Strategic Approach to 8-Azacoumarins

Article abstract of DOI:10.1021/acs.orglett.6b03771

8-Azacoumarins have emerged as a promising class of compounds but are rarely explored due to challenging access. A novel, general, and practical method is provided for this class of compounds. The key lactonization step employs trans-acrylic acid attached pyridine N-oxides as the starting material, with acetic anhydride as both the activation agent and the solvent. Multiple transformations were involved in this reaction, including conjugate addition, nucleophilic aromatic substitution, and elimination. These studies provide the basis for access to 8-azacoumarins, enabling future work including the discovery and development of novel coumarin-type drugs, fluorescent probes, photolabile protecting groups, and other active molecules.

Full text of DOI:10.1021/acs.orglett.6b03771

Letter
pubs.acs.org/OrgLett
Strategic Approach to 8‑Azacoumarins
Dong Wang,* Yuxi Wang, Junjie Zhao, Meng Shen, Jianyong Hu, Zhenlin Liu, Linna Li, Furen Xue,
and Peng Yu*
China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of
Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
*
S Supporting Information
ABSTRACT: 8-Azacoumarins have emerged as a promising
class of compounds but are rarely explored due to challenging
access. A novel, general, and practical method is provided for
this class of compounds. The key lactonization step employs
trans-acrylic acid attached pyridine N-oxides as the starting
material, with acetic anhydride as both the activation agent and
the solvent. Multiple transformations were involved in this
reaction, including conjugate addition, nucleophilic aromatic
substitution, and elimination. These studies provide the basis
for access to 8-azacoumarins, enabling future work including the discovery and development of novel coumarin-type drugs,
fluorescent probes, photolabile protecting groups, and other active molecules.
atural and synthetic coumarins (benzo-α-pyrone) are
Scheme 1. Synthetic Approaches to 8-Azacoumarins
N
some of the most promising targets due to their wide range
1
2
of biological properties, including anticancer, anticoagulant,
3
4
5
anti-HIV, anti-inflammatory, and antibacterial activities.
Furthermore, coumarins have been widely applied in fluorescent
6
7
probes and caging chemistry recently. However, the
application of coumarins in both medicinal and photochemistry
is restricted due to their low aqueous solubility and insufficient
potency. One of the most successful strategies to increase the
hydrophilicity and produce similar biological properties relies on
isostere replacement of a phenyl with a pyridyl, leading to 8-
azacoumarins. Compared to other strategies, this strategy has the
advantage that no additional hydrophilic functionalities need to
be introduced to the core structure. Indeed, the successful
8
applications of this strategy have been reported. Several
promising 8-azacoumarin-type photolabile protecting group8s
have been prepared and characterized by Tamamura et al.
Those azacoumarins show dramatically enhanced water
solubility and photolytic efficiency compared to that of their
coumarin analogues.
To address the problem, we sought to design a new method for
the synthesis of 8-azacoumarins (5) that would greatly extend the
substrate scope. Instead of forming a carbon−carbon bond by
S Ar, the scaffold was constructed by forming a carbon−oxygen
E
bond through nucleophilic aromatic substitution reactions
The substitution of a phenyl by a pyridyl has been used not
(
S Ar). The method is based on a novel synthetic strategy by
N
12
only to improve hydrophilicity but also to improve metabolic
9
which the easily accessible pyridine N-oxides (3) served as the
key precursor (Scheme 1B). Due to the inherent enhanced
electrophilic character of the C2 position in 3, it is attacked by the
stability. Therefore, 8-azacoumarins have emerged as a
promising class of compounds. However, not enough study of
azacoumarins has been performed, most likely because access to
this scaffold is challenging. According to the few reported
approaches, this scaffold was prepared by electrophilic aromatic
carboxyl oxygen anion under Ac O activation conditions, leading
2
to the desired azacoumarin products 5. To the best of our
knowledge, this general approach based on N-oxide chemistry is
unprecedented.
substitution reactions (S Ar), using 2-hydroxyl-6-EDG (elec-
E
tron-donating groups) substituted pyridines as the starting
1
0
The synthesis of pyridine N-oxides 3 was completed in three
material under acidic or PPh activation conditions (Scheme
3
13
14
8
,11
steps (Scheme 2). The Heck reaction of commercially
1A).
