Iridium catalysts with chiral imidazole-phosphine ligands for asymmetric hydrogenation of vinyl fluorides and other olefins

Article abstract of DOI:10.1002/adsc.200800062

New chiral bidentate imidazole-phosphine ligands have been prepared and evaluated for the iridium-catalysed asymmetric hydrogenation of olefins. The imidazole-phosphine-ligated iridium catalysts hydrogenated trisubstituted olefins with the same sense of enantiodiscrimination as known iridium catalysts possessing oxazole and thiazole as N-donors. The imidazole-based catalysts were shown to hydrogenate vinyl fluorides, in some cases with the highest ee values published to date.

Full text of DOI:10.1002/adsc.200800062

FULL PAPERS
DOI: 10.1002/adsc.200800062
Iridium Catalysts with Chiral Imidazole-Phosphine Ligands for
Asymmetric Hydrogenation of Vinyl Fluorides and other Olefins
Päivi Kaukoranta,a Mattias Engman,a Christian Hedberg,b Jonas Bergquist,c
and Pher G. Anderssona,*
a
Department of Biochemistry and Organic Chemistry, Box 576, SE-75123 Uppsala, Sweden
Fax : (+46)-18-471-3818; e-mail: pher.andersson@biorg.uu.se
Department of Chemical Biology, Max Planck Institute of Physiology, Otto Hahn Strasse 11, 442 27 Dortmund, Germany
Department of Physical and Analytical Chemistry, Analytical Chemistry, Box 599, SE-75124 Uppsala, Sweden
b
c
Received: January 29, 2008; Published online: April 11, 2008
Dedicated to Professor Andreas Pfaltz on his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: New chiral bidentate imidazole-phosphine The imidazole-based catalysts were shown to hydro-
ligands have been prepared and evaluated for the iri- genate vinyl fluorides, in some cases with the highest
dium-catalysed asymmetric hydrogenation of olefins. ee values published to date.
The imidazole-phosphine-ligated iridium catalysts
hydrogenated trisubstituted olefins with the same
sense of enantiodiscrimination as known iridium cat- Keywords: asymmetric hydrogenation; iridium; N,P
alysts possessing oxazole and thiazole as N-donors. donating ligand; vinyl fluorides
Introduction
The enantioselective hydrogenation of olefins em-
ploying iridium complexes with chiral N,P-chelating
ligands has recently emerged as a valuable tool in
asymmetric synthesis.[1] Whereas highly enantioselec-
tive hydrogenation using rhodium and ruthenium di-
phosphane complexes is limited to substrates that
contain a coordinating polar group next to the
carbon-carbon double bond, iridium complexes with
chiral N,P-chelating ligands give high enantioselectivi-
ties with both non-functionalised and functionalised
olefins. Pioneering work by Pfaltz and his co-workers
on the first chiral mimic of Crabtreeꢀs catalyst[2,3] have
been followed by a number of reports describing new
chiral N,P-chelating ligands for efficient and sub-
strate-tolerant iridium-catalysed asymmetric hydroge-
nation of double bonds.[4]
Recently our group undertook a kinetic and com-
putational study of the asymmetric hydrogenation of
(E)-1,2-diphenyl-1-propene with Pfaltzꢀs iridium-
PHOX complex.[5] This led us to develop new chiral
N,P-donating oxazole-phosphinite (A) ligands, which
were successfully employed in the Ir-catalysed asym-
Figure 1. Oxazole-phosphinite (A) and thiazole-phosphine
(B) ligands and the new class of imidazole-phosphine (C) li-
metric hydrogenation of olefins (Figure 1).[6] This new
class of aromatic heterocyclic ligands was further ex- gands.
