Regioselective synthesis of arylsulfonyl heterocycles from bromoallyl sulfonesviaintramolecular Heck coupling reaction

Article abstract of DOI:10.1039/d0ob01623c

Indoles, benzofurans and benzosultams endowed with arylsulfonyl groups were prepared in two steps from 2-bromoallyl sulfones.ortho-Halosulfonamides andortho-iodophenol reacted with 2-bromoallyl sulfones in the presence of cesium carbonate to furnish products resulting from a formal vinylic substitution reaction. Palladium-catalyzed intramolecular Heck reaction of these adducts furnished sulfonylated indoles, benzosultams and benzofurans. Isomerization of the double bond participating in the Heck reaction under basic conditions led to the formation of two isomeric products in two cases. Conditions for selectively accessing each of the regioisomeric indoles were developed.

Full text of DOI:10.1039/d0ob01623c

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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
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DOI: 10.1039/D0OB01623C
ARTICLE
Regioselective synthesis of arylsulfonyl heterocycles from
bromoallyl sulfones via intramolecular Heck coupling reaction
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
b
a
Deepak Yadav, Krishna, Sunil K. Sharma and Rajeev S. Menon *
DOI: 10.1039/x0xx00000x
Indoles, benzofurans and benzosultams endowed with arylsulfonyl groups were prepared in two steps from 2-bromoallyl
sulfones. Ortho-halosulfonamides and ortho-iodophenol reacted with 2-bromoallyl sulfones in presence of cesium
carbonate to furnish products resulting from a formal vinylic substitution reaction. Palladium-catalyzed intramolecular
Heck reaction of these adducts furnished sulfonylated indoles, benzosultams and benzofurans. Isomerization of the double
bond participating in the Heck reaction under basic conditions led to the formation of two isomeric products in two cases.
Conditions for selectively accessing each of the regioisomeric indoles were developed.
laboratory have led to the development of transformations of
Introduction
Aryl sulfones constitute an important class of compounds with
versatile reactivity and wide-ranging applications. The
archetypal aryl sulfone, viz., phenyl sulfone, has been termed
as “arguably the most versatile functional group available to
the synthetic chemist”. A number of aryl/heteroaryl sulfones
are known to possess antibacterial, antiviral and other
biological activities. The highly potent HIV non-nucleoside
reverse transcriptase inhibitors (NNTRIs) 1 and 2, and
2-bromoallyl sulfones 4 for the construction of sulfone-
1
0
containing heterocycles.
functioned as synthetic equivalents of allenyl sulfones in the
presence of a base (Cs CO ) and underwent formal vinylic
The 2-bromoallyl sulfones 4
1
1
1
2
3
substitution reactions with sulfonamides to furnish products 5
that contained an electron rich ene-sulfonamide (Scheme 1a).
The pronounced reactivity of the latter was tapped to develop
2
further
cycloisomerisations.
transformations
such
as
catalytic
3
1
0a-c
It is essential to note here that a
4
5
unique feature of unsaturated sulfones, namely the higher
thermodynamic stability of allyl sulfones in comparison with
6
the nonsteroidal anti-inflammatory drug (NSAID) piroxicam 3
are representative examples pertinent to the work presented
in the following sections (Figure 1).
1
2
vinyl sulfones, makes this approach feasible.
R
R
R
Me
Cs2CO3
+
C
(a)
(b)
N
NH
Ts
Br
+
N
CH3CN, 25 °C
-HBr
Ts
SO2Ph
SO2Ph
Ts SO2Ph
Me
Cl
OH
O
4
SO2Ph
5
Cl
NH2
SO2
SONH2
N
N
NH
O
I
H
I
2
Cs CO
Pd(0)
Heck
N
3
N
O
S
Me
H
N
O
Br
3
CH CN, 25 °C
N
2
NHTs
N
H
SO2Ph
SO2Ph
Ts SO2Ph
Ts
1
anti-HIV agents
2
Piroxicam, 3
6
4
7
8
Scheme 1. (a) Base-mediated formal vinylic substitution reaction of 2-bromoallyl
sulfones and sulfonamides, and (b) proposed synthesis of sulfone-bearing indole
derivatives
Figure
sulfones/benzosultam
1.
Selected
biologically
active
heteroaryl
Heteroaryl sulfones containing indole, benzofuran8 and We were interested in investigating the utility of the products
7
9
benzosultam moieties are accessible via a limited number of of formal vinylic substitution reactions for the construction of
metal-catalyzed coupling reactions.
The versatility of sulfonyl indoles and related heterocycles. It was envisaged
heteroaryl sulfones makes general and selective methods for that an intramolecular Heck coupling reaction of adducts 7
their construction highly desirable. Investigations in our generated from o-iodoanilne-derived sulfonamides 6 would
afford sulfonyl indole derivatives 8 (Scheme 1b). Our studies
towards this end culminated in the development of a general
method for the construction of various heteroaryl sulfones.
a. Department of Chemistry, School of Chemical Sciences, Central University of
Haryana,
Mahendergarh,
Haryana
123
029,
India.
E-mail:
rajeevmenon@cuh.ac.in, srajeevmenon@gmail.com
Additionally, some interesting regioselectivity patterns of the
Heck cyclization leading to the formation of indole derivatives
were revealed.
b.
c.
Department of Chemistry, University of Delhi, Delhi-110007, India
Electronic Supplementary Information (ESI) available: Experimental procedures,
†
characterisation data and scanned NMR spectra of new compounds. See
DOI: 10.1039/x0xx00000x
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palladium acetate and triphenylphosphine in DMF in the
presence of triethylamine. The reaction afforded two products
that could be easily separated via column chromatography.
They were identified as the isomeric indoles 8a (36%) and 9a
Results and Discussion
The investigations were initiated by the reaction of N-sulfonyl-
View Article Online
DOI: 10.1039/D0OB01623C
o-iodoaniline derivatives 6a-j with bromoallyl sulfones 4a-b
under the previously developed conditions of formal vinylic
(31%) by means of standard spectroscopic analysis (Scheme 2).
substitution.1
0a
Facile formation of the expected N-vinyl-o-
iodosulfonamides 7a-l was observed (Table 1). The products
were identified by standard spectroscopic analysis. It may be
noted here that the presence of sulfonyl groups on the
nucleophilic nitrogen is essential for the success of the formal
vinylic substituion reaction. N-acyl and N-Boc amines failed to
afford any products whereas unprotected amines readily
reacted to afford -arylsulfonyl acetone as the product. The
latter is presumably formed via the hydrolysis of the labile
enamine formed from the free amine and allenyl sulfone.
Ts
I
5 mol% Pd(OAc)2
0 mol% PPh3
1
+
Me
N
Ts
N
N
Et3N, DMF
60 °C, 30 h
Ts
Ts
9a, 36%
Ts Ts
7a
8a, 31%
Scheme 2. Intramolecular Heck coupling reaction of 7a
It was apparent that concomitant triethylamine-promoted
isomerisation of the double bond led to the formation of
regioisomers 8a and 9a in the Heck cyclization. Back has
observed similar base-assisted isomerisations in the Cu-
catalyzed intramolecular coupling reactions of unsaturated
sulfones. The effect of reaction temperature, base and
solvent on the Heck cyclisation’s efficiency and regioselectivity
was then investigated. The results are summarized in table 2.
Table 1. Preparation of N-vinyl-o-iodosulfonamides 7 via formal vinylic substitution
reactiona
7
a
R2
I
R2
I
Cs2CO3
+
Br
SO2R4
R3
SO R4
2
CH3CN
25 °C, 4 h
R3
N
NH
SO2R1
SO2R1
6a-j
4a-b
7a-l
Table 2. Optimization of conditions for the intramolecular Heck coupling reaction of
7
Entry
2-iodoaniline-
sulfonamide (6)
Bromoallyl
Product
(7)
Yield
(%)b
a.a
sulfone (4)
4a,
1c
1
2
3
Entry Solvent
Base
Temp
(°C)
Yield of 8a
Yield of 9a
6a, R = p-tolyl, R = R =
7a
79
81
83
78
76
(%)b
(%)b
4
H
6a
R = p-tolyl
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
MeCN
MeCN
2 3
DMSO Na CO
DMSO
Et
Et
Et N
Et N
K2CO3
N
N
60
60
40
80
80
80
80
80
80
80
80
80
80
80
31
26
23
16
-
36
43
18
64
46
52
31
23
56
41
26
37
42
49
2
3
4
5
4b,
7b
7c
7d
7e
3
4
R = ph
3
1
2
3
3
6b, R = p-tolyl, R = H, R
Cl
6c, R = p-tolyl, R = Cl, R
4a
4a
4a
3
=
3
1
2
=
H
Cs CO
-
2
3
1
2
6d, R = p-tolyl, R = CH
3
,
NaHCO3
DBU
Et N
19
>5
21
18
14
15
12
17
R3 = H
6
7
6d
4b
4a
7f
7g
74
71
3
1
2
6e, R = p-tolyl, R = H,
Cs CO
2
3
R3 = F
NaHCO3
K2CO3
1
2
3
8
9
6f, R = CH
3
, R = R = H
4a
4b
7h
7i
72
78
1
2
6g, R = CH
3
, R = H,
R3 = Cl
3
Et N
1
2
1
1
1
0
1
2
6h, R = CH
3
, R = CF
3
,
4b
4a
4a
7j
7k
7l
68
63
69
[
2 3
a] Reaction conditions: 7a (0.2 mmol), Pd(OAc) (5 mol%), PPh (10 mol%),
R3 = H
base(3 equiv.), solvent (2 mL). [b] Isolated yields of products. [c] 2 equiv. of Et
3
N
1
2
6i, R = CH
3
, R = CN,
were used.
