Selective reduction of the carbonyl group in β,γ-unsaturated α-ketoesters by transfer hydrogenation with Ru-TsDPEN

Article abstract of DOI:10.1055/s-2004-817765

A convenient and practical method for the selective reduction of C=O bond of a wide spectrum of α-keto β,γ-unsaturated esters via transfer hydrogenation reaction under the catalysis of Ru(p-cymene)(TsDPEN) (TsDPEN: monotosylated 1,2-diphenylethylene-1,2-diamine) was developed.

Full text of DOI:10.1055/s-2004-817765

LETTER
741
Selective Reduction of the Carbonyl Group in b,g-Unsaturated a-Ketoesters
by Transfer Hydrogenation with Ru-TsDPEN
S
a
elective Reduction of
i
the Ca
n
rbonyl
G
roup
j
in
b
,
g
i
-Unsat
e
a
-Ketoeste
G
rs uo,a Dao Li,a Yanhui Sun,b Zhaoguo Zhang*a
b
Received 25 November 2003
However, the catalytic chemoselective reduction of the
carbonyl group of a b,g-unsaturated a-ketoester has never
been reported. Herein, we report our preliminary results
with transition metal-catalyzed transfer hydrogenation
reaction to solve the hard-bitten selectivity problem in
the chemoselective reduction of a-keto b,g-unsaturated
esters.
Abstract: A convenient and practical method for the selective re-
duction of C=O bond of a wide spectrum of a-keto b,g-unsaturated
esters via transfer hydrogenation reaction under the catalysis of
Ru(p-cymene)(TsDPEN) (TsDPEN: monotosylated 1,2-diphenyl-
ethylene-1,2-diamine) was developed.
Key words: ruthenium, transfer hydrogenation, chemoselectivity,
carbonyl, reduction
OH
NaBH4
OH
R1
There have been some reports on the synthesis of a-hy-
droxy b,g-unsaturated esters or acids,1,2 however, many of
these reports have been focused on the biosynthetic meth-
ods.1 Chemical methods for the selective reduction of
such kind of compounds have also been reported with
limited success, all of which need stoichiometrically re-
ductive reagents such as sodium amalgam,2e,f metal boro-
hydride,2a,b,g or dihydropyridine2c,d as hydrogen donors.
O
OR2
R1
O
Pd/C
+
O
OH
OR2
OR2
R1
R1
O
O
Selective reduction of the carbonyl group in an a-keto b,g-
unsaturated ester is somewhat difficult with the general
methods, such as the reduction with sodium borohydride,
because both the carbon-carbon double bond and the ester
group could be reduced further. Some new reducing re-
agents and hydrogen donors that have different selectivity
have been developed in recent years to realize the regio-
selective reduction of a-keto b,g-unsaturated esters
(Scheme 1).1,2 However, regioselective reduction of the
carbonyl group in an a-keto b,g-unsaturated ester still re-
mains a challenging topic. It is important to develop a
practical catalytic method to reduce the carbonyl group of
a-keto b,g-unsaturated esters selectively to achieve a-hy-
droxy b,g-unsaturated esters, which are important units in
many bioactive compounds.3
O
PNAH
OR2
R1
or HEH
O
OH
OR2
Me2PNPH
R1
O
Scheme 1 Selective reduction of a-keto b,g-unsaturated esters
In the course of screening the catalysts, we have tried
some monotosylated diamines such as monotosylated cy-
clohexane-1,2-diamine, monotosylated ethylenediamine,
and some b-amino alcohols as ligands for the selective
reduction of isopropyl 4-phenyl-2-oxo-3-butenoate (1a,
Scheme 2).
Transition metal-catalyzed reaction has been widely
applied in organic synthesis and the corresponding
asymmetric hydrogenation or asymmetric transfer hydro-
genation has been applied as an important tool for the re-
duction of unsaturated functionalities.4 Noyori et al. have
reported the Ru-diamine complex; it could be employed
as catalyst in reducing the carbonyl group of an a,b-unsat-
urated ketone selectively,4f,g and this is one of the most
exciting achievements in asymmetric reduction area.
