Consecutive tandem cycloaddition between nitriles and azides; Synthesis of 5-amino-1H-[1,2,3]-triazoles

Article abstract of DOI:10.1055/s-0032-1317712

Novel 5-amino-1H-1,2,3-triazoles were synthesized by a new synthetic route that involves consecutive tandem cycloaddition between nitriles and azides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317712

LETTER
▌41
lCettoernsecutive Tandem Cycloaddition between Nitriles and Azides; Synthesis of
5-Amino-1H-[1,2,3]-triazoles
Synthesis of 5-Amino-1H-[1,2,3]-triazoles
Ana T. P. C. Gomes,a,b Priscila R. C. Martins,a David R. Rocha,a Maria G. P. M. S. Neves,b Vitor F. Ferreira,a Artur M.
S. Silva,b José A. S. Cavaleiro,*b Fernando de C. da Silva*a
a
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, 24020-150 Niterói, RJ, Brazil
Fax +55(21)26292138; E-mail: gqofernando@vm.uff.br
b
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: jcavaleiro@ua.pt
Received: 19.09.2012; Accepted after revision: 08.11.2012
ter, hydroxyl, keto, aryl, haloalkyl, trimethylsilyl, phenyl-
Abstract: Novel 5-amino-1H-1,2,3-triazoles were synthesized by a
sulfonyl, and phosphonate groups.16–19 Despite being a
new synthetic route that involves consecutive tandem cycloaddition
very versatile reaction, it does not cover the entire range
of 1,2,3-triazole compounds, such as certain amino deriv-
atives.
between nitriles and azides.
Key words: triazoles, tandem cycloaddition, consecutive reaction,
nitriles, azides
Usually, the syntheses of 5-amino-1,2,3-triazoles are car-
ried out from 1,5-regiospecific 1,3-dipolar cycloadditions
between azides and nitriles containing an activated meth-
ylene group (e.g., electron-withdrawing groups such as
cyano,20 phenyl,21 and carboxyl groups22) in a sodium alk-
oxide/alcohol medium.
Triazoles are biologically significant compounds not yet
found in any natural source.1,2 However, the triazole moi-
ety can be found in several bioactive compounds that act
as potential new drugs to treat several diseases; some ex-
amples of significant 1,2,3-triazoles are shown in Figure
1. The acyl-hydrazone derivatives 1 and 2 have shown, re-
spectively, excellent activity against Mycobacterium tu-
berculosis H37Rv (ATCC 27294)3 and strong inhibitory
antiplatelet activity.4 The glycoconjugates 3 and 4 showed
good inhibition respectively against α-glucosidase with
possible use in the treatment5 of diabetes mellitus type II
and in vitro inhibitory profiles against HIV-1 reverse tran-
scriptase.6
N
O
N
N
N
HN
N
H
Br
O
NH
N
Cl
2
N
N
N
N
OMe
O
N
N
In particular, it has been observed that 5-amino-1,2,3-tri-
azoles and derivatives have important pharmacological
properties such as antiallergic,7 antibacterial activity,8 and
act as potassium channel activators9 or A2A adenosine re-
ceptor antagonists.10
O
O
Cl
1
3
The search for new biologically active triazole derivatives
remains a great challenge. The 1,3-dipolar cycloaddition
of azides with alkynes is a most versatile and popular
route for the synthesis of 1,2,3-triazoles.11
N
N
N
O
O
OBn
O
O
The synthetic procedure initially developed by
Huisgen12,13 involves long reaction times, high tempera-
tures, and leads to the formation of mixtures of 1,4- and
1,5-regioisomers. However, the discovery of the Cu(I)-
catalyzed azide–alkyne cycloaddition reaction by
Meldal14 and Sharpless15 brought significant improve-
ments to the synthesis of 1,2,3-triazoles. The combination
of substituents on terminal alkynes and azide derivatives
allows the synthesis of a range of 1,2,3-triazoles with es-
O
4
Figure 1 Structure of some 1H-1,2,3-triazoles that have displayed
significant biological applications
Other methods are available for the synthesis of 1,2,3-tri-
azoles such as the condensation of alkyl diazoacetoace-
tates
with
phenyl-substituted
hydrazines,23,24
condensation of α-diazocompounds with amines followed
by electrocyclization,25,26 cyclization of cyano-2-aryl-hy-
drazones,27 coupling of allyl carbonates with trimethylsi-
lyl azide catalyzed by [Pd2(dba)3],28 NH-arylation
SYNLETT 2013, 24, 0041–0044
Advanced online publication: 06.12.2012
DOI: 10.1055/s-0032-1317712; Art ID: ST-2012-D0795-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