3
R = H
1
2
6j, R = CH
3
, R = CO
2
Me,
The 2-sulfonylmethylindole 8a was obtained in 26% along with
the 2-methyl-3-tosyl indole derivative 9a in 43% yield, when
R3 = H
[
a] Reaction conditions: 6a-j (1 mmol), 4a-b (1.5 mmol), Cs CO (2.5 mmol), three equivalents of the base (Et N) was used (entry 2). When
2 3
3
acetonitrile (10 mmol), 4 h, 25 °C. [b] Yields of products isolated after column
chromatography.
the Heck cyclization was carried out at 40 ˚C, 8a and 9a were
isolated in reduced yields (23% and 18 % respectively, entry 3).
Pleasingly, the yield and selectivity improved significantly
when the reaction was run at 80 ˚C (16% for 8a and 64% for
9
a, entry 4). The use of inorganic bases such as potassium
Once an assortment of N-vinyl-o-iodosulfonamides 7a-l was at
hand, the proposed Heck cyclization was explored. As the
combination of palladium acetate and triphenylphosphine is
known to promote a variety of intramolecular Heck coupling
reaction,13 this catalytic system was selected for the studies.
carbonate or cesium carbonate in DMF led to the formation of
a single product, ie., the disubstituted indole derivative 9a,
albeit in moderate yields of 46% and 52% respectively (entries
5-6). It is conceivable that the enhanced basicity of K
Cs CO in DMF may be responsible for the selective formation
2 3
CO and
2
3
Thus the representative compound 7a was treated with
2
| J. Name., 2012, 00, 1-3
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of 9a. Other bases such as sodium bicarbonate and DBU were Table 4. Regioselective Heck cyclization of N-mesyl-N-vinyl-o-iodosulfonamides 7h-l
View Article Online
DOI: 10.1039/D0OB01623C
R2
not efficient in promoting the reaction (entries 7-8). It was
R2
I
5 mol% Pd(OAc)2
also observed that carrying out the Heck cyclization in
acetonitrile resulted in lower yields and selectivity in
comparison with the reactions in DMF, irrespective of the
bases used (entries 9-12). No improvement in yield or
selectivity was observed when either sodium carbonate or
triethylamine was used as the base in DMSO (entries 13-14).
Although a single product (9a) was obtained when either
cesium carbonate or potassium carbonate was used as the
base, the yields of the product were unsatisfactory. Therefore,
10 mol% PPh3
R3
R3
N
SO R4
2
N
Et3N, DMF
80 °C, 30 h
Ms SO2R4
Ms
7h-l
8g-k
F3C
N
Ts Cl
N
2
SO Ph
N
SO2Ph
Ms
Ms
Ms
8g, 74%
8h, 73%
8i, 61%
2 3 3
the combination of Pd(OAc) , PPh and Et N in DMF at 80 ˚C
(entry 4) was selected for the scope exploration of the
NC
2
MeO C
reaction, as it gave the best yield. Additionally, column
chromatographic separation was necessary in all cases and the
isomeric indoles could be separated easily without much
additional effort.
