Synthesis of cis-3-methyl-4-aminopiperidine derivatives

Article abstract of DOI:10.1080/00397910701865884

A facile approach for the preparation of cis-3-methyl-4-aminopiperidine derivatives is described. The synthesis was carried out via regioselective ring opening of N-benzyl-3-methyl-3,4-epoxi-piperidine (8), which can be easily obtained in two steps from t

Full text of DOI:10.1080/00397910701865884

This article was downloaded by: [Linkopings universitetsbibliotek]
On: 26 February 2013, At: 23:43
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of cis‐3‐methyl‐4‐aminopiperidine
Derivatives
Flaviane Francisco Hilário a , Daniela Cristina dos Santos a , Laurent Frederic
Gil b , Rosemeire Brondi Alves a & Rossimiriam Pereira de Freitas a
a Departamento de Química, Instituto de Ciências Exatas, Universidade
Federal de Minas Gerais, Belo Horizonte, Brazil
b Departamento de Química, ICEB, UFOP, Campus Morro do Cruzeiro, Ouro
Preto, Brazil
Version of record first published: 17 Apr 2008.
To cite this article: Flaviane Francisco Hilário , Daniela Cristina dos Santos , Laurent Frederic Gil , Rosemeire
Brondi Alves & Rossimiriam Pereira de Freitas (2008): Synthesis of cis‐3‐methyl‐4‐aminopiperidine Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:8, 1184-1193
To link to this article: http://dx.doi.org/10.1080/00397910701865884
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 38: 1184–1193, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701865884
Synthesis of cis-3-methyl-4-aminopiperidine
Derivatives
1
1
´
Flaviane Francisco Hilario, Daniela Cristina dos Santos,
Laurent Frederic Gil,2 Rosemeire Brondi Alves,1
and Rossimiriam Pereira de Freitas1
1
´ ˆ
Departamento de Quımica, Instituto de Ciencias Exatas, Universidade
Federal de Minas Gerais, Belo Horizonte, Brazil
2
´
Departamento de Quımica, ICEB, UFOP, Campus Morro do Cruzeiro,
Ouro Preto, Brazil
Abstract: A facile approach for the preparation of cis-3-methyl-4-aminopiperidine
derivatives is described. The synthesis was carried out via regioselective ring
opening of N-benzyl-3-methyl-3,4-epoxi-piperidine (8), which can be easily obtained
in two steps from the corresponding N-benzyl-pyridinium salt (5). Seven new cis-3-
methyl-4-amino and amido piperidines compounds were obtained.
Keywords: 3,4-Disubstituted piperidine, epoxide, pyridinium salt
INTRODUCTION
Functionalized piperidines are of great interest for the pharmaceutical industry
because of their wide range of biological activities. Watson et al. asserted that
during a recent 10-year period, thousands of piperidine-based compounds had
been mentioned in clinical and preclinical studies.[1] The biological import-
ance of piperidines has led to the development of numerous synthetic
approaches to the ring system,[2,3] but the wide variety of functionality and
Received in the USA, October 30, 2007
Address correspondence to Rossimiriam Pereira de Freitas, Departamento de
´ ˆ
Quımica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais, Av.
ˆ
Antonio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. E-mail: rossi@
netuno.lcc.ufmg.br
1184

Cis-3-methyl-4-aminopiperidine Derivatives
1185
substitution patterns present in piperidine targets continue to drive the search
for short, versatile, and stereocontrolled methodologies.[4]
In particular, methods for functionalizing positions 3, 4, and 5 of the ring
are rather limited. For example, there are accounts of the synthesis of 3-amino-
4-alkyl[5] or 4-amino-substituted piperidines in the literature,[6,7] but the
synthesis of 3-alkyl-4-amino piperidine derivatives is much less frequent,
with very few reports to date.[8–10]
Several bioactive compounds present 4-amino-substituted piperidine-type
subunits in their structure, such as the potent opioid agonist fentanyl 1,[11] the
muscarinic antagonist 2,[12] and the potential antimalarial 3[13] (Fig. 1).
Because the number of possible conformations may be considerably reduced,
the introduction of an additional alkyl group to the 4-amino piperidine ring
may be important for the biologic activity of new drug candidates.[14]
4-Amino piperidine derivatives are often obtained from the corresponding
piperidones.[11–13] In this work, we describe a new general approach to syn-
thesize cis-3-alkyl-4-amino and amidopiperidines from pyridinium salts via
the regioselective ring opening of an intermediate epoxy piperidine.
RESULTS AND DISCUSSION
The synthetic route for cis-3-methyl-4-amino-piperidine derivatives is
outlined in Scheme 1. Derivative 1,2,5,6-tetrahydropyridine (6) was
obtained from 3-picoline (4) in two steps: by N-benzylation of the pyridine
compound followed by reduction of the intermediate pyridinium salt 5 with
sodium borohydride in protic solvent, furnishing tetrahydropyridine 6 with
65% yield. The double bond of 6 was epoxidized to produce racemic oxide
8. After preliminary experiments, trifluoroacetic peracid was selected as the
most convenient epoxidizing agent. Using this procedure, it is necessary
both to work on tetrahydropyridine trifluoroacetate salt 7 as the starting
Figure 1. 4-Amino-piperidine derivatives.

Scheme 1. Reagents and conditions: (a) PhCH2Cl, 908C, 2 h, 100%; (b) NaBH4, CH3OH/H2O (7:1), reflux, 2 h, 65%; (c) 1 equiv. of CF3 COOH in
CH2Cl2, rt, 5 min, 100%; (d) CF3CO3H, 08C, 20 min, then Na2SO3 and Na2CO3, 60% after purification; (e) flash chromatography (silica gel or
alumina); (f) NaN3/NH4Cl, DMF, 1208C, 3 h, 91%; (g) LiA1H4, THF, 4 h, rt, 76%; (h) NaCN/LIClO4.3H2O, CH3CN, 1108C, 48 h, 56%.

Cis-3-methyl-4-aminopiperidine Derivatives
1187
material and to treat the crude reaction mixture with sodium sulfite to avoid
the formation of undesirable N-oxides. The conversion was practically quan-
titative, but the purification of epoxide 8 became very difficult because of its
instability, giving diol 9 as a major product after chromatography over both
silica gel and alumina. The ring opening of epoxide 8 with sodium azide
afforded only the 3-alkyl-4-azido derivative 10, with 91% yield after purifi-
cation. The reaction was highly regioselective, with the attack of the nucleo-
phile on the less substituted carbon. Furthermore, it was anti-stereoselective
because only the trans isomer was detected in the crude reaction product
(1H NMR). Reduction of azidoalcohol 10 with LiAlH4 furnished amino-
alcohol 11 with 76% yield.
The stereochemical assignment of product 10 was confirmed unambigu-
ously by the conversion of amino alcohol 11 to the pyridinium salt derivative
14 (Scheme 2) via Zincke’s reaction.[15] Thus, the reaction between 11 and
2,4-dinitrophenylpyridinium chloride salt 13 promoted the selective reaction
of the primary amine of 11, furnishing compound 14 quantitatively. 1H NMR
analysis of this salt showed that the H-4 hydrogen signal was significantly
deshielded (m, d 5.23–5.29 ppm) in relation to precursor amino alcohol 11
(m, d 2.58–2.71 ppm). Other nucleophiles such as amines, cyanide, and orga-
nometallic reagents were also studied. The ring opening of 8 with sodium
cyanide in DMF furnished cis-4-cyano-3-methyl-piperidine 12 with 56%
yield. When Grignard reagents were used, no ring-opened products were
observed under standard reaction conditions, and starting epoxide 8 was com-
pletely recovered. Decomposition occurred with extended reaction time.
Reactions with amines, including ammonia, in the presence of metal salts[16]
were also unsuccessful. In all cases, only complex mixtures were obtained.
Finally, the conversion of aminoalcohol 11 in 4-amido-piperidine derivatives
was accomplished by N-acylation using the corresponding acyl chloride in
the presence of sodium bicarbonate (Scheme 2).
