Organocatalytic synthesis of 1,2,3-triazoles from unactivated ketones and arylazides

Article abstract of DOI:10.1002/chem.201102046

Organo-click reaction: A new and complementary method to Huisgen's metal-catalyzed triazole synthesis is described using unactivated ketones and arylazides as the substrates and proline as an organocatalyst. Dramatic acceleration was observed for this reaction using microwave activation and high regio- and chemoselectivities were obtained for a wide range of ketones and arylazides (see scheme). Copyright

Full text of DOI:10.1002/chem.201102046

COMMUNICATION
DOI: 10.1002/chem.201102046
Organocatalytic Synthesis of 1,2,3-Triazoles from Unactivated Ketones and
Arylazides
Mokhtaria Belkheira,[a, b] Douniazad El Abed,[b] Jean-Marc Pons,*[a] and Cyril Bressy*[a]
The synthesis of 1,2,3-triazoles recently became popular
with the copper-catalyzed version of the azide–alkyne Huis-
gen cycloaddition, developed independently by the groups
of Sharpless[1a] and Meldal.[1b] While this powerful and
highly regioselective reaction can be performed in various
media by using several sources of copper or ruthenium cata-
lysts,[2] it is usually restricted to terminal alkynes.[3]
toesters, b-ketonitriles or b-diketones) and a catalytic
amount of a secondary amine, is described. Nevertheless,
these two approaches are not applicable to unactivated ke-
tones and hence, are in some way of rather limited scope.
Herein, we wish to report the results of our endeavor to-
wards the development of an organocatalytic version of this
method, allowing the conversion of unactivated ketones and
Another access to 1,2,3-triazoles is the highly regioselec-
tive 1,3-dipolar cycloaddition between an azide and an en-
amine. The triazoline intermediate, which can sometimes be
isolated, usually undergoes spontaneous aromatization
under acidic conditions to form the corresponding 1,2,3-tria-
zole.[4] This reaction can benefit from organocatalysis,[5]
which recently emerged as a solution to avoid even trace
amounts of metal residues in the final products. Indeed, the
enamine moiety can be generated in situ from a ketone and
an amine and it can react as a dipolarophile with an azide to
afford the desired five-membered heterocycle. This ap-
proach illustrates a rather unusual use of amino compounds
in organocatalysis. These compounds are more commonly
applied in cycloaddition reactions or in iminium-type activa-
tions,[6] rather than in enamine-type activations,[7] which
proved to be highly successful in organocatalytic reactions.[8]
Two groups have recently reported this organocatalytic
strategy to prepare triazoles; Ramachary et al.[9] in 2008 and
Wang et al.[10] earlier this year while this manuscript was
under the writing process. In the former case, however, the
scope remained rather limited, because only g-activated
enones (Hagemann esters) and sulfonylazides were used. In
the latter case, a regioselective cycloaddition of arylazides
with enamides, formed in situ from activated ketones (b-ke-
arylazides into trisubstitued 1,2,3-triazoles with
degree of regio- and chemoselectivity (Scheme 1).
a high
Scheme 1. Organocatalytic synthesis of triazoles from ketones.
The idea was that a catalytic amount of a bifunctional or-
ganocatalyst,[11] bearing a secondary amine and an acid
moiety, could promote the transformation of a ketone into a
1,2,3-triazole in the presence of an arylazide. Thus, proline
appeared to us as the best organocatalyst candidate.[12]
Initial experiments were conducted by using cyclohexa-
none (1a) and p-methoxyphenylazide (2a) in the presence
of a catalytic amount of L-proline (4) (Table 1). A rapid
screening of solvents showed an interesting catalytic activity
of proline in dichloromethane at 808C in a sealed tube after
92 h (Table 1, entry 1). Changing the ketone/azide ratio
from 1:1 to 2:1 also had a beneficial effect on the efficacy of
the reaction (Table 1, entry 2), while prolonged reaction
times along with reduced amounts of catalyst afforded up to
92% yield of the desired product after 100 h (Table 1,
entry 3). To reduce the long time of conventional heating
(D), microwave irradiation (MW)[13,14] was also tested and
[a] M. Belkheira, Prof. J.-M. Pons, Dr. C. Bressy
Institut des Sciences Molꢀculaires de Marseille (iSm2)
CNRS UMR6263, Aix-Marseille Universitꢀ
Campus Saint Jꢀrꢁme
13397 Marseille Cedex 20 - Service 532 (France)
Fax : (+33)04-91-28-91-87
E-mail: cyril.bressy@univ-cezanne.fr
jean-marc.pons@univ-cezanne.fr
[b] M. Belkheira, Prof. D. El Abed
Universitꢀ d’Oran Es-Sꢀnia
Laboratoire de Rꢀactivitꢀ et Chimie Fine
Dꢀpartement de Chimie, Facultꢀ des Sciences
B.P.1524 El M’naour, 31100, Oran (Algꢀrie)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102046.
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Table 1. Optimization of the organocatalytic triazole synthesis.[a]
Table 2. Scope of arylazides in the organocatalytic triazole synthesis.[a]
Azide
Triazole
D Yield [%][b,d]
MW Yield
[%][c,d]
1
2
3
4
5
6
7
8
9
4-(MeO)PhN3 (2a)
PhN3 (2b)
4-(Br)PhN3 (2c)
4-(Cl)PhN3 (2d)
4-(Me)PhN3 (2e)
4-(NO2)PhN3 (2 f)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
90[e]
85
58
83
85
60
73
80
–
90
68
70
Catalyst
Heating
t [h]
Yield [%][b]
88
1
2
4
4
4
4
5
6
7
8
D
D
92
90
100
1
1
1
1
1
1
100
67
[f]
[f]
–
75[c]
3,4-di
N
89
70
3[e]
4
D
92[c] (90)[d]
85[c] (83)[d]
3-(MeO)PhN3 (2h)
2-(MeO)PhN3 (2i)
2-(CH2OH)PhN3 (2j)
MW
MW
MW
MW
MW
MW
D
75
71
[f]
5
6
7
8
9
10
–
10
3aj
39[g]
48[g]
60
63
[a] Ketone 1a (2 mmol), arylazide (1 mmol) and proline (20 mol%) in
CH2Cl2 (1.5 mL). [b] Heating for 5–6 d. [c] Heating for 1 h. [d] Isolated
yield. [e] 10 mol% of proline were used. [f] Starting materials recovered.
[g] Decomposition of the azide 2j was observed under the reaction condi-
tions.
[f]
–
–
–
[f]
9
[f]
none
[a] Ketone 1a (1 or 2 mmol), arylazide 2a (1 mmol) and catalyst
(20 mol%) in CH2Cl2 (1.5 mL). [b] NMR yield using mesitylene as inter-
nal reference. [c] Ratio ketone/azide=2:1. [d] Isolated yield. [e] Per-
formed with 10 mol% of proline. [f] Starting materials recovered.
were also obtained with halogen-substituted arylazides
owing to decomposition into the corresponding anilines by
loss of nitrogen (Table 2, entries 3 and 4).[17] The position of
the substituent on the aromatic ring appeared to only have a
minor impact on the reaction (Table 2, entries 1, 8 and 9).
The reaction could even be performed with arylazides con-
taining a free hydroxyl group, such as 2j (Table 2, entry 10).
In addition, the reactivity of several ketones was evaluat-
ed (Table 3). Interestingly, among the various ketones exam-
ined (Table 3, entries 1–7), cyclic ketones appeared as the
substrates of choice, as each ring size, with the exception of
cyclopentanone,[18] gave good to excellent yields under both
heating conditions, that is thermal and microwave irradia-
tion. The best yield, however, was obtained with cycloocta-
none (1c), which afforded the corresponding 1,2,3-triazole
in 90% isolated yield (Table 3, entry 3). It is worth noting
that dissymmetrical cyclic ketones afforded high levels of re-
gioselectivity. Hence, 3,3-dimethylcyclohexanone (1e) led to
a single regioisomer 3ea (Table 3, entry 5), in which the het-
erocycle is furthest from the gem-dimethyl group for steric
reasons. On the other hand, 4,4-dimethylcyclohexanone (1 f)
furnished triazole 3 fa, which is an isomer of 3ea. b-Tetra-
lone (1g) also led to the formation of a single regioisomer
3gb (Table 3, entry 7), the structure of which was confirmed
by X-ray analysis[19] (Figure 1). This regioselectivity can be
afforded similar levels of conversion after only one hour
(Table 1, entry 4).
Next, several secondary amines were tested under these
optimized conditions to evaluate their catalytic activity and
determine the structural features of the catalyst required to
promote optimum triazole formation. Hence, we were able
to show that a catalytic amount of L-pipecolinic acid (5),
which bears a larger ring size than proline, did not catalyze
the reaction (Table 1, entry 5). Interestingly, (S)-5-pyrroline-
2-yl-1H-tetrazole (6),[15] having an acid function with a pKa
close (tetrazole pKa =4.86 in H2O) to the pKa of proline
(pKa =4.75 in H2O), was able to promote the transformation
under these conditions, however, in lower yield (60%,
Table 1, entry 6). Surprisingly, pyrrolidine (7) catalyzed the
reaction, whereas morpholine (8) did not, highlighting the
effect of the ring size of the catalyst (Table 1, entries 7 and
8). Moreover, pyrrolidine resulted in lower yields than pro-
line (63 vs. 85%), showing the beneficial effect of the acid
moiety in proline. Finally, an acyclic secondary amine, such
as diethylamine (9), did not catalyze the reaction (Table 1,
entry 9). As expected, no 1,2,3-triazole was observed, when
the reaction was run in the absence of a catalyst (Table 1,
entry 10). Consequently, proline proved to be the best cata-
lyst for this reaction by combining a secondary amine of the
adequate ring size and an acidic function.
With these two sets of optimized conditions in hands, we
then examined the influence of the arylazide.[16,2d] The re-
sults are depicted in Table 2. Excellent results were ob-
served with arylazides functionalized with electron-donating
groups (Table 2, entries 1, 5, 7–9), whereas electron-with-
drawing groups, such as the nitro group, tended to deacti-
vate the arylazide partner (Table 2, entry 6). Lower yields
Figure 1. ORTEP view of the crystal structure of 3gb.
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Chem. Eur. J. 2011, 17, 12917 – 12921

1,2,3-Triazole Synthesis
COMMUNICATION
Table 3. Scope of ketones in the organocatalytic triazole synthesis.[a]
regioselectivity of the addition of the azide to the enamine,
which appears to be exclusive in all the cases illustrated in
Table 3.
In order to evaluate the chemoselectivity of this transfor-
mation, we were able to show that acetophenone did not
poison the catalyst, as the reaction occurred, when subject-
ing an equimolar amount of cyclohexanone (1a) and aceto-
phenone (1j) to the reaction conditions with arylazide 2a
(Scheme 2a). Furthermore, we submitted diazide 2k and cy-
Ketone
Triazole
Azide
D Yield
MW Yield
[%][b,d]
[%][b,c]
1
2
3
2a
90
70
89
83
60
90
2a
2a
2a
4
87
80
5
6
2a
2a
78
61
75
79
Scheme 2. Chemoselectivity of the proline-catalyzed triazole synthesis.
clohexanone (1a) to the reaction conditions (Scheme 2b).
Interestingly, triazole 3ak was formed exclusively and could
be isolated in 63% yield. This chemoselectivity was con-
firmed by the synthesis of 3ak using another pathway (see
Supporting Information).
7
2b
56
58
Concerning the mechanism, we suggest a catalytic cycle
(Scheme 3), in which organocatalyst I forms enamine II by
8
9
2a
2a
2a
51
50
48
45
[e]
[e]
10
–
–
[a] Ketone (2 mmol), arylazide 2a or 2b (1 mmol) and proline (10 or
20 mol%) in CH2Cl2 (1.5 mL); PMP=p-methoxyphenyl. [b] Isolated
yield. [c] Reaction times between 45 h and 6 d. [d] Reaction time: 1 h.
[e] Starting materials recovered.
Scheme 3. Proposed catalytic cycle.
explained by the cycloaddition occurring with the most sta-
bilized enamine. Acyclic ketones gave lower yields under
the same conditions (Table 3, entries 8 and 9). Unfortunate-
ly, phenones, such as acetophenone (Table 3, entry 10), were
unreactive.
The regioselectivity of the reaction results from the com-
bination of two regioselectivities: first, the regioselectivity
resulting from the favored formation (or reactivity, in the
case of dissymmetrical ketones) of one of the two enamine
intermediates (Table 3, entries 5, 7 and 9), and, second, the
condensation, followed by 1,3-dipolar cycloaddition of the
azide with complete regioselectivity to obtain a zwitterionic
form of the triazoline intermediate III. The carboxylate
function can participate in the syn-elimination to regenerate
catalyst I and produce triazole IV, the aromatization being
the driving force of the reaction. This last step of the process
is crucial to perform the reaction catalytically.
In conclusion, we have developed a new organocatalytic
access to highly substituted 1,2,3-triazoles[20] starting from
Chem. Eur. J. 2011, 17, 12917 – 12921
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J.-M. Pons, C. Bressy et al.
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unactivated ketones and arylazides, which is complementary
to the existing methods. Proline was established as an excel-
lent organocatalyst for this reaction, with the acid moiety
being crucial for the elimination step. While the reaction
needed to be run for a prolonged time under thermal condi-
tions, a dramatic acceleration was observed by using micro-
wave activation. A wide range of arylazides and ketones
could be used, with cyclic ketones giving the best results. Fi-
nally, high levels of regio- and chemoselectivity were ob-
served. Extension of this organocatalyzed cycloaddition to
other types of dipoles will be presented in due course.
Experimental Section
General procedure for the organocatalytic triazole synthesis using ther-
mal heating: In a sealed tube arylazide (1 mmol) and ketone (2 mmol)
were dissolved in CH2Cl2 (1.5 mL) and L-proline was added (10 to
30 mol%). The mixture was heated under stirring at 808C in an oil bath.
The reaction was monitored by TLC until the arylazide was consumed
and the crude product was concentrated and purified by flash chromatog-
raphy on silica gel.
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General procedure for the organocatalytic triazole synthesis using micro-
wave heating: In a sealed tube arylazide (1 mmol) and ketone (2 mmol)
were dissolved in CH2Cl2 (1.5 mL) and L-proline was added (10 to
30 mol%). The mixture was heated under stirring at 808C in a micro-
wave reactor (CEM Discover 1–300W oven). After one hour, the crude
product was concentrated and purified by flash chromatography on silica
gel.
[13] For recent representative reviews on microwave-assisted organic
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Acknowledgements
We thank Dr. M. Giorgi for X-ray structure analysis. Financial support
from the Universitꢀ Paul Cꢀzanne, the CNRS, and the Conseil Gꢀnꢀral
des Bouches du Rhꢁne are also gratefully acknowledged.
Keywords: cycloaddition
·
enamines
·
microwave
chemistry · organocatalysis · proline · triazoles
[16] A few articles reported regioselective Huisgen cycloaddition with ar-
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[1] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, B. K. Sharpless,
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´
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[17] The observed aniline is caused exclusively by thermal decomposition
of the azide. We submitted the isolated, corresponding triazole to
the reaction conditions (sealed tube, 808C, CH2Cl2, 6 d) without any
decomposition.
[18] Cyclopentanone reacts faster through aldolisation/crotonisation to
form 2-cyclopentylidenepentanone under the reaction conditions: .
[3] A recent article reported the first example of
a regioselective
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[19] CCDC-752440 contains the supplementary crystallographic data for
this paper. This data can be obtained free of charge from The Cam-
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Chem. Eur. J. 2011, 17, 12917 – 12921

1,2,3-Triazole Synthesis
COMMUNICATION
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[20] A metal-free and base-catalyzed synthesis of 1,2,3-triazoles was re-
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Received: July 4, 2011
Published online: October 7, 2011
Chem. Eur. J. 2011, 17, 12917 – 12921
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www.chemeurj.org
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