One-pot, Pd/Cu-catalysed synthesis of alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxides

Article abstract of DOI:10.1016/j.tetlet.2017.01.041

Enyne-substituted benzoisothiazole derivatives have been synthesised under one-pot, operationally simple conditions using 2-iodo-N-(trimethylsilylethynyl)benzenesulfonamides and terminal alkynes as starting materials and a palladium–copper-based catalytic system. The structure of these heterocycles has been demonstrated by NMR spectroscopy and confirmed by X-ray crystallographic analysis. A plausible reaction mechanism has been proposed.

Full text of DOI:10.1016/j.tetlet.2017.01.041

Accepted Manuscript
One-pot, Pd/Cu-catalysed synthesis of alkynyl-substituted 3-ylidene-dihydro-
benzo[d]isothiazole 1,1-dioxides
Koffi Sénam Etsè, Benjamin Dassonneville, Guillermo Zaragoza, Albert
Demonceau
PII:
S0040-4039(17)30063-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.041
TETL 48544
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 November 2016
11 January 2017
13 January 2017
Please cite this article as: Sénam Etsè, K., Dassonneville, B., Zaragoza, G., Demonceau, A., One-pot, Pd/Cu-
catalysed synthesis of alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxides, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.041
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One-pot, Pd/Cu-catalysed synthesis of alkynyl-substituted 3-ylidene-
dihydrobenzo[d]isothiazole 1,1-dioxides
a
a
b
a,
Koffi Sénam Etsè , Benjamin Dassonneville , Guillermo Zaragoza , Albert Demonceau *
a
Laboratory of Macromolecular Chemistry and Organic Catalysis, Department of Chemistry,
University of Liège, Sart-Tilman (B.6a), 4000 Liège, Belgium
b
Unidade de Difracción de Raios X, Universidade de Santiago de Compostela, Edificio
CACTUS, Campus Vida, 15782 Santiago de Compostela, Spain
A B S T R A C T
Enyne-substituted benzoisothiazole derivatives have been synthesised under one-pot,
operationally simple conditions using 2-iodo-N-(trimethylsilylethynyl)benzenesulfonamides
and terminal alkynes as starting materials and a palladium–copper-based catalytic system. The
structure of these heterocycles has been demonstrated by NMR spectroscopy and confirmed
by X-ray crystallographic analysis. A plausible reaction mechanism has been proposed.
Keywords:
Alkynes
Cyclisation
Heterocycles
Isothiazole 1,1-dioxides
Palladium
_
_________
Corresponding author. Tel.: +32 4366 3495; fax: +32 4366 3497; e-mail address: A.
Demonceau@ulg.ac.be
*
Isothiazole (1, Scheme 1) (1,2-thiazole), 2-R-2H-1,2-thiazines (2), and their benzo-
analogues (3 and 4, respectively) are privileged heterocyclic frameworks that occur in a large
1

number of compounds that exhibit extensive biological activities. In particular, 1,1-dioxide
1
–8
(
sultam) derivatives (5–8) inhibit various enzymes and are antiproliferative agents against
2
9
10,11
vascular smooth muscle cells, rat aortic myocites, and several cancer cell lines.
1,2-
11
Benzothiazine dioxide derivatives also exhibit potent anti-HIV-1 and excellent anti-
1
2
13
inflammatory and analgesic activities. They are known as oxicams, and piroxicam (9,
Scheme 2), meloxicam (10), droxicam, and ampiroxicam are marketed world-wide under
many brandnames.
N
N
N
N
N
N
N
S
S
R
R
S
S
R
1
2
3
4
N
S
O2
5
S
O2
S
S
O2
R
O2
6
7
8
Scheme 1. General structure of 1,2-thiazole (1), 1,2-thiazine (2), and of their benzo- (3 and 4)
and 1,1-dioxide derivatives (5–8).
OH
O
Ar
Ar:
(9)
N
H
N
S
N
S
N
O
2
(10 )
Scheme 2. Molecular structure of piroxicam (9) and meloxicam (10).
We recently became interested in the synthesis of 6H-dibenzo[c,e][1,2]thiazine 5,5-
dioxide derivatives 15b (Scheme 3) containing two benzene rings fused with the thiazine
dioxide motif. To this end, we were inspired by the strategy designed by Witulski and
1
4
Alayrac for the assembly of the carbazole nucleus 15a by an AABC ring-formation
approach based on the synthesis of functionalised tosylynamides 11a, the reliability of the
Sonogashira reaction, and the efficiency of transition-metal-catalysed alkyne
cyclotrimerisation. By analogy, we anticipated that 2-iodobenzenesulfonynamides 11b would
be suitable precursors of diynes 13b (Scheme 3). Contrary to our expectations, application of
the Sonogashira coupling to iodides 11b did not afford the intermediates 13b. Instead,
alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxides 21 were formed
(
Scheme 4), which is the subject of the present communication.
2

