Gold-catalyzed synthesis of tetrazoles from alkynes by Ci￡ C bond cleavage

Article abstract of DOI:10.1002/anie.201308076

Golden duality: Tetrazoles are formed by the reaction of alkynes with TMSN₃ (TMS=trimethylsilyl) in the presence of iPrOH and the gold(I) catalyst [JohnPhosAu(MeCN)]SbF₆. In this transformation gold plays a dual role, first activating the alkyne and then generating a Bronsted acid in situ.

Full text of DOI:10.1002/anie.201308076

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DOI: 10.1002/anie.201308076
Heterocycles
À
Gold-Catalyzed Synthesis of Tetrazoles from Alkynes by C C Bond
Cleavage**
Morgane Gaydou and Antonio M. Echavarren*
Cycloadditions of azides with alkynes to form triazoles under
thermal conditions (Huisgen cycloaddition)[1] or in the
presence of copper [click reaction, copper-catalyzed azide–
alkyne cycloaddition (CuAAC)][2,3] are reactions of funda-
mental importance in organic chemistry. Triazoles can also be
obtained by means of ruthenium,[4] silver,[5] and iridium[6]
catalysis, as well as by a zinc-mediated process.[7] In sharp
contrast, very different reactivity has been observed in the
reaction of terminal alkynes with TMSN3 in the presence of
group 11 metal salts and complexes.[8] Thus, the group of Jiao
recently made the remarkable observation that alkynes (1;
R = alkyl, aryl, alkenyl) react with TMSN3 in the presence of
Scheme 2. Mechanistic proposal for the formation of 2 and 3.[9,10]
Ag2CO3 as catalyst to form nitriles (2; Scheme 1).[9] The same
dipolar cycloaddition and subsequent fragmentation of 6. In
the presence of TFA, protonation of 5 would form 7, which
could evolve by a Schmidt rearrangement[11–13] to give the
amides 3. A somewhat related cleavage of triple bonds to
form nitriles has been reported using TMSN3 and N-
iodosuccinimide, and was proposed to proceed via 2-iodo-
2H-azirines.[14]
We now report that by using the JohnPhos/gold(I) catalyst
Scheme 1. Synthesis of nitriles (2)[9] and carboxamines (3)[10] from
A,[15] which allows performing reactions in the absence of AgI,
2
À
alkynes (1) by aryl–alkyne C(sp ) C(sp) bond cleavage. DMSO=dime-
À
the N-aryltetrazoles 8 are obtained from 1 by C C bond
cleavage with the concomitant insertion of four nitrogen
atoms (Scheme 3). In this transformation gold plays a dual
thylsulfoxide, TFA=trifluoroacetic acid, TMS=trimethylsilyl.
2
À
group has reported the cleavage of the aryl–alkyne C(sp )
C(sp) bond of alkynes (1) using [Au(PPh3)Cl] and AgCO3 in
the presence of H2O and trifluoroacetic acid (TFA) to form
carboxamides.[10]
The formation of nitriles (2)[9] and carboxamides (3)[10]
was proposed to proceed by nucleophilic addition of azide to
(h2-alkyne)metal complexes to form the intermediates 4a,b,
with subsequent protonolysis to give the alkenyl azides 5
(Scheme 2). The nitriles 2 could then be produced by a 1,3-
Scheme 3. Synthesis of N-aryltetrazoles (8) from alkynes (1).
DCE=1,2,-dichloroethane.
[*] M. Gaydou, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
role, first activating the alkyne towards nucleophilic attack
and then generating the Brønsted acid required for the
transformation of the alkenyl azide into the final tetrazole.
We first studied the reaction of the aryl alkynes 1a–c with
Prof. A. M. Echavarren
Departament de Quꢁmica Analꢁtica i Quꢁmica Orgꢂnica
Universitat Rovira i Virgili
C/Marcel·li Domingo s/n, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[16]
TMSN3 and complex A under stoichiometric conditions.
Surprisingly, the reaction gave 5-methyl-1-aryl-1H-tetrazole–
gold(I) complexes (9a–c) as crystalline white solids, whose
structures were determined by X-ray diffraction
(Scheme 4).[17,18] The complex 9a was also obtained in 56%
yield by reaction of neutral [(JohnPhos)AuCl] with phenyl
acetylene (1a) and TMSN3 in the presence of AgSbF6.
[**] We thank the MICINN (CTQ2010-16088/BQU), the European
Research Council (Advanced Grant No. 321066), the AGAUR (2009
SGR 47), and the ICIQ Foundation for financial support. We also
thank the ICIQ X-Ray diffraction unit for the X-ray structures.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308076.
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Table 1: Catalyst and solvent optimization for the formation of 8b.
Entry
[Au]
Solvent
T [8C]
Yield [%][a]
[b]
1
2
3
4
5
6
A
A
A
A
MeCN
MeCN
CH2Cl2
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
23
80
40
110
80
80
80
110
80
80
80
80
80
80
80
80
–
8
–
[b]
9
40
59
78–81
38
8
A
A[c]
7[d]
8
9
10
11
12
13
14
15
16
A[c]
A
B
C
D
D’
E
F
G
7
[b]
–
[b]
–
[b]
–
15
18
–
[b]
[Au(PPh3)Cl]/
Ag2CO3
Scheme 4. Formation of the tetrazole–gold(I) complexes 9a–c and
their X-ray crystal structures. For the ORTEP plots the thermal
ellipsoids are shown at 50%. Au yellow, F green, N blue, O red,
P violet, Sb light blue.
[a] Determined by NMR spectroscopy. [b] No reaction. [c] 10 mol%
catalyst. [d] iPrOH (4–10 equiv).
We have provided evidence that the rate-determining step
in certain catalytic reactions involving alkynes is the ligand
substitution reaction between the complexes [Au-
(product)L]+ and the starting alkyne.[19] The isolation of
stable gold(I) complexes (9a–c) under stoichiometric con-
ditions shows that in this case the development of a catalytic
process for the synthesis of tetrazoles would be a challenging
