CuII-Catalyzed Oxidative Formation of 5-Alkynyltriazoles

Article abstract of DOI:10.1002/asia.201901581

In an alcoholic solvent under the catalysis of Cu(OAc)₂?H₂O, organic azide and terminal alkyne could oxidatively couple to afford 5-alkynyl-1,2,3-triazole (alkynyltriazole) at room temperature under an atmosphere of O₂ in a few hours. The involvement of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) is essential, without which the redox neutral coupling instead proceeds to produce 5-H-1,2,3-triazole (protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between terminal alkyne and organic azide, the copper-catalyzed “click” reaction to afford protiotriazole, to an oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the copper(II)-catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity between alkynyl- and protiotriazole, and other acetylide or triazolide oxidation products is determined by the competition between copper(I)-catalyzed redox neutral cycloaddition and copper(II)/O₂-mediated acetylide oxidation after the formation of copper(I) acetylide.

Full text of DOI:10.1002/asia.201901581

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Cu(II)-Catalyzed Oxidative Formation of 5-Alkynyltriazoles
Authors: Peiye Liu, Christopher J. Brassard, Justin P. Lee, and Lei Zhu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201901581
Link to VoR: http://dx.doi.org/10.1002/asia.201901581
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

10.1002/asia.201901581
Chemistry - An Asian Journal
Cu(II)‐Catalyzed Oxidative Formation of 5‐Alkynyltriazoles
Peiye Liu, Christopher J. Brassard, Justin P. Lee, and Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee,
Florida 32306‐4390, United States
lzhu@chem.fsu.edu
Abstract. In an alcoholic solvent under the catalysis of Cu(OAc)2∙H2O, organic azide and terminal alkyne
could oxidatively couple to afford 5‐alkynyl‐1,2,3‐triazole (alkynyltriazole) at room temperature under
an atmosphere of O2 in a few hours. The involvement of 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) is
essential, without which the redox neutral coupling instead proceeds to produce 5‐H‐1,2,3‐triazole
(protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between
terminal alkyne and organic azide, the copper‐catalyzed “click” reaction to afford protiotriazole, to an
oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the
copper(II)‐catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an
organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity
between alkynyl‐ and protiotriazole, and other acetylide or triazolide oxidation products is determined
by the competition between copper(I)‐catalyzed redox neutral cycloaddition and copper(II)/O2‐mediated
acetylide oxidation after the formation of copper(I) acetylide.
Keywords: alkyne, azide, alkynyltriazole, oxidation, copper
Introduction
Copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) to afford 1,2,3‐triazoles (Scheme 1a)[1] is a
redox‐neutral reaction, in which the copper catalyst needs to be in the +1 oxidation state.[2] Oxidatively
coupled byproducts have been observed since the unveiling of the CuAAC reaction,[1c] several of which
that are of interest in this article are included in Scheme 1b. Our group published a procedure of CuAAC
that starts with a copper(II) acetate precatalyst (Scheme 1c).[3] An induction period under this condition
is required for copper(II) to be reduced to copper(I)[4] by a reaction component, for example, the solvent
1
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
or a reaction substrate, or perhaps a reaction intermediate, from which oxidized byproducts are
expected to form.
Scheme 1. Copper‐catalyzed azide‐alkyne cycloaddition under redox neutral or oxidative conditions.
a. TBTA = tris[(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amine, a ligand known for accelerating copper‐
catalyzed triazole ring formation from azide and terminal alkyne.[5]
Over the years, efforts have been made to selectively amplify the yields of the oxidatively cross‐
coupled products, such as 5,5’‐bis(1,2,3‐triazole)s (bistriazoles)[6] and 5‐alkynyl‐1,2,3‐triazoles
(alkynyltriazoles).[6d, 7] Among those endeavors was the work from our group on the preparation of
bistriazoles (Scheme 1d).[6e] We found that by including K2CO3[6a] under an oxygen atmosphere but
otherwise similar conditions of the reaction in Scheme 1c, bistriazole became the major product while
the other oxidatively coupled alkynyltriazole and the redox neutrally coupled 5‐H‐1,2,3‐triazole
(protiotriazole) were minor. The low production of the cross‐coupled alkynyltriazole as well as the
almost absence of homocoupled diyne was explained by considering azide as a ligand for the copper
catalyst.[6a] The acetylide formed on copper(I) would therefore be consumed by the cycloaddition with
the azide ligand on copper to afford the triazole ring (Scheme 2a), before copper(I) acetylide oxidation
2
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
takes place to produce diynes or alkynyltriazoles.[6e] One potential outcome of this hypothesis is that if
the association between azide and copper is reduced, copper(I) acetylide might be able to last long
enough to engage in oxidative cross‐coupling to afford alkynyltriazole as the major product (Scheme 2b).
Herein, we report the results from testing this hypothesis.
Scheme 2. Copper(I) acetylide (boxed) oxidation in the presence of azide.
