Preparation and ring transformation of isomeric β-lactam derivatives of bicyclic 1,3-thiazines

Article abstract of DOI:10.1016/j.tet.2012.09.102

Ketene-imine cycloaddition reactions between cis- and trans-2-aryl-4a,5,6, 7,8,8a-hexahydro-4H-3,1-benzothazines and chloroacetyl chloride in the presence of base were investigated. Because of the diastereotopic CN faces of cyclohexane-condensed thiazines

Full text of DOI:10.1016/j.tet.2012.09.102

Tetrahedron 69 (2013) 410e417
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation and ring transformation of isomeric
of bicyclic 1,3-thiazines
b-lactam derivatives
a
,
b
,
c
, ,
y
a
,
b
,
c
c
d
d
, ,
z
*
ꢀ
ꢀ
, Ferenc Fulop , Antal Csampai , Pal Sohar
€ €
ꢀ
ꢀ
ꢀ
*
Lajos Fodor
, Peter Csomos
a
Institute of Health Care and Environmental Sanitation Studies, Szent Istv aꢀ n University, H-5700 Gyula, Szent Istv aꢀ n u. 17e19, Hungary
Central Laboratory, County Hospital, H-5701 Gyula, PO Box 46, Hungary
Institute of Pharmaceutical Chemistry, University of Szeged, and Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720 Szeged, E o€ tv o€ s u. 6., Hungary
Institute of Chemistry, E o€ tv o€ s Lor aꢀ nd University, H-1518 Budapest, PO Box 32, Hungary
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2012
Received in revised form 5 September 2012
Accepted 25 September 2012
Available online 5 October 2012
Keteneeimine cycloaddition reactions between cis- and trans-2-aryl-4a,5,6,7,8,8a-hexahydro-4H-
3
,1-benzothazines and chloroacetyl chloride in the presence of base were investigated. Because of the
diastereotopic C]N faces of cyclohexane-condensed thiazines, both of the possible Staudinger addition
product monochloro- -lactam stereoisomers were obtained for both the cis and the trans compounds.
The novel azetidin-2-ones were transformed into the corresponding 3-ethoxycarbonyl-2-aryl-
,5,5a,6,7,8,9,9a-octahydro-4,1-benzothiazepines with sodium ethoxide in one-step procedure.
b
1
a
Keywords:
Keteneeimine cycloaddition
Thiazine
Structural and stereochemical analyses of the synthesized compounds were carried out by means of IR
and NMR spectroscopy.
Ó 2012 Elsevier Ltd. All rights reserved.
b-Lactam isomers
Ring transformation
Thiazepine
Enamine
Stereostructure and conformation
determination by NMR including NOE
1
. Introduction
amides (valuable intermediates in the syntheses of homalium al-
kaloids) have been obtained, and the reaction mechanisms of these
9
1
As well as their significant pharmacological effects,
b
-lactams
transformations have been studied. Regarding ring-contraction re-
actions of halo-azetidin-2-ones, there are interesting recent exam-
2
e12
serve as useful intermediates in organic syntheses.
their use as valuable scaffolds has been exploited in the preparation
of a wide variety of functionalized structures, including natural
products (alkaloids and medicines), aminosugars, different pep-
tidomimetics4 and chiral catalysts. Derivatives of 2-azetidinones
have also been utilized as powerful synthetic intermediates for
a broad range of heterocycles.
obtained either indirectly from
pounds, such as
directly through various ring transformations.
terconversions of heterocyclic rings into other heterocycles are
generally fascinating and frequently elegant tools in synthetic or-
In particular,
10
ples, which lead to the formation of aziridines.
In the course of our recent studies on S- and N-containing
condensed-skeleton heterocycles, we investigated the reactions of
2
3
5
1,3- and 3,1-benzothiazines differently condensed with a b-lactam
11
ring. The ring expansion of 2-chloro-2a-arylazeto[2,1-b][1,3]ben-
zothiazin-1-one derivatives (Fig. 1, compounds of type A) with so-
6
e12
These latter compounds can be
-lactams via bifunctional com-
b
dium methoxide afforded 1,4-benzothiazepines as single products
6
11a,b
b
-amino acid derivatives and amino alcohols, or
in good yields.
Further, the ring transformations of (2R
*
,2aS )-2-
*
7
e11
The in-
chloro-2a-aryl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-
1-ones (Fig. 1, compounds of type B) with sodium ethoxide in eth-
anol provided differently substituted (R
*
)-3-ethoxycarbonyl-2-aryl-
ganic chemistry. Via ring-enlargement reactions of halo-
b-lactams,
3,5-dihydro-4,1-benzothiazepines and 3-ethoxycarbonyl-2-aryl-
11b
numerous ring expansions have been achieved: products such as
1,5-dihydro-4,1-benzothiazepines.
Surprisingly, the tautomers
pyrrolidin-2-ones,7 bicyclic
g
-lactams or macrocyclic
8
b
-amino
obtained could be separated by column chromatography and
proved to be unexpectedly stable in solution, and these pairs of
compounds exhibit the rare phenomenon of desmotropy. Because
of the importance of this phenomenon, as a continuation of our
studies we were interested in the reactivities of their saturated
*
Corresponding authors. E-mail addresses: fodor@pandy.hu (L. Fodor), sohar@
chem.elte.hu (P. Soh ꢀa r).
y
Synthesis.
Spectroscopy.
z
analogues, b-lactam-condensed cis- and trans-2-aryl-4a,5,6,7,8,8a-
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.102

L. Fodor et al. / Tetrahedron 69 (2013) 410e417
411
Ar
COOMe
Ar
Cl
MeO
MeO
S
MeO
MeO
S
NaOMe
MeOH
H
N
NH
O
A
S
S
Ar
Cl
S
NaOEt
EtOH
+
COOEt
COOEt
N
N
N
H
Ar
H
Ar
B
O
Fig. 1. Ring transformation reactions of monochloro azeto[2,1-b][1,3]benzothiazin-1-one (A) and azeto[1,2-a][3,1]benzothiazin-1-one (B) derivatives.
hexahydro-4H-3,1-benzothazines, and set out to investigate their
with chloroacetyl chloride in refluxing toluene. Control of the
reactions with sodium ethoxide in ethanol.
diastereoselectivity in the Staudinger reaction and its investigation
14
are challenging issues. Generally the reaction of a ketene with an
imine produces two new stereogenic centres, thus the product
might be a mixture of cis- and trans-2-azetidinone derivatives,
depending on the ability of the zwitterionic intermediate to un-
2
. Results and discussion
The intermediate cis- and trans-1,3-thiazines 9a and 10a were
14
prepared in two ways (Scheme 1). Compounds 9a and 10a were
first obtained in moderate yields through the sulfur-exchange re-
actions of the corresponding oxazines 5a and 6a (prepared from
amino alcohol 1 or 2 and ethyl benzimidate) by treatment with
dergo isomerization. In our earlier studies, when 2-substituted
1,3-thiazine derivatives were involved in Staudinger reactions, the
addition took place in such a way that the relative configuration of
the vicinal substituents in the
compounds of types A and B).
