Structural and mechanistic studies of the base-induced Sommelet-Hauser rearrangement of: N -α-branched benzylic azetidine-2-carboxylic acid-derived ammonium salts

Article abstract of DOI:10.1039/c7ob01391d

The base-induced Sommelet-Hauser rearrangement of N-α-branched benzylic azetidine-2-carboxylic acid ester-derived ammonium salts to obtain α-arylazetidine-2-carboxylic acid esters was investigated. The substrates, two diastereomeric salts (1S,2S,1′S)- and (1R,2R,1′S)-2, showed different reactivities. The rearrangement of (1S,2S,1′S)-2a proceeded with a perfect N-to-C chirality transfer to provide (R)-3a in 74% yield with 99% ee. However, the rearrangement of (1R,2R,1′S)-2a under the same conditions afforded (S)-3a in only 15% yield with a lower 66% ee, along with the competitive [1,2] Stevens rearrangement product 4a. Structural and mechanistic studies of this rearrangement were carried out to clarify the exact reason. Our results define the scope and limitations of the Sommelet-Hauser rearrangement and provide unique synthetic access to α-aryl amino acid derivatives.

Full text of DOI:10.1039/c7ob01391d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Structural and mechanistic studies of the base-induced
Sommelet–Hauser rearrangement of N-α-branched benzylic
azetidine-2-carboxylic acid-derived ammonium salts
Received 00th January 20xx,
Accepted 00th January 20xx
Eiji Tayama,a Kazutoshi Watanabeb and Sho Sotomeb
DOI: 10.1039/x0xx00000x
The base-induced Sommelet–Hauser rearrangement of N-α-branched benzylic azetidine-2-carboxylic acid ester-derived
ammonium salts to obtain α-arylazetidine-2-carboxylic acid esters was investigated. The substrates, two diastereomeric
salts (1S,2S,1’S)- and (1R,2R,1’S)-2, showed different reactivities. The rearrangement of (1S,2S,1’S)-2a proceeded with a
perfect N-to-C chirality transfer to provide (R)-3a in 74% yield with 99% ee. However, the rerrangement of (1R,2R,1’S)-2a
under the same conditions afforded (S)-3a in only 15% yield with a lower 66% ee, along with the competitive [1,2] Stevens
rearrangement product 4a. Structural and mechanistic studies of this rearrangement were carried out to clarify the exact
reason. Our results expand the scope and limitations of the Sommelet–Hauser rearrangement and provide unique
www.rsc.org/
synthetic
access
to
α-aryl
amino
acid
derivatives.
Scheme 1 Difference in reactivity between (1S,2S,1’S)- and (1R,2R,1’S)-2a in
base-induced S–H rearrangement
Introduction
Azetidine-2-carboxylic acid derivatives are interesting
compounds because of their unique and valuable characters.
The ring-strained four-membered nitrogen-containing
heterocycle is reactive for nucleophilic ring-opening reactions
while still being sufficiently stable to serve as a building block
for synthetic transformations leading to nitrogen-containing
compounds.1 Thus, the development of an efficient synthetic
method for functionalized azetidine-2-carboxylic acid
derivatives has been studied.
Previous work
CO Bu
2t
CO2tBu
OTf
CO2tBu
BuOK
THF
t
N
N
N
(1)
0 °C, 3 h
A
(1S,2S,1'S)-2a
(R)-3a
ring-strained stabilized
carbanionic ylide
74%, 99% ee
Unreported result
Recently, we reported the base-induced Sommelet–Hauser
(S–H) rearrangement2-6 of N-benzylic azetidine-2-carboxylic
CO2tBu
CO Bu
2t
CO2tBu
OTf
acid ester-derived ammonium salts to produce
arylazetidine-2-carboxylic acid esters without a competitive
[1,2] Stevens rearrangement.7,8
For example, the S–H
α-
tBuOK
solvent
N
N
N
(2)
+
0 °C, 3 h
rearrangement of (1S,2S,1’S)-2a9 proceeded with a perfect N-
to-C chirality transfer10 to provide (R)-3a in 74% yield with 99%
ee (Scheme 1, eqn (1)). The ring-strain of the four-membered
(1R,2R,1'S)-2a
(S)-3a
4a
THF:
15%, 66% ee
27%, 89% ee
DMPU: 40%, 85% ee
17%, 95% ee
(single diastereomer)
N-heterocycle, as in (1S,2S,1’S)-2a, enables the efficient
generation of the desired carbanionic ylide intermediate A 11,12
.
Because the undesired ammonium enolate form is unstabilized
by the formation of a ring-strained sp2 α-carbon. Thereby, the
rate of the carbanionic [2,3] sigmatropic rearrangement
leading to (R)-3a is enhanced.
On the other hand, when the reaction of the other
diastereomer (1R,2R,1’S)-2a was carried out under the same
conditions, the corresponding (S)-3a was obtained in only 15%
yield with a lower 66% ee, along with one diastereomer of the
competitive [1,2] Stevens rearrangement product 4a13 in 27%
yield with 89% ee (eqn (2)). Even when the reaction was
carried out at a lower temperature (–40 °C, 3 h), the ratio of
3a/4a (S–H vs. [1,2]) was not improved (3a: 2% yield, 4a: 13%
yield). The use of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) as the solvent improved the yield and ee
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of (S)-3a to 40% and 85%, respectively, but the formation of group in the S–H rearrangement was observed, similar to our
the undesired 4a could not be inhibited.
The rate- previous results.5e,5g
enhancement effect of the S–H rearrangement by the ring-
strain proposed in our previous work (eqn (1)) was not
observed upon changing the diastereomeric salt (1S,2S,1’S)-2a
Table 1 Base-induced S–H rearrangement of (1S*,2S*,1’S*)- and (1R*,2R*,1’S*)-2
into (1R,2R,1’S)-2a
induced S–H rearrangement of N-
azetidine-2-carboxylic acid ester-derived ammonium salts
.
We started to investigate the base-
-branched benzylic
to
α
2
clarify the exact reason and define the scope and limitations.
Results and discussion
We prepared the racemic N-
triflates (1S*,2S*,1’S*)- and (1R*,2R*,1’S*)-2a
by the N-quaternization of the precursor amines 1a
methyl triflate (Scheme 2).15 The salts
were obtained in
diastereomerically pure form because the adjacent 2- and N-
substituents, as in , are in an equatorial position to avoid
α
-methylbenzylic ammonium
as substrates
d14 with
–
d
–
2
entry
diastereomer
(1S*,2S*,1’S*)
(1S*,2S*,1’S*)
(1S*,2S*,1’S*)
(1S*,2S*,1’S*)
(1R*,2R*,1’S*)
(1R*,2R*,1’S*)
(1R*,2R*,1’S*)
(1R*,2R*,1’S*)
R
H
3 (%)a
80
4b (%)a
0
1
2
3c
a
b
c
1
Br
83
0
steric repulsion and the axial lone pair of the nitrogen atom
reacts with methyl triflate.16
CO2tBu
OMe
H
81
0
4
d
a
b
c
61
12d
23e
13e
11e
37h
5
24
Scheme 2 Diastereoselective N-quaternization of (2S*,1’S*)- and (2R*,1’S*)-
1
6
7f
Br
63
CO2tBu
OMe
57
5g
MeOTf
MeOTf
NaHCO3
CH2Cl2
CO2tBu
CO2tBu
8
d
tBuO2C
N
N
a
b
OTf
Ar
N
Ar
Isolated yield unless otherwise noted. The stereochemistry of compounds 4
c
was not determined.
The Hoffmann eliminated product, tert-butyl 4-
Ar
(2S*,1'S*)-1a–d
0 °C to rt
vinylbenzoate (6) was formed in 3% yield, determined by 1H NMR analysis of the
crude product using mesitylene as an internal standard. d Two diastereomers 4d1
H
(1S*,2S*,1'S*)-2a–d
83–96%
e
f
and 4d2 (8/2 dr) were obtained.
Hoffmann eliminated product 6 was isolated in 20% yield. g Determined by 1H
One diastereomer was isolated.
The
a: Ar = Ph, b: Ar = p-Br-C6H4
single diastereomer
c: Ar = tBuOCO-C6H4, d: Ar = p-MeO-C6H4
h
NMR analysis of the crude product using mesitylene as an internal standard.
H
Two diastereomers 4d1 and 4d2 (3/7 dr) were obtained.
MeOTf
CO2tBu
CO2tBu
NaHCO3
N
N
N
Ar
OTf
Next, we examined the reactions of other diastereomers,
tBuO2C
CH2Cl2
Ar
(1R*,2R*,1’S*)-2a–d (Entries 5–8), which would be disfavoured
Ar
(2R*,1'S*)-1a–d
0 °C to rt
MeOTf
for the S–H rearrangement depicted in Scheme 1. A reaction
of (1R*,2R*,1’S*)-2a produced a similar result to the chiral
substrate to give 3a in only 24% yield along with one
diastereomer of 4a in 23% yield (entry 5). When the migrating
group was substituted by a para-bromo or tert-butoxycarbonyl,
(1R*,2R*,1'S*)-2a–d
89–97%
single diastereomer
the yields of
3 were improved to moderate levels (entries 6–7,
First, the reactions of (1S*,2S*,1’S*)-2a
–
d
that would be the
3b: 63% yield, 3c: 57% yield) by the rate-enhancement effect
of the S–H rearrangement by an electron-withdrawing group
(EWG) on the N-benzylic migrating group.5e,5g As the side
preferred diastereomers for the S–H rearrangement depicted
in Scheme 1 were investigated (Table 1, entries 1–4).
reaction of N- -methylbenzyl derivative (1S*,2S*,1’S*)-2a gave
A
α
product, one diastereomer of undesired
13% yield, 4c: 11% yield). Additionally, a Hoffmann elimination
giving and (Scheme 3) was observed in the reaction of
(1R*,2R*,1’S*)-2c (entry 7), and the styryl derivative was
4 was obtained (4b:
almost the same result as the chiral substrate (entry 1). The
desired S–H product 3a was obtained in 80% yield with no
detectable amount of the [1,2] Stevens product 4a. Similarly,
the reactions of the para-bromo and tert-butoxycarbonyl
derivatives, (1S*,2S*,1’S*)-1b and 1c, afforded only 3b and 3c
in approximately 80% yields (entries 2–3), respectively. When
the migrating group was substituted by an electron-donating
group (EDG) such as para-methoxy (entry 4), the yield of 3d
was decreased to 61% with the formation of two
diastereomers 4d1 and 4d2 in a 12% combined yield (8/2 dr,
5
6
6
isolated in 20% yield. Upon the use of the para-methoxy
derivative (1R*,2R*,1’S*)-2d as the substrate, the yield of 3d
was minimized to 5% (entry 8). An undesired [1,2] Stevens
rearrangement proceeded and mainly provided the two
diastereomers 4d1 and 4d2 in a 37% combined yield (3/7 dr).
