Ring-Strain Effects in Base-Induced Sommelet–Hauser Rearrangement: Application to Successive Stereocontrolled Transformations

Article abstract of DOI:10.1002/ejoc.201600611

The base-induced Sommelet–Hauser (S–H) rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts into 2-aryl-substituted derivatives was demonstrated. The ring-strain of four-membered N-heterocycles enables efficient generation of the desired ylide intermediate and enhances the rate of the S–H rearrangement. The asymmetric version of the rearrangement was characterized by excellent levels of successive chirality transmissions. The regio- and stereo-controlled nucleophilic ring opening of the rearrangement products produced quaternary α-aryl amino acid esters with excellent enantiopurities.

Full text of DOI:10.1002/ejoc.201600611

DOI: 10.1002/ejoc.201600611
Full Paper
Ring-Strain Effect
Ring-Strain Effects in Base-Induced Sommelet–Hauser
Rearrangement: Application to Successive Stereocontrolled
Transformations
Eiji Tayama*[a] Kazutoshi Watanabe,[a] and Yoshihiro Matano[a]
Abstract: The base-induced Sommelet–Hauser (S–H) rear- sion of the rearrangement was characterized by excellent levels
rangement of azetidine-2-carboxylic acid ester-derived ammon- of successive chirality transmissions. The regio- and stereo-con-
ium salts into 2-aryl-substituted derivatives was demonstrated. trolled nucleophilic ring opening of the rearrangement prod-
The ring-strain of four-membered N-heterocycles enables effi- ucts produced quaternary α-aryl amino acid esters with excel-
cient generation of the desired ylide intermediate and en- lent enantiopurities.
hances the rate of the S–H rearrangement. The asymmetric ver-
Introduction
ium salt 1c was carried out under the same conditions, the S–
H rearrangement proceeded to afford the α-tolyl derivative 2c
exclusively.[8–10] The use of tBuONa did not give any rearrange-
ment products 2c or 3c. With these results in hand, we started
investigating this base-induced S–H rearrangement as a means
of producing 2-arylazetidine-2-carboxylic acid derivatives.[11]
The base-induced Sommelet–Hauser (S–H) rearrangement of
tetraalkylammonium salts[1,2] is an interesting transformation
enabling the conversion of a readily accessible C–N bond into
a new C–C bond in which one of the carbons is a component
of an aromatic ring.[3–6] However, the utility of this rearrange-
ment is severely limited because of the narrow substrate scope
and competition from several side reactions such as the [1,2]
Stevens rearrangement. In 2007, we reported a successful ex-
ample of the base-induced S–H rearrangement of N-benzylic
amino acid-derived ammonium salts accelerated by an elec-
tron-withdrawing substituent on the N-benzyl aromatic ring.[7e]
Our further investigations clarified the factors leading to en-
hanced rates of the S–H rearrangement. These factors include:
(i) an electron-deficient N-benzylic migrating group, (ii) a THF
solution of tBuOK as a base, and (iii) an amino acid amide-
derived ammonium salt as the substrate.[7] Although the syn-
thesis of various types of α-aryl amino acid derivatives via the
S–H rearrangement has been demonstrated by our group, the
discovery of further enhancement effects is still awaited to ex-
pand the synthetic scope and utility.
Very recently, we reported preliminary results on the base-
induced S–H rearrangement of N-benzyl cyclic amino acid-de-
rived ammonium salts 1a–c (Scheme 1).[3] Reactions of proline
and pipecolinic acid-derived ammonium salts 1a and 1b in THF
with tBuOK did not give S–H products 2a or 2b, instead, the
competitive [1,2] Stevens rearrangement produced α-benzyl-
ated 3a or 3b as a sole product, respectively. Remarkably, when
a reaction of azetidine-2-carboxylic acid ester-derived ammon-
Scheme 1. S–H vs. [1,2] rearrangements. Ring size effect in the base-induced
rearrangements of N-benzyl cyclic amino acid-derived ammonium salts 1.
Results and Discussion
[a] Department of Chemistry, Faculty of Science, Niigata University,
Niigata 950-2181, Japan
We first prepared various N-benzylic azetidine-2-carboxylic acid
ester-derived ammonium salts 1d–k and carried out reactions
using them as substrates (Table 1). Regardless of the electron-
withdrawing and -releasing groups at the para-position on the
N-benzylic substituent, S–H rearrangement products 2d–i were
E-mail: tayama@chem.sc.niigata-u.ac.jp
http://chem.sc.niigata-u.ac.jp/~tayama/english.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600611.
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obtained in approximately 80 % yield (Table 1, Entries 1–6). In methyl triflate.[14d] The S–H rearrangement of (1S,2S,1′S)-5 pro-
all cases, no detectable amounts of the [1,2] Stevens rearrange- ceeded with a perfect level N-to-C chirality transfer to afford
ment products were observed. When a reaction of meta-tolyl desired (R)-6 in 74 % yield with 99 % ee. The absolute configura-
ammonium salt 1j was examined under the same conditions, tions of 5 and 6 were tentatively assigned by analogy to 1d
2,4-dimethyl regioisomer 2j was obtained in 82 % yield without and 2d, as shown in Scheme 3. This result constitutes the first
the formation of any 2,6-dimethyl regioisomer (Table 1, Entry successful example of the S–H rearrangement of an N-α-
7). Similarly, the rearrangement of ortho-tolyl derivative 1k af- branched benzylic ammonium ylide.
forded 2,3-dimethyl derivative 2k in 83 % yield as the sole prod-
uct (Table 1, Entry 8).
Table 1. Base-induced S–H rearrangement of azetidine-2-carboxylic acid es-
ter-derived ammonium salts 1d–k.
Entry
R1
R2
R3
Product
Yield [%][a]
1
2
3
4
5
6
7
8
Br
F
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
2d
2e
2f
2g
2h
2i
78
82
80
83
74
80
82
83
Scheme 3. Asymmetric synthesis of α-arylazetidine-2-carboxylic acid esters
(S)-2 via S–H rearrangement. Conditions: (i) HCl, MeOH, 0 °C to room temp.,
(ii) H2, Pd-C, MeOH, room temp., (iii) ArCH2X (X = Cl or Br), KHCO3, MeCN,
room temp. to reflux.
CF3
CN
Me
OMe
H
2j
2k
H
Furthermore, replacement of the N-1-phenylethyl group, as
in (2R,1′S)-4, followed by an asymmetric S–H rearrangement
was examined (Scheme 3). The removal of the N-1-phenylethyl
group by hydrogenation followed by N-benzylation provided
7c–d in 58–83 % yield with 93–98 % ee. The absolute configura-
tion of 7d was determined to be R on the basis of comparisons
of the sign of the specific rotation value and the compound
HPLC retention time with those of authentic S-isomer (S)-7d
[a] Isolated yield.
This remarkable enhancement noted in the base-induced S–
H rearrangement encouraged us to examine the asymmetric
rearrangement involving N-to-C chirality transmission
(Scheme 2).[12] First, diastereomerically pure (2S,1′S)-4 was pre-
pared by the cyclization of (S)-1-phenylethylamine followed by
chromatographic separation.[13] N-Quaternization with methyl
triflate afforded salt (1S,2S,1′S)-5 as the only detectable dia-
stereomer.[14,15] The adjacent 2- and N-substituents, as in (2S,1′
S)-4, are in an equatorial position to avoid steric repulsive inter-
actions and the axial lone pair of the nitrogen atom reacts with
(94 % ee) prepared from commercially available L-azetidine-2-
carboxylic acid (Scheme 4). On the basis of this determination,
the absolute configurations of (2S,1′S)-4 and (2R,1′S)-4 depicted
in Scheme 2 were clarified. The N-quaternization of (R)-7c–d
with methyl triflate gave 1c–d in good yields as single dia-
stereomers, respectively.[14,15] The stereochemistry of 1d was
determined to be 1R,2R by single-crystal X-ray diffraction of
tetraphenylborate salt 1d-BPh4 prepared by ion exchange (Fig-
Scheme 4. Determination of the absolute configuration of 7d on the basis of
comparison of the specific rotation value sign with that of authentic (S)-7d
prepared from L-azetidine-2-carboxylic acid. Conditions: (i) benzyl chloro-
formate, NaOH, H2O, 0 °C to room temp., (ii) isobutene, H2SO4, CH2Cl2, room
temp., 72 % yield (2 steps) (iii) H2, Pd-C, EtOAc, room temp., (iv) 4-bromo-
benzyl chloride, NaHCO3, MeCN, reflux, 71 % yield (2 steps).
Scheme 2. Asymmetric base-induced S–H rearrangement of N-α-branched
benzylic ammonium salt (1S,2S,1′S)-5 via N-to-C chirality transmission.
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ure 1).[16] The exact reason is unclear at present, but when the Scheme 7 and Figure 2. The absolute configuration of 2c was
S–H rearrangement reactions of (1R,2R)-1c–d in THF were car- determined to be S by comparing its specific rotation value
ried out under the same conditions, yields of S–H rearrange- sign with that of authentic S-isomer sample prepared by the
ment products 2c–d were lowered (2c: 45 % yield, 2d: 62 % debromination of (S)-2d (Scheme 5).
yield). We tested various solvents and found that the use of 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) gave
sufficient yields. Desired compound 2c was obtained in 80 %
yield with 93 % ee from 96 % ee (R)-7c, and 2d was obtained in
87 % yield with 94 % ee from 98 % ee (R)-7d. In these transfor-
mations from (R)-7, 96–97 % N-to-C chirality transmissions were
achieved. The absolute configuration of 2d was confirmed to
be S after its conversion into compound 8 as described in
The question arises as to why the azetidine-2-carboxylic acid
ester-derived ammonium salts 1c undergo base-induced S–H
rearrangement with such remarkably enhanced yields of prod-
ucts 2c. Although the exact reason cannot be advanced at
present, it is safe to say that the carbanionic ylide form A, which
is in resonance with ammonium enolate form B, is generated
efficiently because of the ring-strain of the four-membered N-
heterocycle (Scheme 6).[17] Canonical form A would be desired
for the S–H rearrangement (concerted [2,3] sigmatropic rear-
rangement), which is known to proceed preferentially in a polar
solvent, such as liquid ammonia, DMSO, or HMPA, enabling sta-
bilization of a carbanion.[3,4] Canonical form B is destabilized by
the formation of a ring-strained sp2 α-carbon. Consequently,
the competitive [1,2] Stevens rearrangement from A and B into
3c via a radical cleavage–recombination process would be re-
stricted.
Figure 1. Determination of the absolute configuration of 1d by a single-crys-
tal X-ray diffraction of tetraphenylborate salt (1R,2R)-1d-BPh4 THF adduct.
Scheme 6. Proposition of ring-strain effect in S–H rearrangement.
To demonstrate the further synthetic application of S–H rear-
rangement products 2, nucleophilic ring opening reactions of
N,N-dimethylazetidinium salt 8 prepared from (S)-2d with
methyl triflate were examined in accord with previous work by
Couty and co-workers (Scheme 7).[14] The absolute configura-
Figure 2. Determination of the absolute configuration of 8 by a single-crystal
X-ray diffraction of tetraphenylborate salt (S)-8-BPh4.
Scheme 5. Determination of the absolute configuration of 2c by synthesis of
the authentic S-isomer sample (S)-2c from (S)-2d.
Scheme 7. Ring opening of (S)-8 at the 4-position.
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tion of 8 was directly confirmed to be S on the basis of single- R after debromination to 13 followed by partial N-methylation
crystal X-ray diffraction studies with tetraphenylborate salt (S)- to iodide salt 14; comparisons of the specific rotation sign for
8-BPh4 (Figure 2).[16] When (S)-8 was treated with cesium acet- this synthetically generated 14 to that of authentic (S)-14
ate or methylamine, azetidine ring opening proceeded exclu- (Scheme 9<yschr9 pos="x22">) revealed its configuration to be
sively at the less substituted 4-position to give corresponding R. Salt (S)-14 was synthesized from (S)-2c via the sequence of
α-aryl-γ-oxy-α-amino acid ester (S)-9 or α-aryl-α,γ-diamino acid N-quaternization to (2S)-15 with allyl triflate,[18] ring opening
ester (S)-10 in moderate yields, respectively.
to (S)-16 with dimethylamine at the 4-position, Pd-catalyzed
deallylation to (S)-17, and partial N-methylation. This fact clearly
shows that ring opening of (S)-8 with sodium azide proceeds
with inversion of configuration at the 2-position to form (R)-11
(Scheme 8).[14a,19]
On the other hand, ring opening of (S)-8 prepared from
95 % ee of (S)-2d with sodium azide proceeded exclusively at
the 2-position to yield α-aryl-α-azide-γ-amino acid ester 11
(Scheme 8). Similar regioselectivity (2- vs. 4-position) was re-
ported by Couty's group.[14a] Staudinger reaction of crude 11
afforded α-aryl-α,γ-diamino acid ester 12 in 68 % yield with
95 % ee. The absolute configuration of 12 was assigned to be
Conclusions
In conclusion, we report here successive stereocontrolled trans-
formations via the base-induced Sommelet–Hauser (S–H) rear-
rangement of azetidine-2-carboxylic acid ester-derived ammon-
ium salts to afford various types of α-aryl amino acid deriva-
tives. The transformations proceed with remarkably high levels
of stereoselective transmission; examples of which include: (i)
diastereoselective N-quaternization, (ii) excellent N-to-C chiral-
ity transmission, and (iii) regioselective nucleophilic ring open-
ing. The ring-strain of the four-membered N-heterocycle ena-
bles efficient generation of the desired carbanionic ylide inter-
mediate, and the rate of S–H rearrangement is enhanced. Al-
though the S–H rearrangement still has structural limitations
in that it requires the product to have an o-substituted aryl
component, the method provides efficient access to various
types of α-aryl amino acid derivatives. This study expands the
synthetic scope and utility of not only the S–H rearrangement
but also analogous sigmatropic rearrangements.
Scheme 8. Ring opening of (S)-8 by sodium azide with inversion of configura-
tion at the 2-position.
Experimental Section
General Methods: Infrared spectra (IR) were recorded with a Per-
1
kin–Elmer Spectrum GX FT-IR. H and 13C NMR spectra were meas-
ured with a Varian 400 MHz spectrometer (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 using a Thermo Fisher
Scientific LC/FT-MS spectrometer. Specific rotations were recorded
with 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 per-
formed using a Shimazu HPLC pump LC-20AT and a UV/Vis detector
SPD-20A. Reactions involving air- or moisture-sensitive compounds
were conducted in appropriate round-bottomed flasks with a mag-
netic stirring bar under an argon atmosphere. Tetrahydrofuran (THF)
was purchased from KANTO Chemical Co., Inc., Japan as an anhy-
drous solvent. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU) was purchased from Wako Pure Chemical Industries, Ltd.,
Japan and dried with 4Å molecular sieves. A 1.0
butoxide solution in THF were purchased from Tokyo Chemical In-
dustry (TCI) Co., Ltd., Japan. -Azetidine-2-carboxylic acid was pur-
M potassium tert-
L
chased from Watanabe Chemical Industries, Ltd., Japan. For thin
layer chromatography (TLC) analysis throughout this work, Merck
TLC plates (silica gel 60 F254) or Fuji Silysia Chemical TLC plates (NH,
Fuji Silysia Chemical Ltd., Japan) for strong basic compounds were
used. The products were purified by preparative column chroma-
Scheme 9. Determination of the absolute configuration of 12 by synthesis of
the S-authentic sample (S)-14 from (S)-2c. Conditions: (i) H2, Pd-C, EtOAc,
room temp., (ii) MeI, NaHCO3, room temp., (iii) allyl triflate, NaHCO3, CCl4/
CH2Cl2, 0 °C to room temp., (iv) Me2NH, THF/MeOH, room temp., (v) Pd(OAc)2,
PPh3, 1,3-dimethylbarbituric acid, CH2Cl2, reflux, (vi) MeI, MeCN, room temp.
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tography on silica gel (silica gel 60N, spherical neutral, KANTO
Chemical Co., Inc., Japan) or aminopropyl-modified silica gel (Chro-
NMR (100 MHz, CDCl3): δ = 170.1, 144.8, 132.4, 131.8, 129.5, 128.3,
119.6, 82.0, 75.3, 51.9, 39.6, 28.9, 28.1, 18.6 ppm. HRMS (ESI): calcd.
matorex NH–DM1020, Fuji Silysia Chemical Ltd., Japan) for strongly for C16H23BrNO2 [M + H]+ 340.0907, found 340.0895.
basic compounds.
tert-Butyl
2-(5-Fluoro-2-methylphenyl)-1-methylazetidine-2-
Representative Procedure for Base-induced S–H Rearrange-
ment (in THF): A 1.0 THF solution of potassium tert-butoxide
carboxylate (2e): White solid, m.p. 122–125 °C. IR (film): νmax
=
˜
M
3069, 2972, 2932, 2855, 2784, 1718, 1613, 1590, 1491, 1457, 1416,
1392, 1368, 1252, 1210, 1167, 1156, 1124, 1086, 1053, 1035, 979,
(1.64 mL, 1.64 mmol) was added to a solution of (1R,2R)-1d [671 mg,
1.37 mmol, prepared from 98 % ee of (R)-7d] in THF (12 mL) at 0 °C.
The mixture was stirred for 3 h at the same temperature under
an argon atmosphere. The resulting mixture was quenched with
saturated aqueous ammonium chloride and extracted with ethyl
acetate. The combined extracts were washed with saturated aque-
ous sodium hydrogen carbonate followed by brine. The solution
was dried with sodium sulfate and concentrated. Purification of the
residue by chromatography on silica gel (n-hexane/EtOAc = 30:1 to
15:1 as the eluent) gave (S)-2d (290 mg, 62 % yield) as a colorless
oil. The ee was determined to be 95 % ee by HPLC analysis [Daicel
Chiralpak IC column (25 cm), n-hexane/EtOAc = 99:1 as the eluent,
flow rate: 0.50 mL/min, tR = 8.3 min for (R)-2d (2.7 %) and 9.5 min
for (S)-2d (97.3 %)].
949, 878, 843, 811, 779, 750, 725 cm–1 1H NMR (400 MHz, CDCl3):
.
δ = 7.27 (dd, J = 10.4, 2.8 Hz, 1 H, ArH), 7.00 (dd, J = 8.2, 5.6 Hz, 1
H, ArH), 6.81 (ddd, J = 8.4, 8.2, 2.8 Hz, 1 H, ArH), 3.47 (ddd, J = 8.8,
6.2, 2.4 Hz, 1 H, 4-H), 3.32 (ddd, J = 8.8, 8.2, 6.2 Hz, 1 H, 4-H), 2.96
(ddd, J = 10.3, 8.2, 2.4 Hz, 1 H, 3-H), 2.47 (s, 3 H, NCH3), 2.12 (ddd,
J = 10.3, 8.8, 8.8 Hz, 1 H, 3-H), 2.03 (s, 3 H, ArCH3), 1.43 (s, 9 H,
tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 161.4 (d, J =
241 Hz), 144.9 (d, J = 7 Hz), 131.3 (d, J = 8 Hz), 128.8 (d, J = 3 Hz),
113.0 (d, J = 21 Hz), 112.4 (d, J = 23 Hz), 81.8, 75.3, 51.9, 39.6, 28.7,
28.0, 18.2 ppm. HRMS (ESI): calcd. for C16H23FNO2 [M + H]+
280.1707, found 280.1697.
tert-Butyl 1-Methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]azet-
idine-2-carboxylate (2f): White solid, m.p. 35–37 °C. IR (KBr): νmax
=
˜
Representative Procedure for Base-Induced S–H Rearrange-
2975, 2935, 2870, 2794, 1717, 1619, 1452, 1420, 1391, 1368, 1334,
1300, 1252, 1166, 1123, 1081, 996, 978, 947, 905, 835, 808, 774, 747,
ment (in DMPU): A 1.0
M THF solution of potassium tert-butoxide
729 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 1.3 Hz, 1 H,
.
(0.51 mL, 0.51 mmol) was added to a solution of (1R,2R)-1d [207 mg,
0.422 mmol, prepared from 98 % ee (R)-7d] in DMPU (3.7 mL) at
0 °C. The mixture was stirred for 3 h at the same temperature under
an argon atmosphere. Extractive workup and purification of the
residue by chromatography on silica gel (n-hexane/EtOAc = 100:0,
20:1, to 10:1 as the eluent) gave (S)-2d (125 mg, 87 % yield) as a
colorless oil. The ee was determined to be 94 % ee by HPLC analysis
[Daicel Chiralpak IC column (25 cm), n-hexane/EtOAc = 99:1 as the
eluent, flow rate: 0.50 mL/min, tR = 10.0 min for (R)-2d (3.2 %) and
12.3 min for (S)-2d (96.8 %)].
ArH), 7.39 (dd, J = 8.1, 1.3 Hz, 1 H, ArH), 7.17 (d, J = 8.1 Hz, 1 H,
ArH), 3.49 (ddd, J = 8.7, 6.1, 2.5 Hz, 1 H, 4-H), 3.35 (ddd, J = 8.8, 8.4,
6.1 Hz, 1 H, 4-H), 2.97 (ddd, J = 10.4, 8.4, 2.5 Hz, 1 H, 3-H), 2.48 (s,
3 H, NCH3), 2.13 (s, 3 H, ArCH3), 2.12 (ddd, J = 10.4, 8.8, 8.7 Hz, 1 H,
3-H), 1.43 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
143.5, 137.6, 130.5, 127.9 (q, J = 32 Hz), 124.6 (q, J = 270 Hz), 123.4
(q, J = 4 Hz), 122.3 (q, J = 4 Hz), 82.0, 75.3, 52.0, 39.6, 28.8, 28.0,
19.0 ppm. HRMS (ESI): calcd. for C17H23F3NO2 [M + H]+ 330.1675,
found 330.1664.
(S)-tert-Butyl 1-Methyl-2-(o-tolyl)azetidine-2-carboxylate [(S)-
2c]: Colorless crystals, m.p. 34–37 °C. [α]25849 = –151.2 (c = 1.0, EtOH).
93 % ee [determined by HPLC analysis: Daicel Chiralcel OJ-H column
(25 cm), n-hexane/2-PrOH = 99:1 as the eluent, flow rate: 0.50 mL/
min, tR = 8.7 min for (S)-2c (96.3 %) and 22.1 min for (R)-2c (3.7 %)].
tert-Butyl
2-(5-Cyano-2-methylphenyl)-1-methylazetidine-2-
carboxylate (2g): Colorless crystals, m.p. 118–121 °C. IR (KBr):
νmax = 2974, 2937, 2862, 2785, 2222, 1709, 1604, 1480, 1461, 1435,
˜
1392, 1369, 1255, 1199, 1159, 1120, 1085, 977, 948, 913, 837, 810,
777, 742 cm–1. H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 1.8 Hz, 1
1
IR (film): νmax = 3065, 2972, 2930, 2851, 2782, 1716, 1480, 1457,
˜
H, ArH), 7.44 (dd, J = 8.0, 1.8 Hz, 1 H, ArH), 7.17 (d, J = 8.0 Hz, 1 H,
ArH), 3.48 (ddd, J = 8.6, 6.0, 2.4 Hz, 1 H, 4-H), 3.36 (ddd, J = 8.6, 8.2,
6.0 Hz, 1 H, 4-H), 2.97 (ddd, J = 10.3, 8.2, 2.4 Hz, 1 H, 3-H), 2.47 (s,
3 H, NCH3), 2.14 (s, 3 H, ArCH3), 2.10 (ddd, J = 10.3, 8.6, 8.6 Hz, 1 H,
3-H), 1.43 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.6,
144.1, 139.3, 130.8, 130.3, 129.3, 119.5, 109.5, 82.3, 75.0, 51.9, 39.5,
28.6, 28.0, 19.3 ppm. HRMS (ESI): calcd. for C17H23N2O2 [M + H]+
287.1754, found 287.1745.
1391, 1367, 1288, 1254, 1164, 1125, 1086, 1061, 1037, 975, 950, 908,
845, 823, 762, 746 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.51 (dd,
.
J = 7.4, 1.0 Hz, 1 H, ArH), 7.20 (ddd, J = 7.4, 7.4, 1.0 Hz, 1 H, ArH),
7.13 (ddd, J = 7.4, 7.4, 1.0 Hz, 1 H, ArH), 7.06 (ddd, J = 7.4, 1.0,
1.0 Hz, 1 H, ArH), 3.48 (ddd, J = 8.6, 6.0, 2.4 Hz, 1 H, 4-H), 3.33 (ddd,
J = 8.8, 8.0, 6.0 Hz, 1 H, 4-H), 2.96 (ddd, J = 10.5, 8.0, 2.4 Hz, 1 H, 3-
H), 2.49 (s, 3 H, NCH3), 2.16 (ddd, J = 10.5, 8.8, 8.6 Hz, 1 H, 3-H), 2.08
(s, 3 H, ArCH3), 1.42 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.6, 142.5, 133.3, 130.1, 126.5, 125.5, 125.0, 81.5, 75.7, 52.1,
39.9, 29.0, 28.1, 19.0 ppm. HRMS (ESI): calcd. for C16H24NO2 [M +
H]+ 262.1802, found 262.1793.
tert-Butyl
2-(2,5-Dimethylphenyl)-1-methylazetidine-2-carb-
oxylate (2h): Colorless crystals, m.p. 38–40 °C. IR (KBr): νmax = 2964,
˜
2931, 2861, 2832, 2777, 1713, 1613, 1496, 1457, 1390, 1366, 1295,
1266, 1253, 1198, 1158, 1119, 1085, 1034, 971, 945, 893, 845, 807,
774, 748, 724 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.30 (s, 1 H, ArH),
6.95 (d, J = 7.5 Hz, 1 H, ArH), 6.93 (d, J = 7.5 Hz, 1 H, ArH), 3.48
(ddd, J = 8.5, 6.0, 2.6 Hz, 1 H, 4-H), 3.33 (ddd, J = 8.8, 8.2, 6.0 Hz, 1
H, 4-H), 2.95 (ddd, J = 10.4, 8.2, 2.6 Hz, 1 H, 3-H), 2.50 (s, 3 H, NCH3),
2.34 (s, 3 H, ArCH3), 2.15 (ddd, J = 10.4, 8.8, 8.5 Hz, 1 H, 3-H), 2.03
(s, 3 H, ArCH3), 1.44 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.6, 142.2, 134.8, 130.15, 130.11, 127.2, 125.6, 81.5, 75.8, 52.1,
40.0, 29.2, 28.1, 21.2, 18.6 ppm. HRMS (ESI): calcd. for C17H26NO2 [M
+ H]+ 276.1958, found 276.1952.
(S)-tert-Butyl 2-(5-Bromo-2-methylphenyl)-1-methylazetidine-2-
20
carboxylate [(S)-2d]: Colorless oil. [α]
= –153.0 (c = 1.0, EtOH).
589
95 % ee [determined by HPLC analysis: Daicel Chiralpak IC column
(25 cm), n-hexane/EtOAc = 99:1 as the eluent, flow rate: 0.50 mL/
min, tR = 8.3 min for (R)-2d (2.7 %) and 9.5 min for (S)-2d (97.3 %)].
IR (film): νmax = 3062, 2972, 2930, 2855, 2784, 1717, 1592, 1567,
˜
1477, 1456, 1392, 1367, 1254, 1236, 1162, 1121, 1085, 1055, 1034,
976, 947, 913, 890, 844, 800, 776, 753, 719 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.66 (d, J = 2.4 Hz, 1 H, ArH), 7.25 (dd, J = 8.0, 2.4 Hz, 1
H, ArH), 6.93 (d, J = 8.0 Hz, 1 H, ArH), 3.47 (ddd, J = 8.8, 6.0, 2.6 Hz,
1 H, 4-H), 3.32 (ddd, J = 8.6, 8.2, 6.0 Hz, 1 H, 4-H), 2.94 (ddd, J =
10.5, 8.2, 2.6 Hz, 1 H, 3-H), 2.46 (s, 3 H, NCH3), 2.10 (ddd, J = 10.5,
tert-Butyl 2-(5-Methoxy-2-methylphenyl)-1-methylazetidine-2-
carboxylate (2i): Colorless crystals, m.p. 50–53 °C. IR (film): νmax
2969, 2931, 2853, 2782, 1715, 1609, 1579, 1496, 1457, 1422, 1392,
=
˜
8.8, 8.6 Hz, 1 H, 3-H), 2.02 (s, 3 H, ArCH3), 1.43 (s, 9 H, tBu) ppm. 13
C
Eur. J. Org. Chem. 0000, 0–0
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5 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1367, 1302, 1252, 1217, 1193, 1160, 1120, 1086, 1042, 976, 948, 931,
865, 844, 811, 778, 754, 718 cm–1 1H NMR (400 MHz, CDCl3): δ =
tert-Butyl 1-[(S)-1′-Phenylethyl]azetidine-2-carboxylate [(2S,1′
S)-4 and (2R,1′S)-4]: A mixture of (S)-1-phenylethylamine (400 μL,
3.10 mmol), tert-butyl 2,4-dibromobutanoate (937 mg, 3.10 mmol),
and potassium carbonate (1.29 g, 9.3 mmol) in acetonitrile (16 mL)
was refluxed for 6 h. The resulting mixture was cooled to room
temperature followed by filtered. The filtrate was evaporated and
the residue was purified by chromatography on silica gel (n-hexane/
EtOAc = 7:1 to 4:1 as the eluent) to yield (2S,1′S)-4 (261 mg, 32 %
.
7.14 (d, J = 2.9 Hz, 1 H, ArH), 6.97 (d, J = 8.1 Hz, 1 H, ArH), 6.68 (dd,
J = 8.1, 2.9 Hz, 1 H, ArH), 3.81 (s, 3 H, OCH3), 3.47 (ddd, J = 8.6, 6.0,
2.4 Hz, 1 H, 4-H), 3.31 (ddd, J = 8.8, 8.2, 6.0 Hz, 1 H, 4-H), 2.95 (ddd,
J = 10.4, 8.2, 2.4 Hz, 1 H, 3-H), 2.47 (s, 3 H, NCH3), 2.13 (ddd, J =
10.4, 8.8, 8.6 Hz, 1 H, 3-H), 2.01 (s, 3 H, ArCH3), 1.43 (s, 9 H, tBu) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.4, 157.7, 143.9, 131.0, 125.4,
111.45, 111.39, 81.6, 75.6, 55.2, 52.0, 39.8, 28.9, 28.1, 18.1 ppm.
HRMS (ESI): calcd. for C17H26NO3 [M + H]+ 292.1907, found 292.1899.
yield) as a colorless oil and (2R,1′S)-4 (270 mg, 33 % yield) as a
22
colorless oil. (2S,1′S)-4: [α]
= –111.1 (c = 1.0, EtOH). IR (film):
589
νmax = 3061, 3025, 3003, 2973, 2930, 2869, 2837, 2779, 1742, 1718,
˜
tert-Butyl
2-(2,4-Dimethylphenyl)-1-methylazetidine-2-carb-
1493, 1478, 1453, 1391, 1366, 1319, 1284, 1232, 1213, 1152, 1101,
oxylate (2j): Colorless crystals, m.p. 63–66 °C. IR (KBr): νmax = 2970,
2929, 2850, 2828, 2777, 1714, 1496, 1451, 1392, 1367, 1291, 1256,
˜
1
1071, 1042, 1031, 975, 945, 847, 763, 701 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.36–7.27 (m, 4 H, Ph), 7.22 (dddd, J = 7.4, 6.6, 1.6,
1.6 Hz, 1 H, Ph), 3.62 (dd, J = 8.6, 8.2 Hz, 1 H, 2-H), 3.43 (q, J =
6.6 Hz, 1 H, 1′-H), 3.08 (dddd, J = 8.4, 7.0, 2.8, 0.8 Hz, 1 H, 4-H), 2.73
(ddd, J = 8.9, 8.2, 7.0 Hz, 1 H, 4-H), 2.21 (dddd, J = 10.6, 8.9, 8.6,
8.4 Hz, 1 H, 3-H), 2.12 (dddd, J = 10.6, 8.2, 8.2, 2.8 Hz, 1 H, 3-H), 1.48
(s, 9 H, tBu), 1.23 (d, J = 6.6 Hz, 3 H, 1′-CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.5, 142.9, 128.2, 127.4, 127.0, 80.6, 67.3, 64.8, 49.5,
28.0, 21.2, 20.7 ppm. HRMS (ESI): calcd. for C16H24NO2 [M + H]+
1193, 1162, 1123, 1084, 1054, 1034, 977, 944, 920, 902, 872, 839,
1
812, 768, 750, 721 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38 (d, J =
7.8 Hz, 1 H, ArH), 7.00 (d, J = 7.8 Hz, 1 H, ArH), 6.88 (s, 1 H, ArH),
3.47 (ddd, J = 8.5, 6.1, 2.4 Hz, 1 H, 4-H), 3.32 (ddd, J = 8.8, 8.2,
6.1 Hz, 1 H, 4-H), 2.94 (ddd, J = 10.5, 8.2, 2.4 Hz, 1 H, 3-H), 2.48 (s,
3 H, NCH3), 2.29 (s, 3 H, ArCH3), 2.13 (ddd, J = 10.5, 8.8, 8.5 Hz, 1 H,
3-H), 2.04 (s, 3 H, ArCH3), 1.43 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.7, 139.7, 135.9, 133.1, 131.0, 126.1, 125.0, 81.5, 75.6,
52.1, 39.9, 29.2, 28.1, 20.9, 19.0 ppm. HRMS (ESI): calcd. for
C17H26NO2 [M + H]+ 276.1958, found 276.1950.
22
262.1802, found 262.1794. (2R,1′S)-4: [α] = +56.8 (c = 1.0, EtOH).
589
IR (film): νmax = 3062, 3026, 3003, 2973, 2930, 2870, 2827, 2784,
˜
1735, 1493, 1477, 1453, 1391, 1366, 1302, 1276, 1233, 1208, 1153,
1114, 1081, 1057, 1030, 1012, 975, 947, 846, 762, 700 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.34–7.29 (m, 2 H, Ph), 7.26 (dddd, J = 7.2,
7.2, 1.6, 1.6 Hz, 2 H, Ph), 7.20 (tt, J = 7.2, 1.6 Hz, 1 H, Ph), 3.54 (dddd,
J = 8.2, 6.6, 2.6, 0.6 Hz, 1 H, 4-H), 3.50 (dd, J = 8.2, 8.2 Hz, 1 H, 2-H),
3.36 (q, J = 6.6 Hz, 1 H, 1′-H), 2.96 (ddd, J = 9.2, 8.2, 6.6 Hz, 1 H, 4-
H), 2.22 (dddd, J = 10.5, 9.2, 8.2, 8.2 Hz, 1 H, 3-H), 2.11 (dddd, J =
10.5, 8.2, 8.2, 2.6 Hz, 1 H, 3-H), 1.26 (d, J = 6.6 Hz, 3 H, 1′-CH3), 1.17
(s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.6, 142.2, 128.2,
128.1, 127.3, 80.1, 68.0, 65.4, 50.7, 27.7, 20.8, 20.0 ppm. HRMS (ESI):
calcd. for C16H24NO2 [M + H]+ 262.1802, found 262.1792.
tert-Butyl
2-(2,3-Dimethylphenyl)-1-methylazetidine-2-carb-
oxylate (2k): Colorless crystals, m.p. 47–50 °C. IR (film): νmax = 3064,
3004, 2971, 2930, 2851, 2781, 1717, 1589, 1469, 1458, 1391, 1367,
˜
1279, 1246, 1209, 1201, 1164, 1126, 1085, 1035, 1013, 973, 950, 911,
846, 819, 783, 742, 725 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.38
.
(d, J = 7.8 Hz, 1 H, ArH), 7.11 (dd, J = 7.8, 7.2 Hz, 1 H, ArH), 7.03 (d,
J = 7.2 Hz, 1 H, ArH), 3.47 (ddd, J = 8.6, 6.0, 2.5 Hz, 1 H, 4-H), 3.33
(ddd, J = 8.9, 8.2, 6.0 Hz, 1 H, 4-H), 2.97 (ddd, J = 10.5, 8.2, 2.5 Hz,
1 H, 3-H), 2.48 (s, 3 H, NCH3), 2.24 (s, 3 H, ArCH3), 2.16 (ddd, J =
10.5, 8.9, 8.6 Hz, 1 H, 3-H), 1.95 (s, 3 H, ArCH3), 1.43 (s, 9 H, tBu) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.8, 142.6, 136.4, 131.8, 128.3,
125.1, 123.0, 81.4, 76.0, 51.9, 39.8, 29.5, 28.1, 20.2, 15.3 ppm. HRMS
(ESI): calcd. for C17H26NO2 [M + H]+ 276.1958, found 276.1950.
(1S,2S,1′S)-2-(tert-Butoxycarbonyl)-1-methyl-1-(1′-phenylethyl)-
azetidin-1-ium Trifluoromethanesulfonate [(1S,2S,1′S)-5]: A mix-
ture of (2S,1′S)-4 (447 mg, 1.71 mmol) and sodium hydrogen carb-
onate (0.43 g, 5.1 mmol) in dichloromethane (8.6 mL) was treated
with methyl trifluoromethanesulfonate (387 μL, 3.42 mmol) at 0 °C
and stirred for 1 h at room temperature. The resulting mixture was
evaporated to about 1/2 to 1/3 volume and purified by chromatog-
(R)-tert-Butyl 2-Benzyl-1-methylpyrrolidine-2-carboxylate [(R)-
3a]:[12e] Colorless oil. [α]
= +4.6 (c = 1.0, EtOH). 54 % ee [deter-
22
589
mined by HPLC analysis: Daicel Chiralpak AD-RH column (15 cm),
H2O/MeCN = 60:40 as the eluent, flow rate: 0.50 mL/min, tR
37.8 min for (S)-3a (22.8 %) and 42.1 min for (R)-3a (77.2 %)]. IR
=
raphy on silica gel (CH2Cl2/MeOH = 15:1 to 7:1 as the eluent) to
22
(film): νmax = 3085, 3061, 3027, 2974, 2935, 2844, 2792, 1717, 1604,
afford (1S,2S,1′S)-5 (635 mg, 87 % yield) as a colorless gum. [α]
=
˜
589
1495, 1475, 1453, 1391, 1366, 1304, 1251, 1213, 1158, 1098, 1058,
–26.2 (c = 1.0, EtOH). IR (KBr): νmax = 3059, 2983, 1736, 1630, 1499,
˜
1031, 1002, 941, 879, 849, 763, 736, 700 cm–1 1H NMR (400 MHz,
.
1459, 1421, 1397, 1372, 1274, 1258, 1225, 1156, 1031, 993, 971, 934,
1
881, 839, 773, 756, 708 cm–1. H NMR (400 MHz, CDCl3): δ = 7.60–
CDCl3): δ = 7.25–7.16 (m, 5 H, Ph), 3.28 (d, J = 13.4 Hz, 1 H, CH2Ph),
3.03 (ddd, J = 8.8, 8.8, 2.8 Hz, 1 H, 5-H), 2.68–2.57 (m, 1 H, 5-H), 2.65
(d, J = 13.4 Hz, 1 H, CH2Ph), 2.46 (s, 3 H, NCH3), 2.06–1.93 (m, 1 H,
CH2), 1.81–1.68 (m, 2 H, CH2), 1.68–1.55 (m, 1 H, CH2), 1.45 (s, 9 H,
tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0, 138.1, 130.4, 127.7,
126.1, 80.9, 71.4, 54.4, 40.4, 35.4, 33.7, 28.4, 21.5 ppm. HRMS (ESI):
calcd. for C17H26NO2 [M + H]+ 276.1958, found 276.1951.
7.53 (m, 2 H, Ph), 7.50–7.42 (m, 3 H, Ph), 5.59 (dd, J = 9.8, 9.8 Hz, 1
H, 2-H), 5.28 (q, J = 7.0 Hz, 1 H, 1′-H), 4.90 (ddd, J = 10.0, 10.0,
9.7 Hz, 1 H, 4-H), 3.29 (ddd, J = 9.7, 9.7, 3.4 Hz, 1 H, 4-H), 3.01 (s, 3
H, NCH3), 2.96–2.75 (m, 2 H, 3-H), 1.75 (d, J = 7.0 Hz, 3 H, 1′-CH3),
1.54 (s, 9 H, tBu) ppm. 13C NMR (100 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 ppm. HRMS (ESI): calcd. for C17H26NO2 [M–OTf]+
276.1958, found 276.1948.
tert-Butyl 2-Benzyl-1-methylpiperidine-2-carboxylate (3b):[7a]
Pale yellow oil. IR (film): νmax = 3087, 3063, 3028, 2975, 2934, 2867,
˜
2806, 2718, 1715, 1605, 1496, 1455, 1392, 1367, 1291, 1249, 1147,
(R)-tert-Butyl 2-(2-Ethylphenyl)-1-methylazetidine-2-carboxyl-
1103, 1033, 995, 905, 848, 775, 752, 734, 699 cm–1
.
1H NMR ate [(R)-6]: Colorless oil. [α]
= +159.9 (c = 1.0, EtOH). 99 % ee
23
589
(400 MHz, CDCl3): δ = 7.28–7.17 (m, 5 H, Ph), 3.28 (d, J = 13.4 Hz, 1
H, CH2Ph), 2.82 (d, J = 13.4 Hz, 1 H, CH2Ph), 2.73–2.58 (m, 2 H, 6-H),
2.63 (s, 3 H, NCH3), 1.76–1.66 (m, 1 H, CH2), 1.59–1.50 (m, 4 H, CH2),
1.48 (s, 9 H, tBu), 1.37–1.24 (m, 1 H, CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.9, 137.1, 130.7, 127.7, 126.3, 81.0, 66.2, 52.1, 42.9,
[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)-6 (99.5 %) and 9.6 min for (S)-6 (0.5 %)]. IR (film):
ν
= 3065, 2971, 2931, 2852, 2782, 1714, 1481, 1454, 1391, 1367,
˜
max
1253, 1196, 1164, 1121, 1086, 1045, 1029, 975, 952, 908, 845, 822,
39.7, 33.0, 28.4, 25.6, 21.3 ppm. HRMS (ESI): calcd. for C18H28NO2 [M 760 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.48 (m, 1 H, ArH),
+ H]+ 290.2115, found 290.2112.
7.23–7.14 (m, 3 H, ArH), 3.48 (ddd, J = 8.5, 6.0, 2.4 Hz, 1 H, 4-H),
Eur. J. Org. Chem. 0000, 0–0
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3.34 (ddd, J = 8.9, 8.2, 6.0 Hz, 1 H, 4-H), 2.93 (ddd, J = 10.5, 8.2,
2.4 Hz, 1 H, 3-H), 2.49 (s, 3 H, NCH3), 2.355 (q, J = 7.4 Hz, 1 H,
ArCH2CH3), 2.351 (q, J = 7.4 Hz, 1 H, ArCH2CH3), 2.19 (ddd, J = 10.5,
8.9, 8.5 Hz, 1 H, 3-H), 1.42 (s, 9 H, tBu), 1.19 (dd, J = 7.4, 7.4 Hz, 3 H,
ArCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8, 142.0, 139.3,
127.6, 126.7, 125.4, 125.1, 81.6, 75.7, 52.2, 39.9, 29.8, 28.1, 24.3,
14.5 ppm. HRMS (ESI): calcd. for C17H26NO2 [M + H]+ 276.1958,
found 276.1949.
682 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42 (ddd, J = 8.6, 2.2,
2.2 Hz, 2 H, ArH), 7.19 (ddd, J = 8.6, 2.2, 2.2 Hz, 2 H, ArH), 3.77 (d,
J = 12.8 Hz, 1 H, CH2Ar), 3.60 (ddd, J = 8.4, 8.2, 0.6 Hz, 1 H, 2-H),
3.49 (d, J = 12.8 Hz, 1 H, CH2Ar), 3.27 (dddd, J = 8.2, 6.6, 2.5, 0.6 Hz,
1 H, 4-H), 2.86 (ddd, J = 9.2, 8.0, 6.6 Hz, 1 H, 4-H), 2.31 (dddd, J =
10.5, 9.2, 8.4, 8.2 Hz, 1 H, 3-H), 2.16 (dddd, J = 10.5, 8.2, 8.0, 2.5 Hz,
1 H, 3-H), 1.41 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.8, 136.5, 131.3, 130.7, 121.0, 80.8, 65.2, 61.8, 50.7, 28.0,
21.4 ppm. HRMS (ESI): calcd. for C15H21BrNO2 [M + H]+ 326.0750,
found 326.0737.
(R)-tert-Butyl 1-Benzylazetidine-2-carboxylate [(R)-7c]: A solu-
tion of (2R,1′S)-4 (706 mg, 2.70 mmol) in methanol (13.5 mL) was
treated with approx. 4
M hydrogen chloride in cyclopentyl methyl
(1R,2R)-1-Benzyl-2-(tert-butoxycarbonyl)-1-methylazetidin-1-
ium Trifluoromethanesulfonate [(1R,2R)-1c]: A mixture of (R)-7c
(402 mg, 1.63 mmol, 96 % ee) and sodium hydrogen carbonate
(0.41 g, 4.9 mmol) in dichloromethane (8.2 mL) was treated with
methyl trifluoromethanesulfonate (222 μL, 1.96 mmol) at 0 °C and
stirred for 1 h at room temperature. The resulting mixture was evap-
orated to about 1/2 to 1/3 volume and purified by chromatography
on silica gel (CH2Cl2/MeOH = 20:1 to 10:1 as the eluent) to yield
ether (CPME) (0.81 mL, 3.24 mmol) at 0 °C. After stirring for 30 min
at room temperature, the solution was evaporated. A mixture of the
residue and palladium on activated carbon (loading: 10 wt.-%,
0.15 g) in methanol (13.5 mL) was stirred at room temperature for
2.5 days under a hydrogen atmosphere. The resulting mixture was
filtered through a pad of Celite and the filtrate was concentrated.
A mixture of the residual oil, benzyl bromide (321 μL, 2.70 mmol),
and potassium hydrogen carbonate (1.35 g, 13.5 mmol) in aceto-
nitrile (13.5 mL) was stirred for 1 h at room temperature and re-
fluxed for 0.5 h. The resulting mixture was cooled to room tempera-
ture and filtered. The filtrate was concentrated and the residue was
purified by chromatography on silica gel (CH2Cl2/EtOAc = 20:1 to
10:1 as the eluent) to render (R)-7c (555 mg, 83 % yield) as a color-
less oil. (R)-7c was obtained mainly in the range of 70–83 % yield
(1R,2R)-1c (666 mg, 99 % yield) as colorless crystals, m.p. 91–94 °C.
22
[α]
= +27.3 (c = 1.0, EtOH). IR (film): νmax = 3044, 2982, 2935,
˜
589
1730, 1461, 1395, 1371, 1265, 1225, 1153, 1030, 977, 932, 882, 835,
757, 729, 707 cm–1. H NMR (400 MHz, CDCl3): δ = 7.56–7.39 (m, 5
1
H, Ph), 5.54 (dd, J = 9.8, 9.3 Hz, 1 H, 2-H), 4.77 (ddd, J = 9.8, 9.8,
9.3 Hz, 1 H, 4-H), 4.75 (d, J = 13.0 Hz, 1 H, CH2Ph), 4.65 (d, J =
13.0 Hz, 1 H, CH2Ph), 3.83 (ddd, J = 9.8, 9.8, 3.0 Hz, 1 H, 4-H), 3.11
(s, 3 H, NCH3), 2.96 (dddd, J = 12.1, 9.8, 9.8, 9.8 Hz, 1 H, 3-H), 2.72
20
with 93–96 % ee. [α] = +76.1 (c = 1.0, EtOH). 96 % ee [determined
589
(dddd, J = 12.1, 9.3, 9.3, 3.0 Hz, 1 H, 3-H), 1.39 (s, 9 H, tBu) ppm. 13
C
by HPLC analysis: Daicel Chiralcel OJ-H column (25 cm), n-hexane/
2-PrOH = 99:1 as the eluent, flow rate: 0.50 mL/min, tR = 12.7 min
for (R)-7c (98.2 %) and 13.8 min for (S)-7c (1.8 %)]. IR (film): νmax
NMR (100 MHz, CDCl3): δ = 163.2, 131.7, 130.5, 129.2, 127.2, 120.5
(q, J = 319 Hz), 85.4, 70.3, 67.8, 61.6, 44.2, 27.4, 18.3 ppm. HRMS
(ESI): calcd. for C16H24NO2 [M–OTf]+ 262.1802, found 262.1795.
=
˜
3085, 3062, 3027, 3004, 2975, 2932, 2829, 2702, 1735, 1604, 1494,
1477, 1453, 1391, 1366, 1295, 1238, 1157, 1096, 1052, 1021, 979,
941, 847, 797, 784, 737, 702 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
(1R,2R)-1-(4-Bromobenzyl)-2-(tert-butoxycarbonyl)-1-methyl-
azetidin-1-ium Trifluoromethanesulfonate [(1R,2R)-1d]: Pre-
7.35–7.20 (m, 5 H, Ph), 3.83 (d, J = 12.6 Hz, 1 H, CH2Ph), 3.62 (ddd,
J = 8.4, 8.2, 0.6 Hz, 1 H, 2-H), 3.54 (d, J = 12.6 Hz, 1 H, CH2Ph), 3.28
(dddd, J = 8.4, 6.6, 2.4, 0.6 Hz, 1 H, 4-H), 2.88 (ddd, J = 9.3, 7.9,
6.6 Hz, 1 H, 4-H), 2.32 (dddd, J = 10.4, 9.3, 8.4, 8.4 Hz, 1 H, 3-H), 2.14
pared in 94 % yield from (R)-7d (96 % ee) by the same procedure
23
with (1R,2R)-1c. Colorless gum. [α]
= +23.5 (c = 1.0, EtOH). IR
589
(KBr): νmax = 3049, 2983, 2935, 1736, 1595, 1492, 1468, 1412, 1396,
˜
(dddd, J = 10.4, 8.2, 7.9, 2.4 Hz, 1 H, 3-H), 1.41 (s, 9 H, tBu) ppm. 13
C
1371, 1325, 1263, 1225, 1155, 1074, 1031, 1013, 979, 936, 885, 829,
787, 757, 725 cm–1. 1H NMR (400 MHz, [D6]acetone): δ = 7.72 (d, J =
8.8 Hz, 2 H, ArH), 7.69 (d, J = 8.8 Hz, 2 H, ArH), 5.72 (dd, J = 9.8,
9.8 Hz, 1 H, 2-H), 4.92–4.80 (m, 1 H, 4-H), 4.86 (s, 2 H, CH2Ar), 4.07
(ddd, J = 9.8, 9.8, 3.6 Hz, 1 H, 4-H), 3.34 (s, 3 H, NCH3), 3.15 (dddd,
J = 12.0, 9.8, 9.8, 9.8 Hz, 1 H, 3-H), 2.78–2.65 (m, 1 H, 3-H), 1.44 (s,
9 H, tBu) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 164.5, 135.3,
133.3, 128.5, 125.6, 122.3 (q, J = 320 Hz), 85.9, 71.7, 67.9, 62.9, 45.5,
27.9, 19.3 ppm. HRMS (ESI): calcd. for C16H23BrNO2 [M–OTf ]+
340.0907, found 340.0893.
NMR (100 MHz, CDCl3): δ = 171.9, 137.4, 129.1, 128.3, 127.1, 80.7,
65.1, 62.5, 50.6, 28.0, 21.4 ppm. HRMS (ESI): calcd. for C15H22NO2 [M
+ H]+: 248.1645, found 248.1640.
(R)-tert-Butyl 1-(4-Bromobenzyl)azetidine-2-carboxylate [(R)-
7d]: A solution of (2R,1′S)-4 (268 mg, 1.03 mmol) in methanol
(5.0 mL) was treated with approx. 4
pentyl methyl ether (CPME) (0.31 mL, 1.24 mmol) at 0 °C. After
stirring for 30 min at room temperature, the solution was evapo-
rated. A mixture of the residue and palladium on activated carbon
(loading: 10 wt.-%, 55 mg) in methanol (5.0 mL) was stirred at room
M hydrogen chloride in cyclo-
Synthesis of (S)-tert-Butyl 1-(4-Bromobenzyl)azetidine-2-carb-
temperature for 3 d under a hydrogen atmosphere. The resulting oxylate [(S)-7d] from
L
-Azetidine-2-carboxylic Acid: (Step 1) A
-azetidine-2-carboxylic acid (490 mg, 4.85 mmol) and
sodium hydroxide (388 mg, 9.70 mmol) in water (4.9 mL) was
mixture was filtered through a pad of Celite and the filtrate was
solution of L
concentrated. A mixture of the residual oil, 4-bromobenzyl chloride
(212 mg, 1.03 mmol), and potassium hydrogen carbonate (0.52 g, treated with benzyl chloroformate (0.73 mL, 5.1 mmol) at 0 °C. After
5.2 mmol) in acetonitrile (5.2 mL) was refluxed for 6 h. The resulting
mixture was cooled to room temperature and filtered. The filtrate
was concentrated and the residue was purified by chromatography
on silica gel (CH2Cl2/EtOAc = 15:1 to 10:1 as the eluent) to afford
(R)-7d (224 mg, 67 % yield) as colorless crystals. (R)-7d was obtained
stirring for 1 h at 0 °C and for 1 h at room temperature, the resulting
aqueous mixture was washed with diethyl ether. The aqueous solu-
tion was acidified with 4
M hydrochloric acid and extracted with
ethyl acetate. The combined organic extracts were washed with
water followed by brine, dried with sodium sulfate, and the solvents
evaporated. A solution of the residue in dichloromethane (10 mL)
mainly in the range of 58–79 % yield with 96–98 % ee, m.p. 32–
24
34 °C (96 % ee). [α] = +56.6 (c = 1.0, EtOH). 96 % ee [determined was treated with sulfonic acid (0.05 mL) and isobutene (excess) at
589
by HPLC analysis: Daicel Chiralpak AD-H column (25 cm), n-hexane/
EtOH = 95:5 as the eluent, flow rate: 0.50 mL/min, tR = 8.4 min for
room temperature. The resulting solution was stirred for 11 h at
room temperature. The resulting mixture was treated with saturated
aqueous sodium hydrogen carbonate and extracted with ethyl acet-
ate. The combined extracts were washed brine, dried with sodium
(R)-7d (98.0 %) and 9.2 min for (S)-7d (2.0 %)]. IR (film): νmax = 3002,
˜
2974, 2931, 2829, 1734, 1591, 1485, 1452, 1400, 1391, 1365,
1294, 1239, 1154, 1095, 1068, 1011, 979, 940, 845, 814, 791, 744, sulfate, and concentrated. Purification of the residue by chromatog-
Eur. J. Org. Chem. 0000, 0–0
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7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
raphy on silica gel (n-hexane/EtOAc = 4:1 to 3:1 as the eluent) gave
ture of (S)-2d (182 mg, 0.535 mmol, 93 % ee) and sodium hydrogen
(S)-1-benzyl 2-tert-butyl azetidine-1,2-dicarboxylate[20] (1.02 g, 72 % carbonate (135 mg, 1.61 mmol) in dichloromethane (2.7 mL) was
yield) as a colorless oil. (Step 2) A mixture of the product (439 mg,
1.51 mmol) and palladium on activated carbon (loading: 10 wt.-%,
34 mg) in ethyl acetate (8.0 mL) was stirred for 12 h at room temper-
ature under a hydrogen atmosphere. The resulting mixture was fil-
treated with methyl trifluoromethanesulfonate (121 μL, 1.07 mmol)
at 0 °C and stirred for 1 h at room temperature. The resulting mix-
ture was evaporated to approx. 1/2 to 1/3 volume and purified by
chromatography on silica gel (CH2Cl2/MeOH = 15:1 to 6:1 as the
tered through a pad of Celite and the filtrate was concentrated. A eluent) to render (S)-8 (237 mg, 88 % yield) as a white amorphous.
23
mixture of the residue, 4-bromobenzyl chloride (0.33 g, 1.6 mmol), [α]
and sodium hydrogen carbonate (0.40 g, 4.8 mmol) in acetonitrile
(8.0 mL) was refluxed for 6 h. The resulting mixture was cooled to
= +17.2 (c = 1.0, CHCl3). IR (KBr): νmax = 2981, 2935, 1733,
˜
589
1483, 1469, 1396, 1373, 1274, 1261, 1225, 1146, 1095, 1075, 1031,
974, 942, 894, 857, 832, 809, 791, 767, 734, 694 cm–1 1H NMR
.
room temperature and filtered. The filtrate was concentrated and (400 MHz, CDCl3): δ = 7.51 (dd, J = 8.2, 2.0 Hz, 1 H, ArH), 7.48 (br.
the residue was purified by chromatography on silica gel (n-hexane/
s, 1 H, ArH), 7.18 (d, J = 8.2 Hz, 1 H, ArH), 4.56 (ddd, J = 10.6, 10.2,
9.6 Hz, 1 H, 4-H), 4.31 (ddd, J = 10.2, 9.3, 3.2 Hz, 1 H, 4-H), 3.86 (ddd,
EtOAc = 6:1 to 4:1 as the eluent) to give (S)-7d (348 mg, 71 % yield)
22
as colorless crystals. [α]
= –56.9 (c = 1.0, EtOH). 94 % ee [deter- J = 12.9, 10.6, 9.3 Hz, 1 H, 3-H), 3.64 (s, 3 H, NCH3), 3.00 (s, 3 H,
589
mined by HPLC analysis: Daicel Chiralpak AD-H column (25 cm), n-
NCH3), 2.95–2.80 (br. m, 1 H, 3-H), 2.30 (s, 3 H, ArCH3), 1.49 (s, 9 H,
tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9, 135.4, 134.2, 133.7,
131.8, 131.2, 120.6 (q, J = 319 Hz), 120.3, 86.9, 85.8, 62.8, 51.1, 50.7,
27.4, 27.0, 20.4 ppm. HRMS (ESI): calcd. for C17H25BrNO2 [M–OTf]+
354.1063, found 354.1048.
hexane/EtOH = 95:5 as the eluent, flow rate: 0.50 mL/min, tR
8.5 min (3.2 %) for (R)-7d and 9.3 min (96.8 %) for (S)-7d].
=
(1R,2R)-1-(4-Bromobenzyl)-2-(tert-butoxycarbonyl)-1-methyl-
azetidin-1-ium Tetraphenylborate [(1R,2R)-1d-BPh4]: A mixture
of (1R,2R)-1d [31.4 mg, 0.0640 mmol, prepared from 97 % ee of
(R)-7d] and sodium tetraphenylborate (33 mg, 0.096 mmol) in THF
(0.65 mL) was stirred for 8 h at room temperature. The resulting
mixture was concentrated and the residue was purified by chroma-
tography on silica gel (CH2Cl2/MeOH = 100:1 to 20:1 as the eluent)
(S)-tert-Butyl 4-Acetoxy-2-(5-bromo-2-methylphenyl)-2-(di-
methylamino)butanoate [(S)-9]: A mixture of (S)-8 [142 mg,
0.282 mmol, prepared from 93 % ee of (S)-2d] and cesium acetate
(0.27 g, 1.4 mmol) in DMF (1.4 mL) was stirred for 24 h at room
temperature. The resulting mixture was diluted with water and ex-
tracted with ethyl acetate. The combined extracts were washed
with water followed by brine, dried with sodium sulfate, and the
solvents evaporated. The residue was purified by chromatography
on silica gel (n-hexane/EtOAc = 15:1 to 10:1 as the eluent) to pro-
vide (S)-9 (82.5 mg, 71 % yield) as a white solid, m.p. 53–56 °C.
[α]25289 = –16.3 (c = 1.0, EtOH). 93 % ee [determined by HPLC analysis:
Daicel Chiralpak IC column (15 cm), n-hexane/EtOAc = 98:2 as the
eluent, flow rate: 0.50 mL/min, tR = 13.4 min for (R)-9 (3.5 %) and
to afford (1R,2R)-1d-BPh4 (41.4 mg, 98 % yield) as a white solid.
22
[α]
= +19.5 (c = 1.0, acetone). IR (KBr): νmax = 3054, 2999, 2983,
˜
589
2935, 1745, 1593, 1579, 1490, 1478, 1457, 1426, 1409, 1395, 1370,
1320, 1303, 1255, 1151, 1104, 1073, 1051, 1031, 1013, 936, 880, 835,
822, 785, 735, 708 cm–1. H NMR (400 MHz, [D6]acetone): δ = 7.71
1
(ddd, J = 8.6, 2.2, 2.2 Hz, 2 H, ArH), 7.55 (ddd, J = 8.6, 2.2, 2.2 Hz, 2
H, ArH), 7.39–7.31 (m, 8 H, Ph), 6.94 (dd, J = 7.4, 7.4 Hz, 8 H, Ph),
6.79 (tt, J = 7.4, 1.2 Hz, 4 H, Ph), 5.53 (dd, J = 9.6, 9.6 Hz, 1 H, 2-H),
4.73–4.59 (m, 1 H, 4-H), 4.67 (s, 2 H, CH2Ar), 3.89 (ddd, J = 10.3, 9.6,
3.4 Hz, 1 H, 4-H), 3.22 (s, 3 H, NCH3), 3.07 (dddd, J = 12.2, 10.3, 9.6,
9.6 Hz, 1 H, 3-H), 2.66–2.52 (m, 1 H, 3-H), 1.46 (s, 9 H, tBu) ppm. 13C
NMR (100 MHz, [D6]acetone): δ = 165.0 (q, J = 49 Hz), 164.3, 137.1
(q, J = 2 Hz), 135.1, 133.4, 128.2, 126.1 (q, J = 3 Hz), 125.8, 122.4,
86.1, 71.8, 68.2, 62.7, 45.5, 27.9, 19.3 ppm. HRMS (ESI): calcd. for
14.9 min for (S)-9 (96.5 %)]. IR (film): νmax = 3061, 2976, 2934, 2874,
˜
2838, 2797, 1741, 1714, 1589, 1563, 1467, 1456, 1392, 1367, 1238,
1156, 1090, 1041, 993, 978, 961, 917, 887, 843, 806, 731 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 2.2 Hz, 1 H, ArH), 7.27 (dd,
J = 8.0, 2.2 Hz, 1 H, ArH), 7.00 (d, J = 8.0 Hz, 1 H, ArH), 4.03 (ddd,
J = 10.7, 9.8, 5.0 Hz, 1 H, 4-H), 3.58 (ddd, J = 10.7, 9.8, 6.2 Hz, 1 H,
4-H), 2.54 (ddd, J = 14.6, 9.8, 5.0 Hz, 1 H, 3-H), 2.36 [s, 6 H, N(CH3)2],
2.26 (s, 3 H, ArCH3), 2.13 (ddd, J = 14.6, 9.8, 6.2 Hz, 1 H, 3-H), 1.89
(s, 3 H, OCOCH3), 1.52 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.8, 167.6, 140.4, 135.0, 133.6, 131.3, 129.9, 119.1, 82.2, 71.1,
60.9, 40.1, 32.5, 28.4, 20.8, 20.7 ppm. HRMS (ESI): calcd. for
C19H29BrNO4 [M + H]+ 414.1274, found 414.1257.
C
16H23BrNO2 [M–BPh4]+ 340.0907, found 340.0895. Recrystallization
from ethanol/THF gave a single crystal suitable for X-ray crystallo-
graphic analysis. CCDC-1458117 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
Colorless crystals, m.p. 119–121 °C. [α]15899 = +20.2 (c = 1.0, acetone).
(S)-tert-Butyl 2-(5-Bromo-2-methylphenyl)-2-(dimethylamino)-
4-(methylamino)butanoate [(S)-10]: A mixture of (S)-8 [194 mg,
0.385 mmol, prepared from 95 % ee of (S)-2d] in THF (3.9 mL) was
treated with a 40 wt.-% methylamine methanol solution (0.19 mL,
1.9 mmol) at room temperature and stirred for 7 h. The resulting
mixture was evaporated and the residue was purified by chroma-
tography on aminopropyl-modified silica gel (Chromatorex NH–
DM1020) (n-hexane/EtOAc = 1.5:1 as the eluent) to provide (S)-10
Synthesis of (S)-tert-Butyl 1-Methyl-2-(o-tolyl)azetidine-2-carb-
oxylate [(S)-2c] from (S)-2d: A mixture of (S)-2d (128 mg,
0.376 mmol, 95 % ee), sodium hydrogen carbonate (92 mg,
1.1 mmol), and palladium on activated carbon (loading: 10 wt.-%,
8 mg) in methanol (3.8 mL) was stirred for 2 h at room temperature
under a hydrogen atmosphere. The resulting mixture was filtered
through a pad of Celite and the filtrate was concentrated. The resi-
due was treated with saturated aqueous sodium hydrogen carb-
onate and extracted with ethyl acetate. The combined extracts were
washed with brine, dried with sodium sulfate, and concentrated.
The residue was purified by chromatography on silica gel (n-hex-
22
(119 mg, 80 % yield) as a colorless oil. [α] = –23.8 (c = 1.0, EtOH).
589
95 % ee [determined by HPLC analysis: Daicel Chiralcel OD-H col-
umn (25 cm), n-hexane/2-PrOH/Et2NH = 100:5:0.1 as the eluent,
flow rate: 0.50 mL/min, tR = 10.5 min for (R)-10 (2.5 %) and 11.5 min
ane/EtOAc = 10:1 to 6:1 as the eluent) to give (S)-2c (26.8 mg, 27 %
for (S)-10 (97.5 %)]. IR (film): ν
= 3328, 3058, 2974, 2931, 2870,
˜
max
23
yield) as a colorless oil. [α]
= –165.4 (c = 1.0, EtOH). 94 % ee
589
2835, 2794, 1714, 1589, 1563, 1469, 1391, 1367, 1243, 1155, 1117,
[determined by HPLC analysis: Daicel Chiralcel OJ-H column (25 cm),
n-hexane/2-PrOH = 99:1 as the eluent, flow rate: 0.50 mL/min, tR =
8.6 min for (S)-2c (97.2 %) and 19.7 min for (R)-2c (2.8 %)].
1087, 1045, 978, 916, 885, 845, 804, 773, 749, 730 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.68 (d, J = 2.2 Hz, 1 H, ArH), 7.26 (dd, J =
8.1, 2.2 Hz, 1 H, ArH), 6.99 (d, J = 8.1 Hz, 1 H, ArH), 2.45–2.31 (m, 2
H, CH2), 2.34 [s, 6 H, N(CH3)2], 2.28 (s, 3 H, NHCH3 or ArCH3), 2.24 (s,
(S)-2-(5-Bromo-2-methylphenyl)-2-(tert-butoxycarbonyl)-1,1-di-
methylazetidin-1-ium Trifluoromethanesulfonate [(S)-8]: A mix- 3 H, NHCH3 or ArCH3), 2.05 (ddd, J = 12.0, 11.2, 5.2 Hz, 1 H, CH2),
Eur. J. Org. Chem. 0000, 0–0
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8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1.92 (ddd, J = 14.7, 10.3, 5.2 Hz, 1 H, CH2); 1.52 (s, 9 H, tBu), 1.33
(br., 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.8, 141.0,
134.9, 133.5, 131.4, 129.5, 118.8, 81.9, 71.7, 47.0, 40.1, 36.5, 33.8,
28.4, 20.8 ppm. HRMS (ESI): calcd. for C18H30BrN2O2 [M + H]+
385.1485, found 385.1479.
81.4, 63.2, 54.9, 45.5, 34.5, 27.7, 19.8 ppm. HRMS (ESI): calcd. for
C17H28BrN2O2 [M + H]+ 371.1329, found 371.1317.
(R)-tert-Butyl 2-Amino-4-(dimethylamino)-2-(o-tolyl)butanoate
[(R)-13]: A mixture of (R)-12 (60.8 mg, 0.164 mmol, 95 % ee) and
palladium on activated carbon (loading: 10 wt.-%, 3 mg) in ethyl
acetate (1.6 mL) was stirred for 12 h at room temperature under a
hydrogen atmosphere. The resulting mixture was filtered through a
pad of Celite and the filtrates were washed with ethyl acetate and
saturated aqueous sodium hydrogen carbonate. The filtrate was ex-
tracted with ethyl acetate and the combined extracts were washed
with brine, dried with sodium sulfate, and concentrated. The residue
was purified by chromatography on aminopropyl-modified silica gel
(Chromatorex NH–DM1020) (n-hexane/EtOAc = 2:1 as the eluent) to
give (R)-13 (41.7 mg, 87 % yield) as colorless crystals, m.p. 59–61 °C.
(S)-2-(5-Bromo-2-methylphenyl)-2-(tert-butoxycarbonyl)-1,1-di-
methylazetidin-1-ium Tetraphenylborate [(S)-8-BPh4]: A mixture
of (S)-8 [101 mg, 0.20 mmol, prepared from 93 % ee of (S)-2d] and
sodium tetraphenylborate (103 mg, 0.30 mmol) in THF (2.0 mL) was
stirred for 12 h at room temperature. The resulting mixture was
concentrated. Purification of the residue by chromatography on sil-
ica gel (CH2Cl2/MeOH = 50:1 to 20:1 as the eluent) gave (S)-8-BPh4
(133 mg, 99 % yield) as a white solid with small amounts of impuri-
ties. Recrystallization from ethanol/dichloromethane afforded pure
22
[α] = –6.1 (c = 1.0, EtOH). 95 % ee [determined by HPLC analysis:
589
(S)-8-BPh4 (78.8 mg, 58 % yield) as colorless needles. IR (KBr): νmax
=
˜
Daicel Chiralpak AD-H column (25 cm), n-hexane/EtOH/Et2NH =
97:3:0.1 as the eluent, flow rate: 0.50 mL/min, tR = 12.7 min for (R)-
3053, 3034, 2995, 2983, 1735, 1579, 1479, 1453, 1427, 1394, 1371,
1292, 1250, 1181, 1141, 1090, 1068, 1031, 989, 943, 851, 828, 806,
1
789, 736, 707 cm–1. H NMR (400 MHz, [D6]acetone): δ = 7.64–7.59
13 (97.7 %) and 20.5 min for (S)-13 (2.3 %)]. IR (KBr): νmax = 3359,
˜
3228, 3141, 3070, 2976, 2938, 2859, 2818, 2760, 1716, 1605, 1472,
(m, 1 H, ArH), 7.63 (s, 1 H, ArH), 7.41–7.35 (m, 8 H, Ph), 7.28 (d, J =
8.6 Hz, 1 H, ArH), 6.97 (dd, J = 7.2, 7.2 Hz, 8 H, Ph), 6.82 (tt, J = 7.2,
1.2 Hz, 4 H, Ph), 4.51–4.39 (m, 1 H, 4-H), 3.81–3.67 (m, 2 H, 3- and
4-H), 3.46 (s, 3 H, NCH3), 2.97–2.80 (m, 1 H, 3-H), 2.77 (s, 3 H, NCH3),
2.28 (s, 3 H, ArCH3), 1.44 (s, 9 H, tBu) ppm. 13C NMR (100 MHz,
[D6]acetone): δ = 166.8, 165.0 (q, J = 49 Hz), 137.05, 136.97 (q, J =
2 Hz), 135.2, 134.3, 133.4, 132.3, 126.2 (q, J = 3 Hz), 122.4, 120.5,
87.4, 86.7, 63.5, 51.4, 51.2, 27.6, 27.5, 20.8 ppm. HRMS (ESI): calcd. for
1463, 1452, 1392, 1366, 1313, 1252, 1230, 1164, 1154, 1117, 1087,
1070, 1042, 978, 966, 883, 849, 821, 756, 732 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.61–7.54 (m, 1 H, ArH), 7.22–7.09 (m, 3 H,
ArH), 2.32 (s, 3 H, ArCH3), 2.30–2.18 (m, 3 H, CH2), 2.19 [s, 6 H,
N(CH3)2], 2.18–2.07 (m, 3 H, CH2 and NH2), 1.41 (s, 9 H, tBu) ppm.
13C NMR (100 MHz, CDCl3): δ = 175.2, 141.2, 135.3, 131.7, 127.0,
125.7, 125.5, 81.1, 63.3, 55.0, 45.6, 35.2, 27.7, 20.4 ppm. HRMS (ESI):
calcd. for C17H29N2O2 [M + H]+ 293.2224, found 293.2215.
C
17H25BrNO2 [M–BPh4]+ 354.1063, found 354.1048. Recrystallization
from ethanol/THF gave a single crystal suitable for X-ray crystallo-
graphic analysis. CCDC-1458118 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
(R)-N-[4-(tert-Butoxy)-3-(methylamino)-4-oxo-3-(o-tolyl)]butyl-
N,N,N-trimethylammonium Iodide [(R)-14]: A mixture of (R)-13
(14.2 mg, 0.0486 mmol, 95 % ee) and sodium hydrogen carbonate
(20 mg, 0.24 mmol) in iodomethane (0.5 mL) was stirred for 4 h at
room temperature. The resulting mixture was purified by chroma-
tography on silica gel (CH2Cl2/MeOH = 7:1 to 5:1 as the eluent) to
22
Colorless crystals, m.p. 155–156 °C. [α] = +3.3 (c = 1.0, CHCl3).
589
(R)-tert-Butyl 2-Amino-2-(5-bromo-2-methylphenyl)-4-(dimeth-
ylamino)butanoate [(R)-12]: A mixture of (S)-8 [191 mg,
0.379 mmol, prepared from 95 % ee of (S)-2d] and sodium azide
(124 mg, 1.91 mmol) in DMF (1.9 mL) was stirred for 36 h at room
temperature. The resulting mixture was diluted with water and ex-
tracted with ethyl acetate. The combined extracts were washed
with water followed by brine and dried with sodium sulfate. The
solution was evaporated to afford (R)-tert-butyl 2-azido-2-(5-bromo-
2-methylphenyl)-4-(dimethylamino)butanoate [(R)-11]. The crude
(R)-11 was dissolved in THF (3.4 mL) and water (0.4 mL). Triphenyl-
phosphine (114 mg, 0.435 mmol) was added to the solution and
the mixture was stirred for 3 d at room temperature. The resulting
mixture was diluted with water and extracted with ethyl acetate.
The combined extracts were washed with water followed by brine,
dried with sodium sulfate, and the solvents evaporated. Purification
of the residue by chromatography on aminopropyl-modified silica
gel (Chromatorex NH–DM1020) (n-hexane/EtOAc = 8:1 to 5:1 as the
eluent) gave (R)-12 (96.1 mg, 68 % yield) as colorless crystals, m.p.
provide (R)-14 (12.8 mg, 59 % yield) as a pale yellow solid, m.p.
21
166–167 °C. [α]
= +13.1 (c = 1.0, CHCl3). IR (KBr): νmax = 3439,
˜
589
3002, 2974, 2931, 2804, 1717, 1618, 1480, 1419, 1393, 1368,
1321, 1255, 1211, 1153, 1100, 1070, 1038, 995, 969, 911, 842, 822,
754 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.66–7.59 (m, 1 H, ArH),
.
7.29–7.13 (m, 3 H, ArH), 3.60 (ddd, J = 12.8, 11.4, 5.6 Hz, 1 H, CH2),
3.29 [s, 9 H, N(CH3)3], 2.78 (ddd, J = 12.8, 11.6, 3.2 Hz, 1 H, CH2),
2.66 (ddd, J = 12.8, 11.6, 5.6 Hz, 1 H, CH2), 2.36 (s, 3 H, NCH3 or
ArCH3), 2.33 (s, 3 H, NCH3 or ArCH3), 2.14 (ddd, J = 12.8, 11.4, 3.2 Hz,
1 H, CH2), 1.86 (br., 1 H, NH), 1.45 (s, 9 H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.3, 137.3, 134.8, 132.5, 128.1, 126.3, 126.2,
82.8, 66.6, 64.0, 53.6, 29.8, 27.9, 25.2, 20.5 ppm. HRMS (ESI): calcd.
for C19H33N2O2 [M – I]+ 321.2537, found 321.2529.
(2S)-1-Allyl-2-(tert-butoxycarbonyl)-1-methyl-2-(o-tolyl)azet-
idin-1-ium Trifluoromethanesulfonate [(2S)-15]: A solution of
allyl alcohol (35 μL, 0.51 mmol) and pyridine (41 μL, 0.51 mmol) in
carbon tetrachloride (2.6 mL) was treated with trifluoromethane-
43–45 °C. [α]25829 = –8.2 (c = 1.0, EtOH). 95 % ee [determined by HPLC sulfonic anhydride (86 μL, 0.51 mmol) at 0 °C. The mixture was
analysis: Daicel Chiralpak AD-H column (25 cm), n-hexane/EtOH/
Et2NH = 97:3:0.1 as the eluent, flow rate: 0.50 mL/min, tR = 10.6 min
stirred for 20 min at the same temperature to precipitate a pale-
brown solid. The generated allyl triflate in carbon tetrachloride[18]
was added by decantation to a mixture of (S)-2c (89.3 mg,
0.342 mmol, 93 % ee) and sodium hydrogen carbonate (84 mg,
1.0 mmol) in dichloromethane (1.7 mL) at 0 °C. After stirring for 1 h
for (R)-12 (97.5 %) and 13.9 min for (S)-12 (2.5 %)]. IR (film): νmax
3380, 3262, 3063, 2975, 2941, 2860, 2817, 2767, 1725, 1589, 1565,
=
˜
1477, 1460, 1391, 1367, 1314, 1248, 1153, 1098, 1067, 1040, 980,
1
902, 845, 808, 779, 741 cm–1. H NMR (400 MHz, CD3OD): δ = 7.78 at room temperature, the resulting mixture was evaporated to ap-
(d, J = 2.0 Hz, 1 H, ArH), 7.32 (dd, J = 8.4, 2.0 Hz, 1 H, ArH), 7.07 (d,
J = 8.4 Hz, 1 H, ArH), 2.35 (ddd, J = 11.8, 9.8, 6.0 Hz, 1 H, CH2), 2.29–
prox. 1/2 volume and purified by chromatography on silica gel
(CH2Cl2/MeOH = 20:1 to 10:1 as the eluent) to afford (2S)-15
2.13 (m, 2 H, CH2), 2.25 (s, 3 H, ArCH3), 2.19 [s, 6 H, N(CH3)2], 1.99 (124 mg, 80 % yield, 85:15 mixture of diastereomers) as a colorless
(ddd, J = 11.8, 9.8, 6.0 Hz, 1 H, CH2), 1.42 (s, 9 H, tBu) ppm. 13C NMR gum. [α]
(100 MHz, CDCl3): δ = 174.5, 143.5, 134.2, 133.2, 129.9, 129.0, 119.5,
= +41.4 (c = 1.0, EtOH). IR (film): νmax = 2981, 2935,
21
˜
589
2875, 1731, 1641, 1603, 1460, 1427, 1397, 1372, 1262, 1224, 1156,
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1
1031, 954, 912, 901, 832, 789, 764 cm–1. H NMR (400 MHz, CDCl3): chromatography on silica gel (CH2Cl2/MeOH = 7:1 to 5:1 as the
δ = 7.59–7.47 (m, 1 H, ArH), 7.43–7.35 (m, 2 H, ArH), 7.30–7.24 (m,
1 H, ArH), 6.06–5.90 (m, 0.15 H, CH=CH2), 5.83–5.55 (m, 2.85 H, CH=
CH2), 4.67–4.47 (br. m, 0.15 H, CH2), 4.40–4.25 (m, 1.85 H, CH2), 4.12–
3.90 (m, 1.15 H, CH2), 3.84 (dd, J = 12.9, 6.9 Hz, 0.85 H, CH2), 3.53
(s, 2.55 H, NCH3), 3.44 (dd, J = 12.9, 6.9 Hz, 1 H, CH2), 3.00–2.78 (m,
1.45 H, CH2 and NCH3), 2.34 (s, 3 H, ArCH3), 1.40 (s, 9 H, tBu) ppm.
13C NMR (100 MHz, CDCl3): δ = (major diastereomer) = 166.6, 136.3,
132.3, 130.8, 130.1, 129.2, 129.1, 127.0, 123.9, 120.7 (q, J = 319 Hz),
87.4, 86.4, 63.5, 58.4, 47.0, 27.3, 27.0, 20.9 ppm. HRMS (ESI): calcd.
for C19H28NO2 [M–OTf]+ 302.2115, found 302.2111.
eluent) to afford (S)-14 (30.8 mg, quant.) as a pale yellow solid.
24
[α] = –13.3 (c = 1.0, CHCl3).
589
Acknowledgments
This work was supported by the Union Tool Scholarship Foun-
dation, Japan. A part of this work was conducted in NAIST, sup-
ported by the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), Japan (Nanotechnology Platform Pro-
gram, Synthesis of Molecules and Materials).
(S)-tert-Butyl 2-[Allyl(methyl)amino]-4-(dimethylamino)-2-(o-
tolyl)butanoate [(S)-16]: A solution of (2S)-15 (124 mg,
Keywords: Rearrangement · Ylides · Amino acids · Strained
molecules · Stereochemical transmission
0.275 mmol) in THF (2.8 mL) was treated with a 2
M dimethylamine
methanol solution (0.69 mL, 1.38 mmol) at room temperature and
stirred for 16 h. The resulting mixture was evaporated and the resi-
due was purified by chromatography on aminopropyl-modified sil-
ica gel (Chromatorex NH–DM1020) (n-hexane/EtOAc = 30:1 to 15:1
as the eluent) to provide (S)-16 (58.4 mg, 61 % yield) as a colorless
[1] For a first example, see: M. Sommelet, C. R. Hebd. Seances Acad. Sci. 1937,
205, 56–58.
oil. [α]21 = +18.8 (c = 1.0, EtOH). IR (film): νmax = 3060, 2975, 2857,
[2] For initial studies, see: a) K. P. Klein, D. N. Van Eenam, C. R. Hauser, J. Org.
Chem. 1967, 32, 1155–1160; b) W. H. Puterbaugh, C. R. Hauser, J. Am.
Chem. Soc. 1964, 86, 1108–1110; c) W. H. Puterbaugh, C. R. Hauser, J.
Am. Chem. Soc. 1964, 86, 1105–1107; d) G. C. Jones, W. Q. Beard, C. R.
Hauser, J. Org. Chem. 1963, 28, 199–203; e) W. Q. Beard Jr., C. R. Hauser,
J. Org. Chem. 1961, 26, 371–375; f) W. Q. Beard Jr., C. R. Hauser, J. Org.
Chem. 1960, 25, 334–343; g) C. R. Hauser, D. N. Van Eenam, J. Am. Chem.
Soc. 1957, 79, 5512–5520; h) D. Lednicer, C. R. Hauser, J. Am. Chem. Soc.
1957, 79, 4449–4451; i) W. R. Brasen, C. R. Hauser, Org. Synth. 1954, 34,
61–63; j) S. W. Kantor, C. R. Hauser, J. Am. Chem. Soc. 1951, 73, 4122–
4131.
[3] For a review, see: E. Tayama, Chem. Rec. 2015, 15, 789–800.
[4] For reviews on ammonium ylide rearrangements, see: a) E. Tayama, Het-
erocycles 2016, 92, 793–828; b) R. Bach, S. Harthong, J. Lacour, Compre-
hensive Organic Synthesis II (Eds.: P. Knochel, G. A. Molander), Elsevier,
2014, vol. 3, chapter 3.20, p. 992–1037; c) G. Lahm, J. C. O. Pacheco, T.
Opatz, Synthesis 2014, 46, 2413–2421; d) J. Clayden, M. Donnard, J. Le-
franc, D. J. Tetlow, Chem. Commun. 2011, 47, 4624–4639; e) J. B. Sweeney,
Chem. Soc. Rev. 2009, 38, 1027–1038; f) J. A. Vanecko, H. Wan, F. G. West,
Tetrahedron 2006, 62, 1043–1062; g) L. Kürti, B. Czakó, Strategic Applica-
tions of Named Reactions in Organic Synthesis, Elsevier, Amsterdam, 2005;
h) Nitrogen, Oxygen and Sulfur Ylide Chemistry (Ed.: J. S. Clark), Oxford
University Press, Oxford, UK, 2002; i) I. E. Markó, Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, UK, 1991, vol.
3, chapter 3.10, p. 913–974; j) S. H. Pine, Organic Reactions, John Wiley &
Sons, New York, 1970, vol. 18, chapter 4, p. 403–464.
˜
589
2815, 2764, 1716, 1641, 1479, 1458, 1415, 1391, 1367, 1344, 1304,
1284, 1244, 1156, 1086, 1065, 1041, 1029, 990, 963, 916, 879, 845,
815, 777, 756, 735 cm–1. H NMR (400 MHz, CDCl3): δ = 7.47 (d, J =
1
7.6 Hz, 1 H, ArH), 7.16–7.07 (m, 3 H, ArH), 5.88 (dddd, J = 17.2, 10.3,
6.5, 4.4 Hz, 1 H, CH2CH=CH2), 5.21 (dddd, J = 17.2, 2.0, 2.0, 2.0 Hz,
1 H, CH2CH=CH2), 5.13 (dddd, J = 10.3, 2.0, 2.0, 2.0 Hz, 1 H, CH2CH=
CH2), 3.31 (dd, J = 15.1, 4.4 Hz, 1 H, CH2CH=CH2), 2.81 (dd, J = 15.1,
6.5 Hz, 1 H, CH2CH=CH2), 2.51–2.29 (m, 1 H, CH2), 2.33 [s, 6 H,
N(CH3)2], 2.21–2.05 (m, 1 H, CH2), 2.10 (s, 6 H, CH2NCH3 and ArCH3),
1.99 (ddd, J = 13.7, 12.0, 4.4 Hz, 1 H, CH2), 1.73 (ddd, J = 12.0, 12.0,
4.4 Hz, 1 H, CH2), 1.53 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
δ = 169.2, 138.7, 137.1, 135.8, 131.9, 128.3, 126.6, 124.6, 115.8, 81.6,
72.2, 55.8, 54.5, 45.6, 35.3, 32.2, 28.4, 21.1 ppm. HRMS (ESI): calcd.
for C21H35N2O2 [M + H]+ 347.2693, found 347.2688.
(S)-tert-Butyl 4-(Dimethylamino)-2-(methylamino)-2-(o-tolyl)-
butanoate [(S)-17]: A mixture of (S)-16 (58.4 mg, 0.169 mmol), pal-
ladium acetate (2 mg, 0.009 mmol), triphenylphosphine (5 mg,
0.02 mmol), and 1,3-dimethylbarbituric acid (80 mg, 0.51 mmol)
in dichloromethane (1.7 mL) was refluxed for 2 h under an argon
atmosphere. The resulting mixture was cooled to room temperature
and purified by chromatography on aminopropyl-modified silica gel
(Chromatorex NH–DM1020) (n-hexane/EtOAc = 10:1 to 5:1 as the
eluent) to afford (S)-17 (48.8 mg, 94 % yield) as a colorless oil.
[5] For representative examples of base-induced S–H rearrangements of
ammonium salts, see: a) S. Hanessian, C. Talbot, P. Saravanan, Synthesis
2006, 723–734; b) J. M. Klunder, J. Heterocycl. Chem. 1995, 32, 1687–
1691; c) T. Zdrojewski, A. Jończyk, Tetrahedron Lett. 1995, 36, 1355–1358;
d) A. Jończyk, D. Lipiak, K. Sienkiewicz, Synlett 1991, 493–496; e) A. Jońc-
zyk, D. Lipiak, J. Org. Chem. 1991, 56, 6933–6937.
23
[α] = +9.2 (c = 1.0, EtOH). 93 % ee [determined by HPLC analysis:
589
Daicel Chiralpak AD-H column (25 cm), n-hexane/EtOH/Et2NH =
100:3:0.1 as the eluent, flow rate: 0.50 mL/min, tR = 8.9 min for (S)-
17 (96.3 %) and 9.9 min for (R)-17 (3.7 %)]. IR (film): νmax = 3342,
˜
3059, 2974, 2941, 2857, 2815, 2763, 1723, 1601, 1459, 1391, 1367,
[6] Mechanistic studies: B. Biswas, D. A. Singleton, J. Am. Chem. Soc. 2015,
137, 14244–14247.
1303, 1279, 1243, 1154, 1100, 1072, 1041, 969, 941, 847, 787, 751,
736 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.57–7.51 (m, 1 H, ArH),
.
[7] a) E. Tayama, R. Sato, M. Ito, H. Iwamoto, E. Hasegawa, Heterocycles 2013,
87, 381–388; b) E. Tayama, R. Sato, K. Takedachi, H. Iwamoto, E. Hase-
gawa, Tetrahedron 2012, 68, 4710–4718; c) E. Tayama, K. Takedachi, H.
Iwamoto, E. Hasegawa, Tetrahedron 2010, 66, 9389–9395; d) E. Tayama,
K. Orihara, H. Kimura, Org. Biomol. Chem. 2008, 6, 3673–3680; e) E. Tay-
ama, H. Kimura, Angew. Chem. Int. Ed. 2007, 46, 8869–8871; Angew.
Chem. 2007, 119, 9025.
[8] For previous studies on the base-induced rearrangements of azetidine-
2-carboxylic acid-derived ammonium ylides, see: a) B. Drouillat, E.
d'Aboville, F. Bourdreux, F. Couty, Eur. J. Org. Chem. 2014, 1103–1109; b)
B. Drouillat, F. Couty, J. Marrot, Synlett 2009, 767–770; c) F. Couty, F.
Durrat, G. Evano, J. Marrot, Eur. J. Org. Chem. 2006, 4214–4223.
[9] The rearrangement of the aziridine carboxylic acid ester-derived
ammonium salt (three-membered N-heterocycle) was unsuccessful. A
complex mixture was obtained.
7.20–7.13 (m, 2 H, ArH), 7.13–7.07 (m, 1 H, ArH), 2.38–2.14 (m, 3 H,
CH2), 2.33 (s, 3 H, NCH3 or ArCH3), 2.20 [s, 9 H, N(CH3)2 and NCH3
or ArCH3], 2.01 (ddd, J = 10.6, 7.4, 1.6 Hz, 1 H, CH2), 1.84 (br., 1 H,
NH), 1.41 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.8,
139.5, 136.0, 131.7, 126.9, 126.7, 125.2, 81.2, 66.8, 54.5, 45.8, 30.2,
29.0, 27.9, 20.4 ppm. HRMS (ESI): calcd. for C18H31N2O2 [M + H]+
307.2380, found 307.2369.
(S)-N-[4-(tert-Butoxy)-3-(methylamino)-4-oxo-3-(o-tolyl)]butyl-
N,N,N-trimethylammonium Iodide [(S)-14]: A solution of (S)-17
(20.5 mg, 0.0669 mmol) and iodomethane (9.0 μL, 0.14 mmol) in
acetonitrile (0.46 mL) was stirred for 3 h at room temperature. The
resulting solution was evaporated and the residue was purified by
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[10] For studies on other reactions of azetidine-2-carboxylic acid-derived
ammonium salts, see: a) C. Lo, O. David, F. Couty, Tetrahedron Lett. 2014,
55, 535–537; b) P.-A. Nocquet, D. Hazelard, P. Compain, Eur. J. Org. Chem.
2011, 6619–6623; c) A. Alex, B. Larmanjat, J. Marrot, F. Couty, O. David,
Chem. Commun. 2007, 2500–2502; d) F. Couty, O. David, B. Larmanjat, J.
Marrot, J. Org. Chem. 2007, 72, 1058–1061.
[11] For representative examples of the synthesis of 2-arylazetidine-2-carb-
oxylic acid derivatives, see: a) S. P. Fritz, J. F. Moya, M. G. Unthank, E. M.
McGarrigle, V. K. Aggarwal, Synthesis 2012, 44, 1584–1590; b) B. Drouillat,
K. Wright, J. Marrot, F. Couty, Tetrahedron: Asymmetry 2012, 23, 690–696.
[12] For asymmetric ammonium ylide rearrangements via N-to-C chirality
transmission, see: a) M. Ariza, A. Díaz, R. Suau, M. Valpuesta, Eur. J. Org.
Chem. 2011, 6507–6518; b) L. Palombi, Catal. Commun. 2011, 12, 485–
488; c) P. Tuzina, P. Somfai, Org. Lett. 2009, 11, 919–921; d) E. F. Duran-
Lara, N. Shankaraiah, D. Geraldo, L. S. Santos, J. Braz. Chem. Soc. 2009,
20, 813–819; e) E. Tayama, S. Nanbara, T. Nakai, Chem. Lett. 2006, 35,
478–479; f) E. Tayama, H. Tanaka, T. Nakai, Heterocycles 2005, 66, 95–99;
g) A. P. A. Arboré, D. J. Cane-Honeysett, I. Coldham, M. L. Middleton,
Synlett 2000, 236–238; h) K. W. Glaeske, F. G. West, Org. Lett. 1999, 1,
31–33.
[13] a) S.-h. Ma, D. H. Yoon, H.-J. Ha, W. K. Lee, Tetrahedron Lett. 2007, 48,
269–271; b) F. Couty, G. Evano, M. Vargas-Sanchez, G. Bouzas, J. Org.
Chem. 2005, 70, 9028–9031.
[14] For studies on the N-quaternization of 2-substituted azetidine derivatives
and nucleophilic ring opening of azetidinium salts, see: a) B. Drouillat, K.
Wright, O. David, F. Couty, Eur. J. Org. Chem. 2012, 6005–6012; b) D.-H.
Leng, D.-X. Wang, J. Pan, Z.-T. Huang, M.-X. Wang, J. Org. Chem. 2009, 74,
6077–6082; c) F. Couty, O. David, F. Durrat, Tetrahedron Lett. 2007, 48,
1027–1031; d) F. Couty, O. David, F. Durrat, G. Evano, S. Lakhdar, J. Marrot,
M. Vargas-Sanchez, Eur. J. Org. Chem. 2006, 3479–3490; see also ref.[8]
[15]
[16]
Sodium hydrogen carbonate was added as a scavenger of triflic acid.
CCDC 1458117 {for [(1R,2R)-1d-BPh4]}, and 1458118 {for [(S)-8-BPh4]}
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre.
[17]
For the effect of ring-strain for the stabilization of the carbanion species
was reported in the studies on aziridine-2-carboxylic acid derivatives
(three-membered N-heterocycle), see: A. P. Patwardhan, V. R. Pulgam, Y.
Zhang, W. D. Wulff, Angew. Chem. Int. Ed. 2005, 44, 6169–6172; Angew.
Chem. 2005, 117, 6325.
[18]
L. Jordi, S. Ricart, J. M. Viñas, J. M. Moretó, Organometallics 1997, 16,
2808–2818.
[19] For recent examples of substitutions at tertiary carbon centers, see: a)
R. Y. Liu, M. Wasa, E. N. Jacobsen, Tetrahedron Lett. 2015, 56, 3428–3430;
b) K. Ishihara, H. Hamamoto, M. Matsugi, T. Shioiri, Tetrahedron Lett.
2015, 56, 3169–3171; c) S. V. Pronin, C. A. Reiher, R. A. Shenvi, Nature
2013, 501, 195–199; d) K. Shibatomi, Y. Soga, A. Narayama, I. Fujisawa, S.
Iwasa, J. Am. Chem. Soc. 2012, 134, 9836–9839; e) M. Mascal, N. Hafezi,
M. D. Toney, J. Am. Chem. Soc. 2010, 132, 10662–10664; f) T. Mukaiyama,
K. Kuroda, Y. Maruyama, Heterocycles 2010, 80, 63–82; g) J. E. Green,
D. M. Bender, S. Jackson, M. J. O'Donnell, J. R. McCarthy, Org. Lett. 2009,
11, 807–810; h) T. Mukaiyama, K. Kuroda, Y. Maruyama, Y. Hayashi, Chem.
Lett. 2008, 37, 1072–1073, and references cited therein; see also
ref.[14a,14b]
[20] F. Matsuura, Y. Hamada, T. Shioiri, Tetrahedron 1993, 49, 8211–8222.
Received: May 18, 2016
Published Online: ■
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Ring-Strain Effect
E. Tayama,* K. Watanabe,
Y. Matano .......................................... 1–12
Ring-Strain Effects in Base-Induced
Sommelet–Hauser Rearrangement:
Application to Successive Stereo-
controlled Transformations
The base-induced Sommelet–Hauser N-heterocycles enables efficient gener-
rearrangement of azetidine-2-carb- ation of the desired ylide intermediate
oxylic acid ester-derived ammonium and enhanced rates for the Sommelet–
salts was successfully demonstrated. Hauser rearrangement.
The ring-strain of four-membered
DOI: 10.1002/ejoc.201600611
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