A novel and versatile access to task-specific ionic liquids based on 1,2,3-triazolium salts

Article abstract of DOI:10.1055/s-2008-1042915

Novel task-specific ionic liquids based on 1,2,3-triazolium salts were prepared in a straightforward two-step procedure. Azides and alkynes were transformed into 1,4-disubstituted 1,2,3-triazoles by Cu-catalyzed click reaction. Subsequent alkylation affor

Full text of DOI:10.1055/s-2008-1042915

1058
LETTER
A Novel and Versatile Access to Task-Specific Ionic Liquids Based on
1,2,3-Triazolium Salts
Task-Specific
vIonic Liquid
e
Based on
n1,2,3-Triazolium
S
H
a
lts anelt, Jürgen Liebscher*
Institute of Chemistry, Humboldt-University Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: Liebscher@chemie.hu-berlin.de
Received 15 January 2008
azoles has been known long before the click reaction was
invented, when Gompper treated 1,2,3-triazoles obtained
by 1,3-dipolar addition with alkylating reagents.15 The
alkylation sometimes results in the formation of regioiso-
Abstract: Novel task-specific ionic liquids based on 1,2,3-triazoli-
um salts were prepared in a straightforward two-step procedure.
Azides and alkynes were transformed into 1,4-disubstituted 1,2,3-
triazoles by Cu-catalyzed click reaction. Subsequent alkylation af-
forded 1,3,4-trisubstituted 1,2,3-triazoles as ionic liquids. Useful meric 2- and 3-alkyl triazolium salts.15–17 When soft alky-
functionalities, such as organocatalysts, fluorophors or linkers can
lating reagents were used 1,3-disubstituted products were
be incorporated into the ionic liquids in this way.
formed preferentially.
Key words: ionic liquids, alkylation, heterocycles, click reaction,
We seek to use this sequence to synthesize trisubstituted
1,2,3-triazolium salts
1,2,3-triazolium salts 5 which can be expected to behave
like ILs. So far, only 1-amino-3-alkyl-1,2,3-triazolium
salts have been reported as ILs in the 1,2,3-triazolium se-
Ionic liquids (ILs) are organic salts that are liquids at tem-
ries. These compounds were neither obtained via click
peratures below 100 °C. They have gained wide interest
chemistry nor used in organic synthesis but rather used as
and broad application in academia and also in industry.1–3
energetic fuel.18,19 We aimed to give a proof of principle
ILs can be advantageously used as solvents of low vapor
for simple 1,2,3-triazole-based ILs substituted with sim-
pressure, with special solvent properties within a wide
ple alkyl and benzyl substituents and in particular for the
range of polarity and usually of low toxicity. They can of-
more challenging incorporation of functionalities into the
ten be easily recycled and allow retaining a catalyst for re-
substituents in the 1,2,3-triazole ring. For the present short
peated application. Some ionic liquids are considered to
communication, we chose chiral amines as potential orga-
be ‘green solvents’.2,4 As a more advanced type of ionic
nocatalysts, protected amino groups as possible linkers,
liquids, task-specific ionic liquids (TSILs) have been de-
and fluorophors as functionalities. As can be seen from
veloped.5,6 Here, the ionic liquid does not only act as a sol-
vent but at the same time performs a function, often
catalytic activity. So far such task-specific ionic liquids
were mainly based on imidazolium, pyridinium and am-
monium salts, where the functionality was usually linked
to the N atom by alkylation, e.g. a chiral, (S)-proline-de-
Table 1, the functionalities could be incorporated either
into the azide 1 or in the alkyne 2 or in both. In most cases
high yields of the corresponding 1,4-disubstituted 1,2,3-
triazoles 3 were obtained. The products were further alky-
lated with alkyl iodides or bromides 4 affording the ex-
pected 1,3,4-trialkyl-1,2,3-triazolium salts
5
in
rived pyrrolidin-2-methyl group was covalently bound to
an imidazole group and the imidazolium salts obtained by
further alkylations could successfully be used in asym-
metric Michael additions to nitroolefins.7 In order to intro-
duce the functionality into the ionic liquids, the
functionality has to be furnished with alkylating proper-
ties in most cases to allow covalent connection to the N
atom.
quantitative yields. All the products 5 (except for 5h; mp
79–81 °C) appeared as oils or sticky oils at room temper-
ature and thus are ILs. Therefore, salt metathesis in order
to lower the melting points was not necessary so far.