We applied this S–H rearrangement to the synthesis of an α-
benzo-fused ring substituted azetidine-2-carboxylic ester 3e
separable by silica gel column chromatography, Rf: 4d1
> 4d2).
(Scheme 4), and the results clarified the difference of reactivity
A deactivation effect of an EDG on the N-benzylic migrating
between the (1S,2S,1’S)- and (1R,2R,1’S)-2 diastereomers. The
stereoselective N-quaternization of N-(indan-1-yl)amine
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(2S*,1’S*)-1e followed by the rearrangement of the resulting
salt (1S*,2S*,1’S*)-2e provided the target 3e in 45% yield. The
TLC analysis of the crude product showed some side products
that might cause a lower yield of 3e, but the undesired [1,2]
Stevens product was not obtained. This reaction would
Scheme 5 Base-induced S–H rearrangement of (1R*,2R*,1’S*)-1e via eclipsed-
like conformer E.
proceed via the formation of the ylide
B, the conformer C,
[2,3] sigmatropic rearrangement and aromatization. In the
[2,3] rearrangement step, the steric repulsion between the
indane and azetidine moieties may inhibit the C2–C3 bond
formation and decrease the yield of 3e
.
Scheme 3 Hoffman elimination to 5 and 6 from (1R*,2R*,1’S*)-2c
These results in hand, we proposed a reason for the lower
yield in the S–H rearrangement of (1R,2R,1’S)-2a into (S)-3a
involving the lack of ee (Scheme 1, eqn (2)). First, the ylide
generated from (1S,2S,1’S)-2a
diastereomer for the S–H rearrangement, enables the
formation of the two conformers and (Scheme 6). is
similar to that of described in Scheme 4. is in an eclipsed-
,
which is the desired
Scheme 4 Base-induced S–H rearrangement of (1S*,2S*,1’S*)-2e via conformer
C
F
G
F
C
G
like conformation, but the repulsions arising from the
hydrogen-methyl and methyl-azetidinyl methylene eclipsing
would be small. The [2,3] rearrangement from both
F and G
provides a dearomatized intermediate H followed by a 1,3-
prototropic shift in the presence of tBuOK and tBuOH to give
aromatized (R)-3a in 74% with 99% ee (THF).
Scheme 6 Proposed mechanism for the S–H rearrangement of (1S,1S,1’S)-2a
Me
H
H
Me
Me
CO2tBu
OTf
Me
tBuOK
N
CO2tBu
2
3
2
THF
3
0 °C, 3 h
(1S,2S,1'S)-2a
F
G
[2,3]
CO2tBu
CO2tBu
On the other hand, the N-quaternization of (2R*,1’S*)-1e
gave a 9/1 mixture of (1R*,2R*,1’S*)-2e17 and (1S*,2R*,1’S*)-
2e that was not separable by silica gel column chromatography
(Scheme 5). The rearrangement of the 9/1 mixture failed
completely and gave a complicated mixture (dark purple). The
N
N
aromatization
(1,3-prototropic shift)
H
(R)-3a
H
74%, 99% ee
possible conformer
corresponding ylide
E
, derived from (1R*,2R*,1’S*)-2e and the
D
, would be quite unfavourable for the
[2,3] rearrangement because of the methylene-methyl
eclipsed-like conformation. Although the exact reason for the
formation of side products from 2e is unclear at present, the
Hoffman elimination from 2e might proceed to give indene,
which provides various side products under basic conditions.
The other diastereomer (1R,2R,1’S)-2a forms two
conformers and (Scheme 7). The [2,3] rearrangement from
proceeds with a high degree of N-to-C chirality transfer to
provide (S)-3a with higher ee. is similar to that of described
I
J
I
J
E
in Scheme 5. The methyl-methyl eclipsed-like conformation
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inhibits the [2,3] rearrangement, and a radical cleavage of the [1,2] (13) rearrangement products were obtained without
N–C bond might occur to generate a radical pair intermediate selectivity (12: 21% yield, 13: 28% yield). In this case, a lower
K
.
The intermediate
rearrangement product 4a with an N-to-C chirality transfer by and the desired 12 was obtained in 75% yield. The S–H
recombination.10,13 The radical, as in the intermediate
, is rearrangement from the N- -dimethylbenzyl salt (1R*,2S*)-
delocalized by the phenyl ring to form other radical pair 1419 into 15 did not proceed. The [1,2] rearrangeed 16 was
intermediates such as L 18
The radical recombination of obtained as the only identifiable product.
K provides the [1,2] Stevens reaction temperature (–40 °C) improved the ratio of 12/13,
K
α,α
.
L
followed by aromatization would afford (S)-3a with a lower
degree of N-to-C chirality transfer. The use of DMPU as the
solvent would improve the reactivity of the carbanionic ylide,
Scheme 8 Formation of α-(3,4,5-trimethylphenyl) derivative 10 via ylide
formation, radical cleavage, delocalization and recombination.
and the rate of the [2,3] rearrangement from I is enhanced to
afford (S)-3a in better yield and ee (40% yield, 85% ee).
Scheme 7 Proposed mechanism for the S–H rearrangement of (1R,1R,1’S)-2a
Scheme 9 Base-induced rearrangement of N-α-branched benzylic ammonium
salts (1S*,2S*)-11 and (1R*,2S*)-14
.
CO2tBu
CO2tBu
CO2tBu
N
N
N
tBuOK
+
THF
To support our proposed mechanism described in Scheme 7,
we prepared the 2,6-dimethylbenzyl ammonium salt (1S*,2S*)-
719 and carried out the rearrangement (Scheme 8). The
isolated products were the [1,2] Stevens rearrangement
temp, 3 h
OTf
(1S*,2S*)-11
12: S–H
13: [1,2]
28%
7%a
single diastereomer
0 °C:
21%
75%
product
derivative 10 (17% yield). The ylide
(1S*,2S*)- did not give the [2,3] rearrangement product
to the steric repulsion arising from the two ortho-methyl
substituents.20 The radical cleavage of
generated the
radical pair intermediates and , followed by recombination
that would provide and 10, respectively. This result proved
our proposed reaction pathway from the intermediate into
(S)-3a
Finally, we examined the base-induced S–H rearrangement
of other types of N- -branched benzylic ammonium salts to
9
(56% yield) and the
α
-(3,4,5-trimethylphenyl)
generated from
due
–40 °C:
M
7
8
CO2tBu
CO2tBu
CO2tBu
OTf
tBuOK
THF
N
N
+
M
N
N
O
temp, 3 h
9
(1R*,2S*)-14
15: S–H
0%
16: [1,2]
74%
42%a
L
single diastereomer
0 °C:
.
–40 °C:
0%
a Determined by 1H NMR analysis of the crude product using mesitylene as an internal
standard.
α
define the substrate scope and limitations (Scheme 9). When
a rearrangement of N-diphenylmethyl derivative (1S*,2S*)-
1119 was carried out at 0 °C, the corresponding S–H (12) and
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to 1/3 volume and purified by chromatography on silica gel
Conclusions
(CH2Cl2/MeOH = 15/1 to 7/1 as the eluent) to obtain
22
In conclusion, we demonstrated the base-induced Sommelet–
(1S,2S,1´S)-2a (635 mg, 87% yield) as a colourless gum. [
max/cm-1 3059, 2983, 1736,
α]
589
Hauser (S–H) rearrangement of two diastereomeric salts of N-
–26.2 (c 1.0 in EtOH); IR (KBr)
ν
α
-branched benzylic azetidine-2-carboxylic acid ester-derived
ammonium salts The two diastereomeric salts showed
different reactivities. One diastereomer provided the desired
S–H rearrangement product, -arylazetidine-2-carboxylic acid
esters , in good yield with excellent ee, but the other did not.
1630, 1499, 1459, 1421, 1397, 1372, 1274, 1258, 1225, 1156,
1031, 993, 971, 934, 881, 839, 773, 756, 708; 1H NMR (400
2
.
2
MHz, CDCl3)
δ 7.60-7.53 (2H, m, Ph), 7.50-7.42 (3H, m, Ph),
α
5.59 (1H, dd, J = 9.8, 9.8 Hz, 2-H), 5.28 (1H, q, J = 7.0 Hz, 1´-H),
4.90 (1H, ddd, J = 10.0, 10.0, 9.7 Hz, 4-H), 3.29 (1H, ddd, J =
9.7, 9.7, 3.4 Hz, 4-H), 3.01 (3H, s, NCH3), 2.96-2.75 (2H, m, 3-H),
1.75 (3H, d, J = 7.0 Hz, 1´-CH3), 1.54 (9H, s, tBu); 13C NMR (100
3
Our experimental studies on this rearrangement clarified the
reason for the difference and the reaction mechanisms.
The S–H rearrangement still has structural limitations in that
it requires the product to have an o-substituted aryl
component. Our studies would expand the scope and
limitations of this rearrangement and provide unique synthetic
MHz, CDCl3)
δ 163.8, 131.0, 130.8, 130.0, 129.4, 120.7 (q, J =
318 Hz), 86.0, 72.9, 71.3, 61.4, 39.6, 27.8, 17.9, 14.0; HRMS
(ESI): calcd. for C17H26NO2 [M–OTf]+ 276.1958, found 276.1948.
(1R,2R,1´S)-2-(tert-Butoxycarbonyl)-1-methyl-1-(1´-
phenylethyl)azetidin-1-ium trifluoromethanesulfonate
[(1R,2R,1´S)-2a]
access to α-aryl amino acid derivatives. Further studies are in
progress in our group to demonstrate the synthetic utility of
the S–H rearrangement.
Prepared in 91% yield from (2R,1´S)-tert-butyl 1-(1´-
phenylethyl)azetidine-2-carboxylate [(2R,1´S)-1a]; colourless
max/cm-1 3053,
22
gum; [α
2983, 2935, 1732, 1497, 1459, 1423, 1397, 1371, 1351, 1259,
]
+23.9 (c 1.0 in EtOH); IR (film) ν
Experimental
589
General
1
1224, 1155, 1101, 1030, 987, 935, 881, 836, 775, 756, 708; H
Infrared spectra (IR) were recorded on
a Perkin Elmer
NMR (400 MHz, CDCl3)
δ 7.61-7.55 (2H, m, Ph), 7.51-7.42 (3H,
Spectrum GX FT-IR. 1H and 13C NMR spectra were measured
on a Varian or a Bruker 400 MHz spectrometers (1H: 400 MHz,
13C: 100 MHz). 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 or PU-2089, and a UV/VIS detector UV-
2075. Reversed phase HPLC analyses were performed using a
Shimazu HPLC pump LC-20AT and a UV/VIS detector SPD-20A.
Reactions involving air- or moisture-sensitive compounds were
m, Ph), 5.58 (1H, dd, J = 9.6, 9.6 Hz, 2-H), 5.25 (1H, q, J = 7.0
Hz, 1´-H), 4.83 (1H, ddd, J = 9.6, 9.6, 9.6 Hz, 4-H), 4.04 (1H, ddd,
J = 9.6, 9.6, 3.8 Hz, 4-H), 3.15 (3H, s, NCH3), 2.98-2.75 (2H, m,
3-H), 1.68 (3H, d, J = 7.0 Hz, 1´-CH3), 1.18 (9H, s, tBu); 13C NMR
(100 MHz, CDCl3)
δ 163.1, 131.5, 130.7, 130.1, 129.4, 120.7 (q,
J = 318 Hz), 84.9, 72.9, 69.9, 62.6, 39.3, 27.4, 18.1, 13.5; HRMS
(ESI): calcd. for C17H26NO2 [M–OTf]+ 276.1958, found 276.1949.
(1S*,2S*,1´S*)-2-(tert-Butoxycarbonyl)-1-methyl-1-(1´-
phenylethyl)azetidin-1-ium trifluoromethanesulfonate
[(1S*,2S*,1´S*)-2a]
Prepared in 83% yield from (2S*,1´S*)-1a; white solid; mp 146–
147 °C; IR (KBr) ν
max/cm-1 3053, 2991, 1742, 1500, 1462, 1423,
1390, 1371, 1261, 1225, 1155, 1104, 1071, 1058, 1031, 1015,
conducted in appropriate round-bottomed flasks with
a
magnetic stirring bars under an argon atmosphere.
Tetrahydrofuran (THF) was purchased from KANTO Chemical
Co., Inc., Japan as an anhydrous solvent. 1,3-Dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU) was purchased from
Wako Pure Chemical Industries, Ltd., Japan and dried over
molecular sieves 4Å. A 1.0 M potassium tert-butoxide (tBuOK)
solution in THF were purchased from Tokyo Chemical Industry
(TCI) Co., Ltd., Japan. For thin layer chromatography (TLC)
analysis throughout this work, Merck TLC plates (silica gel 60
F254) was used. The products were purified by preparative
column chromatography on silica gel (silica gel 60N, spherical
neutral, KANTO Chemical Co., Inc., Japan).
992, 968, 932, 871, 840, 776, 757, 709.
(1R*,2R*,1´S*)-2-(tert-Butoxycarbonyl)-1-methyl-1-(1´-
phenylethyl)azetidin-1-ium trifluoromethanesulfonate
[(1R*,2R*,1´S*)-2a]
Prepared in 96% yield from (2R*,1´S*)-1a; colourless gum.
(1S*,2S*,1´S*)-1-(1´-(4´´-Bromophenyl)ethyl)-2-(tert-
butoxycarbonyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate [(1S*,2S*,1´S*)-2b]
Prepared in 95% yield from (2S*,1´S*)-1b; colourless gum; IR
(KBr)
1373, 1259, 1224, 1154, 1079, 1030, 1010, 934, 879, 833, 784,
ν
max/cm-1 2984, 1738, 1593, 1491, 1466, 1421, 1398,
1
756, 732; H NMR (400 MHz, CDCl3)
Representative procedure for preparation of (1S,2S,1´S)-2-(tert-
butoxycarbonyl)-1-methyl-1-(1´-phenylethyl)azetidin-1-ium
trifluoromethanesulfonate [(1S,2S,1´S)-2a]
δ 7.60 (2H, d, J = 8.4 Hz,
ArH), 7.49 (2H, d, J = 8.4 Hz, ArH), 5.58 (1H, dd, J = 9.8, 9.8 Hz,
2-H), 5.30 (1H, q, J = 7.0 Hz, 1´-H), 4.89 (1H, ddd, J = 9.6, 9.6,
9.6 Hz, 4-H), 3.30 (1H, ddd, J = 9.6, 9.6, 2.6 Hz, 4-H), 3.01 (3H, s,
NCH3), 2.97-2.75 (2H, m, 3-H), 1.74 (3H, d, J = 7.0 Hz, 1´-CH3),
A mixture of (2S,1´S)-tert-butyl 1-(1´-phenylethyl)azetidine-2-
carboxylate [(2S,1´S)-1a] (447 mg, 1.71 mmol) and NaHCO3
(0.43 g, 5.1 mmol) in CH2Cl2 (8.6 mL) was treated with MeOTf
1.54 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ 163.6, 132.7,
131.7, 130.0, 125.5, 120.7 (q, J = 318 Hz), 86.2, 72.1, 71.6, 61.5,
(387 ꢀL, 3.42 mmol) at 0 °C and stirred for 1 h at room
temperature. The resulting mixture was evaporated to ca. 1/2
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ARTICLE
Journal Name
1
39.5, 27.8, 17.9, 14.0; HRMS (ESI): calcd. for C17H25BrNO2 [M– 1257, 1224, 1156, 1030, 871, 839; H NMR (400 MHz, CDCl3)
δ
7.50 (2H, d, J = 8.6 Hz, ArH), 6.95 (2H, d, J = 8.6 Hz, ArH), 5.50
OTf]+ 354.1063, found 354.1056.
(1R*,2R*,1´S*)-1-(1´-(4´´-Bromophenyl)ethyl)-2-(tert-
butoxycarbonyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate [(1R*,2R*,1´S*)-2b]
(1H, dd, J = 9.6, 9.2 Hz, 2-H), 5.18 (1H, q, J = 6.8 Hz, 1´-H), 4.78
(1H, ddd, J = 9.8, 9.6, 9.4 Hz, 4-H), 3.82 (3H, s, OCH3), 3.29 (1H,
dd, J = 9.8, 9.4 Hz, 4-H), 3.01 (3H, s, NCH3), 2.92 (1H, dddd, J =
9.8, 9.8, 9.8, 9.6 Hz, 3-H), 2.74 (1H, ddd, J = 9.8, 9.6, 9.2 Hz, 3-
H), 1.72 (3H, d, J = 6.8 Hz, 1´-CH3), 1.54 (9H, s, tBu); 13C NMR
Prepared in 89% yield from (2R*,1´S*)-1b; colourless gum; IR
(film)
1370, 1258, 1225, 1155, 1077, 1030, 1010, 990, 934, 880, 831,
ν
max/cm-1 2983, 1733, 1593, 1491, 1460, 1421, 1397,
(100 MHz, CDCl3) δ 163.5, 161.0, 131.2, 122.7, 120.5 (q, J = 319
1
786, 757, 728; H NMR (400 MHz, CDCl3)
Hz), 114.4, 85.7, 72.5, 70.9, 60.8, 55.1, 39.2, 27.5, 17.4, 13.9;
HRMS (ESI): calcd. for C18H28NO3 [M–OTf]+ 306.2064, found
306.2052.
δ 7.59 (2H, d, J = 8.4
Hz, ArH), 7.52 (2H, d, J = 8.4 Hz, ArH), 5.56 (1H, dd, J = 10.0, 9.4
Hz, 2-H), 5.24 (1H, q, J = 7.0 Hz, 1´-H), 4.76 (1H, ddd, J = 9.8,
9.8, 9.4 Hz, 4-H), 4.06 (1H, ddd, J = 9.8, 9.8, 3.2 Hz, 4-H), 3.13
(3H, s, NCH3), 2.91 (1H, dddd, J = 11.9, 10.0, 9.8, 9.8 Hz, 3-H),
2.79 (1H, dddd, J = 11.9, 9.4, 9.4, 3.2 Hz, 3-H), 1.66 (3H, d, J =
(1R*,2R*,1´S*)-2-(tert-Butoxycarbonyl)-1-(1´-(4´´-
methoxyphenyl)ethyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate [(1R*,2R*,1´S*)-2d]
7.0 Hz, 1´-CH3), 1.21 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ
162.9, 132.4, 131.7, 130.5, 125.3, 120.7 (q, J = 319 Hz), 85.2, (film)
Prepared in 97% yield from (2R*,1´S*)-1d; colourless gum; IR
ν
max/cm-1 2983, 2939, 2842, 1732, 1611, 1584, 1518,
72.1, 70.2, 62.8, 39.1, 27.4, 17.8, 13.3; HRMS (ESI): calcd. for 1462, 1396, 1370, 1257, 1225, 1156, 1064, 1031, 989, 921,
1
C17H25BrNO2 [M–OTf]+ 354.1063, found 354.1056.
