Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry

Article abstract of DOI:10.1016/j.tet.2008.01.102

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, w

Full text of DOI:10.1016/j.tet.2008.01.102

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3837e3858
www.elsevier.com/locate/tet
Simple construction of fused and spiro nitrogen/sulfur containing
heterocycles by addition of thioamides or thioureas on
cycloalkenyl-diazenes: examples of click chemistry
Orazio A. Attanasi a, Lucia De Crescentini a, Gianfranco Favi a, Paolino Filippone a,
a
c
Gianluca Giorgi b, Fabio Mantellini a, , Francesca R. Perrulli , Domenico Spinelli
*
a Istituto di Chimica Organica, Universita` degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
b Dipartimento di Chimica, Universita` degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
c Dipartimento di Chimica Organica ‘A. Mangini’, Universita` di Bologna, Via San Giacomo 11, 40126 Bologna, Italy
Received 2 October 2007; received in revised form 17 December 2007; accepted 25 January 2008
Available online 31 January 2008
Abstract
New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic b-ketoesters and hydrazine derivatives. They furnished new
cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-
2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,20-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,20-
[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown
thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N0-dialkylthioureas on N-1-phenyl-
2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(u-carboxyalkyl)-
4-thiazolidinones.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Based on these properties, it can be reasonably supposed
that the development of synthetic strategies for new
cycloalkyl[d][1,3]thiazolines, spirocycloalkyl-thiazolinones,
spirocycloalkane-1,20-imidazo[2,1-b][1,3]thiazoles, spirocy-
cloalkane-1,20-[1,3]thiazolo[3,2-a]pyrimidines might provide
additional lead molecules for drug discovery. Usually, the syn-
thesis of the thiazole core involves the condensation of amino-
thiols with either nitrile,8 carboxylic acid,9 or ester,10 as well
as by intramolecular dehydration of b-hydroxythioamides un-
der Mitsunobu conditions,11 or with Burgess reagent.12 Other
methods exploit intramolecular cyclization of b-hydroxy-
Thiazoline derivatives represent a family of compounds
with great industrial interest, which have found applications
in food and flavour chemistry.1,2 Thiazolines have also
attracted very significant biochemical interest, owing to the
presence of the thiazoline moiety in the structures of several
naturally occurring molecules with important pharmacological
properties such as antibiotic,3 antihelmintic,4 antifungal,3a or
antitumour drugs.5 Recently, new metabolites derived from
aminoacids containing thiazole rings have been isolated
from marine species: they exhibit antineoplastic and cytotoxic
activity.6 The aminothiazole system has found applications in
drug development for the treatment of allergies, hypertension,
inflammation, schizophrenia, bacterial and HIV infections.7
amides with P2S5 or Lawesson’s reagent,14 by the reaction
13
of amino sugar derivatives with aryl isothiocyanates,15 or by
deselenylation of thioamido selenides.16 We previously re-
ported the synthesis of substituted 2-thiazolin-4-ones III17
and 5,5-disubstituted 3-alkyl-2-(alkylimino)-thiazolidin-4-
ones VI18 from 1,2-diaza-1,3-butadienes I and thioamides II
or thioureas IV, respectively (Scheme 1).
* Corresponding author. Tel.: þ39 0722 303445; fax: þ39 0722 303441.
E-mail address: fabio.mantellini@uniurb.it (F. Mantellini).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.102

3838
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
R2
R2
S
O
R3
NH2
for 2a: CH3COONa,
R3 NH2
n
n
R3
+
H
N
N
H
R2
MeOH, r.t.
R3
S
R1O
N
II
R1
1a-e
O
R1
N
R2
N
for 2b,c: THF, r.t.
N
N
S
N
H
2a-c
3a-h
O
O
n=1,2,3,4
I
O
III
S
O
R4HN NHR4
IV
R2
R2
Cl
NBS, DCM, r.t.
R2=COOR
NH2
PhHN
Cl
O
N
H
R4
N
H
N
2c
H
N
R4
R2
R1O
N
COOR1
N
THF, r.t.
N
Ph
N
N
R2
O
1f
3i
O
R4
N
S
H
I
N
H
R4
N
N
R2
R1=R2=H
N
NaOH(aq)(1%),
DCM, r.t.
O
N
H
R2
N
H
O
V
VI
R2
Br
n
R2
Scheme 1.
n
H
N
Na2CO3(aq), DCM, r.t.
R3
R3
N
R1
N
R1
N
O
O
4
5a-i
More recently,19 we observed a different regioselectivity
leading to new cycloalkyl-thiazolines when this synthetic
methodology was applied to cyclopentenyl- or cyclohexenyl-
1-diazenes. Herein, we enlarge the scope of previous syntheses
by using new cycloheptenyl- and cyclooctenyl-1-diazenes,
which are able to give the corresponding cycloalkyl[d][1,3]-
thiazoline derivatives, that, in turn, can be further converted
into interesting thia-triaza-tricyclo derivatives. We also de-
scribe an efficient strategy for the preparation of unknown
spirocycloalkyl-thiazolinones of different sizes using cyclo-
alkyl-1-diazenes and thioureas. This methodology proceeds
rapidly to completion, is very selective and wide in scope,
produces the compounds in high yields, generates only inof-
fensive by-products (alcohols), requires simple and mild reac-
tion conditions, uses readily available starting materials and
offers a simple product isolation by crystallization in the reac-
tion medium, fulfilling the click chemistry criteria.20 Finally,
in this work we investigate the acidic hydrolysis and the
ring-opening process of cycloalkyl-thiazoline derivatives and
1-thia-3-azaspiro compounds.
Scheme 2.
Table 1
Yields of hydrazones 3aei and 1-cycloalkenyl-1-diazenes 5aei
1
n
R1
R2
2
R3
2a NH2
2b Ot-Bu 3b 86
2a NH2 3c 91
3
Yielda (%)
5
Yieldb (%)
1a
1a
1b
1b
1b
1c
1d
1e
1f
a
1
1
2
2
2
2
3
4
2
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3a 89
5a 78
5b 63
5c 76
5d 60
5e 63
5f 74
5g 82
5h 92
2b Ot-Bu 3d 90
2c NHPh 3e 86
Me CO2Et 2a NH2
CO2Me 2a NH2
3f 93
3g 87
3h 83
H
H
H
CO2Et
H
2a NH2
2c NHPh 3i
95
5i
65
Yields of the pure products 3aei based on the carbonyl compounds 1aef.
Yields of the pure isolated products 5aei based on the hydrazone com-
b
pounds 3aei.
Thioamides 6aei easily added to cycloalkenyl-1-diazenes
5a,c,feh in methanol at room temperature affording new tetrahy-
dro-cyclopenta[d][1,3]thiazolines 9aed (n¼1), hexahydro-1,3-
benzothiazolines 9eem (n¼2), hexahydro-cyclohepta[d][1,3]thi-
azolines 9nep (n¼3) and octahydrocycloocta[d][1,3]thiazolines
9qet (n¼4) in good yields (Scheme 3, Table 2). The reaction
occurs by a preliminary nucleophilic attack by the sulfur of
thioamides 6aei at the terminal carbon atom of the azoeene sys-
tem17,18 of 5 with formation of the respective 1,4-adduct (Michael-
type) cycloalkyl-hydrazones intermediates 7. They immediately
undergo the thiazole ring closure by regioselective internal nucle-
ophilic attack from the imino nitrogen of the thioamides at the
hydrazono moiety, producing interesting cycloalkyl[d][1,3]thiazo-
line derivatives 9. Their structure, proposed on the basis of spectro-
metric (1H and 13C NMR as well as MS) data, was definitively
confirmed by X-ray diffraction determination on 9k (Fig. 1).22
Significant differences in the regioselectivity were observed
in the previous reaction of thioamides on 1,2-diaza-1,3-butadi-
enes under the same experimental conditions.17 In such a case,
the second nucleophilic attack of the imino nitrogen occurs only
at the ester function on the terminal carbon of the azoeene
system leading to the corresponding 2-thiazolin-4-ones III
2. Results and discussion
1-Cycloalkenyl-1-diazenes 5aeh were prepared from
cyclic b-ketoesters 1aee and hydrazine derivatives 2aec
(1 equiv), in methanol (MeOH) or tetrahydrofuran (THF), at
room temperature to achieve the corresponding hydrazones
3aeh. These latter were subjected to bromination by the ac-
tion of N-bromosuccinimide (NBS, 1 equiv) in dichlorome-
thane (DCM) at room temperature to obtain the respective
brominated hydrazones 4. Treatment of 4 with aqueous satu-
rated solution of sodium carbonate at room temperature pro-
vided the new cycloalkenyl-1-diazenes 5aeh in good yields
(Scheme 2, Table 1).21
N-1-Phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxamide 5i
was prepared by reaction at room temperature of 2-chloro-
cyclohexanone 1f with 4-phenylsemicarbazide 2c affording
the relevant halogenated hydrazone 3i that was then treated
at room temperature with sodium hydroxide (1%) (Scheme
2, Table 1).

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3839
N
O
R3
O
R3
R2O
O
S
S
S
H
OR2
N
n
MeOH, r.t.
N
n
R3
NH2
+
R1
NH
N
CONH2
n
H
R1
N
N
R1
N
8
CONH2
CONH2
6a-i
7
5a,c,f-h
n=1,2,3,4
59-97%
R2O
O
S
O
R1
1) NaH (1 equiv.), EtOH, r.t.
2) Amberlyst 15H
n
S
N
n
R3
R1
R3
H2NOC
N
N
for 9c-h,j,q-s
n=1,2,4
N
HN
H
HN CONH2
9a-t
10
Amberlyst 15H
for 9g,s
- CONH2
44-63%
CH3COCH3-H2O
n=2,4
EtO
O
S
EtO
O
S
O
n
R3
R1
H N
R3
O
S
n
n
R1
R3
N
R1
+
O
N
O
NH
12a,b
H
13a,b
11a-j
Scheme 3.
(Scheme 1). By using cycloalkenyl-1-diazenes, no formation of
spirocycloalkyl-thiazolinones 8 by means of the internal nucle-
ophilic attack of the imino nitrogen on the ester function was
observed (Scheme 3). The presence in 9 of both ester and semi-
carbazide groups makes them able to be further modified.
In fact, by treatment of compounds 9ceh,j,qes in ethanol at
room temperature with a stoichiometric amount of sodium
hydride, the internal nucleophilic attack of the semicarbazide
nitrogen at the ester function caused the second ring closure
giving the intermediates 10 (Scheme 3). The spontaneous loss
of the carbamic residue produced the new 6-thia-2,3,8-triaza-tri-
cyclo[3.3.3.01,5]undec-7-en-4-ones 11a,b (n¼1), 10-thia-7,8,12-
triaza-tricyclo[4.3.3.01,6]dodec-11-en-9-ones 11ceg (n¼2) and
12-thia-9,10,14-triaza-tricyclo[6.3.3.01,8]tetradec-13-en-11-ones
11hej (n¼4) (Scheme 3, Table 2). In order to avoid the
formation of decomposition products, it was necessary to
neutralize the reaction mixture by addition of Amberlyst 15H
(2 equiv) immediately after the disappearance of the starting
thiazoles 9.
We have also investigated the reactivity of ethyl 3a-[2-(ami-
nocarbonyl)hydrazino]-2-(4-chlorophenyl)-3a,4,5,6,7,7a-hexa-
hydro-1,3-benzothiazole-7a-carboxylate 9g and of ethyl 3a-
[2-(aminocarbonyl)hydrazino]-2-(4-chlorophenyl)-3a,4,5,6,7,
8,9,9a-octahydrocycloocta[d][1,3]thiazoline-9a-carboxylate 9s
with 4 equiv of Amberlyst 15H in a mixture of acetoneewater
(9:1) at room temperature (Scheme 3, Table 2).23 In these cases
we observed the hydrolytic thiazoline ring-opening with forma-
tion of mixtures of imino- (12a,b) and keto-cycloalkyl (13a,b)
derivatives in different ratios.
1,4-conjugateaddition(Michael-type) of thioureastothe hetero-
diene system of diazenes by a sulfur nucleophilic attack afford-
ing the hydrazone intermediates 15. The further cyclization
process occurred by regioselective internal nucleophilic attack
of the second NH group of thioureas at the ester function giv-
ing 2-imino-4-oxo-1-thia-3-azaspiro[4.4]non-6-ylidenes 16ae
d (n¼1), 2-imino-4-oxo-1-thia-3-azaspiro[4.5]dec-6-ylidenes
16een (n¼2), 2-imino-4-oxo-1-thia-3-azaspiro[4.6]undec-6-
ylidenes 16oeq (n¼3) and 2-imino-4-oxo-1-thia-3-azaspir-
o[4.7]dodec-6-ylidenes 16ret (n¼4) in very good yields
(Scheme 4, Table 3). It has been reported that molecules with
structures similar to 16 exhibit antipsychotic activity.24 The
peculiar regioselectivity observed in the ring closure process
of these reactions could depend on the different nucleophilicity
of thioamides and thioureas together with the diverse nucleo-
philic affinity of ester and hydrazone groups. Also the typical
strain of cyclic azadienes compared with that of open-chain
ones could play an important role.
In the case of the reaction of thiourea 14a or N,N0-dialkylthio-
ureas 14b,c on cycloalkenyl-1-diazenes 5aeh we observed the
same regioselectivity of the second internal nucleophilic attack
as for 1,2-diaza-1,3-butadienes I with the same thiourea deriva-
tives IV (Scheme 1).18 However, thiourea derivatives added to
1,2-diaza-1,3-butadienes with a 2:1 molar ratio thus giving
5,5-disubstituted 3-alkyl-2-(alkylimino)-thiazolidin-4-ones VI.
This can be related to the presence of the strongly acidic
hydrogen on the carbon in a-position with respect to the sulfur
and to the ester group of the thiazolinone V, which makes
possible a further addition on another 1,2-diaza-1,3-butadiene
molecule even in neutral conditions (Scheme 1). Cycloal-
kenyl-1-diazenes 5 lack the above hydrogen and this makes
possible the direct isolation of the spirocycloalkyl-thiazolinone
16 without the formation of further products of reaction.
The reaction of thiourea 14a, N,N0-dimethylthiourea 14b and
N,N0-diethylthiourea 14c on the same cycloalkenyl-1-diazenes
5aeh in methanol at room temperature was parallelly investi-
gated (Scheme 4). The reaction proceeds by means of the

3840
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
Table 2
Yields of cycloalkyl[d][1,3]thiazolines 9aet, thia-triaza-tricyclo derivatives 11aej, iminocycloalkyl derivatives 12a,b and keto-cycloalkyl derivatives 13a,b
5
n
R1
6
R3
9
Yielda (%)
11
Yieldb (%)
12
Yieldc (%)
13
Yieldc (%)
5a
1
H
6a
9a
68
5a
5a
5a
1
1
1
H
H
H
6b
6c
6d
9b
9c
9d
59
91
86
N
11a
11b
54
44
OCH3
CF3
5c
5c
2
2
H
H
6a
6c
9e
9f
93
97
11c
11d
63
56
OCH3
Cl
5c
2
H
6e
9g
64
11e
11f
59
63
12a
67
13a
12
F
5c
5c
2
2
H
H
6f
9h
9i
96
92
F
6g
S
5f
5f
2
2
Me
Me
6a
6e
9j
92
69
11g
62
9k
Cl
N
5f
2
Me
6h
9l
84
CH3
S
5f
2
3
3
Me
H
6i
9m
9n
9o
77
72
82
N
5g
5g
6a
6e
H
Cl
F
5g
5h
3
4
H
H
6f
9p
9q
76
81
F
6a
11h
43
5h
5h
4
4
H
H
6c
6e
9r
9s
82
78
11i
11j
36
45
OCH3
Cl
12b
8
13b
58
F
5h
4
H
6f
9t
83
F
a
b
c
Yields of the pure isolated products 9aet based on the cycloalkenyl-1-diazenes 5a,c,feh.
Yields of the pure isolated products 11aej based on the thiazolines 9ceh,j,qes.
Yields of the pure isolated products 12a,b and 13a,b based on the thiazolines 9g,s.
In order to obtain the corresponding ketone derivatives, we
Surprisingly enough, we achieved the 2-imino-5-(u-carb-
oxyalkyl)-4-thiazolidinone compounds 18aef from 4-oxo-1-
thia-3-azaspiro[4.4]non-6-ylidenes 16b,c (n¼1) or 4-oxo-1-
thia-3-azaspiro[4.5]dec-6-ylidenes 16eeh,l,n (n¼2). Only
from 16g it was possible to isolate the ketone 17a by flash
chromatography.
To obtain the corresponding carboxylic acids 18gei
(n¼3,4) the reaction mixture was refluxed for 3e4 h in the
presence of Amberlyst 15H (Scheme 4, Table 3). It has been
reported that molecules similar to 18 exhibit antitubercular
have also investigated the hydrolysis of the hydrazono moiety
of compounds 16b,c,eeh,l,nep,s by treatment with 4 equiv of
Amberlyst 15H in a mixture of acetoneewater (9:1) at room
temperature (Scheme 4, Table 3).23
Only the treatment of 4-oxo-1-thia-3-azaspiro[4.6]undec-6-
ylidenes 16o,p (n¼3) or of 4-oxo-1-thia-3-azaspiro[4.7]dodec-
6-ylidene 16s (n¼4) led to the formation of the stable 1-thia-
3-azaspiro[4.6]undecan-4,6-diones 17b,c or of 1-thia-3-aza-
spiro[4.7]dodecan-4,6-dione 17d, respectively.

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3841
Figure 1. Crystal structure of compound 9k. Ellipsoids enclose 50% probability.
activity.25 Concerning the formation of 18, they can be derived
from the preliminary hydrolysis of the semicarbazono moiety
of 16 to give rise to the ketones 17, which by a retro-Claisen
reaction occurring with a ring-opening process afford 2-imino-
5-(u-carboxyalkyl)-4-thiazolidinone derivatives 18aei. Their
structure, proposed on the basis of spectrometric (1H and
13C NMR as well as MS) data, was definitively confirmed
by X-ray diffraction determination on 18d (Fig. 2).26
Lastly, we have also investigated the reactivity of two cy-
clic thioureas (five-member ring: imidazolidine-2-thione 19a;
or six-member ring: tetrahydropyrimidine-2-thione 19b) in
methanol at room temperature with cycloalkenyl-1-diazenes
5a,c,g,h: the new 50,60-dihydro-2H-spiro[cycloalkyl-1,20-imi-
dazo[2,1-b][1,3]thiazole]-2,30-dione 2-semicarbazones 21a,c,f
Table 3
Yields of spirocycloalkyl-thiazolinones 16aet, ketones 17aed and 2-imino-
5(u-carboxyalkyl)-4-thiazolidinones 18aei
H
R4
H
O
5
n R1 R2 R3
14 R4 16 Yielda 17 Yieldb 18 Yieldb Yieldc
N
N
R4
R4
OR2
N
(%)
(%)
(%)
(%)
O
HN
S
14a-c
R2O
R1
n
R4
5a 1 H Et NH2 14a H 16a 96
5a 1 H Et NH2 14b Me 16b 87
5a 1 H Et NH2 14c Et 16c 83
5b 1 H Et Ot-Bu 14a H 16d 78
5c 2 H Et NH2 14a H 16e 79
5c 2 H Et NH2 14b Me 16f 82
5c 2 H Et NH2 14c Et 16g 83
5d 2 H Et Ot-Bu 14b Me 16h 76
5e 2 H Et NHPh 14a H 16i 85
5e 2 H Et NHPh 14b Me 16j 92
5e 2 H Et NHPh 14c Et 16k 81
5f 2 Me Et NH2 14a H 16l 89
5f 2 Me Et NH2 14b Me 16m 76
5f 2 Me Et NH2 14c Et 16n 79
5g 3 H Me NH2 14a H 16o 85
5g 3 H Me NH2 14b Me 16p 79
5g 3 H Me NH2 14c Et 16q 84
5h 4 H Et NH2 14a H 16r 89
5h 4 H Et NH2 14b Me 16s 92
5h 4 H Et NH2 14c Et 16t 94
a
R3
N
S
N
R1
N
n
18a 54
18b 61
MeOH, r.t.
H
N
R3
O
5a-h n=1,2,3,4
O
18c 52
18d 49
18e 48
18d 61
15
76-96%
R4
17a
6
R4
N
N R4
Amberlyst 15H
CH3COCH3-H2O
N
O
N R4
H
O
S
S
n
n
18f 52
R3
for 16b,c,e-h,l,n-p,s
N
R1
O
6-73%
R1
N
O
18g 45
18h 12
17a-d
16a-t
17b 69
17c 65
41
40
18i
8
8-61% based on 16
36-41% based on 17
R4
17d 73
18j 11
36
N
O
N
R4
R1
S
Yields of the pure isolated products 16aet based on the cycloalkenyl-1-
diazenes 5aeh.
O
n
b
Yields of the pure isolated 17aed and 18aei based on the spiro
compounds 16.
HO
18a-i
n=1,2,3,4
c
Yields of the pure isolated products 18gei based on the compounds
Scheme 4.
17bed.

