One-pot synthesis of (R)-2-acetoxy-1-indanone from 1,2-indanedione combining metal catalyzed hydrogenation and chemoenzymatic dynamic kinetic resolution

Article abstract of DOI:10.1039/c4cy01099j

Combination of the regioselective hydrogenation of the prochiral diketone 1,2-indanedione with chemoenzymatic dynamic kinetic resolution of the resulting rac-2-hydroxy-1-indanone was investigated. A new simple to operate, one-pot reaction sequence provides the valuable building block (R)-2-acetoxy-1-indanone in moderate enantiopurity (86-92% ee) and a competitive isolated yield (39%) compared with a traditional isolated batch reaction approach.

Full text of DOI:10.1039/c4cy01099j

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One-pot synthesis of IJR)-2-acetoxy-1-indanone
from 1,2-indanedione combining metal catalyzed
hydrogenation and chemoenzymatic dynamic
kinetic resolution†
Cite this: DOI: 10.1039/c4cy01099j
a
b
c
c
a
*
Otto Långvik, Thomas Sandberg, Johan Wärnå, Dmitry Yu. Murzin and Reko Leino
Received 25th August 2014,
Accepted 15th September 2014
Combination of the regioselective hydrogenation of the prochiral diketone 1,2-indanedione with
chemoenzymatic dynamic kinetic resolution of the resulting rac-2-hydroxy-1-indanone was investigated.
A
new simple to operate, one-pot reaction sequence provides the valuable building block
DOI: 10.1039/c4cy01099j
IJR)-2-acetoxy-1-indanone in moderate enantiopurity (86–92% ee) and a competitive isolated yield (39%)
www.rsc.org/catalysis
compared with a traditional isolated batch reaction approach.
the hydrogenation reaction produces an equimolar mixture of
the two 2-hydroxy-1-indanone enantiomers. In earlier work,
1 Introduction
The development of cost efficient, sustainable chemical pro-
cesses for preparation of chiral building blocks is of para-
mount importance in contemporary synthetic and industrial
organic chemistry. In recent years, one-pot reaction sequences
involving various types of cascade, tandem and multi-
component reactions have emerged as a topical research area,
providing several advantages over conventional multi-step
synthetic methods.1–7 Furthermore, in modern catalysis
research, heterogeneous catalysts are receiving increasing
attention also in asymmetric fine chemical synthesis with sev-
eral advantages over their homogeneous counterparts, partic-
ularly due to their simpler work-up, catalyst separation and
recycling. A particular objective of our ongoing work is the
development of selective, one-pot asymmetric synthesis proto-
cols combining heterogeneous metal and enzyme based cata-
lysts separable by filtration, ideally allowing robust access to
chiral small molecules.8–10
we have investigated the chemoenzymatic dynamic kinetic res-
olution (DKR) of rac-2 by use of heterogeneous catalysts.8 The
deprotected chiral reaction product, IJR)-2-hydroxy-1-indanone,
then serves as a vicinal hydroxy ketone building block for fur-
ther utilization, e.g., for production of cis-1-amino-2-indanol,
a widely utilized intermediate for pharmaceuticals, chiral
catalysts, chiral auxiliaries and chiral resolving agents.17–24
The main methodologies traditionally utilized for the prep-
aration of chiral compounds are based on classical racemate
resolution, asymmetric synthesis, and kinetic resolution.
Enzymatic kinetic resolution of racemic starting materials is a
useful tool for obtaining enantiomerically pure products,
being, however, limited to the maximum theoretical yield of
50%.25 In order to overcome this drawback, various types of
DKR processes have been developed where the slower reacting
enantiomer is racemized spontaneously or by a catalytic
process.26–29 In DKR reactions, then, theoretical yields of
100% can be achieved. For example, the chemoenzymatic
DKR of sec-alcohols typically utilizing enzymes, such as CALB,
in combination with homogeneous ruthenium based racemi-
zation catalysts have in recent years emerged as a powerful
tool for the synthesis of enantiomerically pure esters and,
after deprotection, the corresponding chiral parent alcohols.30–34
Examples of heterogeneous or immobilized homogeneous
catalytic systems for dynamic kinetic resolution (DKR)
processes have, likewise, been reported in the literature.35–38
Nevertheless, one-pot cascade or tandem type operations
combining both the hydrogenation and DKR reactions in
single vessels are rare, although a few examples for selected
ketoximes and carbonyl compounds have been described.39–45
In general, while one-pot and cascade-type reaction approaches
Vicinal hydroxy ketones serve as useful starting materials
for various classes of industrially relevant compounds.11–16
As shown recently, the vicinal hydroxy ketone, rac-2-hydroxy-1-
indanone IJrac-2), can be efficiently obtained by regioselective
hydrogenation of the corresponding vicinal dione,
1,2-indanedione (1).9,10 In the absence of asymmetric induction,
a Laboratory of Organic Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland.
E-mail: reko.leino@abo.fi
b Laboratory of Physical Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland
c Laboratory of Industrial Chemistry and Reaction Engineering, Process Chemistry
Centre, Åbo Akademi University, FI-20500 Åbo, Finland
† Electronic supplementary information (ESI) available: 1H-NMR spectra for
(R)-3, 6 and 7, DFT calculations results, chiral GC chromatograms and Ru
catalyst characterization (HR-TEM, TPR, XPS). See DOI: 10.1039/c4cy01099j
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ideally result in overall more efficient chemical processes,
reducing also the number of work-up stages required, the
combination of different types of catalysts, e.g., chemical and
enzymatic, into a single reaction vessel often remains
