Basic Ionic Liquid Promoted Domino Knoevenagel–Thia-Michael Reaction: An Efficient and Multicomponent Strategy for Synthesis of 1,3-Thiazines

Article abstract of DOI:10.1002/jhet.2379

An efficient, three-component strategy for synthesis of 1,3-thiazines with high atom economy in one-pot mediated by room temperature basic ionic liquid is described here. The strategy involves basic ionic liquid, [bmim]OH-catalyzed Knoevenagel condensatio

Full text of DOI:10.1002/jhet.2379

Month 2015
Basic Ionic Liquid Promoted Domino Knoevenagel–Thia-Michael
Reaction: An Efficient and Multicomponent Strategy for Synthesis
of 1,3-Thiazines
*
I. R. Siddiqui, Rahila, Shayna Shamim, Pragati Rai, Shireen, Malik A. Waseem, Arjita Srivastava,
and Anjali Srivastava
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
*
E-mail: dr.irsiddiqui@gmail.com
Received August 11, 2014
DOI 10.1002/jhet.2379
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, three-component strategy for synthesis of 1,3-thiazines with high atom economy in one-pot
mediated by room temperature basic ionic liquid is described here. The strategy involves basic ionic liquid,
[bmim]OH-catalyzed Knoevenagel condensation between ethyl cyanoacetate and aromatic aldehyde and
subsequent thia-Michael addition with substituted thioureas. The reaction sequence is smooth and quantita-
tive under ambient temperature. [bmim]OH was recovered and reused four times without any appreciable
decrease in its reactivity and product yield.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
maintain great importance in organic and medicinal
chemistry as a result of synthetic efficiency and molecular
diversity required in the discovery of new lead com-
pounds [19].
1,3-Thiazines constitute an important class of com-
pounds possessing diverse biological activities such as
antibacterial, insecticidal, fungicidal, antitumor, antioxi-
dant, antipyretic, and calcium channel modulator [1]. In
addition, it is the active core of cephalosporins that are
among the widely used β-lactam antibiotics [2] and are
also known as antiradiation agents and used as radiation
sickness drugs [3].
In addition, ionic liquids (ILs), have received substan-
tial interest from the synthetic community owing to their
properties like negligible vapor pressure, lack of flamma-
bility, wide solvation ability, and high stability. ILs are
also associated with enhancement of yields, increase in
chemoselectivity, regioselectivity, and stereoselectivity,
easy recovery and reuse [4–12]. The basic IL [bmim]
OH has been successfully applied to catalyze
Knoevenagel condensations of aliphatic and aromatic car-
bonyl compounds [13] as well as Michael additions of
active methylene compounds to conjugated ketones, car-
boxylic esters, and nitriles [14]. It has very successfully
replaced conventional bases as it is flexible, non-volatile
and non-corrosive.
Although number of protocols are reported for formation
of 1,3-thiazines [20] but except very few, all of them in-
volves volatile organic solvents, number of steps, low
yield, high temperature, longer reaction time etc. Thus,
there is still need to develop simple, clean eco-efficient
method that offers wider flexibility with maximum func-
tional group tolerating ability. Buoyed from the previous
facts and as part of our ongoing program aimed at the de-
velopment of simple, efficient, eco-compatible protocols
for the synthesis of biodynamic heterocyclic scaffolds
[21], we report herein an efficient synthesis of 1,3-thiazines
mediated by tailor made, task-specific, room temperature
basic ionic liquid (RTBIL), [bmim]OH (Scheme 1).
RESULTS AND DISCUSSION
Based on our progressive endeavors in exploring novel
and practical multicomponent reactions to synthesize bio-
dynamic heterocyclic compounds, we present, herein, the
result of a novel three-component RTBIL-mediated cas-
cade reaction for the efficient synthesis of 1,3-thiazines.
To find the best reaction condition for the synthesis of
1,3-thiazines, thiophene-2-carboxaldehyde 1a, ethyl
cyanoacetate 2 and N-allylthiourea 3b were selected as
model reactants. The reaction condition was optimized
using different solvent as well as bases. Of the bases tested,
Knoevenagel condensation followed by hetero-Michael
addition has considerably attracted attention as a versatile,
expeditious and cost-effective strategy for synthesis of
heterocycles for drug discovery process [15–18]. Multi-
component reactions in which three or more reactants
are combined in a single vessel to generate new molecule
that contain portions of each reactants undoubtedly
© 2015 HeteroCorporation

I. R. Siddiqui, Rahila, S. Sharmim, P. Rai, Shireen, M. A. Waseem, A. Srivastava, and A. Srivastava Vol 000
Scheme 1. RTBIL-mediated one-pot synthesis of 1,3-thiazines.
