Hypervalent Iodine-Mediated Beckmann Rearrangement of Ketoximes

Article abstract of DOI:10.1055/s-0037-1609686

We developed a Beckmann rearrangement employing hypervalent iodine reagent under mild conditions. The reaction of ketoxime with hypervalent iodine afforded the corresponding ketone, but premixing of hypervalent iodine and a Lewis acid was effective for promoting Beckmann rearrangement. Aromatic and aliphatic ketoximes were converted into their corresponding amides in good to high yields.

Full text of DOI:10.1055/s-0037-1609686

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
R. Oishi et al.
Letter
Synlett
Hypervalent Iodine-Mediated Beckmann Rearrangement of
Ketoximes
Ryohei Oishia
Kazutoshi Segia
Hiromi Hamamotob
Akira Nakamuraa,c
PhI(OAc)2 + BF3•Et2O
pre-activation
(70 °C, 30 min)
OH
R2
H
N
N
R2
R1
0
0
0
0
0-
0
0
2
4-
4
6
9
6-
5
1
9
R1
CH3CN, 70 °C
O
Tomohiro Maegawa*a
Yasuyoshi Miki*a,c
0
0
0
0
0-
0
0
3
1-
5
8
0
1-
1
1
0
10 examples
70–98% yields
a School of Pharmaceutical Sciences, Kindai University, 3-4-1 Kowakae,
Higashi-osaka, Osaka, 577-8502, Japan
y_miki@phar.kindai.ac.jp
maegawa@phar.kindai.ac.jp
b Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tem-
paku, Nagoya 468-8502, Japan
c Research Organization of Science and Technology, Research Center for
Drug Discovery and Pharmaceutical Science, Ritsumeikan University,
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
Received: 23.02.2018
Accepted after revision: 26.03.2018
Published online: 23.04.2018
is widely utilized in organic syntheses.4 Beckmann rear-
rangements can be induced using a variety of methods in-
cluding Lewis acid activation, although this requires rela-
tively high temperatures.5 The reaction of oximes with
PhI(OAc)2 has already been reported where the correspond-
ing ketone is obtained by attacking the eliminated acetate
ion of the activated intermediate (Scheme 2).6
DOI: 10.1055/s-0037-1609686; Art ID: st-2018-u0121-l
Abstract We developed a Beckmann rearrangement employing hy-
pervalent iodine reagent under mild conditions. The reaction of ketox-
ime with hypervalent iodine afforded the corresponding ketone, but
premixing of hypervalent iodine and a Lewis acid was effective for pro-
moting Beckmann rearrangement. Aromatic and aliphatic ketoximes
were converted into their corresponding amides in good to high yields.
OAc
O
OH
O
I
PhI(OAc)2
N
O
N
AcO
R1
N
Ph
Key words hypervalent iodine reagent, Beckmann rearrangement,
oxime, amide, Lewis acid
R1
R2
R1
R2
R2
R1
R2
OAc
Scheme 2 Reported transformation of ketoxime to ketone by
Hypervalent iodine is a mild oxidizing reagent with a
reactivity similar to that of heavymetaloxidizing reagents,
but with much lower toxicity. Hypervalent iodine reagents
exhibit versatile and unique reactivity.1 Phenyliodine diace-
tate (PhI(OAc)2) and phenyl iodine bis(trifluoroacetate)
(PhI(OCOCF3)2) are of particular interest.2 We recently de-
veloped a novel decarboxylative halogenation reaction us-
ing a combination of PhI(OAc)2 and LiX.3 In this reaction,
PhI(OAc)2 promotes decarboxylation by reacting with the
associated hydroxy group. We applied this reactivity to the
activation of oximes and hypothesized that oxime groups
would react with hypervalent iodine and undergo
Beckmann rearrangement (Scheme 1).
