Oximinoalkylamines as ligands for Cu-assisted azide-acetylene cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2015.09.106

Oximinoalkylamines were found to be efficient ligands for acceleration of the CuAAC reaction. 'Mixed' oxime-triazole ligands Tz^βOx₂ and Tz₂^βOx demonstrate an approximately 10-fold enhanced acceleration effect co

Full text of DOI:10.1016/j.tetlet.2015.09.106

Accepted Manuscript
Oximinoalkylamines as ligands for Cu-assisted azide-acetylene cycloaddition
Artem N. Semakin, Daniil P. Agababyan, Sohee Kim, Sangyoon Lee, Alexey
Yu. Sukhorukov, Ksenia G. Fedina, Jinho Oh, Sema L. Ioffe
PII:
S0040-4039(15)30148-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.106
TETL 46778
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 July 2015
11 September 2015
24 September 2015
Please cite this article as: Semakin, A.N., Agababyan, D.P., Kim, S., Lee, S., Sukhorukov, A.Y., Fedina, K.G., Oh,
J., Ioffe, S.L., Oximinoalkylamines as ligands for Cu-assisted azide-acetylene cycloaddition, Tetrahedron Letters
(
2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.106
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Graphical Abstract
Oximinoalkylamines as ligands for
Cu-assisted azide-acetylene cycloaddition
Artem N. Semakin, Daniil P. Agababyan, Sohee Kim, Sangyoon Lee, Alexey Yu. Sukhorukov, Ksenia G.
Fedina, Jinho Oh and Sema L. Ioffe
100
80
60
40
20
0

1
Tetrahedron Letters
Oximinoalkylamines as ligands for Cu-assisted azide-acetylene cycloaddition
a,b,
b
c
c
a,
Artem N. Semakinb
, Daniil P. Agababyan , Sohee Kim , Sangyoon Lee , Alexey Yu. Sukhorukov ,
c
a,b
Ksenia G. Fedina , Jinho Oh and Sema L. Ioffe
a
N.D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991, Moscow, Russia
Moscow Chemical Lyceum 1303, Tamozhenniy proezd, 4, 111033, Moscow, Russia
Korea Science Academy of KAIST, 105-47, Baegyanggwanmun-ro, Busanjin-gu, 614-822, Busan, Rep. of Korea
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Oximinoalkylamines were found to be efficient ligands for acceleration of the CuAAC
reaction. “Mixed” oxime-triazole ligands Tz Ox and Tz Ox demonstrate an approximately
2 2


Received in revised form
Accepted
Available online
10-fold enhanced acceleration effect compared to commonly employed ligand TBTA using 0.1
mol% of the [Cu]/L catalytic system. The optimal catalytic system based on readily available

Tz Ox
2
provided 1,4-disubstituted triazoles in high yields with short reaction times.
2
015 Elsevier Ltd. All rights reserved.
Keywords:
CuAAC
click-chemistry
ligands
poly(oximinoalkyl)amines
3
d
3d
The copper-assisted azide-acetylene cycloaddition (CuAAC)
reaction which was discovered about a decade ago represents the
BimPy
2
Scheme 1). Furthermore, Finn and co-workers,
1
recently reported that hybrid tripodal ligands bearing
combinations of different heterocyclic imine fragments
demonstrated much greater activity in comparison to symmetrical
analogs. Such synergy (“mixed ligand approach”) may result
from participation of two different copper atoms in the catalytic
cycle, one of which is involved in acetylide formation, while the
most efficient realization of the click chemistry concept. In recent
years, CuAAC has become an indispensable tool in organic
synthesis, drug discovery, bioconjugation, the design of materials
and supramolecular structures, as well as in many other areas of
2
research.
4
other one activates triple bond by -coordination.
In most cases the use of ligand is crucial for successful
3,4
accomplishment of the CuAAC reaction (Scheme 1). The role
of the ligand in such processes may consist of stabilization of
These publications indicate that the nature of the imine
fragments and their combination in ligands allow tuning of the
ligand properties and rate-acceleration activity for certain tasks.
However, the range of imine-based fragments studied to date in
the CuAAC reaction have been limited to nitrogen-containing
heterocycles such as triazoles, imidazoles, benzimidazoles and
2a,3
copper(I) ions from oxidation and disproportionation, as well
as reaction acceleration (due to formation of soluble copper
acetylide species and pre-organization of the alkyne and azide on
2a,3a
ligated copper complexes),
suppressing side reactions
3
(
dimerization of alkynes and coupling of the copper-triazolyl
pyridines. Acyclic imino-groups have remained out of the focus
of researchers, presumably due to their hydrolytic lability.
4a
5
intermediate with the alkyne), and preventing denaturation of
3l,4a
natural macromolecules in bioconjugation processes.
Many types of CuAAC-accelerating ligands featuring
different coordination, steric and physical properties have been
3
introduced in recent years. The most widely-applied catalytic
3
a
systems for CuAAC are based on polyaza ligands (Scheme 1).
2
Previous studies have revealed that ligands containing donor sp
3
and sp nitrogen atoms incorporated on a tripodal matrix exhibit
exceptional rate-accelerating activity in CuAAC. Noteworthy
3a-e
examples include the widely applied TBTA system introduced
3b
by Sharpless and Fokin and one of the most active ligands
—
——


