Chemo- and diastereoselectivity in the heterogeneous catalytic hydrogenation of 2,2′-pyridoin and its derivatives

Article abstract of DOI:10.1006/jcat.2002.3652

The heterogeneous catalytic hydrogenations of 2,2′-pyridoin and related compounds, such as 2,2′-pyridil and O-acetyl-2,2′-pyridoin, were investigated over noble metal catalysts. The influence of catalytic metals, catalyst supports, solvents, acid additives, prehydrogenation, and hydrogen pressure on the chemo- and diastereoselectivity is discussed in the hydrogenation of 2,2′-pyridoin. Although hydrogenolysis and ring saturation may occur as side reactions, high chemo- (90-100%) and moderate diastereoselectivity values were achieved. Over palladium black in an acetonitrile-water solvent mixture, the hydrogenation resulted in a meso/dl ratio of 72/28, while in the hydrogenation over rhodium on carbon the meso/dl ratio was 29/71. The phenomenon of diastereoselection in the hydrogenation is explained by the stereochemistry of the hydrogen addition, considering the cis-trans isomerization on the catalyst surface, the possible enolization, and the competing C=C and C=O reductions.

Full text of DOI:10.1006/jcat.2002.3652

Journal of Catalysis 209, 472–479 (2002)
doi:10.1006/jcat.2002.3652
Chemo- and Diastereoselectivity in the Heterogeneous Catalytic
Hydrogenation of 2,2ꢀ-Pyridoin and Its Derivatives
Viktor Ha´da, Antal Tungler,1 and La´szlo´ Szepesy
Department of Chemical Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
Received January 11, 2002; revised March 22, 2002; accepted April 5, 2002
==
In the hydrogenation of C C double bonds it was ob-
The heterogeneous catalytic hydrogenations of 2,2ꢀ-pyridoin and
related compounds, such as 2,2ꢀ-pyridil and O-acetyl-2,2ꢀ-pyridoin,
were investigated over noble metal catalysts. The influence of cata-
lytic metals, catalyst supports, solvents, acid additives, prehydro-
genation, and hydrogen pressure on the chemo- and diastereoselec-
tivity is discussed in the hydrogenation of 2,2ꢀ-pyridoin. Although
hydrogenolysisandringsaturationmayoccurassidereactions, high
chemo- (90–100%) and moderate diastereoselectivity values were
achieved. Over palladium black in an acetonitrile–water solvent
mixture, the hydrogenation resulted in a meso/dl ratio of 72/28,
while in the hydrogenation over rhodium on carbon the meso/dl
ratio was 29/71. The phenomenon of diastereoselection in the hy-
drogenation is explained by the stereochemistry of the hydrogen
addition, considering the cis–trans isomerization on the catalyst
served that cis isomers are usually reduced more rapidly
than the corresponding trans isomers. Rates can depend on
the type of compound used, on substitution at the double
bond, and on the catalyst. It was noted that unsaturated cis
acids were more strongly adsorbed on platinum black than
the trans acids and were also reduced more rapidly (9).
The hydrogenation of symmetrical butenes over palladium
on carbon gave similar results (10). During hydrogena-
tion of the double bond cis–trans isomerization can also
take place, which is dependent on the catalyst and reaction
medium. Noble metal catalysts show marked differences in
promoting olefin isomerization (11). The following decreas-
ing isomerization activity was found: Pd ꢂ Rh > Ru > Pt
(12–14).
Bothsymmetricalandunsymmetricalpyridylglycolshave
great synthetic utility; several compounds of these se-
ries possess valuable and specific adrenal cortical in-
hibitory activity. Hence, photochemical, electrochemical,
microbial, and metal reduction have been employed
to prepare these diols. The reductive pinacolization of
2-pyridinecarboxaldehyde (picolinaldehyde) by titanium
==
==
O
surface, the possible enolization, and the competing C C and C
c
reductions. ꢁ 2002 Elsevier Science (USA)
Key Words: heterogeneous catalytic hydrogenation; C C and
==
==
C
O double bonds; diastereoselectivity; cis–trans isomerization;
hydrogenolysis.
INTRODUCTION
2,2ꢀ-Pyridoin has been clearly established as being 1,2- trichloride in acetic acid gave 78% 1,2-di(2-pyridyl)ethane-
di(2-pyridyl)-1,2-ethenediol by infrared studies (1). In neu- diol (hydropyridoin) with a 58/42 meso/dl ratio (15). The
tral, acidic, or alkaline solution 2,2ꢀ-pyridoin exists to 93– reductive dimerization of different pyridineketones to the
98% as 1,2-di(2-pyridyl)-1,2-ethenediol, as proved by titra- corresponding pinacols was investigated, in detail, since
tion with Tillmann’s reagent (2). As a matter of fact, in the pinacol–pinacolone-type rearrangements give as ma-
the hydrogenation of 2,2ꢀ-pyridoin mainly the saturation of jor product the pyridyl analogs of amphenone B. Micro-
==
C C double bond occurs.
bial reduction of 2,2ꢀ-pyridil by Cryptococcus macerans
==
The stereochemistry of hydrogen addition to the C C yielded (R,R)-di(2-pyridyl)ethanediol, with a 6/94 meso/dl
bond has long been of interest (3–5). The suprafacial (syn) ratio and 81% e.e. (16). The absolute stereochemistry of
addition of hydrogen is the most accepted mechanism for (−)-di(2-pyridyl)ethanediol was determined by conversion
metal-catalyzed hydrogenations (Langmuir–Hinshelwood in several steps to (S,S)-(+)-dimethyl diacetyltartrate. For
mechanism) (6). Syn addition nearly always takes place the heterogeneous catalytic hydrogenation of 2,2ꢀ-pyridoin,
with palladium, rhodium, or ruthenium, but over platinum only one example can be found in the literature. This hy-
antarafacial (anti) addition of hydrogen was taken into ac- drogenation was carried out over palladium asbestos, in
count, too (7). Antarafacial addition can be favored by ethanol with hydrochloric acid (17). The meso form of di(2-
strong acids (8).
pyridyl)ethanediol was crystallized; the yield was poor. The
heterogeneous catalytic hydrogenation of analogue com-
pounds was investigated in detail. The hydrogenation of the
ketones benzil and benzoin proceeded chemoselectively
1 To whom correspondence should be addressed. Fax: +36-1-463-1913.
E-mail: tungler.ktt@chem.bme.hu.
472
0021-9517/02 $35.00
c
ꢁ 2002 Elsevier Science (USA)
All rights reserved.

HETEROGENEOUS CATALYTIC HYDROGENATION OF 2,2ꢀ-PYRIDOIN
473
over a 10% Pd/C catalyst, modified with ethylenediamine (Aldrich, Steinheim, Germany), 5% Pd/Al2O3 (Aldrich,
(18). Hydrobenzoin was obtained in 95 and 97% yield Milwaukee, WI), PtO2 (D < 0.05) (Aldrich, Milwaukee,
(meso/dl = 71/29 and 76/24, respectively). The hydrogena- WI), Rh black (D < 0.05) (Aldrich, Milwaukee, WI), and
tion of benzoin and benzil over 10% Pt/C in a methanol 5% Pt/Al2O3 (D = 0.2) (Janssen, Geel, Belgium). A Pd
+PdCl2 solution resulted in diphenyl-ethane (19).
black catalyst (D = 0.014) was prepared according to the
The heterogeneous catalytic hydrogenation of 2,2ꢀ- following procedure: 18 mmol (6.0 g) K2PdCl4 was dis-
pyridoin and its derivatives 2,2ꢀ-pyridil and O-acetyl-2,2ꢀ- solved in 50 ml water and reduced at boiling point with
pyridoin over noble metal catalysts was investigated. The 74 mmol (5.0 g) HCOONa dissolved in 20 ml water. When
effects of catalytic metals, catalyst supports, solvents, acid the reduction was complete, the pH of the suspension was
additives, prehydrogenation, and hydrogen pressure are basic (pH 11). The catalyst was filtered and washed several
discussedinthehydrogenationof2,2ꢀ-pyridoin. Thechemo- times with distilled water. The 5% Rh/C (D = 0.42), 10%
and diastereoselectivity of the hydrogenation were studied Pd/TiO2 (D = 0.41), 10% Pd/SiO2 (D = 0.1), 5% Pt/TiO2,
under different reaction conditions.
and5%Pt/SiO2 catalystswerepreparedasfollows. K2PdCl4
and (NH4)2PtCl6 catalyst precursors were prepared from
PdCl2 (Reanal Fine Chemicals, Budapest, Hungary) and
PtCl4 (Merck, Darmstadt, Germany), respectively. The cal-
culated amount of the catalyst precursor (RhCl3 · 3H2O;
Merck, Darmstadt, Germany), K2PdCl4, and (NH4)2PtCl6)
EXPERIMENTAL AND METHODS
Materials
The reagent 2-pyridinecarboxaldehyde (picolinalde- was added to the aqueous suspension of the support. The
hyde) was supplied by Aldrich (Steinheim, Germany), pH value of the solution was adjusted to 10–11 by addition
while acetic anhydride was purchased from Reanal (Fine of KOH. The suspension was boiled for 1 h, after which
Chemicals, Budapest, Hungary). The solvents, methanol, HCOONa was added to the boiling mixture. After half an
ethyl acetate, acetonitrile, dimethyl formamide, and acetic hourthesuspensionwascooled, andthecatalystwasfiltered
acid, were supplied by Reanal (Fine Chemicals, Budapest, and washed with distilled water. The 5% Pt/SiO2 catalyst
Hungary) in pro analysi grade. The inorganic chemicals was heat treated for 3 h in a hydrogen stream at 400◦C in a
used were supplied by Chemolab (Budapest, Hungary). glass reactor and cooled in nitrogen to room temperature.
Methanol, acetonitrile, and water (HPLC grade) were pur-
chased from Merck (Darmstadt, Germany).
2,2ꢀ-Pyridoin (α-pyridoin) was prepared from 2-
pyridinecarboxaldehyde by means of the well-known acy-
Some of the catalysts used were commercial prod- loin condensation, using potassium cyanide (21, 22).
ucts: 10% Pd/C Selcat (D = 0.5) (20) (Finomvegyszer
2,2ꢀ-Pyridil (α-pyridil) 2 was synthesized from 2,2ꢀ-
Fine Chemicals, Budapest, Hungary), 5% Pt/C (D = 0.36) pyridoin 1 (Scheme 1) in methanol by air oxidation, ac-
(Heraeus, Karlsruhe, Germany), 5% Ru/C (D = 0.38) cording to the published procedure (17).
SCHEME 1. Preparation and heterogeneous catalytic hydrogenation of the substrates.

´
HADA, TUNGLER, AND SZEPESY
474
O-Acetyl-2,2ꢀ-pyridoin 3, the monoacetyl derivative of used prereduction being to avoid corrosion of the metal
2,2ꢀ-pyridoin 1, can be obtained with acetic anhydride catalyst and to ensure that the measured hydrogen con-
(Scheme 1); the diacetyl derivative can be synthesized only sumption arose only from uptake by the substrate. The pre-
from the corresponding potassium endiolate (22, 23).
hydrogenation was carried out at room temperature and
Since protic acid additive was used in the hydrogena- atmospheric pressure in the pure solvent.
tion reactions, the reaction mixture was neutralized with
Analysis
sodium hydroxide after the catalytic hydrogenation. The
meso form of 1,2-di(2-pyridyl)ethanediol (hydropyridoin) 4
was crystallized from water. The dl form was obtained
after evaporation of water in vacuo. The configurations
of the diastereoisomers were determined by compari-
son of the NMR data with the published results (15)
and the use of an optically active NMR shift reagent
(europium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate], Aldrich) in the 1H NMR analysis of the
dl-diastereoisomer.
After the hydrogenation reaction the diacetyl derivative
of hydropyridoin 6 was prepared in order to determine the
ratio of diastereoisomers by liquid chromatographic anal-
ysis, using a reverse-phase column and the gradient elu-
tion method. After the catalyst was filtered, the reaction
mixture was neutralized with sodium hydroxide and con-
centrated in vacuo; the sodium chloride, sulfate, or acetate
was crystallized from methanol and filtered, and the sol-
vent was evaporated. Acetic anhydride was added in ex-
cess. The reaction mixture was stirred for 24 h, poured
onto ice, and concentrated in vacuo. The obtained prod-
uct was dissolved in a 10% sodium hydroxide solution and
extracted three times with 100-ml portions of ethyl acetate.
Theethylacetatesolutionwasdriedoveranhydroussodium
sulfate and concentrated in vacuo, and the product was an-
alyzed by HPLC. The retention times and response factors
of meso- and dl-1,2-di(2-pyridyl)ethanediol diacetate were
determined by analyzing the diacetyl derivatives of the in-
dividual diastereoisomers of 1,2-di(2-pyridyl)ethanediol.
The HPLC analyses were carried out in a Purosphere
RP 18-e column (125 × 4 mm) using a gradient elu-
tion method. Retention data were measured on a
Merck–Hitachi LiChrograph consisting of an L-6200 pro-
grammable pump, a Rheodyne 7125 injector with a
10-µl loop, and an L-4250 UV–vis detector operating at
256 nm. Data acquisition was performed using the D-7000
HPLC System Manager software. Conversion values were
determined—after hydrogenation in the reaction mixture
and before acetylation—under isocratic conditions using
an acetonitrile–water (50 : 50) mobile phase in a Symme-
tryShield RP18 column (3.9 × 150 mm). To determine the
ratio of the diastereoisomers, we developed the following
separation method: the starting eluent was 3% methanol
and 97% water and the gradient was 0 → 15% acetoni-
trile and 97 → 82% water (time of gradient, 50 min). The
retention time difference of the two diacetylhydropyri-
doin diastereoisomers was 1.2 min at around a 50-min
retention time. Their response factors were equal within
the experimental error, as was expected. From the chro-
matograms and based on the integrated peak areas, the
conversion, chemoselectivity, and meso/dl ratios were de-
termined.
The chemoselectivity is reported as the selectivity to
1,2-di(2-pyridyl)ethanediol or its monoacetyl derivative.
The NMR spectra were recorded on a Bruker DRX500
spectrometer, in CDCl3.
Hydrogenation
RESULTS AND DISCUSSION
Catalytic hydrogenation was carried out in a con-
ventional apparatus at room temperature under atmo-
spheric pressure or in a stainless steel autoclave (250 cm3)
(Technoclave, Budapest, Hungary) equipped with a mag-
netic stirrer (stirring speed, 1100 rpm) at room tempera-
ture.
The reactors containing the starting material, prehydro-
genated catalyst, and solvent (and acid) were flushed with
nitrogen and then hydrogen. The autoclave was charged
with hydrogen to the specified pressure. After the hydro-
genation was completed, the catalyst was filtered and the
solvent was distilled off in a vacuum. The obtained products
were analyzed by HPLC and NMR. After the completion
of conversion and chemoselectivity, all the products were
prepared in 97–99% yields.
Effect of Catalytic Metals in the Hydrogenation
of 2,2ꢀ-Pyridoin, 2,2ꢀ-Pyridil, and O-Acetyl-2,2ꢀ-pyridoin
The heterogeneous catalytic hydrogenation of 2,2ꢀ-
pyridoin 1, 2,2ꢀ-pyridil 2, and O-acetyl-2,2ꢀ-pyridoin 3 was
carried out over different carbon-supported precious metal
catalysts; the effects of metals on chemo- and diastereos-
electivity are summarized in Table 1. Using a Pd/C cata-
lyst at atmospheric pressure, no reaction was observed in
the hydrogenation of 2,2ꢀ-pyridoin in ethanol and ethyl ac-
etate solvents without acid additive. No conversion was
obtained even at 15 bar in ethyl acetate, applying a high
0.33 catalyst/reactant ratio (g g−1). For that reason it was
necessary to use an equivalent amount of strong acid with
respect to the substrate. In hydrogenation at atmospheric
pressure the reaction rate was calculated from the average
hydrogen consumption in the 0–40% conversion period.
Before the reactions, a 0.5-h prehydrogenation of the
catalyst was carried out, the main purpose of this frequently

HETEROGENEOUS CATALYTIC HYDROGENATION OF 2,2ꢀ-PYRIDOIN
475
TABLE 1
Effects of Catalytic Metals in the Hydrogenation of 2,2ꢀ-Pyridoin, 2,2ꢀ-Pyridil, and O-Acetyl-2,2ꢀ-Pyridoina
Catalyst
type
Reaction rate
Reaction time
(h)
Conversion
(%)
Chemoselectivity
(%)
meso/dl
ratio
Compound
No.
(ml H2/gcat min−1
)
1
1
2
10% Pd/C
5% Pt/C
5% Rh/C
5% Ru/C
8
11
6
2
2
3
5
100
97
98
100
95
82
60/40
41/59
32/68
37/63
3
4b
—
79
100
2
3
1
2
3
1c
2c
3c
10% Pd/C
5% Pt/C
5% Rh/C
5
9
8
6
4
4
98
92
98
100
96
92
60/40
39/61
32/68
10% Pd/C
5% Pt/C
5% Rh/C
5
3
4
3
6
6
100
87
90
79
82
71
49/51
67/33
65/35
a Conditions: 0.42 g reactant; catalyst/reactant ratio, 0.125 (g g−1); equivalent HCl; 35 ml water; 0.5-h prehydrogenation; atmospheric pressure; room
temperature.
b 13 bar.
c 0.058 g reactant.
The carbon-supported palladium, platinum, and rhodium nitrogen of the pyridine ring. This explains why the chelated
(Nos. 1–3) showed good activity at atmospheric pressure, enediols such as 1,2-di(2-quinolyl)-1,2-ethenediol were
while for ruthenium (No. 4) the reaction rate was lower, not affected under low-pressure hydrogenation conditions
even at 13 bar. Hydrogenation resulted in high chemo- and (26).
moderate diastereoselectivity for both the meso and dl iso-
Using a protic acid additive, the chelated structure can
mers. In the case of rhodium, chemoselectivity was lower, break, which, in solution, gives the trans form of the ene-
but the diastereoselectivity for dl isomers was the highest. diol 8. After the transfer of the first hydrogen atom from
As the hydroxy (or acetoxy) groups are adjacent to the the Pd catalyst surface to the chemisorbed trans enediol
aromatic ring, their hydrogenolysis may be the major side 8, cis–trans isomerization may occur, if it is assumed that
reaction. On a rhodium catalyst, saturation of the aromatic the reaction to the half-hydrogenated state 9 is reversible.
ring can also take place (24). The ruthenium gave the dl di- Geometric isomerization occurs readily in the presence of
astereoisomers with lower diastereoselectivity but at 100% hydrogen. The configuration of the hydrogenation product
chemoselectivity.
is also the result of other competing reactions. There is a
In1,2-di(2-pyridyl)-1,2-ethenediol, anintramolecularhy- pyridoin–enediol equilibrium, where the trans form 8 can
drogen bond can be formed. The downfield shift (δ 12.95) be changed into the cis form 11 via enolization. In the ketol
==
of the hydroxylic proton resonance shows the effect of the form 10, saturation of C O can also occur.
hydrogen bond; hydropyridoin also shows the effect of in-
Assuming the syn addition of hydrogen atoms, the hy-
tramolecular bonding but to a lesser degree (meso, δ 5.58; drogenation of trans enediol 8 results in the 12, 13 dl-
dl, δ 5.24). The lack of the singlet of an aliphatic proton hydropyridoins, while the cis form 11 gives the 14 meso dia-
proves the existence of the enediol structure. The trans, stereoisomer.
double six-membered ring structure 7 (Scheme 2) has been
In the hydrogenation of 2,2ꢀ-pyridoin, palladium can
proposed to be the most reasonable hydrogen-bonded form cause extensive isomerization via the cis-enediol, which re-
(1). This chelated structure is highly conjugated and forms a acts faster, the main hydrogenation product being the meso
quasiaromatic system. Maximum stability is achieved when diastereoisomer. On platinum, rhodium, and ruthenium,
the conjugated system is planar. The cis form can not be which have much lower isomerization activity, the hydro-
planar and chelation, if possible at all, would be extremely genation of the trans-enediol resulted in an excess of the dl-
difficult. The chelated enediols—possessing a conjugated, hydropyridoin.
four-ring system—absorb in the visible region and are thus
The reduction of the keto-compound benzil and its
intensely colored. The conjugated system was also proved derivatives over platinum catalysts has been widely inves-
by determining the dipole moment (25). The factors con- tigated; it takes place via 1,4-addition (1). The first product
tribute to the stability of enediols on the one hand and block is usually the cis form, but in the absence of acids (27), and
the catalytic hydrogenation on the other. This is why the use particularly in the presence of a base such as piperidine,
of a protic acid is necessary to open the chelated structure the cis form is converted to the trans form. The effective
and to eliminate the poisoning of the metal catalysts by the conformation of 2,2ꢀ-pyridil is a skew structure in which the

´
476
HADA, TUNGLER, AND SZEPESY
SCHEME 2. Hydrogenation mechanism of 2,2ꢀ-pyridoin on the surface of metal catalysts.
dihedral angle between the C5H4N–CO planes is 80–83◦. Effect of Catalyst Supports in the Hydrogenation
Each C5H4N–CO moiety is assumed to adopt a flat s–trans
arrangement (28); this structure promotes the formation of
trans-enediol during the catalytic hydrogenation.
of 2,2ꢀ-Pyridoin
The catalyst support has a strong effect on the hy-
Concerning both the chemo- and diastereoselectivity, the drogenation and isomerization activity of catalysts and,
hydrogenation of 2,2ꢀ-pyridil over palladium, platinum, and thus, on the stereoselectivity of the hydrogenation reac-
rhodium catalysts (Table 1) gave similar or almost the same tions. In the hydrogenation of 2,2ꢀ-pyridoin, palladium and
results as the hydrogenation of 2,2ꢀ-pyridoin. This means platinum catalysts with different supports were screened
that the catalytic hydrogenation of 2,2ꢀ-pyridil occurs via (Table 2). All palladium catalysts (Nos. 1–4) gave the meso
the trans-enediol form of 2,2ꢀ-pyridoin, according to the diastereoisomer with different activity and diastereoselec-
same hydrogenation mechanism.
In the hydrogenation of O-acetyl-2,2ꢀ-pyridoin, not only sulted in the highest diastereoselectivity.
==
tivity. The hydrogenation over palladium black (No. 5) re-
the saturation of the C O double bond but also deace-
Carbon-supported platinum (No. 6) gave the dl di-
toxylation can occur. Although the acetoxy functionality on astereoisomer in excess, but Adams Pt (No. 7) and other
the benzylic position can be easily hydrogenolyzed, 80% supported platinum catalysts (Nos. 8–10) mainly gave the
chemoselectivity was achieved over palladium and plat- meso isomer. The hydrogenation of the ketol form 7 has
inum, while for the rhodium on carbon catalyst the chemos- to be taken into account, too, even though it is present in
electivity was 71% (Table 1). The hydrogenation over pal- the reaction mixture only in small concentrations because
ladium (No. 1) was not diastereoselective. Platinum and of the pyridoin–enediol equilibrium. This contributes to
rhodium (Nos. 2 and 3) were less active, and the thermody- the formation of the thermodynamically more stable meso-
namically preferred meso product was obtained in excess.
hydropyridoin.

HETEROGENEOUS CATALYTIC HYDROGENATION OF 2,2ꢀ-PYRIDOIN
477
TABLE 2
Effects of Catalyst Supports in the Hydrogenation of 2,2ꢀ-Pyridoina
Catalyst
type
Reaction rate
Reaction time
(h)
Conversion
(%)
Chemoselectivity
(%)
meso/dl
ratio
No.
(ml H2/gcat min−1
)
1
2
3
4
5
10% Pd/TiO2
5% Pd/Al2O3
10% Pd/C
10% Pd/SiO2
Pd black
5% Pt/C
PtO2
5% Pt/SiO2
5% Pt/TiO2
5% Pt/Al2O3
5% Rh/C
12
2
8
9
2
11
8
—
3
9
6
2
8
2
2
8
2
2
5
6
2
3
8
84
96
100
98
94
97
99
94
84
94
98
98
99
100
100
96
96
95
94
98
95
97
54/46
57/43
60/40
62/38
66/34
41/59
60/40
60/40
63/37
64/36
32/68
—
6
7
8b
9
10
11
12
82
>5
Rh black
14
a Conditions: 0.42 g reactant; catalyst/reactant ratio, 0.125 (g g−1); equivalent HCl; 35 ml water; 0.5-h prehydrogenation; atmospheric pressure; room
temperature.
b 13 bar.
Rhodium black (No. 12) showed high activity, and satu- Furthermore, it was found that a small amount of pyridine
ration of the aromatic rings was observed. The value of the might be enough to inhibit hydrogenolysis (31).
meso/dl ratio is unclear because of the very low chemose-
lectivity.
The hydrogenation of 2,2ꢀ-pyridoin was carried out over
palladium on carbon in water, in acetic acid, and in differ-
ent solvent–water mixtures (Nos. 1–5, Table 3). The high-
est diastereoselectivity for the meso isomer was achieved
in the acetonitrile–water (1 : 1) mixture (No. 5). Over
palladium black in an acetonitrile–water solvent mixture
(No. 6), somewhat more meso product was obtained. The
acetonitrile–watermixturefavorstheformationofthe meso
isomer, whichhasbeenalsoclearlyshowninthe hydrogena-
tion over rhodium on carbon (No. 7) (Table 1).
Effect of Solvents and Acid Additives in the
Hydrogenation of 2,2ꢀ-Pyridoin
Equivalent protic acid in alcohol or acetic acid as a
solvent is frequently used for the selective saturation of
==
the C C double bond in the presence of a pyridine ring
(29, 30). A stochiometric amount of acid does not promote
the hydrogenolysis of the hydroxyl group in pyridoin, and
==
C C bond saturation occurs readily in neutral medium.
The use of half-equivalent hydrochloric acid (No. 8)
had no effect on the chemo- and diastereoselectivity of
TABLE 3
Effects of Solvents and Acid Additives in the Hydrogenation of 2,2ꢀ-Pyridoina
Catalyst
type
Reaction rate
Reaction time
(h)
Conversion
(%)
Chemoselectivity
(%)
meso/dl
ratio
No.