42
A. T. Gomes et al.
LETTER
catalyzed by palladium,29 and addition and cyclization be- triazole derivatives 8a–c were formed (Scheme 3). All the
1
tween ethyl cyanoacetate and aromatic azides.30
obtained compounds were fully characterized by H and
13C NMR spectroscopy and HRMS (ESI) analysis.34
Based on our interest in the establishment of new synthet-
ic methodologies leading to new potential bioactive 1H- The formation of compounds 8a–c results from the addi-
1,2,3-triazoles, the work presented herein describes the tion of a second acetonitrile molecule to C-4. This phe-
synthesis of 5-amino-1H-1,2,3-triazoles by consecutive nomenon was not observed when the reaction was
tandem cycloaddition between nonactivated nitriles and performed with propanonitrile since the C-4 position is
azides. Scheme 1 shows a comparison between literature blocked by the methyl group.
data and the present studies on the synthesis of 5-amino-
1,2,3-triazoles.
O
1) MeCN (excess)
THF, BuLi, 0 °C to r.t.
N
2) H2O
N
EWG
NH2
R
N3
N
NH2
EWG
CN
N
N
5
(a)
(b)
R–N3
R
N
(literature)
R
8a, R = Ph, 41%
8b, R = 4-ClC6H4, 30%
8c, R = 4-MeOC6H4, 46%
R2
R2
CN
N
N
R1–N3
NH2
Scheme 3 Synthesis of 1-(5-amino-1H-1,2,3-triazol-4-yl)ethanone
8a–c
(this work)
N
R1
The proposed mechanism of this reaction is shown in
Scheme 4. This mechanism involves the consecutive tan-
dem cycloaddition of the lithium carbanion of the nitrile
derivatives to the azides 5. When the reactions were per-
formed with one equivalent of nitrile, the addition of wa-
ter causes aromatization and formation of the amino group
at position C-5. When the reaction is conducted with an
excess of acetonitrile, addition of a second acetonitrile
molecule occurs after the cycloaddition, followed by the
addition of water, leading to aromatization, the formation
of the carbonyl group at C-4, and the amino group at C-5.
R1
= Ph, 4-ClC6H4, 4-MeOC6H4,
O
O
O
O
O
R2
= H, Me
Scheme 1 Comparison between literature data (a) and the present
studies (b) on the synthesis of 5-amino-1,2,3-triazoles
Azide derivatives 5 were prepared according to the litera-
ture procedure.3 The reactions of the lithium carbanion,
generated by the addition of BuLi to alkyl nitriles 6, with
azides 5 gave rise to the new 5-amino-1H-1,2,3-triazoles
(7a–h) in good yields (Scheme 2).31 The structures of
R2
N
Li
R2
N
N
1) BuLi,
THF, –78 °C
CH
C
N
R2CH2CN
N
N
R1
2) R1-N3 (5)
N
N
1
R1
these compounds were assigned on the basis of their H
and 13C NMR spectra, and their molecular compositions
were confirmed by HRMS (ESI) analysis.32
If R2 = H and
excess of MeCN
H2O
R2 CH2CN 6 (1 equiv)
1)
R2
Li
N
THF, BuLi, 0 °C to r.t.
