Base and concentration effects on the product distribution in copper-promoted alkyne-azide cycloaddition: additive-free route to 5-iodo-triazoles

Article abstract of DOI:10.1016/j.tetlet.2009.11.089

Formation of 5-iodo-triazoles in CuI-promoted cycloadditions between alkynes and azides is controlled by DMAP and low alkyne concentrations.

Full text of DOI:10.1016/j.tetlet.2009.11.089

Tetrahedron Letters 51 (2010) 550–553
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Base and concentration effects on the product distribution in copper-promoted
alkyne–azide cycloaddition: additive-free route to 5-iodo-triazoles
*
Nicholas W. Smith, Bradley P. Polenz, Shawna B. Johnson, Sergei V. Dzyuba
Department of Chemistry, Texas Christian University, Fort Worth, TX 76129, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Formation of 5-iodo-triazoles in CuI-promoted cycloadditions between alkynes and azides is controlled
by DMAP and low alkyne concentrations.
Received 29 September 2009
Revised 19 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Copper-promoted alkyne–azide cycloaddition, routinely called
‘click-chemistry’, has become one of the premier synthetic tools
that has found numerous applications.1 From the synthetic point
of view, these cycloadditions are characterized by high yields, mild
conditions, and high tolerance to many functional groups.1 In the
case of CuI-promoted alkyne-azide cycloadditions, the presence
of a base is required to facilitate the formation of copper acetylides,
which are the active species for the reaction with the azides.2 In
general, i-Pr2EtN (Hünig’s base) or Et3N has been the bases of
choice for reactions conducted under non-aqueous conditions,
while furnishing 1,4-disubstituted 1,2,3-triazoles as major or
exclusive cycloaddition products.3 Although the effect of organic
bases on this cycloaddition reaction is generally believed to have
no significant impact on the product distribution,4 there are sev-
eral accounts demonstrating that additives might have a profound
effect on the outcome of this reaction.5
During the course of some of our studies on copper-promoted
alkyne-azide cycloadditions, we observed that when Hünig’s base
was substituted with 4-dimethylaminopyridine (DMAP), a forma-
tion of ca. 20% of 5-iodo-1,4-triazole was noted (Scheme 1).6
Although iodo-containing triazoles are sometimes reported as
minor products in various copper-catalyzed and copper-promoted
alkyne–azide cycloadditions,7 there are no reports, to our knowl-
edge, on the ability of DMAP (or any other organic base) to control
the product distribution in the alkyne-azide cycloadditions.8 5-
Iodo-triazoles are valuable synthons for a variety of cross-coupling
reactions.9 In addition, interactions featuring C-Hal compounds are
important in modulating various recognition processes relevant to
supramolecular and biological processes,10 which further increases
the value of 5-iodo-triazoles. The incorporation of iodine onto the
triazole moiety usually requires the presence of electrophilic io-
dine (I+) to produce 5-iodo-triazoles.11 Hence, the formation of
the iodo-triazoles by simply switching the base, that is, from i-
Pr2EtN to DMAP, presents an unexplored and interesting paradigm.
Herein, we wish to report on a base-controlled CuI-promoted
alkyne–azide cycloaddition. We started by screening a range of
conditions, including common aromatic bases that are structurally
related to DMAP, such as pyridine and N,N-dimethylaniline (DMA)
(Table 1).12
Surprisingly, in DMAP-promoted reactions, the formation of the
iodo-trizole correlated with the alkyne concentration. Lowering al-
kyne concentration (from 1.0 M to 3.5 mM) yielded 5-I-triazole 2
as the major cycloaddition product (Table 1, entries 1–3). One of
the possible sources for the formation of 5-I-triazoles is the iodin-
ation of 5-H-triazole, although non-electrophilic nature of iodine in
CuI makes this scenario unlikely. Nonetheless, we investigated the
distribution between 1 and 2 as a function of time. The ratio of
these triazoles was found to be time independent at both 1.0 M
and 3.5 mM concentrations of the alkyne, while using equimolar
amounts of azide, DMAP, and CuI. At 3.5 mM, no 5-H-triazole
was detected at any given time point. Also, when 1 was treated
with an equimolar mixture of DMAP and CuI for 20 h, 5-I-triazole
2 was not detected, and 1 was recovered unchanged. Hence, it is
* Corresponding author. Tel.: +1 817 257 6218; fax: +1 817 257 5851.
