Highly regioselective ring opening of a common N,N-dialkylaziridinium ion by carboxylic acids

Article abstract of DOI:10.3987/COM-17-13770

A variety of optically active amino esters were synthesized via ring-opening reaction of (R)-1-phenyl-3-Azaspiro[2.5]octan-3-ium ion derived from (R)-2-phenyl-2-(piperidin-1-yl)ethan-1-ol in a highly regioselective manner. Ring-opening reaction with carboxylates series generated in situ proceeded smoothly and with excellent yields (85-98%).

Full text of DOI:10.3987/COM-17-13770

HETEROCYCLES, Vol. 96, No. 2, 2018
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HETEROCYCLES, Vol. 96, No. 2, 2018, pp. 219 - 232. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 24th June, 2017, Accepted, 29th December, 2017, Published online, 22nd January, 2018
DOI: 10.3987/COM-17-13770
HIGHLY REGIOSELECTIVE RING OPENING OF A COMMON
N,N-DIALKYLAZIRIDINIUM ION BY CARBOXYLIC ACIDS
Ulises Hernández,1 Manuel Velasco,1 Jaime Vázquez,2 Joel L. Terán,1 Dino
Gnecco,1 María L. Orea,1 David M. Aparicio,1 and Jorge R. Juárez1*
1Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de
Puebla, Edif. IC8 Complejo de Ciencias, C.U., 72570 Puebla, México.
2Universidad Politécnica Metropolitana de Puebla, Popocatépetl s/n, Tres Cerritos,
72480 Puebla, México. E-mail: jorge.juarez@correo.buap.mx
Abstract – A variety of optically active amino esters were synthesized via
ring-opening reaction of (R)-1-phenyl-3-azaspiro[2.5]octan-3-ium ion derived
from (R)-2-phenyl-2-(piperidin-1-yl)ethan-1-ol in a highly regioselective manner.
Ring-opening reaction with carboxylates series generated in situ proceeded
smoothly and with excellent yields (85-98%).
INTRODUCTION
Aziridinium ions have received considerable attention as reactive intermediates in the asymmetric
synthesis of natural products,1-3 biologically active compounds4 and precursors in organic synthesis.5
Nucleophilic ring-opening of N,N-dialkylaziridinium ions have been recognized as efficient synthetic
route to generate a variety of β-substituted amines including 1,2-diamines,6 1,2-amino alcohols,7 β-amino
ethers,8 and β-haloamines.9 The N,N-dialkylaziridinium ions are usually produced in situ from E-amino
alcohols.10 Compared with aziridine congeners, the N,N-dialkylaziridinium ions show a strong
electrophilic character, whereas the unactivated aziridines require activation by a Lewis acid and,
therefore, always becomes aziridinium prior to nucleophilic ring-opening reactions.11 Thus, N,N-dialkyl-
aziridinium ions can be opened by a wide range of nucleophiles with or without rearrangement depending
on the regioselectivity of the nucleophilic attack.10 Until now, opening reaction of aziridinium ions with
carboxylate salts has been scarcely study.12 In this sense, we herein report a high regiospecific
ring-opening reaction of a common N,N-dialkylaziridinium ion I with a variety of aliphatic, aromatic and
DꢀE-unsaturated carboxylic acids (Scheme 1).

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Scheme 1. Ring-opening reaction of aziridinium ion I with various carboxylic acids
RESULTS AND DISCUSSION
Compound 113 was allowed to react with MsCl and TEA as a base in order to trap the corresponding
E-chloropiperidinium chloride 2. This intermediate was isolated as an air-stable white crystalline solid in
79% yield.14 The isolation of a single isomer, compound (S)-2 is consistent with the inclusion of an
aziridinium ion intermediate II (Scheme 2). The structure was fully ascertained by an X-ray diffraction
analysis (Figure 1).
Scheme 2. Synthesis of E-chloropiperidinium chloride (S)-2
Figure 1. ORTEP of compound (S)-2
As we anticipate, this result shows clearly the more nucleophilic character of chloride anion than
mesylate. According to the literature, opening of aziridinium ions usually occurs with a more nucleophilic
species and no participation of chloride anion are present, but what is the competitive effect when a softer
nucleophilic specie, like a carboxylate, are present in the medium reaction. For this precedent, we turned
our attention to the opening reaction of aziridinium ions with diverse carboxylic acids using a modified
version of O’Brien´s method.6 We commence our investigation by the treatment of I with acetic acid.