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Iridium Catalysts with Chiral Imidazole-Phosphine Ligands
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panded with the introduction of the thiazole phos- ever, the synthetic methods available for introducing
phines (B), which were superior to the oxazole li- a fluorine-containing stereogenic centre are still
gands in terms of both selectivity and versatility.[7] scarce.[9] We have recently accomplished this through
The synthetic route to the thiazole-phosphine ligands the iridium-catalysed asymmetric hydrogenation of
allowed structural variations in both the phosphine several vinyl fluorides,[10] and Nelson et al. have re-
and thiazole moieties.
ported on the asymmetric hydrogenation of cyclic
Encouraged by the excellent results accomplished vinyl fluorides using Rh-Walphos.[11] Extending the
for asymmetric hydrogenation utilising ligands A and scope of asymmetric vinyl fluoride hydrogenation
B, we wanted to further develop the heteroaromatic would improve a potentially valuable tool for phar-
moiety and evaluate imidazoles as chiral ligands. Be- maceutical industry.
cause annular isomers could be obtained with the imi-
dazole that corresponds to oxazole and thiazole, imi-
dazole (C) was chosen as a better alternative for the Results and Discussion
new ligand structure (Figure 1). Since oxazole- and
thiazole-based ligands possess somewhat different Synthesis of the Imidazole-Phosphines and
substrate scopes, our hope was that this new set of li- Corresponding Iridium Complexes
gands would enable the enantioselective hydrogena-
tion of additional classes of substrates.
As shown in Scheme 1, the imidazole-phosphine li-
In particular, vinyl fluorides are a class of olefins gands are readily accessible from simple, commercial-
that is difficult to enantioselectively hydrogenate. Or- ly available starting materials. Fischer esterification of
ganofluorine compounds are increasing in popularity 2-aminonicotinic acid gave ester 1, which underwent
within the pharmaceutical and fine chemical indus- condensation with a-bromoacetophenone to give 2 in
tries, and a growing number of active pharmaceutical good yield (84%).[12] The regioselective hydrogenation
products now contain fluorine, such as top selling an- of 2 was first attempted with PtO2, but this gave over-
tidepressants like Fluoxetine and Paroxetine.[8] How- reduction of the phenyl ring, leaving only imidazole
Scheme 1. Synthesis of iridium complexes 12–14: a) 2-butanone, reflux overnight, 84%; b) Pd/C, 100 bar H2, TFA, room tem-
perature, overnight, 92%; c) LiAlH4, THF, room temperature, overnight, 87%; d) preparative HPLC; Chiracel OD; e) TsCl,
pyridine, CH2Cl2, 08C to room temperature, 70%; f) Ar2P
A
ture, overnight; h) [IrCl(COD)]2, CH2Cl2, reflux 1 h then H2O, NaBArF·xH2O, room temperature, 1 h.
AHCTREUNG
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Figure 2. The chromatogram for the chiral separation of the enantiomers of 4 using Chiracel OD-column (20”250 mm)
100% i-PrOH, 3 mLminÀ1. The absolute configurations were assigned by analogy to the corresponding thiazoles, which give
the same elution order in chiral HPLC, sign of optical rotation and sense of enantioselection in asymmetric hydrogenation.[7]
unreduced. We next employed Raney nickel, which values were low (33–84%) for the ethyl a-methyl-
resulted in a complicated mixture. Finally, Pd/C in trans-cinnamate (Table 1, entries 3 and 4)
TFA afforded 3 in good yield (92%). The imidazole
To our surprise the hydrogenation of an allylic alco-
ester derivative 3 was reduced using LiAlH4 to the hol (Table 1, entry 7) gave mixtures of products when
corresponding alcohol 4, which could be resolved into catalysed by complexes 12 and 14, but proceeded
pure enantiomers by surprisingly effective chiral smoothly with complex 13, giving the product in high
HPLC separation (Figure 2). The use of Chiralcel OD ee (92%). The hydrogenation of the corresponding al-
as chiral stationary phase resulted in retention times lylic acetate (Table 1, entry 8) gave low conversions
that differed for the two enantiomers by more than except with complex 13, and low ee values with all
40 min; this permitted the separation of gram quanti- complexes. The asymmetric hydrogenation of an iso-
ties of 4.
