Dearomative [2,3] sigmatropic rearrangement of ammonium ylides followed by 1,4-elimination to form α-(ortho-vinylphenyl)amino acid esters

Article abstract of DOI:10.1039/c8ob01091a

A base-induced dearomative [2,3] sigmatropic rearrangement of amino acid ester-derived ammonium salts followed by 1,4-elimination produced α-(ortho-vinylphenyl)amino acid esters. The reaction of azetidine-2-carboxylic acid-derived ammonium salt, (1S,2S,1′R)-3b, proceeded with a perfect N-to-C chirality transfer to afford α-(ortho-vinylphenyl)azetidine-2-carboxylic acid ester, (R)-5 (99% ee). On the other hand, the reaction of glycine-derived ammonium salt (R)-6a, which involves an efficient chirality transfer from a chiral benzylic carbon to an α-carbon of an ester carbonyl giving the optically active α-(ortho-vinylphenyl)glycine ester, (R)-8a (85% ee), was demonstrated. Although this dearomative [2,3] rearrangement followed by 1,4-elimination has limitations with regard to the structures of the substrates, our method provides unique access to substituted α-arylamino acid derivatives.

Full text of DOI:10.1039/c8ob01091a

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Dearomative [2,3] sigmatropic rearrangement of ammonium
ylides followed by 1,4‐elimination to form ‐(ortho‐
vinylphenyl)amino acid esters
Received 00th January 20xx,
Accepted 00th January 20xx
Eiji Tayama,*a and Sho Sotomeb
DOI: 10.1039/x0xx00000x
A base‐induced dearomative [2,3] sigmatropic rearrangement of amino acid ester‐derived ammonium salts followed by 1,4‐
elimination produced ‐(ortho‐vinylphenyl)amino acid esters. The reaction of azetidine‐2‐carboxylic acid‐derived
ammonium salt (1S,2S,1’R)‐3b proceeded with a perfect N‐to‐C chirality transfer to afford ‐(ortho‐vinylphenyl)azetidine‐2‐
carboxylic acid ester (R)‐5 (99% ee). On the other hand, the reaction of glycine‐derived ammonium salt (R)‐6a, which
involves an efficient chirality transfer from a chiral benzylic carbon to an ‐carbon of an ester carbonyl giving the optically
www.rsc.org/
active ‐(ortho‐vinylphenyl)glycine ester (R)‐8a (85% ee), was demonstrated.
Although this dearomative [2,3]
rearrangement followed by 1,4‐elimination has limitations with regard to the structures of the substrates, our method
provides unique access to substituted ‐arylamino acid derivatives.
Introduction
Previous work (Sommelet–Hauser)
CO2tBu
CO2tBu
OTf
The [2,3] sigmatropic rearrangement involving an aromatic C=C
double bond, such as Sommelet–Hauser (S–H) rearrangement,1‐
is a unique synthetic transformation because the initial [2,3]
rearrangement is a dearomative reaction.8‐10 For example, the
NH2
Ph
[2,3]
tBuOK
N
N
7
A
(1S,2S,1'S)-1
S–H rearrangement of ylide
A depicted in Scheme 1 (eqn (1))
CO2tBu
CO2tBu
proceeds via an initial dearomative [2,3] shift to generate
B
aromatization
N
followed by aromatization. These processes result in the
formation of a new C–C bond between an aromatic (sp2) and an
aliphatic (sp3) carbon under mild conditions. Furthermore,
N
(1)
H
(1,3-prototropic shift)
B
(R)-2
dearomatized B has a cyclohexadienyl fragment, and analogous
derivatives could be used as unique building blocks. However,
their isolation and synthetic applications have been limited.
As mentioned above, we have reported that the base‐
induced S–H rearrangement of N‐(1’‐phenylethyl)azetidine‐2‐
First observation in this work
CO2tBu
OTf
CO2tBu
NH2
Ph
N
N
[2,3]
tBuOK
carboxylic acid ester‐derived ammonium salt, (1S,2S,1’S)‐
prepared from (S)‐(1‐phenylethyl)amine gave ‐(2‐ethylphenyl)
derivative (R)‐
(Scheme 1, eqn (1)).4b,11 To expand the
1,
OH

