Regioselective endocyclic oxidation of enantiopure 3-alkylpiperidines: Synthesis of (3S,5S)-(-)-3-ethyl-5-methylpiperidine

Article abstract of DOI:10.1080/00397910500466454

An efficient regioselective endocyclic oxidation of enantiopure 3-alkylpiperidines 1(a-c) with bromine in acetic acid to generate the corresponding 5-alkylpiperidin-2-ones 3(a-c) as main product is described. In addition, starting from 3a or 3b, the synth

Full text of DOI:10.1080/00397910500466454

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Regioselective Endocyclic Oxidation of
Enantiopure 3‐Alkylpiperidines: Synthesis of
(3S,5S)‐(‐)‐3‐Ethyl‐5‐Methylpiperidine
Alejandro Castro a , Jorge Juárez a , Dino Gnecco a , Joel L. Terán a , Laura
Orea, a & Sylvain Bernès a
a Centro de Química , Instituto de Ciencias BUAP, Ciudad Universitaria ,
Puebla, México
Published online: 16 Aug 2006.
To cite this article: Alejandro Castro , Jorge Juárez , Dino Gnecco , Joel L. Terán , Laura Orea, &
Sylvain Bernès (2006) Regioselective Endocyclic Oxidation of Enantiopure 3‐Alkylpiperidines: Synthesis
of (3S,5S)‐(‐)‐3‐Ethyl‐5‐Methylpiperidine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:7, 935-942, DOI: 10.1080/00397910500466454
To link to this article: http://dx.doi.org/10.1080/00397910500466454
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Synthetic Communicationsw, 36: 935–942, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500466454
Regioselective Endocyclic Oxidation
of Enantiopure 3-Alkylpiperidines: Synthesis
of (3S,5S)-(-)-3-Ethyl-5-Methylpiperidine
´
´
Alejandro Castro, Jorge Juarez, Dino Gnecco, Joel L. Teran,
`
Laura Orea, and Sylvain Bernes
Centro de Quımica, Instituto de Ciencias BUAP, Ciudad Universitaria,
´
Puebla, Mexico
´
Abstract: An efficient regioselective endocyclic oxidation of enantiopure 3-alkylpiper-
idines 1(a–c) with bromine in acetic acid to generate the corresponding 5-alkylpiper-
idin-2-ones 3(a–c) as main product is described. In addition, starting from 3a or 3b, the
.
synthesis of (3S,5S)-(-)-3-ethyl-5-methylpiperidine 6 HCl was achieved. Finally, the
X-ray single-crystal analysis of compound 4 is reported.
Keywords: Chiral piperidines, piperidine-2-ones, regioselective oxidation, synthesis
asymmetric
INTRODUCTION
In general, piperidin-2-ones are versatile synthetic building blocks, which are
used as starting materials to carry out the synthesis of interesting and diversely
functionalized piperidines.[1–6] In this context, we previously reported a facile
procedure to prepare enantiopure piperidine I and its transformation into II.
Then, starting from this compound, the enantioselective synthesis of
(20S,3R)-(þ)-stenusine III was achieved in 70% overall yield[7] (Scheme 1).
Received in the USA October 12, 2005
´ ´
Address correspondence to Jorge Juarez, Centro de Quımica, Instituto de Ciencias
BUAP, Ciudad Universitaria, Edificio 194, Complejo de Ciencias, 72570, Puebla, Pue,
´
Mexico. Tel.: þ 52 (222) 2453277; Fax: 2295551; E-mail: rijuarez@siu.buap.mx
935

936
A. Castro et al.
Scheme 1.
RESULTS AND DISCUSSION
Motivate by these results, we synthesized the enantiopure compounds 1(a–c)
following the procedure described in our previous publication.[7] Now, we
report on the regioselective endocyclic oxidation of 1(a–c). The oxidation
of these compounds with bromine in the presence of acetic acid generated
the regioisomeric mixture 2(a–c) þ 3(a–c) (Scheme 2) in 95% overall
yield in different proportions (determined by 1H NMR from crude reactions).
Separation of regioisomers was accomplished without complication by
flash chromatography. In all cases, the oxidation at C-6 was favored to give,
as the main product, the corresponding 5-alkylpiperidine-2-ones 3(a–c)
(Table 1).
Reaction of 3a with sec-BuLi and iodoethane in presence of HMPA
afforded the diastereoisomeric mixture in 90% yield with a ratio 95:5 (deter-
mined by 1H NMR from crude reactions). Separation of this mixture by flash
chromatography afforded 4 in 85% yield (Scheme 3).
Compound 4 crystallized from chloroform/cyclohexane, and its analysis
of single-crystal with X-ray was performed. The absolute configuration for
C-3 and C-5 was established as (S). According to our knowledge, it is the
first time that an X-ray study for this structure is reported (Figure 1).
Treatment of compound 4 with Red-Al in tetrahydrofuran quantitatively
gave the compound 5. Compound 5 was obtained from 3b following the same
procedure described previously and using iodomethane). Finally, hydrogeno-
lysis of this compound afforded (3S,5S)-(-)-3-ethyl-5-methylpiperidine
Scheme 2.

(3S,5S)-(-)-Ethyl-5-Methylpiperidine Synthesis
Table 1. Regioisomeric ratio of 2(a–c) and 3(a–c)
937
3-Alkylpiperidine 1 3-Alkylpiperidin-2-one 2 (%)a 5-Alkylpiperidin-2-one 3 (%)a
a, R ¼ Me
b, R ¼ Et
c, R ¼ Bn
40
35
2
60
65
98
aThe regioisomeric ratio was determined by H NMR from crude reactions.
1
.
hydrochloride 6 HCl in 95% yield (Scheme 4). (Compound 5 was obtained
starting from 3b following the same procedure described previously and using
iodomethane.)
In conclusion, we here describe an easy procedure to synthesize trans-3,5-
dialkylpiperidines in high yield. In fact, encouraged by these results, we
are preparing trans-3,5-disubstituted piperidin-2-ones, which are useful in
asymmetric synthesis of alkaloids.
EXPERIMENTAL
1H NMR spectra were measured with a Varian VX400 (400 MHz) and 13C
NMR spectra at 100 MHz (TMS as internal reference). The IR spectra were
determined with a Nicolet FT-IR Magna 750 spectrometer. Optical rotations
were determined at room temperature with a Perkin-Elmer 341 polarimeter,
using a 1-dm cell with a total volume of 1 mL, and are referenced to the
D-line of sodium. Mass spectra were recorded with a JEOL JEM-
AX505HA instrument at a voltage of 70 eV.
General Procedure for Synthesis of 1(a–c)
This compounds were prepared starting from (10R)-(-)-1-(20-hydroxy-10-
[7]
phenylethyl)piperidin-2-one, operating as described in Ref.
(20R,3S)-(-)-2-(3-Methylpiperidin-1-yl)-2-phenylethanol (1a). Colorless oil,
1
[a]D 246.8 (c 1.2, CHCl3). IR (KBr) 2927 cm21. H NMR (CDCl3, d ppm,
J Hz): 0.72–0.82 (m, 1H), 0.85 (d, 6.6, 3H), 1.43–1.53 (m, 1H), 1.58–1.68
Scheme 3.

