Asymmetric hydrogenation of N-arylimines catalyzed by the xyl-skewphos/DPEN-ruthenium(II) complex

Article abstract of DOI:10.1002/adsc.201200464

The new catalyst system of RuBr₂[(S,S)-xyl-skewphos][(S,S)-dpen] and potassium tert-butoxide shows high reactivity and enantioselectivity in the hydrogenation of N-arylimines [Xyl-Skewphos=2,4-bis(di-3,5-xylylphosphino) pentane, DPEN=1,2-diphenylethylenediamine]. A range of imines derived from aromatic and heteroaromatic ketones as well as some ferrocenyl and vinylic imines are hydrogenated with a turnover number as high as 18,000 under 10-50 atm of hydrogen to afford the amine products in up to 99% enantiomeric excess. The reaction is applied to the synthesis of a chiral N-arylamine, which is the synthetic intermediate of a biologically active compound. The mode of enantioselection is interpreted by using transition-state models based on the X-ray structure of the Xyl-Skewphos/DPEN-RuBr₂ complex. Copyright

Full text of DOI:10.1002/adsc.201200464

COMMUNICATIONS
DOI: 10.1002/adsc.201200464
Asymmetric Hydrogenation of N-Arylimines Catalyzed by the
Xyl-Skewphos/DPEN-Ruthenium(II) Complex
Noriyoshi Arai,a Noriyuki Utsumi,b Yuki Matsumoto,a Kunihiko Murata,b
Kunihiko Tsutsumi,b and Takeshi Ohkumaa,*
a
Division of Chemical Process Engineering and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University,
Sapporo, Hokkaido 060-8628, Japan
Fax : (+81)-11-706-6598; e-mail: ohkuma@eng.hokudai.ac.jp
Central Research Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., Soka, Saitama 340-0003,
b
Japan
Received: May 25, 2012; Published online: July 29, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200464.
Abstract: The new catalyst system of RuBr
[(S,S)-
with flexible conformation is particularly notewor-
thy.[3] However, the availability of hydrogenation re-
actions employing a catalyst with a high turnover
xyl-skewphos][(S,S)-dpen] and potassium tert-butox-
ACHTUNGTRENNUNG
ide shows high reactivity and enantioselectivity in
the hydrogenation of N-arylimines [Xyl-Skew-
phos=2,4-bis(di-3,5-xylylphosphino)pentane,
number (TON) is still quite limited. The PPF-PACHTUNGTRENNUNG(Xyl)2-
Ir(I) complex is an exception, since it exhibits ex-
tremely high catalytic activity for the hydrogenation
of an a-methoxyimine, achieving a TON of 2 million
to afford the functionalized amine in 80% ee (Fig-
ure 1).[3d,g] This reaction is utilized in the industrial
synthesis of the herbicide (S)-metolachlor. The re-
cently reported DuanPhos-Ir(I) complex also cata-
lyzed the hydrogenation of an imine derived from ani-
line and acetophenone with a substrate-to-catalyst
DPEN=1,2-diphenylethylenediamine]. A range of
imines derived from aromatic and heteroaromatic
ketones as well as some ferrocenyl and vinylic
imines are hydrogenated with a turnover number as
high as 18,000 under 10–50 atm of hydrogen to
afford the amine products in up to 99% enantio-
meric excess. The reaction is applied to the synthe-
sis of a chiral N-arylamine, which is the synthetic in-
termediate of a biologically active compound. The
mode of enantioselection is interpreted by using
transition-state models based on the X-ray structure
of the Xyl-Skewphos/DPEN-RuBr2 complex.
Keywords: amines; asymmetric catalysis; hydroge-
nation; imines; ruthenium
Asymmetric hydrogenation of prochiral imines is
a direct and reliable method to produce optically
active amines, which are widely used as synthetic in-
termediates of biologically important compounds and
chiral auxiliaries.[1] Therefore, the development of
highly reactive and enantioselective catalysts for this
transformation is a significant subject from both sci-
entific and practical points of view. Amine products
in high enantiomeric excesses (ee) of >95% have
become available by using appropriately designed cat-
alyst systems in the past few decades.[2–7] In this
regard, the advancement of the Ir(I) catalysts showing
Figure 1. Structures of chiral diphosphines and diamines that
high enantioselectivity for acyclic imine substrates can be employed in the asymmetric hydrogenation catalysts.
Adv. Synth. Catal. 2012, 354, 2089 – 2095
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2089

Noriyoshi Arai et al.
