Novel β-lactam condensed 3-thiaquinolines: an efficient synthesis and structural characterization

Article abstract of DOI:10.1016/j.tet.2007.09.079

Quinoline analog 2-aryl-4H-3,1-benzothiazine derivatives 8-13, obtained by the condensation of o-aminobenzyl chloride 1 with?substituted thiobenzamides 2-7, were transformed to azeto[2,1-a][3,1]benzothiazin-1-one derivatives 18-23a,b,c and 24d,e by reaction with the corresponding substituted acetyl chlorides 14-17 in the presence of triethylamine. The structures of the new molecules were determined by NMR spectroscopy and electron ionization (EI) mass spectrometry. The typical EI⁺ mass spectrometric fragmentations of 8-13 and 18-23a,b,c and 24d,e are discussed in detail.

Full text of DOI:10.1016/j.tet.2007.09.079

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1002–1011
Novel b-lactam condensed 3-thiaquinolines: an efficient
synthesis and structural characterization
Peter Csomos,a,b,c Lajos Fodor,a,b,c, Gabor Bernath,a,b Jari Sinkkonen,d Jari Salminen,d
*
ꢀ
ꢀ
ꢀ
€
ꢀ
Kirsti Wiinamaki and Kalevi Pihlaja
d
d
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6701, PO Box 121, Hungary
bOrganic Catalysis and Stereochemistry Research Group of the Hungarian Academy of Sciences, Hungary
cCentral Laboratory, County Hospital, H-5701 Gyula, PO Box 46, Hungary
dStructural Chemistry Group, Department of Chemistry, University of Turku, FIN-20014 Turku, Finland
Received 18 June 2007; revised 10 September 2007; accepted 27 September 2007
Available online 2 October 2007
ꢀ
Dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract—Quinoline analog 2-aryl-4H-3,1-benzothiazine derivatives 8–13, obtained by the condensation of o-aminobenzyl chloride 1
with substituted thiobenzamides 2–7, were transformed to azeto[2,1-a][3,1]benzothiazin-1-one derivatives 18–23a,b,c and 24d,e by reaction
with the corresponding substituted acetyl chlorides 14–17 in the presence of triethylamine. The structures of the new molecules were deter-
mined by NMR spectroscopy and electron ionization (EI) mass spectrometry. The typical EI+ mass spectrometric fragmentations of 8–13 and
18–23a,b,c and 24d,e are discussed in detail.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The reaction most widely used for the construction of azeti-
dinone rings is the [2+2] ketene–imine cycloaddition reac-
tion, the Staudinger reaction.2 Several variants of this
reaction have been described, in which the ketene is formed
in situ from precursors.2,14–16 In most cases, the reactions
occur at low temperature and cis selectivity is observed.2
Since the discovery of penicillin, b-lactams (including peni-
cillins, cephalosporins, monobactams, and carbapenems)
have become a major class of antibacterial agents. Because
of their widespread use, bacterial resistance has developed
into a major health problem worldwide over the past few de-
cades.1 This has motivated growing interest in the prepara-
tion and biological evaluation of new types of b-lactams.2
Moreover, some derivatives possess various other useful
pharmacological effects. They include, for example, inhibi-
tors of human leucocyte elastase,3 cholesterol acyl transfer-
ase,4 and thrombin.5 From a synthetic aspect, azetidin-2-one
derivatives are versatile intermediates in the construction of
complex heterocycles,6 non-proteogenic amino acid deriva-
tives, peptides, and peptide turn mimetics.7–9 They can be
utilized in the synthesis of different natural compounds,
such as apiosporamide or taxol derivatives.10,11 In the former
compounds, which contain a relatively strained b-lactam
structural unit, the reaction with nucleophilic reagents usu-
ally takes place at the N1–C2 bond. Further, some b-lactam
derivatives (e.g., a-halo-b-lactams) are versatile synthons
furnishing a wide variety of functionalized lactams.12,13
In an earlier paper,17 we investigated the mechanism of the
reactions between differently substituted 4-thia analogs of
isoquinolines, 4H- and 2H-1,3-benzothiazine derivatives
and substituted acetyl chlorides. The selectivities of the reac-
tions and the stereochemistry of the linearly or angularly
condensed b-lactams formed were also extensively stud-
ied.18–20 During our investigations of the reactivity of the
monochloro-b-lactams prepared, we developed a ring-trans-
formation method for the synthesis of 2-methoxycarbonyl-
3-aryl-4,5-dihydro-1,4-benzothiazepines.21 We recently
extended this ring-enlargement reaction to the preparation
of 2,3-disubstituted 4,1-benzothiazepines. When the mono-
chloro-b-lactam derivative 2-chloro-2a-phenyl-2,2a-dihy-
dro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (18a) was
treated with sodium ethoxide in dry ethanol at ambient
temperature, two products were obtained: 3-ethoxycar-
bonyl-2-phenyl-3,5-dihydro-4,1-benzothiazepine and 3-eth-
oxycarbonyl-2-phenyl-1,5-dihydro-4,1-benzothiazepine,
which are in a tautomeric relationship to each other. Surpris-
ingly these, 4,1-benzothiazepines could be separated by
column chromatography and they manifested the rare phe-
nomenon of desmotropy.22
Keywords: Sulfur, nitrogen heterocycles; b-Lactams; NMR spectroscopy;
Mass spectrometry.
* Corresponding author. Tel.: +36 66 463763; fax: +36 66 526539; e-mail:
fodor@pandy.hu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.079

P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
R2
1003
S
R2
S
110-120 °C
Cl
+
H2N
neat, 30 min.
N
.
NH2 HCl
R1
R1
8–13
2–7
1
2, 8: R1 = R2 = H; 3, 9: R1 = Cl, R2 = H; 4, 10: R1 = CH3, R2 = H; 5, 11: R1 = H,
R2 = Cl; 6, 12: R1 = H, R2 = CH3; 7, 13: R1 = H, R2 = OCH2CH3
Scheme 1. Preparation of starting 4H-3,1-benzothiazine derivatives 8–13.
As a continuation of our investigations in the field of
sulfur- and nitrogen-containing condensed-skeleton hetero-
cycles23–25 and azetobenzothiazines,17–20 our current aim
was the preparation and structure analysis of different regio-
isomeric 3-thioquinoline analog, azeto[1,2-a][3,1]benzothi-
azin-1-one derivatives, which could be useful intermediates
in 4,1-benzothiazepine desmotrope pairs.22
was obtained. The NMR spectrum of the crude product of
the latter reaction revealed a 73:27 mixture of 24d and 24e
(Scheme 2).29
2.2. NMR spectroscopy
The 1H and 13C NMR signals were assigned via the informa-
tion achieved from the DQF-COSY, HSQC (or CH-Shift), and
HMBC (or COLOC) spectra. Measurements were made at
various temperatures; the presented assignments usually re-
late to the temperatures at which the signals were sharpest.
In cases where full assignment was possible at room temper-
ature (+25 ꢀC) and at low temperature (ꢁ60 ꢀC), the results
are presented for both (Tables 1 and 2 in Supplementary data).
2. Results and discussion
2.1. Synthesis
The starting 2-aminobenzyl chloride hydrochloride (1) was
obtained by the treatment of 2-aminobenzyl alcohol with
thionyl chloride.26 Fusion of 1 with thiobenzamides 2–7 pro-
vided the key intermediate 4H-3,1-benzothiazine derivatives
8–13 in moderate to good yields (Scheme 1).27 As concerns
this type of compounds, it is worthy of mention that some
2-(2,4-dihydroxyphenyl)-4H-3,1-benzothiazines were recen-
tly demonstrated to display excellent activities against the
human breast cancer T47D line and strong antifungal
effects against certain strains of molds, yeasts, and dermato-
phytes.28
The starting compounds 10–13 (8,9 were reported previ-
ously27) gave sharp signals and the interpretation of their
NMR spectra was straightforward. The heterocyclic skele-
ton can be assumed to be planar because of the shape of
the H-4 signal. Both of these protons exhibit the same
chemical shift and the signal is a singlet. For compounds
18–23a,b,c and 24d,e, the formation of a four-membered
b-lactam ring makes the structures non-planar and H-4 are
no longer magnetically equivalent: two doublets are ob-
1
served, with a H–1H coupling constant of approximately
For the preparation of our target b-lactam derivatives, we set
out to use the Staudinger reaction. The reaction of 8 with
chloroacetyl chloride (14) in dichloromethane in the
presence of triethylamine failed at room temperature.
When the reaction was carried out in refluxing benzene,18
azeto[2,1-a][3,1]benzothiazin-1-one derivative 18a was ob-
tained in good yield. Similarly, 18b,c, 19–23a,b,c, and 24d,e
were prepared under the conditions given in Section 4 and in
Scheme 2 by the reaction of 4H-3,1-benzothiazine deriva-
tives 8–13 with the corresponding acid chlorides 14–16.
When a-chloro phenylacetyl chloride (17) was used as
ketene source, a diastereomeric mixture of 24d and 24e
16 Hz. NOE difference spectra were also measured in order
to establish the spatial structures of the molecules. However,
only very limited NOE correlations were observed. Typi-
cally, NOE was detected from H-4 to H-5, which can serve
as further confirmation of the assignment, but it does not
furnish information on the 3D structure. When H-4 were
irradiated, no enhancement of the 2a-aryl ring protons was
observed. Further, no NOE was seen from H-2 to the 2a-
aryl protons (structures a and c). Accordingly, it can be as-
sumed that H-2 and 2a-aryl are trans to each other, and
thus 2a-aryl is cis to 2-Cl (a) or 2-Ph (c), as expected for
the Staudinger reaction.2
R2
S3
5
4
R1
R3
CH C
R4
4a
8a
O
R2
6
7
Et3N, reflux
toluene
S
+
2a
N
N
R3
R4
Cl
8
9
O 1 2
R1
8–13
14–17
18–23a,b,c; 24d,e
8: R1 = R2 = H;
18,24: R1 = R2 = H; 19: R1 = Cl, R2 = H;
14: R3 = Cl, R4 = H;
15: R3 = Cl, R4 = Cl;
16: R3 = Ph, R4 = H;
17: R3 = Ph, R4 = Cl
9: R1 = Cl, R2 = H;
20: R1 = CH3, R2 = H; 21: R1 = H, R2 = Cl;
22: R1 = H, R2 = CH3; 23: R1 = H, R2 = OCH2CH3
10: R1 =CH3, R2 = H;
11: R1 = H, R2 = Cl
12: R1 = H, R2 = CH3;
a: R3 = Cl, R4 = H; b: R3 = Cl, R4 = Cl;
c: R3 = Ph, R4 = H; d: R3 = Cl, R4 = Ph
e: R3 = Ph, R4 = Cl
13: R1 = H, R2 = OCH2CH3
Scheme 2. Synthesis of azeto[2,1-a][3,1]benzothiazin-1-one derivatives (18–23)a–c and 24d,e.

