Palladium-catalyzed oxidative annulation of acrylic acid and amide with alkynes: A practical route to synthesize α-pyrones and pyridones

Article abstract of DOI:10.1021/ol500611d

A range of internal alkynes smoothly underwent palladium-catalyzed oxidative annulations with acrylic acid and amide to afford α-pyrones and pyridones in good to excellent yields with high regioselectivity. The usage of O₂ (1 atm) as a stoichiometric oxidant with H₂O as the only byproduct under mild conditions makes this process more attractive and practical.

Full text of DOI:10.1021/ol500611d

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Oxidative Annulation of Acrylic Acid and Amide
with Alkynes: A Practical Route to Synthesize α‑Pyrones and
Pyridones
Yue Yu,† Liangbin Huang,† Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A range of internal alkynes smoothly underwent palladium-catalyzed oxidative annulations with acrylic acid and
amide to afford α-pyrones and pyridones in good to excellent yields with high regioselectivity. The usage of O2 (1 atm) as a
stoichiometric oxidant with H2O as the only byproduct under mild conditions makes this process more attractive and practical.
Scheme 1. Pd-Catalyzed Oxidative Coupling between
Alkynes and Alkenes
fficient and selective synthetic methodologies that include
transition metal catalysis and simple starting materials, for
E
the synthesis of complex molecules, occupy a leading position
in modern organic chemistry. Unsaturated hydrocarbons,
especially alkynes and alkenes, which are important staple
products of petroleum and petrochemical industries, can be
utilized to build multiple new chemical bonds with maximal
atom and step economy.1 In particular, nucleometalation of
carbon−carbon triple bonds has been demonstrated to be one
of the most efficient strategies for its high efficiency in
constructing nucleophile−carbon and carbon−metal bonds in a
single step.2−4 Yamamoto5,6 and Zhang7,8 et al. respectively
utilized the carbonyl oxygen atom and other O-containing
nucleophiles to attack the triple bond, activated by a Au
complex. Lu and others made great contributions to the alkyne
conversions initiated by nucleopalladation.9−16 Recently, our
group developed a series of cross-coupling reactions using
alkynes and alkenes as substrates to construct 1,3-dienes,17
substituted benzenes,18,19 and α-methylene-γ-lactones (Scheme
1).20 In our continued interest in Pd-catalyzed oxidative
coupling between alkynes and alkenes,17−22 we herein report
an efficient and robust strategy to synthesize α-pyrones and
pyridines through the aerobic oxidative annulations between
acrylic acids or amides with alkynes (Scheme 1, pathway d).
This type of oxidative coupling reaction catalyzed by
palladium has provided important innovations for synthetic
chemistry over the past decades.23 Recently, similar reactions of
oxidative annulation or decarboxylation by rhodium or
ruthenium catalysis have been reported by Ackermann,
Miura, Jeganmohan, and Rovis et al. since 2007.24,25 These
reactions have greatly supplemented the study of oxidative C−
H bond transformations proceeding via C−H/O−H or C−H/
N−H bond cleavages, which provide an atom-economical way
to synthesize α-pyrones and pyridines. But oxidative
annulations between internal alkynes and acrylic acid or
amide by palladium catalysis are still a big challenge, because
of the relatively less catalytic activity and the different reaction
mechanism.
To our delight, the desired oxidative annulation between
diphenylethyne 1a and acrylic acid 2a, using 10 mol %
Pd(OAc)2 as the catalyst and 30 mol % CuBr2 at 90 °C under 1
atm of O2, afforded the desired product 3a in 44% yield (Table
1, entry 1). When 2 mL of mixed AcOH/Ac2O (1: 3) was used
as solvent, the product yield increased to 66% (Table 1, entry
2). Further experiments indicated that Pd(OAc)2 was the best
catalyst for this transformation (Table 1, entries 4−5).
Changing the co-oxidant CuBr2 to other copper salts did not
improve the yield (Table 1, entries 6−7). Adjusting the reaction
temperature did not increase the yield of the desired product
(Table 1, entries 8−9). Interestingly, the yield of 3a could be
enhanced significantly by adding 1 equiv of DABCO to the
Received: February 26, 2014
Published: March 27, 2014
© 2014 American Chemical Society
2146
dx.doi.org/10.1021/ol500611d | Org. Lett. 2014, 16, 2146−2149

Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
b
entry
[Pd]
co-oxidant
base
solvent
yield (%)
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
Cu(OAc)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
−
−
−
−
−
−
−
−
−
Ac2O
44
57
66
51
37
54
n.d.
54
43
78
62
82
50
76
51
64
HOAc/Ac2O = 1:1
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
HOAc/Ac2O = 1:3
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
c
8
d
9
10
DABCO
i-Pr2NEt
Et3N
c
11
12
13
14
15
K2CO3
Na2CO3
Li2CO3
Et3N
e
16
a
Unless otherwise noted, all reactions were performed with 1a (0.5 mmol), 2a (0.6 mmol), Pd catalyst (0.05 mol) and co-oxidant (0.15 mmol), base
b
(0.5 mmol) under O2 (1 atm) in the indicated solvent (2.0 mL) at 90 °C for 12 h. Determined by GC using dodecane as the internal standard.
Yields refer to isolated yields. The temperature was 80 °C. The temperature was 100 °C. The reaction was in air instead of pure O2.
c
d
e
reaction system (Table 1, entry 10). During the screening of
bases, the yield increased to 82% when DABCO was replaced
with Et3N (Table 1, entries 11−15). This result suggested that
Et3N promoted the reaction. We proposed that the salt
generated from the reaction of the base with ethylic acid could
better stabilize the PdII species. If the reaction was performed in
air instead of pure O2, the yield would drop to 64% (Table 1,
entry 16).
Scheme 2. Pd-Catalyzed Oxidative Annulations between
Diarylethynes and Acrylic Acid
a
With the optimal reaction conditions in hand, we next
expanded the scope of the Pd-catalyzed oxidative annulations
with respect to a variety of alkynes (Scheme 2). A series of
para-substituted diphenylethynes, including some with elec-
tron-withdrawing and -donating groups, went smoothly to
afford the corresponding α-pyrones in good yields (Scheme 2,
3b−c). The substrate with a substituent on the meta-position
of the phenyl ring could also transform to the desired product
in 81% yield (Scheme 2, 3d). Starting materials containing
−NO2 and −OMe, the strong electron biased groups,
underwent the transformation efficiently which indicated its
good tolerance toward the electron effect (Scheme 2, 3e−f). To
our delight, we found the unsymmetrical diarylethynes could
convert to the α-pyrones with a regioselectivity of >20/1 when
strong electron biased groups were present at the para position
of the aromatic ring (Scheme 2, 3g−i). It was worth noting that
many synthetically relevant functional groups, including nitro,
ester, cyan, and CF3, were tolerated under the reaction
conditions. Furthermore, the diheteroarylethynes were also
subjected to the optimal conditions. 1,2-Di(thiophen-2-yl)-
ethyne showed good reactivity, and the desired product was
obtained in 77% yield (Scheme 2, 3j), while the 1,2-di(pyridin-
2-yl)ethyne exhibited inertness for this transformation (Scheme
2, 3k).
a
Unless otherwise noted, all reactions were performed with 1 (0.5
mmol), 2a (0.75 mmol), Pd(OAc)2 (0.05 mmol), CuBr2 (0.15 mmol),
and Et3N (0.5 mmol) in 2 mL of solvent (HOAc/Ac2O = 1:3) under 1
atm of O2 at 90 °C for 12 h. Yields refer to isolated yields.
ring or not, the transformation afforded the desired products in
good to high yields (Scheme 3, 3l−m). The situation was
similar to the alkynoates when the functional group was ketone
for this transformation (Scheme 3, 3n−p). Finally, the
alkanoates could transfer to the corresponding products with
excellent regioselectivity in 86% yield (Scheme 3, 3q). Inspired
by the recent nucleopalladtion of haloalkynes of Zhu,26−28 we
tried to use haloalkynes as a substrate but failed.
To further explore the utility of this newly developed
reaction for the synthesis of functional molecules, we tested the
oxidative annulations of acrylic acids with alkynes, containing
functional groups (Scheme 3). When the functional group was
ester, no matter whether there are substitutions on the aromatic
2147
dx.doi.org/10.1021/ol500611d | Org. Lett. 2014, 16, 2146−2149

