Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Article abstract of DOI:10.1016/j.tet.2019.01.030

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98% ≥ d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.

Full text of DOI:10.1016/j.tet.2019.01.030

Accepted Manuscript
Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic
sulfamidates
Mustafa Eskici, Abdullah Karanfil
PII:
S0040-4020(19)30057-2
https://doi.org/10.1016/j.tet.2019.01.030
TET 30082
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 September 2018
Revised Date: 4 January 2019
Accepted Date: 15 January 2019
Please cite this article as: Eskici M, Karanfil A, Stereoselective synthesis of cis-2,6-disubstituted
piperidines from 1,2-cyclic sulfamidates, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.01.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Graphical Abstract
Stereoselective Synthesis of cis-2,6-Disubstituted
Piperidines from 1,2-Cyclic Sulfamidates
a
b
Mustafa Eskici * and Abdullah Karanfil
a
Department of Chemistry, Faculty of Arts and Science, Manisa Celal Bayar University,
b
Manisa, Turkey; Turkey; Department of Chemistry, Faculty of Arts and Science, Ordu
University, Ordu, Turkey
Abstract
Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates
is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from
L-
phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl
substituent proceed smoothly to form the N-sulfamate intermediates which on acidic
hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the
alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of
aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates
afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity
(98%≥d.e.) with good chemical yields (68-86%). The present approach provides a novel route
for the stereoselective synthesis of cis-2,6-disubstituted piperidines.
Key Words: 1,2-cyclic sulfamidates, acetylide, ketal, stereoselective synthesis, cyclization,
piperidines.
1
. Introduction
The piperidine, 6-membered nitrogen saturated heterocycle is arguably one of the most
1
observed structural units in natural products and pharmaceuticals. Accordingly
stereoselective synthesis of substituted piperidines has attracted great deal of interest over the
2
years. The piperidine ring system possessing a chiral centre at C-2 and-6 positions is
particularly common substitution system. The 2,6-disubstituted piperidine framework is
present in monocyclic piperidine as well as bicyclic indolizidine alkaloids, and has been
found to occur not only in plants but also insects and amphibians. (-)-Pinidinol 1, (+)-
epidihydropinidine 2, (-)-solenopsin A 3, isosolenopsin A 4, (+)-monomorine I 5 and (-)-
indolizidines 209D 6 are some representative examples of 2,6-disubstituted piperidine
alkaloids (Figure 1). (-)-Pinidinol 1 and (+)-epidihydropinidine 2 are naturally occurring
defense alkaloids isolated from Picea (spruce) and/or Pinus (pine) species and various
3
insects. (-)-Solenopsin A 3 and isosolenopsin A 4 are example constituents of fire ant venom
1

ACCEPTED MANUSCRIPT
4
(
genus Solenopsis). (+)-Monomorine I 5 and (-)-Indolizidine 209D 6 are representative
indolizidine alkaloids that contain cis-2,6-disubstituted piperidine substructure. Most of the
indolizidine alkaloids possess alkyl side chains at the 5 positions (3-and 5-positions for
disubstituted indolizidines). (+)-Monomorine I 5 is a rail pheromone of the pharaoh ant
5
(
Monomotium pharaonis). (-)-Indolizidine 209D 6 alkaloids is a representative alkaloid
6
which can be isolated from the poison frogs dendrobatid species.
Their relatively simple ring structure makes this class of molecules 1-6 an attractive vehicle
for demonstrating the utility of a new synthetic method. Thus, there are variety of methods
developed in the literature for stereoselective synthesis of the 2,6-disubstituted piperidine ring
7
core. These methods include reduction of 2,6-dialkylpyridines, metal-catalysed
8
9
intramolecular cyclizations, intramolecular cyclization via aza-Micheal addition,
1
0
rearrangement of oxime sulfonates, alkylation of pyridinium salts and piperidine
derivatives, reductive aminocyclization, iminium-type alkylations, cycloaddition,
enzymatic reactions. Given widespread distribution and broad range of interesting
biological activities of 2,6-disubstituted piperidine core containing molecules in nature, new
routes for stereoselective synthesis of 2,6-disubstituted piperidines are always valuable.
1
1
12
13
14
1
5
16
Cyclic sulfamidates are readily available and often enantiopure aminoalcohol-derived reactive
electrophiles that have found increasing synthetic utility in organic synthesis. Formation of
sulfamidates activates the hydroxyl towards nucleophilic displacements while providing
1
7
concurrent protection to the nitrogen atom. The reactivity profile of cyclic sulfamidates from
,2-and 1,3-aminoalcohols is considered to be an effective alternative to the reactivity of the
1
related aziridines and azetidines. Nucleophilic cleavage with sulfamidates occur in a
regiospecific manner at the C–O bond, and the nucleophilic attack at the C–N bond is not
generally observed. There is also no specific requirement for the presence and subsequent
removal of an activating group on the nitrogen. These features make cyclic sulfamidates
synthetically versatile electrophilic synthons in synthesis. As a result, reaction of sulfamidates
1
8
19
20
21
with a wide variety of nucleophiles including carbon, nitrogen, oxygen, sulfur,
phosphour and fluoride has been reported.
2
2
23
24
Of particular value is the ring opening reactions with carbon-based nucleophiles that enables
the synthesis of functionalized amine compounds. The reactivity of cyclic sulfamidates
towards synthetically functionalized carbon-based nucleophiles has being explored in organic
1
8
synthesis over the years. We previously reported a synthetically useful level of reactivity of
2
5
cyclic sulfamidates towards acetylides (Scheme 1). Nucleophilic cleavage of 1,2-cyclic
2

