Enantioselective Nickel-Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/jacs.1c01354

The triazole heterocycle has been widely adopted as an isostere for the amide bond. Many native amides are α-chiral, being derived from amino acids. This makes α-N-chiral triazoles attractive building blocks. This report describes the first enantioselective triazole synthesis that proceeds via nickel-catalyzed alkyne-azide cycloaddition (NiAAC). This dynamic kinetic resolution is enabled by a spontaneous [3,3]-sigmatropic rearrangement of the allylic azide. The 1,4,5-trisubstituted triazole products, derived from internal alkynes, are complementary to those commonly obtained by the related CuAAC reaction. Initial mechanistic experiments indicate that the NiAAC reaction proceeds through a monometallic Ni complex, which is distinct from the CuAAC manifold.

Full text of DOI:10.1021/jacs.1c01354

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Enantioselective Nickel-Catalyzed Alkyne−Azide Cycloaddition by
Dynamic Kinetic Resolution
En-Chih Liu and Joseph J. Topczewski*
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ABSTRACT: The triazole heterocycle has been widely adopted as an isostere for the amide bond. Many native amides are α-chiral,
being derived from amino acids. This makes α-N-chiral triazoles attractive building blocks. This report describes the first
enantioselective triazole synthesis that proceeds via nickel-catalyzed alkyne−azide cycloaddition (NiAAC). This dynamic kinetic
resolution is enabled by a spontaneous [3,3]-sigmatropic rearrangement of the allylic azide. The 1,4,5-trisubstituted triazole
products, derived from internal alkynes, are complementary to those commonly obtained by the related CuAAC reaction. Initial
mechanistic experiments indicate that the NiAAC reaction proceeds through a monometallic Ni complex, which is distinct from the
CuAAC manifold.
n 2002, Sharpless1 and Meldal2 made contemporaneous
disclosures that copper could catalyze the alkyne−azide
Scheme 1. E-CuAAC and E-NiAAC Reactions
I
cycloaddition reaction (CuAAC). CuAAC provides exquisite
regioselectivity for the 1,4-disubstituted triazole and is the
quintessential “click” reaction.3,4 With a few noted excep-
tions,5−7 CuAAC is traditionally limited to terminal alkynes.8,9
Other metals can catalyze the alkyne−azide cycloaddition
reaction, including zinc,10 rhodium,11,12 silver,13 iridium,14−16
nickel,17,18 and gold.19 These reactions often provide
complementary selectivity or reactivity relative to CuAAC.
For instance, the ruthenium-catalyzed alkyne−azide cyclo-
addition (RuAAC) typically affords 1,5-disubstituted 1,2,3-
triazole products.20,21
Robust synthetic access has enabled triazole incorporation
into numerous discovery efforts.2,22−29 Triazoles have
applications in chemical biology,30−36 medicinal chemis-
try,24−26,37−40 and materials science.41−47 Particular attention
has been focused on developing enantioselective reactions
because α-chiral triazoles more closely resemble α-chiral
amides (derived from amino acids). However, achieving an
enantioselective alkyne−azide cycloaddition is challenging
because of (i) the linear geometry of the alkyne and azide,
(ii) the reactions’ complex mechanisms,21,48,49 and (iii)
because the cycloaddition does not generate a new sp3
center.50 In 2005, Fokin and Finn disclosed the first
enantioselective CuAAC (E-CuAAC) by kinetic resolution
(Scheme 1a).51 Others expanded E-CuAAC to include
desymmetrization and kinetic resolutions with expanded
scope, either manifold can proceed from α-chiral azides or α-
chiral alkynes (Scheme 1a,b).52−59 Recently, we developed the
first E-CuAAC via dynamic kinetic resolution (DKR) (Scheme
1c).60 While E-CuAAC reactions have advanced, enantiose-
lective variants of other metal-catalyzed alkyne−azide cyclo-
additions have remained elusive.
alkynes,18 which is complementary to CuAAC. A series of
density functional theory (DFT) calculations suggested that
the NiAAC reaction may occur through a monometallic Ni
Received: February 3, 2021
Published: April 2, 2021
We were inspired by a report by Hong and co-workers
describing the first homogeneous NiAAC reaction.17 This
reaction generated 1,4,5-trisubstituted triazoles from internal
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5308

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complex with turnover-limiting azide attack.18 These attributes
appeared to be well-suited for the development of an
enantioselective NiAAC (E-NiAAC) reaction that would
provide complementary access to trisubstituted α-chiral
triazoles that are not directly accessible by E-CuAAC (Scheme
1d). Reported here are the first E-NiAAC reaction enabled by
DKR (Scheme 1d) and the first enantioselective click reaction
that uses a metal other than copper.
noninnocent. A series of solvents were investigated (entries 5
and 7−9). While hexanes resulted in a higher yield, the
enantioselectivity decreased. Toluene was superior to dioxane,
and the system maintained homogeneity. The temperature was
critical given the rate of the Winstein rearrangement61−63,66
and the number of competing reaction pathways (entries 9−
12). Increasing the reaction temperature decreased the
selectivity relative to alkyne trimerization. Lowering the
temperature slightly improved the enantioselectivity but
diminished the conversion. Increasing the concentration
(entry 12) significantly increased the yield. The reaction
conditions outlined in entry 12 were selected as being optimal.
