Synthesis of 1,3-thiazines by a three-component reaction and their transformations into β-lactam-condensed 1,3-thiazine and 1,4-thiazepine derivatives

Article abstract of DOI:10.1080/10426507.2015.1072191

Variously substituted 1,3-thiazines have been prepared by a three-component reaction involving a thioamide, an aldehyde, and an alkene. Two diastereomeric thiazines were transformed by stereoselective Staudinger reaction into the corresponding chloro-β-la

Full text of DOI:10.1080/10426507.2015.1072191

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of 1,3-thiazines by a three-component
reaction and their transformations into β-lactam-
condensed 1,3-thiazine and 1,4-thiazepine
derivatives
Flavie Peudru, Jean-François Lohier, Mihaela Gulea & Vincent Reboul
To cite this article: Flavie Peudru, Jean-François Lohier, Mihaela Gulea & Vincent Reboul (2016)
Synthesis of 1,3-thiazines by a three-component reaction and their transformations into β-
lactam-condensed 1,3-thiazine and 1,4-thiazepine derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 191:2, 220-229, DOI: 10.1080/10426507.2015.1072191
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1072191
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Date: 07 February 2016, At: 08:39

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –
http://dx.doi.org/./..
Synthesis of ,-thiazines by a three-component reaction and their transformations
into β-lactam-condensed ,-thiazine and ,-thiazepine derivatives
Flavie Peudrua, Jean-François Lohiera, Mihaela Guleaa,b, and Vincent Reboula
aLaboratoire de Chimie Moléculaire et Thioorganique, Normandie Université, UMR CNRS , INCM, FR , ENSICAEN & Université de Caen
Basse-Normandie, CAEN, France; bLaboratoire d’Innovation Thérapeutique, UMR  CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch
Cedex, France
ABSTRACT
ARTICLE HISTORY
Received  April 
Accepted  June 
Variously substituted 1,3-thiazines have been prepared by a three-component reaction involving a
thioamide, an aldehyde, and an alkene. Two diastereomeric thiazines were transformed by stereoselective
Staudinger reaction into the corresponding chloro-β-lactam-condensed-1,3-thiazines, and one of them was
rearranged in basic media to afford a highly substituted 1,4-thiazepine. Several of the obtained compounds
(six 1,3-thiazines and one β-lactam-condensed-1,3-thiazine) were analyzed by X-ray crystallography, which
enabled to assign their spatial arrangement and stereochemistry.
KEYWORDS
Three-component reaction;
,-thiazine; Staudinger
reaction;
β-lactam-condensed
,-thiazine; ,-thiazepine
GRAPHICAL ABSTRACT
N,S-heterocycles are present in numerous bioactive natural the approach of the alkene (endo or exo), two diastereoisomers
products and pharmaceutically important molecules. Among can be obtained.
them, 1,3-thiazines have found various applications mainly due
First, we optimized the reaction conditions using thiobenza-
to their biological activities (e.g., enzymes inhibitors, antibac- mide, benzaldehyde, and 1-hexene as starting materials (Scheme
terial, antifungal agents …).1 Moreover, they are convenient 2, Table 1).
precursors for other important N,S-heterocyclic biomolecules,
We found that the use of BF3.OEt2 as Lewis acid (in the
such as β-lactam-condensed 1,3-thiazines (found in the fam- presence of a water-adsorbent agent MgSO4) was better than
ily of cephalosporins) or 1,4-thiazepines. This type of applica- trifluoroacetic acid (TFA) or p-toluenesulfonic acid (PTSA)
tion has been developed in particular in aromatic series (ben- as Brønsted acid (Entries 1–4). In these conditions, the con-
zothiazine and benzothiazepine) by Sohár and co-workers.2 version into 1,3-thiazine 1a was almost total, and the 1:1
Nonetheless, the aliphatic series is still underdeveloped in spite mixture of endo/exo adducts was separable by column chro-
of the potential biological activities. In a continuing study matography on silica gel. However, the reaction time was
on discovery of new N,S-heterocycles,3 we report here the too long (5 days). Finally, the use of microwave activation5
preparation of variously substituted 1,3-thiazines and their (entries 5–7) was very efficient, reducing the reaction time to
transformation into β-lactam-condensed 1,3-thiazines and 1,4- 10 min.
thiazepines.
With these optimized conditions (40 W, 150°C, in 1,2-
Recently, we described an easy and general synthesis of 1,3- dichloroethene, DCE), we examined the scope and limitations
thiazines, via a three-component reaction (3CR) involving a of this reaction. First, the aromatic aldehyde partner was varied
thioamide, an aldehyde, and an alkene.4 The reaction takes place (Figure 1, 1b–1f). Whatever the aldehyde was used, total conver-
via a hetero-Diels-Alder (HDA) reaction between a non-isolable sions were obtained in all the cases, yields were good to excellent
N-thioacyl imine heterodiene, which was obtained by in situ and the two diastereoisomers endo/exo (ratios varying from 1:1
condensation of the thioamide and the aldehyde, and an alkene, to 1:0.5) were separated by column chromatography on silica gel.
affording the 1,3-thiazine cycloadduct (Scheme 1). According to No reaction occurred with aliphatic aldehydes (isobutyralde-
CONTACT Vincent Reboul
, ENSICAEN & Université de Caen Normandie,  Bd. Maréchal Juin , CAEN, France; Mihaela Gulea
vincent.reboul@ensicaen.fr
Normandie Université, Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS , INCM, FR
gulea@unistra.fr Laboratoire d’Innovation Thérapeutique,
UMR  CNRS, Université de Strasbourg, Faculté de Pharmacie,  route du Rhin B.P. ,  Illkirch Cedex, France.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher’s website at http://dx.doi.org/./..
©  Taylor & Francis Group, LLC

PHOSPHORUS, SULFUR, AND SILICON
221
Scheme 
Scheme 
Figure . Synthesis of ,-thiazines a-k.
hyde or trimethylacetaldehyde), ferrocenecarboxaldehyde, and (1j) was obtained as a 1:1.6 endo/exo mixture, whereas the nor-
ethylglyoxalate. bornene adduct (1k) was formed with a total exo-selectivity, as
Then, the nature of the alkene was examined (Figure 1, a single isomer, in 78% yield. The relative stereochemistry was
1g–k). Thiazines derived from aliphatic acyclic alkenes were iso- unambiguously assigned by X-ray crystallography for1j-exo and
lated with good yields. Interestingly, the formation of the styrene 1k-exo. By using ethyl acrylate and ethyl vinyl ether as the alkene
adduct (1h) was highly endo-selective (endo/exo 1:0.2) probably partners, the desired adducts could not be obtained.
due to favorable secondary orbital interactions. However, when
Finally, the thioamide partner was also varied (Figure 2).
the reaction was performed with trans-anethole, an insepara- Thioacetamide or thioformamide6 were used instead of the
ble mixture of 3 diastereoisomers (1i) was obtained: the endo thiobenzamide. Seven expected thiazines (1l–1r) were obtained
and exo adducts (respectively, 56% and 34%), and the epimer at in good yields and for each type of alkene, the ratio
C5 (1i-epi) as minor compound (10%). The cyclohexene adduct endo/exo was similar to those obtained previously. The use of

