Application of P,N-Sulfinyl Imine Ligands to Iridium-Catalyzed Asymmetric Hydrogenation of Olefins

Article abstract of DOI:10.1021/jo035675+

The utility of a novel class of P,N-ligands incorporating a chiral sulfinyl imine moiety is demonstrated in the iridium-catalyzed hydrogenation of both functionalized and unfunctionalized olefins, in which enantioselectivities of up to 94% are achieved. T

Full text of DOI:10.1021/jo035675+

Ap p lica tion of P ,N-Su lfin yl Im in e Liga n d s to Ir id iu m -Ca ta lyzed
Asym m etr ic Hyd r ogen a tion of Olefin s
Laurie B. Schenkel and J onathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California,
Berkeley, California 94720
jellman@uclink.berkeley.edu
Received November 13, 2003
The utility of a novel class of P,N-ligands incorporating a chiral sulfinyl imine moiety is
demonstrated in the iridium-catalyzed hydrogenation of both functionalized and unfunctionalized
olefins, in which enantioselectivities of up to 94% are achieved. The modularity of the P,N-sulfinyl
ligand class is highlighted by the facile preparation of a variety of sterically and electronically
different ligands. Interesting structure-activity data for both the phosphine and sulfinamide
components is provided by this expanded ligand set.
In tr od u ction
The importance of asymmetric catalysis in organic
synthesis has led to the development of a number of
versatile chiral ligand classes.1 A ligand class that is
easily prepared and modified and which can provide
products with high enantioselectivity in a variety of
different reactions is ideal. Recently, we reported on the
synthesis and utility of several novel ligands incorporat-
ing a chiral tert-butanesulfinyl imine moiety (Figure 1).2
The Cu(II) complexes of the bis(sulfinyl)imidoamidine
(SIAM) ligands provide extremely high levels of enantio-
and diastereoselectivity in the Diels-Alder reaction,2a,b
while the P,N-sulfinyl imine ligands provide enantio-
selectivities of up to 94% in the Pd-catalyzed allylic
alkylation reaction.2c With the vast majority of successful
chiral ligands relying on chirality about a carbon center,
these are among a small number of ligands incorporating
only heteroatom chirality for which high levels of enan-
tioselectivity have been achieved.3
F IGURE 1. Bis(sulfinyl)imidoamidine (SIAM) and P,N-sulfi-
nyl imine ligands.
condensation with aldehydes and ketones.4 The ease with
which sulfinyl imines can be prepared allows for facile
modification of their steric and electronic properties,
rendering them attractive as a versatile ligand class.
Previous application of the P,N-sulfinyl imines to the Pd-
catalyzed allylic alkylation reaction demonstrated the
dramatic effect of the phosphine component on reaction
rate and asymmetric induction; however, only ligands
derived from tert-butanesulfinamide and p-toluenesulfi-
namide were explored.2c Recent reports on the prepara-
tion of a variety of sulfinamides with distinct steric and
electronic properties5 prompted us to investigate the
effects of their incorporation into the P,N-sulfinyl imine
scaffold. Here, we report the synthesis of P,N-sulfinyl
imine ligands having diverse substitution on the sulfi-
namide moiety, and their application to the Ir-catalyzed
asymmetric hydrogenation of both functionalized and
unfunctionalized olefins.6 This work further highlights
the modularity of the P,N-sulfinyl imine scaffold by
providing interesting structure-activity data for both the
The asymmetry induced by sulfinyl imine-metal com-
plexes is due to the chirality of the sulfur center of the
sulfinamide component. tert-Butanesulfinamide is a com-
mercially available compound that can readily be trans-
formed into sulfinyl imines in high yields through
(1) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000.
(2) (a) Owens, T. D.; Hollander F.; Oliver, A.; Ellman, J . A. J . Am.
Chem. Soc. 2001, 123, 1539. (b) Owens, T. D.; Souers, A. J .; Ellman,
J . A. J . Org. Chem. 2003, 68, 3. (c) Schenkel, L. B.; Ellman, J . A. Org.