The enantiopure alcohol 4 was converted to its to- (Table 1, entries 9 and 10) resulted in varying conver-
sylate 5 and substitution with Ar2P(BH3)Li and subse- sions and only modest enantioselectivities.
quent deprotection with Et2NH gave the free phos- A comparison of the iridium-catalysed asymmetric
phines 9–11. These were complexed to [IrCl(COD)]2 hydrogenation using imidazole, thiazole and oxazole
and anion exchange with NaBArF gave the iridium ligands is shown in Figure 3. All the complexes of
meric allylic alcohol and the corresponding acetate
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complexes 12–14 in good yields (60–90%).
these three ligand types gave high ee values for the
hydrogenation of non-functionalised olefin (substrates
15, 16, 19 and 20); whereas for functionalised olefins
(substrates 17, 18, 23 and 24), both the conversions
and enantioselectivities were very ligand-dependent.
The calculated structures of the ground state of the
Asymmetric Hydrogenation of Olefins
Complexes 12–14 were evaluated as catalysts for the
asymmetric hydrogenation of some trisubstituted ole- ligand-Ir-ethene complexes were optimised in the
fins that have been used as standard substrates Jaguar program[13] with the B3LYP hybrid density
(Table 1). The new complexes proved to be efficient theory functional and the LACVP basis set. The
catalysts with few exceptions and the selectivities structures are similar and almost overlapping for the
were comparable to those obtained with complexes of complexes of A, B and C, which reflects the similar
A and B. Enantioselectivities varied from good to ex- results for asymmetric hydrogenation of non-function-
cellent for olefins that do not contain polar groups alised olefins (Figure 4). The more disparate results
next to the carbon-carbon double bond (Table 1, en- obtained for hydrogenation of allylic alcohol and ace-
tries 1, 2, 5 and 6). As with ligands A and B, high ee tate and for cinnamate esters may be related to the
values (93–95%) were achieved for the hydrogenation different heteroaromatic moieties of ligands A, B and
of ethyl b-methyl-trans-cinnamate, whereas the ee C. As well, the mechanisms of hydrogenation for
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Table 1. Results of asymmetric hydrogenation with complexes 12–14.[a]
Entry
Substrate
Conv.[b] [%]
ee[c] [%]
93 (R)
Conv.[b] [%]
ee[c] [%]
96 (R)
Conv.[b] [%]
ee[c] [%]
98 (S)
1
2
3
4
15
16
17
18
>99
>99
>99
>99
>99
>99
>99
>99
>99
94 (R)
93 (R)
66 (R)
>99
>99
>99
89 (R)
93(R)
33 (R)
92 (S)
95 (S)
84 (S)
5
6
19
20
>99
>99
70 (S)
90 (R)
>99
>99
31 (S)
89 (R)
>99
>99
72 (R)
86 (S)
7
8
9
21
22
23
24
Complex mixture
>99
>99
50
92 (R)
14 (R)
84 (R)
70 (R)
Complex mixture
23
25
68
37 (R)
61 (R)
63 (R)
20
18 (S)
75 (S)
73 (S)
50
10
>99
>99
[a]
Absolute configurations of products in parantheses after ee value. Reactions conditions: 0.25M substrate in CH2Cl2,
50 bar H2, 0.5 mol% Ir complex, room temperature, overnight.
Determined by H NMR spectroscopy.
Determined by chiral GC/MS or chiral HPLC.
[b]
[c]
1
functionalised and unfunctionalised olefins might be the complex of oxazole-phosphinite, it was interesting
different, as has been discussed.[1c,14]
to evaluate the complex 12 with the same substrate.
Indeed, the complex of imidazole ligand, which has
the most basic N-donor, gives less defluorination and
more enantioselectivity in the hydrogenation of 25
(Table 2).