222
F. PEUDRU ET AL.
Figure . Synthesis of ,-thiazines l-r.
thioformamide led in moderate yield (38%) to the correspond- chloroacetyl chloride in the presence of triethylamine in reflux-
ing 2-H-1,3-thiazine 1r, which represents a possible carbene ing toluene, the corresponding chloro-β-lactam-condensed 1,3-
precursor.7 Four of the obtained compounds (1n-endo, 1o-exo, thiazine 2a was obtained in good yield (71%) as a single
1q-exo, and 1r-exo) were analyzed by X-ray crystallography, diastereoisomer. Similarly, 2b was obtained under similar con-
which enabled to assign their spatial arrangement and stereo- ditions from 1a-exo, in 64% yield (Scheme 3).
chemistry.
The cis spatial arrangement between Ph and Cl groups is
We next turned our attention to synthetic transformations of coherent with the 1,3-benzothiazine series and was confirmed
1,3-thiazines. Here, we first report the synthesis of β-lactam- by the X-ray analysis of 2a (Figure 3). It is interesting to note the
condensed 1,3-thiazine then subsequent rearrangement into a planar geometry of the nitrogen atom and the boat-like confor-
polysubstituted 1,4-thiazepine. We first investigated the [2+2] mation of the thiazine ring with the butyl and phenyl groups in
ketene-imine cycloaddition reaction (Staudinger reaction) with pseudo-equatorial positions and almost in the same plane.
1,3-thiazines 1a (endo and exo), according to a similar proce-
We next attempted the transformation of β-lactam derivative
dure in 1,3-benzothiazine series.2c When 1a-endo was treated by 2a into the corresponding 1,4-thiazepine, using t-BuOK as the
base, in methanol (Scheme 4).2d-f After 4 h at rt, compound 3a
was isolated in 52% yield. The first step of this process is prob-
Table . Conditions optimization.
ably the methanolysis of the β-lactam ring, furnishing the α-
Conversion
chloro-ester. After cyclization into an episulfonium salt, then
Entry
Conditions Solvent
TFA ( equiv) CHCl
Temp. (°C)
Time
(%)a
elimination of HCl, the seven-membered ring is obtained.2g
The desmotrope form of 3a, the corresponding imine, was not
observed compared to the benzothiazepine series.2h,i




 d
 d


PTSA (
equiv),
MgSO
BF.OEt (
equiv),
MgSO
BF.OEt (
equiv),
MgSO
BF.OEt (
equiv), MW
( W)
BF.OEt (
equiv), MW
( W)
CHCl
CHCl
CHCl
CHCl
neat







 d
>
>
>
>
>
 d



 min
 min
 min
BF.OEt (
equiv), MW
( W)
DCE
a
In all cases, theratio endo/exowas/ (measuredby HNMRinthecrudemixture).
Scheme 

PHOSPHORUS, SULFUR, AND SILICON
223
Figure . X-ray structure of 2a (two views).
In summary, 18 variously substituted 1,3-thiazines have been aluminum plates of silica gel 60 F-254 (Merck). Flash chro-
synthesized by an efficient three-component reaction. Starting matography was performed on silica gel column (Merck sil-
from 2,4-diphenyl-6-butyl-1,3-thiazine, the Staudinger reac- ica gel, 40–63 µm) using air pressure. Microwave irradiation
tion provided stereoselectively the corresponding β-lactam, was carried out with microwave oven Discover® LabMate Sys-
which was then transformed into a highly functionalized 1,4- tem from CEM, using 10 mL pressurized vials. Elemental anal-
thiazine. Biological tests are currently in progress to evaluate the ysis was obtained from Thermoquest NA 2500 CHNS-O instru-
inhibitory effect of the prepared compounds against metallo-β- ment. Melting points were determined using an Electrothermal
lactamases.
IA9000 capillary apparatus. X-ray diffraction experiments were
performed with graphite-monochromatized MoKα radiation on
a Bruker Nonius APEX-II Kappa CCD area detector diffrac-
tometer. Additional X-ray structural details are provided in the
Supplemental Materials.
Experimental
Spectroscopy: H and 13C NMR spectra were recorded with a
1
Bruker DRX 400 MHz or a Bruker DRX 500 MHz spectrom-
eter. Samples were dissolved in an appropriate deuterated sol-
vent (CDCl3, acetone-d6, D2O, DMSO-d6). The chemical shifts
(δ) are expressed in ppm relative to internal tetramethylsilane
for 1H and 13C nucleus, and coupling constants are indicated in
Hz. Abbreviations for signal coupling are as follows: s = singlet;
d = doublet; dd = doublet of doublets; t = triplet; q = quar-
tet; quin = quintet; m = multiplet; br = broad signal. To assign
the signals to the different proton and carbon atoms, as well
as the relative stereochemistry of the cycloadducts, additional
2D NMR experiments (COSY, HSQC, HMBC) and NOESY
experiments were performed. Mass spectra were obtained on a
GC/MS Saturn 2000 spectrometer. High-resolution mass spec-
tra (HRMS) were performed on Q-TOF Micro WATERS by elec-
trospray ionization (ESI). Infrared (IR) spectra were recorded
with a Perkin Elmer 16 PC FT-IR spectrometer. Chromatogra-
phy: Thin Layer Chromatography (TLC) was run on pre-coated
General procedure for the synthesis of 1,3-thiazines 1a–r
To a stirred solution of thioamide (1.2 equiv, 1.2 mmol), alde-
hyde (1 equiv, 1 mmol), and alkene (1.2 equiv, 1.2 mmol) in
dichloroethane (0.5 mL) at room temperature is added dropwise
BF3.OEt2 (2 equiv, 2 mmol, 0.25 mL). The solution was placed in
a 10 mL sealed vial equipped with a stirring bar and irradiated
in the microwave oven for 10 min under 40 W (max. 150°C).
The reaction mixture was cooled to room temperature, then
treated with a saturated aqueous solution of NaHCO3 (10 mL)
and extracted with dichloromethane (3 × 15 mL). The com-
bined organic phases were dried with Na2SO4, filtered, and con-
centrated in vacuum. The crude product was purified by flash
chromatography on silica gel (cyclohexane/AcOEt).
6-Butyl-5,6-dihydro-2,4-diphenyl-4H-1,3-thiazine (1a)
was obtained from thiobenzamide, benzaldehyde, and hexene
according to the general procedure, in 96% yield, as a separable
mixture of two diastereoisomers endo and exo (ratio 1:1).
1a-endo: 1H NMR (400 MHz, CDCl3): δ 7.98–7.96 (m, 2H,
Ar), 7.47–7.39 (m, 7H, Ar), 7.28–7.23 (m, 1H, Ar), 4.69 (dd, J =
11.3, 3.1 Hz, 1H, H-4), 3.67 (dddd, J = 15.8, 7.7, 6.0, 3.8 Hz, 1H,
H-6), 2.36 (dt, J = 13.6, 3.4 Hz, 1H, H-5), 1.73–1.63 (m, 2H, H-
7), 1.47–1.44 (m, 1H, H-5), 1.43–1.36 (m, 4H, H-8 and H-9),
0.96 (t, J = 7.2 Hz, 3H, H-10). 13C NMR (100.6 MHz, CDCl3):
Scheme 

