Iridium-catalyzed cycloaddition of azides and 1-bromoalkynes at room temperature

Article abstract of DOI:10.1021/ol402008u

Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.

Full text of DOI:10.1021/ol402008u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iridium-Catalyzed Cycloaddition of Azides
and 1‑Bromoalkynes at Room Temperature
Evelia Rasolofonjatovo, Sewan Theeramunkong, Alexandra Bouriaud,
ꢀ ꢀ
Sergii Kolodych, Manon Chaumontet, and Frederic Taran*
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, F-91191 Gif sur Yvette,
France
frederic.taran@cea.fr
Received July 17, 2013
ABSTRACT
Iridium dimer complexes were found to catalyze the [3 þ 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted
4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted
triazoles.
In addition to their high value as synthetic inter-
mediates,1 1,2,3-triazoles have found widespread applica-
tions in agricultural and medicinal chemistry.2 Since the
discovery of Cu(I)-catalyzed azideꢀalkyne cycloaddition
(CuAAC), a tremendous number of 1,4-disubstituted
triazoles have been synthesized for various applications.
Extensions of this powerful reaction have then been suc-
cessfully developed to give straightforward access to halo-
geno-substituted triazoles that would serve as suitable
precursors to trisubstituted triazoles (Scheme 1A). Thus,
the Cu(I)-catalyzed cycloaddition of azides with iodoalk-
ynes, leading to flexible 5-iodotriazoles, was first disclosed
by Fokin et al.3 and then by Zhu et al.4 To circumvent the
lack of stability of iodoalkynes, both teams developed an
alkyne iodinationꢀcycloaddition one-pot sequence. The
presence of an iodo substituent was then successfully
exploited using Suzuki-type coupling to synthesize fully
substituted triazoles.
Scheme 1. Metal-Catalyzed Routes to Trisubstituted Triazoles
(1) (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302. (b)
Liang, L. Y.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933. (c) Chen,
Z. Y.; Zheng, D. Q.; Wu, J. Org. Lett. 2011, 13, 848. (d) Kappe, C. O.;
Van der Eycken, E. Chem. Soc. Rev. 2010, 39, 1280.
(2) (a) Tullis, J. S.; VanRens, J. C.; Natchus, M. G.; Clark, M. P.; De,
B.; Hsieh, L. C.; Janusz, M. J. Bioorg. Med. Chem. Lett. 2003, 13, 1665.
(b) Alam, M. S.; Huang, J.; Ozoe, F.; Matsumura, F.; Ozoe, Y. Bioorg.
Med. Chem. Lett. 2007, 17, 5086. (c) Chu, C. K.; Baker, D. C. Carbo-
cyclic 7-Deazaguanosine Nucleoside as Antiviral Agent; Plenum Press:
New York, 1993. (d) Miura, S.; Izuta, S. Curr. Drug Targets 2004, 5, 191. (e)
Fan, W. Q.; Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, C. W., Eds.; Elsevier:
Oxford, U.K., 1996; Vol. 4. (f) Kolb, H., C.; Sharpless, K. B. Drug
Discovery Today 2003, 24, 1128.
In comparison with iodoalkynes, bromoalkynes are
advantageous due to their higher stability and their easier
preparation and handling. However, their reactivity to-
ward the Cu-catalyzed [3 þ 2] cycloaddition reaction with
azides appeared to be much lower than that observed with
iodoalkynes. As a matter of fact, only one report describes
the formation of 5-bromotriazoles in a regioselective man-
ner using a catalytic mixture of Cu(I) and Cu(II).5 On the
(3) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin,
V. V. Angew. Chem. Int. Ed. 2009, 48, 8081.
(4) Brotherton, W. S.; Clarck, R. J.; Zhu, L. J. Org. Chem. 2012, 77,
6443.
(5) Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg,
P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett 2005,
20, 3059.
r
10.1021/ol402008u
XXXX American Chemical Society

other hand, ruthenium complexes have been employed to
catalyze the cycloaddition of azides and internal alkynes,
leading to 1,4,5-trisubstituted triazoles (Scheme 1B).6 This
reaction delivers fully substituted triazole heterocycles in
good yields, but it is marred by the need for alkynes to
contain “push-pull” triple bonds or strong H-donors to
direct their regioselectivity.7 It is important to note that
Ru-catalyzed cycloaddition of bromoalkynes has not yet
been described. A complementary process allowing the
regioselective formation of 1,5-disubstituted bromotria-
zoles is therefore highly desirable.