Results and Discussion
(a) Condition screening to amplify the selectivity toward alkynyltriazole. The effects of a basic additive,
solvent, and azide/alkyne ratio were examined using the Cu(OAc)2‐catalyzed reaction between p‐
tolylacetylene and benzyl azide (Table 1) at rt. The reaction components were mixed as described in the
procedure of bistriazole preparation (Scheme 1d),[6e] in which Cu(OAc)2 was dissolved in MeOH, followed
by the addition of azide, basic additive, and alkyne under an oxygen atmosphere. Alkynyltriazole (A)
became the major product when switching the basic additive from K2CO3 (entry 1) to DBN (entry 2). In
addition to protiotriazole (P) and bistriazole (B), diyne (D) and alkyl tolylacetate (E) were the consistent
byproducts. Alkynyltriazole A is the only overlap between the triazolyl‐containing cycloaddition products
(boxed in red, Table 1) and the alkyne oxidation products (boxed in blue). E forms from the oxidative
coupling of alkyne and the alcoholic solvent followed by hydration (Scheme S1). Using iPrOH (entry 3) in
place of MeOH reduced the amount of E yet boosted the production of D. Diyne D instead of
alkynyltriazole A was the major product in aprotic solvents (entries 4‐6). The conversion to A reached
73% when 1 equivalent (0.5 mmol) of benzyl azide was used (entry 7). Finally, when DBN was added
after alkyne, a noticeable increase of the conversion percentage of alkynyltriazole resulted (entry 8). The
effects of two inorganic bases, KOtBu and CsOAc, were examined at the 1:1 azide/alkyne ratio (entries 9
3
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
and 10). Both reactions were slower than the result in entry 8, and did not afford A as the major
products. The contrasting abilities between DBN and K2CO3 in promoting the Glaser coupling to afford
diyne D were shown in the last two entries. In the absence of an azide, diyne D formed in the presence
of DBN (entry 11, similar to the Eglinton method of Glaser coupling[8]), while no conversion of alkyne
was observed while the basic additive was K2CO3 (entry 12) within the same allocated time period.
Table 1. Effects of Basic Additive, Solvent, and Azide/Alkyne Ratio on the Conversion and Selectivity of
the Reaction between Benzyl Azide and p‐Tolylacetylenea
entry Y (mmol)
Z (mmol)
0.25
0.25
0.25
0.25
0.25
0.25
0.50
0.50
0.50
0.50
0
solvent
MeOH
MeOH
iPrOH
DMF
additive
K2CO3
DBN
P (%) B (%) A (%) D (%) E (%) Y* (%)b
1
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
2
2
2
0
0
0
4
3
4
49
0
0
63
0
18
60
60
0
4
0
10
0
0
0
0
4
3
0
0
7
0
13
9
2
19
31
47
72
27
14
11
0
3
DBN
0
7
4
DBN
0
53
20
71
5
5
ACN
DBN
0
8
6
THF
DBN
0
2
7
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DBN
0
73
83
36
6
8c
9d
10e
11
12
DBN
0
0
KOtBu
CsOAc
DBN
60
6
0
0
39
28
100
0
0
65
0
0
K2CO3
0
0
4
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
a. Conditions: Cu(OAc)2 (5 mol%, 0.025 mmol) was dissolved in MeOH (0.5 mL), followed by azide, basic
additive (0.5 mmol), and alkyne, in this order. The column of alkynyltriazole and the row of the “best”
conditions are shaded. The reactions were done under an atmosphere of O2, while the temperature of
the water bath increased from 0 C to rt over 3 h. The percentage numbers were calculated from the 1H
NMR integration data of the mixtures after the reactions ceased based on the conversion of the limiting
reagent (alkyne); b. Y*: unreacted alkyne; c. DBN was added after the addition of alkyne; d. 5 h; e. 22 h.
Based on the data from Table 1, four factors were identified for maximizing the alkynyltriazole
selectivity: (1) the basic additive is DBN (or DBU); (2) the solvent needs to be MeOH or iPrOH; (3) the
ratio of azide and alkyne should be 1/1 or larger, i.e., azide should be in excess; and (4) DBN needs to be
added last, to avoid premature oxidation of alkyne to diyne or tolylacetate. According to these
guidelines distilled from a single pair of substrates, a standard procedure was formulated that is
described in the Experimental Section.
(b) Substrate scope. The isolated yields of alkynyltriazole synthesis from various azides and alkynes
(Charts S1‐2) are listed in Charts 1 and 2. The reactions of most examples completed within 3‐6 h. Given
the multiple (5 as listed in Table 1) possible products, the isolated yields of alkynyltriazoles on average
are modest. All the compounds from this work were isolated from silica gel columns. The mobilities of
alkynyltriazole and protiotriazole are sometimes similar on the silica gel stationary phase, which
contributed to the poor resolution and consequently negatively impacted the isolation yields.
The reactivity dependence on alkyne was examined using benzyl azide as the reference azide partner
(Chart 1). Ethynyl‐substituted arenes or propargylic type alkynes reacted with benzyl azide readily under
the standard conditions (see the caption of Chart 1) to afford alkynyltriazoles as major products. Isolated
yields of slow‐reacting substrates can be maximized by increasing the quantities of DBN (3da, 3ea, 3ha),
azide (3ga) and/or the reaction time (3cf). Aliphatic terminal alkynes are much less reactive substrates
that gave low isolated yields (data not shown). An effective solution for activating unreactive alkynes is
to first transform them into copper(I) acetylide before oxidative coupling with azide (Chart 3), as
described after the section of preliminary mechanistic analysis. The last four compounds in Chart 1
derive from substituted benzyl azides (3ce, 3cf), a picolyl azide (3cp), and an allyl azide (3lj), all of which
have similar reactivity to benzyl azide in alkynyltriazole formation.