OMe
(1S,2S,1'R)-3a
OMe
A'
2
synthetic scope of this transformation, we attempted the
reaction of analogue salt (1S,2S,1’R)‐3a, which was prepared
from (R)‐2‐amino‐2‐phenylethanol (eqn (2)). Interestingly, the
CO2tBu
CO2tBu
CO2tBu
N
N
N
H
(2)
+
reaction produced ortho‐vinylphenyl derivative (R)‐
unexpected side product along with S–H rearrangement
product (R)‐4a. We expected that (R)‐ would be formed via the
5 as an
OMe
OMe
(R)-4a
Sommelet–Hauser
Scheme 1 Unexpected product (R)‐ in the dearomative [2,3] sigmatropic
5
B'
(R)-5
unexpected
[2,3] shift of ylide A’ followed by 1,4‐elimination of
5
rearrangement.
a. Department of Chemistry, Faculty of Science, Niigata University, Niigata, 950‐
2181, Japan. E‐mail: tayama@chem.sc.niigata‐u.ac.jp.
dearomatized B’, and this transformation will expand the
synthetic scope of dearomative [2,3] sigmatropic
rearrangements. The formed ‐(ortho‐vinylphenyl)amino acid
derivatives can serve as interesting building blocks via further
b. Graduate School of Science and Technology, Niigata University, Niigata, 950‐
2181, Japan.
†Electronic Supplementary Informaꢀon (ESI) available: Experimental details of
preparation of substrates
3 and 6, determination of ee, absolute structures, and
copy of NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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functionalization of the double bond.12 Thus, we started to
investigate this successive [2,3] rearrangement–1,4‐elimination.
View Article Online
DOI: 10.1039/C8OB01091A
Results and discussion
We examined the S–H rearrangement of (1S,2S,1’R)‐3a13,14 with
1.2 equivalents of tBuOK in THF at 0 °C for the preparation of
(R)‐4a15 (Table 1, Entry 1). Desired product (R)‐4a was obtained
in 48% yield with 98% ee via N‐to‐C chirality transfer. (R)‐516
was isolated as an unexpected side product in 31% yield with
Scheme 2 The reaction of the salt of the other diastereomer, (1R,2R,1’R)‐3b
.
98% ee. We expected that the yield of (R)‐
by the addition of excess tBuOK because the base‐promoted
1,4‐elimination to produce (R)‐ would be driven to completion.
5 would be improved
5
Thus, substrate (1S,2S,1’R)‐3a was treated with 2.0 equivalents
of tBuOK; however, this change did not improve the reaction
outcome (Entry 2). To enhance the rate of the elimination, we
decided to exchange the methoxy leaving group (OMe), as in
(1S,2S,1’R)‐3a, for an acetoxy (OAc) moiety. The reaction of
acetate (1S,2S,1’R)‐3b with 1.2 equivalents of tBuOK gave only
Scheme 3 Experimental mechanistic study.
This result, depicted in Scheme 3, indicated that (R)‐5 is
mainly derived from dearomatized intermediate B’, which is
generated from the initial [2,3] rearrangement of ylide A’
(Scheme 4). When the leaving group is OMe, as in (1S,2S,1’R)‐
3a, both the aromatization leading to (R)‐4a and the 1,4‐
elimination leading to (R)‐5 could also occur from B’. The use of
OAc as the leaving group enhanced the rate of the 1,4‐
(R)‐
elimination would proceed smoothly. The 47% yield was
reasonable because the maximum yield of (R)‐ is 60% with 1.2
equivalents of tBuOK. As expected, the use of 2.0 equivalents
5 in 47% yield with 99% ee (Entry 3). The desired 1,4‐
5
of tBuOK produced desired (R)‐5 in 89% yield with 99% ee (Entry
4).
elimination and afforded only (R)‐
of tBuOK was used.
5 even when 1.2 equivalents
Table 1 Base‐induced rearrangement of (1S,2S,1’R)‐3 with N‐to‐C chirality transfer
CO2tBu
CO2tBu
OTf
CO2tBu
N
N
tBuOK
N
+
OR
OR
(R)-4
(1S,2S,1'R)-3
(R)-5
tBuO
aromatization
Entry
R
tBuOK (equiv)
(R)‐4a
48%, 98% ee
52%, 95% ee
0%
(R)‐5a
CO2tBu
CO2tBu
CO2tBu
1
2
3
4
Me
Me
Ac
a
a
b
b
1.2
2.0
1.2
2.0
31%, 98% ee
33%, 98% ee
47%, 99% ee
89%, 99% ee
1
N
N
N
[2,3]
H
H
Ac
0%
4
tBuO
OR
OR
B'
OR
a Isolated yield. The ee were determined by chiral HPLC.
A'
1,4-elimination
Scheme 4 Proposed reaction pathway leading to (R)‐5.
The other enantiomer, (S)‐5, could be obtained from the salt
of the other diastereomer, (1R,2R,1’R)‐3b13,14 (Scheme 2). The
reaction of (1R,2R,1’R)‐3b with 2.0 equivalents of tBuOK gave
(S)‐5 in 67% yield with 91% ee. In our previous work, the
analogous diastereomers of the azetidinium salts were found to
With these results in hand, we decided to apply this
successive dearomative [2,3] rearrangement–1,4‐elimination to
acyclic substrates such as glycine‐derived ammonium salt (R)‐
6a18 (Scheme 5). The reaction would proceed with chirality
be
poorly‐tolerated
in
the
dearomative
[2,3]
transfer from a chiral benzylic carbon to an
ester carbonyl to afford optically active, S–H rearrangement
product 7a and ‐(ortho‐vinylphenyl)glycine ester 8a. First, we
‐carbon of the
rearrangement.4a,17 Thus, the yield and ee would be slightly
lower.

