Palladium-catalyzed C - O hydrogenolysis in γ-hydroxy γ-lactams as an efficient approach to 5-alkyl(aryl)pyrrolidin-2-ones

Article abstract of DOI:10.1007/s11172-015-0945-z

5-R-Pyrrolidin-2-ones were synthesized by Pd/Sibunit-catalyzed C - O hydrogenolysis of 5-R-5-hydroxypyrrolidin-2-ones with molecular hydrogen.

Full text of DOI:10.1007/s11172-015-0945-z

Russian Chemical Bulletin, International Edition, Vol. 64, No. 4, pp. 859—863, April, 2015
859
Palladiumꢀcatalyzed C—O hydrogenolysis in ꢀhydroxy ꢀlactams
as an efficient approach to 5ꢀalkyl(aryl)pyrrolidinꢀ2ꢀones
O. V. Turova, V. G. Berezhnaya, E. V. Starodubtseva, V. A. Ferapontov, 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
5ꢀRꢀPyrrolidinꢀ2ꢀones were synthesized by Pd/Sibunitꢀcatalyzed C—O hydrogenolysis of
5ꢀRꢀ5ꢀhydroxypyrrolidinꢀ2ꢀones with molecular hydrogen.
Key words: ꢀhydroxy ꢀlactams, pyrrolidinꢀ2ꢀones, C—O hydrogenolysis, hydrogen, pallaꢀ
dium catalysts.
Alkylꢀ and arylꢀsubstituted pyrrolidinꢀ2ꢀones are the
structural fragments of a number of naturally occurring
substances (e.g., alkaloids1,2), antibiotics,3,4 muscarinic
receptor agonists,5 Na+ channel blockers, antimalarial
agents, and other biologically active compounds.5,6 Sevꢀ
eral approaches have been developed for the synthesis of
5ꢀalkylpyrrolidinꢀ2ꢀones: reduction of the C—Hal bond
of haloꢀsubstituted ꢀlactams,1,5,7—9 alkylation of the
C—Hal bond with the Grignard reagent,2 hydrogenation
of the C=C bond (either endo or exo) of unsaturated
reaction is completed within 2—6 h at 50 C to give
Nꢀbenzylꢀ5ꢀmethylpyrrolidinꢀ2ꢀone (4a) at 100% converꢀ
sion (see Table 1, entries 1—6). In protic solvents (MeOH,
EtOH, CF3CH2OH), hydrogenolysis is accompanied by
substitution of the hydroxy group at the quaternary carbon
with an alkoxy group to yield alkoxy lactams of type 5.
Depending on the nature of the protic solvent and hydroꢀ
genolysis conditions, a 4a : 5 ratio is widely varied, from
0 : 100 to 98 : 2. For instance, lactam 5 was the major
product in the reaction carried out in MeOH at 50 C for
2 h (entry 8); in trifluoroethanol, lactam 4a predominates
(entry 12); while in EtOH lactams 4a and 5´ are obtained
in a 1 : 1 ratio (entry 10). Taking into account these reꢀ
sults, toluene was a solvent of choice for the most syntheꢀ
ses of substituted pyrrolidinꢀ2ꢀones from other substrates
(Table 2). It should be noted that in contrast to substrate 1a
ꢀlactams,3,6 hydrogenation of ꢀketo ester hydrazones,10,11
,
cyclization of linear unsaturated and ꢀhydroxyꢀsubstitutꢀ
ed amides,12,13 rutheniumꢀcatalyzed ring closure of ꢀdiꢀ
azoacetamides.14,15 At the same time, all mentioned apꢀ
proaches are of limited value. The key steps of these methꢀ
ods often require stoichiometric amounts of poorly availꢀ
able or unstable reagents, e.g., hydrides or organometallic
compounds. Moreover, the reactions are often nonꢀseꢀ
lective.
Table 1. PdꢀCatalyzed hydrogenolysis of hydroxy lactam 1a*
In the present work, we describe simple and versatile
procedure towards 5ꢀalkyl(aryl)pyrrolidinꢀ2ꢀones via
Pdꢀcatalyzed hydrogenolysis of ꢀhydroxy ꢀlactams simꢀ
ilar to previously studied16 hydrogenolysis of substituted
3ꢀhydroxyisoindolinꢀ1ꢀones.
