Highly enantioselective hydrogenation of aryl vinyl ketones to allylic alcohols catalyzed by the tol-binap/Dmapen ruthenium(II) complex

Article abstract of DOI:10.1002/anie.200802533

(Chemical Equation Presented) Binap catalyst doesn't dmapen expectations: In basified 2-propanol, [RuCl₂{(S)-tol-binap}{(R)-dmapen}] (1, see picture, Ar=4-CH₃C₆H₄) catalyzes the highly enantioselective hydrogenation of a series of aryl vinyl ketones and affords the allylic alcohols in high yields with up to 98% ee. Formation of the saturated ketones and alcohols is suppressed with triphenylphosphine when necessary.

Full text of DOI:10.1002/anie.200802533

Angewandte
Chemie
DOI: 10.1002/anie.200802533
Asymmetric Hydrogenation
Highly Enantioselective Hydrogenation of Aryl Vinyl Ketones to
Allylic Alcohols Catalyzed by the Tol-Binap/Dmapen Ruthenium(II)
Complex**
Noriyoshi Arai, Keita Azuma, Noriyuki Nii, and Takeshi Ohkuma*
Enantioselective hydrogenation of prochiral ketones
(R1COR2, R1 ¼ R2) requires distinction between two sub-
stituents, R1 and R2, connected to the carbonyl group. In the
reaction of functionalized ketones, a, b, or g-hetero-substi-
tuted alkyl moieties are accurately discriminated from simple
alkyl groups by means of chirally modified transition-metal
catalysts.[1] The synthesis of the xyl-binap/daipen RuII cata-
lyst,[2,3] has made possible the precise differentiation of sp2-
carbon groups (sp2-CG, including aryl, hetero-aryl, and vinyl
groups), from sp3-carbon groups (sp3-CG, primary and
secondary alkyl groups) in the hydrogenation of simple,
unfunctionalized ketones.[4] Tol-binap/a-picolylamine RuII
catalyst[2] effectively discriminates tertiary alkyl groups (sp3-
CG) from both n-alkyl (sp3-CG) and aryl (sp2-CG) groups.[5]
Differentiation of ortho-substituted benzene rings (sp2-CG)
from phenyl (sp2-CG) groups has also been achieved with the
xyl-binap/daipen RuII catalyst.[6] However, accurate distinc-
tion between aryl (sp2-CG) and vinyl (sp2-CG) groups has to
date been a difficult and unrealized target in asymmetric
catalysis. In fact, asymmetric hydrogenation of (E)-chalcone
(1a) catalyzed by the xyl-binap/daipen RuII complex afforded
the allylic alcohol in only 45% ee.[3,7] Borane reduction
catalyzed by chiral oxazaborolidine gave a 66% ee.[8,9] The
best ee value of 75% in the reduction of 1a was achieved by
the use of catecholborane with a chiral gallium catalyst.[10] To
our knowledge, even enzymatic reduction has not succeeded
in this discrimination.[11] Herein we describe for the first time
highly enantioselective hydrogenation of aryl vinyl ketones to
chiral allylic alcohols, catalyzed by the tol-binap/dmapen RuII
complex.[2,12]
1,3-diphenyl-2-propen-1-ol ((S)-2a) in 97% ee and 99% yield
accompanied by 1% of 1,3-diphenyl-1-propanone (4a)
(Scheme 1 and Table 1, entry 1). No saturated alcohol, 1,3-
Scheme 1. Asymmetric hydrogenation of aryl vinyl ketones with
[RuCl2{(S)-tol-binap}{(R)-dmapen}] ((S,R)-3).
diphenyl-1-propanol (5a), was detected. To our knowledge,
this example is the first reduction of 1a with high carbonyl-
and enantioselectivity.[13] When the hydrogenation was con-
ducted at 308C, 4a and 5a were obtained in 8% and 9% yield,
respectively, although the reaction was completed in 1 h
(Table 1, entry 2). Interestingly, the separate experiment
shown in Scheme 2 revealed that the saturated ketone 4a
was produced by an isomerization of (S)-2a under hydro-
genation conditions (see Supporting Information). The cata-
lytic activity of (S,R)-3 with a base is fairly high. Thus, the
reaction of 1a with a substrate:catalyst molar ratio (S/C) of
10000 at 08C under 40 atm of H2 was completed in 3 h to
afford (S)-2a in 97% ee and in 99% yield (Table 1, entry 3).
