Pd-catalyzed Oxidative coupling of Enamides and Alkynes for synthesis of substituted Pyrroles

Article abstract of DOI:10.1021/ol403517p

A novel and efficient palladium(II)-catalyzed alkenyl C-H activation oxidative annulation of enamides with alkynes for the synthesis of substituted pyrroles has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the synthesis of triaryl-substituted pyrroles in high yields.

Full text of DOI:10.1021/ol403517p

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Oxidative Coupling of Enamides and Alkynes for
Synthesis of Substituted Pyrroles
Mi-Na Zhao, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient palladium(II)-catalyzed alkenyl
C−H activation oxidative annulation of enamides with alkynes for the
synthesis of substituted pyrroles has been developed. The reaction
tolerates a wide range of functional groups and is a reliable method for
the synthesis of triaryl-substituted pyrroles in high yields.
yrroles are some of the most important monocyclic
heterocycles which are prevalent in many pharmaceutical
Scheme 1. Transition-Metal-Catalyzed Couplings of
Enamides
P
drugs, biological compounds, and functional materials.1 Over
the past decades, many efforts have been devoted to the
synthesis of various substituted pyrroles.2 Very recently, elegant
strategies, such as multicomponent reactions,3 dehydrogenative
cyclization reactions,4 and oxidative cyclization of N-allyli-
mines,5 have been developed for the synthesis of pyrroles.
Despite these advances, the development of new method-
ologies for the synthesis of substituted pyrroles remains one of
the hottest topics in synthetic chemistry.6
Recently, transition-metal-catalyzed oxidative annulations of
the C−H/N−H bond with alkynes have emerged as an efficient
strategy to synthesize various heterocycles7 such as indoles,7e
carbolines,7f isoquinolines,7i and benzothiazines.7j Enamides
which are a class of versatile building blocks have been widely
applied in asymmetric hydrogenations,8 Lewis acid catalyzed
nucleophilic addition reactions,9 and transition-metal-catalyzed
cross-coupling reactions.10,11 As one of the C−H/N−H bond
annulation reaction precursor, Rh-catalyzed oxidative annula-
tion of enamides with internal alkynes for the synthesis of
substituted pyrroles has been developed by the groups of
Glorius12 as well as Stuart and Fagnou.13 Ru-catalyzed
annulation of enamides with alkynes has also been developed
independently by the groups of Wang14 and Ackermann.15
However, these reactions are restricted to electron-deficient
enamides which display an electron-withdrawing ester group on
the alkenyl moiety. The electron-rich enamides such as aryl-
substituted enamides are still challenging substrates for Rh- or
Ru-catalyzed annulation reactions.12−15
Very recently, we have developed a series of Pd- or Cu-
catalyzed cross-coupling of enamides for the synthesis of
azaheterocycles (Scheme 1, eqs 1 and 2).16 We hypothesized
that the Pd-catalyzed oxidative annulation of enamides with
internal alkynes may be tolerated a broad substrate scope and
show an efficient approach for the synthesis of pyrroles. Herein,
we describe the development of a Pd-catalyzed oxidative
coupling of aryl enamides with internal alkynes for the synthesis
of substituted pyrroles (Scheme 1, eq 3).
We began our study by investigating the palladium-catalyzed
oxidative coupling of enamide 1a and diphenylacetylene 2a. We
were pleased to find that pyrrole 3aa was obtained in 37% yield
in the presence of Cu(OAc)2 (1 equiv) in CH3CN at 120 °C
(Table 1, entry 1). Screening of various solvents, such as DCE,
toluene, t-AmOH, and 1,4-dioxane, suggested that t-AmOH
was the most suitable solvent for this reaction (Table 1, entries
2−5). Further experiments showed that Pd(OAc)2 was the first
choice for catalyst precursor; other palladium salts, such as
PdCl2, Pd(TFA)2, Pd(PPh3)2Cl2, and Pd(dba)2, were inferior
(Table 1, entries 6−9). Indeed, no reaction occurred in the
absence of a palladium catalyst (Table 1, entry 10). However,
the best yield was 42% at this stage.
