An efficient protocol for the preparation of pyridinium and imidazolium salts based on the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tetlet.2008.03.146

We report herein that, in the absence of any nucleophilic counterions, tertiary nitrogen nucleophiles such as pyridines and imidazoles can be alkylated with alcohols, by simply using their ammonium form as the acidic component of the Mitsunobu reaction. This led to efficient preparation of ionic liquids under mild conditions, avoiding the usual anion exchange step.

Full text of DOI:10.1016/j.tetlet.2008.03.146

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Tetrahedron Letters 49 (2008) 3663–3665
An efficient protocol for the preparation of pyridinium
and imidazolium salts based on the Mitsunobu reaction
Sylvain Petit, Rabah Azzouz, Corinne Fruit, Laurent Bischoff *, Francis Marsais
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR CNRS 6014, IRCOF-INSA Rouen, Universite´ de Rouen,
BP08 76131 Mont-Saint-Aignan Cedex, France
Received 8 February 2008; revised 21 March 2008; accepted 28 March 2008
Available online 8 April 2008
Abstract
We report herein that, in the absence of any nucleophilic counterions, tertiary nitrogen nucleophiles such as pyridines and imidazoles
can be alkylated with alcohols, by simply using their ammonium form as the acidic component of the Mitsunobu reaction. This led to
efficient preparation of ionic liquids under mild conditions, avoiding the usual anion exchange step.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Mitsunobu; Pyridinium; Imidazolium; Ionic liquid; Alkylation
Imidazolium and pyridinium-based ionic liquids have
been thoroughly studied over the past two decades and still
receive considerable attention.1 For example, pyridinium
ionic liquids were recently used as catalysts in Morita–Bay-
lis–Hillman reactions2 or for asymmetric reductions of
ketones.3 The role of the counterion may also be of crucial
importance, especially when the imidazolium salts are used
as precursors of nucleophilic carbenes.4 However, the qua-
ternarization of heterocycles such as pyridine or imidazole
derivatives involving alkyl halides generally requires pro-
longed heating5 often incompatible with sensitive sub-
strates. The high energy required by this reaction can
also be delivered by microwave irradiation.6 We were first
intrigued by the possible application of the Mitsunobu
reaction to synthesize N-alkylpyridinium salts under mild
conditions. Recently, we reported our findings regarding
this application of the Mitsunobu reaction in a synthesis
of indoliziniums.7 Since this reaction requires an acidic
nucleophile (NuH), we worked out the alkylation step
using pyridinium and imidazolium salts as nucleophiles.
To the best of our knowledge, the Mitsunobu reaction is
not used with pyridinium nor imidazolium salts as the
acidic nucleophile component. Only one similar example
of intramolecularN-alkylation of apyridine–propanol scaf-
fold showed that this reaction was made possible by the
presence of an acidic NHBoc group at C6, but no pyridini-
um salt was used for this reaction.8
Our first experiment was conducted with pyridinium
chloride in anhydrous methanol with a twofold excess of
triphenyl phosphine PPh3 and diisopropyl azodicarboxyl-
ate DIAD overnight at room temperature. Interestingly,
N-alkylation afforded N-methylpyridinium chloride but in
modest yield (45%). Presumably, activated methanol
(MeOP+Ph3) can undergo a nucleophilic attack either by
pyridine or chloride ion, thus giving chloromethane. Under
the same conditions, a non-nucleophilic counterion such as
N+
R
or
N
R-OH, PPh3, DIAD
CH3CN, rt
-
-
H+
BF4
BF4
or
N
R
N+
-
H3C
+ BF4
N
NH
H3C
-
BF4
*
Corresponding author. Fax: +33 2 35522962.
Scheme 1. Alkylation of pyridinium and N-methylimidazolium salts.