Organic Letters
Letter
low (Scheme 4, 4g). Then, if R is tert-butyl, the acrylic amide
will be easy to hydrolyze to acrylic acid, resulting in the product
4h, with the same structure as that of 3a. In order to confirm
whether the acylation occurred before or after the cyclization,
we tried to test the reaction of acrylic amide under the standard
conditions in the absence of the catalyst and alkyne, and the
acylate was found, which suggested that the acylation occurred
before the cyclization.
Scheme 3. Pd-Catalyzed Oxidative Annulations between
Alkynes and Acrylic Acid
a
On the basis of the above results, a plausible mechanism for
the Pd-catalyzed oxidative annulations is illustrated in Scheme
5. We proposed that the initial step involved the coordination
Scheme 5. Proposed Catalytic Cycle
a
Unless otherwise noted, all reactions were performed with 1 (0.5
mmol), 2a (0.75 mmol), Pd(OAc)2 (0.05 mmol), CuBr2 (0.15 mmol),
and Et3N (0.5 mmol) in 2 mL of solvent (HOAc/Ac2O = 1:3) under 1
atm of O2 at 90 °C for 12 h. Yields refer to isolated yields.
The scope of this oxidative annulation was further expanded
to acrylic amide with internal alkynes (Scheme 4).29 The
Scheme 4. Pd-Catalyzed Oxidative Annulations between
a
Diarylethynes and Acrylic Amide
and ligand exchange of the acrylic derivative 2 with PdII to
provide X−Pd intermediate I.30,31 Then, exo coordination of 1a
and insertion of the diarylethyne molecule into I gave the
vinyl−palladium complex II. Subsequently, the intramolecular
Heck-type process afforded the alkyl-palladium species III,32
which would undergo β-hydride elimination to release product
3 and Pd0. Finally, the catalyst was regenerated to complete the
catalytic cycle. Under the assistance of Cu(II), the oxygen
oxidized the Pd0 to PdII. When acrylic amide was used as the
starting material, the annulation product would undergo
acylation under the acid conditions and afford the observed
product 4.
In summary, we have developed a highly efficient strategy for
the synthesis of α-pyrones and pyridones via Pd-catalyzed
oxidative [4 + 2] annulations between acrylic derivatives and
internal alkynes with high regioselectivity. The usage of O2 (1
atm) as a stoichiometric oxidant with H2O as the only
byproduct under mild conditions makes this process more
attractive and practical. The detailed mechanistic studies and
further applications of this reaction are currently underway in
our laboratory.
a
Unless otherwise noted, all reactions were performed with 1 (0.5
mmol), 2b (0.75 mmol), Pd(OAc)2 (0.05 mmol), CuBr2 (0.15 mmol),
and Et3N (0.5 mmol) in 2 mL of solvent (HOAc/Ac2O = 1:3) under 1
atm of O2 at 90 °C for 12 h. Yields refer to isolated yields.
Determined by GC using dodecane as the internal standard. Yields
refer to isolated yields.
b
ASSOCIATED CONTENT
* Supporting Information
■
S
compatibility of this catalytic system with different functional
groups, including alkyl, halogen, esters, cyan, and nitriles, was
established (Scheme 4, 4b−f). The regioselectivity of the
reaction was excellent when the para substituents of the
aromatic ring were strong electron biased groups, such as OMe,
CN, and NO2 (Scheme 4, 4e−f). Particularly, it was
noteworthy that if the substituent R is OMe, which is a weak
electron-withdrawing group in this situation, it also can
transform to the corresponding product while the yield is too
Experimental section, characterization of all compounds, copies
1
of H and 13C NMR spectra for selected compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jianghf@scut.edu.cn.
2148
dx.doi.org/10.1021/ol500611d | Org. Lett. 2014, 16, 2146−2149

