Oxazolines as chiral building blocks for imidazolium salts and N-heterocyclic carbene ligands

Article abstract of DOI:10.1039/b208045a

Enantiomerically pure imidazolium triflates can be readily prepared from bioxazolines and oxazolineimines; deprotonation of imidazolium triflate 2 gives a chiral N-heterocyclic carbene that can act as a ligand in a catalytically active palladium complex.

Full text of DOI:10.1039/b208045a

Oxazolines as chiral building blocks for imidazolium salts and
N-heterocyclic carbene ligands†
Frank Glorius,* Gereon Altenhoff, Richard Goddard and Christian Lehmann
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim/Ruhr, Germany.
E-mail: glorius@mpi-muelheim.mpg.de; Fax: (+49) 208-306-2994; Tel: (+49) 208-306-2428
Received (in Cambridge, UK) 15th August 2002, Accepted 3rd October 2002
First published as an Advance Article on the web 18th October 2002
Enantiomerically pure imidazolium triflates can be readily
prepared from bioxazolines and oxazolineimines; deproto-
nation of imidazolium triflate 2 gives a chiral N-heterocyclic
carbene that can act as a ligand in a catalytically active
palladium complex.
Presumably AgCl and trifluoromethylsulfonyloxymethyl
pivalate are formed under the reaction conditions. The latter
enables the smooth alkylation of the acid and nucleophile
sensitive oxazolines and subsequent cyclisation to give the
obtained imidazolium salts in high yields. However, treatment
of benzyl substituted bioxazoline 5 under the described reaction
conditions did not give any product 6 due to the formation of a
stable silver complex of 5. In this case stirring of AgOTf and
chloromethyl pivalate in CH2Cl2 for 1 h, followed by filtration
and subsequent addition of the filtrate to 5 led to the formation
of the desired imidazolium salt 6. Difficulties in the purification
of 6 are responsible for the low yield of 36%.
To expand the scope of this new synthetic method we
synthesised unsymmetrical oxazolineimines from readily avail-
able alcohol 78 by oxidation with MnO2 followed by imine
formation with the corresponding aniline derivatives. We were
pleased to find that submission of these oxazolineimines to the
standard cyclisation conditions led to the smooth formation of
the imidazolium triflates 8 and 9 in 80 and 83% yield,
respectively (Scheme 2).9
Transition metal complexes of N-heterocyclic carbenes (NHC)
are an important class of compounds for coordination chemistry
and catalysis.1 The strong s-donor properties of NHC’s
combined with poor p-acceptor ability result in metal com-
plexes with high chemical and thermal stability together with
good catalytic activity. Successful application of these com-
plexes in asymmetric catalysis is evolving,2 but electronic and
steric variations of NHC’s will be necessary for further progress
in this field.
Oxazolines are powerful structural elements, which have
been incorporated in many chiral ligands successfully used in
asymmetric catalysis.3 However, despite their obvious benefits
they have not as yet been used as building blocks to form other
functional groups in chiral ligands. We reasoned that incorpora-
tion of oxazolines into imidazolium salts would lead to valuable
rigid ligand architectures. We began our investigations with
readily available (S)-valinol derived bioxazoline 1.4 In analogy
to procedures for the transformation of glyoxal derived diimines
into imidazolium salts,5 we treated 1 with chloromethyl ethyl
ether in THF at 40 °C. Instead of imidazolium salt formation the
attack of chloride anions led to opening of the oxazoline rings.
The additional use of stoichiometric amounts of silver triflate in
CH2Cl2 was found to give the desired 2, together with other
products in a complex mixture. Screening of other silver salts
with different solvents at various temperatures did not improve
the results. Fortunately, using silver triflate in combination with
chloromethyl pivalate instead of chloromethyl ethyl ether led to
the clean conversion of 1 to imidazolium triflate 2 in an isolated
yield of 80% (Scheme 1).‡ The structure of 2 was unequivocally
determined by an X-ray crystallographic analysis.6 Following
the same procedure (S)-tert-leucinol derived bioxazoline 3 gave
imidazolium triflate 4 in 75% yield. To the best of our
knowledge, these compounds represent the first 4,5-dialkoxy-
substituted 1,3-disubstituted imidazolium salts. Furthermore,
this new method works equally well for milligram and
multigram quantities. In contrast to many other imidazolium
salts7 the resulting triflate salts are readily soluble in CH2Cl2 or
THF and can be purified by column chromatography followed
by crystallisation.
Scheme 2 Reagents and conditions: (i) MnO2, NEt3, EtOH; (ii) aniline
derivative, toluene, reflux; (iii) AgOTf, chloromethyl pivalate, CH2Cl2, 40
°C.
With these imidazolium salts in hand we were prompted to
investigate their transformation into NHC’s and metal com-
plexes thereof. Imidazolium triflate 2 was readily deprotonated
with 10 mol% KOtBu and a stoichiometric amount of KH to
give N-heterocyclic carbene 10 (Scheme 3). This carbene is
reasonably stable in THF at r.t. and was characterized by its
NMR data. In a carbene-typical reaction10 addition of sulfur led
to the formation of imidazole-2(3H)-thione 11. Palladium
complex 12 was best prepared by deprotonation of the
imidazolium salt 2 in the presence of the palladium precursor
with a stoichiometric amount of KOtBu. Purification by flash
Scheme 1
† Electronic supplementary information (ESI) available: spectroscopic data
for 10 and 12. See http://www.rsc.org/suppdata/cc/b2/b208045a/
Scheme 3 Reagents and conditions: (i) KH, KOtBu, THF; (ii) S8, 59% (two
steps); (iii) Pd(OAc)2, KOtBu, NaI, THF, 87%.
2704
CHEM. COMMUN., 2002, 2704–2705
This journal is © The Royal Society of Chemistry 2002

