One-pot multicomponent synthesis of highly functionalised piperidines from aromatic aldehydes, cyanoacetates, nitromethane and ammonium acetate

Article abstract of DOI:10.3184/174751913X13814236405771

An efficient and straightforward multicomponent synthetic protocol has been developed for the preparation of three kinds of highly functionalised piperidines via multicomponent reaction between aromatic aldehydes, ammonium acetate, cyanoacetates and/or nitromethane for the generation of a wide range of structurally interesting and pharmacologically significant compounds. The structure of ethyl 3-cyano-2,4,6-tris(4-methoxyphenyl)-5-nitropiperidine-3- carboxylate, ethyl 3-cyano-2,4,6-tris(3-methoxyphenyl)-5-nitropiperidine-3- carboxylate and diethyl 3,5-dicyano-2,4,6-tris(3-methoxyphenyl)piperidine-3,5- dicarboxylate were further confirmed by X.ray single crystal analysis.

Full text of DOI:10.3184/174751913X13814236405771

684 RESEARCH PAPER
NOVEMBER, 684–689
JOURNAL OF CHEMICAL RESEARCH 2013
One-pot multicomponent synthesis of highly functionalised piperidines from
aromatic aldehydes, cyanoacetates, nitromethane and ammonium acetate
Juanjuan Liu, Zhengquan Zhou, Yan Li, Weijian Ye, Juan Yao and Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University,180 Siwangting Street, Yangzhou 225002, P.R. China
An efficient and straightforward multicomponent synthetic protocol has been developed for the preparation of three kinds of
highly functionalised piperidines via multicomponent reaction between aromatic aldehydes, ammonium acetate, cyanoacetates
and/or nitromethane for the generation of a wide range of structurally interesting and pharmacologically significant
compounds. The structure of ethyl 3-cyano-2,4,6-tris(4-methoxyphenyl)-5-nitropiperidine-3-carboxylate, ethyl 3-cyano-2,4,6-
tris(3-methoxyphenyl)-5-nitropiperidine-3-carboxylate and diethyl 3,5-dicyano-2,4,6-tris(3-methoxyphenyl)piperidine-3,5-
dicarboxylate were further confirmed by X-ray single crystal analysis.
Keywords: multicomponent reaction, polysubstituted piperidine, aromatic aldehyde, cyanoacetate, nitromethane
Piperidinestructuresbelongtoanimportantclassofheterocycles
that constitute the fundamental units of numerous natural
products and synthetic analogues possessing an extensive array
of biological activities.1 These compounds have important roles
in many disease treatments.2 As a result, a large number of
synthetic methods for the preparation of diversely substituted
piperidines have been developed. The Hantzsch procedure,
Paale Knorr synthesis, and aza-Diels–Alder reaction have been
widely used as classic approaches but with some drawbacks
such as multistep synthetic operation, inaccessible starting
materials, limited scope and functional group compatibility.
In spite of these efforts, it is still challenging to prepare
polysubstituted piperidines possessing diverse substituents
directly from readily available precursors in a single synthetic
operation.
used frequently in the construction of carbon backbones.11,12
We have reported a pseudo five-component reaction for the
synthesis of polysubstituted piperidin-2-ones from aromatic
aldehydes, nitromethane, ammonium acetate, and dialkyl
malonates, where piperidine served as Lewis base, conducting
Knoevenagel condensation, Michael addition, nitro-Mannich
reaction and an intramolecular lactamisation.13 Applying this
strategy, several attractive heterocycles could be prepared in
one pot. This reaction mode, especially the conjugate addition
of nitroalkane and aza-Mannich reaction, initiated our interest
in extending the process to these reactions and involved highly
reactive intermediates to produce complex products that are
difficult to access through conventional stepwise approaches.
We now report the synthesis of fully substituted piperidines
between aromatic aldehydes, ammonium acetate, cyanoacetates
and/or nitromethane.
Multicomponent reactions (MCRs) represent a highly
valuable synthetic tool for the construction of novel and complex
molecular structures with a minimum number of synthetic
steps. In this content, MCRs that involve 1,3-dicarbonyl
compounds, aldehydes and nitroalkanes have received much
attention because the formation of different condensation
products can be expected depending on the specific conditions
and structures of the building blocks. Actually, MCRs have been
demonstrated to be a straightforward approach for the synthesis
of piperidines which have been extensively reviewed.3 In this
context, multicomponent coupling reactions for the synthesis
of highly substituted piperidines have received much attention.
Sajadikhahetal.3 reportedthathighlyfunctionalisedpiperidines
derivatives have been synthesised via a multicomponent
coupling reaction of two aromatic aldehydes, two anilines,
and β-ketoesters in the presence of p-TsOH H2O as a catalyst.