O
O
RuL
Ph
Ph
OPr-i
OPr-i
i-PrOH
O
OH
2a
1a
L: monotosylated 1,2-diamines or β-amino alcohols
Scheme 2 Ruthenium-catalyzed selective transfer hydrogenation
reaction of a-keto b,g-unsaturated esters
SYNLETT 2004, No. 4, pp 0741–0743
Advanced online publication: 10.02.2004
0
9.
0
3.
2
0
0
4
DOI: 10.1055/s-2004-817765; Art ID: U25603ST
© Georg Thieme Verlag Stuttgart · New York

742
M. Guo et al.
LETTER
A mixture of ketoester 0.5 mmol, [RuCl2(p-cymene)]2 a-hydroxy esters 3 (Scheme 3). The undesired compound
(2.1 mg, 0.005 mmol) and monotosylated 1,2-diamines or 3 could not be easily separated from the desired com-
amino alcohols (0.01 mmol) as ligands in i-PrOH at 60 °C pound 2; the low regioselectivity toward carbonyl group
(5 mL) under argon atmosphere was monitored by TLC. made this method impractical. Gratifyingly, when we em-
After the starting material was consumed, the solvent was ployed TsDPEN (monotosylate of 1,2-diphenylethylene
removed under reduced pressure and the residue was diamine) as ligand, we achieved very good reactivity and
purified by flash chromatography to give the products.
regioselectivity under room temperature, compound 3 is
not detectable if the reaction time is well controlled.6 In
order to obtain repeatable results, we prepared the catalyst
Ru(p-cymene)(TsDPEN) from [RuCl2(p-cymene)]2 and
TsDPEN and run the reaction in i-PrOH without extra
base (Scheme 4).
O
RuL
OPr-i
R
O
i-PrOH
1
OH
OH
OPr-i
OPr-i
+
R
R
Ph
O
H2N
O
2
3
+
RuCl2
Ratio of 2:3 from 90:10 to 60:40
TsHN
Ph
Scheme 3 Ru-catalyzed transfer hydrogenation reaction of b,g-un-
saturated a-ketoesters with 1,2-diamines or amino alcohols as ligands
2
TsDPEN
RuCl2(p-cymene)
Table 1 Ru-TsDPEN Catalyzed Transfer Hydrogenation Reaction
of b,g-Unsaturated a-Ketoestersa
H
N
Ph
Ph
base
O
O
Ru
R
R
N
Ts
OPr-i
OPr-i
OH
O
2
1
Ru(p-cymene)(TsDPEN)
Entry
1, R
2, Yield (%)b [ee (%)]c
2a, 94 (8)
Scheme 4 Preparation of the 16e catalyst Ru(p-cymene)(TsDPEN)
1
2
3
4
5
6
7
8
9
Phenyl (1a)
To expand the scope of the reaction substrates and study
the effect of substituents on the reactions, we have synthe-
sized different substrates1a,5 with electron-withdrawing or
electron-donating groups (1a–e) and substrates bearing a
heterocycle or conjugated diene substituents (1f–h). All of
these substrates could be transferred to the desired prod-
ucts under the catalysis of Ru(p-cymene)(TsDPEN) with-
in one hour with high yields (Table 1). It is worthy of
noting that, not only the substrates with electron-donating
or electron-withdrawing groups could be efficiently re-
duced, the substrates with a coordinating heteroatom
(1g,h) could also be selectively reduced with no detect-
able reactivity decrease. This provides a convenient and
much mild method for the synthesis of a-hydroxy b,g-un-
saturated esters and the reaction yield is nearly quantita-
tive. When we employed enantiopure (1S,2S)-TsDPEN as
the ligand, the product was obtained with poor to moder-
ate enantioselectivity (Table 1, entries, 1, 4, 6–8). Howev-
er, if the substrate bears an alkyl substituent at g-position,
the selectivity decreases, over-reduction product 3i reach-
es up to 25% (Table 1, entry 9) even if the reaction was
well controlled (once the starting material consumed, the
reaction was quedched with 1 N HCl).