To clarify the reaction pathway leading to (R)‐5, we treated
examined the reaction of (R)‐6a at –40 °C to avoid the
anticipated racemization of 7a and 8a. However, the products
(R)‐4a with tBuOK to prevent E2 elimination in the conversion
1
of S–H rearrangement product (R)‐4a into (R)‐
5
(Scheme 3). H
(
7a: 5% yield, 8a: 73% yield) were obtained as racemates.
NMR analysis of the crude material showed only 2% conversion
without any decomposition.
Interestingly, when the reaction was carried out at –78 °C (3
runs), the enantioselective formation of products 7a and 8a was
achieved, and the desired products were obtained in 88–90%
2 | J. Name., 2012, 00, 1‐3
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ee for (R)‐7a19 and 69–75% ee for (R)‐8a20 although the yields of substrate scopes, our studies will expand the synthetic
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DOI: 10.1039/C8OB01091A
(R)‐8a were slightly lower at this temperature (56–60% yields). applications of ammonium ylide rearrangements and provide a
The stereochemistries of substrate (R)‐6a, products (R)‐7a and unique method of synthesizing
(R)‐8a indicate that the reaction proceeds via intermediate
‐arylamino acid derivatives.
C
.
Table 2 Dearomative [2,3] rearrangement followed by 1,4‐elimination of racemic 6
Desired product (R)‐8a may racemize more easily than (R)‐7a
due to conjugation with the vinyl substituent. Finally, we
attempted the reaction at –92 °C (3 runs) and obtained (R)‐7a
in 7–12% yields with 93–95% ee and (R)‐8a in 48–52% yields
with 81–85% ee.
N
CO2tBu
N
CO Bu
2t
R4
R4
X
2.0 equiv tBuOK
THF
AcO
R3
R3
R1
–40 °C, 3 h
O
R2
R1
R2
8
N
CO Bu
2t
H
N
6
2.0 equiv tBuOK
OtBu
Br
O
O
THF
Entry
R1
Cl
Br
Me
OMe
H
R2
R3
H
H
H
H
Cl
H
H
R4
H
H
H
H
H
H
Me
X
Br
Br
Br
Br
Br
Br
OTf
8 (%)a
OAc
temp., 3 h
1
2
3
4
5
6
7
H
H
H
H
H
Cl
H
b
c
d
e
f
48
50
64
52
46
(R)-6a
C
N
N
2t
CO Bu
2t
CO Bu
+
H
H
g
h
34 + 28 (2,6‐isomer 8g’)
40
OAc
(R)-7a
5%, 0% ee
(R)-8a
73%, 0% ee
a Isolated yield.
–40 °C
–78 °C (3 runs)
–92 °C (3 runs)
7–8%, 88–90% ee
7–12%, 93–95% ee
56–60%, 69–75% ee
48–52%, 81–85% ee
Experimental
General
Scheme 5 Dearomative [2,3] rearrangement followed by 1,4‐elimination of (R)‐6a
with chirality transfer.
Infrared spectra were recorded on a Perkin Elmer Spectrum GX
To define the scope and limitations of this reaction for the
1
FT‐IR spectrometer. H and 13C NMR spectra were measured on
formation of
subjected them to the reaction at –40 °C (Table 2). The
reactions of para‐ and ortho‐substituted substrates 6b
resulted in moderate yields of 8b (Entries 1–5, 46–64%). As
8, we prepared various racemic substrates 6 and
a Varian or a Bruker 400 MHz spectrometers (1H: 400 MHz, 13C:
100 MHz). As an internal standard, Me4Si was used for 1H NMR
(δ 0 ppm) and CDCl3 for 13C NMR (δ 77 ppm). 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 were measured on a Thermo Fisher Scientific
LC/FT‐MS spectrometer. Specific rotations were recorded on a
JASCO polarimeter P–1010. Normal phase HPLC analyses were
performed using a JASCO HPLC pump PU‐2080 and a UV/VIS
detector UV‐2075. Reactions involving air‐ or moisture‐
sensitive compounds were conducted in appropriate round‐
bottomed flasks with a magnetic stirring bar under an argon
atmosphere. Reactions under lower temperature were carried
out using a Constant Temp. Bath with Magnetic Stirrer (PSL‐
1400 and PSL‐1800, EYELA, Japan) and a Ultra‐Cooling Reacter
(UCR‐150, Techno Sigma Co., Ltd., Japan). A 1.0 M tBuOK THF
solution were purchased from Tokyo Chemical Industry (TCI) Co.,
Ltd., Japan. THF was purchased from KANTO Chemical Co., Inc.,
Japan as an anhydrous solvent. 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 (silica gel 60N, spherical
neutral, KANTO Chemical Co., Inc., Japan).
–
f
–f
expected, the reaction of meta‐chloro derivative 6g afforded
both possible regioisomers 8g (2,4‐disubstituted, 34% yield) and
8g’ (2,6‐disubstituted, 28% yield) (Entry 6). In each of the
reactions described above, the corresponding S–H
rearrangement products (analogous to 7a) were observed in
approximately 10% yields.21
transformation to the construction of an
Finally, we applied this
‐quaternary amino

acid (Entry 7). The reaction of alanine‐derived ammonium salt
6h (1/1 mixture of diastereomers) under the same conditions
gave ‐(ortho‐vinylphenyl)alanine ester 8h in 40% yield.
Conclusions
In conclusion, the dearomative [2,3] sigmatropic
rearrangement followed by 1,4‐elimination of ammonium
ylides to provide
‐(ortho‐vinylphenyl)amino acid esters was
successfully demonstrated. This result is a new synthetic
application of dearomatized compound B’. Further studies are
necessary to clarify the origin of the chirality transfer from the
chiral benzylic carbon of (R)‐6a to an
‐carbon of the ester
Representative procedure for the reaction of (1S,2S,1’R)‐3a
carbonyl of (R)‐7a and (R)‐8a. These studies will be reported in
due course.
Although dearomative [2,3] sigmatropic rearrangements,
such as the Sommelet–Hauser rearrangement, still have limited
A solution of (1S,2S,1’R)‐3a (102 mg, 0.224 mmol, 97% ee) in
THF (2.0 mL) was treated with a 1 M tBuOK THF solution (0.27
mL, 0.27 mmol) at 0 °C under an argon atmosphere and stirred
for 3 h at the same temperature. The resulting mixture was
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quenched with saturated NH4Cl aq. and extracted with EtOAc. mL/min, tR = 8.4 min for (S)‐
5
(0.5%) and 8.9 mVieiwnAfrtoicrle (ORn)li‐n5e
‐1
DOI: 10.1039/C8OB01091A
The combined extracts were washed with saturated NaHCO3 aq. (99.5%)]; IR (film)
max/cm 3087, 3062, 2974, 2930, 2852, 2782,
followed by brine, dried over Na2SO4 and evaporated. The 1716, 1626, 1474, 1456, 1412, 1391, 1367, 1289, 1254, 1197,
residue was purified by chromatography on silica gel [n‐ 1164, 1125, 1086, 1043, 1021, 978, 948, 910, 845, 822, 773, 759,
1
hexane/EtOAc = 15/1 to 4/1 as the eluent, Rf: (R)‐
obtain (R)‐
5
> (R)‐4a] to 743; H NMR (400 MHz, CDCl3)