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P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
Another noteworthy difference for compounds 18–23a,b,c
and 24d,e as compared with the starting compounds is the
restricted rotation of the Ph substituents, which demonstrate
a significant broadening of the NMR signals. The com-
pounds are divided below into subsets, structures behaving
similarly being discussed together.
2.2.3. Compounds 24d and 24e. The NMR results on these
two diastereomers were rather similar. In both cases, very
broad and unassignable signals were observed at room tem-
perature. When the temperature was decreased, the signals
sharpened, but remained markedly broad. At ꢁ60 ꢀC, the
signals were sharp enough to allow measurement of the
2D spectra and the assignment of the signals. As a common
feature, the aryl ring at position 2a gave non-symmetric sig-
nals (rotation stopped), whereas the Ph at position 2 gave
symmetric signals. The latter were still very broad at
ꢁ60 ꢀC for 24d. For 24e, they were sharper, which resem-
bles the situation in, for example, 18c. It may therefore be
supposed that for 24e the Ph substituent corresponds to R3.
2.2.1. Structures containing unsubstituted or p-sub-
stituted 2a-aryl rings 18–20a,b,c. The NMR signals for
2-Cl and 2,2-di-Cl-substituted compounds (a and b) were
markedly broadened at room temperature (25 ꢀC). As the
temperature was decreased to ꢁ60 ꢀC, the signals sharpened
and individual signals were detected for each 2a-aryl proton
and carbon. This indicates that the rotation of the 2a-aryl
group is hindered at room temperature and totally restricted
at low temperature, where no symmetric signals are obser-
ved although the aryl group is symmetric. Higher tempera-
tures (up to +55 ꢀC) were also tried for 18b. The signals
proved to be sharper than that at room temperature and the
signals for 2a-Ph were symmetric, indicating faster rotation
of this Ph group. The effect of mono- or di-Cl substitution
did not seem to play an essential role in the hindered rotational
behavior. The 2-Ph-substituted compounds (c) exhibited in-
teresting properties. At room temperature, relatively sharp
signals were observed and both aryl groups (2a-aryl and
2-Ph) exhibited symmetric signals. From this, it can be con-
cluded that 2-Ph presents less steric hindrance for the rota-
tion of 2a-aryl than does the 2-Cl substituent. When the
temperature was lowered, the signals first broadened and
then sharpened again, and at ꢁ60 ꢀC rather sharp signals
were observed. The interesting feature is that the signals
for the 2a-aryl substituent were non-symmetric, while those
for the 2-Ph substituent were symmetric. This shows that the
rotation of the 2a-aryl group is totally restricted, but the ro-
tation of 2-Ph is still fast on the NMR time-scale. This is an
intriguing case where two aryl groups situated on vicinal car-
bons display very different rotational behavior.
In conclusion, it may be stated that the 2-Ph substituent
exhibits less steric hindrance for the rotation of the 2a-aryl
group than do the 2-Cl or 2,2-di-Cl substituents. Further, de-
pending on the substitution of the 2a-aryl group, its rotation
may be restricted or not. However, regardless of the 2a-aryl
group, the rotation of the 2-Ph group is not hindered.
2.3. Mass spectra
The mass spectra of the compounds studied nicely confirmed
the proposed structures. The molecular ions of 8–13 form the
base peaks of the spectra, whereas for the other compounds
ꢂ
ꢂ
they correspond to the ion A+ ¼[MꢁR1(R2)C]C]O]+
(Scheme 3), with the exception of compounds 23a,b,c where
the o-OC2H5 group assumes a predominating role and the
base peak of 23a,b corresponds to [MꢁOC2H5]+ and that of
23c apparently to [MꢁPhC]C]O]+, m/z 270. In fact, the
latter ion was fairly strong for all compounds where R3¼Ph
(Table 6 in Supplementary data) and its relative abundance
(RA) varied from 28% for 18c to 83% for 23c when corrected
ꢂ
ꢂ
for the 13C influence of the ion A+ , [MꢁPhCH]C]O]+ .
[M−S]+
−C2H4O
8–12
C13H8R1(2)+
[M−CH3]+
m/z 209
[M−H]+
−HCN
13
2.2.2. Structures with o-substituted 2a-aryl rings 21–
23a,b,c. For the 2-Cl and 2,2-di-Cl-substituted compounds
(a and b), sharp signals were observed at room temperature.
This indicates that the 2a-aryl group rotates either very slowly
or fast on the NMR time-scale, because the o-substituted 2a-
aryl is not symmetric and the decision cannot be made on the
basis of the symmetry of the NMR signals. We expected the
former possibility, since ortho substitution is more likely to
hinder the rotation as compared with para substitution. To
check on this expectation, we also measured these com-
pounds at low temperatures. As no signal broadening or other
significant changes were observed, the rotation can be consid-
ered to have stopped even at room temperature. For com-
pounds 21c and 22c, the signals were clearly broadened at
room temperature (not so much as to prevent the assignment
at room temperature). This is in harmony with the above con-
clusion that 2-Ph allows the 2a-aryl to rotate more freely. The
signals remained relatively broadened at low temperature,
and the situation with sharp signals and stopped rotation
well below the coalescence was not achieved. Compound
23c behaved like Cl-substituted compounds 23a and 23b,
giving sharp signals at all temperatures. The o-OCH2CH3
substituent is apparently so bulky that it does not permit rota-
tion at all. However, it should be noted that the 2-Ph group in
the c compounds gave symmetric signals in each case.
C7H6S+
[M−H]+
−H
−R
−H
−R
M+
C7H5S+
[M−R]+
−H
−RH
[M−RH]+
Scheme 3. Main (common) fragmentations of 8–13.
2.3.1. 4H-3,1-Benzothiazine derivatives 8–13. As a whole,
the fragmentation of 3,1-benzothiazines 8–13 is fairly
straightforward (Scheme 3 and Table 3 in Supplementary
data).
All of them gave a moderate [MꢁH]+ peak except 13 (RA
2%). Similarly, they all furnished moderate or fair amounts
ꢂ
of [MꢁR1(2)]+ (6–60%) and [MꢁR1(2)H]+ (5–29%). The
highest relative abundance (RA) was observed for the o-Cl
derivative 11, where the Cl can obviously abstract hydrogen
ꢂ
most easily. Similarly, they all exhibited [MꢁS]+ (RA 6–
14%) and [MꢁSH]+ (RA 6–79%). The latter ion was stron-
gest for 12 and 13, with o-CH3 or o-OC2H5, respectively,
where the S atom can easily abstract an hydrogen atom
from these ortho substituents. All of compounds 8–13 also
yielded clear M2+ peaks (Table 3 in Supplementary data),

P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
1005
ꢂ
ꢂ
and clear ions [C13H8R1(2)]+, formed from [MꢁSH]+
through the loss of HCN, except for 13, where the ion with
the same nominal mass corresponds to [MꢁCH3ꢁC2H4O]+
C8H6O+ , the counter ion of A+ , i.e., this ion is resonance-sta-
bilized by the Ph group (Tables 5 and 6 in Supplementary
data).
ꢂ
instead. The last two common ions are C7H6S+ and C7H5S+
with m/z 122 and 121, respectively, the former of which is
obtained directly from the molecular ion and the latter
from the ion [MꢁH]+ but both are also formed via some sec-
ondary ions. ortho Substitution (11–13) clearly increases the
fragmentation in comparison with the unsubstituted or
p-substituted derivatives (8–10), the higher mass fragments
resulting mainly from primary fragmentations or fragmenta-
tions after the loss of a hydrogen atom (Table 4 in Supple-
mentary data).
Similarly, the ion m/z 132, C8H6NO+, was present for all of
the compounds, although it was relatively or very weak for
18–23c and 24d,e. One route to this ion is via [MꢁCl]+,
which was missing from the latter compounds, this possibly
being a reason for the weakness of the former ion. C7H6NS+,
m/z 136 (Table 6 in Supplementary data), was present for
most of the compounds (RA 5–20%), but very weak or miss-
ing for 18–23c and 24d,e (RA 0–4%). One route to this ion is
ꢂ
via A+ , but Cl substitution, and especially o-Cl 21a,b,c,
obviously enhances this process.
2.3.2. Azeto[1,2-a][3,1]benzothiazin-1-one derivatives
18–23a,b,c and 24d,e. The common fragmentations are
summarized in Scheme 4 and Table 5 in Supplementary
data. All 2-Cl and 2,2-di-Cl-substituted compounds lose
Cl, this loss being weakest for p-Cl derivatives, strongest
for o-Cl and moderate for those derivatives without a Cl
substituent on the Ph ring. Obviously the loss of Cl occurs
from C-2 and from the ortho position of the aryl substituent
(or o-Cl enhances the loss of Cl from C-2), whereas the p-Cl
substitution hinders this loss.
