Natural products as templates for bioactive compound libraries. 3*. novel heterocycles and peptidomimetics generated from anabasine by isocyanide-based multicomponent reactions

Article abstract of DOI:10.1007/s10593-012-1033-z

Anabasine served as a starting material for the synthesis of two series of novel, drug-like compounds. On the one hand, anabasine was subjected to a direct Chichibabin amination and elaborated into medicinally relevant, racemic 6-(piperidin-2-yl)imidazo[1,2-a]pyridines via the Groebke-Blackburn reaction. On the other hand, anabasine was used as an amine for the Ugi reaction to provide novel non-racemic anabasine-containing 2-[(2-pyridin-3-yl)piperidin-1-yl] acetamide peptidomimetics with high diastereoselectivity.

Full text of DOI:10.1007/s10593-012-1033-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
NATURAL PRODUCTS AS TEMPLATES FOR BIOACTIVE
COMPOUND LIBRARIES. 3*. NOVEL HETEROCYCLES
AND PEPTIDOMIMETICS GENERATED FROM ANABASINE
BY ISOCYANIDE-BASED MULTICOMPONENT REACTIONS
Y. Sandulenko1 and M. Krasavin1,2**
Anabasine served as a starting material for the synthesis of two series of novel, drug-like compounds.
On the one hand, anabasine was subjected to a direct Chichibabin amination and elaborated into
medicinally relevant, racemic 6-(piperidin-2-yl)imidazo[1,2-a]pyridines via the Groebke–Blackburn
reaction. On the other hand, anabasine was used as an amine for the Ugi reaction to provide novel non-
racemic anabasine-containing 2-[(2-pyridin-3-yl)piperidin-1-yl]acetamide peptidomimetics with high
diastereoselectivity.
Keywords: anabasine, drug-like compounds, peptidomimetics, diastereoselective reactions, Groebke–
Blackburn reaction, Ugi reaction.
Natural products continue to attract significant research efforts due to their ability to provide valuable
starting points for the development of novel modulators of biomolecule function [2]. It is believed that the
propensity of natural products or natural product-derived compounds to be recognized by a therapeutically
relevant protein molecule is linked to their molecular structure that itself was assembled by a series of
biosynthetic enzymes [4]. Natural products have therefore served not only as precursors for semisynthetic
derivative libraries [1, 3] but also inspired a significant interest in developing synthetic methodologies aimed at
skeletally complex, "natural-like" novel synthetic compounds [5].
The alkaloid anabasine (1) derivatives have been prepared and evaluated as agonists and antagonists of
neuronal nicotinic acetylcholine receptors (nAChR) [6]. Targeting this complex family of neurotransmission
receptors (encompassing many receptor subtypes) has been proposed as a promising approach to the treatment
_______
*For Communication 2, see [1].
**To whom correspondence should be addressed, e-mail: m.krasavin@griffith.edu.au.
1Chemical Diversity Research Institute, 2a Rabochaya St., Khimki 114401, Moscow Region, Russia; e-mail:
ys@chemdiv.com.
2Science and Education Center "Innovative Research", Yaroslavl State Pedagogical University, 108
Respublikanskaya St., Yaroslavl 150000, Russia. Current address: Eskitis Institute for Cell and Molecular
Therapies, Griffith University, N75 Don Young Road, Nathan QLD 4111, Australia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 651-657, April, 2012. Original
article submitted March 2, 2012.
606
0009-3122/12/4804-0606©2012 Springer Science+Business Media, Inc.

of such debilitating neurological disorders as Alzheimer's disease, Parkinson's disease, schizophrenia, and
depression [7]. As the relationship between a specific subtype selectivity of alkaloid modulators of nAChRs and
their pharmacodynamic effects is not well understood, development of novel derivatives of anabasine could
provide not only further insights into this relationship, but also new approaches for the discovery of efficacious
CNS therapies.
