Copper-catalyzed huisgen and oxidative huisgen coupling reactions controlled by polysiloxane-supported amines (AFPs) for the divergent synthesis of triazoles and bistriazoles

Article abstract of DOI:10.1002/chem.201202472

An interesting example of a divergent catalysis with a copper(I) and amine-functional macromolecular polysiloxanes system was successfully presented in click chemistry. In this manuscript, we demonstrate the remarkable ability of the secondary amine-functional polysiloxane to induce oxidative coupling in the copper-mediated Huisgen reactions of azides and alkynes, thereby achieving good yields and selectivities. The click reactions mediated by a polysiloxane-supported secondary amine allow the preparation of novel heterocyclic compounds, that is, bistriazoles. Comparably, it is also surprising that the use of a diamine-functional polysiloxane as ligand led to a classic Huisgen [3+2] cycloaddition in excellent yields. From the results of the present amine-functional polysiloxanes-controlled Huisgen reaction or oxidative Huisgen coupling reaction to divergent products and the proposed mechanism, we suggested that the mononuclear bistriazole-copper complex stabilized and dispersed by the secondary amine-functional polysiloxane was beneficial to prevalent the way to oxidative coupling. Copyright

Full text of DOI:10.1002/chem.201202472

FULL PAPER
DOI: 10.1002/chem.201202472
Copper-Catalyzed Huisgen and Oxidative Huisgen Coupling Reactions
Controlled by Polysiloxane-Supported Amines (AFPs) for the Divergent
Synthesis of Triazoles and Bistriazoles
Zhan-Jiang Zheng,[a] Fei Ye,[a] Long-Sheng Zheng,[a] Ke-Fang Yang,[a]
Guo-Qiao Lai,[a] and Li-Wen Xu*[a, b]
Abstract: An interesting example of a
divergent catalysis with a copper(I)
and amine-functional macromolecular
polysiloxanes system was successfully
presented in click chemistry. In this
manuscript, we demonstrate the re-
markable ability of the secondary
reactions mediated by a polysiloxane-
supported secondary amine allow the
preparation of novel heterocyclic com-
pounds, that is, bistriazoles. Compara-
bly, it is also surprising that the use of
a diamine-functional polysiloxane as
ligand led to a classic Huisgen [3+2]
cycloaddition in excellent yields. From
the results of the present amine-func-
tional polysiloxanes-controlled Huisgen
reaction or oxidative Huisgen coupling
reaction to divergent products and the
proposed mechanism, we suggested
that the mononuclear bistriazole–
copper complex stabilized and dis-
persed by the secondary amine-func-
tional polysiloxane was beneficial to
prevalent the way to oxidative cou-
pling.
amine-functional
polysiloxane
to
induce oxidative coupling in the
copper-mediated Huisgen reactions of
azides and alkynes, thereby achieving
good yields and selectivities. The click
Keywords: bistriazoles
·
click
chemistry · copper · oxidative cou-
pling · polysiloxanes
Introduction
creasingly important building blocks and linkers in polymer-
ic materials, drug and medicinal chemistry, bioconjugate
chemistry, surface science, and combinational chemistry.[5]
Undoubtedly, the discovery of the catalytic effect of CuI in
the Huisgen reaction of alkynes and azides was a milestone
in the development of click chemistry.[6] The success of the
CuI-catalyzed Huisgen reaction has been highlighted by nu-
merous reports with clean addition and little byproducts.[4–6]
Because of the established importance of click chemistry
with the triazole motif, most works reported in the past ten
years ignored the isolation and characterization of the
minor amount of side products in this reaction. Interestingly,
only three examples have reported that the minor byproduct
of the Huisgen reaction, bistriazoles, was not a negligible
molecule (Scheme 1).[7] For example in 2007, Burgess
et al.[7a] reported that the bistriazoles could be the major
product in the presence of a catalytic amount of CuSO4
(10 mol%) and one equivalent of Cu power under meticu-
lously modified conditions: 1:1 mixture of MeCN/2m aque-
ous Na2CO3 solution at 258C for 18 h. Jeon et al.[7c] also re-
ported the formation of bistriazoles in low to moderate
yields and selectivities in the presence of CuI or CuBr and
two equivalents of diisopropylethylamine (DIPEA). Howev-
er, it was observed that only the alkynes containing propar-
gylic ethers and acetylenic amides could specifically result in
moderate to good yields in previous reported examples. The
oxidative coupling–click dimerization did not work well
when the alkynes or azides were linked directly with hin-
dered group or aromatic moiety.
Since Sharpless et al. disclosed the concept of click chemis-
try in 2001,[1] the Huisgen [3+2] cycloaddition[2] has emerged
as a powerful chemical reaction to 1,4-disubstituted triazoles
and promoted the progress of click chemistry.[3,4] In the past
decade, the catalytic Huisgen click reaction of azides with
alkynes, with its many creative and effective variations, have
found a wide application in numerous areas due to its privi-
leged status. The reaction is easy to perform with high
yields, little or no byproducts are formed, the reaction can
be carried out under mild conditions, it works well under
many chemical and biological conditions, functional groups
are tolerated, and the reaction is high atom economical.[4] In
particular, the corresponding triazoles motif has become in-
[a] Dr. Z.-J. Zheng, F. Ye, L.-S. Zheng, Dr. K.-F. Yang, Dr. G.-Q. Lai,
Prof. Dr. L.-W. Xu
Key Laboratory of Organosilicon Chemistry and
Material Technology of Ministry of Education
Hangzhou Normal University
Hangzhou 310012 (P. R. China)
Fax : (+86)571-28865135
E-mail: liwenxu@hznu.edu.cn
[b] Prof. Dr. L.-W. Xu
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences
Lanzhou, 730000 (P. R. China)
E-mail: licpxulw@yahoo.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202472.
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Scheme 2. Amine-functional polysiloxanes-controlled divergent synthesis
of triazoles and bistriazoles in the click addition of azides and alkynes.
in the CuI-catalyzed oxidative dimerization of triazoles and
secondary–primary diamine-containing polysiloxane led to a
facile Huisgen [3+2] cycloaddition of azides and alkynes.
Scheme 1. Copper-catalyzed Huisgen-oxidative coupling reaction: previ-
ous work on the synthesis of bistriazoles.[7]
Results and Discussion
Initially, we investigated the reaction of benzyl azide with
phenylacetylene in the presence of various copper salts
(Scheme 3, 5 mol%) and commercially available amine-
Inspired by previous studies on the oxidative Huisgen re-
action and mechanistic investigation,[6,7] we were aware of
the possibility of modifying the stability and the catalytic ac-
tivity of active CuI species with amine-functional polysilox-
anes (AFPs). Amine-functional polysiloxanes or polysilox-
À
ane-supported amines that possess a Si O bond in the main
À
backbone and an amino functional group in the Si C linking
side arm, are among the most important and environmental-
ly benign organosilicon materials in use today, in which
most of the applications of the polysiloxanes in the textile
industry were derived from the extraordinary flexibility and
superhydrophobility of the siloxane backbone.[8] To the best
of our knowledge, very few examples are known where the
polysiloxane-supported amines were used as a macromolec-
ular ligand or functional polymer in catalysis, even as an en-
vironmentally benign supporter in organocatalysts.[9] In a
recent study by our group, we disclosed the effect of amine-
functional polysiloxanes on the copper-catalyzed Buchwald–
Scheme 3. Effect of the amine ligands on the copper-catalyzed Huisgen
[3+2] cycloaddition.
À
Hartwig C N cross-coupling reaction of aryl iodides with
amides for the generation of N-arylated products, which evi-
denced their utility as a potent macromolecular or polymer
ligand with promising activities (see the Supporting Infor-
mation).[10] Also in the past, despite the potential role
played by CuI in the Huisgen reaction, the use of nitrogen-
based ligands was shown to enhance the reaction rate and
restrict the inherent thermodynamic stability of active CuI
catalytic species from unavoidable oxidation under aerobic
conditions.[11] Furthermore, the polysiloxanes have been de-
scribed as a protecting medium that allows the manipulation
and storage of air- and moisture-sensitive N-heterocyclic car-
benes,[12] we thus wondered if such amine-functional polysi-
loxanes would work as a soluble macromolecular or polymer
ligand to generate stable CuI species and give rise to oxida-
tive dimerization. Herein, we report the finding that the syn-
thesis of triazoles and bistriazoles controlled by polysilox-
ane-supported amines (Scheme 2), in which the secondary
amine-functional polysiloxane is indeed an effective ligand
functional polysiloxane (10 mol% referred to the amine
moiety). In these screenings, a mixture of benzyl azide and
phenylacetylene (1:1) in CH2Cl2 was stirred at room temper-
ature overnight. The resulting reaction mixture was then an-
alyzed by GC-MS. As revealed in Table 1, secondary–pri-
mary diamine-functional polysiloxane (1a; AFP-NH2) did
not promote the oxidative Huisgen coupling but led to the
formation of 1,2,3-triazoles in excellent yields (>99%;
Table 1, entries 4 and 5), and interestingly, when CuCl was
used as catalytic source, the secondary amine-functional pol-
ysiloxane (1b; AFP-NH) afforded the bistriazole as major
product in promising yield (58%) and moderate selectivity
(1.5:1) under similar conditions (Table 1, entry 11). Further-
more, experiments performed on various secondary amines
and primary amines did not yield any expected bistriazoles
(Table 1, entries 8–10 and 16–19), highlighting the key role
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Copper-Catalyzed Huisgen and Huisgen-Oxidative Coupling Reactions
Table 1. Screening of catalysts for the copper-catalyzed Huisgen cyclo-
FULL PAPER
tions (Table S1, see the Supporting Information). Among
the solvents examined, dichloromethane was still proven to
be the best solvent. From these experiments, it can be clear-
ly concluded that the amine-functional polysiloxanes are
very efficient macromolecular ligands in the classic or oxida-
tive Huisgen reaction, in which the secondary–primary di-
ACHTUNGTRENNUNGaddition of phenylacetylene and benzyl azide.