Table 1
Optimization of reaction condition for the synthesis of 1,3-thiazine in one-pota.
Entry
Solvent
Ethanol
THF
Acetone
Acetonitrile
Ethanol
Ethanol
[bmim]OH (15)
[bmim]Cl (15)
[bmim]Br (15)
Base (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
NaOH (10)
NaOH (10)
NaOH (10)
NaOH (10)
Et3N (10)
K2CO3 (10)
—
1
1
1
1
1
1
1
2
2
55
30
35
45
35
30
88
32
36
—
—
aReaction conditions: 5.5 mmol thiophene-2-carboxaldehyde, 5 mmol ethyl cyanoacetate, 5 mmol thiourea.
bYield of isolated and purified product.
NaOH was found to be the best base, and with respect to
the solvent-base system, the best results were achieved
using ethanol and NaOH (Table 1, entry 1). In order to
make the synthesis more eco-friendly and from the reports
of ILs in organic transformation, a three-component reac-
tion was performed using different ILs without any inor-
ganic base in one-pot.
It can be inferred from Table 1 that the result of reaction
for the synthesis of 1,3-thiazines in one-pot using different
ILs as base as well as reaction media favor for use of
[bmim]OH because the yield of product was excellent. It
was also observed from the table that the reaction of alde-
hyde with ethyl cyano acetate and thiourea that are easily
achieved by [bmim]OH, proceeded to very small extent
under the catalysis of [bmim]Cl or [bmim]Br. This shows
the vital role of the hydroxyl counter ion of this RTBIL
in this transformation. The yield observed in case of
[bmim]Br and [bmim]Cl might be because of the possibil-
ity of charged and polar intermediates in the reaction path-
ways, and it is reasonable to envisage ion-pairing
formation of those species with ionic components (cations
and anions) [22].
With [bmim]OH as the best promoter, we next
intended to optimize its amount, necessary enough to fur-
nish the desired product in maximum yield 4a. We ana-
lyzed the reaction by varying the loading amount to 5,
10, 15, 20 and 25mol% of [bmim]OH, and the results
are summarized in Table 2. The optimum loading amount
of [bmim]OH was found to be 15mol% (entry 3), as no
improvement in the yield was observed on increasing
the loading amount to 20 and 25 mol% (entries 4 and
5). Whereas, when the amount of [bmim]OH was 5 or
10mol%, the yield observed was drastically low (entries
1 and 2). Reaction efficiency was also investigated by
varying the reaction temperatures. The results demon-
strated that the reaction proceeds smoothly at 60°C; in-
creasing the reaction temperature to 70°C (entry 6) had
no effect in the yield, while on decreasing the reaction
temperature to 50°C, yield of the product 4a reduces
(entry 7). At room temperature, the reaction took longer
time and furnished the product in low yield (entry 8).
Finally, the reaction time was investigated, the desired
product was obtained in good yield in 1h stirring time, on
decreasing reaction time the yield obtained was relatively
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Basic Ionic Liquid Promoted Domino Knoevenagel–Thia-Michael Reaction: An
Efficient and Multicomponent Strategy for Synthesis of 1,3-Thiazines
Table 2
[bmim]OH-mediated three-component synthesis of 1,3-thiazine in one-pota.
Entry
[bmim]OH (mol %)
Time (h)
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
5
10
15
20
25
15
15
15
15
15
1
1
1
1
1
1
1
2
60
60
60
60
60
70
50
rt
53
61
88
88
88
88
65
38
60
88
0.5
2
60
60
aReaction conditions: 5.5 mmol thiophene-2-carboxaldehyde, 5 mmol ethyl cyano acetate,5 mmol thiourea.
bYield of isolated and purified product.
low (entry 9), and no change was observed in the product
yield when stirring time was increased from 1.5 to 2h
(entry 10). Thus, the optimized set of conditions for the
synthesis of 1,3-thiazine in one-pot was achieved
employing 15mol% of [bmim]OH as promoter, 1h stirring
time at 60°C.
After having the optimized set of conditions in hand, we
were set about evaluating the scope of this new protocol by
using various aromatic aldehydes, ethyl cyanoacetate and
substituted thioureas. The results of this study are summa-
rized in Table 3.
of 1,3-thiazines, the methodology presented herein pro-
vides a novel, convenient, efficient, eco-compatible and
cost effective access to a wide variety of 1,3-thiazines.
