One-pot cis -selective route to sugar-fused thiazines via a masking-unmasking strategy in basic ionic liquid

Article abstract of DOI:10.1139/cjc-2016-0155

A novel sequential Knoevenagel condensation, thia-Michael, and amino/mercaptoacetylative ring transformation reaction cascade for cis-selective synthesis of sugar-fused 1,3-thiazine is reported. The expeditious one-pot multicomponent annulation was performed using masked amino acid viz. 2-phenyl-1,3-oxazol-5-one or masked mercaptoacid viz. 2-methyl-2-phenyl-1,3-oxathiolan-5-one, d-xylose/d-glucose, and N-aryldithiocarbamic acid in ionic liquid [bmim]OH. The acetophenone obtained as a by-product and [bmim]OH itself could be easily recycled for further use without loss of efficiency. The envisaged method is operationally simple, high yielding, and excellent diastereoselective in favor of the cis-isomer of fused thiazines.

Full text of DOI:10.1139/cjc-2016-0155

Page 1 of 21
ONEꢀPOT CISꢀSELECTIVE ROUTE TO SUGARꢀFUSED THIAZINES VIA MASKINGꢀ
UNMASKING STRATEGY IN BASIC IONIC LIQUID
a
a
Vijai K. Rai,
* and Rahul K. Kosta
a
Department of Chemistry, Guru Ghasidas Vishwavidyalaya, Bilaspur, C. G., 495 009, India.
*Corresponding author. Tel.: +91 7587178627; fax: +91(77520) 260148
Email: vijaikrai@hotmail.com
[1]

Page 2 of 21
Abstract:
A
novel
sequential
Knoevenagel
condensation,
thiaꢀMichael
and
amino/mercaptoacetylative ring transformation reaction cascade for cisꢀselective synthesis of sugarꢀ
fused 1,3ꢀthiazine is reported. The expeditious oneꢀpot multicomponent annulation was performed
using masked amino acid viz. 2ꢀphenylꢀ1,3ꢀoxazolꢀ5ꢀone or masked mercaptoacid viz. 2ꢀmethylꢀ2ꢀ
phenylꢀ1,3ꢀoxathiolanꢀ5ꢀone, Dꢀxylose/Dꢀglucose and Nꢀaryldithiocarbamic acid in ionic liquid
[
bmim]OH. The acetophenone obtained as a byꢀproduct and [bmim]OH itself, could be easily recycled
for further use without loss of efficiency. The envisaged method is operationally simple, high yielding
and excellent diastereoselective in favor of cisꢀisomer of fused thiazines.
Keywords: carbohydrates, [bmim]OH, stereoselectivity, sugar, 1,3ꢀthiazines.
Introduction: Sugars incorporating intracyclic sulfur atom (thiosugars) and endocyclic nitrogen atom
(iminosugars) are of considerable interest since the discovery of their biological activity as glycosidase
1
inhibitors in 1970’s. Many naturally occurring thiosugars are potential targets for the carbohydrateꢀ
2
,3
based therapeutics, such as thiolactomycin, salacinol, kotalonol, tagetioxin and mycothiol.
Furthermore, sugar mimics with endocyclic nitrogen are arousing a great interest as potential
therapeutic agents against HIV infection, cancer, diabetes and other genetic and metabolic disorders
4
ꢀ7
due to their powerful interference with glycosidase as well as glycotransferases. 1,3ꢀthiazine nucleus
is the active core of cephalosporins, which are among the most widely used βꢀlactam antibiotics and its
derivatives possess remarkable biological activities such as antibacterial, antitumour, insecticidal and
8
ꢀ10
fungicidal.
Thus, heterocyclic system resulting from the annulations of 1,3ꢀthaizines on
biologically versatile iminoꢀ and thiosugars would provide not only an attractive scaffold for
exploiting chemical diversity but also the presence of several free hydroxyl groups render them water
soluble and biodegradable. Inspired by these valid literature reports and in continuation of our ongoing
1
1
12
work on methodology development, especially using carbohydrates, herein, we report an original
[2]

Page 3 of 21
and green route to iminosugar annulated 1,3ꢀthiazines 7 and 8 as well as thiosugar annulated 1,3ꢀ
thiazines 14 and 15 using masked amino acid, 2ꢀphenylꢀ1,3ꢀoxazolanꢀ5ꢀone 2 and masked mercapto
acid, 2ꢀmethylꢀ2ꢀphenylꢀ1,3ꢀoxathiolanꢀ5ꢀone 3 respectively with Dꢀxylose and Dꢀglucose as
renewable feedstock (Scheme 1).
Results and discussion:
,3ꢀthiazine containing a sugar chain, which would underwent intramolecular ring transformation
affording the iminoꢀ/thiosugar annulated 1,3ꢀthiazines (Scheme 2). Limited efforts have been made for
Initial retrosynthetic study revealed to construct 5ꢀaminoꢀ/5ꢀmercaptoꢀ
1
8
,9,12ꢀ14
synthesis of 1,3ꢀthiazines using α,βꢀunsaturated carbonyl systems.
As required, we designed
enones containing sugar chain (6 and 11), which could not only introduce a –SH and –NHR group but
also install a sugar tail to annulate the azaꢀ/ and thiosugar in 1,3ꢀthiazine skeleton. For this purpose, we
tried glycine and mercaptoacetic acid in the present synthetic protocol for construction of the designed
α,βꢀunsaturated carbonyl building block (6 and 11), but were unsuccessful, probably due to the
presence of free –SH and –CO H groups in mercapto acid and –NH and –CO H in glycine. Then, we
2
2
2
activated their methylene groups by converting into masked amino acid, 2ꢀphenylꢀ1,3ꢀoxazolanꢀ5ꢀone
1
5
and masked mercapto acid, 2ꢀmethylꢀ2ꢀphenylꢀ1,3ꢀoxathiolanꢀ5ꢀone (Scheme 3) respectively. These
activated aminoꢀ/ and mercapto acids not only served the purpose as aminoacetyl and mercaptoacetyl
transfer agent respectively in the present synthetic protocol, but also provided a completely new route
for synthesis of target imino/ꢀ and thiosugar annulated 1,3ꢀthiazines, which is hitherto unreported and
are not accessible through any one of the known synthetic routes for the target compounds (Scheme 1).
At the outset, we investigated the optimization of reaction conditions regarding the catalyst and
solvent both. For this purpose, Dꢀxylose 1 (n = 3), 2ꢀphenylꢀ1,3ꢀoxazolanꢀ5ꢀone 2 and dithiocabamic
acid 4 (Ar = Ph) were chosen as model substrates for the synthesis of representative compound 7a
(
Table 1). First, we screened various ionic liquids as catalyst and CH CN as solvent for the present
3
reaction. Surprisingly, the reaction took place with all ILs, and [bmim]Br was found the best among all
3]
[

