Synthesis of 5-Iodo-1,2,3-triazoles from organic azides and terminal alkynes: Ligand acceleration effect, substrate scope, and mechanistic insights

Article abstract of DOI:10.1055/s-0033-1339312

An improved method has been developed for the preparation of 5-iodo-1,2,3-triazoles directly from organic azides and terminal alkynes by a reaction mediated by copper(I) and iodinating agents generated in situ. The major methodological advance of the current procedure is that it provides a high conversion and good iodo/proto selectivity with a broad range of substrates without using an excess of the alkyne, which was required in the previous method. The use of an accelerating ligand is essential to the success of reactions involving unreactive azides or alkynes. New mechanistic insights are provided, including the confirmation that a 1-iodoalkyne is formed as a key intermediate under the established conditions for the reaction.

Full text of DOI:10.1055/s-0033-1339312

2372▌
FEATURE ARTICLE
feature article
Synthesis of 5-Iodo-1,2,3-triazoles from Organic Azides and Terminal
Alkynes: Ligand Acceleration Effect, Substrate Scope, and Mechanistic Insights
5-Iodo-1,2,3-triazoles
David N. Barsoum, Christopher J. Brassard, Jason H. A. Deeb, Najeah Okashah,
Kesavapillai Sreenath, J. Tyler Simmons, Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: lzhu@chem.fsu.edu
Received: 26.03.2013; Accepted after revision: 06.06.2013
in Scheme 1. Copper(II) perchlorate hexahydrate reacts
Abstract: An improved method has been developed for the prepa-
rapidly with sodium iodide to give copper(I) species and
ration of 5-iodo-1,2,3-triazoles directly from organic azides and ter-
triiodide ions; the former catalyzes the cycloaddition of
the azide and the terminal alkyne, and the latter iodinates
minal alkynes by a reaction mediated by copper(I) and iodinating
agents generated in situ. The major methodological advance of the
current procedure is that it provides a high conversion and good io- the cuprous triazolide intermediate to give the corre-
sponding 5-iodo-1,2,3-triazole.6 A similar procedure was
reported concurrently by Årstad and co-workers, who
do/proto selectivity with a broad range of substrates without using
an excess of the alkyne, which was required in the previous method.
The use of an accelerating ligand is essential to the success of reac-
used 125I from Na125I as a radioactive tracer in 5-iodo-
tions involving unreactive azides or alkynes. New mechanistic in-
sights are provided, including the confirmation that a 1-iodoalkyne
1,2,3-triazoles for nuclear imaging applications.7
is formed as a key intermediate under the established conditions for
the reaction.
(a)
–
2 Cu2+
+
3 I–
2 Cu+
+
I3
Key words: azides, alkynes, copper, catalysis, heterocycles, cycli-
zations, triazoles, halogenation, iodine
(b)
R1 N3
CuI
I
–
2 CuI
R1
R1
I3
+
N
N
N
N
1
Introduction
R2
R2
base, r.t.
H
R2
N
N
5-Iodo-1,2,3-triazoles are key intermediates in three-com-
ponent reaction sequences involving azides, alkynes, and
matching partners from a palladium-catalyzed cross-cou-
pling process.1,2 A state-of-the-art method for preparing 5-
iodo-1,2,3-triazoles with a wide substrate scope under
mild reaction conditions was reported by Hein, Fokin, and
co-workers;2 this method entails the activation of a termi-
nal alkyne by formation of a 1-iodoalkyne that undergoes
copper(I)-catalyzed cycloaddition with an azide (Scheme
1). The separate step of converting the terminal alkyne
into a 1-iodoalkyne can be eliminated. To this end, several
methods have been developed, before and after Hein and
Fokin’s work, by which 5-iodo-1,2,3-triazoles can be pre-
pared directly from conjugating terminal alkynes and
azides.3–5 The usefulness of these direct conjugation
methods is, however, limited because they involve corro-
sive iodinating agents, such as iodine chloride,3 or oxidiz-
ing agents, such as N-bromosuccinimide.4 Furthermore,
the substrate scopes of these methods and their efficien-
cies in terms of reaction time and conversion do not yet ri-
val those of Hein and Fokin’s method.2
Scheme 1 (a) A balanced ionic equation for the in situ production of
copper(I) and triiodide from copper(II) and iodide. (b) The products
mediate the coupling reaction between azide and alkyne to give the
corresponding 5-iodo-1,2,3-triazole. The ligands and counterions as-
sociated with copper are omitted from the scheme. The +2 and +1 ox-
idation states of copper are colored blue and orange, respectively.
Azides that are capable of chelating a copper ion at the al-
kylated nitrogen position (chelating azides)8,9 work well
under our initially reported procedure. Other azides lack-
ing this chelating ability appear to have inadequate reac-
tivity, and often require an excess of the alkyne or, in two
cases, the presence of an assisting ligand {tris[(1-benzyl-
1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)}10 to reach
completion.6 Here, we report an optimized method for the
synthesis of 5-iodo-1,2,3-triazoles directly from an azide
and an alkyne, which is more efficient than our previous
procedure in terms of time, conversion, selectivity, and
substrate scope.
The highlights of our current work are: (1) ligand assis-
tance is demonstrated in an expanded collection of sub-
strates, which greatly increases the substrate scope of this
reaction; (2) the need for an excess of the alkyne to con-
vert unreactive azides is eliminated, enhancing the practi-
cality of this method; and (3) the reaction time is reduced
from twelve to six hours. In addition to achieving these
improvements in the synthetic method, we have investi-
gated the effects of various alkali iodides on both the con-
version and selectivity, and we have examined the
Our group has developed a method for preparing 5-iodo-
1,2,3-triazoles from azides and terminal alkynes that is
mediated by copper(I) species and triiodide ions generat-
ed in situ (Scheme 1).6 The postulated mechanism is shown
SYNTHESIS 2013, 45, 2372–2386
Advanced online publication: 19.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339312; Art ID: SS-2013-Z0238-FA
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2373
Biographical Sketches█
Lei Zhu received his BS in fending his PhD dissertation sistant professor in the De-
chemistry from Peking Uni- in January 2003, Lei joined partment of Chemistry and
versity (P. R. of China) in Professor Eric Anslyn’s Biochemistry at Florida
1997. He subsequently en- group at the University of State University (USA) in
tered New York University Texas at Austin (USA) as a August 2005 and was pro-
(USA) for his graduate stud- postdoctoral fellow. Upon moted to associate professor
ies in chemistry under the completing his postdoctoral in 2011.
mentorship of Professor appointment, Lei began his
James Canary. After de- independent career as an as-
David N. Barsoum is at- try in the fall of 2013. He chemistry, and he plans to
tending Florida State Uni- has been working with Dr. continue research in gradu-
versity (USA) where he will Lei Zhu since January 2012. ate school in 2014.
obtain his BS in biochemis- He enjoys merging art with
Christopher J. Brassard is gree, he gained a full-time 2011, he was accepted to the
originally from Leominster, position with ArQule Inc., PhD program at Florida
MA (USA). In 2001 he re- an oncology-based drug- State University (USA),
ceived his BS in biochemis- discovery company. While where he is conducting re-
try
from
Worcester he was there, he earned his search under the guidance of
Institute, Master’s degree in chemis- Dr. Lei Zhu.
Polytechnic
Worcester, MA (USA). try from Northeastern Uni-
Upon completing his de- versity in Boston (USA). In
Jason H. A. Deeb is cur- group, and his research un- has gained of organic com-
rently striving to earn his BS der the guidance of Dr. Lei pounds will aid him in his
in biochemistry at Florida Zhu began in May of 2012. quest to understand the
State University (USA). His After his projected gradua- chemistry of the human
fascination with the synthe- tion in 2014, he plans to ob- brain.
sis of organic compounds tain an MD and he believes
brought him to the Zhu that the knowledge that he
Najeah Okashah is cur- she will complete her degree After her graduation, she is
rently pursuing her BS in in the spring of 2014. She planning on continuing to
biochemistry at Florida has been working with Dr. do research and on pursuing
State University (USA), and Lei Zhu since June 2012. an MD or PhD.
Kesavapillai Sreenath re- obtained his PhD from Ker- cules
for
bioimaging
ceived his BSc (2000) and ala University under the su- applications and on transi-
MSc degrees (2002) in pervision of Dr. Karical R. tion-metal-catalyzed organ-
chemistry from Kerala Uni- Gopidas. His research fo- ic reactions.
versity (India). In 2010, he cuses on fluorescent mole-
J. Tyler Simmons grew up graduate program in chem- on copper-catalyzed organic
in New Brockton, AL istry at Florida State Univer- reactions and on the devel-
(USA), and received his BS sity (USA) and began his opment of fluorescent indi-
in chemistry from Troy Uni- dissertation research under cators
for
mapping
versity (USA) in May 2008. the guidance of Dr. Lei Zhu. biological zinc ions.
Later that year, he joined the Tyler’s research is focused
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2372–2386

2374
D. N. Barsoum et al.
FEATURE ARTICLE
probable involvement of 1-iodoalkynes, formed in situ, as Among the azides that we examined, the chelating azides
key intermediates. The conclusions of these studies col- Z1–Z3 were expected to be highly reactive on the basis of
lectively improve our knowledge of the mechanism of this our previous observations on 2-(azidomethyl)pyridine
reaction.
(Z1).6 Z4 and Z7 are benzylic azides that are also reason-
ably reactive substrates, possibly as a result of interaction
between the aryl ring and copper(I) bound to the alkylated
nitrogen of the azido group.12 Aromatic azides Z10–Z13
were included, as well as aliphatic azides (Z5, Z6, Z8 and
Z9) containing various functional groups, including car-
boxyl (Z5) and hydroxy groups (Z6).
2
Results and Discussion
2.1
Choices of Azides and Alkynes
The alkynes and azides that we used are shown in Figure
1 and Figure 2, respectively. Our aim was to cover a wide
range of functional groups and to generate sufficient data
to be able to comment with confidence on the reactivities
2.2
Reaction Conditions and Isolation Proce-
dures
of various classes of compounds under our developed The reaction conditions are listed in the caption to Scheme
conditions. Both aliphatic and aromatic alkynes were ex- 2.13 In a typical experiment, a solution of the azide in tet-
amined. The effect of exchangeable protons on the io- rahydrofuran or acetonitrile was treated by addition of sol-
do/proto selectivity was studied by using the carboxylic id copper(II) perchlorate hexahydrate and sodium,
acids Y6 and Y1011 and the alcohol Y1. The methyl ke- potassium, or lithium iodide. The reaction mixture then
–
tone Y8 was included to determine whether the iodoform turned muddy brown, indicating the formation of I2/I3
reaction competes with the formation of the 5-iodo-1,2,3- (Figure 3, center). If needed, the accelerating ligand
triazole.
TBTA was added at this stage. Triethylamine or 1,8-diaz-
abicyclo[5.4.0]undec-7-ene (DBU) and the alkyne were
added sequentially, and the mixture was stirred at room
temperature. The azide could also be added after alkyne
without any noticeable difference in the efficiency of the
reaction. The disappearance of the azide, the limiting re-
actant, was monitored by thin-layer chromatography.
Progress of the reaction was usually accompanied by fad-
ing of the dark-brown color of the initial reaction mixture
(Figure 3).
N
N
N
Y1
Y5
Y2
Y3
Y4
O
O
Me2N
OH
Y6
Y7
Y8
O
HO
OH
Y9
Y10
Y11
Y12
Figure 1 Aromatic (black), aliphatic (blue), carboxylated (red), and
other functionalized alkynes (green).
N3
N3
N
N
N
N3
N
N
Z1
Z2
Z3
O
N3
HO
N3
HO
N3
N
Z4
Z5
Z6
O
O
N3
N3
N3
N
H
Z7
Z8
Z9
N3
OH
N3
N3
OH
Figure 3 The colors of a reaction mixture of Cu(ClO4)2·6H2O (0.4
mmol) in THF (1 mL) in the initial state (left); immediately following
the addition of NaI (0.8 mmol), Et3N (0.2 mmol), and propargyl alco-
hol (0.22 mmol) (center); and 20 min after the addition of BnN3 (0.2
mmol) (right).
OMe
MeO
N3
Z10
Z11
Z12
Z13
Figure 2 Chelating (blue), benzylic (red), aromatic (black), and
functionalized aliphatic azides (green).
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2375
Bn
TBTA
H
I
H
N
N
R1
N3
R1
R1
N
N
N
N
N
+
+
R2
R2
R2
N
N
N
N
N
A
B
C
N
Bn
N
conversion = (B+C)/(A+B+C)
selectivity = B/(B+C)
Bn
N
N
Scheme 2 Reaction conditions: azide (A; 0.2 mmol); alkyne (0.22 mmol); THF or MeCN (1 mL); Cu(ClO4)2·6H2O (0.4 mmol); Et3N or DBU
(0.2 mmol); NaI, KI, or LiI (0.8 mmol); r.t.; ≤6 h. TBTA was added (10 mol%) if required.
In most cases, the reaction proceeded to full conversion the iodo/proto selectivity were high, the product was iso-
within six hours. Stoichiometric amounts of alkyne14 were lated either by chromatography on a short column of silica
effective in the current procedure. This is a notable im- gel or by a trituration procedure. The isolated yields are
provement over our previously reported procedure in listed in Tables 1 and 2.
which the use of an excess of the alkyne (2.5 equiv) was
necessary to compensate for the low reactivity of certain
2.3
Reactions Not Requiring an Accelerating Li-
gand
substrates.6 The ability to perform the reactions with equi-
molar amounts of the azide and the alkyne within a few
hours greatly enhances the practicality of this method.
The reactions that did not require an accelerating ligand to
proceed are shown in Table 1. It is evident that all the en-
tries of Table 1 involve either chelating (blue) or benzylic
(red) azides that possess high reactivities under the devel-
oped conditions. All the reactions except one (entry 7)
proceeded to completion within six hours. The reaction
between 3-(azidomethyl)pyridine (Z4) and ethynylben-
zene (Y1) took 24 hours to complete (entry 7), but was
greatly accelerated by the addition of TBTA (see section
2.4). Both triethylamine and DBU worked well as the
base, but triethylamine appeared to afford faster conver-
sions than did DBU. Lithium, sodium, and potassium io-
dides could all be used as the iodine source with minor
differences in reactivity, as discussed briefly in section
2.5.
When the reaction was complete, ethyl acetate and
28−30% aqueous ammonia were added to dilute the reac-
tion mixture. A deep-blue color immediately appeared as
the copper(I) species were converted into tetraamine cop-
per(II) ions under the aerobic conditions and sequestered
to the aqueous phase.15 For substrates containing a car-
boxyl group, a saturated solution of ammonium chloride
was used instead of aqueous ammonia. After two more ex-
tractions with saturated brine, followed by drying, the eth-
yl acetate layer was concentrated to afford the crude
product. The conversion and selectivity data are shown in
Tables 1 and 2, and defined in Scheme 2, were calculated
1
on the basis of H NMR spectroscopic analysis of the
crude products. In cases in which both the conversion and
Table 1 Examples of 5-Iodo-1,2,3-triazole Formation without Ligand Accelerationa
Entry Azide
Alkyne
Product
Me2N
Base Iodide Conversionb Time Selectivityb Yieldc
(%)
(%)
(%)
I
N3
N
Me2N
N
N
1
Et3N LiI
quant
0.5 h 85
44
N
N
Y7
Z1
1T7
N
O
N
O
N3
N
N
2
3
4
DBU KI
Et3N KI
Et3N LiI
quant
quant
quant
3 h
80
53
N
N
I
Z1
Z2
Y8
1T8
N
N
N
N3
N
N
Ph
1.5 h 100
69
I
Y1
2T1
N
O
N3
N
N
O
N
1.5 h 88
31d
I
Z2
Y8
2T8
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2372–2386

2376
D. N. Barsoum et al.
FEATURE ARTICLE
Table 1 Examples of 5-Iodo-1,2,3-triazole Formation without Ligand Accelerationa (continued)
Entry Azide
Alkyne
Product
Base Iodide Conversionb Time Selectivityb Yieldc
(%)
(%)
(%)
I
N
N
N
N
N
Ph
N3
5
DBU KI
DBU KI
quant
4 h
6 h
100
86
Ph
N
N
N
N
N
N
Y1
Y5
Z3
3T1
I
N
N
N
N
N
Ph
N3
6
N
quant
quant
quant
100
87
89
85
N
N
Z3
3T5
I
N3
Ph
N
7
Et3N NaI
24 h 100
25 min100
N
N
N
Y1
Z4
4T1
I
N3
HO
HO
N
N
N
8
Et3N NaI
N
N
Y11
Z4
4T11
I
N3
N3
N3
N3
N3
N
N
N
Ph
Ph
9
N
DBU KI
DBU KI
DBU KI
DBU KI
DBU KI
98
3 h
3 h
1 h
3 h
84
65
72
60
65
57
N
I
Y2
Z4
Z7
Z7
Z7
Z7
7T2
N
N
N
10
11
12
13
N
quant
quant
94
100
78
N
Y3
7T3
I
Me2N
Me2N
N
Ph
N
N
Y7
7T7
N
O
N
O
Ph
N
100
I
Y8
7T8
I
N
Ph
quant
3.5 h 100
N
N
Y9
7T9
a Reaction conditions: azide (0.2 mmol), alkyne (0.22 mmol), Cu(ClO4)2·6H2O (0.4 mmol), alkali metal iodide (0.8 mmol), base (0.2 mmol),
THF (1 mL).
b The conversion and iodo/proto selectivity, as defined in Scheme 2, were calculated from 1H NMR spectra of the crude products after extraction.
c Isolated yield.
d Compound 2T8 was not stable on a silica gel column or in CDCl3.
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2377
The products in entries 1 (1T7), 3 (2T1), and 7 (4T1) were Most reactions show exclusive selectivity toward 5-iodo-
reported in our previous work.6 However, under the cur- 1,2,3-triazoles over their 5-proto counterpart. However,
rent conditions, the reaction times for entries 1 and 3 were the reactions involving 2-ethynylpyridine (Y2), N,N-di-
reduced from 6 hours to 30−90 min. The isolated yield of methylpropargylamine (Y7), or but-3-yn-2-one (Y8)
4T1 (89%, entry 7) was much higher than that previously showed suboptimal iodo/proto selectivity. These three al-
reported (49%). In the presence of 10 mol% TBTA (Table kynes tend to undergo the typical copper(I)-catalyzed
2, entry 1), the yield of 4T1 was increased further to 95% azide−alkyne cycloaddition (CuAAC) rapidly, probably
and the reaction time was reduced to 2.5 hours. These en- because of the ability of the corresponding 1,2,3-triazole
tries represent improvements in the current method over products to act as bidentate accelerating ligands for the
the earlier version.6
CuAAC route. We will test this hypothesis in a future
project.
Table 2 Reactions Aided Significantly by TBTA (10 mol%)a
Entry Azide
Alkyne
Product
Solvent Base Iodide Conv.b Time Selectivityb Yieldc
(%)
(h)
(%)
(%)
I
N3
Ph
N
1
THF
THF
DBU NaI
quant 2.5
100
95
N
N
N
N
Y1
Y5
Y1
Z4
4T1
O
I
O
HO
N
N
HO
N3
2
Et3N KI
quant
6
100
64
N
Z5
5T5
I
HO
HO
N
N3
Ph
3
4
5
6
THF
THF
THF
THF
DBU KI
Et3N KI
Et3N KI
Et3N LiI
quant 2.5
100
100
100
100
73
75
70
64
N
N
Z6
6T1
I
N3
N3
N3
N
N
Ph
N
quant
quant
quant
6
1
6
N
N
Y4
Z7
Z7
Z7
7T4
I
N
Ph
N
N
Y5
7T5
I
O
HO
N
Ph
OH
O
N
N
Y6
Y5
7T6
N
N
O
O
Ph
N
N3
N
H
N
H
7
8
THF
THF
DBU KI
quant
6
6
89
76
75
I
Z8
Z8
8T5
O
N
I
O
O
O
N
OH
N3
Ph
N
N
H
OH
Et3N LiI
75
100
N
H
Y10
8T10
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2372–2386

2378
D. N. Barsoum et al.
FEATURE ARTICLE
Table 2 Reactions Aided Significantly by TBTA (10 mol%)a (continued)
Entry Azide
Alkyne
Product
Solvent Base Iodide Conv.b Time Selectivityb Yieldc
(%)
(h)
(%)
(%)
I
O
O
N3
O
Ph
N
N
Ph
9
THF
Et3N NaI
quant
3
100
99
N
I
Y1
Z9
9T1
N3
O
Ph
N
N
10
THF
THF
THF
Et3N KI
Et3N KI
Et3N KI
71
6
1
3
94
53
93
72
N
Y12
Y1
Z9
9T12
N
N
N
N
Ph
11
12
quant
80
100
100
MeO
N3
MeO
I
Z10
10T1
N
N
I
HO
OH
MeO
N3
MeO
Y11
Z10
10T11
OH
N3
I
Ph
N
OH
13
THF
Et3N LiI
90
24
100
77
N
N
Y1
Y1
Z11
11T1
OH
N
N
OH
N
N3
Ph
14
15
16
17
MeCN Et3N NaI
quant 12
100
100
100
100
55
49
75
75
I
Z12
12T1
I
Ph
N3
OMe
OMe
OMe
MeO
N
THF
THF
THF
Et3N KI
Et3N KI
Et3N KI
80
80
94
1
N
N
N
N
N
N
Z13
Y1
Y5
13T1
I
N3
MeO
N
6
Z13
13T5
I
OH
HO
N3
MeO
N
6.5
Y11
Z13
13T11
a Reaction conditions: azide (0.2 mmol), alkyne (0.22 mmol), Cu(ClO4)2·6H2O (0.4 mmol), TBTA (0.02 mmol, 10 mol%), alkali metal iodide
(0.8 mmol), base (0.2 mmol), solvent (1 mL).
b The conversion and iodo/proto selectivity, as defined in Scheme 2, were calculated from the 1H NMR spectra of the crude products after
extraction.
c Isolated yield.
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2379
ing the progress of the reaction by thin-layer chromatog-
raphy).
2.4
TBTA-Accelerated Reactions
The acceleratory effect of the ligand TBTA was suggested
by a reviewer of our earlier paper,6 which, after revision,
included two reactions aided by TBTA. The current re-
sults demonstrate the scope of TBTA-accelerated reac-
tions under the conditions shown in Scheme 2. The slow
reaction of 3-(azidomethyl)pyridine (Z4) with ethynyl-
benzene (Y1) (Table 1, entry 7) was significantly acceler-
ated by the addition of 10 mol% TBTA (Table 2, entry 1).
In the absence of TBTA, the conversion of aromatic
azides into 5-iodo-1,2,3-triazoles in less than 6 hours
failed, but these reactions proceeded smoothly to comple-
tion with high iodo/proto selectivity in the presence of
TBTA (10 mol%). A few functionalized aliphatic azides
(Z5, Z6, Z8, and Z9), which have little reactivity without
ligand acceleration, were also readily converted into the
5-iodo-1,2,3-triazole products in the presence of TBTA
(10 mol%). The iodo/proto selectivity was high, even with
hydroxylated or carboxylated substrates (entries 2, 3, 6, 8,
12−14, and 17). For reactions involving carboxylated sub-
strates, saturated ammonium chloride solution was used in
the extraction step instead of aqueous ammonia, so that
the carboxylic acid product was neutralized and seques-
tered into the organic solvent.
The reactions that required TBTA to achieve a high con-
version generally gave the corresponding 5-iodo-1,2,3-tri-
azole exclusively. For the two cases that showed less than
100% iodo/proto selectivity, we feel that the data pool is
too small for us to attribute this observation to any struc-
tural feature of the substrates.
2.5
Effects of Alkali Iodides
The differences in reactivity between lithium, sodium, po-
tassium, and cesium iodide in three sets of reactions were
investigated (Table 3). Benzyl azide (Z7) and ethynylben-
zene (Y1) were used as a typical pair of substrates without
special functional groups (Table 3, entry 1), 2-(azido-
methyl)pyridine (Z1) and N,N-dimethylpropargylamine
(Y7) as a pair of reactive substrates that undergo rapid
conversion without ligand acceleration (entry 2), and (2-
hydroxymethyl)phenyl azide (Z11) and ethynylbenzene
(Y1) as a pair of unreactive substrates that require the aid
of TBTA (entry 3). Cesium iodide was the least produc-
tive iodide source in all three reactions. Lithium and sodi-
um iodides gave consistently high conversions, probably
as a result of their high solubilities in tetrahydrofuran.
We have reported syntheses of 4T1 (entry 1) and 9T1 (en-
try 9) previously.6 However, the isolated yields were only
moderate (49% and 58%, respectively) in 12 hours, and an
excess of the alkyne had to be used. In the current work,
with the aid of TBTA (10 mol%), yields of over 95% were
achieved within three hours in both cases from close-to-
equimolar amounts of the azide and alkyne (a 10 mol%
excess of the alkyne was used for convenience in monitor-
Another notable observation is that the pair of reactive
substrates (entry 2) underwent rapid conversion, but with
impaired iodo/proto selectivity. This is a manifestation of
the classical reactivity/selectivity relationship. In this re-
action, the rapid conversion pathways to the 5-iodo-1,2,3-
triazole and to the 5-proto-1,2,3-triazole compete, result-
ing in relatively low selectivity.
Table 3 The Alkali Cation Effecta,b
Entry
Azide
Alkyne
Conv., (time),
selectivity (LiI)
Conv., (time),
selectivity (NaI)
Conv., (time),
selectivity (KI)
Conv., (time),
selectivity (CsI)
N3
76 ± 12% (3 h)
100 ± 0%
81 ± 20% (3 h)
100 ± 0%
51 ± 11% (3 h)
87 ± 5.0%
1
0% (3 h) N.A.
Y1
Z7
N3
Me2N
100% (30 min)
87 ± 10%
100% (30 min)
85 ± 5.5%
100% (30 min)
78 ± 11%
100% (30 min)
40 ± 5.7%
2
3
N
Y7
Z1
N3
59 ± 12% (6 h)
89 ± 9.5%
62 ± 3.6% (6 h)
88 ± 11%
43 ± 12% (6 h)
85 ± 13%
OH
0% (6 h) N.A.
Y1
Z11
a Reaction conditions: (added in order) alkyne (0.22 mmol), THF (1 mL), Cu(ClO4)2·6H2O (0.4 mmol), alkali metal iodide (0.8 mmol), TBTA
(0.02 mmol, 10 mol%; entry 3 only), azide (0.2 mmol), r.t., 3 h (entry 1), 30 min (entry 2), or 6 h (entry 3).
b The conversion and iodo/proto selectivity, as defined in Scheme 2, were calculated from 1H NMR spectra of the crude products. Average
values and standard deviations for triplicate experiments are reported.
© Georg Thieme Verlag Stuttgart · New York
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2380
2.5
D. N. Barsoum et al.
FEATURE ARTICLE
Table 4 1-Iodoalkyne Formation Characterized from the 13C NMR
Mechanistic Discussion
Chemical Shifta
Rapid fading of the brown color of the reaction mixture is
an indication that the reaction is progressing well. In a few
cases, however, complete fading of the color preceded
completion of the reaction. These observations led us to
surmise that the formation of a 1-iodoalkyne may have oc-
curred before the participation of azide. We found that
ethynylbenzene is fully converted into (iodoethynyl)ben-
zene within 20 minutes in the absence of an azide, under
otherwise identical conditions. After filtering the reaction
mixture through Celite16 and removing the solvent, we re-
corded the 13C NMR spectrum. The chemical shift of C*
in the alkyne undergoes a large upfield shift, diagnostic of
the formation of the 1-iodoalkyne (Table 4). The conver-
sion of propargyl alcohol into 3-iodoprop-2-yn-1-ol oc-
curs even in the absence copper(II) perchlorate
hexahydrate (diiodine was used instead of potassium io-
dide),17 although the reaction was less efficient. There-
fore, 1-iodoalkynes are readily formed in the presence of
a base such as triethylamine and an iodinating source such
as diiodine. Consequently, under the conditions for syn-
thesis of 5-iodo-1,2,3-triazoles, a 1-iodoalkyne might
form before entering the catalytic cycle en route to 5-iodo-
1,2,3-triazole. The addition of TBTA has little effect on
the efficiency of formation of the 1-iodoalkyne under the
conditions shown in the footnote to Table 4, suggesting
that TBTA is instead responsible for the acceleration of
one or more elementary steps involving the copper(I) cat-
alyst and the azide.
THF, Cu(ClO4)2⋅6H2O
KI
R
C
C*
H
+
R
C
C*
I
Et3N, r.t., 20 min
Entry
1
Alkyne
δC*(H) (ppm)
δC*(I) (ppm)
77.4
77.1
77.2
80.8
6.33
C
C* H/I
F
C
C* H/I
2
3
4
6.33
10.03
8.93
C
C
C* H/I
N
C* H/I
N
C
C* H/I
5
6
73.9
68.2
2.92
HO
n-C8H17
C
C* H/I
−7.47
a Reaction conditions: (added in order) alkyne (0.22 mmol), THF (1
mL), Cu(ClO4)2·6H2O (0.4 mmol), KI (0.8 mmol), Et3N (0.2 mmol),
r.t., 20 min. The mixture was filtered through Celite and 13C NMR
(125 MHz, CDCl3) spectra of the 1-iodoalkynes were acquired after
solvent removal.
−
drawn at prescribed intervals. After I2/I3 had been
quenched by using a solution of sodium thiosulfate and
the organic fraction had been passed through a pad of
Celite in a Pasteur pipette, the sample was concentrated
and redissolved in CDCl3. The 19F NMR spectra of the al-
iquots were acquired over the course of the reaction with-
out TBTA [Figure 4 (A)]. At the one-hour mark, the
majority of alkyne Y3 had been converted into 1-iodo-
alkyne 3, and the 5-iodo-1,2,3-triazole product 7T13 had
begun to form. At the six-hour mark the experiment was
terminated, at which point the conversion was 28%.
Although 13C NMR spectroscopy is diagnostic in charac-
terizing the 1-iodoalkyne intermediate, the inability to
perform integration and the lengthiness of acquisition of
the spectrum render it ineffective in following the prog-
ress of the reaction. 1H NMR, on the other hand, is fast and
1
quantitative. However, the differences in the H NMR
spectra of alkynes and 1-iodoalkynes are often small, and
the alkynyl C−H signal is often obscured by solvent-
residue peaks. 19F NMR spectroscopy18 has neither of the
shortcomings of 13C NMR, and it affords sufficiently
clean spectra to permit unambiguous assignments and
quantification of various species formed in a reaction.
Conversion of Y13 and Z7 into product 7T13 was signif-
icantly accelerated in the presence of 10 mol% TBTA,
reaching 95% after four hours [Figure 4 (B)]. The rapid
formation of 1-iodoalkyne 3 was not affected by the pres-
ence of TBTA, and alkyne Y13 was barely detectable af-
ter two hours. It is noteworthy that the sample collected at
The reaction between fluorinated alkyne Y13 and benzyl
azide (Z7) was monitored by 19F NMR spectroscopy
(Scheme 3). Aliquots of the reaction mixture were with-
N
N
N3
N
+
F
F
I
Z7
δF = –113.6 ppm
7T13
δF = –111.1 ppm
Y13
F
I
δF = –110.7 ppm
3
Scheme 3 A 19F NMR assay to capture the 1-iodoalkyne intermediate 3. The chemical shifts are referenced to PhCF3 in CDCl3. Reagents and
conditions: azide Z7 (0.4 mmol), alkyne Y13 (0.4 mmol), THF (2 mL), Cu(ClO4)2·6H2O (0.8 mmol), KI (1.6 mmol), Et3N (0.4 mmol). The
reaction was repeated with the inclusion of TBTA (0.04 mmol, 10 mol%).
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2381
son of the kinetic profiles for the reactions in the absence
and presence of TBTA (Figure 4), it appears that TBTA
specifically accelerates the azide/1-iodoalkyne cycloaddi-
tion step, presumably by activating the copper(I) species
in similar way to that in which TBTA assists conventional
CuAAC reactions.8,10,19 The carbon−iodine bond remains
intact throughout this mechanistic pathway. This pathway
accounts for the high iodo/proto selectivity and is more
plausible than the alternative route outlined in Scheme 1
(b), which has also been considered by Hein, Fokin, and
co-workers,2 by others,3,5 and by us.6
3 I–
CuLn
R1 N3
2 Cu2+
2 Cu+
R2
I
L
I
H
–
I3
R1
R2
R2
N
N
N
BH+
B
CuLn–1
I
CuLn
+
2 I–
R2
N
R1
TBTA
(cat.)
N
N
N
I
R1
N
N
L
R2
I
CuLn–1
R2
Scheme 4 Outline of a mechanism involving a 1-iodoalkyne inter-
mediate. The catalytic cycle component is adapted from the work by
Hein, Fokin, and co-workers2 (B = base). Orange, blue, and purple
colors represent the +1, +2, and +3 oxidation states of copper, respec-
tively. A dative bond from the alkylated nitrogen of the azide, which
bears a formal negative charge, to the CuIII center in the intermediate
is used for the purposes of electron bookkeeping. With a chelating
azide or other reactive substrate, TBTA may not be required.
Figure 4 The progress of the reactions shown in Scheme 3: (A) with-
out and (B) with TBTA (10 mol%). Aliquots of reaction mixture were
drawn at prescribed intervals and 19F NMR (376 MHz, CDCl3) spec-
tra were acquired.
Although it is not implausible, it is hard to defend the
presence of the cuprous triazolide intermediate in Scheme
1 (b), given the observed high iodo/proto selectivity with-
out rigorous removal of water [there is crystalline water
present in Cu(ClO4)2·6H2O]. If, for any reason, the 1-io-
doalkyne is formed slowly or is unstable, formation of a
copper(I) acetylide would occur competitively, channel-
ing the reaction toward the typical CuAAC pathway and
lowering the iodo/proto selectivity.
the 15-minute mark contained a small amount of the5-pro-
to-1,2,3-triazole side product (δF = −114.5 ppm), which
was probably formed during workup of the sample. From
Figure 4 (B), it is evident that a large amount of alkyne
starting material is still present 15 minutes into the reac-
tion, and this might undergo a conventional TBTA-accel-
erated CuAAC reaction during the aqueous workup to
afford the 5-proto-1,2,3-triazole. However, when conver-
sion into the 1-iodoalkyne was complete after one hour,
this side product was no longer observed.
2.7 Recommended Procedure
The copper(II) perchlorate hexahydrate that was used in
this work was dried at 40−70 °C in a vacuum oven over-
night to remove adsorbed moisture (but not crystalline
water), and subsequently stored in a dry keeper. The rec-
ommended procedure begins with dissolution of the azide
in tetrahydrofuran to give a 0.2 M solution. LiI (4 equiv),
Cu(ClO4)2·6H2O (2 equiv), triethylamine (1 equiv), and
the alkyne (1 equiv) are then added sequentially. If a non-
chelating azide is used, we recommend that the ligand
TBTA (10 mol%) is included to ensure that the conver-
On the basis of the rapid conversion of alkyne Y13 into 1-
iodoalkyne 3 observed in the 19F NMR experiments (Fig-
ure 4), we conclude that the most appropriate mechanism
is that outlined in Scheme 4, the catalytic component of
which was first proposed by Hein, Fokin, and co-work-
ers.2 I3− generated in situ iodinates the alkyne to form the
1-iodoalkyne with the assistance of the base. Copper(I)
subsequently catalyzes the conjugation step between the
1-iodoalkyne and the azide. On the basis of the compari-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2372–2386

2382
D. N. Barsoum et al.
FEATURE ARTICLE
from all reactions involving this reactant. Cu(ClO4)2·6H2O was
dried in a vacuum oven at 40−70 °C overnight and stored in a dry
keeper before use. Analytical TLC was performed on plates pre-
coated with silica gel 60 F254 or neutral aluminum oxide 60 F254.
Flash column chromatography was performed by using 40−63 μm
(230−400 mesh ASTM) silica gel or alumina (80−200 mesh, pH
9−10) as the stationary phases. Before use, silica gel and alumina
sion occurs in a timely manner, usually no longer than six
hours. When thin-layer chromatography indicates that
conversion is complete, the reaction mixture is partitioned
between ethyl acetate and aqueous ammonia to remove
copper salts quickly and cleanly. After one or two extrac-
tions with saturated brine, followed by drying, the crude
product obtained after solvent removal can be purified by
column chromatography or by a trituration procedure to
afford the analytically pure material.
1
were flame-dried under vacuum to remove adsorbed moisture. H
NMR spectra were recorded at 500 or 300 MHz on Bruker and
Varian spectrometers, respectively. 13C NMR spectra were recorded
at 125 or 75 MHz on Bruker and Varian spectrometers, respective-
ly.19F NMR spectra were recorded at 376 MHz on a 400-MHz
Bruker spectrometer. The chemical shifts (δ) are reported in ppm
relative to the residual CHCl3 or CHD2CN as internal standards.
The following variations may be made without compro-
mising the efficiency of the reaction: (1) The azide can be
added at the end, following the alkyne. (2) Acetonitrile is
another effective solvent, in particular when the substrates
have limited solubility in tetrahydrofuran. (3) Triethyl-
amine can be replaced with DBU. (4) Sodium and potas-
sium iodide, which are less expensive than LiI, are equally
effective under most circumstances. (5) The workup pro-
cedure is dependent on the structure of the product. For
example, if a carboxylic acid is being isolated, a saturated
solution of ammonium chloride or an EDTA solution with
an appropriate pH value shall be used instead of aqueous
ammonia.
4-(Azidomethyl)-1-benzyl-1H-1,2,3-triazole (Z3)
Triazole Z3 was prepared according to Scheme 5.
a
N
N
HO
+
N3
OH
N3
N
N
1
b
c
N
N
N
N
Br
N
2
Z3
Scheme 5 Synthesis of azide Z3. Reagents and conditions: (a)
Cu(OAc)2·H2O (5 mol%), t-BuOH, r.t., 16 h; (b) PBr3, CH2Cl2, r.t.,
4 h; (c) NaN3, DMF, 50 °C, 16 h.
3
Conclusion
Coupling of an organic azide with a terminal alkyne in the
presence of copper(II) perchlorate and an alkali metal io- (1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (1)20
BnN3 (80.7 mg, 0.606 mmol), HC≡CCH2OH (37 mg, 0.67 mmol),
dide under mild conditions gives the corresponding 5-
iodo-1,2,3-triazole. With the addition of the accelerating
ligand TBTA (10 mol%), this procedure can tolerate a
wide variety of functional groups, including carboxyl or
hydroxy groups. Aliphatic and aromatic azides and al-
kynes can be readily converted into 5-iodo-1,2,3-triazoles
with high to exclusive iodo/proto selectivity. Among alka-
li metal iodides, lithium and sodium iodide both afford
consistently high conversions and iodo/proto selectivities.
The intermediacy of a 1-iodoalkyne in this sequence of re-
actions was directly observed by 19F NMR, and is consis-
tent with a mechanism that involves the initial formation
of a 1-iodoalkyne and in which the carbon−iodine bond
remains intact throughout the cyclization steps to afford
the 5-iodo-1,2,3-triazole. This mechanistic pathway best
accounts for the observed high iodo/proto selectivity.2
The minor 5-proto-1,2,3-triazole product that is occasion-
ally observed is attributed to the conventional copper(I)-
catalyzed azide−alkyne click cycloaddition reaction,
which can compete when the substrate structures favor
this route, or when the 1-iodoalkyne is formed slowly or
is unstable.
and t-BuOH (0.5 mL) were added sequentially to an argon-filled
round-bottom flask. A 0.4 M aq soln of Cu(OAc)2·H2O (75 μL, 5
mol% on BnN3) was then added, and the mixture was stirred at r.t.
for 16 h. The mixture was then separated by column chromatogra-
phy (silica gel, 0−5% MeOH−CH2Cl2) to give a white amorphous
solid; yield; 106 mg (93%).
1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.39−7.35 (m, 3 H),
7.28−7.26 (m, 2 H), 5.50 (s, 2 H), 4.75 (s, 2 H), 2.30 (br s, 1 H).
1-Benzyl-4-(bromomethyl)-1H-1,2,3-triazole (2)
A round-bottom flask was charged with triazole 1 (388 mg, 2.05
mmol), CH2Cl2 (5.0 mL), and PBr3 under argon (1.10 g, 4.09
mmol), and the mixture was stirred at r.t. for 4 h. The reaction was
then quenched with H2O (2 mL), and the mixture was extracted with
CH2Cl2 (2 × 10 mL). The organic layers were combined, dried
(Na2SO4), filtered, and concentrated under vacuum. The crude
product was purified by chromatography (silica gel, 30% EtOAc−
CH2Cl2) to give a white amorphous solid; yield; 382 mg (74%).
1H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.40−7.38 (m, 3 H),
7.29−7.26 (m, 2 H), 5.52 (s, 2 H), 4.55 (s, 2 H).
4-(Azidomethyl)-1-benzyl-1H-1,2,3-triazole (Z3)
Compound 2 (56 mg, 0.23 mmol), DMF (2.0 mL), and NaN3 (297
mg, 4.57 mmol) were added sequentially to an argon-filled round-
bottom flask, and the mixture was stirred at 50 °C overnight. The
mixture was then diluted with EtOAc (50 mL) and washed with sat.
aq NH4Cl (3 × 50 mL). The organic layer was dried (Na2SO4) and
concentrated under vacuum to give a white amorphous solid; yield:
290 mg (39%).
CAUTION! Low-molecular-weight organic azides and copper(II)
perchlorate hexahydrate used in this study are potentially explosive.
Appropriate protective measures should always be taken when han-
dling these compounds.
1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.39−7.37 (m, 3 H),
7.29−7.26 (m, 2 H), 5.54 (s, 2 H), 4.47 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 143.1, 134.3, 129.3, 129.0, 128.2,
Reagents and solvents were purchased from various commercial
sources and were used without further purification unless otherwise
stated. BnN3 of 94% purity was purchased from Alfa Aesar, which
probably contributed to the lower-than-expected isolated yields
122.2, 54.4, 45.7.
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2383
HRMS (CI): m/z [M + H]+ calcd for C10H11N6: 215.1045; found:
215.1042.
1H NMR (300 MHz, CDCl3): δ = 4.56 (t, J = 7.2 Hz, 2 H), 2.98 (t,
J = 7.2 Hz, 2 H), 2.70 (s, 3 H), 2.59 (m, 4 H), 1.78 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 192.4, 147.2, 82.3, 55.2, 54.5,
49.8, 27.8, 23.8.
HRMS (ESI): m/z [M + H]+ calcd for C10H15OIN4: 334.02909;
[(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)methyl]dimethylamine
(7T7; Table 1, Entry 11); Typical Procedure Not Requiring
TBTA Ligand
BnN3 (Z7; 27.0 mg, 0.20 mmol) was dissolved in THF (1.0 mL) in
a 10-mL round-bottom flask equipped with a magnetic stirrer bar.
To this soln, KI (132.8 mg, 0.80 mmol) and Cu(ClO4)2·6H2O (148.2
mg, 0.40 mmol) were added, and the mixture was stirred for 3−5
min. DBU (30.0 mg, 0.20 mmol) and Me2NCH2C≡CH (Y7; 18.3
mg, 0.22 mmol) were then added sequentially and the mixture was
stirred at r.t. for up to 6 h. The mixture was then diluted with EtOAc
(50 mL) and 28−30% aq NH3 (25 mL) then transferred to a separa-
tory funnel. The organic layer was washed with sat. brine (2 × 25
mL), separated, and dried (Na2SO4). The solvent was removed un-
der reduced pressure to give a crude product. The conversion and
found: 334.02841.
1-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-iodo-4-phenyl-
1H-1,2,3-triazole (3T1; Table 1, Entry 5)
This was prepared by the typical procedure in 4 h as an off-white
amorphous solid; yield: 76 mg (86%).
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 8.4 Hz, 2 H),
7.48−7.36 (m, 6 H), 7.26−7.24 (m, 3 H), 5.79 (s, 2 H), 5.50 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.2, 142.3, 134.3, 130.2, 129.3,
129.2, 129.1, 128.8, 128.7, 128.3, 127.5, 123.3, 54.5, 46.6.
HRMS (ESI): m/z [M + Na]+ calcd for C18H15IN6Na: 465.03006;
1
selectivity reported in Table 1 were calculated from the H NMR
spectrum of the crude product. The crude product was purified by
chromatography (silica gel, 0−30% gradient EtOAc−CH2Cl2) to
give an off-white amorphous solid; yield: 48 mg (60%).
1H NMR (300 MHz, CDCl3): δ = 7.35−7.32 (m, 3 H), 7.26−7.23 (m,
2 H), 5.60 (s, 2 H), 3.53 (s, 2 H), 2.29 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 148.8, 134.4, 128.9, 128.5, 127.7,
80.9, 54.2, 53.9, 45.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H16IN4: 343.04196; found:
343.04157.
found: 465.02860.
1-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-butyl-5-iodo-1H-
1,2,3-triazole (3T5; Table 1, Entry 6)
This was prepared by the typical procedure in 6 h as a white amor-
phous solid: yield: 73 mg (87%).
1H NMR (300 MHz, CDCl3): δ = 7.41 (s, 1 H), 7.37−7.35 (m, 2 H),
7.26−7.22 (m, 3 H), 5.67 (s, 2 H), 5.49 (s, 2 H), 2.63 (t, J = 7.2 Hz,
2 H), 1.69−1.59 (m, 2 H), 1.39−1.30 (m, 2 H), 0.92 (t, J = 7.2 Hz, 2
H).
13C NMR (125 MHz, CDCl3): δ = 152.5, 142.4, 134.3, 129.3, 129.0,
128.2, 123.1, 78.7, 54.4, 46.3, 31.1, 25.9, 22.4, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H20IN6: 423.07941; found:
423.07844.
{[5-Iodo-1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl]meth-
yl}dimethylamine (1T7;6 Table 1, Entry 1)
This was prepared by the typical procedure in 30 min using Et3N
and LiI instead of DBU and KI, respectively. White amorphous sol-
id; yield: 30.0 mg (44%).
1H NMR (300 MHz, CDCl3): δ = 8.58 (d, J = 4.2 Hz, 1 H), 7.64 (t,
J = 7.8 Hz, 1 H), 7.23 (t, J = 5.4 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H),
5.75 (s, 2 H), 3.56 (s, 2 H), 2.30 (s, 6 H).
[5-Iodo-1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl]methanol
(4T11; Table 1, Entry 8)
This was prepared by the typical procedure in 15 min using Et3N
and NaI instead of DBU and KI, respectively. Off-white amorphous
solid; yield: 54 mg (85%).
13C NMR (125 MHz, DMSO-d6): δ = 154.6, 149.8, 149.1, 137.3,
1H NMR (300 MHz, CDCl3): δ = 8.67 (s, 1 H), 8.60 (d, J = 4.5 Hz,
1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.30 (dd, J = 12.6, 3.1 Hz, 1 H), 5.62
(s, 2 H), 4.72 (d, J = 5.6 Hz, 2 H).
123.3, 121.5, 81.7, 55.8, 54.2, 45.4.
HRMS (CI): m/z [M + H]+ calcd for C11H15IN5: 344.03725; found:
344.03645.
13C NMR (125 MHz, DMSO-d6): δ = 151.3, 149.3, 148.9, 135.4,
131.2, 123.9, 84.2, 54.8, 50.8.
HRMS (ESI): m/z [M + H]+ calcd for C9H10IN4O: 316.98993,
found: 316.99071.
2-[(1-Acetyl-5-iodo-1H-1,2,3-triazol-4-yl)methyl]pyridine(1T8;
Table 1, Entry 2)
This was prepared by the typical procedure in 6 h as an off-white
amorphous solid; yield: 35 mg (53%).
1H NMR (300 MHz, CDCl3): δ = 8.60−8.58 (m, 1 H), 7.68 (t,
J = 7.2 Hz, 1 H), 7.26 (s, 1 H), 7.00 (d, J = 7.8 Hz, 1 H), 5.80 (s, 2
H), 2.74 (s, 3 H).
2-(1-Benzyl-5-Iodo-1H-1,2,3-triazol-4-yl)pyridine (7T2; Table
1, Entry 9)
This was prepared by the typical procedure in 3 h as a white amor-
phous solid; yield: 47 mg (65%).
13C NMR (125 MHz, CDCl3): δ = 192.2, 153.4, 149.9, 147.5, 137.2,
1H NMR (300 MHz, CDCl3): δ = 8.63 (d, J = 4.2 Hz, 1 H), 8.12 (d,
J = 7.8 Hz, 1 H), 7.74 (td, J = 7.8, 1.2 Hz, 1 H), 7.22−7.29 (m, 6 H),
5.67 (s, 2 H).
123.4, 121.6, 82.8, 55.4, 27.7.
HRMS (ESI): m/z [M + Na]+ calcd for C10H9IN4ONa: 350.97187;
found: 350.97127.
13C NMR (125 MHz, CDCl3): δ = 149.9, 149.1, 148.7, 136.7, 134.5,
129.0, 128.6, 127.9, 123.2, 121.9, 77.5, 54.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H12IN4: 363.01066; found:
363.01111.
5-Iodo-1-phenyl-4-(2-pyrrolidin-1-ylethyl)-1H-1,2,3-triazole
(2T1; Table 1, Entry 3)6
This was prepared by the typical procedure in 1.5 h using Et3N and
NaI instead of DBU and KI, respectively. White amorphous solid;
yield: 55 mg (75%).
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 6.9 Hz, 2 H),
7.49−7.39 (m, 3 H), 4.60 (t, J = 7.5 Hz, 2 H), 3.03 (t, J = 7.4 Hz, 2
H), 2.64 (t, J = 6.5 Hz, 4 H), 1.81 (s, 4 H).
3-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)pyridine (7T3; Table
1, Entry 10)
This was prepared by the typical procedure in 3 h as a white amor-
phous solid: yield: 60 mg (72%).
1H NMR (300 MHz, CDCl3): δ = 9.21 (s, 1 H), 8.63 (d, J = 4.2 Hz,
1 H), 8.25 (d, J = 7.8 Hz, 1 H), 7.43−7.34 (m, 5 H), 7.26 (s, 1 H),
5.69 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 149.6, 148.3, 147.8, 134.9, 134.2,
129.1, 128.8, 128.0, 126.7, 123.6, 77.7, 54.6.
1-Acetyl-5-iodo-4-(2-pyrrolidin-1-ylethyl)-1H-1,2,3-triazole
(2T8; Table 1, Entry 4)
This was prepared by the typical procedure in 1.5 h, using Et3N and
LiI instead of DBU and KI, respectively. Off-white amorphous sol-
id; yield: 21 mg (31%).
© Georg Thieme Verlag Stuttgart · New York
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2384
D. N. Barsoum et al.
FEATURE ARTICLE
HRMS (CI): m/z [M + H]+ calcd for C14H12IN4: 363.0107; found:
363.0101.
13C NMR (125 MHz, CDCl3): δ = 152.3, 78.9, 46.3, 31.2, 29.9,
25.8, 22.5, 14.0, 1.2.
HRMS (ESI): m/z [M + H]+ calcd for C9H15IN3O2: 324.02089;
found: 324.02085.
1-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)ethanone (7T8; Table
1, Entry 12)
This was prepared by the typical procedure in 3 h as a white amor-
phous solid; yield: 42 mg (65%).
1H NMR (300 MHz, CDCl3): δ = 7.37−7.30 (m, 5 H), 5.65 (s, 2 H),
4-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)pyridine (7T4; Table
2, Entry 4)
This was prepared by the typical method in 6 h using Et3N instead
of DBU. White amorphous solid; yield: 74 mg (75%).
2.71 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 192.4, 147.6, 133.8, 129.2, 129.0,
128.2, 81.9, 54.3, 27.8.
1H NMR (300 MHz, CDCl3): δ = 8.70 (d, J = 6.0 Hz, 2 H), 7.94 (t,
J = 4.8 Hz, 2 H), 7.37−7.30 (m, 5 H), 5.7 (s, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C11H11IN3O: 327.99468;
13C NMR (125 MHz, CDCl3): δ = 150.2, 147.2, 137.8, 133.9, 129.0,
found: 327.99360.
128.7, 127.8, 121.1, 78.0, 54.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H12IN: 363.01066; found:
363.01026.
1-Benzyl-4-tert-butyl-5-iodo-1H-1,2,3-triazole (7T9; Table 1,
Entry 13)
This was prepared by the typical procedure in 3.5 h as a white amor-
phous solid; yield: 40 mg (57%).
1H NMR (300 MHz, CDCl3): δ = 7.33−7.32 (m, 5 H), 5.59 (s, 2 H),
1-Benzyl-4-butyl-5-iodo-1H-1,2,3-triazole (7T5; Table 2, Entry 5)
This was prepared by the typical method in 1 h, but using 0.4 mmol
of the limiting reactant, BnN3; quantities of all other reagents were
doubled accordingly. Et3N was used instead of DBU. Beige amor-
phous solid; yield: 96 mg (70%).
1H NMR (300 MHz, CDCl3): δ = 7.35−7.33 (m, 3 H), 7.26−7.24 (m,
2 H), 5.57 (s, 2 H), 2.65 (t, J = 7.2 Hz, 2 H), 1.72−1.62 (m, 2 H),
1.41−1.33 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).
1.46 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 157.2, 134.6, 128.8, 128.3, 127.8,
74.0, 54.1, 31.8, 29.5.
HRMS (ESI): m/z [M + H]+ calcd for C13H17IN3: 342.04675; found:
342.04656.
13C NMR (125 MHz, CDCl3): δ = 152.5, 134.5, 128.9, 128.4, 127.8,
4-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)butan-1-ol (6T1;
Table 2, Entry 3); Typical Procedure Requiring TBTA Ligand
HO(CH2)4N3 (Z6, 23.0 mg, 0. 20 mmol) was dissolved in THF (1.0
mL) in a 10-mL round-bottom flask equipped with a magnetic stir-
rer bar. KI (132.8 mg, 0.80 mmol), Cu(ClO4)2·6H2O (148.2 mg,
0.40 mmol), and TBTA (10.6 mg, 0.020 mmol) were added, and the
soln was stirred for 3−5 min. DBU (30.0 mg, 0.20 mmol) and
PhC≡CH (Y1, 22.5 mg, 0.22 mmol) were then added sequentially
and the mixture was stirred at r.t. for up to 6 h. It was then diluted
with EtOAc (50 mL) and 28−30% aq NH3 (25 mL), and transferred
to a separatory funnel. The organic layer was washed with sat. brine
(2 × 25 mL), separated, and dried (Na2SO4). The solvent was re-
moved under reduced pressure to afford the crude product. The con-
version and selectivity reported in Table 2 were calculated from the
1H NMR spectrum of this crude product. The crude product was
then purified by chromatography (silica gel, 0−20% gradient
EtOAc−CH2Cl2) to give a white amorphous solid; yield: 62 mg
(73%).
78.2, 54.2, 31.1, 25.9, 22.3, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H17IN3: 342.04671; found:
342.04605.
1-Benzyl-5-iodo-1H-1,2,3-triazole-4-carboxylic Acid (7T6;
Table 2, Entry 6)
This was prepared by the typical method using Et3N and LiI instead
of DBU and KI, respectively. Sat. aq NH4Cl (pH ~5) was used in-
stead of aq NH3 for extraction. White amorphous solid; yield: 45 mg
(64%).
1H NMR (300 MHz, CDCl3): δ = 7.37−7.34 (m, 3 H), 7.30−7.26 (m,
2 H), 5.66 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 133.7, 129.0, 128.8, 127.9, 101.8,
90.3, 55.6.
HRMS (EI): m/z [M − CO2H]+ calcd for C9H7IN3: 284.0; found:
284.1. No molecular ion was found by EI, CI, or ESI ionization
methods.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 6.6 Hz, 2 H),
7.50−7.40 (m, 3 H), 4.52 (t, J = 7.2 Hz, 2 H), 3.77−3.70 (m, 2 H),
2.14−2.03 (m, 2 H), 1.72−1.63 (m, 2 H).
2-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)-N-phenylacetamide
(8T5; Table 2, Entry 7)
This was prepared by the typical method in 6 h as a white amor-
phous solid; yield: 59 mg (76%).
1H NMR (300 MHz, CDCl3): δ = 7.65 (br s, 1 H), 7.44 (d, J = 7.8
Hz, 2 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.15 (t, J = 7.8 Hz, 1 H), 5.22 (s,
2 H), 2.71 (t, J = 7.2 Hz, 2 H), 1.76−1.66 (m, 2 H), 1.45−1.35 (m, 2
H), 0.95 (t, J = 7.8 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.1, 151.2, 138.9, 129.4, 124.3,
119.6, 84.4, 53.2, 31.3, 25.6, 22.0, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H18IN4O: 385.05253;
found: 385.05206.
13C NMR (125 MHz, CDCl3): δ = 149.8, 130.3, 128.7, 128.6, 127.5,
76.4, 62.0, 50.7, 29.3, 26.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H15IN3O: 344.02598;
found: 344.02580.
3-[(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)methyl]pyridine
(4T1; Table 2, Entry 1)6
This was prepared by the typical method in 2.5 h. NaI was used in-
stead of KI. White amorphous solid; yield: 69 mg (95%).
1H NMR (300 MHz, CDCl3): δ = 8.71 (s, 1 H), 8.61 (d, J = 3.9 Hz,
1 H), 7.92 (d, J = 6.9 Hz, 2 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.47−7.38
(m, 3 H), 7.32−7.30 (m, 1 H), 5.70 (s, 2 H).
[1-(2-Anilino-2-oxoethyl)-5-iodo-1H-1,2,3-triazol-4-yl]acetic
Acid (8T10; Table 2, Entry 8)
This was prepared by the typical method in 6 h using Et3N and LiI
instead of DBU and KI, respectively. Sat. aq NH4Cl (pH ~5) was
used instead of aq NH3 for extraction. Yellow oil; yield: 60 mg
(75%).
1H NMR (300 MHz, DMSO-d6): δ = 10.56 (s, 1 H), 7.59 (d, J = 9.0
Hz, 2 H), 7.34 (t, J = 6.0 Hz, 2 H), 7.12 (t, J = 9.0 Hz, 1 H), 5.33 (s,
2 H), 3.62 (s, 2 H).
3-(4-Butyl-5-iodo-1H-1,2,3-triazol-1-yl)propanoic Acid (5T5;
Table 2, Entry 2)
This was prepared by the typical method in 6 h using Et3N instead
of DBU. Yellow amorphous solid; yield: 56 mg (64%).
1H NMR (300 MHz, CDCl3): δ = 4.61 (t, J = 7.2 Hz, 2 H), 3.07 (t,
J = 7.2 Hz, 2 H), 2.66 (t, J = 7.2 Hz, 2 H), 1.70−1.60 (m, 2 H),
1.43−1.33 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).
Synthesis 2013, 45, 2372–2386
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
5-Iodo-1,2,3-triazoles
2385
13C NMR (125 MHz, DMSO-d6): δ = 170.6, 163.5, 145.5, 138.4,
128.9, 123.8, 119.2, 86.0, 52.9, 32.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H13IN3O: 378.01033;
found: 378.01160.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11IN4NaO3: 408.97735;
found: 408.97657.
[4-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methanol
(12T1; Table 2, Entry 14)
This was prepared by the typical method in 6 h using MeCN, Et3N,
and NaI instead of THF, DBU, and KI, respectively. Light-orange
amorphous solid; yield: 42 mg (55%).
1H NMR (500 MHz, CDCl3): δ = 7.95 (dd, J = 6.2, 1.4 Hz, 2 H),
7.57−7.53 (m, 6 H), 7.47 (t, J = 5.7 Hz, 1 H), 5.45 (t, J = 5.9 Hz, 1
H), 4.64 (d, J = 5.8 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 149.1, 145.0, 135.4, 130.4,
128.7, 128.5, 127.2, 127.1, 126.4, 83.7, 62.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H13IN3O: 378.01033;
5-Iodo-1-(2-phenoxyethyl)-4-phenyl-1H-1,2,3-triazole (9T1;
Table 2, Entry 9)6
This was prepared by the typical method in 3 h using Et3N and NaI
instead of DBU and KI, respectively. White amorphous solid; yield:
78 mg (99%).
1H NMR (300 MHz, CDCl3): δ = 7.93 (dd, J = 8.4, 1.5 Hz, 2 H),
7.40−7.31 (m, 3 H), 7.29 (d, J = 7.5 Hz, 2 H), 6.97 (t, J = 7.4 Hz, 1
H), 6.89 (d, J = 8.8 Hz, 2 H), 4.87 (t, J = 5.8 Hz, 2 H), 4.48 (t,
J = 5.7 Hz, 2 H).
found: 378.01097.
