1,2,3-Triazoles from carbonyl azides and alkynes: Filling the gap

Article abstract of DOI:10.1039/c4cc03614j

Electron deficient azides are challenging substrates in CuAAC reactions. Particularly, when N-carbonyl azides are applied the formation of N-carbonyl triazoles has not yet been observed. We report herein the first example of this class of reaction, with a

Full text of DOI:10.1039/c4cc03614j

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1,2,3-Triazoles from carbonyl azides and alkynes:
filling the gap†
Cite this: Chem. Commun., 2014,
50, 8978
a
b
c
a
´
Estela Haldon, Eleuterio Alvarez, M. Carmen Nicasio* and Pedro J. Perez*
´
´
Received 13th May 2014,
Accepted 17th June 2014
DOI: 10.1039/c4cc03614j
www.rsc.org/chemcomm
Electron deficient azides are challenging substrates in CuAAC reac-
tions. Particularly, when N-carbonyl azides are applied the formation
of N-carbonyl triazoles has not yet been observed. We report herein
the first example of this class of reaction, with a copper-based system
that efficiently enables the synthesis of N-carbamoyl 1,2,3-triazoles
by [3+2] cycloaddition of N-carbamoyl azides and alkynes.
Despite the 1,2,3-triazole ring does not occur in nature, synthetic
molecules that contain this heterocyclic unit show diverse biological
activities.1 The Huisgen thermal 1,3-dipolar cycloaddition reaction2
of alkynes and organic azides is the most straightforward route for
the synthesis of this interesting and notable stable five-membered
Scheme 1 Synthesis of 1,2,3-triazoles and oxazoles via CuAAC.
heterocycle. However, the selectivity of the process is low, yielding react with alkynes, in the presence of the corresponding catalyst,
mixtures of 1,4- and 1,5-disubstituted regioisomers. A major devel- rendering products derived from the reaction of ketenimine
opment in the field was made, independently, in 2002 by the groups species, formed upon ring-opening of the triazole-cuprate inter-
of Meldal3 and Sharpless:4 the copper-catalyzed version of the mediates, with nucleophiles.9 Scarcely, a few systems have
Huisgen reaction, which remarkably improved the reaction rate been described in which the presence of certain ligands10a or
and the selectivity, since it provided exclusively 1,4-disubstituted the use of copper(I) complexes10b,c allowed the formation of the
1,2,3-triazoles in very high yields, overcoming the drawbacks of the 1,2,3-triazoles, particularly when N-sulfonyl azides are applied
original Huisgen procedure. Since then, the copper-catalyzed azide– (Scheme 1b).10 A few years ago, we found that the complex
alkyne cycloaddition (CuAAC)5 (Scheme 1a) has found tremendous [Tpm*,BrCu(NCMe)]BF4 (Tpm*,Br = tris(3,5-dimethyl-4-bromo-
applications in several disciplines5–8 due to its versatility, in terms of pyrazolyl)methane) also promoted the exclusive formation of
both reaction conditions and functional group compatibility.
N-sulfonyl-1,2,3-triazoles in the cycloaddition reaction of N-sulfonyl
However, electron deficient azides are challenging substrates azides with terminal alkynes.11 Shortly after we found that when
since they do not very frequently provide the corresponding N-carbonyl azides were applied under the same catalytic conditions,
1,2,3-triazoles. Thus, N-sulfonyl or N-phosphoryl azides usually 1,5-disubstituted oxazoles were isolated as products12a (Scheme 1c)
instead of the expected 1,2,3-N-carbonyl triazoles. To date, and to
a
´
´
Laboratorio de Catalisis Homogenea, Unidad Asociada al CSIC, CIQSO-Centro de
the best of our knowledge, the direct formation of N-carbonyl-
1,2,3-triazoles by CuAAC using N-carbonyl azides as substrates
(Scheme 1d) remains undescribed. Herein, we report the syn-
thesis of 1,4-disubstituted N-carbamoyl 1,2,3-triazoles from the
cycloaddition reaction of N-carbamoyl azides and alkynes catalyzed
by [Tpa*Cu]PF6, (Tpa* = tris(3,5-dimethyl-pyrazolylmethyl)amine),
which can be considered the first example of the formation of
N-carbonyl 1,2,3,-triazole derivatives from a CuAAC reaction of a
N-carbonyl azide. It is worth mentioning that the products prepared
by this methodology have been described to be potent inhibitors of
serine hydrolases.13
´
´
´
Investigacion en Quımica Sostenible and Departamento de Quımica y Ciencias de
los Materiales, Campus de El Carmen s/n, Universidad de Huelva, 21007-Huelva,
Spain. E-mail: perez@dqcm.uhu.es
b
c
´
Instituto de Investigaciones Quımicas Isla de la Cartuja, CSIC-Universidad de
´
Sevilla, Avenida de Americo Vespucio 49, 41092-Sevilla, Spain
´
´
Departamento de Quımica Inorganica, Universidad de Sevilla, Aptdo 1203,
41071-Sevilla, Spain. E-mail: mnicasio@us.es
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, analytical and spectroscopic data, and X-ray crystallographic data.
