synthesis of Azaarene-substituted Hydroxycoumarins Possessing
High Biological Activities via Three-Component C(sp3)-H Functionalization
Haoxun Dong, Lubin Xu, Shuai-Shuai Li, Liang Wang, Chang-Lun Shao, and Jian Xiao
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00082 • Publication Date (Web): 12 Aug 2016
Downloaded from http://pubs.acs.org on August 14, 2016
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Facile Synthesis of Azaarene-substituted
Hydroxycoumarins Possessing High Biological
Activities via Three-Component C(sp3)-H
Functionalization
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Haoxun Dong, §, † Lubin Xu,§, † Shuai-Shuai Li†, Liang Wang † Chang-Lun Shao‡ and Jian Xiao†*
† College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao
266109, China
‡ Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and
Pharmacy, Ocean University of China, Qingdao 266003, China.
E-mail:chemjianxiao@163.com.
KEYWORDS: three-component, C(sp3)-H functionalization, 2-alkylazaarenes, aryl aldehydes,
4-hydroxycoumarins, 3-benzyl-4-hydroxycoumarins, biological activities.
ABSTRACT: An unprecedented three-component C(sp3)-H functionalization of 2-
alkylazaarenes with aryl aldehydes and 4-hydroxycoumarins was realized, providing azaarene-
substituted 3-benzyl-4-hydroxycoumarins in good to excellent yields. These new target
compounds displayed broad-spectrum antibacterial activities, providing a new type of
antibacterial skeleton.
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INTRODUCTION
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4-Hydroxycoumarin and its derivatives are core fragments which have been found in numerous
natural products, drugs, pesticides and rodenticides.1 Among these compounds, 3-benzyl
substituted 4-hydroxycoumarins have attracted much attention recently owing to their ever-
increasing application in biological and medicinal fields. A number of 3-benzyl-4-
hydroxycoumarins, for examples, Phenprocoumon, Difenacoum, Coumatetralyl and Warfarin
have exhibited multifarious biological activities such as anti-HIV,2 antiviral,3 anticoagulant,4
antioxidant5 and anticancer activities6 (Figure 1). On account of these findings, much attention
has been directed towards the synthesis of 3-benzyl substituted 4-hydroxycoumarins.7 However,
to the best of our knowledge, there is still no protocol available for straightforward synthesis of
azaarene-substituted 3-benzyl-4-hydroxycoumarins, which might have great potential for
production of new biologically and medicinally important compounds.
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Figure 1. Examples of 3-benzyl-4-hydroxycoumarins
C2-alkylated azaarenes are key structural motifs of numerous natural products,
pharmaceuticals, catalysts and functional materials.8 Therefore, it is extremely valuable to
develop an efficient method for preparation of highly functionalized C2-substituted azaarenes.9
Traditionally, harsh conditions, e.g. stoichiometric amount of strong bases like BuLi or LDA, are
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required for functionalization of 2-methylazaarenes via deprotonation of the acidic protons on
methyl group, followed by nucleophilic additions to electrophiles.10 Recently, the direct
functionalization of 2-methylazaarenes could be implemented under the catalysis of transition
metal.11 However, the employment of transition metal catalysts suffers from enviromental
detriment and high cost, as well as tedious purification of the final products. To circumvent these
drawbacks, we developed the first organocatalyic or Brønsted acid catalyzed C(sp3)−H
functionalization of 2-alkylazaarenes with isatins, leading to facile synthesis of biologically
important azaarene-substituted 3-hydroxy-2-oxindoles in one step (Scheme 1, a).12a On the basis
of that work, a catalyst-free direct C(sp3)−H functionalization of 2-alkylazaarenes by use of
carboxylic acid-tethered substrates were further developed in our group to synthesize the
azaarene-substituted 3,4-dihydro(thio)-coumarins in a single step (Scheme 1, b).12b The above
success inspired us to conduct in-depth studies of in situ generated Brønsted acid catalyzed
C(sp3)−H functionalization for efficient construction of highly functionalized azaarenes (Scheme
1, c).