5
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Chart 1. Alkynyltriazole Synthesis Starting from (Substituted) Benzyl Azides, and an Allylic Azidea,b
R
Cu(II)(OAc)2, DBN, O2
N
Bn N3
2a
+
R
R
MeOH, 0 oC - rt
N
N
1
3
Bn
F
Cl
tol
Ph
N
3da, 41%c
3aa, 67%
tol
3ba, 63%
Ph
3ca, 82%
N
N
N
N
N
N
N
N
N
F
Cl
Bn
Bn
N
N
Bn
Bn
Br
F3C
MeO2C
3ea, 44%c
3ga, 38%d
3fa, 52%
N
N
N
Br
F3C
MeO2C
N
N
N
N
N
N
Bn
Bn
Bn
F
MeO
3ha, 62%c
3ia, 35%
3ja, 60%
3ce, 58%
OPh
OEt
EtO
EtO
EtO
N
N
N
N
N
N
F
N
MeO
N
N
PhO
N
N
N
N
Bn
Bn
Bn
Br
F
F
3cf, 53%e
3lj, 47%
3cp, 82%
N
N
N
F
N
N
F
N
N
N
N
N
N
Ph
OMe
a. Alkynyltriazoles are marked as 3<letter1><letter2>. “letter1” comes from the alkyne precursor (Chart
S1), and “letter2” is inherited from the azide starting material (Chart S2). b. Reagents and conditions
(standard): azide (0.5 mmol), alkyne (0.5 mmol), Cu(OAc)2∙H2O (0.025 mmol), DBN (0.5 mmol), MeOH
(0.5 mL), 0 – rt, O2, 3 h; c. DBN (1.0 mmol), 6 h; d. azide (1.0 mmol); e. azide (1.0 mmol) 18 h.
6
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Chart 2. Alkynyltriazole Synthesis Starting from p‐Tolylacetylene (1a)a,b
a. Alkynyltriazoles are marked as 3<letter1><letter2>. “letter1” comes from the alkyne precursor (Chart
S1), and “letter2” is inherited from the azide starting material (Chart S2); b. Reagents and conditions
(standard): azide (0.5 mmol), alkyne (0.5 mmol), Cu(OAc)2∙H2O (0.025 mmol), DBN (0.5 mmol), MeOH
(0.5 mL), 0 – rt, O2, 3 h ; c. 0.3 mmol DBN; d. TBTA and 2 molar equiv. of azide; e. EtOH was used as the
solvent; f. 1.0 mmol reaction.
7
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
The reactivity dependence on the azide structure was studied by pairing p‐tolylacetylene (1a) with
various azides (Chart 2). In addition to substituted benzyl and allyl azides as already described in Chart 1,
primary aliphatic azides worked similarly well as benzyl azide in the production of alkynyltriazoles (e.g.,
3ah). Functional groups such as amino (3al), hydroxyl (3ag), pyridyl (3ab, 3ac), and ester (3ak) were
compatible with the reaction conditions. Aromatic (e.g., 3am) and secondary aliphatic (3an) azides were
more sluggish substrates, which required the addition of TBTA, a ligand known for accelerating the
triazole formation,[5, 9] and an excess amount of azide for the selectivity of alkynyltriazole to be attractive
for isolation. No azide decomposition product was observed. Therefore, the surplus azide, if needed,
could be recovered rather easily during the product isolation stage.
Figure 1. Reactivity rankings of azides and alkynes to afford alkynyltriazoles. a. TBTA is a ligand known
for accelerating the copper(I)‐catalyzed triazolyl formation from azide and alkyne; b. PA =
phenylacetylene; c. see a later section on this subject; d. e.g., 1‐ethynylpyrene.
The reactivity rankings of azides and alkynes are illustrated in Figure 1. Benzyl azide (including
substituted) and aliphatic azides are easily reacting azides, while most soluble ethynylarenes and
propargylic ethers/amines are favored alkyne substrates. In general, alkynes with low reactivity can be
activated by using more DBN or transforming to the more reactive copper(I) acetylide (vida infra), while
uncooperative azides (e.g., aromatic and secondary azides) can be compensated by using excess
amounts of them in conjunction with the triazole formation‐catalyzing ligand TBTA. Our method
however failed to afford alkynyltriazoles from tertiary alkyl group‐substituted azides and acetylenes,
8
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
likely attributable to the formidable steric effect that tertiary alkyl imposes upon the immediately
adjacent azido or ethynyl groups. Highly electron‐deficient alkynes such as ethynyl ketones failed to
result in alkynyltriazole formations for a different reason. These alkynes (1) are not as prone to oxidation
but highly reactive in the cycloaddition with an azide,[10] and (2) tend to undergo the redox neutral
Michael addition with MeOH in the presence of a base. Therefore, protiotriazole, bistriazole, and the
solvent adduct to the alkyne were common products from these reactions (Scheme S2).
