BIS-E-chloromethylidene derivatives of 4-thio- and 4-selenomorpholinamines

Full text of DOI:10.1007/s10593-012-1155-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
BIS-E-CHLOROMETHYLIDENE DERIVATIVES
OF 4-THIO- AND 4-SELENOMORPHOLINAMINES
A. V. Martynov1, N. A. Makhaeva1, L. I. Larina1, and S. V. Amosova1*
Keywords: hydrazine hydrate, propargyl bromide, selenium dichloride, 4-selenomorpholinamine, sulfur
dichloride, 4-thiomorpholinamine.
It is known that the reaction of bis(2-haloethyl) sulfides with substituted amines gives 4-thiomorpholine
and its N-substituted derivatives [1], while the reaction with hydrazine hydrate yields 4-thiomorpholinamine [1,
2]. 4-Selenomorpholinamine is unknown, but 4-selenomorpholine and a series of its N-substituted derivatives
have been reported [3, 4].
We have developed a general method for the preparation of the previously unknown bis-E-chloro-
methylidene derivatives of 4-thiomorpholinamine 3 and 4-selenomorpholinamine 4. The method is composed of
two stages, the first of which is a stereo- and regioselective reaction of sulfur or selenium dichloride with
propargyl bromide, occuring as an anti-Markovnikov addition to give the E,E-bis(3-bromo-1-chloro-1-propen-
2-yl) sulfide (1) or selenide (2) in high yields [5, 6]. The second stage is a chemoselective nucleophilic
substitution of the bromine atoms in the bromomethylene fragments of sulfide 1 and selenide 2 with hydrazine
hydrate in the presence of NaOH to give the heterocycles 3 and 4 in high yields. This second stage includes the
alkylation of one hydrazine amino group with two bromomethyl groups of the divinylchalcogenides 1 and 2,
giving the unsymmetrical 1,1-disubstituted hydrazine derivatives, which is a typical feature of the reaction
between hydrazine and alkyl halides [7].
NH2
.
NH2NH2 H2O
Br
Br
CHCl3
N
HC
NaOH, EtOH
XCl2
+
2
Br
Cl
Cl
Cl
X
Cl
X
1, 2
3, 4
1, 3 X = S, 2, 4 X = Se
The presence in compounds 1-4 of a =CHCl fragment is indicated by the value of the direct coupling
constant (1JCH = 199-203 Hz) in the 13C NMR spectra, pointing to a direct carbon–halogen bond [8]. The
structure of selenide 2 [5] and the 4-selenomorpholinamine 4 was also confirmed by the presence of a direct
13
spin-spin coupling between the selenium atom and the C= carbon atom (1JC–Se = 101-113 Hz) in the C NMR
spectra. The E,E configuration of the divinylchalcogenides 1 and 2, as well as the heterocycles 3 and 4
_______
*To whom correspondence should be addressed, e-mail: amosova@irioch.irk.ru.
1A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St.,
Irkutsk 664033, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1526-1528, September 2012.
Original article submitted March 30, 2012.
0009-3122/12/4809-1425©2012 Springer Science+Business Media New York
1425

follows from the fine structure in the 13C NMR spectra characterized by a trans-vicinal spin-spin coupling
15
between the vinyl proton and the carbon atom of the CH2 group (3JCH = 6.2-7.0 Hz) [9]. The N NMR spectra
of heterocycles 3 and 4 clearly reveal the signals of the two different nitrogen atoms, and in the case of the
heterocycle 3 it is possible to observe the fine structure in the NH2 15N NMR signal due to a spin-spin
interaction of the nitrogen atom and proton. The mass spectra of heterocycles 3 and 4 are characterized by
intensive molecular ions and the ion fragments [M-NH2]+ and [M-Cl]+.
Hence the two-stage method we have discovered offers the possibility of preparing novel and promising
chloromethylidene derivatives of 4-thiomorpholinamine and 4-selenomorpholinamine from the available
propargyl bromide, sulfur and selenium dichlorides, and hydrazine hydrate. These are intermediate products for
further functionalization, due to the presence of chlorine atoms on a double bond and free amino groups in their
structure.
1H, 13C, 77Se, and 15N NMR spectra were recorded on a Bruker DPX-400 instrument (400, 100, 76, and
1
13
40 MHz, respectively) using CDCl3 as solvent. Chemical shifts were referred to TMS (for H and C nuclei),
77
15
Me2Se (for the Se nuclei at 0.0 ppm), or MeNO2 (for the N nuclei at 0.0 ppm). Mass spectra were recorded
on a Shimadzu QP5050A instrument (EI, 70 eV) with an SPB-5ms column (60 m). Elemental analysis was
carried out on a Thermo Finnigan EA 1112 analyzer.
Propargyl bromide was obtained by the bromination of propargyl alcohol using PBr3 [10].
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 using methods [5, 6] in 80 and 90% yields, respectively.
(2E,6E)-2,6-Bis(chloromethylidene)thiomorpholin-4-amine (3). Sulfide 1 (0.682 g, 2 mmol) in EtOH
(9 ml) was slowly added dropwise to a solution of NaOH (0.200 g, 5 mmol) in hydrazine hydrate (3.100 g, 62
mmol) at 0°C under an argon atmosphere. The mixture was stirred for 8 h at 20°C, diluted with water (9 ml),
and extracted with CHCl3. The extract was dried over MgSO4. Solvent was removed under reduced pressure.
The product obtained was purified by column chromatography on silica gel using EtOAc–CHCl3 (5:95) as
1
eluent. Yield 0.314 g (74%), a yellow oil. H NMR spectrum, , ppm (J, Hz): 3.40 (2H, s, NH2); 3.87 (4H, d,
4J = 0.9, 2CH2); 6.27 (2H, t, 4J = 0.9, 2 =CH). 13C NMR spectrum, , ppm (J, Hz): 57.5 (tdt, 1J = 140.8, 3J = 6.3,
3J = 4.4, 2CH2); 115.5 (dt, 1J = 199, 3J = 4.8, 2C-Cl); 128.9 (dt, 2J = 4.0, 2J = 4.0, C–S–C). 15N NMR spectrum,
1
15
32
, ppm (J, Hz): -315.2 (t, J = 3.9, NH2); -295.0 (s, N). Mass spectrum, m/z (Irel, %): (35Cl, N, S): 212 [M]+
(36), 195 [M-NH2]+ (3), 177 [M-Cl]+ (38), 175 (100), 158 (8), 145 (18), 131 (16), 114 (3), 92 (34), 71 (43), 69
(34), 45 (57), 39 (71). Found, %: C 34.50; H 3.91; Cl 33.86; N 13.20; S 15.54. C6H8Cl2N2S. Calculated, %:
С 34.13; H 3.82; Cl 33.59; N 13.27; S 15.19.
(2E,6E)-2,6-Bis(E-chloromethylidene)selenomorpholin-4-amine (4). Compound 4 was prepared
similarly to compound 3 from NaOH (0.150 g, 3.8 mmol), hydrazine hydrate (0.500 g, 10.0 mmol), and the
selenide 2 (0.970 g, 2.5 mmol) in EtOH (10 ml) by stirring over 12 h and subsequent isolation by column
1
chromatography on silica gel (eluent EtOAc–CHCl3, 5:95). Yield 0.433 g (67%), a yellow oil. H NMR
4
4
13
spectrum, , ppm (J, Hz): 3.15 (2H, s, NH2); 3.98 (4H, d, J = 1.3, 2CH2); 6.38 (2H, t, J = 1.3, 2 =CH). C
1
3
3
1
3
NMR spectrum, , ppm (J, Hz): 58.2 (tdt, J = 140.8, J = 6.2, J = 4.8, 2CH2); 117.2 (dt, J = 200.1, J = 4.6,
2C-Cl); 124.4 (d, J = 3.6, JSe–C = 101.0, C-Se-C). Se NMR spectrum, , ppm: 404.4. 15N NMR spectrum, ,
ppm (J, Hz): -314.2 (NH2); -298.3 (N). Mass spectrum, m/z (Irel, %): (35Cl, 15N, 80Se): 260 [M]+ (6), 243
[M-NH2]+ (1), 225 [M-Cl]+ (9), 197 (1), 193 (4), 159 (10), 140 (8), 119 (15), 39 (100). Found, %: C 28.34;
H 3.58; Cl 27.24; N 11.19; Se 30.11. C6H8Cl2N2Se. Calculated, %: С 27.93; H 3.13; Cl 27.48; N 10.86;
Se 30.60.
3
1
77
This work was carried out with the financial support of the Russian Foundation for Basic Research
(grant 11-03-00810-a).
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