Entry
Solvent
T/C
t/h Conversion
Yield (%)
(%)
4a
5
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
THF
22
22
50
50
22
50
22
50
50
50
50
50
2
65
2
6
2
2
2
2
6
118
100
190
100
153
100
195
100
100
188
196
100
100
100
100
100
100
100
110
114
191
150
185
—
—
—
—
—
Results and Discussion
The starting ꢀhydroxy ꢀlactams 1 were synthesized
by amidation of unsaturated lactones 2 and by the reacꢀ
tion of Nꢀbenzylsuccinimide 3 with either benzylmagneꢀ
sium chloride or sodium borohydride (Scheme 1). Hydroꢀ
genolysis of substrates 1 was carried out over Pd0 supportꢀ
ed on mesoporous carbon Sibunit (Pd/Sibunit) catalyst.17
The effect of the solvent on composition of hydroꢀ
genolysis products was examined with the model hydroxy
lactam 1a (Table 1). In aprotic media (toluene, THF), the
THF
—
МеОН
МеОН
МеОН
EtOH
EtOH
CF3CH2OH
100
196
119
150
115
9
10
11
12
2
6
2
>95 1<5
* Reaction conditions: 1a (0.23 mmol), solvent (2 mL), 1%
Pd/Sibunit, 1a : Pd = 100, H2 (20 atm).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 0859—0863, April, 2015.
1066ꢀ5285/15/6404ꢀ0859 © 2015 Springer Science+Business Media, Inc.

860
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 4, April, 2015
Turova et al.
Scheme 1
1, 2, 4: R1= Me, R2 = Bn (a); R1 = R2 = Me (b); R1 = Ph, R2 = Me (c); R1 = R2 = Bn (d); R1 = H, R2 = Bn (e)
5, 5´, 5: R1 = Me, R2 = Bn, R3 = Me (5), Et (5´), CF3CH2 (5)
1
(see Table 1), dibenzylꢀsubstituted compound 1d gives only
lactam 4d in both methanol and aprotic solvents (see
Table 2, entry 7). Slow rate of hydrogenolysis of 5ꢀphenylꢀ
substituted hydroxy lactam 1c is also noteworthy. Comꢀ
plete conversion of 1c was achieved only within 24 h at
50 C (entry 4), which can be due to the presence of the
bulky phenyl group in the molecule.
To suggest the plausible mechanism of hydrogenolyꢀ
sis, we performed deuterolysis of substrate 1a with molecꢀ
ular deuterium and determined the content of deuterium
bonded to some carbon atoms for the reaction product
Dnꢀ4a by H NMR. It was found that deuterolysis of
hydroxy lactam 1a leads to an isotopic enrichment (from
30 to 70%) at the C(4), C(5), and C(6) carbon atoms;
whereas, no deuteration at the C(3) and benzyl group
occurs (Scheme 2). These results suggest the most likely
mechanism of the catalytic cycle involving heterolysis of
the molecular hydrogen (deuterium) at the Pd0 atoms to
give anionic hydride (deuteride) complex A and its subseꢀ
quent reaction with the starting hydroxy lactam to yield
acyliminium intermediate B. Complex B further decayed
to give product Dnꢀ4a and the Pd0 species thus resuming
Scheme 2

C—O Hydrogenolysis in ꢀhydroxy ꢀlactams
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 4, April, 2015
861
Table 2. Synthesis of substituted pyrrolidinꢀ2ꢀones 4a—e by catꢀ
alytic hydrogenolysis of hydroxy lactams 1*
Series II 2400 analyzer. High resolution electrospray ionization
(ESI) mass spectrometry was performed on a Bruker microTOF
instrument.
