Synthesis of pyrroles by click reaction: Silver-catalyzed cycloaddition of terminal alkynes with isocyanides

Article abstract of DOI:10.1002/anie.201302604

Just click with silver: Pyrroles are prepared by the co-cyclization of terminal alkynes and isocyanides in a silver-catalyzed click reaction. This route represents an extremely simple, efficient, and atom-economic approach to substituted pyrroles in good yields with high selectivity, thus complementing the click method for the rapid formation of multifunctional heterocycles. Copyright

Full text of DOI:10.1002/anie.201302604

Angewandte
Chemie
DOI: 10.1002/anie.201302604
Cycloaddition
Synthesis of Pyrroles by Click Reaction: Silver-Catalyzed
Cycloaddition of Terminal Alkynes with Isocyanides**
Meng Gao, Chuan He, Hongyi Chen, Ruopeng Bai, Ben Cheng, and Aiwen Lei*
Dedicated to Professor Irina Petrovna Beletskaya
Pyrroles and their partially saturated derivatives represent an
important class of five-membered heterocycles,[1] which are
the basic constituents of numerous natural products, biolog-
ically active alkaloids, pharmaceuticals, and agrochemicals.[2]
This key heterocyclic core has also found broad use in both
organic synthesis and material science.[3] Because of their
characteristic properties, numerous processes have been
developed for the construction and modification of the
pyrrole structure,[4] although most of these methods are
limited to the use of elaborately designed starting materials
Scheme 1. Proposed click synthesis of pyrroles.
and suffer from low efficiency and selectivity. Thus, the
development of a straightforward, convenient, and regiose-
À
lective route to pyrrole derivatives from basic chemical
materials is highly attractive.
efforts toward the C H functionalization/alkynylation, silver
salts have displayed a great potential in the mediation of
In 2001, Sharpless et al. introduced the concept of “click
chemistry” for conducting organic reactions with high effi-
ciency, selectivity, and yield under mild reaction conditions
with a wide variety of readily available starting materials with
orthogonal protecting groups.[5] It is well known that the
copper-catalyzed azide–alkyne cycloaddition (CuAAC) has
emerged as the premier example of click chemistry and plays
a significant role not only in organic synthesis, but also in
medicinal chemistry, surface and polymer chemistry, and
bioconjugation applications.[5,6] Actually, isocyanides and
azides have a certain structural similarity. Compared to the
copper-catalyzed cycloaddition of azides to terminal alkynes
for the synthesis of 1,4-triazoles, the co-cyclization of
isocyanides with terminal alkynes will directly give pyrrole
derivatives (Scheme 1). However, this strategy has been
rarely used and cannot really be classified as a “click”
synthesis of pyrroles.[7] Recently, based on the continued
highly selective chemical transformations involving terminal
alkynes.[8] Herein, we communicate our efforts in the silver-
catalyzed synthesis of pyrroles by the cycloaddition of
terminal alkynes and isocyanides. This protocol addresses
the previous limitations and furnishes a diverse collection of
valuable substituted pyrroles with high efficiency and selec-
tivity under mild conditions, thus complementing the click
method for the rapid construction of multifunctional hetero-
cycles.
Our initial efforts focused on the reaction of phenyl-
acetylene 1a and ethyl 2-isocyanoacetate 2a by using one
equivalent of Ag2CO3 as the mediator. To our delight, we
indeed obtained the corresponding pyrrole cycloaddition
product in moderate yield (Table 1, entry 1). Notably, in this
reaction, no by-product resulting from the homocoupling of
the terminal alkyne was observed. This interesting trans-
formation to the pyrrole heterocycles encouraged us to
further examine the feasibility of this efficient cycloaddition.
After many optimization efforts, the use of 10 mol%
Ag2CO3 as the catalyst in N-methyl-2-pyrrolidone (NMP) at
808C turned out to give the best result (Table 1, entry 11). To
enhance the conversion of the terminal alkyne, ethyl 2-
isocyanoacetate 2a (1.5 equiv) was employed in the reaction.
Increasing the amount of Ag2CO3 did not improve the yield
observably (Table 1, entries 1–5). The reaction also pro-
ceeded in other solvents, such as dimethyl sulfoxide
(DMSO), toluene, N,N-dimethylformamide (DMF), and
dioxane, but gave the products in lower yields (Table,
entries 5–8). When the reaction temperature was lowered to
608C, a yield of only 59% could be achieved (Table 1,
entry 9). It is noteworthy that Ag2CO3 played a critical role in
the reaction; other silver salts, such as Ag2O and AgNO3,
were totally ineffective (Table 1, entries 12 and 13). For
comparison, copper salts were also tested in this reaction.
