Palladium-catalyzed sequential one-pot reaction of aryl bromides with O-homoallylhydroxylamines: Synthesis of N-aryl-β-amino alcohols

Article abstract of DOI:10.1039/b701509g

The palladium-catalyzed sequential one-pot N-arylation-carbo-amination-C- arylation of O-homoallylhydroxylamines with two different aryl bromides provides rapid entry to differentially arylated N-aryl-3-arylmethylisoxazolidines in good yields with excelle

Full text of DOI:10.1039/b701509g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Palladium-catalyzed sequential one-pot reaction of aryl bromides with
O-homoallylhydroxylamines: synthesis of N-aryl-b-amino alcohols†
Jinsong Peng,a,b Dahong Jiang,a,b Wenqing Lina and Yuanwei Chen*a
Received 31st January 2007, Accepted 6th March 2007
First published as an Advance Article on the web 21st March 2007
DOI: 10.1039/b701509g
The palladium-catalyzed sequential one-pot N-arylation–carbo-amination–C-arylation of
O-homoallylhydroxylamines with two different aryl bromides provides rapid entry to differentially
arylated N-aryl-3-arylmethylisoxazolidines in good yields with excellent diastereoselectivity. The
obtained isoxazolidines can be reductively cleaved to cis-N-aryl-b-amino alcohols in short times and in
high yields at room temperature.
the one-pot diarylation process of O-homoallylhydroxylamine, we
Introduction
set out to examine the selective addition reaction of two different
The synthesis of isoxazolidine derivatives has received much
aryl bromides (eqn (2)). A transformation of this type would lead
attention as they are useful synthons for the construction of
to the formation of two C–N bonds, one C–C bond and one ring
biologically important amino acids, b-lactams, b-amino alcohols,
in a single operation.
amino carbohydrates and alkaloids.1 The 1,3-dipolar cycloaddi-
tion of nitrones with alkenes was among the important reactions
for the construction of substituted isoxazolidines. However, this
synthetic methodology usually failed to control the stereose-
lectivity in reactions of acyclic nitrones with simple terminal
alkenes.2 A number of different synthetic methods have been
devised for their preparation.3 Over the past several years, the
palladium-catalyzed tandem synthesis of pyrrolidine derivatives
was reported via intramolecular insertion of an olefin into a
Pd(Ar)(ArNR) intermediate.4 Recently, Dongol and Tay3d re-
ported the Pd-catalyzed cascade reaction of N-Boc protected O-
homoallylhydroxylamines with aryl iodides to afford the corre-
sponding isoxazolidines, contaminated by substantial Heck type
side products with modest diastereoselectivity. Herein, we report
on stereocontrolled palladium-catalyzed syntheses of differentially
arylated N-aryl-3-arylmethylisoxazolidines via sequential one-pot
diarylation of O-homoallylhydroxylamines with two different aryl
bromides.
In order to carry out this process, we judiciously screened
the palladium catalyst, ligand and reaction temperature. Some
results from that study are summarized in Table 1. We chose
to employ monodentate ligands for the first step of the re-
action sequence. Chelating bis(phosphine) ligands, which have
been found to be effective in a broad range of carboam-
ination processes,4e were employed for the second reaction
of the sequence. Using a catalyst comprising Pd2(dba)3/P(o-
tol)3/Xantphos, no desired product was formed (entry 1, Table 1).
