Using sulfinamides as high oxidation state sulfur reagent for preparation of sulfenamides

Article abstract of DOI:10.1016/j.tetlet.2018.03.033

Traditional preparation of sulfenamides require the use of low oxidation state of sulfur reagent such as RSCl, (RS)₂ or RSH, which are toxic, odorous and difficult to deal with due to the harsh reaction conditions. Here high oxidation state of

Full text of DOI:10.1016/j.tetlet.2018.03.033

Accepted Manuscript
Using Sulfinamides as High Oxidation State Sulfur Reagent for Preparation of
Sulfenamides
Long-jun Ma, Guang-xun Li, Jin Huang, Jin Zhu, Zhuo Tang
PII:
S0040-4039(18)30330-7
https://doi.org/10.1016/j.tetlet.2018.03.033
TETL 49802
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
1 February 2018
12 March 2018
13 March 2018
Please cite this article as: Ma, L-j., Li, G-x., Huang, J., Zhu, J., Tang, Z., Using Sulfinamides as High Oxidation
State Sulfur Reagent for Preparation of Sulfenamides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.033
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Using Sulfinamides as High Oxidation State Sulfur Reagent for
Preparation of Sulfenamides
Long-jun Ma, [a,b] Guang-xun Li, *[c] Jin Huang, [c] Jin Zhu, *[a] and Zhuo Tang *[c]
aChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041(China)
E-mail: jinzhu@cioc.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China
cNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Science, Chengdu,
Sichuan 610041(China) E-mail: ligx@cib.ac.cn; E-mail: tangzhuo@cib.ac.cn
Abstract: Traditional preparation of sulfenamides require the use of low oxidation state of sulfur
reagent such as RSCl, (RS)2 or RSH, which are toxic, odorous and difficult to deal with due to the
harsh reaction conditions. Here high oxidation state of sulfur reagent—aliphatic sulfinamide, were
used for preparation of sulfenamide in one step efficiently. Different aromatic amines with all sorts
of functional groups, especially amino groups and hydroxyl groups, were transformed to the
corresponding sulfenamides in moderate yields, which was difficult to obtain with previous
methods.
Keywords: Sulfenamides; Sulfinamides; Catecholborane; Tert-butylsulfinamide
Introduction
Sulfenamides, with a sulfur–nitrogen bond, has garnered great attention in the chemical
community over the years due to their unique bond properties and widespread applications. For
example, such compounds were found to be superior to elemental sulfur as cross-linking agents in
the vulcanization of natural and synthetic rubber.1 Meanwhile, sulfenamides were efficiently
applied in agriculture as fungicides, pesticides, plant growth regulators, Figure 1. In addition,
sulfenamides have displayed many interesting biological activities such as inhibitors of platelet
lipoxygenase, antiasthmatic agent, and antitumor activities, Figure 1.1a For synthetic chemists,
sulfenamides are useful reagent in organic synthesis. For instance: oxidation of alcohol as a
catalyst in the presence of N-chlorosuccinimide,2 introduction of sulfur for functionalization of
alkenes,3 introduction of sulfur for asymmetric functionalization of active methenyl groups,4
served as an useful nitrogen protecting method, especially in the peptide synthesis.5

Figure 1 Biological applications of sulfenamides in agriculture and medicines
Because of their industrial applications, their utility as synthetic reagents, and their interesting
biological activities, synthetic routes to sulfenamides have been developed over years.6 These
methods can be categorized according to the oxidation state of sulfur in sulfur-containing reagent,
scheme (scheme 1): 1) use of sulfur reagents RSCl (eq.1);7 2) use of disulfides RSSR in which the
oxidation state of sulfur is lower by one unit (eq. 2);8 3) use of thiols RSH in which the oxidation
state of sulfur is lower by two units. However, using of RSCl as sulfur reagents was restricted to
its thermal and moisture sensitivity.9 Meanwhile, using of disulfides RSSR as sulfur reagent was
subjected to the slightly lower yield due to the production of byproducts (R1S)2NR2. In addition,
the direct cross dehydration with RSH and amines or imines, were limited to aromatic thiols.10
Generally, the above methods were suffered from the toxic sulfur reagent, the side products as
well as the ungenerous substrates. Therefore, using of odorless high oxidation sulfur reagent as
substrate for preparation of sulfenamides was significant.
Scheme 1 Background researches of sulfenamides preparation