(1S*,2S*,1´S*)-2-(tert-Butoxycarbonyl)-1-(1´-(4´´-(tert-
butoxycarbonyl)phenyl)ethyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate [(1S*,2S*,1´S*)-2c]
876, 839, 785, 755, 732; H NMR (400 MHz, CDCl3) δ 7.53 (2H,
d, J = 8.8 Hz, ArH), 6.95 (2H, d, J = 8.8 Hz, ArH), 5.53 (1H, dd, J =
9.8, 9.4 Hz, 2-H), 5.17 (1H, q, J = 6.8 Hz, 1´-H), 4.72 (1H, ddd, J =
10.0, 9.8, 9.4 Hz, 4-H), 4.05 (1H, ddd, J = 9.8, 9.8, 3.0 Hz, 4-H),
3.81 (3H, s, OCH3), 3.13 (3H, s, NCH3), 2.90 (1H, dddd, J = 11.9,
10.0, 9.8, 9.8 Hz, 3-H), 2.77 (1H, dddd, J = 11.9, 9.4, 9.4, 3.0 Hz,
3-H), 1.65 (3H, d, J = 6.8 Hz, 1´-CH3), 1.20 (9H, s, tBu); 13C NMR
Prepared in 94% yield from (2S*,1´S*)-1c; colourless
max/cm-1 2981, 2935, 1739, 1715, 1613,
amorphous; IR (KBr)
ν
1460, 1426, 1396, 1371, 1276, 1258, 1224, 1159, 1120, 1064,
1030, 994, 970, 933, 870, 840, 778, 756, 716; 1H NMR (400
(100 MHz, CDCl3) δ 162.9, 161.0, 131.2, 123.2, 120.6 (q, J = 319
Hz), 114.3, 84.6, 72.5, 69.6, 62.0, 55.1, 38.9, 27.2, 17.5, 13.3;
HRMS (ESI): calcd. for C18H28NO3 [M–OTf]+ 306.2064, found
306.2057.
MHz, CDCl3) δ 8.06 (2H, ddd, J = 8.6, 2.0, 2.0 Hz, ArH), 7.66 (2H,
ddd, J = 8.6, 2.0, 2.0 Hz, ArH), 5.66 (1H, dd, J = 9.6, 9.6 Hz, 2-H),
5.42 (1H, q, J = 7.2 Hz, 1´-H), 4.99 (1H, ddd, J = 10.3, 9.6, 9.6 Hz,
4-H), 3.27 (1H, ddd, J = 10.3, 6.9, 5.0 Hz, 4-H), 3.01 (3H, s,
NCH3), 2.94-2.81 (2H, m, 3-H), 1.78 (3H, d, J = 7.2 Hz, 1´-CH3),
(1S*,2S*,1´S*)-2-(tert-Butoxycarbonyl)-1-(2´,3´-dihydro-1´H-inden-
1´-yl)-1-methylazetidin-1-ium trifluoromethanesulfonate
[(1S*,2S*,1´S*)-2e]
1.59 (9H, s, tBu), 1.54 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ
164.5, 163.7, 135.0, 134.3, 130.3, 130.0, 120.7 (q, J = 318 Hz), Prepared in 94% yield from (2S*,1´S*)-1e; white solid; mp 126–
86.2, 81.8, 72.2, 71.6, 61.7, 39.7, 28.1, 27.8, 18.1, 14.0; HRMS 127 °C; IR (KBr)
max/cm-1 3054, 2989, 2947, 2862, 1742, 1462,
(ESI): calcd. for C22H34NO4 [M–OTf]+ 376.2482, found 376.2465. 1420, 1396, 1373, 1342, 1265, 1225, 1160, 1048, 1030, 1004,
ν
(1R*,2R*,1´S*)-2-(tert-Butoxycarbonyl)-1-(1´-(4´´-(tert-
butoxycarbonyl)phenyl)ethyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate [(1R*,2R*,1´S*)-2c]
975, 934, 910, 889, 860, 834, 805, 760, 713; 1H NMR (400 MHz,
CDCl3) 7.48 (1H, d, J = 7.5 Hz, ArH), 7.42 (1H, ddd, J = 7.5, 7.5,
δ
1.0 Hz, ArH), 7.35 (1H, d, J = 7.5 Hz, ArH), 7.29 (1H, ddd, J = 7.5,
7.5, 1.0 Hz, ArH), 5.68 (1H, d, J = 9.0 Hz, 1´-H), 5.65 (1H, dd, J =
9.6, 9.6 Hz, 2-H), 5.09 (1H, ddd, J = 9.6, 9.6, 9.6 Hz, 4-H), 3.85
(1H, ddd, J = 9.6, 9.6, 3.6 Hz, 4-H), 3.17-2.83 (4H, m, 3-H and
3´-H), 2.80-2.68 (1H, m, 2´-H), 2.74 (3H, s, NCH3), 2.50 (1H,
dddd, J = 15.8, 9.0, 9.0, 9.0 Hz, 2´-H), 1.52 (9H, s, tBu); 13C NMR
Prepared in 94% yield from (2R*,1´S*)-1c; colourless gum; IR
(KBr)
ν
max/cm-1 2982, 2937, 1731, 1716, 1614, 1578, 1459,
1426, 1396, 1371, 1257, 1225, 1160, 1122, 1080, 1065, 1031,
990, 934, 882, 866, 846, 778, 755, 715; 1H NMR (400 MHz,
CDCl3)
δ 8.05 (2H, d, J = 8.4 Hz, ArH), 7.67 (2H, d, J = 8.4 Hz,
(100 MHz, CDCl3)
δ 164.0, 146.2, 133.6, 131.2, 127.9, 125.92,
ArH), 5.61 (1H, dd, J = 9.6, 9.6 Hz, 2-H), 5.34 (1H, q, J = 6.8 Hz,
1´-H), 4.85 (1H, ddd, J = 10.0, 9.6, 9.6 Hz, 4-H), 4.07 (1H, ddd, J
= 9.6, 9.6, 3.6 Hz, 4-H), 3.16 (3H, s, NCH3), 2.99-2.76 (2H, m, 3-
H), 1.71 (3H, d, J = 6.8 Hz, 1´-CH3), 1.59 (9H, s, tBu), 1.18 (9H, s,
125.91, 120.7 (q, J = 319 Hz), 86.0, 79.4, 71.4, 62.7, 39.4, 30.9,
27.8, 25.8, 18.8; HRMS (ESI): calcd. for C18H26NO2 [M–OTf]+
288.1958, found 288.1952.
tBu); 13C NMR (100 MHz, CDCl3)
δ 164.6, 163.0, 135.5, 134.2,
(1R*,2R*,1´S*)-2-(tert-Butoxycarbonyl)-1-(2´,3´-dihydro-1´H-inden-
1´-yl)-1-methylazetidin-1-ium trifluoromethanesulfonate
[(1R*,2R*,1´S*)-2e]
130.2, 130.0, 120.7 (q, J = 318 Hz), 85.2, 81.7, 72.3, 70.2, 62.9,
39.4, 28.0, 27.4, 18.1, 13.4; HRMS (ESI): calcd. for C22H34NO4
[M–OTf]+ 376.2482, found 376.2468.
Prepared in 89% yield from (2R*,1´S*)-1e
showed a 9/1 mixture of (1R*,2R*,1´S*) and (1S*,2R*,1´S*)
diastereomers; colourless gum; IR (film)
max/cm-1 2981, 1734,
1463, 1396, 1371, 1356, 1259, 1224, 1154, 1052, 1030, 1004,
.
1H NMR analysis
(1S*,2S*,1´S*)-2-(tert-Butoxycarbonyl)-1-(1´-(4´´-
methoxyphenyl)ethyl)-1-methylazetidin-1-ium
ν
trifluoromethanesulfonate [(1S*,2S*,1´S*)-2d]
1
978, 935, 903, 860, 834, 759, 724; H NMR (400 MHz, CDCl3)
7.59 (0.9H, d, J = 7.6 Hz, ArH(1R*,2R*,1´S*)), 7.48-7.39 (0.1H, m,
ArH(1S*,2R*,1´S*)), 7.42 (0.9H, ddd, 7.6, 7.6, 1.0 Hz,
δ
Prepared in 96% yield from (2S*,1´S*)-1d; colourless gum; IR
(KBr)
ν
max/cm-1 2984, 1738, 1611, 1519, 1464, 1397, 1372,
J
=
6 | J. Name., 2012, 00, 1-3
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ArH(1R*,2R*,1´S*)), 7.38 (0.1H, d, J = 7.6 Hz, ArH(1S*,2R*,1´S*)), 7.33 (rac)-tert-Butyl 2-(2-ethylphenyl)-1-methylazetidine-2-carboxylate
(1H, d, J = 7.6 Hz, ArH), 7.26 (1H, dd, J = 7.6, 7.6 Hz, ArH), 5.67 3a
ν
max/cm-1 3066,
(0.9H, dd, J = 7.6, 7.6 Hz, 2-H(1R*,2R*,1´S*)), 5.63 (0.9H, d, J = 8.4
Colourless crystals; mp 40–42 °C; IR (KBr)
Hz, 1´-H(1R*,2R*,1´S*)), 5.57 (0.1H, d, J = 8.4 Hz, 1´-H(1S*,2R*,1´S*)),
5.03 (0.1H, ddd, J = 9.2, 4.0, 2.0 Hz, 2-H(1S*,2R*,1´S*)), 4.95 (0.1H,
ddd, J = 10.0, 10.0, 9.6 Hz, 4-H(1S*,2R*,1´S*)), 4.75 (0.9H, ddd, J =
10.0, 10.0, 10.0 Hz, 4-H(1R*,2R*,1´S*)), 4.22 (0.9H, ddd, J = 10.0,
10.0, 4.4 Hz, 4-H(1R*,2R*,1´S*)), 4.14 (0.1H, dddd, J = 9.6, 9.6, 4.0,
2.0 Hz, 4-H(1S*,2R*,1´S*)), 3.32 (0.1H, dddd, J = 12.4, 9.6, 9.6, 9.6
Hz, 3-H(1S*,2R*,1´S*)), 3.24-3.01 (1.1H, m), 3.01-2.74 (3.1H, m),
2.86 (2.7H, s, NCH3 (1R*,2R*,1´S*)), 2.64-2.45 (1H, m, 2´-H), 2.34
(0.9H, ddd, J = 8.4, 7.6, 7.6 Hz, 2´-H(1R*,2R*,1´S*)), 2.30-2.21 (0.1H,
m, 2´-H(1S*,2R*,1´S*)), 1.58 (0.9H, s, tBu(1S*,2R*,1´S*)), 1.41 (8.1H, s,
3010, 2974, 2934, 2875, 2840, 2778, 1710, 1480, 1453, 1389,
1366, 1287, 1252, 1235, 1207, 1197, 1167, 1126, 1087, 1033,
973, 957, 946, 906, 844, 822, 795, 765, 743.
