Simple and effective synthetic approach to chiral 2-amino-4-piperidinyl pyridine derivatives

Article abstract of DOI:10.1080/00397911.2011.565453

(Chemical Equation Presented) A facile way has been developed to provide a series of novel chiral N-(4- (piperidin-1-yl)pyridin-2-yl)amide derivatives as potential stereoselective catalysts. The key intermediate, 2-amino-4-piperidinyl pyridine, was obtained by nucleophilic substitution of 2-amino-4-chloropyridine with piperidine in good yields (up to 96%). The total control of enantioselectivity was obtained for the synthesis of L-proline and (R)-1,10-bi(2-naphthol) derivatives. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.565453

Synthetic Communications1, 42: 2707–2714, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.565453
SIMPLE AND EFFECTIVE SYNTHETIC APPROACH TO
CHIRAL 2-AMINO-4-PIPERIDINYL PYRIDINE
DERIVATIVES
Hua Tian, Qing-Wen Liu, Hao Xu, Wen-Bo Huang, Jian Lin,
and Suo-Qin Zhang
Department of Chemistry, Jilin University, Changchun, China
GRAPHICAL ABSTRACT
Abstract A facile way has been developed to provide a series of novel chiral N-(4-
(piperidin-1-yl)pyridin-2-yl)amide derivatives as potential stereoselective catalysts. The
key intermediate, 2-amino-4-piperidinyl pyridine, was obtained by nucleophilic substitution
of 2-amino-4-chloropyridine with piperidine in good yields (up to 96%). The total control of
enantioselectivity was obtained for the synthesis of L-proline and (R)-1,10-bi(2-naphthol)
derivatives.
Keywords 2-Amino-4-piperidinyl pyridine; chiral catalysts; DMAP; PPY
INTRODUCTION
In past decades, 4-dimethylaminopyridine (DMAP) and 4-pyrrolidinopyridine
(PPY) have been extensively used as potential nucleophilic catalysts in acylation
reactions and related transformations.[1–6] Because chiral DMAP and PPY deriva-
tives have been successfully employed as chiral nucleophilic catalysts in a wide range
of asymmetric synthetic processes,[7–14] various chiral 4-(N,N-disubstituted-amino)
pyridine derivatives have been described over the years.[15–20] Such compounds
Received December 16, 2010.
Address correspondence to Suo-Qin Zhang, Department of Chemistry, Jilin University,
Changchun 130012, China. E-mail: suoqin@jlu.edu.cn
2707

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H. TIAN ET AL.
Figure 1. Structure of compounds 1a–1f.
require the presence of a stereogenic center to induce stereoselectivity during the cata-
lytic process.[21–24] However, preparation of these new catalysts tends to involve com-
plex routes of synthesis and does not generally allow facile structural modifications.
This article describes a simple and effective synthetic approach to chiral
2-amino-4-piperidinyl pyridine derivatives (Fig. 1).
RESULTS AND DISCUSSION
Our approach is based on the design of a convenient synthetic way to chiral
2-amino-4-piperidinyl pyridine derivatives, which will allow rapid optimization. Fur-
thermore, the stereogenic centers are positioned distant from the catalytic site (the
nitrogen atom of the pyridinyl group) to avoid the reactivity problem. The general
structure for this new family of N-(4-(piperidin-1-yl) pyridin-2-yl) amide derivatives
1 is represented in Scheme 1.
The synthesis of compound 4 (Scheme 1) has already been described in the
literature.[25] Initially, a synthetic route reported by Badawneh et al.[26] was applied
to synthesize target compounds (Scheme 1). Intermediates 2 were prepared through
the acylation reaction of 2-amino-4-chloropyridine with corresponding acid chloride.
Subsequent nucleophilic substitution of the 4-chlorosubstituent with excess piperi-
dine afforded the target compounds 1. Because of poor yields (total yield no more
than 35%), an alternative strategy was applied to synthesize target molecules, which
is shown in Scheme 2. Intermediate 2-amino-4-piperidinyl pyridine 3 was synthesized
Scheme 1. First synthetic route of compounds 1a–1f. Reagents and conditions: (i) N-protected L-prolyl
chloride=(R)-1,10-binaphthyl-2,20-diylphosphorochloridate=(R)-[1,10-binaphthalene]-2,2-disulfonyl dichlo-
ride, N(Et)3, DCM, 0–5 ꢀC, rt, 6 h; (ii) piperidine, 160 ꢀC, 24h.