Table 1. Optimization of the Reactiona
entry
catalyst
conditions
yield of 3a (%)b
1
none
110 °C, toluene
0
Using a high-throughput screening approach for reac-
tion discovery, we recently showed that [Ir(cod)Cl]2 is
able to promote a 1,3-dipolar cycloaddition of azides with
bromoalkynes, leading to 1,5-disubstituted 4-bromotria-
zoles in low yields. On the basis of this preliminary result,
we describe here our attempts to optimize this unprece-
dented Ir-catalyzed transformation and to study its scope
(Scheme 1C).
2
[Ir(cod)(PPh2Me)2]PF6 25 °C, CH2Cl2
3
3
Ir(cod)(acac)
25 °C, CH2Cl2
25 °C, CH2Cl2
25 °C, CH2Cl2
25 °C, CH2Cl2
25 °C, toluene
25 °C, dioxane
25 °C, MeCN
25 °C, MeOH
40 °C, CH2Cl2
25 °C, DCE
6
4
[Ir(cod)Cl]2
10
17
61
19
16
24
trace
18
37
33
5
[Ir(cod)OPh]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
[Ir(cod)OMe]2
6
7
8
9
10
11
12
13
Using benzyl azide 1a and bromoalkyne 2a as model
substrates, we first investigated the influence of a series of
iridium complexes on the reaction (Table 1).
25 °C, CHCl3
The use of a dimeric iridium complex is crucial, as only a
small amount of cycloadduct was formed with a mono-
meric species (Table 1, entries 2 and 3). No reaction took
place in the absence of Ir catalyst even at high temperature
(Table 1, entry 1). Among the dimeric iridium species,
[Ir(cod)OMe]2 was found to be the most powerful, leading
to the regioselective formation of the 4-bromo-1,5-triazole
3a in 61% isolated yield in CH2Cl2 at room temperature
(Table 1, entry 6). Addition of phosphines or N-based
ligands was detrimental to the reaction efficiency. Chan-
ging the solvent or temperature resulted in lower yields and
degradation of bromoalkyne 2a. No trace of 5-bromo-1,4-
triazole regioisomer was detected under all tested condi-
tions described in Table 1.
a Conditions: inert atmosphere and substrates at 0.2 M. b Isolated
yields.
Table 2. Alkyne Scope of the Ir-Catalyzed Cycloaddition with
Azidesa
entry
X
yield of 3 (%)b
3/4
The reaction was found to be quite selective for bro-
moalkyne substrates (Table 2). Chloroalkynes were indeed
almost unreactive toward the iridium complex, and io-
doalkynes underwent degradation under the reaction con-
ditions (Table 2, entries 1 and 3).
1
2
3
4
5
Cl
Br
I
10
71
0
100/0
100/0
H
10
0
0/100
CO2Me
a Conditions: inert atmosphere and substrates at 0.2 M; 1.5 equiv of
alkyne was used. b NMR yield.
Polarized disubstituted alkynes such as aryl propiolates
were also unreactive in the reaction (Table 2, entry 5).
Interestingly, terminal alkynes reacted with opposite re-
gioselectivity under the reaction conditions, affording pure
1,4-disubstituted triazoles in low yields (Table 2, entry 4).
We next probed the scope of azides and bromoalkynes
using [Ir(cod)OMe]2 under the optimized conditions
(Scheme 2). Successful attempts proceeded at ambient
temperature and delivered regioselectively the desired
4-bromo-1,5-triazoles after overnight reaction in reason-
able to excellent yields. With regard to the dipole partner,
reactions of alkyl azides were most efficient, whereas the
use of aromatic azides led to only traces of the correspond-
ing cycloadducts (data not shown). The electronic features
of the alkyne component appeared to have a considerable
effect on the reaction. As evidenced by compounds 3c
(94% yield), 3g (80% yield), and 3k (22% yield), electron-
rich arylalkynes demonstrated the best dipolarophile abil-
ities, although electron-poor bromoalkynes gave the cor-
responding 4-bromotriazoles in poor yields. The reaction
was compatible withsulfur-containing substrates (3h,l) but
was found sensitive to steric hindrance, as no reaction was
observed with 1-azidoadamantane and product 3j was
obtained in only 23% yield from 2-methyl-3-butyn-2-ol.
Remarkably, the reaction appeared tolerant to unpro-
tected phenol (3g, 80% yield), although 12% of the
5-bromo isomer was recovered in this particular case.
(6) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(b) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680. (c)
Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
(7) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Regioselective Formation of 1,5-Disubstituted
4-Bromotriazoles 3 through the Ir-Catalyzed Cycloaddition
Reaction
Figure 1. X-ray structure of 3c.
