Reactions of 1,2-diaza-1,3-dienes with thiol derivatives: a versatile construction of nitrogen/sulfur containing heterocycles

Article abstract of DOI:10.1016/j.tet.2008.07.030

The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines, 1,4-benzothiazines and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol affords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines.

Full text of DOI:10.1016/j.tet.2008.07.030

Tetrahedron 64 (2008) 9264–9274
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactions of 1,2-diaza-1,3-dienes with thiol derivatives: a versatile construction
of nitrogen/sulfur containing heterocycles
,
a
a
a
a
Orazio A. Attanasi a , Paolino Filippone , Samuele Lillini , Fabio Mantellini , Simona Nicolini ,
*
b
b
b
b,
*
´
Jesus M. de los Santos , Roberto Ignacio , Domitila Aparicio , Francisco Palacios
a
`
Istituto di Chimica Organica, Universita degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti, 24, 61029 Urbino (PU), Italy
b
´
´
Departamento de Qu´ımica Organica I, Facultad de Farmacia, Universidad del Paıs Vasco, Apartado 450, 01080 Vitoria, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2008
Received in revised form 18 June 2008
Accepted 10 July 2008
Available online 15 July 2008
The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines, 1,4-benzothiazines
and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes
bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization
is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol af-
fords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with
1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Furthermore, it is known that the presence of phosphorus sub-
stituents could regulate important biological functions,6 and the
Nitrogen-containing heterocycles are undoubtedly one of the
most important targets in organic chemistry. They are widely dis-
tributed in natural products and in pharmaceutical agents, and
numerous studies for their chemistry and synthesis have been
reported.1 Consequently new reactions, in which nitrogen-con-
taining heterocycles can be prepared in a chemo- and stereo-
selective way, will be broadly applicable for endeavours in natural
product synthesis and medicinal chemistry. The 1,4-thiazine ring
system is important in organic chemistry because it constitutes the
skeleton of natural products such as the two cytotoxic terpene
quinones, conicaquinones A and B,2a xanthiazone2b and xanthisi-
de,2c and it is known to play an important role in pigments and
dyestuffs.3 In addition, 1,4-thiazine derivatives also exhibit poten-
tial biological activities. Among these, 1,4-thiazine-3-carboxylic
acid derivatives are well known for their antibacterial activity,4a
aroyldihydro-1,4-thiazines are effective antiinflammatories,4b and
some bicyclic thiazines are attracting the increasing interest in
medicinal chemistry due to their hepatoprotective,4c calcium
antagonistic,4d vasopressin receptor antagonistic4e and anticancer
activities.4f,g Similarly, there is a wide precedence documenting the
potential of their benzo derivatives, 1,4-benzothiazines and their
analogues, for biological and therapeutic activity. For example,
these compounds were reported as calcium channel blockers,5a–c
Na/H exchange inhibitors,5d antifungal,5e,f antibacterial,5f anti-
microbial5g and antihypertensive5h,i agents, to name just a few.
introduction of organophosphorus functionalities in simple
synthons may afford useful substrates for the preparation of
biologically active compounds. In this context, carboxylated 1,2-
diaza-1,3-butadienes7 have been widely used for the preparation of
heterocyclic compounds,8 while phosphorylated 1,2-diaza-1,3-
butadienes have been used for the preparation of
a-amino-
phosphonates,9 pyridazines,10 pyrazines and quinoxalines.8d As
part of our ongoing research programs on the preparation of
three,11 five12 and six13 membered nitrogen-containing heterocy-
cles, as well as the synthesis of new amino phosphorus de-
rivatives,9,14 here we report the behaviour of thiol derivatives I
towards 1,2-diaza-1,3-dienes II. The obtained hydrazones III pro-
vide flexible access to different classes of nitrogen/sulfur containing
heterocycles by means of controlled regioselective cyclizations
(Chart 1). The presence of different functional groups in many po-
sitions of these heterocycles merits especial emphasis since such
compounds are, in turn, potential starting materials for further
interesting structural modifications, making them suitable for more
complex heterocyclic systems.
In this work, we also investigated the use of polymer-bound 1,2-
diaza-1,3-butadienes as building blocks for the facile solid-phase
preparation of thiazine and benzothiazine derivatives.
2. Results and discussion
4-Phosphinyl and 4-phosphonyl-1,2-diaza-1,3-butadienes15
1a,b (R1¼P(O)Ph2, P(O)(OEt)2; R2¼OEt), easily reacted with 2-
mercaptoethylamine hydrochloride 2a (R3¼H, Y¼NH3Cl) in
* Corresponding authors.
E-mail address: orazio.attanasi@uniurb.it (O.A. Attanasi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.030

O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
Cyclization A
9265
a spontaneous loss of a hydrazinecarboxylate residue affords thi-
azines 5a–k (Scheme 1). The structure of compounds 5 was con-
firmed by NOE experiments (DPFGSE–NOE sequence).16 For
example, irradiation of the methyl signal of compound 5h in
DMSO-d6 at 2.27 ppm enhances the NH signal at 7.28 ppm and vice
versa. This evidence suggests the proximity of these two groups,
which is in good agreement with the proposed mechanism. The
mercapto group demonstrated better nucleophilicity than
the amino moiety. In fact, the same products 5 were obtained when
the thiolamines hydrochloride 2a,b were treated with the appro-
priate base before the reaction with 1,2-diaza-1,3-butadienes 1. The
overall yields of 5 are not influenced from the sequence of base
addition.
N
R1
Y
SH
( )n
+
E
N
Y
S
N
( )n
N
R1
E
I
II
Cyclization B
Cyclization C
III
E = CONR2, P(O)Ph2, P(O)(OEt)2 Cyclization A
E = CO2R Cyclization A, or B, or C depending on Y
Chart 1. Synthesis and regioselective cyclizations of functionalized thio-
hydrazones III.
dichloromethane (DCM) at room temperature in the presence of
triethylamine to give 5-methyl-3,4-dihydro-2H-1,4-thiazine-2-
phosphine oxides 5a and -2-phosphonates 5b (Cyclization A, Chart
1, Scheme 1, Table 1). Similarly, the synthesis of 3,4-dihydro-2H-1,4-
thiazine containing ester or amide groups 5c–e was achieved by
reaction of 1,2-diaza-1,3-butadienes 1c–e (R1¼CO2Me, CO2Et,
CONMe2; R2¼NH2) and 1f (R1¼CO2Me, R2¼Ot-Bu) with the same 2a
in methanol (MeOH) at room temperature in the presence of so-
dium acetate. This process was extended to the preparation of
optically active 3-ethyl-(3R)-3,4-dihydro-2H-1,4-thiazine-3,6-
dicarboxylate 5f–k (Scheme 1, Table 1) by using chiral aminothiol
1,4-Thiazines substituted with phosphorus containing func-
tional groups have received scarce attention and only one example
of 1,4-thiazine derivatives with a phosphonate group at the posi-
tion 2 of the heterocyclic system has been described.17 To the best of
our knowledge, this strategy describes the first example of 1,4-
thiazine derivatives with a phosphine oxide group as well as the
first example of optically active phosphorylated [R1¼P(O)Ph2,
P(O)(OEt)2] 1,4-thiazine derivatives. Hydrazone 1,4-adduct in-
termediate 3a was isolated when 2-(butylamino)ethanethiol 2c
(R3¼H, Y¼NHBu) was added to 1,2-diaza-1,3-butadiene 1e
(R1¼CONMe2, R2¼NH2) in MeOH at room temperature (Scheme 1,
Table 1). Surprisingly, the reaction between 2c and 1,2-diaza-1,3-
butadienes 1c,f (R1¼CO2Me, R2¼NH2, Ot-Bu) containing an ester
group in position 4 of the heterodiene system furnished new and
interesting 2-[1-(4-butyl-3-oxo-1,4-thiazinan-2-yliden)ethyl]-1-
hydrazinecarboxylates 7a,b (Cyclization B, Chart 1). Also in this
case, the first step of the mechanism involves the nucleophilic at-
tack of the sulfur to the terminal carbon atom of the diene 1 with
the formation of the hydrazones 3. The subsequent intramolecular
nucleophilic attack of the nitrogen at the ester function with loss of
an alcohol molecule produces intermediates 6 that tautomerize to
give the final 1,4-thiazinan-3-ones 7a,b (Scheme 1, Table 1). The
different regioselectivity observed in the cyclization can be as-
cribed to the presence of a bulky group onto the nitrogen atom.
Hydrazone 3a (R1¼CONMe2) is not prone to cyclization reaction to
yield 7, probably because the amido moiety is less activated to-
wards the nucleophilic attack with respect to the ester function.
The methodology for the preparation of 2-substituted 1,4-thiazines
5 can also be applied to the synthesis of their benzo derivatives,
when functionalized 2-aminothiophenols 8a–c were used. Thus,
Michael addition of 8a–c to phosphorylated 1,2-diaza-1,3-butadi-
enes 1a,b in DCM or to carboxylated 1,2-diaza-1,3-butadienes
1c,d,h,i in MeOH at room temperature was also investigated. The
nucleophilic attack of the mercapto group of compounds 8 at the
terminal carbon atom of the heterodiene system followed by cy-
clization and spontaneous elimination of hydrazine residue leads to
2-substituted-1,4-benzothiazines 9a–j in good yields (Scheme 2,
Table 2). Also the structure of compounds 9 was confirmed by NOE
experiments (DPFGSE–NOE sequence).16 In this case, irradiation of
the methyl signal of compound 9d at 2.17 ppm enhances the NH
signal at 8.65 ppm and vice versa. Unfortunately, all attempts to
obtain 1,4-thiazines 5a–k or 1,4-benzothiazines 9a–j in good yields
with the same procedure failed because of the different electronic
effects by the substituents. For this reason, we used the most
suitable reaction conditions depending on the nature of the
substrate.
derivative like
L
-cysteine ethyl ester hydrochloride 2b (R3¼CO2Et,
Y¼NH3Cl). This reaction proceeds by means of preliminary sulfur-
nucleophilic attack of the 2-aminoethanothiols 2 on the terminal
carbon atom of the 1,2-diaza-1,3-butadiene system 1 to lead the
hydrazone 1,4-adducts (Michael type) 3 as evidenced by the dis-
appearance of typical red colour of the 1,2-diaza-1,3-butadienes 1.
At this time a stoichiometric amount of triethylamine in the case of
1a,b or of sodium acetate in the case of 1c–g was added to the crude
to obtain the free amino moiety, that gives a subsequent internal
nucleophilic attack at the carbon of the hydrazono group with
formation of the thiomorpholine intermediates 4. Then,
N
S
O
N
S
O
H
N
N
COR2
COR2
N
H
N
H
6
7a,b
2c
Y = NH(CH2)3CH3
R3 = H
Cyclization B
CH3OH, rt,
for 1c,f + 2c
R1 = COOMe
R3
Y
R1
R1
SH
2a-c
N
COR2
R3
N
COR2
N
S
N
H
CH2Cl2, rt for1a,b
CH3OH, rt for1c-g
1a−g
Y
3a
CH2Cl2, (CH3CH2)3N, rt
2a,b
for 1a,b + 2a,b
Y = NH3Cl
R
3 = H, or COOEt
Cyclization A
CH3OH, CH3COONa,
rt for 1c−g + 2a,b
S
R1
S
R1
We have also studied the reaction of 1,2-diaza-1,3-butadienes
1a,c with 2-mercaptoethanol 2d at room temperature, in DCM in
the case of 1a, or in MeOH for 1c to tentatively obtain 2,3-dihydro-
1,4-oxathiine 10 (Scheme 3).