task, since this ligand substitution would be particularly slow.
Thus, either no reaction or very poor yields of the tetrazole 8d
were obtained with complex A in MeCN, CH2Cl2, or toluene
(Table 1, entries 1–4). Better results were obtained in 1,2-
dichloroethane at 808C (Table 1, entries 5 and 6). In contrast,
the related gold(I) catalysts B and C, and complexes D–G
with NHC (N-heterocyclic carbene), phosphite, or less-bulky
phosphine ligands led to poor results (Table 1, entries 9 and
16).
A further improvement was achieved by performing the
reaction in the presence of iPrOH (Table 1, entry 7). Under
these reaction conditions, aryl-, heteroaryl-, and alkyl-sub-
stituted alkynes react with TMSN3 to give the corresponding
tetrazoles 8 (Scheme 5). Lower yields of the tetrazoles 8g and
8k were obtained from employing aryl alkynes substituted
with electron-withdrawing groups. In the case of p-nitro-
phenylacetylene (1c), no tetrazole was formed and the
alkenyl azide 5c was isolated instead (23% yield). Diphenyl
acetylene, having an internal alkyne, failed to give the
corresponding tetrazole. Aliphatic alkynes also reacted to
give tetrazoles (8m–o). Interestingly, whereas cyclohexylace-
tylene provided 8m in good yield as the sole product, 1-
pentyne gave 8n along with 1-methyl-5-propyl-1H-tetrazole
(8n’; 10:1 ratio) and cyclopropylacetylene gave 8o and 8o’
(1:3 ratio).
and HN3, formed in situ from TMSN3 and iPrOH, to give 4b,
which undergoes protodeauration to give 5 (Scheme 6), and is
in accordance with that proposed for the formation of nitriles
and carboxamides.[9,10] Protonation of 5 would give the
iminodiazonium cation 7, which could evolve to form the
nitrilium cation 10 by migration of R group (path a).
Competitive migration of the methyl group (path b) explains
the formation of regioisomers 8n’ and 8o’ in the reactions of
1-pentyne and cyclopropylacetylene. It is interesting that
preferential migration of the methyl group has been observed
in the Schmidt reaction of methyl cyclopropyl ketone in
aqueous sulfuric acid at lower acid strengths.[12a] Finally,
a formal 1,3-dipolar cycloaddition of HN3 to 10 would lead to
8.[20,21] It is important to note that nitrilium cations 10 have
been reported to give also triazolium salts by reaction of the
initial azide addition product with a second nitrilium cati-
on,[21b] a process that was not observed under these reaction
conditions.
Although formation of digold(I) intermediates (11) by
reaction of 4b with a second equivalent of a gold(I) complex
cannot be entirely excluded,[22] the following experiments
using (1-azidovinyl)benzene (5a, R = Ph) as the substrate
strongly suggest that the transformation of 4b into 7 is
All these results can be accommodated by a mechanism
proceeding by reaction between a (h2-alkyne)gold(I) complex
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additional results, including two labeling experiments. First,
reaction of [D]-1a led to [D]-9a, with the deuterium labeling
at the methyl group (Scheme 7). Additionally, when the
reaction of 1a, TMSN3, and complex A was carried out in
CH2Cl2 containing 1.1 equivalents of D2O, the deuterated
complex [D2]-9a was obtained.
Scheme 7. Deuterium-labeling experiments.
Tetrazoles, which are important in medicinal chemistry
and as energetic materials, have been obtained by 1,3-dipolar
cycloaddition of azides with activated nitriles[28,29] and by
cycloaddition of hydrazoic acid with the Ugi adducts gen-
erated in situ from carbonyl compounds, amines, and isoni-
triles.[30,31] This new reaction demonstrates that this new class
of heterocyclic compounds can be prepared under relatively
mild reaction conditions from readily available alkynes in
a process in which gold(I) catalyzes the formation of alkenyl
azides by nucleophilic attack onto the alkynes, as has been
shown in the formation of carboxamides.[10] In addition, gold
presumably provides the Brønsted acid required for the
protodeauration and final formation of tetrazoles from the
intermediate alkenyl azides under anhydrous, catalytic con-
ditions. Further work aimed at developing new catalysts for
the synthesis of tetrazoles from alkynes is in progress.
Scheme 5. Gold(I)-catalyzed synthesis of tetrazoles from the aryl- and
alkyl-substituted alkynes 1. Yields refer to isolated compounds.
Received: September 14, 2013
Published online: November 13, 2013
Scheme 6. Mechanistic proposal for the formation of the tetrazoles 8
from 4b.
Keywords: azides · cycloadditions · gold · heterocycles ·
.
rearrangement
a Brønsted acid catalyzed reaction: 1) reaction of 5a with
TMSN3 and iPrOH with A under the standard reaction
conditions gave 8a (42% yield by NMR); 2) in the absence of
iPrOH, 5a gave 8a in only 12% yield; 3) only traces of 8a
were obtained in the absence of gold catalyst A; 4) replacing
iPrOH and A by HOAc (2 equiv) led to 8a in 78% yield.[23]
Presumably, under the gold(I)-catalyzed conditions, the
Brønsted acid [JohnPhosAu(iPrOH)]SbF6 is formed, which
mediates the transformation of 4b into 7.[24,25] Protonation by
this acid could also facilitate the associative displacement of
the tetrazole ligands by the incoming alkyne in 9 under
catalytic conditions.
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