Synthesis of E,E-bis(chloromethylidene) derivatives of N- organylthiomorpholines and-selenomorpholines and their quaternary salts

Article abstract of DOI:10.1080/17415993.2014.928296

An efficient method for preparation of hitherto unknown E,E-bis(chloromethylidene) derivatives of-organylthiomorpholines and-selenomorpholines by the reaction of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide and selenide with primary amines in benzene o

Full text of DOI:10.1080/17415993.2014.928296

This article was downloaded by: [Universite Laval]
On: 28 June 2014, At: 12:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Sulfur Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gsrp20
Synthesis of E,E-bis(chloromethylidene)
derivatives of N-organylthiomorpholines
and -selenomorpholines and their
quaternary salts
Alexander V. Martynova, Nataliya A. Makhaevaa & Svetlana V.
Amosovaa
a A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch,
Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk,
Russia
Published online: 19 Jun 2014.
To cite this article: Alexander V. Martynov, Nataliya A. Makhaeva & Svetlana V. Amosova
(2014): Synthesis of E,E-bis(chloromethylidene) derivatives of N-organylthiomorpholines
and -selenomorpholines and their quaternary salts, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2014.928296
To link to this article: http://dx.doi.org/10.1080/17415993.2014.928296
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Journal of Sulfur Chemistry, 2014
http://dx.doi.org/10.1080/17415993.2014.928296
Synthesis of E,E-bis(chloromethylidene) derivatives of
N-organylthiomorpholines and -selenomorpholines and their
quaternary salts
Alexander V. Martynov, Nataliya A. Makhaeva and Svetlana V. Amosova∗
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
1 Favorsky Street, 664033 Irkutsk, Russia
(Received 24 April 2014; accepted 22 May 2014)
An efficient method for preparation of hitherto unknown E,E-bis(chloromethylidene) derivatives of
N-organylthiomorpholines and -selenomorpholines by the reaction of E,E-bis(3-bromo-1-chloro-1-
propen-2-yl) sulfide and selenide with primary amines in benzene or THF as well as with ethylammonium
bromide in ethanol in the presence of Na2CO3 has been described. Heterocylization of the above sulfide and
selenide by reaction with diethylamine in THF affords the unknown E,E-bis(chloromethylidene) deriva-
tives of heterocyclic quaternary salts-4,4-diethyl-1,4-thiazinan-4-onium and -1,4-selenazinan-4-onium
bromides.
RNH2, Et3N
Br
N
R
N
C6H6 or THF
Et
Et
Br
Br
NHEt2
Cl
Cl
Cl
Cl
Cl
Cl
THF, 20oC
Z
Z
Z
EtNH2 HBr
EtOH, Na2CO3
Z = S, Se
R = 4-CH3C6H4, 4-CH3C(O)C6H4, CH2=CHCH2, HOCH2CH2CH2, CH3CH2
Keywords: E,E-bis(3-bromo-1-chloro-1-propen-2-yl) chalcogenides; amines; heterocyclization;
N-organyl chalcogenomorpholines; 1,4-chalcogenazinan-4-onium bromides
1. Introduction
Recently, we have developed regio- and stereoselective method for high-yield synthesis of hitherto
unknown E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide (1) and selenide (2) by anti-addition
of sulfur dichloride or selenium dichloride to propargyl bromide against Markovnikov rule.[1,2]
Heterocyclization of chalcogenides 1 and 2 by reaction with sodium sulfide or selenide and
∗Corresponding author. Email: amosova@irioch.irk.ru
© 2014 Taylor & Francis

2
A.V. Martynov et al.
Y
Z
Cl
Cl
Z
S
S
Se Se
Se
Y
S
Se
S
Figure 1. Structure of E,E-bis(chloromethylidene) derivatives of the 1,4-dithiane type heterocycles.
NH2
N
Cl
Cl
Z
Z = S, Se
Figure 2. Structure of E,E-bis(chloromethylidene) derivatives of 4-thio- and 4-selenomorpholinamines.
hydrazine hydrate has led to hitherto unknown E,E-bis(chloromethylidene) derivatives of the 1,4-
dithiane type heterocycles [2] (Figure 1), 4-thio- and 4-selenomorpholinamines [3] (Figure 2).
However, bis(chloromethylidene) derivatives of N-substituted thio- and selenomorpholine as well
astheirquaternarysaltsareunknown. Intheliterature, thereisonlyoneworkdescribingquaternary
thiomorpholine salts, bearing the methylidene group in 3-position, which have been prepared by
cyclization of HC≡CCH2SCH2CH2NRR1 (R = R1 = Me, Et, RR1 = (CH2)5, CH2CH2OCH2CH2)
in H2O at 80◦C followed by neutralization of the product with HI.[4] At the same time N-
substituted thio- and selenomorpholines as well as their derivatives possess a number of useful
properties. Thus, N-substituted thiomorpholines, containing aromatic substituents with electron-
withdrawing groups in its structure, show nonlinear optical properties.[5] Complexes of 4,4-
dialkylthiomorpholinium derivatives and tetracyanoquinodimethane (1 : 2) have been thoroughly
investigated as promising organic conductors.[6–10] N-Substituted selenomorpholines and their
salts are found to inhibit the metabolism of Escherichia coli [11] and are more effective for
the uptake of selenium by radish than sodium selenite.[12,13] Quaternary ammonium salts of
thiomorpholine containing propargyl substituent at the nitrogen atom inhibit the growth of bacteria
and fungi,[14] while similar salts with sulfanyl group at the nitrogen atom exert bactericide activity
and are active against corrosion.[15] Quaternary thiomorpholinium salts of polyepihalohydrin
could be used as flocculating agents, corrosion inhibitors and biocides.[16] So, our interest in
the synthesis of novel chalcogenomorpholines such as bis(chloromethylidene) derivatives of N-
substituted thio- and selenomorpholines capable of further transformation due to the presence of
the exocyclic double bonds in their structure is justifiable.
