Microwave irradiation as an effective means of synthesizing uninfstituted N-linked 1,2,3-triazoles from vinyl acetate and azides

Article abstract of DOI:10.1055/s-0029-1218366

N-Linked 1,2,3-triazoles have been prepared by a reaction of azides with vinyl acetate under microwave irradiation. Additionally, a microwave-assisted, two-step, one-pot procedure from halides involving azideinfstitution in diethyl ether, followed by -reaction with vinyl acetate, has effectively been employed. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218366

LETTER
3275
Microwave Irradiation as an Effective Means of Synthesizing Unsubstituted
N-Linked 1,2,3-Triazoles from Vinyl Acetate and Azides
U
nsubstituted
i
N-Link
g
ed 1, 2,3-Tr
i
nazoles e Grann Hansen, Henrik Helligsø Jensen*
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
Fax +45 86196199; E-mail: hhj@chem.au.dk
Received 10 August 2009
result.13 In both academia and industry, it is now consid-
ered to be standard laboratory equipment.
Abstract: N-Linked 1,2,3-triazoles have been prepared by a reac-
tion of azides with vinyl acetate under microwave irradiation. Ad-
ditionally, a microwave-assisted, two-step, one-pot procedure from
halides involving azide substitution in diethyl ether, followed by
reaction with vinyl acetate, has effectively been employed.
In this paper, we report an improved and simple method
with which to obtain C-unsubstituted 1,2,3-triazoles in a
microwave-assisted 1,3-dipolar cycloaddition reaction
between an azide and vinyl acetate (Scheme 1, path a).
The use of microwave heating enables clean reactions to
take place in reasonable reaction times and can give good
to excellent yields. The efficiency of the reaction is dem-
onstrated by the synthesis of both simple and sterically de-
manding 1,2,3-triazoles. Additionally, 1,2,3-triazoles
have been synthesized directly from various alkyl halides
in a multicomponent, one-pot procedure employing tetra-
butylammonium azide (TBAN3) for formation of the po-
tentially explosive intermediate azides in situ (Scheme 1,
path b).
Key words: 1,2,3-triazole, vinyl acetate, microwave irradiation,
one-pot reaction, 1,3-dipolar cycloaddition
Many pharmaceutical and agrochemical compounds pos-
sess nitrogen-containing heteroaromatic motifs1 such as
the 1,2,3-triazole unit present in, for example, the market-
ed b-lactamase inhibitor Tazopram, which contains a
C-unsubstituted 1,2,3-triazole.2 The Meldal–Sharpless
Cu(I)-catalyzed Huisgen cycloaddition offers an ideal
protocol for the synthesis of isomerically pure 1,4-substi-
tuted 1,2,3-triazoles.3 There is, however, only a limited
number of reports concerning the synthesis of C-unsubsti-
tuted 1,2,3-triazoles.4
vinyl acetate, μw
R
N3
(a)
C-Linked triazoles can efficiently be prepared in a two-
step procedure5 or by treatment of a terminal alkyne with
a cuprous azide complex,6 as inspired by the Meldal–
Sharpless protocol. For N-linked, C-unsubstituted 1,2,3-
triazoles it was recently reported that TMS-acetylene
could be used under Cu(I) catalysis at ambient tempera-
ture in methanol to give unsilylated triazoles.7 Alterna-
tively, this heteroaromatic function has been introduced
through reaction of an azide with acetylene gas in a sealed
container.8 Additionally, substitution of a halide by 1,2,3-
triazole or TMS-triazole have been employed but this re-
sulted in the formation of regioisomeric mixtures.9 C-Un-
substituted 1,2,3-triazoles have also been prepared by
reaction of an azide with an alkene such as vinyl acetate,10
phenyl vinyl sulfoxide11 or norbornadiene,12 with either
concomitant elimination or, in the latter case, retro-Diels–
Alder reaction, to achieve aromatization. Conventional
heating has been used in all the reactions employing al-
kenes reported thus far, requiring reaction times up to
days and resulting in only moderate to fair yields of the
C-unsubstituted 1,2,3-triazoles.
