Synthesis of versatile bifunctional derivatives of chiral diamines obtained through anchimerically assisted nucleophilic substitution reactions on diastereomeric phenylprolinols

Article abstract of DOI:10.3987/COM-12-S(N)82

Diastereomeric [(S)-1-benzylpyrrolidin-2-yl]-(R)-[(phenyl)- methanamine] and [(S)-1-benzylpyrrolidin-2-yl]-(S)-[(phenyl)methanamine], were synthesized by selective internal backside nucleophilic substitution of the corresponding activated phenylprolinols. X-Ray diffraction structures of crystalline acetamide derivatives confirmed the anticipated stereochemistry for a SNib reaction mechanism. In order to apply this reaction to the synthesis of bifunctional analogs, a series of fragments such as a thiourea moiety and sulfonamide functions were introduced for the functionalization of the primary amino group in the substrate, obtaining more stable and potentially useful derivatives.

Full text of DOI:10.3987/COM-12-S(N)82

HETEROCYCLES, Vol. 86, No. 2, 2012, pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2012, Accepted, 24th August, 2012, Published online, 10th September, 2012
DOI: 10.3987/COM-12-S(N)82
SYNTHESIS OF VERSATILE BIFUNCTIONAL DERIVATIVES OF
CHIRAL DIAMINES OBTAINED THROUGH ANCHIMERICALLY
ASSISTED NUCLEOPHILIC SUBSTITUTION REACTIONS ON
DIASTEREOMERIC PHENYLPROLINOLS
Jorge Vargas-Caporali, Carlos Cruz-Hernández, and Eusebio Juaristi*
Department of Chemistry, Center for Research and Advanced Studies of the
National Polytechnic Institute, P. O. Box 14-740, 07000 México, D. F., Mexico
Abstract
Diastereomeric
[(S)-1-benzylpyrrolidin-2-yl]-(R)-[(phenyl)-
methanamine] and [(S)-1-benzylpyrrolidin-2-yl]-(S)-[(phenyl)methanamine], were
synthesized by selective internal backside nucleophilic substitution of the
corresponding activated phenylprolinols. X-Ray diffraction structures of
crystalline acetamide derivatives confirmed the anticipated stereochemistry for a
SNib reaction mechanism. In order to apply this reaction to the synthesis of
bifunctional analogs, a series of fragments such as a thiourea moiety and
sulfonamide functions were introduced for the functionalization of the primary
amino group in the substrate, obtaining more stable and potentially useful
derivatives.
INTRODUCTION
(N-Alkyl-pyrrolidin-2-yl)(phenyl)methanamine derivatives (Scheme 1) are useful pharmaceuticals in the
treatment of diverse behavioural disorders such as: dementia, schizophrenia, and Parkinson’s disease.1
*
*
N
HN
R'
R
Scheme 1. Basic structure of pyrrolidine phenylmethanamine derivatives
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday

Furthermore, the development of synthetic methodologies to obtain this type of chiral diamines is
important because of the promising structural features which could make these molecules helpful in
asymmetric catalysis either as organocatalysts per se2 or as chiral ligands in coordination complexes used
as catalysts.3
One of the principal routes for the preparation of β-aminopyrrolidines consists in the rearrangement
reaction of piperidine or pyrrolidine derivatives via internal backside nucleophilic substitution (SNib).4 A
salient feature of its mechanism is the anchimeric assistance of the heterocyclic nitrogen (Scheme 2).
Cl
*
-Nuc: -OH, -OAc
N
Nuc
*
N
-Nuc
1. SOCl2
*
-Nuc
N+
Cl-
2. base
N
OH
*
N
Nuc
*
-Nuc: -CN, :NH2R, :NHRR'
N
Cl
Scheme 2. Mechanism of the nucleophilic displacement reaction on 3-chloromethyl-N-ethylpiperidine
This anchimeric mechanism is well known since 19485-7 and it was observed that strong nucleophiles
such as amines are likely to favour formation of the pyrrolidinic framework, whereas weaker nucleophiles

(OH, OAc) tend to generate mixtures of 5- and 6-membered ring products. Additionally, it is also
worthy to mention that a similar behaviour is observed when linear β-aminoalcohols or polysubstituted
pyrrolidinic β-aminoalcohols are used as starting materials in the Mitsunobu reaction.8
Nevertheless, the majority of recent studies have pursued the selective formation of six-membered
derivatives,9 which exhibit biological activity as nonpeptidic NK-1 antagonists,10 anticancer drugs and
anti-malarial agents.11 In this context, the enantioselective ring expansion of prolinols, has been
intensively studied by J. Cossy and coworkers,12 whereas diverse methodologies have been developed to
gain access to chiral piperidine derivatives13 and analogous nitrogenated heterocycles.14

On the other hand, few reports have focused in the development of enantioselective preparation of
aminomethyl-pyrrolidine derivatives.8b,15 In this report we present our approach for the enantioselective
synthesis of [(S)-1-benzylpyrrolidin-2-yl]-(R)-[(phenyl)methanamine] and [(S)-1-benzylpyrrolidin-2-yl]-
(S)-[(phenyl)methanamine], (S,R)-1 and (S,S)-1, which are potential chiral building blocks for the
preparation of new functionalized (S)-proline derivatives (Scheme 3).
(S)
(R)
(S)
(S)
N
N
H
NH2
H
H2N
(S,R)-1
(S,S)-1
Scheme 3. Diastereomeric (1-benzylpyrrolidin-2-yl)(phenyl)methanamines
RESULTS AND DISCUSSION
Synthesis of azide precursors via SNib reaction on chlorophenylpiperidines derived from
enantiopure carbinols (S,R)- and (S,S)-7. Diastereomeric (N-benzylpyrrolidin-2-yl)(phenyl)methanols,
(S,R)- and (S,S)-7 were prepared following a slightly modified synthetic methodology previously reported
by Almansa et al.3a (Scheme 4). In particular, increased reaction times were used for the Swern
oxidation,16 and the Grignard reaction was carried out at room temperature, and LiBr was used instead of
CeCl3 to increase the reactivity of (unstable) aldehyde (S)-6.17 Commercially available phenylmagnesium
bromide can be used although if prepared in situ, careful remotion of bromine (generated from PhBr) is
necessary to avoid side reactions.18,19
O
O
O
i
ii
iii
Cl-
N
N
H2
N
N
+
H
OH
O
O
OH
(S)-2
(S)-3
(S)-4
(S)-5
iv
v
(S)
(R)
(S)
H
O
vi
(S)
+
N
N
N
H
OH
HO
H
(S,R)-7
(S,S)-7
(S)-6
Scheme 4. Reagents and conditions: (i) 4 equiv SOCl2 added at 0 °C in MeOH then reflux, 3 h, 99% ; (ii)
1.1 equiv PhCH2Br, 2.2 equiv Et3N, CH2Cl2, rt, 24 h, 90%; (iii) 3 equiv LiAlH4 added at 0 °C to THF
soln. and then reflux, 5 h, 98%; (iv) 3.0 equiv DMSO, 1.51 equiv ClCOCOCl, CH2Cl2, -78 °C, 3 h; (v)
4.51 equiv Et3N, 0 °C, 3 h, 99%. (vi) PhMgBr, LiBr, THF, rt, overnight.

The conversion of the hydroxy group in (S,R)- and (S,S)-7 into the desired amino group was
accomplished by first reacting each amino alcohol with methanesulfonyl chloride and then carrying out
the displacement reaction with azide, using NaN3 as the source of N-nucleophile. Specifically, the
reaction between the amino alcohol (S,S)-7 and mesyl chloride afforded halogenated piperidine (R,R)-8,
which is the product of ring expansion. The immediate internal nucleophilic attack from the pyrrolidinic
nitrogen towards the carbon attached to the ephemeral methanesulfonyl group gives rise to the formation
of the aziridinium ion, which is opened by a second addition of the chloride ion present in the reaction
(Scheme 5). This result is in accordance with those observed with 1-ethylpyrrolidine-2-methanol and
other analogs.7,12
Cl-
N+
(R) Cl
(S)
(S)
i
(R)
N
N
OH
H
H
(R,R)-8
(S,S)-7
Scheme 5. Reagents and conditions: (i) 1.6 equiv. Et3N, 1.5 equiv MeSO2Cl, CH2Cl2, rt, 5 h
Light sensitive piperidine (R,R)-8 was recrystallized to give suitable crystals for X-ray diffraction analysis,
confirming the predicted relative configuration of both stereocenters (Figure 1).20
Figure 1. X-Ray diffraction structure and solid-state conformation of (R,R)-8 (thermal ellipsoids shown at
30% probability)
The chlorinated piperidine (R,R)-8 was subjected to nucleophilic substitution reaction conditions using a
solution of sodium azide in DMSO-DMF, and irradiated with microwaves for two hours (40 Watts) in order

to reduce the reaction time (ca. 8 h under normal heating conditions). Even though the desired pyrrolidinic
derivative (S,S)-9 was obtained, the main product corresponded to (R,R)-10, originating from ring
expansion (Scheme 6).
-
(R)
(R)
(R)
(R)
N3
N+
Cl
N3
(S)
(S)
i
N
N
N
+
N3
H
H
-
N3
(R,R)-8
(S,S)-9
(R,R)-10
Scheme 6. Reagents and conditions: (i) 1.1 equiv NaN3, DMF:DMSO (4:1), MW 40 watts, 55 °C, 2 h,
90% overall yield, (S,S)-9:(R,R)-10 (1:1.75)
By contrast, amino alcohol (S,R)-7 gave rise to the analogous chloropiperidine (S,R)-8 as described
previously by Langlois et al.9b However, it is important to point out that when (S,R)-8 reacted with NaN3
under the same conditions used with (R,R)-8, this conveniently afforded only the target azide (S,R)-9
(Scheme 7). The regioselective attack of the nucleophile can be explained by the development of a partial
positive charge in the transition state, which seems to be more stabilized at the C–Ph atom (Scheme 7).21
Cl
-
N3
(R)
(S)
(R)
(S)
(R)
i
ii
N+
(S)
N
N
H
N
H
H
N3
HO
(S,R)-8
(S,R)-9
(S,R)-7
Scheme 7. Reagents and conditions: (i) 1.6 equiv Et3N, 1.5 equiv MeSO2Cl, CH2Cl2, rt, 5 h, 89%. (ii) 1.1
equiv NaN3, DMF:DMSO (4:1), MW, 40 watts, 55 °C, 2 h, 90%.
The contrasting reactivity behaviour in (S,R)-8 and (R,R)-8 might be explained as follows: in the case of the
aziridinium ion generated from chloropiperidine (S,R)-8, the bulky N-benzyl and phenyl groups are
oriented to the same side (syn), which provokes steric repulsion that might induce an elongation and
weakening of the N-C(Ph) bond. This effect facilitated the selective azide attack leading to the selective
formation of pyrrolidinic product. By contrast, in the case of chloropiperidine (R,R)-8, the N-benzyl group
is oriented anti to the phenyl group, so that no repulsive steric interaction between these groups takes place,
and non-selective azide attack generates a mixture of the five and six-membered heterocyclic products.