[*] M. Gao,[+] C. He,[+] H. Chen, R. Bai, B. Cheng, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei, 430072 (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences
730000 Lanzhou (P. R. China)
[+] These authors contributed equally to this work.
[**] This work was supported by the 973 Program (2012CB725302) and
the National Natural Science Foundation of China (21025206,
21272180). We are also grateful for support from the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1030).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302604.
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Table 1: Optimization of conditions for the reaction of phenylacetylene
(1a) and ethyl 2-isocyanoacetate (2a).[a]
Entry
Cat. (equiv)
T [8C]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
Ag2CO3 (1.0)
Ag2CO3 (0.5)
Ag2CO3 (0.2)
Ag2CO3 (0.1)
Ag2CO3 (0.05)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.1)
AgNO3 (0.2)
Ag2O (0.2)
100
100
100
100
100
100
100
100
60
80
80
80
80
dioxane
dioxane
dioxane
dioxane
DMF
DMSO
NMP
toluene
NMP
NMP
NMP
NMP
NMP
60
82
80
77
49
31
87
77
59
88
89
trace
trace
trace
0
9
10
11
12
13
14
15
Cu(OAc)2 (0.2)
CuI (0.2)
80
80
NMP
NMP
[a] Reactions were carried out on a scale of 0.25 mmol of 1a and
0.38 mmol of 2a in the presence of silver or copper salts in 3 mL of
solvent under N2 atmosphere for 2 h. [b] Yields of isolated products. The
entry in bold marks the optimized reaction conditions.
However, both CuII and CuI salts, such as Cu(OAc)2 and CuI,
respectively, turned out to be ineffective (Table 1, entries 14
and 15).
With the optimized conditions in hand, various terminal
alkynes 1 were reacted with different isocyanides 2 to access
the corresponding pyrrole products 3 (Scheme 2). The
reaction was readily extended to a variety of aryl-substituted
terminal alkynes, and both electron-withdrawing and elec-
tron-donating substituents were well tolerated under the
reaction conditions (3a–3j). It is noteworthy that steric
effects had little influence on this cycloaddition reaction.
Regardless of the substitution pattern of the aryl ring (ortho,
meta, or para) of the aryl acetylenes used in the reaction, the
corresponding pyrrole products (3b–3j) were obtained in
good yields. Several interesting functional groups, such as
methylthio, methylsulfonyl, and ethynyl, were well tolerated
in the cycloaddition (3e, 3 f, and 3g). Moreover, alkyl-
substituted terminal alkynes were also found to be suitable
reaction partners. Various aliphatic terminal alkynes, includ-
ing those with cyclopropyl, n-butyl, n-amyl, and terminal
hydroxy groups, smoothly reacted with ethyl 2-isocyanoace-
tate 2a to afford the corresponding pyrrole products in good
yields (3k–3n). Meanwhile, internal alkynes 1q and 1r could
also be employed to give the pyrrole scaffold without any
difficulties (3q, 3r, respectively). In addition, various isocya-
nides 2 could be used to access the pyrrole ring, both diethyl
isocyanomethylphosphonate 2o and methyl 2-isocyanoace-
tate 2p could react satisfactorily and gave the products in
excellent yields (3o and 3p, respectively).
Scheme 2. Cycloaddition of alkynes 1 and isocyanides 2. Reaction
conditions: 1 (0.5 mmol), 2 (0.75 mmol), Ag2CO3 (10 mol%) in 2 mL
of NMP at 808C under N2 atmosphere for 1 h. Yields of isolated
products are given.
To elucidate the role of the silver catalyst in this cyclo-
addition, the stoichiometric reaction between phenylacety-
lene 1a and ethyl 2-isocyanoacetate 2a with Ag2CO3 was
monitored by in situ IR spectroscopy (Figure 1, see the
Figure 1. Profile of the stepwise stoichiometric reaction between 1a,
Ag2CO3, and 2a in DMSO at 808C monitored by in situ IR spectros-
copy.
2
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Supporting Information for more details). When one equiv-
alent of Ag2CO3 was added to the solution of 1a in DMSO,
the band of 1a (765 cmÀ1) disappeared quickly with concom-
itant appearance of the band for AgHCO3 (802 cmÀ1) and
a new component A (754 cmÀ1). It is reasonable to assume
that component A might be the silver–acetylide complex A.
