Iridium-Catalyzed Highly Regioselective Azide-Ynamide Cycloaddition to Access 5-Amido Fully Substituted 1,2,3-Triazoles under Mild, Air, Aqueous, and Bioorthogonal Conditions

Article abstract of DOI:10.1021/acs.orglett.7b03123

A highly regioselective method to access 5-amido fully substituted 1,2,3-triazoles by iridium-catalyzed azide-ynamide cycloaddition under mild, air, aqueous, and bioorthogonal conditions is reported. The excellent regioselectivities may derive from the strong coordination between the carbonyl oxygen of ynamide and the -acidic iridium. Since the iridium ion is insensitive to oxygen/water and exhibits low cytotoxicity, it could catalyze this reaction in both organic and biological environments efficiently. Preparation in gram-scale and application in carbohydrates highlight this method.

Full text of DOI:10.1021/acs.orglett.7b03123

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Iridium-Catalyzed Highly Regioselective Azide−Ynamide
Cycloaddition to Access 5‑Amido Fully Substituted 1,2,3-Triazoles
under Mild, Air, Aqueous, and Bioorthogonal Conditions
Wangze Song*,†,§ and Nan Zheng‡,§
†School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, P. R. China
‡School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, P. R. China
§State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, 116024, P. R. China
S
* Supporting Information
ABSTRACT: A highly regioselective method to access 5-
amido fully substituted 1,2,3-triazoles by iridium-catalyzed
azide−ynamide cycloaddition under mild, air, aqueous, and
bioorthogonal conditions is reported. The excellent regiose-
lectivities may derive from the strong coordination between
the carbonyl oxygen of ynamide and the π-acidic iridium. Since
the iridium ion is insensitive to oxygen/water and exhibits low
cytotoxicity, it could catalyze this reaction in both organic and
biological environments efficiently. Preparation in gram-scale
and application in carbohydrates highlight this method.
trisubstituted 1,2,3-triazoles, was first reported by Fokin and
Jia.10 However, for the synthesis of 5-amido fully substituted
1,2,3-triazoles, regiomers are occasionally obtained when alkyl
substituted internal ynamides are used as substrates (Scheme
5-Amido fully substituted 1,2,3-triazole, as the unique fully
substituted-1,2,3-triazole, is an important drug scaffold and has
diverse biological activities.1 It is the core structure of the heat
shock protein 90 (HSP90) inhibitor2a and the selective
lysophosphatidic acid receptor-1 (LPA1) anatagonist.2b How to
efficiently access it with high regioselectivity is a long-standing
problem. It seems that Huisgen 1,3-dipolar cycloaddition
between azides and internal alkynes is one of the most ideal
atom-efficient ways. However, low regioselectivities are acquired
by azide−alkyne cycloaddition (AAC) at high temperature
without any catalysts.3 The concept of “Click Chemistry” is
proposed due to the excellent performance of copper-catalyzed
AAC (CuAAC) reaction, which was independently developed by
theMeldal andSharpless groups in2001.4 However, theextended
application of CuAAC is often limited by several serious
drawbacks. First, the high cytotoxicity of copper ions and the
reductants (such as sodium ascorbate) are not biocompatible.5
Cu-free strain-promoted AAC (SPAAC) is an alternative to solve
the cytotoxicity issue, but the substrates for SPAAC are limited
and complicated.6 Second, it is still a challenge for the electron-
rich internal alkynes to accomplish CuAAC under mild and
bioorthogonal conditions. Ynamides,7 as the versatile electron-
rich internal alkynes, could react with azides by copper-catalyzed
cycloaddition. However, 4-amido-fully substituted triazoles are
afforded exclusively at high temperature (Scheme 1a).8
Haloalkynes are used to prepare 5-halo-1,2,3-triazoles, which
could be further derivatized to 5-amido fully substituted triazoles
afterhalogenexchange andtreatmentwithbase.9 Itisanadvanced
modification for CuAAC, but not an atom- or step-economic
strategy (Scheme 1a). Ruthenium, as a novel catalyst for the AAC
reaction to selectively prepare 1,5-disubstituted and 1,4,5-
1b).2a Recently, the Lop
́
ez and Mascarenas group reported Ru-
̃
catalyzed azide-thioalkyne cycloadditions in aqueous media.10d
The Hong group developed nickel-catalyzed AAC (NiAAC) to
regioselectively synthesize disubstituted 1,2,3-triazoles under air
and water.11a The Huang group disclosed a rhodium-catalyzed
AAC (RhAAC) to give 5-amino-substituted 1,2,3-trazoles
efficiently.11b Taran, Jia, Sun, and others reported iridium-
promoted azide−alkyne cycloaddition in organic solvents or
water.12 The development and application of various transition
metal catalysts in AAC reactions indicated that the metal-
catalyzed azide−alkyne cycloaddition (MAAC) has become
popular and is the focus of many chemists.13 Herein, we report a
highly regioselective method to access 5-amido fully substituted
1,2,3-triazoles by Ir-catalyzed azide−ynamide cycloaddition
under mild, air, aqueous, and bioorthogonal conditions (Scheme
1c). A much stronger coordination between ynamides and
iridium would lead to high regioselectivities for the AAC reaction.