The phosphine ligand is generally air-sensitive due to it being
easily oxidized. Therefore, phosphine ligand has rarely been
used in palladium-catalyzed oxidative coupling reactions. Huang
and co-workers reported an elegant palladium-catalyzed
oxidative carbonylation reaction using Xantphos as the ligand.17
Herein, we found that phosphine ligands can improve the
Received: December 4, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Pd-Catalyzed Oxidative Coupling Enamides 1
with Diphenylacetylene 2a for the Synthesis of Substituted
Pyrroles
a
entry
catalyst
ligand
solvent
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
CH3CN
DCE
37
19
15
42
30
34
27
32
24
0
2
3
toluene
4
t-AmOH
1,4-dioxane
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
5
6
7
Pd(TFA)2
Pd(PPh3)2Cl2
Pd(dba)2
8
9
10
11
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
dppf
dppe
36
50
52
48
86
20
dppp
Xantphos
Xantphos oxide
a
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), catalyst (5 mol
%), ligand (10 mol %), Cu(OAc)2 (1 equiv), solvent (3 mL), 12 h;
isolated yields.
conversion of our palladium-catalyzed oxidative reactions. A
series of bisphosphine ligands show positive effect for the
reaction (Table 1, entries 11−15). In particular, Xantphos (4,5-
bis(diphenylphosphino)-9,9-dimethyl xanthene) was found to
be the most effective ones to give pyrrole 3aa in 86% yield
(Table 1, entry 15). Although the 31P NMR spectrum of the
crude reaction mixture indicated that most of the Xantphos has
been oxidized in the reaction,18 the oxidized Xantphos ((9,9-
dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine oxide))
did not promote the reaction (Table 1, entry 16). And the
stoichiometric reaction also confirmed that the Xantphos
indeed promoted the reaction (Scheme 2). Therefore,
Xantphos should be the real ligand in the reaction.
Scheme 2. Stoichiometric Reactions
a
Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol), Pd(OAc)2 (5
mol %), Xantphos (10 mol %), Cu(OAc)2 (1 equiv), t-AmOH (3 mL),
12 h; isolated yields. CH3CN was used as solvent.
enamides. Enamides with an electron-withdrawing group such
as fluoro, chloro and bromo, were well tolerated and afforded
the corresponding pyrroles 3ma−oa in 76%-84% yields. 2-
Naphthyl enamide 1p and thienyl enamide 1q proceeded
smoothly as well to give the desired pyrroles 3pa−qa in 63%,
56% yield respectively when acetonitrile was used as the
solvent. In addition, the N-propionyl enamide 1r shows similar
reactivity with 1a to give the corresponding N-propionyl
pyrrole 3ra in 70% yield. However, no reaction occurred when
the aliphatic enamides and electron-deficient enamides such as
1s,t were used as the substrates.
With the optimized reaction conditions established, a series
of enamides 1 was investigated for extending the substrate
scope (Scheme 3). This transformation displayed high
functional group tolerance and proved to be a quite general
methodology for preparation of triaryl-substituted pyrroles.
Enamides with electron-neutral or electron-donating groups on
aryl rings, such as alkyl, phenyl, methoxyl, [1,3]dioxolyl, and
amino, all gave the corresponding N-acetyl-substituted pyrroles
3ba−la in good to high yields. o-Methyl substituted enamides
1e and 1f were transformed efficiently into corresponding
pyrroles 3ea and 3fa in 81−83% yields implying that the
transformation was insensitive to steric hindrance of the
Next, various internal alkynes 2 were investigated to extend
the substrate scope, and the results are summarized in Scheme
4. Overall, this transformation showed broad substrate
tolerance among internal alkynes. Symmetric diaryl-substituted
B
dx.doi.org/10.1021/ol403517p | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 4. Pd-Catalyzed Oxidative Coupling Enamide 1a
with Alkynes 2 for the Synthesis of Substituted Pyrroles
Scheme 5. Plausible Mechanism for Palladium-Catalyzed
Oxidative Coupling of Enamides with Alkynes
a
Pd(0) species. The Pd(0) was reoxidized by Cu(OAc)2 to
regenerate the active Pd(OAc)2 catalyst. Since the C−H
activation of enamide by Pd(OAc)2 is fast step,11b,16a we
assumed that the reductive elimination of Pd(II) from the
vinylamido complexe C is the rate-determining step.20 The
Xantphos ligand is likely promoted reductive elimination of
Pd(II) from intermediate C due to the wide bite-angle of bis-
phosphine.17c
In summary, we have developed a palladium-catalyzed
alkenyl C−H activation annulation of aryl enamides with
alkynes for the synthesis of triaryl- substituted pyrroles. This
palladium-catalyzed oxidative annulation reaction tolerates a
wide range of functional groups and is a reliable procedure for
rapid elaboration of readily available aryl enamides into a
variety of valuable substituted pyrroles in high yields. Further
studies on the transition-metal-catalyzed transformations of
enamides are in progress in our laboratory.
a
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and spectral data for all
products and X-ray data of 3ah and 3ai (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Reaction conditions: 1a (0.2 mmol), 2 (0.22 mmol), Pd(OAc)2 (5
■
S
mol %), Xantphos (10 mol %), Cu(OAc)2 (1 equiv), t-AmOH (3 mL),
12 h; isolated yields. The regioisomeric ratio was determined by
NMR analysis.
