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G. Tocco et al. / Tetrahedron Letters 54 (2013) 6237–6241
Table 1
ZnO and temperature effect on reaction between indole 1a and TsCl 2a
Ts
ZnO, 80 °C
solvent free
+
TsCl
+
N
N
H
N
2a
H
Ts
1a
Entry
4aa
5aa
ZnO/1a
Time (h)
Temperature (°C)
Yield (%)
4aa 5aa
1
2
3
4
5
6
7
8
17/1
17/1a
17/1
17/1
17/1
17/1
7.5/1
3/1
6
6
6
1
3
1.5
2
2
2
3
3
6
6
rt
rt
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
45
65
65
80
80
80
80
80
80
80
80
50
48
98
95
96
97
—
65
60
—
Scheme 1. Synthesis of 2-sulfonyl indoles.
9
3a/1
2/1
In the last decade, some interesting examples of the use of zinc-
mediated Friedel–Crafts acylation or sulfonylation of aromatic
substrates have been reported. Particularly, the inexpensive and
non-toxic ZnO is indeed one of the most interesting solids in
surface synthetic organic chemistry.
10
11
12
13
1/1
0.1/1
—
—
a
THF, DCE, DMF, and toluene were used as solvents.
In fact, it has been recently reported its application in the acyl-
ation of aromatic substrates.14
Thus, in the quest of developing an alternative mild and versa-
tile protocol, we report the regioselective direct one-pot synthesis
of 2-and 3-arylsulfonyl-1H-indoles, carried out under solvent-free
conditions and in the presence of ZnO (Schemes 1 and 2).
Firstly, our efforts have been focused on the synthetic procedure
paying particular attention to the role of the oxide and the effect of
the substituent on the aromatic rings of both 1 and 2.
The amount of the oxide and the temperature were determi-
nants for the proceeding of the reaction, as showed by the typical
experiment between 1a and 2a. Fixing the temperature at 80 °C
and the ZnO/1a ratio at 3/1, showed to be the best way to run
the reaction.15 Particularly, the reaction did not proceed in the
presence of the indicated solvents. (Table 1)
indole 7, usually obtained via direct oxidation of the correspondent
sulfide,16 were also isolated (Tables 3 and 4). Further investigation
is now in progress to understand the reaction mechanism.
The role of indole was more deeply investigated. Electron with-
drawing groups inhibited the electrophilic substitution reaction,
while the other substrates underwent C-sulfonylation with a regi-
oselectivity strictly related to the employed sulfonyl chloride (Ta-
ble
5 and Scheme 3). Specifically, the amount of N-isomer
increased with highly reactive sulfonyl reagents such as 2f, 2h,
and 2j.
Moreover, 1-substituted indoles gave poor results, especially
when electron withdrawing groups were present on nitrogen
(Scheme 4).
Then, the scope of the reaction was extended to a wide variety
of aryl sulfonyl chlorides. (Table 2)
As shown, the 3-sulfonyl derivatives were always obtained in
moderate to excellent yields. In particular, under our operative
conditions, the formation of 1-(arylsulfonyl)-1H-indole isomer 5
is extremely reduced (entries 4–6, 8, 9) or totally inhibited (entries
1–3, 7,10). Noteworthy, the reaction was less regioselective when
strongly deactivated substrates were used (entries 5 and 9). No
C-2 or C-5 isomers were ever detected.
Notably, when indoles 1a, 1b, 1j, and 1l and sulfonyl chlorides
2f, 2h, 2j, and 2k supporting strong electron withdrawing groups
were used, the correspondent 2-sulfinyl indole 6 or 3-sulfinyl
Table 2
C-3 sulfonylation of indole 1a with arylsulfonyl chlorides 2b–k
SO2Ar
ZnO, Δ
+
ArSO2Cl
+
N
H
N
H
N
solvent free
2
SO2Ar
1a
4
5
Entry Sulfonyl Chloride
(4)
Yield (%) (5)
Yield (%) Time (h)
1
2
3
PhSO2Cl
2b 4ab 98
—
—
—
—
—
—
2
2
3
4-C(Me)3PhSO2Cl 2c 4ac 96
4-ClPhSO2Cl
2d 4ad 94
2e 4ae 85
4
5
5ae 10
3
3
2f 4af 45a
5af 20
5ag 10
—
5ai
6
7
8
4-OMePhSO2Cl
3-NO2PhSO2Cl
3,5-diMePhSO2Cl 2i
2g 4ag 60
3
3
3
2h 4ah Tracesa,b
—
5
4ai
80
9
2j
4aj
40a
5aj 15
3
3
10
3-CF3PhSO2Cl
2k 4ak Tracesa,b
—
—
a
C-Arylsulfinyl indole was also isolated.
GC yields.
b
Scheme 2. Synthesis of 3-sulfonyl indoles.
Tocco, Graziella