Besides, thecytotoxicityofiridiumionismuchlowercomparedto
copper and ruthenium ions.14 Moreover, the catalytic activity of
iridium could be maintained and robust in various biological
media and air.
Substrate 1a was prepared according to Hsung’s method.15 We
first optimized the cycloaddition between 1a and 2a using
dichloromethane (DCM) as solvent at rt without inert gas
Received: October 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03123
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Organic Letters
Letter
regioselectivity (Table 1, entry 7). This Ir-catalyzed [3 + 2]
cycloaddition proceeded well in various polar and nonpolar
solvents, such as THF, toluene, EtOH, and MeCN, and especially
smoothly in water with high yields and regioselectivities (Table 1,
entries 8 and 9). The other conditions could be found in the
Supporting Information. Remarkably, this reaction could be
carried out under mild, air, and aqueous conditions, which paved
the way to investigate the application in bioorthogonal fields.
With the optimized conditions in hand, we explored the scope
of Ir-catalyzed azide−ynamide cycloaddition. Various cyclic and
acyclic ynamides were used as substrates at rt in organic solvent or
water without inert gas protection to afford 5-amido-fully
substituted 1,2,3-triazoles in good yields (up to 96%) and
excellent regioselectivities (more than 20:1) (Scheme 2). For
cyclic ynamides, the yield (3b) for an electron-donating aryl
substrate was slightly higher (96%) than the phenyl one (3a). But
theyieldof3cwithanelectron-withdrawing arylgroupreducedto
85%. If pyrrolidinone was used instead of oxazolidione, the yield
of 3d dropped to 86%. The introduction of bulky groups to the
Scheme 1. Synthesis of 5-Amido Fully Substituted 1,2,3-
Triazoles
Scheme 2. Substrate Scope of the Ir-Catalyzed Azide−
a
Ynamide Cycloaddition
protection (Table 1). The CuAAC failed to occur for the internal
alkyne 1a in the presence of CuI or CuSO4 (Table 1, entries 1 and
a
Table 1. Optimization of Reaction Conditions
yield (3a + 3a′)
b
b
entry
cat.
solv
DCM
[%]
3a/3a′
−
−
−
1
2
3
4
5
6
7
8
9
CuI
0
0
0
CuSO4
DCM
DCM
DCM
DCM
[Cp*RhCl2]2
[Rh(cod)Cl]2
[Cp*Ru(cod)Cl]
complex
85
−
4:1
4:1
1:0
1:0
1:0
[Cp*Ru(PPh3)2Cl] DCM
79
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
DCM
96
water
87
c
other solvent
>90
a
Conditions: 1a (1.0 equiv), 2a (1.5 equiv), solvent (0.1 M), catalyst
b
(2.5 mol %), at rt under air for 12 h. Determined by 1H NMR of the
crude mixture with an internal standard. Other solvents were
c
evaluated (including THF, toluene, EtOH, MeCN), all giving a high
yield. Cp* = pentamethylcyclopentadiene, cod = 1,5-cyclooctadiene.