Witulski and Alayrac:14
R3
R1
R1
R
R1
R
R3
R4
R
R4
I
C
R2
12
(PPh
R2
14
A
A
A
B
N
Ts
[
PdCl
2
3
)
2
], CuI
[Rh]
R2
N
Ts
N
Ts
11a
13a
15a
R3
Our tentative approach:
R1
R4
R1
R
R
R
I
R2
R2
12
14
R2
N
N
N
[
M]
[M]
S
S
S
O
2
R'
R'
R'
O
2
O
2
11b
13b
15b
Scheme 3. AABC ring-formation approach to substituted carbazoles (15a) or
dibenzothiazine 5,5-dioxides (15b) by transition-metal-catalysed alkyne cyclotrimerisation.
We first synthesised ynamide 18 from the precursor N-phenyl 2-
iodobenzenesulfonamide 16 by adapting the route described by Feldman and Witulski as
15,16
shown in Scheme 4.
Thus, deprotonation of sulfonamide 16 with potassium
hexamethyldisilazane (KHMDS) in toluene, followed by addition of the readily available
1
7b
trimethylsilylethynyliodonium triflate 17 gave a 70–77% yield of the desired ynamide 18, as
isolable, colourless crystals that were fully characterised by spectroscopy and by single crystal
X-ray diffraction (See Supplementary Data). Then, as mentioned above, treatment of 18 with
1
4,15
trimethylsilylacetylene (19a) under classical Sonogashira conditions failed. Despite several
attempts, indeed, the expected diyne 20a did not form, but enyne-substituted isothiazole
derivative 21a in 88% yield resulting from a 5-exo-dig cyclisation. Finally, desilylation with
14–16
tetrabutylammonium fluoride (TBAF) in wet THF furnished 22a in 90% yield.
3

TMS
N
KHMDS
toluene, 0 °C, 30 min
I
I
H
N
Ph
S
O
Ph
I+
-
S
O
Ph
then TMS
OTf (17 )
2
2
0
°C–rt, 24 h
16
(70–77%)
18
TMS
PdCl
(19a )
, CuI
, THF, rt
88%)
2
3 2
(PPh )
NEt
3
(
TMS
H
TMS
TMS
TMS
Ph
H
TBAF
N
N
Ph
N
THF–H O
2
S
S
S
O2
0
°C–rt, 30 min
(90%)
Ph
O2
O2
20a
21a
22a
Scheme 4. Synthesis of benzoisothiazole 1,1-dioxide 22a.
The elucidation of the structure of compound 21a was not an easy task. The IR
spectrum includes the typical absorption band of only one alkyne functional group and the
–
1
shift of the CC stretch to 2111 cm might be attributed to conjugation. In addition, the bands
–1
for the symmetric and asymmetric vibrations of the SO group appear at 1179 and 1340 cm ,
2
1
13
respectively. The H and C NMR spectra contain the characteristic signals for two
trimethylsilyl groups, a doublet at 9.27 ppm assignable to C(7)H shifted downfield by the
neighbouring SO group, and a set of peaks attributed to unsaturated carbons and the
2
corresponding hydrogens that are difficult to draw any firm information. Fortunately, the
1
8
exact molecular structure of 21a was unambiguously assured by X-ray analysis (Fig. 1),
which featured a benzoisothiazole 1,1-dioxide core with a Z-configured 1,3-
bis(trimethylsilyl)prop-2-yne-1-ylidene substituent at position 7 (Fig. 1). The C7–C14 and
C18–C19 distances are characteristic of carbon–carbon double and triple bonds, respectively.
The geometrical parameters around the vinylic atoms C7 and C14 are in good agreement with
2
sp hybridisation. Only slight deviations of 6.9° (C19–C18–C14) and 1.8° (Si2–C19–C18) to
1
80° for acetylenic carbons C18 and C19, respectively, are observed, indicating that there is
no constraint in the binding of the trimethylsilylacetylene fragment to the vinyl group. Sultam
1a is a sterically demanding compound and the dihedral angle of 69.8° between the planes
C1C6) and (C8C13) (Fig. 1) shows that both aromatic rings are almost perpendicularly
2
(
oriented in the solid state. This conformation is likely stabilised by the trimethylsilyl group
via intramolecular interactions between C15–H15C and  (C8C13) aromatic ring, and weak
4

