Synthesis and application of chiral N-heterocyclic carbene-oxazoline ligands: Iridium-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1002/chem.200501500

Two libraries of enantiomerically pure imidazolium salts bearing an oxazoline unit were synthesized. Deprotonation of the imidazolium salts and complexation of the resulting oxazoline-carbene ligands to iridium(i) was achieved in one step by mixing the im

Full text of DOI:10.1002/chem.200501500

DOI: 10.1002/chem.200501500
Synthesis and Application of Chiral N-Heterocyclic Carbene–Oxazoline
Ligands: Iridium-Catalyzed Enantioselective Hydrogenation
Steve Nanchen and Andreas Pfaltz*[a]
Abstract: Two libraries of enantiomeri-
cally pure imidazolium salts bearing an
oxazoline unit were synthesized. De-
protonation of the imidazolium salts
and complexation of the resulting oxa-
zoline–carbene ligands to iridium(i)
was achieved in one step by mixing the
imidazolium salts with NaOtBu and
[(h4-cod)IrCl]2 in THF at room temper-
ature. The air-stable complexes were
purified by flash chromatography. All
complexes were analyzed by two-di-
mensional (2D) NMR methods and
one compound from each family was
characterized by X-ray structure analy-
sis. The two libraries of iridium com-
plexes were successfully tested in the
asymmetric hydrogenation of unfunc-
tionalized and functionalized olefins.
Enantioselectivities of up to 90% ee
were obtained with trans-a-methylstil-
bene. Upon complexation of imidazoli-
um salt 15p with R1 = phenyl, C H
À
bond activation of the phenyl ring gave
rise to iridiumACHTREU(NG iii) complex 17, which
was fully characterized by NMR spec-
troscopy and X-ray structure analysis.
Complex 17 proved to be catalytically
inactive in the hydrogenation.
Keywords: asymmetric catalysis
·
carbene ligands · enantioselectivity ·
hydrogenation · iridium
Introduction
Chiral phosphino-oxazolines A (PHOX ligands) and related
compounds such as B are highly versatile and efficient li-
gands for the enantioselective iridium-catalyzed hydrogena-
tion of imines and a wide range of functionalized and un-
functionalized olefins.[1–4] To improve the enantioselectivity
and widen the application range, many variants of ligands A
and B have been synthesized, giving rise to a large library of
P,N ligands.[5] In addition we developed a series of pyridyl-
phosphinites C and related pyridine- and quinoline-derived
ligands, which were devised to mimic the coordination
sphere of the Crabtree catalyst ([IrACTHERNGU(PCy3)ACHTRE(UNG pyridine)-
ACHTREUNG
(cod)]PF6).[6] These ligands also showed high asymmetric in-
duction in iridium-catalyzed hydrogenations.[7] Other groups
have also reported efficient P,N ligands containing a pyri-
dine or oxazole as the coordinating unit.[8,9]
Recently, Burgess and co-workers synthesized chiral iridi-
um complexes from ligands E containing a seven-membered
chelate ring, in which phosphorus was replaced by an N-het-
erocyclic carbene unit (NHC).[10,11] Among the various de-
rivatives tested, one particular structure 1, with R1 = 1-ada-
mantyl (1-Ad) and R2 = 2,6-diisopropylphenyl clearly gave
the best enantioselectivities with
98% ee for trans-a-methylstilbene.
[a] S. Nanchen, Prof. A. Pfaltz
Although high enantioselectivities
were observed for a range of sub-
strates with this ligand, the overall
performance was still inferior to the
Department of Chemistry, University of Basel
St-Johanns Ring 19, 4056 Basel (Switzerland)
Fax :ACHTREUNG(+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
most efficient P,N ligands. We
became interested in evaluating
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
NHC–oxazoline ligands that form a six-membered chelate
ring because the most efficient P,N ligands for iridium-cata-
lyzed hydrogenation all form such chelate rings.[12]
Previously reported ligands D were thought to be good
candidates for this study.[13] In addition, in view of the good
results obtained with ligands B, we devised a second genera-
tion of oxazoline-carbene ligands (structure F), in which the
R1 substituents are derived from a carboxylic acid. There-
fore, ligand libraries of high structural diversity can be pre-
pared, starting from different carboxylic acid derivatives.
We report herein the synthesis of two libraries of iridi-
um(oxazoline-carbene) complexes Ir-D and Ir-F and their
application in the asymmetric iridium-catalyzed hydrogena-
tion.
Scheme 1. Synthesis of iridium complexes D: i) NEt3, CH2Cl2, RT, 10 h,
Results and Discussion
(83–99%); ii) Burgess reagent, THF, reflux, 4 h, (50–66%); iii) imidazole,
À
DMF, 808C, 8 h; iv) NaBArF (BArF = tetrakis
A
Synthesis of chiral imidazolium salts: The syntheses of imi-
dazolium salts 6a–g and 15a–p, which are precursors of li-
gands D and F, are summarized in Schemes 1 and 2. Imida-
zolium salts 6a–g were synthesized by using a pathway in
which the imidazolium salt moiety is introduced in the last
step, thus allowing easy variation of the imidazolin-2-ylidene
substituents. This route differs from the previously published
synthesis[13] that starts from an imidazole and introduces the
oxazoline ring at the end. The key intermediates, chlorome-
thyloxazolines 5,[14] were prepared by condensation of chloro-
phenyl]borate), CH2Cl2, RT, 15 min, (58–78% over two steps); v) [{(h4-
cod)IrCl}2], NaOtBu, THF, RT, 3 h, (44–65%).
acetyl chloride 3 with (S)-tert-leucinol or (S)-valinol, fol-
lowed by ring-closure by using Burgess reagent.[15,16] After
purification by distillation, chloromethyloxazolines 5 were
allowed to react with a range of imidazoles, which were
either commercially available or prepared according to liter-
ature procedures.[17–19] The resulting imidazolium chlorides
Scheme 2. Synthesis of iridium complexes F: i) (S)-serine methyl ester hydrochloride, NEt3, CH2Cl2, RT, 10 h, (80–93%); ii) Burgess reagent, THF,
reflux, 4 h, (65–72%); iii) 1,2-dichlorethane, reflux, 20 h, (91%); iv) DIBAL, THF, RT, 12 h, (52–78%); v) NEt3, TsCl, CH2Cl2, RT, (50–83%); vi) imida-
À
zole, DMF, 808C, 8 h; vii) NaBArF (BArF = tetrakis
d)IrCl}2], NaOtBu, THF, 3 h, (48–83%).
[3,5-bis(trifluoromethyl)phenyl]borate), acetone, RT, 15 min, (50–78% over two steps); viii) [{(h4-co-
ACHTREUNG
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4551

A. Pfaltz and S. Nanchen
À
were treated with NaBArF (BArF = tetrakisACHTREU[NG 3,5-bis(tri-
fluoromethyl)phenyl]borate) to give the corresponding
À
BArF salts 6a–g in moderate-to-high yield.
