New synthesis of 3,3-disubstituted piperidin-2-ones from esters and 1-(3-halopropyl)-2,5-dimethylpyrroles

Article abstract of DOI:10.1007/s11172-019-2674-1

3,3-Disubstituted piperidin-2-ones were obtained by alkylation of carboxylic acid esters with 1-(3-halopropyl)-2,5-dimethylpyrroles using lithium diisopropylamide as a base followed by the removal of 2,5-dimethylpyrrole protection and intramolecular cycli

Full text of DOI:10.1007/s11172-019-2674-1

Russian Chemical Bulletin, International Edition, Vol. 68, No. 11, pp. 2108—2113, November, 2019
2108
New synthesis of 3,3-disubstituted piperidin-2-ones
from esters and 1-(3-halopropyl)-2,5-dimethylpyrroles
V. D. Gvozdev, K. N. Shavrin, and O. M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. E-mail: vgvozdev2006@yandex.ru
3,3-Disubstituted piperidin-2-ones were obtained by alkylation of carboxylic acid esters
with 1-(3-halopropyl)-2,5-dimethylpyrroles using lithium diisopropylamide as a base followed
by the removal of 2,5-dimethylpyrrole protection and intramolecular cyclization. The overall
yields of the target products amounted to 78% in two synthetic steps.
Key words: piperidin-2-ones, esters, alkylation, protection groups, 2,5-dimethylpyrrole
protection, cyclization.
A lactam fragment is found in natural compounds and
Results and Discussion
is a structural part of many pharmaceuticals.1—4 The in-
troduction of a lactam fragment is used for the rational
modification of known biologically active compounds.5
Lactams are also the starting compounds for the synthesis
of practically important polyamides.6 Therefore, the de-
velopment of new convenient and efficient methods for
obtaining this class of compounds is still a challenge.
One of the synthetically and practically valuable types
of lactams are 3,3-disubstituted piperidin-2-ones. Com-
pound of this type possess anticonvulsant properties7,8 and
exhibit other types of biological activity.9,10 The most
commonly used general approaches to their synthesis are
the alkylation of N-protected δ-valerolactams11—14 or
their 3-monosubstituted derivatives,15—17 as well as the
cyanoethylation of disubstituted acetic acid esters with
subsequent reductive cyclization.18—23 There are examples
of the formation of 3,3-disubstituted piperidin-2-ones by
reductive cyclization of δ-azido esters.24 Note that despite
the versatility and good yields of the final products, the
last two approaches involve the use of highly toxic (acrylo-
nitrile) or explosive (azides) reagents. Therefore, the
development of alternative methods for the construction
of 3,3-disubstituted piperidin-2-ones is of undoubted
interest.
The starting 1-(3-bromopropyl)-2,5-dimethyl-1H-
pyrrole (1a) was obtained by the condensation of com-
mercially available 3-bromopropylamine hydrobromide
with hexane-2,5-dione upon treatment with an equimolar
amount of KOH gradually added to the reaction mixture
(Scheme 1). In contrast to the procedure described ear-
lier29 using methanol as a solvent, we applied less toxic
ethanol that practically did not affect the yield of the final
product, which after vacuum distillation was 68%. It should
be noted that such a yield is achieved only when the reac-
tion was carried out under argon, while in air deep re-
sinification of the reaction mixture occurs decreasing the
yield of product 1a to 30—35%. Most likely, this is ex-
plained by the high sensitivity of compound 1a to oxygen,
which is confirmed by its rapid polymerization in air ac-
companied by turning the color to deep red.
Scheme 1
In continuation of our works25—28 on the elaboration
of new approaches to nitrogen heterocycles, we suggested
that such lactams can be obtained by the alkylation
of enolates of the corresponding esters with 1-(3-halo-
propyl)-2,5-dimethylpyrroles followed by the removal of
the dimethylpyrrole protection29 and intramolecular
cyclization of δ-amino esters formed. The present work
is devoted to the confirmation of this hypothesis and the
development a new approach to the synthesis of six-
membered lactams.
Reagents and conditions: i. EtOH, KOH, reflux, 2 h; ii. NaI,
acetone, 20 °C, 48 h.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2108—2113, November, 2019.