COMMUNICATIONS
molar ratio (S/C) of 10,000 to give the amine product
in 92% ee quantitatively.[3s]
We have previously studied the asymmetric hydro-
genation of ketones catalyzed by the chiral diphos-
phine/diamine-Ru(II) complexes.[8] A variety of aro-
matic, heterocyclic, and a,b-unsaturated ketones as
well as some types of aliphatic ketones are converted
with a high TON to the alcoholic products in high ee.
Hydrogenations of acetophenone with the BINAP/
DPEN-Ru(II) catalyst (TON=2.4 million, 80% ee)[9]
and with the Xyl-BINAP/DAIPEN-Ru(II) catalyst
(TON=100,000, 99% ee)[10] are typical examples
(Figure 1). However, the efficiency of these catalyst
systems for the asymmetric hydrogenation of imines
is not sufficiently high compared with that for the re-
action of ketones. For example, the hydrogenation of
an imine derived from aniline and acetophenone was
catalyzed by the RuCl2ACTHNUTRGENN[UG (R,R)-et-duphos]ACHTUNGTERN[NUGN (R,R)-dach]-
Scheme 1. Asymmetric hydrogenation of acetophenone
imines 1.
tert-C4H9OK system with an S/C of 100 to give the
amine in 94% ee (97% conversion).[5c] The same
imine was hydrogenated with the RuHCl[(R)-binap]-
ACHTUNGTRENNUNG[(R,R)-dach]-i-C3H7OK catalyst (S/C=500) quantita-
tively to afford the product in 71% ee.[5b] We expected 2’-methoxyphenyl (N-OMP) group of the amine prod-
that the catalyst performance of the diphosphine/dia- uct 2a is known to be easily removed with a reductive
mine-Ru(II) complexes would be appropriately tuna- treatment.[3i,u] When 1a (443 mg, 1.97 mmol) was hy-
ble by changing the electronic and/or structural fea- drogenated with (SP,SN)-3 (2.0 mg, 1.9 mmol, S/C=
tures of the chiral ligands. Recently, we found that 1000) and t-C4H9OK (10.8 mg, 96.2 mmol) in toluene
a Ru complex bearing Xyl-Skewphos and a-picolyla- (2.3 mL) at 408C under 10 atm of H2 for 15 h, the R
mine exhibits remarkably high catalytic activity in the amine product (R)-2a was obtained quantitatively in
hydrogenation of a sterically congested ketone with 99% ee (Table 1, entry 1). The reactions in THF and
a bicycloACHTUNGTRENNUNG
[2.2.2] skeleton.[11] The structure of Xyl-
Skewphos with two diarylphosphinyl moieties con-
nected with a flexible C3-alkyl chain seems to be ap-
propriate for the catalyst performance. We herein de-
scribe the enantioselective hydrogenation of N-aryl-
ketimines with the Xyl-Skewphos/DPEN-Ru(II) cata-
lyst with a TON as high as 18,000 to produce the
amine product in up to 99% ee.
Table 1. Hydrogenation of 1a catalyzed by the Ru complex
(SP,SN)-3.[a]
Entry S/C[b] Solvent[c] H2
[atm] [h]
Time
Yield
[%][d]
ee
[%][e]
1
2
3
4
1000 toluene 10
15
15
15
15
24
24
24
>99 (99) 99
RuBr
Scheme 1] was readily prepared by the reaction of
RuBr2A
[(S,S)-xyl-skewphos][11] and an equivalent of
2ACHTUNGTRENNUNG[(S,S)-xyl-skewphos]ACHTUGNTRNE[NUNG (S,S)-dpen] [(SP,SN)-3 in
1000 THF
1000 TBME
1000 IPA
10
10
10
>99
>99
<1
99
99
n.d.[f]
CHTUNGTRENNUNG
5[g,h] 5000 toluene 10
>99 (99) 99
>99 (99) 99
(S,S)-DPEN in DMF at 258C for 17 h (see the Sup-
porting Information). The 31P{1H} NMR spectrum
(CDCl3, À258C) showed two AB quartets at 41.6 and
65.0 ppm with JP, P =41.6 Hz (ca. 60%) and 48.0 and
59.7 ppm with JP, P =45.2 Hz (ca. 40%). The latter sig-
nals were broadened in the measurement at 258C. A
comparison with the reported 31P NMR signals of
6[g,i]
7[g,j]
10,000 toluene 50
20,000 toluene 50
90 (90)
99
[a]
Unless otherwise stated, the reactions were conducted at
408C using 1.7–2.0 mmol of imine 1a (0.83M) in solvent
containing a Ru complex (SP,SN)-3 and t-C4H9OK (42–
75 mM).