challenging. For example, the combination of regioselective
hydrogenation with subsequent DKR reaction is particularly
demanding, especially in terms of retaining the catalytic
activities and selectivities of the different catalysts involved
throughout the whole reaction process. Thus, mutually
compatible tailored catalyst combinations are required, not
undergoing severe catalyst inactivation or poisoning path-
ways induced by the reaction products, starting materials or
intermediates. Ideally, this type of heterogeneous reaction
sequences could also further be converted to flow type
systems,46–48 receiving increasing interest both in industry
and academic laboratories in recent years.49–54
In the present paper, we describe our work on the combi-
nation of the two earlier published reactions by us, namely,
the regioselective hydrogenation of 1,2-indanedione9 and the
chemoenzymatic dynamic kinetic resolution of rac-2 (ref. 8)
into a new one-pot reaction sequence (Scheme 1). Initial
experiments were also carried out on the potentially regio-
selective hydrogenation of two other vicinal diketones,
9,10-phenanthrenequinone and 1,2-naphthoquinone. Limita-
tions and scope of the one-pot approach are discussed.
10% (w/w) lipase and 5% (w/w) sucrose.60 RuIJOH)3/Al2O3 was
prepared according to literature procedures.8,61 The hydrogen
and argon gases used were of high quality grade, 99.999%
and 99.9999%, respectively (Linde Gas – AGA).
2.2 Catalyst characterization
The metal loading of the Ru catalyst was determined by using
an inductively coupled plasma optical emission spectrometer
(ICP–OES; PerkinElmer, Optima 5300 DV) working at λ =
240.272 nm. The ICP sample (16 mg) was applied in a teflon
bomb together with aqua regia (2.5 mL) and HF (0.5 mL).
The sample was digested in a microwave oven (Anton Paar,
Multiwave 3000) and diluted to 100 mL volume with
deionized water (18 MΩ) prior to analysis. The Ru catalyst
samples for high resolution transmission electron spectros-
copy (HRTEM) analyses were prepared as a suspension in
ethanol, and for calculating the diameter of particles, more
than 100 particles for each sample were taken (in one or
more picture). The HRTEM measurements were performed
with LEO 912 Omega, voltage 120 kV. The metal dispersion
of the Pd catalyst was determined by applying CO pulse
chemisorption method using Micromeritics Auto-Chem 2900
apparatus. The Pd dispersion was calculated assuming an
adsorption stoichiometry of 1/1 for CO/Pd.62 The specific sur-
face area of the Pd/Al2O3 catalyst was measured by nitrogen
physisorption using an automatic physisorption apparatus
(Sorptomatic 1900, Carlo Erba Instruments). BET method
was used for calculation of the surface area. The catalyst was
degassed prior to the surface area measurement in vacuum
at 150 °C. Temperature programmed reduction (TPR) of the
RuIJOH)3/Al2O3 catalyst was performed with an AutoChem
Micromeritics apparatus by using the following temperature
ramp: 10 °C min−1 to 400 °C. X-Ray photoelectron spectros-
copy (XPS) was conducted with Kartos Axis Ultra electron
spectrometer equipped with a delay line detector. The binding
energy scale was referenced to the C 1s first line of aliphatic
carbon, set at 285.0 eV. Processing of the spectra was accom-
plished with the Kratos software.
Scheme
1 One-pot reaction combining the regioselective
hydrogenation of 1,2-indanedione (1) and chemoenzymatic dynamic
kinetic resolution of the intermediate rac-2-hydroxy-1-indanone
IJrac-2) producing IJR)-2-acetoxy-1-indanol ij(R)-3].
2.3 Quantum mechanical calculations
The TURBOMOLE program package63,64 version 6.1 was used
for conducting the quantum mechanical calculations deter-
mining the optimized structure of 1. The calculations were
performed by applying density functional theory65 with the
B3LYP hybrid exchange-correlation functional66–68 in combi-
nation with the MARI-J approximation69–71 and the TZVP
basis set72 for all atoms, as implemented in the TURBOMOLE
program package. For determining the charge delocalization
in 1, the GAMESS software73 was applied using the Hartree–Fock
(HF) theory74 with the basis set 6-31G* 75–77 obtaining cor-
responding electrostatic potential fit (ESP) charges.
2 Experimental
2.1 Materials
The starting material 1 was prepared according to literature
procedures with 1H and 13C NMR spectroscopic data
and melting point identical to those reported previously.55–59
The other diketones, 1,2-naphthoquinone (4) (97%) and
9,10-phenanthrenequinone (5) (95%), were purchased from
Sigma-Aldrich and used without further purification. The
Pd/Al2O3 catalyst used for the hydrogenation reactions was
purchased from Aldrich (product 205710; 5 wt% Pd) and
sieved prior to use (<63 μm). The enzyme, lipase AK (from
Pseudomonas fluorescens), was purchased from Sigma-Aldrich
and used after immobilization on celite and in trial reactions
without immobilization. The immobilization of lipase AK on
celite was carried out as described in the literature using
2.4 Reaction setup
The hydrogenation and one-pot reactions were conducted in
a five-necked 100 mL round-bottom flask equipped with a
mechanical stirrer (gas tight adaptor), gas inlet (7 μm gas
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disperser merged in the solvent), in situ thermocouple record-
ing the temperature, funnel (with degassing capability), rub-
ber septa for sampling and condenser further connected to
an oil bubbler for gas outlet. The one-pot reactions were
performed using hydrogen gas under atmospheric pressure
at 40 °C. The Pd catalyst for hydrogenation was pretreated
under H2 flow (1 atm.) for 2 h at elevated temperature (250 °C)
in order to ensure that all active metal is in metallic form
(oxidation state zero).9,43 Efficient stirring (500 rpm) and
