One step cascade synthesis of 4,5-disubstituted-1,2,3-(NH)-triazoles

Article abstract of DOI:10.1021/ol8002783

(Chemical Equation Presented) A Lewis base-catalyzed three-component cascade reaction was developed for the synthesis of 4,5-disubstituted-1,2,3-(NH) -triazoles. More than 25 new (NH)-triazoles were prepared in good to excellent yields under mild conditions. The availability of the C-4 vinyl group allows easy conversion into other triazole derivatives.

Full text of DOI:10.1021/ol8002783

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1493-1496
One Step Cascade Synthesis of
4,5-Disubstituted-1,2,3-(NH)-Triazoles
Sujata Sengupta, Haifeng Duan, Weibing Lu, Jeffrey L. Petersen, and
Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity, Morgantown,
West Virginia 26506
Xiaodong.Shi@mail.wVu.edu
Received February 6, 2008
ABSTRACT
A Lewis base-catalyzed three-component cascade reaction was developed for the synthesis of 4,5-disubstituted-1,2,3-(NH)-triazoles. More than
25 new (NH)-triazoles were prepared in good to excellent yields under mild conditions. The availability of the C-4 vinyl group allows easy
conversion into other triazole derivatives.
Since the recent discovery of the Cu-catalyzed azide-alkyne
1,3-dipolar cycloaddition (CuAAC, often referred to as
“click-chemistry”), the 1,2,3-triazole compounds have re-
ceived considerable attention from scientists in various
fields.1 Within the last 5 years, the importance of these
compounds has been continuously demonstrated in research
fields as diverse as material science,2 chemical biology,3 and
medicinal chemistry.4
Despite being a very efficient method for the synthesis of
N-substituted triazole (reaction A), one limitation of the
CuAAC is the lack of reactivity toward unsubstituted azides,
such as NaN3 and HN3. Therefore, to prepare the N-
unsubstituted triazoles (NH-triazole) by CuAAC, the organic
azides are usually applied with removable N-protecting
groups (reaction B) followed by deprotection.5 Meanwhile,
the thermal reactions between alkyne and NaN3/HN3 gave
low yields, and the preparation of substituted alkynes was
usually challenging and had high costs.6 Therefore, an
efficient synthesis of substituted NH-triazoles (as a comple-
mentary approach for the CuAAC reaction) is highly
(1) For reviews, see: (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Kolb,
H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004-2021. (c) Bock, V. D.; Hiemstra, H.; Van Maarseveen, J. H. Eur. J.
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D.; Leigh, D. A.; Lusby, P. J.; Walker, D. B. J. Am. Chem. Soc. 2006, 128,
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2004, 126, 15046-15047. (b) Moorhouse, A. D.; Santos, A. M.; Gunarat-
nam, M.; Moore, M.; Neidle, S.; Moses, J. E. J. Am. Chem. Soc. 2006,
128, 15972-15973. (c) Kumar, R.; El-Sagheer, A.; Tumpane, J.; Lincoln,
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C.; Tseng, H.-R. Angew. Chem., Int. Ed. 2006, 45, 5276-5281. (c)
Sugawara, A.; Sunazuka, T.; Hirose, T.; Nagai, K.; Yamaguchi, Y.; Hanaki,
H.; Sharpless, K. B.; Omura, S. Bioorg. Med. Chem. Lett. 2007, 17, 6340-
6344. (d) Chen, H.; Taylor, J. L.; Abrams, S. R. Bioorg. Med. Chem. Lett.
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Hwang, C. K. Tetrahedron Lett. 2005, 46, 1483-1487.
10.1021/ol8002783 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/11/2008