Few 8-azacoumarins, however, were prepared by this
method. Due to the inherent poor nucleophilicity of pyridines,
this method is only suitable for those electron-rich pyridines,
resulting in a limited number of accessible targets.
Received: December 19, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of the N-Oxide Precursors
appropriate solvent as no product could be detected using
trifluoroacetic anhydride (TFAA) as the solvent (entry 11).
With the optimized conditions in hand, the scope of the
lactonization with a range of pyridine and quinoline derivatives
18
was examined (Scheme 3). We were pleased to observe modest
Scheme 3. Substrate Scope for the Lactonization of Various
a
Heterocyclic N-Oxides
available 3-bromopyridine derivatives 6 with methyl acrylate
15
derivatives provided the E-isomer 7 stereoselectively, which
was hydrolyzed and chemoselectively oxidized to afford 3 in
good yields.
The lactonization reaction of quinoline N-oxide (3r) was
selected as the model reaction for the optimization of the
16
reaction condition (Table 1). Based on our previous findings,
a
Table 1. Reaction Optimization for the Lactonization
entry
1
additive
PyBroP
base
solvent
DCE
t (°C)
yield (%)
NaOAc
reflux
reflux
120
n/a
<10
15
b
2
Ac O
2
b
3
NaOAc
NaOAc
NaOAc
Ac O
2
4
Ac O
2
120
51
c
5
b
Ac O
2
120
n/a
61
6
Et N
3
Ac O
2
120
7
Na CO
Ac O
120
41
2
3
2
a
b
Unless otherwise noted, all reactions were conducted at 0.20 M
8
b
K CO
Ac O
2
reflux
120
61
2
3
3
3
3
,
d
concentration with N-oxide (1.0 equiv), K CO (3.0 equiv), and H O
2 3 2
b
9
1
1
K CO
Ac O
2
65
2
(
7.0 equiv) in Ac O at reflux. Reaction run at 120 °C.
2
0
1
K CO
Ac O
2
120
90
2
K CO
TFAA
reflux
n/a
2
a
Unless otherwise noted, all reactions were conducted at 0.20 M
concentration with N-oxide (150 mg, 1.0 equiv), base (3.0 equiv), and
to excellent yields in all cases examined, with excellent
regioselectivity (C2 vs C4). In none of these instances did we
observe the C4-lactonized regioisomeric products. There is no
general conclusion about the effects of electron density on
pyridine/quinoline N-oxide reactivity. Those electron-rich
substrates afford yields similar to those of electron-poor
substrates (3f vs 3h). Remarkably, those examples containing a
carboxylic ester (3h) or reactive halide (3b−3d, 3m, 3n) were
also effective in the transformation, suggesting a general
compatibility with base-sensitive functionality. It is worth noting
that 5p was synthesized successfully, indicating that the carbon−
carbon double bond of the substrate is not essential for this
lactonization reaction.
b
c
H O (7.0 equiv). No water was added. 14.0 equiv of H O was
added. Reaction run at 0.10 M.
2
2
d
2
-quinolinone product should be formed under PyBrop
(bromotripyrrolidinophosphonium hexafluorophosphate) acti-
vation conditions. This condition was first chosen, as the 2-
quinolinone product might be cyclized in situ to afford the
desired product. However, several spots, including the 2-
quinolinone byproduct, were detected (entry 1, Table 1).
Gratifyingly, the desired product was detected utilizing Ac O as
2
both the activating reagent and the solvent under reflux
conditions (entry 2). It is found that both base and water are
critical for this transformation. The yield of the reaction was
improved with sodium acetate (entry 3), and dramatic
improvement was observed when water was added to the
reaction mixture (51% yield, entry 4). However, an excess
amount of water was detrimental to the product yield (entry 5).
