Bicyclic imidazoles for modular synthesis of chiral imidazolium salts

Article abstract of DOI:10.1021/ol1003737

The preparation of new chiral bicyclic imidazoles 5 and their transformation into imidazolium salts 6 and 7 are reported. The utility of the salts as precursors for chiral N-heterocyclic carbenes was demonstrated by the synthesis of C-N-C pincer Ni-complex 13h, the structure of which was characterized by single-crystal X-ray analysis.

Full text of DOI:10.1021/ol1003737

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1764-1767
Bicyclic Imidazoles for Modular
Synthesis of Chiral Imidazolium Salts
Kazuhiro Yoshida,* Shingo Horiuchi, Tomoko Takeichi, Hiroaki Shida,
Tsuneo Imamoto, and Akira Yanagisawa*
Department of Chemistry, Graduate School of Science, Chiba UniVersity,
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
kyoshida@faculty.chiba-u.jp
Received February 12, 2010
ABSTRACT
The preparation of new chiral bicyclic imidazoles 5 and their transformation into imidazolium salts 6 and 7 are reported. The utility of the salts
as precursors for chiral N-heterocyclic carbenes was demonstrated by the synthesis of C-N-C pincer Ni-complex 13h, the structure of which
was characterized by single-crystal X-ray analysis.
Chiral N-heterocyclic carbenes (NHCs) have recently re-
ceived growing attention in the fields of coordination
chemistry and asymmetric catalysis.1 Among the chiral
NHCs reported so far, those generated from bicyclic azolium
salts, such as triazolium salts 1-3 or imidazolium salt 4,
are one of the successful classes of compounds used for
Figure 1. Known chiral bicyclic azolium salts.
various asymmetric reactions (Figure 1).2 These NHCs,
which are classified as NHCs that possess a chiral component
on the nitrogen atom, present an advantage for asymmetric
induction, which arises from the restriction of unfavorable
internal rotation around the N-C (substituent) axis due to
the fused bicyclic molecular structure. The common features
of azolium salts 1-4 are their possession of aryl groups on
the nitrogen atom,3 which likely affects both reactivity and
selectivity, and their method of preparation. Condensation
using C1-fragments to construct the azolium rings has been
employed as the final transformation step to access these
salts.
(1) For recent reviews, see: (a) N-Heterocyclic Carbenes in Synthesis;
Nolan, S. P., Ed.; Wiley-VCH; Weinheim, Germany, 2006. (b) N-
Heterocyclic Carbenes in Transition Metal Catalysis; Glorius, F., Ed.;
Springer; Berlin, Germany, 2007. (c) Enders, D.; Niemeier, O.; Henseler,
A. Chem. ReV. 2007, 107, 5606–5655. (d) D´ıez-Gonza´lez, S.; Marion, N.;
Nolan, S. P. Chem. ReV. 2009, 109, 3612–3676.
(2) For examples, see: (a) Knight, R. L.; Leeper, F. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 1891–1894. (b) Enders, D.; Kallfass, U. Angew.
Chem., Int. Ed. 2002, 41, 1743–1745. (c) Kerr, M. S.; Read de Alaniz, J.;
Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298–10299. (d) Glorius, F.;
Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704–
2705. (e) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005,
70, 5725–5728. (f) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem.,
Int. Ed. 2006, 45, 1463–1467. (g) Takikawa, H.; Hachisu, Y.; Bode, J. W.;
Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492–3494. (h) Seayad, J.;
Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 953–956. (i) Ma,
Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Lan, J.; Yang, S.; You, J. AdV.
Synth. Catal. 2008, 350, 2645–2651. (j) Wang, X.-N.; Shao, P.-L.; Lv, H.;
Ye, S. Org. Lett. 2009, 11, 4029–4031. For a review, see: (k) Arduengo,
A. J., III; Iconaru, L. I. Dalton Trans. 2009, 6903–6914.
In 2008, Ishida and Saigo reported an efficient method
for the preparation of chiral N-alkyl bicyclic imidazolium
salts, which involved the alkylation of morpholine-fused
(3) For examples of related chiral N-alkyl azolium salts, see: (a) Struble,
J. R.; Bode, J. W. Tetrahedron 2008, 64, 6961–6972. (b) Enders, D.; Han,
J.; Henseler, A. Chem. Commun. 2008, 3989–3991. (c) Metallinos, C.; Xu,
S. Org. Lett. 2010, 12, 76–79.
10.1021/ol1003737  2010 American Chemical Society
Published on Web 03/16/2010

imidazoles.4 Although the alkylation of existing imidazoles
is a well-known strategy for the preparation of azolium salts,
it is not common for chiral bicyclic azolium salts.
Herein we report the preparation of new chiral bicyclic
imidazoles5 5 and the transformation of 5 into chiral
imidazolium salts, including N-alkyl imidazolium salts 6 and
bisimidazolium salts6 7 (Figure 2). As 7 are prepared with
available (S)-N-formylvaline with (R)-2-phenylglycinol and
the resulting 8a was treated with tosyl chloride under basic
conditions to produce oxazoline 9a. Bicyclic imidazole (R)-
5a was obtained by dehydration of 9a with phosphorus
pentoxide. The introduction of a formyl group on the
N-terminus8 of 8a was critical to the success of the reaction.
Other synthetic routes in which the imidazole ring was
constructed from imine oxazoline and electrophilic C1-
fragments were unsuccessful. As the dehydrating agent,
phosphorus pentoxide showed the best result for the final
step and low yields were observed with other reagents, such
as POCl3. When we tried to prepare (R)-5b, which has a
methyl group at the R1 position, by means of the same
procedure using (S)-N-formylalanine instead of (S)-N-
formylvaline as the starting material, the final dehydration
step of the oxazole ring was unsuccessful.
Figure 2. Modular synthesis of chiral bicyclic imidazolium salts 6
and 7.
We also prepared chiral pyrrolidine-fused imidazole 5c,
which has a simpler structure than 5a and 5b (Scheme 2). A
the intent of applying them to metal-catalyzed asymmetric
reactions,1a,b,d,7 the synthesis and the crystal structure of a
new chiral Ni-complex are also presented.
Scheme 2. Preparation of Chiral Pyrrolidine-Fused Imidazole 5c
First of all, we tried to prepare chiral oxazolidine-fused
imidazole (R)-5a (Scheme 1). After many attempts, we found
Scheme 1
.
Preparation of Chiral Oxazolidine-Fused Imidazoles
5a and 5b
synthetic route that was based on Browne’s procedure9
starting from commercially available urocanic acid 10 was
employed for this purpose and racemic 5c was efficiently
furnished. Enantiomerically pure (R)-5c and (S)-5c were
obtained from the racemic product by separation, using
preparative HPLC with a chiral column.
The results of the synthesis of N-alkyl imidazolium salts
6 and bisimidazolium salts 7 are summarized in Table 1.
When the reaction of 5a with iodomethane was performed
at 70 °C in acetonitrile, the desired N-methyl imidazolium
salt 6a10 was obtained in good yield, as expected (entry 1).
On the other hand, when the reaction of 5a with dibro-
momethane was performed, only decomposed products were
formed instead of bisimidazolium salt 7a (entry 2). The
reaction with 1,2-dibromoethane was also unsuccessful and
N-2-bromoethyl imidazolium salt was obtained as the major
product with a trace amount of 7b (entry 3). These results
can be attributed to the steric interaction between the two
imidazoles. In fact, for the synthesis of 7c and 7d, which
that a stepwise construction of two rings from diamide 8a,
which contains all the components required for the bicyclic
structure, is the appropriate approach to obtain (R)-5a.
Compound 8a was prepared by the condensation of readily
(4) Matsuoka, Y.; Ishida, Y.; Saigo, K. Tetrahedron Lett. 2008, 49,
2985–2989.
(5) For examples of known chiral bicyclic imidazoles, see: (a)
Tschamber, T.; Siendt, H.; Tarnus, C.; Deredas, D.; Frankowski, A.;
Kohler, S.; Streith, J. Eur. J. Org. Chem. 2002, 702–712. (b) Weinberg,
K.; Jankowski, S.; Le Nouen, D.; Frankowski, A. Tetrahedron Lett. 2002,
43, 1089–1092. (c) Frankowski, A.; Deredas, D.; Dubost, E.; Gessier, F.;
Jankowski, S.; Neuburger, M.; Seliga, C.; Tschamber, T.; Weinberg, K.
Tetrahedron 2003, 59, 6503–6520. (d) Deredas, D.; Skowron, M.; Salomon,
E.; Tarnus, C.; Tschamber, T.; Wolf, W. M.; Frankowski, A. Tetrahedron
2007, 63, 2915–2922.
(8) Fu¨rstner and co-workers reported a powerful method for the synthesis
of imidazolium salts from N-formylamines, see: Fu¨rstner, A.; Alcarazo, M.;
Ce´sar, V.; Lehmann, C. W. Chem. Commun. 2006, 2176–2178.
(9) (a) Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager,
A. J. Med. Chem. 1991, 34, 725–736. (b) Pirrung, M. C.; Pei, T. J. Org.
Chem. 2000, 65, 2229–2230.
(6) You et al. reported chiral bistriazolium salts and their applications
to asymmetric intermolecular benzoin condensation. See ref 2i.
(7) (a) Lowry, R. J.; Veige, M. K.; Cle´ment, O.; Abboud, K. A.;
Ghiviriga, I.; Veige, A. S. Organometallics 2008, 27, 5184–5195, and
references cited therein. (b) Ma, G.-N.; Zhang, T.; Shi, M. Org. Lett. 2009,
11, 875–878
.
(10) See the Supporting Information for the crystal structure of 6a.
Org. Lett., Vol. 12, No. 8, 2010
1765

Table 1. Synthesis of Chiral Imidazolium Salts 6 and 7 from Imidazoles 5a
a All reactions were carried out in CH3CN or MeOH at 70-80 °C. b Isolated yields.
have long cross-linkers, the reaction proceeded without any
problems (entries 4 and 5). Moreover, the reaction of 5a with
Merrifield resin11 gave corresponding imidazolium salt 6b
(entry 6). Pyrrolidine-fused imidazolium salts were likewise
prepared. The reaction of 5c with iodomethane, isopropyl
bromide, and 2-bromomethylpyridine gave N-alkylated salts
6c-e, respectively (entries 7-9). In contrast to 5a, the
reaction of more compact 5c produced methylene, ethylene,
and propylene bridged bisimidazolium salts 7e-g regardless
of the lengths of the cross-linkers (entries 10-12). These
results suggest that the steric bulkiness of the isopropyl group
of 5a is responsible for the failure of the formation of 7a
and 7b (entries 2 and 3). The last example is the formation
of bisimidazolium salt 7h that has a pyridyl moiety in the
cross-linker (entry 13). The reaction of 5c with 2,6-
bis(bromomethyl)pyridine12 proceeded well to give desired
product 7h in 97% yield.
The synthesized imidazolium salts can be utilized as
precursors for chiral NHCs. For example, we tried to
synthesize C-N-C pincer Ni-complex1a,13 13h from 7h
(Scheme 3). The transformation was performed by reacting
(12) Danopoulos, A. A.; Tulloch, A. A. D.; Winston, S.; Eastham, G.;
Hursthouse, M. B. Dalton Trans. 2003, 1009–1015.
(11) Wang, Z.; Yan, J.; Zhang, X.; Wang, L. Synlett 2009, 3744–3750.
1766
Org. Lett., Vol. 12, No. 8, 2010

Scheme 3
.
Synthesis of C-N-C Pincer Ni-Complex 13h from
7h
NiCl2(DME) with a silver complex that was prepared from
7h and Ag2O, followed by counteranion exchange with
AgBF4.14 As a result, chiral complex 13h was obtained in
45% yield. Similar to the general agreement for NHC
complexes, 13h was found to be quite stable in air. Its
purification was possible even by open silica gel column
chromatography.
A single crystal suitable for X-ray single-crystal structure
determination was obtained by slow diffusion of pentane into
a solution of 13h in CH2Cl2. The structure of 13h displays
an expected C2-symmetric chiral environment with square-
planar coordination geometry (Figure 3).15
In conclusion, we have prepared new chiral bicyclic
imidazoles 5 and applied them to the modular synthesis of
imidazolium salts 6 and 7. Obviously, this approach can
provide a wide variety of imidazolium salts beyond the range
we have demonstrated here. Our ongoing study is focusing
Figure 3. Crystal structure of 13h: Hydrogen atoms are omitted
-
for clarity (perspective view). Hydrogen atoms, CH2Cl2, and BF4
anion are omitted for clarity (top and front views).
on various asymmetric reactions using these salts, and the
results will be reported in due course.
Acknowledgment. We appreciate the financial support
from the Uehara Memorial Foundation and NOVARTIS
Foundation (Japan) for the Promotion of Science. We also
thank Nippon Chemical Industrial Co., Ltd. for lending
Daicel Chiralcel OD-H (2 cm × 25 cm).
(13) (a) Pugh, D.; Danopoulos, A. A. Coord. Chem. ReV. 2007, 251,
610–641. (b) Poyatos, M.; Mata, J. A.; Peris, E. Chem. ReV. 2009, 109,
3677–3707.
(14) Inamoto, K.; Kuroda, J.; Kwon, E.; Hiroya, K.; Doi, T. J.
Organomet. Chem. 2009, 694, 389–396.
1
Supporting Information Available: H NMR and 13C
(15) The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 761554. These data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 IEZ, UK; fax (+44) 1223-336-033; e-mail
deposit@ccdc.cam.ac.uk).
NMR spectra of new compounds and X-ray crystal structure
files (CIF) for 6a and 13h. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1003737
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