Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones

Article abstract of DOI:10.1021/acs.orglett.6b01290

A series of modular and rich electronic tridentate ferrocene aminophosphoxazoline ligands (f-amphox) have been successfully developed and used in iridium-catalytic asymmetric hydrogenation of simple ketones to afford corresponding enantiomerically enriched alcohols under mild conditions with superb activities and excellent enantioselectivities (up to 1"000"000 TON, almost all products up to >99% ee, full conversion). The resulting chiral alcohols and their derivatives are important intermediates in pharmaceuticals.

Full text of DOI:10.1021/acs.orglett.6b01290

Letter
pubs.acs.org/OrgLett
Iridium Catalysts with f‑Amphox Ligands: Asymmetric
Hydrogenation of Simple Ketones
Weilong Wu,†,∥ Shaodong Liu,‡,∥ Meng Duan,§ Xuefeng Tan,† Caiyou Chen,† Yun Xie,† Yu Lan,*,§
Xiu-Qin Dong,*,† and Xumu Zhang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
‡Department of Chemistry and Chemical Biology & Department of Pharmaceutical Chemistry, Rutgers, The State University of New
Jersey, Piscataway, New Jersey 08854, United States
§School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
S
* Supporting Information
ABSTRACT: A series of modular and rich electronic tridentate
ferrocene aminophosphoxazoline ligands (f-amphox) have been
successfully developed and used in iridium-catalytic asymmetric
hydrogenation of simple ketones to afford corresponding enantio-
merically enriched alcohols under mild conditions with superb
activities and excellent enantioselectivities (up to 1 000 000 TON, almost all products up to >99% ee, full conversion). The
resulting chiral alcohols and their derivatives are important intermediates in pharmaceuticals.
atalytic asymmetric hydrogenation of prochiral ketones is
Cone of the most powerful and convenient methods to
approach chiral alcohols, which are important structural motifs in
many pharmaceutical products,1 such as ezetimine, duloxetine,
aprepitant, crizotinib, and montelukast (Figure 1). Owing to this
great importance, much effort has been devoted to developing
efficient catalytic methodologies to access chiral alcohols in the
last decades.
our group utilized the strategy of “NH effect” in the first chiral
tridentate bis(oxazolinylmethyl)amine (ambox) ligands and
applied in Ru-catalyzed transfer hydrogenation of simple
ketones.4 Later our group developed more sterically hindered
chiral tridentate NNN Indan-ambox ligand, and the asymmetric
hydrogenation of various ketones was achieved up to 97% ee
catalyzed by chiral ruthenium−Indan−ambox complex.5 The N−
H moiety of the Indan-ambox ligand of the ruthenium catalyst is
crucial for achieving high activity and enantioselectivity. Recently,
Zhou and co-workers developed another tridentate spiro
pyridine−aminophosphine ligands SpiroPAP.6 Chiral alcohols
were produced with up to 99.9% ee and 4 550 000 TON in the
iridium−SpiroPAP catalytic system, although multistep compli-
cated reactions were involved to synthesize these ligands. Despite
the great success that has been achieved, it is still necessary to
develop effective and readily available ligands especially for
asymmetric hydrogenation of various simple ketones. Based on
our experience in this area, we made effort to design and
synthesize electron-donating and steric hindered ligands for
asymmetric hydrogenation of various ketonestoachieve excellent
enantioselectivities and activities. We introduced a chiral
ferrocenylphosphine motif to replace one oxazoline in ambox
(aminobisoxazoline) ligands forming air-stable and high active
ferrocene aminophosphoxazoline (f-amphox) ligands (Figure 2).
Herein we have successfully developed a novel modular electron-
donating tridentate ligands f-amphox and applied them in
iridium-catalytic asymmetric hydrogenation of various ketones
with excellent enantioselectivities and high activities.
Figure 1. Related chiral pharmaceuticals containing key chiral structural
motifs.