2. Results and discussion
In order to synthesize novel nitrogen, chalcogen-containing heterocycles we have employed the
heterocyclization reaction of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide (1) and selenide
(2) with primary and secondary amines. Both aliphatic, such as allylamine, 3-aminopropanol and
ethylamine as a salt EtNH2· HBr, and aromatic, such as p-toluidine and p-aminoacetophenone,
have been used as primary amines. Heterocylizations with primary amines are found to easily

Journal of Sulfur Chemistry
3
proceed at room temperature in benzene or THF and in several hours to afford N-R-2(E),6(E)-
bis(chloromethylidene) thiomorpholines (3a–d) and -selenomorpholines (4a–d) in high yields
(Scheme 1).
R
C6H6 or THF, 20 oC
Et3N
Br
Br
N
H2NR
+
Et3N HBr
+
Cl
Cl
Cl
Cl
Z
Z
1,2
3a-d, 4a-d
N
3a
Z
R
Yield, %
95
S
S
S
S
Se
4-CH3C6H4
4-CH3C(O)C6H4 87
CH2CH=CH2 97
CH2CH2CH2OH 95
4-CH3C6H4 96
(
)
3b
3c
3d
4a
4b
4c
4d
(
)
Se 4-CH3C(O)C6H4 62
Se CH2CH=CH2 95
Se CH2CH2CH2OH 77
Scheme 1. Preparation of bis(E-chloromethylidene) derivatives of N-organylthiomorpholines
and selenomorpholines by heterocyclization of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide
and selenide with primary amines.
In the case of ethylammonium bromide, heterocyclization is carried out in alcoholic medium
by the generation of ethylamine in situ by reaction of Na2CO3 with the salt in ethanol (Scheme 2).
This procedure also furnishes corresponding N-ethylchalcogenomorpholines 3e and 4e in up to
87% yields.
Et
EtOH, 55oC
Na2CO3
Br
Br
N
+
NaBr
+
EtNH2 HBr
Cl
Cl
Cl
Cl
Z
Z
1,2
3e (87%), 4e (85%)
Z = S (1, 3e), Se (2, 4e)
Scheme 2. Preparation of bis(E-chloromethylidene) derivatives of N-ethylthiomorpholines and
-selenomorpholinesby heterocyclization of E,E-bis(3-bromo-1-chloro-1-propen-2-yl)sulfideand
selenide with the primary ethylammonium salt.
1
Structures of heterocyles 3 and 4 have been proved by the H, 13C NMR spectroscopy and
mass spectrometry. In the 1H NMR spectra, apart from the signals of the substituents at nitrogen
atom, triplet signals of vinyl protons at 6.13–6.26 ppm range are present which are shifted up-field
compared to the signals of bis(E-chloromethylidene) substituted thio- and selenomorpholin-4-
amines (δ 6.38 and 6.38 ppm, correspondingly [3]), as well as doublet signals of methylene
protons in δ 3.69–4.52 ppm range, which up-field or downfield shifts compared to the signals of

4
A.V. Martynov et al.
bis(E-chloromethylidene) substituted thio- and selenomorpholin-4-amines (δ 3.87 and 3.98 ppm,
correspondingly [3]) are influenced to a great extent by the substituent at nitrogen atom. The 13
C
NMR spectra of the heterocycles 3 and 4 are characterized by doublet–triplet signals of the carbon
atoms of =CHCl group at δ 112.4–114.9 ppm, the same way as the proton signals shifted up-field
compared to the signals of bis(E-chloromethylidene) substituted thio- and selenomorpholin-4-
amines (δ 115.5 and 117.2 ppm, correspondingly [3]), as well as multiplet signals of carbon of the
CH2 group in the morpholine ring at δ 50.1–53.2 ppm, which manifest themselves in a stronger
field compared to the signals of the CH2 group of bis(E-chloromethylidene) substituted thio- and
selenomorpholin-4-amines (δ 57.5 and 58.2 ppm, correspondingly [3]). E,E-Configuration of the
heterocycles 3 and 4 follows from fine structures of the 13C NMR spectra characterized by trans-
vicinal spin-spin coupling constants between vinyl proton and carbon atom of the CH2 group
(3JCH 6.6–7.0 Hz).[17] Their values coincide with the values of the constants for both the parent
chalcogenides 1 and 2 (3JCH 7–7.4 Hz [2]) and the 1,4-dithiane type heterocycles (3JCH 6.7–7.3 Hz
[2]) prepared by heterocyclization of the chalcogenides 1 and 2 by reaction with sodium sulfide
and selenide. E,E-Configuration of the 1,4-dithane-type heterocycles was in turn unambiguously
proved by the XRD.[2]
Massspectraofthechalcogenomorpholines 3and 4, exceptforthepropanolicderivatives 3d and
4d, are characterized by pronounced molecular ions. Further decomposition of these compounds
under electron impact depends on substituent at nitrogen atom. In a case of N-allylmorpholines
3c and 3c, the main processes involve the splitting out of the CH = CH2 fragment and chlorine
atom, while for N-aryl-substituted morpholines 3a, 3b, 4a and 4b, mainly chlorine abstraction
occurs. In a case of morpholines 3c and 4c, molecular ions are also detected, but the main process
is the formation of fragment ions [M – C2H4OH]+ and [M – C3H6OH]+.
For bifunctional 3-aminopropanol nucleophile, participation in the reaction of both func-
tional groups, amine and alcoholic ones, is possible. But neither generation of sodium 3-
aminopropanolate in ethanol under the action of sodium ethanolate nor the application of sodium
3-aminopropanolate preliminary synthesized from 3-aminopropanol and NaOH leads to the for-
mation of the substitution products of bromine atoms in bromomethyl groups of chalcogenides
1 and 2 by the hydroxy-group of 3-aminopropanol both in ethanol and DMSO. In all cases, the
only reaction products are chalcogenides 3d and 4d.
The reaction of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide (1) and selenide (2) with
secondary amine, diethylamine, also follows the heterocyclization path. Even in the presence of
a large excess of diethyl amine, substitution of the bromine atoms by amino-group at both bro-
momethyl groups does not take place. The reaction delivers the heterocycles containing quaternary
nitrogen atom, 4,4-diethyl-2(E),6(E)-bis(E-chloromethylidene)-1,4-thiazinan-4-onium bromide
(5) and 4,4-diethyl-2(E),6(E)-bis(E-chloromethylidene)-1,4-selenazinan-4-onium bromide (6).
Separation of the heterocycles 5 and 6 and diethylammonium bromide formed in the reaction
has been achieved by treatment of the reaction mixture with NaHCO3 solution resulting in the
regeneration of the parent diethylamine which further is separated from this mixture to give pure
heterocycles 5 or 6 (Scheme 3).
The formation of the heterocycles 5 and 6 was confirmed by the 1H and 13C NMR spectroscopy,
mass spectrometry data as well as elemental analysis. In the 1H NMR spectra, singlet signals of
vinyl and methylene protons of chalcogenomorpholine ring and methylene and methyl protons
of the ethyl group in a ratio of 2 : 4 : 4 : 6 are distinctly observed, while the 13C NMR spectra
are characterized by doublet–triplet signals of the =CHCl group (δ 124.18 and 122.70 ppm) and
triplet–doublet signals of the CH2 group of the morpholine rings (δ 56.10 and 56.95 ppm). Fine
structures of these signals confirm, on one hand, direct bonding of the carbon atom of the =CHCl
group to the halogen atom (1JCH 199–202 [18]) and indicate, on the other hand, retention of the
configuration of the parent E,E-bis(chlorovinyl) chalcogenides 1 and 2 in the heterocycle prepared
since the 3JCH values between the carbon atom of the methylene group and vinyl proton of the

Journal of Sulfur Chemistry
5
Br
CH3 CH3
THF, 20oC
N
Z
Br
Br
NHEt2
Et2NH HBr
+
+
Cl
Cl
Cl
Cl
Z
1, 2
5 (89%), 6 (50%)
Z = S (1, 5), Se (2, 6)
Scheme 3. Preparation of bis(E-chloromethyliodene) derivatives of 4,4-diethyl-1,4-thiazinan-
4-onium and -1,4-selenazinan-4-onium bromides by heterocylization of E,E-bis(3-bromo-1-
chloro-1-propen-2-yl) sulfide and selenide with diethylamine.
=CHCl group (6 Hz) practically agree with the similar values for chalcogenides 1 and 2 (7 Hz
[2]). Mass spectra of the heterocycles 5 and 6 are characterized by lack of the molecular ions and
in general coincide with the mass spectra of N-ethylchalcogenomorpholines 3e and 4e, which
is due to thermal decomposition of quaternary ammonium salts accompanied by the release of
C2H5Br during analysis and generation in the mass spectrometer of the heterocycles 3e and 4e.
3. Conclusion
Hitherto unknown E,E-bis(chloromethylidene) derivatives of N-organyl-substituted thio- and
selenomorpholines 3 and 4 and their quaternary salts 5 and 6 have been prepared. Het-
erocycles 3–6 are conceptually the bridged derivatives of E,E-bis(2-chlorovinyl) sulfide
and selenide and could be modified through participation of the chlorine atoms at double
bonds in the cross-coupling reactions to form functionally substituted derivatives of thio-
and selenomorpholines similar to the modification of E,E-bis(chloromethylidene)-1,4-dithiane
in cross-coupling with phenylacetylene.[19] Judging from the known biological activity in
certain derivatives of selenomorpholine,[20–22] including N-allylselenomorpholine and N-
arylselenomorpholines,[13,23]itmaybesuggestedthatheterocycles4 possesspotentialbiological
activity as well.
4. Experimental
4.1. General
The 1H (400.13 MHz) and 13C (100.61 MHz) NMR spectra were recorded on a Bruker DPX-400
spectrometer in 5–10% solutions in CDCl3, chemical shifts (δ) are expressed in ppm downfield
from hexamethyldisiloxane as an internal standard. Electron ionization mass spectra (EI-MS) were
determined on Agilent 5975 at 70 eV. The C, H, N, S analyses were done by Thermo Finnigan EA
1112 elemental analyzer. Se and Cl contents were determined by iodometric titration and by the
method of volumetric deposition in the presence of an indicator. Melting points of the compounds
were determined with PolyTherm A melting point apparatus are reported uncorrected.
E,E-Bis(3-bromo-1-chloro-1-propen-2-yl) sulfide (1) and E,E-bis(3-bromo-1-chloro-1-
propen-2-yl) selenide (2) were prepared in 90% and 80% yields from propargyl bromide and
sulfur dichloride or selenium dichloride, correspondingly, as described earlier.[1,2] Amines
(Et3N, Et2NH, CH2=CHCH2NH2, HOCH2CH2CH2NH2) were distilled over powdered potassium

6
A.V. Martynov et al.
hydroxide or recrystallized from EtOH (4-CH3C6H4NH2, CH3C(O)C6H4NH2, EtNH2·HBr) prior
to use. Benzene was stirred with H2SO4, decanted and distilled before use. THF was refluxed over
KOH, distilled off and redistilled over sodium metal with the addition of benzophenone.
4.2. General procedure for the synthesis of N-R-2(E),6(E)-bis(chloromethylidene)
thiomorpholines (3a-d)
A mixture of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) sulfide (1) (2–2.6 mmol), primary amine
(2–5.1 mmol) and Et3N (4–7.6 mmol) in ratio 1 : 1 : 2 (3a, 3b), 1 : 2 : 2 (3c) or 1 : 2 : 4 (3d) was
stirred in benzene (3a, 3c) or THF (3b, 3d) at 20◦C (3a, 3c, 3d) or at reflux (3b) 24 h (3b, 3d) or
48 h (3a, 3c).
4.2.1. N-(4-Methylphenyl)-2(E),6(E)-bis(chloromethylidene) thiomorpholine (3a)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with water and dried over K2CO3. The solvents were evacuated in vacuo. Yield 619 mg (95%).
1
4
Brown oil. H NMR (400.13 MHz, CDCl3): δ 2.25 (s, 3H, CH3), 4.37 (d, J = 1.3 Hz, 4H, 2
4
3
2,6
3
CH2), 6.08 (t, J = 1.3 Hz, 2H, 2 =CHCl), 6.80 (d, J = 8.4 Hz, 2H, 2 CarH=), 7.07 (d, J =
8.4 Hz, 2H, 2 CarH=). 13C NMR (100.61 MHz, CDCl3): δ 20.49 (q. t, JCH = 126.0, JCH
=
3,5
1
3
1
3
3
1
4.2 Hz, CH3), 50.18 (t. d. t, JCH = 141.2, JCH = 6.2, JCH = 4.4 Hz, CH2), 112.38 (d. t, JCH
3
1
2
2,6
= 200.0, JCH = 4.6 Hz, =CHCl), 115.82 (d. d, JCH = 155.9, JCH = 5.1 Hz, Car), 130.05 (d.
m, 1JCH = 155.5 Hz, 3,5Car), 145.80 (s, =C). EI-MS (m/z, %) (for isotopes 14N, 35Cl): 285 (M+
100), 250 ([M – Cl]+ 73), 214 (20), 158 (11), 144 (30), 118 (55), 91 (83), 65 (20). Anal. Calc. for
C13H13NCl2S: C, 54.55; H, 4.58; N, 4.89; Cl, 24.77; S, 11.20. Found: C, 54.30; H, 4.90; N, 4.62;
Cl, 24.51; S, 11.15%.
4.2.2. N-(4-acetylphenyl)-2(E),6(E)-bis(chloromethylidene) thiomorpholine (3b)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with 5% HCl solution and dried over K2CO3. The solvents were evacuated in vacuo.Yield 399 mg
(87%), light-brown oil. 1H NMR (400.13 MHz, CDCl3): δ 2.51 (s, 3H, CH3), 4.49 (d, 3J = 1.3 Hz,
4H, 2 =CCH2N), 6.15 (t, 3J = 1.3 Hz, 2H, 2 =CHCl), 6.85 (d, 3J = 9 Hz, 2H, 2,6CarH=), 7.90 (d,
3J = 9 Hz, 2H, 2 3,5CarH=). 13C NMR (100.61 MHz, CDCl3): 26.18 (q, 1JCH = 127.2 Hz, CH3),
1
3
3
1
3
49.37 (t. d. t, JCH = 142, JCH = 6.2, JCH = 3.9 Hz, CH2N), 113.26 (d. t, JCH = 200, JCH
=
4.4 Hz, =CHCl), 113.65 (d. d, 1JCH = 158, 2JCH = 5.2 Hz, 2,6Car), 128.24 (t, 2JCH = 7, CH2C=),
130.30 (s, =C–C=O), 130.79 (d. d, 1JCH = 160, 2JCH = 5.2 Hz, 3,5Car), 151.35–151.80 (m, =CN),
196.30–196.56 (m, C=O). EI-MS (m/z, %) (for isotopes 14N, 35Cl): 313 (M+ 98), 298 ([M –
CH3]+ 17), 278 ([M – Cl]+ 100), 192 (24), 149 (22), 132 (65). Anal. Calc. for C14H13NOCl2S:
C, 53.51; H, 4.17; N, 4.46; Cl, 22.56; S, 10.20. Found: C, 53.85; H, 4.09; N, 4.67; Cl, 22.75; S,
10.41%.
4.2.3. N-Allyl-2(E),6(E)-bis(chloromethylidene) thiomorpholine (3c)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with water and dried over K2CO3. The solvents were evacuated in vacuo and the crude product was
further purified by extraction with Et2O. Yield 592 mg (97%), brown oil. 1H NMR (400.13 MHz,
CDCl3): 3.15 (d. t, 3J = 6.6, 4J = 1.1 Hz, 2H, CH2CH=CH2), 3.69 (d, 4J = 1.1 Hz, 4H, 2 NCH2C=),
5.20–5.25 (m, 2H, =CH2), 5.80–5.87 (m, 1H, =CH), 6.13 (t, 4J = 1.1 Hz, 2H, =CHCl). 13C NMR
(100.61 MHz, CDCl3): 52.35 (t. d. t, 1JCH = 140.4, 2JCH = 5.2, 3JCH = 5.2 Hz, NCH2), 57.24 (t. m,
1JCH = 128.8 Hz, CH2CH=CH2), 113.12 (d. t, 1JCH = 199, 3JCH = 4.8 Hz, =CHCl), 119.05 (d. d. t,
1JCH = 154.8, 1JCH = 158.6, 3JCH = 5.5 Hz, =CH2), 130.07 (m, =C), 134.31 (d. m, 1JCH = 154.8 Hz,

Journal of Sulfur Chemistry
7
=CH). EI-MS (m/z, %) (for isotopes 14N, 35Cl): 235 (M+ 64), 208 ([M – CH=CH2]+ 15), 200
([M – Cl]+ 100), 164 (17), 128 (32), 108 (20), 92 (15), 71 (24). Anal. Calc. for C9H11NCl2S:
C, 45.77; H, 4.69; N, 5.93; Cl, 30.02; S, 13.58. Found: C, 45.34; H, 4.63; N, 6.03; Cl, 29.79; S,
13.23%.