3842
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
Under the same experimental conditions, the cyclic thio-
urea tetrahydropyrimidine-2-thione 19b reacted with the
N1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide 5i, but
the reaction stopped with the formation of 2-(1,4,5,6-tetrahy-
dropyrimidin-2-ylthio)cyclohexan-1-one N-phenylsemicarb-
azone 20a. As a matter of fact the absence of the ester group
on the terminal carbon of the heterodiene system prevents the
formation of the thiazolinone system (Scheme 5, Table 4). On
the other hand, the treatment of 5i with 14b,c gave the usual
a-thiohydrazone 1,4-adduct intermediates 22, which by further
internal nucleophilic attack of the NH of the thioureic group
at the hydrazono double bond determines the closure to the
hexahydro-1,3-benzothiazol-3a(4H)-yl-N-phenylhydrazinecarb-
oxamides 23a,b in good yields (Scheme 5, Table 4). The fur-
ther cyclization as for compounds 22 does not proceed in the
case of 20a probably because of the three fused strained rings.
Figure 2. Ortep drawing of 18d. Ellipsoids of non-hydrogen atoms enclose
50% probability.
(m¼1) or the 60,70-dihydro-2H,50H-spiro[cycloalkyl-1,20-
[1,3]thiazolo[3,2-a]pyrimidine]-2,30-dione 2-semicarbazones
21b,d,e,g (m¼2) were obtained in good yields (Scheme 5,
Table 4). Interestingly, compounds 21 represent the spiro-tri-
cyclic counterpart of the relevant spiro-bicyclic 16 previously
obtained (Scheme 4).
3. Conclusion
The present investigation has evidenced a different behaviour
in the reactions of thioamides and thioureas on 1,2-diaza-1,3-bu-
tadienes (I) or cycloalkyl-1-diazenes (5) and demonstrates that
the use of these cyclic azoalkenes provides straightforward ac-
cess to new classes of interesting heterocycles. As a matter of
fact in the whole the syntheses realized indicate that 5 can react
with different sulfur activated nucleophiles showing an interest-
ing variegate reactivity: (1) with thioamides the bicyclic thiazo-
lines 9 and the tricyclic pyrazolinones 11 can be obtained; (2)
with open-chain thioureas 14 the spirothiazolines 16 and 17 or
the bicyclothiazolines 23 can be synthesized; (3) with cyclic
thioureas 19 (containing a five- or a six-member ring) the tricy-
clic 21 can be obtained. These one-pot synthetic methodologies
proceed under very mild reaction conditions using easily avail-
able starting materials and provide interesting new products in
high yields without complicated work-up procedures. In partic-
ular, the reactions of thioureas with cycloalkyl-1-diazenes fur-
nish crude products (16, 17, 21) at a high purity degree by
direct precipitation from the reaction mixture. Moreover, the
acidic hydrolysis with ring-opening of 17 furnishes the acids
18 with a core structure similar to that of some antitubercular
drugs. In conclusion, we described the syntheses of different
S
m
NH
R1
N
R1
HN NH
n
m
R2
S
N
19a,bm=1,2
N
n
MeOH, r.t.
76%
O
N
HN
5a,c,g-i n=1,2,3,4
O
20a n=2, m=2,
R2
R1=H, R2=NHPh
H
R4
H
N
N
R4
MeOH, r.t.
R1=COOMe, COOEt
74-94%
S
14b,c
m
N
N
O
R4
R4
S
N
n
H
N
N
R2
NH
R1
S
21a-g n=1,2,3,4, m=1,2
O
n
R2=NH2
N
HN
R1
O
S
N
R4
n
R2
23a,b n=2, R1=H
R2=NHPh, R4=Me, Et
R4
N
HN
O
22
NH
R2
Scheme 5.
Table 4
Yields of 2-(1,4,5,6-tetrahydropyrimidin-2-ylthio)cyclohexan-1-one N-phenylsemicarbazone 20a, spiro-cycloalkyl-1,20-imidazo[2,1-b][1,3]thiazoles 21a,c,f, spiro-
cycloalkyl-1,20-[1,3]thiazolo[3,2-a]pyrimidines 21b,d,e,g and hexahydro-1,3-benzothiazoles 23a,b
5
n
R1
R2
14
R4
19
m
20
Yielda (%)
21
Yielda (%)
23
Yielda (%)
5a
5a
5c
5c
5g
5h
5h
5i
1
1
2
2
3
4
4
2
2
2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
H
NH2
NH2
19a
19b
19a
19b
19b
19a
19b
19b
1
2
1
2
2
1
2
2
21a
21b
21c
21d
21e
21f
85
88
76
79
74
88
94
NH2
NH2
NH2
NH2
NH2
21g
NHPh
NHPh
NHPh
20a
76
5i
H
14a
14b
Me
Et
23a
23b
85
88
5i
H
a
Yields of the pure isolated products 20a, 21aeg and 23a,b based on cycloalkenyl-1-diazenes 5a,b,gei.

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3843
new classes of polyheterocyclics of interest as targets in organic,
biological, medicinal and agricultural chemistry: all the exam-
ined syntheses usually occur with excellent yields (82e97%).
reaction was allowed to stand under magnetic stirring at room
temperature (4 h) until the disappearance of the reagents (mon-
itored by TLC chromatography). The reaction solvent was then
evaporated under reduced pressure and the products 3aeh were
crystallized by adding ethyl acetateecyclohexane to the crude.
To a magnetically stirred solution of hydrazones 3aeh in
dichloromethane (150 mL), N-bromosuccinimide (1.0 equiv)
was added portion-wise at room temperature obtaining a-bro-
mohydrazones 4 that were treated with aqueous saturated solu-
tion of sodium carbonate (20 mLꢂ3). Then, the mixture was
dried on sodium sulfate. Dichloromethanewas evaporatedunder
reduced pressure and the final cycloalkenyl-1-diazenes 5aeh
were purified by chromatography on silica gel column (elution
mixtures: ethyl acetateecyclohexane). In the synthesis of
N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide 5i,
4-phenylsemicarbazide 2c (1.0 mmol) was added at room tem-
perature to solution of 2-chloro-cyclohexanone 1f (1.0 mmol)
in tetrahydrofuran (25 mL). The reaction was allowed to stand
under magnetic stirring at room temperature (14.0 h) until the
disappearance of the reagents (monitored by TLC chromatogra-
phy). The reaction solvent was then evaporated under reduced
pressure, the crude was dissolved in dichloromethane (80 mL)
and treated with an aqueous solution of sodium hydroxide
(1%, 20 mLꢂ3). Dichloromethane was evaporated under
reduced pressure and the final product 5i was crystallized
from diethyl etherelight petroleum ether (at 40e60 ꢀC).
4. Experimental
4.1. General experimental section
Ethyl 2-oxocyclopentanecarboxylate, ethyl 2-oxocyclohexa-
necarboxylate, ethyl 4-methyl-2-oxocyclohexanecarboxylate,
methyl 2-oxocycloeptanecarboxylate, ethyl 2-oxocyclooctane-
carboxylate, 2-chlorocycloesanone, semicarbazide hydro-
chloride, 4-phenylsemicarbazide, tert-butyl carbazate,
N-bromosuccinimide, thiobenzamide, thionicotinamide, 4-
methoxythiobenzamide, 4-(trifluoromethyl)thiobenzamide,
4-chloro-thiobenzamide, 2,4-difluorothiobenzamide, thio-
phene-2-thiocarboxyamide, 2-methylthiazole-4-thiocarboxy-
amide, thioisonicotinamide, sodium hydride, Amberlyst 15H,
thiourea, N,N0-dimethylthiourea, N,N0-diethylthiourea, imid-
azolidine-2-thione, tetrahydropyrimidine-2-thione were com-
mercial materials and were used without further purification.
Solvents were purchased and used without further purification
with the exception of THF, which was distilled over sodium hy-
droxide. Melting points were determined in open capillary tubes
and are uncorrected. FTIR spectra were obtained as Nujol mulls.
Mass spectra (MS) were carried out by electron impact (EI) at an
1
ionizing voltage of 70 eV. H (400 MHz) and 13C (100 MHz)
spectra were recorded in CDCl3 or in DMSO-d6, as specified
below. Chemical shifts (dH) are reported in parts per million
(ppm), relative to TMS as internal standard. All coupling
constant (J) values are given in hertz. Chemical shifts (dC) are
reported in parts per million (ppm), relative to CDCl3 or
DMSO-d6, as internal standard in a broad band decoupled
mode; the multiplicities were obtained using 135ꢀ and 90ꢀ
DEPT experiments to aid in assignment (q¼methyl,
t¼methylene, d¼methine, s¼quaternary). The abbreviations
used are as follows: s, singlet; d, doublet; dd, double-doublet;
t, triplet; q, quartet; qui, quintet; oc, octet; m, multiplet; br,
broad; cy, cycloalkylic; alk, alkyl; Ar, aromatic. All the NH
and NH2 exchanged with D2O. Precoated silica gel plates
0.25 mm were employed for analytical thin layer chromatogra-
phy and silica gel 35e70 mm for column chromatography. All
new compounds showed satisfactory elemental analysis (C
ꢁ0.35; H ꢁ0.30; N ꢁ0.30). The nomenclature was generated
using ACD/IUPAC Name (version 3.50, 5Apr. 1998), Advanced
Chemistry Development Inc., Toronto, ON (Canada).
4.2.1. Ethyl 2-[2-(aminocarbonyl)-1-diazenyl]-1-cyclo-
pentene-1-carboxylate (5a)
Red powder, mp 106e108 ꢀC; IR (Nujol) nmax 3402, 3237,
1
1718, 1694 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.28 (t, 3H,
3
3J¼7.2 Hz, OCH2CH3), 2.02 (qui, 2H, J¼7.2 Hz, cy), 2.67e
2.72 (m, 2H, cy), 2.90e2.95 (m, 2H, cy), 4.26 (q, 2H,
3J¼7.2 Hz, OCH2CH3), 6.46 (br s, 2H, NH2); 13C NMR
(100 MHz, CDCl3) d 14.0 (q), 20.1 (t), 29.5 (t), 34.7 (t),
61.2 (t), 145.6 (s), 159.0 (s), 162.4 (s), 164.2 (s); MS (EI)
m/z (%) 213 (5) [Mþþ2], 211 (4) [Mþ], 167 (46), 140 (36),
122 (100). Anal. Calcd for C9H13N3O3: C, 51.18; H, 6.20;
N, 19.89. Found: C, 51.10; H, 6.13; N, 19.96.
4.2.2. tert-Butyl 2-[2-(ethoxycarbonyl)-1-cyclopentenyl]-1-
diazene-1-carboxylate (5b)
Red oil; IR (Nujol) nmax 3376, 3200, 1717, 1703 cmꢃ1; H
1
NMR (400 MHz, CDCl3) d 1.30 (t, 3H, 3J¼7.2 Hz, OCH2CH3),
3
1.60 (s, 9H, C(CH3)3), 2.01 (qui, 2H, J¼7.8 Hz, cy), 2.63e
2.69 (m, 2H, cy), 2.90e2.97 (m, 2H, cy), 4.29 (q, 2H,
3J¼7.2 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3) d 14.0
(q), 20.2 (t), 27.7 (q), 29.3 (t), 34.7 (t), 61.1 (t), 84.8 (s),
144.7 (s), 159.3 (s), 161.2 (s), 164.6 (s); MS (EI) m/z (%) 270
(6) [Mþþ2], 268 (4) [Mþ], 211 (13), 195 (45), 168 (100),
136 (17), 122 (36). Anal. Calcd for C13H20N2O4: C, 58.19; H,
7.51; N, 10.44. Found: C, 58.24; H, 7.53; N, 10.36.
4.2. General procedure for the synthesis of cycloalkenyl-1-
diazenes 5aei
Semicarbazidehydrochloride2a(1.0 mmol)ortert-butylcarb-
azate 2b (1.0 mmol) or 4-phenylsemicarbazide 2c (1.0 mmol)
was added at room temperature to a magnetically stirred solution
of cyclic b-dicarbonyl compounds 1aee (1.0 mmol) in methanol
(30 mL) in the case of 2a, or in tetrahydrofuran (30 mL) in the
cases of 2b,c. The semicarbazide hydrochloride 2a was pre-
treated with an equimolecular amount of sodium acetate. The
4.2.3. Ethyl 2-[2-(aminocarbonyl)-1-diazenyl]-1-cyclo-
hexene-1-carboxylate (5c)
Red powder, mp 110e112 ꢀC; IR (Nujol) nmax 3358, 3220,
1
1721, 1695 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.32 (t, 3H,

3844
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3J¼7.2 Hz, OCH2CH3), 1.67e1.80 (m, 4H, cy), 2.36e2.39
(m, 2H, cy), 1.77e1.88 (m, 4H, cy), 2.63e2.72 (m, 4H, cy),
3.82 (s, 3H, OCH3), 5.40 and 6.10 (2br s, 2H, NH2); 13C
NMR (100 MHz, CDCl3) d 13.4 (t), 24.3 (t), 26.0 (t), 31.2
(t), 31.3 (t), 52.3 (q), 152.9 (s), 157.2 (s), 161.9 (s), 169.9
(s); MS (EI) m/z (%) 227 (2) [Mþþ2], 225 (4) [Mþ], 195
(2), 182 (7), 168 (8), 154 (100), 139 (38), 122 (100), 109
(81). Anal. Calcd for C10H15N3O3: C, 53.32; H, 6.71; N,
18.66. Found: C, 53.26; H, 6.69; N, 18.72.
3
(m, 2H, cy), 2.66e2.69 (m, 2H, cy), 4.30 (q, 2H, J¼7.2 Hz,
OCH2CH3), 5.37 and 6.14 (2br s, 2H, NH2); 13C NMR
(100 MHz, CDCl3) d 14.2 (q), 20.9 (t), 21.2 (t), 21.7 (t),
28.0 (t), 61.4 (t), 148.0 (s), 151.5 (s), 162.5 (s), 168.6 (s);
MS (EI) m/z (%) 225 (14) [Mþ], 208 (2), 197 (5), 154 (37),
137 (71), 125 (100), 109 (100). Anal. Calcd for
C10H15N3O3: C, 53.32; H, 6.71; N, 18.66. Found: C, 53.42;
H, 6.67; N, 18.59.
4.2.8. Ethyl 2-[2-(aminocarbonyl)-1-diazenyl]-1-cyclo-
octene-1-carboxylate (5h)
4.2.4. tert-Butyl 2-[2-(ethoxycarbonyl)-1-cyclohexenyl]-1-
diazene-1-carboxylate (5d)
Red powder, mp 72e74 ꢀC; IR (Nujol) nmax 3385, 3154,
1
Red oil; IR (Nujol) nmax 3407, 3196, 1734, 1689 cmꢃ1; H
1721, 1659 cmꢃ1
;
1H NMR (400 MHz, CDCl3) d 1.13 (t,
NMR (400 MHz, CDCl3)
d
1.28 (t, 3H, 3J¼7.2 Hz,
3
3H, J¼7.2 Hz, OCH2CH3), 1.25e1.41 (m, 6H, cy), 1.67e
OCH2CH3), 1.55 (s, 9H, C(CH3)3), 1.68e1.74 (m, 4H, cy),
2.18e2.27 (m, 2H, cy), 2.57e2.63 (m, 2H, cy), 4.27 (q, 2H,
3J¼7.2 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3) d 14.1
(q), 21.0 (t), 21.2 (t), 27.6 (q), 38.7 (t), 40.4 (t), 62.7 (t),
84.2 (s), 147.2 (s), 151.3 (s), 161.3 (s), 169.0 (s); MS (EI)
m/z (%) 284 (3) [Mþþ2], 282 (1) [Mþ], 225 (21), 209 (36),
180 (100), 153 (42), 136 (79). Anal. Calcd for C14H22N2O4:
C, 59.56; H, 7.85; N, 9.92. Found: C, 59.43; H, 7.81; N, 9.96.
1.73 (m, 2H, cy), 2.43e2.48 (m, 2H, cy), 2.52e2.60 (m, 2H,
3
cy), 4.13 (q, 2H, J¼7.2 Hz, OCH2CH3), 6.21 and 6.67 (2br
s, 2H, NH2); 13C NMR (100 MHz, CDCl3) d 13.9 (q), 21.7
(t), 25.8 (t), 25.9 (t), 27.6 (t), 29.6 (t), 29.9 (t), 60.9 (t),
150.4 (s), 153.6 (s), 162.7 (s), 168.9 (s); MS (EI) m/z (%)
254 (3) [Mþþ1], 211 (5), 182 (33), 165 (100), 153 (100),
135 (92), 107 (100). Anal. Calcd for C12H19N3O3: C, 56.90;
H, 7.56; N, 16.59. Found: C, 56.92; H, 7.63; N, 16.54.
4.2.5. Ethyl 2-[2-(anilinocarbonyl)-1-diazenyl]-1-cyclo-
hexene-1-carboxylate (5e)
4.2.9. N1-Phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxy-
amide (5i)
Red powder, mp 90e92 ꢀC with decomposition; IR (Nujol)
Red powder, mp 86e88 ꢀC; IR (Nujol) nmax 3257, 3165,
nmax 3365, 3172, 1718, 1674 cmꢃ1 1H NMR (400 MHz,
;
1
1704, 1679 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.68e1.78
CDCl3) d 1.33 (t, 3H, 3J¼7.2 Hz, OCH2CH3), 1.74e1.79
(m, 4H, cy), 2.30e2.41 (m, 2H, cy), 2.46e2.55 (m, 2H, cy),
7.16 (t, 1H, 3J¼7.2 Hz, Ar), 7.28e7.40 (m, 3H, Ar and
(m, 4H, cy), 2.35e2.39 (m, 2H, cy), 2.67e2.71 (m, 2H, cy),
3
3
4.32 (q, 2H, J¼7.2 Hz, OCH2CH3), 7.14 (t, 1H, J¼7.2 Hz,
Ar), 7.35 (t, 2H, 3J¼8.4 Hz, Ar), 7.62 (d, 2H, 3J¼8.4 Hz,
Ar), 8.31 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 14.2 (q), 20.9 (t), 21.2 (t), 21.9 (t), 28.1 (t), 61.5 (t), 119.4
(d), 124.7 (d), 129.1 (d), 136.6 (s), 148.1 (s), 151.5 (s), 157.3
(s), 168.4 (s); MS (EI) m/z (%) 303 (3) [Mþþ2], 301 (11)
[Mþ], 272 (17), 256 (37), 228 (100), 209 (46), 180 (17), 165
(15), 109 (64). Anal. Calcd for C16H19N3O3: C, 63.77; H,
6.35; N, 13.94. Found: C, 63.65; H, 6.27; N, 13.99.
3
C]CH), 7.70 (d, 2H, J¼8.4 Hz, Ar), 8.46 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 21.4 (t), 21.7 (t), 22.4 (t),
27.1 (t), 119.4 (d), 124.6 (d), 129.0 (d), 137.0 (s), 151.5 (d),
155.5 (s), 157.8 (s); MS (EI) m/z (%) 229 (18) [Mþ],
152 (73), 137 (100), 109 (100). Anal. Calcd for C13H15N3O:
C, 68.10; H, 6.59; N, 18.33. Found: C, 68.22; H, 6.54; N,
18.42.
4.3. General procedure for the synthesis of tetrahydro-
cyclopenta[d][1,3]thiazolines 9aed, hexahydro-1,3-
benzothiazolines 9eem, hexahydro-cyclohepta[d]-
[1,3]thiazolines 9nep and octahydrocycloocta[d]-
[1,3]thiazolines 9qet
4.2.6. Ethyl 2-[2-(aminocarbonyl)-1-diazenyl]-4-methyl-1-
cyclohexene-1-carboxylate (5f)
Red powder, mp 72e74 ꢀC; IR (Nujol) nmax 3399, 3180,
1729, 1686 cmꢃ1
;
1H NMR (400 MHz, CDCl3) d 1.03 (d,
3
3H, 3J¼6.0 Hz, CHCH3), 1.31 (t, 3H, J¼7.2 Hz, OCH2CH3),
1.34e1.42 (m, 1H, cy), 1.76e1.85 (m, 3H, cy), 2.54e2.74 (m,
Cycloalkenyl-1-diazenes 5a,c,feh (1.0 mmol) were added
at room temperature to a magnetically stirred solution of
aryl thioamides 6aei (1.0 mmol) in methanol (10 mL). The re-
action was allowed to stand under magnetic stirring at room
temperature (0.5e1.5 h) until the disappearance of the re-
agents (monitored by TLC chromatography). The compounds
9cee,g,k,l crystallized directly from the reaction medium and
were collected as pure products by filtration. In the other
cases, the reaction solvent was evaporated under reduced pres-
sure and the final cycloalkyl[d][1,3]thiazolines 9a,b,hej,met
were purified by chromatography on silica gel column (elution
mixtures: ethyl acetateecyclohexane) and crystallized from
ethyl acetateecyclohexane.
3
3H, cy), 4.27 (q, 2H, J¼7.2 Hz, OCH2CH3), 6.12 and 6.17
(2br s, 2H, NH2); 13C NMR (100 MHz, CDCl3) d 14.2 (q),
21.2 (t), 27.5 (d), 28.0 (t), 29.3 (t), 29.8 (t), 61.4 (t), 146.7
(s), 151.2 (s), 162.4 (s), 168.6 (s); MS (EI) m/z (%) 239 (4)
[Mþ], 224 (4), 208 (1), 168 (27), 151 (45), 139 (92), 123
(100), 111 (52). Anal. Calcd for C11H17N3O3: C, 55.22; H,
7.16; N, 17.56. Found: C, 55.31; H, 7.25; N, 17.50.
4.2.7. Methyl 2-[2-(aminocarbonyl)-1-diazenyl]-1-cyclo-
heptene-1-carboxylate (5g)
Red powder, mp 86e89 ꢀC; IR (Nujol) nmax 3365, 3218,
1
1726, 1695 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.54e1.67