With the optimized conditions identified, the scope with
respect to the alkyne was investigated (Table 2). With the
azide as the limiting reagent, the model product 3a was
isolated in 88% yield with 90:10 er. Electron-rich (3a, 3b),
This study began with allylic azide 1a, alkynonitrile 2a, and
Ni(COD)2 (Table 1). Allylic azide 1a was chosen on the basis
a
Table 1. Optimization of E-NiAAC by DKR
a
T
yield of
amount of 2a
consumed (%)
Table 2. Alkyne Scope of E-NiAAC
b
b
c
entry ligand solvent (°C) 3a (%)
er
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
hexanes
DCE
50
50
50
50
50
50
50
50
50
60
40
40
0
11
27
56
52
0
82
0
62
56
56
86
0
98
59
58
72
24
78
0
77
84
64
65
−
51:49
61:39
17:83
87:13
−
83:17
−
89:11
88:12
91:9
90:10
PhMe
PhMe
10
11
12
PhMe
PhMe
d
a
Reactions were conducted with allylic azide 1a (0.05 mmol) and
alkynonitrile 2a (0.075 mmol) in PhMe (0.10 M) with 10 mol %
Ni(COD)2 and 10 mol % ligand. All yields and er values are averages
of duplicate trials. See the Supporting Information for full details.
b
Yields were determined by supercritical fluid chromatography (SFC)
analysis using 2′,4′,6′-trimethylacetophenone as an internal standard.
c
Enantiomeric ratios were determined by SFC with a chiral stationary
d
phase. The reaction concentration was 0.25 M. Ligand structures:
of prior work60 and because it is known to participate readily in
the Winstein rearrangement,61 a sigmatropic reaction that is
responsible for racemization in this system.62,63 Several
competing reactions were identified, including (i) the
Staudinger reduction with a phosphine ligand,64 and (ii)
alkyne [2 + 2 + 2] cyclotrimerization resulting in arene 4.65
Only traces of triazole 3a were observed using chiral
monodentate or bidentate phosphine ligands (entry 1 and
the Supporting Information). The PYBOX scaffold (L2) is
privileged in E-CuAAC reactions;60 however, this reactivity did
not translate to the NiAAC system (entry 2). A screen of
alternate ligand scaffolds identified aminophosphine ligands as
being promising (entries 3−6 and the Supporting Informa-
tion). In these initial results, L5 gave a moderate yield and
promising enantioselectivity (entry 5). Dimethylation of L5
produced a ligand that was inactive for the E-NiAAC reaction
(L6; entry 6), suggesting that the primary amine is
a
Yields are reported for isolated and purified products. Regioisomeric
ratios (rr) were determined by SFC analysis. Enantiomeric ratios (er)
were determined by SFC with a chiral stationary phase. Yields, rr
values, and er values are averages of duplicate trials. See the
Supporting Information for details.
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-neutral (3c, 3d), and -deficient (3e, 3f) substituents on the
aryl group had a minimal effect on the enantioselectivity.
Arenes with strong electron-withdrawing groups (3e, 3f) did
suffer a decrease in regioselectivity. This is expected given the
similar electronic natures of the two groups (e.g., −CN vs −4-
C6H4CF3, 3e). Both ortho (3g) and meta (3h) substituents
were tolerated. Both electron-rich (3i) and electron-deficient
(3j) heterocycles could be incorporated. Beyond alkynonitriles,
alkynoesters (3k−m), a trifluoromethyl alkyne (3n), and a
thioalkyne (3o) also provided the corresponding E-NiAAC
products with good selectivity.
The scope of allylic azides was explored (Table 3). The
pendent aryl tolerated both electron-rich and electron-deficient
a
Table 3. Azide Scope of E-NiAAC
Figure 1. Initial E-NiAAC mechanistic investigation. (A) Reaction
progress plots showing the er of 1a and 3a vs time (linear fit), the
conversion of 1a vs time (logarithmic fit), and the yield of 3a vs time
(logarithmic fit). (B) Plot of ligand L5 ee vs product 3a ee (linear fit).
