Unexpected regioselectivity in the reaction between cycloalkenyl-1-diazenes and thioamides: useful entry to fused cycloalkyl-thiazoline and cycloalkyl-thiazoline-pyrazole systems

Article abstract of DOI:10.1016/j.tetlet.2007.02.041

New tetrahydro-3aH-cyclopenta[d][1,3]thiazolines and hexahydro-1,3-benzothiazolines were obtained in satisfactory yields by reaction of cycloalkenyl-1-diazenes with thioamides. These thiazolines were converted into unknown fused cycloalkyl-thiazoline-pyra

Full text of DOI:10.1016/j.tetlet.2007.02.041

Tetrahedron Letters 48 (2007) 2449–2451
Unexpected regioselectivity in the reaction between
cycloalkenyl-1-diazenes and thioamides: useful entry to fused
cycloalkyl-thiazoline and cycloalkyl-thiazoline–pyrazole systems
Orazio A. Attanasi,a Stefano Berretta,a Lucia De Crescentini,a Gianfranco Favi,a
Paolino Filippone,a Gianluca Giorgi,b Samuele Lillinia and Fabio Mantellinia,*
a
` `
Istituto di Chimica Organica della Facolta di Scienze e Tecnologie, Universita degli Studi di Urbino ‘Carlo Bo’,
Via I Maggetti 24, 61029 Urbino, Italy
`
Dipartimento di Chimica, Universita degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
b
Received 10 January 2007; revised 7 February 2007; accepted 9 February 2007
Available online 15 February 2007
Abstract—New tetrahydro-3aH-cyclopenta[d][1,3]thiazolines and hexahydro-1,3-benzothiazolines were obtained in satisfactory
yields by reaction of cycloalkenyl-1-diazenes with thioamides. These thiazolines were converted into unknown fused cycloalkyl-
thiazoline–pyrazole systems.
Ó 2007 Elsevier Ltd. All rights reserved.
S
In previous papers, we reported the reaction of 1,2-
R1O
N
R2
+
diaza-1,3-butadienes I with thioamides II to provide
substituted 2-thiazolin-4-ones IV in high yields.1 The
mechanism involves a preliminary sulfur nucleophilic
attack of compounds II at the azo-ene system with
formation of hydrazones III2 that spontaneously cyclize
by nitrogen internal nucleophilic attack at the ester
function leading to the final 2-thiazolin-4-ones IV
(Scheme 1).
N
R3
NH2
O
II
I
R3
R3
HN
R1O
S
S
R2
N
R2
N
N
N
N
When this synthetic methodology was applied to the
cycloalkenyl-1-diazenes,3 some significant differences in
the behaviour of these reactions were observed. In fact,
cycloalkenyl-1-diazenes 1a–c easily reacted with aryl thio-
amides 2a–i in methanol at room temperature to give
the exclusive formation of aryl-4,5,6,6a-tetrahydro-
3aH-cyclopenta[d][1,3]thiazolines 5a–d or aryl-3a,4,
5,6,7,7a-hexahydro-1,3-benzothiazolines 5e–m in excel-
lent yields (Scheme 2, Table 1).
H
O
O
III
IV
Scheme 1.
ene system of cycloalkenyl-1-diazenes 1a–c with forma-
tion of cycloalkyl-hydrazones 3. These intermediates
immediately undergo the ring closure by regioselective
internal nucleophilic attack of the nitrogen at the
hydrazono moiety, producing the new fused cyclo-
alkyl-thiazoline derivatives 5a–m.4 In these cases, no
formation of spiro cycloalkyl-thiazolinones 4 by means
of the nucleophilic attack at the ester function was
observed, probably on account of the strong strain of
these compounds (Scheme 2). Hence, cycloalkenyl-
1-diazenes furnished new examples of aminothiazoline
ring systems as supported by X-ray diffraction study
The reaction pathway proceeds via SH nucleophilic
attack of thioamides 2a–i in its tautomeric thioloimido
form at the carbon atom in position four of the azo-
Keywords: Cycloalkenyl-1-diazenes; Michael additions; Thioamides;
Thiazolines.