Asymmetric Hydrogenation of Vinyl Fluorides
We have studied defluorination and enantioselection
Given that catalyst 12, with a basic imidazole
in the asymmetric hydrogenation of 25 by iridium ligand, performed well in the hydrogenation of 25, we
complexes a (oxazole-phosphinite) and b (thiazole- wanted to evaluate this ligand class with other vinyl
phosphine) and found that the electronic properties fluorides (Table 3). The best results, up to 86% ee,
of the ligand backbone and the phosphorus atom in- were achieved with the Z-isomers of allylic acetates
fluenced the chemoselectivity of asymmetric hydroge- and alcohols (Table 3, entries 4 and 6). Defluorination
nation of fluoroolefins by N,P-ligated iridium cata- was also lowest with these substrates. Remarkably,
lysts.[10] Because the complex of the more basic thia- catalysts 12 and 14 hydrogenated allylic acetates to
zole ligand was shown to give less defluorination than the same enantiomer of product, regardless of the
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Figure 3. Comparision of imidazole, thiazole and oxazole ligands in iridium-catalysed asymmetric hydrogenation of trisubsti-
tuted olefins. The results for the hydrogenations with a and b are found in previous reports.[6,7] The hydrogenation of sub-
strates 18–20 has not been evaluated with catalyst a.
Table 2. The pKa values of the ligand backbone nitrogen in a, b, and 12 compared to the defluorination ratio, conversion and
enantiomeric excess of the product after hydrogenation of 25.[a]
[b]
pKa
0.8
2.5
7.0
X:Y
Conv. [%]
60:40
43
68:32
31
79:21
16
ee [%]
4 (S)
12 (R)
72 (S)
[a]
Reaction conditions: 100 bar H2, 72 h, 408C in CH2Cl2.
pKa values correspond to the unsubstituted heterocycles.[15]
[b]
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THF was freshly distilled under N2 from a deep-blue solu-
tion of sodium-benzophenone ketyl prior to use. CH2Cl2 was
freshly distilled under N2 from powdered CaH2 prior to use.
Flash chromatography was performed using silica gel 60 Š
(37–70 mm). Analytical TLC was carried out utilising
0.25 mm plates precoated with silica gel 60 UV254 and spots
were visualised by the use of UV light or ethanolic phospho-
molybdic acid (5%) followed by heating. For NMR spectros-
copy, samples were dissolved in CDCl3 and analysed at
room temperature. 1H (300, 400 or 500 MHz), 13C (75 or
100 MHz) and 19F (282 or 376 MHz) NMR spectra were re-
corded on a 300, 400 or 500 MHz spectrometer whereas 31P
(121 MHz) NMR spectra were recorded on a 300 MHz spec-
trometer in C6D6. The relative shifts for phosphorus are re-
ported relative to external H3PO4. Chemical shifts for pro-
tons are reported using the residual CHCl3 as internal refer-
ence (d=7.26). Carbon signals are referenced to the shift
from the 13C signal of CDCl3 (d=77.0). The chemical shifts
for fluorine are reported relative to external CFCl3. Mass
spectra were measured at 70 eV (EI). IR spectra was mea-
sured using an FT-IR apparatus. Optical rotation was mea-
sured using a sodium lamp (589 nm). The samples were di-
rectly infused into an orthogonal acceleration time-of-flight
mass spectrometer Agilent LC/MSD TOF (AgilentTechnol-
ogies, Santa Clara, CA, USA). Detection was performed in
positive ion mode. The voltage applied at the sampling ca-
pillary at the entrance of the mass spectrometer was 4.0 kV.
Nitrogen at 3008C and 7 LminÀ1 was used as drying gas.
Nebuliser gas at 15 LminÀ1 was used. Voltages fixed at frag-
mentor, skimmer and octopole guides were 215 V, 60 V and
250 V, respectively. The ion pulser at the TOF analyser was
set up to a measurement a frequency of 0.5 cycles/s. Agilent
TOF software and Agilent TM QS software were used to
record and analyse mass spectra, respectively. Standard au-
totune of masses was performed in the TOF-MS instrument
before the experimental runs, and typical mass errors of 1–
3 ppm were achieved in the calibration. Melting points are
reported as their uncorrected values. Substrates 25–32 were
synthesised according to published procedures.[10]
Figure 4. The calculated structures of the ground state of the
ligand-Ir-ethene complex (B3LYP/LACVP). a (oxazole):
light grey, b (thiazole): black, 12 (imidazole): dark grey.