Lett. 2003, 5, 545. (d) Souers, A. J .; Owens, T. D.; Ellman, J . A. Inorg.
Chem. 2001, 40, 5299.
(4) (a) Weix, D. J .; Ellman, J . A. Org. Lett. 2003, 5, 1317. (b) Liu,
G.; Cogan, D.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J . Org. Chem.
1999, 64, 1278.
(3) For leading references, phosphorus ligands, see: (a) Ohashi, A.;
Kikuchi, S.-I.; Yasutake, M.; Imamoto, T. Eur. J . Org. Chem. 2002,
2535. (b) Dubrovina, N. V.; Tararov, V. I.; Monsees, A.; Kadyrov, R.;
Fischer, C.; Bo¨rner, A. Tetrahedron: Asymmetry 2003, 14, 2739. (c)
Sua´rez, A.; Pizzano, A. Tetrahedron: Asymmetry 2001, 2501. (d) Albert,
J .; Cadena, J . M.; Granell, J .; Muller, G.; Ordinas, J .; Panyella, D.;
Puerta, C.; San˜udo, C.; Valerga, P. Organometallics 1999, 18, 3511.
For sulfoximines, see: (a) Bolm, C.; Verrucci, M.; Simic´, O.; Cozzi, P.
G.; Raabe, G.; Okamura, H. Chem. Commun. 2003, 2826. (b) Bolm,
C.; Simic´, O. J . Am. Chem. Soc. 2001, 123, 3830. (c) Harmata, M.;
Ghosh, S. K. Org. Lett. 2001, 3, 3321. For sulfoxides, see: (a)
Ferna´ndez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651.
(5) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Senanayake, C. H. J . Am. Chem. Soc. 2002, 124, 7880. (b) Han, Z.;
Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum, D. A.; Senanayake,
C. H. Tetrahedron Lett. 2003, 44, 4195.
(6) For leading references on related systems for Ir-catalyzed
asymmetric hydrogenations, see: (a) Bunlaksananusorn, T.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 3941. (b) Xu, G.;
Gilbertson, S. R. Tetrahedron Lett. 2003, 44, 953. (c) Hou, D.-R.;
Reibenspies, J .; Colacot, T. J .; Burgess, K. Chem. Eur. J . 2001, 7, 5391.
(d) Perry M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J . H.;
Burgess, K. J . Am. Chem. Soc. 2003, 125, 113. (e) Helmchen, G.; Pfaltz,
A. Acc. Chem. Res. 2000, 33, 336.
10.1021/jo035675+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/23/2004
1800
J . Org. Chem. 2004, 69, 1800-1802

Asymmetric Hydrogenation of Olefins
SCHEME 1. P r ep a r a tion of P ,N-Su lfin yl Im in e Liga n d s a n d Th eir Ir id iu m Com p lexes
TABLE 1. Op tim iza tion of th e Asym m etr ic
while in dichloroethane, chlorobenzene, and chloroform
product was obtained in good to high yields (entries 3-5),
and in chloroform with good selectivity (entry 5). Meth-
ylene chloride proved to be the most effective solvent with
complete conversion occurring within 1 h at 50 bar H2
and with 94% ee (entry 6). Furthermore, the use of crude
catalyst (entry 7) did not result in a reduction of either
the conversion or enantioselectivity, eliminating the need
for purification of the complexes.
Hyd r ogen a tion of r-Meth ylstilben ea
The counterion for the iridium complex of 12 played a
critical role in catalyst performance. In analogy with
related P,N-ligand iridium catalyst systems, the non-
coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate (BARF) counterion was required for efficient catalyst
turnover and high selectivity.6 When the coordinating
chloride counterion was employed, no product was ob-
served, even with higher catalyst loading and extended
reaction times (entry 8). An examination of pressure
effects revealed that between 25 and 100 bar H2 there
was little impact on reaction rate or selectivity (entries
9-10); however, at atmospheric pressure (entry 11) there
was a dramatic decrease in both reaction rate and
selectivity.