Changing the mono(phosphine) ligand from P(o-tol)3 to (furyl)3P,
the monoarylation product of the primary hydroxylamine was
obtained and the second step of the reaction did not pro-
ceed, perhaps due to failure in the ligand exchange (entry 2,
Table 1). BINAP, 2-di-tert-butylphosphinobiphenyl (4) and 2-
dicyclohexylphosphinobiphenyl (5) were found to be highly effec-
tive and selective for the Pd-catalyzed monoarylation of primary
aliphatic amines.4d,6 When we examined this type of phosphine
ligands, we were pleased to find that the ligand combination of
4/Xantphos provided the desired product 12a7 in 55% isolated
yield (entries 3–5, Table 1). We then carefully screened various
bis(phosphine) ligands (dppe, dppb, dppf and DPE-phos5) for
Results and discussions
It was known that both palladium-catalyzed N-arylations of
amines and Pd-catalyzed carboamination reactions are very
sensitive to catalyst structure and ligand.4 To determine the
feasibility of the N-arylation–carboamination process, we first
examined the reaction of O-homoallylhydroxylamine (1) with 2.05
equiv. of bromobenzene. We were pleased to find that the use of a
catalyst comprising Pd2(dba)3 and Xantphos (2)5 in the presence of
NaOtBu (2.4 equiv.) in toluene provided the desired cis product 3 in
82% isolated yield (eqn (1)). Having demonstrated the viability of
aKey Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan
Province and Union Laboratory of Asymmetric Synthesis, Chengdu Institute
of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041,
China. E-mail: chenyw@cioc.ac.cn
bGraduate School of Chinese Academy of Sciences, Beijing, 100039, China
† Electronic supplementary information (ESI) available: NMR data. See
DOI: 10.1039/b701509g
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Table 1 Pd-Catalyzed sequential one-pot reaction condition optimi-
transformation (entries 1–8, Table 2). The tandem transformations
of substrates 1 and 6–11, which bear substituents at the 1-position,
proceeded with high levels of diastereoselectivity.7 Reactions of 1-
aryl-O-homoallylhydroxylamines 1 and 6–9 exclusively afforded
3,5-cis-disubstituted isoxazolidines (entries 1–12, Table 2). Trans-
formation of 1-styryl-O-homoallylhydroxylamine 10 also pro-
ceeded (entry 13, Table 2), and 1-alkyl-O-homoallylhydroxylamine
11 was transformed to 3,5-cis-disubstituted products as their cis
isomers (entry 14, Table 2).
The sequential one-pot differential diarylation of O-homo-
allylhydroxylamine was further utilized for the synthesis of cis-
N-aryl-b-amino alcohols8 13a–c (Scheme 1). The most common
methods for the reductive ring opening of isoxazolidines include
LiAlH4, catalytic hydrogenation and zinc in acetic acid.9 Our initial
screening with these methods proved unsuccessful in providing
the desired N-aryl-b-amino alcohols. When N-aryl-3-arylmethyl-
isoxazolidines were subjected to a reaction mixture of chlorotri-
methyl silane, water and KI in acetonitrile at room temperature,10
the desired cis-b-amino alcohol11 was formed in high yield (>97%).
zationa
Entry
L1/Temp
L2/Temp
Yield (%)b
1
2
3
4
5
6
7
8
9
P(o-tol)3/100 ◦
C
C
Xantphos/100 ◦
Xantphos/100 ◦
Xantphos/100 ◦
C
C
C
0
0c
(furyl)3P/100 ◦
BINAP/100 ◦
C
0c
4/60 ◦
4/40 ◦
5/40 ◦
4/40 ◦
4/40 ◦
4/40 ◦
4/40 ◦
C
C
C
C
C
C
C
Xantphos/90 ◦
Xantphos/90 ◦
Xantphos/90 ◦
C
C
23d
55
16
29
27
32
18
C
Dppe/100 ◦
C
Dppb/100 ◦
Dppf/100 ◦
DPE-phos/100 ◦
C
C
10
C
a Conditions: 1.0 equiv. of hydroxylamine, 1.0 equiv. of PhBr, 2.4 equiv.
of NaOtBu, 1.5 mol% Pd2(dba)3, 3 mol% L1, toluene (0.2 M), then 3
mol% L2, 1.2 equiv. of p-CN–C6H4Br. b Yield of isolated product. c N-
Phenyl-3-phenyl-O-homoallylhydroxylamine was isolated. d N-Biarylation
product was also isolated from the reaction mixture.
the second reaction of the sequence, however, worse results were
observed (entries 7–10, Table 1).
