Tandem sp3 C-H functionlization/decarboxylation of 2-alkylazaarenes with coumarin-3-carboxylic acids

Article abstract of DOI:10.1021/ol403541g

The catalyst-free sp³ C-H functionalization of 2-alkylazaarenes has been achieved in the reaction with (thio)coumarin-3-carboxylic acids. Followed by a tandem decarboxylation, this method provides facile synthesis of biologically important azaarene-substituted 3,4-dihydro(thio)coumarins in a single step in high yields.

Full text of DOI:10.1021/ol403541g

Letter
pubs.acs.org/OrgLett
Tandem sp3 C−H Functionlization/Decarboxylation of
2‑Alkylazaarenes with Coumarin-3-carboxylic Acids
Lubin Xu,† Zhuzhou Shao,† Liang Wang, and Jian Xiao*
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
S
* Supporting Information
ABSTRACT: The catalyst-free sp3 C−H functionalization of
2-alkylazaarenes has been achieved in the reaction with
(thio)coumarin-3-carboxylic acids. Followed by a tandem
decarboxylation, this method provides facile synthesis of
biologically important azaarene-substituted 3,4-dihydro(thio)-
coumarins in a single step in high yields.
3,4-Dihydrocoumarins constitute an exceptional class of
structural motifs which have been found widely present in
natural products and biologically active molecules.1 The
compounds of this family exhibit a broad spectrum of
pharmacological properties such as protein transacetylase,
protein kinase, reductase inhibitory, antioxidant, and blocking
of ATP-sensitive potassium channel activities.2
Scheme 1. sp3 C−H Functionalization of 2-Alkylazaarenes
Furthermore, this type of compound can be applied as a
flavoring agent in the food industry.3 Consequently, there has
been growing interest in modification and functionalization of
this class of compounds from both organic and medicinal
chemists, aiming to find new applications from these
compounds. Among this, the conjugate addition of various
nucleophiles to coumarins provides one of the most
straightforward methods for the synthesis of diversified 3, 4-
dihydrocoumarins.4 However, much remains to be explored on
the derivatization of heteroarenes with coumarins and 3,4-
dihydrocoumarins despite universal biological properties and
applications in drug discovery and material sciences of
heteroarenes.5
Significant progress has been achieved for the development
of direct sp3 C−H bond functionalization of 2-alkylazaarenes
without resorting to the expensive noble transition metals such
as Pd and Rh.6,7 Various alkylated pyridine derivatives can be
synthesized using much cheaper and greener Lewis acid
catalysts in an efficient manner, which are important structural
motifs present in natural products, pharmaceuticals, and
functional materials.8 However, the research on nonmetal or
catalyst-free versions of this reaction is highly desirable and
environmentally valuable since no extra effort is needed to
remove the toxic metal residues. In this context, we presented
the first Brønsted acid-catalyzed sp3 C−H functionalization of
2-methylazaarenes, leading to facile synthesis of biologically
important azaarene-substituted 3-hydroxy-2-oxindoles in one
step (Scheme 1a).9a
alkylazaarenes in a more efficient way. As such, coumarin-3-
carboxylic acid came into our sight and was selected as a
suitable substrate for this purpose. Although pyridine and 3,4-
dihydrocoumarin are all important motifs in natural products,
to the best of our knowledge, no direct method for the
synthesis of azaarene-substituted 3,4-dihydrocoumarins has
been reported, while it holds great potential for production
of new biologically important compounds and new pharma-
ceuticals. As a continuation of development of an efficient and
green manner to construct biologically and medicinally
important molecules,9 herein we present the catalyst-free
tandem sp3 C−H activation/decarboxylation of 2-alkylazaar-
enes with coumarin-3-carboxylic acids to furnish the azaarene-
substituted 3,4-dihydrocoumarin derivatives in one step
(Scheme 1b).
To test our hypothesis, the initial study was conducted on
the reaction of 2,6-lutidine 1a and coumarin-3-carboxylic acid
2a in 1,4-dioxane under catalyst-free conditions. To our delight,
the reaction proceeded successfully and the corresponding
product 3a was obtained in 94% yield without any catalyst in
dioxane at 120 °C (Table 1, entry 1). The lower temperature
gave inferior results (Table 1, entries 2 and 3), and no reaction
occurred when the temperature was decreased to 80 °C (Table
As further research in this field, we proposed that if
introducing a carboxyl group in some electron-deficient olefins,
the substrate could be served as a Brønsted acid to activate 2-
alkylazaarenes, thus triggering the reaction in the absence of
catalyst, which can be called “self-activation”, to functionalize 2-
Received: December 6, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization Studies
Scheme 2. Substrate Scope of 2-Alkylazaarenes and
a,b
Coumarin-3-carboxylic Acids
b
entry
catalyst
solvent
temp (°C)
yield (%)
1
dioxane
dioxane
dioxane
dioxane
THF
120
100
90
94
90
77
0
2
3
4
80
5
120
120
120
120
120
120
120
120
120
120
120
120
120
120
64
69
87
62
62
64
67
88
66
75
52
76
86
74
6
DMF
7
toluene
DMSO
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
8
9
Sc(OTf)3
10
11
12
13
14
15
16
17
18
Yb(OTf)3
La(OTf)3
Cu(OTf)2
AgOTf
Zn(OTf)2
TFA
TfOH
CH3COOH
p-FC6H4COOH
a
Reactions were conducted with 1a (0.75 mmol), 2a (0.3 mmol), and
b
catalyst (10 mol %) in 1 mL of solvent for 48 h. Isolated yield.
1, entry 4). Other solvents also worked well at 120 °C without
catalyst, although the yield was not improved (Table 1, entries
5−8). A variety of Lewis acids and Brønsted acids (10 mol %)
were also investigated at 120 °C for comparison with the
catalyst-free condition, and it was found that all of the tested
Lewis acids and Brønsted acids catalysts gave moderate to good
yields (Table 1, entries 9−18), which provides the rare example
that both Lewis acids and Brønsted acids catalysts are all
effective in a single sp3 C−H activation reaction. However, all
of the results were inferior to those under catalyst-free
conditions, which eventually corroborated our hypothesis.
With the optimized conditions in hand, the substrate scope
was investigated and the results are shown in Scheme 2. A
series of 2-substituted pyridines were examined under the
optimized conditions, and corresponding products 3a−h were
produced in good to excellent yields. No reaction occurred for
2-benzylpyridine (3i) probably due to the steric hindrance
caused by the phenyl group. Notably, when γ-methylpyridine
was employed, the analogous product 3j was not detected.
However, if a nitro group was introduced at the β-position of 4-
picoline, the reaction proceeded exclusively in the γ-position
and afforded the corresponding product 3f in 76% yield.
Notably, when 2,6-dimethyl-3-nitropyridine was employed, two
regioisomeric products (3g and 3h) could be isolated in higher
yield (84% yield) with less sterically hindered 6-methyl product
3g as the major product. Pyrazine and pyrimidine derivatives
were also well tolerated to furnish the products 3k and 3l in
85% and 52% yields, respectively. This tandem conjugate
addition/decarboxylation reaction also worked well with 2-
methylquinolines (or 1-methylisoquinoline) bearing a variety of
substituents on the ring of quinoline, leading to the products
(3m−p) in good to excellent yields. Subsequently, a variety of
substituted coumarin-3-carboxylic acids were subjected to the
reaction (3q−w), and it was found that both electron-donating
a
Reactions were conducted with azaarene 1 (0.75 mmol) and
coumarin-3-carboxylic acid 2 (0.3 mmol) in 1 mL of dioxane at 120
b
°C for 48 h. The yields indicated are isolated yields by column
chromatography.
and -withdrawing substituents, such as OMe, NO2, and halogen
groups, on the phenyl ring of coumarins were well-tolerated,
giving rise to the desired products in yields ranging from 50%
to 96% (3q−u). The electron-rich aryl-substituted coumarins
were more favored for the transformation (3q, 96% and 3r,
86%). If the C5, C7 positions were substituted with two
chlorine atoms or the C6, C8-positions were occupied by two
tert-butyl groups, no desired products could be obtained even
when the reactions were heated to 140 °C (3v and 3w), and the
reason might be the steric hindrance caused by those
substituents.