A few more fragmentations may be mentioned. Compounds
22a,b readily lost o-CH3 and 23a,b o-OC2H5, to give very
strong [MꢁCH3]+ or [MꢁOC2H5]+ (Table 6 in Supplemen-
tary data). Compounds 18b, 21–23b all gave the ion m/z
ꢂ
ꢂ
299 corresponding to [MꢁHCl]+ (18b), [MꢁClꢁCl]+
(21b,23b) and [MꢁCH3ꢁCl]+ (22b) (see Table 6 in Supple-
mentary data); in fact, 20b and 20a, 22a, 23a also gave
moderate peaks (m/z 313, 279, 279, and 309, respectively)
ꢂ
corresponding to [MꢁHCl]+ . Compounds 18–23c and
24d,e in turn furnished the ion m/z 210 (18c and 20c only
C7H6NS+
m/z 136
a
weak one), C14H10S+, obtained via
a concerted
mechanism from the intermediate [MꢁC8H6NOS]+, e.g.,
C14H10SCl+ for 24d and 24e. The other ions listed in Table
6 in Supplementary data are characteristic only of the com-
pounds they represent. Elemental compositions were deter-
mined for several of them by means of accurate mass
measurements, as indicated in the table.
C8H6NO+
[M−Cl]+
C14H10NS+
m/z 132
[M−R3(R4)C=C=O]+
A
+
Except 18−23c,
24d,e
−H
18,24d,e
18−23c
C8H6O+
[A−S]+
[A−H]+
M
Three more ions deserve special mention: m/z 204, C15H10N+,
for 21a,b and for 22a,b,c, m/z 180, C13H10N+, for 23a,b,c and
m/z 155 for 19a,b,c and 21a,b,c, C7H4SCl+. As shown by the
B/E and B2/E metastability studies, the first is formed via the
loss of Cl from the intermediate C15H14NCl+ for 21a,b and
C7H6S+
−H
[A−SH]+
−HCN
m/z 122
C13H8R1(2)+
−H
C7H5S+
m/z 121
ꢂ
from A+ for 22a,b,c. The second originates from the interme-
ꢂ
diate C14H10NO+, and the third from [MꢁCl]+ and A+ .
Scheme 4. Main (primary) fragmentations of 18–23a,b,c and 24d,e.
ꢂ
The base peak always corresponds to A+ ¼[MꢁR3(R4)-
3. Conclusion
ꢂ
C]C]O]+ , even in the case of 21c, if it is taken into
account that its 13C counterpart is responsible for m/z 260
being the base peak. In fact, A+ꢂ corresponds to the regener-
ation of 8–13. All of 18–23a,b,c and 24d,e gave moderate
This paper has described the syntheses of 3-thiaquinoline
analog 2-aryl-4H-3,1-benzothiazine derivatives 8–13 and
their transformation to azeto[2,1-a][3,1]benzothiazin-1-one
derivatives 18–23a,b,c and 24d,e. Their structures were con-
firmed by 1H and 13C NMR spectroscopy and electron ioni-
zation (EI) mass spectrometry and their fragmentation
behavior under EI is discussed in some detail. The b-lactams
obtained are useful starting materials for the preparation of
4,1-benzothiazepine derivatives, which exhibit the rare phe-
nomenon of desmotropy. Further investigations on the syn-
theses of these desmotrope pairs are under way.
ꢂ
peaks for [AꢁH]+, [AꢁS]+ , and [AꢁSH]+ (Scheme 4 and
Table 5 in Supplementary data), the latter two of which
were very much enhanced for o-CH3-substituted 22a,b,c,
ꢂ
and also [AꢁS]+ for o-OC2H5-substituted 23a,b,c. The
interesting ions include C13H8R1(2)+ (cf. also Table 3 in
Supplementary data), formed from [AꢁSH]+ similarly as
in the case of 8–13, through loss of HCN. C7H6S+ and
C7H5S+ (Table 5 in Supplementary data) were also typical
for the 4H-3,1-benzothiazines (Table 3 in Supplementary
data).
4. Experimental
There were a few ions, which were common for most or all
of these compounds. The ion m/z 224 appeared in all the
spectra, although it is a primary fragment only for com-
pounds 18, 24d and 24e and was very weak for compounds
20. All 2-Ph substituted derivatives 18–23c exhibited the ion
4.1. General methods
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were

1006
P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
performed with a Perkin–Elmer 2400 CHNS elemental
analyser. IR spectra were recorded in KBr pellets with a
UNICAM SP 100 double beam spectrometer. Merck
Kieselgel 60F254 plates were used for TLC: the eluent was
n-hexane–ethyl acetate 9:1. o-Aminobenzyl alcohol was
purchased from Fluka. Thiobenzamides were prepared by
sulfurization from the corresponding benzamides, using
the Lawesson reagent.30 Compounds 8 and 9 were prepared
by the given general procedure; their physical data were
identical to the published data.27
4.4. General procedure for the preparation of 4H-3,1-
benzothiazine derivatives 8–13 from 2-aminobenzyl
chloride hydrochloride (1)
To a stirred and cooled (10–15 ꢀC) mixture of thionyl chlo-
ride (6.5 mL, 89 mmol) and chloroform (30 mL), 2-amino-
benzyl alcohol (5 g, 41 mmol) dissolved in chloroform
(100 mL) was added dropwise over 1 h. After the addition,
the reaction was stirred for a further 1 h at room temperature
and then evaporated (50 ꢀC). The crystalline residue was
taken up in diethyl ether (40 mL), filtered and washed with
diethyl ether (2ꢃ40 mL). Compound 1 was used without
further purification.
4.2. NMR spectroscopy
NMR spectra were acquired with a Bruker Avance 500 spec-
trometer operating at 500.13 MHz for 1H and at 125.77 MHz
for 13C, or with a JEOL JNM-L-400 spectrometer operating
For the transformation of compound 1, the method of
El-Desoky27 was used with slight modifications, as follows.
2-Aminobenzyl chloride hydrochloride (1) (15 mmol) was
thoroughly mixed with the appropriate thioamide (2–7)
(15 mmol) and the mixture was maintained at 110–120 ꢀC
for 30 min. To the melt, CHCl3 (30 mL) was added and
the solid formed was suspended. To the suspension, water
was added (10 mL) and the water phase was made just alka-
line with 10% NaOH solution under intensive shaking. The
organic layer was separated, extracted with water (30 mL),
dried (Na2SO4), filtered, and evaporated. The residues thus
obtained were purified by column chromatography with
n-hexane–ethyl acetate 9:1 as eluent to give 8–13. Benzothi-
azine derivatives 8 and 9 are known compounds.27
1
at 399.78 MHz for H and at 100.54 MHz for 13C. The
spectra were recorded at variable temperatures (from
ꢁ60 ꢀC to +55 ꢀC) in CDCl3 (see Tables 1 and 2 in
Supplementary data). Proton and carbon spectra were refer-
enced internally to the TMS (tetramethylsilane) signal at
0.00 ppm.
1D proton spectra consisting of 32k data points were acquired
with normal single-pulse excitation and a 45ꢀ flip angle. 1D
carbon spectra consisting of 65k data points were acquired
with normal single-pulse excitation, broad-band proton
decoupling, a 45ꢀ flip angle and spectral widths of 30 kHz,
and with 0.3–1.0 Hz exponential weighting applied prior to
Fourier transformation. NOE difference experiments were
carried out with saturation times of 6–8 s, and enhancements
were expressed as a percentage, integrated with respect to the
irradiated spin (set to ꢁ100%). 2D heteronuclear one-bond
correlation experiments were performed by using either car-
bon-detected CH-shift correlations with partial homonuclear
decoupling in the f1 dimension (Jeol spectrometer) or proton-
detected HSQC with gradient selection (Bruker). Long-range
heteronuclear correlation experiments included either car-
bon-detected COLOC (Jeol) or proton-detected HMBC
with gradient selection (Bruker). The one-bond coupling
constant was 145 Hz and the long-range coupling constants
were 8–10 Hz in proton–carbon correlation spectra. 2D ho-
monuclear H,H-correlation experiments were performed by
using phase-sensitive double quantum filtered COSY. The
spectral widths of the 2D spectra were optimized from the
1D spectra. All spectra were recorded with standard pulse
sequences.
4.4.1. 2-(4-Methylphenyl)-4H-3,1-benzothiazine (10).
Pale-yellow crystalline powder, mp: 104–106 ꢀC (from di-
isopropyl ether), lit.31 mp: 109–110 ꢀC, yield 82%. Anal.
Calcd for C15H13NS (239.34): C, 75.28; H, 5.47; N, 5.85;
S, 13.40. Found: C, 75.11; H, 5.29; N, 5.89; S, 13.26. nmax
(KBr disc) 1546, 1431, 1192, 1050, 1029, 937, 771, 752,
1
709, 643 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 8.03 (m, 2H,
20,60-H), 7.43 (m, 1H, 8-H), 7.36 (m, 1H, 7-H), 7.26 (m,
2H, 30,50-H), 7.24 (m, 1H, 6-H), 7.15 (m, 1H, 5-H), 3.98
(s, 2H, 4-H), 2.41 (s, 3H, CH3) ppm. 13C NMR d (CDCl3,
25 ꢀC): 161.0 (2-C), 144.5 (8a-C), 142.0 (40-C), 135.3 (10-
C), 129.2 (30-C), 129.2 (50-C), 128.4 (7-C), 128.2 (20-C),
128.2 (60-C), 127.4 (6-C), 126.9 (8-C), 126.8 (5-C), 119.8
ꢂ
(4a-C), 28.6 (4-C), 21.5 (CH3) ppm. MS (EI): M+ ¼239 (100).
4.4.2. 2-(2-Chlorophenyl)-4H-3,1-benzothiazine (11).