ACCEPTED MANUSCRIPT
sulfamidates 7 with acetylides 8 proceeded smoothly in a regioselective fashion to form N-
sulfamate 9 which on acidic hydrolysis produced the alkynylated amines 10. Primary carbon-
centered sulfamidates were found to be particularly effective in the alkylation reaction
furnishing the related alkynylated amines in high yields. Once the acetylide component
possesses an orthoester functionality, nucleophilic addition of triethylorthopropiolate 11 gave
2
6
N-sulfamate intermediate 12. Acidic hydrolysis not only cleaved the N-sulfamate but also
led to concurrent hydrolysis of orthoester to the corresponding ethylester. Thermal cyclization
of amino-α,β-unsaturated esters 13 upon hydrogenation enabled synthesis of the alkyl
substituted piperidine lactams 14, in which [N─C─C] fragment from the sulfamidate and
[
C─C─C] fragment from the propiolate are combined to form the piperidine ring. This
approach represents a new cyclization strategy for the synthesis of the substituted piperidin-2-
ones. The efficiency of the cyclization process was demonstrated by the synthesis of the
hemlock alkaloid (S)-coniine 15 from L-norvaline.
O
O
Bn
SO Li
Bn
S
3
R1
Li
N
R1
NH
R1
BnN
8
H
O
R
10
R
R
7
9
(
EtO) C
Li
3
11
O
SO Li
O
3
HN
BnN
R
C(OEt)3
NHBn
15
H
H /Pd
2
HN
R
OEt
12
(S)-Coniine
13
R
14
Scheme1. Reactivity of 1,2-cyclic sulfamidates towards acetylides.
Inspired by the synthesis of the substituted piperidin-2-one system, we envisaged that once a
ketal protected acetylide is used as the nucleophilic component, a similar cyclization approach
could enable the stereoselective synthesis of 2,6-disubstituted piperidines. In this
communication we report our preliminary results for stereoselective synthesis of cis-2,6-
disubstituted piperidines from 1,2-cyclic sulfamidates and the ketal protected acetylide with a
phenyl substituent.
2
. Results and discussion
Ketal protected terminal alkyne 16 was lithiated with n-butyllithium in THF at -10 °C for 1h
2
7
(
Scheme 2). The resulting acetylide 17 solution was reacted with 18a as the model
sulfamidate for 24h to form N-sulfamate 19. Treatment with 5M HCl solution is generally
2
5
considered to be the standard acidic conditions for cleavage of N-sulfamate. Under these
conditions (5M HCl) the hydrolysis reaction on 19 afforded alkynylated amine 20a with ketal
group intact along with ketal group hydrolyzed product 21a in varying yields. We previously
observed that the acetal group was adequately stable to 5M HCl allowing the corresponding
alkynylated acetal product to be isolated in good yield. The relative unstability of the ketal
group to 5M HCl called for investigations of hydrolysis conditions in more details. After
extensive experimentation, we were able to obtain the desired alkynylated amine 20a with the
ketal group intact in good yields. The best conditions that avoids the ketal hydrolysis was
found to be dropwise addition of H O and conc. H SO to the etheric N-sulfamate solution.
2
2
4
3

ACCEPTED MANUSCRIPT
The labile ketone by product 21a could be obtained as the sole reaction product when the
hydrolysis was performed with conc. HCl solution.
Having established the optimum hydrolysis conditions, the scope of the acetylenic
substitution reactions was examined with the structural variations in sulfamidates 18a-f
(
Scheme 3). A representative set of 1,2-cyclic sulfamidates 18a-f was synthesized for scaning
26
of the structural affects on substitution. We preferred to use the benzyl group for N-
protection considering the ease of installation and subsequent removal by hydrogenation as
well as its stability under the basic conditions. Enantiomerically pure primary carbon-centered
sulfamidates 18a–d were prepared from L-phenyalanine, alanine, valine, norvaline. Optically
pure secondary carbon-centered 1,2-cyclic sulfamidate 18e was prepared from (S)-ethyl
lactate. Primary carbon-centered sulfamidates 18a-d were all found to be effective in the
alkylation reaction delivering the expected β-alkynylated amines 20a-d in good yields. The
2
5a
lability of the sulfamidate 18f toward elimination was already reported. Using the similiar
reaction conditions, the alkylation reaction of 18f led to the formation of the substitution
product 20f in 22% yield along with N-benzyl cinnamylamine 22 in 54% yield. This result is
in paralel to our previous observations; sulfamidate 18f generally favors the elimination
pathway in displacement reactions. Ring-opening reactions of 18a-f usually required two
equivalent of acetylide 17 for completion in 24h. Inclusion of 7,5% HMPA by volume was
found to enhance reaction rates such that 1.1 equivalent of 17 was suffice for the reaction to
be completed in several hours. Therefore, HMPA was frequently used as polar additive in
reaction mixtures to avoid the excess use of synthetically valuable alkyne 16.
4

ACCEPTED MANUSCRIPT
We envisaged that ketal amine 20a-e could be converted readily into disubstituted piperidines
2
4a-c in a stereoselective manner using palladium-catalyzed hydrogenation. Combination of
5

