indole to conduct the experiments, the desirable product 3n and
3o were obtained. To be continued, we used N-methyl indole as
the reaction substrate, and the product 3p was obtained in 79%
yield. It was noteworthy that indoles with substituents (Ph or Me)
at the 2-position gave the desired products 3q (74%) and 3r (79%)
smoothly, furthermore, we used 3-methyl indole as the reactant,
we acquired the 2-thiolated indole (3s) with a good yield (70%).
control experiment indicates that TBAI plays a crucial role in this
reaction. Furthermore, in the absence of indole, the product 4-
Methylphenyl disulfide (4a)was obtained in 96% yield under the
optimized reaction conditions, meanwhile, iodide ion was
oxidized into iodine (scheme 3c). 4a was detached and structure
confirmation by Nuclear magnetic resonance. So we can
concluded that the disulfide compound was the reaction
intermediate undoubtedly. In the presence of 1.5 equivalents
iodine, indole (1a) smoothly reacted with 4-Methylphenyl
disulfide (4a) to give the corresponding 3-(p-Tolylthio)-1H-
indole (3a) in 98% yield (scheme 3d). next, we exchanged iodine
for tetrabutylammonium iodide to participate the reaction, we did
not obtain the product 3a (scheme 3e).
We also explored the various sulfonyl chloride for the reaction,
when naphthalenesulfonyl chloride was used for the reaction
under standard condition, the product 3t was attained in 64%
yield. Then, we utilized ethanesulfonyl chloride and
propanesulfonyl chloride to involve the reaction respectively, the
products 3u and 3v were obtained in 67%, 59% yield individually.
The yield of 3v was lower than 3u, it could engendered by steric
effects. And then, we used pyridine-3-sulfonyl chloride to
conduct the experiment, it also can obtain the desirable product
3w with decent yield (62%). It can certify the reaction has a good
substrate suitableility.
Scheme 2 Large-scale synthesis of 3a
To demonstrate the reaction efficiency of this TBAI promoted
thioltion reaction system, we tried to synthesis 3a (Scheme 2) in
large scale. The reaction of indole (1a, 10 mmol) and the p-
Toluenesulfonyl chloride (2a, 20 mmol) gave the desired product
3a in 91% yield under the optimal conditions. The method could
be used to prepare precursors of some important bioactive
molecules.
Scheme 4 Possible mechanism.
On the basis of the above experimental results, a possible
reaction mechanism was proposed in Scheme 4. Initially,
disulfide compound 4 is generated from sulfonyl chloride 2 in the
presence of reducing reagent TBAI and weak reducibility solvent
DMF.12 Then, disulfide compound 4 reacts with the preceding
ferous iodine to give the R2SI 5.13 Owing to the electronegativity
of iodine is superior to sulphur, so we think the iodine indicates
negative charge, the sulphur displays positive charge. In this
hypothesis, the sulfenyl iodine is nucleophilic attacked by indole
to generate the thioether (3), and the regenerate iodide reacts with
sulfonyl chloride (2) to obtain disulfide compounds (4) once
again. Thus repeatedly to promoted the reaction continually.
Conclusion
In conclusion, we have demonstrated an easy and efficient
TBAI-promoted C(3)–H sulfenylation of free (N–H) indoles in
one pot. In the presence of TBAI, the reactions performed well
under mild conditions without reject of air and moisture, and
generated highly regioselective indole thioethers in excellent
yields. Additionally, a broad range of indoles and sulfonyl
chlorides were tolerated in this method, and the method can be
performed on a large scale without any problem. More
significantly, compared with the traditional method of using
disulfide as raw material, sulfonyl chloride raw materials are
cheap and easily available. Further reaction mechanism and
synthetic application studies are currently underway in our labs.
Scheme 3 Control experiments
During above reactions, we observed that the color of
mixtures changed from light yellow to purple-black. So we
speculated that the reaction involves the formation of iodine.
Control experiments were carried out in order to elucidate the
reaction mechanism (Scheme 3). When the radical inhibitor
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2equiv) was
employed under the optimal conditions, we could also get 3a in
92% yield (Scheme 3a), which implies that the reaction was not a
radical process. Then, in the absence of tetrabutylammonium
iodide, we did not get the desired product 3a (Scheme 3b). This
Acknowledgment
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21502049 and 51573040), the
Planned Science and Technology Project of Hunan Province,
China (No. 2015WK3003), and Hunan Provincial Innovation
Foundation for Postgraduate (No. CX2015B076).
Supplementary data