An efficient synthesis of polysubstituted pyrroles via copper-catalyzed coupling of oxime acetates with dialkyl acetylenedicarboxylates under aerobic conditions

Article abstract of DOI:10.1039/c3cc44896g

A Cu-catalyzed [3+2]-type condensation reaction of oxime acetates and dialkyl acetylenedicarboxylates that provides highly substituted pyrroles under aerobic conditions is described. The newly formed pyrroles are easily employed for further transformations to prepare pyrrolo[2,1-a]isoquinoline skeletons. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc44896g

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An efficient synthesis of polysubstituted pyrroles via
copper-catalyzed coupling of oxime acetates with
dialkyl acetylenedicarboxylates under aerobic
conditions†
Cite this: Chem. Commun., 2013,
49, 9597
Received 30th June 2013,
Accepted 20th August 2013
DOI: 10.1039/c3cc44896g
Xiaodong Tang, Liangbin Huang, Chaorong Qi, Wanqing Wu and Huanfeng Jiang*
www.rsc.org/chemcomm
A Cu-catalyzed [3+2]-type condensation reaction of oxime acetates enabled widely applicable oxidative alkyne annulations with
and dialkyl acetylenedicarboxylates that provides highly substi- enamines to provide pyrroles (Fig. 2A). Milstein’s group10e and
tuted pyrroles under aerobic conditions is described. The newly Saito’s group10f have used various amino alcohols and secondary
formed pyrroles are easily employed for further transformations to alcohols or ketones to synthesize pyrroles, catalyzed by a Ru
prepare pyrrolo[2,1-a]isoquinoline skeletons.
complex (Fig. 2B). Very recently, Glorius10g and Yoshikai10h et al.
independently developed a remarkably mild oxidative cyclization
Pyrroles are important heterocyclic compounds and are present of imines to pyrroles with the use of molecular oxygen as the sole
in many biologically active natural products,1 agro-chemicals, oxidant (Fig. 2C). Recently, oxime esters have been widely used as
functional materials,2 and pharmaceutical compounds (Fig. 1).3 substrates for transition metal-catalyzed coupling reactions.11–14
Recently, they have been used as solar batteries and organic On the basis of our previous Cu-catalyzed synthesis of pyrroles10a
semiconductors.4 Thus, many synthetic methods have been and other heterocyclic compounds,15 using oxime esters as sub-
developed for constructing pyrroles,5 including classical Knorr strates, herein, we disclose a novel and useful method to construct
reaction,6 cycloadditions,7 and multicomponent8 and tandem polysubstituted pyrroles via the Cu-catalyzed [3+2]-type condensa-
reactions.9 However, they suffer from several drawbacks such as tion reaction of oxime acetates and dialkyl acetylenedicarboxylates
complicated operations, harsh reaction conditions, and poor (Fig. 2D).
availability of the starting materials and functional group tolerance.
To overcome these limitations, new strategies, for example, metal with dimethyl acetylenedicarboxylates (2a; 0.6 mmol), NaHSO3
catalyzed reactions,10 have been developed.
(0.6 mmol), CuCl (10 mol%) in DMSO at 120 1C under a pure O2
We initially studied the reaction of oxime acetate (1a; 0.5 mmol)
Recently, the development of transition metal-catalyzed atmosphere (Table 1, entry 1), and the desired pyrrole 3a could be
dehydrogenative coupling reactions to construct pyrroles has
drawn much attention. Ag,10a Cu,10b and Ru10c,d catalysts have
Fig. 1 Selected examples for pyrrole-containing bioactive natural products and
pharmaceutical compounds.
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn;
Fax: +86 20-87112906; Tel: +86 20-87112906
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds and copies of 1H and 13C NMR spectra for
selected compounds. See DOI: 10.1039/c3cc44896g
Fig. 2 Synthesis of pyrroles via dehydrogenative coupling.