Recently, the atom and step economic synthesis of these cyclic
compounds by Michael addition employing nitroalkanes as
a useful building block for the formation of carbon–carbon
bond has also received attention.4–10 Moreover, nitroalkenes
generated from nitromethane and carbonyl compounds are
known to be the most active alkenes for the reaction and
Results and discussion
Our initial test reaction was run by mixing
p-methoxybenzaldehyde, nitromethane, ethyl cyanoacetate,
and ammonium acetate together in the presence of inorganic
weak base K2CO3 and Cs2CO3, or strong base NaOH in ethanol
at room temperature for 18 h, but no reaction occurred as
indicated by TLC result (Scheme 1). Then, using available
organic base such as triethylamine and piperidine as a prompter,
p-methoxybenzaldehyde (3 equiv.), nitromethane (1 equiv.),
ethyl cyanoacetate (1 equiv.) and ammonium acetate (1 equiv.)
were stirred at room temperature in ethanol in the presence of
triethylamine or piperidine (0.5 equiv.). After 18 h, the result
showed that triethylamine or piperidine gave the product 2a
in yield at 36% and 32% respectively. To improve the product
yields and to optimise the reaction conditions, triethylamine
was used in 1 equimolar and 2 equimolar, a reaction was
carried out under similar conditions. The yield of the product
2a was observed in 43% and 61% respectively. Encouraged
by these results, we further investigated for the best reaction
conditions. The increase in the quantity of triethylamine from
H3CO
OCH3
H
N
CHO
Selected
conditions
EtO2C
NC
O
CH NO
+
+ AcONH4
+
NC
3
2
NO2
O
OCH3
OCH3
Scheme 1 Optimisation of promoters, solvents and temperature in the synthesis of 2a.
* Correspondent. E-mail: wangcd@yzu.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2013 685
Table 1 One-pot multicomponent synthesis of products 2a–i and 3a–g
2 to 5 equimolar enhanced the product yield from 61 to 87%.
We also varied the solvent to determine which one would lead
to a high yield of product 2a. Among those tested, EtOH gave
the best result. The result showed that EtOH, DMF, MeCN, or
toluene gave the product 2a in yields of 87%, 52%, 61% and
41% respectively. Furthermore, faster reaction also occurred
on increasing the temperature from room temperature to
reflux and the reaction time can be reduced to 10 h, but the
reaction gave a lower yield of 2a (72%). In order to evaluate the
efficiency of triethylamine as a promoter, reactants 1a–e were
reacted with nitromethane, ethyl cyanoacetate, and ammonium
acetate in the presence of 5 equimolar of triethylamine to
generate product 2a–e; the results are summarised in Table 1
and Scheme 2. Reconsidering the possible mechanism of our
expected one-pot reaction, we knew that the Michael addition
of the nitromethane to the arylidene cyanoacetate condensate
in the presence of base is a key step. Thus, when nitromethane
is replaced with ethyl cyanoacetate, the one-pot reaction
should work. So the reaction was carried out with substituted
benzaldehyde 1b, 1e, 1f or 1g (3 equiv.), ethyl cyanoacetate
Entry
1
2
3
4
5
6
7
8
ArCHO
X
NO2
NO2
NO2
NO2
NO2
CO2Et
CO2Et
CO2Et
CO2Et
Y
H
H
H
H
Product
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
Yield/%a
87
51
74
68
48
56
44
67
57
81
97
93
73
4-CH3OC6H4 (1a)
3-CH3OC6H4 (1b)
4-CH3C6H4 (1c)
2-ClC6H4 (1d)
3-thienyl (1e)
4-ClC6H4 (1f)
4-BrC6H4 (1g)
3-CH3OC6H4 (1b)
3-thienyl (1e)
C6H5 (1h)
4-CH3OC6H4 (1a)
2-CH3OC6H4 (1i)
2-ClC6H4 (1d)
2-BrC6H4 (1j)
2-naphthyl (1k)
3-PhOC6H4 (1l)
H
CN
CN
CN
CN
9
10
11
12
13
14
15
16
3d
3e
3f
84
83
80
3g
aIsolated yield.
CHO
H
N
H
R
R
R
O
N
CH3NO2
R
EtO2C
NC
X
Et3N
Et3N
+
AcONH4
NC
NO2
Y
1a-l
NC
O
R
R
O
2a-i
3a-g
Scheme 2 One-pot multicomponent synthesis of functionalised piperidines 2a–i and functionalised piperidinones 3a–g.