Pale-yellow crystalline powder, mp: 51–53 ꢀC (from diiso-
propyl ether), yield 74%. Anal. Calcd for C14H10ClNS
(259.75): C, 64.73; H, 3.88; N, 5.39; S, 12.34. Found: C,
64.58; H, 4.02; N, 5.46; S, 12.50. nmax (KBr disc) 1605,
1574, 1538, 1502, 1486, 1448, 1408, 1304, 1253, 1196,
1170, 1105, 1012, 948, 890, 855, 820, 790, 758, 707,
4.3. Mass spectrometry
The 70 eV low-resolution spectra were recorded with a VG
ZABSpec instrument equipped with an OPUS V3.3 data
system. The samples were introduced through a solids-inlet
system, which was slightly heated to improve evaporation.
The accelerating voltage was 8 kV, the temperature of the
source was 433 K, and the trap current was 200 mA. The ac-
curate mass measurements were performed at a resolution of
8000–10,000 (10% valley definition) by a voltage scanning
technique, using perfluorokerosene as a reference com-
pound. To clarify the fragmentation pathways, B/E scans
(FFR1) were also applied. The demonstration of some parent
ions also required the use of B2/E spectra. For linked scans,
the resolution was 2000–2500.
1
638 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.56 (m, 1H, 60-H),
7.46 (m, 1H, 30-H), 7.42 (m, 1H, 8-H), 7.37 (m, 1H, 7-H),
7.34 (m, 1H, 40-H), 7.33 (m, 1H, 50-H), 7.29 (m, 1H, 6-H),
7.15 (m, 1H, 5-H), 4.06 (s, 2H, 4-H) ppm. 13C NMR
d (CDCl3, 25 ꢀC): 160.3 (2-C), 143.6 (8a-C), 138.1 (10-C),
132.4 (20-C), 130.8 (40-C), 130.4 (60-C), 130.4 (30-C), 128.6
(7-C), 128.3 (6-C), 127.1 (5-C), 127.1 (8-C), 126.8 (50-C),
ꢂ
118.7 (4a-C), 29.1 (4-C) ppm. MS (EI): M+ ¼259 (100).
4.4.3. 2-(2-Methylphenyl)-4H-3,1-benzothiazine (12).
Pale-yellow crystalline powder, mp: 52–53 ꢀC (from diiso-
propyl ether), lit.31 mp: 54.5–56 ꢀC, yield 46%. Anal. Calcd

P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
1007
for C15H13NS (239.34): C, 75.28; H, 5.47; N, 5.85; S, 13.40.
Found: C, 75.56; H, 5.31; N, 5.67; S, 13.32. nmax (KBr disc)
1665, 1602, 1550, 1478, 1451, 1380, 1291, 1248, 1188, 1121,
5.38, (s, 1H, 2-H), 3.76 (d, J¼16.5 Hz, 1H, 4-H), 3.60 (d,
13
J¼16.5 Hz, 1H, 4-H) ppm. C NMR d (CDCl3, ꢁ60 ꢀC):
159.6 (1-C), 135.8 (10-C), 132.6 (8a-C), 129.0 (40-C),
128.8 (30-C), 128.6 (5-C), 128.6 (7-C), 127.7 (20-C), 127.6
(50-C), 126.6 (60-C), 124.8 (6-C), 120.5 (4a-C), 120.2 (8-
C), 70.1 (2a-C), 66.8 (2-C), 30.0 (4-C) ppm. MS (EI):
1096, 1037, 965–835, 761, 708, 667 cmꢁ1 1H NMR
.
d (CDCl3, 25 ꢀC): 7.59 (m, 1H, 60-H), 7.41 (m, 1H, 8-H),
7.36 (m, 1H, 7-H), 7.32 (m, 1H, 40-H), 7.28 (m, 1H, 6-H),
7.26 (m, 2H, 30,50-H), 7.16 (m, 1H, 5-H), 4.06 (s, 2H,
ꢂ
M+ ¼301 (22).
13
4-H), 2.54 (s, 3H, CH3) ppm. C NMR d (CDCl3, 25 ꢀC):
162.7 (2-C), 143.9 (8a-C), 138.5 (10-C), 136.9 (20-C), 131.1
(30-C), 130.0 (60-C), 129.9 (40-C), 128.5 (7-C), 127.9 (6-C),
127.1 (5-C), 126.9 (8-C), 125.7 (50-C), 118.5 (4a-C), 29.1
4.5.2. 2,2-Dichloro-2a-phenyl-2,2a-dihydro-2H,4H-
azeto[1,2-a][3,1]benzothiazin-1-one (18b). White crystal-
line powder, mp: 152–154 ꢀC (from methanol–chloroform),
yield 72%. Anal. Calcd for C16H11Cl2NOS (336.24): C,
57.15; H, 3.30; N, 4.17; S, 9.54. Found: C, 56.89; H, 3.49;
N, 4.08; S, 9.48. nmax (KBr disc) 1788, 1572, 1488, 1448,
1354, 1219, 1186, 1160, 1097, 1078, 1060, 1036, 963,
948, 858, 848, 817, 776, 758, 717, 692, 674, 649 cmꢁ1. 1H
NMR d (CDCl3, ꢁ60 ꢀC): 7.88 (m, 1H, 8-H), 7.83 (m, 1H,
20-H), 7.56 (m, 1H, 30-H), 7.47 (m, 1H, 7-H), 7.43 (m,
1H, 40-H), 7.28 (m, 1H, 50-H), 7.26 (m, 1H, 6-H), 7,23 (m,
1H, 5-H), 7,10 (m, 1H, 60-H), 3.82 (d, J¼16.4 Hz, 1H,
4-H), 3.46 (d, J¼16.4 Hz, 1H, 4-H) ppm. 13C NMR
d (CDCl3, ꢁ60 ꢀC): 157.5 (1-C) 136.1 (10-C), 131.8 (8a-C),
129.4 (40-C), 129.1 (30-C), 128.9 (5-C), 128.7 (7-C), 127.7
(50-C), 127.2 (20-C), 126.0 (60-C), 125.5 (6-C), 121.7 (4a-C),
120.2 (8-C), 88.4 (2-C), 79.9 (2a-C), 29.5 (4-C) ppm. MS
ꢂ
(4-C), 20.4 (CH3) ppm. MS (EI): M+ ¼239 (100).
4.4.4. 2-(2-Ethoxyphenyl)-4H-3,1-benzothiazine (13).
Pale-yellow crystalline powder, mp: 62ꢁ64 ꢀC (from diiso-
propyl ether), yield 76%. Anal. Calcd for C16H15NOS
(269.36): C, 71.34; H, 5.61; N, 5.20; S, 11.90. Found: C,
71.42; H, 5.70; N, 5.36; S, 12.02. nmax (KBr disc) 1596,
1580, 1542, 1490, 1478, 1448, 1391, 1292, 1257, 1238,
1189, 1117, 1038, 960–870, 780–720, 708, 670, 652,
1
628 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.75 (m, 1H, 60-H),
7.40 (m, 1H, 8-H), 7.37 (m, 1H, 40-H), 7.35 (m, 1H, 7-H),
7.25 (m, 1H, 6-H), 7.15 (m, 1H, 5-H), 7.03 (m, 1H, 50-H),
6.96 (m, 1H, 30-H), 4.14 (q, J¼7.8 Hz, 2H, CH3–CH2),
3.89 (s, 2H, 4-H), 1.45 (t, J¼7.8 Hz, 3H, CH3–CH2) ppm.
13C NMR d (CDCl3, 25 ꢀC): 160.6 (2-C), 156.6 (20-C),
144.0 (8a-C), 131.1 (40-C), 129.4 (60-C), 129.0 (10-C),
128.3 (7-C), 127.6 (6-C), 126.8 (8-C), 126.7 (5-C), 120.7
(50-C), 120.1 (4a-C), 112.7 (30-C), 64.6 (CH2), 28.7 (4-C),
ꢂ
(EI): M+ ¼335 (24).
4.5.3. (2R*,2aR*)-2,2a-Diphenyl-2,2a-dihydro-2H,4H-
azeto[1,2-a][3,1]benzothiazin-1-one (18c). White crystal-
line powder, mp: 156–158 ꢀC (from methanol), yield 86%.
Anal. Calcd for C22H17NOS (343.44): C, 76.94; H, 4.99;
N, 4.08; S, 9.34. Found: C, 76.74; H, 4.88; N, 4.02; S,
9.25. nmax (KBr disc) 1768, 1597, 1578, 1492, 1455, 1415,
1350, 1337, 1239, 1198, 1167, 995–855, 755, 732, 696,
ꢂ
14.8 (CH3) ppm. MS (EI): M+ ¼269 (100).
4.5. General procedure for azetobenzothiazines
18–23a,b,c and 24d,e
To a stirred solution of the 4H-3,1-benzothiazine derivatives
8–13 (2.0 mmol) in anhydrous benzene (10 mL) (18a,b,
19a,b, 22a,b, 21a and 20b for 12h; 21b, 23b for 8h and
20a, 23a for 4h) or toluene (18c, 19c, 20c, 22c and 24d,e
for 4h and 21c, 23c for 12h), the appropriate acid chloride
derivative 14–17 (3.0 mmol) was added. The solution was
refluxed and triethylamine (0.4 mL, 3.0 mmol) in anhydrous
toluene or benzene (20 mL) was added dropwise over 4 h at
reflux. The addition of appropriate acid chloride derivative
14–17 (3.0 mmol) and triethylamine (0.4 mL, 3.0 mmol)
was repeated one or two more times under the same condi-
tions as above. The reaction mixture was then cooled and ex-
tracted with brine (20 mL), and the organic layer was dried
with Na2SO4. After evaporation, the residue was taken up in
benzene (5 mL) and passed through a short column of silica,
the solvent was evaporated off, and the oily residue crystal-
lized on trituration with ethanol.
660 cmꢁ1
.