Page 4 of 21
(Table 1, entries 1ꢀ3). However, yields were not satisfactory. With the hope of increasing yield, we
tried the reaction in other solvents such as THF, MeOH and 1,4ꢀdioxne using [bmim]Br as catalyst.
Although, among MeOH, CH CN, THF and 1,4ꢀdioxne, THF was found to be the best solvent, but
3
there was no satisfactory increase in the yield (Table 1, entries 1, 4ꢀ6). This indicated that [bmim]Br
was not an efficient catalyst for the present reaction. Then, we turned our attention to use a basic IL
[
bmim]OH as a catalyst, which evidenced its catalytic efficacy in the reaction affording 7a in excellent
yield (Table 1, entry 9). This is in conformity with the earlier report on [bmim]OHꢀcatalyzed
1
6
Knoevenagel condensationꢀring transformation reactions. In addition, several imidazoliumꢀbased ILs
were tested by varying their alkyl substituents and [bmim]OH was found to be the most effective
catalyst (Table 1, entries 7ꢀ9).
The optimum catalyst loading for [bmim]OH was found to be 15 mol%. When the amount of the
catalyst decreased to 10 mol% from 15 mol% relative to substrates, the yield of the product 7a reduced
and more time was required to complete the reaction (Table 1, entries 9 and 13), but the use of 20
mol% did not affect the yield (Table 1, entries 9 and 14). However, the reaction did not occur without
using a catalyst (Table 1, entry 15). Optimization of the solvent for the synthesis of 7a using
[
(
bmim]OH was also undertaken and it was found that amongst MeOH, CH CN, THF and 1,4ꢀdioxane
3
Table 1, entries 9ꢀ12), the best solvent in terms of yield and reaction time was THF (Table 1, entry 9).
It was noted that a higher reaction temperature, for example, in a refluxing solvent instead of at rt, has
no any appreciable effect on the yield. In the same way we also performed a controlled reaction taking
masked mercapto acid and compound 14a was synthesized using the same protocol optimized for 7a.
1
7
The [bmim]OH was prepared employing the known method. Usually imidazolium salts undergo
deprotonation in the presence of strong bases such as KH, NaH, LDA, KHMDS or DABCO and
1
8
affords Nꢀheterocyclic carbenes. However, the ionic liquid [bmim]OH is highly stable during the
1
9
17
reaction process under ambient conditions and can be used in reactions without any difficulty. The
[4]

Page 5 of 21
stability and catalytic efficiency of [bmim]OH is furthermore evidenced by a variety of reactions viz.,
2
0
16
17
21
Henry, Knoevenagel, Michael, and Mannich reaction etc. reported in literature.
With the aim to establish its solventꢀfree version and to compare the synthetic efficiency, a
o
model experiment was carried out at 90 C in a microwave (Chemical Laboratory Microwave Oven,
Model; BPꢀ310/50, 23o volt, 50 Hz power input). Various mineral catalysts were screened for the
o
formation of 7a at 90 C. Among the catalysts tested, Kꢀ10 clay gave the best result (Table 2, entry 3).
CeCl .7H O and CeCl .7H O/NaIꢀsystem afforded the product 7a in moderate yields (Table 2, entries
3
2
3
2
1ꢀ2), while poor yields of 7a was obtained in the case of silica gel and neutral or acidic alumina (Table
2, entries 4ꢀ6). Moreover, the reaction did not take place using basic alumina (Table 2, entry 7) as well
as in the absence of catalyst (Table 2, entry 8). It was observed that significantly lower yield of 7a was
obtained in solventꢀfree condition (Table 2, entry 3) rather than its [bmim]OH catalyzed version
(Table 1, entry 9). Thus, [bmim]OH stands out as the choice, with its fast conversion and quantitative
yield of the target compound in the present investigation. Next, in order to investigate the substrate
scope for the general validity of the present investigation, a variety of dithiocarbamic acids 4 and
sugars 1 by varying the masked acids, were used employing the present optimized reaction conditions
and different iminoꢀ and thiosugar annulated 1,3ꢀthiazines were synthesized (Table 3). The yields were
consistently good and excellent diastereoselctivity were achieved in favor of cis isomer (Table 3).
Thus, the present optimized synthesis for the target iminoꢀ/ and thiosugar annulated 1,3ꢀ
thiazines (7, 8 and 14, 15) was successful by stirring a mixture of Dꢀxylose/Dꢀglucose 1, 2ꢀphenylꢀ1,3ꢀ
oxazolanꢀ5ꢀone 2 or 2ꢀmethylꢀ2ꢀphenylꢀ1,3ꢀoxathiolanꢀ5ꢀone 3, dithiocarbamic acid 4 and [bmim]OH
5
in THF at room temperature for 6.5ꢀ8 h (Table 3). The pure products 7, 8 and 14, 15 were extracted
with ether leaving the [bmim]OH behind which can be recycled easily for further use without loss of
efficiency (Table 4). Isolation and purification by flash chromatography on silica gel using hexaneꢀ
[5]

Page 6 of 21
EtOAc (8:2) as elluent, afforded 7, 8 and 14, 15 in 84ꢀ93% yields with >94% diastereoselectivity
1
(
Table 3) in favor of isomer with cis ring junction as determined by H NMR spectroscopy.
The ring transformation step involves the intramolecular nucleophilic substitution via
displacement of hydroxide occurs with inversion of configuration, which is supported by coupling
constant between Hꢀ6 and Hꢀ7 of synthesized compounds. In products 7, 8 and 14, 15, the rings are cis
fused as indicated by the coupling constants of ring junction protons 4aꢀH and 8aꢀH (J4a,8a=4.3ꢀ4.8
Hz). At cisꢀjunctions of compounds 7, 8, 14 and 15, 4aꢀH is equatorial and 8aꢀH is axial, as indicated by their
coupling constant (for example 14a; J4aH,8aH = 4.5 Hz, J and J8aH,8H = 7.5 Hz, Jtrans). The cis stereochemistry
cis
was also supported by NOE interaction experiments. For example, 11.1% and 12.4 NOEs were
observed between 4aꢀH and 8aꢀH in products 7a and 14a, respectively, indicating that the 4aꢀH and
8aꢀH are located on the same face of the molecule, hence confirming the cis fusion of the rings. The
chiral carbons of the precursor carbohydrates retain their configuration in the product if they are not
involved in any bond breaking/formation. The reactions were clean and all the synthesized products
1
13
were characterized by their H NMR, C NMR, IR and mass spectroscopic data.
The formation of iminoꢀ and thiosugar annulated 1,3ꢀthiazines 7,8 and 14,15 can be
rationalized by initial [bmim]OH catalyzed Knoevenagel condensation between Dꢀxylose or Dꢀ
glucose and masked acids 2 or 3 followed by Michael type addition of Nꢀaryldithiocarbamic acid 4 to
arylidenes 6 or 11 respectively, generated in situ, to afford the corresponding thiaꢀMichael adducts 10
or 12. These thiaꢀMichael adducts undergo intramolecular nucleophilic attack of the nitrogen atom of
the NHAr group of 4 at the carbonyl carbon (Cꢀ5) of the masked acid 2 or 3 to yield the target
compounds 7,8 (Scheme 4) and 14,15 (Scheme 5). This conclusion is based on the observation that
the representative intermediate compounds 9a (n=3, Ar=Ph) and 12a (n=3, Ar=Ph) could be isolated in
4
6% and 49% yield respectively, these could be converted into the corresponding thiazines 7a and 14a
in quantitative yields. Presumably, the ring transformation step is promoted by [bmim]OH owing to
6]
[

Page 7 of 21
the acidic character of Cꢀ2 proton of the imidazolium cation in the reaction by polarizing the carbonyl
group of the adduct 9 or 12, thereby enhancing the electrophilicity of the carbonyl carbon, which
facilitates the nucleophilic attack of the NHAr of 4. Furthermore, the imidazolium hydroxide perhaps
helps in increasing the nucleophilicity of 2 or 3 via formation of 2΄ or 3΄ (Scheme 6) while, in case of
ionic liquids with halide ion and other solvents, the mechanism seems to be operated via enol form of
the masked amino acid 1, stabilized by imidazolium moiety.
In conclusion, we report for the first time a general, efficient and green method for preparation of
synthetically and pharmaceutically important iminoꢀ and thiosugar annulated 1,3ꢀthiazines using Dꢀ
xyolose and Dꢀglucose, as bioꢀrenewable feedstock. The developed methodology opens up a
conceptually new aspect for sugar annulated 1,3ꢀthiazine chemistry and would be a good alternative to
the existing procedures for such fine chemicals to cater the need of industries and academia.
Experimental
Reagents were obtained from commercial suppliers, and used without further purification unless
otherwise specified by a reference. All reactions were performed using ovenꢀdried glassware. Melting
points were determined by open glass capillary method and are uncorrected. IR spectra in KBr were
1
recorded on a PerkinꢀElmer 993 IR spectrophotometer. H NMR spectra were recorded on a Bruker
1
3
WMꢀ40 C (400 MHz) FT spectrometer in DMSOꢀd ꢁD O using TMS as internal reference. C NMR
6
2
spectra were recorded on the same instrument at 100 MHz in DMSOꢀd and TMS was used as internal
6
reference. Mass (EI) spectra were recorded on a JEOL Dꢀ300 mass spectrometer. Elemental analyses
were carried out in a Coleman automatic carbon, hydrogen and nitrogen analyzer. A Chemical
Laboratory Microwave Oven (Model; BPꢀ310/50, 230 volt, 50 Hz power input) was used. All
chemicals used were reagent grade and were used as received without further purification. Silica gelꢀG
was used for TLC.
[7]

Page 8 of 21
General procedure for the synthesis of iminosugar annulated 1,3ꢀthiazines 7, 8 and thiosugar
annulated 1,3ꢀthiazines 14 and 15
A mixture of Dꢀxylose/Dꢀglucose 1 (5.0 mmol), 2ꢀmethylꢀ2ꢀphenylꢀ1,3ꢀoxathiolanꢀ5ꢀone 2
(
5.0 mmol) or 2ꢀphenylꢀ1,3ꢀoxazolanꢀ5ꢀone 3 (5.0 mmol), Nꢀaryldithiocarbamic acid 4 (5.0 mmol),
bmim]OH 5 (0.75 mmol) in 15 mL THF was stirred at room temperature for 6.5ꢀ8 h. After
[
completion of the reaction as indicated by TLC, the product was extracted with ether (3 × 15 mL). The
combined ether extracts were dried over anhydrous sodium sulfate and evaporated under reduced
pressure to leave the crude product, which was recrystallized from ethanol to afford a diastereomeric
mixture >94:<6 of 7, 8 or 14, 15 in favor of cis isomer (in the crude products, the ratio was >92:<8) as
1
determined by the H NMR spectroscopy (Table 3). The product on second recrystallization from
ethanol furnished an analytical pure sample of a single diastereomer 7, 8 or 14, 15. The cis
stereochemistry was assigned to 7, 8 or 14, 15, as the coupling constant (J3a,7a = 4.3–4.8 Hz) of the
major cis diastereomer was lower than that for minor trans diastereomer (J3a,7a = 11.4 Hz). After
isolation of the product, the remaining aqueous layer containing the ionic liquid was washed with ether
o
(
15 mL) to remove any organic impurity, dried under vacuum at 90 C to afford [Bmim]OH, which
was used in subsequest runs without further purification (Table 4).
Compound 7a: R (15% EtOAc/hexane) 0.52. IR (KBr) υmax 3351, 3325, 3011, 1685, 1605, 1584,
f
ꢀ1 1
1
455, 1055 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.17 (ddd, J
= 9.8 Hz, J6H,1'Ha = 6.3 Hz,
6
2
6H,7H
J6H,1'Hb = 3.2 Hz, 1 H, Hꢀ6), 3.49 (dd, J1'Ha,Hb = 11.2 Hz, J6H,1'Ha = 6.3 Hz, 1 H, Haꢀ1'), 3.78 (dd, J6H,7H
.8 Hz, J7H,8H = 9.1 Hz, 1 H, Hꢀ7), 3.92 (dd, J1'Ha,Hb = 11.2 Hz, J6H,1'Hb = 3.2 Hz, 1 H, Hbꢀ1'), 4.08 (dd,
J7H,8H = 9.1 Hz, J8H,8aH = 7.6 Hz, 1 H, Hꢀ8), 5.01 (dd, J8H,8aH = 7.6 Hz, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ8a),
=
9
13
6
.16 (dd, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ4a), 7.18ꢀ7.73 (m, 10 Harom). C NMR (DMSOꢀd /TMS) δ: 29.9,
6
48.7, 51.8, 63.5, 71.4, 83.1, 125.8, 126.9, 128.1, 129.3, 131.5, 132.1, 133.8, 134.5, 170.7, 173.8, 192.2.
[8]

Page 9 of 21
+
Mass (m/z): 445 (MH ). Anal. Calcd for C H N O S : C, 56.74; H, 4.53; N, 6.30%. Found: C, 56.99;
2
1
20
2
5 2
C, 4.31; N, 6.18%.
Compound 7b: R (15% EtOAc/hexane) 0.49. IR (KBr) υmax 3353, 3321, 3009, 1688, 1608, 1588,
f
ꢀ1 1
1
450, 1051 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.15 (ddd, J
= 9.8 Hz, J6H,1'Ha = 6.5 Hz,
6
2
6H,7H
J6H,1'Hb = 3.3 Hz, 1 H, Hꢀ6), 3.48 (dd, J1'Ha,Hb = 11.5 Hz, J6H,1'Ha = 6.5 Hz, 1 H, Haꢀ1'), 3.77(dd, J6H,7H
.8 Hz, J7H,8H = 9.3 Hz, 1 H, Hꢀ7), 3.94 (dd, J1'Ha,Hb = 11.5 Hz, J6H,1'Hb = 3.3 Hz, 1 H, Hbꢀ1'), 4.05 (dd,
J7H,8H = 9.3 Hz, J8H,8aH = 7.7 Hz, 1 H, Hꢀ8), 5.03 (dd, J8H,8aH = 7.7 Hz, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ8a),
=
9
1
3
6
.12 (dd, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ4a), 7.18ꢀ7.59 (m, 7 Harom), 7.63ꢀ7.85 (m, 2 Harom). C NMR
(
DMSOꢀd /TMS) δ: 31.2, 49.1, 51.5, 63.8, 71.5, 83.3, 126.5, 127.3, 128.2, 129.1, 129.8, 130.5, 131.3,
6
+
1
34.2, 170.2, 173.5, 192.1. Mass (m/z): 479 (MH ). Anal. Calcd for C H ClN O S : C, 52.66; C,
21
19
2
5 2
4.00; N, 5.85%. Found: C, 52.33; H, 4.17; N, 5.59%.
ꢀ1
1
Compound 7c: IR (KBr) υmax 3349, 3328, 3015, 1687, 1597, 1581, 1449, 1057 cm . H NMR
(
DMSOꢀd + D O/TMS) δ: 3.19 (ddd, J
= 9.7 Hz, J6H,1'Ha = 6.3 Hz, J6H,1'Hb = 3.1 Hz, 1 H, Hꢀ6),
6
2
6H,7H
3.45 (dd, J1'Ha,Hb = 11.8 Hz, J6H,1'Ha = 6.3 Hz, 1 H, Haꢀ1'), 3.69 (s, 3H, OMe), 3.79 (dd, J6H,7H = 9.7 Hz,
J7H,8H = 9.1 Hz, 1 H, Hꢀ7), 3.93 (dd, J1'Ha,Hb = 11.8 Hz, J6H,1'Hb = 3.1 Hz, 1 H, Hbꢀ1'), 4.09 (dd, J7H,8H
=
9.1 Hz, J8H,8aH = 7.5 Hz, 1 H, Hꢀ8), 5.02 (dd, J8H,8aH = 7.5 Hz, J4aH,8aH = 4.5 Hz, 1 H, Hꢀ8a), 6.15 (dd,
1
3
J4aH,8aH = 4.5 Hz, 1 H, Hꢀ4a), 7.17ꢀ7.81 (m, 9 Harom). C NMR (DMSOꢀd /TMS) δ: 30.5, 48.4, 51.3,
6
54.7, 63.1, 71.2, 83.9, 125.8, 126.6, 127.3, 128.1, 129.2, 130.1, 131.3, 133.9, 170.1, 173.9, 192.5.
+
Mass (m/z): 475 (MH ). Anal. Calcd for C H N O S : C, 55.68; H, 4.67; N, 5.90%. Found: C, 55.89;
2
2
22
2
6 2
C, 4.30; N, 6.21%.
Compound 8a: R (15% EtOAc/hexane) 0.47. IR (KBr) υmax 3357, 3320, 3019, 1688, 1605, 1585,
f
ꢀ1 1
1
455, 1055 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.21 (ddd, J
= 6.3 Hz, J1'H,2'Ha = 5.9 Hz,
6
2
6H,1'H
J1'H,2'Hb = 2.9 Hz, 1 H, Hꢀ1'), 3.32 (dd, J6H,7H = 9.9 Hz, J6H,1'H = 6.3 Hz, 1 H, Hꢀ6), 3.50 (dd, J2'Ha,Hb
=
[9]

Page 10 of 21
11.8 Hz, J6H,1'Ha = 5.9 Hz, 1 H, Haꢀ2'), 3.79 (dd, J6H,7H = 9.9 Hz, J7H,8H = 9.4 Hz, 1 H, Hꢀ7), 3.88 (dd,
J2'Ha,Hb = 11.8 Hz, J6H,1'Hb = 2.9 Hz, 1 H, Hbꢀ2'), 4.21 (dd, J7H,8H = 9.4 Hz, J8H,8aH = 7.3 Hz, 1 H, Hꢀ8),
4
7
1
.95 (dd, J8H,8aH = 7.3 Hz, J4aH,8aH = 4.8 Hz, 1 H, Hꢀ8a), 6.21 (dd, J4aH,8aH = 4.8 Hz, 1 H, Hꢀ4a), 7.02ꢀ
1
3
.69 (m, 10 Harom). C NMR (DMSOꢀd /TMS) δ: 30.3, 41.3, 51.3, 70.8, 72.1, 77.6, 85.5, 126.8, 127.6,
6
+
28.3, 129.3, 131.5, 132.6, 133.3, 134.9, 170.8, 173.1, 192.1. Mass (m/z): 475 (MH ). Anal. Calcd for
C H N O S : C, 55.68; H, 4.67; N, 5.90%. Found: C, 55.37; C, 4.81; N, 6.08%.
22
22
2
6 2
Compound 8b: R (15% EtOAc/hexane) 0.53. IR (KBr) υmax 351, 3319, 3011, 1683, 1608, 1588, 1451,
f
ꢀ1 1
1
051 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.20 (ddd, J
= 6.5 Hz, J1'H,2'Ha = 5.7 Hz, J1'H,2'Hb =
6
2
6H,1'H
3.1 Hz, 1 H, Hꢀ1'), 3.37 (dd, J6H,7H = 9.6 Hz, J6H,1'H = 6.5 Hz, 1 H, Hꢀ6), 3.53 (dd, J2'Ha,Hb = 12.0 Hz,
J6H,1'Ha = 5.7 Hz, 1 H, Haꢀ2'), 3.77 (dd, J6H,7H = 9.6 Hz, J7H,8H = 9.1 Hz, 1 H, Hꢀ7), 3.86 (dd, J2'Ha,Hb
2.0 Hz, J6H,1'Hb = 3.1 Hz, 1 H, Hbꢀ2'), 4.23 (dd, J7H,8H = 9.1 Hz, J8H,8aH = 7.1 Hz, 1 H, Hꢀ8), 4.93 (dd,
J8H,8aH = 7.1 Hz, J4aH,8aH = 4.7 Hz, 1 H, Hꢀ8a), 6.18 (dd, J4aH,8aH = 4.7 Hz, 1 H, Hꢀ4a), 7.13ꢀ7.65 (m, 7
=
1
1
3
Harom), 7.69ꢀ7.81 (m, 2 Harom). C NMR (DMSOꢀd /TMS) δ: 31.8, 41.0, 51.7, 70.3, 72.5, 77.0, 85.1,
6
+
1
25.2, 126.7, 127.5, 128.3, 128.9, 130.8, 131.6, 133.5, 170.7, 173.5, 192.1. Mass (m/z): 509 (MH ).
Anal. Calcd for C H ClN O S : C, 51.91; H, 4.16; N, 5.50%. Found: C, 51.59; C, 4.41; N, 5.23%.
2
2
21
2
6 2
Compound 8c: R (15% EtOAc/hexane) 0.56. IR (KBr) υmax 3349, 3323, 3009, 1685, 1601, 1581,
f
ꢀ1 1
1
459, 1058 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.24 (ddd, J
= 6.1 Hz, J1'H,2'Ha = 5.9 Hz,
6
2
6H,1'H
J1'H,2'Hb = 2.8 Hz, 1 H, Hꢀ1'), 3.31 (dd, J6H,7H = 9.8 Hz, J6H,1'H = 6.1 Hz, 1 H, Hꢀ6), 3.49 (dd, J2'Ha,Hb
=
11.9 Hz, J6H,1'Ha = 5.9 Hz, 1 H, Haꢀ2'), 3.69 (s, 3H, OMe), 3.78 (dd, J6H,7H = 9.8 Hz, J7H,8H = 9.5 Hz, 1
H, Hꢀ7), 3.85 (dd, J2'Ha,Hb = 11.9 Hz, J6H,1'Hb = 2.8 Hz, 1 H, Hbꢀ2'), 4.20 (dd, J7H,8H = 9.5 Hz, J8H,8aH
=
7.6 Hz, 1 H, Hꢀ8), 4.97 (dd, J8H,8aH = 7.6 Hz, J4aH,8aH = 4.7 Hz, 1 H, Hꢀ8a), 6.20 (dd, J4aH,8aH = 4.7 Hz, 1
1
3
H, Hꢀ4a), 7.11ꢀ7.81 (m, 9 Harom). C NMR (DMSOꢀd /TMS) δ: 32.2, 41.6, 51.1, 54.6, 70.1, 72.7,
6
77.3, 85.7, 127.8, 128.6, 129.5, 130.5, 131.8, 132.5, 133.9, 145.3, 170.2, 173.4, 192.8. Mass (m/z): 505
[10]

Page 11 of 21
+
(
MH ). Anal. Calcd for C H N O S : C, 54.75; H, 4.79; N, 5.55%. Found: C, 54.87; C, 4.65; N,
23 24 2 7 2
5.29%.
Compound 14a: R (15% EtOAc/hexane) 0.49. IR (KBr) υmax 3353, 3321, 3017, 1688, 1599, 1588,
f
ꢀ1 1
1
450, 1049 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.34 (ddd, J
= 9.7 Hz, J6H,1'Ha = 6.1 Hz,
6
2
6H,7H
J6H,1'Hb = 3.5 Hz, 1 H, Hꢀ6), 3.49 (dd, J1'Ha,Hb = 11.7 Hz, J6H,1'Ha = 6.1 Hz, 1 H, Haꢀ1'), 3.79 (dd, J6H,7H
.7 Hz, J7H,8H = 9.2 Hz, 1 H, Hꢀ7), 3.95 (dd, J1'Ha,Hb = 11.7 Hz, J6H,1'Hb = 3.5 Hz, 1 H, Hbꢀ1'), 4.06 (dd,
J7H,8H = 9.2 Hz, J8H,8aH = 7.5 Hz, 1 H, Hꢀ8), 5.05 (dd, J8H,8aH = 7.5 Hz, J4aH,8aH = 4.5 Hz, 1 H, Hꢀ8a),
=
9
13
6
.17 (dd, J4aH,8aH = 4.5 Hz, 1 H, Hꢀ4a), 7.09ꢀ7.76 (m, 5 Harom). C NMR (DMSOꢀd /TMS) δ: 26.5,
6
+
4
9.6, 50.9, 62.7, 77.4, 86.7, 127.9, 128.6, 129.4, 131.5, 170.2, 173.6, 192.8. Mass (m/z): 358 (MH ).
Anal. Calcd for C H NO S : C, 47.04; H, 4.23; N, 3.93%. Found: C, 46.72; C, 4.49; N, 4.27%.
1
4
15
4 3
Compound 14b: R (15% EtOAc/hexane) 0.51. IR (KBr) υmax 3357, 3319, 3021, 1691, 1605, 1591,
f
ꢀ1 1
1
448, 1055 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.38 (ddd, J
= 9.9 Hz, J6H,1'Ha = 6.2 Hz,
6
2
6H,7H
J6H,1'Hb = 3.4 Hz, 1 H, Hꢀ6), 3.47 (dd, J1'Ha,Hb = 11.3 Hz, J6H,1'Ha = 6.2 Hz, 1 H, Haꢀ1'), 3.82 (dd, J6H,7H
.9 Hz, J7H,8H = 9.5 Hz, 1 H, Hꢀ7), 3.92 (dd, J1'Ha,Hb = 11.3 Hz, J6H,1'Hb = 3.4 Hz, 1 H, Hbꢀ1'), 4.03 (dd,
J7H,8H = 9.5 Hz, J8H,8aH = 7.3 Hz, 1 H, Hꢀ8), 5.02 (dd, J8H,8aH = 4.5 Hz, J4aH,8aH = 7.3 Hz, 1 H, Hꢀ8a),
=
9
1
3
6
.13 (dd, J4aH,8aH = 4.5 Hz, 1 H, Hꢀ4a), 7.12ꢀ7.62 (m, 2 Harom), 7.71ꢀ7.79 (m, 2 Harom). C NMR
(
DMSOꢀd /TMS) δ: 26.1, 50.7, 51.3, 62.2, 77.0, 86.2, 126.8, 129.2, 130.1, 132.3, 135.2, 173.2, 192.3.
6
+
Mass (m/z): 392 (MH ). Anal. Calcd for C H ClNO S : C, 42.90; H, 3.60; N, 3.57%. Found: C,
14
14
4 3
43.27; C, 3.39; N, 3.72%.
Compound 14c: R (15% EtOAc/hexane) 0.55. IR (KBr) υmax 3352, 3327, 3013, 1683, 1601, 1585,
f
ꢀ1 1
1
458 and 1053 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.36 (ddd, J
= 9.7 Hz, J6H,1'Ha = 6.3 Hz,
6
2
6H,7H
J6H,1'Hb = 3.5 Hz, 1 H, Hꢀ6), 3.51 (dd, J1'Ha,Hb = 11.5 Hz, J6H,1'Ha = 6.3 Hz, 1 H, Haꢀ1'), 3.71 (s, 3H,
OMe), 3.81 (dd, J6H,7H = 9.7 Hz, J7H,8H = 9.1 Hz, 1 H, Hꢀ7), 3.94 (dd, J1'Ha,Hb = 11.5 Hz, J6H,1'Hb = 3.5
[11]

Page 12 of 21
Hz, 1 H, Hbꢀ1'), 4.08 (dd, J7H,8H = 9.1 Hz, J8H,8aH = 7.6 Hz, 1 H, Hꢀ8), 5.04 (dd, J8H,8aH = 7.6 Hz,
1
3
J4aH,8aH = 4.4 Hz, 1 H, Hꢀ8a), 6.16 (dd, J4aH,8aH = 4.4 Hz, 1 H, Hꢀ4a), 7.11ꢀ7.82 (m, 4 Harom). C NMR
(
DMSOꢀd /TMS) δ: 26.6, 50.2, 51.7, 54.4, 62.8, 77.6, 85.9, 125.1, 127.2, 128.8, 133.2, 173.5, 192.0.
6
+
Mass (m/z): 388 (MH ). Anal. Calcd for C H NO S : C, 46.49; H, 4.42; N, 3.61%. Found: C, 46.68;
1
5
17
5 3
H, 4.11; N, 3.24%.
Compound 15a: R (15% EtOAc/hexane) 0.51. IR (KBr) υ 3347, 3321, 3010, 1684, 1599, 1583,
f
max
ꢀ1 1
1
458, 1057 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.29 (ddd, J
= 6.7 Hz, J1'H,2'Ha = 5.5 Hz,
6
2
6H,1'H
J1'H,2'Hb = 2.6 Hz, 1 H, Hꢀ1'), 3.46 (dd, J6H,7H = 9.9 Hz, J6H,1'H = 6.7 Hz, 1 H, Hꢀ6), 3.57 (dd, J2'Ha,Hb
1.8 Hz, J6H,1'Ha = 5.5 Hz, 1 H, Haꢀ2'), 3.81 (dd, J6H,7H = 9.9 Hz, J7H,8H = 9.2 Hz, 1 H, Hꢀ7), 3.91 (dd,
J2'Ha,Hb = 11.8 Hz, J6H,1'Hb = 2.6 Hz, 1 H, Hbꢀ2'), 4.28 (dd, J7H,8H = 9.2 Hz, J8H,8aH = 7.2 Hz, 1 H, Hꢀ8),
=
1
5.01 (dd, J8H,8aH = 7.2 Hz, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ8a), 6.25 (dd, J4aH,8aH = 4.3 Hz, 1 H, Hꢀ4a), 7.09ꢀ
1
3
7
.69 (m, 5 Harom). C NMR (DMSOꢀd /TMS) δ: 33.1, 41.8, 51.8, 70.4, 72.3, 77.2, 85.9, 126.3, 129.2,
6
+
1
31.8, 134.5, 173.9, 192.5. Mass (m/z): 388 (MH ). Anal. Calcd for C H NO S : C, 46.49; H, 4.42;
15
17
5 3
N, 3.61%. Found: C, 46.73; C, 4.29; N, 3.89%.
Compound 15b: R (15% EtOAc/hexane) 0.56. IR (KBr) υ 3353, 3320, 3013, 1687, 1605, 1587,
f
max
ꢀ1 1
1
450, 1053 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.31 (ddd, J
= 6.3 Hz, J1'H,2'Ha = 5.8 Hz,
6
2
6H,1'H
J1'H,2'Hb = 2.9 Hz, 1 H, Hꢀ1'), 3.49 (dd, J6H,7H = 9.8 Hz, J6H,1'H = 6.3 Hz, 1 H, Hꢀ6), 3.53 (dd, J2'Ha,Hb
1.6 Hz, J6H,1'Ha = 5.8 Hz, 1 H, Haꢀ2'), 3.86 (dd, J6H,7H = 9.8 Hz, J7H,8H = 9.1 Hz, 1 H, Hꢀ7), 3.89 (dd,
J2'Ha,Hb = 11.6 Hz, J6H,1'Hb = 2.9 Hz, 1 H, Hbꢀ2'), 4.25 (dd, J7H,8H = 9.1 Hz, J8H,8aH = 7.6 Hz, 1 H, Hꢀ8),
=
1
4
7
7
.99 (dd, J8H,8aH = 7.6 Hz, J4aH,8aH = 4.1 Hz, 1 H, Hꢀ8a), 6.21 (dd, J4aH,8aH = 4.1 Hz, 1 H, Hꢀ4a), 7.18ꢀ
1
3
.61 (m, 2 Harom), 7.71ꢀ7.83 (m, 2 Harom). C NMR (DMSOꢀd /TMS) δ: 33.5, 41.3, 51.5, 70.9, 72.9,
6
+
7.5, 85.2, 126.5, 127.9, 133.8, 134.6, 173.2, 192.6. Mass (m/z): 422 (MH ). Anal. Calcd for
C H ClNO S : C, 42.70; H, 3.82; N, 3.32%. Found: C, 42.59; C, 3.91; N, 3.61%.
15
16
5 3
[12]

Page 13 of 21
Compound 15c: R (15% EtOAc/hexane) 0.46. IR (KBr) υmax 3350, 3318, 3017, 1681, 1601, 1580,
f
ꢀ1 1
1
455, 1051 cm . H NMR (DMSOꢀd + D O/TMS) δ: 3.28 (ddd, J
= 6.4 Hz, J1'H,2'Ha = 5.3 Hz,
6
2
6H,1'H
J1'H,2'Hb = 2.8 Hz, 1 H, Hꢀ1'), 3.43 (dd, J6H,7H = 9.7 Hz, J6H,1'H = 6.4 Hz, 1 H, Hꢀ6), 3.58 (dd, J2'Ha,Hb
=
11.9 Hz, J6H,1'Ha = 5.3 Hz, 1 H, Haꢀ2'), 3.67 (s, 3H, OMe), 3.88 (dd, J6H,7H = 9.7 Hz, J7H,8H = 9.3 Hz, 1
H, Hꢀ7), 3.85 (dd, J2'Ha,Hb = 11.9 Hz, J6H,1'Hb = 2.8 Hz, 1 H, Hbꢀ2'), 4.29 (dd, J7H,8H = 9.3 Hz, J8H,8aH
=
7.5 Hz, 1 H, Hꢀ8), 4.96 (dd, J8H,8aH = 7.5 Hz, J4aH,8aH = 4.4 Hz, 1 H, Hꢀ8a), 6.22 (dd, J4aH,8aH = 4.4 Hz, 1
1
3
H, Hꢀ4a), 7.03ꢀ7.81 (m, 4 Harom). C NMR (DMSOꢀd /TMS) δ: 32.9, 41.7, 51.2, 54.3, 70.6, 72.6,
6
+
7
7.8, 85.3, 126.8, 128.4, 130.5, 134.5, 173.5, 192.9. Mass (m/z): 418 (MH ). Anal. Calcd for
C H NO S : C, 46.03; H, 4.59; N, 3.35%. Found: C, 46.31; C, 4.29; N, 3.21%.
16
19
6 3
Procedure for isolation of intermediate 9a (n=3, Ar=Ph) and 12a (n=3, Ar=Ph) and their
cyclization into corresponding thiazines 7a and 14a.
The procedure followed was the same as described above for the synthesis of 7a and 14a except that
the time of stirring in this case was 4.5 h instead of 8h for 7a and 7.5 h for 14b. The adducts 9a and
1
2a were purified by silica gel column chromatography (hexaneꢀEtOAc, 8:2) to obtain an analytical
pure sample of 9a and 12a in 46% and 49% yields respectively. A mixture of intermediates 9a or 12a
2.0 mmol) and [bmim]OH 5 (0.30 mmol) in 10 mL THF was stirred at room temperature for next 4h
(
to give the corresponding product 7a and 14a quantitatively and was isolated and purified in the same
way as described above for the compounds 7a and 14a. The ionic liquid [bmim]OH was also
recovered by following the same procedure as described in case of above compounds 7a and 14a.
ꢀ1 1
Compound 9a: IR (KBr) υmax 3348, 3018, 1770, 1605, 1588, 1455, 1058 cm . H NMR (DMSOꢀd +
6
D O/TMS) δ: 3.48 (dd, J
2
2'H, 3'H
= 4.3 Hz, J1'H, 2'H = 6.8 Hz, 1 H, Hꢀ2'), 3.59 (ddd, J2'H, 3'H = 4.3 Hz, J3'H,
=
5.8 Hz, J3'H, 4'Hb = 3.1 Hz, 1 H, Hꢀ3'), 3.73 (dd, J3'H, 4'Ha = 5.8 Hz, J4'Ha, 4'Hb = 10.6 Hz, 1 H, Haꢀ4'),
.98 (dd, JNCH,SCH = 4.2 Hz, JSCH,1'H = 5.5 Hz, 1 H, SCH), 4.09 (dd, J1'H, 2'H = 6.8 Hz, J1'H, SCH = 5.5 Hz,
4
'Ha
3
[13]

Page 14 of 21
1
H, Hꢀ1'), 4.27 (dd, J3'H, 4'Hb = 3.1 Hz, J4'Ha, 4'Hb = 10.6 Hz, 1 H, Hbꢀ4'), 5.81 (d, JNCH,SCH = 4.2 Hz, 1 H,
1
3
NCH), 7.13–7.71 (m, 10 Harom). C NMR (DMSOꢀd /TMS) δ: 38.7, 52.3, 67.5, 70.2, 71.8, 74.4, 92.4,
6
+
1
25.1, 126.2, 127.9, 128.8, 129.5, 130.2, 135.9, 138.3, 173.9, 192.5. Mass (m/z): 463 (MH ). Anal.
Calcd for C H N O S : C, 54.53; H, 4.79; N, 6.06%. Found: C, 54.81; C, 4.47; N, 6.28%.
2
1
22
2
6 2
ꢀ1 1
Compound 12a: IR (KBr) υmax 3351, 3013, 1773, 1601, 1585, 1451, 1053 cm . H NMR (DMSOꢀd +
6
2
D O/TMS) δ: 2.26 (s, 3 H, Me), 3.43 (dd, J2'H, 3'H = 4.1 Hz, J1'H, 2'H = 6.4 Hz, 1 H, Hꢀ2'), 3.56 (ddd, J2'H,
=
4.1 Hz, J3'H, 4'Ha = 5.8 Hz, J3'H, 4'Hb = 2.9 Hz, 1 H, Hꢀ3'), 3.79 (dd, J3'H, 4'Ha = 5.8 Hz, J4'Ha, 4'Hb = 10.9
Hz, 1 H, Haꢀ4'), 3.88 (dd, J1'H, 2'H = 6.4 Hz, J SCHacyclic,1'H = 5.5 Hz, 1 H, Hꢀ1'), 3.97 (dd, JSCHcyclic,
3
'H
=
4.4 Hz, J SCHacyclic,1'H = 5.5 Hz, 1 H, SCHacyclic), 4.09 (dd, J3'H, 4'Hb = 2.9 Hz, J4'Ha, 4'Hb = 10.9
SCHacyclic
1
3
Hz, 1 H, Hbꢀ4'), 4.27 (d, JSCHcyclic, SCHacyclic = 4.4 Hz, 1 H, SCHcyclic), 7.07–7.83 (m, 10 Harom). C
NMR (DMSOꢀd /TMS) δ: 23.1, 38.5, 62.7, 68.1, 70.5, 72.2, 73.9, 125.5, 126.7, 128.3, 129.0, 130.5,
6
+
1
31.5, 132.2, 139.3, 168.1, 171.8 and 192.2. Mass (m/z): 496 (MH ). Anal. Calcd for C H NO S : C,
2
2
25
6 3
53.31; H, 5.08; N, 2.83%. Found: C, 53.07; C, 5.21; N, 3.17%.
Acknowledgements
We sincerely thank the CSIR, New Delhi (01(2441ꢁ10ꢁEMRꢀII) for financial support. We are also
thankful to Prof. J. S. Dangi, Pharmacy Institute, Guru Ghasidas Vishwavidyalaya, for providing
necessary facilities during the work.
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Horvath, S. J. Carbohydr. Res., 1983, 113, 166–171.
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Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
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(a) Nishimura,Y. In Studies in Natural Products Chemistry; AttaꢀurꢀRahman, Ed.; Elsevier
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P.; Dennis, J. W. Clin. Cancer. Res., 1995, 1, 935.
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(a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. M.; Begovic, M. E.;
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Diabetes, 1991, 40, 825.
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(a) Patel, H. S.; Patel, N. P. Orient. J. Chem., 1997, 13, 69–72, (b) Madkour, H. M. F.; Salem,
M. A. I.; Soliman, E. A.; Mahmoud, N. F. H. Phosphorus, Sulfur Silicon Relat. Elem., 2001,
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70, 15–27.
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Ingarsal, N.; Amutha, P.; Nagarajan, S. J. Sulfur Chem., 2006, 27, 455–459.
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(a) Bózsing, D.; Sohár, P.; Gigler, G.; Kovács, G. Eur. J. Med. Chem., 1996, 31, 663–671, (b)
Tozkoparan, B; Aktay, G.; Yeilada, E. Il Farmaco, 2002, 57, 145–152.
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(a) Rai, V. K.; Rai, P. K.; Bajaj, S.; Kumar, A. Green Chem., 2011, 13, 1217ꢀ1223. (b) Rai, V.
K.; Sharma, R.; Kumar, A. Tetrahedron Lett., 2013, 54, 1071ꢀ1075. (c) Rai, V. K.; Sharma, N.;
Kumar, A. Synlett, 2013, 24, 97ꢀ101. (d) Rai, V. K.; Rai, P. K.; Thakur, Y. Tetrahedron Lett.,
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013, 54, 6469–6473.
1
(a) Rai, V. K.; Sahu, G. P.; Rai, A. Tetrahedron Lett., 2015, 56, 2664–2668. (b) Yadav, L. D.
S.; Patel, R.; Rai, V. K.; Srivastava, V. P. Tetrahedron Lett., 2007, 48, 7793–7795.
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(a) Noshio, T.; Konno, Y.; Ori, M.; Sakamoto, M. Eur. J. Org. Chem., 2001, 3533–3537, (b)
Koketsu, M.; Tanaka, K.; Takenaka, Y.; Kwong, C. D.; Ishihara, H. Eur. J. Pharm. Sci., 2002,
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5, 307–310, (c) Murai, T.; Niwa, H.; Kimura, T.; Shibahara, F. Chem. Lett., 2004, 33, 508–
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09, (d) Yadav, L. D. S.; Singh, A. Tetrahedron Lett., 2004, 44, 5637–5640, (e) Huang, S.;
Pan, Y.; Zhu, Y.; Wu, A. Org. Lett., 2005, 7, 3797–3799, (f) Rasˇovic´, A.; Steel, P. J.;
Kleinpeter, E.; Markovic´, R. Tetrahedron, 2007, 63, 1937–1945.
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Yadav, L. D. S.; Rai, V. K.; Yadav, B. S. Tetrahedron, 2009, 65, 1306–1315.
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[16]

Page 17 of 21
Table 1. Optimization of reaction conditions for the formation of representative compound 7a
a
b
Entry Catalyst (mol %)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
[Bmim]Br (15)
[Bmim]Cl (15)
CH CN
8
8
8
8
8
52
46
49
34
59
56
74
88
92
82
85
72
78
93
3
CH CN
3
[Bmim]PF (15)
CH CN
6
3
[Bmim]Br (15)
[Bmim]Br (15)
[Bmim]Br (15)
[Emim]OH (15)
[Mpim]OH (15)
[Bmim]OH (15)
[Bmim]OH (15)
[Bmim]OH (15)
[Bmim]OH (15)
[Bmim]OH (10)
[Bmim]OH (20)
ꢀ
MeOH
THF
1,4ꢀDioxane 8
THF
THF
THF
8
8
8
8
0
1
2
3
4
5
CH CN
3
1,4ꢀDioxane 8
MeOH
THF
8
10
8
THF
THF
10
a
o
Time for completion of reaction at 90 C (indicated by TLC).
b
Yield of isolated and purified product 7a.
[17]

Page 18 of 21
Table 2 MW assisted synthesis of 7a.
Entry
Catalyst System
MW
a
b,c
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
CeCl .7 H O
15
13
12
18
20
20
20
43
51
57
24
11
17
3
2
CeCl .7 H O/NaI
3
2
Kꢀ10 clay
Silica gel
Neutral alumina
Acidic alumina
Basic alumina
–
20
–
a
b
c
o
Time for completion of the reaction at 90 C.
Yield of isolated and purified product 7a.
1
13
The product 7a was characterized by IR, H NMR, C NMR and EIMS data.
[18]

Page 19 of 21
Table 3 Oneꢀstep synthesis of iminoꢀ/ and thiosugar annulated 1,3ꢀthiazines 7, 8 and 14 and 15.
a
b,c
d
Entry
Product
7a
Time (h)
Ar
Ph
X
Yield (%)
93
cis:trans ratio
97:03
1
2
3
4
5
6
7
8
9
8
NCOPh
7b
6.5
8
4ꢀClC H
6
4
NCOPh
93
95:05
7c
4ꢀMeOC H
6
4
4
4
4
NCOPh
84
98:02
8a
8
Ph
NCOPh
88
95:05
8b
7.5
8
4ꢀClC H
6
4
NCOPh
91
95:05
8c
4ꢀMeOC H
6
NCOPh
89
97:03
14a
14b
14c
15a
15b
15c
7.5
8
Ph
S
S
S
S
S
S
91
95:05
4ꢀClC H
93
96:04
6
4
8
4ꢀMeOC H
90
98:02
6
10
11
12
6.5
7.5
7.5
Ph
90
98:02
4ꢀClC H
91
95:05
6
4
4ꢀMeOC H
90
97:03
6
a
b
c
1
Stirring time at room temperature.
Yield of isolated and purified products.
1
All compounds gave C, H and N analyses within ± 0.37%, and satisfactory spectral (IR, H NMR,
3
C NMR and EIMS) data.
Table 4 Recyclability of TSIL.
Table 3, Entry 1 Run 1
Run 2
93
Run 3
92
Run 4
92
Run 5
91
Yield (%)
93
[19]

Page 20 of 21
N
OH
OH OH
HO
O
H
Ph
Ph
O
O
N
7
N
8
OH
H
S
OH
H
2
OH
6
CHOH n
5
5
8a
OH X
or
S
X
H
O
CH OH
ArHN
SH
S
2
1S
a
and
4
THF, r.t.
H
O
n = 3,4
4
3
4
2
N
S
N
S
1
O
Ar
Ar
O
Me
8
1
, X = NCOPh
5, X = S
3
7, X = NCOPh
4, X = S
1
Scheme 1 Synthesis of iminoꢀ/ and thiosugar annulated 1,3ꢀthiazines.
OH
OH
OH
HO
O
H
OH
S
OH
S
N
S
S
NHAr
SH
HO
3CC
Me
Ph
or
X
CHOH 3
HX
Ph
O
O
O
O
CH OH
2
Masked
mercapto acid
Masked
amino acid
O
N
S
O
N
S
Ar
Ar
X = S , NCOPh
Scheme 2 Retroꢀsynthetic scheme for the target compounds.
S
O
Ph
LIBr
H O
HSCH COOH
O
2
Me
O
-
Ph
Me
2
3
1
5
Scheme 3 Formation of masked mercapto acid 3.
CH OH
CH OH
2
2
OH
OH
CHOH n
CHOH n
N
S
H
H
O
H
H
S
S
H
S
S
Ph
O
O
HS
NHAr
N
2
OH
NH
CHOH n
N
N
Ar
NHAr
CH OH
4
Ph
O
δ
2
N
δ
O
N
Ph
O
O
O
9
OH
1
OH
6
O
5
δ
H
Ph
n = 3,4
δ
H
THF, r. t.
10, n = 3
N
N
N
N
OH
OH
OH
OH
H
H
OH
cyclodehydration
OH
S
S
cyclodehydration
H O
S
S
10
n = 4
;
N
N
-H O
2
OH
-
OH
OH
N
2
N
N
Ar
5
Ar
N
OH
H
H
O
O
O
O
Ph
Ph
7
8
[20]

Page 21 of 21
Scheme 4 Plausible mechanism for the formation of iminosugar annulated 1,3ꢀthiazines 7 and 8.
CH OH
2
CH OH
2
CHOH n
CHOH n
S
S
Me
Ph
H
O
H
S
S
S
O
H
HS
NHAr
O
Me
Ph
3
CHOH n
S
NHAr
Me
Ph
Oδ
-PhCOMe
4
O
CH OH
δ
12
2
N
N
O
O
1
OH
11
δ
H
5
n = 3,4
δ
H
THF,r. t.
N
N
N
N
OH
OH
OH
OH
OH
OH
H
H
H
H
OH
OH
H
S
S
OH
OH
OH
S
S
S
S
OH
S
S
OH
SH
-
H O
OH
SH
N
2
N
N
Ar
-
H O
2
OH
OH
N
Ar
S
Ar
OH
S
H
O
15
Ar
H
H
O
O
O
;
1
4
OH
13, n = 3
13, n = 4
Scheme 5 Plausible mechanism for the formation of thiosugar annulated 1,3ꢀthiazines 14 and 15.
N
N
O
Ph
O
O
Ph
O
O
2
'
2
N
N
OH
OH
S
S
Me
Me
O
O
O
Ph
Ph
3
N
3'
N
Scheme 6 Role of [bmim]OH in Knoevenagel condensation.
[21]