The hydrogenation of a series of aryl vinyl ketones (1) to
the aromatic allylic alcohols (2) was achieved in high
enantiomeric excess using the chiral ruthenium complex 3
(Scheme 1). The results are summarized in Table 1. The
chalcone 1b, methyl-substituted at the 4’ position (Ar in
Scheme 1), was hydrogenated (S/C = 1000, 08C, 8 atm H2)
with 98% ee (Table 1, entry 4). Hydrogenation of 2’-F-
First, we chose (E)-chalcone (1a) as a standard substrate.
Hydrogenation of 1a (225.2 mg, 1.1 mmol) in 2-propanol
(2.5 mL) with [RuCl2{(S)-tol-binap}{(R)-dmapen}] ((S,R)-3;
1.1 mg, 1.1 mmol, substrate/catalyst ratio (S/C) = 1000)[12] and
t-C4H9OK (10 mmoldmꢀ3 in 2-propanol, 0.50 mL, 5.0 mmol)
at 08C under 8 atm of H2 was completed in 5 h to afford (S)-
[*] Prof. Dr. N. Arai, K. Azuma, N. Nii, Prof. Dr. T. Ohkuma
Division of Chemical Process Engineering, Graduate School of
Engineering
Hokkaido University, Sapporo 060-8628 (Japan)
Fax: (+81)11-706-6598
E-mail: ohkuma@eng.hokudai.ac.jp
[**] This work was supported by a Grant-in-Aid from the Japan Society
for the Promotion of Science (JSPS) (No. 18350046). Tol-
binap=2,2’-bis(di-4-tolylphosphanyl)-1,1’-binaphthyl. Dmapen=2-
dimethylamino-1-phenylethylamine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802533.
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Table 1: Asymmetric hydrogenation of aryl vinyl ketones with [RuCl2{(S)-
tol-binap}{(R)-dmapen}] (see Scheme 1).[a]
triphenylphosphine (Table 1, entry 10), whereas, without the
additive the reaction also afforded saturated ketone and
alcohol side-products in 2% and 5% yields, respectively.[14]
Substituents on the b-phenyl group (R2 in Scheme 1) had
little effect on the reactivity of the enone and the enantio-
selectivity of the hydrogenation. The reaction of 1i (R2 = 4-
CH3C6H4) and 1j (R2 = 4-ClC6H4) under the regular condi-
tions gave the allylic alcohols 2i (97% ee, 93% yield) and 2j
(97% ee, 99% yield), respectively (Table 1, entries 11 and
12). The b,b-disubstituted enone, 1k, was a difficult substrate
to hydrogenate because of steric hindrance at the b-position.
Complete conversion with an S/C of 1000 was achieved after
43 h under 50 atm of H2, affording 2k in 89% ee (Table 1,
entry 13). The tert-butyl-substituted enone 1l was also hydro-
genated with an excellent enantioselectivity, while the reac-
tivity was relatively lower (Table 1, entry 14). The reaction of
1-phenyl-2-buten-1-one gave a complex mixture as deproto-
nation occurs at the allylic position.