intramolecular H-bonds between C16–H16C and nitrogen atom N1 (Fig. 1) (See also
Supplementary Data). However, in solution at room temperature, the ortho (9 and 13) and
meta (10 and 12) carbons and hydrogens are equivalent in NMR spectroscopy, indicating that
the phenyl group is freely rotating around the N1–C8 bond.
Figure 1. ORTEP representation of isothiazole 21a, with thermal ellipsoids drawn at the 50%
probability level. Hydrogen atoms were removed for clarity.
To the best of our knowledge, enyne-containing benzoisothiazole 1,1-dioxides 21 have
1
9
a structure hitherto unknown. Only the syntheses of related sultams 23 and isoindolin-1-ones
2
0
2
4 (Scheme 5) have been reported, albeit using different methodologies. It has also been
2
5
reported recently by Kumara Swamy et al. that when 2-iodobenzenesulfonynamide 25 was
treated with a variety of nitrogen (amines and sulfonamides), carbon and oxygen (phenols)
nucleophiles in the presence of a palladium catalyst, 1,2-benzothiazine 1,1-dioxides 26 were
synthesised through a 6-endo-dig tandem cyclisation (Scheme 6). By contrast, the use of
alcohols as nucleophiles resulted in a 5-exo-dig cyclisation, without incorporation of the
2
5
nucleophile. In the present case, in the absence of nucleophile and using a Pd/Cu catalytic
system, addition of a terminal alkyne to 2-iodobenzenesulfonynamide 18 led to the formation
of enyne-substituted isothiazoles 21, which might result from the so-called tandem Heck–
2
1d,i
22c
Sonogashira reaction or alkynylation–carbopalladation reaction, a process that has been
rarely described in the past, notably in the coupling of certain vinyl or aryl halides with
2
1
22
terminal alkynes or as a side reaction. In many respects, this process is very similar to the
-exo-dig cyclisation of 2-iodobenzynamides through a tandem palladium-catalysed Heck–
Suzuki–Miyaura coupling reaction with arylboronic acids, leading to 3-
5
2
0c,d
(
arylmethylene)isoindolin-1-ones.
5

Ph
Me
N
Et
N
Bn
S
S
O2
O2
2
3a 19a
23b 19b
Ph
H
Ar
Ph
R1
R2
N
Ph
N
C
C
O
O
2
4a 20a
24b 20b
Scheme 5. Structures of representative substituted 3-methylenebenzoisothiazole dioxides 23
and enyne-containing isoindolinones 24.
Ph
Me
Nu
Me
NuH (Nu = NR'R" or OAr)
PdCl (PPh ) , base
N
2
3 2
S
O2
Ph
N
DMSO
0 °C, 12 h
7
Me
I
26
S
Me
O
2
Ph
2
5
Me
AlkOH
N
Me
PdCl
2 3 2
(PPh )
S
K CO3 or KOtBu
2
O2
2
7
Scheme 6. Reactions of 2-iodobenzenesulfonynamide 25 with nitrogen and oxygen
nucleophiles.
Having established the structure of compound 21a, we next carried out the reaction of
ynamide 18 with terminal alkyne 19j in the presence of PdCl (PPh ) or Pd(PPh ) , CuI and
2
3
2
3 4
NEt in THF at room temperature (Table 1). The yield of isothiazole 21j was higher (80%)
3
2
3
from the reaction with PdCl (PPh ) than that from the reaction with Pd(PPh ) (70%).
2
3
2
3 4
Furthermore, in the absence of CuI, the yield of 21a or 21j dropped to 5–10%. When the
reaction was carried out only with CuI, without any palladium catalyst, the yields were
equally low (< 10%). We also found that triethylamine was a base of choice as was observed
2
3
previously. The effect of other bases, e.g. K CO and Cs CO , was also investigated (Table
2
3
2
3
1
). The use of Cs CO instead of NEt under the same reaction conditions afforded a lower
2
3
3
yield (55–60%), whereas in the presence of K CO the yields dropped again to 40–55%.
2
3
6