A careful screening of base/quantity of water (entries 6−10) led
to the identification of the optimum condition for this reaction
The formation of azacoumarins (5) from N-oxides (3) in
Ac O under basic conditions implies a complex reaction
2
manifold. Remarkably, it seems that the double bond geometry
was converted from trans to cis directly. Two possible reaction
pathways leading to 5 are depicted in Scheme 4. In pathway 1, the
activated pyridine acetate 9 is formed in the first step. Subsequent
conjugate addition of acetate anion or hydroxide furnishes
isomeric intermediates 10 and 10′. Nucleophilic attack of the
carboxyl oxygen anion to the C2 position of 10 affords lactone
11. Finally, rearomatization of 11 under basic conditions
followed by elimination affords 5. Water could improve the
yield of the reaction probably by dissolving more K CO in the
(
90% yield, entry 10). It is worth noting that the double bond
geometry is converted from trans to cis in this transformation
17
without any photoirradiation. Ac O seems to be the only
2
2
3
B
DOI: 10.1021/acs.orglett.6b03771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Proposed Reaction Mechanism
reaction media. In pathway 2, based on the known N-oxide
chemistry, intermediate 13 and regioisomer 14 would be
Scheme 6. Lactonization Reactions in Pivalic Anhydride
1
9
formed irreversibly in refluxing Ac O. Subsequent basic
2
hydrolysis produces 6-pyridone byproduct (16) and 2-pyridone
intermediate 15, which would be converted to the cis isomer 15′
under the reversible acetate anion conjugate addition conditions.
Finally, lactonization of 15′ by Ac O activation of the carboxylic
2
acid group offers 5.
for 5a was similar to that in Ac O (68% vs 70%), the lactonization
reaction should proceed via pathway 1.
Several azacoumarins were chosen to evaluate their aqueous
solubility and fluorescent properties. As expected, 5e showed
hydrophilicity higher than that of 6-Me-coumarin (Table 2). The
2
Pathway 1 is more reasonable than pathway 2. First, no 6-
pyridone byproduct 16a (R = H) was detected in the reaction
media. Regioisomeric products (2- and 6-pyridones) are usually
19
formed in Ac O-mediated N-oxide rearrangement reactions.
2
Indeed, both 18 and 19 were isolated (6.4:1 ratio) when 17, the
methyl ester analogue of 3a (R = H), was subjected to the
lactonization reaction conditions (Scheme 5). Second, it is
Table 2. Hydrophilic Properties of 6-Me-Coumarin and 5e
a
b
compd
log P
Cs (mM)
Scheme 5. Synthesis of Pyridone Intermediates
6
-Me-coumarin
2.31
1.69
2.6
6.2
5
e
a
b
Calculated by ChemBioDraw Ultra 12.0. Concentration at
saturation in PBS (0.1% DMSO).
log P value of 5e was lower, and the C value was 2-fold higher
s
than that of 6-Me-coumarin. Fluorescent properties of 5d, 5e,
and the coumarin analogues were measured in PBS (Table 3). To
Table 3. Fluorescent Properties of Compounds 5d and 5e
a
b
c
compd
λex (nm)
λem (nm)
Φ
rational to assume that the yield for 15a from 3a is similar to the
yield (40%) for 18 from 17. If the reaction proceeds via pathway
d
5d
367
441
0.122
0.070
d
2
, the yield for 5a from 3a should be lower than 40% as the
5e
368
b
435
a
c
formation of 5a involves the irreversible formation of 15a in the
first step. Therefore, pathway 2 is unlikely to occur as the yield
Excitation maxima. Emission maxima. Quantum yields were
calculated by using quinine in 0.1 N H SO (Φ = 0.577) as the
standard. 100 μM in PBS.
2
4
d
(70%) for 5a is much higher than the yield for 15a. Subsequent
hydrolysis of 18 led to 15a, which was converted to 5a as
expected under the lactonization reaction conditions (Scheme
our delight, both 5d and 5e exhibited fluorescence, characterized
by large Stokes shifts, whereas no fluorescence was detected for
6-Br-coumarin or 6-Me-coumarin. These preliminary data
indicate that 8-azacoumarins are a promising class of fluorescent
probes.
5
).
Pathway 1 was further evidenced by reactions in Scheme 6.