c
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Table 1 Screening for optimal reaction conditionsa
Table 2 Cu(I)-catalyzed synthesis of substituted pyrroles from oxime acetates
and dialkyl ethylenedicarboxylatesa
Entry
[M]
Additive
NaHSO3
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuBr
CuI
Cu(OAc)2
CuBr2
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
71
53
84 (80)
73
57
48
41
0
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
Na2SO3
9
0
10
11c
12d
CuCl
CuCl
CuCl
48
61
25
DMSO
DMSO
a
Reaction conditions: unless otherwise noted, all reactions were performed
with 1a (0.5 mmol), 2a (0.6 mmol), catalyst (10 mol%), additive (0.6 mmol)
and DMSO (2 mL) at 120 1C under O2 atmosphere for 12 h. b Determined
using GC based on 1a. Under air. d Under N2.
c
detected in 71% GC yield. Low conversion was observed with-
out additives (entry 2). To our delight, the addition of Na2SO3
could increase the yield and 3a was formed in 80% isolated
yield (entry 3). Encouraged by these results, different copper
catalysts were evaluated for the reaction between 1a and 2a
(entries 4–7). When CuBr, CuI, Cu(OAc)2 and CuBr2 were used,
the yields were decreased. No reaction occurred in the presence
of PdCl2 (entry 8) and the absence of metal catalysts resulted in
no product formation (entry 9). Changing the solvent to DMF
was less effective (entry 10). The yield also became lower when
the reaction was performed under an air atmosphere (entry 11).
Under an atmosphere of N2, the yield sharply declined to 25%
a
The reactions were carried out at 120 1C, using 1 (0.5 mmol), 2 (0.6 mmol),
Na2SO3 (0.6 mmol), CuCl (10 mol%) in DMSO (2 mL) at 120 1C under O2
atmosphere for 12 h. Yields refer to the isolated yields.
(entry 12). These observations suggested that copper species that the alkyl oxime acetates could also be transformed into
was necessary and O2 played an important role in this process. the desired pyrrole 3u. However, cyclic ketone oxime acetates
Thus, the optimal reaction conditions were 1a (0.5 mmol), 2a were not applicable to this system. When diethyl acetylene-
(0.6 mmol), Na2SO3 (0.6 mmol), CuCl (10 mol%) in 2 mL DMSO dicarboxylate was reacted with acetophenone oxime acetate and
at 120 1C under a pure O2 atmosphere.
propiophenone oxime acetate, 3v and 3w were obtained in 79%
Having identified our optimized reaction conditions, we then and 89% yields, respectively. However, methyl propiolate, methyl
investigated the scope of this transformation, and the results but-2-ynoate and methyl 3-phenylpropiolate were not suitable
are presented in Table 2. Generally, the reaction of oxime substrates for this reaction.
acetates with dimethyl acetylenedicarboxylate (DMAD) pro-
The newly formed pyrroles bearing the free NH functionalities
ceeded smoothly and gave the desired products 3 in moderate are easily transformed to more complicated organic architectures.
to good yields. para-Substituted acetophenone oxime acetates We used ruthenium-catalyzed aerobic oxidative coupling of 3a
having electron-withdrawing groups gave lower yields than and 3l with 3-hexyne to deliver the corresponding pyrrolo-
those with electron-donating groups (3a–3f). When 20-methyl- [2,1-a]isoquinolines 4a and 4l, in excellent yields (Fig. 3).16
acetophenone, 30-methylacetophenone and 30,40-dimethylaceto- Notably, pyrrolo[2,1-a]isoquinolines are indispensable structural
phenone oxime acetates were used as the substrates, 3g–3i motifs of inter alia bioactive lamellarine alkaloids.17
could be isolated in 80%, 73%, and 66% yields, respectively.
Based on the experimental results and previous reports,13,14
In addition, 1-acetylnaphthalene oxime acetate also underwent a plausible mechanism for this transformation is proposed in
the desired transformation to give the corresponding pyrrole 3j in Scheme 1. Firstly, in the presence of the Cu catalyst, the oxime
88% yield. A heteroaromatic substrate such as thiophene oxime acetate was easily transformed to copper enamide intermediate
acetate could give 3k in 62% yield. Propiophenone, substituted 2 and this process produced another CuII. Intermediate 2 could
propiophenone, and n-butyrophenone oxime acetates gave react with dimethyl acetylenedicarboxylate to give intermediate 3.
good to excellent yields of the tetrasubstituted pyrroles 3l–3t. Then, a single-electron-transfer (SET) process occurred and inter-
Tetrasubstituted pyrroles were obtained in higher yields than the mediate 4 was formed, followed by a radical addition to afford
corresponding trisubstituted pyrroles. It is worth mentioning intermediate 5. Finally, the dehydrogenation process of 5 gave
c
9598 Chem. Commun., 2013, 49, 9597--9599
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2005, 44, 2295; (e) H. Garrido-Hernandez, M. Nakadai, M. Vimolratana,
Q. Y. Li, T. Doundoulakis and P. G. Harran, Angew. Chem., Int. Ed.,
2005, 44, 765; ( f ) J. Ewing, G. K. Hughes, E. Ritchie and W. C.
