One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from aldehydes and amines

Article abstract of DOI:10.1055/s-0029-1218267

A one-pot, three-step synthesis of 1,4-disubstituted 1,2,3-triazoles from aldehyde and amine has been developed by in situ transformation of aldehyde into alkyne, followed by diazo-transfer of amine into azide and subsequent cycloaddition. This procedure allowed the synthesis of fluorescent amino acid derivatives as well as glycoconjugate mimetics. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218267

LETTER
2977
One-Pot Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Aldehydes and
Amines
Synthesis of
1
t
é
bstituted 1,
p
2,3-Triazole
hane Maisonneuve, Juan Xie*
PPSM, Institut d’Alembert, ENS de Cachan, CNRS UMR 8531, 61 Avenue du Président Wilson, 94235 Cachan, France
Fax +33(1)47405586; E-mail: joanne.xie@ens-cachan.fr
Received 17 July 2009
With a continuing interest in click chemistry,18 we decid-
ed to investigate a one-pot synthesis of 1,4-disubstituted
1,2,3-triazoles from aldehydes and amines, in light of the
great variety of commercially available aldehydes and
Abstract: A one-pot, three-step synthesis of 1,4-disubstituted
1,2,3-triazoles from aldehyde and amine has been developed by in
situ transformation of aldehyde into alkyne, followed by diazo-
transfer of amine into azide and subsequent cycloaddition. This pro-
cedure allowed the synthesis of fluorescent amino acid derivatives amines. Such chemistry should not only circumvent the
as well as glycoconjugate mimetics.
isolation of the alkyne and azide intermediates, hence sav-
ing time, reagents, and solvents, but also broaden the
scope and application of the CuAAC. Herein, we report a
one-pot, three-step synthesis of triazoles from alkyl
amines and aryl or alkyl aldehydes.
Key words: aldehydes, amines, cycloadditions, one-pot reaction,
triazoles
The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition1
between terminal alkynes and organic azides (also known
as ‘click chemistry’) has been extensively used and found
wide application in organic synthesis, medicinal chemis-
try, molecular biology, polymer and materials science be-
cause of its high efficiency, versatility, regioselectivity,
and excellent functional-group compatibility.2 The cop-
per-catalyzed alkyne–azide cycloaddition (CuAAC) usu-
ally proceeds at room temperature in water with a variety
of organic co-solvents, such as t-BuOH, EtOH, THF,
DMSO, MeCN, CH2Cl2, or PEG-400. In addition, the
1,2,3-triazole ring is resistant to hydrolysis, oxidation, re-
duction, or other modes of cleavage. Due to their electron-
ic properties, 1,2,3-triazoles have been employed as rigid
linking units to mimic amide and ester bonds.2d,3 These
important features have allowed the synthesis of complex
molecules including dendrimers, bioconjugates, function-
alized polymers, and various bioactive compounds.
Homologation of an aldehyde to the corresponding alkyne
can be easily realized using the Bestmann–Ohira reagent
under mild basic conditions.15,19 One-step transformation
of an amine to azide is possible with the diazo-transfer
reaction, usually catalyzed by transition-metal ions such
as Cu(II), Ni(II), or Zn(II) under basic conditions. Triflu-
oromethanesulfonyl (triflyl) azide has been successfully
used to convert various amines to organic azides in the
presence of Cu(II) as an efficient catalyst.13,20 However,
triflyl azide is hard to handle because of its inherent ten-
dency to explode. Furthermore, excess triflyl azide usual-
ly has to be used since it is difficult to determinate its
exact concentration in CH2Cl2 solution.13 In 2007, God-
dard–Borger and Stick reported the synthesis of imida-
zole-1-sulfonyl azide hydrochloride as an efficient and
shelf-stable diazo-transfer reagent.21 This reagent, as an
efficient alternative to triflyl azide, converted a diverse
range of amines into the corresponding azides with excel-
lent yield.21,22 We thus decided to use imidazole-1-sulfo-
nyl azide 2 as the diazo-transfer reagent in order to control
the quantity of 2 (1 equiv/amine), which is of crucial im-
portance to realize a one-pot reaction. It should be noted
that, in the presence of catalytic Cu(I), sulfonyl azide it-
self can react with terminal alkyne to N-sulfonyltriazole
which can then rearrange to a keteneimine intermediate,
leading to amidines, imidates, or amides in the presence of
amines, alcohols, or water, respectively.23 Our prelimi-
nary experiments indicated that ethynyl pyrene did not
react with imidazole-1-sulfonyl azide 2 in the presence of
CuSO4 and K2CO3 in a mixture of CH2Cl2–MeOH; condi-
tions generally used for the one-pot diazo-transfer reac-
tion. Another advantage to use 2 is its easy detection on
TLC which is useful to follow the diazo-transfer reaction.