224
F. PEUDRU ET AL.
δ 159.5 (C-2), 145.1, 139.1, 130.3, 128.4, 128.1, 126.7, 126.5,
62.9 (C-4), 41.9 (C-6), 36.7 (C-5), 36.6 (C-7), 28.2 (C-8), 22.5
(C-9), 13.9 (C-10). HRMS (ESI, m/z) calcd. for [C20H24NS]+:
310.1629; found: 310.1631. IR (neat): 1602 (C = N), 1446, 909,
761, 731, 689 (C-S) cm−1
.
1
1a-exo: H NMR (400 MHz, CDCl3): δ 7.92–7.90 (m, 2H,
Ar), 7.40–7.31 (m, 5H, Ar), 7.26–7.23 (m, 3H, Ar), 5.16 (dd,
J = 11.4, 3.2 Hz, 1H, H-4), 3.10 (dddd, J = 12.0, 7.8, 6.0, 3.7
Hz, 1H, H-6), 1.98–1.92 (m, 2H, H-5), 1.69–1.62 (m, 2H, H-7),
1.47–1.23 (m, 4H, H-8 and H-9), 0.87 (t, J = 7.1 Hz, 3H, H-
1c-endo: 1H NMR (400 MHz, CDCl3): δ 7.91–7.89 (m, 2H,
10). 13C NMR (100.6 MHz, CDCl3): δ 159.7 (C-2), 143.1, 139.3, Ar), 7.70–7.67 (m, 2H, Ar), 7.56–7.54 (m, 2H, Ar), 7.47–7.38
130.3, 128.3, 128.2, 126.8, 126.7, 126.4, 59.2 (C-4), 37.3 (C-6), (m, 3H, Ar), 4.71 (dd, J = 11.4, 3.0 Hz, 1H, H-4), 3.66 (dddd,
36.6 (C-7), 33.8 (C-5), 28.3 (C-8), 22.4 (C-9), 13.8 (C-10). HRMS J = 16.1, 7.7, 5.9, 3.8 Hz, 1H, H-6), 2.31 (dt, J = 13.6, 3.5 Hz,
(ESI, m/z) calcd. for [C20H24NS]+: 310.1629; found: 310.1621. 1H, H-5), 1.78–1.58 (m, 2H, H-7), 1.50–1.32 (m, 5H, H-5, H-8
IR (neat): 2927, 1602 (C = N), 1446, 928, 763, 721, 689 (C-S) and H-9), 0.93 (t, J = 7.2 Hz, 3H, H-10). 13C NMR (100.6 MHz,
cm−1
.
CDCl3): δ 160.5 (C-2), 150.4, 138.8, 132.4, 130.7, 128.3, 127.7,
126.5, 119.0, 110.6, 62.6 (C-4), 41.8 (C-6), 36.6 (C-7), 36.3 (C-
6-Butyl-5,6-dihydro-2-phenyl-4-p-tolyl-4H-1,3-thiazine
(1b) was obtained from thiobenzamide, 4-methyl benzalde- 5), 28.2 (C-8), 22.5 (C-9), 13.9 (C-10). HRMS (ESI m/z) calcd.
hyde, and hexene according to the general procedure, in 98% for [C21H23N2S]+ 335.1582; found: 335.1577. IR (neat): 2927,
yield, as a separable mixture of two diastereoisomers endo and 2227 (CN), 1604 (C = N), 766, 690 (C-S) cm−1
.
1
exo (ratio 1:0.9).
1c-exo: H NMR (400 MHz, CDCl3): δ 7.97–7.89 (m, 2H,
Ar), 7.77–7.75 (m, 1H, Ar), 7.67–7.64 (m, 1H, Ar), 7.55–7.53 (m,
2H, Ar), 7.48–7.36 (m, 3H, Ar), 5.11 (dd, J = 6.3, 4.2 Hz, 1H, H-
4), 3.14–3.08 (m, 1H, H-6), 2.04–1.91 (m, 2H, H-5), 1.77–1.59
(m, 2H, H-7), 1.49–1.30 (m, 4H, H-8 and H-9), 0.92 (t, J = 7.2
Hz, 3H, H-10). 13C NMR (100.6 MHz, CDCl3): δ 161.0 (C-2),
148.9, 138.7, 132.2, 130.5, 128.2, 127.6, 126.7, 118.8, 110.5, 58.5
(C-4), 37.6 (C-6), 36.5 (C-7), 33.6 (C-5), 28.3 (C-8), 22.3 (C-9),
13.8 (C-10). HRMS (ESI m/z) calcd. for [C21H23N2S]+ 335.1582;
found: 335.1569. IR (neat): 2926, 2227 (CN), 1605 (C = N), 907,
1b-endo: 1H NMR (400 MHz, CDCl3): δ 7.96–7.94 (m, 2H,
Ar), 7.44–7.38 (m, 3H, Ar), 7.35–7.33 (m, 2H, Ar), 7.23–7.21
(m, 2H, Ar), 4.65 (dd, J = 11.3, 3.1 Hz, 1H, H-4), 3.65 (dddd,
J = 15.7, 7.6, 6.0, 3.8 Hz, 1H, H-6), 2.39 (s, 3H, Me), 2.33
(dt, J = 13.6, 3.5 Hz, 1H, H-5), 1.78–1.59 (m, 2H, H-7), 1.52–
1.33 (m, 5H, H-5, H-8, and H-9), 0.95 (t, J = 7.2 Hz, 3H,
H-10). 13C NMR (100.6 MHz, CDCl3): δ 159.1 (C-2), 142.2,
139.2, 136.2, 130.2, 129.1, 128.1, 126.6, 126.5, 62.6 (C-4), 41.9
(C-6), 36.7 (C-7), 36.6 (C-5), 28.2 (C-8), 22.5 (C-9), 21.0
(Me), 13.9 (C-10). HRMS (ESI, m/z) calcd. for [C21H26NS]+:
324.1786; found: 324.1774. IR (neat): 2927, 1601 (C = N), 1575,
730, 690 (C-S) cm−1
.
6-Butyl-5,6-dihydro-4-(2-hydroxyphenyl)-2-phenyl-4H-
1,3-thiazine (1d) was obtained from thiobenzamide, salicy-
laldehyde, and hexene according to the general procedure, in
72% yield, as a separable mixture of two diastereoisomers endo
and exo (ratio 1:0.5).
1445, 1274, 1225, 926, 814, 763, 712, 689 (C-S), 610 cm−1
.
1
1b-exo: H NMR (400 MHz, CDCl3): δ 7.96–7.93 (m, 2H,
Ar), 7.46–7.38 (m, 3H, Ar), 7.18 (s, 4H, Ar), 5.19 (dd, J = 5.5,
4.0 Hz, 1H, H-4), 3.17–3.10 (m, 1H, H-6), 2.36 (s, 3H, Me), 2.05–
2.00 (m, 1H, H-5), 1.93 (m, 1H, H-5), 1.75–1.66 (m, 2H, H-7),
1.50–1.28 (m, 4H, H-8 and H-9), 0.92 (t, J = 7.0 Hz, 3H, H-
10). 13C NMR (100.6 MHz, CDCl3): δ 159.6 (C-2), 140.1, 139.4,
136.3, 130.3, 129.0, 128.2, 126.7, 126.5, 59.1 (C-4), 37.3 (C-6),
36.6 (C-7), 33.9 (C-5), 28.3 (C-8), 22.5 (C-9), 21.0 (Me), 13.9 (C-
10). HRMS (ESI, m/z) calcd. for [C21H26NS]+: 324.1786; found:
324.1800. IR (neat): 2925, 1605 (C = N), 1445, 927, 810, 763,
1d-endo: 1H NMR (400 MHz, CDCl3): δ 7.85–7.82 (m, 2H,
Ar), 7.49–7.38 (m, 3H, Ar), 7.20–7.12 (m, 2H, Ar), 6.90–6.85
(m, 2H, Ar), 4.84 (dd, J = 11.3, 2.6 Hz, 1H, H-4), 3.75–3.68 (m,
1H, H-6), 2.54 (ddd, J = 13.5, 4.5, 2.9 Hz, 1H, H-5), 1.85–1.76
(m, 1H, H-7), 1.70–1.64 (m, 2H, H-5 and H-7), 1.57–1.49 (m,
4H, H-8 and H-9), 0.95 (t, J = 7.2 Hz, 3H, H-10). 13C NMR
(100.6 MHz, CDCl3): δ 164.5 (C-2), 157.3, 137.9, 131.2, 128.5,
128.4, 127.2, 126.6, 125.8, 119.3, 117.7, 63.2 (C-4), 42.6 (C-6),
36.8 (C-7), 34.8 (C-5), 28.5 (C-8), 22.5 (C-9), 13.9 (C-10). HRMS
(ESI m/z) calcd. for [C20H24NOS]+ 326.1579; found: 326.1590.
731, 690 (C-S) cm−1
.
6-Butyl-5,6-dihydro-4-benzonitrile-2-phenyl-4H-
1,3-thiazine (1c) was obtained from thiobenzamide, 4-
cyanobenzaldehyde, and hexene according to the general
procedure, in 44% yield, as a separable mixture of two
diastereoisomers endo and exo (ratio 1:0.5).
IR (neat): 2926, 1588 (C = N), 1455, 1224, 751, 688 (C-S) cm−1
.
1
1d-exo: H NMR (400 MHz, CDCl3): δ 7.86–7.84 (m, 2H,
Ar), 7.49–7.39 (m, 3H, Ar), 7.21–7.17 (m, 1H, Ar), 7.08–7.06