2-AMINO-4-PIPERIDINYL PYRIDINE DERIVATIVES
2709
Scheme 2. Second synthetic route of compounds 1a–1f. Reagents and conditions: (i) piperidine, autoclave,
250 ꢀC, 48 h; (ii) N-protected L-prolyl chloride (R)-1,10-binaphthyl-2,20-diylphosphorochloridate=(R)-
[1,10-binaphthalene]-2,2-disulfonyl dichloride, N(Et)3, DCM, 0–5 ꢀC, rt, 15 h.
by nucleophilic substitution of 2-amino-4-chloropyridine with piperidine as structure
backbone. Then, the desired compounds were obtained with excellent yield (total
yield up to 80%).
Apparently, the synthesis of compound 3 has become a key point in the whole
synthetic route 2. In the structure of compound 4, an amino group is substituted at
C-2 position of pyridine, which made the nucleophilic substitution at C-4 position
much more difficult. Therefore, some optimization work has been done, which is
summarized in Table 1.
As shown in Table 1, when the mixture of 2-amino-4-chloropyridine and pip-
eridine was heated up to 105 ꢀC for 24 h in the presence of a series of bases (entries
1–3), the reaction did not proceed. However, when the reaction mixture was taken
into an autoclave and heated up to 200 ꢀC for 24 h without any base, the product
was obtained, in a yield of 43%. Through optimizing of process conditions, such
as temperature and reaction time, the desired compound 3 was obtained, which
Table 1. Reaction of 2-amino-4-chloropyridine with piperidine
Entry
Base
Temp. (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
K2CO3
NaOH
Cs2CO3
None
105
105
105
200
250
250
300
24
24
24
24
24
48
48
<1
<1
<1
43a,b
,
None
None
None
60a b
89a,b
86a,b
aIsolated yield after silica-gel column chromatography.
bReacted in an autoclave.

2710
H. TIAN ET AL.
was suitable for use in the next step without any further purification in a greatly
increased yield of 96% (entry 6).
Then, compound 3 was coupled with corresponding acid chloride to yield
chiral 2-amino-4-piperidinyl pyridine derivatives 1a–1f in an enantiomercally pure
form (ee ¼ 100%). Our first attempt was to obtain N-protected derivatives of
L-proline amide 1a, 1b, 1c, and 1d. The synthesis of 1a was carried out as outlined
in Scheme 2. Treatment of N-benzyloxycarbonyl-L-proline with thionyl chloride
furnished the corresponding acid chloride, which was then coupled with 3 to afford
amide 1a in yields of 80%. In a similar fashion, 1b, 1c, and 1d were obtained in yields
of 80%, 75%, and 72% respectively. With a view toward maximizing both catalyst
rigidity and potential for p–p interaction, (R)-1,10-bi(2-naphthol)-derived structures
(1e and 1f) were synthesized in yields of 84% and 90% respectively.
CONCLUSION
In conclusion, the key intermediate 2-amino-4-piperidinyl pyridine 3 has been
successfully synthesized with excellent yield. A simple and effective synthetic route
for the preparation of a family of novel chiral N-(4-(piperidin-1-yl) pyridin-2-yl)
amide derivatives 1 has been developed. These six compounds are closely related
to DMAP but contain a stereogenic center. An investigation of the catalytic proper-
ties of these interesting molecules will be reported in due course.
EXPERIMENTAL
Infrared (IR; KBr pellets) spectra were recorded in the 350–4000 cmꢁ1 range on
a Perkin-Elmer spectrophotometer. Elemetal analyses (C, H, and N) were performed
1
on a Perkin-Elmer 2400 CHN elemental analyzer. All H NMR spectra (300 MHz)
were reported as chemical shifts downfield with tetramethylsilane (TMS) as internal
standard (d scale) and CDC13 as the solvent. All 13C NMR spectra (75 MHz) were
determined with complete proton decoupling and reported in d. The enantiomeric
excess was determined by chiral high-performance liquid chromatogrephy (HPLC)
with Daicel Chiralpak AD-H (4.6 mm ꢂ 250 mm) column. All reagents and solvents
for the reactions were of analytical grade and were dried and distilled if necessary.
2-Amino-4-piperidinyl Pyridine (3)
An autoclave was charged with 2-amino-4-chloropyridine (2.7 g, 21.0 mmol)
and piperidine (30.0 mL, 0.28 mol). The reaction mixture was placed in a 250 ꢀC
preheated oven for 48 h, and then cooled to ambient temperature. The residue pip-
eridine was removed by rotary evaporation and gentle heating. Purification of the
residue by flash column chromatography with DCM=MeOH (10:1) gave 3.3 g
(89%) 2-amino-4-piperidinyl pyridine as a yellow oil. IR (KBr): n 3450, 3171,
1
3154 cmꢁ1. H NMR (300 MHz, CDCl3), d: 7.56 (d, J ¼ 9.0 Hz, 1H), 6.20–6.17 (m,
1H), 5.95–5.87 (m, 1H), 5.49 (br s, 2H), 3.36–3.31 (m, 4H), 1.65–1.59 (m, 6H). 13C
NMR (75 MHz, CDCl3), d: 156.6, 156.5, 140.0, 100.7, 89.9, 47.3, 25.4, 24.0. (EI)
m=z 178 (relintensity) (Mþ þ 1) Analysis calculated for C10H15N3: C, 67.76, H,
8.53; N, 23.71. Found: C, 67.80; H, 8.54; N, 23.69.

2-AMINO-4-PIPERIDINYL PYRIDINE DERIVATIVES
2711
General Procedure for Preparing of Compounds 1a–1d
A mixture of N-protected L-proline (6.0 mmol) and thionyl chloride (10 mL)
was refluxed for 3 h. Thionyl chloride was removed by rotary evaporation and gentle
heating. The resulting residue was taken into dichloromethane (DCM) (5 mL) and
then cooled to 0 ꢀC, and a solution of 2-amino-4-piperidinylpyridine (5.0 mmol)
and triethylamine (TEA) (6.0 mmol) in dichloromethane was added dropwise over
30 min. The solution was allowed to warm to room temperature and stirred for an
additional 15 h. The organic layer was washed with brine (2 ꢂ 20 mL) and dried over
anhydrous Na2SO4. After the removal of solvent under reduced pressure, the residue
was purified through column chromatography on silica gel (DCM=MeOH 10:1) to
give 1a–1d as a white solid.
(S)-Benzyl-2-((4-(piperidin-1-yl)pyridin-2-yl)carbamoyl)pyrrolidine-
1-carboxylate (1a)
20
White solid, mp. 124.2–126.0 ꢀC. ½aꢃD ¼ ꢁ109(c ¼ 0.5, CHCl3). IR (KBr): n
1
3276, 2936, 2855, 1694 cmꢁ1. H NMR (300 MHz, CDCl3), d: 9.02 (br s, 1H), 7.92
(d, J ¼ 6.0 Hz, 1H), 7.72 (s, 1H), 7.37–7.19 (m, 5H), 6.43 (d, J ¼ 3.0 Hz, 1H),
5.27–5.09 (m, 2H), 4.50–4.33 (m, 1H), 3.57–3.43 (m, 2H), 3.39–3.34 (m, 4H),
2.36–2.17 (m, 1H), 2.07–1.89 (m, 3H), 1.68–1.59 (m, 6H). 13C NMR (75 MHz,
CDCl3), d: 170.6, 156.5, 152.3, 152.2, 147.7, 136.2, 128.2, 128.0, 127.8, 104.9, 97.6,
67.2, 61.3, 47.2, 46.9, 29.0, 25.0, 24.4, 24.2. (EI) m=z 409 (rel. intensity) (Mþ þ 1).
Analysis calculated for C23H28N4O3: C, 67.63; H, 6.91; N, 13.72; O, 11.75. Found:
C, 67.70; H, 6.80; N, 13.69; O, 11.80.
(S)-tert-Butyl-2-((4-(piperidin-1-yl)pyridin-2-yl)carbamoyl)-
pyrrolidine-1-carboxylate (1b)
20
White solid, mp 45–47 ꢀC. ½aꢃD ¼ ꢁ62(c ¼ 0.5, CHCl3). IR (KBr): n 3252, 2940,
1
2864, 1699, 1300 cmꢁ1. H NMR (300 MHz, CDCl3), d: 9.06 (br s, 1H), 7.89 (d,
J ¼ 6.0 Hz, 1H), 7.75 (d, J ¼ 3.0 Hz, 1H), 6.43–6.41 (m, 1H), 4.46–4.22 (m, 1H),
3.53–3.36 (m, 6H), 2.25–2.11 (m, 1H), 1.96–1.86 (m, 3H), 1.68–1.60 (m, 6H), 1.45
(s, 9H).13C NMR (75 MHz, CDCl3), d: 170.1, 156.3, 153.6, 152.2, 147.5, 104.6,
97.0, 80.0, 61.3, 56.5, 47.0, 29.4, 28.1, 24.8, 24.2, 24.0. (EI) m=z 375 (rel. intensity)
(Mþ þ 1). Analysis calculated for C20H30N4O3: C, 64.15; H, 8.07; N, 14.96; O,
12.82. Found: C, 64.23; H, 8.00; N, 14.69; O, 12.80.
(S)-1-(2-(Naphthalen-1-yl)acetyl)-N-(4-(piperidin-1-yl)pyridin-
2-yl)pyrrolidine-2-carboxamide (1c)
20
White solid, mp 169.7–171.0 ꢀC. ½aꢃD ¼ ꢁ82(c ¼ 0.5, CHCl3). IR (KBr): n 3202,
1
2938, 2879, 1697, 1656, 783 cmꢁ1. H NMR (300 MHz, CDCl3), d: 9.34 (br s, 1H),
8.02–7.99 (m, 1H), 7.92 (d, J ¼ 6.0 Hz, 1H), 7.87–7.83 (m, 1H), 7.78–7.75 (m, 1H),
7.67 (d, J ¼ 3.0 Hz, 1H), 7.52–7.47 (m, 2H), 7.41 (d, J ¼ 3.0 Hz, 1H), 7.39 (s, 1H), 6.42–
6.39 (m, 1H), 4.76–4.73 (m, 1H), 4.17 (d, J ¼ 1.5 Hz, 2H), 3.53–3.48 (m, 1H),
3.40–3.30 (m, 5H), 2.37–2.31 (m, 1H), 2.09–1.92 (m, 3H), 1.68–1.60 (m, 6H).

2712
H. TIAN ET AL.
13C NMR (75 MHz, CDCl3), d: 170.9, 170.2, 156.5, 152.4, 147.7, 133.7, 132.1, 130.6,
128.5, 127.6, 126.7, 126.2, 125.6, 125.4, 123.6, 104.8, 97.7, 61.1, 47.7, 47.3, 39.5, 28.1,
25.1, 24.9, 24.2. (EI) m=z 443 (rel. intensity) (Mþ þ 1). Analysis calculated for
C27H30N4O2: C, 73.28; H, 6.83; N, 12.66; O, 7.23. Found: C, 72.3; H, 6.80; N,
12.69; O, 7.25.
(S)-1-(2-(Naphthalen-2-yl)acetyl)-N-(4-(piperidin-1-yl)pyridin-2-yl)
pyrrolidine-2-carboxamide (1d)
20
White solid, mp 86–88 ꢀC. ½aꢃD ¼ ꢁ122(c ¼ 0.5, CHCl3). IR (KBr): n 3215,
1
2958, 2880, 1696, 1664, 785 cmꢁ1. H NMR (300 MHz, CDCl3), d: 9.38 (br s, 1H),
7.92 (d, J ¼ 6.0 Hz, 1H), 7.80–7.67 (m, 5H), 7.46–7.42 (m, 3H), 6.42–6.39 (m, 1H),
4.75–4.72 (m, 1H), 3.92 (s, 2H), 3.72–3.64 (m, 1H), 3.55–3.47 (m, 1H), 3.40–3.30
(m, 4H), 2.38–2.31 (m, 1H), 2.14–1.88 (m, 3H), 1.68–1.59 (m, 6H). 13C NMR
(75 MHz,CDCl3), d: 171.1, 169.9, 156.6, 152.4, 148.0, 133.4, 132.3, 131.6, 128.3,
127.6, 127.5, 127.4, 127.2, 125.9, 125.6, 104.9, 97.6, 61.0, 47.6, 47.3, 42.1, 27.8,
25.1, 24.9, 24.3. (EI) m=z 443 (rel. intensity) (Mþ þ 1). Analysis calculated for
C27H30N4O2: C, 73.28; H, 6.83; N, 12.66; O, 7.23. Found: C, 72.32; H, 6.84; N,
12.60; O, 7.30.
(4R)-4-((4-(Piperidin-1-yl)pyridin-2-yl)amino)dinaphtho[2,1-d:
1’,2’-f][1,3,2]dioxaphosphepine-4-oxide (1e)
1,10-Binaphthyl-2,20-diylphosphorochloridate (2.3 g, 6.0 mmol) was added to a
stirred solution of 2-amino-4-piperidinyl pyridine (0.88 g, 5.0 mmol) and TEA
(0.8 mL, 6.0 mmol) in DCM (10 mL) at room temperature and stirred for an
additional 15 h. The organic layer was washed with brine (2 ꢂ 20 mL) and dried over
anhydrous Na2SO4. After the removal of the solvent under reduced pressure, the
residue was purified through column chromatography on silica gel (DCM=MeOH
10:1) to give 1e as a white solid (2.1 g, 84%). White solid, mp 228.2–229.3 ꢀC.
20
½aꢃD ¼ ꢁ370(c ¼ 0.2, CHCl3). IR (KBr): n 3374, 3065, 2935, 2853, 1634, 1224,
1
750 cmꢁ1. H NMR (300 MHz, CDCl3), d: 8.03 (d, J ¼ 9.0 Hz, 1H), 7.95–7.88 (m,
2H), 7.80 (d, J ¼ 9.0 Hz, 1H), 7.68 (d, J ¼ 9.0 Hz, 1H), 7.57 (d, J ¼ 9.0 Hz, 1H),
7.47–7.41 (m, 3H), 7.38–7.21 (m, 3H), 6.75 (d, J ¼ 6.0 Hz, 1H), 6.37 (s, 1H), 5.24–
5.22 (m, 1H), 3.45 (br s, 1H), 3.01–2.86 (m, 4H), 1.52–1.37 (m, 6H). 13C NMR
(75 MHz, CDCl3), d: 157.0, 156.6, 149.1, 147.7, 147.6, 135.7, 132.4, 131.4, 131.2,
130.6, 130.3, 128.4, 128.3, 127.0, 126.8, 126.2, 125.9, 125.1, 124.5, 122.1, 121.9,
121.8, 121.6, 98.4, 95.5, 46.7, 25.0, 23.8. (EI) m=z 508 (rel. intensity) (Mþ þ 1).
Analysis calculated for C30H26N3O3P: C, 71.00; H, 5.16; N, 8.28; O, 9.46; P, 6.10.
Found: C, 69.70; H, 5.08; N, 8.29; O, 9.50; P, 6.15.
(R)-4-(4-(Piperidin-1-yl)pyridin-2-yl)dinaphtho[2,1-d:1’,2’f][1,3,2]-
dithiazepine-3,3,5,5-tetraoxide (1f)
(R)-[1,10-Binaphthalene]-2,20-disulfonyl dichloride (2.7 g, 6.0 mmol) was added
to a stirred solution of 2-amino-4-piperidinyl pyridine (0.88 g, 5.0 mmol) and TEA
(0.8 mL, 6.0 mmol) in DCM (10 mL) at room temperature and stirred for an