Corresponding author. Tel.: +7-495-362-3440; fax: +7-499-135-5328; e-mail: artyomsemakin@mail.ru
Corresponding author. Tel.: +7-499-135-5329; fax: +7-499-135-5328; e-mail: sukhorukov@ioc.ac.ru

2
Tetrahedron
Table 1
Oxime and mixed oxime-heterocycle ligands in the model
CuAAC reaction
Ligand
Structure
no ligand
Conversion
Entry
1
a
Name
(%)
13
TBTA
2
>99
3
(Tz )
3
DMG
PAO
18
Scheme 1. Ligand-accelerated CuAAC reaction.
4
5
45
32
On the contrary, the oxime-group, which is stable under a
6
wide range of conditions, appears to be a prospective binding

BnH Ox
motif for the design of new ligands for CuAAC. Oximes are
well-known to form complexes with copper(I) and (II) as well
7
other d-block metals and such complexes have been widely

8
6
7
Bn Ox
38
58
2
applied in catalytic systems for cross-coupling reactions. The
oxime group possesses various opportunities to tune its
electronic, steric and hydro-lipophilic properties by the
introduction of substituents at the carbon and oxygen atoms as
well as by deprotonation of the OH-group under basic

BnH Ox
6,7a
conditions. Furthermore, the ability of the NOH group to form
6,7a
hydrogen bonds
may contribute to coordination of the

8
9
H Ox
2
54
83
substrate by an oxime-ligated acetylide in bioconjugation
9
processes. However, to the best of our knowledge, application of
copper-oxime complexes or any copper salt/oxime catalytic
systems to the CuAAC reaction has not been described.

Et Ox
2
In the present report we demonstrate that the oxime group,
either alone or in combination with nitrogen heterocycles, may
serve as a binding fragment for the design of highly active rate-
accelerating ligands for use in the CuAAC reaction.

10
Bn Ox
2
93
The effect of the oxime ligand on conversion was initially
studied in a model [3+2]-cycloaddition reaction between benzyl
azide and phenylacetylene in aqueous methanol employing 1
4
mol% of CuSO with 4 mol% of sodium ascorbate as the
reducing agent (Cu(II)Cu(I)) (Table 1).

1
1
1
2
Ox
Ox
3
95
88
Widely applied oxime ligands such as dimethylglyoxime
(DMG) and pyridine-2-carbaldoxime (PAO) (Table 1, entries 3-
4
), as well as known mono-, bis-, tris-, tetra- and
10
hexa(oxyminoalkyl)amines (Table 1, entries 5-15) which were
readily available by oximinoalkylation of primary and secondary
amines and ammonia were selected. For a more comprehensive
study of the oxime-group effect “mixed” tripodal ligands


2
Ox
(tris(iminomethyl)amines) bearing one or two oximinoalkyl
groups in combination with pyridinylmethyl,
benzimidazolylmethyl or triazolylmethyl donor “arms” (Table 1,
entries 16-20) were also synthesized.