Many organic azides and terminal alkynes are not com-
mercially available. Moreover, low molecular weight or-
ganic azides can be unstable4 and difficult to handle. To
avoid the isolation of azide partner and in searching for
step-economic synthesis, one-pot CuAAC with in situ
generated organic azides has been developed for alkyl or
aryl halides,5 a-haloketones,6 tosylates,7 boronic acids,8
epoxides,9 secondary alcohols,10 glucals,11 unprotected
monosaccharides,12 alkyl13 and aromatic amines.14 One-
pot synthesis of triazoles with in situ generated terminal
alkynes15 or benzyne16 has also been explored. However,
to the best of our knowledge, there is only one report con-
cerning an in situ generated aromatic azide and benzyne
for benzyne click chemistry.17
We started our investigation with fluorescent pyrene car-
boxaldehyde 3 because pyrenyl-substituted molecules ex-
hibited attractive fluorescent properties24 useful for the
labeling of biomolecules25 or for the detection of metal
SYNLETT 2009, No. 18, pp 2977–2981
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218267; Art ID: D19109ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2978
S. Maisonneuve, J. Xie
LETTER
Table 1 One-Pot, Three-Step Synthesis of 1,2,3-Triazoles from Pyrene Carboxaldehyde and Amino Esters
O
O
P
OMe
OMe
K2CO3, CH2Cl2–MeOH (1:1), r.t., 6 h
N
N
N
N2
1
R
CHO
N
SO2N3
RNH2, CuSO4, r.t., 1–4 h
then
N
2
3
then Na ascorbate or ascorbic acid, r.t., overnight
Entry
1
Amine
Product
Yield (%)a,b
45
Yield (%)a,c
N
N
O
N
NH3Cl
57
CO2Me
O
4
5
12
OH
N
N
OH
N
O
CO2Me
2
3
4
32
30
27
67
NH3Cl
O
13
14
15
Ph
N
Ph
N
N
CO2Me
O
92
46
NH3Cl
O
6
7
i-Bu
N
N
i-Bu
N
O
CO2Me
NH3Cl
O
N
N
N
O
5
6
7
26
52
51
51
CO2Me
NH3Cl
O
8
9
16
17
CO2Me
N
CO2Me
NH3Cl
N
N
CO2Me
CO2Me
CONH
O
O
OH
OH
N
N
N
O
NH3Cl
O
10
18
19
N
CO2Bn
OBn
N
N
H
N
8
32
+
–
O
NH3
CF3CO2
O
11
a Isolated yield.
b Conditions: 1.2 equiv of Na ascorbate were used.
c Conditions: 4 equiv of ascorbic acid were used.
Synlett 2009, No. 18, 2977–2981 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
2979
ions.26 As azide precursors, natural amino acids deriva- We subsequently tested the scope of this one-pot process
tives were chosen in order to obtain fluorescent amino ac- with other aromatic aldehydes (Table 2). Reaction of al-
ids derivatives. Compound 3 was treated with 1.8 dehydes 20–22 with Tyr-OMe led successfully to the cor-
equivalents of the Bestmann–Ohira reagent (1) and 4 responding triazoles 23–25 in 45–75% yields.