1066-5285/19/6811-2108 © 2019 Springer Science+Business Media, Inc.

3,3-Disubstituted piperidin-2-ones
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
2109
Bromide 1a was converted to the corresponding iodide 1b
in 92% yield under the standard Finkelstein reaction con-
ditions (NaI, acetone, room temperature) (see Scheme 1).
We showed that addition of an equimolar amount of
bromide 1a to a solution of lithium enolate, obtained by
deprotonation of ethyl cyclohexanecarboxylate 2a with
lithium diisopropylamide in THF, at –60÷–50 °C fol-
lowed by a slow warming-up of the resulting mixture to
room temperature gave the corresponding alkylated ester
3a (Scheme 2). According to the NMR spectra, the
content of compound 3a in the reaction mixture obtained
after the standard aqueous work-up and removal of the
solvent was ~90%. In a separate experiment, product 3a
was isolated pure in 82% yield by flash chromatography
on silica gel.
We tested two methods for the cleavage of the 2,5-di-
methylpyrrole protection in compound 3a described in
the work,29 namely, the reflux in an aqueous ethanol solu-
tion in the presence of an excess of hydroxylamine hydro-
chloride and a similar process with the addition of
0.5 equiv. (based on the amount of hydroxylamine hydro-
chloride) of KOH. It turned out that in the first case,
prolonged heating (48 h) of the reaction mixture did not
cause a noticeable conversion of the starting ester, whereas
in the second case, the reaction was completed in 24 h.
According to the 1H NMR spectrum of the reaction
mixture recorded after the reflux for 24 h, the main prod-
ucts were hexane-2,5-dione dioxime and amino ester 4a
in a ratio of ~1 : 1. Despite the potential tendency to cyclize
to the corresponding lactam 5a, compound 4a turned out
to be quite stable and was isolated by vacuum distillation
in 76% yield based on ethyl cyclohexanecarboxylate 2a.
The cyclization of ester 4a to lactam 5a was successfully
accomplished by refluxing a solution of 4a in o-xylene for
2 h; the yield of product 5a after recrystallization was 87%
(see Scheme 2).
A fairly wide range of esters 2b—i can be involved into
similar transformations. Note that in these cases, in con-
trast to the reaction involving ethyl cyclohexanecarboxyl-
ate 2a, the removal of the 2,5-dimethylpyrrole protection
is accompanied by a spontaneous cyclization of amino
esters 4b—i to the corresponding lactams 5b—i (Scheme 3).
We studied the transformation 3→5 using 1H NMR spectro-
1
scopy and ester 3e as a model compound. The H NMR
spectra of reaction mixtures lacked the signals of amino
ester 4e thus indicating that the formation of compound
4e is much slower than its cyclization to lactam 5e.
Hexane-2,5-dione dioxime that resulted from the
destruction of the pyrrole ring by hydroxylamine is easily
separable by washing with an aqueous potassium hydr-
oxide. This allowed us to obtain products 5 with a purity
of more than 95% only by recrystallization.
When α,α-disubstituted esters 2b—g were used as the
starting compounds, the yields of the corresponding
3,3-disubstituted lactams were 62—78%. At the same time,
an attempt to extend this approach to the synthesis of
monosubstituted piperidin-2-ones from esters bearing two
α-protons at the alkoxycarbonyl group was less successful.
Thus, under similar conditions ethyl isovalerate 2h gave
3-isopropylpiperidin-2-one 5h in 32% yield only. Most
likely, this is explained by the presence of an acidic
α-proton in product 3h, which can be involved into the
exchange with the corresponding enolate to regenerate the
starting ester 2h. This assumption is confirmed by the
NMR spectra of the reaction mixture, which demonstrate
the absence of the signals for the starting ester 2h and the
presence of the intense signals for bromide 1a and uniden-
tified side products, whose pattern corresponds to the
signals for self-condensation products of ester 2h.
Replacing bromide 1a as an alkylating agent with iodide
1b did not improve the yield of compound 5h significantly,
which in this case amounted 35%.
Scheme 2
Reagents and conditions: i. Pri2NLi, THF, –60÷–50 °C; ii. 1a, THF, –50÷>20 °C; iii. EtOH, H2O, NH2OH•HCl, KOH, reflux,
24 h; iv. о-xylene, reflux, 2 h.