In conclusion, we have developed a new method to synthesize cis-3-
methyl-4-amino-substituted piperidines (11) employing N-benzyl-3-methyl-
pyridinium salt (5) as a starting material and ring opening of epoxides as a
Scheme 2. Reagents and conditions: (a) butanol, reflux, overnight, 100%; (b) RCOCl,
NaHCO3/H2O/CH3COCH3, 2 h at 08C then rt, 24 h, 92–97%.

´
F. F. Hilario et al.
1188
key step. We have demonstrated the high regio- and stereoselective addition of
azide nucleophile to 3-methyl-3,4-epoxi-piperidine. Further transformations of
the azide group gave 4-amino- and 4-amido-piperidine derivatives, subunits
found in a large number of bioactive compounds. The assignment of the
major regioisomer was confirmed by Zincke’s reaction.
EXPERIMENTAL
Melting points were determined on a Mettler FP82HT apparatus and are
1
uncorrected. H NMR and 13C NMR spectra were recorded on a Bruker
Avance DPX spectrometer, at 200 MHz and 50.32 MHz respectively, using
CDCl3, D2O, or CDCl3/CD3OD mixture as the solvent. Chemical shifts are
reported in d units downfield from TMS and coupling constants are given in
hertz. Elemental analyses were carried out on a Perkin-Elmer 2400 CHN
apparatus. IR spectra were recorded on a Mattson Instruments Galaxy 3000
appartus. Column chromatography was performed with silica gel 0.063–
0.200 mm/70–230 mesh (Merck). The term “standard workup” means that
the organic layer was dried over anhydrous Na2SO4 and filtered and that the
solvent was removed under reduced pressure.
3-Benzyl-1-methyl-7-oxa-3-aza-bicyclo[4.1.0]heptane (8)
Trifluoroacetic anhydride (3.77 mL, 26.74 mmol) was added dropwise, at
0 8C, to a stirred solution of 50% hydrogen peroxide (760 mL, 13.37 mmol)
in CH2Cl2 (50 mL). After further stirring during 1.5 h at 0 8C, the salt 7 was
added [obtained from tetrahydropyridine 6 (1.000 g, 5.35 mmol) and trifluor-
oacetic acid (1.02 mL, 13.37 mmol) in CH2Cl2]. The ice bath was removed,
and the reaction mixture was stirred for 20 min. Saturated aqueous sodium
sulfite (Na2SO3) was then added, and the organic layer was separated,
washed with aqueous sodium bicarbonate and water, and submitted to
standard workup to provide 8 as a colorless oil. The epoxide 8 was used
without further purification because of their instability in the presence of
silica gel or alumina column (ring opening giving diol 9). A small sample
can be isolated by chromatography for characterization. IR (NaCl, cm21): n
1
3030, 2960, 2820, 1500, 1450, 1250, 750, 700; H NMR (CDCl3, 200 MHz)
d ppm 1.31 (s, 3H, CH3); 1.93–2.02 (m, 2H, H-5); 2.22–2.28 (m, 2H, H-6);
2.66 (d, 1H, J ¼ 13.00 Hz, H-2); 2.75 (d, 1H, J ¼ 13.00 Hz, H0-2); 3.05
(t, 1H, J ¼ 2.00 Hz, H-4); 3.46 (s, 2H, CH2Ph); 7.25–7.31 (m, 5H, Ph); 13C
NMR (CDCl3, 50.32 MHz) d ppm 22.19 (CH3); 25.56 (C-5); 45.72 (C-6);
56.64 (C-2); 56.92 (C-4); 57.84 (C-3); 62.17 (CH2Ph); 127.06, 128.19,
129.07 (5C, Ph); 137.75 (C-ipso).

Cis-3-methyl-4-aminopiperidine Derivatives
1189
1-Benzyl-3.4-dihydroxy-3-methyl-piperidine (9)
This was obtained from flash chromatography (silica gel) of the epoxide 8
using hexane/EtOAc gradient (97/3, 95/5, 93/7, 90/10, 80/20) and
methanol. Yellow oil. IR (NaCl, cm21): n 3350, 2960, 2820, 1500, 1450,
1
1360, 1280, 1150, 1080, 750, 700; H NMR (CDCl3, 200 MHz) d ppm 1.20
(s, 3H, CH3); 1.51–1.61 (m, 1H, H-5); 2.00–2.02 (m, 1H, H0-5); 2.24
(d, 1H, J ¼ 10.65 Hz, H-2); 2.44–2.49 (m, 3H, H0-2 and H-6); 2.75 (sl, 2H,
OH); 3.45–3.59 (m, 3H, H-4 and CH2Ph); 7.29 (m, 5H, Ph); 13C NMR
(CDCl3, 50.32 MHz) d ppm 21.62 (CH3); 30.15 (C-5); 48.93 (C-6); 60.64
(C-2); 71.04 (C-3); 73.03 (C-4); 62.57 (CH2Ph); 127.35, 128.50, 129.09
(5C, Ph); 138.31 (C-ipso); anal. calcd. for C13H19NO2: C, 70.56; H, 8.65; N,
6.33; found: C, 70.52; H, 8.35; N, 6.36.
4-Azido-1-benzyl-3-hydroxy-3-methyl-piperidine (10)
Ammonium chloride (0.499 g, 9.33 mmol) and sodium azide (0.756 g,
11.62 mmol) were added to a solution of the epoxide 8 (0.500 g, 2.46 mmol)
in 20 mL of dimethylformamide. The mixture was stirred at 120 8C for 3 h.
After complete conversion to the corresponding product 10 as indicated by
thin-layer chromatography (TLC), the solvent was removed under reduced
pressure. The residue was diluted with water and extracted with dichloro-
methane (3 ꢀ 20 mL). The combined organic extracts were submitted to
standard workup, and the crude product was purified by silica-gel column
chromatography using a hexane/EtOAc gradient (100/0, 98/2, 96/4, 94/6,
92/8) to give the azido alcohol 10 (0.551 g, 91%) as a yellow oil. IR (NaCl,
cm21): n 3300, 2960, 2820, 2050, 1500, 1450, 1350, 1120, 750, 700;
1H NMR (CDCl3, 200 MHz) d ppm 1.19 (s, 3H, CH3); 1.72 (qd, 1H,
J ¼ 14.37 Hz, 3.97 Hz, H-5); 2.02–2.16 (m, 1H, H0-5); 2.27–2.33 (m, 3H,
H-2 and H-6); 2.45-2.55 (m, 1H, H0-6); 3.42 (t, 1H, J ¼ 3.89 Hz, H-4); 3.51
(s, 2H, CH2Ph); 7.21–7.35 (m, 5H, Ph); 13C NMR (CDCl3, 50.32 MHz) d
ppm 22.68 (CH3); 26.88 (C-5); 48.54 (C-6); 60.29 (C-2); 70.25 (C-3); 64.88
(C-4); 62.45 (CH2Ph); 127.48, 128.55, 129.07 (5C, Ph); 137.92 (C-ipso).
4-Amino-1-benzyl-3-hydroxy-3-methyl-piperidine (11)
A solution of the azidoalcohol 10 (1.000 g, 4.07 mmol) in 20 mL of dry THF
was added slowly to an ice-cold suspension of LiAlH4 (0.262 g, 6.91 mmol) in
dry THF (20 mL), stirred magnetically. The ice bath was removed, and the
reaction mixture was stirred for 4 h. After the complete formation of
product 11, as indicated by TLC, a saturated Rochelle salt solution (30 mL)
was slowly added to the reaction mixture and stirred to produce a clean
mixture. This mixture was extracted with CH2Cl2 (60 mL), and the organic