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Scheme 1. Synthesis of Azaarene-substituted 3-Benzyl-4-hydroxycoumarins via Three-
component C(sp3)−H Functionalization
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As a continuation of developing efficient C(sp3)−H functionalization strategy to construct
biologically and pharmaceutically important molecules,12-13 herein, we reported an
unprecedented three-component C(sp3)−H functionalization process14 for one step construction
of azaarene-substituted 3-benzyl-4-hydroxycoumarins in good to excellent yields. This protocol
has the advantages of direct C(sp3)-H functionalization and multi-component reaction, which
features high atom-economy, operational simplicity, and no environmentally detrimental
byproducts. Notably, although multi-component reactions have been in-depth investigated for
creation of structurally diverse compound libraries, the catalyst-free multi-component reaction
still remains a great challenge.15
RESULTS AND DISCUSSION
Initially, the three-component reaction of 4-hydroxycoumarin, benzaldehyde and 2,6-lutidine in
dioxane was examined under catalyst-free conditions (Table 1, entry 1). Consistent with our
hypothesis, this reaction proceeded smoothly at 120°C, furnishing the desired product 4{1,1,1} in
o
91% yield. Decreasing the temperature to 100 C resulted in lower yield, and no reaction
o
occurred at 80 C (Table 1, entries 2-3). Remarkably, screening of solvents indicated that the
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option of solvent was crucial to the success of this transformation, which did not work in other
solvents such as DMSO, THF and DCE (Table 1, entries 4-8).
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Table 1. Optimization of Reaction Conditionsa
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Entry Solvent
T (°C )
120
100
80
120
120
120
120
120
Yield (%)b
1
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8
dioxane
dioxane
dioxane
DMSO
EtOH
THF
91
85
0
trace
0
0
0
0
DCE
H2O
a Reactions were conducted with 1 (0.5 mmol), 2{1} (1 mmol), 3{1} (1 mmol) in 1 mL of solvent
for 48 h in a sealed tube. b Isolated yield.
Under the optimized conditions, a series of substituted 4-hydroxycoumarin derivatives 4 and 6
were synthesized in a 10 mL glass vial using 1:2:2 molar ratio of 4-hydroxycoumarin/aromatic
aldehydes/azaarenes (Scheme 2).
A wide range of sterically and electronically diverse aldehydes, azaarenes and 4-
hydroxycoumarins were examined to investigated the generality of this transformation, and the
results are shown in Scheme 3. Most of the sterically and electronically diverse substrates were
well tolerated. Good yields could be achieved with either electron-donating or electron-
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withdrawing group substituted aromatic aldehydes as substrates (Scheme 3, 4{1,1-7,1}). Notably,
2-bromobenzaldehyde (4{1,4,1}, 37%) gave lower yield than 3-bromobenzaldehyde (4{1,3,1},
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Scheme 2. Synthetic Route and Building Blocks for 4 and 6.
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96%), probably due to the steric hindrance. When anisaldehyde was employed, the analogous
product 4{1,8,1} was not detected, even under the catalysis of strong Lewis acids and Bronsted
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acids, which might be ascribed to the strong electron-donating effect of methoxyl group.
Subjection of other 2-methylpyridines to this reaction could also furnish the desired products in
Scheme 3. Three-Component Reactions of 4-Hydroxycoumarin, Aromatic Aldehyde and 2-
Alkylpyridines.
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excellent yields (Scheme 3). Notably, when 2, 6-dimethyl-3-nitropyridine was employed, only
less sterically hindered 6-methyl was functionalized (4{1,3,1}), whereas the regioisomeric 2-
methyl product was not detected. Subsequently, substituted 4-hydroxycoumarins were also
evaluated under the optimal condition. Both the electron-donating group such as methyl
substitutent and electron-withdrawing group such as fluoro substitutent could provide the desired
product 4{2,1,1} and 4{3,1,1} in 74% yield and 71% yield correspondingly.
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When 2-methylquinolines were employed as substrates, the desired products 6 were
obtained in good yields (Scheme 4), along with 2-alkenylquinolines as byproducts.16 The
comparatively lower yields illustrated the different reactivity between C(sp3)−H bond of 2-
methylquinolines and 2-methylpyridines. As shown in Scheme 4, formation of product 6{1,1-
13,1} was more favored for electron-deficient aldehydes than electron-rich ones. 2,6-
dimethylquinoline 5{2} and 1-methylisoquinoline 5{4} were also well tolerated to furnish the
desired products in good yields. Considering that 3-benzyl substituted 4-hydroxycoumarins
exhibit multifarious biological activities and have promising application in medicinal chemistry,
the current protocol provides an efficient strategy to construct such type of compounds.
