Palladium-catalyzed diastereoselective hydrogenation of N-substituted 3-methyleneisoindolin-1-ones

Article abstract of DOI:10.1007/s11172-012-0154-y

An asymmetric synthesis of chiral N-substituted 3-methylisoindolin-1-ones was performed using the Pd⁰-catalyzed diastereoselective hydrogenation of their 3-methylene-substituted precursors, that has not been investigated earlier. The highest diastereoselectivity (67% de) was achieved when the hydrogenation was carried out in methanol mediated by a palladium catalyst (Pd/C) modified with cinchonidine.

Full text of DOI:10.1007/s11172-012-0154-y

Russian Chemical Bulletin, International Edition, Vol. 61, No. 6, pp. 1133—1137, June, 2012
1133
Palladiumꢀcatalyzed diastereoselective hydrogenation
of Nꢀsubstituted 3ꢀmethyleneisoindolinꢀ1ꢀones
Zh. R. Sagirova, E. V. Starodubtseva, O. V. Turova, and M. G. Vinogradov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: ving@ioc.ac.ru
An asymmetric synthesis of chiral Nꢀsubstituted 3ꢀmethylisoindolinꢀ1ꢀones was performed
using the Pd0ꢀ catalyzed diastereoselective hydrogenation of their 3ꢀmethyleneꢀsubstituted
precursors, that has not been investigated earlier. The highest diastereoselectivity (67% de) was
achieved when the hydrogenation was carried out in methanol mediated by a palladium catalyst
(Pd/C) modified with cinchonidine.
Key words: asymmetric synthesis, diastereoselective hydrogenation, Pd0, chiral Nꢀsubstiꢀ
tuted 3ꢀmethylisoindolinꢀ1ꢀones.
NꢀSubstituted isoindolinꢀ1ꢀones are structural blocks
of a number of natural alkaloids such as neuvamine1 (1),
chilenine2 (2), deoxychilenine3 (3), magallanesine4 (4).
They are also of interest for the preparation of neurolepꢀ
tics, for example, pasinoclone5 (5) and pagoclone6 (6),
enzyme inhibitors, for example, 7—9,7—9 as well as vasoꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1124—1128, June, 2012.
1066ꢀ5285/12/6106ꢀ1133 © 2012 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Sagirova et al.
20
dilatory, anesthetic, antiꢀulcer agents, and other pharmaꢀ
ceutically actives compounds.10,11 In addition, isoindoꢀ
linꢀ1ꢀones with the C(3)ꢀstereogenic center can be used as
efficient chiral inductors in asymmetric synthesis, for exꢀ
ample, in the Diels—Alder reaction.12 Therefore, develꢀ
opment of new, convenient approaches to the synthesis of
substituted chiral isoindolinꢀ1ꢀones is a relevant problem.
Several methods for the asymmetric synthesis of Nꢀsubꢀ
stituted 3ꢀalkylisoindolinꢀ1ꢀones are known. They are
based on the cyclization reactions of the enamides of
a iodoꢀsubstituted aromatic carboxylic acid catalyzed by
chiral palladium complexes (the intramolecular Heck reꢀ
action);11 cyclocondensation of dilithiated Nꢀacylꢀsubstiꢀ
tuted chiral benzylamines with dialkyl carbonate;12 alkylaꢀ
tion with organometallic reagents of the C=O bond of
phthalimide containing a chiral inductor at the nitrogen
atom;13—16 and on the reaction of phthalic dialdehyde
with a chiral amine with subsequent diastereoselective
electrophilic alkylation of the isoindolinone fragment.17
However, the methods outlined above include application
of the stoichiometric amounts of organometallic reagents,
and vigorous conditions are required for certain steps, at
which racemization of the intermediate or the target chiral
compounds can occur. In addition, the yields of the target
product calculated on the starting substrate, as a rule, are
not very high. In this respect, the asymmetric catalysis, in
particular, a diastereoselective hydrogenation, has an adꢀ
vantage, allowing one to obtain optically active products
from prochiral substrates with high conversion in one step.