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
Gvozdev et al.
Схема 3
Compound
2—5
b
c
d
e
R1
R2
R3
Compound
2—5
f
g
h
i
R1
R2
R3
Me
Me
Me
Et
Et
Et
Me
Et
—(CH2)2N(Me)(CH2)2—
—(CH2)3N(Et)CH2—
Et
Et
Et
Et
—(CH2)2O(CH2)2—
—(CH2)4—
Pri
H
—(CH2)3—
Reagents and conditions: i. Pri2NLi, THF, –60÷–50 °C; ii. 1a, THF, –50÷>20 °C; iii. EtOH, H2O, NH2OH•HCl, KOH, reflux,
24—40 h.
Using this approach, we synthesized a new lactam 5i
bearing a spiro-fused four-membered ring from ethyl
cyclobutanecarboxylate 2i in 23% yield. According to the
spectrum of the reaction mixture recorded after the alkyl-
ation step, the starting ester 2i was completely consumed,
while a large amount of unreacted bromide 1a was present.
Apparently, the strained cyclobutane enolate arising in
the course of the reaction is involved not only into the
substitution of the bromine atom in compound 1a, but
also into the side processes. Therefore, it could be expected
that the replacement of bromide 1a with a more active
iodide 1b would increase the yield of lactam 5i. Indeed,
the use of iodide 1b allowed us to increase the yield of
lactam to 56% based on ester 2i (Scheme 4).
via alkylation of enolates of the corresponding esters with
1-(3-halopropyl)-2,5-dimethylpyrroles followed by the
removal of the dimethylpyrrole protection by treatment
with hydroxylamine. This approach is advantageous over
the widely used syntheses by the reductive cyclization of
γ-cyano esters since it does not require the use of highly
toxic acrylonitrile or its derivatives.
Experimental
GLC analysis of starting compounds and products was
performed on a Hewlett—Packard 5890 Series II instrument
equipped with an HP-1 capillary column (30 m×0.153 mm) and
a Hewlett—Packard 3396A automatic integrator. 1Н and 13С NMR
spectra were recorded on a Bruker AC-200p spectrometer in
CDCl3 using residual signals of the solvent as references.
High-resolution lectrospray ionization (ESI) mass spectra
were recorded on a Bruker micrOTOF II instrument. The measure-
ments were performed in a positive ion mode (the capillary
voltage was 4500 V). The scanning range of masses m/z was from 50
to 3000 Da, external or internal calibration (Electrospray Calib-
rant Solution, Fluka) was used. Compounds were syringed as
solutions in acetonitrile at a flow rate of 3 μL min–1. The nebulizer
gas was nitrogen (4 L min–1), the interface temperature was 180 °C.
Commercially available 3-bromopropylamine hydrobromide,
hexane-2,5-dione, and esters 2a—e,h were used as purchased.
Ethyl 1-methylpiperidine-4-carboxylate (2f) was synthesized by
reductive methylation of ethyl piperidine-4-carboxylate accord-
ing to the procedure described in patent.30 Ethyl 1-ethylpiperid-
ine-3-carboxylate (2g) was prepared by alkylation of ethyl piper-
idine-3-carboxylate with iodoethane under conditions earlier
described for the synthesis of ethyl 1-propylpiperidine-3-carb-
oxylate.31 Ethyl cyclobutanecarboxylate (2i) was synthesized by
esterification of cyclobutanecarboxylic acid under earlier de-
scribed conditions.32 Tetrahydrofuran was dried by distillation
over LiAlH4 immediately prior to use.
Scheme 4
Reagents and conditions: i. Pri2NLi, THF, –60÷–50 °C; ii. 1b,
THF, –50÷>20 °C; iii. EtOH, H2O, NH2OH•HCl, KOH, reflux,
24 h.