If the structure of anabasine (1) is altered significantly via semisynthetic modifications and the affinity
toward nAChRs is lost, such derivatives will still retain their ''natural-likeness'' and will serve as potential
starting points for modulating other important biological processes (such as the known aromatase-inhibiting
activity of anabasine derivatives [8]).
Herein, we describe a novel evolution of natural anabasine (1) core into two distinct novel series of drug-like
alkaloid derivatives using two prominent isocyanide-based multicomponent processes – the Ugi and the Groebke–
Blackburn reactions [9].
Natural anabasine (1) was converted to the racemic 5-(piperidin-2-yl)pyridin-2-amine (2) using a direct
Chichibabin amination procedure, as was described earlier [10]. The racemization took place most likely due to
the harsh conditions of the amination. We viewed the amino pyridine 2 as a starting material for the Groebke–
Blackburn reaction with aldehydes and isocyanides, however, requiring protection of the highly nucleophilic
piperidine nitrogen atom. Protection of compound 2 was achieved by treatment with Boc anhydride in THF, and
the resulting protected derivative 3 was efficiently transformed into a diverse set of imidazo[1,2-a]-pyridi-nes
4a–e using an earlier developed Groebke–Blackburn reaction protocol involving the use of an equimolar
amount of trimethylsilyl chloride as a Lewis acid promoter described by us [11]. Compounds 4a–e were
deprotected (following brief chromatographic fractionation) using a 4 M solution of HCl in dioxane, and the
final secondary amine imidazo[1,2-a]pyridines 5a–e were purified and characterized.
NaNH2
N,N-dimethyl-
Boc2O
THF
aniline
N
N
N
140°C
18 h
12%
H
H
room temp., 18 h
83%
N
H2N
O
OBu-t
H2N
N
N
(+)-1
2
3
R1CHO
R2NC
HCl
Dioxane
N
N
H
. HCl
room temp., 2 h
20–53%
(from 3)
N
1 equiv. TMSCl
MeCN, 70°C
18 h
N
O
N
OBu-t
N
R2
R2
R1
N
H
R1
N
H
4a–e
5a–e
TABLE 1. Anabasine-including Imidazo[1,2-a]pyridines 5a–e Prepared in
This Work
Compound
R1
R2
Yield, %
Ph
t-Bu
53
40
40
25
20
5a
5b
5c
5d
5e
4-ClC6H4
Ph
3,5-(MeO)2C6H3
i-Pr
4-FC6H4
4-FC6H4
3,5-(MeO)2C6H3
Me2CHCH2CH2
607

The notable feature of compound 5a–e is the presence of a secondary amine functionality that may
either insure continued affinity of these compounds to nAChRs (in this case new subtype selectivity profiles
will thus result from the lipophilic appendages in the imidazo nucleus) or be used as a functionality for
introduction of further diversity into these compounds and further optimization of their biological profiles. Due
to the racemization that took place during Chichibabin amination toward compound 2, all compounds 5a–e
(Table 1) were found to be racemic (by the absence of optical rotation compared to the starting (+)-anabasine
((+)-1): []25 = +17.5° (c = 1.00, MeOH), reported values vary significantly in the literature [12]).
The secondary amine functionality of anabasine (1) itself can be viewed as a potential amine component
for the Ugi reaction with aldehydes and isocyanides. However, it is a sterically hindered functionality, and given
its secondary amine character, introducing it efficiently into the Ugi reaction (using the free base anabasine (1))
presented a particular challenge. The traditional methods of performing the Ugi reaction under mineral (H2SO4,
HCl) or Lewis acid (TMSCl, BF3·OEt2, ZnCl2) catalysis gave only negligible conversion into the expected Ugi
adducts. Gratifyingly, the same reaction performed in the presence of an equimolar amount of trifluoroacetic
acid (that we have previously used to promote a similarly challenging hydrazo-Ugi reaction [13]) led to
noticeable (yet still rather low) conversions of anabasine (1) into the dipeptoid-modified compounds 6a–e
(Table 2).
R1CHO, R2NC
N
O
N
*
TFA, dioxane
room temp., 48 h
H
R1
N
NH
N
R2
(+)-1
6a–e
TABLE 2. Anabasine-including Dipeptoids 6a–e Prepared in This Work
Com-
pound
Yield based on
anabasine (1) recovery, %
R1
R2
Isolated yield, %
4-ClC6H4
t-Bu
9
9
64
59
71
56
66
6a
3,5-(MeO)2C6H3
4-MeC6H4
cyclohexyl
Ph
6b
6c
6d
6e
8
Et
4-FC6H4
4-MeC6H4CH2
27
13
5-Methyl-2-thienyl
The Ugi reaction produces an additional stereocenter and, in principle, compounds 6a–e could be
obtained as diastereomeric mixtures. However, most likely due to the sterically demanding amine component
(anabasine) and the low conversions, all compounds 6a–e were obtained as a single diastereomer (with a
1
complete absence of an additional set of signals in the reaction mixture's H NMR spectrum) and without
racemization! Although we were not able to obtain a single crystal of these compounds to unequivocally
establish the relative stereochemistry of these optically active adducts, we have tentatively assigned it as shown
below.
Me
S
Cl
Bu-t
HN
H
HN
H
N
N
H
H
O
O
N
N
Me
(+)-6a
(-)-6e
Through-space interactions observed in NOESY spectra of some of the Ugi adducts 6.
608

These stereochemical assignments are based on the weak through-space interactions between the
methine protons in some of the adducts. Additionally, the diastereomer under consideration has been shown to
have a lower energy compared to the other for all five adducts, as calculated by ChemSoftTM 3D Generator.
In summary, we have established novel routes for evolution of natural anabasine into two
chemotypically distinct drug-like compound series, based on isocyanide multicomponent chemistry. While the
Groebke–Blackburn reaction led to the formation of a fused imidazo cycle, the Ugi reaction produced
distereomerically and optically pure anabasine-including dipeptoids. These compounds can be viewed as
starting points for the development of novel nAChR modulators, as well as other important biological targets.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on Bruker DPX-400 spectrometer (400 and 100 MHz
respectively) in DMSO-d6 using TMS as internal standard. Elemental analyses were obtained at the Research
Institute for Chemical Crop Protection (Moscow, Russia) using a Carlo Erba Strumentazione 1106 analyzer.
Melting points were measured with a Buchi В-520 melting point apparatus and were not corrected. Optical
rotations were measured on a Rudolph APV-6W automatic polarimeter. Analytical thin-layer chromatography was
carried out on EM Separations Technology F254 silica gel plates. Compounds were visualized with short-
wavelength UV light. LCMS analyses were obtained on a PE SCIEX API 150EX mass spectrometer following
separation on a Shimadzu LC-10AD liquid chromatography system equipped with a Shimadzu SP D-10A
UV-Vis detector (254 nm) and Sedex 75 ELSD detector. All solvents and reagents were obtained from
commercial sources and used without purification. All reactions were run in oven-dried glassware in an
atmosphere of nitrogen.
(±)-5-(Piperidin-2-yl)pyridin-2-amine (2). A mixture of (S)-anabasine ((+)-1) hydrochloride (3.0 g, 15.1
mmol) and NaNH2 (1.8 g, 46.1 mmol) was stirred at 140°C in freshly distilled of N,N-dimethylaniline (10 ml) for
18 h. It was then cooled to room temperature and carefully quenched with water (50 ml). The aqueous phase
was extracted with ether (4–5×50 ml), and the combined extracts were dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. Repeated chromatography on silica allowed for a nearly complete separation of the
desired product from the unreacted anabasine ((+)-1) and the isomeric 3-(piperidin-2-yl)pyridin-2-amine. Yield
1
319 mg (12%). Yellow viscous oil. [α]25 +0.05° (c = 1.00, MeOH). H NMR spectrum, ppm: 8.12 (1H, s,
589
H-2); 7.55-7.51 (1H, m, H-4); 6.55-6.50 (1H, m, H-5); 4.78 (2H, br. s, NH2); 4.47-4.42 (1H, m, 2'-CH);
2.97-2.81 (2H, m, 6'-CH2); 2.03-1.42 (6H, m, 3',4',5'-CH2). 13C NMR spectrum, , ppm: 161.3; 147.0; 139.2;
134.3; 107.5; 58.4; 48.2; 34.9; 25.6; 25.1. Mass spectrum, m/z: 178.6 [M+H]+. Found, %: C 67.81; H 8.55;
N 23.71. C10H15N3. Calculated, %: C 67.76; H 8.53; N 23.71.