The objective of the present work was to study catalytꢀ
ic diastereoselective hydrogenation as a new efficient apꢀ
proach to heterocyclic synthons containing a chiral isoinꢀ
dolinone fragment. As the substrates, we used unsaturated
precursors with a chiral substituent at the nitrogen atom,
derived from available (S)ꢀ1ꢀphenylethylamine or (R)ꢀ1ꢀ
(1ꢀnaphthyl)ethylamine. The hydrogenation catalyst was
Pd0 on a highly porous carbon support Sibunit. The studꢀ
ies included development of a convenient procedure for
the preparation of the starting prochiral substrates, as well
as investigation of influence of hydrogenation parameters
and modification of the palladium catalyst on diastereoꢀ
selectivity of the process.
CH2Cl2), whereas for the mixture of diastereomers, []D
–18 (c 1, CH2Cl2). It is obvious that the isolated isomer
was a minor component of the mixture. The cyclic strucꢀ
ture of amide 11a was confirmed by H and 13C NMR
1
spectroscopy. The 1H NMR spectrum of the minor hydrꢀ
oxylactam 11a exhibited chemical shifts for the protons of
the methyl and hydroxyl groups at  1.64 and 2.40, respecꢀ
tively. In the 13C NMR spectrum, the chemical shift
(89.70) yielded by the minor isomer indicated the presꢀ
ence of the quaternary carbon atom C(3). In the 13C NMR
spectrum of the mixture of diastereomers, the signal for
the atom C(3) of the predominant isomer overlaped with
the signal of the minor isomer.
Scheme 1
Dehydration of hydroxylactams 11 was performed
without preliminary separation of the diastereomers under
various conditions. The dehydration in the presence of
P2O5 or in aqueous HCl (see Refs 16 and 18) has proved
inefficient because side products were formed in considerꢀ
able amounts. At the same time, in the system EtONa—
EtOH the dehydration was selective, this procedure has
not been used earlier for the preparation of alkylideneisoinꢀ
dolinones from hydroxylactams of the type 11. The develꢀ
oped procedure allowed us to synthesize methyleneisoinꢀ
dolinones 12 in quantitative yields.
Studies of the diastereoselective hydrogenation of subꢀ
strates 12 showed that the nature of the solvent influenced
both the rate and the diastereoselectivity of the reaction.
The solvent effect was compared for the complete converꢀ
sion of substrate 12a (Table 1). In polar solvents (aqueous
dioxane, alcohols), the reaction proceeded with comparaꢀ
bly low diastereoselectivity (20—30% de). The highest de
Results and Discussion
NꢀSubstituted 3ꢀmethyleneisoindolinꢀ1ꢀones were
synthesized from commercially available oꢀacetylbenzoic
acid (10) in two steps (Scheme 1). In the first step, the
mixed anhydrides method was used to obtain hydroxyꢀ
lactam 11 in 95% yield from the keto acid as a mixture of
two diastereomers in the ratio of 2 : 1. Hydroxylactam 11
is thermodynamically more stable form of the amide as
compared to the acyclic form. Using fractional crystalliꢀ
zation, we successfully isolated one of the diastereomers
20
11a, rotational angle of which was []D +89 (c 0.75,

Hydrogenation of 3ꢀmethyleneisoindolinꢀ1ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1135
Table 1. Diastereoselective hydrogenation of substrates 12a,ba
Entry Substrate
Solvent
/h deb (%)
1
2
3
12а
12а
12а
Toluene
Dioxane
Dioxane—H2O
(2.5 vol.%)
Methanol
Ethanol
Trifluoroethanol
Toluene
2
4
2
46
<5
20
4
5
6
7
12а
12а
12а
12bс
1
1
1
7
28
32
20
30
a The catalyst: Pd(1%)/Sibunit, the molar ratio 12a/Pd = 200,
[12] = 0.13 mol L–1; 20 atm. H2, 45 C. The conversion of
compound 12 in all the experiments was 100%.
b According to the 1H NMR data.
Table 2. Diastereoselective hydrogenation of substrates 12a,b on
a Pd/Sibunit catalyst modified with chiral aminoalcohols A—D*
c 12b/Pd = 100, T = 60 C.
Entry Substrate Modiꢀ
ficator
Solvent
Conversion de
value (46%) was achieved when the hydrogenation of the
substrate was carried out in toluene (see Table 1, entry 1).
A suggestion might be made that the introduction of
more bulky 1ꢀ(1ꢀnaphthyl)ethyl substituent at the nitroꢀ
gen atom could lead to an increase in diastereoselectivity.
However, when the hydrogenation of this substrate was
carried out in toluene, a significant decrease in the de
values and retardation of the reaction took place as comꢀ
pared to the hydrogenation of substrate 12a (see Table 1,
cf. entries 1 and 7).
%
1
2
12а
12а
A
A
Toluene
Dioxane—H2O
(2.5 vol.%)
Methanol
167
190
55
60
3
4
5
6
7
12а
12а
12а
12а
12b
A
B
C
D
A
100
100
100
100
100
67
57
55
38
50
Methanol
Methanol
Methanol
Methanol
Diastereoisomers 13a were separated by column chroꢀ
matography which resulted in the isolation of the predomꢀ
inant levorotatory diastereoisomer as an individual comꢀ
pound, []D20 –58 (c 0.8, CH2Cl2).
In order to further increase diastereoselectivity of
hydrogenation of substrate 12a, we studied a possibility of
modification of the catalyst with chiral aminoalcohols
capable of adopting coordination to palladium.
* The molar ratio 12/Pd = 100, modificator/Pd = 2, [12] =
= 0.13 mol L–1; 20 atm. H2, 60 C, 20 h.
the palladium catalyst modified with cinchonidine was
used. This reaction is a new, convenient approach to the
synthesis of heterocyclic synthons containing a chiral
isoindolinone fragment.
As it is seen from Table 2, the modification of the
catalyst with chiral aminoalcohols caused an increase in
stereoselectivity of hydrogenation. As in the cases of
Pdꢀcatalyzed hydrogenation of unsaturated carboxylic
acids, (–)ꢀcinchonidine turned out to be the most effiꢀ
cient modificator.19—24
Modification of the catalyst leads to a decrease in the
reaction rate. The reduction of catalytic activity appears
to be a result of complexation with cinchonidine (the comꢀ
plete conversion was reached within 20 h in MeOH at
60 C). The diastereoselectivity of the reaction increased
in both nonpolar medium (toluene) and polar solvents
(aqueous dioxane, methanol). The highest de value (67%)
for the hydrogenation of substrate 12a was achieved in
methanol (see Table 2, entry 3).
Experimental
Commercially available 2ꢀacetylbenzoic acid, (R)ꢀ(+)ꢀ1ꢀ(1ꢀ
naphthyl)ethylamine, (R)ꢀ(–)ꢀ2ꢀphenylglycinol, (1R,2S)ꢀ(–)ꢀ
2ꢀmethylaminoꢀ1ꢀphenylꢀ1ꢀpropanol hydrochloride (Acros),
ethyl chloroformate (Aldrich), (S)ꢀ(–)ꢀ1ꢀethylꢀ1ꢀphenylamine
(Zeeland Chemicals, INC), (–)ꢀcinchonidine (Fluka), (S)ꢀ(–)ꢀ
3ꢀdimethylaminoꢀ1ꢀphenylpropanꢀ1ꢀol hydrochloride, metallic
sodium, and Pd(1%)/Sibunit were used without additional puriꢀ
fication.
Methanol was dried by reflux over magnesium with subseꢀ
quent distillation under argon; ethanol was refluxed over calciꢀ
um with subsequent distillation under argon; toluene and THF
were refluxed over sodium in the presence of benzophenone
under argon with subsequent distillation; triethylamine was reꢀ
fluxed over potassium hydroxide with subsequent distillation.
Melting points were measured on a Kofler heating stage. 1H
and 13C NMR spectra were recorded on Bruker AMꢀ300 and
Bruker DRXꢀ500 spectrometers (300.13, 500.13 (1H) and 75.47
To summon up, we are the first to study a diastereoꢀ
selective hydrogenation of Nꢀsubstituted 3ꢀmethyleneꢀ
isoindolinꢀ1ꢀones in the presence of Pd0 on a carbon supꢀ
port. The highest diastereoselectivity was achieved when
(
13C) MHz) in CDCl3, using Me4Si as an internal standard.

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Sagirova et al.
