One-pot, three-component synthesis of 1,4,5-trisubstituted 1,2,3-triazoles starting from primary alcohols

Article abstract of DOI:10.1002/ejoc.201200830

A novel, one-pot, three-component approach for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles through the cycloaddition of a wide range of primary alcohols with sodium azide and active methylene ketones in the presence of N-(p-toluenesulfonyl)imidazole, tetrabutylammonium iodide, and triethylamine in DMF/DMSO has been developed.

Full text of DOI:10.1002/ejoc.201200830

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200830
One-Pot, Three-Component Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles
Starting from Primary Alcohols
Guanyi Jin,[a] Jian Zhang,[a] Dan Fu,[a] Jingjing Wu,[a] and Song Cao*[a]
Keywords: Multicomponent reactions / Nitrogen heterocycles / Alcohols / Ketones
A novel, one-pot, three-component approach for the synthe-
sis of 1,4,5-trisubstituted 1,2,3-triazoles through the cycload-
dition of a wide range of primary alcohols with sodium azide
and active methylene ketones in the presence of N-(p-tolu-
enesulfonyl)imidazole, tetrabutylammonium iodide, and tri-
ethylamine in DMF/DMSO has been developed.
et al. developed the first regiospecific synthesis of 1,4,5-tri-
substituted 1,2,3-triazoles by treatment of aryl azides with
β-keto esters, 1,3-diketones, or 3-keto-3-phenylpropionitrile
by using diethylamine (5 mol-%) as an organocatalyst.[15]
Although these methods exhibited high specificity and
selectivity for the synthesis of 1,4,5-trisubstituted 1,2,3-tri-
azoles, they are associated with several shortcomings that
include the use of unstable and dangerous organic azides,[16]
the use of expensive metal catalysts, limited variation of the
azides (most substrates are aryl azides), a lack of versatility,
and multistep procedures. In view of these limitations, there
is still a need for a mild and widely applicable approach
for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from
simple and easily available starting materials. In this com-
munication, we report a direct, one-pot, three-component
protocol for the synthesis of 1,4,5-trisubstituted 1,2,3-tri-
azoles from readily available primary alcohols, sodium az-
ide, and active methylene ketones in the presence of tetra-
butylammonium iodide (TBAI), triethylamine (TEA), and
N-(p-toluenesulfonyl)imidazole (TsIm) in a mixed DMF/
DMSO solvent system (Scheme 1).
Introduction
1,2,3-Triazoles are an important class of heterocyclic
compounds that have attracted a great deal of attention
from synthetic and medicinal chemists due to their poten-
tial biological activities.[1] However, most of the research
has been focused on the synthesis and bioassay of 1,4- or
1,5-disubstituted 1,2,3-triazoles.[2] In recent years, 1,4,5-tri-
substituted 1,2,3-triazoles have found important applica-
tions in various areas, especially as medicine against many
diseases[3] including influenza A virus,[4] herpes simplex
viruses type-1 (HSV-1),[5] and human platelet aggregation.[6]
However, up to now, only a few methods for the synthesis
of fully substituted 1,2,3-triazoles have been described.[7] In
2009, Fokin and co-workers developed a general and highly
efficient copper(I)-catalyzed method for the chemo- and re-
gioselective synthesis of 1,4,5-trisubstituted 5-iodo-1,2,3-tri-
azoles from organic azides and iodoalkynes.[8] These 5-
iodo-1,2,3-triazoles are useful and versatile synthetic inter-
mediates that can be easily modified to allow further func-
tionalization at the C-5 position.[9] One of the most attract-
ive approaches to the synthesis of fully decorated 1,2,3-tri-
azoles is the direct Pd- or Cu-catalyzed arylation of 1,4-
disubstituted triazoles with aryl halides.[10] Some other
known methods for the synthesis of fully substituted 1,2,3-
triazoles include cycloadditions of azides with bromomag-
nesium acetylides, followed by reaction with an electro-
phile;[11] reactions of azides with active methylene com-
pounds;[3b,12] Ru-catalyzed cycloadditions of azides and in-
ternal alkynes;[13] the one-pot, three-component reactions Scheme 1. Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles through
of arylazides, amines, and diketene.[14] More recently, Wang
the one-pot, three-component reaction of primary alcohols, sodium
azide, and active methylene ketones.