À
The weakly coordinating BArF counterion was used for
two reasons. First, it allowed simple purification of imidazo-
lium salts 6a–g by standard chromatography on silica gel,
which was not possible with the corresponding chloride
Scheme 3. Synthesis of complex 17: i) [ {h(4-cod)IrCl}2], NaOtBu, THF,
RT, 3 h, (84%).
À
salts. Second, the BArF ion is known to improve the per-
formance of iridium complexes as hydrogenation catalysts
compared to other weakly coordinating anions such as hexa-
fluorophosphate, tetrafluoroborate, or triflate anions.[20,21]
In the synthesis of ligands F, the imidazolium moiety was
again introduced in the last step (Scheme 2). Oxazolines 12
were obtained by reacting (S)-serine methyl ester hydro-
chloride 9, either with commercially available benzimidate
hydrochloride 8, or with acyl chlorides 10 followed by ring-
closure by using Burgess reagent. Reduction of the ester
group by using diisobutylaluminum hydride (DIBAL) in
THF gave oxazoline alcohols 13 in moderate-to-good yields.
Tosylation and subsequent nucleophilic substitution with a
range of imidazoles yielded the corresponding imidazolium
1
signal at d=À14.6 ppm in the H NMR spectrum. The crys-
tal structure of compound 17 shows the iridium atom in a
pseudo-octahedral coordination environment with the iridi-
um atom lying within 0.02 Š in the best plane fitted through
the carbene atom C13, the phenyl C1 atom, and the mid-
points of the cyclooctadiene double bonds (Figure 1). This
geometry implies that the hydride is located trans to the ox-
azoline ring. Since complex 17 proved to be unreactive in
hydrogenation, no other complexes of this type were synthe-
sized.
À
tosylates, which were converted into BArF salts 15a–p by
anion exchange with NaBArF, followed by flash chromatog-
raphy on silica gel. By this method, four different sets of li-
gands (R1 = tert-butyl, adamantyl, 2,6-dimethylphenyl, and
phenyl) with various R2 groups were prepared.
Preparation of the Ir complexes: Cationic iridium(i) com-
plexes 7a–f and 16a–o were synthesized in a one-step proce-
dure, starting from the corresponding imidazolium salts 6a–
g and 15a–o (Schemes 1 and 2). Deprotonation at the imida-
zolium ring[22] by using sodium tert-butoxide in the presence
of [{(h4-cod)IrCl}2] allowed simultaneous generation and
complexation of the N-heterocyclic carbene.[23] The chloride
anions were removed from the reaction mixture by precipi-
tation as NaCl. The resulting yellow-orange crystalline
Figure 1. Structure of the cation of 17. Selected bond lengths [Š] and
À
À
À
À
angles [8]: Ir1 C1 2.029(4), Ir1 N1 2.159(3), Ir1 C13 2.054(4), Ir1 C23
À
À
À
À
À
BArF salts were purified by flash chromatography on silica
gel.
2.281(4), Ir1 C24 2.300(4), Ir1 C27 2.226(4), Ir1 C28 2.248(4), C23 C24
À
1.380(7), C27 C28 1.373(7); N2-C13-N3 104.3(3), N1-Ir1-C1 78.27(15),
C13-Ir1-N1 78.34(14).
Whereas complexation of imidazolium salts 6a–f was suc-
cessful, no complex formation was observed with imidazoli-
um salt 6g, even when more forcing conditions with a strong
base such as nBuLi were applied. In this particular case,
steric hindrance by the two tert-butyl substituents seems to
prevent complexation of imidazolium salt 6g to the iridium
center. However, the analogous imidazolium salt 15e, which
also contains two tert-butyl groups, was metalated in respect-
able yield (59%).
1
Structural analysis of the Ir complexes: All 13C and H reso-
nances of complexes 7a–f and 16a–o were assigned by
standard two-dimensional (2D) NMR techniques. In the
13C NMR spectra, a shift of the NCN signal from d=
134(Æ3) ppm for the imidazolium salts to d=173(Æ4) ppm
for the carbene complexes was observed upon NHC com-
plexation.
Under the reaction conditions described above, complexa-
tion of imidazolium salt 15p gave an unexpected product 17
as a colorless powder in 84% yield (Scheme 3). Full charac-
terization, including single-crystal X-ray diffraction analysis,
allowed the assignment of structure 17.[24] Apparently, com-
plexation of ligand 15p was accompanied by insertion of the
Single crystals suitable for X-ray analysis were obtained
for complexes 7c and 16q, the latter being an analogue of
À
complex 16b containing PF6 instead of BArFÀ as counterion
(Figures 2 and 3).[25] In both crystal structures, the iridium
atom adopts a nearly square-planar coordination geometry
with the cod double bonds perpendicular to the coordina-
tion planes. The bond angles observed at the carbene cen-
ters (N2-C14-N3 104.88 for 7c and N2-C1-N1 104.38 for
16q) are in good agreement with the value expected for a
singlet N-heterocyclic carbene.[26]
À
iridium(i) center into one of the ortho C H bonds of the
phenyl substituents at the oxazoline ring.
À
The presence of an Ir-bound hydride, resulting from C H
activation, was proven by the observation of a hydride
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Ir-Catalyzed Enantioselective Hydrogenation
FULL PAPER
Table 1. Structural data of complexes 7c and 16q compared with those
of complexes 18,[27] 19,[28] and 20.[29]
Figure 2. Structure of the cation of 7c. Selected bond lengths [Š] and
À
À
À
À
angles [8]: Ir1 C14 2.034(4), Ir1 N1 2.089(4) Ir1 C15 2.175(3), Ir1 C16
À
À
À
À
2.193(4), Ir1 C19 2.105(5), Ir1 C20 2.136(3), C15 C16 1.388(6), C19
C20 1.418(7); N2-C14-N3 104.8(3), N1-Ir1-C14 82.28(15).
Ir–(C=C) distance to the Ir
Ir–(C=C) 13C NMR chemical
atom [pm][a]
shift [ppm]
trans to N
trans to P/C
trans to N
trans to P/C
18
19
20
204
203
201
211
212
212
207
205
67.5 67.4
69.2 64.9
64.5 60.6
65.7 60.1
66.2 56.0
95.0 90.0
102.8 96.6
99.8 97.4
84.6 82.9
80.8 79.9
7c 200
16q 200
[a] Distance calculated from the midpoint of the C=C bond to the iridium
atom.
2,6-diisopropylphenyl, and one threonine-derived phosphin-
ite-oxazoline iridium complex (19). All reactions were set
up under inert atmosphere with 1 mol% catalyst and
0.1 mmol of substrate in CH2Cl2 (0.5 mL).
