Hydrogenolysis of the C-O bond of hydroxylactams as a convenient method for the synthesis of substituted isoindolin-1-ones

Article abstract of DOI:10.1007/s11172-013-0137-7

A simple and efficient method for the synthesis of isoindolin-1-ones containing alkyl or aryl substituents at positions 2 and (or) 3 was suggested. The method is based on the earlier unknown Pd⁰-catalyzed hydrogenolysis of hydroxylactams.

Full text of DOI:10.1007/s11172-013-0137-7

Russian Chemical Bulletin, International Edition, Vol. 62, No. 4, pp. 1032—1037, April, 2013
1032
Hydrogenolysis of the C—O bond of hydroxylactams as a convenient
method for the synthesis of substituted isoindolinꢀ1ꢀones
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
A simple and efficient method for the synthesis of isoindolinꢀ1ꢀones containing alkyl or aryl
substituents at positions 2 and (or) 3 was suggested. The method is based on the earlier unknown
Pd0ꢀcatalyzed hydrogenolysis of hydroxylactams.
Key words: hydroxylactams, monoꢀ and disubstituted isoindolinꢀ1ꢀones, C—Oꢀhydroꢀ
genolysis, palladium catalyst.
Alkylꢀ and arylꢀsubstituted isoindolinꢀ1ꢀones are strucꢀ
hydride reduction of which gives the target 3ꢀalkylꢀ or
3ꢀarylꢀsubstituted isoindolinꢀ1ꢀones. To accomplish these
transformations, twoꢀ or threeꢀcomponent systems such
tural fragments of a number of natural alkaloids.1—4 They
are also of interest as synthons for the preparation of new
potential neuroleptics,5,6 enzyme inhibitors,7—9 and other
pharmacologically active compounds.10,11 Relatively readily
available hydroxylactams (A) commonly obtained by the
addition of Grignard reagents to one of the carbonyl groups
of phthalimide can be used as the intermediates in the
synthesis of substituted isoindolinꢀ1ꢀones (Scheme 1).
as
BF3—Et3SiH,12,13
TsOH—TiCl4—Et3SiH,14
CF3COOH—Et3SiH,15—17 CF3COOH—NaCNBH3,18 or
HCl—NaCNBH3 were used.18 A disadvantage of this twoꢀ
step reduction is the need to use a considerable (up to
fivefold) excess of the hydride agent with respect to hydrꢀ
oxylactam A. Besides, a high acidity of the reaction mediꢀ
um can cause undesired side processes.
Recently, a possibility of the palladiumꢀcatalyzed hyꢀ
drogenolysis of benzyl alcohols or their esters using
triethylsilane19 or polymethylhydrosiloxane as the hydride
donors was shown.20 In the present work, we report the
first examples of the palladiumꢀcatalyzed hydrogenolysis
of the C—O bond of hydroxylactams of the type A with
molecular hydrogen, which, to the best of our knowledge,
are not described in the literature.
Scheme 1
Results and Discussion
Amidation of methyl 2ꢀacetylbenzoate with ammonia
or lower amines R´NH2 (R´ = Me, Et) or amidation of
ketoacids 1 by the mixed anhydride method (Scheme 2)
gave hydroxylactams 2.
Hydroxylactams 2 are a cyclic form of amides derived
from 2ꢀacetylꢀ and 2ꢀbenzoylbenzoic acid (1a,b). For the
most substrates obtained, the cyclic form 2 is considerably
more stable than the openꢀchain form of the correspondꢀ
ing amides. Hydroxylactam 2b was synthesized by the adꢀ
dition of PhMgBr to phthalimide.21
In our earlier work22 dealt with hydrogenation of
3ꢀmethyleneisoindolinꢀ1ꢀones, Pd0 supported on the highly
porous carbon support sibunit was used as the catalyst.23
In the present work, we used the same catalyst for the
i. HX or Lewis acid; ii. Hydride reduction.
Treatment of hydroxylactams A with protonic or Lewis
acid leads to the intermediate acyliminium ions B,
* Dedicated to Academician of the Russian Academy of Sciences
I. P. Beletskaya on the occasion of her anniversary.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 1031—1036, April, 2013.
1066ꢀ5285/13/6204ꢀ1032 © 2013 Springer Science+Business Media, Inc.

Synthesis of substituted isoindolinꢀ1ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1033
Scheme 2
The most reactive substrates are the 2,3ꢀdisubstituted hyꢀ
droxylactams with bulky substituents at the nitrogen atom.
At the same time, under the standard conditions 3ꢀmethꢀ
ylꢀ and 2,3ꢀdimethylꢀsubstituted hydroxylactams 2a and
2c (R´ = H, CH3, respectively) showed a lower reactivity
as compared to the majority of substrates tested (entries 1
and 4). However, the addition of the acid cocatalyst (HCl)
made it possible to achieve a complete conversion of these
reagents at room temperature within 2 h (entries 2 and 6).