Entry
Cu catalyst
Ligand
T [oC]
Products[a]
4a
5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CuSO4·5H2O
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1b
1b
–
1b
1b
1 f
1g
1h
1d
20
20
20
20
20
20
20
20
20
20
20
0
–
–
–
–
–
–
–
–
–
7
–
Cu
Cu
U
AHCTUNGTREGaNNNU mine-functional polysiloxane 1a lead to the formation of
the triazole and the secondary amine-functional polysilox-
ane 1b resulted in the bistriazole.
CuI
>99
>99
>99 (93)[b]
93
80
90
70
39
13
36
22
44
>99
>99
18
CuBr
CuCl
CuI
CuI
CuI
By using the secondary amine-functional polysiloxane 1b
as ligand and the conditions noted in Table 1 (entry 12), the
oxidative Huisgen coupling reaction of various azides and
alkynes were carried out at 08C in good yields and selectivi-
ties (Scheme 4). Simple functionalized aromatic alkynes re-
acted with benzyl azides and ethyl 2-azidoacetate very effi-
ciently, giving the expected bistriazoles as major products in
good yields. To the best of our knowledge, this protocol ex-
hibited the best selectivity and conversion in comparison to
previous reports.[7] For example, the best yield of compound
5a reached 49% when lower temperature (À358C) and high
NaOH concentrations were used,[7b] whereas the CuI–polysi-
loxane-supported secondary amine catalyst system gave
better conversion and selectivity (80%). With substituted
benzyl azides, no significant difference was observed with ar-
–
–
58
CuI
CuCl
CuCl
CuCl
CuCl
CuBr
CuCl
CuCl
CuCl
CuCl
85 (80)[b]
0
–
À10
78 (75)[b]
0
51
–
–
–
–
0
0
0
0
21
[a] Reagents and reaction conditions: phenylacetylene (1 mmol), benzyl
azide (1 mmol), copper salt (0.05 mmol, 5 mol%), nitrogen ligand
(10 mol% refer to one nitrogen atom), solvent (4 mL). Yields deter-
mined by gas chromatography and GC-MS. [b] The yield of the isolated
product is given within the parentheses.
of the secondary amine-func-
tionalized polysiloxane 1b in
this oxidative Huisgen reaction.
It is interesting that ligands 1c
and 1d, being also secondary
amines, only resulted in the tri-
azole in good yields (Table 1,
entries 8 and 9) but no bistria-
zole was detected. Thus, these
data show that the catalytic ac-
tivity of CuI is significantly
modified and enhanced by the
amine-functional polysiloxanes
with a sensitive function and
effect of the ligand in this oxi-
dative Huisgen reaction. The
effect of temperature on the ox-
idative coupling reaction was
also studied, and good to high
yields (78–85% yield) as well
as good selectivities (up to
ꢀ7:1) were obtained at lower
temperature (0 or À108C,
Table 1, entries 12, 14) and
even CuBr could led to moder-
ate yield at 08C (51% yield).
After selection of the most effi-
cient hydrophobic macromolec-
ular ligand and copper catalyst,
we screened different solvents
Scheme 4. AFP 1b promoted copper-catalyzed oxidative Huisgen coupling reaction of various azides and al-
to adjust the reaction condi- kynes to bistriazoles.
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L.-W. Xu et al.
Scheme 5. Synthesis of the sugar-based bistriazole 7.
omatic alkynes functionalized with methyl or halide groups.
With ethyl 2-azidoacetate, the oxidative Huisgen coupling
reaction gave the expected bistriazole 5e in good yield
(73%). The reaction shown in Scheme 5 is interesting, be-
cause it highlights the fact that the core of the sugar-based
bistriazole 7 is chiral and the diastereoselectivity is high
(85:15).