When the solvent was switched from Ac O to pivalic anhydride,
2
5
a was obtained in 68% yield, whereas no reaction was detected
with 17. Pathway 2 is unlikely to happen due to the lower
nucleophilicity of pivalic anhydride. Considering that the yield
In conclusion, we have presented a facile and general synthesis
of 8-azacoumarins, which have emerged as a promising class of
C
DOI: 10.1021/acs.orglett.6b03771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compounds but are rarely explored. Starting from commercially
available 3-bromopyridine derivatives, most target compounds
were prepared in four consecutive steps in modest to excellent
yields. Multiple transformations were involved in the key
Chamberlin, A. R.; Sandler, J.; Fenical, W.; Cui, J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H.-R.; Evans, P. A.; Richardson, A. D.; Harper,
M. K.; Ireland, C. M.; Vong, B. G.; Brady, T. P.; Theodorakis, E. A.; La
Clair, J. J. ChemBioChem 2006, 7, 409−416.
(7) (a) Furuta, T.; Torigai, H.; Sugimoto, M.; Iwamura, M. J. Org.
lactonization reaction, including conjugate addition, S Ar, and
N
Chem. 1995, 60, 3953−3956. (b) Nomura, W.; Narumi, T.; Ohashi, N.;
Serizawa, Y.; Lewin, N. E.; Blumberg, P. M.; Furuta, T.; Tamamura, H.
ChemBioChem 2011, 12, 535−539.
elimination. Notably, a compound library of 8-azacoumarins,
readily accessible by this procedure, would be valuable resources
in efforts to develop molecules with potential applications in
medicinal chemistry. This is currently under study in our
laboratory and will be reported in due course.
(8) (a) Narumi, T.; Takano, H.; Ohashi, N.; Suzuki, A.; Furuta, T.;
Tamamura, H. Org. Lett. 2014, 16, 1184−1187. (b) Takano, H.; Narumi,
T.; Ohashi, N.; Suzuki, A.; Furuta, T.; Nomura, W.; Tamamura, H.
Tetrahedron 2014, 70, 4400−4404. (c) Takano, H.; Narumi, T.;
Nomura, W.; Furuta, T.; Tamamura, H. Org. Lett. 2015, 17, 5372−5375.
ASSOCIATED CONTENT
Supporting Information
■
(9) Wang, T.; Yin, Z.; Zhang, Z.; Bender, J. A.; Yang, Z.; Johnson, G.;
*
S
Yang, Z.; Zadjura, L. M.; D’Arienzo, C. J.; DiGiugno Parker, D.;
Gesenberg, C.; Yamanaka, G. A.; Gong, Y.-F.; Ho, H.-T.; Fang, H.;
Zhou, N.; McAuliffe, B. V.; Eggers, B. J.; Fan, L.; Nowicka-Sans, B.;
Dicker, I. B.; Gao, Q.; Colonno, R. J.; Lin, P.-F.; Meanwell, N. A.;
Kadow, J. F. J. Med. Chem. 2009, 52, 7778−7787.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03771.
Experimental procedures and spectral data for all new
compounds (PDF)
(
(
10) Atkins, R. L.; Bliss, D. E. J. Org. Chem. 1978, 43, 1975−1980.
11) Yavari, I.; Adib, M.; Hojabri, L. Tetrahedron 2002, 58, 6895−6899.
AUTHOR INFORMATION
Corresponding Authors
(12) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev.
■
2
(
012, 112, 2642−2713.
13) Different synthetic schemes were employed for 3a, 3h−3j, 3p and
*
E-mail: wangdong@tust.edu.cn.
E-mail: yupeng@tust.edu.cn.
3q; see the Supporting Information for details.
*
(14) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518−5526. (b) Heck,
R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320−2322.
ORCID
(15) (a) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003,
Dong Wang: 0000-0002-4855-0576
Notes
44, 8487−8491. (b) Dalence, M.; Johansson, M.; Thornqvist Oltner, V.;
Toftered, J.; Wensbo, D. W.O. Patent 2009007420A1, 2009.
(
16) Wang, D.; Zhao, J.; Wang, Y.; Hu, J.; Li, L.; Miao, L.; Feng, H.;
Desaubry, L.; Yu, P. Asian J. Org. Chem. 2016, 5, 1442−1446.
17) For selected examples of photoirradiated conversion of double
The authors declare no competing financial interest.