1ꢀBenzylꢀ5ꢀhydroxyꢀ5ꢀmethylpyrrolidinꢀ2ꢀone (1a)18. To
a solution of unsaturated lactone 2a (2.2 mL, 25 mmol) in water
(3 mL), benzylamine (2.9 mL, 26.5 mmol) was added and the
mixture was stirred at room temperature for 1 h. The reaction
mixture was extracted with dichloromethane (3×3 mL) and dried
with anhydrous MgSO4. Removal of the solvent in vacuo to dryꢀ
ness and recrystallization of the residue from diethyl ether afꢀ
forded product 1a in the yield of 1.72 g (33%), colorless crystals,
m.p. 76—78 C (cf. Ref. 19: m.p. 64—66 C). 1H NMR (CDCl3),
: 1.35 (s, 3 H, CH3); 2.07—2.18 (m, 2 H, C(O)CH2);
2.32—2.43 (m, 1 H, C(O)CH2CHaHb); 2.53—2.64 (m, 1 H,
C(O)CH2CHaHb); 4.13 (br.s, 1 H, OH); 3.98 (m, 1 H, CHaHbPh,
J = 15.4 Hz); 4.98 (m, 1 H, CHaHbPh, J = 15.4 Hz); 7.35—7.20
(m, 5 H, Ph). 13C NMR (CDCl3), : 27.03, 29.06, 34.83, 42.22,
90.39, 127.06, 127.65, 128.45, 138.52, 175.41. Found (%): C, 70.09;
H, 7.40; N, 6.85. C12H15NO2. Calculated (%): C, 70.22;
H, 7.37; N, 6.82. MS (ESI), m/z: 206.1185 [M + H]+, 228.1003
[M + Na]+, 244.0738 [M + K]+. Calculated: for [C12H16NO2]+,
206.1181 [M + H]+; for [C12H15NNaO2]+, 228.1000 [M + Na]+;
for [C12H15NKO2]+, 244.0740 [M + K]+.
Entry Substrate
Solvent
t/h
Conversion (%)
1
2
3
4
5
6
7
8
1а
1b
1c
1c
1d
1d
1d
1е
Toluene
Toluene
Toluene
Toluene
Toluene
THF
16
12
18
24
12
12
12
12
100
100
178
100
100
100
100
100
МеОН
Toluene
* Reaction conditions: 1 (0.23 mmol), solvent (2 mL), 1%
Pd/Sibunit, 1 : Pd = 100, H2 (20 atm), 50 C. Hydrogenolysis of
substrates 1 selectively gives pyrrolidinꢀ2ꢀones 4 (1H NMR data).
the next catalytic cycle (the left part of Scheme 2). Furtherꢀ
more, the presence of deuterium at the C(4) and C(6)
positions of the target product indicates that acyliminium
intermediate B undergoes at least partial deprotonation to
give unsaturated heterocycles C and D involved also in
hydride reduction (deuteration) with complex A (the right
part of Scheme 2). These steps have the very high rate,
since enamines C and D were not detected in the reaction
mixtures. Apparently, upon decay of complex B enamines
C and D retain the bonding with the Pd0 species due to
 coordination with the C=C bond, which have to favor
their rapid hydride reduction.
In summary, we developed simple and versatile proceꢀ
dure towards 5ꢀalkyl and 5ꢀarylpyrrolidinꢀ2ꢀones via the
Pdꢀcatalyzed hydrogenolysis of the C—O bond of the relꢀ
atively available ꢀhydroxy ꢀlactams. This method can be
applied for the synthesis of both monoꢀ and disubstituted
pyrrolidinꢀ2ꢀones.
5ꢀHydroxyꢀ1,5ꢀdimethylpyrrolidinꢀ2ꢀone (1b)20. Colorless
crystals, m.p. 65—67 C (cf. Ref 21: m.p. 66—68 C), yield 2.4 g
1
(74%). H NMR (CDCl3), : 1.40 (s, 3 H, CH3); 2.02—2.08
(m, 2 H, C(O)CH2); 2.16—2.27 (m, 1 H, C(O)CH2CHaHb);
2.39—2.50 (m, 1 H, C(O)CH2CHaHb); 2.69 (s, 3 H, CH3); 5.16
(br.s, 1 H, OH). 13C NMR (CDCl3), : 23.77, 25.53, 29.24,
34.38, 89.61, 174.52.
5ꢀHydroxyꢀ1ꢀmethylꢀ5ꢀphenylpyrrolidinꢀ2ꢀone (1c)22. Step 1.
To 3ꢀbenzoylpropionic acid (15 g, 0.084 mol), acetyl chloride
(150 mL, 2.1 mol) was added and the mixture was stirred at room
temperature for 1 h. The acetyl chloride excess was removed
in vacuo. Recrystallization of the residue from diethyl ether afꢀ
forded 5ꢀphenylfuranꢀ2(3H)ꢀone, light yellow powder, m.p.
86—88 C (cf. Ref. 23: 88—89 C), yield 11.7 g (87%). 1H NMR
(CDCl3), : 3.42 (d, 2 H, CH2, J = 2.3 Hz); 5.79 (m, 1 H, CH);
7.38—7.47 (m, 3 H, mꢀPh, pꢀPh); 7.58—7.63 (m, 2 H, oꢀPh).