Organic Letters
Letter
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2013, 78, 11427−
11432. (f) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2009, 74, 6295−6298. (g) Ueura, K.; Satoh, T.; Miura, M. Org. Lett.
2007, 9, 1407−1409. (h) Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2012, 48, 2030−2032. (i) Reddy, M. C.; Manikandan, R.;
Jeganmohan, M. Chem. Commun. 2013, 49, 6060−6062. (j) Hyster, T.
K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565−10569. (k) Danoun,
G.; Mamone, P.; Gooßen, L. J. Chem.Eur. J. 2013, 19, 17287−
17290. (l) Mamone, P.; Danoun, G.; Gooßen, L. J. Angew. Chem., Int.
Ed. 2013, 125, 6836−6840.
Author Contributions
†Y.Y. and L.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21172076 and 21202046), the National Basic Research
Program of China (973 Program) (2011CB808600), the
G u a n g d o n g N a t u r a l S c i e n c e F o u n d a t i o n
(10351064101000000), and the Fundamental Research Funds
for the Central Universities (2014ZP0004 and 2014ZZ0046).
(25) For reactions of palladium-catalyzed oxidative annulation, see:
(a) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 5916−5921. (b) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.;
Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem.
Soc. 2013, 135, 1236−1239. (c) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J.
Am. Chem. Soc. 2008, 130, 17676−17677. (d) Wasa, M.; Yu, J.-Q. J.
Am. Chem. Soc. 2008, 130, 14058−14059. (e) Mei, T.-S.; Leow, D.;
Xiao, H.; Laforteza, B. N.; Yu, J.-Q. Org. Lett. 2013, 15, 3058−3061.
(f) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010, 12, 2511−2513.
(g) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 121,
8035−8038. (h) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908−
2911. (i) Zhang, N.; Li, B.; Zhong, H.; Huang, J. Org. Biomol. Chem.
2012, 10, 9429−9439. (j) Zhong, H.; Yang, D.; Wang, S.; Huang, J.
Chem. Commun. 2012, 48, 3236−3238. (k) Lu, S.; Lin, Y.; Zhong, H.;
Zhao, K.; Huang, J. Tetrahedron Lett. 2013, 54, 2001−2005.
(26) Chen, X.; Chen, D.; Lu, Z.; Kong, L.; Zhu, G. J. Org. Chem.
2011, 76, 6338−6343.
REFERENCES
■
(1) Trotus,
1761−1782.
̧
I.-T.; Zimmermann, T.; Schuth, F. Chem. Rev. 2014, 114,
̈
(2) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285−2310.
(3) Luo, Y.; Pan, X.; Yu, X.; Wu, J. Chem. Soc. Rev. 2014, 43, 834−
846.
(4) Abu Sohe, S. M.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269−2281.
(5) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 10921−10925.
(6) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J.
Am. Chem. Soc. 2002, 124, 12650−12651.
(7) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am. Chem. Soc. 2012, 134,
17412−17415.
(27) Chen, X.; Kong, W.; Cai, H.; Kong, L.; Zhu, G. Chem. Commun.
2011, 47, 2164−2166.
(8) Ji, K.; Zhao, Y.; Zhang, L. Angew. Chem., Int. Ed. 2013, 52, 6508−
(28) Chen, D.; Cao, Y.; Yuan, Z.; Cai, H.; Zheng, R.; Kong, L.; Zhu,
G. J. Org. Chem. 2011, 76, 4071−4074.
6512.
(9) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi, S.
J. Org. Chem. 1979, 44, 55−63.
(29) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12,
5462−5465.
(10) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343−4345.
(11) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903−3906.
(12) Lei, A.; Lu, X. Org. Lett. 2000, 2, 2699−2702.
(13) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604−7605.
(14) Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47, 5442−5445.
(15) Feng, C.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 17710−17712.
(16) Zhao, P.; Chen, D.; Song, G.; Han, K.; Li, X. J. Org. Chem. 2011,
77, 1579−1584.
(30) Miyoshi, Y.; Akatsuka, T.; Okuoka, S.-i.; Tsukajima, A.; Makino,
M.; Saito, M.; Yonehara, K. Chem.Eur. J. 2012, 18, 7941−7949.
(31) Yonehara, K.; Miyoshi, Y.; Tsukajima, A.; Akatsuka, T.; Saito, M.
Adv. Synth. Catal. 2011, 353, 1071−1075.
(32) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65−87.
(17) For reviews, see: Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45,
1736−1748.
(18) (a) Zhou, P.; Jiang, H.; Huang, L.; Li, X. Chem. Commun. 2011,
47, 1003−1005. (b) Shen, Y.; Jiang, H.; Chen, Z. J. Org. Chem. 2010,
75, 1321−1324.
(19) Zhou, P.; Huang, L.; Jiang, H.; Wang, A.; Li, X. J. Org. Chem.
2010, 75, 8279−8282.
(20) Huang, L.; Wang, Q.; Liu, X.; Jiang, H. Angew. Chem., Int. Ed.
2012, 51, 5696−5700.
(21) Wang, Q.; Huang, L.; Wu, X.; Jiang, H. Org. Lett. 2013, 15,
5940−5943.
(22) Wen, Y.; Huang, L.; Jiang, H.; Chen, H. J. Org. Chem. 2012, 77,
2029−2034.
(23) For oxidative coupling reactions catalyzed by palladium, see:
(a) Liu, Q.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2013, 52,
13871−13873. (b) Liu, Q.; Li, G.; He, J.; Liu, J.; Li, P.; Lei, A. Angew.
Chem., Int. Ed. 2010, 49, 3371−3374. (c) Liu, C.; Wang, J.; Meng, L.;
Deng, Y.; Li, Y.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144−5148.
(d) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A.
Angew. Chem., Int. Ed. 2012, 51, 5204−5207. (e) Liu, C.; Tang, S.;
Zheng, L.; Liu, D.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51,
5662−5666. (f) Shi, R.; Lu, L.; Zhang, H.; Chen, B.; Sha, Y.; Liu, C.;
Lei, A. Angew. Chem., Int. Ed. 2013, 52, 10582−10585.
(24) For reactions of oxidative annulation or decarboxylation by
rhodium or ruthenium catalysis, see: (a) Ackermann, L. Acc. Chem. Res.
2014, 47, 281−295. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278−3281. (c) Ackermann, L.; Fenner, S. Org.
Lett. 2011, 13, 6548−6551. (d) Ackermann, L.; Pospech, J.; Graczyk,
K.; Rauch, K. Org. Lett. 2012, 14, 930−933. (e) Itoh, M.; Shimizu, M.;
2149
dx.doi.org/10.1021/ol500611d | Org. Lett. 2014, 16, 2146−2149