Table 2 Crystallographic data of piperidine 2a, 2b and 2h
Entry
Piperidine 2a
Piperidine 2b
Piperidine 2h
Empirical formula
C30H31N3O7
C30H31N3O7
C34H35N3O7
Formula weight
Wavelength/Å
Temperature/K
Crystal system
space group
545.58
0.71073 Å
296(2) K
Monoclinic,
P 21/n
545.58
0.71073 Å
296(2) K
Monoclinic,
P21/c
597.65
0.71073 Å
296(2) K
Triclinic,
P-1
a=15.855(4) Å
b=9.453(3) Å
c=19.618(5) Å
α=90.00 °
β=102.669(5) °
γ=90.00 °
2868.7(14) Å3
4
a=13.6475(17) Å
b=17.409(2) Å
c=12.1547(14) Å
α=90 °
β=103.603(4) °
γ=90 °
2806.8(6) Å3
4
a=10.6012(14) Å
b= 11.1276(17) Å
c=14.251(2) Å
α=85.303(5)°
β=72.887(4) °
γ=79.968(4) °
1581.3(4) Å3
2
Unit cell dimensions
Volume/Å3
Z
Calculated density /g cm–3
Absorption correction/mm–1
F(000)
1.263
None
1152
1.291
0.093
1152
1.255
0.088
632
Crystal size/mm
θ range for data collection
0.4×0.35×0.3
1.50 to 25.00 °
0.35×0.33×0.30
1.54 to 25.00 °
0.35×0.33×0.30
1.86 to 25.00 °
–18<=h<= 18,
–11<=k<=10,
–23<=l<=23
–16<=h<= 15,
–19<=k<=20,
–14<=l<= 14
–12<=h<= 12,
–13<=k<= 13,
–16<=l<= 15
h,k,l ranges
15595/5049
[R(int)=0.0780]
30317/4950
[R(int)=0.0688]
22197/5578
[R(int)=0.0538]
Reflections collected/unique
Completeness
100.0%
99.9%
99.9%
Data/restraints/parameters
Goodness-of-fit on F2
5049/0/389
1.019
4945/32/388
1.035
5572/328/426
1.075
R1 = 0.0474,
R1 =0.0544,
R1 =0.0575,
Final R indices [I>2sigma(I)]
wR2 =0.0888
wR2 = 0.1245
R1 = 0.1099,
wR2 = 0.1506
wR2 = 0.1367
R1 =0.0996,
wR2 = 0.1579
R1 = 0.1234,
R indices (all data)
wR2 = 0.1025
Largest diff. peak and hole/e Å–3
0.273 and –0.172
0.193 and –0.180
0.396 and –0.274
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686 JOURNAL OF CHEMICAL RESEARCH 2013
(2 equiv.), andammoniumacetate(1 equiv.)atroomtemperature
in ethanol in the presence of triethylamine, the final products
were 3,5-dicyanopiperidine-3,5-dicarboxylate 2f–i. Further
optimisation with the ratio of modified substrates also revealed
that substituted benzaldehyde (2 to 2.5 equiv.), nitromethane
(1 equiv.), ethyl cyanoacetate (1 equiv.), and ammonium acetate
(1 equiv.) were used, the cyclic amide 3a–g were obtained easily
similar to our previous results.13 With the reaction conditions
optimised, we next examined the substrate scope of the reaction
(Table 1, Scheme 2). The results showed that aromatic groups
bearing electron-withdrawing or electron-donating groups
were tolerated as well as aromatic rings substituted in the ortho,
meta and para positions.
The product was characterised as ethyl 3-cyano-2,4,6-tris(4-
methoxyphenyl)-5-nitropiperidine-3-carboxylate (2a) on the
basis of its spectral and analytical data. The stereochemistry
of 2a was obtained from a single crystal X-ray analysis. The
ORTEP diagram of 2a is shown in Fig. 1. The structure of 2b
and 2h were further confirmed by X-ray single crystal analysis
and their spectral and analytical data (Figs 2 and 3). The results
of X-ray single crystal analysis indicated that C4 position ester
group of compound 2h is slightly disordered. Crystallographic
data of 2a, 2b and 2h are listed in Table 2. Crystallographic
data for 2a, 2b and 2h have been deposited with the Cambridge
Crystallographic Data Centre with the deposition number
CCDC 903672, 945884 and 945885. These data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax (+44) 1223 336033, E-mail:
deposit@ccdc.cam.ac.uk].
The high diastereocontrol in the reactions is worth further
comment. The reaction mechanism (Scheme 3) is believed
to involve Knoevenagel condensation reaction of aromatic
aldehyde with ethyl cyanoacetate and Michael addition of the
nitromethane to the arylidene cyanoacetate condensate (A), in
the presence of base, ethyl 2-cyano-4-nitro-3-arylbutanoate (B)
formed an anionic intermediate (C), followed by nucleophilic
addition in intermediate arylimine to form 2-(3-amino-2-nitro-
1,3-diarylpropyl)cyanoacetate (D). Next, the Schiff base was
afforded from the intermediate (D) and aromatic aldehyde,
finally by intramolecular nucleophilic addition of intermediate
arylimine (E) to form the cyclic amine 2a–e. In the process,
when nitromethane was replaced with ethyl cyanoacetate, the
final products were 3,5-dicyanopiperidine-3,5-dicarboxylate
2f–i. Furthermore, the intramolecular lactamisation in
2-(3-amino-2-nitro-1,3-diarylpropyl)cyanoacetate (D) gave the
cyclic amide 3a–g with elimination of alcohol.
In summary, a facile and efficient synthesis of highly
functionalised piperidines is developed via MCRs between
aromatic aldehydes, ammonium acetate, cyanoacetates and/or
nitromethane for the generation of a wide range of structurally
interesting and pharmacologically significant compounds.
The structure of ethyl 3-cyano-2,4,6-tris(4-methoxyphenyl)-5-
nitropiperidine-3-carboxylate (2a), ethyl 3-cyano-2,4,6-tris(3-
methoxyphenyl)-5-nitropiperidine-3-carboxylate (2b) and
diethyl
3,5-dicyano-2,4,6-tris(3-methoxyphenyl)piperidine-
3,5-dicarboxylate (2h) was further confirmed by X-ray single
crystal analysis. Further work on the utilisation and extension
of the scope of the methodology is currently under investigation
in our laboratory.
Fig. 1 Molecular structure of piperidine 2a, non-hydrogen atoms are
shown at the 30% probability level.
Fig. 2 Molecular structure of piperidine 2b, non-hydrogen atoms are
shown at the 30% probability level.
Fig. 3 Molecular structure of piperidine 2h, non-hydrogen atoms are
shown at the 30% probability level.
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JOURNAL OF CHEMICAL RESEARCH 2013 687
O
O
N
N
N
CO2Et
CO2Et
H
B-
OEt
R
H
N
CH3NO2
R
H
R
H
NO2
3
A
B
R
EtO
O
R
N
N
CN
CO2Et
NO2
NH2
-EtOH
O
CH
NH
NH
R
R
O2N
3a-g
H-B
NO2
R
C
D
R
CHO
R
EtO
O
R
EtO
O
N
EtO
O
R
NH2
NC
N
NC
NH
R
R
NO2
NO2
R
R
NO2
R
R
2a-e
D
E
Scheme 3 Possible mechanism in the synthesis of product 2a–e and 3a–g.
Ethyl 3-cyano-2,4,6-tris(4-methoxyphenyl)-5-nitropiperidine-3-
carboxylate (2a): White solid, yield 87%, m.p. 215.2–215.9 °C (PE/EA);
1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.42 (d, J=8.4 Hz, 2H), 7.39
(d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.80
(d, J=9.0 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 5.20 (dd, J=11.4, 9.6 Hz, 1H),
4.49 (s, 1H), 4.37 (d, J=9.0 Hz, 1H), 4.09 (d, J=12.0 Hz, 1H), 3.80–3.75
(m, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 3.68 (s, 3H), 2.11 (d, J=9.6 Hz, 1H),
0.76 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 164.8,
159.6, 159.5, 129.7, 128.8, 128.7, 124.3, 115.6, 114.2, 114.0, 113.6, 90.6,
65.4, 64.5, 62.6, 60.5, 55.1, 50.8, 13.6; IR (KBr, cm–1): 3191, 3078, 2948,
2838, 2256, 1695, 1613, 1551, 1574, 1454, 1421, 1343, 1256, 958, 830, 751;
MS(EI): 546.22 [(M+1)+, 100%]; Anal. Calcd for C30H31N3O7: C, 66.04;
H, 5.73; N, 7.70. Found: C, 66.22; H, 5.60; N, 7.52%.
Ethyl 3-cyano-2,4,6-tris(3-methoxyphenyl)-5-nitropiperidine-
3-carboxylate (2b): White solid, yield 51%, m.p. 179.6–180.1 °C (PE/
EA); 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.32–7.26 (m, 3H), 7.12
(s, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.06 (d, J=7.8 Hz, 2H), 7.01 (s, 2H), 6.96
(d, J=8.4 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 5.44
(d, J=3.6 Hz,1H), 4.84 (t, J=4.2 Hz, 1H), 4.54 (d, J=7.8 Hz, 1H), 4.38
(s, 1H), 3.96–3.89 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 3.62 (t,
J=7.2 Hz, 1H), 0.85 (t, J=6.0 Hz, 3H); 13C NMR (DMSO-d6, 150 MHz) δ
(ppm): 164.4, 161.7, 159.4, 159.2, 158.9, 154.9, 136.0, 133.8, 132.5, 130.0,
129.7, 129.3, 123.0, 119.9, 119.7, 115.0, 114.1, 113.9, 113.7, 102.6, 89.9, 65.8,
64.7, 62.3, 59.3, 55.2, 55.1, 55.0, 51.2, 13.3; IR (KBr, cm–1): 3019, 2953,
2854, 2216, 1728, 1643, 1608, 1443, 1382, 1273, 972, 885, 758; MS(EI):
546.28 [(M+1)+, 100%]; Anal. Calcd for C30H31N3O7: C, 66.04; H, 5.73; N,
7.70. Found: C, 66.24; H, 5.62; N, 7.60%.
Experimental
All melting points were determined in a Yanaco melting point
apparatus and are uncorrected. IR spectra were recorded in a Nicolet
FT-IR 5DX spectrometer. The 1H NMR (600 MHz) and 13C NMR
(150 MHz) spectra were recorded in a Bruker AV-600 spectrometer
with TMS as internal reference in CDCl3 solutions. The J values
are given in hertz. Only discrete or characteristic signals for the
1H NMR are reported. The MS spectra were obtained on a ZAB-HS
mass spectrometer with 70 eV. X-ray crystallographic analysis
was performed with
a Smart-1000 CCD diffractometer using
monochromatic Mo KR radiation (λ) 0.71073 Å and integrated with the
SAINT-Plus program. All calculations were performed with programs
from the SHELXTL crystallographic software package. The elemental
analyses were performed in a Perkin-Elmer 240C instrument. Flash
chromatography was performed on silica gel (230–400 mesh) eluting
with ethyl acetate-hexanes mixture. All reactions were monitored
by TLC. All reagents and solvents were purchased from commercial
sources and purified commonly before used.