Figure 3. Structure of the cation of 16q. Selected bond lengths [Š] and
À
À
À
À
angles [8]: Ir1 C1 2.042(3), Ir1 N3 2.094(2), Ir1 C15 2.159(3), Ir1 C16
À
À
À
À
2.167(3), Ir1 C19 2.115(3), Ir1 C20 2.124(3), C15 C16 1.383(6), C19
C20 1.403(5); N2-C1-N1 104.3(3), N3-Ir1-C1 79.47(11).
In the hydrogenation of trans-a-methylstilbene 21, up to
90% ee was obtained with the best catalysts of type D and F
(7a and 16b; Table 2). For type D catalysts (7a–f), the
choice of R1 = tert-butyl is crucial for activity as well as
enantioselectivity; a decrease from 90 to 50% ee was ob-
served when R1 = tert-butyl was replaced by an isopropyl
group. The strong influence of the oxazoline substituent is
consistent with the findings of Burgess and co-workers for li-
gands of type E, which were rationalized by computational
studies that suggested a strong steric interaction between
the R1 substituent and the substrate.[30] Although the R2 sub-
stituent at the imidazolin-2-ylidene unit plays a less impor-
tant role, the asymmetric induction increases when the size
of R2 is reduced (see complexes 7a, 7c, and 7d).
The 13C NMR chemical shifts of the cyclooctadiene olefin-
ic C atoms and the Ir–(C=C) distances trans to the oxazoline
and trans to the NHC moiety were compared with those of
the most efficient P,N ligands developed in our laboratory
(Table 1). According to the observed values, the trans influ-
ence of the imidazolin-2-ylidene group lies between that of
the phosphine and the oxazoline groups. This is reflected by
the Ir–(C=C) distances trans to the coordinating units, which
increase from 200–204 pm for the oxazoline to 205–207 pm
for the imidazolin-2-ylidene and 211–212 pm for the phos-
phine group.
As shown in the crystal structures of complexes 7c
(Figure 2) and 16q (Figure 3), the ligand arrangement
around the iridium atoms in the two complexes is very simi-
lar. In both complexes, the six-membered chelate rings give
rise to rigid structures with the R1 and R2 substituents point-
ing in the same direction.
Both activity and enantioselectivity of type F catalysts
strongly depend on the oxazoline substituent. High conver-
sion was obtained for R1 = tert-butyl and 1-adamantyl, with
the exception of complexes 16e and 16j bearing a tert-butyl
group at the NHC unit. In these two catalysts, the coordina-
tion sphere seems to be too congested to allow high catalytic
activity. With R1 = 2,6-dimethylphenyl, activities were low-
to-moderate (16k–o). As for the D series, the best enantio-
selectivities were recorded for catalysts with a tert-butyl
Enantioselective hydrogenation: To investigate the potential
of these complexes, we tested them in the asymmetric hy-
drogenation of four different unfunctionalized alkenes (21–
24) and one a,b-unsaturated carboxylic ester (25). For each
substrate, our complexes were compared with Burgess’ best
group at the oxazoline ring (16a–e). Replacement of R1
=
tert-butyl by 1-adamantyl reduced the enantioselectivities by
about 20%. With R1 = 2,6-dimethylphenyl, the asymmetric
induction was even lower. Only the catalysts bearing small
catalyst [Ir(1)ACHTREUNG
(cod)]BArF, with R1 = 1-adamantyl and R2 =
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4553

A. Pfaltz and S. Nanchen
Table 2. Hydrogenation of trans-a-methylstilbene 21.[a]
served formation of R products starting from both the E
and Z olefins is in contrast to the general trend that E and
Z olefins give products of opposite configuration.[5] A possi-
ble explanation of these unexpected results could be that
cis–trans isomerization takes place during hydrogenation
such that the reaction of the less-stable Z isomer 23 pro-
ceeds mainly through the E isomer 22.[31] Second, catalysts
16e, 16j, and 16o with a tert-butyl group on the NHC
moiety not only gave low conversion but also no asymmetric
induction (see Table 4).
The terminal olefin 2-(4-methoxyphenyl)-1-butene 24 is a
much more reactive substrate than those discussed so far.
Since previous work on substrate 24 showed that low hydro-
gen pressure increases the asymmetric induction,[5,32] catalyst
screening was performed at 1 bar H2 gas pressure (Table 5).
For type D catalysts, R1 = tert-butyl was required for
high activity. In this series, the importance of the R2 sub-
stituent was demonstrated by a remarkable inversion of
enantioselectivity from 15% ee (R) to 79% ee (S) when R2
= methyl was replaced by an isopropyl group. With a value
of 79% ee, complex 7c was the most selective catalyst of
both the 7a–f and the 16a–o libraries.
Catalyst
Yield [%][b]
ee [%][c]
7a
7b
7c
7d
>99
25[d]
>99
76
90 (R)
55 (R)
87 (R)
59 (R)
84 (R)
85 (R)
89 (R)
90 (R)
79 (R)
87 (R)
78 (R)
69 (R)
72 (R)
61 (R)
71 (R)
66 (R)
68 (R)
59 (R)
rac
7e
96
7 f
99
16a
16b
16c
16d
16e
16 f
16g
16h
16i
16j
16k
16l
16m
16n
16o
>99
>99
>99
>99
66
97
>99
>99
>99
70
27
92
15
58
7
>99
>99
50 (R)
32 (R)
98 (S)
99 (R)
Type F catalysts gave low-to-moderate enantioselectivi-
ties. The best enantiomeric excesses of substrate 24 were
again observed with R1 = tert-butyl, even though the differ-
ence between the tert-butyl and the 1-adamantyl substituent
was less pronounced than for substrates 21, 22, and 23.
[11]
[Ir(1)
(cod)]BArF
19[4]
[a] See Schemes 1 and 2 for formulae for catalysts. [b] Determined by
GC. [c] Determined by HPLC. [d] 5 mol% catalyst.
R2 substituents such as methyl and isopropyl in addition to
the presence of substituent R1 = tert-butyl reached 90% ee,
a trend already observed in the D series.
Table 3. Hydrogenation of (E)-2-(4-methoxyphenyl)-2-butene 22.[a]
Hydrogenation of (E)-2-(4-methoxyphenyl)-2-butene 22
and (Z)-2-(4-methoxyphenyl)-2-butene 23 showed similar
trends (Tables 3 and 4). Contrary to trans-a-methylstilbene,
the highest enantioselectivity values, 87% ee for alkene 22
and 73% ee for alkene 23, were obtained with type F cata-
lysts 16b and 16c, respectively.
Among type D catalysts, complex 7a, which bears the
least bulky substituent on the NHC ring, was again the most
selective catalyst with 76% ee for substrate 22 and 56% ee
for substrate 23.
