A New Multicomponent Multicatalyst Reaction (MC)2R: Chemoselective Cycloaddition and Latent Catalyst Activation for the Synthesis of Fully Substituted 1,2,3-Triazoles

Article abstract of DOI:10.1021/acs.orglett.6b00975

A multicomponent multicatalyst reaction (MC)²R for constructing fully substituted 1,2,3-triazoles is reported. An application of chemoselectivity and latent catalysis in a sequence of multicatalytic reactions confers control over a number of undesired processes, where all of the reagents coexist in the same reaction vessel. The sequence of a chemoselective copper-catalyzed azide alkyne cycloaddition followed by a palladium/copper-catalyzed Sonogashira cross-coupling afforded 1,2,3-triazoles regioselectively with good to high yields and a broad scope.

Full text of DOI:10.1021/acs.orglett.6b00975

Letter
pubs.acs.org/OrgLett
A New Multicomponent Multicatalyst Reaction (MC)2R:
Chemoselective Cycloaddition and Latent Catalyst Activation for the
Synthesis of Fully Substituted 1,2,3-Triazoles
Kosuke Yamamoto, Theodora Bruun, Jung Yun Kim, Lei Zhang, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada
M5S 3H6
S
* Supporting Information
ABSTRACT: A multicomponent multicatalyst reaction (MC)2R for constructing fully substituted 1,2,3-triazoles is reported. An
application of chemoselectivity and latent catalysis in a sequence of multicatalytic reactions confers control over a number of
undesired processes, where all of the reagents coexist in the same reaction vessel. The sequence of a chemoselective copper-
catalyzed azide alkyne cycloaddition followed by a palladium/copper-catalyzed Sonogashira cross-coupling afforded 1,2,3-
triazoles regioselectively with good to high yields and a broad scope.
Scheme 1. Chemoselectivity and Latent Catalyst Activation
Enabled (MC)2R
hen a number of substrates are placed in a single
Wreaction vessel containing several catalysts, the selective
and orderly assembly of these components is challenging but
necessary if a single product is to emerge. The role of metal
catalysts is to ensure that desired reactions occur in a specific
order so as to minimize “off-path” or “parasitic” processes. As
a result, significant a research effort has been invested in the
development of switchable or latent catalysis based on heat,1
light,2 or mechanical3 stimuli to gain temporal control. In
seeking to achieve subtle catalyst control in more complex
reaction sequences, we have studied the use of multiple
catalysts that confer chemoselectivity and latent activation in
multicomponent reactions,4 where closely related reactants
coexist with a number of possible interfering processes
(Scheme 1).
We now report a copper-catalyzed cycloaddition of an
organic azide with two closely related alkyne species with
differential rates of reactivity affording remarkable chemo-
selectivity. The resulting cycloadduct, an iodotriazole, is stable
under the reaction conditions at room temperature. Upon
heating the reaction mixture, the latent Pd catalyst is
activated, promoting a Pd/Cu cocatalyzed Sonogashira
reaction to provide a fully substituted triazole. We
demonstrate the importance of the choice of catalysts in
providing the chemoselectivity and latent activation that led to
temporal control and the minimization of interfering
processes in the reaction pathway.
Based on our strategy, we accessed two modes of copper
catalysis in the direct synthesis of fully substituted 1,2,3-
triazoles. These important motifs are used in a wide range of
applications, including medicinal chemistry, crop science,
materials, and bioconjugation.5 Preexisting methods that
accessed these fully substituted triazoles were limited by
selectivity and scope. For example, Fokin and co-workers6
reported a regioselective ruthenium-catalyzed azide alkyne
cycloaddition (RuAAC) of internal alkynes that contained
directing groups or an electronic bias. Other approaches
include one-pot copper-catalyzed azide alkyne cycloaddition
Received: April 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00975
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Organic Letters
Letter
(CuAAC) of terminal alkynes followed by copper-catalyzed
C−H arylation7 or CuAAC followed by an oxidative
alkynylation, incorporating 2 equiv of an alkyne.8 Recently,
Xu and co-workers reported the one-pot synthesis of 5-aryl-
1,2,3-triazoles using a stoichiometric Cu and Pd catalyst by
transmetalation between a copper-triazolide and a Pd-aryl
species.9 Conversely, the (MC)2R provided a divergent and
regioselective synthesis with alkyne differentiation, affording
products with good to high yields.
The recent study of the CuAAC indicated that the CuAAC
with iodoalkynes may proceed via a different activation
pathway from that with terminal alkynes.10 Furthermore, the
reactivity of iodoalkynes toward CuAAC exceeds that of
terminal alkynes.10a We observed a chemoselective copper-
catalyzed formation of 5-iodotriazole 4a from benzyl azide 1a
and a mixture of iodoalkyne 2a in the presence of phenyl
acetylene 3a in an equimolar ratio in THF (Table 1, entry 1).
diyne 7 and 8 would reduce the maximum possible yield of
the final product even if diynes do not undergo the CuAAC.