E-mail address: laurent.bischoff@insa-rouen.fr (L. Bischoff).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.146

3664
S. Petit et al. / Tetrahedron Letters 49 (2008) 3663–3665
Table 2
tetrafluoroborate afforded a quantitative yield of the pyrid-
inium salt. In the following experiments (Scheme 1), we
used pyridinium tetrafluoroborate and N-methylimidazo-
lium tetrafluoroborate as model substrates. Using 5 M
equiv of methanol in acetonitrile, we were pleased to find
out that the methylation of pyridinium took place
quantitatively within 2 h at room temperature. Even 1.1
or 1.5 M equiv of methanol gave a satisfactory yield (see
Table 1, footnotes a and b), but completion of the reaction
required longer reaction times. As described in Table 1,
screening various alcohols gave access to the expected N-
alkylpyridinium salts in good yields. In addition, those
salts were extracted in water, allowing an easy separation
of the by-products of the Mitsunobu reaction. The same
reaction conditions applied to N-methylimidazolium also
gave good yields of quaternary products. This can lead to
Yields of alkylation with n-BuOH, different counterions
X
PyridineꢁHX
89
95
90
MIMꢁHX
72
90
72
BF4
PF6
CF3SO2O
(CF3SO2)2N
100
100
The choice of the counterion at the protonation stage
makes this method a convenient preparation of various
pyridinium and imidazolium salts in good yields.
We further focused our attention towards two substrates
having a very low nucleophilicity, that is, 2,6-lutidine and
acridine. The latter was methylated using our standard con-
ditions, but with longer reaction times (24 h). Acridinium
gave a modest 50% yield, whereas 2,6-lutidinium was
smoothly quaternarized at room temperature (Scheme 2).
An interesting feature of the Mitsunobu reaction could
arise from the ammonium acidity. As depicted in Scheme
3, when both ammonium salts are present in the reaction
medium, a selectivity can be obtained owing to the pKa dif-
ference. Tuning the excess of Mitsunobu reagent afforded
the selective alkylation of the most acidic ammonium salt,
that is, pyridinium, while the amino group of ethanolamine
was kept protected under its protonated form.
For instance, the alkylation of pyridinium tetra-
fluoroborate by ethanolamine tetrafluoroborate was
conducted with a 1:1.5:1.5:1.2 M ratio of pyridinium:
PPh3:DIAD:alcohol and afforded a 70% yield. No alkyl-
ation occurred on the amino group of ethanolamine and
no polymer nor aziridine formation was observed. A simi-
lar result was obtained with phenyl glycinol tetrafluoro-
borate, which was able to alkylate pyridine with a 65%
yield under the same conditions. This could provide an effi-
cient route towards various chiral ionic liquids.
ꢀ
ionic liquids, avoiding a subsequent halide/BF4 exchange
step, usually required in the preparation of ILs.1
These results show that this method constitutes a very
efficient alkylation protocol and does not require harsh
conditions, such as heating pyridine or N-methylimidazole
in the presence of a large excess of the alkyl halide. Even a
secondary alcohol such as isopropanol reacted under those
conditions, albeit with lower yields. As far as the aqueous
work-up is concerned, n-octyl pyridinium tetrafluoroborate
and N-octyl-N0-methyl imidazolium (OMIM-BF0-methyl-
imidazolium (OMIM–BF4) were poorly soluble in water
and were extracted at higher aqueous dilutions.
Another major advantage in this method lies in the pos-
sibility of changing the counterion by simply using another
strong acid in the previous protonation step. Hexafluoro-
phosphate salts were prepared in water and freeze-dried
before being redissolved in acetonitrile, whereas triflate
and bis-trifluorosulfonimide salts could be directly gener-
ated in acetonitrile prior to the Mitsunobu alkylation. By
using the standard conditions with n-butanol (Table 2),
N-butylpyridinium and BMIM salts were obtained in good
yields. As shown by these results, changing the counterions
even increased the yields obtained in the quaternarization
process. In particular, the bis-trifluoromethanesulfonimide
is the most efficient counterion for this transformation.
Nevertheless, we performed most of our study with tetra-
fluoroborate salts, since they are the cheapest and most
used compounds in these series.
Me-OH, PPh3, DIAD
N
N+
CH3CN, rt
100%
H+
-
-
BF4
BF4
same
conditions
50%
N+
BF
N+
BF
Me
-
-
H
4
4
Scheme 2. Alkylation of poorly nucleophilic substrates.
Table 1
Yields of alkylation, molar equiv alcohol/PPh3/DIAD = 5/2/2
Alcohol R–OH
PyridineꢁHBF4
N-MethylimidazoleꢁHBF4
100
85
72
83
100
84
100 (100)a
100 (100)a
89 (75)b
86
-
MeOH
EtOH
2 BF4
N+
N
-
H+
BF4
PPh3, DIAD
CH3CN, rt
n-BuOH
n-Octanol
CH2@CH–CH2OH
PhCH2OH
i-PrOH
R
OH
95 (82)a
92 (85)a
60
+
NH3
R
R = H : 70%
R = Ph : 65%
- NH3
70
BF4
+
a
Molar equiv alcohol/PPh3/DIAD = 1.1/1.5/1.5.
Molar equiv alcohol/PPh3/DIAD = 1.5/2/2.
b
Scheme 3. pKa-directed alkylation: protonation as a protection.

S. Petit et al. / Tetrahedron Letters 49 (2008) 3663–3665
3665
N-Ethyl, N0-ethylimidazolium tetrafluoroborate (EMIM, BF4):9a 1H
NMR (D2O, 300 MHz): 1.45 (t, J = 7.4 Hz, 3H), 3.84 (s, 3H), 4.18 (t,
J = 7.4 Hz, 2H), 7.37 (s, 1H), 7.44 (s, 1H), 8.65 (s, 1H).
In summary, we have developed a very simple and effi-
cient procedure10 for the quaternarization of pyridiniums
and N-methylimidazoliums. The ion-exchange step usually
required in the synthesis of ionic liquids could be avoided.
Other nitrogen nucleophiles are currently under investiga-
tion in our laboratory.
N-Butyl, N 0 -methylimidazolium tetrafluoroborate (BMIM, BF4):6b
1H NMR (D2O, 300 MHz): 0.87 (t, J = 7.4 Hz, 3H), 1.26 (hex, J =
7.7 Hz, 2H), 1.79 (quint, J = 7.0 Hz, 2H), 3.83 (s, 3H), 4.14 (t,
J = 7.0 Hz, 2H), 7.36 (d, J = 1.5 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H),
H-2 exchanged in D2O; 1H NMR (acetone-d6, 300 MHz): 0.92 (t,
J = 7.4 Hz, 3H), 1.36 (hex, J = 7.7 Hz, 2H), 1.90 (quint, J = 7.4 Hz,
2H), 4.02 (s, 3H), 4.33 (t, J = 7.3 Hz, 2H), 7.70 (s, 1H), 7.77 (s, 1H),
9.09 (s, 1H); 13C NMR (acetone-d6, 75 MHz): 13.2, 19.4,32.2, 36.0,
49.6, 122.8, 124.2, 137.1.
Acknowledgements
S.P. is grateful to the Re´gion Haute Normandie for gen-
erous financial support. We gratefully acknowledge
Charles Furet and Alexandre Gourlain for technical
assistance.
N-Methyl, N0-octylimidazolium tetrafluoroborate (OMIM, BF4): 1H
NMR (D2O, 300 MHz): 0.81 (t, J = 6.6 Hz, 3H), 1.15–1.3 (m, 10H),
1.81 (quint, J = 7.2 Hz, 2H), 3.84 (s, 3H), 4.13 (t, J = 7.0 Hz, 2H),
7.38 (s, 1H), 7.42 (s, 1H), 8.65 (s, 1H).
N-Allyl, N0-methylimidazolium tetrafluoroborate:9b 1H NMR (D2O,
300 MHz): 3.83 (s, 3H), 4.74 (d, J = 6.2 Hz, 2H), 5.30 (d, J = 18.6 Hz,
1H), 5.38 (d, J = 10.4 Hz, 3H), 5.90–6.05 (m, 1H), 7.38–7.40 (m, 2H),
8.66 (s, 1H).
References and notes
1. Welton, T. Chem. Rev. 1999, 99, 2071; Wasserscheid, P.; Welton, T.
Ionic Liquids in Synthesis; Wiley-VCH: Germany, 2003. Chapter 3;
Binnemans, K. Chem. Rev. 2005, 105, 4148.
2. Zhao, S.-H.; Zhang, H.-R.; Feng, L.-H.; Chen, Z.-B. J. Mol. Catal. A:
Chem. 2006, 258, 251.