´
F. F. Hilario et al.
1190
extract was submitted to standard workup. The amino alcohol 11 (0.680 g,
76%) was obtained as a white solid after purification of the crude product
by silica-gel column chromatography using CH2Cl2/CH3OH gradient (100/
0, 90/10, 80/20, 0/100). Mp: 64.0–66.0 8C; IR (KBr, cm21): n 3500,
1
3400, 3300, 2960, 2820, 1570, 1500, 1450, 1360, 1130, 750, 700; H NMR
(D2O, 200 MHz) d ppm 1.14 (s, 3H, CH3); 1.36–1.52 (m, 1H, H-5); 1.80–
1.97 (m, 2H, H-2 and H0-5); 2.17–2.28 (m, 1H, H-6); 2.58–2.71 (m, 2H,
H0-2 and H-4); 2.84–2.89 (m, 1H, H0-6); 3.42 (d, 1H, J ¼ 13.21 Hz,
CH2Ph); 3.74 (d, 1H, J ¼ 13.21 Hz, CH2Ph); 7.39–7.40 (m, 5H, Ph); 13C
NMR (CDCl3, 50.32 MHz) d ppm 20.50 (CH3); 31.45 (C-5); 51.34 (C-6);
56.52 (C-4); 62.52 (CH2Ph); 62.94 (C-2); 71.40 (C-3); 127.11, 128.32,
128.88 (5C, Ph); 138.56 (C-ipso). Anal. calcd. for C13H20N2O: C, 70.87; H,
9.15; N, 12.72. Found: C, 70.55; H, 9.00; N, 12.27.
1-Benzyl-4-carbonitrile-3-hydroxy-3-methyl-piperidine (12)
.
Potassium cyanide (0.321 g, 5.00 mmol), LiClO4 3H2O (0.237 g, 1.48 mmol)
dissolved in 5 mL of acetonitrile, and epoxide 7 (0.200 g, 0.99 mmol) dissolved
in 5 mL of acetonitrile were added to a two-necked flask coupled to a reflux
condenser with exit to a saturated sodium hydroxide solution. The mixture
was stirred at 110 8C for 48 h. After complete conversion to the corresponding
product 12 as indicated by TLC, the reaction mixture was cooled at room temp-
erature, diluted with water (20 mL), and extracted with ether (3 ꢀ 20 mL). The
combined organic extracts were submitted to standard workup, and the crude
product was purified by silica-gel column chromatography using hexane/
EtOAc gradient (100/0, 98/2, 96/4, 94/6, 92/8, 90/10, 80/20, 50/50,
0/100) to give the compound 12 (0.127 g, 56%) as a yellow solid. Mp:
68.4–71.6 8C; IR (KBr, cm21): n 3200, 2960, 2820, 2260, 1480, 1430, 1340,
1
1100, 750, 700; H NMR (CDCl3, 200 MHz) d ppm 1.36 (s, 3H, CH3); 1.80
(qd, 1H, J ¼ 13.93 Hz, 3.18 Hz, H-5); 2.00–2.17 (m, 1H, H0-5); 2.29–2.53
(m, 3H, H-2 and H-6); 2.67–2.69 (m, 2H, H-4 and H0-6); 2.67–2.69 (m, 1H,
H-4); 3.55 (s, 2H, CH2Ph); 3.89 (sl, 1H, OH); 7.22–7.44 (m, 5H, Ph); 13C
NMR (CDCl3, 50.32 MHz) d ppm 24.36 (CH3); 25.23 (C-5); 37.13 (C-4);
49.22 (C-6); 61.07 (C-2); 68.43 (C-3); 62.25 (CH2Ph); 120.35 (CN); 127.56,
128.55, 129.01 (5C, Ph); 137.40 (C-ipso). Anal. calcd. for C14H18N2O: C,
73.01; H, 7.88; N, 12.16. Found: C, 72.47; H, 7.46; N, 11.76.
General Method for the Preparation of the 3-Alkyl-4-amido-
piperidines 15a–d
Sodium bicarbonate aqueous solution and acetone (5 mL) were added to
amino alcohol 11. Then this solution was cooled at 0 8C and stirred. An
acyl chloride solution in acetone at 0 8C was added to the amino alcohol

Cis-3-methyl-4-aminopiperidine Derivatives
1191
solution, and the resulting mixture was stirred for 2 h. The ice bath was
removed, and the reaction mixture was stirred for 24 h. After complete
formation of the 3-alkyl-4-amido-piperidines 15a–d as indicated by TLC,
the solvent was removed under reduced pressure. The residue obtained was
diluted with water and extracted with dichloromethane (3 ꢀ 20 mL). The
combined organic extracts were submitted to standard workup, and the
crude product was purified by silica-gel column chromatography using
CH2Cl2/CH3OH gradient (100/0, 98/2, 95/5, 90/10, 0/100) to give the
3-alkyl-4-amido-piperidines 15a–d.
4-Benzamide-1-benzyl-3-hydroxy-3-methyl-piperidine (15a)
This was obtained from amino alcohol 11 (0.090 g, 0.41 mmol): Yield:
0.127 g; 96%; white crystals. Mp: 210.2–213.8 8C; IR (KBr, cm21): n
3350, 3250, 2900, 2750, 1640, 1600, 1500, 1450, 1360, 1130, 750, 700; H
1
NMR (CDCl3/CD3OD, 200 MHz) d ppm 1.27 (s, 3H, CH3); 1.58–1.96
(m, 2H, H-5); 2.12 (d, 1H, J ¼ 11.29 Hz, H-2); 2.21–2.27 (m, 1H, H-6);
2.72 (d, 1H, J ¼ 11.29 Hz, H0-2); 2.81–2.87 (m, 1H, H0-6); 3.50 (d, 1H,
J ¼ 13.17 Hz, CH2Ph); 3.62 (d, 1H, J ¼ 13.17 Hz, CH2Ph); 3.92–4.00
(m, 1H, H-4); 7.22–7.31 (m, 5H, Ph); 7.40–7.57 (m, 3H, H-30, H-40, and
H-50 of the Ph0); 7.80 (d, 2H, J ¼ 6.68 Hz, H-20 and H-60 of the Ph0);
13C NMR (CDCl3/CD3OD, 50.32 MHz) d ppm 20.69 (CH3); 29.17 (C-5);
52.55 (C-6); 56.78 (C-4); 62.73 (CH2Ph); 64.63 (C-2); 72.55 (C-3); 127.65,
´
128.64, 128.91, 129.35, 132.23 (5C, Ph and 5C, Ph); 134.32 (C-ipso benzoil);
138.24 (C-ipso); 170.56 (C55Oamide). Anal. calcd. for C20H24N2O2: C, 74.04;
H, 7.46; N, 8.64; Found: C, 73.84; H, 7.14; N, 8.41.
4-Acetamide-1-benzyl-3-hydroxy-3-methyl-piperidine (15b)
This was obtained from amino alcohol 11 (0.129 g, 0.58 mmol): Yield:
0.144 g; 94%; white solid. IR (KBr, cm21): n 3300, 3200, 2850, 2700,
1
1650, 1540, 1500, 1450, 1360, 1130, 750, 700; H NMR (CDCl3, 200 MHz)
d ppm 1.18 (s, 3H, CH3); 1.41–1.62 (m, 1H, H-5); 1.73–1.81 (m, 1H, H0-
5); 1.93–2.18 (m, 2H, H-6 and H-2); 2.01 (s, 3H, CH3CO); 2.60–2.74
(m, 2H, H0-6 and H0-2); 3.44 (d, 1H, J ¼ 13.21 Hz, CH2Ph); 3.54 (d, 1H,
J ¼ 13.21 Hz, CH2Ph); 3.69–3.80 (m, 1H, H-4); 4.63 (sl, 1H, OH); 6.26
(d, 1H, J ¼ 6.76 Hz, NH); 7.21–7.27 (m, 5H, Ph); 13C NMR (CDCl3,
50.32 MHz) d ppm 20.89 (CH3); 23.21 (CH3CO); 29.10 (C-5); 51.85 (C-6);
56.19 (C-4); 62.35 (CH2Ph); 64.06 (C-2); 72.04 (C-3); 127.15, 128.32,
128.87 (5C, Ph); 138.38 (C-ipso); 172.27 (C55Oamide). Anal. calcd. for
C15H22N2O2: C, 68.67; H, 8.45; N, 10.68. Found: C, 68.35; H, 8.20; N, 10.27.