[b]
[c]
[d]
Substrate/catalyst molar ratio.
RuCl2ACHTUNGTRENNUNG[(S,S)-skewphos]ACHUTNGTREN[NGUN (S,S)-dpen] suggested that the
IPA=2-propanol. TBME=t-C4H9OCH3.
Yield of (R)-2a determined by GC analysis. The isolated
yield is stated in parentheses.
Determined by chiral HPLC analysis.
Not determined.
The initial concentration of 1a was 2.2M.
6.9 mmol of 1a were used.
10 mmol of 1a were used.
former AB quartet corresponded to the cis-RuBr2
complex, and the latter one was derived from the
complex with the trans geometry.[12] We decided to
use the diastereomeric mixture of (SP,SN)-3 as the cat-
alyst precursor for the hydrogenation of imines.
We selected an imine 1a derived from acetophe-
none and 2-methoxyaniline as a typical substrate to
optimize the reaction conditions (Scheme 1). The N-
[e]
[f]
[g]
[h]
[i]
[j]
20 mmol of 1a were used.
2090
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2089 – 2095

Asymmetric Hydrogenation of N-Arylimines Catalyzed by the Xyl-Skewphos/DPEN-Ruthenium(II) Complex
Table 3. Asymmetric hydrogenation of imines.[a]
t-C4H9OCH3 resulted in comparable results (entries 2
and 3). Interestingly, no conversion was observed in
2-propanol, which is the most preferable solvent for
the hydrogenation of ketones with the diphosphine/di-
amine-Ru(II) catalysts (entry 4).[8] The hydrogenation
with 3 at an S/C of 5000 (10 atm) or 10,000 (50 atm)
in toluene was completed within 24 h without loss of
enantioselectivity (entries 5 and 6). The highest TON
of 18,000 with this catalyst system was achieved in the
reaction at an S/C of 20,000 in 24 h (entry 7).
We next examined the effect of N-substituents of
imine substrates on the reactivity and enantioselectiv-
ity in the hydrogenation catalyzed by the 3/t-C4H9OK
system (Table 2). The reaction of N-arylimines, 1a–1f,
with an electron-donating or electronn-withdrawing
group at an S/C of 3000–5000 under 10 atm of H2 was
completed in 24–30 h to afford the amine products in
94–99% ee (entries 1–6). The electronic properties of
the substituents on the N-aryl groups did not have
much influence on the enantioselectivity. Hydrogena-
tion of the N-benzyl- and N-propylimines, 1g and 1h,
was relatively slow (entries 7 and 8). Isomerization of
the ketimine 1g to the aldimine is considered to be
the main reason for the low ee value of the amine 2g.
No conversion was observed in the hydrogenation of
the N-diphenylphosphinylimine 1i (entry 9).
Entry Imine
S/C[b] H2 [atm] Yield [%][c] ee [%][d]
1
4a
3000 10
3000 10
3000 10
10,000 50
3000 10
1500 10
3000 10
3000 10
3000 10
10,000 50
3000 10
500 10
21
99
99
99
99
99
99
99
99
98
99
99
98
99
99
98
99
99
93
99[h]
83
98
99
98
99
91
99
99
99
98
98
98
93
96
96
95
64
85
39
>99[i]
2
4b
3
4
5
6
4c
4c[e]
4d
4e[f]
4f
A series of N-OMP imines 4 was hydrogenated
with the (SP,SN)-3/t-C4H9OK catalyst system (Table 3).
The imines derived from the 3’- and 4’-substituted
acetophenones, 4b–d and 4f–h, were quantitatively
converted to the amine products in 98–99% ee (S/C=
3000, 10 atm H2, 24 h; entries 2, 3, 5, and 7–9). The
7
8
4g
9
4h
10
11
12
13
14
15
16
17
18
19
20
4h[e]
4i
4j[f]
4k[f]
4l[f]
4m
4n
500 10
500 10
3000 10
3000 10
500 10
Table 2. Hydrogenation of acetophenone imines 1.[a]
4o[f,g]
4p
Entry
1
S/C[b]
Yield [%][c]
ee [%][d]
3000 10
500 10
1000 10
4q[f]
6[f]
1
2
3
4
5
6
7
8
9
1a[e]
1b
1c
5000
4500
3000
3000
3000
3000
3000
2000
1000
99
99
99
99
99
97
97
99
97
94
27
[a]
Unless otherwise stated, the reactions were conducted at
408C for 15–24 h using 3.0–5.7 mmol of imine 4 (0.8–
2.2M) in toluene containing Ru complex (SP,SN)-3 and t-
C4H9OK (75–87 mM).
