Metal-Free 1,2,3-Triazole Synthesis in Deep Eutectic Solvents

Article abstract of DOI:10.1055/s-0039-1690736

The metal-free regioselective preparation of 1,5- and 1,4-disubstituted triazoles is reported through a cycloaddition-elimination sequence. Reactions were carried out in environmentally friendly deep eutectic solvent (DES) and pure products were isolated

Full text of DOI:10.1055/s-0039-1690736

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Metal-Free 1,2,3-Triazole Synthesis in Deep Eutectic Solvents
Filip Sebest
Samuel Haselgrove
Andrew J. P. White
Silvia Díez-González*
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Imperial College London, Department of Chemistry,
MSRH, 80 Wood Lane, White City, London, W12 0BZ, UK
Published as part of the ISySyCat2019 Special Issue
Received: 08.09.2019
Accepted after revision: 14.10.2019
Published online:
cause of their low cost and environment-friendliness (i.e.,
biodegradability, water tolerance).10
With a reliable access to 1,2,3-triazolines in hand, we
decided to revisit their use as triazole precursors. Several
organocatalysts8c,11 as well as transition-metal salts12–17
have been reported for the oxidation of transient triazolines
into their corresponding triazoles. However, these methods
either require the use of toxic mediators (up to 12 equiva-
lents) or are restricted to triazolines bearing strong elec-
tron-withdrawing groups. Our preliminary attempts to ex-
pand the scope of triazoline derivatives that might undergo
aromatisation only led to disappointing results and the
model triazoline was either recovered or underwent severe
decomposition.18
Alternatively, reported examples of thermal azide–
alkene cycloadditions followed by elimination of a leaving
group to produce triazoles typically employ electron-rich
alkenes and high temperatures (up to 200 °C),19 which lim-
its their scope. However, the reported increased thermal
stability of triazolines in DES could be particularly useful in
these reactions.
DOI: 10.1055/s-0039-1690736; Art ID: st-2019-b0473-c
Abstract The metal-free regioselective preparation of 1,5- and 1,4-
disubstituted triazoles is reported through a cycloaddition–elimination
sequence. Reactions were carried out in environmentally friendly deep
eutectic solvent (DES) and pure products were isolated without the
need for chromatographic techniques.
Key words alkene, azide, deep eutectic solvent, triazole, triazoline,
metal-free synthesis
Triazoles, which are very useful heterocyclic motifs in a
breadth of fields, including chemical biology and materials,1
are typically prepared by metal-mediated azide–alkyne cy-
cloaddition reactions.2 Careful choice of the metal source
and cycloaddition partners can deliver a range of 1,2,3-tri-
azoles regioselectively. However, this approach is not with-
out downsides and even the ever popular copper version of
this reaction, considered a prime example of ‘click’ chemis-
try,3 is limited to terminal or iodo alkynes.4
In consequence, it is not surprising that metal-free
strategies5 have gathered steady interest and current re-
ported alternatives include reactions of azides with
strained alkynes,6 enamines,7 and enolates.8 Triazoles can
also be accessed from related 1,2,3-triazolines via dehydro-
genation or elimination strategies, but the relative instabili-
ty of triazolines has prevented their widespread applica-
tion. We have recently reported a general and scalable
preparation of diversely functionalised triazolines via ther-
mal azide–alkene cycloadditions in deep eutectic solvents
(DESs).9 The reaction medium was found to be crucial since
only DES led to synthetically useful yields, probably due to
the increased stability of these cycloadducts in this solvent
(choline chloride/urea, 1:2). Moreover, DESs made of urea,
glycerol, water or choline chloride are particularly promis-
ing in synthesis from a Green chemistry point of view be-
Model triazoline 1a was prepared in high yield in DES by
following our previously reported methodology and the
conditions for methanol elimination were optimised (Table
1). Simply heating 1a in DES at 100 °C produced 39% of de-
sired triazole 2a with the remainder being unreacted start-
ing material (entry 1). Complete conversions could be
achieved at 55 °C in the presence of tetramethylguanidine
(TMG) in either DES or tert-butyl methyl ether as solvent
(entries 2 and 3). Alternative bases were tested in TBME to
avoid miscibility issues and comparable results were ob-
tained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (entries 4 and 5),
but no reaction was observed with pyridine, 2,6-lutidine,
NEt3 or K2CO3. Pleasingly, triazole 2a could be easily isolated
pure after washing with water and ice-cold pentane.