4-Cyclohex-1-en-1-yl-5-iodo-1-(2-phenoxyethyl)-1H-1,2,3-tri-
azole (9T12; Table 2, Entry 10)
This was prepared by the typical method in 6 h using Et3N instead
of DBU. Off-white amorphous solid; yield: 42 mg (53%).
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 7.5 Hz, 2 H), 6.96 (t,
J = 7.4 Hz, 1 H), 6.87 (dd, J = 7.8, 1.0 Hz, 2 H), 6.42 (t, J = 1.9 Hz,
1 H), 4.78 (t, J = 5.9 Hz, 2 H), 4.41 (t, J = 5.8 Hz, 2 H), 2.55−2.51
(m, 2 H), 2.25−2.19 (m, 2 H), 1.81−1.75 (m, 2 H), 1.74−1.63 (m, 2
H).
13C NMR (125 MHz, DMSO-d6): δ = 158.1, 151.5, 129.7, 129.0,
128.2, 121.6, 114.7, 76.4, 66.2, 49.7, 27.5, 25.6, 22.8, 22.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H19IN3O: 396.05728;
found: 396.05703.
5-Iodo-1-(4-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (13T1;
Table 2, Entry 15)
This was prepared by the typical method in 1 h, but using Et3N in-
stead of DBU and 0.4 mmol of the limiting reactant, azide Z13; all
other reagents were doubled accordingly. White amorphous solid;
yield: 74 mg (49%).
1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 2 H),
7.53−7.43 (m, 5 H), 7.07 (d, J = 8.4 Hz, 2 H), 3.91 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 160.3, 148.8, 130.4, 129.8,
128.7, 128.5, 128.1, 127.2, 114.5, 83.8, 55.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H13IN3O: 378.01033;
found: 378.00982.
5-Iodo-1-(3-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (10T1;
Table 2, Entry 11)
This was prepared by the typical method in 1 h, but using Et3N in-
stead of DBU with 0.4 mmol of the limiting reactant azide Z10;
quantities of all other reagents were doubled accordingly. White
amorphous solid; yield: 141 mg (93%).
1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 1 H),
7.54−7.42 (m, 5 H), 7.16−7.10 (m, 3 H), 3.89 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 160.2, 150.5, 138.0, 130.2, 130.2,
4-Butyl-5-iodo-1-(4-methoxyphenyl)-1H-1,2,3-triazole (13T5;
Table 2, Entry 16)
This was prepared by the typical method in 6 h using Et3N instead
of DBU. Off-white amorphous solid; yield: 54 mg (75%).
1H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 9.0 Hz, 2 H), 7.03 (d,
J = 9.0 Hz, 2 H), 3.88 (s, 3 H), 2.73 (t, J = 7.9 Hz, 2 H), 1.79−1.69
(m, 2 H), 1.47−1.37 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 160.6, 152.4, 130.1, 127.4, 114.4,
79.9, 55.7, 31.2, 26.1, 22.4, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H17IN3O: 358.04162;
found: 358.04165.
128.8, 128.7, 117.9, 118.8, 116.3, 112.2, 55.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H13IN3O: 378.01033;
found: 378.01095.
[5-Iodo-1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]methanol
(13T11; Table 2, Entry 17)
This was prepared by the typical method in 6.5 h using Et3N instead
of DBU. White amorphous solid; yield: 49 mg (75%).
1H NMR (300 MHz, CDCl3): δ = 7.42 (d, J = 9.0 Hz, 2 H), 7.05 (d,
J = 9.0 Hz, 2 H), 4.81 (d, J = 6.6 Hz, 2 H), 3.90 (s, 3 H), 2.15 (t,
J = 7.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 160.2, 151.0, 129.7, 127.6,
114.5, 85.5, 55.6, 55.0.
HRMS (CI): m/z [M + H]+ calcd for C10H11O2IN3: 331.98963;
found: 331.98965.
[5-Iodo-1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]methanol
(10T11; Table 2, Entry 12)
This was prepared by the typical method in 3 h using Et3N instead
of DBU. White amorphous solid; yield: 48 mg (72%).
1H NMR (300 MHz, CDCl3): δ = 7.46 (t, J = 7.8 Hz, 1 H),
7.20−7.04 (m, 3 H), 4.83 (d, J = 6.6 Hz, 2 H), 3.87 (s, 3 H), 2.30 (t,
J = 6.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 160.4, 151.4, 137.8, 130.3, 118.3,
116.4, 111.8, 80.0, 56.9, 55.9.
HRMS (ESI): m/z [M + Na]+ calcd for C10H10IN3O2Na: 353.97154;
found: 353.97106.
1-Benzyl-4-(4-fluorophenyl)-5-iodo-1H-1,2,3-triazole (7T13)
This was prepared by the typical method in 6 h using Et3N instead
of DBU. Amorphous white solid; yield: 55 mg (71%).
1H NMR (300 MHz, CDCl3): δ = 7.94−7.89 (m, 2 H), 7.38−7.32 (m,
5 H), 7.18−7.12 (m, 2 H), 5.67 (s, 2 H).
[2-(5-Iodo-4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methanol
(11T1; Table 2, Entry 13)
This was prepared by the typical method in 24 h using Et3N and LiI
instead of DBU and KI, respectively. White amorphous solid; yield:
58 mg (77%).
13C NMR (125 MHz, CDCl3): δ = 163.9, 161.9, 149.5, 134.2, 129.4,
129.3, 129.0, 128.6, 127.9, 126.4, 126.3, 115.7, 115.5, 76.3, 54.5.
HRMS (EI): m/z [M]+ calcd for C15H11FN3I: 378.9982; found:
378.9978.
1H NMR (300 MHz, CDCl3): δ = 8.05 (dd, J = 8.4, 1.5 Hz, 2 H),
7.73 (d, J = 6.7 Hz, 1 H), 7.63 (td, J = 7.6, 1.2 Hz, 1 H), 7.55−7.45
(m, 4 H), 7.40 (d, J = 6.8 Hz, 1 H), 4.39 (d, J = 6.2 Hz, 2 H), 2.49
(t, J = 6.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 148.4, 139.5, 134.2, 130.8,
130.3, 128.8, 128.5, 128.0, 127.8, 127.7, 127.0, 84.4, 58.5.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2372–2386

2386
D. N. Barsoum et al.
FEATURE ARTICLE
19F NMR Experiment
(8) Kuang, G.-C.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.;
Zhu, L. J. Org. Chem. 2010, 75, 6540.
(9) Kuang, G.-C.; Guha, P. M.; Brotherton, W. S.; Simmons, J.
T.; Stankee, L. A.; Nguyen, B. T.; Clark, R. J.; Zhu, L. J. Am.
Chem. Soc. 2011, 133, 13984.
(10) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853.
(11) To the best of our knowledge, carboxyl-containing
substrates have not previously been shown to participate in
the formation of 5-iodo-1,2,3-triazoles.
BnN3 (Z7, 53 mg, 0.4 mmol), THF (2 mL), Cu(ClO4)2·6H2O (296
mg, 0.8 mmol), KI (264 mg, 1.6 mmol), and, if needed, TBTA (21
mg, 0.04 mmol) were added sequentially to a glass vial containing
a stirrer bar, and the mixture was stirred for ~5 min. Et3N (40 mg,
0.4 mmol) and 4-fluoro-1-ethynylbenzene (Y13, 48 mg, 0.4 mmol)
were then added, and the mixture was stirred at r.t. Aliquots of the
mixture (~0.1 mL) were taken at various reaction times. The sam-
ples were diluted with EtOAc then added to a test tube containing
aq Na2S2O3 to quench the I2. The organic layer was removed, passed
through a Celite pad to remove Cu, and concentrated under reduced
pressure. The residue was dissolved in CDCl3 and one drop of
PhCF3 was added as a reference standard (−63.72 ppm). All spectra
were acquired at 376 MHz at r.t.
(12) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem.
Int. Ed. 2005, 44, 2210.
(13) In a few cases the scale was doubled, as indicated in the
experimental section.
(14) A 10 mol% excess of the alkyne was used for convenience
in monitoring the azide as the limiting reagent.
Acknowledgment
(15) The following experiment showed that the oxidant is O2, not
perchlorate or its derivatives. When 28−30% aq NH3 was
added to a suspension of CuCl in EtOAc, the aqueous phase
immediately turned deep blue, thereby precluding the
involvement of perchlorate in the oxidation of copper(I).
When CuCl was added to a stirred mixture of EtOAc and aq
NH3 purged with argon for 10 min, the solution turned from
clear to a pale light blue. The minimal blue coloration may
have been the result of minor oxidation of copper(I) by the
residual O2 in the solution. Two to three minutes after argon
purging was terminated, the solution turned to deep blue,
suggesting rapid aerobic oxidation of most, if not all, the
copper(I) ions to form tetraammine copper(II) ions.
(16) Pelletier, G.; Lie, S.; Mousseau, J. J.; Charette, A. B. Org.
Lett. 2012, 14, 5464.
This work was supported by the NSF (CHE-1213574).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
References
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