An efficient synthesis of (R)- and (S)-2-(aminomethyl)piperidine dihydrochloride

Article abstract of DOI:10.1016/j.tetasy.2008.09.015

The synthesis of the dihydrochloride salts of (R)-1 and (S)-1 2-(aminomethyl)piperidine is reported starting from either (S) or (R) lysine, respectively. A key step in the synthetic protocol involves the in situ formation of aziridinium 8, which then undergoes an intramolecular ring opening with concomitant piperidinium ring formation, in a stereoselective manner. The route offers a practical synthesis of (R)-1 and (S)-1, and it should make them more accessible for exploration in asymmetric catalysis or as building blocks in pharmaceutical research.

Full text of DOI:10.1016/j.tetasy.2008.09.015

Tetrahedron: Asymmetry 19 (2008) 2330–2333
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient synthesis of (R)- and (S)-2-(aminomethyl)piperidine
dihydrochloride
*
Gildas Deniau, Thomas Moraux, David O’Hagan , Alexandra M. Z. Slawin
School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the dihydrochloride salts of (R)-1 and (S)-1 2-(aminomethyl)piperidine is reported start-
ing from either (S) or (R) lysine, respectively. A key step in the synthetic protocol involves the in situ for-
mation of aziridinium 8, which then undergoes an intramolecular ring opening with concomitant
piperidinium ring formation, in a stereoselective manner. The route offers a practical synthesis of (R)-1
and (S)-1, and it should make them more accessible for exploration in asymmetric catalysis or as building
blocks in pharmaceutical research.
Received 10 September 2008
Accepted 17 September 2008
Available online 22 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral diamines form an important class of compounds that
have found a wide range of applications in chemistry, particularly
as bidentate ligands for the design of asymmetric catalysts.1,2 The
enantiomers of 2-(aminomethyl)piperidine (R)-1 and (S)-1 are
attractive structural motifs; however, they have not been widely
used in the design of chiral ligands, most probably, due to their
limited availability.3,4 Indeed, (R)-1 and (S)-1 are not commercially
available, although these enantiomers have been prepared by the
resolution of the racemate,4 or from the enantiomers of pipecolic
acid by a sequential amidation and reduction protocol.5,6 These
methods do not constitute a practical route to (R)-1 and (S)-1 in
reasonable quantities, and consequently the exploration of these
stereoisomers in bidentate ligand design has been limited. Beyond
asymmetric catalysis, enantiopure amines continue to find an
important role as building blocks in pharmaceutical development,
and a ready source of (R)-1 and (S)-1 would also contribute to that
activity (see Fig. 1).7,8
Herein, we report an efficient synthesis of the enantiomers of 2-
(aminomethyl)piperidine dihydrochloride (R)-1 and (S)-1 from the
amino acids (S)-L- and (R)-D-lysine (see Scheme 1).
(S)- -Lysine monohydrochloride (S)-2 was perbenzylated by
L
treatment with benzyl bromide in ethanol using K2CO3 as a base,
following the protocol of Beaulieu and Wernic.9 This resulted in
an efficient conversion to the pentabenzyl amino acid derivative
(S)-3 in almost quantitative yield. Reduction of (S)-3 with LiAlH4
gave the corresponding alcohol (S)-4 in 89% yield. With (S)-4 in
hand, two routes to the 1,1-dibenzyl-2-((dibenzylamino)methyl)-
piperidinium chloride 5 were explored. The first attempt involved
the use of fluorinating reagent Et2NSF3 (DAST). It is known that the
treatment of N,N-dibenzyl-a-aminoalcohols with DAST produces
an aziridinium intermediate in situ, which then undergoes ring
opening by fluoride ion attack (paths b and c) to predominantly
form the most substituted alkyl fluorine (path b).10 In our case,
(Scheme 2), it was anticipated that the peripheral dibenzylamine
moiety of (S)-4 would compete with the fluoride ions to open the
aziridinium intermediate (S)-8 by a 6-exo-tet ring closure process
(path a) to produce piperidinium (R)-5. It was also expected that
the stereochemical course of aziridinium ring opening (paths a
and b) would occur with an inversion of configuration as illus-
trated in Scheme 2.
The DAST reaction at room temperature gave a mixture of com-
pounds 5, 6 and 7 in a ratio of 83:15:2, but with a moderate overall
conversion. When silica gel (SiO2) was added as a suspension in
DCM to the reaction mixture (SiO2–DAST, 6.0:1.5 equiv), the con-
version to piperidinium 5 increased to 80% with only very minor
traces of the fluorinated products 6 and 7. The silica is clearly
sequestering fluoride ions from solution, and is rendering the reac-
tion cleaner and more efficient overall. Other reagents were then
NH2+, Cl-
NH3+, Cl-
NH2+, Cl-
NH3+, Cl-
(R)-1
(S)-1
Figure 1. (R)- and (S)-2-(aminomethyl)piperidine dihydrochloride.
* Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail address: do1@st-and.ac.uk (D. O’Hagan).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.015

G. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2330–2333
2331
O
O
BnBr 7eq, K2CO3
H2N
Bn2N
OH
OBn
NH3+, Cl-
EtOH 60°C, 4d
NBn2
96%
(S)-2
(S)-3
L- Lysine.HCl
LiAlH4, THF
-10°C,1h
89%
20% Pd(OH)2
HCO2NH4
(TfO)2O or DAST
Bn2N
NH2+, Cl-
NH3+, Cl-
N+Bn2, Cl-
NBn2
OH
MeOH, rt, 24h
DCM, rt, 14-36h
NBn2
77%
80%
(S)-4
(R)-1
(R)-5
Scheme 1. The synthetic route from (S)-L-lysine (S)-2 to (R)-1.
a
c
Bn2N
Bn2N
OH
N+
F-
Bn
NBn2
Bn
b
(S)-4
(S)-8
path a
path b
path c
Bn
Bn
Bn2N
Bn2N
N+
F
NBn2
+
+
NBn2
F
NBn2
(R)-5
(R)-6
(S)-7
Scheme 2. Reaction pathways on treatment of (S)-4 with DAST.
investigated to promote the activation of the primary alcohol 4,
and Ms2O, MsCl and Tf2O were all explored. Such reagents had pre-
viously been used to generate aziridinium rings from N,N-diben-
zyl-a
-aminoalcohols.11 Reactions involving Ms2O/Et3N (1.5 equiv)
and MsCl failed; however treatment with triflic anhydride (Tf2O)
promoted an efficient cyclisation and generated piperidine (R)-5
in a good 88% yield. It appears from our experiments that DAST
and particularly Tf2O are suitable reagents to promote the conver-
sion of (S)-4 to (R)-5. Several attempts at debenzylation with
hydrogen using 10% Pd/C at high pressure (30 bar/2 d) gave only
poor results, however, a transfer hydrogenation using ammonium
formate (5 equiv) with 20% Pd(OH)2 as the catalyst gave piperidine
(R)-1 in good yield. The stereochemistry of this process was unam-
biguously established by X-ray structure analysis of the debenzy-
lated product (R)-1 after hydrogenation (Fig. 2). Samples of each
enantiomer of 1 were prepared starting with the appropriate enan-
tiomer of the amino acid lysine. Enantiopurity was established by
titration of racemic and enantiopure samples of 1 with (S)-O-meth-
ylmandelic acid. In the case of racemic 1, the 1:1 ratio of the diaste-
reoisomeric salts was easily resolvable and observed in solution by
1H NMR (400 MHz, [2H4]-MeOD), whereas no such signal resolu-
Figure 2. X-ray structure determination of (R)-1 was used to assign absolute
configuration.
tion was observed in the case of the enantiopure material. This
method allowed us to be confident of an enantiopurity of >95% ee.
Crystal data for (R)-1 C6H16Cl2N2, M = 187.11, Monoclinic,
space group P2(1), a = 7.036(2), b = 9.112(2), c = 7.702(2) Å,

2332
G. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2330–2333
b = 106.010(7)°, V = 474.6(2) Å3, F(000) = 200, Z = 2, Dc =
1.309 Mg mꢀ3 = 0.621 mmꢀ1 (Mo K
, k = 0.71073 Å). The data
were collected at T = 93(2) K, 3060 reflections (2.75 < h < 25.35°)
were measured on a Rigaku Saturn 92 detector with 007 generator
yielding 1638 unique data (Rmerg = 0.0170). Conventional R =
1138, 1028, 969, 745, 698; 1H NMR (300 MHz, CDCl3): d 7.17–7.40
(25H, m, Ar–H), 5.23 (1H, d, J = 12.3 Hz, PhCHAHBO), 5.11 (1H, d,
J = 12.3 Hz, PhCHAHBO), 3.89 (2H, d, J = 13.9 Hz, 2 ꢃ PhCHAHBN),
3.49 (2H, d, J = 13.9 Hz, 2 ꢃ PhCHAHBN), 3.42–3.52 (4H, dd,
PhCH2N0), 3.32 (1H, dd, J = 6.2 Hz, J = 8.7 Hz, CHN), 2.33 (2H, t,
J = 6.8 Hz, CH2N0), 1.14–1.76 (6H, m, CH2); 13C (75 MHz, CDCl3):
172.9 (CO2), 140.0 (2 ꢃ C, Ar), 139.6 (2 ꢃ C, Ar), 136.1 (Ar), 128.8
(4 ꢃ C, Ar), 128.7 (4 ꢃ C, Ar), 128.5 (2 ꢃ C, Ar), 128.4 (2 ꢃ C, Ar),
128.3 (Ar), 128.2 (4 ꢃ C, Ar), 128.1 (4 ꢃ C, Ar), 126.9 (2 ꢃ C, Ar),
126.7 (2 ꢃ C, Ar), 65.8 (PhCH2O), 60.6 (CHN), 58.2 (2 ꢃ PhCH2N0),
54.4 (2 ꢃ PhCH2 N), 53.0 (CH2N0), 29.3 (CH2), 26.6 (CH2), 23.7
(CH2); HRMS (+EI) calcd for C41H45N2O2 ([MH]+): 597.3481. Found:
597.3477 (ꢀ0.6 ppm).
,
l
a
0.0194 for 1638 reflections with I > 2r, GOF = 1.053; 112 refined
parameters, Flack parameter = 0.00(5). The largest peak in the
residual map is 0.156 e Åꢀ3. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication CCDC 701754.
3. Conclusion
In conclusion, we have described a straightforward four step
4.3. (S)-2,6-Bis(dibenzylamino)hexan-1-ol (S)-4
synthesis of (R)-1 and (S)-1 2-(aminomethyl)piperidineꢁHCl from
either D- or L-lysine. The key step involves the cyclisation of 4 via
A solution of the benzyl ester 3 (125.5 g, 210 mmol) in THF
(600 mL) was added dropwise over 45 min at ꢀ10 °C to a suspen-
sion of LiAlH4 (11.97 g, 0.315 mmol, 1.5 equiv) in dry THF
(300 mL). The mixture was stirred for 3 h at this temperature,
and the excess of hydride was quenched by successive addition
of EtOAc and 1 M aq NaOH. The mixture was extracted into EtOAc,
the organic extracts were combined and the solvent was removed
under reduced pressure. The product was distilled (120 °C,
0.01 mbar) to give the aminoalcohol (S)-4 as a viscous clear oil
the aziridinium intermediate 8. The overall yield of 1 from lysine
is 53%, and this should allow (R)-1 and (S)-1 to be prepared on a
sufficient scale for consideration as building blocks for the devel-
opment of ligands for catalysis or for their inclusion in novel bioac-
tive discovery in pharmaceuticals research.
4. Experimental
4.1. General
(92.1 g, 89%). ½a D20
ꢂ
¼ þ49:5 (c 0.8, CHCl3); IR (film, cmꢀ1) 3443,
3027, 2935, 2799, 2360, 1602, 1494, 1453, 1365, 1129, 1028,
747, 698; 1H NMR (300 MHz, CDCl3): 7.19–7.38 (20H, m, Ar–H),
3.75 (2H, d, J = 13.3 Hz, PhCHAHBN), 3.57 (2H, d, J = 13.6 Hz,
PhCHAHBN0), 3.48 (2H, d, J = 13.6 Hz, PhCHAHBN0), 3.31–3.45 (2H,
m, CH2OH), 3.32 (2H, d, J = 13.3 Hz, PhCHAHBN), 3.14 (1H, br s,
OH), 2.67–2.77 (1H, m, CHN), 2.34–2.47 (2H, m, CH2N0), 1.40–
1.63 (3H, m), 1.00–1.37 (3H, m); 13C NMR (75 MHz, CDCl3): 139.9
(2 ꢃ C, Ar), 139.3 (2 ꢃ C, Ar), 129.0 (4 ꢃ C, Ar), 128.7 (4 ꢃ C, Ar),
128.4 (4 ꢃ C, Ar), 128.1 (4 ꢃ C, Ar), 127.1 (2 ꢃ C, Ar), 126.7 (2 ꢃ C,
Ar), 60.8 (CH2OH), 58.9 (CHN), 58.4 (2 ꢃ PhCH2N0), 53.1
(2 ꢃ PhCH2 N), 52.8 (CH2N0), 27.3 (CH2), 24.7 (CH2), 24.5 (CH2);
HRMS (+EI) calcd for C34H41N2O ([MH]+): 493.3221. Found:
493.3219 (+0.4 ppm).
All reagents were of synthetic grade, and used without further
purification. Solvents were dried on a M Braun SPS-800 column
system. All moisture-sensitive reactions were carried out under a
positive pressure of nitrogen in oven-dried glassware (140 °C). Col-
umn chromatography was performed using silica gel 60 (40–
63 lm) from Apollo Scientific Ltd. GC–MS analyses were obtained
using an Agilent 5890 gas chromatograph equipped with an
Agilent 5973N mass-selective detector. High-resolution mass
spectrometry was performed on a Waters LCT or GCT time-
of-flight mass spectrometer. NMR spectra were recorded on either
Bruker AV-300 (1H at 300.06 MHz, 13C at 75.45 MHz, 19F at
282.34 MHz), or Bruker AV-400 (1H at 400 MHz, 13C at 100 MHz),
or Bruker AV-500 (1H at 499.90 MHz, 19F at 470.33 MHz). Chemical
shifts d are reported in parts per million (ppm), and quoted relative
to internal standard Me4Si for 1H and 13C NMR and to external
standard CFCl3 for 19F NMR. 1H, 13C and 19F NMR data were as-
signed on a routine basis by a combination of one- and two-
dimensional experiments (COSY, HSQC, HMBC, NOESY). Melting
4.4. (R)-1,1-Dibenzyl-2 ((dibenzylamino)methyl)piperidinium
chloride (R)-5
4.4.1. Cyclisation with DAST
Silica gel (3.46 g, 0.12 mmol) and then DAST (3.8 mL,
28.8 mmol) were added to a solution of (S)-4 (9.45 g, 19.2 mmol)
in DCM (200 mL) at 0 °C. The mixture was stirred at 20 °C for
24 h, and the reaction mixture was quenched with saturated NaCl
solution, before extraction into DCM. The organic layers were
evaporated to dryness to provide a solid amorphous material.
The material was resuspended and stirred as a powder in Et2O to
wash off any organic soluble residues. Filtration gave product
(R)-5 (7.76 g, 80%) as an off white powder. Mp: 96–97 °C;
points were measured using
a
GallenKamp Griffin MPA350ꢁ
BM2.5 melting point apparatus, and are uncorrected. Optical
rotations were determined using a Perkin Elmer Model 341 polar-
imeter.
½
a 2D0
values are measured at 589 nm and given in
ꢂ
10ꢀ1 deg cm2 gꢀ1. Elemental analyses were carried out on a CE
instrument EA 1110 CHNS analyser. IR spectra were recorded on
a Perkin Elmer Spectrum GX FT-IR system as KBr disc or as thin
film on NaCl plates.
½
a 2D0
ꢂ
¼ ꢀ73:5 (c 1.1, CHCl3); IR (film, cmꢀ1) 2348, 2283, 1187,
4.2. (S)-Benzyl 2,6-bis(dibenzylamino)hexanoate (S)-3
1128, 929, 751, 744, 591, 545; 1H NMR (300 MHz, CDCl3): 7.23–
7.75 (20H, m, Ar-H), 4.91 (2H, m), 4.27 (1H, d, J = 38.5 Hz), 4.23
(1H, d, J = 38.8 Hz), 3.72–3.42 (3H, m), 3.21 (1H, m), 2.93 (2H, dd,
J = 12.7 Hz, J = 9.8 Hz), 2.51 (1H, d, J = 2.5 Hz), 2.21–2.28 (2H, m),
1.23–1.90 (6H, m, CH2); 13C NMR (75 MHz, CDCl3): 138.5 (4 ꢃ C,
Ar), 133.8 (2 ꢃ C, Ar), 133.7 (2 ꢃ C, Ar), 130.7 (Ar), 130.5 (Ar),
129.3 (2 ꢃ C, Ar), 129.2 (4 ꢃ C, Ar), 129.1 (2 ꢃ C, Ar), 128.4 (4 ꢃ C,
Ar), 127.1 (2 ꢃ C, Ar), 67.0 (CHN), 63.7 (PhCH2 N), 59.0
(2 ꢃ PhCH2N0), 57.7 (PhCH2N), 57.3 (CH2N), 52.7 (CH2N0), 25.9
(CH2), 22.1 (CH2), 20.8 (CH2); HRMS (ES+) calcd for C34H39N2
([M]+): 475.3113. Found: 475.3113 (ꢀ0.1 ppm).
Anhydrous K2CO3 (242.14 g, 1.752 mol) and benzyl bromide
(182 mL, 1.53 mol) were added to a solution of (S)-L-lysine (40 g,
0.219 mol) in EtOH (400 mL). After stirring at 60 °C for 4 days,
the resulting white slurry was filtered over CeliteÒ, and the solids
were washed with EtOAc. After evaporation of solvents, the residue
was re-dissolved in EtOAc and washed with saturated NaCl solu-
tion. EtOAc was removed under reduced pressure, and the residue
was distillated (100 °C, 0.01 mbar) to give (S)-3 as a light yellow oil
(125.5 g, 96%). ½a D20
ꢂ
¼ ꢀ46:9 (c 1.6, CHCl3), {lit. ½a D20
¼ ꢀ52:5 (c 2.8,
ꢂ
CHCl3)}; IR (film, cmꢀ1) 3029, 2942, 2798, 1731, 1494, 1454, 1365,

G. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2330–2333
2333
4.4.2. Cyclisation with trifluoromethanesulfonic anhydride
4.6. (S)-(2-(Aminomethyl)piperidine dihydrochloride (S)-1
At first, Et3 N (0.85 mL, 6.09 mmol) and a catalytic amount of
DMAP (50 mg, 0.41 mmol) were added to a solution of (S)-4 (1 g,
2.03 mmol) in DCM (25 mL). The mixture was cooled to 0 °C and
the triflic anhydride (0.68 mL, 4.06 mmol) was added. The reaction
mixture was stirred for 2 h at 0 °C and at ambient temperature for
another 12 h. The reaction was then quenched with saturated NaCl
solution and the products were extracted into DCM. The organic
extracts were then washed with saturated NaHCO3 solution, dried
and evaporated. Resuspension in Et2O as described above (4.4.1)
gave (R)-5 (0.92 g, 88%) as an off-white powder. Spectroscopic
analyses were identical to that described in Section 4.4.1.
½
a 2D0
ꢂ
¼ ꢀ2:9 (c 1.4, MeOH). Lit.12 ꢀ5.7 (c 0.42, MeOH); lit.13 ꢀ4.7
(c 2.8, MeOH). Analytical data were otherwise identical to (R)-1.
Acknowledgements
We thank the University of St. Andrews for an Interdisciplinary
Studentship (G.D.) and the EPSRC for a DTA Studentship (T.M.).
References
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Ammonium formate (315.3 mg, 5 mmol) and a suspension of
20% Pd(OH)2 (250 mg) were added to
a solution of (R)-5a
(510 mg, 1 mmol) in MeOH (25 mL). The mixture was stirred for
24 h at ambient temperature. The black suspension was then fil-
tered through CeliteÒ, and 1 M HCl in Et2O (4 mL) was added to
the filtrate. Solvents were removed under reduced pressure and
the crude product was re-crystallised from MeOH/Et2O to yield
(R)-2-(aminomethyl)-piperidine dihydrochloride 1 (144 mg, 77%)
as a colourless crystalline solid.
Mp: 213–215 °C; ½a D20
ꢂ
¼ þ2:3 (c 1.4, MeOH); IR (KBr, cmꢀ1
)
3416, 2955 (br), 2842 (br), 1584, 1514, 1484, 1476, 1440, 1407,
1133, 1022, 1008; 1H NMR (300 MHz, CD3OD): 4.77 (5 H, s,
5 ꢃ NH), 3.38–3.48 (1H, m, CHN), 3.34–3.42 (1H, m, CHAHBN),
3.28 (1H, dd, J = 5.8 Hz, J = 13.6 Hz, CHAHBN0), 3.14 (1H, dd, J =
6.5 Hz, J = 13.6 Hz, CHAHBN0), 3.00 (1H, dt, J = 3.3 Hz, J = 12.5 Hz,
CHAHBN), 1.46–2.04 (6H, m, 3 ꢃ CH2); 13C NMR (75 MHz, CD3OD):
55.8 (CHN), 46.5 (CH2N), 42.9 (CH2N0), 27.8 (CH2), 23.3 (CH2), 23.0
(CH2); Anal. Calcd for C6H16N2Cl2: C, 38.51; H, 8.62; N, 14.97.
Found: C, 38.86; H, 8.31; N, 14.66; HRMS (+CI) calcd for C6H15N2
([M]+): 115.1235. Found: 115.1236 (+0.4 ppm).
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