Cu(II)-Catalyzed Oxidative Formation of 5,5′-Bistriazoles

Article abstract of DOI:10.1021/acs.joc.6b01907

Copper(II) acetate under aerobic conditions catalyzes the formation of 5,5′-bis(1,2,3-triazole)s (5,5′-bistriazoles) from organic azides and terminal alkynes. This reaction is an oxidative extension of the widely used copper-catalyzed azide-alkyne “click”

Full text of DOI:10.1021/acs.joc.6b01907

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Featured Article
Cu(II)-Catalyzed Oxidative Formation of 5,5’-Bistriazoles
Christopher J. Brassard, Xiaoguang Zhang, Christopher R. Brewer, Peiye Liu, Ronald J Clark, and Lei Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01907 • Publication Date (Web): 14 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cu(II)ꢀCatalyzed Oxidative Formation of 5,5’ꢀ
Bistriazoles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Christopher J. Brassard, Xiaoguang Zhang, Christopher R. Brewer, Peiye Liu, Ronald J. Clark,
Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way,
Tallahassee, FL 32306ꢀ4390, USA
KEYWORDS. CuAAC, copper catalysis, oxidative coupling, 5,5’ꢀbistriazole, TBTA.
ABSTRACT. Copper(II) acetate under aerobic conditions catalyzes the formation of 5,5’ꢀ
bis(1,2,3ꢀtriazole)s (5,5’ꢀbistriazoles) from organic azides and terminal alkynes. This reaction is
an oxidative extension of the widely used copperꢀcatalyzed azideꢀalkyne ‘click’ cycloaddition.
The inclusions of potassium carbonate as an additive and methanol or ethanol as the solvent, and
in most instances an atmosphere of dioxygen, promote the oxidative reaction to afford 5,5’ꢀ
bistriazole at the expanse of 5ꢀprotioꢀ1,2,3ꢀtriazole (5ꢀprotiotriazole). If needed, tris[(1ꢀbenzylꢀ
1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)methyl]amine (TBTA) as a ligand additive further accelerates the
formation of 5,5’ꢀbistriazoles. A convenient procedure to prepare TBTA is also reported to
facilitate the adoption of this method by the individuals who wish to make 5,5’ꢀbistriazoles for
various purposes. Aromatic azideꢀderived 5,5’ꢀbistriazoles possess rigid axially chiral structures
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 46
1
2
3
4
5
6
with a broad distribution of dihedral angles, which may be explored as chiral ligands in
enantioselective catalysis if decorated with proper functional groups.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Introduction
Copper(I)ꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) affords 1,4ꢀdisubstitutedꢀ1,2,3ꢀ
triazoles (‘H’ in Scheme 1, or ‘5ꢀprotiotriazole’).1,2,3 5,5’ꢀBis(1,2,3ꢀtriazole)s (‘B’, or ‘5,5’ꢀ
bistriazole’) and 5ꢀalkynylꢀ1,2,3ꢀtriazoles (‘A’, or ‘5ꢀalkynyltriazole’) are the side products from
unintended oxidation (Scheme 1).4,5 The formation of 5,5’ꢀbistriazole likely results from the
oxidative homocoupling of copper(I) triazolide intermediate, a step bearing resemblance to the
aromatic GlaserꢀHay reaction reported by Do and Daugulis.6 This hypothesis provides a
mechanistic foundation for the selective formation of a 5,5’ꢀbistriazole that puts two azide and
two alkyne molecules together in a single step. In addition to providing axially chiral 5,5’ꢀ
bistriazoles with hopefully an adequate structural diversity for exploring the utility in asymmetric
catalysis, this reaction is interesting mechanistically in the context of the widely used CuAAC
reactions5,7ꢀ15 and the intensely studied copperꢀmediated oxidative coupling reactions.16ꢀ19
Scheme 1. 5,5’ꢀBistriazole (B) and 5ꢀalkynyltriazole (A) are side products from CuAAC that
likely result from oxidative interception of the Cu(I) triazolide intermediate (bracketed)
ACS Paragon Plus Environment
2

Page 3 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Several methods for preparing 5,5’ꢀbistriazoles via the model of oxidative interception of
CuAAC have been reported over the past decade;20ꢀ26 four of which are shown in Scheme 2.
These works were also summarized in a review article on the synthesis of broadly defined
bistriazoles that include 5,5’ꢀbistriazoles.27 Angell and Burgess were the first to report the
selective formation of 5,5’ꢀbistriazole by the inclusion of a base in a CuAAC method (Scheme
2a).20 The effect of a base to favor the oxidative reaction was analyzed. Furthermore, the specific
effect of carbonate as a bridging ligand for copper centers, in addition to being a base, was
postulated. CuevasꢀYañez and coworkers reported the beneficial effect of lowering temperature
(ꢀ35 °C) in the selective formation of 5,5’ꢀbistriazole (Scheme 2b), at the expense of a long
reaction time (48 h).22 Xu and coworkers’ procedure includes an organic amine base (or ligand)
in place of an inorganic base for 5,5’ꢀbistriazole synthesis (Scheme 2c),24 while in the work by
Li, Zhang, and coworkers, the strongly basic sodium ethoxide was used (Scheme 2d).25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 46
1
2
3
4
Scheme 2. Selected known methods to prepare 5,5’ꢀbistriazoles.
5
6
7
8
9
R
R'
Cu powder (1 equiv.)
CuSO4 (10 mol%)
N
N
N
N
N
R
R' N3
+
(a)
1:1 mixture of CH3CN
and aq. Na2CO3 (2 M)
N
R'
R
air, 25 oC, 18 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Angell and Burgess, Angew. Chem. Int. Ed. 2007, 46, 3649.
Ph
CuI (5 mol%)
R
NaOH (15 equiv.)
BaCl2 (30 mol%)a
N
N
N
N
N
R
+
Ph
N3
(b)
4 Å molecular sieves
-35 oC, CH3OH, 48 h
N
R
Ph
2011
Cuevas-Yañez and coworkers, Tetrahedron Lett.
, 52, 3514.
N
N
CuCl (5 mol %)
R'
N
R
ligand (10 mol %)b
R
+
R'
N3
(c)
0 oC, CH2Cl2, 24 h
R
N
N
R'
N
Xu and coworkers, Chem. Eur. J. 2012, 18, 14094.
R
R'
CuBr (10 mol %)
N
EtOH, EtONa (2.0 equiv.)
N
N
N
R
R' N3
+
(d)
air, 0 oC, 20-48 h
N
N
R'
R
Zhang and coworkers, Tetrahedron 2013, 69, 9939.
a. BaCl2 was used in the workup;22 b. polysiloxaneꢀsupported amines.
In addition to using a copper catalyst in the +1 oxidation state (in the case of Angell and
Burgess’ report, copper(I) is presumed to form from the comproportionation of copper powder
and copper(II) sulfate28), these empirical pioneering works have offered a common denominator
for achieving selective 5,5’ꢀbistriazole formation that is the inclusion of a base (blue in Scheme
2). However, the existing methods in general require a relatively long time (12ꢀ48 h, red in
Scheme 2), and have thus far limited substrate scopes. In particular, 5,5’ꢀbistriazoles derived
from aromatic azides have not been reported but for one isolated case.29
ACS Paragon Plus Environment
4