(C) Plot of the relative catalyst loading vs the relative initial rate,
normalized to a catalyst loading of 5 mol % (linear fit).
a
Yields are reported for isolated and purified products. Regioisomeric
ratios (rr) were determined by SFC analysis. Enantiomeric ratios (er)
were determined by SFC with a chiral stationary phase. Yields, rr
values, and er values are averages of duplicate trials. See the
Supporting Information for details.
nonlinear effect (Figure 1b), indicating that only 1 equiv of
ligand L5 is involved in the enantiodetermining step. Lastly,
the reaction was found to be first-order in catalyst by initial
rates (Figure 1c).74 This result is consistent with the DFT
calculations on NiAAC18 and contrasts with the higher order
with respect to the catalyst for the CuAAC reaction.48
Together, the data in Figure 1b,c indicate that NiAAC likely
proceeds through a mononuclear L5−Ni complex. This is
distinct from CuAAC, which is thought to proceed through
[L2Cu2X2] dimers or higher-order oligomers.
In conclusion, ligand L5 can promote an E-NiAAC reaction
by DKR. This is the first enantioselective alkyne−azide
cycloaddition that is reported to be catalyzed by a metal
other than copper. The E-NiAAC reaction provides synthetic
access to 1,4,5-trisubstituted α-chiral triazoles that are not
directly accessible by E-CuAAC. Furthermore, preliminary
mechanistic experiments indicate that the nature of the NiAAC
catalyst is a monometallic L1 species, which is distinct from
CuAAC.
groups (3p−r). The cyclohexyl core was modified (3s−v). In
the acyclic allylic azide 1w, both the (E)- and (Z)-alkene
isomers were observed (7:1 E/Z). Interestingly, triazole 3w
was isolated as a single isomer.
A series of preliminary mechanistic experiments were
conducted to contrast E-CuAAC and E-NiAAC (Figure 1).
First, the er of azide 1a and triazole 3a were determined as a
function of reaction time course (Figure 1a). At very early time
points, a slight enrichment of the azide er was measurable (up
to 55:45), indicating that this DKR67−70 likely occurs in a
nonideal kinetic regime.71 The er of triazole 3a was constant as
a function of reaction progress, and the smooth time-course
data indicated well-behaved kinetics. Next, a nonlinear
experiment was conducted.72 E-CuAAC reactions are known
to proceed with positive55,73 or negative52,60 nonlinear effects.
In contrast, the E-NiAAC reaction did not demonstrate a
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by Triazolyllithium with Electrophiles. J. Organomet. Chem. 2017, 834,
83−87.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01354.
■
sı
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CCDC 2060693, 2069885, and 2069888 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44
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AUTHOR INFORMATION
Corresponding Author
Joseph J. Topczewski − Department of Chemistry, University
of Minnesota Twin Cities, Minneapolis, Minnesota 55455,
United States; orcid.org/0000-0002-9921-5102;
Email: jtopczew@umn.edu
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Functional Theory Calculations. R. Soc. Open Sci. 2016, 3, 160090.
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Author
En-Chih Liu − Department of Chemistry, University of
Minnesota Twin Cities, Minneapolis, Minnesota 55455,
United States; orcid.org/0000-0002-5985-2705
(15) Chen, R.; Zeng, L.; Lai, Z.; Cui, S. Iridium-Catalyzed Hydroxyl-
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Complete contact information is available at:
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(16) Wu, Z. G.; Liao, X. J.; Yuan, L.; Wang, Y.; Zheng, Y. X.; Zuo, J.
L.; Pan, Y. Visible-Light-Mediated Click Chemistry for Highly
Regioselective Azide−Alkyne Cycloaddition by a Photoredox
Electron-Transfer Strategy. Chem. - Eur. J. 2020, 26, 5694−5700.
(17) Kim, W. G.; Kang, M. E.; Lee, J. B.; Jeon, M. H.; Lee, S.; Lee, J.;
Choi, B.; Cal, P. M. S. D.; Kang, S.; Kee, J. M.; et al. Nickel-Catalyzed
Azide−Alkyne Cycloaddition to Access 1,5-Disubstituted 1,2,3-
Triazoles in Air and Water. J. Am. Chem. Soc. 2017, 139, 12121−
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Victor Young, Jr., and Margaret Clapham for
assistance with diffraction analysis of compounds 3a, 3r, and
3w. We thank Juliana Alexander for the preparation of
ynamides. E.-C.L acknowledges support from the Wayland
Nolan Fellowship and the Doctoral Dissertation Fellowship.
This research was supported by the National Institute of
General Medical Sciences of the National Institutes of Health
under Award R35GM124718. We also acknowledge NIH
Shared Instrumentation Grant S10OD011952. Funding from
the University of Minnesota is acknowledged.
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