Synthesis of functionalised piperidines 2a–i and 3a–g; general
procedure
The appropriate substituted aromatic aldehyde (6 mmol for 2a–i,
5 mmol for 3a–g), ammonium acetate (2 mmol, 254 mg), nitromethane
(2 mmol, 122 mg for 2a–e and 3a–g) and/or ethyl 2-cyanoacetate
(2 mmol, 226 mg for 2a–e or 4 mmol, 452 mg for 2f–i respectively)
were dissolved in triethylamine (10.0 mmol, 1.01 g) and 15 mL of
ethanol at room temperature, and the resultant mixture was stirred
at room temperature for 18 h, and the completion of reaction was
confirmed by TLC (EtOAc/hexanes 1:1). After the reaction was
complete, the precipitated solid was filtered and was washed with
cooled ethanol (5 mL) twice, then dried in the air to give the desired
products. If in the reaction mixture the precipitates were unaffordable,
the ethanol was removed under reduced pressure. Subsequently,
the residues were added with water (15 mL) and were extracted with
dichloromethane (3×15 mL), the organic phase was washed with water
and brine, dried over anhydrous sodium sulfate. The crude products
were purified by flash chromatography (silica gel, EtOAc/hexanes,
1/2) to give products 2a–i and 3a–g.
Ethyl 3-cyano-5-nitro-2,4,6-tri-p-tolylpiperidine-3-carboxylate
1
(2c): White solid, yield 74%, m.p. 185.3–185.8 °C (PE/EA); H NMR
(DMSO-d6, 600 MHz) δ (ppm): 7.41 (t, J=9.0 Hz, 4H), 7.29 (d, J=7.2 Hz,
2H), 7.22 (d, J=7.2 Hz, 2H), 7.16 (t, J=8.4 Hz, 4H), 5.34 (d, J=3.0 Hz,
1H), 4.83 (t, J=3.6 Hz, 1H), 4.52 (d, J=7.8 Hz, 1H), 4.37 (s, 1H), 3.93–
3.88 (m, 2H), 3.44 (t, J=7.2 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.26 (s,
3H), 0.84 (t, J=5.4 Hz, 3H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm):
164.70, 154.93, 144.41, 138.6, 138.2, 134.7, 130.0(2C), 129.9(2C),
129.4(2C), 129.2(2C), 128.8(2C), 127.4(2C), 115.8, 101.1, 90.5, 65.6,
64.8, 62.8, 62.2, 51.0, 21.3, 20.6, 20.5, 13.5; IR (KBr, cm–1): 2924, 2322,
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688 JOURNAL OF CHEMICAL RESEARCH 2013
2251, 1907, 1742, 1550, 1513, 1463, 1378, 1244, 1124, 1049, 857, 803, 710;
MS(EI): 498.45 [(M+1)+, 100%]; Anal. Calcd for C30H31N3O4: C, 72.41;
H, 6.28; N, 8.44. Found: C, 72.23; H, 6.20; N, 8.68%.
Diethyl
3,5-dicyano-2,4,6-tri(thiophen-3-yl)piperidine-3,5-
dicarboxylate (2i): White solid, yield 57%, m.p. 182.5–183.1 °C (PE/
EA); 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.63 (s, 2H), 7.62–7.61 (m,
2H), 7.56–7.54 (m, 2H), 7.35 (d, J=5.4 Hz,1H), 7.19 (d, J=4.8 Hz, 2H),
4.73 (d, J=3.0 Hz, 2H), 4.22 (s, 1H), 4.03–3.92 (m, 4H), 3.92 (s, 1H), 0.89
(t, J=6.6 Hz, 6H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 165.7, 137.5,
133.1, 127.2, 126.7, 126.4, 126.1, 124.3, 115.3, 63.0, 62.9, 56.3, 47.2, 13.4;
IR (KBr, cm–1): 2981, 2251, 1734, 1592, 1443, 1316, 1293, 1242, 1167,
1129, 1095, 1024, 929, 873, 839, 787; MS(EI): 526.11 [(M+1)+, 100%];
Anal. Calcd for C25H23N3O4S3: C, 57.12; H, 4.41; N, 7.99. Found: C, 57.28;
H, 4.60; N, 7.82%.
Ethyl
2,4,6-tris(2-chlorophenyl)-3-cyano-5-nitropiperidine-3-
carboxylate (2d): White solid, yield 68%, m.p. 184.3–184.9 °C (PE/
1
EA); H NMR (DMSO-d6, 600 MHz) δ (ppm): 8.11 (d, J=7.2 Hz, 1H),
8.06 (d, J=7.8 Hz, 1H), 7.99 (d, J=6.6 Hz, 1H), 7.49 (t, J=9.0 Hz, 3H),
7.47 (d, J=9.6 Hz, 1H), 7.44 (d, J=7.8 Hz, 2H), 7.39 (t, J=7.8 Hz, 3H),
5.48 (t, J=10.2 Hz, 1H), 5.17 (s, 1H), 5.12 (d, J=9.0 Hz, 1H), 4.99 (d,
J=11.4 Hz, 1H), 4.33 (s, 1H), 3.92–3.87 (m, 2H), 0.88 (t, J=6.6 Hz, 3H);
13C NMR (DMSO-d6, 150 MHz) δ (ppm): 163.4, 134.5, 133.6, 133.1,
130.9, 130.5, 130.4, 130.1, 129.6, 129.5, 129.4, 129.1, 127.8, 127.3, 89.5,
63.2, 62.0, 60.6, 57.7, 46.4, 13.1; IR (KBr, cm–1): 3075, 2928, 2749, 2355,
2257, 1936, 1819, 1691, 1583, 1552, 1476, 1443, 1415, 1370, 1341, 1287,
1200, 1156, 1119, 1043, 956, 833, 755; MS(EI): 558.17 [(M+1)+, 100%];
Anal. Calcd for C27H22Cl3N3O4: C, 58.03; H, 3.97; N, 7.52. Found: C,
58.22; H, 4.08; N, 7.66%.