Solvent
(ml H2/gcat min−1
)
1
2
3
4
5
H2O
AcOH
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
Pd black
5% Rh/C
5% Rh/C
5% Rh/C
5% Rh/C
10% Pd/C
8
9
12
6
9
3
3
6
6
3
2
2
2
3
2
6
6
3
3
6
5
100
100
99
98
100
99
100
95
97
94
93
99
70
84
89
94
27
60/40
54/46
54/46
64/36
71/29
72/28
37/63
32/68
30/70
33/67
75/25
MeOH–H2O (1 : 1)
DMF–H2O (1 : 1)
MeCN–H2O (1 : 1)
MeCN–H2O (1 : 1)
MeCN–H2O (1 : 1)
H2O
6
7
84
8b
9c
10b
11d
100
100
98
H2O
MeOH–H2O (1 : 1)
MeOH
—
100
a Conditions:0.42greactant;catalyst/reactantratio, 0.125(gg−1);equivalentHCl(exceptAcOHisthesolvent);35mlsolvent;0.5-hprehydrogenation;
atmospheric pressure; room temperature.
b 0.5 equivalent HCl.
c 0.5 equivalent H2SO4.
d 0.80 g reactant; catalyst/reactant ratio, 0.375 (g g−1); 40 ml solvent; 8 equivalent AcOH; 12 bar.

´
478
HADA, TUNGLER, AND SZEPESY
TABLE 4
Effects of Prehydrogenation and Hydrogen Pressure in the Hydrogenation of 2,2ꢀ-Pyridoina
Catalyst
type
Reaction rate
Reaction time
(h)
Conversion
(%)
Chemoselectivity
(%)
meso/dl
ratio
No.
Prehydrogenation
(ml H2/gcat min−1
)
1b
2b
3c
4c
5
5% Rh/C
5% Rh/C
Pd black
Pd black
5% Pt/C
5% Pt/C
5% Pt/C
+
6
6
3
3
3
6
6
2
1
2
100
100
99
100
97
89
94
99
96
95
46
95
30/70
29/71
72/28
66/34
41/59
48/52
46/54
+
+
4
11
—
—
6d
7e
100
100
a Conditions: 0.42 g reactant; catalyst/reactant ratio, 0.125 (g g−1); equivalent HCl; 35 ml water; atmospheric pressure; room temperature.
b 0.5 equivalent H2SO4.
c MeCN–H2O (1 : 1) solvent.
d 14 bar.
e 14 bar; catalyst/reactant ratio, 0.05 (g g−1).
rhodium on carbon. Using sulfuric acid, however, both genation of 2,2ꢀ-pyridoin; it is, thus, a preliminary study for
chemo- and diastereoselectivity increased (No. 9). Over chirally modified systems. With palladium, the main hydro-
rhodium on carbon in a methanol–water mixture (No. 10), genation product is the meso diastereoisomer because of
a similar stereoselectivity but higher chemoselectivity were extensive isomerization and the difference in hydrogena-
observed. Simultaneously applied high pressure and acidic tion rates for the trans- and cis-enediols. Platinum, rhodium,
medium (No. 11) resulted in extensive hydrogenolysis and and ruthenium possess much lower isomerization activity;
ring saturation.
consequently, in the hydrogenation via the trans-enediol
the dl-hydropyridoin was formed in excess. The supported
platinum catalysts gave both the meso and the dl products
with different meso/dl ratios, which was explained by com-
Effect of Prehydrogenation and Hydrogen Pressure
in the Hydrogenation of 2,2ꢀ-Pyridoin
==
peting enolization and C O reduction. Solvents showed a
It was assumed that the prehydrogenation of the catalysts
and the hydrogen pressure can both affect the ratio of re-
action rates of hydrogenation and isomerization and may,
therefore, have an effect on the stereoselectivity as well.
The two systems that afforded the highest diastereosele-
ctivity were chosen and tested to determine whether
the preliminary saturation of the catalysts with hydrogen
and the higher hydrogen pressure improved the stereose-
lectivity.
The hydrogenation over rhodium on carbon, with or
without prehydrogenation (Nos. 1 and 2; Table 4), gave
similar stereoselectivity; without prehydrogenation the
chemoselectivity was higher.
marked effect on the diastereoselectivity. Hydrogenations
without prehydrogenation and at higher pressure did not
improve the stereoselectivity. The hydrogenation of 2,2ꢀ-
pyridil occurs via the 2,2ꢀ-pyridoin intermediate; we assume
that the hydrogenation mechanism is the same, because
chemo- and diastereoselectivity are the same. The hydro-
genation of O-acetyl-2,2ꢀ-pyridoin resulted only in the ther-
modynamically more stable meso product. In the hydro-
genation of 2,2ꢀ-pyridoin, the best catalyst for producing
meso-hydropyridoin was palladium black and that for the
dl isomer was rhodium on carbon.