´
F. F. Hilario et al.
1192
4-Propionamide-1-benzyl-3-hydroxy-3-methyl-piperidine (15c)
This was obtained from amino alcohol 11 (0.150 g, 0.68 mmol). Yield:
0.173 g; 92%; white solid. IR (KBr, cm21): n 3200, 3100, 2960, 2820,
1650, 1600; 1530, 1440, 1350, 1130, 750, 700; 1H NMR (CDCl3,
200 MHz) d ppm 1.15 (s, 3H, CH3); 1.18 (t, 3H, CH3CH2CO); 1.45–1.62
(m, 1H, H-5); 1.74–1.83 (m, 1H, H0-5); 2.03–2.15 (m, 2H, H-6 and H-2);
2.60–2.74 (m, 2H, H0-6 and H0-2); 2.25 (q, 2H, J ¼ 7.56 Hz, CH3CH2CO);
3.45 (d, 1H, J ¼ 13.20 Hz, CH2Ph); 3.55 (d, 1H, J ¼ 13.20 Hz, CH2Ph);
3.71–3.82 (m, 1H, H-4); 5.87 (d, 1H, J ¼ 6.70 Hz, NH); 7.22–7.30 (m, 5H,
Ph); 13C NMR (CDCl3, 50.32 MHz) d ppm 10.06 (CH3CH2CO); 20.90
(CH3); 29.27 (C-5); 29.68 (CH3CH2CO); 51.88 (C-6); 56.02 (C-4); 62.41
(CH2Ph); 64.12 (C-2); 72.02 (C-3); 127.20, 128.37, 128.92 (5C, Ph); 138.44
(C-ipso); 175.86 (C55Oamide).
4-(30-Iodobenzamide)-1-benzyl-3-hydroxy-3-methyl-piperidine (15d)
This was obtained from amino alcohol 11 (0.117 g, 0.53 mmol). Yield:
0.232 g; 97%; yellow crystals. Mp: 198.9–201.0 8C; IR (KBr, cm21): n
3350, 3300, 3180, 2960, 2820, 1630, 1590, 1530, 1450, 1350, 1130, 750,
1
700; H NMR (CDCl3/CD3OD, 200 MHz) d ppm 1.26 (s, 3H, CH3); 1.62–
1.93 (m, 2H, H-5); 2.10 (d, 1H, J ¼ 11.47 Hz, H-2); 2.19–2.25 (m, 1H,
H-6); 2.72 (d, 1H, J ¼ 11.47 Hz, H0-2); 2.80–2.86 (m, 1H, H0-6); 3.49
(d, 1H, J ¼ 13.17 Hz, CH2Ph); 3.61 (d, 1H, J ¼ 13.17 Hz, CH2Ph); 3.93–
3.98 (m, 1H, H-4); 7.18 (t, 1H, J ¼ 7.83 Hz, H-50 of the 3-iodo benzoyl
group); 7.25–7.37 (m, 5H, Ph); 7.77 (d, 1H, J ¼ 7.91 Hz, H-40 or H-60 of
the 3-iodo benzoyl group); 7.84 (d, 1H, J ¼ 7.97 Hz, H-40 or H-60 of the
group 3-iodo benzoyl); 8.14 (s, 1H, H-20 of the 3-iodo benzoyl group); 13C
NMR (CDCl3/CD3OD, 50.32 MHz) d ppm 20.33 (CH3); 28.74 (C-5); 52.09
(C-6); 56.45 (C-4); 62.32 (CH2Ph); 64.24 (C-2); 72.09 (C-3); 93.98 (C-I);
´
126.55 (C-6of the 3-iodo benzoyl group); 127.18, 128.25, 128.93 (5C, Ph);
´
130.16 (C-5of the 3-iodo benzoyl group); 136.03 (C-ipso); 136.27 (C-2of the
´
´
3-iodo benzoyl group); 137.83 (C-1 of the 3-iodo benzoyl group); 140.60
´
(C-4of the 3-iodo benzoyl group); 168.28 (C55Oamide). Anal. calcd. for
C20H23IN2O2: C, 53.34; H, 5.15; N, 6.22; Found: C, 53.48; H, 4.87; N, 5.91.
ACKNOWLEDGMENTS
´
The authors thank Conselho Nacional de Desenvolvimento Cientıfico e
´
Tecnologico (CNPq) for the fellowships to F. F. H. and D. C. S.

Cis-3-methyl-4-aminopiperidine Derivatives
1193
REFERENCES
1. Watson, P. S.; Jiang, B.; Scout, B. A diastereoselective synthesis of 2,4-disubsti-
tuted piperidines: Scaffolds for drug delivery. Org. Lett. 2000, 2, 3679–3681.
2. Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Recent advances in
the synthesis of piperidones and piperidines. Tetrahedron 2003, 59, 2953–2989.
3. Buffat, M. G. P. Synthesis of piperidines. Tetrahedron 2004, 60, 1701–1729.
4. Williams, J. T.; Bahia, P. S.; Kariuki, B. M.; Spencer, N.; Philp, D.; Snaith, J. S.
Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations:
Switching between kinetic and thermodynamic control with Brønsted and Lewis
acid catalysts. J. Org. Chem. 2005, 2460–2471.
5. Hu, X. E.; Kim, N. K.; Ledoussal, B.; Colson, A. O. Regio- and stereo-controlled
copper organometallic addition to a piperidinyl aziridine: synthesis of trans
3-amino-4-alkyl-piperidines. Tetrahedron Lett. 2002, 43, 4289–4293.
6. Ashwell, M. A.; Solvibile, W. R.; Han, S.; Largis, E.; Mulvey, R.; Tillet, J. 4-Ami-
nopiperidine ureas as potent selective agonists of the human b3-adrenergic
receptor. Bioorg. Med. Chem. Lett. 2001, 11, 3123–3127.
7. Manetti, D.; Martini, C. G.; Dei, S.; Galeotti, N.; Guandalini, L.; Romanelli, M. N.;
Scapecci, S.; Teodori, E.; Bartolini, A.; Gualtieri, F. 4-Aminopiperidine deriva-
tives as a new class of potent cognition enhancing drugs. Bioorg. Med. Chem.
Lett. 2003, 13, 2303–2306.
8. Ivanovic, M. D.; Micovic, I. V.; Vuckovic, S. M.; Prostran, M. S.; Todorovic, Z.;
Kiricojevic, V. D.; Djordjevic, J. B.; Dosen-Micovic, L. The synthesis and prelimi-
nary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl
analogues. J. Serb. Chem. Soc. 2004, 69, 511–526.
9. Lukyanenko, E. R.; Borisenko, A. A.; Grishina, G. V. Novel stereoselective
synthesis of chiral nonracemic cis and trans-3-alkyl-4-aminopiperidines. Chem.
Heterocycl. Compd. 2004, 40, 525–527.
10. Einsiedel, J.; Weber, K.; Thomas, C.; Lehmann, T.; Hubner, H.; Gmeiner, P.
Stereocontrolled dopamine receptor binding and subtype selectivity of Clebopride
analogues synthesized from aspartic acid. Bioorg. Med. Chem. Lett. 2003, 13,
3293–3296.
11. Janssen, P. A. A review of the chemical features associated with strong morphine-
like activity. Brit. J. Anaesth. 1962, 34, 260–268.
´
12. Diouf, O.; Gadeau, S.; Chelle, F.; Gelbcke, M.; Talaga, P.; Christophe, B.;
Gillard, M.; Massingham, R.; Guyaux, M. A new series of M3 muscarinic antag-
onists based on the 4-amino-piperidine scaffold. Bioorg. Med. Chem. Lett. 2002,
12, 2535–2539.
13. Brinner, K. M.; Powles, M. A.; Schmatz, D. M.; Ellman, J. A. Potent 4-aminopi-
peridine based antimalarial agents. Bioorg. Med. Chem. Lett. 2005, 15, 345–348.
14. Martinez, R.; Rubio, M. F.; Alfaro, L. J.; Salcedo, R. Conformational analysis of
analogs of fentanyl: A theoretical approach. Possible influence of the anomeric
effect on its biological activity. J. Mol. Struct. (Theochem.) 1995, 342, 141–146.
15. Viana, G. H. R.; Santos, I. C.; Alves, R. B.; Gil, L.; Marazano, C.; Gil, R. P. F.
Microwave-promoted synthesis of chiral pyridinium salts. Tetrahedron Lett.
2005, 46, 7773–7776.
16. Chini, M.; Crotti, P.; Macchia, F. Regioalternating selectivity in the metal salt
catalyzed aminolysis of styrene oxide. J. Org. Chem. 1991, 56, 5939–5942.