IR spectra were recorded on a Specord Mꢀ82 spectrometer (in
KBr pellets). High resolution mass spectra (ESI) were acquired
using a MicrOTOF II (Bruker Daltonics) instrument. Elemental
analysis was performed on a Perkin—Elmer Series II 2400
analyzer. Angles of optical rotation of the hydrogenation prodꢀ
ucts were measured on a Spectropolyarimetr PUꢀ12 instrument.
(3R)ꢀ and (3S)ꢀ3ꢀHydroxyꢀ3ꢀmethylꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]ꢀ
isoindolinꢀ1ꢀone (11a). Amidation of keto acid 10 was performed
by the mixed anhydrides method similarly to the procedure deꢀ
scribed earlier.25 Triethylamine (8.5 mL, 60.9 mmol) and ethyl
chloroformate (5.9 mL, 60.9 mmol) were added dropwise to
a stirred solution of 2ꢀacetylbenzoic acid (10 g, 60.9 mmol) in
THF (150 mL) cooled in an iceꢀwater bath, and the reaction
mixture was stirred for another 20 min. After addition of (S)ꢀ(–)ꢀ
1ꢀethylꢀ1ꢀphenylamine (6.7 mL, 60.9 mmol), the mixture was
stirred at ~20 C for 5 h. A precipitate formed was filtered off
and the solvent was evaporated. Combined precipitates were
dissolved in CH2Cl2, the solution was sequentially washed
with water, aqueous sodium bicarbonate, water, and saturated
aq. NaCl. The organic layer was dried with MgSO4 and the
drying agent was filtered off. The filtrate on standing yielded
white crystals (1.5 g) of the minor diastereoisomer 11a. The
remaining solution was concentrated and the residue was recrysꢀ
tallized from ethyl acetate. The main product was a mixture of
diastereomers (14 g) in the ratio ~2 : 1. The total yield was 15.5 g
(95%), m.p. 154—156 C (cf. Ref. 16: m.p. 69—73 C),
[]D20 –18 (c 1, CH2Cl2). Found (%): C, 76.34; H, 6.67; N, 5.20.
C17H17NO2. Calculated (%): C, 76.38; H, 6.41; N, 5.24.
1H NMR (CDCl3), : 1.60, 1.70 (both s, 3 H, C(OH)CH3); 1.92,
1.93 (both d, 3 H, CH(N)CH3, J = 7.3 Hz (predominant isoꢀ
mer), J = 7.2 Hz (minor isomer)); 2.80, 3.00 (both s, 1 H, OH);
5.00 (m, 1 H, CH(N)CH3); 7.10—7.35 (m, 5 H, Ph); 7.40—7.75
(m, 4 H, Ph). 13C NMR (CDCl3), : 18.4, 20.8 (CH(N)CH3);
24.8, 24.9 (C(OH)CH3); 50.8, 51.7 (CH(N)CH3); 89.6, 89.7
(C(OH)CH3); 121.4—124.5 (Ph); 127.0—128.5 (Ph); 129.7—132.3
(Ph); 142.0, 143.1 (Ph); 147.6, 147.8 (Ph); 166.4, 166.9 (C=O).
IR, /cm–1: 3207 (OH), 1666 (NC=O), 1343 (CH), 772 (oꢀPh).
Found: m/z 267.1335 [M]+. Calculated: M = 267.3224. Minor
diastereoisomer: m.p. 167—169 C, []D20 +89 (c 0.75, CH2Cl2).
1H NMR (CDCl3), : 1.64 (s, 3 H, C(OH)CH3); 1.96 (d, 3 H,
CH(N)CH3, J = 7.2 Hz); 2.40 (br.s, 1 H, OH); 5.00 (q, 1 H,
CH(N)CH3, J = 7.2 Hz); 7.22—7.35 (m, 5 H, Ph); 7.47—7.60
(m, 3 H, Ph); 7.78 (d, 1 H, Ph, J = 7.2 Hz). 13C NMR (CDCl3),
: 20.9 (CH(N)CH3); 24.9 (C(OH)CH3); 51.8 (CH(N)CH3);
89.7 (C(OH)CH3); 121.4—124.5 (Ph); 127.0—128.5 (Ph);
129.7—132.3 (Ph); 143.1 (Ph); 147.6 (Ph); 166.9 (C=O).