N
SO2Ph
N
Ts
Ms
j, 58%
Ms
8k, 63%
8
Initially, all the N-tosyl derivatives (7a-g) were subjected to the
optimized conditions for Heck cyclization (Table 3). All but one It is clear from the results depicted in tables 3 and 4, that
of these substrates afforded the easily separated regioisomeric either the 2-substituted indoles 8 or the 2,3-disubstituted
mixture of indoles (8a-f and 9a-g) in good overall yields. The indoles 9 could be selectively accessed via this method by the
fluorinated analog 7g afforded only the 2,3-disubstituted correct selection of N-sulfonyl group in the first step of the
indole 9g in 61% yield. The 2,3-disubstituted indole derivatives sequence.
9
were the major products in all the cases.
The development of regioselective indole synthesis prompted
us to test the method’s applicability for the construction of
related heterocycles. We envisaged that an analogous
synthetic route starting from 2-iodophenol 10 may lead to the
formation of related sulfonyl benzofuran derivatives. It is
noteworthy here that phenolic nucleophiles have been
successfully used in our laboratory for the construction of
Table 3. Intramolecular Heck reaction of N-tosyl-N-vinyl-o-iodosulfonamides 7a-g.a
SO2R4
R2
R3
5 mol% Pd(OAc)2
R2
R3
I
R2
R3
10 mol% PPh3
+
Me
SO R4
N
Et3N, DMF
80 °C, 30 h
N
2
N
Ts SO2R4
Ts
Ts
7a-g
8a-f
9a-g
1
4
chromene derivatives from 2-bromoallyl sulfones. Thus, the
cesium carbonate-mediated reaction of 2-iodophenol 10 with
2-bromoallyl sulfones 4a-b was carried out. Surprisingly, the
vinyl sulfones 11a-b were isolated as the products instead of
the expected allyl sulfones. Apparently, the isomerisation of
the O-vinyl derivatives to the more substituted alkene (vinyl
sulfone) is favoured under the reaction condition. The
geometry of the trisubstituted double bond is not clear at this
stage. The enol ethers 11a-b were then subjected to the
conditions of intramolecular Heck reaction. Here also, two
regioisomeric benzofurans were obtained; the 2-
sulfonylmethyl benzofurans 12a-b were the major products
and the disubstituted isomers 13a-b were isolated in minor
amounts (Scheme 3).
Cl
Me
SO2R4
N
Ts
4
N
Cl
N
2
SO R
N
Ts
Ts
Ts
Ts
Ts
8
c, 14%
8d, 13%
8e, R4 = p-tolyl, 13%
8f, R4 = Ph, 15%
8
8
a, R4 = p-tolyl, 16%
b, R4 = Ph, 16%
Ts
Ts
Cl
Me
Me
SO2R4
N
SO2R4
Cl
N
Ts
Me
Ts
Me
N
9c, 69%
9d, 68%
Me
N
Ts
Ts
Ts
9
9
a, R4 = p-tolyl, 64%
b, R4 = Ph, 62%
9e, R4 = p-tolyl, 72%
9f, R4 = Ph, 69%
Me
F
N
Ts
g, 61% (only product)
9
[
(
a] Reaction conditions: 7a-g(0.4 mmol), Pd(OAc)
2
(5 mol%), PPh
3
(10 mol%), Et
3
N
1.2 mmol), DMF (4 mL).
SO R
I
SO2R
I
2
Cs CO3
2
Br
+
Heck cyclization reactions of the N-mesyl derivatives 7h-l
under the same conditions, however, led to the selective
formation of 2-sulfonylmethyl indole derivatives 8g-k (Table 4).
Interestingly, the disubstituted indole regioisomers 9 were not
at all formed in these reactions. Notably, indoles having cyano
and ester functional groups (8j & 8k) could be constructed by
this method.
CH CN
O
Me
OH
3
25 °C,4 h
10
4
a-b
11a, R = p-tolyl, 64%
11b, R = Ph,67%
5
1
mol% Pd(OAc)2
0 mol% PPh3
SO R
2
+
Me
Et N, DMF
3
O
SO R
2
O
80 °C, 30 h
12a, R = p-tolyl, 63%
1
1
3a, R = p-tolyl, 16%
3b, R = Ph,16%
12b, R = Ph, 64%
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SO2R1
N
Scheme 3. Synthesis of sulfonyl benzofurans 12 and 13 from o-iodophenol
View Article Online
DOI: 10.1039/D0OB01623C
PhO2S
PhO2S
+
I
We then examined the suitability of this method for the
synthesis of benzosultam derivatives. The latter class of
compounds is well-known for their favourable biological
activities. Thus, 2-bromobenzenesulfonamides 14a-b were
reacted with bromoallyl sulfone 4a in the presence of cesium
carbonate in acetonitrile. The formal vinylic substitution
reaction proceeded smoothly to afford the N-vinyl
sulfonamides 15a-b in good yields. Further treatment of the
latter compounds under the conditions of Heck cyclization led
Cs2CO3
I
C
17
Br
SO2Ph
N
SO2Ph CH3CN, 25 °C
SO2R1
4b
1:5 mixture
ref. 10a
7
1
5
Cs2CO3
SO2Ph
SO2R1
2
Cs CO
3
N
I
I
SO2Ph
17
N
SO2R1
to the formation of disubstituted benzosultams 16a-b in Scheme 5. Mechanistic rationalization for the formal vinylic substitution of 4b
moderate yields (Scheme 4). Interestingly, only the
It is apparent that the regioselectivity of the Heck cyclization of
7 is influenced by steric factors. The oxidative addition of
Pd(0) to the N-tosyl derivative 7a is expected to generate the
organopalladium intermediate 18. As the conditions are basic
disubstituted benzosultam derivatives were obtained.
Br
16
Br
Br
Ts
H
Cs2CO3, CH3CN
5 °C, 4 h
N
+
Ts
S
R
N
2
O2
S
O2
R
4
a
1
1
4a, R = phenyl
4b, R = 3-chlorophenyl
1
1
5a, R = phenyl, 69%
5b, R = 3-chlorophenyl, 71%
3
(Et N), a dynamic equilibrium of regioisomeric alkenes 18a
(allyl sulfone) and 18b (vinyl sulfone) is expected to exist in the
reaction medium. Either of these alkenes may interact with
the Pd-centre to form the -complex in the Heck reaction. In
the case of 7a (and other derivatives with arylsulfonamide
groups) the dominant steric interaction is presumably the one
between the arene rings of the sulfonamide and sulfone.
Therefore, alkene-palladium bond formation preferentially
occurs at the α-sulfonyl end of the less hindered alkene 18b,
leading to the formation of 3-sulfonyl indole 9a as the major
product. In the case of N-mesyl derivatives such as 7h,
however, the decisive steric interaction is the one between
sulfonyl arene and the metal center of 19. Thus, the less-
hindered alkene 19a (allyl sulfone) interacts with palladium so
as to minimize steric repulsions between arylsulfonyl group
and metal centre. This eventually leads to the formation of 2-
substituted indole 8g (Scheme 6). The selective formation of
disubstituted benzosultams 16a-b (Scheme 4) may also be
explained on the basis of analogous steric repulsion between
N-aryl groups and sulfonylarene rings in 15a-b. . Similarly, it
may be presumed that the O-vinyl derivatives 11a-b furnished
Ts
5
1
mol% Pd(OAc)2
0 mol% PPh3
Me
R
N
S
Et3N, DMF
O2
80 °C, 30 h
1
1
6a, R = phenyl, 57%
6b, R = 3-chlorophenyl, 59%
Scheme 4. Synthesis of benzosultam derivatives via regioselective Heck cyclization.
The generation of N-vinyl derivatives 7 and the formation of
regioisomeric products 8 and 9 in their Heck cyclization may be
rationalized as follows. The treatment of bromoallyl sulfone 4b
with cesium carbonate has been shown to generate a 1:5
mixture of propargyl and allenyl sulfones. It is also well-
known that allenyl, proargyl and acetylenic sulfones exist in
1
0a
1
1b
equilibrium under basic conditions. It is therefore likely that
the sulfonamide anion 17, generated from 6 by cesium
carbonate-mediated deprotonation, undergoes an aza-Michael
addition to the allenyl sulfone (Scheme 5). Alternatively, the
capture of sulfonamide nucleophile 17 by acetylenic sulfone,
that may be present in the system, could lead to a vinyl
sulfone. The latter may then isomerise to the more
thermodynamically stable allyl sulfone 7. On the other hand,
the cesium carbonate-mediated reaction of 4a-b with the
phenol 10 afforded only vinyl sulfones 11a-b as the products
as depicted in scheme 3. It is likely that the energy benefit
from extended conjugation in 11 is sufficient to offset the
inherent thermodynamic stability of the corresponding allyl
sulfone. The scenario is different for the sulfonamides 7 in
which the nitrogen lone pair is already conjugated to the
sulfonamide part and no significant energy gain is available
from extended conjugation to the sulfone group.