(c) Comparison of outcomes with those of existing methods. Several other procedures that focused on
the preparation of alkynyltriazoles from terminal alkynes and organic azides (or azide precursors) are
listed in chronological order in Table 2. The goals of the current work therefore are to admit more azides
and alkynes as substrates amenable to alkynyltriazole synthesis, and to offer an explanation to the base‐
dependent selectivity between alkynyltriazole and bistriazole. Porco and co‐workers first reported that
the participations of a nitrogen‐based ligand (e.g., TMEDA, DIPEA) and molecular oxygen favor
alkynyltriazole over protiotriazole (entry 1).[7a] The procedures in entries 2 and 3 started not with azides,
but aryl boronic acids[7b] or organic halides[7c] as azide precursors by way of Chan‐Lam coupling and
nucleophilic substitution, respectively, with NaN3. Therefore, the azide scope was limited to aryl azides
in the former case and benzyl/allyl azides or azidoacetate in the latter. Presumably the azide ion acted
as a ligand to copper(I/II) as it was used in excess in both procedures. MeOH was emphasized as the only
solvent that was effective in the procedure in entry 3.[7c] The method listed in entry 4 also used an
alcohol as the solvent (EtOH or MeOH).[6d] The effectiveness of an alcoholic solvent and a nitrogen ligand
was replicated in the current work. A higher temperature was reported to favor the formation of
alkynyltriazoles (at 60 C) over bistriazoles (at 0 C).[6d] In the procedure of entry 5,[7d] H2O2 was
employed as the terminal oxidant in the alkynyltriazole formation starting from ethyl propiolate, an
electron‐deficient alkyne that was problematic under other conditions.[7d]
What these reported procedures share are (1) the use of copper(I) salt as the copper source, (2)
molecular oxygen as the oxidant (because open air conditions were used), (3) the ratio of azide to alkyne
is 1 to 2 or smaller, and (4) diynes and/or protiotriazoles were the major byproducts. Points #2 and #4
were also found in our work, while points #1 and #3 deviate from our preferred conditions. The room
for improvement from the previous works includes the relatively narrow substrate scopes that
collectively scatter over a large swarth of the structural landscape, the lack of rationale on different
reactivities between substrate classes, and in many cases seemingly long reaction times.
9
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
The unique and helpful features of the current procedure (Table 2, entry 6) include the use of
copper(II) as the copper source of this reaction, a reliable approach to optimizing alkynyltriazole
selectivity based on substrate structures (Figure 1), and short reaction times (3‐6 hours of most
examples). Including the compounds in Chart 3 that are to be discussed after the mechanistic analysis,
the current work provides the largest scopes of azides and alkynes that can be selectively transformed
to alkynyltriazoles. Of note, which is mechanistically revealing but may or may not be considered as an
improvement, is that an excess of azide over alkyne would elevate the rate of the reaction and the
selectivity of alkynyltriazole, which stoichiometrically requires the opposite ratio.
Table 2. Procedures of Alkynyltriazole Formation from Terminal Alkyne and Organic Azide (or Precursor)
entry
Cu source
Cu(MeCN)PF6
CuI/CuSO4
Cu2O
oxidant
NMO/air
Not specified
Air
additive
TMEDA
solvent
DCM
reference
1
2
3
4
5
6
7a
a
NaN3
Dioxane/water
MeOH
EtOH
7b
a
NaN3
7c
CuBr
air
KOH
DIEA
DBN
6d
CuCN
H2O2
THF
7d
Cu(OAc)2
O2
MeOH
This work
a. an excess amount of NaN3 was used.
(d) Mechanistic issues. The mechanistic aspects of the alkynyltriazole formation from terminal alkyne
and organic azide were briefly commented in the four previous papers on this topic (entries 1‐4, Table
2).[6d, 7a‐c] Based on those and our own observations, a reaction network is sketched in Scheme 3 to
account for the products that have appeared under the current reaction conditions. The red arrows
denote oxidation reactions, while the blue arrows represent redox neutral reactions. In this model, the
reaction would start with a terminal alkyne in the presence of an azide and an alcoholic solvent.
Copper(I) acetylide needs to form first (step a), which would undergo either redox neutral cycloaddition
with the azide (step b), or oxidation (step d). If either cycloaddition or oxidation of copper(I) acetylide is
10
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
heavily favored, byproducts P and B from the former or D and E from the latter would dominate the
reaction outcome. Only if the two reactions – cycloaddition and oxidation of copper(I) acetylide – are
delicately balanced would the reaction be channeled through step c, during which copper(I) acetylide is
oxidatively couple with the cycloaddition product triazolide to afford alkynyltriazole A. The study of the
reaction ingredients that impact the balance of cycloaddition and oxidation steps is described in the rest
of this section to paint a fuller mechanistic picture, from which the selectivity of various reaction
products can be predicted and therefore controlled by subtle changes of reaction conditions.
Scheme 3. A sketch of the reaction network.a
N
N
(e)
(f)
N
P
B
R
R
R'
Cu
(b)
(c)
(a)
(c)
N
N
R
H
R
R
Cu
Nu
R
N
(d)
A
R'
D, E
a. Blue steps are redox neutral, while red steps are oxidations. Step (a): copper(I) acetylide formation;
(b) cycloaddition with an azide; (c) co‐oxidation of copper(I) acetylide and triazolide; (d) oxidation of
copper(I) acetylide in the presence of a nucleophile (Nu‐); (e) protonation of triazolide; and (f) oxidation
of triazolide to afford bistriazole. A: alkynyltriazole; B: bistriazole; D: diyne; E: substituted acetate (the
“ester”); P: protiotriazole. Also see structures in Table 1.