91.1 (C(OH)CH3); 121.1—148.6 (Ar); 166.8 (C=O). IR, /cm–1
:
3312 (OH), 1667 (NC=O). Found: m/z 317.1320 [M]+. Calcuꢀ
lated: M = 317.3181.
3ꢀMethyleneꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]isoindolinꢀ1ꢀone (12a).
Sodium ethoxide was used for the dehydration. Metallic sodium
(344 mg, 1.5 mgꢀat.) was gradually dissolved in anhydrous EtOH
(60 mL) under argon, followed by addition of hydroxylactam
11a (2 g, 7.48 mmol), and the mixture was refluxed for 7 h under
argon. Then, ethanol was evaporated, the residue was dissolved
in CH2Cl2 and neutralized with 0.1 M aq. HCl, the organic layer
was separated, whereas the aqueous layer was extracted with
CH2Cl2. The combined extracts were washed with water and
saturated aq. NaCl, dried with MgSO4. Pure product as a light
yellow oil was obtained after evaporation of the solvent. The
yield was 1.8 g (97%). Found (%): C, 81.34; H, 6.54; N, 5.35.
C17H15NO. Calculated (%): C, 81.90; H, 6.06; N, 5.62. 1H NMR
(CDCl3), : 1.88 (d, 3 H, CH(N)CH3, J = 7.2 Hz), 4.60, 5.09
(both s, 2 H, C=CH2); 5.95 (q, 1 H, CH(N)CH3, J = 7.2 Hz);
7.35 (m, 5 H, Ph); 7.58 (m, 3 H, Ph); 7.89 (d, 1 H, Ph, J = 7.2 Hz).
13C NMR (CDCl3), : 17.0 (CH(N)CH3); 48.8 (CH(N)CH3);
91.6 (C=CH2); 119.6—140.3 (Ar); 131.9 (C=CH2); 167.3 (C=O).
Found: m/z 249.1229 [M]+. Calculated: M = 249.3071.
3ꢀMethyleneꢀ2ꢀ[(1R)ꢀ1ꢀ(1ꢀnaphthyl)ethyl]isoindolinꢀ1ꢀone
(12b). The substrate was obtained by dehydration of hydroxyꢀ
lactam 11b (470 mg, 1.48 mmol) according to the procedure
given above for the synthesis of compound 12a. The yield of the
pure product (a light yellow oil) was 420 mg (95%). Found (%):
C, 82.01; H, 5.77; N, 4.48. C17H15NO. Calculated (%): C, 84.25;
H, 5.72; N, 4.68. 1H NMR (CDCl3), : 2.05 (d, 3 H, CH(N)CH3,
J = 7.0 Hz); 4.76, 4.95 (both s, 2 H, C=CH2); 6.55 (q, 1 H,
CH(N)CH3, J = 7.0 Hz); 7.50 (m, 6 H, naphthyl); 7.84 (m, 4 H,
Ar); 8.08 (m, 1 H, Ph). 13C NMR (CDCl3), : 17.5 (CH(N)CH3);
47.1 (CH(N)CH3); 91.8 (C=CH2); 119.6—140.2 (Ar); 135.8
(C=CH2); 167.3 (C=O). IR, /cm–1: 1703 (NC=O), 1639
(=CH2), 780 (oꢀPh). Found: m/z 299.1204 [M]+. Calculated:
M = 299.3658.
Diastereoselective catalytic hydrogenation of enamides 12a,b.
A. The catalyst Pd(1%)/Sibunit (21.3 mg, 0.0020 mgꢀat. of Pd)
was placed into a preꢀevacuated glass tube for hydrogenation
filled with argon, which was then reꢀevacuated and refilled with
argon. A solution of substrate (0.4011 mmol) in an appropriate
solvent (3 mL) was added to the catalyst, and the tube was placed
into an autoclave made of stainless steel (50 cm3), preliminary
filled with argon. The autoclave was purged with purified hydroꢀ
gen, and the pressure of H2 was increased to 20 atm. Then, the
reaction mixture was stirred at a desired temperature using
a magnetic stirrer. After the experiment was completed, the solꢀ
vent was evaporated, the residue was dissolved in ethyl acetate
and passed through a layer of silica gel. After the solvent was
evaporated on a rotary evaporator, the conversion of the subꢀ
strate and the de value were determined by 1H NMR.