Figure 2 compares the NMR spectra of azides (S,R)-9, (S,S)-9, and (R,R)-10, where the assignments were
3
based on one- and two-dimensional NMR experiments. Salient observations are, (1) J1/5 = 3.72 Hz in
(S,R)-9 is smaller than 3J1/5 = 7.45 Hz in (S,S)-9, which is similar to the trend observed in the corresponding
starting amino alcohols (S,R)- and (S,S)-7. (2) Upfield shifts are observed for protons farther from the
substituted carbons and for exocyclic methine proton H(5) in azide (S,S)-9, with respect to those of its
(S,R)-9 diastereomer. (3) The methine proton H(1) in (S,S)-9 appears at lower field relative to the same
proton in diastereomer (S,R)-9. (4) The difference in chemical shifts for the AB system in benzylic protons
H(6) is largest in (R,R)-10 relative to both diastereomers (S,S)-9 and (S,R)-9.
6
6
3
2
5
Ph
H
4
N
6
2, 3
5
1
H
1
4
N3
4
Ph
2
3
(S,R)-9
3
2
Ph
N3
5 6
6
4
N
6
H
2, 3
H
1
4
4
5
1
Ph
2
3
(S,S)-9
6
3
2
1
N3
Ph
1
4
5
6
2
N
5
4
6
5
3
4
3
Ph
(R,R)-10
Figure 2. Segments of the 1H NMR spectra of (S,R)-9, (S,S)-9 and (R,R)-10
Confirmation of the configurational assignment by means of X-Ray diffraction analysis.
Reduction of the azide function by means of catalytic hydrogenation afforded the diastereomeric
N-benzylated diamines, (S,S)-1 and (S,R)-1, which were acetylated to give crystalline derivatives (S,S)-11
and (S,R)-11 (Scheme 8).

(S)
(R)
(S)
(R)
(S)
(R)
i
ii
N
N
N
H
H
H
HN
N3
N
H
H
O
(S,R)-9
(S,R)-1
(S,R)-11
(S)
(S)
(S)
(S)
(S)
(S)
i
ii
N
H
N
N
N3
NH2
N
H
H
H
O
(S,S)-9
(S,S)-1
(S,S)-11
Scheme 8. Reagents and conditions: (i) H2, 60-70 psi, EtOH, rt, 2-3 h, 90-96%. (ii) 1.3 equiv Et3N, 1.2
equiv MeCOCl, THF, rt, 48 h, 62% yield for (S,R)-11 and 90% for (S,S)-11
Figure 3 presents the structure and solid-state conformation of compounds (S,S)-11 and (S,R)-11. In these
structures22,23 it is possible to confirm the anticipated configurations for the stereogenic centers in each
diastereomer, allowing for the unambiguous conclusion that amino alcohol (S,R)-7 led to azide (S,R)-9 by a
double nucleophilic attack (SN2ib) via the aziridinium ion intermediate from piperidine (S,R)-8. A similar
conclusion can be reached for amino alcohol (S,S)-7, which gives rise to the corresponding azide (S,S)-9
with overall retention of configuration. The orientation of the hydrogen atoms bonded to the stereogenic
carbons is also appreciated. For amide (S,S)-11 these hydrogens are oriented in opposite direction (anti)
while in the diastereomer (S,R)-11 they are gauche-oriented.
(S,S)-1122
(S,R)-1123
Figure 3. X-Ray crystallographic structure and solid-state conformation of (S,S)-11 and (S,R)-11 (Thermal
ellipsoids of 30% probability)

Azido-piperidine (R,R)-10 was reduced according to the same procedure followed in the reduction of
(S,S)-9 and (S,R)-9 affording diamine (R,R)-12, which was also acetylated to give crystalline amide
(R,R)-13 (Scheme 9).
O
(R) NH2
(R)
N3
(R)
NH
i
ii
(R)
N
N
(R)
(R)
N
(R,R)-10
(R,R)-12
(R,R)-13
Scheme 9. Reagents and conditions: (i) H2, 70 psi, EtOH, rt, 17 h, 95%. (ii) 1.3 equiv Et3N, 1.2 equiv
MeCOCl, THF, rt, 48 h, 79%.
Figure 4 presents the structure and solid-state conformation of (R,R)-13 obtained by X-ray diffraction
analysis. The cis configuration of the substituents at the stereogenic carbons is clearly appreciated, and this
observation helps discard the possibility of a simple nucleophilic substitution in (R,R)-8, that would have
resulted in inversion of the configuration at C(3).
Figure 4. X-Ray diffraction crystallographic structure and solid-state conformation of (R,R)-13 (ellipsoids
shown at 30% probability)24
Debenzylation reaction to obtain pharmacophore (R,R)-14.
Deprotection of diamine (R,R)-12 afforded derivative (R,R)-14, that offers an attractive strategy for the
enantioselective preparation of various commercial drugs such as CP-122,721, CP-99994, among others,
which are important neurokinin-1 receptor antagonists (Scheme 10).10b,13a

R
R
O
H
H
(R) NH2
(R)
(R)
(R)
(R)
(S)
(S)
NH2
N
N
i
OMe
Me
(R)
N
N
N
N
H
H
H
(CP-99,994)
(CP-122,721)
R = H
R = OCF3
(R,R)-12
(R,R)-14
Scheme 10. Reagents and conditions: (i) 1000 psi H2, 15% w-w Pd(OH)2, EtOH, 60 °C, 80%
Conversion of the primary amino group into a thiourea moiety.
Chiral thioureas are important compounds due to its great versatility as Brønsted acid activators of prochiral
substrates,25 chiral solvating agents in the enantiodiscrimination of carboxylic compounds,26 and more
recently as catalysts in organocatalytic Mannich, aza-Henry, and Michael reactions (Figure 5).27
CF3
S
S
R
N
N
F3C
N
N
H
H
H
H
N
H
N
Me
Me
Ar
Jacobsen thioureas
Takemoto thiourea
Figure 5. Examples of important thiourea organocatalysts
The conversion of primary amino group of derivatives (S,R)-1 and (S,S)-1 into a thiourea moiety was easily
carried out by treatment of each diamine with phenyl isothiocyanate at room temperature, giving rise to the
expected thioureas (S,R)-15 and (S,S)-15 (Scheme 11).28
(S)
(S)
(R)
(S)
(S)
(S)
(R)
(S)
S
N
i
i
N
N
N
N
H
or
H
NH2
N
H
S
N
H2N
H
H
H
H
N
H
(S,S)-15
(S,R)-15
(S,R)-1
(S,S)-1
Scheme 11. Reagents and conditions: (i) 1.6 equiv Ph–N=C=S, THF, rt, 2 days, 70-71% for both
diastereomers

Incorporation of a sulfonamide function at the amino group.
We also developed the synthesis of sulfonamide derivatives as described in Scheme 12, and it was possible
to obtain a crystal structure of compound (S,R)-17, which is shown in Figure 6.
(S)
(R)
(S)
(S)
(S)
(R)
(S)
i
i
(S)
N
N
N
N
or
H
NH2
H
H
H
H
O
R
H2N
HN
O
N
S
S
O
O
R
R = NO2, (S,S)-16
R = Me, (S,S)-17
R = NO2, (S,R)-16
R = Me, (S,R)-17
(S,R)-1
(S,S)-1
Scheme 12. Reagents and conditions: (i) 1.1 equiv Et3N, 1.05 equiv ArSO2Cl, THF, rt, 12 h. (S,R)-16, 67%;
(S,S)-16, 69%; (S,R)-17, 67%; (S,S)-17, 78%
Figure 6. X-Ray diffraction crystallographic structure and solid-state conformation of (S,R)-17 (Thermal
ellipsoids shown at 30% probability). Splitting of the position in C(4) was required because of the presence
of disorder in the organization of the crystalline lattice of sulfonamide molecules.29
CONCLUSIONS
Pyrrolidinic diamines (S,R)-1 and (S,S)-1 were synthesized by anchimerically assisted nucleophilic
substitution reaction (SNib) from carbinols (S,R)-7 and (S,S)-7, respectively. The overall retention of
configuration could be confirmed by analysis of the NMR spectra of azides (S,R)-9 and (S,S)-9 and by
examination of X-ray structures of crystalline derivatives (S,R)-11 and (S,S)-11.
The ring-expansion product (R,R)-10 was obtained solely from the diastereomeric carbinol (S,S)-7, as
corroborated through the X-Ray crystallographic structure of its aminoamide derivative (R,R)-13. The
relevant pharmacophore (R,R)-14 could be readily prepared from (R,R)-10.