938
A. Castro et al.
Figure 1. Molecular structure of 4 determined by x-ray single-crystal diffraction (dis-
placement ellipsoids at the 20% probability level for non-H atoms). The first indepen-
dent molecule of the symmetric unit is represented.
(m, 3H), 1.72 (m, 1H), 1.89–1.96 (AB, 10.2, 1H), 2.71–2.81 (m, 2H), 3.14
(br, OH), 3.58–3.63 (AB, 10.2, 1H), 3.66–3.71 (AB, 9.9, 1H), 3.95–4.01
(AB, 9.9, 1H), 7.15–7.34 (m, 5H). 13C NMR (CDCl3): 19.6, 25.7, 31.8,
32.9, 46.4, 59.8, 60.6, 70.1, 127.6, 127.9, 128.8, 135.2. HRMS (FAB):
Calcd. for C14H21NO: 219.1623. Found: 219.1601.
(20R,3S)-(-)-2-(3-Ethylpiperidin-1-yl)-2-phenylethanol (1b). Colorless oil,
1
[a]D 251.4 (c 1.0, CHCl3). IR (KBr) 2928 cm21. H NMR (CDCl3, d ppm,
J Hz): 0.68–0.77 (m, 1H), 0.88 (t, 7.5, 3H), 1.13–1.27 (m, 2H), 1.43–1.51
(m, 2H), 1.60–1.70 (m, 3H), 1.95 (AB, 10.5, 10.8, 1H), 2.76–2.80 (m, 2H),
3.59 (AB, 5.1, 1H), 3.69 (AB, 5.1, 5.4, 1H), 3.97 (AB, 9.6, 10.2, 1H),
7.15–7.34 (m, 5H). 13C NMR (CDCl3): 11.6, 25.7, 27.1, 30.7, 38.6, 46.9,
58.8, 59.8, 70.1, 127.6, 127.9, 128.8, 135.2. HRMS (FAB): Calcd. for
C15H23NO: 233.1780. Found: 233.1754.
Scheme 4.