B (diastereoselective hydrogenation of substrate 12a in the
presence of modificators). The catalyst (21.3 mg, 0.0020 mgꢀat.
of Pd) and a modificator (0.0040 mmol) were placed into a glass
tube for hydrogenation, which then was evacuated and filled with
argon, followed by addition of anhydrous methanol (1.5 mL). In
the case when aminoalcohol hydrochlorides were used as modifꢀ
icators, HCl was neutralized with the equimolar amount of triꢀ
ethylamine. Then, the reaction mixture was stirred for 30 min
under argon at ~20 C, followed by addition of the substrate
(0.1000 mmol) in anhydrous methanol (1.5 mL) and the tube
(3S)ꢀ and (3R)ꢀ3ꢀHydroxyꢀ3ꢀmethylꢀ2ꢀ[(1R)ꢀ1ꢀ(1ꢀnaphthꢀ
yl)ethyl]isoindolinꢀ1ꢀone (11b). The synthesis was carried out
starting from keto acid 10 and (R)ꢀ(+)ꢀ1ꢀ(naphthꢀ1ꢀyl)ethylꢀ
amine according to the procedure given above for the preparaꢀ
tion of hydroxylactam 11a. The yield was 2.6 g (70%), m.p.
162—164 C, a mixture of diastereomers in the ratio ~3 : 1.
Found (%): C, 77.81; H, 5.71; N, 4.18. C17H15NO. Calculatꢀ
1
ed (%): C, 79.47; H, 6.03; N, 4.41. H NMR (CDCl3), : 1.09,
1.55 (both s, 3 H, C(OH)CH3); 2.03, 2.06 (both d, 3 H,
CH(N)CH3, J = 7.1 Hz (predominant isomer), J = 7.0 Hz (miꢀ
nor isomer)); 6.07, 6.30 (both q, 1 H, CH(N)CH3, J = 7.1 Hz
(minor isomer), J = 7.0 Hz (predominant isomer)); 7.40—7.55
(m, 7 H, naphthyl); 7.85 (m, 2 H, Ph); 8.00 (d, 1 H, Ph, J = 7.2 Hz);
8.10, 8.18 (both d, 1 H, oꢀPh, J = 8.1 Hz). 13C NMR (CDCl3),
: 19.7 (CH(N)CH3); 25.2 (C(OH)CH3); 46.8 (CH(N)CH3);

Hydrogenation of 3ꢀmethyleneisoindolinꢀ1ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1137
was placed into an autoclave, which was preliminary filled with
argon. The autoclave was purged with purified hydrogen, and
the pressure of H2 was increased to 20 atm. Then, the reaction
mixture was stirred using a magnetic stirrer for 20 h at 60 C. The
workꢀup operations were performed as described in procedure A.
(3R)ꢀ and (3S)ꢀ3ꢀMethylꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]isoindolinꢀ
1ꢀone (a mixture of two diastereomers 13a). 1H NMR (CDCl3),
: 1.11, 1.41 (both d, 3 H, CH(N)CH3, J = 7.2 Hz (minor isomer),
J = 7.2 Hz (predominant isomer)); 1.80 (m, 3 H, CH3CHPh);
4.25, 4.59 (both q, 1 H, CHCH3, J = 7.2 Hz (predominant
isomer), J = 7.2 Hz (minor isomer)); 5.70 (m, 1 H, CH3CHPh);
7.25—7.55 (m, 8 H, Ar); 7.87 (m, 1 H, oꢀPh). 13C NMR (CDCl3),
: 17.4 (CHCH3 (minor isomer)); 18.6 (CHCH3 (predominant
isomer)); 20.1 (CH(N)CH3 (minor isomer)); 20.7 (CH(N)CH3
(predominant isomer)); 49.6 (CHCH3 (minor isomer)); 50.8
(CHCH3 (predominant isomer)); 55.3 (CH(N)CH3 (minor isoꢀ
mer)); 55.7 (CH(N)CH3 (predominant isomer)); 121.9—147.4
(Ar); 168.6 (C=O).