small hydrogenation catalyst particle size (<63 μm) were
employed to obtain data in the kinetic regime without exter-
nal and internal mass transfer limitations. After Pd-catalyst
pretreatment, the reaction vessel was cooled down and the
degassed (three vacuum-argon cycles) RuIJOH)3/Al2O3, lipase
AK and 4 Å molecular sieves were introduced.
the catalysts were removed by filtration through Celite. Chro-
matographic separation was performed using automated
flash system (CombiFlash Companion) equipped with a 4 g
(20–40 μm) silica column using EA:hexane as the eluent system
(gradient program). Yield of the product IJR)-2-acetoxy-1-indanol
according to GC chromatogram was 51% (peak area) and the
isolated yield was 39% (89 mg, 0.47 mmol), colorless oil.
2.7 Product analyses
Samples (0.15 mL) from the reactor were taken through a gas
tight septum, filtered using a 0.2 μm syringe filter and
diluted with three parts of the same solvent after which 1 μL
of the solution was injected to the gas chromatograph. The
product distribution was monitored by GC or GC/MS. The GC
apparatus used was Agilent Technologies 6850 GC equipped
with a Varian CP-7502 column (25.0 m × 250 μm × 0.25 μm),
1/50 split, FID detector and He was applied as a carrier gas.
The chiral-GC analyses were conducted using the following
temperature program: injector 230 °C, detector 280 °C, oven
Tinitial = 130 °C (0 min), rate 2.2° min−1, Tfinal = 185 °C
(10 min). The GC/MS apparatus used was Agilent Technologies
7890 A GC equipped with 5975 C MS detector (EI), HP-5MS
column (30 m × 250 μm × 0.25 μm), 1/50 split and He as a
carrier gas. The NMR spectra of the isolated compounds were
recorded on a Bruker Avance 600 MHz NMR spectrometer
equipped with a BBI-5 mm-Zgrad-ATM probe at 25 °C operat-
ing at 600.13 MHz for 1H and 150.92 MHz for 13C.
2.5 Hydrogenation of 1,2-naphthoquinone and
9,10-phenanthrenequinone
The hydrogenations of 1,2-naphthoquinone (4) and
9,10-phenanthrenequinone (5) were performed by dissolving
1.2 mmol of 4 or 5 in 60 mL ethyl acetate (EA). The hydroge-
nation reactions were started by introducing the deoxygen-
ated solution into the reaction vessel with H2-flow atmosphere
(1 atm.) containing the Pd/Al2O3 catalyst (51.1 mg, 2 mol% Pd).
After 2.5 h reaction time at 40 °C, an in situ derivatization was
applied by addition of 1 mL acetic anhydride and 1 mL pyri-
dine whereafter stirring was continued for 20 min. The prod-
ucts were separated after filtration of the catalyst, by traditional
column chromatography using EA:hexane mixture as the
eluent. The isolated yields for 1,2-diacetoxynaphthalene (6)
was 85% and for 9,10-diacetoxyphenanthrene (7) 78%.
3 Results and discussion
3.1 Catalyst characterization
Based on the ICP–OES results, the heterogeneous RuIJOH)3/
Al2O3 catalyst contains a 1.9% (w/w) metal loading. The mean
Ru-particle size, based on high resolution TEM, was deter-
mined to 1.3 0.4 nm. The TPR of the catalyst confirms that
no reduction takes place at temperatures below 70 °C in H2
atmosphere and that the maxima for the H2 uptake is at 137,
244, and 338 °C.8 The XPS data displayed binding energy
peaks at 463.5 and 485.7 eV defining the oxidation state of
the ruthenium species to +III, i.e., RuIJOH)3/Al2O3.8
The values for the metal dispersion and the corresponding
average metal particle sizes of the Pd-catalyst were deter-
mined to be 22% and 5.1 nm, respectively. The BET specific
surface area of the Pd catalyst is, according to nitrogen
physisorption measurements, 174 m2 g−1.
2.6 One-pot reaction sequence
In the one-pot reaction sequence 1,2-indanedione (175 mg,
1.2 mmol) and dodecane as an internal standard (68 μL,
0.3 mmol) were dissolved in ethyl acetate (EA), 60 mL, and
transferred to a funnel directly connected to the hydrogena-
tion vessel. Deoxygenation of the solution was carried out in
the funnel by bubbling with H2 (15 min) shortly before reac-
tion. The reaction was started by introducing the deoxygen-
ated solution into the reaction vessel with H2 atmosphere
containing the Pd catalyst (51.2 mg, 2 mol%), lipase
(125 mg), Ru-catalyst (85 mg, 1.5 mol%) and pre-dried
molecular sieves (30 mg), ensuring dry reaction conditions.
Trifluoroethyl acetate (545 μL, 4.8 mmol, 4 equivalents)
was introduced to the reaction mixture in the reactor 15 min
after the reaction had started in five portions with 30 min
intervals through the septa using a syringe. It should be
noted, however, that for the kinetic experiments, in order
to simplify the experimental procedure, the full amount of
the acyl donor was added directly in the beginning of the
reactions. This data, then, was used for plotting of the con-
centration profiles (Fig. 1–4) and calculation of the kinetic
parameters (Table 3). The hydrogen flow rate during the reac-
tions was 25–35 mL min−1 and the reaction mixtures were
kept at 40 °C using a PEG-bath. Prior to product isolation,
3.2 Hydrogenation
The utilization of 1 as a starting material for further synthetic
applications is attractive. This compound is readily available,
in part due to its application as a forensic fingerprint
reagent.78,79 Our recently reported regioselective hydrogena-
tion of 1 is an efficient and practical method for preparation
of rac-2 (Scheme 2)9 compared with the traditional literature
route starting from 1-indanone, providing rac-2 after hydroly-
sis of the corresponding 2-diazo-1-indanone, in turn obtained
by oxidation of the 2-oximino-1-indanone intermediate.55,58
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Table 1 Conversion and selectivity for the hydrogenation of 1 (1.2 mmol)
to rac-2 using Pd/Al2O3 catalyst (51.1 mg, 2 mol%)
In our earlier study, the regioselective hydrogenation was
investigated and the influence of some fundamental reaction
parameters, including the choice of the solvent and catalyst,
were determined.9 Conclusively, by using EA as the solvent
and Pd/Al2O3 (2 mol%) as the catalyst, reproducible results
were obtained with 1 being reduced to rac-2 with very high
initial selectivity (99%) at up to 50% conversion. At longer
reaction times, higher conversions were achieved at lower
selectivity due to consecutive hydrogenation. Nevertheless,
acceptable selectivities (92%) towards the desired alcohol
were obtained at a reasonably high (84%) conversion level
(Table 1, entries 1–4).9
Entry
Conversion of 1 [%]
Selectivity towards rac-2 [%]
1
2
3
4
56
84
87
90
99
92
87
42
compound 1 in the hydrogenation reaction, the atomic
charges were calculated (for details, see Experimental sec-
tion). While the difference between the atomic charges of the
two carbonyl carbons is moderate, the results obtained sup-
port the earlier suggested property of delocalization of the
benzylic CO double bond to the aromatic region and thus
resulting in the relatively higher reactivity of the carbonyl
group in position 2 (Fig. S4, ESI†). However, in order to fully
explain the behaviour of 1 in the heterogeneously catalyzed
hydrogenation reactions, more thorough calculations would
be needed, including calculations of the different adsorption
modes of the substrate to the catalyst surface.
3.2.1 Antiaromatic character of 1,2-indanedione.
Preliminary quantum mechanical calculations were carried
out in order to elucidate the potentially antiaromatic
character of the starting material 1. According to literature,
antiaromatic compounds contain 4n (n ≠ 0) π-electrons in a
cyclic and planar or nearly planar system consisting of alter-
nating single and double bonds.80 Three additional charac-
teristics possessed by antiaromatic compounds are: 1)
decreased thermodynamic stability; 2) tendency to alterna-
tion of bond lengths; and 3) small energy gap between
the highest occupied (HOMO) and the lowest unoccupied
molecular orbitals (LUMO).80 Tyutyulkov and coworkers have
earlier performed quantum chemical calculations for the
enolic anion form of 1, with results supporting the anti-
aromatic character of the anionic structure.81 In the earlier
study, some characteristic properties of antiaromatic struc-
tures, including Jahn–Teller distortion, negative net charge
in the five-membered carbon ring and spectroscopic data
supporting the proposal of a small band gap between the
HOMO–LUMO, were observed.81 Furthermore, compound 1
and the related reactive radical structures have been studied
using electron spin resonance by other investigators.82–84
As the tendency to alternation of bond lengths is one of
the characteristics possessed by antiaromatic compounds,
the bond lengths of 1 were evaluated here using quantum
mechanical calculations with the TURBOMOLE program
package (for details, see experimental section). The calcula-
tions performed clearly indicate the unmodified structure 1
to be less antiaromatic compared to its enolic counterpart
with the calculated bond lengths of 1 not significantly differ-
ing from the expected ones, also not indicating any signifi-
cant Jahn–Teller distortions (Fig. S3, ESI†).
Conclusively, as indicated by the results obtained herein,
the non-ionized form of 1 shows only one antiaromatic fea-
ture, namely the small band gap between the HOMO and
LUMO, −0.246 Eh and −0.110 Eh, respectively.
3.3 One-pot hydrogenation and esterification of
1,2-naphthoquinone and 9,10-phenanthrenequinone
In order to further develop and apply the regioselective hydro-
genation of vicinal diketones to other potential structures, pre-
liminary hydrogenation studies were carried out by using 4 and
5 as the starting materials. These hydrogenations were initially
carried out under similar reaction and pretreatment conditions
as used for 1. While investigating the hydrogenation of 5, it
became evident, however, that the conditions used for 1 were
not applicable for this compound. In the GC analysis, no product
was observed although during the hydrogenation reaction a clear
color change from yellow to colorless, characteristic for diones,
was observed. The disappearance of the product was then shown
to result from back-oxidation of the product to starting material
in air atmosphere prior to analysis. The reduction-oxidation
equilibrium shifts rapidly towards the oxidized form upon expo-
sure to air after venting of the hydrogenation reactor. An in situ
derivatization, by acylation, was applied in order to avoid oxida-
tion of the products and also enabling easier separation and
increasing the isolated yield. This sequence provided, for the two
different starting materials, the corresponding diacetates 6 and 7
in isolated yields of 85% and 78%, respectively (Schemes 3 and 4).
The isolated diacetate products are likely formed by rearrange-
ment of the hydroxy ketones by proton transfer and subse-
quent aromatization (Schemes 3 and 4).
As the benzylic charge delocalization likely results in dif-
ferent atomic charges on the carbonyl groups in position 1
and 2, and is likely to influence the chemical behaviour of
The hydrogenation and derivatization or protection of the
diols formed, i.e., reductive acetylation, is a well-known trans-
formation for quinone type structures.85–88 Hydrogenations of
compounds 4 and 5 initially proceed similar to that of 1, pos-
sibly forming hydroxy ketones as intermediates, which then
Scheme 2 Hydrogenation of 1 to rac-2 with H2 using Pd/Al2O3 (2 mol%)
as the catalyst.
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are rapidly and spontaneously rearranged to form more stable
and energetically favored aromatic diols, or alternatively are
easily oxidized back to the starting material. Notably, because
of the symmetric structure of 5 the hydrogenation cannot pro-
ceed in a regioselective manner. Nevertheless, the successful
in situ derivatizations of the reaction products indicate that
the envisioned conceptually related one-pot hydrogenation
and esterification sequence should be feasible.
catalyzed DKR reactions have been converted into flow type
reaction applications.46–48 In the literature, the reported
one-pot catalyst systems suffer, however, from often reduced
catalytic activities. The racemization catalysts may be inhibited
to various degrees by the starting materials or products.8,45
Activity of the enzyme may, in turn, be inhibited by acidic
catalysts used for racemization.92,93
During our development of the chemoenzymatic DKR of
rac-2,8 several potential racemization catalysts were investi-
gated. In addition to the catalysts studied in the earlier
paper, we have now additionally investigated VOSO4 for race-
mization of (S)-2. Racemizations of various benzylic alcohols
using VOSO4 have been reported earlier.94 Racemization of
(S)-2 (0.02 M) at 40 °C using EA as the solvent in the presence
of 0.02 M VOSO4 proved, however, unsuccessful and any sig-
nificant racemization could not be detected during the course
of a 5 h reaction. The previously developed heterogeneously
catalyzed DKR,8 converting rac-2 into IJR)-1-oxoindan-2-yl-butanoate
(Scheme 5) in 85–90% conversion and up to 92% ee was,
therefore, considered sufficiently efficient for combining the
DKR with hydrogenation experiments.
Scheme 3 Hydrogenation (a) and subsequent esterification (b) of 4 to
6 with H2 (1 atm.) and Pd/Al2O3 as catalyst.
3.5 One-pot combination of hydrogenation and DKR
The primary aim of the present work was to combine the ear-
lier described regioselective hydrogenation of 1 and the DKR
of rac-2 into a one-pot reaction sequence (Scheme 6). The
results are presented in Table 2. An interesting observation
during the earlier reported DKR (Scheme 5) was the minor
formation of 1 as an undesired by-product.8 The aim here
was to employ reductive reaction conditions and to utilize
catalytic hydrogenation of compound 1, a more benign and
accessible starting material compared to rac-2, further to
rac-2 producing after DKR the desired chiral product (R)-3.
The initial one-pot experiments combining the hydrogena-
tion and DKR were conducted by switching the reaction
atmosphere from hydrogen gas to argon during the reaction,
similar to the earlier reported, conceptually related one-pot
type reaction sequence of Bäckvall and co-workers.41 Thus, in
the first experiments performed here, the gas feed was
changed from hydrogen to argon after two hours of reaction.
In this time, the earlier reported regioselective hydrogenation
proceeds rapidly providing reasonable conversion.9 In this
work it became evident, however, that the introduction of
argon did not enhance the conversion or selectivity of the
one-pot reaction sequence. Therefore, in further experiments
only hydrogen gas was used. For selection of solvent, methyl-
tert-butyl ether (MTBE) and EA were considered. While MTBE
Scheme 4 Hydrogenation (a) and subsequent esterification (b) of 5 to
7 with H2 (1 atm.) and Pd/Al2O3 as catalyst.
3.4 Dynamic kinetic resolution
Lipase catalyzed kinetic resolution is a powerful tool for pro-
duction of enantiomerically pure compounds. Prerequisites
for a viable resolution process include the correct selection of
a suitable enzyme, active acyl donor, low water content in the
reaction media and rapid in situ racemization of the starting
material. The most efficient sec-alcohol racemization catalysts
developed to date are based on soluble half-sandwich ruthe-
nium complexes.89–91 For these homogeneous catalysts,
strictly anhydrous and oxygen-free reaction conditions are
often required. Moreover, efficient procedures for separation and
recycling of the homogeneous catalysts are seldom available.
Heterogeneous catalysts, in general, enable easier recycling
by simple filtration. Several examples of heterogeneous
DKR processes have been reported in literature.35,92–96 The
majority of the heterogeneously catalyzed DKRs utilize tran-
sition metal, Brönsted or Lewis acid based racemization
catalysts.35,92–96 Furthermore, some of these heterogeneously
Scheme 5 DKR of rac-2 using RuIJOH)3/Al2O3 as the racemization catalyst
in combination with lipase AK yielding IJR)-1-oxo-indan-2-yl-butanoate
with high ee 92% and 90% conversion.8
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Table 2 One-pot sequence combining hydrogenation and DKR produc-
ing (R)-3 from 1 (1.2 mmol) over Pd/Al2O3 (2.0 mol%)
Entry
Solvent Acyl donora (equivalents)
Yieldb [%]
eeb,c [%]
1
2
3
4
5
MTBE
EA
EA
EA
EA
8 (3,7)
—
9 (1)
9 (2.5)
9 (4)d
52
34
33
40
51
28
90
91
86
86
Scheme 6 One-pot reaction sequence including: i) hydrogenation of 1; ii)
racemization of (S)-2 and (R)-2; iii) acylation of the formed (R)-2 with
acyl donor forming (R)-3.
a
Number of equivalents acyl donor related to the amount starting
b
c
material 1.
According to GC chromatogram.
ee
=
d
100·IJij(R)-3]-ij(S)-3])/IJij(R)-3] + ij(S)-3]). Added in portions.
was initially used with good results for the DKR, as reported
earlier,8 EA was here found more suitable for the one-pot
sequence with better dissolution properties for starting mate-
rial 1 compared to MTBE. The ether required surprisingly
long time to dissolve 1 at the desired concentrations and at
higher concentrations resulted in slightly hazy solutions, also
observed earlier in the hydrogenation reaction.9
The limiting step in the one-pot reaction appears to be, at
least partially, the hydrogenation of compound 1 to rac-2.
This was somewhat unexpected, as in the earlier work on
regioselective hydrogenation,9 a long reaction time (20 h)