Table 1
Influence of both the palladium source and the base on the synthesis of benzoisothiazole
a
dioxide 21j
OMe
MeO
MeO
[
Pd], CuI
1
8 +
base, THF, rt
TMS
Ph
MeO
1
9j
N
S
O
2
2
1j
-
------------------------------------------------------------------------------
b,c
Catalyst
Yield, %
-
----------------------------------------------------
Base: NEt3
K CO
Cs CO
2
3
2
3
-
-----------------------------------------------------------------------------
b
c
c
PdCl (PPh )
80
70
42
54
2
3 2
c
c
c
Pd(PPh3)4
55
58
-
------------------------------------------------------------------------------
a
Reaction conditions: ynamide 18, 1.1 mmol; alkyne 19j, 1.2 mmol; [Pd], 0.055 mmol; CuI,
0
.11 mmol; base, 36 mmol; THF, 5 mL. The resulting reaction mixture was stirred at room
temperature and followed by TLC until the reaction was complete.
b
Isolated yield.
c
1
Determined by H NMR spectroscopy using CH Br as an internal standard.
2
2
We next explored the substrate scope of terminal alkynes 19 (Table 2). In some cases,
in particular when R was an alkyl group (1-propyne (Entry 2) and 1-hexyne (Entry 3)), low
yields of 30–40% were obtained. The yield was even lower with propiolic acid (Entry 5)
whereas propargylic alcohol (Entry 4) gave an appreciable yield of 72%. When R was the
phenyl group (Entry 6) or a phenyl derivative (Entries 7–11), the yields ranged from 58% to
8
0%, irrespective of the stereoelectronic properties of the substituents on the phenyl ring.
However, with only 25% yield, 2,4,6-trimethylphenylacetylene (Entry 7) was a notable
7

exception. It should also be noted that some benzoisothiazole 1,1-dioxides 21 are not very
stable and that signs of decomposition were observed during their purification (Table 2,
footnote c).
Table 2
a
Influence of the terminal alkyne 19a–k on the synthesis of benzoisothiazole dioxides 21a–k
R
TMS
PdCl
2
(PPh
3 2
) , CuI
18 + R
NEt
3
, THF, rt
N
Ph
19a-k
S
O2
21a-k
-
-------------------------------------------------------------
Entry 21
R
Yield, %
-
-------------------------------------------------------------
b
1
2
3
4
5
6
7
8
9
1
1
21a TMS
21b Me
88
40
30
72
22
61
25
68
58
80
68
b
b,c
b,c
b,c
b
21c
n-Bu
21d CH OH
2
21e
21f
CO H
2
Ph
b,c
b
21g 2,4,6-Me -C H
3
6
4
4
2
21h 2-MeO-C H
6
b,c
b
21i
4-MeO-C H
6
0
1
21j
3,5-(MeO) -C H
2
6
3
b,c
21k 4-CF -C H
3
6
4
-
-------------------------------------------------------------------------
a
Reaction conditions: ynamide 18, 1.1 mmol; alkyne 19, 1.2 mmol; PdCl (PPh ) , 0.055
2
3 2
mmol; CuI, 0.11 mmol; NEt , 10 mL; THF, 5 mL. The resulting reaction mixture was stirred
3
at room temperature and followed by TLC until the reaction was complete.
b
Isolated yield.
c
This compound was partly contaminated by some unidentified degradation products.
8