The results with type F catalysts confirmed the trend that
the R1 substituent has a strong influence on both activity
and enantioselectivity. Similar to the hydrogenation of trans-
a-methylstilbene, catalysts with R1 = tert-butyl gave by far
the highest enantiomeric excesses followed by catalysts with
R1 = 1-adamantyl and R1 = 2,6-dimethylphenyl substitu-
ents. The R2 substituent at the NHC unit allowed fine
tuning of the enantioselectivity of substrates 22 and 23.
While the highest enantiomeric excesses were obtained for
substrate 22 with a small R2 group such as methyl (16a) and
isopropyl (16b), the best enantioselectivities for substrate 23
were obtained with R2 = 2,4,6-trimethylphenyl (16c).
Two further aspects of the hydrogenation of alkene 23
with Ir-F catalysts are remarkable. First, the three catalysts
16k, 16l, and 16n produce the opposite enantiomer. The ob-
Catalyst
Yield [%][b]
ee [%][c]
7a
7b
7c
7d
7e
7 f
>99
5
76 (R)
–
69 (R)
9 (R)
>99
>99
>99
>99
>99
>99
>99
>99
50
>99
>99
>99
>99
87
83
89
20
84
6
>99
>99
69 (R)
69 (R)
85 (R)
87 (R)
75 (R)
84 (R)
80 (R)
69 (R)
71 (R)
61 (R)
73 (R)
75 (R)
74 (R)
59 (R)
11 (R)
61 (R)
rac
16a
16b
16c
16d
16e
16 f
16g
16h
16i
16j
16k
16l
16m
16n
16o
[11]
[Ir(1)
A
91 (S)
99 (R)
19[4]
[a] See Schemes 1 and 2 for formulae for catalysts. [b] Determined by
GC. [c] Determined by HPLC.
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Ir-Catalyzed Enantioselective Hydrogenation
FULL PAPER
Table 4. Hydrogenation of (Z)-2-(4-methoxyphenyl)-2-butene 23.[a]
Table 5. Hydrogenation of 2-(4-methoxyphenyl)-1-butene 24 at 1 bar H2
gas pressure.[a]
Catalyst
Yield [%][b]
ee [%][c]
Catalyst
Yield [%][b]
ee [%][c]
7a
7b
7c
7d
7e
7 f
97
3
>99
65
91
97
>99
>99
>99
>99
68
>99
>99
>99
>99
79
56 (S)
– (S)
7a
7b
7c
7d
7e
7 f
>99
2
15 (R)
–
41 (S)
27 (S)
30 (S)
46 (S)
56 (S)
66 (S)
73 (S)
50 (S)
rac
33 (S)
43 (S)
66 (S)
10 (S)
rac
>99
>99
>99
>99
>99
>99
>99
>99
0
>99
>99
>99
>99
0
>99
90
20
>99
0
>99
>99
79 (S)
54 (S)
70 (S)
78 (S)
69 (S)
66 (S)
55 (S)
65 (S)
–
62 (S)
56 (S)
56 (S)
65 (S)
–
16a
16b
16c
16d
16e
16 f
16g
16h
16i
16j
16k
16l
16m
16n
16o
16a
16b
16c
16d
16e
16 f
16g
16h
16i
16j
16k
16l
16m
16n
16o
89
>99
38
>99
18
95
25 (R)
38 (R)
17 (S)
41 (R)
rac
29 (S)
20 (S)
rac
27 (S)
–
[11]
[Ir(1)
A
78 (R)
72 (S)
19[4]
>99
[11]
[Ir(1)
A
89 (R)
94 (S)
19[4]
[a] See Schemes 1 and 2 for formulae for catalysts. [b] Determined by
GC. [c] Determined by HPLC.
[a] See Schemes 1 and 2 for formulae for catalysts. [b] Determined by
GC. [c] Determined by HPLC.
Complexes 16e, 16j, and 16o, bearing a tert-butyl substitu-
ent on the NHC moiety, showed no catalytic activity.
Finally, our catalyst library was tested in the hydrogena-
tion of (E)-2-methylcinnamic acid ethyl ester 25 (Table 6).
Type D complexes gave moderate enantioselectivities of up
to 59% ee (7a). Complexes with less sterically hindered R2
substituents such as methyl (7a), isopropyl (7c), and isobu-
tyl (7d) were again the most enantioselective catalysts.
Higher enantioselectivities were obtained with catalysts of
type F. Contrary to previous substrates 21–24, the R2 sub-
stituent in complexes 16a–j plays a more important role
than the R1 substituent. The best enantiomeric excesses,
76% and 72% ee, were obtained with R2 = 2,4,6-trimethyl-
phenyl (16c and 16h).
Moreover, in contrast to the results obtained with unfunc-
tionalized alkenes, catalysts with R1 = 1-adamantyl showed
higher ee values than their analogues with R1 = tert-butyl.
With R1 = 2,6-dimethylphenyl (16k–o), enantioselectivities
were moderate. Contrary to catalysts 16a–j, no positive
effect on the asymmetric induction was observed with R2 =
2,4,6-trimethylphenyl.
Table 6. Hydrogenation of (E)-2-methylcinnamic acid ethyl ester 25.[a]
Catalyst
Yield [%][b]
ee [%][c]
7a
7b
>99
0
59 (R)
–
7c
7d
7e
7 f
>99
93
54 (R)
13 (S)
48 (R)
55 (R)
12 (R)
38 (R)
72 (R)
30 (R)
rac
16 (R)
46 (R)
76 (R)
44 (R)
36 (R)
50 (R)
41 (R)
30 (R)
27 (R)
rac
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
96
>99
>99
>99
>99
70
16a
16b
16c
16d
16e
16 f
16g
16h
16i
16j
16k
16l
16m
16n
16o
Conclusion
[11]
[Ir(1)
(cod)]BArF
–
>99
–
19[4]
94 (R)
Simple and efficient syntheses for two families of chiral iri-
dium(oxazoline-carbene) complexes D and F with a six-
membered chelate ring have been developed. The modular
[a] See Schemes 1 and 2 for formulae for catalysts. [b] Determined by
GC. [c] Determined by HPLC.
Chem. Eur. J. 2006, 12, 4550 – 4558
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4555

A. Pfaltz and S. Nanchen
was added (30 mL). The mixture was filtered and concentrated in vacuo.
The crude product was purified by chromatography on silica gel (5”
20 cm column, Rf =0.57, AcOEt) eluting with AcOEt to yield a white
solid (4a, 4.14 g, 83%).
nature of these ligands allowed the preparation of a wide
range of derivatives.
The complexes were tested in the iridium-catalyzed asym-
metric hydrogenation of olefins. Among type D complexes,
catalyst 7a gave the highest enantiomeric excesses for all
substrates except terminal olefin 24. Remarkably, catalyst
7a is the one bearing the least bulky R2 substituent at the
NHC moiety.