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3845
4.3.1. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-phenyl-
4.3.4. Ethyl3a-[2-(aminocarbonyl)hydrazino]-2-[4-(trifluoro-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]thiazoline-6a-
carboxylate (9a)
methyl)phenyl]-4,5,6,6a-tetrahydro-3aH-cyclo-
penta[d][1,3]thiazoline-6a-carboxylate (9d)
Colourless powder, mp 141e143 ꢀC with decomposition;
IR (Nujol) nmax 3474, 3375, 3216, 3176, 1708, 1684,
Colourless powder, mp 146e148 ꢀC; IR (Nujol) nmax 3472,
3391, 3243, 3114, 1714, 1700, 1564 cmꢃ1
;
1H NMR
1555 cmꢃ1
;
1H NMR (400 MHz, CDCl3) d 1.27 (t, 3H,
(400 MHz, DMSO-d6) d 1.23 (t, 3H, J¼7.2 Hz, OCH2CH3),
3
3J¼7.2 Hz, OCH2CH3), 1.73e1.85 (m, 2H, cy), 2.09e2.28
1.54e1.64 (m, 1H, cy), 1.78e1.85 (m, 1H, cy), 2.00e2.19
3
3
(m, 3H, cy), 2.73e2.81 (m, 1H, cy), 4.24 (q, 2H, J¼7.2 Hz,
(m, 3H, cy), 2.71e2.87 (m, 1H, cy), 4.18 (q, 2H, J¼7.2 Hz,
OCH2CH3), 4.91 (br s, 1H, NH), 5.67 (br s, 2H, NH2), 6.60
(s, 1H, NH), 7.46 (t, 2H, 3J¼7.6 Hz, Ar), 7.52 (t, 1H,
3J¼6.4 Hz, Ar), 7.78 (d, 2H, 3J¼7.6 Hz, Ar); 13C NMR
(100 MHz, CDCl3) d 14.0 (q), 22.8 (t), 37.6 (t), 40.0 (t),
62.5 (t), 71.4 (s), 110.8 (s), 128.4 (d), 128.6 (d), 131.8 (d),
132.1 (s), 160.8 (s), 166.7 (s), 171.1 (s); MS (EI) m/z (%)
348 (8) [Mþ], 319 (42), 303 (67), 275 (100), 275 (64), 259
(43), 231 (100), 203 (86), 183(49), 126 (72). Anal. Calcd for
C16H20N4O3S: C, 55.16; H, 5.79; N, 16.08. Found: C, 55.04;
H, 5.84; N, 16.00.
OCH2CH3), 5.58 (s, 1H, NH), 5.87 (br s, 2H, NH2), 6.89 (s,
1H, NH), 7.87 (d, 2H, 3J¼8.4 Hz, Ar), 8.00 (d, 2H,
3J¼8.4 Hz, Ar); 13C NMR (100 MHz, DMSO-d6) d 13.7 (q),
22.6 (t), 37.0 (t), 40.9 (t), 62.0 (t), 72.5 (s), 111.9 (s), 121.8
1
3
(s, JCF¼271.6 Hz), 125.7 (d, JCF¼3.0 Hz), 128.9 (d), 131.5
2
(s, JCF¼31.9 Hz), 131.8 (s), 160.1 (s), 162.4 (s), 170.6 (s);
MS (EI) m/z (%) 416 (2) [Mþ], 399 (2), 342 (46), 327
(100), 298 (64), 270 (100), 156 (97). Anal. Calcd for
C17H19F3N4O3S: C, 49.03; H, 4.60; N, 13.45. Found: C,
49.09; H, 4.53; N, 13.51.
4.3.2. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(3-pyridyl)-
4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]thiazoline-
6a-carboxylate (9b)
4.3.5. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-phenyl-
3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9e)
Colourless powder, mp 144e146 ꢀC; IR (Nujol) nmax 3476,
Colourless powder, mp 133e135 ꢀC with decomposition;
3354, 3243, 3165, 1735, 1691 cmꢃ1 1H NMR (400 MHz,
;
IR (Nujol) nmax 3473, 3256, 3156, 1732, 1682 cmꢃ1 1H
;
CDCl3) d 1.28 (t, 3H, 3J¼6.8 Hz, OCH2CH3), 1.70e1.87
(m, 2H, cy), 2.11e2.29 (m, 3H, cy), 2.77e2.82 (m, 1H, cy),
4.26 (q, 2H, 3J¼6.8 Hz, OCH2CH3), 4.93 (br s, 1H, NH),
5.62 (br s, 2H, NH2), 6.73 (s, 1H, NH), 7.38 (ddd, 1H,
NMR (400 MHz, CDCl3)
OCH2CH3), 1.40e1.52 (m, 1H, cy), 1.53e1.56 (m, 1H, cy),
1.59e1.66 (m, 2H, cy), 1.90e1.98 (m, 1H, cy), 2.07e2.11
(m, 1H, cy), 2.18e2.26 (m, 2H, cy), 4.17 (q, 2H, J¼6.8 Hz,
d
1.27 (t, 3H, 3J¼6.8 Hz,
3
3
5
3
3J¼7.6 Hz, J¼4.8 Hz, J¼0.4 Hz, Ar), 8.10 (ddd, 1H, J¼
8.0 Hz, 4J¼2.4 Hz, 4J¼2.0 Hz, Ar), 8.70 (dd, 1H,
3J¼4.8 Hz, 4J¼1.6 Hz, Ar), 8.70 (d, 1H, 4J¼1.2 Hz, Ar);
13C NMR (100 MHz, CDCl3) d 14.0 (q), 22.8 (t), 37.6 (t),
40.0 (t), 62.6 (t), 72.0 (s), 111.3 (s), 123.5 (d), 128.4 (d),
135.9 (s), 149.0 (s), 152.0 (s), 160.8 (s), 163.1 (s), 170.9 (s);
MS (EI) m/z (%) 349 (5) [Mþ], 304 (85), 276 (100), 232
(69), 204 (26), 157 (48), 110 (78). Anal. Calcd for
C15H19N5O3S: C, 51.56; H, 5.48; N, 20.04. Found: C, 51.55;
H, 5.51; N, 20.13.
OCH2CH3), 5.18 (br s, 1H, NH), 5.72 (br s, 2H, NH2), 6.56
(br s, 1H, NH), 7.36 (dt, 2H, 3J¼6.8 Hz, 4J¼1.2 Hz, Ar),
7.43 (dt, 1H, 3J¼7.2 Hz, 4J¼1.2 Hz, Ar), 7.76 (dt, 2H,
3J¼7.2 Hz, 4J¼1.2 Hz, Ar); 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 (EI) m/z (%) 362 (1) [Mþ], 317
(2), 288 (65), 273 (67), 244 (42), 216 (46), 170 (100), 141
(53). Anal. Calcd for C17H22N4O3S: C, 56.38; H, 6.12; N,
15.46. Found: C, 56.38; H, 6.12; N, 15.38.
4.3.3. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(4-methoxy-
phenyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]thiazo-
line-6a-carboxylate (9c)
4.3.6. Ethyl3a-[2-(aminocarbonyl)hydrazino]-2-(4-methoxy-
phenyl)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9f)
Colourless powder, mp 148e150 ꢀC; IR (Nujol) nmax
3465, 3286, 1742, 1676, 1686, 1585 cmꢃ1
;
1H NMR
Colourless powder, mp 144e146 ꢀC; IR (Nujol) nmax 3463,
3
(400 MHz, DMSO-d6) d 1.20 (t, 3H, J¼7.2 Hz, OCH2CH3),
1.52e1.63 (m, 1H, cy), 1.77e1.83 (m, 1H, cy), 2.00e2.11
(m, 3H, cy), 2.72e2.80 (m, 1H, cy), 3.82 (s, 3H, OCH3),
3253, 1737, 1694, 1653, 1604 cmꢃ1
;
1H NMR (400 MHz,
3
DMSO-d6) d 1.20 (t, 3H, J¼6.8 Hz, OCH2CH3), 1.30e1.38
(m, 1H, cy), 1.44e1.53 (m, 1H, cy), 1.52e1.68 (m, 2H, cy),
1.71e1.83 (m, 1H, cy), 1.89e2.00 (m, 1H, cy), 2.01e2.13
(m, 1H, cy), 2.29e2.36 (m, 1H, cy), 3.81 (s, 3H, OCH3),
3
4.16 (q, 2H, J¼7.2 Hz, OCH2CH3), 5.43 (s, 1H, NH), 5.86
(br s, 2H, NH2), 6.76 (br s, 1H, NH), 7.02 (d, 2H,
3J¼6.8 Hz, Ar), 7.72 (d, 2H, 3J¼6.8 Hz, Ar); 13C NMR
(100 MHz, DMSO-d6) d 14.5 (q), 23.2 (t), 37.8 (t), 41.3 (t),
56.2 (q), 62.6 (t), 72.7 (s), 112.5 (s), 114.8 (d), 125.4 (s),
130.6 (d), 160.8 (s), 162.7 (s), 163.3 (s), 171.6 (s); MS
(EI) m/z (%) 378 (1) [Mþ], 304 (25), 289 (100), 260
(13), 232 (75), 198 (25), 156 (61). Anal. Calcd for
C17H22N4O4S: C, 53.95; H, 5.86; N, 14.80. Found: C,
53.87; H, 5.94; N, 14.71.
3
4.13 (q, 2H, J¼6.8 Hz, OCH2CH3), 5.41 (s, 1H, NH), 5.83
(br s, 2H, NH2), 6.77 (br s, 1H, NH), 7.01 (d, 2H,
3J¼6.8 Hz, Ar), 7.73 (d, 2H, 3J¼6.8 Hz, Ar); 13C NMR
(100 MHz, DMSO-d6) d 13.8 (q), 20.1 (t), 20.9 (t), 29.6 (t),
35.6 (t), 55.4 (q), 61.5 (t), 68.8 (s), 93.6 (s), 124.0 (d), 125.6
(d), 129.7 (d), 160.2 (s), 162.0 (s), 164.7 (s), 170.4 (s); MS
(EI) m/z (%) 392 (12) [Mþ], 318 (4), 303 (61), 274 (9), 252
(14), 261 (5), 245 (29), 170 (81), 133 (100), 110 (73). Anal.

3846
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
Calcd for C18H24N4O4S: C, 55.09; H, 6.16; N, 14.28. Found:
C, 55.15; H, 6.11; N, 14.16.
(d), 131.3 (d), 136.7 (s), 160.7 (s), 161.0 (s), 170.3 (s); MS
(EI) m/z (%) 368 (1) [Mþ], 323 (22), 294 (81), 279 (46),
250 (42), 237 (11), 220 (100), 204 (100), 193 (21), 165
(100). Anal. Calcd for C15H20N4O3S2: C, 48.90; H, 5.47; N,
15.21. Found: C, 48.78; H, 5.54; N, 15.13.
4.3.7. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(4-chloro-
phenyl)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9g)
Colourless powder, mp 163e165 ꢀC; IR (Nujol) nmax 3473,
4.3.10. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-5-methyl-2-
phenyl-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9j)
Colourless powder, mp 138e140 ꢀC; IR (Nujol) nmax 3484,
3364, 3269, 3148, 1737, 1676 cmꢃ1 1H NMR (400 MHz,
;
3314, 3256, 3156, 1732, 1682 cmꢃ1
DMSO-d6) d 1.18 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.27e1.35
(m, 1H, cy), 1.43e1.53 (m, 1H, cy), 1.55e1.67 (m, 2H, cy),
1.71e1.81 (m, 1H, cy), 1.89e1.98 (m, 1H, cy), 2.07e2.19
;
1H NMR (400 MHz,
3
3
(m, 1H, cy), 2.29e2.38 (m, 1H, cy), 4.14 (q, 2H, J¼7.2 Hz,
CDCl3) d 0.87 (d, 3H, 3J¼6.4 Hz, CHCH3), 1.20 (t, 3H,
3J¼7.2 Hz, OCH2CH3), 1.30e1.38 (m, 1H, cy), 1.41e1.68
(m, 2H, cy), 1.91e2.03 (m, 2H, cy), 2.26e2.34 (m, 1H, cy),
2.40e2.50 (m, 1H, cy), 4.00e4.14 (m, 2H, OCH2CH3), 4.89
(br s, 1H, NH), 5.66 and 5.87 (2br s, 2H, NH2), 6.59 (s, 1H,
OCH2CH3), 5.48 (s, 1H, NH), 5.80 (br s, 2H, NH2), 6.88 (br
s, 1H, NH), 7.53 (d, 2H, 3J¼8.8 Hz, Ar), 7.78 (d, 2H,
3J¼8.8 Hz, Ar); 13C NMR (100 MHz, DMSO-d6) d 13.8 (q),
20.0 (t), 20.9 (t), 29.5 (t), 35.8 (t), 61.7 (t), 69.4 (s), 93.8
(s), 128.8 (d), 129.7 (d), 131.9 (s), 136.5 (s), 160.3 (s),
164.6 (s), 170.2 (s); MS (EI) m/z (%) 324 (12), 322 (37),
309 (5), 307 (14), 278 (12), 252 (14), 250 (43), 205 (100),
189 (6), 167 (21), 137 (82), 111 (87). Anal. Calcd for
C17H21ClN4O3S: C, 51.45; H, 5.33; N, 14.12. Found: C,
51.43; H, 5.37; N, 14.15.
3
NH), 7.30e7.45 (m, 3H, Ar), 7.70 (d, 2H, J¼6.8 Hz, Ar);
13C NMR (100 MHz, CDCl3) d 13.6 (q), 21.2 (q), 26.6 (d),
27.0 (t), 29.2 (t), 37.2 (t), 61.7 (t), 66.4 (s), 95.2 (s), 127.7
(d), 128.4 (d), 131.6 (d), 132.8 (s), 161.1 (s), 162.5 (s),
171.6 (s); MS (EI) m/z (%) 376 (1) [Mþ], 302 (100), 287
(8), 258 (43), 230 (75), 184 (27), 169 (3), 152 (14). Anal.
Calcd for C18H24N4O3S: C, 57.43; H, 6.43; N, 14.88. Found:
C, 57.34; H, 6.49; N, 14.96.
4.3.8. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(2,4-difluoro-
phenyl)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9h)
4.3.11. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(4-chloro-
phenyl)-5-methyl-3a,4,5,6,7,7a-hexahydro-1,3-
benzothiazole-7a-carboxylate (9k)
Colourless powder, mp 119e122 ꢀC; IR (Nujol) nmax 3423,
1
3278, 3169, 1724, 1691 cmꢃ1; H NMR (400 MHz, CDCl3)
d 1.13 (t, 3H, 3J¼7.2 Hz, OCH2CH3), 1.16e1.46 (m, 4H,
Colourless powder, mp 156e158 ꢀC; IR (Nujol) nmax 3477,
cy), 1.51e1.60 (m, 1H, cy), 1.76e2.19 (m, 3H, cy), 4.08 (q,
3254, 1738, 1639, 1612, 1586 cmꢃ1
;
1H NMR (400 MHz,
3
3
2H, J¼7.2 Hz, OCH2CH3), 5.10 (br s, 1H, NH), 5.85 (br s,
CDCl3) d 0.92 (d, 3H, J¼6.4 Hz, CHCH3), 1.06e1.18 (m,
3H, OCH2CH3), 1.24e1.44 (m, 2H, cy), 1.54e1.73 (m, 2H,
cy), 1.93e2.06 (m, 1H, cy), 2.27e2.36 (m, 1H, cy), 2.41e
2.53 (m, 1H, cy), 4.06e4.22 (m, 2H, OCH2CH3), 4.97 (br s,
1H, NH), 5.68 (br s, 2H, NH2), 6.50 (s, 1H, NH), 7.35 (d,
3
4
2H, NH2), 6.74 (dt, 1H, J¼8.8 Hz, J¼2.4 Hz, Ar), 6.76e
6.87 (m, 2H, NH and Ar), 7.83e7.91 (m, 1H, Ar); 13C
NMR (100 MHz, CDCl3) d 13.6 (q), 20.0 (t), 20.6 (t), 28.7
(t), 34.6 (t), 61.7 (t), 67.7 (s), 92.1 (s), 104.1 (d, 2JCF¼25.8 Hz,
2
3
3
3
3JCF¼5.3 Hz), 111.6 (d, JCF¼21.2 Hz), 117.4 (s, JCF
¼
2H, J¼9.2 Hz, Ar), 7.66 (d, 2H, J¼9.2 Hz, Ar); 13C NMR
(100 MHz, CDCl3) d 13.6 (q), 21.3 (q), 26.7 (d), 27.0 (t),
29.2 (t), 37.2 (t), 61.9 (t), 66.4 (s), 95.4 (s), 128.7 (d), 129.0
(d), 131.3 (s), 137.8 (s), 160.9 (s), 161.4 (s), 171.6 (s); MS
(EI) m/z (%) 338 (15), 336 (38), 323 (34), 321 (90), 294
(13), 292 (36), 266 (23), 264 (64), 223 (26), 221 (71), 184
(100), 151 (61). Anal. Calcd for C18H23ClN4O3S: C, 52.61;
H, 5.64; N, 13.63. Found: C, 52.53; H, 5.68; N, 13.71.
4
3
10.7 Hz, JCF¼3.1 Hz), 131.6 (s, JCF¼9.1 Hz), 160.8 (s,
1JCF¼256.5 Hz, 3JCF¼12.1 Hz), 161.0 (s, 3JCF¼4.4 Hz), 161.4
1
3
(s), 164.4 (s, JCF¼253.4 Hz, JCF¼11.3 Hz), 170.2 (s); MS
(EI) m/z (%) 398 (7) [Mþ], 369 (31), 353 (65), 325 (100),
309 (58), 281 (37), 239 (67), 179 (15), 211 (42), 167 (26),
152 (14). Anal. Calcd for C17H20F2N4O3S: C, 51.25; H,
5.06; N, 14.06. Found: C, 51.21; H, 5.11; N, 14.11.
4.3.9. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(2-thienyl)-
3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9i)
4.3.12. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-5-methyl-2-
(2-methyl-1,3-thiazol-4-yl)-3a,4,5,6,7,7a-hexahydro-1,3-
benzothiazole-7a-carboxylate (9l)
Colourless powder, mp 47e49 ꢀC; IR (Nujol) nmax 3458,
Colourless powder, mp 97e99 ꢀC; IR (Nujol) nmax 3458,
3402, 3264, 3136, 1716, 1702, 1587 cmꢃ1
;
1H NMR
3384, 3251, 3134, 1717, 1703, 1625 cmꢃ1
;
1H NMR
(400 MHz, CDCl3) d 1.30 (t, 3H, 3J¼7.2 Hz, OCH2CH3),
(400 MHz, CDCl3) d 0.92 (d, 3H, J¼6.4 Hz, CHCH3), 1.24
(t, 3H, 3J¼6.4 Hz, OCH2CH3), 1.33e1.42 (m, 1H, cy),
1.55e1.71 (m, 2H, cy), 1.84e1.99 (m, 2H, cy), 2.26e2.35
(m, 1H, cy), 2.41e2.51 (m, 1H, cy), 2.73 (s, 3H,
N]CCH3), 4.10e4.20 (m, 2H, OCH2CH3), 4.81 (br s, 1H,
NH), 5.76 (br s, 2H, NH2), 6.36 (br s, 1H, NH), 7.81 (br s,
1H, Ar); 13C NMR (100 MHz, CDCl3) d 13.7 (q), 19.08 (q),
21.3 (q), 26.6 (d), 27.0 (t), 29.2 (t), 37.4 (t), 62.0 (t), 65.4
3
1.44e1.76 (m, 4H, cy), 1.94e2.17 (m, 2H, cy), 2.24e2.38
3
(m, 2H, cy), 4.24 (q, 2H, J¼7.2 Hz, OCH2CH3), 5.08 (br s,
3H, NH2 and NH), 6.13 (br s, 1H, NH), 7.08 (dd, 1H,
3J¼5.2 Hz, 3J¼3.6 Hz, Ar), 7.46 (dd, 1H, 3J¼4.0 Hz,
4J¼1.2 Hz, Ar), 7.51 (dd, 1H, 3J¼5.2 Hz, 4J¼1.2 Hz, Ar);
13C NMR (100 MHz, CDCl3) d 14.0 (q), 20.5 (t), 21.2 (t),
29.1 (t), 35.9 (t), 62.2 (t), 68.8 (s), 93.4 (s), 127.7 (d), 131.1