Substrate/catalyst molar ratio.
Yield of isolated product.
Determined by chiral HPLC analysis.
10 mmol of 4 were used.
0.6–1.6 mmol of 4 were used.
1d
1e
99
1f[e]
1g
99[f]
83
[b]
[c]
[d]
[e]
[f]
1h
85
97
1i[g]
<1[h]
n.d.[i]
[a]
Unless otherwise stated, the reactions were conducted at
408C under 10 atm of H2 for 24 h using 3.0–6.9 mmol of
imine 1 (0.83M) in toluene containing a Ru complex
(SP,SN)-3 and t-C4H9OK (76–87 mM).
Substrate/catalyst molar ratio.
[g]
[h]
[j]
The N-4-CH3OC6H4 imine was used as substrate.
Yield of a diastereomeric mixture. dl:meso=96:4.
Data of the dl product.
[b]
[c]
[d]
[e]
[f]
Yield of isolated (R)-2.
Determined by chiral HPLC analysis.
The initial concentration of 1 was 2.2M.
Reaction for 30 h.
1.0 mmol of 1i was used.
Determined by GC analysis.
electronic properties of the substituents on the phenyl
rings little affected the reactivity and enantioselectivi-
ty. Complete conversion in the reaction of the 4’-
CH3O (electron-donating) and 4’-Cl (electron-with-
drawing) substituted imines, 4c and 4h, with an S/C of
[g]
[h]
[i]
Not determined.
Adv. Synth. Catal. 2012, 354, 2089 – 2095
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2091

Noriyoshi Arai et al.
COMMUNICATIONS
Scheme 2. Preparation of a chiral synthetic intermediate of the enantiomer of a bioactive compound.
10,000 was achieved under 50 atm of H2 (entries 4 and C4H9OK system. Fortunately, the structure of the cis-
10). The reaction rate and stereoselectivity were de- diastereomer of (SP,SN)-3 was determined by a single
creased in the hydrogenation of 2’-CH3 and 2’-F sub- crystal X-ray analysis as shown in Figure 2.[19] It was
stituted imines, 4a and 4e (entries 1 and 6). The 3/t- expected to be closely related with the structure of
C4H9OK system also exhibited excellent catalyst per- the cis-RuH2 species. (SP,SN)-3 has a Ru center with
À
À
formance in the reaction of the imine formed from 2’- a distorted octahedral geometry [Br(2) Ru P(1)
À
À
À
acetonaphthone 4i (entry 11). The reactivity of the angle: 1748). The torsion angle of Br(2) Ru N(1)
À
À
À
pyridylimines, 4j and 4k, was relatively low, but the ee H(1) (268) is smaller than that of Br(2) Ru N(1)
values of the products were maintained at a high level H(2) (1438), indicating that in these amino protons
(entries 12 and 13). Interestingly, the ferrocenyl imine H(1) and H(2) are differentiated to be axial (Hax) and
4l was also a preferable substrate resulting in 5l in equatorial (Heq), respectively, by the skewed DPEN-
96% ee quantitatively (entry 14). To the best of our Ru chelate structure. The short distance between
knowledge, this is the first example of asymmetric hy- Br(2) and H(1) of 2.79 ꢁ suggests the existence of
drogenation of ferrocenylimines.[13] The phenyl ethyl a hydrogen bond. The strong trans-effect of P(1) is
À
and phenyl n-propyl imines, 4m and 4n, were hydro- supported by the longer Br(2) Ru bond length
genated with high reactivity and enantioselectivity (2.65 ꢁ) than that of Br(1) Ru bond (2.57 ꢁ).
À
(entries 15 and 16). The reaction of the phenyl cyclo-
Figure 3 schematically illustrates the molecular
propylimine 4o (PG=4-CH3OC6H4),[14] a secondary models of cis-RuH
[(S,S)-xyl-skewphos]
[(S,S)-dpen]
alkylimine, with an S/C of 500 required 24 h for com- [(SP,SN)-RuH2] and plausible diastereomeric transition
pletion to give amine 5o in a moderate ee (entry 17). states (TSs) TSSi and TSRe in the hydrogenation of the
The 2-methyl-1-propenyl methylimine 4p, an a,b-un-
saturated imine, was selectively converted to the allyl-
ic amine 5p in 85% ee (entry 18). An n-alkyl methyli-
mine 4q was reduced with insufficient enantioselectiv-
ity (entry 19). Notably, the double hydrogenation of
a diimine 6 afforded the diamine product 7 as a 96:4
(dl:meso) diastereomeric mixture (entry 20). The ee
value of the major chiral isomer was >99%.