E/Z configuration of the starting material (Table 3,
entries 3 and 4). The hydrogenations of the unsaturat-
ed esters (Table 3, entries 1 and 2) by both 12 and 14
gave better enantioselectivities than previously pub-
lished. The E-isomer of the unsaturated ester gave
higher ee than the Z-isomer. The tetrasubstituted
vinyl fluorides were hydrogenated with modest ee
values (Table 3, entries 7 and 8).
Ethyl 2-Phenylimidazo
(2)
A
Conclusions
2-Aminonicotinic acid ethyl ester (6.0 g, 36.13 mmol), phe-
nacyl bromide (7.19 g, 36.16 mmol) and 2-butanone (90 mL)
were weighed into a 250-mL round-bottomed flask equipped
with a condenser, and the mixture was heated to reflux and
stirred for 18 h. The mixture was allowed to cool to room
temperature, and the formed white precipitate was filtered
off. The precipitate was then dissolved in H2O (150 mL) and
10% Na2CO3 (aqueous) was added until pH 12. Thereafter
the aqueous solution was extracted with CH2Cl2 (3”
200 mL) and the combined organic phases were dried over
Na2SO4, filtered and concentrated under vacuum to give the
product as yellow oil; yield: 8.14 g (84%).
In conclusion, we have shown that imidazole-phos-
phine ligands are selective and efficient in the asym-
metric iridium-catalysed hydrogenation of olefins.
The imidazole ligand class resulted in high enantiose-
lectivities for a range of non-functionalised olefins. In
addition, the imidazole-phosphine based catalysts
were found to hydrogenate vinyl fluorides efficiently,
in some cases giving the highest ee values published
so far.
Experimental Section
Ethyl 2-Phenyl-5,6,7,8-tetrahydroimidazo
dine-8-carboxylate (3)
A
General Remarks
Pd/C (10% on activated carbon, 0.6 g),
All the reactions were run with dry glassware and under a
nitrogen atmosphere unless other conditions are stated.
22.53 mmol) and TFA (50 mL) were added to a glass liner
(size: 100 mL) and placed into a high-pressure autoclave.
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Table 3. Hydrogenation of fluorine-containing olefins.[a]
Entry Substrate
Conv. [%] X:Y
ee [%] Abs. Conf. Conv. [%] X:Y
ee [%] Abs. Conf.
1
25 16
83:17 72
(S)
82
72:28 55
(R)
2
3
4
5
6
7
26 99
27 99
28 99
29 99
30 99
66:34 46
50:50 17
84:16 85
43:57 52
(R)
(R)
(R)
(S)
(R)
-
93
99
99
99
99
97
65:35 29
57:43 11
87:13 85
51:49 60
(S)
(S)
(S)
(R)
92:8
80
-
93:7
86
(S)
31
32
-
-
-
58:42 59
46:54 25
(+)-(2S*,3S*)
8
-
-
-
35
(+)-(2R*,3S*)
[a]
Reaction conditions: 0.5–1.5 mol% catalyst, room temperature to 408C, dry CH2Cl2, 30–100 bar H2.
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The autoclave containing the reaction mixture was sealed,
pressurised to 100 bar H2 and the mixture was stirred for 18
h at room temperature. The pressure was released and the
mixture was filtered through Celite and rinsed with CH2Cl2.
The filtrate was concentrated under vacuum to give the
product as a yellow oil; yield: 4.6 g (92%).
20 mL). The combined organic phases were washed with
H2O, brine, dried over MgSO4 and concentrated under
vacuum to give the crude product.
The crude product was purified by flash column chroma-
tography on silica gel using EtOAc:toluene 1:19 as eluent
resulting in a white foam; yield: 0.41 g (85%).