Taylor, Nature, 1952, 169, 618.
2 (a) D. Curran, J. Grimshaw and S. D. Perera, Chem. Soc. Rev., 1991,
20, 391; (b) S. Gabriel, M. Cecius, K. Fleury-Frenette, D. Cossement,
M. Hecq, N. Ruth, R. Jerome and C. Jerome, Chem. Mater., 2007,
19, 2364; (c) S. Z. Pu, G. Liu, L. Shen and J. K. Xu, Org. Lett., 2007,
9, 2139.
3 (a) L. Zeng, E. W. Miller, A. Pralle, E. Y. Isacoff and C. J. Chang,
J. Am. Chem. Soc., 2006, 128, 10; (b) B. R. Clark, R. J. Capon, E. Lacey,
S. Tennant and J. H. Gill, Org. Lett., 2006, 8, 701.
Fig. 3 Transformations of pyrroles.
4 (a) C. F. Lee, L. M. Yang, T. Y. Hwu, A. S. Feng, J. C. Tseng and
T. Y. Luh, J. Am. Chem. Soc., 2000, 122, 4992; (b) A. Kreutzberger and
P. A. Kalter, J. Org. Chem., 1960, 25, 554.
5 (a) Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. D. Milton,
M. Hidai and S. Uemura, Angew. Chem., Int. Ed., 2003, 42, 2681;
(b) O. V. Larionov and A. D. Meijere, Angew. Chem., Int. Ed., 2005,
44, 5664; (c) S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem.
´
Soc., 2005, 127, 9260; (d) R. Martın, M. R. Rivero and S. L. Buchwald,
Angew. Chem., Int. Ed., 2006, 45, 7079; (e) E. M. Beck, N. P. Grimster,
R. Hatley and M. J. Gaunt, J. Am. Chem. Soc., 2006, 128, 2528;
( f ) D. S. Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007,
129, 12366; (g) S. J. Hwang, S. H. Cho and S. Chang, J. Am. Chem.
Soc., 2008, 130, 16158; (h) X. P. Fu, J. J. Chen, G. Y. Li and Y. H. Liu,
Angew. Chem., Int. Ed., 2009, 48, 5500; (i) M. Fujiwara, M. Kawatsura,
S. Hayase, M. Nanjo and T. Itoha, Adv. Synth. Catal., 2009, 351,
123; ( j) Y. D. Lu and B. A. Arndtsen, Angew. Chem., Int. Ed., 2008,
47, 5430.
6 L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635.
Scheme 1 Possible reaction mechanism.
7 (a) Y. J. Kim, J. Kim and S. B. Park, Org. Lett., 2009, 11, 17; (b) J. L.
Bullington, R. R. Wolff and P. F. Jackson, J. Org. Chem., 2002,
67, 9439; (c) K. C. Washizuka, S. Minakata, I. Ryu and M. Komatsu,
Tetrahedron, 1999, 55, 12969.
the desired pyrrole product with the generation of H+, while
CuII was reduced to CuI that could enter into the next catalytic
cycle. Theoretically, the reaction can be redox-neutral, but under
an atmosphere of N2, the yield was only 25%. Up until now the
role of O2 was unknown, however, in this work it has been shown
to promote the reaction significantly. Further mechanistic study
is underway in our laboratory.
´
´
8 (a) V. Estevez, M. Villacampa and J. C. Menendez, Chem. Soc. Rev.,
2010, 39, 4402; (b) G. Balme, Angew. Chem., Int. Ed., 2004, 43,
6238; (c) B. Khalili, P. Jajarmi, B. Eftekhari-Sis and M. M.
