Asymmetric transfer hydrogenation of benzaldehydes

Article abstract of DOI:10.1021/ol0002119

(Equation Presented) A combined system of RuCl[(R,R)-YCH(C₆H₅)CH(C₆H₅)NH ₂](η⁶-arene) (Y = NSO₂C₆H₄-4-CH₃ or O) and t-C₄H₉OK catalyzes the asymmetric transfer hydrogenation of various benzaldehyde-1-d derivatives with 2-propanol to yield (R)-benzyl-1-d alcohols in 95-99% ee and with >99% isotopic purity. Reaction of benzaldehydes with a DCO₂D-triethylamine mixture and the R,R catalyst affords the S deuterated alcohols in 97-99% ee.

Full text of DOI:10.1021/ol0002119

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3425-3427
Asymmetric Transfer Hydrogenation of
Benzaldehydes
Issaku Yamada and Ryoji Noyori*
Department of Chemistry and Research Center for Materials Science,
Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan
noyori@chem3.chem.nagoya-u.ac.jp
Received August 1, 2000
ABSTRACT
A combined system of RuCl[(R,R)-YCH(C H )CH(C H )NH ](η6-arene) (Y ) NSO C H -4-CH or O) and t-C H OK catalyzes the asymmetric transfer
6
5
6
5
2
2
6
4
3
4 9
hydrogenation of various benzaldehyde-1-d derivatives with 2-propanol to yield (R)-benzyl-1-d alcohols in 95−99% ee and with >99% isotopic
purity. Reaction of benzaldehydes with a DCO D-triethylamine mixture and the R,R catalyst affords the S deuterated alcohols in 97−99% ee.
2
Chiral deuterated benzyl alcohol and its derivatives serve as
useful probes in stereochemistry and mechanistic organic
chemistry.1 Although various asymmetric metal hydride
reductions of benzaldehydes are known,2 more useful hy-
drogenative methods have yet to be developed. Currently,
the best methods3 for asymmetric hydrogenation of aromatic
ketones saturate benzaldehydes with only moderate enanti-
oselectivity. For example, hydrogenation of benzaldehyde-
1-d (1a) with RuCl2[(S)-tolbinap][(S)-daipen]4 and t-C4H9OK
yielded (S)-benzyl-1-d alcohol [(S)-2a] in 46% ee,5 while a
reaction with Ru(OCOCH3)2 [(R)-binap] under acidic condi-
tions produced (S)-2a in 65% ee.6 Other chiral Ru and Rh
complexes exhibit even less satisfactory stereoselectivity and/
or catalytic activity. In the present study, we disclose the
first highly enantioselective catalytic transfer hydrogenation
of benzaldehydes utilizing a chiral diamine-based or amino
alcohol-based Ru(η6-arene) catalyst and 2-propanol or formic
acid as a hydrogen donor.7-9
When a 0.1 M solution of 1a in 2-propanol containing
RuCl[(R,R)-tsdpen](η6-p-cymene) [(R,R)-3a]8,10 and t-C4H9-
OK (aldehyde:Ru:base ) 200:1:5) was mixed in an atmo-
sphere of Ar at 22 °C for 30 min, (R)-2a was obtained in
98% ee11 and in 100% yield. The formation of d0 and d2
products was negligible. Unlike reduction of aromatic ketones
(6) Ohta, T.; Tsutsumi, T.; Takaya, H. J. Organomet. Chem. 1994, 484,
191-193.
(7) (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
(b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-
2061.
(1) (a) Arigoni, D.; Eliel, E. L. Top. Stereochem. 1969, 4, 127-244. (b)
Floss, H. G.; Lee, S. Acc. Chem. Res. 1993, 26, 116-122. (c) Parry, R. J.;
Trainor, D. A. J. Am. Chem. Soc. 1978, 100, 5243-5244. (d) Mu, Y.; Omer,
C. A.; Gibbs, R. A. J. Am. Chem. Soc. 1996, 118, 1817-1823.
(2) Stoichiometric methods: (a) Noyori, R.; Tomino, I.; Yamada, M.;
Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717-6725. (b) Midland, M.
M.; Greer, S.; Tramontano, A.; Zderis, S. A. J. Am. Chem. Soc. 1979, 101,
2352-2355. Catalytic methods: (c) Corey, E. J.; Link, J. O. Tetrahedron
Lett. 1989, 30, 6275-6278. (d) Keck, G. E.; Krishnamurthy, D. J. Org.
Chem. 1996, 61, 7638-7639.
(8) (a) Hashiguchi, S.; Fujii, A.; Takehara, T.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 7562-7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-
2522. (c) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (d) Hashiguchi, S.; Fujii,
A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 288-290. (e) Matsumura, K.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739.
(9) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori,
R. Chem. Commun. 1996, 233-234.
(3) Reviews: (a) Ohkuma, T.; Noyori, R. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 1, Chapter 6.1. (b) Noyori, R.; Ohkuma, T. Pure Appl. Chem.
1999, 71, 1493-1501. (c) Noyori, R.; Ohkuma, T. Angew. Chem. In press.
(4) 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, 1703-1707.
(10) TsDPEN ) anion of N-tosyl-1,2-diphenylethylenediamine, [N(SO2-
C6H4-4-CH3)CH(C6H5)CH(C6H5)NH2]-.
(11) The ee value of the alcohols was determined by 500 MHz 1H NMR
analysis of the MTPA esters. The inherent errors are considered to be within
(1%. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(5) Unpublished results.
10.1021/ol0002119 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

Table 1. Asymmetric Transfer Hydrogenation of
Benzaldehydes Using 2-Propanola or Formic Acidb
alcohol 2d
time convnc % eee
Ru(II)
cat.
hydrogen
source
aldehyde
(h)
(%)
(config)
1a
1a f
1a
1a
1a
1a
1b
1c
1d
1e
5h
(R,R)-3a
(R,R)-3a
(R,R)-3b
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
0.5
0.8
0.5
0.33
0.75
7
1
1
1
1
0.25
0.1
4
4
14
100
100
100
97
98
99
99
87
97
98
97
90
93
92
97
99
95
98 (R)
96 (R)
97 (R)
96 (R)
95 (R)
96 (R)
98 (R)
99 (R)
96 (R)
96 (R)
72 (R)
24 (R)
98 (S)
98 (S)
99 (S)
99 (S)
97 (S)
(R,R)-3bg (CH3)2CHOH
(R,R)-3c
(R,R)-3d
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3b
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3a
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
(CH3)2CHOH
DCO2D
DCO2D
DCO2D
DCO2D
DCO2D
6
7a i
7b
7c
7d
7e
6
2
a The reaction was carried out at room temperature using a 0.1 M solution
of 1 (1.0 mmol) in 2-propanol (1:Ru:t-C4H9OK ) 200:1:4). b The reaction
was carried out at 28 °C using an acetonitrile solution of 7 (10 mmol)
(7:Ru:DCO2D:(C2H5)3N ) 200:1:200:200). c Determined by GLC analysis.
The value is close to yield; no byproduct was detected. d The d1 content
was >99%. e Determined by 1H NMR analysis of the corresponding MTPA
ester. f Reaction using 10 mmol of 1a. g The Ru catalyst was generated in
situ from [RuCl2(η6-benzene)]2, (R,R)-HTsDPEN, and KOH (0.5:1:5).
h 5:Ru:t-C4H9OK ) 100:1:6. i Reaction using 1.0 mmol of 7a.
When [RuCl(η6-benzene)]2 was mixed with (R,R)-1,2-
diphenylethanolamine9 and t-C4H9OK in a 0.5:1:1 molar ratio
in 2-propanol at 28 °C for 1 h, RuCl[(R,R)-OCH(C6H5)CH-
(C6H5)NH2](η6-benzene) [(R,R)-4] was generated, as sub-
stantiated by electrospray ionization mass analysis showing
an [M + 1]+ peak at 428.14 Reaction of [RuCl(η6-benzene)]2,
(R,R)-1,2-diphenylethanolamine, and triethylamine (0.5:1:7
molar ratio) in 2-propanol at 90 °C also produced (R,R)-4
in 93% yield. A systematic investigation using this simple
η6-benzene-Ru complex and a series of para-substituted
benzaldehyde-1-d derivatives (1:4:t-C4H9OK ) 200:1:4, [1]
) 0.1 M in 2-propanol, 28 °C, 0.5-6 h) provided interesting
information, albeit with moderate enantioselectivity. The %
ee of the R product and the relative rates of reduction (in
parentheses) were p-CH3O, 61% (0.55); p-CH3, 49% (0.95);
H, 45% (1.0); p-Br, 37% (1.5); p-CF3, 20% (1.6).15 The
in which enantiomeric purity of the alcoholic products
deteriorates as the reaction proceeds,7,8 the reaction of
benzaldehyde and its derivatives 1a-e showed a consistently
high enantioselectivity throughout the reaction. This was due
to the favorable alcohol/carbonyl thermodynamic balance.12
However, unnecessary prolonged standing after 100% con-
version should be avoided to preserve a high degree of kinetic
stereoselection.
Table 1 lists some examples of the reactions. The diamine-
based Ru complexes (R,R)-3b-d possessing an η6-benzene,
-mesitylene, or -hexamethylbenzene ligand can also be used.
A gram-scale reaction was performed with high reproduc-
ibility without any special techniques.13 An Ru catalyst
generated in situ from [RuCl2(η6-arene)]2, N-monotosylated
(R,R)-1,2-diphenylethylenediamine, and KOH afforded a
similar result. Thus, this asymmetric catalysis provides a
convenient way to obtain chiral deuterated benzyl alcohols.
Nonaromatic aldehydes provide a lower enantioselectivity.
For example, reaction of trans-cinnamaldehyde-1-d (5)
catalyzed by (R,R)-3b produced (R)-cinnamyl-1-d alcohol
in 72% ee, while dihydrocinnamaldehyde-1-d (6), an alkanal,
with (R,R)-3a afforded the R alcohol in only 24% ee.
(13) Transfer hydrogenation of 1a in 2-propanol catalyzed by (R,R)-3a:
A mixture of 1a (1.07 g, 10.0 mmol), 3a (31.8 mg, 50 µmol),8b and 1.0 M
t-C4H9OK in t-C4H9OH (50 µL, 0.05 mmol) in 2-propanol (100 mL) was
stirred at 22 °C for 50 min. After dilution with water, the product was
extracted with ethyl acetate, and the organic layer was washed with an
aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. Bulb-
to-bulb distillation at 100-101 °C/15 mmHg afforded (R)-2a (1.00 g, 92%
yield) in 96% ee.11 1H NMR of benzylic proton of (R)-MTPA ester: S
isomer, δ 5.31; R isomer, δ 5.36.
(14) 1H NMR (CDCl3): δ 4.41 (m, 1, CHO), 4.75 (m, 1, CHN), 5.30
(br s, 6, η6-C6H6), 5.36 (m, 1, NH), 5.49 (m, 1, NH), 6.9-7.5 (m, 10, C6H5).
For a similar complex, see: Hennig, M.; Pu¨ntener, K.; Scalone, M.
Tetrahedron: Asymmetry 2000, 11, 1849-1958. Structural determination
by ESI mass spectroscopy: Kenny, J. A.; Versluis, K.; Heck, A. J. R.;
Walsgrove, T.; Wills, M. Chem. Commun. 2000, 99-100.
(12) (a) Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C. C. J.
Am. Chem. Soc. 1949, 71, 3622-3629. (b) Hach, V. J. Org. Chem. 1973,
38, 293-299.
3426
Org. Lett., Vol. 2, No. 22, 2000

presence of an electron-withdrawing group in the aromatic
ring has been found to facilitate the hydrogen transfer
reaction, in accordance with the hydridic nature of the
reducing species involved in the metal-ligand bifunctional
catalysis.7,8c,16,17 The ee value of the chiral alcohols increased
from 20% for the p-CF3 derivative to 61% for the p-CH3O
derivative. Under such conditions, the olefinic and saturated
aldehydes, 5 and 6, again yielded a near-racemic alcohol
(<5% ee).
Formic acid serves as an exellent hydrogen donor. This
transfer hydrogenation forming CO2 occurs irreversibly to
completion under truly kinetic control.7,8b By reversing the
isotope labeling pattern in the substrate and hydrogen donor,
another efficient asymmetric method has been developed.
For example, when an acetonitrile solution of the p-meth-
oxybenzaldehyde (7c), chiral catalyst (R,R)-3a, and a 1:1
mixture of DCO2D and triethylamine (aldehyde:Ru:formic
acid ) 200:1:200 molar ratio) was stirred at 28 °C for 14 h,
(S)-2c was obtained in 99% ee and with a 97% conversion.18
The p-methoxy alcohol with a low oxidation potential12 did
not cause any ee erosion under such conditions. Examples
are given in Table 1. The d1 content in the benzyl alcohols
is >99%. The benefit of this procedure is the need for only
a stoichiometric amount (not in excess) of the deuterium
source with respect to the substrate (1-2 g), because
deuterated 2-propanol as a reducing agent must be used as
a solvent.
Overall, these Ru-catalyzed reactions serve as efficient
hydrogenative methods of converting benzaldehydes to chiral
deuterated alcohols with a high enantiomeric and isotopic
purity.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research (No. 07CE2004)
from the Ministry of Education, Science, Sports and Culture,
Japan.
(15) The enantioselectivity was kinetically determined with a conversion
of 22-65%.11
(16) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122,
1466-1478.
(17) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Anderssen, P. G. J.
Am. Chem. Soc. 1999, 121, 9580-9588.
(18) Transfer hydrogenation of 7c with DCO2D catalyzed by (R,R)-3a:
A mixture of 7c (1.37 g, 10.0 mmol), (R,R)-3a (32 mg, 0.05 mmol), DCO2D
(0.48 g, 10 mmol), and (C2H5)3N (1.01 g, 10 mmol) in acetonitrile (10
mL) was magnetically stirred at 28 °C for 14 h. The mixture was diluted
with water and extracted with ethyl acetate. The organic layer was washed
with an NaHCO3 solution and brine, dried over Na2SO4, and concentrated.
Bulb-to-bulb distillation of the residue afforded (S)-2c (1.329 g, 96% yield)
in 99% ee.11 1H NMR of benzylic proton of (S)-MTPA ester: S isomer, δ
5.28; R isomer, δ 5.26.
Supporting Information Available: Procedures for the
transfer hydrogenation of benzaldehydes, GC behavior of
products, and [R]D values and NMR data of chiral alcohols.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0002119
Org. Lett., Vol. 2, No. 22, 2000
3427