b-lactams formed was cis (Fig. 1,
12
11a,b
phosphorus pentasulfide (Scheme 1). For the target thiazines, we
additionally devised another convenient method, which provided
the intermediate thiazines in relatively good overall yields. We
succeeded in obtaining thiobenzamides 7aec, 8aec in excellent
yields in a one-step process, through the reactions of amino alco-
hols 1 and 2 with substituted methyl dithiobenzoates under acid
catalysis. The direct one-pot ring closure of thiobenzamides in 10%
hydrochloric acid in ethanol provided thiazines 9aec and 10aec in
moderate yields. It is noteworthy that the preparation of this type
of compounds (which possess 1,3-thiazine or 1,3-thiazole sub-
structures) from bifunctional amino alcohols generally needs an
additional step for protection (usually with acetyl, mesyl or tosyl) of
the hydroxy group during the synthesis of the thioamide or in the
ring-closure step.13
To our surprise, the Staudinger
reactions of our cis and trans thiazines, 9aec and 10aec, each fur-
nished two diastereomers, 11 and 12, and 13 and 14, respectively,
15
which were separated by column chromatography. Structural
investigations revealed a cis relationship between the chloro and
aryl substituents in all four products 11e14. Thus, four of the eight
possible diastereomers were isolated: 11aec and 13aec were ob-
tained as cis and trans major
b-lactam products, while isomers
12aec and 14aec were obtained as minor products. Similar ex-
amples usually occur when a chiral imine is utilized in the asym-
16
metric Staudinger reaction for the preparation of b-lactams.
As we were interested in how the reaction conditions influence
the diastereoselectivity of the cycloaddition reaction, the effects of
different solvents, different reaction temperatures and different
sequences of addition of the reagents were examined in the cases of
compounds 11a and 12a. The results are presented in Table 1. The
For the preparation of monochloro-b-lactams 11e14 (Scheme 2),
we used the Staudinger reaction of cyclic C]N moiety of 9 and 10
Scheme 1. Preparation of cis- and trans-2-aryl-1,2,4a,5,6,7,8,8a-octahydro-4H-3,1-benzothiazines.

412
L. Fodor et al. / Tetrahedron 69 (2013) 410e417
Scheme 2. Staudinger cycloadditions of cyclohexane-condensed thiazines and ring transformations of the tricyclic
b-lactam derivatives obtained.
Table 1
Effects of the reaction conditions on the diastereoselectivity of the formation of 11a and 12a
ꢀ
equiva
Finally added reagentb
Relative amounts of productsc
Solvent
Temperature ( C)
Reaction time (h)
11a
12a
d
d
1.
2.
3.
4.
5.
6.
CH
CHCl
Dioxane
Toluene
Toluene
Chlorobenzene
2
Cl
2
8
48
18
18
18
18
18
3
3
3
3
3
3
Et
Et
Et
Et
3
3
3
3
N
N
N
N
d
d
d
d
d
3
Reflux
Reflux
Reflux
Reflux
Reflux
d
77
74
74
75
23
26
26
25
ClCH
2
COCl
Et
3
N
a
b
c
Added as three times 1 equiv.
This reagent was added dropwise to the reaction mixture (for additional information, see Experimental section).
Proportions calculated on the basis of the H-2 lines in the 1H NMR spectra of the crude products.
No reaction occurred.
d
use of different reaction conditions did not have any significant
3. Structure
effect on the rate of formation of the diastereomers 11a and 12a. At
ꢀ
8
C, no reaction took place (entry 1). Variation of the reaction
The structures of the new compounds follow straightforwardly
from the spectroscopic data (Tables 2e4). Only a few additional
remarks are necessary.
temperature by refluxing in different solvents, and variation of the
sequence of the addition of the reagents did not markedly influence
the diastereoselectivity (entries 2e6).
The treatment of monochloro-
cess of sodium ethoxide in ethanol provided cis-4,1-thiazepines
5aec in moderate yields. From azetidinone derivatives 13 and 14
trans thiazepines 16aec were obtained in only poor yields, even
when the amount of base or the reaction time was increased.
Compounds 16aec are very sensitive to hydrolysis, and readily de-
compose under column chromatography conditions.
The cis and trans configurations of the 1,2-disubstituted cyclo-
hexane ring in 7aec and 8aec, respectively, are confirmed by the
b-lactams 11 and 12 with an ex-
17a
13
field effect, which is reflected in the C-4a and C-8a lines in the
C
1
NMR spectra shifted upfield by w4.2 ppm for the more crowded cis
1
8
isomers 7aec relative to those for the trans counterparts 8aec.
19
In accord with our earlier findings
cyclohexane derivatives with CH R- and NHR -type substituents, in
the cis isomers 9aec and 12aec the bulkier CH S group on the
on 1,2-disubstituted
0
2
2

L. Fodor et al. / Tetrahedron 69 (2013) 410e417
413
Table 2
Characteristic IR frequencies and 1H NMR datab of compounds 5a, 6a, 7aec and 16aecc
a
C]O bandd
g
C
ArH bandd
CH
s (3H)
XCH
2ꢁdd
e
H-8a m (1H)f
H-2 ,6 wd (2H)
0
0
g
H-3 ,5 d/t (2H)
0
0
h
H-4 t (1H)
0
NH or CH (1H)i
Compound
n
3
2
5
6
7
7
7
8
8
8
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
a
a
b
c
a
b
c
1649
1643
1518
1552
1505
1560
1541
1557
1602
1601
1598
1603
1599
1601
1775
1766
1764
1752
1755
1755
1760
1773
1766
1771
1760
1771
1656
1633
1668
1628
1630
1631
725
775
716
823
821
714
829
823
763
838
821
763
761
823
732
843
797
759
840
750
750
790
800
752
787
770
757
829
823
758
873
848
d
d
d
d
4.19, 4.31
3.95, 4.31
w3.5, 3.65
3.60, 3.77
3.50, 3.64
3.40, 3.69
3.40, 3.66
3.41, 3.70
2.96, 3.24
2.99, 3.28
2.96, 3.24
2.86, 2.92
2.88, 2.93
2.84, 2.90
2.39, 3.10
2.41, 3.09
2.36, 3.09
2.57, 2.86
2.59, 2.85
2.55, 2.85
2.64, 2.76
2.63, 2.76
2.76, 2.88
2.42, 2.51
2.40, 2.52
2.43,k 2.50
3.00, 3.20
2.99, 3.18
2.98, 3.18
2.64, 3.92
2.57, 3.71
2.55, 3.67
3.72
3.02
5.04
4.99
5.04
4.55
4.50
4.58
3.77
3.78
3.76
3.08
3.08
3.06
4.27
4.26
4.25
3.61
3.56
3.58
3.52
3.50
3.60
2.91
2.84
2.89
5.21
5.18
5.18
4.47
4.18
4.15
7.96
7.94
7.75
7.73
7.68
7.72
7.66
7.66
7.79
7.77
7.70
7.78
7.75
7.68
7.75
w7.7
w7.6
7.60
w7.55
w7.45
7.58
7.53
7.50
7.59
7.53
7.48
w7.35 m (5H)
7.27
7.24
w7.3 m (5H)
7.29
7.38
7.37
7.47
7.38
7.21
7.40
7.35
7.21
7.38k
7.37
7.18
w7.4
7.36
7.16
w7.4
7.40
7.22
7.46
7.43
7.24
7.43
7.39
7.35
7.45
7.41
7.25
7.43
7.42
7.40
d
d
d
8.44
8.60
8.45
7.62
7.73
7.60
d
2.40
d
d
7.46
d
d
2.40
d
d
a
b
c
7.37k
d
d
d
2.37
d
d
d
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
d
d
d
d
2.36
d
d
5.07
5.06
5.03
5.09
5.09
5.08
5.02
5.00
5.51
4.98
4.97
4.96
w3.8
w3.7
w3.8
w3.7
6.35
6.22
d
d
2.40
d
d
7.40
d
d
2.39
d
d
7.37
d
d
2.43
d
d
7.40
d
d
2.40k
d
d
k
d
7.32
7.15
d
d
2.37
d
d
7.39
7.33
d
d
2.32
7.17
a
ꢂ1
In KBr discs (cm ). Further bands,
n
OH and
nNH (one or two broad bands) for 7, 8, 15 and 16: 3332e3310;
gC
Ar
CAr band (mono-subst. benzene ring in a-type compounds):
6
90e704, split with the second maximum at 683 (10a), 686 (11a).