resulted in high (>85%) conversion of 1. The high conversion
(>85%) in turn resulted in significantly decreased selectivity
(less than 40%) due to the consecutive hydrogenation of rac-2
In the one-pot sequence reactions using EA as the solvent
and trifluoroethyl butyrate (8) as the acyl donor, we observed,
not surprisingly, both the corresponding acetate and
butanoate products in 1.7 : 1, product ratios, respectively. In
previous work, Park and co-workers have reported the utiliza-
tion of EA in a dual role, both as an acetyl donor and a solvent,
in lipase catalyzed esterification reactions.97–99 Generally, a
significant molar excess of the solvent acting as the acetyl
donor compared to the amount of substrate drives the reac-
tion equilibrium heavily to the right without a substantial
backward reaction. In the one-pot sequence reactions investi-
gated here, the use of EA as the acetyl donor also proved fea-
sible at first, retaining the high product ee (>90% after 21 h)
value throughout the whole reaction (Table 2, entry 2) in the
absence of other acyl donors. For increasing the conversion
and yield, an activated acetyl donor was desirable. Therefore,
trifluoroethyl acetate (9) was added to the one-pot sequence
reaction mixture. By carrying out one-pot reactions with fur-
ther increased amounts of acyl donor, the yield consequently
increased as expected (Table 2, entries 3–5).
Fig. 1 2-Acetoxy-1-indanone concentration during the one-pot reac-
tions using ■ 93 mg, ○ 130 mg and ▲ 163 mg of lipase AK, 51.6–51.9
mg Pd/Al2O3, 89.5–90.1 mg RuIJOH)3/Al2O3 and 4 equivalents (550 μL)
of the acyl donor 9 at 40 °C.
To further study the advantages and limitations of the
one-pot reaction sequence, reactions with different enzyme
amounts (93, 130, and 163 mg) were performed. Changes in
the enzyme amount were expected to influence the reaction
rate of the lipase AK catalyzed resolution of the rac-2 interme-
diate to the acetylated end product (kA, Scheme 6). In order
to produce an efficient DKR type reaction, the ee value
should be kept as low as possible for compound 2. Therefore,
the change in the acetylation rate was consequently assumed
to influence the IJR)-2 : IJS)-2 ratio IJkA : kRS2). The rate by which
the acetylated end product was formed (kA) was, nevertheless,
influenced only slightly by the variation of the enzyme
amount (Fig. 1). Subsequently, the concentrations of the com-
ponents in the three separate one-pot reactions are similar.
One example of the kinetic curves obtained is shown in Fig. 2
(130 mg lipase AK). Conclusively, these results demonstrate
that the enzyme catalyzed resolution in the one-pot sequence
is not the rate limiting step and good kinetic resolution is
accomplished with the reaction conditions applied.
Fig.
2
Concentration profiles of
▼
1,2-indanedione,
■
2-hydroxy-1-indanone, ○ 2-acetoxy-1-indanone for one-pot reaction
using 51.6 mg Pd/Al2O3, 89.5 mg RuIJOH)3/Al2O3, 130 mg lipase AK and
4 equivalents (550 μL) of the acyl donor 9 at 40 °C.
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to diols.9 During the development of the one-pot reaction
sequence described here, the 2 mol% loading of Pd was consid-
ered to be sufficiently high for obtaining satisfactory reaction
rates while avoiding the diol formation from over hydrogenation.
Suppression of the consecutive hydrogenation to diols is particu-
larly essential in the one-pot approach where, in the presence of
an enzyme, lipase catalyzed acetylation of the isomeric alcohols
would result in undesired mixtures of acetylated products.
Additionally, also the racemization rate (rRS2) decreases
under the applied one-pot conditions resulting in increased
ee of the 2-hydroxy-1-indanone intermediate (Fig. 3).
The compounds present in the one-pot reaction sequence,
particularly the esterified product, appear to inhibit the
RuIJOH)3/Al2O3 racemization catalyst as shown in Fig. 3(A),
where ee of the intermediate compound 2 vs. the concentra-
tion of the 2-acetoxy-1-indanone end product exhibit linear
dependence. However, the amount of the enzyme catalyst is
not influencing the racemization rate. Similar observations
have been made in earlier studies, suggested to be a conse-
quence of the adsorption of the esters present in the reaction
mixture on the heterogeneous Ru catalyst surface active sites.8,43
Hence, in order to improve the conversion and yield and
to decrease the influence of the acyl donor (9) on the racemi-
zation catalyst activity, the acetyl donor was added in five
portions during the first two hours of the reaction, providing
the end product in 51% yield (according to GC). The stepwise
addition of the acyl donor also further enhanced the efficiency
of the racemization catalyst RuIJOH)3/Al2O3 to some degree.
Despite of this, the intermediate product 2 in the one-pot
sequence did not remain fully racemic throughout the reaction.
Thus, when the one-pot reaction sequence was carried out
according to the method described in the Experimental sec-
tion (see: 2.6 One-pot reaction sequence), acceptable yields
and high ee values of the product (Table 1) (R)-3 were
obtained. Overall, at least conceptually, combination of the
regioselective hydrogenation of 1 yielding rac-2 with the sub-
sequent DKR producing (R)-3 enables an efficient reaction
operation without the need for separation of the intermediate
hydrogenation product. Furthermore, the reductive reaction
conditions employed here enhance the efficiency of the DKR
of rac-2, eliminating the formation of the oxidized DKR
byproduct reported previously.8
For better understanding of the reaction network, kinetic
modelling of the one–pot process was performed with three
different concentrations of the enzyme.
The following rate equations were used:
khK1C1
r(h)