1H NMR d (CDCl3, ꢁ60 ꢀC): 8.00 (m, 1H,
8-H), 7.48 (m, 1H, 7-H), 7.27 (m, 1H, 5-H), 7.22 (m, 1H,
6-H), 7.17 (m, 3H, 300,400,500-H), 7.13* (m, 1H, 50-H), 7.11
(m, 1H, 40-H), 7.10* (m, 1H, 60-H), 7.08* (m, 1H, 30-H),
7.06* (m, 1H, 20-H), 7.04 (m, 2H, 200,600-H), 5.06 (s, 1H, 2-
H), 3.74 (d, J¼16.4 Hz, 1H, 4-H), 3.56 (d, J¼16.4 Hz, 1H,
13
4-H) ppm. C NMR d (CDCl3, ꢁ60 ꢀC): 164.7 (1-C)
137.2 (10-C), 133.5 (8a-C), 131.2 (100-C), 129.3 (200,600-C),
128.6 (5-C), 128.5 (7-C), 128.3 (300,500-C), 128.2* (30-C),
128.0 (400-C), 127.7 (40-C), 127.0* (20-C), 127.0* (50-C),
126.3* (60-C), 124.0 (6-C), 120.1 (8-C), 120.9 (4a-C), 69.9
(2a-C), 68.9 (2-C), 28.9 (4-C) ppm (*assignment uncertain).
ꢂ
MS (EI): M+ ¼343 (6).
4.5.4. (2R*,2aS*)-2-Chloro-2a-(4-chlorophenyl)-2,2a-di-
hydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (19a).
White crystalline powder, mp: 195–196 ꢀC (from methanol),
yield 59%. Anal. Calcd for C16H11Cl2NOS (336.24): C,
57.15; H, 3.30; N, 4.17; S, 9.54. Found: C, 56.87; H, 3.42;
N, 4.12; S, 9.67. nmax (KBr disc) 1778, 1582, 1493, 1456,
1408, 1360, 1302, 1248, 1217, 1172, 1091, 1070, 1012,
972, 947, 918, 887, 856, 828, 782, 757, 740, 658,
4.5.1. (2R*,2aS*)-2-Chloro-2a-phenyl-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (18a). White
crystalline powder, mp: 118–120 ꢀC (from methanol), yield
52%. Anal. Calcd for C16H12ClNOS (301.79): C, 63.68; H,
4.01; N, 4.64; S, 10.63. Found: C, 63.39; H, 3.87; N, 4.71; S,
10.82. nmax (KBr disc) 1770, 1598, 1577, 1492, 1455, 1408,
1354, 1300, 1250, 1217, 1165, 1066, 1027, 1014, 972, 942,
926, 885, 857, 840, 756, 739, 695 cmꢁ1. 1H NMR d (CDCl3,
ꢁ60 ꢀC): 7.90 (m, 1H, 8-H), 7.70 (m, 1H, 20-H), 7.54 (m, 1H,
30-H), 7.46 (m, 1H, 7-H), 7.42 (m, 1H, 40-H), 7.30 (m, 1H, 50-
H), 7.23 (m, 1H, 5-H), 7,22 (m, 1H, 6-H), 7,17 (m, 1H, 60-H),
1
632 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.87 (m, 1H, 8-H),
7.40 (m, 1H, 7-H), 7.36 (m, 2H, 20,60-H), 7.33 (m, 2H,
30,50-H), 7.17 (m, 1H, 5-H), 7.16 (m, 1H, 6-H), 5.27 (s,
1H, 2-H), 3.72 (d, J¼16.5 Hz, 1H, 4-H), 3.58 (d,
13
J¼16.5 Hz, 1H, 4-H) ppm. C NMR d (CDCl3, 25 ꢀC):
159.3 (1-C), 135.1 (40-C), 135.0 (10-C), 133.0 (8a-C),

1008
P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
128.9 (20,60-C), 128.8 (7-C), 128.6 (5-C), 128.6 (30,50-C),
124.9 (6-C), 120.6 (8-C), 120.5 (4a-C), 69.9 (2a-C), 67.3
acetate), yield 61%. Anal. Calcd for C17H13Cl2NOS
(350.26): C, 58.29; H, 3.74; N, 4.00; S, 9.15. Found: C,
58.62; H, 3.39; N, 4.15; S, 9.22. nmax (KBr disc) 1775,
1610, 1580, 1492, 1455, 1365, 1300, 1223, 1182, 1171,
1155, 1086, 1040, 1030, 1018, 972, 947, 885, 860, 850–
740, 671 cmꢁ1. 1H NMR d (CDCl3, ꢁ60 ꢀC): 7.87 (m, 1H,
8-H), 7.71 (m, 1H, 20-H), 7.46 (m, 1H, 7-H), 7.36 (m,
1H, 30-H), 7.25 (m, 1H, 6-H), 7.21 (m, 1H, 5-H), 7.07 (m,
1H, 50-H), 6.98 (m, 1H, 60H), 3.81 (d, J¼16.6 Hz, 1H, 4-
H), 3.46 (d, J¼16.6 Hz, 1H, 4-H), 2.38 (s, 3H, CH3) ppm.
13C NMR d (CDCl3, ꢁ60 ꢀC): 157.5 (1-C), 139.6 (40-C),
133.1 (10-C), 131.8 (8a-C), 129.9 (30-C), 128.9 (5-C),
128.6 (7-C), 128.2 (50-C), 127.1 (20-C), 126.1 (60-C), 125.5
(6-C), 121.7 (4a-C), 120.8 (8-C), 88.4 (2-C), 80.0 (2a-C),
ꢂ
(2-C), 20.2 (4-C) ppm. MS (EI): M+ ¼335 (23).
4.5.5. 2a-(4-Chlorophenyl)-2,2-dichloro-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (19b). White
crystalline powder, mp: 132–134 ꢀC (from methanol–chlo-
roform), yield 75%. Anal. Calcd for C16H10Cl3NOS
(370.38): C, 51.84; H, 2.72; N, 3.78; S, 8.65. Found: C,
52.02; H, 2.59; N, 3.74; S, 8.49. nmax (KBr disc) 1790,
1597, 1579, 1492, 1456, 1403, 1364, 1302, 1228, 1167,
1094, 1035, 1010, 942, 886, 854, 815, 765, 748, 669 cmꢁ1
.
1H NMR d (CDCl3, ꢁ60 ꢀC): 7.86 (m, 1H, 8-H), 7.80 (m,
1H, 20-H), 7.52 (m, 1H, 30-H), 7.46 (m, 1H, 7-H), 7.27 (m,
1H, 6-H), 7.24 (m, 2H, 5,50-H), 7.04 (m, 1H, 60-H), 3.84
(d, J¼16.5 Hz, 1H, 4-H), 3.46 (d, J¼16.5 Hz, 1H,
ꢂ
29.6 (4-C), 21.4 (CH3) ppm. MS (EI): M+ ¼349 (26).
13
4-H) ppm. C NMR d (CDCl3, ꢁ60 ꢀC): 157.3 (1-C),
4.5.9. (2R*,2aR*)-2a-(4-Methylphenyl)-2-phenyl-2,2a-di-
hydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (20c).
White crystalline powder, mp: 128–130 ꢀC (from methanol),
yield 81%. Anal. Calcd for C23H19NOS (357.47): C, 77.28;
H, 5.36; N, 3.92; S, 8.97. Found: C, 77.11; H, 5.10; N, 3.87;
S, 9.13. nmax (KBr disc) 1769, 1597, 1575, 1492, 1452, 1358,
135.2 (40-C), 134.8 (10-C), 131.6 (8a-C), 129.4 (30-C),
128.9 (5-C), 128.8 (20-C), 128.8 (7-C), 127.8 (50-C), 127.5
(60-C), 125.7 (6-C), 121.4 (4a-C), 120.8 (8-C), 88.2 (2-C),
ꢂ
79.4 (2a-C), 29.4 (4-C) ppm. MS (EI): M+ ¼369 (24).
4.5.6. (2R*,2aR*)-2a-(4-Chlorophenyl)-2-phenyl-2,2a-di-
hydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (19c).
White crystalline powder, mp: 184–186 ꢀC (from metha-
nol–chloroform), yield 89%. Anal. Calcd for C22H16ClNOS
(377.89): C, 69.92; H, 4.27; N, 3.71; S, 8.49. Found: C, 70.11;
H, 4.16; N, 3.70; S, 8.31. nmax (KBr disc) 1765, 1580, 1490,
1452, 1400, 1348, 1230, 1198, 1169, 1088, 1065, 1008,
930–770, 752, 720, 695 cmꢁ1. 1H NMR d (CDCl3, ꢁ60 ꢀC):
7.99 (m, 1H, 8-H), 7.48 (m, 1H, 7-H), 7.27 (m, 1H, 5-H),
7.22 (m, 1H, 6-H), 7.20 (m, 3H, 300,400,500-H), 7.08* (m, 1H,
20-H), 7.03* (m, 1H, 60-H), 7.03 (m, 2H, 200,600-H), 7,02* (m,
2H, 30,50-H), 5.06 (s, 1H, 2-H), 3.74 (d, J¼16.4 Hz, 1H, 4-
H), 3.52 (d, J¼16.4 Hz, 1H, 4-H) ppm. 13C NMR d (CDCl3,
ꢁ60 ꢀC): 164.5 (1-C), 136.0 (40-C), 133.2 (10-C), 133.3 (8a-
C), 130.8 (100-C), 129.2 (200,600-C), 128.7 (5-C), 128.6*
(30-C), 128.5 (7-C), 128.5 (300,500-C), 128.5* (50-C), 128.2
(400-C), 127.6* (60-C), 127.0* (20-C), 124.2 (6-C), 120.7 (4a-
C), 120.1 (8-C), 69.4 (2a-C) 68.9 (2-C), 28.9 (4-C) ppm
1240, 1162, 1092, 1070, 1025, 970–718, 695 cmꢁ1 1H
.