In light of these results and of mechanisms proposed by Dougherty et al. for the
2
1a
synthesis of enyne-substituted fluorenes and by Teply et al. for the synthesis of enyne-
2
1c
21d,e
substituted isochromene derivatives, we propose the mechanism sketched in Scheme 7.
2
4
Oxidative addition of phenyl iodide 18 to an in situ generated Pd(0) species provides the -
arylpalladium(II) intermediate A, which then inserts into the tethered alkyne to form the -
vinylpalladium(II) 5-exo-dig cyclisation intermediate C. Transmetallation with alkynyl copper
generated in situ from terminal alkyne 19 provides the -alkynylpalladium(II) intermediate D,
which after reductive elimination affords enyne-substituted isothiazole 21. Another
mechanism cannot be excluded a priori, although it is less likely: an intermolecular addition
2
2e,26
of a terminal alkyne 19 to the triple bond of the substrate 18, followed by cyclisation.
TMS
TMS
L
I
L
L
Pd
TMS
Pd
I
I
N
N
N
S
O2
S
O2
Ph
Ph
S
Ph
O
2
I
L
A
B
Pd
1
8
TMS
Ph
L
R
(19 )
CuI, NEt
3
PdCl
2
L
2
Pd0L
2
L = PPh
3
C
N
R
R
S
R
O
2
L
L
L
Cu
R
TMS
Ph
Pd
Pd
TMS
Ph
TMS
Ph
L
N
N
N
S
O2
S
O
S
O
2
2
21
E
D
Scheme 7. Plausible mechanism for the synthesis of enyne-substituted benzoisothiazole
dioxides 21.
If the mechanism outlined above proves to be correct, it then becomes easy to explain
the difference in reactivity between tosylynamide 11a (Scheme 3) and benzenesulfonynamide
1
8 (Scheme 4) when both substrates are treated with a terminal alkyne under the same
Sonogashira conditions: In contrast to compound 18, tosylynamide 11a cannot undergo a 4-
exo-dig cyclisation to yield the corresponding highly strained 4-membered ring, and that is
likely the major reason why here the Sonogashira coupling works so well to provide diynes
1
4,26
1
3a (Scheme 3). However, 5-endo-dig cyclisations with 11a were reported after activation
2
7
by a nucleophile.
9

In conclusion, our initial aim was to access the 6H-dibenzo[c,e][1,2]thiazine 5,5-
dioxide scaffold 15b. We have shown, however, that the desired diyne precursor 13b was not
formed under classical Sonogashira conditions, in marked contrast to the related tosylamide
system 13a, but alkynyl-substituted 3-ylidene-dihydrobenzo[d]isothiazole 1,1-dioxide 21,
most probably via a tandem Heck–Sonogashira reaction. Their structure was confirmed by X-
ray crystallographic studies. Work is currently underway in our laboratory to expand the
scope of this reaction and to get some mechanistic insight.
Acknowledgements
We thank the University of Liège for a research grant and N. Smargiasso (Laboratory
of Mass Spectrometry, University of Liège) for high resolution mass spectrometry analyses.
Supplementary data
1
13
Supplementary data (experimental procedures, characterisation, H, C, and IR spectra
of compounds, and X-ray structure of compounds 18, 21a, 21h, and 21j) associated with this
article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.xx.yyy.
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We thank a referee for valuable comments.
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One-pot, Pd/Cu-catalysed synthesis of alkynyl-substituted 3-ylidene-
dihydrobenzo[d]isothiazole 1,1-dioxides
Koffi Sénam Etsè, Benjamin Dassonneville, Guillermo Zaragoza, Albert Demonceau
R
TMS
TMS
I
PdCl (PPh ) , CuI
2
3 2
+
R
N
Ph
N
NEt , THF, rt
3
S
S
Ph
O2
O
2
1
1 examples
(
R = Alk, CHOH, Ar, SiMe)
(22–88%)
2
3
1
4

Highlights
A one-pot, Pd/Cu-catalysed approach to enyne-substituted benzoisothiazole 1,1-dioxides is
described.
A plausible mechanism involves a rarely described tandem Heck–Sonogashira coupling
reaction.
This method can be applied to access new molecular scaffolds of interest in medicinal
chemistry.
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5