The reactivity of 3ꢀmethylꢀsubstituted hydroxylactams 2
was much higher as compared to that of 3ꢀphenylꢀsubꢀ
stituted substrates containing the same amide fragments
(cf. entries 7 and 8, 9 and 10, 14 and 15).
Unlike the most substrates obtained in the highly stable
cyclic form 2, the amidation of ꢀketoacid 1b with steriꢀ
cally hindered tertꢀbulylamine initially led to the formaꢀ
tion of the openꢀchain form of benzamide 4 as the only
initial product (Scheme 3).
R = Me (a), Ph (b)
studies of hydrogenolysis of hydroxylactams 2 (see Scheme 2).
We found that hydrogenolysis readily occurred in MeOH
at room temperature. For the most substrates under study,
the complete conversion in this solvent was reached within
2 h with the formation of isoindolinones 3 as the only
reaction products (Table 1). Hydrogenolysis in the nonꢀ
polar solvent toluene proceeded considerably slower than
in MeOH.
Scheme 3
Table 1 shows that the efficiency of hydrogenolysis
depends on the nature of substituents at positions 2 and 3.
Table 1. Synthesis of substituted isoindolinꢀ1ꢀones 3 by catalytic
hydrogenolysis of hydroxylactamsa
Entry Substrate
Substituents
/h
Conversion
(S)
of S (%)
R
R´
1
2a
2a
2b
2c
2c
2c
2d
2e
2f
2g
2h
2ic
4
Me
Me
Ph
Me
Me
Me
Me
Ph
H
H
H
Me
Me
Me
Et
Et
Bn
Bn
2
2
2
2
20
2
2
20
2
20
2
2
7
100
100
4
Nonetheless, it could be suggested that under condiꢀ
tions of Pdꢀcatalyzed reduction it would be possible for
the openꢀchain form of amide 4 to close the ring to yield
the cyclic form (lactam 2k) with subsequent hydrogenolysis
of the C—O bond of the latter. This suggestion was conꢀ
firmed experimentally (entry 13). The 1H NMRꢀmonitorꢀ
ing of the process of reduction of amide 4 in the presence
of Pd/C catalyst shows that in the reaction mixture amide
4 and hydroxylactam 2k are at equilibrium. In this case
both the conversion of the openꢀchain form of amide to
the cyclic configuration and subsequent hydrogenolysis of
2k are slow processes. After the reaction mixture was reꢀ
duced for 20 h, it contained the intermediate 2k and isoꢀ
indolinone 3k in the molar ratio 1 : 1.
By analogy with the reduction of hydroxylactams
of the type A by the systems acid—hydride agent that
involves the intermediate acyliminium ion B (see
Scheme 1),12—17 it can be assumed that hydrogenolysis of
substrates 2 in MeOH also follows the ionic mechaꢀ
nism, including a Pdꢀcatalyzed heterolysis of molecular
2b
3
4
5
6b
7
8
9
10
11
12
13
14
15
10
100
100
100
100
100
100
100
52
Me
Ph
Me
pꢀМеОꢀBn
Me (S)ꢀСН(Me)Ph
Ph
Me
Ph
But
20
2
20
2l
2m
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
100
50
a Reaction conditions: the substrate (S) (0.37 mmol), Pd(1%)/C,
the molar ratio S/Pd = 100, the solvent MeOH (3 mL), 20 atm
(H2), 22 C.
b A 1.38 M solution of HCl in dioxane (20 mol.% calculated on
the substrate) was added as a cocatalyst.
c Hydrogenolysis gave a mixture of two diastereoisomers 3i in
the ratio 1 : 1.

1034
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Sagirova et al.
hydrogen and the formation of the ionic intermediate D
(Scheme 4).
mechanism of hydrogenolysis is considered to be the
most probable.
Experimental
Scheme 4
Commercially available 2ꢀacetylbenzoic acid, 2ꢀbenzoylꢀ
benzoic acid, phthalimide, ethyl chloroformate, ammonia,
methylamine, ethylamine, benzylamine, pꢀmethoxybenzylꢀ
amine, anisidine, tertꢀbulylamine, bromobenzene (Aldrich),
(S)ꢀ(–)ꢀ1ꢀethylꢀ1ꢀphenylamine (Zeeland chemicals, INC), meꢀ
tallic sodium, magnesium turnings, Pd(1%)/sibunit were used
without preliminary purification. Methyl 2ꢀacetylbenzoate 1a
was synthesized according to the procedure published earlier.33
Methanol, ethanol, THF, diethyl ether, and triethylamine
were dried and distilled under argon.