PhI(OAc)2
We hypothesized that the addition of a Lewis acid
would suppress the nucleophilic attack of acetate ion and
activate
a
hypervalent iodine reagent, resulting in
Beckmann rearrangement. We chose 4′-methoxyacetophe-
none oxime (1a) as a substrate, and the reaction was con-
ducted using 1.2 equivalents of PhI(OAc)2 and 5 equivalents
of BF3·Et2O as the Lewis acid. In the first attempt, tetra-
hydrofuran (THF) was used as the solvent, but the desired
reaction did not proceed; ketone 3 was obtained at a 70%
yield and 15% of ketoxime 1a was recovered (Table 1, entry
1). Running the reaction in 2,2,2-trifluoroethanol (TFE),
which is often used in reactions with hypervalent iodine,7
afforded a trace amount of amide 2a (Table 1, entry 2).
CH3CN and CH2Cl2 were effective solvents for amide forma-
tion (Table 1, entries 3 and 4) and the use of CH2Cl2 afforded
amide 2a in 52% yield (Table 1, entry 4). The reaction with-
out PhI(OAc)2 gave poor results (Table 1, entries 5 and 6),
which indicates that PhI(OAc)2 plays an important role in
this reaction.
Beckmann rearrangement is the most important and
powerful strategy for constructing amides from oximes and
OCOR
R1
R1
O
OH
R2
O
I
H2O
PhI(OCOR)2
N
NH
N
N
Ph
R2
R2
R1
R1
R2
Scheme 1 Hypervalent iodine mediated Beckmann rearrangement
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
R. Oishi et al.
Letter
Synlett
Table 1 Investigation of Reaction Conditions for Beckmann
Table 2 Optimization of Reaction Conditions for Beckmann
Rearrangement
Rearrangement
OH
OH
N
O
H
N
PhI(OAc)2
N
BF3•Et2O (5.0 equiv)
+
O
solvent, r.t.
MeO
MeO
1a
MeO
MeO
H
N
1a
2a
3
hypervalent
iodine
BF3•Et2O (2.4 equiv)
O
(1.2 equiv)
Entry
PhI(OAc)2 Solvent
(equiv)
Time
(h)
Yield of 2a
(%)
Yield of 3
(%)
conditions
CH3CN
pre-activation
MeO
2a
1
2
3
4
5
6
1.2
1.2
1.2
1.2
–
THF
21
21
20
3
–
3
70
37
13
30
3
Entry
Hypervalent iodine Pre-activation
Conditions
Yield (%)
TFE
1
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OCOCF3)2
PhI(OH)OTs
PhI(OAc)2
PhI(OAc)2
r.t., 24 h
r.t., 8 h
64
CH3CN
CH2Cl2
CH3CN
CH2Cl2
27
52
3
2a
3
r.t., 24 h
r.t., 8 h
trace
91
70 °C, 30 min
70 °C, 30 min
70 °C, 1.5 h
70 °C, 1.5 h
70 °C, 15 min
70 °C, 24 h
r.t., 8 h
24
21
4
70 °C, 5 min
70 °C, 5 h
70 °C, 5 h
70 °C, 5 h
70 °C, 24 h
97
–
15
3
5
67
6
27
Intriguingly, pre-activation of PhI(OAc)2 with BF3·Et2O
before the addition of ketoxime enhanced the Beckmann
reaction, and the product was obtained at a high yield
(Table 2). After pre-activation of 1.2 equivalents of
PhI(OAc)2 with 2.4 equivalents BF3·Et2O in CH3CN at room
temperature for 24 h, the Beckmann rearrangement pro-
ceeded to give the corresponding amide 2a at a 64% yield
after 8 h at room temperature (Table 2, entry 1) whereas
the use of CH2Cl2 as a solvent afforded poor result (Table 2,
entry 2). When pre-activation was conducted at 70 °C for
30 min, amide 2a was successfully obtained at a 91% yield at
room temperature after 8 h (Table 2, entry 3). These are
mild reaction conditions for a Beckmann rearrangement.