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Table 1 Preliminary Optimisation Studiesa
F3C
F3C
N
N
base (1.0 equiv.)
N
N
N
N
solvent, 55 °C, 16 h
– MeOH
MeO
1a
2a
Entry
Base
–
Solvent
Recov. 1a Conv. 2a
Yield 2a
(%)
(%)b
(%)b
1c
2
DES
58
0
39
–
Figure 1 Structure of 2b′-A, one of the two independent molecules
present in the crystal of 2b′
TMG
DES
>95
95
93
88
85
89
72
–
3
TMG
DBU
DBN
LiHMDS
–
TBME
TBME
TBME
TBME
TBME
MeOH
0
4
0
93
CF3
5
0
93
N
Ar
TMG (1.0 equiv.)
N
N
6
0
78
DES, 90 °C, 24 h
– MeOH
OMe
7d
8
29
0
33
N3
2a, 77% one pot
80% over two steps
KOH (2 M)
>95
93
a Reaction conditions: Triazoline 1a (0.25 mmol), base (0.25 mmol), solvent
(1 mL).
N
DES
80 °C, 96 h
Ar
TMG (1.0 equiv.)
DES, 55 °C, 16 h
N
N
b 1H NMR yields/recoveries are the average of two independent experi-
ments and were determined with respect to 1,3,5-trimethoxybenzene as
internal standard.
86%
after column
chromatography
– MeOH
MeO
93%
1a
c Reaction carried out at 100 °C.
d Reaction carried out with 4 Å molecular sieves.
Scheme 2 Comparison of syntheses of 1,5-disubstituted triazole 2a
An excellent result was also obtained with KOH in
MeOH (Table 1, entry 8), conditions previously reported for
an analogous process with piperidine as the leaving
group.20 However, this system has poor functional group
tolerance and, for example, when we submitted triazoline
1b to this system, competitive hydration of the nitrile group
was observed even at room temperature (Scheme 1). The
obtained pair of triazoles was separated by column chroma-
tography and the structure of undesired 2b′ was confirmed
by X-ray diffraction analysis (Figure 1).21
We selected a TMG/DES combination for the optimisa-
tion of a cycloaddition–elimination cascade. Together with
the benefits of DES noted in the introduction, TMG is
cheaper than DBU or DBN, relatively non-toxic, and pres-
ents good miscibility with DES and very high water solubil-
ity, making its removal from the reaction mixture straight-
forward. For this reaction sequence, heating at 90 °C was re-
quired as full conversions could not be achieved at lower
temperatures even after 48 h (Table 2, entries 1–4). Increas-
ing the TMG loading had little effect on the outcome of the
reaction, while halving it led to a noticeable drop in yield
(entries 4–6). No triazoline was observed in any of these re-
actions and a control without TMG only delivered 29% yield
of triazole 2a and significant decomposition into the corre-
sponding aniline (entry 7). These results imply that the cyc-
loaddition reaction is the limiting step and that an excess of
base with respect to intermediate triazoline 1a prevents its
decomposition prior to methanol elimination.
R
N
Ar
N
N
Ar
N3
OR'
DES, 24 h
– R'OH
R
3X
(2.0 equiv.)
F3C
NC
N
N
N
N
N
N
O
3a, 82%
3b, 74%
TMG (1 equiv.), 80 °C
no base, 90 °C
R' = Et
R' = Me
Scheme 3 One-pot preparation of 1,4-disubstituted triazoles 3 (isolat-
ed yields)
H2N
O
NC
NC
N
N
N
N
N
aq. KOH (2 M, 8.0 equiv.)
MeOH, RT, 16 h
N
N
N
N
MeO
1b
2b, 25%
2b', 33%
Scheme 1 Elimination of MeOH from triazoline 1b using KOH (isolated yields)
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Table 2 Optimisation of a One-Pot Azide–Alkene Cycloaddition–Elimination Cascadea
CF3
F3C
F3C
N
N
TMG
N
N
N
N
OMe
DES, 24 h
– MeOH
MeO
N3
1a
2a
Entry
T (°C)
TMG (equiv)
Recov. azide (%)b
Conv. 2a (%)b
1
70
80
80
90
90
90
90
1.0
1.0
1.0
1.0
2.0
0.5
–
35
20
17
<5
<5
9
42
62
74
92
89
73
29
2
3c
4
5
6
7d
<5
a Reaction conditions: Azide (1.0 mmol), alkene (4.0 mmol) in DES (2 mL).
b 1H NMR yields/recoveries are the average of two independent experiments and were determined with respect to 1,3,5-trimethoxybenzene as internal standard.
c 48 h.
d 41% of 4-trifluoromethylaniline was also observed.
Overall, triazole 2a can be isolated in comparably high
yields after one or two separate reactions from the starting
azide-alkene pair. However, the one-pot strategy signifi-
cantly shortens the synthesis and eliminates the need for
tedious purification because the final triazole can be isolat-
ed analytically pure after a simple work-up and washings
with cold pentane (Scheme 2).22,23
Table 3 Alternative Leaving Groups in Triazole Preparationa
CF3
N
Ar
conditions
– R'OH
N
N
R
OR'
(2.0 equiv.)
2X
R
N3
Entry
1
Alkene
Triazole
2
Conditions
Yield (%)
N
N
N
N
N
Ar
N
N
N
N
N
2c
DES or toluene, 80–90 °C, 24 h
0 (hydrolysis)
Ph
OSiMe3
Ph
Ar
N
1. Toluene, 100 °C, 48 h
2. TMG (1 equiv), 55 °C, 16 h
2
3
4
2a
2d
2e
40
9b
Me
OSiMe3
OSiMe3
Me
Ar
N
TMG (1 equiv), DES, 90 °C, 24 h
TMG (2 equiv), DES, 50 °C, 24 h
t-Bu
t-Bu
Ar
N
24
Ad
OTf
Ad
Ar
N
N
5
2f
TMG (2 equiv), DES, 90 °C, 24 h
7b
OTf
a Reaction conditions: Azide (1.0 mmol), alkene (2.0 mmol) in solvent (2 mL).
b 1H NMR yields are the average of two independent experiments and were determined with respect to 1,3,5-trimethoxybenzene as internal standard.
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The effect of the electronic nature of the alkene substit-
uents on the overall regioselectivity of the azide–alkene cy-
cloaddition reactions is well established;24 hence, the pres-
ent methodology can be applied to access either 1,5- or 1,4-
disubstituted triazoles. Indeed, two examples of the latter
were prepared from commercially available 1-propenyl
ethyl ether (3a) and 4-methoxybut-3-en-2-one (3b)
(Scheme 3). Pleasingly, the presence of an electron-with-
drawing group in triazole 3b obviated the need for a base in
the reaction media.25
Next, alternative leaving groups were investigated. Silyl
enol ethers, although commercially available, displayed
limited reactivity and underwent severe hydrolysis/decom-
position under most conditions tested (Table 3, entries 1–
3). This could sometimes be mitigated by using toluene as
solvent and adding TMG only once the starting azide had
been consumed (entry 2).
(4) (a) Haldón, E.; Nicasio, M. C.; Pérez, P. J. Org. Biomol. Chem.
2015, 13, 9528. (b) Díez-González, S. Catal. Sci. Technol. 2011, 1,
166. (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(5) For reviews, see: (a) Jalani, H. B.; Karagöz, A. Ç.; Tsogoeva, S. B.
Synthesis 2017, 49, 29. (b) Lima, C. G. S. C.; Ali, A.; van Berkel, S.
S.; Westemann, B.; Paixao, M. W. Chem. Commun. 2015, 51,
10784. (c) For a highlight on metal- and azide-free methodolo-
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2015, 7, 901; and references therein.
(6) For selected leading references, see: (a) Agard, N. J.; Prescher, J.
A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046. (b) van
Berkel, S. S.; Dirks, A. J.; Debets, M. F.; van Delft, F. L.;
Cornelissen, J. J. L.; Nolte, R. J. M.; Rutjes, F. P. J. T. ChemBioChem
2007, 8, 1504. (c) Laughlin, S. T.; Baskin, J. M.; Amacher, S. L.;
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Ramakumar, K.; Narayana, V. V. Chem. Eur. J. 2008, 14, 9143.
(b) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.
Eur. J. 2011, 17, 3584. (c) Li, W.; Du, J.; Huang, J.; Jia, Q.; Zhang,
K.; Wang, J. Green Chem. 2014, 16, 3003.
In reactions with triflate enol ethers, two equivalents of
the base were used to minimise any acid-driven decompo-
sition. Two challenging substrates were tested (Table 3, en-
tries 4 and 5) and while triazole 2e was isolated in 24%
yield, a trisubstituted triflate enol ether led to severe de-
composition and a low conversion into the desired triazole.
In summary, we have developed a one-pot cycloaddi-
tion–elimination cascade in DES to access either 1,4- or 1,5-
disubstituted triazoles. This metal-free methodology does
not require any purification step and minimises the need
for volatile organic solvents. In spite of their relatively limit-
ed availability, enol ethers are the best candidates for this
methodology because they do not decompose in the reac-
tion and only produce alcohols as elimination by-products.
(8) For selected leading references, see: (a) Cheng, G.; Zeng, X.;
Shen, J.; Wang, X.; Cui, X. Angew. Chem. Int. Ed. 2013, 52, 13265.
(b) Ramachary, D. B.; Shashank, A. B.; Karthik, S. Angew. Chem.
Int. Ed. 2014, 53, 10420. (c) Li, W.; Wang, J. Angew. Chem. Int. Ed.
2014, 53, 14186.
(9) Sebest, F.; Casarrubios, L.; Rzepa, H. S.; White, A. J. P.; Díez-
González, S. Green Chem. 2018, 20, 4023.
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M.; Ramón, D. J. Eur. J. Org. Chem. 2016, 612. (b) García-Álvarez,
J. Eur. J. Inorg. Chem. 2015, 5147. (c) Zhang, Q.; De Oliveira
Vigier, K.; Royer, S.; Jêrome, F. Chem. Soc. Rev. 2012, 41, 7108.
(11) Li, W.; Du, Z.; Zhang, K.; Wang, J. Green Chem. 2015, 17, 781.
(12) KMnO4: (a) Kadaba, P. K.; Edelstein, S. B. J. Org. Chem. 1990, 55,
5891. (b) Kadaba, P. K.; Parmley, G.; Crooks, P. A.; Agha, B. J. Het-
erocycl. Chem. 1993, 30, 1191.
(13) NiO2: Kadaba, P. K. J. Prakt. Chem. 1982, 324, 857.
(14) CuI: Janreddy, D.; Kavala, V.; Kuo, C.-W.; Chen, W.-C.; Ramesh,
C.; Kotipalli, T.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. Adv.
Synth. Catal. 2013, 355, 2918.
Funding Information
(15) Cu(OAc)2: Rohilla, S.; Patel, S. S.; Jain, N. Eur. J. Org. Chem. 2016,
847.
(16) Cu(OTf)2: Chen, Y.; Nie, G.; Zhang, Q.; Ma, S.; Li, H.; Hu, Q. Org.
Lett. 2015, 17, 1118.
This research was financially supported by Imperial College London
and by the Engineering and Physical Sciences Research Council (EPS-
RC) (DTP studentship to F.S. and EP/K030760).
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es
R
esearc
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C
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c
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0
3
0
7
6
0)
(17) CuO nanoparticles: Gangaprasad, D.; Raj, J. P.; Kiranmye, T.;
Sasikala, R.; Karthikeyan, K.; Rani, S. K.; Elangovan, J. Tetrahe-
dron Lett. 2016, 57, 3105.
Supporting Information
(18) See the Supporting Information for further details.
(19) (a) Huisgen, R.; Möbius, L.; Szeimies, G. Chem. Ber. 1965, 98,
1138. (b) Huisgen, R.; Möbius, L.; Szeimies, G. Chem. Ber. 1965,
98, 1153. (c) Roque, D. R.; Neill, J. L.; Antoon, J. W.; Stevens, E. P.
Synthesis 2005, 2497.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690736. Included are FAIR data for
NMR spectra, and crystallographic dat.
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References and Notes
(20) Munk, M. E.; Kim, Y. K. J. Am. Chem. Soc. 1964, 86, 2213.
(21) CCDC 1949637 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(1) (a) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013,
113, 4905. (b) Themed issue on Click Chemistry: Finna, M. G.;
Fokina, V. V. Eds. Chem. Soc. Rev. 2010, 39, 1221–1408.
(c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
(2) (a) Wang, C.; Ikhlef, D.; Kahlal, S.; Saillard, J.-Y.; Astruc, D. Coord.
Chem. Rev. 2016, 316, 1. (b) Liao, Y.; Lu, Q.; Chen, G.; Yu, Y.; Li,
C.; Huang, X. ACS Catal. 2017, 7, 7529.
The
Cambridge
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Data
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www.ccdc.cam.ac.uk/getstructures.
(22) Procedure for the Preparation of 5-methyl-1-[4-(trifluoro-
methyl)phenyl]-1H-1,2,3-triazole (2a): 1,1,3,3-Tetra-methyl-
guanidine (0.25 mL, 2 mmol) was added into a solution of 1-
azido-4-trifluoromethylbenzene (0.37 g,
2 mmol) and 2-
(3) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed.
2001, 40, 2004.
methoxypropene (0.77 mL, 8.00 mmol) in DES (4 mL) in a vial
that was fitted with a screw cap. The mixture was stirred vigor-
ously at 90 °C for 24 h before being allowed to cool to room
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temperature and diluted with water (8 mL). The aqueous layer
was extracted with EtOAc (3 × 6 mL) and the combined organic
layers were washed with water and brine, dried over MgSO4, fil-
tered and concentrated under reduced pressure to give crude
product that was washed with ice-cold pentane to yield the title
compound (0.35 g, 77%) as a pale-brown solid; mp 104.6–
107.1 °C. IR: 3091, 3004, 2984, 1615 (m), 1525, 1443, 1421 (m),
1413 (m), 1323 (m), 1267 (m), 1233, 1209, 1180, 1156 (m),
1114 (s), 1087 (m), 1067 (s), 1043 (m), 1035 (m), 1009 (m), 972
(m), 862, 847 (s), 825 (s), 781, 707, 698, 657 (m) cm–1. 1H NMR
(CDCl3, 400 MHz):  = 7.84 (d, J = 8.5 Hz, 2 H), 7.66 (d, J = 8.5 Hz,
2 H), 7.62 (s, 1 H), 2.42 (s, 3 H). 13C NMR (CDCl3, 101 MHz):  =
139.2, 133.9, 133.3, 131.4 (q, J = 33 Hz), 126.8 (q, J = 3 Hz),
125.0, 123.5 (q, J = 273 Hz), 9.5. 19F NMR (CDCl3, 377 MHz):  = –
62.8 (s). HRMS (ES+): m/z [M + H]+ calcd for C10H9N3F3:
228.0749; found: 228.0753.
(23) Sebest, F.; Haselgrove, S.; White, A. J. P.; Díez-González, S. Impe-
rial College Research Services Data Repository: UK, 2019, DOI:
10.14469/hpc/6043 and sub-collections therein..
(24) (a) Huisgen, R. In 1,3-Dipolar Cycloadditions Chemistry, Vol. 1;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984, 1.
(b) L’Abbé, G. Chem. Rev. 1969, 69, 345.
(25) For
a related preparation of 4-acyltriazoles in DES, see:
(a) Martins, M. A. P.; Paveglio, G. C.; Rodrigues, L. V.; Frizzo, C.
P.; Zanatta, N.; Bonacorso, H. G. New J. Chem. 2016, 40, 5989.
(b) See also: Thomas, J.; Goyvaerts, V.; Liekens, S.; Dehaen, W.
Chem. Eur. J. 2016, 22, 9966.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E