4.2.4. N-(3-Hydroxypropyl)-2(E),6(E)-bis(chloromethylidene) thiomorpholine (3d)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with water and dried over K2CO3. The solvents were evacuated in vacuo. Yield 480 mg (95%),
brown viscous oil. 1H NMR (400.13 MHz, CDCl3): 1.76 (quint, 3J = 5.8 Hz, CH2CH2CH2), 2.73
(t, 3J = 6.1 Hz, 2H, NCH2CH2), 3.76 (d, 3J = 1.1 Hz, 4H, 2 =CCH2N), 3.79 (t, 2H, 3J = 5.3 Hz,
HOCH2), 6.16 (t, 3J = 1.1 Hz, 2H, 2 =CHCl). 13C NMR (100.61 MHz, CDCl3): 28.76 (t, 1JCH
=
125.9 Hz, CH2CH2CH2), 51.64 (t. t, 1JCH = 133.0, 2JCH = 3.9 Hz, NCH2CH2), 52.22 (t. d. t, 1JCH
= 139.5, 3JCH = 5.2, 3JCH = 4.8 Hz, =CCH2N), 61.62 (t. t, 1JCH = 141.2, 2JCH = 3.9 Hz, HOCH2),
113.28 (d. t, 1JCH = 199.4, 3JCH = 4.6 Hz, =CHCl), 129.37 (d. t, 2JCH = 4.1, 2JCH = 3.9 Hz, =C).
EI-MS (m/z, %) (for isotopes 14N, 35Cl): 253 (M+ 9), 236 ([M – OH]+ 3), 218 ([M – Cl]+ 29),
208 ([M – (CH2)2OH]+ 100), 194 ([M – (CH2)3OH]+ 18), 182 (15), 160 (7). Anal. Calc. for
C9H13NOCl2S: C, 42.53; H, 5.16; N, 5.51; Cl, 27.90; S, 12.62. Found: C, 42.33; H, 5.28; N, 5.41;
Cl, 27.60; S, 12.91%.
4.3. General procedure for the synthesis of N-R-2(E),6(E)-bis (chloromethylidene)
selenomorpholines (4a–d)
A mixture of E,E-bis(3-bromo-1-chloro-1-propen-2-yl) selenide (2) (2–7.6 mmol), primary amine
(2–9 mmol) and Et3N (4–19 mmol) in a ratio of 1 : 1 : 2 (4a, 4b) or 1 : 2 : 4 (4c, 4d) was stirred
in benzene (4a, 4c, 4d) or THF (4b) at 20◦C 48 h in an argon atmosphere.
4.3.1. N-(4-Methylphenyl)-2(E),6(E)-bis(chloromethylidene) selenomorpholine (4a)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with water and dried over K2CO3. Yield 640 mg (96%), brown powder, m.p. 75–76◦C (hexane).
1H NMR (400.13 MHz, CDCl3): 2.24 (s, 3H, CH3), 4.45 (d, 4J = 1.6 Hz, 4H, 2 CH2), 6.13 (t, 4J =
1.6 Hz, 2H, 2 =CHCl), 6.78 (d, 3J = 8.2 Hz, 2H, 2 3,5CarH=), 7.06 (d, 3J = 8.2 Hz, 2H, 2 2,6CarH=).
13C NMR (100.61 MHz, CDCl3): 20.52 (q, m, 1JCH = 125.6 Hz, CH3), 50.88 (t. d. t, 1JCH = 140.9,
3JCH = 7.0, 3JCH = 4.2 Hz, CH2), 113.30 (d. t, 1JCH = 200.6, 3JCH = 4.9 Hz, =CHCl), 115.36 (d.
d, 1JCH =161.3, 2JCH = 5.4 Hz, 2,6Car), 127.0.9 (q, 2JCH = 4.0 Hz, =C), 128.75 (d. d, 2JCH = 6.2,
2JCH = 7.3 Hz, =C), 130.14 (d. m, 1JCH = 155.9 Hz, 3,5Car). EI-MS (m/z, %) (for isotopes 80Se,
14N, 35Cl): 333 (M+ 72), 298 ([M – Cl]+ 14), 252 (7), 218 (38), 179 (18), 144 (62), 118 (63), 91
(100), 65 (33), 49 (15). Anal. Calc. for C13H13NCl2Se: C, 46.87; H, 3.93; N, 4.20; Cl, 21.29; Se,
23.70. Found: C, 46.65; H, 3.96; N, 3.95; Cl, 21.57; Se, 23.50%.
4.3.2. N-(4-acetylphenyl)-2(E),6(E)-bis(chloromethylidene) selenomorpholine (4b)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with 5% HCl solution and dried over K2CO3. The solvents were evacuated in vacuo and the
residue was further purified by column chromatography (silicagel, eluent-hexane : chloroform =
1 : 1).Yield 1.712 g (62%), brown viscous oil. 1H NMR (400.13 MHz, CDCl3): 2.50 (s, 3H, CH3),
4.52 (d, 3J = 1.5 Hz, 4H, 2 =CCH2N), 6.18 (t, 3J = 1.5 Hz, 2H, 2 =CHCl), 6.83 (d, 3J = 9.1 Hz,
2H, 2 2.6CarH=), 7.89 (d, 3J = 9.1 Hz, 2H, 2 3,5CarH=). 13C NMR (100.61 MHz, CDCl3): 26.12 (q,

8
A.V. Martynov et al.
1JCH = 127.1 Hz, CH3), 50.12 (t. m, 1JCH = 141.7 Hz, CH2N), 113.24 (d. d, 1JCH = 158.7, 2JCH
5.0 Hz, 2,6Car), 113.86 (d. t, 1JCH = 201.2, 3JCH = 4.2 Hz, =CHCl), 126.55 (d. t, 3JCH = 4.2, 2JCH
=
=
4.2 Hz, =C–C=O), 127.82 (t, 2JCH = 6.5 Hz, CH2C=), 130.60 (d. d, 1JCH =159.5, 2JCH = 6.9 Hz,
C ), 149.90-151.20 (m, =C–N), 196.15-196.40 (m, C=O). EI-MS (m/z, %) (for isotopes 80Se,
3,5
ar
14N, 35Cl): 361 (M+ 96), 346 ([M – CH3]+ 24), 326 ([M – Cl]+ 37), 290 (8), 266 (17), 246 (66),
192 (70), 172 (22), 155 (36), 132 (100), 104 (29), 91 (52). Anal. Calc. for C14H13NOCl2Se: C,
46.56; H, 3.63; N, 3.88; Cl, 19.63; Se, 21.86. Found: C, 46.87; H, 3.95; N, 3.61; Cl, 19.84; Se,
21.72%.
4.3.3. N-Allyl-2(E),6(E)-bis(chloromethylidene) selenomorpholine (4c)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with 5% HCl solution and dried over K2CO3. The solvents were evacuated in vacuo and the
residue was further purified by extraction with hexane. Yield 600 mg (95%), brown viscous oil.
1H NMR (400.13 MHz, CDCl3): 3.11 (d. t, 3J = 6.5, 4J = 1.2 Hz, 2H, CH2CH=CH2), 3.81 (d, 4J
4
= 1.2 Hz, 4H, 2 NCH2C=CH), 5.19–5.24 (m, 2H, =CH2), 5.78–5.88 (m, 1H, =CH), 6.21 (t, J
= 1.2 Hz, 2H, =CHCl). 13C NMR (100.61 MHz, CDCl3): 134.49 (d. m, 1JCH = 154.9 Hz, =CH),
1
1
3
125.80 (m, =C), 118.98 (d. d. t, JCH = 154.6, JCH = 154.6, JCH = 5.7 Hz, =CH2), 114.36 (d.
1
3
3
1
t, JCH = 200, JCH = 5, JSeH = 38 Hz, =CHCl), 56.00 (t. m, JCH = 131.3 Hz, CH2CH=CH2),
53.24 (t. d. t, 1JCH = 139.5, 2JCH = 5.0, 3JCH = 5.5 Hz, NCH2). EI-MS (m/z, %) (for isotopes 80Se,
14N, 35Cl): 283 (M+ 100), 256 ([M – CH=CH2]+ 25), 248 ([M – Cl]+ 79), 202 (30), 168 (48),
153 (28), 128 (77), 118 (50), 108 (29), 93 (36). Anal. Calc. for C9H11NCl2Se: C, 38.19; H, 3.91;
N, 4.95; Cl, 25.05; Se, 27.90. Found: C, 38.46; H, 4.20; N, 4.97; Cl, 24.66; Se, 27.88%.
4.3.4. N-(3-Hydroxypropyl)-2(E),6(E)-bis(chloromethylidene) selenomorpholine (4d)
The resulting reaction mixture was diluted with chloroform, the chloroform solution was rinsed
with 5% NaHCO3 solution and dried over K2CO3. The solvents were evacuated in vacuo and
the residue was further purified by extraction with MeOH. Yield 567 mg (77%), brown viscous
oil. 1H NMR (400.13 MHz, CDCl3): 1.76 (quint, 3J = 5.4 Hz, 2H, CH2CH2CH2), 2.71 (t, 3J =
6.0 Hz, 2H, NCH2CH2), 3.79 (t, 3J = 5.3 Hz, 2H, HOCH2), 3.88 (d, 3J = 0.9 Hz, 4H, 2 =CCH2N),
6.26 (t, 3J = 0.9 Hz, 2H, 2 =CHCl). 13C NMR (100.61 MHz, CDCl3): 28.58 (t, 1JCH = 126.0 Hz,
CH2CH2CH2), 50.91 (t, 1JCH =132.9 Hz, NCH2CH2), 53.24 (t, 2JCH = 138.4 Hz, =CCH2N), 62.47
(t. t, 1JCH = 142.0, 2JCH = 3.7 Hz, HOCH2), 114.87 (d. t, 1JCH = 200.9, 3JCH = 4.6 Hz, =CHCl),
125.15 (d. t, 2JCH = 4.1, 2JCH = 3.9 Hz, =C). EI-MS (m/z, %) (for isotopes 80Se, 14N, 35Cl): 301
(M+ 6), 284 ([M – OH]+ 1), 256 ([M – C2H4OH]+ 100), 242 ([M – C3H6OH]+ 11), 227 (36),
182 (29). Anal. Calc. for C9H13NOCl2Se: C, 35.90; H, 4.35; N, 4.65; Cl, 23.55; Se, 26.23. Found:
C, 36.20; H, 4.52; N, 4.77; Cl, 23.36; Se, 26.32%.
4.4. General procedure for the synthesis of N-ethyl-2(E),6(E)-bis
(chloromethylidene)thiomorpholine- and selenomorpholines (3e, 4e)
A solution of sulfide 1 or selenide 2 (1.1 mmol), EtNH.2HBr (1.1 mmol) and NaHCO3 (3.3 mmol)
in 15 ml EtOH was stirred 10 h at room temperature and 7 h at 50–55◦C. The reaction mixture
was diluted with H2O (20 ml), extracted with CHCl3, chloroform extract was rinsed with 15%
solution of HCl and the resulting water solution was carefully neutralized with Na2CO3, extracted
with Et2O, the ether extract was dried over K2CO3.

Journal of Sulfur Chemistry
9
4.4.1. N-Ethyl-2(E),6(E)-bis(chloromethylidene) thiomorpholine (3e)
1
3
Yield 194 mg (87%), brown oil. H NMR (400.13 MHz, CDCl3): 1.14 (t, J = 7.0 Hz, 3H,
3
3
CH2CH3), 2.59 (q, J = 7.2 Hz 2H, CH2CH3), 3.71 (d, J = 1.1 Hz, 4H, 2 NCH2C=CH), 6.13
(t, 3J = 1.1 Hz, 2H, =CHCl). 13C NMR (100.61 MHz, CDCl3): 12.60 (q. t, 1JCH = 125.9, 2JCH
3.0 Hz, NCH2CH3), 47.85 (t. q, 1JCH = 133.0, 2JCH = 3.8 Hz, NCH2CH3), 52.19 (t. d. t, 1JCH
=
=
139.0, 2JCH = 4.8, 3JCH = 4.8 Hz, NCH2C=), 112.83 (d. t, 1JCH = 199.0, 3JCH = 4.6 Hz, =CHCl),
130.14 (d. t, 2JCH = 3.4, 2JCH = 3.4 Hz, =C). EI-MS (m/z, %) (for isotopes 14N, 35Cl): 223 (M+
44), 208 ([M – CH3]+ 73), 188 ([M – Cl]+ 100), 173 (5), 155 (12), 152 (16), 131 (16), 116 (35),
96 (79), 82 (13), 71 (40), 56 (36). Anal. Calc. for C8H11NCl2S: C, 42.87; H, 4.95; N, 6.25; Cl,
31.63; S, 14.31. Found: C, 42.82; H, 4.80; N, 5.97; Cl, 31.73; S, 13.92%.
4.4.2. N-Ethyl-2(E),6(E)-bis(chloromethylidene) selenomorpholine (4e)
1
3
Yield 255 mg (85%), yellow oil. H NMR (400.13 MHz, CDCl3): 1.11 (t, J = 7.2 Hz, 3H,
3
3
CH2CH3), 2.54 (q, J = 7.2 Hz, 2H, CH2CH3), 3.84 (d, J = 1.1 Hz, 4H, NCH2C=), 6.20 (t,
3J = 1.1 Hz, 2H, =CHCl). 13C NMR (100.61 MHz, CDCl3): 12.91 (q. t, JCH = 125.9, JCH
=
1
2
3.0 Hz, NCH2CH3), 46.60 (t. q, 1JCH = 133.2, 2JCH = 3.8, NCH2CH3), 53.16 (t. d. t, 1JCH = 139.1,
2JCH = 5.5, 3JCH = 4.2 Hz, NCH2C=), 114.35 (d. t, 1JCH = 200.1, 3JCH = 5.0 Hz, =CHCl), 125.90
(d. t, 2JCH = 3.4, 2JCH = 3.4 Hz, =C). EI-MS (m/z, %) (for isotopes 80Se, 14N, 35Cl): 271 (M+ 36),
256 ([M – Me]+ 58), 236 ([M – Cl]+ 37), 182 (32), 155 (89), 140 (28), 119 (64), 116 (100), 96
(84), 75 (41), 56 (40). Anal. Calc. for C8H11NCl2Se: C, 35.45; H, 4.09; N, 5.17; Cl, 26.16; Se,
29.13. Found: C, 35.56; H, 4.17; N, 4.96; Cl, 26.03; Se, 29.35%.
4.5. General procedure for the synthesis of 4,4-diethyl-2(E),6(E)-bis
(chloromethylidene)-1,4-thiazinan-4-onium and -1,4-selenazinan-4-onium bromides
(5,6)
A solution of sulfide 1 or selenide 2 (4.0 mmol) and Et2NH (10.0 mmol) in 20 ml THF was stirred
for 20 h at room temperature. The deposits settled out were filtered off and dissolved in 5%
NaHCO3. The resulting solution was evaporated dry in vacuo, the residue was extracted with
CHCl3 and the chloroform solution was dried over K2CO3.
4.5.1. 4,4-Diethyl-2(E),6(E)-bis (chloromethylidene)-1,4-thiazinan-4-onium bromide (5)
1
Yield 956 mg (89%), light-brown powder, m.p. 195–200◦C with decomp. (EtOH). H NMR
3
3
(400.13 MHz, CDCl3): 1.43 (t, J = 7.2 Hz, 6H, CH3), 3.72 (q, J = 7.2 Hz, 4H, NCH2CH3),
5.17 (s, 4H, NCH2C=), 6.63 (s, 2H, =CHCl). 13C NMR (100.61 MHz, CDCl3): 7.41 (q, 1JCH
129.1 Hz, NCH2CH3), 53.46 (t, 1JCH = 145.4 Hz, NCH2CH3), 56.95 (t. d, 1JCH = 147.8, 3JCH
=
=
5 Hz, =CCH2N), 121.71 (s, =C), 122.70 (d. t, 1JCH = 199.4, 3JCH = 5 Hz, =CHCl). EI-MS (m/z,
%) (for isotopes 14N, 35Cl): 223 ([M – C2H5Br]+ 60), 208 (74), 188 (100), 145 (12), 116 (23.5),
96 (33.5), 71 (38). Anal. Calc. for C10H16NBrCl2S: C, 36.06; H, 4.84; N, 4.20; Br, 23.99; Cl,
21.29; S, 9.63. Found: C, 35.78; H, 4.73; N, 4.35; Br, 23.84; Cl, 21.39; S, 9.88%.
4.5.2. 4,4-Diethyl-2(E),6(E)-bis (chloromethylidene)-1,4-selenazinan-4-onium bromide (6)
1
Yield 760 mg (50%), light-brown powder, m.p. 194–197◦C with decomp. (EtOH). H NMR
3
3
(400.13 MHz, CDCl3): 1.44 (t, J = 7.2 Hz, 6H, CH3), 3.68 (q, J = 7.2 Hz, 4H, NCH2CH3),
5.19 (s, 4H, NCH2C=), 6.78 (s, 2H, =CHCl). 13C NMR (100.61 MHz, CDCl3): 7.85 (q, 1JCH
=

10 A.V. Martynov et al.
128.5 Hz, NCH2CH3), 53.73 (t, 1JCH = 144.8 Hz, NCH2CH3), 59.10 (t. d, 1JCH = 145.8, 3JCH
=
6 Hz, =CCH2N), 118.12 (d. t, JCH = 5.2, 2JCH = 5.0 Hz, =C), 124.18 (d. t, JCH = 202.0, 3JCH
= 5 Hz, =CHCl). EI-MS (m/z, %) (for isotopes 80Se, 14N, 35Cl): 271 ([M – C2H5Br]+ 94), 256
(100), 236 (63), 190 (14), 182 (30), 155 (59), 119 (35), 96 (47), 73 (26), 56 (32). Anal. Calc. for
C10H16NBrCl2Se: C, 31.61; H, 4.24; N, 3.69; Br, 21.02; Cl, 18.66; Se, 20.78 Found: C, 31.39; H,
4.12; N, 3.74; Br, 20.90; Cl, 18.50; Se, 20.60%.