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After 30 min, we obtained the corresponding regioisomeric mixture of esters 3a + 4a in a 99:1 ratio,15
which are consistent with previous reports, where the nucleophiles attacks were performed at the more
electrophilic benzylic carbon in the intermediate ion (Table 1, entry 1).6,16
Therefore, a series of carboxylic acids was tested in order to know the scope and limitation of this
opening reaction. The use of aliphatic carboxylic acids afforded the desired amino ester 3 as a major
regioisomer in excellent chemical yields (Table 1, entries 2-6). For aromatic carboxylic acids with
electron-donating or electron-withdrawing groups on the phenyl ring compound 3 was obtained as a
major regioisomer in good yields (Entries 7ꢀ14). Interestingly, carboxylic acids containing pyridine
moiety was well tolerated and gave the desired product in good yield (Entry 15). In addition, aromatic
olefinic acid gave good yield (Entry 16).
Table 1. Summary of regioselective synthesis of amino esters derivatives
Entry
1
RCO2H
Producta
Regioselectivityb 3:4
3 Yield (%)c
AcOH
99:1
93
3a
2
3
Br-(CH2)4-CO2H
98:2
98:2
94
95
3b
3c
Me-(CH2)24- CO2H
4
5
98:2
97:3
93
90
3d
3e
6
7
8
97:3
97:3
97:3
92
91
89
3f
3g
3h

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9
97:3
97:3
87
91
3i
3j
10
11
97:3
90
3k
12
13
97:3
97:3
85
94
3l
3m
14
15
16
97:3
97:3
98:2
93
91
92
3n
3o
3p
aEnantiomeric purities were measurement by UHPLC normal phase; with an ULTRON ES-Pepsin
b
Chiral column (all products show >99% ee). Ratio of regioisomeric amino esters 3 and 4 in the crude
product mixtures determined by 1H NMR spectroscopy. cIsolated yield after silica gel chromatography.
A single crystal of amino ester 3p was obtained and X-ray crystallography analysis showed a (S)
configuration for the new stereocenter and therefore a bimolecular nucleophilic ring opening reaction of
aziridinium ion was proposed at this point (Figure 2).17
Figure 2. ORTEP of compound 3p
In line with the model proposed by Anderson,16a the stereochemical outcome of the reaction is consistent
with the participation of an aziridinium ion where competition between bimolecular and monomolecular
substitution is possible, for this reason chiral acids were allowed to react with 1 (Scheme 3). The

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223
corresponding amino esters, derived from (S)-Naproxen® 3q and (S)-3-phenylbutyric acid 3r, were
1
13
obtained in good to excellent chemical yield. For both cases, the H and C NMR spectra showed the
presence of only one isomer, indicating a total stereoselectivity of the reaction, in consequence, no
participation of carbocation intermediate was unambiguously confirmed. Finally, L-proline N-Boc
protected was tested, affording the desired amino ester 3s in 96% yield as a single diastereoisomer which
exist in rotameric form.
Scheme 3. Synthesis of amino esters coming from chiral acids
Finally, in order to examine reactions with more aziridinium ions derived from amino alcohols with
different substituents at the ring nitrogen and/or other sites to show the scope and limitation of the present
method, compounds 5, 8, 11 and 14 were subject to optimized reaction conditions using acetic acid as
nucleophile. Compounds 5 and 8, derived from (R)-(-)-2-phenylglycinol, afforded the regioisomeric
mixture 6:7 and 9:10 in a 99:1 ratio respectively, in favor of the benzylic opening amino ester compound
(Scheme 4).
X
N
R
O
X
N
R
X
N
R
MsCl, Et3N, 0 °C
then AcOH
+
O
OH
Ph
Ph
O
Ph
O
5
8
6 : 7 (99:1)
9 : 10 (99:1)
X = CH2, R = Et
X = O, R = H
Scheme 4. Synthesis of amino esters coming from heterocycles derived from phenylglycinol
Interestingly, when piperidine 11, derived from (R)-(-)-2-amino-1-butanol, was allowed to react under the
same conditions, the inseparable regioisomeric mixture 12:13 in 37:62 ratio in favor of the less
substituted opening regioisomer 13 was obtained, while piperidine 14, derived from
(S)-(+)-2-amino-3-methyl-1-butanol, afforded the inseparable regiosiomeric mixture 15:16 in 50:50 ratio
(Scheme 5).

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Scheme 5. Synthesis of amino esters coming from piperidines derived from other chiral amino alcohols
Notably, the reactions exhibit high regioselectivity in the opening of aziridinium ion when a benzylic
position is present on the aziridinium ion despite we use a soft nucleophile.
In conclusion, aliphatic and aromatic carboxylic acids react with 1 to afford, via an aziridinium
intermediate, the corresponding amino ester in good to excellent yield and high regioselectivity. In
addition, we demonstrated opening reaction occurs preferentially at benzylic position following possibly a
SN2 type mechanism despite the soft nucleophilic character of carboxylate specie; the developed method
is clean and efficient.
EXPERIMENTAL
All reagents and solvents were purchased from commercial sources. 1H NMR and 13C NMR spectra were
recorded at 500 MHz and 125 MHz, respectively, in CDCl3 using a Bruker Avance III Spectrometer.
Chemical shifts are given in ppm and reported to the residual solvent peak (CHCl3 7.26 ppm and 77.16
ppm). Data are reported as follows: chemical shift (G), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), coupling constant(s) (J, Hz), and integration. Analytical TLC was performed on
silica gel 60 F254 plates. Column chromatography was carried out on silica gel 60 (63-200 Pm). IR spectra
were obtained using an FT-IR spectrometer, Spectrum One, Perkin Elmer. Mass spectra were recorded on
JEOL The MStation JMS-700 at a voltage of 70 eV. X-Ray diffraction analysis was performed on a
diffractometer Agilent Gemini Atlas fitted with an Atlas CCD detector, using Cu-.D (λ = 1.54184)
radiation, and equipped with an Oxford Technologies Cryojet crystal cooling apparatus and a
diffractometer STOE Stadivari using Ag-.D (λ = 0.56083) and equipped with a Pilatus-100 K detector.
Optical rotations were measured on the Perkin-Elmer 341 polarimeter at room temperature. Enantiomeric
purity measurements were performed by chiral UHPLC analysis in normal phase with an Agilent 1260

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225
Infinity Analytical SFC System equipped with an Agilent 6120 quadrupole LC/MS, using an ULTRON
ES-Pepsin chiral column (Shinwa Chemical Industries LTD, 4.6 x 150 mm, 5 Pm particle size).
Experimental procedure for intermediate 2.
o
To a stirred solution of β-amino alcohol 1 (0.5 g, 2.43 mmol) in CHCl3 (10 mL) at 0 C in presence of
triethylamine (1.01 mL, 7.30 mmol). Then, methanesulfonyl chloride (0.41 mL, 5.35 mmol) was added
dropwise at a rate to keep the reaction temperature bellow 5 oC. After 30 min, the reaction was monitored
by TLC (CH2Cl2/MeOH, 95:5), indicating that the reactants were consumed. The reaction mixture was
allowed to warm at room temperature for 16 h. Solvent was removed under vacuum, and the residue was
dissolved in CH2Cl2 and washed with water and brine before drying over anhydrous sodium sulfate.
Solvent was removed under vacuum and the crude product was purified by column chromatography
(CH2Cl2/MeOH, 97:3) gave the desired E-chloropiperidinium chloride (S)-2.
Intermediate: (S)-1-(2-chloro-2-phenylethyl)piperidin-1-ium chloride (2). The desired pure product
20
1
was obtained in 79% yield (500 mg) as white solid; mp 180 °C; [α]D +23.6 (c 1.0, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 12.69 (br s, 1H), 7.49-7.26 (m, 5H), 5.85-5.83 (dd, J = 7.2, 4.5 Hz, 1H), 3.88-3.41
(d, J = 12.0 Hz, 1H), 3.50-3.41 (m, 2H), 3.18-3.16 (d, J = 12.1 Hz, 1H), 2.80-2.74 (m, 1H), 2.64-2.56 (m,
13
1H), 2.29-2.13 (m, 2H), 1.86-1.80 (m, 2H), 1.71-1.69 (m, 1H), 1.53 (m, 2H); C NMR (125 MHz,
CDCl3) δ 138.3, 129.4, 129.2, 127.0, 64.6, 55.5, 54.7, 53.8, 22.5, 21.8; HRMS (ESI): m/z [M+H]+ calcd
for C13H20Cl2N: 261.0973, found: 261.0970.
General procedure and compound characterization data for products 3a-s.
o
To a stirred solution of compound 1 (0.5 g, 2.43 mmol) in CHCl3 (10 mL) at 0 C in presence of
triethylamine (1.01 mL, 7.30 mmol). Then, methanesulfonyl chloride (0.22 mL, 2.92 mmol) was added
dropwise at a rate to keep the reaction temperature bellow 5 oC. After 30 min, the reaction was monitored
by TLC (CH2Cl2/MeOH, 95:5), indicating the reactants were consumed. Triethylamine (0.50 mL, 3.65
mmol) was added. Finally, the corresponding carboxylic acid (1.2 equiv.) was added and the reaction
mixture was allowed to warm to room temperature for 16 h. After completion of the reaction as indicated
by TLC, the crude product was purified by column chromatography (CH2Cl2/MeOH, 97:3) provided the
corresponding product 3.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl acetate (3a). The desired pure product was obtained in 93% yield
(560 mg) as orange oil; [α]D +52.9 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2932, 2858, 1736, 1230; H NMR
20
1
(500 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 5.97-5.94 (dd, J = 9.0, 4.0 Hz, 1H), 2.85-2.80 (dd, J = 13.6, 9.0
13
Hz, 1H), 2.54-2.49 (m, 3H), 2.42-2.41 (m, 2H), 2.09 (s, 3H), 1.56-1.51 (m, 4H), 1.42-1.37 (m, 2H); C