7.56 (1H, dd, J = 7.6, 1.2 Hz,
5
(19.0 mg, 31% yield, 98% ee) as a colourless oil and ArH), 7.45 (1H, dd, J = 7.6, 1.2 Hz, ArH), 7.29 (1H, ddd, J = 7.6,
(R)‐4a (33.1 mg, 48% yield, 98% ee) as a colourless oil.
Representative procedure for the reaction of (1S,2S,1’R)‐3b
7.6, 1.2 Hz, ArH), 7.21 (1H, ddd, J = 7.6, 7.6, 1.2 Hz, ArH), 6.54
(1H, dd, J = 17.1, 11.0, CH=CH2), 5.61 (1H, dd, J = 17.1, 1.2 Hz,
CH=CH2), 5.21 (1H, dd, J = 11.0, 1.2 Hz, CH=CH2), 3.48 (1H, ddd,
J = 8.4, 6.2, 2.4 Hz, 4‐H), 3.33 (1H, ddd, J = 8.8, 8.4, 6.2 Hz, 4‐H),
2.97 (1H, ddd, J = 10.5, 8.4, 2.4 Hz, 3‐H), 2.48 (3H, s, NCH3), 2.19
(1H, ddd, J = 10.5, 8.8, 8.4 Hz, 3‐H), 1.37 (9H, s, tBu); 13C NMR
A solution of (1S,2S,1’R)‐3b (106 mg, 0.219 mmol, 99% ee) in
THF (2.0 mL) was treated with a 1 M tBuOK THF solution (0.44
mL, 0.44 mmol) at 0 °C under an argon atmosphere and stirred
for 3 h at the same temperature. The resulting mixture was
quenched with saturated NH4Cl aq. and extracted with EtOAc.
The combined extracts were washed with saturated NaHCO3 aq.
(100 MHz, CDCl3)
 170.5, 141.6, 134.3, 134.1, 127.5, 126.8,
125.2, 125.1, 115.8, 81.7, 75.4, 52.1, 39.9, 29.7, 28.0; HRMS
(ESI): calcd for C17H24NO2 [M + H]+ 274.1802, found 274.1793.
(S)‐tert‐Butyl 1‐methyl‐2‐(2‐vinylphenyl)azetidine‐2‐carboxylate
[(S)‐5]
1
followed by brine, dried over Na2SO4 and evaporated. H NMR
analysis of the crude product showed only (R)‐
5 as the product.
Purification of the crude product by chromatography on silica
gel (n‐hexane/EtOAc = 20/1 to 10/1 as the eluent) afforded (R)‐ Colourless oil; [
24

]
–146.9 (c 1.0 in EtOH) for 91% ee
589
5
(53.1 mg, 89% yield, 99% ee) as a colourless oil.
[determined by HPLC analysis: Daicel Chiralcel OD‐H column (25
Representative procedure for the reaction of (R)‐6a
cm), n‐hexane/iPrOH = 99.8/0.2 as the eluent, flow rate = 0.50
mL/min, tR = 9.2 min for (S)‐5 (95.5%) and 9.9 min for (R)‐5
(4.5%)].
(R)‐tert‐Butyl 2‐(2‐(2‐acetoxyethyl)phenyl)‐2‐
(dimethylamino)acetate [(R)‐7a]
A 1 M tBuOK THF solution (1.05 mL, 1.05 mmol) was added
slowly to a solution of (R)‐6a (212 mg, 0.527 mmol, >99% ee) in
THF (4.2 mL) at –92 °C under an argon atmosphere and the
mixture was stirred for 3 h at the same temperature. The
26
resulting mixture was poured into saturated NH4Cl aq. and Colourless oil; [

]
–83.1 (c 1.0 in EtOH) for 95% ee
589
extracted with EtOAc. The combined extracts were washed [determined by HPLC analysis: Daicel Chiralpak AD‐H column
with saturated NaHCO3 aq. followed by brine, dried over Na2SO4 (25 cm), n‐hexane/iPrOH = 95/5 as the eluent, flow rate = 0.50
and evaporated. Purification of the residue by chromatography mL/min, tR = 8.5 min for (S)‐7a (2.3%) and 9.7 min for (R)‐7a
on silica gel (n‐hexane/EtOAc = 8/1 to 2/1 as the eluent, Rf: (R)‐ (97.7%)]; IR (film)
8a > (R)‐7a) afforded (R)‐8a (71.0 mg, 52% yield, 85% ee) as a 1449, 1391, 1367, 1238, 1143, 1105, 1045, 947, 901, 835, 757;
colourless oil and (R)‐7a (11.5 mg, 7% yield, 95% ee) as a 1H NMR (400 MHz, CDCl3)
7.61‐7.55 (1H, m, ArH), 7.27‐7.18

max/cm‐1 3060, 2978, 2866, 2820, 2773, 1741,

colourless oil.
(3H, m, ArH), 4.34 (1H, dt, J = 11.0, 7.6 Hz, CH2O), 4.26 (1H, dt, J
= 11.0, 7.6 Hz, CH2O), 4.11 (1H, s, NCHCO), 3.10 (2H, dd, J = 7.6,
7.6 Hz, CH2Ar), 2.28 (6H, s, N(CH3)2), 2.07 (3H, s, COCH3), 1.38
(R)‐tert‐Butyl 2‐(2‐(2‐methoxyethyl)phenyl)‐1‐methylazetidine‐2‐
carboxylate [(R)‐4a]
(9H, s, tBu); 13C NMR (100 MHz, CDCl3)
 170.97, 170.95, 136.5,
25
Colourless oil; [

]
+143.4 (c 1.0 in EtOH) for 98% ee
589
135.8, 130.3, 128.6, 127.8, 127.0, 81.3, 70.5, 64.7, 43.0, 31.9,
27.9, 21.0; HRMS (ESI): calcd for C18H28NO4 [M + H]+ 322.2013,
found 322.2005.
[determined by HPLC analysis: Daicel Chiralcel OD‐H column (25
cm), n‐hexane/iPrOH = 99.5/0.5 as the eluent, flow rate = 0.50
mL/min, tR = 10.3 min for (R)‐4a (98.8%) and 12.6 min for (S)‐4a
(1.2%)]; IR (film) 
max/cm‐1 3065, 2974, 2929, 2853, 2782, 1715,
1482, 1455, 1392, 1367, 1255, 1194, 1162, 1120, 1086, 1039, Colourless oil; [
974, 922, 908, 845, 762; 1H NMR (400 MHz, CDCl3)
(R)‐tert‐Butyl 2‐(dimethylamino)‐2‐(2‐vinylphenyl)acetate [(R)‐8a]
20