b
alkynes with either electron-donating or -withdrawing groups
on the aromatic rings reacted efficiently to give the
corresponding substituted pyrroles 3ab−af in good to high
yields (76−86%). Symmetrical aliphatic alkynes such as 4-
octyne, underwent the desired reaction to give the correspond-
ing pyrrole 3ag in moderate yield. Unsymmetrical alkynes were
also tolerated in the reaction. The pyrrole 3ah was obtained as
single regioisomer in 78% yield when ethyl 3-phenylpropiolate
2h was employed as the substrate (see the X-ray diffraction
structure of 3ah in Scheme 4). Methyl phenyl alkyne 2i
underwent the reaction to give two regioisomers 3ai and 3ai′ in
total 69% yield with a 6.5:1 ratio.
On the basis of the aforementioned results and previous
studies, a tentative mechanism for the reaction is proposed in
Scheme 5. The alkenyl C−H bond of enamide 1a is first
activated by the Pd(OAc)2 to form a palladium intermediate
A.11b,16a,19 Coordinative insertion of alkyne 2 into the Pd−C
bond of intermediate A gives the intermediate B. Intra-
molecular deprotonated cyclization of intermediate B generates
a six-membered palladacycle C. Finally, reductive elimination of
intermediate C affords the N-acetyl-substituted pyrrole 3 and
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guanzhh@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (grant nos. 21272183 and
21002077) and the Fund of the Rising Stars of Shanxi Province
(2012KJXX-26).
REFERENCES
■
(1) (a) Dipakranjan, M.; Brateen, S.; Bidyut, K. D. Pyrrole and Its
Derivatives. In Heterocycles in Natural Product Synthesis; Majumdar, K.
C., Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp
187−220. (b) Wang, M.; Xu, H.; Liu, T.; Feng, Q.; Yu, S.; Wang, S.;
Li, Z. Eur. J. Med. Chem. 2011, 46, 1463. (c) Fan, H.; Peng, J. N.;
Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264.
C
dx.doi.org/10.1021/ol403517p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084.
(3) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev.
́ ́
(13) (a) Stuart, D.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem.
Soc. 2010, 132, 18326. (b) Huestis, M. P.; Chan, L.; Stuart, D. R.;
Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338.
(14) Li, B.; Wang, N.; Liang, Y.; Xu, S.; Wang, B. Org. Lett. 2013, 15,
136.
2010, 39, 4402. (b) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12,
312. (c) Soleimani, E.; Zainali, M. J. Org. Chem. 2011, 76, 10306.
(d) Morin, M. S. T.; St-Cyr, D. J.; Arndtsen, B. A. Org. Lett. 2010, 12,
4916. (e) Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Org. Lett.
2011, 13, 4668. (f) Wang, X.; Xu, X.-P.; Wang, S.-Y.; Zhou, W.; Ji, S.-J.
Org. Lett. 2013, 15, 4246. (g) Zhang, M.; Fang, X.; Neumann, H.;
Beller, M. J. Am. Chem. Soc. 2013, 135, 11384. (h) Wu, G.; Su, W. Org.
Lett. 2013, 15, 5278. (i) Hu, P.; Huang, S.; Xu, J.; Shi, Z.-J.; Su, W.
Angew. Chem., Int. Ed. 2011, 50, 9926.
(15) (a) Wang, L.; Ackermann, L. Org. Lett. 2013, 15, 176.
(b) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764.
(16) (a) Chen, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Angew.
Chem., Int. Ed. 2013, 52, 14196. (b) Zhao, M.-N.; Ren, Z.-H.; Wang,
Y.-Y.; Guan, Z.-H. Chem. Commun. 2012, 48, 8105. (c) Ran, L.; Ren,
Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Green Chem. 2014, 16, 112. (d) Zhao,
M.-N.; Liang, H.; Ren, Z.-H.; Guan, Z.-H. Adv. Synth. Catal. 2013, 355,
221. (e) Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green
Chem. 2011, 13, 1664. (f) Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.;
Guan, Z.-H. Chem.Eur. J. 2014, DOI: 10.1002/chem.201304565.
(17) (a) Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am.
Chem. Soc. 2012, 134, 9902. (b) Xie, P.; Xia, C.; Huang, H. Org. Lett.
2013, 15, 3370. (c) Liu, H.; Laurenczy, G.; Yan, N.; Dyson, P. J. Chem.
Commun. 2014, 50, 341.
(4) (a) Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140. (b) Srimani,
D.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 4012.
(c) Iida, K.; Miura, T.; Ando, J.; Saito, S. Org. Lett. 2013, 15, 1436.
(5) (a) Li, M.; Wu, K.; Liu, C.; Lei, A. Chem. Commun. 2013, 49,
5853. (b) Shi, Z. Z.; Suri, M.; Glouris, F. Angew. Chem., Int. Ed. 2013,
52, 4892. (c) Chen, Z.; Lu, B.; Ding, Z.; Gao, K.; Yoshikai, N. Org.