equivalents of K2CO3 in a 1:1 mixture of CH2Cl2 and
Synthesis of triazole-linked glycopeptides and oligosac-
MeOH at room temperature. Upon complete homologa-
charides has recently been reported, providing useful
tion of the aldehyde (TLC monitoring, 6 h), amine·HCl
building blocks or mimetics of natural ones.29 We there-
(1.2 equiv), CuSO4 (1.2 equiv), and imidazole-1-sulfonyl
fore also examined the possibility of preparing glycocon-
jugates by this one-pot procedure. Treatment of galactosyl
aldehyde 26 with Tyr-OMe led to the desired glycosyl de-
azide 2 (1.2 equiv) were then added to the reaction mix-
ture. After disappearance of 2 on TLC (1–4 h), sodium
ascorbate (1.2 equiv) was then introduced to accomplish
the cycloaddition. As shown in the Table 1, for amino es-
rivative 27 in 49% yield (Scheme 1). Reaction of alde-
hyde 26 with the C-glycosyl ethylamine 2830 afforded the
ters 4–8, the corresponding triazoles were isolated in 27–
corresponding triazole-linked C-disaccharide 29.
45% yields (entries 1–5). Careful examination of the liter-
In summary, a one-pot, three-step sequential synthesis of
ature data showed that basic conditions could influence
triazoles has been developed from various aldehydes and
amines. To the best of our knowledge, the present work is
the first example of in situ generation of both terminal
alkyne and organic azide for the click reaction. Not only
aryl aldehydes, but also glycosyl aldehydes can be used as
alkyne precursors. As azide precursors, amino esters,
dipeptides as well as C-glycosyl amines have been proven
successful. We have demonstrated that this procedure can
be used for the synthesis of fluorescent amino acid and
peptide derivatives and for the synthesis of glycoconju-
gate mimetics.
the CuAAC and favor the formation of byproducts.27
Since the CuAAC is usually realized under neutral condi-
tions with CuSO4/Na ascorbate as catalyst, we decided to
introduce ascorbic acid in place of sodium ascorbate dur-
ing the third step, to neutralize the reaction mixture
(K2CO3 in excess) and reduce Cu(II) to Cu(I). Improved
yields were thus obtained; compounds 12–16 being isolat-
ed in 46–92% yield.28 For the amino esters of Asp and Tyr
9 and 10 (entries 6 and 7), the corresponding triazoles
were obtained in 51% yield. One-pot reaction of the
dipeptide 11 led also to the corresponding triazole 19 in
32% yield (entry 8).
Table 2 One-Pot, Three-Step Synthesis of 1,2,3-Triazoles from Tyr-OMe·HCl and Aldehydes
N
N
OH
1, K2CO3, CH2Cl2–MeOH (1:1), r.t., 1–6 h
RCHO
N
then 2, Tyr-OMe⋅HCl, CuSO4, r.t., 1–4 h
then ascorbic acid, r.t., one night
R
CO2Me
Entry
Aldehyde
Product
Yield (%)a
OH
NO2
NO2
N
N
1
2
3
75
N
CHO
20
CO2Me
23
OH
Br
Br
N
N
57
45
N
CHO
CO2Me
21
24
OH
Ph2N
Ph2N
N
N
N
CHO
CO2Me
22
25
a Isolated yield.
Synlett 2009, No. 18, 2977–2981 © Thieme Stuttgart · New York

2980
S. Maisonneuve, J. Xie
LETTER
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OH
N
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O
N
CHO
1, K2CO3, r.t., 4 h
CH2Cl2, MeOH (1:1)
N
O
O
CO2Me
O
O
then 2, 10, 5 h
then ascorbic acid
r.t., overnight
O
O
O
O
O
26
26
49%
27
OBn
O
BnO
BnO
1, K2CO3, r.t., 4 h
CH2Cl2–MeOH (1:1)
AcHN
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N
N
OBn
O
then 2,
O
N
BnO
BnO
5 h
O
O
AcHN
28
O
O
NH2
29
then ascorbic acid
r.t., overnight
24%
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Scheme 1 One-pot, three-step synthesis of glycoconjugates
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(28) General Procedure
To a solution of aldehyde (1 equiv) in a mixture MeOH–
CH2Cl2 (4 mL/4 mL for 0.5 mmol of aldehyde) were added
K2CO3 (4 equiv) and the Bestmann–Ohira reagent (1.8
equiv). The mixture was stirred at r.t. until complete
conversion of aldehyde to alkyne (TLC monitoring –
6 h maximum). Amine hydrochloride salt (1.2 equiv),
CuSO5·5H2O (1.2 equiv) and the imidazole-1-sulfonyl azide
(1.2 equiv) were then added to the reaction mixture and
stirred at r.t. to transform the amine into the azide
intermediate. Reaction was judged to be complete when
imidazole-1-sulfonyl azide spot disappeared on TLC (4 h
maximum). Finally, ascorbic acid (4 equiv) was added, and
the reaction was stirred at r.t. overnight. The mixture was
filtered through a pad of Celite, washed with MeOH, and the
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Synlett 2009, No. 18, 2977–2981 © Thieme Stuttgart · New York

LETTER
solvents evaporated under vacuum. The residue was purified
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
2981
3.67 (dd, 1 H, J = 6.4, 10.1 Hz), 3.90 (dd, 1 H, J = 7.4, 10.1
Hz), 3.95–3.97 (m, 1 H), 4.11–4.13 (m, 1 H), 4.25 (t, 1 H,
J = 6.8 Hz), 4.37 (dd, 1 H, J = 2.8, 5.0 Hz), 4.39–4.51 (m, 6
H), 4.55–4.59 (m, 3 H), 4.70 (dd, 1 H, J = 2.3, 7.8 Hz), 5.19
(d, 1 H, J = 1.8 Hz), 5.60 (d, 1 H, J = 5.0 Hz), 6.60 (d, 1 H,
J = 9.6 Hz), 7.20–7.33 (m, 15 H), 7.65 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 23.4, 24.3, 25.1, 26.1, 26.3 (CH3),
32.4, 46.9 (CH2), 47.8, 64.7, 65.3 (CH); 67.6 (CH2), 70.8,
70.9 (CH); 72.0, 72.3 (CH2), 72.7, 73.2 (CH), 73.4 (CH2),
74.2, 75.1, 77.3 (CH), 96.7 (CH), 109.0, 109.3 (C), 123.6,
127.8, 127.9, 128.6, 128.7 (CH), 137.3, 137.5, 138.2, 145.1,
170.0 (C). ESI-HRMS: m/z calcd for C44H54N4NaO10:
821.3738; found: 821.3732.
by column chromatography on silica gel (40–63 mM) to
afford the triazoyl compound.
Analytical Data for Selected Compounds
Compound 12: mp 191 °C; Rf = 0.55 (EtOAc–cyclohexane
= 1:1); [a]D –89.2 (c 0.48, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d = 3.89 (s, 3 H), 5.37 (s, 2 H, CH2), 8.01–8.29 (m,
9 H), 8.67 (d, 1 H, J = 9.2 Hz). 13C NMR (100 MHz, CDCl3):
d = 51.0 (CH2), 53.3 (CH3), 124.3, 124.7, 125.0, 125.3,
126.2, 127.3, 127.5, 128.0, 128.4, 128.7 (CH), 131.0, 131.4,
131.5, 148.0, 166.9 (C). ESI-HRMS: m/z calcd for
C21H15N3NaO2: 364.1062; found: 364.1057.
Compound 29: mp 114 °C; Rf = 0.48 (EtOAc); [a]D –35.2 (c
0.47, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 1.31 (s, 3
H), 1.36 (s, 3 H), 1.45 (s, 3 H), 1.60 (s, 3 H), 1.83 (s, 3 H),
1.83–2.01 (m, 2 H), 3.52–3.53 (m, 1 H), 3.61–3.63 (m, 1 H),
(29) Dondoni, A. Chem. Asian J. 2007, 2, 700.
(30) Xie, J.; Thellend, A.; Becker, H.; Vidal-Cros, A. Carbohydr.
Res. 2001, 334, 177.
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