In conclusion, we proposed an original general ap-
proach to piperidin-2-ones substituted at the position 3

3,3-Disubstituted piperidin-2-ones
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
2111
1-(3-Bromopropyl)-2,5-dimethyl-1H-pyrrole (1a). A solution
of KOH (7.4 g, 0.12 mol) in a mixture of ethanol (100 mL) and
water (10 mL) was added to a refluxing solution of 3-bromo-
propylamine hydrobromide (21.9 g, 0.1 mol) and hexane-2,5-
dione (11.4 g, 0.1 mol) in ethanol (80 mL) under argon over
30 min. The resulting mixture was refluxed with stirring for 2 h
under argon, then cooled to room temperature, and poured into
water (300 mL). The precipitated brown oil was extracted three
times with CH2Cl2, the combined organic layers were dried with
anhydrous Na2SO4, and the solvent was evaporated. Compound
1a (14.7 g, 68%) was isolated from the residue by vacuum distil-
lation collecting the fraction with b.p. 85—89 °C (0.5 Torr).
1H NMR, δ: 2.15—2.29 (m, 2 H, NCH2CH2CH2Br); 2.30 (s, 6 H,
2 CH3); 3.46 (t, 2 H, NCH2CH2CH2Br, J = 6.3 Hz); 3.96 (t, 2 H,
NCH2CH2CH2Br, J = 7.4 Hz); 5.83 (br.s, 2 H, 2 СH=).
13C NMR, δ: 12.4 (2 CH3), 30.2, 33.7 (NCH2CH2CH2Br), 42.0
(NCH2CH2CH2Br), 105.2 (2 CH=), 127.4 (2 CCH3). The
spectral data of compound 1a are consistent with those published
previously.33
3.64—3.74 (m, 2 H, СH2N); 4.17 (q, 2 H, OCH2, J = 6.9 Hz);
5.79 (s, 2 H, 2 СH=). 13C NMR, δ: 12.5 (2 CH3 at pyrrole ring),
14.3 (CH3CH2O), 23.1 (C(2), C(6) in cyclo-С6), 25.7, 25.9
(CH2CH2CH2N, C(4) in cyclo-С6), 34.1 (C(3), C(5) in cyclo-С6),
37.3 (CH2CH2CH2N), 43.8 (CH2N), 46.5 (C(1) in cyclo-С6),
60.1 (OCH2), 105.1 (2 CH=), 127.2 (2 CCH3), 176.4 (C=O).
Ethyl 1-(3-aminopropyl)cyclohexanecarboxylate (4a). The
residue obtained by concentration of the reaction mixture as
described above was dissolved in a mixture of ethanol (60 mL)
and water (20 mL), then hydroxylamine hydrochloride (5.52 g,
80 mmol) and powdered KOH (2.52 g, 45 mmol) were added.
The mixture was refluxed under argon for 24 h and concentrated
in vacuo to dryness. The residue was treated with CH2Cl2
(100 mL) and water (20 mL). The organic layer was separated,
the aqueous layer was extracted with CH2Cl2 (2×20 mL). The
combined organic layers were washed with 25% aqueous KOH
(100 mL), dried with anhydrous Na2SO4, and the solvent was
evaporated. Vacuum distillation of the residue afforded com-
pound 4a (3.23 g, 76% based on ester 2a) with a purity of ~93%
as a colorless liquid, b.p. 88—92 °C (0.5 Torr). MS (ESI), found:
m/z 214.1808, calculated for [С12Н23NO2 + H]+: m/z 214.1802.
1H NMR, δ: 1.05—1.54 (m, 14 H, 6 CH2, NH2); 1.18 (t, 3 H,
CH3, J = 7.1 Hz); 1.91—2.06 (m, 2 H, C2HH, C6HH); 2.55
(t, 2 H, CH2NH2, J = 6.8 Hz); 4.06 (q, 2 H, OCH2, J = 7.1 Hz).
13C NMR, δ: 14.3 (CH3), 23.2 (C(2), C(6) in cyclo-С6), 25.9,
28.3 (CH2CH2CH2NH2, C4 in cyclo-С6), 34.1 (C(3), C(5)
in cyclo-С6), 37.7 (CH2CH2CH2NH2), 42.6 (CH2NH2), 46.5
(C(1) in cyclo-С6), 59.9 (OCH2), 176.6 (C=O).
Bromide 1a is stable upon storage in a tightly closed vessel
at low temperatures for several months, but it rapidly oxidizes
in air.
1-(3-Iodopropyl)-2,5-dimethyl-1H-pyrrole (1b). Bromide 1a
(10.8 g, 0.05 mol) was added to a solution of anhydrous NaI
(15 g, 0.1 mol) in anhydrous acetone (100 mL) and the resulting
mixture was stirred for 48 h at room temperature under argon.
The precipitate of sodium bromide was filtered off, washed with
acetone (20 mL), and the filtrate was concentrated. Water (50 mL)
and CH2Cl2 (50 mL) were added to the residue, the organic
layer was separated, the aqueous layer was extracted with CH2Cl2
(2×20 mL). The combined organic layers were dried with an-
hydrous Na2SO4, the solvent was evaporated to obtain a light red
liquid (12.1 g, 92%), which according to the NMR spectroscopy
data was iodide 1b with a purity of ~95%. Found (%): С, 41.31;
Н, 5.23; N, 5.20. С9H14IN. Calculated (%): C, 41.08; H, 5.36;
2-Azaspiro[5.5]undecan-1-one (5a). Amino ester 4а (3.23 g,
15 mmol) was dissolved in о-xylene (40 mL) and the resulting
solution was refluxed for 2 h. Then, the solvent was evaporated
in vacuo and the dark solid residue was recrystallized from
hexane—THF to obtain lactam 5а (2.18 g, 87%) with a purity
of >95%. MS (ESI), found: m/z 168.1388, calculated for
[С10Н17NO + H]+: m/z 168.1383. 1H NMR, δ: 1.19—1.68 (m,
8 H, 4 CH2); 1.70—2.02 (m, 6 H, 3 CH2); 3.20—3.34 (m, 2 H,
NCH2); 6.12 (br.s, 1 H, NH). 13C NMR, δ: 20.2 (C(4)), 20.9
(C(8), C(10)), 25.7 (C(9)), 29.0 (C(5)), 33.6 (C(7), C(11)), 36.3
(C(6)), 42.5 (C(3)), 178.8 (C=O).
Synthesis of piperidin-2-ones 5b—i from esters 2b—i (gen-
eral procedure). A 1.6 M solution of BunLi in hexane (13.7 mL,
22 mmol) was added to diisopropylamine (2.2 g, 22 mmol) in
anhydrous THF (50 mL) at –50÷–60 °C under dry argon. The
resulting mixture was stirred for 10 min at the same temperature
followed by a dropwise addition of a solution of the correspond-
ing ester 2 (20 mmol) in THF (10 mL). After 10 min, 1-(3-bromo-
propyl)-2,5-dimethylpyrrole (1a) (4.32 g, 20 mmol) or 1-(3-iodo-
propyl)-2,5-dimethylpyrrole (1b) (5.26 g, 20 mmol) was added
to the mixture, the temperature was gradually raised to ambient,
and the mixture was stirred for 2 h. Water (30 mL) and CH2Cl2
(50 mL) were added and the organic layer was separated. The
aqueous layer was additionally extracted with CH2Cl2 (2×20 mL),
the combined organic layers were dried with anhydrous Na2SO4,
and the solvent was evaporated. The residue was dissolved in
a mixture of ethanol (60 mL) and water (20 mL), followed by
the addition of hydroxylamine hydrochloride (5.52 g, 80 mmol)
and powdered KOH (2.52 g, 45 mmol). The reaction mixture
was refluxed under argon for 24—40 h until the complete con-
sumption of esters 3 (GLC monitoring). The solvent was evapo-
rated in vacuo to dryness, CH2Cl2 (100 mL), water (20 mL) were
added to the residue, the organic layer was separated, and the
1
N, 5.32. H NMR, δ: 2.07—2.25 (m, 2 H, NCH2CH2CH2I);
2.26 (s, 6 H, 2 CH3); 3.19 (t, 2 H, NCH2CH2CH2I, J = 6.7 Hz);
3.86 (t, 2 H, NCH2CH2CH2I, J = 7.5 Hz); 5.74 (br.s, 2 H,
2 СH=). 13C NMR, δ: 2.0 (NCH2CH2CH2I), 12.7 (2 CH3), 34.4
(NCH2CH2CH2I), 44.1 (NCH2CH2CH2I), 105.5 (2 CH=),
127.5 (2 CCH3).