Compound 4a: M.p. 69–708C; [a]2D0 =À18.7 (c=1.00, CHCl3); 1H NMR
(400.1 MHz, CDCl3, 300 K): d=6.75 (br, 1H; NH), 4.10 (mc, 2H;
ClCH2), 3.86 (mc, 2H; CH2OH, CHCC
2.13 (br, 1H; OH), 0.97 ppm (s, 9H;
(100.6 MHz, CDCl3, 300 K): d=167.4 (NHCO), 63.1 (NCH2OH), 60.5
(NCHC(CH3)3), 43.3 (ClCH2), 34.0 (C(CH3)3), 27.2 ppm (C(CH3)3); IR
ACHTREUNG
CACHTREUNG
A
N
ACHTREUNG
The most selective catalysts in the F series were found to
be equivalent or superior to type D complexes. Good enan-
tioselectivities were generally induced by catalysts with a
bulky tert-butyl or adamantyl–oxazoline unit in combination
with a smaller methyl or isopropyl group at the NHC
moiety. The functionalized substrate 25 was an exception.
Here, the most efficient catalyst was complex 16h bearing
two bulky groups (1-adamantyl and 2,4,6-trimethylphenyl).
The six-membered chelate complexes differ strongly from
the seven-membered chelate analogues E developed by Bur-
gess. Whereas only one particular complex of type E ([Ir(1)-
(KBr): n˜ =3405 (mbr), 3277 (m), 2963 (m), 1665 (s), 1636 (s), 1531 (s),
1369 (w), 1276 (w), 1088 (w), 1049 (m), 911 (w), 771 (w), 666 cmÀ1 (w);
MS (FAB): m/z (%): 194 (100) [M+H]+; elemental analysis calcd (%)
for C8H16ClNO2 (193.67): C 49.61, H 8.33, N 7.23, O 16.52; found: C
49.22, H 8.37, N 7.04, O 16.68.
General procedure for the preparation of chloromethyloxazolines 5a and
5b: A solution of chloroacetamide 4a (1.29 g, 6.65 mmol) and methyl-N-
triethylammoniosulfonyl-carbamate (1.74 g, 7.32 mmol) in THF (20 mL)
was refluxed for 12 h. The mixture was concentrated in vacuo. The resi-
due was diluted with dichloromethane and extracted three times with
water. The organic layer was dried over anhydrous magnesium sulfate
and concentrated in vacuo. The crude product was purified by distillation
(508C, 0.1 mbar) to yield a colorless oil (5a, 1.45 g, 50%).
ACHTREUNG
(cod)]BArF with R1 = 1-adamantyl and R2 = 2,6-diisopro-
Compound 5a: [a]2D0 =À108.5 (c=0.94, CHCl3); 1H NMR (400.1 MHz,
pylphenyl) was found to give high enantioselectivities, sever-
al representatives of type D and F were identified that in-
duced similar ee levels. In contrast to the Burgess’ catalysts,
which require large substituents both at the NHC and oxa-
zoline units for high enantioselectivity, the six-membered
chelate analogues D and F in general give better results
with less sterically demanding ligands. However, despite the
wide range of D and F type catalysts investigated, the enan-
CDCl3, 300 K): d=4.28 (mc, 1H; CH2O), 4.15 (mc, 1H; CH2O), 4.10
(mc, 2H; ClCH2), 3.91 (mc, 1H; NCHC
(CH3)3); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K): d=162.4 (OCN),
76.1 (NCHCH(CH3)2), 69.8 (CH2O), 36.5 (ClCH2), 33.8 (C(CH3)3),
25.8 ppm (C(CH3)3); IR (NaCl): n˜ =2957 (s), 2906 (m), 2870 (m), 1671
ACHTRE(UNG CH3)3), 0.89 ppm (s, 9H; C-
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
(s), 1479 (m), 1430 (w), 1395 (w), 1360 (m), 1243 (m), 1155 (w), 983 (s),
944 (w), 892 (w), 733 cmÀ1 (w); MS (FAB, Xe, 8 kV): m/z (%): 176 (100)
[M+H]+; elemental analysis calcd (%) for C8H14ClNO (175.66): C 54.70,
H 8.03, N 7.97; found: C 53.83, H 7.90, N 8.03.
General procedure for the preparation of imidazolium salts 6a–g: A solu-
tion of chloromethyloxazoline 5a (235 mg, 1.33 mmol) and 1-methyl-1H-
imidazole (93 mg, 1.33 mmol) in DMF (0.4 mL) was heated at 808C for
8 h. The mixture was concentrated in vacuo at 808C and the residue was
diluted in CH2Cl2 (5 mL). NaBArF (1.18 g, 1.33 mmol) was added to the
solution, which was then stirred at room temperature for 30 min. The
mixture was filtered and concentrated in vacuo. The crude product was
purified by chromatography on silica gel (5”8 cm column) eluting with
CH2Cl2 (1 L) to yield a white solid (6a, 1.13 g, 78%).
tiomeric excesses are not as high as those obtained with
Burgess’ best complex [Ir(1)ACHTER(UNG cod)]BArF. Nevertheless, our
results indicate that carbene-oxazoline ligands of this type
have considerable potential. Their modular nature, which
enables easy tuning of the ligand structure, suggests that
these ligands could be applied in other areas of asymmetric
catalysis.
Compound 6a: M.p. 103–1048C; [a]2D0 =À8.2 (c=0.50, CHCl3); 1H NMR
(400.1 MHz, CDCl3, 300 K): d=8.31 (s, 1H; NCHN), 7.69 (mc, 8H; BArF
ortho-CH), 7.53 (mc, 4H; BArF para-CH), 7.15 (mc, 1H; imid CH), 6.95
(mc, 1H; imid CH), 4.71 (mc, 2H; NCH2), 4.27 (mc, 1H; oxaz CH2), 4.14
(mc, 1H; oxaz CH2), 3.88 (mc, 1H; oxaz CH), 3.70 (s, 3H; NCH3),
Experimental Section
0.82 ppm (s, 9H; tBu CH3); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K):
1
d=162.1 (q, J
A
General: Reactions with air- or moisture-sensitive compounds were per-
formed under Ar gas by using standard Schlenk techniques or under pu-
rified N2 gas in an MBraun glovebox. Glassware was oven- and flame-
dried prior to use. All chemicals were purchased from Fluka Chemie
GmbH (Buchs, Switzerland) with the exception of 3,5-bis(trifluorometh-
yl)-bromobenzene, which was obtained from Fluorochem Ltd (Derby-
shire, UK). Diethyl ether, pentane, and tetrahydrofuran were dried over
sodium/benzophenone, dichloromethane over CaH2 and all were freshly
distilled under a stream of nitrogen prior to use. Melting points were
measured with a Büchi 535 melting point apparatus and were not correct-
ed. Optical rotations: sodium lamp, 1-dm cuvette, c in g per 100 mL.