desirable. Herein, we report a L-proline catalyzed cascade
reaction as an efficient approach for the synthesis of 4,5-
disubstituted-NH-triazoles.
Our interest in developing new synthetic methods by an
organo catalyst promoted cascade reaction recently led to
the discovery of the successful intermolecular double-
Michael addition between nitro and carbonyl activated
olefins7 as shown in Scheme 1A. The key to this new
amount of NaN3 (2-4 equiv) at 80-90 °C. With the
optimized condition, some NH-triazoles were prepared in
good to excellent yields (54%-96%). However, as pointed
out by the authors, the reaction yields highly depended on
the substrates, and the synthesis of the olefin precursor was
challenging (unfavored equilibrium in the Henry reaction)
and in some cases gave low yields. Therefore, as a general
problem, all the thermal cyclization approaches suffered from
limited substrate scope.
In our recently reported cascade double-Michael addition
between nitroalkene 1a and enone 2, a formal allylic nitro
nucleophile was generated under mild conditions. Moreover,
the attempt on [3 + 2]11 cycloaddition of 1a and electron-
rich alkene 3, forming isoxazole-N-oxide 4, revealed the
formation of 1,3-diene A as activated intermediate. We then
wondered whether N3- could quench the diene intermediate
to produce NH-triazole 6, which would avoid the synthesis
of R-nitroalkene starting material (more complicated 1,2-
disubstituted nitroalkenes) in the 1,3-dipolar cycloaddition
and significantly increase the reaction substrate scope.
Our initial attempt was to treat 1a and 3 with the addition
of NaN3 to quench intermediate A. However, only isoxazole
4 was obtained with no formation of triazole, even in the
presence of excess NaN3. It suggested that the 1-alkyl diene
A is a highly reactive intermediate, which was fully quenched
Scheme 1
-
by allylic nitro carbanion and not by the N3 . To avoid this
nitro carbanion addition, an alternate approach was designed
by treating nitroalkene 1 with aryl aldehyde 5 to form the
-
1-aryl diene A′ followed by N3 1,3-dipolar cycloaddition
to give triazole 6 (Scheme 2B). As expected, the reaction of
methodology was the introduction of a â-alkyl group on the
nitroalkene, which allowed the â-elimination to give the allyl-
ic nitro compounds as the stable product rather than the highly
reactive nitroalkenes. Moreover, we recently discovered that
the treatment of nitroalkene 1 with electron enriched olefins
gave isoxazole-N-oxide as shown in Scheme 1B.8 The poten-
tial applications of functional 1,2,3-triazole derivatives and
the recent discovery of organo catalyst mediated cascade reac-
tions mentioned above initiated our interest in extending this
approach to the synthesis of NH-triazoles through cascade
reactions from simple, readily available starting materials.
Besides the CuAAC approach, another method for the
synthesis of 1,2,3-triazole is the 1,3-dipolar cycloaddition
between â-nitrostyrene and NaN3, which was first reported
by Zefirov in 1971.9 With DMSO as the solvent at room
temperature, the authors reported the formation of 4-phenyl-
1,2,3-triazole in 65% yield. However, a recent study by
Quiclet-Sire and Zard indicated that this result was not
reproducible.10 Instead, they developed an optimized ap-
proach using an R-substituted nitroalkene and an excess
Scheme 2
nitroalkene 1a, benzylaldehyde, and NaN3 produced the
desired 1,2,3-NH-triazole 6a at room temperature. The
screening of the reaction conditions is summarized in Table
1.
(6) (a) Loren, J. C.; Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Synlett.
2005, 18, 2847-2850. (b) Yap, A. H.; Weinreb, S. M. Tetrahedron Lett.
2006, 47, 3035-3038. (c) Shchetnikov, G. T.; Peregudov, A. S.; Osipov,
S. N. Synlett 2007, 136-140. (d) Skarpos, H.; Osipov, S. N.; Vorob’eva,
D. V.; Odinets, I. L.; Lork, E.; Roschenthaler, G. V. Org. Bio. Chem. 2007,
5, 2361-2367.
(7) Sun, X.; Sengupta, S.; Petersen, J. L.; Wang, H.; Lewis, J. P.; Shi,
X. Org. Lett. 2007, 9, 4495-4498.
(8) Manuscript in preparation.
(11) Selected examples of nitro compound [3+2] reactions: (a) Voituriez,
A.; Moulinas, J.; Kouklovsky, C.; Langlois, Y. Synthesis 2003, 9, 1419-
1426. (b) Roger, P. Y.; Durand, A. C.; Rodriguez, J.; Dulcere, J. P. Org.
Lett. 2004, 6, 2027-2029. (c) Kunetsky, R. A.; Dilman, A. D.; Struchkova,
M. I.; Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis 2006, 13,
2265-2270. (d) Arrieta, A.; Otaegui, D.; Zubia, A.; Cossio, F. P.; Diaz-
Ortiz, A.; de la Hoz, A.; Herrero, M. A.; Prieto, P.; Foces-Foces, C.; Pizarro,
J. L.; Arriortua, M. I. J. Org. Chem. 2007, 72, 4313-4322.
(9) Zefirov, N. S.; Chapovskaya, N. K.; Kolesnikov, V. V. J. Chem.
Soc., Dalton Trans. 1971, 17, 1001-1002.
(10) Quiclet-Sire, B.; Zard, S. Z. Synthesis 2005, 19, 3319-3326.
1494
Org. Lett., Vol. 10, No. 7, 2008