2). Neither Rh(III) nor Rh(I) could generate any desired
cycloaddition product in this transformation (Table 1, entries 3
and 4). [Cp*Ru(cod)Cl] and [Cp*Ru(PPh3)2Cl] were reported
to catalyze the [3 + 2] reaction with excellent yields and
regioselectivities in RuAAC.10 However, only mediocre regiose-
lectivities were acquired for azide−ynamide cycloaddition (Table
1, entries 5and6). Itwasnotaregioselective reactionforRuas the
catalyst. [Ir(cod)Cl]2 was demonstrated to be the best catalyst for
this process due to the nearly quantitative yield and absolute
a
Conditions: 1 (1.0 equiv), 2 (1.5 equiv), and DCM or water (0.1 M)
were sequentially added to a vial containing the [Ir(cod)Cl]2 (2.5 mol
%) under air. The vial was closed, and the mixture was stirred at rt for
12 h. Regioselectivities (3/3′) were >20:1 unless otherwise noted
1
(determined by H NMR of the crude reaction mixture). Yield of
b
isolated product. The isolated yields of the reactions carried out in
water are shown in brackets.
B
DOI: 10.1021/acs.orglett.7b03123
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Organic Letters
Letter
adjacent position of ynamides notably led to the decrease of the
yield to 77% (3e, phenyl substituted) and 82% (3f, benzyl
substituted) respectively. The alkyl substituted internal alkyne
could be tolerated in this process in spite of the low yield (78%)
for 3g. For acylic ynamides, the reactions could also occur. The
yieldforthen-butylsubstituted internal alkynewas73% (3h), and
for the tert-butyl one it was 70% (3i). The absolute
regioselectivities were confirmed by 3d, 3e, and 3h (see
Supporting Information). We also evaluated different azides for
this cycloaddition. We were pleased to find that alkyl and aryl
azides as substrates could give desired products ingood yields and
excellent regioselectivities. The electronic effect was not obvious
for 3j and 3k. The yield decreased to 74% for 3l when aryl azide
wasusedasthesubstrate. Goodyields(3mand3n)wereobtained
for ethyl or butyl azides as substrates. When water was used
instead of organic solvent, a similar trend was observed (Scheme
2, brackets). The yields in water were not as high as in the case of
organic solvent due to the relatively poor solubility of some azides
and ynamides.
Scheme 4. Proposed Mechanism for Ir-Catalyzed Azide−
Ynamide Cycloaddition
Subsequently, the applicability of this reaction was examined.
We scaled up the reaction to the gram scale. Treatment with 1a
(6.0 mmol, 1.12 g) under the standard conditions afforded 3a in
88% yield (5.28 mmol, 1.69 g) after column chromatography
(Scheme 3a). This highly efficient cycloaddition could be further
Scheme 3. Application of Ir-Catalyzed Azide−Ynamide
Cycloaddition
coordinated site at the other moiety of ynamide. 4-Amido fully
substituted 1,2,3-triazoles are therefore not observed. Then
reductive eliminationofintermediate Bgenerates intermediateC.
The final products, 5-amido fully substituted 1,2,3-triazoles, are
formed from intermediate C.
The low cytotoxicity of the iridium ion encouraged us to
investigate the bioorthogonality of this cycloaddition under
various biological conditions, which mimicked in vitro and in vivo
environments (Table 2). Phosphate-buffered saline (PBS) with
varying pH were tested first. The cycloaddition could occur
efficiently with high regioselectivities in PBS with the pH ranging
from an acidic value (5.7) to a basic one (8.0), which represented
the typical in vitro and in vivo environments (Table 2, entries 2−
4). DMEM and cell lysates were frequently used as in vitro
extended to the synthesis of non-natural carbohydrates using
glycosyl azide and ynamide as substrates. The functionalization of
carbohydrates is crucial in glycomics study. This method could
potentially be applied in bioconjugation to reveal delicate
biological processes (Scheme 3b).
a
Table 2. Exploration of the Bioorthogonality of the Reaction
The Ir-catalyzed azide−ynamide cycloaddition could result in
excellent regioselectivities under mild, air, and aqueous
conditions. To further understand the Ir-catalyzed process, we
performed a mechanistic study. According to a previous report,
tosyl ynamide 1p could not achieve the cycloaddition.12a But in
our study, when the tosyl ynamide was replaced by carbonyl
ynamide, highly regioselective products were obtained. When an
extra carbon was introduced between the alkyne and amide, the
reaction failed to occur for 1q, which disclosed the position of the
amide connected with the alkyne was crucial for this cyclo-
addition. The electronic difference between 1a and 1q may be
another factor for this Ir-catalyzed cycloaddition (Scheme 4a).
Basedontheabove-mentionedexperiments, themechanismofIr-
catalyzed azide−ynamide cycloaddition is proposed in Scheme
4b. Thecycloaddition isinitiated bythecombination ofπ-acidicIr
with ynamide and azide to give intermediate A. The azide
coordinates with Ir by the internal N atom in intermediate A.16
We hypothesize the coordination of carbonyl oxygen with Ir in
intermediate B leads to the high regioselectivities.17 There is no
b
entry
conditions
yield (3a) [%]
3a/3a′
1
2
3
4
5
6
7
8
water
87
89
84
83
85
90
85
86
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
PBS (pH = 5.7)
PBS (pH = 7.4)
PBS (pH = 8.0)
cell cultured media (DMEM)
cell lysates (UM-1)
50% normal mouse serum
100% lung cancer patient serum
a
Conditions: 1a (1.0 equiv), 2a (1.5 equiv), [Ir(cod)Cl]2 (2.5 mol %),
biological media (0.1 M); the mixture was stirred at rt for 12 h in air.
b
Determined by 1H NMR of the crude reaction mixture with an
internal standard.
C
DOI: 10.1021/acs.orglett.7b03123
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Organic Letters
Letter
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conversion. The desired triazoles were afforded in good yields
and excellent regioselectivities, indicating that the reaction could
be carried out under both extra- and intracellular environments
(Table 2, entries 5, 6). Serum was most commonly used to mimic
the blood to provide an in vivo biological condition. Expectedly,
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serum and 100% lung cancer patient serum (Table 2, entries 7, 8).
The excellent yields and regioselectivities of the Ir-catalyzed
cycloaddition under various bioorthogonal conditions exhibited
significant potential for further applications.
In summary, we have developed iridium-catalyzed azide−
ynamide cycloaddition for the synthesis of 5-amido-fully
substituted 1,2,3-triazoles under mild, air, aqueous, and
bioorthogonal conditions. This strategy shows broad substrate
scope, high yields, and excellent regioselectivities. It switches the
intrinsic regioselectivities for CuAAC and improves the initial
regioselectivities for RuAAC to afford 5-amido fully substituted
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and insensitive to oxygen/water, determining its biocompatibility
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* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03123.
Detailed experimental procedures and characterization of
new compounds (1H NMR, 13C NMR, HRMS) (PDF)
14726. (d) Destito, P.; Couceiro, J. R.; Faustino, H.; Lop
́
ez, F.;
AUTHOR INFORMATION
Mascarenas, J. L. Angew. Chem., Int. Ed. 2017, 56, 10766.
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Choi, B.; Cal, P. M. S. D.; Kang, S.; Kee, J.-M.; Bernardes, G. J. L.; Rohde,
J.-U.; Choe, W.; Hong, S. Y. J. Am. Chem. Soc. 2017, 139, 12121. (b) Liao,
Y.; Lu, Q.; Chen, G.; Yu, Y.; Li, C.; Huang, X. ACS Catal. 2017, 7, 7529.
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(b) Luo, Q.; Jia, G.; Sun, J.; Lin, Z. J. Org. Chem. 2014, 79, 11970.
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Corresponding Author
*E-mail: wzsong@dlut.edu.cn.
ORCID
Wangze Song: 0000-0003-1012-4456
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the Fundamental
Research Funds for the Central Universities (No. DUT16RC(3)
070), China Postdoctoral Science Foundation (No.
2017M611216), and National Natural Science Foundation of
China (Nos. 21702025, 51703018). We thank Prof. Qing Wang,
Prof. Yong Luo, and Prof. Gray Guishan Xiao inDalian University
of Technology for generously providing biological samples.
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