Having identified optimal reaction conditions for the
asymmetric hydrogenation of R-methylstilbene with 12,
we next investigated the effects that modification of the
sulfinamide component would have on catalyst turnover
and enantioselectivity. A diverse set of sulfinyl imine
ligands and their iridium complexes were prepared
(Scheme 1) from a collection of sulfinamides with a wide
range of steric and electronic properties (Figure 2).
Notably, the iridium complex of 11 (Scheme 1) could not
be prepared, most likely due to the extremely hindered
environment caused by the o-isopropyl groups.
entry
solvent
pressure (bar)
X-
convb (%) % eec
1
THF
toluene
dichloroethane
chlorobenzene
CHCl3
CH2Cl2
CH2Cl2
50
50
50
50
50
50
50
50
100
25
1
BARF
BARF
BARF
BARF
BARF
BARF
BARF
Cl
0
0
50
94
65
>99
>99
0
2
3
69
74
87
94
94
4
5
6
7d
8e,f CH2Cl2
9
10
11
CH2Cl2
CH2Cl2
CH2Cl2
BARF
BARF
BARF
>99
>99
70
92
91
3
a
Reactions were run at room temperature for 1 h with 5 mol %
catalyst loading. b Determined by 1H NMR. c Determined by chiral
HPLC. Experiment was run with crude catalyst. e Experiment
d
run with 10 mol % catalyst for 18 h. f See the Supporting
Information for preparation of the chloride complex.
sulfinamide and phosphine components. Furthermore,
enantioselectivities of up to 94% in the Ir-catalyzed
hydrogenation reaction establish the versatility of this
novel ligand class.
Resu lts a n d Discu ssion
Table 2 summarizes the results of the enantioselective
hydrogenation of R-methylstilbene using the Ir complexes
12-18. We were optimistic that increasing the steric bulk
of the sulfinamide component by the incorporation of
1-adamantanesulfinamide 20 and 3-ethylpentanesulfi-
namide 21 would further improve the enantioselectivity.
Unfortunately, complexes 13 and 14 (entries 2 and 3)
were inferior to complex 12 (entry 1) in terms of both
reaction rate and selectivity. These results could poten-
tially be attributed to an unfavorable geometry about the
Application of the P,N-sulfinyl imine ligands to the
asymmetric hydrogenation of unfunctionalized olefins
began with ligand 4, which is prepared via Ti-mediated
condensation with aldehyde 1 (Scheme 1). Previous use
of 4 in the Pd-catalyzed allylic alkylation reaction had
shown that it provides a highly selective and robust
catalyst;2c thus, we were optimistic that its iridium
complex would perform well. Preparation of the iridium
complex 12 was carried out in a two-step, one-pot process
in 90% yield (Scheme 1). When 12 was utilized in the
hydrogenation of R-methylstilbene, a dramatic effect on
both rate of reaction and enantioselectivity was observed
when the solvent, pressure, and counterion were varied
(Table 1). Similar to the iridium catalysts reported by
both Crabtree7 and Pfaltz,8 P,N-sulfinyl imine-Ir com-
plexes require chlorinated solvents for turnover. In both
THF and toluene (entries 1-2) no product was observed,
(7) Crabtree, R. Acc. Chem. Res. 1979, 12, 331.
(8) (a) Menges, F.; Neuberger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
(b) Menges, F.; Pfaltz, A. Adv. Synth. Catal. 2002, 344, 40. (c)
Blackmond, D. G.; Lightfoot, A.; Pfaltz, A.; Rosner, T.; Schnider, P.;
Zimmerman, N. Chirality 2000, 12, 442. (d) Cozzi, P. G.; Zimmerman,
N.; Hilgraf, R.; Schaffner, S.; Pfaltz, A. Adv. Synth. Catal. 2001, 343,
450. (e) Hilgraf, R.; Pfaltz, A. Synlett. 1999, 11, 1814. (e) Lightfoot, A.;
Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897.
J . Org. Chem, Vol. 69, No. 6, 2004 1801

Schenkel and Ellman
TABLE 3. Su lfin yl Im in e Com p lexes in th e
Hyd r ogen a tion of F u n ction a lized Olefin sa
F IGURE 2. Sulfinamides selected for incorporation into P,N-
sulfinyl imine scaffold.