Clean NMR spectra were obtained for all ILs 5 as well as
for their precursors 3.20 Mixtures of regioisomers were not
observed. The location of the substituent R3 at position 3
was proved by NOESY investigation showing proximity
We report here a versatile novel access to new task-specif- of the groups R3 and R2 in products 5.
ic ionic liquids which are based on 1,2,3-triazoles ob-
In summary, we have found a straightforward and very
tained by click chemistry. This highly current
methodology is based on the reaction of azides 1 with
alkynes 2 in the presence of Cu(I) catalysts, which can
also be obtained in situ from Cu(II). Since its development
in 20028,9 numerous applications of this reaction have
been reported linking relevant R1 and R2 groups together
via a 1,2,3-triazole ring.10–14 The N-alkylation of 1,2,3-tri-
versatile access to trisubstituted 1,2,3-triazolium salts as a
novel class of ILs by copper-catalyzed click reaction of
N
R3X
4
R1
N
R1
R1
N
N
+
1
+
N
CuI, DIPEA
N
N
N
N
R3
X–
MeCN,
reflux, 8–51 h
solvent, r.t., argon
50–97%
R2
R2
R2
quantitative
yields
2
SYNLETT 2008, No. 7, pp 1058–1060
x
x.
x
x.
2
0
0
8
3
5
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1042915; Art ID: G01308ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

LETTER
Task-Specific Ionic Liquids Based on 1,2,3-Triazolium Salts
1059
Table 1 1,4-Disubstituted 1,2,3-Triazoles 3 and 1,3,4-Trisubstituted 1,2,3-Triazolium Salts 5a
3/5 R1
R2
R3
X
Solvent
CuI
(equiv) (h)
Time
Yield Mp
(%) of 3 (°C) of 3 (equiv) (h)
4
Time
a
benzyl
benzyl
n-Bu
Me
Me
I
CHCl3
CHCl3
1.05
1.05
3
91
93
54–55
33
10
1b
8
b
n-pentyl
OTs
72
48
MeOH–CHCl3
(2:1)
c
4-benzyloxybenzyl n-pentyl
Me
Et
I
1.05
1.05
77
36
97
50
93–95
60–62
7
15
96
d
3-methoxybenzyl
benzyl
3-phthalimidopropyl
Br
DMF
137c
O
O
CH2
e
f
Me
n-Pr
Me
Me
I
I
I
I
CHCl3
1.05
1.05
5d
73
90
88
88
96
81
83
59
oil
oil
oil
6
10
28
8
51
8
N
Cbz
CH2
NH
O
C
3-methoxybenzyl
DMF
MeOH
DMF
(CH2)3
CH2
N
g
h
n-pentyl
Cbz
CH2
NH
O
C
3-phthalimidopropyl
1.05
165–166 28
8
(CH2)3
a Quantitative yields were obtained for all products 5, which appeared as sticky oils (except for 5h which was a solid with mp 79–81 °C).
b MeCN (50 mL) was used as solvent.
c Because of the low boiling point of EtBr a large excess was used together with the same volume of MeCN as solvent.
d The procedure described by Fazio et al.21 was adopted, but as shown with the other examples, equimolar quantities of CuI were sufficient as
well.
azides 1 with alkynes 2. This methodology allows to link References and Notes
functionalities, such as organocatalytic moieties, fluoro-
phors, reactive groups for further linking and should also
(1) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, 2nd
ed., Vol. 1; Wiley-VCH: Weinheim, 2008.
be applicable to other functionalities, such as ligands for
metal complexes or biomolecules. In principle it should
be further possible to link three functionalities via a 1,2,3-
triazolium salt, if the alkylating reagent 4 is functionalized
as well. Such investigations as well as applications of the
novel ILs 5 in organic synthesis are currently underway in
our laboratories. We are using the ILs 5 as such or in com-
bination with other cheaper and commercially available
IL lacking functional groups. Here, the former provides
the functionality and the latter acts as the solvent.
