Aminomethylation of morpholinium and N-methylmorpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates

Article abstract of DOI:10.1007/s10593-016-1843-5

[Figure not available: see fulltext.]The structure of reaction products obtained from 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates, primary amines, and formaldehyde substantially depends on the nature of counter-ion (morpholinium or N-methylmorpholinium), as well as on the primary amine structure and the ratio of reactants. Aminomethylation of these thiolates with highly nucleophilic amines RCH₂NH₂ and excess formalin (2 equiv and more) produced 7-RCH₂-9,9-dimethyl-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile salts, which gave the respective bispidines upon acidification. Performing this reaction with aromatic amines in the case of N-methylmorpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate led to analogous bispidines, while the morpholinium salt gave 3-aryl-8,8-dimethyl-7-[(morpholin-4-yl)methyl]-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-7,9-dicarbonitriles. The treatment of thiolates with 1 equiv of НСНО and 1 equiv of RCH₂NH₂ led to 7-RCH₂-4-amino-9,9-dimethyl-2-oxo-6-thioxo-3,7-diazabicyclo[3.3.1]non-3-ene-1-carbonitriles. The molecular and crystal structures of key compounds were studied in detail by X-ray structural analysis.

Full text of DOI:10.1007/s10593-016-1843-5

DOI 10.1007/s10593-016-1843-5
Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
Aminomethylation of morpholinium and
N-methylmorpholinium 3,5-dicyano-4,4-dimethyl-
6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates
Victor V. Dotsenko1*, Konstantin А. Frolov1, Sergey G. Krivokolysko1,
Elena A. Chigorina2, Tatyana M. Pekhtereva3, Sergey Yu. Suykov3,
Elena S. Papayanina4, Artem О. Dmitrienko5 and Ivan S. Bushmarinov5
1 Kuban State University, 149 Stavropol'skaya St., Krasnodar 350040, Russia
е-mail: victor_dotsenko@bigmir.net
2 Federal State Unitary Enterprise "IREA", Bogorodsky val 3, 107076 Moscow, Russia
e-mail: echigorina@mail.ru
3 L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry,
70 R. Luxemburg St., Donetsk 83114, Ukraine
4 University of Erlangen-Nürnberg, Institute of Organic Chemistry II,
42 Henkestr., Erlangen 91054, Germany; е-mail: infou_nmr@bigmir.net
5 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences
28 Vavilova St., Moscow 117813, Russia; е-mail: ib@ineos.ac.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(2), 116–127
Submitted February 10, 2016
Accepted February 24, 2016
The structure of reaction products obtained from 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates, primary amines,
and formaldehyde substantially depends on the nature of counter-ion (morpholinium or N-methylmorpholinium), as well as on the
primary amine structure and the ratio of reactants. Aminomethylation of these thiolates with highly nucleophilic amines RCH2NH2 and
excess formalin (2 equiv and more) produced 7-RCH2-9,9-dimethyl-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile
salts, which gave the respective bispidines upon acidification. Performing this reaction with aromatic amines in the case of
N-methylmorpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate led to analogous bispidines, while the
morpholinium salt gave 3-aryl-8,8-dimethyl-7-[(morpholin-4-yl)methyl]-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-
7,9-dicarbonitriles. The treatment of thiolates with 1 equiv of НСНО and 1 equiv of RCH2NH2 led to 7-RCH2-4-amino-9,9-dimethyl-2-oxo-
6-thioxo-3,7-diazabicyclo[3.3.1]non-3-ene-1-carbonitriles. The molecular and crystal structures of key compounds were studied in detail by
X-ray structural analysis.
Keywords: bispidines, 3,7-diazabicyclo[3.3.1]nonanes, pyrido[2,1-b][1,3,5]thiadiazines, tetrahydropyridine-2-thiolates, aminomethyla-
tion, Mannich reaction, recyclization, tandem reactions, X-ray structural analysis.
An unusual synthesis of pyrido[3,2-е][1,3]thiazine deriva-
tives 1 by aminomethylation of morpholinium 3,5-dicyano-
4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate (2а)
using 4 equiv of formaldehyde and 1 equiv of benzylamine
or furfurylamine was recently described by Nikishin1,2
(Scheme 1).
Scheme 1
These findings were clearly different from both the
general trends of Mannich reactions, as well as the results
of our studies regarding the aminomethylation reactions of
analogous pyridine-2-thiolates and related compounds,3–23
therefore we decided to study this reaction in detail and to
0009-3122/16/5202-0116©2016 Springer Science+Business Media New York
116

Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
Scheme 2
determine the structure of the obtained products. Since the
morpholinium salt 2a and N-methylmorpholinium salt 2b
were reported in a dissertation2 with the same designation,
we decided to investigate the reactivity of both salts under
the conditions of aminomethylation reaction. We found that
the results of the aforementioned publications1,2 could not
be reproduced even when all the indicated conditions were
followed exactly. For example, refluxing alcohol solutions
of thiolates 2a,b with 1 equiv of PhCH2NH2 and 4 equiv of
НСНО as 37% formalin for 2 h failed to produce a
precipitate of the product. It was shown by HPLC-MS and
1H NMR analysis of the yellow resinous residue obtained
after evaporation of the reaction solution that in both cases
the only reaction products were the respective 7-benzyl-
9,9-dimethyl-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-
1,5-dicarbonitrile salts 3a,b (Scheme 2). Previously we had
described19 the formation of similar salts (''bispidinates'')
during aminomethylation of 3,5-bisnucleophilic pyridine
substrates. Careful acidification of the reaction mixture led
to the formation of crystalline 7-benzyl-9,9-dimethyl-2-oxo-
4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile
(4а) (37% yield from salt 2a, 39% yield from salt 2b). The
application of a method that we previously tested with
analogous substrates,7,8,19 based on a brief heating of thio-
late and amine with a large excess of formalin (≥ 10 equiv),
allowed to increase the yield of compound 4а to 46%.
Other aliphatic amines reacted analogously with the
thiolates 2a,b in the presence of excess НСНО, producing
after acidification the bispidines 4b,с (Scheme 2). It should
be emphasized that the obtained results were entirely
predictable and closely matched the behavior of analogous
tetrahydropyridine derivatives under the Mannich reaction
conditions.4,7,8,19
relative to the carbonyl and thione groups. The substituent in
both conformers had an equatorial orientation (the torsion
angle C(12)–N(2)–C(6)–C(4) was 178.84(18)°) and assumed
an –sc conformation relative to the N(2)–C(6) bond (the torsion
angle C(6)–N(2)–С(12)–С(13) was –69.0(2)°). Both confor-
mers occupied equivalent positions in the crystal, resulting
in disordered oxygen and sulfur atom positions in the
carbonyl and thione groups populated in 0.590(6) : 0.410(6)
ratio. The N(2) nitrogen atom had a pyramidal configuration,
with the sum of valence angles at the atom equal to 332.1°.
The molecules were linked in the crystal structure with
N(1)–H(1)···N(4i) hydrogen bonds [i: 1 – x, –1/2 + y, 1/2 – z]
(H···N 2.38 Å, N–H···N 140°) as infinite chains along the
b axis.
The bispidines 4 were isolated as bright-yellow crystals,
readily soluble in acetone, hot alcohols, АсОН, insoluble in
ether and cold EtOH. IR spectra of diazabicyclononanes 4
featured a weak absorption band, corresponding to the
stretching vibrations of non-conjugated C≡N groups (2246–
2258 cm–1). 1Н NMR spectra of compounds
4а–с,е contained characteristic singlets of diastereotopic
methyl groups at 1.29–1.36 and 1.46–1.56 ppm, signals of
It should be noted that our attempts to obtain the
bispidine 4d (R = 2-furyl) failed: treating the thiolate 2а
with furfurylamine (1 equiv) and excess НСНО under
various conditions gave only intractable resinous mixtures.
