Mitsunobu alkylation of imidazole: A convenient route to chiral ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2004.11.144

The Mitsunobu protocol offers a convenient route from imidazole to N-alkyl-substituted imidazoles, precursors to imidazolium-based ionic liquids, and is particularly useful for preparing chiral ionic liquids.

Full text of DOI:10.1016/j.tetlet.2004.11.144

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 631–633
Mitsunobu alkylation of imidazole: a convenient route to
chiral ionic liquids
Eun Jin Kim,a Soo Y. Koa,* and Edward K. Dziadulewiczb
aDepartment of Chemistry and Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
bNovartis Institute for Medical Sciences, London WCIE 6BN, UK
Received 2 September 2004; revised 11 November 2004; accepted 26 November 2004
Abstract—The Mitsunobu protocol offers a convenient route from imidazole to N-alkyl-substituted imidazoles, precursors to imi-
dazolium-based ionic liquids, and is particularly useful for preparing chiral ionic liquids.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Imidazole functional group playsimportant rolesin
1
numerousbioactive compounds. Recently, the interest
Imidazoles are generally synthesized via condensation
reactionsof ring fragments, each at an appropriate oxi-
dation level.1 A typical example for N(1)-alkylimidaz-
olesisthoes involving glyoxal [providing C(4) and
C(5)], formaldehyde [C(2)] an amine and ammonia.8
An alkyl substituent on N(1) of imidazoles would come
in the form of the amine employed in thisapproach. A
convenient alternative toward N-alkyl-substituted imi-
dazoleswould be an alkylation of imidazole nitrogen
with suitable electrophiles. The cheap price of imidazole
would certainly make thisalternative approach esem
desirable. Usual SN2-type alkylationswith alkyl halides
are, however, not very reliable due to frequent bis-alkyl-
ation problems(yielding yms metrical imidazolium
salts).9
in this heterocyclic system has widened as it is a precur-
sor to a class of compounds called room temperature
ionic liquids.2 Ionic liquids, of which imidazolium salts
are most widely used, have gained initial notice of synthetic
chemists as environmentally friendly ÔgreenÕ organic sol-
vents, and continue to hold their attention as reaction
catalysts or promoters.3 While imidazolium-based ionic
liquidsare generally of type that includestwo different
unfunctionalized alkyl substituents—methyl and butyl,
for example—on N(1) and N(3), and a variety of coun-
ter anions, interests in catalytic and promoting activities
of these salts have prompted syntheses of novel imidazo-
lium structures containing functionalized alkyl substitu-
ents.4 Of these, chiral ionic liquids have a potential to be
used as asymmetric organocatalysts.5 While initial re-
sults of asymmetric inductions by some of the earlier
chiral ionic liquid compoundswere not particularly
encouraging,6 more recent reports using well designed
salts show some promises.7 Asa general rule, a tsudy
of asymmetric catalysts is logically conducted using chi-
ral counterpartsthat faithfully represent the tsructures
of established symmetric (achiral) catalysts. In imidazo-
lium-based ionic liquids, either of the two N-substitu-
entswould be a good place to inesrt a chirality.
Therefore, synthetic routes yielding such N-substituted
imidazole precursors are sought after.
The pKa of imidazole isca. 14.5, placing it below car-
boxylic acids, phenols and imides in the acidity scale.1
Imidazole would, therefore, be less reactive than these
typical nucleophilesin a Mitusnobu-type alkylation.
On the other hand, the substrate (imidazole) is cheap,
and alcohols, the electrophilic partner in the Mitsun-
obu-type alkylation and through which the N-substitu-
ent would be introduced, occur with a wider diversity
than aminesor alkyl halidesin termsof functionality
and chirality, rendering the Mitsunobu approach worth
exploring.10
When imidazole wasreacted with repreesntative alco-
hols under the usual Mitsunobu conditions, (PPh3–
DEAD or –DIPAD [diethyl or diisopropyl azodicarb-
oxylate]), the N-alkylimidazoleswere obtained in yields
around 20%. Through the optimization of the reaction
Keywords: N-Substituted imidazole; Chiral ionic liquids; Mitsunobu
reaction.