A mechanism for the hydrogenation of 1 using (S,R)-3 in
basified 2-propanol (based on our previous mechanistic study
of the hydrogenation of alkyl aryl ketones catalyzed by a tol-
binap/dpen RuII complex)[2,15,16] is proposed in Scheme 3. In
this mechanism, the {RuCl2} complex 3 is first converted to a
cationic {RuH} species 6 with 2 equivalents of base and a
hydride source, hydrogen. Complex 6 coordinates to H2 to
form cationic 7 and subsequent deprotonation with a base
affords the active {RuH2} complex 8. The ketone 1 is readily
reduced by 8, giving the alcoholic product 2 and the amide
complex 9. Protonation of 9 by the alcoholic solvent
regenerates 6, whereas reaction of 9 with H2 partially
regenerates 8. The reaction of 8 with 1 proceeds through a
pericyclic six-membered transition state (TS) 10, in which the
Entry
1
S/C[b] ((S,R)-3) H2 [atm] t [h] Yield [%][c] ee [%][d]
1
2[e]
3
4
5
1a
1a
1000
1000
8
8
40
8
8
8
8
8
8
8
5
1
3
4
15.5
3
2
3
5
8
99 (1)
91[f] (8)
99 (1)
100 (1)
95 (<1)
96 (1)
94 (2)
96 (2)
96 (1)
98 (<1)
93 (1)
97
96
97
98
97
96
92
95
95
92
97
97
89
1a[g] 10000
1b
1c
1d
1e
1 f
1g
1h
1i
1000
1000[h]
1000
1000
1000
1000
1000[h]
1000
1000
1000
1000
6
7[i]
8[j]
9[i]
10[i]
11
12
13
14
8
8
50
8
13
5
43
8
1j
1k
1l
99 (<1)
97 (<1)
86 (<1)[k] 97
[a] Unless otherwise stated, reactions were conducted at 08C using 0.5–
1.0 mmol of ketone (0.16–0.33m) in 2-propanol containing (S,R)-3
(0.037–0.37mm) and t-C4H9OK (1.7 mm). [b] Substrate/catalyst molar
ratio. [c] Yield of isolated (S)-2. Yield of the saturated ketone is stated in
parentheses. [d] Data for (S)-2 determined by chiral HPLC analysis or
comparison with the literature. [e] Reaction at 308C. [f] Contaminated by
5a (9%). [g] Reaction using 10.8 mmol (2.3 g) of 1a. [h] One equiv of
P(C6H5)3 to 3 was added. [i] Reaction in a 2:1 mixture of 2-propanol and
DMF. [j] Reaction in a 1:1 mixture of 2-propanol and DMF. [k] 13% of 1l
was recovered.
Scheme 2. Isomerization of (S)-2a to 4a.
substituted ketone 1c was relatively slow under the standard
conditions (08C, 8 atm H2), and the saturated ketone 4c and
the saturated alcohol 5c were obtained in 3% and 5% yield,
respectively. This problem was solved by an addition of
triphenylphosphine (1 equiv to 3) to the reaction system. The
desired (S)-2c was obtained in 97% ee and 95% yield without
detectable amounts of the by-products (Table 1, entry 5).
Triphenylphosphine is believed to inhibit the coordination of
the allylic alcohols 2 to the ruthenium center responsible for
the isomerization to ketones 4 depicted in Scheme 2, thus
lessening the formation of saturated by-products.
Substrates with electron-withdrawing F and CF3 at the 4’
position, 1d and 1e, were hydrogenated to give the allylic
alcohols 2d in 96% ee (96% yield) and 2e in 92% ee (94%
yield), respectively (Table 1, entries 6 and 7). The reaction of
1e was conducted in a 2:1 mixture of 2-propanol and DMF as
1e has low solubility in 2-propanol. An electron-donating
methoxy group at the 4’ position (1 f) did not affect the
reactivity and enantioselectivity, affording 2 f in 95% ee and
96% yield (Table 1, entry 8). The 2’-naphthyl enone, 1g, is
also a good substrate for this reaction, affording 2g in 95% ee
and 96% yield (Table 1, entry 9). The hydrogenation of 2’-
furyl enone, 1h, resembles that of the 2’-fluorophenyl
substrate, 1c. The allylic alcohol product 2h was selectively
obtained in 92% ee and 98% yield in the presence of
Scheme 3. Proposed mechanism of hydrogenation of 1 by (S,R)-3 in
_
_
basified 2-propanol. PP=(S)-tol-binap[2]; NH2N(CH3)2 =(R)-dmapen.[2]
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Figure 1. Structure of {RuH2} species (S,R)-8 and diastereomeric transition states in the hydrogenation of 1a. In the transition states 10Re and
10Si, some aromatic groups in the tol-binap and dmapen ligands are omitted for clarity. Ar=4-CH3C6H4; *=RuII.
d+
dꢀ
d+
catalyst Hdꢀ Ru
quadrupole coordinates to the
2a: Ruthenium complex (S,R)-3 (1.1 mg, 1.1 mmol) and 1a
(225.2 mg, 1.1 mmol) were placed in a 100 mL glass autoclave
equipped with a Teflon-coated magnetic stirring bar. A solution in
2-propanol (3.0 mL) of t-C4H9OK (1.7 mm, 0.56 mg, 5.0 mmol), which
had been degassed by four freeze-thaw cycles, was added to the
precooled (ice-bath) autoclave. Hydrogen was introduced into the
autoclave at a pressure of 8 atm, and the reaction mixture was
vigorously stirred at 08C for 5 h. After carefully venting the hydrogen
gas, the solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel, giving (S)-2a
(colorless oil, 225.2 mg, 99% yield, 97% ee), accompanied by 4a
(2.5 mg, 1% yield). The enantiomeric excess of 2a and the absolute
configuration of the major isomer were determined by HPLC
analysis. Column, CHIRALCEL OD-H; eluent, hexane:2-propa-
nol = 9:1; flow, 1.0 mLminꢀ1; column temp, 408C; detection, UV
254 nm; tR ((S)-2a) 12.8 min (98.5%); tR ((R)-2a) 15.8 min (1.5%),
compare with literature values: tR = 13.41 min for (S)-2a, tR =
17.40 min for (R)-2a.[20] 1H NMR (270 MHz, CDCl3): d = 2.01 (br s,
1H, OH), 5.40 (br m, 1H, CHOH), 6.39 (dd, 1H, J = 15.9, 6.5 Hz,
ꢀ
ꢀ
N
ꢀ
H
dꢀ
carbonyl Cd+
dipole (see Scheme 3).[15]
=
O
Complex (S,R)-8 is expected to have a trans-RuH2
geometry owing to the strong trans s-donating property of
the hydride (Figure 1).[17,18] The skewed five-membered
chelate ring formed by dmapen has two diastereotopic
amino protons adjacent to C1. The axially oriented hydrogen
(Hax) is more reactive than the equatorial one (Heq), because
the smaller dihedral angle of the Hdꢀ Ru
N
Hax
d+
dꢀ
d+
ꢀ
ꢀ
ꢀ
moiety suitably stabilizes TS 10. Ketone 1a approaches the
catalyst reaction site with the Re face (to form TS 10Re) or Si
face (to form TS 10Si). TS 10Re, which affords the allylic
alcohol (S)-2a, is more favored than 10Si (which forms (R)-
2a), as the “sickle-shape” vinylic group of 1a fits well with the
ꢀ ꢀ
channel formed by the Arax P Areq (Ar= 4-CH3C6H4) struc-
ture of tol-binap in 10Re, whereas the formation of 10Si leads to
a nonbonded repulsive interaction between the phenyl group
=
=
CH(OH)CH CH), 6.70 (d, 1H, J = 15.9 Hz, CH(OH)CH CH), 7.21–
of 1a and the Arax P Areq channel.[19] Thus, the chiral
ꢀ ꢀ
7.45 ppm (m, 10H, aromatics).
environment of the tol-binap/dmapen RuII catalyst differ-
entiates between aromatic and vinylic groups.
Received: May 30, 2008
Revised: July 15, 2008
Published online: August 27, 2008
In conclusion, we report herein the first example of highly
enantioselective hydrogenation of aryl vinyl ketones to allylic
alcohols. Unlike other methods (including enzymatic reduc-
tions), the chiral environment of the tol-binap/dmapen RuII
catalyst achieves accurate discrimination between aromatic
and vinylic groups by their shape.
Keywords: allylic compounds · asymmetric catalysis ·
.
hydrogenation · ketones · ruthenium
[1] Recent reviews: a) T. Ohkuma, R. Noyori in Comprehensive
Asymmetric Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Berlin, 1999, pp. 199 – 246; b) T. Ohkuma,
M. Kitamura, R. Noyori in Catalytic Asymmetric Synthesis, 2nd
ed. (Ed.: I. Ojima), Wiley-VCH, New York, 2000, pp. 1 – 110;
c) T. Ohkuma, R. Noyori in Transition Metals for Organic
Synthesis, Vol. 2 , 2nd ed. (Eds.: M. Beller, C. Bolm), Wiley-VCH,
Experimental Section
The general procedure for hydrogenation of aryl vinyl ketones is as
follows: hydrogenation of 1a illustrates the typical reaction procedure
using standard Schlenk techniques. For full reaction conditions and
spectroscopic data, see the Supporting Information.
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Communications
Weinheim, 2004, pp. 29 – 113; d) T. Ohkuma, R. Noyori in The
[11] G. Kumaraswamy, S. Ramesh, Green Chem. 2003, 5, 306 – 308.
[12] Asymmetric hydrogenation of a-branched aromatic ketones
catalyzed by tol-binap/dmapen RuII complex. See: N. Arai, H.
Ooka, K. Azuma, T. Yabuuchi, N. Kurono, T. Inoue, T. Ohkuma,
Org. Lett. 2007, 9, 939 – 941.
[13] Conjugate reduction of 1a by hydrogenation or transfer hydro-
genation with metal complexes. See: a) L. Dahlenburg, K.
Herbst, A. Zahl, J. Organomet. Chem. 2000, 616, 19 – 28; b) J.
Hannedouche, J. A. Kenny, T. Walsgrove, M. Wills, Synlett 2002,
263 – 266; c) D. Xue, Y.-C. Chen, X. Cui, Q.-W. Wang, J. Zhu, J.-
G. Deng, J. Org. Chem. 2005, 70, 3584 – 3591. See also
reference [7].
Handbook of Homogeneous Hydrogenation, Vol. 3 (Eds.: J. G.
de Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007, pp. 1105 –
1163.
[2] Xyl-binap = 2,2’-bis(di-3,5-xylylphosphanyl)-1,1’-binaphthyl.
Daipen = 1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenediamine. Tol-
binap = 2,2’-bis(di-4-tolylphosphanyl)-1,1’-binaphthyl.
Dmapen = 2-dimethylamino-1-phenylethylamine. Dpen = 1,2-
diphenylethylenediamine.
[3] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K.
Murata, E. Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1998, 120, 13529 – 13530.
[4] R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40 – 75; Angew.
Chem. Int. Ed. 2001, 40, 40 – 73.
[14] Isolated 2h was readily decomposed at ambient temperature.
[15] C. A. Sandoval, T. Ohkuma, K. Muæiz, R. Noyori, J. Am. Chem.
Soc. 2003, 125, 13490 – 13503.
[16] 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, S. H. Bergens, J. Am. Chem. Soc. 2006,
128, 13700 – 13701; c) S. A. French, D. Di Tommaso, A. Zanotti-
Gerosa, F. Hancock, C. R. A. Catlow, Chem. Commun. 2007,
2381 – 2388.
[5] a) T. Ohkuma, C. A. Sandoval, R. Srinivasan, Q. Lin, Y. Wei, K.
Muæiz, R. Noyori, J. Am. Chem. Soc. 2005, 127, 8288 – 8289. For
hydrogenation of acyl silanes, see:b) N. Arai, K. Suzuki, S.
Sugizaki, H. Sorimachi, T. Ohkuma, Angew. Chem. 2008, 120,
1794 – 1797; Angew. Chem. Int. Ed. 2008, 47, 1770 – 1773.
[6] T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori,
Org. Lett. 2000, 2, 659 – 662.
[7] Hydrogenation of 1a with a chiral iridium catalyst gave the
allylic alcohol in 9% ee and 56% yield. See: C. Bianchini, E.
Farnetti, L. Glendenning, M. Graziani, G. Nargin, M. Peruzzini,
E. Rocchini, F. Zanobini, Organometallics 1995, 14, 1489 – 1502.
[8] a) X. Gao, H. B. Kagan, Chirality 1998, 10, 120 – 124; b) G.
Wang, X. Liu, G. Zhao, Synlett 2006, 1150 – 1154. See also: c) N.
Kawai, S. M. Hande, J. Uenishi, Tetrahedron 2007, 63, 9049 –
9056.
[9] For asymmetric borane reduction catalyzed by chiral oxazabor-
olidines, see: E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110,
2092 – 2118; Angew. Chem. Int. Ed. 1998, 37, 1986 – 2012.
[10] S. Woodward, A. Ford (The University of Hull), UK-GB
2339780A, 1998.
[17] a) F. Maseras, A. Lledꢀs, E. Clot, O. Eisenstein, Chem. Rev. 2000,
100, 601 – 636; b) G. J. Kubas, J. Organomet. Chem. 2001, 635,
37 – 68.
[18] Repulsive interaction between the filled p and d orbitals has also
been postulated: K. G. Caulton, New J. Chem. 1994, 18, 25 – 41.
[19] Hydrogenation of 1-benzoylcyclohexene with (S,R)-3 under the
regular reaction conditions resulted in recovery of the substrate.
This result is explained by using the enantioface-selection
models shown in Figure 1. Both cyclohexenyl and phenyl
ꢀ ꢀ
groups have repulsive interactions with the Arax P Areq channel
of tol-binap in TS 10Re and TS 10Si.
[20] H.-F. Duan, J.-H. Xie, W.-J. Shi, Q. Zhang, Q.-L. Zhou, Org. Lett.
2006, 8, 1479 – 1481.
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