NMR d (CDCl3, 25 ꢀC): 7.97 (m, 1H, 8-H), 7.40 (m, 1H,
7-H), 7.18 (m, 1H, 5-H), 7.13 (m, 1H, 6-H), 7.11 (m, 3H,
300,400,500-H), 7.03 (m, 2H, 200,600-H), 6.98 (m, 2H, 20,60-H),
6.84 (m, 2H, 30,50-H), 4.96 (s, 1H, 2-H), 3.65 (d,
J¼16.5 Hz, 1H, 4-H), 3.55 (d, J¼16.5 Hz, 1H, 4-H), 2.16
13
(s, 3H, CH3) ppm. C NMR d (CDCl3, 25 ꢀC): 164.4 (1-
C), 137.5 (40-C), 134.6 (10-C), 134.1 (8a-C), 131.8 (100-C),
129.5 (200,600-C), 128.5 (5-C), 128.4 (7-C), 128.4 (30,50-C),
128.3 (300,500-C), 127.9 (400-C), 127.0 (20,60-C), 123.9 (6-C),
121.3 (4a-C), 120.5 (8-C), 70.2 (2a-C), 69.6 (2-C), 29.3
ꢂ
(4-C), 21.0 (CH3) ppm. MS (EI): M+ ¼357 (4).
4.5.10. (2R*,2aS*)-2-Chloro-2a-(2-chlorophenyl)-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(21a). White crystalline powder, mp: 153–156 ꢀC (from
methanol), yield 66%. Anal. Calcd for C16H11Cl2NOS
(336.24): C, 57.15; H, 3.30; N, 4.17; S, 9.54. Found: C,
57.59; H, 3.12; N, 4.09; S, 9.12. nmax (KBr disc) 1788,
1602, 1582, 1567, 1495, 1470, 1458, 1431, 1412, 1360,
1300, 1277, 1236, 1218, 1158, 1080, 1050, 1039, 1012,
ꢂ
(*assignment uncertain). MS (EI): M+ ¼377 (6).
4.5.7. (2R*,2aS*)-2-Chloro-2a-(4-methylphenyl)-2,2a-di-
hydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (20a).
White crystalline powder, mp: 196–198 ꢀC (from metha-
nol–ethyl acetate), yield 57%. Anal. Calcd for C17H14ClNOS
(315.82): C, 64.65; H, 4.47; N, 4.44; S, 10.15. Found: C,
64.82; H, 4.62; N, 4.40; S, 10.23. nmax (KBr disc) 1772,
1580, 1490, 1455, 1400, 1361, 1300, 1220, 1170, 1095,
1072, 1018, 975, 920, 882, 840, 815, 798, 755, 740,
967, 910, 890–820, 750–695, 672 cmꢁ1
.
1H NMR
d (CDCl3, 25 ꢀC): 7.84 (m, 1H, 8-H), 7.49 (m, 1H, 30-H),
7.42 (m, 1H, 7-H), 7.32 (m, 1H, 40-H), 7.20 (m, 2H, 5,6-
H), 7.15 (m, 1H, 50-H), 7.01 (m, 1H, 60-H), 5.36 (s, 1H, 2-
H), 3.72 (d, J¼16.6 Hz, 1H, 4-H), 3.60 (d, J¼16.6 Hz, 1H,
13
4-H) ppm. C NMR d (CDCl3, 25 ꢀC): 160.4 (1-C), 133.7
(10-C), 133.4 (8a-C), 132.8 (20-C), 131.5 (30-C), 130.2 (40-
C), 128.7 (7-C), 128.4 (5-C), 127.9 (60-C), 126.2 (50-C),
125.1 (6-C), 120.9 (8-C), 120.7 (4a-C), 70.1 (2a-C), 67.0
1
695 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.87 (m, 1H, 8-H),
7.39 (m, 1H, 7-H), 7.30 (m, 2H, 20,60-H), 7.16 (m, 2H,
30,50-H), 7.15 (m, 1H, 5-H), 7.14 (m, 1H, 6-H), 5.26 (s, 1H,
2-H), 3.69 (d, J¼16.0 Hz, 1H, 4-H), 3.60 (d, J¼16.0 Hz,
1H, 4-H), 2.35 (s, 3H, CH3) ppm. 13C NMR d (CDCl3,
25 ꢀC): 159.6 (1-C), 139.0 (40-C), 133.3 (8a-C), 133.2 (10-
C), 129.0 (30,50-C), 128.6 (7-C), 128.6 (5-C), 127.4 (20,60-
C), 124.7 (6-C), 120.8 (4a-C), 120.6 (8-C), 70.4 (2a-C), 67.4
ꢂ
(2-C), 29.0 (4-C) ppm. MS (EI): M+ ¼335 (18).
4.5.11. 2a-(2-Chlorophenyl)-2,2-dichloro-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (21b). White
crystalline powder, mp: 187–188 ꢀC (from methanol–chlo-
roform), yield 79%. Anal. Calcd for C16H10Cl3NOS
(370.38): C, 51.84; H, 2.72; N, 3.78; S, 8.65. Found: C,
51.59; H, 2.95; N, 3.60; S, 8.88. nmax (KBr disc) 1790,
1602, 1580, 1493, 1468, 1457, 1430, 1365, 1300, 1272,
1224, 1200, 1176, 1130, 1088, 1045, 965, 944, 886, 860,
ꢂ
(2-C), 29.3 (4-C), 21.2 (CH3) ppm. MS (EI): M+ ¼315 (30).
4.5.8. 2,2-Dichloro-2a-(4-methylphenyl)-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (20b). White
crystalline powder, mp: 154–156 ꢀC (from methanol–ethyl
1
831, 808, 770–705, 672, 638 cmꢁ1. H NMR d (CDCl3,

P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
1009
25 ꢀC): 7.84 (m, 1H, 8-H), 7.52 (m, 1H, 30-H), 7.43 (m, 1H,
7-H), 7.33 (m, 1H, 40-H), 7.24 (m, 1H, 6-H), 7.20 (m, 1H, 5-
H), 7.14 (m, 1H, 50-H), 6.98 (m, 1H, 60H), 3.76 (d,
J¼16.5 Hz, 1H, 4-H), 3.47 (d, J¼16.5 Hz, 1H, 4-H) ppm.
13C NMR d (CDCl3, 25 ꢀC): 158.1 (1-C), 134.7 (10-C),
133.0 (8a-C), 132.9 (20-C), 131.6 (30-C), 130.4 (40-C),
128.8 (7-C), 128.6 (5-C), 127.2 (60-C), 126.1 (50-C), 125.7
(6-C), 121.8 (4a-C), 121.1 (8-C), 88.2 (2-C), 79.5 (2a-C),
136.4 (10-C), 134.9 (20-C), 133.2 (8a-C), 132.5 (30-C), 129.2
(40-C), 128.7 (7-C), 128.6 (5-C), 125.9 (60-C), 125.5 (6-C),
125.1 (50-C), 122.1 (4a-C), 121.1 (8-C), 88.3 (2-C), 80.4
ꢂ
(2a-C), 29.6 (4-C), 21.4 (CH3) ppm. MS (EI): M+ ¼349 (56).
4.5.15. (2R*,2aR*)-2a-(2-Methylphenyl)-2-phenyl-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(22c). White crystalline powder, mp: 198–200 ꢀC (from
methanol–ethyl acetate), yield 71%. Anal. Calcd for
C23H19NOS (357.47): C, 77.28; H, 5.36; N, 3.92; S, 8.97.
Found: C, 76.96; H, 5.54; N, 3.78; S, 8.81. nmax (KBr disc)
1764, 1604, 1578, 1492, 1454, 1409, 1349, 1300, 1265,
1238, 1200, 1167, 1095, 1057, 1030, 970–850, 786, 755,
720, 700 cmꢁ1. 1H NMR d (CDCl3, 25 ꢀC): 7.95 (m, 1H, 8-
H), 7.43 (m, 1H, 7-H), 7.21 (m, 1H, 5-H), 7.17 (m, 1H, 6-
H), 7.16 (m, 1H, 400-H), 7.09 (m, 3H, 40,300,500-H), 7.04 (m,
1H, 60-H), 7.00 (m, 1H, 50-H), 6.97 (m, 2H, 200,600-H), 6.86
(m, 1H, 30-H), 4.89 (s, 1H, 2-H), 3.66 (d, J¼16.4 Hz, 1H, 4-
H), 3.57 (d, J¼16.4 Hz, 1H, 4-H), 1.98 (s, 3H, CH3) ppm.
13C NMR d (CDCl3, 25 ꢀC): 165.0 (1-C), 135.6 (20-C),
134.8 (10-C), 134.5 (8a-C), 131.8 (30-C), 131.7 (100-C),
130.1 (200,600-C), 128.4 (7-C), 128.4 (5-C), 128.3 (40-C),
128.2 (400-C), 127.9 (300,500-C), 127.1 (60-C), 124.8 (50-C),
124.2 (6-C), 121.4 (4a-C), 120.8 (8-C), 70.5 (2a-C), 69.3
ꢂ
29.4 (4-C) ppm. MS (EI): M+ ¼369 (19).
4.5.12. (2R*,2aR*)-2a-(2-Chlorophenyl)-2-phenyl-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(21c). Whitecrystalline powder, mp: 225–228 ꢀC (frommeth-
anol–chloroform), yield 78%. Anal. Calcd for C22H16ClNOS
(377.89): C, 69.92; H, 4.27; N, 3.71; S, 8.49. Found: C, 69.67;
H, 4.11; N, 3.76; S, 8.52. nmax (KBr disc) 1771, 1600, 1579,
1492, 1468, 1452, 1405, 1350, 1275, 1225, 1200, 1170,
1148, 1080, 1029, 960, 951, 885, 861, 845, 780–730, 719,
1
692 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.93 (m, 1H, 8-H),
7.43 (m, 1H, 7-H), 7.22 (m, 1H, 5-H), 7.19 (m, 1H, 6-H),
7.17 (m, 1H, 400-H), 7.15 (m, 1H, 60-H), 7.11 (m, 4H,
40,50,300,500-H), 7.07 (m, 1H, 30-H), 7.03 (m, 2H, 200,600-H),
4.96 (s, 1H, 2-H), 3.69 (d, J¼16.5 Hz, 1H, 4-H), 3.59 (d,
13
J¼16.5 Hz, 1H, 4-H) ppm. C NMR d (CDCl3, 25 ꢀC):
ꢂ
165.4 (1-C), 134.8 (20-C), 134.2 (8a-C), 132.2 (10-C), 131.5
(100-C), 131.1 (30-C), 130.4 (200,600-C), 129.4 (40-C), 128.5 (7-
C), 128.4 (60-C), 128.3 (5-C), 128.1 (400-C), 127.7 (300,500-C),
125.8 (50-C), 124.4 (6-C), 121.2 (4a-C), 120.9 (8-C), 69.8
(2-C), 29.2 (4-C), 21.0 (CH3) ppm. MS (EI): M+ ¼357 (16).
