A NaH-promoted N-detosylation reaction of diverse p-toluenesulfonamides

Article abstract of DOI:10.1016/j.tetlet.2020.152442

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.

Full text of DOI:10.1016/j.tetlet.2020.152442

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
⇑
Corresponding authors.
E-mail addresses: yhu@szhct.edu.cn (Y. Hu), zhangshilei@suda.edu.cn (S. Zhang),
huyanwei@suda.edu.cn (Y. Hu).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2020.152442
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,
https://doi.org/10.1016/j.tetlet.2020.152442

W. Sun et al.
Tetrahedron Letters xxx (xxxx) xxx
a) NaH-mediated benzylation and debenzylation
OH
OBn
NaH, BnBr
(classical method)
NaH, Pd(OAc)2
(our previous work)
1
2
b) NaH-mediated tosylation and detosylation
TsCl, NaH, DMF
(classical method)
N
Ts
N
H
NaH, DMF or DMA
(this work)
4a
3a
Scheme 1. The NaH-mediated ‘reversible’ reactions.
Table 1
Optimization of the reaction condition.a
Scheme 2. Substrate scope for the detosylation of indole-based sulfonamides.
detosylation reagents.9a In addition, the potentially reactive alkyl
chloride of 4d and acidic acetyl group of 4h did not affect the deto-
sylation reaction, smoothly delivering the indole products 3d and
3h. Gratifyingly, scale-up of 4a1 to 1g level gave target product
3a in good yield (85%).
Encouraged by the success of indoles, we next tried to expand
the substrate scope to other heterocycles and secondary amines
(Scheme 3). To our delight, many types of biologically important
azaheterocycles, such as 1H-indazole (6a-c), benzimidazole (6d-
h), benzotriazole (6l), dibenzopyrrole (6i-k) and phenothiazine
(6m), could be produced from their Ts-protected precursors under
the NaH/DMA conditions. It seems that the nitro group has some
adverse impact on the reaction by generating messy byproducts,
but still could afford deprotection products in moderate yields
(6c and 6e). The competitive ester group in benzimidazole 5f sur-
vived the detosylation conditions to give 6f in 84% yield. Moreover,
it was demonstrated the methodology was also suitable for various
Ts-protected common secondary amines, represented by the gen-
eration of tetrahydroquinoline 6n, N-methylaniline 6o, dipheny-
lamine 6p, and dibenzylamine 6q.
Entry Substrate NaH
(eq.)
Solvent
Temp
(°C)
Time
(h)
Yield
(%)b
1
2
3
4a1
4a1
4a1
2
2
2
THF
toluene
1,4-
dioxane
DME
DMF
DMA
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
60
60
60
12
12
12
NR
NR
NR
4
5
6
7
8
9
10
11
12
13
14
15
16
4a1
4a1
4a1
4a1
4a1
4a1
4a1
4a1
4a1
4a2
4a3
4a4
4a5
2
2
2
2
2
2
2
1.4
1.8
2
2
2
60
60
60
60
25
40
80
60
60
60
60
60
25
12
3
3
1
8
6
2
12
4.5
2
NR
90
92
88
89
87
89
64
91
72
0c
3
2
0.5
70
83
2
aReaction conditions: 4a (0.2 mmol, 1 equiv) and NaH (1.4–2.0 equiv) in dry solvent
(1.5 mL) was stirred under N2 for specified time. bIsolated yield. cNo desired 3a was
detected, and 4a3 was recovered in 78% yield.
groups were evaluated under the optimial deprotection conditions
(Table 1, entries 13–16). Although 4-methoxybenzenesulfonyl pro-
tected indole 4a2 gave 3a in good yield (Entry 13), no desired
deprotective product was detected in the case of 4-nitrobenzene-
sulfonyl substrate 4a3 (Entry 14). Methanesulfonyl (Entry 15)
and trifluoromethanesulfonyl (Entry 16) also proved to be good
leaving groups under NaH/DMA conditions.
With the optimized conditions in hand, we then investigated
the substrate scope of the detosylation reaction. As shown in
Scheme 2, a number of Ts-protected indoles bearing electron-
donating and electron-withdrawing substituents were successfully
detosylated by NaH in DMA at 60 °C. The corresponding Ts-free
products 3a-s were isolated in moderate to excellent yields
(52–96%). It is worthy noting that substrate 4b containing an ester
moiety also generated desired product 3b by selectively deprotect-
ing the tosyl group, which was difficult to achieve for other basic
Scheme 3. Substrate scope for the detosylation of Ts-protected azaheterocycles
and secondary amines.
2

W. Sun et al.
Tetrahedron Letters xxx (xxxx) xxx
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152442.
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Acknowledgments
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