Copper (I)-mediated synthesis of trisubstituted 1,2,3-triazoles

Article abstract of DOI:10.1055/s-2005-921919

A copper-catalysed coupling of bromo-alkynes and organic azides is described. This coupling results in the formation of bromo-containing trisubstituted 1,2,3-triazole derivatives in high yield and a regioselective manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921919

LETTER
3059
Copper(I)-Mediated Synthesis of Trisubstituted 1,2,3-Triazoles
Synthesis of
Tris
r
i
d 1, 2,3-
a
T
riazoles n H. M. Kuijpers,a Guido C. T. Dijkmans,a Stan Groothuys,a Peter J. L. M. Quaedflieg,b Richard H. Blaauw,c
Floris L. van Delft,a Floris P. J. T. Rutjes*a
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: F.Rutjes@science.ru.nl
b
DSM Research, Life Sciences–Advanced Synthesis, Catalysis and Development, P.O. Box 18, 6160 MD Geleen, The Netherlands
c
Chiralix B.V., Toernooiveld 100, 6525 EC Nijmegen, The Netherlands
Received 15 September 2005
Given the fact that the acetylene proton plays an essential
role in the proposed mechanism for the Cu(I)-catalysed
‘click reaction’, we were intrigued by the question if
bromo-substituted acetylenes would also undergo [3+2]
cycloaddition under similar conditions. Bromoacetylenes9
are stable compounds, readily prepared in quantitative
yields from acetylenes upon the action of NBS and cata-
lytic AgNO3 and would afford versatile trisubstituted tri-
azoles in one step. Thus, we selected p-nitrobenzylazide
(1) and methyl bromopropiolate (2) for model studies, the
results of which are summarised in Table 1. In the first ex-
periment (entry 3), a 1:1 mixture of 1 and 2 in THF was
subjected to 10 mol% of CuI. It was intriguing to find that
a reaction took place and a 4:1 mixture of bromo- and
iodo-substituted 1,4-disubstituted triazole10 was formed.
More promising than that, the low yield (32%) of this re-
action could easily be raised to 78% upon heating to 55 °C
(entry 4).11 Encouraged by these results and the finding
that Cu-catalysis plays an essential role in this mechanism
(entries 1 and 2), we investigated the influence of other Cu
salts (e.g., CuCN, Cu(OAc)2, CuBr, CuCl) and solvents
(e.g., CH2Cl2, DMF, MeCN, Et2O and toluene). In most
cases, however, only small amounts of the desired com-
pound could be isolated. Much to our satisfaction though,
upon the combined action of CuI and Cu(OAc)2, the con-
version could be greatly improved to 66% at room tem-
perature (entry 6) and was driven to completion upon
prolonging the reaction time or heating to 50 °C (entries 7
and 9).
Abstract: A copper-catalysed coupling of bromo-alkynes and
organic azides is described. This coupling results in the formation
of bromo-containing trisubstituted 1,2,3-triazole derivatives in high
yield and a regioselective manner.
Key words: 1,4,5-trisubstituted-1,2,3-triazole, click reaction,
[3+2] dipolar cycloaddition, Cu-catalysis, glycopeptide
1,2,3-Triazoles are versatile compounds, which are
applied for strongly varying purposes including anti-
corrosive agents, dyes, agrochemicals and photographic
materials.1 Although the 1,2,3-triazole structural moiety
does not occur in nature, it features in diverse biologically
active substances displaying anti-HIV2 and anti-
microbial3 behaviour as well as selective b3-adrenergic re-
ceptor agonism.4 After the synthesis of 1,2,3-triazoles had
been studied intensively for many years,5 recently a new
and powerful method was developed. The groups of
Meldal and Sharpless independently discovered that Cu(I)
salts efficiently catalyse the [3+2] cycloaddition between
organic azides and acetylenes (‘click reactions’) giving
the corresponding 1,4-disubstituted-1,2,3-triazoles regio-
selectively in generally high yields.6 Most of these proce-
dures, however, lead to disubstituted triazoles, while
methods for the synthesis of trisubstituted triazoles are
less well studied. The latter methods are frequently ham-
pered by a lack of regioselectivity or by a restriction in
choice of functional groups.7 Chen et al. recently pub-
lished a method for the preparation of 5-iodo-1,4-disubsti-
tuted-1,2,3-triazoles from acetylenes and azides using a
combination of stoichiometric amounts of CuI and ICl
The methodology was applicable to a variety of substrates
with yields averaging around 70%.8 Although this repre-
sents a one-pot procedure to this compound class,
equimolar quantities of copper salts are required.
In cases where CuI was used, a small amount of the corre-
sponding 5-iodotriazole 4 was also formed. To circum-
vent the formation of iodide 4 a CuBr/Cu(OAc)2 couple
was used, which provided solely the 5-bromo-1,4-disub-
stituted triazole 3, albeit that the reaction proceeded sig-
nificantly slower (entry 10). In general, elevating the
temperature (entries 7 and 8) and increasing the amount of
catalyst (entries 11 and 12) independently accelerated the
reaction rate.
Prompted by this report, we wish to disclose our own
results in this area, focusing on the synthesis of trisub-
stituted 1,2,3-triazoles from organic azides and bromo-
acetylenes, mediated by a catalytic amount of a Cu(I)/
Cu(II) mixture.
We also investigated the possibility of synthesising 5-io-
dotriazoles starting from the corresponding iodo-acetyl-
enes using the CuI/Cu(OAc)2 couple, unfortunately the
iodoacetylenes appeared too unstable to survive the reac-
tion conditions so that in some cases no reaction occurred.
SYNLETT 2005, No. 20, pp 3059–3062
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-921919; Art ID: G30005ST
© Georg Thieme Verlag Stuttgart · New York

3060
B. H. M. Kuijpers et al.
LETTER
Table 1 Optimisation of the [3+2] Cycloaddition Conditions
NO2
NO2
Br
5 mol% of each catalyst
+
THF, temperature
N
CO2Me
N
N
N3
3: X = Br
4: X = I
1
2
X
CO2Me
Entry
1
Catalyst
Temp
r.t.
Time (h)
22
Conversiona
Trace
12%
Yield (%)d
3:4
–
100:0
100b:0
80:20
84b:16
n.d.
2
–
55 °C
r.t.
22
3
Cul
22
32%e
78%e
trace
4
Cul
55 °C
r.t.
22
5
Cu(OAc)2
CuI/Cu(OAc)2
CuI/Cu(OAc)2
CuI/Cu(OAc)2
CuI/Cu(OAc)2
CuBr/Cu(OAc)2
CuBr/Cu(OAc)2
CuBr/Cu(OAc)2
40
6
r.t.
16
66%
95:5
7
50 °C
reflux
r.t.
16
>99%
>99%
97%
99%
95%
93%
94:6
8
16
93b:7
95:5
9
40
10
11
12
r.t.
40
29%
100:0
100:0
100:0
r.t.
40
56%
50 °C
16
>99%
97%c
a Conversion determined by 1H NMR.
b Small amounts of the regioisomer were also detected.
c The amount of 20 mol% of both catalysts was used.
d Isolated yields.
e The amount of 10 mol% of catalyst was used.
Method A:
5 mol% CuI, 5 mol% Cu(OAc)2
THF, 50 °C
R2
azoles. In cases where a mixture of halide substituents is
not desired, Method B can be applied which leads solely
to the bromo-substituted triazoles.
R1
N
R1
N3
N
N
+
Br
R2
Method B:
20 mol% CuBr, 20 mol%
Cu(OAc)2
Br
THF, 50 °C
1) BuLi, –95 °C
N
N
Scheme 1 Optimised cycloaddition conditions
N
N
N
N
2) benzaldehyde
–95 °C
X
The optimal conditions that we eventually selected are
shown in Scheme 1. Using Method A, the reactions gen-
erally proceeded faster, but with the formation of small
amounts of the 5-iodotriazole by-products. This may not
be an issue in the case that the halide substituent is directly
reacted further to introduce other substituents such as in
palladium-catalyzed cross-coupling reactions as reported
by Chen et al.12 Alternatively, both halides can be ex-
changed by lithium, using BuLi at low temperature and
subsequently reacted with an appropriate electrophile
such as benzaldehyde to give the corresponding adduct 6
(Scheme 2). In connection with the previously mentioned
Pd-catalysed functionalisation, this example underlines
the versatility of these 5-halo-1,4-disubstituted-1,2,3-tri-
OH
6: 90%
5: X = Br:I 95:5
Scheme 2 Example of halogen–metal exchange
Having selected these two methods, an array of triazole
products was prepared. Figure 1 shows the products of the
reaction of p-nitrobenzylazide (1) with different acetyl-
enes. It becomes clear that the reaction tolerates different
acetylenes including electron-donating, electron-with-
drawing and sterically demanding ones as in the case of
products 10a and 10b. The yields are generally high for
both conditions, with a clear difference in reaction rate.
Synlett 2005, No. 20, 3059–3062 © Thieme Stuttgart · New York

LETTER
Synthesis of Trisubstituted 1,2,3-Triazoles
3061
NO2
several substituted benzylic azides were also successfully
used, leading to triazoles 11, 13–15. Again, it is clear that
Method B proceeds considerably slower than Method A.
However, by elongating the reaction times, the CuBr-me-
diated reactions can generally be driven to completion.
NO2
N
N
N
N
N
N
OH
We recently reported a method for the synthesis of stable
triazole-linked glycopeptides13 using ‘click chemistry’ to
couple acetylene-containing amino acids to azido-func-
tionalised monosaccharides and vice versa. Halide-con-
taining derivatives of these glycopeptides can be
synthesised using the aforementioned conditions, exem-
plified in Scheme 3. Thus, the bromo-substituted propar-
gylglycine derivative 16 was coupled to azidogalactoside
17, resulting in fair yields of the glycosidic amino acid
derivative 18 using both methods.
Br
Br
BocHN
CO2Me
7a: 88%a,b (16 h)
7b: 85% (76 h)
8a: 85%b (16 h)
8b: 92% (75 h)
Method A:
Method B:
NO2
NO2
N
N
N
N
N
N
Br
O
Br
OBn
Br
OAc
AcO
BnO
BnO
10a: 63% (16 h)b
10b: 99% (69 h)
OBn
OMe
Method A:
O
N
20 mol% CuI,
20 mol% Cu(OAc)2
THF, 50 °C
9a: 85%c,d (50 h)
9b: 83% (124 h)
N
N
AcO
BocHN
CO2Me
Method A:
Method B:
16
+
OAc
Br
a Reactions performed at r.t.
b Isolated as a 95:5 Br:I mixture.
c Isolated as a 84:16 Br:I mixture.
OAc
BocHN
CO2Me
AcO
AcO
Method B:
O
20 mol% CuBr,
20 mol% Cu(OAc)2
THF, 50 °C
18a: 16 h, 85% (Br:I 84:16)
18b: 50 h, 65%
N3
d Reactions were carried out with 20 mol% of each catalyst.
OAc
17
Figure 1 Variation of the bromoacetylene
Scheme 3 Synthesis of a 5-bromotriazole-linked glyco-amino acid
The products of the coupling of methyl bromopropiolate
(2) with a selection of organic azides are displayed in
Figure 2.
This new procedure provides, in addition to the Chen
method, an efficient and straightforward pathway into the
synthesis of trisubstituted 1,2,3-triazoles starting from
bromo-alkynes. In contrast to the method of Chen, only
catalytic amounts of catalyst are required. Furthermore,
the use of hazardous and strongly corrosive ICl is avoided.
NO2
OAc
AcO
O
N
To the best of our knowledge, these are the first examples
where isolable disubstituted acetylenes participate in a
Cu-mediated [3+2] cycloaddition. At present, the exact
mechanism remains unclear to us. One possibility is that
only Cu(I) species are involved. In this case the mecha-
nism would proceed via Cu–Br exchange, followed by cy-
cloaddition and subsequent reaction of the Cu(I)–triazole
complex with ‘Br+’. Other possibilities include an oxida-
tive addition–reductive elimination cycle, in which initial
oxidative addition of the bromoalkyne to Cu(I) leads to a
Cu(III) species, which is then followed by cycloaddition
to a Cu(III)–triazole complex, and subsequent reductive
elimination to the corresponding halo-triazole.
N
N
AcO
N
OAc
Br
N
N
CO2Me
Br
CO2Me
11a: 99%a (16 h)
11b: 97% (16 h)
12a: 83%a (16 h)
12b: 99% (140 h)
Method A:
Method B:
Br
Me
CO2Me
N
N
N
N
N
N
N
CO2Me
N
N
Br
CO2Me
Br
Br
CO2Me
In conclusion, we have shown that the Cu-catalysed reac-
tion between bromoalkynes and organic azides proceeds
readily to form the corresponding 5-bromo-1,2,3-triazole
derivatives in high yield and a regioselective manner. This
procedure therefore offers facile access to a variety of
halide-containing trisubstituted triazoles. The halogen
substituent offers multiple pathways for further metal-
mediated derivatisation. Further studies into the scope and
13a: 81%a,b (16 h) 14a: 80%a,b (40 h)
13b: 99% (164 h)
15a: 81%a,b (40 h)
Method A:
Method B:
a Isolated as a 95:5 Br:I mixture.
b Reactions were performed at r.t.
Figure 2 Variation of the azide
The reaction allows a variety of different azides, including applications of this method, as well as the exact mecha-
sterically demanding ones resulting in the monosaccha- nism, are currently under investigation.
ride-substituted triazoles 12a and 12b. Furthermore,
Synlett 2005, No. 20, 3059–3062 © Thieme Stuttgart · New York

3062
B. H. M. Kuijpers et al.
LETTER
1H- and 13C nuclear magnetic resonance (NMR) spectra were re-
corded on a Varian Inova 400 (400 MHz) or a Bruker DMX300
(300 MHz) spectrometer. The chemical shifts (d) are given in ppm
downfield from tetramethylsilane. Optical rotations were measured
on a Perkin-Elmer 241 polarimeter. IR spectra were recorded on an
ATI Mattson, Genesis series FTIR spectrometer. Low-resolution
mass spectra were recorded on a Thermo Finnigan LCQ, high-reso-
lution spectra were recorded on a Fisons (VG) 7070. Commercially
available reagents were used as received.
Acknowledgment
SenterNovem (Ministry of Economic Affairs, The Netherlands) is
gratefully acknowledged for providing financial support.
References
(1) For reviews see: (a) Fan, W.-Q.; Katritzky, A. R. In
Comprehensive Heterocyclic Chemistry II, Vol. 4;
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Elsevier: Oxford, 1996, 1–126. (b) Dehne, H. In Methoden
der organischen Chemie (Houben–Weyl), Vol. E8d;
Schaumann, E., Ed.; Thieme: Stuttgart, 1994, 305–405.
(c) Abu-Orabi, S. T.; Alfah, M. A. I.; Jibril Mari’I, F. M.;
Ali, A. A.-S. J. Heterocycl. Chem. 1989, 26, 1461.
(2) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.;
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(5) (a) Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967,
100, 2494. (b) For a recent review on synthesis of 1,2,3-
triazoles, see: Tome, A. C. In Science of Synthesis, Vol. 13;
Thieme: Stuttgart, 2004, 415–601.
(6) (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.
(7) For a selection of recent entries into trisubstituted triazole
synthesis, see: (a) Holzer, W.; Ruso, K. J. Heterocycl.
Chem. 1992, 29, 1203. (b) Ohta, S.; Kawasaki, I.; Uemura,
T.; Yamashita, M.; Yoshioka, T.; Yamaguchi, S. Chem.
Pharm. Bull. 1997, 45, 1140. (c) Uhlmann, P.; Felding, J.;
Vedsø, P.; Begtrup, M. J. Org. Chem. 1997, 9177.
(d) Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.;
Begtrup, M. Synthesis 1998, 1181. (e) Krasiński, A.; Fokin,
V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
(8) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314.
General Procedure for Method A
To a solution of the bromoacetylene (1 equiv) and the azide deriva-
tive (1 equiv) in dry THF (0.5 M) was added CuI (5 mol%) and
Cu(OAc)2 (5 mol%) The reaction was stirred at 50 °C. The solution
was concentrated, H2O was added and the product was extracted
with CH2Cl2 (2 × ). The combined organic layers were washed with
aq NaHCO3, aq NaCl, dried over MgSO4, and evaporated in vacuo.
The product was purified by flash chromatography using EtOAc–
heptane mixtures.
