Cu(II)-catalyzed tandem synthesis of 2-imino[1,3]benzothiazines from 2-aminoaryl acrylates via thioamidation and concomitant chemoselective thia-Michael addition

Article abstract of DOI:10.1016/j.tetlet.2014.12.058

An efficient copper-catalyzed tandem approach for the synthesis of 2-imino[1,3]benzothiazines by the reaction of easily accessible 2-aminoaryl acrylates with isothiocyanates via in situ thioamidation and concomitant chemoselective intramolecular thia-Mich

Full text of DOI:10.1016/j.tetlet.2014.12.058

Accepted Manuscript
Cu(II)-catalyzed tandem synthesis of 2-imino[1,3]benzothiazines from 2-ami-
noaryl acrylates via thioamidation and concomitant chemoselective thia-Mi-
chael addition
Rakesh K. Saunthwal, Monika Patel, Sushil Kumar, Akhilesh K. Verma
PII:
S0040-4039(14)02124-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.058
TETL 45582
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 October 2014
2 December 2014
10 December 2014
Please cite this article as: Saunthwal, R.K., Patel, M., Kumar, S., Verma, A.K., Cu(II)-catalyzed tandem synthesis
of 2-imino[1,3]benzothiazines from 2-aminoaryl acrylates via thioamidation and concomitant chemoselective thia-
Michael addition, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.058
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Cu(II)-catalyzed tandem synthesis of
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2-Imino[1,3]benzothiazines from 2-aminoaryl acrylates
via thioamidation and concomitant chemoselective
thia-Michael addition
Rakesh K. Saunthwal, Monika Patel, Sushil Kumar and Akhilesh K. Verma*
Intramolecular
thia-Michael addition
a
H
H
b
R3
H
R3 NCS
trigger by
nitrogen b
N
N
N
N
2a_j
R3
NH2
R1
S
S
Cu(OTf)2
COOR2
R1
R1
COOR2
COOR2
24 examples;
3a_o and 4a-i
1a_i
R1 = H, Me, Cl, F; R2 = Me, Et, n-Bu, t-Bu; R3 = subsituted aryl, alkyl
P
(upto 80% yields)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Cu(II)-catalyzed tandem synthesis of 2-imino[1,3]benzothiazines from 2-
aminoaryl acrylates via thioamidation and concomitant chemoselective thia-
Michael addition
Rakesh K. Saunthwal, Monika Patel, Sushil Kumar and Akhilesh K. Vermab*
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient copper-catalyzed tandem approach for the synthesis of 2-imino[1,3]benzothiazines
by the reaction of easily accessible 2-aminoaryl acrylates with isothiocyanates via in situ
thioamidation and concomitant chemoselective intramolecular thia-Michael addition is
described. Intramolecular cyclization was selectively triggered by the nitrogen ‘b’ of the
thiourea intermediate P.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Alkene, copper-catalyzed , aminoaryl acrylates ,
chemoselective , thia-Michael addition
Nitrogen and sulfur-containing compounds are privileged
heterocyclic moieties due to their significant biological and
pharmaceutical activities1 and their applications as an organic
electroluminescent devices.2 Benzothiazine core moiety is
present in pheofungins which is require for the protein N-
acetylation in aspergillus nidulans (Figure1, i). The derivatives of
1,3-benzothiazines have shown significant antiproliferative and
anticancer activity3 (Figure 1, ii and iii). Because of the important
biological activities of these compounds, significant efforts are
being continued and are still require for the development of an
efficient methods for their synthesis. Though various synthetic
approaches are available for the construction of benzothiazines
nucleus,4 a need for novel and versatile protocols for their
efficient synthesis attracts the interest of an organic chemist.
Significant advances have been made for the conjugate addition
of amines (aza-Michael addition)8 and thiols (thia-Michael
addition)9 to prepare their respective β-addition products.
Intermolecular conjugate additions of amines and thiols have
been well recognized; however intramolecular conjugate
additions of thiols have not been much explored.
Figure 1. Significant examples of biologically active benzothiazines.
Literature survey revealed that in recent years, synthesis
of heterocycles by tandem/domino approach5 has been emerged
as an attractive strategy in the field of organic synthesis. Copper-
catalyzed conjugate addition (Michael-addition)6 is one of the
most powerful carbon-carbon bond forming reaction and has
been extensively explored for the synthesis of wide variety of
biologically active heterocycles and natural products7.
Scheme 1. Previous synthetic approaches
In 2002, Katritzky10a reported an elegant approach for the
synthesis of [1,3]benzothiazine by direct ortho-lithiation of
thiophenols by reacting with N,N-bis[(benzotriazol-1-
yl)methyl]amines as 1,3-biselectrophile synthons (Scheme 1, a).
Later in 2008 Wu and co-workers reported tandem synthesis of
1,3-benzothiazines starting from 2-alkynylbenzenamines under
silver catalysis (Scheme 1, b).10b Valliribera10c reported synthesis
of 4H-3,1-benzothiazines from amidoaryl acrylates using
* Corresponding author. Tel.: +91 1127666646 (Ext. 175)
E-mail address: averma@acbr.du.ac.in (Akhilesh K. Verma)

