Bicyclic 1,2,3-triazolium ionic liquids: Synthesis, characterization, and application to rutaecarpine synthesis

Article abstract of DOI:10.1021/ol201793v

Starting with commercial reagents, bicyclic 1,2,3-triazolium ionic liquids [b-3C-tr][NTf₂] (1) and [b-4C-tr][NTf₂] (2) were synthesized in four steps with high overall isolated yields of 68% and 76%, respectively. Since the C-5 hydrogen is acidic, under basic condition ionic liquids 1 and 2 were readily methylated with methyl iodide to afford chemically stable ionic liquids 7 and 8 at room temperature (88% and 82%, respectively). Ionic liquid 1 was used as the ionic solvent to demonstrate its usefulness for the synthesis of rutaecarpine, a natural product.

Full text of DOI:10.1021/ol201793v

ORGANIC
LETTERS
2
011
Vol. 13, No. 16
434–4437
Bicyclic 1,2,3-Triazolium Ionic Liquids:
Synthesis, Characterization, and
Application to Rutaecarpine Synthesis
4
Ming-Chung Tseng, Hui-Ting Cheng, Meng-Jane Shen, and Yen-Ho Chu*
Department of Chemistry and Biochemistry, National Chung Cheng University,
1
68 University Road, Minhsiung, Chiayi 62102, Taiwan, ROC
cheyhc@ccu.edu.tw
Received July 5, 2011
ABSTRACT
2 2
Starting with commercial reagents, bicyclic 1,2,3-triazolium ionic liquids [b-3C-tr][NTf ] (1) and [b-4C-tr][NTf ] (2) were synthesized in four steps
with high overall isolated yields of 68% and 76%, respectively. Since the C-5 hydrogen is acidic, under basic condition ionic liquids 1 and 2 were
readily methylated with methyl iodide to afford chemically stable ionic liquids 7 and 8 at room temperature (88% and 82%, respectively). Ionic liquid
1
was used as the ionic solvent to demonstrate its usefulness for the synthesis of rutaecarpine, a natural product.
This paper reports the development of a bicyclic 1,2,3-
triazolium ionic liquid system based on the Huisgen [3 þ 2]
negligible vapor pressure that are well suited for a myriad
of applications, including electrolytes for solar cells and
1
cycloaddition of azides and alkynes (click reaction) with
2
solvents for organic synthesis.
Today, the research on ionic liquids continues to be
dominated by imidazolium salts with fluorine-containing
specific aims to study its chemical stability and usefulness
as reaction medium for organic synthesis. Ionic liquids are
low-melting molten salts composed entirely of ions, and
2
anions. Studies of 1,2,3-triazolium ionic liquids, however,
2
3
are most recent. In our laboratory, we have been inter-
many of them are liquid at room temperature. Ionic
liquids carry numerous desirable properties such as wide
liquid range, thermal stability, excellent solubility with
many small molecules, attractive recyclability, and
ested in developing new ionic liquids and have a program
to evaluate ionic liquids as novel and stable media for
(
3) (a) Jeong, Y.; Kim, D.-Y.; Choi, Y.; Ryu, J.-S. Org. Biomol.
(
1) For recent reviews on click chemistry, see: (a) Kappe, C. O.; Van
Chem. 2011, 9, 374. (b) Jeong, Y.; Ryu, J.-S. J. Org. Chem. 2010, 75,
4183. (c) Fletcher, J. T.; Keeney, M. E.; Walz, S. E. Synthesis 2010, 3339.
(d) Khan, S. S.; Hanelt, S.; Liebscher, J. ARKIVOC 2009, xii, 193. (e)
Hanelt, S.; Liebscher, J. Synlett. 2008, 1058.
(4) (a) Chen, C.-W.; Tseng, M.-C.; Hsiao, S.-K.; Chen, W.-H.; Chu,
Y.-H. Org. Biomol. Chem. 2011, 9, 4188. (b) Tseng, M.-C.; Chu, Y.-H.