Page 5 of 46
The Journal of Organic Chemistry
1
2
3
4
Results and Discussion
5
6
7
8
(a) Modifying the CuAAC reaction toward 5,5’-bistriazoles. Herein we report a simple
procedure to prepare 5,5’ꢀbistriazoles based on the mechanistic postulate illustrated in Scheme 1
that improves upon the known methods in two aspects: (1) reducing the reaction time from
overnight or longer to within 3 h, and (2) expanding the substrate scope to include aromatic
azideꢀderived 5,5’ꢀbistriazoles. Our group has demonstrated that CuAAC can be catalyzed by
Cu(OAc)2⋅H2O without having a reducing agent to deliberately generate a copper(I) species.30
The absence of a reducing agent renders our method particularly amenable for tweaking to favor
the oxidatively coupled 5,5’ꢀbistriazoles. Ligand tris[(1ꢀbenzylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀ
yl)methyl]amine (TBTA) will be included in the procedure if needed due to its known effect of
accelerating the triazolyl ring formation step.31ꢀ33 The high cost of TBTA might be viewed as an
inconvenience. To alleviate this concern, we developed a costꢀeffective procedure to prepare
TBTA in gram scales within a few hours of total production time, which is described in the
Experimental Section.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 46
1
2
3
4
5
6
Table 1. Effect of base, solvent, and copper(II) source on the conversion and selectivity of the
reaction between 1a (benzylazide) and 2a (phenylacetylene).a
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
1
Base
ꢀ
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
Cu(II) salt
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
conversionb
15%
14%
17%
> 99%
0
Selectivity (3aa/4aa/5aa)c
0/89/11
12/58/30
67/20/13
70/8/22
ꢀ
2
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
TEA
3
4
5
6
7%
23/9/68
19/64/17
3/68/29
85/4/10
ꢀ
7
13%
> 99%
11%
0%
8
DBU
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14
tBuOH
MeCN
MeOH
MeOH
MeOH
43%
98%
87%
90%
38/53/9
69/8/23
67/8/25
66/12/22
CuSO4
Cu(ClO4)2
a. Reagents and conditions: 1a (0.55 mmol in 0.25 mL solvent), Cu(II) (0.025 mmol), base (1.0
mmol), and 2a (0.5 mmol in 0.25 mL solvent), added in this order, 1 h at rt under air; b. the
percentage of reacted alkyne, which is the limiting reagent; c. the ratio showing the distribution
of converted alkyne into three possible products 3aa, 4aa, and 5aa, based on 1H NMR spectra of
crude products. The homocoupled diyne was not observed.
Using the reaction between benzylazide (1a) and phenylacetylene (2a), which have been the
most common pair of substrates for the optimization of 5,5’ꢀbistriazole formation, it was
ACS Paragon Plus Environment
6

Page 7 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
determined that the inclusions of K2CO3 as a base additive, methanol as the solvent, and
Cu(OAc)2⋅H2O in solid form as the catalyst resulted in the selective formation of 5,5’ꢀbistriazole
3aa (70% selectivity; 54% isolated yield) in 1 h (Table 1, entry 4). K2CO3 was reported to have
the second best solubility in methanol among the alkali carbonates after Cs2CO3.34 Upon
dissolution, K2CO3 deprotonates methanol to produce an appropriate amount of methoxide,35,36
which we postulate to be involved as a ligand for copper in this reaction. This argument is
consistent with the report that sodium ethoxide was the choice of base in the 5,5’ꢀbistriazole
synthesis by Li, Zhang, and coworkers (Scheme 2d).25 We tried sodium methoxide as the base in
two reactions (see Table S2). Good selectivity values were obtained, consistent with the
proposed function of methoxide as a ligand for copper that favors the formation of 5,5’ꢀ
bistriazole. Yet the reaction became slower with an increasing amount of sodium methoxide.
Sodium methoxide was not considered further because K2CO3 worked well enough in this work.
K3PO4 (entry 6) in place of K2CO3 resulted in 7% conversion. Organic bases such as TEA (entry
7) or DBU (entry 8) did not deliver satisfactory values of either conversion or selectivity toward
5,5’ꢀbistriazole (3aa).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Regarding the solvent, both methanol and ethanol resulted in good selectivity for 5,5’ꢀ
bistriazole. However, the conversion value in ethanol after 1 h was low (11%, entry 9). The
reactions in tꢀbutanol (entry 10) and acetonitrile (entry 11) were sluggish on both conversion and
selectivity fronts. The effect of the third variable, the copper(II) source, was studied in methanol.
All copper(II) salts tested gave similar marks on conversion and selectivity (entries 4, 12ꢀ14).
The close reactivity can be explained by the fact that these salts likely rearrange in the presence
of carbonate and methoxide to afford similar copper(II) cluster structures. (CuOH)2CO3, a
compound that may bear similarity to the copper(II) species suspected to have formed under the
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 46
1
2
reported conditions, is competent in oxidative coupling reactions.37 Cu(OAc)2 was selected for
further experiments, which based on our experience gives the most consistent reaction outcome.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2.a Effect of TBTA, NaNO2, O2, and reactant stoichiometry on reaction conversionb and
selectivityc.
Selectivity
entry 1b/2b
Additive
Conversionb
(3bb/4bb/5bb)c
1
2
3
4
5
6
7
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
2/1
None, air
12
28
ꢀ
TBTA (5 mol%)d air
54/34/12
40/48/12
50/35/15
39/48/13
61/24/15
50/40/10
TBTA (20 mol%) air
58
TBTA (20 mol%), O2
51
TBTA (20 mol%), O2, NaNO2 (0.5 mmol)
TBTA (20 mol%), O2, NaNO2 (0.5 mmol)
TBTA (20 mol%), O2, NaNO2 (0.5 mmol)
92
> 99
73
1/2
a. Reagents and conditions: the limiting reagent was set at 0.5 mmol. 1b (variable in 0.25 mL
MeOH), Cu(OAc)2 H2O (0.025 mmol), K2CO3 (0.5 mmol), and 2b (0.5 mmol in 0.25 mL
MeOH), added in this order, 3 h at rt; b. the percentage of the reacted limiting reagent; c. the
ratio showing the distribution of converted alkyne into three possible products 3bb, 4bb, and
1
5bb, based on H NMR spectra of crude products; d. the percentage is based off the limiting
reagent.
A less reactive pair of substrates, 4ꢀazidoanisole (1b) and 1ꢀdecyne (2b), was used to study
how other reaction parameters affect the conversion and selectivity of the 5,5’ꢀbistriazole
forming reaction (Table 2).38 In the absence of 1b, oxidative homocoupling of alkyne 2b was not
ACS Paragon Plus Environment
8

Page 9 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
observed under the conditions listed for Table 1, entry 4 in 3 h. The inclusion of 4ꢀazidoanisole
(1b) resulted in a 12% conversion of 2b (Table 2, entry 1). Adding ligand TBTA up to 20 mol %
helped the conversion, with 40% selectivity to 5,5’ꢀbistriazole (entries 2 and 3). With the
understanding that O2 is the stoichiometric oxidant,39 an O2 atmosphere was provided, which
increased the selectivity to 5,5’ꢀbistriazole with a drop in conversion (entry 4). The inclusion of
NaNO2, which is both an oxidant and a ligand for copper(II), drove the reaction almost to
completion (entry 5), with a similar selectivity spread to that of entry 3. By doubling the amount
of azide 1b under the conditions of entry 5, a complete conversion of 2b was achieved with 61%
selectivity toward 5,5’ꢀbistriazole (entry 6, 52% isolated yield for 3bb). Reversing the
stoichiometric ratio (i.e., using an excess of alkyne) slowed down the reaction with a reduction in
5,5’ꢀbistriazole selectivity (entry 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on the data in Tables 1 and 2, the following reaction parameters were selected for
favoring 5,5’ꢀbistriazole formation: (1) 5ꢀ10 mol% Cu(OAc)2 as the catalyst; (2) 0.5ꢀ2 molar
equivalents K2CO3 relative to the limiting reagent alkyne as the additive; (3) MeOH or EtOH as
the solvent; (4) TBTA as an optional ligand for accelerating the triazolyl ring formation; (5) an
O2 atmosphere for favoring the oxidative reaction; (6) an excess amount of azide to increase the
selectivity toward 5,5’ꢀbistriazole; and (7) NaNO2 as an oxidative analog of acetate to push up
the conversion and selectivity towards 5,5’ꢀbistriazole, if needed. The decision on whether to
include TBTA, O2, or NaNO2 is made based on the compromise between reaction speed and
selectivity under individual circumstances. The effectiveness of this method was tested using
various azides and alkynes (Figures S1ꢀ2). Using this method, the reactions were completed
within 3 h to provide > 50% isolated yields of 5,5’ꢀbistriazole products. The data (Tables 3ꢀ5) are
described separately based on the nature of the azide component.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 46
1
2
3
4
5
6
7
8
9
(b) Scope of substrates organized by the nature of azides. Benzylazide (1a) has been the most
studied azide substrate in 5,5’ꢀbistriazole forming reactions.20,22ꢀ25,40 Using the current method,
5,5’ꢀbistriazoles derived from 1a and paraꢀsubstituted phenylacetylenes readily formed. The
selectivity and isolated yields of entries 1ꢀ6 in Table 3 are listed in the ascending order of
Hammett constant (σ)41 of the paraꢀsubstituent. Phenylacetylenes equipped with electronꢀ
withdrawing paraꢀsubstituents (entries 3ꢀ6) require EtOH as the solvent with the assistance of
TBTA to afford a complete conversion and good selectivity toward 5,5’ꢀbistriazole within 3 h;
the reactions of these substrates in MeOH gave worse selectivity toward 5,5’ꢀbistriazoles. The
reactions between 1a and phenylacetylenes substituted with electronꢀdonating groups (entries 1ꢀ
2) proceeded smoothly in MeOH without TBTA. We defer to a future mechanistic study to
provide an explanation for this empirical electronic correlation with the choice of solvent.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. 5,5’ꢀBistriazoles derived from benzylazide.a
Solvent/
ligand
Isolated yield
(%)
entry
1
5,5’ꢀBistriazole
Selectivity (3/4/5)
MeOH/
none
82/7/11
58
66
63
MeOH/
none
2
3
75/13/12
82/14/4
EtOH/
TBTA
ACS Paragon Plus Environment
10

Page 11 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
EtOH/
TBTA
4
5
6
7
86/10/4
90/6/4
60
72
68
67
EtOH/
TBTA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
CN
Ph
EtOH/
TBTA
77/13/10
Ph
N
N
NC
3ah
N
EtOH/
TBTA
79/8/13
N
N
N
N
Ph
EtOH/
TBTA
8
77/18/5
62
71
17
17
Ph
3aj
N
N
N
N
MeOH/
none
9b
80/13/7
MeOH/
none
10c
11d
ꢀ
ꢀ
MeOH/
TBTA
a. Reagents and conditions: benzylazide (1.0 mmol), Cu(OAc)2 (0.025 mmol), TBTA (0.025
mmol if needed), K2CO3 (0.5ꢀ2 mmol, see the Experimental Section), and alkyne (0.5 mmol) in
MeOH or EtOH (0.5 mL) at rt for 3 h; b. azide: 0.5 mmol; alkyne: 1.0 mmol; Cu(OAc)2⋅H2O:
0.050 mmol; c. azide: 2.0 mmol; Cu(OAc)2⋅H2O: 0.1 mmol; under an atmosphere of O2; d. 6 h, 0
°C – rt.
The reactions between benzylazide and 3/4ꢀethynylpyridine using the combination of TBTA
and EtOH resulted in acceptable conversions and selectivity within 3 h (entries 7ꢀ8, Table 3).
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 46
1
2
3
4
5
6
7
8
9
Benzylazide also reacted well with the aliphatic 1ꢀdecyne (entry 9), in MeOH without TBTA. A
cyclic 5,5’ꢀbistriazole was prepared from 1,7ꢀoctadiyne (entry 10). Ethynyltrimethylsilane was
used to react with benzylazide based on the suggestion from a reviewer. This reaction afforded
the desilylated 5,5’ꢀbistriazole 3an (entry 11) in 17% isolated yield. The reaction was extended
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
to 6 h, yet there was evidence based on the H NMR that the desilylation was not complete.
Furthermore, the desilylated 5ꢀalkynyltriazole could react with benzylazide to afford 4,5’ꢀ
bistriazole, which might have complicated the analysis of the reaction mixture. Therefore, we did
not determine the selectivity values. Compound 3an was previously reported by Angell and
Burgess with 25% isolated yield from a reaction that lasted 18 h.20
Aliphatic azideꢀengaged 5,5’ꢀbistriazole formations are listed in Table 4. Both primary (entries
1ꢀ4) and secondary (entry 7) aliphatic azides underwent rapid conversions to 5,5’ꢀbistriazoles
with good selectivity. Two macrocyclic 5,5’ꢀbistriazoles (entries 5ꢀ6) were obtained from 1,6ꢀ
bis(azido)hexane in moderate yields. How to selectively produce macrocyclic 5,5’ꢀbistriazoles of
arbitrary ring sizes with good isolated yields is an aim of future studies.
Table 4.a 5,5’ꢀBistriazoles derived from aliphatic azides.
Solvent/
ligandb
Isolated
Yield (%)
entry
1
5,5’ꢀBistriazole
Selectivity (3/4/5)
N
N
Hex
MeOH/
TBTA
(0.1)
N
82/10/8
81
81
3ca
3da
N
Hex
N
N
N
N
PhO
EtOH/
TBTA
(0.025)
N
2
87/10/3
N
OPh
N
N
ACS Paragon Plus Environment
12

Page 13 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MeOH/
none
3c
4
74/9/17
55
61
32
12
53
MeOH/
TBTA
(0.1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
75/11/14
EtOH/
TBTA
(0.1)
5
ꢀ
EtOH/
TBTA
(0.1)
6
ꢀ
MeOH/
TBTA
(0.025)
7
69/23/8
a. Reagents and conditions: azide (0.5ꢀ1.0 mmol, see the Experimental Section),
Cu(OAc)2⋅H2O (0.025 mmol), TBTA (0.025ꢀ0.10 mmol, if needed); K2CO3 (0.25ꢀ1.5 mmol, see
the Experimental Section), and alkyne (0.5 mmol) in MeOH or EtOH (0.5ꢀ1 mL, see the
Experimental Section) at rt for 3 h under an atmosphere of O2; b. mmol in parentheses; c. NaNO2
(0.5 mmol) and an increasing amount of azide (2.5 mmol) were used.
Aromatic azideꢀinvolved reactions require the participation of TBTA under an atmosphere of
O2 to reach satisfactory conversions and selectivity favoring 5,5’ꢀbistriazoles (Table 5). On a
side note, to the best of our knowledge, this is the first report of copperꢀcatalyzed triazolyl ring
formation reaction that was done under an O2 atmosphere. The conventional wisdom “calls for
complete exclusion of oxygen from the reaction medium”7 because of the requirement of copper
in the +1 oxidation state for the cycloaddition step. Yet the rapid triazolyl ring formation
observed in this work under an atmosphere of O2 underscores that the threshold for the copper(I)
catalyst can be deceptively low.42
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 46
1
2
3
4
5
6
7
8
9
The selectivity toward 5,5’ꢀbistriazole of the examples starting with aromatic azides ranges in
the 60sꢀ70s%, whereas the 5,5’ꢀbistriazole selectivity values from benzyl (Table 3) and aliphatic
(Table 4) azides are higher. MeOH worked well as the solvent when neither alkyne nor aromatic
azide substrate bears an electronꢀwithdrawing substituent (entries 1ꢀ10, Table 5). All other
substrate pairs gave good conversion and selectivity in EtOH. In addition to paraꢀsubstituted
azidobenzenes, metaꢀ and orthoꢀazidoanisoles also resulted in >50% isolated yields for 5,5’ꢀ
bistriazoles in four examples (entries 7ꢀ9, 11). For a subset of substrates (entries 5, 7, 8, 11) the
reactions were run at 0 °C to obtain acceptable isolated yields (i.e., > 50%). The effect of a low
temperature for favoring 5,5’ꢀbistriazole formation has been reported by others.22,24,25 The
tradeoff however is the time of the reaction. In the current work, the majority of the reactions do
not require a temperature below rt to result in a favorable 5,5’ꢀbistriazole formation with an
isolated yield over 50%. Therefore, the effect of temperature was not studied systematically.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. 5,5’ꢀBistriazoles derived from aromatic azides.a
Isolated
Yield (%)
entry
1
5,5’ꢀBistriazole
Selectivity (3/4/5)
Solvent
MeOH
63/12/25
59
2
3
69/11/20
69/18/13
MeOH
MeOH
59
55
N
N
O
N
N
N
O
3bl
N
N
N
ACS Paragon Plus Environment
14

Page 15 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4b
5c
6
76/10/14
MeOH
MeOH
MeOH
62
56
63
N
N
N
3ia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
65/12/24
N
N
N
65/18/17
O
N
N
N
7c
68/9/23
MeOH
MeOH
62
51
3ka
N
N
N
O
8c
66/3/31
9d
10d, e
11c
72/18/10
MeOH
MeOH
EtOH
EtOH
54
56
52
52
65/19/16
O
N
N
N
CO2Me
66/29/5
MeO2C
N
3km
N
N
O
12
72/19/9
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 46
1
2
3
4
N
N
O
N
Cl
3bf
5
6
7
8
13
14
75/13/12
EtOH
EtOH
70
61
Cl
N
O
N
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
74/20/6
a. Reagents and conditions: azide (1.0 mmol), Cu(OAc)2⋅H2O (0.025 mmol), TBTA (0.1
mmol), K2CO3 (0.5ꢀ2.0 mmol, see the Experimental Section), and alkyne (0.5 mmol) in MeOH
or EtOH (0.5 mL) at rt under an O2 atmosphere for 3 h; b. no TBTA was needed; c. the reaction
was run at 0 °C; d. NaNO2 (0.5 mmol) was included; e. azide (2.5 mmol, 5 molar equivalents)
was used.
(c) The range of dihedral angles of the axially chiral 5,5’-bistriazoles. The Xꢀray single crystal
structures of ten 5,5’ꢀbistriazoles are shown in Table 6. The dihedral angle along the C5ꢀC5’ axis
varies from 43° to 130°. The dihedral angle value of BINAP class of ligands is a critical
parameter in determining the enantioselectivity of the reactions they are involved in.43 Tetraarylꢀ
substituted 5,5’ꢀbistriazoles have similarly rigid axially chiral structures with a broader range of
dihedral angle distribution than that of BINAPs, which shall introduce new opportunities in
developing chiral ligands for asymmetric catalysis.40
Table 6. Single crystal structures of 5,5’ꢀbistriazoles and measured dihedral angles (in absolute
values in ascending order).
|Dihedral
angle|
Table Entry
ChemDraw
Ellipsoid
5
12
43.20
ACS Paragon Plus Environment
16

Page 17 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N
N
N
Ph
Ph
N
3ak
3
10
46.16
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
4
1
2
73.35
81.57
N
N
PhO
N
3da
N
OPh
N
N
5
5
2
3
83.12
86.21
3
4
8
5
89.40
95.06
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 46
1
2
3
4
5
6
7
8
9
4
5
6
6
105.55
130.89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(d) Mechanistic discussion. As shown in Scheme 1, the triazolide intermediate from the
CuAAC reaction could be oxidatively coupled to afford 5,5’ꢀbistriazole. This hypothesis finds
precedence in the “aromatic GlaserꢀHay” reaction,6 in which the conjugate base of an aromatic
heterocycle is oxidized by copper(II) salts to the homocoupled dimer under aerobic conditions.
This comparison offers an explanation to the need of both copper(II) and a strong base for an
efficient formation of 5,5’ꢀbistriazole in the current work – copper(II) is the oxidant, while the
base minimizes the possibility of triazolide protonation to give 5ꢀprotiotriazole. As shown in
Scheme 3a, we prepared an Nꢀheterocyclic carbene (NHC)ꢀstabilized copper(I) triazolide based
on the procedure by Straub and coworkers,44 which was treated with Cu(ClO4)2 and DBU to
afford 5,5’ꢀbistriazole as the major product (57%) in 3 h. The rest of the triazolide was turned
into 5ꢀprotiotriazole. The sources of proton include the moisture in the air and in the solvent.
When the base (DBU) was taken away (Scheme 3b), copper(I) triazolide was also fully
converted within 3 h with a reduced 5,5’ꢀbistriazole percentage at 42%. Therefore, it can be
concluded that the presence of DBU suppressed the 5ꢀprotiotriazole formation by making proton
less available. Without copper(II) and base under otherwise identical conditions (Scheme 3c),
38% of copper(I) triazolide was converted after 21 h to 5ꢀprotiotriazole only.
ACS Paragon Plus Environment
18

Page 19 of 46
The Journal of Organic Chemistry
1
2
Scheme 3. The conversion of NHCꢀCu(I)ꢀtriazolide to 5,5’ꢀbistriazole and 5ꢀprotiotriazolea
3
4
5
6
7
8
9
Ph Bn
Bn
N
Ar
Ph
THF, 0.5 mL
RT, air, 3 h
N
N
N
N
N
N
N
N
N
N
N
(a)
Cu
+
Cu(ClO4)2
0.1 mmol
+
DBU
H
+
N
N
Ar
Bn Ph
Ph
43%
Bn
0.05 mmol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.2 mmol
57%
Ph Bn
Bn
N
Ar
Ph
N
N
THF, 0.5 mL
RT, air, 3 h
N
N
N
N
N
N
N
N
N
Cu(ClO4)2
0.1 mmol
H
Cu
+
+
(b)
N
N
Bn
0.05 mmol
Ar
Bn Ph
Ph
58%
42%
Ph Bn
Bn
Ar
Ph
THF, 0.5 mL
RT, air, 21 h
N
N
N
N
N
N
N
N
N
N
N
Cu
H
(c)
+
N
N
N
Bn
0.05 mmol
Ar
Bn Ph
Ph
38%
0
a. Ar = 2,6ꢀdiisopropylphenyl; the red numbers under 5,5’ꢀbistriazole are the percentage of the
5,5’ꢀbistriazole from the converted starting material.
Treating 5ꢀprotiotriazoles with either potassium carbonate or alkoxides in the presence of a
catalytic or stoichiometric amount of copper(II) salts for the purpose of replicating the “aromatic
GlaserꢀHay” reaction was however unsuccessful. No trace of 5,5’ꢀbistriazole was observed using
several different bases or either catalytic or stoichiometric amount of copper(II) acetate (Scheme
S1). Similar lack of reactivity of 5ꢀprotiotriazoles in homocoupling was also reported in the
previous works on 5,5’ꢀbistriazole synthesis.20,22,25 The comparison of the observations listed in
Schemes 3 and S1 suggest that the activation barrier to reach triazolide is much higher from 5ꢀ
protiotriazole than from terminal alkyne and azide, under copperꢀcatalyzed conditions.
It was remarked by Angell and Burgess that 5,5’ꢀbistriazole formation under basic conditions
“is surprising because it has been stated several times that the pH value is relatively unimportant
for copperꢀmediated cycloadditions to give triazoles”.20 It now can be understood that in those
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 46
1
2
3
4
5
6
7
8
9
referred “copperꢀmediated cycloadditions”, sodium ascorbate, or other reducing reagents, was
used to mop up any oxidant to keep the level of copper(II) at a minimum. Therefore, oxidative
reactions were suppressed regardless of the pH. On the contrary, none of the reported procedures
of 5,5’ꢀbistriazole synthesis12ꢀ18 has a reducing reagent such as sodium ascorbate to ensure
copper in the +1 oxidation state, which means that the copper(I) catalyst being used in these
earlier reports of 5,5’ꢀbistriazole synthesis could be relatively easily oxidized to copper(II), likely
by O2, to allow oxidative coupling to take place, especially when 5ꢀprotiotriazole formation is
not competitive in the presence of a protonꢀabsorbing strong base. Particularly illuminating is the
example described by Oladeinde et al.,21 in which a typical CuAAC condition of CuSO4/sodium
ascorbate results in a 5ꢀprotiotriazole as the major product, while switching to a CuI/DIPEA
system without protection against oxidant by sodium ascorbate flips the major product to the
5,5’ꢀbistriazole. Copper(II) alone without the assistance of a base would not favor 5,5’ꢀ
bistriazole because triazolide protonation outcompetes oxidative coupling under those conditions
to give 5ꢀprotiotriazole as the predominantly favored product.30
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
The reaction between benzylazide and 1ꢀdecyne (Scheme 4) was monitored using H NMR.
The conversion values at each time point of the three products are plotted in Figure S4. A few
observations yield clues to the mechanism of this reaction: (1) the formation of diyne, the
oxidative coupling product of the alkyne, was not observed; (2) 5ꢀalkynyltriazole appeared at the
very early stage of the reaction, the production of which did not persist throughout the reaction;
(3) 5,5’ꢀbistriazole and 5ꢀprotiotriazole compete with each other; and (4) unlike Cu(OAc)2ꢀ
catalyzed CuAAC reaction that we reported before,45 the 5,5’ꢀbistriazole formation in the current
case does not have a perceptible induction period.
ACS Paragon Plus Environment
20

Page 21 of 46
The Journal of Organic Chemistry
1
2
3
4
Scheme 4. Reaction between 1a and 2b, and observations in the 1H NMR monitoring experiment
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on the above analysis and observations, one possible model (Scheme 5) is drawn that
starts with the formation of a copper(II)/azide complex (I). Subsequent in situ reduction of I to II
via, for example, alcoholic solvent oxidation,46 ushers the azide substrate into the catalytic cycle.
The steps primarily responsible for 5,5’ꢀbistriazole B are marked by bold black arrows, whereas
routes leading to side products H and A are marked by red arrows. Cycloaddition of II with
alkyne RCCH in the presence of a base to afford copper(I) triazolide (III) follows,47 which
recruits either an alkyne (IV’) or an azide (IV and V) to initiate the second triazolide
formation.48,49 The oxidation of copper(I) bistriazolide V by copper(II) salts gives B,50 while the
resulting copper(I) is recycled back to copper(II) via aerobic oxidation. In this model, only
mononuclear copper complexes are drawn; in reality, these complexes might contain biꢀ or
multinuclear copper centers.51ꢀ53 Protonation of a copper(I) triazolide (III, IV, IV’, V) may occur
to afford the 5ꢀprotiotriazole side product H (Scheme 5, red arrows inside circle), although the
presence of a base reduces the propensity of protonation. Also, intermediate IV’ may undergo
oxidation to form 5ꢀalkynyltriazole A (red arrow on lower right of Scheme 5).
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 46
1
2
Scheme 5. Mechanistic model of 5,5’ꢀbistriazole (B) formationa
3
4
5
6
X
7
8
9
CuII
N
X
N
N
X-
(I)
R'
MeO-
AcO-
R
R'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
K2CO3
CuI
MeOH
N
N
N
N
N
(B)
N
N
N
X
R'
R
N
(II)
RCCH
R'
2 CuI
O2
base
R'
CuI
R'N3
N
N
N
R
R'
(IV)
R'N3
N
CuI
(III)
H2O2
or H2O
2 CuII
N N
R
R'
N
N
N
base
[base(H)]+
RCCH
H+
H+
RCCH
N
N
N
N
N
R'
R
H+
N
R'
R
R
CuI
R
H+
H
R
R'
N
(H)
[O]
CuI
N
N
R
R'
N
R
R'
(V)
N
N
N
N
N
R'N3
(IV')
(A)
a. The nuclearity of the species is not restricted to monocopper. The major steps that involve
copper(II) and base are shaded. Counter ion ‘X’ is added for the purpose of balancing charges.
The likely candidates for X are methoxide (or ethoxide) and acetate. The precise structures of the
copper complexes are not known at this point. [O] = oxidation, possibly by copper(II).
The following features of the model in Scheme 5 are consistent with experimental
observations: (1) the saturation of copper(II) centers by the azide substrate ensures that any
copper(I) acetylide is being rapidly transformed to triazolide. Therefore, alkynylated side product
A only appears at the early stage of the reaction before the steady state is reached, and the diyne
species was not even observed. Several methods for selective formation of 5ꢀalkynyltriazole
have been reported.4,25,54ꢀ57 How to favor 5ꢀalkynyltriazole over 5,5’ꢀbistriazole is an interesting
mechanistic question to answer in the future. (2) The involvement of the strong base K2CO3,
ACS Paragon Plus Environment
22

Page 23 of 46
The Journal of Organic Chemistry
1
2
which effectively deprotonates methanol, and to a lesser extent ethanol,35 increases the rate of the
induction reaction to produce the copper(I) catalyst via alcohol oxidation. This model also
highlights the requirements of both copper(II) and the carbonate base/ligand (shaded in Scheme
5) in 5,5’ꢀbistriazole formation – copper(II) recruits the azide substrate and acts as the oxidant in
the triazolide homocoupling step, while carbonate deprotonates methanol and alkyne, and
minimizes 5ꢀprotiotriazole formation.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion
In summary, comparing to the existing methods of 5,5’ꢀbistriazole synthesis, the current
method provided high conversion and good selectivity for 5,5’ꢀbistriazole more rapidly with a
larger substrate scope that includes aromatic azides. The reported 5,5’ꢀbistriazoles were prepared
quickly (< 3 h) and economically with good isolated yields (> 50%). Based on the preliminary
mechanistic analysis, the functions of copper(II) salt and carbonate base were defined in a model
consistent with the experimental observations. Under a broader mechanistic context, this reaction
could also be viewed as the interception of the alkyne oxidative homocoupling pathway by the
introduction of an azide. The rigid axially chiral 5,5’ꢀbistriazoles derived from aryl azide and
aryl alkyne could conceivably be developed into ligands in assisting asymmetric catalysis.
Experimental Section
(1) Materials and general methods. Reagents and solvents were purchased from various
commercial sources and used without further purification unless otherwise stated. Analytical thin
layer chromatography (TLC) was performed using precoated TLC plates with silica gel 60 F254.
Flash column chromatography was performed using 40−63 ꢁm (230−400 mesh ASTM) silica gel
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 46
1
2
3
4
as the stationary phases. Silica was flameꢀdried under vacuum to remove adsorbed moisture
5
6
7
8
1
13
before use. H and C NMR spectra were recorded at 500 and 125 MHz respectively, at 295 K
unless otherwise noted. The chemical shifts (δ) are recorded in ppm relative to the residual
CHCl3 or CHD2CN as internal standards. High resolution mass spectra (HRMS) were obtained
under electrospray ionization (ESI) using a timeꢀofꢀflight (TOF) analyzer. Benzylazide
purchased from various vendors gave inconsistent results, suggesting that batchꢀtoꢀbatch
impurities affect the reaction outcome differently. Therefore, the benzylazide used in this study
was prepared from benzylbromide and NaN3 and rigorous purified. It has been consistently
observed that aromatic azides produced from diazotization of aniline derivatives followed by
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
substitution with NaN3 without solid phase filtration to remove the H NMR invisible inorganic
impurity gave complete reactions with good selectivity to 5,5’ꢀbistriazoles within 3 h. The
rigorously purified aromatic azides react more sluggishly under the same conditions. All the data
listed in Table 5 were collected using azides purified via chromatography.
(2) Convenient synthesis of TBTA. (a) The “4-hour procedure”. Benzylazide (2.0 mL, d =
1.066 g/mL, 16 mmol) was dissolved in tertꢀbutanol (7.5 mL) in a 100ꢀmL roundꢀbottom flask
equipped with a magnetic stir bar. Tripropargyl amine (712 ꢀL, d = 0.927 g/mL, 5.0 mmol) was
subsequently added, and the flask was placed in a water bath at rt. Cu(OAc)2·H2O (36 mg, 0.18
mmol) was added, and the reaction flask was left uncovered (to prevent pressure buildup in case
of unexpectedly strong heat release) while stirring for 5 min. The flask was then closed with a
rubber septum equipped with an argon balloon. The reaction mixture was left stirring for up to
2.5 h, during which a precipitate formed and eventually the reaction mixture gelled. Diethyl ether
(20 mL) was added to the flask, and the stirring was kept for another 10ꢀ20 min. The product was
collected via vacuum filtration. The collected amorphous solid was washed with diethyl ether (15
ACS Paragon Plus Environment
24

Page 25 of 46
The Journal of Organic Chemistry
1
2
3
4
mL × 3) before airꢀdried for 30 min. The yield was 2.5 g (94%). The total experiment time was ~
5
6
1
4 h. The compound is stored in a desiccator at rt for permanent storage. H NMR (300 MHz,
7
8
9
CDCl3): δ/ppm 7.66 (s, 3H), 7.35ꢀ7.32 (m, 6H), 7.26ꢀ7.23 (m, 9H), 5.50 (s, 6H), 3.69 (s, 6H).
This compound has been reported.31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b) A modified TBTA synthesis. Benzylazide (2.0 mL, d = 1.066 g/mL, 16 mmol) was
dissolved in tertꢀbutanol (20 mL) in a 100ꢀmL roundꢀbottom flask equipped with a magnetic stir
bar. Tripropargyl amine (712 ꢀL, d = 0.927 g/mL, 5.0 mmol) was subsequently added, and the
flask was placed in a water bath at rt. Cu(OAc)2·H2O (18 mg, 90 ꢀmol) was added, and the
reaction flask was left uncovered while stirring for 5 min. The flask was then closed with a
rubber septum equipped with an argon balloon. The reaction mixture was left stirring overnight,
during which a precipitate formed. Diethyl ether (20 mL) was added to the flask, and the stirring
was kept for another 10ꢀ20 min. The product was collected via vacuum filtration. The collected
amorphous solid was washed with diethyl ether (15 mL × 3) before airꢀdried for 30 min. The
compound can be further dried under vacuum in a desiccator equipped with Drierite. The yield
was 2.5 g (94%). The total experiment time was ~ 1 day. The compound is stored in a desiccator
for permanent storage. The key modifications are to use more solvent and less copper so that the
reaction mixture would not solidify before completion. The cost is more time.
(c) Procedure for experiments in Table 1 to produce 3aa. To a 25ꢀmL roundꢀbottom flask
equipped with a magnetic stir bar, benzylazide (73 mg, 0.55 mmol) in 0.25 mL of solvent was
added. While stirring at rt, Cu(II) source (0.025 mmol), base/additive (1.0 mmol), and
phenylacetylene (51 mg, 0.5 mmol) in 0.25 mL of the solvent were added sequentially. The flask
was sealed with a rubber septum, and vented with a needle to air. The reaction mixture was
stirred for 1 h at rt, followed by dilution with EtOAc (50 mL). The resulting solution was
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 46
1
2
3
4
5
6
transferred to a separation funnel, and the organic layer was washed with a saturated NaCl
solution before being dried over anhydrous Na2SO4. Following filtration, the solution was
7
8
9
1
concentrated under reduced pressure. H NMR of the residue was acquired, based on which the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
conversion and selectivity from the limited reagent phenylacetylene was calculated. The data are
listed in Table 1. Under the conditions shown in entry 4, Table 1, 3aa was isolated via silica
column chromatography eluted by EtOAc in hexanes (up to 5/95) as a white amorphous solid in
1
54% yield (63 mg). Rf = 0.53 (dichloromethane). H NMR (500 MHz, CDCl3): δ/ppm 7.44 (d, J
= 5.0 Hz, 4H), 7.26ꢀ7.18 (m, 6H), 7.13 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.5 Hz, 4H), 6.80 (d, J =
13
5.0 Hz, 4H), 4.68 (d, J = 15.0 Hz, 2H), 4.62 (d, J = 15.0 Hz, 2H); C{1H} NMR (125 MHz,
CDCl3): δ/ppm 148.0, 133.1, 129.4, 129.2, 129.0, 129.0, 128.9, 128.4, 126.0, 120.0, 52.9; HRMS
(ESI+) (m/z): [M+H]+ calcd. for C30H25N6 469.2141, found 469.2124. This compound has been
reported.20
(d) Procedure for experiments in Table 2 to produce 3bb. The procedure for the reactions in
Table 2 was similar to that of Table 1. 1ꢀDecyne (2b) was the limiting reagent at 0.5 mmol. For
entry 1, 4ꢀazidoanisole (1b, 0.55 mmol, 1.1 molar equivalent) was dissolved in MeOH (0.25
mL). Cu(OAc)2⋅H2O (0.025 mmol), K2CO3 (0.5 mmol), and alkyne 2b (0.5 mmol) in MeOH
(0.25 mL) were added sequentially. For the following entries, the effect of additional changes
(TBTA, O2, NaNO2, azide/alkyne stoichiometry successively) was most reliably observed when
a doubleꢀquantity reaction mixture was evenly split, while the new component was added to one
of the two reaction mixtures. The experimental results were shown as flow charts in Figure S3.
The data reported in Table 2 were averages of the duplicated reactions, if applicable. Under the
conditions shown in entry 6, Table 2, a white amorphous powder was isolated via silica column
chromatography eluted by EtOAc in hexanes (up to 20/80) in 52% yield (74 mg). Rf = 0.34
ACS Paragon Plus Environment
26