*
Corresponding author. Tel.: +82 2 3277 3283; fax: +82 2 3277
2384; e-mail: sooyko@mm.ewha.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.144

632
E. J. Kim et al. / Tetrahedron Letters 46 (2005) 631–633
ployed. Empolying PBu3–ADDP (1,10-azodicarbonylpi-
Table 1. Mitsunobu alkylation of imidazole
peridine, 1 equiv each, Conditions B), the modified
protocol developed for Mitsunobu alkylations of nitro-
gen nucleophiles, the yield with a primary alcohol
improved a little (entry 5), while those with the b-
branched alcoholsimproved to ca. 60% (entries8 and
12).11 On the other hand, the Conditions B were not
effective at all with secondary alcohols.
N
N
Mitsunobu Conditions
+
ROH
N
R
N
H
C: PBu3-TMAD (10 eq.)
D: PBu3-CMBP (10 eq.)
A: PPh3-DIPAD (10 eq.)
B: PBu3-ADDP (1 eq.)
Entry
ROH
ConditionsYield (%)
PBu3–TMAD
(N,N,N0,N0-tetramethylazodicarboxa-
1
2
A
C
63
89
OH
mide) protocol, a more recent variant, hasbeen known
to be particularly effective for less reactive Mitsunobu
nucleophiles(with larger p Ka) and sterically bulky alco-
hols.12 The results of primary alcohols were similar with
PBu3–TMAD (1 equiv each) to those obtained under
the Conditions B, while with secondary alcohols the
TMAD protocol did produce the desired products,
albeit in low yields. Big improvements were observed
throughout the every class of alcohols when the PBu3–
TMAD reagentswere employed in excess(10 equiv
each, Conditions C). Yieldsaround 90% were obtained
with achiral primary alcohols(entries2 and 6), while
with chiral b-branched primary alcohols(entries9 and
13) and chiral a-branched secondary alcohols (entries
16 and 19), the yieldsranged 75–94%. The product iso-
lation wasagain very ismple under the Conditions C.
3
A
78
Ph
Ph
OH
OH
4
5
6
A
B
C
62
71
94
7
A
B
37
57
76
70
OH
OH
8
Ph
9
10
C
D
11
12
13
14
A
B
39
65
94
79
C
D
15
16
17
A
C
D
61a
75a
18
After the reaction wascomplete, TMAD–H formed
2
OH
wasprecipitated and filtered off, and the filtrate was
subjected to simple acid–base aqueous extractions to
remove most of the by-products and the unreacted
reagents.
18
19
20
A
C
D
72b
88
Ph
OH
41
a With inversion of configuration (>99% ee).
b With inversion of configuration (86% ee).
PBu3–CMBP (cyanomethylenetributylphosphorane)
protocol, reported to be effective for Mitsunobu alkyla-
13
tionsof nitrogen nucleophile,s
resulted in slightly
conditions, improved yields were obtained. The results
are summarized in Table 1.
lower yieldswith chiral b-branched primary alcohols
(entries10 and 14), or much lower yieldswith chiral sec-
ondary alcoholswith the stereogenic center at the carbi-
When imidazole (20 equiv) wasreacted with n-butanol
in the presence of excess PPh3–DIPAD (10 equiv each),
N-butylimidazole wasobtained in 63% yield (entry 1).
The reaction conditions( Conditions A) were devised so
that an excessive use of inactive but cheap imidazole
substrate and the Mitsunobu reagents would drive the
reaction to a maximum extent with a potentially valu-
able alcohol asthe limiting agent. After the reaction
wascomplete, mots of the by-productsand the unre-
acted reagents were sufficiently removed through simple
acid–base aqueous extractions, and a subsequent flash
silica chromatography afforded the desired product in
pure form. Under these conditions (A), other primary
alcoholsreacted similarly to give the corresponding N-
alkylimidazoles(entries3 and 4). Chiral primary alco-
holswith the stereogenic center at the b-position reacted
under the Conditions A to produce the desired N-alkyl-
imidazolesin yieldslower than 40% (entries7 and 11),
while chiral secondary alcohols with the stereogenic
center at the carbinol carbon fared better under these
conditions( A) to yield the corresponding chiral imid-
azolesin 60–70% (entries15 and 18).
nol carbon (entries17 and 20) than the PBu –TMAD
3
conditions( C).
The configuration of the stereogenic carbinol carbon
had been inverted in the process of the reaction, which
wasconfirmed by comparing with authentic asmples
independently prepared with corresponding chiral
amines via condensation procedure. In the case of 2-hex-
anol, the inversion of configuration was virtually com-
plete so that (R)-N-sec-hexylimidazole wasproduced in
>99% ee from (S)-2-hexanol (entries15 and 16). On
the other hand, the reaction at the benzylic site was
not completely stereoselective and (S)-N-sec-phenethyl-
imidazole of 86% ee wasproduced from enantio-pure
(R)-a-methylbenzyl alcohol (entry 18).
N-Substituted imidazoles thus prepared can be con-
verted to imidazolium salts by simple alkylation with
appropriate electrophiles. Two of the chiral N-substi-
tuted imidazolesprepared in thistsudy, namely
N-sec-
hexylimidazole and N-sec-phenethylimidazole, both
having the stereogenic center adjacent to the ring nitro-
gen, were reacted with MeI to produce the correspond-
ing imidazolium salts in quantitative yields. Both these
asltsare liquidsat room temperature. Further tsudies
In order to further improve the yieldsof the reactions, a
range of sets of variant Mitsunobu reagents were em-

E. J. Kim et al. / Tetrahedron Letters 46 (2005) 631–633
633
Rosa, J. N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron
2001, 57, 4189; (e) Tsuchimoto, T.; Maeda, T.; Shirakawa,
E.; Kawakami, Y. Chem. Commun. 2000, 1573; (f) Song,
C. E.; Shim, W. H.; Roh, E. J.; Lee, S.-G.; Choi, J. H.
Chem. Commun. 2001, 1122.
with these and other chiral ionic liquids will be reported
in due course.
In conclusion, the Mitsunobu protocol, specifically that
using PBu3–TMAD in excess, offers a convenient route
from imidazole to N-alkyl-substituted imidazoles, pre-
cursors to imidazolium-based ionic liquids, and is par-
ticularly useful for preparing chiral ionic liquids.
4. Recent examples: (a) Li, D.; Shi, F.; Peng, J.; Guo, S.;
Deng, Y. J. Org. Chem. 2004, 69, 3582; (b) Li, D.; Shi, F.;
Guo, S.; Deng, Y. Tetrahedron Lett. 2004, 45, 265; (c)
Wasserscheid, P.; Drießen-Ho¨lscher, B.; Hal, R. v.;
Steffens, H. C.; Zimmermann, J. Chem. Commun. 2003,
2038; (d) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.;
Weaver, K. J.; Forbes, D. C.; Davis, J. H., Jr. J. Am.
Chem. Soc. 2002, 124, 5962; (e) Visser, A. E.; Swatloski, R.
P.; Reichert, W. M.; Mayton, R.; Sheff, S.; Wierzbicki, A.;
Davis, J. H., Jr.; Rogers, R. D. Chem. Commun. 2001, 135;
(f) Larsen, A. S.; Holbrey, J. D.; Tham, F. S.; Reed, C. A.
J. Am. Chem. Soc. 2000, 122, 7264; (g) Merrigan, T. L.;
Bates, E. D.; Dorman, S. C.; Davis, J. H., Jr. Chem.
Commun. 2000, 2051.
Representative procedure of the Mitsunobu alkylation
(Conditions C): PBu3 (10 mmol) and imidazole
(20 mmol) were placed in a dry flask. Benzene (30 mL)
wasadded followed by ( S)-2-hexanol (1 mmol). The
mixture wascooled in an ice bath. TMAD (10 mmol)
wasadded. The mixture wasstirred at 0 ꢁC for 10 min,
then heated to 60 ꢁC overnight. The reaction mixture
wasdiluted with hexane (30 mL) and filtered. The fil-
trate wasextracted with 1 N HCl (2 · 60 mL). The com-
bined aq phases were washed with EtOAc (2 · 60 mL).
The aq phase was made basic (pH ꢀ 13) by adding
2 N NaOH. It wasthen extracted with chloroform
(3 · 60 mL). Drying and concentration of the organic
phase yielded the crude product, which was then purified
on a flash silica column (EtOAc–MeOH 9:1) to afford
(R)-N-sec-hexylimidazole in 75% yield.
5. Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.;
Gaumont, A.-C.; Plaquevent, J.-C. Tetrahedron: Asym-
metry 2003, 14, 3081.
6. (a) Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P.
Tetrahedron Lett. 1997, 38, 3097; (b) Earle, M. J.;
McCormac, P. B.; Seddon, K. R. Green Chem. 1999, 23.
7. (a) Wasserscheid, P.; Bo¨smann, A.; Bolm, C. Chem.
Commun. 2002, 200; (b) Ishida, Y.; Miyauchi, H.; Saigo,
K. Chem. Commun. 2002, 2240; (c) Bao, W.; Wang, Z.; Li,
Y. J. Org. Chem. 2003, 68, 591; (d) Levillain, J.; Dubant,
G.; Abrunhosa, I.; Gulea, M.; Gaumont, A.-C. Chem.
Commun. 2003, 2914; (e) Jodry, J.; Mikami, K. Tetrahe-
Acknowledgements
´
dron Lett. 2004, 45, 4429; (f) Pegot, B.; Vo-Thanh, G.;
Thiswork wasuspported by the KOSEF (R01-2002-
000-00274-0).
Gori, D.; Loupy, A. Tetrahedron Lett. 2004, 45, 6425.
8. (a) Gridnev, A. A.; Mihaltseva, I. M. Synth. Commun.
1994, 23, 1547; (b) Wolkenberg, S. E.; Wisnoski, D. D.;
Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsay, C. W. Org.
Lett. 2004, 6, 1453.
References and notes
9. Hardacre, C.; Holbrey, J. D.; McMath, S. E. J. Chem.
Commun. 2001, 22, 367.
10. There isa literature precedent for the Mitusnobu alkyl-
ation of imidazole. See: Nicolaou, K. C.; Cao, G.-Q.;
Pfefferkorn, J. A. Angew. Chem., Int. Ed. 2000, 39,
739.
1. (a) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.;
Longman: Singapore, 1997, Chapter 8; (b) Grimmett, M.
R. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Boulton, A. J., Eds.; Academic Press: New York, 1980;
Vol. 27.
ˆ
11. Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett.
1993, 34, 1639.
12. Tsunoda, T.; Yamamiya, Y.; Kawamura, Y.; Ito, S.
Tetrahedron Lett. 1995, 6, 2529.
13. (a) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.;
2. For reviews, see: (a) Wilkes, J. S. Green Chem. 2002, 4, 73;
(b) Sheldon, R. Green Chem. 2002, 4, 73; (c) Wasserscheid,
P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772; (d)
Welton, T. Chem. Rev. 1999, 99, 2071; (e) Chauvin, Y.;
Olivier, H. CHEMTECH 1995, 26.
ˆ
ˆ
3. Recent examples: (a) Gu, Y.; Shi, F.; Deng, Y. J. Org.
Chem. 2004, 69, 391; (b) Shi, F.; Xion, H.; Gu, Y.; Guo,
S.; Deng, Y. Chem. Commun. 2003, 1054; (c) Kim, E. J.;
Ko, S. Y.; Song, C. E. Helv. Chim. Acta 2003, 86, 894; (d)
Yamamoto, H.; Ito, S. Tetrahedron Lett. 1996, 37, 2463;
(b) Zaragosa, F.; Stephensen, H. J. Org. Chem. 2001, 66,
2518; (c) Bombrun, A.; Casi, G. Tetrahedron Lett. 2002,
43, 2187.