ACCEPTED MANUSCRIPT
aqueous HCl and Pd/C in MeOH was successfully used in several stereoselective synthesis of
1
3c,18c
substituted piperidines.
Attempts to construct the piperidine ring from amines 20a-e
using acidic palladium-catalyzed hydrogenation in one pot operation failed (Scheme 3). All
attempts led to isolation of unexpected acyclic amines 23a-c instead. Formation of acyclic
amines 23a-c could be explained on the basis of kinetics of the reactions involved in this one
pot multistep process; saturation of triple bond, ketal deprotection, debenzylation, cyclization
and reduction of the activated aromatic carbonyl group in acidic environment. Saturation of
triple bond, ketal deprotection, carbonyl reduction are apparently kinetically more favourable
reactions as indicated by the isolation of acyclic amines from the reactions. Sluggish
debenzylation step could be responsible for the failure. Direct conversion of the ketone 21a
into the corresponding piperidine using HCl and Pd/C in MeOH conditions in one pot
operation was not successful either.
Fortunately, performing the reactions in step-wise manner allowed us to overcome formation
of acyclic amines. Thus, alkynylated ketal amines 20a-e was initially hydrogenated in the
absence of acid to carry out saturation and sluggish debenzylation reactions (Scheme 4). The
crude debenzylated amines 25a-d were subject to the kinetically fast ketal deprotection
reaction with aqueous HCl conditions which led to insitu formation of cyclic imines (by
TLC). At this stage, cyclic imines could not be characterized spectroscopically due to
decomposition on chromatography. It is important that the crude cyclic imines isolated should
be strictly free of water for smooth stereoselective hydrogenation. Exposure of the crude
cyclic imines in MeOH containing etheric anhydrous HCl to palladium-catalyzed
hydrogenation gratifyingly afforded the corresponding cis-disubstituted piperidines 24a-d in
2
8 1
excellent diastereoselectivity with good chemical yields over three steps. H NMR spectrum
of cis-disubstituted piperidines showed the presence of only one diastereoisomer which
indicates hydrogenation operating with 98%≥d.e stereoselectivity. It is critical that
atmospheric palladium-catalyzed hydrogenation be performed under anhydrous conditions;
otherwise formation of acyclic amines may cause a problem to varying extents, thereby
rendering efficiency of the hydrogenation step.
6

ACCEPTED MANUSCRIPT
Application of the step-wise reaction strategy to lactate-derived alkynylated amine 20e did not
lead to good stereoselectivity for synthesis of 2,4-disubstituted piperidine system. In this case,
2
,4-disubstituted piperidine 27 was obtained as approximately a 4:1 inseparable mixture of
two diastereosimers (Scheme 5).
Characterization data for known alanine-derived cis-piperidine 24b ((2S,6S)-2-methyl-6-
2
0
phenylpiperidine,
(2S,6R)-2-methyl-6-phenylpiperidine, ꢁ = +33.4 (c=1,25 CHCl )) was already available in
ꢀ ꢂ
ꢃ
3
ꢀ ꢂ
ꢁ = -35.6 (c=1,38 CHCl )) and alanine-derived trans-piperidine
ꢃ
3
20
(
1
3f
the literature. Optical rotation for (2S,6S)-2-methyl-6-phenylpiperidine 24b was measured
in this work as ꢁ = -34.2 (c=1, CHCl ). Comparision of NMR data and optical rotation of
4b with literature data indicated disubstituted piperidine 24b in cis configuration.
30
ꢀ ꢂ
ꢃ
3
2
Configuration of other disubstituted piperidines 24a, 24c, 24d was assigned as cis-
configuration using the analogy to 24b and NOESY NMR. The observed stereochemical
outcome of palladium catalyzed hydrogenation can be explained on the base that attack of
hydrogen from the less hindered side of cyclic iminium intermediate 26a-d in the transition
2
9
state leading to cis-2,6-disubstituted piperidines (Figure 2).
7

ACCEPTED MANUSCRIPT
3
. Conclusions
In summary a new method for stereoselective synthesis of cis-2,6-disubstituted piperidines
from 1,2-cyclic sulfamidates is developed. Regioselective ring-opening reactions of 1,2-cyclic
sulfamidates derived from
L-phenylalanine, alanine, valine, norvaline with ketal protected
acetylide with a phenyl substituent proceed efficiently to give alkynylated amines with the
ketal group intact after acidic hydrolysis. Hydrogenation of the alkynylated amine products,
debenzylation, ketal deprotection, subsequent cyclization and stereoselective hydrogenation
of the cyclic iminium ion intermediates afford the corresponding cis-disubstituted piperidines
in high diastereoselectivity (98%≥d.e.). The present approach represents a novel route for the
stereoselective synthesis of cis-2,6-disubstituted piperidines. Application of this methodology
with the use of the ketal protected acetylides with an alkyl group for natural product synthesis
containing 2,6-disubstituted piperidine unit is currently ongoing in our laboratory and will be
reported elsewhere.
4
. Experimental section
4
.1. General methods
1
13
H and C NMR spectra were recorded in CDCl on a Varian AS 400 MHz NMR
3
spectrometer with TMS as an internal. Chemical shifts are expressed in δ (parts per million)
units downfield from TMS. IR spectra were recorded on a Perkin Elmer Spectrum BX
spectrometer as thin films on NaCl plates. Optical rotations were measured with Rudolph
Research Analytical Autopol I Automatic Polarimeter. LC/MS Q-TOF were taken from
Giresun Univesity, Giresun, Turkey with an Agilent 6230 Q-TOF LC/MS instrument. THF
and ether were freshly distilled from LiAlH before use. TLC was performed using aluminum
4
plates coated with silica gel (254 nm) and use of the basic permanganate dying system. Flash
column chromatography was carried out using silica gel (0.063-0.2 mm). Removal of solvents
in vacuo was achieved using a IKA rotary evaporator at room temperature unless otherwise
stated. Yields refer to isolated material, homogeneous by TLC and NMR spectroscopy, unless
otherwise stated. Phenyl ketal alkyne 16 was synthesized from propiophenone according to
2
7
literature protocols. 1,2-Cyclic sulfamidates 18a-f were prepared according to literature
2
6
protocols.
4
.2. General procedure for the nucleophilic substitution of 1,2-cyclic sulfamidates 18a-f
with phenyl ketal alkyne 16
To a solution of terminal alkyne 16, 2 mmol in 10 mL freshly distilled dry THF under argon
atmosphere, cooled at -10 °C over ice-salt bath was added dropwise n-butyllithium (1.3 mL,
2
.1 mmol, 15% solution in hexane) and the solution was stirred at this temperature for 1 h (1.1
mmol 16 and 1.2 mmol n-butyllithium were sufficient if 0.75 mL HMPA was used as co-
solvent). A solution of 1,2-cyclic sulfamidate (1 mmol) in 3 mL dry THF was then added to
the resulting acetylide solution via a syringe. After stirring at –10 ºC for 5-6 h, the reaction
mixture was allowed to warm up to room temperature gradually with stirring overnight (a few
hours if HMPA was used, overnight for 18e). TLC monitoring showed complete consumption
of sulfamidate. The resulting mixture was then added one drop conc. H SO and one drop
2
4
H O sequentially (total 4 drops H SO and 4 drops H O) with stirring for 1-2h to hydrolyze
2
2
4
2
the N-sulfamate intermediate before neutralization with saturated NaHCO3 solution.
Extraction with ether (3x20mL) and drying over anhydrous Na SO followed by evaporation
2
4
of volatiles in vacuo gave the crude product. Purification by column chromatography using
8

ACCEPTED MANUSCRIPT
EtOAc/Hexane solvent systems (containing 0.5% triethylamine) afforded compounds 20a-f
and 22 as an oil. Ketal protected alkynylated amines 20a-f are sensitive compounds for
chromatographic purification; a small extent of decomposition was sometimes observed.
4
.2.1. (S)-N-Benzyl-1-phenyl-5-(2-phenyl-1,3-dioxolan-2-yl)pent-4-yn-2-amine 20a
Obtained as a pale yellow oil (358 mg, 90% yield). TLC, Rf: 0.42 [(EtOAc:hexane) 1:3];
30
-1
1
ꢁ =+0.36 (c=6.0, CHCl ); IR (film); υ /cm ; 3357 (NH), 2234 (C≡C); H NMR δ (400
ꢀ ꢂ
ꢃ
3 max H
MHz, CDCl ) (ppm) 2.37 (1H, dd, J=5.6 and 16.8), 2.43 (1H, dd, J=6.0 and 16.8), 2.80 (1H,
3
dd, J=7.2 and 13.6), 2.86 (1H, dd, J=6.0 and 13.6), 2.98-3.04 (1H, m), 3.76 (1H, d, J=13.2),
3
7
8
1
3
.84 (1H, d, J=13.2), 4.07-4.15 (2H, m), 4.19-4.25 (2H, m), 7.14-7.38 (13H, m, Ar-H), 7.69-
1
3
.72 (2H, m, Ar-H); C NMR δ (100 MHz, CDCl ) (ppm) 23.67, 4074, 51.32, 57.40, 65.23,
C
3
0.89, 84.33, 102.63, 126.17, 126.65, 127.19, 128.28, 128.50, 128.67, 128.74, 129.38, 129.63,
+
38.97, 139.82, 140.50; LC/MS Q-TOF (m/z): [M+H] found 398.2116, C H NO requires
27
28
2
98.2120.
4
.2.2. (S)-5-(benzylamino)-1,6-diphenylhex-2-yn-1-one 21a
Obtained as a pale yellow oil (312 mg, 89% yield). TLC, Rf: 0.47 [(EtOAc:hexane) 1:3]; δH
400 MHz, CDCl ) (ppm) 2.60 (1H, dd, J=5.2 and 17.2), 2.68 (1H, dd, J=5.6 and 17.2), 2.89-
(
3
2
.99 (2H, m), 3.14-3.20 (1H, m), 3.84 (1H, d, J=13.2), 3.93 (1H, d, J=13.2), 7.21-7.33 (10H,
m, Ar-H),7.45-7.50 (2H, m, Ar-H), 7.59-7.63 (1H, m, Ar-H), 8.16-8.19 (2H, m, Ar-H); δC
100 MHz, CDCl ) (ppm) 24.32, 40.84, 51.43, 57.11, 81.82, 94.00, 126.85, 127.30, 128.24,
(
3
1
28.70, 128.78, 128.85, 129.56, 129.82, 134.22, 137.14, 138.41, 140.12, 178.22; LC/MS Q-
+
TOF (m/z): [M+H] found 354.1867, C H NO requires 354.1858. The title compound was
2
5
23
prone to decomposition.
.2.3. (S)-N-Benzyl-5-(2-phenyl-1,3-dioxolan-2-yl)pent-4-yn-2-amine 20b
Obtained as a pale yellow oil (267 mg, 83% yield). TLC, Rf: 0.35 [(EtOAc:hexane) 1:1];
4
3
0
-1
ꢀ
(
(
ꢁ = -15.0 (c=1.0, CHCl ); IR (film) υ /cm : 3317 (N−H),3029, 2964, 2927, 2892, 2233
ꢂ
ꢃ
3 max
C≡C), 1493, 1451, 1275, 1152, 1067, 1028, 966, 754, 698; δ (400 MHz, CDCl ) (ppm) 1.19
3H, d, J=6.4), 2.44 (2H, d, J=6.0), 2.95 (1H, septet, J=6.0), 3.80 (2H, br, s), 4.09-4.24 (4H,
H
3
m), 7.24-7.38 (8H, m, Ar-H), 7.69-7.72 (2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 20.42,
C
3
2
1
3
6.41, 51.09, 51.25, 65.04, 80.16, 84.25, 102.40, 125.85, 126.92, 128.04, 128.18, 128.42,
+
29.07, 139.45, 140.31; LC/MS Q-TOF (m/z): [M+H] found 322.1819, C H NO requires
21
23
2
22.1807.
4
.2.4. (R)-N-Benzyl-2-methyl-6-(2-phenyl-1,3-dioxolan-2-yl)hex-5-yn-3-amine 20c
Obtained as a pale yellow oil (310 mg, 89% yield). TLC, Rf: 0.38 [(EtOAc:hexane) 1:3];
3
0
-1
ꢀ
(
(
ꢁ = -31.0 (c=2.0, CHCl ); IR (film) υ /cm : 3337 (N−H), 3028, 2958, 2891, 2232
ꢂ
ꢃ
3 max
C≡C), 1493, 1450, 1274, 1152, 1066, 1028, 965, 750, 697; δ (400 MHz, CDCl ) (ppm) 0.95
H
3
3H, d, J=6.8), 0.98 (3H, d, J=6.8), 1.87-1.95 (1H, m), 2.43 (1H, dd, J=6.4 and 16.8), 2.51-
.61 (2H, m), 3.77 (1H, d, J=12.8), 3.88 (1H, d, J=12.8), 4.09-4.15 (2H, m) 4.17-4.24 (2H,
m), 7.25-7.39 (8H, m, Ar-H), 7.70-7.73 (2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 18.54,
2
C
3
1
1
8.76, 21.00, 30.83, 51.65, 61.10, 65.03, 79.81, 84.96, 102.44, 125.87, 126.82, 128.13,
28.17, 128.31, 129.04, 139.51, 140.78 ; LC/MS Q-TOF (m/z): [M+H] found 350.2124,
+
C H NO requires 350.2120.
23
27
2
9

ACCEPTED MANUSCRIPT
4
.2.5. (S)-N-Benzyl-1-(2-phenyl-1,3-dioxolan-2-yl)hept-1-yn-4-amine 20d
Obtained as a pale yellow oil (307 mg, 88% yield). TLC, Rf: 0.39 [(EtOAc:hexane) 1:2];
3
0
-1
ꢀ
(
(
ꢁ = -25.7 (c=1.0, CHCl ); IR (film) υ /cm : 3326 (N−H), 3030, 2952, 2924, 2890, 2235
ꢂ
ꢃ
3 max
C≡C), 1490, 1451, 1272, 1152, 1065, 1026, 965, 752, 699; δ (400 MHz, CDCl ) (ppm) 0.92
3H, t, J=7.2), 1.34-1.44 (2H, m), 1.47-1.57 (2H, m), 2.43 (1H, dd, J=5.6 and 16.8), 2.54 (1H,
H
3
dd, J=5.6 and 16.8), 2.80 (1H, quintet, J=6.0), 3.76 (1H, d, J=12.80), 3.84 (1H, d, J=12.80),
.09-4.15 (2H, m), 4.21-4.24 (2H, m), 7.23-7.40 (8H, m, Ar-H), 7.69-7.74 (2H, m, Ar-H); δC
100 MHz, CDCl ) (ppm) 14.19, 16.07, 23.90, 36.57, 50.96, 55.30, 65.04, 80.06, 84.40,
4
(
3
1
02.43, 125.87, 126.87, 128.09, 128.17, 128.36, 129.06, 139.48, 140.55; LC/MS Q-TOF
+
(m/z): [M+H] found 350.2121, C H NO requires 350.2120.
23 27 2
4
.2.6. (S)-N-Benzyl-2-methyl-4-(2-phenyl-1,3-dioxolan-2-yl)but-3-yn-1-amine 20e
Obtained as a pale yellow oil (257 mg, 80% yield). TLC, Rf: 0.27 [(EtOAc:hexane) 1:1];
3
0
-1
ꢀ
(
(
ꢁ = -24.7 (c=1.3, CHCl ); IR (film) υ /cm : 3333 (N−H), 3025, 2974, 2935, 2890, 2229
ꢂ
ꢃ
3 max
C≡C), 1493, 1451, 1272, 1172, 1068, 1029, 965, 744, 699; δ (400 MHz, CDCl ) (ppm) 1.22
3H, d, J=6.8), 2.70 (2H, m), 2.82 (1H, septet, J=6.8), 3.78 (1H, d, J=13.2), 3.84 (1H, d,
H
3
J=13.2), 4.07-4.14 (2H, m), 4.18-4.23 (2H, m), 7.23-7.38 (8H, m, Ar-H), 7.67-7.71 (2H, m,
Ar-H); δ (100 MHz, CDCl ) (ppm) 18.41, 26.62, 53.34, 54.24, 65.00, 79.28, 89.51, 102.42,
C
3
1
25.89, 126.95, 128.02, 128.17, 128.40, 129.07, 139.44, 140.02; LC/MS Q-TOF (m/z):
+
[
M+H] found 322.1807, C H NO requires 322.1807.
21 23 2
4
.2.7. N,2-Dibenzyl-4-(2-phenyl-1,3-dioxolan-2-yl)but-3-yn-1-amine 20f
Obtained as an orange oil (88 mg, 22% yield). TLC, Rf: 0.39 [(EtOAc:hexane) 1:1]; IR (film)
-1
υmax/cm : 3327 (N−H), 3064, 3025, 2896, 2845, 2229 (C≡C), 1493, 1454, 1272, 1146, 1065,
1
026, 967, 744, 699; δ (400 MHz, CDCl ) (ppm) 2.72-2.91 (4H, m), 2.97-3.04 (1H, m), 3.77
H
3
(1H, d, J=13.2), 3.84 (1H, d, J=13.2), 4.04-4.11 (4H, m), 7.20-7.37 (13H, m, Ar-H), 7.60-7.63
(
2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 34.47, 38.71, 52.26, 53.50, 64.95, 81.00, 87.93,
C
3
1
1
3
02.37, 125.96, 126.37, 126.96, 128.04, 128.14, 128.25, 128.41, 129.08, 129.23, 139.02,
+
39.14, 140.20 ; LC/MS Q-TOF (m/z): [M+H] found 398.2104, C H NO requires
27
27
2
98.2120.
4
.2.8. N-Benzyl cinnamylamine 22
Obtained as a pale yellow oil (120 mg, 54% yield). TLC, Rf: 0.19 [(EtOAc:hexane) 1:1]; IR
-1
(
film) υmax/cm : 3312 (N−H), 1646 (C=C), 1599, 1491, 1449 (aromatic), 736, 698; δ (400
H
MHz, CDCl ) (ppm) 3.46 (2H, dd, J=1,2 and 6.0), 3.86 (2H, br s), 6.34 (1H, dt, J=6.4 and
3
1
6.0), 6.56 (1H, d, J=15.6), 7.21-7.40 (10H, m, Ar-H).
4
.3. General procedure for synthesis of acyclic amines 23a-c
To a solution of the aminoketal alkynes 20a-c (1.18 mmol) in methanol (15 mL) containing
,5 mL 1N HCl was added Pd/C (80 mg) at room temperature. The resulting solution was
1
flushed with argon several times and a stream of hydrogen was bubbled through the solution
for 72 hours. After completion of the reaction, mixture was filtered through a pad of Celite
and evaporation of the volatiles in vacuo give the crude product. The resulting residue was
dissolved in DCM and washed with saturated NaHCO (3x10 mL), drying over anhydrous
3
Na SO followed by evaporation of volatiles in vacuo gave the crude product. Purification by
2
4
flash column chromatography eluting with the (DCM/MeOH 90:10 to 95:5 gradient) solvent
system (containing 0.5% triethylamine) afforded the acyclic amines 23a-c.
1
0

ACCEPTED MANUSCRIPT
4
.3.1. (R)-1,6-Diphenylhexan-2-amine 23a
Obtained as an off-white solid (287 mg, 96% yield); mp 81-84 °C TLC, Rf: 0.4
3
0
-1
[
(
(
(MeOH:DCM) 1:9];
ꢁ = -12.8 (c=1.33, CHCl ); IR (film) υ /cm : 3652, 3366, 3282
ꢀ ꢂ
ꢃ
3 max
N−H), 3025, 2929, 2853, 2851, 1602, 1496, 1454, 1029, 744, 699; δ (400 MHz, CDCl )
H
3
ppm) 1.37-1.72 (6H, series of multiplet), 2.49 (1H, dd, J=8.8 and 13.6), 2.65 (2H, t, J=7.6),
.81 (1H, dd, J=4.8 and 13.6), 2.97-3.04 (1H, m), 7.18-7.34 (10H, m, Ar-H); δ (100 MHz,
2
C
CDCl ) (ppm) 25.91, 31.56, 35.89, 37.39, 44.62, 52.69, 125.66, 126.19, 128.27, 128.38,
3
+
1
28.42, 129.29, 139.57, 142.57 ; LC/MS Q-TOF (m/z): [M+H] found 254.1913, C H N
18 23
requires 254.1909.
4
.3.2. (S)-6-phenylhexan-2-amine 23b
Obtained as a viscous pale yellow oil (159 mg, 76% yield). TLC, Rf: 0.1 [(MeOH:DCM) 1:9];
30
-1
ꢁ = +3.2 (c=4.67, CHCl ); IR (film) υ /cm : 3351, 3280, 3170 (N−H), 3084, 3061,
ꢀ ꢂ
ꢃ
3 max
3
026, 2929, 2856, 1663, 1603, 1583, 1495, 1453, 1372, 747, 699; δ (400 MHz, CDCl )
H 3
(ppm) 1.05 (3H, d, J=6.0), 1.33-1.67 (6H, series of multiplet), 2.61 (1H, d, J=7.6), 2.63 (1H,
d, J=7.6), 2.83-2.90 (1H, m), 7.15-7.18 (3H, m, Ar-H), 7.25-7.29 (2H, m, Ar-H) ; LC/MS Q-
+
TOF (m/z): [M+H] found 178.1599, C H N requires 178.1596.
12
19
4
.3.2. (R)-2-methyl-7-phenylheptan-3-amine 23c
Obtained as an off-white solid (191 mg, 79% yield); mp 63-65 °C ; TLC, Rf: 0.46
-1
[
1
(MeOH:DCM) 1:9]; IR (film) υmax/cm : 3372, 3299 (N−H), 3084, 3025, 2931, 2857, 1603,
495, 1453, 1366, 1030, 747, 698; δ (400 MHz, CDCl ) (ppm) 0.86 (3H, d, J=6.8), 0.90 (3H,
H
3
d, J=7.2), 1.25-1.68 (6H, series of multiplet), 2.50-2.54 (1H, m), 2.62 (2H, t, J=8.0), 7.15-7.18
(
3H, m, Ar-H), 7.25-7.29 (2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 17.11, 19.23, 26.31,
C 3
3
1.66, 33.21, 34.49, 35.95, 56.49, 125.59, 128.22, 128.35, 142.66; LC/MS Q-TOF (m/z):
+
[
M+H] found 206.1903, C H N requires 206.1909.
14 23
4
.4. General procedure for synthesis of piperidines 24a-d and 27
To a solution of the aminoketal alkynes 20a-d (1.15 mmol) in methanol (25 mL) was added
Pd/C (35 mg) and Pd(OH) (35 mg) at room temperature. The resulting solution was flushed
2
with argon several times and a stream of hydrogen was bubbled through the solution for
overnight. After completion of the reaction, mixture was filtered through a pad of Celite and
evaporation of the volatiles in vacuo give the crude product. The residue was dissolved in
MeOH (30 mL) and 1N HCl (2 mL) was added under argon atmosphere. After stirring at
room tempature for 5h, the volatiles was evaporated in vacuo. The residue was dissolved in
DCM (10 mL) and washed with saturated NaHCO (3x10 mL), drying over anhydrous
3
Na SO followed by evaporation of volatiles in vacuo gave the crude product. The crude
2
4
product was dissolved in MeOH (30 mL) and Pd/C (80 mg) and 0.8 mL anhydrous eteric HCl
was added. The resulting solution was flushed with argon several times and a stream of
hydrogen was bubbled through the solution for overnight. After completion of the reaction,
mixture was filtered through a pad of Celite . The resulting residue was dissolved in DCM
(
10 mL) and washed with saturated NaHCO (3x10 mL), drying over anhydrous Na SO
3
2
4
followed by evaporation of volatiles in vacuo gave the crude product. Purification by flash
column chromatography eluting with Hexane/EtOAc 5:1 to 2:1 gradient for 24a,c,d; with
acetone for 24b; with DCM/MeOH 90:10 to 95:5 gradient solvent systems for 27 afforded the
piperidines.
1
1

ACCEPTED MANUSCRIPT
4
.4.1. (S)-1-(2-phenyl-1,3-dioxolan-2-yl)heptan-4-amine 25d
The crude product was purified by passing through a small pad of silica gel. Obtained as
colourless viscous oil (146 mg, 90% yield). TLC, Rf: 0.18 [(MeOH:DCM) 1:9]; IR (film)
-1
υmax/cm : 3378, 3305 (N−H), 3058, 3030, 2952, 2929, 2879, 1664, 1462, 1448, 1118, 1040,
48, 766, 702; δ (400 MHz, CDCl ) (ppm) 0.85-0.88 (3H, m), 1.17-1.46 (8H, m), 1.85-1.90
9
H
3
(2H, m), 2.61-2.67 (1H, m), 3.72-3.76 (2H, m), 3.97-4.00 (2H, m), 7.25-7.33 (3H, m, Ar-H),
7
4
.41-7.44 (2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 14.12, 19.20, 20.13, 37.94, 40.06,
0.52, 50.79, 64.43, 110.34, 125.65, 127.68, 128.00, 142.62; LC/MS Q-TOF (m/z): [M+H]
C 3
+
found 264.1969, C H NO requires 264.1964.
1
6
25
2
4
.4.2. (2R,6S)-2-Benzyl-6-phenylpiperidine 24a
Obtained as a pale yellow oil which solidifies on storage in the refrigerator (240 mg, 83%
30
yield); mp 46-47 °C; TLC, Rf: 0.53 [(EtOAc:hexane) 1:3]; ꢁ = -139.5 (c=2.67, CHCl ); IR
ꢀ ꢂ
ꢃ
3
-1
(
film) υmax/cm : 3308 (N−H), 3026, 2930, 2852, 2792, 2711, 1603, 1493, 1453, 1326, 1305,
1
112, 752, 699; δ (400 MHz, CDCl ) (ppm) 1.27-1.37 (1H, m), 1.45-1.59 (2H, m), 1.74-1.84
H
3
(2H, m), 1.91-1.96 (1H, m), 2.71 (1H, dd, J=8.4 and 13.6), 2.84 (1H, d, J=5.2 and 13.6), 2.93-
2
2
1
.99 (1H, m), 3.59-3.63 (1H, m), 7.20-7.40 (10H, m, Ar-H); δ (100 MHz, CDCl ) (ppm)
C 3
5.34, 32.21, 35.02, 40.94, 59.03, 62.32, 126.21, 126.64, 126.93, 128.32, 128.45, 129.26,
+
39.27, 145.60; LC/MS Q-TOF (m/z): [M+H] found 252.1744, C H N requires 252.1752.
18
21
4
.4.3. (2S,6S)-2-Methyl-6-phenylpiperidine 24b
Obtained as a pale yellow oil (163 mg, 81% yield). TLC, Rf: 0.28 [(MeOH:DCM) 1:9];
3
0
13f
20
ꢃ
-1
ꢀ
ꢁ
ꢂ
= -34.2 (c=1.0, CHCl ), Lit.,
ꢀ
ꢁ
ꢂ
= -35.6 (c=1.38, CHCl ); IR (film) υ /cm : 3307
ꢃ
3
3
max
(
N−H), 3085, 3026, 2929, 2854, 2795, 2705, 1665, 1452, 1275, 1116, 752, 699; δ (600
H
MHz, CDCl ) (ppm) 1.14 (3H, d, J=4.4), 1.16-1.28 (1H, m), 1.46-1.57 (2H, m), 1.77-1.81
3
(1H, m), 1.89-1.93 (1H, m), 2.81-2.87 (1H, m), 3.69 (1H, dd, J=1.6 and 7.2), 7.25-7.27 (1H,
m, Ar-H), 7.32-7.35 (2H, m, Ar-H), 7.40-7.41 (2H, m, Ar-H); δ (100 MHz, CDCl ) (ppm)
C
3
2
2.97, 25.37, 33.80, 34.18, 53.22, 62.47, 126.74, 126.99, 128.28, 145.30; LC/MS Q-TOF
+
(m/z): [M+H] found 176.1429, C H N requires 176.1439.
12 17
4
.4.4. (2R,6S)-2-Isopropyl-6-phenylpiperidine 24c
Obtained as a pale yellow oil (159 mg, 68% yield). TLC, Rf: 0.45 [(EtOAc:hexane) 1:3];
3
0
-1
ꢀ ꢂ
ꢁ = -65.8 (c=1.33, CHCl ); IR (film) υ /cm : 3085, 3062, 3026, 2933, 2870, 2854, 2787,
ꢃ
3 max
2
712, 1603, 1494, 1453, 1371, 1300, 1113, 753, 699; δ (400 MHz, CDCl ) (ppm) 0.97 (3H,
H 3
d, J=3.6), 0.98 (3H, d, J=3.6), 1.15-1.25 (1H, m), 1.42-1.53 (2H, m), 1.63 (1H, septet, J=6.4),
.70-1.81 (3H, m), 1.91-1.96 (1H, m), 2.45 (1H, ddd, J=2.8, 6.4 and 11.2), 3.66 (1H, dd, ,
1
J=2.4 and 10.4), 7.24-7.28 (1H, m, Ar-H), 7.32-7.36 (2H, m, Ar-H), 7.41-7.44 (2H, m, Ar-
H),; δ (100 MHz, CDCl ) (ppm) 18.92, 19.05, 25.51, 28.53, 33.40, 55.09, 62.60, 63.59,
C
3
+
1
26.74, 126.88, 128.28, 146.11; LC/MS Q-TOF (m/z): [M+H] found 204.1748, C H N
14 21
requires 204.1752.
4
.4.5. (2S,6S)-2-phenyl-6-propylpiperidine 24d
Obtained as a pale yellow oil (201 mg, 86% yield). TLC, Rf: 0.25 [(EtOAc:hexane) 1:3];
30
-1
ꢁ = -52.9 (c=1.33, CHCl ); IR (film) υ /cm : 3310 (N−H), 3064, 3025, 2952, 2929,
ꢀ ꢂ
ꢃ
3 max
2
851, 2789, 2711, 1602, 1493, 1454, 1325, 1303, 1113, 752, 699; δ (400 MHz, CDCl )
H 3
(ppm) 0.94 (3H, t, J=7.2), 1.12-1.22 (1H, m), 1.34-1.54 (5H, m), 1.68-1.74 (1H, m), 1.76-1.81
(1H, m), 1.88-1.92 (2H, m), 2.65-2.71 (1H, m), 3.63-3.67 (1H, m), 7.22-7.41 (5H, m, Ar-H);
δ (100 MHz, CDCl ) (ppm) 14.25, 19.09, 25.41, 32.15, 34.79, 39.59, 57.55, 62.54, 126.75,
C
3
1
2

ACCEPTED MANUSCRIPT
+
1
26.94, 128.30, 145.65; LC/MS Q-TOF (m/z): [M+H] found 204.1755, C H N requires
14
21
2
04.1752.
4
.4.5. (S)-5-methyl-2-phenylpiperidine 27
Obtained as an inseparable 4:1 mixture of diastereomers, dark red oil (123 mg, 61% yield).
3
0
-1
TLC, Rf: 0.19 [(MeOH:DCM) 1:9]; ꢁ = +25.7 (c=1.0, CHCl ); IR (film) υ /cm : 3316
ꢀ ꢂ
ꢃ
3 max
(N−H), 3081, 3058, 3030, 2924, 2868, 2845, 2784, 2733, 1602, 1493, 1454, 1379, 1116, 755,
6
99; major diastereomer : δ (400 MHz, CDCl ) (ppm) 0.89 (3H, d, J=6.8), 1.12-1.22 (1H,
H 3
m), 1.55-1.91 (4H, m), 2.39 (1H, t, J=11.2), 3.11 (1H, dq, J=2 and 11.6), 3.57 (1H, dd, J=2.4
and 11.2), 7.22-7.41 (5H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 19.42, 30.88, 33.93, 34.29,
C
3
5
4.74, 61.71, 126.80, 127.27, 128.41 (two overlapped peaks); minor diastereomer: δ (400
H
MHz, CDCl ) (ppm) 1.13 (3H, d, J=6.8), 1.55-1.91 (4H, m), 2.41 (1H, t, J=11.2), 2.82 (1H,
3
dq, J=1.6 and 11.8), 2.97 (1H, dd, J=3.6 and 12.0), 3.67 (1H, dd, J=3.2 and 10.0), 7.22-7.41
(
1
5H, m, Ar-H); δ (100 MHz, CDCl ) (ppm) 17.25, 27.68, 29.13, 30.46, 51.82, 61.09, 126.70,
26.95, 128.35, 143.98; LC/MS Q-TOF (m/z): [M+H] found 176.1442, C H N requires
12 17
C 3
+
1
76.1439.
Acknowledments
The authors gratefully acknowledges Manisa Celal Bayar University for financial support
through projects (FEF-2014-068 and 2016-036).
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2
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