4.5.16. (2R*,2aS*)-2-Chloro-2a-(2-ethoxyphenyl)-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(23a). White crystalline powder, mp: 177–179 ꢀC (from
methanol–chloroform), yield 65%. Anal. Calcd for
C18H16ClNO2S (345.84): C, 62.51; H, 4.66; N, 4.05; S,
9.27. Found: C, 62.44; H, 4.75; N, 3.99; S, 9.19. nmax (KBr
disc) 1782, 1598, 1582, 1489, 1460, 1448, 1388, 1345,
1287, 1253, 1155, 1121, 1056, 1042, 928, 882, 856, 840,
ꢂ
(2a-C) 69.6 (2-C), 29.0 (4-C) ppm. MS (EI): M+ ¼377 (17).
4.5.13. (2R*,2aS*)-2-Chloro-2a-(2-methylphenyl)-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(22a). White crystalline powder, mp: 120–123 ꢀC (from
methanol–ethyl acetate), yield 47%. Anal. Calcd for
C17H14ClNOS (315.82): C, 64.65; H, 4.47; N, 4.44; S,
10.15. Found: C, 64.36; H, 4.61; N, 4.53; S, 10.22. nmax
(KBr disc) 1782, 1600, 1580, 1483, 1456, 1362, 1300,
1240, 1217, 1200, 1170, 1096, 1062, 1032, 1010, 914,
1
822, 798, 767, 750, 698 cmꢁ1. H NMR d (CDCl3, 25 ꢀC):
7.82 (m, 1H, 8-H), 7.40 (m, 1H, 7-H), 7.32 (m, 1H, 40-H),
7.19 (m, 1H, 5-H), 7.18 (m, 1H, 6-H), 6.96 (m, 1H, 30-H),
6.84 (m, 1H, 60-H), 6.80 (m, 1H, 50-H), 5.25 (s, 1H, 2-H),
4.23 (m, 1H, CH2–CH3), 4.07 (m, 1H, CH2–CH3), 3.72 (d,
J¼16.5 Hz, 1H, 4-H), 3.69 (d, J¼16.5 Hz, 1H, 4-H), 1.51
1
857, 842, 800, 778, 752, 719, 698, 630 cmꢁ1. H NMR
d (CDCl3, 25 ꢀC): 7.87 (m, 1H, 8-H), 7.42 (m, 1H, 7-H),
7.27 (m, 1H, 30-H), 7.26 (m, 1H, 40-H), 7.18 (m, 2H, 5,6-
H), 7.04 (m, 1H, 50-H), 6.91 (m, 1H, 60-H), 5.31 (s, 1H, 2-
H), 3.68 (d, J¼16.5 Hz, 1H, 4-H), 3.58 (d, J¼16.5 Hz, 1H,
13
(t, J¼7.2 Hz, 3H, CH3) ppm. C NMR d (CDCl3, 25 ꢀC):
160.9 (1-C), 155.3 (20-C), 133.8 (8a-C), 130.4 (40-C),
128.5 (7-C), 128.4 (5-C), 126.7 (60-C), 124.8 (6-C), 124.5
(10-C), 121.0 (4a-C), 120.8 (8-C), 119.5 (50-C), 112.4 (30-
C), 69.2 (2a-C), 67.0 (2-C), 64.0 (CH2O), 29.1 (4-C), 14.8
13
4-H), 2.51 (s, 3H, CH3) ppm. C NMR d (CDCl3, 25 ꢀC):
159.9 (1-C), 136.1 (10-C), 133.7* (8a-C), 133.7* (20-C),
132.2 (30-C), 129.0 (40-C), 128.6 (7-C), 128.4 (5-C), 126.7
(60-C), 125.2 (50-C), 124.9 (6-C), 120.9 (4a-C), 120.7 (8-
C), 70.7 (2a-C), 66.7 (2-C), 29.1 (4-C), 21.4 (CH3) ppm
ꢂ
(CH3) ppm. MS (EI): M+ ¼245 (55).
4.5.17. 2,2-Dichloro-2a-(2-ethoxyphenyl)-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (23b). White
crystalline powder, mp: 187–191 ꢀC (from methanol–ethyl
acetate), yield 70%. Anal. Calcd for C18H15Cl2NO2S
(380.29): C, 56.85; H, 3.89; N, 3.68; S, 8.43. Found: C,
56.69; H, 4.12; N, 3.61; S, 8.22. nmax (KBr disc) 1778,
1598, 1582, 1492, 1455, 1362, 1289, 1254, 1165, 1130,
ꢂ
(*assignment uncertain). MS (EI): M+ ¼315 (38).
4.5.14. 2,2-Dichloro-2a-(2-methylphenyl)-2,2a-dihydro-
2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (22b). White
crystalline powder, mp: 146–148 ꢀC (from methanol–ethyl
acetate), yield 52%. Anal. Calcd for C17H13Cl2NOS
(350.26): C, 58.29; H, 3.74; N, 4.00; S, 9.15. Found: C,
58.06; H, 3.92; N, 4.24; S, 9.32.nmax (KBr disc) 1872, 1578,
1492, 1450, 1370, 1302, 1223, 1173, 1150, 1088, 1040,
1109, 1073, 1047, 927, 883, 855, 810, 770–710, 672 cmꢁ1
.
1H NMR d (CDCl3, 25 ꢀC): 7.81 (m, 1H, 8-H), 7.40 (m,
1H, 7-H), 7.33 (m, 1H, 40-H), 7.20 (m, 1H, 6-H), 7.19
(m, 1H, 5-H), 6.98 (m, 1H, 30-H), 6.78 (m, 1H, 60-H), 6.77
(m, 1H, 50-H), 4.25 (m, 1H, CH2–CH3), 4.13 (m, 1H, CH2–
CH3), 3.74 (d, J¼16.5 Hz, 1H, 4-H), 3.58 (d, J¼16.5 Hz,
1H, 4-H), 1.58 (t, J¼7.2 Hz, 3H, CH3) ppm. 13C NMR
d (CDCl3, 25 ꢀC): 158.7 (1-C), 155.5 (20-C), 133.3 (8a-C),
130.6 (40-C), 128.6 (5-C), 128.5 (7-C), 125.8 (60-C), 125.5
1
973, 946, 884, 860–740, 674 cmꢁ1. H NMR d (CDCl3,
25 ꢀC): 7.86 (m, 1H, 8-H), 7.43 (m, 1H, 7-H), 7.30 (m, 1H,
30-H), 7.27 (m, 1H, 40-H), 7.22 (m, 1H, 6-H), 7.18 (m, 1H,
5-H), 7.02 (m, 1H, 50-H), 6.87 (m, 1H, 60H), 3.73 (d,
J¼16.5 Hz, 1H, 4-H), 3.46 (d, J¼16.5 Hz, 1H, 4-H), 2.51
(s, 3H, CH3) ppm. 13C NMR d (CDCl3, 25 ꢀC): 157.7 (1-C),

1010
P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
(10-C), 125.4 (6-C), 122.2 (4a-C), 121.1 (8-C), 119.4
(50-C), 112.3 (30-C), 88.4 (2-C), 78.6 (2a-C), 64.2 (CH2O-
(m, 2H, 5,30-H), 7.15 (m, 3H, 300,400,500-H), 7.07 (m, 1H, 40-
H), 6.94 (m, 1H, 50-H), 6.87 (m, 1H, 60-H), 3.79 (d,
J¼16.5 Hz, 1H, 4-H), 3.43 (d, J¼16.5 Hz, 1H, 4-H) ppm.
13C NMR d (CDCl3, ꢁ60 ꢀC): 161.5 (1-C), 136.5 (10-C),
133.7 (100-C), 132.4 (8a-C), 129.8 (500-C), 128.9* (5-
C), 128.8* (400-C), 128.5* (30-C), 128.4* (7-C), 128.3 (10-
C), 128.0 (300-C), 127.7 (600-C), 127.5 (200-C), 127.2 (20-C),
127.2 (50-C), 126.4 (60-C), 125.0 (6-C), 122.0 (4a-C),
120.9 (8-C), 82.1 (2-C), 78.8 (2a-C), 29.4 (4-C) ppm
ꢂ
C), 29.6 (4-C), 14.8 (CH3) ppm. MS (EI): M+ ¼379 (46).
4.5.18. (2R*,2aR*)-2a-(2-Ethoxyphenyl)-2-phenyl-2,2a-
dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(23c). White crystalline powder, mp: 175–178 ꢀC (from
methanol–ethyl acetate), yield 86%. Anal. Calcd for
C24H21NO2S (387.50): C, 74.39; H, 5.46; N, 3.61; S, 8.27.
Found: C, 74.36; H, 5.60; N, 3.58; S, 8.12. nmax (KBr disc)
1762, 1600, 1578, 1493, 1454, 1409, 1392, 1356, 1288,
1247, 1170, 1128, 1109, 1095, 1060, 1048, 945, 920, 885,
ꢂ
(*assignment uncertain). MS (EI): M+ ¼377 (11).