N
R
N
N
1) TBAN3, μw
(b)
R
X
2) vinyl acetate, μw
Scheme 1 Microwave-assisted synthesis of C-unsubstituted 1,2,3-
triazoles from azides (path a) or halides (path b) and vinyl acetate
In this synthetic approach, azides were simply dissolved
in reagent grade vinyl acetate and heated under micro-
wave irradiation to 120 °C until full consumption of the
starting material was observed (Table 1). The azides em-
ployed in this study were either commercially available
(1j), prepared as described in the literature (1k),14 or pre-
pared by substitution of a halide or mesylate with NaN3 in
DMF under microwave heating15 (see Supporting Infor-
mation). One exception is 4-azidobutan-1-ol (1h), which
was formed directly in 94% yield from THF in a one-pot
reductive ring-opening–iodination–azidation sequence
employing NaBH4, iodine, sodium azide, and water (see
Supporting Information for details).
A range of benzylic azides (Table 1, entries 1–5) were
found to react readily to form the desired triazole products
in high yields (76–99%) within four to seven and a half
hours, while primary azides (Table 1, entries 6–9) were
found to react somewhat slower, however, the products
were still obtained in high yields (62–86%). 1-Adamantyl
azide (1j) reacted significantly more sluggishly, albeit still
Microwave reactors have, within the last decade, become
a popular means of heating reaction mixtures and much
progress in synthetic organic chemistry has occurred as a
SYNLETT 2009, No. 20, pp 3275–3278
x
x
.x
x
.2
0
0
9
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218366; Art ID: G26109ST
© Georg Thieme Verlag Stuttgart · New York

3276
S. G. Hansen, H. H. Jensen
LETTER
triazol-1-yl)butan-1-ol as the main product in 75% yield
(Table 1, entry 8). In contrast, similar acetylation was not
observed for the 5-azidopentan-1-ol (1g, Table 1, entry 7).
Table 1 Formation of 1,2,3-Triazoles by Microwave-Assisted 1,3-
Dipolar Cycloaddition of Alkyl Azides 1 to Vinyl Acetate16
O
μw (120 °C)
N
R
+
N
N
R
N3
To illustrate the efficiency of this microwave-assisted cy-
cloaddition, a reaction with benzyl azide (1a) in refluxing
vinyl acetate using conventional heating, was carried out.
The reaction did not reach completion, and only 55% of
the triazole product could be obtained after seven days (cf.
99% yield within five hours, Table 1, entry 1).
O
1
2
Entry
1
Azide
Time (h) Yield (%)a
N3
5
4
99
77
The use of a Lewis acid or a Brønsted base [Yb(OTf)3
(15%) or Na2CO3] as described by Fan et al.8 was not ben-
eficial to the reaction under either conventional or micro-
wave heating.
1a
N3
2
3
Br
In an attempt to circumvent the risk of working with po-
tentially explosive organic azides, we looked into a meth-
od for carrying out the 1,3-dipolar cycloaddition without
having to isolate the unstable azides. It is known that 1,4-
disubstitued 1,2,3-triazoles can be prepared in a two-step,
one-pot procedure, in which intermediate azides are pre-
pared from boronic acids,14 halides,17 anilines/amines,18
or by conjugate addition19 and react further with an appro-
priate alkyne in the presence of a Cu(I) catalyst. We envi-
sioned that by forming the azides in situ in the microwave
reactor from the easily handled alkyl halides and an azide
donor, before carrying out the cycloaddition in the same
microwave reactor vial, we would have an alternative way
of forming C-unsubstituted 1,2,3-triazoles (see Table 3
below).
1b
N3
5
76
F3C
1c
N3
4
5
6
5
88
64
86
MeO
1d
N3
7.5
9.5
1e
N3
1f
Table 2 Solvent-Screening for the Microwave-Assisted 1,3-Dipo-
lar Cycloaddition with Varying Equivalents of Vinyl Acetate
HO
N3
7
8
7
6
62
O
1g
HO
μw (120 °C)
N
R
+
N
N
R
N3
75b
N3
O
1
2
1h
N3
Entry
R
Solvent
Vinyl acetate Time
Yield
(%)a
O
BnO
BnO
9
10
97
(equiv)
(h)
BnO
OMe
1
Bn
Bn
Bn
DMF
5
5
9
56
33
63
64
62
94
94
96
80
86
74
67
80
1i
2
MeOH
MeOH
MeOH
dioxane
Et2O
15
15
20
21
14
16
26
18
24
13
24
36
10
11
24
78
90
N3
3
10
10
5
1j
4
n-nonyl
Bn
N3
5
3.5
MeO
6
Bn
5
1k
7
Bn
Et2O
10
10
5
a Isolated yield after flash chromatographic purification.
b The isolated 1,2,3-triazole was O-acetylated.
8
n-nonyl
Bn
Et2O
9
THF
in acceptable yield (78%, Table 1, entry 10). Of the azides
investigated in this study, p-methoxyphenyl azide14 was
found to be the fastest reacting azide; in this case the start-
ing material was fully consumed in only three and a half
hours to give the corresponding 1,2,3-triazole in 90%
yield (Table 1, entry 10). Surprisingly, the 4-azidobutan-
1-ol (1h) was acetylated under the cycloaddition condi-
tions, resulting in the formation of O-acetylated 4-(1,2,3-
10
11
12
13
Bn
toluene
toluene
toluene
MeCN
5
Bn
10
10
5
n-nonyl
Bn
a Isolated yield after flash chromatographic purification.
Synlett 2009, No. 20, 3275–3278 © Thieme Stuttgart · New York

LETTER
Unsubstituted N-Linked 1,2,3-Triazoles
3277
It was found that both NaN3 and tetrabutylammonium yields (64–70%). As expected from our previous results,
azide (TBAN3) reacted more readily with vinyl acetate the benzylic halides 3a–b (Table 3, entries 1 and 2) react-
than with benzyl bromide. Therefore, a screening of sol- ed faster than the alkyl halides 3c–d (Table 3, entries 3
vents in which both the substitution step and cycloaddi- and 4).
tion can proceed, was undertaken (Table 2).
In conclusion, we have presented a method for obtaining
All solvents tested enabled triazole formation to some ex- N-linked C-unsubstituted 1,2,3-triazoles in good to excel-
tent. Carrying out the reaction in DMF (Table 2, entry 1), lent yields in a clean and efficient microwave-assisted
however, resulted in incomplete consumption of benzyl reaction. In addition, a multicomponent, one-pot protocol
azide and only a moderate amount of the triazole (56%) for the synthesis of 1,2,3-triazoles from alkyl halides was
could be obtained. This is in accordance with the observa- established. Considering the yields, the operational ease
tions that even small amounts (5–10% compared to the with which these reactions can be carried out and the in-
amount of azide) of DMF remaining from the previous expensive chemicals involved, we believe this protocol
step significantly retarded triazole formation, even in neat will be of great benefit to medicinal- and synthetic organic
vinyl acetate. Moderate yields (33–64%) were obtained in chemistry.
methanol and dioxane (Table 2, entries 2–5), whereas the
reaction proceeded smoothly and in good yields (67–
86%) in THF, toluene, and acetonitrile (Table 2, entries
9–13). Diethyl ether was found to be a superior solvent for
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
the cycloaddition; this solvent offered a clean reaction in
excellent yields (>94%, Table 2, entries 6–8).
Acknowledgment
The feasibility of a one-pot multicomponent azidation–
cycloaddition reaction sequence (Table 3) was explored
by first treating an alkyl halide with 1.05 equivalents of
tetrabutylammonium azide (TBAN3) in diethyl ether un-
der microwave irradiation. Reactions typically reached
full conversion after 10–15 min at 100 °C. Vinyl acetate
(10 equiv) was then added to the reaction mixture, which
was further heated until full consumption of the interme-
diate alkyl azide was observed. This approach resulted in
good overall yields of the C-unsubstituted 1,2,3-triazoles
(Table 3).
We gratefully acknowledge OChem Graduate School, Department
of Chemistry, Aarhus University for support.
References and Notes
(1) Fan, W.-Q.; Katritzky, A. R. In Comprehensive
Heterocyclic Chemistry II, Vol. 4; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996, 1–126.
(2) (a) Micetich, R. G.; Maiti, S. N.; Spevak, P.; Hall, T. W.;
Yamabe, S.; Ishida, N.; Tanaka, M.; Yamazaki, T.; Nakai,
A.; Ogawa, K. J. Med. Chem. 1987, 30, 1469. (b) Maiti,
S. N.; Babu, R. P. K.; Shan, R. Top. Heterocycl. Chem. 2006,
207.
(3) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596.
(4) Dahl, R. S.; Finney, N. S. J. Am. Chem. Soc. 2004, 126,
8356.
All four tested alkyl halides 3a–d were converted into
their corresponding 1-alkyl-1,2,3-triazoles in good overall
Table 3 Two-Step, One-Pot, Microwave-Assisted Azidation–
Cycloaddition of Alkyl Halides 320
1) TBAN3, Et2O
μw (100 °C)
N
R
N
N
R
X
2) vinyl acetate
μw (120 °C)
(5) Yap, A. H.; Weinreb, W. M. Tetrahedron Lett. 2006, 47,
3035.
3
2
(6) Lu, L.-H.; Wu, J.-H.; Yang, C.-H. J. Chin. Chem. Soc. 2008,
55, 414.
(7) Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron Lett.
2008, 49, 7030.
(8) Fan, H.; Xu, G.; Chen, Y.; Jiang, Z.; Zhang, S.; Yang, Y.; Ji,
R. Eur. J. Med. Chem. 2007, 42, 1137.
(9) Machin, P. J.; Hurst, D. N.; Bradshaw, R. M.; Blaber, L. C.;
Burden, D. T.; Melarange, R. A. J. Med. Chem. 1984, 27,
503.
(10) (a) Reisser, F. Belgian Patent 82-10558, 1983. (b) Tanaka,
M.; Yamazaki, T.; Kajitani, M. Eur. Pat. Appl. 158494,
1985. (c) Biagi, G.; Livi, O.; Scartoni, V.; Verugi, E.
Farmaco, Ed. Sci. 1988, 43, 597. (d) Biagi, G.;
Dell’omodarme, G.; Ferretti, M.; Giorgi, I.; Livi, O.;
Scartoni, V. Farmaco 1990, 45, 1181.
(11) Freeze, S.; Norris, P. Heterocycles 1999, 51, 1807.
(12) Yokoyama, M.; Nakao, E.; Sujino, K.; Watanabe, S.; Togo,
H. Heterocycles 1990, 31, 1669.
Entry
1
R–X
Time (h)
9
Yield (%)a
Cl
64
3a
Br
2
3
4
9
24
36
68
70
70
Br
3b
Br
3c
Br
(13) (a) Microwaves in Organic Synthesis, 2nd ed.; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2006. (b) Abid, M.; Torok, B.;
Huang, X. Aust. J. Chem. 2009, 62, 208.
3d
a Isolated yield after flash chromatographic purification.
Synlett 2009, No. 20, 3275–3278 © Thieme Stuttgart · New York

3278
S. G. Hansen, H. H. Jensen
LETTER
(14) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2007, 48, 3525.
(15) Microwave-Assisted Preparation of Alkyl Azides;
General Procedure
J = 0.8 Hz, 1 H), 7.40–7.32 (m, 3 H), 7.28–7.24 (m, 2 H),
5.57 (s, 2 H). NMR spectral data was in accordance with
literature values, see: Chuprakov, S.; Chernyak, N.; Dudnik,
A. S.; Gevorgyan, V. Org. Lett. 2007, 9, 2333.
Alkyl halide (1 equiv) and NaN3 (1.1 equiv) in DMF was
mixed in a Biotage vial of 0.5–2.0 mL. The vial was sealed,
and irradiated at 100 °C for 10–60 min. When the reaction
was complete as monitored by TLC analysis, the reaction
mixture was diluted with Et2O and the organic phase was
washed several times with H2O and brine and dried over
MgSO4. The solvent was removed at atmospheric pressure
and room temperature (as small organic azides do not
tolerate vacuum evaporation), and the isolated alkyl azide
was sufficiently pure for the next reaction. WARNING:
organic azides are potentially explosive substances and
proper safety precautions such as a blast shield should be
taken when handling these compounds.
Benzyl Azide (1a): BnCl (1.20 mL, 10.4 mmol) and NaN3
(726 mg, 11.2 mmol) in DMF (12 mL) were irradiated for 10
min at 100 °C to give benzyl azide as a colorless oil (1.17 g,
84%). 1H NMR (CDCl3): d = 7.40–7.31 (m, 5 H), 4.35 (s, 2
H). NMR spectral data was in accordance with literature
values, see: Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem.
2006, 71, 6697.
(17) (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.;
Van der Eycken, E. Org. Lett. 2004, 6, 4223. (b) Feldman,
A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897.
(18) (a) Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett.
2007, 9, 1809. (b) Beckmann, H. S. G.; Wittmann, V. Org.
Lett. 2007, 9, 1.
(19) Sreedhar, B.; Surendra Reddy, P.; Sailendra Kumar, N.
Tetrahedron Lett. 2006, 47, 3055.
(20) Microwave-Assisted One-Pot Formation of 1,2,3-
Triazole from Alkyl Halides; General Procedure
WARNING: Excess azide can potentially react with
acetic acid to form explosive hydrazoic acid. Thus, vinyl
acetate should not be added before the azidation reaction
has run to completion, and proper safety precautions
should be taken when handling these compounds.
Alkyl halide (1 equiv) and tetrabutylammonium azide (1.05
equiv) were dissolved in diethyl ether (1 mL) in a sealed
Biotage vial and irradiated at 100 °C until TLC analysis
indicated full consumption of the starting material. Vinyl
acetate (10 equiv) was then added and the reaction mixture
was irradiated at 120 °C until TLC analysis showed
disappearance of the intermediate azide. The reaction
mixture was then diluted with diethyl ether and the organic
phase was washed with H2O and brine then dried over
MgSO4, concentrated under reduced pressure and purified
by column chromatography on silica gel.
(16) Microwave-Assisted 1,2,3-Triazole Formation from
Azides; General Procedure
Alkyl azide (0.24–0.58 mmol) and vinyl acetate (1.50 mL)
were mixed in a Biotage vial (0.5–2.0 mL). The vial was
sealed and irradiated at 120 °C until full conversion was
achieved as monitored by TLC analysis. The reaction
mixture was concentrated under reduced pressure and the
crude product was purified by flash column chromatography
on silica gel.
1-Benzyl-1H-1,2,3-triazole (2b): Benzyl azide (1b; 68 mg,
0.51 mmol) in vinyl acetate (1.5 mL) was irradiated at
120 °C for 5 h. Column chromatography (EtOAc–CH2Cl2,
1:9; Rf = 0.41) afforded the triazole as colorless crystals (81
mg, 99%). 1H NMR (CDCl3): d = 7.71 (s, 1 H), 7.47 (d,
1-Benzyl-1H-1,2,3-triazole: BnCl (50 mL, 0.35 mmol) and
TBAN (104 mg, 0.36 mmol) in Et2O (1.0 mL) was irradiated
at 100 °C for 15 min. Vinyl acetate (0.32 mL, 3.5 mmol) was
added and the reaction mixture was irradiated at 120 °C for
9 h. Flash column chromatography (EtOAc–CH2Cl2, 1:9;
Rf = 0.41) afforded the triazole as colorless crystals (36 mg,
64%).
Synlett 2009, No. 20, 3275–3278 © Thieme Stuttgart · New York

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