In the hydrogenation over palladium black, without pre-
hydrogenation (No. 4), the meso/dl ratio was smaller and
the reaction rate somewhat higher. This is in accordance
with the former observation that Pd catalysts reduced in situ
have higher activity for hydrogenation, and consequently
lower activity for isomerization.
Over platinum on carbon (Nos. 5–7), increasing the pres-
sureatthesamecatalyst/reactantratio(g g−1)decreasedthe
chemoselectivity; however, with a lower catalyst/reactant
ratio chemoselectivity was preserved.
APPENDIX
2,2ꢀ-Pyridoin
NMR data: 1H NMR (500 MHz, CDC13): δ = 7.20
(t, J = 5.9 Hz, 2H, Ar–H), 7.85 (t, J = 7.9 Hz, 2H, Ar–H),
7.92 (d, J = 8.1 Hz, 2H, Ar–H), 8.49 (d, J = 4.8 Hz, 2H,
Ar–H), 12.95 (brs, 2H, OH); 13C NMR (125 MHz, CDC13):
δ = 119.7 (Ar–CH), 121.3 (Ar–CH), 136.1 (C), 137.7 (Ar–
CH), 145.8 (Ar–CH), 156.8 (Ar–C).
Mp 156◦C (17).
CONCLUSION
2,2ꢀ-Pyridil
The purpose of this work was to explore the effects of
reaction conditions on the stereoselectivity in the hydro- (t, J = 6.2 Hz, 2H, Ar–H), 7.95 (t, J = 7.6 Hz, 2H, Ar–H),
NMR data: 1H NMR (500 MHz, CDC13): δ = 7.51

HETEROGENEOUS CATALYTIC HYDROGENATION OF 2,2ꢀ-PYRIDOIN
479
8.24 (d, J = 7.8 Hz, 2H, Ar–H), 8.61 (d, J = 4.5 Hz, 2H, (d, J = 7.9 Hz, 2H, Ar–H), 7.57 (t, J = 7.7 Hz, 2H, Ar–
Ar–H); 13C NMR (125 MHz, CDC13): δ = 122.8 (Ar–CH), H), 8.55 (d, J = 4.5 Hz, 2H, Ar–H); 13C NMR (125 MHz,
128.3 (Ar–CH), 137.6 (Ar–CH), 149.9 (Ar–CH), 152.2 (Ar– CDCl3): δ = 21.0 (CH3), 76.9 (CH), 122.8 (Ar–CH), 123.6
C), 197.3 (CO).
(Ar–CH), 136.5 (Ar–CH), 149.6 (Ar–CH), 155.9 (Ar–C),
170.0 (COO).
Mp 154–155◦C (17).
O-Acetyl-2,2ꢀ-pyridoin
ACKNOWLEDGMENTS
NMR data: 1H NMR (500 MHz, CDC13): δ = 2.17
(s, 3H, CH3), 5.25 (s, 1H, CH), 7.26 (t, J = 6.1 Hz, 1H, Ar–
H), 7.32 (d, J = 7.9 Hz, 1H, Ar–H), 7.37 (d, J = 7.8 Hz, 1H,
Ar–H), 7.56 (t, J = 6.1 Hz, 1H, Ar–H), 7.73 (t, J = 7.6 Hz,
1H, Ar–H), 7.93 (t, J = 7.7 Hz, 1H, Ar–H), 8.24 (d,
J = 7.3 Hz, 1H, Ar–H), 8.62 (d, J = 4.7 Hz, 1H, Ar–H);
13C NMR (125 MHz, CDC13): δ = 21.1 (CH3), 66.9 (CH),
122.1 (Ar–CH), 122.7 (Ar–CH), 123.1 (Ar–CH), 124.4 (Ar–
CH), 137.1 (Ar–CH), 138.2 (Ar–CH), 148.7 (Ar–CH), 149.5
(Ar–CH), 155.9 (Ar–C), 155.9 (Ar–C), 170.9 (COO), 194.2
(CO).
The authors acknowledge the financial support of the Hungarian OTKA
Foundation (contract T 029557) as well as that of the Ministry of Education
(FKFP 0017/1999).
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CDCl3): δ = 21.0 (CH3), 76.3 (CH), 123.2 (Ar–CH), 123.4
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