Stereoselective synthesis of activated 2-arylazetidines via imino-aldol reaction

Article abstract of DOI:10.1039/c5ob01140j

A simple and efficient synthetic route to substituted N-sulfinyl and N-sulfonyl azetidines is described involving imino-aldol reaction of ester enolates with racemic and non-racemic aldimines for obtaining β-amino esters as a key step. These β-amino ester

Full text of DOI:10.1039/c5ob01140j

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DOI: 10.1039/C5OB01140J
Journal Name
ARTICLE
Stereoselective Synthesis of Activated 2-Arylazetidines via Imino-
Aldol Reaction
Manas K. Ghorai,a Subhomoy Das, Kalpataru Das, Amit Kumar
Received 00th January 20xx,
Accepted 00th January 20xx
A simple and efficient synthetic route to substituted N-sulfinyl and N-sulfonyl azetidines is described involving imino-aldol
reaction of ester enolates with racemic and non-racemic aldimines for obtaining β-amino esters as a key step. These β-amino
esters on subsequent reduction followed by TsCl/KOH mediated cyclization produced the corresponding racemic and non-
racemic azetidines with high yield and stereoselectivity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Azetidines are four membered nitrogen containing strained
heterocycles of immense biological and pharmacological
importance.1 Several racemic as well as chiral azetidines exhibit
a diverse range of biological activities e. g. compounds 1-2 show
inhibition property against thrombin,1a,b
protein kinase C inhibitory activity,1c 4-5 exert inhibitory effect
against angiotensin-converting enzyme,1d
is potentially
capable of introducing some functional groups at the 3
3 possesses potent
6
׳-
nitrogen atom, such as a fluorescent or a chemiluminescent
probe, an intercalator and DNA scissors.1e Due to high ring
strain, the synthesis of substituted azetidines and further
structural modifications still remains a challenge. However,
many useful strategies have been developed for the synthesis
of substituted azetidines.2 Imino-aldol reaction (addition of
ester enolate to imine) is one of the prominent routes for the
synthesis of β-amino esters,3 non proteinogenic β-amino
acids4a-b and β-lactam antibiotics4c via the formation of carbon-
carbon bonds.4d Lewis acid promoted reaction between a silyl
enol ether and an imine is another useful method for the
synthesis of β-amino esters.5 In most of the cases effective
Lewis acid-activation of the aldimines is required because of
poor electrophilicity of the stable N-substituted imines.6 Some
other methods are also known to generate β-amino esters.7
Recently, the synthesis of 2,4-disubstituted azetidines via Lewis
acid catalyzed imino-aldol reaction was reported,8 however, the
substrate scope of the strategy is narrow. We have developed
an efficient route to various racemic and nonracemic azetidines
via imino-aldol reaction of ester enolates with N-sulfonyl or
Fig. 1. Some Biological Active Compounds Containing Azetidine
N-sulfinyl aldimines as the key step and describe our results in
detail as an article.
Results and discussion
We envisioned that N-sulfonyl azetidine 5 could be synthesized
easily from the precursor β-amino ester derivative
would be obtained through imino-aldol reaction of
3
1
which
and
2
(Scheme 1).9a We further anticipated that various chiral
azetidines could be synthesized from chiral β-amino esters 11
which could easily be obtained from the imino-aldol reaction
utilizing chiral sulfinimines 10 as the source of chirality (Scheme
5).9b Enantiopure sulfinimines10 have been extensively used by
Davis group for the stereoselective synthesis of α-amino acids,11
N-sulfinyl-cis-aziridine-2-carboxylic acids,12 taxol C-13 side
a.Department of Chemistry, Indian Institute of Technology Kanpur,
Kanpur 208016, India. E-mail: mkghorai@iitk.ac.in
†Electronic Supplementary Information (ESI) available: Copies of 1H, and 13C NMR
Spectra and HPLC chromatogram. See DOI: 10.1039/x0xx00000x
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Journal Name
Table 1. Synthesis of 2-aryl-N-sulfonylazetidines
View Article Online
DOI: 10.1039/C5OB01140J
Ent
ry
1
Ar
C6H5
Ar1
R1
R2
3a,b
%
4c,d% 5e,f%
yield yield yield
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-FC6H4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
H
3a
100
3b
100
3c
90
3d
100
3e
100
3f
98
3g
99
3h
97
3i
4a
100
4b
100
4c
90
4d
100
4e
100
4f
5a
98
5b
95
5c
85
5d
92
5e
97
5f
2
3
2-ClC6H4
4-NO2C6H4
4-OMeC6H4
4-ClC6H4
C6H5
H
Scheme 1. Retrosynthetic analysis for the preparation of N-sulfonyl azetidines
H
4
H
5
H
6
H
99
4g
97
4h
98
4i
93
5g
91
5h
90
5i
7
C6H5
4-OMeC6H4
4-t-BuC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
H
8
C6H5
H
Scheme 2. Synthesis of N-sulfonyl aldimines
9
C6H5
Me
Me
Me
98
3j
96
3k
97
100
4j
95
5j
10
11
2-ClC6H4
4-OMeC6H4
Et
chain13 and β-amino acids14 employing N-sulfinyl auxiliary as a
C-N bond activating as well as stereodirecting group.
95
4k
95
95
5k
94
Et
Initially, for the synthesis of β-amino esters a number of N-
sulfonyl aldimines 2a
yields by refluxing N-sulfonyl amine
aromatic aldehydes in dry benzene in the presence of catalytic
amount of BF3.OEt2.
–
g
(Scheme 2) were prepared in excellent
aAll reactions were carried out with 2a–g (1.0 mmol), 1a,b (1.1 mmol), and LDA (1.1
equiv) in dry THF under argon for 2 h at −78 °C. bYields of isolated products (%)
after column chromatographic separation. cAll reactions were carried out with 3a–
k (1.0 mmol), LAH (2.0 equiv) in dry THF under argon for 1–1.5 h at 0 °C to rt. dYields
of isolated products (%) of 4a–k after column chromatographic separation. eAll
reactions were carried out with 4a–k (1.0 mmol), TsCl (1.1 mmol) and KOH (3.0
6
and the corresponding
7
Next, the ester enolate from t-butyl acetate was generated
by the treatment of LDA and reacted with N-tosyl phenyl
aldimine 2a to afford the corresponding addition product N-
tosyl-β-amino ester 3a in quantitative yield. 3a was reduced to
the corresponding γ-amino alcohol 4a by the treatment of
LiAlH4.15 After usual work up, the crude γ-amino alcohol 4a was
treated with TsCl in the presence of excess KOH in THF under
refluxing condition to produce 2-phenyl-N-tosyl azetidine 5a in
excellent yield in a short period of time (Scheme 3).16 The
Mitsunobu protocol16 was also found to be equally effective in
the cyclization step for the synthesis of 5a from 4a, but the
byproduct Ph3PO generated in this reaction made the
purification process difficult.
f
equiv) in dry THF under argon for 1 h under refluxing condition. Yield of isolated
products (%) of 5a–k after column chromatographic separation.
To generalize this strategy a number of N-sulfonyl aldimines
2b
formation of N-sulfonyl-β-amino esters 3b
Reduction of 3b with LAH followed by cyclization of the γ-
amino alcohols 4b using TsCl and KOH in refluxing THF
afforded the corresponding azetidines 5b in almost
were
–k
were reacted with different ester enolates leading to the
–k
in excellent yields.
–k
–k
–k
quantitative yields (Table 1). All the compounds 5a–k
characterized by spectroscopic data.
The present protocol was extended to provide azetidines
with substitution both at 2- and 4- positions. For this purpose,
compound 3a was converted to N-tosyl-β-amino aldehyde
7 by
the treatment of DIBAL-H. Next, the compound was reacted
7
with ethylmagnesium bromide to afford the γ-amino alcohols
8a and 8b (dr 30:70) in 85% combined yield as a mixture of
diastereomers. The pure diastereomers 8a and 8b were
separated via flash column chromatography and they were
individually reacted with tosyl chloride and KOH in THF to
furnish diastereopure 2,4-disubstituted-N-tosyl azetidines 5l
and 5m respectively, in high yields (Scheme 4).
Scheme 3. Synthesis of 2-aryl-N-sulfonylazetidines
2 | J. Name., 2012, 00, 1-3
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of sulfinyl amides with alkyl halides are known in the
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literature.17 A number of enantiopure N-sulfinyl azetidines
were obtained in good yields and excellent
DOI: 10.1039/C5OB011124b0J
–
e
diastereoselectivity from 11b–e following the same procedure
(Table 3).
Table 3. Synthesis of γ-amino alcohols 11a
–
e and 2-aryl/alkyl-N-sulfinylazetidines
12a from N-sulfinyl-β-amino esters 10a
–
e
–
e
Scheme 4. Synthesis of 2,4-disubstituted 2-phenyl-N-tosylazetidine
Entry
Ester
10
Alcohol
11 (% yield)
11a (95)
11b (81)
11c (75)
11d (73)
11e (78)
Azetidine
12 (% yield)
12a (70)
12b (82)
12c (85)
dea
After successful demonstration of our strategy for the
synthesis of a variety of racemic azetidines 5a–m, we extended
1
2
3
4
5
10a
10b
10c
10d
10e
>99%
>99%
>99%
>99%
>99%
our protocol for the synthesis of chiral azetidines employing
enantiomerically pure N-sulfinyl imines as the source of
chirality. To optimize the reaction condition for the imino aldol
reaction, different bases (e.g. LDA, NaHMDS, and KHMDS) and
solvents were explored to generate the enolate from the methyl
acetate ester. Among the bases studied, KHMDS was found to
be the best. The enolate generated from methyl acetate upon
treatment with KHMDS in THF at 78 °C was reacted with (S)-
(+)-N-sulfinimine10 9a (Ar = Ph) to produce the N-sulfinyl-β-
amino ester 10a (de 84%) in 68% yield. The protocol was
12d (75)
12e (81)
a12a–e were obtained as single diastereomer after column chromatography.
In order to ascertain the stereoselectivity (de/ee) of the
products in the described imino-aldol reaction, as
representative example, β-amino ester 10a (de 84%) was
converted to 2-phenyl-N-tosylazetidine (R)-5a as shown in
scheme 5. The N-sulfinyl auxiliary of 10a was removed by the
treatment of TFA in MeOH following a reported procedure18
(Scheme 5). The crude concentrate of the reaction mixture was
treated with tosyl chloride and triethylamine in
dichloromethane to produce N-tosyl-β-amino ester 13 which
was reduced to N-tosyl-γ-amino alcohol (R)-4a by the treatment
of LAH. The usual intramolecular cyclization of (R)-4a using TsCl
and excess KOH in THF at refluxing condition afforded the chiral
2-phenyl-N-tosylazetidine (R)-5a in 75% yield with 84% ee.19
a
generalized with a number of (S)-(+)-N-sulfinimines 9b–e to
produce the corresponding imino-aldol products 10b
93% yield and dr up to >99:1 (Table 2).
–e
in 65–
Table 2. Synthesis of N-sulfinyl-β-amino ester 10a–e
Entry
R
Imine
9
9a
9b
9c
9d
9e
Product
10
10a
10b
10c
10d
10e
Time
(h)
9
8.5
8.5
10
9
Yield
(%)
68
93
72
dra
1
2
3
4
5
C6H5
92:8
96:4
97:3
98:2
>99:1
2-ClC6H4
3-BrC6H4
4-MeC6H4
c-Hex
65
75
aDetermined by 1H NMR spectra.