Melting points were determined on a Kofler heating stage.
Flashꢀchromatography was performed on a column with silica
gel 60 (Fluka), using the system ethyl acetate—light petroleum
(2 : 1) as the eluent. 1H and 13C NMR spectra were recorded on
a Bruker AMꢀ300 spectrometer. High resolution mass spectra
(ESI) were recorded on a Bruker maXis instrument.34
3ꢀHydroxyꢀ3ꢀmethylisoindolinꢀ1ꢀone (2a). A solution of meꢀ
thyl 2ꢀacetylbenzoate (10 g, 0.06 mol) in methanol (150 mL) was
saturated with ammonia (9.5 g, 0.56 mol). The reaction mixture
was stirred for three weeks at ~20 C. The solvent was evaporatꢀ
ed, a solid residue was crystallized from ethyl acetate. Light
yellow crystals. The yield was 8.5 g (93%), m.p. 111—113 C
(cf. Ref. 35: m.p. 139—140 C). Found (%): C, 66.38; H, 5.59;
N, 8.65. C9H9NO2. Calculated (%): C, 66.25; H, 5.56; N, 8.58.
1H NMR (DMSOꢀd6), : 1.79 (s, 3 H, CH3); 3.98 (s, 1 H, OH);
7.18 (s, 1 H, NH); 7.31—7.45 (m, 1 H, Ph); 7.52 (d, 1 H, Ph,
J = 7.4 Hz); 7.58 (s, 2 H, Ph). 13C NMR (DMSOꢀd6), : 26.6;
84.8; 121.8; 122.3; 128.8; 131.0; 132.0; 150.5; 167.4. Found: m/z
186.0533 [M]+. Calculated: M = 186.1631.
3ꢀHydroxyꢀ3ꢀphenylisoindolinꢀ1ꢀone (2b). Magnesium turnꢀ
ings (0.7 g, 0.029 mol) were placed in a glass flask (100 mL),
a crystal of iodine was added, and the mixture was heated for 1 h
at 100 C under argon. After cooling, anhydrous diethyl ether
(30 mL) and one tenth of the required amount of PhBr (0.43 g,
0.003 mol) were added. After the reaction was initiated, the rest
of the solution of PhBr (3.87 g, 0.024 mol) in diethyl ether
(10 mL) was added dropwise, then the reaction mixture was
refluxed for 1 h with stirring. A solution of phthalimide (2 g,
0.014 mol) in anhydrous THF (20 mL) was added dropwise to
the cooled (ice bath) Grignard reagent, and the mixture was
stirred for 3 h at ~20 C. After the solvent was evaporated, the
residue was dissolved in CH2Cl2, sequentially washed with satuꢀ
rated aqueous NH4Cl, NaHCO3, and NaCl, then dried with
MgSO4. The solvent was evaporated, the residue was purified by
column chromatography (silica gel), eluent ethyl acetate—light
petroleum (2 : 1). Rf = 0.73. White crystals. The yield was 0.9 g
(30%), m.p. 160—162 C (cf. Ref. 36: m.p. 164—165 C). Found (%):
C, 74.43; H, 4.95; N, 6.24. C14H11NO2. Calculated (%): C, 74.65;
H, 4.92; N, 6.22. 1H NMR (DMSOꢀd6), : 7.26—7.41 (m, 4 H,
Ph); 7.41—7.56 (m, 4 H, Ph); 7.65 (d, 1 H, Ph, J = 7.1 Hz); 9.23
(s, 1 H, OH). 13C NMR (DMSOꢀd6), : 87.3; 122.5; 122.8;
125.4; 127.7; 128.2; 128.9; 130.6; 132.3; 142.1; 150.8; 168.3.
Found: m/z 248.2391 [M]+. Calculated: M = 248.2384.
To confirm this suggestion, we carried out a Pdꢀcataꢀ
lyzed hydrogenolysis of hydroxylactam 2f in CD3OD and
determined the isotopic composition of the reaction prodꢀ
uct 3f. As we have shown24 earlier for the Ruꢀcatalyzed
reduction of methyl levulinate with molecular hydrogen in
MeOD, a rapid H/Dꢀexchange between the H2 and the
deuterated solvent was observed in the course of this reacꢀ
tion, most likely proceeding through the step of heterolyꢀ
sis of H2 on the metal complex. This exchange, in turn,
led to the isotopic enrichment of the reduction product,
resulting from the involvement of the active particles
Ru—D generated in MeOD by the H/Dꢀexchange in the
catalytic cycle. In the present work, a similar result was
obtained in the hydrogenolysis of substrate 2f in CD3OD
under conditions given in the note to the Table 1. In this
experiment, isoindolinone 3f isolated from the reaction
mixture contained (according to the 1H NMR data) 75%
of deuterium at position C(3). It is obvious that the hydroꢀ
genolysis process includes the heterolysis of the H2 moleꢀ
cules on Pd0 atoms (see Scheme 4, steps ii, iii) with the
formation of ionic intermediates D and E, which are inꢀ
volved in subsequent H/Dꢀexchange with deuteromethaꢀ
nol due to the rapid steps (iii—v) of the catalytic cycle
involving intermediates E—G. More recently, both the
experimental25—31 and the theoretical32 studies indicated
an important role of transition metal anionic complexes,
including Pd0 complexes, in the organic reactions cataꢀ
lyzed by metal complexes.