́
(
ACKNOWLEDGMENTS
bond geometries, see: (a) Horaguchi, T.; Hosokawa, N.; Tanemura, K.;
Suzuki, T. J. Heterocycl. Chem. 2002, 39, 61−67. (b) Cho, S.-Y.; Song, Y.-
K.; Kim, J.-G.; Oh, S.-Y.; Chung, C.-M. Tetrahedron Lett. 2009, 50,
■
This work was supported financially by the Tianjin Natural
Science Foundation of China (15JCYBJC53400), National
Natural Science Foundation of China (No. 81673296), Interna-
tional Science & Technology Cooperation Program of China
4
769−4772. (c) Sakai, H.; Hirano, T.; Mori, S.; Fujii, S.; Masuno, H.;
Kinoshita, M.; Kagechika, H.; Tanatani, A. J. Med. Chem. 2011, 54,
055−7065.
18) Reflux temperature was applied for most substrates because
7
(
(
1
2013DFA31160), and Start-up Foundation from TUST (1185/
0243). The authors are thankful to the Research Center of
substantial improvement of the product yield was observed when the
reaction temperature was increased to reflux for pyridine N-oxide
substrates.
Modern Analytical Technology, Tianjin University of Science
and Technology, for NMR measurements and high-resolution
mass analysis.
(19) (a) Robison, M. M.; Robison, B. L. J. Org. Chem. 1956, 21, 1337−
1
341. (b) New, J. S.; Yevich, J. P.; Temple, D. L., Jr.; New, K. B.; Gross, S.
M.; Schlemmer, R. F., Jr.; Eison, M. S.; Taylor, D. P.; Riblet, L. A. J. Med.
Chem. 1988, 31, 618−624. (c) Wiegand, C.; Herdtweck, E.; Bach, T.
Chem. Commun. 2012, 48, 10195−10197.
REFERENCES
■
(
1) (a) Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli,
C.; Zunino, F. Bioorg. Med. Chem. 2010, 18, 3543−3550. (b) Thakur, A.;
Singla, R.; Jaitak, V. Eur. J. Med. Chem. 2015, 101, 476−495. (c) Nasr, T.;
Bondock, S.; Youns, M. Eur. J. Med. Chem. 2014, 76, 539−548. (d) Cao,
D.; Liu, Y.; Yan, W.; Wang, C.; Bai, P.; Wang, T.; Tang, M.; Wang, X.;
Yang, Z.; Ma, B.; Ma, L.; Lei, L.; Wang, F.; Xu, B.; Zhou, Y.; Yang, T.;
Chen, L. J. Med. Chem. 2016, 59, 5721−5739.
(
2) (a) Watzka, M.; Geisen, C.; Bevans, C. G.; Sittinger, K.; Spohn, G.;
Rost, S.; Seifried, E.; Mueller, C. R.; Oldenburg, J. J. Thromb.
Haemostasis 2011, 9, 109−118. (b) Weigt, S.; Huebler, N.; Strecker,
R.; Braunbeck, T.; Broschard, T. H. Reprod. Toxicol. 2012, 33, 133−141.
(
3) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H.;
McMahon, J. B.; Currens, M. J.; Buckheit, R. W.; Hughes, S. H.; Cragg,
G. M.; Boyd, M. R. J. Med. Chem. 1992, 35, 2735−2743.
(
4) Stefani, H. A.; Gueogjan, K.; Manarin, F.; Farsky, S. H. P.;
Zukerman-Schpector, J.; Caracelli, I.; Pizano Rodrigues, S. R.; Muscara,
M. N.; Teixeira, S. A.; Santin, J. R.; Machado, I. D.; Bolonheis, S. M.;
Curi, R.; Vinolo, M. A. Eur. J. Med. Chem. 2012, 58, 117−127.
(
5) Basanagouda, M.; Shivashankar, K.; Kulkarni, M. V.; Rasal, V. P.;
Patel, H.; Mutha, S. S.; Mohite, A. A. Eur. J. Med. Chem. 2010, 45, 1151−
157.
6) Alexander, M. D.; Burkart, M. D.; Leonard, M. S.; Portonovo, P.;
Liang, B.; Ding, X.; Joullie, M. M.; Gulledge, B. M.; Aggen, J. B.;
1
(
́
D
DOI: 10.1021/acs.orglett.6b03771
Org. Lett. XXXX, XXX, XXX−XXX