E-mail address: s.dzyuba@tcu.edu (S.V. Dzyuba).
Scheme 1. Base-specific distribution of 5-R-triazoles. Conditions: [alkyne] = 1.0 M;
ratios: alkyne/azide/base/CuI—1.0/1.0/1.0/1.0.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.089

N. W. Smith et al. / Tetrahedron Letters 51 (2010) 550–553
551
Table 1
the formation of 3 was significantly suppressed (Table 1, entry 6).
Even though, the rate of the reaction was inhibited, 5-I-triazole 2
was obtained as the major product and the only cycloaddition
product.
Base/concentration effects on the 5-iodo-triazole formationa
The effect of both pyridine and DMA resembled that of DMAP,
yet neither was as efficient in promoting the formation of 5-I-tria-
zole 2 (Table 1, entries 7–11). Although at 3.5 mM concentration
DMA afforded 5-I-triazole as the major cycloaddition product, yet
an appreciable amount of 5-H-triazole was still obtained. Impor-
tantly, the conversions with DMA and pyridine were inferior to
those of DMAP. Neither DMA nor pyridine promoted the formation
of diyne 3, which is consistent with both of these bases being
weaker than DMAP. Hünig’s base (Table 1, entries 12–14) was
completely insensitive to any concentration variations. Thus,
DMAP appears to be the most efficient base in promoting the for-
mation of 5-I-triazoles.
Although the exact mechanism of a typical CuI-catalyzed/pro-
moted alkyne-azide cycloaddition remains to be clarified,1a,2 the
optimization studies (Table 1) provided some mechanistic insight
about the formation of 5-I-triazoles (Scheme 2). It is largely ac-
cepted that copper-complexes could form various aggregates,15
and therefore it is likely that at high concentrations these aggre-
gates, A, might be responsible for promoting the alkyne–azide
cycloaddition leading to the formation of 5-H triazoles. It is plausi-
ble that upon dilution, the Cu-acetylides A disaggregate to form a
bis-copper acetylide complex B (Scheme 2). This complex B might
be responsible for the formation of diyne 3 (Table 1), which be-
comes the major product in dilute media. This observation is sup-
ported by the mechanistic rationale for the terminal alkyne
homocoupling (known as the Glaser alkyne homocoupling16),
which is proposed to involve bis-copper acetylides. Furthermore,
the use of DMAP, a strongly coordinating, sterically unbiased li-
gand (in comparison with Hunig’s base) for Cu-complexes should
assist in stabilization of B. In agreement with this proposal, we ob-
served that the decrease in alkyne homocoupling was facilitated by
the decrease in the amount of DMAP. Apparently, other bases are
inferior to DMAP in aiding the stabilization of B, thus the formation
of the diyne 3 was not observed.
Entry
Base
[Alkyne], mM
Product distributionb (%)
1
2
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMAP
DMAP
DMAP
DMAPc
DMAPd
DMAPe
Pyridine
Pyridine
DMA
DMA
DMA
iPr2EtN
iPr2EtN
iPr2EtN
1000
35
3.5
3.5
3.5
3.5
1000
3.5
1000
35
3.5
88
64
21
—
—
—
84
76
12
30
58
23
44
96
16
24
—
—
64
—
—
—
—
6
21
77
56
4
—
—
—
—
—
—
—
—
100
100
36
100
100
100
1000
35
3.5
a
b
c
Ratios: alkyne/azide/base/CuI—1.0/1.0/1.0/1.0.
Determined by 19F NMR on a crude reaction mixture.
Ratios: alkyne/azide/base/CuI—1.0/1.5/1.0/1.0.
Ratios: alkyne/azide/base/CuI—1.0/3.0/1.0/1.0.
Ratios: alkyne/azide/base/CuI—1.0/3.0/0.3/1.0.
d
e
plausible that the formation of 5-I-triazole takes place via a distinct
Cu-intermediate, which is stabilized by DMAP.
Next, we varied the amount of CuI. Not surprisingly, decreasing
CuI content led to inferior conversions. Increasing the amount of
CuI to 2.0 equiv had no apparent impact on the rate of formation
of the iodo-triazole 2. Also, the application of CuCl proved to be
inefficient in promoting the cycloaddition.