Du and co-worker’s recent research indicated that catecholborane (HBCat) could react with
tert-butylsulfinamide to afford compound 1 via coordination of oxygen and boron, Scheme 2.11
We hypothesized that suitable nucleophiles could react with compound 1 due to the possibility of
intensified electrophilic property of sulfur through intramolecular coordination between the Lewis
basic oxygen and the Lewis acid boron. Meanwhile, we speculated that amine could be used as
proper nucleophiles to react with compound 1 and afford corresponding sulfenamides via
transition state TS1 according to Zeng’s work.12 Herein we developed an interesting method for
preparation of sulfenamides with aliphatic sulfinamides. To the best of our knowledge, reduction
of sulfinamides to sulfenamides were rarely seen despite the oxidation of sulfenamindes to
sulfinamides were easy.13
Scheme 2. Hypothesis of this work
Initially, the reaction was investigated with tert-butylsulfenamide, HBCat and aromatic amine
at 70 ℃. As expected, we found the target product with low yield, (Table 1, entry 1). Then the
reaction solvent as well as the reaction temperature were screened, which revealed that the
reaction yield could be slightly increased with toluene as solvent at 80 ℃, (Table 1, entries 2-7).
However the reaction yield was generally low (<30%). To our delight, we found TEA could
catalyze the reaction with higher yield (Entry 8). Therefore different catalysts including organic
base and inorganic base were screened. The results revealed that DMAP was the optimal catalysts
with 74% yield, (Entries 8-13). Further optimizing reaction temperature with DMAP as catalyst
revealed that 80 ℃ was still optimal, (Table 1, entries 14-15). Therefore the optimal reaction
condition was considered as: DMAP as catalyst at 80 ℃ in toluene for 24 h under nitrogen.

Table 1. Reaction condition screeninga
entry
1
solvent
toluene
benzene
1,2-DCE
THF
cat.
temp. (℃)
70
yieldb (%)
24
-
2
-
70
20
3
-
70
12
4
-
70
5
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-
60
5%
6
-
80
29%
27%
51%
47%
30%
30%
74%
25%
67%
72%
7
-
90
8
TEA
DIPEA
DBU
DABCO
DMAP
K2CO3
DMAP
DMAP
80
9
80
10
11
12
13
14
15
80
80
80
80
75
90
a Condition: 2 (0.25 mmol), 3a (0.25 mmol), 4 (0.3 mmol),
catalyst (10 mol%), solvent in 0.125 M concentration for 16 h; b
the reaction yield was calculated based on purification with fast
silicon column.
With the optimal reaction condition, we explored the substrates scope, (Scheme 3). Firstly,
aromatic amines with alkoxy groups were investigated, which revealed that corresponding
sulfenamides (5b-5f) could be obtained with moderate to excellent yield (60-85%). Then
sulfenamides with methyl groups (5h-5i), halogen groups (5j-5k) or trifluoromethyl (5l) were
obtained under the optimal reaction condition in moderate yield (60-79%). Based on the above
results, we could conclude that the method was general for aromatic amines with electron
withdrawing groups or electron donating groups.

Scheme 3. Investigation of the scope of the aromatic amines

Then we turned to investigate aromatic amines with active hydroxyl group, amino groups or
sulfonamide, the results revealed that these aromatic amines could be transformed to the related
sulfenamides (5m-5q) with moderate yields (40-65%). To the best of our knowledge, these
substrates were inefficient with previous methods. Meanwhile, we found that sulfenamide 5q was
selectively obtained with benzene-1,3-diamine as substrate. Moreover, secondary aromatic amines
were also investigated and the corresponding sulfenamides (5r-5s) were obtained with moderate
yield (70-75%). Benzylamine, butan-1-amine and pyrrolidine were investigated, which revealed
that the corresponding sulfenamides could not be obtained, (Scheme 3). We speculated that
aliphatic amine might coordinate with boron and retard the nucleophilic reaction. Finally,
Heterocyclic amines such as pyridin-2-amine was investigated which demonstrated that
heterocyclic amines didn’t work in this reaction (Scheme 3).
On the other hand, other alkyl (branched or unbranched) sulfinamides were explored under the
optimized reaction condition, the corresponding sulfenamides (5t-5w) were obtained with
moderate yields (60-75%). Moreover, aromatic sulfinamide 3e was investigated under the optimal
reaction conditions, Scheme 3. Interestingly, the corresponding sulfenamide 6a was obtained in
70% yield. Meanwhile, we found the production of unsymmetrical diaryl sufide 6b in 10% yield.
We speculated that diaryl sufide 6b might be formed via the rearrangement of sulfenamide 6a
under high reaction temperature according to the literature.14
Scheme 3 investigation of aromatic sulfinamide as substrate
To verify the proposed reasonable mechanism, the reaction mixture was analyzed with HRMS
and the existence of the reaction byproduct was proved by finding the related oxidation
products.15(Figure 2).

Figure 2. Detection of the by-product of the reaction
Conclusion
In summary, we have developed an efficient method for preparation of sulfenamides with high
oxidation state odorless sulfinamides as sulfur reagent. This method was efficient for transforming
all sorts of aromatic amines to corresponding sulfenamides. Especially, the method was efficient
for aromatic amines with active hydroxyl, amino or sulfonamido groups, which were incapable
with previous methods. Moreover, aliphatic and aromatic sulfinamides could be used as substrate
for preparation of the corresponding sulfenamides. The reaction mechanisms and the application
of this method for preparation and screening of biologically active compound are underway in our
lab.
Acknowledgements
This work was supported financially by the Natural Science Foundation of China
(21402188) and Natural Science Foundation of Sichuan province, China (2017JY0055).
Supplementary data
Supplementary data (detailed experimental procedure and spectroscopic data) associated
with this article can be found, in the online version.
Notes and references
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Graphical abstract

Highlights
Better functional group tolerance;
Odorless aliphatic sulfenamide were used as sulfur reagent;
Easy to perform in one step;