Step 2. To 5ꢀphenylfuranꢀ2(3H)ꢀone (1 g, 6.24 mmol), 33%
aqueous methylamine (8 mL) was added and the mixture was
stirred at room temperature for 1 h. Removal of the volatiles
in vacuo and recrystallization of the residue from water afforded
compound 1c, white powder, m.p. 131—133 C (cf. Ref. 22: m.p.
130—135 C), yield 0.7 g (59%). 1H NMR (CDCl3), : 2.26—2.55
(m, 3 H, C(O)CH2CHaHb); 2.58—2.75 (m, 1 H, C(O)CH2CHaHb);
2.62 (s, 3 H, CH3); 5.22 (br.s, 1 H, OH); 7.25—7.45 (m, 5 H,
Ph). 13C NMR (CDCl3), : 25.19, 29.56, 37.44, 92.96, 125.46,
128.08, 128.65, 142.42, 175.73.
Experimental
Commercially available lactone 2a (ꢀangelica lactone),
3ꢀbenzoylpropionic acid, succinic and acetic anhydrides, benzoyl
chloride, acetyl chloride, benzylamine, aqueous methylamine,
anhydrous sodium acetate, magnesium (chips), sodium boroꢀ
hydride, and Pd/Sibunit were used as purchased.
Solvents for catalytic studies and synthesis of the Grignard
reagent were dehydrated and distilled under argon prior to use.
Methanol was dehydrated by reflux over magnesium; ethanol
was refluxed over calcium; benzene, toluene, THF, and diethyl
ether were refluxed over sodium in the presence of benzophenone.
Argon was purified by passing through the columns loaded
with nickelꢀchrome catalyst, Kieselgel impregnated with copper
(80 C), and molecular sieves (4 Å). Hydrogen was purified by
passing through the columns loaded with nickelꢀchrome catalyst
and molecular sieves (4 Å).
1,5ꢀDibenzylꢀ5ꢀhydroxypyrrolidinꢀ2ꢀone (1d)24. Step 1. To
a solution of succinic anhydride (5 g, 0.05 mol) in chloroform
(50 mL), a solution of benzylamine (5.7 mL, 0.05 mol) in chloroꢀ
form (10 mL) was added and the mixture was stirred for 1 h.
NꢀBenzylsuccinic acid monoamide was collected by filtration
and used on the next step without further purification. White
powder, m.p. 130—132 C (cf. Ref. 25: m.p. 144 C), yield 10.05 g
1
(97%). H NMR (DMSOꢀd6), : 2.35—2.47 (m, 4 H, 2 CH2);
1H and 13C NMR spectra were run on a Bruker AMꢀ300
instrument (working frequencies of 300.13 and 75.47 MHz, reꢀ
spectively). Melting points were measured with a Kofler apparatus.
Elemental analyses were carried out with a Perkin—Elmer
4.27 (d, 2 H, PhCH2, J = 6.0 Hz); 7.19—7.45 (m, 5 H, Ph); 8.35
(t, 1 H, NH, J = 6.0 Hz).
Step 2. To Nꢀbenzylsuccinic acid monoamide, calcined soꢀ
dium acetate (1.02 g, 12.15 mmol) and acetic anhydride (50 mL)

862
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 4, April, 2015
Turova et al.
were added and the mixture was refluxed for 2 h. Removal of the
solvent in vacuo and recrystallization of the residue from diethyl
ether afforded Nꢀbenzylsuccinimide (3), white crystals, m.p.
96—98 C (cf. Ref. 26: m.p. 102—103 C), yield 8.7 g (92%).
1H NMR (CDCl3), : 2.68 (s, 4 H, 2 CH2); 4.65 (s, 2 H, PhCH2);
7.28—7.39 (m, 5 H, Ph).
uated and refilled with argon. After adding the solvent (2 mL),
the ampule was transferred into filled with argon stainless steel
autoclave (50 cm3). The autoclave was flushed with purified
hydrogen and the hydrogen pressure was adjusted to 20 atm.
Then, the reaction mixture was magnetically stirred at temperaꢀ
ture indicated in Table 1. After completion of the experiment,
the reaction mixture was filtered through a silica gel pad (1.5 cm
thick) to remove the catalyst, the products were eluted with ethyl
acetate. After removal of the solvent in vacuo, the residue was
subjected to NMR spectroscopy, mass spectrometry, and eleꢀ
mental analyses.
