A facile access to pyrroles from amino acids via an aza-Wacker cyclization

Article abstract of DOI:10.1021/jo800433b

(Chemical Equation Presented) A facile and efficient synthesis of pyrroles from readily available amino acids is described. The key step in the method is an aza-Wacker oxidative cyclization catalyzed by palladium(II)/Cu(OTf) ₂. A series of pyrroles were obtained by this method under mild conditions.

Full text of DOI:10.1021/jo800433b

SCHEME 1. Synthesis of 2 by Aza-Wacker Oxidative
Cyclization
A Facile Access to Pyrroles from Amino Acids
via an Aza-Wacker Cyclization
Zuhui Zhang, Jintang Zhang, Jiajing Tan, and
Zhiyong Wang*
Hefei National Laboratory for Physical Science at
Microscale, Joint Laboratory of Green Synthetic Chemistry
and Department of Chemistry, UniVersity of Science and
Technology of China, Hefei, Anhui 230026, China
TABLE 1. Optimazation of Aza-Wacker Cyclizationa
zwang3@ustc.edu.cn
ReceiVed February 22, 2008
entry solvent catalyst (10 mol %)
oxidant
yieldb (%)
1
2
3
4
5
6
7
8
9
MeOH
EtOH
i-PrOH
THF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
air
air
air
air
air
air
air
air
air
air
air
O2
23
25
trace
trace
trace
trace
trace
trace
41
44
45
50
52
Tol
DMF
DMSO
CHCl3
EtOH
PdCl2
A facile and efficient synthesis of pyrroles from readily
available amino acids is described. The key step in the
method is an aza-Wacker oxidative cyclization catalyzed by
palladium(II)/Cu(OTf)2. A series of pyrroles were obtained
by this method under mild conditions.
10 EtOH
11 EtOH
12 EtOH
13 EtOH
14 EtOH
15 EtOH
16 EtOH
PdCl2(MeCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
CuCl2 (10 mol %)
Cu(OTf)2 (10 mol %)
Cu(OTf)2 (50 mol %)
Cu(OTf)2 (100 mol %)
69
80
88
a Reaction conditions: 0.2 M of 1a in solvent. b Isolated yield.
The pyrrole derivatives are widespread in numerous natural
products, and many of them display diverse biological activities.1
Besides, pyrrole is one common structural unit in many organic
materials.2 In the preparation of pyrrole derivatives, however,
many disadvantages including harsh reaction conditions and poor
yields limit the application of classical methods, such as Knorr
reaction and Paal-Knorr reaction.3,4 Although some novel
strategies have been developed to synthesize pyrrole derivatives
recently,5,6 the preparation of pyrrole derivatives by more
efficient and facile methods is still desired.
Encouraged by these results, we envisioned that the Wacker
reaction can be applied to the synthesis of pyrrole ring 2, as
shown in Scheme 1. The substrates 1 for the aza-Wacker
oxidative reaction can be obtained from the natural amino
acids. In 1996, the Cushman group11 reported an interesting
work on the application of amino acids for pyrrole synthesis
via aldol condensation, but the yields were always 5-44%,
which somewhat restricted its application.
On the other hand, the palladium(II)-catalyzed Wacker-
type oxidative cyclization is a well-known process for the
formation of heterocycles.7–9 Recently, we have focused our
research on Wacker reactions and have developed some
methods for the preparation of chromanones and quinolines.10
(5) For recent reports, see: (a) St.Cyr, D. J.; Arndtsen, B. A. J. Am. Chem.
Soc. 2007, 129, 12366. (b) Wan, X. B.; Xing, D.; Fang, Z.; Li, B. J.; Zhao, F.;
Zhang, K. Y.; Yang, L. P.; Shi, Z. J. J. Am. Chem. Soc. 2006, 128, 12046. (c)
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S. M.; Scheidt, W. R.; Scheidt, K. A. J. Org. Chem. 2007, 72, 3941. (i) Mart´ın,
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5180 J. Org. Chem. 2008, 73, 5180–5182
10.1021/jo800433b CCC: $40.75 2008 American Chemical Society
Published on Web 05/31/2008