TABLE 2. Su lfin yl Im in e Com p lexes 12-18 in th e
Hyd r ogen a tion of r-Meth ylstilben ea
a
Reactions run with 5 mol % catalyst at 50 bar H2 in CH2Cl2
at room temperature for 2 h. Determined by 1H NMR. c Deter-
b
mined by chiral HPLC.
convb
%
entry
R
Ar
complex
(%) eec
the P,N-sulfinyl imine-Ir complexes. Two functionalized
olefins were selected, and our expanded set of catalyst
precursors was tested under the previously optimized
conditions. When utilized in the asymmetric hydrogena-
tion of R,â-unsaturated ester 25, the P,N-sulfinyl imines
were efficient catalysts; however, the enantioselectivities
did not exceed 65% (Table 3, entries 1-5). Similar results
were observed for hydrogenation of the allylic alcohol 26
(entries 6-10), with complex 12 again providing the
highest enantioselectivity (entry 6).
1
2
3
4
5
6
(R)-t-Bu
(S)-1-adamantyl
(S)-3-ethylpentane o-tol
(S)-p-tolyl
(S)-mesitylene
(R)-t-Bu
o-tol
o-tol
12
13
14
15
16
17
>99 94
58 84
75 84
o-tol
o-tol
>99
52
5
7
3,5-dimethyl-
phenyl
53 57
7
(R)-t-Bu
Ph
18
20 55
a
Reactions were run at room temperature for 2 h with 5 mol %
crude catalyst. Determined by 1H NMR. c Determined by chiral
b
HPLC.
In summary, the work presented here serves to sig-
nificantly expand the scope of the P,N-sulfinyl imine-
based catalysts. The ease with which a variety of steri-
cally and electronically distinct ligands could be prepared
allowed us to gain valuable structure-activity informa-
tion for these ligands in the Ir-catalyzed enantioselective
hydrogenation of olefins. Notably, enantioselectivities of
up to 94% are observed for the hydrogenation of a
challenging unfunctionalized olefin substrate. The N-
sulfinyl imine-based P,N-ligand class is easily prepared
and has now been successfully applied with high enan-
tioselectivity to two different transition-metal-catalyzed
reactions.
metal center, enforced by the increased steric bulk of the
sulfinamide substituent. Comparison of the data for
complexes 12-14 (entries 1-3) versus that for complexes
15 and 16 (entries 4 and 5) clearly indicates the negative
impact that the arenesulfinyl imines have on the enan-
tioselectivity of the reaction. While the p-toluenesulfinyl
imine complex 15 was competitive with the tert-butane-
sulfinyl imine in terms of catalytic turnover, very little
selectivity was observed. This result is consistent with
the low selectivities that we have seen in previous studies
with ligands derived from p-toluenesulfinyl imines.2b,c
Although we had hoped that the complex incorporating
the mesitylenesulfinyl imine ligand 8 would provide
improved selectivity over the complex incorporating the
p-toluenesulfinyl imine ligand 7, only very poor enanti-
oselectivity and inefficient catalysis were observed (entry
5). A limited survey of complexes 17 and 18 bearing
different aryl phosphine components (entries 6 and 7)
illustrates that, in analogy with our P,N-sulfinyl imine
ligands in the allylic alkylation reaction2c and Pfaltz’ P,N-
oxazoline ligands in hydrogenation reactions,8e the o-tolyl
substitution is required for both high turnover and
enantioselectivity.
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE0139468). We thank
Daniel Weix for help with the preparation of several
sulfinamides. The Center for New Directions in Organic
Synthesis is supported by Bristol-Myers-Squibb as
sponsoring member and Novartis as a supporting
member.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, spectral data, and characterization for all relevant
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Encouraged by the performance of complex 12 in the
asymmetric hydrogenation of an unfunctionalized olefin,
we were interested in examining the substrate scope of
J O035675+
1802 J . Org. Chem., Vol. 69, No. 6, 2004