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3847
(s), 95.2 (s), 120.0 (d), 148.2 (s), 158.7 (s), 160.8 (s), 166.6 (s),
171.7 (s); MS (EI) m/z (%) 396 (1) [Mþꢃ1], 323 (100), 308
(4), 279 (15), 264 (1), 251 (100), 224 (3), 210 (12), 184
(10), 167 (5). Anal. Calcd for C16H23N5O3S2: C, 48.35; H,
5.83; N, 17.62. Found: C, 48.33; H, 5.88; N, 17.57.
(36), 293 (100), 265 (3), 263 (10), 255 (8), 227 (39), 183
(74), 144 (62). Anal. Calcd for C17H21ClN4O3S: C, 51.45;
H, 5.33; N, 14.12. Found: C, 51.38; H, 5.39; N, 14.16.
4.3.16. Methyl 3a-[2-(aminocarbonyl)hydrazino]-2-(2,4-di-
fluorophenyl)-4,5,6,7,8,8a-hexahydro-3aH-cyclohepta-
[d][1,3]thiazoline-8a-carboxylate (9p)
Colourless powder, mp 108e110 ꢀC; IR (Nujol) nmax 3478,
3272, 1734, 1681, 1641, 1598 cmꢃ1 1H NMR (400 MHz,
;
4.3.13. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-5-methyl-2-
(pyridyl)-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazole-7a-
carboxylate (9m)
Colourless powder, mp 112e114 ꢀC; IR (Nujol) nmax 3453,
DMSO-d6) d 1.07e1.15 (m, 1H, cy), 1.25e1.34 (m, 1H, cy),
1.52e1.78 (m, 4H, cy), 1.87e1.97 (m, 1H, cy), 2.01e2.11
(m, 1H, cy), 2.26e2.38 (m, 2H, cy), 3.70 (s, 3H, OCH3),
5.71 (br s, 3H, NH2 and NH), 6.70 (br s, 1H, NH), 7.20 (t,
1
3261, 3143, 1718, 1701 cmꢃ1; H NMR (400 MHz, CDCl3)
d 0.86 (d, 3H, 3J¼6.4 Hz, CHCH3), 1.14e1.21 (m, 3H,
OCH2CH3), 1.32e1.42 (m, 1H, cy), 1.55e1.73 (m, 2H, cy),
1.89e1.99 (m, 2H, cy), 2.26e2.35 (m, 1H, cy), 2.39e2.49
(m, 1H, cy), 4.00e4.16 (m, 2H, OCH2CH3), 5.71 and 5.76
(2br s, 3H, NH2 and NH), 6.58 (s, 1H, NH), 7.54 (d, 2H,
3J¼4.4 Hz, Ar), 8.65 (d, 2H, 3J¼4.4 Hz, Ar); 13C NMR
(100 MHz, CDCl3) d 13.6 (q), 21.2 (q), 26.5 (d), 26.9 (t),
29.2 (t), 37.0 (t), 62.0 (t), 66.7 (s), 95.7 (s), 121.3 (d), 139.8
(d), 150.1 (s), 160.8 (s), 161.1 (s), 171.4 (s); MS (EI) m/z
(%) 377 (4) [Mþ], 348 (19), 332 (28), 304 (100), 287 (17),
260 (39), 231 (56), 210 (11), 183 (23), 152 (4). Anal. Calcd
for C17H23N5O3S: C, 54.10; H, 6.14; N, 18.55. Found: C,
54.03; H, 6.19; N, 18.58.
3
3
1H, J¼7.6 Hz, Ar), 7.40 (t, 1H, J¼7.6 Hz, Ar), 7.96e8.07
(m, 1H, Ar); 13C NMR (100 MHz, DMSO-d6) d 23.0 (t),
23.1 (t), 30.3 (t), 30.9 (t), 39.6 (t), 53.0 (q), 75.6 (s), 98.9
2
2
(s), 104.8 (d, JCF¼26.5 Hz), 112.3 (d, JCF¼22.0 Hz), 117.3
3
3
(s, JCF¼8.3 Hz), 132.4 (d, JCF¼9.8 Hz), 159.0 (s), 160.1
1
3
(s), 160.5 (s, JCF¼254.2 Hz, JCF¼12.9 Hz), 164.1 (s,
1JCF¼251.1 Hz, JCF¼12.1 Hz), 171.4 (s); MS (EI) m/z (%)
3
323 (40), 265 (38), 211 (7), 184 (36), 139 (100). Anal. Calcd
for C17H20F2N4O3S: C, 51.25; H, 5.06; N, 14.06. Found: C,
51.19; H, 5.13; N, 14.12.
4.3.17. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-phenyl-
3a,4,5,6,7,8,9,9a-octahydrocycloocta[d][1,3]thiazoline-9a-
carboxylate (9q)
4.3.14. Methyl 3a-[2-(aminocarbonyl)hydrazino]-2-phenyl-
4,5,6,7,8,8a-hexahydro-3aH-cyclohepta[d][1,3]thi-
azoline-8a-carboxylate (9n)
Colourless powder, mp 148e150 ꢀC; IR (Nujol) nmax 3452,
Colourless powder, mp 149e152 ꢀC; IR (Nujol) nmax 3465,
3333, 3251, 3231, 1729, 1684 cmꢃ1
;
1H NMR (400 MHz,
3
3318, 3262, 3196, 1724, 1678 cmꢃ1
;
1H NMR (400 MHz,
DMSO-d6) d 1.10e1.78 (m, 7H, cy), 1.22 (t, 3H, J¼7.2 Hz,
OCH2CH3), 1.86e1.94 (m, 1H, cy), 2.03e2.12 (m, 1H, cy),
2.41e2.55 (m, 3H, cy), 4.10e4.22 (m, 2H, OCH2CH3), 5.25
(s, 1H, NH), 5.38 (br s, 2H, NH2), 6.66 (br s, 1H, NH), 7.47
DMSO-d6) d 1.03e1.12 (m, 1H, cy), 1.27e1.38 (m, 1H, cy),
1.56e1.73 (m, 4H, cy), 1.91e2.02 (m, 1H, cy), 2.07e2.15
(m, 1H, cy), 2.30e2.42 (m, 2H, cy), 3.72 (s, 3H, OCH3),
5.25 and 5.74 (2br s, 3H, NH2 and NH), 6.66 (s, 1H, NH),
7.45e7.61 (m, 3H, Ar), 7.83 (d, 2H, 3J¼7.6 Hz, Ar); 13C
NMR (100 MHz, DMSO-d6) d 23.0 (t), 23.1 (t), 30.3 (t),
31.0 (t), 39.8 (t), 53.0 (q), 75.8 (s), 100.5 (s), 128.0 (d),
128.7 (d), 131.7 (d), 132.6 (s), 160.2 (s), 164.7 (s), 171.5
(s); MS (EI) m/z (%) 363 (1) [Mþþ1], 287 (21), 270 (1),
254 (3), 229 (16), 224 (3), 184 (16), 152 (40), 123 (43), 103
(100). Anal. Calcd for C17H22N4O3S: C, 56.43; H, 6.12; N,
15.46. Found: C, 56.48; H, 6.03; N, 15.46.
3
3
(t, 2H, J¼7.6 Hz, Ar), 7.54 (t, 1H, J¼7.2 Hz, Ar), 7.82 (d,
2H, J¼7.2 Hz, Ar); 13C NMR (100 MHz, DMSO-d6) d 13.9
3
(q), 21.8 (t), 23.2 (t), 24.9 (t), 25.8 (t), 30.2 (t), 33.6 (t),
61.7 (t), 75.9 (s), 98.7 (s), 128.0 (d), 128.7 (d), 131.7 (d),
132.9 (s), 160.2 (s), 165.3 (s), 170.9 (s); MS (EI) m/z (%)
390 (9) [Mþ], 361 (53), 345 (79), 317 (100), 301 (38), 273
(56), 244 (31), 224 (75), 196 (38), 166 (63). Anal. Calcd for
C19H26N4O3S: C, 58.44; H, 6.71; N, 14.35. Found: C, 58.51;
H, 6.76; N, 14.27.
4.3.15. Methyl3a-[2-(aminocarbonyl)hydrazino]-2-(4-chloro-
phenyl)-4,5,6,7,8,8a-hexahydro-3aH-cyclohepta-
[d][1,3]thiazoline-8a-carboxylate (9o)
4.3.18. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-
(4-methoxyphenyl)-3a,4,5,6,7,8,9,9a-octahydro-
cycloocta[d][1,3]thiazoline-9a-carboxylate (9r)
Colourless powder, mp 164e166 ꢀC; IR (Nujol) nmax 3432,
Colourless powder, mp 139e143 ꢀC; IR (Nujol) nmax 3483,
3347, 3223, 3165, 1738, 1659 cmꢃ1
;
1H NMR (400 MHz,
3268, 3204, 1737, 1678 cmꢃ1; H NMR (400 MHz, DMSO-
1
DMSO-d6) d 1.03e1.14 (m, 1H, cy), 1.30e1.39 (m, 1H, cy),
1.50e1.69 (m, 4H, cy), 1.91e2.02 (m, 1H, cy), 2.09e2.17
(m, 1H, cy), 2.30e2.41 (m, 2H, cy), 3.72 (s, 3H, OCH3),
5.27 and 5.72 (2br s, 3H, NH2 and NH), 6.71 (s, 1H, NH),
7.56 (d, 2H, J¼7.2 Hz, Ar), 7.84 (d, 2H, J¼7.2 Hz, Ar);
13C NMR (100 MHz, DMSO-d6) d 23.8 (t), 31.0 (t), 32.2 (t),
53.7 (q), 76.8 (s), 101.3 (s), 129.4 (d), 130.0 (d), 132.1 (s),
137.1 (s), 161.0 (s), 164.3 (s), 172.1 (s); MS (EI) m/z (%)
397 (2) [Mþþ1], 368 (4), 366 (14), 339 (24), 337 (69), 295
d6) d 1.13e1.24 (m, 1H, cy), 1.28 (t, 3H, 3J¼7.2 Hz,
OCH2CH3), 1.30e1.70 (m, 6H, cy), 1.91e2.02 (m, 1H, cy),
2.10e2.22 (m, 1H, cy), 2.46e2.58 (m, 3H, cy), 3.88 (s, 3H,
OCH3), 4.19e4.27 (m, 2H, OCH2CH3), 5.26 (s, 1H, NH),
5.71 (br s, 2H, NH2), 6.71 (br s, 1H, NH), 7.09 (d, 2H,
3J¼8.8 Hz, Ar), 7.85 (d, 2H, 3J¼8.8 Hz, Ar); 13C NMR
(100 MHz, DMSO-d6) d 14.5 (q), 22.5 (t), 23.9 (t), 25.6 (t),
26.5 (t), 30.3 (t), 34.4 (t), 56.2 (q), 62.4 (t), 76.4 (s), 99.2
(s), 114.7 (d), 126.2 (s), 130.5 (d), 160.9 (s), 162.7 (s),
3
3

3848
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
165.2 (s), 171.7 (s); MS (EI) m/z (%) 420 (4) [Mþ], 397 (14),
375 (57), 347 (100), 331 (47), 303 (25), 271 (81), 177 (58).
Anal. Calcd for C20H28N4O4S: C, 57.12; H, 6.71; N, 13.32.
Found: C, 57.23; H, 6.72; N, 13.21.
(1.0 mmol) was added at room temperature. The reaction easily
took place (0.5e1.0 min) at room temperature (monitored by
TLC chromatography). Then, on the disappearance of 9, 2 equiv
of Amberlyst 15H was added under magnetic stirring to the
crude and the reaction was allowed to stand at room temperature
for 2 min. The mixture was filtered and the solvent was evapo-
rated under reduced pressure. The products 11aej were
obtained pure by chromatography on silica gel column (elution
mixtures: ethyl acetateecyclohexane).
4.3.19. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(4-chloro-
phenyl)-3a,4,5,6,7,8,9,9a-octahydrocycloocta[d][1,3]-
thiazoline-9a-carboxylate (9s)
Colourless powder, mp 160e162 ꢀC with decomposition;
IR (Nujol) nmax 3465, 3395, 3255, 3124, 1725, 1708,
1590 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6) d 1.07e1.16
4.4.1. 7-(4-Methoxyphenyl)-6-thia-2,3,8-triaza-tricyclo-
[3.3.3.01,5]undec-7-en-4-one (11a)
Colourless oil; IR (Nujol) nmax 3426, 3257, 3143,
;
1694 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.81e1.91 (m,
3
(m, 1H, cy), 1.23 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.29e1.74
(m, 6H, cy), 1.86e1.94 (m, 1H, cy), 2.01e2.12 (m, 1H, cy),
2.40e2.51 (m, 3H, cy), 4.10e4.24 (m, 2H, OCH2CH3), 5.27
(s, 1H, NH), 5.72 (br s, 2H, NH2), 6.73 (br s, 1H, NH), 7.54
(d, 2H, 3J¼8.0 Hz, Ar), 7.84 (d, 2H, 3J¼8.0 Hz, Ar); 13C
NMR (100 MHz, DMSO-d6) d 13.8 (q), 21.8 (t), 23.3 (t),
24.9 (t), 25.8 (t), 30.1 (t), 34.6 (t), 61.8 (t), 76.3 (s), 98.8
(s), 128.8 (d), 129.8 (d), 131.7 (s), 136.5 (s), 160.2 (s),
164.2 (s), 170.8 (s); MS (EI) m/z (%) 422 (2) [Mþꢃ2], 276
(3), 274 (10), 224 (2), 222 (6), 198 (17), 166 (100). Anal.
Calcd for C19H25ClN4O3S: C, 53.70; H, 5.93; N, 13.18.
Found: C, 53.79; H, 5.86; N, 13.13.
2H, cy), 2.19e2.24 (m, 2H, cy), 2.44e2.48 (m, 1H, cy),
2.65e2.70 (m, 1H, cy), 3.85 (s, 3H, OCH3), 4.90 (br s, 1H,
3
3
NH), 6.90 (d, 2H, J¼8.8 Hz, Ar), 7.77 (d, 2H, J¼8.8 Hz,
Ar), 8.12 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 24.5 (t), 29.7 (t), 39.0 (t), 40.4 (q), 55.4 (s), 68.9 (s), 114.0
(s), 124.4 (d), 130.6 (d), 162.9 (s), 168.7 (s), 174.0 (s); MS
(EI) m/z (%) 289 (66) [Mþ], 261 (47), 229 (42), 182 (100),
154 (16), 124 (32). Anal. Calcd for C14H15N3O2S: C, 58.11;
H, 5.22; N, 14.52. Found: C, 58.03; H, 5.29; N, 14.43.
4.3.20. Ethyl 3a-[2-(aminocarbonyl)hydrazino]-2-(2,4-di-
fluorophenyl)-3a,4,5,6,7,8,9,9a-octahydrocycloocta-
[d][1,3]thiazoline-9a-carboxylate (9t)
4.4.2. 7-(4-Trifluoromethyl-phenyl)-6-thia-2,3,8-triaza-
tricyclo[3.3.3.01,5]undec-7-en-4-one (11b)
Colourless oil; IR (Nujol) nmax 3443, 3324, 3232, 3157,
1697 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.76e2.05 (m, 2H,
cy), 2.17e2.32 (m, 2H, cy), 2.53e2.59 (m, 1H, cy), 2.69e
2.76 (m, 1H, cy), 4.77 (br s, 1H, NH), 7.68 (d, 2H, 3J¼8.4 Hz,
Colourless powder, mp 171e174 ꢀC with decomposition;
IR (Nujol) nmax 3434, 3206, 3116, 1728, 1696 cmꢃ1 1H
;
NMR (400 MHz, DMSO-d6) d 1.10e1.20 (m, 1H, cy), 1.22
(t, 3H, 3J¼7.2 Hz, OCH2CH3), 1.25e1.73 (m, 6H, cy),
1.84e1.93 (m, 1H, cy), 2.01e2.11 (m, 1H, cy), 2.40e2.49
(m, 3H, cy), 4.09e4.20 (m, 2H, OCH2CH3), 5.30 (s, 1H,
NH), 5.73 (br s, 2H, NH2), 6.70 (br s, 1H, NH), 7.22 (t, 1H,
3
Ar), 7.93 (d, 2H, J¼8.4 Hz, Ar), 8.31 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 24.6 (t), 27.0 (t), 39.3 (t), 61.4 (s),
1
3
69.6 (s), 123.8 (s, JCF¼271.0 Hz), 125.9 (d, JCF¼3.8 Hz),
2
129.3 (d), 134.0 (s, JCF¼32.6 Hz), 135.4 (s), 168.1 (s), 173.8
3
3J¼8.0 Hz, Ar), 7.40 (t, 1H, J¼7.6 Hz, Ar), 8.00e8.10 (m,
(s); MS (EI) m/z (%) 327 (100) [Mþ], 298 (47), 269 (35), 181
(86), 154 (24), 124 (36). Anal. Calcd for C14H12F3N3OS: C,
51.37; H, 3.70; N, 12.84. Found: C, 51.29; H, 3.75; N, 12.90.
1H, Ar); 13C NMR (100 MHz, DMSO-d6) d 13.8 (q), 21.8
(t), 23.2 (t), 25.0 (t), 25.8 (t), 30.0 (t), 33.5 (t), 61.8 (t), 75.6
(s), 97.1 (s), 104.8 (d, 2JCF¼25.8 Hz), 112.3 (d,
3
2JCF¼20.5 Hz), 117.7 (s, JCF¼9.3 Hz), 132.4 (s), 159.5 (s),
4.4.3. 11-Phenyl-10-thia-7,8,12-triaza-tricyclo-
[4.3.3.01,6]dodec-11-en-9-one (11c)
1
3
160.2 (s), 160.5 (s, JCF¼254.1 Hz, JCF¼12.8 Hz), 164.0 (s,
3
1JCF¼250.4 Hz, JCF¼12.2 Hz), 170.8 (s); MS (EI) m/z (%)
Colourless oil; IR (Nujol) nmax 3428, 3219, 3160,
1687 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.37e1.56 (m, 3H,
cy), 1.59e1.66 (m, 1H, cy), 1.86e1.93 (m, 1H, cy), 1.98e
2.04 (m, 1H, cy), 2.06e2.22 (m, 2H, cy), 5.92 (br s, 1H, NH),
426 (14) [Mþ], 396 (45), 381 (86), 331 (100), 309 (12), 280
(5), 167 (14). Anal. Calcd for C19H24F2N4O3S: C, 53.51; H,
5.67; N, 13.14. Found: C, 53.64; H, 5.73; N, 13.11.
3
6.21 (br s, 1H, NH), 7.47 (dt, 2H, J¼8.0 Hz, 4J¼1.6 Hz, Ar),
4.4. General procedure for the synthesis of 6-thia-2,3,8-
triaza-tricyclo[3.3.3.01,5]undec-7-en-4-ones 11a,b, 10-thia-
7,8,12-triaza-tricyclo[4.3.3.01,6]dodec-11-en-9-ones 11ceg
and 12-thia-9,10,14-triaza-tricyclo[6.3.3.01,8]tetradec-
13-en-11-ones 11hej
7.51 (dt, 1H, 3J¼7.2 Hz, 4J¼1.4 Hz, Ar), 7.84 (dt, 2H,
3J¼7.2 Hz, 4J¼1.6 Hz, Ar); 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 (EI) m/z (%) 273 (91) [Mþ], 245 (58), 215 (72), 195
(100), 167 (42), 139 (13). Anal. Calcd for C14H15N3OS: C,
61.51; H, 5.53; N, 15.37. Found: C, 61.59; H, 5.44; N, 15.29.
To a magnetically stirred solution of aryl-4,5,6,6a-tetrahy-
dro-3aH-cyclopenta[d][1,3]thiazolines 9c,d (1.0 mmol), or
aryl-3a,4,5,6,7,7a-hexahydro-1,3-benzothiazolines
(1.0 mmol) or aryl-3a,4,5,6,7,8,9,9a-octahydrocyclooc-
9eeh,j
4.4.4. 11-(4-Methoxy-phenyl)-10-thia-7,8,12-triaza-tricyclo-
[4.3.3.01,6]dodec-11-en-9-one (11d)
Colourless oil; IR (Nujol) nmax 3443, 3354, 3232, 3178,
;
1693 cmꢃ1 1H NMR (400 MHz, CDCl3) 1.15e1.31 (m,
ta[d][1,3]thiazolines 9qes (1.0 mmol) in tetrahydrofuran
(30 mL)
a
stoichiometric amount of sodium hydride