Page 27 of 46
The Journal of Organic Chemistry
1
2
(dichloromethane). 1H NMR (500 MHz, CDCl3): δ/ppm 6.83 (d, J = 7.5 Hz, 4H), 6.75 (d, J = 7.5
Hz, 4H), 3.80 (s, 6H), 2.59ꢀ2.47 (m, 4H), 1.69ꢀ1.57 (m, 4H), 1.32ꢀ1.24 (m, 22H), 0.87 (t, J = 7.5
Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 160.0, 149.2, 129.1, 124.7, 121.4, 114.5,
77.2, 55.7, 31.9, 29.6, 29.4, 29.3, 28.9, 25.4, 22.7, 12.2; HRMS (ESI+) (m/z): [M+H]+ calcd. for
C34H49N6O2 573.3914, found 573.3917.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(e) General procedure and characterization data for the 5,5’-bistriazoles listed in Table 3
(e.g., 3ac, entry 1). To a 25ꢀmL roundꢀbottom flask equipped with a stir bar, benzylazide (0.133
g, 1.0 mmol) was added and dissolved in MeOH (0.25 mL). Cu(OAc)2⋅H2O (5.0 mg, 0.025
mmol, 5 mol % of the limiting reagent alkyne) and K2CO3 (0.138 g, 1.0 mmol) were added. 4ꢀ
Ethynylanisole (66.7 mg, 0.5 mmol) was dissolved in MeOH (0.25 mL), and was added
dropwise via a syringe over 10 min to the reaction mixture. The reaction mixture was stirred for
3 h at rt under an atmosphere of air. The reaction mixture was then diluted with EtOAc (50 mL).
After solvent removal under reduced pressure, the crude product was purified on a silica column
eluted by an increasing proportion of DCM in hexanes (70/30 to 100/0), followed by 1% EtOAc
in DCM. Rf = 0.29 (dichloromethane). A white amorphous solid was isolated in 58% yield (78
mg). 1H NMR (300 MHz, CDCl3): δ/ppm 7.35 (d, J = 9.0 Hz, 4H), 7.15ꢀ7.05 (m, 6H), 6.80 (d, J
= 7.8 Hz, 4H), 6.72 (d, J = 8.4 Hz, 4H), 4.67 (d, J = 14.4 Hz, 2H), 4.60 (d, J = 15.0 Hz, 2H), 3.75
(s, 6H); 13C{1H} NMR: (125 MHz, CDCl3): δ/ppm 160.0, 147.8, 133.2, 128.8, 128.6, 128.2,
127.2, 121.9, 119.1, 114.4, 55.3, 52.6; HRMS (ESI+) (m/z): [M+H]+ calcd. for C32H29N6O2
529.2352, found 529.2358. This compound has been reported.25 For compounds in entries 3ꢀ8,
EtOH was used in place of MeOH, and TBTA (0.013 g, 0.025 mmol, 5 mol % of the limiting
reagent alkyne) was added before the addition of the alkyne (0.5 mmol). Other changes in
conditions for the rest of the entries in Table 3 are noted individually. 5,5’ꢀBistriazoles were
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 46
1
2
3
4
5
6
7
8
9
purified using silica column chromatography eluted by hexanes containing an increasing amount
of EtOAc or DCM. If needed, the product can be further purified via trituration using hexanes.
Table 3, entry 2, 3ad: A reduced amount of K2CO3 (0.5 mmol) was used. A white amorphous
powder was isolated via silica column chromatography eluted by EtOAc in hexanes (up to 15/85)
in 66% yield (82 mg). Rf = 0.53 (dichloromethane). 1H NMR (500 MHz, CDCl3): δ/ppm 7.32 (d,
J = 8.2 Hz, 4H), 7.14 (t, J = 7.0 Hz, 2H), 7.70 (t, J = 7.5 Hz, 4H), 7.00 (d, J = 8.5 Hz, 4H), 6.79
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(d, J = 7.5 Hz, 4H), 4.68 (d, J = 14.8 Hz, 2H), 4.57 (d, J = 14.8 Hz, 2H), 2.29 (s, 6H); C{1H}
NMR (125 MHz, CDCl3): δ/ppm 148.0, 138.9, 133.1, 129.7, 128.8, 128.6, 128.3, 126.5, 125.8,
119.7, 52.6, 21.3; HRMS (ESI+) (m/z): [M+H]+ calcd. for C32H29N6 497.2454, found 497.2430.
This compound has been reported.24
Table 3, entry 3, 3ae: A white amorphous solid was isolated via silica column chromatography
eluted by EtOAc in hexanes (up to 10/90) in 63% yield (79 mg). Rf = 0.57 (dichloromethane). 1H
NMR (500 MHz, CDCl3): δ/ppm 7.33 (dd, J = 9.0, 5.5 Hz, 4H), 7.15 (t, J = 7.0 Hz, 2H), 7.09 (t,
J = 7.5 Hz, 4H), 6.85 (dd, J = 9.0, 8.5 Hz, 4H), 6.81 (d, J = 7.0 Hz, 4H), 4.74 (d, J = 15.0 Hz,
2H), 4.62 (d, J = 15.0 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 163.0 (d, J(13Cꢀ19F) =
248.0 Hz), 147.2, 132.9, 128.9, 128.2, 127.6 (d, J(13Cꢀ19F) = 8.2 Hz), 125.3 (d, J(13Cꢀ19F) = 2.9
Hz), 119.4, 116.0 (d, J(13Cꢀ19F) = 21.7 Hz), 52.9; HRMS (ESI+) (m/z): [M+H]+ calcd. for
C30H23F2N6 505.1952, found 505.1958. This compound has been reported.24
Table 3, entry 4, 3af: A white amorphous solid was isolated via silica column chromatography
eluted by EtOAc in hexanes (up to 20/80) in 60% yield (81 mg). Rf = 0.61 (dichloromethane). 1H
NMR (300 MHz, CDCl3): δ/ppm 7.29ꢀ7.26 (m, 4H), 7.17ꢀ7.06 (m, 10H), 6.81 (d, J = 7.2 Hz,
13
4H), 4.76 (d, J = 15.0 Hz, 2H), 4.61 (d, J = 15.0 Hz, 2H); C{1H} NMR (125 MHz, CDCl3):
ACS Paragon Plus Environment
28

Page 29 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
δ/ppm 147.0, 135.1, 132.8, 129.3, 129.0, 128.2, 127.6, 127.0, 119.7, 53.0; HRMS (ESI+) (m/z):
[M+H]+ calcd. for C30H23Cl2N6 537.1361, found 537.1366. This compound has been reported.24
Table 3, entry 5, 3ag: A white amorphous solid was isolated via silica column chromatography
eluted by dichloromethane/hexanes (60/40 to 90/10) in 72% yield (112 mg). Rf = 0.64
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(dichloromethane). H NMR (500 MHz, CDCl3): δ/ppm 7.28 (d, J = 8.5 Hz, 4H), 7.20ꢀ7.15 (m,
6H), 7.09 (t, J = 7.4 Hz, 4H), 6.80 (d, J = 7.6 Hz, 4H), 4.75 (d, J = 14.9 Hz, 2H), 4.61 (d, J =
14.9 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 147.0, 132.7, 132.2, 128.9, 128.1,
127.9, 127.1, 123.2, 119.6, 52.9; HRMS (ESI+) (m/z): [M+H]+ calcd. for C30H2379Br81BrN6
627.0330 found 627.0351.
Table 3, entry 6, 3ah: A light peach amorphous solid was isolated via silica column
chromatography eluted by EtOAc/hexanes (up to 10/90) in 68% yield (88 mg). Rf = 0.29
1
(dichloromethane). H NMR (500 MHz, CDCl3): δ/ppm 7.41 (d, J = 10.0 Hz, 4H), 7.37 (d, J =
10.0 Hz, 4H), 7.16ꢀ7.06 (m, 6H), 6.82 (d, J = 7.2 Hz, 4H), 4.90 (d, J = 15.0 Hz, 2H), 4.60 (d, J =
15.0 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 146.2, 133.2, 132.8, 132.5, 129.3,
129.1, 128.2, 126.0, 120.4, 118.3, 112.5, 53.3; HRMS (ESI+) (m/z): [M+CH3CN+Na]+ calcd. for
C34H25N9Na 582.2131, found 582.2120. This compound has been reported.58
Table 3, entry 7, 3ai: A white amorphous solid was isolated via silica column chromatography
eluted by EtOAc in dichloromethane (up to 40/60) in 67% yield (78.8 mg). Rf = 0.21
1
(dichloromethane/EtOAc 1:1). H NMR (500 MHz, CDCl3): δ/ppm 8.56 (dd, J = 2.5, 1.0 Hz,
2H), 8.43 (dd, J = 4.5, 1.5 Hz, 2H), 7.55 (ddd, J = 8.0, 2.0, 1.5 Hz, 2H), 7.11ꢀ7.04 (m, 8H), 6.83
(dd, J = 8.0, 1.5 Hz, 4H), 4.95 (d, J = 15.0 Hz, 2H), 4.61 (d, J = 15.0 Hz, 2H); C{1H} NMR
13
(125 MHz, CDCl3): δ/ppm 149.8, 146.7, 145.5, 132.7, 132.6, 129.2, 129.0, 128.0, 125.2, 123.6,
119.8, 53.2; HRMS (ESI+) (m/z): [M+H]+ calcd. for C28H23N8 471.2046, found 471.2042.
ACS Paragon Plus Environment
29