PHOSPHORUS, SULFUR, AND SILICON
225
(m, 1H, Ar), 6.92–6.86 (m, 2H, Ar), 4.90 (dd, J = 8.9, 3.7 Hz, 3.69 (dddd, J = 16.2, 7.5, 6.0, 4.1 Hz, H-6endo), 3.54–3.48 (m,
1H, H-4), 3.49–3.42 (m, 1H, H-6), 2.24–2.16 (m, 2H, H-5), 1.98– 2H, CH2), 3.45–3.38 (m, 1H, CH2), 3.26–2.90 (m, 13H, CH2),
1.80 (m, 2H, H-7), 1.70–1.48 (m, 4H, H-8 and H-9), 0.97 (t, J = 2.85–2.78 (m, H-6exo), 2.14–2.09 (m, H-5endo), 1.86–1.82 (m, H-
7.2 Hz, 3H, H-10). 13C NMR (100.6 MHz, CDCl3): δ 164.1 (C-2), 5exo), 1.70–1.53 (m, 4H, H-7), 1.45–1.27 (m, H-5endo, and H-
157.4, 138.0, 131.2, 128.5, 128.4, 126.7, 126.5, 125.8, 119.3, 117.6, 8 and H-9), 0.94 (t, J = 7.2 Hz, 3H, H-10), 0.89 (t, J = 6.9
58.6 (C-4), 39.7 (C-6), 37.1 (C-7), 32.9 (C-5), 28.8 (C-8), 22.4 Hz, 3H, H-10). 13C NMR (100.6 MHz, CDCl3): δ 158.2 (C-2),
(C-9), 13.9 (C-10). HRMS (ESI m/z) calcd. for [C20H24NOS]+ 143.8, 140.2, 139.8, 139.5, 139.4, 139.3, 138.9, 138.8, 135.4, 135.3,
326.1579; found: 326.1577. IR (neat): 2926, 1586 (C = N), 1452, 135.2, 134.9, 133.3, 133.2, 133.0, 132.9, 132.4, 132.3, 131.8, 131.7,
1242, 749, 688 (C-S) cm−1
6-Butyl-5,6-dihydro-4-(2,4-dichlorophenyl)-2-phenyl-
.
131.25, 131.21, 130.2, 128.3, 128.2, 126.5, 126.3, 65.8 (CH2),
60.0 (C-4endo), 57.3 (C-4exo) 42.3 (C-6endo), 37.2 (C-6exo), 36.8
4H-1,3-thiazine (1e) was obtained from thiobenzamide, (C-5endo), 36.7 (C-7), 36.5 (C-7), 35.4 (CH2), 35.3 (CH2), 35.2
2,4-dichlorobenzaldehyde, and hexene according to the gen- (CH2), 35.1 (CH2), 34.5 (CH2), 34.4 (CH2), 34.0 (C-5exo), 33.6
eral procedure, in 69% yield as a unseparable mixture of two (CH2), 33.3 (CH2), 28.3 (C-8), 28.1 (C-8), 22.5 (C-9), 13.9 (C-9),
diastereoisomers endo and exo (ratio 1:0.9).
13.8 (C-10). HRMS (ESI m/z) calcd. for [C30H34NS]+ 440.2410;
found: 440.2412. IR (neat): 2925, 1592 (C = N), 1445, 908, 731,
689 (C-S) cm−1
.
6-(2-Bromoethyl)-5,6-dihydro-2,4-diphenyl-4H-1,3-
thiazine (1g) was obtained from thiobenzamide, benzaldehyde,
and 4-bromo-1-butene according to the general procedure, in
94% yield, as a separable mixture of two diastereoisomers endo
and exo (ratio 1:1.6).
1
1e-endo/1e-exo: H NMR (400 MHz, CDCl3): δ 7.93–7.91
(m, 2H, Ar), 7.50–7.39 (m, 5H, Ar), 7.31–7.26 (m, 1H, Ar), 5.27
(dd, J = 7.7, 3.6 Hz, H-4exo), 4.97 (dd, J = 11.0, 2.8 Hz, H-4endo),
3.72–3.65 (m, H-6endo), 3.23–3.17 (m, H-6exo), 2.43–2.38 (m, H-
5endo), 2.11–2.05 (m, H-5exo), 1.86–1.79 (m, 2H, H-7), 1.64–1.56
(m, H-5exo), 1.51–1.33 (m, 4H, H-8 and H-9), 1.22–1.13 (m, H-
5endo), 0.93 (t, J = 7.2 Hz, 3H, H-10). 13C NMR (100.6 MHz,
CDCl3): δ 160.7 (C-2), 141.0, 139.7, 139.1, 138.9, 133.1, 132.9,
132.7, 132.6, 130.6, 130.5, 130.1, 129.8, 129.2, 128.9, 128.3, 128.2,
127.5, 127.2, 126.5, 126.4, 59.5 (C-4endo), 55.4 (C-4exo) 42.1 (C-
6endo), 38.7 (C-6exo), 36.7 (C-7), 36.6 (C-7), 34.4 (C-5endo), 31.6
(C-5exo), 28.7 (C-8), 28.2 (C-8), 22.5 (C-9), 22.4 (C-9), 13.9 (C-
10), 13.8 (C-10). HRMS (ESI m/z) calcd. for [C20H22Cl2NS]+
378.0850; found: 378.0851. IR (neat) 2927, 1600 (C = N), 1467,
1g-endo: 1H NMR (400 MHz, CDCl3): δ 7.93–7.91 (m, 2H,
Ar), 7.47–7.38 (m, 8H, Ar), 4.70 (dd, J = 11.2, 3.1 Hz, 1H, H-4),
3.94 (dddd, J = 15.9, 8.2, 5.4, 4.1 Hz, 1H, H-6), 3.57–3.53 (m,
2H, H-8), 2.35 (dt, J = 13.5, 3.8 Hz, 1H, H-5), 2.27 (m, 1H, H-
7), 2.17–2.12 (m, 1H, H-7), 1.45–1.39 (m, 1H, H-5). 13C NMR
(100.6 MHz, CDCl3): δ 158.5 (C-2), 144.6, 138.8, 130.6, 128.5,
128.2, 126.9, 126.7, 126.6, 62.6 (C-4), 40.0 (C-6), 39.6 (C-7), 35.8
(C-5), 29.1 (C-8). HRMS (ESI, m/z) calcd. for [C18H19BrNS]+:
360.0422; found: 360.0405. IR (neat): 2921, 1714, 1661, 1597 (C
= N), 1578, 1447, 1273, 1207, 759, 712, 687 (C-S) cm−1
.
1
762, 688 (C-S) cm-−1
.
1g-exo: H NMR (400 MHz, CDCl3): δ 7.95–7.92 (m, 2H,
Ar), 7.49–7.37 (m, 5H, Ar), 7.32–7.27 (m, 3H, Ar), 5.10 (dd, J =
6.4, 4.6 Hz, 1H, H-4), 3.58–3.53 (m, 2H, H-8), 3.51–3.46 (m, 1H,
H-6), 2.37–2.20 (m, 2H, H-7), 2.05–2.01 (m, 2H, H-5). 13C NMR
(100.6 MHz, CDCl3): δ 158.5 (C-2), 143.0, 139.0, 130.6, 128.5,
128.3, 126.9, 126.7, 126.5, 58.5 (C-4), 39.4 (C-7), 36.2 (C-6), 33.1
(C-5), 29.4 (C-8). HRMS (ESI, m/z) calcd. for [C18H19BrNS]+:
360.0422; found: 360.0436. IR (neat): 2922, 1601 (C = N), 1577,
6-Butyl-5,6-dihydro-2-phenyl-4-(paracyclophanyl)-
4H-1,3-thiazine (1f) was obtained from thiobenzamide,
2-paracyclophane-aldehyde, and hexene according to the gen-
eral procedure, in 98% yield as a unseparable mixture of two
diastereoisomers endo and exo (ratio 1:1.4).
1445, 1340, 1255, 1028, 935, 912, 762, 689 (C-S) cm−1
.
5,6-Dihydro-2,4,6-triphenyl-4H-1,3-thiazine (1h) was
obtained from thiobenzamide, benzaldehyde, and styrene
according to the general procedure, in 94% yield, as a separable
mixture of two diastereoisomers endo and exo (ratio 1:0.2).
1
1f-endo/1f-exo: H NMR (400 MHz, CDCl3): δ 8.15–8.12
(m, 4H, Ar), 7.53–7.51 (m, 6H, Ar), 6.82–6.80 (m, 2H, Ar), 6.66–
6.64 (m, 1H, Ar), 6.56–6.48 (m, 10H, Ar), 6.28 (s, 1H, Ar), 5.28
(t, J = 4.2 Hz, H-4exo), 4.67 (dd, J = 11.0, 2.8 Hz, H-4endo),
1h-endo: 1H NMR (400 MHz, CDCl3): δ 7.97–7.94 (m, 2H,
Ar), 7.48–7.29 (m, 13H, Ar), 4.90 (dd, J = 11.4, 3.2 Hz, 1H,

