Nickel-Catalyzed Azide-Alkyne Cycloaddition to Access 1,5-Disubstituted 1,2,3-Triazoles in Air and Water

Article abstract of DOI:10.1021/jacs.7b06338

Transition-metal-catalyzed or metal-free azide-alkyne cycloadditions are methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Although the copper-catalyzed cycloaddition to access 1,4-disubstituted products has been applied to biomolecular reaction systems, the azide-alkyne cycloaddition to access the complementary 1,5-regioisomers under aqueous and ambient conditions remains a challenge due to limited substrate scope or moisture-/air-sensitive catalysts. Herein, we report a method to access 1,5-disubstituted 1,2,3-triazoles using a Cp₂Ni/Xantphos catalytic system. The reaction proceeds both in water and organic solvents at room temperature. This protocol is simple and scalable with a broad substrate scope including both aliphatic and aromatic substrates. Moreover, triazoles attached with carbohydrates or amino acids are prepared via this cycloaddition.

Full text of DOI:10.1021/jacs.7b06338

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Communication
Nickel-Catalyzed Azide–Alkyne Cycloaddition to Access
1,5-Disubstituted 1,2,3-Triazoles in Air and Water
Woo Gyum Kim, Mi Eun Kang, Jae Bin Lee, Min Ho Jeon, Sungmin Lee,
Jungha Lee, Bongseo Choi, Pedro M. S. D. Cal, Sebyung Kang, Jung-Min Kee,
Gonçalo J.L. Bernardes, Jan-Uwe Rohde, Wonyoung Choe, and Sung You Hong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06338 • Publication Date (Web): 16 Aug 2017
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Nickel-Catalyzed Azide–Alkyne Cycloaddition to Access
1,5-Disubstituted 1,2,3-Triazoles in Air and Water
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Woo Gyum Kim,† Mi Eun Kang,† Jae Bin Lee,† Min Ho Jeon,† Sungmin Lee,‡ Jungha Lee,‡ Bongseo
Choi,§ Pedro M. S. D. Cal,∥ Sebyung Kang,§ Jung-Min Kee,‡ Gonçalo J. L. Bernardes,∥,# Jan-Uwe
Rohde,‡ Wonyoung Choe,‡ and Sung You Hong*,†
†School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil,
Ulsan 44919, Republic of Korea
‡Department of Chemistry, UNIST, 50 UNIST-gil, Ulsan 44919, Republic of Korea
§School of Life Sciences, UNIST, 50 UNIST-gil, Ulsan 44919, Republic of Korea
∥Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-
028, Lisboa, Portugal
#Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom
Supporting Information Placeholder
cologically important, the CuAAC reactions have flourished in
medicinal chemistry, materials science, and chemical biology.1,2,4
ABSTRACT: Transition-metal-catalyzed or metal-free azide–
alkyne cycloadditions are versatile and indispensable synthetic
methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Alt-
hough the copper-catalyzed cycloaddition to access 1,4-
disubstituted products has been successfully applied to bio-
molecular reaction systems, the azide–alkyne cycloaddition to
access the complementary 1,5-regioisomers under aqueous and
ambient conditions remains a formidable challenge due to limited
substrate scope or moisture-/air-sensitive catalysts. Herein, we
report a general synthetic method to access 1,5-disubstituted
1,2,3-triazoles using a Cp2Ni/Xantphos catalytic system. The
reaction proceeds both in water and organic solvents at room tem-
perature. This protocol is operationally simple and scalable with a
broad substrate scope including both aliphatic and aromatic sub-
strates. Moreover, triazoles attached with carbohydrates or amino
acids are readily prepared via this nickel-catalyzed azide–alkyne
cycloaddition.