Most previously reported methods employing Lewis acids
have required high reaction temperatures, usually reflux
conditions. In addition, the rearrangement reaction was
greatly accelerated at 70 °C, and the reaction was complete
after 5 min (Table 2, entry 4). The reaction also proceeded
with other hypervalent iodine reagents, such as
PhI(OCOCF3)2 or PhI(OH)OTs, but the yields were decreased
to 67% and 27%, respectively (Table 2, entries 5 and 6). Reac-
tions employing other Lewis acids, such as SnCl4 and ZnCl2,
gave high yields but required 5 h and 24 h, respectively, for
completion (Table 2, entries 7 and 8).
Optimized reaction conditions and substrate scope were
also investigated. Although the reaction of p-methoxy-
acetophenone oxime (1a) at room temperature afforded a
91% yield (Table 3, entry 1), the reaction of o-methoxyaceto-
phenone oxime (1b) at room temperature resulted in a
moderate yield (52%, Table 3, entry 3). Raising the reaction
temperature to 70 °C greatly enhanced the reactivity in
both cases and the reactions were complete after only 5
min with improved yields (Table 3, entries 2 and 4). These
data warranted further exploration of heating conditions.
Non-substituted acetophenone oximes 1c also underwent
Beckmann rearrangement and afforded a 98% yield after 30
7b
8c
88
88
aCH2Cl2 was used as a solvent instead of CH3CN.
b 2.4 equiv of SnCl4 was used instead of BF3·Et2O.
c 2.4 equiv of ZnCl2 was used instead of BF3·Et2O.
min (Table 3, entry 5). Reactions of acetophenone oxime
with electron-withdrawing groups, such as Cl and NO2,
required more time than with substrates bearing electron-
donating groups, but afforded the corresponding amides 2d
and 2e in 97% and 79% yields after 4 h and 19 h, respectively
(Table 3, entries 6 and 7). Indole ketoxime protected with a
benzenesulfonyl group 1f was also converted into the am-
ide 2f in 90% yield (Table 3, entry 8). Under the same condi-
tions, aliphatic ketoxime 1g gave amide 2g in moderate
yield (70%) after 5 h (Table 3, entry 9). The reaction of benzo-
phenone oxime 1h gave the corresponding amide 2h at a
94% yield within 15 min (Table 3, entry 10).
A plausible reaction mechanism is indicated below
(Scheme 3). First, PhI(OAc)2 activates the hydroxy group of
the oxime by substitution with an acetoxy group. The rear-
rangement occurs concomitantly with the elimination of
iodosobenzene and the acetoxy group. Pre-activation of
PhI(OAc)2 with BF3·Et2O form the active species8 which may
accelerate the substitution of the hydroxy group of the
oxime or generate active species in situ. In addition,
BF3·Et2O may suppress the nucleophilicity of the acetoxy
anion, thereby preventing conversion to the corresponding
ketone.6 Then, one of the substituents of oxime 1 transfers
to the nitrogen atom and the generated cation reacts with
H2O to afford the amide 2.
In conclusion, we developed a novel Beckmann rear-
rangement employing PhI(OAc)2 and BF3·Et2O. Pre-activa-
tion of PhI(OAc)2 and BF3·Et2O was an effective means of
promoting the reaction without resorting to reflux condi-
tions.9 Both aromatic and aliphatic ketoximes were convert-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
R. Oishi et al.
Letter
Synlett
Table 3 Substrate scope
BF3
OH
R2
N
O
O
OH
N
1
R1
O
O
1
BF3•Et2O
R1
BF3•Et2O (2.4 equiv)
R2
PhI(OAc)2
Ph
I
pre-activation
H
N
R2
PhI(OAc)2
OAc•BF3
R1
70 °C
70 °C, 30 min
pre-activation
2
O
BF3
Entry
1a
Ketoxime 1
Amide 2
Time
8 h
Yield(%)
91
BF3
O
OH
R1
N
H
N
R1
H2O
NH
O
I
OAc•BF3
N
R2
O
O
O
+
R2
N
MeO
PhI=O
Ph
2
MeO
2a
R1
R2
1a
2
1a
2a
5 min
24 h
97
52
Scheme 3 Plausible reaction mechanism of PhI(OAc)2–BF3·Et2O
mediated Beckmann rearrangement
3a
OH
MeO
MeO
N
H
N
O
ed into their corresponding amides in good to high yields.
Further investigation of the reaction mechanism and the
development of a pre-activation system for PhI(OAc)2 are in
progress.
2b
2b
1b
4
5
1b
1c
5 min
97
30 min 98
OH
N
H
N
O
Funding Information
2c
This work was partially supported by the MEXT-Supported Program
for the Strategic Research Foundation at Private Universities, 2014-
2018 (S1411037) and also by Grant-in-Aid for Young Scientists (B)
(15K18840) from the Japan Society for the Promotion of Science
6
4 h
97
79
OH
N
H
N
O
(JSPS).
)(
Cl
Cl
2d
1d
7b
19 h
Acknowledgment
OH
N
H
N
We thank for the fruitful and helpful comment from the reviewers.
O
O2N
O2N
2e
Supporting Information
1e
8
1 h
90
70
Supporting information for this article is available online at
OH
H
N
https://doi.org/10.1055/s-0037-1609686.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
N
O
N
SO2Ph
N
SO2Ph
References and Notes
2f
1f
(1) For recent reviews see: (a) Hypervalent Iodine Chemistry
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(f) Ochiai, M. Synlett 2009, 159. (g) Dohi, T.; Kita, Y. Chem.
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Int. Ed. 2011, 50, 1524. (i) Merritt, E. A.; Olofsson, B. Synthesis
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1722. (k) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116,
3328.
9
5 h
OH
H
N
N
O
2g
1g
1h
10
15 min 94
OH
N
H
N
O
2h
a The reaction was conducted at r.t.
b 4.8 equiv of BF3·Et2O was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
R. Oishi et al.
Letter
Synlett
(2) (a) Nakamura, A.; Tanaka, S.; Imamiya, A.; Takane, R.; Ohta, C.;
Fujimura, K.; Maegawa, T.; Miki, Y. Org. Biomol. Chem. 2017, 15,
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(9) The experimental Procedures and Characterization Data
The solution of PhI(OAc)2 (0.48 mmol) and BF3·Et2O (0.96 mmol)
in CH3CN (1.0 mL) was stirred at 70 °C for 30 min. Then p-
methoxyacetophenone (1a, 0.40 mmol) was added to the above
mixture and stirred 70 °C for 5 min. Cooling to r.t., 0.5% aq
Na2SO3 was added to the reaction mixture and extracted with
CHCl3. Combined organic layer was washed with water, dried
over Na2SO4, and concentrated in vacuo. The residue was puri-
fied by SiO2 column chromatography (n-hexane/AcOEt = 1:1)
and preparative TLC (n-hexane/AcOEt = 5:1) to give N-(4-
methoxyphenyl)acetamide (2a, 97%) as white solid.
N-(4-Methoxyphenyl)acetamide (2a)
(4) (a) Croig, D.; Trost, B. M.; Fleming, I.; Ley, S. V. In Comprehensive
Organic Synthesis;
7
V
o.
l
Pergamon Press: Oxford, 1991, 689.
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White solid. 1H NMR (CDCl3): δ= 2.14 (3 H, s), 3.78 (3 H, s),
6.85 (2 H, d, J = 8.8 Hz), 7.28 (1 H, br), 7.38 (2 H, d, J = 8.8 Hz).
13C NMR (CDCl3): δ = 24.1, 55.4, 113.9, 122.0, 131.1, 156.3,
168.7.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D