Because alkyne deprotonation needs to occur in the early stage of the reaction (i.e., before
cycloaddition to form triazolide),[4, 11] the selectivity of the products would then have to be determined
in the subsequent oxidation and cycloaddition steps. To study the product distribution free from the
dictates of the likely slow deprotonation step under different conditions, we elected to use lithium
phenylacetylide as a substrate to react with an azide in the presence of Cu(OAc)2 with or without DBN.
The experiments shown in Scheme 4 were done in THF instead of MeOH so that acetylide would not be
reprotonated to alkyne as would have been in a protic solvent.
11
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Scheme 4. Reaction between 2‐picolyl azide and lithium phenylacetylide.a
a. 2‐Picolyl azide (0.5 mmol), Cu(OAc)2(H2O) catalyst, and DBN (0.5 mmol or null) were dissolved in THF
(0.5 mL) to form solution “CuZ”. Lithium phenylacetylide solution (0.5 mL, 1 M in THF) was referred as
solution “LiY”, which was added dropwise after the reaction mixture was cooled to ‐78 C. The reaction
was kept at ‐78 C for 3 h (i) before warming up to rt over the next 3 h (ii). The distribution of products
was analyzed using 1H NMR spectroscopy after quenching with an EDTA solution (pH = 14, 0.02 M).
Table 3. The Outcomes of the Reaction in Scheme 4.a
entry
DBN
0
Cu(OAc)2(H2O)
0
P
0
3
2
8
1
B
0
A
0
D
Y*
83
19
38
5
1
2
3
4
5
17
68
53
53
71
0
5 mol%
5 mol%
25 mol%
25 mol%
5
4
1 eq.
0
0
7
25
0
10
28
1eq
0
a. Sorted in ascending order of alkynyltriazole (A) percentage (shaded column).
12
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Figure 2. The formation of alkynyltriazole (A, red crosses), bistriazole (B, gray pluses), and diyne (D, blue
triangles) over time in the reactions of entries 4 (a, without DBN) and 5 (b, with DBN) in Table 3. Y*:
terminal alkyne recovered from workup.
Benzyl azide was initially used in place of 2‐picolyl azide in the reaction shown in Scheme 4. Over 80%
of phenylacetylide was converted to diyne, while 1,5‐disubstituted‐1,2,3‐triazole was observed as a
minor product (data not shown), resulting from nucleophilic attack of acetylide to the terminal nitrogen
of benzyl azide.[12] In order to guide this reaction to the pathways of copper‐catalyzed triazole ring
production, 2‐picolyl azide, a good copper(II) ligand[3a, 13] and a favored substrate of copper‐catalyzed
triazole formation,[4] was used to study the product distribution of oxidative coupling between azide and
phenylacetylide. The outcomes of the reaction in Scheme 4 are listed in Table 3 in the ascending order
of the conversion percentage of lithium phenylacetylide (LiY) to alkynyltriazole (A). The observations
with regard to individual components in the reaction mixture are summarized as the following:
(1) Alkynyltriazole (A): A high copper loading (e.g., 25 mol%) in combination with 1 eq. of DBN
produced most alkynyltriazole (entry 5). The formation of alkynyltriazole was at best very slow at ‐78 C
(Figure 2).
(2) Bistriazole (B): The presence of DBN eliminated bistriazole (entries 3 and 5). The absence of DBN
and a high copper loading (entry 4) are required for the appearance of bistriazole, which would not form
at ‐78 C (Figure 2b).
(3) Diyne (D): A major fraction of diyne appeared immediately after mixing at ‐78 C (Figure 2). The
rapid oxidation of lithium phenylacetylide to diyne by copper(II) at such a low temperature was reported
13
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
by Lei and coworkers.[14] The reduced copper(I) accompanying the formation of diyne would capture
unreacted acetylide to form copper(I) acetylide, which was oxidized much slower than lithium acetylide
at ‐78 C. As the temperature rose, DBN facilitated the oxidation of copper(I) acetylide to lead to the
further formation of diyne and alkynyltriazole (Figure 2b), while without DBN the diyne formation did
not reoccur to a meaningful extent (Figure 2a).
Chart 3. Alkynyltriazole Synthesis Starting from Aliphatic Cu(I) Acetylidea
CuI (20 mol%)
R
H
R
Cu
NH4OH, EtOH
Argon, 16 h, rt
1
1'
R
(Cu(OAc)2), DBN, O2
MeOH, 0 oC - rt
N
N
R' N3
2
R
Cu
+
R
N
1'
3
R'
MeO
N
N
N
Oct
N
PhO
N
N
N
N
N
N
Ph
N
N
Oct
nBu
nBu
Oct
Oct
nBu
nBu
Oct
3km, 49% (45%)
3ka, 62% (46%)
3mi, 52% (69%)
3mh, 46% (50%)
N
N
Oct
N
N
N
N
N
PhO
N
N
NO2
Cl
Cl
Cl
Cl
O2N
3nh, 30% (34%)
3os, 52% (48%)
3oi, 65% (64%)
a. Reagents and conditions (standard): azide (0.5 mmol), copper(I) acetylide (0.5 mmol), DBN (0.5
mmol), MeOH (2.5 mL), 0 – rt, O2, 18 h. The isolated yields in the presence of Cu(OAc)2∙H2O (0.025
mmol) are shown in the parentheses in red.
Based on the results illustrated in Figure 2, the oxidation of copper(I) acetylide can be intercepted by
an azide to selectively form alkynyltriazole in the presence of DBN under an atmosphere of O2. Using
copper(I) acetylide instead of terminal alkyne eliminates the potentially slow formation of copper(I)
acetylide, therefore presenting a promising alternative to activate an unreactive terminal alkyne toward
alkynyltriazole formation. For example, after transforming a sluggish aliphatic alkyne substrate to
copper(I) acetylide,[15] which was subsequently subjected to alkynyltriazole formation conditions,
14
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
alkynyltriazoles could be isolated in reasonable yields. Removal of Cu(OAc)2 from the reaction did not
noticeably affect the isolated yields (Chart 3), suggesting that the copper in copper(I) acetylide is
oxidized by O2 to produce the oxidizing agent for the alkynyltriazole formation. The base‐dependent
selectivity of the reaction starting with terminal alkyne was reproduced. Namely, DBN led to
alkynyltriazole while K2CO3 resulted in bistriazole. Therefore, the selectivity between alkynyl‐, bis‐, and
protio‐triazoles is determined after the formation of copper(I) acetylide.
Figure 3. The production of alkynyltriazole as a function of reaction time and concentrations of (a)
benzyl azide, (b) p‐tolylacetylene, (c) Cu(OAc)2, and (d) DBN.
The dependence of alkynyltriazole formation on the four reaction components in reactions starting
from terminal alkynes – azide, alkyne, Cu(OAc)2, and DBN – were studied in time course experiments on
the reaction between p‐tolylacetylene and benzyl azide. The alkynyltriazole formation became faster
15
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
when the azide concentration ([azide]) increased (Figure 3a, see Figure S1 for the production over time
of other products), while the opposite was true when the [alkyne] went up (Figure 3b). In addition to
slowing down the reaction, increasing [alkyne] increased the percentage of the protiotriazole side
product relative to alkynyltriazole (Figure S2). The catalyst Cu(OAc)2 at 5 mol% was sufficient to
complete the reaction in 3 h (Figure 3c, Figure S3). Finally, increasing [DBN] accelerated the oxidation of
alkyne to alknyltriazole and diyne (Figure 3d). When [DBN] was too high, the alkynyltriazole yield
suffered because of competitive formation of a larger amount of diyne (Figure S4). In summary,
increasing the concentrations of azide and DBN results in higher rates of alkynyltriazole formation. DBN
at a sufficiently high concentration however would also produce more of the diyne side product.
Scheme 5. Mechanistic Model of Alkynyltriazole (A) Formationa
a. Bold arrows emphasize the productive (solid arrowheads in‐cycle) and unproductive (hollow
arrowheads off‐cycle) steps that DBN and azide accelerate in the formation of alkynyltriazole.
16
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Based on the reactions starting from terminal alkyne, lithium acetylide, or copper(I) acetylide, a
mechanistic model is sketched as Scheme 5. When a reaction is initiated via the addition of
Cu(OAc)2∙H2O and an azide into a solution of lithium acetylide at ‐78 C, acetylide would immediately
coordinate with copper(II), which would be followed by the rapid inner sphere electron transfer reaction
to produce diyne and copper(I) (Step I). Copper(I) would react with lithium acetylide to form copper(I)
acetylide (Step II). Copper(I) acetylide would bind azide to form a copper(I)/acetylide/azide ternary
complex (Step III), which upon warming up from ‐78 C would collapse to copper(I) triazolide (Step IV). If
an acetylide binds to copper(I) at this point via ligand exchange (Step V), or already is in the coordination
sphere of a triazolide‐bound copper(I), oxidation would follow to likely first give a higher valency copper
species (Step VI), followed by reductive elimination to afford alkynyltriazole (Step VII). The oxidation and
cycloaddition steps are accelerated by DBN and azide, respectively, and depending on the relative
difficulty of each step the quantities of these two ingredients need to be determined accordingly.
There are multiple exits of the catalytic cycle that are either reduction/oxidation (VII and VIII) or
protonation (XI) steps. Copper(I) acetylide and copper(I) triazolide may undergo either homo‐ or hetero‐
oxidative coupling reactions to afford alkynyltriazole (Steps VI/VII), diyne (Step VIII), and bistriazole (Step
IX). The participation of DBN preferentially accelerates copper(I) acetylide‐involved oxidation steps (VI‐
VIII). Azide binding/cycloaddition steps (III/IV and X) would compete with copper(I) acetylide oxidation.
An observation to illustrate the tug of war between oxidation and cycloaddition was made in the
oxidative triazole formation between benzyl azide and an equal molar mixture of p‐tolylacetylene and
ethynyl methyl ketone, the latter alkyne is highly reactive in cycloaddition reaction.[10] The major
oxidative coupling products from this experiment was the alkynyltriazole derived solely from p‐
tolylacetylene, and the bistriazole derived solely from ethynyl methyl ketone (Scheme S3). It can be
explained and was suggested by 1H NMR time course data that ethynyl methyl ketone dominated the
reaction early to form acetylide followed by the rapid cycloaddition to triazolide. The oxidation follows
to result in bistriazole. Copper could then be made available to engage p‐tolylacetylene. The resulting p‐
tolylacetylide oxidation was now competitive with cycloaddition with benzyl azide to produce the
alkynyltriazole. For terminal alkynes that are not as acidic as ethynyl carbonyls, on balance extra
amounts of azide would augment the production of alkynyltriazole in the expense of diyne.