Scheme 1. Synthesis of 1,5-Disubsituted 1,2,3-Triazoles
Switching the regiochemical outcome is one of the critical is-
sues in modular synthetic approaches involving carbon–
heteroatom bond-forming processes.1 It is particularly important
to impart a high level of regiocontrol to the Huisgen 1,3-dipolar
cycloaddition, which directly assembles two molecular bricks, an
organic azide and an alkyne, with ideal atom economy.1,2 The
thermal cycloaddition exhibits high activation barriers and poor
regioselectivity at elevated temperatures. Rapid and regioselective
formation of 1,4-disubstituted products has been accomplished by
the copper-catalyzed azide–alkyne cycloaddition (CuAAC), since
the first independent reports by the groups of Sharpless and
Meldal.3 The main features of this widely utilized click chemistry
include operational simplicity, mild conditions, a broad substrate
scope, bioorthogonality, favorable kinetics, and high yields. The
transformation proceeds not only in organic solvents, but also in
aqueous media at room temperature. As the 1,4-disubstituted
1,2,3-triazole scaffold is chemically stable, aromatic, and pharma-
Synthetic pathways complementary to the CuAAC have been
developed to access 1,5-disubstituted 1,2,3-triazoles. As illustrat-
ed in Scheme 1a, a metal acetylide reacts with an organic azide to
afford a 4-metalated triazole.5 Subsequent aqueous quenching can
lead to product formation.5a,5c,5d Kwok et al. introduced a metal-
free synthetic route to furnish 1,5-diaryl-1,2,3-triazoles (Scheme
1b).6 Fokin, Jia, and co-workers reported the ruthenium-catalyzed
azide–alkyne cycloaddition (RuAAC), obtaining a range of de-
sired products under inert atmosphere (Scheme 1c).7 However, the
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RuAAC reactions using [Cp*RuCl] complexes are typically sensi-
metallocene complexes were ineffective (entries 2–4; see the
tive to water and air, and proceed at elevated temperatures.8 These
conditions limit their application in biochemical research. Perti-
nent to these precedents, the development of convenient synthetic
methods compatible with aqueous and ambient conditions remains
a formidable challenge.9 Herein we report a general synthetic
strategy to access 1,5-disubstituted 1,2,3-triazoles by the nickel-
catalysis. Notably, functionalization of carbohydrates and amino
acids has been also accomplished via this newly developed nickel-
catalyzed azide–alkyne cycloaddition (NiAAC) in water at room
temperature.
Supporting Information, Tables S1 and S2). Yet, more sterically
demanding Cp-based complexes resulted in comparable or unsat-
isfactory results (Table S2). Replacement of Xantphos with other
P- or N-ligands caused diminished or no catalytic activity (Table
S3). The use of DPEphos as the ligand, which has a similar struc-
ture to Xantphos (Table 1, entry 6; see also Scheme 1), furnished
3aa in 76% yield. Geometrical constraints such as the rigidity of
the backbone and a wide bite angle may play a critical role in
determining the reactivity of the NiAAC.10 Among the mild bases
screened, Cs2CO3 was optimal (Supporting Information, Table
S4). The reaction was less effective when the precatalyst/ligand
loading was reduced (Table 1, entry 8). Elevated temperatures
(entries 9 and 10) lowered the reaction yield and regioselectivity,
presumably due to catalyst decomposition or the involvement of
the thermal pathway. A shortened reaction time (1.5 h) did not
significantly affect the yield (entry 11). The reaction proceeded
well in other solvents including DMF, DCM, and even water (en-
tries 12–14) with similar yields and regioselectivity. Intriguingly,
this NiAAC reaction is highly compatible with water as the sole
solvent and can be carried out under air at room temperature.
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Table 1. Optimization of Reaction Conditionsa
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yield [%]b
entry
change from above conditions
3aa
94
0
4aa
6
1
2
None
no Cp2Ni
Scheme 2. Substrate Scope of the NiAACa
0
3
NiCl2⋅6H2O (instead of Cp2Ni)
Cp2Ru (instead of Cp2Ni)
no Xantphos
0
0
4
0
0
5
0
0
6
DPEphos (instead of Xantphos)
no Cs2CO3
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Cp2Ni (5 mol%)/Xantphos (5 mol%)
75 °C
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100 °C
9
1.5 h
6
DMF (instead of toluene)
DCM (instead of toluene)
water (instead of toluene), 1.5 h
8
3
6
aReaction conditions: 1a (0.38 mmol), 2a (0.46 mmol, 1.2 equiv),
Cp2Ni (10 mol%), Xantphos (10 mol%), Cs2CO3 (1.0 equiv) in
b
toluene (2.0 mL) at rt under air for 12 h. Isolated yield. Bn, ben-
zyl; Cp, cyclopentadienyl.
We initiated our investigation of the NiAAC by treating two
simple substrates, benzyl azide 1a and phenyl acetylene 2a, with a
catalytic amount of nickel precatalyst at room temperature with-
out any efforts to exclude air and moisture (Table 1). All reagents
including precatalysts, ligands, and solvents were used as-
received from standard suppliers with no extra purification steps.