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3849
2H, cy), 1.43e1.71 (m, 3H, cy), 1.91e2.20 (m, 3H, cy),
4.4.8. 13-Phenyl-12-thia-9,10,14-triaza-tricyclo-
3.85 (s, 3H, OCH3), 5.21 (br s, 1H, NH), 6.91 (d, 2H,
3J¼7.2 Hz, Ar), 7.83 (d, 2H, 3J¼7.2 Hz, Ar), 8.79 (br s,
1H, NH); 13C NMR (100 MHz, CDCl3) d 20.3 (t), 20.7 (t),
29.1 (t), 31.3 (t), 55.5 (q), 63.6 (s), 98.9 (s), 114.0 (d),
124.4 (s), 130.6 (d), 136.1 (s), 169.2 (s), 175.4 (s); MS
(EI) m/z (%) 303 (69) [Mþ], 275 (38), 244 (21), 196
(100), 169 (72), 138 (66). Anal. Calcd for C15H17N3O2S:
C, 59.39; H, 5.65; N, 13.85. Found: C, 59.47; H, 5.71;
N, 13.77.
[6.3.3.01,8]tetradec-13-en-11-one (11h)
Colourless oil; IR (Nujol) nmax 3445, 3234, 3168,
1701 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.26e1.46 (m,
;
4H, cy), 1.52e1.83 (m, 4H, cy), 1.97e2.09 (m, 2H, cy),
2.26e2.33 (m, 1H, cy), 2.41e2.47 (m, 1H, cy), 5.20 (br s,
1H, NH), 7.43 (t, 2H, 3J¼7.2 Hz, Ar), 7.51 (t, 1H,
3
3J¼7.2 Hz, Ar), 7.88 (d, 2H, J¼8.0 Hz, Ar), 8.1 (br s, 1H,
NH); 13C NMR (100 MHz, CDCl3) d 23.0 (t), 25.0 (t), 25.4
(t), 28.3 (t), 29.7 (t), 32.8 (t), 69.8 (s), 104.1 (s), 128.5 (d),
128.6 (d), 132.0 (d), 132.4 (s), 166.7 (s), 177.2 (s); MS (EI)
m/z (%) 301 (100) [Mþ], 273 (75), 243 (92), 223 (58), 195
(34), 166 (60). Anal. Calcd for C16H19N3OS: C, 63.76; H,
6.35; N, 13.94. Found: C, 63.82; H, 6.36; N, 13.89.
4.4.5. 11-(4-Chloro-phenyl)-10-thia-7,8,12-triaza-tricyclo-
[4.3.3.01,6]dodec-11-en-9-one (11e)
Colourless oil; IR (Nujol) nmax 3426, 3211, 3154, 1703,
;
1649 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.45e1.66 (m,
4H, cy), 1.81e1.88 (m, 1H, cy), 1.95e2.05 (m, 1H, cy),
2.05e2.24 (m, 2H, cy), 5.17 (br s, 1H, NH), 7.40 (d, 2H,
4.4.9. 13-(4-Methoxy-phenyl)-12-thia-9,10,14-triaza-
tricyclo[6.3.3.01,8]tetradec-13-en-11-one (11i)
Colourless oil; IR (Nujol) nmax 3424, 3356, 3224, 3176,
3
3J¼7.8 Hz, Ar), 7.78 (d, 2H, J¼7.8 Hz, Ar), 9.02 (br s, 1H,
NH); 13C NMR (100 MHz, CDCl3) d 20.0 (t), 20.5 (t), 28.6
(t), 31.0 (t), 64.0 (s), 99.2 (s), 128.9 (d), 129.8 (d), 130.4 (s),
138.6 (s), 167.9 (s), 175.4 (s); MS (EI) m/z (%) 309 (16)
[Mþþ2], 307 (46) [Mþ], 281 (2), 283 (8), 250 (16), 248
(46), 196 (100), 168 (39), 167 (54). Anal. Calcd for
C14H14ClN3OS: C, 54.63; H, 4.58; N, 13.65. Found: C,
54.71; H, 4.52; N, 13.71.
1694 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.26e1.36 (m,
;
3H, cy), 1.48e1.82 (m, 3H, cy), 2.03e2.16 (m, 2H, cy),
2.21e2.31 (m, 2H, cy), 2.35e2.41 (m, 1H, cy), 2.45e2.56
(m, 1H, cy), 3.86 (s, 3H, OCH3), 5.13 (br s, 1H, NH), 6.92
3
3
(d, 2H, J¼6.8 Hz, Ar), 7.77 (d, 2H, J¼6.8 Hz, Ar), 8.41
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 23.1 (t),
25.1 (t), 25.5 (t), 27.1 (t), 29.1 (t), 32.6 (t), 55.2 (q), 70.3
(s), 102.3 (s), 114.1 (d), 125.7 (s), 129.8 (d), 160.3 (s),
167.6 (d), 178.3 (s); MS (EI) m/z (%) 331 (84) [Mþ], 303
(54), 273 (100), 195 (53), 165 (37). Anal. Calcd for
C17H21N3O2S: C, 61.61; H, 6.39; N, 12.68. Found: C, 61.71;
H, 6.32; N, 12.73.
4.4.6. 11-(2,4-Difluoro-phenyl)10-thia-7,8,12-triaza-
tricyclo[4.3.3.01,6]dodec-11-en-9-one (11f)
Colourless oil; IR (Nujol) nmax 3428, 3369, 3219, 3160,
;
1687 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.40e1.63 (m,
4H, cy), 1.69e1.75 (m, 1H, cy), 1.85e1.91 (m, 1H, cy),
2.09e2.21 (m, 2H, cy), 5.12 (br s, 1H, NH), 6.81e6.92 (m,
2H, Ar), 7.90e7.98 (m, 1H, Ar), 8.01 (br s, 1H, NH);
13C NMR (100 MHz, CDCl3) d 19.8 (t), 20.2 (t), 28.0 (t),
4.4.10. 13-(4-Chloro-phenyl)-12-thia-9,10,14-triaza-
tricyclo[6.3.3.01,8]tetradec-13-en-11-one (11j)
Colourless oil; IR (Nujol) nmax 3431, 3232, 3143,
2
30.8 (t), 63.2 (s), 97.6 (s), 104.5 (d, JCF¼25.8 Hz), 111.9
1698 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.26e1.35 (m,
;
2
2
(d, JCF¼21.3 Hz), 116.8 (s, JCF¼10.6 Hz), 132.0 (d,
2H, cy), 1.46e1.58 (m, 2H, cy), 1.59e1.70 (m, 2H, cy),
1.71e1.81 (m, 2H, cy), 1.95e2.05 (m, 2H, cy), 2.24e2.28
(m, 1H, cy), 2.40e2.44 (m, 1H, cy), 4.58 (br s, 1H, NH),
3JCF¼10.7 Hz), 161.2 (s, JCF¼245.0 Hz, JCF¼12.2 Hz),
1
3
1
3
162.1 (s), 164.9 (s, JCF¼254.0 Hz, JCF¼12.2 Hz), 175.4
(s); MS (EI) m/z (%) 309 (100) [Mþ], 281 (43), 231 (57),
195 (100), 137 (21). Anal. Calcd for C14H13F2N3OS:
C, 54.36; H, 4.24; N, 13.58. Found: C, 54.29; H, 4.21;
N, 13.65.
3
3
7.39 (d, 2H, J¼8.4 Hz, Ar), 7.80 (d, 2H, J¼8.4 Hz, Ar),
7.94 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 22.8
(t), 24.9 (t), 25.3 (t), 26.0 (t), 28.2 (t), 32.5 (t), 70.4 (s),
103.8 (s), 128.8 (d), 129.8 (d), 130.8 (s), 138.2 (s), 165.1
(s), 177.0 (s); MS (EI) m/z (%) 337 (36) [Mþþ2], 335 (100)
[Mþ], 309 (13), 307 (42), 223 (67), 195 (38), 165 (69).
Anal. Calcd for C16H18ClN3OS: C, 57.22; H, 5.40; N, 12.51.
Found: C, 57.32; H, 5.46; N, 12.53.
4.4.7. 4-Methyl-11-phenyl-10-thia-7,8,12-triaza-tricyclo-
[4.3.3.01,6]dodec-11-en-9-one (11g)
Colourless oil; IR (Nujol) nmax 3430, 3394, 3256, 3104,
1683 cmꢃ1
;
CHCH3), 1.08e1.29 (m, 2H, cy), 1.46e1.52 (m, 1H, cy),
1H NMR (CDCl3) d 0.96 (d, 3H, 3J¼6.4 Hz,
4.5. General procedure for the syntheses of ethyl 1[(4-chloro-
benzoyl)thio]-2-iminocycloalkylcarboxylates 12a,b and ethyl
1[(4-chlorobenzoyl)thio]-2-oxocycloalkylcarboxylates 13a,b
3
1.67e1.72 (m, 2H, cy), 2.22 (d, 1H, J¼14.4 Hz, cy), 2.45
3
(d, 1H, J¼11.6 Hz, cy), 4.90 (br s, 1H, NH), 7.40 (t, 2H,
3J¼7.6 Hz, Ar), 7.46 (t, 1H, 3J¼7.6 Hz, Ar), 7.82 (d, 2H,
3J¼7.2 Hz, Ar), 8.62 (br s, 1H, NH); 13C NMR (CDCl3)
d 21.5 (q), 26.9 (t), 27.2 (d), 28.1 (t), 38.9 (t), 63.0 (s), 99.5
(s), 128.4 (d), 128.5 (d), 132.0 (d), 132.2 (s), 166.0 (s),
176.1 (s); MS (EI) m/z (%) 287 (100) [Mþ], 231 (18), 211
(3). Anal. Calcd for C15H17N3OS: C, 62.69; H, 5.96; N,
14.62. Found: C, 62.60; H, 5.91; N, 14.67.
To a magnetically stirred solution of ethyl 3a-[2-(aminocarbo-
nyl)hydrazino]-2-(4-chlorophenyl)-3a,4,5,6,7,7a-hexahydro-1,3-
benzothiazole-7a-carboxylate9g(1.0 mmol) orethyl 3a-[2-(ami-
nocarbonyl)hydrazino]-2-(4-chlorophenyl)-3a,4,5,6,7,8,9,9a-oc-
tahydrocycloocta[d][1,3]thiazoline-9a-carboxylate 9s (1.0 mmol)
in acetoneewater¼9:1 (30 mL) 4 equiv of Amberlyst 15H was

3850
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
added at room temperature. The mixture was allowed to stand
at room temperature under magnetic stirring (6.0e15.0 h) until
the disappearance of the reagents (monitored by TLC chroma-
tography). The resin was removed by filtration and the reaction
solvent was evaporated under reduced pressure. Then the
crude was chromatographed on silica gel column (elution
mixtures: ethyl acetateecyclohexane) to obtain pure products
12a,b and 13a,b that were crystallized from ethyl acetatee
cyclohexane.
4.5.4. Ethyl 1[(4-chlorobenzoyl)thio]-2-oxocyclooctane-
carboxylate (13b)
Colourless powder, mp 118e121 ꢀC; IR (Nujol) nmax 3198,
1746, 1731, 1647 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 0.86e
3
0.92 (m, 1H, cy), 1.19 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.17e
1.25 (m, 2H, cy), 1.55e1.80 (m, 3H, cy), 2.00e2.07 (m, 2H,
cy), 2.31e2.44 (m, 2H, cy), 2.71e2.81 (m, 2H, cy), 4.14 (t,
2H, 3J¼7.2 Hz, OCH2CH3), 7.31 (d, 2H, 3J¼8.4 Hz, Ar),
3
7.64 (d, 2H, J¼8.4 Hz, Ar); 13C NMR (100 MHz, CDCl3)
d 14.1 (q), 23.7 (t), 25.4 (t), 25.8 (t), 28.8 (t), 38.1 (t), 39.7
(t), 62.1 (t), 67.6 (s), 127.4 (d), 132.0 (d), 133.8 (s), 140.9
(s), 166.2 (s), 189.6 (s), 202.3 (s); MS (EI) m/z (%) 370 (29)
[Mþþ2], 368 (100) [Mþ], 324 (3), 322 (8), 296 (24), 294
(77), 256 (23), 211 (37), 183 (27), 155 (23). Anal. Calcd for
C18H21ClO4S: C, 58.61; H, 5.74; S, 8.69. Found: C, 58.50;
H, 5.69; S, 8.79.
4.5.1. Ethyl 1[(4-chlorobenzoyl)thio]-2-iminocyclohexane-
carboxylate (12a)
Colourless powder, mp 142e145 ꢀC; IR (Nujol) nmax 3252,
1758, 1738, 1674 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.22e
1.30 (m, 3H, OCH2CH3), 1.84e1.98 (m, 4H, cy), 2.22e2.32
(m, 1H, cy), 2.65e2.78 (m, 3H, cy), 4.17e4.31 (m, 2H,
OCH2CH3), 5.32 (br s, 1H, NH), 7.37 (d, 2H, 3J¼8.4 Hz,
Ar), 7.73 (d, 2H, 3J¼8.4 Hz, Ar); 13C NMR (100 MHz,
CDCl3) d 13.8 (q), 22.2 (t), 26.1 (t), 36.7 (t), 40.4 (t), 62.5 (t),
67.5 (s), 104.4 (s), 128.5 (d), 128.8 (d), 134.4 (s), 140.0 (s),
168.2 (s), 188.4 (s); MS (EI) m/z (%) 341 (9) [Mþþ2],
339 (31) [Mþ], 296 (23), 294 (67), 267 (31), 265 (100),
225 (42), 199 (31), 182 (58), 154 (26). Anal. Calcd for
C16H18ClNO3S: C, 56.55; H, 5.34; N, 4.12. Found: C, 56.43;
H, 5.39; N, 4.23.
4.6. General procedure for the syntheses of 4-oxo-1-
thia-3-azaspiro[4.4]non-6-ylidenes 16aed, 4-oxo-1-
thia-3-azaspiro[4.5]dec-6-ylidenes 16een, 4-oxo-1-thia-3-
azaspiro[4.6]undec-6-ylidenes 16oeq and 4-oxo-1-thia-3-
azaspiro[4.7]dodec-6-ylidenes 16ret
Cycloalkenyl-1-diazenes 5aeh (1.0 mmol) were added to a
magnetically stirred solution of thioureas 14aec (1.0 mmol) in
methanol (4 mL) at room temperature. The reaction was al-
lowed to stand under magnetic stirring at room temperature
(0.1e1.5 h) until the disappearance of the reagents (monitored
by TLC chromatography). Compounds 16 crystallized directly
from the reaction medium and were collected as pure products
by filtration.
4.5.2. Ethyl 1[(4-chlorobenzoyl)thio]-2-iminocyclooctane-
carboxylate (12b)
Colourless powder, mp 151e154 ꢀC; IR (Nujol) nmax 3247,
1765, 1724, 1658 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.22e
1.35 (m, 3H, OCH2CH3), 1.40e1.50 (m, 2H, cy), 1.54e1.64
(m, 2H, cy), 1.67e1.75 (m, 3H, cy), 1.87e1.94 (m, 1H, cy),
2.06e2.13 (m, 1H, cy), 2.20e2.30 (m, 2H, cy), 2.50e2.59
(m, 1H, cy), 4.17e4.32 (m, 2H, OCH2CH3), 5.04 (br s, 1H,
4.6.1. 2-(2-Imino-4-oxo-1-thia-3-azaspiro[4.4]non-6-
yliden)-1-hydrazinecarboxamide (16a)
3
3
NH), 7.37 (d, 2H, J¼8.4 Hz, Ar), 7.73 (d, 2H, J¼8.4 Hz,
Ar); 13C NMR (100 MHz, CDCl3) d 13.9 (q), 22.8 (t), 23.1
(t), 24.4 (t), 25.7 (t), 29.1 (t), 34.7 (t), 62.1 (t), 71.2 (s),
107.8 (s), 128.7 (d), 129.3 (d), 131.2 (s), 137.9 (s), 161.8
(s), 173.0 (s); MS (EI) m/z (%) 369 (13) [Mþþ2], 367 (43)
[Mþ], 340 (9), 338 (32), 322 (56), 295 (27), 293 (100), 183
(7), 168 (4). Anal. Calcd for C18H22ClNO3S: C, 58.77; H,
6.03; N, 3.81. Found: C, 58.61; H, 5.96; N, 3.77.
Colourless powder, mp 233e236 ꢀC with decomposition;
IR (Nujol) nmax 3457, 3185, 3158, 1728, 1705, 1650,
1586 cmꢃ1 1H NMR (400 MHz, DMSO-d6) d 1.66e1.75
;
(m, 1H, cy), 2.10e2.17 (m, 2H, cy), 2.30e2.48 (m, 3H, cy),
6.04 (br s, 2H, NH2), 8.84 (s, 1H, NH), 9.08 (s, 1H, NH),
9.21 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d 22.8
(t), 27.9 (t), 38.6 (t), 71.0 (s), 156.1 (s), 156.4 (s), 180.4 (s),
189.0 (s); MS (EI) m/z (%) 241 (9) [Mþ], 224 (17), 198
(42), 182 (90), 156 (23), 143 (43), 129 (100), 114 (86).
Anal. Calcd for C8H11N5O2S: C, 39.83; H, 4.60; N, 29.03.
Found: C, 39.76; H, 4.68; N, 29.08.
4.5.3. Ethyl 1[(4-chlorobenzoyl)thio]-2-oxocyclohexane-
carboxylate (13a)
Colourless powder, mp 127e129 ꢀC; IR (Nujol) nmax1756,
1
1725, 1713, 1628 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.24
4.6.2. 2-[3-Methyl-2-(methylimino)-4-oxo-1-thia-3-aza-
spiro[4.4]non-6-yliden]-1-hydrazinecarboxamide (16b)
Colourless powder, mp 201e204 ꢀC with decomposition;
IR (Nujol) nmax 3387, 3191, 1731, 1708, 1653, 1632 cmꢃ1
1H NMR (400 MHz, DMSO-d6) d 1.74e1.81 (m, 1H, cy),
2.01e2.20 (m, 2H, cy), 2.29e2.49 (m, 3H, cy), 3.02 (s, 3H,
NCH3), 3.07 (s, 3H, NCH3), 6.08 (br s, 2H, NH2), 9.14 (s,
1H, NH); 13C NMR (100 MHz, DMSO-d6) d 22.4 (t), 27.6
(t), 29.3 (q), 38.1 (q), 62.7 (s), 151.7 (s), 155.2 (s), 156.3
(s), 173.7 (s); MS (EI) m/z (%) 269 (52) [Mþ], 252 (4), 225
(4), 210 (6), 196 (6), 170 (42), 157 (100), 127 (22), 112
(t, 3H, 3J¼7.2 Hz, OCH2CH3), 1.84e1.99 (m, 4H, cy),
2.27e2.29 (m, 1H, cy), 2.65e2.76 (m, 3H, cy), 4.23 (q, 2H,
3J¼7.2 Hz, OCH2CH3), 7.38 (d, 2H, 3J¼8.4 Hz, Ar), 7.81
;
3
(d, 2H, J¼8.4 Hz, Ar); 13C NMR (100 MHz, CDCl3) d 13.8
(q), 22.2 (t), 26.1 (t), 36.7 (t), 40.4 (t), 62.5 (t), 67.5 (s),
128.5 (d), 128.8 (d), 134.4 (s), 140.0 (s), 168.2 (s), 188.4
(s), 201.0 (s); MS (EI) m/z (%) 342 (2) [Mþþ2], 340 (9)
[Mþ], 156 (6), 139 (100), 127 (3). Anal. Calcd for
C16H17ClO4S: C, 56.38; H, 5.03; S, 9.41. Found: C, 56.41;
H, 5.12; S, 9.50.

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3851
(22). Anal. Calcd for C10H15N5O2S: C, 44.60; H, 5.61; N,
26.00. Found: C, 44.66; H, 5.65; N, 26.03.
63.6 (s), 148.2 (s), 151.0 (s), 156.9 (s), 173.0 (s); MS (EI) m/z
(%) 283 (21) [Mþ], 266 (13), 240 (2), 224 (96), 210 (9), 170
(7), 157 (100), 141 (14). Anal. Calcd for C11H17N5O2S: C,
46.63; H, 6.05; N, 24.72. Found: C, 46.67; H, 6.09; N, 24.68.
4.6.3. 2-[3-Ethyl-2-(ethylimino)-4-oxo-1-thia-3-aza-
spiro[4.4]non-6-yliden]-1-hydrazinecarboxamide (16c)
Colourless powder, mp 192e193 ꢀC; IR (Nujol) nmax 3392,
4.6.7. 2-[3-Ethyl-2-(ethylimino)-4-oxo-1-thia-3-aza-
spiro[4.5]dec-6-yliden]-1-hydrazinecarboxamide (16g)
Colourless powder, mp 200e202 ꢀC; IR (Nujol) nmax 3436,
3258, 3138, 1720, 1698, 1644 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6) d 1.08 (t, 3H, 3J¼7.2 Hz, NCH2CH3), 1.16 (t,
3
1
3H, J¼7.2 Hz, NCH2CH3), 1.71e1.91 (m, 1H, cy), 2.01e
3165, 1713, 1703, 1643, 1591 cmꢃ1; H NMR (DMSO-d6)
2.12 (m, 2H, cy), 2.18e2.40 (m, 3H, cy), 3.10 (q, 2H,
d
1.09 (t, 3H, 3J¼7.2 Hz, NCH2CH3), 1.15 (t, 3H,
3
3J¼7.2 Hz, NCH2CH3), 3.67 (q, 2H, J¼7.2 Hz, NCH2CH3),
3J¼7.2 Hz, NCH2CH3), 1.39e1.48 (m, 2H, cy), 1.79e2.06
(m, 4H, cy), 2.27e2.38 (m, 1H, cy), 3.01 (d, 1H,
3J¼15.6 Hz, cy), 3.14e3.28 (m, 2H, NCH2CH3), 3.69 (q,
6.06 (br s, 2H, NH2), 9.36 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 12.3 (q), 15.7 (q), 22.5 (t), 27.6 (t),
37.3 (t), 38.2 (t), 46.3 (t), 62.3 (s), 148.9 (s), 155.8 (s),
156.3 (s), 173.5 (s); MS (EI) m/z (%) 297 (67) [Mþ], 280
(1), 253 (4), 238 (12), 224 (6), 198 (38), 185 (100), 157
(15), 112 (20). Anal. Calcd for C12H19N5O2S: C, 48.47; H,
6.44; N, 23.55. Found: C, 48.39; H, 6.45; N, 23.42.
3
2H, J¼7.2 Hz, NCH2CH3), 5.84 and 6.17 (2br s, 2H, NH2),
9.59 (s, 1H, NH); 13C NMR (DMSO-d6) d 12.4 (q), 15.8 (q),
22.2 (t), 23.7 (t), 24.1 (t), 36.4 (t), 37.1 (t), 46.3 (t), 63.2 (s),
148.2 (s), 148.5 (s), 156.9 (s), 172.6 (s); MS (EI) m/z (%)
311 (25) [Mþ], 294 (9), 252 (100), 238 (5), 153 (2), 110
(11). Anal. Calcd for C13H21N5O2S: C, 50.14; H, 6.80; N,
22.49. Found: C, 50.19; H, 6.75; N, 22.55.
4.6.4. tert-Butyl 2-(2-imino-4-oxo-1-thia-3-aza-
spiro[4.4]non-6-yliden)-1-hydrazinecarboxylate (16d)
Colourless powder, mp 167e169 ꢀC with decomposition;
IR (Nujol) nmax 3429, 3203, 3136, 1724, 1711, 1685,
4.6.8. tert-Butyl 2-[3-methyl-2-(methylimino)-4-oxo-1-thia-
3-azaspiro[4.5]dec-6-yliden]-1-hydrazinecarboxylate (16h)
Colourless powder, mp 152e154 ꢀC; IR (Nujol) nmax 3296,
1594 cmꢃ1 1H NMR (400 MHz, CDCl3) d 1.42 (s, 9H,
;
C(CH3)3), 1.72e1.81 (m, 1H, cy), 2.16e2.28 (m, 2H, cy),
2.38e2.44 (m, 2H, cy), 2.45e2.60 (m, 1H, cy), 5.07 (br s,
1H, NH), 8.13 (br s, 1H, NH), 8.80 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 23.2 (t), 27.7 (t), 28.2 (q), 39.3
(t), 70.5 (s), 81.2 (s), 153.1 (s), 159.6 (s), 181.5 (s), 189.9
(s); MS (EI) m/z (%) 298 (2) [Mþ], 242 (100), 225 (35), 198
(65), 182 (41), 169 (44), 156 (16), 129 (100), 114 (87).
Anal. Calcd for C12H18N4O3S: C, 48.31; H, 6.08; N, 18.78.
Found: C, 48.28; H, 6.11; N, 18.84.
3175, 1718, 1704, 1678, 1629 cmꢃ1 1H NMR (400 MHz,
;
CDCl3) d 1.45 (s, 9H, C(CH3)3), 1.54e1.63 (m, 2H, cy),
1.97e2.14 (m, 4H, cy), 2.52e2.59 (m, 1H, cy), 2.74e2.81
(m, 1H, cy), 3.10 (s, 3H, NCH3), 3.20 (s, 3H, NCH3), 7.98
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 22.5 (t),
23.6 (t), 23.9 (t), 28.1 (t), 29.2 (q), 37.0 (q), 38.6 (q), 63.4
(s), 81.2 (s), 150.8 (s), 151.8 (s), 152.9 (s), 173.4 (s); MS
(EI) m/z (%) 341 (1) [Mþþ1], 284 (56), 267 (4), 240 (3),
224 (20), 211 (9), 184 (4), 170 (7), 157 (100), 116 (13).
Anal. Calcd for C15H24N4O3S: C, 52.92; H, 7.11; N, 16.46.
Found: C, 52.86; H, 7.14; N, 16.40.
4.6.5. 2-(2-Imino-4-oxo-1-thia-3-azaspiro[4.5]dec-6-
yliden)-1-hydrazinecarboxamide (16e)
Colourless powder, mp 186e189 ꢀC with decomposition;
4.6.9. N1-Phenyl-2-(2-imino-4-oxo-1-thia-3-aza-
IR (Nujol) nmax 3404, 3216, 3176, 1735, 1712, 1675 cmꢃ1
;
spiro[4.5]dec-6-yliden)-1-hydrazinecarboxamide (16i)
Colourless powder, mp 196e198 ꢀC with decomposition; IR
1H NMR (400 MHz, DMSO-d6) d 1.34e1.40 (m, 2H, cy),
1.75e1.97 (m, 4H, cy), 2.17e2.27 (m, 1H, cy), 2.95e3.06
(m, 1H, cy), 5.69 and 6.39 (2br s, 2H, NH2), 8.73 (s, 1H,
NH), 8.95 (s, 1H, NH), 9.54 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 23.8 (t), 24.0 (t), 25.3 (t), 37.1 (t),
72.9 (s), 149.0 (s), 157.2 (s), 179.9 (s), 187.9 (s); MS (EI)
m/z (%) 256 (3) [Mþþ1], 226 (14), 167 (22), 153 (100), 111
(77). Anal. Calcd for C9H13N5O2S: C, 42.34; H, 5.13; N,
27.43. Found: C, 42.26; H, 5.06; N, 27.49.
(Nujol) nmax 3405, 3206, 3163, 1732, 1716, 1637, 1564 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6) d 1.39e1.50 (m, 2H, cy),
1.79e2.03 (m, 4H, cy), 2.23e2.34 (m, 1H, cy), 3.00e3.07
(m, 1H, cy), 7.02 (t, 1H, 3J¼7.2 Hz, Ar), 7.33 (d, 2H,
3J¼7.2 Hz, Ar), 7.38 (d, 2H, 3J¼7.6 Hz, Ar), 8.28 (s, 1H,
NH), 8.81 (s, 1H, NH), 9.07 (s, 1H, NH), 10.14 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6) d 23.9 (t), 25.6 (t), 37.0 (t),
72.9 (s), 118.1 (d), 122.5 (d), 129.0 (d), 138.5 (s), 150.6 (s),
153.2 (s), 179.1 (s), 188.0 (s); MS (EI) m/z (%) 331 (1) [Mþ],
284 (1), 256 (12), 212 (21), 196 (17), 182 (14), 153 (81), 129
(64), 119 (100). Anal. Calcd for C15H17N5O2S: C, 54.37; H,
5.17; N, 21.13. Found: C, 54.34; H, 5.12; N, 21.15.
4.6.6. 2-[3-Methyl-2-(methylimino)-4-oxo-1-thia-3-aza-
spiro[4.5]dec-6-yliden]-1-hydrazinecarboxamide (16f)
Colourless powder, mp 191e194 ꢀC with decomposition; IR
(Nujol) nmax 3465, 3244, 3191, 3142, 1722, 1696, 1652 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6) d 1.39e1.48 (m, 2H, cy),
1.81e2.10 (m, 4H, cy), 2.29e2.38 (m, 1H, cy), 2.95e3.03
(m, 1H, cy), 3.04 (s, 3H, NCH3), 3.10 (s, 3H, NCH3), 5.94 (br
s, 2H, NH2), 9.48 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6) d 22.2 (t), 23.7 (t), 24.1 (t), 29.0 (q), 36.5 (t), 38.3 (q),
4.6.10. N1-Phenyl-2-[3-methyl-2-(methylimino)-4-oxo-1-
thia-3-azaspiro[4.5]dec-6-yliden]-1-hydrazinecarbox-
amide (16j)
Colourless powder, mp 206e208 ꢀC; IR (Nujol) nmax 3368,
3188, 1720, 1699, 1646, 1598 cmꢃ1 1H NMR (400 MHz,
;

3852
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
DMSO-d6) d 1.44e1.52 (m, 2H, cy), 1.80e1.93 (m, 2H, cy),
1.98e2.14 (m, 2H, cy), 2.30e2.41 (m, 1H, cy), 3.01e3.12
(m, 1H, cy), 3.04 (s, 3H, NCH3), 3.18 (s, 3H, NCH3), 7.03
156.8 (s), 172.9 (s); MS (EI) m/z (%) 297 (10) [Mþ], 280
(6), 238 (47), 225 (5), 157 (70), 104 (100). Anal. Calcd for
C12H19N5O2S: C, 48.47; H, 6.44; N, 23.55. Found: C, 48.54;
H, 6.39; N, 23.61.
3
3
(t, 1H, J¼7.2 Hz, Ar), 7.32 (t, 2H, J¼7.2 Hz, Ar), 7.40 (d,
3
2H, J¼7.6 Hz, Ar), 8.10 (s, 1H, NH), 10.17 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6) d 22.2 (t), 23.8 (t), 24.4 (t),
29.1 (q), 36.5 (t), 38.3 (q), 63.7 (s), 118.2 (d), 122.6 (d),
129.0 (d), 138.4 (s), 149.9 (s), 150.8 (s), 153.0 (s), 173.0 (s);
MS (EI) m/z (%) 359 (28) [Mþ], 267 (96), 240 (18), 224 (52),
211 (23), 185 (8), 157 (80). Anal. Calcd for C17H21N5O2S:
C, 56.81; H, 5.89; N, 19.48. Found: C, 56.78; H, 5.96; N, 19.44.
4.6.14. 2-[3-Ethyl-2-(ethylimino)-8-methyl-4-oxo-1-thia-3-
azaspiro[4.5]dec-6-yliden]-1-hydrazinecarboxamide (16n)
Colourless powder, mp 193e196 ꢀC with decomposition;
IR (Nujol) nmax 3382, 3246, 3176, 1717, 1704, 1663 cmꢃ1
;
3
1H NMR (400 MHz, DMSO-d6) d 0.96 (d, 3H, J¼6.0 Hz,
CHCH3), 1.01e1.11 (m, 4H, cy and NCH2CH3), 1.15 (t, 3H,
3J¼7.6 Hz, NCH2CH3), 1.50e1.69 (m, 2H, cy), 1.81e1.90
(m, 1H, cy), 1.97e2.05 (m, 1H, cy), 2.26e2.38 (m, 1H, cy),
3.06e3.13 (m, 1H, cy), 3.14e3.30 (m, 2H, NCH2CH3), 3.70
(q, 2H, 3J¼7.6 Hz, NCH2CH3), 5.56 and 6.41 (2br s, 2H,
NH2), 9.58 and 9.63 (2s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6) d 13.1 (q), 16.5 (q), 22.5 (q), 28.8 (t), 31.5 (d),
31.7 (t), 36.6 (t), 37.8 (t), 47.1 (t), 63.4 (s), 148.8 (s), 149.2
(s), 157.5 (s), 173.3 (s); MS (EI) m/z (%) 325 (11) [Mþ], 308
(3), 293 (5), 279 (9), 266 (33), 252 (4), 237 (3), 220 (30),
185 (30), 167 (34), 149 (100). Anal. Calcd for C14H23N5O2S:
C, 51.67; H, 7.12; N, 21.52. Found: C, 51.58; H, 7.17; N, 21.57.
4.6.11. N1-Phenyl-2-[3-ethyl-2-(ethylimino)-4-oxo-1-thia-3-
azaspiro[4.5]dec-6-yliden]-1-hydrazinecarboxamide (16k)
Colourless powder, mp 186e188 ꢀC; IR (Nujol) nmax 3454,
;
3179, 1721, 1708, 1664, 1584 cmꢃ1 1H NMR (400 MHz,
DMSO-d6) d 1.09e1.20 (m, 6H, 2NCH2CH3), 1.42e1.51
(m, 2H, cy), 1.81e1.91 (m, 2H, cy), 1.98e2.09 (m, 2H, cy),
2.30e2.40 (m, 1H, cy), 3.01e3.09 (m, 1H, cy), 3.16e3.34
(m, 2H, NCH2CH3), 3.70e3.82 (m, 2H, NCH2CH3), 7.02 (t,
1H, 3J¼7.2 Hz, Ar), 7.31 (t, 2H, 3J¼7.2 Hz, Ar), 7.38 (d,
3
2H, J¼7.6 Hz, Ar), 8.05 (s, 1H, NH), 10.16 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6) d 15.5 (q), 15.8 (q), 22.2
(t), 23.8 (t), 24.6 (t), 36.6 (t), 37.3 (t), 46.4 (t), 63.4 (s),
118.3 (d), 122.7 (d), 129.0 (d), 138.3 (s), 148.0 (s), 150.3
(s), 153.0 (s), 172.7 (s); MS (EI) m/z (%) 387 (27) [Mþ],
295 (100), 266 (12), 252 (37), 239 (19), 185 (42). Anal. Calcd
for C19H25N5O2S: C, 58.89; H, 6.50; N, 18.07. Found: C,
58.93; H, 6.46; N, 18.00.
4.6.15. 2-(2-Imino-4-oxo-1-thia-3-azaspiro[4.6]undec-
6-yliden)-1-hydrazinecarboxamide (16o)
Colourless powder, mp 185e187 ꢀC; IR (Nujol) nmax 3416,
3220, 3168, 1719, 1701, 1641, 1564 cmꢃ1
;
1H NMR
(400 MHz, DMSO-d6) d 1.36e1.57 (m, 5H, cy), 1.81e1.90
(m, 1H, cy), 1.97e2.07 (m, 1H, cy), 2.24e2.31 (m, 1H, cy),
3.11e3.18 (m, 2H, cy), 5.67 and 6.43 (2br s, 2H, NH2), 8.74
(s, 1H, NH), 8.96 (s, 1H, NH), 9.50 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 25.1 (t), 26.6 (t), 27.5 (t), 29.6 (t),
37.4 (t), 74.2 (s), 150.6 (s), 156.9 (s), 179.1 (s), 189.0 (s); MS
(EI) m/z (%) 269 (5) [Mþ], 253 (17), 227 (66), 210 (100), 195
(100), 183 (17), 168 (35), 152 (100). Anal. Calcd for
C10H15N5O2S: C, 44.60; H, 5.61; N, 26.00. Found: C, 44.53;
H, 5.68; N, 26.13.
4.6.12. 2-(2-Imino-8-methyl-4-oxo-1-thia-3-azaspiro-
[4.5]dec-6-yliden)-1-hydrazinecarboxamide (16l)
Colourless powder, mp 212e215 ꢀC with decomposition;
IR (Nujol) nmax 3354, 3162, 3139, 1721, 1698, 1608 cmꢃ1
;
3
1H NMR (400 MHz, DMSO-d6) d 0.96 (d, 3H, J¼6.4 Hz,
CHCH3), 0.98e1.13 (m, 1H, cy), 1.40e1.50 (m, 1H, cy),
1.56e1.63 (m, 1H, cy), 1.85e1.96 (m, 2H, cy), 2.20e2.30
(m, 1H, cy), 3.08e3.17 (m, 1H, cy), 5.60 and 6.17 (2br s,
2H, NH2), 8.72 (s, 1H, NH), 8.94 (s, 1H, NH), 9.50 (s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6) d 21.9 (q), 31.1 (q),
32.7 (t), 33.4 (t), 36.6 (t), 72.5 (s), 148.9 (s), 157.1 (s),
178.9 (s), 187.8 (s); MS (EI) m/z (%) 269 (2) [Mþ], 252 (5),
226 (11), 210 (42), 196 (11), 184 (12), 167 (15), 152 (75),
129 (43), 110 (100). Anal. Calcd for C10H15N5O2S: C,
44.60; H, 5.61; N, 26.00. Found: C, 44.27; H, 5.76; N, 26.05.
4.6.16. 2-[3-Methyl-2-(methylimino)-4-oxo-1-thia-3-aza-
spiro[4.6]undec-6-yliden]-1-hydrazinecarboxamide (16p)
Colourless powder, mp 199e201 ꢀC; IR (Nujol) nmax 3374,
;
3192, 1716, 1694, 1657, 1625 cmꢃ1 1H NMR (400 MHz,
DMSO-d6) d 1.38e1.61 (m, 5H, cy), 1.74e1.81 (m, 1H, cy),
1.98e2.08 (m, 1H, cy), 2.28e2.40 (m, 2H, cy), 2.70e2.78
(m, 1H, cy), 3.02 (s, 3H, NCH3), 3.06 (s, 3H, NCH3), 5.59
and 6.45 (2br s, 2H, NH2), 9.58 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 25.0 (t), 25.6 (t), 27.2 (t), 28.9 (q),
29.6 (t), 37.0 (q), 38.2 (t), 64.2 (s), 150.5 (s), 151.1 (s),
156.7 (s), 174.3 (s); MS (EI) m/z (%) 297 (28) [Mþ], 280
(3), 254 (3), 238 (42), 225 (4), 199 (23), 157 (100), 141
(30). Anal. Calcd for C12H19N5O2S: C, 48.47; H, 6.44; N,
23.55. Found: C, 48.55; H, 6.39; N, 23.42.
4.6.13. 2-[3,8-Dimethyl-2-(methylimino)-4-oxo-1-thia-3-
azaspiro[4.5]dec-6-yliden]-1-hydrazinecarboxamide (16m)
Colourless powder, mp 201e203 ꢀC; IR (Nujol) nmax 3419,
;
3214, 1716, 1703, 1665, 1587 cmꢃ1 1H NMR (400 MHz,
DMSO-d6) d 0.96 (d, 3H, 3J¼6.4 Hz, CHCH3), 1.10e1.21
(m, 1H, cy), 1.51e1.63 (m, 2H, cy), 1.81e1.89 (m, 1H, cy),
2.00e2.09 (m, 1H, cy), 2.29e2.39 (m, 1H, cy), 3.01e3.10
(m, 1H, cy), 3.03 (s, 3H, NCH3), 3.07 (s, 3H, NCH3), 5.81
and 6.15 (2br s, 2H, NH2), 9.55 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 21.8 (q), 29.0 (t), 31.0 (d), 32.0 (q),
36.0 (t), 38.2 (t), 38.3 (q), 63.1 (s), 148.2 (s), 150.9 (s),
4.6.17. 2-[3-Ethyl-2-(ethylimino)-4-oxo-1-thia-3-aza-
spiro[4.6]undec-6-yliden]-1-hydrazinecarboxamide (16q)
Colourless powder, mp 204e207 ꢀC; IR (Nujol) nmax 3416,
;
3296, 3095, 1717, 1695, 1658 cmꢃ1 1H NMR (400 MHz,

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3853
3
DMSO-d6) d 1.05 (t, 3H, J¼7.2 Hz, NCH2CH3), 1.14 (t, 3H,
322 (1), 280 (15), 256 (2), 241 (18), 213 (8), 185 (100), 157
(18). Anal. Calcd for C15H25N5O2S: C, 53.07; H, 7.42; N,
20.63. Found: C, 53.01; H, 7.39; N, 20.52.
3J¼7.2 Hz, NCH2CH3), 1.38e1.59 (m, 5H, cy), 1.70e1.81
(m, 1H, cy), 1.91e2.02 (m, 1H, cy), 2.27e2.38 (m, 2H, cy),
2.65e2.75 (m, 1H, cy), 3.11e3.26 (m, 2H, NCH2CH3), 3.64
(q, 2H, 3J¼7.2 Hz, NCH2CH3), 5.46 and 6.51 (2br s, 2H,
NH2), 9.57 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d 12.4 (q), 15.9 (q), 25.0 (t), 25.6 (t), 27.3 (t), 29.6 (t), 36.9
(t), 37.1 (t), 46.3 (t), 63.8 (s), 148.4 (s), 150.8 (s), 156.7 (s),
174.1 (s); MS (EI) m/z (%) 325 (23) [Mþ], 282 (3), 266 (25),
227 (13), 185 (100). Anal. Calcd for C14H23N5O2S: C, 51.67;
H, 7.12; N, 21.52. Found: C, 51.78; H, 7.16; N, 21.49.
4.7. General procedure for the syntheses of 3-ethyl-2-(ethyl-
imino)-1-thia-3-azaspiro[4.5]decane-4,6-dione 17a, 1-thia-
3-azaspiro[4.6]undecan-4,6-diones 17b,c, 3-methyl-2-(methyl-
imino)-1-thia-3-azaspiro[4.7]dodecan-4,6-dione 17d and
2-imino-5-(u-carboxyalkyl)-4-thiazolidinones 18aei
To a magnetically stirred solution of 4-oxo-1-thia-3-aza-
spiro[4.4]non-6-ylidenes 16b,c (1.0 mmol) or 4-oxo-1-thia-3-
azaspiro[4.5]dec-6-ylidenes 16eeh,l,n (1.0 mmol) or 4-oxo-
1-thia-3-azaspiro[4.6]undec-6-ylidenes 16o,p (1.0 mmol) or
4-oxo-1-thia-3-azaspiro[4.7]dodec-6-ylidene 16s (1.0 mmol)
in acetoneewater¼9:1 (30 mL) 4 equiv of Amberlyst 15H
was added at room temperature. The mixture was allowed to
stand at room temperature under magnetic stirring (6e15 h)
until the disappearance of the reagents (monitored by TLC
chromatography). The resin was removed by filtration, the re-
action solvent was evaporated under reduced pressure. Then
the crude was chromatographed on silica gel column (elution
mixtures: ethyl acetateecyclohexane) to obtain pure products
18aef that were crystallized from ethyl acetateecyclohexane.
In the case of the reaction of 16g along with 18e, product 17a
was isolated and crystallized from ethyl acetateecyclohexane.
In the case of the reactions of 16o,p and 16s only products
17bed were isolated. To obtain the pertinent 2-imino-5-(u-
carboxyalkyl)-4-thiazolidinones 18gei, compounds 16o,p,s,
or pure 17bed were refluxed under magnetic stirring in aceto-
neewater¼9:1 (30 mL) in the presence of 4 equiv of Amber-
lyst 15H. At the disappearance of the reagents (4.0e9.0 h)
(monitored by TLC chromatography) the resin was removed,
the reaction solvent was evaporated under reduced pressure,
products 18gei were purified by flash chromatography on a sil-
ica gel column (elution mixtures: ethyl acetateecyclohexane)
and crystallized from diethyl etherelight petroleum ether
(40e60 ꢀC).
4.6.18. 2-(2-Imino-4-oxo-1-thia-3-azaspiro[4.7]dodec-
6-yliden)-1-hydrazinecarboxamide (16r)
Colourless powder, mp 218e220 ꢀC with decomposition;
IR (Nujol) nmax 3404, 3162, 3114, 1719, 1701, 1663,
1592 cmꢃ1 1H NMR (400 MHz, DMSO-d6) d 1.04e1.13
;
(m, 1H, cy), 1.30e1.61 (m, 6H, cy), 1.65e1.78 (m, 1H, cy),
1.88e1.97 (m, 1H, cy), 2.53e2.61 (m, 2H, cy), 2.64e2.74
(m, 1H, cy), 5.39 and 6.39 (2br s, 2H, NH2), 8.80 (s, 1H,
NH), 8.99 (s, 1H, NH), 9.44 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 24.3 (t), 24.8 (t), 25.2 (t), 25.7 (t),
26.6 (t), 33.8 (t), 74.8 (s), 149.0 (s), 156.9 (s), 179.9 (s),
187.9 (s); MS (EI) m/z (%) 283 (14) [Mþ], 266 (8), 241
(78), 224 (53), 209 (100), 198 (28), 185 (40), 155 (35), 129
(100), 111 (67). Anal. Calcd for C11H17N5O2S: C, 46.63; H,
6.05; N, 24.72. Found: C, 46.74; H, 5.97; N, 24.65.
4.6.19. 2-[3-Methyl-2-(methylimino)-4-oxo-1-thia-3-aza-
spiro[4.7]dodec-6-yliden]-1-hydrazinecarboxamide (16s)
Colourless powder, mp 196e198 ꢀC; IR (Nujol) nmax 3362,
;
3164, 1732, 1721, 1692, 1649, 1576 cmꢃ1 1H NMR
(400 MHz, DMSO-d6) d 1.21e1.30 (m, 1H, cy), 1.33e1.59
(m, 6H, cy), 1.92e2.01 (m, 1H, cy), 2.18e2.24 (m, 1H, cy),
2.40e2.53 (m, 2H, cy), 2.68e2.80 (m, 1H, cy), 3.02 (s, 3H,
NCH3), 3.04 (s, 3H, NCH3), 5.68 and 6.45 (2br s, 2H, NH2),
9.55 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d 24.2
(t), 24.8 (t), 25.0 (t), 25.1 (t), 25.8 (t), 28.9 (q), 33.5 (t),
38.2 (q), 65.2 (s), 148.9 (s), 151.3 (s), 156.8 (s), 173.0 (s);
MS (EI) m/z (%) 311 (7) [Mþ], 295 (3), 267 (53), 252
(100), 238 (56), 212 (43), 184 (13), 157 (85). Anal. Calcd
for C13H21N5O2S: C, 50.14; H, 6.80; N, 22.49. Found: C,
50.06; H, 6.85; N, 22.58.
4.7.1. 3-Ethyl-2-(ethylimino)-1-thia-3-azaspiro[4.5]decane-
4,6-dione (17a)
Colourless powder, mp 90e92 ꢀC; 1H NMR (400 MHz,
CDCl3) d 1.19e1.26 (m, 6H, 2NCH2CH3), 1.64e1.71 (m,
1H, cy), 1.79e1.85 (m, 1H, cy), 2.00e2.10 (m, 2H, cy),
2.18e2.23 (m, 1H, cy), 2.49e2.76 (m, 3H, cy), 3.29e3.35
(m, 2H, NCH2CH3), 3.79 (q, 2H, 3J¼7.2 Hz, NCH2CH3);
13C NMR (100 MHz, CDCl3) d 12.5 (q), 15.7 (q), 22.4 (t),
25.7 (t), 29.7 (t), 38.2 (t), 38.7 (t), 47.3 (t), 65.3 (s), 147.2
(s), 171.6 (s), 202.0 (s). Its low stability does not allow
a more complete characterization.
4.6.20. 2-[3-Ethyl-2-(ethylimino)-4-oxo-1-thia-3-aza-
spiro[4.7]dodec-6-yliden]-1-hydrazinecarboxamide (16t)
Colourless powder, mp 201e204 ꢀC; IR (Nujol) nmax 3385,
3275, 3142, 1715, 1693, 1640 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6) d 1.05 (t, 3H, 3J¼7.2 Hz, NCH2CH3), 1.15 (t,
3
3H, J¼7.2 Hz, NCH2CH3), 1.16e1.23 (m, 1H, cy), 1.28e
1.63 (m, 6H, cy), 1.86e1.95 (m, 1H, cy), 2.36e2.46 (m, 2H,
cy), 2.71e2.83 (m, 2H, cy), 3.16e3.32 (m, 2H, NCH2CH3),
4.7.2. 2-Imino-1-thia-3-azaspiro[4.6]undecan-4,6-dione
(17b)
3
3.63 (q, 2H, J¼7.2 Hz, NCH2CH3), 5.84 and 6.53 (2br s,
2H, NH2), 9.54 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6) d 12.3 (q), 15.8 (q), 24.3 (t), 24.8 (t), 24.9 (t), 25.0 (t),
25.8 (t), 33.5 (t), 36.9 (t), 46.2 (t), 64.6 (s), 148.5 (s), 149.2
(s), 156.7 (s), 172.7 (s); MS (EI) m/z (%) 339 (20) [Mþ],
Colourless powder, mp 112e114 ꢀC; IR (Nujol) nmax 1735,
1
1669, 1632 cmꢃ1; H NMR (DMSO-d6) d 1.24e1.43 (m, 2H,
cy), 1.50e1.60 (m, 1H, cy), 1.69e1.81 (m, 1H, cy), 1.95e2.13
(m, 3H, cy), 2.45e2.56 (m, 2H, cy), 2.81e2.93 (m, 1H, cy),