General Procedure for Method B
To a solution of the bromoacetylene (1 equiv) and the azide deriva-
tive (1 equiv) in dry THF (0.5 M) was added CuBr (20 mol%) and
Cu(OAc)2 (20 mol%) The reaction was stirred at 50 °C. The solu-
tion was concentrated, H2O was added and the product was extract-
ed with CH2Cl2 (2 ×). The combined organic layers were washed
with aq NaHCO3, aq NaCl, dried over MgSO4, and evaporated in
vacuo. The product was purified by flash chromatography using
EtOAc–heptane mixtures.
Data of Representative Products
Bromotriazole 3
White solid, 204 mg (0.60 mmol, 97%). Rf = 0.38 (EtOAc–heptane,
1
1:1). IR (film): n = 2954, 1722, 1519, 1342 cm–1. H NMR (400
MHz, CDCl3): d = 8.26–8.23 (m, 2 H), 7.46–7.44 (m, 2 H), 5.73 (s,
2 H), 3.99 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 160.1, 148.4,
140.0, 138.2, 128.9, 124.5, 116.6, 52.7, 52.3. HRMS (CI): m/z calcd
for C11H9BrN4O4 [M + H]+: 340.9885; found: 340.9887.
Bromotriazole 8b
White solid, 111 mg (0.34 mmol, 92%). Rf = 0.22 (EtOAc–heptane,
1
2:1). IR (film): n = 3357, 2848, 1611, 1538, 1517 cm–1. H NMR
(400 MHz, CDCl3): d = 8.24–8.22 (d, J = 8.4 Hz, 2 H), 7.44–7.42
(d, J = 8.4 Hz, 2 H), 5.65 (s, 2 H), 4.01 (q, J = 6.0 Hz, 2 H), 2.90 (t,
J = 6.0 Hz, 2 H), 2.48 (t, J = 6.0 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 148.2, 145.4, 140.9, 128.8, 124.4, 110.2, 61.0, 52.1,
28.3. HRMS (CI): m/z calcd for C11H11Br81N4O3 [M]: 327.9994;
found: 327.9993. HRMS (CI): m/z calcd for C11H11Br79N4O3 [M+]:
326.0014; found: 326.0001.
(9) Leroy, J. Synth. Commun. 1992, 576.
(10) The regiochemistry was determined via reduction to the 5-
hydrogen-1,2,3-triazole, using i-PrMgCl and subsequent
quenching with MeOH, followed by comparison to the
known 1,4-disubstituted triazole.
(11) Heating of the reaction mixture to temperatures higher than
50 °C led to the formation of small amounts of the 1,5-
regioisomer, which was probably formed via a thermal [3+2]
cycloaddition.
(12) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314.
(13) Kuijpers, B. H. M.; Groothuys, S.; Keereweer, A. R.;
Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.;
Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123.
Bromotriazole 18b
Colorless oil, 89 mg (0.13 mmol, 65%). Rf = 0.54 (EtOAc–heptane,
1
2:1). IR (film): n = 2971, 1748, 1368 cm–1. H NMR (400 MHz,
CDCl3): d = 6.01 (t, J = 10.0 Hz, 1 H), 5.78 (d, J = 9.2 Hz, 1 H), 5.58
(d, J = 8.0 Hz, 1 H), 5.56 (d, J = 3.2 Hz, 1 H), 5.25 (dd, J = 3.2, 10.0
Hz, 1 H), 4.69–4.64 (m, 1 H), 4.26–4.14 (m, 3 H), 3.75 (s, 3 H), 2.22
(s, 3 H), 2.06 (s, 3 H), 2.03 (s, 3 H), 1.98 (s, 3 H), 1.44 (s, 9 H). 13
C
NMR (75 MHz, CDCl3): d = 170.4, 170.1, 170.0, 168.8, 155.3,
143.2, 111.2, 86.0, 79.8, 73.9, 71.1, 66.9, 66.7, 61.3, 52.6, 52.5,
28.4, 27.4, 20.7, 20.6, 20.2. HRMS (FAB): m/z calcd for
C25H36BrN4O13: 679.1462 [M + H]+; found: 679.1469.
Synlett 2005, No. 20, 3059–3062 © Thieme Stuttgart · New York