DOI: 10.1002/chem.201405501
Communication
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Organocatalysis
An Enolate-Mediated Organocatalytic Azide–Ketone [3+2]-
Cycloaddition Reaction: Regioselective High-Yielding Synthesis of
Fully Decorated 1,2,3-Triazoles
Adluri B. Shashank, S. Karthik, R. Madhavachary, and Dhevalapally B. Ramachary*[a]
For example, 1,4-diaryl-5-methyl(alkyl)-1,2,3-triazoles have
Abstract: An enolate-mediated organocatalytic azide–
ketone [3+2]-cycloaddition (OrgAKC) reaction of a variety
of enolizable arylacetones and deoxybenzoins with aryl
azides was developed for the synthesis of fully decorated
1,4-diaryl-5-methyl(alkyl)-1,2,3-triazoles in excellent yields
with high regioselectivity at 258C for 0.5–6 h. This reaction
has an excellent outcome with reference to reaction rate,
yield, regioselectivity, operation simplicity, and availability
of substrates and catalyst. This reaction has advantages
over the previously known metal-mediated reactions.
a significant role in pharmaceutical chemistry (A–C) and
herein, we have shown interest in developing a single-step
general protocol for their high-yielding regioselective synthe-
sis. Very little is known about the regioselective synthesis of
1,4-diaryl-5-methyl(alkyl)-1,2,3-triazoles. When we analyzed the
previous approaches, we found that metal-catalyzed or ther-
mally-induced coupling reactions of internal alkynes with aryl
azides lack regioselectivity and also generality.[4] An alternative
approach to such 1,4-diaryl-5-methyl(alkyl) 1,2,3-triazoles is the
use of in situ generated metalated triazoles, in which metal
acetylides (metal=Li, Mg, Zn and Te) were treated with organ-
ic azides followed by further in situ reaction with various elec-
trophiles.[5] However, this approach is limited because of the
reverse selectivity and high reactivity of the metalated tria-
zoles. Other routes include palladium- or copper-catalyzed ary-
lation of 1,4-disubtituted 1,2,3-triazoles with aryl halides
(Scheme 1a)[6] and/or the copper-catalyzed cycloaddition of or-
ganic azides with 1-iodoalkynes or 1-n-butyltelluro alkynes fol-
lowed by palladium-catalyzed arylation of the corresponding
5-iodo-1,2,3-triazoles or 5-telluro-1,2,3-triazoles with arylboron-
ic acid or potassium aryltrifluoroborates, respectively
(Scheme 1b).[7] Alternative routes include bulky ruthenium-cat-
alyzed azide-internal alkyne cycloaddition reactions,[8] conden-
sation of N-tosylhydrazones and anilines under stoichiometric
amounts of copper salts and excess additives at higher tem-
peratures,[9] and amine/acid-catalyzed three-component con-
densation of aldehydes, nitroalkanes/malononitrile, and organ-
ic azides at higher temperatures for longer reaction times.[10] A
strain-promoted [3+2]-cycloaddition reaction of aryl
Even though the thermally-induced Huisgen [3+2]-cycloaddi-
tion of alkynes with azides has been known for over one cen-
tury to make 1,2,3-triazoles, these compounds came to the
limelight only in the last two decades due to their excellent
copper-catalyzed regioselective synthesis developed by the
Meldal and Sharpless groups.[1] Recently 1,2,3-triazoles have
become important compounds with unique chemical and
physical properties and are widely used as pharmaceuticals.[2]
Many of the 1,2,3-triazoles have found wide range applications
in medicinal, organic, bioorganic, polymer, and materials
chemistry.[2] Design and utilization of 1,2,3-triazoles has mainly
depended on their 1,4-disubstitutions or 1,4,5-trisubstitutions
and for to this reason, the development of more general cata-
lytic methods for their selective fully decorated synthesis is of
significant interest.[3]
azides with functionalized cyclooctynes[11] and amino
acid catalyzed enamine-mediated azide–carbonyl
[3+2]-cycloaddition reaction of active methylenes or
symmetrical ketones with aryl azides furnished the
1,4,5-trisubstituted 1,2,3-triazoles at higher tempera-
tures (Scheme 1c).[12]
In many of the above methods, either they used
costly and less reactive alkynes or noncommercial
substrates other than the simple arylacetones as starting mate-
rials. Also the requirement of toxic transition-metal catalysts,
heavy ligands and reagents, higher temperatures, longer reac-
tion times, and loading stoichiometric amounts of catalysts
made the above reaction conditions inferior. These drawbacks
inspired us to develop a general metal-free protocol for the
high-yielding regioselective synthesis of 1,4-diaryl-5-methyl-
(alkyl)-1,2,3-triazoles by using a recently discovered enolate-
[a] A. B. Shashank, S. Karthik, R. Madhavachary, Prof. Dr. D. B. Ramachary
Catalysis Laboratory, School of Chemistry
University of Hyderabad, Hyderabad-500 046 (India)
Fax: (+91)40-23012460
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405501. It contains experimental proce-
dures and analytical data for all new compounds.
Chem. Eur. J. 2014, 20, 1 – 6
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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