(±)-tert-Butyl 2-(6-Aminopyridin-3-yl)piperidine-1-carboxylate (3). A mixture of compound 2
(1.83 g, 10.3 mmol) prepared as described in [9] and Boc2O (2.25 g, 10.3 mmol) in THF (20 ml) was stirred at
room temperature for 18 h. The solvent was removed under reduced pressure and the residue was triturated with
1
hexane and dried in vacuo. Yield 2.37 g (83%). White foam. H NMR spectrum, ppm: 8.03 (1H, s, H-2');
7.69-7.64 (1H, m, H-4'); 6.54-6.47 (1H, m, H-5'); 5.33-5.27 (1H, m, 2-CH); 4.71 (2H, br. s, NH2); 3.48-3.33
(2H, m, 6-CH2); 1.72-1.32 (6H, m, 3,4,5-CH2); 1.53 (9H, s, C(CH3)3). 13C NMR spectrum, ppm: 154.2; 154.0;
148.4; 135.3; 129.7; 107.8; 80.0; 57.2; 40.2; 33.1; 28.1; 25.8; 20.2. Mass spectrum, m/z: 278.4 [M+H]+. Found,
%: C 65.04; H 8.44; N 15.23. C15H23N3O2. Calculated, %: C 64.96; H 8.36; N 15.15.
Imidazo[2,1-a]pyridines 5a–e (General Method). A mixture of amine 3 (100 mg, 0.36 mmol) and
aldehyde (0.36 mmol) in anhydrous acetonitrile (2 ml) was stirred at 80°C under argon for 2 h. Isocyanide
(0.36 mmol) and Me3SiCl (39 mg, 0.36 mmol) were added to the mixture and the stirring continued at 70°C for
additional 18 h. The solvent was removed under reduced pressure, the residue was diluted with CH2Cl2 (25 ml)
and 10% aqueous Na2CO3 (25 ml), and the biphasic mixture was transferred into a separatory funnel. The organic
609

layer was separated, and the aqueous layer was extracted with CH2Cl2 (225 ml). The combined organic solutions
were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was subjected to
chromatography on silica gel using mixtures of EtOAc–hexane of appropriate polarity (20–60%). The fractions
enriched in the target compounds (as evidenced by TLC and verified by LC-MS) were combined, the solvent
was evaporated, and the residue was dissolved in a minimum amount of dioxane, and 4 M HCl solution in
dioxane (2 ml) was added. After stirring at room temperature for 2 h, the solvent was removed in vacuo and the
residue was crystallized from MeOH to provide the desired compound as hydrochloride salt.
(±)-N-(tert-Butyl)-2-phenyl-6-(piperidin-2-yl)imidazo[1,2-a]pyridin-3-amine Hydrochloride (5a).
1
Mp = 138-139°C (MeOH). H NMR spectrum, ppm (J, Hz): 10.01 (1H, br. s) and 9.59 (1H, br. s, N+H2); 9.01
(1H, s, t-BuNH); 8.09 (2H, m, H-5,7); 8.04-7.98 (1H, m, H-8); 7.93-7.86 (1H, m, H Ph); 7.59-7.41 (4H, m,
H Ph); 4.55-4.49 (1H, m, 2'-CH); 3.05-2.97 (1H, m) and 2.12-1.59 (7H, m, 3',4',5',6'-CH2); 1.01 (9H, s,
C(CH3)3). 13C NMR spectrum, ppm: 137.1; 131.4; 131.1; 129.2; 128.8; 128.5; 128.2; 126.2; 125.4; 124.9;
112.8; 69.8; 56.8; 56.2; 44.9; 29.7; 22.46; 21.0. Mass spectrum, m/z: 386.0 [M+H]+. Found, %: C 68.73; H 7.71;
N 14.63. C22H29ClN4. Calculated, %: C 68.64; H 7.59; N 14.55.
(±)-2-(4-Chlorophenyl)-N-phenyl-6-(piperidin-2-yl)imidazo[1,2-a]pyridin-3-amine Hydrochloride
1
(5b). Mp = 127-130°C (MeOH). H NMR spectrum, ppm (J, Hz):9.38-9.08 (2H, m, N+H2); 8.65 (1H, s,
H-5); 8.58 (1H, s, NHAr); 8.14-7.91 (4H, m, H Ph); 7.58 (2H, d, J = 8.6, H-3,5 Ar); 7.21-7.16 (2H, m, H-7,8);
6.84-6.76 (1H, m, H Ph); 6.70 (2H, d, J = 8.6, H-2,6 Ar); 4.53-4.49 (1H, m, 2'-CH); 3.43 (1H, d, J = 12.5) and
3.07-3.02 (1H, m, 6'-CH2); 2.02-1.54 (6H, m, 3',4',5'-CH2). 13C NMR spectrum, ppm: 144.3; 138.5; 134.4;
130.9; 129.5; 129.1; 128.5; 126.8; 126.3; 123.8; 121.1; 119.6; 117.6; 114.1; 113.5; 56.6; 44.9; 29.3; 22.3; 21.2.
Mass spectrum, m/z: 440.1 [M+H]+. Found, %: C 65.79; H 5.55; N 12.73. C24H24Cl2N4. Calculated, %: C 65.61;
H 5.51; N 12.75.
(±)-N-(4-Fluorophenyl)-2-(3,5-dimethoxyphenyl)-6-(piperidin-2-yl)imidazo[1,2-a]pyridin-3-amine
1
Hydrochloride (5c). Mp = 145-147°C (MeOH). H NMR spectrum, , ppm (J, Hz): 9.01 (1H, s, NHAr); 8.68
(2H, d, J = 12.6, N+H2); 8.11 (2H, dd, J = 30.6, J = 8.9, H-3,5 4-FC6H4); 7.80-7.70 (2H, m, H-5,7); 7.13 (2H, d,
J = 1.9, H-2,6 3,5-(MeO)2C6H3); 7.03 (2H, t, J = 8.9, H-2,6 4-FC6H4); 6.75-6.73 (1H, m, H-8); 6.62-6.57 (1H,
m, H-4 3,5-(MeO)2C6H3); 4.63-4.52 (1H, m, 2'-CH); 3.84 (6H, s, 2OCH3); 3.18-3.06 (2H, m, 6'-CH2); 2.10-1.56
(6H, m, 3',4',5'-CH2). 13C NMR spectrum, ppm (J, Hz): 160.8; 156.3 (d, JC–F = 235.5); 140.9; 137.9; 131.5;
130.7; 128.6; 126.7; 123.7; 121.3; 115.9 (d, JC–F = 22.8); 144.7 (d, JC–F = 7.4); 113.6; 104.8; 101.9; 56.6; 55.2;
44.9; 29.3; 22.2; 21.2. Mass spectrum, m/z: 483.8 [M+H]+. Found, %: C 64.74; H 5.89; N 11.72.
C26H28ClFN4O2. Calculated, %: C 64.66; H 5.84; N 11.60.
(±)-N-(4-Fluorophenyl)-2-isopropyl-6-(piperidin-2-yl)imidazo[1,2-a]pyridin-3-amine Hydrochloride
1
(5d). Mp = 116-118°C (MeOH). H NMR spectrum, ppm (J, Hz): 9.38-9.29 (1H, m) and 9.28-9.12 (1H, m,
N+H2); 8.55 (1H, s, NHAr); 8.34 (1H, s, H-5); 8.15-8.02 (2H, m, H-3,5 Ar); 7.02 (2H, t, J = 8.9, H-2,6 Ar);
6.74-6.64 (2H, m, H-7,8); 4.61-4.45 (1H, m, H-2'); 3.43 (1H, d, J = 12.8) and 3.09-2.93 (1H, m, 6'-CH2); 3.15
(1H, sept, J = 6.7, CHMe2); 1.88-1.49 (6H, m, 3',4',5'-CH2); 1.29 (6H, d, J = 6.7, CH(CH3)2). 13C NMR spectrum,
ppm (J, Hz):156.2 (d, JC–F = 234.9); 141.7; 137.9; 137.0; 131.7; 127.1; 123.7; 120.6; 115.8 (d, JC–F = 22.2);
114.5 (d, JC–F = 8.0); 112.9; 56.4; 44.9; 29.4; 24.5; 22.2; 21.2; 20.8. Mass spectrum, m/z: 389.9 [M+H]+. Found,
%: C 64.91; H 6.83; N 14.47. C21H26ClFN4. Calculated, %: C 64.85; H 6.74; N 14.41.
(±)-2-(3,5-Dimethoxyphenyl)-N-(3-methylbutyl)-6-(piperidin-2-yl)imidazo[1,2-a]pyridin-3-amine
Hydrochloride (5e). Mp = 128-130°C (MeOH; decomp.). 1H NMR spectrum, ppm (J, Hz): 9.60-9.49 (1H, m)
and 9.47-9.40 (1H, m, N+H2); 8.89 (1H, s, NHAlk); 8.35 (1H, s, H-5); 8.04-7.98 (2H, m, H-7,8); 7.20 (2H, d,
J = 2.2, H-2,6 Ar); 6.64 (1H, s, H-4 Ar); 4.63-4.52 (1H, m, 2'-CH); 3.84 (6H, s, 2OCH3); 3.47 (1H, d, J = 11.3)
and 3.18-3.06 (1H, m, 6'-CH2); 3.02 (2H, t, J = 6.6, NHCH2CH2CHMe2); 2.10-1.56 (7H, m, 3',4',5'-CH2, CHMe2);
1.44 (2H, q, J = 7.5, CHCH2CH2CHMe2); 0.81 (6H, d, J = 6.4, CH(CH3)2). 13C NMR spectrum, , ppm: 160.8;
136.1; 131.5; 128.9; 128.5; 126.5; 125.7; 124.1; 112.6; 105.2; 101.5; 56.6; 55.4; 45.1; 44.9; 38.8; 29.2; 25.1;
22.2 (2C); 21.2. Mass spectrum, m/z: 460.3 [M+H]+. Found, %: C 65.32; H 7.59; N 12.17. C25H35ClN4O2.
Calculated, %: C 65.41; H 7.69; N 12.21.
610

Anabasine-including Dipeptoids 6a–e (General Method). TFA (3.08 mmol) was added to a mixture
of natural anabasine free base ((+)-1) (500 mg, 3.08 mmol), aldehyde (3.08 mmol), and isocyanide (3.08 mmol)
in dioxane (5 ml). The mixture was stirred at room temperature for 48 h. The solvent was removed under
reduced pressure, the residue was dissolved in CH2Cl2 (5 ml), and the solution was stirred with sat. aq. NaHCO3
(3 ml) for 2 h. The organic layer was separated and dried over anhydrous Na2SO4, and the product was isolated
by silica gel chromatography (eluent 5–10% THF–CH2Cl2).
(+)-N-(tert-Butyl)-2-(4-chlorophenyl)-2-[2-(pyridin-3-yl)piperidin-1-yl]acetamide (6a). Viscous oil.
1
[α]25 +28.9° (c = 1.00, MeOH). H NMR spectrum, ppm (J, Hz): 8.50 (1H, br. s, H-2 Py); 8.37-8.28 (1H,
589
m, H-6 Py); 7.67 (1H, d, J = 8.0, H-4 Py); 7.29-7.13 (5H, m, H Ar, H-5 Py); 5.42-5.30 (1H, m, CONH); 4.00 (1H,
s, CHCO); 3.79 (1H, dd, J = 10.3, J = 2.1, 2-CH piperidine); 2.90-2.71 (2H, m, 6-CH2 piperidine); 1.80-1.37 (6H,
m, 3,4,5-CH2 piperidine); 1.30 (9H, s, C(CH3)3). 13C NMR spectrum, ppm: 168.9; 148.7; 148.0; 139.2; 135.8;
134.6; 132.6; 129.1; 127.8; 123.0; 66.4; 62.5; 50.9; 46.7; 36.0; 28.2; 25.5; 24.1. Mass spectrum, m/z: 386.1
[M+H]+. Found, %: C 68.44; H 7.25; N 10.73. C22H28ClN3O. Calculated, %: C 68.47; H 7.31; N 10.89.
(+)-N-Cyclohexyl-2-(3,5-dimethoxyphenyl)-2-[2-(pyridin-3-yl)piperidin-1-yl]acetamide
(6b).
Amorphous solid. [α]25589 +10.6° (c = 1.00, MeOH). Mp 67–69°C. 1H NMR spectrum, ppm (J, Hz): 8.49 (1H,
br. s, H-2 Py); 8.31-8.21 (1H, m, H-6 Py); 7.65 (1H, d, J = 7.7, H-4 Py); 7.12 (1H, dd, J = 8.2, J = 4.8, H-5 Py);
6.48 (2H, d, J = 1.6, H-2,6 Ar); 6.31-6.25 (1H, m, H Ar); 5.76-5.58 (1H, m, CONH); 4.08 (1H, s, CHCO);
3.85-3.74 (2H, m, 2-CH piperidine, CONHCH); 3.68 (6H, s, 2OCH3); 2.95-2.67 (2H, m, 6-CH2 piperidine);
1.91-1.23 (13H, m, 3,4,5-CH2 piperidine, H c-Hex); 1.14-0.89 (3H, m, H c-Hex). 13C NMR spectrum,
ppm:168.6; 160.1; 148.6; 147.7; 139.4; 134.6; 123.0; 105.7; 104.1; 98.6; 66.8; 62.1; 54.6; 47.3; 47.0; 35.7;
32.5; 25.4; 24.8; 24.3; 24.2 (2C); 24.0. Mass spectrum, m/z: 438.8 [M+H]+. Found, %: C 71.48; H 8.14; N 9.66.
C26H35N3O3. Calculated, %: C 71.37; H 8.06; N 9.60.
(–)-2-(4-Methylphenyl)-N-phenyl-2-[2-(pyridin-3-yl)piperidin-1-yl]acetamide (6c). Brown viscous
1
oil. [α]25 -1.5° (c = 1.00, MeOH). H NMR spectrum, ppm (J, Hz): 8.65-8.38 (1H, m, H-2 Py); 8.48 (1H,
589
br. s, CONH); 8.20 (1H, d, J = 4.5, H-6 Py); 7.75 (1H, br. s, H-4 Py); 7.50 (2H, d, J = 7.7, H Ar); 7.39-7.24
(4H, m, H Ar, H Ph, H-5 Py); 7.19-7.05 (4H, m, H Ph); 4.48 (1H, s, CHCO); 3.95 (1H, d, J = 7.7, 2-CH
piperidine); 3.15–2.91 (2H, m, 6-CH2 piperidine); 2.34 (3H, s, 4-CH3C6H4); 1.86-1.40 (6H, m, 3,4,5-CH2
piperidine). 13C NMR spectrum, ppm:169.1; 148.5; 147.7; 139.2; 137.2; 137.0; 135.2; 133.3; 128.7; 128.4;
128.1; 123.7; 123.1; 119.4; 67.4; 62.3; 46.8; 35.2; 25.3; 23.9; 20.6. Mass spectrum, m/z: 386.6 [M+H]+. Found,
%: C 77.77; H 6.98; N 10.82. C25H27N3O. Calculated, %: C 77.89; H 7.06; N 10.90.
(–)-N-(4-Fluorophenyl)-2-[2-(pyridin-3-yl)piperidin-1-yl]butanamide (6d). Beige solid. Mp 86-88°C
1
(EtOAc). [α]25 -179.4° (c = 1.00, MeOH). H NMR spectrum, ppm (J, Hz): 8.43 (1H, br. s, H-2 Py);
589
8.26-8.09 (2H, m, CONH, H-6 Py); 7.68 (1H, d, J = 7.8, H-4 Py); 7.45-7.37 (2H, m, H Ar); 7.24-7.15 (1H, m,
H-5 Py); 6.94 (2H, t, J = 8.5, H Ar); 3.59 (1H, dd, J = 10.6, J = 2.5, CHCO); 3.20 (1H, d, J = 12.1, 2-CH piperidine);
3.01 (1H, t, J = 7.4) and 2.78 (1H, t, J = 11.5, 6-CH2 piperidine); 1.86-1.21 (8H, m, 3,4,5-CH2 piperidine, CH3CH2);
13
0.93 (3H, t, J = 7.4, CH3CH2). C NMR spectrum, ppm (J, Hz):169.9; 158.7 (d, JC–F = 243.5); 148.4; 147.8;
139.8; 135.0; 133.2; 123.2; 121.3 (d, JC–F = 8.0); 114.9 (d, JC–F = 22.8); 65.1; 62.9; 46.2; 37.2; 25.8; 24.2; 22.1;
10.5. Mass spectrum, m/z: 342.5 [M+H]+. Found, %: C 70.41; H 7.19; N 12.47. C20H24FN3O. Calculated, %:
C 70.36; H 7.09; N 12.31.
N-(4-Methylbenzyl)-2-(5-methyl-2-thienyl)-2-[2-(pyridin-3-yl)piperidin-1-yl]acetamide (6e). Off-
1
white solid. Mp 101-103°C (EtOAc; decomp.). [α]25 -9.7° (c = 1.00, MeOH). H NMR spectrum, ppm (J,
589
Hz): 8.23-8.10 (1H, m, H-2 Py); 8.05-7.93 (1H, m, H-6 Py); 7.71 (1H, d, J = 7.8, H-4 Py); 7.25-6.98 (6H, m,
4-MeC6H4, H-5 Py, CONH); 6.63 (1H, d, J = 3.4, H-4 thiophene); 6.52 (1H, dd, J = 3.4, J = 1.1,
H-3 thiophene); 4.33 (2H, dd, J = 14.7, J = 5.8) and 4.39 (2H, dd, J = 14.7, J = 5.8, 4-MeC6H4CH2); 4.35 (1H, s,
CHCO); 3.73 (1H, d, J = 8.1, 2-CH piperidine); 3.15 (1H, d, J = 12.1) and 2.75 (1H, t, J = 12.1, 6-CH2 piperidine);
2.40 (3H, s, 5-CH3 thiophene); 2.31 (3H, s, 4-CH3C6H4); 1.81-1.35 (6H, m, 3,4,5-CH2 piperidine). 13C NMR
spectrum, ppm:168.4; 148.3; 147.6; 139.9; 139.4; 139.0; 136.5; 134.8; 134.4; 128.7; 127.5; 125.1; 124.3;
611

123.0; 62.9; 62.4; 47.3; 42.5; 36.5; 25.5; 24.3; 20.5; 14.7. Mass spectrum, m/z: 420.7 [M+H]+. Found, %:
C 71.56; H 7.03; N 10.06. C25H29N3OS. Calculated, %: C 71.56; H 6.97; N 10.01.
This research was supported by the Federal Agency for Science and Innovation (Russian Federation
Government Contract 02.740.11.0092).
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