In conclusion, we developed a simple and convenient
method for the synthesis of 3ꢀsubstituted and 2,3ꢀdisubꢀ
stituted isoindolinꢀ1ꢀones based on the earlier unknown
reaction of hydrogenolysis of hydroxylactams. An ionic
3ꢀHydroxyꢀ2,3ꢀdimethylisoindolinꢀ1ꢀone (2c) was obtained
by the amidation of methyl ester of ketoacid 1a (10 g, 0.06 mol)

Synthesis of substituted isoindolinꢀ1ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1035
with methylamine (17.4 g, 0.56 mol) similarly to compound 2a.
White powder. The yield was 6.2 g (62%), m.p. 127—130 C
(cf. Ref. 37: m.p. 134—136 C). Found (%): C, 67.54; H, 6.21;
N, 7.82. C10H11NO2. Calculated (%): C, 67.78; H, 6.26; N, 7.90.
1H NMR (DMSOꢀd6), : 1.58 (s, 3 H, CH3—C(OH)); 2.88
(s, 3 H, NCH3); 6.21 (s, 1 H, OH); 7.42—7.55 (m, 1 H, Ph); 7.65
(s, 3 H, Ph). 13C NMR (DMSOꢀd6), : 22.8; 23.9; 87.2; 121.8;
122.1; 128.9; 130.7; 131.8; 148.9; 165.3. Found: m/z 200.0682
[M]+. Calculated: M = 200.1896.
2ꢀEthylꢀ3ꢀhydroxyꢀ3ꢀmethylisoindolinꢀ1ꢀone (2d) was obꢀ
tained by the amidation of methyl 2ꢀacetylbenzoate (10 g,
0.06 mol) with anhydrous ethylamine (25.2 g, 0.56 mol) similarꢀ
ly to compound 2a. White powder. The yield was 8.6 g (80%),
m.p. 124—126 C (cf. Ref. 35: m.p. 128—130 C). Found (%):
C, 69.23; H, 6.82; N, 7.27. C11H13NO2. Calculated (%):
C, 69.09; H, 6.85; N, 7.32. 1H NMR (DMSOꢀd6), : 1.28 (t, 3 H,
CH3, J = 7.2 Hz); 1.73 (s, 3 H, CH3); 2.85 (s, 1 H, OH); 3.32—3.44
(m, 1 H, CHaHbCH3); 3.45—3.60 (m, 1 H, CHaHbCH3);
7.41—7.50 (m, 1 H, Ph); 7.51—7.60 (m, 2 H, Ph); 7.67 (d, 1 H,
Ph, J = 7.4 Hz). 13C NMR (DMSOꢀd6), : 14.54; 24.9; 32.4;
87.8; 121.8; 122.0; 128.9; 130.7; 131.8; 135.3; 149.1. Found: m/z
214.0838 [M]+. Calculated: M = 214.2162.
2ꢀEthylꢀ3ꢀhydroxyꢀ3ꢀphenylisoindolinꢀ1ꢀone (2e). Triethylꢀ
amine (2.2 g, 0.02 mol) and ethyl chloroformate (2.4 g, 0.02 mol)
were sequentially added dropwise to a cooled (0 C) solution of
ketoacid 1b (5 g, 0.02 mol) in anhydrous THF (150 mL). Anꢀ
hydrous ethylamine (1 g, 0.02 mol) was added after 20 min. The
reaction mixture was stirred for 5 h at ~20 C. A white precipiꢀ
tate was filtered off and the solvent was evaporated. The comꢀ
bined precipitates were dissolved in CH2Cl2, the solution was
washed with water, saturated aq. NaHCO3, and brine and dried
with MgSO4. The solvent was evaporated, the residue was crysꢀ
tallized from ethanol. White crystals. The yield was 3 g (54%),
m.p. 168—170 C (cf. Ref. 38: m.p. 168—170 C). Found (%):
C, 76.51; H, 5.95; N, 5.55. C16H15NO2. Calculated (%): C, 75.87;
H, 5.97; N, 5.53. 1H NMR (DMSOꢀd6), : 1.00 (t, 3 H, CH3,
J = 7.2 Hz); 2.96—3.10 (m, 1 H, CHaHbCH3); 3.32—3.47
(m, 1 H, CHaHbCH3); 7.04 (s, 1 H, OH); 7.23 (d, 1 H, Ph,
J = 6.4 Hz); 7.33 (s, 5 H, Ph); 7.56—7.57 (m, 2 H, Ph); 7.71
(d, 1 H, Ph, J = 6.3 Hz). 13C NMR (DMSOꢀd6), : 14.0; 33.5;
90.5; 122.2; 122.6; 125.8; 127.9; 128.4; 129.0; 130.7; 132.3;
140.2; 149.6; 166.3. Found: m/z 276.0995 [M]+. Calculated:
M = 276.2856.