2) H2O
N
N
N
N
C
R2
N
R1
N3
N
N
Me
N
N
N
N
NH2
N
5
Me
HN
R1
N
R1
H2N
HN
R1
R1
7a, R1 = Ph, R2 = H, 84%
7b, R1 = Ph, R2 = Me, 61%
7a–h
R
2 = H or Me
H2O
7c, R1 = 4-ClC6H4, R2 = H, 82%
7d, R1 = 4-ClC6H4, R2 = Me, 76%
7e, R1 = 4-MeOC6H4, R2 = H, 85%
7f, R1 = 4-MeOC6H4, R2 = Me, 86%
7g, R1 = galactopyranosyl, R2 = H, 82%
7h, R1 = galactopyranosyl, R2 = Me, 54%
O
NH
N
N
N
N
Me
H2O
Me
N
N
H2N
8a–c
R1
H2N
R1
Scheme 2 Synthesis of 5-amino-1H-1,2,3-triazoles 7a–h
Scheme 4 Proposed mechanism for the formation of aminotriazoles
7a–h and 8a–c
However, when the reaction was performed under the
same conditions but with an excess of acetonitrile,33 new
Synlett 2013, 24, 41–44
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 5-Amino-1H-[1,2,3]-triazoles
43
(18) Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R. Jr. J.
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In conclusion, this study reports a new methodology with
which to prepare novel 5-amino-1H-1,2,3-triazoles in-
volving consecutive tandem cycloaddition between non-
activated nitriles and azides. This approach allows the
synthesis of 5-amino-1,2,3-triazoles that are not easily ob-
tained by other procedures under mild conditions.
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(31) Preparation of Compounds 7a–h; General Procedure:
To a solution of BuLi (2 mmol) in anhydrous THF (1.5 mL),
was added a solution of the nitrile (acetonitrile or
propionitrile; 2 mmol) in anhydrous THF (2 mL) at 0 °C and
under an argon atmosphere. After 5 min, a solution of azide
derivative 5 (2 mmol) in anhydrous THF (2 mL) was added.
The reaction was allowed to warm to r.t. and monitored by
TLC. Distilled H2O (10 mL) was then added and the mixture
was extracted with EtOAc. The organic layer was dried with
sodium sulfate, filtered, and evaporated under reduced
pressure. The residue was purified by column
Acknowledgment
Thanks are due to the University of Aveiro (Aveiro, Portugal) and
Universidade Federal Fluminense (Niterói, RJ, Brazil), CNPq,
CAPES, FAPERJ and FCT/CAPES collaborative programme for
funding. This work was partially supported by CNPq-FAPERJ.
A.T.P.C.G. also thanks FCT for her research grant
(SFRH/BPD/79521/2011).
References and Notes
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chromatography on silica gel eluting with increasing
polarity gradient mixture of hexane and EtOAc.
(32) 1-Phenyl-1H-1,2,3-triazole-5-amine (7a): Yield: 84%;
white solid; mp 107.4–108.2 °C. IR (KBr): 3446 (N-H) cm–1;
1H NMR (CDCl3–MeOD, 300 MHz): δ = 5.64 (br s, 2 H,
NH2), 6.75 (s, 1 H, H-4), 6.78–6.93 (m, 1 H, H-4′), 7.07–
7.11 (m, 2 H, H-3′ and H-5′), 7.24–7.30 (m, 2 H, H2′–H-6′);
13C NMR (CDCl3–MeOD, 75 MHz): δ = 128.8 (C-Ph),
120.0 (C-2′ and C-6′), 125.8 (C-4′), 130.1 (C-3′ and C-5),
134.60, 135.5; HRMS (ESI): m/z [M + H]+ calcd for C8H9N4:
161.1833; found: 161.0924.
4-Methyl-1-phenyl-1H-1,2,3-triazole-5-amine (7b):
Yield: 61%; white solid; mp 127.5–128.9 °C. IR (KBr):
3381 (N-H) cm–1; 1H NMR (CDCl3–MeOD, 300 MHz): δ =
δ 2.23 (s, 3 H, CH3), 3.82 (br s, 2 H, NH2), 7.41–7.58 (m,
5 H, H-Ph); 13C NMR (CDCl3–MeOD, 75 MHz): δ = 9.5
(CH3), 123.8 (C-Ph), 126.0, 128.8 (C-Ph), 129.6 (C-Ph),
135.60, 137.5; HRMS (ESI): m/z [M + H]+ calcd for
C9H11N4: 175.2099; found: 175.0977.