HPLC analysis: Shimadzu Systems, SCL-10 A system controller, CTO-
10 AC column oven, LC10-AD pump system, DGU-14 A degasser, SPD-
M10 A diode-array detector or UV/Vis detector (220 and 254 nm).
135.7 (NCHN), 135.1 (br, 8C; BArF ortho-CH), 129.3 (qq, 2J
ACHTREUNG
31.12 Hz, 3J(B,C)=2.9 Hz, 8C; BArF C ipso to CF3), 124.9 (q, 1J
A
ACHTREUNG
AHCTREUNG
46.7 (NCH2), 37.0 (NCH3), 33.8 (tBu C), 25.8 ppm (3C; tBu CH3); IR
(KBr): n˜ =3185 (w), 2967 (w), 1686 (w), 1610 (w), 1356 (m), 1277 (s),
1115 (sbr), 887 (w), 838 (w), 743 (w), 711 (w), 682 (w), 671 (w), 623 cmÀ1
(w); MS (FAB): m/z (%): 222 (100) [MÀBArF]+; elemental analysis
calcd (%) for C44H32BF24N3O (1085.52): C 48.68, H 2.97, N 3.87; found:
C 48.72, H 2.99, N 3.84.
General procedure for the preparation of iridium complexes 7a–f and
16a–p: Freshly sublimed NaOtBu (14.3 mg, 0.148 mmol) was added to a
solution of imidazolium salt 6a (161 mg, 0.148 mmol) and [(h4-cod)IrCl]2
(50 mg, 0.074 mmol) in THF (10 mL). The reaction mixture was stirred at
room temperature for 3 h and was then concentrated in vacuo. The crude
product was purified by chromatography on silica gel (3”20 cm column)
eluting with CH2Cl2 to yield a yellow/orange solid (7a, 134 mg, 65%).
General procedure for the preparation of chloroacetamides 4a and 4b:
A
solution of (S)-tert-leucinol (3.02 g, 25.8 mmol) and triethylamine
(5.2 g, 51.6 mmol) in CH2Cl2 (100 mL) was cooled to À208C under argon
gas. Chloroacetyl chloride (2.91 g, 25.8 mmol) was added dropwise over
5 min. The cooling bath was removed and the mixture was stirred at
room temperature for 12 h. After concentration in vacuo, ethyl acetate
Compound 7a: [a]2D0 =+48 (c=0.159, CHCl3); 1H NMR (500.1 MHz,
CDCl3, 295 K): d=7.70 (mc, 8H; BArF ortho-CH), 7.53 (mc, 4H; BArF
4556
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4550 – 4558

Ir-Catalyzed Enantioselective Hydrogenation
FULL PAPER
para-CH), 6.81 (mc, 1H; imid CH), 6.79 (mc, 1H; imid CH), 4.98 (mc,
1H; NCH2), 4.61 (mc, 1H; oxaz CH2), 4.49 (mc, 1H; cod CH), 4.38 (mc,
2H; NCH2, oxaz CH2), 4.15 (mc, 2H; cod CH), 3.86 (mc, 1H; cod CH),
3.80 (mc, 1H; oxaz CH), 3.74 (s, 3H; NCH3), 2.29 (mc, 2H; cod CH2),
2.11 (mc, 2H; cod CH2), 2.00 (mc, 2H; cod CH2), 1.75 (mc, 1H; cod
CH2), 1.63 (mc, 1H; cod CH2), 0.73 ppm (s, 9H; tBu CH3); 13C{1H} NMR
(125.7 MHz, CDCl3, 295 K): d=174.1 (NCN), 165.1 (OCN), 161.7 (q,
Compound 12p: [a]2D0 =+99.3 (c=1.36, CHCl3); 1H NMR (400.1 MHz,
CDCl3, 300 K): d=7.97 (mc, 2H; arom CH), 7.49 (mc, 1H; arom CH),
7.40 (mc, 2H; arom CH), 4.95 (mc, 1H; oxaz CH), 4.69 (mc, 1H; oxaz
CH2), 4.59 (mc, 1H; oxaz CH2), 3.81 ppm (s, 3H; OCH3); 13C{1H} NMR
(100.6 MHz, CDCl3, 300 K): d=172.0 (CO2CH3), 166.7 (NCO), 132.3
(arom CH), 129.0 (2C; arom CH), 128.8 (2C; arom CH), 127.3 (arom
C), 70.0 (oxaz CH2), 69.0 (oxaz CH), 53.1 ppm (CO2CH3); IR (NaCl):
n˜ =2953 (w), 1742 (s), 1642 (m), 1450 (w), 1362 (m), 1210 (m), 1090 (m),
1026 (w), 971 (w), 779 (w), 697 cmÀ1 (m); MS (FAB): m/z (%): 206 (100)
[M+H]+; elemental analysis calcd (%) for C11H11NO3 (205.21): C 64.38,
H 5.40, N 6.83; found: C 64.26, H 5.66, N 7.06.
1J
ortho-CH), 128.9 (qq, 2J
ipso to CF3), 124.5 (q, 1J
CH), 121.1 (imid CH), 117.5 (sept, 3J
AHCTREUNG
ACHTREUNG
A
A
C
AHCTREUNG
85.4 (cod CH), 81.9 (cod CH), 73.3 (oxaz CH), 72.8 (oxaz CH2), 64.4
(cod CH), 59.0 (cod CH), 46.8 (NCH2), 38.0 (NCH3), 34.0 (cod CH2),
33.5 (tBu C), 31.1 (cod CH2), 29.9 (cod CH2), 28.3 (cod CH2), 25.1 ppm
(3C; tBu CH3); IR (KBr): n˜ =2971 (w), 1648 (w), 1610 (w), 1435 (w),
1355 (m), 1277 (s), 1124 (sbr), 960 (w), 894 (w), 839 (w), 712 (w), 682
(w), 671 cmÀ1 (w); MS (FAB): m/z (%): 522 (100) [MÀBArF]+; elemental
analysis calcd (%) for C52H43BF24IrN3O (1384.91): C 45.10, H 3.13, N
3.03; found: C 45.25, H 3.24, N 2.87.
General procedure for the preparation of oxazoline alcohols 13p,a,f,k:
Ester 12p (11.0 g, 53.9 mmol) and dried THF (300 mL) were added
under argon gas to a 2 L round-bottomed flask equipped with a ther-
mometer and an addition funnel. A solution of DIBAL in THF (170 mL,
1.0 mmolmLÀ1) was added dropwise at À108C. The mixture was stirred
overnight at room temperature. A solution of the Seignette salt (400 mL,
20% w/w) was carefully added with stirring and the mixture was extract-
ed three times with ethyl acetate. The combined organic layers were
dried over magnesium sulfate and concentrated in vacuo to yield a
yellow oil. The crude product was purified by chromatography on silica
gel (7”20 cm column, Rf =0.33) eluting with AcOEt to yield a white
solid (13p, 6.4 g, 67%).