We have realized our best results by using the secondary–
primary diamine-functional polysiloxane 1a with CuX (X=
Cl, Br, I) in the click Huisgen reaction of benzyl azide with
phenylacetylene (Table 1). For compassion, to explore the
scope of the CuCl/1a catalytic system in this reaction, simi-
lar alkynes bearing aromatic rings were submitted to various
azides under the optimized reaction conditions. As shown in
Scheme 6, a broad range of substrates were led to high
levels of selective synthesis of triazoles in excellent yields
(79–99%). The production of general triazoles in the pres-
ence of the CuI–polysiloxane-supported diamine system is
expected to be of most interest for the comparable study of
the divergent mechanistic procedure induced by the poly-
siolxane-supported secondary amine. Therefore the kinetic
significance of alkyne deprotonation was further investigat-
ed by using kinetic isotope exchange (KIE) experiments
Figure 1. Time courses of triazole or bistriazole product formation as de-
&
termined by GC-MS. =Classic copper-catalyzed Huisgen cycloaddition
of azide 2a and alkyne 3a to triazole 4a promoted by the primary amine
*
1a. =Copper-catalyzed oxidative Huisgen cycloaddition of azide 2a and
~
alkyne 3a to bistriazole 5a promoted by the secondary amine 1b.
=
Copper-catalyzed oxidative Huisgen cycloaddition of azide 2a and
[D]phenylacetylened to bistriazole 5a promoted by the secondary amine
1b.
(Figure 1) with deuterium. The kinetic significant of alkyne
(for example, phenylacetylene (3a)) deprotonation revealed
that a primary deuterium KIE (KH/KD) of 2.8 was observed
in the oxidative Huisgen coupling reaction shown in
Figure 1. This result suggested that deprotonation of the
alkyne component is the rate-determining step.
Perhaps the most intriguing outcome was that the
copper-catalyzed Huisgen reaction of azides and alkynes to
divergent products did depend on the amine-functional pol-
ysiloxanes. The main chain of the two polymeric ligands 1a
and 1b was the same but the side chain was functionalized
differently by a secondary amine or a secondary–primary
diimine, respectively, which led to a divergent Huisgen
[3+2] cycloaddition and oxidative Huisgen coupling reac-
tion. In the CuCl-catalyzed click reactions of azides and al-
kynes in all cases the oxidative Huisgen coupling occurred
with good yields and selectivities when 1b was used as a
ligand but almost complete conversion of the Huisgen reac-
tion to triazoles was observed when 1a was used. In the
past years, the mechanistic investigations have revealed
that the active CuI catalytic species are formed from CuI or
CuII salts in the presence of ligands,[13] and the click addi-
tion presumably involved the formation of binuclear CuI
complexes in the rate-determining step.[14] Two copper cen-
ters that are involved in the Huisgen cycloaddition resulted
in accelerated cycloaddition, especially in the pre-equilibri-
um step prior to the formation of the in-cycle copper(I)–
Scheme 6. AFP 1a promoted copper-catalyzed Huisgen reaction of vari-
ous azides and alkynes to triazoles.
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Copper-Catalyzed Huisgen and Huisgen-Oxidative Coupling Reactions
FULL PAPER
acetylide. Direct evidence for the existence of the mononu-
clear or binuclear CuI–triazole complex or intermediate was
also provided by Straub et al. in 2007.[15] Consistent with
prior experimental and mechanistic results by other
groups,[13–15] the origin of this difference in the chemoselec-
tivity between the two ligands can be rationalizes as follows
(Schemes 7 and 8).
tion by slow deprotonation of the alkyne prior to the inter-
action between the azide and the copper(I)–acetylide. Con-
sequently, the following [3+2] cycloaddition was observed as
another kinetically significant steps to the desired triazole,[16]
and a copper triazolide complex would be stabilized and dis-
persed by the secondary amine-functional polysiloxane 1b
by two-coordination to yield a mononuclear polysiloxane@-
copper complex Vb that could led to the formation of a bis-
triazole–copper complex VIIb through transmetalation and
oxidative addition. Then the intermediate VIIb subsequently
gives the bistriazole through reductive elimination and re-
generates the active copper catalyst (Scheme 8). As also
shown in Figure 1, in comparison to the Huisgen [3+2] cy-
cloaddition, the domino oxidative Huisgen coupling process
occurred slowly and the reaction involving [D]phenylacety-
lene sustained a longer induction period, indicating that the
rate-determining step of the oxidative coupling to generate
the triazole–CuI–acetylide intermediate VIb and the bistria-
zole–CuI intermediate VIIb through deprotonation of the
terminal alkyne and oxidative addition, respectively.