2ꢀBenzylꢀ3ꢀhydroxyꢀ3ꢀmethylisoindolinꢀ1ꢀone (2f) was obꢀ
tained from ketoacid 1a (10 g, 0.06 mol) and benzylamine (6.4 g,
0.06 mol) similarly to compound 2e. Crystallized from benzene.
Yellow crystals. The yield was 8.5 g (55%), m.p. 157—159 C
(cf. Ref. 35: m.p..166—168 C). Found (%): C, 75.96; H, 5.96;
N, 5.65. C16H15NO2. Calculated (%): C, 75.87; H, 5.97; N, 5.53.
1H NMR (DMSOꢀd6), : 1.43 (s, 3 H, CH3); 4.45 (d, 1 H,
CHaHb, J = 15.9 Hz); 4.79 (d, 1 H, CHaHb, J = 15.9 Hz); 6.42
(s, 1 H, OH); 7.20—7.37 (m, 5 H, Ph); 7.49—7.59 (m, 1 H, Ph);
7.61—7.68 (m, 2 H, Ph); 7.71 (d, 1 H, Ph, J = 7.4 Hz). 13C NMR
(DMSOꢀd6), : 25.4; 87.9; 121.9; 122.4; 126.6; 127.3; 128.1;
129.1; 130.3; 132.2; 138.9; 149.1; 166.2. Found: m/z 276.0995
[M]+. Calculated: M = 276.2856.
Found (%): C, 79.57; H, 5.45; N, 4.41. C21H17NO2. Calculated
(%): C, 79.98; H, 5.43; N, 4.44. H NMR (DMSOꢀd6), : 4.23
1
(d, 1 H, CHaHb, J = 15.4 Hz); 4.52 (d, 1 H, CHaHb, J = 15.5 Hz);
7.09 (s, 1 H, OH); 7.11—7.33 (m, 11 H, Ph); 7.51—7.59 (m, 2 H,
Ph); 7.75 (d, 1 H, Ph, J = 7.0 Hz). 13C NMR (DMSOꢀd6),
: 122.5; 122.9; 125.9; 126.4; 127.7; 127.8; 127.9; 128.3; 129.2;
130.3; 132.5; 138.1; 139.9; 149.6; 166.9. Found: m/z 338.1151
[M]+. Calculated: M = 338.3550.
3ꢀHydroxyꢀ2ꢀ(pꢀmethoxybenzyl)ꢀ3ꢀmethylisoindolinꢀ1ꢀone
(2h) was obtained from ketoacid 1a (10 g, 0.06 mol) and pꢀmethꢀ
oxybenzylamine (8.4 g, 0.06 mol) similarly to compound 2e.
White powder. The yield was 12.6 g (73%), m.p. 164—166 C.
Found (%): C, 72.38; H, 6.09; N, 4.91. C17H17NO3. Calculatꢀ
ed (%): C, 72.07; H, 6.05; N, 4.94. 1H NMR (DMSOꢀd6), : 1.41
(s, 3 H, CH3); 3.71 (s, 3 H, OCH3); 4.35 (d, 1 H, CHaHb,
J = 15.6 Hz); 4.71 (d, 1 H, CHaHb, J = 15.5 Hz); 6.37 (s, 1 H, OH);
6.85 (d, 2 H, Ph, J = 8.5 Hz); 7.28 (d, 2 H, Ph, J = 8.5 Hz);
7.48—7.53 (m, 1 H, Ph); 7.61 (m, 2 H, Ph); 7.67 (d, 1 H, Ph,
J = 7.4 Hz). 13C NMR (DMSOꢀd6), : 25.5; 40.4; 54.9; 87.9; 113.6;
121.9; 122.3; 128.7; 129.0; 130.3; 130.9; 132.1; 149.1; 158.1;
166.1. Found: m/z 306.1101 [M]+. Calculated: M = 306.3116.
3ꢀHydroxyꢀ3ꢀmethylꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]isoindolinꢀ1ꢀone
(2i) was obtained from ketoacid 1a (10 g, 0.06 mol) and (S)ꢀ(–)ꢀ
1ꢀethylꢀ1ꢀphenylamine (7.4 g, 0.06 mol) according to the proceꢀ
dure.22
3ꢀHydroxyꢀ2ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylisoindolinꢀ1ꢀone
(2l) was obtained from ketoacid 1a (10 g, 0.06 mol) and anisidine
(7.4 g, 0.06 mol) similarly to compound 2e. White powder. The
yield was 9.5 g (56%), m.p. 135—137 C. Found (%): C, 71.58;
H, 5.65; N, 5.23. C16H15NO3. Calculated (%): C, 71.36; H, 5.61;
N, 5.20. 1H NMR (DMSOꢀd6), : 1.58 (s, 3 H, CH3); 3.83
(s, 3 H, OCH3); 3.88 (s, 1 H, OH); 6.88 (d, 2 H, Ph, J = 8.9 Hz);
7.32 (d, 2 H, Ph, J = 8.8 Hz); 7.29—7.48 (m, 2 H, Ph); 7.58
(d, 2 H, Ph, J = 3.9 Hz). 13C NMR (DMSOꢀd6), : 24.8; 55.2;
89.2; 113.9; 122.1; 122.7; 128.3; 129.1; 129.4; 130.3; 132.5;
148.9; 158.1; 165.4. Found: m/z 292.0944 [M]+. Calculated:
M = 292.2850.
3ꢀHydroxyꢀ2ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀphenylisoindolinꢀ1ꢀone
(2m) was obtained from ketoacid 1b (5 g, 0.02 mol) and anisidine
(2.5 g, 0.02 mol) similarly to compound 2e. White powder.
The yield was 4.8 g (66%), m.p. 200—202 C (cf. Ref. 40:
m.p. 200—201 C). Found (%): C, 76.76; H, 5.19; N, 4.26.
C21H17NO3. Calculated (%): C, 76.12; H, 5.17; N, 4.23.
1H NMR (DMSOꢀd6), : 3.69 (s, 3 H, OCH3); 6.83 (d, 2 H, Ph,
J = 8.9 Hz); 7.18—7.35 (m, 8 H, Ph, OH); 7.53—7.63 (m, 3 H,
Ph); 7.82 (d, 1 H, Ph, J = 7.2 Hz). 13C NMR (DMSOꢀd6),
: 55.1; 92.0; 113.5; 122.8; 122.9; 126.0; 127.7; 127.8; 128.2,
128.9; 129.3; 130.0; 132.9; 140.0; 149.5; 157.3; 166.2. Found:
m/z 354.1101 [M]+. Calculated: M = 354.3544.
2ꢀBenzoylꢀtertꢀbulylbenzamide (4) was obtained from ketoꢀ
acid 1b (5 g, 0.02 mol) and tertꢀbulylamine (1.5 g, 0.02 mol)
similarly to compound 2e. White powder. The yield was 3.6 g
(58%), m.p. 98—100 C. Found (%): C, 77.34; H, 6.79; N, 5.01.
C18H19NO2. Calculated (%): C, 76.84; H, 6.81; N, 4.98.
1H NMR (DMSOꢀd6), : 1.07 (s, 9 H, 3 CH3); 7.41—7.49
(m, 3 H, Ph); 7.57—7.67 (m, 5 H, Ph); 7.98 (s, 1 H, Ph).
13C NMR (DMSOꢀd6), : 27.9; 50.6; 128.0; 128.2; 128.4; 128.5;
128.9; 129.6; 129.9; 132.6; 137.3; 137.4; 139.0; 166.7; 196.5.
Found: m/z 304.1308 [M]+. Calculated: M = 304.3388.
PdꢀCatalyzed hydrogenolysis of hydroxylactams 2 (general
procedure). A mixture of Pd(1%)/sibunit (39 mg, 0.0037 mgꢀat.
2ꢀBenzylꢀ3ꢀhydroxyꢀ3ꢀphenylisoindolinꢀ1ꢀone (2g) was obꢀ
tained from ketoacid 1b (5 g, 0.02 mol) and benzylamine (2.1 g,
0.02 mol) similarly to compound 2e. The product was crystalꢀ
lized from benzene. Light yellow crystals. The yield was 4.6 g
(67%), m.p. 144—146 C (cf. Ref. 39: m.p. 145—147 C).

1036
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Sagirova et al.
of Pd) and hydroxylactam 2 (0.3700 mmol) were placed in
a glass tube preliminary evacuated and filled with argon, then anꢀ
hydrous methanol (3 mL) was added. The tube was placed in
a steel autoclave (50 mL), which then was purged and filled with
purified hydrogen (20 atm). The reaction mixture was stirred
with a magnetic stirrer (700 rpm) at ~20 C for a required time
(see Table 1). Once the reaction was completed, the solution
was passed through a layer of silica gel to remove the catalyst,
the solvent was evaporated. The conversion level was deterꢀ
mined by 1H NMR spectroscopy.
3ꢀMethylisoindolinꢀ1ꢀone (3a). Yellow crystals, m.p. 98—100 C
(cf. Ref. 41: m.p. 117—118 C). Found (%): C, 73.67; H, 6.26;
N, 9.49. C9H9NO. Calculated (%): C, 73.45; H, 6.16; N, 9.52.
1H NMR (CDC13), : 1.51 (d, 3 H, CHCH3, J = 6.7 Hz); 4.71
(q, 1 H, CHCH3, J = 6.5 Hz); 7.40—7.50 (m, 2 H, Ph);
7.51—7.59 (m, 1 H, Ph); 7.85 (d, 1 H, Ph, J = 7.0 Hz); 8.02
(s, 1 H, NH). 13C NMR (CDC13), : 20.3; 52.8; 122.2; 123.8;
128.1; 131.7; 131.9; 134.2; 149.0; 171.3. Found: m/z 170.1598
[M]+. Calculated: M = 170.1637.
7.43—7.55 (m, 2 H, Ph); 7.89 (d, 1 H, Ph, J = 7.4 Hz). 13C NMR
(CDC13), : 18.0; 43.5; 43.7; 53.4; 54.9; 121.9; 123.8; 127.5;
128.0; 128.1; 128.7; 131.5; 131.7; 137.3; 147.0; 168.1. Found:
m/z 260.3518 [M]+. Calculated: M = 260.2862.
2ꢀBenzylꢀ3ꢀphenylisoindolinꢀ1ꢀone (3g). White powder, m.p.
102—106 C (cf. Ref. 45: m.p. 136 C). Found (%): C, 84.57;
H, 5.74; N, 4.71. C21H17NO. Calculated (%): C, 84.25; H, 5.72;
N, 4.68. 1H NMR (CDC13), : 3.73 (d, 1 H, CHaHbPh, J = 4.8 Hz);
5.24 (s, 1 H, CHPh); 5.38 (d, 1 H, CHaHbPh, J = 4.8 Hz);
7.01—7.10 (m, 3 H, Ph); 7.13—7.19 (m, 2 H, Ph); 7.22—7.26
(m, 3 H, Ph); 7.30—7.36 (m, 3 H, Ph); 7.41—7.50 (m, 2 H, Ph);
7.91—7.98 (m, 1 H, Ph). 13C NMR (CDC13), : 44.0; 63.8;
123.3; 123.9; 127.7; 127.9; 128.5; 128.6; 128.8; 129.3; 132.0;
136.8; 137.1; 146.5; 168.7. Found: m/z 322.3671 [M]+. Calculatꢀ
ed: M = 322.3556.
2ꢀ(pꢀMethoxybenzyl)ꢀ3ꢀmethylisoindolinꢀ1ꢀone (3h). Colorꢀ
less oil. Found: C, 76.43; H, 6.54; N, 5.36. C17H17NO2. Calcuꢀ
lated (%): C, 76.38; H, 6.41; N, 5.24. 1H NMR (CDC13), : 1.14
(d, 3 H, CHCH3, J = 6.7 Hz); 3.95 (d, 1 H, NCHaCHb,
J = 15.0 Hz); 4.09 (q, 1 H, CHCH3, J = 6.7 Hz); 4.91 (d, 1 H,
NCHaCHb, J = 15.0 Hz); 6.55 (d, 2 H, Ph, J = 8.6 Hz); 6.93
(d, 2 H, Ph, J = 8.6 Hz); 7.09—7.27 (m, 3 H, Ph); 7.53 (d, 1 H, Ph,
J = 7.4 Hz). 13C NMR (CDC13), : 17.4, 42.4, 54.2, 54.6, 113.5,
121.5, 122.8, 127.4, 128.6, 128.7, 130.9, 146.4, 158.3, 167.2.
Found: m/z 290.3731 [M]+. Calculated: M = 290.3122.
3ꢀMethylꢀ2ꢀ[(1S)ꢀ1ꢀphenylethyl]isoindolinꢀ1ꢀone (3i). Colorꢀ
less oil22 was obtained as a mixture of two diastereoisomers (1 : 1).
2ꢀtertꢀBulylꢀ3ꢀphenylisoindolinꢀ1ꢀone (3k). 1H NMR
(CDC13), : 1.20 (s, 9 H, 3 CH3); 5.83 (s, 1 H, CHPh); 7.12—7.40
(m, 9 H, Ph).
3ꢀPhenylisoindolinꢀ1ꢀone (3b). Colorless oil.42 Found (%):
C, 80.74; H, 5.26; N, 6.72. C14H11NO. Calculated (%): C, 80.36;
H, 5.30; N, 6.69. 1H NMR (DMSOꢀd6), : 5.73 (s, 1 H, CHPh);
7.27—7.39 (m, 6 H, Ph); 7.42—7.59 (m, 2 H, Ph); 7.72 (d, 1 H,
Ph, J = 7.1 Hz); 9.06 (s, 1 H, NH). 13C NMR (DMSOꢀd6),
: 59.5; 122.8; 123.4; 126.5; 127.8; 128.1; 128.7; 131.3; 131.8;
139.6; 148.1; 169.6. Found: m/z 232.1989 [M]+. Calculated:
M = 1232.233.
2,3ꢀDimethylisoindolinꢀ1ꢀone (3c). Colorless oil.43 Found (%):
C, 74.96; H, 6.79; N, 8.75. C10H11NO. Calculated (%): C, 74.51;
1
H, 6.88; N, 8.69. H NMR (CDC13), : 1.48 (d, 3 H, CHCH3,
J = 6.8 Hz); 3.11 (s, 3 H, NCH3); 4.41 (q, 1 H, CHCH3,
J = 6.7 Hz); 7.37—7.44 (m, 2 H, Ph); 7.46—7.52 (m, 1 H, Ph);
7.80 (d, 1 H, Ph, J = 7.4 Hz). 13C NMR (CDC13), : 17.9; 26.9;
57.5; 121.8; 123.3; 128.0; 131.2; 131.3; 132.0; 146.7; 168.0.
Found: m/z 184.2231 [M]+. Calculated: M = 184.1902.
2ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀmethylisoindolinꢀ1ꢀone (3l). Cream
powder, m.p. 85—86 C (cf. Ref. 46: m.p. 88—90 C). Found (%):
C, 75.92; H, 6.14; N, 5.49. C16H15NO2. Calculated (%): C, 76.34;
1
H, 5.97; N, 5.53. H NMR (CDC13), : 1.42 (d, 3 H, CHCH3,
J = 6.7 Hz); 3.82 (s, 3 H, OCH3); 5.09 (q, 1 H, CHCH3,
J = 6.7 Hz); 6.97 (d, 2 H, Ph, J = 8.9 Hz); 7.41—7.51 (m, 4 H,
Ph); 7.55—7.61 (m, 1 H, Ph); 7.90 (d, 1 H, Ph, J = 7.5 Hz).
13C NMR (CDC13), : 18.7; 55.5; 57.4; 114.4; 122.0; 124.0;
125.4; 128.3; 130.0; 131.9; 132.7; 146.4; 157.5; 166.9. Found:
m/z 276.3124 [M]+. Calculated: M = 276.2856.
2ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀphenylisoindolinꢀ1ꢀone (3m). 1H NMR
(CDC13), : 3.68 (s, 3 H, OCH3); 6.05 (s, 1 H, CHPh);
6.71—6.84 (m, 2 H, Ph); 7.14—7.52 (m, 10 H, Ph); 7.81—7.91
(m, 1 H, Ph).
2ꢀEthylꢀ3ꢀmethylisoindolinꢀ1ꢀone (3d). Colorless oil.43
Found (%): C, 74.87; H, 7.61; N, 8.03. C11H13NO. Calculated (%):
1
C, 75.40; H, 7.48; N, 7.99. H NMR (CDC13), : 1.22 (t, 3 H,
CHaHbCH3, J = 7.2 Hz); 1.44 (d, 3 H, CHCH3, J = 6.7 Hz);
3.22—3.36 (m, 1 H, CHaHbCH3); 3.89—4.10 (m, 1 H, CHaHbCH3);
4.54 (q, 1 H, CHCH3, J = 6.7 Hz); 7.36—7.45 (m, 2 H, Ph);
7.48—7.55 (m, 1 H, Ph); 7.80 (d, 1 H, Ph, J = 7.5 Hz). 13C NMR
(CDC13), : 13.7; 18.1; 34.6; 55.1; 121.8; 123.4; 128.0; 131.2;
132.1; 146.8; 167.7. Found: m/z 198.2631 [M]+. Calculated:
M = 198.2168.
2ꢀEthylꢀ3ꢀphenylisoindolinꢀ1ꢀone (3e). White powder, m.p.
80—82 C (cf. Ref. 44: m.p. 97—98 C). Found (%): C, 81.14;
H, 6.59; N, 5.87. C16H15NO. Calculated (%): C, 80.98; H, 6.37;
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1
N, 5.90. H NMR (CDC13), : 1.12 (t, 3 H, CH3, J = 7.2 Hz);
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Received December 14, 2012;
in revised form February 22, 2013