TABLE 2. Synthesis of Pyrrole by Aza-Wacker Cyclizationa
SCHEME 2. Proposed Mechanism of the Aza-Wacker
Reaction for the Building of the Pyrrole Ring
precipitation was formed, which perhaps resulted in the loss of
the catalytic activity and the reduction of the reaction yield.
Therefore, some oxidants other than air were added to the
reaction in order to solve this problem (entries 12-16).
Cu(OTf)2 presented a higher activity than O2 and CuCl2, giving
the product 2a with a yield up to 88% (entry 16).
The effect of ligands on the reaction was also investigated.
Various ligands, such as pyridine (20 mol %), 2,2′-bipyridine
(10 mol %), 1,10-phenanthroline (10 mol %), N,N,N′,N′-
tetramethylethane-1,2-diamine (10 mol %), ethane-1,2-diamine
(10 mol %), and 1,4-diazabicyclo[2.2.2]octane (10 mol %), were
used in the reaction. However, we hardly observed the effect
of these ligands on the reaction.
Afterward, the scope of the reaction was extended to different
substrates, which can be derived from different amino acids,
including phenylalanine (1a), glycin (1b), alanine (1c), valine
(1d), leucine (1e), methionine (1f), tyrosine (1h), and lysine
(1g). Then these amino acid derivatives were employed in the
reaction (Table 2). From Table 2, it was found that almost all
the reactions can be carried out smoothly to afford the
corresponding pyrrole derivatives with good yields, including
1,2,3-trisubstituted pyrrole 2i and the annulated pyrrole 2j
(entries 9 and 10). When a methyl group is located at the end
of the olefin, the desired product 2k was obtained with a low
yield (entry 11), perhaps due to the uncertain orientation of the
ꢀ-hydride elimination because of the existence of the methyl
group.
a Reaction conditions: 1 (1 mmol), PdCl2(PhCN)2 (0.1 mmol), and
Cu(OTf)2 (1 mmol) in 5 mL of ethanol at 30 °C for 24 h. b Isolated
yield.
Initially, Pd(OAc)2 was employed as a catalyst, and various
solvents were screened in the presence of air at 30 °C (Table 1,
entries 1-8). The experimental results show that EtOH was a
slightly better solvent (entry 2). Then different palladium sources
were tested under the same conditions (entries 9-11). It was
found that PdCl2(PhCN)2 and PdCl2(MeCN)2 had catalytic
activities higher than those of PdCl2 or Pd(OAc)2 (entries 11
and 12). Nevertheless, the yield of 2a (45%) needed to be
enhanced, and the reaction conditions needed to be optimized
further. In the reaction, it was observed that black palladium
A possible mechanism for the reaction is shown in Scheme
2. Initially, aminopalladation of the complex A leads to
intermediate B, which undergoes a ꢀ-hydride elimination to form
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J. Org. Chem. Vol. 73, No. 13, 2008 5181

C.12 After isomerization of C, the intermediate D is obtained,
which is converted to pyrrole 2a via a spontaneous dehydration.
Pd(0) is eventually reoxidized by Cu(OTf)2.
In conclusion, we have developed a new and facile method
for the synthesis of pyrrole derivatives. The key step in this
protocol is an aza-Wacker cyclization, which makes use of
Cu(OTf)2 as the oxidant. In particular, this strategy allows the
natural amino acids to be the starting materials for the
construction of differently substituted pyrroles.
acetate three times. The combined organic extracts were dried using
anhydrous Na2SO4 and evaporated under reduced pressure; the
mixture was then purified by column chromatography over silica
gel to afford product 2a (248 mg, 88% yield) with high purity: 1H
NMR (CDCl3, 300 MHz, ppm) δ ) 7.27-7.11 (m, 5H), 5.81 (d,
J ) 2.7 Hz, 1H), 5.66 (d, J ) 2.7 Hz, 1H), 4.16 (s, 2H), 2.39 (s,
3H), 1.44 (s, 9H); 13C NMR (CDCl3, 75 MHz, ppm) δ ) 150.4,
140.4, 133.7, 132.1, 128.7, 128.3, 126.0, 111.7, 110.3, 83.5, 35.9,
28.0, 16.5; IR (liquid film, cm-1) ν ) 3028, 2978, 2929, 1734,
1536, 1454, 1386, 1327, 1255, 1172, 1121, 1021, 851, 788, 698.
HRMS (m/z): (M+) calcd for C17H21NO2, 271.1572; found,
271.1579.
Experimental Section
Acknowledgment. The authors are grateful for support from
the Natural Science Foundation of China (30572234) and the
Chinese Academy of Sciences.
Typical Procedure for the Synthesis of Pyrrole. To a solution
of 1a (1 mmol, 291 mg) in 5 mL of EtOH were added Cu(OTf)2
(1 mmol, 290 mg) and PdCl2(PhCN)2 (0.1 mmol, 38 mg) one by
one. After the mixture was stirred at 30 °C for 24 h, the ethanol
was removed by reduced pressure. Ten milliliters of water was then
added to the residue, and the mixture was extracted with ethyl
Supporting Information Available: Preparation of starting
materials and characterization data for products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) In aza-Wacker reaction, cis-stereochemistry was proposed in amino-
palladium; see: Liu, G. S.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
JO800433B
5182 J. Org. Chem. Vol. 73, No. 13, 2008