1ꢀBenzylꢀ5ꢀmethylpyrrolidinꢀ2ꢀone (4a)28. Colorless oil.
1H NMR (CDCl3), : 1.05 (d, 3 H, CH3, J = 6.4 Hz); 1.41—1.55
(m, 1 H, C(O)CH2CHaHb); 1.97—2.12 (m, 1 H, C(O)CH2CHaHb);
2.20—2.46 (m, 2 H, C(O)CH2); 3.35—3.49 (sext, 1 H, CH,
J = 6.4 Hz); 4.00 (d, 1 H, CHaHbPh, J = 14.7 Hz); 4.98 (d, 1 H,
CHaHbPh, J = 14.7 Hz); 7.10—7.25 (m, 5 H, Ph). 13C NMR
(CDCl3), : 19.30, 26.35, 29.95, 43.55, 52.50, 127.04, 127.61,
128.27, 136.61, 174.52. Found (%): C, 76.30; H, 7.75; N, 7.66.
C12H15NO. Calculated (%): C, 76.16; H, 7.99; N, 7.40. MS
(ESI), m/z: 190.2222 [M + H]+, 212.1038 [M + Na]+, 228.0839
[M + K]+. Calculated: for [C12H16NO]+, 190.1232 [M + H]+;
for [C12H15NNaO]+, 212.1051 [M + Na]+; for [C12H15NKO]+,
228.0791 [M + K]+.
Step 3. A threeꢀneck flask (205 mL, predried) equipped with
two dropping funnels with pressureꢀequalization arms and a reꢀ
flux condenser with a drying tube was flushed with argon and
charged with magnesium chips (1 g, 0.04 mmol) and anhydrous
diethyl ether (20 mL). Then, a solution of BnCl (4.7 mL,
0.04 mmol) in anhydrous diethyl ether (40 mL) was added dropꢀ
wise. After addition of approximately 1/10 of the BnCl solution,
formation of the Grignard reagent began (exothermic reaction,
the clear solution became turbid). The rest of the BnCl solution
was added dropwise with a rate to maintain a gentle reflux. After
cessation of the reaction, the mixture was cooled (ice/NaCl coolꢀ
ing bath) and a solution of Nꢀbenzylsuccinimide (3) (7.5 g,
0.04 mol) in THF (85 mL) was added dropwise with vigorous
stirring. The reaction mixture was refluxed for 4 h and cooled to
0 C. The mixture was washed with saturated aqueous NH4Cl
(~100 mL), the organic phase was separated, the aqueous layer
was extracted with diethyl ether (2×70 mL). The combined orꢀ
ganic layers were washed with brine and dried with anhydrous
MgSO4. Removal of the solvent in vacuo afforded the target
product 1d, white powder, m.p. 112—114 C (cf. Ref. 27: m.p.
130—132 C, yield 4.8 g (52%). 1H NMR (CDCl3), : 1.70—1.81
(m, 1 H, C(O)CH2CHaHb); 1.94—2.06 (m, 1 H, C(O)CH2CHaHb);
2.27—2.47 (m, 2 H, C(O)CH2); 2.87 (d, 1 H, C(OH)CHaHbPh,
J = 13.7 Hz); 3.09 (d, 1 H, C(OH)CHaHbPh, J = 13.7 Hz); 4.54
(d, 1 H, NCHaHbPh, J = 15.1 Hz); 4.71 (d, 1 H, NCHaHbPh,
J = 15.1 Hz); 7.10—7.44 (m, 10 H, 2 Ph). 13C NMR (CDCl3),
: 27.78, 32.06, 41.52, 43.66, 91.15, 125.93, 126.07, 126.81, 127.26,
127.38, 128.84, 133.80, 137.40, 173.40. Found (%): C, 76.59;
H, 6.54; N, 4.98. C18H19NO2. Calculated (%): C, 76.84; H, 6.81;
N, 4.98. MS (ESI), m/z: 282.1489 [M + H]+, 304.1308 [M + Na]+,
320.1047 [M + K]+. Calculated: for [C18H20NO2]+, 282.1494
[M + H]+; for [C18H19NNaO2]+, 304.1313 [M + Na]+; for
[C18H19NKO2]+, 320.1053 [M + K]+.