2
Tetrahedron
Lawesson's reagent (Scheme 1, c). Recently Reboul and co-
Table 2. Synthesis of 2-imino[1,3]benzothiazinesa,b
workers developed interesting approach for the synthesis of
enantiopure 1,3-benzothiazines by the reaction of cyclic
sulfenamides with terminal alkynes (Scheme 1, d).10d
In continuation of our ongoing research on the synthesis of
heterocycles by tandem approach,11 and our interest to expand the
scope of the intramolecular thia-Michael addition;12 herein we
wish to report an efficient tandem approach for the synthesis of
2-imino[1,3]benzothiazines by the reaction of easily accessible 2-
aminophenyl acrylates with isothiocyanates via in situ formation
of thioamides and concomitant chemoselective intramolecular
thia-Michael addition.
3a, 70%
3b, 68%
3c, 71%
H
H
N
N
N
N
Table 1. Optimization of reaction conditionsa
S
S
NO2
NO2
COOMe
COOEt
3d, 80%
3e, 75%
3h, 65%
3f, 72%
3i, 65%
Entry
1
2
3
4
5
6
7
8
Solvent
MeCN
MeCN
MeCN
MeCN
DMF
THF
THF
THF
DCE
DCE
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Cat./mol% Time[h] T (°C) Yield (%)b
AgOTf/5
12
12
18
12
12
12
36
36
36
36
36
18
36
36
36
36
36
36
36
36
36
25
70
70
70
70
25
25
50
70
70
70
70
50
70
70
70
70
70
70
70
70
00
10
15
25
25
32
50
55
55
70
25
54
30
45
35
20
30
50
45
48
00
AgOTf/5
AgOTf/5
3g, 70%
3j, 64%
AgOTf/10
AgOTf/10
AgOTf/10
AgOTf/10
AgOTf/10
AgOTf/10
Cu(OTf)2/10
Cu(OTf)2/10
Cu(OTf)2/10
Cu(OTf)2/10
Cu(OTf)2/5
CuI/10
3k, 62%
3l, 75%
9
10
11
12
13
14
15
16
17
18
19
20
2115
3m, 60%b
3n, 65%
3o, 78%
Pd(OAc)2/10
PdCl2/10
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Cu(OTf)2 (10 mol %), 70
°C, 2 mL DCE, 36 h. b 48 h. c Isolated yields.
AgNO3/10
AgSbF5/10
AgOAc/10
-
After optimizing the reaction conditions, we examined
the substrate scope of the developed chemistry by using a variety
of 2-aminoaryl acrylates 1a–d and isothiocyanates 2a–h (Table
2). The substrates 1a–d required for the reaction was readily
prepared by the Heck coupling14 of the respective
bromo/iodoanilines with acrylates. Reaction of acrylate 1a with
phenylisothiocyanate 2a provided the desired product 3a in 70%
yield. Isothiocyanate 2b bearing electron-donating substituents at
ortho position of the phenyl ring provided the products 3b in
68% yield. However, isothiocyanates 2c, 2d and 2e bearing
electron−withdrawing groups afforded the products 3c–g
comparatively in higher yields. In the case of n-butyl acrylate 1c,
product 3h–l was obtained in moderate yields (Table 2, compare
3h vs 3a; 3j vs 3b and 3l vs 3d). The reaction of 1c with
cyclohexyl substituted isothiocyanate 2h required longer reaction
time for the completion of the reaction and afforded the desired
product 3m in 60% yield. Reaction of tert-butyl acrylate 1d with
4-methylphenylisothiocyanate 2f and 2d afforded the desire
product 3n and 3o in 65% and 78% yield respectively.
DCE
DCE
a
Reactions were performed using 0.5 mmol of 1a, isothiocyanates 2a (0.5
mmol) in 2.0 mL solvent. b Isolated yield.
To identify the optimal conditions for the reaction, a
number of catalyst reported in the literature such as Ag(I),10b
Cu(II)13 and Pd(II)14 catalyst with various protic/aprotic organic
solvents were examined in the reaction of 2-aminophenyl
acrylate 1a with phenylisothiocyanate (2a) (Table 1). When 5
mol % of AgOTf was used as catalysts in MeCN at 25 °C for 12
h, the desired product was not obtained (Table 1, entry 1).
Increase in the reaction temperature and time provided the
product 3a in 10 and 15% yields respectively (Table 1, entries 2–
3). Increase of the catalyst loading provided the product 3a in
improved yield (Table 1, entry 4). Similar result was observed
using DMF as solvent; however THF and DCE provided the
product in improved yield (Table 1, entries 5–9). Use of
Cu(OTf)2 in DCE was found more effective in comparison to
AgOTf, and afforded the desired product in 70% yields (Table 1,
entry 10). Inferior results were observed when reaction was
performed using Cu(OTf)2 in THF (Table 1, entry 11). Lowering
of the reaction time, temperature and catalyst loading leads to the
incomplete conversion of the substrate (Table 1, entries 12–14).
Other catalysts such as CuI, Pd(OAc)2, PdCl2, AgNO3, AgSbF5
and AgOAc were found inferior for the reaction (Table 1, entries
15–20). In the absence of metal-catalyst the desired product 3a
was not obtained (Table 1, entry 21).15
Success of the chemoselective addition of the
unsubstituted aminoacrylates onto isothiocyanates encouraged us
for the addition of the substituted acrylates onto isothiocyanates
to synthesize functionalized benzothiazines. Under the optimized
reaction conditions (Table 1, entry 10); the reaction of the
acrylates 1e−i with isothiocyanates 2d−f and 2i−j provided the
corresponding products 4a−i in good yields (Table 3). During the
course of the reaction it was observed that the nature of the
substituent’s attached to the aryl ring of isothiocyanates and the
acrylates were responsible for the success of the reaction.

3
Substrates 1e−g bearing electron-releasing substituent’s provided
the respective products 4a–e comparatively in higher yields.
Table 3. Synthesis of substituted 2-imino[1,3]benzothiazinesa
The crystal structure of product 3c clearly indicates
the formation of products 3 with exocyclic imino group. From
intermediate P cyclization can occur by involving nitrogen a
through intermediate R; ii) by involving nitrogen
b via
intermediate Q (Scheme 2, i). The possible reason for the
preferential involvement of the nitrogen b over nitrogen a, could
due to the difference in the nucleophilicity. The lone pair of
nitrogen ‘a’ are delocalized with adjacent acrylate and making it
less nuclophilic than nitrogen b (Scheme 2, ii).
4a, 75%
4b, 74%
4c, 80%
4f, 60%b
4i, 68%
Scheme 3. Reaction of phenylisocyanate with acrylate 1.
After obtaining the successful results with
arylisothiocyanates, we tried to synthesize benzoxazines 7 by the
reaction of isocyanates 5 with 2-aminoaryl acrylates 1a and 1c;
unfortunately we did not obtained the desired product. The
careful spectral analysis of the reaction shows the formation of
the urea intermediate 6. The probable reason could be the low
nucleophilicity of oxygen in comparison to the sulfur (Scheme
3).
4d, 75%
4g, 63%
4e, 71%
4h, 75%
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Cu(OTf)2 (10 mol %), 70
°C, 2 mL DCE, 36 h. b 48 h. c Isolated yields.
The substrate 3h bearing chloro substituent, on reaction
with isopropyl isothiocyanate 2i afforded the desired product 4f
in 60% yield in 42 h. However, the reaction of substrate 3h with
isothiocyanate 2j bearing an electron-releasing methyl group
provided the desired product in 63% yields. The substrate 1i
bearing fluoro substituent afforded the desired products 4h−i in
moderate to good yields.
Figure 2. ORTEP drawing of compound 3c drawn at 50%
probability level.
The structure of the synthesize benzothiazines was fully
1
characterized by the H, 13C NMR, HRMS and finally by the X-
Scheme 4. Plausible mechanism.
ray crystallographic studies of compound 3c (Figure 2).16
A
plausible mechanism for the above transformation based on
the previously reported copper chemistry17 is described in
Scheme 4. Reaction of 2-aminoaryl acrylates with
isothiocyanates would form the intermediate P, which can attack
on acrylate intramolecularly by two routes. Presumably,
CuO(Tf)2 and intermediate P generates copper complex Q, which
renders the acrylate susceptible to attack by the nucleophile.
Sulfur being more nucleophilic than nitrogen triggers the
intramolecular attacks at β-carbon of acrylate and generates
intermediate T, which tautomerizes to give product 3 and 4
(Scheme 4).
In conclusion, the chemistry described herein provides
a facile and direct synthesis of medicinally useful benzothiazines
from easily accessible starting material in good yields under mild
reaction conditions. The chemistry appears to involve the in situ
thioamidation by the reaction of 2-aminoaryl acrylates with
isothiocyanates followed by successive chemoselective
intramolecular thia-Michael addition. Further investigation of the
Scheme 2. Explanation for the preferential formation of exocyclic
imine (3) over endocyclic imine (3’).

4
Tetrahedron
Z.; Wang, T. L.; Chang, H. C.; Chen, Y. T.; Kuo, T. S. Organometallics,
scope and application of the developed chemistry are currently
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underway and will be reported in due course.
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The Research work was supported by Department of Science and
Technology (DST) and University of Delhi. R.K.S. and M.P. are
thankful to UGC, DST for fellowship.
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
125.
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Feringa, B. L. Chem. Commun. 2005, 1711.
(18) General procedure for the synthesis of 1,3−benzothiazine (3a-3o and
4a-4i). An oven-dried Schlenk tube with a Teflon screw valve was charged
with 0.5 mmol of isothiocyanates, 0.5 mmol of the 2-aminophenylacrylate
1a-i and Cu(OTf)2 (10 mol %). The Schlenk tube was capped with a rubber
septum and then evacuated and backfilled with nitrogen. The septum was
then replaced with a Teflon screw valve, and the Schlenk tube was sealed.
The reaction mixture was heated to 70 °C until 2-aminophenylacrylate 1a-i
had been completely consumed (36 h) (as determined by TLC) and was
allowed to cool at room temperature. The reaction mixture was diluted with
ethyl acetate (10 mL) and water (15 mL). Organic layer was concentrated
under reduced pressure. The crude material so obtained was purified by
column chromatography on silica gel using hexane-ethyl acetate mixture (80:
20). (Z)-Methyl 2-(2-(phenylimino)-2,4-dihydro-1H-benzo[d][1,3]thiazin-
4-yl) acetate (3a). The product was obtained as
a yellow needles
(DCM/Ether), (109.2 mg, 70%): mp 110–112 °C; 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 7.3 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.26–7.24 (m,
1H), 7.19–7.13 (m, 2H), 7.06 (t, J = 7.3 Hz, 2H), 4.47 (dd, J = 8.8 and 5.9
Hz, 1H), 3.66 (s, 3H), 2.87–2.80 (m, 1H), 2.77–2.71 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 170.8, 148.6, 142.9, 141.0, 128.9, 128.7, 126.4, 124.3, 123.6,
122.2, 120.5, 51.9, 41.3, 40.3; IR spectrum in film (vmax, cmꢀ1) 3344, 2951,
1731, 1655, 1614, 1580, 1537, 1480, 1439, 1314, 1231, 1150, 753; HRMS
(ESI) (M)+ Calcd for C17H16N2O2S 312.0932, found 312.0930.

Highlights

The manusript appears to involve the in situ thioamidation by the reaction of 2-
aminoaryl acrylates with isothiocyanates followed by successive chemoselective
intramolecular thia-Michael addition.


A facile and direct synthesis of medicinally useful benzothiazines from easily
accessible starting material in good yields under mild reaction conditions.
A novel access to substituted 1,3-benzothiazines embedded with exocyclic imine
groups which could be useful for the medicinal utility of the molecule and could be
easily diversified.


The mechanism of the reaction is supported by isolating the P intermediate
(Thiourea).
This chemistry involved the preferential intramolecular conjugate additions of
thiourea (generated in situ in the reaction) to form 1,3-benzothiazines. The structure
of the cyclized product was confirmed by X-ray crystallographic studies.