Ethyl 1-[3-(2,5-dimethyl-1H-pyrrolyl)propyl]cyclohexane-
carboxylate (3a). A 1.6 М solution of BunLi in hexane (13.7 mL,
22 mmol) was added to diisopropylamine (2.2 g, 22 mmol) in
anhydrous THF (50 mL) at –50÷–60 °C under argon. The re-
sulting mixture was stirred for 10 min at the same temperature
followed by a dropwise addition of a solution of ethyl cyclo-
hexanecarboxylate 2a (3.12 g, 20 mmol) in THF (10 mL). After
10 min, bromide 1a (4.32 g, 20 mmol) was added to the reaction
mixture, the temperature was gradually raised to ambient, and
the mixture was stirred for 2 h. Then, water (30 mL) and CH2Cl2
(50 mL) were added and the organic layer was separated. The
aqueous layer was additionally extracted with CH2Cl2 (2×20 mL),
the combined organic layers were dried with anhydrous Na2SO4,
and the solvent was evaporated. The residue was subjected to
flash chromatography on silica gel (eluent hexane—Et2O,
20 : 1→10 : 1) to isolate ester 3a (4.77 g, 82%) as a dense yel-
low liquid. MS (ESI), found: m/z 292.2267, calculated for
[С18Н29NO2 + H]+: m/z 292.2271. 1H NMR, δ: 1.10—1.68 (m,
12 H, 6 CH2); 1.28 (t, 3 H, CH3CH2O, J = 6.9 Hz); 2.02—2.16
(m, 2 H, C2HH, C6HH, cyclo-C6); 2.22 (s, 6 H, 2 СH3);

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Gvozdev et al.
aqueous layer was extracted with CH2Cl2 (2×20 mL). The com-
bined organic layers were washed with 25% aqueous KOH
(100 mL), dried with anhydrous Na2SO4, the solvent was
evaporated, and the residue was recrystallized from HF—hexane
to give piperidones 5b—i.
3,3-Dimethylpiperidin-2-one (5b) was obtained from ethyl
isobutyrate (2b) and bromide 1a in 78% yield. 1H NMR, δ: 1.19
(s, 6 H, 2 CH3); 1.59—1.68 (m, 2 H, CH2); 1.70—1.84 (m, 2 H,
CH2); 3.22—3.31 (m, 2 H, NCH2); 6.59 (br.s, 1 H, NH).
13C NMR, δ: 19.4 (C(5)), 27.5 (2 CH3), 36.0 (C(4)), 37.8 (C(3)),
42.9 (C(6)), 178.7 (C=O). The spectral data of compound 5b
agree with those published earlier.11
3-Ethyl-3-methylpiperidin-2-one (5c) was obtained from
ethyl 2-methylbutanoate (2c) and bromide 1a in 69% yield.
1H NMR, δ: 0.90 (t, 3 H, CH2CH3, J = 7.4 Hz); 1.21 (s, 3 H, CH3);
1.67—1.88 (m, 4 H, 2 CH2); 1.42—1.63 (m, 2 H, CH2CH3);
3.21—3.36 (m, 2 H, NCH2); 6.24 (br.s, 1 H, NH). 13C NMR,
δ: 8.5 (CH2CH3), 19.4 (C(5)), 25.5 (CH3), 31.9 (CH2CH3), 32.1
(C(4)), 41.2 (C(3)), 42.6 (C(6)), 178.5 (C=O). The spectral data
of compound 5e agree with those published earlier.7
9-Oxa-2-azaspiro[5.5]undecan-1-one (5d) was obtained from
methyl tetrahydro-2H-pyran-4-carboxylate (2d) and bromide 1a
in 71% yield. MS (ESI), found: m/z 170.1183, calculated for
[С9Н15NO2 + H]+: m/z 170.1176. 1H NMR, δ: 1.38 (dddd,
2 H, C(7)HH, C(11)HH, J = 13.8 Hz, J = 5.2 Hz, J = 3.2 Hz,
J = 1.4 Hz); 1.69—1.86 (m, 4 H, C(4)H2, C(5)H2); 2.14 (ddd,
2 H, C(7)HH, C(11)HH, J = 13.8 Hz, J = 9.3 Hz, J = 4.1 Hz);
3.20—3.31 (m, 2 H, NCH2); 3.61 (ddd, 2 H, C(8)HH, C(10)HH,
J = 11.6 Hz, J = 9.3 Hz, J = 3.2 Hz); 3.87 (ddd, 2 H, C(8)HH,
C(10)HH, J = 11.6 Hz, J = 5.2 Hz, J = 4.1 Hz); 6.64 (br.s, 1 H,
NH). 13C NMR, δ: 18.5 (C(4)), 31.2 (C(5)), 34.2 (С(7), С(11)),
38.5 (C(6)), 42.3 (C(3)), 63.4 (C(8), C(10)), 177.4 (C=O).
7-Azaspiro[4.5]decan-6-one (5e) was obtained from ethyl
cyclopentanecarboxylate 2e and bromide 1a in 67% yield.
1H NMR, δ: 1.41—1.89 (m, 10 H, 5 СH2); 2.03—2.19 (m, 2 H,
СH2); 3.24—3.33 (m, 2 H, NCH2); 6.48 (br.s, 1 H, NH).
13C NMR, δ: 20.2 (C(9)), 25.8 (C(2), C(3)), 34.5 (C(10)), 38.7
(C(1), C(4)), 42.5 (C(8)), 48.5 (C(5)), 179.4 (C=O). The spec-
tral data of compound 5e agree with those published earlier.12
9-Methyl-2,9-diazaspiro[5.5]undecan-1-one (5f) was ob-
tained from ester 2f and bromide 1a in 65% yield. MS (ESI),
found: m/z 183.1478, calculated for [С10Н18N2O + H]+: m/z
183.1482. 1H NMR, δ: 1.38—1.52 (m, 2 H, C(7)HH, C(11)HH);
1.63—1.79 (m, 4 H, C(4)H2, C(5)H2); 2.01—2.19 (m, 4 H,
C(7)HH, C(8)HH, C(10)HH, C(11)HH); 2.22 (s, 3 H, NCH3);
2.51—2.68 (m, 2 H, C(8)HH, C(10)HH); 3.15—3.28 (m, 2 H,
C(3)H2); 6.40 (br.s, 1 H, NH). 13C NMR, δ: 18.8 (C(4)), 31.2
(C(5)), 33.6 (С(7), С(11)), 37.3 (C(6)), 42.4 (C(3)), 45.7 (CH3),
51.8 (C(8), C(10)), 177.1 (C=O).
J = 6.9 Hz); 0.93 (d, 3 H, CH3, J = 7.1 Hz); 1.43—1.94 (m, 4 H,
C(4)H2, C(5)H2); 2.21 (ddd, 1 H, C(3)H, J = 10.5 Hz, J = 6.1 Hz,
J = 3.8 Hz); 2.51 (d.sept, 1 H, CH(CH3)2, J = 3.8 Hz, J = 6.9 Hz);
3.17—3.31 (m, 2 H, NCH2); 6.72 (br.s, 1 H, NH). The spectral
data of compound 5h agree with those published earlier.34
A similar experiment with iodide 1b instead of bromide 1a
gave lactam 5h in 35% yield.
6-Azaspiro[3.5]nonan-5-one (5i) was obtained from ester 2i
and iodide 1b in 56% yield. MS (ESI), found: m/z 140.1073,
1
calculated for [С8Н13NO + H]+: m/z 140.1070. H NMR, δ:
1.59—1.83 (m, 4 H, C(8)H2, C(9)H2); 1.86—2.09 (m, 4 H,
C(2)H2, C(1)HH, C(3)HH); 2.47—2.68 (m, 2 H, C(1)HH,
C(3)HH); 3.19—3.32 (m, 2 H, NCH2); 6.22 (br.s, 1 H, NH).
13C NMR, δ: 15.8 (C(2)), 19.3 (C(8)), 30.6 (C(1), C(3)), 33.3
(C(9)), 42.5 (C(7)), 43.1 (C(4)), 177.2 (C=O).
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1
and bromide 1a in 32% yield. H NMR, δ: 0.83 (d, 3 H, CH3,

3,3-Disubstituted piperidin-2-ones
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Received July 30, 2019;
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