Switchable reactivity between vinyl azides and terminal alkyne by nano copper catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00373

A novel nano copper-catalyzed substrate-dependent chemodivergent transformation of vinyl azides with a terminal alkyne is disclosed. 2,5-Disubstituted pyrroles were selectively obtained in high yield with aryl alkynes and aliphatic alkynes, whereas 2,3,4-trisubstituted pyrroles were formed with silylated alkynes. This switchable method provides a controllable and facile access to both multisubstituted pyrrole scaffolds with high efficiency, excellent regioselectivity, and good functional group compatibility.

Full text of DOI:10.1021/acs.orglett.9b00373

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Switchable Reactivity between Vinyl Azides and Terminal Alkyne by
Nano Copper Catalysis
Jinghe Cen, Yaodan Wu, Jianxiao Li, Liangbin Huang, Wanqing Wu, Zhongzhi Zhu, Shaorong Yang,*
and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A novel nano copper-catalyzed substrate-dependent chemodivergent transformation of vinyl azides with a
terminal alkyne is disclosed. 2,5-Disubstituted pyrroles were selectively obtained in high yield with aryl alkynes and aliphatic
alkynes, whereas 2,3,4-trisubstituted pyrroles were formed with silylated alkynes. This switchable method provides a
controllable and facile access to both multisubstituted pyrrole scaffolds with high efficiency, excellent regioselectivity, and good
functional group compatibility.
Scheme 1. Reactions between Azides and Terminal Alkyne
ransition-metal-catalyzed C−C and C−N bond forma-
T
tions are indispensable tools in organic synthesis allowing
for the constitution of basis backbones that are prevalent
building blocks of active molecules in the life sciences and in
many material precursors.1 Recently, vinyl azides as a pivotal
three-atom synthon for the construction of C−C and C−N
bonds have attracted considerable attention in synthetic
chemistry,2 since they are readily available from azides and
the corresponding alkenes or alkynes.3 Moreover, the synergy
of the azides group and the alkene makes vinyl azides exhibit
unique reactivity which is not found in azides or alkene alone.4
Generally, azides and alkynes tend to undergo Huisgen 1,3-
dipolar cycloaddition (one of the most popular click reactions)
under thermal,5 strain promoted,6 and transition-metal-
catalyzed conditions (Scheme 1a).7 Among them is a classic
example of a Cu-catalyzed azide−alkyne cycloaddition
(CuAAC) independently reported by Meldal and Sharpless
in 2002.8
In line with our interest in the conformation of nitrogen
heterocycles with vinyl azides,9 we were curious about the
reactivity of vinyl azides with unactivated terminal alkyne
under copper catalysis. However, when conducting the
reaction with vinyl azides and terminal alkynes in our copper
catalytic system, we obtained multisubstituted pyrroles instead
of the 1,2,3-triazoles from CuAAC disclosed separately by Bi
and Kirshning, respectively.10 Furthermore, an interesting
switchable reaction was observed in this conversion by varying
the substituent R4 of the terminal alkyne (Scheme 1b). We
speculate that these unexpected consequences might be
attributed to the combination of the unique features of vinyl
azides and a special copper catalytic system. Compared to the
Cu-catalyzed azide-terminal alkyne cycloaddition to form
1,2,3-triazole which is well established, the Cu-catalyzed
cascade reaction of vinyl azides and terminal alkynes to
generate pyrroles is still unknown and remains a challenge. In
this paper, we present a novel nano copper-catalyzed
switchable reaction between vinyl azides and terminal alkynes
to synthesize multisubstituted pyrroles. Significantly, aliphatic
and aromatic alkynes were selectively transformed into the
corresponding 2,5-disubstitued pyrroles, while silyl-alkynes
were converted into 2,3,4-trisubstituted pyrroles.
We embarked on the investigation with the reaction of 1-
ethynyl-4-methoxybenzene 1a and (1-azidovinyl) benzene 2a
in the presence of 30 mol % of catalyst, at 135 °C in DCE
Received: January 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
under a nitrogen atmosphere (Table 1). The click reaction
product 3a′ was obtained in 76% yield with CuTC as the
Scheme 2. Substrate Scope of Alkynes
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
yield of 3a (%)
yield of 3a′ (%)
1
2
3
4
5
6
7
CuTC
CuI
n.d.
19
45
60
81(77)
76
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
CuCl
CuSCN
CuNPs
Cu dust
−
b
23
n.d.
a
Reactions were run with 1a (0.1 mmol) and 2a (0.18 mmol), catalyst
a
Reaction conditions: CuNPs (30 mol %), alkyne 1 (0.2 mmol), vinyl
azides 2a (0.36 mmol), DCE (5 mL) were stirred for 3 h at 135 °C
(30 mol %) in 4 mL of DCE under a nitrogen atmosphere. Yields
were determined by 1H NMR using bromochloromethane as the
b
b
under a nitrogen atmosphere. Isolated yields. 1 mmol scale.
internal standard. Isolated yields.
a
Scheme 3. Substrate Scope of Vinyl Azides
catalyst (Table 1, entry 1). Interestingly, 2,5-disubstituted
pyrrole 3a was observed when copper(I) halides were used
(Table 1, entries 2−3). Furthermore, the yield of 3a rose to
60% using CuSCN as the catalyst (entry 4). Other copper salts
such as CuBr and CuCN could also execute this reaction but
with lower efficiencies (see the Supporting Information (SI)).
Gratifyingly, the reaction gave full conversion with 77%
isolated yield of 3a when using copper nanoparticles (CuNPs)
as the catalyst (entry 5). In contrast, only a 23% yield of 3a was
produced when commercial Cu dust was chosen as the catalyst
(entry 6). A control experiment confirmed that the omission of
copper salts completely shut down the cascade reactions (entry
7). Moreover, the CuNPs catalyst was found to be recyclable
without loss of activity (for details, please see SI).
With the established cascade reaction conditions in hand, we
examined the scope of alkynes, and the results are summarized
in Scheme 2. For aryl alkynes the position of the substituents
on the aromatic ring (para, meta, and ortho positions) did not
significantly affect the reaction efficiency. This transformation
could also tolerate aryl alkynes with electron-donating as well
as electron-withdrawing substituents on the aryl rings. For
instance, the 4-Me2N and 4-CF3 alkynes could be converted
into the desired products in 82% and 56% yields, respectively
(3d and 3g). To our delight, the free amino group and fluoride
containing groups were compatible functional groups for these
transformations (3c, 3e, 3j). It is noteworthy that the reaction
of alkyl alkynes worked efficiently in the current protocol, and
the corresponding 2,5-disubstituted pyrroles were obtained in
moderate yields (3m−3u). When 1 mmol of 1a was used as
the substrate, the pyrrole product 3a was obtained in 70% yield
(Scheme 2). Unfortunately, an attempt to extend this approach
to the coupling of an internal alkyne (3v) was unsuccessful.
Various vinyl azides were also studied (Scheme 3). We were
pleased to find that common functionalities including the
halogens (4c−4e, 4j, 4k), cyano (4g), and acetoxyl (4h) were
able to be incorporated into the desired products. Unexpect-
edly, vinyl azides bearing the ortho methyl substituent
performed poorly along with deactivating the catalyst (4l).
a
Reaction conditions: CuNPs (30 mol %), alkyne 1 (0.2 mmol), vinyl
azides 2 (0.36 mmol), DCE (5 mL) were stirred for 3 h at 135 °C
under a nitrogen atmosphere. Isolated yields. Detected by GC-MS.
b
The erosion in yields might be attributed to increased steric
hindrance. Unfortunately, substrates such as α-alkyl vinyl
azides and β-methyl vinyl azides failed to be transferred into
the corresponding products (4n and 4o).
To extend the scope of this strategy, an intriguing question is
whether silylated alkynes can be used as a coupling partner and
consequently afford 2,5-disubstituted pyrroles. To our surprise,
the reaction gave 2,3,4-trisubstituted pyrroles instead of 2,5-
disubstituted pyrroles under the standard conditions (Scheme
4). The structural analysis indicated that two vinyl azides were
involved in the generation of the major product. As expected,
the reaction efficiency could be significantly enhanced by
simply increasing the amount of vinyl azides. A series of
silylated alkynes including TMS-, TES-, and TIPS-substituted
alkynes were shown to be viable substrates. The structure of 5c
was further confirmed by single-crystal X-ray analysis (CCDC:
B
DOI: 10.1021/acs.orglett.9b00373
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Letter
a
Scheme 4. Synthesis of 2,3,4-Trisubstituted Pyrroles
Scheme 5. Mechanistic Studies and Control Experiments
a
Reaction conditions: CuNPs (30 mol %), alkyne 1 (0.2 mmol), vinyl
azides 2 (0.50 mmol), DCE (5 mL) were stirred for 3 h at 135 °C
under a nitrogen atmosphere. Isolated yields.
1865535). Notably, when a β-substituted vinyl azide and a
terminal vinyl azide were chosen to be the substrates, the cross-
coupled product (5i) was obtained as the major product.
To obtain a better understanding of these transformations,
several control experiments were performed (Scheme 5, eqs
1−6). 2H-Azirine was proposed as an intermediate of the
transformations;11 therefore, the 2H-azirine 6a was prepared
and subjected to the reaction with alkyne 1a and 1w in the
presence of Cu NPs. The corresponding products 3a and 5c
were obtained in 86% and 84% yields, respectively (eqs 1 and
2). These results indicate that 2H-azirine could be a key
intermediate in both reactions. Considering that the copper
acetylide might be the intermediate in these reactions,
(phenylethynyl)copper 7a and ((triisopropylsilyl)ethynyl)-
copper 10a were prepared and reacted under the standard
conditions. However, the reaction gave no 2,5-disubstituted
pyrroles but only 2,3,4-trisubstituted pyrroles as the main
product (eqs 3 and 4). These results indicate that the copper
acetylide was the intermediate in the assembly of 2,3,4-
trisubstituted pyrroles but not for the synthesis of 2,5-
disubstituted pyrroles. Furthermore, when the 1,2,3-triazole
3a′ which is potentially generated through a [3 + 2]
cycloaddition was employed as the substrate, the reaction
did not proceed (eq 5). This result excludes a 1,2,3-triazole
intermediate in this transformation. In addition, an inter-
molecular competition experiment was conducted by subject-
ing an equivalent amount of 1a and 1w with vinyl azides 2a. To
our surprise, the reaction gave the corresponding products 3a
and 5c without any crossover product (eq 6). Moreover, both
reactions were completely suppressed in the presence of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (for details,
see SI).
chemodivergent transformations is depicted in Scheme 6. The
vinyl azides 2 undergo thermal decomposition to form 2H-
azirine I. In the generation of the 2,5-disubstituted pyrrole
(path a), the 2H-azirine initially undergoes an SET reduction
with CuNPs to produce the iminyl Cu(II) intermediate II.
This C-radical is trapped by the terminal alkyne via
intermolecular radical addition to generate intermediate III.
Scheme 6. Mechanism for the Chemodivergent Reaction
Based on the reported literature12 and the above
experimental observations, a plausible mechanism for these
C
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Letter
Subsequently, the radical is captured by the intramolecular
copper(II) species to afford the copper adduct IV, which then
undergoes reductive elimination to regenerate the active
copper species and produces the 3H-pyrroles. Finally, 2,5-
disubstituted pyrrole 3 is achieved via the isomerization of the
3H-pyrrole. For the synthesis of the 2,3,4-trisubstituted pyrrole
(path b), the CuNPs initially react with the terminal alkyne to
form a copper acetylide V. Subsequently, the 2H-azirine
undergoes a nucleophilic ring opening with copper acetylide V,
resulting in the iminyl copper intermediate VI, which is
protonated to give the NH imine (detected by GCMS; see SI).
Then the iminyl copper intermediate VI reacts with another
2H-azirine molecule, leading to intermediate VII and VIII,
which are keto−enol tautomers. Intramolecular cyclization of
VIII furnishes intermediate IX, which undergoes protonolysis
to release intermediate X along with the initial copper species.
Further elimination of NH3 and isomerization provide the
2,3,4-trisubstituted pyrrole 5.
In conclusion, we have developed a nano copper-catalyzed
switchable reaction to assemble 2,5-disubstituted pyrroles and
2,3,4-trisubstituted pyrroles with simple and readily accessible
starting materials. The utilization of inexpensive, readily
available, recyclable, and environmentally friendly a copper
nanoparticle catalyst makes this reaction particularly attractive.
Further efforts to elucidate the detailed mechanism and to
explore the difference between common alkynes and silylated
alkynes are currently underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00373.
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
Accession Codes
CCDC 1865535 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: lisryang@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
Wanqing Wu: 0000-0001-5151-7788
Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Key Research and Develop-
ment Program of China (2016YFA0602900), the National
Natural Science Foundation of China (21420102003 and
21642005), and the Fundamental Research Funds for the
Central Universities (2018ZD16).
D
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