According to HPLC-MS data, besides the bispidine 4d the
mixture contained at least two additional compounds with
higher molecular mass.
The structure of diazabicyclononanes 4 was confirmed
by a set of spectral methods, as well as the X-ray structural
analysis results for compound 4а (Fig. 1).
Compound 4а existed in crystalline state as two conformers
that differed by the orientation of benzyl substituent
Figure 1. The molecule of compound 4a with atoms represented
by thermal vibration ellipsoids of 50% probability. The bonds
involving the minor component are shown as dotted lines.
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Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
Scheme 3
Figure 2. The molecule of compound 5a with atoms represented
by thermal vibration ellipsoids of 50% probability.
CH2NCH2 group in the region of 3.00–3.97 ppm, as well as
a broadened NH proton singlet in the downfield region at
13.55–13.81 ppm.
half-boat conformation. The phenyl substituent at the N(3)
atom occupied an axial position, enabling stereoelectronic
interactions lp-N(3)–C(2)–S(1) and lp-N(3)–C(4)–N(5) (the
respective pseudodihedral angles were 178° and 175°),
analogously to the conformational features observed for
aryl-substituted 1,3,5-thiadiazinanes.24 The presence of
anomeric effect was also indicated by the bond lengths:25 the
N(3)–C(4) bond (1.4330(15) Å) was substantially shortened
compared to the С(4)–N(5) bond (1.4970(15) Å), while the
S(1)–C(2) bond was lengthened to 1.8428(12) Å, compared
to the values typical for C(sp3)–S bonds (1.817 Å).26
Crystals of compound 5a were formed by van der Waals
interactions, among which the relatively close intermolecular
contact (Fig. 3) of cyano group with the S–CH2 bond should
be noted: N(3)···S(2i) (3.1704(12) Å) and N(3)···H(2Bi)–C(2i)
(N···C 3.1855(17) Å), with the С(12)≡N(3)···S(1i) angle
The different reactivity of morpholinium and N-methyl-
morpholinium salts 2a,b was observed by using the less
reactive anilines ArNH2 in the reaction instead of primary
amines RCH2NH2. For example, the N-methylmorpho-
linium thiolate 2b reacted with p-toluidine and excess
НСНО, giving the expected diazabicyclononane 4e, while
aminomethylation of the morpholinium salt 2а unexpectedly
led to 3-aryl-8,8-dimethyl-7-[(morpholin-4-yl)methyl]-6-oxo-
3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-
7,9-dicarbonitriles 5а–с (Scheme 3). Obviously, the change
in reaction direction was caused by blocking of the reaction
site at the С-5 atom, which was subjected to competing
aminomethylation with the participation of morpholine at
the first reaction step, with the preferential formation of
betaine intermediate А. The latter further reacted with
ArNH2 and НСНО as an S,N-bisnucleophile, with the
closure of 1,3,5-thiadiazine ring. As we have shown several
times in the past,3,12–14,16,17,21–23 the formation of pyrido[2,1-b]-
[1,3,5]thiadiazine system is a general outcome of amino-
methylation reactions for all partially hydrogenated pyri-
dine-2-thiolates that do not contain an electron-with-
drawing substituent at the С-5 atom.
The structure of compounds 5а–с was confirmed by spectral
data sets, including one-dimensional 13C (DEPT-135, APT) and
two-dimensional (1Н–13С HSQC, 1Н–13С HMBC) NMR expe-
riments, as well as single crystal X-ray structural analysis of
8,8-dimethyl-7-[(morpholin-4-yl)methyl]-6-oxo-3-phenyl-
3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-7,9-di-
carbonitrile (5а) (Fig. 2). The S(1)–C(2)–N(3)–C(4)–N(5)–C(9A)
ring in the central bicyclic system assumed a chair confor-
mation, while the N(5)–C(6)–C(7)–C(8)–C(9)=C(9A) ring had a
Figure 3. The C≡N···(CH2–S) contact in the crystal of compound
5а. Only the atoms participating in the interaction have been
identified, the index i in superscript corresponds to symmetry
operation (1 + x, –1 + y, +z).
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Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
equal to 168.32(12) Å, indicating the directional nature of
Thus, we have clearly established that aminomethylation
of thiolates 2a,b either by literature procedures1,2 or in the
presence of excess formalin led to bispidines 4 or
pyridothiadiazines 5, depending on the structure of primary
amine and the substrates 2a,b. The direction of this
reaction was substantially affected not only by the nature of
reactants, but also by their ratio, in particular the amount of
formalin used. We noticed that 4 equiv of formaldehyde
were used1,2 for the synthesis of pyridothiazines 1, while
the thiolate 2а and НСНО actually reacted in equimolar
ratio. It should also be noted that the formation of
bispidines 4 was observed in all cases when the amount of
formaldehyde used in the reaction was equal or higher
than required by the reaction stoichiometry (2 equiv).
Detailed analysis of spectral data and HPLC-MS results
for compounds 1a,b1,2 allowed to make the following
conclusions: a) the described compounds arise from the
condensation of thiolates 2 with НСНО and primary amine
in 1:1:1 ratio, and b) the presented spectral data of the
products do not correspond to the reported pyrido[3,2-е]-
[1,3]thiazine structures of compounds 1a,b. In order to
reproduce these results, we proposed that the amount of
formaldehyde actually used in the reaction was 1 equiv
instead of the indicated 4 equiv*. Indeed, the interaction of
thiolate 2а, 1 equiv of НСНО, and 1 equiv of benzylamine
(or furfurylamine) in aqueous EtOH led to the formation of
products identical to those described in the literature1,2 as
pyrido[3,2-е][1,3]thiazines 1a,b. In order to establish the
actual structure, the obtained samples were characterized
by a set of spectral methods (IR, 1Н NMR, 13С NMR, solid
C≡N···S interaction.
The Cambridge Crystallographic Data Center (CCDC)27
contains only one example of geometrically analogous
intermolecular contact in crystals of (4-oxo-3-phenyl-1,3-
thiazolidin-2-ylidene)malononitrile.28 At the same time, the
complete interaction map prediction procedure29 performed
with CCDC Mercury 3.5 program indicated that the
position of cyano group nitrogen atom in the crystal
structure 5а corresponds to the region of maximum
probability for the formation of contact involving the
oxygen atom of carbonyl group. The complete interaction
mapping procedure relied on statistical data about
intermolecular contacts between the most common
functional groups and therefore was not applied to nitriles
(due to the relatively small number of similar structures
available from CCDC), but we can assume that the nitrogen
atom of C≡N group has similar electronic properties to the
oxygen atom of C=O group, and thus the aforementioned
C≡N···CH2–S contact is energetically favorable and
significant for the formation of crystal structure, instead of
being forced.
IR spectra of compounds 5а–с, unlike the spectra of
diazabicyclononanes 4а–с,е, contained two absorption
bands corresponding to the stretching vibrations of
conjugated (2201–2204 cm–1) and non-conjugated (2247–
2249 cm–1) nitrile groups. An interesting feature of the
HPLC-MS data (obtained with ES-API ionization) for the
compounds 5а–с was the absence of molecular ion
peaks, while the peaks of [M–CH2N(CH2CH2)2O+2H]+
and [M–CH2N(CH2CH2)2O]– ions were observed instead.
1
state 13С DEPT-135 and APT, Н–13С HSQC, 1Н–13С
1
A complete assignment of Н and 13С NMR signals for
HMBC, and NOESY), as well as HPLC-MS and
elemental analysis. It was established that the obtained
compounds had the structure of 7-RCH2-4-amino-9,9-
dimethyl-2-oxo-6-thioxo-3,7-diazabicyclo-[3.3.1]non-3-ene-
1-carbonitriles 6a,b. Besides that, the structure of 4-amino-
7-benzyl-9,9-dimethyl-2-oxo-6-thioxo-3,7-diazabicyclo[3.3.1]-
non-3-ene-1-carbonitrile (6a) was studied by X-ray
structural analysis (Fig. 5).
compounds 5а–с was based on the analysis of two-
1
1
dimensional Н–13С HSQC and Н–13С HMBC spectra for
compound 5а. The most significant correlations of Н–13С
HMBC NMR spectrum for compound 5а are shown in
1
Figure 4.
The low quality of the studied crystals resulted in a
relatively low accuracy of intermolecular distances (the
average accuracy of С–С bond lengths was 0.012 Å),
which did not allow to discuss in detail the molecular
geometry of compound 6а. Nevertheless, we should note
that both rings of the 3,7-diazabicyclo[3.3.1]non-3-ene
system assumed a sofa conformation with the С(9) atom
deviating from the plane of other atoms. Molecules of
compound 6а formed ribbons in the crystal structure along
the crystallographic axis a, linked by N(2)–H(2A)···N(11)
(N···N 2.933(9) Å, N–H···N 163(8)°) and N(2)–H(2B)···O
(22) (N···O 2.821(8) Å, N–H···O 170(8)°) hydrogen bonds,
and the positions of hydrogen bond acceptors matched the
predictions made from the complete interaction maps for
carbonyl groups.29
2.01–2.04
2.45–2.50
3.28–3.31
2.58
2.73
H
H
H
N
H
Me
H
Me
H
N
O
58.4
38.1
55.6
116.9
53.8
65.7
162.4
N
147.5
O
N
S
59.5 52.2
H
H
5.19
5.82
5.21
5.40
N
H
H
143.6
* This assumption was confirmed during the private communication with
the authors of works:1,2 instead of 37% formalin, HCHO solution with
lower concentration with a density of d ~ 1.01 g/ml, obtained by separa-
tion of the paraformaldehyde from formalin stored in the cold, was used.
Figure 4. The principal correlations in the 1Н–13С HMBC
spectrum of compound 5а.
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Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
Scheme 4
Figure 6. The correlations in 1Н–13С HMBC spectra of compounds
6a,b.
Figure 5. The molecule of compound 6a with atoms represented
by thermal vibration ellipsoids of 50% probability.
A possible mechanism for the formation of bicyclic
systems 6a,b is presented in Scheme 4. The initial products
of С(5)-aminomethylation 7a,b probably undergo recycli-
zation to piperidines 8a,b, followed by cascade cyclization
process that leads to the formation of compounds 6a,b.
Compounds 6a,b are pale-yellow or white powders,
practically insoluble in alcohols, acetone, MeCN, pyridine,
THF, water, and aqueous acids. Compounds 6a,b have
limited solubility in DMSO and in hot АсОН. There is a
weak absorption band in IR spectra of compounds 6a,b,
corresponding to the stretching vibrations of non-conjugated
C≡N group at 2245–2247 cm–1, and a wide carbonyl
absorption band at 1661–1662 cm–1. The absorption bands
corresponding to stretching vibrations of N–H bonds are
observed at 3294–3296 cm–1. Cross peaks were observed in
2D NOESY spectra of compounds 6a,b between the proton
signals of methyl groups and the 5-CH protons, as well as
between the protons of 8-CH2 group and those of СН3 and
The aminomethylation reaction of thiolates 2a,b is
generally quite sensitive both towards the ratio of reactants
used and their nature. Thus, even a small excess of НСНО
relative to the starting thiolates 2 resulted in preferential
formation of bispidines 4. At the same time, when thiolate
2а and formaldehyde were used in equimolar ratio, the
addition of excess amine did not affect the direction of
reaction and helped to increase the yield of compounds 6.
The reaction of thiolate 2а with 1 equiv of formaldehyde
and 1 equiv of aromatic amine (p-toluidine or p-anisidine)
according to an analogous scheme did not result in the
formation of bicyclic structures 6: after refluxing for 30 min
and cooling of the reaction mixture the starting thiolate 2а
crystallized in 31–33% yield. Quite interesting results were
obtained by refluxing an ethanol solution containing
equimolar amounts of furfurylamine, formaldehyde, and
thiolate 2а without the addition of water: yellow crystals
were isolated from the reaction mixture, the analysis of
which by spectral methods revealed that this sample was
structurally closely related (but not identical!) to compound
1
СН2Ar groups. The most significant correlations in Н–13С
HMBC spectra of compounds 6a,b are shown in Figure 6.
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Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
1
Scheme 5
6b. According to Н NMR data for a crude sample of
bicyclic compound 6b, the new compound was also
detected there as impurity (~7–10 mol %) and represented
an isomer of compound 6b.
1
Based on the spectral data set (IR, Н and 13С NMR,
1
1
DEPT-135, Н–13С HSQC, Н–13С HMBC, and NOESY),
as well as the results of HPLC-MS analysis, the structure
of 4-amino-7-(2-furylmethyl)-9,9-dimethyloxo-2-thioxo-
3,7-diazabicyclo-[3.3.1]non-3-ene-1-carbonitrile (9) was
1
assigned to the obtained isomer (Scheme 5). Н NMR
spectra of compounds 6b and 9 were quite similar (Fig. 7),
and the mass spectra of compounds 9 and 6b contained
molecular ion peaks at m/z values of 317.1 [М+Н]+ and
1
315.0 [M–Н]–. Key differences were found in 2D Н–13С
HMBC spectra: the С(6)=S carbon signal (191.9 ppm) in
the spectrum of compound 6b gave cross peaks with three
groups of protons: 8-CH2 (3.83/3.92 ppm), 5-CH (4.00 ppm),
and NCH2Fur (5.09/5.27 ppm), while 1Н–13С HMBC
spectrum of compound 9 only contained correlations of the
С=S carbon signal (209.0 ppm) with the 8-CH2 protons
(3.71/3.79 ppm). The 5-CH proton singlet (4.00 ppm) in
spectrum of compound 6b gave cross peaks with the sig-
nals of С=S and С-4 carbon atoms (191.9 and 170.9 ppm),
but not with С=О carbon atom (172.3 ppm), while the
spectrum of bicyclic compound 9 contained cross peaks of
5-СН proton singlet (3.40 ppm) with the signals of С=О
(161.7 ppm) and С-4 carbon atoms (164.5 ppm), but not
with the C=S carbon signal (209.0 ppm).
Thus, the aminomethylation reaction of thiolate 2а with
formaldehyde and primary amines of benzyl type at the
ratio of 1:1:1 proceeded non-selectively at the positions
С-3 and С-5, at least in the case of furfurylamine
(Scheme 5). This was indirectly supported by the low
yields of products 6a,b. Compound 9 probably can be
considered to be the product of kinetic control, and also
had a better solubility compared to the compound 6b.
Obviously, the reaction proceeded through the formation of
intermediates 10 and 11, which were isomeric to the
intermediates 7 and 8.
[2,1-b][1,3,5]thiadiazines and 2) unusual cascade process
leading to the formation of 3,7-diazabicyclo[3.3.1]non-
3-ene derivatives. Detailed study of the new reactions will
be the topic of our further studies.
Experimental
IR spectra were recorded on an Infraspek FSM-1201
1
To summarize these observations, the following
conclusions can be made:
FT-IR spectrometer with ATR accessory. Н NMR spectra
were acquired on Bruker DPX-400 (400 MHz, compounds
2b, 4a,b), Bruker Avance II 400 (400 MHz, compounds
5a, 6a,b, 9), and Bruker Avance 500 (500 MHz, the rest of
the compounds) spectrometers in 1:2 CCl4–DMSO-d6
(compounds 5a, 6a,b, 9) or DMSO-d6 (the rest of the
compounds), with TMS as internal standard. 13С NMR
spectra were acquired on a Bruker Avance 500 (126 MHz)
spectrometer in DMSO-d6 (compounds 2а, 4а,е, 5с) and on
a Bruker Avance II 400 (101 MHz) spectrometer in 1:2
CCl4–DMSO-d6 (the rest of the compounds), with TMS as
internal standard. 13C APT NMR spectra were acquired on a
Bruker Avance 500 (126 MHz) spectrometer in DMSO-d6,
with TMS as internal standard. 13C DEPT-135 NMR
spectra, as well as two-dimensional NMR spectra (NOESY,
– the published results1,2 describing the synthesis of
pyrido[3,2-е][1,3]thiazine derivatives by aminomethylation
of morpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-
tetrahydropyridine-2-thiolate are in doubt and can be explained
by inaccurate experimental data and erroneous interpretation of
spectral features;
– the direction of aminomethylation reactions of
morpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetra-
hydropyridine-2-thiolate and the analogous N-methyl-
morpholinium salt with primary amines and formaldehyde
substantially depend on the structure of cationic part in the
starting salts 2a,b and the nucleophilicity of primary
amines, as well as the amount of formaldehyde used in the
reaction;
1
1H–13C HSQC, H–13C HMBC) were acquired on a Bruker
– two previously unreported reactions were identified,
demonstrating new directions of aminomethylation in
N,C,S-polynucleophilic substrates of pyridine series: 1) the
reaction leading to 7-[(morpholin-4-yl)methyl]pyrido-
Avance II 400 spectrometer in 1:2 CCl4–DMSO-d6, with
TMS as internal standard. HPLC-MS analysis of
compound 2b was performed on a Shimadzu LC-10AD
liquid chromatograph with Shimadzu SP D-10A UV-Vis
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Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
Figure 7. 1Н NMR spectra of the isomeric compounds 9 and 6b (400 MHz, 1:2 СCl4–DMSO-d6).
(254 nm) and Sedex 75 ELSD detectors, in combination with
PE SCIEX API 150EX mass spectrometer, with electro-
spray ionization at atmospheric pressure (ES-API). HPLC-MS
analysis for the rest of the compounds was performed on an
Agilent 1200 instrument, Rapid Resolution HT Cartrige
4.6×30 mm, 1.8 µm, Zorbax SB-C18 column, DAD and
MS detectors, ES-API ionization. Mass spectra were
recorded on a Minpribor МХ1321 spectrometer using a
system for direct introduction of sample, ionization
methods: fast atom bombardment (FAB, compound 5с)
and electron impact (EI, the ionization chamber
temperature was 200°С and ionizing electron energy was
70 eV, compounds 4а, 5с). Elemental analysis was
performed on a Carlo-Erba 1106 Elemental Analyzer. The
individuality of the synthesized compounds was
controlled by TLC on Silufol UV 254 plates in 1:1
acetone–hexane system, visualization with iodine vapor or
UV light.
The reaction mixture was maintained at 20°С for 48 h, the
product was filtered off, washed with Me2CO and Et2O,
giving thiolates 2a,b, which were used in subsequent
reactions without additional purification.
Morpholinium 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-
tetrahydropyridine-2-thiolate (2а). Yield 87%, beige
powder, mp 217–219°С (decomp.) (mp 213–215°С1).
IR spectrum, ν, cm–1: 3223, 3198 (N–H), 2253 (5-C≡N),
1
2185 (3-C≡N), 1674 (С=О). H NMR spectrum, δ, ppm:
1.02 (3Н, s, CH3); 1.19 (3Н, s, CH3); 3.09–3.11 (4H, m,
СН2NCH2); 3.73–3.75 (4Н, m, CH2OCH2); 4.14 (1H, s,
+
5-CH); 8.67 (2Н, very br. s, NH2 ); 9.39 (1H, s, NH).
13C NMR spectrum, δ, ppm: 23.5; 26.8; 35.3; 42.9; 47.1;
63.3; 85.7; 116.3; 122.7; 161.1; 167.3. 13C APT NMR
spectrum, δ, ppm: 23.4* (CH3); 26.7* (CH3); 35.3 (C-4);
42.9 (CH2NCH2); 47.1* (C-5); 63.2 (CH2OCH2); 85.7
(C-3); 116.2 (5-CN); 122.6 (3-CN); 161.0 (C=О); 167.2
(C-2). 13C DEPT-135 NMR spectrum, δ, ppm: 23.0 (CH3);
26.4 (CH3); 42.6* (CH2NCH2); 46.8 (C-5); 62.9*
(CH2OCH2). Mass spectrum, m/z: 410.8 [2М–2C4H9NO–H]–,
205.8 [М–C4H9NO–H]–, 88.2 [C4H9NO+H]+.
The starting 3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-
tetrahydropyridine-2-thiolates 2a,b were obtained
according to
a
published procedure30 with some
modifications: cyanothioacetamide32 (1.30 g, 13.0 mmol)
and base (morpholine or N-methylmorpholine) (19.5 mmol)
were added to a solution of isopropylidene cyanoacetic
ester31 (3.0 g, 19.6 mmol) in 96% EtOH (12 ml). The
mixture was stirred at room temperature, a precipitate of
salt 2а formed after 1–2 min, salt 2b – after 20–25 min.
* Here and further an asterix in 13С APT and DEPT-135 NMR
spectra indicates opposite phase signals. The assignment of
signals was based on 1H–13C HMBC spectra (see the
Supplementary information).
122

Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
N-Methylmorpholinium
3,5-dicyano-4,4-dimethyl-
Synthesis of 7-R-9,9-dimethyl-2-oxo-4-thioxo-3,7-diaza-
6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate (2b). Yield
82%, pale-yellow powder, mp 193–195°С (mp 190–192°С30).
IR spectrum, ν, cm–1: 3153, 3104 (N–H), 2251 (5-C≡N),
bicyclo[3.3.1]nonane-1,5-dicarbonitriles 4а–с,e (General
method). A mixture of thiolate 2a,b (1.1 mmol), 37%
formalin that was free of paraform impurity (0.7 ml,
9.5 mmol), and the respective primary amine (1.1 mmol) in
96% EtOH (10 ml) was heated until dissolution, the
obtained light-yellow solution was refluxed with vigorous
stirring for 1–2 min. After 24 h, the reaction mixture
was acidified with a 1:3 solution of concd. HCl in EtOH
to рН 3–4. The yellow crystalline product was filtered off
after 3–4 days and then recrystallized from a suitable
solvent (n-BuOH for compounds 4а,е, EtOH for compound
4b, double recrystallization from n-BuOH – for compound
4с).
1
2175 (3-C≡N), 1701 (С=О). H NMR spectrum, δ, ppm:
1.02 (3Н, s, CH3); 1.19 (3Н, s, CH3); 2.80 (3H, s,
NCH3); 3.11–3.33 (4H, m, СН2NCH2); 3.63–3.91 (4Н,
m, CH2OCH2); 4.15 (1H, s, 5-CH); 9.40 (1H, s, NH);
9.60 (1Н, very br. s, NH+). Mass spectrum, m/z: 432.5
[2М–2C5H11NO+H2O]+.
Synthesis of 7-benzyl-9,9-dimethyl-2-oxo-4-thioxo-
3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile (4а) by
the reaction of thiolates 2a,b with 1 equiv of
benzylamine and 4 equiv of НСНО. Following a
published procedure,1,2 thiolate 2a (2.94 g, 10 mmol) was
added to a hot solution of benzylamine (1.1 ml, 10 mmol)
and 37% formalin (3.0 ml,* 40 mmol) in 96% EtOH
(15 ml). The mixture was refluxed for 40 min, during this
time no precipitation was observed. The reaction with
thiolate 2b (3.08 g, 10 mmol) was performed analogously.
7-Benzyl-9,9-dimethyl-2-oxo-4-thioxo-3,7-diazabicyclo-
[3.3.1]nonane-1,5-dicarbonitrile (4а) was obtained from
thiolate 2b. Yield 170 mg (46%), bright-yellow crystals.
The spectral characteristics of the sample were identical to
those given above.
