Asymmetric hydrogenation of tri-substituted alkenes with Ir-NHC-thiazole complexes

Article abstract of DOI:10.1016/j.tetlet.2006.08.039

An efficient chiral N-heterocyclic carbene ligand for the Ir-catalyzed asymmetric hydrogenation of largely unfunctionalized tri-substituted olefins has been developed. The Ir-NHC-thiazole catalyst is able to reduce a large variety of substrates with excellent conversions and good enantioselectivities with ee's ranging from 34% to 90%, depending on the geometry around the double bond of the substrates.

Full text of DOI:10.1016/j.tetlet.2006.08.039

Tetrahedron Letters 47 (2006) 7477–7480
Asymmetric hydrogenation of tri-substituted alkenes
with Ir-NHC-thiazole complexes
Klas Ka¨llstro¨m and Pher G. Andersson*
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden
Received 29 June 2006; revised 2 August 2006; accepted 10 August 2006
Abstract—An efficient chiral N-heterocyclic carbene ligand for the Ir-catalyzed asymmetric hydrogenation of largely unfunctional-
ized tri-substituted olefins has been developed. The Ir-NHC-thiazole catalyst is able to reduce a large variety of substrates with excel-
lent conversions and good enantioselectivities with ee’s ranging from 34% to 90%, depending on the geometry around the double
bond of the substrates.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
examples include Ru-catalyzed metathesis,8,9 Rh-cata-
lyzed hydrosilylation10 and conjugate addition of aryl-
boronic acid derivatives to enones.11
N-Heterocyclic carbenes (NHCs) and their transition
metal complexes have recently attracted much interest
in organic and organometallic chemistry.1 Due to strong
carbon–metal r-bonds, NHCs are well suited to act as
ligands in various transition metal catalyzed reactions.
The organometallic complexes derived from NHCs tend
to be air stable and the carbene binds to the metal more
strongly than electron rich phosphines.2 Their powerful
r-donating and weak p-accepting properties result in
metal centers that are electron rich when compared to
the corresponding phosphine complexes.3
Ever since Pfaltz first reported the successful Ir-cata-
lyzed hydrogenation of largely unfunctionalized olefins
using the Ir–PHOX complex,12 a chiral mimic of Crab-
tree’s catalyst,13 there have been a number of reports in
the literature employing chiral N,P-ligands for this type
of hydrogenation.14 However, Ir-catalyzed asymmetric
hydrogenation is still highly substrate dependent and
the development of new efficient chiral ligands that
tolerate a broad range of substrates remains a challenge.
Complexes containing carbene based ligands tend to be
highly active in oxidative addition reactions and hence
are attractive alternatives to phosphine based ligand
systems.
Inspired by this, we decided to synthesize an imidazole
analogue of our recently published phosphine-thiazole
ligand 4 (Scheme 1).15
We reasoned that exchanging the phosphine moiety with
a NHC functionality would produce an interesting
Recently, Burgess and co-workers reported that chiral
Ir-imidazol-2-ylidene-oxazoline complexes can be used
for the asymmetric hydrogenation of olefins with great
success, enantiomeric excesses over 99% were obtained.4
OTs
CO Et
CO Et
2
2
O
N
N
S
Br
Ph
Chiral imidazolylidenes were first reported several dec-
S
ades ago by Muller and co-workers5 and several others
¨
3
1
2
have been reported more recently.6–8 Even so there have
been relatively few reports on optically active electron
rich carbene ligands in asymmetric catalysis, some
PAr
2
N
S
Ph
4
*
Corresponding author. Tel.: +46 18 471 3801; fax: +46 18 471
3818; e-mail: Pher.Andersson@kemi.uu.se
Scheme 1. Synthetic route leading to the phosphine–thiazole ligand.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.039

7478
K. Ka¨llstro¨m, P. G. Andersson / Tetrahedron Letters 47 (2006) 7477–7480
ligand structure that might perform well in various
asymmetric catalytic reactions, especially in the Ir-cata-
lyzed hydrogenation of olefins.
I
Ph
N
Ph
BAr
N
F
N
N
i
Ir
The synthesis of the NHC ligand 6 started from the pre-
viously described tosylate 3 (Scheme 1), which in turn
can be prepared in enantiomerically pure form by a pre-
viously reported synthetic protocol (Scheme 1).15 The
tosylate is first converted into the iodide 5 via a Finkel-
stein reaction, by treatment with 5 equiv of NaI in
refluxing acetone. Nucleophilic substitution with
N-phenylimidazole (1 equiv) proceeded smoothly in
DMF at 60 °C (48 h), giving 6 in reasonable yield. The
major by-product observed in this reaction was the elim-
ination product 7. In an attempt to reduce the reaction
time, the temperature was increased (80 °C), resulting
in 70% of 7 (Scheme 2). However, decreasing the
temperature below 60 °C did not produce the desired
product 6 in higher yield.
N
N
Ph
Ph
S
S
6
8
Scheme 3. Synthesis of Ir-complex 8. Reagents and conditions: (i)
[IrCl(COD)2], BuOLi, THF, reflux, 1 h, then rt overnight, then H2O,
t
NaBArFÆ3H2O, rt, 1 h, 30%.
3), resulted in products having opposite absolute config-
urations, also the observed enantioselectivity for the cis
conformation was lower. Introducing an electron donat-
ing group in the para position, that is, substrate 12
(entry 4) proved to be beneficial, 79% ee. Substrate 13
(entry 5) was reduced with better enantioselectivity than
for the previously reported phosphine thiazole com-
plexes, 55% ee.15 Interestingly, moving the methyl group
to the b-position, that is, substrate 14 (entry 6) did not
increase the enantioselectivity, 70% ee.
Complex formation was accomplished by dissolving the
ligand 6, [IrCl(COD)]2, and tBuOLi in THF, then reflux-
ing for 1 h to generate the carbene and then stirring at
rt overnight. The solvent was then evaporated and the
residue was dissolved in CH2Cl2 (5 ml). Ion exchange
was accomplished by addition of H2O (2 ml) followed
by 1.2 equiv of NaBArF and stirring vigorously for
30 min, yielding complex 8 in 30% isolated yield
(Scheme 3).
Also, trans- and cis-b-methyl cinnamates 15 and 16
(entries 7 and 8) show reversed enantiofacial selectivity
when compared to our phosphine thiazole complexes.15
With this complex, tetra-substituted olefins showed no
conversion at all under the conditions used.
The new complex 8 proved to be efficient in the hydro-
genation of various standard substrates with ee’s rang-
ing from 34% to 90% (Table 1). The hydrogenation of
9 at different pressures of H2 showed 50 bar to be opti-
mal for this substrate and this pressure was therefore
used for all subsequent experiments (Table 1).
Unfortunately, substrate 18 (entry 10) was reduced with
both low selectivity and conversion. The differences in
enantioselectivity compared to our previously published
phosphine-thiazole complex may be a result of either
two factors, the N-phenylimidazole provides a less effi-
cient chiral environment around the Ir atom, or that
the complex formed coordinates through a seven-mem-
bered chelate resulting in a more open structure com-
pared to the phosphine-thiazole ligand 4.
All the substrates evaluated showed good activity and
full conversions were obtained for almost all substrates
within two hours.
In conclusion, we have synthesized a new NHC ligand
applying the same chiral scaffold as earlier reported by
us. The Ir-NHC thiazole complex was tested and evalu-
ated in the asymmetric hydrogenation of olefins. This
new complex proved to be efficient in the hydrogenation
of various tri-substituted olefins, with ee’s ranging from
34% to 90% depending on the geometry around the dou-
ble bond in the substrates. We have also shown that this
new complex was more selective for substrates contain-
ing bulky substituents, such as 13.
Substrate 9 (entry 1) proved to be the best substrate in
terms of enantioselectivity. The trans and cis isomers
of (1-methylpropenyl)benzene 10 and 11 (entries 2 and
OTs
I
i
N
N
S
Ph
Ph
S
3
5
I
2. Experimental
Ph
N
ii
iii
N
S
N
7 +
+ 6
Ph
2.1. 4-Iodomethyl-2-phenyl-4,5,6,7-tetrahydro-benzo-
thiazole (5)
N
7 70%
Ph
S
6 50%
Compound 3 (0.43 g, 1.1 mmol) was dissolved in ace-
tone (13 ml), and NaI (0.83 g, 5.5 mmol) was added.
The resulting mixture was stirred at 60 °C overnight.
The solvent was removed, the residue dissolved in tolu-
ene and the solution was poured into aq NaHCO3 (10%,
20 ml). The organic layer was washed with brine (20 ml)
Scheme 2. Finkelstein reaction and nucleophilic substitution reaction
between iodide 5 and N-phenylimidazole. Reagents and conditions: (i)
NaI, Acetone, 60 °C, overnight, quantitative; (ii) N-phenylimidazole,
DMF, 60 °C, 48 h, 50%; (iii) N-phenylimidazole, DMF, 80 °C, 12 h,
25%.