1ꢀBenzylꢀ5ꢀhydroxypyrrolidinꢀ2ꢀone (1e)26. To a 0 C soluꢀ
tion of Nꢀbenzylsuccinimide 3 (3 g, 16 mmol) in CH2Cl2—
MeOH (80 mL, 1 : 3), NaBH4 (1.5 g, 40 mmol) was added porꢀ
tionwise over a period of 2 h with stirring. Then water (50 mL)
was added and the volatiles were removed in vacuo. The precipꢀ
itate formed was collected by filtration, washed with water and
airꢀdried. The filtrate was extracted with dichloromethane, dried
with MgSO4, and the solvent was removed in vacuo to give the
addition crop of the target product. The products were comꢀ
bined and recrystallized from benzene. White powder, m.p.
110—111 C (cf. Ref. 26: m.p. 105—106 C), yield 1.73 g (57%).
1H NMR (CDCl3), : 1.84—1.97 (m, 1 H, C(O)CH2CHaHb);
2.16—2.39 (m, 2 H, C(O)CH2); 2.50—2.70 (m, 1 H,
C(O)CH2CHaHb); 4.27 (d, 1 H, OH, J = 7.8 Hz); 4.17 (d, 1 H,
NCHaHbPh, J = 14.8 Hz); 4.85 (d, 1 H, NCHaHbPh, J = 14.8 Hz);
5.03—5.12 (m, 1 H, CH); 7.22—7.38 (m, 5 H, Ph). 13C NMR
(CDCl3), : 28.10, 29.00, 43.42, 82.47, 127.67, 128.35, 128.76,
136.55, 174.98.
1,5ꢀDimethylpyrrolidinꢀ2ꢀone (4b)29. Colorless oil. 1H NMR
(CDCl3), : 1.17 (d, 3 H, CH3CH, J = 6.3 Hz); 1.47—1.59 (m, 1 H,
C(O)CH2CHaHb); 2.10—2.43 (m, 3 H, C(O)CH2CHaHb); 2.74
(s, 3 H, CH3N); 3.50—3.57 (m, 1 H, CH). 13C NMR (CDCl3),
: 19.72, 26.61, 27.26, 30.19, 55.63, 174.94.
1ꢀMethylꢀ5ꢀphenylpyrrolidinꢀ2ꢀone (4c)30. Colorless oil.
1H NMR (CDCl3), : 1.84—1.94 (m, 1 H, C(O)CH2CHaHb);
2.38—2.60 (m, 3 H, C(O)CH2CHaHb); 2.66 (s, 3 H, CH3);
4.45—4.54 (m, 1 H, CH); 7.18 (d, 2 H, oꢀPh, J = 7.3 Hz);
7.27—7.41 (m, 3 H, mꢀPh, pꢀPh).
1,5ꢀDibenzylpyrrolidinꢀ2ꢀone (4d)31. Colorless oil. 1H NMR
(CDCl3), : 1.68—1.81 (m, 1 H, C(O)CH2CHaHb); 1.83—1.98
(m, 1 H, C(O)CH2CHaHb); 2.23—2.32 (m, 2 H, C(O)CH2);
2.57 (dd, 1 H, CHCHaHbPh, J1 = 13.7 Hz, J2 = 8.5 Hz); 3.02
(dd, 1 H, CHCHaHbPh, J1 = 13.3 Hz, J2 = 4.3 Hz); 3.62—3.75
(m, 1 H, CH); 4.01 (d, 1 H, NCHaHbPh, J = 14.9 Hz); 5.10
(d, 1 H, NCHaHbPh, J = 14.9 Hz); 7.03—7.40 (m, 10 H, 2 Ph).
13C NMR (CDCl3), : 23.63, 29.73, 39.08, 44.33, 57.89, 126.63,
127.47, 127.98, 128.51, 128.61, 129.11, 136.65, 136.94, 175.06.
Found (%): C, 80.46; H, 7.32; N, 5.29. C18H19NO. Calculatꢀ
ed (%): C, 81.47; H, 7.22; N, 5.28. MS (ESI), m/z: 266.1543
[M + H]+, 288.1362 [M + Na]+, 304.1111 [M + K]+. Calculatꢀ
ed for [C18H20NO]+, 266.1545 [M + H]+; for [C18H19NNaO]+,
288.1364 [M + Na]+; for [C18H19NKO]+, 304.1104 [M + K]+.