Finally, a variety of bifunctional compounds with potential applications in asymmetric catalysis could be
generated in good yields via the incorporation of thiourea and sulfonamide moieties in (S,R)-1 and (S,S)-1.
EXPERIMENTAL
General
Commercially available reagents were used as received. Anhydrous solvents were obtained by routine
distillation techniques.30 TLC: Merck DC-F254 plates, detection UV light, iodine vapor. Flash
chromatography: Merck silica gel (0.040–0.063 mm). Melting points: Melt Temp ‘Electrothermal’
apparatus, uncorrected. Optical rotations were measured in a Perkin-Elmer 241 polarimeter. NMR spectra
were obtained with JEOL GSX-270 (270 MHz), Bruker Advance 300 (300 MHz), JEOL Eclipse 400 (400
MHz) and Jeol ECA-500 (500 MHz) spectrometers. Chemical shifts (δ) are given in parts per million
relative to tetramethylsilane as internal reference, giving coupling constants J in hertz (Hz). IR spectra
were recorded on a Varian Model 640 apparatus. Mass spectra were obtained in a Hewlett–Packard
HP-5986 instrument 5989-AMS-ENGINE, Thermo Electron Trace-DSQ spectrometer, at 20 eV.
High-resolution mass spectra (HRMS) were obtained on one HPLC 1100 coupled to MSDTOF Agilent
Technologies apparatus mod. 1069A. Elemental analyses were obtained using a Thermo-Finnigan
CHNS/O 1112 apparatus. The structural X-ray crystallographic data were obtained on an Enraf-Nonius
Kappa CCD diffractometer. Microwave irradiation experiments were achieved in a single-mode Discover
System reactor from CEM Corporation.
Synthesis of (S)-proline methyl ester hydrochloride, (S)-3. SOCl2 (76 mL, 1.04 mol) was added
dropwise to a solution of (S)-proline (28.64 g, 0.25 mol) in MeOH (500 mL) at 0 °C. When the addition
was complete, the mixture was refluxed for 2.5 h. After cooling to room temperature, the solvent was
evaporated under reduced pressure. The resultant (S)-3 was obtained in 99% yield (42 g, 0.25 mol) as pale
25
yellow oil and was used in the alkylation step without further purification.

D -34 (c 3.66, MeOH)
25
{lit.,31

D -33.9 (c 3.55, MeOH)}; δH (D2O, 270 MHz): 2.35-2.52 (m, 3H); 2.71-2.78 (m, 1H);
3.64-3.88 (m, 3H); 4.16 (s, 3H). δC (D2O, 68 MHz): 23.8, 28.6, 47.0, 54.4, 60.2, 170.9. Spectroscopic
data in accordance with those reported in lit.31
Synthesis of N-benzyl (S)-proline methyl ester, (S)-4. Et3N (77 mL, 55.9 g, 0.55 mol) was added
dropwise to a cold solution of (S)-3 (41.2g, 0.25 mol) in dry CH2Cl2 under inert atmosphere. Then, benzyl
bromide (33.2 mL, 47.74 g, 0.28 mol) was added to the thick reaction mixture, allowing it to reach room
temperature after complete addition. This solution was stirred during 17 h and latter, it was extracted with
CH2Cl2 (3 x 400 mL). The combined organic layers were dried over MgSO4. After filtration and
evaporation of the solvents, the crude residue was purified by distillation under reduced pressure (120 °C,

0.5-1 mmHg), giving 49.6 g (0.23 mol) of the product, (S)-4, as a clear oil in 91% yield. Rf 0.7
25
25
(hexane:AcOEt, 7:3),

D –65 (c 3.0, CH2Cl2) {Aldrich, 97% ee,

D –62.0 (neat)}, δH (CDCl3, 300
MHz): 1.71-1.79 (m, 1H); 1.88-2.0 (m, 2H); 2.06-2.17 (m, 1H); 2.39 (dd, 1H, J = 17 Hz); 3.0-3.08 (m,
1H); 3.25 (dd, 1H, J = 6.4Hz); 3.57 (d, 1H, J = 12.75 Hz); 3.64 (s, 3H); 3.89 (d, 1H, J = 12.75 Hz);
7.24-7.35 (m, 5H). δC (CDCl3, 75 MHz): 23.4, 29.8, 52.1, 53.7, 59.2, 65.7, 127.5, 128.6, 129.7, 138.5,
174.9. Chemical shifts in accordance with those reported in the literature.32
Reduction of amino ester (S)-4 to obtain N-benzyl (S)-prolinol, (S)-5. 25.75 g (0.68 mol) of LiAlH4
were slowly added via powder funnel to a cooled solution of (S)-4 (49.6 g, 0.23 mol) in anhydrous THF
(400 mL) under N2. After stirring for one hour at 0 °C, the suspension was allowed to reach room
temperature and then, it was refluxed during 3 h. The mixture was cooled again at 0 °C in order to quench
the reaction. Quenching was carried out by carefully adding the cold content on 1.5 L of ice, this last in
turn contained in a 4 L Erlenmeyer flask equipped with a cooling bath. Once the frost has melted, the
resulting magnesia is poured onto a celite pad to remove suspended alkalis and the solid residue was
washed with 300 mL of hot AcOEt. The resultant biphasic filtrate was separated and THF was removed
from the aqueous layer in a rotary evaporator, extracting again the residual liquid previously cooled with
a similar amount of AcOEt. The combined organic layers were dried with Na2SO4 and concentrated, and
the crude was distilled under reduced pressure (110 °C, 1.5 mmHg), obtaining 41.8 g (0.22 mol) of the
25
desired amino alcohol (S)-5 as a colourless liquid in 97% yield. Rf 0.4 (hexane:AcOEt, 7:3),


D -60 (c
25
1.0, CHCl3) {lit.,33


D -59.9 (c 1.0, CHCl3)}, δH (CDCl3, 500 MHz): 1.60-1.69 (m, 2H); 1.78 (sext.,
1H, J = 6.5 Hz); 1.84-1.92 (m, 1H); 2.23 (dd, 1H, J = 0.95 Hz, 8.45 Hz); 2.64-2.59 (m, 1H); 2.92 (quint.,
1H, J = 4.7 Hz); 3.26 (br, 1H); 3.31 (d, 1H, J = 12.95 Hz); 3.45 (dd, 1H, J = 2.65 Hz, 10.8 Hz); 3.59 (dd,
1H, J = 3Hz, 10.75 Hz); 3.95 (d, 1H, J = 12.95 Hz); 7.18-7.23 (m, 1 H); 7.27 (d, 4H, J = 4.05 Hz). δH
(CDCl3, 125 MHz): 23.45, 27.94, 54.57, 58.86, 62.41, 64.56, 127.13, 128.53, 128.91, 139.40. IR (ATR,
cm-1): νmax 3420, 3060, 3026, 2960, 2872, 2796, 1738, 1602, 1494, 1452, 1374, 1352, 1250, 1210, 1076,
1030, 912, 848, 740, 700. Spectroscopic data in accordance with those reported in the literature.34
Swern Oxidation of N-benzylprolinol (S)-5 to the corresponding aldehyde, (S)-6. 21.05 mL (31.56 g,
0.25 mol) of oxalyl chloride were dissolved with 600 mL of dry CH2Cl2 under nitrogen atmosphere in a
2-L three-necked round bottomed flask equipped with magnetic stirring, two addition funnels and two or
three evolving gas traps. The solution was cooled at -78 °C and then, 38.6 mL of DMSO (42.4 g, 0.54
mol) were added dropwise, allowing time for the system to depressurise the immediately evolved CO2.
After completion of addition, the reaction mixture was stirred during one hour. Then, 41.8 g (0.22 mol) of
(S)-5 dissolved in 100 mL of dry CH2Cl2 were added over a period of 20 min. The resulting thick mixture
was left under these conditions for 3 h more and latter, Et3N (142 mL, 103 g, 1.02 mol) were added

leaving the reaction mixture to reach 0 °C and stirring during 3 h at this temperature. Then, 300 mL of
brine were added and the organic layer was washed thrice to remove the maximum amount of Me2S. The
organic layer was dried over Na2SO4 and after filtration and evaporation of the solvent; the resultant
crude aldehyde (S)-6 was dried under vacuum for a prolonged period. Then, 39 g of aldehyde (S)-6 were
obtained (94.2% yield) as a crude orange oil which was used in the next step without further purification
due to quick decomposition. Rf 0.5 (hexane/AcOEt, 7:3), δH (CDCl3, 270 MHz): 1.79-1.91 (m, 4H);
2.34-2.44 (m, 1H); 2.95-3.02 (m, 1H); 3.06-3.15 (m, 1H); 3.65 (d, 1H, J = 12.9); 3.75 (d, 1H, J = 12.9);
7.22-7.35 (m, 5H); 9.3 (dd, 1H, J = 3.7 Hz, 0.78 Hz). δC (CDCl3, 68 MHz): 23.47, 26.51, 53.99, 59.44,
71.55, 127.34, 128.82, 129.08, 138.31, 202.75. HR-ESI-TOF [M+H]+ (m/z) calculated for C12H16NO:
190.1226; found: 190.1226, (error = -0.2141). Chemical shifts in accordance with those reported in the
literature.35
Grignard reaction to obtain the mixture of diastereomeric amino alcohols (S,R)- and (S,S)-7. 27.5 g
(1.13 mol) of clean Mg and 200 mL of anhydrous THF were added in a 1-L round-bottomed flask
equipped with a magnetic stir bar and conditioned with inert atmosphere. Afterwards, 119 mL (177 g,
1.13 mol) of freshly distilled bromobenzene were added dropwise to the cooled heterogeneous mixture.
Once the content became homogeneous, 17.9 g (0.21 mol) of LiBr dissolved in 100 mL of anhydrous
THF were added at 0 °C to the Grignard solution and stirred during 1 h at this temperature. Then, 39 g
(0.21 mol) of (S)-6 dissolved in dry THF (100 mL) were added via cannula and the final solution was
stirred during 4 h at 0 °C and left to reach room temperature overnight. The reaction was quenched by
adding in cold 200 mL of a saturated aqueous solution of NH4Cl. When Grignard reagent was eliminated,
filtering and washing of solid precipitates, and extraction of residual liquids were carried out following
the same techniques described above for (S)-5. AcOEt was evaporated under vacuum obtaining the
diastereomeric mixture crude. Amino alcohols were separated by column chromatography using gradient
(hexane:AcOEt, 95:5→85:15), obtaining 23.71 g (0.09 mol) of (S,R)-7 and 21.9 g (0.08 mol) of (S,S)-7 (d.
r. 52:48, 81% overall yield).
(R)-[(2S)-1-Benzylpyrrolidin-2-yl](phenyl)methanol, (S,R)-7. Yellow oil; Rf 0.55 (hexane/AcOEt, 7:3)
25
25

