Diastereoselective hydrogenation of o-toluic acid derivatives over supported
rhodium and ruthenium heterogeneous catalysts
Mich e` le Besson,*† Pierre Gallezot, Samuel Neto and Catherine Pinel
Institut de Recherches sur la Catalyse-CNRS, 2 avenue Albert Einstein, 69626 Villeurbanne Cedex, France
Asymmetric hydrogenation of an o-toluic acid derivative to
2
-methylcyclohexanoic acid with high optical selectivity (up
to 95%) was performed by using (S)-pyroglutamic acid
methyl ester as a chiral auxiliary and Rh–Al
catalyst.
2 3
O as the
Diastereoselective catalytic hydrogenation with heterogeneous
metal catalysts has been applied for the reduction of CNC, CNO
1,2
or CNN bonds. Modest to high diastereoselectivities were
obtained, depending on the chiral auxiliary used and the nature
of the heterogeneous catalyst. Recently, this method was
proposed to hydrogenate aromatic rings.3 Thus, (S)-N-
,4
(
2-methylbenzoyl)proline methyl ester was hydrogenated quan-
titatively on pretreated Rh–Al in the presence of a bulky
2 3
O
t / min
amine (ethyldicyclohexylamine = EDCA); the cis isomer was
obtained preferentially (yield > 97%) with diastereoisomeric
excess (de) values reaching 67%. We now report on the use of
a pyroglutamic acid derivative as a chiral auxiliary which
permits the diastereoselective reduction of aromatic moities
with higher than 90% de.
Fig. 1 Distribution of products versus time for hydrogenation of 1 over Ru–
C (entry 5, Table 1). Reaction conditions: 2.26 mmol 1, 0.063 mmol Ru, 130
ml EtOH, room temp., 5 MPa H . Less than 3% of the trans compound was
2
5
detected. (5) 1, (/) 2, (-) 3a and (:) 3b.
Substrate 1 was synthesized with a 82% yield, after
purification, by coupling under mild conditions o-toluoyl
chloride with pyroglutamic acid methyl ester (Scheme 1). ‡ The
cyclohexenic compound 2 was formed transiently and consec-
utively hydrogenated to 3. An overview of the most significant
catalytic results is summarized in Table 1.
6
hydrogenation was carried out in a stirred autoclave at a
hydrogen pressure of 5 MPa at room temperature. The substrate
was dissolved in EtOH and supported rhodium or ruthenium
catalysts (2–5 mol%) were added. EDCA (2–3 equiv. with
respect to metal) was optionally added. The typical product
distribution as a function of time (entry 5) is given in Fig. 1 for
a hydrogenation performed over Ru–C catalyst. The aromatic
substrate was hydrogenated to 3a and b with a constant de; some
In all reactions, only small amounts of trans-cyclohexane
derivative were found ( < 3%) and the absolute configuration of
the major cis product was (1S,2R,2AS). Hydrogenation of (S)-N-
(2-methylbenzoyl) pyroglutamic acid methyl ester 1 in the
presence of Rh–C catalyst resulted in 35% de, whereas on Rh–
Al O the conversion was slightly lower, although the diaster-
eoselectivity was 90%. Addition of a bulky amine (EDCA) to
the reaction medium lowered the reaction rate in both cases, but
excellent diastereoisomeric excesses were observed, both on
carbon (90% de) and on alumina (95% de). Compound 2 was
detected in significant amounts only in the case of Rh–C; its
hydrogenation gave preferentially 3b and lowered the de.
In the case of the ruthenium catalyst, high diastereoselectiv-
ities were achieved without amine, irrrespective of the support
2
3
O
CO2Me
N
COCl
i
O
(
74 and 85% de on carbon and alumina, respectively). However,
Me
Me
1
it was found that the reaction was slower on the alumina-
supported catalyst. The semi-hydrogenated compound 2 was
H2
Metal–support
Table 1 Results for hydrogenation of o-toluic acid derivatives 1
Conversion
b
EDCA: (%) after Yield 2 De
O
O
O
CO2Me
CO Me
2
CO Me
N
N
2
N
Entry Metal–support
metal
a
24 h
(%)
b
(%)b,c
O
O
O
1
2
3
4
5
6
7
Rh–C (Aldrich, 3.6%)
Rh–Al (Degussa, 3.7%)
Rh–C (Aldrich, 3.6%)
Rh–Al (Degussa, 3.7%)
Ru–C (Aldrich, 5%)
Ru–Al (Degussa, 3.7%)
Ru–C (Aldrich, 5%)
—
—
2
100
89
49
49
99
61
61
d
13
5
3.5
2
19
11
10
35
90
90
95
74
85
83
+
2 3
O
Me
a
Me
3b
Me
3
2
O
2 3
3
(
1R, 2S, 2'S)
(1S, 2R, 2'S)
e
—
—
3
e
O
2 3
e
H2
a
Molar ratio. b Determined by GC analysis (DB 1701). c The determination
Metal–support
of the major configuration (1S,2R,2AS) was carried out by measuring the
d
Scheme 1 Reagents and conditions: i, (S)-pyroglutamic acid methyl ester,
toluene, 80 °C, N
optical purity of the hydrolyzed product. The conversion was complete
e
2
after 100 min reaction. Pretreated under H
2
at 300 °C for 2 h.
Chem. Commun., 1998
1431
Besson, Michele