We applied the asymmetric hydrogenation of N-ar-
ylimines to the synthesis of a chiral intermediate 9 for
the enantiomer of C5a receptor antagonist 10.[15] The
outline is shown in Scheme 2. The imine 8 was
smoothly hydrogenated with the (SP,SN)-3/t-C4H9OK
system under the regular conditions (S/C=3000,
10 atm H2, 408C, 24 h) to afford quantitatively the
amine product 9 in 93% ee.
The reactive species of the previous trans-
RuCl2(diphosphine)
have been reported to be trans-RuH2(diphosphine)-
ACHTUNGTRENNUNG
(diamine),[8,16–18] which exhibited less satisfactory cata-
A
catalysts
lytic activity and enantioselectivity in the hydrogena-
tion of imines. Thus, we considered that cis-RuH2
Figure 2. ORTEP drawing of the cis diastereomer of (SP,SN)-
3. All protons except those on the diamine ring are omitted
could be the active catalytic species of the (SP,SN)-3/t- for clarity.
2092
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2089 – 2095

Asymmetric Hydrogenation of N-Arylimines Catalyzed by the Xyl-Skewphos/DPEN-Ruthenium(II) Complex
Figure 3. Structure of the (SP,SN)-RuH2 species (*=Ru) and diastereomeric transition states in the hydrogenation of the N-
phenylimine 1c. The structures of these models are simplified for clarity. Ar=3,5-xylyl.
N-phenylimine 1c with the RuH2 species based on the in the hydrogenation of N-arylimines, which other re-
1
(SP,SN)-3 structure. A H NMR measurement suggest- lated diphosphine/diamine-Ru(II) catalysts have not
ed that 1c predominantly has an E geometry in a ben- achieved. The reaction is carried out with a TON as
zene or toluene solution. The more hydridic HA bind- high as 18,000 under 10–50 atm of H2 to afford the
ing to Ru at the trans position to the phosphorus amine products in up to 99% ee. A series of imines
atom acts as a nucleophile. The hydrogenation of derived from aromatic and heteroaromatic ketones is
imines proceeds via the six- membered TS, TSSi or smoothly converted to the desired chiral amines, al-
dÀ
d+
dÀ
d+
À
À
À
TSRe in which the HA Ru
N
Hax1 quadrupole though sterically hindered imines and aliphatic sub-
of the Ru complex interacts with the Cd+=NdÀ dipole strates result in insufficient stereoselectivity. Some
in the imine, as we have proposed for the mechanism ferrocenyl and vinylic imines as well as a diimine are
of hydrogenation of ketones.[8,16,17] The TSSi is prefera- also found to be the appropriate substrates for this re-
ble to the TSRe, resulting in (R)-2c or (S)-2c, respec- action. The asymmetric hydrogenation is applied to
tively, because the TSRe suffers two non-bonded repul- the synthesis of a chiral N-Ar amine, which is a key
sions between an axial P-xylyl group of Xyl-Skewphos synthetic intermediate of the enantiomer of a biologi-
and a C-phenyl ring of 1c, as well as between cally active compound. Furthermore, the mode of
a phenyl moiety of DPEN and an N-phenyl group of enantioselection is interpreted by using transition-
1c. The secondary attractive interaction between the state models based on the X-ray structure of the Xyl-
Heq2 and the C-phenyl ring of 1c appears to stabilize Skewphos/DPEN-RuBr2 complex.
the TSSi.
In summary, the new catalyst system of RuBr2
A
ACHTUNGTRENUN[NG (S,S)-dpen] and t-C4H9OK exhib-
Adv. Synth. Catal. 2012, 354, 2089 – 2095
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2093

Noriyoshi Arai et al.
COMMUNICATIONS
Experimental Section
Laghmari, P. Lhoste, D. Sinou, J. Chem. Soc. Chem.
Commun. 1991, 1684–1685; f) A. G. Becalski, W. R.
Cullen, M. D. Fryzuk, B. R. James, G.-J. Kang, S. J.
Rettig, Inorg. Chem. 1991, 30, 5002–5008; g) M. J.