7,9,9-Trimethyl-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]-
nonane-1,5-dicarbonitrile (4b) was obtained from thiolate
2b. Yield 84 mg (29%), bright-yellow crystals, mp 222–
224°С, Rf 0.65. IR spectrum, ν, cm–1: 3065 (N–H), 2251
1
Samples of reaction mixtures were analyzed by Н NMR
and HPLC-MS, and no significant amounts of compound
1а (M 326.4) were found. The main products in the
reaction mixture were 7-benzyl-9,9-dimethyl-2-oxo-
4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile
salts 3a,b. Longer refluxing of the reaction mixture also did
not result in the formation of product 1а; evaporation of the
solvent gave yellow resin, which according to HPLC-MS
also predominantly consisted of salt 3а or 3b. After
maintaining the obtained solution for one week at 25°С, it
was treated by careful addition of a mixture consisting of
concd. HCl and EtOH (1:1) until рН 3–4 was reached.
After 96 h, the crystalline precipitate was filtered off,
washed with cold EtOH and Et2O. The yield of 7-benzyl-
9,9-dimethyl-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-
1,5-dicarbonitrile (4а) in analytically pure form was 1.25 g
(37%, from thiolate 2а) or 1.31 g (39%, from thiolate 2b),
bright-yellow crystals, mp 208–210°С, Rf 0.70. IR
spectrum, ν, cm–1: 3252, 3188 (N–H), 2258 (2 C≡N), 1726
1
(2C≡N), 1718 (С=О). H NMR spectrum, δ, ppm: 1.31
(3Н, s) and 1.46 (3Н, s, 9,9-(CH3)2); 2.29 (3Н, s, NCH3);
3.00–3.13 (4H, m, 6,8-СН2); 13.55 (1H, s, NH). Mass
spectrum, m/z: 263.1 [М+H]+, 261.1 [M–H]–. Found, %:
C 55.18; H 5.08; N 21.40. C12H14N4ОS. Calculated, %:
C 54.94; H 5.38; N 21.36.
9,9-Dimethyl-2-oxo-7-(2-phenylethyl)-4-thioxo-3,7-di-
azabicyclo[3.3.1]nonane-1,5-dicarbonitrile (4с) was obtained
from thiolate 2а. Yield 124 mg (32%), bright-yellow fine
crystalline powder, mp 174–176°С, Rf 0.70. IR spectrum,
ν, cm–1: 3438, 3220, 3174 (N–H), 2246 (2C≡N), 1729
(С=О). 1H NMR spectrum, δ, ppm: 1.29 (3Н, s, CH3); 1.46
(3Н, s, CH3); 2.61–2.64 (2Н, m, CH2CH2Ph); 2.70–2.73
(2Н, m, CH2CH2Ph); 3.14–3.25 (4H, m, 6,8-СН2); 7.14–
7.24 (5H, m, H Ph); 13.61 (1H, s, NH). 13C APT NMR
spectrum, δ, ppm: 20.3* (CH3); 23.3* (CH3); 31.9
(CH2CH2Ph); 38.3 (C-9); 52.0 (C-1(5)); 52.2 (С-5(1)); 54.9
(NCH2); 56.3 (NCH2); 60.4 (NCH2); 115.0 (C≡N); 116.1
(C≡N); 125.9* (C Ar); 128.2* (C Ar); 128.6* (C Ar); 139.4
(C Ar); 164.5 (C=O); 200.6 (C=S). Mass spectrum, m/z: 353.0
[М+H]+, 351.2 [M–H]–. Found, %: C 64.68; H 5.88;
N 15.86. C19H20N4ОS. Calculated, %: C 64.75; H 5.72;
N 15.90.
1
(С=О). H NMR spectrum, δ, ppm (J, Hz): 1.30 (3Н, s,
CH3); 1.46 (3Н, s, CH3); 3.00 (1H, d, 2J = 11.6), 3.10 (1H, d,
2J = 11.6) and 3.19–3.23 (2H, m, 6,8-СН2); 3.70 (2Н, АВ
2
3
quartet, J = 13.7, NCH2Ph); 7.15 (2Н, d, J = 7.5, H Ph);
7.24–7.31 (3H, m, H Ph); 13.81 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 20.3 (CH3); 23.3 (CH3); 38.3 (C-9); 51.9
(C-1(5)); 52.0 (С-6(8)); 54.4 (С-5(1)); 58.3 (С-8(6)); 60.4
(NCH2Ph); 114.9 (C≡N); 115.9 (C≡N); 127.5 (C Ar); 128.2
(C Ar); 128.4 (C Ar); 136.3 (C Ar); 164.5 (C=O); 200.6
(C=S). Mass spectrum (ES-API), m/z: 339.1 [М+H]+, 337.0
[M–H]–. Mass spectrum (EI), m/z (Irel, %): 338 [М]+ (8),
133 (13), 120 [PhCH2NH=CH2]+ (8), 92 (9), 91 [PhCH2]+
(100), 65 (10), 43 (19). Found, %: C 63.84; H 5.45; N 16.50.
C18H18N4ОS. Calculated, %: C 63.88; H 5.36; N 16.55.
9,9-Dimethyl-7-(4-methylphenyl)-2-oxo-4-thioxo-
3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile (4е) was
obtained from thiolate 2b. Yield 137 mg (39%), dark-
yellow crystals, mp 200–202°С, Rf 0.84. IR spectrum, ν,
cm–1: 3419, 3227, 3109 (N–H), 2253 (2C≡N), 1713 (С=О).
1H NMR spectrum, δ, ppm (J, Hz): 1.36 (3Н, s) and 1.56
(3Н, s, 9,9-(CH3)2); 2.19 (3Н, s, ArCH3); 3.79–3.97 (4H,
3
m, 6,8-СН2); 6.82 (2H, d, J = 8.2, H Ar); 7.04 (2H, d,
3J = 8.2, H Ar); 13.75 (1H, s, NH). 13C NMR spectrum, δ,
ppm: 19.9 (CH3); 20.1 (CH3); 23.5 (CH3); 38.5 (C-9); 49.8
(C-1(5)); 51.8 (С-5(1)); 53.1 (NCH2); 60.3 (NCH2); 114.7
(C≡N); 115.8 (C≡N); 116.9 (C Ar); 129.5 (C Ar); 130.2
(C Ar); 145.2 (C Ar); 164.4 (C=O); 200.3 (C=S). 13C APT
* Error in the calculation was made in the paper:1 40 mmol of 37% forma-
lin (d 1.1 g / ml) correspond to the volume of 3.0 ml instead of 3.6 ml as
the authors indicated. However, in general it does not change the picture
as a reproduction of the method with specified amount, as well as with a
greater excess of HCHO, leads to the same result.
123

Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
2
NMR spectrum, δ, ppm: 19.9* (CH3); 20.0* (CH3); 23.5*
(CH3); 38.4 (C-9); 49.9 (C-1(5)); 51.8 (С-5(1)); 53.1 (NCH2);
60.3 (NCH2); 114.7 (CN); 115.8 (CN); 116.9* (C Ar); 129.5*
(C Ar); 130.2 (C Ar); 145.2 (C Ar); 164.3 (C=O); 200.3
(C=S). Mass spectrum, m/z: 339.1 [М+H]+, 337.0 [M–H]–.
Found, %: C 63.80; H 5.44; N 16.57. C18H18N4ОS. Calculated,
%: C 63.88; H 5.36; N 16.55.
Synthesis of 3-aryl-8,8-dimethyl-7-[(morpholin-4-yl)-
methyl]-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b]-
[1,3,5]thiadiazine-7,9-dicarbonitriles 5а–с (General
method). A mixture of thiolate 2a (320 mg, 1.09 mmol),
the corresponding primary amine (1.05–1.15 equiv), and
37% formalin that was free of paraform impurity (1 ml,
13.6 mmol) was stirred and refluxed in 96% EtOH (10 ml)
for 1–2 min and maintained at 25°С for 24 h. The
crystalline precipitates of thiadiazines 5а–с were filtered
off and washed with EtOH.
