Tetrahedron Letters
A NaH-promoted N-detosylation reaction of diverse
p-toluenesulfonamides
b
a
a
a
Wanwan Sun a,1, Xiaobei Chen b,1, Ying Hu c, , Huihui Geng , Yuanrui Jiang , Yuxin Zhou , Wenjing Zhu ,
⇑
Min Hu a, Haohua Hu a, Xingyi Wang a, Xinli Wang a, Shilei Zhang a, , Yanwei Hu a,
⇑
⇑
a Jiangsu Key Laboratory of Neuropsychiatric Diseases & College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
b State Key Laboratory of Bioreactor Engineering, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology,
Shanghai 200237, China
c Department of Pharmacy, Suzhou Vocational Health College, 28 Kehua Road, Suzhou 215009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A NaH-mediated detosylation reaction of various Ts-protected indoles, azaheterocycles, anilines and
dibenzylamine was reported. The method features cheap reagent, convenient operations, mild reaction
conditions and broad substrate scope. Moreover, this study revealed that the loading of NaH in tosylation
reactions of nitrogen-containing compounds with NaH as a base in DMA or DMF should be controlled due
to the possibility of adverse detosylation.
Received 2 July 2020
Revised 29 August 2020
Accepted 1 September 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Sodium hydride
Detosylation
P-toluenesulfonamides
Indole
The protection and deprotection of nitrogen-containing com-
pounds are very important topics in synthetic organic chemistry.
Among various protecting groups for amines, sulfonyl plays a vital
role due to the advantages of being stable to many reaction condi-
tions as well as easy preparation and isolation. Nevertheless, the
desulfonylation procedure is usually distinguished as a trouble-
some issue. To date, a lot of methods have been developed to
remove the sulfonyl groups, and some representative ones are as
follows: i) reductive cleavages of NAS bond with alkaline metals
[1], Mg [2], Al [3], SmI2 [4], Red-Al [5], low valent titanium [6],
organic electron donors [7], ii) basic conditions such as Grignard
reagent [8], MOH [9], M2CO3 [10], NaOMe [11], NaOt-Bu [12],
KPPh2 [13], LiSiMe2Ph [14], TBAF [15], iii) acidic conditions such
as HBr [16], HF [17], H2SO4 [18], iv) other approaches including
electrochemistry [19], photoinduced electron transfer [20] et al.
However, many of these strategies suffer from harsh reaction con-
ditions and low functional group tolerance. Therefore, develop-
ment of mild and efficient deprotection protocols for sulfonyl
groups (especially the most commonly used tosyl group) is
urgently required.
Recently, we disclosed a palladium-catalyzed debenzylation
method using sodium hydride (NaH) as reducing reagent
a
(Scheme 1a, 2 ? 1) [21], which could be considered as a reverse
process for the benzylation of phenol (1 ? 2). In the continuous
explorations in the field, we occasionally found that a detosylation
reaction took place when treating N-tosyl-indole with NaH in DMF
(Scheme 1b, 4a1 ? 3a). We were surprised because the tosylation
of indole (3a ? 4a1) also frequently applied NaH as a base in the
same solvent [10a,15]. Our discovery means excessive NaH is actu-
ally detrimental to the tosylation reaction. However, to our knowl-
edge, it has never been reported in previous literatures. To confirm
this finding and get insight into the novel detosylation reaction, a
series of experiments were conducted (Table 1).
We began our studies using Ts-protected indole 4a1 as a model
substrate to optimize the reaction conditions. First, several sol-
vents were tested (Table 1, entries 1–7). DMF, DMA and DMSO
were identified as effective reaction media to promote the detosy-
lation process [22,23] (Table 1, entries 5–7), whereas other sol-
vents could not give any product (Table 1, entries 1–4). We
speculate only polar aprotic solvents have the ability to activate
sodium hydride to break the NAS bond. Although the reaction tem-
perature was found to significantly alter the reaction speed, it
almost had no effect on the yield (Table 1, entries 6, 8–10). Finally,
evaluation of NaH loading revealed 2 equivalents provided the best
result (Table 1, entries 6, 11–12). Moreover, several other sulfonyl
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Corresponding authors.
1
These authors contributed equally to this work.
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: W. Sun, X. Chen, Y. Hu et al., A NaH-promoted N-detosylation reaction of diverse p-toluenesulfonamides, Tetrahedron Letters,