Unfortunately, the expected intramolecular nucleophilic attack
of the oxygen derived from 2d did not occur and only hydrazones
3b,c were recovered. The subsequent addition of catalytic sodium
R3
R3
NH
NH
N
H
R2OC
N
H
5a−k
4
Scheme 1.

9266
O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
Table 1
Yields of hydrazone 3a, 3,4-dihydro-2H-1,4-thiazines 5a–k and 1,4-thiazinan-3-ones 7a,b
1
R1
R2
2
R3
Y
3
Yielda (%)
5
Yielda (%)
7
Yielda (%)
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1g
1c
1e
1f
POPh2
OEt
OEt
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
2c
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NH3Cl
NHBu
NHBu
NHBu
5a
5b
5c
5d
5e
5c
5f
5g
5h
5i
87
90
74
63
82
65
83
89
77
93
76
87
PO(OEt)2
CO2Me
CO2Et
CONMe2
CO2Me
POPh2
PO(OEt)2
CO2Me
CO2Et
CONMe2
CO2t-Bu
CO2Me
CONMe2
CO2Me
NH2
NH2
NH2
Ot-Bu
OEt
OEt
NH2
NH2
NH2
NH2
NH2
NH2
Ot-Bu
5j
5k
7a
7b
96
94
H
H
3a
94
a
Yield of isolated purified compounds based on 1,2-diaza-1,3-butadienes 1.
Similarly, polymer-bound 1,2-diaza-1,3-butadienes 14a,b readily
SH
reacted with 5 equivof 2-aminothiophenol 8a, at roomtemperature,
in MeOH/THF (1:1) affording directly 2-substituted-1,4-benzothi-
azines 9c,d (Scheme 4, Table 3). The overall yields referred to the
multistep-process of the solid-phase reactions are comparable with
thecorrespondingonesobtained in solution. Toimprovethescopeof
this synthetic methodology, the reaction of 2-mercaptoethylamine
hydrochloride 2a and 2-aminothiophenol 8a with cycloalkenyl-1-
diazenes 15a–d19 in MeOH was performed (Scheme 5). The treat-
ment of 15b,c with 2a under the usual reaction conditions
provides interesting fused cycloalkyl-1,4-thiazine derivatives like
ethyl-2,3,5,6,7,8-hexahydro-8aH-1,4-benzothiazine-8a-carboxylate 17a
(n¼2) or methyl-3,5,6,7,8,9-hexahydrocyclohepta[b][1,4]thiazine-
9a(2H)-carboxylate 17b (n¼3) in good yields (Scheme 5, Table 4). In
the case of reaction between 15a,c,d and 8a we achieved attractive
fused cycloalkyl-1,4-benzothiazine derivatives like ethyl-1,2,3,3a-
tetrahydrobenzo[b]cyclopenta[e][1,4]thiazine-3a-carboxylate 18a
(n¼1), or methyl-5a,6,7,8,9,10-hexahydrobenzo[b]cyclohepta[e][1,4]-
thiazine-5a-carboxylate 18b (n¼3), or ethyl-6,7,8,9,10,11-hexahydro-
5aH-benzo[b]cycloocta[e][1,4]thiazine-5a-carboxylate 18c (n¼4) in
good yields (Scheme 5, Table 4). This behaviour proves that this easy
procedure can be successfully employed for further synthetic applica-
tions in the construction of interesting polyfused heterorings.
R4
NH2
1
S
R
8a−c
Cyclization A
R1
N
COR3
R4
N
H
R2
N
1a-d,h,i
CH2Cl2, rt
R2
for 1a,b+ 8a−c
CH3OH, rt
9a−j
for 1c,d,h,i + 8a
Scheme 2.
hydride at room temperature in MeOH to 3c (R1¼CO2Me) promotes
the internal nucleophilic attack of the hydrazonic nitrogen to the
ester function (Cyclization C, Chart 1) with consequent loss of an
alcohol molecule producing substituted pyrazolone intermediate
11. This latter gives 4-[(2-hydroxyethyl)sulfanyl]-5-methyl-2,3-
dihydro-1H-3-pyrazolone 12a, by spontaneous hydrolysis of the
ureidic bond (Scheme 3, Table 2). Also in these conditions, no for-
mation of oxathiine 10 was detected. This fact is probably due to the
lower nucleophilicity of the oxygen with respect to the nitrogen.
Considering the mild and simple conditions required from these
reactions in the liquid phase, we have also investigated this syn-
thetic methodology in solid phase. Polymer-bound 1,2-diaza-1,3-
butadienes 14a,b prepared from polymer-bound p-toluenesulfonyl
hydrazide 1318 were allowed to stand at room temperature in
methanol–tetrahydrofuran (THF) (1:1) with 5 equiv of 2-mercap-
Then, we extended our investigation to the additions of 2-
mercaptobenzimidazole 19a, and 1H-1,2,3-triazole-3-thiol 19b on
1,2-diaza-1,3-butadiene 1d at room temperature in MeOH (Scheme
6). The nucleophilic attack of the mercapto moiety of the com-
pounds 19a,b at the terminal carbon of the heterodiene system of
1,2-diaza-1,3-butadiene 1d led to hydrazone 1,4-adducts 20a, 23a,
isolated by chromatography on silica in excellent yields. The sub-
sequent addition of catalytic sodium hydride to a solution of 20a or
toethylamine hydrochloride 2a or L-cysteine ethyl ester hydro-
chloride 2b. After 10 min, the resin was washed and then treated
with 2 equiv of sodium acetate in MeOH/THF (1:1) at room tem-
perature obtaining 3,4-dihydro-2H-1,4-thiazines 5c,d,h,i directly in
solution with a satisfactory degree of purity (Scheme 4, Table 3).
Table 2
Yields of hydrazones 3b,c, 1,4-benzothiazines 9a–j and 4-[(2-hydroxyethyl)sulfanyl]-5-methyl-2,3-dihydro-1H-3-pyrazolone 12a
1
R1
R2
R3
2
3
Yielda (%)
8
R4
9
Yielda (%)
12
Yielda (%)
Yieldb (%)
1a
1b
1c
1d
1h
1i
1a
1b
1a
1b
1a
1c
POPh2
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
OEt
OEt
NH2
NH2
NH2
NH2
OEt
OEt
OEt
OEt
OEt
NH2
8a
8a
8a
8a
8a
8a
8b
8b
8c
8c
H
H
H
H
H
H
Cl
Cl
CF3
CF3
9a
9b
9c
9d
9e
9f
9g
9h
9i
77
74
62
78
74
65
89
91
86
88
PO(OEt)2
CO2Me
CO2Et
CO2Bn
CO2Me
POPh2
PO(OEt)2
POPh2
PO(OEt)2
POPh2
9j
2d
2d
3b
3c
97
89
CO2Me
12a
58
75
a
Yield of isolated purified compounds based on 1,2-diaza-1,3-butadienes 1.
Yield of isolated purified compound based on hydrazone 3c.
b

O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
9267
S
R1
R2
R1
R1
S
N
NH3+Cl-
NH2
-Cl+NH3
2a
SH
n
n
O
NH
O
10
N
N
O
CH3OH, rt;
NH2
15a−d
16
SH
CH3OH, rt,
HO
Cyclization A
CH3OH, rt
Cyclization A
R1
R1
CH3COONa
NH2
COR3
SH
HO
N
COR3
2d
N
8a
S
N
H
R1
N
R1
CH2Cl2, rt for 1a
CH3OH, rt for 1c
R2
S
R2
S
N
1a,c
3b,c
n
n
N
CH3OH, NaH, rt for
3c R1 = COOMe
R2 = Me,R3 = NH2
Cyclization C
17a,b
18a−c
Scheme 5.
OH
S
OH
O
O
O
S
Table 4
N
HN
NH2
HN
HN
Yields of fused cycloalkyl-1,4-thiazines 17a,b, and fused cycloalkyl-1,4-benzothi-
azines 18a–c
R1
n
2
17
Yielda (%)
8
18
Yielda (%)
12a
11
15
15b
15c
15a
15c
15d
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
2
3
1
3
4
2a
2a
17a
17b
95
67
Scheme 3.
8a
8a
8a
18a
18b
18c
59
87
76
S
R1
a
Yield of isolated purified compounds based on cycloalkenyl-1-diazenes 15.
R3
N
H
5c,d,h,i
(Scheme 6, Table 5), in a similar way to that described for 12a (Cy-
clization C, Chart 1).
In this case, the ring closure process leading to the formation of
1,4-thiazines (Cyclization A) does not occur, probably because the
aromaticity of mercaptobenzimidazole 19a, and 1H-1,2,3-triazole-
3-thiol 19b makes the nitrogen a weak nucleophile.
i: CH3OH/THF (1:1), rt
ii: CH3OH/THF (1:1), rt,
R3
-Cl+NH3
SH
CH3COONa
2a,b
Cyclization A
O
S
O
O
S
O
NH2
N
N
R1
N
H
13
14a,b
SH
MeOH/THF (1:1), rt;
O
H
N
S
S
N
N
NH2
Cyclization A
N
CONH2
N
CONH2
8a
NH
NH
N
O
OEt
20a
CH3OH, NaH, rt
Cyclization C
S
R1
21
N
H
O
9c,d
CH3OH, rt for 1d
R1=CO2Et,
S
N
N
Scheme 4.
SH
NH
N
N
H
R2=Me, R3=NH2
NH
23a (R1¼CO2Et) in MeOH at room temperature promotes the in-
ternal nucleophilic attack of the hydrazonic nitrogen to the ester
function producing 4-(1H-benzo[d]imidazol-2-ylsulfanyl)-5-methyl-
19a
22a
SH
NH
N
N
H
R1
2,3-dihydro-1H-3-pyrazolone
22a
or
5-methyl-4-(1H-1,2,4-
S
N
N
N
COR3
19b
N
CONH2
N
triazol-3-ylsulfanyl)-2,3-dihydro-1H-3-pyrazolone 25a, respectively
N
NH
CH3OH, rt for 1d
R1=CO2Et,
R2
O
OEt
1d
R2=Me, R3=NH2
23a
Table 3
Overall yields of 3,4-dihydro-2H-1,4-thiazines 5c,d,h,i and 1,4-benzothiazines 9c,d
obtained in solid phase
CH3OH, NaH, rt Cyclization C
14
14a CO2Me 2a
14b CO2Et 2a
R1
2
R3
5
Yielda (%) Purity (%)
8
9
Yielda (%)
O
O
H
H
5c
5d 16
14
96
94
95
98
CONH2
N
NH
NH
NH
S
S
N
N
N
14a CO2Me 2b CO2Et 5h 31
14b CO2Et
14a CO2Me
14b CO2Et
2b CO2Et 5i
47
NH
NH
N
8a 9c
8a 9d 28
23
25a
24
a
Yield of isolated purified compounds based on polymer-bound p-toluene-
sulfonyl hydrazide 13.
Scheme 6.

9268
O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
Table 5
Yields of fused 4-substituted hydrazones 20a, 23a and 4-substituted pyrazol-3-ones 22a, 25a
1
R1
R2
R3
19
20
Yielda (%)
93
22
Yielda (%)
89
Yieldb (%)
97
23
Yielda (%)
95
25
Yielda (%)
92
Yieldc (%)
98
1d
1d
CO2Et
CO2Et
Me
Me
NH2
NH2
19a
19b
20a
22a
23a
25a
a
b
c
Yield of isolated purified compounds based on 1,2-diaza-1,3-butadienes 1.