226
F. PEUDRU ET AL.
1j-endo: 1H NMR (400 MHz, CDCl3): δ 7.99–7.96 (m, 2H,
Ar), 7.50–7.48 (m, 2H, Ar), 7.45–7.37 (m, 6H, Ar), 4.71 (d, J =
3.2 Hz, 1H, H-4), 4.16–4.13 (m, 1H, H-6), 2.11–2.05 (m, 1H, H-
5), 1.94–1.81 (m, 2H, H-7), 1.77–1.57 (m, 4H, H-9 and H-10),
1.13–1.03 (m, 2H, H-8). 13C NMR (100.6 MHz, CDCl3): δ 159.5
(C-2), 143.4, 139.3, 130.3, 128.3, 128.1, 127.5, 126.5, 126.4, 66.1
(C-4), 42.9 (C-6), 37.6 (C-5), 31.1 (C-7), 25.4 (C-10), 19.6 (C-9),
19.0 (C-8). HRMS (ESI, m/z) calcd. for [C20H22NS]+: 308.1473;
found: 308.1472. IR (neat): 2923, 1603 (C = N), 1576, 1446,
1225, 1207, 1073, 1027, 986, 936, 911, 760, 724, 689 (C-S), 648
H-4), 4.79 (dd, J = 12.3, 3.5 Hz, 1H, H-6), 2.56–2.51 (dt, J =
13.8, 3.5 Hz, 1H, H-5), 1.97–1.87 (ddd, J = 13.7, 12.2, 11.5 Hz,
1H, H-5). 13C NMR (100.6 MHz, CDCl3): δ 159.1 (C-2), 144.6,
140.5, 138.8, 130.4, 128.8, 128.4, 128.2, 127.9, 127.4, 126.8, 126.7,
126.5, 63.0 (C-4), 45.7 (C-6), 37.1 (C-5). HRMS (ESI, m/z) calcd.
for [C22H20NS]+: 330.1316; found: 330.1321. IR (neat): 1599 (C
= N), 1547, 1489, 1446, 1338, 1288, 1221, 938, 910, 761, 749,
732, 687 (C-S) cm−1
.
1
1h-exo: H NMR (400 MHz, CDCl3): δ 7.98–7.96 (m, 2H,
Ar), 7.47–7.26 (m, 13H, Ar), 5.36 (t, J = 4.5 Hz, 1H, H-4),
4.27 (dd, J = 8.6, 5.0 Hz, 1H, H-6), 2.34–2.27 (m, 2H, H-5).
13C NMR (100.6 MHz, CDCl3): δ 159.7 (C-2), 142.6, 141.0,
139.0, 130.6, 128.7, 128.5, 128.3, 127.83, 127.81, 127.0, 126.8,
126.5, 59.5 (C-4), 40.8 (C-6), 34.5 (C-5). HRMS (ESI, m/z) calcd.
for [C22H20NS]+: 330.1316; found 330.1332. IR (neat): 1600 (C
cm−1
.
1j-exo: 1H NMR (400 MHz, CDCl3): δ 8.02–8.00 (m, 2H, Ar),
7.52–7.45 (m, 3H, Ar), 7.42–7.38 (m, 2H, Ar), 7.33–7.29 (m, 1H,
Ar), 7.27–7.25 (m, 2H, Ar), 5.31 (d, J = 2.7 Hz, 1H, H-4), 3.45
(q, J = 3.6 Hz, 1H, H-6), 1.99–1.95 (m, 1H, H-5), 1.88–1.80 (m,
3H, H-8, H-9 and H-7), 1.77–1.66 (m, 3H, H-7 and H-10), 1.57–
1.52 (m, 1H, H-8), 1.42–1.37 (m, 1H, H-9). 13C NMR (100.6
MHz, CDCl3): δ 159.6 (C-2), 142.1, 139.3, 130.3, 128.3, 128.2,
126.8, 126.7, 126.3, 66.5 (C-4), 37.3 (C-5), 36.2 (C-6), 30.5 (C-7),
26.7 (C-10), 25.3 (C-9), 20.5 (C-8). HRMS (ESI, m/z) calcd. for
[C20H22NS]+: 308.1473; found: 308.1475. IR (neat): 2925, 1600
(C = N), 1575, 1488, 1443, 689, 933, 763, 743, 704, 688 (C-S),
= N), 1577, 1490, 1447, 1027, 936, 762, 690 (C-S), 666 cm−1
.
5,6-Dihydro-6-(4-methoxyphenyl)-5-methyl-2-4-
diphenyl-4H-1,3-thiazine (1i) was obtained from thioben-
zamide, benzaldehyde, and anethole according to the general
procedure, in 98% yield, as a unseparable mixture of three
diastereoisomers 1i-exo, 1i-endo, and 1i-epi (ratio 1:0.6:0.18).
674 cm−1
.
5,6-Dihydro-2,4-diphenyl-4H-norbornano[5,6-e]-1,3-
thiazine (1k) was obtained from thiobenzamide, benzaldehyde,
and norbornene according to the general procedure, in 78%
yield, as a single diastereoisomer 1k-exo.
1i-endo/1i-exo/1i-epi: 1H NMR (400 MHz, CDCl3): δ 7.89–
7.86 (m, 1H, Ar), 7.77–7.74 (m, 1H, Ar), 7.36–7.14 (m, 10H, Ar),
6.79–6.73 (m, 2H, Ar), 5.01 (d, J = 4.7 Hz, H-4epi), 4.90 (d, J =
3.8 Hz, H-4exo), 4.36 (d, J = 9.9 Hz, H-4endo), 4.22 (d, J = 3.5
Hz, H-6epi), 4.21 (d, J = 10.9 Hz, H-6endo), 4.05 (d, J = 7.6 Hz,
H-6exo), 3.68 (s, Me), 2.24–2.18 (m, H-5epi), 2.15–2.11 (m, H-
5exo), 1.98–1.91 (m, H-5endo), 0.82 (d, J = 7.1 Hz, CH3epi), 0.67
(d, J = 7.1 Hz, CH3exo), 0.56 (d, J = 6.5 Hz, CH3endo). 13C NMR
(100.6 MHz, CDCl3): δ 159.2 (C-2endo), 159.0 (C-2epi), 158.8 (C-
2exo), 143.8, 142.8, 140.3, 139.1, 139.0, 138.6, 132.9, 131.8, 131.1,
130.5, 130.43, 130.40, 129.6, 129.5, 129.3, 128.4, 128.3, 128.3,
128.2, 128.1, 128.04, 128.00, 127.1, 127.0, 126.9, 126.7, 126.5,
126.4, 114.2, 114.0, 113.7, 70.5 (C-4endo), 66.5 (C-4exo), 63.1 (C-
4epi), 55.2 (Me), 51.3 (C-6endo), 48.2 (C-6exo), 44.6 (C-6epi), 38.4
(C-5endo), 36.0 (C-5epi), 35.6 (C-5exo), 16.3 (C-8endo), 14.8 (C-
8exo), 14.7 (C-8epi). HRMS (ESI m/z) calcd. for [C24H24NOS]+
374.1579; found: 374.1569. IR (neat): 2960, 1607 (C = N), 1510,
1
1k-exo: H NMR (400 MHz, CDCl3): δ 8.07–8.04 (m, 2H,
Ar), 7.56–7.54 (m, 2H, Ar), 7.48–7.35 (m, 6H, Ar), 4.02 (d, J =
10.4 Hz, 1H, H-4), 3.20 (dd, J = 7.9, 1.3 Hz, 1H, H-6), 2.46
(d, J = 3.8 Hz, 1H, H-7), 2.38 (d, J = 10.2 Hz, 1H, H-11),
2.25 (d, J = 3.7 Hz, 1H, H-10), 2.00 (dd, J = 10.5, 9.3 Hz, 1H,
H-5), 1.75–1.67 (m, 1H, H-8), 1.61–1.53 (m, 1H, H-9), 1.39–
1.32 (m, 2H, H-11 and H-8), 1.22–1.16 (m, 1H, H-9). 13C NMR
(100.6 MHz, CDCl3): δ 165.2 (C-2), 144.4, 138.6, 130.6, 128.6,
128.2, 128.1, 127.3, 126.9, 69.6 (C-4), 55.7 (C-5), 49.6 (C-6), 44.0
(C-7), 40.7 (C-10), 34.0 (C-11), 29.8 (C-9), 29.1 (C-8). HRMS
(ESI, m/z) calcd. for [C21H22NS]+: 320.1473; found: 320.1472.
IR (neat): 2951, 1563 (C = N), 1447, 1222, 1046, 1023, 995,
929, 765, 754, 702, 692 (C-S) cm−1. Anal. Calcd.: C, 78.95; H,
6.63; N, 4.38; S, 10.04; found: C, 79.08; H, 6.51; N, 4.46; S,
9.88.
1248, 765, 691 (C-S) cm−1
.
5,6-Dihydro-2,4-diphenyl-4H-cyclohexa[5,6-e]-1,3-
thiazine (1j) was obtained from thiobenzamide, benzaldehyde,
and cyclohexene according to the general procedure, in 76%
yield, as a separable mixture of two diastereoisomers endo and
exo (ratio 1:1.6).
6-Butyl-5,6-dihydro-2-methyl-4-phenyl-4H-1,3-thiazine
(1l) was obtained from thioacetamide, benzaldehyde, and
hexene according to the general procedure, in 91% yield, as a
separable mixture of two diastereoisomers endo and exo (ratio
1:1.4).

PHOSPHORUS, SULFUR, AND SILICON
227
and cyclooctene according to the general procedure, in 99%
yield, as a separable mixture of two diastereoisomers endo and
exo (ratio 1:1).
1l-endo: 1H NMR (400 MHz, CDCl3): δ 7.37–7.29 (m, 4H,
Ar), 7.27–7.22 (m, 1H, Ar), 4.40–4.36 (m, 1H, H-4), 3.50 (dddd,
J = 16.6, 7.7, 6.0, 3.7 Hz, 1H, H-6), 2.22 (d, J = 2.0 Hz, 3H,
CH3), 2.21–2.17 (m, 1H, H-5), 1.55–1.46 (m, 2H, H-7), 1.40–
1.30 (m, 4H, H-8 and H-9), 1.29–1.25 (m, 1H, H-5), 0.90 (t, J =
7.1 Hz, 3H, H-10). 13C NMR (100.6 MHz, CDCl3): δ 158.9 (C-2),
145.1, 128.5, 126.8, 126.7, 62.7 (C-4), 41.7 (C-6), 36.6 (C-5), 36.3
(C-7), 28.2 (C-8), 27.9 (CH3), 22.4 (C-9), 13.8 (C-10). HRMS
(ESI, m/z) calcd. for [C15H22NS]+: 248.1473; found: 248.1479.
IR (neat): 2956, 2928, 1633 (C = N), 1542, 1451, 1132, 758, 698
1n-endo: 1H NMR (400 MHz, CDCl3): δ 7.48–7.46 (m, 2H,
Ar), 7.38–7.34 (m, 2H, Ar), 7.26–7.21 (m, 1H, Ar), 4.45 (s, 1H,
H-4), 3.86 (qt, J = 4.9, Hz, 1H, H-6), 2.41–2.37 (m, 1H, H-5),
2.23 (d, J = 2.0 Hz, 3H, CH3), 1.79–1.71 (m, 4H, CH2), 1.57–
1.55 (m, 4H, CH2), 1.34–1.24 (m, 2H, CH2), 1.22–1.16 (m, 1H,
CH2), 0.86–0.78 (m, 1H, CH2). 13C NMR (100.6 MHz, CDCl3):
δ 160.4 (C-2), 143.5, 128.0, 127.2, 126.2, 66.1 (C-4), 47.8 (C-6),
36.6 (C-5), 30.4, 28.6, 27.6 (CH3), 27.8, 24.6, 24.5, 19.9. HRMS
(ESI, m/z) calcd. for [C17H24NS]+: 274.1629; found: 274.1630.
IR (neat): 2914, 1628 (C = N), 1466, 1449, 1129, 769, 735, 712
(C-S) cm−1
.
1
1l-exo: H NMR (400 MHz, CDCl3): δ 7.26–7.22 (m, 2H,
Ar), 7.16–7.09 (m, 3H, Ar), 4.81 (t, J = 4.8 Hz, 1H, H-4), 2.93–
2.87 (m, 1H, H-6), 2.17 (d, J = 1.2 Hz, 3H, CH3), 1.85–1.79
(m, 1H, H-5), 1.74–1.68 (m, 1H, H-5), 1.53–1.48 (m, 2H, H-
7), 1.28–1.15 (m, 4H, H-8 and H-9), 0.78 (t, J = 6.8 Hz, 3H,
H-10). 13C NMR (100.6 MHz, CDCl3): δ 159.0 (C-2), 143.0,
128.2, 126.63, 126.61, 58.6 (C-4), 37.1 (C-6), 36.5 (C-7), 33.4
(C-5), 28.2 (C-8), 28.0 (CH3), 22.3 (C-9), 13.8 (C-10). HRMS
(ESI, m/z) calcd. for [C15H22NS]+: 248.1473; found: 248.1482.
IR (neat): 2928, 1633 (C = N), 1544, 1450, 1134, 752, 728, 698
(C-S) cm−1
.
1
1n-exo: H NMR (400 MHz, CDCl3): δ 7.35–7.31 (m, 2H,
Ar), 7.27–7.22 (m, 1H, Ar), 7.15–7.13 (m, 2H, Ar), 4.99 (d, J =
3.3 Hz, 1H, H-4), 3.16–3.11 (m, 1H, H-6), 2.28 (d, J = 0.7 Hz,
3H, CH3), 2.16–2.11 (m, 1H, H-5), 1.84–1.76 (m, 1H, CH2),
1.71–1.55 (m, 9H, CH2), 1.48–1.46 (m, 1H, CH2), 1.38–1.33 (m,
1H, CH2). 13C NMR (100.6 MHz, CDCl3): δ 160.1 (C-2), 142.2,
128.3, 126.7, 126.6, 68.2 (C-4), 39.1 (C-6), 36.3 (C-5), 30.3, 28.2,
28.0, 27.7 (CH3), 27.4, 25.0, 23.6. HRMS (ESI, m/z) calcd. for
[C17H24NS]+: 274.1629; found: 274.1628. IR (neat): 2919, 1629
(C-S) cm−1
.
5,6-Dihydro-2-methyl-4,6-diphenyl-4H-1,3-thiazine (1m)
was obtained from thioacetamide, benzaldehyde, and styrene
according to the general procedure, in 91% yield, as a separable
mixture of two diastereoisomers endo and exo (ratio 1:0.2).
(C = N), 1448, 1134, 729, 697 (C-S) cm−1
.
5,6-Dihydro-2-methyl-4-(2-methoxyphenyl)-4H-
norbornano[5,6,e]-1,3-thiazine (1o) was obtained from
thioacetamide, 2-methoxybenzaldehyde, and norbornene
according to the general procedure, in 84% yield, as a single
diastereoisomers 1o-exo.
1m-endo: 1H NMR (400 MHz, CDCl3): δ 7.28–7.23 (m, 8H,
Ar), 7.22–7.15 (m, 2H, Ar), 4.58 (dd, J = 12.4, 3.4 Hz, 1H, H-4),
4.56–4.52 (m, 1H, H-6), 2.32 (dt, J = 13.8, 3.5 Hz, 1H, H-5), 2.20
(d, J = 2.0 Hz, 3H, CH3), 1.78–1.69 (m, 1H, H-5). 13C NMR
(100.6 MHz, CDCl3): δ 158.9 (C-2), 144.6, 140.5, 128.8, 128.5,
127.9, 127.4, 126.9, 126.6, 62.9 (C-4), 45.7 (C-6), 36.9 (C-5)
27.8 (CH3). HRMS (ESI, m/z) calcd. for [C17H18NS]+: 268.1160;
found: 268.1165. IR (neat): 1630, 1607 (C = N), 1493, 1454,
1o-exo: 1H NMR: (400 MHz, CDCl3): δ 7.46 (dd, J = 7.5, 1.7
Hz, 1H, Ar), 7.25–7.21 (m, 1H, Ar), 7.03 (dt, J = 7.5, 1.0 Hz,
1H, Ar), 6.88 (dd, J = 8.2, 0.9 Hz, 1H, Ar), 4.30 (dq, J = 7.5, 1.0
Hz, 1H, H-4), 3.81 (s, 3H, Me), 3.05 (dd, J = 10.7, 2.0 Hz, 1H,
H-6), 2.28 (d, J = 2.0 Hz, 3H, CH3), 2.24 (d, J = 2.7 Hz, 2H, H-7
and H-11), 2.01 (d, J = 3.6 Hz, 1H, H-10), 1.81 (dd, J = 10.0,
8.3 Hz, 1H, H-5), 1.64–1.55 (m, 1H, H-8), 1.51–1.43 (m, 1H,
H-9), 1.3–1.18 (m, 2H, H-8 and H-11), 1.13–1.05 (m, 1H, H-
9). 13C NMR: (100.6 MHz, CDCl3): δ 164.9 (C-2), 157.0, 133.1,
129.6, 127.8, 121.3, 110.6, 60.9, 55.6 (Me), 54.4 (C-5), 49.1 (C-6),
44.0 (C-7), 40.6 (C-10), 34.2 (C-11), 29.9 (C-9), 29.5 (C-8), 29.4
(CH3). HRMS (ESI, m/z) calcd. for [C17H22NOS]+: 288.1422;
found: 288.141. IR (neat): 2952, 1612 (C = N), 1492, 1240, 1135,
1250, 1128, 761, 746, 694 (C-S) cm−1
.
1m-exo: 1H NMR (400 MHz, CDCl3): δ 7.36–7.23 (m, 8H,
Ar), 7.19–7.17 (m, 2H, Ar), 5.06 (t, J = 4.2 Hz, 1H, H-4),
4.13 (dd, J = 7.3, 6.3 Hz, 1H, H-6), 2.34 (d, J = 1.2 Hz, 3H,
CH3), 2.18 (d, J = 4.6 Hz, 1H, H-5), 2.16 (dd, J = 4.9, 1.6
Hz, 1H, H-5). 13C NMR (100.6 MHz, CDCl3): δ 159.0 (C-2),
142.4, 140.9, 128.6, 128.4, 127.6, 127.5, 126.9, 126.6, 58.8 (C-4),
40.6 (C-6), 34.2 (C-5), 27.8 (CH3). HRMS (ESI, m/z) calcd. for
[C17H18NS]+: 268.1160; found: 268.1171. IR (neat): 1632 (C =
N), 1492, 1450, 1128, 760, 731, 695 (C-S) cm−1
.
5,6-Dihydro-2-methyl-4-phenyl-4H-cycloocta[5,6-e]-1,3-
thiazine (1n) was obtained from thioacetamide, benzaldehyde,
1029, 751, 731 cm−1
.

228
F. PEUDRU ET AL.
5,6-Dihydro-2-methyl-4-phenyl-4H-norbornano[5,6-e]-
1,3-thiazine (1p) was obtained from thioacetamide, benzalde-
hyde, and norbornene according to the general procedure, in
99% yield, as a single diastereoisomers 1p-exo.
1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 3.0 Hz, 1H, H-
2), 7.29–7.28 (m, 4H, Ar), 7.24–7.17 (m, 1H, Ar), 3.57 (dd, J =
10.6, 3.2 Hz, 1H, H-4), 2.96 (dd, J = 7.9, 1.3 Hz, 1H, H-6), 2.20–
2.14 (m, 2H, H-11 and H-7), 2.05–2.03 (m, 1H, H-10), 1.86–
1.81 (m, 1H, H-5), 1.57–1.49 (m, 1H, H-8), 1.44–1.36 (m, 1H,
H-9), 1.23–1.14 (m, 2H, H-11 and H-8), 1.07–1.00 (m, 1H, H-
9). 13C NMR (100.6 MHz, CDCl3): δ 157.7 (C-2), 143.9, 128.5,
128.4, 127.2, 67.7 (C-4), 55.6 (C-5), 48.4 (C-6), 44.2 (C-7), 41.0
(C-10), 34.0 (C-11), 29.9 (C-9), 29.4 (C-8). HRMS (ESI, m/z)
calcd. for [C15H18NS]+: 244.1160 found: 244.1170. IR (neat):
2956, 1572 (C = N), 1451, 1309, 890, 787, 766, 751, 700 (C-S)
1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 4.4 Hz, 4H, Ar),
7.31–7.28 (m, 1H, Ar), 3.64 (dq, J = 10.8, 2.0 Hz, 1H, H-4),
3.06 (dd, J = 8.0, 1.1 Hz, 1H, H-6), 2.29 (d, J = 2.0 Hz, 3H,
CH3), 2.26 (d, J = 4.0 Hz, 1H, H-7), 2.20 (dt, J = 10.4, 1.7 Hz,
1H, H-11), 2.07 (d, J = 3.7 Hz, 1H, H-10), 1.82 (dd, J = 10.1,
8.7 Hz, 1H, H-5), 1.66–1.57 (m, 1H, H-8), 1.53–1.45 (m, 1H,
H-9), 1.31–1.24 (m, 1H, H-8), 1.21 (dt, J = 10.4, 1.3 Hz, 1H,
H-11), 1.16–1.09 (m, 1H, H-9). 13C NMR (100.6 MHz, CDCl3):
δ 165.1 (C-2), 144.2, 128.4, 128.3, 126.9, 68.6 (C-4), 53.9 (C-5),
48.8 (C-6), 43.9 (C-7), 40.6 (C-10), 33.8 (C-11), 29.8 (C-9), 29.3
(C-8) 29.2 (CH3). HRMS (ESI, m/z) calcd. for [C16H20NS]+:
258.1316; found: 258.1337. IR (neat): 2955, 1614 (C = N), 1451,
1135, 1118, 751, 731, 698 (C-S) cm−1. Anal. Calcd.: C, 74.66;
H, 7.44; N, 5.44; S, 12.46; found: C, 74.84; H, 7.29; N, 5.51; S,
12.08.
cm−1
.
Synthesis of β-lactam derivatives 2 and thiazepine 3
3-Butyl-8-chloro-1,5-diphenyl-2-thia-6-aza-
bicyclo[4.2.0]octan-7-one (2a): To a stirred solution of thiazine
1a-endo (0.3 mmol) in anhydrous toluene (1.5 mL) was added
triethylamine (0.15 mmol, 0.5 equiv). The solution was refluxed
and a solution of chloroacetyl chloride (0.45 mmol, 1.5 equiv)
in anhydrous toluene (9 mL) was added dropwise over 1 h and
a half. The addition of triethylamine (0.5 equiv, 0.15 mmol) was
repeated two more times, each 45 min. The reaction mixture was
then cooled, filtered, extracted with brine, dried with Na2SO4,
and concentrated in vacuo. The crude material was purified
by flash chromatography on silica gel (cyclohexane/AcOEt) to
afford 2a, as colorless crystals, in 71% yield.
5,6-dihydro-2-methyl-4-(thiophen-2-yl)-4H-
norbornano[5,6-e]-1,3-thiazine (1q) was obtained from
thioacetamide, 3-thiophenecarboxaldehyde, and norbornene
according to the general procedure, in 98% yield, as a single
diastereoisomers 1q-exo.
1H NMR (400 MHz, CDCl3): δ 7.26–7.24 (m, 1H, Ar), 7.10–
7.07 (m, 2H, Ar), 3.74 (dd, J = 10.8, 1.9 Hz, 1H, H-4), 3.00 (dd,
J = 8.1, 1.0 Hz, 1H, H-6), 2.20 (d, J = 2.0 Hz, 3H, CH3), 2.17 (d,
J = 3.8 Hz, 1H, H-7), 2.09–2.05 (m, 2H, H-10 and H-11), 1.82–
1.77 (m, 1H, H-5), 1.59–1.51 (m, 1H, H-8), 1.49–1.41 (m, 1H,
H-9), 1.24–1.08 (m, 3H, H-11, H-9 and H-8). 13C NMR (100.6
MHz, CDCl3): δ 164.9 (C-2), 145.1, 127.2, 125.8, 121.7, 63.8 (C-
4), 52.7 (C-5), 48.8 (C-6), 43.8 (C-7), 40.9 (C-10), 33.8 (C-11),
29.7 (C-9), 29.2 (C-8) 29.0 (CH3). HRMS (ESI, m/z) calcd. for
[C14H18NS2]+: 264.0881; found: 264.0880. IR (neat): 2952, 1610
1H NMR (400 MHz, CDCl3): δ 7.41–7.33 (m, 5H, Ar), 7.26–
7.17 (m, 5H, Ar), 5.19 (s, 1H, H-8), 5.12 (dd, J = 12.7, 5.3
Hz, 1H, H-5), 3.34–3.27 (m, 1H, H-3), 2.30 (dt, J = 14.2,
5.2, 3.4 Hz, 1H, H-4), 2.05–1.97 (m, 1H, H-4), 1.63–1.59 (m,
2H, H-9), 1.40–1.32 (m, 4H, H-10 and H-11), 0.91 (t, J = 7.1
Hz, 3H, H-12). 13C NMR (100.6 MHz, CDCl3): δ 165.2 (C-7),
139.3, 139.0, 128.7, 128.3, 128.2, 127.7, 127.6, 127.4, 71.1 (C-8),
70.9 (C-1), 55.5 (C-5), 42.2 (C-3), 36.3 (C-9), 32.5 (C-4), 28.6
(C-10), 22.4 (C-11), 13.8 (C-12). HRMS (ESI, m/z) calcd. for
[C22H25NOSCl]+: 386.1344; found: 386.1345. IR (neat): 1765 (C
(C = N), 1132, 791, 772, 761 (C-S) cm−1
.
= O), 696 (C-S) cm−1
.
5,6-Dihydro-4-phenyl-4H-norbornano[5,6-e]-1,3-
thiazine (1r) was obtained from thioformamide, benzaldehyde,
and norbornene according to the general procedure, in 38%
yield, as a single diastereoisomers 1r-exo.
3-Butyl-8-chloro-1,5-diphenyl-2-thia-6-aza-
bicyclo[4.2.0]octan-7-one (2b) was obtained from thiazine
1a-exo, according the same procedure as 2a, as yellow oil, in
64% yield.

PHOSPHORUS, SULFUR, AND SILICON
229
Acknowledgments
The authors thank Prof. A.-C. Gaumont, the director of their laboratory, for
helpful discussions. R. Legay and K. Jarsalé are acknowledged for the NMR
analyses and mass spectra, respectively.
Funding
The authors acknowledge for financial support (grant for F.P.) the Cen-
tre National de la Recherche Scientifique (CNRS) and the Région Basse-
Normandie.
1H NMR (400 MHz, CDCl3): δ 7.31–7.24 (m, 5H, Ar), 7.21–
7.09 (m, 5H, Ar), 5.43 (t, J = 5.8 Hz, 1H, H-5), 5.10 (s, 1H, H-
8), 3.26–3.21 (m, 1H, H-3), 2.42 (ddd, J = 14.5, 4.8, 2.9 Hz, 1H,
H-4), 2.07 (ddd, J = 14.6, 9.4, 6.3 Hz, 1H, H-4), 1.72–1.66 (m,
2H, H-9), 1.49–1.31 (m, 4H, H-10 and H-11), 0.93 (t, J = 7.1
Hz, 3H, H-12). 13C NMR (100.6 MHz, CDCl3): δ 163.9 (C-7),
139.2, 136.5, 128.64, 128.62, 128.3, 127.9, 127.6, 127.4, 71.6 (C-
1), 69.4 (C-8), 50.8 (C-5), 39.2 (C-3), 35.7 (C-9), 31.7 (C-4), 28.8
(C-10), 22.4 (C-11), 13.9 (C-12). HRMS (ESI, m/z) calcd. for
[C22H25NOSCl]+: 386.1334; found: 386.1345. IR (neat): 1771 (C
References
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= O), 698 (C-S) cm−1
.
Methyl-7-butyl-4,5,6,7-tetrahydro-3,5-diphenyl-1,4-
thiazepine-2-carboxylate (3a): A stirred solution of 2a (0.16
mmol) and potassium tert-butoxide (0.32 mmol, 2 equiv) in
methanol (2 mL) under a nitrogen atmosphere was refluxed for
4 h. The reaction mixture was evaporated and the crude product
was dissolved in dichloromethane (7 mL). The organic phase
was washed with water (4 mL), dried with Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by flash
chromatography on silica gel (cyclohexane/AcOEt) to afford 3a
as a yellow oil in 52% yield.
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1H NMR (400 MHz, CDCl3): δ 7.40–7.38 (m, 4H, Ar), 7.37–
7.32 (m, 6H, Ar), 5.48–5.45 (m, 1H, H-5), 4.38 (s, 1H, NH), 3.47
(s, 3H, H-13), 2.99–2.92 (m, 1H, H-7), 2.53–2.45 (m, 1H, H-6),
2.32–2.27 (m, 1H, H-6), 1.82–1.78 (m, 1H, H-7), 1.69–1.55 (m,
4H, H-9 and H-10), 0.90 (t, J = 7.1 Hz, 3H, H-10). 13C NMR
(100.6 MHz, CDCl3): δ 170.0 (C-12), 164.4 (C-2), 143.9, 139.6,
129.8, 129.3, 128.34, 128.31, 128.2, 126.7, 61.4 (C-5), 51.3 (C-
13), 48.0 (C-7), 42.7 (C-6), 36.3 (C-8), 29.5 (C-9), 22.5 (C-10),
13.9 (C-11). HRMS (ESI, m/z) calcd. for [C22H24NaNOSCl]+:
404.1600; found: 404.1660. IR (neat): 1681 (C = O), 699 (C-S)
cm−1
.