The production of enantioenriched chiral compounds was first
reported by Knowles et al. in 1968.2 The milestone research work
was reported by Noyori and co-workers in the 1990s, who
developed highly effective catalytic system BINAP−ruthenium−
diamine complexes for the asymmetric hydrogenation of
ketones.3 The exceptionally high reactivities and enantioselectiv-
ities due to the cooperative action of the Ru−H and NH2 group
through metal−ligand bifunctional mechanism involving “NH
effect”. Promoted by these exciting results, major progress has
been made over the past decades. We have proposed an
exploration of tridentate ligands for simple ketones. In 1998,
The modular chiral f-amphox ligands were easily made via
three-step reaction using the commercially available (S)-Ugi’s
Received: May 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that the configuration of the ligand is very critical for
enantioselectivity and reactivity.
Encouraged by these excellent results, a study of the reaction
with [Ir(COD)Cl]2/ligand L3 was performed in various solvents
and bases. The results were summarized in the Supporting
Information. With the optimized conditions in hand (S/C =
10 000, Ir-amphox L3/20 atm H2/0.1 mol % K2CO3/room
temperature), a series of alkyl aryl ketones were hydrogenated
smoothly to get various chiral alcohols in quantitative yields with
94−99.9% ee (Scheme 2). The substrates bearing electron-
Figure 2. Examples of excellent NH−tridentate ligands in asymmetric
hydrogenation of ketones.
amine (Scheme 1). A series of chiral f-amphox ligands L1−L6
were efficiently prepared according to the simple synthetic
Scheme 2. Asymmetric Hydrogenation of Various Ketones
with Ir-L3
Scheme 1. Synthetic Route of f-Amphox Ligands L1−L7
a
route.7−9 (SC, RFC)-3 was easily obtained7 and subsequently
reacted with various 2-chloromethyloxazoline8 in the presence of
K2CO3 as hydrogen chloride scavenger generating the desired f-
amphox ligands L1−L6 in good yields.9 In addition, we
synthesized ligand L7, which is the diasteroisomer of ligand L3
to investigate the relationship between enantioselectivity and
configuration of ligand.
With the chiral f-amphox ligands L1−L7 in hand, we began our
studies by evaluating them for asymmetric hydrogenation of
acetophenone 1−1 serving as the model substrate with the
catalyst generated in situ by mixing [Ir(COD)Cl]2 with ligands
L1−L7 in iPrOH. As shown in Table 1, ligands L1−L6 displayed
Table 1. Asymmetric Hydrogenation of Acetophenone 1-1
a
Catalyzed by Ir/L1−L7 Complexes
a
The yield was isolated yield. ee was determined by GC or HPLC on
chiral stationary phase (see the Supporting Information).
donating groups (1−4 ≈ 1−8, 1−19 ≈ 1−22) and electron-
withdrawing groups(1−9≈ 1−18)onthe phenylringperformed
well with excellent results, and the position of the substituent
groups on the phenyl group of the substrates had little influence
on the reactions. It is worth noting that the reduction of
heterocyclic aromatic ketones (1−25 ≈ 1−26) can also achieve
>99% ee. To our delight, more challenging substrates aliphatic
ketones, such as cyclopropyl methyl ketone (1−27) and
cyclohexyl methyl ketone (1−28) were also proceeded efficiently
(83%−96% ee).
As we expected, Ir-L3 complex is very stable and highly active.
When the catalyst loading was decreased to 0.0002 mol % (S/C =
500 000), the product (R)-2−1 was obtained in >99% ee and
>99% conversion within only 36 h at room temperature under an
initialhydrogen pressureof 50atm. When thecatalystloading was
further lowered to 0.0001 mol % (S/C = 1 000 000), the reaction
still proceeded well under 80 atm H2 pressure and provided (R)-
2−1 in >99% ee with >99% conversion within only 48 h (Scheme
3). We found that our catalytic system Ir-amphox L3 has more
advantages than previous reported catalytic system.10 We used
K2CO3 as the base, which is weaker than KOtBu and owned
stronger tolerance of base sensitive group. For more challenging
b
c
entry
ligand
conversion (%)
ee (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
>99
>99
>99
>99
>99
65
99.1
99.6
99.9
98.9
95.6
91.8
54.4
45
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.2 M, 0.001
mmol % [Ir(COD)Cl]2, 0.0021 mmol % ligand, [KOtBu] = 0.002 M,
solvent volume = 1.0 mL, room temperature (25−30 °C).