Yield of isolated purified 22a based on hydrazone 20a.
Yield of isolated purified 25a based on hydrazone 23a.
3. Conclusion
used are as follows: s, singlet; d, doublet; dd, double-doublet; t,
triplet; q, quartet; ept, eptet; m, multiplet; br, broad. All the NH and
NH2 exchanged with D2O. Precoated silica gel plates 0.25 mm were
employed for analytical thin layer chromatography and silica gel
The present investigation demonstrates that the reactions of
1,2-diaza-1,3-dienes and thiol derivatives provide straightforward
access to different classes of sulfur containing compounds. As
a matter of fact in the whole the syntheses realized indicate that
1,2-diaza-1,3-butadienes 1 or cycloalkenyl-1-diazenes 15 can react
with different sulfur nucleophiles showing varied reactivity: (1)
with aliphatic 2a,b and aromatic 8, 1,2-aminothiols 3,4-dihydro-
2H-1,4-thiazines 5, fused cycloalkyl-1,4-thiazine 17, 1,4-benzothia-
zines 9 and fused cycloalkyl-1,4-benzothiazine 18 can be obtained
(Cyclization A); (2) with 2-(butylamino)ethanethiol 2c, 1,4-
thiazinan-3-ones 7 can be prepared (Cyclization B); (3) with
2-mercaptoethanol 2d, or 2-mercaptobenzimidazole 19a, or 1H-
1,2,3-triazole-3-thiol 19b, new substituted sulfanyl-2,3-dihydro-
1H-3-pyrazolones 12, 22, 25 can be achieved (Cyclization C). The
strategy previously described in the point (1) has also been used for
the preparation of optically active functionalized 1,4-thiazines with
amide, esters, phosphine oxide or phosphonate as substituents.
These heterocycles may be important synthons in organic synthe-
sis,3 organocatalysis20 and for the preparation of biologically active
compounds of interest in medicinal chemistry.2–5 These synthetic
methodologies proceed under mild conditions, using easily avail-
able starting materials and furnish interesting new products
without complicated work-up procedures. These aspects have
allowed us to obtain many cyclic compounds such as 3,4-dihydro-
2H-1,4-thiazines 5 and 1,4-benzothiazines 9 by means of solid-
phase reactions too.
35–70
m 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,
5 Apr. 1998), Advanced Chemistry Development Inc., Toronto, ON
(Canada).
4.2. General procedure for the synthesis of 3,4-dihydro-2H-
1,4-thiazines 5a–k and fused cycloalkyl-1,4-thiazines 17a,b
To an ice-cooled solution of 1,2-diaza-1,3-butadienes 1a,b as
a mixture of E/Z isomers (1.0 mmol) and triethylamine (139
1 mmol) in dichloromethane (5 mL), the corresponding 2-mer-
captoethylamine hydrochloride 2a (1 mmol) or -cysteine ethyl
mL,
L
ester hydrochloride 2b (1 mmol) was added. The reaction was
allowed to stir at room temperature for 30 min. The solvent was
removed by rotary evaporation and the residue was stirred with
diethyl ether and then it was filtered through a sintered glass
vacuum filtration funnel. The solid was washed with ether and the
filtrate was concentrated to dryness in vacuum. The crude products
were purified by crystallization or by flash-column chromatogra-
phy (silica gel, AcOEt) to afford 1,4-thiazines 5a,b,f,g derived from
phosphine oxides and phosphonates. To obtain 2-carboxylated 3,4-
dihydro-2H-1,4-thiazines 5c–e,h–k or fused cycloalkyl-1,4-thi-
azines 17a,b, a stoichiometric amount of 1,2-diaza-1,3-butadienes
1c–g (1 mmol) as a mixture of E/Z isomers21 or cycloalkenyl-1-
diazenes 15b,c19 was added to a solution of 2-mercaptoethylamine
4. Experimental
4.1. General
hydrochloride 2a (1 mmol) or L-cysteine ethyl ester hydrochloride
2b (1 mmol) in MeOH (20 mL). The reaction was allowed to stand at
room temperature for 10 min until complete disappearance of the
reagents (monitored by TLC). Sodium acetate (1 mmol) was then
added to the mixture and the solution was allowed to stand at room
temperature in MeOH under magnetic stirring for 8–14 h. The
solvent was removed under reduced pressure, the crude was dis-
solved in ethyl acetate and washed with a saturated solution of
Na2CO3 (2ꢂ10 mL). The organic layer was dried over anhydrous
Na2SO4 and the solvent was evaporated under reduced pressure.
The final products 5c–e,h–k, 17a,b were purified by chromatogra-
phy on silica (elution mixture: ethyl acetate, cyclohexane).
2-Mercaptoethylamine hydrochloride,
L-cysteine ethyl ester
hydrochloride, 2-(butylamino)ethanethiol, 2-aminothiophenol,
2-amino 4-chlorothiophenol, 2-amino 4-(trifluoromethyl)-thio-
phenol, 2-mercaptobenzimidazole, 1H-1,2,3-triazole-3-thiol, 3-
mercapto-2-butanone and Amberlyst 15H were commercial
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 hydroxide.
Melting points were determined on in open capillary tubes and are
uncorrected. IR–FT spectra were obtained as Nujol mulls, as solids
in KBr or as neat oils in NaCl. Mass spectra (MS) were made by
electron impact (EI) at an ionizing voltage of 70 eV or by chemical
ionization (CI). HRMS were recorded on an MAT95S mass spec-
trometer. 1H (300, 400 MHz), 13C (75, 100 MHz) and 31P NMR (120,
160 MHz) spectra were recorded on a 300 MHz or 400 MHz spec-
trometers, respectively, 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 constants (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 (CH3¼methyl,
CH2¼methylene, CH¼methine, C¼quaternary). The abbreviations
4.2.1. 5-Methyl-3,4-dihydro-2H-1,4-thiazin-6-
yl(diphenyl)phosphine oxide 5a
Compound 5a (274 mg, 87%) was obtained as a colourless
solid as described in the general procedure: mp 74–75 ꢀC; IR
(KBr) nmax 3255, 3041, 1722, 1546, 1434, 1167, 1113 cmꢃ1 1H NMR
;
(400 MHz, CD3OD)
d 2.05 (s, 3H), 2.64–2.68 (m, 2H), 3.57–3.60
(m, 2H), 7.43–7.72 (m, 10H); 13C NMR (75 MHz, CD3OD)
d 21.8 (d,
3JPC¼4.0 Hz), 25.6 (d, JPC¼4.5 Hz), 45.8, 75.7 (d, JPC¼130.0 Hz),
3
1
1
129.5, 129.6, 132.8, 132.9, 133.0, 133.1, 134.8 (d, JPC¼109.3 Hz),
2
152.1 (d, JPC¼15.5 Hz); 31P NMR (120 MHz, CDCl3)
d 34.2; MS (EI)
m/z (%) 315 (Mþ, 100), 314 (Mþꢃ1, 65), 238 (5), 201 (24), 114 (8),
77 (10); Calcd for
315.0853.
C
17H18NOPS [Mþ] 315.0847. Found [Mþ]

O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
9269
4.2.2. Diethyl-(5-methyl-3,4-dihydro-2H-1,4-thiazin-6-
4.2.7. Ethyl-(3R)-6-(diethoxyphosphoryl)-5-methyl-3,4-dihydro-
yl)phosphonate 5b
2H-1,4-thiazine-3-carboxylate 5g
Compound 5b (225 mg, 90%) was obtained as a colourless oil as
described in the general procedure: IR (film) nmax 3413, 1623, 1469,
Compound 5g (287 mg, 89%) was obtained as a colourless oil as
described in the general procedure: IR (neat) nmax 3266, 2983, 1744,
1250, 1021 cmꢃ1
;
1H NMR (300 MHz, CDCl3)
d
1.25–1.31 (m, 6H),
1247, 1028 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 1.23–1.34 (m, 9H),
2.05 (d, 3H, 4JPH¼1.6 Hz), 2.63–2.69 (m,1H), 2.95–2.99 (m,1H), 3.33–
2.03 (d, 3H, 4JPH¼1.9 Hz), 2.69–2.74 (m,1Hanti), 3.26–3.30 (m,1Hsyn),
3.40(1H, m), 3.61–3.68 (m,1H), 4.04–4.25(4H, m), 8.30 (brs,1H); 13
C
4.14–4.24 (m, 6H), 4.33–4.39 (m, 1H), 4.60 (dd, 1H, JHH¼11.0 Hz,
3
NMR (100 MHz, CDCl3)
d
14.4, 16.2, 16.4, 34.9, 53.7 (d, 4JPC¼4.4 Hz),
3JHH¼11.2 Hz); 13C NMR (75 MHz, CDCl3)
d 14.1, 14.4, 14.6, 16.6 (d,
61.3, 61.4, 61.8, 63.9, 64.0, 64.4, 64.4, 80.1 (d,1JPC¼191.9 Hz),148.3 (d,
3JPC¼5.5 Hz), 37.4, 61.5, 62.0, 64.2 (d, JPC¼8.1 Hz), 64.6 (d,
2
2JPC¼23.0 Hz); 31P NMR (120 MHz, CDCl3)
d
18.7; MS (CI) m/z (%) 252
2JPC¼6.9 Hz), 66.6, 79.6 (d, JPC¼192.8 Hz), 146.6, 170.3; 31P NMR
1
(Mþþ1, 2), 218 (10), 216 (100), 170 (95), 114 (10), 83 (15); Calcd for
(120 MHz, CDCl3)
d
17.8; MS (CI) m/z (%) 324 (Mþþ1, 10), 288 (95),
C9H18NO3PS [Mþ] 251.0757. Found [Mþ] 251.0768.
242 (100), 83 (10); Calcd for C12H22NO5PS [Mþ] 323.0956. Found
20
[Mþ] 323.0960; [
a
]
ꢃ6.67 (c 0.50, CH2Cl2).
D
4.2.3. Methyl-5-methyl-3,4-dihydro-2H-1,4-thiazine-6-
carboxylate 5c
4.2.8. 3-Ethyl-6-methyl-(3R)-5-methyl-3,4-dihydro-2H-1,4-
thiazine-3,6-dicarboxylate 5h
Compound 5c (128 mg, 74% starting from 1c; 112 mg, 65%
starting from 1f; 24 mg, 14% starting from 14a) was obtained as
a colourless powder as described in the general procedure: mp 66–
Compound 5h (188 mg, 77%) was obtained as a yellow oil as
described in the general procedure; IR (Nujol) nmax 3324, 1772,
68 ꢀC; IR (Nujol) nmax 3278, 1753, 1690, 1569 cmꢃ1
;
1H NMR
1732, 1564 cmꢃ1 1H NMR (400 MHz, DMSO-d6)
; d 1.18 (t, 3H,
(400 MHz, CDCl3)
d
2.33 (s, 3H), 2.80–2.83 (m, 2H), 3.60–3.63 (m,
23.1
3J¼7.2 Hz), 2.27 (s, 3H), 2.71 (dd, 1H, 2J¼12.8 Hz, 3J¼2.4 Hz), 2.99–
2H), 3.69 (s, 3H), 4.42 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
3.07 (m, 1H), 3.52 (s, 3H), 4.08–4.18 (m, 2H), 4.47–4.52 (m, 1H), 7.28
(CH3), 23.8 (CH2), 44.3 (CH2), 51.1 (CH2), 84.7 (C), 149.6 (C), 166.5
(C); MS: m/z (%) 173 (Mþ, 100). Anal. Calcd for C7H11NO2S: C, 48.54;
H, 6.40; N, 8.09. Found: C, 48.60; H, 6.37; N, 8.42.