D –69 (c 1.16, CHCl3) {lit.,3a

D –69.2 (c 1.3, CHCl3)}, δH (CDCl3, 400 MHz): 1.28-1.43,
1.6–1.83 (1H and 3H, respectively, 2m, CH2CH2CH), 2.36 (1H, q, J = 8.65 Hz, 1 x CH2CHHN),
2.89–2.98 (1H, m, CH-CHOH), 3.03–3.14 (1H, m, 1 x CH2CHHN), 3.5, 4.22 (1H each, 2d, J = 12.88 Hz
each, CH2Ph), 4.93 (1H, d, J = 2.92 Hz, CH-OH), 7.34–7.59 (10H, m, ArH); δC (CDCl3, 100 MHz): 23.3,
24.1 (CH2CH2CH), 54.81 (CH2CH2N), 58.36 (NCH2Ph), 69.28 (CH2CHN), 70.22 (CH-OH), Ar: 125.61,
126.9, 127.31, 128.24, 128.55, 128.91, 139.11 (C-ipso), 141.63 (C-ipso). Chemical shifts and other
spectroscopic data are in agreement with those reported in the literature.3a

(S)-[(2S)-1-Benzylpyrrolidin-2-yl](phenyl)methanol, (S,S)-7. White solid, mp 72-74 °C (AcOEt/
25
25
hexane); Rf 0.33 (hexane/AcOEt, 7:3);

D +118.3 (c 1.04, CHCl3) {lit.,3a

D +101.8 (c 1.1,
CHCl3)}, δH (CDCl3, 270 MHz): 1.71–1.84, 1.91–2.04 (3H and 1H, respectively, 2m, CH2CH2CH),
2.36–2.48, 2.92–3.01 (1H each, 2m, CH2CH2N), 3.05–3.14 (1H, m, -CHN), 3.35, 3.66 (1H each, 2d, J =
12.9 Hz each, N-CH2Ph), 4.39 (1H, d, J = 5.2 Hz, *CH-OH), 7.20–7.41 (10H, m, ArH); δC (CDCl3, 68
MHz): 24.26, 29.33 (CH2CH2CH), 54.22 (CH2CH2N), 61.19 (NCH2Ph), 70.15 (CH2CHN), 75.19
(CH-OH), Ar: 126.12, 127.03, 127.10, 128.24, 128.32, 128.65, 139.40 (C-ipso), 143.69 (C-ipso).
Chemical shifts and other spectroscopic data are in agreement with those reported in the literature.3a
General procedure for the synthesis of 1-benzyl-3-chloro-2-phenylpiperidines. A determined amount
of the required diastereomer 7 was dissolved with CH2Cl2 in a three-necked round-bottomed flask
equipped with magnetic stirring and conditioned with nitrogen atmosphere. Subsequently, 1.6 equivalents
of Et3N and 1.5 equivalentes of MeSO2Cl are simultaneously added at 0 °C. The reaction mixture was left
stirring during three more hours at this temperature. After this time, the reaction was ended by extracting
twice with saturated aqueous solution of NaHCO3 and latter with brine, then the organic layer was dried
with Na2SO4. Activated charcoal is incorporated to the organic phase and the mixture was slightly heated
before pouring onto a compressed celite pad in a porous glass filter. Solvent was evaporated under
reduced pressure and the resultant oil is dissolved again in a minimum volume of heated hexane:AcOEt
(95:5) mixture. The saturated solution is cooled thus precipitating colourless crystals which were filtrated
and dried under vacuum.
(2R,3R)-1-Benzyl-3-chloro-2-phenylpiperidine, (R,R)-8. The general procedure described above was
followed with 5.5 g (0.02 mol) of (S,S)-8, 4.6 mL (3.34 g, 0.03 mol) of Et3N and 2.4 mL (3.55 g, 0.03
mol) of MeSO2Cl and 100 mL of CH2Cl2 to afford the desired piperidine (R,R)-8 (5.8 g, 98.4% yield), as
25
a colourless solid, mp 94-96 °C (AcOEt/hexane); Rf 0.58 (hexane/AcOEt, 9:1);


D +20 (c 1.07,
CHCl3), δH (CDCl3, 500 MHz): 1.48-1.55, (m, 1H, CH2-CH2-CH2-), 1.96 (tdd, 1H, J = 13.5, 3.5, 3.2 Hz,
-CHCl-CH2-), 2.04 (td, 1H, J = 12.0, 3.2 Hz, -CH2-N), 2.14-2.25 (m, 2H, -CHCl-CH2-CH2-), 2.93 (d, 1H,
J = 14.0 Hz, NCH2Ph), 3.06 (ddd, 1H, J = 12.0, 5.0, 3.2 Hz, -CH2-CH2-N), 3.54 (d, 1H, J = 2.2,
-CHPh-CHCl-), 3.93 (d, 1H, J =14.0 Hz, NCH2Ph), 4.22 (ddd, 1H, J = 3.2, 2.2, 1.7 Hz, CHPh-CHCl ),
7.18-7.37 (m, 8H, ArH), 7.46-7.51 (m, 2H, Ar). δC (CDCl3, 125 MHz): 20.07 (CH2-CH2-CH2-), 33.56
(-CHCl-CH2-), 53.28 (CH2-N), 59.17 (NCH2Ph), 64.00 (-CHCl-), 71.38 (-CHPh-CHCl-), ArC: 126.73,
127.57, 127.93, 128.14, 128.57, 129.00, 138.85 (NCH2Ph, Cipso), 140.52 (-CHPh-CHCl-, Cipso). IR
(ATR, cm-1): νmax 3060, 3023, 2954, 2929, 2804, 1600, 1492, 1449, 1315, 1304, 1133, 1099, 1065, 1028,
996, 941, 885, 755, 737, 703, 640, 600. HR-ESI-TOF [M+H]+ calculated for C18H21ClN: 286.1357;
found: 286.1357 (error = -0.0139).

(2S,3R)-1-Benzyl-3-chloro-2-phenylpiperidine, (S,R)-8. The general procedure described for the
synthesis of piperidines was followed with 4.0 g (0.02 mol) of (S,R)-8, 3.34 mL (2.43 g, 0.02 mol) of
Et3N and 1.74 mL (2.58 g, 0.02 mol) of MeSO2Cl and 80 mL of CH2Cl2 to afford the desired piperidine
(S,R)-8 (4.27 g, 99% yield), as a colourless solid, mp 60-61 °C (AcOEt/hexane); Rf 0.67 (hexane/AcOEt,
25
298
9:1);

D +25 (c 1.0, CHCl3), {lit.,9b


D +27(c 1.6, CHCl3)}, δH (CDCl3, 500 MHz): 1.63-1.81 (m,
3H); 2.00-2.06 (m, 1H); 2.35-2.40 (m, 1H); 2.87 (d, 1H, J = 13.5 Hz); 2.93 (m, 1H); 3.19 (d, 1H, J = 9.55
Hz); 3.68 (d, 1H, J = 13.5 Hz); 3.96 (ddd, 1H, J = 11.55, 9.55, 4.5 Hz); 7.18-7.49 (m, 10H, ArH). δC
(CDCl3, 125 MHz): 25.41, 36.38, 52.23, 59.50, 63.66, 75.64, 126.85, 127.93, 128.19, 128.45, 128.58,
139.38, 141.44. HR-ESI-TOF [M+H]+ calculated for C18H21ClN: 286.1357; found: 286.1358 (error =
0.3559). Chemical shifts are in agreement with those reported in the literature.9b
General procedure for the nucleophilic substitution reaction employing NaN3. A determined amount
of the required piperidine 8 were dissolved in 10-20 mL of DMF, and added to a 100-mL long-necked
flask (special for MW equipment use) containing 1.1 equiv of NaN3 previously homogenized in 30-40
mL of DMF:DMSO (9:1). This mixture was stirred and later, the flask was placed inside the microwave
equipment to irradiate the reaction with 40 Watts of power in order to heat at 55 °C. The reaction was
irradiated during 2 h under controlled temperature by using simultaneous external cooling with
compressed air. At the end of this period, the reaction was cooled to room temperature and subsequently
added to a flask with 100 mL of brine at 0 °C to facilitate the extraction with petroleum ether (3 x 50 mL).
The combined organic layers were washed with 30 mL of water to remove residual polar solvents, dried
with Na2SO4 and concentrated in the rotary evaporator. The crude was dried under reduced pressure and
purified by flash chromatography (2% AcOEt in hexane) to give the corresponding azides.
(S)-2-[(R)-Azido(phenyl)methyl]-1-benzylpyrrolidine, (S,R)-9. The general procedure described above
was followed with 2.54 g (9 mmol) of chloropiperidine (S,R)-8, 0.64 g (10 mmol) of NaN3 and 50 mL of
DMF:DMSO (4:1) to afford 2.3 g (8 mmol) of the desired azide (S,R)-9 as a clear oil in 89 % yield, Rf
25
0.59 (hexane:AcOEt, 9:1),