Lett. 2013, 15, 1966.
(18) After the mixture was washed with dilute NH3·H2O, Xantphos
oxide and a trace of Xantphos were observed by TLC detection of the
crude reaction mixture.
(19) (a) Sasano, K.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2013,
135, 10954. (b) Newkome, G. R.; Theriot, K. J.; Cheskin, B. K.; Evans,
D. W.; Baker, G. R. Organometallics 1990, 9, 1375.
(6) For selected examples, see: (a) Hu, Y.; Wang, C.; Wang, D.; Wu,
F.; Wan, B. Org. Lett. 2013, 15, 3146. (b) Ngwerume, S.; Lewis, W.;
Camp, J. E. J. Org. Chem. 2013, 78, 920. (c) Gao, M.; He, C.; Chen, H.
Y.; Bai, R. P.; Cheng, B.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 6958.
(d) Tang, X.; Huang, L.; Qi, C.; Wu, W.; Jiang, H. Chem. Commun.
2013, 49, 9597. (e) Billedeau, R. J.; Klein, K. R.; Kaplan, D.; Lou, Y.
Org. Lett. 2013, 15, 1421. (f) Liu, J. Q.; Fang, Z. X.; Zhang, Q.; Liu, Q.;
Bi, X. H. Angew. Chem., Int. Ed. 2013, 52, 6953. (g) Chen, F.; Shen, T.;
Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (h) Xin, X.; Wang, D.; Li,
X.; Wan, B. Angew. Chem., Int. Ed. 2012, 51, 1693.
(20) Hartwig, J. F. Nature 2008, 455, 314 and references cited
therein.
(7) For selected reviews and examples, see: (a) Wencel-Delord, J.;
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
(b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(c) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879. (d) Ackermann, L. Acc. Chem. Res. 2014, DOI: 10.1021/
ar3002798. (e) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.;
Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572. (f) Ding, S.; Shi, Z.;
Jiao, N. Org. Lett. 2010, 12, 1540. (g) Chen, J.; Pang, Q.; Sun, Y.; Li, X.
J. Org. Chem. 2011, 76, 3523. (h) Ma, W.; Graczyk, K.; Ackermann, L.
Org. Lett. 2012, 14, 6318. (i) Zhong, H.-B.; Yang, D.; Wang, S.-Q.;
Huang, J.-H. Chem. Commun. 2012, 48, 3236. (j) Dong, W.; Wang, L.;
Parthasarathy, K.; Pan, F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52,
11573. (k) Wang, L.; Huang, J.; Peng, S.; Liu, H.; Jiang, X.; Wang, J.
Angew. Chem., Int. Ed. 2013, 52, 1768. (l) Li, B.; Feng, H.; Wang, N.;
Ma, J.; Song, H.; Xu, S.; Wang, B. Chem.Eur. J. 2012, 18, 12873.
(m) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.Eur. J. 2011, 17, 12573.
(n) Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W. J. Org. Chem.
2013, 78, 12494.
(8) (a) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713.
(b) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599. (c) Guan,
Z.-H.; Zhang, Z.-Y.; Ren, Z.-H.; Wang, Y.-Y.; Zhang, X. J. Org. Chem.
2011, 76, 339. (d) Tang, W.; Capacci, A.; Sarvestani, M.; Wei, X.; Yee,
N. K.; Senanayake, C. H. J. Org. Chem. 2009, 74, 9528.
(9) (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292
and references therein. (b) Chang, L.; Kuang, Y.; Qin, B.; Zhou, X.;
Liu, X.; Lin, L.; Feng, X. Org. Lett. 2010, 12, 2214. (c) Lei, C.-H.;
Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. J. Am. Chem. Soc. 2013,
135, 4708. (d) Tong, S.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X.
Angew. Chem., Int. Ed. 2012, 51, 4417. (e) Yang, L.; Wang, D.-X.;
Huang, Z.-T.; Wang, M.-X. J. Am. Chem. Soc. 2009, 131, 10390.
(10) (a) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455. (b) Liu, Y.;
Li, D.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50, 7333. (c) Hesp, K.
D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 11430.
(11) (a) Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.; Loh,
T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701. (b) Xu, Y.-H.; Chok, Y. K.;
Loh, T.-P. Chem. Sci. 2011, 2, 1822. (c) Zhou, H.; Chung, W.-J.; Xu,
Y.-H.; Loh, T.-P. Chem. Commun. 2009, 3472. (d) Zhou, H.; Xu, Y.-
H.; Chung, W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 5355.
(12) Rakshit, S.; Patureau, F.-W.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 9585.
D
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