(R)-(2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyri-
din-8-yl)methanol (4)
A
Typical Procedure for Preparationof Compounds 9–
11
Compound 3 (3.4 g, 12.5 mmol) dissolved in THF( 30 mL)
A
(R)-(8)-[(Diphenylphosphino)methyl]-2-phenyl-5,6,7,8-tetra-
was added slowly to a slurry of LiAlH4 (0.95 g, 25 mmol) in
THF (30 mL) at 08C. The mixture was allowed to warm to
room temperature and stirred for 18 h. The mixture was
thereafter cooled to 08C and quenched by addition of H2O,
2M NaOH and H2O. The resulting mixture was stirred at
room temperature for 4 h and then filtered through Celite
and rinsed with THF. The filtrate was concentrated under
vacuum to give the crude product as a white oil; yield: 2.5 g
(87%).
hydroimidazo
A
6
(0.15 g,
0.37 mmol) was dissolved in dry Et2NH (15 mL)and the mix-
ture was evacuated and backfilled by N2 (”3). The mixture
was stirred at room temperature overnight. The solvent was
removed under reduced pressure and the residue was puri-
fied by flash column chromatography on silica gel using 3%
Et3N in toluene as eluent. The flash chromatography afford-
ed the product as a clear oil; yield: 0.094 g (65%).
The racemic alcohol was resolved into its enantiomers by
chiral HPLC: Chiracel OD (5”19 cm), EtOH 100%,
80 mLminÀ1, 0.4 g loading, tR1 =3.5 min (R), tR2 =7.2 min
(S). Analytical chiral HPLC: Chiracel OD (20” 250 mm),
Typical Procedure for Preparationof Iridium
Complexes 12–14
G
Complex (R)-12: Compound 9 (0.07 g, 0.18 mmol) was dis-
solved in CH2Cl2 (5 mL) and [IrCl(COD)]2 (0.06 g,
100% i-PrOH, 3.0 mLminÀ1,
tR1 =19.5 min (R), tR2 =
AHCTREUNG
61.6 min (S). The absolute configurations were assigned by
analogy to the corresponding thiazoles, which give the same
elution order in chiral HPLC, sign of optical rotation and
sense of enantioselection in asymmetric hydrogenation.[7]
0.09 mmol) was added. The mixture was stirred under reflux
for 1 h and then allowed to cool down to room temperature.
H2O (4 mL) was added followed by NaBArF (0.20 g,
0.21 mmol) and the mixture was stirred vigorously for
30 min. The two phases were separated and and the organic
phase was dried over MgSO4, filtered and concrentrated
under vacuum. The crude product was dissolved in absolute
EtOH and H2O was added until a precipitate was formed.
The precipitate was filtered and washed with ice cold aque-
ous EtOH (80%). After drying under reduced pressure, was
analytically pure complex afforded as an orange solid; yield:
0.19 g (68%).
(R)-(2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyri-
T
din-8-yl)methyl 4-Methylbenzenesulfonate (5)
The optically pure alcohol 4 (0.70 g, 3.1 mmol) was dissolved
in CH2Cl2 (10 mL) and pyridine (10 mL) was added. The re-
action mixture was cooled to 08C (ice/water bath) and a so-
lution of TsCl (1.75 g, 9.2 mmol) in CH2Cl2 (10 mL) was
added dropwise. The temperature was allowed to rise to
room temperature and the mixture was stirred overnight.
The mixture was poured into a 10% Na2CO3 (aqueous)
(30 mL) solution and the two phases were separated. The
aqueous phase was extracted with CH2Cl2 (2”20 mL) and
the combined organic phases were washed with water
(50 mL) and brine (50 mL) followed by drying over MgSO4,
filtration and removal of the solvent to give the crude mate-
rial as slightly purple oil; yield: 1.36 g.
General Procedure for the Hydrogenation of Olefins
(Table 1)
A vial was charged with a substrate (0.25 mmol) and catalyst
(0.5 mol%) and 1 mL of anhydrous CH2Cl2 was added. The
vial was placed in a high-pressure equipment which was
purged with three times with H2 before it was pressurised to
50 bars. The mixture was stirred at room temperature over-
night. The pressure was released and solvent was removed
under vacuum. The residue was dissolved in Et2O:pentane
(1:5) and filtered through short plug of silica. The solvent
was evaporated and the conversion was determined by
1H NMR and enantiomer excess by GC/MS (G-TA) or
chiral HPLC.