3854
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
8.98 (s, 1H, NH), 9.21 (s, 1H, NH); 13C NMR (DMSO-d6)
d 25.0 (t), 27.6 (t), 29.4 (t), 35.9 (t), 42.2 (t), 78.1 (s), 180.7
(s), 186.6 (s), 206.0 (s); MS (EI) m/z (%) 212 (41) [Mþ],
184 (59), 155 (56), 150 (43), 129 (100), 109 (30). Anal. Calcd
for C9H12N2O2S: C, 50.92; H, 5.70; N, 13.20. Found: C,
50.78; H, 5.81; N, 13.32.
(t), 33.0 (t), 33.5 (t), 38.1 (t), 47.1 (t), 48.0 (d), 151.4 (s),
174.2 (s), 178.0 (s); MS (EI) m/z (%) 258 (90) [Mþ], 240
(31), 225 (26), 215 (20), 185 (26), 157 (100). Anal. Calcd
for C11H18N2O3S: C, 51.14; H, 7.02; N, 10.84. Found: C,
51.05; H, 7.08; N, 10.97.
4.7.7. 5-(2-Imino-4-oxo-1,3-thiazolidin-5yl)pentanoic
acid (18c)
4.7.3. 3-Methyl-2-(methylimino)-1-thia-3-azaspiro[4.6]-
undecan-4,6-dione (17c)
Colourless powder, mp 97e100 ꢀC; IR (Nujol) nmax 3212,
Colourless powder, mp 84e87 ꢀC; IR (Nujol) nmax 1709,
2987, 3178, 1708, 1665, 1606 cmꢃ1 1H NMR (400 MHz,
;
1
1663, 1654 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.01e1.15
DMSO-d6) d 1.17e1.28 (m, 1H, alk), 1.35e1.54 (m, 3H,
alk), 1.59e1.68 (m, 1H, alk), 1.84e2.01 (m, 1H, alk), 2.20
(m, 1H, cy), 1.61e1.88 (m, 4H, cy), 2.03e2.17 (m, 2H, cy),
2.58e2.74 (m, 2H, cy), 2.84e2.91 (m, 1H, cy), 3.16 (s, 6H,
2NCH3); 13C NMR (100 MHz, CDCl3) d 25.5 (t), 26.6 (t),
26.8 (t), 30.1 (t), 35.8 (t), 38.7 (q), 42.2 (q), 68.0 (s), 151.0
(s), 172.7 (s), 204.7 (s); MS (EI) m/z (%) 240 (100) [Mþ],
225 (5), 212 (11), 183 (36), 167 (2), 138 (6). Anal. Calcd
for C11H16N2O2S: C, 54.98; H, 6.71; N, 11.66. Found: C,
55.08; H, 6.63; N, 11.62.
3
3
(t, 2H, J¼7.2 Hz, alk), 4.21 and 4.24 (2d, 1H, J¼4.0 Hz,
3J¼3.6 Hz, cy), 8.76 (s, 1H, NH), 8.78 (s, 1H, NH), 11.80
(br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6) d 24.1
(t), 26.5 (t), 32.5 (t), 33.5 (t), 56.4 (d), 174.4 (s), 181.4
(s), 189.6 (s); MS (EI) m/z (%) 216 (26) [Mþ], 200 (100),
171 (34), 143 (16), 113 (8). Anal. Calcd for C8H12N2O3S:
C, 44.43; H, 5.59; N, 12.95. Found: C, 44.37; H, 5.58; N,
12.89.
4.7.4. 3-Methyl-2-(methylimino)-1-thia-3-azaspiro[4.7]-
dodecan-4,6-dione (17d)
4.7.8. 5-[3-Methyl-2-(methylimino)-4-oxo-1,3-thiazolidin-
5yl]pentanoic acid (18d)
Colourless powder, mp 60e62 ꢀC; IR (Nujol) nmax 1743,
1732, 1621, 1504 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
Colourless powder, mp 120e122 ꢀC; IR (Nujol) nmax 1739,
1718, 1638, 1459 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.22e
1.30 (m, 1H, alk), 1.39e1.55 (m, 3H, alk), 1.66e1.75 (m, 1H,
d 0.96e1.06 (m, 1H, cy), 1.45e1.53 (m, 1H, cy), 1.60e1.83
(m, 6H, cy), 1.90e1.97 (m, 1H, cy), 2.15e2.23 (m, 1H, cy),
2.43e2.49 (m, 1H, cy), 2.98e3.05 (m, 1H, cy), 3.10 (s, 3H,
NCH3), 3.18 (s, 3H, NCH3); 13C NMR (100 MHz, CDCl3)
d 24.0 (t), 25.4 (t), 25.6 (t), 26.8 (t), 29.3 (q), 30.2 (t), 34.4
(q), 38.1 (q), 71.3 (s), 151.4 (s), 171.1 (s), 206.4 (s); MS
(EI) m/z (%) 254 (100) [Mþ], 225 (52), 210 (2), 196 (36),
153 (42), 124 (16). Anal. Calcd for C12H18N2O2S: C, 56.67;
H, 7.13; N, 11.01. Found: C, 56.72; H, 7.21; N, 11.20.
3
alk), 1.95e2.05 (m, 1H, alk), 2.19 (t, 2H, J¼7.2 Hz, alk),
3.00 (s, 3H, NCH3), 3.03 (s, 3H, NCH3), 4.33 and 4.36
3
3
(2d, 1H, J¼4.0 Hz, J¼4.4 Hz, cy), 12.02 (br s, 1H, OH);
13C NMR (100 MHz, CDCl3) d 24.0 (t), 26.3 (t), 29.3 (q),
33.1 (t), 33.5 (t), 38.3 (q), 48.3 (d), 154.8 (s), 174.2 (s),
178.4 (s); MS (EI) m/z (%) 244 (35) [Mþ], 226 (100), 198
(14), 170 (9), 157 (68). Anal. Calcd for C10H16N2O3S:
C, 49.16; H, 6.60; N, 11.47. Found: C, 49.23; H, 6.56;
N, 11.52.
4.7.5. 4-[3-Methyl-2-(methylimino)-4-oxo-1,3-thiazolidin-
5yl]butanoic acid (18a)
Colourless powder, mp 153e155 ꢀC; IR (Nujol) nmax 2682,
4.7.9. 5-[3-Ethyl-2-(ethylimino)-4-oxo-1,3-thiazolidin-5yl]-
pentanoic acid (18e)
1
1705, 1653, 1457 cmꢃ1; H NMR (CDCl3) d 1.68e1.89 (m,
3H, alk), 2.13e2.24 (m, 1H, alk), 2.38 (t, 2H, 3J¼7.2 Hz,
alk), 3.13 (s, 3H, NCH3), 3.15 (s, 3H, NCH3), 4.07 and 4.09
(2d, 1H, 3J¼4.4 Hz, 3J¼4.0 Hz, cy), 9.20 (br s, 1H, OH);
13C NMR (CDCl3) d 21.8 (t), 29.3 (q), 32.7 (t), 33.2 (t),
38.3 (q), 48.1 (d), 154.5 (s), 174.0 (s), 177.7 (s); MS (EI)
m/z (%) 230 (31) [Mþ], 212 (100), 184 (6), 171 (1), 157
(60). Anal. Calcd for C9H14N2O3S: C, 46.94; H, 6.13; N,
12.16. Found: C, 46.99; H, 6.18; N, 12.04.
Colourless powder, mp 164e166 ꢀC; IR (Nujol) nmax 3109,
1
1732, 1667, 1501 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.17
(t, 3H, 3J¼7.2 Hz, NCH2CH3), 1.23 (t, 3H, 3J¼7.2 Hz,
NCH2CH3), 1.36e1.61 (m, 2H, alk), 1.70 (qui, 2H,
3J¼7.6 Hz, alk), 1.75e1.88 (m, 1H, alk), 2.11e2.21 (m, 1H,
3
3
alk), 2.38 (t, 2H, J¼7.2 Hz, alk), 3.33 (q, 2H, J¼7.2 Hz,
NCH2CH3), 3.76 (q, 2H, 3J¼7.2 Hz, NCH2CH3), 4.01 and
3
3
4.04 (2d, 1H, J¼4.0 Hz, J¼4.0 Hz, cy), 10.21 (br s, 1H,
OH); 13C NMR (100 MHz, CDCl3) d 12.4 (q), 15.5 (q), 24.0
(t), 26.1 (t), 33.1 (t), 33.6 (t), 37.8 (t), 46.9 (t), 47.9 (d),
150.9 (s), 174.1 (s), 178.8 (s); MS (EI) m/z (%) 272 (100)
[Mþ], 257 (26), 229 (17), 198 (5), 185 (36), 157 (43), 144
(98), 129 (56). Anal. Calcd for C12H20N2O3S: C, 52.92; H,
7.40; N, 10.29. Found: C, 52.85; H, 7.42; N, 10.34.
4.7.6. 4-[3-Ethyl-2-(ethylimino)-4-oxo-1,3-thiazolidin-5yl]-
butanoic acid (18b)
Colourless powder, mp 80e82 ꢀC; IR (Nujol) nmax 3119,
1
1704, 1649, 1459 cmꢃ1; H NMR (400 MHz, CDCl3) d 1.12
(t, 3H, 3J¼7.2 Hz, NCH2CH3), 1.19 (t, 3H, 3J¼7.2 Hz,
NCH2CH3), 1.61e1.84 (m, 3H, alk), 2.08e2.19 (m, 1H,
3
3
alk), 2.36 (t, 2H, J¼6.8 Hz, alk), 3.31 (q, 2H, J¼7.2 Hz,
4.7.10. 5-(2-Imino-4-oxo-1,3-thiazolidin-5yl)-3-methyl-
pentanoic acid (18f)
NCH2CH3), 3.71 (q, 2H, 3J¼7.2 Hz, NCH2CH3), 4.00 and
3
3
4.03 (2d, 1H, J¼4.0 Hz, J¼4.0 Hz, cy), 10.63 (br s, 1H,
Colourless powder, mp 164e166 ꢀC; IR (Nujol) nmax 3247,
OH); 13C NMR (100 MHz, CDCl3) d 12.6 (q), 15.6 (q), 22.0
3114, 3038, 1705, 1687, 1667 cmꢃ1 1H NMR (400 MHz,
;

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3855
DMSO-d6) d 0.87 (d, 3H, 3J¼6.4 Hz, alk), 1.03e1.47 (m, 2H,
4.7.14. 7-[3-Methyl-2-(methylimino)-4-oxo-1,3-thiazolidin-
5yl]heptanoic acid (18j)
alk), 1.57e1.71 (m, 1H, alk), 1.77e1.89 (m, 1H, alk), 1.90e
2.07 (m, 2H, alk), 2.14e2.23 (m, 1H, alk), 4.18e4.24 (m,
1H, cy), 8.76 (s, 1H, NH), 8.95 (br s, 1H, NH), 12.01 (br s,
1H, OH); 13C NMR (100 MHz, DMSO-d6) d 19.4 (q), 29.3
(t), 30.2 (d), 33.7 (t), 41.1 (t), 56.6 (d), 173.6 (s), 181.3 (s),
189.5 (s); MS (EI) m/z (%) 230 (4) [Mþ], 212 (83), 184
(53), 168 (79), 142 (79), 129 (100), 116 (100). Anal. Calcd
for C9H14N2O3S: C, 46.94; H, 6.13; N, 12.16. Found: C,
46.98; H, 6.08; N, 12.19.
Colourless powder, mp 116e118 ꢀC; IR (Nujol) nmax 1743,
1732, 1621, 1504 cmꢃ1; 1H NMR (400 MHz, CDCl3) d 1.12e
1.38 (m, 4H, alk), 1.51e1.72 (m, 3H, alk), 1.83e1.89 (m, 2H,
alk), 2.18e2.29 (m, 1H, alk), 2.36 (t, 2H, 3J¼7.2 Hz, alk), 3.11
(s, 3H, NCH3), 3.13 (s, 3H, NCH3), 4.19 and 4.21 (2d, 1H, 3J¼
4.0 Hz, 3J¼4.0 Hz, cy), 10.72 (br s, 1H, OH); 13C NMR
(100 MHz, CDCl3) d 24.0 (t), 26.1 (t), 27.5 (t), 28.5 (t), 29.7
(q), 33.4 (t), 33.9 (t), 38.8 (q), 48.6 (d), 157.8 (s), 169.0 (s),
176.4 (s); MS (EI) m/z (%) 272 (65) [Mþ], 255 (17), 227 (100),
198 (53), 157 (21), 127 (6). Anal. Calcd for C12H20N2O3S:
C, 52.92; H, 7.40; N, 10.29. Found: C, 52.81; H, 7.53; N, 10.42.
4.7.11. 5-[3-Ethyl-2-(ethylimino)-4-oxo-1,3-thiazolidin-
5yl]-3-methylpentanoic acid (18g)
Colourless powder, mp 113e116 ꢀC; IR (Nujol) nmax 3118,
1
1769, 1703, 1556 cmꢃ1; H NMR (400 MHz, CDCl3) d 0.99
4.8. General procedure for the syntheses of 2-(1,4,5,6-
tetrahydropyrimidin-2-ylthio)cyclohexan-1-one
N-phenylsemicarbazone 20a, 50,60-dihydro-2H-
spiro[cycloalkane-1,20-imidazo[2,1-b][1,3]thiazole]-2,30-
dione 2-semicarbazones 21a,c,f and 60,70-dihydro-2H,50H-
spiro[cycloalkane-1,20-[1,3]thiazolo[3,2-a]pyrimidine]-2,30-
dione 2-semicarbazones 21b,d,e,g
3
3
(d, 3H, J¼7.2 Hz, alk), 1.16 (t, 3H, J¼7.2 Hz, NCH2CH3),
3
1.22 (t, 3H, J¼7.2 Hz, NCH2CH3), 1.36e1.44 (m, 1H, alk),
1.49e1.86 (m, 2H, alk), 1.98 (oc, 1H, 3J¼4.4 Hz, alk),
2.01e2.23 (m, 2H, alk), 2.29e2.38 (m, 1H, alk), 3.30 (q,
2H, 3J¼7.2 Hz, NCH2CH3), 3.73 (q, 2H, 3J¼7.2 Hz,
NCH2CH3), 3.96e4.04 (m, 1H, cy), 9.20 (br s, 1H, OH);
13C NMR (100 MHz, CDCl3) d 12.4 (q), 15.5 (q), 19.4 (q),
26.8 (t), 30.1 (d), 33.4 (t), 37.8 (t), 41.2 (t), 46.9 (t), 48.2
(d), 151.0 (s), 174.1 (s), 178.2 (s); MS (EI) m/z (%) 286
(70) [Mþ], 271 (21), 243 (18), 185 (32), 157 (48), 144
(100), 129 (54). Anal. Calcd for C13H22N2O3S: C, 54.52; H,
7.74; N, 9.78. Found: C, 54.64; H, 7.83; N, 9.84.
Cycloalkenyl-1-diazenes 5a,c,gei (1.0 mmol) were added
at room temperature to a magnetically stirred solution of imi-
dazolidine-2-thione 19a or tetrahydropyrimidine-2-thione 19b
(1.0 mmol) in methanol (4 mL) at room temperature. The re-
action was allowed to stand under magnetic stirring at room
temperature (0.1e1.5 h) until the disappearance of the re-
agents (monitored by TLC chromatography). Then, the reac-
tion solvent was evaporated under reduced pressure and the
final product 20a was purified by chromatography on silica
gel column (elution mixtures: ethyl acetateecyclohexane)
and crystallized from ethyl acetateecyclohexane. Compounds
21aeg crystallized directly from the reaction medium and
were collected as pure products by filtration.
4.7.12. 6-(2-Imino-4-oxo-1,3-thiazolidin-5yl)hexanoic
acid (18h)
Colourless powder, mp 106e109 ꢀC; IR (Nujol) nmax 3243,
3177, 3092, 1713, 1674, 1611 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6) d 1.13e1.47 (m, 6H, alk), 1.55e1.68 (m, 1H,
alk), 1.91e2.00 (m, 1H, alk), 2.15e2.31 (m, 2H, alk), 4.19
3
3
and 4.21 (2d, 1H, J¼4.0 Hz, J¼4.0 Hz, cy), 8.74 (s, 1H,
NH), 8.94 (br s, 1H, NH), 11.98 (br s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6) d 21.4 (t), 22.5 (t), 24.1 (t), 28.9 (t),
32.8 (t), 53.6 (d), 152.6 (s), 176.8 (s), 180.0 (s); MS (EI) m/
z (%) 230 (100) [Mþ], 213 (63), 185 (31), 143 (14), 114 (4).
Anal. Calcd for C9H14N2O3S: C, 46.94; H, 6.13; N, 12.16.
Found: C, 47.02; H, 6.02; N, 12.04.
4.8.1. 2-(1,4,5,6-Tetrahydropyrimidin-2-ylthio)cyclohexan-
1-one N-phenylsemicarbazone (20a)
Colourless powder, mp 181e184 ꢀC; IR (Nujol) nmax 3388,
1
3195, 1691, 1686, 1586 cmꢃ1; H NMR (400 MHz, DMSO-
d6) d 1.29e1.37 (m, 1H, cy), 1.52e1.57 (m, 1H, cy), 1.79e
1.94 (m, 7H, cy), 2.99e3.03 (m, 1H, cy), 3.10e3.23 (m, 2H,
NCH2), 3.40e3.45 (m, 2H, NCH2), 5.96e6.00 (m, 1H, cy),
7.00 (t, 1H, 3J¼7.2 Hz, Ar), 7.31 (t, 2H, 3J¼8.0 Hz, Ar),
4.7.13. 6-[3-Methyl-2-(methylimino)-4-oxo-1,3-thiazolidin-
5yl]hexanoic acid (18i)
3
7.45 (d, 2H, J¼8.0 Hz, Ar), 8.14 (s, 1H, NH), 8.31 (s, 1H,
Colourless powder, mp 93e95 ꢀC; IR (Nujol) nmax 1725,
NH), 9.82 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d 20.8 (t), 24.1 (t), 24.3 (t), 26.4 (t), 29.3 (t), 40.3 (t), 42.4
(t), 62.1 (d), 118.1 (d), 122.2 (d), 128.9 (d), 138.9 (d), 149.8
(s), 153.3 (s), 177.5 (s); MS (EI) m/z (%) 345 (18) [Mþ],
268 (11), 230 (100), 213 (7), 186 (12), 172 (17). Anal. Calcd
for C17H23N5OS: C, 59.10; H, 6.71; N, 20.27. Found: C,
59.01; H, 6.78; N, 20.35.
1712, 1626, 1479 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d 1.32e1.51 (m, 4H, alk), 1.57e1.68 (m, 2H, alk), 1.72e
1.80 (m, 1H, alk), 2.06e2.18 (m, 1H, alk), 2.32 (t, 2H,
3J¼7.2 Hz, alk), 3.11 (s, 3H, NCH3), 3.13 (s, 3H, NCH3),
3
3
4.03 and 4.05 (2d, 1H, J¼4.0 Hz, J¼4.0 Hz, cy), 10.53 (br
s, 1H, OH); 13C NMR (100 MHz, CDCl3) d 24.3 (t), 26.4
(t), 28.3 (t), 29.1 (q), 33.1 (t), 33.7 (t), 38.3 (q), 48.4 (d),
154.5 (s), 174.3 (s), 178.7 (s); MS (EI) m/z (%) 258 (100)
[Mþ], 241 (34), 214 (85), 185 (37), 156 (28). Anal. Calcd
for C11H18N2O3S: C, 51.14; H, 7.02; N, 10.84. Found: C,
51.04; H, 7.13; N, 10.72.
4.8.2. 50,60-Dihydro-2H-spiro[cyclopentane-1,20-imid-
azo[2,1-b][1,3]thiazole]-2,30-dione 2-semicarbazone (21a)
Colourless powder, mp 182e183 ꢀC; IR (Nujol) nmax 3446,
3254, 3172, 1709, 1645, 1602 cmꢃ1 1H NMR (400 MHz,
;

