A novel method for tosyloxylation of anilides using phenyliodine bistrifluoroacetate (PIFA)

Article abstract of DOI:10.1016/j.tetlet.2011.06.041

The direct tosyloxylation of anilides was described in this Letter. In the presence of phenyliodine bis(trifluoroacetate) (PIFA) and BF₃· Et₂O, the reaction of anilides with TsOH provided para-tosyloxylated products with high regiose

Full text of DOI:10.1016/j.tetlet.2011.06.041

Tetrahedron Letters 52 (2011) 4324–4326
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Tetrahedron Letters
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A novel method for tosyloxylation of anilides using phenyliodine
bistrifluoroacetate (PIFA)
⇑
Huan Liu, Yuanzhen Xie, Yonghong Gu
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 March 2011
Revised 5 June 2011
Accepted 10 June 2011
Available online 17 June 2011
The direct tosyloxylation of anilides was described in this Letter. In the presence of phenyliodine bis(tri-
fluoroacetate) (PIFA) and BF3ÁEt2O, the reaction of anilides with TsOH provided para-tosyloxylated prod-
ucts with high regioselectivity under mild conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Over the past two decades, hypervalent iodine compounds have
been the focus of great attention in organic synthesis due to their
unique features as mild, environmentally friendly and selective
oxidizing properties.1 Many new applications of hypervalent io-
dine compounds in the formation of C–O2, C–N3 and C–C4 bonds
have been developed. Among them [hydroxyl(tosyloxy)iodo]ben-
zene (PhI(OH)(OTs), Koser’s reagent) mediated tosyloxylation is
one of the attractive processes.5 Tosyloxylation of ketone with
3.0 equiv of TsOHÁH2O in the reaction improved the yield of 2a to
35% (entry 2). Thus, we investigated the use of other hypervalent io-
dine compoundsas the oxidantand TsOH as a nucleophile. When the
combination of phenyliodine(III) diacetate (PIDA) and TsOHÁH2O
was employed, the reaction gave product 2a in 36% yield (entry 4).
When more reactive PIFA was used, the reaction proceeded effi-
ciently to give 2a in 61% yield (entry 6). Using BF3ÁOEt2 as a Lewis
acid accelerated the reaction and dramatically improved the yield
of 2a (entry 7). After careful optimization of reaction conditions
(solvent and temperature), the best result was achieved when the
reaction was carried out in the presence of 1.5 equiv of PIFA and
1.5 equiv of BF3ÁOEt2 with 3.0 equiv of TsOHÁH2O in CH3CN at room
temperature for 0.5 h.
PhI(OH)(OTs) provided
a-tosyloxyketones, which are valuable
intermediates to synthesize heterocyclic compounds.6 Despite
numerous studies of oxidation of ketone with PhI(OH)(OTs), com-
parably, little has been known about the tosyloxylation of aromat-
ics with hypervalent iodine compounds. In 2006, Koser et al. found
that oxidative substitution of polycyclic aromatic hydrocarbons
with PhI(OH)(OTs) provided the corresponding sulfonates in mod-
erate yields.7 Recently Parakash and coworkers reported a tosyl-
oxylation of substituted phenols with PhI(OH)(OTs).8 It was
founded that ortho-substituted phenol could be tosyloxylated at
para-position of phenol using PhI(OH)(OTs) as an oxidant. How-
ever, for this reaction is required an electron withdrawing substi-
tuent at the ortho position of phenol. In our recent studies, we
found that oxidation of anilides with phenyliodine(III) bis(trifluo-
roacetate) (PIFA) in the presence of AcOH or alcohols provided
the para-oxygenated products.9 In continuation of our interest in
hypervalent iodine chemistry, we herein report a novel tosyloxyla-
tion of anilide using phenyliodine(III) bis(trifluoroacetate) (PIFA)
with toluenesulfonic acid (TsOH) to provide aryl tosylate, an
important structure motif in coupling reactions10 and medicinal
chemistry.11
Table 1
Optimization of reaction conditionsa
TsOH.H2O (3.0 equiv)
NHAc
NHAc
oxidant (1.5 equiv)
additive (1.5 equiv)
solvent, rt, 0.5 h
TsO
1a
2a
Entry
Oxidant
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PIDA
PIDA
PIFA
PIFA
PIFA
PIFA
None
None
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CF3CH2OH
CH2Cl2
12c
35
51
36
45
61
93
<5
<5
BF3ÁOEt2
None
BF3ÁOEt2
None
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
Acetanilide (1a) was employed as the substrate for optimizing
reaction conditions and the results are outlined in Table 1. Initially
PhI(OH)(OTs) was chosen as a tosyloxylating reagent, treatment of
1a with 1.5 equiv of PhI(OH)(OTs) in CH3CN afforded only 12% of
para-tosyloxylated product 2a (entry 1). Interestingly, adding
a
Unless otherwise specified, all the reactions were carried out in the presence of
0.2 mmol of 1a, 0.6 mmol of TsOHÁH2O, 0.3 mmol of oxidant and 0.3 mmol of
additive in 1 mL of solvent at room temperature for 0.5 h.
b
⇑
Isolated yield after column chromatography.
0.3 mmol of PhI(OH)OTs was used, no TsOHÁH2O was employed.
Corresponding author. Tel.: +86 551 3602470; fax: +86 551 3601592.
E-mail address: ygu01@ustc.edu.cn (Y. Gu).
c
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.041

H. Liu et al. / Tetrahedron Letters 52 (2011) 4324–4326
4325
Table 2
Table 2 (continued)
Direct sulfonyloxylation of anilides with PIFAa
Entry
Substrate
NHAc
Product
Yieldb
R2
N
R2
N
TsOH.H2O (3 equiv)
PIFA (1.5 equiv)
BF3 OEt2 (1.5 equiv)
NHAc
R3
R3
O
O
15
62g
.
R1
TsO
R1
S
O
p
O
O2N Ph
O
1a
2o
CH3CN, rt, 0.5 h
2
1
a
Unless otherwise specified, all the reactions were carried out in the presence of
Entry
1
Substrate
NHAc
Product
Yieldb
93
0.2 mmol of 1, 0.6 mmol of TsOHÁH2O, 0.3 mmol of PIFA and 0.3 mmol of BF3ÁOEt2 in
1 mL of CH3CN at room temperature for 0.5 h.
NHAc
b
Isolated yield after column chromatography.
The reaction was carried out at 50 °C.
The yield in parenthesis based on the recovered starting materials.
0.3 mmol of PhI(OH)(OTs) was used instead of PIFA.
p-methoxybenzenesulfonic acid was used instead of TsOH.
p-nitrobenzenesulfonic acid was used instead of TsOH.
c
d
2a
TsO
1a
NHAc
e
NHAc
f
g
2
3
97
85
TsO
TsO
1b
NHAc
2b
NHAc
With an optimized reaction condition in hand, we started an
investigation of substrate scope and results are summarized in
Table 2. In the presence of 1.5 equiv of PIFA and 1.5 equiv of
BF3ÁOEt2, the reactions of anilides with TsOHÁH2O provided the
corresponding para-tosyloxylated products in 16–97% yields.
These reactions are tolerant to a variety of functional groups, such
as alkyl, methoxyl, fluoride, chloride, bromide, ester groups (en-
tries 2–10). Generally the electron donating substitute at the ani-
lide facilitates the reaction. For example, tosyloxylation of 2-
methoxyanilide (1d) with TsOH and PIFA provided the corre-
sponding product 2d in excellent yield (entry 4). In contrast,
when an electron withdrawing group, such as an ester group,
was introduced at the ortho position of anilide, the reaction gave
only 16% para-tosyloxylated product 2h with most of starting
materials recovered (entry 8). Prolonged reaction time and higher
temperature were not effective in this transformation. Next we
examined the substitution effect on the acetamino group. Tosyl-
oxylation of N-methylacetanilide (1k) proceeded well to give 2k
in 65% yield at 50 °C for 0.5 h (entry 11). Notably, the reaction
of the electron-deficient trifluoroacetanilide (1l) with PIFA and
TsOH provided only the trace amount of tosyloxylated product
2l. When PhI(OH)(OTs) was used as the oxidant instead of PIFA,
the reaction gave 2l in 44% yield (entry 12). When R3 of anilide
is substituted with the bulky t-butyl group, the reaction provided
the para-tosyloxylated product 2m in 39% yield probably due to
steric effect (entry 13). Finally, other sulfonyloxylations were also
explored. Both electron-rich and electron-deficient sulfonic acids
are good substrates in this transformation. The reaction of 1a
with p-methoxybenzenesulfonic acid or p-nitrobenzenesulfonic
acid afforded the desired product 2n or 2o in 66% and 62% yield,
respectively (entries 14 and 15).
2c
1c
NHAc
NHAc
4
92
OMe
2d
NHAc
OMe
TsO
TsO
1d
NHAc
5
56c
F
F
2e
1e
NHAc
NHAc
6
36(68)d
27(56)d
16
Cl
1f
NHAc
Cl
TsO
TsO
TsO
2f
NHAc
7
Br
Br
1g
2g
NHAc
NHAc
8
CO2Me
1h
CO2Me
2h
NHAc
NHAc
9
92
TsO
TsO
1i
1j
2i
NHAc
NHAc
10
88
2j
A possible mechanism of PIFA-induced tosyloxylation of ani-
lides is proposed in Scheme 1. The mechanism of this reaction pro-
ceeds through the electrophilic substitution pathway, similar to
the previously postulated for the acetoxylation of anilides by PIFA.
NAc
NAc
11
12
65c
44e
2k
TsO
TsO
1k
NHCOCF3
NHCOCF3
Ph
1l
O
NHC
2l
O
NHC
I
CF3COO
NH
N
+ PhI(OCOCF3)2
O
O
13
14
39
A
TFA
CF3COO
O
1
TsO
2m
1m
NHAc
PhI
NHAc
CF3COO
O
O
NH
N
N
66f
TsOH
S
1a
O
p
MeO Ph
O
O
2n
OTs
B
2
C
Scheme 1. Proposed mechanism for the tosyloxylation of anilides.

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H. Liu et al. / Tetrahedron Letters 52 (2011) 4324–4326
Hata, K.; Hamamoto, H.; Shiozaki, Y.; Cämmerer, S. B.; Kita, Y. Tetrahedron
2007, 63, 4052; (i) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.;
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First, a nucleophilic attack of PIFA with anilide 1 forms the iodoni-
um intermediate A, followed by cleavage of N–I bond to furnish
iodobenzene and a nitrenium ion B, which is stabilized by the
charge delocalization on the phenyl ring. The charge extensively
delocalized intermediate C is highly preferred and trapped with
TsOH to give the para-substituted products 2.
In summary, we have developed a novel method for the direct
tosyloxylation of anilides. Using PIFA as an oxidant, the reactions
of anilides with TsOH provided para-tosyloxylated anilides with
high regioselectivity in good yields. Further work on hypervalent
iodine compound-mediated oxidation of other aromatic com-
pounds is underway in our laboratory.
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Acknowledgments
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21072180) and National Basic Research Pro-
gram of China (2006CB922001) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
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