1ꢀBenzylpyrrolidinꢀ2ꢀone (4e)32. Colorless oil. 1H NMR
(CDCl3), : 1.99 (pent, 2 H, CH2CH2CH2CO, J = 7.6); 2.45 (t, 2 H,
CH2CH2CH2CO, J = 8.1 Hz); 3.27 (t, 2 H, NCH2CH2CH2CO,
J = 7.0 Hz); 4.46 (s, 2 H, CH2Ph); 7.21—7.38 (m, 5 H, Ph).
1ꢀBenzylꢀ5ꢀmethylꢀ5ꢀmethoxypyrrolidinꢀ2ꢀone (5). 1H NMR
(CDCl3), : 1.35 (s, 3 H, CH3); 1.95—2.06 (m, 1 H,
C(O)CH2CHaHb); 2.15—2.25 (m, 1 H, C(O)CH2CHaHb);
2.48—2.57 (m, 2 H, C(O)CH2CHaHb); 2.96 (s, 3 H, OCH3);
4.12 (d, 1 H, CHaHbPh, J = 15.2 Hz); 4.70 (d, 1 H, CHaHbPh,
J = 15.2 Hz); 7.20—7.33 (m, 5 H, Ph).
Hydrogenolysis (general procedure). A glass ampule for
hydrogenolysis (preliminary evacuated and refilled with argon)
was charged with a 1% Pd/Sibunit (25 mg, 2.35•10–3 mgꢀatom
of Pd) and substrate 1 (0.23 mmol). The ampule was again evacꢀ
1ꢀBenzylꢀ5ꢀethoxyꢀ5ꢀmethylpyrrolidinꢀ2ꢀone (5´). 1H NMR
(CDCl3), : 1.03 (t, 3 H, OCH2CH3, J = 6.9 Hz); 1.37 (s, 3 H, CH3);
2.0—2.5 (m, 4 H, CH2CH2); 2.92—3.05 (m, 1 H, OCHaHbCH3);

C—O Hydrogenolysis in ꢀhydroxy ꢀlactams
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 4, April, 2015
863
3.18—3.30 (m, 1 H, OCHaHbCH3); 4.21 (d, 1 H, CHaHbPh,
J = 15.2 Hz); 4.63 (d, 1 H, CHaHbPh, J = 15.2 Hz); 7.21—7.33
(m, 5 H, Ph).
1ꢀBenzylꢀ5ꢀmethylꢀ5ꢀ(2,2,2ꢀtrifluoroethoxy)pyrrolidinꢀ2ꢀone
(5). 1H NMR (CDCl), : 1.42 (s, 3 H, CH3); 1.95—2.06 (m, 1 H,
C(O)CH2CHaHb); 2.15—2.25 (m, 1 H, C(O)CH2CHaHb);
2.48—2.57 (m, 2 H, C(O)CH2CHaHb); 3.21—3.38 (m, 1 H,
OCHaHbCF3); 3.45—3.55 (m, 1 H, OCHaHbCF3); 4.19 (m, 1 H,
CHaHbPh, J = 15.3 Hz); 4.71 (m, 1 H, CHaHbPh, J = 15.3 Hz);
7.20—7.33 (m, 5 H, Ph).
Deuterolysis of hydroxy lactam 1a was carried out similarly
to hydrogenolysis. Reaction conditions: 1% Pd/Sibunite, toluene,
deuterium pressure of 20 atm., 50 C, 2 h. For products Dnꢀ4a,
the percentage of deuterium bonded to the carbon atoms were as
follows: C(3), 0; C(4), 70; C(5), 60; C(6), 30; Bn, 0 (1H NMR
data).
13. H. Takahata, E.ꢀC. Wang, T. Yamazaki, Synth. Commun.,
1988, 18, 1159.
14. M. Grohmann, S. Buck, L. Schäffler, G. Maas, Adv. Synth.
Catal., 2006, 348, 2203.
15. V. K.ꢀY. Lo, Z. Guo, M. K.ꢀW. Choi, W.ꢀY. Yu, J.ꢀS. Huang,
C.ꢀM. Che, J. Am. Chem. Soc., 2012, 134, 7588.
16. Zh. R. Sagirova, E. V. Starodubtseva, O. V. Turova, M. G.
Vinogradov, Russ. Chem. Bull. (Int. Ed.), 2013, 62, 1032 [Izv.