Furthermore, the distribution between 1 and 2 proved to be
fairly insensitive to the nature of the solvent. Among the solvents
screened (CH3CN, THF, and DMSO), CH3CN appeared the most effi-
cient in terms of product distribution and conversion.
Further, azides could also act as ligands and stabilize the subse-
quent copper complexes. Hence, it could be expected that the in-
crease in the amount of azide would disrupt complex B and
promote a formation of complex C. Relative inability of pyridine
and DMA to stabilize B, as compared to DMAP, allows the azide
to compete for the coordination site and afford C. This would ex-
plain the formation of 2 and the lack of 3 (Table 1, entries 8 and
After some experimentation, we identified the concentration of
the azide as one of the complementary factors in controlling the
formation of 5-iodo-triazole. Conducting the reaction in the dilute
solution (3.5 mM alkyne) with 1.5 equiv of the azide completely
suppressed the formation of 1, and afforded 5-I-triazole 2 as the
only cycloaddition product (entry 4). Unfortunately, this set of con-
ditions also promoted the homocoupling of the alkyne yielding
diyne 3 (entry 4). This side reaction was previously reported for
some Cu-catalyzed and Cu-promoted alkyne-azide cycloaddi-
tions,3b,13 however, the effect of neither the base nor concentration
had been examined. In order to suppress the formation of 3, we
conducted reactions under inert atmosphere (N2) and/or using de-
gassed CH3CN, albeit with no success, as the amount of the pro-
duced diyne was largely unaffected.
However, further increasing concentration of the azide to
3.0 equiv (Table 1, entry 5) allowed to increase the amount of 2,
while decreasing the diyne 3 formation.14 In order to suppress
the formation of 3, we varied the amount of DMAP. It appeared that
higher concentrations of DMAP led to increased amounts of 3,
which is expected due to an enhanced rate of deprotonation of
4-fluorophenylacetylene. On the other hand, at 0.3 equiv of DMAP,
R1
I
R1
H
N
N
DMAP
dilution
N
N
R
CuLn
m
N
N
A
R
R
L
L
Cu
with iPr2EtN
with DMAP
R
R
iPr2EtN
Cu
B
R1
concentration
independent
L
N
N
L
N
R1 N3
L
Cu
R
Cu
L
R1
N
N
R1
L
N
R1
N
F
N
L
N
N
L
N
Cu
Cu
Cu
N
L
L
R
L
L
R
Cu
Cu
Cu
R
C
D
E
L
L
Scheme 2. A tentative mechanism of 5-I-triazole formation.

552
N. W. Smith et al. / Tetrahedron Letters 51 (2010) 550–553
Table 2
iodo-triazoles. No alkyne homocoupling products were observed.
Synthesis of 5-I-triazolesa
The effect of varying other conditions, that is, concentrations of
DMAP and CuI as well as the solvent was virtually identical to
the results obtained with 4-fluoro-phenylacetylene.
In conclusion, we found that the identity of the organic base, as
well as the concentration of the alkyne, could play major roles in
determining the nature of the products in the CuI-promoted al-
kyne–azide cycloaddition. Low concentrations of the alkyne and
the use of DMAP led to the formation of 5-I-triazoles as the only
cycloaddition products. The expanded scope of this transformation
will be reported in the due course.
Entry
R1
R2
Isolated yield (%)
1b
2
3
H
Br
4-MeO
4-NO2
4-NO2
H
C6H5
4-F-C6H4
C6H5
C6H5
C6H5
iPr
77
24
37
65
78
0
4
5c
6
Acknowledgments
7
Br
iPr
0
a
b
c
Conditions: [alkyne] = 3.5 mM, ratios: alkyne/azide/DMAP/CuI—1.0/2.0/0.3/1.0.
Reaction time 48 h.
3.0 equiv of azide.
We would like to acknowledge the donorsof the AmericanChem-
icalSociety Petroleum ResearchFund(47965-G7)and TCU for partial
support of this research. N.W.S. would like to thank ACS Division of
Medicinal Chemistry for the predoctoral fellowship sponsored by
Wyeth. S.V.D. is a recipient of the 2009 TCU-JFSR award.