1
790–725, 700, 671 cmꢁ1. H NMR d (CDCl3, 25 ꢀC): 7.93
Acknowledgements
(m, 1H, 8-H), 7.41 (m, 1H, 7-H), 7.22 (m, 1H, 5-H), 7.16
(m, 1H, 6-H), 7.11 (m, 2H, 40,400-H), 7.08 (m, 2H, 300,500-
H), 6.97 (m, 2H, 200,600-H), 6.95 (m, 1H, 60-H), 6.74 (m,
1H, 50-H), 6.47 (m, 1H, 30-H), 4.86 (s, 1H, 2-H), 3.81 (m,
1H, CH2–CH3), 3.71 (d, J¼16.7 Hz, 1H, 4-H), 3.66 (d,
J¼16.7 Hz, 1H, 4-H), 3.16 (m, 1H, CH2–CH3), 1.35 (t,
The authors express their thanks to the Hungarian Scientific
ꢀ
Research Foundation (OTKA), and to Ms. E. Juhasz Dinya
for technical assistance. We are indebted to Professor G.
Dombi for measuring the IR spectra.
13
J¼7.2 Hz, 3H, CH3) ppm. C NMR d (CDCl3, 25 ꢀC):
165.8 (1-C), 154.5 (20-C), 134.6 (8a-C), 132.4 (100-C),
129.8 (200,600-C), 129.6 (40-C), 128.4 (5-C), 128.3 (7-C),
127.7 (400-C), 127.3 (300,500-C), 127.2 (60-C), 125.5 (10-C),
124.1 (6-C), 121.4 (4a-C), 120.7 (8-C), 119.1 (50-C), 111.4
(30-C), 69.5 (2-C), 68.9 (2a-C), 62.7 (CH2O–C), 29.2 (4-
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.09.079.
ꢂ
C), 14.71 (CH3) ppm. MS (EI): M+ ¼387 (15).
References and notes
4.5.19. (2R*,2aS*)-2-Chloro-2,2a-diphenyl-2,2a-dihy-
dro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (24d).
White crystalline powder, mp: 151–156 ꢀC [compound 24d
was separated from 24e by column chromatography with n-
hexane–benzene 1:1 (Rf 0.39), followed by n-hexane–ben-
zene 1:2 as eluent (Rf 0.45)], yield 72%. Anal. Calcd for
C21H16ClNOS (377.89): C, 69.92; H, 4.27; N, 3.71; S, 8.49.
Found: C, 69.55; H, 4.49; N, 3.74; S, 8.62. nmax (KBr disc)
1779, 1600, 1581, 1492, 1445, 1367, 1302, 1245, 1218,
1172, 1108, 1090, 1070, 1039, 1025, 952, 938, 862, 840,
1. Brown, E. D.; Wright, G. D. Chem. Rev. 2005, 105, 759–774.
ꢀ
2. Gomez-Gallego, M.; Mancheno, M. J.; Sierre, M. A.
Tetrahedron 2000, 56, 5743–5774.
3. Buynak, J. D.; Rao, A. S.; Ford, G. P.; Carver, C.; Adam, G.;
Geng, B.; Bachmann, B.; Shobbasy, S.; Lackey, S. J. Med.
Chem. 1997, 40, 3423–3433.
4. Burnett, D. A.; Caplen, M. A.; Davis, H. R., Jr.; Burrie, R. E.;
Clader, J. W. J. Med. Chem. 1994, 37, 1733–1736.
5. Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Frederici, M. E.;
Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem. 1995, 3,
1123–1143.
1
823, 793, 741, 714, 702, 692 cmꢁ1. H NMR d (CDCl3,
ꢁ60 ꢀC): 8.00 (m, 1H, 8-H), 7.98 (m, 1H, 20-H), 7.69 (m,
2H, 200,600-H), 7.63 (m, 1H, 30-H), 7.52 (m, 3H, 300,400,500-H),
7.48 (m, 1H, 7-H), 7.46 (m, 1H, 40-H), 7.35 (m, 1H, 50-H),
7.27 (m, 1H, 60-H), 7.21 (m, 1H, 6-H), 7.13 (m, 1H, 5-H),
3.60 (d, J¼16.5 Hz, 1H, 4-H), 3.42 (d, J¼16.5 Hz, 1H, 4-
€ €
ꢀ
6. Fulop, F.; Bernath, G.; Pihlaja, K. Adv. Heterocycl. Chem.
1998, 69, 349–477.
7. Vitis, L. D.; Troisi, L.; Grantino, C.; Pindinelli, E.; Ronzini, L.
Eur. J. Org. Chem. 2007, 356–362.
13
H) ppm. C NMR d (CDCl3, ꢁ60 ꢀC): 161.5 (1-C), 137.0
8. F€ulop, F. Chem. Rev. 2001, 101, 2181–2204.
€
(10-C), 132.8 (100-C), 132.1 (8a-C), 129.8 (300,500-C), 129.1
(30-C), 129.0 (400-C), 128.8 (5-C), 128.8 (40-C), 128.5 (7-C),
127.7 (50-C), 127.7 (200,600-C), 127.2 (20-C), 126.9 (60-C),
125.1 (6-C), 121.0 (4a-C), 120.6 (8-C), 80.1 (2-C), 77.4
9. Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377–386.
10. Williams, D. R.; Kammler, D. C.; Donnel, A. F.; Goundry,
W. R. F. Angew. Chem., Int. Ed. 2005, 44, 6715–6718.
11. Ge, H.; Spletstoser, J. T.; Yang, Y.; Kayser, M.; Georg, G. I.
J. Org. Chem. 2007, 72, 756–759.
12. Van Brabant, W.; Dejaegher, Y.; Van Landeghem, R.; De
Kimpe, N. Org. Lett. 2006, 4943–4950.
13. Dejaegher, Y.; Denolf, B.; Stevens, C. V.; De Kimpe, N.
Synthesis 2005, 193–198.
14. De Kimpe, N. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.,
Eds.; Pergamon: Oxford, 1996; Vol. 1B, pp 507–589.
15. Lal, B.; Bhedi, D. N.; Gidwani, R. M.; Sankar, C. Tetrahedron
1994, 50, 9167–9174.
ꢂ
(2a-C), 29.6 (4-C) ppm. MS (EI): M+ ¼377 (11).
4.5.20. (2R*,2aR*)-2-Chloro-2,2a-diphenyl-2,2a-dihy-
dro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (24e).
White crystalline powder, mp: 218–226 ꢀC [compound
24d was separated from 24e by column chromatography
with n-hexane–benzene 1:1 (Rf 0.24), followed by n-hex-
ane–benzene 1:2 as eluent (Rf 0.30)], yield 17%. Anal. Calcd
for C21H16ClNOS (377.89): C, 69.92; H, 4.27; N, 3.71; S,
8.49. Found: C, 69.61; H, 4.66; N, 3.80; S, 8.69. nmax (KBr
disc) 1780, 1600, 1582, 1493, 1445, 1365, 1300, 1244,
1218, 1172, 1110, 1090, 1071, 1040, 1026, 951, 939, 862,
16. Cremonesi, G.; Croce, P. D.; Rosa, C. L. Helv. Chim. Acta
2005, 88, 1580–1588.
1
840, 822, 793, 744, 714, 699 cmꢁ1. H NMR d (CDCl3,
ꢀ
ꢀ
17. Fodor, L.; Szabo, J.; Sohar, P. Tetrahedron 1981, 37, 963–966.
18. Fodor, L.; Szabo, J.; Szucs, E.; Bernath, G.; Sohar, P.; Tamas, J.
ꢁ60 ꢀC): 7.99 (m, 1H, 8-H), 7.67 (m, 1H, 20-H), 7.47 (m,
ꢀ
}
ꢀ
ꢀ
ꢀ
1H, 7-H), 7.35 (m, 2H, 200,600-H), 7.22 (m, 1H, 6-H), 7.21
Tetrahedron 1984, 40, 4089–4095.

P. Csomoꢀs et al. / Tetrahedron 64 (2008) 1002–1011
1011
ꢀ
ꢀ
19. Sohar, P.; Fodor, L.; Szabo, J.; Bernath, G. Tetrahedron 1984,
ꢀ
ꢀ
ꢀ
25. Csomos, P.; Fodor, L.; Mandity, I.; Bernath, G. Tetrahedron
ꢀ
40, 4387–4393.
2007, 63, 4983–4989.
ꢀ
20. Fodor, L.; Bernath, G.; Sinkkonen, J.; Pihlaja, K. J. Heterocycl.
Chem. 2002, 39, 927–931.
26. Grell, W.; Humaus, R.; Griss, G.; Santer, R.; Rupprecht, E.;
Mark, M.; Luger, P.; Nar, H.; Wittneben, H. J. Med. Chem.
1998, 41, 5219–5246.
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
21. Fodor, L.; Szabo, J.; Bernath, G.; Parkanyi, L.; Sohar, P.
Tetrahedron Lett. 1981, 22, 5077–5078.
ꢀ
27. El-Desoky, S. I.; Kandeel, E. M.; Abd-el-Raham, A. H.
J. Heterocycl. Chem. 1999, 36, 153–160.
ꢀ
22. Csomos, P.; Fodor, L.; Sinkkonen, J.; Pihlaja, K.; Bernath, G.
Tetrahedron Lett. 2006, 47, 5665–5667.
ꢀ
61, 9257–9262.
28. Matysiak, J. Bioorg. Med. Chem. 2006, 14, 2613–2619.
29. The compounds studied were racemates. In Scheme 2, C-2 [for
18–23a,c and 24d] is drawn in R*.
ꢀ
23. Csomos, P.; Fodor, L.; Sohar, P.; Bernath, G. Tetrahedron 2005,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
24. Csomos, P.; Zupko, I.; Rethy, B.; Fodor, L.; Falkay, G.;
Bernath, G. Bioorg. Med. Chem. Lett. 2006, 16, 6273–
ꢀ
30. Fontrodona, X.; Dıaz, S.; Linden, A.; Villalgordo, J. M.
Synthesis 2001, 2021–2027.
31. Kippenberg, H. Chem. Ber. 1897, 27, 1141–1147.
6276.