[a] Shanghai Key Laboratory of Chemical Biology, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Fax: +86-21-64252603
Results and Discussion
E-mail: scao@ecust.edu.cn
Homepage: http://pharmacy.ecust.edu.cn/s/48/t/73/a/10983/
In our preceding paper, we reported a novel and efficient
info.jspy
protocol for the synthesis of 1,4-disubstituted 1,2,3-tri-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200830.
azoles by the CuI-catalyzed, one-pot, three-component re-
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G. Jin, J. Zhang, D. Fu, J. Wu, S. Cao
SHORT COMMUNICATION
action of primary alcohols, sodium azide, and terminal alk- Table 2. Effect of the solvent on the yield of 3n at 80 °C.[a]
ynes.[17] To extend our previous work, we tried to prepare
Entry
Solvent (10 mL)
Yield [%][b]
1,4,5-trisubstituted 1,2,3-triazoles from primary alcohols,
sodium azide, and active methylene ketones. In 2007, Rad
et al. synthesized a variety of azides from alcohols by using
a TsIm/TEA/TBAI/DMF system.[18] Encouraged by their
results, in our initial studies, benzyl alcohol, sodium azide,
and acetylacetone were selected as representative substrates
to investigate the possibility of the formation of trisubsti-
tuted triazoles in one pot in the presence of TsIm, TEA,
and TBAI (Scheme 2). It was found that 3n could be ob-
tained efficiently in our preliminary experiment (the 1H
NMR and 13C NMR spectra of compound 3n were iden-
tical to those in the literature[7g]).
1
2
3
4
5
THF
1,4-dioxane
DMSO
0
0
10
61
91
DMF
DMSO + DMF (5 mL + 5 mL)
[a] Reaction conditions: benzyl alcohol (2.5 mmol), solvent (5 mL),
TsIm (5 mmol), sodium azide (5 mmol), TBAI (0.08 mmol), TEA
(5 mmol), 80 °C, 10 h. Then, acetylacetone (3 mmol), potassium
hydroxide (3 mmol), and solvent (5 mL) were added to the reaction
solution. Reaction was continued for 12 h at 80 °C. [b] Yield ob-
tained by GC analysis.
With the optimized reaction conditions in hand, we set
out to survey the generality and scope of this novel, one-
Table 3. One-pot, three-component synthesis of 1,4,5-trisubstituted
1,2,3-triazoles.[a]
Scheme 2. Model reaction for the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles.
Generally, base plays an important role in the formation
of fully substituted 1,2,3-triazoles. For example, Wang used
diethylamine as a catalyst[15] and Cottrell used K2CO3[12] as
a base to improve the efficiency of the cyclization of azides
and active methylene ketones, respectively. Thus, our first
effort focused on the search of a suitable base. As indicated
in Table 1, among the various bases tested, KOH promoted
the reaction effectively and 1.2 equiv. of KOH gave an excel-
lent yield of the cyclization product (Table 1, entry 7),
whereas only low yield of 3n was obtained when dieth-
ylamine was used as the base (Table 1, entry 2).
Table 1. Effect of base on the yield of 3n at 80 °C.[a]
Entry
Base
Yield [%][b]
1
2
3
4
5
6
7
none
31
30
68
25
40
52
91
diethylamine (1.2 equiv.)
K2CO3 (1.2 equiv.)
pyridine (1.2 equiv.)
KOH (0.4 equiv.)
KOH (0.8 equiv.)
KOH (1.2 equiv.)
[a] Reaction conditions: benzyl alcohol (2.5 mmol), DMF (5 mL),
TsIm (5 mmol), sodium azide (5 mmol), TBAI (0.08 mmol), TEA
(5 mmol), 80 °C, 10 h. Then, acetylacetone (3 mmol), base, and
DMSO (5 mL) were added to the reaction solution. Reaction was
continued for 12 h at 80 °C. [b] Yield obtained by GC analysis.
The yields were also significantly affected by the solvent.
The best result was obtained when the reaction was con-
ducted in a mixture of DMF/DMSO (Table 2, entry 5). It
should be noted that all solvents were purchased commer-
cially and used without further drying. There is almost no
difference in yield between dry and “wet” DMF/DMSO.
Finally, the influence of reaction temperature on the yield
was also examined. The reaction proceeded smoothly at
80 °C for 22 h in DMF/DMSO, affording the expected
product in 91% yield.
[a] Reaction conditions: alcohol 1 (2.5 mmol), DMF (5 mL), TsIm
(5 mmol), sodium azide (5 mmol), TBAI (0.08 mmol), TEA
(5 mmol), 80 °C, 10 h. Then, active methylene ketone 2 (3 mmol),
potassium hydroxide (3 mmol), and DMSO (5 mL) were added to
the reaction solution. Reaction was continued for 12 h at 80 °C.
[b] Isolated yield.
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Three-Component Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles
Scheme 3. Proposed reaction mechanism.
pot, three-component reaction; a variety of primary ylate undergoes nucleophilic substitution with the azide ion
alcohols and several active methylene ketones were exam- to afford an alkyl azide (R1N3). Enolate II is generated by
ined under the optimized conditions (Table 3). In most active methylene ketone I in the presence of KOH. Cycload-
cases, this three-component reaction proceeded efficiently dition between enolate II and the alkyl azide can provide
to give the corresponding 1,4,5-trisubstituted 1,2,3-tri- intermediate III, and the reaction is finalized by dehy-
azoles, and no regioisomers were observed. Aliphatic dration of the alcohol group by a strong base, resulting in
alcohols, even methanol and ethanol, reacted efficiently to the loss of water and the formation of triazole product IV.