After extensive screening of precatalysts, ligands, and additives
(see the Supporting Information, Tables S1–S4), the reaction con-
ditions were optimized to achieve high yield and excellent regi-
oselectivity. Under the standard conditions, the desired 1,5-
disubstituted triazole 3aa was isolated in 94% yield with only 6%
of 4aa (entry 1). The regioisomers were readily separated by flash
column chromatography. In the absence of the nickelocene
(Cp2Ni) precatalyst or the bidentate Xantphos ligand, the 1,2,3-
triazole core was not formed (entries 2–5). Control experiments
showed that nickel precatalysts lacking the Cp ligands or other
aReaction conditions: 1 (0.38 mmol), 2 (0.46 mmol, 1.2 equiv),
Cp2Ni (10 mol%), Xantphos (10 mol%), Cs2CO3 (1.0 equiv) in
water (2.0 mL) at rt under air for 1.5 h. Isolated yields of 1,5-
products. b12 h.
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With the optimized conditions based on the Cp2Ni/Xantphos
To expand the repertoire of the NiAAC, this newly developed
click reaction was explored to include biomolecules such as car-
bohydrates and amino acids. In particular, glycoconjugates feature
unparalleled branched structures, compared with oligopeptides or
oligonucleotides, with diverse configurations and glycosidic link-
ages.4a,13 Their effective functionalization has been achieved by
producing non-natural glycoconjugates and amino acid deriva-
tives. Both O- and N-linked sugars were well-tolerated in this
NiAAC (3la–3oa). In addition, the cycloaddition reaction could
be scaled up to a 1 gram of 1m with an increased reaction yield of
82% (3ma). Remarkably maltose azide 1p, a disaccharide moiety,
could be incorporated affording the cycloaddition product in 74%
yield, albeit in DCM, due to the solubility problem. Finally, both
carbohydrate 1o and amino acid 2o were subjected to the NiAAC,
and non-natural glycoamino acid 3oo was successfully prepared
in 65% yield, presenting the potential of biomolecule conjugation.
However, the attempted NiAAC reactions with unprotected sugars
were not successful (see the Supporting Information, Section III-
5).
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8
catalytic system in hand, the substrate scope and generality of this
NiAAC reaction were investigated under aqueous conditions at
room temperature (Scheme 2). Owing to the poor solubilities of
the precatalyst, ligand, and substrates in water, the reactions were
conducted as aqueous suspensions. The reactions of various az-
ides (1b and 1e–1k) produced the corresponding 1,5-disubstituted
triazoles in moderate to excellent isolated yields (63–95%) with
high regioselectivity ranging from 11.4:1 to >99:1 for 3/4. How-
ever, the regioselectivity was significantly decreased when phenyl
azide 1c (3.2:1 ratio) or 1-azidoadamantane 1d was used (4.5:1
ratio). This can be attributed to the steric congestion between the
substrates and catalytic Ni species containing Cp and Xantphos
ligands. Various functional groups of 1, including fluorinated
arenes and fused cyclic moieties, were compatible with the reac-
tion conditions. In particular, the hydroxyl and ester functional
groups remained intact during the catalysis, as illustrated in the
cases of 3ha and 3ia.
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Regarding the organic alkyne partner 2, aliphatic and aromatic
alkynes with diverse functional groups, including methoxy-,
amine-, nitro-, chloro-, and methyl moieties, were well-tolerated.
Yet, ortho-OMe-substituted alkyne 2c showed no reactivity owing
to the steric effect. The NiAAC reaction is strongly favored with
less-sterically hindered meta- and para-substituted substrates 2d
and 2e. It has been previously reported that the RuAAC reactions
are significantly affected by the steric factor of alkynes.7b Howev-
er, the contribution of electronic factor cannot be ruled out (3ab,
3ag, and 3ah). The cycloaddition of the electronically unbiased
internal alkyne 2l afforded 3al in 88% yield. Unsymmetrical in-
ternal alkynes 2m and 2n also participated in the NiAAC to give
fully-substituted triazoles,7,8,11 albeit with poor regioselectivity.
The regiochemical assignments were confirmed by 2D NMR
spectra (Supporting Information, Section V),3,8b,11 assisted by the
13C chemical shifts of the triazole CH.12 In addition, single-crystal
X-ray crystallographic analyses unambiguously determined the
structures of the 1,5-disubstituted triazoles 3ja and 3ah (Support-
ing Information, Section VI).
