General Cycloaddition between a Trimethylsilyl-Capped Alkyne and an Azide Catalyzed by an N-Heterocyclic Carbene-Copper Complex and Pyridine-Biscarboxamide

Article abstract of DOI:10.1002/adsc.201501171

With an externally provided catalytic amide facilitator and an N-heterocyclic carbene-copper (NHC-Cu) complex, the cycloaddition of an azide and a trimethylsilyl (TMS)-capped alkyne can proceed smoothly. This protocol can be applied to a variety of TMS-capped substrates, with electron-rich alkynes generally giving higher yields and nitroaromatic alkynes giving lower yields. For special applications of this protocol, a substrate containing both a terminal alkyne and a TMS-capped alkyne can sequentially react with different azides without isolation of intermediates; and a macrocyclic product can also be formed efficiently without the complication of polymer formation.

Full text of DOI:10.1002/adsc.201501171

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DOI: 10.1002/adsc.201501171
General Cycloaddition Between a Trimethylsilyl-Capped Alkyne
and an Azide Catalyzed by an N-Heterocyclic Carbene-Copper
Complex and Pyridine-Biscarboxamide
a
a,
Haochen Xu and Zhihua Sun *
a
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road,
Shanghai 201620, Peopleꢀs Republic of China
Fax: (+86)-21-6779-1432; phone: (+86)-21-6779-1432; e-mail: sungaris@gmail.com
Received: December 29, 2015; Revised: March 23, 2016; Published online: April 25, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501171.
Abstract: With an externally provided catalytic
amide facilitator and an N-heterocyclic carbene-
copper (NHC-Cu) complex, the cycloaddition of an
azide and a trimethylsilyl (TMS)-capped alkyne can
proceed smoothly. This protocol can be applied to
a variety of TMS-capped substrates, with electron-
rich alkynes generally giving higher yields and ni-
troaromatic alkynes giving lower yields. For special
applications of this protocol, a substrate containing
both a terminal alkyne and a TMS-capped alkyne
can sequentially react with different azides without
isolation of intermediates; and a macrocyclic prod-
uct can also be formed efficiently without the com-
plication of polymer formation.
Keywords: catalysis; click chemistry; copper;
CuAAC; cycloaddition; N-heterocyclic carbenes
Scheme 1. Copper-catalyzed cycloaddition reactions of
azides and TMS-capped alkynes.
[
1]
“
Click chemistry”, a copper-catalyzed 1,3-dipolar cy-
cloaddition reaction between an azide and a terminal
alkyne (CuAAC), has extensive applications in medic-
[
2]
[3]
inal chemistry, materials science, and chemical conducted with TMS-capped alkynes when there is
[
4]
biology due to the mild reaction conditions and ex- a nearby amide group that facilitates simultaneous re-
cellent reaction specificity. In recent years, significant moval of the TMS group during the cycloaddition
progress has been made in many aspects of CuAAC process [Eq. (3) in Scheme 1]. However, the re-
methodology to meet demands from diverse applica- quirement of an amide moiety in the reaction sub-
tions. For example, N-heterocyclic carbene (NHC) strate severely limits the utility of this transformation.
copper complexes were used as highly efficient cata- Therefore, in this report, we investigate CuAAC for
lysts for the reaction. In order to efficiently form TMS-capped alkynes where the amide facilitator is
macrocylic cycloaddition products, copper-catalyzed provided externally as a catalyst so that the reaction
azide iodoalkyne cycloaddition (CuAiAC) was devel- can be generally applicable to a wide range of TMS-
[8]
[
5]
[
6]
oped [Eq. (1) in Scheme 1]. Direct CuAAC of capped substrates [Eq. (4) in Scheme 1].
TMS-capped alkyne was reported using CuBr, but the
We began our investigation by screening several
reaction was limited to the highly reactive benzyl amide facilitators and NHC-Cu complexes (Figure 1).
[
7]
azide [Eq. (2) in Scheme 1]. We previously showed The screening uses TMS-capped phenylethyne and n-
that an NHC-Cu complex-catalyzed CuAAC can be octyl azide as the substrates and was performed in 1:1
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Figure 1. Structures of amide facilitators (L) and NHC-Cu complexes used in this work.