give the corresponding fully substituted 1,2,3-triazoles in
high yields (Table 3, entries 1–9). The synthesis of 3a–i is
particularly useful. Small alkyl organic azides such as
methyl azide, ethyl azide, and n-propyl azide are generally
Conclusions
not only toxic and expensive but also explosive when heated
or shaken. This new approach avoids the isolation of or-
ganic azides and can be expanded to prepare 1-alkyl-4,5-
trisubstituted 1,2,3-triazoles when small alkyl azides are un-
stable or unavailable. However, when secondary alcohols
were used as substrates, very few cyclization products were
obtained. Furan-2-ylmethanol and (6-chloropyridin-3-yl)-
methanol also worked well with this protocol (Table 3, en-
tries 16–19). When 2,2-difluoro-2-phenylsulfanylethanol
(Table 3, entries 10–12) was used, the desired products were
obtained only in moderate yield. Additionally, the results
also indicated that acetylacetone and 3-oxo-3-phenylprop-
anenitrile could afford higher yields of the 1,2,3-triazoles
than ethyl acetoacetate. When the reaction of aliphatic pri-
mary alcohols and sodium azide with ethyl acetoacetate was
conducted under the same reaction conditions, almost no
cycloaddition product was detected. The reaction of an un-
symmetrical diketone such as 1-phenylbutane-1,3-dione
with benzyl alcohol and sodium azide gave a mixture of
regioisomeric 1,4,5-trisubstituted 1,2,3-triazole products
(Table 3, entry 20), and the ratio of regioisomers was nearly
1:1. Unfortunately, the reaction did not proceed well with
ethyl 4,4-difluoroacetoacetate or ethyl 4,4,4-trifluoroaceto-
acetate as substrates, as the desired products were not iso-
lated (Table 3, entries 21–22). Because of the low pKa values
of fluorinated substrates (ethyl trifluoroacetoacetate, pKa =
7.63; ethyl acetoacetate, pKa = 11), they might form more
stable enolates, precluding further transformation.
In summary, we developed a novel method for the syn-
thesis of 1,4,5-trisubstituted 1,2,3-triazoles by the one-pot,
three-component cycloaddition of primary alcohols, so-
dium azide, and active methylene ketones at 80 °C in the
presence of N-(p-toluenesulfonyl)imidazole, tetrabutylam-
monium iodide, and triethylamine in DMF/DMSO. The
mild reaction conditions, high yields, and one-pot reaction
without the necessity to isolate the unstable and hazardous
azides (especially aliphatic azide) are main merits of this
method. The most remarkable feature of this method is that
it provides easy access to fully substituted 1,2,3-triazoles
from commercially available primary alcohols.
Experimental Section
General Procedure for the Preparation of 3a–s: To a stirred solution
of alcohol 1 (2.5 mmol) in DMF (5 mL) was successively added
TsIm (1.11 g, 5 mmol),[18] sodium azide (0.33 g, 5 mmol), TBAI
(0.04 g, 0.08 mmol), and TEA (0.50 g, 5 mmol). The mixture was
stirred for 10 h at 80 °C. Then, the mixture was cooled to room
temperature, active methylene ketone 2 (3 mmol), potassium hy-
droxide (0.17 g, 3 mmol), and DMSO (5 mL) were added to the
solution. The reaction was continued for 12 h (TLC) at 80 °C and
then quenched with H2O (10 mL). The resulting suspension was
filtered, and the filtrate was diluted with CH2Cl2, washed success-
ively with H2O and brine, dried with anhydrous MgSO4, and con-
centrated under reduced pressure to leave the crude product. The
resultant crude residue was purified by chromatography on silica
gel (petroleum ether/EtOAc = 10:1) to afford target compound 3.
On the basis of the above observations, a mechanism for
the formation of 3a–s is briefly outlined in Scheme 3. In the
first step, the base-activated alcohol reacts with TsIm to
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, full characterization data, and cop-
give an alkyl tosylate (R1OTs). Subsequently, the alkyl tos- ies of the H NMR and 13C NMR spectra for all compounds.
1
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G. Jin, J. Zhang, D. Fu, J. Wu, S. Cao
SHORT COMMUNICATION
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Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072057), the Key Pro-
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Received: June 21, 2012
Published Online: ᭿
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Three-Component Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles
Multicomponent Reactions
G. Jin, J. Zhang, D. Fu, J. Wu,
S. Cao* ............................................. 1–5
One-Pot, Three-Component Synthesis of
1,4,5-Trisubstituted 1,2,3-Triazoles Start-
ing from Primary Alcohols
A series of 1,4,5-trisubstituted 1,2,3-tri-
azoles was synthesized through the cyclo-
addition of a wide range of primary al-
cohols with sodium azide and active meth-
ylene ketones in the presence of N-(p-tolu-
enesulfonyl)imidazole (TsIm), tetrabutyl-
ammonium iodide (TBAI), and triethyl-
amine (TEA) by using a mixed DMF/
DMSO solvent system.
Keywords: Multicomponent reactions / Ni-
trogen heterocycles / Alcohols / Ketones
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