If a terminal alkyne is used as the starting material, as the way that most of the reactions were done in
the current work, the deprotonative Cu(I) acetylide formation would be turnover determining (Step II).
This step, however, may take place with the cycloaddition partner azide already installed as a ligand,
17
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
which would accelerate the following triazolide formation steps (III and IV). If the reaction were to start
with the premade Cu(I) acetylide,[15] then the azide binding (Step III) would be relatively slow. In this
event, as reflected in the experimental observations, an excess amount of azide has to be used to
suppress the production of diyne to favor the alkynyltriazole formation, and the reaction has to be run
at rt or higher to convert the premade, polymeric Cu(I) acetylide,[15] as compared to the reactions of
lithium acetylide taking place at ‐78 C.[14]
Conclusion
In summary, we have demonstrated that the outcome of the copper‐catalyzed oxidative coupling
between azide and terminal alkyne is determined by the competition between the cycloaddition to form
triazolide and the copper(I) acetylide oxidation. Depending on the nature of a basic additive, one
outcome would be favored over the other. K2CO3 would result in bistriazole as have been demonstrated
previously, while DBN leads to the formation of alkynyltriazole as the major product. Critical to the
preference of alkynyltriazole is the ability of DBN to promote copper(I) acetylide oxidation chemistry,
which can be intercepted by an azide substrate to afford alkynyltriazole. In this case, the oxidation of
copper(I) acetylide to diyne or other nucleophile‐coupled products are major side reactions, which can
be offset by introducing an excess of azide to increase the selectivity for alkynyltriazole. The procedure
developed in this work has been applied to prepare alkynyltriazoles from a variety of terminal alkynes
and azides. This report (1) increases the versatility of copper‐catalyzed azide‐alkyne coupling reactions,
and (2) contributes to the broader mechanistic understanding of copper‐catalyzed oxidation reactions.
Experimental Section
1. General information. Reagents and solvents (including the solution of lithium phenylacetylide, 1 M
in THF) were purchased from various sources and used without further purification. HPLC grade MeOH
was used for the preparation of alkynyltriazoles. TLC silica gel 60 F254 was applied for thin layer
chromatography. Column chromatography was performed with silica gel as the stationary phase. 1H and
13C NMR spectra were recorded at 400/500/600 and 100/125/150 MHz, respectively, at 295 K unless
otherwise noted. All chemical shifts were reported in δ units relative to tetramethylsilane. High‐
resolution mass spectra were recorded using electrospray ionization or DART (Direct analysis in real
time) using a time‐of‐flight analyzer. Commercial benzyl azide was purified by column chromatography
18
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
before use. Aromatic azides were synthesized by diazotization of aniline derivatives.[16] Other organic
azides were synthesized by nucleophilic substitution of organic halides and NaN3.[17] CAUTION! Low
molecular weight organic azides are potentially explosive. Appropriate protective measures should
always be applied when handling these chemicals.
2. Standard procedure starting from terminal alkyne (Entry 9, Table 1). In a 50‐mL round‐bottom
flask with a stirring bar, copper(II) acetate monohydrate (5.0 mg, 0.025 mmol) was added and dissolved
by a solution of organic azide (0.5 mmol) in MeOH (0.25 mL). The flask was purged with oxygen and
sealed with a rubber septum. Then the flask was placed on an ice bath and an oxygen balloon was
equipped. DBN (62.0 mg, 0.5 mmol) was weighed in a vial and transferred to the flask via a syringe while
stirring. After that, a solution of alkyne (0.5 mmol) in MeOH (0.25 mL) was added into the flask dropwise
via a syringe. The reaction mixture was stirring at 0 C and was warmed up to rt over the course of the
reaction (3 h). The reaction mixture was then diluted with ethyl acetate (50 mL) and washed with a
saturated NH4Cl solution. The organic layer was dried on anhydrous Na2SO4 and the solvent was
removed under reduced pressure. The final product was isolated by silica column chromatography.
3.Standard procedure starting from copper(I) acetylide (Chart 3). In a 50‐mL round‐bottom flask with
a stirring bar, copper(I) acetylide[15b] (0.5 mmol) was dissolved in MeOH (1.0 mL). The flask was purged
with oxygen and sealed with a rubber septum. Then the flask was placed on an ice bath and an oxygen
balloon was equipped. An azide (0.5 mmol) was dissolved in MeOH (1.0 mL) and transferred to the
stirring reaction mixture. After that, DBN (62 mg, 0.5 mmol) was added via a MeOH (0.5 mL) solution.
The reaction mixture was stirring at 0 C and was warmed up to rt over the course of the reaction. The
reaction mixture was then diluted with ethyl acetate (50 mL) and washed with a saturated NH4Cl
solution. The organic layer was dried on anhydrous Na2SO4 and the solvent was removed under reduced
pressure. The final product was isolated by silica column chromatography.
Acknowledgements
This work was supported by the National Science Foundation (CHE1566011).
Supporting information for this article is accessible via the following weblink XXXXX.