5-Nitro-2-oxo-4,6-diphenylpiperidine-3-carbonitrile (3a): White
solid, yield 81%, m.p. 199.5–200.3 °C (PE/EA); H NMR (DMSO-d6,
1
600 MHz) δ (ppm): 8.80 (s, 1H), 7.45 (d, J=7.2 Hz, 2H), 7.40 (d,
J=7.2 Hz, 2H), 7.40–7.35 (m, 3H), 7.34–7.31 (m, 3H), 5.52 (t,
J=4.2 Hz,1H), 5.41 (d, J=4.2 Hz,1H), 5.04 (d, J=13.2 Hz,1H), 4.53 (dd,
J=3.0, 12.6 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 163.7,
135.6, 135.1, 129.0, 128.5, 127.4, 126.4, 117.7, 89.0, 56.7, 42.7, 34.9, 30.7;
IR (KBr, cm–1): 3035, 2900, 2255, 1689, 1559, 1496, 1458, 1395, 1372,
1331, 1282, 1137, 1080, 1003, 920, 776, 756; MS(EI): 320.29 [(M–1)+,
100%]; Anal. Calcd for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C,
67.42; H, 4.78; N, 13.26%.
Ethyl
3-cyano-5-nitro-2,4,6-tri(thiophen-3-yl)piperidine-3-
carboxylate (2e): White solid, yield 48%, m.p. 174.1–174.9 °C (PE/
1
EA); H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.71 (d, J=4.8 Hz, 1H),
7.63 (d, J=4.8 Hz, 1H), 7.58–7.55 (m, 2H), 7.52–7.50 (m, 1H), 7.46 (d,
J=4.8 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H), 7.21 (d, J=5.4 Hz, 1H), 7.12 (d,
J=4.8 Hz, 1H), 5.47 (s,1H), 4.88 (d, J=10.2 Hz, 1H), 4.69 (d, J=10.8 Hz,
1H), 4.53 (d, J=4.2 Hz, 1H), 4.07–3.97 (m,2H), 3.59 (t, J=10.8 Hz, 1H),
0.93 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 167.4,
138.3, 137.9, 134.4, 127.1, 127.0, 126.8, 126.1, 126.0, 124.5, 124.0, 122.2,
115.9, 84.4, 62.8, 62.6, 58.0, 53.2, 43.9, 13.5; IR (KBr, cm–1): 3102, 2975,
2932, 2376, 2247, 1725, 1586, 1552, 1516, 1468, 1377, 1291, 1249, 1170,
1121, 1040, 926, 860, 845, 782; MS(EI): 472.08 [(M–1)+, 100%]; Anal.
Calcd for C21H19N3O4S3: C, 53.26; H, 4.04; N, 8.87. Found: C, 53.40; H,
4.28; N, 8.98%.
4,6-Bis(4-methoxyphenyl)-5-nitro-2-oxopiperidine-3-carbonitrile
(3b): White solid, yield 97%, m.p. 241.7–242.5 °C (PE/EA); H NMR
1
(DMSO-d6, 600 MHz) δ (ppm): 8.74 (s, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.23
(d, J=9.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 5.41
(t, J=3.6 Hz,1H), 5.31 (d, J=4.2 Hz,1H), 4.96 (d, J=12.6 Hz,1H), 4.41
(dd, J=3.6, 13.2 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H); 13C NMR (DMSO-d6,
150 MHz) δ (ppm): 163.7, 159.2, 159.1, 149.4, 128.6, 127.6, 127.4, 126.9,
114.3, 113.8, 89.4, 56.2, 55.1, 45.1, 42.0, 35.2; IR (KBr, cm–1): 3075, 2960,
2844, 2258, 2044, 1696, 1606, 1583, 1549, 1514, 1457, 1306, 1256, 1176,
1092, 1030, 971, 895, 845; MS(EI): 380.04 [(M–1)+, 100%]; Anal. Calcd
for C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 63.12; H, 5.08; N,
11.26%.
Diethyl
2,4,6-tris(4-chlorophenyl)-3,5-dicyanopiperidine-
3,5-dicarboxylate (2f): White solid, yield 56%, m.p. 203.6–203.8 °C
(PE/EA); 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.62 (d, J=7.8 Hz,
2H), 7.54 (d, J=7.2 Hz, 2H), 7.54–7.49 (m, 8H), 4.72 (s, 2H), 4.24 (s,
1H), 4.12 (s, 1H), 3.97–3.88 (m, 4H), 0.84 (t, J=6.6 Hz, 6H); 13C NMR
(DMSO-d6, 150 MHz) δ (ppm): 165.0, 135.5, 134.4, 133.6, 131.6, 131.2,
129.7, 129.0, 128.3, 114.8, 66.0, 63.1, 56.3, 50.3, 13.4; IR (KBr, cm–1):
2993, 2374, 2249, 2027, 1908, 1740, 1635, 1597, 1549, 1489, 1448, 1371,
1222, 1096, 1043, 1011, 824, 731; MS(EI): 608.10 [(M–1)+, 100%];
Anal. Calcd for C31H26Cl3N3O4: C, 60.95; H, 4.29; N, 6.88. Found: C,
61.15; H, 4.43; N, 6.70%.
Diethyl 2,4,6-tris(4-bromophenyl)-3,5-dicyanopiperidine-3,5-
dicarboxylate (2g): White solid, yield 44%, m.p. 218.6–219.0 °C
(PE/EA); 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.68 (d, J=7.8 Hz,
2H), 7.63 (d, J=7.2 Hz, 4H), 7.54 (d, J=7.8 Hz, 2H), 7.46 (d,
J=7.8 Hz, 4H), 4.70 (s, 2H), 4.24 (s, 1H), 4.10 (s, 1H), 3.98–3.87 (m,
4H), 0.84 (t, J=7.2 Hz, 6H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm):
165.0, 135.9, 132.1, 132.0, 131.4, 131.2, 130.0, 123.7, 122.3, 114.8, 66.0,
63.1, 56.2, 50.4, 13.4; IR (KBr, cm–1): 2989, 2901, 2856, 2359, 2251,
2081, 2024, 1911, 1737, 1641, 1551, 1486, 1445, 1370, 1243, 1124,
1077, 1041, 1010, 982, 909, 819, 723; MS(EI): 742.96 [(M+2)+, 100%];
Anal. Calcd for C31H26Br3N3O4: C, 50.03; H, 3.52; N, 5.65. Found: C,
50.22; H, 3.68; N, 5.69%.
4,6-Bis(2-methoxyphenyl)-5-nitro-2-oxopiperidine-3-carbonitrile
(3c): White solid, yield 93%, m.p. 211.2–212.0 °C (PE/EA); H NMR
1
(DMSO-d6, 600 MHz) δ (ppm): 8.68 (s, 1H), 7.36–7.34 (m, 2H), 7.31 (t,
J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.8 Hz, 1H), 6.95 (dt,
J=3.0, 7.2 Hz, 2H), 5.62 (d, J=4.2 Hz, 1H), 5.49 (t, J=3.6 Hz, 1H), 5.06
(d, J=12.6 Hz, 1H), 4.80 (dd, J=3.6, 12.6 Hz, 1H), 3.93 (s, 3H), 3.88
(s, 3H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 164.0, 156.7, 155.8,
129.8, 129.7, 126.7, 126.4, 122.9, 122.2, 120.8, 120.5, 117.8, 111.3, 110.8,
83.8, 55.8, 51.5, 37.0, 34.3, 30.7; IR (KBr, cm–1): 3041, 2249, 1689, 1595,
1554, 1494, 1463, 1401, 1341, 1293, 1247, 1166, 1101, 1025, 971, 896, 758;
MS(EI): 382.19 [(M+1)+, 100%]; Anal. Calcd for C20H19N3O5: C, 62.99;
H, 5.02; N, 11.02. Found: C, 63.18; H, 5.24; N, 11.20%.
4,6-Bis(2-chlorophenyl)-5-nitro-2-oxopiperidine-3-carbonitrile
(3d): White solid, yield 73%, m.p. 208.1–209.0 °C (PE/EA); H NMR
1
(DMSO-d6, 600 MHz) δ (ppm): 8.89 (s, 1H), 7.61 (t, J=7.2 Hz, 2H),
7.52 (d, J=7.2 Hz, 1H), 7.44–7.40 (m, 4H), 7.29 (d, J=7.2 Hz, 1H), 5.88
(d, J=4.8 Hz, 1H), 5.49 (t, J=3.6 Hz, 1H), 5.32 (d, J=12.6 Hz, 1H), 5.18
(dd, J=3.0, 13.2 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 163.8,
133.2, 132.1, 131.6, 131.4, 130.6, 130.3, 129.6, 128.2, 128.1, 127.8, 117.4,
83.8, 53.8, 34.6; IR (KBr, cm–1): 3074, 2257, 2043, 1692, 1582, 1551, 1476,
1445, 1340, 1291, 1206, 1166, 1095, 1041, 969, 888, 838, 756; MS(EI):
390.24 [(M+1)+, 100%]; Anal. Calcd for C18H13Cl2N3O3: C, 55.40; H,
3.36; N, 10.77. Found: C, 55.48; H, 3.44; N, 10.62%.
Diethyl
3,5-dicyano-2,4,6-tris(3-methoxyphenyl)piperidine-3,5-
dicarboxylate (2h): White solid, yield 67%, m.p. 189.2–189.5 °C (PE/EA);
1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.33 (d, J=7.2 Hz, 1H), 7.31 (t,
J=7.8 Hz, 2H), 7.24 (s, 1H), 7.13 (s, 2H), 7.08 (d, J=7.2 Hz, 1H), 7.04 (d,
J=7.8 Hz, 2H), 6.98–6.96 (m, 2H), 6.95 (d, J=2.4 Hz, 1H), 4.63 (s, 2H),
4.06 (s, 1H), 3.97 (s, 1H), 3.95–3.87 (m, 4H), 3.77 (s, 6H), 3.73 (s, 3H), 0.83
(t, J=6.6 Hz, 6H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 165.3, 159.0,
158.9, 138.1, 134.2, 129.9, 129.3, 121.8, 120.1, 115.5, 115.2, 114.1, 114.0,
113.8, 66.9, 62.8, 56.5, 55.0, 51.2, 13.4; IR (KBr, cm–1): 2953, 2841, 2374,
2245, 1941, 1730, 1598, 1483, 1457, 1376, 1252, 1165, 1089, 1037, 932, 860,
788, 732; MS(EI): 598.46 [(M+1)+, 75%]; Anal. Calcd for C34H35N3O7: C,
68.33; H, 5.90; N, 7.03. Found: C, 68.47; H, 6.07; N, 7.22%.
4,6-Bis(2-bromophenyl)-5-nitro-2-oxopiperidine-3-carbonitrile
(3e): White solid, yield 84%, m.p. 228.0–228.7 °C (PE/EA); H NMR
1
(DMSO-d6, 600 MHz) δ (ppm): 8.91 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.68
(d, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.44 (dt, J=3.6, 7.8 Hz, 2H),
7.34 (t, J=7.2 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H),
5.80 (d, J=4.2 Hz, 1H), 5.59 (t, J=4.2 Hz, 1H), 5.33 (d, J=12.6 Hz, 1H),
5.12 (dd, J=3.6, 9.0 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm):
163.8, 133.7, 133.6, 133.1, 132.9, 130.8, 128.7, 128.3, 128.2, 124.1, 121.9,
117.4, 84.0, 56.1, 42.0, 34.7; IR (KBr, cm–1): 3084, 2948, 2258, 2039,
JCR1302089_FINAL.indd 688
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JOURNAL OF CHEMICAL RESEARCH 2013 689
1689, 1572, 1550, 1470, 1442, 1408, 1371, 1336, 1290, 1205, 1166, 1097,
1026, 968, 896, 835, 753; MS(EI): 478.98 [(M+2)+, 100%]; Anal. Calcd
for C18H13Br2N3O3: C, 45.12; H, 2.73; N, 8.77. Found: C, 45.30; H, 2.62; N,
8.86%.
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged. This is a project funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions.
4,6-Di(naphthalen-1-yl)-5-nitro-2-oxopiperidine-3-carbonitrile (3f):
1
White solid, yield 83%, m.p. 248.4–248.9 °C (MeOH/EA); H NMR
(DMSO-d6, 600 MHz) δ (ppm): 9.08 (s, 1H), 8.64 (d, J=9.0 Hz, 1H), 8.25
(d, J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.96
(d, J=7.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.82 (t, J=7.2 Hz, 1H), 7.70
(t, J=7.8 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.54 (t,
J=7.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 6.77 (d,
J=10.8 Hz, 1H), 5.70 (dd, J=3.0, 13.2 Hz, 1H), 5.54 (d, J=12.6 Hz, 1H),
5.44 (t, J=3.6 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δ (ppm): 164.1,
133.7, 133.1, 130.5, 130.1, 129.5, 129.4, 129.3, 127.5, 127.4, 126.4, 126.1,
125.5, 125.4, 124.4, 124.3, 122.2, 121.2, 117.8, 87.0, 52.7, 38.2, 35.4; IR
(KBr, cm–1): 3068, 2257, 2043, 1691, 1588, 1550, 1511, 1481, 1364, 1333,
1285, 1210, 1168, 1091, 1024, 973, 916, 777; MS(EI): 420.35 [(M–1)+,
100%]; Anal. Calcd for C26H19N3O3: C, 74.10; H, 4.54; N, 9.97. Found: C,
74.26; H, 4.68; N, 9.82.
Received 28 July 2013; accepted 23 August 2013
Paper 1302089 doi: 10.3184/174751913X13814236405771
Published online: 11 November 2013
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Tetrahedron, 2013, 69, 7011.
1
(3g): White solid, yield 80%, m.p. 207.6–208.1 °C (PE/EA); H NMR
6
7
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(DMSO-d6, 600 MHz) δ (ppm): 8.87 (s, 1H), 7.42 (t, J=7.8 Hz, 2H), 7.39
(t, J=7.8 Hz, 4H), 7.21 (s, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.15 (t, J=7.2 Hz,
3H), 7.09 (d, J=7.8 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 6.98 (d,
J=7.8 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H), 5.52 (t, J=4.8 Hz, 1H), 5.04 (d,
J=10.2 Hz, 1H), 4.67 (d, J=12.0 Hz, 1H), 4.39 (t, J=12.0 Hz, 1H); 13C
NMR (DMSO-d6, 150 MHz) δ (ppm): 162.0,156.7, 156.5, 156.4, 138.6,
137.3, 130.8, 130.5, 130.1, 123.5, 123.4, 123.0, 120.0, 119.0, 118.2, 118.1,
118.0, 116.2,90.2, 59.1, 45.2, 40.5, 30.7; IR (KBr, cm–1): 3126, 3059, 2983,
2908, 2256, 1947, 1866, 1688, 1587, 1558, 1486, 1456, 1373, 1325, 1253,
1213, 1160, 1096, 1071, 1044, 1017, 946, 896, 872, 787; MS(EI): 506.28
[(M+1)+, 100%]; Anal. Calcd for C30H23N3O5: C, 71.28; H, 4.59; N, 8.31.
Found: C, 71.36; H, 4.74; N, 8.30%.
8
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