2J = 11.9, 2-CHВ); 5.79 (1Н, d, J = 13.0, 4-CHВ);
7.07–7.13 (4H, m, H Ar). Mass spectrum, m/z: 339.2
[М–СН2N(CH2CH2)2O+2H]+, 337.2 [M–СН2N(CH2CH2)2O]–.
Found, %: C 63.29; H 6.35; N 15.96. C23H27N5О2S.
Calculated, %: C 63.13; H 6.22; N 16.01.
3-(4-Fluorophenyl)-8,8-dimethyl-7-[(morpholin-4-yl)-
methyl]-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b]-
[1,3,5]thiadiazine-7,9-dicarbonitrile (5с). Yield 239 mg
(50%), colorless fine crystals, mp 201–203°С, Rf 0.65.
IR spectrum, ν, cm–1: 2247, 2204 (2C≡N), 1684 (С=О).
1H NMR spectrum, δ, ppm (J, Hz): 1.13 (3Н, s, CH3);
1.21 (3Н, s, CH3); 1.97–2.00 (2Н, m) and 2.41–2.43 (2Н,
2
m, N(CH2CH2)2O); 2.55 (1Н, d, J = 13.9) and 2.78
(1Н, d, J = 13.9, СН2N(CH2CH2)2O); 3.25–3.28 (4H,
2
m, N(CH2CH2)2O); 5.17–5.22 (2Н, m, 2,4-CHА); 5.42 (1Н,
d, 2J = 12.6, 2-CHВ); 5.81 (1Н, d, 2J = 13.5, 4-CHВ); 7.15–
7.19 (2H, m, H Ar); 7.23–7.26 (2H, m, H Ar). 13C NMR
spectrum, δ, ppm (J, Hz): 21.7 (CH3); 24.6 (CH3); 38.0
(C-8); 52.7 (С-2); 53.9 (N(CH2CH2)2O); 55.9 (С-7); 58.4
(СН2N(CH2CH2)2O); 60.3 (С-4); 65.7 (N(CH2CH2)2O);
8,8-Dimethyl-7-[(morpholin-4-yl)methyl]-6-oxo-
3-phenyl-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]-
thiadiazine-7,9-dicarbonitrile (5а). Yield 156 mg (34%),
colorless needles, mp 191–193°С, Rf 0.64. IR spectrum, ν,
cm–1: 2249, 2204 (2C≡N), 1684 (С=О). 1H NMR spectrum,
δ, ppm (J, Hz): 1.16 (3Н, s, CH3); 1.24 (3Н, s, CH3); 2.01–
2.04 (2Н, m) and 2.45–2.50 (2Н, m, N(CH2CH2)2O,
2
94.6 (С-9); 115.4 (9-CN); 115.8 (d, JНF = 22.2, C-3,5 Ar);
3
117.4 (7-CN); 118.9 (d, JНF = 8.0, C-2,6 Ar); 140.4 (d,
4JНF = 2.3, C-1 Ar); 147.8 (C-9a); 157.5 (d, 1JНF = –237.1, C-4
Ar); 162.9 (C=O). Mass spectrum (ES-API), m/z: 343.0
[М–CH2N(CH2CH2)2O+2H]+, 341.1 [M–CH2N(CH2CH2)2O]–,
88.2 [O(CH2CH2)2NH2]+. Mass spectrum (EI), m/z (Irel, %):
341 [М–CH2N(CH2CH2)2O]+ (10), 137 (12), 123 (16), 100
[CH2N(CH2CH2)2O]+ (100), 95 (9), 56 (15). Mass spectrum
(FAB), m/z (Irel, %): 342.0 [М–CH2N(CH2CH2)2O+H]+.
Found, %: C 60.13; H 5.65; N 15.89. C22H24FN5О2S.
Calculated, %: C 59.85; H 5.48; N 15.86.
2
overlap with DMSO signal); 2.58 (1Н, d, J = 13.9) and
2.73 (1Н, d, 2J = 13.9, СН2N(CH2CH2)2O); 3.28–3.31 (4H,
m, N(CH2CH2)2O); 5.19 (1Н, d, 2J = 13.9) and 5.82 (1Н, d,
2
2J = 13.9, 4-CH2); 5.21 (1Н, d, J = 12.7) and 5.40 (1Н, d,
2J = 12.7, 2-CH2); 6.96 (1H, t, 3J = 7.2, Н-4 Ph); 7.16 (2H, d,
3J = 8.1, Н-2,6 Ph); 7.28–7.32 (2H, m, Н-3,5 Ph). 13C NMR
spectrum, δ, ppm: 21.6 (CH3); 24.5 (CH3); 38.1 (C-8);
52.2 (С-2); 53.8 (N(CH2CH2)2O); 55.6 (С-7); 58.4
(СН2N(CH2CH2)2O); 59.5 (С-4); 65.7 (N(CH2CH2)2O);
94.3 (С-9); 114.9 (9-CN); 116.7 (C-2,6 Ph); 116.9 (7-CN);
121.5 (C-4 Ph); 129.0 (C-3,5 Ph); 143.6 (С-1 Ph); 147.5
(C-9a); 162.4 (C=O). 13C APT NMR spectrum, δ, ppm:
21.6* (CH3); 24.6* (CH3); 38.0 (C-8); 52.3 (С-2); 53.9
(N(CH2CH2)2O); 55.9 (С-7); 58.4 (СН2N(CH2CH2)2O);
59.7 (С-4); 65.7 (N(CH2CH2)2O); 94.5 (С-9); 115.4
(9-CN); 116.9* (C-2,6 Ph); 117.4 (7-CN); 121.7* (C-4 Ph);
129.3* (C-3,5 Ph); 143.7 (С-1 Ph); 147.8 (C-9a); 162.8
(C=O). 13C DEPT-135 NMR spectrum, δ, ppm: 21.3 (CH3);
24.3 (CH3); 51.9* (С-2); 53.6* (N(CH2CH2)2O); 58.1*
(СН2N(CH2CH2)2O); 59.2* (С-4); 65.4* (N(CH2CH2)2O);
116.5 (C-2,6 Ph); 121.2 (C-4 Ph); 128.8 (C-3,5 Ph). Mass
spectrum, m/z: 325.0 [М–СН2N(CH2CH2)2O+2Н]+, 323.1
[М–СН2N(CH2CH2)2O]–. Found, %: C 62.61; H 6.09; N 16.60.
C22H25N5О2S. Calculated, %: C 62.39; H 5.95; N 16.54.
8,8-Dimethyl-3-(4-methylphenyl)-7-[(morpholin-4-yl)-
methyl]-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b]-
[1,3,5]thiadiazine-7,9-dicarbonitrile (5b). Yield 47 mg (10%),
colorless needles, mp 184–186°С, Rf 0.64. IR spectrum, ν,
cm–1: 2247, 2201 (2C≡N), 1693 (С=О). 1H NMR spectrum,
δ, ppm (J, Hz): 1.12 (3Н, s) and 1.20 (3Н, s, 8,8-(CH3)2);
1.95–2.00 (2Н, m, N(CHАCH2)2O); 2.21 (3Н, s, ArCH3);
2.43–2.50 (3Н, m, CHАN(CHВCH2)2O, overlap with
DMSO signal); 2.77 (1Н, d, 2J = 13.0, СНВN(CH2CH2)2O);
3.25–3.30 (4H, m, N(CH2CH2)2O, overlap with H2O
signal); 5.16–5.22 (2Н, m, 2,4-CHА); 5.41 (1Н, d,
Synthesis of 4-amino-7-benzyl-9,9-dimethyl-2-oxo-
6-thioxo-3,7-diazabicyclo[3.3.1]non-3-ene-1-carbonitrile
(6a). Benzylamine (0.60 ml, 5.49 mmol) was added to a
mixture of 96% EtOH (8 ml) and distilled Н2О (5 ml),
followed by the addition of 37% formalin (d 1.1 g/ml,
0.28 ml, 3.68 mmol). The mixture was stirred for 2–3 min,
and then thiolate 2a (1.082 g, 3.68 mmol) was added. The
reaction mixture was stirred and refluxed for 2 h
(precipitation of the product started after 15–20 min). The
pale-yellow precipitate was filtered off after 24 h and
washed with EtOH. Yield 0.458 g. Additional crop of the
product can be obtained by maintaining the filtrate for 72 h
at 20°С. The total yield of the crude bicyclic product 6а
was 493 mg (41%). Analytically pure sample of this
compound can be obtained by recrystallization from a large
volume of АсОН (solubility ~30 mg in 10–15 ml АсОН,
the precipitate was white, amorphous powder, Rf 0.50, mp
>350°С (subl. from 302°С) (mp 290–293°С1,2)) or from
DMSO (slow precipitation of yellow crystalline
agglomerates, no melting or decomposition was observed
below 350°С). When using an equimolar amount of
benzylamine, the yield decreased to 19%. When the
reaction was performed under analogous conditions, but
without the addition of water, product 6a was obtained in
17% yield, and contained the starting thiolate 2а as
impurity. IR spectrum, ν, cm–1: 3294 (N–H), 2245 (C≡N),
1
1662 (С=О). H NMR spectrum, δ, ppm (J, Hz): 1.10 (3Н,
s, CH3); 1.13 (3Н, s, CH3); 3.76 (1Н, d, 2J = 14.7) and 3.85
124

Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
2
(1Н, d, J = 14.7, 8-СН2); 4.06 (1Н, s, 5-СН); 5.06 (1Н, d,
was refluxed in a flask with reflux condenser for 45 min,
while the initially heterogeneous mixture turned into a red
2J = 14.7) and 5.43 (1Н, d, J = 14.7, NCH2Ph); 7.20 (2Н,
2
d, 3J = 7.1, Н-2,6 Ph); 7.28–7.33 (3H, m, H-3,4,5 Ph); 8.81
(1Н, br. s) and 9.03 (1Н, br. s, NH2). 13C NMR spectrum, δ,
ppm: 21.3 (CH3); 22.9 (CH3); 35.8 (C-9); 50.2 (C-1); 53.3
(C-8); 55.2 (NCH2Ph); 59.8 (C-5); 116.3 (C≡N); 127.3
(C-2,6 Ph); 127.6 (C-4 Ph); 128.4 (C-3,5 Ph); 134.6 (C-1
Ph); 171.2 (C-4); 172.4 (C=O); 192.4 (C=S). 13C APT
NMR spectrum, δ, ppm: 21.3* (CH3); 23.0* (CH3); 35.9
(C-9); 50.4 (С-1); 53.5 (C-8); 55.3 (NCH2Ph); 60.0* (C-5);
116.6 (C≡N); 127.3* (C-2,6 Ph); 127.8* (C-4 Ph); 128.6*
(C-3,5 Ph); 134.7 (C-1 Ph); 171.4 (C-4); 172.7 (C=O); 192.4
(C=S). 13C DEPT-135 NMR spectrum, δ, ppm: 21.1 (CH3);
22.7 (CH3); 53.1* (C-8); 55.0* (NCH2Ph); 59.6 (C-5);
127.1 (C-2,6 Ph); 127.4 (C-4 Ph); 128.2 (C-3,5 Ph). Mass
spectrum, m/z: 327.0 [М+H]+, 325.0 [M–H]–. Found, %:
C 62.50; H 5.64; N 17.20. C17H18N4ОS. Calculated, %:
C 62.55; H 5.56; N 17.16.
solution containing a small amount of crystalline
precipitate. The solution was maintained for 72 h at 20°С,
the crystalline precipitate that formed was filtered off and
washed with EtOH. The obtained mixture (291 mg)
consisted of fine white needles ("white fraction", Rf 0.0)
and large bright-yellow crystals (''yellow fraction'', Rf 0.50),
which was mechanically/manually separated. According to
1Н NMR spectral data, the ''white fraction'' was the starting
thiolate 2а, while the ''yellow fraction'' (~90 mg, ~12%)
was pure bicyclic compound 9, mp 242–244°С. Compound
9 was insoluble in EtOH, moderately soluble in acetone,
readily soluble in DMSO. IR spectrum, ν, cm–1: 3296
(N–H), 2247 (C≡N), 1661 (С=О). 1H NMR spectrum, δ, ppm
(J, Hz): 1.12 (3Н, s, CH3); 1.17 (3Н, s, CH3); 3.40 (1Н, s,
2
2
5-CH); 3.71 (1Н, d, J = 12.6) and 3.79 (1Н, d, J = 12.6,
2
2
8-СН2); 4.30 (1Н, d, J = 15.3) and 4.69 (1Н, d, J = 15.3,
NCH2Fur); 6.25–6.26 (1H, m, Н-3 Fur); 6.30–6.32 (1H, m,
Н-4 Fur); 7.41–7.42 (1H, m, H-5 Fur); 9.55 (1Н, br. s) and
9.80 (1Н, br. s, NH2). 13C NMR spectrum, δ, ppm: 22.5
(CH3); 22.7 (CH3); 37.2 (C-9); 41.8 (NCH2Fur); 51.9 (C-5);
54.1 (C-8); 57.1 (C-1); 108.6 (C-3 Fur); 110.1 (C-4 Fur);
117.0 (C≡N); 142.3 (C-5 Fur); 148.8 (C-2 Fur); 161.7
(C=O); 164.5 (C-4); 209.0 (C=S). 13C DEPT-135 NMR
spectrum, δ, ppm: 22.2 (CH3); 22.5 (CH3); 41.5* (NCH2Fur);
51.6 (C-5); 53.8* (C-8); 108.3 (C-3 Fur); 109.9 (C-4 Fur);
142.1 (C-5 Fur). Mass spectrum, m/z: 317.0 [М+H]+, 315.0
[M–H]–. Found, %: C 60.07; H 5.15; N 17.68. C15H16N4О2S.
Calculated, %: C 56.95; H 5.10; N 17.71.
Synthesis of 4-amino-7-[(furan-2-yl)methyl]-9,9-
dimethyl-2-oxo-6-thioxo-3,7-diazabicyclo[3.3.1]non-3-ene-
1-carbonitrile (6b). Furfurylamine (0.24 ml, 2.69 mmol)
was added to a mixture of 96% EtOH (5 ml) and distilled
H2O (2 ml), followed by the addition of 37% formalin
(d 1.1 g/ml) (0.18 ml, 2.40 mmol). The mixture was heated
to reflux, and thiolate 2a (707 mg, 2.40 mmol) was added.
The reaction mixture was stirred and refluxed for 1 h. After
maintaining for 24 h, the precipitate was filtered off and
washed with EtOH. Yield 77 mg (10%), pale-yellow
1
amorphous powder, Rf 0.45. According to Н NMR data,
the obtained sample contained up to 10 mol % of the
isomeric compound 9 as impurity. Analytically pure
sample of this compound can be obtained by recrystal-
lization from АсОН. The purified sample decomposed
above 330°С (mp 310–312°С1,2). IR spectrum, ν, cm–1:
3296 (N–H), 2247 (C≡N), 1661 (С=О). 1H NMR spectrum,
δ, ppm (J, Hz): 1.09 (3Н, s, CH3); 1.11 (3Н, s, CH3); 3.83
X-ray structural study of compounds 4a, 5a, 6а.
Crystals of compound 4а (C18H18N4OS, M 338.42) were
obtained by crystallization from n-BuOH. X-ray structural
studies were performed on an Xcalibur 3 automatic four-
circle diffractometer (MoKα radiation, graphite mono-
chromator, CCD detector, ω-scanning, 2θmax 65.3°). The
structure was solved by direct method using the SHELX-97
software suite.33
2
2
(1Н, d, J = 14.5) and 3.92 (1Н, d, J = 14.5, 8-СН2); 4.00
2
(1Н, s, 5-СН); 5.09 (1Н, d, J = 14.9) and 5.27 (1Н, d,
2J = 14.9, NCH2Fur); 6.32–6.36 (2H, m, H-3,4 Fur); 7.48–
7.49 (1H, m, H-5 Fur); 8.71 (1Н, br. s) and 8.96 (1Н, br. s,
NH2). 13C NMR spectrum, δ, ppm: 21.1 (CH3); 22.9 (CH3);
35.7 (C-9); 48.8 (NCH2Fur); 50.1 (C-1); 53.7 (C-8); 59.8
(C-5); 109.5 (C-3 Fur); 110.2 (C-4 Fur); 116.7 (C≡N);
142.6 (C-5 Fur); 147.6 (C-2 Fur); 170.9 (C-4); 172.3
(C=О); 191.9 (C=S). 13C APT NMR spectrum, δ, ppm:
21.1* (CH3); 22.9* (CH3); 35.8* (C-9); 48.8 (NCH2Fur);
50.1 (C-1); 53.7 (C-8); 59.9* (C-5); 109.5* (C-3 Fur);
110.5* (C-4 Fur); 116.7 (C≡N); 143.2* (C-5 Fur); 147.7
(C-2 Fur); 171.2 (C-4); 172.7 (C=О); 191.9 (C=S).
DEPT-135 13C NMR spectrum, δ, ppm: 20.9 (CH3); 22.7
(CH3); 48.6* (NCH2Fur); 53.5* (C-8); 59.6 (C-5); 109.2*
(C-3 Fur); 110.0* (C-4 Fur); 142.3* (C-5 Fur). Mass
spectrum, m/z: 317.0 [М+H]+, 314.8 [M–H]–.
Crystals of compound 5a (C22H25N5O2S, M 423.53) were
obtained from aqueous EtOH. X-ray structural studies were
performed on a Bruker APEX II CCD single crystal
diffractometer at 100 K (MoKα radiation). The structure
was solved by charge-flipping algorithm (olex2.solve) and
refined by method of least squares with Olex2 program34
using the SHELXL 2014/7 software suite.35
Crystals of compound 6а, obtained from DMSO, were
of very low quality. X-ray structural studies were
performed on a Bruker APEX DUO CCD single crystal
diffractometer at 100 K (CuKα radiation). The sample was
a
twinned crystal; indexing was performed with
CELL_NOW program, but the attempts to integrate the two
basic domains were not successful. As a result, the
structure was solved and refined by using integrated data
from one domain without taking into account the twinning,
which led to high values of probability factors, for
example, R1 was 13.8%. However, the difference Fourier
map for the structure of compound 6а did not contain extra
peaks, the thermal vibration ellipsoids on all atoms were
acceptable, and the analysis of bond lengths and valence
Synthesis of 4-amino-7-[(furan-2-yl)methyl]-9,9-
dimethyl-6-oxo-2-thioxo-3,7-diazabicyclo[3.3.1]non-3-ene-
1-carbonitrile (9). A mixture of furfurylamine (0.22 ml,
2.5 mmol) and 37% formalin (d 1.1 g/ml) (0.20 ml,
2.7 mmol) in 96% EtOH (5 ml) was heated to reflux, and
the thiolate 2a (736 mg, 2.5 mmol) was added. The mixture
125

Chemistry of Heterocyclic Compounds 2016, 52(2), 116–127
angles with CCDC MOGUL program36 did not reveal
substantial deviations from the average values at CCDC,
indirectly confirming the correctness of the determined
structure. The structure was solved by charge-flipping method
(olex2.solve) and refined by method of least squares with
Olex2 program34 using the SHELXL 2014/7 software
suite.35
The complete crystallographic information about
structures of compounds 4–6а was deposited at the
Cambridge Crystallographic Data Center (deposits CCDC
1057031, CCDC 1057070, CCDC 1057027, respectively).
Litvinov, V. P. Russ. Chem. Bull., Int. Ed. 2007, 56, 1053.
[Izv. Akad. Nauk, Ser. Khim. 2007, 1014.]
11. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P.;
Rusanov, E. B. Dokl. Chem. 2007, 413(1), 68. [Dokl. Akad.
Nauk 2007, 413, 345.]
12. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P.
Monatsh. Chem. 2008, 139, 271.
13. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P.
Monatsh. Chem. 2008, 139, 657.
14. Dotsenko, V. V.; Frolov, K. A.; Krivokolysko, S. G.;
Litvinov, V. P. Russ. Chem. Bull., Int. Ed. 2009, 58, 1479.
[Izv. Akad. Nauk, Ser. Khim. 2009, 1436.]
15. Frolov, K. A.; Dotsenko, V. V.; Krivokolysko, S. G.;
Litvinov, V. P. Chem. Heterocycl. Compd. 2010, 46, 1142.
[Khim. Geterotsikl. Soedin. 2010, 1413.]
16. Frolov, K. A.; Dotsenko, V. V.; Krivokolysko, S. G.;
Litvinov, V. P. Chem. Heterocycl. Compd. 2012, 48, 1117.
[Khim. Geterotsikl. Soedin. 2012, 1197.]
17. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Russ.
Chem. Bull., Int. Ed. 2012, 61, 131. [Izv. Akad. Nauk, Ser.
Khim. 2012, 129.]
The Supplementary information file, containing spectra
of the obtained compounds, as well as X-ray structural
analysis data for compounds 4a, 5a, 6а, is available online
at http://link.springer.com/journal/10593.
The authors I. S. Bushmarinov and A. O. Dmitrienko
would like to acknowledge the financial support received
from the Russian Science Foundation (grant 14-13-00884).
18. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Russ.
Chem. Bull., Int. Ed. 2012, 61, 136. [Izv. Akad. Nauk, Ser.
Khim. 2012, 134.]
The authors express their gratitude to the late professor
Dr. Chem. Oleg V. Shishkin (29.07.1966–17.07.2014) and
his colleagues (Scientific-Technological Complex ''Institute
of Single Crystals'', Kharkiv, Ukraine) for X-ray structural
studies of compound 4а.
19. Chigorina, Е. А.; Dotsenko, V. V. Chem. Heterocycl. Compd.
2012, 48, 1722. [Khim. Geterotsikl. Soedin. 2012, 1838.]
20. Frolov, K. A.; Dotsenko, V. V.; Krivokolysko, S. G.;
Zubatyuk, R. I.; Shishkin, O. V. Chem. Heterocycl. Compd.
2013, 49, 472. [Khim. Geterotsikl. Soedin. 2013, 507.]
21. Osolodkin, D. I.; Kozlovskaya, L. I.; Dueva, E. V.;
Dotsenko, V. V.; Rogova, Y. V.; Frolov, K. A.;
Krivokolysko, S. G.; Romanova, E. G.; Morozov, A. S.;
Karganova, G. G.; Palyulin, V. A.; Pentkovski, V. M.;
Zefirov, N. S. ACS Med. Chem. Lett. 2013, 4, 869.
The authors also appreciate the assistance from
Candidate of Chemical Sciences A. V. Mazepa (A. V.
Bogatsky Physical Chemistry Institute, Odessa, Ukraine)
for the recording of mass spectra (EI, FAB), as well as
A. Yu. Kostyuk (Scientific Production Company Mikrokhim
Ltd., Rubezhnoye, Ukraine) for recording the IR spectra.
22. (a) Dotsenko, V. V.; Frolov, K. A.; Pekhtereva, T. M.;
Papaianina, O. S.; Suykov, S. Yu.; Krivokolysko, S. G. ACS
Comb. Sci. 2014, 16, 543. (b) Dotsenko, V. V.; Chigorina, E. A.;
Papaianina, E. S.; Frolov, K. A.; Krivokolysko, S. G.
Macroheterocycles 2015, 8, 310.
23. Dotsenko, V. V.; Frolov, K. A.; Krivokolysko, S. G. Chem.
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127