Purification by flash column chromatography on silica gel
using EtOAc:toluene (1:4) as eluent gave pure compound as
slightly purple white solid; yield: 0.83 g (70%).
Typical Procedure for Preparationof Compounds 6–8
(R)-8-[(Diphenylphosphino)methyl]-2-phenyl-5,6,7,8-
tetrahydroimidazo[1,2-a]pyridine·borane adduct (6): Diphe-
G
nylphosphine·borane adduct (0.35 g, 1.77 mmol) was dis-
solved in dry THF (2.5 mL) and cooled to À788C under N2.
n-BuLi (1.6M in hexane, 1.18 mL) was added dropwise. The
reaction mixture was stirred for 10 min at À788C and then
General Procedure for the Hydrogenation of Vinyl
Fluorides
A vial was charged with substrate and catalyst (0.5–1.5
mol%) and CH2Cl2 (1–2 mL) was added. For 100 bar hydro-
genations the vial was placed in high-pressure steel equip-
ment, which was purged three times with H2 before it was
pressurised to 100 bar, heated to working temperature and
held at this pressure for 63–72 h. One hour before the end
30 min at 08C.
A solution of tosylate (R)-5 (0.45 g,
1.18 mmol) in anhydrous DMF (2.5 mL) was added drop-
wise and the mixture was stirred overnight at room tempera-
ture. The reaction mixture was poured into aqueous
NaHCO3 (10%,15 mL) and extracted with CH2Cl2 (3”
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of the reaction, the heating was turned off. The pressure was
released and the solvent was evaporated off.
2003, 125, 113–123; d) W. Tang, W. Wang, X. Zhang,
Angew. Chem. 2003, 115, 973–976; Angew. Chem. Int.
Ed. 2003, 42, 943–946; e) G. Xu, S. R. Gilbertson, Tet-
rahedron Lett. 2003, 44, 953–955; f) T. Bunlaksananur-
son, K. Polborn, P. Knochel, Angew. Chem. 2003, 115,
4071–4073; Angew. Chem. Int. Ed. 2003, 42, 3941–
3943; g) A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hçr-
mann, S. McIntyre, F. Menges, M. Schçnleber, S. P.
Smidt, B. Wüstenberg, N. Zimmermann, Adv. Synth.
Catal. 2003, 345, 33–43; h) W. J. Drury III, N. Zimmer-
mann, M. Keenan, M. Hayashi, S. Kaiser, R. Goddard,
A. Pfaltz, Angew. Chem. 2004, 116, 72–76; Angew.
Chem. Int. Ed. 2004, 43, 70–74; i) A. Trifonova, J. S.
Diesen, P. G. Andersson, Chem. Eur. J. 2006, 12, 2318–
2328; j) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem.
2006, 118, 5318–5321; Angew. Chem. Int. Ed. 2006, 45,
5194–5197; k) J. J. Verendel, P. G. Andersson, Dalton
Trans. 2007, 47, 5603–5610; l) M. N. Cheemala, P. Kno-
chel, Org. Lett. 2007, 9, 3089–3092; m) P. Cheruku, A.
Paptchikhine, M. Ali, J.-M. Neudçrfl, P. G. Andersson,
Org. Biomol. Chem. 2008, 6, 366–373.
For hydrogenations at pressures up to 30 bar the vial was
placed in a EndeavorTM Catalyst screening system. Vessels
were purged three times with Ar (10 atm), and then flushed
and pressurised with H2 to working pressure and stirred at
700 rpm for 24 h. In all cases, conversions were measured by
1H NMR after evaporation of solvent. 1.5 mL of
Et2O:pentane (1:1) were added, the solution was filtered
through a short plug of silica. The silica plug was rinsed with
3 mL Et2O:pentane (1:1). The solvent was evaporated and
the ee was determined by GC-MS (G-TA or B-DM, 908C
30 min, 18CminÀ1 1308C, 20 8CminÀ1 1758C, 14.5 psi,
1.5 mLminÀ1) or HPLC (Chiralcel OB-H, i.d. 4.6 mm ”
25 cm 3% i-PrOH: 97% n-hexane 0.5 mLminÀ1, 220 nm).
Supporting Information
Characterisation data for all compounds and separation data
for the hydrogenated olefins are given in the Supporting In-
formation.
[5] P. Brandt, C. Hedberg, P. G. Andersson, Chem. Eur. J.
2003, 9, 339–347.
Acknowledgements
[6] K. Källstrçm, C. Hedberg, P. Brandt, A. Bayer, P. G.
Andersson, J. Am. Chem. Soc. 2004, 126, 14308–14309.
[7] C. Hedberg. K. Källstrçm, P. Brandt, L. K. Hansen,
P. G. Andersson, J. Am. Chem. Soc. 2006, 128, 2995–
3001.
[8] a) Review: M. S. Butler, J. Nat. Prod. 2004, 67, 2141–
2153; b) Review: G. A. Patani, E. J. LaVoie, Chem.
Rev. 1996, 96, 3147–3176; c) Minireview: I. Ojima,
ChemBioChem 2004, 5, 628–635; d) Minireview: H.-J.
Bçhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004,
5, 637–643.
We would like to thank The Swedish Research Council (VR),
AstraZeneca and Ligbank (Activity 3, contract FP6–505267–
1) for support of this work. We would also like to thank As-
traZeneca Discovery Chemistry (Sçdertälje) and Tanja Lars-
son for resolving the imidazole alcohol and Dr. T. L. Church
for carefully reading of the manuscript.
References
[9] K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004,
104, 1–16.
[1] Representative reviews: a) X. Cui, K. Burgess, Chem.
Rev. 2005, 105, 3272–3296; b) K. Källstrçm, I. Mun-
slow, P. G. Andersson, Chem. Eur. J. 2006, 12, 3194–
3200; c) S. J. Roseblade, A. Pfaltz, C. R. Chim. 2007,
10, 178–187; d) T. L. Church, P. G. Andersson, Coord.
Chem. Rev. 2008, 252, 513–531.
[2] R. H. Crabtree, Acc. Chem. Res. 1979, 12, 331–337.
[3] A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem.
1998, 110, 3047–3050; Angew. Chem. Int. Ed. 1998, 37,
2897–2899.
[10] M. Engman, J. S. Diesen, A. Paptchikhine, P. G. Ander-
sson, J. Am. Chem. Soc. 2007, 129, 4536–4537.
[11] T. D. Nelson, M. H. Kress, S. W. Krska, J. V. Mitten, U.
Sun, PCT Int. Appl. 2006, WO-2006069287 A1; CAN
145, 103564.
[12] H. Mitsudera, M. Konope, Y. Ishida, K. Matsuura, Eur.
Pat. Appl. 1990, EP 404190A1 19901227; CAN 114,
185501; AN 1991, 185501.
[13] Jaguar, version 6.5, Schrodinger, LLC, New York, 2005.
[14] J. Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zhu, K.
Burgess, Chem. Eur. J. 2007, 13, 7162–7170.
[4] a) J. Blankenstein, A. Pfaltz, Angew. Chem. 2001, 113,
4577–4579; Angew. Chem. Int. Ed. 2001, 40, 4445–
4447; b) F. Menges, M. Neuburger, A. Pfaltz, Org. Lett.
2002, 4, 4713–4716; c) M. C. Perry, X. Cui, M. Powell,
D. Hou, J. Reibenspies, K. Burgess, J. Am. Chem. Soc.
[15] T. Eicher, S. Hauptmann, The Chemistry of Heterocy-
cles, 2nd edn., Wiley-VCH, Weinheim, 2003.
1176
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1168 – 1176