CCDC 1002750 (1), 1002751 (4), 1002752 (5) and 1002753 (8). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc03614j
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Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Yieldb
1
2
3
4
5
6
7
8
9
[Tpa*Cu]PF6
DCE
DCE
CHCl3
DCE
DCE
None
DCE
DCE
DCE
70
—
—
[Tpm*,BrCu(CNMe)]BF4
[Tpm*,BrCu(CNMe)]BF4
c
[TpaCu]PF6
—
[Tpa*,BrCu]PF6
50
70
65e
70 f
—
d
[Tpa*Cu]PF6
[Tpa*Cu]PF6
[Tpa*Cu]PF6
None
Scheme 2 Reaction intermediates for the formation of triazoles and
oxazoles through CuAAC.
a
Reactions conditions: phenyl acetylene (1.2 mmol), N-morpholino
As mentioned above, we encountered a different reactivity
for N-carbonyl azides in the CuAAC that led to the isolation of
1,5-disubstituted oxazole derivatives. Mechanistic studies showed12b
that the reaction proceeded not through the copper–acetylide inter-
mediate usually invoked to trigger the formation of a triazolyl–
cuprate intermediate, but with the intermediacy of copper–nitrene
species formed from the azide reactant (Scheme 2). Therefore, this
distinct behaviour seems to govern the reaction outcome: triazoles
required a copper-acetylide species whereas oxazoles formed from a
copper nitrene intermediate. With this idea in mind, we thought
about the electronic characteristics that N-carbonyl azide would
require to disfavour the formation of the latter. We turned our
attention to N-carbamoyl azides, a class of carbonyl azides that
require gentle heating to promote N2 extrusion.14 This feature, along
with the delocalization of electronic density along the N–C(O)–N
moiety due to conjugation,15 could disfavour the extrusion of
dinitrogen and concomitant formation of the copper–nitrene inter-
mediate, with the subsequent appearance of copper-acetylides as
more probable intermediates.
b
carbamoyl azide (1 mmol), catalyst (5 mol%), solvent (1 mL). Isolated
yields. Tpa = tris(pyrazolylmethyl)amine. Tpa*,Br = tris(3,5-dimethyl-
c
d
4-bromo-pyrazolylmethyl)amine. e 10 mol% [Tpa*Cu]PF6. Phenyl acetylene
f
(1 mmol), N-morpholino carbamoyl azide (2.5 mmol).
We tested other catalyst precursors but neither of them resulted
to be active in this transformation (Table 1, entries 1–5). Having
identified the most promising catalyst precursor, other parameters
were examined. The use of the neat conditions, the increase of the
catalyst loading and the modification of the phenyl acetylene/
N-morpholinocarbamoyl azide ratio did not produce any signifi-
cant effect on the yield (entries 6–8). It is worth mentioning that
the control experiment carried out without the copper complex
resulted in no product formation (entry 9). Finally, the reaction did
not proceed when the organic azide was generated in situ from the
corresponding organic halide.
The scope of this transformation with regard to the alkyne
reactant is shown in Scheme 4. The reactions proceeded smoothly
at 40 1C with different aryl-substituted acetylenes affording
1,4-disubstituted 1,2,3-N-carbamoyl triazoles in good yields (1–4).
The outcome was largely unaffected by the electronic
nature of the substituents on the aromatic ring of the alkyne.
With the above idea in mind, we examined the potential of
complex [Tpa*Cu]PF6 as the catalyst precursor in the reaction of
N-morpholinocarbamoyl azide and phenyl acetylene (Scheme 3).