3. Xiao, Y.; Malhotra, S. V. Tetrahedron: Asymmetry 2006, 17, 1062.
4. Magna, L.; Chauvin, Y.; Niccolai, G. P.; Basset, J.-M. Organome-
tallics 2003, 22, 4418.
5. Tolstikova, L. L.; Shainyan, B. A. Russ. J. Org. Chem. 2006, 42,
1068.
6. (a) Khadilkar, B. M.; Rebeiro, G. L. Org. Process Res. Dev. 2002, 6,
826; (b) Namboodiri, V. V.; Varma, R. S. Tetrahedron Lett. 2002, 43,
5381.
7. Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. J. Org. Chem. 2008,
73, 1154.
8. Lawton, G. R.; Ji, H.; Silverman, R. B. Tetrahedron Lett. 2006, 47,
6113.
9. (a) Egashira, M.; Yamamoto, Y.; Fukutake, T.; Yoshimoto, N.;
Morita, M. J. Fluorine Chem. 2006, 127, 1261; (b) Zhao, D.; Fei, Z.;
Geldbach, T. J.; Scopelliti, R.; Laurenczy, G.; Dyson, P. J. Helv.
N-Benzyl, N0-methylimidazolium tetrafluoroborate:9c 1H NMR (D2O,
300 MHz): 3.82 (s, 3H), 5.32 (s, 2H), 7.25–7.40 (m, 7H), 8.69 (s, 1H).
N-Isopropyl, N-methylimidazolium tetrafluoroborate: 1H NMR (D2O,
0
300 MHz): 1.48 (d, J = 6.8 Hz, 6H), 3.82 (s, 3H), 4.56 (hept, J =
6.6 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 8.70 (s,
1H).
N-Methylpyridinium tetrafluoroborate: 1H NMR (D2O, 300 MHz):
4.38 (s, 3H), 8.03 (t, J = 6.7 Hz, 2H), 8.52 (t, J = 7.8 Hz, 1H), 8.76 (d,
J = 6.3 Hz, 2H); 13C NMR (D2O, 75 MHz): 48.4, 128.2, 145.3, 145.6.
N-Ethylpyridinium tetrafluoroborate: 1H NMR (D2O, 300 MHz): 1.60
(t, J = 7.4 Hz, 3H), 4.61 (q, J = 7.4 Hz, 2H), 8.02 (t, J = 6.8 Hz, 2H),
8.50 (t, J = 7.8 Hz, 1H), 8.82 (d, J = 5.7 Hz, 2H); 13C NMR (D2O,
75 MHz): 15.5, 57.2, 128.1, 143.8, 145.3.
N-Butylpyridinium tetrafluoroborate :9d 1H NMR (D2O, 300 MHz):
0.91 (t, J = 7.3 Hz, 3H), 1.32 (hex, J = 7.5 Hz, 2H), 1.96 (quint,
J = 7.5 Hz, 2H), 4.58 (t, J = 7.3 Hz, 2H), 8.03 (t, J = 6.8 Hz, 2H),
8.51 (td, J = 7.8, 1.1 Hz, 1H), 8.80 (d, J = 5.5 Hz, 2H); 13C NMR
(D2O, 75 MHz): 12.5, 18.6, 32.5, 61.6, 128.1, 144.1, 145.3.
N-Octylpyridinium tetrafluoroborate: 1H NMR (D2O, 300 MHz): 0.82
(t, J = 6.4 Hz, 3H), 1.5–1.7 (m,10H), 1.99 (quint, J = 7.5 Hz, 2H),
4.58 (t, J = 7.3 Hz, 2H), 8.03 (t, J = 7.1 Hz, 2H), 8.51 (t, J = 7.9 Hz,
1H), 8.80 (d, J = 5.6 Hz, 2H).
´
Chim. Acta 2005, 88, 665; (c) Rangits, G.; Kollar, L. J. Mol. Catal. A:
Chem. 2006, 246, 59; (d) Behar, D.; Neta, P.; Schultheisz, C. J. Phys.
Chem. A 2002, 106, 3139.
1
N-Allylpyridinium tetrafluoroborate: H NMR (D2O, 300 MHz): 5.21
10. The following procedure for the synthesis of BMIMꢁBF4 is illustra-
tive: An ice-cold methanolic solution of N-methylimidazole was
treated with an equimolar amount of aqueous HBF4. After stirring
15 min at rt, the solvents were removed in vacuo. The salt obtained
can be either taken-up in water and freeze-dried or dried under
vacuum. 1 mmol of this salt was dissolved in anhydrous acetonitrile
(10 mL). Triphenylphosphine (2 mmol) and n-butanol (5 mmol) were
added, followed by a dropwise addition of diisopropyl azodicarbox-
ylate (2 mmol). The resulting pale orange solution was stirred 15 h at
rt and concentrated in vacuo. The residue was extracted with water
(10 mL), the aqueous layer washed with ether (4 ꢂ 10 mL). Evapo-
ration to dryness or freeze-drying afforded BMIMꢁBF4 as a colourless
oil. In case of residual starting N-methylimidazolium salt, the ionic
liquid can be dissolved in dichloromethane and filtered through a pad
of potassium carbonate. Although most of these compounds were
already described in the literature, we have listed below their NMR
data in D2O, as their spectra are often given in different solvents such
as acetone-d6, CD2Cl2 or CDCl3 /DMSO-d6. Purities were checked
with BMIM, BF4 and N-butylpyridinium, BF4, as satisfactory
elemental analyses were obtained for these compounds.
(d, J = 6.2 Hz, 2H), 5.46 (d, J = 17.4 Hz, 1H), 5.53 (d, J = 10.4 Hz,
1H), 6.15 (m, 1H), 8.07 (t, J = 7 Hz, 2H), 8.55 (t, J = 7.8 Hz, 1H),
8.82 (d, J = 4.9 Hz, 2H); 13C NMR (D2O, 75 MHz): 63.4, 122.9,
128.2, 129.9, 144.2, 145.8.
N-Benzylpyridinium tetrafluoroborate:2 1H NMR (D2O, 300 MHz):
5.74 (s, 2H), 7.42 (m, 5H), 7.99 (t, J = 7.1 Hz, 2H), 8.48 (t, J = 7.9 Hz,
1H), 8.83 (d, J = 5.5 Hz, 2H); 13C NMR (D2O, 75 MHz): 64.5, 128.2,
129.0, 129.4, 129.8, 132.6, 144.2, 145.8.
N-Isopropylpyridinium tetrafluoroborate: 1H NMR (D2O, 300 MHz):
1.63 (d, J = 6.8 Hz, 6H), 4.90 (hept, J = 6.6 Hz, 1H), 8.05 (d,
J = 6.7 Hz, 2H), 8.59 (t, J = 7.5 Hz, 1H), 8.87 (d, J = 5.6 Hz, 2H).
N-Methyl-2,6-lutidinium tetrafluoroborate: 1H NMR (D2O, 300
MHz): 2.77 (s, 6H), 4.05 (s, 3H), 7.69 (d, J = 7.9 Hz, 2H), 8.15 (t,
J = 7.9 Hz, 1H); 13C NMR (D2O, 75 MHz): 21.0, 39.7, 127.0, 143.9,
155.8.
N-(2-Aminoethyl)pyridinium bis-tetrafluoroborate: 1H NMR (D2O,
300 MHz): 3.70 (t, J = 6.4 Hz, 2H), 4.90 (t, J = 6.4 Hz, 2H), 8.15 (t,
J = 6.2 Hz, 2H), 8.64 (t, J = 6.6, 1H), 8.93 (d, J = 6.5 Hz, 2H).
N-[(2S)-2-Amino-2-phenylethyl]pyridinium bis-tetrafluoroborate: 1H
NMR (D2O, 300 MHz): 4.17 (d, J = 7.7 Hz, 2H), 6.25 (t, J = 7.7 Hz,
1H), 8.11 (t, J = 6.8 Hz, 2H), 8.59 (t, J = 6.7, 1H), 9.04 (d, J = 6.0 Hz,
2H).
N,N0-Dimethylimidazolium tetrafluoroborate: 9a 1H NMR (D2O,
300 MHz): 3.76 (s, 6H), 7.28 (s, 2H), 8.50 (s, 1H); 13C NMR (D2O,
75 MHz): 35.5, 123.3, 136.5.