Three-component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines

Article abstract of DOI:10.1021/ol201891r

Polysubstituted pyrroles are regiospecifically synthesized via the copper-catalyzed three-component reaction of α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed

Full text of DOI:10.1021/ol201891r

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4668–4671
Three-Component Synthesis of
Polysubstituted Pyrroles from r-
Diazoketones, Nitroalkenes, and Amines
Deng Hong, Yuanxun Zhu, Yao Li, Xufeng Lin, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Received July 13, 2011
ABSTRACT
Polysubstituted pyrroles are regiospecifically synthesized via the copper-catalyzed three-component reaction of R-diazoketones, nitroalkenes,
and amines under aerobic conditions. The cascade process involves an NꢀH insertion of carbene, a copper-catalyzed oxidative dehydrogenation
of amine, and a [3 þ 2] cycloaddition of azomethine ylide.
Pyrroles represent an important class of heterocycles in
organic chemistry. They are structural units in many
natural products and pharmaceuticals and are key inter-
mediates for the synthesis of a variety of biologically active
molecules and functional materials.1 As the world’s
leading cholesterol-lowering drug, atorvastatin calcium
(Lipitor) is a prime example.2 The conventional methods
for the construction of a pyrrole ring include the Hantzsch
reaction,3 the PaalꢀKnorr synthesis,4 and various cy-
cloaddition methods.5 A number of metal-catalyzed ap-
proaches were also developed.6 Still, general and efficient
strategies for the synthesis of pyrroles from simple and
readily available precursors are of great value due to the
continuedimportanceof the pyrrolecoreinbothbiological
and chemical fields.
Multicomponent reactions (MCRs) have emerged as
powerful and bond-forming efficient tools in organic,
combinatorial, and medicinal chemistry for their facileness
and efficiency as well as their economy and ecology in
organic synthesis.7 These features make MCRs well suited
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J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105,
1001. (e) Enders, D.; Huttl, M. R. M.; Grondal, C.; Rabbe, G. Nature
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r
10.1021/ol201891r
Published on Web 08/10/2011
2011 American Chemical Society