Then, one equivalent of 2a was added to the solution. The
concentration of component A decreased very fast while the
concentration of product 3a (768 cmÀ1) increased slowly. This
result indicated that when 2a reacted with component A,
a probably insoluble complex C was formed, which slowly
released the product 3a into the solution.
Scheme 4. Proposed mechanism for the silver-catalyzed cycloaddition
of terminal alkynes with isocyanides.
To verify the involvement of silver acetylide as a critical
intermediate in the reaction, the prepared silver phenyl-
acetylide[9] was reacted with 2a under the standard conditions
in the absence of silver catalyst (Scheme 3). The desired
According to the above information, a reaction mecha-
nism is proposed in Scheme 4. In the presence of Ag2CO3
catalyst, both the silver–acetylide complex A and silver–
isocyanide complex B would be generated from 1a and 2a,
respectively.[10,12] Subsequently, the cycloaddition between
complex A and complex B would afford the key intermediate
complex C.[13] Finally, protonation and tautomerization gives
the pyrrole product 3a.
In summary, we have demonstrated a silver-catalyzed
click synthesis of pyrroles by the co-cyclization of terminal
alkynes and isocyanides. From a synthetic point of view, this
protocol represents an extremely simple, efficient, and atom-
economic way to construct substituted pyrroles in good yields
with high selectivity, thus complementing the click method for
the rapid formation of multifunctional heterocycles. Further
detailed mechanistic studies about this transformation are
currently under way in our laboratory.
Scheme 3. Reaction of silver phenylacetylide with 2a.
product 3a was obtained in 70% yield, thus suggesting that
component A in Figure 1 is the silver–acetylide intermediate
complex A.[10]
Moreover, we noticed that silver salts could also coor-
dinate to the isocyano group and activate isocyanides 2 in
some cycloaddition reactions.[11] Thus, the investigation of the
stoichiometric reaction of ethyl 2-isocyanoacetate 2a with
Ag2CO3 was also monitored by in situ IR spectroscopy
(Figure 2, see the Supporting Information for more details).
Experimental Section
General procedure for the preparation of pyrroles (e.g., 3a): A
mixture of phenylacetylene 1a (0.5 mmol), ethyl 2-isocyanoacetate
2a (0.75 mmol), and Ag2CO3 (0.05 mmol) in NMP (3 mL) was stirred
under an N2 atmosphere at 808C for 1 h. After completion of the
reaction, as indicated by TLC and GC-MS, the solid was filtered off
and washed with dichloromethane. After removal of the solvent of
the filtrate, the pure product was obtained by flash column
chromatography on silica gel (eluent: petroleum ether/ethyl ace-
tate = 8:1) to afford 3a in 89% yield. The spectroscopic data of all
products are presented in the Supporting Information. The spectro-
scopic features of all obtained compounds were analogous to the
spectroscopic data reported in the literature. For 3a: 1H NMR
(400 MHz, CDCl3): d = 9.42 (brs, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.39
(t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 2.8 Hz, 1H),
6.37 (t, J = 2.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.26 ppm (t, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 161.2, 135.3, 132.1,
129.6, 127.6, 126.9, 121.8, 118.2, 112.5, 60.3, 14.2 ppm. HRMS (ESI)
calcd for [C13H14NO2]+ [M+H]+: 216.1019; found: 216.1019.
Figure 2. Profile of the stoichiometric reaction between 2a and Ag2CO3
in DMSO at 808C monitored by in situ IR spectroscopy.
When one equivalent of Ag2CO3 was added to a solution of
2a in DMSO, the band of 2a (1209 cmÀ1) disappeared upon
the generation of a new component B (1191 cmÀ1). This new
component B could be identified as complex B of silver(I) and
isocyanide. Based on these results, we believe that the
silver(I) catalyst activates both the terminal alkyne and the
isocyanide in the cycloaddition.
Received: March 28, 2013
Published online: && &&, &&&&
Keywords: click chemistry · cycloaddition · pyrroles · silver ·
.
terminal alkynes
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Cycloaddition
M. Gao, C. He, H. Chen, R. Bai, B. Cheng,
A. Lei*
&&&& — &&&&
Synthesis of Pyrroles by Click Reaction:
Silver-Catalyzed Cycloaddition of
Terminal Alkynes with Isocyanides
Just click with silver: Pyrroles are pre-
pared by the co-cyclization of terminal
alkynes and isocyanides in a silver-cata-
lyzed click reaction. This protocol repre-
sents an extremely simple, efficient, and
atom-economic approach to substituted
pyrroles in good yields with high selec-
tivity, thus complementing the click
method for the rapid formation of multi-
functional heterocycles.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!