*
Corresponding author. Fax: +39 0722303441; e-mail: f.mantellini@
uniurb.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.041

2450
O. A. Attanasi et al. / Tetrahedron Letters 48 (2007) 2449–2451
Table 1. Yields of aryl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]-
S
thiazolines 5a–d, aryl-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazolines
5e–m, 6-thia-2,3,8-triaza-tricyclo[3.3.3.01,5]undec-7-en-4-ones 7a,b and
10-thia-7,8,12-triaza-tricyclo[4.3.3.01,6]dodec-11-en-9-ones 7c–g
O
2
2
NH
R
2
OEt
N
1
n
R1
2
R2
5
Yielda
(%)
7
Yieldb
(%)
n
+
1
N
R
SH
CONH
2
1a
1
H
2a
5a 68
1a-c
NH
R
O
n=1,2
2a-i
1a
1a
1a
1b
1b
1b
1
1
1
2
2
2
H
H
H
H
H
H
2b
2c
2d
2a
2c
2e
5b 59
5c 91
5d 86
5e 93
N
7a 54
7b 44
7c 63
7d 56
7e 59
OCH3
CF3
N
2
2
R
O
R
EtO
S
S
n
H
n
NH
N
N
H
1
1
R
N
CONH
2
R
N
CONH
2
4
3
5f
97
OCH3
Cl
5g 64
5h 96
EtO
O
S
n
2
F
1
R
R
1b
2
H
H
2f
7f 63
N
F
HN
HN CONH
2
1b
1c
1c
2
2
2
2g
5i
5j
92
92
S
5a-m
Scheme 2. Reagent and condition: (i) MeOH, rt.
Me 2a
Me 2e
7g 62
of compound 5k (Fig. 1).5 It is known that this latter
class of compounds find applications for the treatment
of allergies, hypertension, inflammation, schizophrenia,
bacterial and HIV infections.6
Cl
5k 69
N
1c
1c
2
2
Me 2h
Me 2i
5l
84
S
CH3
The contemporary presence of both ester and hydrazine
functions makes compounds 5 able to give further trans-
formations. In fact, by treatment of compounds 5c–h,j
in THF at room temperature in the presence of a stoichio-
metric amount of sodium hydride, the internal nucleo-
philic attack of the hydrazine nitrogen at the carbonyl
group determined the second ring closure to obtain
intermediates 6 (Scheme 3). The spontaneous loss of
carbamic residue produced the new and interesting 6-
thia-2,3,8-triaza-tricyclo[3.3.3.01,5]undec-7-en-4-ones 7a,b
and 10-thia-7,8,12-triaza-tricyclo[4.3.3.01,6]dodec-11-en-
9-ones 7c–g in good yields (Scheme 3, Table 1).7
5m 77
N
a Yield of pure isolated products 5a–m based on cycloalkenyl-1-diaz-
enes 1a–c.
b Yield of pure isolated products 7a–g based on thiazolines 5c–h,j.
In conclusion, this Letter shows a different behaviour
between 1,2-diaza-1,3-butadienes and cycloalkenyl-1-
diazenes in the reaction with aryl-thioamides. In this
way, it is possible to obtain new aryl-4,5,6,6a-tetra-
hydro-3aH-cyclopenta[d][1,3]thiazolines and aryl-3a,4,
5,6,7,7a-hexahydro-1,3-benzothiazolines that are valu-
able derivatives in consideration of their potential phar-
macological and biological activities. In addition, by a
simple workup procedure, these cycloalkyl-thiazolines
can be used in the construction of attractive and
unknown fused cycloalkyl-thiazoline–pyrazoles, which
are not easy to obtain by other methods.
Figure 1. Crystal structure of compound 5k. Ellipsoids enclose 50%
probability.

O. A. Attanasi et al. / Tetrahedron Letters 48 (2007) 2449–2451
2451
evaporated under reduced pressure and the final aryl
thiazolines 5a,b,h–j,m were purified by chromatography
on silica column (elution mixtures: ethyl acetate–cyclohex-
ane) and crystallized from ethyl acetate–cyclohexane.
Spectral data for 5e: ethyl 3a-[2-(aminocarbonyl)hydra-
zino]-2-phenyl-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazoline-
7a-carboxylate. White powder, mp 152–154 °C. IR (Nujol):
EtO
O
S
O
n
1
S
R
n
i
2
2
1
R
R
H NOC
N
R
2
ii
N
N
N
HN
H
m
max = 3473, 3256, 3156, 1732, 1682 cmÀ1 1H NMR
.
HN CONH
2
6
(400 MHz, CDCl3): d 1.27 (t, 3H, J = 6.8 Hz), 1.40–1.52
(m, 1H), 1.53–1.56 (m, 1H), 1.59–1.66 (m, 2H), 1.90–1.98
(m, 1H), 2.07–2.11 (m, 1H), 2.18–2.26 (m, 2H), 4.17 (q, 2H,
J = 6.8 Hz), 5.18 (br s, 1H), 5.72 (br s, 2H), 6.56 (br s, 1H),
7.36 (dt, 2H, J1 = 6.8 Hz, J2 = 1.2 Hz), 7.43 (dt, 2H,
J1 = 7.2 Hz, J2 = 1.2 Hz), 7.76 (dt, 2H, J1 = 7.2 Hz,
J2 = 1.2 Hz). 13C NMR (100 MHz, CDCl3): d 13.8 (q),
20.3 (t), 20.9 (t), 29.0 (t), 35.3 (t), 61.9 (t), 68.1 (s), 93.5 (s),
128.0 (d), 128.4 (d), 131.8 (d), 132.7 (s), 161.2 (s), 167.4 (s),
170.4 (s). MS: m/z (%) = 362 (M+, 1), 317 (2), 288 (65), 273
(67), 244 (42), 216 (46), 170 (100). Anal. Calcd for
C17H22N4O3S: C, 56.33; H, 6.12; N, 15.46. Found: C,
56.38; H, 6.16; N, 15.38.
5c-h,j
n=1,2
O
n
1
S
R
2
R
H
N
N
N
H
7a-g
Scheme 3. Reagents and conditions: (i) NaH (1 equiv), MeOH, rt; (ii)
5. Crystallographic data (excluding structure factors) for
compound 5k have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publica-
tion No. CCDC 636093. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
Amberlyst 15H, MeOH, rt.
Acknowledgements
This work was supported by the financial assistance
from the Ministero dell’Universita, dell’Istruzione e del-
la Ricerca (MIUR)-Roma and Universita degli Studi di
Urbino ‘Carlo Bo’.
`
6. (a) Umemura, K.; Watanabe, K.; Ono, K.; Yamamura, M.;
Yoshimura, J. Tetrahedron Lett. 1997, 38, 4811; (b) Badorc,
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A.; Bordes, M. F.; de Cointet, P.; Savi, P.; Lale, A.; Petitou,
M.; Maffrand, J. P.; Herbert, J. M. J. Med. Chem. 1997, 40,
3393; (c) Rzasa, R. M.; Shea, H. A.; Romo, D. J. Am.
Chem. Soc. 1998, 120, 591; (d) Kearney, P. C.; Fernandez,
M.; Flygare, J. A. J. Org. Chem. 1998, 63, 196; (e) Naidu, B.
N.; Sorenson, M. E.; Zhang, Y.; Kim, O. K.; Matiskella, J.
D.; Wichtowski, J. A.; Connolly, T. P.; Li, W.; Lam, K. S.;
Bronson, J. J.; Pucci, M. J.; Clark, J. M.; Ueda, Y. Biorg.
Med. Chem. Lett. 2004, 14, 5573.
References and notes
1. (a) Attanasi, O. A.; De Crescentini, L.; Foresti, E.;
Galarini, R.; Santeusanio, S.; Serra Zanetti, F. Synthesis
1995, 1397; (b) Attanasi, O. A.; De Crescentini, L.; Favi,
G.; Filippone, P.; Lillini, S.; Mantellini, F.; Santeusanio, S.
Org. Lett. 2005, 7, 2469.
7. General procedure for the synthesis of 6-thia-2,3,8-triaza-
tricyclo[3.3.3.01,5]undec-7-en-4-ones 7a,b and 10-thia-7,
8,12-triaza-tricyclo[4.3.3.01,6]dodec-11-en-9-ones 7c–g. To
a magnetically stirred solution of aryl-4,5,6,6a-tetrahydro-
3aH-cyclopenta[d][1,3]thiazolines 5a–d or aryl-3a,4,
5,6,7,7a-hexahydro-1,3-benzothiazolines 5e–m in tetra-
hydrofuran (30 mL) a stoichiometric amount of sodium
hydride (0.1 equiv) was added. The reaction easily took
place (0.5–1 min.) at room temperature. Then, at the
disappearance of 5 2 equiv of Amberlyst 15H were added
under magnetic stirring to the crude and the reaction was
allowed to stand under this condition for 10 min. The
reaction mixture was filtered and the solvent was evapo-
rated under reduced pressure. Products 7a–g were obtained
pure by chromatography on silica column (elution mix-
tures: ethyl acetate–cyclohexane).
2. (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Santeusanio, S. Arkivoc 2002, 274, and the
references cited therein; (b) Attanasi, O. A.; De Crescentini,
L.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.;
Santeusanio, S. J. Org. Chem. 2003, 68, 1947; (c) Attanasi,
O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantel-
lini, F.; Santeusanio, S. J. Org. Chem. 2004, 69, 2686; (d)
Attanasi, O. A.; Baccolini, G.; Boga, C.; De Crescentini, L.;
Filippone, P.; Mantellini, F. J. Org. Chem. 2005, 70, 4033;
(e) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Synlett 2006,
1734; (f) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Giorgi, G.; Mantellini, F.; Mazzanti, A. Synlett 2006, 2403;
(g) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.;
Lillini, S.; Mantellini, F.; Perrulli, F. R. Synlett 2006,
2731.
Spectral data for 11-phenyl-10-thia-7,8,12-triaza-tricy-
clo[4.3.3.01,6]dodec-11-en-9-one 7c: colourless oil, IR
3. Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Lillini, S.; Mantellini, F. Synlett 2006, 2735.
(Nujol): mmax = 3428, 3219, 3160, 1687 cmÀ1 1H NMR
.
(400 MHz, CDCl3): d 1.32–1.56 (m, 3H), 1.59–1.66 (m, 1H),
1.86–1.93 (m, 1H), 1.98–2.04 (m, 1H), 2.06–2.22 (m, 2H),
5.92 (br s, 1H), 6.21 (br s, 1H), 7.47 (dt, 2H, J1 = 7.2 Hz,
J2 = 1.6 Hz), 7.51 (dt, 2H, J1 = 7.2 Hz, J2 = 1.4 Hz), 7.84
(dt, 2H, J1 = 7.2 Hz, J2 = 1.6 Hz). 13C NMR (100 MHz,
CDCl3): d 20.1 (t), 20.5 (t), 28.7 (t), 31.0 (t), 63.7 (s), 99.0
(s), 128.6 (d), 129.0 (d), 131.8 (d), 132.4 (s), 169.4 (s), 175.3
(s). MS: m/z (%) = 273 (M+, 100). Anal. Calcd for
C14H15N3OS: C, 61.51; H, 5.53; N, 15.37. Found: C,
61.59; H, 6.44; N, 15.29.
4. General procedure for the synthesis of 2-aryl-4,5,6,6a-tetra-
hydro-3aH-cyclopenta[d][1,3]thiazolines 5a–d or 2-aryl-
3a,4,5,6,7,7a-hexahydro-1,3-benzothiazolines 5e–m. Aryl
thioamides 2a–i (1 mmol) were added to a magnetically
stirred solution of cycloalkenyl-1-diazenes 1a–c1 (1 mmol)
in methanol (10 mL). The reaction was allowed to stand at
room temperature until the disappearance of the reagents
(0.5–1.5 h). Compounds 5c–e,g,k,l crystallized directly from
the reaction medium. They were collected as pure products
by filtration. In the other cases, the reaction solvent was