Pd
(1)
(2)
(3)
(4)
(5)
1 K1C1  KADCAD
kR3KR2KAEDCR2CAD
1 KR2CR2  KS2CS2  KAEDCAD
r(R2R3)

En
kS3KS2KAEDCS2CAD
1 KR2CR2  KS2CS2  KAEDCAD
r(S2S3)

En
kRSAKS2CS2
r(S2R2)


Ru
Ru
1 K CAD
AD
kRSAKR2CR2
r(R2S2)
Ru
Ru
1 K CAD
AD
In eqn (1) kh is a lumped constant containing also the
hydrogen concentration, C1 and K1 denote concentrations of
compound 1 and its adsorption coefficient on Pt. Besides the
reactant, also the acylation agent was assumed to be
adsorbed on the platinum surface with the adsorption coeffi-
cient KAD. This was included in the model due to the nature
of the acyl donor, which can block the catalyst surface,
thereby decreasing the catalyst activity. The enzymatic reac-
tions rIJR2→R3) and rIJS2→S3) were assumed to proceed by bind-
ing of both reagents in a mechanism conceptually similar to
sequential bisubstrate reactions. Finally, for the racemization
reactions, adsorptions of (R)-2 and (S)-2 were considered to
be inferior to the much stronger adsorption of the acyl
Fig. 3 (A) Enantiomeric excess (ee = 100·IJij(R)-3]-ij(S)-3])/IJij(R)-3] + ij(S)-3]))
of 2-hydroxy-1-indanone versus concentration of 2-acetoxy-
1-indanone in one-pot reactions using ■ 93 mg, ○ 130 mg and ▼ 163 mg
lipase AK; (B) enantiomeric excess (ee) of 2-hydroxy-1-indanone versus
2-hydroxy-1-indanone concentration in one-pot reactions using ■ 93 mg,
○ 130 mg and ▼ 163 mg lipase AK.
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donor. In eqn (1)–(5) ρRu, ρpd, ρEn etc., correspond to the bulk
densities of ruthenium, palladium and lipase, respectively.
The generation rates for the compounds can be subse-
quently written
to include the deactivation function101
C1  C1,
qdeact