D –97 (c 1.0, CHCl3), δH (CDCl3, 500 MHz): 1.55-1.69 (m, 2H,
CH2CH2CH), 1.71-1.84 (m, 1H, CH2CH2CH), 1.87-1.96 (m, 1H, CH2CH2CH), 2.25 (ddd, 1H, J = 9.9,
9.35, 6.3 Hz, CH2CH2N), 2.92 (ddd, 1H, J = 8.8, 4.65, 4.1 Hz, NCHCH2), 3.03 (ddd, 1H, J = 9.2, 7.1, 2.1
Hz, CH2CH2N), 3.48, 3.93 (d, 1H each, J = 12.89 Hz, NCH2Ph), 4.57 (d, 1H, J = 4.1 Hz, CHCHN3),
7.21-7.35 (m, 10H, ArH); δC (CDCl3, 125 MHz): 23.59 (CH2-CH2-CH2-), 26.00 (CH2CH2CH), 54.86
(CH2CH2N), 59.71 (NCH2Ph), 67.2 [CH(Ph)N3], 69.65 (NCHCH2), ArC: 126.87, 126.98, 127.56, 128.26,
128.36, 128.81, 138.46 (NCH2Ph, Cipso), 139.40 [CH(Ph)N3, Cipso]. IR (ATR, cm-1): νmax 2967, 2796,
2097 (N3), 1495, 1452, 1351, 1288, 1269, 1122, 1074, 1029, 846, 740, 697. MS (IE) m/z (%): 65.1
(22.96), 77.1 (8.88), 89.1 (8.2), 90.1 (8.88), 91.1 (100), 92.1 (9.62), 104.1 (13.7), 118.1 (25.06), 146

(11.38), 160.2 (29.52), 194.2 (10.52), 236.3 (10.6). HR-ESI-TOF [M+H]+ (m/z) calculated for C18H21N4:
293.1760; found: 293.1764, (error = 1.1143).
(S)-2-[(S)-Azido(phenyl)methyl]-1-benzylpyrrolidine, (S,S)-9, and (2R,3R)-3-azido-1-benzyl-2-
phenyl piperidine, (R,R)-10. The general procedure described above was followed with 2.73 g (9.6
mmol) of chloropiperidine (R,R)-8, 0.64 g (10.5 mmol) of NaN3 and 50 mL of DMF:DMSO (4:1) to
obtain 0.86 g (3 mmol, 31% yield) of the desired azide (S,S)-9 and 1.5 g (5.3 mmol, 55% yield) of
azidopiperidine (R,R)-10 both as colourless oils.
25
(S)-2-[(S)-Azido(phenyl)methyl]-1-benzylpyrrolidine, (S,S)-9. Rf 0.41 (hexane:AcOEt, 9:1),

D
+84 (c 1.0, CHCl3). δH (CDCl3, 500 MHz): 1.39-1.52 (m, 2H, one for each CH2CH2CH), 1.53-1.61 (m,
1H, CH2CH2CH), 1.61-1.72 (m, 1H, CH2CH2CH), 2.30 (td, 1H, J = 9.42, 6.3 Hz, CH2CH2N), 2.91 (ddd,
1H, J = 10.0, 6.52, 2.97 Hz, CH2CH2N), 3.07 (ddd, 1H, J = 8.95, 7.45, 3.94 Hz, NCHCH2), 3.53, 4.31 (d,
1H each, J = 13.03 Hz, NCH2Ph), 4.39 (d, 1H, J = 7.45 Hz, CHCHN3), 7.22-7.43 (m, 10H, ArH); δC
(CDCl3, 125 MHz): 23.72 (CH2-CH2-CH2-), 28.51 (CH2CH2CH), 54.70 (CH2CH2N), 61.02 (NCH2Ph),
67.43 [CH(Ph)N3], 71.19 (NCHCH2), ArC: 126.81, 127.84, 128.02, 128.22, 128.39, 128.83, 138.16
(NCH2Ph, Cipso), 139.82 [CH(Ph)N3, Cipso]. IR (ATR, cm-1): νmax 3032, 2970, 2939, 2866, 2796, 2090
(N3), 1493, 1453, 1343, 1275, 1249, 1098, 1027, 917, 870, 818, 751, 699, 657, 606. MS (EI) m/z (%):
65.1 (13.66), 91.0 (100), 160.2 (70.71), 161.2 (9.31). HR-ESI-TOF [M+H]+ calculated for C18H21N4:
293.1760; found: 293.1767, (error = 2.1376).
25
(2R,3R)-3-Azido-1-benzyl-2-phenyl piperidine, (R,R)-10. Rf 0.54 (hexane:AcOEt, 9:1),


D -36.7
(c 1.09, CHCl3). δH (CDCl3, 500 MHz): 1.47-1.54 (m, 1H, CH2CH2CH2), 1.72 (tdd, 1H, J = 13.39, 4.01,
3.22 Hz, -CH2CH2CHN3), 1.91 (tt, 1H, CH2CH2CH, J = 12.82, 3.46 Hz), 1.99 (ddd, 1H, J = 12.17, 11.46,
2.46 Hz, CH2CH2N), 2.11 (dddd, 1H, J = 13.69, 6.17, 3.22, 1.63 Hz, CH2CH2N), 2.88 (d, 1H, J = 13.75
Hz, NCH2Ph), 3.03 (dtd, 1H, J = 11.01, 3.03, 1.43 Hz, CH2CH2N), 3.41 [d, 1H, J = 2.43,
NCH(Ph)CH(N3)], 3.62 [dd, 1H, J = 5.87, 3.01 Hz, CH(Ph)CH(N3)], 13.88 (d, 1H, J = 13.75 Hz,
NCH2Ph), ArH: 7.18-7.23 (m, 1H), 7.24-7.31 (m, 5H), 7.33-7.39 (m, 2H), 7.47-7.54 (2H); δC (CDCl3,
125 MHz): 20.48 (CH2-CH2-CH2-), 29.83 (CH2CH2CHN3), 52.95 (CH2CH2N), 59.48 (NCH2Ph), 63.40
[CH(Ph)CH(N3)], 70.75 [NCH(Ph)CH(N3)], ArC: 126.71, 127.58, 128.10, 128.37, 128.56, 128.59, 138.63
(NCH2Ph, Cipso), 140.43 [CH(Ph)CH(N3), Cipso]. IR (ATR, cm-1): νmax 3858.0, 3740, 3618, 3028, 2942,
2792, 2360, 2104 (N3), 1700, 1650, 1494, 1452, 1332, 1268, 1132, 1070, 1032, 962, 898, 744, 702.
MS (EI) m/z (%): 65.1 (24.31), 91.1 (100), 104.1 (13.76), 118.1 (25.34), 146.2 (10.39),160.2 (29.13),
194.2 (10.24), 236.3 (9.67). HR-ESI-TOF [M+H]+ calculated for C18H21N4: 293.1760; found: 293.1762,
(error = 0.4321).
General procedure for the catalytic hydrogenation of azido group. A determined amount of the

required azide 9 was dissolved in 50 mL of EtOH in a PYREX® heavy wall centrifuge bottle which was
conditioned with inert atmosphere. Subsequently, 10 % w/w of palladium on charcoal (1 %) was added to
the solution, the recipient was placed in the hydrogenator and then, the system was purged twice with
hydrogen pressure. Finally 60-70 psi were charged leaving the reaction mixture under mechanical stirring
during 2-5 h. The reaction was monitored by TLC and once the initial azide is depleted, the mixture is
poured onto a celite pad to remove the catalyst and the filtrate was concentrated under vacuum. The crude
was purified with column chromatography, using CH2Cl2:AcOEt (9:1) as eluent, obtaining the
corresponding diamine.
(R)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methanamine, (S,R)-1. The general procedure described
above was used with 2.48 g (9.31 mmol) of azide (S,R)-9 and 0.25 g of Pd/C (1% w/w) suspended in 50
mL of EtOH under 60 psi of H2 pressure during 3 h. The diamine (S,R)-1 was obtained after
chromatography with 90% yield as a yellow oil, improved purification could be achieved by Kugelrohr
25
distillation (150 °C, 0.5-1 mmHg). Rf 0.63 (CH2Cl2:AcOEt, 9:1),

D –44 (c 1.05, CHCl3), δH (CDCl3,
500 MHz): 1.36 (ddd, 1H, J = 17.54, 12.9, 8.73 Hz, CH2CH2CH), 1.54-1.7 (m, 2H, CH2CH2CH),
1.70-1.84 (b, 2H, NH2), 1.89 (dddd, 1H, J = 12.9, 9.1, 6.38, 4.1 Hz, one for CH2CH2CH), 2.20 (td, J =
9.52, 7.2 Hz, CH2CH2N), 2.77 (ddd, 1H, J = 9.24, 6.23, 3.44 Hz, NCHCH2), 3.00 (ddd, 1H, J = 8.99, 6.84,
2.29 Hz, CH2CH2N), 3.38, 4.10 (d, 2 X 1H, J = 13.1 Hz, NCH2Ph), 4.24 [d, 1H, J = 3.29 Hz,
CHCH(Ph)NH2], 7.19-7.27 (m, 2H, ArH), 7.29-7.37 (m, 6H, ArH), 7.38-7.42 (m, 2H, ArH). (CDCl3, 125
MHz): 23.46 (CH2-CH2-CH2-), 23.97 (CH2CH2CH), 54.77 [CHCH(Ph)NH2], 55.06 (CH2CH2N), 59.02
(NCH2Ph), 69.97 (NCHCH2), ArC: 126.75, 126.81, 126.99, 128.27, 128.39, 128.75, 140.00 (NCH2Ph,
Cipso), 143.69 [CH(Ph)NH2, Cipso]. IR (ATR, cm-1): νmax 3025, 2961, 2871, 2787, 1681, 1602, 1494,
1451, 1373, 1290, 1207, 1118, 1071, 1028, 912, 873, 736, 697, 648. HR-ESI-TOF [M+H]+ calculated
for C18H23N2: 267.3881; found: 267.1855, (error = 0.8407).
(S)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methanamine, (S,S)-1. The general procedure described
above was used with 3.66 g (13.41 mmol) of azide (S,S)-9 and 0.37 g of Pd/C (1% w/w) suspended in 100
mL of EtOH under 60 psi of H2 pressure during 2 h. The diamine (S,S)-1 was obtained after
25
chromatography with 97% yield as a yellow oil. Rf 0.68 (CH2Cl2:AcOEt, 9:1),

D +41 (c 1.0, CHCl3),
δH (CDCl3, 500 MHz): 1.54-1.7 (m, 3H, CH2CH2CH), 1.73-1.81 (m, 1H one for CH2CH2CH), 1.82-1.92
(b, 2H, NH2), 2.31 (td, J = 9.16, 6.35 Hz, CH2CH2N), 2.92 (ddd, 1H, J = 9.99, 6.34, 3.62 Hz, NCHCH2),
3.01 (ddd, 1H, J = 9.02, 6.45, 2.86 Hz, CH2CH2N), 3.44 (d, 1H, J = 13.32 Hz, NCH2Ph), 3.84 [d, 1H, J =
6.59 Hz, CHCH(Ph)NH2], 3.97 (d, 1H, J = 13.32 Hz, NCH2Ph), 7.2-7.27 (m, 2H, ArH), 7.28-7.37 (m, 6H,
ArH), 7.37-7.42 (m, 2H, ArH). (CDCl3, 125 MHz): 24.33 (CH2-CH2-CH2-), 28.62 (CH2CH2CH), 54.74
[CHCH(Ph)NH2], 60.54 (CH2CH2N), 61.83 (NCH2Ph), 70.35 (NCHCH2), ArC: 126.71 , 126.88, 127.42,

128.13, 128.19, 128.50, 140.37 (NCH2Ph, Cipso), 144.55 [CH(Ph)NH2, Cipso]. IR (ATR, cm-1): νmax IR
(cm-1): 3060, 3025, 2964, 2870, 2787, 1663, 1601, 1493, 1451, 1352, 1122, 1069, 1028, 910, 870, 737,
697, 673, 597, 568. HR-ESI-TOF [M+H]+ calculated for C18H23N2: 267.3881; found: 267.1857, (error =
0.4665).
(2R,3R)-1-Benzyl-2-phenylpiperidin-3-amine, (R,R)-12. The general procedure described above was
used with 4.67 g (15.8 mmol) of azide (R,R)-10 and 0.47 g of Pd/C (1% w/w) suspended in 100 mL of
EtOH under 60 psi of H2 pressure overnight. The diamine (R,R)-12 was obtained after chromatography
with 97% yield as a yellow oil (15.3 mmol, 4.08 g). δH (CDCl3, 500 MHz): 1.45-1.52 (m, 1H,
CH2CH2CH2CH), 1.58 (br, 2H, NH2), 1.69-1.87 (m, 2H, CH2CH2CH), 1,90-2.02 (m, 2H,
CH2CH2CH2CH), 2.83-2.88 (m, 1H, CH2CH2CH), 2.85 (d, 1H, J = 13.92 Hz, NCH2Ph), 3.00 (dt, 1H, J =
11.54, 4.00 Hz, CH2CH2CH2CH), 3.40 (d, 1H, J = 2.32 Hz, CHCHNBn), 3.93 (d, 1H, J = 13.92 Hz,
NCH2Ph), 7.18-7.45 (m, 10H, ArH); δC (CDCl3, 125 MHz): 19.95 (CH2CH2CH2CH), 32.24
(CH2CH2CH2CH), 51.98 (CH2CH2CHNH2), 53.67 (CH2CH2CH2CH), 59.68 (NCH2Ph), 72.62
(CHCHNBn) ArC: 126.61, 126.97, 128.10, 128.17, 128.32, 128.38, 139.45 (NCH2Ph, Cipso), 142.01
[CH(Ph)CH, Cipso]. HR-ESI-TOF [M+H]+ calculated for C18H23N2: 267.1855; found: 267.1856, (error
= 0.0922).
General procedure for the acetylation reaction. A determined amount of the required diamine was
dissolved with anhydrous THF in a round-bottomed flask equipped with magnetic stirring and
conditioned with nitrogen atmosphere. Subsequently, 1.3 equivalents of Et3N and 1.2 equivalents of
MeCOCl were simultaneously added at 0 °C. Then, the reaction mixture was left stirring during 48 h at
room temperature. After this time, the reaction was concentrated and the crude was extracted twice with
brine and AcOEt. Subsequently, the organic layer was dried with Na2SO4, the solvent was evaporated
under reduced pressure and the resultant concentrate is supported on silica and purified using
CH2Cl2:AcOEt (9:1) as eluent in flash chromatography, obtaining the corresponding acetamides.
N-{(R)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}acetamide, (S,R)-11. The general procedure
which was described above was followed using 2.13 g (8 mmol) of (S,R)-1, 1.5 mL (1.05 g, 10.4 mmol)
of Et3N and 0.7 mL (0.75 g, 9.6 mmol) of MeCOCl and 30 mL of THF to obtain the acetamide (S,R)-11
in 62 % of isolated yield after recrystallization, as a white solid, mp 180-181 °C (AcOEt/hexane); Rf 0.48
25
(CH2Cl2/MeOH, 9:1);

D –62 (c 1.0, CHCl3), δH (CDCl3, 500 MHz): 1.36-1.48 (m, 1H, CH2CH2CH),
1.48-1.62 (m, 3H, CH2CH2CH), 2.05 (s, 3H, CH3CO), 2.23 (td, 1H, J = 9.04, 8.45 Hz, CH2CH2N), 2.88
(td, 1H, J = 7.59, 4.96 Hz, CH2CHN), 2.94 (ddd, 1H, J = 9.54, 7.11, 2.63 Hz, CH2CH2N), 3.28 (d, 1H, J =
12.82 Hz, NCH2Ph), 4.04 (d, 1H, J = 12.89 Hz, NCH2Ph), 5.07 (t, 1H, J = 5.12 Hz, CHCHNHAc), 6.35
(d, 1H, J = 4.15 Hz, NH), 7.18-7.35 (m, 10H, ArH); δC (CDCl3, 125 MHz): 21.78 (COCH3), 23.41

(CH2-CH2-CH2-), 26.00 (CH2CH2CH), 53.54 (CH2CH2N), 54.18 [CH(Ph)NHAc], 58.25 (NCH2Ph), 67.26
(NCHCH2), ArC: 126.29, 126.84, 127.03, 128.22, 128.30, 128.73, 139.04 (NCH2Ph, Cipso), 140.24
[CH(Ph)NHAc, Cipso], 170.35 [NH(C=O)CH3]. IR (ATR, cm-1): νmax 3323, 2793, 1640, 1550, 1455,
1132, 1029, 978, 845, 739, 696, 644, 581. MS (IE) m/z (%): 91.1 (42), 160.05 (100), 161.05 (11).
HR-ESI-TOF [M+H]+ (m/z) calculated for C20H25N2O: 309.1961; found: 309.1968, (error = 2.1343).
N-{(S)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}acetamide, (S,S)-11. The general procedure which
was described above was followed using 1.15 g (4.3 mmol) of (S,R)-1, 0.8 mL (0.57 g, 5.6 mmol) of Et3N
and 0.37 mL (0.41 g, 5.2 mmol) of MeCOCl and 15 mL of THF to obtain the acetamide (S,R)-11 in 90%
25
of yield, as a white solid, mp 136 °C (AcOEt/hexane); Rf 0.53 (CH2Cl2/MeOH, 9:1);

D +76 (c 1.0,
CHCl3), δH (CDCl3, 500 MHz): 1.58-1.72 (m, 2H, CH2CH2CH), 1.72-1.78 (m, 1H, CH2CH2CH),
2.07-2.13 (m, 1H, CH2CH2CH), 2.13 (s, 3H, CH3CO), 2.24 (td, 1H, J = 9.85, 6.35 Hz, CH2CH2N), 2.90
(ddd, 1H, J = 9.20, 6.77, 2.36 Hz, CH2CH2N), 2.97 (d, 1H, J = 13.03 Hz, NCH2Ph), 3.19 (ddd, 1H, J =
9.49, 4.77, 2.11 Hz, NCHCH2), 3.26 (d, 1H, J = 12.89 Hz, NCH2Ph), 5.06 (dd, 1H, J = 8.31, 2.0 Hz,
CHCHNHCOCH3), 6.85 (d, 1H, J = 8.02 Hz, NH), 7.09-7.39 (m, 10H, ArH); δC (CDCl3, 125 MHz):
23.50 (COCH3), 24.17 (CH2-CH2-CH2-), 30.61 (CH2CH2CH), 55.25 (CH2CH2N), 55.74
[CH(Ph)NHCOCH3], 60.52 (NCH2Ph), 67.74 (NCHCH2), ArC: 125.94, 126.82, 126.85, 128.16, 128.39,
128.56, 139.53 (NCH2Ph, Cipso), 141.46 [CH(Ph)NHAc, Cipso], 169.84 [NH(C=O)CH3]. IR (ATR,
cm-1): 3337, 2970, 2801, 1646, 1534, 1373, 1295, 1140, 1111, 744, 700, 627. HR-ESI-TOF [M+H]+
(m/z) calculated for C20H25N2O: 309.1961; found: 309.1963, (error = 0.5172).
N-[(2R,3R)-1-Benzyl-2-phenylpiperidin-3-yl]acetamide, (R,R)-13. The general procedure which was
described above was followed using 4.1 g (15.3 mmol) of (R,R)-12, 2.8 mL (2.02 g, 20 mmol) of Et3N
and 1.3 mL (1.44 g, 18.4 mmol) of MeCOCl and 100 mL of THF to obtain the acetamide (S,R)-11 in 79%
of isolated yield after recrystallization, as a white solid, mp 160-161 °C (AcOEt/hexane); Rf 0.61
25
(CH2Cl2/MeOH, 9:1);