3

13
Ox
3
75
Even more promising results were obtained for “mixed”
tripodal ligands bearing, in addition to oxyminoalkyl fragments,


pyridinylmethyl (Py Ox
2
,
2
Py Ox), benzimidazolylmethyl



(
Bim Ox
2
) or triazolylmethyl (Tz Ox
2
, Tz
2
Ox) binding “arms”.
Like TBTA, in the presence of these ligands, full conversion of
benzyl azide was observed (Table 1, entries 16-20). Furthermore,


1
1
4
5
EDA Ox
4
73
83
Tz Ox demonstrated higher rate-acceleration than TBTA in the
2
kinetic experiment (for details see ESI).
For a more detailed comparison of the most active oxime-
based catalytic systems (Table 1, entries 10,11 and 16-20)
experiments were performed with shorter reaction periods and 10
times lower loading of the copper salt and ligand (Scheme 2, А).
Using 0.1 mol% of the [Cu]/TBTA catalytic system resulted in
only 13% conversion of benzyl azide after 2 h. Remarkably,

TREN Ox
6
under low catalyst loading conditions all studied oxime-based

ligands displayed higher catalytic activity than TBTA and Ox
3
β
β
(Scheme 2, A). In the cases of ligands Tz Ox
2
and Tz
2
Ox
almost full conversion (86% and 96%, respectively) was
achieved within 2 h (Scheme 2, A).

16
Py Ox
2
>99

1
1
1
7
8
9
Py
2
Ox
>99
>99
>99

Bim Ox
2

Tz Ox
2

2
20
Tz
Ox
>99
a
1
Determined by H NMR spectroscopy (in CDCl
standard after aqueous work-up of the reaction mixture.
3
) with an internal
In the absence of ligand the conversion of starting compounds
did not exceed 13% after 24 h (Table 1, entry 1), however
addition of 1 mol% of the reference ligand TBTA led to full
conversion (Table 1, entry 2). Dimethylglyoxime (DMG)
resulted in low conversion of the initial reagents (Table 1, entry
3), while with PAO only a moderate increase of conversion was
observed (Table 1, entry 4).
Scheme 2. Oxime-based ligands and TBTA in the model CuAAC
reaction. (A) Comparison of different ligands. Conditions: 0.1 mol% of
Remarkably, in the oximinoalkyamine series (Table 1, entries
β
β
2 2
[Cu]/L, 2 h, r.t. (B) Comparison of TBTA, Tz Ox and Tz Ox at different
5
-15), all studied ligands displayed significantly enhanced
catalytic activity under same reaction conditions with the best
results (conversion >90%) achieved using bis(-
oximinoalkyl)amine Bn Ox (Table 1, entry 10) and tris-oxime
(Table 1, entry 11). The presence of extra oxime groups
Table 1, entries 14, 15) as well as elongation of the
oximinoalkyl arms by one CH unit resulted in a slight decrease
of ligand activity (cf. entries 11-13).
[Cu]/L loadings (1 mol%, 0.1 mol%, 0.01 mol%), 24 h, r.t.

2

Additional comparative experiments confirmed that ligands
Ox
3
β
β
Tz Ox
2 2
and Tz Ox demonstrated better performance than
(
TBTA when employing both 0.1 mol% and 0.01 mol% of the
2
β
[
2
Cu]/L catalytic systems (Scheme 2, B). Ligand Tz Ox

4
Tetrahedron
a
a
a
a
maintained high activity in the model reaction even when 0.01
17
q
r
s
4-EtO C-C H
4
Ph
Ph
n-Bu
2
4
3
3
2
98
99
96
96
2
6
mol% of the [Cu]/L catalytic system was used.
18
4-NO -C H
2
6
4
In experiments using a higher concentration of benzyl azide (1
1
1
19
20
4-NO
2
-C
6
H
4
M) and 1.05 equivalents of phenylacetylene full conversion of
the azide was reached in less than 15 minutes for both ligands
Tz Ox and Tz Ox (1 mol% [Cu]/L).
2 2
t
4-NO -C H
4
CH OH
2
6
β
β
a
b
Product isolation procedures: crystallization from the reaction mixture;
c
Thus, replacement of one or two triazolyl fragments in TBTA
with oxime groups resulted in significant synergistic
enhancement of ligand activity in the CuAAC reaction.
column chromatography; aqueous work-up with ethyl acetate (for details,
see ESI).