Chem. Commun. 2010, 46, 2983. (c) Tseng, M.-C.; Tseng, M.-J.; Chu,
Y.-H. Chem. Commun. 2009, 7503. (d) Tseng, M.-C.; Kan, H.-C.; Chu,
Y.-H. Tetrahedron Lett. 2007, 48, 9085. (e) Lin, Y.-L.; Kan, H.-C.; Chu,
Y.-H. Tetrahedron 2007, 63, 10949. (f) Kan, H.-C.; Tseng, M.-C.; Chu,
Y.-H. Tetrahedron 2007, 63, 1644. (g) Cheng, J.-Y.; Chu, Y.-H. Tetra-
hedron Lett. 2006, 47, 1575.
der Eycken, E. Chem. Soc. Rev. 2010, 39, 1280. (b) Baskin, J. M.;
Bertozzi, C. R. Aldrichim. Acta 2010, 43, 15. (c) Angell, Y. L.; Burgess,
K. Chem. Soc. Rev. 2007, 36, 1674. (d) Wu, P.; Fokin, V. V. Aldrichim.
Acta 2007, 40, 7. (e) Binder, W. H.; Kluger, C. Curr. Org. Chem. 2006, 10,
1
791. (f) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
(2) For recent reviews on ionic liquids, see: (a) Giernoth, R. Angew.
Chem., Int. Ed. 2010, 49, 2834. (b) Coleman, D.; Gathergood, N. Chem.
Soc. Rev. 2010, 39, 600. (c) Huo, C.; Chan, T. H. Chem. Soc. Rev. 2010,
9, 2977. (d) Sowmiah, S.; Srinivasadesikan, V.; Tseng, M.-C.; Chu,
Y.-H. Molecules 2009, 14, 3780. (e) Plechkova, N. V.; Seddon, K. R.
Chem. Soc. Rev. 2008, 37, 123.
3
1
0.1021/ol201793v r 2011 American Chemical Society
Published on Web 07/28/2011

2
d,4
chemical and biochemical applications.
Since 1,2,3-
These tandem reactions needed no harsh conditions,
avoided the isolation of potentially hazardous organic
azide, and proceeded smoothly in DMSO at ambient
temperature. Both reactions furnished in 6 h each with
high isolated yields (80% for 4 and 81% for 6 over two
steps, respectively). The next reaction sequence proceeded
with an intramolecular N-alkylation of the 1,2,3-triazoles 4
or 6 under the condition of the Finkelstein cyclization (KI
triazoles are reported to be chemically stable and nearly
impossible to oxidize or reduce and, also, from our own
experience on bicyclic imidazolium-based ionic liquids
4
aꢀc,f,g
such as [b-3C-im][NTf ] and [b-4C-im][NTf ],
2
we
2
decided toinvestigatebicyclictriazolium ionicliquidsaswe
believed that these ionic liquids would potentially provide
the needed chemical stability as useful media for organic
synthesis and the desired property for biochemical
applications.
We recently reported the synthesis of [b-3C-im][NTf2]
and [b-4C-im][NTf ] and found that both ionic liquids are
far more chemically stable than the common [bmim][PF ],
6
inrefluxedCH CN) for8 h toformcleanlythecorrespond-
3
ing triazolium iodide salts, followed by metathesis with
LiNTf at ambient temperature for 12 h to finally afford
2
the desired ionic liquid product 1 or 2 with high isolated
yields in two steps (85% for 1 and 94% for 2, respectively).
Starting from butyl bromide, the overall isolated yields for
2
4
f,g
[bdmim][PF ], and [bdmim][NTf ]. Because of this in-
6 2
triguing property, we went further to explore other bicyclic
this four-step synthesis of [b-3C-tr][NTf ] (1) and [b-4C-
2
ionic liquids, and herein, we present [b-3C-tr][NTf ] (1)
2
tr][NTf ] (2) ionic liquids were 68% and 76%, respectively.
2
and [b-4C-tr][NTf ] (2), a novel class of room temperature
2
Both bicyclic ionic liquids 1 and 2 are pale yellow liquids
at room temperature. We were interested in incorporating
low-melting, hydrophobic [NTf ] anion for ionic liquids
2
mainly because of its water inmiscibility and very low
water content; that is, they could be used directly as
substitutes to molecular solvents for organic synthesis.
Moreover, the conformationally constrained and nonpla-
nar structure of bicyclic ionic liquids further ensured their
liquid state at room temperature. In addition to its immis-
cibility with water, ionic liquids 1 and 2 are readily miscible
with polar organic solvents such as methanol, ethanol,
acetone, dichloromethane, chloroform, tetrahydrofuran,
ethyl acetate, acetonitrile, DMSO, and DMF but practi-
cally insoluble in less polar solvents including diethyl ether,
hexane, benzene, and toluene.
Figure 1. Bicyclic ionic liquids.
On first glance, 1,2,3-triazolium ionic liquids 1 and 2
lack the acidic hydrogens at position 2, which prevents
imidazolium ionic liquids such as [bmim][PF ] from being
ionicliquids, for use asalternativestomolecular solventsin
reactions.
Liebscher and co-workers reported first the synthesis of
6
innocent solventsbydeprotonationand carbene formation
2
d
1
the click reaction.
,3,4-trisubstituted 1,2,3-triazolium salts by making use of
3
under basic conditions. Accordingly, the problems asso-
ciated with acidic C-2 hydrogens in [bmim]-based ionic
liquids could be totally avoided in our ionic liquids 1 and 2.
It has been shown in the literature, however, that the aryl
hydrogens on 1,2,3-triazolium salts are acidic and can be
rapidly deprotonated by bases, and the resulting triazo-
lium anions have been reported to react with various
d,e
Our synthesis of bicyclic triazolium
ionic liquids (1 and 2) is outlined in Scheme 1. First, a two-
step, one-pot reaction process involved in situ formation of
1
-butyl azide from 1-butyl bromide reaction with sodium
azide, followed by the Cu-catalyzed Huisgen [3 þ 2] 1,3-
dipolar cycloaddition with 5-chloropentyne 3 or 6-chlor-
ohexyne 5 to yield the 1,2,3-triazoles 4 or 6, respectively.
5
electrophilic reagents. Moreover, 1,2,3-triazolium salts
2 2
Scheme 1. Synthesis of Bicyclic 1,2,3-Triazolium Ionic Liquids [b-3C-tr][NTf ] (1) and [b-4C-tr][NTf ] (2)
Org. Lett., Vol. 13, No. 16, 2011
4435

nonexchangeable position) on the butyl group. Results
from Table 1 showed that, under strongly basic conditions
Scheme 2. Synthesis of [b-3C-mtr][NTf
NTf ] (8)
2
] (7) and [b-4C-mtr]-
(0.1 M KOD in the 7:3 mixture of CD OD and D O), ionic
liquids 7 and 8 were practically resistant to deuterium
3 2
[
2
isotope exchanges and chemically stable for up to 1 week
(only 8% and 5% exchanged, respectively) while ionic
liquids 1 and 2 were completely exchanged immediately
after mixing with the deuterium solvent (i.e., within 3 min).
Under neutral conditions (CD OD/D O = 7:3, v/v), all
3
2
ionic liquids studied proceeded no solvent deuterium iso-
tope exchanges and were chemically stable for 24 h at
ambient temperature (entries 1ꢀ4, Table 1). Ionic liquids
1
and 2, however, exchanged slowly with deuterium solvent
(75% and 11%, respectively) and ionic liquids 7 and 8 gave
no detectable exchanges for up to 1 week. We reasoned that
the nonplanar, constrained fused tetrahydropyridinotriazo-
lium ring structure in ionic liquids 2 and 8 appears to make
wererecentlyreportedasabnormalN-heterocycliccarbene
NHC) precursors that could form complexes, via C-5
(
6
hydrogen, with transition metals. All these aforemen-
tioned results prompted us to synthesize C-5 methylated
ionic liquids 7 and 8 (Scheme 2) and systematically in-
vestigate the susceptibility of all bicyclic 1,2,3-triazolium
ionic liquids 1, 2, 7, and 8 to solvent deuterium isotope
the hydrogen and CH group at C-5 less accessible than
3
those of the dihydropyrrolotriazolium ring in ionic liquids 1
and 7 for solvent exchange; that is, ionic liquids 2 and 8 are
more chemically stable than 1 and 7, respectively. The
results of solvent deuterium isotope exchange experiments
demonstrate that the C-5 position of bicyclic triazolium
ionic liquids can be made less acidic by simply replacing the
hydrogen with a methyl group. Table 1 summarizes ex-
change rates of all ionic liquids studied in deuterium solvents
under neutral and basic conditions. In comparison with
bicyclic [b-3C-im][NTf ] and [b-4C-im][NTf ] ionic liquids
1
exchange by H NMR.
Scheme 2 illustrates the preparation of ionic liquids 7
and 8. At ambient temperature, both ionic liquids 7 and 8
could be readily achieved with high isolated yields from 1
and 2 (88% and 82%, respectively) by substitution of
hydrogen with methyl group at C-5 position using methyl
2
2
1
iodide and sodium hydride (Scheme 2). Our H NMR
study of solvent deuterium isotope exchanges with ionic
liquids 1, 2, 7 and 8 clearly indicated that, as expected, both
previously reported (Figure 1), both 7 and 8 developed in
7
this work are far more superior in chemical stability.
The success of the development of bicyclic 1,2,3-triazolium
ionic liquids prompted us to initiate a preliminary program
to investigate its usefulness as ionic solvents for synthesis of
natural products. We chose rutaecarpine (9) as our initial
synthetic target on which to test and support our design that
synthesis of natural products could be promoted in these
ionic liquids. Rutaecarpine 9, a cytotoxic alkaloid first
isolated in 1915 from the dried fruit of the plant Evodia
Table 1. Study of Chemical Stability of Ionic Liquids 1, 2, 7, and
8
1
in Neutral and Basic Conditions by H NMR
a
conversion (%) of H/D exchange at C-5
neutral conditions
basic conditions
8
9
rutaecarpa, exhibits important biological activities and, for
exactly this reason, has been the subject of a number of total
entry ionic liquid 3 min 24 h 1 wk 3 min 24 h 1 wk
b
b
b
b
b
b
b
b
1
2
3
4
1
2
7
8
75
100
100
100
100
10,11
syntheses and bioactivity investigations.
Scheme 3 illus-
11
b
100
b
100
b
b
trates our initial success of rutaecarpine synthesis of which
the middle CD rings were concomitantly assembled from an
8
b
b
b
b
5
a
Experimental conditions: ionic liquid (0.1 M) in CD
v/v, 0.5 mL) or in CD OD/D
KOD. The progress of deuterium exchange could be readily monitored
3
OD/D
2
O (7:3,
(7) Under the same basic conditions, the times required at 50%
deuterium exchange (t1/2) for [b-3C-im][NTf ] and [b-4C-im][NTf ] were
3
2
O (7:3, v/v, 0.5 mL) containing 0.1 M
2
2
4
f
1
b
1
140 and 28 h, respectively. These results clearly indicate that ionic
liquids 7 and 8 are far more chemically stable: only 8% and 5%
exchanged, respectively, after 168 h (1 week).
by H NMR. Not detectable by H NMR.
1 and 2 were chemically reactive and exchanged with
deuterium solvents (entries 1 and 2, Table 1).
The solvent deuterium isotopeexchanges were measured
under two (neutral and strongly basic) experimental con-
1
ditions by observing the changes in the H NMR integrals
(8) This plant has a history of use in Chinese medicine for gastro-
intestinal disorders, postpartum hemorrhage, and migraine.
(
9) For a recent review on biological activities of rutaecarpine, see:
Jia, S.; Hu, C. Molecules 2010, 15, 1873.
10) For a recent review on rutaecarpine synthesis, see: Lee, S. H.;
(
Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.; Lee, E.-S.; Jahng,
Y. Molecules 2008, 13, 272.
of the C-5 position hydrogens (i.e., H for 1 and 2, CH for 7
3
and 8) to that of the terminal methyl hydrogens (a
(11) Since its discovery, there have been 146 publications (SciFinder
on June 29, 2011) on the synthesis of rutaecarpine. For selected examples
of recent syntheses of rutaecarpine, see: (a) Zhang, C.; De, C. K.; Mal,
R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416. (b) Hamid, A.; Elomri,
A.; Daich, A. Tetrahedron Lett. 2006, 47, 1777.
(12) The starting 2-aminobenzamide 10 could be readily prepared in
high isolated yield (90%) from the reaction of tryptamine with isatoic
anhydride in DMF for 30 min at ambient temperature.
(
5) (a) Begtrup, M. J. Chem. Soc., Chem. Commun. 1975, 334. (b)
Begtrup, M. Acta Chem. Scand. B 1975, 29, 141.
6) Mathew, P.; Neels, A.; Albrecht, M. J. Am. Chem. Soc. 2008, 130,
3534.
(
1
4
436
Org. Lett., Vol. 13, No. 16, 2011

Scheme 3. Synthesis of Rutaecarpine in Molecular and Ionic Solvents
1
2
2
(
-aminobenzamide 10 reaction with the Vilsmeier reagent
conditions, a microwave reaction of 10 with DMF in DMF
solvent gaveno trace of9 or 11(entry 4, Scheme 3). Scheme
S1 (Supporting Information) illustrates a plausible me-
chanism for the synthesis of rutaecarpine 9.
In summary, we have developed a novel class of room-
temperature, bicyclic 1,2,3-triazolium ionic liquids 1, 2, 7,
and 8 that appear to fulfill practical requirement as
solvents for chemical reactions such as rutaecarpine synth-
esis. Further studies to evaluate its reaction scope under
various conditions are in progress. Moreover, these new
ionic liquids may open exciting perspectives for use in
various synthetic applications of natural and non-natural
products of biological significance.
N,N-dimethylformiminium chloride) in ionic liquid 1.
We envisaged that this concurrent formation of CD
rings, if formed, would be challenging to assemble due
primarily to the harsher reactions likely required to drive
the reaction to completion. We therefore decided to em-
ploy microwaves to deliberately promote such double
cyclization reaction. In our hands, after several initial trials
in screening experimental conditions, it was quickly re-
vealed that microwave irradiation (60 W) with tempera-
ture controlled at 150 °C produced best results.
Withmicrowaves, reactionof 10inionic liquid1 withthe
Vilsmeier reagent for 50 min cleanly furnished the desired
natural product 9 with 68% isolated yield after column
chromatography (entry 1, Scheme 3). In our hand, this
ionic solvent appeared to be thermally stable under the
experimental condition. If performed in DMF molecular
solvent, lower yield with significant contamination of a
fully aromatized 7,8-dehydrorutaecarpine (11) was ob-
tained (entry 3). Albeit the less reactive DMF could replace
the Vilsmeier reagent for the synthesis of 9, poor yield
along with contamination of 11 was observed (entry 2).
This resultofthe reaction formation of9 and 11withDMF
in ionic liquid 1 is consistent with our recent report on the
weak Lewis acidic nature of ionic liquid, which likely
Acknowledgment. We gratefully acknowledge support
of this work by the National Science Council (NSC-100-
2113-M-194-003-MY3), the College of Science at the Na-
tional Chung Cheng University, and a multiyear Grant-in-
Aide from the ANT Technology (Taipei, Taiwan). We also
thank reviewers for valuable and constructive comments.
1
0
Supporting Information Available. Scheme S1, experi-
1
13
mental procedures, and H and C NMR data and
spectra of all ionic liquids (1, 2, 7, and 8) and rutaecarpine
9. This material is available free of charge via the Internet
at http://pubs.acs.org.
4
a
activates DMF. Moreover, under identical experimental
Org. Lett., Vol. 13, No. 16, 2011
4437