Determined by GC. Determined by GC on a Supelco chiral β-
b
c
dex-120 solid phase.
high reactivities and excellent enantioselectivities (Table 1,
entries 1−6). The ligand L3 afforded the best result with 99.9%
ee and >99% conversion (Table 1, entry 3). Ligand screening
resultsdemonstratedthatthesubstituentsontheoxazolineandP-
phenyl ring had a significant effect on the enantioselectivity. Low
enantioselectivity and reactivity was obtained when the ligand L7
wasappliedintothistransformation (Table1, entry7). Itisshown
B
DOI: 10.1021/acs.orglett.6b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
isomer CP1. The coordination of one molecule hydrogen on
complex CP1 generates an octahedral intermediate CP2 with
14.0 kcal/mol endothermic. The hydrogenation on the Re-face of
N5takesplaceviaaconcertedfour-memberedringtypetransition
state TS1, which is a hydride iridium intermediate CP3. The
overall activation free energy of this step is 24.1 kcal/mol. In
another case, the corresponding hydrogenation on the Si-face of
N5 could occur from intermediate CP4 to afford intermediate
CP6 with an activation free energy of 28.4 kcal/mol via transition
state TS6. The computational results indicate that the formation
of intermediate CP3 is kinetically and thermodynamically
favorable. The hydrogenation of acetophenone 1−1 with
intermediate CP3 could take place via transition state TS2 or
TS3, which forms the major product b-R or its enantioisomer 2−
1′,respectively. TherelativeenthalpyofTS2is1.8kcal/mollower
than that of TS3. Therefore, 2−1 is the major product, and the
theoretical predicated ee% is 90.1%, which is a little lower than
that of experimental observation. Moreover, the calculated free
energy difference in gas phase is 3.0 kcal/mol, which indicates
99% ee. Therefore, the computational deviation of enatioselec-
tivity would be attributed to the solvent effect calculation. The
geometry information on TS2 and TS3 is shown in Figure 3. In
transition state TS2, the lengths of forming C−H bond and
breaking Ir−H bond are 1.65 and 1.79 Å, which are significantly
longer and shorter than the corresponding typical single bonds,
respectively. However, the lengths of the forming O−H bond and
breaking N−H bond are 1.92 and 1.03 Å, respectively, which are
closed to a corresponding typical intermediate CP3 and
phenylethanol with dehydrogenated intermediate CP1. There-
fore, the hydrogenation step could be descripted as a polarized
concerted hydride transfer followedby N−H···O hydrogenbond.
Moreover, intrinsic reaction coordinate calculations indicate that
transition state TS2 linked the reactant acetophenone with
hydrogenated proton transfer. In geometry information on
transition state TS3, the distance between the phenyl group of
reacting acetophenone and the equatorial phenyl of ligand is only
Scheme 3. Asymmetric Hydrogenation of Acetophenone 1−1
with High S/C
substrate 2-pyridyl ketone 1−25, our catalytic system displayed
higher activity and enanoselectivity and did not need to add
additive borate to block pyridine. In addition, our chiral f-amphox
ligands were synthesized from much more easily available
materials, suchaschiralaminoalcohol, chlorodiphenylphosphine.
Density functional theory calculations as implemented in the
Gaussian09seriesofprograms11 havebeenappliedtogainfurther
insights into mechanism and the origins of enantioselectivity for
reactant 1−1 with ligand L3 based on the previous study of
mechanism.12 All stationary points are optimized at B3LYP/6-
31G(d)13 leveloftheory(LANL08(f)basissetforIratom14). The
harmonicvibrationalfrequencieswerecomputedatthesamelevel
of theory to check whether the optimized structure is at an energy
minimum or a transition state and to evaluate the corrections of
enthalpyandGibbsfreeenergy. Solvent effects werecomputedby
PCM salvation model15 at the M05-2X/6-311+G(d,p)16 level of
theory (LANL08(f) basis set for Ir atom) using the gas phase
optimized structures. The values given by kcal/mol are the M05-
2X calculated relative free energies in DCM solvent.
As shown in Figure 3, there are two possible conformational 7
isomers of the active catalyst hydrideiridium(III) species, which is
endo-CP1 and exo-CP4. The isomerization barrier from CP1 to
CP4 is only 10.9 kcal/mol via transition state TS4. The
conformation of iridium-contained six-membered ring for CP1
andCP4isboattype, althoughthesixatomsofthatringarealmost
on the same plane. In conformational isomer CP4, the methyl
group on C4 is equatorial, which leads to a strong static repulsion
toward neighbored C2 and C6 moieties. Therefore, the relative
free energy of CP4 is 8.4 kcal/mol higher than its conformational
Figure3. DFTcomputedenergysurfacesoftheindium-catalyzedasymmetrichydrogenationofacetophenone. Thevaluesgivenbykcal/molaretheM05-
2X calculated relative free energies in DCM solvent. The values in brackets are the M05-2X calculated relative enthalpy in DCM solvent. The values in
parentheses are the B3LYP calculated relative free energies in gas phase. Distances in geometry information are valued in Å.
C
DOI: 10.1021/acs.orglett.6b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2.58 Å, which indicates a significant repulsion. Therefore, the
relative energy of transition state TS3 is higher than that of TS2.
To better illustrate the steric repulsions at different regions of
hydrogenation step, a bottom-view 2D contour map along the z-
axis of the van der Waals surface of intermediate CP3 is plotted in
Figure 4. In this map, the z-axis is defined as the reacting Ir−H
51302327) and the National Institutes of Health (NIH R01
GM077437).
REFERENCES
■
(1) (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(b) Noyori, R. Adv. Synth. Catal. 2003, 345, 15. (c) Hagmann, W. K. J.
Med. Chem. 2008, 51,4359. (d)Zhao, M. M.;McNamara, J. M.;Ho,G.-J.;
Emerson, K. M.;Song, Z. J.; Tschaen, D. M.;Brands, K. M. J.;Dolling, U.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 2002, 67, 6743. (e) Li, W.;
Sun, X.; Zhou, L.; Hou, G.; Yu, S.; Zhang, X. J. Org. Chem. 2009, 74, 1397.
(f) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(2) (a) Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445.
(b) Horner, L.; Siegel, H.; Bthe, H. Angew. Chem., Int. Ed. Engl. 1968, 7,
942.
(3)(a)Haack, K.;Hashiguchi, S.;Fujii, A.;Ikariya, T.;Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285. (b) Hashiguchi, S.; Noyori, R. Acc.
Chem. Res. 1997, 30, 97. (c) Doucet, H.; Ohkuma, T.; Murata, K.;
Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703. (d) Ohkuma, T.;
Koizumi, M.; Doucet, H.; Pharm, T.; Kozawa, M.; Murata, K.; Katayama,
E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120,
13529.
Figure 4. Bottom-view 2D contour maps of the van der Waals surface of
intermediate CP3. Distances are valued in Å. Negative distance (blue)
indicates the atoms on complex is farther away from substrate; positive
distance (red) indicates the atoms on complex is closer to substrate.
(4) Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817.
(5) Li, W.; Hou, G.; Wang, C.; Jiang, Y.; Zhang, X. Chem. Commun.
2010, 46, 3979.
(6) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2011, 50, 7329.
(7) Nie, H.; Zhou, G.; Wang, Q.; Chen, W.; Zhang, S. Tetrahedron:
Asymmetry 2013, 24, 1567.