DMF: H O at 608C for 12 h. The choices of solvents, phenyl ring with electron-withdrawing groups (Cl or
2
reaction temperature, and time were based on some CN, entries 6–11 in Table 2) could be well tolerated as
preliminary studies (data not shown) covering a varie- well as a pyridylalkyne (entry 15), but with NO -sub-
2
ty of mixed solvent systems (H O mixed with toluene, stituted phenylalkynes the yields dropped to <50%
2
THF, n-BuOH, CH CN, DMF, or acetone), a tempera- (entries 12–14). On the azide substrate side, the alkyl
3
ture range from room temperature to 908C and azides (n-octyl or benzyl) always performed better
a time range from 2–24 h.
than the phenyl azide. This trend holds for TMS-
The amide facilitators cover simple alkyl amides, capped alkylalkyne (entries 16–18 in Table 2), which
phenyl bis-carboxamides, as well as pyridine mono- performed similarly as phenyl- or Cl-phenylalkynes.
and bis-carboxamides specially chosen to allow poten- From the 18 results in Table 2, we can conclude that
tial coordination with the catalytic copper center so our new CuAAC protocol using an external amide fa-
that one amide group can get close to the TMS group cilitator and an NHC-Cu complex can be generally
during the cycloaddition. Both the amide facilitator
and the NHC-Cu (preformed in DMF with CuCl,
Table 1. Screening of amide facilitators and NHC-Cu com-
plexes.
NaOBu-t, and the corresponding NHC precursors in
[
9]
their imidazolium forms ) were used in catalytic
amounts (0.1 equiv,). As shown in Table 1, CuCl
alone or an NHC-Cu complex is not efficient to cata-
lyze the desired reaction (entries 1 and 2 in Table 1).
CuCl and the amide facilitator combinations (en-
tries 3–7 in Table 1) can produce some desired prod-
uct but the best combination (with L-d) still only gave
2
8% isolated yield. The combinations of NHC-Cu
and L-d are consistently better performers (entries 8–
2 in Table 1), and the best result was achieved with
NHC-Cu-e (entry 12, 89%). For comparison, using
Entry Catalyst
Isolated yield
[%]
1
1
2
3
4
5
6
7
8
9
1
1
1
1
CuCl
NHC-Cu-e
CuCl+L-a
CuCl+L-b
CuCl+L-c
CuCl+L-d
CuCl+L-e
L-d+NHC-Cu-a
L-d+NHC-Cu-b
L-d+NHC-Cu-c
L-d+NHC-Cu-d
L-d+NHC-Cu-e
trace
5
trace
trace
5
28
8
32
30
[7]
the previously reported CuBr catalytic procedure,
only 23% yield was achieved for this model reaction
(
entry 13).
Using the best catalyst combination (L-d and NHC-
Cu-e), we studied the substrate scope of this pyridine
biscarboxamide and NHC-Cu promoted CuAAC pro-
tocol. The results are summarized in Table 2.
As shown in Table 2, for aromatic alkynes, phenyl-
ethynes with no substitution or with an electron-do-
nating substitution on the phenyl ring (CH O) gave
the best results with generally over 70% isolated
yields (entries 1–5 in Table 2). Substitution on the
0
1
2
3
36
42
89
3
CuBr (15%), Et N (1 equiv.), 1008C 23%
3
in DMF
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Table 2. Substrate scope of azide and TMS-capped alkyne cycloaddition.
1
2
[b]
Entry
R
R
Product
3b
Isolated yield
Yield using the reported CuBr procedure
[
a]
[c]
1
2
3
4
88%
78%
91%
76%
90% (94/97%)
3c
28%
3d
3e
5
3f
90%
6
7
3g
3h
82%
59%
6%
8%
8
9
3i
83%
75%
68%
76%
35%
22%
36%
3j
not detected
not detected
not detected
1
1
1
1
0
1
2
3
3k
3l
3m
3n
1
1
1
1
4
5
6
7
3o
3p
3q
3r
49%
75%
83%
58%
[
a]
[c]
55% (76/86%)
not detected
not detected
1
8
3s
73%
[
[
[
a]
Reaction conducted at room temperature.
b]
[7]
Reaction conducted using the reported procedure with CuBr as the catalyst.
c]
[7]
Yield as reported in the original paper.
applicable to a variety of TMS-capped alkynes with- ative to the TMS group. For comparison, yields for se-
out the restriction of earlier examples that require an lected reactions using the CuBr procedure are also in-
amide group in the substrate at a suitable position rel- cluded in the last column of Table 2. The entry 1 of
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Scheme 2. Sequential CuAAC with a substrate containing
both a terminal alkyne and a TMS-capped alkyne without
isolation of intermediates.