Table 1. Screening of the Reaction Conditionsa
Table 2. Reaction Substrate Scopea
temp time convn yield
solvent
cat.b
(°C)
(h)
(%)c
(%)d
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
rt
80
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
10
8
8
8
8
8
8
8
20
20
12
12
12
12
20
40
100
100
15
28
35
90
12
14
L-Pro
pyrrolidine
pyrrolidine/AcOH
DMAP
DIPEA (1.0)
NaOt-Bu (1.0)
glycine
P(OMe)3
imidazole
L-Pro
20
time yield
(h)
35 trace
30 trace
trace trace
entry
1
5
(%)b
1
2
3
4
5
6
7
8
9
1a: R1 ) Ph; R2 ) H
Ar ) Ph
Ar ) p-NO2-Ph
Ar ) m-NO2-Ph
Ar ) o-NO2-Ph
Ar ) p-CN-Ph
Ar ) p-Cl-Ph
Ar ) p-OMe-Ph
Ar ) 2,6-di-Cl-Ph
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
6a: 89
6b: 88
6c: 85
6d: 81
6e: 78
6f: 74
6g: 40d
6h: 76
6i: 76
6j: 75
6k: 81
6l: 83
6m: 56d
6n: 72
6o: 78
6p: 74
6q: 71
1a
1a
1a
1a
1a
1a
1a
1a
90
20
10 DMSO
11 DMSO
12 THF
13 MeCN
14 MeOH
trace trace
40 trace
58
58
65
48
60
45
55
64
40
56
L-Pro
L-Pro
15 Acetone L-Pro
16 MeNO2 L-Pro
5b
5c
5d
5e
10 1a
11 1a
12 1a
13 1a
14 1b: R1; R2 ) -(CH2)4-
15 1b
16 1b
a Reactions were carried out at room temperature, 1a:5a ) 1:2. b 20%
catalyst loading. c Conversion based on the consumption of the starting
material 1a from NMR. d NMR yield was determined by 1,3,5-trimethoxy-
benzene as internal standard.
5g
Ar ) Ph
Ar ) p-NO2-Ph
Ar ) p-Cl-Ph
The treatment of sodium azide with 1a and 5a in DMSO
gave the NH-triazole 6a in poor yield without the addition
of a Lewis base (LB) catalyst (entry 1). As reported in our
previous paper, sodium azide not only is the reactant but
also serves as the Lewis base in the activation of 1a.
However, as a less effective Lewis base catalyst, the reaction
proceeded slowly at room temperature. Increasing the
reaction temperature resulted in the significant polymerization
of the nitroalkene 1a (entry 2). Further addition of different
Lewis base catalysts revealed proline as the best catalyst.
Screening of the solvents gave DMSO as the solvent of
choice. Considering the low cost, good reaction performance,
and easy handling, L-proline was selected as the catalyst.
The optimal reaction condition is shown in entry 3. Different
nitroalkene and aromatic aldehydes were then applied to
evaluate the reaction substrate scope, and the results are
shown in Table 2.
As shown in Table 2, a large number of aryl aldehydes
and â-alkyl nitroalkenes are suitable for this transformation.
Various 4,5-disubstituted NH-triazoles can be efficiently
synthesized from this cascade process. Based on the reaction
mechanism shown in Scheme 2B, the major competing side
reaction is the polymerization of the nitroalkene 1. Therefore,
less hindered nitroalkenes (1c, 1d) gave moderate yields of
6 due to the decomposition of 1. An excess amount of
aldehyde (2.0 equiv) was also found to be important for the
best product yields. The application of a stoichiometric
amount of aldehyde (1.0 equiv) generally gave 10-20%
lower yields of 6, varying by substrates. This may be due to
17 1b
18 1b
19 1b
5c
5d
5f
10 6r: 73
6s: 65d
10 6t: 58c
8
20 1c: R1 ) CH3; R2 ) H
21 1c
Ar ) p-NO2-Ph
5c
8
8
8
6u: 55
6v: 56
6w: 81
22 1d: R1 ) H; R2 ) R3 ) Me 5c
23 1e: R1 ) p-Cl-Ph; R2 ) H 5c
a Compounds 1 (1.0 equiv), 5 (2.0 equiv), L-Pro (20%), and NaN3 (1
equiv) were dissolved in DMSO (0.2 M of 1) and stirred at rt. Reactions
were monitored by TLC. b Isolated yields. c 6t was characterized by X-ray
crystallography. d Heating at 80 °C.
the decomposition of the reactant aldehyde. The electron
density on the aryl group of the aldehydes also influences
the reaction performance. Nonsubstituted aromatic aldehydes
and electron deficient aromatic aldehydes work well in this
cascade approach. Electron-donating group substituted aryl
aldehydes (entries 7, 13, 19), on the other hand, gave poor
yields at room temperature (less than 20%). This is due to
slow kinetics in the Henry reaction and the competition of
compound 1 polymerization. Raising the reaction temperature
to 80 °C produced the desired triazole 6 in good yields.
Substituted azides (n-hexanyl azide and phenyl azide) have
also been applied in this cascade process, and no triazole
product was observed. This is probably due to the slow 1,3-
dipolar addition between substituted azide and diene inter-
mediate A′, which can be associated with either weaker
-
nucleophilicity of the azide or slow elimination of NO2 .
-
the formation of oxidative NO2 byproduct, which causes
However, as a good nucleophile, the NH-triazoles can be
Org. Lett., Vol. 10, No. 7, 2008
1495