Finally, we found the use of palladacycle precatalyst developed
by the Buchwald group was important in restoring reactivity
for the formation of iodotriazole 4a (entry 9).
XPhos-Pd-G3 releases the active monoligated Pd0 catalysts
in the presence of base.13 Catalyst activation could occur with
carbonate bases as low as room temperature. However, with a
weaker base such as KOAc, the precatalyst remained
inactive.14 When subjecting the iodoalkyne to the XPhos-
Pd-G3 in the presence of KOAc and excess phenyl acetylene,
we did not observe any diyne cross-coupling product (eq 1).
However, by using a Pd(OAc)2/XPhos system instead of the
precatalyst, a decomposition of iodoalkyne was observed. The
inactive precatalyst prevented possible interference of the
chemoselective CuAAC and further enforced the desired
reaction pathway.
Table 1. Competition Studies of the CuAAC for
Iodoalkynes in the Presence of Terminal Alkynes and Pd
a
Concurrently, we sought conditions for the Cu/Pd-
catalyzed Sonogashira cross-coupling of iodotriazole 4a with
phenyl acetylene. While a number of conditions have been
reported,15 we also observed this transformation was possible
using the palladium catalyst XPhos-Pd-G3 at 85 °C (eq 2).16
b
entry
solvent
[Pd]/L
base
yield (%) (4a:5:6:7:8)
1
2
3
4
5
6
7
8
9
THF
−
−
−
−
−
−
−
−
Et3N
KOAc
KOAc
KOAc
KOAc
KOAc
91:0:9:3:0
dioxane
toluene
THF
80:0:16:0:0
c
36:0:0:32:n.d.
76:0:23:1:1
81:0:8:0:<1
2:0:0:8:17
THF
THF
Pd(OAc)2
The use of CuI in combination with the precatalyst was
THF
Pd2dba3
<1:9:1:3:31
important in affording high yields.17 In contrast, we observed
c
THF
Pd(OAc)2/XPhos
XPhos-Pd-G3
4:10:1:4:n.d.
1
a negligible amount of 9a and 95% of unreacted 4a by H
THF
66:7:7:8:2
NMR analysis, when the same reaction was performed at
room temperature. The use of KOAc as a weak base allowed
us to control the release of the active Pd0 catalysts by
elevating the temperature (Scheme 2).
a
Representative reaction procedure: in a 2 dram vial under an argon
atmosphere, benzyl azide 1a (0.2 mmol), iodoalkyne 2a (1 equiv), and
phenyl acetylene 3a (1 equiv) were dissolved in THF. CuI (10 mol %)
and TBTA (10 mol %) were added, followed by the addition of
additives as indicated. The mixture was stirred for 16 h. Yields were
determined via H NMR spectroscopy of the crude mixture using
b
1
Scheme 2. Latent Activation of the Palladacycle Precatalyst
c
1,3,5-trimethoxybenzene as the internal standard. Not determined.
TBTA = Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine. XPhos-
Pd-G3 = (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-
biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methane-
sulfonate.
However, the chemoselectivity deteriorated in dioxane, and 5-
iodotriazole 6 was formed either through a σ-metathesis of a
copper-triazolide with a iodoalkyne 2a or via CuAAC with in
situ generated iodoethynylbenzene (entry 2).10a,b We observed
a significant amount of diyne 7 in toluene by the copper-
catalyzed Cadiot−Chodkiewicz cross-coupling (entry 3).11
The addition of a base also affected the selectivity of the
CuAAC, and KOAc gave better selectivity than Et3N (entry 4
and 5). The palladium catalyst and added ligand played an
important role in the reaction outcome. For example, with the
use of Pd(OAc)2 or Pd2dba3, we observed diyne 8 as a major
product formed by the Cu/Pd catalyzed homocoupling of
iodoalkyne (entries 6 and 7).12 Parasitic reactions that formed
We next optimized the “all-in-one” process (Table 2; see
Table S2 for full optimizations). Heating the reaction mixture
from the outset, we observed a 30% yield of the desired
product 9a at 85 °C with 1.5 equiv of phenyl acetylene (entry
1).18 Having demonstrated the latent catalyst activation
approach, we subsequently used room temperature followed
by heating at 85 °C. From the optimization results, we found
the reaction could be conducted at a lower catalyst loading
and the optimal reaction time for the CuAAC was found to
be 4 h. Under optimized conditions, we were able to access
the desired (MC)2R product 9a in 73% yield (entry 2). The
B
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Organic Letters
Letter
a
a
Table 2. Optimization of the “All-in-One” (MC)2R
Scheme 3. Triazole Scope of the (MC)2R
b
yield (%)
entry
x
y
temp (°C)
9a
5
10
1
2
10
5
2
1
1
85
30
14
4
3
6
0
c
rt (4 h) then 85
rt (4 h)
73
1
d
3
5
5
a
Representative reaction procedure: in a microwave vial under an
argon atmosphere, CuI, TBTA, XPhos-Pd-G3, and KOAc were added,
followed by the addition of iodoalkyne (0.2 mmol) and azide (1.1
equiv). The mixture was dissolved in THF (0.1 M), and the phenyl
acetylene (1.5 equiv) was subsequently added. The mixture was stirred
b
at rt for the period indicated followed by heating for 20 h. Yields were
1
determined via H NMR spectroscopy of the crude mixture using
c
d
1,3,5-trimethoxybenzene as the internal standard. Isolated yield. The
reaction was stopped after 4 h. Iodotriazole 4a was observed in 80%
NMR yield.
chemoselective CuAAC coupled with the latent Pd activation
provided strong temporal control of the multicomponent
reaction sequence where all of the closely related reactants
and reagents could be placed in one reaction compartment
from the outset.
We turned our attention toward demonstrating the scope of
the (MC)2R (Scheme 3). Good yields were obtained with
various acetylenes, affording triazoles with R3 bearing electron-
rich and -poor aryl and alkyl groups (9a−9g). Various
iodoalkynes could be employed, providing triazoles with C4
substitution (R2) including styrenyl (9j), phenoxy (9l), sulfide
(9m), and amino groups (9n−9u).19,20 In addition, a number
of azides bearing heteroaromatic and alkyl groups were also
tolerated (9h, 9i, 9r, 9s, 9u). The reaction could also be
performed on 2 mmol scale, affording 9p in 81% yield.
During the studies, we found that both R1 and R2 influence
the ratio of the desired three-component product 9 vs a
deiodinated product 11. For example, we observed a large
amount of deiodinated triazole 11 when R1 is an aryl group
(9t), or when R2 is a carboxylate group (9k).21
The highly efficient diversity-generating CuAAC/Sonoga-
shira process provided an opportunity for further functional-
ization. For example, we developed a method for the
cyclization of products bearing the N-tosylamino or
benzylsulfide group (Scheme 4). Subjecting 9p or 9q to
Cs2CO3 in dioxane at 120 °C followed by treatment with
KOt-Bu at room temperature allowed us to access
triazolopyridines 12 in a one-pot manner. The iodocyclization
of triazole 9m gave exclusively iodo-substituted 6-endo-dig
cyclized product 13. The structure of 13 was confirmed by X-
ray crystal structure analysis.
a
See Supporting Information for reaction details. Iodoalkyne 2 (0.2
mmol), azide 1 (1.1 equiv), and terminal alkyne 3 (1.5−3.0 equiv)
were dissolved in THF. CuI, TBTA, and XPhos-Pd-G3 were added.
The mixture was stirred at rt until 2 was consumed followed by
heating at 85 °C for 15−24 h. The reported yields were isolated yields
b
after column chromatography. Reaction performed on 2 mmol scale.
c
Reaction performed with 4 Å molecular sieves as a additive. Fc =
ferrocenyl.
a
Scheme 4. Derivatization of Triazoles
In summary, we have demonstrated the advantage of a
multicatalyst approach by coupling chemoselectivity with
latent catalysis activation in achieving control in a sequence
of catalytic reactions, where all reagents including closely
related substrates coexist in the same vessel. This multi-
component multicatalytic reaction provided direct access to
fully substituted 1,2,3-triazoles with selectivity, a broad scope,
and good to high yields.
a
The yields were isolated yields after column chromatography.
C
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Organic Letters
Letter
1128. For a review on the application of CuAAC in multi-
ASSOCIATED CONTENT
* Supporting Information
■
component reactions, see: (n) Hassan, S.; Muller, T. J. J. Adv. Synth.
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S
Catal. 2015, 357, 617.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00975.
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Detailed experimental procedures and full compound
characterization data (PDF)
X-ray crystal structure of 13 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mlautens@chem.utoronto.ca (M.L.).
Notes
(10) (a) Barsoum, D. N.; Okashah, N.; Zhang, X.; Zhu, L. J. Org.
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Chem. 2015, 80, 9542. (b) Lal, S.; Rzepa, H. S.; Díez-Gonzalez, S.
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B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48,
8018.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(15) For examples of cross-coupling reactions of iodotriazoles, see:
■
The authors thank the Natural Sciences and Engineering
Research Council (NSERC), the University of Toronto, and
Alphora Research Inc. for financial support. We thank the
Canada Council for the Arts for a Killam Fellowship. T.B.
thanks NSERC-USRA for funding. L.Z. thanks the Ontario
Graduate Scholarship for funding. K.Y. thanks JSPS for
funding. The authors wish to acknowledge the Canadian
Foundation for Innovation, Project Number 19119, and the
Ontario Research Fund for funding of the Centre for
Spectroscopic Investigation of Complex Organic Molecules
and Polymers.
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