2
1
References
[1] Amosova SV, Musalov MV, MartynovAV, PotapovVA. Regio- and stereoselective addition of selenium dihalogenides
to propargyl halogenides. Russ J Gen Chem. 2011;81:1239–1240.
[2] MartynovAV, Larina LI, Amosova SV. Novel bis[(E)-1-(halomethyl)-2-chlorovinyl] chalcogenides as starting mate-
rialfortheefficientsynthesisofbis(chloromethylidene)-1,4-dichalcogenanes.TetrahedronLett. 2012;53:1218–1221.
[3] Martynov AV, Makhaeva NA, Larina LI, Amosova SV. Bis-E-chloromethylidene derivatives of 4-thio- and
4-selenomorpholinamines. Chem Heterocycl Compd. 2012;48:1425–1427.
[4] Moskowitz H, Boutroy M, Miocque M. Synthèse de méthylène morpholiniums et thiamorpholiniums. [Synthesis of
methylene morpholiniums and thiamorpholiniums]. C r. 1977;284:69–71. French.
[5] Kagawa H, Sagawa M, Tsunoda A, Kaji M. Organic nonlinear optical materials and devices. Japanese patent JP
06,347,846 A. 1994 Dec 22.
[6] KolbertAC,Verel R, De Groot H,Almeida M. Determination of the spin density distribution in the organic conductor
DMTM(TCNQ)2 with 13C magic angle spinning NMR. Molecular Phys. 1997;91:725–730.
[7] Zimmer G, Kolbert AC, Mehring M, Rachdi F, Bernier P, Almeida M. Proton and carbon-13 NMR in the organic
conductor DMTM(TCNQ)2. Synth Metals. 1993;56:1821–1826.
[8] Musfeldt JL, Homes CC, Almeida M, Tanner DB. Temperature dependence of the infrared and optical properties of
N-dimethyl thiomorpholinium(tetracyanoquinodimethane)2. Phys Rev B. 1992;46:8777–8789.
[9] Kolbert AC, Zimmer G, Rachdi F, Bernier P, Almeida M, Mehring M. Locally resolved proton Knight
shifts and the order-disorder phase transition in the organic conductor N,N-dimethylthiomorpholinium bis-
tetracyanoquinodimethane [DMTM(TCNQ)2]. Phys Rev B. 1992;46:674–681.
[10] Rachdi M, Nunes T, Ribet M, Bernier P, Helmle M, Mehring M, Almeida M. Extremely large locally resolved
carbon-13 Knight shifts in the organic conductor N,N-dimethyl-thiomorpholinium bis(tetracyanoquinodimethane)
[DMTM(TCNQ)2]. Phys Rev B. 1992;45:8134–8137.
[11] Li X, Liu Y, Wu J, Qu S-Sh. Microcalorimetric study on the action of selenomorpholine derivatives on growth
metabolism of Escherichia coli. Chin J Appl Chem. 2002;19:645–648.
[12] Wu J, Gong F, Huang Z, Liu X, Wang G, Xu H. Investigation of plant systemic organoseleno compounds. IV. Effects
of the derivatives of selenamorpholine on the selenium content of radish. J Plant Nutr. 2000;23:349–356.
[13] Xu H, Wu J, Hu L, Liu X. Preparation of selenamorpholine derivatives as selenium enriching agent for plants.
Chinese patent CN 1,336,372 A. 2002 Feb 20.
[14] HsuACT. Iodopropargylated heterocyclic quaternary ammonium antimicrobial agents. European patent EP 539,114
A2. 1993 Apr 28.
[15] Quinlan PM. Thioether-containing quaternary ammonium derivatives of 1,4-thiazines. United States patent US
4,146,709 A. 1979 Mar 27.
[16] Quinlan PM. Thiazine quaternary ammonium salts of polyepihalohydrin. United States patent US 4,316,007A. 1982
Feb 16.
[17] Breitmaier E. Structure elucidation by NMR in organic chemistry: a practical guide. Chichester: Wiley; 2002. p. 26.
[18] Stothers JB. Carbon-13 nuclear magnetic resonance spectroscopy. New York: Academic Press; 1972.
[19] Martynov AV, Makhaeva NA, Amosova SV. Cross-coupling of 2,5-bis(chloromethylidene)-1,4-dithiane with
phenylacetylene as an example of preparation of symmetric bridging bisenyne compounds. Russ J Org Chem.
2013;49:1720–1721.
[20] Hu L-M, Feng J-H, Chen Zh-Y, Liu Zh-J, Xu H-Sh. Synthesis and biological activities of 4-arylmethylidene-l-aryl-
2-(selenomorpholin-4-yl)-2-imidazolin-5-one. Chin J Chem. 2003;21:1642–1646.
[21] Li X, LiuY,Wu J, Qu S-Sh.Action of the selenomorpholine compounds on the bacterium growth by microcalorimetry.
Chin J Chem. 2002;20:829–833.
[22] Li X, Liu Y, Wu J, Liang H, Qu S. The action of the selenomorpholine compounds on Escherichia coli growth by
microcalorimetry. J Therm Anal Calorim. 2002;67:589–595.
[23] Plenevaux A, Cantineau R, Brihaye C, Lemaire C, Christiaens L, Guillaume M. Synthesis and tissue distribution of
four selenium-labeled tertiary amines, potential brain pH imaging agents. Nucl Med Biol. 1990;17:601–607.