2-(Phenylseleno)ethanesulfon-amide as a novel protecting group for aniline that can be deprotected by a radical reaction

Article abstract of DOI:10.1016/j.tetlet.2016.05.002

Anilines were protected as 2-(phenylseleno)ethanesulfonanilide (SeES anilide) via sulfonylation by 2-chlorosulfonyl chloride followed by the conjugate addition of benzeneselenol. The SeES anilide was deprotected by radical reduction using tributyltin hydride in the presence of AIBN. The corresponding anilines were obtained in high yields when the hydride and AIBN were added to the system slowly. Since the radical reaction proceeds under neutral conditions, chemoselective deprotection of the SeES group was accomplished. The SeES anilide was stable under various conditions, including some severe conditions.

Full text of DOI:10.1016/j.tetlet.2016.05.002

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-(Phenylseleno)ethanesulfon-amide as a novel protecting group for
aniline that can be deprotected by a radical reaction
⇑
Nobuhiro Kihara , Yuji Mitsuhashi, Makoto Sato, Shun-ichi Hirose, Erika Goudo, Yoshinori Uzawa,
Natsumi Shirai, Sari Hamamoto, Ryo Iwasaki, Akane Fujioka
Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Anilines were protected as 2-(phenylseleno)ethanesulfonanilide (SeES anilide) via sulfonylation by 2-
chlorosulfonyl chloride followed by the conjugate addition of benzeneselenol. The SeES anilide was
deprotected by radical reduction using tributyltin hydride in the presence of AIBN. The corresponding
anilines were obtained in high yields when the hydride and AIBN were added to the system slowly.
Since the radical reaction proceeds under neutral conditions, chemoselective deprotection of the SeES
group was accomplished. The SeES anilide was stable under various conditions, including some severe
conditions.
Received 21 March 2016
Revised 23 April 2016
Accepted 2 May 2016
Available online xxxx
Keywords:
2-(Phenylseleno)ethanesulfonamide
Tributyltin hydride
Radical deprotection
Chemoselectivity
Ó 2016 Published by Elsevier Ltd.
Slow addition
Introduction
The protecting group of an amine is one of the most important
tools in organic synthesis. The sulfonamide group has been consid-
ered as one of the most stable protecting groups of amines as it
strongly resists both nucleophiles and electrophiles.1 Because of
the stability of the sulfonamide group, severe reaction conditions
are necessary for their deprotection; therefore, their use has been
limited in organic synthesis. Recently, novel sulfonamides that
can be selectively deprotected under mild reaction conditions have
been reported.2 However, more efficient deprotection strategies
are desired.
Scheme 1.
decompose to afford an aminyl radical that can be reduced to an
amine.
Radical reactions proceed under neutral conditions with high
chemoselectivity. If sulfonamide could be deprotected by a radical
reaction, it can be a potentially useful protecting group for an
amine.3 Zard et al. reported that the 2-(alkylsulfonyl)ethyl radical
produced from allylsulfone decomposes with the release of olefin
and sulfur dioxide to form an alkyl radical (Scheme 1).4 Further,
Moutrille and Zard reported the formation of amidyl radical from
allylsulfonamide in the same manner.5 These reactions prompted
us to develop a novel sulfonamide that can be deprotected by rad-
ical reduction. The b-radical of alkylsulfonamide produced from
the abstraction of the phenylseleno group can be expected to
Results and discussion
N-Methylaniline 1a was used as a precursor for the novel sul-
fonamide. Thus, 1a was treated with 2-chloroethanesulfonyl chlo-
ride 2, a cheap sulfonylation agent, in the presence of triethylamine
to afford the vinylsulfonamide 3a. The conjugate addition of ben-
zeneselenol to 3a afforded the 2-(phenylseleno)ethanesulfonamide
(SeES amide) 4a (Scheme 2). Both the reactions proceeded in high
yield. The crude product of 3a was analytically pure and could be
used in the second step without further purification.
The radical deprotection of the SeES group was investigated.
The reduction of 4a was carried out using tributyltin hydride as
the reducing agent to optimize the deprotection conditions. The
addition of tributyltin hydride to the reaction system all at once
⇑
Corresponding author. Tel.: +81 463 59 4111; fax: +81 463 58 9684.
E-mail address: kihara@kanagawa-u.ac.jp (N. Kihara).
http://dx.doi.org/10.1016/j.tetlet.2016.05.002
0040-4039/Ó 2016 Published by Elsevier Ltd.