Scheme 5. Synthesis of chiral 2-Aryl-N-tosylazetidine from chiral β-amino ester
The addition product 10a was then converted into N-
sulfinyl-γ-amino alcohol 11a by the treatment of LAH. When 11a
was reacted with tosyl chloride and KOH in THF under our
optimized reaction condition, (Ss,2R)-2-phenyl-N-sulfinyl
azetidine 12a was obtained in 70% yield. Synthesis of four to six
membered N-sulfinyl heterocycles via intramolecular alkylation
Conclusions
In summary, we have developed a simple and efficient synthetic
route to a variety of 2-aryl-N-sulfonylazetidines and 2-alkyl/aryl-
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N-sulfinylazetidines utilizing imino-aldol reaction of ester To a suspension of lithium aluminium hydride (4.64 mmol) and
View Article Online
DOI: 10.1039/C5OB01140J
enolates with N-sulfonyl/chiral N-sulfinyl aldimines as the key dry THF (5.0 mL), a solution of β-amino ester 3a–k (2.32 mmol)
step.
dissolved in dry THF (10 mL) was slowly added at 0 °C and the
mixture was stirred at rt for 1–1.5 h. Then it was quenched with
ethyl acetate (5.0 mL) at 0 °C and reaction mixture was filtered
through sintered funnel. Further, water (10 mL) was added to
filtrate resulting the formation of white precipitate which was
separated again by filtra
times. In the filtrate, organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 x 10 mL). The
ethyl acetate layer was washed with brine solution (10 mL),
dried over anhydrous Na2SO4. The organic layer was
concentrated to give the crude product which was purified by
silica gel column chromatography (Ethyl acetate/petroleum
Experimental
General Remarks
Analytical thin layer chromatography (TLC) was carried out
using silica gel 60 F254 pre-coated plates. Visualization was
accomplished with UV lamp or I2
size was used for flash column chromatography using the
combination of ethyl acetate and petroleum ether as eluent.
Unless noted, all reactions were carried out in oven-dried
glassware under an atmosphere of nitrogen/argon using
anhydrous solvents. Where appropriate, all reagents were
purified prior to use following the guidelines of Perrin and
Armerego.20 All commercial reagents were used as received.
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded at 400 MHz/500 MHz. Chemical shifts were recorded
in parts per million (ppm, δ) relative to tetramethyl silane (δ
ether) to afford γ-amino alcohol 4a–k.
General procedure C: The cyclization of γ-amino alcohols (4ak) to
2-aryl-N-sulfonylazetidines (5ak) (Scheme 3, Table 1)
To a suspension of powdered KOH (21.3 mmol) in dry THF (10
mL), a solution of 4a
Then TsCl (7.81 mmol) was added portion wise at rt and the
reaction mixture was refluxed for 30 min (1 h for scheme
table ). After completion of the reaction, cold water was added
–k (7.1 mmol) in 25 mL dry THF was added.
1
0.00). H NMR splitting patterns are designated as singlet (s),
5
,
doublet (d), doublet of doublet (dd), triplet (t), quartet (q),
multiplet (m). Carbon nuclear magnetic resonance (13C NMR)
spectra were recorded at 100 MHz/125 MHz. Mass spectra (MS)
were obtained using ESI mass spectrometer (TOF). IR spectra
were recorded in KBr for solids. Melting points were
determined using a hot stage apparatus and are uncorrected.
Optical rotations were measured using a 2.0 mL cell with a 1.0
3
and the reaction mixture was extracted with ethyl acetate
twice. The combined organic layer was washed with brine, dried
over anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The crude azetidines 5a–k were
purified by column chromatography on silica gel using ethyl
acetate and petroleum ether as the eluent.
dm path length and are reported as [α]25 (c in g per 100 mL
D
solvent) at 25 °C. Enantiomeric excess were determined by
HPLC using chiralpak Cellulose 1 analytical column (detection at
254 nm).
General procedure D: The addition of K-enolate of methyl acetate
to N-aryl/alkyl)idene-p-toluenesulfinamide (9ae) (Table 2)
In a 25 mL dry two-necked round bottom flask fitted with
magnetic stir bar, nitrogen balloon, and rubber septum were
placed 1.0 mL of anhydrous tetrahydrofuran (THF) and 1.64 mL
KHMDS (1.5 M solution in toluene) (0.45 mmol) and the solution
was cooled to −78 °C. Then 0.07 mL (0.45 mmol) of methyl
acetate was added slowly into the reaction vessel at the same
temperature. The reaction mixture was stirred for another 1 h
and a solution of 0.1 g (0.30 mmol) of aryl/alkyl-N-sulfinyl imine
General procedure A: The addition of Li-enolate of ester to N-
sulfonimine (scheme 3, Table 1)
To a solution of diisopropylamine (4.24 mmol) in anhydrous
tetrahydrofuran (15 mL), n-butyl lithium (2.5 M solution in
hexane, 4.24 mmol) was added slowly at 0 °C and the solution
was stirred for 20 min at the same temperature. Then the
reaction flask was placed at −78 °C bath and ester (t-
butylacetate/ethyl isobutyrate) (4.24 mmol) was added. The
reaction mixture was stirred for another 1 h at the same
9a
–
e
in 1.0 mL of THF was added drop wise at −78 °C and the
10 h. Then the reaction was
mixture was stirred for 8.5
–
quenched with saturated NH4Cl solution (2.0 mL) at −78 °C, and
the mixture was allowed to warm to rt. The mixture was
extracted with ethyl acetate (3 x 4.0 mL) and the combined layer
were washed with saturated brine (5.0 mL), dried over
anhydrous Na2SO4. The organic layer was concentrated to give
the crude product which was purified by silica gel column
chromatography (15% ethyl acetate/petroleum ether) to afford
temperature. A solution of N-sulfonyl aldimine 2a–g (3.86
mmol) in THF (10 mL) was added drop wise and stirring was
continued for 2 h at the same temperature. The reaction was
quenched with saturated aqueous NH4Cl solution (10 mL) at −78
°C, and the mixture was allowed to warm to rt. The reaction
mixture was extracted with ethyl acetate (3 x 15 mL) and the
combined organic phase was washed with saturated brine (10
mL), dried over anhydrous Na2SO4. The organic layer was
concentrated to give the crude product which was purified by
silica gel column chromatography (Ethyl acetate/petroleum
β-amino ester 10a–e.
2-Phenyl-1-tosylazetidine (5a):
The general method described above was followed when 4a
C
ether) to afford β-amino esters 3a–k.
(100 mg, 0.32 mmol) was reacted with KOH (54 mg, 0.96 mmol)
and TsCl (67 mg, 0.35 mmol) at refluxing THF for 30 min. to
afford 92 mg of 5a as a white solid in 98% yield; mp 104–108 °C,
General procedure B: The reduction of β-amino ester (3ak) to γ-
aminoalcohol (4a–k) (Scheme 3, Table 1)
4 | J. Name., 2012, 00, 1-3
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Rf 0.52 (40% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3062, 2982, 2936, 1595, 1466, 1394, 1354, 1340, 1302, 1280,
1246, 1217, 1174, 1112, 1088, 1067, 1018, 974, 930, 842; 1H
NMR (400 MHz, CDCl3) δ 2.08–2.18 (m, 1H), 2.20–2.28 (m, 1H),
2.36 ( s, 3H); 3.64–3.75 (m, 2H), 4.80 (t, J = 8.3 Hz, 1H), 7.19–
7.35 (m, 7H), 7.61 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.6, 25.8, 47.2, 65.6, 126.3, 127.9, 128.4, 128.5, 129.6, 132.1,
140.5, 143.9; HRMS (ESI-TOF) calcd. for C16H18NO2S (M++H):
288.1058, found: 288.1056.
2-(4-Chlorophenyl)-1-tosylazetidine (5e):
The general method
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described above wDaOsI:f1o0l.l1o0w39e/Cd5wOBh0e1n1440eJ
C
(100 mg, 0.29 mmol) was reacted with KOH (49 mg, 0.87 mmol)
and TsCl (61 mg, 0.32 mmol) at refluxing THF for 30 min. to
afford 92 mg of 5e as a white solid in 97% yield; mp 165–170 °C;
Rf 0.36 (40% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3068, 3030, 2986, 2938, 2862, 1596, 1566, 1490, 1459, 1409,
1384, 1340, 1298, 1265, 1235, 1180, 1133, 1085, 1065, 1041,
1014, 982, 911, 863, 835, 799; 1H NMR (400 MHz, CDCl3) δ 2.04–
2.13 (m, 1H), 2.20–2.28 (m, 1H), 2.38 (s, 3H), 3.63–3.73 (m, 2H),
4.77 (t, J = 8.3 Hz, 1H), 7.19–7.29 (m, 6H), 7.60 (d, J = 8.3 Hz, 2H);
2-(2-Chlorophenyl)-1-tosylazetidine (5b):
The general method
C
described above was followed when 4b 13C NMR (100 MHz, CDCl3) δ 21.5, 25.7, 47.2, 64.8, 127.7, 128.4,
(100 mg, 0.29 mmol) was reacted with KOH (48 mg, 0.87 mmol) 128.6, 129.7, 132.0, 133.7, 139.1, 144.1; HRMS (ESI-TOF) calcd.
and TsCl (61 mg, 0.32 mmol) at refluxing THF for 30 min. to for C16H17ClNO2S (M++H): 322.0669, found: 322.0664.
afford 90 mg of 5b as a white solid in 95% yield; mp 160–165 °C;
Rf 0.35 (40% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3064, 3030, 2985, 2928, 2876, 1596, 1574, 1490, 1460, 1408,
1386, 1342, 1298, 1265, 1234, 1180, 1129, 1088, 1065, 1042,
1014, 976, 912, 868, 835; 1H NMR (400 MHz, CDCl3) δ 1.95–1.99
(m, 1H), 2.37–2.42 (m, 1H), 2.42 (s, 3H), 3.63–3.70 (m, 1H),
3.74–3.79 (m, 1H), 5.14 (t, J = 8.3 Hz, 1H), 7.15–7.34 (m, 5H),
7.69 (d, J = 8.3 Hz, 2H), 7.85 (dd, J = 7.8, 1.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.6, 24.9, 47.5, 62.9, 127.1, 127.9, 128.6,
128.7, 128.9, 129.8, 131.0, 131.2, 138.3, 144.2; HRMS (ESI-TOF)
calcd. for C16H17ClNO2S (M++H): 322.0669, found: 322.0666.
1-(4-Fluorophenylsulfonyl)-2-phenylazetidine (5f):
The general method described above was followed when 4f
C
(100 mg, 0.32 mmol) was reacted with KOH (54 mg, 0.96 mmol)
and TsCl (67 mg, 0.35 mmol) at refluxing THF for 30 min. to
afford 88 mg of 5f as a white solid in 93% yield; mp 126–128 °C;
Rf 0.32 (20% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3068, 2957, 2925, 2883, 1589, 1491, 1454, 1405, 1343, 1291,
1229, 1157, 1091, 1018, 956, 926, 841, 817; 1H NMR (400 MHz,
CDCl3) δ 2.10
–2.22 (m, 1H), 2.26
–2.35 (m, 1H), 3.70
–
–
3.79 (m,
7.73 (m,
2H), 4.87 (t, J = 8.3 Hz, 1H), 7.08
–7.34 (m, 7H), 7.70
2H); 13C NMR (100 MHz, CDCl3 ) δ 25.7, 47.1, 65.8, 116.1, 126.2,
2-(4-Nitrophenyl)-1-tosylazetidine (5c):
128.5, 130.9, 132.1, 140.1, 164.1, 166.6; HRMS (ESI-TOF) calcd.
The general method
C
described above was followed when 4c for C15H15FNO2S (M++H): 290.0651, found: 290.0650.
(100 mg, 0.28 mmol) was reacted with KOH (47 mg, 0.84 mmol)
and TsCl (59 mg, 0.31 mmol) at refluxing THF for 30 min. to
afford 81 mg of 5c as a white solid in 85% yield; mp 175–178 °C;
Rf 0.32 (40% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3068, 3027, 2995, 2923, 2852, 1598, 1515, 1492, 1439, 1347,
1317, 1302, 1291, 1238, 1211, 1182, 1156, 1108, 1089, 1070,
1-(4-Methoxyphenylsulfonyl)-2-phenylazetidine (5g):
The general method described above was followed when 4g
C
(100 mg, 0.31 mmol) was reacted with KOH (52 mg, 0.93 mmol)
and TsCl (65 mg, 0.34 mmol) at refluxing THF for 30 min. to
afford 86 mg of 5g as a white solid in 91% yield; mp 116–118 °C;
Rf 0.32 (35% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3071, 3032, 3004, 2980, 2956, 2885, 2840, 1596, 1496, 1455,
1439, 1413, 1364, 1338, 1310, 1300, 1258, 1234, 1188, 1154,
1095, 1061, 1023, 956, 927, 832, 803; 1H NMR (400 MHz, CDCl3)
δ 2.09–2.18 (m, 1H), 2.21–2.29 (m, 1H), 3.64–3.83 (m, 5H), 4.80
(t, J = 8.3 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 7.18–7.34 (m, 5H), 7.66
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3 ) δ 25.8, 47.0, 55.6,
65.5, 114.1, 126.3, 127.1, 127.9, 128.4, 130.5, 140.6, 163.3;
HRMS (ESI-TOF) calcd. for C16H18NO3S (M++H): 304.1007, found:
1
1026, 1014, 957, 932, 904, 857, 820, 800; H NMR (400 MHz,
CDCl3) δ 2.10–2.19 (m, 1H), 2.36–2.47 (m, 4H), 3.75–3.83 (m,
2H), 4.96 (t, J = 8.3 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.57 (d, J =
8.6 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 5.1 Hz, 2H); 13C
NMR (100 MHz CDCl3) δ 21.5, 25.5, 47.4, 64.3, 123.8, 127.0,
128.4, 129.8, 131.9, 144.5, 147.6, 147.8; HRMS (ESI-TOF) calcd.
for C16H17N2O4S (M++H): 333.0909, found: 333.0910.
2-(4-Methoxyphenyl)-1-tosylazetidine (5d):
The general method
C described above was followed when 4d 304.1007.
(100 mg, 0.29 mmol) was reacted with KOH (49mg, 0.87 mmol)
and TsCl (61 mg, 0.32 mmol) at refluxing THF for 30 min. to
afford 87 mg of 5d as a white solid in 92% yield; mp 68–72 °C;
Rf 0.40 (40% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3068, 2980, 2924, 2855, 1594, 1512, 1466, 1390, 1361, 1322,
1282, 1251, 1176, 1148, 1110, 1092, 1063, 1024, 981, 932, 895,
1-(4-tert-Butylphenylsulfonyl)-2-phenylazetidine (5h):
The general method
C described above was followed when 4h
(100 mg, 0.28 mmol) was reacted with KOH (47 mg, 0.84 mmol)
and TsCl (59 mg, 0.31 mmol) at refluxing THF for 30 min. to
afford 85 mg of 5h as a white solid in 90% yield; mp 122–124 °C;
Rf 0.38 (20% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3063, 3032, 2951, 1596, 1476, 1401, 1361, 1340, 1311, 1293,
1269, 1230, 1202, 1160, 1114, 1090, 1066, 1024, 958, 926, 834,
810; 1H NMR (400 MHz, CDCl3) δ 1.27 (s, 9H), 2.10–2.27 (m, 2H),
3.70–3.74 (m, 2H), 4.84 (t, J = 8.3 Hz, 1H), 7.18–7.34 (m, 5H),
7.43 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H); 13C NMR (100
MHz, CDCl3 ) δ 25.8, 31.1, 35.2, 47.0, 65.6, 125.9, 126.3, 127.9,
1
865, 832; H NMR (400 MHz, CDCl3) δ 2.08–2.21 (m, 2H), 2.35
(s, 3H), 3.59–3.69 (m, 2H), 3.70 (s, 3H), 4.70 (t, J = 8.3 Hz, 1H),
6.75–6.79 (m, 2H), 7.22–7.26 (m, 4H), 7.58 (d, J = 8.3 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 21.5, 25.9, 47.0, 55.2, 65.5, 113.8,
127.7, 128.3, 129.5, 132.2, 132.6, 143.8, 159.4; HRMS (ESI-TOF)
calcd. for C17H20NO3S (M++H): 318.1164 found: 318.1162.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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COMMUNICATION
Journal Name
128.3, 128.4, 140.5, 156.8; HRMS (ESI) calcd. for C19H24NO2S (25% Ethyl Acetate/Petroleum Ether); IR νmax (cmV-1ie,wKABrtric)le3O0n3lin2e,
(M++H): 330.1528, found: 330.1526.
2972, 2929, 2876, 1599, 1493, 1453, 1388, 1337, 1305, 1250,
1218, 1186, 1157, 1085, 1042, 1011, 978, 952, 819, 755; 1H NMR
(400 MHz, CDCl3) δ 0.84 (t, J = 7.3 Hz, 3H), 1.67–1.77 (m, 2H),
1.83–1.88 (m, 1H), 2.34–2.39 (m, 4H), 3.77–3.80 (m, 1H), 4.61
DOI: 10.1039/C5OB01140J
3,3-Dimethyl-2-phenyl-1-tosylazetidine (5i):
The general method
C described above was followed when 4i
(t, J = 8.3 Hz, 1H), 7.19–7.33 (m, 7H), 7.59 (d, J = 7.6 Hz, 2H); 13
C
(100 mg, 0.30 mmol) was reacted with KOH (50 mg, 0.90 mmol)
and TsCl (63 mg, 0.33 mmol) at refluxing THF for 30 min. to
afford 90 mg of 5i as a white solid in 95% yield; mp 132–134 °C;
Rf 0.38 (20% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3087, 3062, 3033, 2966, 2924, 2876, 1596, 1492, 1458, 1391,
1376, 1342, 1298, 1275, 1232, 1180, 1157, 1088, 1052, 1029,
NMR (100 MHz, CDCl3) δ 8.4, 21.5, 28.7, 31.6, 61.2, 62.1, 126.3,
127.8, 128.3, 128.4, 129.5, 132.7, 140.8, HRMS (ESI-TOF) calcd.
for C18H22NO2S (M++H): 316.1371, found: 316.1373.
(2R, 4S)-2-Ethyl-4-phenyl-1-tosylazetidine (5m):
1017, 975, 909, 869, 816, 802, 763; 1H NMR (400 MHz, CDCl3) δ The general method
C described above was followed when 7b
0.69 (s, 3H), 0.90 (s, 3H), 2.39 (s, 3H), 3.35–3.41 (m, 2H), 4.46 (s, (100 mg, 0.30 mmol) was reacted with KOH (50 mg, 0.90 mmol)
1H), 7.18–7.29 (m, 7H), 7.62 (d, J = 8.3 Hz, 2H); 13C NMR (100 and TsCl (63 mg, 0.33 mmol) at refluxing THF for 1.5 h to afford
MHz, CDCl3) δ 21.6, 22.9, 27.2, 36.0, 60.6, 74.5, 126.3, 127.6, 72 mg of 5m as a white solid in 76% yield; Low melting solid; Rf
128.0, 128.5, 129.5, 131.9, 137.0, 143.9; HRMS (ESI-TOF) calcd. 0.34 (25% Ethyl Acetate/Petroleum Ether); IR νmax (cm-1, KBr)
for C18H22NO2S (M++H): 316.1371, found: 316.1370.
3032, 2972, 2929, 2876, 1599, 1493, 1453, 1388, 1337, 1305,
1250, 1218, 1186, 1157, 1085, 1042, 1011, 978, 952, 819, 755;
1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 7.5 Hz, 3H), 1.35 (m, 1H),
1.69–1.77 (m, 1H), 2.14–2.24 (m, 2H), 2.27 (s, 3H), 4.25–4.31 (m,
2-(2-Chlorophenyl)-3,3-dimethyl-1-tosylazetidine (5j):
The general method
C described above was followed when 4j
1H), 5.11 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.3 Hz, 2H), 7.09–7.23
(100 mg, 0.27 mmol) was reacted with KOH (46 mg, 0.81 mmol)
and TsCl (57 mg, 0.30 mmol) at refluxing THF for 30 min. to
afford 90 mg of 5j as a white solid in 95% yield; mp 137–139 °C;
Rf 0.47 (25% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
3065, 3026, 2987, 2961, 2927, 2881, 1595, 1571, 1493, 1461,
1438, 1371, 1343, 1304, 1290, 1270, 1235, 1203, 1168, 1138,
1087, 1064, 1047, 1016, 975, 905, 864, 849, 819, 763; 1H NMR
(m, 7H); 13C NMR (100 MHz, CDCl3) δ 8.5, 21.4, 26.7, 30.9, 64.7,
127.1, 127.3, 127.9, 128.2, 129.0, 137.0, 138.9, 142.5; HRMS
(ESI-TOF) calcd. for C18H22NO2S (M++H): 316.1371, found:
316.1373.
(Ss,2R)-(+)-2-phenyl-1-(p-tolylsulfinyl)azetidine (12a):
(400 MHz, CDCl3) δ 0.71 (s, 3H), 0.96 (s, 3H), 2.40 (s, 3H), 3.34 The general method C described above was followed when 11a
(d, J = 7.6 Hz, 1H), 3.45 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H), 7.13–7.27 (100 mg, 0.35 mmol) was reacted with KOH (50 mg, 1.05 mmol)
(m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.79 (d, and TsCl (73 mg, 0.39 mmol) at refluxing THF for 1 h to afford
J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.6, 22.9, 27.6, 66 mg of 12a as a white solid in 70% yield; mp 56–58 °C; Rf 0.45
36.3, 60.7, 71.6, 126.7, 128.5, 128.6, 128.9, 129.5, 129.7, 131.9, (30% ethyl acetate in petroleum ether); [α]25 D = +257.1 (c 0.375
135.4, 144.1; HRMS (ESI-TOF) calcd. for C18H21ClNO2S (M++H): in CH2Cl2); IR νmax (KBr, cm-1) 2956, 2878, 1597, 1492, 1452,
350.0982, found: 350.0982.
1091, 1066, 812; 1H NMR (500 MHz, CDCl3) δ 2.22–2.28 (m, 1H),
2.40 (s, 3H), 2.43–2.49 (m, 1H), 2.73–2.75 (m, 1H), 3.96–4.02 (m,
1H), 5.29–5.33 (m, 1H), 7.21–7.59 (m, 9H); 13C NMR (125 MHz,
CDCl3) δ 21.5, 26.6, 37.5, 61.7, 125.7, 126.7, 128.0, 128.7, 129.6,
139.7, 141.2, 141.6; HRMS (ESI-TOF) calcd for C16H18NOS (M++H)
272.1109, found 272.1109.
2-(4-Methoxyphenyl)-3,3-dimethyl-1-tosylazetidine (5k):
The general method
C described above was followed when 4k
(100 mg, 0.27 mmol) was reacted with KOH (46 mg, 0.82 mmol)
and TsCl (57 mg, 0.30 mmol) at refluxing THF for 30 min. to
afford 90 mg of 5k as a white solid in 94% yield; mp 141–143 °C;
Rf 0.32 (25% Ethyl Acetate/Petroleum Ether); IR νmax (KBr, cm-1)
(Ss,2R)-(+)-2-(2-chlorophenyl)-1-(p-tolylsulfinyl)azetidine (12b):
3069, 2960, 2927, 2862, 2836, 1594, 1515, 1462, 1392, 1372, The general method C described above was followed when 11b
1335, 1303, 1253, 1177, 1157, 1109, 1089, 1065, 1037, 982, (100 mg, 0.31 mmol) was reacted with KOH (52 mg, 0.93 mmol)
1
933, 898, 873, 840, 812, 765; H NMR (400 MHz, CDCl3) δ 0.78 and TsCl (65 mg, 0.34 mmol) at refluxing THF for 1 h to afford
(s, 3H), 0.94 (s, 3H), 2.47 (s, 3H), 3.39 (d, J = 7.3 Hz, 1H), 3.46 (d, 77 mg of 12b as a white solid in 82% yield; mp 70 °C; Rf 0.23
J = 7.3 Hz, 1H), 3.79 (s, 3H), 4.45 (s, 1H), 6.86–6.89 (m, 2H), 7.24– (30% ethyl acetate in petroleum ether); [α]25 D = +87.7 (c 0.65 in
7.27 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H); 13
C
CH2Cl2); IR νmax (KBr, cm-1) 2968, 2873, 1592, 1469, 1089, 1065,
NMR (100 MHz, CDCl3 ) δ 21.5, 22.8, 27.0, 36.2, 55.2, 60.5, 74.4, 1036, 824, 754; 1H NMR (400 MHz, CDCl3): δ 2.04–2.13 (m, 1H),
113.6, 127.1, 127.6, 128.5, 129.2, 129.5, 143.8, 159.2; HRMS 2.43 (s, 3H), 2.63–2.71 (m, 1H), 2.74–2.79 (m, 1H), 4.04–4.10 (m,
(ESI-TOF) calcd. for C19H24NO3S (M++H): 346.1477, found: 1H), 5.64 (t, J = 8.6 Hz, 1H), 7.24– 7.38 (m, 4H), 7.65 (d, J = 8.0
346.1474.
Hz, 2H), 7.83 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
21.4, 25.6, 37.6, 58.8, 125.5, 126.9, 127.1, 128.6, 129.5, 129.6,
131.9, 139.3, 139.7, 141.3; HRMS (ESI-TOF) calcd for
C16H17ClNOS (M++H) 306.0719, found 306.0719.
(2S, 4S)-2-Ethyl-4-phenyl-1-tosylazetidine (5l):
The general method
C described above was followed when 7a
(100 mg, 0.30 mmol) was reacted with KOH (50 mg, 0.90 mmol)
and TsCl (63 mg, 0.33 mmol) at refluxing THF for 1.5 h to afford
66 mg of 5l as a white solid in 70% yield; mp 130–132 °C; Rf 0.36
(Ss,2R)-(+)-2-(3-bromophenyl)-1-(p-tolylsulfinyl)azetidine
(12c):
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
The general method
COMMUNICATION
C
described above was followed when 11c 7H), 7.61 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
View Article Online
DOI: 10.1039/C5OB01140J
(100 mg, 0.27 mmol) was reacted with KOH (46 mg, 0.81 mmol) 21.6, 25.8, 47.2, 65.6, 126.3, 127.9, 128.4, 128.5, 129.6, 132.1,
and TsCl (57 mg, 0.30 mmol) at refluxing THF for 1 h to afford 140.5, 143.9; HRMS (ESI-TOF) calcd. for C16H18NO2S (M++H):
81 mg of 12c as a white solid in 85% yield; mp 89–92 °C; Rf 0.35 288.1058, found: 288.1056; ee 84%. The enantiomeric excess
(30% ethyl acetate in petroleum ether); [α]25 D = +135.5 (c 0.62 was determined by chiral HPLC analysis (Cellulose 1), n-
in CH2Cl2); IR νmax (KBr, cm-1) 2921, 2852, 1593, 1426, 1359, hexane/i-propanol = 90:10, flow rate = 1.0 mL/min, tR (2) = 11.35
1
1092, 1030, 810; H NMR (400 MHz, CDCl3, ppm): δ 2.13–2.19 min (major).
(m, 1H), 2.36 (s, 3H), 2.65–2.68 (m, 1H), 3.89–3.96 (m, 1H), 5.19
(t, J = 8.0 Hz, 1H), 7.24–7.46 (m, 5H); 7.58 (d, J = 8.3 Hz, 2H), 7.67
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 21.4, 26.4, 37.5, 60.8,
122.8, 125.3, 125.6, 128.6, 129.6, 130.2, 131.0, 139.3, 141.3,
143.9; HRMS (ESI-TOF) calcd for C16H17BrNOS (M++H) 350.0214,
found 350.0214.
Acknowledgements
M.K.G. is grateful to DST, India, for financial support. S.D thanks
to U.G.C, India for a research fellowship.
(Ss,2R)-(+)-2-p-tolyl-1-(p-tolylsulfinyl)azetidine (12d):
Notes and references
1
The general method C described above was followed when 11d
(a) B. I. Ericksson, S. Carlsson, M. Halvarsson, B. Risberg, and
C. Mattsson, Thromb. Haemostosis, 1997, 78, 1404; (b) I. Kirk,
(Astrazeneca AB), PCT Int. Appl. WO 2000041716, 2000;
Chem. Abstr., 2000, 123, 99559; (c) D.-G. Liu, and G.-Q. Lin,
Tetrahedron Lett., 1999, 40, 337; (d) T. Shioiri, Y. Hamada, and
F. Matsuura, Tetrahedron, 1995, 51, 3939; (e) S. Obika, J-i.
Andoh, M. Onoda, O. Nakagawa, A. Hiroto, T. Sugimoto, and
T. Imanishi, Tetrahedron Lett., 2003, 44, 5267; (f) T. Takemoto,
K. Nomoto, S. Fushiya, R. Ouchi, G. Kusano, H. Hikino,; S-i.
Takagi, Y. Matsuura, and M. Kakudo, Proc. Jpn. Acad. Ser. B,
1978, 54, 469; (g) S. Singh, G. Crossaley, S. Ghosal, Y. Lefievre,
and M. W. Pennington, Tetrahedron Lett., 2005, 46, 1419; (h)
(100 mg, 0.33 mmol) was reacted with KOH (56 mg, 0.99 mmol)
and TsCl (69 mg, 0.36 mmol) at refluxing THF for 1 h to afford
71 mg of 12d as a colorless liquid in 75% yield; Rf 0.37 (30% ethyl
acetate in petroleum ether); [α]25 D = +208.4 (c 0.475 in CH2Cl2);
IR νmax (neat, cm-1) 2924, 2855, 1598, 1459, 1362, 1176, 1099,
1
809, 719; H NMR (400 MHz, CDCl3): δ 2.16–2.28 (m, 2H), 2.33
(s, 3H), 2.44 (s, 3H), 3.67–3.72 (m, 1H), 3.75–3.79 (m, 1H), 4.80
(t, J = 8.3 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.29–7.33 (m, 4H), 7.68
(d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 21.3, 21.7, 26.0,
47.3, 65.8, 126.4, 128.6, 129.3, 129.7, 132.0, 137.7, 137.9,
144.0; HRMS (ESI-TOF) calcd for C17H20NOS (M+H)+ 286.1266,
found 286.1266.
K. Isono, K. Asahi, and S. Suzuki, J. Am. Chem. Soc., 1969, 91
,
7490; (i) T. Akihisa, S. Mafune, M. Ukiya, Y. Kimura, K.
Yasukawa, T. Suzuki, H. Tokuda, N. Tanabe, and T. Fukuoka, J.
Nat. Prod., 2004, 67, 479; (j) D. Jin, S. Takai, M. Yamada, M.
Sakaguchi, and M. Miyazaki, Life Sci., 2002, 71, 437; (k) E.
Ziemińska, A. Stafiej, and J. W. Łazarewicz, Neurochem. Int.,
2003, 43, 481; (l) Y. Ohfune, M. Tomita, and K. Nomoto, J. Am.
Chem. Soc., 1981, 103, 2409; (m) Q. Cheng, H. Kiyota, M.
Yamaguchi, T. Horiguchi, and T. Oritani, Bioorg. Med. Chem.
Lett., 2003, 13, 1075; (n) A. W. Bannon, M. W. Decker, M. W.
Holladay, P. Curzon, D. Donnelly-Roberts, P. S. Puttfarcken, R.
S. Bitner, A. Diaz, A. H. Dickenson, R. D. Porsolt, M. Williams,
and S. P. Arneric, Science, 1998, 279, 77; (o) K. J. af Forselles,
J. Root, T. Clarke, D. Davey, K. Aughton, K. Dack, and N. Pullen,
Br J. Pharmacol., 2011, 164, 1847; (p) K. Lu, Y. Jiang, B. Chen,
E. M. Eldemenky, G. Ma, M. Packiarajan, G. Chandrasena, A.
D. White, K. A. Jones, B. Li, and S.-P. Hong, Bioorg. Med. Chem.
Lett., 2011, 11, 5310.
(Ss,2R)-(+)-2-cyclohexyl-1-(p-tolylsulfinyl)azetidines (12e):
The general method C described above was followed when 11e
(100 mg, 0.34 mmol) was reacted with KOH (57 mg, 1.02 mmol)
and TsCl (71 mg, 0.37 mmol) at refluxing THF for 1 h to afford
64 mg of 12e as a colorless liquid in 81% yield; Rf 0.42 (30% ethyl
acetate in petroleum ether); [α]25 D = +65.0 (c 0.2 in CH2Cl2); IR
νmax (neat, cm-1) 3484, 2925, 2852, 1597, 1492, 1448, 1397,
1378, 1350, 1302, 1263, 1236, 1177, 1163, 1092, 1068, 1047,
1017, 994, 974, 940, 922, 889, 811; 1H NMR (400 MHz, CDCl3): δ
0.88–1.04 (m, 2H), 1.18–1.28 (m, 3H), 1.57–1.79 (m, 5H), 1.89–
1.99 (m, 2H), 2.05–2.09 (m, 1H), 2.37 (s, 3H), 2.60 (td, J = 8.9 Hz,
3.9 Hz, 1H), 3.86 (dd, J = 16.9 Hz, 9.2 Hz, 1H), 4.01 (dd, J = 16.3
Hz, 8.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H);
13C NMR (125 MHz, CDCl3): δ 21.1, 21.4, 25.8, 26.5, 27.8, 29.0,
37.2, 44.3, 64.7, 125.6, 129.5, 140.2, 141.0; HRMS (ESI-TOF)
calcd for C16H24NOS (M+H)+ 278.1579, found 278.1572.
2
(a) L. Kiss, S. Mangelinckx, F. Fülöp, and N. De Kimpe, Org.
Lett., 2007,
9, 4399; (b) F. Couty, G. Evano, M. Vargass-
Sanchez, and G. Bouzas, J. Org. Chem., 2005, 70, 9028; (c) D.
Enders, and J. Gries, Synthesis, 2005, 3508; (d) W. V.
Branbandt, G. Verniest, D. De Smaele, G. Duvey, and N. De
Kimpe, J. Org. Chem. 2006, 71, 7100; (e) L.-G. Meng, P. Cai, Q.
Guo, and S. Xue, J. Org. Chem., 2008, 73, 8491; (f) M.
Sivaprakasam, F. Couty, O. David, J. Marrot, R. Sridhar, B.
Srinivas, and K. R. Rao, Eur. J. Org. Chem., 2007, 5734; (g) H.
(R)-2-Phenyl-1-tosylazetidine ((R)-5a):
The general method
C described above was followed when (R)-
Lu, and C. Li, Org. Lett., 2006,
Testaferri, A. Temperini, R. Terlizzi, L. Bagnoli, F. Marini, and
C. Santi, Org. Biomol. Chem., 2007, , 3510; (i) E. Banide, V. L.
8, 5365; (h) M. Tiecco, L.
4a (100 mg, 0.32 mmol) was reacted with KOH (54 mg, 0.96
mmol) and TsCl (67 mg, 0.35 mmol) at refluxing THF for 45 min.
5
to afford 70 mg of (R)-5a as a white solid in 75% yield; mp 104
–
=
de Talancé, G. Schmidt, H. Lubin, S. Comesse, L. Dechoux, L.
Hamon, and C. Kadouri-Puchot, Eur. J. Org. Chem., 2007,
4517; (j) F. Couty, and D. Prim, Tetrahedron: Asymmetry,
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Organic & Biomolecular Chemistry
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