When aliphatic aldehydes were subjected to this reaction, disappointedly, no desired
products were obtained. Ketones were also examined under the standard reaction condition,
however, no C(sp3)-H functionalization products were obtained and only nucleophilic coupling
products between 4-hydroxycoumarin with ketones were observed, in which 2,6-lutidine served
as a base. The employment of ketones like acetophenone, cyclohexanone and 1, 3-diketone
afforded the products 7{1,3,1}17, 8{1,3,3}18 and 9{1,3,2}19 in 47%, 88% and 77% yields,
respectively (Scheme 5). The structure of product 7{1,3,1} has been unambiguously confirmed
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Scheme 4. Three-Component Reactions of 4-Hydroxycoumarin, Aromatic Aldehyde and 2-
5
6
Methylquinolinesa, b
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a Reactions were conducted with 1 (0.5 mmol), aromatic aldehyde 2{2,3,5,9-13} (1 mmol) and
azaarene 5{1-4} (1 mmol) in 1 mL of dioxane at 120 °C for 48 h. b Isolated yield of purified
products.
by X-ray crystallography. Intriguingly, when 5,5-dimethylcyclohexane-1,3-dione was subjected
to the reaction instead of 4-hydroxycoumarin, only bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-
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ones) 10{1,1,4} was isolated in 67% yield.20 These results indicated that this three component
C(sp3)-H functionalization could work merely with aromatic aldehydes, not working for aliphatic
aldehydes and ketones. Ketone substrates such as cyclohexanone and 1,3-diketone operate by the
other reaction pathway, which could be explained by the fact that ketones are less electrophilic
than aldehyde.
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To probe the mechanistic pathway, control experiments were conducted as shown in
Scheme 6. The formation of benzoic acid was observed when benzaldehyde was dissolved in
dioxane under 120 oC under air atmosphere, and this reaction could proceed via addition of
Scheme 5. Ketones as Substrates
10 mol% benzoic acid, affording the desired product 4{1,1,1} in 83% yield (eq. 1). Compound
12{1} and 13{1} were prepared and subjected to the standard reaction conditions (eq. 2 and 3).
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However, only trace of 4{1,1,1} was detected even in the presence of water (eq. 2, condition a-b).
In contrast, 10 mol% benzoic acid could catalyze this reaction smoothly to afford the product
4{1,1,1} in 72% yield, demonstrating that the direct addition of C(sp3)−H bond to ortho-quinone
methides intermediate21 was possible (eq. 2, condition c). The direct addition of 4-
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hydroxycoumarin to 2-alkenylazaarenes was also examined, however, no desired product 4{1,1,1}
could be obtained, even under the catalysis of 10 mol% benzoic acid (eq. 3). On the basis of the
experimental results, a plausible reaction mechanism is proposed as outlined in Scheme 7. Trace
of aryl aldehyde is oxidized to aryl carboxylic acid under air atmosphere at high temperature,
which serves as Brønsted acid catalyst to activate the 2-methylazaarenes, affording an enamine
intermediate A via transition state I. Condensation of aryl aldehyde with 4-hydroxycoumarin
produces ortho-quinone methide intermediate B, which is then attacked by electron-rich
intermediate A to furnish the product 4 or 6 via the well-organized transition state II.
Scheme 6. Control Experiments
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Scheme 7. The Proposed Reaction Pathway
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To examine the biological activities of these synthetically new molecules, the antibacterial
activities of products 4 and 6 were evaluated (Table 2). It was found that they were against a
panel of pathogenic bacteria such as S. epidermidis, S. aureus and B. cereus, etc. For instance,
compound 6{1,13,1} exhibited strong inhibitory activity against S. aureus and B. cereus with the
MIC value of 1.56 μM, which were 80 percent and 40 percent, respectively than that of
ciprofloxacin (MIC = 1.25 μM). The preliminary bioassay results showed that these new
synthetic compounds had broad-spectrum antibacterial effects and potentially acted as lead
compounds for further modification and commercial application.