Inspired by the success in coumarin-3-carboxylic acid, we
intended to extend the reaction scope to thiocoumarin-3-
carboxylic acid.10 Thiocoumarins and its derivatives also exhibit
a broad spectrum of pharmacological properties although there
are no reported methods for functionalization of such
compounds.11 Gratifyingly, when thiocoumarin-3-carboxylic
B
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Letter
acid 4 was subjected to the reaction, the corresponding product
5 could be isolated in good to excellent yields (Scheme 3).
electron deficient but also activated the 2-methylpyridine
substrate to drive the reaction to completion. Furthermore,
the carboxyl group brings the nucleophile closer to the Michael
acceptor by hydrogen bonding so that the nucleophile can
approach the electron-deficient alkene more readily. These
factors caused by the carboxyl group can facilitate the
transformation dramatically, thus rendering the reaction
proceed very well in the absence of catalyst.
Scheme 3. Reaction of 2-Alkylazaarenes with Thiocoumarin-
a,b
3-carboxylic Acid
On the basis of the above-mentioned information, the
proposed reaction mechanism is outlined in Scheme 5. It could
Scheme 5. Proposed Reaction Mechanism
a
Reactions were conducted with azaarenes 1 (0.75 mmol) and 4 (0.3
b
mmol) in 1 mL of dioxane at 120 °C for 48 h. Isolated yield.
When 2,6-dimethyl-3-nitropyridine was exploited, two regioiso-
meric products (5i and 5j) were isolated in similar yield, which
implies that the 2- and 6-methyl groups are of comparable
reactivity associated with the thiocoumarin-3-carboxylic acid 4.
To shed light on the reaction mechanism, coumarin 6,
coumarin-3-acetic acid 7, and 2H-chromene-3-carboxylic acid 8
were prepared and subjected to the standard conditions
(Scheme 4). All of these substrates did not react with 2,6-
be conceived that 2-methylazaarenes 1 and coumarin-3-
carboxylic acid 2 were bound together via a hydrogen-bonding
interaction, followed by protonation of 2-methylazaarenes 1 to
give pyridinium A. As a result of the enhanced acidity of the
benzylic protons, C−H cleavage would occur to afford an
enamine intermediate, which attacked the electron-deficient
alkene via the well-organized transition state B to form the
intermediate C. In the transition state B, hydrogen-bonding
interaction helps the enamine approach the electron-deficient
alkene moiety. The next tautomerization, decarboxylation, and
isomerization would produce 3. In the whole process, it was
proposed that hydrogen bonding plays a key role for the
success of this transformation.
Scheme 4. Control Experiment
In summary, we present a facile catalyst-free tandem
conjugate addition/decarboxylation of 2-alkylazaarenes with
(thio)coumarin-3-carboxylic acids via sp3 C−H activation for
the efficient construction of azaarene substituted 3,4-dihydro-
(thio)coumarins. A broad scope of coumarins, thiocoumarins,
and azaarenes can be tolerated, and the coupled products were
isolated in good to excellent yields. This method proves to be
an efficient and innovative approach to this biologically
important architecture in a single step. The success of this
reaction should broaden the library of coumarins or
thiocoumarins in pharmaceutical chemistry and extend the
synthetic utility of sp3 C−H functionalization in organic
synthesis.
lutidine 1a under standard reaction conditions. No reaction of
coumarin 6 and coumarin-3-acetic acid 7 indicated that the
direct connection of carboxyl group to the alkene at C-3
position was a crucial factor for this reaction. Failure of the
reaction of 2H-chromene-3-carboxylic acid 8 implied that
electron deficiency of alkene was indispensable. Toward this
end, more control experiments were carried out with the
introduction of ester, acetyl, and nitro groups (9a, 9b, and 9c)
into the C-3 position of coumarin instead of the carboxyl
group. However, no reaction occurred under the standard
conditions (condition a), even in the presence of Sc(OTf)3
(condition b) or TFA (condition c). Base addition such as Et3N
and DBU was also detrimental to this reaction. In view of the
above-mentioned experimental results, it can be concluded that
the carboxyl group in C-3 position of coumarin was crucial for
the success of this reaction, which not only rendered the alkene
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional experimental procedures and spectrascopic data of
new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chemjxiao@gmail.com.