further functionalized in a regio- and enantioselective manner
through readily available reactions, such as alkylation,12
acetylation,13 and Michael addition,14 thereby allowing the
formation of fully substituted 1,2,3-triazoles in simple steps.
Compared to the thermal-1,3-dipolar addition (Zard’s
method), this cascade approach generates the activated
intermediate in situ. This method successfully avoids the
difficult synthesis of the R-nitroalkene reactants (i.e., 1 vinyl-
2-aryl nitroalkene), therefore significantly extending the
reaction substrate scope. Moreover, the application of â-alkyl
nitroalkene 1 allows the formation of a more reactive
nitroalkene (1,3-diene) intermediate, which leads to mild
reaction conditions and easy incorporation of other functional
groups on the C-4, C-5 side chain. Some examples of side-
chain modification are shown in Scheme 3.
Scheme 3
In conclusion, based on the Lewis base-catalyzed cascade
nitroalkene-aldehyde-azide condensation, a new synthesis for
NH-1,2,3-triazole was developed. The overall yields of this
reaction are good, especially taking into consideration that
this cascade method combines two reactions in “one-step”.
Notably, many of the products reported in Table 2 cannot
be prepared from the CuAAC reaction (lack of reactivity at
internal alkyne) nor by the thermal 1,3-dipolar cyclization
(difficulty in the preparation of highly functional olefins).
With the advantages of readily available starting materials,
mild reaction condition and high atom-efficiency, this method
provides a complementary approach for the synthesis of
substituted 1,2,3-NH-triazoles. Development of these com-
pounds as asymmetric ligands is currently under investigation
and will be reported in due course.
Acknowledgment. We thank the C. Eugene Bennett
Department of Chemistry, the Eberly College of Arts and
Science, and the WV Nano Initiative at West Virginia
University for financial support.
(12) (a) Majumdar, S.; Spaeth, M. M.; Sivendran, S.; Juntunen, J.;
Thomas, J. D.; Sloan, K. B. Tetrahedron Lett. 2007, 48, 4609-4611. (b)
Csampai, A.; Kover, P.; Hajos, G.; Riedl, Z. J. Mol. Struct. 2002, 616,
73-78.
(13) Rheingold, A. L.; Liable-Sands, L. M.; Trofimenko, S. Inorg. Chim.
Acta 2002, 330, 38-43.
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44, 2393-2397. (b) Diner, P.; Nielsen, M.; Marigo, M.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2007, 46, 1983-1987. (c) Wang, J.; Li, H.; Zu, L.;
Wang, W. Org. Lett. 2006, 8, 1319-1394.
Supporting Information Available: Experimental de-
tails, spectrographic data, and XRD information. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8002783
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Org. Lett., Vol. 10, No. 7, 2008