(br s, 1H); 13C NMR (100 MHz, CDCl3)
d 14.0 (CH3), 22.6 (CH3), 26.1
(CH2), 51.1 (CH), 55.4 (CH3), 62.2 (CH2), 86.0 (C), 148.4 (C), 166.2 (C),
169.8 (C); MS: m/z (%) 245 (Mþ, 54), 214 (33), 201 (100), 185 (69),
172 (42), 157 (16), 141 (100), 113 (51), 82 (13). Anal. Calcd for
4.2.4. Ethyl-5-methyl-3,4-dihydro-2H-1,4-thiazine-6-
carboxylate 5d
C10H15NO4S: C, 51.59; H, 7.58; N, 15.04. Found: C, 51.49; H, 7.62; N,
15.12.
Compound 5d (118 mg, 63% starting from 1d; 30 mg, 16%
starting from 14b) was obtained as a yellow powder as described in
the general procedure: mp 58–60 ꢀC; IR (Nujol) nmax 3310, 1768,
4.2.9. Diethyl-(3R)-5-methyl-3,4-dihydro-2H-1,4-thiazine-3,6-
dicarboxylate 5i
1702, 1578 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.29 (t, 3H,
Compound 5i (239 mg, 93% starting from 1d; 122 mg, 47%
starting from 14b) was obtained as a yellow oil as described in the
general procedure; IR (Nujol) nmax 3352, 1745, 1685, 1579,
3J¼7.2 Hz), 2.33 (s, 3H), 2.81–2.84 (m, 2H), 3.60–3.64 (m, 2H), 4.16
(q, 2H, 3J¼7.2 Hz), 4.38 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 14.7
(CH3), 23.3 (CH3), 24.2 (CH2), 44.5 (CH2), 60.1 (CH2), 85.5 (C), 149.5
(C), 166.4 (C); MS: m/z (%) 187 (Mþ, 100), 149 (23), 125 (17), 111 (25),
97 (38), 83 (39), 69 (62), 57 (100). Anal. Calcd for C8H13NO2S: C,
51.31; H, 7.00; N, 7.48. Found: C, 51.26; H, 6.97; N, 7.52.
1523 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d 1.25–1.32 (m, 6H), 2.38 (s,
3H), 2.76 (dd, 1H, 2J¼12.4 Hz, 3J¼8.4 Hz), 3.09–3.15 (m, 1H), 4.15 (q,
2H, 3J¼7.2 Hz), 4.19–4.22 (m, 1H), 4.26 (q, 2H, 3J¼7.2 Hz), 4.85 (br s,
1H); 13C NMR (100 MHz, CDCl3)
d 14.1 (CH3), 14.4 (CH3), 22.7 (CH3),
26.3 (CH2), 55.4 (CH), 60.0 (CH2), 62.3 (CH2), 86.6 (C), 147.9 (C),
165.8 (C), 169.9 (C); MS: m/z (%) 259 (Mþ, 75), 231 (8), 214 (20), 186
(100). Anal. Calcd for C11H17NO4S: C, 50.95; H, 6.61; N, 5.40. Found:
C, 51.01; H, 6.60; N, 5.38.
4.2.5. N6,N6,5-Trimethyl-3,4-dihydro-2H-1,4-thiazine-6-
carboxamide 5e
Compound 5e (152 mg, 82%) was obtained as a yellow powder
as described in the general procedure: mp 76–78 ꢀC; IR (Nujol) nmax
3324, 1772, 1732, 1564 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.69
(s, 3H), 2.68–2.72 (m, 2H), 2.86 (s, 6H), 3.32–3.41 (m, 2H), 5.53 (br s,
1H); 13C NMR (100 MHz, DMSO-d6)
19.0 (CH3), 23.4 (CH2), 28.1
4.2.10. Ethyl-6-[(dimethylamino)carbonyl]-(3R)-5-methyl-3,4-
dihydro-2H-1,4-thiazine-3-carboxylate 5j
Compound 5j (196 mg, 76%) was obtained as a yellow oil as
described in the general procedure; IR (Nujol) nmax 3298,1776,1749,
d
(CH3), 36.3 (CH3), 43.0 (CH2), 85.5 (C), 136.1 (C), 169.1 (C); MS: m/z
(%) 186 (Mþ, 93), 141 (71), 114 (100), 82 (16), 68 (37), 83 (39), 69
(62), 57 (100). Anal. Calcd for C8H14N2OS: C, 51.59; H, 7.58; N, 15.04.
Found: C, 51.49; H, 7.62; N, 15.12.
1541 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.18 (t, 3H, 3J¼7.2 Hz),
1.72 (s, 3H), 2.80 (dd, 1H, 2J¼12.8 Hz, 3J¼3.6 Hz), 2.85 (s, 6H), 3.03
(dd, 1H, 2J¼12.8 Hz, 3J¼4.0 Hz), 4.10 (q, 2H, 3J¼7.2 Hz), 4.38 (m, 1H),
5.90 (d, 1H, 3J¼4.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d 14.1 (CH3),
4.2.6. Ethyl-(3R)-6-8-diphenylphosphoryl-5-methyl-3,4-dihydro-
2H-1,4-thiazine-3-carboxylate 5f
Compound 5f (321 mg, 83%) was obtained as a yellow oil as
described in the general procedure: IR (neat) nmax 3244, 3047, 1738,
18.8 (CH3), 25.5 (CH2), 36.1 (CH3), 53.5 (CH), 60.7 (CH2), 86.5 (C),
134.7 (C), 168.5 (C), 170.4 (C); MS: m/z (%) 258 (Mþ, 63), 214 (33),
186 (83), 168 (100), 142 (21), 113 (7), 81 (36). Anal. Calcd for
C11H18N2O3S: C, 51.14; H, 7.02; N, 10.84. Found: C, 51.23; H, 6.96; N,
1540, 1439, 1167 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
2
1.19 (t, 3H,
10.71.
4
J¼7.2 Hz), 2.14 (t, 3H, JPH¼1.0 Hz), 2.66 (ddd, 1H, JHH¼12.4 Hz,
3JHH¼7.2 Hz, 4JPH¼1.7 Hz), 2.87 (dt,1H, 2JHH¼12.4 Hz, J¼3.0 Hz), 4.14
(q, 2H, J¼7.2 Hz), 4.21 (dd, 1H, J¼7.2 Hz, J¼3.0 Hz), 5.32 (d, 1H,
4.2.11. 6-(tert-Butyl) 3-ethyl-(3R)-5-methyl-3,4-dihydro-2H-1,4-
thiazine-3,6-dicarboxylate 5k
3JHH¼3.0 Hz), 7.31–7.72 (m, 10H); 13C NMR (75 MHz, CDCl3)
d
14.2,
Compound 5k (250 mg, 87%) was obtained as a yellow oil as
described in the general procedure; IR (Nujol) nmax 3373,1745,1685,
3
3
21.6 (d, JPC¼5.0 Hz), 27.1 (d, JPC¼4.5 Hz), 55.5, 62.1, 80.1 (d,
1JPC¼123.4 Hz), 127.9, 128.0, 128.2, 128.3, 128.3, 128.4, 128.5, 130.7,
131.3, 131.4, 131.5, 131.7, 131.7, 131.8, 133.5 (d, 1JPC¼109.3 Hz), 133.7
(d, 1JPC¼107.8 Hz),148.3 (d, 2JPC¼15.1 Hz),170.1; 31P NMR (120 MHz,
1586, 1527 cmꢃ1
; d 1.28 (t, 3H,
1H NMR (400 MHz, CDCl3)
3J¼7.2 Hz), 1.45 (s, 9H), 2.32 (s, 3H), 2.68–2.75 (m, 1H), 3.06–3.12
(m, 1H), 4.12–4.19 (m, 1H), 4.23 (q, 2H, 3J¼7.2 Hz), 4.75 (br s, 1H);
CDCl3)
d
29.3; MS (EI) m/z (%) 387 (Mþ, 100), 314 (40), 207 (50), 185
13C NMR (100 MHz, CDCl3)
d 14.0 (CH3), 22.6 (CH3), 26.5 (CH2), 28.3
(15), 112 (20), 77 (22); Calcd for C20H22NO3PS [Mþ] 387.1058. Found
(C), 55.3 (CH), 62.2 (CH2), 80.0 (C), 88.3 (C),146.8 (C),165.3 (C),170.0
20
[MþꢃCO2Et] 314.0775; [
a
]
ꢃ7.01 (c 0.50, CH2Cl2).
(C); MS: m/z (%) 287 (Mþ, 23), 231 (97), 214 (25), 158 (100),140 (12),
D

9270
O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
114 (30), 82 (20), 68 (23). Anal. Calcd for C13H21NO4S: C, 54.33; H,
7.37; N, 4.87. Found: C, 54.40; H, 7.40; N, 4.82.
4.3.2. 2-[1-(4-Butyl-3-oxo-1,4-thiazinan-2-yliden)ethyl]-1-
hydrazinecarboxamide 7a
Compound 7a (261 mg, 96%) was obtained as a colourless
powder as described in the general procedure: mp 170–171 ꢀC; IR
4.2.12. Ethyl-2,3,5,6,7,8-hexahydro-8aH-1,4-benzothiazine-8a-
carboxylate 17a
Compound 17a (215 mg, 95%) was obtained as a yellow oil as
described in the general procedure; IR (Nujol) nmax 1763, 1710,
(Nujol) nmax 3311, 1763, 1712 cmꢃ1 1H NMR (400 MHz, DMSO-d6)
;
d
0.90 (t, 3H, 3J¼7.2 Hz),1.31–1.42 (m, 2H),1.58–1.65 (m, 2H),1.99 (s,
3H), 2.56–2.61 (m, 2H), 2.84–2.95 (m, 4H), 6.91 (d, 1H, 3J¼3.2 Hz),
1586 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.20 (t, 3H, 3J¼7.2 Hz),
8.73 (d, 1H, 3J¼3.2 Hz), 9.47 (br s, 2H); 13C NMR (100 MHz, DMSO-
1.35–1.42 (m, 2H), 1.43–1.58 (m, 1H), 1.65–1.71 (m, 1H), 1.74–1.82
(m, 1H), 2.03–2.10 (m, 1H), 2.27–2.32 (m, 2H), 2.53–2.58 (m, 1H),
2.73–2.81 (m, 1H), 3.54–3.62 (m, 1H), 3.85–3.93 (m, 1H), 4.10–4.23
d6) d 11.1 (CH3), 13.5 (CH3), 19.3 (CH3), 27.7 (CH2), 30.9 (CH2), 46.2
(CH2), 46.4 (CH2), 90.3 (C), 148.8 (C), 153.1 (C), 163.1 (C); MS: m/z (%)
272 (Mþ, 4), 229 (100), 187 (14), 172 (1), 156 (34), 144 (100), 129
(100). Anal. Calcd for C11H20N4O2S: C, 48.51; H, 7.40; N, 20.57; S,
11.77. Found: C, 48.59; H, 7.42; N, 20.60; S, 11.75.
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 13.8 (CH2), 21.3 (CH2), 23.2
(CH2), 26.2 (CH2), 36.8 (CH2), 46.4 (C), 47.7 (CH2), 61.3 (CH2), 162.3
(C), 170.2 (C); MS: m/z (%) 227 (Mþ, 8), 182 (16), 125 (55), 111 (100).
Anal. Calcd for C11H17NO2S: C, 58.21; H, 7.54; N, 6.16. Found: C,
58.17; H, 7.60; N, 6.18.
4.3.3. tert-Butyl 2-[1-(4-butyl-3-oxo-1,4-thiazinan-2-yliden)ethyl]-
1-hydrazinecarboxylate 7b
Compound 7b (118 mg, 63%) was obtained as a colourless
powder as described in the general procedure: mp 130–132 ꢀC; IR
4.2.13. Methyl-3,5,6,7,8,9-hexahydrocyclohepta[b][1,4]thiazine-
9a(2H)-carboxylate 17b
(Nujol) nmax 3249, 1766, 1737, 1593 cmꢃ1 1H NMR (400 MHz,
;
Compound 17b (152 mg, 67%) was obtained as a yellow oil as
described in the general procedure; IR (Nujol) nmax, 1789, 1713,
DMSO-d6)
d
0.90 (t, 3H, 3J¼7.2 Hz), 1.31–1.42 (m, 2H), 1.58–1.65 (m,
2H), 1.99 (s, 3H), 2.56–2.61 (m, 2H), 2.84–2.95 (m, 4H), 6.91 (d, 1H,
1516 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.34–1.63 (m, 4H), 1.66–
3J¼3.2 Hz), 8.73 (d, 1H, 3J¼3.2 Hz), 9.47 (br s, 2H); 13C NMR
1.79 (m, 2H), 1.90–2.03 (m, 1H), 2.14–2.21 (m, 1H), 2.28–2.34 (m,
1H), 2.42–2.50 (m, 2H), 3.01–3.09 (m, 1H), 3.75 (s, 3H), 3.88–3.93
(100 MHz, DMSO-d6) d 13.4 (CH3), 13.5 (CH3), 19.4 (CH3), 27.7 (CH2),
32.7 (CH2), 45.0 (CH2), 45.5 (CH2), 80.4 (C), 149.1 (C), 153.7 (C), 167.4
(C); MS: m/z (%) 272 (Mþ,11), 273 (6), 229 (83), 186 (8),156 (21),144
(100). Anal. Calcd for C11H20N4O2S: C, 48.51; H, 7.40; N, 20.57; S,
11.77. Found: C, 48.59; H, 7.42; N, 20.60; S, 11.75.
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 24.0 (CH2), 24.1 (CH2), 28.7
(CH2), 30.1 (CH2), 35.6 (CH2), 39.5 (CH2), 48.2 (C), 49.7 (CH2), 53.0
(CH3), 168.1 (C), 172.4 (C); MS: m/z (%) 227 (Mþ, 28), 211 (20), 181
(33), 167 (42), 149 (100), 137 (63), 123 (82), 111 (100). Anal. Calcd for
C
11H17NO2S: C, 58.21; H, 7.54; N, 6.16. Found: C, 58.34; H, 7.46; N,
6.04.
4.4. General procedure for the synthesis of 1,4-benzothiazines
9a–j and fused cycloalkyl-1,4-benzothiazines 18a–c
4.3. General procedure for the synthesis of hydrazone 3a and
1,4-thiazinan-3-ones 7a,b
To an ice-cooled solution of 1,2-diaza-1,3-butadiene 1a,b as
a mixture of E/Z isomers (1.0 mmol) in dichloromethane (5 mL), the
corresponding 2-aminothiophenol 8a–c (1 mmol) was added.
The reaction was allowed to stir at room temperature for 30 min.
The solvent was removed by rotary evaporation and the residue
was stirred with diethyl ether and then it was filtered through
a sintered glass vacuum filtration funnel. The solid was washed
with ether and the filtrate was concentrated to dryness in
vacuum. The crude products were purified by crystallization or
by flash-column chromatography (silica gel, AcOEt) to afford 1,4-
benzothiazines 9a,b,g–j derived from phosphine oxides and phos-
phonates. To prepare 9c–f or 18a–c a stoichiometric amount of
1,2-diaza-1,3-butadienes 1c,d,h,i (1 mmol) as a mixture of E/Z iso-
mers or cycloalkenyl-1-diazenes 15a,c,d (1 mmol) was added to
a solution of 2-aminothiophenol 8a (1 mmol) in MeOH (20 mL). The
reaction was allowed to stand at room temperature for 20–24 h
until the disappearance of the reagents (monitored by TLC). Then,
the solvent was removed under reduced pressure. The products
9c–f and 18a–c were purified by chromatography on silica (elution
mixture: ethyl acetate, cyclohexane 50:50).
To synthesize 3a a stoichiometric amount of 2-(butylamino)-
ethanethiol 2c (1 mmol) was added to a solution of 1,2-diaza-1,3-
butadiene 1e (1 mmol) as a mixture of E/Z isomers in MeOH
(20 mL). The reaction was allowed to stand at room temperature for
10 min until complete disappearance of the reagents (monitored by
TLC). The solvent was removed under reduced pressure and the
product 3a was purified by chromatography on silica (elution
mixture: ethyl acetate, MeOH 90:10). To obtain products 7a,b
a stoichiometric amount of 2-(butylamino)ethanethiol 2c (1 mmol)
was added to a solution of 1,2-diaza-1,3-butadienes 1c,f (1 mmol)
as a mixture of E/Z isomers in MeOH (20 mL). The reaction was
allowed to stand at room temperature for 0.5–1 h until complete
disappearance of the reagents (monitored by TLC). The solvent was
removed under reduce pressure and the 1,4-thiazinan-3-ones 7a,b
were purified by chromatography on silica (elution mixture: ethyl
acetate, MeOH 90:10).
4.3.1. 2[2-{[2-(Butylamino)ethyl]sulfanyl}-3-(dimethylamino)-1-
methyl-3-oxopropylidene]-1-hydrazinecarboxamide 3a
4.4.1. 3-Methyl-4H-1,4-benzothiazin-2-yl(diphenyl)-
phosphine oxide 9a
Compound 9a (279 mg, 77%) was obtained as a yellow solid as
described in the general procedure: mp 209–210 ꢀC; IR (KBr) nmax
Compound 3a (299 mg, 94%) was obtained as a colourless
powder as described in the general procedure: mp 161–163 ꢀC; IR
(Nujol) nmax 3311, 1763, 1712 cmꢃ1 1H NMR (400 MHz, DMSO-d6)
;
d
0.85 (t, 3H, 3J¼7.2 Hz), 1.18 (t, 3H, 3J¼7.2 Hz), 1.19–1.42 (m, 4H),
3250, 3052, 1616, 1466, 1429, 1162, 1103 cmꢃ1
;
1H NMR (400 MHz,
4
3
1.87 (s, 3H), 2.56–2.92 (m, 4H), 4.02–4.15 (m, 4H), 6.05 (br s, 2H),
CDCl3)
d
2.32 (d, 3H, JPH¼1.6 Hz), 6.57 (td, 1H, JHH¼7.6 Hz,
9.33 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
12.3 (CH3), 13.9
4JHH¼0.8 Hz), 6.60 (br s,1H), 6.74 (dd,1H, 3JHH¼7.6 Hz, 4JHH¼1.2 Hz),
3
4
3
(CH3), 14.8 (CH2), 14.9 (CH2), 19.7 (CH2), 29.4 (CH2), 30.7 (CH2),
35.4 (CH3), 36.6 (CH3), 67.5 (CH), 144.1 (C), 157.0 (C), 169.8 (C);
MS: m/z (%) 318 (Mþ, 1), 272 (26), 255 (11), 229 (100), 208 (5),
186 (12), 156 (100), 143 (100), 129 (100), 111 (100). Anal. Calcd for
6.79 (td, 1H, JHH¼7.6 Hz, JHH¼0.8 Hz), 6.87 (td, 1H, JHH¼7.6 Hz,
4JHH¼1.2 Hz), 7.43–7.54 (m, 6H), 7.78–7.83 (m, 4H); 13C NMR
3
1
(100 MHz, CDCl3)
d
19.6 (d, JPC¼2.8 Hz), 86.8 (d, JPC¼115.2 Hz),
114.5,124.3,126.5,126.6,126.8,127.0,127.2,127.5,127.7,127.8,128.3,
128.4, 128.6, 128.8, 131.5, 131.6, 131.7, 131.8, 131.8, 131.9, 132.2, 133.3,
C
13H26N4O3S: C, 49.03; H, 8.23; N, 17.59. Found: C, 48.98; H, 8.22;
N, 17.60.
141.7, 154.6 (d, 2JPC¼16.9 Hz); 31P NMR (160 MHz, CDCl3)
d 27.3; MS

O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
9271
(EI) m/z (%) 363 (Mþ, 24), 201 (36), 162 (35), 149 (100), 108 (30), 69
3J¼7.6 Hz), 6.69 (br s, 1H), 6.82–6.91 (m, 3H); 13C NMR (100 MHz,
(24); Calcd for C21H18NOPS [Mþ] 363.0847. Found [Mþ] 363.0848.
CDCl3) d 12.4 (CH3), 27.6 (CH2), 51.8 (CH3), 89.5 (C), 114.1 (CH), 120.3
(C), 124.8 (CH), 126.8 (CH), 127.2 (CH), 139.4 (CH), 157.6 (C), 163.8
(C); MS: m/z (%) 235 (Mþ, 70), 220 (3), 204 (5), 176 (100), 160 (5),
130 (10). Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95.
Found: C, 61.36; H, 5.52; N, 5.86.
4.4.2. Diethyl-(3-methyl-4H-1,4-benzothiazin-2-yl)-
phosphonate 9b
Compound 9b (221 mg, 74%) was obtained as a yellow oil as
described in the general procedure: IR (film) nmax 3415, 1621, 1471,
1226,1022 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
data for the enamine:
4.4.7. 6-Chloro-3-methyl-4H-1,4-benzothiazin-2-
yl(diphenyl)phosphine oxide 9g
Compound 9g (353 mg, 89%) was obtained as a yellow solid as
described in the general procedure: mp 147–148 ꢀC (dec); IR (KBr)
3
4
4
1.34 (td, 6H, JHH¼7.2 Hz, JPH¼0.4 Hz), 2.31 (d, 3H, JPH¼2.0 Hz),
3
3.92–4.15 (m, 4H), 6.09 (br s, 1H), 6.51 (d, 1H, JHH¼7.6 Hz), 6.86–
3
6.99 (m, 3H); data for the imine: 1.06 (td, 3H, JHH¼7.2 Hz,
4JPH¼0.4 Hz), 1.16 (td, 3H, JHH¼7.2 Hz, JPH¼0.4 Hz), 2.48 (d, 3H,
nmax 3258, 3172, 3052, 1568, 1453, 1168, 1099 cmꢃ1
;
1H NMR
3
4
2
4
4JPH¼4.0 Hz), 3.64 (d, 1H, JPH¼20.1 Hz), 3.92–4.15 (m, 4H), 7.10–
(300 MHz, CDCl3)
d
2.31 (d, 3H, JPH¼0.9 Hz), 6.58 (s, 1H), 6.65 (d,
7.31 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
15.9 (d, 3JPC¼2.2 Hz)minor
,
1H, 3JHH¼8.1 Hz), 6.68 (br s, 1H), 6.79 (d, 1H, 3JHH¼8.1 Hz), 7.43–7.56
3
3
3
16.0 (d, JPC¼3.0 Hz)minor, 16.1 (d, JPC¼6.9 Hz)major, 19.5 (d, JPC
¼
(m, 6H), 7.76–7.82 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 19.5 (d,
3
1
1.9 Hz)major, 28.4 (d, JPC¼2.7 Hz)minor, 34.8 (d, JPC¼143.6 Hz)minor
,
3JPC¼3.0 Hz), 87.3 (d, 1JPC¼111.2 Hz), 114.7, 124.0, 127.2, 128.5, 131.6,
2
2
61.9 (d, JPC¼5.1 Hz)major
,
63.1 (d, JPC¼7.3 Hz)minor
,
63.5 (d,
131.7, 131.9, 131.9, 131.9, 133.1, 133.2, 142.9, 154.0 (d, 2JPC¼16.5 Hz);
2JPC¼7.1 Hz)minor, 82.6 (d, 1JPC¼210.3 Hz)major, 114.4, 118.4, 118.4, 119.1,
31P NMR (120 MHz, CDCl3) 27.1; MS (EI) m/z (%) 397 (Mþ, 4), 281
d
124.3,126.4,126.7,126.8,127.1,127.2,140.9,142.0 (d, 4JPC¼2.3 Hz)minor
,
(40), 207 (100), 183 (20), 133 (8); Calcd for C21H17ClNOPS [Mþ]
397.0457. Found [Mþ] 397.0453.
2
2
154.0 (d, JPC¼25.8 Hz)major, 156.4 (d, JPC¼1.5 Hz)minor
;
31P NMR
(160 MHz, CDCl3)
177 (10), 162 (70), 149 (100), 130 (10), 108 (34), 82 (12); Calcd for
13H18NO3PS [Mþ] 299.0745. Found [Mþ] 299.0736.
d
14.9major, 17.5minor; MS (EI) m/z (%) 299 (Mþ, 20),
4.4.8. Diethyl-(6-chloro-3-methyl-4H-1,4-benzothiazin-2-
yl)phosphonate 9h
C
Compound 9h (303 mg, 91%) was obtained as a yellow solid as
described in the general procedure: mp 129–130 ꢀC (dec); IR (KBr)
4.4.3. Methyl-3-methyl-4H-1,4-benzothiazine-2-carboxylate 9c
Compound 9c (137 mg, 62% starting from 1c; 51 mg, 23% start-
ing from 14a) was obtained as a yellow powder as described in the
general procedure: mp 136–137 ꢀC; IR (Nujol) nmax 3228, 1786,
nmax 1722, 1625, 1568, 1459, 1219, 1020, 963 cmꢃ1
;
1H NMR
4
(400 MHz, CDCl3)
d
1.33–1.37 (m, 6H), 2.27 (d, 3H, JPH¼2.1 Hz),
4.06–4.14 (m, 4H), 6.73–6.79 (m, 3H), 7.73 (d, 1H, 4JHH¼4.8 Hz); 13
C
3
3
1725, 1568 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
2.31 (s, 3H), 3.73 (s,
NMR (75 MHz, CDCl3)
d
16.0 (d, JPC¼7.0 Hz), 19.2 (d, JPC¼2.6 Hz),
2
1
3H), 5.81 (br s, 1H), 6.41 (d, 1H, 3J¼7.6 Hz), 6.60–6.90 (m, 3H); 13C
62.1 (d, JPC¼5.5 Hz), 82.2 (d, JPC¼209.8 Hz), 114.7, 116.8 (d,
4
NMR (100 MHz, CDCl3)
d
21.1 (CH3), 51.6 (CH3), 83.3 (C), 114.3 (CH),
3JPC¼3.5 Hz), 123.9, 126.9, 132.7, 142.3 (d, JPC¼1.0 Hz), 154.0 (d,
120.2 (C), 124.8 (CH), 126.6 (CH), 127.0 (CH), 139.0 (CH), 1514 (C),
161.8 (C); MS: m/z (%) 221 (Mþ, 70), 162 (100), 130 (10). Anal. Calcd
for C11H11NO2S: C, 61.25; H, 5.01; N, 6.33. Found: C, 61.32; H, 4.99;
N, 6.35.
2JPC¼25.5 Hz); 31P NMR (120 MHz, CDCl3)
d 14.9; MS (EI) m/z (%)
333 (Mþ, 8), 211 (16), 196 (60), 183 (100), 148 (30), 107 (18), 69 (16);
Calcd for C13H17ClNO3PS [Mþ] 333.0355. Found [Mþ] 333.0355.
4.4.9. 3-Methyl-6-(trifluoromethyl)-4H-1,4-benzothiazin-2-
yl(diphenyl)phosphine oxide 9i
Compound 9i (371 mg, 86%) was obtained as a yellow solid as
described in the general procedure: mp 159–160 ꢀC (dec); IR (KBr)
4.4.4. Ethyl-3-methyl-4H-1,4-benzothiazine-2-carboxylate 9d
Compound 9d (183 mg, 78% starting from 1d; 66 mg, 28%
starting from 14b) was obtained as a yellow powder as described in
the general procedure: mp 128–130 ꢀC; IR (Nujol) nmax 3316, 1778,
nmax 3452, 3052, 1739, 1436, 1225, 1128, 1031 cmꢃ1
;
1H NMR
4
1713, 1561 cmꢃ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.17 (t, 3H,
(400 MHz, CDCl3)
d
2.24 (d, 3H, JPH¼1.4 Hz), 6.76 (d, 1H,
3J¼7.2 Hz), 2.17 (s, 3H), 4.03 (q, 2H, 3J¼7.2 Hz), 6.59 (d, 1H,
3JHH¼8.0 Hz), 6.88 (br s,1H), 6.99 (d,1H, 3JHH¼8.0 Hz), 7.43–7.47 (m,
3J¼7.6 Hz), 6.74–6.79 (m, 2H), 6.86–6.90 (m, 1H), 8.65 (s, 1H); 13C
6H), 7.51–7.80 (m, 4H), 7.88 (d, 1H, JHH¼2.9 Hz); 13C NMR
4
3
1
NMR (100 MHz, DMSO-d6)
d
14.4 (CH3), 19.8 (CH3), 59.7 (CH2), 85.8
(100 MHz, CDCl3)
d
19.4 (d, JPC¼2.9 Hz), 85.0 (d, JPC¼115.9 Hz),
3
3
(C), 114.6 (CH), 119.4 (C), 124.0 (CH), 125.6 (CH), 126.9 (CH), 139.0
(C), 152.8 (C), 162.8 (C); MS: m/z (%) 235 (Mþ, 88), 207 (19), 190 (10),
162 (100). Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95.
Found: C, 61.38; H, 5.63; N, 5.90.
111.2 (q, JFC¼3.6 Hz), 120.7 (q, JFC¼4.0 Hz), 123.2, 123.7 (q,
1JFC¼270.1 Hz), 126.4, 129.7 (q, JFC¼33.0 Hz), 131.6, 131.7, 131.8,
2
132.0, 132.0, 132.8, 142.3, 154.7 (d, JPC¼16.6 Hz); 31P NMR
2
(120 MHz, CDCl3)
d
27.5; 19F NMR (282 MHz, CDCl3)
d
ꢃ63.2; MS
(EI) m/z (%) 431 (Mþ, 8), 281 (10), 231 (6), 217 (100), 201 (50), 157
(18), 132 (16), 77 (8); Calcd for C22H17F3NOPS [Mþ] 431.0721. Found
[Mþ] 431.0731.
4.4.5. Benzyl-3-methyl-4H-1,4-benzothiazine-2-carboxylate 9e
Compound 9e (220 mg, 74%) was obtained as a yellow powder
as described in the general procedure: mp 152–154 ꢀC; IR (Nujol)
nmax 3257, 1792, 1741, 1537 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
2.30
4.4.10. Diethyl-[3-methyl-6-(trifluoromethyl)-4H-1,4-benzo-
thiazin-2-yl]phosphonate 9j
Compound 9j (323 mg, 88%) was obtained as a yellow solid as
described in the general procedure: mp 123–124 ꢀC; IR (KBr) nmax
(s, 3H), 5.20 (s, 2H), 5.66 (br s,1H), 6.39 (d,1H, 3J¼8.0 Hz), 6.80–6.90
(m, 3H), 7.28–7.42 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
21.8 (CH3),
66.6 (CH2), 91.1 (C), 114.7 (CH), 120.9 (C), 125.2 (CH), 127.0 (CH),
127.2 (CH), 128.3 (CH), 128.4 (CH), 129.0 (CH), 136.8 (C), 139.3 (C),
152.2 (C), 163.3 (C); MS: m/z (%) 297 (Mþ, 50), 220 (1), 206 (4), 190
(3),162 (100),149 (4),118 (12). Anal. Calcd for C17H15NO2S: C, 68.66;
H, 5.08; N, 4.71. Found: C, 68.53; H, 5.13; N, 4.75.
3275, 1625, 1533, 1465, 1328, 1225, 1117, 1025 cmꢃ1
;
1H NMR
4
(300 MHz, CDCl3)
d
1.32–1.38 (m, 6H), 2.28 (d, 3H, JPH¼1.7 Hz),
4.08–4.16 (m, 4H), 6.91 (br s, 1H), 6.92 (d, 1H, 3JHH¼8.0 Hz), 7.06 (d,
3
4
1H, JHH¼8.0 Hz), 7.85 (d, 1H, JHH¼4.8 Hz); 13C NMR (75 MHz,
3
3
CDCl3)
d
16.1 (d, JPC¼7.0 Hz), 19.2 (d, JPC¼2.6 Hz), 62.2 (d,
4.4.6. Methyl-3-ethyl-4H-1,4-benzothiazine-2-carboxylate 9f
Compound 9f (153 mg, 65%) was obtained as a yellow powder as
described in the general procedure: mp 120–122 ꢀC; IR (Nujol) nmax
2JPC¼5.0 Hz), 81.7 (d, 1JPC¼211.3 Hz), 111.0 (q, 3JFC¼3.4 Hz), 120.8 (q,
3JFC¼4.0 Hz), 123.6, 123.8 (q, JFC¼270.4 Hz), 126.4, 129.4 (q,
1
2JFC¼32.6 Hz), 141.6 (d, JPC¼1.0 Hz), 154.0 (d, JPC¼25.0 Hz); 31P
4
2
3275, 1765, 1735, 1521 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.20 (t,
NMR (120 MHz, CDCl3)
d
14.5; 19F NMR (282 MHz, CDCl3)
d
ꢃ63.2;
3H, 3J¼7.2 Hz), 2.71 (q, 2H, 3J¼7.2 Hz), 3.74 (s, 3H), 6.43 (d, 1H,
MS (EI) m/z (%) 367 (Mþ, 8), 281 (6), 230 (45), 217 (100), 207 (12),

9272
O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
157 (20); Calcd for C14H17F3NO3PS [Mþ] 367.0619. Found [Mþ]
367.0618.
the complete disappearance of the reagents (monitored by
TLC) furnishing methyl-3-[2-(aminocarbonyl)hydrazono]-2-[(2-
hydroxyethyl)sulfanyl]butanoate 3c, or ethyl-3-[2-(aminocarbon-
yl)hydrazono]-2-(1H-benzo[d]imidazol-2-ylsulfanyl)butanoate 20a,
or ethyl-3-[2-(aminocarbonyl)hydrazono]-2-(1H-1,2,4-triazol-3-
ylsulfanyl)butanoate 23a. Then the solvent was removed under
reduced pressure and the crude mixture was purified by chroma-
tography on silica (elution mixture: ethyl acetate) obtaining the
pure products 3c, 20a, 23a. To achieve the 4-substituted-5-methyl-
2,3-dihydro-1H-3-pyrazolones 12a, 22a, 25a a catalytic amount of
sodium hydride (0.1 mmol) was added to a solution of the pure
hydrazones 3c, 20a, 23a (1 mmol) in MeOH (15 mL) or directly to
the crude hydrazones in solution obtained as previously described.