Burk, J. E. Feaster, J. Am. Chem. Soc. 1992, 114, 6266–
6267; h) C. Lensink, J. G. de Vries, Tetrahedron: Asym-
metry 1992, 3, 235–238; i) M. J. Burk, J. P. Martinez,
J. E. Feaster, N. Cosford, Tetrahedron 1994, 50, 4399–
4428; j) J. M. Buriak, J. A. Osborn, Organometallics
1996, 15, 3161–3169; k) F. Spindler, H.-U. Blaser, Adv.
Synth. Catal. 2001, 343, 68–70; l) G. Shang, Q. Yang, X.
Zhang, Angew. Chem. 2006, 118, 6508–6510; Angew.
Chem. Int. Ed. 2006, 45, 6360–6362; m) C. Li, J. Xiao, J.
Am. Chem. Soc. 2008, 130, 13208–13209; n) N. Yoshika-
wa, L. Tan, J. C. McWilliams, D. Ramasamy, R. Shep-
pard, Org. Lett. 2010, 12, 276–279.
Typical Procedure for the Asymmetric
Hydrogenation of 1a with (SP,SN)-3
Ruthenium complex (SP,SN)-3 (1.1 mg, 1.1 mmol), 1a (2.43 g,
11.0 mmol), and t-C4H9OK (42.1 mg, 0.38 mmol) were
placed in a 100-mL glass autoclave equipped with a Teflon-
coated magnetic stirring bar. Toluene (5.0 mL) which had
been degassed by three freeze-thaw cycles was added to this
autoclave. Hydrogen was introduced into the autoclave at
a pressure of 10 atm, and then the reaction mixture was vig-
orously stirred at 408C for 24 h. After carefully venting the
hydrogen gas, the solvent was removed under reduced pres-
sure. The residue was purified by silica-gel column chroma-
tography giving (R)-2a as a colorless oil; yield: 2.44 g (99%,
99% ee). [a]D25: À38.7 (c 1.11, CHCl3); literature[3u] [a]D:
À32.3 (c 1.03, CHCl3), 97% ee (R). 1H NMR (400 MHz,
CDCl3): d=1.55 (d, 3H, J=6.7 Hz), 3.89 (s, 3H), 4.41–4.52
(m, 1H), 4.62 (br s, 1H), 6.33 (dd, 1H, J=7.9, 1.4 Hz), 6.57–
6.64 (m, 1H), 6.66–6.72 (m, 1H), 6.76 (dd, 1H, J=7.9,
1.4 Hz), 7.18–7.40 (m, 5H). The enantiomeric excess of 2a
was determined by HPLC analysis [CHIRALCEL OD-H
column (4.6ꢂ250 mm), 308C, hexane:2-propanol=99:1, 1.0
mLminÀ1, 254 nm]: tR of (S)-2a=6.6 min (0.7%), tR of (R)-
2a=9.4 min (99.3%).
[3] For selected studies using Ir catalysts, see: a) F. Spin-
dler, B. Pugin, H.-U. Blaser, Angew. Chem. 1990, 102,
561–562; Angew. Chem. Int. Ed. Engl. 1990, 29, 558–
559; b) T. Morrimoto, N. Nakajima, K. Achiwa, Synlett
1995, 748–750; c) K. Tani, J. Onouchi, Y. Yamagata, Y.
Kataoka, Chem. Lett. 1995, 955–956; d) H.-U. Blaser, F.
Spindler, Top. Catal. Zeitschrift wurde erst 1994 gerꢀn-
det! 1977, 4, 275–282; e) P. Schnider, G. Koch, R.
Prꢃtꢆt, G. Wang, F. M. Bohnen, C. Krꢇger, A. Pfaltz,
Chem. Eur. J. 1997, 3, 887–892; f) G. Zhu, X. Zhang,
Tetrahedron: Asymmetry 1998, 9, 2415–2418; g) H.-U.
Blaser, H.-P. Buser, K. Coers, R. Hanreich, H.-P. Jalett,
E. Jelsch, B. Pugin, H.-D. Schnider, F. Spindler, A.
Wegmann, Chimia 1999, 53, 275–280; h) S. Kainz, A.
Brinkmann, W. Leitner, A. Pfaltz, J. Am. Chem. Soc.
1999, 121, 6421–6429; i) D. Xiao, X. Zhang, Angew.
Chem. 2001, 113, 3533–3536; Angew. Chem. Int. Ed.
2001, 40, 3425–3428; j) C. Moessner, C. Bolm, Angew.
Chem. 2005, 117, 7736–7739; Angew. Chem. Int. Ed.