(10)
C01  C1,
where C1 is the concentration of 1, C0 is the initial concen-
tration of the substrate 1, C1,∞ is the concentration at infinite
time, which was also considered as an adjustable parameter
in the data fitting.
1
dC1
dt
dCR2
dt
dCS2
dt
dCR3
dt
dCS3
dt

 r(h)
,
 r(R2R3)
,
 r(S2S3)
,
 0.5r(h)  r(R2R3)  r(R2S2)  r(S2R2)
(6)
The deactivation function, used in earlier work101 to
explain the activity profile in the hydrogenation of cyclo-
hexene, is based on the assumption that a decline in catalyst
activity is proportional to the amount of product formed and
could be related to catalyst fouling.
Calculations made with eqn (2)–(5) and (9) allowed further
simplifications but neglecting adsorption terms in denomina-
tors of all rate expressions. The final expressions for the reac-
tion rates are
 0.5r(h)  r(S2S3)  r(R2S2)  r(S2R2)
The kinetic modelling was performed for all reaction rates
and three reaction sets together. For the parameter estima-
tion, a set of differential equations describing the changes in
the concentration profiles of the reagents and products with
time was solved by means of ModEst software.100 Using
Levenberg–Marquardt simplex method, the target function,
which was defined as incompliance between the experimental
and calculated values of concentrations was used to solve the
system. The sum of the residual squares between the model
and the experimental data was minimized using the follow-
ing objective function;
C1  C1,
C01  C1,
C1  C1,
C01  C1,
r(h)  khK1C1Pd

 khPd
(11)
r(R2→R3) = kR3KR2KAEDCR2
C
ADρEn = k′R3CR2
C
ADρEn
(12)
(13)
(14)
(15)
2
2
Q  xexp  xest

x
 xest,it


(7)

exp,it
r(S2→S3) = − kS3KS2KAEDCS2CADρEn = kS′ 3CS2CADρEn
r(S2→R2) = kRSAKS2CS2ρRu = kR′ SACS2ρRu
t
i
where xexp is the experimental value and xest denotes the
predictions given by the model, i is the component index and
t is the time value. The quality of the fit and accuracy of the
model description was defined by the degree of explanation
R2; which reflects comparison between the residuals given by
the model to the residuals of the simplest model one may
think of, i.e., the average value of all the data points. The R2
value is given by the expression
r(R2→S2) = kRSAKR2 R2ρRu = kR′ SA
C CR2ρRu
The estimated values of the parameters as well as the rela-
tive standard errors (in %) are presented in Table 3. The fit
of the kinetic model to the experimental data for the three
different reactions is displayed Fig. 4.
2
y
y
model  yexperiment




R2 100
4 Conclusions
(8)
2
model  yexperiment
Combination of the regioselective heterogeneously catalysed
hydrogenation of the prochiral diketone 1,2-indandione with
dynamic kinetic resolution of the resulting rac-2-hydroxy-1-
indanone using a heterogeneous Ru catalyst for racemization
and an enzyme, lipase AK, for acylation, has been investi-
gated. A new, simple to operate one-pot reaction sequence
provides the valuable building block IJR)-2-acetoxy-1-indanone
in moderate enantiopurity (86–92%) in a reasonable reac-
tion time (20 h). In contrast to a multi-step reaction
approach in separate reactors, the one-pot, heterogeneously
Preliminary calculations demonstrated that the descrip-
tion of the hydrogenation reaction is mediocre due to strong
catalyst deactivation, which could not be sufficiently well
described assuming only adsorption of the acyl donor on Pd
surface acting as a catalyst poison.
In previous work,42 where also hydrogenation and
chemoenzymatic DKR were combined in a one-pot fashion,
the hydrogenation of acetophenone on palladium was found
to undergo strong deactivation, similar to the current case
where palladium is inhibited in the hydrogenation of com-
pound 1. For the sake of modelling, an empirical time depen-
dent function for the catalyst activity was proposed.42 Since a
physical meaning in such dependence is unclear it was
decided to use a more mechanistically based assumption.
The expression for hydrogenation was modified
Table 3 Estimated parameter values and the corresponding relative
standard error. Degree of explanation 92.94%
Parameter
Value
Relative standard error [%]
k′h [h−1
]
3.22
8.1
7.0
17.2
50.9
2.5
k′R3 [h−1
k′RSA [h−1
k′S3 [h−1
1,∞ [mol L−1
]
2.09 × 10−3
2.56 × 10−2
3.52 × 10−5
6.37 × 10−3
]
khK1C1
r(h)

Pdqdeact
(9)
]
1 K1C1  KADCAD
C
]
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Overall, the readily available 1,2-indanedione can be transferred
to a useful chiral building block with high regioselectivity and
moderate stereoselectivity using economically viable heteroge-
neous catalysts in a practical catalytic operation.
Acknowledgements
The authors thank Alexey Kirilin (Laboratory of Industrial
Chemistry and Reaction Engineering, Åbo Akademi
University) for preparation of the RuIJOH)3/Al2O3 catalyst
and temperature programmed reduction analyses. The
authors also thank Sten Lindholm (Laboratory of Analytical
Chemistry, Åbo Akademi University) for ICP analyses, Päivi
Mäki-Arvela (Laboratory of Industrial Chemistry and Reaction
Engineering, Åbo Akademi University) for the CO pulse
chemisorption analyses, Atte Aho (Laboratory of Industrial
Chemistry and Reaction Engineering, Åbo Akademi
University) for nitrogen physisorpiton analyses and Krisztian
Kordas and Anne-Riikka Leino (Microelectronics and
Materials Physics Laboratories, Department of Electrical and
Information Engineering, University of Oulu) for the HRTEM
analyses. The Magnus Ehrnrooth foundation, Makarna
Olins Stipendiefond at the Student Union of Åbo Akademi
University and Rector of Åbo Akademi University are
gratefully acknowledged for the financial support to OL.
Notes and references
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