This complex has been found to promote the formation of oxazoles
from N-carbonyl azides and alkynes.12b Pleasingly, the reaction
proceeded with the isolation of a product whose spectroscopic
features did not resemble those of an oxazole but those of a triazole
derivative. For instance, a distinct sharp singlet resonance was
1
observed in the high frequency region of its H NMR spectrum at
d 8.37 and a strong absorption (ca. 1686 cmÀ1) was also found in the
typical carbonyl region of its IR spectrum (see ESI† for more details).
The presence of the 1,2,3-triazole structure was confirmed from an
X-ray analysis (Scheme 3). Isolated yield was 70%.
Scheme 4 [3+2] Cycloaddition of N-morpholinocarbamoyl azide with
1-alkynes catalyzed by [Tpa*Cu]PF6. Reaction conditions: azide (1 mmol),
alkyne (1.2 mmol), DCE (1 mL), 40 1C, 24 h. Isolated yields based on azide
Scheme 3 Reaction of N-morpholinocarbamoyl azide and phenyl acetylene
catalyzed by [Tpa*Cu]PF6.
a
(average of two runs). The reaction was performed at 60 1C.
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Scheme 5 [3+2] Cycloaddition of N-carbamoyl azide with phenyl
acetylene catalyzed by [Tpa*Cu]PF6. Reaction conditions: azide (1 mmol),
alkyne (1.2 mmol), DCE (1 mL), 40 1C, 24 h. Isolated yields based on azide
(average of two runs).
Moreover, the process was compatible with the presence
of a sulphur-containing heterocycle on the alkyne (5). Alkyl-
substituted acetylenes were also tested as substrates, but the
reactions had to be carried out at higher temperatures (60 1C) to
reach good conversions. Once more, the products were
obtained in high yields regarding the nature of the alkyl group
(6–9). As commonly observed in CuAAC reactions, internal
alkynes were totally inert under these conditions.16
To further explore the scope of the reaction, different
N-carbamoyl azide substrates were subjected to this [3+2]
cycloaddition reaction with phenyl acetylene (Scheme 5). In
all cases, the corresponding N-carbamoyl 1,2,3-triazoles were
formed under the reaction conditions, although yields were
lower than that found for the model substrate.
Scheme 6 Mechanistic proposal for the formation of oxazoles (a) and
triazoles (b) through the reaction of carbonyl azides and terminal alkynes
catalyzed by [Tpa*Cu]PF6.
CuAAC reaction with N-carbamoyl azides as substrates. This
mild protocol represents a powerful alternative to existing
procedures for the preparation of this class of bioactive com-
pounds from readily available starting material. Further inves-
tigations to extend the scope of this transformation are ongoing
in our laboratory.
We thank MINECO (CTQ2011-28942-CO2-01, CTQ2011-27033)
´
and Junta de Andalucıa (Proyecto P07-FQM-02745, P10-FQM-06292).
N-Carbamoyl triazoles have proven to be potent serine hydro-
lase inhibitors.13 The reported method for the synthesis of these
compounds consists of a two step procedure which involves the
preparation of 1H-1,2,3-triazole via CuAAC and its subsequent
coupling with a N-aminecarbonyl chloride. Mixtures of N1- and
N2-carbamoylated regioisomers are obtained. Instead, with our
synthetic approach only the N1-regioisomer is achieved in good
yields in a one-step catalytic procedure.13a In addition, the
precatalyst [Tpa*Cu]PF6 is easy to make17 and sufficiently stable
to moisture and air to be weighted on a benchtop.
Scheme 6 displays a general mechanistic explanation for the
reaction of several azides and alkynes in the presence of this
type of copper catalysts. Two possible pathways can be invoked
to explain the formation of 1,2,3-triazoles from N-sulfonyl- or
N-carbamoyl azides or that of oxazoles from N-carbonyl azides. In
the latter, the metal centre prefers the azide group to form a nitrene
intermediate, which reacts further with the alkyne12b rendering the
formation of the oxazole (Scheme 6, cycle A). On the other hand,
the N-sulfonyl- or N-carbamoyl azides do not lead to nitrene
intermediates, since the formation of copper acetylides must be
favored. From here, interaction with the azide and subsequent
formation of the triazolyl–cuprate could explain the formation of
the triazole derivatives (Scheme 6, cycle B). The intermediacy of two
copper centres for the [3+2] reaction to occur has been previously
proposed by several groups.18 In our case, we cannot rule out the
assistance of a second molecule of the catalyst in the process.
In summary, we have discovered a Cu(I) precursor that for
the first time allows the formation of N-carbonyl triazoles by
EH thanks MEC for a research grant.
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