for the construction of diversified heterocyclic scaffolds
from readily available materials.8 Recently, this strategy
has found its applications in the synthesis of pyrroles.9
As a part of our ongoing research on development of
multicomponent approaches to heterocycles,10 we were
interested in the rapid construction of a polysubstituted
pyrrole ring via the copper-catalyzed three-component reac-
tion of R-diazoketones, nitroalkenes and amines under
aerobic conditions. The reaction involves the assembling of
the pyrrole core from [1 þ 2þ 2] atom fragments (Scheme 1).
reaction temperature (Table 1, entry 14). When the reac-
tionwas carried out at25°C, itdid notoccur atall (Table1,
entry 15). Solvent also highly affected the reaction
(Table 1, entries 16ꢀ18). Since this reaction involved an
oxidation process, we examined the other oxidant instead
of air. When t-BuOOH was added, yield was slightly
improved (Table 1, entry 19), similar with the case of
bubbling the reaction with oxygen (Table 1, entry 20).
Finally, we selected CuOTf (10 mol %) as catalyst and
THF as solvent to perform the reaction under atmosphere
for 12 h.
Scheme 1. Synthesis of Pyrroles via MCRs
Table 1. Optimization of Reaction Conditionsa
entry
solvent
THF
temp
Lewis acid
yield (%)b
We began our studies by evaluating the reaction of
2-diazo-1-phenylethanone (1a), (2-nitrovinyl)benzene (2a),
and phenylmethanamine (3a) using Cu(OTf)2 as catalyst.
Simple heating of a mixture of the three components and
Cu(OTf)2 in THF under atmosphere led to the formation
of the desired product 4a, albeit in only 44% yield (Table 1,
entry 1). We then examined other triflates, such as AgOTf
(Table 1, entry 2), Zn(OTf)2 (Table 1, entry 3), Sc(OTf)3
(Table 1, entry 4), Yb(OTf)3 (Table 1, entry 5), and
In(OTf)3 (Table 1, entry 6), but found that they did not
work for this one-pot reaction. By altering Cu(OTf)2 to
CuOTf (Table 1, entry 7), the reaction proceeded well and
gave a better yield (50%). It meant that either Cu (II) or Cu
(I) would be essential for this reaction. Thus, we tested
copper sources. CuBr2 (Table 1, entry 8), Cu(OAc)2
(Table 1, entry 9), and CuO (Table 1, entry 10) were found
to be able to promote the reaction but in relatively lower
yields. CuBr (Table 1, entry 11) or CuI (Table 1, entry 12)
worked for this reaction with comparative yields. Increas-
ing the amount of catalyst to 20 mol % only slightly raised
the yield (Table 1, entry 13). Further screening of reaction
conditions revealed that the yields largely depended on the
1
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
50 °C
Cu(OTf)2
AgOTf
44
0
2
THF
3
THF
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
In(OTf)3
CuOTf
NR
NR
NR
NR
50
30
10
<5
46
48
52c
20
0
4
THF
5
THF
6
THF
7
THF
8
THF
CuBr2
9
THF
Cu(OAc)2 H2O
3
10
11
12
13
14
15
16
17
18
19
20
THF
CuO
THF
CuBr
THF
CuI
THF
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
THF
THF
25 °C
refluex
DCE
toluene
1.4-dioxane
THF
0
80 °C
40
41
52d
53e
reflux
reflux
reflux
THF
a Reaction conditions: 1a (0.75 mmol), 2a (0.5 mmol), 3a (0.75
mmol), catalyst (0.05 mmol), solvent (8 mL), air, 12 h. b Yield of the
isolated product. c Catalyst (0.10 mmol). d t-BuOOH (0.75 mmol) was
added. e Reaction was under oxygen (1 atm).
(9) (a) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72, 1811.
(b) Martın, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett.
´
With the optimized reaction conditions in hand, we tested
the substrate diversity. A steady increment of yields could be
seen by varying the substituent on 1 from electron donating
group to electron withdrawing group (Table 2, entries 1ꢀ5
and 16ꢀ18). When the nitro group occupied on the para
position (1e), the highest yield was reached (Table 2, entry 5).
Structure of 4b was confirmed by X- ray analysis (Figure 1).
When ethyl R-diazoacetate was used instead of R-Diazoke-
tone, reaction occurred, but without isolable products. Then,
we examined the substitute effect on Michael acceptor 2
(Table 2, entries 6ꢀ13). The yields varied from 49% to 70%
without significant trends.
2007, 9, 3379. (c) Yan, R. L.; Luo, J.; Wang, C. X.; Ma, C. W.; Huang,
G. S.; Liang, Y. M. J. Org. Chem. 2010, 75, 5395. (d) Maiti, S.; Biswas, S.;
Jana, U. J. Org. Chem. 2010, 75, 1674. (e) Ackermann, L.; Sandmann,
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Commun. 2011, 47, 3275. (b) Chen, Z. B.; Hong, D.; Wang, Y. G. J. Org.
Chem. 2009, 74, 903. (c) Shen, Y.; Cui, S. L.; Wang, J.; Chen, X. P.; Lu,
P.; Wang, Y. G. Adv. Synth. Catal. 2010, 352, 1139. (d) Hong, D.; Lin,
X. F.; Zhu, Y. X.; Lei., M.; Wang., Y. G. Org. Lett. 2009, 11, 5678. (e)
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Aliphatic nitroalkenes also afforded the corresponding
products, but with relatively lower yields (Table 2, entries
14 and 15). With substituents occupied R-position of
Org. Lett., Vol. 13, No. 17, 2011
4669

nitroalkenes (2lꢀ2o), reactions performed smoothly and
the desired products were obtained (Table 2, entries
16ꢀ21). Substituent effect on the benzyl amine was not
significant (Table 2, entries 22ꢀ26). When n-butyl amine
or n-octyl amine was used instead of 3a, no desired product
was detected. Similar result was observed for 2-phenyl-
ethanamine. When allyl amine was used, the desired 4A
was obtained in 46% yield (Table 2, entry 27). Altering the
primary amine into secondary amine, neither N-methyl-
benzylamine nor N-sulfonylbenzylamine worked for the
reaction and 2 was recovered quantitatively.
Table 2. Copper-Catalyzed Multicomponent Synthesis of Pyr-
role 4 a
Figure 1. X-ray crystal structure of 4b.
On the basis of these results, a tentative mechanism for
this three-component reaction is postulated in Scheme 2.
In the presence of copper catalyst, R-ketocarbene gen-
erated from R-diazoketone 1a is traped by benzylamine
(3a) to form A through NꢀH insertion.11 Then, amine A
undergoes a copper-catalyzed oxidative dehydrogena-
tion to form imine B through activation of sp3 CꢀH
adjacent to nitrogen.12 B then generates azomethine
ylide C, which is trapped by the trans nitroalkene 2a to
produce the pyrrolidine 5 via a copper-catalyzed exo-
selective [3 þ 2] cycloaddition.13 Finally, 4a is obtained
by the thermal extrusion of HNO2 accompanying the
(11) (a) Alonso, M. E; Morales, A.; Chitty., A. W. J. Org. Chem.
1982, 47, 3747. (b) Yates, P. J. Am. Chem. Soc. 1952, 74, 5376.
(12) For selected examples of imine formations via the copper-cata-
lyzed oxidative dehydrogenation of amines, see: (a) Li, Z.; Li, C. ꢀJ.
J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 6968. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (d)
Basle, O.; Li, C.-J. Green Chem. 2007, 9, 1047. (e) Li, Z.; Bohle, D. S.; Li,
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C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (f) Basle, O.; Li, C.-J.
Org. Lett. 2008, 10, 3661. (g) Shen., Y.-M.; Li., M.; Tan., Z.; Guo., C.-C.
Chem. Commun. 2009, 953. (h) Yu, C. G.; Zhang, Y.; Zhang, S. L.; Li, H.;
Wang, W. Chem. Commun. 2011, 47, 1036.
(13) For recent reviews about the [3 þ 2] cycloadditions of azo-
methine ylides, see: (a) Engels, B.; Christl, M. Angew. Chem., Int. Ed.
2009, 48, 7968. (b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887.
(c) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132. (d) Nair,
V; Suja, T. D. Tetrahedron 2007, 63, 12247. For selected examples, see:
(e) Li, G. Y.; Chen, J.; Yu, W. Y.; Hong, W.; Che, C. M. Org. Lett. 2003,
5, 2153. (f) Teng, H. L.; Huang, H.; Tao, H. Y.; Wang, C. J. Chem.
Commun. 2011, 47, 5494. (g) Xue, Z. Y.; Fang, X.; Wang, C. J. Org.
Biomol. Chem. 2011, 9, 3622. (h) Arai, T.; Yokoyama, N.; Mishiro, A.;
Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895. (i) Arai, T.; Mishiro, A.;
Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338.
(j) Padilla, S.; Tejero, R.; Adrio, J.; Carretero, J. C. Org. Lett. 2010, 12,
5608.
a Reaction conditions: 1 (1.5 mmol), 2 (1 mmol), 3 (1.5 mmol),
Cu(OTf) (0.1 mmol), THF (8 mL), air, 12 h. b Yield of the isolated
product.
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Org. Lett., Vol. 13, No. 17, 2011

Scheme 2. Possible Mechanism for the Formation of 4a
Scheme 3. Concise Synthesis of Polycyclic Compounds 6
compounds and photophysical materials. The structure
of compound 6b was unambiguously confirmed by single
crystal X-ray analysis (Figure 3).
dehydrogenative aromatization. The pyrrolidine 5 could
be separated before the reaction was completed and its
structure was unambiguously confirmed by single-crys-
tal X-ray analysis (Figure 2).
Figure 3. X-ray crystal structure of 6b.
In summary, we have developed an efficient approach to
polysubstitutedpyrroles via a copper-catalyzedthree-com-
ponent reaction of R-diazoketones, nitroalkenes, and
amines under aerobic conditions. The cascade process
involves an NꢀH insertion of carbene, a copper-catalyzed
oxidative dehydrogenation of amine, and a [3 þ 2] cy-
cloaddition of azomethine ylide. Due to the easy avail-
ability of the starting materials and potential utilities of
products, this method might be useful in organic synthesis
and medicinal chemistry.
Figure 2. X-ray crystal structure of 5.
Acknowledgment. We thank the National Nature Science
Foundation of China (No. 21032005 and 20972137) for
financial support.
A demonstration of the interesting synthetic utility of
this method is shown in Scheme 3. The resulting products
4g and 4t could be easily transformed to the polycyclic
compounds 6a and 6b via the Pd-catalyzed intramolecular
CꢀC coupling reaction, and the products are potentially
useful scaffolds for the synthesis of biologically active
Supporting Information Available. Detailed experimen-
1
tal procedures, characterization data, copies of H, 13C
spectra, and crystallographic information files (CIF) for
compounds 4b, 5 and 6b. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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