Readily available ligand Tz Ox
2
was chosen for substrate
12
Notably, rapid conversions and high product yields were
achieved using stoichiometric amounts of azide and alkyne.
Thus, an excess of one of the reactants, typical for other CuAAC
scope studies, utilizing various azides and alkynes and
employing 1 mol% CuSO , 1 mol% Tz Ox and 4 mol% of
4 2

sodium ascorbate as the catalytic system (Table 2). Almost all
substrates provided nearly quantitative isolated yields of triazoles
catalytic systems was not needed, demonstrating the high

potential of Tz Ox
2
for large-scale ligand-accelerated CuAAC
1
with full conversion achieved in relatively short reaction
processes.
periods (typically, 2-4 h, Table 2).
In summary, the oxime group may be considered as an
efficient binding motif for the design of ligands to accelerate the
CuAAC reaction. A series of new highly active N3 and N4 type
ligands containing -oximinolalkyl arms were introduced.
Replacement of one or two triazolylmethyl “arms” of the
commonly employed ligand tris(benzyltriazolyl)amine (TBTA)
with oximinoalkyl fragments led to a synergistic enhancement of
activity in ligand-accelerated CuAAC reactions. The best
oximinoalkylamine ligands are easily available via a modular
Table 2

Substrate scope of CuAAC reaction employing Tz Ox
ligand
2
as the
10
approach.
Acknowledgments
This work was supported by Russian Science Foundation
(
Grant 14-50-00126).
Yield
1
2
Time
h)
Entry
1
R
R
(
%)
(
References and notes
a
1
2
3
4
5
6
a
b
c
d
e
f
Bn
Bn
Bn
Bn
Bn
Bn
Ph
3
2
4
4
2
2
99
97
97
94
99
97
1
.
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(CH ) OH
2 2
1
2
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b
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b
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0
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j
n-C H
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Ph
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2
3
2
96
99
95
7
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k
l
2 2
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a
a
a
a
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1
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1
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1
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98
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96
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n
o
p
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1
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6
4
Ph
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6
4
Ph

5
3
m
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8
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4
.
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4
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V.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12705–12712.
5
6
.
.
Few ligands containing imino-groups have been studied in
3
a,k
CuAAC.
(a) The Chemistry of Hydroxylamines, Oximes and Hydroxamic
Acids, Part 1; Rappoport, Z.; Liebman, J. F.; Eds.; Wiley
Interscience: Chichester, England, 2009. (b) Kalia, J; Raines, R. T.
Angew. Chem. Int. Ed. 2008, 47, 7523–7526.
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7
8
.
.
2
5, 134–194; b) Kukushkin, V. Yu. Pombeiro, A. J. L. Coord.
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Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer, M. Org. Lett.
11. These conditions are commonly employed in the CuAAC reaction
3
i,n
with other ligands (for example, see refs. ).

2
12. Although ligand Tz Ox displayed a slightly higher accelerating
effect in the model CuAAC reaction (Scheme 2), it is less
synthetically available since expensive dipropargylamine is used
as a starting material. Furthermore, due to its hydrophilicity ligand
2
004, 6, 913–916. (c) Alonso, D. A.; Nájera, C.; Pacheco, M. C.

Org. Lett. 2000, 2, 1823–1826.
Tz Ox2 can be easily removed together with copper salts from
9
.
Being a strong hydrogen bond donor, the oxime group is
considered as a mimetic of the imidazole fragment of histidine, an
amino acid which is known to accelerate CuAAC reactions
hydrophobic products by aqueous extraction.