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N. Kihara et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Me
N
Cl
Cl
Et3N
S
S
Ph
+
PhNHMe
O
O
O
O
3a
1a
2
Me
PhSe
PhSeH
S
SeES
N
O
O
Ph
4a
SeES-
Scheme 2.
afforded ethanesulfonamide 5a as the sole product. The primary
radical produced by the abstraction of the phenylseleno group
was trapped by tributyltin hydride before releasing ethylene.
Therefore, it was deduced that the slow addition of tributyltin
hydride was necessary to minimize the simple reduction. The solu-
tion of tin hydride and the initiator was added simultaneously to
the reaction system over a period of 20 h. First, the reaction was
attempted using 0.2 equiv of AIBN as the initiator. However, the
result obtained under this condition was not very reproducible.
The reproducibility improved with increasing amounts of AIBN.
At least, 1 equiv of AIBN was necessary to obtain reproducible
results. The yield of the reaction was maximum when 2 equiv of
AIBN was used; the use of 3 equiv of AIBN decreased the yield.
Therefore, 2 equiv of AIBN was used in further investigations.
The results are summarized in Table 1. The yield of 1a signifi-
cantly improved with increasing amounts of tributyltin hydride.
At least 4 equiv of tributyltin hydride was necessary to afford 1a
in good yield. When the reaction was carried out at 60 °C, a signif-
icant amount of 5a was produced. However, the yield decreased
when the reaction was carried out at 100 °C, and the highest yield
of 1a was obtained when the reaction was carried out at 80 °C.
The possible reaction mechanism is shown in Scheme 3. The tri-
butyltin radical abstracts the phenylseleno group to form the b-
sulfonyl radical. When the concentration of tributyltin hydride
was high, the b-sulfonyl radical was directly reduced by tributyltin
hydride to afford 5. When the concentration of tin hydride was
kept to a minimum by slow addition, the reaction proceeded in
an intramolecular fashion with the sequential release of ethylene
and sulfur dioxide. High reaction temperatures are necessary
because of the higher activation energy required for releasing ethy-
lene from the primary radical. However, higher reaction tempera-
tures decreased the efficiency of the radical initiator. The resulting
Scheme 3.
aminyl radical abstracts hydrogen from tributyltin hydride to
afford amine 1, and regenerates the tributyltin radical, thus com-
pleting the cycle. It was deduced that 1 equiv of tributyltin hydride
was used for the reduction of the SeES group, whereas 3 equiv of
tributyltin hydride was used for the reduction of the released
SO2. Because the resulting thiol (or tin sulfide) inhibited the radical
reaction, an excess amount of AIBN was necessary to consume the
radical scavengers.
One can suppose that benzeneselenol produced by the hydroly-
sis of PhSeSnBu3 strongly inhibited the radical reaction. Thus, the
radical reduction of N-methyl-2-(phenylthio)ethanesulfonanilide,
sulfur analogue of SeES amide 4a, was examined. Because of less
reactivity of the phenylthio group toward radical, higher tempera-
ture (160 °C) was necessary. However, excess initiator (6 equiv of
di-tert-butyl peroxide) and excess Bu3SnH (4 equiv) were also nec-
essary to obtain 1a in good yield (72%). These results indicate that
SO2 is the main source of radical scavenger although we cannot
exclude the possibility that benzeneselenol inhibited the radical
reaction in the case of 4a.
To avoid using excess tin hydride, we examined other hydride
sources such as triarylmethane, silanes, cyclohexadiene, benzoth-
iazoline, and benzoxazoline. Triarylmethanes acted as the hydride
sources. However, the best yield of 1a was less than 10% when 4-
methoxytriphenylmethane was used under xylene reflux condi-
tion. When tris(trimethylsilyl)silane6 (TMS3SiH) was used, 65% of
1a was obtained with 1 equiv of TMS3SiH. Excess TMS3SiH was
unnecessary because TMS3SiH did not reduce SO2 although the
efficiency and the reproducibility were lower than those of Bu3-
SnH. Other hydride sources did not afford 1a at all.
Table 1
Optimization of the reaction conditions for the deprotection of the SeES groupa
The radical deprotection of some SeES-protected amines 4 was
investigated. The results are summarized in Table 2. The SeES
group bound to the amino group of aniline derivatives was
smoothly deprotected under the standard conditions. When the
allyl group was introduced at the ortho-position (4d and 4e), no
radical cyclization product was observed although the system
became complex, and the yields of the starting amines were lower.
The SeES group could be selectively deprotected from 4g even in
the presence of the ester group because of the high chemoselectiv-
ity of the radical reaction under neutral conditions. Since aryl bro-
mide and 1,4-phenylenediamine interfered with the radical
reaction, the radical reduction of 4h and 4i was incomplete. In
the case of 4h, 1h was obtained in lower yield while over-reduction
product 1b was observed only in the yield of 1%. When 4j was
Bu3SnH (equiv)
Temperature (°C)
Yield (%)
1a
5a
1.0
2.0
3.0
4.0
3.0
3.0
3.0
80
80
80
80
60
100
Reflux
6
7
6
2
4
35
4
4
49
81
92
29
72
55
a
Reactions were carried out in toluene. Bu3SnH and AIBN were added dropwise
over the period of 20 h.
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N. Kihara et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2
Radical deprotection of SeES-protected amine 4a
Chart 1.
Amine
Preparation of
Solvent
Temp.
(°C)
Yield of 1
(%)
4b (%)
MeNH–Ph
1a
H2N–Ph
1b
BuNH–Ph
1c
66
37
42
Toluene 80
Toluene 80
Toluene 80
92c
79d
75c
36
43
Toluene 80
Toluene 80
21d
28d
d
51
32
61
Toluene 80
Toluene 80
Toluene 80
Toluene 80
79
87e
Scheme 4.
32d,f
The stability of the SeES protecting group under various reac-
tion conditions was studied as shown in Scheme 4. Sulfonamide
4a was stable even under strongly acidic conditions. When 4a
was treated with sodium methoxide, 4a was slowly converted into
the ether 9. However, 9 could be reverted to 4a by treating with
PhSeNa. Although 4a was inert to sodium borohydride, it reacted
with lithium aluminum hydride to afford the ethanesulfonamide
5a. Although reversion of sulfonamide 5a to 4a was not attained,
the former was so stable under lithium aluminum hydride condi-
tion that no deprotection of 5a to afford 1a was observed either.
As expected, 4a reacted rapidly with ozone to afford 3a, which
easily reverted to 4a, as shown in Scheme 2.
40
72
40
54e,g
35d
34c
Xylene
120
Xyleneh Reflux
a
Bu3SnH (4 equiv) and AIBN (100 mol%) were added dropwise over the period of
20 h.
b
Yield from 1 to 4 (two steps). Yields were not optimized.
GC yield.
c
d
e
f
Isolated after acetylation of the reaction mixture.
Isolated yield.
18% of SeES amide was recovered.
49% of SeES amide was recovered.
1,10-azobis(cyclohexane-1-carbonitrile) was used as the initiator.
Conclusion
g
h
We have developed a novel sulfonamide, 2-(phenylseleno)
ethanesulfonamide (SeES amide), as an effective protecting group
for aniline derivatives. SeES anilide was stable under various reac-
tion conditions; however, it could be readily deprotected in good
yield by a radical reaction. High chemoselectivity was achieved
because the radical reaction proceeded under neutral conditions.
Tin-free deprotection and application of the intermediary aminyl
radical are in progress.
treated under the standard deprotection conditions, only trace
amounts of 1j were observed, although neither 4j nor 5j was recov-
ered and PhSeSnBu3 was obtained. Therefore, the release of SO2 is
slow in the case of 4j. The lower efficiency for the SO2-release can
be explained by the absence of an aromatic or related conjugate
substituent that stabilizes the aminyl radical intermediate.5,7 To
enhance the SO2-release, the reaction of 4j was carried out at
higher temperatures, and the maximum yield of 35% was obtained
when the reaction was carried out at 120 °C. Similarly, the depro-
tection of 4k gave 1k in 34% yield when the reaction was carried
out under xylene-reflux condition.
The chemoselective deprotection of SeES group was demon-
strated. The radical reduction of 4a in the presence of Boc-, Cbz-,
and Ts-protected N-butylanilines 6, 7, and 8 was carried out
(Chart 1). The deprotection proceeded without the loss of the yield
of 1a. No N-butylaniline was observed, and 6, 7, and 8 were quan-
titatively recovered, respectively. The stability of Ts group under
the deprotection condition indicates the importance of the
phenylseleno group for the deprotection reaction.
Supplementary data
Supplementary data (experimental details and spectroscopic and
analytical data) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2016.05.002.
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