ically pure imidazolium salts, which opens up the possibility of
synthesising a new class of N-heterocyclic carbenes for
asymmetric catalysis.
We thank Professor A. Fürstner for generous support. F. G.
thanks the Fonds der Chemischen Industrie for a Liebig
fellowship.
Notes and references
‡
General imidazolium triflate formation: to a mixture of bioxazoline 1
(5.0 g, 22.2 mmol) and AgOTf (6.8 g, 26.6 mmol) were added CH2Cl2 (75
mL) and then chloromethyl pivalate (4.6 mL, 31.2 mmol). The tube was
sealed and stirred in the dark at 40 °C for 24 h. After the solution was cooled
to r.t. the mixture was filtered, the solvent evaporated in vacuo and the
resulting oil was chromatographed on silica gel (4 3 10 cm, CH2Cl2–MeOH
20+1). Subsequent crystallisation from a solvent mixture comprising THF
(30 mL), toluene (150 mL) and pentane (50 mL) gave 6.85 g (80%) of
imidazolium triflate 2 as colorless crystals.
Rf = 0.37 (CHCl3–MeOH 93+7); [a]20 = 55.0 (c 1.0, CH2Cl2); IR
D
Fig. 1 Structure of 12. Selected distances (Å) and angles (°): Pd–C1
2.035(3), Pd–I 2.6139(5), C8…C8* 3.838(11), C11…C11* 3.819(12); C1–
Pd–C1* 179.0(3), mean plane (C1–C6, N1, N2, O1, O2, Pd)/mean plane
(C1*–C6*, N1*, N2*, O1*, O2*, Pd) 50(1).
(KBr): 3110, 2970, 1731, 1532, 1481, 1285, 1261, 1154, 1032, 966, 917,
1
882, 826, 755, 638; H NMR (400 MHz, CDCl3): d 8.73 (s, 1H, NCHN),
5.07 (dd, J 7.9, 9.0 Hz, 2H, CH2), 4.98–4.93 (m, 2H, CHCH2), 4.83 (dd, J
4.1, 9.0 Hz, 2H, CH2), 2.33 (m, 2H, CHCH3), 1.03 (d, J 6.9 Hz, 6H, CH3),
0.99 (d, J 6.9 Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3): d 125.6 (NCO),
120.6 (q, J 320 Hz, CF3), 116.3 (NCHN), 79.1 (CH2), 63.9 (CHCH2), 31.1
(CHCH3), 17.6 (CH3), 16.7 (CH3); 19F NMR (300 MHz, CDCl3): d 278.7
(CF3); MS (EI), m/z (%) 386 (0.4) [M+], 237 (100), 169 (5), 69 (7); MS
(ESI+): m/z (%) 237 (100). HRMS (EI): calc. for C13H21N2O2 (cation):
237.1603, found 237.1605. Anal. Calc. for C14H21F3N2O5S: C, 43.52; H,
5.48. Found C, 43.44; H, 5.55%.
chromatography yielded the air-stable complex 12 in 87% yield.
Unlike related palladium complexes,11 12 was formed solely as
the trans isomer. The structure was validated by an X-ray
structure analysis (Fig. 1).6 In the crystal the molecule adopts a
conformation in which the two imidazolylidene ligands are
twisted relative to one another, resulting in short H…H contacts
(2.06, 2.15 Å)12 between the methyne H atoms of isopropyl
groups on adjacent ligands, presumably caused by steric
interaction between the chirally positioned isopropyl groups
and the iodide ligands.
Lee and Hartwig recently reported on the enantioselective a-
arylation of amides, giving oxindole 14 in an isolated yield of
74% with 57% ee using 5 mol% of catalyst.13 We chose 13 as
substrate to test the imidazolium triflates 2, 4 and 6 (Table 1).
Using imidazolium salt 2 as a NHC precursor and a Pd(0) or
Pd(2) source in a 1+1 ratio gave a very good yield of oxindole
14 with an ee of around 30% (entries 1 and 2). Complex 12
could also be used as a catalyst precursor; however, higher
temperature and a longer reaction time were needed (entry 3).
Interestingly, 40% of complex 12 were recovered after
completion of the reaction. Slightly better results were obtained
with the tBu-substituted imidazolium triflate 4. With Pd2(dba)3
the reaction was run at r.t. and gave the product 14 in a very
good yield and with 43% ee (entry 4). At a slightly higher
temperature the reaction could also be brought to completion
using only 1 mol % of the catalyst (entry 6).
1 W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41, 1291; D. Bourissou,
O. Guerret, F. P. Gabbaï and G. Bertrand, Chem. Rev., 2000, 100, 39.
2 M. T. Powell, D.-R. Hou, M. C. Perry, X. Cui and K. Burgess, J. Am.
Chem. Soc., 2001, 123, 8878; T. J. Seiders, D. W. Ward and R. H.
Grubbs, Org. Lett., 2001, 3, 3225; J. J. Van Veldhuizen, S. B. Garber, J.
S. Kingsbury and A. H. Hoveyda, J. Am. Chem. Soc., 2002, 124,
4954.
3 Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer, Berlin, 1999; A. K. Ghosh, P. Mathivanan and
J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1; T. G. Gant and A. I.
Meyers, Tetrahedron, 1994, 50, 2297.
4 D. Müller, G. Umbricht, B. Weber and A. Pfaltz, Helv. Chim. Acta,
1991, 74, 232; G. Helmchen, A. Krotz, K.-T. Ganz and D. Hansen,
Synlett, 1991, 257.
5 A. J. Arduengo III, R. Krafczyk, R. Schmutzler, H. A. Craig, J. R.
Goerlich, W. J. Marshall and M. Unverzagt, Tetrahedron, 1999, 55,
14523.
6 Crystal data: for 2: [C13H21N2O2]+[CF3O3S]2, from THF/toluene/
pentane, orthorhombic, space group P212121 (no. 19), M = 386.39, a =
9.6882(3), b = 11.0578(3), c = 16.3800(5) Å, U = 1754.8(1) Å3, T =
100 K, Z = 4, m(Mo-Ka) = 0.242 mm21, 22778 refl. meas., 3622
unique (Rint = 0.081), R = 0.037 [I > 2s(I)], wR(F2) = 0.084 (all
In conclusion, we report a new straightforward method to
transform bioxazolines and oxazolineimines into enantiomer-
data), Flack param.
= 20.05(7). For 12·2(CHCl3): [C26H40I2-
N4O4Pd]·2[CHCl3], from chloroform–heptane, orthorhombic, space
group P21212 (no. 18), M = 1071.56, a = 12.257(3), b = 13.001(3), c
= 12.305(3) Å, U = 1960.9(7) Å3, T = 200 K, Z = 2, m(Mo-Ka) =
2.49 mm21, 68069 reflections measured, 6714 unique (Rint = 0.087),
chloroform disordered, R = 0.043 [I > 2s(I)], wR(F2) = 0.085 (all
data), Flack parameter = 20.02(3). CCDC 191920 and 1919201. See
http://www.rsc.org/suppdata/cc/b2/b208045a/ for crystallographic data
in CIF format.
Table 1 Enantioselective a-arylation of amide 13
7 A. J. Arduengo III, H. V. Rasila Dias, R. L. Harlow and M. Kline, J. Am.
Chem. Soc., 1992, 114, 5530; W. A. Herrmann, C. Köcher, L. J.
Goossen and G. R. J. Artus, Chem. Eur. J., 1996, 2, 1627.
8 L. N. Pridgen and G. Miller, J. Heterocycl. Chem., 1983, 20, 1223; J. V.
Allen and J. M. J. Williams, Tetrahedron: Asymmetry, 1994, 5, 277.
9 For a related triazolium salt, see: D. Enders and U. Kallfass, Angew.
Chem., Int. Ed., 2002, 41, 1743.
Entry
Catalyst
T/°C
Time/h
Yielda (%) % Eeb
1
2
3
4
5
6c
7
2 + Pd2(dba)3
2 + Pd(OAc)2
12
4 + Pd2(dba)3
4 + Pd(OAc)2
4 + Pd2(dba)3
6 + Pd2(dba)3
50
50
90
20
50
50
50
5
5
85
92
95
95
90
97
90
28 (+)
32 (+)
30 (+)
43 (+)
35 (+)
37 (+)
11 (+)
20
14
14
14
16
10 A. J. Arduengo III, Acc. Chem. Res., 1999, 32, 913.
11 W. A. Herrmann, M. Elison, J. Fischer, C. Köcher and G. R. J. Artus,
Angew. Chem., Int. Ed. Engl., 1995, 34, 2317; D. Enders and H. Gielen,
J. Organomet. Chem., 2001, 617–618, 70.
12 Using a calculated C–H distance of 0.98 Å. For a discussion of short
H…H contacts, see: J. D. Dunitz and A. Gavezzotti, Acc. Chem. Res.,
1999, 32, 677.
a Isolated yield. b Determined by HPLC with Chiralcel OD–H. c 1 mol%
catalyst.
13 S. Lee and J. F. Hartwig, J. Org. Chem., 2001, 66, 3402.
CHEM. COMMUN., 2002, 2704–2705
2705