11). It is plausible that C is still a bis-copper complex, since similar
types of complexes were proposed in the formation of triazoles.1a,2
The subsequent cascade probably proceeds from D to E to F, all of
which are reminiscent to those suggested for the formation of the
5-H triazoles.1a,2 Finally, DMAP, pyridine, and DMA, might provide
extra stabilization of one or more of the D, E, and F complexes,
(which was suggested for pyridine2c) and allow for an efficient
intramolecular delivery of iodine to furnish 5-I-triazole, whereas
the bulkier ligand iPr2EtN does not,2c thus leading to 5-H-triazole.
With optimized conditions at hand, we probed several alkyne–
azide combinations (Table 2). The reaction rate was slow due to
low concentrations that were required to achieve the exclusive for-
mation of 5-I-triazole. Since product distribution was time inde-
pendent, we increased the reaction times to 72 h, in order to
achieve appreciable conversions. Chromatography-free removal
of the reagents and unreacted starting materials afforded iodo-tri-
azoles in low to moderate yields (entries 1–4). Increasing the
amount of the azide from 2.0 equiv to 3.0 equiv had a marginal im-
pact on the yield (entries 4 and 5). The aliphatic alkyne failed to re-
act, as only the unchanged starting materials were recovered
(entries 6 and 7).
Supplementary data
Supplementary data (synthesis and characterization data for
the described compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.11.089.
References and notes
1. For some recent reviews see: (a) Meldal, M.; Christian, W. Chem. Rev. 2008, 108,
2952–3015; (b) Franc, G.; Kakkar, A. Chem. Commun. 2008, 5267–5276; (c)
Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674–1689; (d) Wu, P.; Fokin,
V. V. Aldrichim. Acta 2007, 40, 7–17.
2. (a) Aucagne, V.; Berná, J.; Crowley, J. D.; Goldup, S. M.; Hänni, K. D.; Leigh, D. A.;
Lusby, P. J.; Ronaldson, V. E.; Slawin, A. M. Z.; Viteisi, A.; Walker, D. B. J. Am.
Chem. Soc. 2007, 129, 11950–11963; (b) Straub, B. F. Chem. Commun. 2007,
3868–3870; (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51–68; (d) Himo, F.; Lowell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216.
3. For some examples see: (a) van Maarseveen, J. H.; Horne, W. S.; Ghadiri, M. R.
Org. Lett. 2005, 7, 4503–4506; (b) Jang, H.; Fafarman, A.; Holub, J. M.;
Kirshenbaum, K. Org. Lett. 2005, 7, 1951–1954; (c) Bock, V. D.; Perciaccante,
R.; Jansen, T. P.; Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2006, 8, 919–922;
(d) Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X.; Chen, M.; Fang, L.; Sun, D.;
Wang, P. G. J. Med. Chem. 2008, 51, 7417–7427; (e) Morales-Sanfrutos, J.;
Ortega-Muñoz, M.; Lopez-Jaramillo, J.; Hernandez-Mateo, F.; Santoyo-
Gonzalez, F. J. Org. Chem. 2008, 73, 7772–7774.
In addition, we examined the effect of DMAP on the formation
of 5-iodo-1,4-disubstituted triazoles using propargyl-containing
substrates (Table 3). In general, these reactions are less efficient
than the arylacetylene series (Table 2), however, the unreacted
starting materials were easily recovered using flash column chro-
matography. Importantly, DMAP and low alkyne concentration
were still the determining factors in facilitating the formation of
4. Inorganic bases, under oxidative conditions, have been shown to have
a
profound impact by promoting the formation of 5,50-bistriazoles: Angell, Y.;
Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 3649–3651.
5. (a) Radionov, V. O.; Presolski, S. I.; Diaz Diaz, D.; Fokin, V. V.; Finn, M. G. J. Am.
Chem. Soc. 2007, 129, 12705–12712; (b) Radionov, V. O.; Presolski, S. I.;
Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12696–12704;
(c) Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A., Jr. Tetrahedron 2006, 62, 6405–
6411.
Table 3
Syntheses of 5-iodo-triazole from propargyl-containing substratesa
6. The ratio between the 5-H and 5-I was determined from 1H NMR of the crude
mixture: the CH2-protons of 5-I-triazole appear as
a singlet (5.8 ppm)
downfield relative to the CH2-protons of 5-H-triazole (5.7 ppm).
