Synthesis of piperidine derivatives fused to a tetrahydrofuran ring

Article abstract of DOI:10.1134/S1070428014010102

Intramolecular nucleophilic opening of the oxirane ring in tert-butyl 6-(2-hydroxyethyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate by the action of excess potassium hydroxide in 75% aqueous dimethyl sulfoxide at 110-120 C gave tert-butyl (3aR,7aS)-3a-hydroxyhexahydrofuro[2,3-c]pyridine-6(2H)- carboxylate whose treatment with POCl₃ resulted in elimination of water molecule and tert-butoxycarbonyl group with formation of 2,3,4,5,6,7-hexahydrofuro[2,3-c]pyridine hydrochloride. The latter reacted with electrophiles (acetic anhydride, methanesulfonyl chloride, and benzaldehyde in combination with sodium triacetoxyhydridoborate) in the presence of triethylamine, yielding the corresponding N-substituted 2,3,4,5,6,7- hexahydrofuro[ 2,3-c]pyridine derivatives.

Full text of DOI:10.1134/S1070428014010102

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 54–58. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.I. Moskalenko, V.I. Boev, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1, pp. 61–65.
Synthesis of Piperidine Derivatives Fused
to a Tetrahydrofuran Ring
A. I. Moskalenkoa and V. I. Boevb
a Lipetsk State Pedagogical University, ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
b Timiryazev Russian State Agrarian University, Moscow, Russia
Received June 21, 2013
Abstract—Intramolecular nucleophilic opening of the oxirane ring in tert-butyl 6-(2-hydroxyethyl)-7-oxa-3-
azabicyclo[4.1.0]heptane-3-carboxylate by the action of excess potassium hydroxide in 75% aqueous dimethyl
sulfoxide at 110–120°C gave tert-butyl (3aR,7aS)-3a-hydroxyhexahydrofuro[2,3-c]pyridine-6(2H)-carboxylate
whose treatment with POCl3 resulted in elimination of water molecule and tert-butoxycarbonyl group with
formation of 2,3,4,5,6,7-hexahydrofuro[2,3-c]pyridine hydrochloride. The latter reacted with electrophiles
(acetic anhydride, methanesulfonyl chloride, and benzaldehyde in combination with sodium triacetoxy-
hydridoborate) in the presence of triethylamine, yielding the corresponding N-substituted 2,3,4,5,6,7-hexa-
hydrofuro[2,3-c]pyridine derivatives.
DOI: 10.1134/S1070428014010102
Many oxygen-containing piperidine derivatives
exhibit high biological activity; in particular, they act
as strong inhibitors toward some glucosidases and
related enzymes [1, 2]. An example is Cisapride (I),
an efficient serotonin 5-HT4 receptor agonist, which is
used to enhance gastrointestinal motility with no any
undesirable side effect [3, 4]. Diastereoisomeric amino
hydroxy piperidine alkaloids II–IV isolated from
marine organisms have attracted much attention due to
their anticancer activity [5–8]. Therefore, synthesis of
new oxygen-containing piperidine derivatives seems to
be promising from the viewpoint of design of efficient
biologically active compounds and building blocks for
fine organic synthesis.
hydrofuran ring. As starting compound we used acces-
sible 1-Boc-piperidin-4-one (V) which was brought
into the Wittig–Horner reaction [10–12] with phospho-
nate VI. Depending on the conditions, unsaturated
ester VII was formed as the major product or a mixture
of esters VII and VIII was obtained. When the reac-
tion was carried out in the presence of sodium hydride
as deprotonating agent at room temperature (reaction
time 12 h), the conversion of ketone V was as low as
~30%, and ester VII was the only product. Under more
severe conditions, by heating equimolar amounts of the
reactants in boiling tetrahydrofuran in the presence of
potassium tert-butoxide for 4 h, we obtained a mixture
of esters VII and VIII, the conversion of V being
complete (Scheme 1).