Table 2. Antibacterial Test for Compound 4 and 6a
Compound S.epidermi T.halophilus
B.subtilis
K.rhizophila V.parahae
molyticus
S.aureus
B.cereus
N.brasilie
nsis
dis
4{1,2,1}
4{1,3,1}
4{1,5,1}
4{1,6,1}
4{1,7,1}
4{1,3,2}
50.0
25.0
50.0
>100
100
100
25.0
100
50.0
100
25.0
50.0
50.0
100
100
50.0
50.0
50.0
50.0
100
100
100
50.0
>100
50.0
25.0
100
25.0
100
50.0
25.0
25.0
100
100
50.0
>100
25.0
25.0
100
>100
25.0
100
50.0
>100
>100
100
50.0
100
4{1,5,2}
4{1,1,3}
6{1,1,1}
6{1,2,1}c
100
50.0
25.0
6.25
100
50.0
50.0
12.5
100
50.0
25.0
12.5
100
25.0
25.0
>100
>100
>100
>100
25.0
100
50.0
50.0
3.13
50.0
>100
>100
6.25
>100
50.0
50
12.5
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6{1,10,1}
100
12.5
6.25
12.5
50.0
6.25
3.13
12.5
6{1,11,1}
6{1,3,1}
6.25
6.25
25.0
3.13
6.25
3.13
6.25
3.13
25.0
25.0
6.25
6.25
12.5
25.0
6.25
6.25
6
7
8
9
6{1,5,1}
6{1,12,1}
25.0
12.5
25.0
3.13
12.5
3.13
12.5
0.625
>100
6.25
12.5
3.13
6.25
6.25
6.25
2.50
12.5
12.5
25.0
6.25
12.5
3.13
25.0
0.156
6.25
6.25
3.13
3.13
25.0
12.5
12.5
0.313
100
100
6.25
6.25
12.5
1.56
6.25
3.13
3.13
1.25
6.25
12.5
25.0
1.56
6.25
12.5
6.25
0.625
12.5
25.0
50.0
6.25
25.0
6.25
25.0
0.313
6{1,7,1}
6{1,13,1}
6{1,1,2}
6{1,1,3}
6{1,1,4}
Ciprofloxa
cinb
25.0
>100
25.0
12.5
>100
5.00
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a Data are expressed in MIC values (μM). b Ciprofloxacin was used as a positive control.
CONCLUSION
In conclusion, an unprecedented three-component C(sp3)-H functionalization of 2-alkylazaarenes
with aryl aldehydes and 4-hydroxycoumarins was realized, providing azaarene-substituted 3-
benzyl-4-hydroxycoumarins in good to excellent yields. The mechanistic studies imply that in
situ oxidation of aryl aldehydes to aryl carboxylic acids is crucial to the success of this
transformation. Furthermore, these new target compounds displayed broad-spectrum
antibacterial activities, providing a new type of antibacterial skeleton. The subsequent in-depth
studies on bioactivity and structure-activity relationship as well as further application of this
synthetic strategy are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental details and spectroscopic characterization of all the compounds and 1H and 13C
spectra for all products.
Crystallographic information file for compound 7{1,3,1}.
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AUTHOR INFORMATION
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Corresponding Author
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E-mail:chemjianxiao@163.com.
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Author Contributions
§These authors contributed equally to this work.
Funding Sources
We are grateful to the National Natural Science Foundation of China (No. 21102142). Financial
supports from Talents of High Level Scientific Research Foundation (Nos. 6631112323,
6631115015) of Qingdao Agricultural University is also gratefully acknowledged.
Notes
The authors declare no competing financial interest..
ACKNOWLEDGMENT
We thank Prof Teck-Peng Loh (University of Science and Technology of China and Nanyang
Technological University) for HRMS determination.
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2012, 2, 8277. (c) Rao, P.; Konda, S.; Iqbal, J.; Oruganti, S. InCl3 catalyzed three-component
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ACS Combinatorial Science
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Facile Synthesis of Azaarene-substituted Hydroxycoumarins Possessing High
Biological Activities via Three-Component C(sp3)-H Functionalization
Haoxun Dong,§† Lubin Xu,§† Shuai-Shuai Li,† Liang Wang,† Chang-Lun Shao‡ and Jian Xiao†*
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An unprecedented three-component C(sp3)-H functionalization of 2-alkylazaarenes with aryl aldehydes
and 4-hydroxycoumarins was realized, providing azaarene-substituted 3-benzyl-4-hydroxycoumarins in
good to excellent yields. These new target compounds displayed broad-spectrum antibacterial activities,
providing a new type of antibacterial skeleton.
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