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13. E. Deniau, D. Enders, A. Couture, P. Grandclaudon, Tetraꢀ
hedron: asymmetry, 2003, 14, 2253.
14. A. A. Bahajaj, J. M. Vernon, G. D. Wilson, Tetrahedron,
2004, 60, 1247.
15. M.ꢀD. Chen, X. Zhou, M.ꢀZ. He, Y.ꢀP. Ruan, P.ꢀQ. Huang,
Tetrahedron, 2004, 60, 1651.
16. A. ChihabꢀEddine, A. Daich, A. Jilale, B. Decroix, Heteroꢀ
cycles, 2002, 58, 449.
17. J. PérardꢀViret, T. Prangé, A. Tomas, J. Royer, Tetrahedron,
2002, 58, 5103.
18. K. J. Kapples, G. M. Shutske, J. Heterocycl. Chem., 1997,
34, 1335.
19. Y. Nitta, J. Watanabe, T. Okuyama, T. Sugimura, J. Catalyꢀ
sis, 2005, 236, 164.
20. T. Sugimura, J. Watanabe, T. Okuyama, Y. Nitta, Tetraꢀ
hedron: asymmetry, 2005, 16, 1573.
21. G. Szöllõsi, S.ꢀI. Niwa, T. A. Hanaoka, F. Mizukami, J. Mol.
Catal. A: Chem., 2005, 230, 91.
Chromatographic separation of diastereomers 13a. The comꢀ
pound was subjected to chromatography on a column (51×1.4 cm)
filled with silica gelꢀ60, eluent light petroleum—ethyl acetate
(5 : 1). The column was loaded with 200 mg of the product to
eventually isolate 75 mg of the predominant diastereomer.
(–)ꢀ3ꢀMethylꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]isoindolinꢀ1ꢀone (preꢀ
20
dominant diastereoisomer 13a), light yellow oil, []D –58
(c 0.8, CH2Cl2). 1H NMR (CDCl3), : 1.43 (d, 3 H, CH(N)CH3,
J = 7.2 Hz); 1.80 (d, 3 H, CH3CHPh, J = 7.2 Hz); 4.25 (q, 1 H,
CHCH3, J = 7.2 Hz); 5.70 (q, 1 H, CH3CHPh, J = 7.2 Hz); 7.3
(m, 5 H, Ph); 7.5 (m, 3 H, Ph); 7.86 (d, 1 H, oꢀPh, J = 7.2 Hz).
13C NMR (CDCl3), : 18.6 (CHCH3); 20.7 (CH(N)CH3); 50.8
(CHCH3); 55.7 (CH(N)CH3); 121.9—147.4 (Ar); 168.6 (C=O).
(3S)ꢀ and (3R)ꢀ3ꢀMethylꢀ2ꢀ[(1R)ꢀ1ꢀ(1ꢀnaphthyl)ethyl]ꢀ
isoindolinꢀ1ꢀone (a mixture of two diastereomers 13b), light
yellow oil. 1H NMR (CDCl3), : 0.50, 1.41 (both d, 3 H, CHCH3,
J = 6.6 Hz (minor isomer), J = 6.7 Hz (predominant isomer));
1.80, 1.92 (both d, 3 H, CH(N)CH3, J = 6.9 Hz (minor isomer),
J = 7.0 Hz (predominant isomer)); 3.71, 4.64 (both q, 1 H,
CHCH3, J = 6.6 Hz (predominant isomer), J = 6.6 Hz (minor
isomer)); 6.37, 6.55 (both q, 1 H, CH(N)CH3, J = 6.6 Hz (preꢀ
dominant isomer), J = 7.1 Hz (minor isomer)); 7.40—8.35 (m,
11 H, Ar).
22. G. Szöllõsi, R. Balázsik, M. Bartók, Appl. Catal. A: General,
2007, 319, 193.
23. G. Szöllõsi, T. Varga, K. Felföldi, S. Cserényi, M. Bartók,
Catal. Commun., 2008, 9, 421.
24. M. Maris, W.ꢀR. Huck, T. Mallat, A. Baiker, J. Catalysis,
2003, 219, 52.
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Received December 20, 2011;
in revised form April 24, 2012