C
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Guillerm, G. Bioorg. Med. Chem. Lett. 2003, 13, 1713. (g) Heasley, B.
H.; Jarosz, R.; Carter, K. M.; Jenny Van, S.; Lynch, K. R.; Macdonald,
T. L. Bioorg. Med. Chem. Lett. 2004, 14, 4069. (h) Zhu, Y.; Pavlos, C.
M.; Toscano, J. P.; Dore, T. M. J. Am. Chem. Soc. 2006, 128, 4267.
(9) (a) Niu, R.; Xiao, J.; Liang, T.; Li, X. Org. Lett. 2012, 14, 676.
(b) Xiao, J. Org. Lett. 2012, 14, 1716. (c) Liang, T.; Xiao, J.; Xiong, Z.
Y.; Li, X. J. Org. Chem. 2012, 77, 3583. (d) Xiao, J.; Zhao, K.; Loh, T.
P. Chem. Commun. 2012, 48, 3548. (e) Huang, F.; Xu, L.; Xiao, J. Chin.
J. Chem. 2012, 30, 2721. (f) Niu, R.; Yang, S.; Xiao, J.; Liang, T.; Li, X.
Chin. J. Catal. 2012, 33, 1636.
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21102142) and the Outstanding Young Scientist
Award Foundation of Shandong Province (Nos. BS2011YY007,
BS2013YY002). Financial support from the Talents of High
Level Scientific Research Foundation (No. 631223) of Qingdao
Agricultural University is also gratefully acknowledged.
(10) Meth-Cohn, O.; Tarnowski, B. Synthesis 1978, 56.
(11) For examples, see: (a) Meth-Cohn, O.; Tarnowski, B. Adv.
Heterocycl. Chem. 1980, 26, 115. (b) Kumar, S.; Singh, B. K.; Kalra, N.;
Kumar, V.; Kumar, A.; Prasad, A. K.; Raj, H. G.; Parmar, V. S.; Ghosh,
B. Bioorg. Med. Chem. 2005, 13, 1605. (c) Reddy, P. V. K.; Kumar, P.
N.; Chandramouli, G. V. P. J. Heterocycl. Chem 2005, 42, 283.
(d) Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava,
A.; Supuran, C. T. J. Med. Chem. 2010, 53, 335.
REFERENCES
■
(1) (a) Murray, R. D. H. Nat. Prod. Rep. 1989, 6, 591. (b) Murray, R.
D. H. Nat. Prod. Rep. 1995, 12, 477. (c) Estevez-Braun, A.; Gonzalez,
A. G. Nat. Prod. Rep. 1997, 14, 464. (d) McGlacken, G. P.; Fairlamb, I.
J. S. Nat. Prod. Rep. 2005, 22, 369. (e) Asai, F.; Iinuma, M.; Tanaka, T.;
Mizuno, M. Phytochemistry 1991, 30, 3091. (f) Asai, F.; Iinuma, M.;
Tanaka, T.; Mizuno, M. Heterocycles 1992, 33, 229. (g) Asai, F.;
Iinuma, M.; Tanaka, T.; Mizuno, M. Phytochemistry 1992, 31, 2487.
(2) For recent examples, see: (a) Roelens, F.; Huvaere, K.; Dhooge,
W.; Van Cleemput, M.; Comhaire, F.; De Keukeleire, D. Eur. J. Med.
Chem. 2005, 40, 1042. (b) Kumar, A.; Singh, B. K.; Tyagi, R.; Jain, S.
K.; Sharma, S. K.; Prasad, A. K.; Raj, H. G.; Rastogi, R. C.; Watterson,
A. C.; Parmar, V. S. Bioorg. Med. Chem. 2005, 13, 4300. (c) Modranka,
J.; Albrecht, A.; Jakubowski, R.; Krawczyk, H.; Rozalski, M.; Krajewska,
U.; Janecka, A.; Wyrebska, A.; Rozalska, B.; Janecki, T. Bioorg. Med.
Chem. 2012, 20, 5017. (d) Yang, J.; Liu, G.-Y.; Dai, F.; Cao, X.-Y.;
Kang, Y.; Hu, L.-M.; Tang, J.-J.; Li, X.-Z.; Jin, X.-L.; Zhou, B. Bioorg.
Med. Chem. Lett. 2011, 21, 6420.
(3) (a) Haser, K.; Wenk, H. H.; Schwab, W. J. Agric. Food Chem.
2006, 54, 6236. (b) Adams, T. B.; Greer, D. B.; Doull, J.; Munro, I. C.;
Newberne, P.; Portoghese, P. S.; Smith, R. L.; Wagner, B. M.; Weil, C.
S.; Woods, L. A.; Ford, R. A. Food Chem. Toxicol. 1998, 36, 249.
(4) (a) Peng, S.; Wang, L.; Guo, H.; Sun, S.; Wang, J. Org. Biomol.
́
Chem. 2012, 10, 2537. (b) Gonzalo, B.; Carmen Munoz, M.; Jose, R.
̃
P.; Amparo, S.-M. Adv. Synth. Catal. 2013, 355, 1071. (c) Lee, Y. T.;
Das, U.; Chen, Y. R.; Lee, C. J.; Chen, C. H.; Yang, M. C.; Lina, W.
Adv. Synth. Catal. 2013, 355, 3154.
(5) (a) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058.
(b) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459.
(c) Laird, T. Org. Process Res. Dev. 2006, 10, 851. (d) Henry, G. D.
Tetrahedron 2004, 60, 6043. (e) Michael, J. P. Nat. Prod. Rep. 2005, 22,
627.
(6) For reviews on sp3 C−H bond activation, see: (a) Tobisu, M.;
Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (b) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (c) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.Eur. J. 2010, 16, 2654.
(d) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931.
(7) For representative examples, see: (a) Qian, B.; Guo, S.; Xia, C.;
Huang, H. Adv. Synth. Catal. 2010, 352, 3195. (b) Rueping, M.;
Tolstoluzhsky, N. Org. Lett. 2011, 13, 1095. (c) Komai, H.; Yoshino,
T.; Matsunaga, S.; Kanai, M. Org. Lett. 2011, 13, 1706. (d) Qian, B.;
Xie, P.; Xie, Y.; Huang, H. Org. Lett. 2011, 13, 2580. (e) Yan, Y.; Xu,
K.; Fang, Y.; Wang, Z. J. Org. Chem. 2011, 76, 6849. (f) Liu, J. Y.; Niu,
H. Y.; Wu, S.; Qu, G. R.; Guo, H. M. Chem. Commun. 2012, 9723.
(g) Qian, B.; Shi, D.; Yang, L.; Huang, H. Adv. Synth. Catal. 2012, 354,
2146. (h) Guan, B. T.; Wang, B.; Nishiura, M.; Hou, Z. Angew. Chem.,
Int. Ed. 2013, 52, 4418. (i) Li, Y.; Guo, F.; Zha, Z.; Wang, Z. Chem.
Asian J. 2013, 8, 534.
(8) (a) Henry, G. D. Tetrahedron 2004, 60, 6043. (b) Michael, J. P.
Nat. Prod. Rep. 2005, 22, 627. (c) Chiu, Y.-H.; dos Santos, O.; Canary,
J. W. Tetrahedron 1999, 55, 12069. (d) Pickaert, G.; Cesario, M.;
Ziessel, R. J. Org. Chem. 2004, 69, 5335. (e) Ziessel, R.; Pickaert, G.;
Camerel, F.; Donnio, B.; Guillon, D.; Cesario, M.; Prange,
Chem. Soc. 2004, 126, 12403. (f) Behr, J.-B.; Gourlain, T.; Helimi, A.;
́
T. J. Am.
D
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