Scheme 3. Two-Step Synthesis of Trisubstituted Triazoles by Ir-
Catalyzed [3 þ 2] Cycloaddition Followed by Pd-Catalyzed
Suzuki Coupling Reactionsa
a Overall isolated yields.
No trace of 5-bromo regioisomer was observed by crude
NMR analysis of other reactions. The structures of com-
pounds 3 were assigned by comparison to published
analytical data and further proven by the X-ray crystal-
lography of the representative product 3c (Figure 1).
We then tried to apply this new Ir-catalyzed reac-
tion to the preparation of 1,4,5-trisubstituted triazoles 5
by forming the 4-bromotriazole and immediately employ-
ing Pd-catalyzed Suzuki type reactions with appropriate
arylboronic acids (Scheme 3). The 4-bromotriazole
products were partially purified by filtration through
silica gel to remove iridium salts prior to the Pd-cou-
pling step.
complex A (Scheme 4).8 Unlike the mechanism described
for CuAAC,9 where the azide terminal nitrogen atom
becomes an electrophilic center after coordination with
copper, subsequent complexation of the azide partner by Ir
may leadtoanti-nucleophilicattackofthe N-30 atom ofthe
azide moiety to the C-1 atom of the π-coordinated triple
bond, resulting in the formation of the stabilized Ir carbe-
noid B. Such azide behavior was recently proposed as a key
stepina samarium-catalyzed cycloaddition of alkyneswith
azides leading to 1,5-disubstituted 1,2,3-triazoles.10 Given
the regioselective outcome of this Ir-catalyzed [3 þ 2]
cycloaddition, the other alternative would consist of the
attack of the N-10 atom of the azide at the C-2 atom of the
triple bond. This combination would lead to the nonstabi-
lized iridium carbenoid B0 andthereforeisthoughttobeless
probable. Intermediate B can then undergo a “Cope-like”
This simple two-step procedure allowed the formation
of fully substituted triazoles in moderate to good global
yields (Scheme 3).
Although the mechanistic underpinnings for this Ir-
catalyzed reaction would need a specific study, we propose
a tentative hypothesis. The low reactivity and the reverse
regioselectivity observed with terminal alkynes (Table 2)
suggest that the reactions do not proceed through transi-
tional debromination of bromoalkynes. The reaction may
thus be initiated by electrophilic activation of the alkyne by
the IrI complex, leading to the formation of the π-alkynyl
(8) For similar examples, see: (a) Genin, E.; Antoniotti, S.; Michelet,
V.; Genet, J.-P. Angew. Chem. Int. Ed. 2005, 44, 4949. (b) Beller, M.;
Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int. Ed. 2004, 43, 3368.
(9) (a) Fokin, V. V.; Hein, J. E. Chem. Soc. Rev. 2010, 39, 1302. (b)
ꢀ
Dꢀez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166. (c) Worrell, B. T.;
Fokin, V. V. Science 2013, 340, 457.
(10) Hong, L.; Lin, W.; Zhang, F.; Liu, R.; Zhou, Z. Chem. Commun.
2013, 49, 5589.
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, we have developed an unprecedented
Ir-catalyzed [3 þ 2] cycloaddition of bromoalkynes with
azides, offering a direct and regioselective route to 4-bromo-
1,5-triazoles. Post-functionalization of 4-bromotriazoles
smoothly afforded fully substituted heterocycles. Despite
some limitations in terms of alkyne substrate scope, this
new reaction represents a valuable complement to CuAAC
and RuAAC reactions, offering complete control over the
placement of substituents around the triazole heterocycle
core.
Scheme 4. Postulated Mechanism
Acknowledgment. We thank D. Buisson (CEA) for
experimental assistance with MS and LC/MS measure-
ꢀ
ments and Dr. P. Thuery (CEA) for structural elucidation
by X ray crystallography. This work was supported by the
ANR (ClickScreen project) and by the European commu-
nity (BioChemLig project).
cyclization to yield metallacycle C,11 which would finally
deliver 4-bromo-1,5-triazole 3 upon iridium CꢀN reduc-
tive elimination.
Supporting Information Available. Text and figures
giving experimental procedures for synthesis and full
characterization data for compounds; 1H NMR and 13
C
NMR spectra of products 3, and the crystal structure of
product 3c. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Crabtree et al. previously proposed a “Cope-like” cyclization of
an Ir carbenoid species in the context of iridium hydride catalyzed
intramolecular oxygen transfer from nitro groups to alkyne triple bonds:
Li, X.; Incarvito, C. D.; Vogel, T.; Crabtree, R. H. Organometallics 2005,
24, 3066.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX