Studies on isocyanides. A facile synthesis of 4,5-dihydro-1,4- benzothiazepin-3(2H)-ones via post-condensation modifications of the Ugi reaction

Article abstract of DOI:10.1016/j.tetlet.2005.09.071

A series of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones 9 was prepared via Ugi 4-CC, S_N aliph, and S_N arom. This procedure, which resembles the well-known Hulme's and Zhu's protocols, allows a facile access to the above heterocyclic sy

Full text of DOI:10.1016/j.tetlet.2005.09.071

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7977–7979
Studies on isocyanides. A facile synthesis of
4,5-dihydro-1,4-benzothiazepin-3(2H)-ones via
post-condensation modifications of the Ugi reaction
Ana G. Neo,a Carlos F. Marcos,a Stefano Marcaccinib,* and Roberto Pepinob
aDepartamento de Quı´mica Orga´nica, Facultad de Veterinaria, Universidad de Extremadura, Avenida de la Universidad s/n,
E-10071 Ca´ceres, Spain
`
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita di Firenze, via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
b
Received 30 August 2005; revised 12 September 2005; accepted 13 September 2005
Abstract—A series of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones 9 was prepared via Ugi 4-CC, SN aliph, and SN arom. This
procedure, which resembles the well-known HulmeÕs and ZhuÕs protocols, allows a facile access to the above heterocyclic system.
Further transformations of the cyclized products appear to be feasible.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Several derivatives of 2,3-dihydro-1,5-benzothiazepin-
4(5H)-one1 (1) have received considerable attention
because of their pharmacological activities. Besides their
use for the treatment of cardiovascular diseases,2 some
members of this class of compounds act as potent brady-
kinin agonists,3 growth hormone secretagogues,4 ligands
for Src H2 protein,5 spasmolytics,6 and squalene synthe-
tase inhibitors.7
reactions,9 we wish to report a viable synthesis of 4,5-
dihydro-1,4-benzothiazepin-3(2H)-ones by exploiting
the Ugi four-component condensation.10 As the starting
carbonyl component we chose the commercially avail-
able 2-chloro-5-nitrobenzaldehyde (3) in which the chlor-
ine atom is readily displaced by nucleophiles. Aldehyde
3 reacted smoothly with amines 4, isocyanides 5, and
chloroacetic acid (6) in methanol at room temperature
to give the Ugi-4CC adducts 7 in fair to good yields.11
Since both the chlorine atoms of 7 are reactive toward
nucleophiles, in earlier experiments we attempted to
promote the formation of an intramolecular sulfur
bridge by reacting 7 with sulfides and hydrogen sulfides.
Unfortunately, these attempts failed, giving intractable
gums.
Isomeric derivatives of 4,5-dihydro-1,4-benzothiazepin-
3(2H)-one (2) are by far less known and, to the best of
our knowledge, only one report dealing with their syn-
thesis has appeared in the literature.8
H
O
H
N
N
In an alternative approach, we attempted to achieve
the formation of the sulfur bridge in two separate
steps. The first step consisted of the reaction between
7 and thiourea. This reaction occurred very easily in
acetone and compounds 7 were almost quantitatively
converted into the corresponding isothiouronium
salts 8. In some reactions, salts 8 precipitated from
the mother liquors in an almost pure form. However,
the isolation of 8 was unnecessary and the follow-
ing step could be performed on the crude product aris-
ing from the evaporation of the reaction mixture
(Scheme 1).
O
S
S
1
2
In continuation of our studies on the synthesis of hetero-
cyclic compounds by isocyanide-based multi-component
Keywords: Ugi reaction; Isocyanides; 1,4-Benzothiazepinones; Aro-
matic nucleophilic substitution.
*
Corresponding author. Tel.: +39 055 457 3510; fax: +39 055 457
3531; e-mail: stefano.marcaccini@unifi.it
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.071

7978
A. G. Neo et al. / Tetrahedron Letters 46 (2005) 7977–7979
H2N
NH2
O2N
CHO
Cl
CONHR1
S
R
NH2
O2N
R
N
acetone, rt, o. n.
MeOH, rt, 24 h
4
3
O
Cl
Cl
R1
Cl
CO2H
NC
7
6
5
Na2S
or NaSH
EtOH
CONHR1
KOH, EtOH
2 h, reflux
CONHR1
O2N
R
N
R
O2N
N
O
Cl
O
+
-
NH2 Cl
S
S
NH2
9
8
H
CONHR1
N
S
Fe, AcOH
PhNCS
CONHR1
Ph
40
70 ˚C
R
EtOH
R
H2N
2 h
N
HN
rt, overnight
N
9k
O
O
S
S
R = tetrahydrofurfuryl
R1 = cyclohexyl
10k
11k
4
a
b
c
d
e
f
R
C6H5CH2
4-ClC6H4CH2
C5H5S a
(CH3)2CHCH2
C5H9O b
3,4-
(OCH2O)C6H3CH2
g
h
n-C8H17
4-NO2C6H4CH2
a) 2-thienylmethyl; b)
tetrahydrofurfuryl
5
a
b
c
R1
4-C2H5OC6H4
c-C6H11
n-C6H13
7,8,9
R
R1
7
9
Yield (%) Yield (%)a
a
b
c
d
e
f
g
h
i
C6H5CH2
4-ClC6H4CH2
C5H5S
(CH3)2CHCH2
C5H9O
3,4-(OCH2O)C6H3CH2
n-C8H17
4-NO2C6H4CH2
C5H5S
4-ClC6H4CH2
C5H9O
4-C2H5OC6H4
4-C2H5OC6H4
4-C2H5OC6H4
4-C2H5OC6H4
4-C2H5OC6H4
c-C6H11
4-C2H5OC6H4
c-C6H11
c-C6H11
n-C6H13
87
65
72
89
40
67
82
72
92
54
72
71
95
67
91
75
65
40
60
65
47
62
j
k
c-C6H11
a) Based on 7
Scheme 1. 4,5-Dihydro-1,4-benzothiazepin-3(2H)-ones via Ugi-4CC, aliphatic SN, and aromatic SN.
The cyclization of isothiouronium salts 8 took place suc-
cessfully upon heating with 2 equiv of potassium
hydroxide in ethanol to give the benzothiazepinones 9
in fair to excellent yields.12,13
In order to evaluate the possibility of obtaining deriva-
tives of 9 via transformation of the nitro group, we per-
formed the reduction of 9k with iron powder in acetic
acid.9a,f The crude amine 10k was allowed to react with

A. G. Neo et al. / Tetrahedron Letters 46 (2005) 7977–7979
7979
11. 2-(N-Benzyl-N-chloroacetyl)amino-2-(2-chloro-5-nitro)phen-
ylacetic acid N-(4-ethoxy)phenyl amide (7a): A solution of
2-chloro-5-nitrobenzaldehyde (3) (1.11 g, 6.0 mmol) in
MeOH (10 mL) was treated with benzylamine (4a)
(642 mg, 6.0 mmol). The resulting mixture was stirred
for 15 min at rt and then treated with a solution of the 4-
ethoxyphenyl isocyanide (5a) (839 mg, 5.7 mmol) in
MeOH (5 mL) and chloroacetic acid (6) (567 mg,
6.0 mmol), in the order given. The resulting mixture was
stirred for 24 h at rt and then cooled and filtered. The
collected product was washed with cold i-PrOH, i-Pr2O,
and pentane, in the order given, and dried to give 2.94 g
(87%) of almost pure 7a.
phenyl isothiocyanate to give the thiourea 11k in 65%
overall yield.
In conclusion, the present method allows a facile prepa-
ration of derivatives containing the 1,4-benzothiazin-3-
one core by means of a three-step synthesis. The first
and the second steps are very easy to perform, simply
by mixing the reagents. The purification of both the
Ugi adducts 7 and the isothiouronium salts 8 is unneces-
sary and also the last step is experimentally simple. The
final benzothiazinones are obtained in good yields and
the substituents in position 4 and at the amide nitrogen
can be easily changed by changing the amine and the
isocyanide in the Ugi reaction. A further advantage lies
in the possibility of transforming the nitro group in
position 7.
White solid; mp 177–178 ꢁC (EtOH) IR (cmÀ1): m 3251,
3078, 2979, 1679, 1653, 1612, 1531, 1511, 1476, 1466, 1411,
1346, 1304, 1244, 1204, 1167, 1117, 1049, 921, 836, 798,
742, 697, 521; 1H NMR (200 MHz, CDCl3): d 8.50 (d, 1H,
J = 10.2 Hz), 8.25 (dd, 1H, J = 11.7 Hz, J = 2.4 Hz),
7.34–7.06 (m, 9H), 6.76 (d, 2H, J = 8.8 Hz), 6.71 (d, 1H,
J = 11.2 Hz), 4.91 (s, 2H), 4.18 (s, 2H), 3.98 (q, 2H,
J = 7.0 Hz), 1.39 (t, 3H, J = 6.8 Hz); 13C NMR (50 MHz,
CDCl3): d 168.62, 165.35, 156.11, 146.44, 142.01, 135.36,
133.94, 130.59, 129.96, 129.84, 128.71, 127.69, 125.73,
124.69, 121.98, 114.61, 63.75, 59.60, 59.44, 50.19, 41.96,
15.01. Anal. Calcd for C25H23Cl2N3O5 (516.37): C, 58.15;
H, 4.49; N, 8.14. Found: C, 58.37; H, 4.60; N, 7.86.
Detailed experimental procedures, physical, analytical,
and spectral data of compounds 7b–k are reported in the
Supplementary data.
Acknowledgments
A.G.N. is grateful to Junta de Extremadura for a
research grant.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.071.
12. 4-Benzyl-7-nitro-3-oxo-2,3,4,5-tetrahydrobenzo[1,4]thiaze-
pin-5-carboxylic acid N-(4-ethoxy)phenyl amide (9a): A
saturated solution of 7a (1.55 g, 3.0 mmol) in acetone was
treated with finely ground thiourea (297 mg, 3.9 mmol)
and the resulting mixture stirred for 16 h at rt. TLC showed
the absence of the starting product. Removal of the solvent
left a residue, which was treated with EtOH (25 ml) and
then with a solution of KOH (337 mg, 6.0 mmol) in water
(2 mL). The resulting mixture was refluxed for 2 h under
stirring. Removal of the solvent left a residue, which was
stirred with water (60 mL). The resulting suspension was
extracted with CHCl3 (3 · 50 mL). The combined extracts
were dried (Na2SO4) and the solvent removed to give a
residue, which was recrystallized from EtOH to afford
1.43 g (71%) of pure 9a.
References and notes
1. Review: Levai, A. J. Heterocycl. Chem. 2000, 37, 199–214.
2. Ferrari, R. Eur. Heart J. 1997, 18, A56–A70.
´
3. Amblard, M.; Daffix, I.; Bedos, P.; Berge, G.; Pruneau,
´
D.; Paquet, J.-L.; Luccarini, J.-M.; Belichard, P.; Dodey,
P.; Martinez, J. J. Med. Chem. 1999, 42, 4185–4192.
4. Huang, P.; Loew, G. H.; Funamizu, H.; Mimura, M.;
Ishiyama, N.; Hayashida, M.; Okuno, T.; Shimada, O.;
Okuyama, A.; Ikegami, S.; Nakano, J.; Inoguchi, K. J.
Med. Chem. 2001, 44, 4082–4091.
5. Lesuisse, D.; Deprez, P.; Albert, E.; Duc, T. T.; Sortais,
B.; Gofflo, D.; Jean-Baptiste, V.; Marquette, J.-P.; Schoot,
B.; Sarubbi, E.; Lange, G.; Broto, P.; Mandine, E. Bioorg.
Med. Chem. Lett. 2001, 11, 2127–2131.
White solid, mp 204.5–205.5 ꢁC. IR (cmÀ1): m 3323, 1697,
1659, 1595, 1572, 1520, 1469, 1427, 1415, 1336, 1308, 1264,
1230, 1172, 1156, 1113, 1083, 1061, 1036, 823, 758, 744,
702, 657; 1H NMR (200 MHz, CDCl3): d 8.04 (d, 1H,
J = 8.7 Hz), 7.84 (s, 1H), 7.48–7.35 (m, 6H), 7.03 (d, 2H,
J = 8.8 Hz), 6.78 (s, 1H), 6.76 (d, 2H, J = 8.8 Hz), 5.31 (d,
1H, J = 13.8 Hz), 5.04 (s, 1H), 4.26 (d, 2H, J = 15.0 Hz),
3.96 (q, 2H, J = 6.9 Hz), 3.36 (d, 1H, J = 14.5 Hz), 1.37 (t,
3H, J = 6.9 Hz); 13C NMR (50 MHz, CDCl3): d 165.88,
156.40, 155.21, 144.68, 136.46, 129.81, 129.33, 129.21,
129.11, 128.90, 127.66, 123.43, 121.26, 114.79, 66.67, 63.69,
52.34, 33.07, 14.71.
6. Narita, H.; Gaino, M.; Suzuki, T.; Kurosawa, H.; Inoue,
H.; Nagao, T. Chem. Pharm. Bull. 1990, 38, 407–410.
7. Hamanaka, E. S.; Hayward, C. M.; Hawkins, J. M. U.S.
Patent 5,770,594, 1998; Chem. Abstr. 1996, 125, 168038s.
´
´
´
´
´
8. Szabo, J.; Fodor, L.; Katocs, A; Bernath, G.; Sohar, P.
Chem. Ber. 1986, 119, 2904–2913.
9. See for example: (a) Faggi, C.; Marcaccini, S.; Pepino, R.;
Pozo, M. C. Synthesis 2002, 2756–2760; (b) Faggi, C.;
Anal. Calcd for C25H23N3O5S (477.53): C, 62.88; H, 4.85;
N, 8.80. Found: C, 62.61; H, 4.96; N, 8.99. Detailed
experimental procedures, physical, analytical, and spectral
data of compounds 9b–k are reported in the Supplemen-
tary data.
´
Garcıa-Valverde, M.; Marcaccini, S.; Pepino, R.; Pozo, M.
C. Synthesis 2003, 1553–1558; (c) Marcaccini, S.; Pepino,
´
R.; Pozo, M. C.; Basurto, S.; Garcıa-Valverde, M.;
Torroba, T. Tetrahedron Lett. 2003, 44, 3999–4001; (d)
´
Marcaccini, S.; Miguel, D.; Torroba, T.; Garcıa-Valverde,
13. The formation of the internal nucleophile represents the key
step in this synthesis. From this point of view the present
methodology is substantially analogous to those described
by Hulme and Zhu groups: (a) Tempest, P.; Ma, V.; Kelly,
M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963–4966; (b) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C.
Tetrahedron Lett. 2003, 44, 1947–1950; (c) Cristau, P.; Vors,
J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079–4082.
M. J. Org. Chem. 2003, 68, 3315–3318; (e) Marcos, C. F.;
Marcaccini, S.; Pepino, R.; Polo, C.; Torroba, T. Synthesis
2003, 691; (f) Marcaccini, S.; Miliciani, M.; Pepino, R.
Tetrahedron Lett. 2005, 46, 711–713.
10. Reviews: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168–3210; (b) Ugi, I.; Werner, B.; Do¨mling, A.
Molecules 2003, 8, 53–66.