tert-Butyl 1-methyl-2-(1’-phenylethyl)azetidine-2-carboxylate 4a
22
Colourless oil;
[
α
]
–34.2 (c 1.0 in EtOH); 89% ee
589
[determined by HPLC analysis: Daicel Chiralcel OJ-H column (25
cm), n-hexane/iPrOH = 95/5 as the eluent, flow rate = 0.50
mL/min, tR = 9.0 min (94.3%) and 11.8 min (5.7%)]; IR (film)
ν
1495, 1475, 1451, 1391, 1367, 1282, 1247, 1214, 1168, 1120,
max/cm-1 3060, 3027, 2973, 2931, 2878, 2832, 2779, 1717,
tBu(1R*,2R*,1´S*)); 13C NMR (100 MHz, CDCl3)
δ [assigned only
1
1085, 1043, 1029, 981, 948, 910, 847, 828, 789, 770, 699; H
(1R*,2R*,1´S*)] 163.5, 146.6, 133.2, 131.2, 127.6, 127.1, 125.5,
120.7 (q, J = 319 Hz), 85.6, 79.4, 71.2, 62.6, 40.1, 30.8, 27.7,
26.4, 18.2; HRMS (ESI): calcd. for C18H26NO2 [M–OTf]+
288.1958, found 288.1948.
NMR (400 MHz, CDCl3)
δ 7.32-7.25 (2H, m, Ph), 7.24-7.18 (3H,
m, Ph), 3.29 (1H, q, J = 7.2 Hz, 1’-H), 3.12 (1H, ddd, J = 8.3, 5.9,
2.6 Hz, 4-H), 2.90 (1H, ddd, J = 8.8, 8.3, 5.9 Hz, 4-H), 2.36 (1H,
ddd, J = 10.4, 8.3, 2.6 Hz, 3-H), 2.33 (3H, s, NCH3), 2.04 (1H,
ddd, J = 10.4, 8.8, 8.3 Hz, 3-H), 1.48 (9H, s, tBu), 1.30 (3H, d, J =
Representative procedure for base-induced rearrangement of
(1R,2R,1’S)-2a
7.2 Hz, 1’-CH3); 13C NMR (100 MHz, CDCl3)
δ 170.9, 142.0,
A solution of (1R,2R,1’S)-2a (225 mg, 0.529 mmol) in THF (4.8
mL) was treated with a 1 M solution of tBuOK in THF (0.63 mL,
0.63 mmol) at 0 °C under an argon atmosphere and stirred for
3 h at the same temperature. The resulting mixture was
quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The combined extracts were washed with saturated
aqueous NaHCO3 followed by brine, dried over Na2SO4, and
concentrated. Purification of the residue by chromatography
on silica gel (n-hexane/EtOAc = 20/1 to 5/1 as the eluent, Rf: 3a
129.0, 127.6, 126.3, 81.4, 76.8, 51.4, 45.3, 40.0, 28.3, 25.0,
14.2; HRMS (ESI): calcd. for C17H26NO2 [M+H]+ 276.1958, found
276.1953.
(rac)-tert-Butyl 1-methyl-2-(1’-phenylethyl)azetidine-2-
carboxylate 4a
Colourless oil.
tert-Butyl 2-(5-bromo-2-ethylphenyl)-1-methylazetidine-2-
carboxylate 3b
>
4a) afforded (S)-3a (21.2 mg, 15% yield) as a colourless oil Colourless crystals; mp 72–74 °C; IR (KBr) ν
max/cm-1 3065,
and 4a (39.4 mg, 27% yield) as a colourless oil.
3015, 2967, 2931, 2859, 2786, 1713, 1590, 1561, 1477, 1458,
1390, 1365, 1250, 1209, 1195, 1161, 1122, 1084, 1054, 974,
956, 944, 914, 892, 841, 832, 789, 768, 748; 1H NMR (400 MHz,
(R)-tert-Butyl 2-(2-ethylphenyl)-1-methylazetidine-2-carboxylate
(R)-3a7
23
CDCl3)
δ 7.66 (1H, d, J = 2.2 Hz, ArH), 7.32 (1H, dd, J = 8.2, 2.2
Colourless oil; [
α
]
+159.9 (c 1.0 in EtOH); 99% ee
589
Hz, ArH), 7.04 (1H, d, J = 8.2 Hz, ArH), 3.47 (1H, ddd, J = 8.6,
6.0, 2.4 Hz, 4-H), 3.33 (1H, ddd, J = 8.6, 8.4, 6.0 Hz, 4-H), 2.91
(1H, ddd, J = 10.3, 8.4, 2.4 Hz, 3-H), 2.46 (3H, s, NCH3), 2.29
(2H, q, J = 7.6 Hz, CH2CH3), 2.14 (1H, ddd, J = 10.3, 8.6, 8.6 Hz,
3-H), 1.43 (9H ,s, tBu), 1.17 (3H, t, J = 7.6 Hz, CH2CH3); 13C NMR
[determined by HPLC analysis: Daicel Chiralcel OD-RH column
(15 cm), H2O/MeCN = 30/70 as the eluent, flow rate = 0.50
mL/min, tR = 8.6 min for (R)-3a (99.5%) and 9.6 min for (S)-3a
(0.5%)]; IR (film)
1481, 1454, 1391, 1367, 1253, 1196, 1164, 1121, 1086, 1045,
1029, 975, 952, 908, 845, 822, 760; 1H NMR (400 MHz, CDCl3)
ν
max/cm-1 3065, 2971, 2931, 2852, 2782, 1714,
(100 MHz, CDCl3)
δ 170.3, 144.2, 138.4, 129.7, 129.4, 128.3,
δ
119.5, 81.9, 75.1, 52.0, 39.6, 29.6, 28.1, 23.9, 14.3; HRMS (ESI):
calcd. for C17H25BrNO2 [M+H]+ 354.1063, found 354.1055.
tert-Butyl 2-(1’-(4-bromophenyl)ethyl)-1-methylazetidine-2-
carboxylate 4b
7.54-7.48 (1H, m, ArH), 7.23-7.14 (3H, m, ArH), 3.48 (1H, ddd, J
= 8.5, 6.0, 2.4 Hz, 4-H), 3.34 (1H, ddd, J = 8.9, 8.2, 6.0 Hz, 4-H),
2.93 (1H, ddd, J = 10.5, 8.2, 2.4 Hz, 3-H), 2.49 (3H, s, NCH3),
2.355 (1H, q, J = 7.4 Hz, CH2CH3), 2.351 (1H, q, J = 7.4 Hz,
CH2CH3), 2.19 (1H, ddd, J = 10.5, 8.9, 8.5 Hz, 3-H), 1.42 (9H, s, Colourless oil; IR (film)
tBu), 1.19 (3H, dd, J = 7.4, 7.4 Hz, CH2CH3); 13C NMR (100 MHz, 1590, 1488, 1457, 1403, 1392, 1367, 1247, 1213, 1166, 1121,
CDCl3) 170.8, 142.0, 139.3, 127.6, 126.7, 125.4, 125.1, 81.6, 1087, 1076, 1043, 1010, 974, 948, 911, 847, 822, 788, 766,
75.7, 52.2, 39.9, 29.8, 28.1, 24.3, 14.5; HRMS (ESI): calcd. for 722; 1H NMR (400 MHz, CDCl3)
C17H26NO2 [M+H]+ 276.1958, found 276.1949.
ν
max/cm-1 2973, 2931, 2833, 2781, 1716,
δ
δ 7.41 (2H, ddd, J = 8.4, 2.2, 2.2
Hz, ArH), 7.09 (2H, ddd, J = 8.4, 2.2, 2.2 Hz, ArH), 3.24 (1H, q, J
= 7.2 Hz, 1’-H), 3.08 (1H, ddd, J = 8.4, 6.0, 2.4 Hz, 4-H), 2.90
(1H, ddd, J = 8.6, 8.4, 6.0 Hz, 4-H), 2.32 (1H, ddd, J = 10.6, 8.4,
2.4 Hz, 3-H), 2.30 (3H, s, NCH3), 1.93 (1H, ddd, J = 10.6, 8.6, 8.4
Hz, 3-H), 1.50 (9H, s, tBu), 1.24 (3H, d, J = 7.2 Hz, 1’-CH3); 13C
(S)-tert-Butyl 2-(2-ethylphenyl)-1-methylazetidine-2-carboxylate
(S)-3a
23
]
Colourless oil; [
α
–108.8 (c 1.0 in EtOH); 66% ee
589
[determined by HPLC analysis: Daicel Chiralcel OD-RH column
(15 cm), H2O/MeCN = 40/60 as the eluent, flow rate = 0.50
mL/min, tR = 13.4 min for (R)-3a (16.9%) and 15.0 min for (S)-
3a (83.1%)].
NMR (100 MHz, CDCl3)
δ 170.8, 141.1, 130.9, 130.6, 120.2,
81.6, 76.6, 51.4, 44.1, 39.7, 28.3, 24.0, 14.0; HRMS (ESI): calcd.
for C17H25BrNO2 [M+H]+ 354.1063, found 354.1051.
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ARTICLE
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tert-Butyl 2-(5-(tert-butoxycarbonyl)-2-ethylphenyl)-1-
(8.5 mg, 9% yield) as a colourless oil. The pure 4d2 could not
be obtained because of inseparable impurities.
Representative procedure for base-induced rearrangement of
(1R*,2R*,1’S*)-2d
methylazetidine-2-carboxylate 3c
Colourless oil; IR (film)
1609, 1574, 1475, 1457, 1414, 1392, 1367, 1307, 1247, 1164,
ν
max/cm-1 2974, 2932, 2856, 2784, 1712,
1127, 1086, 1059, 981, 948, 917, 882, 845, 822, 789, 766, 735; The reaction was performed by the same procedure depicted
1H NMR (400 MHz, CDCl3)
8.16 (1H, d, J = 1.7 Hz, ArH), 7.82 above using (1R*,2R*,1’S*)-2d (123 mg, 0.270 mmol), THF (2.4
δ
(1H, dd, J = 8.1, 1.7 Hz, ArH), 7.21 (1H, d, J = 8.1 Hz, ArH), 3.49 mL), a 1 M solution of tBuOK in THF (0.32 mL, 0.32 mmol). 1H
(1H, ddd, J = 8.5, 6.0, 2.4 Hz, 4-H), 3.36 (1H, ddd, J = 8.6, 8.2, NMR analysis of the crude material using mesitylene as an
6.0 Hz, 4-H), 2.92 (1H, ddd, J = 10.3, 8.2, 2.4 Hz, 3-H), 2.51 (3H, internal standard determined the yield of 3d (5% yield), 4d1
s, NCH3), 2.39 (2H, q, J = 7.4 Hz, CH2CH3), 2.15 (1H, ddd, J = (10% yield) and 4d2 (33% yield). Purification of the crude
10.3, 8.6, 8.5 Hz, 3-H), 1.59 (9H, s, tBu), 1.42 (9H, s, tBu), 1.20 material by chromatography on silica gel (n-hexane/EtOAc =
(3H, t, J = 7.4 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3)
δ 170.6, 7/1 to 3/1 as the eluent, Rf: 3d > 4d1 > 4d2) gave 4d2 (22.4 mg,
166.1, 144.5, 142.2, 129.2, 127.8, 127.7, 126.6, 81.8, 80.4, 27% yield) as colourless crystals. The product 3d was not
75.3, 52.1, 39.6, 29.7, 28.2, 28.1, 24.5, 14.3; HRMS (ESI): calcd. isolated because of small amount. The pure 4d1 could not be
for C22H34NO4 [M+H]+ 376.2482, found 376.2474.
tert-Butyl 2-(1’-(4’’-(tert-butoxycarbonyl)phenyl)ethyl)-1-
methylazetidine-2-carboxylate 4c
obtained because of inseparable impurities.
tert-Butyl 2-(2-ethyl-5-methoxyphenyl)-1-methylazetidine-2-
carboxylate 3d
Colourless oil; IR (film) ν ν
max/cm-1 2975, 2932, 2834, 2781, 1712, Colourless oil; IR (film) max/cm-1 2969, 2932, 2853, 2834, 2782,
1609, 1574, 1476, 1457, 1414, 1392, 1367, 1293, 1249, 1213, 1714, 1609, 1578, 1496, 1464, 1424, 1391, 1367, 1253, 1216,
1166, 1115, 1087, 1045, 1018, 975, 948, 911, 848, 779, 734, 1160, 1120, 1086, 1044, 978, 948, 931, 863, 844, 812, 773,
711; 1H NMR (400 MHz, CDCl3)
1
7.92 (2H, ddd, J = 8.2, 1.6, 1.6 751, 705; H NMR (400 MHz, CDCl3)
δ
δ
7.14 (1H, d, J = 3.1 Hz,
Hz, ArH), 7.27 (2H, ddd, J = 8.2, 1.6, 1.6 Hz, ArH), 3.34 (1H, q, J ArH), 7.08 (1H, d, J = 8.3 Hz, ArH), 6.75 (1H, dd, J = 8.3, 3.1 Hz,
= 7.2 Hz, 1’-H), 3.06 (1H, ddd, J = 8.4, 6.0, 2.6 Hz, 4-H), 2.90 ArH), 3.82 (3H, s, OCH3), 3.46 (1H, ddd, J = 8.6, 6.0, 2.6 Hz, 4-
(1H, ddd, J = 8.6, 8.2, 6.0 Hz, 4-H), 2.33 (1H, ddd, J = 10.4, 8.2, H), 3.32 (1H, ddd, J = 8.8, 8.0, 6.0 Hz, 4-H), 2.91 (1H, ddd, J =
2.6 Hz, 3-H), 2.31 (3H, s, NCH3), 1.96 (1H, ddd, J = 10.4, 8.6, 8.4 10.5, 8.0, 2.6 Hz, 3-H), 2.47 (3H, s, NCH3), 2.29 (2H, q, J = 7.6
Hz, 3-H), 1.59 (9H, s, tBu), 1.51 (9H, s, tBu), 1.27 (3H, d, J = 7.2 Hz, CH2CH3), 2.17 (1H, ddd, J = 10.5, 8.8, 8.6 Hz, 3-H), 1.43 (9H,
Hz, 1’-CH3); 13C NMR (100 MHz, CDCl3)
130.0, 129.1, 128.6, 81.6, 80.7, 76.7, 51.4, 44.6, 39.7, 28.3, CDCl3)
28.2, 24.0, 14.0; HRMS (ESI): calcd. for C22H34NO4 [M+H]+ 75.4, 55.0, 51.9, 39.6, 29.6, 28.0, 23.4, 14.6; HRMS (ESI): calcd.
δ
170.8, 165.9, 147.2, s, tBu), 1.16 (3H, t, J = 7.6 Hz, CH2CH3); 13C NMR (100 MHz,
δ
170.6, 157.4, 143.2, 131.4, 128.5, 111.6, 111.2, 81.5,
376.2482, found 376.2474.
tert-Butyl 4-vinylbenzoate 621
for C18H28NO3 [M+H]+ 306.2064, found 306.2054.
tert-Butyl 2-(1’-(4’’-methoxyphenyl)ethyl)-1-methylazetidine-2-
carboxylate 4d1
Colourless oil; IR (film) ν
max/cm-1 3089, 2977, 2930, 1711, 1629,
1608, 1567, 1474, 1456, 1402, 1392, 1368, 1311, 1293, 1255, Colourless oil; IR (film) ν
max/cm-1 2973, 2931, 2834, 2779, 1715,
1166, 1118, 1107, 1015, 989, 915, 861, 850, 783, 713; 1H NMR 1612, 1582, 1512, 1457, 1391, 1367, 1274, 1246, 1215, 1177,
1
7.94 (2H, ddd, J = 8.4, 1.8, 1.8 Hz, ArH), 1129, 1094, 1063, 1039, 974, 948, 927, 913, 832, 787, 754; H
(400 MHz, CDCl3) δ
7.44 (2H, ddd, J = 8.4, 1.8, 1.8 Hz, ArH), 6.75 (1H, dd, J = 17.6, NMR (400 MHz, CDCl3)
δ
7.05 (2H, ddd, J = 8.6, 2.6, 2.6 Hz,
11.2 Hz, CH=CH2), 5.85 (1H, dd, J = 17.6, 0.6 Hz, CH=CH2), 5.36 ArH), 6.78 (2H, ddd, J = 8.6, 2.6, 2.6 Hz, ArH), 3.76 (3H, s,
(1H, dd, J = 11.2, 0.6 Hz, CH=CH2), 1.59 (9H, s, tBu); 13C NMR OCH3), 3.33 (1H, ddd, J = 7.5, 6.0, 3.6 Hz, 4-H), 3.07 (1H, q, J =
(100 MHz, CDCl3)
116.1, 80.9, 28.2.
δ
165.5, 141.4, 136.1, 131.1, 129.7, 125.9, 7.2 Hz, 1’-H), 3.02 (1H, ddd, J = 8.4, 8.4, 6.0 Hz, 4-H), 2.45-2.34
(2H, m, 3-H), 2.27 (3H, s, NCH3), 1.37 (3H, d, J = 7.2 Hz, 1’-CH3),
Representative procedure for base-induced rearrangement of
1.28 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ 171.0, 157.9,
(1S*,2S*,1’S*)-2d
136.0, 129.0, 113.4, 80.9, 77.2, 55.2, 52.0, 42.4, 39.2, 28.0,
22.5, 17.6; HRMS (ESI): calcd. for C18H28NO3 [M+H]+ 306.2064,
found 306.2053.
A solution of (1S*,2S*,1’S*)-2d (146 mg, 0.321 mmol) in THF
(2.9 mL) was treated with a 1 M solution of tBuOK in THF (0.39
mL, 0.39 mmol) at 0 °C under an argon atmosphere and stirred
for 3 h at the same temperature. The resulting mixture was
quenched with saturated aqueous NH4Cl and extracted with Colourless crystals; mp 52–57 °C; IR (KBr) ν
max/cm-1 2998, 2972,
EtOAc. The combined extracts were washed with saturated 2956, 2913, 2842, 2787, 1709, 1613, 1581, 1512, 1476, 1460,
tert-Butyl 2-(1’-(4’’-methoxyphenyl)ethyl)-1-methylazetidine-2-
carboxylate 4d2
aqueous NaHCO3 followed by brine, dried over Na2SO4, and 1437, 1391, 1366, 1341, 1304, 1282, 1248, 1212, 1197, 1179,
concentrated. First, 1H NMR analysis of the crude material 1149, 1131, 1096, 1062, 1035, 1004, 980, 943, 911, 845, 822,
1
using mesitylene as an internal standard determined the yield 787, 751, 726; H NMR (400 MHz, CDCl3)
δ 7.14 (2H, ddd, J =
of 3d (73% yield), 4d1 (10% yield) and 4d2 (3% yield). 8.6, 2.6, 2.6 Hz, ArH), 6.83 (2H, ddd, J = 8.6, 2.6, 2.6 Hz, ArH),
Purification of the crude material by chromatography on silica 3.79 (3H, s, OCH3), 3.23 (1H, q, J = 7.2 Hz, 1’-H), 3.13 (1H, ddd, J
gel (n-hexane/EtOAc = 7/1 to 3/1 as the eluent, Rf: 3d
>
4d1
>
= 8.4, 6.2, 2.4 Hz, 4-H), 2.90 (1H, ddd, J = 8.4, 8.2, 6.2 Hz, 4-H),
4d2) gave 3d (60.2 mg, 61% yield) as a colourless oil and 4d1 2.34 (1H, ddd, J = 10.5, 8.2, 2.4 Hz, 3-H), 2.33 (3H, s, NCH3),
8 | J. Name., 2012, 00, 1-3
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2.01 (1H, ddd, J = 10.5, 8.4, 8.4 Hz, 3-H), 1.49 (9H, s, tBu), 1.27 material using mesitylene as an internal standard determined
(3H, d, J = 7.2 Hz, 1’-CH3); 13C NMR (100 MHz, CDCl3)
171.0, the yield of 12 (85% yield) and 13 (7% yield). Purification of
δ
158.0, 134.0, 129.9, 113.0, 81.3, 76.9, 55.1, 51.4, 44.4, 40.0, the crude material by chromatography on silica gel (n-
28.3, 24.8, 14.4; HRMS (ESI): calcd. for C18H28NO3 [M+H]+ hexane/EtOAc = 15/1 to 7/1 as the eluent) gave 12 (52.8 mg,
306.2064, found 306.2056.