(2) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72,
1391.
(3) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, 2nd
ed., Vol. 2; Wiley-VCH: Weinheim, 2008.
(4) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S.
Tetrahedron 2005, 61, 1015.
(5) Davis, J. H. Synthesis of Task-Specific Ionic Liquids; Wiley-
VCH: Weinheim, 2003.
(6) Vaultier, M.; Kirschning, A.; Singh, V. Task-Specific Ionic
Liquids as New Phases for Supported Organic Synthesis;
Wiley-VCH: Weinheim, 2007.
(7) Luo, S. Z.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.
P. Angew. Chem. Int. Ed. 2006, 45, 3093.
(8) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
(9) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(10) Cheng, L. J.; Chen, Q.; Liu, J.; Du, Y. G. Carbohydr. Res.
2007, 342, 975.
Acknowledgment
We thank Bayer Services GmbH & Co. OHG, BASF AG, and Sasol
GmbH for donation of chemicals.
Synlett 2008, No. 7, 1058–1060 © Thieme Stuttgart · New York

1060
S. Hanelt, J. Liebscher
LETTER
128.7 (CHPh), 134.2 (NNNCH2C), 136.3 (NCOOCH2C),
(11) (a) Gil, M. V.; Arevalo, M. J.; Lopez, O. Synthesis 2007,
1589. (b) Zeitler, K.; Mager, I. Adv. Synth. Catal. 2007, 349,
1851.
(12) Geci, I.; Filichev, V. V.; Pedersen, E. B. Chem. Eur. J. 2007,
13, 6379.
(13) Lenda, F.; Guenoun, F.; Martinez, J.; Lamaty, F.
Tetrahedron Lett. 2007, 48, 805.
(14) Castagnolo, D.; Dessi, F.; Radi, M.; Botta, M. Tetrahedron:
Asymmetry 2007, 18, 1345.
142.6 (CHCOOCH2C), 154.2 (NCOOCH2Ph), 172.2
(CHCOOCH2).
Compound 3g: [a]D25 –260.7 (c 0.033, CHCl3). H NMR
(300.13 MHz, CDCl3): d = 0.83 (t, J = 6.5 Hz, 3 H,
CH2CH2CH2CH2CH3), 1.27 (m, 5 H, CH2CH2CH2CH2CH3
+ NCbzCHCHH), 1.61 (m, 3 H, NCbzCHCHHCH2), 1.89
(m, 2 H, CH2CH2CH2CH2CH3), 2.60 (m, 2 H,
CH2CH2CH2CH2CH3), 3.15 (m, 1 H, NCbzCHH), 3.33 (m,
1 H, NCbzCHH), 4.10 (m, 1 H, NCbzCH), 4.48 (m, 2 H,
CHCH2NNN), 5.13 (m, 2 H, PhCH2), 6.88 (s, 0.7 H,
CHtriazole), 7.10 (s, 0.3 H, CHtriazole), 7.31 (m, 5 H, Ph).
13C NMR (75.47 MHz, CDCl3): d = 13.8
(15) Gompper, R. Chem. Ber. 1957, 90, 382.
(16) Wamhoff, H. 1,2,3-Triazoles and their Benzo Derivatives;
Pergamon Press: Oxford / New York / Sydney, 1984.
(17) Begtrup, M. Acta Chem. Scand. 1971, 25, 249.
(18) Kaplan, G.; Drake, G.; Tollison, K.; Hall, L.; Hawkins, T.
J. Heterocycl. Chem. 2005, 42, 19.
(CH2CH2CH2CH2CH3), 22.2 (CH2CH2CH2CH2CH3), 23.1
(NCbzCHCHH), 25.3 (CH2CH2CH2CH2CH3), 27.8
(CH2CH2CH2CH2CH3), 28.9 (NCbzCHCH2CH2), 31.1
(CH2CH2CH2CH2CH3), 46.8 (NCbzCH2), 51.5 (CH2NNN),
57.1 (CHCH2NNN), 66.9 (PhCH2), 121.2 (CHtriazole), 127.7–
128.4 (CHPh), 136.3 (CPh), 148.3 (Ctriazole), 154.5 (NCOO).
