Synthesis of new 1, 3-thiazepine derivatives

Article abstract of DOI:10.1002/jhet.44

Condensation of thiourea derivatives with 1, 4-dibromobutane gave 1, 3-thiazepine derivatives (1a, b, c - 3a, b, c). Elementary analysis, MS and ¹H NMR spectra confirmed the identity of the products. The molecular structure of 2b was determined

Full text of DOI:10.1002/jhet.44

298
Synthesis of New 1,3-Thiazepine Derivatives
Marta Struga,a* Jerzy Kossakowski,a Barbara. Miroslaw,b Anna E. Koziol,b
Vol 46
and Andrzej Zimniakc
aMedical University, Department of Medical Chemistry, 02-007 Warsaw, Poland
bFaculty of Chemistry, Maria Curie-Sklodowska University, 20-031 Lublin, Poland
cMedical University, Department of Physical Chemistry, 02-097 Warsaw, Poland
*E-mail: marta.struga@wum.edu.pl
Received August 11, 2008
DOI 10.1002/jhet.44
Published online 20 March 2009 in Wiley InterScience (www.interscience.wiley.com).
Condensation of thiourea derivatives with 1,4-dibromobutane gave 1,3-thiazepine derivatives (1a, b, c
1
ꢀ 3a, b, c). Elementary analysis, MS and H NMR spectra confirmed the identity of the products. The
molecular structure of 2b was determined by an X-ray analysis.
J. Heterocyclic Chem., 46, 298 (2009).
INTRODUCTION
The second method for preparation of noncondensed
1,3-thiazepine ring systems is cyclization of compounds
possessing N and S atoms in their chains. In this case,
amines, aldehydes and halogen derivatives are utilized
as highly effective cyclization reagents. Following this
way, the reaction of 4-bromobutyl isothiocyanate with
aromatic amines served as general preparative method
for homologous 2-arylimino-1,3-thiazepines [16]. Fur-
ther-more, hexahydro-1,3-thiazepin-4-ones were ob-
tained via cyclocondensation of 4-mercapto-butyric acid
alkyl ester with alkyl or aryl-aldehydes [17]. Moreover,
2H-hexa-hydro-1,3-thiazepine derivatives substituted by
a nitro-methylene group in the second position were
obtained in reaction of 1-methylo-thiolo-propylamine
with 2,2,2-tri-halo-1-nitroethane [18]. 1,3-Thiazepine
ring system was also synthesized by the alkilation of N-
[1-mercapto-1-alkylamino-methylidene]-benzenesulfona-
mide sodium salt with dihaloalkanes [19].
Derivatives of 1,3-thiazepine rings are important
because of their biological activity [1–4]. The 1,3-thia-
zepine rings is present in Omipatrilat, which is currently
in the phase IV of clinical trials. By inhibiting the activ-
ity of the angiotensin converting enzyme (ACE), that
causes blood vessels to constrict, Omapatrilat lowers
blood pressure. Another advantage of this drug is inhibi-
tion of the enzyme known as neutral endopeptidase
(NEP), which causes blood vessels to relax [5,6].
The noncondensed 1,3-thiazepine rings can be pre-
pared by using various methods. They can be divided
into two main groups.
The first synthetic route is based on the cycloconden-
sation of thiourea derivatives resulting in 1,3-thiazepine
ring systems. Following this way, diethyl allylmalonate
reacted with thiourea in an unique manner giving an
excellent yield of ethyl 2-amino-7-methyl-4-oxo-4,5,6,7-
tetrahydro-1,3-thiazepine-5-carboxylate [7,8]. By this
method, 2-amino derivatives of 7-methyl-4-oxo-4,5,6,7-
tetrahydro-1,3-thiazepine-5-carboxylic acid ester in reac-
tion of 1-alkyl-3-pent-4-enoyl-thiourea with Br2 were
obtained [9,10]. Furthermore, 4-bromo-butyryl chloride
was also used as a cyclizing agent of N,N’-diphenylth-
iourea [11]. Condensation reaction of 4-amino-butan-1-
ol with isothiocyanate leads to thiourea derivatives.
Cyclization reaction of these thiourea derivatives in acidic
solution resulted in 4-substituted (methyl, benzyl and
propyl) imino-4,5,6,7-tetrahydro-1,3-thiazepine [12–15].
In the present paper the 1,3-thiazepine system was
obtained by the condensation reaction of thiourea deriv-
atives with 1,4-dibromobutane.
RESULTS AND DISCUSSION
The preparation of nine new 1,3-thiazepine deriva-
tives of 10-isopropyl-8-methyl-4-azatricyclo [5.2.2.02,6
]
undec-8-ene-3,5-dione, 1-isopropyl-7-methyl-4-azatricy-
clo-[5.2.2.02,6]undec-8-ene-3,5-dione and 1,7,8,9,10-
C
V
2009 HeteroCorporation

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Synthesis of New 1,3-Thiazepine Derivatives
299
Scheme 1
70. This value matches with the composition C5H10 for
which the isopentene cation-radical structure
[(CH3)2CHCH ¼¼ CH2]þꢁ could be proposed, resulting
from the sequential cleavage of the parent molecule. It
might be assumed that above fragmentation path corre-
sponds to the presence of the isopropyl substituent in
the parent compounds 1a, 2a, and 2b, which is absent in
3a. Formation of the isopentene moiety from 2a and 2b
requires
a rearrangement of isopropyl substituent,
whereas in 1a the isopentane moiety already occurs as a
part of condensed rings, serving as precursor for isopen-
tene. The weak signal in the spectrum of 3a at m/z 70
(13) occurs in close sequence of other signals showing
similar intensity and was not referred to above fragmen-
tation. Proposed fragmentation paths are shown in the
Figure 1.
penta-methyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione
(Scheme 1) is described.
Anhydrides and imides obtained in Diels-Alder reac-
tion were used as starting materials. Anhydride or imide
1 was obtained in the reaction of enantiomeric (R)-(-)-a-
phellandrene with furan-2,5-dione or pyrrole-2,5-dione
[20,21]. The reaction of a-terpinene with furan-2,5-
dione or pyrrole-2,5-dione gave compound 2 [21–23]
while compound 3 was obtained in reaction of 1,2,3,4,5-
penta-methylcyclopentadiene with furan-2,5-dione or
pyrrole-2,5-dione [24,25].
Above results concerning the m/z values of molecular
ions and also the fragmentation patterns confirm the
expected composition of investigated compounds.
The structure of 1,3-thiazepine and the exocyclic im-
ino form of thiourea fragment were confirmed by the X-
ray crystallography of 2b. In its crystal structure two
conformations of thiazepine ring are stabilized. The dis-
order of S1 and C4 atoms results in twist chair (TC)
and deformed boat (B) conformers which are energeti-
cally nearly equivalent [28]. The major component (TC)
Obtained tricyclic anhydrides or imides were sub-
jected to the reaction of hydrazine (80 % aqueous solu-
tion) as described previously [26,27].
In order to obtain the corresponding thiourea deriva-
tives of above compounds they were subjected to the
reaction with phenyl-, 4-methoxyphenyl-, cyclohexyl-
isothiocyanate [27].
Table 1
Products were transformed into 1,3-thiazepine deriva-
tives by condensation with 1,4-dibromobutane. This
method of synthesis of 1,3-thiazepine noncondensed
rings has not been described in literature so far. The
general synthetic pathway is given in Scheme 1. For-
mula of the investigated compounds is given in Table 1.
Obtained compounds were purified by flash chroma-
Structure of the investigated compounds 1a,b,c–3a,b,c.
R1
R2
C6H5A
(4ꢀOCH3)C6H5A
C6H11
1
1a
1b
1c
tography. Elementary analysis, MS and H NMR spectra
confirmed the identity of the products. The molecular
structure of 2b was determined by an X-ray analysis.
Compounds investigated using EI MS show distinct
signals of molecular ions at the expected m/z values, i.e.
for 1a, 2a, and 3a the value 437 was noted, and for 2b
the corresponding value was 467.
2a
2b
2c
In the spectrum of 3a an intense (100%) signal due to
the ion [M-135]þꢁ has been observed, apparently due to
the elimination of phenylisothiocyanate (PhNCS). Anal-
ogous splitting was noted for 2a and 1a, whereas in
case of 2b, consequently, 4-methoxyphenylisothiocya-
nate (CH3O-PhNCS) was severed. However, the inten-
sities of these signals for 2a, 1a, and 2b were only 6, 20
and 2 %, respectively.
3a
3b
3c
Furthermore, in the fragmentation patterns of 1a, 2a,
and 2b the most intense (100%) signal appeared at m/z
Journal of Heterocyclic Chemistry
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300
M. Struga, J. Kossakowski, Barbara.Miroslaw, A. E. Koziol, and A. Zimniak
Vol 46
room temperature. After hydrogen evolution ceased, 1,4-
dibromobutane (15 mmol) was added to the reaction
mixture, after 5 and 15 min. respectively. The mixture
was stirred for 6 h. Evaporation in vacuum gave a resi-
due which was then purified by column chromatography
(chloroform was used as eluant). The compound was
crystallized from ethanol.
10-Isopropyl-8-methyl-4-{2-[(Z)-phenylimino]-1,3-thiazep-an-
3-yl}-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (1a). Yield
1
30 %; mp 174-175ꢂC; H NMR (CDCl3):d 0.83 (d, J ¼
6.6 Hz, 3H, CH3); 0.91 (d, J ¼ 6.6 Hz, 3H, CH3); 1.01-
1.17 (m, 2H, CH2); 1.27-1.42 (m, 2H, CH2); 1.52-1.63
(m, 1H, CH); 1.77 (s, 3H, CH3), 1.81-1.85 (m, 3H, CH,
CH2); 2.0-2.09 (m, 2H, CH); 2.67-2.85 (m, 2H, CH2-N);
3.2-3.24 (m, 2H, CHAC¼¼O); 3.87-3.95 (m, 2H,
CH2AS); 5.74 (d, J ¼ 6.3 Hz, 1H, CH¼¼); 6.82-7.04 (m,
5H, phenyl). Anal. Calcd for C25H31N3O2S: C, 68.62;
H, 7.14; N, 9.6. Found: C, 68.46; H, 6.98; N, 9.60. ei
Figure 1. Selected proposed fragmentation patterns for investigated
compounds. The relative intensities of the signals are given for each
fragment in parentheses. The dashed arrows indicate multistep
fragmentation.
ms: m/z ¼ 437 (58%).
with the population of about 88 % is presented on
Figure 2.
10-Isopropyl-4-{2-[(Z)-4-methoxy-phenylimino]-1,3-thiaze-pan-
3-yl}-8-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
1
(1b). Yield 40%; mp 178-179ꢂC; H NMR (CDCl3): d
0.82 (d, J ¼ 6.6 Hz, 3H, CH3); 0.91 (d, J ¼ 6.6 Hz, 3H,
CH3); 1.01-1.18 (m, 2H, CH2); 1.27-1.46 (m, 2H, CH2);
1.52-1.63 (m, 1H, CH); 1.76 (s, 3H, CH3), 1.81-1.85 (m,
3H, CH, CH2); 2.0-2.09 (m, 2H, CH); 2.67-2.85 (m, 2H,
CH2AN); 3.2-3.24 (m, 2H, CHAC¼¼O); 3.79 (s, 3H,
OCH3); 3.87-3.95 (m, 2H, CH2AS); 5.74 (d, J ¼ 6.3
Hz, 1H, CH¼¼); 6.82-7.04 (m, 4H, CH phenyl). Anal.
Calcd for C26H33N3O3S: C, 66.78; H, 7.11; N, 8.99.
Found: C, 66.70; H, 7.09; N, 9.03. esi ms: m/z ¼ 468.2
EXPERIMENTAL
Melting points were determined in a Kofler’s apparatus and
are uncorrected. The 1H NMR spectra were recorded on a Bruker
AVANCE DMX400 spectrometer, operating at 400 MHz. The
chemical shift values are expressed in ppm relative to TMS as an
internal standard. Elemental analyses were recorded with a CHN
2400 Perkin-Elmer model. Mass spectra of 1a, 2a, 3a, and 2b
were recorded on an AMD-604 double focusing spectrometer
with BE geometry (AMD Intectra, Germany). EI low resolution
spectra were obtained with electron energy 70 eV, acceleration
voltage 8 kV and ion source temperature 220ꢂC. Samples were
introduced using a direct insertion probe heated, when required,
in the range 30–120ꢂC. Mass spectral ESI measurements for 1b,
3b, 1c, 2c, 3c were carried out on Waters ZQ Micromass instru-
ments with quadrupol mass analyzer. The spectra were per-
formed in the positive ion mode at a declustering potential of
40–60 V. The sample was previously separated on a UPLC col-
umn (C18) using UPLC ACQUITYTM system by Waters con-
nected with DPA detector.
[M þ H]þ (100%).
4-{2-[(Z)-Cyclohexylimino]-1,3-thiazepan-3-yl}-10-isopro-
pyl-8-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
1
(1c). Yield 40%; mp 173-174ꢂC; H NMR (CDCl3): d
0.82 (d, J ¼ 8.4 Hz, 3H, CH3); 0.91 (d, J ¼ 8.4 Hz, 3H,
Diffraction data for 2b were measured at 292 K on a KM4
diffractometer using variable scan speed in the x/2y scan
mode and graphite monochromated Cu Ka radiation (k ¼
˚
1.54178 A). A single crystal of dimensions 0.46 ꢃ 0.43 ꢃ
0.43 mm3 was used for the data collection.
Flash chromatography was performed on Merck silica gel
60 (200-400 mesh) using chloroform as eluant. Analytical
TLC was carried out on silica gel F254 (Merck) plates (0.25
mm thickness).
˚
Figure 2. Perspective view of the molecule 2b. Bond lengths (A)
1,3-THIAZEPINE DERIVATIVES (1a,b,c–3a,b,c)
within the 1,3-thiazepine ring are: C2–S1 1.769(3), S1–C7 1.785(4),
C7–C6 1.497(6), C6–C5 1.511(5), C5–C4 1.476(6), C4–N3 1.501(5),
N3–C2 1.390(4). The endocyclic torsion angle values (ꢂ) for TC con-
former are: S1–C2–N3–C4 31.0(4), C2–N3–C4–C5 -91.7(4), N3–C4–
C5–C6 79.9(5), C4–C5–C6–C7 -59.8(6), C5–C6–C7–S1 71.0(5) C6–
C7–S1–C2 –79.0(4), C7–S1–C2–N3 38.4(4).
General procedure. Sodium hydride dispersion
(60%) in mineral oil (0.44 g, ꢄ10 mmol) was added in
a single portion to a stirred solution of thiourea deriva-
tive (10 mmol) in anhydrous N,N-dimethylformamide at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of New 1,3-Thiazepine Derivatives
301
CH3); 0.98-1.23 (m, 2H, CH2); 1.4-1.74 (m, 14H, CH2,
CH); 1.77 (s, 3H, CH3), 1.83-1.91 (m, 2H, CH2); 2.10-
2.12 (m, 2H, CH); 2.95-2.99 (m, 1H, CHAC¼¼O); 3.2-
3.26 (m, 3H, CHAC¼¼O, CH2AN); 3.55-3.57 (m, 2H,
CH2AS); 4.03 (d, J ¼ 8.8 Hz, 1H, CHAN¼¼); 5.96 (d,
1H, CHA). Anal. Calcd for C25H37N3O2S: C, 67.68; H,
8.41; N, 9.47. Found: C, 68.04; H, 8.52; N, 9.51. esi
tion to The Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44 1223 336 033; e-mail: depos-
it@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.
uk).
4-{2-[(Z)-Cyclohexylimino]-1,3-thiazepan-3-yl}-1-isoprop-yl-7-
methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (2c). Yield
21%, mp 151-152ꢂC; 1H NMR (CDCl3): d 0.85-0.88
(m, 6H, CH2); 0.99 (d, J ¼ 7.2 Hz, 3H, CH3); 1.12 (d, J
¼ 6.8 Hz, 3H, CH3); 1.25-1.32 (m, 7H, CH, CH2); 1.5
(s, 3H, CH3); 1.74-1.91 (m, 4H, CH2); 2.33-2.37 (m,
2H, CH2); 2.54-2.64 (m, 2H, CHAC¼¼O); 3.37-3.43 (m,
2H, CH2AN); 3.52-3.56 (m, 2H, CH2AS); 4.36-4.42 (m,
1H, CHAN¼¼); 5.87 (dd, J ¼ 8.8 Hz, 2H, CH¼¼). Anal.
Calcd for C25H37N3O2S: C, 67.68; H, 8.41; N, 9.47.
Found: C, 67.25; H, 8.82; N, 9.32. esi ms: m/z ¼ 444.1
ms: m/z ¼ 444.1 [M þ H]þ (100%).
1-Isopropyl-7-methyl-4-{2-[(Z)-phenylimino]-1,3-thiazep-an-
3-yl}-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (2a). Yield
1
45%; mp 147-148ꢂC; H NMR (CDCl3): d 0.99 (d, J ¼
6.8 Hz, 3H, CH3); 1.11 (d, J ¼ 6.4 Hz, 3H, CH3); 1.22-
1.35 (m, 2H, CH2); 1.4-1.47 (m, 3H, CH, CH2); 1.51 (s,
3H. CH3); 1.71-1.77 (m, 2H, CH2); 1.9-1.97 (m, 2H,
CH2); 2.63 (dd, J ¼ 8 Hz, 2H, CHAC¼¼O), 2.98-3.06
(m, 2H, CH2AN); 3.77-3.84 (m, 2H, CH2AS); 6.04 (dd,
J ¼ 8.4 Hz, 2H, CH¼¼); 6.68 (d, J ¼ 7.6 Hz, 2H, CH
phenyl); 6.98-7.03 (m, 1H, CH phenyl); 7.2-7.24 (m,
2H, CH phenyl). Anal. Calcd for C25H31N3O2S: C,
68.62; H, 7.14; N, 9.60. Found: C, 68.76; H, 7.10; N,
[M þ H]þ (100%).
1,7,8,9,10-Pentamethyl-4-{2-[(Z)-phenylimino]-1,3-thiazep-an-
3-yl}-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (3a). Yield
1
41%; mp 107-108ꢂC; H NMR (CDCl3): d 0.61 (d, J ¼
6.4 Hz, 3H, CH3); 1.22-1.32 (m, 2H, CH2); 1.36 (s, 6H,
CH3); 1.62 (s, 6H, CH3); 1.6-1.64 (m, 1H, CH); 1.96-
1.99 (m, 2H, CH2); 2.91-3.18 (m, 4H, CHAC¼¼O,
CH2AN); 3.75-3.78 (m, 2H, CH2AS); 6.77-7.07 (m, 5H,
CH phenyl). Anal. Calcd for C25H31N3O2S: C, 68.62; H,
7.14; N, 9.59. Found: C, 68.28; H, 6.92; N, 9.16. ei ms:
9.51. ei ms: m/z ¼ 437 (50%).
1-Isopropyl-4-{2-[(Z)-4-methoxy-phenylimino]-1,3-thiaz-epan-
3-yl}-7-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
1
(2b). Yield 49%; mp 185-186ꢂC; H NMR (CDCl3): d
0.99 (d, J ¼ 6.8 Hz, 3H, CH3); 1.12 (d, J ¼ 6 Hz, 3H,
CH3); 1.26-1.37 (m, 2H, CH2); 1.4-1.46 (m, 3H, CH,
CH2); 1.5 (s, 3H. CH3); 1.71-1.73 (m, 2H, CH2); 1.96-
1.98 (m, 2H, CH2); 2.62 (dd, J ¼ 8 Hz, 2H,
CHAC¼¼O), 2.99-3.07 (m, 2H, CH2AN); 3.75-3.78 (m,
2H, CH2AS); 3.75 (s, 3H, OACH3); 6.04 (dd, J ¼ 8.4
Hz, 2H, CH¼¼); 6.6-6.66 (m, 2H, CH phenyl); 6.76-6.81
(m, 2H, CH phenyl). Anal. Calcd for C26H33N3O3S: C,
66.78; H, 7.11; N, 8.99. Found: C, 66.49; H, 7.11; N,
8.99. ei ms: m/z ¼ 467 (73%).
m/z ¼ 437 (28%).
1,7,8,9,10-Pentamethyl-4-{2-[(Z)-4-methoxy-phenylimino]-
1,3-thiazepan-3-yl}-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-di-one
1
(3b). Yield 19%; mp 126-127ꢂC; H NMR (CDCl3): d
0.61 (d, J ¼ 6.4 Hz, 3H, CH3); 1.22-1.32 (m, 2H, CH2);
1.36 (s, 6H, CH3); 1.62 (s, 6H, CH3); 1.6-1.64 (m, 1H,
CH); 1.96-1.99 (m, 2H, CH2); 2.91-3.18 (m, 4H,
CHAC¼¼O, CH2AN); 3.75-3.78 (m, 2H, CH2AS); 3.77
(s, 3H, OACH3); 6.57-6.63 (m, 2H, CH phenyl); 6.78
(d, 2H, CH phenyl). Anal. Calcd for C26H33N3O3S: C,
66.78; H, 7.11; N, 8.99. Found: C, 66.56; H, 7.2; N,
Crystal data for 2b: monoclinic, space group P21/c, a
˚
¼ 14.407(3), b ¼ 11.586(2), c ¼ 14.851(3) A, b ¼
8.99. esi ms: m/z ¼ 468.2 [M þ H]þ (100%).
3
ꢂ
˚
92.92(3) , V ¼ 2475.7(8) A , Z ¼ 4, dcalc ¼ 1.255 g/
cm3, l(Cu Ka) ¼ 1.415 mmꢀ1. In the y range 3.07–
73.51ꢂ, 4971 reflections were collected of which 4793
were unique (Rint ¼ 0.0264). The structure was solved
by direct methods using SHELXS-97 program [29] and
refined by full-matrix least-squares on F2 using
SHELXL-97 program [29]. The non-H atoms were
refined with anisotropic displacement parameters, except
of S1A and C4A atoms. The two atoms of thiazepine
ring are disordered over two positions with sof’s of
0.877(4) and 0.123(4) for S1, C4, and S1A, C4A,
respectively. H-atom positions were calculated from the
geometry. H-atoms were given isotropic factors of 1.2
or 1.5 Ueq of the bonded C-atoms; the C–H bond ‘ri-
ding’ model was used in the refinement.
4-{2-[(Z)-Cyclohexylimino]-1,3-thiazepan-3-yl}-4-aza-tri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione (3c). Yield 23%; mp
1
112-113ꢂC; H NMR (CDCl3): d 0.61 (d, J ¼ 5.6 Hz, 3H,
CH3); 1.05-1.26 (m, 6H, CH2); 1.32 (s, 6H, CH3); 1.38-1.95
(m, 9H, CH, CH2); 1.53 (s, 6H, CH3); 2.7-2.73 (m, 2H,
CH2AN); 2.8-2.84 (m, 2H, CHAC¼¼O); 3.3-3.36 (m, 2H,
CH2AS); 3.94-4.0 (m, 1H, CHAN¼¼). Anal. Calcd for
C25H37N3O2S: C, 67.68; H, 8.41; N, 9.47. Found: C, 67.60;
H, 8.52; N, 9.40. esi ms: m/z ¼ 444.1 [M þ H]þ (100%).
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M. Struga, J. Kossakowski, Barbara.Miroslaw, A. E. Koziol, and A. Zimniak
Vol 46
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet