Synthesis of 2,3,4,7-tetrahydro[1,4]thiazepines from thiazolidines and β-enaminonitriles

Article abstract of DOI:10.1016/j.tet.2008.02.027

A wide library of 2,3,4,7-tetrahydro[1,4]thiazepines have been prepared by simple heating of thiazolidine and β-enaminonitrile derivatives in acetonitrile. The procedure, whose yields depend on the nature and position of the substituents, gave good results if the substituents were not very bulky but it is less effective when starting from 2-substituted thiazolidines.

Full text of DOI:10.1016/j.tet.2008.02.027

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3691e3700
www.elsevier.com/locate/tet
Synthesis of 2,3,4,7-tetrahydro[1,4]thiazepines from thiazolidines
and b-enaminonitriles
*
Luis A. Calvo, Alfonso Gonzalez-Ortega , Rocıo Marcos, Monica Perez, M. Carmen Sanudo
´
´
´
´
~
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
Received 1 January 2008; received in revised form 7 February 2008; accepted 7 February 2008
Available online 12 February 2008
Abstract
A wide library of 2,3,4,7-tetrahydro[1,4]thiazepines have been prepared by simple heating of thiazolidine and b-enaminonitrile derivatives in
acetonitrile. The procedure, whose yields depend on the nature and position of the substituents, gave good results if the substituents were not
very bulky but it is less effective when starting from 2-substituted thiazolidines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: b-Enaminonitrile; Tetrahydro[1,4]thiazepine; Thiazolidine
1. Introduction
posed, the rearrangement of the N-vinylthiazolidine cycle
with ring enlargement to give 2,3,4,7-tetrahydro[1,4]thiaze-
pines is probably the most feasible pathway (Scheme 2).3
In view of the singularity of the 2,3,4,7-tetrahydro[1,4]thi-
azepine cycle, in this paper we have carried out a systematic
study of the former reaction with the aim of determining the
scope and generality of this synthetic method. For this purpose
several enamines and thiazolidines bearing different alkyl or
aryl substituents have been tested (Scheme 3) and we have
attempted to determine the scope and limitations derived
from their nature and position. The results are accompanied
by a brief study regarding the optimisation of the reaction
conditions carried out with simple commercial substrates.
Thiazepinones, benzothiazepines and other thiazepine de-
rivatives are moieties whose biological activity has received
much attention.1 However, 2,3,4,7-tetrahydro[1,4]thiazepines
are relatively unknown heterocycles and may be due to the
absence of adequate methods of synthesis no pharmacological
tests have been published. Typically, they have been prepared
from unsaturated a,b-carbonyls, leading to imines or en-
amines, which upon reduction gave hexahydro[1,4]thiaze-
pines2 (Scheme 1).
In a recent exploratory work, we have confirmed that they
can be prepared with a higher degree of functionalisation by
reaction of b-aminocrotonitrile with proline derivatives.
Among the different mechanistic interpretations that we pro-
R1
R2
S
R2
R3
H
N
R1
NC
R3
-NH3
N
R4
+
R2
R2
NC
O
S
S
N
NH2
S
R4
SH
+
R2
R1
NH2
N
H
R1
R1
H
R1
R1
R1
R2
Scheme 1.
NC
R4
NH
NC
NC
R4
NH
R3
R2
R3
N
R2
R4
S
HS
S
R3
* Corresponding author.
E-mail address: algon@qo.uva.es (A. Gonzalez-Ortega).
Scheme 2.
´
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.027

3692
L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
Table 1
Preparation of thiazepines 4ahego from 1 and 2a
.
.
HCl
R2
R3
HCl
H
H
N
R1
N
S
R4
NC
R1
NH2
S
NC
R4
H
N
R1
R2
R3
NH
R3
1a-g
2h-o
2p
CH3CN
Δ
+
R2
R4
NC
NH2
1 = H
S
R2 = R3 = R4 = H
S
2h-o
a
R
R
R
h
i
1a-g
1 = Me
2 = Et, R3 = R4 = H
4ah-4go
b
c
d
e
f
R
1 = Et
j
R
2 = i-Pr, R3 = R4 = H
R1
R2
R3
R1 = CH2CH2Ph
k
l
R
R
2 = Ph, R3 = R4 = H
2 = R4 = H,R3 = Me
Entry
Starting
R4
Thiazepine (%)
R1 = i-Pr
1
1aþ2h
1bþ2h
1bþ2i
1bþ2j
1bþ2k
1bþ2l
1bþ2m
1bþ2n
1bþ2o
1cþ2h
1cþ2i
1cþ2j
1cþ2k
1cþ2l
1dþ2h
1dþ2i
1dþ2j
1dþ2k
1dþ2l
1eþ2h
1eþ2i
1eþ2j
1eþ2k
1eþ2l
1fþ2h
1fþ2i
H
H
H
Et
H
H
H
H
H
H
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
Me
4ah (25)
4bh (75)
4bi (69)
4bj (67)
4bk (60)
4bl (62)
4bm (47)
4bn (47)
4bo (20)
4ch (74)
4ci (64)
4cj (41)
4ck (51)
4cl (60)
4dh (61)
4di (61)
4dj (41)
4dk (51)
4dl (50)
4eh (62)b
4ei (41)
4ej (<5)
dc
m R2 = R4 = H, R3 = Ph
n
R
1 = t-Bu
2
Me
Me
Me
Me
Me
Me
Me
Me
Et
R2 = R3 = H, R4 = Me
R2 = R3 = H, R4 = Ph
g
R1 = Ph
3
o
4
i-Pr
Ph
H
H
5
H
Scheme 3.
6
Me
Ph
H
7
H
2. Results and discussion
2.1. Optimization of the reaction conditions
8
H
9
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
a
H
H
Et
Et
i-Pr
Ph
H
H
Et
H
Optimization of the reaction conditions has been carried out
using b-aminocrotonitrile 1b and thiazolidine 2h. At room
temperature, nitrogen exchange resulting from conjugate addi-
tioneelimination was observed leading to 3-(thiazolidine-3-
yl)but-2-enenitrile 3bh as the only product. Heating of the
reaction was necessary to accomplish the formation of 2,3,
4,7-tetrahydro[1,4]thiazepine 4bh (Scheme 4). Among all
the solvents tested (methanol, ethanol, acetonitrile and tolu-
ene) acetonitrile gave the best yields.
Et
H
Et
Me
H
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
i-Pr
H
Et
i-Pr
Ph
H
H
H
H
Me
H
H
i-Pr
i-Pr
Et
i-Pr
Ph
H
H
H
i-Pr
i-Pr
t-Bu
t-Bu
H
Me
H
4el (49)
4fh (61)b
dc
dc
dc
4fl (40)
4fm (<5)
4fn (<5)
4gh (31)
4gi (29)
dc
.
HCl
H
N
Me
NH2
H
+
NC
Et
i-Pr
Ph
H
H
CH3CN
20 ºC
S
1fþ2j
t-Bu
t-Bu
t-Bu
t-Bu
H
1b
2h
1fþ2k
1fþ2l
H
Me
Ph
H
Δ
CH3CN
Me
1fþ2m
1fþ2n
1gþ2h
1gþ2i
1gþ2j
1gþ2k
1gþ2l
1gþ2m
1gþ2n
H
t-Bu
Ph
H
Me
H+
H
H
NC
NC
NH
N
Ph
Ph
Et
i-Pr
Ph
H
H
CH3CN, Δ
S
S
4bh
H
Ph
Ph
H
4gk (41)
4gl (48)
4gm (43)
4gn (17)
3bh
Me
Ph
H
Scheme 4.
Ph
Ph
H
H
It should be pointed out that the slightly acidic conditions
provided by the thiazolidine hydrochloride were necessary
(rate of enaminonitrile/thiazolidine 1:1.2) for the reaction to
proceed. All attempts to carry out the reaction with the free
amine were unsuccessful.
Standard procedure: refluxing acetonitrile, 2 h; ratio of enaminonitrile/
thiazolidine 1:1.2.
b
Refluxing acetonitrile 6 h.
The presence of thiazepine in the reaction mixture was not observed.
c
According to previous tests, refluxing acetonitrile was used
in general as standard solvent. However, in those cases in
which low yields were obtained, other conditions were also
tested. Among these, multicomponent reactions (3-CR) from
b-enaminonitrile, aldehyde and cysteamine derivatives were
also examined.
t-Bu) (entry 2, 10, 15, 20, and 25) led in all cases to the
expected 2,3,4,7-tetrahydro[1,4]thiazepines. The reactivity
diminishes considerably as the size of R1 increases although
longer reaction times balance partially the final outcome.
The lowest yields were obtained using 1g (entry 32) and 1a
(entry 1). In the first case phenyl conjugation reduces notably
the reactivity of 1g; on the contrary, 1a reacts too fast giving
complex mixtures. Compound 1a was scarcely used (only in
the synthesis of 4ah) due to its difficult preparation and
manipulation,4 which lowers appreciably the yield.
2.2. Scope and limitations
2.2.1. Effect of the R1, R2 and R3 substituents
As observed in Table 1, the reaction of thiazolidine 2h with
b-alkylenaminonitriles 1bef (R1¼Me, Et, CH2CH2Ph, i-Pr,
A more general behaviour was observed when different C-4
substituted thiazolidines (2iek) react with b-aminocrotonitrile

L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
3693
1b (Table 1, entry 2e5). The variation of yields can be
explained in terms of the steric effect.
The equilibrium between thiazolidines 2, their tautomers 9
and their precursors 10 and 115 might explain the formation
of compounds 6e8 (Scheme 6). In the same way we could for-
mulate an equilibrium of the thiazolidine derivative 3 with 12,
10 and 5, and probably the influence of R4 in the former equi-
libria causes the process to evolve towards 4 (when R4¼H) or
6e8 (when R4sH). Formation of 5 not only takes place from
12 by losing an imine molecule 10, but also by reaction of ciste-
amine hydrochloride 11 with b-aminocrotonitrile 1b.
When the size of R1 and R2 was simultaneously increased,
the decrease in the reactivity and yield could not always be
compensated by increasing the reaction times or the tempera-
ture, because in many cases much degradation of the reagents
was produced. For example, yields were less than 50% when
R1¼i-Pr and R2sH (entry 21e23), and null when R1¼t-Bu
and R2sH (entry 26e28). These observations were consistent
with the mechanism depicted in Scheme 2, where the first step
leading to nitrogen exchange should be highly affected by the
steric hindrance of R1 and R2.
H
N
.
Cl
HCl
H
N
HCl
.
NH
NH3
H2N
HS
R4
R4
9
R4
10
+
For the same reason, the size of R3, which is placed far
away from the nitrogen atom, has little influence on the reac-
tivity. Thus, when R1¼t-Bu and R2¼Et (entry 26) nitrogen
exchange did not take place and formation of 4fi was not
observed, whereas 4fl (R1¼t-Bu and R3¼Me, entry 29) was
obtained in moderate yield (40%).
S
HS
H
2
11
1b
-(NH4Cl)
NC
Me
R4
NC
6-8
NH
S
R4
10
+
N
H
5
Me
H
HS
N
H
4
2.2.2. Influence of the R4 substituent
1b +
2
NH3
The anomalous behaviour of 2n (R4¼Me) and 2o (R4¼Ph)
with respect to the previous thiazolidines deserves some discus-
sion on the influence of the substituents attached to C-2. Thus,
the reaction of 2-methylthiazolidine hydrochloride 2n with
b-aminocrotonitrile 1b at room temperature led to a complex
mixture of products in which 3bn (6%), 5 (15%), 6bn
(<5%), 7bn (11%) and 8bn (9%) (Scheme 5) could be identi-
fied. However, when the reaction of 1b and 2n was performed
in refluxing acetonitrile, the intermediates 3 and 5 disappeared,
the thiazepine 4bn (25%) was isolated in low yield and the
proportion of 6bne8bn increased. As expected, 2-phenylthia-
zolidine hydrochloride 2o is less reactive than its regioisomers
2k (R2¼Ph) and 2m (R3¼Ph), and was proven to be inert at
room temperature. By performing the reaction of 1b and 2o
in refluxing acetonitrile, degradation of the b-aminocrotonitrile
1b occurred in high extent, while formation of thiazepine 4bo
(20%) and dihydropyridine 6bo (37%) was observed.
NC
Me
NC
Me
CN
Cl
N
N
Me
N
H
HS
S
S
3
R4
NH4Cl
12
R4
Cl
R4
Scheme 6.
Further Hantzsch type reaction would afford 6boebn or
7boebn from 1b, 5 and 10boebn (Scheme 7). Similar expla-
nations have been reported by other authors regarding the trans-
formation of analogues to 5 into thiazolopyridines.6 Moreover,
we have observed that compounds 7boebn can be prepared by
heating a mixture of 5,7 acetaldehyde (or benzaldehyde) and
cisteamine hydrochloride 11 without formation, in this particu-
lar case, of compounds 6boebn.
10n R4= M e
NC
Me
.
HCl
H
N
10o R4= Ph
NC
Me
R4
R4
CH3CN
R4
+
+
H
N
NC
Me
CN
Me
S
NH2
R4
NH
R4
S
CN
NC
Me
HCl
2n
2o
3bn
1b
3bo
- (NH3)
NH2 NH
HS
HN
Me
5
NH2
1b
HS
NC
Me
NC
Me
NC
Me
S
- (NH3)
+
NH
NH
+
R4
N
S
R4
N
H
HS
NH2
-
HS
CN
Me
NC
CN
Me
NC
Me
5
4bn
4bo
Me
S
6bo
6bn
N
H
7bo
7bn
R4
R4
Me
CN
Me
NC
Me
CN
Me
NC
Me
CN
Me
Scheme 7.
+
+
N
S
N
H
N
S
6bn R4= Me
7bn R4= Me
7bo R4= Ph
8bn
Formation of 8shouldproceedbyselfcondensationoftheetha-
nimine 10n to crotonimine 13 (Scheme 8), followed by conjugate
additionoftheenamine5andfinalcyclizationtoN/S-aminal. This
6bo R4= Ph
Scheme 5.

3694
L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
Me
CN
Me
13
HN
H
HN
10n
HN
Me
HS
5
Me
HN
Me
N
CN
Me
CN
HN
HS
Me
8bn
S
Scheme 8.
pathway has been proved by means of a multicomponent reaction
from crotonaldehyde, b-aminocrotonitrile and cysteamine hydro-
chloride, leading to 8bn (41%) with moderate yield.
Figure 1. X-ray of 7bn.
The synthesis of thiazepines from b-enaminonitriles and
2-substituted thiazolidines (R4sH) is not useful for synthetic
purposes, although such experiments were useful to get infor-
mation about possible multicomponent reactions involving 7
and 8. The former has been studied, along with the synthesis
of thiazepines 4, in different extension. Thus, the synthesis of
thiazepines 4 from b-enaminonitriles, cysteamine hydrochlo-
ride and aldehydes gave worse results than the reaction between
enaminonitriles and thiazolidine derivatives. The only yield
that was improved corresponds to the preparation of benzothi-
azepines 4bp, 4ep and 4gp from b-enaminonitriles, o-amino-
thiophenol and formaldehyde (Scheme 9). While work in
progress shows that thiazolopyridines 8 can be obtained from
1,2-aminothiols, a,b-unsaturated aldehydes and b-enaminoni-
triles, their synthesis should be fully detailed in a future paper.
Figure 2. X-ray of 7bo.
downfield from SiMe4 as an internal standard; 13C NMR spectra
were carried out with complete 1H decoupling and the assign-
ments were made by additional DEPT experiments. Mass
spectra were taken at an ionizing voltage of 70 eV on a
HewlettePackard GC (5980)eMS (5988A) spectrometer.
The starting b-enaminonitriles were purchased from the
usual suppliers (1b) or prepared by literature procedures (1a,4
1cef,10 and 1g11).
HCl
S
NC
R1
H2N
O
CN
+
NH2
+
HS
H
H
N
H
R1
2p
1b R1= Me
1e R1= i-Pr
1f R1= t-Bu
1g R1= Ph
4bp 46%
4ep 41%
4fp
0%
4gp 40%
Scheme 9.
3.2. Preparation of thiazolidine hydrochlorides 2heo:
general procedure
Finally, in order to establish that intermediate 5 might be
a precursor of thiazolopyridines 7, two experiments from cys-
teamine hydrochloride 11, 57 and acetaldehyde or benzalde-
hyde were performed, giving a mixture of diastereomers of 7
from which the major isomer could be isolated and its stereo-
chemistry confirmed by X-ray analysis (Figs. 1 and 2).8,9
A mixture of aldehyde (44 mmol) and the corresponding
2-aminothiol hydrochloride12 (44 mmol) in 15 cm3 of dry eth-
anol was stirred at room temperature for 24 h. The solvent was
removed and the concentrate was washed with dry THF. The
solid residue thus obtained (2heo) gave the sufficient purity
(93e97%) for it to be used in subsequent stages.
3. Experimental
3.1. General
3.3. Reaction of b-enaminonitriles 1 with thiazolidine
hydrochlorides 2. Preparation of 4 and 6e8: general
procedure
Melting points were measured on a Reichert-Jung Thermo
Galen and are uncorrected. IR spectra were obtained on a
PerkineElmer 1720 X spectrometer. NMR spectrawere recorded
on a Bruker AC300 spectrometer, and chemical shifts are given
A solution of b-enaminonitriles 1 (7.8 mmol) and thiazol-
idine hydrochlorides 2 (9.4 mmol) in 5 cm3 of dry acetonitrile

L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
3695
was refluxed for the time specified in Table 1. At the end of the
reaction the solvent was removed and the residue was poured in
50 cm3 of water and extracted with dichloromethane (3ꢀ
50 cm3). The organic layer was dried over Na2SO4 and removed
in vacuo. The product was chromatographed on silica gel
(0.040e0.063 mm) using hexane/ethyl acetate (3:1) (4biegi,
4bkeck, 4clegl and 4fnegn), hexane/ethyl acetate (5:2)
(4dkegk and 4bl), dichloromethane/diethyl ether (20:1)
(4ahebh, 4bm and 6boebn), or dichloromethane (4chegh,
4bjedj, 4bn, 4bo, 4fm, 4gm, 7boebn and 8bn) as eluent.
163.0 (C). GCeMS (EI) m/z: 246 (5) [Mþþ2], 183 (100).
Anal. Calcd for C14H16N2S: C, 68.81; H, 6.60; N, 11.46.
Found: C, 68.90; H, 6.51; N, 11.34.
3.3.5. 5-(iso-Propyl)-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4eh)
Yellow solid. Mp 104e105 ꢂC. IR (KBr): 3367, 2969,
2923, 2176, 1584, 1522, 1122, 744 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d 1.15 (d, J¼7.0 Hz, 6H, CH(CH3)2),
2.91 (m, 2H, SeCH2), 3.05 (m, 1H, CH), 3.50 (s, 2H,
SeCH2eC]), 3.72 (m, 2H, NeCH2), 4.35 (br, 1H, NH).
13C NMR (75.4 MHz, CDCl3): d 20.3 (2CH3), 28.9 (CH2),
31.8 (CH2), 33.9 (CH), 45.9 (CH2), 77.7 (C), 122.7 (C),
168.5 (C). GCeMS (EI) m/z: 184 (5) [Mþþ2], 139 (100).
Anal. Calcd for C9H14N2S: C, 59.30; H, 7.74; N, 15.37.
Found: C, 59.12; H, 7.85; N, 15.25.
3.3.1. 2,3,4,7-Tetrahydro[1,4]thiazepine-6-carbonitrile
(4ah)
Yellow oil. Rf 0.35 (dichloromethane/diethyl ether (20:1)).
IR (film): 3362, 2921, 2169, 1619, 1587, 1526, 1364,
1
1004 cmꢁ1. H NMR (300 MHz, CDCl3): d 2.88e2.92 (m,
2H, SeCH2), 3.43 (s, 2H, ]CeCH2), 3.65e3.70 (m, 2H,
NeCH2), 4.97 (br, 1H, NH), 6.78 (d, J¼7.7 Hz, 1H, ]CH).
13C NMR (75.4 MHz, CDCl3): d 29.3 (CH2), 32.7 (CH2),
47.4 (CH2), 80.9 (C), 123.1 (C), 149.5 (CH). Anal. Calcd
for C6H8N2S: C, 51.40; H, 5.75; N, 19.98. Found: C, 51.55;
H, 5.69; N, 20.05.
3.3.6. 5-(tert-Butyl)-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4fh)
Yellow solid. Mp 122e123 ꢂC. IR (KBr): 3389, 2959,
2906, 2163, 1560, 1509, 1482, 1218, 979 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 1.32 (s, 9H, C(CH3)3), 2.91 (m, 2H,
SeCH2), 3.55 (s, 2H, SeCH2eC]), 3.65 (m, 2H, Ne
CH2), 4.51 (br, 1H, NH). 13C NMR (75.4 MHz, CDCl3):
d 28.5 (3CH3), 31.2 (CH2), 31.9 (CH2), 37.6 (C), 47.2
(CH2), 76.9 (C), 123.7 (C), 171.2 (C). GCeMS (EI) m/z:
198 (5) [Mþþ2], 139 (100). Anal. Calcd for C10H16N2S:
C, 61.18; H, 8.21; N, 14.27. Found: C, 61.05; H, 8.15; N,
14.35.
3.3.2. 5-Methyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-carbo-
nitrile (4bh)
Colourless solid. Mp 68e69 ꢂC. IR (KBr): 3332, 2178,
1609, 1543, 1335, 1100, 746 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 1.92 (s, 3H, CH3), 2.85 (dd, J¼5.6 Hz, 2H,
SeCH2), 3.37 (s, 2H, SeCH2eC]), 3.60 (q, J¼5.6 Hz, 2H,
NeCH2), 5.03 (br, 1H, NH). 13C NMR (75.4 MHz, CDCl3):
d 21.7 (CH3), 27.4 (CH2), 31.2 (CH2), 44.4 (CH2), 76.6 (C),
123.3 (C), 159.8 (C). Anal. Calcd for C7H10N2S: C, 54.51;
H, 6.54; N, 18.16. Found: C, 54.35; H, 6.69; N, 18.05.
3.3.7. 5-Phenyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-carbo-
nitrile (4gh)
Yellow solid. Mp 105e106 ꢂC. IR (KBr): 3316, 2964,
2178, 1589, 1523, 1465, 1335, 699 cmꢁ1
.
1H NMR
3.3.3. 5-Ethyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-carbo-
nitrile (4ch)
(300 MHz, CDCl3): d 3.05 (m, 2H, SeCH2), 3.71 (s, 2H,
SeCH2eC]), 3.85 (m, 2H, NeCH2), 4.54 (br, 1H, NH),
7.51 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz, CDCl3): d 30.4
(CH2), 32.1 (CH2), 47.3 (CH2), 81.1 (C), 122.8 (C), 128.8
(3CH), 130.8 (2CH), 136.8 (C), 161.9 (C). GCeMS (EI)
m/z: 218 (5) [Mþþ2], 216 (100). Anal. Calcd for C12H12N2S:
C, 66.63; H, 5.59; N, 12.95. Found: C, 66.78; H, 5.42; N,
12.81.
Yellow solid. Mp 79e80 ꢂC. IR (KBr): 3334, 2970, 2933,
2172, 1598, 1527, 1466, 1109, 746 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d 1.16 (t, J¼7.6 Hz, 3H, CH3), 2.31 (q,
J¼7.6 Hz, 2H, CH2CH3), 2.93 (m, 2H, SeCH2), 3.46 (s, 2H,
SeCH2eC]), 3.67 (m, 2H, NeCH2), 3.70 (br, 1H, NH).
13C NMR (75.4 MHz, CDCl3): d 12.8 (CH3), 28.3 (CH2),
29.8 (CH2), 31.8 (CH2), 45.6 (CH2), 77.5 (C), 122.9 (C),
165.4 (C). GCeMS (EI) m/z: 170 (5) [Mþþ2], 139 (100).
Anal. Calcd for C8H12N2S: C, 57.11; H, 7.19; N, 16.65.
Found: C, 57.02; H, 7.24; N, 16.56.
3.3.8. 3-Ethyl-5-methyl-2,3,4,7-tetrahydro[1,4]thiazepine-
6-carbonitrile (4bi)
Colourless solid. Mp 120e121 ꢂC. IR (KBr): 3331,
1
2963, 2924, 2177, 1603, 1527, 1328, 1060, 1030 cmꢁ1. H
3.3.4. 5-Phenethyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4dh)
NMR (300 MHz, CDCl3):
d
1.01 (t, J¼7.5 Hz, 3H,
CH2CH3), 1.61 (m, 2H, CH2CH3), 2.09 (s, 3H, CH3), 2.69
(dd, J¼12.9, 10.9 Hz, 1H, SeCHH), 2.91 (d, J¼16.2 Hz,
1H, SeCHHeC]), 3.03 (dd, J¼12.9, 2.9 Hz, 1H, SeCHH),
3.82 (m, 1H, NeCHeEt), 3.86 (m, 2H, NH), 4.04 (d, J¼
16.2 Hz, 1H, SeCHHeC]). 13C NMR (75.4 MHz, CDCl3):
d 10.7 (CH3), 22.8 (CH3), 28.4 (CH2), 29.0 (CH2), 36.2
(CH2), 57.9 (CH), 78.5 (C), 122.9 (C), 158.5 (C). Anal. Calcd
for C9H14N2S: C, 59.30; H, 7.74; N, 15.37. Found: C, 59.18;
H, 7.62; N, 15.52.
Colourless solid. Mp 105e106 ꢂC. IR (KBr): 3333, 2925,
2175, 1600, 1537, 1459, 701 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 2.62 (t, J¼6.5 Hz, 2H, CH2eCH2Ph), 2.90 (m, 2H,
SeCH2), 2.95 (m, 2H, CH2ePh), 3.54 (s, 2H, SeCH2eC]),
3.55 (m, 2H, NeCH2), 4.15 (br, 1H, NH), 7.40 (m, 5H,
5ꢀHPh). 13C NMR (75.4 MHz, CDCl3): d 28.3 (CH2), 31.6
(CH2), 34.6 (CH2), 38.7 (CH2), 45.6 (CH2), 79.0 (C), 122.6
(C), 126.5 (CH), 128.4 (2CH), 128.6 (2CH), 139.9 (C),

3696
L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
3.3.9. 3,5-Diethyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-carbo-
nitrile (4ci)
Yellow oil. Rf 0.35 (hexane/ethyl acetate (3:1)). IR (film):
3319, 2969, 2928, 2181, 1596, 1532, 1460, 1378, 1339,
1242, 1078 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.96 (t,
.
J¼7.5 Hz, 3H, CH3), 1.14 (t, J¼7.6 Hz, 3H, ]CeCH2CH3),
1.55 (m, 2H, CH2CH3), 2.30 (q, J¼7.6 Hz, 2H, ]Ce
CH2CH3), 2.63 (dd, J¼12.9, 10.9 Hz, 1H, SeCHH), 2.84 (d,
J¼16.2 Hz, 1H, SeCHHeC]), 2.95 (dd, J¼12.9, 2.8 Hz,
1H, SeCHH), 3.78 (m, 1H, J¼10.9, 2.8 Hz, NeCH), 3.97
(d, J¼16.2 Hz, 1H, SeCHHeC]), 4.15 (br, 1H, NH). 13C
NMR (75.4 MHz, CDCl3): d 10.6 (CH3), 12.8 (CH3), 28.3
(CH2), 28.7 (CH2), 29.7 (CH2), 36.0 (CH2), 53.4 (C), 57.7
(CH), 122.7 (C), 164.4 (C). GCeMS (EI) m/z: 198 (5)
[Mþþ2], 121 (100). Anal. Calcd for C10H16N2S: C, 61.18;
H, 8.21; N, 14.27. Found: C, 61.31; H, 8.17; N, 14.19.
1H, SeCHHeC]), 3.88 (m, 1H, NeCH), 4.05 (br, 1H,
NH), 4.07 (d, J¼16.2 Hz, 1H, SeCHHeC]), 7.44 (m, 3H,
3ꢀHPh), 7.52 (m, 2H, 2ꢀHPh). 13C NMR (75.4 MHz,
CDCl3): d 10.9 (CH3), 29.3 (CH2), 30.1 (CH2), 36.3 (CH2),
59.1 (CH), 79.6 (C), 122.9 (C), 128.7 (2CH), 128.9 (2CH),
130.7 (CH), 137.1 (C), 160.9 (C). GCeMS (EI) m/z: 246 (5)
[Mþþ2], 169 (100). Anal. Calcd for C14H16N2S: C, 68.81;
H, 6.60; N, 11.46. Found: C, 68.94; H, 6.45; N, 11.34.
3.3.13. 5-Methyl-3-(iso-propyl)-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4bj)
Yellow solid. Mp 124e125 ꢂC. IR (KBr): 3331, 2961,
2187, 1602, 1430, 1321, 1027, 806 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d 1.01 (d, J¼5.9 Hz, 3H, CH(CH3)CH3),
1.03 (d, J¼5.9 Hz, 3H, CH(CH3)CH3), 1.71 (m, 1H,
CH(CH3)2), 2.06 (s, 3H, ]CeCH3), 2.66 (dd, J¼12.8,
11.1 Hz, 1H, SeCHH), 2.88 (d, J¼16.3 Hz, 1H, SeCHHe
C]), 3.11 (dd, J¼12.8, 2.8 Hz, 1H, SeCHH), 3.86 (m, 2H,
NH, NeCH), 4.04 (d, J¼16.3 Hz, 1H, SeCHHeC]). 13C
NMR (75.4 MHz, CDCl3): d 13.0 (CH3), 18.1 (CH3), 18.3
(CH3), 28.7 (CH2), 30.1 (CH2), 33.3 (CH), 62.0 (CH), 77.2
(C), 122.3 (C), 164.5 (C). Anal. Calcd for C10H16N2S: C,
61.18; H, 8.21; N, 14.27. Found: C, 61.04; H, 8.29; N, 14.41.
3.3.10. 3-Ethyl-5-phenethyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4di)
Yellow solid. Mp 78e79 ꢂC. IR (KBr): 3314, 2967, 2929,
2174, 1594, 1531, 1455, 1068, 752, 701 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 0.85 (t, J¼7.4 Hz, 3H, CH3), 1.30 (m,
2H, CH2CH3), 2.48e2.69 (m, 3H, SeCHH, CH2CH2Ph),
2.85e3.15 (m, 4H, SeCHHeC], SeCHH, CH2Ph), 3.67
(m, 1H, NeCH), 3.85 (br, 1H, NH), 4.01 (d, J¼16.3 Hz, 1H,
SeCHHeC]), 7.24 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz,
CDCl3): d 10.5 (CH3), 28.4 (CH3), 28.9 (CH2), 34.7 (CH2),
35.8 (CH2), 38.7 (CH2), 57.7 (CH), 122.8 (C), 128.7 (CH),
126.5 (CH), 128.4 (2CH), 128.6 (2CH), 140.0 (C), 162.3 (C).
GCeMS (EI) m/z: 274 (5) [Mþþ2], 91 (100). Anal. Calcd for
C16H20N2S: C, 70.55; H, 7.40; N, 10.28. Found: C, 70.68; H,
7.29; N, 10.21.
3.3.14. 5-Ethyl-3-(iso-propyl)-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4cj)
Yellow solid. Mp 78e79 ꢂC. IR (KBr): 3319, 2963, 2928,
2187, 1623, 1594, 1461, 1412, 1080, 1038, 800 cmꢁ1 1H
.
NMR (300 MHz, CDCl3):
d
0.99 (d, J¼5.9 Hz, 3H,
CH(CH3)CH3), 1.01 (d, J¼5.9 Hz, 3H, CH(CH3)CH3), 1.18
(t, J¼7.6 Hz, 3H, CH2CH3), 1.83 (m, 1H, CH(CH3)2), 2.35
(q, J¼7.6 Hz, 2H, CH2CH3), 2.72 (dd, J¼12.8, 11.1 Hz, 1H,
SeCHH), 2.90 (d, J¼16.3 Hz, 1H, SeCHHeC]), 2.96 (dd,
J¼12.8, 2.8 Hz, 1H, SeCHH), 3.71 (m, 1H, NeCH), 3.91
(br, 1H, NH), 4.01 (d, J¼16.3 Hz, 1H, SeCHHeC]). 13C
NMR (75.4 MHz, CDCl3): d 13.0 (CH3), 18.5 (CH3), 18.8
(CH3), 28.4 (CH2), 30.0 (CH2), 33.3 (CH), 33.6 (CH2), 61.7
(CH), 76.9 (C), 122.7 (C), 164.3 (C). GCeMS (EI) m/z: 212
(5) [Mþþ2], 121 (100). Anal. Calcd for C10H16N2S: C,
61.18; H, 8.21; N, 14.27. Found: C, 61.35; H, 8.32; N, 14.04.
3.3.11. 3-Ethyl-5-(iso-propyl)-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4ei)
Yellow solid. Mp 77e78 ꢂC. IR (KBr): 3362, 3321, 2964,
2928, 2182, 2163, 1592, 1538, 1518, 1094, 801 cmꢁ1 1H
.
NMR (300 MHz, CDCl3): d 1.02 (t, J¼7.5 Hz, 3H, CH3),
1.12 (d, J¼6.8 Hz, 3H, CH(CH3)CH3), 1.14 (d, J¼6.8 Hz,
3H, CH(CH3)CH3), 1.61 (m, 2H, CH2CH3), 2.64 (dd,
J¼12.9, 10.8 Hz, 1H, S]CHH), 2.96 (d, J¼16.2 Hz, 1H,
SeCHHeC]), 2.97 (dd, J¼12.9, 2.9 Hz, 1H, SeCHH),
3.12 (m, 1H, CHCH3), 3.72 (m, 1H, NeCH), 3.83 (br, 1H,
NH), 3.96 (d, J¼16.2 Hz, 1H, SeCHHeC]). 13C NMR
(75.4 MHz, CDCl3): d 10.6 (CH3), 20.3 (CH3), 21.0 (CH3),
29.1 (CH2), 29.3 (CH2), 33.9 (CH), 36.3 (CH2), 58.2 (CH),
77.6 (C), 122.4 (C), 167.2 (C). Anal. Calcd for C11H18N2S:
C, 62.81; H, 8.63; N, 13.32. Found: C, 62.68; H, 8.54; N,
13.45.
3.3.15. 5-Phenethyl-3-(iso-propyl)-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4dj)
Colourless solid. Mp 97e98 ꢂC. IR (KBr): 3324, 2961,
2923, 2171, 1597, 1522, 1456, 1372, 1072, 736, 689 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 0.83 (d, J¼7.0 Hz, 3H,
CH(CH3)CH3), 0.87 (d, J¼7.0 Hz, 3H, CH(CH3)CH3), 1.62
(m, 1H, CH(CH3)2), 2.62e2.68 (m, 3H, SeCHH, CH2CH2Ph),
2.86e2.95 (m, 4H, SeCHHeC], SeCHH, CH2Ph), 3.61 (m,
2H, NeCH, NH), 4.03 (d, J¼16.2 Hz, 1H, SeCHHeC]),
7.27 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz, CDCl3): d 18.1
(CH3), 18.6 (CH3), 28.4 (CH2), 33.0 (CH), 33.1 (CH2), 34.8
(CH2), 38.7 (CH2), 61.4 (CH), 77.1 (C), 123.0 (C), 126.5
(CH), 128.5 (2CH), 128.6 (2CH), 140.0 (C), 162.5 (C).
GCeMS (EI) m/z: 288 (5) [Mþþ2], 91 (100). Anal. Calcd
for C17H22N2S: C, 71.28; H, 7.74; N, 9.78. Found: C, 71.12;
H, 7.59; N, 9.89.
3.3.12. 3-Ethyl-5-phenyl-2,3,4,7-tetrahydro[1,4]thiazepine-
6-carbonitrile (4gi)
Yellow solid. Mp 114e115 ꢂC. IR (KBr): 3307, 2962,
2878, 2180, 1589, 1532, 1076, 768, 696 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 1.10 (t, J¼7.3 Hz, 3H, CH3), 1.67 (m,
2H, CH2CH3), 2.70 (dd, J¼13.1, 10.75 Hz, 1H, SeCHH),
3.05 (dd, J¼10.7, 2.7 Hz, 1H, SeCHH), 3.15 (d, J¼16.2 Hz,

L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
3697
3.3.16. 5-Methyl-3-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4bk)
128.8 (2CH), 128.9 (3CH), 129.5 (2CH), 130.9 (CH), 136.8
(C), 141.6 (C), 161.1 (C). GCeMS (EI) m/z: 294 (5)
[Mþþ2], 246 (100). Anal. Calcd for C18H16N2S: C, 73.94;
H, 5.52; N, 9.58. Found: C, 73.82; H, 5.59; N, 9.67.
Colourless solid. Mp 132e133 ꢂC. IR (KBr): 3312, 2917,
2176, 1599, 1518, 1398, 1316, 727, 701 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 2.11 (s, 3H, CH3), 3.06 (m, 2H,
SeCH2), 3.08 (d, J¼16.0 Hz, 1H, SeCHHeC]), 4.02 (d,
J¼16.0 Hz, 1H, SeCHHeC]), 4.06 (br, 1H, NH), 4.80 (m,
1H, NeCH), 7.33e7.42 (m, 5H, 5ꢀHPh). 13C NMR
(75.4 MHz, CDCl3): d 23.4 (CH3), 29.4 (CH2), 38.3 (CH2),
62.5 (CH), 81.3 (C), 122.4 (C), 126.3 (2CH), 128.9 (CH),
129.4 (2CH), 141.3 (C), 158.5 (C). GCeMS (EI) m/z: 232
(5) [Mþþ2], 184 (100). Anal. Calcd for C13H14N2S: C,
67.79; H, 6.13; N, 12.16. Found: C, 67.65; H, 6.19; N, 12.29.
3.3.20. 2,5-Dimethyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4bl)
Yellow solid. Mp 92e93 ꢂC. IR (KBr): 3314, 2178, 1605,
1542, 1463, 1378, 1330, 644 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 1.28 (d, J¼6.5 Hz, 3H, CHeCH3), 2.03 (s, 3H,
]CeCH3), 3.32e3.49 (m, 2H, NeCH2), 3.38 (d, J¼16.8 Hz,
1H, SeCHHeC]), 3.55 (d, J¼16.8 Hz, 1H, SeCHHeC]),
3.65 (m, 1H, SeCHeCH3), 4.52 (br, 1H, NH). 13C NMR
(75.4 MHz, CDCl3): d 20.7 (CH3), 22.0 (CH3), 26.6 (CH2),
39.4 (CH), 50.8 (CH2), 76.3 (C), 123.5 (C), 159.5 (C).
GCeMS (EI) m/z: 170 (5) [Mþþ2], 107 (100). Anal. Calcd
for C8H12N2S: C, 57.11; H, 7.19; N, 16.65. Found: C, 57.28;
H, 7.25; N, 16.49.
3.3.17. 5-Ethyl-3-phenyl-2,3,4,7-tetrahydro[1,4]thiazepine-
6-carbonitrile (4ck)
Yellow solid. Mp 73e74 ꢂC. IR (KBr): 3302, 3030, 2969,
2926, 2180, 1600, 1532, 1112, 1085, 1051, 731, 703 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 1.16 (t, J¼7.6 Hz, 3H, CH3),
2.37 (q, J¼7.6 Hz, 2H, CH2CH3), 3.01 (dd, J¼13.5, 10.9 Hz,
1H, SeCHH), 3.09 (d, J¼16.0 Hz, 1H, SeCHHeC]), 3.12
(dd, J¼13.5, 2.9 Hz, 1H, SeCHH), 3.96 (d, J¼16.0 Hz, 1H,
SeCHHeC]), 4.07 (br, 1H, NH), 4.75 (m, 1H, NeCH),
7.35 (m, 3H, 3ꢀHPh), 7.40 (m, 2H, 2ꢀHPh). 13C NMR
(75.4 MHz, CDCl3): d 12.7 (CH3), 29.6 (CH2), 30.3 (CH2),
38.1 (CH2), 62.6 (CH), 80.6 (C), 122.0 (C), 126.3 (2CH),
128.8 (CH), 129.3 (2CH), 141.3 (C), 164.2 (C). GCeMS
(EI) m/z: 246 (5) [Mþþ2], 198 (100). Anal. Calcd for
C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C, 68.92;
H, 6.54; N, 11.35.
3.3.21. 5-Ethyl-2-methyl-2,3,4,7-tetrahydro[1,4]thiazepine-
6-carbonitrile (4cl)
Yellow solid. Mp 131e132 ꢂC. IR (KBr): 3290, 3065,
2969, 2935, 2186, 1630, 1595, 1453, 1215, 1021 cmꢁ1. H
1
NMR (300 MHz, CDCl3):
d
1.17 (t, J¼7.6 Hz, 3H,
CH2CH3), 2.33 (q, J¼7.6 Hz, 2H, CH2CH3), 3.32e3.49 (m,
2H, NeCH2), 3.38 (d, J¼16.7 Hz, 1H, SeCHHeC]), 3.56
(d, J¼16.7 Hz, 1H, SeCHHeC]), 3.67 (m, 1H, SeCH),
4.44 (br, 1H, NH). 13C NMR (75.4 MHz, CDCl3): d 12.8
(CH3), 20.6 (CH3), 26.8 (CH2), 29.6 (CH2), 39.5 (CH), 51.4
(CH2), 76.6 (C), 122.8 (C), 164.7 (C). Anal. Calcd for
C9H14N2S: C, 59.30; H, 7.74; N, 15.37. Found: C, 59.21; H,
7.79; N, 15.46.
3.3.18. 5-Phenethyl-3-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4dk)
Yellow solid. Mp 98e99 ꢂC. IR (KBr): 3297, 3026, 2910,
2182, 1599, 1526, 1495, 1450, 1170, 1073, 1023, 715,
3.3.22. 2-Methyl-5-phenethyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4dl)
694 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 2.68 (m, 2H,
Yellow solid. Mp 151e152 ꢂC. IR (KBr): 3306, 3064,
SeCH2), 2.89e2.98 (m, 4H, CH2CH2Ph), 3.07 (d, J¼16.1 Hz,
1H, SeCHHeC]), 3.90 (br, 1H, NH), 4.0 (d, J¼16.1 Hz, 1H,
SeCHHeC]), 4.62 (m, 1H, NeCH), 7.10 (m, 2H, 2ꢀHPh),
7.20 (m, 5H, 5ꢀHPh), 7.35 (m, 3H, 3ꢀHPh). 13C NMR
(75.4 MHz, CDCl3): d 29.6 (CH2), 34.5 (CH2), 38.3 (CH2),
39.0 (CH2), 62.3 (CH), 81.0 (C), 122.2 (C), 126.1 (2CH),
126.5 (CH), 128.4 (2CH), 128.6 (3CH), 129.3 (2CH), 139.7
(C), 141.6 (C), 161.9 (C). GCeMS (EI) m/z: 322 (5)
[Mþþ2], 183 (100). Anal. Calcd for C20H20N2S: C, 74.96;
H, 6.29; N, 8.74. Found: C, 74.82; H, 6.24; N, 8.86.
2925, 2175, 1601, 1594, 1464, 1172, 697 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d 1.22 (d, J¼6.2 Hz, 3H, CH3), 2.57 (m,
2H, CH2CH2Ph), 2.90 (t, J¼7.5 Hz, 2H, CH2Ph), 3.27 (m,
2H, NeCH2), 3.39 (m, 1H, SeCHHeC]), 3.44 (m, 1H,
SeCH), 3.54 (d, J¼16.7 Hz, 1H, SeCHHeC]), 4.19 (br,
1H, NH), 7.18e7.34 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz,
CDCl3): d 20.5 (CH3), 26.7 (CH2), 34.7 (CH2), 38.5 (CH2),
39.3 (CH), 51.3 (CH2), 77.4 (C), 122.7 (C), 126.5 (CH),
128.5 (2CH), 128.6 (2CH), 140.0 (C), 162.7 (C). GCeMS
(EI) m/z: 260 (5) [Mþþ2], 91 (100). Anal. Calcd for
C15H18N2S: C, 69.73; H, 7.02; N, 10.84. Found: C, 69.63;
H, 6.95; N, 10.95.
3.3.19. 3,5-Diphenyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4gk)
Colourless solid. Mp 187e188 ꢂC. IR (KBr): 3338, 2923,
2181, 1586, 1559, 1514, 1445, 1333, 1272, 1255, 750,
3.3.23. 2-Methyl-5-(iso-propyl)-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4el)
696 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 3.04e3.19 (dd,
Yellow solid. Mp 113e114 ꢂC. Rf 0.29 (CH2Cl2). IR (KBr):
3362, 2168, 1586, 1525, 1460, 1377, 1360, 1147, 1127,
J¼10.1, 2.8 Hz, 2H, SeCH2), 3.37 (d, J¼15.8 Hz, 1H,
SeCHHeC]), 4.04 (d, J¼15.8 Hz, 1H, SeCHHeC]),
4.27 (br, 1H, NH), 4.76 (m, 1H, NeCH), 7.48e7.54 (m,
10H, 2Ph). 13C NMR (75.4 MHz, CDCl3): d 31.6 (CH2),
38.4 (CH2), 64.0 (CH), 83.3 (C), 122.5 (C), 126.3 (2CH),
1004 cmꢁ1
. d 1.12 (d,
1H NMR (300 MHz, CDCl3):
J¼7.0 Hz, 6H, CH(CH3)2), 1.28 (d, J¼6.6 Hz, 3H,
SeCHeCH3), 3.06 (m, 1H, CH(CH3)2), 3.28e3.45 (m, 2H,
NeCH2), 3.37 (d, J¼16.8 Hz, 1H, SeCHH), 3.57 (d,

3698
L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
J¼16.8 Hz, 1H, SeCHH), 3.62e3.70 (m, 1H, SeCHeCH3),
4.44 (br, 1H, NH). 13C NMR (75.4 MHz, CDCl3): d 20.4
(CH3), 20.5 (CH3), 20.5 (CH3), 27.3 (CH2), 33.6 (CH2), 39.6
(CH), 51.6 (CH2), 76.7 (C), 122.6 (C), 167.8 (C). Anal. Calcd
for C10H16N2S: C, 61.18; H, 8.21; N, 14.27. Found: C, 61.35;
H, 8.26; N, 14.15.
(75.4 MHz, CDCl3): d 28.9 (3CH3), 31.7 (CH2), 37.6 (C),
48.8 (CH), 53.0 (CH2), 77.2 (C), 123.4 (C), 127.4 (2CH),
127.9 (CH), 140.5 (C), 170.3 (C). Anal. Calcd for
C16H20N2S: C, 70.55; H, 7.40; N, 10.28. Found: C, 70.42;
H, 7.34; N, 10.37.
3.3.28. 2,5-Diphenyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4gm)
3.3.24. 5-(tert-Butyl)-2-methyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4fl)
Yellow solid. Mp 186e187 ꢂC. Rf 0.31 (CH2Cl2). IR (KBr):
3390, 2167, 1588, 1571, 1513, 1491, 778, 764 cmꢁ1. 1H NMR
(300 MHz, CDCl3): d 3.70 (d, J¼16.7 Hz, 1H, CHHeCeCN),
3.84 (d, J¼16.7 Hz, 1H, CHHeCeCN), 3.82e3.92 (m, 1H,
NeCHH), 4.02e4.12 (m, 1H, NeCHH), 4.41 (q, J¼3.7 Hz,
1H, SeCHePh), 4.65 (t, J¼5.7 Hz, 1H, NH), 7.27e7.56 (m,
10H, 2Ph). 13C NMR (75.4 MHz, CDCl3): d 29.6 (CH2),
49.2 (CH), 52.4 (CH2), 79.0 (C), 122.9 (C), 127.4
(2CH), 127.9 (CH), 128.7 (4CH), 128.8 (2CH), 130.8
(CH), 136.5 (C), 140.5 (C), 161.3 (C). Anal. Calcd for
C18H16N2S: C, 73.94; H, 5.52; N, 9.58. Found: C, 73.80; H,
5.48; N, 9.67.
Colourless solid. Mp 116e117 ꢂC. IR (KBr): 3400, 2955,
2916, 2163, 1556, 1515, 1484, 1465, 1363, 1220, 1028,
978 cmꢁ1
. d 1.27 (d,
1H NMR (300 MHz, CDCl3):
J¼6.7 Hz, 3H, CH3), 1.35 (s, 9H, C(CH3)3), 3.18e3.28 (m,
1H, NeCHH), 3.31e3.38 (m, 1H, NeCHH), 3.37 (d,
J¼16.4 Hz, 1H, SeCHH), 3.57e3.65 (m, 1H, SeCHeCH3),
3.67 (d, J¼16.4 Hz, 1H, SeCHH), 4.56 (br, 1H, NH). 13C
NMR (75.4 MHz, CDCl3): d 20.1 (CH3), 28.5 (3CH3), 30.0
(CH2), 37.5 (C), 39.0 (CH), 53.0 (CH2), 75.7 (C), 123.8 (C),
170.6 (C). Anal. Calcd for C11H18N2S: C, 62.81; H, 8.63; N,
13.32. Found: C, 62.72; H, 8.57; N, 13.41.
3.3.25. 2-Methyl-5-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4gl)
3.3.29. 5,7-Dimethyl-2,3,4,7-tetrahydro[1,4]thiazepine-6-
carbonitrile (4bn)
Yellow solid. Mp 67e68 ꢂC. IR (KBr): 3325, 2924, 2181,
Colourless solid. Mp 119e120 ꢂC. IR (KBr): 3319, 2168,
1590, 1570, 1445, 1029, 772, 699 cmꢁ1
.
1H NMR
1593, 1542, 1376, 628 cmꢁ1. H NMR (300 MHz, CDCl3):
1
(300 MHz, CDCl3): d 1.31 (d, J¼6.7 Hz, 3H, CH3), 3.35 (m,
1H, NeCHH), 3.52 (d, J¼16.7 Hz, 1H, SeCHHeC]), 3.68
(dd, J¼14.7, 7.02 Hz, 1H, NeCHH), 3.56 (d, J¼16.7 Hz,
1H, SeCHHeC]), 3.81 (m, 1H, SeCHeCH3), 4.57 (br,
1H, NH), 7.50 (m, 5H, Ph). 13C NMR (75.4 MHz, CDCl3):
d 20.3 (CH3), 28.1 (CH2), 39.6 (CH), 52.5 (CH2), 78.7 (C),
122.1 (C), 127.4 (CH), 128.7 (CH), 129.2 (CH), 130.7 (CH),
131.3 (CH), 136.6 (C), 161.4 (C). GCeMS (EI) m/z: 232 (5)
[Mþþ2], 169 (100). Anal. Calcd for C13H14N2S: C, 67.79;
H, 6.13; N, 12.16. Found: C, 67.89; H, 6.08; N, 12.25.
d 1.49 (d, J¼7.3 Hz, 3H, CHeCH3), 2.08 (s, 3H, ]CeCH3),
2.87e2.92 (m, 1H, SeCHH), 3.04e3.13 (m, 1H, SeCHH),
3.39e3.43 (m, 1H, NeCHH), 3.95e4.06 (m, 1H, NeCHH),
4.25 (q, J¼7.3 Hz, 1H, CHeCH3), 4.24 (br, 1H, NH). 13C
NMR (75.4 MHz, CDCl3): d 20.3 (CH3), 22.7 (CH3), 30.5
(CH2), 34.3 (CH), 45.7 (CH2), 84.6 (C), 121.1 (C), 158.6
(C). GCeMS (EI) m/z: 170 (5) [Mþ2], 168 (100). Anal. Calcd
for C8H12N2S: C, 57.11; H, 7.19; N, 16.65. Found: C, 57.32;
H, 7.15; N, 16.57.
3.3.30. 5-(tert-Butyl)-7-methyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4fn)
3.3.26. 5-Methyl-2-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4bm)
Oil. 1H NMR (300 MHz, CDCl3): d 1.35 (s, 9H, C(CH3)3),
2.74e2.82 (m, 1H, SeCHH), 2.97e3.06 (m, 1H, SeCHH),
3.27e3.37 (m, 1H, NeCHH), 3.95e4.03 (m, 1H, NeCHH),
4.16 (q, J¼7.1 Hz, 1H, CHeCH3), 4.26 (br, 1H, NH). 13C
NMR (75.4 MHz, CDCl3): d 20.1 (CH3), 28.5 (3CH3), 29.7
(CH2), 37.8 (CH), 48.2 (CH2), 76.6 (C), 120.1 (C), 172.3
(C). Anal. Calcd for C11H18N2S: C, 62.81; H, 8.63; N,
13.32. Found: C, 62.70; H, 8.58; N, 13.47.
Colourless solid. Mp 130e131 ꢂC. Rf 0.45 (CH2Cl2/petro-
leum ether (10:1)). IR (KBr): 3396, 2178, 1603, 1490, 1449,
1081, 908, 753, 700 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d 2.04 (s, 3H, CH3), 3.48 (d, J¼16.7 Hz, 1H, SeCHH), 3.76
(d, J¼16.7 Hz, 1H, SeCHH), 3.83 (t, J¼5.8 Hz, 2H, NeCH2),
4.42 (t, J¼5.7 Hz, 1H, SeCH), 4.82 (t, J¼5.5 Hz, 1H, NH),
7.25e7.42 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz, CDCl3):
d 22.2 (CH3), 28.1 (CH2), 49.0 (CH), 51.2 (CH2), 77.4 (C),
123.1 (C), 127.3 (2CH), 127.9 (CH), 128.7 (2CH), 140.9
(C), 159.1 (C). Anal. Calcd for C13H14N2S: C, 67.79; H,
6.13; N, 12.16. Found: C, 67.62; H, 6.08; N, 12.28.
3.3.31. 7-Methyl-5-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4gn)
Oil. 1H NMR (300 MHz, CDCl3): d 1.61 (t, J¼7.3 Hz, 3H,
CH3), 2.87e2.95 (m, 1H, SCHH), 3.12e3.20 (m, 1H, SCHH),
3.47e3.61 (m, 1H, NCHH), 4.05e4.15 (m, 1H, NCHH), 4.24
(q, J¼7.3 Hz, 1H, CHeCH3), 4.93 (br, 1H, NH), 7.37e7.60
(m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz, CDCl3): d 20.6
(CH3), 30.9 (CH2), 36.8 (CH), 47.7 (CH2), 85.7 (C), 118.9
(C), 129.0 (2CH), 130.8 (CH), 132.5 (2CH), 137.0 (C),
160.7 (C). Anal. Calcd for C13H14N2S: C, 67.79; H, 6.13; N,
12.16. Found: C, 67.70; H, 6.10; N, 12.24.
3.3.27. 5-(tert-Butyl)-2-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4fm)
Oil. 1H NMR (300 MHz, CDCl3): d 1.38 (s, 9H, C(CH3)3),
3.62e3.71 (m, 1H, NeCHH), 3.60 (d, J¼16.5 Hz, 1H,
SeCHH), 3.78 (d, J¼16.5 Hz, 1H, SeCHH), 3.87e3.96 (m,
1H, NeCHH), 4.28 (q, J¼3.8 Hz, 1H, CHePh), 4.58 (br,
1H, NH), 7.28e7.41 (m, 5H, 5ꢀHPh). 13C NMR

L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
3699
3.3.32. 5-Methyl-7-phenyl-2,3,4,7-tetrahydro[1,4]-
thiazepine-6-carbonitrile (4bo)
7.27e7.44 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz, CDCl3):
d 20.6 (CH3), 24.4 (CH3), 28.6 (CH2), 43.5 (CH), 47.0
(CH), 52.5 (CH2), 69.8 (C), 79.3 (C), 118.0 (C), 120.3 (C),
128.1 (2C), 128.6 (C), 129.1 (2C), 137.4 (C), 151.1 (C).
Anal. Calcd for C17H17N3S: C, 69.12; H, 5.80; N, 14.22.
Found: C, 69.23; H, 5.76; N, 14.17.
Colourless solid. Mp 138e139 ꢂC. IR (KBr): 3357, 2164,
1601, 1523, 1366, 762, 704 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 2.18 (s, 3H, CH3), 2.79e2.75 (m, 2H, SeCH2),
3.35e3.41 (m, 2H, NeCH2), 4.71 (br, 1H, NH), 4.79 (s, 1H,
PheCH), 7.26e7.61 (m, 5H, 5ꢀHPh). 13C NMR (75.4 MHz,
CDCl3): d 23.3 (CH3), 29.9 (CH2), 45.7 (CH2), 45.8 (CH),
80.5 (C), 122.9 (C), 127.2 (CH), 127.8 (CH), 128.6 (CH),
141.7 (C), 151.8 (C). GCeMS (EI) m/z: 232 (5) [Mþþ2], 230
(100). Anal. Calcd for C13H14N2S: C, 67.79; H, 6.13; N,
12.16. Found: C, 67.57; H, 6.27; N, 12.31.
3.3.37. 5,7-Dimethyl-3,7,8,8a-tetrahydro-2H-thiazolo[3,2-a]-
pyridine-6-carbonitrile (8bn)
Yellow oil. Rf 0.33 (CH2Cl2). IR (film): 3516, 2956, 2927,
2174, 1589, 1424, 1374, 1326, 1259, 1190, 1033, 980, 718,
635 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 1.12 (d, J¼
7.0 Hz, 3H, CH3eCH), 1.74 (ddd, J¼12.9, 10.7, 5.7 Hz, 1H,
CHHeCH), 1.97 (ddd, J¼12.9, 3.2, 2.5 Hz, 1H, CHHeCH),
2.18 (s, 3H, CH3eC]), 2.60e2.55 (m, 1H, CHeCH3),
3.08e2.94 (m, 2H, CH2eS), 3.66e3.59 (m, 1H, CHHeN),
3.85e3.77 (m, 1H, CHHeN), 4.52 (dd, J¼10.7, 3.2 Hz, 1H,
SeCHeN). 13C NMR (75.4 MHz, CDCl3): d 19.7 (CH3),
21.8 (CH3), 28.6 (CH), 29.0 (CH2), 33.7 (CH2), 51.2 (CH2),
58.5 (CH), 81.0 (C), 122.9 (C), 150.9 (C). Anal. Calcd for
C10H14N2S: C, 61.82; H, 7.26; N, 14.42. Found: C, 61.71; H,
7.19; N, 14.51.
3.3.33. 2,4,6-Trimethyl-1,4-dihydropyridine-3,5-dicarbo-
nitrile (6bn)
Colourless solid. Mp 193e194 ꢂC. IR (KBr): 3291,
3243, 3125, 2973, 2199, 1659, 1516, 1385, 1291, 617 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 1.33 (d, J¼6.6 Hz, 3H,
CHeCH3), 2.03 (s, 6H, 2CH3), 3.30 (q, J¼6.6 Hz, 1H,
CHeCH3), 7.26 (br, 1H, NH). 13C NMR (75.4 MHz,
CDCl3): d 18.2 (CH3), 22.9 (CH3), 30.5 (CH3), 85.2 (C),
119.0 (C), 146.0 (C). Anal. Calcd for C10H11N3: C, 69.34;
H, 6.40; N, 24.26. Found: C, 69.41; H, 6.47; N, 24.13.
3.4. Preparation of 2,5-dihydrobenzo[b][1,4]thiazepine-3-
carbonitriles 4bp, 4ep and 4gp from 2-aminothiophenol,
formaldehyde and b-enaminonitriles 1: general procedure
3.3.34. 2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarbonitrile (6bo)
Colourless solid. Mp 218e219 ꢂC. IR (KBr): 3313, 3258,
2193, 1669, 1503, 1278, 739, 700 cmꢁ1
.
1H NMR
A mixture of 2-aminothiophenol (1.95 g, 15.6 mmol), para-
formaldehyde (1.00 g, 11.0 mmol) and b-enaminonitriles 1
(7.8 mmol) in 5 cm3 of dry acetonitrile was refluxed for 2 h.
At the end of the reaction the procedure was continued as in
the previous case. The product was chromatographed on silica
gel (0.040e0.063 mm) using hexane/ethyl acetate (3:1) (4bp
and 4gp) or hexane/ethyl acetate (4:1) (4ep) as eluent.
(300 MHz, CDCl3): d 2.01 (s, 6H, 2CH3), 4.33 (s, 1H, CH),
6.78 (s, 1H, NH), 7.24e7.41 (m, 5H, 5ꢀHPh). 13C NMR
(75.4 MHz, CDCl3): d 18.2 (CH3), 42.0 (CH), 84.7 (C),
118.8 (C), 127.6 (CH), 128.1 (CH), 129.0 (CH), 142.5 (C),
145.6 (C). Anal. Calcd for C15H13N3: C, 76.57; H, 5.57; N,
17.86. Found: C, 76.70; H, 5.51; N, 17.75.
3.3.35. 5,7,8a-Trimethyl-3,7,8,8a-tetrahydro-2H-thiazolo-
[3,2-a] pyridine-6,8-dicarbonitrile (7bn)
3.4.1. 4-Methyl-2,5-dihydrobenzo[b][1,4]thiazepine-3-
carbonitrile (4bp)
Yellow oil. Rf 0.31 (hexane/ethyl acetate (3:1)). IR (film):
Colourless solid. Mp 131e132 ꢂC. IR (KBr): 3449, 2977,
2879, 2238, 2187, 1585, 1404, 1367, 1266, 1135, 986,
3336, 2921, 2188, 1606, 1585, 1471, 1309, 1121, 748 cmꢁ1
.
857 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
1.42 (d,
1H NMR (300 MHz, CDCl3): d 2.35 (s, 3H, CH3), 3.55 (s,
2H, SeCH2), 6.40 (br, 1H, NH), 6.90 (dd, J¼8.1, 1.1 Hz,
1H, ]CH), 7.00 (ddd, J¼7.8, 7.5, 1.2 Hz, 1H, ]CH), 7.20
(ddd, J¼8.1, 7.5, 1.1 Hz, 1H, ]CH), 7.40 (dd, J¼7.8,
1.2 Hz, 1H, ]CH). 13C NMR (75.4 MHz, CDCl3): d 26.5
(CH3), 36.2 (CH2), 83.3 (C), 121.8 (C), 122.0 (CH), 123.5
(CH), 127.8 (C), 128.5 (CH), 133.9 (CH), 142.6 (C), 150.1
(C). GCeMS (EI) m/z: 204 (5) [Mþþ2], 150 (100). Anal.
Calcd for C11H10N2S: C, 65.32; H, 4.98; N, 13.85. Found:
C, 65.24; H, 4.84; N, 13.94.
J¼6.3 Hz, 3H, CHeCH3), 1.60 (s, 3H, ]CeCH3), 2.21 (d,
J¼1.3 Hz, 3H, CH3eCe(N,S)), 2.50e2.64 (m, 2H, 2CH),
3.05e3.19 (m, 2H, SeCH2), 3.86e3.91 (m, 2H, NeCH2).
13C NMR (75.4 MHz, CDCl3): d 18.4 (CH3), 20.5 (CH3),
24.6 (CH3), 28.5 (CH2), 30.9 (CH), 45.5 (CH), 52.5 (CH2),
69.4 (C), 79.7 (C), 118.6 (C), 120.4 (C), 150.1 (C). Anal.
Calcd for C12H15N3S: C, 61.77; H, 6.48; N, 18.01. Found:
C, 61.70; H, 6.42; N, 18.15.
3.3.36. 5,8a-Dimethyl-7-phenyl-3,7,8,8a-tetrahydro-2H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (7bo)
3.4.2. 4-(iso-Propyl)-2,5-dihydrobenzo[b][1,4]thiazepine-3-
carbonitrile (4ep)
Yellow oil. Rf 0.45 (hexane/ethyl acetate (3:1)). IR (film):
3447, 3291, 3206, 3076, 2193, 1633, 1594, 1584, 1543,
1477, 1350, 772, 751, 704 cmꢁ1 1H NMR (300 MHz,
.
Colourless solid. Mp 142e143 ꢂC. IR (KBr): 3449, 2977,
2879, 2238, 2187, 1585, 1404, 1367, 1266, 1135, 986,
857 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.74 (s, 3H,
.
]CeCH3), 2.31 (d, J¼1.4 Hz, 3H, CH3), 2.92 (d,
J¼11.9 Hz, 1H, CHeCN), 3.13e3.23 (m, 2H, SeCH2), 3.68
(dd, J¼11.9, 1.4 Hz, 1H, CHePh), 3.95 (m, 2H, NeCH2),
CDCl3): d 1.31 (d, J¼6.9 Hz, 6H, CH(CH3)2), 3.41 (m, 1H,
CH(CH3)2), 3.58 (s, 2H, SeCH2eC]), 6.30 (br, 1H, NH),

3700
L.A. Calvo et al. / Tetrahedron 64 (2008) 3691e3700
Yakugaku Zasshi 1996, 116, 106; (c) Lee, C. L.; Lam, Y.; Lee, S. Y.
Tetrahedron Lett. 2001, 42, 109; (d) Upreti, M.; Seema, S.; Dandia, A.;
Pant. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1997,
36B, 1181; (e) Dandia, A.; Sehgal, V.; Upreti, M. Phosphorus, Sulfur
Silicon Relat. Elem. 1995, 105, 93; (f) Van den Hoven, B. G.; Alper, H.
J. Am. Chem. Soc. 2001, 123, 1017.
6.91 (dd, J¼8.1, 1.1 Hz, 1H, ]CH), 7.02 (ddd, J¼7.8, 7.5,
1.2 Hz, 1H, ]CH), 7.21 (ddd, J¼8.1, 7.5, 1.1 Hz, 1H,
]CH), 7.41 (dd, J¼7.8, 1.2 Hz, 1H, ]CH). 13C NMR
(75.4 MHz, DMSO-d6): d 19.8 (2CH3), 35.5 (CH), 36.6
(CH2), 79.6 (C), 121.9 (C), 123.2 (CH), 123.7 (CH), 128.1
(CH), 128.1 (C), 133.0 (CH), 143.2 (C), 160.1 (C). GCeMS
(EI) m/z: 232 (5) [Mþþ2], 187 (100). Anal. Calcd for
C13H14N2S: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.89;
H, 6.19; N, 12.05.
2. (a) Mushkalo, L. K.; Lanovaya, Z. I. Ukr. Khim. Zh. 1955, 21, 631; (b)
Mushkalo, L. K.; Shokol, Z. I. Zh. Obshch. Khim. 1960, 30, 1023; (c)
Hankovszky, O. H.; Hideg, K.; Lloyd, D. J. Chem. Soc., Perkin Trans.
1 1974, 1619.
´
3. Calvo, L.; Gonzalez-Ortega, A.; Perez, M.; Sanudo, M. C. Synlett 2005,
´
~
239.
4. Xiang, Y. B.; Drenkard, S.; Baumann, K.; Hickey, D.; Eschenmoser, A.
Helv. Chim. Acta 1994, 77, 2209.
3.4.3. 4-Phenyl-2,5-dihydrobenzo[b][1,4]thiazepine-3-
carbonitrile (4gp)
5. (a) Fulop, F.; Mattinen, J.; Pihlaja, K. Tetrahedron 1990, 46, 6545; (b)
¨
Lambert, J. B.; Majchrzak, M. W. J. Am. Chem. Soc. 1980, 102, 3588;
Yellow solid. Mp 133e134 ꢂC. IR (KBr): 3447, 3291,
3206, 3077, 2193, 1634, 1594, 1584, 1543, 1477, 1350, 772,
´
´
(c) Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2003, 3025; (d) Fernandez,
¨
1
751, 704 cmꢁ1. H NMR (300 MHz, CDCl3): d 3.70 (s, 2H,
~
X.; Dunach, E. Tetrahedron: Asymmetry 2001, 1279.
6. Caballero, E.; Puebla, P.; Medarde, M.; Honores, Z.; San Feliciano, A.
Tetrahedron 1999, 55, 7915 and references there in.
SeCH2), 6.60 (br, 1H, NH), 6.88 (dd, J¼8.1, 1.1 Hz, 1H,
]CH), 7.02 (ddd, J¼7.8, 7.5, 1.2 Hz, 1H, ]CH), 7.22
(ddd, J¼8.1, 7.5, 1.1 Hz, 1H, ]CH), 7.42 (dd, J¼7.8,
1.2 Hz, 1H, ]CH), 7.50 (m, 3H, 3ꢀHPh), 7.59 (m, 2H,
2ꢀHPh). 13C NMR (75.4 MHz, CDCl3): d 36.8 (CH2), 84.9
(C), 121.9 (C), 122.0 (CH), 123.5 (CH), 127.6 (C), 128.3
(2CH), 128.5 (CH), 129.0 (2CH), 130.4 (CH), 133.9 (CH),
138.0 (C), 142.56 (C), 153.8 (C). GCeMS (EI) m/z: 266 (5)
[Mþþ2], 212 (100). Anal. Calcd for C16H12N2S: C, 72.70;
H, 4.58; N, 10.60. Found: C, 72.84; H, 4.62; N, 10.50.
7. Compound 5 was prepared in situ by reaction of 1b and 11 (ratio 1:1.5) in
refluxing methanol for 2 h. The 1H NMR spectrum showed a technical
yield of 90% and a shift of the equilibrium towards the cyclic tautomer.
.
IR (film): 3313, 2193, 1603 cmꢁ1 1H RMN (300 MHz, CDCl3): d 1.68
(s, 3H, CH3), 2.09 (s, 1H, NH), 2.69 (d, J¼16.7 Hz, 1H, CHHeCN),
2.74 (d, J¼17.6 Hz, 1H, CHHeCN), 3.00e3.20 (m, 3H, SeCH2,
NeCHH), 3.45 (m, 1H, NeCHH), 7.40 (dd, J¼7.8, 1.3 Hz, 1H, ]CH).
13C RMN (75.4 MHz, CDCl3): d 28.4 (CH3), 32.8 (CH2), 37.7 (CH2),
51.2 (CH2), 75.0 (C), 117.1 (C).
8. Deposition number CCDC 670615.
9. Deposition number CCDC 668565.
10. Hackler, R. E.; Burow, K. W.; Kaster, S. V.; Wickiser, D. I. J. Heterocycl.
Chem. 1989, 26, 1575.
References and notes
11. Ridge, D. N.; Hanifin, J. W.; Harten, L. A.; Johnson, B. D.; Menschik, J.;
Nicolau, G.; Sloboda, A. E.; Watts, D. E. J. Med. Chem. 1979, 22, 1385.
12. Larice, J. L.; Roggero, J.; Metzger, J. Bull. Soc. Chim. Fr. 1967, 3637.
1. (a) Strzelczyk, M.; Matyjewska, H.; Strozynski, H. Pol. J. Pharmacol.
Pharm. 1990, 42, 377; (b) Ueyama, N.; Wakabayashi, S.; Tomiyama, T.