Direct synthesis of 1,4-disubstituted-5-alumino-1,2,3-triazoles: Copper-catalyzed cycloaddition of organic azides and mixed aluminum acetylides

Article abstract of DOI:10.1002/anie.200907016

Chemical Equation Presented Al together now: Aluminotriazoles are obtained in a fully chemo- and regioselective manner by a copper-catalyzed cycloaddition of organic azides with mixed-aluminum acetylides (see scheme). The carbon-aluminum bond, which is unaffected by the first transformation, is still able to react further with different electrophiles.

Full text of DOI:10.1002/anie.200907016

Angewandte
Chemie
DOI: 10.1002/anie.200907016
Cycloaddition Reactions
Direct Synthesis of 1,4-Disubstituted-5-alumino-1,2,3-triazoles:
Copper-Catalyzed Cycloaddition of Organic Azides and Mixed
Aluminum Acetylides**
Yuhan Zhou, Thomas Lecourt, and Laurent Micouin*
Dedicated to Professor Alexandre Alexakis on the occasion of his 60th birthday
The development of functionnalized organometallic com-
pounds is a dramatically growing field, and considerably
broadens the scope of these nucleophilic reagents.[1] An
important breakthrough in the preparation of these reactive
species, which contain sensitive functional groups, has been
the discovery of alternative synthetic pathways to the
Grignard or Barbier oxidative addition of activated metals
to organic halides, such as halogen–metal exchange[2] or new
selective-metalation processes.[3] Both approaches enable the
preparation of numerous functional organometallic reagents,
and are powerful tools, especially in the field of aromatic or
heterocyclic chemistry.[4] Using these methods, which are
important classes of functional organometallic reagents.
However, despite some very recent important works on the
preparation and reactivity of organoaluminum compounds,[7]
the development of functional organoaluminum reagents is
still underinvestigated. In this paper, we report that functional
organoaluminum reagents are accessible by a post-modifica-
tion of aluminum acetylides using a copper-catalyzed [3 + 2]
cycloaddition reaction.
The reaction of alkynes with organoazides has emerged as
a very popular transformation since the groups of Meldal and
Sharpless reported that this reaction can be dramatically
accelerated by copper(I) catalysts.[8] Starting from terminal
alkynes, this reaction regioselectively delivers a 1,4-disub-
stitued-5-cuprotriazole intermediate, which has been isolated
and fully characterized.[9] Similar metalated triazoles have
also been described, starting from gold(I) acetylides.[10]
À
based on the selective formation of a carbon metal bond in
the presence of sensitive functional groups, the metallic bond
is established after the functional groups are introduced.
However, one can conceive an alternative strategy, with the
formation of the metallic bond prior to functional group
À
Although a new carbon metal bond is formed during this
À
introduction. Such an approach is only possible if the carbon
process, the reactivity of these intermediates has only been
sparingly exploited. On the other hand, the uncatalyzed
exothermic reaction of azides with lithium or magnesium
acetylides has been reported to regioselectively deliver 1,5-
disubstitued-4-metallotriazole intermediates, which can be
trapped by different electrophiles.[11] This different behavior
between metallic species can be explained by a distinct
mechanistic pathway: nucleophilic acetylides add directly
onto organoazides leading to compound 1, whereas copper
acetylides undergo a [3+2] cycloaddition process with the
possible involvement of a bimetallic intermediate leading to 2
(Scheme 1).[12]
metal bond is kinetically and/or thermodynamically stable
enough to withstand functional group manipulations. As a
matter of fact, numerous examples of such a strategy have
recently been reported using organoboron or organotin
reagents, which shows that several synthetic transformations
can be conducted on remotely embedded functional groups of
these compounds.[5]
If one considers the difference in electronegativity
between a metal and a carbon atom as an empirical criterion
for the development of functionalized organometallic com-
pounds, as proposed by Knochel and co-workers in their
seminal review on this field,[6] it is striking to see that the
The reaction of dimethylphenylalkynylaluminum 3 (pre-
pared by a base-catalyzed metalation reaction in toluene)[13]
with benzylazide was first investigated in THF (Table 1). No
À
À
carbon aluminum bond can be located between the carbon
À
zinc and the carbon magnesium bond, which are two very
[*] Dr. Y. Zhou, Dr. T. Lecourt, Dr. L. Micouin
UMR 8638, Universitꢀ Paris Descartes, CNRS, Facultꢀ de Pharmacie
4 avenue de l’Observatoire, 75006 Paris (France)
Fax: (+33)1-4329-1403
E-mail: laurent.micouin@univ-paris5.fr
Homepage: http://www.ssmip.cnrs.fr/eq3_micouin.html
Dr. Y. Zhou
State Key Laboratory of Fine Chemicals
School of Chemical Engineering, Dalian University of Technology
Dalian 116012 (P. R. China)
[**] Financial support from the ANR (ANR blanc AluMeth) is acknowl-
edged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907016.
Scheme 1. Syntheses of metalated triazoles from metal acetylides.
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Table 1: Optimization of the reaction conditions: catalyst and ligands.[a]
Table 2: Solvent compatibility study.[a]
Conversion [%][b]
Entry
Cat.
Ligand (mol%) T [8C]
t [h]
Conversion [%][b]
Entry
Ligand
Solvent
t [h]
1
2
3
4
5
6
7
8
9
10
11
12
13
–
–
–
–
–
–
–
–
–
RT
150[d]
RT
RT
RT
RT
RT
RT
RT
RT
RT
55
24
1.5
24
48
24
24
24
24
24
48
24
24
48
n.r.
75[c]
80
80
55
50
60
75
79
92
81
86
99
1
2
3
4
5
6
7
8
–
–
toluene
toluene
toluene
toluene
CH2Cl2
n-hexane
MTBE
24
48
24
48
24
24
24
48
89
92
93
CuBr
CuBr
CuCN
CuCl2
CuI
CuI
CuI
CuI
CuI
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
97 (92)[c]
90
75
95
MTBE
97 (89)[c]
PPh3 (20)
PPhMe2 (20)
PPhMe2 (20)
PMDTA (10)
PMDTA (10)
PMDTA (10)
ꢀ
[a] Reaction conditions: PhC CAlMe·THF (0.6 mmol), BnN3 (0.6 mmol),
solvent (2 mL). [b] Determined by GC after hydrolytic workup with
mesitylene as an internal standard. [c] Yield of isolated product given in
parentheses. MTBE=methyl tert-butyl ether.
CuI
CuI
55
ꢀ
[a] Reaction conditions: PhC CAlMe2 (0.6 mmol), BnN3 (0.6 mmol),
THF (2 mL). [b] Determined by GC methods after hydrolysis, with
mesitylene as internal standard; n.r.=no reaction. [c] Mixture of
regioisomers. [d] Heated under microwave conditions. Bn=benzyl.
reaction was observed at room temperature (Table 1, entry 1)
and heating under microwave activation led to a mixture of
regioisomers after hydrolysis (Table 1, entry 2). The addition
of copper salts led to a dramatic improvement in the rate of
reaction at room temperature (Table 1, entries 3–6). How-
ever, longer reaction times did not improve the conversion
(Table 1, entries 3 and 4). The inclusion of various ligands was
then investigated. Of the different ligands examined (phos-
phines, carbenes, amines, phenanthrolines), the addition of
phosphines led to an improvement in conversion (Table 1,
entries 8–10). Finally, 99% conversion could be obtained
using copper iodide and [Me2N(CH2)2]2NMe (PMDTA) in
THF at 558C.
Scheme 2. Deuteration study. 93% deuterated product.
PMDTA=[Me2N(CH2)2]2NMe.
Table 3: Scope of the reaction.[a]
Entry
R1
R2[b]
Product
Yield[c] [%]
1
2
3
4
Ph
Bn
Bn
Bn
Ph
4
9a
9b
9c
92
96
91
87
The influence of the solvent on the reaction was then
investigated. Although the reaction in toluene led to a
complex mixture, the addition of one equivalent of THF,
presumably leading to the in situ formation of a THF–
complex, resulted in a large improvement of the reaction
conversion (Table 2, entries 1 and 2). Therefore, without any
ligand, 89% conversion was achieved at room temperature
after 24 hours. Best results were obtained using 10% copper
iodide and 10% of ligand (Table 2, entry 4). A lower
reactivity was observed in dichloromethane and hexane
(Table 2, entries 5 and 6), whereas a good conversion was
obtained using methyl tert-butyl ether but with the formation
of a small proportion of side products (Table 2, entry 8).
The exclusive regioselective formation of a 1,4-disub-
stitued-5-aluminotriazole was assessed by a deuterolysis
experiment (Scheme 2). The high percentage of deuterium
incorporation ensured that the metallic bond was still intact
after the triazole formation.
nPr
tBu
Ph
5
Ph
9d
97
6
Ph
9e
57[d]
7
8
Bn
Bn
9 f
96
98
Cl(CH2)3
9g
1
2
ꢀ
[a] Reaction conditions: R C CAlMe2·THF (0.6 mmol), R N3 (0.6 mmol),
toluene (2 mL). [b] Dotted line indicates point of attachment. [c] Yield of
isolated product. [d] 96 h reaction time, 22% yield of recovered azide.
azides are known to be poorly regioselective, with the notable
exception of 1-iodoalkynes, as recently reported by Hein,
Fokin, and co-workers.[14] Interestingly, some functional
groups bearing basic (Table 3, entry 5) or electrophilic
(entry 6) character were well-tolerated in this transformation.
The reactivity of these new aluminated heterocycles was
then explored (Scheme 3). As an example, compound 6 led to
Optimized experimental conditions were then applied to a
variety of dimethylaluminum alkynides and azides (Table 3).
In all the cases, the 1,4-disubstitued triazoles were obtained as
unique regioisomers. This selectivity is noteworthy, as the
copper-catalyzed cycloadditions of internal alkynes and
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secondary carbon atom of the polarized metallic acetylide
could explain the excellent regioselectivity of the process.[16]
Furthermore, the known stability of 1-alumino-1-metalloal-
kenes[17] would explain the excellent stability of the carbon
aluminum bond during the catalytic cycle.
À
In summary, we have reported a copper-catalyzed cyclo-
addition of organic azides with dialkyl aluminum acetylides.
The regioselectivity of this reaction, combined with the
reactivity of the final aluminotriazoles, enables a rapid and
simple access to 1,4,5-trisubstituted triazoles. In a more
general context, we have shown that complex heterocyclic
organoaluminum compounds can be prepared from simple
mixed alkynylaluminum reagents by chemical transforma-
tion, without affecting the metallic bond. Extension of this
concept, as well as the exploration of the functional group
tolerance of organoaluminum reagents, is currently underway
in our laboratory.
Scheme 3. Reaction conditions: a) NBS (3 equiv), RT, 4 h. b) NIS
(3 equiv), RT, 4 h; then 558C, 2 h. c) NCS (3 equiv), RT, 4 h.
d) ClCO2Bn (2 equiv), RT, 7 h. e) ClCO2Me (2 equiv), RT, 7 h. NBS=N-
bromosuccinimide, NCS=N-chlorosuccinimide, NIS=N-iodosuccin-
imide.
Experimental Section
Representative procedure (compound 12): [Me2N(CH2)2]2NMe
(12.5 mL, 0.06 mmol) was added dropwise to a dry, argon-flushed
flask that was charged with CuI (11.4 mg, 0.06 mmol), toluene (2 mL)
and a magnetic stirrer. After 10 minutes, dimethylphenylalkynylalu-
minum (as a solution in toluene, prepared according to Ref. [13])
complexed by THF (0.41 mL, 0.6 mmol) and benzyl azide (80 mL,
94%, 0.6 mmol) were added sequentially. After stirring at room
temperature for 48 hours, NCS (240 mg, 1.8 mmol) and dried THF
(2 mL) were added at 08C. The mixture was stirred at room
temperature for 4 hours and poured into a cooled 2m aqueous
solution of Rochelleꢀs salts (CAUTION: gas evolution). The organic
phase was separated and the aqueous layer was extracted with ethyl
acetate (2 ꢁ 20 mL). The organic layer was dried over anhydrous
magnesium sulfate; the solvent was evaporated, and the crude residue
was purified by column chromatography on silica gel (cHex/EtOAc
93:7) to give 12 as a colorless liquid (120 mg, 74% yield).
triazoles 10–12 by reaction with several N-halo-succinimides.
Reactions with chloroformates led to the corresponding 1,4-
disubstituted-triazoloesters 13 and 14. These transformations
clearly show that, despite its stability during triazole forma-
À
tion, the carbon aluminum bond is still reactive enough to be
engaged in further synthetic transformations.
Although a detailed examination of the mechanism of this
new reaction has not yet been completed, a closely related
mechanism to the one recently proposed for the copper-
catalyzed cycloaddition reaction with iodoalkynes could be
responsible for the highly regioselective formation of the 1,4-
disubstitued-5-metallotriazoles (Scheme 4).[14] Such a path-
way would involve a transient sp2 geminal organobimetallic
intermediate, which is already suspected to be a key
intermediate in the CuAAC (copper(I)-catalyzed azo–
alkyne cycloaddition) reaction.[15] The regioselective forma-
tion of a six-membered transition state from the reaction of
the terminal azide nitrogen with the positively charged
Received: December 13, 2009
Revised: January 5, 2010
Published online: March 2, 2010
Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Chemie Early View. The Editor.
Keywords: aluminum · click chemistry · copper · cycloaddition ·
.
regioselectivity
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