K. Ka¨llstro¨m, P. G. Andersson / Tetrahedron Letters 47 (2006) 7477–7480
Table 1. Ir-catalyzed hydrogenation of substrates 9–18
7479
H
2
R1
H
R
R1 R2
H
(50 bar), CH Cl
2 2
2
R3
R3
Complex (0.5 mol%)
H
H
Entry
1
Substrate
Conversion (%)
ee (%)
Absolute configuration
C H
6
5
9
10
11
12
13
>99
>99
76
90a (>99)d
(S)
(S)
(R)
(S)
(R)
Ph
C H
6
5
2
3
4
5
70b (99)d
C H
6
5
34b
p
-MeO-C H
6
4
>99
>99
79b (99)d
70b (55)d
6
7
14
15
>99
>99
70b (98)d
63b (98)d
(S)
(R)
C H
6
5
COOEt
5
C H
6
8
16
>99
34b (rac.)d
(S)
(S)
COOEt
HO
9
17
18
>99
30
80c (99)d
C H
6
5
C H
6
5
10
rac.b
OAc
a HPLC (Chiralcel-OJ column, hexane: i-PrOH, 99:1).
b GC–MS (G-Ta, 60 °C, 30 min, 5 °C/min, 75 °C, 100 kPa).
c GC (CP-Chirasil-Dex CB, isotherm 130 °C).
d Values within brackets refer to the ee obtained with Ir-4 complex.15
and H2O (20 ml). The combined organic layers were
dried (MgSO4) and evaporated to dryness. Purification
by flash chromatography (toluene–EtOAc 9:1) yielded
2.2. 2-Phenyl-4-(3-phenyl-3H-imidazol-1-ylmethyl)-
4,5,6,7-tetrahydro-benzothiazole iodide (6)
pure 5, as
a
yellow solid in quantitative yield
Compound 5 (0.147 g, 0.41 mmol) was dissolved in
DMF (1.0 ml), and N-phenylimidazole (0.059 g, 0.41
mmol) was added. The resulting mixture was heated at
60 °C for 48 h. The solvent was removed under vacuum.
Purification by flash chromatography (CH2Cl2–MeOH
9:1) yielded 6, as a pale yellow solid in 50% yield
(0.39 g); mp 52.5–53.9 °C; Rf 0.89 (toluene–EtOAc
20
1
9:1); ½aꢀD +40.2 (c 0.90, CHCl3); H NMR (400 MHz,
CDCl3) d: 1.75–1.89 (m, 2H, CH2),1.93–2.03 (m, 1H,
CH2), 2.10–2.19 (m, 1H, CH2), 2.72–2.85 (m, 2H, CH2),
3.08–3.15 (m, 1H, CH), 3.43 (dd, J = 9.4, 9.7 Hz, 1H,
CH2I), 3.42 (dd, J = 3.3, 9.7 Hz, 1H, CH2I), 7.35–7.44
(m, 3H, ArH), 7.85–7.90 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3) d: 21.5, 25.6, 31.7, 39.7, 71.1,
126.0, 127.9, 128.4, 144.6, 150.6, 160.3, 172.3; MS (EI)
(m/z) (rel intensity) 356.3 (MH+, 20%), 228.1 (100%).
(0.102 g, 0.21 mmol); mp: decomposed at 278 °C; Rf
20
0.22 (CH2Cl2–MeOH 9:1); ½aꢀD +25.2 (c 0.70, CHCl3);
1H NMR (400 MHz, CDCl3) d: 1.55–1.72 (m, 1H,
CH2), 1.75–1.92 (m, 1H, CH2), 1.98–2.12 (m, 1H, CH2),
2.21–2.34 (m, 1H, CH2), 2.70–2.83 (m, 2H, CH2)

7480
K. Ka¨llstro¨m, P. G. Andersson / Tetrahedron Letters 47 (2006) 7477–7480
5. Coleman, A. W.; Hitchcock, P. B.; Lappert, M. F.;
3.46–3.58 (m, 1H, CH), 4.93 (dd, J = 7.1, 13.7 Hz, 1H,
CH2I), 5.02 (dd, J = 5.1, 13.7 Hz, 1H, CH2I), 7.22–
7.37 (m, 3H, ArH), 7.42–7.55 (m, 3H) 7.59–7.75 (m,
6H, ArH), 10.53 (s, 1H, ArH); 13C NMR (100 MHz,
CDCl3) d: 21.5, 23.5, 26.4, 37.7, 53.5, 120.1, 121.9,
124.1, 125.9, 128.9, 129.9, 130.2, 130.5, 132.7, 133.4,
134.3, 136.1, 149.5, 165.2.; MS (EI) (m/z) (rel intensity)
499.5 (M+, 100%).
Maskell, R. K.; Muller, J. H. J. Organomet. Chem. 1983,
¨
250, C9–C14.
6. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
7. Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
8. Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.;
Hoveyda, A. J. Am. Chem. Soc. 2002, 124, 4954.
9. (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett.
2001, 3, 3225; (b) Van Veldhuizen, J. J.; Gillingham, D.
G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. J. Am. Chem.
Soc. 2003, 125, 12502.
Acknowledgements
10. (a) Herrman, W. A.; Gooßen, L. J.; Kocher, C.;
Artus, G. R. J. Angew. Chem., Int. Ed. 1996, 35, 2805;
(b) Enders, D.; Gielen, H.; Runsink, J.; Breuer, K.;
Brode, S.; Boehn, K. Eur. J. Inorg. Chem. 1998, 913;
(c) Enders, D.; Gielen, H. Organomet. Chem. 2001,
This work was supported by grants from the Swedish
Research Council (VR).
References and notes
´
617, 70; (d) Cesar, V.; Bellmin-Laponnaz, S.; Gade, L.
H. Angew. Chem., Int. Ed. 2004, 43, 1014; (e) Duan,
W.-L.; Shi, M.; Rong, G.-B. Chem. Commun. 2003,
2916.
1. For recent reviews see: (a) Cui, X.; Burgess, K. Chem. Rev.
2005, 105, 3272; (b) Perry, M. C.; Burgess, K. Tetra-
hedron: Asymmetry 2003, 14, 951; (c) Hermann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1290; (d) Hermann, W.
A.; Ko¨cher, C. Angew. Chem., Int. Ed. 1997, 36, 2162.
2. Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 2370.
11. Ma, Y.; Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus,
M. B. Angew. Chem., Int. Ed. 2003, 42, 5871.
12. Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int.
Ed. 1998, 37, 2897.
13. Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331.
14. Ka¨llstro¨m, K.; Munslow, I.; Andersson, P. G. Chem. Eur.
J. 2006, 12, 3194.
15. Hedberg, C.; Ka¨llstro¨m, K.; Brandt, P.; Hansen, L. K.;
Andersson, P. G. J. Am. Chem. Soc. 2006, 128, 2995.
3. Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J.
Am. Chem. Soc. 1999, 121, 2674.
4. Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.;
Reibenspies, J. H.; Burgess, K. J. Am. Chem. Soc. 2003,
125, 113.