2
-substituted benzofurans 12a-b as major products as there is
no O-substituent to exert any steric repulsion.
Me
PdLn
PdLn
S
O
I
O
Pd(0)
Et3N
O
Et3N
Heck
O
9a
S
N
S
O
N
N
S
O
O
Major
Ts Ts
O
Me
7
a
Me
Me
More crowded, 18a
Favoured, 18b
sulfonamide-sulfonylarene interaction dominant
Me
PdLn
PdLn
S
O
O
O
I
O
Heck
S
Et3N
8g
Pd(0)
3
N
S
O
N
S
O
N
Et N
Me
O
Ms Ts
Me
Me
O
7h
More crowded, 19b
Favoured, 19a
sulfonylarene-PdLn interaction dominant
Scheme 6. Plausible steric control of regioselectivity of Heck cyclization
4
| J. Name., 2012, 00, 1-3
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ARTICLE
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F. Piscitelli, A. Coluccia, A. Brancale, G. VLiaewRAertigcilenOan,liAne.
Conclusions
Sansone, C. Giardano, J. Balzarini, G. Maga, S. Zanoli, A.
DOI: 10.1039/D0OB01623C
In summary, a two-step, regioselective synthesis of arylsulfonyl
group-bearing indoles, benzofurans and benzosultams from
readily available starting materials were developed. The Heck
cyclization led to the formation of two regioisomeric products
in the case of indoles and benzofurans, as the participating
double bond isomerized in the presence of base used in the
reaction. The regioselectivity of indole-forming Heck
cyclization was heavily dependent on the nature of N-sulfonyl
group of the starting sulfonamide. Exclusive selectivity in
favour of the more substituted regioisomer was observed in
the formation of benzosultams. Interestingly, the precursors
Samuele, R. Cirilli, F. La Torre, A. Lavecchia, E. Novellino
and R. Silvestri, J. Med. Chem., 2009, 52, 1922–1934.
T. J. Schnitzer, J. M. Popovich, G. B. Andersson and T. P.
Andriacchi, Arthritis Rheum., 1993, 36, 1207-1213.
(a) D. Gao, M. Parvez and T. G. Back, Chem. Eur. J.,
6
7
2
010, 16, 14281-14284; (b) J. S. Yadav, B. V. S. Reddy,
A. D. Krishna and T. Swamy, Tetrahedron Lett., 2003,
4
4, 6055-6058; (c) B. Prasad, R. Adepu, S. Sandra, D.
Rambabu, G. R. Krishna, C. M. Reddy, G. S. Deora, P.
Misra and M. Pal, Chem. Commun., 2012, 48, 10434-
1
0436; (d) S. E. Lopez, R. Gallagher, R. J. Gilliland, I.
Ghiviriga and W. R. Dolbier Jr., J. Fluor. Chem., 2017,
193, 118-125; (e) C. C. Chen and J. Waser, Org. Lett.,
2
015, 17, 736-739.
for Heck coupling reaction were generated conveniently via a
8
(a) R. J. Reddy, J. J. Kumar, A. H. Kumari and G. R.
Krishna, Adv. Synth. Catal., 2020, 362, 1317-1322; (b)
M.-Y. Chang, Y.-S. Wu and H.-Y. Chen, Org. Lett., 2018,
2
Cs
2
CO
3
-mediated formal substitution reaction at the sp -
carbon of 2-bromoallyl sulfones. As the Heck coupling reaction
itself constitutes a formal substitution reaction at an
unsaturated carbon, the sequence of reactions may be viewed
as two consecutive formal vinylic substitution reactions.
2
0, 1824-1827; (c) J. Liu, Z. Liu, P. Liao and X. Bi, Org.
Lett., 2014, 16, 6204-6207; (d) E. J. Emmet, B. R. Hayter
and M. C. Willis, Angew. Chem. Int. Ed., 2013, 52,
1
2679-12683.
(a) S. Debnath and S. Mondal, Eur. J. Org. Chem., 2018,
33-956; (b) A. S Reddy, A. L. S. Kumari, S. Saha and K.