1-(4-Chlorophenyl)-1H-1,2,3-triazole-5-amine (7c):
Yield: 82%; brown solid; mp 118.6–119.7 °C. IR (KBr):
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 41–44

44
A. T. Gomes et al.
LETTER
3297 (N-H), 831 (C-Cl) cm–1; 1H NMR (DMSO-d6, 500
MHz): δ = 5.78 (br s, 2 H, NH2), 7.06 (s, 1 H, H-4), 7.75 (s,
4 H, H-2′, H-3′, H-5′ and H-6′); 13C NMR (CDCl3, 125
MHz): δ = 116.97 (C-5), 125.31 (C-Ph), 128.55 (C-1′),
129.43 (C-Ph), 132.70 (C-6′), 134.58 (C-4′); HRMS (ESI):
m/z [M + H]+ calcd for C8H8ClN4: 195.6284; found:
195.0431.
1-(4-Chlorophenyl)-4-methyl-1H-1,2,3-triazole-5-amine
(7d): Yield: 76%; yellow solid; mp 139.6–140.3 °C; IR
(KBr): 3340 (N-H), 834 (C-Cl) cm–1; 1H NMR (CDCl3–
MeOD, 300 MHz): δ = 2.25 (s, 3 H, CH3), 7.51 (s, 2 H, H-3′
and H-5′), 7.52 (s, 2 H, H-2′ and H-6′); 13C NMR (CDCl3–
MeOD, 75 MHz): δ = 9.4 (CH3), 124.9 (C-3′ and C-5′), 126.4
(C-5), 129.7 (C-2′ and C-6′), 134.0 (C-4), 134.6 (C-1′), 137.4
(C-4′); HRMS (ESI): m/z [M + H]+ calcd for C9H10ClN4:
209.6550; found: 209.0586.
1-(1,2:3,4-Di-O-isopropylideno-α-D-galactopyranosyl)-
1H-1,2,3-triazole-5-amine (7g): Yield: 82%; yellow solid;
mp 179.0–181.4 °C; IR (KBr): 3410 (N-H), 2922 (C-C sugar
unit), 2853 (C-C sugar unit), 1002–1212 (C-O-C sugar unit)
cm–1; 1H NMR (CDCl3–MeOD, 500 MHz): δ = 1.28 (s, 3 H,
CH3), 1.36 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 1.51 (s, 3 H,
CH3), 4.14–4.25 (m, 2 H, H-5′ and H-6′), 4.26–4.40 (m, 2 H,
H-4′ and H-6′), 4.49 (dd, J = 2.5, 4.0 Hz, 1 H, H-2′), 4.64
(dd, J = 7.8, 2.5 Hz, 1 H, H-3′), 5.50 (d, J = 4.0 Hz, 1 H, H-
1′), 7.04 (s, 1 H, H-4); 13C NMR (CDCl3–MeOD, 125 MHz):
δ = 24.4 (CH3), 24.8 (CH3), 25.9 (CH3), 26.0 (CH3), 49.6 (C-
6′), 68.6 (C-5′), 70.4 (C-2′), 70.6 (C-3′), 71.1 (C-4′), 96.1 (C-
1′), 109.3, 109.8; HRMS (ESI): m/z [M + H]+ calcd for
C14H23N4O5: 327.3557; found: 327.1659.
1-(1,2:3,4-Di-O-isopropylideno-α-D-galactopyranosyl)-4-
methyl-1H-1,2,3-triazole-5-amine (7h): Yield: 54%; white
solid; mp 204.2–205.6 °C; IR (KBr): 3450 (N-H), 2987 (C-
C sugar unit), 2851 (C-C sugar unit), 1070–1237 (C-O-C
sugar unit) cm–1; 1H NMR (CDCl3–MeOD, 300 MHz): δ 1H
NMR (CDCl3–MeOD, 300 MHz): δ = 1.36 (s, 3 H, CH3),
1.49 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 1.57 (s, 3 H, CH3),
2.34 (s, 3 H, CH3), 4.15–4.20 (m, 1 H, H-5′), 4.45–4.55 (m,
2 H, H-6′), 4.31 (dd, J = 7.9, 1.9 Hz, 1 H, H-4′), 4.34 (dd, J
= 5.0, 2.5 Hz, 1 H, H-2′), 4.65 (dd, J = 7.9, 2.6 Hz, 1 H, H-
3′), 5.58 (d, J = 5.0 Hz, 1 H, H-1′′); 13C NMR (CDCl3–
MeOD, 75 MHz): δ = 24.3 (CH3), 24.6 (CH3), 25.6 (CH3),
25.8 (CH3), 44.4 (C-6′), 65.6 (C-5′), 70.4 (C-2′), 70.6 (C-3′),
70.8 (C-4′), 97.3 (C-1′), 107.9, 108.7; HRMS (ESI): m/z [M
+ H]+ calcd for C15H25N4O5: 341.3823; found: 341.1695.
(33) Preparation of 8a–c; General Procedure: To a solution of
BuLi (2 mmol) in anhydrous THF (1.5 mL), was added a
solution of the acetonitrile (4 mmol) in anhydrous THF (2.0
mL) at 0 °C under an argon atmosphere. After 5 min, a
solution of azide derivative 5 (2 mmol) in anhydrous THF
(2.0 mL) was added. The reaction was allowed to warm to
r.t. with monitoring by TLC. Distilled water (10 mL) was
then added, the mixture was extracted with EtOAc and the
organic layer was dried with sodium sulfate, filtered, and
evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel and eluted with
increasing polarity gradient mixture of hexane and ethyl
acetate.
(34) 4-Methyl-1-(5-amino-1-phenyl-1H-1,2,3-triazole-4-
yl)ethanone (8a): Yield: 41%; white solid; mp 208.4–
209.8 °C; IR (KBr): 3293 (N-H), 1664 (C=O) cm–1; 1H
NMR (CDCl3, 300 MHz): δ = 2.16 (s, 3 H, CH3), 7.10 (t, J =
7.9 Hz, 1 H, H-4′), 7.30 (d, J = 7.9 Hz, 2 H, H-3′ and H-5′),
7.50 (d, J = 7.9 Hz, 2 H, H-2′ and H-6′), 7.60 (br s, 2 H,
NH2); 13C NMR (CDCl3, 75 MHz): δ = 24.5 (CH3), 119.9 (C-
2′ and C-6′), 124.3 (C-4′), 128.9 (C-3′ and C-5′), 137.9,
168.5; HRMS (ESI): m/z [M + H]+ calcd for C10H11N4O:
203.2200; found: 203.1021.
1-[5-Amino-1-(4-chlorophenyl)-1H-1,2,3-triazole-4-
yl]ethanone (8b): Yield: 30%; white solid; mp 210.7–
211.2 °C; IR (KBr): 3359 (N-H), 1658 (C=O) cm–1; 1H
NMR (CDCl3, 500 MHz): δ = 2.64 (m, 3 H, COCH3), 5.66
(s, 2 H, NH2), 7.49 (d, J = 7.5 Hz, 2 H, H-3′ and H-5′), 7.56
(d, J = 7.5 Hz, 2 H, H-2′ and H-6′); 13C NMR (CDCl3, 125
MHz): δ = 26.2 (CH3), 125.0 (C3′ and C-5′), 129.6 (C-5),
130.3 (C-2′ and C-6′), 132.6 (C-4′), 135.7 (C-1′), 144.2 (C-
4), 193.8 (C=O); HRMS (ESI): m/z [M + H]+ calcd for
C10H10ClN4O: 237.6651; found: 237.0536.
1-[5-Amino-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-
yl]ethanone (8c): Yield: 46%; brown solid; mp 206.4–
207.8 °C; IR (KBr): 3324 (N-H), 1656 (C=O) cm–1; 1H
NMR (CDCl3, 300 MHz): δ = 2.66 (s, 3 H, CH3), 3.88 (s,
3 H, OCH3), 5.54 (br s, 2 H, NH2), 7.07 (d, J = 9.0 Hz, 2 H,
H-3′ and H-5′), 7.42 (d, J = 9.0 Hz, 2 H, H-2′ and H-6′); 13
C
NMR (CDCl3, 75 MHz): δ = 26.2 (CH3), 55.6 (OCH3), 115.3
(C-3′ and C-5′), 125.8 (C-3′ and C-5′), 129.6, 144.5, 160.5
(C=O); HRMS (ESI): m/z [M + H]+ calcd for C10H13N4O2:
233.2460; found: 233.1031.
Synlett 2013, 24, 41–44
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