75% yield) as colourless crystals.
tert-Butyl 2-(2,3-dihydro-1H-inden-4-yl)-1-methylazetidine-2-
carboxylate 3e
tert-Butyl 2-(2-benzylphenyl)-1-methylazetidine-2-carboxylate 12
Colourless crystals; mp 50–52 °C; IR (KBr) ν
max/cm-1 3061, 3025,
Yellow oil; IR (film)
ν
max/cm-1 3059, 2964, 2932, 2844, 1780, 2972, 2934, 2856, 2782, 1715, 1599, 1495, 1479, 1452, 1391,
1716, 1592, 1472, 1447, 1391, 1367, 1286, 1252, 1200, 1163, 1364, 1253, 1236, 1196, 1161, 1124, 1085, 1038, 975, 953, 906,
1
1
1123, 1086, 1063, 1014, 950, 915, 845, 819, 779, 744, 720; H 844, 818, 767, 753, 741, 705; H NMR (400 MHz, CDCl3)
δ 7.58
NMR (400 MHz, CDCl3) 7.29 (1H, dd, J = 7.6 Hz, ArH), 7.16 (1H, dd, J = 7.8, 1.4 Hz, ArH), 7.30-7.17 (4H, m, ArH), 7.16-7.07
δ
(1H, dd, J = 7.6, 7.0 Hz, ArH), 7.11 (1H, d, J = 7.0 Hz, ArH), 3.47 (3H, m, ArH), 6.86 (1H, ddd, J = 7.6, 1.4, 0.6 Hz, ArH), 3.73 (2H,
(1H, ddd, J = 8.4, 6.2, 2.4 Hz, 4-H), 3.30 (1H, ddd, J = 8.9, 8.2, s, CH2Ph), 3.47 (1H, ddd, J = 8.5, 6.2, 2.4 Hz, 4-H), 3.33 (1H,
6.2 Hz, 4-H), 2.90 (1H, ddd, J = 10.5, 8.2, 2.4 Hz, 3-H), 2.87 (2H, ddd, J = 8.8, 8.1, 6.2 Hz, 4-H), 2.89 (1H, ddd, J = 10.4, 8.1, 2.4
t, J = 7.4 Hz, indenyl-CH2), 2.67-2.51 (2H, m, indenyl-CH2), 2.50 Hz, 3-H), 2.51 (3H, s, NCH3), 2.17 (1H, ddd, J = 10.4, 8.8, 8.5 Hz,
(3H, s, NCH3), 2.15 (1H, ddd, J = 10.5, 8.9, 8.4 Hz, 3-H), 2.09- 3-H), 1.44 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
1.92 (2H, m, indenyl-CH2), 1.42 (9H, s, tBu); 13C NMR (100 MHz, 142.5, 140.3, 136.3, 129.8, 129.4, 128.3, 126.7, 126.0, 125.9,
CDCl3) 170.5, 144.1, 140.1, 139.3, 126.0, 122.7, 122.1, 81.4, 125.4, 81.9, 75.7, 52.2, 39.9, 37.6, 29.8, 28.2; HRMS (ESI):
δ 170.7,
δ
75.4, 52.2, 40.1, 32.5, 31.0, 28.7, 28.1, 25.3; HRMS (ESI): calcd. calcd. for C22H28NO2 [M+H]+ 338.2115, found 338.2111.
for C18H26NO2 [M+H]+ 288.1958, found 288.1957.
tert-Butyl 2-benzhydryl-1-methylazetidine-2-carboxylate 13
Colourless crystals; mp 80 82 °C; IR (KBr)
max/cm-1 3087, 3064,
3026, 3001, 2966, 2930, 2825, 2776, 1711, 1497, 1472, 1449,
max/cm-1 3066, 3005, 2971, 2928, 2854, 1392, 1370, 1280, 1269, 1250, 1217, 1168, 1153, 1118, 1086,
2780, 1716, 1586, 1474, 1391, 1367, 1328, 1251, 1213, 1166, 1031, 989, 949, 848, 760, 739, 702; 1H NMR (400 MHz, CDCl3)
1118, 1083, 1056, 1032, 999, 949, 903, 846, 814, 768; 1H NMR 7.29-7.23 (4H, m, Ph), 7.22-7.15 (4H, m, Ph), 7.12 (1H, ddd, J =
(400 MHz, CDCl3) 7.06-6.97 (3H, m, ArH), 3.07 (1H, d, J = 14.8 6.8, 1.6, 1.6 Hz, Ph), 4.33 (1H, s, CHPh2), 3.06-2.97 (2H, m, 4-H),
tert-Butyl 2-(2,6-dimethylbenzyl)-1-methylazetidine-2-carboxylate
–
ν
9
Colourless oil; IR (film)
ν
δ
δ
Hz, CH2Ar), 3.07-2.98 (2H, m, 4-H), 2.86 (1H, d, J = 14.8 Hz, 2.61 (1H, ddd, J = 10.2, 5.2, 5.2 Hz, 3-H), 2.35 (3H, s, NCH3),
CH2Ar), 2.35 (3H, s, NCH3), 2.32-2.21 (1H, m, 3-H), 2.28 (6H, s, 2.13 (1H, ddd, J = 10.2, 8.6, 8.6 Hz, 3-H), 1.16 (9H, s, tBu); 13C
ArCH3), 1.87 (1H, ddd, J = 10.0, 8.6, 8.6 Hz, 3-H), 1.47 (9H, s, NMR (100 MHz, CDCl3)
tBu); 13C NMR (100 MHz, CDCl3)
172.5, 138.0, 135.4, 127.8, 128.2, 127.3, 126.2, 126.1, 81.1, 76.8, 54.8, 52.6, 38.5, 27.7,
126.0, 81.0, 74.1, 51.8, 38.1, 34.1, 28.2, 26.1, 21.0; HRMS (ESI): 23.4; HRMS (ESI): calcd. for C22H28NO2 [M+H]+ 338.2115, found
δ 170.4, 141.7, 141.0, 130.9, 128.9,
δ
calcd. for C18H28NO2 [M+H]+ 290.2115, found 290.2104.
tert-Butyl 1-methyl-2-(3,4,5-trimethylphenyl)azetidine-2-
carboxylate 10
338.2111.
tert-Butyl 1-methyl-2-(2’-phenylpropan-2’-yl)azetidine-2-
carboxylate 16
Colourless crystals; mp 54–57 °C; IR (KBr) ν ν
max/cm-1 2973, 2929, Colourless oil; IR (film) max/cm-1 3089, 3057, 2977, 2929, 2834,
2841, 2782, 1712, 1607, 1578, 1486, 1454, 1413, 1391, 1366, 2783, 1713, 1600, 1496, 1476, 1444, 1391, 1366, 1273, 1247,
1312, 1268, 1254, 1197, 1169, 1123, 1084, 1036, 1016, 993, 1217, 1151, 1122, 1084, 1063, 1031, 976, 952, 908, 848, 822,
947, 931, 874, 845, 810, 766, 746, 715; 1H NMR (400 MHz, 780, 760, 734, 699; 1H NMR (400 MHz, CDCl3)
δ
7.31-7.21 (4H,
CDCl3)
δ 6.95 (2H, s, ArH), 3.33-3.23 (2H, m, 4-H), 2.81 (1H, m, Ph), 7.15 (1H, tt, J = 6.8, 1.4 Hz, Ph), 3.32 (1H, ddd, J = 8.6,
ddd, J = 10.9, 7.3, 5.6 Hz, 3-H), 2.47-2.34 (1H, m, 3-H), 2.30 6.3, 3.0 Hz, 4-H), 2.87 (1H, ddd, J = 8.8, 8.6, 6.3 Hz, 4-H), 2.58
(3H, s, NCH3), 2.28 (6H, s, 3,5-ArCH3), 2.15 (3H, s, 4-ArCH3), (1H, ddd, J = 10.8, 8.6, 3.0 Hz, 3-H), 2.47 (1H, ddd, J = 10.8, 8.8,
1.47 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ
172.4, 137.6, 8.6 Hz, 3-H), 2.32 (3H, s, NCH3), 1.51 (3H, s, 2’-CH3); 1.41 (3H, s,
136.1, 133.9, 124.8, 81.2, 74.5, 51.3, 39.6, 29.3, 28.1, 20.8, 2’-CH3), 1.18 (9H ,s, tBu); 13C NMR (100 MHz, CDCl3)
δ
170.2,
15.2; HRMS (ESI): calcd. for C18H28NO2 [M+H]+ 290.2115, found 147.6, 127.6, 126.8, 125.7, 81.0, 79.7, 51.8, 43.2, 42.3, 27.85,
290.2106.
27.80, 24.4, 22.7; HRMS (ESI): calcd. for C18H28NO2 [M+H]+
290.2115, found 290.2111.
Representative procedure for base-induced rearrangement of
(1S*,2S*)-11
A solution of (1S*,2S*)-11 (102 mg, 0.209 mmol) in THF (1.9
mL) was treated with a 1 M solution of tBuOK in THF (0.25 mL,
0.25 mmol) at –40 °C under an argon atmosphere and stirred
for 3 h at the same temperature. The resulting mixture was
poured into saturated aqueous NH4Cl and the mixture was
extracted with EtOAc. The combined extracts were washed
with saturated aqueous NaHCO3 followed by brine, dried over
Na2SO4, and concentrated. 1H NMR analysis of the crude
Acknowledgements
The authors are grateful to Prof. Dr. Mineo Sato at Niigata
University (Faculty of Engineering) for the X-ray single-crystal
structural analyses.
Notes and references
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
1
2
For reviews: (a) D. Antermite, L. Degennaro and R. Luisi, Org.
Biomol. Chem., 2017, 15, 34; (b) F. Couty, B. Drouillat, G.
Evano and O. David, Eur. J. Org. Chem., 2013, 2045.
Initial studies on S–H rearrangement: (a) K. P. Klein, D. N.
Van Eenam and C. R. Hauser, J. Org. Chem., 1967, 32, 1155;
(b) W. H. Puterbaugh and C. R. Hauser, J. Am. Chem. Soc., 10 Asymmetric ammonium ylide rearrangements via N-to-C
(1S,2S,1’S)-2a-BPh4 prepared by ion exchange.
1553028 contains the supplementary crystallographic data
for this paper. These data are provided free of charge by the
CCDC-
CCDC
via
www.ccdc.cam.ac.uk/data_request/cif.
Experimental details: see the ESI.
1964, 86, 1108; (c) W. H. Puterbaugh and C. R. Hauser, J. Am.
Chem. Soc., 1964, 86, 1105; (d) G. C. Jones, W. Q. Beard and
C. R. Hauser, J. Org. Chem., 1963, 28, 199; (e) W. Q. Beard, Jr.
and C. R. Hauser, J. Org. Chem., 1961, 26, 371; (f) W. Q.
Beard, Jr. and C. R. Hauser, J. Org. Chem., 1960, 25, 334; (g)
chirality transmission: (a) M. Ariza, A. Díaz, R. Suau and M.
Valpuesta, Eur. J. Org. Chem., 2011, 6507; (b) L. Palombi,
Catal. Commun., 2011, 12, 485; (c) P. Tuzina and P. Somfai,
Org. Lett., 2009, 11
, 919; (d) E. F. Duran-Lara, N.
Shankaraiah, D. Geraldo and L. S. Santos, J. Braz. Chem. Soc.,
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Lett., 2006, 35, 478; (f) E. Tayama, H. Tanaka and T. Nakai,
Heterocycles, 2005, 66, 95; (g) A. P. A. Arboré, D. J. Cane-
Honeysett, I. Coldham and M. L. Middleton, Synlett, 2000,
C. R. Hauser and D. N. Van Eenam, J. Org. Chem., 1958, 23
,
865; (h) D. N. Van Eenam and C. R. Hauser, J. Am. Chem. Soc.,
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236; (h) K. W. Glaeske and F. G. West, Org. Lett., 1999, 1, 31.
Hauser, Org. Synth., 1954, 34, 61; (l) S. W. Kantor and C. R. 11 Previous studies on ring-strained azetidinium ylides: (a) A.
Hauser, J. Am. Chem. Soc., 1951, 73, 4122; (m) M. Sommelet,
C. R. Hebd. Seances Acad. Sci. 1937, 205, 56.
For a review on the S–H rearrangement: E. Tayama, Chem.
Rec., 2015, 15, 789.
For reviews on ammonium ylide rearrangements: (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, Elsevier, 2014, ch. 3.20, vol.3;
(c) G. Lahm, J. C. O. Pacheco and 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,
Alex, B. Larmanjat, J. Marrot, F. Couty and O. David, Chem.
Commun., 2007, 2500; (b) F. Couty, O. David, B. Larmanjat
and J. Marrot, J. Org. Chem., 2007, 72, 1058; see also, ref. 5b.
12 Recent studies on azetidinic carbanions: (a) G. Parisi, M.
Zenzola, E. Capitanelli, C. Carlucci, G. Romanazzi, L. Pisano, L.
Degennaro and R. Luisi, Pure. Appl. Chem., 2016, 88, 631; (b)
G. Parisi, E. Capitanelli, A. Piero, G. Romanazzi, G. J. Clarkson,
L. Degennaro and R. Luisi, Chem. Commun., 2015, 51, 15588;
(c) L. Degennaro, M. Zenzola, P. Trinchera, L. Carroccia, A.
Giovine, G. Romanazzi, A. Falcicchio and R. Luisi, Chem.
Commun., 2014, 50, 1698.
3
4
Chem. Soc. Rev., 2009, 38, 1027; (f) J. A. Vanecko, H. Wan 13 The stereochemistry of the [1,2] Stevens rearrangement
and F. G. West, Tetrahedron, 2006, 62, 1043; (g) L. Kürti and
B. Czakó, Strategic Applications of Named Reactions in
Organic Synthesis, Elsevier, Amsterdam, 2005; (h) Nitrogen,
Oxygen and Sulfur Ylide Chemistry, ed. J. S. Clark, Oxford
University Press, Oxford, 2002; (i) I. E. Markó, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I.
products
Because the [1,2] Stevens rearrangement mainly proceeds
via radical pair intermediate with the retention of
configuration. See ref. 4b, 4h and 4i. Thereby, 4a was
obtained in 89% ee. Other related examples: see ref. 10b,
10c, 10e and 10h.
4 was not determined, but they can be predicted.
a
Fleming, Pergamon, Oxford, 1991, ch. 3.10, vol. 3; (j) S. H. 14 Diastereomers (2S*,1’S*)- and (2R*,1’S*)-
Pine, in Organic Reactions, John Wiley & Sons, Inc., New
York, 1970, ch. 4, vol. 18.
1
were easily
separable by silica gel column chromatography. The
stereochemistry of (2S,1’S)- and (2R,1’S)-1a was assigned in
our previous work, see ref. 7. The stereochemistry of 1b
was assigned by analogy. Examples of chromatographic
separation of other analogs of , see: (a) S.-h. Ma, D. H. Yoon,
5
Representative
rearrangements of ammonium salts: (a) A. C. Colgan, H.
Müller-Bunz and E. M. McGarrigle, J. Org. Chem., 2016, 81
examples
of
base-induced
S–H
–e
,
1
11394; (b) G. Casoni, E. L. Myers and V. K. Aggarwal,
Synthesis, 2016, 48, 3241; (c) E. Tayama, R. Sato, M. Ito, H.
Iwamoto and E. Hasegawa, Heterocycles, 2013, 87, 381; (d)
H.-J. Ha and W. K. Lee, Tetrahedron Lett., 2007, 48, 269; (b) F.
Couty, G. Evano, M. Vargas-Sanchez and G. Bouzas, J. Org.
Chem., 2005, 70, 9028.
E. Tayama, R. Sato, K. Takedachi, H. Iwamoto and E. 15 Sodium hydrogen carbonate was added as a scavenger of
Hasegawa, Tetrahedron, 2012, 68, 4710; (e) E. Tayama, K.
Takedachi, H. Iwamoto and E. Hasegawa, Tetrahedron, 2010,
66, 9389; (f) E. Tayama, K. Orihara and H. Kimura, Org. 16 Studies on N-quaternization of N-benzylic 2-substituted
triflic acid, which may cause the decomposition of the tert-
butyl ester.
Biomol. Chem., 2008,
6
, 3673; (g) E. Tayama and H. Kimura,
azetidine derivatives: (a) F. Couty, O. David, F. Durrat, G.
Evano, S. Lakhdar, J. Marrot and M. Vargas-Sanchez, Eur. J.
Org. Chem., 2006, 3479; (b) F. Couty, F. Durrat, G. Evano and
D. Prim, Tetrahedron Lett., 2004, 45, 7525; See also ref. 7.
Angew. Chem. Int. Ed., 2007, 46, 8869; (h) S. Hanessian, C.
Talbot and P. Saravanan, Synthesis, 2006, 723; (i) J. M.
Klunder, J. Heterocyclic Chem., 1995, 32, 1687; (j) T.
Zdrojewski and A. Jończyk, Tetrahedron Lett., 1995, 36, 1355; 17 The relative stereochemistry of (1R*,2R*,1’S*)-2e was
(k) A. Jończyk, D. Lipiak and K. Sienkiewicz, Synlett, 1991,
493; (l) A. Jończyk and D. Lipiak, J. Org. Chem., 1991, 56
6933.
Mechanistic studies on the S–H rearrangement: B. Biswas
and D. A. Singleton, J. Am. Chem. Soc., 2015, 137, 14244.
E. Tayama, K. Watanabe and Y. Matano, Eur. J. Org. Chem.,
2016, 3631.
determined by the single-crystal X-ray diffraction of the
tetraphenylborate salt [(1R*,2R*,1’S*)-2e-BPh4] prepared by
ion exchange. CCDC-1553029 contains the supplementary
crystallographic data for this paper. These data are provided
,
6
7
8
free
of
charge
by
the
CCDC via
Experimental
www.ccdc.cam.ac.uk/data_request/cif.
details: see the ESI.
Previous studies on the base-induced rearrangements of 18 Previously, it was reported that this type of intermediate
azetidine-2-carboxylic acid-derived ammonium ylides: (a) B.
Drouillat, E. d’Aboville, F. Bourdreux and F. Couty, Eur. J. Org.
Chem., 2014, 1103; (b) B. Drouillat, F. Couty and J. Marrot,
would be generated in an ylide rearrangement under aprotic
conditions: S. Okazaki, N. Shirai and Y. Sato, J. Org. Chem.,
1990, 55, 334; see also, ref. 4i.
Synlett, 2009, 767; (c) F. Couty, F. Durrat, G. Evano and J. 19 The stereochemistry was tentatively determined by analogy
Marrot, Eur. J. Org. Chem., 2006, 4214. with our previous work, see ref. 7.
The stereochemistry of (1S,2S,1’S)-2a was determined by the 20 Previous examples of isolation of dearomatized product from
9
single-crystal X-ray diffraction of the tetraphenylborate salt
N-benzylic ammonium ylide: see ref. 2g, 2h and 2i.
10 | J. Name., 2012, 00, 1-3
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21 T. Tanako, K. Hiramatsu, Y. Kobayashi and H. Ohno,
Tetrahedron, 2005, 61, 6726.
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