C. Kumara Swamy, Adv. Synth. Catal., 2016, 358, 1625-
9
1
9
Acknowledgements
1
638.
DY acknowledges the award of a Senior Research Fellowship
from the Council of Scientific and Industrial Research (CSIR),
India. RSM acknowledges the Science and Engineering
Research Board, Department of Science and Technology (SERB-
DST), India, for an Early Career Award Grant
0
(a) S. Undeela, S. Thadkapally, J. B. Nanubolu, K. K.
Singarapu and R. S. Menon, Chem. Commun., 2015, 51,
1
3748-13751; (b) S. Undeela, G. Ravikumar, J. B.
Nanubolu, K. K. Singarapu and R. S. Menon, Chem.
Commun., 2016, 52, 4824-4827; (c) S. Undeela, R.
Chandra, J. B. Nanubolu and R. S Menon, Org. Biomol.
Chem., 2019, 17, 369-373.
(ECR/2016/001401).
1
1
1
2
For reviews on the chemistry of allenyl sulfones, see:
(
a) T. G. Back, K. N. Clary and D. Gao, Chem. Rev., 2010,
1
10, 4498-4553; (b) T. G. Back, Tetrahedron, 2001, 57,
Conflicts of interest
There are no conflicts to declare.
5263-5301; (c) D. Yadav and R. S. Menon, Org. Biomol.
Chem., 2020, 18, 365-378.
(a) T. Hirata, Y. Sasada, T. Ohtani, T. Asada, H.
Kinoshita, H. Senda and K. Inomata, Bull. Chem. Soc.
Jpn., 1992, 65, 75-96; (b) K. Inomata, T. Hirata, H.
Suhara, H. Kinoshita, H. Kotake and H. Senda, Chem.
Lett., 1988, 2009-2012.
Notes and references
1
1
3
4
S. E. Gibson and R. J. Middleton, Contemp. Org. Synth.,
1
(a) N. S. Simpkins, Sulfones in Organic Synthesis,
1
996, 3, 447-471.
Pergamon Press, Oxford, 1993; (b) R. Alba Andrea-
Nekane, X. Companyó and R. Rios, Chem. Soc. Rev.,
(a) A. Kumar, S. Thadkappaly and R. S. Menon, J. Org.
Chem., 2015, 80, 11048-11056; (b) S. Thadkappaly, A.
C. Kunjachan and R. S. Menon, Beilstein J. Org. Chem.,
2
010, 39, 2018-2033; (c) M. Nielsen, C. B. Jacobsen, N.
Holub, M. W. Paixão and K. A. Jørgensen, Angew.
Chem. Int. Ed., 2010, 49, 2668-2679.
2
016, 12, 16-21.
1
1
5
6
S. Debnath and S. Mondal, J. Org. Chem., 2015, 80,
2
3
A. El-Awa, M. N. Noshi, X. M. du Jourdin and P. L.
Fuchs, Chem. Rev., 2009, 109, 2315-2349. (The
quotation from this review, however, may be
interpreted in the context of sulfone chemistry).
(a) C. J. Dinsmore, T. M. Williams, T. J. O'Neill, D. Liu, E.
Rands, J. C. Culberson, R. B. Lobell, K. S. Koblan, N. E.
Kohl and J. B. Gibbs, Bioorg. Med. Chem. Lett., 1999, 9,
3
940-3948.
J. Maruyama, H. Yamashita, T. Watanabe, S. Arai and A.
Nishida, Tetrahedron, 2009, 65, 1327-1335.
3
301-3306; (b) N. Neamati, A. Mazumder, H. Zhao, S.
Sunder, T. R. Burke Jr., R. J. Schultz and Y. Pommier,
Antimicrob. Agents Chemother., 1997, 41, 385-393; (c)
S. Harguindey, J. L. Arranz, J. D. P. Orozco, C. Rauch, S.
Fais, R. A. Cardone and S. J. Reshkin, J. Transl. Med.,
2
013, 11, 282-299; (d) V. Famiglini and R. Silvestri,
Antivir. Chem. Chemother., 2018, 26, 1-19.
4
R. Silvestri, G. De Martino, G. La Regina, M. Artico, S.
Massa, L. Vargiu, M. Mura, A. G. Loi, T. Marceddu and
P. La Colla, J. Med. Chem., 2003, 46, 2482–2493.
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