Akad. Nauk, Ser. Khim., 2013, 1031].
17. V. A. Semikolenov, Russ. Chem. Rev., 1992, 61, 168.
18. A. Padwa, K. R. Crawford, P. Rashatasakhon, M. Rose,
J. Org. Chem., 2003, 68, 2609.
19. M. Winn, H. E. Zaugg, J. Org. Chem., 1968, 33, 3779.
20. P. Rashatasakhon, A. Padwa, Org. Lett., 2003, 5, 189.
21. C. Wedler, B. Costisella, H. Schick, J. Prakt. Chem., 1990,
332, 557.
22. E. Walton, J. Chem. Soc., 1940, 438.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 13ꢀ03ꢀ00423).
23. S. I. Zav´yalov, A. G. Zavozin, N. E. Kravchenko, Bull.
Acad. Sci. USSR, Div. Chem. (Engl. Transl.), 1991, 40, 1090
[Izv. Akad. Nauk, Ser. Khim., 1991, 1212].
24. X. Zheng, X.ꢀJ. Dai, H.ꢀQ. Yuan, C.ꢀX. Ye, J. Ma, P.ꢀQ.
Huang, Angew. Chem., Int. Ed., 2013, 52, 3494.
25. A. Valla, D. Cartier, F. Zentz, R. Labia, Synth. Commun.,
2006, 36, 3591.
26. A. V. Sadovoy, A. E. Kovrov, G. A. Golubeva, L. A. Sviridoꢀ
va, Chem. Heterocycl. Compd. (Engl. Transl.), 2011, 46, 1215
[Khim. Geterotsikl. Soedin., 2010, 1505].
References
1. O. Provot, J. P. Célérier, H. Petit, G. Lhommet, J. Org.
Chem., 1992, 57, 2163.
2. A. Kamimura, Y. Nagata, A. Kadowaki, K. Uchida, H. Uno,
Tetrahedron, 2007, 63, 11856.
3. S. Hashiguchi, H. Natsugari, M. Ochiai, J. Chem. Soc.,
Perkin Trans. 1, 1988, 2345.
27. G. Tsolomiti, A. Tsolomitis, Heterocycl. Commun., 2006,
12, 93.
4. O. Miyata, S. Takahashi, A. Tamura, M. Ueda, T. Naito,
Tetrahedron, 2008, 64, 1270.
28. M. Grohmann, S. Buck, L. Schäffler, G. Maas, Adv. Synth.
Catal., 2006, 348, 2203.
5. R. Amstutz, B. Ringdahl, B. Rarlén, M. Roch, D. J. Jenden,
J. Med. Chem., 1985, 28, 1760.
6. A. Tanaka, T. Usuki, Tetrahedron Lett., 2011, 52, 5036.
7. P. Chen, D.ꢀJ. Suh, M. B. Smith, J. Chem. Soc., Perkin
Trans. 1, 1995, 1317.
29. N. A. Morozova, V. A. Sedavkina, A. Yu. Egorova, Chem.
Heterocycl. Compd. (Engl. Transl.), 1994, 30, 308 [Khim.
Geterotsikl. Soedin., 1994, 349].
30. J. Iley, R. Tolando, L. Constantino, J. Chem. Soc., Perkin
Trans. 2, 2001, 1299.
8. J. M. McIntosh, S. O. Acquaah, Can. J. Chem., 1988,
66, 1752.
9. M. B. Smith, B. T. Dembofsky, Y. Chan Son, J. Org. Chem.,
1994, 59, 1719.
10. J. E. Baldwin, R. M. Adlington, J. C. Bottaro, A. U. Jain,
J. N. Kolhe, M. W. D. Perry, I. M. Newington, J. Chem.
Soc., Chem. Commun., 1984, 1095.
31. J. F. Bower, J. Švenda, A. J. Williams, J. P. H. Charmant,
R. M. Lawrence, P. Szeto, T. Gallagher, Org. Lett., 2004,
6, 4727.
32. K. M. Orrling, X. Wu, F. Russo, M. Larhed, J. Org. Chem.,
2008, 73, 8627.
11. J. E. Baldwin, R. M. Adlington, A. U. Jain, J. N. Kolhe,
M. W. D. Perry, Tetrahedron, 1986, 42, 4247.
12. H. Lu, C. Li, Tetrahedron Lett., 2005, 46, 5983.
Received October 24, 2014;
in revised form January 19, 2015