Scheme 3. Synthesis of a macrocycle using an azido TMS-
capped alkyne substrate.
Table 2 showed that the CuBr procedure can produce
a high yield at 1008C (90% in our hand vs. the report-
ed 94/97% using different solvent systems), but our lytic Cu center; and (ii) the presence of bis-carboxa-
new procedure can achieve 88% at room temperature mide can ensure that at least one amide group is close
for the highly reactive benzyl azide. A similar result is to the TMS during cycloaddition. At this stage, it is
achieved for entry 16 with the highly reactive benzyl not very clear why L-d is better than L-e. Neverthe-
azide. Overall, considering results for entries 1, 2, 6– less, we propose the following mechanism for the
11, and 16–18, our NHC-Cu plus amide facilitator CuAAC of TMS-capped alkyne (Figure 2).
procedure is much more suitable to a wide range of In summary, we have shown that CuAAC can be
substrates than the high temperature CuBr procedure. smoothly performed between an azide and a TMS-
We next turned our attention to special applications capped alkyne using catalytic amounts of an NHC-Cu
of our new CuAAC protocol. One application is that complex and an amide facilitator (such as a pyridine
if a reaction substrate contains both a TMS-capped biscarboxamide). The reaction protocol is generally
alkyne and a terminal alkyne, one should be able to compatible to a large number of substrate variants.
sequentially direct the cycloaddition with azides in Special applications of this protocol include sequen-
the absence and presence of an amide facilitator. We tial direction of CuAAC on a terminal alkyne and
demonstrate this utility in the reaction shown in a TMS-capped alkyne; and the synthesis of a macrocy-
Scheme 2. Compound 4 was first treated with phenyl cle bridged by a triazole ring to avoid polymerization
azide in the presence of NHC-Cu-e to form a triazole
with its terminal alkyne. Without intermediate isola-
tion, to the reaction mixture was further added the
amide facilitator L-d and benzyl azide to form the
second triazole ring to give product 5 in 86% overall
isolated yield. This process is clearly advantageous in
that no deprotection step or intermediate isolation is
necessary.
Another application of our new protocol is the syn-
thesis of large macrocycles bridged by a triazole ring
formed through CuAAC. Based on our previous
[
8]
study, CuAAC with TMS-capped alkyne is less
prone to polymerization when an azide group is pres-
ent in the same substrate. To demonstrate this utility,
we compared the cyclization reactions of two sub-
strates. As shown in Scheme 3, the azido terminal
alkyne substrate 6a gave a polymer product with
NHC-Cu catalysis, and no desired macrocyclic prod-
uct 7 was isolatable. In contrast, the azido TMS-
capped alkyne 6b gave the desired macrocyclic prod-
uct 7 in 78% isolated yield.
Based on the efficiencies of different amide facilita-
tors (see Table 1), we believe that L-d is superior to
others due to two factors: (i) the pyridine moiety and Figure 2. Proposed mechanism for CuAAC of TMS-capped
the carboxamides can help coordinate with the cata- alkynes catalyzed by NHC-Cu and pyridine biscarboxamide.
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with uncapped terminal alkyne substrates. Our new
procedure should complement existing CuAAC pro-
tocols in organic synthesis.
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General Procedure for the Synthesis of 3a–3s
NHC-e precusor (0.058 mmol) and potassium tert-butoxide
(0.058 mmol) were stirred in DMF (2 mL) in a reaction
vessel. After 0.5 h, a mixture of azide (0.58 mmol), TMS-
capped alkyne (0.58 mmol), CuCl (0.058 mmol), pyridine-
2
,6-dicarboxamide (0.058 mmol) and water (2 mL) was
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added. The mixture was stirred at 608C for 12 h. After the
completion of the reaction, the mixture was quenched by
30 mL water and then was extracted with ethyl acetate. The
combined organic layer was loaded on a silica gel column
and eluted with 10–20% ethyl acetate in hexane to afford
the desired product 3a–3s.
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Acknowledgements
The authors thank Dr Erkang Fan at the University of Wash-
ington and Dr Bing Wang at Fudan University for helpful
discussions and are grateful for financial support from
Shanghai Municipal Education Commission (No.14ZZ159).
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