The reaction mixture was allowed to stand at room temperature for
48–72 h until the complete disappearance of the starting reagent
(monitored by TLC, mixture: ethyl acetate). Pyrazolones 12a, 22a,
25a directly precipitated from the reaction medium and they were
collected by filtration as pure products.
4.4.11. Ethyl-1,2,3,3a-tetrahydrobenzo[b]cyclopenta[e][1,4]-
thiazine-3a-carboxylate 18a
Compound 18a (154 mg, 59%) was obtained as a yellow powder
as described in the general procedure: mp 56–58 ꢀC; IR (Nujol) nmax
3318, 1763, 1743, 1565 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 0.96 (t,
3H, 3J¼7.2 Hz), 1.95–2.05 (m, 2H), 2.05–2.20 (m, 1H), 2.62–2.70 (m,
1H), 2.80–3.02 (m, 2H), 3.98 (q, 2H, 3J¼7.2 Hz), 7.10 (dt, 1H,
3J¼7.6 Hz, 4J¼1.2 Hz), 7.20 (dt, 1H, 3J¼7.6 Hz, 4J¼1.2 Hz), 7.29 (dd,
1H, 3J¼8.0 Hz, 5J¼1.2 Hz), 7.40 (dd, 1H, 3J¼8.0 Hz, 5J¼1.2 Hz); 13C
NMR (100 MHz, CDCl3)
d 13.7 (CH3), 21.6 (CH2), 34.8 (CH2), 36.8
(CH2), 48.2 (C), 62.0 (CH2), 120.5 (C), 126.4 (CH), 126.7 (CH), 127.0
(CH), 127.2 (CH), 142.4 (C), 170.1 (C), 170.8 (C); MS: m/z (%) 261 (Mþ,
20), 231 (6), 217 (9), 202 (13), 188 (100), 173 (20). Anal. Calcd for
C
14H15NO2S: C, 64.34; H, 5.79; N, 5.36. Found: C, 64.40; H, 5.80; N,
5.32.
4.4.12. Methyl-5a,6,7,8,9,10-hexahydrobenzo[b]cyclohepta[e][1,4]-
thiazine-5a-carboxylate 18b
4.5.1. Ethyl-2-(diphenylphosphoryl)-2-[(2-hydroxyethyl)sulfanyl]-
1-methylethylidene-1-hydrazinecarboxylate 3b
Compound 18b (239 mg, 87%) was obtained as a yellow powder
as described in the general procedure: mp 62–64 ꢀC; IR (Nujol) nmax
Compound 3b (408 mg, 97%) was obtained as a colourless solid
as described in the general procedure: mp 125–126 ꢀC; IR (KBr)
3324, 1775, 1588 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.60–1.79 (m,
nmax 3411, 3171, 1725, 1525, 1437, 1230, 1185, 1044 cmꢃ1 1H NMR
;
4H), 1.92–2.05 (m, 2H), 2.15–2.22 (m, 1H), 2.32–2.39 (m, 1H), 2.79–
2.85 (m, 1H), 2.90–2.97 (m, 1H), 3.52 (s, 3H), 7.06 (dt, 1H, 3J¼7.6 Hz,
4J¼1.2 Hz), 7.16 (dt,1H, 3J¼7.6 Hz, 4J¼1.6 Hz), 7.25 (dd,1H, 3J¼7.6 Hz,
5J¼1.2 Hz), 7.40 (dd, 1H, 3J¼8.0 Hz, 5J¼1.2 Hz); 13C NMR (100 MHz,
(300 MHz, CDCl3) d 1.23–1.34 (m, 3H), 2.01 (s, 3H), 2.58–2.76 (m,
2H), 3.57–3.63 (m, 2H), 4.12–4.16 (m, 2H), 4.30 (br s, 1H), 4.64 (d,
2
1H, JPH¼9.3 Hz), 7.39–7.92 (m, 10H), 8.75 (br s, 1H); 13C NMR
3
(100 MHz, CDCl3)
d
13.6, 14.1, 34.7 (d, JPC¼5.7 Hz), 52.2 (d,
CDCl3)
d
25.7 (CH2), 27.3 (CH2), 30.6 (CH2), 34.0 (CH2), 40.3 (CH2),
1JPC¼67.7 Hz), 60.9, 61.2, 128.1, 128.2, 128.3, 128.4, 129.8, 130.3,
52.2 (CH2), 53.0 (CH3), 122.6 (C), 126.4 (CH), 126.5 (CH), 126.6 (CH),
127.0 (CH), 141.4 (C), 166.4 (C), 171.6 (C); MS: m/z (%) 275 (Mþ, 15),
261 (5), 250 (8), 230 (130), 216 (100). Anal. Calcd for C15H17NO2S: C,
64.43; H, 6.22; N, 5.09. Found: C, 64.48; H, 6.20; N, 5.07.
130.5, 130.6, 130.8, 130.9, 130.9, 131.0, 131.1, 131.2, 131.4, 131.7, 131.7,
131.8, 131.8, 148.6, 153.8; 31P NMR (120 MHz, CDCl3)
d 29.3; MS (CI)
m/z (%) 421 (Mþþ1, 100); Calcd for C20H25N2O4PS [Mþ] 420.1368.
Found [Mþ] 420.1377.
4.4.13. Ethyl-6,7,8,9,10,11-hexahydro-5aH-benzo[b]cycloocta[e]-
[1,4]thiazine-5a-carboxylate 18c
4.5.2. Methyl-3-[2-(aminocarbonyl)hydrazono]-2-[(2-
hydroxyethyl)sulfanyl]butanoate 3c
Compound 18c (230 mg, 76%) was obtained as a yellow powder
Compound 3c (221 mg, 89%) was obtained as a colourless
powder as described in the general procedure: mp 160–162 ꢀC; IR
as described in the general procedure: mp 57–59 ꢀC; IR (Nujol) nmax
3276, 1736, 1561 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
1.05 (t, 3H,
(Nujol) nmax 3308, 1784, 1731, 1598 cmꢃ1 1H NMR (400 MHz,
;
3J¼7.2 Hz), 1.41–1.50 (m, 1H), 1.56–1.67 (m, 3H), 1.73–1.90 (m, 4H),
2.09–2.16 (m, 1H), 2.53–2.60 (m, 1H), 2.69–2.76 (m, 1H), 2.81–2.94
(m, 1H), 4.05 (q, 2H, 3J¼7.2 Hz), 7.05–7.09 (m, 1H), 7.13–7.17 (m, 1H),
7.20–7.22 (m, 1H), 7.34–7.36 (m, 1H); 13C NMR (100 MHz, CDCl3)
DMSO-d6)
d
1.83 (s, 3H), 2.54 (t, 2H, 3J¼6.4 Hz), 3.48 (t, 2H,
3J¼6.4 Hz), 3.65 (s, 3H), 4.44 (s, 1H), 4.85 (s, 1H), 6.28 (br s, 2H), 9.30
(s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 13.1 (CH3), 33.2 (CH2), 52.6
(CH3), 54.7 (CH), 60.3 (CH2), 142.7 (C), 157.0 (C), 169.4 (C); MS: m/z
(%) 249 (Mþ, 10), 232 (10), 219 (28), 205 (22), 191 (38), 165 (45), 149
(100). Anal. Calcd for C8H15N3O4S: C, 38.55; H, 6.06; N, 16.86.
Found: C, 38.42; H, 6.11; N, 16.72.
d
13.7 (CH3), 24.5 (CH2), 25.0 (CH2), 26.4 (CH2), 26.8 (CH2), 28.4
(CH2), 31.3 (CH2), 36.2 (CH2), 52.3 (CH2), 62.1 (CH2), 121.7 (C), 126.3
(CH), 127.0 (CH), 127.6 (CH), 140.7 (C), 167.3 (C), 171.1 (C). MS: m/z
(%) 303 (Mþ, 10), 230 (100). Anal. Calcd for C17H21NO2S: C, 67.30; H,
6.98; N, 4.62. Found: C, 64.48; H, 6.20; N, 5.07.
4.5.3. 4-[(2-Hydroxyethyl)sulfanyl]-5-methyl-2,3-dihydro-1H-3-
pyrazolone 12a
4.5. General procedure for the synthesis of
hydrazones 3b,c, 20a, 23a and 4-substituted-5-methyl-2,3-
dihydro-1H-3-pyrazolones 12a, 22a, 25a
a
-substituted
Compound 12a (101 mg, 58% starting from 1c, 130 mg, 75%
starting from 3e) was obtained as a colourless powder as described
in the general procedure: mp 184–187 ꢀC; IR (Nujol) nmax 3159,
1736, 1606 cmꢃ1; 1H NMR (400 MHz, DMSO-d6)
d 2.60 (s, 3H), 2.48
To an ice-cooled solution of 1,2-diaza-1,3-butadiene 1a as
a mixture of E/Z isomers (1.0 mmol) in dichloromethane (5 mL), 2-
mercaptoethanol 2d (1 mmol) was added. The reaction was
allowed to stir at room temperature for 30 min. The solvent was
removed by rotary evaporation and the crude product was purified
by flash-column chromatography (silica gel, AcOEt) and recrystal-
(m, 2H), 3.38 (t, 2H, 3J¼6.8 Hz), 4.81 (br s, 1H), 10.16 (br s, 2H); 13
C
NMR (100 MHz, DMSO-d6) d 10.2 (CH3), 38.0 (CH2), 60.3 (CH2), 90.4
(C), 143.5 (C), 162.1 (C); MS: m/z (%) 174 (Mþ, 58), 156 (25), 143 (30),
130 (40), 99 (56), 85 (23), 57 (50), 44 (100). Anal. Calcd for
C6H10N2O2S: C, 41.37; H, 5.79; N, 16.08. Found: C, 41.31; H, 5.82; N,
16.16.
lized from AcOEt to afford
phosphine oxide. To obtain
a
-substituted hydrazone 3b derived from
-substituted hydrazones 3c, 20a, 23a,
a
4.5.4. Ethyl-3-[-2-(aminocarbonyl)hydrazono]-2-(1H-
2-mercaptoethanol 2d or 2-mercaptobenzimidazole 19a or 3-
mercapto-1,2,4-triazole 19b (2 mmol) was added to a solution
of 1,2-diaza-1,3-butadienes 1c,d (1 mmol) as a mixture of E/Z iso-
mers in MeOH (20 mL). The reaction mixture was allowed to stand
at room temperature under magnetic stirring for 5 h until
benzo[d]imidazol-2-ylsulfanyl)butanoate 20a
Compound 20a (312 mg, 93%) was obtained as a colourless
powder as described in the general procedure: mp 198–200 ꢀC; IR
(Nujol) nmax 3302, 1789, 1767, 1714, 1516 cmꢃ1; 1H NMR (400 MHz,
DMSO-d6)
d
1.12–1.19 (m, 3H), 1.95 (s, 3H), 4.16 (q, 2H, 3J¼7.2 Hz),

O.A. Attanasi et al. / Tetrahedron 64 (2008) 9264–9274
9273
5.45 (s, 1H), 6.30 (br s, 2H), 6.35 (br s, 1H), 7.05–7.14 (m, 2H), 7.38–
7.50 (m, 2H), 9.50 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
13.8
9c,d were purified by chromatography on silica (elution mixture:
ethyl acetate, cyclohexane 50:50).
d
(CH3), 14.3 (CH3), 56.2 (CH), 61.7 (CH2), 110.6 (CH), 120.9 (CH), 121.4
(CH), 122.1 (CH), 141.3 (C), 143.4 (C), 147.2 (C), 156.7 (C), 158.2 (C),
167.9 (C); MS: m/z (%) 335 (Mþ, 1), 261 (2), 246 (9), 185 (2), 162 (49),
150 (100). Anal. Calcd for C14H17N5O3S: C, 50.14; H, 5.11; N, 20.88.