2005, 44, 7564–7567; k) A. Dervisi, C. Carcedo, L. Ooi,
Adv. Synth. Catal. 2006, 348, 175–183; l) T. Imamoto, N.
Iwadate, K. Yoshida, Org. Lett. 2006, 8, 2289–2292;
m) A. Trifonova, J. S. Diesen, P. G. Andersson, Chem.
Eur. J. 2006, 12, 2318–2328; n) T. Yamagata, H. Tadao-
ka, M. Nagata, T. Hirao, Y. Kataoka, V. Ratovelomana-
na-Vidal, J. P. Genet, K. Mashima, Organometallics
2006, 25, 2505–2513; o) S.-F. Zhu, J.-B. Xie, Y.-Z.
Zhang, S. Li. Q.-L. Zhou, J. Am. Chem. Soc. 2006, 128,
12886–12891; p) M. N. Cheemala, P. Knochel, Org. Lett.
2007, 9, 3089–3092; q) M. T. Reetz, O. Bondarev,
Angew. Chem. 2007, 119, 4607–4610; Angew. Chem.
Int. Ed. 2007, 46, 4523–4526; r) C. Li, C. Wang, B.
Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2008, 130,
14450–14451; s) W. Li, G. Hou, M. Chang, X. Zhang,
Adv. Synth. Catal. 2009, 351, 3123–3127; t) Z. Han, Z.
Wang, X. Zhang, K. Ding, Angew. Chem. 2009, 121,
5449–5453; Angew. Chem. Int. Ed. 2009, 48, 5345–5349;
u) N. Mrsic, A. J. Minnaard, B. L. Feringa, J. G. de V-
ries, J. Am. Chem. Soc. 2009, 131, 8358–8359; v) G.
Hou, F. Gosselin, W. Li, J. C. McWilliams, Y. Sun, M.
Weisel, P. D. OꢈShea, C. Chen, I. W. Davies, X. Zhang,
J. Am. Chem. Soc. 2009, 131, 9882–9883; w) G. Hou, R.
Tao, Y. Sun, X. Zhang, F. Gosselin, J. Am. Chem. Soc.
2010, 132, 2124–2125; x) A. Baeza, A. Pfaltz, Chem.
Eur. J. 2010, 16, 4003–4009.
Acknowledgements
This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 24350042).
References
[1] Recent reviews: a) T. Ohkuma, M. Kitamura, R.
Noyori, in: Catalytic Asymmetric Synthesis, 2nd edn.,
(Ed.: I. Ojima), Wiley-VCH, New York, 2000, pp 1–
110; b) F. Spindler, H.-U. Blaser, in: Transition Metals
for Organic Synthesis, 2nd edn., Vol. 2, (Eds.: M.
Beller, C. Bolm), Wiley-VCH, Weinheim, 2004,
pp 113–123; c) F. Spindler, H.-U. Blaser, in The Hand-
book of Homogeneous Hydrogenation, Vol. 3, (Eds.:
J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim,
2007, pp 1193–1200; d) L. Xu, X. Wu, J. Xiao, in: Sci-
ence of Synthesis: Stereoselective Synthesis, Vol. 2, (Ed.:
G. A. Molander), Thieme, Stuttgart, 2010, pp 251–309;
e) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010,
352, 753–819; f) N. Fleury-Brꢃgeot, V. de La Fuente, S.
Castillꢄn, C. Claver, ChemCatChem 2010, 2, 1346–1371;
g) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011,
111, 1713–1760.
[2] For selected studies using Rh catalysts, see: a) A. Levi,
G. Modena, G. Scorrano, J. Chem. Soc. Chem.
Commun. 1975, 6–7; b) J. Bakos, I. Tꢄth, B. Heil, L.
Markꢄ, J. Organomet. Chem. 1985, 279, 23–29; c) G.-J.
Kang, W. R. Cullen, M. D. Fryzuk, B. R. James, J. P.
Kutney, J. Chem. Soc. Chem. Commun. 1988, 1466–
1467; d) Y. N. C. Chan, J. A. Osborn, J. Am. Chem. Soc.
1990, 112, 9400–9401; e) J. Bakos, ꢅ. Orosz, B. Heil, M.
2094
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2089 – 2095

Asymmetric Hydrogenation of N-Arylimines Catalyzed by the Xyl-Skewphos/DPEN-Ruthenium(II) Complex
[4] For selected studies using Pd catalysts, see: a) H. Abe,
H. Amii, K. Uneyama, Org. Lett. 2001, 3, 313–315;
b) Y.-Q. Wang, Y. G. Zhou, Synlett 2006, 1189–1192;
c) Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang,
Angew. Chem. 2006, 118, 3916–3919; Angew. Chem.