(3S,5S)-(-)-Ethyl-5-Methylpiperidine Synthesis
939
(20R,3R)-(-)-2-(3-Benzylpiperidin-1-yl)-2-phenylethanol (1c). Yellow oil,
1
[a]D 244.2 (c 1.0, MeOH). IR (KBr) 2922 cm21. H NMR (CDCl3, d ppm,
J Hz): 1.11–1.15 (m, 1H), 1.73–1.76 (m, 2H), 1.86 (m, 1H), 2.28 (m, 1H),
2.56–2.65 (m, 3H), 2.73–2.79 (m, 1H), 3.34 (m, 1H), 3.71 (m, 1H), 4.02–
4.15 (AB, 4.4, 6.4, 2H), 4.34 (AB, 4.8, 5.2, 1H), 7.17–7.54 (m, 10H). 13C
NMR (CDCl3): 23.9, 29.2, 37.3, 40.9, 51.3, 57.9, 60.8, 73.0, 127.4, 129.4,
130.0, 130.3, 130.7, 131.1, 132.9, 139.5. HRMS (FAB): Calcd. for
C20H25NO: 295.1936. Found: 295.1912.
General Procedure for Synthesis of 2(a–c) and 3(a–c)
[7]
Compounds 1(a–c) were oxidized operating as described in Ref.
(10R,3S)-(-)-1-(20-Hydroxy-10-phenylethyl)-3-methylpiperidin-2-one (2a). White
crystal, mp: 116 8C. [a]D 257.5 (c 0.7, CHCl3). IR (KBr) 1615 cm21. 1H NMR
(CDCl3, d ppm, J Hz): 1.28 (d, 7.2, 3H), 1.45 (m, 1H), 1.71 (m, 2H), 1.95
(m, 1H), 2.52 (m, 1H), 2.9 (m, 1H), 3.21 (m, 1H), 4.11 (AB, 8.7, 2H), 5.87
(dd, 8.7, 1H), 7.23–7.35 (m, 5H). 13C NMR (CDCl3): 18.1, 21.1, 28.6,
36.5, 43.3, 58.9, 61.2, 127.4, 127.7, 128.4, 137.1, 175.1. HRMS (FAB):
Calcd. for C14H19NO2: 233.1416. Found: 233.1394.
(10R,3S)-(-)-3-Ethyl-1-(20-Hydroxy-10-phenylethyl)piperidin-2-one (2b). White
1
crystal, Mp: 80 8C. [a]D 228.1 (c 0.7, CHCl3). IR (KBr) 1613 cm21. H
NMR (CDCl3, d ppm, J Hz): 0.93 (t, 7.2, 7.6, 3H), 1.48 (m, 1H), 1.56–1.73
(m, 3H), 1.85–1.95 (m, 2H), 2.34 (m, 1H), 2.84 (m, 1H), 3.16 (m, 1H),
3.78 (t, 5.2, OH), 4.09 (AB, 8.8, 2H), 5.81 (dd, 9.0, 1H), 7.20–7.35
(m, 5H). 13C NMR (CDCl3): 11.4, 21.5, 25.2, 25.5, 43.1, 43.7, 58.5, 61.6,
127.4, 127.6, 128.4, 136.9, 174.4. HRMS (FAB): Calcd. for C15H21NO2:
247.1572. Found: 247.1549.
(10R,3R)-(þ)-3-Benzyl-1-(20-Hydroxy-10-phenylethyl)piperidin-2-one (2c).
Yellow oil, [a]D þ15.4 (c 1.4, CHCl3). IR (KBr) 1611 cm21
.
1H NMR
(CDCl3, d ppm, J Hz): 1.41 (m, 1H), 1.63 (m, 2H), 1.71 (m, 1H), 2.7
(m, 1H), 2.8 (m, 1H), 2.83 (AB, 4.0, 1H), 3.16 (m, 1H), 3.32 (AB, 4.0, 1H),
3.85 (br, OH), 4.14 (AB, 5.2, 5.6, 2H), 5.89 (dd, 5.2, 5.6, 1H), 7.18–7.33
(m, 10H). 13C NMR (CDCl3): 21.3, 25.1, 38.0, 43.5, 43.6, 58.4, 61.4, 125.9,
127.4, 127.6, 128.1, 128.3, 129.2, 136.7, 139.5, 173.5. HRMS (FAB):
Calcd. for C20H23NO2: 309.1729. Found: 309.1704.
(10R,5S)-(-)-1-(20-Hydroxy-10-phenylethyl)-5-methylpiperidin-2-one
(3a).
White crystal, mp: 114 8C. [a]D 286.8 (c 1.1, CH2Cl2). IR (KBr)
1
1614 cm21. H NMR (CDCl3, d ppm, J Hz): 0.93 (d, 6.4, 3H), 1.43–1.54
(m, 1H), 1.80 (br, 2H), 2.41–2.60 (m, 2H), 2.87 (dd, 10.4, 11.6, 1H), 2.98
(m, 1H), 3.71 (t, 4.8, OH), 4.00–4.19 (AB, 4.4, 8.0, 2H), 5.89 (dd, 5.2, 9.6,
1H), 7.22–7.34 (m, 5H). 13C NMR (CDCl3): 18.7, 29.0, 29.1, 32.0, 49.8,
57.8, 61.1, 127.3, 128.0, 128.4, 137.0, 171.1. HRMS (FAB): Calcd. for
C14H19NO2: 233.1416. Found: 233.1396.

940
A. Castro et al.
(10R,5S)-(-)-5-Ethyl-1-(20-hydroxy-10-phenylethyl)piperidin-2-one (3b). Color-
1
less oil, [a]D 274.2 (c 1.1, CH2Cl2). IR (KBr) 1617 cm21. H NMR (CDCl3,
d ppm, J Hz): 0.84 (t, 7.2, 3H), 1.21–1.33 (m, 2H), 1.41–1.48 (m, 1H),
1.50–1.56 (m, 1H), 1.85–1.91 (m, 1H), 2.39–2.48 (m, 1H), 2.53–2.60
(m, 1H), 2.89 (dd, 10, 1H), 3.02 (m, 1H), 3.77 (br, OH), 4.04 (m, 1H), 4.16
(dd, 5.2, 11.4, 1H), 5.87 (dd, 5.2, 9.2, 1H), 7.22–7.32 (m, 5H). 13C NMR
(CDCl3): 11.3, 26.1, 26.5, 31.9, 35.5, 48.3, 58.0, 61.1, 127.3, 127.4, 128.4,
137.0, 171.4, HRMS (FAB): Calcd. for C15H21NO2: 247.1572. Found:
247.1545.
(10R,5R)-(-)-5-Benzyl-1-(20-hydroxy-10-phenylethyl)piperidin-2-one(3c). Color-
less oil, [a]D 288.7 (c 0.8, CHCl3). IR (KBr) 1612 cm21. 1H NMR (CDCl3, d
ppm, J Hz): 1.28 (br, OH), 1.52 (m, 1H), 1.83 (m, 1H), 1.95 (m, 1H), 2.41–
2.62 (m, 4H), 2.90–3.03 (m, 2H), 4.06 (m, 2H), 5.74 (dd, 6.8, 7.2, 1H),
7.03–7.33 (m, 10H). 13C NMR (CDCl3): 26.5, 31.7, 35.6, 39.4, 53.4, 59.0,
61.6, 126.2, 127.4, 127.6, 128.3, 128.5, 128.6, 136.6, 138.8, 160.0. HRMS
(FAB): Calcd. for C20H23NO2: 309.1729. Found: 309.1701.
Synthesis of Compound 4
HMPA (0.21 mL) and sec-BuLi (3.1 mmol) were added to a solution of 3a
(0.11 g, 0.47 mmol) in THF (5 mL) under nitrogen atmosphere at 2788C.
The mixture was stirred for 1 h, and iodoethane (1.2 mmol) was added. The
reaction was stirred for 2.5 h. Finally, the mixture was treated with a
saturated solution of NH4Cl (8.0 mL), extracted with ethyl acetate
(3 ꢀ 40 mL), dried with Na2SO4, and finally concentrated under reduced
pressure. The reaction crude was purified by flash chromatography (SiO2,
AcOEt–petroleum ether ¼ 6:4) to give 4 in 85% yield.
(10R,3S,5S)-(-)-3-Ethyl-1-(20-hydroxy-10-phenylethyl)-5-methylpiperidin-2-one
(4). Colorless crystal, mp: 92 8C. [a]D 255.6 (c 1.0, CH2Cl2). IR (KBr)
1
1613cm21. H NMR (CDCl3, d ppm, J Hz): 0.92 (d, 6.4, 3H), 0.98 (t, 7.2,
7.6, 3H), 1.53–1.63 (m, 2H), 1.68 (m, 1H), 1.85–1.96 (m, 2H), 2.40
(m, 1H), 2.85 (dd, 9.2, 1H), 2.95 (m, 1H), 3.77 (br, OH), 4.03 (AB, 5.2,
10.0, 1H), 4.16 (AB, 5.2, 10.2, 1H), 5.89 (dd, 5.2, 9.4, 1H), 7.20–7.33
(m, 5H). 13C NMR (CDCl3): 12.1, 18.7, 25.4, 25.9, 32.7, 41.7, 49.6, 57.7,
61.3, 127.3, 127.3, 128.4, 137.2, 174.6. HRMS (FAB): Calcd for
C16H23NO2: 261.1729. Found: 261.1701.
Crystal Structure of Compound 4
Colorless prism, 0.60 ꢀ 0.24 ꢀ 0.18 mm3, C16H23NO2. Triclinic, P1,
˚
a ¼ 5.6790(9), b ¼ 11.5567(13), c ¼ 12.7780(15) A, a ¼ 69.216(9),
23
b ¼ 89.592(12), g ¼ 78.718(11)8, V ¼ 767.12(17) A3, Z ¼ Z0 ¼ 2,
˚
.
rcalc ¼ 1.131 g cm
. A set of 5256 reflections was collected at

(3S,5S)-(-)-Ethyl-5-Methylpiperidine Synthesis
941
˚
T ¼ 296(1) K using Mo-Ka radiation (l ¼ 0.71073 A, Bruker P4 diffract-
ometer), corresponding to 2umax ¼ 52.58. 3030 independent reflections
(Rint ¼ 0.0216) were used for the refinement of 350 parameters, without
neither restraints nor constraints (SHELXTL 5.10 package). The asymmetric
unit contains two independent molecules with identical geometries within
experimental errors, and no evidences for non-crystallographic symmetry
were found. H atoms of the hydroxyl groups were found on difference maps
and refined with free coordinates, whereas remaining H atoms were placed
on idealized positions and refined using a riding model. Final R indices:
R1 ¼ 0.0436 for 2243 reflections with I . 2s(I) and wR2 ¼ 0.1309 for all
data. CCDC deposition number: 262022. Structure factors and raw files are
available on request to the authors.
Synthesis of Compound 5
Red-Al (1.0 mmol, solution 65% in toluene) was added to a solution of 4
(0.07 g, 0.26 mmol) in anhydrous THF (5 mL) under nitrogen atmosphere
and stirred for 24 h at room temperature. Then, the mixture was cooled at
08C and quenched with a saturated solution of NH4Cl (1.0 mL). Afterward,
the reaction was filtered and dried with Na2SO4. Finally, the solvent was
removed in vacuo to give 5 in quantitative yield.
(10R,3S,5S)-(-)-2-(3-Ethyl-5-methylpiperidin-1-yl)-2-phenylethanol (5).
1
Colorless oil, [a]D 240.9 (c 0.7, CH2Cl2). IR (KBr) 1025 cm21. H NMR
(CDCl3, d ppm, J Hz): 0.85–0.95 (m, 6H), 1.16–1.41 (m, 4H), 1.57–1.67
(m, 1H), 1.86–1.93 (m, 1H), 2.13–2.22 (m, 2H), 2.29–2.37 (m, 2H), 3.25
(br, OH), 3.46–3.59 (m, 1H), 3.62–3.73 (m, 1H), 3.96 (dd, 9.4, 9.6, 1H),
7.11–7.33 (m, 5H). 13C NMR (CDCl3): 12.5, 19.6, 26.2, 27.9, 35.0, 37.1,
54.3, 57.4, 60.0, 70.0, 127.2, 127.5, 128.4, 134.7. HRMS (FAB): Calcd. for
C16H25NO: 247.1936. Found: 247.1908.
.
Synthesis of Compound 6 HCl
.
Pd/C 10% (0.045 g) was added to a solution of 5 HCl (0.07 g, 0.25 mmol) in
methanol (5 mL) under hydrogen atmosphere, and the mixture was stirred for
96 h at room temperature. The reaction crude was filtered, and the solvent was
.
removed in vacuo to give 6 HCl in 95% yield.
.
(3S,5S)-(-)-3-Ethyl-5-methylpiperidine hydrochloride (6 HCl). White solid.
1
Mp: 193–1958C. [a]D 222.83 (c 0.6, CH2Cl2). IR (KBr) 1458 cm21. H
NMR (CDCl3, d ppm, J Hz): 0.98 (t, 7.0, 7.8, 3H), 1.06 (d, 7.0, 3H), 1.15–
1.24 (m, 1H), 1.38–1.50 (m, 2H), 1.55–1.62 (m, 1H), 1.82–1.88 (m, 1H),
2.08–2.13 (m, 1H), 2.79–2.96 (m, 2H), 3.12–3.20 (m, 2H), 9.11 (br, 1H).
13C NMR (CDCl3): 11.3, 18.3, 24.4, 24.9, 31.2, 34.4, 47.4, 49.3. HRMS
(FAB): Calcd. for C8H18ClN: 163.1128. Found: 163.1103.

942
A. Castro et al.
ACKNOWLEDGMENTS
We are grateful to CONACyT for financial support (Project J35088-E) and
BUAP (Project VIEP II-110G02). A.C.C. thanks to CONACyT for the
doctoral scholarship (166996).
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´
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