Hashemi, J. Org. Chem., 2008, 73, 2090; (d) B. Jiang, Y. Li, M. S. Tu,
S. L. Wang, S. J. Tu and G. G. Li, J. Org. Chem., 2012, 77, 7497.
9 (a) Y. J. Jiang, W. C. Chan and C. M. Park, J. Am. Chem. Soc., 2012,
134, 4104; (b) B. M. Trost, J. P. Lumb and J. M. Azzarelli, J. Am. Chem.
Soc., 2011, 133, 740; (c) Q. Cai, F. T. Zhou, T. F. Xu, L. B. Fu and
K. Ding, Org. Lett., 2011, 13, 340.
In conclusion, a novel and useful method has been developed
to construct highly substituted pyrroles via a copper-catalyzed
coupling reaction of dialkyl acetylenedicarboxylates with oxime
acetates under aerobic conditions. This novel method tolerates a
wide range of functionalities. The newly formed pyrroles bearing
free NH functionalities are easily employed for further trans-
formations to prepare useful pyrrolo[2,1-a]isoquinoline skeletons,
which may find applications in natural product synthesis.
The authors thank the National Natural Science Foundation
of China (20932002, 21172076 and 21202046), the National Basic
Research Program of China (973 Program) (2011CB808600),
Guangdong Natural Science Foundation (10351064101000000),
China Postdoctoral Science Foundation (2012T50673) and the
Fundamental Research Funds for the Central Universities
(2012ZP0003 and 2012ZB0011) for financial support.
10 (a) W. B. Liu, H. F. Jiang and L. B. Huang, Org. Lett., 2010, 12, 312;
(b) R. L. Yan, J. Luo, C. Y. Wang, C. W. Ma, G. S. Huang and
Y. M. Liang, J. Org. Chem., 2010, 75, 5395; (c) B. Li, N. C. Wang,
Y. J. Liang, S. S. Xu and B. Q. Wang, Org. Lett., 2013, 15, 136;
(d) L. Wang and L. Ackermann, Org. Lett., 2013, 15, 176; (e) D. Srimani,
Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2013, 52, 4012;
( f ) K. Iida, T. Miura, J. Ando and S. Saito, Org. Lett., 2013, 15, 1436;
(g) Z. Z. Shi, M. Suri and F. Glorius, Angew. Chem., Int. Ed., 2013,
52, 4892; (h) Z. Y. Chen, B. L. Lu, Z. H. Ding, K. Gao and N. Yoshikai,
Org. Lett., 2013, 15, 1966.
11 T. Gerfaud, L. Neuville and J. Zhu, Angew. Chem., Int. Ed., 2009,
48, 572.
12 Y. C. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676.
13 Z. H. Ren, Z. Y. Zhang, B. Q. Yang, Y. Y. Wang and Z. H. Guan,
Org. Lett., 2011, 13, 5394.
14 Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756.
15 (a) L. B. Huang, H. F. Jiang, C. R. Qi and X. H. Liu, J. Am. Chem. Soc.,
2010, 132, 17652; (b) X. W. Li, L. B. Huang, H. J. Chen, W. Q. Wu,
H. W. Huang and H. F. Jiang, Chem. Sci., 2012, 3, 3463; (c) H. F.
Jiang, W. Zeng, Y. B. Li, W. Q. Wu, L. B. Huang and W. Fu, J. Org.
Chem., 2012, 77, 5179; (d) H. W. Huang, X. C. Ji, W. Q. Wu,
L. B. Huang and H. F. Jiang, J. Org. Chem., 2013, 78, 3374.
Notes and references
1 (a) B. M. Trost and G. B. Dong, Org. Lett., 2007, 9, 2357; (b) A. Fu¨erstner, 16 L. Ackermann, L. H. Wang and A. V. Lygin, Chem. Sci., 2012,
Angew. Chem., Int. Ed., 2003, 42, 3582; (c) G. Balme, Angew. Chem., Int. Ed., 3, 177.
2004, 43, 6238; (d) D. E. N. Jacquot and M. Zollinger, Angew. Chem., Int. Ed., 17 T. Fukuda, F. Ishibashi and M. Iwao, Heterocycles, 2011, 83, 491.
c
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Chem. Commun., 2013, 49, 9597--9599 9599