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NMR (125 MHz, CDCl3) δ 170.2, 139.8, 128.3, 127.8, 126.4, 72.9, 64.4, 54.6, 26.0, 24.2, 21.3; HRMS
(ESI): m/z [M+H]+ calcd for C15H22NO2: 248.1651, found: 248.1650.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 5-bromopentanoate (3b). The desired pure product was obtained
20
in 94% yield (843 mg) as orange oil; [α]D +41.5 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2853, 1732,
1
1257, 698; H NMR (500 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 6.00-5.97 (dd, J = 9.3, 3.7 Hz, 1H),
3.41-3.38 (m, 2H), 2.84-2.79 (dd, J = 13.6, 9.3 Hz, 1H), 2.55-2.49 (m, 3H), 2.43-2.37 (m, 4H), 1.93-1.87
(m, 2H), 1.82-1.77 (m, 2H), 1.55-1.52 (m, 4H), 1.42-1.39 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.2,
139.5, 128.3, 127.8, 126.4, 72.7, 64.4, 54.6, 33.5, 33.1, 31.7, 25.9, 24.1, 23.5; HRMS (ESI): m/z [M+H]+
calcd for C18H27BrNO2: 368.1225, found: 368.1222.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl hexacosanoate (3c). The desired pure product was obtained in
95% yield (1351 mg) as orange solid; mp 52 °C; [α]D +10.4 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2920,
20
1
2851, 1736, 1466, 1263, 1162; H NMR (500 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 5.99-5.96 (dd, J = 9.1,
3.9 Hz, 1H), 2.83-2.78 (dd, J = 13.5, 9.1 Hz, 1H), 2.53-2.50 (dd, J = 13.5, 3.9 Hz, 1H), 2.51 (m, 2H),
2.45-2.39 (m, 2H), 2.35-2.28 (m, 2H), 1.65-1.59 (m, 2H), 1.55-1.50 (m, 4H), 1.41-1.37 (m, 2H),
13
1.29-1.25 (br, 44H), 0.89-0.86 (t, J = 6.9 Hz, 3H); C NMR (125 MHz, CDCl3) δ 172.8, 139.8, 128.2,
127.6, 126.3, 72.5, 64.4, 54.6, 34.5, 31.8, 29.6, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 26.0, 24.9, 24.2,
22.6, 14.0; HRMS (ESI): m/z [M+H]+ calcd for C39H70NO2: 584.5407, found: 584.5401.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-phenylacetate (3d). The desired pure product was obtained in
93% yield (732 mg) as orange oil; [α]D20 +48.6 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2953, 2853, 1733, 1663,
1
1496, 1454; H NMR (500 MHz, CDCl3) δ 7.31-7.23 (m, 10H), 5.98-5.96 (dd, J = 9.2, 3.6Hz, 1H),
3.70-3.67 (d, J = 15.0 Hz, 1H), 3.65-3.62 (d, J = 15.0 Hz, 1H), 2.80-2.75 (dd, J = 13.6, 9.2 Hz, 1H),
2.51-2.48 (dd, J = 13.6, 3.7 Hz, 1H), 2.46-2.45 (m, 2H), 2.34-2.33 (m, 2H), 1.50-1.45 (m, 4H), 1.38-1.35
13
(m, 2H); C NMR (125 MHz, CDCl3) δ 170.6, 139.5, 134.1, 129.3, 128.4, 128.3, 127.7, 126.9, 126.3,
73.4, 64.4, 54.6, 41.7, 26.0, 24.1; HRMS (ESI): m/z [M+H]+ calcd for C21H26NO2: 324.1964, found:
324.1951.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-(3,4-dimethoxyphenyl)acetate (3e). The desired pure product
20
was obtained in 90% yield (840 mg) as orange oil; [α]D +39.4 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933,
1
2834, 1732, 1141, 1026; H NMR (500 MHz, CDCl3) δ 7.31-7.25 (m, 5H), 6.83-6.77 (m, 3H), 5.98-5.95
(dd, J = 9.0, 3.8 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.63-3.60 (d, J = 14.8 Hz, 1H), 3.60-3.67 (d, J = 15.1
Hz, 1H), 2.81-2.77 (dd, J = 13.6, 9.0 Hz, 1H), 2.53-2.50 (dd, J = 13.6, 3.8 Hz, 1H), 2.47-2.45 (m, 2H),
13
2.36-2.34 (m, 2H), 1.50-1.46 (m, 4H), 1.38-1.34 (m, 2H); C NMR (125 MHz, CDCl3) δ 170.8, 148.7,
147.9, 139.5, 128.2, 127.7, 126.5, 126.3, 121.4, 112.2, 111.0, 73.4, 64.3, 55.8, 55.7, 54.5, 41.2, 25.9,
24.1; HRMS (ESI): m/z [M+H]+ calcd for C23H30NO4: 384.2175, found: 384.2188.