]
–137.9 (c 1.0 in EtOH) for 85% ee
589
 7.55‐7.51 [determined by HPLC analysis: Daicel Chiralpak AD‐H column
(1H, m, ArH), 7.26‐7.15 (3H, m, ArH), 3.55 (2H, t, J = 7.6 Hz, (25 cm), n‐hexane/iPrOH = 99.5/0.5 as the eluent, flow rate =
CH2O), 3.48 (1H, ddd, J = 8.7, 6.1, 2.4 Hz, 4‐H), 3.39‐3.32 (1H, m, 0.50 mL/min, tR = 8.1 min for (S)‐8a (7.6%) and 9.2 min for (R)‐
4‐H), 3.34 (3H, s, OCH3), 2.96 (1H, ddd, J = 10.4, 8.0, 2.4 Hz, 3‐H), 8a (92.4%)]; IR (film) 
max/cm‐1 3085, 3063, 2978, 2932, 2866,
2.65 (1H, dt, J = 14.4, 7.6 Hz, CH2Ar), 2.59 (1H, dt, J = 14.4, 7.6 2819, 2772, 1741, 1730, 1626, 1479, 1459, 1449, 1413, 1392,
Hz, CH2Ar), 2.49 (3H, s, NCH3), 2.21 (1H, ddd, J = 10.4, 8.8, 8.7 1367, 1256, 1221, 1143, 1089, 1045, 993, 947, 903, 881, 866,
Hz, 3‐H), 1.44 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
  7.58‐7.53 (1H,
170.7, 836, 808, 771, 750; 1H NMR (400 MHz, CDCl3)
142.6, 134.0, 128.8, 126.7, 126.0, 125.5, 81.8, 75.6, 72.7, 58.5, m, ArH), 7.50‐7.45 (1H, m, ArH), 7.29‐7.23 (2H, m, ArH), 7.24 (1H,
52.2, 39.8, 31.7, 29.9, 28.1; HRMS (ESI): calcd for C18H28NO3 [M dd, J = 17.1, 10.8 Hz, CH=CH2), 5.62 (1H, dd, J = 17.1, 1.6 Hz,
+ H]+ 306.2064, found 306.2054.
(R)‐tert‐Butyl 1‐methyl‐2‐(2‐vinylphenyl)azetidine‐2‐carboxylate
CH=CH2), 5.34 (1H, dd, J = 10.8, 1.6 Hz, CH=CH2), 4.13 (1H, s,
NCHCO), 2.26 (6H, s, N(CH3)2), 1.37 (9H, s, tBu); 13C NMR (100
[(R)‐5]
MHz, CDCl3)  170.8, 138.0, 134.9, 134.5, 128.4, 127.82, 127.76,
126.3, 116.4, 81.2, 71.1, 43.1, 27.9; HRMS (ESI): calcd for
C16H24NO2 [M + H]+ 262.1802, found 262.1792.
tert‐Butyl 2‐(5‐chloro‐2‐vinylphenyl)‐2‐(dimethylamino)acetate
(8b)
19
Colourless oil; [

]
+158.3 (c 1.0 in EtOH) for 99% ee
589
[determined by HPLC analysis: Daicel Chiralcel OD‐H column (25
cm), n‐hexane/iPrOH = 99.5/0.5 as the eluent, flow rate = 0.50
4 | J. Name., 2012, 00, 1‐3
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Page 5 of 6
Organic & Biomolecular Chemistry
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Journal Name
Colourless oil; IR (film)
ARTICLE

max/cm‐1 3086, 2979, 2868, 2823, 2775, 1253, 1217, 1144, 1096, 1043, 988, 934, 900, 878, 838, 780, 754;
View Article Online
1739, 1625, 1591, 1478, 1415, 1392, 1368, 1255, 1221, 1144, 1H NMR (400 MHz, CDCl3)
DOI: 10.1039/C8OB01091A
 7.61 (1H, dd, J = 8.0, 1.2 Hz, ArH),
1117, 1097, 1082, 1045, 990, 955, 914, 866, 827, 785, 753, 734; 7.34 (1H, dd, J = 8.0, 1.2 Hz, ArH), 7.21 (1H, dd, J = 8.0, 8.0 Hz,
1H NMR (400 MHz, CDCl3)
7.60 (1H, d, J = 2.4 Hz, ArH), 7.41 ArH), 6.75 (1H, dd, J = 17.8, 11.5 Hz, CH=CH2), 5.71 (1H, dd, J =
(1H, d, J = 8.4 Hz, ArH), 7.23 (1H, dd, J = 8.4, 2.4 Hz, ArH), 7.16 11.5, 1.7 Hz, CH=CH2), 5.54 (1H, dd, J = 17.8, 1.7 Hz, CH=CH2),
(1H, dd, J = 17.4, 10.9 Hz, CH=CH2), 5.61 (1H, dd, J = 17.4, 1.6 Hz, 4.29 (1H, s, NCHCO), 2.21 (6H, s, N(CH3)2), 1.39 (9H, s, tBu); 13
CH=CH2), 5.36 (1H, dd, J = 10.9, 1.6 Hz, CH=CH2), 4.07 (1H, s, NMR (100 MHz, CDCl3) 170.7, 137.8, 137.1, 133.2, 132.6, 128.7,
NCHCO), 2.27 (6H, s, N(CH3)2), 1.39 (9H, s, tBu); 13C NMR (100 128.0, 127.0, 122.6, 81.3, 70.5, 43.1, 27.9; HRMS (ESI): calcd for
MHz, CDCl3)
170.1, 136.3, 136.2, 133.7, 128.3, 128.1, 127.6, C16H23ClNO2 [M + H]+ 296.1412, found 292.1402.