Int. Ed. 2006, 45, 3832–3835; d) Y.-Q. Wang, C.-B. Yu,
D.-W. Wang, X.-B. Wang, Y. G. Zhou, Org. Lett. 2008,
10, 2071–2074.
Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124, 6508–
6509; c) K. Matsumura, N. Arai, K. Hori, T. Saito, N.
Sayo, T. Ohkuma, J. Am. Chem. Soc. 2011, 133, 10696–
10699.
[11] K. Tsutsumi, T. Katayama, N. Utsumi, K. Murata, N.
Arai, N. Kurono, T. Ohkuma, Org. Process Res. Dev.
2009, 13, 625–628.
[12] O. M. Akotsi, K. Metera, R. D. Reid, R. McDonald,
[5] For selected studies using Ru catalysts, see: a) W. Op-
polzer, M. Wills, C. Starkemann, G. Bernardinelli, Tet-
rahedron Lett. 1990, 31, 4117–4120; b) K. Abdur-
Rashid, A. J. Lough, R. H. Morris, Organometallics
2001, 20, 1047–1049; c) C. J. Cobley, J. P. Henschke,
Adv. Synth. Catal. 2003, 345, 195–201.
[6] For the Fe-catalyzed reaction, see: S. Zhou, S. Fleisch-
er, K. Junge, M. Beller, Angew. Chem. 2011, 123, 5226–
5230; Angew. Chem. Int. Ed. 2011, 50, 5120–5124.
[7] For selected studies using Ti and Zr catalysts, see:
a) C. A. Willoughby, S. L. Buchwald, J. Am. Chem. Soc.
1992, 114, 7562–7564; b) C. A. Willoughby, S. L. Buch-
wald, J. Am. Chem. Soc. 1994, 116, 8952–8965; c) M.
Ringwald, R. Stꢇrmer, H. H. Brintzinger, J. Am. Chem.
Soc. 1999, 121, 1524–1527.
[8] Reviews: a) R. Noyori, T. Ohkuma, Angew. Chem.
2001, 113, 40–75; Angew. Chem. Int. Ed. 2001, 40, 40–
73; b) T. Ohkuma, Proc. Jpn. Acad. Ser. B 2010, 86,
202–219.
[9] H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M.
Kozawa, E. Katayama, A. F. England, T. Ikariya, R.
Noyori, Angew. Chem. 1998, 110, 1792–1796; Angew.
Chem. Int. Ed. 1998, 37, 1703–1707.
S. H. Bergens, Chirality, 2000, 12, 514–522.
[13] For asymmetric hydrosilylation with a titanocene cata-
lyst, see: X. Verdaguer, U. E. W. Lange, M. T. Reding,
S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 6784–
6785.
[14] Attempts to prepare the corresponding N-OMP imine
with sufficient purity were unsuccessful.
[15] K. Schnatbaum, D. Scharn, E. Locardi, T. Polakowsli,
U. Richter, U. Reineke, G. Hummel, (Jerini AG.), PCT
Int. WO2006/128670A1, 2006.
[16] C. A. Sandoval, T. Ohkuma, K. MuÇiz, R. Noyori, J.
Am. Chem. Soc. 2003, 125, 13490–13503.
[17] a) N. Arai, K. Azuma, N. Nii, T. Ohkuma, Angew.
Chem. 2008, 120, 7567–7570; Angew. Chem. Int. Ed.
2008, 47, 7457–7460; b) N. Arai, M. Akashi, S. Sugizaki,
H. Ooka, T. Inoue, T. Ohkuma, Org. Lett. 2010, 12,
3380–3383.
[18] a) K. Abdur-Rashid, S. E. Clapham, A. Hadzovic, J. N.
Harvey, A. J. Lough, R. H. Morris, J. Am. Chem. Soc.
2002, 124, 15104–15118; b) R. J. Hamilton, C. G. Leong,
G. Bigam, M. Miskolzie, S. H. Bergens, J. Am. Chem.
Soc. 2005, 127, 4152–4153.
[19] CCDC 883851 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] a) T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M.
Kozawa, K. Murata, E. Katayama, T. Yokozawa, R.
Noyori, J. Am. Chem. Soc. 1998, 120, 13529–13530;
b) T. Ohkuma, M. Koizumi, K. MuÇiz, G. Hilt, C.
Adv. Synth. Catal. 2012, 354, 2089 – 2095
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2095