(8)Ye,M.-C.;Li,B.;Zhou,J.;Sun,X.-L.;Tang,Y. J.Org.Chem. 2005,70,
6108.
(9) (a) Guillemot, G.; Neuburger, M.; Pfaltz, A. Chem. - Eur. J. 2007, 13,
8960. (b) Sheng, C.; Che, X.; Wang, W.; Wang, S.; Cao, Y.; Yao, J.; Miao,
bond. The 2D contour map clearly indicates that the right part is
occupied by the cyclopentadinene moiety and equatorial phenyl
group in ligand, which block the right part when the hydro-
genation takes place. Therefore, when acetophenone reacts with
intermediate CP3, the larger group should be arranged at left.
Insummary, wehavesuccessfully developedaseriesofmodular
and electron-donating tridentate ferrocene aminophosphoxazo-
line ligands (f-amphox) for iridium-catalytic asymmetric hydro-
genation of various simple ketones. Excellent enantioselectivities
(upto99.9% ee) andsuperbactivities (upto1 000 000TON)has
been achieved using Ir-f-amphox catalyst. The great performance
of the reaction and the easy preparation of the catalyst make this
asymmetric hydrogenation highly practical, and it should have a
great impactinthefieldof asymmetrichydrogenation andorganic
chemistry. Further investigation for challenging substrates is
underway and will be reported in due course.
Z.; Zhang, W. Eur. J. Med. Chem. 2011, 46, 1706. (c) Breton, P.; Andre-
́
Barres, C.; Langlois, Y. Preparation of functionalized oxazolines. Synth.
́
Commun. 1992, 22, 2543. (d) Shang, Z.-L.; Shang, Z.-C.; Yu, Q.-S. Synth.
Commun. 2002, 32, 3461.
(10) Ohkuma, T.;Koizumi, M.; Yoshida, M.; Noyori, R. Org. Lett. 2000,
2, 1749.
(11) Frisch, M. J.; et al. Gaussian 09, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2013. The full author list is shown in the Supporting
Information.
ASSOCIATED CONTENT
* Supporting Information
■
(12) For selected examples, see: (a) Nozaki, H.; Takaya, H.; Moriuti, S.;
Noyori, R. Tetrahedron 1968, 24, 3655. (b) Abdur-Rashid, K.; Clapham,
S. E.; Hadzovic, A.; Harvey, J. N.; Lough, A. J.; Morris, R. H. J. Am. Chem.
Soc. 2002, 124, 15104. (c) Matsumura, K.; Arai, N.; Hori, K.; Saito, T.;
Sayo, N.; Ohkuma, T. J. Am. Chem. Soc. 2011, 133, 10696.
(d) Prokopchuk, D.; Morris, R. Organometallics 2012, 31, 7375.
(e) Dub, P.; Henson, N.; Martin, R.; Gordon, J. J. Am. Chem. Soc.
2014, 136, 3505.
(13) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(14) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (b) Hay, P.
J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 284. (c) Hay, P. J.; Wadt, W. R. J.
Chem. Phys. 1985, 82, 299.
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b01290.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xumu@whu.edu.cn.
*E-mail: xiuqindong@whu.edu.cn.
*E-mail: lanyu@cqu.edu.cn.
Author Contributions
(15)Marenich, A.V.;Cramer, C. J.;Truhlar, D.G. J. Phys.Chem. B2009,
113, 6378.
(16) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput.
2006, 2, 364.
∥W.W. and S.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the grant from Wuhan University (203273463,
203410100064), the support of the Important Sci-Tech
Innovative Project of Hubei Province (2015ACA058), and
“111” Project of the Ministry of Education of China for financial
support and the National Natural Science Foundation of China
(Grant No. 21372179, 21432007, 21502145, 21372266,
D
DOI: 10.1021/acs.orglett.6b01290
Org. Lett. XXXX, XXX, XXX−XXX