p-CF3C6H4 (1b)
p-MeOC6H4 (1c)
p-BrC6H4 (1d)
2b, 95
2c, 93
2d, 92 (6)
2, 4-Dichlorophenyl (1e)
(E)-PhCH=CH (1f)
2-Furanyl (1g)
2e, 91
2f, 99 (7)
2g, 99 (59)
2h, 95 (65)
2i + 3i, 99 (2i:3i = 4:1)
2-Thiophenyl (1h)
Et2CH (1i)
a All reactions were run with ketoester (0.5 mmol), Ru (p-cymene)
(TsDPEN) (3 mg, 0.005 mmol) in i-PrOH (5 mL) at r.t. for 1 h under
argon atmosphere.
b Isolated yields.
c Ee obtained when enatiopure (1S, 2S)-TsDPEN was employed as
ligand.
In all these reactions, the catalysts for transfer hydrogena-
tion were formed in situ with [RuCl2(p-cymene)]2 and the
ligands in the presence of at least 2 equivalents of base.
However, under all these conditions, the reaction was very
slow and we had to raise the temperature to 60 °C for the
complete conversion of the starting materials. And the
reaction usually resulted in the mixture of a-hydroxy
b,g-unsaturated esters 2 and undesired b,g-saturated
In conclusion, we have found a convenient and practical
method for the selective reduction of C=O bond of a wide
spectrum of a-keto b,g-unsaturated esters with Ru(p-
cymene)(TsDPEN) as catalyst. The transition metal
catalyzed transfer hydrogenation reaction with good
Synlett 2004, No. 4, 741–743 © Thieme Stuttgart · New York

LETTER
Selective Reduction of the Carbonyl Group in b,g-Unsaturated a-Ketoesters
743
selectivity and high efficiency provides the possibilities to
provide the optically active a-hydroxy b,g-unsaturated
esters with chiral catalysts.
References
(1) (a) Schummer, A.; Yu, H.; Simon, H. Tetrahedron 1991, 47,
9019. (b) Bonnaffé, D.; Simon, H. Tetrahedron 1992, 48,
9695. (c) Casy, G.; Lee, T. V.; Lovell, H. Tetrahedron Lett.
1992, 33, 817. (d) Casy, G.; Lee, T. V.; Lovell, H.; Nichols,
B. J.; Sessions, R. B.; Holbrook, J. J. J. Chem. Soc., Chem.
Commun. 1992, 924.
(2) (a) Sugimura, H.; Yoshida, K. J. Org. Chem. 1993, 58,
4484. (b) Mikami, K.; Wakabayashi, H.; Nakai, T. J. Org.
Chem. 1991, 56, 4337. (c) Ohno, A.; Yasuma, T.;
Nakamura, K.; Oka, S. Bull. Chem. Soc. Jpn. 1986, 59,
2905. (d) Meijer, L. H. P.; Pandit, U. Tetrahedron 1985, 41,
467. (e) Bougault, J. Ann. Chim. (Paris) 1908, 157.
(f) Erlenmeyer, E. Jr. Chem. Ber. 1903, 36, 2527.
(g) Cordier, P. Bull. Soc. Chim. Fr. 1956, 564.
A general procedure was as follows: A degassed Schlenk reaction
tube was charged successively with the ketoester (0.5 mmol), i-
PrOH (5 mL) under argon atmosphere. The reaction mixture was
degassed for three times by the circulation of freeze-pump-thaw,
then Ru(p-cymene)(TsDPEN) (3 mg, 0.005 mmol) was added under
argon atmosphere. The reaction mixture was then stirred at argon
atmosphere for about 1 h to effect a complete conversion of the sub-
strate. The solvent was removed under reduced pressure and the res-
idue was purified by flash chromatography to give the product.
Representative analytical data: Compound 2a: 1H NMR (300 MHz,
CDCl3): d = 7.41–7.26 (m, 5 H), 6.82 (dd, J = 15.9, 1.5 Hz, 1 H),
6.24 (dd, J = 15.9, 5.7 Hz, 1 H), 5.13 (hept, J = 6.0 Hz, 1 H),
4.81–4.76 (m, 1 H), 3.13 (d, J = 5.7 Hz, 1 H), 1.32 (d, J = 6.0 Hz,
3 H), 1.28 (d, J = 6.0 Hz, 3 H). 13C NMR (75.4 MHz, CDCl3):
d = 172.95, 136.30, 131.88, 128.55, 127.91, 126.63, 125.57, 71.25,
70.21, 21.73, 21.70. IR (KBr): 3451, 1729, 1201, 1106 cm–1. MS:
m/z (%) = 220 (2.88) [M+]. HRMS: calcd for C13H16O3: 220.1100;
(3) Parker, D. J. Chem. Soc., Perkin Trans. 2 1983, 83.
(4) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562.
(b) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 233. (c) Gao, J.-X.;
Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087.
(d) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
1
found: 220.1099. Compound 2h: H NMR (300 MHz, CDCl3):
d = 7.16–7.15 (m, 1 H), 6.98–6.89 (m, 3 H), 6.08 (dd, J = 15.9, 5.4
Hz, 1 H), 5.17–5.04 (m, 1 H), 4.74–4.73 (m, 1 H), 3.34 (broad, 1 H),
1.29 (d, J = 6.0 Hz, 3 H), 1.26 (m, J = 6.3 Hz, 3 H). 13C NMR (75.4
MHz, CDCl3): d = 172.57, 141.18, 127.32, 126.31, 124.92, 124.90,
124.64, 70.87, 70.16, 21.63, 21.60. IR (KBr): 3465, 1731, 1271,
1105 cm–1. MS: m/z (%) = 226 (17.91) [M+]. HRMS: calcd for
C11H14O3S: 226.0664; found: 226.0667.
(e) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (f) Haack,
K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
(g) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997,
36, 288. (h) Matsumura, K.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (i) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(j) Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999,
64, 2186. (k) Koike, T.; Murata, K.; Ikariya, T. Org. Lett.
2000, 2, 3833. (l) Noyori, R.; Ohkuma, T. Angew. Chem.
Int. Ed. 2001, 40, 40. (m) Ohkuma, T.; Ooka, H.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 2675.
Acknowledgment
We thank the National Natural Science Foundation of China,
Chinese Academy of Sciences and the Science and Technology
Commission of Shanghai Municipality for financial support.
(5) (a) Reimer, M. J. Am. Chem. Soc. 1931, 53, 3147.
(b) Friedemann, E. Helv. Chim. Acta. 1931, 14, 783.
(c) Stecher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74,
4392. (d) Anke, T.; Schramm, G.; Schwalge, B.; Steffan, B.;
Steglich, W. Liebigs Ann. Chem. 1984, 1616.
(6) The reaction process can be monitored by TLC, GC or
HPLC. The unsaturated ketoester are generally consumed
within 1 h. Once the starting material was consumed, the
reaction can be quenched with 1 N HCl. The double bond in
the product will be slowly reduced at elevated temperature
(80 °C) and prolonged reaction time (10–120 h). However, it
is relatively stable at r.t. under the catalysis of Ru(p-cymene)
(TsDPEN), no significant amount (<1%) of 3 was detected 5
h after the consumption of the starting material.
Synlett 2004, No. 4, 741–743 © Thieme Stuttgart · New York