Having established the utility of the Cp2Ni/Xantphos catalytic
system for azide–alkyne cycloaddition, we turned our attention to
the Ni species that may be present in solution. Literature reports
indicate that reaction of Cp2Ni with mono- and bidentate phos-
phine ligands may, in some cases, give CpNi(P-ligand)2 and Ni(P-
ligand)4 complexes.14,15 The formal one-electron reduction steps
of the Ni center (from NiII to NiI to Ni0) upon coordination of the
phosphine ligands may be explained by successive dissociation of
Cp• radicals.16,17 Indeed, the analysis of the reaction between
Cp2Ni and Xantphos by EPR spectroscopy and mass spectrometry
gave results consistent with the presence of CpNi(Xantphos) and
Ni(Xantphos)2 (see the Supporting Information, Section VII). The
EPR spectrum of the reaction mixture shows a triplet resonance
signal centered at g = 2.088 with a hyperfine splitting constant of
a = 104 G (Figure S26), as expected for a paramagnetic NiI center
(S = 1/2) coupled to two 31P nuclei.14,16–18 Moreover, these param-
eters are similar to those reported for related Ni complexes, such
as CpNi(dppe).14,16
Next, the high-resolution ESI mass spectrum (Supporting In-
formation, Section VII-2, Figure S27) of the reaction mixture
exhibits the most-abundant peak at m/z 701.1671, which is at-
tributed to [CpNi(Xantphos)]+. Measured and calculated isotope
distributions were well-matched. In addition, a peak at m/z
630.1638 is assigned to [Ni(Xantphos)2+2Na]2+.15 Because the
reactions in this study were performed under air, it may seem
likely that CpNi(Xantphos), at least in part, undergoes oxidization,
giving rise to the corresponding NiII complex [CpNi(Xantphos)]+
detected in positive ESI mode. Taken together, this preliminary
investigation agrees with the reaction sequences (i) Cp2Ni →
[CpNi(Xantphos)] → [Ni(Xantphos)2] and (ii) [CpNi(Xantphos)]
→ [CpNi(Xantphos)]+. More detailed studies are needed, however,
to confirm the presence of these species and to determine which
ones are involved in the NiAAC reaction.
Scheme 3. Expanded Scope with Respect to Non-natural Car-
bohydrates and Amino Acidsa
Scheme 4. Tentative Reaction Mechanism of the NiAAC
aReaction conditions: 1 (0.38 mmol), 2 (0.46 mmol, 1.2 equiv),
Cp2Ni (20 mol%), Xantphos (20 mol%), Cs2CO3 (1.0 equiv) in
water (2.0 mL) at rt under air for 17 h. Isolated yields of 1,5-
products. b1m (1.0 g, 2.68 mmol). c1 (0.19 mmol), 12 h in DCM.
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Based on previous literature reports19 and our experimental re-
sults, a tentative reaction mechanism is suggested as shown in
Scheme 4. Alkyne and azide coordinate to Ni, forming intermedi-
ate A, while the spectator ligands (Cp and/or Xantphos) may
change their bonding modes to accommodate the new ligands.
Because both internal and terminal alkynes participate in this
cycloaddition (vide supra, see Scheme 2), the formation of a nick-
el-acetylide species is excluded. The C–N bond formation be-
tween alkyne and azide giving complex B determines 1,5-
regioselectivity, analogous to the RuAAC pathway.7b Subsequent
reductive elimination leads to the formation of cyclized target
product 3, while regenerating NiLn through association (or change
of bonding mode) of the spectator ligands.
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In summary, we have developed the nickel-catalyzed azide–
alkyne cycloaddition to access 1,5-disubstituted 1,2,3-triazoles
from readily available substrates and inexpensive reagents at
room temperature. The Cp2Ni precatalyst and Xantphos ligand
were critical to accomplish the catalytic manifold, insensitive to
molecular oxygen and water. This methodology exhibits a broad
substrate scope, good functional group tolerance, high yields, and
high regioselectivity, complementing the classical copper-
catalyzed click chemistry that produces 1,4-disubstituted 1,2,3-
triazoles. The synthetic utility of this nickel-catalyzed pathway
has been highlighted by the functionalization of carbohydrates
and amino acids. Further mechanistic studies of catalyst activation
and intermediate formation are underway.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures, HRMS-ESI data, and NMR
(1H, 13C, 19F, NOESY, and HSQC) spectra (DOCX)
Single crystal X-ray data for 3ah and 3ja (CIF)
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(12) Creary, X.; Anderson, A.; Brophy, C.; Crowell, F.; Funk, Z. J. Org.
Chem. 2012, 77, 8756.
AUTHOR INFORMATION
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Corresponding Author
*syhong@unist.ac.kr
ORCID
Woo Gyum Kim: 0000-0002-9807-4141
Gonçalo J. L. Bernardes: 0000-0001-6594-8917
Sung You Hong: 0000-0002-5785-4475
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Research Foundation of
Korea (NRF-2016K1A3A1A25003511) and the IT R&D program
of MOTIE/KEIT (10046306). J.-U.R. acknowledges support from
the UNIST Research Fund (2013-1.130085.01).
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