Found: C, 50.05; H, 5.04; N, 20.97.
Acknowledgements
The Italian authors thank the Ministero dell’Universita`, dell’Is-
truzione e della Ricerca (MIUR)-Roma and the Universita degli Studi
`
di Urbino ‘Carlo Bo’ and the Spanish authors thank the University of
4.5.5. 4-(1H-Benzo[d]imidazol-2-ylsulfanyl)-5-methyl-2,3-
dihydro-1H-3-pyrazolone 22a
´
the Basque Country (UPV, GIU 06/51) and Direccion General de
Investigacio´ n del Ministerio de Ciencia y Tecnologı´a (MCYT, Madrid
Compound 22a (219 mg, 89% starting from 1d; 240 mg, 97%
starting from 20a) was obtained as a colourless powder as de-
scribed in the general procedure: mp 212–214 ꢀC; IR (Nujol) nmax
´
DGI, CTQ2006-09323) for financial support. A Ramon y Cajal con-
tract to J. M. S. and Predoctoral Fellowship to R.I. from Ministerio de
´
Ciencia y Tecnologıa is acknowledged.
3306,1765,1723,1618 cmꢃ1; 1H NMR (400 MHz, DMSO-d6)
d
2.16 (s,
3H), 7.03–7.07 (m, 2H), 7.30–7.38 (m, 2H), 10.43 (br s, 1H), 11.92 (br
s, 2H); 13C NMR (100 MHz, DMSO-d6)
12.6 (CH3), 79.2 (C), 113.7
References and notes
d
(CH), 120.9 (CH), 151.7 (C), 153.0 (C), 153.5 (C), 164.4 (C); MS: m/z (%)
246 (Mþ, 100), 213 (12), 162 (50), 150 (93), 118 (32), 97 (38). Anal.
Calcd for C11H10N4OS: C, 53.65; H, 4.09; N, 22.75. Found: C, 53.70; H,
4.04; N, 22.61.
1. (a) Schreiber, S. L. Science 2000, 287, 1964–1969; (b) Teague, S. J.; Davis, A. M.;
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Oxford, 1984; Vol. 3, pp 1037–1038.
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1075; (b) Renfroe, H. B. Eur. Pat. Appl. US 84-625946, 1986; Chem. Abstr. 1986,
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78–83; (d) Erker, T.; Schreder, M. E.; Studenik, C. Arch. Pharm. Med. Chem. 2000,
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J. Med. Chem. 1983, 26, 1614–1619.
4.5.6. Ethyl-3-[-2-(aminocarbonyl)hydrazono]-2-(1H-1,2,4-triazol-
5-ylsulfanyl)butanoate 23a
Compound 23a (272 mg, 95%) was obtained as a colourless
powder as described in the general procedure: mp 128–130 ꢀC; IR
(Nujol) nmax 3274, 1789, 1765, 1534 cmꢃ1 1H NMR (400 MHz,
;
DMSO-d6)
d
1.15 (t, 3H, 3J¼6.8 Hz),1.91 (s, 3H), 3.16 and 3.17 (2s,1H),
4.12 (q, 2H, 3J¼6.8 Hz), 5.08 (s, 1H), 6.19 (br s, 2H), 8.95 (s, 1H), 9.41
(s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 13.8 (CH3), 14.1 (CH3), 56.3
(CH), 61.5 (CH2), 141.6 (C), 144.9 (CH), 156.7 (C), 158.3 (C), 168.1 (C);
MS: m/z (%) 287 (Mþþ1, 8), 246 (4),197 (100),187 (20),155 (38),129
(27), 113 (100). Anal. Calcd for C9H14N6O3S: C, 37.76; H, 4.93; N,
29.35. Found: C, 37.65; H, 4.99; N, 29.22.
5. (a) Corelli, F.; Manetti, F.; Tafi, A.; Campiani, G.; Nacci, V.; Botta, M. J. Med. Chem.
1997, 40, 125–131; (b) Watanabe, Y.; Osanai, K.; Nishi, T.; Miyawaki, N.; Shii, D.;
Honda, T.; Shibano, T. Bioorg. Med. Chem. Lett. 1996, 6, 1923–1926; (c) Fujita, M.;
Ito, S.; Ota, A.; Kato, N.; Yamamoto, K.; Kawashima, Y.; Yamauchi, H.; Iwao, J.
J. Med. Chem. 1990, 33, 1898–1905; (d) Yamamoto, T.; Hori, M.; Watanabe, I.;
Harada, K.; Ikeda, S.; Ohtaka, H. Chem. Pharm. Bull. 2000, 48, 843–849; (e)
Fringuelli, R.; Schiaffella, F.; Vecchiarelli, A. J. Chemother. 2001, 13, 9–14; (f)
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2006, 43, 1371–1378; (g) Armesine, D.; Trapani, G.; Arrivo, V.; Laraspata, E.;
Morlacchi, F. J. Heterocycl. Chem. 2000, 37, 1611–1616; (h) Cecchetti, V.; Tab-
arrini, O.; Schaiaffella, F.; Fravolini, A. Bioorg. Med. Chem. Lett. 2000, 10, 465–
468; (i) Prasad, R. N. J. Med. Chem. 1968, 12, 290–294.
6. For reviews, see: (a) Handbook of Organophosphorus Chemistry; Engel, R., Ed.; M.
Dekker: New York, NY, 1992; (b) Kafarski, P.; Lejezak, B. Phosphorus Sulfur 1991,
63, 193–215; (c) Hoagland, R. E. In Biologically Active Natural Products; Culter,
H. G., Ed.; ACS Symposium Series; American Chemical Society: Washington,
DC, 1988; Vol. 380, p 182; (d) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in
Everyday Living; American Chemical Society: Washington DC, 1987; p 333.
7. For reviews of 1,2-diaza-butadienes, see: (a) Attanasi, O. A.; Caglioti, L. Org. Prep.
Proced. Int. 1986, 18, 299–327; (b) Attanasi, O. A.; Filippone, P. Synlett 1997,
1128–1140; (c) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.;
Santeusanio, S. Arkivoc 2002, 274–292.
4.5.7. 5-Methyl-4-(1H-1,2,4-triazol-3-ylsulfanyl)-2,3-dihydro-1H-
3-pyrazolone 25a
Compound 25a (181 mg, 92% starting from 1d; 193 mg, 98%
starting from 23a) was obtained as a colourless powder as de-
scribed in the general procedure: mp 242–244 ꢀC; IR (Nujol) nmax
3243, 1787, 1723, 1576 cmꢃ1. 1H NMR (400 MHz, DMSO-d6)
d
1.99 (s,
3H), 4.13 (br s, 1H), 6.96 (s, 1H), 7.80 (br s, 1H), 9.04 (br s, 1H). 13
C
NMR (100 MHz, DMSO-d6)
d 13.6 (CH3), 75.6 (C), 150.0 (C), 153.7
(CH),165.8 (C). MS: m/z (%) 197 (Mþ,100),155 (23),129 (10), 97 (63),
86 (15). Anal. Calcd for C11H10N4OS: C, 36.54; H, 3.58; N, 35.51.
Found: C, 36.70; H, 3.64; N, 35.40.
4.6. General procedure for the synthesis of 3,4-dihydro-2H-
1,4-thiazines 5c,d,h,i and 1,4-benzothiazines 9c,d in solid
phase
8. For recent communications, see: (a) Attanasi, O. A.; Davoli, P.; Favi, G.; Fili-
ppone, P.; Forni, A.; Moscatelli, G.; Prati, F. Org. Lett. 2007, 9, 3461–3464; (b)
Attanasi, O. A.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.; Spinelli, D.; Stenta,
M. Adv. Synth. Catal. 2007, 349, 907–915; (c) Schmidt, A.; Karapetyan, V.; At-
tanasi, O. A.; Favi, G.; Go¨rls, H.; Mantellini, F.; Langer, P. Synlett 2007, 2965–
2968; (d) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini, S.;
Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006, 71, 5897–5905;
(e) Attanasi, O. A.; Baccolini, G.; Boga, C.; De Crescentini, L.; Filippone, P.;
Mantellini, F. J. Org. Chem. 2005, 70, 4033–4037; (f) Attanasi, O. A.; De Cres-
centini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Santeusanio, S. J. Org. Chem.
2004, 69, 2686–2692; (g) Schantl, J. G.; Na`denik, P. Synlett 1998, 786–788.
9. Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M. Tetrahedron 2005, 61,
2815–2830; (b) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M. Tetra-
hedron Lett. 2004, 45, 4345–4348.
To a magnetically stirred solution of N]N-polymer-bound 1,2-
diaza-1,3-butadiene 14a,b prepared starting from polymer-bound
p-toluenesulfonyl hydrazide 13 (1 mmol),18 the thiolamine 2a,b
(5 equiv) was added at room temperature in MeOH/THF (1:1,
10 mL). After 10 min, the solution was filtered and the resin was
washed with MeOH, THF, DCM (3ꢂ5 mL), and then treated with
sodium acetate (2 equiv) in MeOH/THF (1:1, 10 mL). The mixture
was allowed to stand at room temperature for 24–28 h under
magnetic stirring, obtaining the 3,4-dihydro-2H-1,4-thiazines
5c,d,h,i directly in solution in satisfactory purity. To synthesize
compounds 9c,d, 2-aminothiophenol 8a (5 equiv) in MeOH/THF
(1:1, 10 mL) was added to N]N-polymer-bound 1,2-diaza-1,3-bu-
tadienes 14a,b prepared starting from polymer-bound p-toluene-
sulfonyl hydrazide (1 mmol). The reaction mixture was allowed to
stand at room temperature under magnetic stirring for 6–8 h fur-
nishing directly 1,4-benzothiazines 9c,d in solution. The products
´
10. Palacios, F.; Aparicio, D.; Lopez, Y.; de los Santos, J. M.; Alonso, C. Eur. J. Org.
Chem. 2005, 1142–1147.
11. (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem. 2006, 71,
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J. M.; Gil, J. I.; Alonso, J. M. J. Org. Chem. 2002, 67, 7283–7288; (c) Palacios, F.;
´
Ochoa de Retana, A. M.; Martınez de Marigorta, E.; de los Santos, J. M. Eur. J. Org.
Chem. 2001, 2401–2414.

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ˇ
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20. For recent reviews, see: (a) Lelais, G.; MacMillan, D. W. C. In New Frontiers in
Asymmetric Catalysis; Mikani, K., Lautens, M., Eds.; John Wiley: New York, NY,
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hydrazone derivatives bearing a good leaving group at C
a-carbon atom of the
hydrazono carbon-nitrogen double bond.9
16. (a) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem. Soc. 1994, 116,
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21. (a) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671–672;
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