Compound 5a: 1H NMR (400.13 MHz, CD3CN): d = 0.92
(t, J = 7.6 Hz, 3 H, CH2CH2CH2CH3), 1.40 (sext, J = 7.4 Hz,
2 H, CH2CH2CH2CH3), 1.65 (m, 2 H, CH2CH2CH2CH3),
2.81 (t, J = 7.2 Hz, 2 H, CH2CH2CH2CH3), 4.12 (s, 3 H,
N+Me), 5.82 (s, 2 H, CH2NNN), 7.46 (m, 5 H, Ph), 8.70 (s,
1 H, CH). Signals at d = 2.81 and 4.12 ppm showed a weak
(19) Drake, G.; Kaplan, G.; Hall, L.; Hawkins, T.; Larue, J.
J. Chem. Cryst. 2007, 37, 15.
(20) Preparation of 3; General Procedure: The azide 1 (20
mmol) was dissolved in the appropriate solvent (50 mL) and
CuI (see Table 1) was added. The flask was flushed with
argon and the mixture was kept under argon until the workup
procedure (balloon) was followed. DIPEA (see Table 1) and
the alkyne 2 (10 mmol) were added one after the other, the
latter in portions under stirring. If the alkyne was a solid or a
sticky liquid, the solvent quantity of 50 mL was shared for
dissolving the azide and the alkyne. After a short time an
exothermic reaction started and the pace of the addition of
the alkyne was adjusted accordingly. Cooling by a water-
bath might be advisable. After complete addition of the
alkyne stirring was continued at r.t. The mixture was diluted
with CHCl3 (50 mL) and filtered. The filtrate was evaporated
and the residue was purified by column chromatography
(Kieselgel 60; MeOH–CHCl3, 1:19). If DMF was used as
solvent, the reaction mixture was diluted with CHCl3 (250
mL), filtered and the filtrate was washed with H2O (3 × 150
mL) and dried with Na2SO4 before volatile compounds were
removed under vacuum. Eventually the washing procedure
had to be repeated.
cross peak with each other in the NOESY spectrum. 13
C
NMR (100.61 MHz, CD3CN): d = 13.5 (CH2CH2CH2CH3),
22.2 (CH2CH2CH2CH3), 23.4 (CH2CH2CH2CH3), 29.0
(CH2CH2CH2CH3), 38.5 (N+Me), 57.1 (PhCH2), 117.9
(CHtriazole), 128.8 (CHo), 129.6 (CHm), 130.0 (CHp), 133.0
(CPh), 145.5 (Ctriazole).
Compound 5e: [a]D25 –36.1 (c 0.024, CHCl3). 1H NMR
(300.13 MHz, CDCl3): d = 1.87 (m, 4 H, NCbzCHCH2CH2),
3.40 (m, 2 H, NCbzCH2), 4.06 (s, 3 H, N+Me), 4.21 (m, 1 H,
NCbzCH), 4.89 (m, 2 H, PhCH2NNN), 5.45 (m, 2 H,
COOCH2), 5.34 (s, 1 H, NCOOCH2Ph), 5.42 (s, 1 H,
NCOOCH2Ph), 7.27 (m, 10 H, 2 × Ph), 8.87 (s, 1 H,
CHtriazole). 13C NMR (75.47 MHz, CDCl3): d = 23.1
(NCbzCH2CH2), 29.9 (NCbzCHCH2), 39.3 (N+Me), 46.3
(NCbzCH2), 54.2 (PhCH2NNN), 57.0 (COOCH2), 58.6
(NCbzCH), 66.5 (PhCH2OCON), 123.3 (CHtriazole), 127.0–
130.6 (CHPh), 135.9 (NNNCH2C), 138.3 (NCOOCH2C),
142.3 (CHCOOCH2C), 153.9 (NCOOCH2Ph), 171.5
(CHCOOCH2).