2-AMINO-4-PIPERIDINYL PYRIDINE DERIVATIVES
2713
additional 15 h. The organic layer was washed with brine (2 ꢂ 20 mL) and dried over
anhydrous Na2SO4. After the removal of solvent under reduced pressure, the residue
was purified through column chromatography on silica gel (DCM=MeOH 10:1) to
20
give 1f as white solid (2.5 g, 90%). White solid, mp 205.2–207.0 ꢀC. ½aꢃD ¼ þ181
1
(c ¼ 0.2, CHCl3). IR (KBr): n 3042, 2985, 1654, 754 cmꢁ1. H NMR (300 MHz,
CDCl3), d: 8.29–8.19 (m, 5H), 8.08 (d, J ¼ 9.0 Hz, 2H), 7.70–7.65 (m, 2H),
7.45–7.39 (m, 4H), 6.70–6.66 (m, 2H), 3.40–3.30 (m, 4H), 1.69–1.59 (m, 6H). 13C
NMR (75 MHz, CDCl3), d: 156.7, 149.9, 147.5, 135.6, 135.1, 131.6, 130.8, 129.3,
128.7, 128.2, 128.1, 123.1, 109.7, 108.8, 47.0, 25.0, 24.0. (EI) m=z 556 (rel. intensity)
(Mþ þ 1). Analysis calculated for C30H25N3O4S2: C, 64.84; H, 4.53; N, 7.56; O,
11.52; S, 11.54. Found: C, 64.70; H, 4.48; N, 7.49; O, 11.50; S, 11.45.
ACKNOWLEDGMENTS
The authors thank the sophisticated instrumentation faculty at the department
1
of analytical chemistry in Jilin University, Xu-Yang Luo for recording H and 13C
NMR spectra, and Qin-Wen Liu for recording the mass spectra.
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