Scheme 7. Proposed mechanistic steps in the polysiloxane-supported
copper-catalyzed Huisgen reaction of azides and alkynes promoted by di-
amine 1a.
Conclusion
In summary, we have demonstrated an interesting example
of a divergent catalysis[17] with a copper(I) catalyst control-
led by amine-functional macromolecular polysiloxanes. We
successfully demonstrated the remarkable ability of the sec-
ondary amine-functional polysiloxane 1b to induce oxidative
coupling in the copper-mediated Huisgen reactions of gener-
al azides and alkynes by achieving good yields and selectivi-
ties. The reactions described here allow the preparation of
novel heterocyclic compounds, that is, bistriazoles. Compa-
rably, it is also surprising that the use of the diamine-func-
tional polysiloxane 1a as ligand led to a classic Huisgen
[3+2] cycloaddition in excellent yields. From the results of
the present amine-functional polysiloxanes-controlled Huis-
gen reaction or oxidative Huisgen coupling reaction to di-
vergent products and the proposed mechanism, we suggest-
ed that the mononuclear bistriazole–copper complex, stabi-
lized and dispersed by the secondary amine-functional poly-
siloxane, was beneficial to prevalent the way to oxidative
coupling. This contrasts with the diamine-functional polysi-
loxane for which proposed binuclear CuI complexes exist
predominantly. Although the mechanism is unclear at pres-
ent, we believed that it should be possible to open up a
simple and flexible entry to the synthesis of pharmaceutical
useful triazole or bistriazole products with environmentally
benign polysiloxane-based amine ligands and provide a
foundation for the enantioselective oxidative coupling of tri-
azoles with chiral amine-functional polysiloxanes. Further
investigations are ongoing to clarify the true mechanism of
the oxidative Huisgen coupling and the effect of the polysi-
loxane and the amine moiety on the oxidative coupling reac-
tion.
Scheme 8. Proposed mechanistic steps in the polysiloxane-supported
copper-catalyzed oxidative Huisgen coupling reaction of azides and al-
kynes promoted by the secondary amine 1b.
For the copper-mediated click addition assisted by the di-
amine-functional polysiloxane 1a, we believed that the exis-
tence of diamine–CuI complexes with multi-coordination led
to well-accepted mechanistic significance of copper(I)–ace-
tylide, and the diamine accelerated the transmetalation of
intermediate Va (Scheme 7). In the case of the secondary
amine-functional polysiloxane 1b, we assumed that a stable
mononuclear CuI complex with linear two-coordination was
formed directly from CuCl involving the single nitrogen
ligand 1b and then induced the copper(I)–acetylide forma-
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L.-W. Xu et al.
Pꢂrez, D. O. Jimꢂnez, G. Lopez-Valdez, D. Corona, E. Cuevas-
YaÇez, Tetrahedron Lett. 2011, 52, 3514–3517; c) M. Kwon, Y. Jang,
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Acknowledgements
This Project was supported by the National Natural Science Founder of
China (No. 20973051 and 21173064), the Zhejiang Provincial Natural Sci-
ence Foundation of China (Q12B020037), the Qianjiang talent project of
Zhejiang Province of China (No. 2010R0017), and the Program for Ex-
cellent Young Teachers in Hangzhou Normal University (HNUEYT,
JTAS 2011-01-014) is appreciated. X.L.W thanks Dr. Li Li (Hangzhou
Normal University) for her helpful suggestions.
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À
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polysiloxanes; please see the Supporting Information. The amine-
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lysts in several organic transformations.
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Received: July 11, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Copper-Catalyzed Huisgen and Huisgen-Oxidative Coupling Reactions
FULL PAPER
Click Chemistry
Z.-J. Zheng, F. Ye, L.-S. Zheng,
K.-F. Yang, G.-Q. Lai,
L.-W. Xu* ..................... &&&& — &&&&
Copper-Catalyzed Huisgen and Oxida-
tive Huisgen Coupling Reactions
Controlled by Polysiloxane-Supported
Amines (AFPs) for the Divergent
Synthesis of Triazoles and Bistriazoles
Click, click, hurray: The remarkable
ability of the secondary amine-func-
tional polysiloxane 1b to induce oxida-
tive coupling in the copper-mediated
Huisgen reaction of general azides and
alkynes, thereby achieving good yields
and selectivities, is successfully demon-
strated, whereas the use of the dia-
mine-functional polysiloxane 1a led to
the classic Huisgen [3+2] cycloaddition
in excellent yields (see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!