Preparation of 5; General Procedure: A solution of the
1,2,3-triazole 3 (20 mL) and the alkylating reagent 4 (see
Table 1) in anhyd MeCN (30 mL) was refluxed (see
Table 1). All volatile compounds were removed under
vacuum with a rotary evaporator leaving behind the ionic
liquid as an oil or a sticky oil.
Compound 3a: 1H NMR (300.13 MHz, CDCl3): d = 0.87 (t,
J = 7.2 Hz, 3 H, CH2CH2CH2CH3), 1.32 (sext, J = 7.4 Hz, 2
H, CH2CH2CH2CH3), 1.58 (m, 2 H, CH2CH2CH2CH3), 2.68
(t, J = 7.8 Hz, 2 H, CH2CH2CH2CH3), 5.46 (s, 2 H,
CH2NNN), 7.19 (s, 1 H, CH), 7.27 (m, 5 H, Ph). 13C NMR
(75.47 MHz, CDCl3): d = 13.7 (CH2CH2CH2CH3), 22.1
(CH2CH2CH2CH3), 25.3 (CH2CH2CH2CH3), 31.3
(CH2CH2CH2CH3), 53.8 (PhCH2), 120.5 (CHtriazole), 127.8
(CHo), 128.4 (CHm), 128.9 (CHp), 134.8 (CPh), 148.8
(Ctriazole).
Compound 5g: [a]D25 –72.9 (c 0.02, CHCl3). 1H NMR
(300.13 MHz, CD3CN): d = 0.87 (t, J = 6.5 Hz, 3 H,
CH2CH2CH2CH2CH3), 1.31 (m, 5 H, CH2CH2CH2CH2CH3
+ NCbzCHCHH), 1.58 (m, 3 H, NCbzCHCHHCH2), 1.87
(m, 2 H, CH2CH2CH2CH2CH3), 2.39 (m, 2 H,
CH2CH2CH2CH2CH3), 3.16 (m, 1 H, NCbzCHH), 3.34 (m,
1 H, NCbzCHH), 3.90 (m, 1 H, NCbzCH), 4.07 (s, 3 H,
N+Me), 4.51 (m, 2 H, CHCH2NNN), 5.12 (m, 2 H, PhCH2),
7.35 (m, 5 H, Ph), 8.55 (s, 1 H, CHtriazole). 13C NMR (75.47
MHz, CD3CN): d = 14.0 (CH2CH2CH2CH2CH3), 22.6
(CH2CH2CH2CH2CH3), 23.5 (NCbzCHCHH), 25.7
(CH2CH2CH2CH2CH3), 27.1 (CH2CH2CH2CH2CH3), 28.6
(NCbzCHCH2CH2), 31.2 (CH2CH2CH2CH2CH3), 38.3
(N+Me), 47.3 (NCbzCH2), 51.6 (CH2NNN), 57.6
(CHCH2NNN), 67.0 (PhCH2), 118.1 (CHtriazole), 128.1–
129.7 (CHPh), 137.8 (CPh), 146.8 (Ctriazole), 155.6 (NCOO).
(21) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.
H. J. Am. Chem. Soc. 2002, 124, 14397.
Compound 3e: [a]D25 –80.3 (c 0.02, CHCl3). 1H NMR
(300.13 MHz, CDCl3): d = 1.96 (m, 4 H, NCbzCHCH2CH2),
3.48 (m, 2 H, NCbzCH2), 4.30 (m, 1 H, NCbzCH), 5.00 (m,
2 H, PhCH2NNN), 5.17 (m, 2 H, COOCH2), 5.34 (s, 1 H,
NCOOCH2Ph), 5.42 (s, 1 H, NCOOCH2Ph), 7.23 (m, 10 H,
2 × Ph), 7.56 (s, 1 H, CHtriazole). 13C NMR (75.47 MHz,
CDCl3): d = 23.5 (NCbzCH2CH2), 30.0 (NCbzCHCH2), 46.4
(NCbzCH2), 53.7 (PhCH2NNN), 57.9 (COOCH2), 58.7
(NCbzCH), 66.5 (PhCH2OCON), 123.3 (CHtriazole), 127.2–
Synlett 2008, No. 7, 1058–1060 © Thieme Stuttgart · New York

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