7. (a) Pérez-Castro, I.; Caamaño, O.; Fernández, F.; Carcía, M. D.; López, C.; De
Clercq, E. Org. Biomol. Chem. 2007, 3805–3813; (b) Tanaka, K.; Kageyama, C.;
Fukase, K. Tetrahedron Lett. 2007, 48, 6475–6479; (c) Ito, S.; Satoh, A.;
Nagatomi, Y.; Hirata, Y.; Suzuku, G.; Kimura, T.; Satow, A.; Maehara, S.;
Hikichi, H.; Hata, M.; Kawamoto, H.; Ohta, H. Bioorg. Med. Chem. 2008, 16,
9817–9829.
8. DMAP was recently shown to accelerate 1,4-triazole formation catalyzed by
copper-carbene ligands, without inducing the formation of any other
cyloaddition products: Teyssot, M.-L.; Chevry, A.; Tra, M.; El-Ghozzi, M.;
Avignant, D.; Gautier, A. Chem. Eur. J. 2009, 15, 6322–6326.
9. (a) Dinér, P.; Andersson, T.; Kjellén, J.; Elbing, K.; Hohmann, S.; GrØtli, M. New J.
Chem. 2009, 33, 1010–1016; (b) Deng, J.; Wu, Y.-M.; Chen, Q.-Y. Synthesis 2005,
2730–2738.
10. (a) Voth, A. R.; Ho, P. S. Curr. Top. Med. Chem. 2007, 7, 1336–1348; (b) Tatko, C.
D.; Waters, M. L. Org. Lett. 2004, 6, 3969–3972; (c) Kobayashi, K.; Ishii, K.;
Sakamoto, S.; Shirasaka, T.; Yamaguchi, K. J. Am. Chem. Soc. 2003, 125, 10615–
10624.
11. For some examples on the synthesis of iodo-triazoles, see: (a) Wu, J.; Deng, Y.-
M.; Chen, Q.-Y. Synthesis 2005, 1314–1318; (b) Li, L.; Zhang, G.; Zhu, A.; Zhang,
Entry
R1
R2
Isolated yield (%)
1
2
3
4
5
6
NO2
MeO
tBu
H
NO2
MeO
H
H
NO2
MeO
MeO
MeO
22
12
34
39
23
33
a
[Alkyne] = 3.5 mM, ratios: alkyne/azide/DMAP/CuI—1.0/1.0/1.0/1.0.

N. W. Smith et al. / Tetrahedron Letters 51 (2010) 550–553
553
L. J. Org. Chem. 2008, 73, 3630–3633; (c) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.;
Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018–8021.
12. The fluoro-containing alkyne was chosen for the convenience of identifying the
product distribution using 19F NMR due to non-overlapping resonances of
compounds 1 (ꢀ113.7 ppm), 2 (ꢀ112.9 ppm), and 3 (ꢀ108.9 ppm) (Table 1).
However, we have also screened the effect of bases and concentrations on the
CuI-promoted cycloaddition between phenylacetylene and benzyl azide, that
is, non electron-effect biased substrates, and the results appeared in
correlation with the trends observed in Table 1.
compared to some literature examples, fewer reagents as well as conditions
that do not require a strong oxidant and/or strong electrophile might prove
useful in certain cases. For some examples on facile alkyne homocoupling
reactions see: (a) Li, L.; Wang, J.; Zhang, G.; Liu, Q. Tetrahedron Lett. 2009, 50,
4033–4036; (b) Adimurthy, S.; Malakar, C. C.; Beifuss, U. J. Org. Chem. 2009, 74,
5648–5651; (c) Li, D.; Yin, K.; Li, J.; Jia, X. Tetrahedron Lett. 2008, 49, 5918–
5919; (d) Kamata, K.; Yamaguchi, S.; Kotani, M.; Yamaguchi, K.; Mizuno, N.
Angew. Chem., Int. Ed. 2008, 47, 2407–2410. .
15. (a) Mykhalichko, B. M.; Temkin, O. N.; Mys’kiv, M. G. Russ. Chem. Rev. 2000, 69,
957–984; (b) Xie, X.; Auel, C.; Henze, W.; Gschwind, R. J. Am. Chem. Soc. 2003,
125, 1595–1601.
13. TornØe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
14. It would be of interest to point out that in the absence of the azide (ratio:
alkyne/DMAP/CuI—1.0/1.0/0.5), DMAP promoted
diynes. Although the rates of this transformation are fairly slow (20 h), as
a
clean formation of the
16. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,
2632–2657.