Compound 13p: M.p. 99–1008C; [a]2D0 =+89.0 (c=1.00, CHCl3);
1H NMR (400.1 MHz, CDCl3, 300 K): d=7.97 (mc, 2H; arom CH), 7.42
(mc, 1H; arom CH), 7.31 (mc, 2H; arom CH), 4.30–4.50 (m, 3H; 2”
oxaz CH2, 1”oxaz CH), 3.99 (mc, 1H; CH2OH), 3.65 (mc, 1H; CH2OH),
3.53 ppm (br, 1H; OH); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K): d=
166.0 (NCO), 131.9 (arom CH), 128.7 (2C; arom CH), 128.6 (2C; arom
CH), 127.5 (arom C), 69.5 (oxaz CH2), 68.5 (oxaz CH), 64.1 ppm
(CH2OH); IR (KBr): n˜ =3266 (sbr), 2928 (m), 1652 (s), 1500 (m), 1363
(m), 1276 (m), 1098 (m), 958 (m), 783 (w), 693 cmÀ1 (m); MS (FAB): m/z
(%): 178 (100) [M+H]+; elemental analysis calcd (%) for C10H11NO2
(177.20): C 67.78, H 6.26, N 7.90, O 18.06; found: C 67.60, H 6.28, N
7.87, O 17.80.
General procedure for the preparation of compounds 11a,f,k: A solution
of (S)-serine methyl ester hydrochloride (6.00 g, 38.6 mmol) and triethyl-
amine (11.7 g, 115.7 mmol) in CH2Cl2 (150 mL) was cooled to À108C
under argon gas. Pivaloyl chloride (4.65 g, 38.6 mmol) was added drop-
wise over 5 min. The mixture was stirred at room temperature for 12 h
and was then diluted with water (100 mL). The dichloromethane layer
was separated, dried over magnesium sulfate, and concentrated in vacuo
to yield a yellow oil. The crude product was purified by chromatography
on silica gel (7”30 cm column, Rf =0.43) eluting with a mixture of
AcOEt and hexane (4:1) to yield a colorless oil (11a, 5.90 g, 80%).
Compound 11a: [a]2D0 =+24.6 (c=1.00, CHCl3); 1H NMR (400.1 MHz,
CDCl3, 300 K): d=6.61 (br, 1H; NH), 4.63 (mc, 1H; NHCHCO2CH3),
3.93 (mc, 2H; CH2OH), 3.78 (s, 3H; CO2CH3), 2.68 (br, 1H; OH),
1.23 ppm (s, 9H; C
d=179.7 (NCO), 171.6 (CO2CH3), 64.1 (CH2OH), 55.2 (NHCHCO2),
53.2 (CO2CH3), 39.2 (C(CH3)3), 27.8 ppm (C(CH3)3); IR (NaCl): n˜ =3396
ACHTREUNG
(CH3)3); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K):
A
ACHTREUNG
(sbr), 2960 (s), 2878 (m), 1744 (s), 1645 (s), 1521 (s), 1438 (m), 1368 (m),
1204 (s), 1081 (m), 979 (w), 938 (w), 857 cmÀ1 (w); MS (FAB): m/z (%):
204 (100) [M+H]+, 57 (66); elemental analysis calcd (%) for C9H17NO4
(203.24): C 53.19, H 8.43, N 6.89; found: C 52.88, H 8.54, N 7.00.
General procedure for the preparation of tosylate 14p,a,f,k: Triethyl-
AHCTREaUNG mine (3.98 g, 39.4 mmol) was added dropwise to a solution of alcohol
13p (6.35 g, 35.8 mmol) and tosyl chloride (13.65 g, 71.6 mmol) in di-
chloromethane (40 mL). The mixture was stirred at room temperature
for 8 h and was then concentrated in vacuo to remove the solvent. The
crude product was purified by chromatography on silica gel (7”25 cm
column, Rf =0.48, AcOEt/hexane 1:1) eluting with a mixture of AcOEt
and hexane (from 3:7 to 7:3) to yield a colorless oil that crystallized on
standing (14p, 8.41 g, 71%).
Compound 14p: M.p. 109–1108C; [a]2D0 =+96.5 (c=1.00, CHCl3);
1H NMR (400.1 MHz, CDCl3, 300 K): d=7.86 (mc, 2H; tos CH), 7.77
(mc, 2H; tos CH), 7.49 (mc, 1H; arom CH), 7.40 (mc, 2H; arom CH),
7.30 (mc, 2H; arom CH), 4.49 (mc, 2H; oxaz CH, oxaz CH2), 4.34 (mc,
1H; oxaz CH2), 4.27 (mc, 1H; CH2OH), 4.04 (mc; CH2OH), 2.43 ppm (s,
3H; tos CH3); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K): d=145.4 (tos
C), 132.9 (tos C), 132.3 (arom CH), 130.3 (2C; tos CH), 128.8 (2C; arom
CH), 128.8 (2C; arom CH), 128.4 (2C; tos CH), 127.3 (arom C), 71.1
(CH2), 70.3 (CH2), 65.4 (oxaz CH), 22.1 ppm (tos CH3), 1 quat C not de-
tected; IR (NaCl): n˜ =2976 (w), 1648 (m), 1452 (w), 1366 (s), 1269 (w),
1176 (s), 1023 (m), 969 (m), 837 (m), 690 (m), 555 cmÀ1 (m); MS (FAB):
m/z (%): 332 (100) [M+H]+; elemental analysis calcd (%) for
C17H17NO4S (331.39): C 61.61, H 5.17, N 4.23, O 19.31; found: C 61.56, H
5.20, N 4.19, O 19.50.
General procedure for the preparation of esters 12a,f,k: A solution of
amide 11a (2.40 g, 12.6 mmol) and methyl N-triethylammoniosulfonyl-
carbamate (3.29 g, 13.8 mmol) in THF (40 mL) was refluxed for 12 h.
The mixture was concentrated in vacuo and the residue was diluted in di-
chloromethane. The organic layer was extracted three times with water,
dried over magnesium sulfate, and concentrated in vacuo to give an oil
that was purified by distillation (458C, 0.08 mbar) to yield a colorless oil
(12a, 1.51 g, 65%).
Compound 12a: [a]2D0 =+150.9 (c=0.94, CHCl3); 1H NMR (400.1 MHz,
CDCl3, 300 K): d=4.67 (mc, 1H; oxaz CH), 4.42 (mc, 1H; oxaz CH2),
4.34 (mc, 1H; oxaz CH2), 3.74 (s, 3H; CO2CH3), 1.20 ppm (s, 9H; C-
ACHTREUNG
(CH3)3); 13C{1H} NMR (100.6 MHz, CDCl3, 300 K): d=177.3 (NCO),
172.3 (CO2CH3), 69.8 (oxaz CH2), 68.5 (oxaz CH), 52.9 (CO2CH3), 33.8
(C(CH3)3), 28.1 ppm (C(CH3)3); IR (NaCl): n˜ =2975 (s), 1742 (s), 1651
A
ACHTREUNG
(s), 1482 (m), 1438 (m), 1396 (w), 1363 (m), 1300 (m), 1144 (s), 1061 (w),
981 (m), 785 (w), 728 cmÀ1 (w); MS (FAB): m/z (%): 186 (100) [M+H]+;
elemental analysis calcd (%) for C9H15NO3 (185.22): C 58.36, H 8.16, N
7.56; found: C 58.17, H 7.98, N 7.61.
