Copper-mediated reaction of zirconacyclopentadienes with azides: A one-pot three-component synthesis of multiply substituted pyrroles from one azide and two alkynes

Article abstract of DOI:10.1021/om400988g

A general method for the synthesis of multiply substituted pyrroles through zirconocene-mediated coupling of two alkynes and an azide in the presence of CuCl has been achieved.

Full text of DOI:10.1021/om400988g

Communication
pubs.acs.org/Organometallics
Copper-Mediated Reaction of Zirconacyclopentadienes with Azides:
A One-Pot Three-Component Synthesis of Multiply Substituted
Pyrroles from One Azide and Two Alkynes
Yiqing Zhou,† Xiaoyu Yan,† Chao Chen,† and Chanjuan Xi*,†,‡
†Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, People’s Republic of China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: A general method for the synthesis of multiply substituted pyrroles
through zirconocene-mediated coupling of two alkynes and an azide in the presence of
CuCl has been achieved.
zirconocene compound/CuCl system, and azide served as a
one-atom-unit substrate in this cyclization reaction (Scheme 1).
yrrole is one of the most important heterocycles: it is
Pfound in a broad range of natural products and drug
molecules1 and is also of growing relevance in materials
science.2 Accordingly, substantial attention has been paid to
develop efficient methods for the synthesis of pyrroles. Most of
the known methods for the construction of the pyrrole ring
proceed via various types of cycloadditions or cycloisomeriza-
tions of acyclic precursors.3 Direct coupling of two internal
alkynes with nitrogen sources to construct pyrroles is rare, to
the best of our knowledge.
Scheme 1. Zr-Mediated Coupling Reaction of Two Alkynes
and Azide To Afford Pyrroles in the Presence of CuCl
Zirconocene-mediated coupling methods are well-established
as important synthetic routes to a variety of heterocyclic
compounds and functionalized molecules.4 In a manifestation
of this chemistry, a zirconocene reagent couples with two
alkynes to produce a zirconacyclopentadiene in high yield.
These zirconacyclopentadienes are useful synthons for hetero-
cycles, which are obtained by reactions with main-group-
element dihalides such as Me2SnBr2, PhPCl2, PhAsCl2, Se2Cl2,
S2Cl2, and SOCl2, developed by Fagan, Nugent, and others.5,6
However, the synthesis of pyrroles with this method has not
been successful, although the reaction of azametallacyclopen-
tenes with CO to form pyrroles has been reported.7 Tilley and
a co-worker have reported that the reaction of zirconacyclo-
pentadienes with nitrosobenzene gave pyrroles in the presence
of AlCl3.6c This reaction has a strict limitation for substituents
in the zirconacyclopentadienes. Azides are a class of important
synthetic substrates, which participate in a wide range of
reactions for constructing new carbon−nitrogen bonds.8,9 More
recently, we reported the reaction of alkenylzirconocenes with
acyl azides in the presence of CuCl to afford enamides.10 As
part of our continuing interest in the development of
synthetically useful methods from zirconacycles,11 we inves-
tigated the reaction of zirconacyclopentadienes with azides. In
this paper we report the first cyclization of two molecular
alkynes with an azide to give multiply substituted pyrrole
derivatives; the reactions were achieved by utilization of a
A typical procedure was as follows: zirconacyclopentadiene
1a was prepared by the reported method using the Negishi
reagent (Cp2ZrBu2, reaction of 0.6 mmol of Cp2ZrCl2 toward 2
equiv of nBuLi)12a with 1 mmol of 3-hexyne in 3 mL of THF.12
To a solution of 1a in THF was added 1.0 mmol of CuCl and
0.6 mmol of benzyl azide 2a (Scheme 2). The mixture was
stirred for 3 h at 50 °C. After the usual workup, column
chromatographic separation gave the pure compound 3aa in
65% yield. In the absence of copper(I) salts the reaction did not
proceed and the starting material remained.
Scheme 2. Reaction of Zirconacyclopentadiene 1a with
Azide 2a in the Presence of CuCl
Received: October 9, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om400988g | Organometallics XXXX, XXX, XXX−XXX

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Communication
Further study involving the use of symmetrically and
unsymmetrically13,14 substituted monocyclic as well as bicyclic
zirconacyclopentadienes15 bearing alkyl and aryl groups 1a−k
(Table 1, entries 1−11) resulted in the formation of pyrroles in
high yield in most cases. Representive results are summarized in
Table 1. When the zirconacyclopentadiene 1i was a mixture of
two regioisomers during preparation, the product 3ia was also a
mixture of two regioisomers (entry 9). The trimethylsilyl-
substituted zirconacyclopentadiene 1l was treated with azide 2a
to afford the desired product 3la in moderate yield (entry 12).
Indenylzirconacyclopentadiene did not react with azides. It is
noteworthy that in all of the reactions copper metal was
obtained as a red precipitate after workup, which was confirmed
by an XPS analysis (see the Supporting Information).
To establish the full scope of the reaction, we next explored a
range of azide substrates. Alkyl-, aryl-, allyl-, acyl-, and
CH2CO2Et-substituted azides were chosen as representative
examples. In most cases the corresponding products were
obtained in moderate to high yields. The results are
summarized in Table 2. Alkyl-substituted azide afforded the
corresponding pyrroles 3bb and 3fb in 60% and 57% yields,
respectively (entries 1 and 2). When aryl azide was used, the
Table 1. CuCl-Mediated Reaction of
a
Zirconacyclopentadienes 1 with 2a
Table 2. CuCl-Mediated Reaction of
Zirconacyclopentadienes 1 with Azides 2
a
a
All of the reactions were carried out at 50 °C for 3 h, unless otherwise
b
c
d
a
noted. Isolated yields. Reaction time 12 h. A mixture of two
regioisomers was obtained in a ratio of 4:1; the minor isomer was 1-
benzyl-3,4-diethyl-2,5-diphenyl-1H-pyrrole.
All of the reactions were carried out at 50 °C for 3 h, unless otherwise
b
c
d
noted. Isolated yields. Reaction time 12 h. 0.6 equiv of azide was
added.
B
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Communication
pyrroles 3bc and 3dc were obtained in 81% and 58% yields,
respectively (entries 3 and 4). Addition of allyl azides similarly
gave 3ad and 3ae in 43% and 52% yields, respectively (entries 5
and 6). Interestingly, ethyl azidoacetate could also be used in
this reaction, and the pyrroles 3bf and 3df were obtained in
74% and 62% yields, respectively (entries 7 and 8). When 1,2-
bis(azidomethyl)benzene was used, a double-cyclization
reaction proceeded to give the 1,2-bis((1H-pyrrol-1-yl)methyl)-
benzene derivative 3ag in 39% isolated yield. It is worth noting
that, when acyl azide was used, the desired pyrrole was not
observed but a diene was obtained after workup.
reaction mechanism and application of this chemistry are in
progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text and figures giving experimental procedures, full character-
ization data, including 1H NMR and 13C NMR data for all new
compounds and spectra for all compounds, and XPS measure-
ments and analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
On the basis of these results, we propose the following
possible mechanism for this reaction (Scheme 3). First, the
AUTHOR INFORMATION
Corresponding Author
*C.X.: tel, +86-10-62782695; e-mail, cjxi@tsinghua.edu.cn.
Notes
■
Scheme 3. Proposed Mechanism for the Formation of
Pyrroles
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Basic Research
Program of China (973 program) (2012CB933402) and
National Natural Science Foundation of China (Nos.
21272132 and 21032004). We thank Dr. Zhanping Li
(Tsinghua University) for his kind help with the measurement
of XPS data.
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