19
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
References
[1]
a) C. W. Tornøe, M. Meldal, in Peptides 2001, Proc. Am. Pept. Symp., American Peptide Society
and Kluwer Academic Publishers, San Diego, 2001, pp. 263‐264; b) C. W. Tornøe, C. Christensen,
M. Meldal, J. Org. Chem. 2002, 67, 3057‐3064; c) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.
Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596‐2599.
[2]
[3]
a) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952‐3015; b) J. E. Hein, V. V. Fokin, Chem.
Soc. Rev. 2010, 39, 1302‐1315.
a) W. S. Brotherton, H. A. Michaels, J. T. Simmons, R. J. Clark, N. S. Dalal, L. Zhu, Org. Lett. 2009,
11, 4954‐4957; b) G.‐C. Kuang, H. A. Michaels, J. T. Simmons, R. J. Clark, L. Zhu, J. Org. Chem.
2010, 75, 6540‐6548.
[4]
G.‐C. Kuang, P. M. Guha, W. S. Brotherton, J. T. Simmons, L. A. Stankee, B. T. Nguyen, R. J. Clark,
L. Zhu, J. Am. Chem. Soc. 2011, 133, 13984‐14001.
[5]
[6]
T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853‐2855.
a) Y. Angell, K. Burgess, Angew. Chem. Int. Ed. 2007, 46, 3649‐3651; b) J. González, V. M. Pérez,
D. O. Jiménez, G. Lopez‐Valdez, D. Corona, E. Cuevas‐Yañez, Tetrahedron Lett. 2011, 52, 3514‐
3517; c) Z.‐J. Zheng, F. Ye, L.‐S. Zheng, K.‐F. Yang, G.‐Q. Lai, L.‐W. Xu, Chem. Eur. J. 2012, 18,
14094‐14099; d) L. Li, X. Fan, Y. Zhang, A. Zhu, G. Zhang, Tetrahedron 2013, 69, 9939‐9946; e) C.
J. Brassard, X. Zhang, C. R. Brewer, P. Liu, R. J. Clark, L. Zhu, J. Org. Chem. 2016, 81, 12091‐12105.
a) B. Gerard, J. Ryan, A. B. Beeler, J. A. Porco Jr., Tetrahedron 2006, 62, 6405‐6411; b) D. Yang, N.
Fu, Z. Liu, Y. Li, B. Chen, Synlett 2007, 278‐282; c) F. Alonso, Y. Moglie, G. Radivoy, M. Yus,
Synlett 2012, 23, 2179–2182; d) H. Amdouni, G. Robert, M. Driowya, N. Furstoss, C. Métier, A.
Dubois, M. Dufies, M. Zerhouni, F. Orange, S. Lacas‐Gervais, K. Bougrin, A. R. Martin, P.
Auberger, R. Benhida, J. Med. Chem. 2017, 60, 1523‐1533.
[7]
[8]
G. Eglinton, A. R. Galbraith, Chem. Ind. (London) 1956, 737‐738.
[9]
H. A. Michaels, L. Zhu, Chem. Asian J. 2011, 6, 2825–2834.
[10]
[11]
X. Zhang, P. Liu, L. Zhu, Molecules 2016, 21, 1697.
a) L. Jin, D. R. Tolentino, M. Melaimi, G. Bertrand, Sci. Adv. 2015, 1, e1500304; b) L. Zhu, C. J.
Brassard, X. Zhang, P. M. Guha, R. J. Clark, Chem. Rec. 2016, 16, 1501–1517.
A. Krasiński, V. V. Fokin, K. B. Sharpless, Org. Lett. 2004, 6, 1237‐1240.
W. S. Brotherton, P. M. Guha, P. Hoa, R. J. Clark, M. Shatruk, L. Zhu, Dalton Trans. 2011, 40,
3655‐3665.
[12]
[13]
[14]
[15]
R. Bai, G. Zhang, H. Yi, Z. Huang, X. Qi, C. Liu, J. T. Miller, A. J. Kropf, E. E. Bunel, Y. Lan, A. Lei, J.
Am. Chem. Soc. 2014, 136, 16760–16763.
a) C. Theunissen, M. Lecomte, K. Jouvin, A. Laouiti, C. Guissart, J. Heimburger, E. Loire, G. Evano,
Synthesis 2014, 46, 1157‐1166; b) X. Wang, X. Wang, X. Wang, J. Zhang, C. Liu, Y. Hu, Chem. Rec.
2017, 17, 1231‐1248.
[16]
[17]
M. Kurumi, K. Sasaki, H. Takata, T. Nakayama, Heterocycles 2000, 53, 2809‐2819.
D. N. Barsoum, C. J. Brassard, J. H. A. Deeb, N. Okashah, K. Sreenath, J. T. Simmons, L. Zhu,
Synthesis 2013, 45, 2372‐2386.
20
This article is protected by copyright. All rights reserved.

10.1002/asia.201901581
Chemistry - An Asian Journal
Graphical Abstract
+
Cu
R
H
AZIDE
N N
R
Cu
N
R
R'
DBN
Cu
[O]
[O]
DBN
[O]
R
R
N N
N N
N
N
R
R'
R
R'
R'
R
N
N N
R
37 examples
The selectivity for alkynyltriazole over diyne and bistriazole depends the quantities of DBN and azide –
the former accelerates copper(I) acetylide oxidation, while the latter promotes triazolide formation.
21
This article is protected by copyright. All rights reserved.