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[Cu-Ln]. Paths 2 and 3 involve
oxidative Huisgen coupling reac-
tions. On the other hand, if
a new molecule of Glc-N3 is
brought into the coordination
sphere of the copper atom,
a six-membered ring intermedi-
ate can be created, which can
form a bis-triazolyl-CuI s-com-
plex, from which a dimeric tria-
zolyl species IV can be obtained
through reductive elimination
(Path 3), but also two molecules
of the 5-protonated triazole II
can be generated as a result of
Scheme 5. Pd-catalyzed Sonogashira cross-couplings with 5-iodo-1,2,3-triazoles.
protonation. The protonation steps in Path 1 and Path 3 are
therefore critical for the optimal formation of the 5-protonated
triazoles II under most of the conditions presented in the liter-
ature. Similarly, the structure of the bis-triazolyl-CuI s-complex
probably largely determines the structure of bis-triazole IV.
When an excess of cupper(I) halide (CuX) is used, halogena-
tion of the alkyne becomes prevalent (Path 4) and the rate of
1,3-dipolar cycloaddition of azides to halogenated alkynes
(CꢁCX) predominates. The use of CuI and CuBr typically pro-
vided the 5-halogenated triazoles V as the main products.[22,45]
In contrast, chlorination of the alkyne position in Path 4 is
probably much slower than the cycloaddition cascades
through Paths 1–3 because the coordination of chloride to
copper is much weaker than for bromide or iodide.[59] The
major compounds isolated under chlorination conditions are
therefore derivatives II–IV.
Table 3. Synthesis of 5-alkynyl-1,2,3-triazoles 15.[a]
Entry
R1
Alkyne (R2)
Product
Yield [%][b]
1[c]
2
Ph
Ph
Ph
Ph
15cc
15cc
15aa
15ab
15ac
15af
15ba
15bb
15bc
15bf
20
93
49
86
87
73
45
71
92
72
3
CH2OAc
CH2OAc
4
CH2OAc
6-OMe-2-naphthyl
5
CH2OAc
Ph
6
CH2OAc
SiMe3
7
8
9
10
6-OMe-2-naphthyl
6-OMe-2-naphthyl
6-OMe-2-naphthyl
6-OMe-2-naphthyl
CH2OAc
6-OMe-2-naphthyl
Ph
SiMe3
[a] Reaction conditions: 5-Iodo-1,2,3-triazole 4a–c (1 equiv), alkyne 2a–c,f
(2 equiv), CuI (0.1 equiv), [Pd(PPh3)4] (0.05 equiv), K3PO4 (1.1 equiv).
[b] The value indicated is the isolated yield of 5-alkynyl-1,2,3-triazole 15
and the remaining material was composed of 5-proto triazoles 3.
[c] 5-Iodo-1,2,3-triazole 4c (1 equiv), alkyne 2c (2 equiv), CuI (0.1 equiv),
[PdCl2(PPh3)2] (0.05 equiv), Et3N (1.1 equiv).
As discussed above, compounds 11 a and 11 c are produced
via hindered copper-associated glucosyl-triazoles, and it is rea-
sonable to assume that the preferred conformation around the
N-glucosidic bond minimized the existing steric interactions
between the glucopyranose ring and the complexed copper
atom. To this end, the smaller group (anomeric proton) should
be directed toward the copper atom in the intermediates
along Path 3 in the reaction (Scheme 4). When dimerization oc-
curred to produce acetylated bis-triazoles, probably for kinetic
and steric reasons, the conformation of the N-glucosidic bond
remained unchanged.
of the reduced products 5 (Table 3). The reaction was per-
formed with three 5-iodo-1,2,3-triazoles 4a–c and four alkynes
2a–c and f, and afforded a collection of nine 5-alkynyl-1,2,3-tri-
azoles 15. The yields obtained were good to excellent, except
for the cross couplings with propargyl acetate (2a; entries 3
and 7). Methanolysis of the acetyl protecting groups afforded
the O-unprotected glucose-based 1,4,5-trisubstituted 1,2,3-tria-
zoles 16 in good yields.
Synthesis of 5-aryl-1,2,3-triazoles through Pd-catalyzed
Suzuki cross-couplings
Synthesis of 5-alkynyl-1,2,3-triazoles through Pd-catalyzed
Sonogashira cross-couplings
The conditions reported in the literature[34,36,60] for Suzuki
cross-couplings on a triazole ring (Scheme 6) are very diverse
and the efficiency of the coupling reactions seem to be sub-
strate-dependent, with a marked influence of the steric hin-
drance at the halogenated carbon atom. In the present study,
several coupling conditions were therefore evaluated by using
1-(2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl)-4-phenyl-5-iodo-
1,2,3-triazole (4c) for optimization (Table 4). The major com-
pound isolated was 5-proto-triazole 3c when [PdCl2(PPh3)2]
was used (Table 4, entries 1–5). Zask et al.[61] reported that alk-
oxide bases react with halogenated aryls in the presence of
palladium to provide the reduced aromatic derivatives, as we
The convenient access to 5-halogeno-1,2,3-triazoles 3, 4, and 9
paved the way for a study of Pd-catalyzed cross-couplings
under Sonogashira conditions with alkynes[60] (Scheme 5), or
under Suzuki conditions with aryl boronic acids.[34,36,60]
Application of the standard Sonogashira conditions tested
initially (Table 3, entry 1) afforded the desired cross-coupling
product 15 in only 20% yield, whereas the reduced product 5
represented ca. 80% yield. Changing the base from triethyl-
amine to potassium phosphate and using [Pd(PPh3)4] instead
of [PdCl2(PPh3)2] afforded the desired 5-alkynyl-1,2,3-triazoles
15 in significantly improved yields, along with a small portion
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Chem. Eur. J. 2014, 20, 1 – 11
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