b
In CDCl
8H): 0.9e2.55, in overlap with the multiplet of H-4a, except for 5a, 7 and 11, where the H-4a signals (m, 1H) are as follows: 2.00 (5a), 2.10ꢃ0.04 (Dn: 24 Hz, 7), 2.30 (Dn: 12 Hz,
1); CH and CH (Et), t and qa (J: 7.1): 0.82, 3.82 (15a, 16a), 0.91, 3.87 (15b), 0.88, 3.86 (15c), 0.71, 3.63 (16b), 0.67, 3.60 (16c); OH, br: 2.96e3.46 (7, 8).
Assignments were supported by 2D-HMQC (except for 5a), HMBC (except for 5a and 7a), for 7b,c, 8a and 11a also by 2D-COSY, and for 11e14 also by DIFFNOE
measurements.
3
or DMSO-d
6
(16) solution at 500 MHz. Chemical shifts in parts per million (
d
TMS¼0 ppm), coupling constants in hertz. Further signals: CH
2
(c-hexane), 5e8 signals
(
1
3
2
c
d
Split band, second maximum at 1762 (11a), 818 (9b), 784 (11c), 768 (12c).
e
2
ꢁ1H, X: O (5e8), S (9e16), J (ꢃ0.2): 10.4, 4.4, 3.4 (5a), 11.7, 2.6, 2.6 (8), 12.2, 5.6, 3.8 (9), 13.9, 12.3, 2.8 (11), 14.0, 3.5, 2.9 (12), 13.8, 11.2, 3.0 (14), 14.5, 10.5, 6.5 (15); t and
dd, J: 10.6, 4.4 (6a), 11.6, 3.8 (13), dd and t, J: 10.5, 3.5 (7), 12.0, 11.6, 4.0 (10c), d and dd, J: 14.6, 5.9 (16).
f
qa, J: 4.6 (5a, 9c), dt, J: 10.8, 3.7 (10), 11.5, 3.8 (13), 12.8, 3.6 (14a), 11.3, 3.5 (14b), td, J: 12.5, 4.5 (11c), with coalesced lines: m (6a, 11a, 14c), ws (12), wddd (7), wdqa (8,
1
1b, 16c), wqa (9a,b, 15, 16a), wtqa (16b).
Part of an AA BB C (for a-type compound) or AA’BB’ spectrum (b- and c-type compounds), J: 8.5 (7b,c, 9b, 10b, 16b), 8.0 (8c, 9a,c, 10c, 14c, 15c, 16c), 8.8 (13b, 15b), br (11, 12).
wd, J: 8.6 (11b,c), 8.9 (12b).
g
h
i
0
0
NH, br (7), NH, wd (8, 15, 16a), NH, d (J: 7.7 Hz, 16b,c), CHCl, s (11e14).
Overlapping signals [with the CH qa (15a)].
2
k
condensed cyclohexane ring is equatorial. The situation was the
opposite in 11aec, which adopted a rigid conformation with the
condensed 2-chloro-2a-aryl-2,2a-dihydro-5,6-dimethoxy-1H,8H-
11a
azeto[2,1-b][1,3]benzothiazin-1-one analogues
(Fig. 1, com-
cyclohexane carrying an axial CH
group, as unambiguously reflected by the coupling patterns ob-
2
S group and an equatorial NCH
2
pounds of type A) are the proofs of an identical configuration with
the cis orientation of the Ar/Ph group and the chlorine atom. For
instance, the lines of the carbons carrying the chlorine atom appear
in the region between 68.4 and 70.7 ppm for 11e14, and between
71.0 and 72.0 ppm for the linearly condensed analogues (Fig. 1,
servable in the dd split of the signals due tothe geminal H-4ax and H-
2
3
3
4
4
eq [ J(H-4ax/H-4eq)¼13.9 Hz, J(H-4ax/H-4a)¼12.3 Hz and J(H-
eq/H-4a)¼2.8 Hz]. The corresponding coupling patterns obtained
11a
for the analogous signals of 9aec and 12aec, respectively, suggest
compounds of type A) of the a-type molecules.
1
the equatorial orientation of the CH
2
S group and the axial orientation
The ranges of the chemical shifts of the CH group in the H- and
2
13
of the NCH group on the condensed cyclohexane ring [ J(H-4ax/H-
2
C NMR spectra of 11e14 are 4.96e5.09 and 68.9e70.4 ppm, re-
3
2
4
4
eq)¼12.2 Hz, J(H-4/H-4a)¼5.6 and 3.8 Hz for 9aec, J(H-4ax/H-
spectively. For their linearly condensed analogues (Fig. 1, com-
3
eq)¼14.0 Hz, J(H-4/H-4a)¼3.5 and 2.9 Hz for 12aec (the
pounds of type A), the corresponding signals are discernible in the
11a
axialeequatorial and equatorialeequatorial coupling constants for
these compounds cannot be distinguished.)]. The pronounced
downfield shift of the H-8a signal measured for 11aec points to the
shift intervals 5.09e5.14 and 68.3e69.2 ppm, respectively.
The annellation of the two six-membered rings of the precursors
(9 and 10) remains unaltered in the azetidinones 11e14. Accord-
13
proximity of the
b-lactam carbonyl oxygen, as evidenced by the HF-
ingly, the C NMR lines of C-4a and C-8a are upfield-shifted in the
cis isomers 11 and 12 relative to those of their trans counterparts. In
the cis annellated diastereomers 11aec and 12aec, values of 51.9
and 53.7 ppm, respectively, were measured for the C-8a signal,
while the corresponding lines of the trans annellated analogues
13a,b and 14aec were at 57.5 and 60.3 ppm, respectively. Reflecting
6
-31G(d) modelling of 11a (Fig. 2). In its optimized structure, the
ꢁ
distance between H-8a andtheoxygenatomwasfoundto be 2.683 A.
The relative configurations of the stereogenic centres of the
condensed azetidinone ring carrying Ph/Ar and chlorine sub-
stituents are also to be considered. The very similar chemical shifts
of the carbons in the four-membered ring to those of the linearly
13
a similar tendency, the C-4a line was at 35.3 and 33.2 ppm in the
C

414
L. Fodor et al. / Tetrahedron 69 (2013) 410e417
Table 3
Table 4
1
3C NMR chemical shiftsa of compounds 5a, 6a, 7aec and 16aecb,c
13
C NMR chemical shiftsa of the Ph/Ar carbons in compounds 5a, 6a, 7aec and
1
6aecb
d
C-4ae C-5e C-6e C-7e C-8e C-8ae CHClf NCSg C]Xh
Compound XCH
2
0
0
0
0
0
0
i
i
Compound
C-(1 )
C-(2 ,6 )
C-(3 ,5 )
C-(4 )
5
6
7
7
7
8
8
8
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
a
a
b
c
a
b
c
69.3
70.6
64.3
64.5
64.2
63.8
64.1
63.7
31.3
31.3
31.2
32.3
32.2
32.3
27.6
27.5
27.6
33.7
33.7
33.7
31.7
31.5
30.9
32.8
32.8
32.8
39.3
39.3
39.2
39.8
39.2
39.9
32.0 32.8 22.1 25.2 24.7 51.4
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
154.9
156.1
199.2
197.4
198.9
199.4
197.7
199.1
157.3
155.8
156.8
156.5
155.3
156.4
i
i
37.8 34.7 25.9 26.2 28.1 57.9
42.4 25.8 24.3 22.8 28.8 54.2
41.8 26.2 23.9 23.1 28.3 55.0
42.5 25.8 24.3 22.8 28.8 54.1
46.5 28.8 25.8 25.5 33.0 56.9
46.2 28.8 25.8 25.4 32.8 57.4
46.5 28.8 25.8 25.5 33.1 56.7
5a
6a
7a
7b
7c
8a
8b
8c
134.6
134.6
142.4
137.8
139.6
142.1
137.9
139.3
140.1
138.5
137.5
139.9.