D +3.3 (c 1.0, CHCl3). δH (CDCl3, 500 MHz): 1.51-1.58 (m, 1H,
CH2CH2CH2CH), 1.59-1.80 (m, 2H, CH2CH2CH), 1.86 (s, 3H, CH3CO), 1.92-1.98 (m, 1H, CH2CH2CH),
2.02 (ddd, 1H, J = 11.89, 11.86, 2.94 Hz, CH2CH2CH2), 2.87 (d, 1H, J = 13.89 Hz, NCH2Ph), 3.02 (ddd,
1H, J = 11.81, 3.97, 3.94 Hz, CH2CH2CH2), 3.46 (d, 1H, J = 2.58 Hz, CHCHNBn), 3.95 (d, 1H, J = 13.89
Hz, NCH2Ph), 4.14 (dd, 1H, J = 8.88, 2.72 Hz, CH2CHNHAc), 6.30 (d, 1H, J = 8.73 Hz, NH), 7.19-7.40
(m, 10H, ArH); δC (CDCl3, 125 MHz): 20.60 (COCH3), 23.28 (CH2-CH2-CH2-), 29.77 (CH2CH2CH),
50.12 (CH2CH2N), 53.35 [CH(Ph)NHCOCH3], 59.36 (NCH2Ph), 70.45 (NCHCH2), ArC: 126.87, 127.33,
127.80, 128.16, 128.24, 128.57, 138.59 (NCH2Ph, Cipso), 140.34 [CH(Ph)NHAc, Cipso], 168.93
[NH(C=O)CH3]. IR (ATR, cm-1): 3244, 3060, 2944, 2793, 2359, 2162, 1978, 1651, 1625, 1538, 1495,
1449, 1370, 1288, 1225, 1203, 1134, 1105, 1030, 737, 701, 598. HR-ESI-TOF [M+H]+ (m/z) calculated

for C20H25N2O: 309.1961; found: 309.1965, (error = 1.1640).
(2R,3R)-2-Phenylpiperidin-3-amine, (R,R)-14. 0.54 g (1.8 mmol) of diamine (R,R)-12 was dissolved in
50 mL of EtOH acidified with 0.12 mL of AcOH (0.12 g, 2 mmol) under inert atmosphere in a quartz
glass for hydrogenation reactor. Subsequently, 15% w/w Pd(OH)2 (1%) was added to the solution and
then, the recipient was placed inside a reactor with mechanical stirring. Afterwards, the system was
purged twice with hydrogen pressure. Finally, the reactor was charged with 1000 psi of hydrogen pressure
and heated at 60 °C during 72 h. After this period, temperature was automatically set to room temperature
and the suspension is poured onto a celite pad to remove the catalyst and the filtrate was concentrated
under vacuum. The crude was purified with column chromatography, using CH2Cl2:MeOH:NH4OH(conc)
(90:9:1) as eluent, obtaining the corresponding diamine in 80% yield as a yellow oil. δH (CDCl3, 500
MHz): 1.32-1.45 (m, 1H, CH2CH2CHNH2), 1.63-1.79 (m, 2H, CH2CH2CHNH2), 1.81-1.92 (m, 1H,
CH2CH2CHNH2), 2.68 (td, 1H, J = 11.77, 2.65 Hz, CH2CH2NH), 2.90 (d, 1H, J = 1.83 Hz,
CH2CH2CHNH2), 3.11 (dd, 1H, J = 10.39, 3.06 Hz, CH2CH2NH), 3.74 (d, 1H, J = 1.22 Hz, CHCHNH),
7.07-7.32 (m, 5H, ArH); δC (CDCl3, 125 MHz): 19.48 (NHCH2-CH2-CH2-), 31.94 (NHCH2-CH2-CH2-),
47.28 (NHCH2CH2CH2), 50.48 (CH2CHNH2), 64.60 [CH(Ph)NH], ArC: 126.30, 126.71, 128.07, 142.45
[CH(Ph), Cipso]. Chemical shifts and other spectroscopic data are in agreement with those reported in the
literature.13a
General procedure for the conversion of amino group into a thiourea functionality. A determined
amount of the required diamine was dissolved with anhydrous THF in a round-bottomed flask equipped
with magnetic stirring and conditioned with nitrogen atmosphere. Subsequently, 1.6 equivalents of
Edman reagent were added at 0 °C. Then, the reaction mixture was left stirring during 48 h at room
temperature. After this time, the reaction was concentrated and the crude was extracted twice with brine
and AcOEt. Subsequently, the organic layer was dried with Na2SO4, the solvent was evaporated under
reduced pressure and the resultant concentrate is supported on silica and purified by flash
chromatography using hexane:AcOEt (8:2) as eluent, giving rise to a pure thiourea.
1-{(R)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-3-phenylthiourea, (S,R)-15. The general
procedure described above was followed with 1.4 g (5.3 mmol) of (S,R)-1, 1.6 mL (1.14 g, 8.4 mmol) of
PhN=C=S and 50 mL of THF to afford 1.49 g of the desired thiourea (S,R)-15 (3.7 mmol, 71% yield), as
25
a pale yellow foam, Rf 0.34 (hexane/AcOEt, 7:3);

D -45 (c 1.0, CHCl3), δH (DMSO-d6, 120 °C, 500
MHz): 1.48-1.68 (m, 5H), 2.21-2.28 (m, 1H), 2.76-2.88 (m, 2H), 3.31 (d, 1H, J = 12.8 Hz), 3.99 (d, 1H, J
=12.6 Hz), 5.69 (s, 1H), 7.05-7.40 (m, 15H). δC (DMSO-d6, 120 °C, 125 MHz): 22.71, 26.88, 53.85,
58.48, 58.98, 68.06, 114.86, 123.88, 124.78, 124.85, 126.98, 127.21, 127.49, 128.53, 128.96, 129.16,
129.25, 140.19, 182.22. IR (ATR, cm-1): νmax 2966, 2798, 1597, 1521, 1494, 1451, 732, 695.

HR-ESI-TOF [M+H]+ calculated for C25H28N3S: 402.1998; found: 402.2002 (error = 0.8792).
1-{(S)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-3-phenylthiourea, (S,S)-15. The
general
procedure described above was followed with 1.25 g (4.7 mmol) of (S,S)-1, 1.43 mL (1.02 g, 7.5 mmol)
of PhN=C=S and 40 mL of THF to afford 1.31 g of the desired thiourea (S,S)-15 (3.3 mmol, 69% isolated
25
yield), as a white solid, mp 155-156 °C; Rf 0.38 (hexane/AcOEt, 7:3);

D –212 (c 1.02, CHCl3), δH
(DMSO-d6, 120 °C, 500 MHz): 1.61 (s, 2H), 1.85 (br, 1H), 2.04 (br, 1H), 2,17 (br, 1H), 2.55 (br, 1H),
2.83 (br, 1H), 3.12 (br, 1H), 3.21 (br, 1H), 5.53 (br, 1H), 6.71 (br, 1H), 7.14-7.46 (m, 15H). δC
(DMSO-d6, 120 °C, 125 MHz): 24.14, 31.22, 55.11, 60.36, 61.77, 68.49, 125.68, 126.32, 126.69, 127.01,
127.93, 128.16, 128.73, 130.32, 136.29, 139.50, 141.34, 150.00, 181.08. IR (ATR, cm-1): νmax 3140,
2956, 1595, 1491, 1449, 1243, 1067, 794, 750, 668, 696. HR-ESI-TOF [M+H]+ calculated for
C25H28N3S: 402.1998; found: 402.1997 (error = -0.3639). Anal. Calcd for C25H27N3S: C, 74.77; H, 6.78;
N, 10.46. Found: C, 74.98; H, 7.02; N, 10.66.
General procedure for the conversion of amino group into a sulfonamide functionality. A
determined amount of the required diamine was dissolved with anhydrous THF in a round-bottomed flask
equipped with magnetic stirring and conditioned with nitrogen atmosphere. Subsequently, 1.1 equiv of
Et3N were added at room temperature. Afterwards, 1.05 equiv. of the required 4-substituted
benzenesulfonyl chloride, dissolved in dry THF, was slowly added to the mixture at 0 °C and stirred
during 1-2 h at this temperature. Then, the reaction was left stirring overnight at room temperature and
later, the solution was concentrated and the crude was extracted twice with brine and CH2Cl2. The
combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resultant
concentrate is supported on silica and purified by flash chromatography using Hexane:AcOEt (8:2) as
eluent, giving rise to the corresponding sulfonamide.
N-{(R)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-4-nitrobenzenesulfonamide, (S,R)-16. The
general procedure described above was followed with 1.4 g (5.3 mmol) of (S,R)-1, 0.81 mL (0.59 g, 5.8
mmol) of Et3N, 1.22 g (5.5 mmol) of 4-nitrobenzenesulfonyl chloride and 50 mL of THF; obtaining after
recrystallization, 1.6 g of sulfonamide (S,R)-16 (3.54 mmol, 67% isolated yield) as pale yellow crystals,
25
mp 162-163 °C (AcOEt/hexane); Rf 0.26 (hexane/AcOEt, 7:3);

D -92 (c 1.0, CHCl3), δH (CDCl3,
500 MHz): 1.32-1.35 (m, 1H), 1.56-1.60 (m, 2H), 1.75-1.77 (m, 1H), 2.22 (dd, 1H, J = 8.6, 17.95 Hz),
2.75 (ddd, 1H, J = 7.95, 4.5, 8.0 Hz), 3.03-3.04 (m, 1H), 3.18 (d, 1H, J = 13.4 Hz), 3.76 (d, 1H, J = 13.35
Hz), 4.53 (d, 1H, J = 4.5 Hz), 7.25 (m, 10H); 7.74 (d, 2H, J = 8.95Hz), 7.99 (d, 2H, J = 8.95Hz). δC
(CDCl3, 125 MHz): 21.72, 25.31, 53.97, 57.15, 57.21, 67.68, 123.80, 127.37, 127.40, 127.81, 128.26,
128.30, 128.62, 128.71, 137.71, 138.15, 145.37, 149.78. IR (ATR, cm-1): νmax 3172, 2880, 1527, 1338,
1309, 1172, 1127, 1090, 858, 735, 687. HR-ESI-TOF [M+H]+ calculated for C24H26N3O4S: 452.1638;

found: 452.1638 (error = -0.1212). Anal. Calcd for C24H25N3O4S: C, 63.84; H, 5.58; N, 9.31; S, 7.10.
Found: C, 63.98; H, 5.63; N, 9.13; S, 6.86.
N-{(S)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-4-nitrobenzenesulfonamide,
(S,S)-16.
The
general procedure described above was followed with 1.48 g (5.6 mmol) of (S,S)-1, 0.85 mL (0.62 g, 6.1
mmol) of Et3N, 1.34 g (6 mmol) of 4-nitrobenzenesulfonyl chloride and 50 mL of THF to obtain 1.71 g of
25
sulfonamide (S,S)-16 (3.79 mmol, 68%) as a yellow resin-like oil; Rf 0.54 (hexane/AcOEt, 7:3);

D
+94 (c 1.05, CHCl3), δH (CDCl3, 500 MHz): 1.22-1.28 (m, 1H), 1.60-1.66 (m, 1H), 1.70-1.80 (m, 2H),
1.89-1.98 (m, 1H), 2.39-2.46 (m, 1H), 2.93-2.99 (m, 1H), 3.04-3.10 (m, 1H), 3.30 (d, 1H, J = 12.95 Hz),
3.41 (d, 1H, J = 12.95 Hz), 4.26 (d, 1H, J = 5.1 Hz), 6.99 (m, 2H), 7.08 (m, 3H), 7.20 (m, 2H), 7.29 (m,
3H), 7.67 (d, 2H, J = 9.1Hz), 8.07 (d, 2H, J = 9.05 Hz). δC (CDCl3, 125 MHz): 24.20, 29.26, 54.66,
61.07, 61.20, 68.67, 123.69, 127.25, 127.39, 127.65, 128.25, 128.37, 128.62, 128.87, 139.05, 139.14,
146.88, 149.52. IR (ATR, cm-1): νmax 3292, 2962, 2800, 1606, 1527, 1494, 1347, 1309, 1106, 1091, 853,
926, 735, 699, 605. HR-ESI-TOF [M+H]+ calculated for C24H26N3O4S: 452.1638; found: 452.1647
(error = 1.8691).
N-{(R)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-4-methylbenzenesulfonamide, (S,R)-17. The
general procedure for sulfonamide synthesis was followed with 1.4 g (5.3 mmol) of (S,R)-1, 0.81 mL
(0.59 g, 5.8 mmol) of Et3N, 1.06 g (5.6 mmol) of 4-methylbenzene-1-sulfonyl chloride and 50 mL of
THF; obtaining after recrystallization, 1.5 g of sulfonamide (S,R)-17 (3.57 mmol, 67% isolated yield) as
25
white crystals, mp 140 °C; Rf 0.49 (hexane/AcOEt, 7:3);


D -104 (c 1.0, CHCl3), δH (CDCl3, 500
MHz): 1.21-1.31 (m, 1H, CH2CH2CH-), 1.45-1.68 (m, 2H, CH2CH2CH-), 1.81 (dddd, 1H, J = 13.35,
10.27, 8.16, 5.51 Hz, CH2CH2CH-), 2.13 (td, 1H, J = 9.16, 8.45 Hz, CHNCH2CH2), 2.27 (s, 3H,
C6H5CH3), 2.64 (td, 1H, J = 8.16, 4.41 Hz, NCHCHPh), 2.97 (ddd, 1H, J = 9.45, 7.59, 2.58 Hz,
CHNCH2CH2), 3.00, 3.57 (d, 2 x 1H, J = 13.25 Hz, NCH2Ph), 4.37 (d, 1H, J = 4.41 Hz, NCHCHPh),
5.5-6.0 (br, 1H, NH), 6.98-7.02 (m, 2H, ArH), 7.14-7.18 (m, 2H, ArH), 7.19-7.3 (m, 6H, ArH), 7.3-7.35
(m, 2H, ArH), 7.53-7.57 (m, 2H, ArH). δC (CDCl3, 125 MHz): 21.41 (-C6H4CH3), 21.48 (-CH2CH2CH-),
24.89 (CH2CH2CH-), 53.72 (CHNCH2CH2), 56.58 (NCHCHPh), 56.77 (NCH2Ph), 67.92 (NCHCHPh),
ArC: 126.99, 127.16, 127.26, 127.44, 127.98, 128.25, 128.31, 129.26, 135.92 (NCH2Ph, Cipso), 138.22
(SO2C6H4, Cipso), 138.63 (NCHCHPh, Cipso), 143.25 (C6H4-CH3, Cipso). IR (ATR, cm-1): νmax 3303,
2926, 2801, 1599, 1423, 1321, 1152, 1054, 839, 807, 755, 697, 670, 590. MS (IE) m/z (%): 160.1 (100),
161.1 (12.96). HR-ESI-TOF [M+H]+ calculated for C25H29N2O2S: 421.1944; found: 421.1943 (error =
-0.3007).
N-{(S)-[(S)-1-Benzylpyrrolidin-2-yl](phenyl)methyl}-4-methylbenzenesulfonamide, (S,S)-17. The
general procedure for sulfonamide synthesis was followed with 1.4 g (4.24 mmol) of (S,S)-1, 0.65 mL

(0.47 g, 4.7 mmol) of Et3N, 0.88 g (4.6 mmol) of 4-methylbenzenesulfonyl chloride and 40 mL of THF;
obtaining after recrystallization, 1.38 g of sulfonamide (S,S)-17 (3.28 mmol, 77% isolated yield) as white
25
crystals, mp 137-138 °C (AcOEt/hexane); Rf 0.54 (hexane/AcOEt, 7:3);

D +127 (c 0.98, CHCl3), δH
(CDCl3, 500 MHz): δH (CDCl3, 500 MHz): 1.49-1.71 (m, 3H, -CH2CH2CH-), 1.89 (ddd, 1H, J = 17.61,
12.39, 8.95 Hz, -CH2CH2CH-), 2.28 (ddd, 1H, J = 9.74, 9.09, 6.8 Hz, CHNCH2CH2), 2.35 (s, 3H,
C6H5CH3), 2.82 (ddd, 1H, J = 9.88, 6.52, 3.44 Hz, CHNCH2CH2), 3.04 (dt, 1H, J = 9.16, 4.03 Hz,
NCHCHPh), 3.13, 3.38 (d, 2 x 1H, J = 12.96 Hz, NCH2Ph), 4.28 (d, 1H, J = 4.03, NCHCHPh), 7.08-7.19
(m, 9H, ArH), 7.21-7.33 (m, 3H, ArH), 7.54-7.58 (m, 2H, ArH). δC (CDCl3, 125 MHz): 21.41
(-C6H4CH3), 23.91 (-CH2CH2CH-), 29.34 (-CH2CH2CH-), 54.32 (CHNCH2CH2), 60.33 (NCHCHPh),
60.68 (NCH2Ph), 68.80 (NCHCHPh), ArC: 126.82, 126.96, 127.03, 128.09, 128.30, 128.62, 129.14,
137.75 (NCH2Ph, Cipso), 139.06 (SO2C6H4-, Cipso), 140.31 (NCHCHPh, Cipso), 142.75 (C6H4-CH3,
Cipso). IR (ATR, cm-1): νmax 3303, 2926, 2801, 1599, 1423, 1321, 1152, 1054, 839, 807, 755, 697, 670,
590. HR-ESI-TOF [M+H]+ calculated for C25H29N2O2S: 421.1944; found: 421.1949 (error = 1.1237).
Anal. Calcd for C25H28N2O2S C, 71.40; H, 6.71; N, 6.66. Found: C, 71.04; H, 6.89; N, 6.98.
ACKNOWLEDGMENT
We are indebted to CONACyT for financial support via (project No. 130826). Jorge Vargas-Caporali and
Carlos Cruz-Hernández are grateful to CONACyT for their doctoral fellowships.
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Jaworska, M. Wełniak, J. Zięciak, A. Kozakiewicz, and A. Wojtczak, ARKIVOC, 2011, ix, 189.
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Å, c = 7.7750(0) Å, α = 90 °, β = 99.759(0) °, γ = 90 °, V = 784.82 Å3, crystal size: 0.625 x 0.55 x
0.5 mm3, R1 = 0.0393, (wR2 = 0.0994). CCDC 898455 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
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Å, c = 16.3680(0) Å, α = 90 °, β = 97.510(0) °, γ = 90 °, V = 1743.02 Å3, crystal size: 0.8 x 0.1 x
0.08 mm3, R1 = 0.0568, (wR2 = 0.1362). CCDC 898459 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
23. Crystal data for (S,R)-11: C20H24N2O, orthorhombic, space group P212121, a = 8.4980(0) Å, b =
9.8990(0) Å, c = 21.46999(0) Å, α = 90 °, β = 90 °, γ = 90 °, V = 1806.09 Å3, crystal size: 0.425 x
0.375 x 0.125 mm3, R1 = 0.0730, (wR2 = 0.2048). CCDC 898457 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
24. Crystal data for (R,R)-13: C20H24N2O, orthorhombic, space group P31, a = 20.573(0) Å, b =
20.573(0) Å, c = 11.2766(0) Å, α = 90 °, β = 90 °, γ = 120 °, V = 4129.48 Å3, crystal size: 0.25 x
0.25 x 0.15 mm3, R1 = 0.0774, (wR2 = 0.1998). CCDC 898456 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
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29. Crystal data for (S,R)-17: C25H28N2O2S, monoclinic, space group P2, a = 10.2330(0) Å, b =

9.7000(0) Å, c = 11.6750(0) Å, α = 90 °, β = 101.2099 °, γ = 90 °, V = 1136.75 Å3, crystal size: 0.45
x 0.3 x 0.125 mm3, R1 = 0.0432, (wR2 = 0.1117). CCDC 898458 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
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