3856
O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
DMSO-d6) d 1.60e1.72 (m, 1H, cy), 1.92e2.03 (m, 1H, cy),
2.19e2.30 (m, 2H, cy), 2.36e2.45 (m, 2H, cy), 3.55e3.71
4.8.6. 60,70-Dihydro-2H,50H-spiro[cycloheptane-1,20-
[1,3]thiazolo[3,2-a]pyrimidine]-2,30-dione
2-semicarbazone (21e)
3
(m, 2H, NCH2), 4.14 (t, 2H, J¼8.0 Hz, NCH2), 6.20 (br s,
2H, NH2), 9.28 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6) d 22.4 (t), 27.6 (t), 29.5 (t), 41.6 (t), 60.7 (t), 71.6 (s),
154.9 (s), 156.5 (s), 158.1 (s), 167.2 (s); MS (EI) m/z (%)
268 (2) [Mþþ1], 267 (11) [Mþ], 250 (7), 224 (8), 208 (4),
195 (100), 181 (3), 168 (32), 155 (89), 139 (10), 127 (36),
102 (51). Anal. Calcd for C10H13N5O2S: C, 44.93; H, 4.90;
N, 26.20. Found: C, 44.86; H, 4.95; N, 26.12.
Colourless powder, mp 198e201 ꢀC; IR (Nujol) nmax 3432,
3179, 3162, 1732, 1705, 1672 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6) d 1.36e1.80 (m, 8H, cy), 1.97e2.03 (m, 1H, cy),
2.28e2.39 (m, 2H, cy), 2.69e2.74 (m, 1H, cy), 3.36e3.43
(m, 2H, NCH2), 3.46e3.60 (m, 2H, NCH2), 5.61 and 6.14
(2br s, 2H, NH2), 9.55 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6) d 19.1 (t), 25.0 (t), 25.7 (t), 27.2 (t), 29.6 (t), 36.5
(t), 45.9 (t), 62.8 (s), 148.9 (s), 150.9 (s), 156.7 (s), 173.0 (s);
MS (EI) m/z (%) 309 (4) [Mþ], 293 (7), 265 (17), 249 (38),
236 (100), 209 (37), 195 (38), 181 (64), 168 (52), 154 (68),
143 (42), 114 (59). Anal. Calcd for C13H19N5O2S: C, 50.47;
H, 6.19; N, 22.64. Found: C, 50.52; H, 6.14; N, 22.59.
4.8.3. 60,70-Dihydro-2H,50H-spiro[cyclopentane-1,20-
[1,3]thiazolo[3,2-a]pyrimidine]-2,30-dione 2-
semicarbazone (21b)
Colourless powder, mp 218e220 ꢀC; IR (Nujol) nmax 3452,
3283, 3180, 3131, 1717, 1690, 1637 cmꢃ1
;
1H NMR
4.8.7. 50,60-Dihydro-2H-spiro[cyclooctane-1,20-imid-
azo[2,1-b][1,3]thiazole]-2,30-dione 2-semicarbazone (21f)
Colourless powder, mp 170e173 ꢀC; IR (Nujol) nmax 3459,
(400 MHz, DMSO-d6) d 1.67e1.84 (m, 3H, cy), 2.02e2.10
(m, 1H, cy), 2.14e2.19 (m, 1H, cy), 2.30e2.47 (m, 3H, cy),
3.39e3.46 (m, 2H, NCH2), 3.47e3.65 (m, 2H, NCH2), 6.18
(br s, 2H, NH2), 9.29 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6) d 19.0 (t), 22.5 (t), 27.7 (t), 40.5 (t), 45.9 (t),
61.4 (s), 149.3 (s), 155.7 (s), 156.4 (s), 172.5 (s); MS (EI)
m/z (%) 281 (14) [Mþ], 264 (8), 237 (11), 221 (100), 209
(78), 197 (35), 181 (26), 167 (47), 154 (29), 143 (8), 114
(25). Anal. Calcd for C11H15N5O2S: C, 49.96; H, 5.37; N,
24.89. Found: C, 50.02; H, 5.29; N, 24.97.
3277, 3193, 3156, 1713, 1633, 1596 cmꢃ1
;
1H NMR
(400 MHz, DMSO-d6) d 1.17e1.55 (m, 8H, cy), 2.26e2.32
(m, 1H, cy), 2.42e2.48 (m, 1H, cy), 2.52e2.58 (m, 1H, cy),
3
2.70e2.76 (m, 1H, cy), 3.64 (t, 2H, J¼8.2 Hz, NCH2), 4.12
3
(t, 2H, J¼8.2 Hz, NCH2), 5.87 and 6.40 (2br s, 2H, NH2),
9.57 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d 24.2
(t), 24.6 (t), 24.9 (t), 25.6 (t), 33.7 (t), 40.1 (t), 41.5 (t), 60.3
(t), 74.7 (s), 148.6 (s), 156.8 (s), 157.4 (s), 166.7 (s); MS
(EI) m/z (%) 309 (2) [Mþ], 292 (2), 266 (18), 250 (18), 237
(100), 224 (3), 209 (54), 196 (67), 182 (37), 154 (25), 142
(58), 114 (93). Anal. Calcd for C13H19N5O2S: C, 50.47; H,
6.19; N, 22.64. Found: C, 50.40; H, 6.11; N, 22.69.
4.8.4. 50,60-Dihydro-2H-spiro[cyclohexane-1,20-imid-
azo[2,1-b][1,3]thiazole]-2,30-dione 2-semicarbazone (21c)
Colourless powder, mp 163e166 ꢀC; IR (Nujol) nmax 3416,
1
3339, 3125, 1716, 1695 cmꢃ1; H NMR (DMSO-d6) d 1.34e
1.47 (m, 2H, cy), 1.72e1.82 (m, 1H, cy), 1.85e1.96 (m, 2H,
3
4.8.8. 60,70-Dihydro-2H,50H-spiro[cyclooctane-1,20-[1,3]thi-
azolo[3,2-a]pyrimidine]-2,30-dione 2-semicarbazone (21g)
Colourless powder, mp 190e193 ꢀC with decomposition; IR
cy), 2.20e2.32 (m, 2H, cy), 3.02 (d, 1H, J¼15.2 Hz, cy),
3
3.64e3.80 (m, 2H, NCH2), 4.18 (t, 2H, J¼9.2 Hz, NCH2),
5.80 and 6.36 (2br s, 2H, NH2), 9.60 (s, 1H, NH); 13C NMR
(DMSO-d6) d 22.0 (t), 23.5 (t), 23.9 (t), 36.8 (t), 41.5 (t), 60.4
(t), 73.0 (s), 147.7 (s), 156.8 (s), 157.5 (s), 166.3 (s); MS (EI)
m/z (%) 281 (3) [Mþ], 264 (2), 238 (22), 222 (19), 209 (100),
181 (31), 155 (86), 138 (34). Anal. Calcd for C11H15N5O2S:
C, 49.96; H, 5.37; N, 24.89. Found: C, 49.86; H, 5.42; N, 24.92.
(Nujol) nmax 3463, 3307, 3165, 3146, 1732, 1711, 1658 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6) d 1.23e1.38 (m, 1H, cy),
1.63 (m, 5H, cy), 1.66e1.80 (m, 1H, cy), 1.82e1.90 (m, 1H,
cy), 2.19e2.24 (m, 1H, cy), 2.40e2.48 (m, 2H, cy), 2.73e
2.79 (m, 1H, cy), 3.16e3.21 (m, 2H, cy), 3.35e3.42 (m, 2H,
3
NCH2), 3.56 (t, 2H, J¼6.0 Hz, NCH2), 5.78 and 6.47 (2br s,
2H, NH2), 9.55 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
d 19.0 (t), 24.3 (t), 24.8 (t), 24.9 (t), 25.0 (t), 25.7 (t), 33.3 (t),
40.2 (t), 45.8 (t), 63.7 (s), 149.0 (s), 149.2 (s), 156.8 (s),
171.8 (s); MS (EI) m/z (%) 323 (6) [Mþ], 306 (10), 279 (21),
264 (16), 251 (100), 225 (35), 210 (65), 196 (36), 184 (23),
172 (4), 159 (14), 119 (73). Anal. Calcd for C14H21N5O2S: C,
51.99; H, 6.54; N, 21.65. Found: C, 52.10; H, 6.46; N, 21.57.
4.8.5. 60,70-Dihydro-2H,50H-spiro[cyclohexane-1,20-
[1,3]thiazolo[3,2-a]pyrimidine]-2,30-dione
2-semicarbazone (21d)
Colourless powder, mp 212e213 ꢀC; IR (Nujol) nmax 3461,
3184, 3147, 1722, 1699, 1656 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6) d 1.18e1.31 (m, 2H, cy), 1.77e1.87 (m, 5H, cy),
2.00e2.07 (m, 1H, cy), 2.26e2.32 (m, 1H, cy), 2.96e3.02
(m, 1H, cy), 3.40e3.45 (m, 2H), 3.56e3.65 (m, 2H), 5.16
and 6.35 (2br s, 2H, NH2), 9.57 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 19.1 (t), 22.4 (t), 23.7 (t), 24.1 (t),
40.3 (t), 46.0 (t), 62.2 (s), 148.6 (s), 149.0 (s), 156.9 (s),
171.7 (s); MS (EI) m/z (%) 295 (8) [Mþ], 278 (3), 251 (17),
235 (154), 223 (100), 195 (17), 182 (28), 167 (40), 154
(15), 142 (52), 113 (36). Anal. Calcd for C12H17N5O2S: C,
48.80; H, 5.80; N, 23.71. Found: C, 48.90; H, 5.83; N, 23.72.
4.9. General procedure for the synthesis of 2-[hexahydro-1,3-
benzothiazol-3a(4H)-yl]-N-phenylhydrazinecarboxamides
23a,b
To a magnetically stirred solution of N,N0-dialkylthioureas
14b,c (1.0 mmol) in methanol (5 mL) at room temperature
N1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide 5i
(1.0 mmol) was added. The reaction was allowed to stand

O.A. Attanasi et al. / Tetrahedron 64 (2008) 3837e3858
3857
(d) Elmore, S.; Mottram, D. J. J. Agric. Food Chem. 1997, 45, 3603e
3607; (e) Ong, P.; Acree, T. J. Agric. Food Chem. 1998, 46, 2282e2286.
2. (a) Hartman, G.; Jin, Q. Z.; Collins, G.; Lee, K.; Ho, C. T.; Chang, S. J. J.
Agric. Food Chem. 1983, 31, 1030e1033; (b) Bultery, R.; Stean, D.; Ling,
L. J. Agric. Food Chem. 1994, 42, 791e795; (c) Pattenden, G.; Mulqueen,
B.; Falck, J. Tetrahedron Lett. 1994, 35, 5705e5708; (d) Fuganti, C.;
Gatti, F. G.; Serra, S. Tetrahedron 2007, 63, 4762e4767.
under magnetic stirring at room temperature (1.5e3.0 h) until
the disappearance of the reagents (monitored by TLC chroma-
tography). Then, the reaction solvent was evaporated under re-
duced pressure and the final products 23a,b were purified by
chromatography on silica gel column (elution mixtures: ethyl
acetateecyclohexane) and crystallized from ethyl acetatee
cyclohexane.
3. (a) Hayashi, K.; Sato, C.; Hiki, S.; Kumagai, T.; Tamai, S.; Abe, T.;
Nagao, Y. Tetrahedron Lett. 1999, 40, 3761e3764; (b) Ino, A.; Murabaya-
shi, A. Tetrahedron 1999, 55, 10271e10282; (c) Higashibayashi, S.;
Kohno, M.; Goto, T.; Suzuki, K.; Mori, T.; Hashimoto, K.; Nakata, M.
Tetrahedron Lett. 2004, 45, 3707e3712; (d) Mori, T.; Higashibayashi,
S.; Goto, T.; Kohno, M.; Satouchi, Y.; Shinko, K.; Suzuki, K.; Suzuki,
S.; Tohmiya, H.; Hashimoto, K.; Nakata, M. Tetrahedron Lett. 2007,
48, 1331e1335.
4.9.1. 2-[3-Methyl-2-(methylimino)hexahydro-1,3-benzothi-
azol-3a(4H)-yl]-N-phenylhydrazinecarboxamide (23a)
Colourless powder, mp 137e139 ꢀC; IR (Nujol) nmax 3491,
;
3304, 3259, 1716, 1666, 1620, 1580 cmꢃ1 1H NMR
(400 MHz, CDCl3) d 1.36e1.47 (m, 3H, cy), 1.60e1.69 (m,
2H, cy), 1.78e1.85 (m, 1H, cy), 2.00e2.06 (m, 2H, cy),
2.87 (s, 3H, NCH3), 3.07 (s, 3H, NCH3), 3.58e3.65 (m, 1H,
cy), 4.29 (br s, 1H, NH), 6.52 (br s, 1H, NH), 7.05 (dt, 1H,
3J¼7.2 Hz, 4J¼0.8 Hz, Ar), 7.29 (t, 2H, 3J¼7.6 Hz, Ar),
4. (a) Caujolee, R.; Baziard-Mouysset, G.; Favrot, J. D.; Payard, M.; Loui-
seau, P. R.; Amarouch, H.; Linas, M. D.; Seguela, J. P.; Louiseau,
P. M.; Bories, C.; Gayral, P. J. Med. Chem. 1993, 28, 29e35.
5. (a) Chaviara, A. T.; Christidis, P. C.; Papageorgiou, A.; Chrysogelou, E.;
Hadjipavlou-Litina, D. J.; Bolos, C. A. J. Inorg. Biochem. 2005, 99,
2102e2109;(b)Rostom, S. A. F. Bioorg. Med. Chem. 2006, 14, 6475e6485.
6. (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771e1791; (b) Michael, J. P.;
Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1e23; (c) Gu, X.-H.;
Wan, X.-Z.; Jiang, B. Bioorg. Med. Chem. Lett. 1999, 9, 569e572.
7. (a) Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem. 1988, 63,
196e200; (b) Reid, C. W.; Blackburn, N. T.; Legaree, B. A.; Auzanneau,
F.; Clarke, A. J. FEBS Lett. 2004, 574, 73e79; (c) Bonde, C. G.; Gaikwad,
N. J. Bioorg. Med. Chem. 2004, 12, 2151e2161; Ritter, T. K.; Wong, C. H.
Tetrahedron Lett. 2001, 42, 615e618; (d) Kim, S. K.; Son, H.; Nam, G.;
Chi, D. Y.; Kim, J. H. Bioorg. Med. Chem. 2000, 10, 1143e1145.
8. Brown, R. S.; Dowden, J.; Moreau, C.; Potter, V. L. Tetrahedron Lett.
2002, 43, 6561e6562; (b) Mulqueen, G.; Pattenden, G.; Whiting, D.
Tetrahedron 1993, 49, 5359e5364.
3
7.46 (d, 2H, J¼8.4 Hz, Ar), 8.16 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 21.3 (t), 23.0 (t), 28.7 (t), 31.2 (t), 31.3
(q), 40.1 (q), 44.8 (d), 82.0 (s), 118.8 (d), 123.1 (d), 129.0
(d), 138.1 (s), 155.4 (s), 157.2 (s); MS (EI) m/z (%) 333 (2)
[Mþ], 241 (18), 212 (31), 184 (47), 169 (21), 155 (100), 140
(5), 112 (64). Anal. Calcd for C16H23N5OS: C, 57.63; H,
6.95; N, 21.00. Found: C, 57.73; H, 7.01; N, 20.96.
4.9.2. 2-[3-Ethyl-2-(ethylimino)hexahydro-1,3-benzothi-
azol-3a(4H)-yl]-N-phenylhydrazinecarboxamide (23b)
Colourless powder, mp 146e150 ꢀC; IR (Nujol) nmax 3356,
9. Vorbrugen, H.; Krolikiewick, K. Tetrahedron 1993, 49, 9353e9372.
¨
10. Busacca, C.; Dong, Y.; Spinelli, E. Tetrahedron Lett. 1996, 37, 2935e
2938.
1
3295, 3225, 1673, 1625 cmꢃ1; H NMR (400 MHz, DMSO-
d6) d 1.04e1.12 (m, 6H, 2NCH2CH3), 1.31e1.40 (m, 2H,
cy), 1.45e1.58 (m, 3H, cy), 1.71e1.75 (m, 1H, cy), 1.81e
1.87 (m, 1H, cy), 2.02e2.07 (m, 1H, cy), 3.06e3.10 (m, 2H,
NCH2CH3), 3.11e3.20 and 3.22e3.35 (2 m, 2H, NCH2CH3),
`
11. Galeotti, N.; Montagne, C.; Pioncet, J.; Join, P. Tetrahedron Lett. 1992,
33, 2807e2810.
12. (a) Wipf, P.; Fritc, P. Tetrahedron Lett. 1994, 35, 5397e5400; (b) Muir,
J. C.; Pattenden, G.; Ye, T. Tetrahedron Lett. 1998, 39, 2861e2864; (c)
Ino, A.; Murabayashi, A. Tetrahedron 2001, 57, 1897e1902.
13. Aitken, R. A.; Armstrong, D. P.; Galt, R. H. B.; Mesher, S. T. E. J. Chem.
Soc., Perkin Trans. 1 1997, 935e942.
3
3.57 (t, 1H, J¼5.2 Hz, cy), 5.37 (s, 1H, NH), 6.93 (t, 1H,
3
3J¼6.8 Hz, Ar), 7.26 (t, 2H, J¼6.8 Hz, Ar), 7.36 (br s, 1H,
3
NH), 7.45 (d, 2H, J¼7.6 Hz, Ar), 8.54 (br s, 1H, NH); 13C
´
14. (a) Tarraga, A.; Molina, P.; Curiel, D.; Bautista, D. Tetrahedron: Asym-
NMR (100 MHz, DMSO-d6) d 14.2 (q), 16.8 (q), 21.3 (t),
21.9 (t), 29.4 (t), 37.1 (t), 43. 9 (d), 47.9 (t), 81.4 (s), 118.1
(d), 121.7 (d), 128.6 (d), 139.4 (s), 154.5 (s), 156.5 (s); MS
(EI) m/z (%) 362 (1) [Mþþ1], 339 (1), 261 (7), 246 (9), 229
(27), 211 (7), 175 (11), 132 (17), 119 (41), 110 (100). Anal.
Calcd for C18H27N5OS: C, 59.80; H, 7.53; N, 19.37. Found:
C, 59.67; H, 7.82; N, 19.52.
metry 2002, 13, 1621e1628; Knapp, S.; Yang, C.; Haimowitz, T. Tetra-
hedron Lett. 2002, 43, 7101e7104; (b) Bernardi, L.; Bovini, B. F.;
Comes-Franchini, M.; Femoni, C.; Fochi, M.; Ricci, A. Tetrahedron:
Asymmetry 2004, 15, 1133e1140; (c) Lu, S.-F.; Du, D.-M.; Zhang,
S.-W.; Xu, J. Tetrahedron: Asymmetry 2004, 15, 3433e3441.
15. Abdel-Jalil, R. J.; Saeed, M.; Voelter, W. Tetrahedron Lett. 2001, 42,
2435e2437.
16. Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Tetrahedron: Asymmetry 2002, 13, 429e435.
17. (a) Attanasi, O. A.; De Crescentini, L.; Foresti, E.; Galarini, R.; Santeusa-
nio, S.; Serra Zanetti, F. Synthesis 1995, 1397e1400; (b) Attanasi, O. A.;
De Crescentini, L.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.;
Santeusanio, S. Org. Lett. 2005, 7, 2469e2471.
Acknowledgements
The authors thank MIUR (Roma) [PRIN 2005
`
(2005034305)] and the Universita degli Studi di Urbino for
18. Attanasi, O. A.; Filippone, P.; Foresti, E.; Guidi, B.; Santeusanio, S.
Tetrahedron 1999, 55, 13423e13444.
the financial support of these investigations. They also thank
Dr. Stefano Beretta and Mr. Benoit Caprin for their precious
collaboration in the synthetic development of the work.
19. Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.; Filippone, P.;
Giorgi, G.; Lillini, S.;Mantellini, F. TetrahedronLett. 2007, 48, 2449e2451.
20. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004e2021.
References and notes
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3858
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as supplementary publication no. CCDC 636093. Copies of the data
can be obtained free of charge, on application to CCDC, 12 Union
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deposit@ccdc.cam.ac.uk].