Novel route to spiropiperidines using N-methyl-4-piperidone, malononitrile and electrophiles

Article abstract of DOI:10.1016/j.tetlet.2011.12.129

A new pathway to spiropiperidine rings via sequential one pot reaction of N-methyl-4-piperidone, malononitrile, and electrophiles or Michael acceptor in the presence of triethyl amine in ethanol under reflux condition is reported.

Full text of DOI:10.1016/j.tetlet.2011.12.129

Tetrahedron Letters 53 (2012) 1282–1286
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel route to spiropiperidines using N-methyl-4-piperidone, malononitrile
and electrophiles
⇑
Neelakandan Vidhya Lakshmi, G.A. Suganya Josephine, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new pathway to spiropiperidine rings via sequential one pot reaction of N-methyl-4-piperidone, mal-
ononitrile, and electrophiles or Michael acceptor in the presence of triethyl amine in ethanol under reflux
condition is reported.
Received 7 October 2011
Revised 28 December 2011
Accepted 31 December 2011
Available online 8 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spiro-oxindoles
Spiropiperidine
Ketones
Aldehydes
Malononitrile
The synthesis of piperidine rings has achieved much attention
as they display a fascinating array of biological applications such
as spasmolytic activity and potent cytotoxicity toward human Molt
4/C8 and CEM T-lymphocytes as well as murine P388 and L1210
leukemic cells.1 Spiropiperidine nucleus is frequently recognized
in several natural alkaloids since it possesses high agonistic activ-
ity and selectivity as Ro64-6198 and also shows anxiolytic
properties.2
The oxindole framework bearing a spirocyclic quaternary ste-
reocenter at the C3 position is a significant privileged heterocyclic
scaffold since it appears in a plethora of natural alkaloids, such as
horsifiline, spirotryprostatine A and B, elacomine etc and also acts
as potent nonpeptide inhibitor of the p53-MDM2 interaction.3,4 In-
spite of the enormous importance of spiro-oxindoles and spiropi-
peridine derivatives due to their biological activities, only a few
reports are existing on the assembly of spiro derivatives that incor-
porate both bioactive moieties in a single framework.5
Recently, Alizadeh et al. have synthesized spiro-oxindoles via
four component reaction of amines, isatin, 1-phenyl-2-(1,1,1-tri-
phenyl-k5-phosphanylidene)-1-ethanone, and alkyl acetoacetate.6
We have recently reported the synthesis of spiro-oxindoles via
1,3-dipolar cycloaddition and vinylogous nucleophilic addition7
and also developed a new pathway to spiro-oxindoles through a
one-pot reaction of isatin, sarcosine, and 3-phenyl-5-isoxazolone.8
On the basis of our progressive endeavors in exploring new meth-
odologies toward spiro-oxindoles, we herein wish to report a
sequential one pot reaction involving isatin, N-methyl-4-piperi-
done and malononitrile in the presence of triethyl amine in ethanol
under reflux to furnish spiroderivatives containing both spiro-
oxindoles and spiropiperidines. Here, the unsaturated 2-(1-
methyl-piperidin-4-ylidene)-malononitrile formed in situ from N-
methyl-4-piperidone and malononitrile dimerizes to yield the di-
mer spiro-piperidinoisoquinoline9 which plays a major role in
the synthesis of spiro-oxindoles. To the best of our knowledge, this
is the first report on the dimer (spiro-piperidinoisoquinoline) of 2-
(1-methyl-piperidin-4-ylidene)-malononitrile involved to synthe-
size functionalized spiro-oxindoles.
Initially, in our pilot experiment, a mixture of N-methyl-4-pip-
eridone 1 (1.0 mmol) and malononitrile 2 (1.0 mmol) in ethanol
was stirred at room temperature in the presence of triethyl amine
for 5 min to afford the dimer spiro-piperidinoisoquinoline 3 which
was also confirmed by spectroscopic studies (Scheme 1).9,10
The dimer spiro-piperidinoisoquinoline 3 was treated with isat-
in 4a in the presence of triethyl amine in various solvents like eth-
anol, toluene, and acetonitrile under reflux condition which led to
the formation of functionalized spiro-oxindole containing spiropi-
peridine ring 5a as a single diastereomer (Scheme 2, Table 1).
Moreover, the sequential one pot reaction of N-methyl-4-pip-
eridone 1 (1.0 mmol), malononitrile 2 (1.0 mmol), and isatin 4a
(1.0 mmol) in ethanol under reflux in the presence of triethyl
amine also resulted in the formation of spiro-oxindole containing
spiropiperidine ring 5a as a single diastereomer which was proved
by 1H NMR spectroscopy.
The best result was obtained by refluxing an equimolar mixture
of N-methyl-4-piperidone 1, malononitrile 2 (1.0 mmol) in ethanol
⇑
Corresponding author.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.129

N. V. Lakshmi et al. / Tetrahedron Letters 53 (2012) 1282–1286
1283
CN
NC
N
N
NC
NC
O
H2N
CN
NEt3
dimerization
+
NC
ethanol
N
N
CN
1
2
2a
3
Scheme 1. Synthesis of dimer spiro-piperidinoisoquinoline 3.
CN
N
NC
O
HN
O
N
N
NC
NC
H2N
O
N
H2N
N
H
4a
H
NC
NEt3
O
N
H
ethanol, reflux
3
rac- 5a
Scheme 2. Synthesis of spiro-oxindole derivatives containing spiropiperidine ring 5a.
singlets were observed at d 2.13 and 2.17 ppm which showed the
presence of protons of two –NCH3 groups. The characteristic sing-
lets at d 8.29, 9.07, and 10.02 ppm were assigned to –NH2 protons,
–NH proton of the imine group and –NH proton of the oxindole
ring, respectively, which proved the incorporation of oxindole ring
in the structure. The amide carbonyl carbon atom of oxindole ring
resonated at d 172.6 ppm in 13C NMR spectrum. The presence of a
molecular ion peak at m/z 470.20 in the mass spectrum which fur-
ther supported the formation of the product 5a.12
Table 1
Synthesis of spiro-oxindoles having spiropiperidine ring 5a by Scheme 2
Entry
Solvent
Reflux temperaturea(°C)
Yieldb (%)
1
2
3
Ethanol
Acetonitrile
Toluene
79
82
110
82
79
67
a
Reflux temperature of the solvent.
Isolated yield by recrystallization.
b
The IR spectrum of compound 7 showed peaks at 1739 and
1706 cmÀ1 for indandione carbonyl groups. The 1H NMR spectrum
of compound 7 exhibited four characteristic singlets at d 2.09, 2.15,
8.20, and 8.60 ppm for two –NCH3 protons, –NH2 protons and –NH
proton of imine group, respectively. The two keto carbonyl carbon
for 5 min followed by the addition of isatin 4a (1.0 mmol) and the
reflux was continued until the completion of the reaction to yield
the spiro-oxindole 5a with good yield (85%) (Scheme 3, Table 2).11
The optimized protocol of this cyclization reaction was then ex-
panded to a variety of substituted isatin derivatives 4a–h and other
cyclic ketones such as ninhydrin 6, acenaphthenequinone 8, and
indeno[1,2-b]quinoxalin-11-one 10 to provide spiro frameworks
containing spiro piperidine ring 5a–h, 7, 9, and 11, respectively,
as single diastereomer with good yields (71–85%) as evidenced
by TLC and spectral analysis (Table 2 and Schemes 3 and 4).
The structures of the compounds 5a–h, 7, 9, and 11 were con-
firmed by spectroscopic studies and elemental analysis. In IR spec-
trum of compound 5a, the absorptions at frequencies 2249 and
1742 cmÀ1 correspond to cyano and amide functional groups. In
the 1H NMR spectrum, there are thirteen aliphatic protons. Two
atoms of indandione showed peaks at d 194.2 and 195.0 ppm in 13
C
NMR spectrum. These observed chemical shift values confirmed
the proposed structure. A distinguishing peak was observed at m/
z 483.32 in the mass spectrum. The relative stereochemistry of
the products 5a–h, 9, and 11 was established through single–crys-
tal X-ray analysis of compound 5a (Fig. 1).13
On the basis of the above results, a tentative mechanistic inter-
pretation to explain the formation of product 5a is proposed
(Scheme 5). Usually, N-methyl-4-piperidone 1 involves Knoevena-
gel condensation with malononitrile 2 to give 2-(1-methyl-piperi-
din-4-ylidene)-malononitrile 2a which is unstable and dimerizes
CN
N
NC
O
HN
O
R1
N
N
NC
NC
H2N
O
O
N
H2N
CN
CN
R1
N
NEt3
4a-h
R
+
H
O
NC
ethanol, reflux
N
NEt3
ethanol, reflux
N
R
1
2
3
rac- 5a-h
Scheme 3. Synthesis of spiro-oxindole derivatives containing spiropiperidine ring 5a–h by sequential one pot approach.

1284
N. V. Lakshmi et al. / Tetrahedron Letters 53 (2012) 1282–1286
Table 2
Synthesis of spiro-oxindoles having spiropiperidine ring 5a–h by sequential one pot
approach (Scheme 3)
Entry Isatin (4a–h)
R
R1
Product (5)a Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
H
H
H
H
Cl
Br
5a
5b
5c
45
45
65
65
65
65
65
65
85
83
82
81
81
80
78
81
Methyl 5d
Allyl
Benzyl
Propargyl
Methyl
H
H
H
H
5e
5f
5g
5h
4g
4h
a
The products were characterized by spectral and elemental analysis.
Isolated yield by recrystallization.
b
in situ to give spiro-piperidinoisoquinoline 3.9 The dimer 3 adds on
to isatin keto carbonyl group 4a to yield 3-hydroxyoxindole 3a in
presence of triethyl amine. The intermediate 3a cyclizes intramo-
lecularly via the nucleophilic attack of the –OH group on the cyano
triple bond resulting in the formation of imine intermediate 3b.
The intermediate 3b involves proton transfer to afford product 5a.
The promising results prompted us to extend the protocol by
replacing cyclic ketones with aromatic aldehydes (12a–h) under
identical conditions (Scheme 6). The dimer 3 formed in situ from
N-methyl-4-piperidone 1 and malononitrile 2 undergoes nucleo-
philic addition with aromatic aldehydes (12a–h) to furnish 3-
aryl-3H-spiro[piperidine-4’,7-pyrano[3,4,5-de]isoquinoline] deriv-
atives (13a–h) in good yields (76–82%) (Table 3).
Figure 1. ORTEP diagram of compound 5a.
The dimer 3 undergoes Michael addition with derivatives of isa-
tylidene malononitrile (14a–h) instead of nucleophilic addition as
in Scheme 5 to provide spiro-oxindoles (15a–h) in good yields (72–
78%) (Table 4). The reaction is diastereoselective since only one
diastereomer was formed in all the reactions.
With a view to explore the generality of the reaction, various
derivatives of isatylidene malononitrile (14a–h) as Michael accep-
tor and dimer 3 were exploited to synthesize a library of spiro-
oxindoles containing spiro piperidine rings (15a–h) under opti-
mized conditions (Scheme 7).
The spiro-oxindoles 15a–h were confirmed by spectral and ele-
mental analysis. The IR spectrum of compound 15a showed peaks
at 2232 and 1695 cmÀ1 for cyano and amide functional groups. The
1H NMR spectrum of compound 15a exhibited four characteristic
singlets at d 2.04, 2.21, 7.12, and 8.30 ppm for two –NCH3 protons,
O
OH
OH
NH2
NH
O
O
CN
CN
O
6
50 min
O
H
N
N
(80%)
rac-7
NC
HN
CN
O
O
H2N
O
N
O
O
CN
NEt3
50 min
N
8
H
+
ethanol, reflux
N
CN
(78%)
rac-9
CN
1
2
NC
N
HN
O
H2N
N
N
N
N
O
H
65 min
10
N
(71%)
rac 11
Scheme 4. Synthesis of spiroframeworks containing spiropiperidine rings 7, 9 and 11.

N. V. Lakshmi et al. / Tetrahedron Letters 53 (2012) 1282–1286
1285
CN
NC
N
N
NC
NC
O
H2N
CN
CN
NEt3
dimerization
+
NC
ethanol
reflux
N
N
1
2
2a
3
CN
CN
NC
NC
HN
HN
N
N
CN
O
..
H2N
H
N
HN
N
H
..
HO
O
NC
NC
N
O
nucleophilic
attack
N
N
4a
O
O
N
H
N
N
H
3
3a
3b
Proton transfer
CN
N
NC
HN
O
H2N
N
R1
H
O
N
R
rac-5a-h
Scheme 5. Plausible mechanism for the synthesis of spiro-oxindoles containing spiropiperidine ring 5a–h.
CN
NC
N
N
N
HN
O
NC
NC
O
CN
CN
NEt3
H2N
R2CHO
H2N
12a-h
+
N
ethanol, reflux
N
NC
H
R2
1
2
3
rac- 13a-h
Scheme 6. Synthesis of 3-aryl-3H-spiro[piperidine-4’,7-pyrano[3,4,5-de]isoquinoline] derivatives 13a–h.
–NH2 protons and –NH proton of imine group (D2O exchangeable)
respectively. A broad singlet at d 10.67 ppm indicates the presence
of –NH proton of oxindole ring (D2O exchangeable).
The amide carbonyl carbon atom of oxindole ring showed a sig-
nal at d 166.3 ppm in 13C NMR spectrum. A distinguishing peak
was observed at m/z 518.43 in the mass spectrum. The stereo-
chemistry of the products 15a–h was assigned by analogy of com-
pound 5a.
In summary, we have demonstrated a simple, facile, and novel
reaction for the synthesis of spiro-frameworks containing spiropi-
peridine ring from cyclic ketones such as isatin, ninhydrin, ace-
naphthenequinone, and indeno[1,2-b]quinoxalin-11-one. The
Knoevenagel condensation product of N-methyl-4-piperidone and
malononitrile was dimerized to form spiro-piperidinoisoquinoline
which attacks cyclic ketones and aromatic aldehydes to provide a
Table 3
Synthesis of 3-aryl-3H-spiro[piperidine-4’,7-pyrano [3,4,5-de]isoquinoline] deriva-
tives 13a–h
Entry R2CHO (12a–h) R2
Product (13)a Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
C6H5
13a
13b
13c
13d
13e
13f
70
70
70
70
70
70
70
70
76
78
78
80
82
78
76
76
1-Napthyl
2-Napthyl
4-ClC6H4
4-BrC6H4
4-CH3C6H4
12g
12h
4-OCH3C6H4 13g
4-FC6H4 13h
a
The products were characterized by spectral and elemental analysis.
Isolated yield by recrystallization.
b

1286
N. V. Lakshmi et al. / Tetrahedron Letters 53 (2012) 1282–1286
CN
N
NC
CN
NC
HN
H2N
NC
NC
R1
N
N
NC
NC
O
O
N
R
R1
N
CN
H2N
NEt3
14a-h
H
+
O
ethanol, reflux
NC
N
CN
N
R
1
2
3
rac- 15a-h
Scheme 7. Synthesis of spiro-oxindoles containing spiropiperidine ring derivatives 15a–h.
3. (a) Basavaiah, D.; Reddy, R. K. Org. Lett. 2007, 9, 57; (b) Kumar, R. R.; Perumal,
S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009, 44,
3821; (c) Badillo, J. J.; Arevalo, G. E.; Fettinger, J. C.; Franz, A. K. Org. Lett. 2011,
13, 418; (d) Lu, C.; Xiao, Q.; Floreancig, P. E. Org. Lett. 2010, 12, 5112; (e) Cheng,
M. –N.; Wang, H.; Gong, L. –Z. Org. Lett. 2011, 13, 2418.
4. (a) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639; (b)
Babu, A. R. S.; Raghunathan, R.; Baskaran, S. Tetrahedron 2009, 65, 2239; (c)
Smet, M.; Oosterwijck, C. V.; Hecke, K. V.; Meervelt, L. V.; Vandendriessche, A.;
Dehaen, W. Synlett 2004, 2388; (d) Cravotto, G.; Giovenzana, G. B.; Pilati, T.;
Sisti, M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447.
Table 4
Synthesis of spiro-oxindoles having spiropiperidine rings 15a–h
Entry (14a–h)
R
R1
Product (15)a Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
H
H
H
H
H
Cl
Br
15a
15b
15c
85
85
85
95
95
95
95
95
75
78
78
78
76
75
72
72
Methyl 15d
Allyl
Benzyl
Propargyl
Methyl
H
H
H
H
15e
15f
5. Kumar, R. S.; Perumal, S. Tetrahedron Lett. 2007, 48, 7164.
6. Alizadeh, A.; Mokhtari, J. Tetrahedron 2011, 67, 3519.
14g
14h
15g
15h
7. (a) Lakshmi, N. V.; Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2010, 51,
1064; (b) Lakshmi, N. V.; Thirumurugan, P.; Perumal, P. T. Synlett 2010, 955; (c)
Babu, T. H.; Joseph, A. A.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett.
2010, 51, 994; (d) Babu, T. H.; Karthik, K.; Perumal, P. T. Synlett 2010, 1128.
