One-step synthesis of substituted 3,5-dicyanospiro-4-(piperidine-4′)- 1H,4H-dihydropyridine-2-thiolates and 2,6-diamino-3,5-dicyanospiro-4- [(piperidine-4′) or (2′-oxoindole-3′)]-4H-thiopyrans

Article abstract of DOI:10.1080/10426500902855075

A new, one-step method for the synthesis of substituted 3,5-dicyanospiro-4(piperidine-4′)-1H,4H-dihydropyridine-3-thiolates and 2,6-diamino-3,5-dicyanospiro-4-[(piperidine-4′) or (2′ -oxoindole-3′)]-4H-thiopyrans using a multicomponent reaction of N-substituted piperidine-4-ones and isatins with derivatives of cyanoacetic acid is described. The regioselectivity of this reaction can be controlled by varying the substituents at the nitrogen atom of the piperidine-4-ones. The multicomponent reaction of N-alkylpiperidine-4-ones with malononitrile and cyanothioacetamide gives spiro-4-(1′ -alkylpiperidine-4′)-1H,4H- dihydropyridine-2-thiolates, whereas a similar reaction of N-(acyl) alkoxycarbonylpiperidine-4-ones leads exclusively to spiro-4-(1′ -(acyl)alkoxycarbonylpiperidine-4′)-4H-thiopyrans. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500902855075

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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One-Step Synthesis of
Substituted 3,5-Dicyanospiro-4-
(piperidine-4′)-1H,4H-
dihydropyridine-2-thiolates
and 2,6-Diamino-3,5-
dicyanospiro-4-[(piperidine-4′)
or (2′-oxoindole-3′)]-4H-
thiopyrans
Anatoliy M. Shestopalov a , Alexander A. Shestopalov
a , Lyudmila A. Rodinovskaya a & Anna V. Gromova a
a N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences , Moscow, Russia
Published online: 28 Apr 2009.
To cite this article: Anatoliy M. Shestopalov , Alexander A. Shestopalov , Lyudmila
A. Rodinovskaya & Anna V. Gromova (2009) One-Step Synthesis of Substituted
3,5-Dicyanospiro-4-(piperidine-4′)-1H,4H-dihydropyridine-2-thiolates and 2,6-
Diamino-3,5-dicyanospiro-4-[(piperidine-4′) or (2′-oxoindole-3′)]-4H-thiopyrans,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:5, 1100-1114, DOI:
10.1080/10426500902855075
To link to this article: http://dx.doi.org/10.1080/10426500902855075
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Phosphorus, Sulfur, and Silicon, 184:1100–1114, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902855075
One-Step Synthesis of Substituted 3,5-Dicyanospiro-4-
(piperidine-4ꢀ)-1H,4H-dihydropyridine-2-thiolates and
2,6-Diamino-3,5-dicyanospiro-4-[(piperidine-4ꢀ) or
(2ꢀ-oxoindole-3ꢀ)]-4H-thiopyrans
Anatoliy M. Shestopalov, Alexander A. Shestopalov,
Lyudmila A. Rodinovskaya, and Anna V. Gromova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy
of Sciences, Moscow, Russia
A new, one-step method for the synthesis of substituted 3,5-dicyanospiro-4-
(piperidine-4ꢀ)-1H,4H-dihydropyridine-3-thiolates and 2,6-diamino-3,5-dicyano-
spiro-4-[(piperidine-4ꢀ) or (2ꢀ-oxoindole-3ꢀ)]-4H-thiopyrans using a multicompo-
nent reaction of N-substituted piperidine-4-ones and isatins with derivatives of
cyanoacetic acid is described. The regioselectivity of this reaction can be con-
trolled by varying the substituents at the nitrogen atom of the piperidine-4-ones.
The multicomponent reaction of N-alkylpiperidine-4-ones with malononitrile and
cyanothioacetamide gives spiro-4-(1ꢀ-alkylpiperidine-4ꢀ)-1H,4H-dihydropyridine-
2-thiolates, whereas a similar reaction of N-(acyl)alkoxycarbonylpiperidine-4-ones
leads exclusively to spiro-4-(1ꢀ-(acyl)alkoxycarbonylpiperidine-4ꢀ)-4H-thiopyrans.
Keywords Cyanothioacetamide; malononitrile; multicomponent reaction; spiro-
heterocycles; thiopyrans
INTRODUCTION
Substituted 3,5-dicyano-pyridine-2-(thiones)thioles are known sub-
strates for biologically active compounds.1 Among them are com-
pounds acting as adenosine (A1) agonists,2 vasodilators,3 antianginal
preparates,4 and inhibitors of the prion replication.5 Most methods
for their synthesis are based on laborious procedures, which often
Received 10 November 2007; accepted 24 January 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
We thank the Presidium of the Russian Academy of Sciences (P-8, 2007) for partial
financial support of this work.
Address correspondence to Anatoliy M. Shestopalov, N. D. Zelinsky Institute of
Organic Chemistry, Russian Academy of Sciences, 119991, Moscow, Russia. E-mail:
shchem@dol.ru
1100

Synthesis of Dihydropyridine-2-thiolates and 4H-Thiopyrans
1101
include two or three separate steps. Usually an unsaturated nitrile
or thioamide is prepared first, which is then reacted with cyanoth-
ioacetamide or malononitrile to produce the desired heterocycle.6–8
6-Amino-4-aryl-3,5-dicyanopyridine-2-(thiones)thioles are typically
prepared by the reaction of arylidene-malononitriles or arylidenecyan-
othioacetamides with cyanothioacetamide or malononitrile in refluxing
ethanol in the presence of N-methylmorpholine as a catalyst.1,5–8
Alternatively, these compounds can be obtained by recyclization of
4-aryl-2,6-diamino-3,5-dicyano-4H-thiopyrans in refluxing ethanol
in the presence of alkaline catalysts.7,8 It also has been demon-
strated that the described stepwise method can be applied for the
synthesis of spiro-conjugated molecules; for example 6-amino-3,5-
dicyanospirocyclohexan-1,4-dihydropyridine-2-thiole was prepared
from cyclohexylidenemalononitrile and cyanothioacetamide.9 Here we
report a multicomponent reaction of N-substituted piperidin-4-ones
with malononitrile and cyanothioacetamide. We have discovered that
the regioselectivity of this reaction depends on the nature of the sub-
stituent at the nitrogen atom of the piperidine-4-one ring, and can be
easily controlled just by varying the starting materials. Based on this
discovery, we have developed regioselective multicomponent methods
for the synthesis of novel 1,4-dihydropyridines and 4H-thiopyrans
spiroconjugated with heterocycles.
RESULTS AND DISCUSSION
N-Alkylpiperidine-4-ones 1 were reacted with cyanothioacetamide (2)
and cyanoacetic ester 3 in ethanol in the presence of triethylamine at
room temperature to give substituted spiro-piperidinepyridines 10a–d
with 92–95% yields. Most likely, the first step of this process is the
simultaneous formation of electrophiles (unsaturated nitriles 4 or 6)
and nucleophiles 5 or 7, which then react with each other in a Michael
addition and form adduct 8. The subsequent 1,6-elimination of ethanol
from the Michael adduct leads to the formation of pyridine ring 9
1
(Scheme 1). According to the H NMR spectra in DMSO-d6, the het-
erocycles obtained exist in the betaine form 10; a similar phenomenon
was previously observed for the hydrogenated 4-pyridylpyridine-2(1H)-
thiones and pyridoquinuclidine-2(1H)-thiones, when the basic pyridine
and quinuclidine rings acted as proton acceptors.1,10,11
The formation of the betaine structures 10 suggests that the N-
alkylpiperidine ring is basic enough to autocatalyze the described reac-
tion. In our experiments, we did not observe the formation of pyridine-
2-(1H)-thione salts with triethylamine, which is characteristic for other

1102
A. M. Shestopalov et al.
SCHEME 1
hydrogenated pyridine-2(1H)-thiones,12 probably due to the higher ba-
sicity of the piperidine cycle compared to that of triethylamine. Accord-
ingly, we have prepared compounds 10a–d from the same starting ma-
terials in ethanol at room temperature without adding triethylamine
with 90–92% yields.
Contrary to the described reaction, N-acetyl and N-ethoxycarbonyl
piperidine-4-ones 11a,b, which lack basicity at the nitrogen atom, react
with cyanothioacetamide (2) and cyanoacetic ester 3 only in the pres-
ence of an excess of N-methylmorpholine and form spiro-piperidine-
pyridinethiolate salts 12a,b (Scheme 2). In this reaction, an excess of
N-methylmorpholine was used to drive the final pyridines into the het-
erogeneous phase and to increase their yields. A similar salification

Synthesis of Dihydropyridine-2-thiolates and 4H-Thiopyrans
1103
SCHEME 2
method was used previously to isolate hydrogentated pyridine-2(1H)-
thiones.1,12
To further extend the spectrum of the compounds accessible by
this multicomponent reaction, we have substituted cyanoacetic es-
ter (3) for malononitrile (13). A three-component condensation of
N-alkylpiperidine-4-ones 1a–e, cyanothioacetamide, and malonon-
itrile in ethanol at room temperature leads to 6-amino-spiro-
piperidinethiolates 14a-e in 75–92% yields (Scheme 3, method A). This
reaction proceeds without an alkaline catalyst, which suggests that it is
autocatalyzed by the N-alkylpiperidine-4-ones. This notion is partially
supported by the betaine structures of compounds 14.
The same compounds 14a,b,e were obtained by the reaction
of two equivalents of cyanothioacetamide with corresponding N-
alkylpiperidine-4-ones 1a,b,e in 84–87% yields (Scheme 3, method
B). However, this method does not have any preparative value, since
first cyanothioacetamide is prepared from malononitrile and hydro-
gen sulfide, and then hydrogen sulfide is eliminated in the course of
the multicomponent condensation from one of the cyanothioacetamide
molecules. Therefore, it is more advantageous to synthesize compounds
14a–e directly from malononitrile and cyanothioacetamide.
Surprisingly, when N-acetyl and N-ethoxycarbonylpiperidine-4-ones
11a–c were used in the condensation with cyanothioacetamide and
malononitrile, the regioselectivity of the reaction was changed. Ac-
cordingly, the three-component condensation of 11a–c with cyanoth-
ioacetamide and malononitrile in the presence of N-methylmorpholine
in ethanol at room temperature produced 2,6-diamino-3,5-dicyano-
4H-spiropiperidinethiopyrans 15 instead of the expected pyridines 14
(Scheme 4).
Compounds 15 were much more stable than their 4-aryl-
substituted analogs,7,8 and they did not undergo recyclization into

1104
A. M. Shestopalov et al.
SCHEME 3
SCHEME 4
6-aminopyridines 14 even after refluxing in ethanol or after heating
in DMSO at 100–110◦C in the presence of N-methylmorpholine.
The structures and purities of compounds 10–15 were supported by
elemental analysis, and by IR and NMR spectroscopy (Table I). In the
IR spectra, betaines 10 and 14 show characteristic weak (shoulder)
wide bands for the NH and NH2 groups at 3100–3400 cm−1 [1,12–14]
.
The 1H NMR spectra of compounds 10–15 contain signals for the spiro-
conjugated piperidine ring in addition to the signals of the NH and
NH2 groups (Table I). The resonance peaks of the N+H protons in the
1H NMR spectra of betaines 10 and 14 appear at 9.1–9.4 ppm as broad
singlets (Table I), while the spectra of 12 and 15 do not show such

1105

1106

1107

1108

1109

1110
A. M. Shestopalov et al.
FIGURE 1
peaks. The N+H proton of compounds 10 and 14 is very mobile and
undergoes fast H/D-exchange in the presence of D2O.
We assumed that the observed difference in the reactivities of N-
substituted piperidine-4-ones 1 and 11 is governed by two factors:
by the relative conformational stabilities of 1 and 11 and their corre-
sponding intermediates, and by the high basicity of the piperidine ring,
which can autocatalyze a recyclization of 2,6-diamino-3,5-dicyano-4H-
thiopyrans into 6-amino-3,5-dicyanopyridine-2(1H)-thiones.7,8
N-alkylpiperidine-4-ones 1 adopt preferably the chair conformation
and can undergo conformational transformation with equatorial-axial
reorientation of the ring substituent (Figure 1).13 However, the com-
plete a ↔ e conversion requires inversion of all bonds in the piperidine
ring. In N-acetyl and N-alkoxycarbonylpiperidine-4-ones 11, the p-π
conjugation of the N-C(O)-R fragment prohibits such bond inversions
at the nitrogen atom, hinders conformational a ↔ e transformations,
and results in the flattening of the piperidine ring. Moreover, solvolysis
of the polar N-C(O)-R groups by the polar solvents further prohibits
any transformation movements and fixes the substituent of the nitro-
gen atom in the equatorial position. Thus, acetyl and alkoxycarbonyl
substituents in compounds 11 serve as conformational anchors and
prevent any a ↔ e transformations.
Such conformational differences between 1 and 11 probably account
for their different regioselectivities in the reactions with cyanothioac-
etamide and malononitrile. It is logical to assume that the reactions
of N-alkylpiperidine-4-ones 1 with cyanothioacetamide and malonon-
itrile also proceed through the formation of thiopyrans 15. However,
the conformational mobility of the N-alkylpiperidine ring and its high
basicity result in subsequent recyclization of the thiopyrans into the
more stable spiro-pyridines 14 just at room temperature (Scheme 5).
We have decided to support these assumptions by using a het-
erocyclic ketone, such as isatin, in this reaction, which is fixed
in one conformation and cannot undergo any kind of transfor-
mational changes. Accordingly, a three-component condensation of
isatins 19, cyanothioacetamide, and malononitrile in ethanol at room

Synthesis of Dihydropyridine-2-thiolates and 4H-Thiopyrans
1111
SCHEME 5
temperature in the presence of N-methylmorpholine produced the
predicted 2,5-diamino-4H-spiro-(2-oxoindole)thiopyrans 20 in 87–90%
yields (Scheme 6).
SCHEME 6
Similarly to thiopyrans 15, compounds 20 also were thermodynam-
ically stable and did not undergo recyclization at 100–110◦C in DMF
in the presence of an alkaline catalyst. The structures of 20 were sup-
ported by elemental analysis and by IR and NMR spectroscopy (Table
I). The 1H NMR spectra of compounds 20 show the characteristic broad
singlets of the NH2 group in the 7.01–7.11 ppm region. The IR spectra
of 20 display the high intensity absorption bands of the conjugated CN
groups in the 2182–2195 cm−1, as well as the characteristic bands of
C(O)NR and NH2 groups (Table I).
EXPERIMENTAL
Melting points were determined on a Kofler stage. Infrared spectra
were obtained using a Perkin-Elmer 557 instrument in KBr pellets.
1H NMR spectra were recorded using a Bruker AM-300 (300 MHz)

1112
A. M. Shestopalov et al.
spectrometer in DMSO-d6 solutions. Elemental analysis was carried
out with a Perkin-Elmer C, H, N analyzer.
Substituted 3,5-Dicyano-2-oxo-spiro-4-(piperidine-4ꢀ)-
1,2,3,4-tetrahydro-pyridine-6-thiolates (10): General Procedure
A reaction mixture containing piperidin-4-one 1a–d (10 mmol), cyan-
othioacetamide 2 (1.0 g, 10 mmol), ethyl 2-cyanoacetate 3 (1.13 g,
10 mmol), and triethylamine (0.2 mL, 3 mmol) in ethanol (25 mL)
was stirred at room temperature for 10 h. Then the reaction mix-
ture was left at 4◦C overnight. The precipitate formed was separated
by filtration, washed with ethanol (2 × 5 mL) and petroleum ether
(2 × 10 mL), and dried in an oven (5 h at 70◦C) to give analyti-
cally pure compounds 10a–d after recrystallization from nitromethane
(Table I).
N-Methylmorpholine-3,5-dicyano-2-oxo-spiro-4-(piperidine-
4ꢀ)-1,2,3,4-tetrahydropyridine-6-thiolates (12): General
Procedure
A reaction mixture containing piperidin-4-one 11a,b (10 mmol), cyan-
othioacetamide 2 (1.0 g, 10 mmol), ethyl 2-cyanoacetate 3 (1.13 g, 10
mmol), and N-methylmorpholine (1.5 g, 15 mmol) in ethanol was stirred
at room temperature for 2 h and then filtered. The filtrate was kept at
4◦C for 3 days. The precipitate formed was separated by filtration,
washed with ethanol (2 × 5 mL) and petroleum ether (2 × 10 mL),
and dried in air. Compounds 12 were recrystallized from nitromethane
(Table I).
Substituted 6-Amino-3,5-dicyano-spiro-4-(piperidine-4ꢀ)-
1,4-dihidropyridine-2-thiolates (14): General Procedure
Method A
A reaction mixture containing piperidin-4-one 1 (10 mmol), cyanoth-
ioacetamide 2 (1.0 g, 10 mmol), and malononitrile 13 (0.66 g, 10 mmol)
in ethanol (25 mL) was stirred at room temperature for 2 h and then
filtered. The filtrate was kept at 4◦C for 3 days. The precipitate formed
was separated by filtration, and washed with ethanol (2 × 5 mL) and
petroleum ether (2 × 10 mL) to give analytically pure compounds 14a–e
after recrystallization from nitromethane (Table I).

Synthesis of Dihydropyridine-2-thiolates and 4H-Thiopyrans
1113
Method B
A reaction mixture containing the corresponding piperidin-4-one
1a,b,e (10 mmol), cyanothioacetamide 2 (2.0 g, 20 mmol), and triethy-
lamine (0.2 mL, 3 mmol) in ethanol (25 mL) was stirred at 50◦C for 1 h
(H2S formation) and then filtered. The filtrate was kept at 4◦C for 3
days. The precipitate formed was separated by filtration, and washed
with ethanol (2 × 10 mL) and petroleum ether (2 × 5 mL) to give
analytically pure compounds 14a,b,e (Table I).
Substituted 2,6-Diamino-3,5-dicyano-spiro-4-(piperidine-4ꢀ)-
4H-thiopyrans (15): General Procedure
A reaction mixture containing piperidin-4-one 11a-c (10 mmol), cyan-
othioacetamide 2 (1.0 g, 10 mmol), malononitrile 13 (0.66 g, 10 mmol),
and triethylamine (0.2 mL, 3 mmol) in ethanol (20 mL) was stirred at
room temperature for 1 h and then filtered. The filtrate was then kept
at 4◦C for 2 days. The precipitate formed was separated by filtration,
and washed with ethanol (2 × 5 mL) and petroleum ether (2 × 10 mL)
to give analytically pure compounds 15a–c after recrystallization from
isopropanol (Table I).
Substituted 2,6-Diamino-3,5-dicyano-spiro-4-(2ꢀ-oxoindol-3ꢀ)-
4H-thiopyrans (20): General Procedure
To a stirring reaction mixture of isatin 19 (10 mmol), cyanothioac-
etamide 2 (1.0 g, 10 mmol), and malononitrile 13 (0.66 g, 10 mmol)
in ethanol (30 mL), N-methylmorpholine (0.2 mL) was added at room
temperature. The reaction mixture was stirred at room temperature for
an additional 6 h. The precipitate formed was separated by filtration,
and washed with ethanol (2 × 10 mL) and petroleum ether (2 × 10
mL). Compounds 20a–c were than recrystallized from a DMF:ethanol
mixture (3:1) to give analytically pure samples (Table I).
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