138.3
137.2
137.0
135.6
133.9
135.6
134.3
132.4
140.2
138.8
137.9
135.8
134.4
132.6
141.7
140.0
138.8
141.6
140.4
128.0
127.5
127.6
127.1
128.5
127.2
127.2
128.5
127.2
126.7
127.9
126.5
126.9
128.2
126.8
129.4
131.1
128.4
128.4
129.0
129.1
129.6
129.0
129.1
129.6
128.7
128.8
129.3
128.7
128.8
129.3
129.6
128.5
130.5
130.6
131.6
140.7
142.3
131.7
140.4
142.4
130.5
136.5
140.6
130.5
136.5
140.6
128.2
135.7c
139.4
129.0
135.5
139.3
129.0
135.1
138.6
129.3
135.4
139.3
128.7
135.6
139.7
129.5
134.3
139.3
i
i
a
b
c
29.0 27.5 24.5 22.6 32.9 55.9
29.0 27.5 24.5 22.5 32.9 56.0
29.1 27.5 24.6 22.6 32.9 55.9
9a
9b
9c
i
i
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
34.7 36.2 26.3 26.6 33.6 61.7
i
i
34.7 36.1 26.3 26.5 33.5 61.7
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
i
i
34.8 36.2 26.3 26.6 33.6 61.6
35.4 31.9 20.4 25.5 27.2 51.9 69.8 69.4 163.4
35.2 31.9 20.4 25.5 27.2 51.9 69.7 68.8 163.2
35.5 31.9 20.4 25.6 27.1 51.9 69.9 69.4 163.4
33.3 25.7 25.2 22.3 28.3 53.7 69.1 70.7 161.3
33.2 25.7 25.2 22.2 28.3 53.7 68.9 70.3 161.1
33.3 25.8 25.3 22.3 28.3 53.6 69.1 70.7 161.3
35.5 32.5 25.7 24.8 33.5 57.6 70.4 69.0 165.4
35.5 32.4 25.6 24.7 33.6 57.5 70.2 68.4 165.2
35.4 31.8 25.7 24.7 33.6 56.9 69.9 68.9 163.5
c
c
c
129.0
129.6
128.9
130.5
129.0
128.2
129.8
128.2
129.3
129.1
129.6
128.5
128.7
129.7
j
j
41.5 31.6 25.8 25.8 29.7 60.3 69.1 70.3 161.5
j
j
c
c
41.4 31.6 25.8 25.8 29.6 60.3 68.9 69.8 161.3
128.8
129.1
j
j
41.6 31.6 25.9 25.9 29.6 60.2 70.3 69.1 161.5
37.0 29.4 20.8 25.5 31.2 52.3 155.6 93.6 167.9
36.8 29.5 20.8 25.5 31.2 52.3 154.1 94.3 167.5
36.9 29.5 20.9 25.5 31.2 52.2 155.8 92.9 167.9
130.6
129.1
129.6
130.2
128.7
128.6
131.5
129.7
129.1
129.6
128.6
128.9
129.3
i
i
42.3 32.7 25.7 25.9 33.2 52.3 155.7 93.6 168.0
h
i
c
c
40.6 32.9 25.8 25.9 32.1 58.1 155.7 90.6 167.3
128.7
i
i
40.6 32.9 25.8 25.9 32.1 58.1 157.0 89.6 167.5
128.5
129.0
16c
a
In CDCl
3
or DMSO-d (16b,c) solution at 500 MHz. Chemical shifts in parts per
6
a
million (
d
TMS¼0 ppm).
In CDCl
3
or DMSO-d
6
(13c and 16b,c) solution at 500 MHz. Chemical shifts in
b
Further signals: CH
3
(Et): 14.3ꢃ0.2 (15, 16), CH
3
(Ar): 21.7ꢃ0.1, CH
2
(Et): 60.5
parts per million (d
TMS¼0 ppm).
b
(
15b), 60.3 (15a,c, 16a), 59.5 (16b), 59.3 (16c), Ph/Ar signals: see in Table 3.
Assignments were supported by 2D-HMQC (except for 5a), HMBC (except for 5a
Assignments were supported by 2D-HMQC (except for 5a), HMBC (except for 5a
and 7a) and DEPT measurements (except for 7a,b).
c
c
and 7a) and DEPT measurements (except for 7a,b).
Reversed assignment is also possible.
d
X: O (5e8), S (9e16).
The numbering of the carbon atom 5, 6, 9 and 10 was also used for all the other
e
compounds.
f
<
ce:glyph name¼"dbnd"/>CeNH in 15 and 16.
g
h
i
<
ce:glyph name¼"dbnd"/>CeS in 15 and 16.
X: N (5a, 6a, 9aec, 10aec), S (7, 8), O (11e16).
Reversed assignment is also possible.
Two overlapping lines.
j
NMR spectra of cis compounds 11aec and 12a-c, respectively, and at
3
5.5 and w41.5 ppm were measured for 13a,b and 14aec.
The final question to be clarified is the stereostructures of these
azetidinones as concerns the mutual positions of the substituents
in the four-membered ring and the hydrogens on the junctions of
the cyclohexane-condensed thiazine moieties.
To solve this problem, we compared the spectral data of the
products formed as mixtures in the Staudinger cycloaddition re-
action (the pairs 11 and 12, and 13 and 14, respectively).
The all-cis configuration in 11aec and the trans position of the
annellational H’s and those ones in the four-membered ring for
2
Fig. 2. Calculated structure of 11a containing the CH S moiety in the axial position on
the cyclohexane ring. The optimization was carried out by the HF-6-31G(d) method.
1
2aec follow from the following facts. Both the H-8a and H-4a
but moderate difference in the H-4a shifts lends further support to
thepresumedconfigurationsgivenfor13aecand14aecinScheme2.
The above stereostructures were definitively confirmed by
DIFFNOE measurements of 11e14 compounds. Mutual and con-
siderable NOEs were observed for 12aec and 14aec between the
ortho H’s of the Ph/Ar groups and H-8a, demonstrating their cis 1,3-
diaxial position on the molecular skeleton. Similar interactions
were not observed for cis and trans diastereomers isomers 11aec
and 13aec, respectively, in which the Ph/Ar group and H-8a are on
opposite sides of the molecular skeleton. On the other hand, in 13a
the cis arrangement of H-4a and the Ph group was also evidenced
by the results of DIFFNOE measurements.
signals of 11aec (at w4.25 and 2.30 ppm) are significantly
downfield-shifted as compared with those of 12aec (w3.58 and
w1.65 ppm). These differences can be interpreted in terms of the
17
anisotropic neighbouring effect of the Ph/Ar and the carbonyl
17
group, respectively. The former causes a stronger shielding on the
signal of the near-lying H-4a, while the latter results in a downfield
shift of the signal of H-8a, which is positioned nearly in the plane of
the lactam moiety.