8. Lakshmi, N. V.; Arun, Y.; Perumal, P. T. Tetrahedron Lett. 2011, 52, 3437.
9. Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Niazimbetova, Z. I.; Evans, D. H. Tetrahedron 2003, 59, 7491.
a
The products were characterized by spectral and elemental analysis.
Isolated yield by recrystallization.
b
series of spiropiperidine derivatives. Moreover a further delinea-
tion to replace isatin by isatylidene malononitrile as Michael
acceptor to synthesize spiro-oxindoles containing spiro piperidine
rings is also discussed. The simplicity of the approach makes this
strategy useful for the synthesis of novel spiro frameworks. Further
studies to delineate the scope and limitations of the present meth-
odology are underway.
10. Spectral data of compound 3: 1H NMR (500 MHz, DMSO-d6): d 1.46–1.49 (m,
1H), 1.61–1.64 (m, 1H), 2.00 (s, 3H, -NCH3), 2.11–2.12 (m, 3H), 2.14–2.16 (m,
1H), 2,2 (s, 3H, -NCH3), 2.42–2.44 (m, 1H), 2.66–2.68 (m, 2H), 2.77 (d, 1H,
J = 7.0 Hz), 2.92–2.95 (m, 1H), 3.10–3.12 (m, 1H), 3.19–3.21 (m, 1H), 5.68 (t, 1H,
J = 2.5 Hz), 7.27 (s, 2H, –NH2, D2O exchangeable). 13C NMR (125 MHz, DMSO-
d6): 26.6, 33.2, 43.8, 45.7, 46.1, 50.9, 51.8, 53.1, 53.3, 54.6, 55.3, 81.0, 113.2,
113.3, 116.1, 120.2, 126.7, 142.9. MS (EI): (m/z) 323.12 [M+H]+.
11. Typical experimental procedure for 5a: A mixture of N-methyl-4-piperidone 1
(1.0 mmol), malononitrile 2 (1.0 mmol) in the presence of triethyl amine was
refluxed in ethanol for 5 min. After that, isatin 4a (1.0 mmol) was added and
was refluxed for 40 min and cooled to room temperature. The solid formed in
the reaction mixture was filtered and dried under vacuum. The crude solid
product was purified by recrystallization in ethanol to obtain the pure product
5a in good yield (85%).
Acknowledgment
One of the authors, N.V. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship.
12. Spectral data of compound 5a (Table 1, entry 1): White solid. mp 284–286 °C. Rf
0.25 (50% EtOAc/Petroleum ether); mmax (KBr): 3449, 3314, 2943, 2797, 2249,
1742, 1635, 1583, 1471, 1323, 1211, 1123, 1082, 791, 749 cmÀ1 1H NMR
.
(500 MHz, DMSO-d6): d 1.14 (t, 1H, J = 10.7 Hz), 1.61 (t, 1H, J = 11.45 Hz), 1.86–
1.89 (m, 2H), 1.94–1.96 (m, 1H), 2.02–2.04 (m, 1H), 2.13 (s, 3H, –NCH3), 2.17 (s,
3H, –NCH3), 2.50–2.52 (m, 1H), 2.69–2.72 (m, 2H), 2.81–2.83 (m, 1H), 3.07–
3.09 (m, 1H), 3.31–3.33 (m, 2H), 6.77 (d, 1H, J = 7.65 Hz, Ar-H), 6.90–6.93 (m,
2H, Ar-H), 7.29 (t, 1H, J = 7.65 Hz, Ar-H), 8.29 (s, 2H, –NH2, D2O exchangeable),
9.07 (br s, 1H, –NH, D2O exchangeable), 10.02 (br s, 1H, –NH, D2O
exchangeable). 13C NMR (125 MHz, DMSO-d6): 31.2, 31.9, 37.9, 43.7, 45.6,
46.0, 51.3, 52.7, 55.3, 58.3, 81.2, 81.3, 111.2, 114.0, 119.4, 122.9, 123.2, 124.9,
125.6, 131.7, 142.7, 160.0, 172.6. MS (EI): (m/z) 470.20 [M+H]+. Anal. Calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.129.
References and notes
C
26H27N7O2: C 66.51; H 5.80; N 20.88. Found: C 66.54; H 5.78; N 20.93.
13. Crystallographic data for compound 5a in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC-833093. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).
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