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(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-(4-isobutylphenyl)propanoate (3f). The desired pure product
was obtained as diastereomer mixture in 92% yield (881 mg, 3f = 1:1) as orange oil; FT-IR Qmax/cm-1
1
2932, 2868, 1734, 1091, 1019; H NMR (500 MHz, CDCl3) δ 7.29-7.04 (m, 18 H), 5.95-5.92 (m, 2H),
3.77-3.71 (m, 2H), 2.78-2.69 (m, 2H), 2.51-2.48 (m, 4H), 2.45-2.43 (m, 4H), 2.39-2.35 (m, 4H),
2.24-2.22 (m, 2H), 1.86-1.81 (m, 2H), 1.52-1.45 (m, 8H), 1.40-1.37 (m, 6H), 1.30-1.26 (m, 2H),
0.90-0.89 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 173.6, 173.5, 140.3, 139.8, 139.6, 137.6, 137.6, 129.1,
128.3, 128.1, 127.7, 127.5, 127.3, 127.3, 126.2, 126.0, 73.3, 73.0, 64.5, 64.2, 54.5, 54.2, 45.3, 45.2, 44.9,
44.9, 30.1, 30.1, 25.9, 25.8, 24.1, 24.0, 22.3, 22.3, 18.2, 18.2; HRMS (ESI): m/z [M+H]+ calcd for
C26H36NO2: 394.2746, found: 394.2736.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl benzoate (3g). The desired pure product was obtained in 91% yield
(685 mg) as orange oil; [α]D -8.6 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2853, 1717, 1266, 1069; H
NMR (500 MHz, CDCl3) δ 8.10-7.25 (m, 10H), 6.20-6.18 (dd, J = 8.5, 3.9 Hz, 1H), 3.03-2.98 (dd, J =
13.8, 8.5 Hz, 1H), 2.74-2.70 (dd, J = 13.8, 3.9 Hz, 1H), 2.59-2.56 (m, 2H), 2.52-2.49 (m, 2H), 1.54-1.49
20
1
13
(m, 4H), 1.40-1.37 (m, 2H); C NMR (125 MHz, CDCl3) δ 165.7, 139.9, 132.8, 130.5, 129.6, 128.4,
128.3, 127.8, 126.3, 74.0, 64.5, 54.6, 26.0, 24.1; HRMS (ESI): m/z [M+H]+ calcd for C20H24NO2:
310.1807, found: 310.1789.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 3-nitrobenzoate (3h). The desired pure product was obtained in
89% yield (768 mg) as yellow oil; [α]D -2.3 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2852, 1727, 1533,
20
1349; 1H NMR (500 MHz, CDCl3) δ 8.90-8.86 (m, 1H), 8.42-8.36 (m, 2H), 7.67-7.64 (m, 1H), 7.44-7.31
(m, 5H), 6.24-6.22 (dd, J = 8.9, 3.8 Hz, 1H), 3.03-2.98 (dd, J = 13.8, 8.9 Hz, 1H), 2.72-2.68 (dd, J = 13.8,
3.8 Hz, 1H), 2.60-2.58 (m, 2H), 2.49-2.44 (m, 2H), 1.52-1.48 (m, 4H), 1.40-1.36 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 163.6, 148.2, 139.0, 135.3, 129.5, 128.5, 128.1, 127.2, 126.4, 125.7, 124.5, 74.9, 64.3,
54.7, 26.0, 24.0; HRMS (ESI): m/z [M+H]+ calcd for C20H23N2O4: 355.1658, found: 355.1656.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 4-nitrobenzoate (3i). The desired pure product was obtained in
87% yield (751 mg) as yellow oil; [α]D20 -11.0 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2934, 2853, 1723, 1525,
1346; 1H NMR (500 MHz, CDCl3) δ 8.30-8.22 (m, 4H), 7.43-7.31 (m, 5H), 6.23-6.20 (dd, J = 9.0, 3.8 Hz,
1H), 3.00-2.96 (dd, J = 13.8, 9.0 Hz, 1H), 2.71-2.68 (dd, J = 13.8, 3.8 Hz, 1H), 2.60-2.56 (m, 2H),
13
2.46-2.44 (m, 2H), 1.52-1.48 (m, 4H), 1.40-1.37 (m, 2H); C NMR (125 MHz, CDCl3) δ 163.9, 150.4,
139.0, 136.0, 130.7, 128.5, 128.2, 126.4, 123.5, 74.9, 64.4, 54.7, 26.0, 24.1; HRMS (ESI): m/z [M+H]+
calcd for C20H23N2O4: 355.1658, found: 355.1653.
tert-Butyl 4-(((S)-1-phenyl-2-(piperidin-1-yl)ethoxy)carbonyl)phenylcarbamate (3j). The desired pure
product was obtained in 91% yield (940 mg) as orange oil; [α]D -36.6 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1
20
1
2935, 2852, 1709, 1152, 1050; H NMR (500 MHz, CDCl3) δ 8.01-7.25 (m, 9H), 6.76 (br, 1H),

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6.17-6.15 (dd, J = 8.4, 3.9 Hz, 1H), 3.01-2.96 (dd, J = 13.8, 8.5 Hz, 1H), 2.73-2.69 (dd, J = 13.8, 4.0 Hz,
1H), 2.56-2.48 (m, 4H), 1.52 (s, 9H), 1.50-1.48 (m, 4H), 1.38-1.35 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 165.3, 152.1, 142.6, 140.0, 130.9, 128.3, 127.7, 126.3, 124.7, 117.3, 81.1, 73.8, 64.5, 54.6, 28.2, 26.0,
24.1; HRMS (ESI): m/z [M+H]+ calcd for C25H33N2O4: 425.2440, found: 425.2428.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-(4-chlorobenzoyl)benzoate (3k). The desired pure product was
obtained in 90% yield (981 mg) as orange oil; [α]D20 +20.0 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2934, 2853,
1
1717, 1674, 1454, 1267; H NMR (500 MHz, CDCl3) δ 8.15-7.12 (m, 13H), 5.98-5.96 (dd, J = 8.5, 4.2
Hz, 1H), 2.68-2.64 (dd, J = 13.6, 8.5 Hz, 1H), 2.46-2.43 (dd, J = 13.6, 4.2 Hz, 1H), 2.38-2.37 (m, 2H),
13
2.30-2.25 (m, 2H), 1.50-1.38 (m, 4H), 1.36-1.25 (m, 2H); C NMR (125 MHz, CDCl3) δ 195.5, 164.6,
141.2, 139.4, 138.8, 135.5, 132.4, 130.7, 130.4, 129.5, 129.0, 128.7, 128.2, 127.9, 127.3, 126.5, 74.6, 63.8,
54.5, 25.9, 24.0; HRMS (ESI): m/z [M+H]+ calcd for C27H27ClNO3: 448.1679, found: 448.1681.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-methylbenzoate (3l). The desired pure product was obtained in
85% yield (669 mg) as yellow oil; [α]D20 +11.0 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2932, 2853, 1719, 1455,
1
1251, 1075; H NMR (500 MHz, CDCl3) δ 7.98-7.15 (m, 9H), 6.26-6.24 (dd, J = 9.2, 3.3 Hz, 1H),
3.13-3.08 (dd, J = 13.8, 9.2 Hz, 1H), 2.77-2.74 (dd, J = 13.8, 3.4 Hz, 1H), 2.70-2.64 (m, 2H), 2.60-2.56
(m, 2H), 2.57 (s, 3H), 1.62-1.58 (m, 4H), 1.45-1.40 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 166.6, 140.3,
139.6, 131.8, 131.5, 131.2, 130.5, 128.5, 128.0, 126.4, 125.6, 125.3, 73.0, 63.9, 54.3, 25.4, 23.9, 21.7;
HRMS (ESI): m/z [M+H]+ calcd for C21H26NO2: 324.1964, found: 324.1961.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 3-methylbenzoate (3m). The desired pure product was obtained in
94% yield (740 mg) as yellow oil; [α]D20 -13.8 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2853, 1718, 1454,
1
1274, 1081; H NMR (500 MHz, CDCl3) δ 7.90-7.24 (m, 9H), 6.20-6.17 (dd, J = 8.4, 4.0 Hz, 1H),
3.01-2.98 (dd, J = 13.7, 8.4 Hz, 1H), 2.74-2.70 (dd, J = 13.7, 4.0 Hz, 1H), 2.57-2.48 (m, 4H), 2.39 (s, 3H),
13
1.53-1.49 (m, 4H), 1.40-1.35 (m, 2H); C NMR (125 MHz, CDCl3) δ 165.8, 140.0, 138.0, 133.5, 130.1,
128.3, 128.1, 127.7, 126.7, 126.3, 73.9, 64.5, 54.6, 26.0, 24.1, 21.2; HRMS (ESI): m/z [M+H]+ calcd for
C21H26NO2: 324.1964, found: 324.1962.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 4-methylbenzoate (3n). The desired pure product was obtained in
93% yield (732 mg) as orange oil; [α]D20 -14.8 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2853, 1715, 1543,
1
1266, 1019; H NMR (500 MHz, CDCl3) δ 7.99-7.22 (m, 9H), 6.19-6.16 (dd, J = 8.4, 3.9 Hz, 1H),
3.01-2.96 (dd, J = 13.8, 8.5 Hz, 1H), 2.73-2.70 (dd, J = 13.8, 4.0 Hz, 1H), 2.57-2.49 (m, 4H), 2.39 (s, 3H),
13
1.53-1.48 (m, 4H), 1.39-1.34 (m, 2H); C NMR (125 MHz, CDCl3) δ 165.7, 143.4, 140.0, 129.6, 129.0,
128.3, 127.8, 127.7, 126.3, 73.8, 64.5, 54.6, 26.0, 24.1, 21.6; HRMS (ESI): m/z [M+H]+ calcd for
C21H26NO2: 324.1964, found: 324.1960.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl nicotinate (3o). The desired pure product was obtained in 91%

HETEROCYCLES, Vol. 96, No. 2, 2018
229
yield (687 mg) as orange oil; [α]D20 +3.4 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2931, 2853, 1721, 1590, 1419;
1H NMR (500 MHz, CDCl3) δ 9.29-9.23 (m, 1H), 8.78-8.77 (m, 1H), 8.33-8.31 (m, 1H), 7.43, -7.28 (m,
6H), 6.22-6.20 (dd, J = 8.8, 3.8 Hz, 1H), 3.00-2.96 (dd, J = 13.8, 8.9 Hz, 1H), 2.71-2.68 (dd, J = 13.8, 3.8
13
Hz, 1H), 2.59-2.55 (m, 2H), 2.48-2.44 (m, 2H), 1.52-1.48 (m, 4H), 1.40-1.35 (m, 2H); C NMR (125
MHz, CDCl3) δ 164.4, 153.3, 150.9, 139.3, 137.1, 128.5, 128.1, 126.5, 126.4, 123.2, 74.5, 64.4, 54.7,
26.0, 24.1; HRMS (ESI): m/z [M+H]+ calcd for C19H23N2O2: 311.1760, found: 311.1754.
(S)-1-Phenyl-2-(piperidin-1-yl)ethyl cinnamate (3p). The desired pure product was obtained in 92%
20
yield (783 mg) as white solid (recryst. from n-hexane/CH2Cl2); mp 82 °C; [α]D -35.1 (c 1.0, CH2Cl2);
1
FT-IR Qmax/cm-1 2933, 2853, 1709, 1636, 978; H NMR (500 MHz, CDCl3) δ 7.70-7.67 (d, J = 16.0 Hz,
1H), 7.53-7.24 (m, 10H), 6.54-6.50 (d, J = 16.0 Hz, 1H), 6.11-6.08 (dd, J = 8.8, 3.9 Hz, 1H), 2.96-2.92
(dd, J = 13.7, 8.8 Hz, 1H), 2.64-2.60 (dd, J = 13.7, 4.0 Hz, 1H), 2.55-2.53 (m, 2H), 2.48-2.47 (m, 2H),
13
1.57-1.51 (m, 4H), 1.42-1.37 (m, 2H); C NMR (125 MHz, CDCl3) δ 166.1, 144.8, 139.9, 134.3, 130.2,
128.8, 128.3, 128.0, 127.8, 126.4, 118.3, 73.2, 64.3, 54.6, 25.9, 24.1; HRMS (ESI): m/z [M+H]+ calcd for
C22H26NO2: 336.1964, found: 336.1951.
(2S)-(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 2-(2-methoxynaphthalen-6-yl)propanoate (3q). The desired
pure product was obtained in 98% yield (996 mg) as white solid; mp 71 °C; [α]D20 +17.3 (c 1.0, CH2Cl2);
FT-IR Qmax/cm-1 2934, 2852, 1730, 1605, 1154, 1031; 1H NMR (500 MHz, CDCl3) δ 7.69-7.10 (m, 11H),
5.96-5.94 (dd, J = 9.0, 3.5 Hz, 1H), 3.90-3.87 (m, 1H), 3.89 (s, 3H), 2.71-2.66 (dd, J = 13.8, 9.0 Hz, 1H),
2.48-2.45 (dd, J = 13.8, 3.5 Hz, 1H), 2.30-2.28 (m, 2H), 2.16-2.14 (m, 2H), 1.55-1.54 (d, J = 7.2 Hz, 3H),
13
1.28-1.23 (m, 4H), 1.20-1.17 (m, 2H); C NMR (125 MHz, CDCl3) δ 173.5, 157.4, 139.7, 135.6, 133.5,
129.1, 128.8, 128.3, 127.7, 126.8, 126.4, 126.3, 126.0, 118.7, 105.4, 73.5, 64.2, 55.2, 54.3, 45.5, 25.8,
23.9, 18.3; HRMS (ESI): m/z [M+H]+ calcd for C27H32NO3: 418.2382, found: 418.2374.
(3S)-(S)-1-Phenyl-2-(piperidin-1-yl)ethyl 3-phenylbutanoate (3r). The desired pure product was
obtained in 94% yield (804 mg) as red oil; [α]D +62.5 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2852,
20
1733, 1494, 1452; 1H NMR (500 MHz, CDCl3) δ 7.22-7.11 (m, 10H), 5.87 (dd, J = 9.2, 3.5 Hz, 1H)
3.23-3.16 (m, 1H), 2.81-2.76 (dd, J = 13.7, 9.3 Hz, 1H), 2.64-2.60 (m, 1H), 2.53-2.49 (m, 1H), 2.48-2.41
13
(m, 3H), 2.40-2.35 (m, 2H), 1.44-1.41 (m, 4H), 1.32-1.29 (m, 2H), 1.19-1.17 (d, J = 7.0 Hz, 3H); C
NMR (125 MHz, CDCl3) δ 171.4, 145.7, 139.4, 128.4, 128.3, 128.3, 127.9, 126.8, 126.7, 126.4, 126.3,
126.0, 72.4, 63.4, 54.0, 42.9, 36.3, 25.3, 23.8, 21.9; HRMS (ESI): m/z [M+H]+ calcd for C23H30NO2:
352.2277, found: 352.2274.
(2S)-tert-Butyl (S)-1-phenyl-2-(piperidin-1-yl)ethyl pyrrolidine-1,2-dicarboxylate (3s). The desired
pure product was obtained as a rotameric mixture (ratio 67:33) in 96% yield (941 mg) as yellow oil;
[α]D +32.5 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2802, 1747, 1698, 1157, 1087; (major rotamer) H
20
1