Similarly, due to the shielding effect of the proximal phenyl
ring, the H-8a signal for 14aec is significantly upfield-shifted
(
2.88ꢃ0.04 ppm) relative to that for 13aec (3.50 ppm). A similar

L. Fodor et al. / Tetrahedron 69 (2013) 410e417
415
4
. Summary
stopped and the reaction mixture was allowed to warm up to room
temperature. The vessel was stoppered and allowed to stand for 2
days at the same temperature. After evaporation, the residue was
triturated with diethyl ether (30 mL) and the white crystalline
product obtained was filtered off and washed with the same solvent
(2ꢁ10 mL). The benzimidate was then liberated by a standard pro-
In summary, the Staudinger cycloaddition reactions of cis- and
trans-2-aryl-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothazines
and
chloroacetyl chloride in the presence of base stereoselectively pro-
vided lactams 2-chloro-2a-aryl-2,2a,4a,5,6,7,8,8a-octahydro-2H,4H-
azeto[1,2-a][3,1]benzothiazin-1-ones, in which the aryl substituent
is cis to the chloro substituent. Because of the nature of the saturated
condensed thiazines, two diastereomers were formed for both the
21
cedure and distilled with a Kugelrohr apparatus.
5.4. General procedure for thiobenzamide derivatives 7aec or
8aec
cis and the trans compounds. The
were transformed into the corresponding 3-ethoxycarbonyl-2-aryl-
,5,5a,6,7,8,9,9a-octahydro-4,1-benzothiazepines, which were iden-
tified by NMR measurements as enamine tautomers.
b-lactam derivatives prepared
1
To a solution of amino alcohol 1 or 2 (1.3 g, 10 mmol) in dry
ethanol (10 mL), the corresponding methyl dithiobenzoates 4aec
(11 mmol) and two drops of trifluoromethanesulfonic acid were
5
5
. Experimental section
added. The reaction mixture was refluxed for 5 days. After evapo-
ration, the residue was washed with n-hexane (3ꢁ30 mL) and
crystallized from n-hexane (n-hexane/diisopropyl ether for 7b and
.1. General
8b) to give a pale-orange crystalline powder of 7aec or 8aec.
Melting points were determined on a Kofler micro melting
apparatus. Elemental analyses were performed with
a
Per-
5.4.1. N-[cis-2-(Hydroxymethyl)cyclohexyl]-N-(phenylthiocarbonyl)
amine (7a). A pale-yellow crystalline powder, mp: 143e145 C,
yield 83%, 2.07 g. Anal. Calcd for C14H19NOS (249.37): C, 67.43; H,
7.68; N, 5.62; S, 12.86. Found: C, 67.67; H, 7.92; N, 5.35; S, 13.06.
ꢀ
kineElmer 2400 CHNS elemental analyser. Merck Kieselgel 60F254
plates were used for TLC, and Merck silica gel 60 (0.063e0.100) for
column chromatography. Amino alcohols 1 and 2 were prepared as
20
described previously.
1H and 13C NMR spectra were recorded in CDCl
13c, 16b,c) solution in 5 mm tubes at room temperature, on
3
or DMSO-d
6
5.4.2. N-[cis-2-(Hydroxymethyl)cyclohexyl]-N-[(4-chlorophenyl)thi-
(
ocarbonyl]amine(7b). A pale-yellow crystalline powder, mp:
1
ꢀ
a Bruker DRX 500 spectrometer at 500 MHz ( H) and 126 MHz
158e160 C, yield 88%, 2.50 g. Anal. Calcd for C14
H18ClNOS (283.82): C,
1
3
(
C), with the deuterium signal of the solvent as the lock and TMS
59.25; H, 6.39; N, 4.94; S,11.30. Found: C, 58.94; H, 6.62; N, 5.13; S,11.56.
as internal standard. The standard Bruker micro program NOE-
MULT.AU to generate NOE was used with a selective preirradiation
5.4.3. N-[cis-2-(Hydroxymethyl)cyclohexyl]-N-[(4-methylphenyl)thi-
time. DEPT spectra were run in a standard manner, using only the
ocarbonyl]amine (7c). A pale-yellow crystalline powder, mp:
ꢀ
ꢀ
Q¼135 pulse to separate CH/CH
3
and CH
2
lines phased ‘up’ and
122e123 C, yield 72%, 1.90 g. Anal. Calcd for C15H21NOS (263.40): C,
‘down’, respectively. The 2D HSC and HMBC spectra were obtained
68.40; H, 8.04; N, 5.32; S,12.17. Found: C, 68.10; H, 8.40; N, 5.61; S,12.36.
by using the standard Bruker pulse programs.
5
.4.4. N-[trans-2-(Hydroxymethyl)cyclohexyl]-N-(phenyl-
5
.2. General procedure for oxazine derivatives 5a and 6a
thiocarbonyl)amine (8a). A pale-yellow crystalline powder, mp:
ꢀ
1
55e159 C, yield 86%, 2.14 g. Anal. Calcd for C14
H19NOS (249.37): C,
To a solution of amino alcohol 1 or 2 (1.3 g, 10 mmol) in dry
67.43; H, 7.68; N, 5.62; S,12.86. Found: C, 67.37; H, 7.93; N, 65.29; S,13.15.
ethanol (10 mL), ethyl benzimidate (2.0 g, 11 mmol) and two drops
of diluted glacial acetic acid (one drop diluted with 1 mL of dry
ethanol) were added. The reaction mixture was refluxed for 12 h.
Ethyl benzimidate (0.5 g, 2.75 mmol) was then added and the so-
lution was refluxed for a further 24 h. After evaporation, the residue
was purified by column chromatography (n-hexane/ethyl acetate
5.4.5. N-[trans-2-(Hydroxymethyl)cyclohexyl]-N-[(4-chlorophenyl)
thiocarbonyl]amine (8b). A pale-yellow crystalline powder, mp:
ꢀ
140e142 C, yield 85%, 2.41 g. Anal. Calcd for C14
H18ClNOS (283.82): C,
59.25; H, 6.39; N, 4.94;S,11.30. Found: C, 59.41; H, 6.28; N, 4.72; S,11.51.
4
:1) to give a white crystalline powder of 6a, or upon standing in
5.4.6. N-[trans-2-(Hydroxymethyl)cyclohexyl]-N-[(4-methylphenyl)
a refrigerator 5a.
thiocarbonyl]amine (8c). A pale-yellow crystalline powder, mp:
ꢀ
1
24e126 C, yield 78%, 2.05 g. Anal. Calcd for C15
H21NOS (263.40): C,
5
.2.1. (4aR
*
,8aS
*
)-2-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-3,1-
68.40;H, 8.04;N,5.32;S,12.17. Found:C,68.11;H, 7.82;N, 5.18;S,12.44.
5.5. General procedure for thiazine derivatives 9aec or 10aec
Method A (for 9a or 10a)
benzoxazine (5a). A colourless oil at room temperature, a white
crystalline powder in refrigerator, mp: 21e23 C, yield 75%, 1.61 g.
Anal. Calcd for C14
C, 77.84; H, 7.77; N, 6.80.
ꢀ
H17NO (215.29): C, 78.10; H, 7.96; N, 6.51. Found:
5
.2.2. (4aR
*
,8aR
*
)-2-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-3,1-
The method of Simon et al. was used with slight modifications,
as follows.
ꢀ
12
benzoxazine (6a). A white crystalline powder, mp: 104e106 C,
yield 82%, 1.77 g. Anal. Calcd for C14
H
17NO (215.29): C, 78.10; H,
Oxazine 5a or 6a (2.15 g, 10 mmol) was homogenized thor-
oughly with phosphorus pentasulfide (6 g, 13.5 mmol) and the
mixture was heated in an oil bath at 120 C for 3 h. To the melt,
7.96; N, 6.51. Found: C, 77.91; H, 8.25; N, 6.61.
ꢀ
5
.3. Preparation of ethyl benzimidate 3a
chloroform (30 mL) was added and the solid formed was sus-
pended. To the suspension, water was added (10 mL) and the
aqueous phase was made just alkaline with 10% sodium hydroxide
solution under intensive shaking. The organic layer was separated,
extracted with water (30 mL), dried (sodium sulfate), filtered, and
evaporated. The residues thus obtained were purified by column
chromatography with n-hexane/ethyl acetate 4:1 as eluent to give
thiazine 9a or 10a.
For the preparation of ethyl benzimidate, the method of Yadav
21
et al. was used, with slight modifications (because of the larger
scale), as follows.
To a stirred and ice-cooled mixture of dry ethanol (35 mL, 0.6 mol)
and benzonitrile (5.2 mL, 0.05 mol), acetyl chloride (28.4 mL, 0.4 mol)
was added dropwise over 30 min. After the addition, the stirring was

416
L. Fodor et al. / Tetrahedron 69 (2013) 410e417
ꢀ
Method B (for 9aec or 10aec)
crystalline powder, mp: 153e155 C, yield 52%, 0.48 g. Anal. Calcd for
18ClNOS (307.84): C, 62.43; H, 5.89; N, 4.55; S, 10.42. Found: C,
62.74; H, 6.21; N, 4.31; S, 10.20.
16
C H
To a solution of thiobenzamides 7aec or 8aec (4 mmol) in dry
ethanol (10 mL), 20% hydrochloric acid in ethanol (10 mL) was added.
The reaction mixture was refluxed for 2 h. After evaporation the res-
iduewas taken upin dichloromethane (40mL), afteraddition of water
5.6.1.2. (2S
*
,2aR
*
,4aR
*
, 8aS )-2-Chloro-2a-(4-chlorophenyl)-2,2a,4a,
5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(11b). A white crystalline powder, mp: 160e162 C, yield 58%, 0.59 g.
*
ꢀ
(40 mL) the mixture was neutralized by the addition of potassium
carbonate with intensive swirling of the phases. After separation of
the phases,theorganicphasewasextracted withwater, dried (sodium
sulfate) and evaporated. The residue was purified by column chro-
matography (n-hexane/ethyl acetate 100:1) to give 9aec or 10aec.
Anal. Calcd for C H Cl NOS (342.28): C, 56.14; H, 5.01; N, 4.09; S,
9.37. Found: C, 56.32; H, 5.37; N, 3.81; S, 9.62.
16
17
2
5.6.1.3. (2S
*
,2aR
*
,4aR
*
,
*
8aS )-2-Chloro-2a-(4-methylphenyl)-2,2a,
4
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
ꢀ
5
.5.1. (4aR
*
,8aS
*
)-2-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothia-
(11c). A white crystalline powder, mp: 145e147 C, yield 45%, 0.43 g.
Anal. Calcd for C H20ClNOS (321.87): C, 63.44; H, 6.26; N, 4.35; S,
9.96. Found: C, 63.68; H, 6.41; N, 4.61; S, 10.12.
zine (9a). A colourless oil, which turns pale-yellow upon standing,
yield 38%, 0.87 g (method A), yield 56%, 0.52 g (method B). Anal. Calcd
for C14H17NS (231.36): C, 72.68; H, 7.41; N, 6.05; S, 13.86. Found: C,
17
72.42; H, 7.18; N, 6.31; S, 14.02.
5.6.2. Minor isomers of cis compounds 12aec
5
.6.2.1. (2R
*
,2aS
*
,4aR
*
, 8aS )-2-Chloro-2a-phenyl-2,2a,4a,5,6,7,8,8a-
*
5
3
.5.2. (4aR
*
,8aS )-2-(4-Chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-
*
octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (12a). A white
crystalline powder, mp: 166e168 C, yield 16%, 0.15 g. Anal. Calcd for
ꢀ
12
,1-benzothiazine (9b). Awhite crystalline powder, mp: 45e46 C(lit.
ꢀ
ꢀ
mp: 47e49 C), yield 52%, 0.55 g. Anal. Calcd for C14
H16ClNS (265.80): C,
16
C H18ClNOS (307.84): C, 62.43; H, 5.89; N, 4.55; S, 10.42. Found: C,
6
3.26; H, 6.07; N, 5.27; S,12.06. Found: C, 62.96; H, 6.38; N, 5.44; S,.12.41.
62.55; H, 6.01; N, 4.22; S, 10.15.
5
3
.5.3. (4aR
*
,8aS
*
)-2-(4-Methylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-
5
.6.2.2. (2R
*
,2aS
*
,4aR
*
,
8aS )-2-Chloro-2a-(4-chlorophenyl)-2,2a,
*
ꢀ
,1-benzothiazine (9c). A white crystalline powder, mp: 59e62 C,
yield 62%, 0.61 g. Anal. Calcd for C15
.80; N, 5.71; S, 13.07. Found: C, 73.68; H, 8.10; N, 5.85; S, 13.31.
4
(
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
12b). A white crystalline powder, mp: 195e197 C, yield 19%, 0.19 g.
Anal. Calcd for C16
H19NS (245.38): C, 73.42; H,
ꢀ
7
H17Cl
2
NOS (342.28): C, 56.14; H, 5.01; N, 4.09; S,
9
.37. Found: C, 56.41; H, 5.36; N, 3.94; S, 9.52.
5
.5.4. (4aR
*
,8aR
*
)-2-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-3,1-
ꢀ
benzothiazine (10a). A white crystalline powder, mp: 59e60 C,
yield 42%, 0.97 g (method A), yield 56%, 0.52 g (method B). Anal.
Calcd for C14
Found: C, 72.38; H, 7.70; N, 6.28; S, 14.04.
5
.6.2.3. (2R
*
,2aS
*
,4aR
*
, 8aS )-2-Chloro-2a-(4-methylphenyl)-2,2a,
*
4
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
H
17NS (231.36): C, 72.68; H, 7.41; N, 6.05; S, 13.86.
ꢀ
(12c). A white crystalline powder, mp: 206e207 C, yield 14%,
0
4
.14 g. Anal. Calcd for C17H20ClNOS (321.87): C, 63.44; H, 6.26; N,
.35; S, 9.96. Found: C, 63.71; H, 6.42; N, 4.18; S, 9.69.49.
5
3
(
(
6
.5.5. (4aR
*
,8aR
*
)-2-(4-Chlorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-
ꢀ
,1-benzothiazine (10b). A white crystalline powder, mp: 68e70 C
lit. mp: 70e71 C), yield 54%, 0.57 g. Anal. Calcd for C14
265.80): C, 63.26; H, 6.07; N, 5.27; S, 12.06. Found: C, 63.42; H,
.29; N, 5.41; S, 11.85.
5.6.3. Major isomers of trans compounds 13aec
12
ꢀ
H16ClNS
5
.6.3.1. (2S
*
,2aR
*
,4aR
*
, 8aR )-2-Chloro-2a-phenyl-2,2a,4a,5,6,7,8,8a-
*
octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (13a). A white
crystalline powder, mp: 97e100 C, yield 58%, 0.54 g. Anal. Calcd for
ꢀ
C
16
H
18ClNOS (307.84): C, 62.43; H, 5.89; N, 4.55; S, 10.42. Found: C,
5
3
.5.6. (4aR
*
,8aR
*
)-2-(4-Methylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-
62.73; H, 6.21; N, 4.80; S, 10.16.
ꢀ
,1-benzothiazine (10c). A white crystalline powder, mp: 82e84 C,
yield 60%, 0.59 g. Anal. Calcd for C15H19NS (245.38): C, 73.42; H,
5
.6.3.2. (2S
*
,2aR
*
,4aR
*
, 8aR )-2-Chloro-2a-(4-chlorophenyl)-2,2a,
*
7.80; N, 5.71; S, 13.07. Found: C, 73.70; H, 7.98; N, 5.52; S, 13.86.
4
(
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
13b). A white crystalline powder, mp: 113e116
ꢀ
C,
yield 50%, 0.51 g. Anal. Calcd for C16
H
17Cl
2
NOS (342.28): C,
5
.6. General procedure for azetothiazine derivatives 11aec
56.14; H, 5.01; N, 4.09; S, 9.37. Found: C, 56.40; H, 5.28; N, 3.98;
and 14aec
S, 9.52.
To a stirred solution of the corresponding 3,1-thiazine derivatives
aec or 10aec (3.0 mmol) in anhydrous toluene, chloroacetyl chlo-
5
.6.3.3. (2S
*
,2aR
*
,4aR
*
, 8aR )-2-Chloro-2a-(4-methylphenyl)-2,2a,
*
9
4
(
0
4
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
13c). A white crystalline powder, mp: 127e130 C, yield 49%,
.47 g. Anal. Calcd for C17
.35; S, 9.96. Found: C, 63.74; H, 6.46; N, 4.18; S, 10.21.
ride(0.24 mL, 3.0 mmol)wasadded. The solutionwasheatedtoreflux
and triethylamine (0.40 mL, 3.0 mmol) in anhydrous toluene (20 mL)
was added dropwise over 4 h at reflux. The addition of the acid
chloride (0.24 mL, 3.0 mmol) and triethylamine (0.40 mL, 3.0 mmol)
was repeated under the same conditions as above. The reaction
mixture was then passed through a short column of silica, washed
further with n-hexane/ethyl acetate 4:1 (100 mL), the solvent was
evaporated off, and the oily residue purified by column chromatog-
raphy to give isomers of 11aec and 12aec for the cis compounds and
ꢀ
H20ClNOS (321.87): C, 63.44; H, 6.26; N,
5.6.4. Minor isomers of trans compounds 14aec
5.6.4.1. (2R ,2aS ,4aR , 8aR )-2-Chloro-2a-phenyl-2,2a,4a,5,6,7,8,8a-
*
*
*
*
octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (14a). A white
crystalline powder, mp: 100e102 C, yield 18%, 0.17 g. Anal. Calcd for
ꢀ
13aec and 14aec for the trans compounds. Afterevaporation, the oily
C H ClNOS (307.84): C, 62.43; H, 5.89; N, 4.55; S, 10.42. Found: C,
1
6 18
residues crystallized on trituration with diisopropyl ether.
62.70; H, 5.93; N, 4.32; S, 10.70.
5
.6.1. Major isomers of cis compounds 11aec
.6.1.1. (2S ,2aR ,4aR , 8aS )-2-Chloro-2a-phenyl-2,2a,4a,5,6,7,8,8a-
octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (11a). A white
5
.6.4.2. (2R ,2aS ,4aR , 8aR )-2-Chloro-2a-(4-chlorophenyl)-2,2a,
*
*
*
*
5
*
*
*
*
4a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
(14b). A white crystalline powder, mp: 174e175 C, yield 12%,
ꢀ

L. Fodor et al. / Tetrahedron 69 (2013) 410e417
417
ꢀ
powder, mp: 192e193 C, yield 21%, 0.10 g. Anal. Calcd for
0
.12 g. Anal. Calcd for C16
H17Cl
2
NOS (342.28): C, 56.14; H, 5.01; N,
4
.09; S, 9.37. Found: C, 56.30; H, 5.28; N, 4.34; S, 9.54.
19 2
C H25NO S (331.47): C, 68.85; H, 7.60; N, 4.23; S, 9.67. Found: C,
68.66; H, 7.86; N, 4.40; S, 9.98.
5
.6.4.3. (2R
*
,2aS
*
,4aR
*
, 8aR )-2-Chloro-2a-(4-methylphenyl)-2,2a,
*
4
a,5,6,7,8,8a-octahydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one
Acknowledgements
ꢀ
(14c). A white crystalline powder, mp: 156e158 C, yield 16%, 0.15 g.
Anal. Calcd for C17
H
20ClNOS (321.87): C, 63.44; H, 6.26; N, 4.35; S,
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA K-83874 and K-68887) for financial
support. The European Union and the European Social Fund also
provided financial support for the project under grant agreement
9
.96. Found: C, 63.65; H, 6.35; N, 4.21; S, 10.31.
5
.7. General procedure for thiazepine derivatives 15aecand16aec
The isomeric mixture of azeto-3,1-thiazines 11aec and 12aec or
ꢀ
no. TAMOP 4.2.1./B-09/KMR-2010-0003.
1
3aec and 14aec (1.5 mmol) was dissolved in ethanol (10 mL). To
References and notes
this stirred solution, sodium ethoxide (100 mg, 1.41 mmol for the
mixture of 11aec and 12aec; 200 mg, 2.82 mmol for the mixture of
1. (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Curr. Opin. Drug. Discov. Dev. 2010,
13, 685; (b) qysek, R.; Katarzyna Borsuk, K.; Furman, B.; Ka1u
A.; Chmielewski, M. Curr. Med. Chem. 2004, 11, 1813; (c) Deshmukh, A. R. A. S.;
Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A.
Curr. Med. Chem. 2004, 11, 1889; (e) Alcaide, B.; Almendros, P. Curr. Med. Chem.
2004, 11, 1921.
z_ a, Z.; Kazimierski,
1
3aec and 14aec) was added. The reaction mixture was refluxed
for 4 h. After the further addition of sodium ethoxide (100 mg,
.41 mmol), the mixture was next refluxed for 2 h. After cooling
1
down to room temperature, ethyl acetate (40 mL) was added to the
reaction mixture and it was filtered through a thin pad of Celite and
washed with ethyl acetate (40 mL). After evaporation, the residue
was subjected to column chromatography, using n-hexane/ethyl
acetate 9:1, followed by n-hexane/ethyl acetate 4:1 as eluent. After
evaporation of the corresponding fractions, the residues crystal-
lized on trituration with n-hexane (3 mL).
2
. (a) Hocquemiller, A.; Cave, A.; Husson, H.-P. Tetrahedron 1977, 33, 645; (b)
Matsuyama, H.; Kurosawa, A.; Takei, T.; Ohira, N.; Yoshida, M.; Iyoda, M. Chem.
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M. R. Synlett 2001, 1531.
3. Bose, A. K.; Mathur, C.; Wagle, D. R.; Naqvi, R.; Manhas, M. S. Heterocycles 1994,
39, 491.
4
. Martinek, T. A.; F u€ l o€ p, F. Chem. Soc. Rev. 2012, 41, 687.
5. Kiss, L.; F u€ l o€ p, F. Synlett 2010, 1302.
. (a) Oiarbide, M.; Palomo, C. In Heterocyclic Scaffolds I, b-Lactams; Maes, B. U. W.,
6
Banik, B. K., Eds.; Topics in Heterocyclic Chemistry; Springer: Heidelberg, 2010;
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. Rao, S. N.; O’Ferrall, R. A. M. J. Org. Chem. 1990, 55, 3244; (b) Van Brabandt, W.;
5
.7.1. (4aR
*
,8aS )-3-Ethoxycarbonyl-2-phenyl-1,5,5a,6,7,8,9,9a-octa-
*
hydro-4,1-benzothiazepine (15a). A yellow crystalline powder, mp:
14e116 C, yield 82%, 0.39 g. Anal. Calcd for C18
8.10; H, 7.30; N, 4.41;S,10.10. Found:C, 68.32;H, 7.21;N, 4.16; S,10.31.
ꢀ
1
6
2
H23NO S (317.45): C,
7
De Kimpe, N. J. Org. Chem. 2005, 70, 3369.
8
9
. Dekeukeleire, S.; D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2009, 74, 1644.
. (a) Begley, M. J.; Crombie, L.; Haigh, D.; Jones, R. C. F.; Osborne, S.; Webster, R.
A. B. J. Chem. Soc., Chem. Commun. 1993, 2027; (b) Banfi, L.; Guanti, G.; Rasparini,
M. Tetrahedron Lett. 1998, 39, 9539.
5
9
.7.2. (4aR ,8aS )-3-Ethoxycarbonyl-2-(4-chlorophenyl)-1,5,5a,6,7,8,-
*
*
,9a-octahydro-4,1-benzothiazepine (15b). A yellow crystalline pow-
der, mp: 157e160 C, yield 61%, 0.32 g. Anal. Calcd for C18
ꢀ
2
H22ClNO S
10. (a) Mollet, K.; D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2011, 76, 264; (b)
D’hooghe, M.; Mollet, K.; Dekeukeleire, S.; De Kimpe, N. Org. Biomol. Chem.
(
4
351.89): C, 61.44; H, 6.30; N, 3.98; S, 9.11. Found: C, 61.80; H, 6.16; N,
.18; S, 9.42.
2010, 8, 607.
1
1. (a) Fodor, L.; Csom oꢀ s, P.; Cs aꢀ mpai, A.; Soh aꢀ r, P. Synthesis 2010, 2943; (b) Csom oꢀ s,
P.; Fodor, L.; Cs ꢀa mpai, A.; Soh ꢀa r, P. Tetrahedron 2010, 66, 3207; (c) Fodor, L.;
Csom oꢀ s, P.; Cs aꢀ mpai, A.; Soh aꢀ r, P. Tetrahedron 2012, 68, 851.
5
9
.7.3. (4aR ,8aS )-3-Ethoxycarbonyl-2-(4-methylphenyl)-1,5,5a,6,7,8,-
*
*
1
2. Simon, L.; Talpas, G. S.; F u€ l o€ p, F.; Bern ꢀa th, G.; Soh ꢀa r, P. Acta Chim. Hung. 1985,
18, 37.
3. (a) Leflemme, N.; Dallemagne, P.; Rault, S. Tetrahedron Lett. 2004, 45, 1503; (b)
Mercey, G.; Br eꢀ geon, D.; Gaumont, A.-C.; Levillain, J.; Gulea, M. Tetrahedron Lett.
008, 49, 6553.
4. (a) Cossío, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925; (b) Brandi, A.;
,9a-octahydro-4,1-benzothiazepine (15c). A yellow crystalline pow-
der, mp: 135e137 C, yield 55%, 0.27 g. Anal. Calcd for C19
331.47): C, 68.85; H, 7.60; N, 4.23; S, 9.67. Found: C, 69.16; H, 7.47; N,
.10; S, 9.89.
1
ꢀ
2
H25NO S
1
(
4
2
1
Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988; (c) Xu, J. Arkivoc 2009, ix, 21.
15. Staudinger cycloaddition reactions of regioisomeric cis- and trans-2-aryl-
5
.7.4. (4aR ,8aR )-3-Ethoxycarbonyl-2-phenyl-1,5,5a,6,7,8,9,9a-oc-
*
*
4
(
a,5,6,7,8,8a-hexahydro-4H-1,3-benzothazines provided only one diastereomer
Soh ꢀa r, P.; Szab oꢀ , J.; Simon, L.; Talpas, G. S.; Sz u} cs, E.; Bern aꢀ th, G. Org. Magn.
tahydro-4,1-benzothiazepine (16a). A yellow crystalline powder,
mp: 173e174 C, yield 42%, 0.20 g. Anal. Calcd for C18
317.45): C, 68.10; H, 7.30; N, 4.41; S, 10.10. Found: C, 68.42; H, 7.54;
N, 4.23; S, 10.38.
ꢀ
H23NO
2
S
Reson. 1991, 29, 687 ).
(
16. (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999,
3223; (b) Todorova, A. R.; Kurteva, V. B.; Bontchev, R. P.; Vassilev, N. G. Tetra-
hedron 2009, 65, 10339.
1
7. Soh aꢀ r, P. In Nuclear Magnetic Resonance Spectroscopy; CRC: Boca Raton, FL, 1983;
5
9
.7.5. (4aR
*
,8aR
*
)-3-Ethoxycarbonyl-2-(4-chlorophenyl)-1,5,5a,6,7,8,-
(a) Vol. 2, p 154; (b) Vol. 2, p 25; (c) Vol. 3, pp 4e6; (d) Vol. 1, pp 35e40; (e) Vol.
1, pp 32, 33 and Vol. 2, p 2.
,9a-octahydro-4,1-benzothiazepine (16b). A yellow crystalline pow-
der, mp: 222e225 C, yield 23%, 0.12 g. Anal. Calcd for C18
351.89): C, 61.44; H, 6.30; N, 3.98; S, 9.11. Found: C, 61.65; H, 6.56; N,
ꢀ
18. The numbering in this Part is that prescribed by the IUPAC rule for perhy-
drobenzothiazines (see Scheme 1).
2
H22ClNO S
(
19. (a) Sohar, P.; Gera, L.; Bernath, G. Org. Magn. Reson. 1980, 14, 204; (b) Sohar, P.;
ꢀ ꢀ ꢀ
3
.77; S, 8.91.
F u€ l o€ p, F.; Bern ꢀa th, G. Org. Magn. Reson.1984, 22, 527; (c) Soh aꢀ r, P.; St ꢀa jer, G.; Szab oꢀ ,
A. E.; F u€ l o€ p, F.; Szunyog, J.; Bern aꢀ th, G. J. Chem. Soc., Perkin Trans. 2 1987, 599.
0. F u€ l o€ p, F.; Bern ꢀa th, G.; Argay, G.; K ꢀa lm ꢀa n, A.; Soh aꢀ r, P. Tetrahedron 1984, 40,
2
5.7.6. (4aR
*
,8aR
*
)-3-Ethoxycarbonyl-2-(4-methylphenyl)-1,5,5a,6,7,-
2053.
8,9,9a-octahydro-4,1-benzothiazepine (16c). A yellow crystalline
21. Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem. 2005, 452.