C


117.1, 81.6, 71.0, 43.1, 27.9; HRMS (ESI): calcd for C16H23ClNO2 tert‐Butyl 2‐(4‐chloro‐2‐vinylphenyl)‐2‐(dimethylamino)acetate
[M + H]+ 296.1412, found 292.1404.
(8g)
tert‐Butyl 2‐(5‐bromo‐2‐vinylphenyl)‐2‐(dimethylamino)acetate
(8c)
Yellow oil; IR (film) 
max/cm‐1 3087, 2978, 2933, 2868, 2822,
2774, 1740, 1626, 1591, 1560, 1476, 1414, 1391, 1368, 1279,
Colourless oil; IR (film)

max/cm‐1 3086, 2978, 2868, 2822, 2775, 1255, 1221, 1144, 1044, 988, 948, 920, 880, 851, 836, 792, 752,
1
1739, 1626, 1585, 1556, 1476, 1414, 1392, 1367, 1255, 1220, 724; H NMR (400 MHz, CDCl3)
 7.52 (1H, d, J = 8.4 Hz, ArH),
1144, 1106, 1080, 1046, 989, 951, 907, 867, 826, 784, 752; 1H 7.45 (1H, d, J = 2.2 Hz, ArH), 7.24 (1H, dd, J = 8.4, 2.2 Hz, ArH),
NMR (400 MHz, CDCl3) 7.75 (1H, d, J = 2.0 Hz, ArH), 7.39 (1H, 7.17 (1H, dd, J = 17.4, 11.1 Hz, CH=CH2), 5.64 (1H, dd, J = 17.4,

dd, J = 8.6, 2.0 Hz, ArH), 7.34 (1H, d, J = 8.6 Hz, ArH), 7.15 (1H, 1.3 Hz, CH=CH2), 5.39 (1H, dd, J = 11.1, 1.3 Hz, CH=CH2), 4.06 (1H,
dd, J = 17.3, 10.9 Hz, CH=CH2), 5.62 (1H, dd, J = 17.3, 1.2 Hz, s, NCHCO), 2.25 (6H, s, N(CH3)2), 1.38 (9H, s, tBu); 13C NMR (100
CH=CH2), 5.36 (1H, dd, J = 10.9, 1.2 Hz, CH=CH2), 4.06 (1H, s, MHz, CDCl3)
NCHCO), 2.26 (6H, s, N(CH3)2), 1.39 (9H, s, tBu); 13C NMR (100 126.3, 117.8, 81.5, 70.7, 43.1, 27.9; HRMS (ESI): calcd for
MHz, CDCl3)
170.1, 136.8, 136.5, 133.7, 131.2, 131.0, 127.9, C16H23ClNO2 [M + H]+ 296.1412, found 292.1406.
 170.4, 139.6, 133.7, 133.6, 133.0, 129.9, 127.8,

121.8, 117.1, 81.6, 70.9, 43.1, 27.9; HRMS (ESI): calcd for tert‐Butyl 2‐(6‐chloro‐2‐vinylphenyl)‐2‐(dimethylamino)acetate
C16H23BrNO2 [M + H]+ 340.0907, found 340.0897.
tert‐Butyl 2‐(dimethylamino)‐2‐(5‐methyl‐2‐vinylphenyl)acetate
(8d)
(8g’)
Colourless oil; IR (film) 
max/cm‐1 3083, 2979, 2866, 2820, 2774,
1742, 1624, 1587, 1559, 1453, 1406, 1392, 1367, 1319, 1251,
Yellow oil; IR (film) 
max/cm‐1 3083, 2978, 2866, 2820, 2772, 1220, 1148, 1090, 1049, 1008, 952, 906, 843, 813, 792, 747, 710;
1740, 1611, 1494, 1456, 1414, 1391, 1367, 1255, 1215, 1144, 1H NMR (400 MHz, CDCl3)
 7.64 (1H, dd, J = 17.4, 10.9 Hz,
1
1094, 1046, 994, 963, 904, 870, 825, 789, 756; H NMR (400 CH=CH2), 7.45 (1H, dd, J = 8.0, 1.2 Hz, ArH), 7.33 (1H, dd, J = 8.0,
MHz, CDCl3)  7.38 (1H, s, ArH), 7.37 (1H, d, J = 8.0 Hz, ArH), 7.20 1.2 Hz, ArH), 7.18 (1H, ddd, J = 8.0, 8.0, 0.5 Hz, ArH), 5.59 (1H,
(1H, dd, J = 17.3, 10.9 Hz, CH=CH2), 7.07 (1H, dd, J = 8.0, 1.6 Hz, dd, J = 17.4, 1.5 Hz, CH=CH2), 5.30 (1H, dd, J = 10.9, 1.5 Hz,
ArH), 5.58 (1H, dd, J = 17.3, 1.6 Hz, CH=CH2), 5.28 (1H, dd, J = CH=CH2), 4.67 (1H, s, NCHCO), 2.28 (6H, s, N(CH3)2), 1.32 (9H, s,
10.9, 1.6 Hz, CH=CH2), 4.08 (1H, s, NCHCO), 2.33 (3H, s, ArCH3), tBu); 13C NMR (100 MHz, CDCl3)

169.7, 140.5, 135.9, 135.2,
2.26 (6H, s, N(CH3)2), 1.38 (9H, s, tBu); 13C NMR (100 MHz, CDCl3) 132.3, 129.0, 128.6, 125.0, 116.0, 81.1, 70.1, 43.9, 27.8; HRMS
170.9, 137.6, 135.0, 134.6, 134.2, 128.7, 128.6, 126.1, 115.5, (ESI): calcd for C16H23ClNO2 [M + H]+ 296.1412, found 292.1408.

81.1, 71.1, 43.3, 27.9, 21.1; HRMS (ESI): calcd for C17H26NO2 [M tert‐Butyl 2‐(dimethylamino)‐2‐(2‐vinylphenyl)propanoate (8h)
+ H]+ 276.1958, found 276.1950.
tert‐Butyl 2‐(dimethylamino)‐2‐(5‐methoxy‐2‐vinylphenyl)acetate
(8e)
Colourless oil; IR (film) 
max/cm‐1 3084, 3061, 2978, 2932, 2870,
2833, 2791, 1720, 1622, 1598, 1567, 1475, 1455, 1410, 1391,
1367, 1242, 1163, 1104, 1052, 1023, 977, 908, 844, 808, 757; 1H
Colourless oil; IR (film)   7.53‐7.46 (1H, m, ArH), 7.48 (1H, dd, J
max/cm‐1 3083, 2977, 2867, 2833, 2773, NMR (400 MHz, CDCl3)
1738, 1606, 1569, 1494, 1463, 1392, 1367, 1287, 1245, 1217, = 17.4, 10.9 Hz, CH=CH2), 7.43‐7.36 (1H, m, ArH), 7.25‐7.17 (2H,
1144, 1099, 1045, 991, 963, 901, 870, 828, 789, 754, 734, 696; m, ArH), 5.53 (1H, dd, J = 17.4, 1.6 Hz, CH=CH2), 5.17 (1H, dd, J
1H NMR (400 MHz, CDCl3)

7.42 (1H, d, J = 8.6 Hz, ArH), 7.15 = 10.9, 1.6 Hz, CH=CH2), 2.34 (6H, s, N(CH3)2), 1.57 (3H, s, 2‐CH3),
(1H, dd, J = 17.3, 10.9 Hz, CH=CH2), 7.13 (1H, d, J = 2.8 Hz, ArH), 1.48 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)

171.1, 140.6,
6.82 (1H, ddd, J = 8.6, 2.8, 0.4 Hz, ArH), 5.53 (1H, dd, J = 17.3, 137.4, 137.2, 127.4, 127.2, 127.0, 126.9, 114.3, 81.3, 70.8, 39.9,
1.6 Hz, CH=CH2), 5.23 (1H, dd, J = 10.9, 1.6 Hz, CH=CH2), 4.09 (1H, 28.3, 23.3; HRMS (ESI): calcd for C17H26NO2 [M + H]+ 276.1958,
s, NCHCO), 3.81 (3H, s, OCH3), 2.26 (6H, s, N(CH3)2), 1.38 (9H, s, found 276.1954.
tBu); 13C NMR (100 MHz, CDCl3)
 170.7, 159.3, 135.7, 134.1,
130.5, 127.4, 114.62, 114.58, 112.3, 81.2, 71.1, 55.3, 43.3, 27.9;
HRMS (ESI): calcd for C17H26NO3 [M + H]+ 292.1907, found
Conflicts of interest
292.1899.
There are no conflicts to declare.
tert‐Butyl 2‐(3‐chloro‐2‐vinylphenyl)‐2‐(dimethylamino)acetate
(8f)
Colourless oil; IR (film) 
max/cm‐1 3086, 3058, 2978, 2867, 2821,
Notes and references
2774, 1740, 1633, 1589, 1562, 1443, 1392, 1367, 1300, 1272,
1
Initial reports on S–H rearrangement: (a) W. R. Brasen and C.
R. Hauser, Org. Synth., 1954, 34, 61; (b) S. W. Kantor and C. R.
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J. Name., 2013, 00, 1‐3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
Journal Name
Hauser, J. Am. Chem. Soc., 1951, 73, 4122; (c) M. Sommelet, 11 For a review on 2‐arylazetidine derivatives: D. VAienwtAerrtimcleitOen,linLe.
C. R. Hebd. Seances Acad. Sci. 1937, 205, 56. Degennaro and R. Luisi, Org. Biomol. CDheOmI: 1.,02.1001397/,C185O,B3041.091A
Representative reviews on ylide rearrangements including S– 12 Studies on ‐(vinylphenyl)amino acid derivatives: (a) S.
2

H rearrangement: (a) E. Tayama, Heterocycles, 2016, 92, 793;
(b) R. Bach, S. Harthong and J. Lacour, in Comprehensive
Organic Synthesis, II, ed. P. Knochel and G. A. Molander,
Sheffer‐Dee‐Noor and D. Ben‐Ishai, Tetrahedron, 1994, 50,
7009; (b) L. R. Morris, R. A. Mock, C. A. Marshall and J. H. Howe,
J. Am. Chem. Soc., 1959, 81, 377.
Elsevier, 2014, ch. 3.20, vol.3; (c) G. Lahm, J. C. O. Pacheco and 13 The stereochemistry of (1S,2S,1’R)‐3a
–
b
and (1R,2R,1’R)‐3b
T. Opatz, Synthesis, 2014, 46, 2413; (d) J. Clayden, M. Donnard,
J. Lefranc and D. J. Tetlow, Chem. Commun., 2011, 47, 4624;
(e) J. B. Sweeney, Chem. Soc. Rev., 2009, 38, 1027.
For a review on base‐induced S–H rearrangement: E. Tayama, 14 Substrates (1S,2S,1’R)‐3a
Chem. Rec., 2015, 15, 789.
were determined by analogy with (1S,2S,1’S)‐1 and analogous
ammonium salt derivatives. See ref. 4a, 4b and other
references therein.
3
4
–
b
and (1R,2R,1’R)‐3b were
prepared by N‐quaternization of precursor tertiary amines.
The ee of the tertiary amines; (1S,2S,1’R)‐3a: 97% ee,
(1S,2S,1’R)‐3b: 98% ee and (1R,2R,1’R)‐3b: 99% ee. Details:
see ESI.
Recent examples of base‐induced S–H rearrangement: (a) E.
Tayama, K. Watanabe and S. Sotome, Org. Biomol. Chem.,
2017, 15, 6668; (b) E. Tayama, K. Watanabe and Y. Matano,
Eur. J. Org. Chem., 2016, 3631; (c) A. C. Colgan, H. Müller‐Bunz 15 The stereochemistry of (R)‐4a was determined by analogy
and E. M. McGarrigle, J. Org. Chem., 2016, 81, 11394; (d) G. with (R)‐ and (R)‐
2
5.
Casoni, E. L. Myers and V. K. Aggarwal, Synthesis, 2016, 48
,
16 The stereochemistry of (R)‐5 was determined by the specific
3241; (e) E. Tayama, R. Sato, M. Ito, H. Iwamoto and E.
rotation value after conversion into (R)‐2 by hydrogenation.
Details: see ESI.
K. Takedachi, H. Iwamoto and E. Hasegawa, Tetrahedron, 17 According to our previous study, the initial [2,3]
Hasegawa, Heterocycles, 2013, 87, 381; (f) E. Tayama, R. Sato,
2012, 68, 4710; (g) E. Tayama, K. Takedachi, H. Iwamoto and
E. Hasegawa, Tetrahedron, 2010, 66, 9389; (h) E. Tayama, K.
rearrangement of (1R,2R,1’R)‐3b would proceed via eclipsed‐
like conformation which decreases the yield and the rate of
chirality transmission. The details: see ref. 4a.
Orihara and H. Kimura, Org. Biomol. Chem., 2008,
6, 3673; (i)
E. Tayama and H. Kimura, Angew. Chem. Int. Ed., 2007, 46
,
18 Substrates (R)‐6a was prepared by N‐quaternization of (R)‐2‐
(dimethylamino)‐2‐phenylethyl acetate with tert‐butyl
8869; (j) S. Hanessian, C. Talbot and P. Saravanan, Synthesis,
2006, 723.
bromoacetate.
The ee of (R)‐2‐(dimethylamino)‐2‐
5
6
A recent example of fluoride ion‐induced S–H rearrangement:
phenylethyl acetate was >99% ee. Details: see ESI.
T. Mita, M. Sugawara and Y. Sato, J. Org. Chem., 2016, 81
,
19 The stereochemistry of (R)‐7a was determined by analogy
5236.
with (R)‐8a.
Examples of transition metal‐catalyzed S–H rearrangement: 20 The stereochemistry of (R)‐8a was determined by comparison
(a) X. Xu, C. Li, M. Xiong, Z. Tao and Y. Pan, Chem. Commun.,
2017, 53, 6219; (b) Y. Li, Y. Shi, Z. Huang, X. Wu, P. Xu, J. Wang
and Y. Zhang, Org. Lett., 2011, 13, 1210; (c) M. Liao, L. Peng
and J. Wang, Org. Lett., 2008, 10, 693.
of the specific rotation value with the S‐authentic sample
after
conversion
into
(R)‐2‐(dimethylamino)‐2‐(2‐
ethylphenyl)ethanol. Details: see ESI.
21 We do not present their spectroscopic characterization in this
manuscript because of small amounts.
7
8
Mechanistic studies on S–H rearrangement: B. Biswas and D.
A. Singleton, J. Am. Chem. Soc., 2015, 137, 14244.
Identification
of
dearomative
[2,3]
sigmatropic
rearrangement products from ammonium ylides: (a) K. Narita,
N. Shirai and Y. Sato, J. Org. Chem., 1997, 62, 2544; (b) Y. Sato,
N. Shirai, Y. Machida, E. Ito, T. Yasui, Y. Kurono and K. Hatano,
J. Org. Chem., 1992, 57, 6711; (c) T. Kitano, N. Shirai, M. Motoi
and Y. Sato, J. Chem. Soc. Perkin Trans. 1, 1992, 2851; (d) T.
Kitano, N. Shirai and Y. Sato, Chem. Pharm. Bull., 1992, 40
,
768; (e) T. Kitano, N. Shirai and Y. Sato, Synthesis, 1991, 996;
(f) F. Sumiya, N. Shirai and Y. Sato, Chem. Pharm. Bull., 1991,
39, 36; (g) N. Shirai, F. Sumiya, Y. Sato and M. Hori, J. Org.
Chem., 1989, 54, 836; (h) N. Shirai, F. Sumiya, Y. Sato and M.
Hori, J. Chem. Soc., Chem. Commun., 1988, 370; (i) C. R.
Hauser and D. N. V. Eenam, J. Org. Chem., 1958, 23, 865; (j) C.
R. Hauser and D. N. V. Eenam, J. Am. Chem. Soc., 1957, 79
5512.
,
9
Isolation of dearomative [2,3] sigmatropic rearrangement
product from sulfonium ylides: (a) C. C. McComas and D. L. V.
Vranken, Tetrahedron Lett., 2003, 44, 8203; (b) R. Berger, J. W.
Ziller and D. L. V. Vranken, J. Am. Chem. Soc., 1998, 120, 841;
(c) M. Hori, T. Kataoka, H. Shimizu, M. Kataoka, A. Tomoto and
M. Kishida, Tetrahedron Lett., 1983, 24, 3733; (d) Y. Hayashi
and R. Oda, Tetrahedron Lett., 1968, 9, 5381.
10 Examples of [2,3] sigmatropic rearrangement involving an
aromatic C=C double bond: (a) T. Hameury, J. Guillemont, L. V.
Hijfte, V. Bellosta and J. Cossy, Synlett, 2008, 2345; (b) J.
Clayden and M. N. Kenworthy, Org. Lett., 2002,
4
, 787; (c) A.
Garbi, L. Allain, F. Chorki, M. Ourévitch, B. Crousse, D. Bonnet‐
Delpon, T. Nakai and J.‐P. Bégue, Org. Lett., 2001,
3, 2529; (d)
K. Tomooka, M. Harada, T. Hanji and T. Nakai, Chem. Lett.,
2000, 1394.
6 | J. Name., 2012, 00, 1‐3
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