Preparation of ester 12p: Ethyl benzimidate hydrochloride (5.00 g,
26.9 mmol) was dissolved in dichloromethane (100 mL). The solution was
extracted three times with an aqueous solution of NaHCO3 and concen-
trated in vacuo to yield an oil (3.77 g). The oil was dissolved in 1,2-di-
chlorethane (150 mL) and (S)-serine methyl ester hydrochloride (4.32 g,
27.8 mmol) was added. The suspension was refluxed for 20 h, then was
filtered and concentrated in vacuo to remove the solvent. The crude
product was purified by chromatography on silica gel (7”30 cm column,
Rf =0.57) eluting with a mixture of AcOEt and hexane (3:1) to yield a
colorless oil (12p, 5.02 g, 91%).
General procedure for the preparation of imidazolium salts 15a–p: A sol-
ution of tosylate 14a (400 mg, 1.28 mmol) and 1-methyl-1H-imidazole
(105 mg, 1.28 mmol) in DMF (0.5 mL) was heated at 808C for 8 h. The
mixture was concentrated in vacuo at 808C and the residue was diluted
in acetone (5 mL). NaBArF (1.13 g, 1.28 mmol) was added to the solution
that was stirred at room temperature for 30 min. The mixture was filtered
and concentrated in vacuo to remove the solvent. The crude product was
purified by chromatography on silica gel (5”10 cm column) eluting with
CH2Cl2 (1 L) to yield a white solid (15a, 1.06 g, 0.973 mmol, 76%).
Chem. Eur. J. 2006, 12, 4550 – 4558
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4557

A. Pfaltz and S. Nanchen
Compound 15a: M.p. 120–1218C; [a]2D0 =+35.5 (c=1.00, CHCl3);
1H NMR (500.1 MHz, CDCl3, 295 K): d=8.45 (s, 1H; NCHN), 7.69 (mc,
8H; BArF ortho CH), 7.52 (mc, 4H; BArF para CH), 7.07 (mc, 1H; imid
CH), 6.92 (mc, 1H; imid CH), 4.40 (mc, 1H; oxaz CH2), 4.30 (mc, 1H;
oxaz CH), 4.05 (mc, 1H; NCH2), 3.81 (mc, 2H; oxaz CH2, NCH2), 3.72
(s, 3H; NCH3), 1.16 ppm (s, 9H; tBu CH3); 13C{1H} NMR (125.7 MHz,
mann, Adv. Synth. Catal. 2003, 345, 33–44; b) for a recent review,
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CDCl3, 295 K): d=178.0 (OCN), 161.7 (q, 1J
(B,C)=49.9 Hz, 4C; BArF
quat C ipso to B), 135.3 (NCHN), 134.7 (br, 8C; BArF ortho CH), 129.0
(qq, 2J
A
G
1
(q, J
A
117.5 (sept, 3J
(oxaz CH), 54.1 (NCH2), 36.5 (NCH3), 33.5 (tBu C), 27.4 ppm (3C; tBu
CH3); IR (KBr): n˜ =3163 (w), 3098 (w), 2980 (w), 1655 (w), 1610 (w),
1577 (w), 1562 (w), 1482 (w), 1356 (m), 1282 (s), 1122 (sbr), 932 (w), 889
(w), 839 (w), 745 (w), 713 (w), 682 (w), 671 (w), 624 cmÀ1 (w); MS
(FAB): m/z (%): 222 (100) [MÀBArF]+; elemental analysis calcd (%) for
C44H32BF24N3O (1085.52): C 48.68, H 2.97, N 3.87; found: C 48.63, H
3.15, N 3.64.
General procedure for catalytic hydrogenation at elevated pressure: In a
glovebox, 0.1 mmol substrate, 1 mol% iridium complex, and 0.5 mL
CH2Cl2 were added to a 60-mL autoclave (Premex AG, Lengnau, Swit-
zerland) with four glass inserts (1.5 mL) and magnetic stirrer bars. The
autoclave was pressurized to 50 bar H2 gas (Carbagas, Switzerland,
99.995%) and the mixture was stirred for 2 h. After pressure release, the
solvent was evaporated and heptane (3 mL) was added. The resulting
suspension was filtered through a short plug of silica gel (0.5”6 cm) elut-
ing with a mixture of hexane and Et2O (1:1) and the filtrate was analyzed
by GC and chiral HPLC to determine conversion and enantioselectivity
(for analytical procedures and data, see reference [3]).
General procedure for catalytic hydrogenation at low pressure (1 bar
H2): A solution of 0.1 mmol substrate with 1 mol% iridium complex in
dry CH2Cl2 (2–3 mL) was prepared under inert atmosphere in a 20 mL
Schlenk flask (1~1.5 cm). The mixture was stirred for 0.5–2 h with slow
bubbling of hydrogen gas through the solution introduced through a
stainless-steel needle. The temperature was kept constant at 258C by
using a water bath. Work-up and analyses were performed as described
for the hydrogenation at high pressure.
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ylidene on the DMSO scale: R. W. Alder, M. E. Blake, J. M. Oliva,
J. Phys. Chem. A 1999, 103, 11200–11211. For N,N-di-tert-butyl-imi-
dazolin-2-ylidene, a pKa of 20 on the THF scale was reported: Y.-J.
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265.
Crystal structure analysis: CCDC-288265 (7c), CCDC-288267 (16q), and
CCDC-288266 (17) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
À
[24] Burgess and co-workers observed the formation of a similar C H in-
sertion product. See Supporting Information of references [10] and
[11].
Acknowledgements
[25] Synthesis of 16q was achieved by reacting [{(h4-cod)IrCl}2] and
NaOtBu in THF at room temperature with the corresponding imida-
zolium salt bearing a chloride counterion, followed by addition of
TlPF6 in CH2Cl2 at room temperature.
Financial support by the Swiss National Science Foundation is gratefully
acknowledged. We thank Dr. Sylvia Schaffner, Markus Neuburger, and
Stefan Kaiser for the crystal structure analyses. We also thank Novartis
(Basel) and OMG AG & Co (Germany) for free samples of valuable
starting materials.
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2000, 100, 39–91.
[27] S. P. Smidt, PhD thesis, University of Basel (Switzerland), 2003.
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Received: December 1, 2005
Published online: March 24, 2006
4558
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