While developing general procedures for the pre-
paration of piperidine derivatives containing a tetra-
hydrofuran fragment [9], we have synthesized new
compounds in which piperidine ring is fused to a tetra-
Isomerization of ester VII by the action of lithium
diisopropylamide (LDA) in THF also afforded com-
pound VIII. Ester VIII was then reduced with lithium
O
OMe
OH
OH
OH
HN
N
NH2
NH2
NH2
MeO
NH2
R
N
H
R
N
H
R
N
H
Cl
O
F
II
III
IV
I
R =
.
Me
54

SYNTHESIS OF PIPERIDINE DERIVATIVES FUSED TO A TETRAHYDROFURAN RING
55
Scheme 1.
O
LDA, –78°C
NaH, 20°C, 12 h
COOEt
COOEt
+
(EtO)2P(O)CH2COOEt
N
N
N
Boc
Boc
Boc
V
VI
VII
VII
VIII
t-BuOK, 60°C, 4 h
V
+
VI
+
VIII
Boc = t-BuOC(O).
Scheme 2.
CH2OH
CH2OH
O
OH
LiAlH4
3-ClC6H4CO3H
CH2Cl2, 20°C
KOH, DMSO/H2O
110–120°C
THF, 0°C
VIII
N
N
N
O
Boc
Boc
Boc
IX
X
XI
tetrahydridoaluminate to unsaturated alcohol IX in
71% yield. The oxidation of the double bond in IX
with 3-chloroperoxybenzoic acid in methylene
chloride gave 63% of epoxy derivative X as a 1:1
mixture of diastereoisomers (according to the GC/MS
of the Boc protecting group to produce unsaturated
N-unsubstituted secondary amine XIII which was
isolated as hydrochloride. The NH hydrogen atom in
XIII was replaced by acetyl, methanesulfonyl, and
benzyl groups by reactions with the corresponding
electrophiles according to [16, 17]. The structure of
compounds VII–XI and XIII–XVI was determined on
the basis of their elemental compositions, IR and
1H NMR spectra, and GC/MS data.
1
and H NMR data). With account taken of published
data [13, 14], the final step in the synthesis of target
compound XI was intramolecular nucleophilic opening
of the oxirane ring in X by the action of excess potas-
sium hydroxide in 75% aqueous dimethyl sulfoxide at
110–120°C. As a result, we isolated 54% of new piper-
idine derivative XI with a fused tetrahydrofuran ring
EXPERIMENTAL
(Scheme 2). The product was a single
stereoisomer analogous to benzofuran
derivative XII described in [14]. We can
conclude that intramolecular oxirane ring
The IR spectra were recorded in KBr on a Specord
75IR spectrometer. The H NMR spectra were
OH
1
measured on a Varian Mercury Plus 400 instrument
(400 MHz) using hexamethyldisiloxane as internal
reference. The mass spectra (atmospheric pressure
chemical ionization) were obtained on a Thermo
Finnigan Surveyor MSQ mass spectrometer (USA).
The purity of the isolated compounds was checked by
O
XII
opening in X is also stereospecific.
Treatment of tertiary alcohol XI with POCl3
according to the procedure described in [15] led to
elimination of water molecule with simultaneous loss
Scheme 3.
Ac2O, CH2Cl2
N
O
Ac
XIV
POCl3
–H2O
Et3N
MeSO2Cl, CH2Cl2
XI
· HCl
–Et3N·HCl
N
HN
O
O
O
MeSO2
PhCH2
XIII
XV
PhCHO, NaBH(OAc)3
CH2Cl2
N
XVI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

MOSKALENKO, BOEV
56
TLC on Silufol UV-254 plates using hexane–ethyl
acetate (1:1 by volume); spots were developed by
treatment with a solution of ninhydrin in isopropyl
alcohol on heating. Silica gel 60 (Merck) was used for
column chromatography.
tert-Butyl 4-(2-ethoxy-2-oxoethyl)-1,2,3,6-tetra-
hydropyridine-1-carboxylate (VIII). A solution of
2.37 g (8.8 mmol) of compound VII in 200 mL of
anhydrous THF was cooled to –78°C, a solution of
15.4 mmol of lithium diisopropylamide in 15 mL of
THF was added under stirring in an argon atmosphere,
the mixture was stirred for 30 min at –78°C, 1.2 mL of
glacial acetic acid in 10 mL of THF was added, and the
mixture was stirred for 20 min at that temperature. The
mixture was then allowed to warm up to room
temperature, 200 mL of a saturated aqueous solution of
sodium hydrogen carbonate and 70 mL of ethyl acetate
were added, the mixture was shaken, the organic layer
was separated, and the aqueous layer was extracted
with 100 mL of ethyl acetate. The extract was com-
bined with the organic phase, washed with brine, and
dried over anhydrous sodium sulfate. Removal of the
solvent under reduced pressure left 2.36 g (99.9%) of
compound VIII as a light yellow thick oily material.
IR spectrum, ν, cm–1: 1718, 1685 (C=O), 1628 (C=C).
1H NMR spectrum (CDCl3), δ, ppm: 1.27 t (3H, Me),
1.48 s (9H, CMe3), 2.13 s (2H, CH2), 3.03 s (2H,
CH2O), 3.51 t (2H, CH2N), 3.88 s (2H, CH2N), 4.15 q
(2H, CH2O), 5.53 s (1H, HC=C). Mass spectrum, m/z
(Irel, %): 170.24 (100) [M – 101 + 2H]+. Found, %:
C 62.03; H 8.41; N 5.16. C14H23NO4. Calculated, %:
C 62.45; H 8.55; N 5.20. M 269.28.
tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperi-
dine-1-carboxylate (VII). a. Phosphonate VI, 5.66 g
(25 mmol), was dissolved in 40 mL of anhydrous THF,
0.96 g (25 mmol) of a 60% suspension of sodium
hydride in mineral oil was added in portions under
stirring and cooling with cold water, the mixture was
stirred for 0.5 h, 4.0 g (20 mmol) of ketone V in 40 mL
of THF was added, and the mixture was stirred for
20 h at room temperature. The mixture was treated
with 150 mL of water and 70 mL of ethyl acetate and
shaken, the organic layer was separated, and the aque-
ous layer was extracted with ethyl acetate (2×70 mL).
The extracts were combined with the organic phase,
washed with water and brine, and dried over anhy-
drous sodium sulfate. The solvent was removed under
reduced pressure, and the residue (6.81 g) was subject-
ed to chromatography on silica gel. Elution with ethyl
acetate–hexane (1:3) gave 2.41 g of compound VII,
and with ethyl acetate–hexane (1:1), 3.18 g of unre-
acted ketone V. Yield of VII 100% (on the reacted
ketone V), mp 85–86°C [10]. IR spectrum, ν, cm–1:
1
1706, 1684 (C=O), 1643 (C=C). H NMR spectrum
tert-Butyl 4-(2-hydroxyethyl)-1,2,3,6-tetrahydro-
pyridine-1-carboxylate (IX). A solution of 2.58 g
(9.6 mmol) of compound VIII in 80 mL of anhydrous
THF was cooled to 0°C, 0.63 g (16.6 mmol) of LiAlH4
was added in portions under stirring, and the mixture
was stirred for 3 h at room temperature. The mixture
was then cooled to 0°C, 1.8 mL of water and 10 mL of
10% H2SO4 were added dropwise, the mixture was
stirred for 0.5 h, 70 mL of ethyl acetate was added, and
the mixture was filtered through a thin layer of celite.
The precipitate was washed with 80 mL of ethyl
acetate, and the organic layer was separated from the
filtrate, washed with brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under
reduced pressure to isolate 1.54 g (71%) of compound
IX as a light yellow thick oily substance. IR spectrum,
ν, cm–1: 3242 (OH), 1684 (C=O), 1625 (C=C). 1H NMR
spectrum (CDCl3), δ, ppm: 1.48 s (9H, CMe3), 2.12 s
(2H, CH2), 2.58 t (2H, CH2C=C), 3.51 t (2H, CH2N),
3.48 t (2H, CH2N), 3.71 t (2H, CH2O), 3.83 s (2H,
CH2N), 5.47 s (1H, HC=C). Mass spectrum, m/z (Irel,
%): 227.67 (22.4) [M + H]+, 128.36 (100) [M – 101 +
2H]+. Found, %: C 63.18; H 9.13; N 5.98. C12H21NO3.
Calculated, %: C 63.44; H 9.25; N 6.17. M 227.30.
(CDCl3), δ, ppm: 1.28 t (3H, Me), 1.47 s (9H, CMe3),
2.25 t (2H, CH2), 2.98 t (2H, CH2), 3.49 m (4H,
NCH2), 4.16 q (2H, CH2O), 5.73 s (1H, HC=C). Mass
spectrum, m/z (Irel, %): 170.22 (100) [M – 101 + 2H]+.
Found, %: C 62.18; H 8.43; N 5.31. C14H23NO4. Cal-
culated, %: C 62.45; H 8.55; N 5.20. M 269.28.
b. Potassium tert-butoxide, 11.20 g (100 mmol),
was added in portions under stirring and cooling with
ice water to a mixture of 19.90 g (100 mmol) of ketone
V and 22.40 g (100 mmol) of phosphonate VI in
200 mL of anhydrous THF, and the mixture was heated
for 4 h under reflux in an argon atmosphere. The
solvent was distilled off under reduced pressure,
250 mL of ethyl acetate and 150 mL of 5% aqueous
HCl were added to the residue, the mixture was
shaken, and the organic layer was separated, washed
with brine, and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure, and
the residue (34.21 g) was subjected to chromatography
on silica gel. Elution with ethyl acetate–hexane (1:3)
gave in succession 21.0 g (78%) of VII (mp 84–85°C)
and 1.32 g (4.9%) of VIII as a light yellow thick
material which crystallized on storage.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

SYNTHESIS OF PIPERIDINE DERIVATIVES FUSED TO A TETRAHYDROFURAN RING
57
1
(C=C). H NMR spectrum (DMSO-d6), δ, ppm: 1.68–
tert-Butyl 6-(2-hydroxyethyl)-7-oxa-3-azabicyclo-
[4.1.0]heptane-3-carboxylate (X). 3-Chloroperoxy-
benzoic acid, 1.70 g (9.91 mmol), was added under
stirring to a solution of 1.50 g (6.61 mmol) of com-
pound IX in 15 mL of anhydrous methylene chloride.
After 18 h, the precipitate of 3-chlorobenzoic acid was
filtered off, and the filtrate was diluted with 40 mL of
methylene chloride, washed with three portions of
7% aqueous potassium hydroxide and with water, and
dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure to obtain 1.02 g
(63%) of compound X as a colorless thick oily sub-
stance. IR spectrum, ν, cm–1: 3238 (OH), 1685 (C=O),
2.03 m (4H, CH2), 3.94 s (2H, CH2N), 4.01 t (2H,
+
OCH2), 10.63 br.s (2H, NH2 ). Mass spectrum, m/z
(Irel, %): 126.41 (100) [M + H]+. Found, %: C 51.83;
H 7.28; N 8.43. C7H11NO · HCl. Calculated, %:
C 52.01; H 7.43; N 8.67. M 125.43 (fee base).
1-(3,4,5,7-Tetrahydrofuro[2,3-c]pyridin-6(2H)-
yl)ethanone (XIV) was synthesized according to [17].
Yield 94%. IR spectrum, ν, cm–1: 1668 (C=O), 1645
1
(C=C). H NMR spectrum (CDCl3), δ, ppm: 1.71–
1.93 m (4H, CH2), 2.03 s (3H, CH3), 2.87 t (2H,
NCH2), 3.58 s (2H, NCH2), 3.89 t (2H, OCH2). Mass
spectrum, m/z (Irel, %): 168.53 (100) [M + H]+. Found,
%: C 64.75; H 7.63; N 8.21. C9H13NO2. Calculated, %:
C 64.67; H 7.78; N 8.38. M 167.48.
1
868 (oxirane) [18]. H NMR spectrum (CDCl3), δ,
ppm: 1.48 s (9H, CMe3), 1.78 m (2H, CH2C), 1.82 m
(2H, CH2C), 1.97 m (2H, CH2CN), 2.01 m (2H,
CH2CN), 2.12 br.s (1H, OH), 2.98 m (2H, CH2N),
3.04 m (2H, CH2N), 3.31 m (2H, CH2N), 3.56 m (2H,
CH2N), 3.68 t (1H, 5-H), 3.72 t (1H, 5-H), 3.76 t (2H,
CH2O), 3.81 t (2H, CH2O). Mass spectrum, m/z
(Irel, %): 144.32 (100), 144.26 (78) [M – 101 + 2H]+.
Found, %: C 59.03; H 8.53; N 5.64. C12H21NO4. Cal-
culated, %: C 59.26; H 8.64; N 5.76. M 243.32.
6-Methylsulfonyl-2,3,4,5,6,7-hexahydrofuro-
[2,3-c]pyridine (XV) was synthesized according to
[17]. Yield 95%. IR spectrum, ν, cm–1: 1648 (C=C);
1322, 1178 (SO2). 1H NMR spectrum (CDCl3), δ, ppm:
1.74–1.98 m (4H, CH2), 2.89 t (2H, NCH2), 3.01 s
(3H, SO2CH3), 3.61 s (2H, NCH2), 3.98 t (2H, OCH2).
Mass spectrum, m/z (Irel, %): 204.26 (100) [M + H]+.
Found, %: C 47.43; H 6.52; N 7.04. C8H13NO3S. Cal-
culated, %: C 47.29; H 6.40; N 6.90. M 203.56.
tert-Butyl (3aR,7aS)-3a-hydroxyhexahydrofuro-
[2,3-c]pyridine-6(2H)-carboxylate (XI). Potassium
hydroxide, 1.12 g (20 mmol), was added to a solution
of 0.486 g (2 mmol) of compound X in 45 mL of
75% aqueous dimethyl sulfoxide, and the mixture was
heated for 2 h at 110–120°C, cooled, diluted with
100 mL of water, and extracted with ethyl acetate
(3×50 mL). The extract was washed with two portions
of water and with brine and dried over anhydrous
sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue (0.45 g) was subject-
ed to chromatography on silica gel using ethyl acetate–
hexane (1:1) as eluent. Yield 0.262 g (54%), colorless
oily substance. IR spectrum, ν, cm–1: 3248 (OH), 1683
6-Benzyl-2,3,4,5,6,7-hexahydrofuro[2,3-c]pyri-
dine (XVI) was synthesized according to [16]. Yield
76%. IR spectrum: ν 1638 cm–1 (C=C). 1H NMR spec-
trum (CDCl3), δ, ppm: 1.64–1.92 m (4H, CH2), 2.68 m
(2H, NCH2), 3.54–3.63 m (4H, NCH2, CH2Ph), 3.95 t
(2H, OCH2), 7.18–7.32 m (5H, Ph). Mass spectrum,
m/z (Irel, %): 216.31 (100) [M + H]+. Found, %:
C 76.83; H 7.98; N 6.34. C14H17NO. Calculated, %:
C 78.14; H 7.91; N 6.51. M 215.42.
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