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HETEROCYCLES, Vol. 96, No. 2, 2018
NMR (500 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 6.07-6.03 (m, 1H), 4.29-4.26 (dd, J = 8.6, 3.5 Hz, 1H),
3.63-3.54 (m, 1H), 3.44-3.34 (m, 1H), 2.80-2.76 (dd, J = 13.4, 9.7 Hz, 1H), 2.56-2.46 (m, 3H), 2.35-2.29
(m, 2H), 2.24-2.14 (m, 2H), 2.02-1.93 (m, 1H), 1.90-1.82 (m, 1H), 1.53-1.50 (m, 4H), 1.41-1.38 (m, 2H),
13
1.22 (s, 9H); C NMR (125 MHz, CDCl3) δ 172.0, 153.7, 138.9, 128.1, 127.7, 126.4, 79.4, 72.3, 64.4,
58.9, 54.6, 46.1, 30.6, 28.2, 27.9, 24.0, 23.2; HRMS (ESI): m/z [M+H]+ calcd for C23H35N2O4: 403.2597,
found: 403.2587.
Regioisomer: (R)-2-Phenyl-2-(piperidin-1-yl)ethyl acetate (4a). The desired pure product was obtained
in 91% yield (548 mg) as yellow oil; [α]D -10.0 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2929, 2853, 1740,
20
1226; 1H NMR (500 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 4.51-4.48 (dd, J = 11.4, 6.3 Hz, 1H), 4.36-4.32
(dd, J = 11.4, 6.5 Hz, 1H), 3.63-3.60 (t, J = 6.4 Hz, 1H), 2.40-2.36 (m, 4H), 1.97 (s, 3H), 1.55-1.51 (m,
13
4H), 1.39-1.34 (m, 2H); C NMR (125 MHz, CDCl3) δ 170.9, 138.5, 128.4, 128.0, 127.3, 68.3, 64.9,
51.7, 26.2, 24.4, 20.9; HRMS (ESI): m/z [M+H]+ calcd for C15H22NO2: 248.1651, found: 248.1648.
Regioisomer: (R)-2-Phenyl-2-(piperidin-1-yl)ethyl benzoate (4g). The desired pure product was
20
obtained in 89% yield (670 mg) as orange oil; [α]D -8.1 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2933, 2853,
1733, 1262; 1H NMR (500 MHz, CDCl3) δ 7.97-7.25 (m, 10H), 4.79-4.76 (dd, J = 11.4, 6.2 Hz, 1H),
4.62-4.59 (dd, J = 11.4, 6.3 Hz, 1H), 3.83-3.81 (t, J = 6.2 Hz, 1H), 2.62-2.47 (m, 4H), 1.59-1.57 (m, 4H),
1.42-1.35 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 166.3, 132.8, 130.1, 129.5, 128.5, 128.2, 128.2, 128.0,
127.5, 68.5, 65.5, 51.8, 25.9, 24.3, HRMS (ESI): m/z [M+H]+ calcd for C20H24NO2: 310.1807, found:
310.1803.
(S)-2-((S)-3-Ethylpiperidin-1-yl)-1-phenylethyl acetate (5). The desired pure product was obtained in
91% yield (537 mg) as orange oil; [α]D20 +53.3 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2930, 2851, 1737, 1231,
1026; 1H NMR (500 MHz, CDCl3) δ 7.34-7.27 (m, 5H), 5.98-5.96 (dd, J = 8.9, 4.0 Hz, 1H), 2.91-2.82 (m,
2H), 2.88-2.84 (dd, J = 13.6, 9.0 Hz, 1H), 2.57-2.54 (dd, J = 13.6, 4.0 Hz, 1H), 2.12-2.03 (m, 1H), 2.09 (s,
3H), 1.74-1.68 (m, 2H), 1.64-1.50 (m, 2H), 1.43-1.35 (m, 1H), 1.25-1.17 (m, 2H), 0.88-0.85 (t, J = 7.5 Hz,
13
3H), 0.84-0.78 (m, 1H); C NMR (125 MHz, CDCl3) δ 170.23, 139.67, 128.37, 127.86, 126.46, 73.00,
64.08, 59.90, 54.88, 37.62, 30.32, 27.10, 25.32, 21.37, 11.35. HRMS (ESI): m/z [M+H]+ calcd for
C17H25NO2: 276.1978, found: 276.1964.
(S)-2-Morpholino-1-phenylethyl acetate (8). The desired pure product was obtained in 93% yield (559
mg) as yellow oil; [α]D20 +70.1 (c 1.0, CH2Cl2); FT-IR Qmax/cm-1 2958, 2854, 1733, 1229, 1115, 1026; 1H
NMR (500 MHz, CDCl3) δ 7.35-7.28 (m, 5H), 5.98-5.96 (dd, J = 9.2, 3.9 Hz, 1H), 3.71-3.64 (m, 4H),
2.86-2.82 (dd, J = 13.4, 9.3 Hz, 1H), 2.58-2.57 (m, 2H), 2.56-2.52 (dd, J = 13.4, 4.0 Hz, 1H), 2.48-2.47
13
(m, 2H), 2.10 (s, 3H); C NMR (125 MHz, CDCl3) δ 170.23, 139.11, 128.41, 128.02, 126.44, 72.33,
66.94, 64.00, 53.71, 21.32; HRMS (ESI): m/z [M+H]+ calcd for C14H19NO3: 250.1443, found: 250.1437.

HETEROCYCLES, Vol. 96, No. 2, 2018
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ACKNOWLEDGEMENTS
We are grateful to VIEP-BUAP for financial support, U.H.P and M.V.X thanks to CONACyT for the
scholarships (297948 and 277416) and projects CONACyT (173585, 225041 and 268178), A. Mendoza
and S. Bernès for the measurement of crystals in the X-ray Laboratories of CQ-ICUAP and IF-BUAP,
respectively.
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17. Deposition number CCDC-1551647 for compound 3p.