After the successful application of 15mol% of [bmim]
OH in promoting the reaction, we addressed the issue of
its recyclability. [bmim]OH was recovered and reused four
times without any appreciable decrease in its activity and
yield of the product (Fig. 1).
First recycled [bmim]OH gave no product loss, and only
3, 3 and 5% product loss occurred after second, third, and
fourth recycling. The IL remained intact as evidenced by
1H NMR.
A wide range of aromatic aldehydes underwent conden-
sation with active methylene compound ethyl cyano
acetate and N-substituted thioureas by this procedure in
one-pot in the presence of [bmim]OH yielding corres-
ponding 1,3-thiazines. All of the reactions proceeded
smoothly under the optimal conditions, affording annulated
products with good to excellent yields. Aldehydes having
both electron-donating and electron-withdrawing substitu-
ents that were well tolerated, providing the desired prod-
ucts. However, those with electron-donating substituent
offered the products with slightly lower yields and took
longer to form the respective products (Table 3, entries 6
and 7). In addition, thioureas with different substituents
(3a, b) worked well. Heteroaromatic aldehydes such as
thiophene-2-carboxaldehyde and furan-2-carbaldehyde
(entries 1, 2, 9, and 10) also underwent smooth condensa-
tion. Thus, the IL [bmim]OH efficiently promoted the reac-
tion as base as well as acted as alternative reaction media.
Compared with other reported methods for the preparation
On the basis of previous observations, a mechanistic
sequence is proposed for this [bmim]OH-catalyzed reac-
tion. The strategy involves formation of intermediate I
from Knoevenagel condensation between aromatic alde-
hyde and enolate ion of ethyl cyanoacetate. The activated
olefinic group of intermediate ethyl 2-cyano-3-phenyl
acrylate acted as acceptor in nucleophilic conjugate addi-
tion with thiourea effecting on thia-Michael addition.
Hetero-Michael product II on subsequent dehydrative
intramolecular nucleophilic addition yielded 2-amino-4-
ethoxy-6-phenyl-6H-1,3-thiazine-5-carbonitrile (Scheme 2).
CONCLUSIONS
In conclusion, the present procedure using RTBIL
[bmim]OH provides an efficient and convenient method
for the three-component domino reaction of aldehydes,
ethyl cyanoacetate and thioureas without the requirement
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. R. Siddiqui, Rahila, S. Sharmim, P. Rai, Shireen, M. A. Waseem, A. Srivastava, and A. Srivastava Vol 000
Table 3
RTBIL-mediated three-component synthesis of 1,3-thiazinesa.
Entry
1(a–f)
3(a–b)
Product 4(a–l)
Time (h)
Yield (%)b
1
1
84
2
3
1
1
86
76
4
5
6
1
77
76
78
1.5
1.5
(Continues)
Journal of Heterocyclic Chemistry
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Basic Ionic Liquid Promoted Domino Knoevenagel–Thia-Michael Reaction: An
Efficient and Multicomponent Strategy for Synthesis of 1,3-Thiazines
Table 3
(Continued)
7
1
85
8
1
86
9
1
1
80
82
10
11
1
87
12
1
88
aReaction conditions: 5.5 mmol aldehyde, 5 mmol ethyl cyano acetate, 5 mmol thiourea mixed in 15 mol% [bmim]OH stirred at 60°C for 1–1.5 h.
bYield of isolated and purified product.
EXPERIMENTAL
Materials and method. All chemicals were used as
of any other inorganic base, catalyst and additional solvent.
The efficiency, simplicity and milder reaction conditions of
the protocol are the additional attributes in the context of
green chemistry. In addition, general applicability and
avoidance of hazardous organic solvent and toxic catalysts,
excellent yield of products with high selectivity, makes the
protocol preferable for the synthesis of 1,3-thiazines and
other related biodynamic heterocyclic scaffolds.
received without further purification. NMR spectra were
recorded on a Bruker Avance DPX-400 FT Spectrophotometer
1
(400 MHz for H NMR, 100 MHz for 13C NMR) using CDCl3
as solvent and TMS as internal reference. Mass spectra were
recorded on a JEOL SX-102(FAB) mass spectrophotometer at
70 ev. Elemental analyses were carried out in Coleman
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. R. Siddiqui, Rahila, S. Sharmim, P. Rai, Shireen, M. A. Waseem, A. Srivastava, and A. Srivastava Vol 000
reaction, 20 mL of water was added and stirred well. The
product was extracted with EtOAc (3 × 20 mL). The residue
was purified by silica gel (mesh 60–120) chromatography
(hexane–EtOAc) to afford the analytically pure compound 4 in
88% yield. After isolation of the product, the remaining
aqueous layer containing the IL was washed with (C2H5)2O
(2 × 10 mL), to remove organic impurity and filtered. The
filtrate was extracted with CH2Cl2 (2 × 10 mL), dried over
MgSO4 and evaporated under reduced pressure to afford
[bmim]OH, which was reused four times.
Characteristic data of products. 4a. 4-Ethoxy-2-methylamino-
6-thiophen-2-yl-6H-[1,3]thiazine-5-carbonitrile.
Yellowish
solid; IR (KBr, cmÀ1): νmax = 3370, 3332, 3079, 3032, 2225,
1
1645, 1540, 1460, 1375, 1045; H NMR (CDCl3, 400 MHz): δ
7.12–6.80 (m, 3Harom), 8.21 (br s, 1H, NH), 4.80 (s, 1H, thiazine–
H), 4.16 (q, 2H, J = 7.1 Hz, methylene H of O–CH2CH3), 3.73 (s,
3H, N–CH3), 1.18 (t, 3H, J = 7.1 Hz, methyl H of O–CH2CH3);
13CNMR (CDCl3, 100 MHz): δ = 173.7, 169.5, 139.4, 126.4,
125.3, 123.4, 117.3, 69.4, 57.8, 30.1, 26.5, 14.8. EIMS: (m/z):
279 (M+), Anal. Calcd. For C12H13N3OS2: C 51.59, H 4.69, N
15.04; found C 51.51, H 4.61, N 15.11.
Figure 1. Recycling of [bmim]OH.
automatic carbon, hydrogen and nitrogen analyzer. Silica gel-G
was used for TLC. Melting points were determined by open
glass capillary method and are uncorrected.
Preparation of 1-butyl-3-methylimidazolium hydroxide
4b. 2-Allylamino-4-ethoxy-6-thiophen-2-yl-6H-[1,3]thiazine-
5-carbonitrile. Yellowish solid; IR (KBr, cmÀ1): νmax = 3369,
3325, 3071, 3025, 2230, 1631, 1542, 1445, 1370, 1040; 1H
NMR (CDCl3, 400 MHz): δ 7.14–6.76 (m, 3Harom), 5.74–5.06
(m, 5H, allylic H), 8.25 (br s, 1H, NH), 4.80 (s, 1H, thiazine–
H), 4.27 (q, 2H, J = 7.4 Hz, methylene H of O–CH2CH3), 1.19
(t, 3H, J = 7.4 Hz, methyl H of O–CH2CH3). 13C NMR (CDCl3,
100 MHz): δ = 173.9, 169.8, 139.6, 134.4, 126.5, 125.1, 123.5,
[bmim]OH.
earlier reported procedure [14].
The basic IL was synthesized according to an
4-Ethoxy-6-(phenyl)-6H-[1,3]thiazine-5-carbonitrile derivative:
typical procedure. A mixture of thiophene-2-carboxaldehyde
(5.5 mmol) and ethyl cyanoacetate (5.0 mmol) in [bmim]OH
was stirred at 60°C for approximately 10–15 min. After
formation of Knoevenagel adduct as evidenced by TLC, N-
allyl thiourea (5 mmol) was added. After completion of the
Scheme 2. Tentative mechanism of the [bmim]OH-mediated three-component synthesis of 1,3-thiazines in one-pot.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Basic Ionic Liquid Promoted Domino Knoevenagel–Thia-Michael Reaction: An
Efficient and Multicomponent Strategy for Synthesis of 1,3-Thiazines
117.4, 115.3, 69.3, 57.8, 45.8, 30.1, 14.9. EIMS: (m/z): 305 (M+),
Anal. Calcd. For C14H15N3OS2: C 49.79, H 4.18, N 15.84; found
C 49.71, H 4.25, N 15.77.
4Harom), 5.72–5.08 (m, 5H, allylic H), 8.25 (br s, 1H, NH), 4.26
(s, 1H, thiazine–H), 4.12 (q, 2H, J = 7.5 Hz, methylene H of O–
CH2CH3), 1.19 (t, 3H, J = 7.5 Hz, methyl H of O–CH2CH3).
13C NMR (CDCl3, 100 MHz): δ = 173.9, 169.4, 139.3, 134.4,
132.4, 129.4, 128.8, 117.6, 115, 69.6, 58.2, 45.8, 29.3, 14.9.
EIMS: (m/z): 333 (M+), Anal. Calcd. For C16H16ClN3OS: C
57.56, H 4.83, N 12.59; found C 57.49, H 4.88, N 12.51.
4c. 4-Ethoxy-2-methylamino-6-phenyl-6H-[1,3]thiazine-5-
carbonitrile.
max = 3388, 3331, 3082, 3030, 2225, 1644, 1539, 1475,
Yellowish solid; IR (KBr, cmÀ1):
ν
1376,1040; 1H NMR (CDCl3, 400 MHz): δ 7.72–7.25 (m,
5Harom), 8.17 (br s, 1H, NH), 4.23 (s, 1H, thiazine–H), 4.23
(q, 2H, J = 6.9 Hz, methylene H of O–CH2CH3), 3.69 (s, 3H,
N–CH3), 1.20 (t, 3H, J = 6.9 Hz, methyl H of O–CH2CH3).
13CNMR (CDCl3, 100 MHz): δ = 173.4, 169.7, 141.1, 128.4,
127.8, 117.3, 69.4, 57.8, 29.6, 26.5, 14.9. EIMS: (m/z): 273
(M+), Anal. Calcd. For C14H15N3OS: C 61.51, H 5.53, N
15.37; found C 61.59, H 5.45, N 15.31.
4i. 4-Ethoxy-6-furan-2-yl-2-methylamino-6H-[1,3]thiazine-
5-carbonitrile. Yellowish solid; IR (KBr, cmÀ1): νmax = 3384,
3322, 3079, 3019, 2235, 1620, 1566, 1467, 1370, 1035; 1H
NMR (CDCl3, 400 MHz): δ 7.18–6.79 (m, 3Harom), 8.20 (br s,
1H, NH), 4.66 (s, 1H, thiazine–H), 4.31 (q, 2H, J = 7.2 Hz,
methylene H of O–CH2CH3), 3.50 (s, 3H, N–CH3), 1.20 (t, 3H,
J = 7.2 Hz, methyl
H
of O–CH2CH3). 13CNMR (CDCl3,
4d.
2-Allylamino-4-ethoxy-6-phenyl-6H-[1,3]thiazine-5-
100 MHz): δ = 173.5, 168.7, 152.6, 141.3, 117.3, 110.8, 105.6,
69.6, 57.8, 30.4, 26.5, 14.9. EIMS: (m/z): 263 (M+), Anal.
Calcd. For C12H13N3O2S: C 54.74, H 4.98, N 15.96; found C
54.83, H 4.91, N 15.91.
carbonitrile.
Yellowish solid; IR (KBr, cmÀ1): νmax = 3405,
3349, 3070, 3026, 2240, 1614, 1542, 1440, 1370, 1032; 1H
NMR (CDCl3, 400 MHz): δ 7.69–7.23 (m, 5Harom), 5.72–5.11
(m, 5H, allylic H), 8.25 (br s, 1H, NH), 4.26 (s, 1H, thiazine–H),
4.16 (q, 2H, J = 7.3 Hz, methylene H of O–CH2CH3), 1.20 (t,
3H, J = 7.3 Hz, methyl H of O–CH2CH3). 13CNMR (CDCl3,
100 MHz): δ = 173.7, 169.2, 141.2, 134.4, 128.6, 128, 127.9,
117.3, 115.3, 69.6, 57.6, 45.8, 29.5, 15.2. EIMS: (m/z): 299
(M+), Anal. Calcd. For C16H17N3OS: C 64.19, H 5.72, N 14.04;
found C 69.09, H 5.79, N 14.08.
4j. 2-Allylamino-4-ethoxy-6-furan-2-yl-6H-[1,3]thiazine-5-
carbonitrile.
Yellowish solid; IR (KBr, cmÀ1): νmax = 3390,
3330, 3083, 3026, 2230, 1640, 1542, 1470, 1376, 1030; 1H
NMR (CDCl3, 400 MHz): δ 7.22–6.83 (m, 3Harom), 5.74–5.12
(m, 5H, allylic H), 8.25 (br s, 1H, NH), 4.64 (s, 1H, thiazine–
H), 4.30 (q, 2H, J = 6.8 Hz, methylene H of O–CH2CH3), 1.20
(t, 3H, J = 6.8 Hz, methyl H of O–CH2CH3). 13C NMR (CDCl3,
100 MHz): δ = 173.3, 169.1, 152.7, 141.3, 134.4, 117.6, 115.3,
111.2, 105.8, 69.4, 58.2, 45.8, 30.6, 15.4. EIMS: (m/z): 289
(M+), Anal. Calcd. For C14H15N3O2S: C 58.11, H 5.23, N
14.52; found C 58.18, H 5.29, N 14.59.
4e. 4-Ethoxy-6-(4-methoxy-phenyl)-2-methylamino-6H-[1,3]
thiazine-5-carbonitrile.
max = 3398, 3358, 3083, 3029, 2210, 1644, 1545, 1470, 1370,
Yellowish solid; IR (KBr, cmÀ1):
ν
1039; 1H NMR (CDCl3, 400 MHz): δ 7.19–6.95 (m, 4Harom),
8.16 (br s, 1H, NH), 4.24 (s, 1H, thiazine–H), 4.30 (q, 2H,
J = 7.6 Hz, methylene H of O–CH2CH3), 3.72 (s, 3H, O–CH3),
3.56 (s, 3H, N–CH3), 1.19 (t, 3H, J = 7.6 Hz, methyl H of O–
CH2CH3). 13C NMR (CDCl3, 100 MHz): δ = 173.6, 169.2,
160.1, 133.4, 128.7, 117.1, 114.4, 69.4, 57.8, 56.1, 29.5, 26.5,
14.9. EIMS: (m/z): 303 (M+), Anal. Calcd. For C15H17N3O2S: C
59.38, H 5.65, N 13.85; found C 59.31, H 5.57, N 13.92.
4k. Ethoxy-2-methylamino-6-(4-trifluoromethyl-phenyl)-6H-
[1,3]thiazine-5-carbonitrile.
Yellowish solid; IR (KBr,
cmÀ1): νmax = 3387, 3331, 3086, 3029, 2220, 1633, 1545, 1463,
1377, 1230, 1040; 1H NMR (CDCl3, 400 MHz): δ 7.70–7.26
(m, 4Harom), 8.25 (br s, 1H, NH), 4.45 (s, 1H, thiazine–H), 4.10
(q, 2H, J = 7.6 Hz, methylene H of O–CH2CH3), 3.78 (s, 3H,
N–CH3), 1.17 (t, 3H, J = 7.6 Hz, methyl H of O–CH2CH3). 13C
NMR (CDCl3, 100 MHz): δ = 173.8, 168.5, 144.7, 129.5, 128.4,
125.9, 119.2, 117.6, 69.5, 57.6, 29.3, 26.5, 14.9. EIMS: (m/z):
333 (M+), Anal. Calcd. For EIMS: (m/z): 341 (M+), Anal.
Calcd. For C15H14F3N3OS: C 52.78, H 4.13, N 12.31; found C
52.66, H 4.19, N 12.38.
4f. 2-Allylamino-4-ethoxy-6-(4-methoxy-phenyl)-6H-[1,3]thiazine-
5-carbonitrile.
Yellowish solid; IR (KBr, cmÀ1): νm1ax = 3388,
3323, 3085, 3028, 2220, 1630, 1539, 1450, 1373, 1042; H NMR
(CDCl3, 400 MHz): δ 7.21–6.96 (m, 4Harom), 5.72–5.09 (m, 5H,
allylic H), 8.25 (br s, 1H, NH), 4.24 (s, 1H, thiazine–H), 4.11 (q, 2H,
J= 6.9 Hz, methylene H of O–CH2CH3), 3.72 (s, 3H, O–CH3), 1.20
(t, 3H, J= 6.9 Hz, methyl H of O–CH2CH3). 13C NMR (CDCl3,
100 MHz): δ = 173.7, 169.1, 160.3, 134.4, 133.4, 128.8, 117.3, 115,
114.3, 69.1, 57.8, 56.3, 46.2, 29.5, 15.1. EIMS: (m/z): 329 (M+),
Anal. Calcd. For C17H19N3O2S: C 61.98, H 5.81, N 12.76; found C
61.88, H 5.88, N 12.68.
4l. 2-Allylamino-4-ethoxy-6-(4-trifluoromethyl-phenyl)-6H-
[1,3]thiazine-5-carbonitrile.
Yellowish solid; IR (KBr,
cmÀ1): νmax = 3377, 3325, 3087, 3038, 2239, 1635, 1550, 1470,
1370, 1241, 1036; 1H NMR (CDCl3, 400 MHz): δ 7.26–7.02 (m,
4Harom), 5.71–5.20 (m, 5H, allylic H), 8.25 (br s, 1H, NH), 4.43
(s, 1H, thiazine–H), 4.20 (q, 2H, J = 7.5 Hz, methylene H of O–
4g.
thiazine-5-carbonitrile.
max = 3394, 3318, 3089, 3023, 2230, 1635, 1560, 1475, 1376,
6-(4-Chlorophenyl)-4-ethoxy-2-methylamino-6H-[1,3]
CH2CH3), 1.19 (t, 3H, J = 7.5 Hz, methyl H of O–CH2CH3). 13
C
Yellowish solid; IR (KBr, cmÀ1):
NMR (CDCl3, 100 MHz): δ = 173.9, 169.2, 144.5, 134.4, 129.6,
128.5, 126.5, 119.4, 117.3, 115.6, 69.9, 58.5, 45.8, 29.5, 14.8.
EIMS: (m/z): 367 (M+), Anal. Calcd. For C17H16F3N3OS: C
55.58, H 4.39, N 11.44; found C 55.48, H 4.31, N 11.52.
ν
1022, 737; 1H NMR (CDCl3, 400 MHz): δ 7.22–7.05 (m,
4Harom), 8.22 (br s, 1H, NH), 4.26 (s, 1H, thiazine–H), 4.19 (q,
2H, J = 7.3 Hz, methylene H of O–CH2CH3), 3.71 (s, 3H, N–
CH3), 1.22 (t, 3H, J = 7.3 Hz, methyl H of O–CH2CH3). 13C
NMR (CDCl3, 100 MHz): δ = 173.7, 168.8, 139.2, 132.1, 129.4,
128.9, 117.3, 69.3, 57.8, 29.3, 26.5, 14.8. EIMS: (m/z): 307
(M+), Anal. Calcd. For C14H14ClN3OS: C 54.63, H 4.58, N
13.65; found C 54.52, H 4.65, N 13.58.
Acknowledgments. Authors gratefully acknowledge the financial
support from Council of Scientific and Industrial Research (CSIR)
and are thankful to the SAIF, Punjab University Chandigarh for
providing all the spectroscopic and analytical data.
4h.
thiazine-5-carbonitrile.
max = 3380, 3328, 3086, 3023, 2225, 1630, 1540, 1460, 1375,
1030, 730; 1H NMR (CDCl3, 400 MHz): δ 7.21–7.06 (m,
2-Allylamino-6-(4-chloro-phenyl)-4-ethoxy-6H-[1,3]
REFERENCES AND NOTES
Yellowish solid; IR (KBr, cmÀ1):
ν
[1] (a) Patel, H. S.; Patel, N. P. Orient J Chem 1997, 13, 69; (b)
Madkour, H. M. F.; Salem, M. A. I.; Soliman, E. A.; Mahmoud, N. F. H.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. R. Siddiqui, Rahila, S. Sharmim, P. Rai, Shireen, M. A. Waseem, A. Srivastava, and A. Srivastava Vol 000
[17] Nising, C. F.; Brase, S. Chem Soc Rev 2008, 37, 1218.
[18] Hong, Y.; Shen, Z.; Hu, X.; Mo, W.; He, X.; Hu, B.; Sun, N.
Arkivoc 2009, xiv, 146.
[19] (a) Domling, A.; Wang, W.; Wang, K. Chem Rev 2012, 112,
3083; (b) Isambert, N.; Sanchez Duque, M. M.; Plaquevent, J. C.;
Gnisson, Y.; Rodriguez, J.; Constantieux, T. Chem Soc Rev 2011, 40,
1347; (c)Marson, C. M. Chem Soc Rev 2012, 41, 7712.
[20] (a) Yavari, I.; Bayat, M. J.; Souri, S.; Sirouspour, M. Helv
Chim Acta 2009, 92, 1903; (b) Spitz, C.; Lohier, J.; Reboul, V.;
Metzner, P. Org Lett 2009, 11, 2776; (c) Nishio, T.; Konno, Y.; Ori, M.;
Sakamoto, M. Eur J Org Chem 2001, 3553; (d) Qiu, G.; Hu, Y.;
Ding, Q.; Peng, Y.; Huc, X.; Wu, J. Chem Commun 2011, 47, 9708;
(e)Ding, Q.; Liu, X.; Yu, J.; Zhang, Q.; Wang, D.; Cao, B.; Peng, Y. Tet-
rahedron 2012, 68, 3937; (f) Yuskovet, V. N.; Ivin, B. A.; Tetrahedron
Lett 2003, 44, 5279; (g) Nagaraj, A.; Reddy, C. S. J Iran Chem Soc
2008, 2, 262; (h) Ingarsal, N.; Amutha, P.; Nagarjan, S.; J Sulphur Chem
2006, 5, 455; (i) Rathod, S. P.; Charjan, A. P.; Rajput, P. R. Rasayan J
Chem 2010, 2, 363.
Phosphorus Sulfur Silicon Relat Elem 2001, 170, 15; (c) Ingarsal, N.;
Amutha, P.; Nagarajan, S. J Sulfur Chem 2006, 27, 455; (d) Tozkoparan, B.;
Aktay, G.; Yeilada, E.; Il Farmaco 2002, 57, 145; (e) Ei-Subbagh, H. I.;
Abadi, A.; A1-Khawad, I. E.; A1- Pashood, K. A. Arch Pharm 1999,
332, 19; (f) Malinka, W.; Kaczmarz, M.; Filipek, B.; Sepa, J.; Gold, B.
Il Farmaco 2002, 57, 737; (g) Bózsing, D.; Sohár, P.; Gigler, G.; Kovács,
G. Eur J Med Chem 1996, 31, 663; (h) Lavilla, R. J. J Chem Soc Perkin
Trans 1 2002, 1141; (i) Tu, S.; Miao, C.; Fang, F. Bioorg Med Chem Lett
2004, 14, 1533; (j) Radhakrishnan, S. R.; Perumal, P. T. Tetrahedron 2005,
61, 2465; (k) Nguyen, J. T.; Velazquez, C. A.; Knaus, E. E. Bioorg Med
Chem 2005, 13, 1725.
[2] Campaigne, E.; Nargund, P. K. J Org Chem 1964, 29, 224.
[3] Barret, G. C.; Kane, V. V.; Lowe, G. J Chem Soc 1964, 783.
[4] Wilkes, J. S. Green Chem 2002, 4, 73.
[5] Yao, Q. Org Lett 2002, 4, 2197.
[6] Zerth, H. M.; Leonard, N. M.; Mohan, R. S. Org Lett 2003, 5, 55.
[7] Buu, O. N. V.; Aupoix, A. V.; Hong, N. D. T.; Vo-Thanh, G.
New J Chem 2009, 33, 2060.
[21] (a) Siddiqui, I. R.; Waseem, M. A.; Shamim, S.; Shireen,
Srivastava, A.; Srivastava, A.; Tetrahedron Lett 2013, 54, 4154; (b)
Siddiqui, I. R.; Abumhdi, A. A. H.; Shamim, S.; Shireen, Waseem, M. A.;
Rahila; Srivastava, A.; Srivastava, A. RSC Advances 2013, 3, 10173; (c)
Siddiqui, I. R.; Shireen, Shamim, S.; Abumhdi, A. A. H.; Waseem, M. A.;
Srivastava, A.; Rahila; Srivastava, A. New J Chem 2013, 37, 1258; (d)
Siddiqui, I. R.; Shamim, S.; Kumar, D.; Shireen; Waseem, M. A.; New J
Chem 2012, 36, 2209; (e) Siddiqui, I. R.; Singh, A.; Shamim, S.; Srivastava, V.;
Singh, P. K.; Yadav, S.; Singh, R. K. P. Synthesis 2010, 10, 1613.
[22] Dupont, J. P.; Suarez, A. Z. Phys Chem Chem Phys 2006, 8,
2441.
[8] Kumar, A.; Pawar, S. S. J Org Chem 2004, 69, 1419.
[9] Mi, X.; Luo, S.; Cheng, J. P. J Org Chem 2005, 70, 2338.
[10] Guo, H. M.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.
Chem Commun 2005, 1450.
[11] Wang, R.; Twamley, B.; Shreeve, J. M. J Org Chem 2006, 71, 426.
[12] Hapiot, P.; Lagrost, C. Chem Rev 2008, 108, 2238.
[13] Ranu, B. C.; Jana, R. Eur J Org Chem 2006, 16, 3767.
[14] Ranu, B. C.; Banerjee, S. Org Lett 2005, 7, 3049.
[15] Kumar, A.; Ahmad, I.; Rao, M. S. J Sulphur Chem 2009, 30, 570.
[16] Reiter, M.; Turner, H.; Gouverneur, V. Chem Eur J 2006, 12, 7190.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet