Base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamine derivatives

Article abstract of DOI:10.1016/j.tet.2018.12.058

The base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamines giving α-(2-hydroxyphenyl)amides was successfully demonstrated. The substrates were prepared from N-substituted hydroxylamines by N-acylation followed by copper(I)-mediated O-arylation with boronic acids. Treatment of the substrates with lithium hexamethyldisilazide (LiHMDS) in THF at 0 °C to room temperature generated the corresponding amide enolates. The aromatic [3,3] rearrangement of the enolates provided the desired products in moderate to good yields. A crossover experiment produced only intramolecular products and clarified that the reaction proceeds via the aromatic [3,3] sigmatropic rearrangement, not a bond-cleavage–recombination process. Our method is a formal α-arylation of amides.

Full text of DOI:10.1016/j.tet.2018.12.058

Tetrahedron 75 (2019) 665e673
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Tetrahedron
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Base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-
O-arylhydroxylamine derivatives
,
Eiji Tayama a *, Kazuki Hirano b
a Department of Chemistry, Faculty of Science, Niigata University, Niigata, 950-2181, Japan
b Graduate School of Science and Technology, Niigata University, Niigata, 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The base-promoted aromatic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxylamines giving a-
Received 12 November 2018
Received in revised form
20 December 2018
Accepted 27 December 2018
Available online 28 December 2018
(2-hydroxyphenyl)amides was successfully demonstrated. The substrates were prepared from N-
substituted hydroxylamines by N-acylation followed by copper(I)-mediated O-arylation with boronic
acids. Treatment of the substrates with lithium hexamethyldisilazide (LiHMDS) in THF at 0 ꢀC to room
temperature generated the corresponding amide enolates. The aromatic [3,3] rearrangement of the
enolates provided the desired products in moderate to good yields. A crossover experiment produced
only intramolecular products and clarified that the reaction proceeds via the aromatic [3,3] sigmatropic
Keywords:
Sigmatropic rearrangement
rearrangement, not a bond-cleavageerecombination process. Our method is a formal
a-arylation of
amides.
a
-Arylations
© 2018 Elsevier Ltd. All rights reserved.
Amide enolates
Hydroxamic acids
Hydroxylamines
1. Introduction
which involves an NeN bond cleavage, is one of the well-known
examples of the aromatic sigmatropic rearrangement [4e7]. In
addition, their heteroatomeheteroatom bonds frequently make the
preparation of the substrates difficult or complicated. Therefore,
the development of an efficient synthetic route to substrates and
successful rearrangement are necessary to show the synthetic
utility of the aromatic sigmatropic rearrangements.
Aromatic sigmatropic rearrangement is a unique synthetic
transformation that enables the formation of carbonecarbon (CeC)
bonds between aromatic (sp2) and aliphatic (sp3) carbons under
simple and mild conditions [1]. However, applications as a syn-
thetic method have been limited in a specific area because of the
narrow substrate scopes. For example, in the
a
-arylation of
a
-
Previously, Endo et al. studied the series of these rearrange-
ments involving an NeN or NeO bond cleavage, e.g., the rear-
rangements of N-acyl-N0-arylhydrazines [8] (Scheme 2, Eq. (1) and
carbonyl compounds, the transition metal catalyzed reactions have
been studied by many researchers and advanced greatly because of
the wide substrate scopes (Scheme 1, Eq. (1)) [2]. On the other hand,
a similar transformation could be drawn by a base-promoted aro-
matic [3,3] sigmatropic rearrangement (Eq. (2)). The [3,3] rear-
rangement of an enolate B, generated from carbonyl compound A,
into the dearomatized intermediate C followed by isomerization,
O-acyl-N-arylhydroxylamines [9] (Eq. (2))) giving
a-(2-
aminophenyl)carbonyl derivatives. Their group also reported an
acid-catalyzed rearrangement of N-acetoacetyl-O-arylhydroxyl-
amines to provide benzofuran derivatives [10] by a [3,3] rear-
rangement of the enol followed by acid-catalyzed intramolecular
cyclization (Eq. (3)). These reactions under the acidic conditions
gave cyclized products such as indoles or benzofuran derivatives.
Surprisingly, to the best of our knowledge, the base-promoted
provides the formal a-arylated product D. To achieve this trans-
formation, a YeZ bond, as in A, should be easily cleavable, such as a
nitrogenenitrogen (NeN) or a nitrogeneoxygen (NeO) bond, to
obtain the driving force to generate the energetically unfavorable
dearomatized intermediate C. This requirement results in the nar-
row substrate scope although the Fischer indole synthesis [3],
rearrangement of N-acyl-O-arylhydroxylamines 1 to afford
a-(2-
hydroxyphenyl)carbonyl derivatives 2 has never been reported
(Eq. (4)). Thus, we started to study the rearrangement. Substrate
preparations, optimization reaction conditions, scope and limita-
tions were described.
* Corresponding author.
E-mail address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
https://doi.org/10.1016/j.tet.2018.12.058
0040-4020/© 2018 Elsevier Ltd. All rights reserved.

666
E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
Scheme 1.
a-Arylation of carbonyl compounds.
Scheme 3. Representative examples for preparation of 1.
temperature after the addition of LDA, the yield of 2a was decreased
to 36% (Entry 3). Undesirable deprotonation and/or side reactions
might have proceeded. Thus, the a-deprotonation with LDA was
carried out at 0 ꢀC for 1 h; then, the temperature was raised to room
temperature, and the mixture was reacted for 3 h for the desired
[3,3] rearrangement (Entry 4). As expected, the yield of 2a was
improved to 57%. Longer reaction time (6 h) did not show further
improvements (Entry 5). The use of excess amounts of LDA (2.5
equivalents) lowered the yield of 2a with no recovery of 1a (Entry
6). The reaction in Et2O showed low reactivity (Entry 7). Although
the exact reason is unclear at present, the use of a bulkier base
LiTMP (lithium 2,2,6,6-tetramethylpiperidide) did not afford 1a at
all (Entry 8). However, when the reaction was carried out with
lithium hexamethyldisilazide (LiHMDS), the reaction proceeded
more cleanly with LDA. The desired 2a was obtained in 77% yield
with the recovery of 1a in 3% yield (Entry 9). The less basicity of
LiHMDS than LDA would prevent undesirable side reactions. The
use of sodium and potassium hexamethyldisilazide (NaHMDS,
KHMDS) or TMEDA as an additive for LiHMDS did not show further
improvements (Entries 10e12).
Scheme 2. Aromatic [3,3] rearrangement of hydrazine and hydroxylamine derivatives.
2. Results and discussion
With optimized conditions (Table 1, Entry 9) in hand, we pre-
pared various N-acyl-O-arylhydroxylamines 1 and subjected them
to certain conditions to define the substrate scope and limitations
of this reaction (Table 2). First, the reactions of three different N-
acyl derivatives 1bed (R1 ¼ H, Me, Ph) were examined to clarify
First, we prepared substrate 1 from N-hydroxyphthalimide in 4
steps according to the literature [11] depicted in Scheme 3, Eq. (1).
However, the overall yields of 1 were unsatisfactory in many cases
[12]. Thus, we improved the preparative route, and the represen-
tative examples are shown as Eqs. (2) and (3). Compounds 1a and
1b were prepared by N-acylation of N-methylhydroxylamine fol-
lowed by O-arylation [13]. Since compound 3b is very soluble in
H2O, a condition of N-acetylation was modified to avoid extractive
workup.
With substrate 1 in hand, we started to investigate the base-
promoted [3,3] rearrangement using 1a as a model compound
(Table 1). First, a reaction of 1a with 1.2 equivalents of LDA was
examined in THF at 0 ꢀC for 1 h. The [3,3] rearranged product 2a was
obtained in 26% yield with recovery of 1a in 36% yield (Entry 1). The
yield of 2a was improved to 47% by extending the reaction time to
3 h (Entry 2). When the reaction temperature was raised to room
effects of sterically factor of a-substituent or acidity of a-proton
(Entries 1e3). The corresponding products 2bed were obtained in
moderate yields with the recovery of the substrate 1. A clear dif-
ference was not observed. Next, substituent effects on the O-aryl
moiety were investigated. Reactions of para-methyl-, phenyl-,
methoxy-, and fluoro-derivatives 1eeh proceeded to provide 2eeh
in reasonable yields (Entries 4e7, 68e88%). However, the reaction
of para-cyano-derivative 1i resulted in low yield of 2i (30%) without
recovery of 1i (Entry 8). As a side product, 4-cyanophenol derived
by NeO bond cleavage was isolated in 19% yield. In analogy with 1e,
reactions of N-acetyl- and N-phenylacetyl-derivatives 1jek affor-
ded 2jek (Entries 9, 10). When unsymmetrical O-(2-

E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
667
Table 1
Optimization of reaction conditions in the [3,3] rearrangement of 1a.
Entry
Base (eq.)
Solvent
Temp. Time
0 ꢀC, 1 h
Yield (%)a,b
1
2
3
4
5
6
7
8
LDA (1.2)
LDA (1.2)
LDA (1.2)
LDA (1.2)
THF
THF
THF
THF
THF
THF
Et2O
THF
THF
THF
THF
THF
26
47
36
57
58
36
35
0
77
70
53
61
0
ꢀC, 3 h
0 ꢀC, add. to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 6 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
0 ꢀC, 1 h to rt, 3 h
LDA (1.2)
LDA (2.5)
LDA (1.2)c
LiTMP (1.2)d
LiHMDS (1.2)e
NaHMDS (1.2)e
KHMDS (1.2)f
LiHMDS (1.2)e þ TMEDA (1.2)
9
10
11
12
a
Isolated yield.
b
c
d
e
f
Recovery of 1a, Entry 1: 36%; Entry 2: 25%; Entry 6: 0%; Entry 7: 57%; Entry 8: 99%; Entry 9: 3%; Entry 11: 38%; Entry 12: 20%.
Prepared from diisopropylamine and n-butyllithium in Et2O.
Prepared from 2,2,6,6-tetramethylpiperidine and n-butyllithium in THF.
Commercially available 1.0 M THF solution.
Commercially available 0.5 M KHMDS toluene solution.
Table 2
Base-promoted aromatic [3,3] rearrangement of 1.
Entry
R1
R2
R3
R4
Yield (%)a,b
1
2
3
4
5
6
7
8
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
b
c
d
e
f
g
h
i
78
62
65
88
68
77
86
30
68
90
91
84
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
H
Ph
CH2Ph
CH2Ph
Me
Ph
OMe
F
CN
Me
Me
H
9
j
k
l
10
11
12
Scheme 4. Preparations and the reactions of N-benzylic derivatives 1n and 1o.
H
m
a
Isolated yield.
the same conditions provided the desired substrates 1 in acceptable
overall yields (1n: 39%, 1o: 34%). The base-promoted [3,3] rear-
b
Recovery of 1, Entry 1: 16%; Entry 2: 34%; Entry 4: 5%; Entry 5: 13%; Entry 6:
12%; Entry 7: 10%; Entry 8: 0%; Entry 9: 18%; Entry 11: 8%.
rangement of 1n and 1o gave the corresponding
a-(2-
hydroxyphenyl)acetamide 2n (64% yield) and 2o (78% yield),
respectively.
methylphenyl)- (1l) and O-(2,3-dimethylphenyl)- (1m) derivatives
were subjected to the reaction, the [3,3] rearrangement proceeded
with an unsubstituted ortho-position of the O-aryl to afford 2l and
2m in good yields (Entries 11, 12).
To show further substrate scope on the N-substituent, as in
substrate 1, N-benzylic derivatives 1n and 1o were prepared, and
their reactions were examined (Scheme 4). Reductive amination of
benzaldehyde or acetophenone with O-benzylhydroxylamine via
formation of O-benzyl oximes 4 gave N-benzylic-O-benzylhydrox-
ylamines 5 in moderate yields. N-Acylation to 6 followed by
hydrogenolysis of benzyl ether afforded N-benzylic hydroxamic
acids 3 in excellent yields [14]. Cu(I)-mediated O-arylation under
A crossover experiment was examined to clarify a mechanism of
this reaction (Scheme 5). When an equimolar mixture of 1b and 1e
was treated with LiHMDS, only the intramolecular products 2b and
2e were produced without formation of the intermolecular prod-
ucts 2j and 2a. This observation suggests that the products 2 are
formed via the concerted aromatic [3,3] sigmatropic rearrange-
ment of amide enolate E depicted in Scheme 2, Eq. (4), not a bond-
cleavageerecombination process.
The product 2a was easily converted into 3-benzyl benzofuran-
2(3H)-one 7a by acid-mediated cyclization [15] (Scheme 6). Our
method would be an efficient synthetic route to various types of 3-

668
E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
3. Experimental section
General: Infrared spectra (IR) were recorded on a Perkin Elmer
Spectrum GX FT-IR or a JASCO FT/IR-4600 spectrometer. 1H and 13
C
NMR spectra were measured on a Varian (1H: 400 MHz, 13C:
100 MHz) or a Bruker spectrometer (1H: 400 MHz, 13C: 100 MHz).
Me4Si (
DMSO‑d6 for 1H NMR. The residual protons (
as an internal standard in acetone-d6 for 1H NMR. CDCl3
77.00 ppm) or DMSO‑d6 39.51 ppm) were used as an internal
d
0 ppm) was used as an internal standard in CDCl3 and
d
2.05 ppm) were used
(d
(
d
standard for 13C NMR. The splitting patterns are denoted as follows:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br,
broad peak. High-resolution mass spectra (ESI) were measured on a
Thermo Fisher Scientific LC/FT-MS spectrometer. Reactions
involving air- or moisture-sensitive compounds were conducted in
appropriate round-bottomed flasks with a magnetic stirring bar
under an argon atmosphere. Anhydrous tetrahydrofuran (THF) was
purchased from KANTO Chemical Co., Inc., Japan. Anhydrous
diethyl ether (Et2O) was obtained by distillation from sodium
benzophenone under an argon atmosphere prior to use. LiHMDS,
NaHMDS, and KHMDS solution were purchased from Sigma-
Aldrich. TMEDA was distilled from KOH under an argon atmo-
sphere. For thin layer chromatography (TLC) analysis throughout
this work, Merck TLC plates (silica gel 60 F254) were used. The
products were purified by preparative column chromatography on
silica gel (60N, spherical neutral) purchased from KANTO Chemical
Co., Inc., Japan.
Scheme 5. A crossover experiment between 1b and 1e.
Scheme 6. Conversion of 2a into benzofuranone derivative 7a.
substituted benzofuran-2(3H)-one derivatives which would be
valuable building blocks for biologically active compounds [16].
Finally, we attempted construction of an all-carbon quaternary
stereocenter by this [3,3] rearrangement to explore further syn-
3.1. Representative procedure for the preparation of N-methyl-N-
phenoxy-3-phenylpropanamide (1a)
(Step 1) A solution of N-methylhydroxylamine hydrochloride
(164 mg, 1.96 mmol) and triethylamine (0.51 mL, 3.7 mmol) in
CH2Cl2 (23 mL) was treated with 3-phenylpropionyl chloride
(0.24 mL,1.6 mmol) at 0 ꢀC. After stirring for 1 h at 0 ꢀC and for 1 h at
room temperature. The resulting mixture was treated with satu-
rated aq. NH4Cl and extracted with EtOAc. The combined extracts
were washed with brine, dried over Na2SO4, and evaporated. Pu-
rification of the residue by chromatography on silica gel (n-hexane/
EtOAc ¼ 1/1 as the eluent) gave N-hydroxy-N-methyl-3-
phenylpropanamide (3a) (284 mg, 99% yield) as a colorless oil.
(Step 2) A mixture of 3a (122 mg, 0.681 mmol), phenylboronic acid
thetic applications (Scheme 7). When a reaction of
a,a-disubsti-
tuted 1p was carried out under the same conditions, the desired 2p
was obtained in only 21% yield with the recovery of 1p in 57% yield.
Longer reaction time and higher reaction temperature (50 ꢀC) did
not improve the yield of 2p. The [3,3] rearrangement might be
inhibited because of steric reasons.
In conclusion, we have demonstrated the base-promoted aro-
matic [3,3] sigmatropic rearrangement of N-acyl-O-arylhydroxyl-
amines 1 to afford a-(2-hydroxyphenyl)amides 2 in moderate to
good yields [17]. The reaction proceeds via a formation of amide
enolate generated from 1 with LiHMDS followed by [3,3] rear-
rangement between an enolate double bond and an aromatic
(196 mg, 1.61 mmol), pyridine (61 mL, 0.75 mmol), copper(I) chlo-
ride (77 mg, 0.78 mmol), and MS 4 Å (0.22 g) in 1,2-dichloroethane
(3.4 mL) was stirred for 48 h at room temperature under an air at-
mosphere. The color of the mixture was changed from brown into
green. The resulting mixture was filtered through a pad of Celite
and the filtrate was evaporated. The residue was purified by chro-
matography on silica gel (n-hexane/EtOAc ¼ 5/1 as the eluent) to
afford 1a (158 mg, 91% yield) as a yellow oil. IR (film) nmax 3061,
3027, 2931, 2869, 1678, 1591, 1484, 1454, 1414, 1381, 1331, 1202,
1178, 1157, 1097, 1073, 1022, 998, 946, 922, 893, 858, 813, 752,
double bond. This transformation would be a formal a-arylation of
amide without using a transition metal catalyst. The scope and
limitations of this rearrangement were also investigated. A cross-
over experiment suggested that the reaction proceeds via a
concerted aromatic [3,3] sigmatropic process, not a bond-cleava-
geerecombination. Efficient synthetic routes into substrates 1 via
copper(I)-mediated O-arylation of N-acylhydroxylamine with
boronic acids are also provided. Our results would expand the
synthetic utility of aromatic sigmatropic rearrangements.
698 cmꢁ1 1H NMR (400 MHz, CDC13)
; d 7.35e7.27 (2H, m, ArH),
7.27e7.19 (2H, m, ArH), 7.19e7.11 (3H, m, ArH), 7.06 (1H, tt, J ¼ 7.4,
1.0 Hz, ArH), 6.94e6.88 (2H, m, ArH), 3.27 (3H, s, NCH3), 2.95 (2H, t,
J ¼ 7.8 Hz, CH2), 2.70 (2H, t, J ¼ 7.8 Hz, CH2) ppm; 13C NMR
(100 MHz, CDCl3)
d 174.9, 157.4, 140.8, 129.8, 128.31, 128.30, 126.0,
123.2, 112.7, 34.1, 34.0, 30.3 ppm; HRMS (ESI): [M þ H]þ, found
256.1327. C16H18NO2 requires 256.1332.
3.2. Representative procedure for the preparation of N-methyl-N-
phenoxyacetamide (1b)
(Step 1) A solution of N-methylhydroxylamine hydrochloride
(194 mg, 2.32 mmol) and Na2CO3 (0.49 g, 4.6 mmol) in THF (3.9 mL)
Scheme 7. An attempt of construction of all-carbon quaternary stereocenter by [3,3]
rearrangement of 1p.

E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
669
was treated with acetyl chloride (0.15 mL, 2.1 mmol) at 0 ꢀC and
stirred for 14 h at room temperature. The resulting mixture was
evaporated and the residue was purified by chromatography on
silica gel (n-hexane/EtOAc ¼ 1/1 as the eluent) to give N-hydroxy-
N-methylacetamide (3b) (141 mg, 75% yield) as a colorless oil. (Step
2) A mixture of 3b (251 mg, 2.82 mmol), phenylboronic acid
(693 mg, 5.68 mmol), pyridine (0.25 mL, 3.1 mmol), copper(I)
chloride (291 mg, 2.94 mmol), and MS 4 Å (0.65 g) in 1,2-
dichloroethane (14 mL) was stirred for 48 h at room temperature
under an air atmosphere. The resulting mixture was filtered
through a pad of Celite and the filtrate was evaporated. The residue
was purified by chromatography on silica gel (n-hexane/EtOAc ¼ 4/
1 as the eluent) to afford 1b (377 mg, 81% yield) as a colorless oil. IR
(film) nmax 3061, 3041, 3016, 2976, 2933, 1681, 1592, 1484, 1412,
1378, 1344, 1293, 1203, 1179, 1158, 1138, 1075, 1036, 1023, 998, 947,
yield). White solid, mp 74e75 ꢀC; IR (KBr) nmax 3059, 3031, 2962,
2930, 1672, 1602, 1513, 1484, 1449, 1416, 1380, 1338, 1265, 1216,
1186, 1155, 1097, 1075, 1033, 1002, 947, 910, 857, 831, 761, 700 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d 7.56e7.50 (4H, m, ArH), 7.45e7.39 (2H,
m, ArH), 7.33 (1H, tt, J ¼ 7.4, 1.4 Hz, ArH), 7.27e7.21 (2H, m, ArH),
7.20e7.13 (3H, m, ArH), 6.98 (2H, ddd, J ¼ 8.8, 2.6, 2.6 Hz, ArH), 3.31
(3H, s, NCH3), 2.97 (2H, t, J ¼ 7.9 Hz, CH2), 2.73 (2H, t, J ¼ 7.9 Hz, CH2)
ppm; 13C NMR (100 MHz, CDCl3)
d 175.0, 156.9, 140.9, 140.1, 136.5,
128.8, 128.6, 128.40, 128.37, 127.1, 126.8, 126.1, 113.2, 34.2, 34.1,
30.4 ppm; HRMS (ESI): [M þ H]þ, found 332.1637. C22H22NO2 re-
quires 332.1645.
3.7. N-(4-Methoxyphenoxy)-N-methyl-3-phenylpropanamide (1g)
Prepared by the same procedure with 1a using 4-
methoxyphenylboronic acid instead of phenylboronic acid (15%
overall yield). Pale brown oil; IR (film) nmax 3061, 3026, 3000, 2933,
2835, 1675, 1602, 1501, 1454, 1441, 1415, 1382, 1296, 1245, 1196,
1103, 1073, 1034, 1004, 947, 922, 828, 778, 750, 700 cmꢁ1; 1H NMR
894, 813, 756, 691 cmꢁ1 1H NMR (400 MHz, CDC13)
; d 7.40e7.33
(2H, m, Ph), 7.10 (1H, tt, J ¼ 7.4, 1.1 Hz, Ph), 7.02e6.97 (2H, m, Ph),
3.29 (3H, s, NCH3), 2.10 (3H, s, COCH3) ppm; 13C NMR (100 MHz,
CDCl3)
d 173.3, 157.4, 129.9, 123.3, 112.8, 33.9, 20.3 ppm; HRMS
(ESI): [M þ H]þ, found 166.0861. C9H12NO2 requires 166.0863.
(400 MHz, CDC13) d 7.28e7.22 (2H, m, ArH), 7.20e7.13 (3H, m, ArH),
6.84 (4H, s, ArH), 3.78 (3H, s, OCH3), 3.26 (3H, s, NCH3), 2.95 (2H, t,
3.3. N-Methyl-N-phenoxypropionamide (1c)
J ¼ 7.9 Hz, CH2), 2.71 (2H, t, J ¼ 7.9 Hz, CH2) ppm; 13C NMR
(100 MHz, CDCl3)
d 174.9, 155.6, 151.2, 141.0, 128.40, 128.38, 126.0,
Prepared from propanoyl chloride by the same procedure with
1a (75% overall yield). Yellow oil; IR (film) nmax 3062, 3041, 2979,
2940, 2880,1684, 1591,1484,1416,1377,1293, 1202, 1178, 1158,1111,
1074, 1051, 1022, 926, 893, 816, 753, 691 cmꢁ1; 1H NMR (400 MHz,
114.9,114.0, 55.7, 34.0, 33.9, 30.4 ppm; HRMS (ESI): [M þ H]þ, found
286.1430. C17H20NO3 requires 286.1438.
3.8. N-(4-Fluorophenoxy)-N-methyl-3-phenylpropanamide (1h)
CDC13)
d
7.39e7.32 (2H, m, Ph), 7.09 (1H, tt, J ¼ 7.2, 1.1 Hz, Ph),
7.01e6.96 (2H, m, Ph), 3.30 (3H, s, NCH3), 2.40 (2H, q, J ¼ 7.6 Hz,
Prepared by the same procedure with 1a using 4-
fluorophenylboronic acid instead of phenylboronic acid (75%
overall yield). Yellow oil; IR (film) nmax 3064, 3027, 2933, 2870,
1678,1603,1498, 1453,1413,1381, 1331, 1230, 1185, 1114,1095,1073,
CH2CH3), 1.10 (3H, t, J ¼ 7.6 Hz, CH2CH3) ppm; 13C NMR (100 MHz,
CDCl3)
d 176.8, 157.6, 129.9, 123.2, 112.7, 34.2, 25.6, 8.4 ppm; HRMS
(ESI): [M þ H]þ, found 180.1017. C10H14NO2 requires 180.1019.
1031, 1006, 946, 923, 833, 781, 749, 700 cmꢁ1
CDC13)
;
1H NMR (400 MHz,
7.28e7.22 (2H, m, ArH), 7.21e7.12 (3H, m, ArH), 7.04e6.96
3.4. N-Methyl-N-phenoxy-2-phenylacetamide (1d)
d
(2H, m, ArH), 6.89e6.82 (2H, m, ArH), 3.26 (3H, s, NCH3), 2.95 (2H, t,
Prepared from phenylacetyl chloride by the same procedure
with 1a (63% overall yield). Purple oil; IR (film) nmax 3062, 3030,
2975, 2934, 1677, 1591, 1483, 1455, 1411, 1375, 1289, 1199, 1157, 1115,
J ¼ 7.8 Hz, CH2), 2.69 (2H, t, J ¼ 7.8 Hz, CH2) ppm; 13C NMR
(100 MHz, CDCl3)
d
175.1, 159.8, 157.4, 155.3 (d, J ¼ 2 Hz), 140.8,
128.4, 127.3 (d, J ¼ 231 Hz), 116.4 (d, J ¼ 24 Hz), 114.1 (d, J ¼ 8 Hz),
1089, 1023, 1002, 948, 893, 814, 755, 736, 693 cmꢁ1 1H NMR
;
34.12, 34.06, 30.3 ppm; HRMS (ESI): [M þ H]þ, found 274.1235.
(400 MHz, CDC13)
7.09 (1H, tt, J ¼ 7.4, 1.0 Hz, ArH), 6.99e6.94 (2H, m, ArH), 3.70 (2H, s,
CH2), 3.29 (3H, s, NCH3) ppm; 13C NMR (100 MHz, CDCl3)
173.6,
d
7.38e7.31 (2H, m, ArH), 7.29e7.17 (5H, m, ArH),
C16H17FNO2 requires 278.1238.
d
3.9. N-(4-Cyanophenoxy)-N-methyl-3-phenylpropanamide (1i)
157.3, 134.1, 129.9, 129.4, 128.3, 126.8, 123.3, 112.9, 39.5, 34.2 ppm;
HRMS (ESI): [M þ H]þ, found 242.1167. C15H16NO2 requires
242.1176.
Prepared by the same procedure with 1a using 4-
cyanophenylboronic acid instead of phenylboronic acid (38%
overall yield). Colorless oil; IR (film) nmax 3100, 3063, 3027, 2934,
2871, 2227, 1682, 1601, 1495, 1453, 1413, 1379, 1327, 1296, 1218,
3.5. N-Methyl-3-phenyl-N-(p-tolyloxy)propanamide (1e)
1160, 1110, 1073, 1031, 1010, 945, 921, 839, 777, 752, 701 cmꢁ1 1H
;
Prepared by the same procedure with 1a using p-tolylboronic
acid instead of phenylboronic acid (76% overall yield). Yellow oil; IR
(film) nmax 3061, 3028, 2924, 2867, 1676, 1605, 1500, 1452, 1413,
1381, 1331, 1291, 1200, 1179, 1160, 1101, 1072, 1032, 1012, 946, 923,
NMR (400 MHz, CDC13)
d
7.62 (2H, ddd, J ¼ 9.0, 2.4, 2.4 Hz, ArH),
7.25 (2H, dddd, J ¼ 7.1, 7.1, 1.5, 1.5 Hz, ArH), 7.18 (1H, tt, J ¼ 7.1, 1.5 Hz,
ArH), 7.15e7.11 (2H, m, ArH), 7.01 (2H, ddd, J ¼ 9.0, 2.4, 2.4 Hz, ArH),
3.28 (3H, s, NCH3), 2.95 (2H, t, J ¼ 7.8 Hz, CH2), 2.66 (2H, t, J ¼ 7.8 Hz,
816, 779, 750, 700 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d
7.27e7.20
CH2) ppm; 13C NMR (100 MHz, CDCl3)
d 175.3, 160.7, 140.4, 134.4,
(2H, m, ArH), 7.19e7.08 (5H, m, ArH), 6.80 (2H, ddd, J ¼ 8.8, 2.5,
2.5 Hz, ArH), 3.26 (3H, s, NCH3), 2.94 (2H, t, J ¼ 7.7 Hz, CH2), 2.69
(2H, t, J ¼ 7.7 Hz, CH2), 2.30 (3H, s, ArCH3) ppm; 13C NMR (100 MHz,
128.4, 128.3, 126.1, 118.2, 113.7, 106.9, 34.7, 34.1, 30.2 ppm; HRMS
(ESI): [M þ H]þ, found 281.1280. C17H17N2O2 requires 281.1285.
CDCl3)
d
174.8, 155.2, 140.9, 132.7, 130.2, 128.33, 128.30, 126.0, 112.6,
3.10. N-Methyl-N-(p-tolyloxy)acetamide (1j)
33.9, 30.3, 20.4 ppm (one overlapping peak); HRMS (ESI): [M þ H]þ,
found 270.1484. C17H20NO2 requires 270.1489.
Prepared by the same procedure with 1b using p-tolylboronic
acid instead of phenylboronic acid (53% overall yield). Yellow oil; IR
(film) nmax 3031, 2925, 2871, 1678, 1606, 1502, 1413, 1376, 1344,
1290, 1200, 1162, 1138, 1037, 1000, 947, 818, 767, 735, 700 cmꢁ1; 1H
3.6. N-([1,10-Biphenyl]-4-yloxy)-N-methyl-3-phenylpropanamide
(1f)
NMR (400 MHz, CDC13)
J ¼ 8.8, 2.5, 2.5 Hz, ArH), 3.27 (3H, s, NCH3), 2.32 (3H, s, ArCH3), 2.09
(3H, s, COCH3) ppm; 13C NMR (100 MHz, CDCl3)
173.2, 155.3,132.7,
d 7.18e7.12 (2H, m, ArH), 6.87 (2H, ddd,
Prepared by the same procedure with 1a using 4-
biphenylboronic acid instead of phenylboronic acid (56% overall
d

670
E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
130.3, 112.6, 35.8, 20.4, 20.2 ppm; HRMS (ESI): [M þ H]þ, found
combined extracts were dried over Na2SO4. Evaporation of volatiles
and purification of the residue by chromatography on silica gel (n-
hexane/CH2Cl2 ¼ 1/1 as the eluent) gave N,O-dibenzylhydroxyl-
amine (5n) (455 mg, 71% yield) as a colorless oil. (Step 3) A solution
of 5n (316 mg, 1.48 mmol), DMAP (95 mg, 0.78 mmol), pyridine
(0.24 mL, 3.0 mmol), in CH2Cl2 (3.0 mL) was treated with acetic
anhydride (0.21 mL, 2.2 mmol) at room temperature. After stirring
for 2 h at the same temperature, the resulting mixture was treated
with saturated aq. NaHCO3 and extracted with CH2Cl2. The com-
bined extracts were washed with brine, dried over Na2SO4, and
evaporated. Purification of the residue by chromatography on silica
gel (n-hexane/EtOAc ¼ 2/1 as the eluent) afforded N-benzyl-N-
(benzyloxy)acetamide (6n) (367 mg, 97% yield) as a colorless oil.
(Step 4) A mixture of 6n (236 mg, 0.924 mmol) and Pd-C (loading:
10 wt%, 20 mg) in MeOH (9 mL) was stirred at room temperature for
3 h under a hydrogen atmosphere. The resulting mixture was
filtered through a pad of Celite and the filtrate was evaporated to
afford N-benzyl-N-hydroxyacetamide (3n) (152 mg, quant.) as a
brown oil. (Step 5) A mixture of 3n (140 mg, 0.848 mmol), phe-
180.1016. C10H14NO2 requires 180.1019.
3.11. N-Methyl-2-phenyl-N-(p-tolyloxy)acetamide (1k)
Prepared from phenylacetyl chloride by the same procedure
with 1a using p-tolylboronic acid instead of phenylboronic acid
(66% overall yield). White solid, mp 48e49 ꢀC; IR (KBr) nmax 3082,
3059, 3033, 2983, 2917, 2864, 1675, 1603, 1500, 1453, 1406, 1377,
1327, 1286, 1199, 1176, 1159, 1108, 1088, 1029, 1011, 969, 948, 906,
851, 826, 747, 737, 699 cmꢁ1; 1H NMR (400 MHz, CDC13)
d 7.30e7.18
(5H, m, ArH), 7.14 (2H, d, J ¼ 8.6 Hz, ArH), 6.87 (2H, d, J ¼ 8.6 Hz,
ArH), 3.69 (2H, s, CH2), 3.27 (3H, s, NCH3), 2.33 (3H, s, ArCH3) ppm;
13C NMR (100 MHz, CDCl3)
d 173.5, 155.2, 134.2, 132.8, 130.3, 129.4,
128.3, 126.7, 112.8, 39.4, 34.1, 20.5 ppm; HRMS (ESI): [M þ H]þ,
found 256.1327. C16H18NO2 requires 256.1332.
3.12. N-Methyl-3-phenyl-N-(o-tolyloxy)propanamide (1l)
Prepared by the same procedure with 1a using o-tolylboronic
acid instead of phenylboronic acid (62% overall yield). Colorless oil;
IR (film) nmax 3061, 3027, 2928, 2864, 1676, 1604, 1587, 1484, 1454,
1414, 1380, 1341, 1303, 1218, 1172, 1113, 1095, 1073, 1044, 986, 946,
nylboronic acid (237 mg, 1.94 mmol), pyridine (80 mL, 0.99 mmol),
copper(I) chloride (90 mg, 0.91 mmol), and MS 4 Å (0.17 g) in 1,2-
dichloroethane (4.2 mL) was stirred for 38 h at room temperature
under an air atmosphere. The resulting mixture was filtered
through a pad of Celite and the filtrate was evaporated. The residue
was purified by chromatography on silica gel (n-hexane/EtOAc ¼ 5/
1 as the eluent) to afford 1n (142 mg, 69% yield) as a colorless oil. IR
(film) nmax 3062, 3032, 2930, 1676, 1589, 1485, 1435, 1388, 1346,
1244, 1193, 1156, 1083, 1030, 979, 895, 811, 755, 736, 698 cmꢁ1; 1H
924, 859, 848, 831, 751, 700 cmꢁ1 1H NMR (400 MHz, CDC13)
;
d
7.28e7.21 (2H, m, ArH), 7.20e7.11 (5H, m, ArH), 6.97 (1H, ddd,
J ¼ 7.4, 7.4, 0.8 Hz, ArH), 6.83 (1H, d, J ¼ 8.0 Hz, ArH), 3.29 (3H, s,
NCH3), 2.95 (2H, t, J ¼ 8.0 Hz, CH2), 2.69 (2H, t, J ¼ 8.0 Hz, CH2), 2.24
(3H, s, ArCH3) ppm; 13C NMR (100 MHz, CDCl3)
d 174.9, 155.2, 140.9,
131.5, 128.4, 127.2, 126.0, 124.5, 122.9, 110.5, 34.2, 33.9, 30.5,
15.7 ppm (one overlapping peak); HRMS (ESI): [M þ H]þ, found
270.1483. C17H20NO2 requires 270.1489.
NMR (400 MHz, CDC13)
J ¼ 7.4, 1.2 Hz, ArH), 7.00e6.94 (2H, m, ArH), 4.85 (2H, s, CH2), 2.11
(3H, s, COCH3) ppm; 13C NMR (100 MHz, CDCl3)
172.9, 157.4, 135.5,
d 7.37e7.25 (7H, m, ArH), 7.08 (1H, tt,
d
129.9, 128.9, 128.5, 127.8, 123.3, 113.2, 50.0, 20.7 ppm; HRMS (ESI):
3.13. N-(2,3-Dimethylphenoxy)-N-methyl-3-phenylpropanamide
(1m)
[M þ H]þ, found 242.1170. C15H16NO2 requires 242.1176.
3.15. N-Phenoxy-N-(1-phenylethyl)acetamide (1o)
Prepared from phenylacetyl chloride by the same procedure
with 1a using 2,3-dimethylphenylboronic acid instead of phenyl-
boronic acid (63% overall yield). Colorless oil; IR (film) nmax 3061,
3026, 2924, 2865, 1675, 1605, 1581, 1494, 1466, 1413, 1381, 1340,
1301, 1231, 1175, 1114, 1091, 1058, 1030, 990, 948, 926, 892, 844, 811,
Prepared from acetophenone by the same procedure with 1n.
The yields were depicted in Scheme 4. Colorless oil; IR (film) nmax
3062, 3033, 2983, 2937, 2877, 1683, 1591, 1489, 1455, 1428, 1374,
1337, 1295, 1193, 1156, 1131, 1073, 1025, 981, 935, 914, 893, 832, 822,
773, 750, 699 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
7.28e7.21 (2H, m,
781, 755, 700 cmꢁ1; 1H NMR (400 MHz, CDC13)
d 7.42e7.36 (2H, m,
ArH), 7.20e7.12 (3H, m, ArH), 7.03 (1H, dd, J ¼ 8.0, 7.2 Hz, ArH), 6.88
(1H, d, J ¼ 7.2 Hz, ArH), 6.70 (1H, d, J ¼ 8.0 Hz, ArH), 3.28 (3H, s,
NCH3), 2.95 (2H, t, J ¼ 7.9 Hz, CH2), 2.69 (2H, t, J ¼ 7.9 Hz, CH2), 2.28
(3H, s, ArCH3), 2.14 (3H, s, ArCH3) ppm; 13C NMR (100 MHz, CDCl3)
ArH), 7.31e7.18 (5H, m, ArH), 6.98 (1H, t, J ¼ 7.2 Hz, ArH), 6.93 (2H,
d, J ¼ 7.6 Hz, ArH), 5.84 (1H, q, J ¼ 7.2 Hz, 1-H), 2.03 (3H, s, COCH3),
1.55 (3H, d, J ¼ 7.2 Hz, 2-H) ppm; 13C NMR (100 MHz, CDCl3)
d 174.7,
159.5, 139.8, 129.5, 128.2, 127.8, 127.7, 122.7, 120.1, 115.3, 112.8, 56.7,
21.6, 17.2 ppm; HRMS (ESI): [M þ H]þ, found 256.1326. C16H18NO2
requires 256.1332.
d
174.8, 155.0, 141.0, 138.8, 128.38, 128.35, 126.3, 126.0, 124.6, 122.9,
108.3, 34.1, 33.9, 30.5, 19.7, 11.2 ppm; HRMS (ESI): [M þ H]þ, found
284.1638. C18H22NO2 requires 284.1645.
3.16. N-Methyl-N-phenoxy-2-phenylpropanamide (1p)
3.14. N-Benzyl-N-phenoxyacetamide (1n)
Prepared from 2-phenylpropanoyl chloride by the same pro-
A mixture of benzaldehyde (0.38 mL, 3.7 mmol) and O-benzyl-
hydroxylamine hydrochloride (774 mg, 4.85 mmol) in pyridine
(10.5 mL) was stirred for 14 h at room temperature. The resulting
mixture was evaporated and the residue was diluted with H2O. The
mixture was extracted with EtOAc and the combined extracts were
washed with brine, dried over Na2SO4, and evaporated. Purification
of the residue by chromatography on silica gel (n-hexane/
EtOAc ¼ 10/1 to 5/1 as the eluent) afforded benzaldehyde O-benzyl
oxime (4n) (669 mg, 82% yield) as a colorless oil. (Step 2) A solution
of 4n (662 mg, 2.99 mmol) in CH2Cl2 (6.2 mL) was treated with
sodium cyanoborohydride (398 mg, 6.33 mmol) at room tempera-
ture. The mixture was stirred for 21 h at the same temperature. The
resulting mixture was evaporated and the residue was diluted with
a 1 M aq. NaOH. The mixture was extracted with CH2Cl2 and the
cedure with 1a (63% overall yield).
phenylpropanoyl chloride is as follows:
phenylpropanoic acid (292 mg, 1.94 mmol) and DMF (15
A
preparation of 2-
solution of 2-
L,
A
m
0.19 mmol) in CH2Cl2 (8 mL) was treated with oxalyl chloride
(0.70 mL, 8.3 mmol) at room temperature under an argon atmo-
sphere. The resulting solution was evaporated to provide crude 2-
phenylpropanoyl chloride (331 mg, quant.) as a yellow oil. The
product was used without purifications. Colorless oil; IR (film) nmax
3061, 3028, 2976, 2932, 2872, 1669, 1592, 1484, 1454, 1411, 1377,
1289, 1199, 1179, 1157, 1117, 1072, 1050, 1022, 993, 928, 892, 821,
752, 717, 697 cmꢁ1; 1H NMR (400 MHz, CDC13)
d 7.32e7.13 (7H, m,
ArH), 7.05 (1H, t, J ¼ 7.4 Hz, ArH), 6.88e6.82 (2H, m, ArH), 3.96 (1H,
q, J ¼ 7.0 Hz, 2-H), 3.25 (3H, s, NCH3), 1.44 (3H, d, J ¼ 7.0 Hz, 3-H)
ppm; 13C NMR (100 MHz, CDCl3)
d 176.5, 157.4, 140.7, 129.8, 128.4,

E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
671
127.6, 126.7, 123.1, 112.8, 42.2, 34.4, 19.3 ppm; HRMS (ESI): [M þ
242.1176.
H]þ, found 256.1326. C16H18NO2 requires 256.1332.
3.21. 2-(2-Hydroxy-5-methylphenyl)-N-methyl-3-
3.17. Representative procedure for the base-promoted [3,3]
rearrangement of 1a into 2-(2-hydroxyphenyl)-N-methyl-3-
phenylpropanamide (2a)
phenylpropanamide (2e)
Colorless gum; IR (KBr) nmax 3313, 3130, 3058, 3025, 2933, 2605,
1636, 1603, 1590, 1499, 1452, 1404, 1373, 1265, 1249, 1154, 1119,
(Table 1, Entry 9) A 1 M LiHMDS THF solution (0.34 mL,
0.34 mmol) was added to a solution of 1a (70.8 mg, 0.277 mmol) in
THF (1.4 mL) at 0 ꢀC under an argon atmosphere. The mixture was
stirred for 1 h at 0 ꢀC and for 3 h at room temperature. The resulting
mixture was quenched with saturated aq. NH4Cl and extracted with
EtOAc. The combined extracts were washed with brine, dried over
Na2SO4, and evaporated. Purification of the residue by chroma-
tography on silica gel (n-hexane/EtOAc ¼ 5/1 to 1/1 as the eluent)
gave 2a (54.4 mg, 77% yield) as a yellow gum. IR (film) nmax 3302,
3086, 3028, 2940, 2865, 2783, 2728, 2634, 1636, 1601, 1548, 1490,
1455, 1409, 1308, 1247, 1158, 1105, 1074, 1043, 936, 835, 787, 755,
1075, 1030, 897, 858, 817, 783, 699 cmꢁ1 1H NMR (400 MHz,
;
CDC13)
d 10.43 (1H, s, OH), 7.27e7.21 (2H, m, ArH), 7.18 (1H, tt,
J ¼ 7.2, 1.6 Hz, ArH), 7.16e7.11 (2H, m, ArH), 6.96 (1H, dd, J ¼ 8.1,
2.2 Hz, ArH), 6.85 (1H, d, J ¼ 8.1 Hz, ArH), 6.71 (1H, d, J ¼ 2.2 Hz,
ArH), 5.84 (1H, br q, J ¼ 4.8 Hz, NH), 3.57 (1H, dd, J ¼ 13.4, 10.1 Hz,
CH), 3.38 (1H, dd, J ¼ 10.1, 5.7 Hz, CH2), 3.02 (1H, dd, J ¼ 13.4, 5.7 Hz,
CH2), 2.65 (3H, d, J ¼ 4.8 Hz, NCH3), 2.20 (3H, s, ArCH3) ppm; 13C
NMR (100 MHz, CDCl3) d 176.1, 153.8, 139.1, 130.9, 129.7, 129.1, 128.8,
128.4, 126.5, 124.0, 118.6, 57.2, 37.7, 26.5, 20.3 ppm; HRMS (ESI):
[M þ H]þ, found 270.1482. C17H20NO2 requires 270.1489.
699 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
10.71 (1H, s, OH), 7.26e7.09
3.22. 2-(4-Hydroxy-[1,10-biphenyl]-3-yl)-N-methyl-3-
(6H, m, ArH), 6.95 (1H, dd, J ¼ 7.8, 1.2 Hz, ArH), 6.86 (1H, dd, J ¼ 7.2,
1.6 Hz, ArH), 6.75 (1H, ddd, J ¼ 7.8, 7.2, 1.2 Hz, ArH), 5.86 (1H, br,
NH), 3.54 (1H, dd, J ¼ 13.2, 9.6 Hz, CH), 3.42 (1H, dd, J ¼ 9.6, 6.2 Hz,
CH2), 3.07 (1H, dd, J ¼ 13.2, 6.2 Hz, CH2), 2.66 (3H, d, J ¼ 4.8 Hz, CH3)
phenylpropanamide (2f)
Colorless gum; IR (KBr) nmax 3297, 3131, 3027, 2956, 2932, 2863,
2764, 2464, 1638, 1602, 1482, 1408, 1377, 1292, 1267, 1162, 1122,
ppm; 13C NMR (100 MHz, CDCl3)
d
176.1, 156.2, 138.9, 130.5, 129.3,
1077, 1049, 1027, 904, 858, 834, 771, 762, 698 cmꢁ1 1H NMR
;
128.8, 128.4, 126.5, 124.1, 119.9, 118.8, 57.4, 37.7, 26.6 ppm; HRMS
(400 MHz, DMSO‑d6)
d
10.11 (1H, s, OH), 7.92 (1H, q, J ¼ 4.8 Hz, NH),
(ESI): [M þ H]þ, found 256.1327. C16H18NO2 requires 256.1332.
7.54e7.48 (3H, m, ArH), 7.42 (2H, dd, J ¼ 8.0, 7.4 Hz, ArH), 7.35 (1H,
dd, J ¼ 8.4, 2.4 Hz, ArH), 7.28 (1H, tt, J ¼ 7.4, 1.2 Hz, ArH), 7.27e7.18
(4H, m, ArH), 7.15 (1H, tt, J ¼ 7.0, 1.8 Hz, ArH), 6.89 (1H, d, J ¼ 8.4 Hz,
ArH), 4.10 (1H, dd, J ¼ 9.2, 6.0 Hz, CH), 3.29 (1H, dd, J ¼ 13.6, 9.2 Hz,
CH2), 2.94 (1H, dd, J ¼ 13.6, 6.0 Hz, CH2), 2.51 (3H, d, J ¼ 4.8 Hz, CH3)
3.18. 2-(2-Hydroxyphenyl)-N-methylacetamide (2b)
Colorless gum; IR (KBr) nmax 3371, 3068, 3013, 2974, 2937, 2878,
2729, 2628, 1628, 1599, 1510, 1460, 1403, 1313, 1265, 1248, 1183,
ppm; 13C NMR (100 MHz, DMSO‑d6)
d 173.2, 154.7, 140.4, 140.1,
1167, 1127, 1106, 1038, 941, 928, 876, 840, 796, 756, 712 cmꢁ1
;
1H
131.0, 128.8, 128.7, 128.1, 127.0, 126.8, 126.4, 126.01, 125.97, 116.1,
47.7, 38.0, 25.8 ppm (one overlapping peak); HRMS (ESI): [M þ H]þ,
found 332.1637. C22H22NO2 requires 332.1645.
NMR (400 MHz, CDC13)
d
9.88 (1H, s, OH), 7.16 (1H, ddd, J ¼ 7.9, 7.4,
1.6 Hz, ArH), 7.02 (1H, dd, J ¼ 7.6, 1.6 Hz, ArH), 6.95 (1H, dd, J ¼ 7.9,
1.2 Hz, ArH), 6.82 (1H, ddd, J ¼ 7.6, 7.4, 1.2 Hz, ArH), 6.52 (1H, br,
NH), 3.57 (2H, s, CH2), 2.79 (3H, d, J ¼ 4.8 Hz, CH3) ppm; 13C NMR
3.23. 2-(2-Hydroxy-5-methoxyphenyl)-N-methyl-3-
phenylpropanamide (2g)
(100 MHz, CDCl3)
d
174.0, 155.9, 130.6, 129.1, 121.5, 120.3, 117.6, 40.4,
26.7 ppm; HRMS (ESI): [M þ H]þ, found 166.0860. C9H12NO2 re-
quires 166.0863.
Pale brown gum; IR (film) nmax 3301, 3110, 3028, 3001, 2939,
2833, 1640, 1607, 1544, 1496, 1453, 1433, 1410, 1374, 1297, 1244,
3.19. 2-(2-Hydroxyphenyl)-N-methylpropanamide (2c)
1212, 1180, 1153, 1112, 1067, 1042, 978, 911, 850, 815, 786, 699 cmꢁ1
;
1H NMR (400 MHz, CDC13)
d 10.20 (1H, br, OH), 7.26e7.19 (2H, m,
Colorless gum; IR (film) nmax 3287, 2974, 2939, 2877, 2730, 2631,
1641, 1601, 1548, 1503, 1489, 1454, 1410, 1373, 1325, 1244, 1159, 1117,
1062, 1026, 1000, 985, 936, 909, 836, 754 cmꢁ1; 1H NMR (400 MHz,
ArH), 7.17 (1H, tt, J ¼ 7.2, 1.4 Hz, ArH), 7.14e7.09 (2H, m, ArH), 6.87
(1H, d, J ¼ 8.7 Hz, ArH), 6.71 (1H, dd, J ¼ 8.7, 2.9 Hz, ArH), 6.49 (1H,
d, J ¼ 2.9 Hz, ArH), 6.11 (1H, br q, J ¼ 4.8 Hz, NH), 3.67 (3H, s, OCH3),
3.54 (1H, dd, J ¼ 13.1, 9.4 Hz, CH), 3.43 (1H, dd, J ¼ 9.4, 5.7 Hz, CH2),
3.06 (1H, dd, J ¼ 13.1, 5.7 Hz, CH2), 2.64 (3H, d, J ¼ 4.8 Hz, NCH3)
CDC13)
d
10.17 (1H, br, OH), 7.16 (1H, ddd, J ¼ 8.0, 7.6, 1.4 Hz, ArH),
6.99 (1H, dd, J ¼ 7.4, 1.4 Hz, ArH), 6.93 (1H, d, J ¼ 8.0 Hz, ArH), 6.81
(1H, dd, J ¼ 7.6, 7.4 Hz, ArH), 6.21 (1H, br, NH), 3.55 (1H, q, J ¼ 7.2 Hz,
2-H), 2.82 (3H, d, J ¼ 5.2 Hz, NCH3), 1.58 (3H, d, J ¼ 7.2 Hz, 3-H) ppm;
ppm; 13C NMR (100 MHz, CDCl3)
d 175.8, 152.9, 149.8, 138.9, 128.8,
128.4, 126.5, 125.0, 119.1, 116.1, 113.9, 56.5, 55.7, 37.4, 26.5 ppm;
HRMS (ESI): [M þ H]þ, found 286.1431. C17H20NO3 requires
286.1438.
13C NMR (100 MHz, CDCl3)
d 177.4, 155.7, 129.2, 128.9, 126.0, 120.1,
118.2, 46.2, 26.7, 16.8 ppm; HRMS (ESI): [M þ H]þ, found 180.1016.
C
10H14NO2 requires 180.1019.
3.24. 2-(5-Fluoro-2-hydroxyphenyl)-N-methyl-3-
3.20. 2-(2-Hydroxyphenyl)-N-methyl-2-phenylacetamide (2d)
phenylpropanamide (2h)
Colorless gum; IR (KBr) nmax 3419, 3293, 3087, 2942, 2730, 2624,
Colorless gum; IR (film) nmax 3291, 3112, 3029, 2941, 2686, 2621,
1633,1602,1531,1493,1453,1408,1275,1249,1160,1093,1040, 930,
1641, 1614, 1545, 1494, 1440, 1411, 1373, 1247, 1182, 1143, 1073, 1030,
884, 862, 834, 819, 785, 757, 698 cmꢁ1
;
1H NMR (400 MHz,
1009, 964, 944, 914, 870, 819, 786, 699 cmꢁ1 1H NMR (400 MHz,
;
DMSO‑d6)
d
9.77 (1H, s, OH), 8.20 (1H, q, J ¼ 4.8 Hz, NH), 7.31e7.24
CDC13) d 10.56 (1H, br, OH), 7.26e7.20 (2H, m, ArH), 7.18 (1H, tt,
(2H, m, ArH), 7.24e7.15 (4H, m, ArH), 7.05 (1H, ddd, J ¼ 7.9, 7.3,
1.4 Hz, ArH), 6.78 (1H, dd, J ¼ 7.9, 1.4 Hz, ArH), 6.73 (1H, ddd, J ¼ 7.9,
7.3, 1.4 Hz, ArH), 5.13 (1H, s, CH), 2.60 (3H, d, J ¼ 4.8 Hz, CH3) ppm;
J ¼ 7.0, 1.6 Hz, ArH), 7.13e7.08 (2H, m, ArH), 6.88e6.80 (2H, m, ArH),
6.63 (1H, ddd, J ¼ 9.1, 2.3,1.0 Hz, ArH), 6.21 (1H, br q, J ¼ 5.2 Hz, NH),
3.55e3.42 (2H, m, CH and CH2), 3.08 (1H, ddd, J ¼ 15.2,10.8,10.8 Hz,
CH2), 2.66 (3H, d, J ¼ 5.2 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3)
13C NMR (100 MHz, DMSO‑d6)
d 172.3, 154.9, 140.1, 129.6, 128.4,
128.1, 127.7, 126.4, 118.7, 115.3, 51.1, 25.9 ppm (one overlapping
d
175.6, 157.5, 155.1, 151.9 (d, J ¼ 2 Hz), 138.5, 128.5, 127.7 (d,
peak); HRMS (ESI): [M þ H]þ, found 242.1172. C15H16NO2 requires
J ¼ 209 Hz),125.2 (d, J ¼ 7 Hz),119.2 (d, J ¼ 8 Hz),116.6 (d, J ¼ 23 Hz),

672
E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
115.3 (d, J ¼ 22 Hz), 55.9, 37.4, 26.6 ppm; HRMS (ESI): [M þ H]þ,
2732, 1630, 1609, 1577, 1496, 1454, 1409, 1377, 1280, 1257, 1219,
1160, 1086, 1029, 983, 886, 860, 815, 790, 749, 699 cmꢁ1 1H NMR
(400 MHz, CDC13) 10.72 (1H, s, OH), 7.27e7.21 (2H, m, ArH), 7.18
found 274.1232. C16H17FNO2 requires 274.1238.
;
d
3.25. 2-(5-Cyano-2-hydroxyphenyl)-N-methyl-3-
phenylpropanamide (2i)
(1H, tt, J ¼ 7.4, 1.4 Hz, ArH), 7.15e7.11 (2H, m, ArH), 6.64 (1H, d,
J ¼ 7.6 Hz, ArH), 6.59 (1H, d, J ¼ 7.6 Hz, ArH), 5.73 (1H, br q,
J ¼ 4.8 Hz, NH), 3.60 (1H, dd, J ¼ 13.4, 10.4 Hz, CH), 3.34 (1H, dd,
J ¼ 10.4, 5.6 Hz, CH2), 3.01 (1H, dd, J ¼ 13.4, 5.6 Hz, CH2), 2.62 (3H, d,
Colorless gum; IR (KBr) nmax 3329, 3127, 3062, 3028, 2941, 2589,
2224, 1640, 1597, 1493, 1454, 1406, 1372, 1288, 1270, 1218, 1158,
1114, 1066, 1030, 914, 832, 788, 770, 699 cmꢁ1; 1H NMR (400 MHz,
J ¼ 4.8 Hz, NCH3), 2.24 (3H, s, ArCH3), 2.21 (3H, s, ArCH3) ppm; 13
C
NMR (100 MHz, CDCl3) d 176.3, 154.1, 139.2,137.8, 128.8, 128.4, 127.1,
CDC13)
d
12.12 (1H, s, OH), 7.45 (1H, d, J ¼ 8.6, 2.0 Hz, ArH),
126.5, 126.1, 121.4, 121.1, 57.7, 37.7, 26.5, 20.1, 12.0 ppm; HRMS (ESI):
7.27e7.17 (3H, m, ArH), 7.14 (1H, d, J ¼ 2.0 Hz, ArH), 7.10e7.06 (2H,
m, ArH), 7.02 (1H, d, J ¼ 8.6 Hz, ArH), 6.31 (1H, br q, J ¼ 4.8 Hz, NH),
3.52 (1H, dd, J ¼ 9.1, 6.9 Hz, CH), 3.44 (1H, dd, J ¼ 13.2, 9.1 Hz, CH2),
3.07 (1H, dd, J ¼ 13.2, 6.9 Hz, CH2), 2.71 (3H, d, J ¼ 4.8 Hz, CH3) ppm;
[M þ H]þ, found 284.1636. C18H22NO2 requires 284.1645.
3.30. N-Benzyl-2-(2-hydroxyphenyl)acetamide (2n)
13C NMR (100 MHz, CDCl3)
d
175.5, 161.4, 137.8, 135.0, 133.4, 128.7,
White solid, mp 113e115 ꢀC; IR (KBr) nmax 3306, 3219, 3075,
3030, 2938, 2889, 2713, 1613, 1595, 1557, 1510, 1498, 1456, 1415,
1375, 1362, 1344, 1311, 1270,1227, 1185, 1101, 1071, 1042, 1028, 1006,
938, 923, 907, 871, 849, 824, 788, 747, 698 cmꢁ1; 1H NMR (400 MHz,
128.6, 126.9, 125.2, 120.1, 119.6, 101.9, 56.8, 37.6, 26.6 ppm; HRMS
(ESI): [M þ H]þ, found 281.1279. C17H17N2O2 requires 281.1285.
3.26. 2-(2-Hydroxy-5-methylphenyl)-N-methylacetamide (2j)
CDC13) d 9.59 (1H, br, OH), 7.33e7.23 (3H, m, ArH), 7.23e7.18 (2H,
m, ArH), 7.16 (1H, ddd, J ¼ 7.7, 7.7, 1.4 Hz, ArH), 6.99 (1H, dd, J ¼ 7.7,
1.4 Hz, ArH), 6.94 (1H, dd, J ¼ 7.7, 1.4 Hz, ArH), 6.81 (1H, ddd, J ¼ 7.7,
7.7, 1.4 Hz, ArH), 6.46 (1H, br, NH), 4.38 (2H, d, J ¼ 5.6 Hz, NCH2),
Colorless gum; IR (KBr) nmax 3288, 2942, 1636, 1611, 1554, 1510,
1411, 1356, 1266, 1214, 1169, 1113, 1059, 924, 873, 818, 769, 723,
703 cmꢁ1; 1H NMR (400 MHz, CDC13)
d
9.58 (1H, s, OH), 6.97 (1H, d,
3.56 (2H, s, CH2CO) ppm; 13C NMR (100 MHz, CDCl3)
d 173.2, 155.9,
J ¼ 8.0, 1.8 Hz, ArH), 6.85 (1H, d, J ¼ 8.0 Hz, ArH), 6.82 (1H, d,
J ¼ 1.8 Hz, ArH), 6.40 (1H, br, NH), 3.52 (2H, s, CH2), 2.79 (3H, d,
J ¼ 4.4 Hz, NCH3), 2.23 (3H, s, ArCH3) ppm; 13C NMR (100 MHz,
137.1, 130.5, 129.1, 128.8, 127.75, 127.73, 121.4, 120.4, 117.8, 44.0,
40.7 ppm; HRMS (ESI): [M þ H]þ, found 242.1171. C15H16NO2 re-
quires 242.1176.
CDCl3)
d 174.0, 153.5, 131.0, 129.48, 129.47, 121.3, 117.5, 40.5, 26.7,
20.3 ppm; HRMS (ESI): [M þ H]þ, found 180.1014. C10H14NO2 re-
3.31. 2-(2-Hydroxyphenyl)-N-(1-phenylethyl)acetamide (2o)
quires 180.1019.
Colorless gum; IR (KBr) nmax 3351, 3066, 3033, 2973, 2927, 2870,
1624, 1596, 1535, 1495, 1455, 1409, 1362, 1347, 1263, 1233, 1178,
1153, 1131, 1098, 1073, 1039, 1013, 954, 926, 910, 864, 846, 789, 749,
3.27. 2-(2-Hydroxy-5-methylphenyl)-N-methyl-2-
phenylacetamide (2k)
698 cmꢁ1; 1H NMR (400 MHz, CDC13)
d 9.83 (1H, br, OH), 7.31e7.20
Colorless gum; IR (KBr) nmax 3302, 3111, 3059, 3026, 2941, 2920,
(5H, m, ArH), 7.14 (1H, ddd, J ¼ 7.6, 7.6, 1.4 Hz, ArH), 6.98 (1H, dd,
J ¼ 7.6, 1.4 Hz, ArH), 6.92 (1H, dd, J ¼ 7.6, 1.4 Hz, ArH), 6.80 (1H, ddd,
J ¼ 7.6, 7.6, 1.4 Hz, ArH), 6.69 (1H, br d, J ¼ 6.8 Hz, NH), 5.04 (1H dq,
J ¼ 6.8, 6.8 Hz, NCH), 3.55 (1H, d, J ¼ 6.4 Hz, CH2), 3.50 (1H, d,
J ¼ 6.4 Hz, CH2), 1.44 (3H, d, J ¼ 6.8 Hz, CH3) ppm; 13C NMR
2600,1638,1607, 1540, 1499, 1451, 1410,1375,1253,1221,1160, 1121,
1101, 1078, 1055, 1032, 922, 816, 786, 757, 728, 697 cmꢁ1 1H NMR
;
(400 MHz, DMSO‑d6)
d
9.55 (1H, s, OH), 8.20 (1H, q, J ¼ 4.4 Hz, NH),
7.31e7.15 (5H, m, ArH), 7.00 (1H, d, J ¼ 1.6 Hz, ArH), 6.86 (1H, dd,
J ¼ 8.0, 1.6 Hz, ArH), 6.67 (1H, d, J ¼ 8.0 Hz, ArH), 5.09 (1H, s, CH),
2.60 (3H, d, J ¼ 4.4 Hz, NCH3), 2.14 (3H, s, ArCH3) ppm; 13C NMR
(100 MHz, CDCl3)
d 172.5, 155.8, 142.3, 130.6, 129.0, 128.7, 127.5,
126.0, 121.5, 120.3, 117.6, 49.4, 40.7, 21.6 ppm; HRMS (ESI): [M þ
(100 MHz, DMSO‑d6)
d
172.3, 154.9, 140.1, 129.6, 128.4, 128.1, 127.7,
H]þ, found 256.1325. C16H18NO2 requires 256.1332.
126.4, 118.7, 115.3, 51.1, 40.0, 25.9 ppm (one overlapping peak);
HRMS (ESI): [M þ H]þ, found 256.1326. C16H18NO2 requires
256.1332.
3.32. 2-(2-Hydroxyphenyl)-N-methyl-2-phenylpropanamide (2p)
White solid, mp 53e57 ꢀC; IR (KBr) nmax 3360, 3060, 3026, 2984,
2941, 1805, 1632, 1599, 1534, 1493, 1463, 1447, 1407, 1381, 1292,
1245, 1208, 1187, 1159, 1129, 1112, 1080, 1031, 1015, 888, 854, 822,
3.28. 2-(2-Hydroxy-3-methylphenyl)-N-methyl-3-
phenylpropanamide (2l)
787, 755, 699 cmꢁ1 1H NMR (400 MHz, acetone-d6)
; d 10.31 (1H, s,
Colorless gum; IR (film) nmax 3322, 3087, 3027, 2923, 2779, 2635,
OH), 7.69 (1H, br, NH), 7.30 (1H, dd, J ¼ 8.0, 1.2 Hz, ArH), 7.27e7.16
(4H, m, ArH), 7.09e7.04 (2H, m, ArH), 6.88 (1H, dd, J ¼ 8.0, 1.2 Hz,
ArH), 6.86 (1H, dd, J ¼ 8.0, 1.2 Hz, ArH), 6.80 (1H, dd, J ¼ 8.0, 1.2 Hz,
ArH), 2.83 (3H, d, J ¼ 4.8 Hz, NCH3), 1.88 (3H, s, 3-H) ppm; 13C NMR
1630, 1605, 1590, 1494, 1468, 1408, 1379, 1251, 1221, 1160, 1089,
1072, 1030, 998, 909, 846, 767, 745, 699 cmꢁ1 1H NMR (400 MHz,
;
CDC13)
d 10.81 (1H, s, OH), 7.26e7.19 (2H, m, ArH), 7.17 (1H, tt,
J ¼ 7.2, 1.6 Hz, ArH), 7.14e7.08 (2H, m, ArH), 7.05 (1H, ddd, J ¼ 7.2,
1.6, 0.8 Hz, ArH), 6.74 (1H, dd, J ¼ 7.6, 1.6 Hz, ArH), 6.67 (1H, dd,
J ¼ 7.6, 7.2 Hz, ArH), 5.92 (1H, br, NH), 3.57 (1H, dd, J ¼ 13.3, 9.9 Hz,
CH), 3.41 (1H, dd, J ¼ 9.9, 5.8 Hz, CH2), 3.04 (1H, dd, J ¼ 13.3, 5.8 Hz,
CH2), 2.61 (3H, d, J ¼ 4.8 Hz, NCH3), 2.27 (3H, s, ArCH3) ppm; 13C
(100 MHz, CDCl3) d 177.9, 156.8, 144.6, 129.5, 128.4, 127.4, 127.0,
126.6, 119.7, 119.6, 55.3, 27.6, 27.2 ppm (one overlapping peak);
HRMS (ESI): [M þ H]þ, found 256.1327. C16H18NO2 requires
256.1332.
NMR (100 MHz, CDCl3)
d
176.2, 154.4, 139.0, 130.5, 128.8, 128.4,
3.33. Cyclization of 2a into 3-benzylbenzofuran-2(3H)-one (7a)
128.2, 127.6, 126.5, 123.6, 119.4, 57.5, 37.6, 26.5, 16.4 ppm; HRMS
(ESI): [M þ H]þ, found 270.1479. C17H20NO2 requires 270.1489.
A solution of 2a (253 mg, 0.991 mmol) in benzene (22 mL) was
treated with a 1 M HCl aq. (2.2 mL) and the mixture was refluxed for
2 days. The resulting mixture was cooled to room temperature,
treated with saturated aq. NH4Cl, and extracted with CH2Cl2. The
combined extracts were dried over Na2SO4 and evaporated. The
residue was purified by chromatography on silica gel (n-hexane/
3.29. 2-(2-Hydroxy-3,4-dimethylphenyl)-N-methyl-3-
phenylpropanamide (2m)
Colorless gum; IR (KBr) nmax 3318, 3105, 3061, 3028, 2924, 2861,

E. Tayama, K. Hirano / Tetrahedron 75 (2019) 665e673
Int. Ed. 56 (2017) 10938e10941;
673
EtOAc ¼ 15/1 to 10/1 as the eluent) to afford 7a (189 mg, 85% yield)
as a white solid, mp 55e57 ꢀC. IR (KBr) nmax 3082, 3060, 3028, 2932,
2916, 2885, 1799, 1620, 1600, 1495, 1478, 1462, 1444, 1336, 1324,
1295, 1229, 1174, 1155, 1123, 1080, 1061, 1032, 1016, 988, 960, 941,
923, 889, 873, 812, 753, 710, 699 cmꢁ1; 1H NMR (400 MHz, CDC13)
(b) T. Tomakinian, C. Kouklovsky, G. Vincent, Synlett 26 (2015) 1269e1275;
(c) H. Gao, Q. Xu, C. Keene, L. Kürti 20 (2014) 8883e8887;
(d) N. Takeda, M. Ueda, S. Kagehira, H. Komei, N. Tohnai, M. Miyata, T. Naito,
O. Miyata, Org. Lett. 15 (2013) 4382e4385;
(e) H. Wang, L.L. Anderson, Org. Lett. 15 (2013) 3362e3365;
(f) H. Gao, D.H. Ess, M. Yousufuddin, L. Kürti, J. Am. Chem. Soc. 135 (2013)
7086e7089.
d
7.32e7.21 (4H, m, ArH), 7.18e7.13 (2H, m, ArH), 7.05e6.99 (1H, m,
[7] Aromatic sigmatoropic rearrangements involving heteroatomeheteroatom
bond cleavage. A review: (a) T. Yanagi, K. Nogi, H. Yorimitsu, Tetrahedron
Lett. 59 (2018) 2951e2959. See also recent examples:;
ArH), 7.03 (1H, d, J ¼ 8.0 Hz, ArH), 6.82e6.77 (1H, m, ArH), 4.00 (1H,
dd, J ¼ 9.2, 4.8 Hz, 3-H), 3.50 (1H, dd, J ¼ 13.8, 4.8 Hz, CH2Ph), 3.03
(1H, dd, J ¼ 13.8, 9.2 Hz, CH2Ph) ppm; 13C NMR (100 MHz, CDCl3)
(b) L.L. Baldassari, A.C. Mantovani, S. Senoner, B. Maryasin, N. Maulide,
D.S. Lüdtke, Org. Lett. 20 (2018) 5881e5885;
d
176.4, 153.6, 136.6, 129.3, 128.8, 128.5, 127.1, 126.6, 124.8, 123.8,
110.6, 44.9, 37.1 ppm; HRMS (ESI): [M þ H]þ, found 225.0909.
(c) L. Shang, Y. Chang, F. Luo, J. He, X. Huang, L. Zhang, L. Kong, K. Li, B. Peng,
J. Am. Chem. Soc. 139 (2017) 4211e4217;
C
15H13O2 requires 255.0910.
ꢀ
(d) D. Kaldre, B. Maryasin, D. Kaiser, O. Gajsek, L. Gonzalez, N. Maulide, Angew.
Chem. Int. Ed. 56 (2017) 2212e2215.
[8] Y. Endo, T. Uchida, K. Shudo, Tetrahedron Lett. 38 (1997) 2113e2116.
[9] (a) Y. Endo, T. Uchida, S. Hizatate, K. Shudo, Synthesis (1994) 1096e1105;
(b) Y. Endo, S. Hizatate, K. Shudo, Tetrahedron Lett. 32 (1991) 2803e2806. See
also the related works reported by other groups:;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2018.12.058.
(c) N. Duguet, A.M.Z. Slawin, A.D. Smith, Org. Lett. 11 (2009) 3858e3861;
(d) Z. Mao, S.W. Baldwin, Org. Lett. 6 (2004) 2425e2428;
(e) P.S. Almeida, S. Prabhakar, A.M. Lobo, M.J. Marcelo-Curto, Tetrahedron Lett.
32 (1991) 2671e2674.
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€
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[3,3] rearranged 2a and cyclized 7a were not obtained.
3446e3449;
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