With the optimized reaction condition in hand, we prepared
a large range of differentially arylated N-aryl-3-arylmethyl-
isoxazolidine derivatives (Table 2). As shown in Table 2, this
method is effective for the conversion of a variety of O-homoallyl-
hydroxylamines to N-aryl-3-arylmethylisoxazolidine derivatives.
In general, electron-neutral, -deficient or -rich aryl bromides as
the first coupling partner are efficiently transformed in the first
step of the sequential reaction (entries 1–3, Table 2). Electron-
neutral, -deficient, or hetero aryl bromides as the second coupling
partner provide the best yield in the second step of the sequential
Scheme 1 Synthesis of N-aryl-b-amino alcohols 13a–c.
A proposed reaction mechanism of the tandem one-pot ary-
lation of O-homoallylhydroxylamines to isoxazolidine derivatives
is shown in Scheme 2. This transformation presumably occurs
through initial Pd/4-catalyzed N-arylation of hydroxylamine 1a
Table 2 Palladium-catalyzed stereoselective synthesis of N-aryl-3-arylmethylisoxazolidine derivativesa
Entry
R
Ar1
Ar2
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
Ph, 1
Ph
p-CN-Ph
12a
12b
12c
12d
12e
12f
12g
12h
12i
55
52
64
58
63
66
64
62
51
54
67
57
53
49
Ph, 1
p-Cl–Ph
p-MeO–Ph
Ph
Ph
Ph
Ph
Ph
p-CO2tBu–Ph
p-NO2–Ph
p-CN–Ph
Ph
p-NO2–Ph
p-biphenyl
p-CN–Ph
p-CN–Ph
p-(1,3-Dioxolan-2-yl)phenyl
p-Biphenyl
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Ph
Ph, 1
Ph, 1
Ph, 1
p-Me–Ph, 6
6
6
2-Thienyl, 7
7
p-Me–Ph
p-CO2tBu–Ph
p-Me–Ph
Ph
Ph
12j
p-Cl–Ph, 8
p-MeO–Ph, 9
(E)-styryl, 10
TBSOCH2, 11
12k
12l
12m
12n
a Conditions: 1.0 equiv. of hydroxylamine, 1.0 equiv. of Ar1Br, 2.4 equiv. of NaOtBu, 1.5 mol% Pd2(dba)3, 3 mol% 4, toluene (0.2 M), 40–60 ◦C, then 3
◦
mol% Xantphos, 1.2 equiv. of Ar2Br, 90 C. b Yield of isolated product. c This material contained ca. 17% of the corresponding (E)-1-phenylhexa-2,5-
dien-1-hydroxylamine as an inseparable impurity.
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which the R group is oriented in the pseudoaxial position. The
alkene insertion via 15a would afford intermediate 16a, which
would provide the observed cis-3,5-disubstituted product 17a
upon C–C bond-forming reductive elimination.
Conclusions
In summary, we have successfully developed an efficient protocol
for the palladium-catalyzed stereoselective synthesis of N-aryl-3-
arylmethylisoxazolidines via sequential N-arylation–cyclization–
C-arylation of O-homoallylhydroxylamines with two different aryl
bromides. The selective diarylation is achieved in a one-pot process
by an in situ modification of the palladium catalyst via phosphine
ligand exchange. The obtained isoxazolidines can be reductively
cleaved to N-aryl-b-amino alcohols in short times and in high
yields at room temperature.
Experimental
Scheme 2 Proposed catalytic cycle.
Chemicals and solvents were all purchased from commercial
supplies and purified by standard techniques. NMR spectra were
recorded on a Bruker-300 MHz spectrometer, 13C NMR spectra
were recorded at 75 MHz. Chemical shifts (d) are given in parts per
million (ppm) downfield relative to CDCl3. Coupling constants are
given in hertz (Hz). Unless otherwise stated deuterochloroform
(CDCl3) was used as solvent. In assignment of the 1H NMR
spectra, multiplicities and abbreviations used are as follows; Ar =
aromatic, Ph = phenyl, Py = pyridyl, d = doublet, dd = doublet of
doublets, m = multiplet, q = quartet, s = singlet, t = triplet. High-
resolution mass spectra were recorded on a Bruker BIO TOF Q
mass spectrometer.
with the first aryl bromide to form intermediate 14 and Pd(0),
then a key substitution of the Xantphos ligand for 4 is proposed
to occur. Oxidative addition of the second aryl bromide to the
Xantphos/Pd(0) species is followed by reaction of the resulting
complex with 14 and base to afford an intermediate [Pd(Ar)-
(RONAr)] complex 15. A syn insertion of the alkene into the Pd–N
in 15 then affords the carboamination intermediate 16. Complex
16 undergoes C–C bond forming reductive elimination to afford
the product 17.
The palladium-catalyzed conversion of 1-substituted O-
homoallylhydroxylamines to cis-3,5-disubstituted isoxazolidines
(Table 2) proceeds with excellent levels of diastereoselectivity. To
explain the stereochemical outcome of these transformations, we
suggest that the stereochemistry determining step is the insertion
of the alkene into the Pd–N bond of intermediate 15 (Scheme 2).
As shown below (Scheme 3), the conversion of 1-substituted N-
aryl-O-homoallylhydroxylamine 14 to cis-3,5-disubstituted isoxa-
zolidine 17a proceeds via conformer 15a. In this conformer 15a,
the R substituent is oriented in the pseudoequatorial position to
minimize nonbonding interactions with the N-aryl group and C-3
hydrogen, moreover, N-aryl group is oriented in the pseudoaxial
position to minimize interaction with the aryl group or phosphine
ligand bound to the Pd complex. The combination of these two
interactions would disfavor reaction through conformer 15b in
General procedure for the preparation of
O-homoallylhydroxylamine substrates
A solution of DEAD (1.5 equiv.) in dry THF (0.25 M) was
added dropwise to a solution of the homoallylic alcohol,3 triph-
enylphosphine (1.2 equiv.) and N-hydroxyphthalimide (1.2 equiv.)
in dry THF (0.25 M) under nitrogen at 0 ◦C. The mixture was
allowed to warm to room temperature and stirred for five hours.
THF was then evaporated and the residue was purified by
flash chromatography on silica gel, eluting with 5–10% ethyl
acetate–hexane. The product was dissolved in dichloromethane
(ca. 0.3 M). Hydrazine hydrate (3 equiv.) was added and the
mixture was stirred at room temperature for four hours. The
Scheme 3 Proposed stereochemistry of 3,5-disubstituted isoxazolidines.
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mixture was filtered through celite, washing with dichloromethane,
and the dichloromethane was removed under reduced pressure.
The residue was purified by flash chromatography on silica gel,
eluting with 5–10% ethyl acetate–petroleum ether.
organic extracts were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was then purified
by flash chromatography on silica gel, eluting with 5–30% ethyl
acetate–petroleum ether.
Hydroxylamine 6. 1H (300 MHz, CDCl3) d 7.17–7.26 (m, 4H),
5.73–5.78 (m, 1H), 5.20 (br, 2H), 5.02–5.11 (m, 2H), 4.50–4.55
(m, 1H), 2.57–2.60 (m, 1H), 2.38–2.44 (m, 1H), 2.36 (s, 3H). 13C
(75 MHz, CDCl3) d 138.2, 137.4, 134.5, 129.1, 126.7, 116.9, 86.4,
40.4, 21.1.
( )-(3R,5R)-3-(4-Cyanobenzyl)-2,5-diphenylisoxazolidine (12a).
Yield 55%; 1H (300 MHz, CDCl3) d 7.60–7.63 (d, J = 8.1 Hz, 2H),
7.37–7.48 (m, 7H), 7.19–7.24 (m, 2H), 6.93–6.95 (m, 1H), 6.79–
6.82 (m, 2H), 5.09–5.15 (m, 1H), 4.12–4.15 (m, 1H), 3.24–3.32 (dd,
J = 13.5, 9 Hz, 1H), 2.95–3.01 (dd, J = 13.5, 2 Hz, 1H), 2.82–2.86
(m, 1H), 2.11–2.15 (m, 1H). 13C (75 MHz, CDCl3) d 151.4, 144.7,
138.4, 132.3, 130.4, 129.1, 128.7, 128.3, 126.5, 121.7, 118.9, 113.8,
110.5, 79.8, 68.8, 43.7, 42.8. HRMS-ESI (m/z): [M + Na]+ calcd
for C23H20N2NaO, 363.1468; found, 363.1463.
Hydroxylamine 7. 1H (300 MHz, CDCl3) d 7.28–7.30 (m, 1H),
6.98–7.03 (m, 2H), 5.78–5.80 (m, 1H), 5.32 (br, 2H), 5.05–5.15
(m, 2H), 4.81 (m, 1H), 2.70–2.75 (m, 1H), 2.17–2.56 (m, 1H). 13
C
(75 MHz, CDCl3) d 144.6, 133.98, 126.5, 125.6, 125.1, 117.4, 81.7,
( )-(3R,5R)-2-(4-Chlorophenyl)-3-(4-cyanobenzyl)-5-phenyl-
isoxazolidine (12b). Yield 52%; H (300 MHz, CDCl3) d 7.61–
40.3.
1
Hydroxylamine 8. 1H (300 MHz, CDCl3) d 7.32–7.35 (m, 2H),
7.24–7.27 (m, 2H), 5.68–5.77 (m, 1H), 5.08 (br, 2H), 5.01–5.08 (m,
2H), 4.52–4.56 (t, J = 6 Hz, 1H), 2.52–2.59 (m, 1H), 2.37–2.42 (m,
1H). 13C (75 MHz, CDCl3) d 139.98, 133.9, 133.4, 128.6, 128.1,
117.4, 85.7, 40.3.
7.63 (d, J = 8.1 Hz, 2H), 7.37–7.46 (m, 5H), 7.32–7.35 (d, J =
9 Hz, 2H), 7.15–7.18 (d, J = 6.9 Hz, 2H), 6.70–6.73 (d, J = 9 Hz,
2H), 5.05–5.11 (m, 1H), 4.07 (m, 1H), 3.21–3.24 (dd, J = 13.5,
9 Hz, 1H), 2.95–3.00 (dd, J = 13.5, 5.1 Hz, 1H), 2.83–2.87 (m,
1H), 2.14 (m, 1H). 13C (75 MHz, CDCl3) d 150.0, 144.4, 138.1,
133.2, 132.3, 130.4, 128.8, 128.6, 126.6, 126.5, 115.1, 113.3, 110.6,
79.9, 68.9, 43.7, 42.7. HRMS-ESI (m/z): [M + Na]+ calcd for
C23H19ClN2NaO, 397.1085; found, 397.1081.
Hydroxylamine 9. 1H (300 MHz, CDCl3) d 7.23–7.26 (m, 2H),
6.88–6.92 (m, 2H), 5.70–5.79 (m, 1H), 5.18 (br, 2H), 5.00–5.08 (m,
2H), 4.46–4.51 (t, J = 6 Hz, 1H), 3.80 (s, 3H), 2.57–2.62 (m, 1H),
2.39–2.42 (m, 1H). 13C (75 MHz, CDCl3) d 152.2, 127.4, 126.1,
121.0, 109.9, 106.8, 79.1, 48.1, 33.3.
( )-(3R,5R)-2-(4-Methoxyphenyl)-3-(4-cyanobenzyl)-5-phenyl-
1
isoxazolidine (12c). Yield 64%; H (300 MHz, CDCl3) d 7.61–
7.64 (d, J = 9 Hz, 2H), 7.34–7.47 (m, 7H), 6.62–6.65 (d, J = 9 Hz,
2H), 6.41–6.43 (d, J = 9 Hz, 2H), 4.95–5.01 (m, 1H), 4.15 (m, 1H),
3.83 (s, 3H), 3.21–3.28 (dd, J = 13.5, 9 Hz, 1H), 3.02–3.08 (dd,
Hydroxylamine 10. 1H (300 MHz, CDCl3) d 7.29–7.44 (m, 5H),
6.62–6.67 (d, J = 15 Hz, 1H), 6.12–6.20 (dd, J = 15, 9 Hz, 1H),
5.74 (m, 1H), 5.30 (br, 2H), 5.08–5.17 (m, 2H), 4.15–4.18 (m, 1H),
2.35–2.51 (m, 2H). 13C (75 MHz, CDCl3) d 135.2, 134.4, 129.7,
128.7, 128.1, 126.4, 125.5, 116.4, 81.8, 38.5.
J = 13.5, 4.5 Hz, 1H), 2.86–2.90 (m, 1H), 2.14–2.21 (m, 1H). 13
C
(75 MHz, CDCl3) d 154.5, 143.8, 142.6, 137.2, 132.6, 130.4, 128.7,
128.6, 126.3, 118.7, 113.4, 110.8, 110.0, 80.5, 67.9, 55.1, 43.6, 42.4.
HRMS-ESI (m/z): [M + Na]+ calcd for C24H22N2NaO2, 393.1578;
found, 393.1573.
Hydroxylamine 11. 1H (300 MHz, CDCl3) d 5.78–5.87 (m, 1H),
5.38 (br, 2H), 5.02–5.12 (m, 2H), 3.62–3.68 (m, 3H), 2.26–2.32 (m,
2H), 0.89 (s, 9H), 0.06 (s, 6H). 13C (75 MHz, CDCl3) d 134.9, 116.8,
84.0, 63.7, 34.5, 25.9, 18.3, −5.4.
( )-(3R,5R)-3-[4-(1,3-Dioxolan-2-yl)benzyl]-2,5-diphenylisoxa-
zolidine (12d). Yield 58%; 1H (300 MHz, CDCl3) d 7.32–7.45 (m,
11H), 6.87–6.90 (m, 3H), 5.81 (s, 1H), 5.02 (m, 1H), 4.17 (m, 1H),
4.10–4.14 (m, 4H), 3.28–3.35 (dd, J = 13.5, 8.8 Hz, 1H), 2.82–2.89
(dd, J = 13.5, 5 Hz, 1H), 2.66–2.71 (m, 1H), 2.05 (m, 1H). 13C
(75 MHz, CDCl3) d 151.9, 140.9, 138.4, 135.1, 129.5, 128.7, 128.5,
128.2, 126.6, 126.5, 121.4, 114.0, 109.3, 79.9, 69.6, 67.7, 43.8, 43.0.
HRMS-ESI (m/z): [M + Na]+ calcd for C25H25NNaO3, 410.1731;
found, 410.1734.
General procedure for the palladium-catalyzed sequential one-pot
synthesis of N-aryl-3-arylmethylisoxazolidines using two different
aryl bromides
A flame-dried tube was cooled under a stream of nitrogen
and charged with Pd2(dba)3 (1.5 mol% complex, 3 mol% Pd),
2-di-tert-butylphosphinobiphenyl (3 mol%), and NaOtBu (2.4
equiv.). The tube was purged with nitrogen, and toluene (10 mL
mmol−1 hydroxylamine substrate), the hydroxylamine substrate
(1.0 equiv.), and the first aryl bromide (1 equiv.) were added via
a syringe. The mixture was heated to 40–60 ◦C with stirring until
the hydroxylamine substrate had been consumed as judged by
TLC. A 0.01 M toluene solution of Xantphos (3 mol%) was added
and the reaction mixture was heated to 90 ◦C for 15 min to allow
the ligand exchange process to occur. The second aryl bromide
(1.2 equiv.) in toluene (4 mL mmol−1 hydroxylamine substrate)
was then added, and heating was continued until the intermediate
N-aryl hydroxylamine was completely consumed. The reaction
mixture was then cooled to room temperature, quenched with
saturated aqueous ammonium chloride (2 mL), and diluted with
ethyl acetate (10 mL). The layers were separated and the aqueous
layer was extracted with (2 × 10 mL) ethyl acetate. The combined
( )-(3R,5R)-3-(4-Phenylbenzyl)-2,5-diphenylisoxazolidine (12e).
Yield 63%; 1H (300 MHz, CDCl3) d 7.31–7.64 (m, 16H), 6.95–7.01
(m, 3H), 5.15–5.20 (m, 1H), 4.25 (m, 1H), 3.33–3.40 (dd, J = 13.5,
8 Hz, 1H), 3.01–3.07 (dd, J = 13.5, 6 Hz, 1H), 2.85–2.89 (m, 1H),
2.23–2.27 (m, 1H). 13C (75 MHz, CDCl3) d 151.3, 139.4, 138.5,
138.1, 134.2, 130.0, 128.6, 128.5, 128.2, 127.6, 127.2, 127.1, 126.6,
126.5, 121.3, 114.3, 80.0, 69.5, 43.9, 42.5. HRMS-ESI (m/z): [M
+ Na]+ calcd for C28H25NNaO, 414.1832; found, 414.1837.
(
)-2-{[(3R,5R)-2-Phenyl-5-p-tolylisoxazolidin-3-yl]methyl}-
pyridine (12f). Yield 66%; 1H (300 MHz, CDCl3) d 8.62–8.64 (m,
1H), 7.59–7.60 (m, 1H), 7.16–7.38 (m, 8H), 6.88–6.92 (m, 3H),
5.06–5.11 (m, 1H), 4.53 (m, 1H), 3.36–3.43 (dd, J = 13.5, 9 Hz,
1H), 3.11–3.17 (dd, J = 13.5, 5.5 Hz, 1H), 2.82–2.86 (m, 1H), 2.38
(s, 3H), 2.15–2.19 (m, 1H). 13C (75 MHz, CDCl3) d 159.2, 151.7,
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149.3, 138.0, 136.5, 135.6, 129.2, 128.9, 126.7, 124.6, 121.6, 121.2,
113.9, 79.8, 67.8, 45.1, 43.6, 21.2. HRMS-ESI (m/z): [M + Na]+
calcd for C22H22N2NaO, 353.1632; found, 353.1638.
9 Hz, 2H), 6.88–6.92 (m, 3H), 5.06–5.12 (m, 1H), 4.13–4.14 (m,
1H), 3.85 (s, 3H), 3.26–3.33 (dd, J = 13.5, 7.8 Hz, 1H), 2.92–2.98
(dd, J = 13.5, 6.3 Hz, 1H), 2.76–2.80 (m, 1H), 2.31 (s, 3H),
2.15–2.19 (m, 1H). 13C (75 MHz, CDCl3) d 161.8, 151.9, 141.4,
139.2, 138.6, 131.6, 129.5, 128.1, 126.4, 121.3, 114.3, 113.7, 79.9,
69.7, 54.2, 43.8, 43.0, 25.1. HRMS-ESI (m/z): [M + Na]+ calcd
for C24H25NNaO2, 382.1782; found, 382.1786.
(
)-3-{[(3R,5R)-2-Phenyl-5-p-tolylisoxazolidin-3-yl]methyl}-
pyridine (12g). Yield 64%; 1H (300 MHz, CDCl3) d 8.62–8.64 (m,
2H), 8.17 (br, 1H), 7.68–7.70 (m, 1H), 7.18–7.38 (m, 6H), 6.89–
6.93 (m, 3H), 5.05–5.11 (m, 1H), 4.51 (m, 1H), 3.34–3.41 (dd, J =
13.5, 9 Hz, 1H), 3.12–3.18 (dd, J = 13.5, 5 Hz, 1H), 2.81–2.85
(m, 1H), 2.38 (s, 3H), 2.13–2.17 (m, 1H). 13C (75 MHz, CDCl3) d
151.9, 148.9, 148.6, 138.0, 137.6, 136.1, 135.5, 129.2, 128.9, 126.7,
122.5, 121.2, 113.9, 79.8, 67.8, 45.2, 43.6, 21.2. HRMS-ESI (m/z):
[M + Na]+ calcd for C22H22N2NaO, 353.1630; found, 353.1634.
( )-(3R,5R)-3-Benzyl-2-(4-nitrophenyl)-5-styrylisoxazolidine
1
(12m). Yield 53%; H (300 MHz, CDCl3) d 8.19–8.22 (d, J =
9 Hz, 2H), 7.33–7.49 (m, 5H), 7.04–7.21 (m, 5H), 6.73–6.80 (m,
3H), 6.18–6.26 (dd, J = 15.9, 7.5 Hz, 1H), 4.66–4.69 (m, 1H),
4.19–4.22 (m, 1H), 3.23–3.31 (dd, J = 13.5, 9 Hz, 1H), 3.03–3.09
(dd, J = 13.5, 4.8 Hz, 1H), 2.74–2.78 (m, 1H), 2.02–2.07 (m, 1H).
13C (75 MHz, CDCl3) d 156.2, 147.1, 139.3, 135.6, 135.4, 130.2,
128.7, 128.5, 126.7, 126.0, 125.4, 124.6, 123.4, 112.5, 80.2, 67.6,
41.9, 41.8. HRMS-ESI (m/z): [M + Na]+ calcd for C24H22N2NaO3,
409.1527; found, 409.1531.
(
)-4-{[(3R,5R)-2-Phenyl-5-p-tolylisoxazolidin-3-yl]methyl}-
pyridine (12h). Yield 62%; 1H (300 MHz, CDCl3) d 8.51–8.53 (d,
J = 6 Hz, 2H), 7.27–7.36 (m, 6H), 7.16–7.18 (d, J = 6 Hz, 2H),
6.86–6.90 (m, 3H), 5.03–5.09 (m, 1H), 4.54 (m, 1H), 3.37–3.44
(dd, J = 13.5, 9 Hz, 1H), 3.10–3.16 (dd, J = 13.5, 5.6 Hz, 1H),
2.83–2.87 (m, 1H), 2.38 (s, 3H), 2.14–2.18 (m, 1H). 13C (75 MHz,
CDCl3) d 151.8, 150.3, 144.2, 136.8, 135.5, 129.2, 128.9, 126.7,
124.6, 121.5, 113.9, 79.8, 67.8, 45.1, 43.6, 21.1. HRMS-ESI (m/z):
[M + Na]+ calcd for C22H22N2NaO, 353.1631; found, 353.1635.
( )-{[(3R,5R)-2-(p-Biphenyl)-3-benzylisoxazolidin-5-yl]meth-
1
oxy}(tert-butyl)dimethylsilane (12n). Yield 49%; H (300 MHz,
CDCl3) d 7.51–7.59 (m, 4H), 7.26–7.45 (m, 10H), 6.91–6.94 (d, J =
9 Hz, 2H), 4.42 (m, 1H), 3.88–3.93 (m, 1H), 3.23 (dd, J = 13.5,
8.8 Hz, 1H), 2.87 (dd, J = 13.5, 6 Hz, 1H), 2.42 (m, 1H), 1.97 (m,
1H), 0.96 (s, 9H), 0.15 (s, 6H). 13C (75 MHz, CDCl3) d 151.3, 139.4,
136.5, 131.2, 129.9, 128.7, 128.2, 127.6, 127.2, 126.0, 125.7, 114.3,
80.1, 69.5, 65.5, 43.9, 42.6, 25.8, 18.1, −5.7. HRMS-ESI (m/z):
[M + Na]+ calcd for C29H37NNaO2Si, 482.2493; found, 482.2496.
( )-tert-Butyl-4-[(3R,5R)-3-benzyl-5-(thiophen-2-yl)isoxazolidin-
1
2-yl]benzoate (12i). Yield 51%; H (300 MHz, CDCl3) d 7.94–
7.97 (d, J = 9 Hz, 2H), 7.37–7.40 (m, 6H), 7.13–7.14 (m, 1H),
7.02–7.05 (m, 1H), 6.79–6.82 (d, J = 9 Hz, 2H), 5.26–5.31 (m,
1H), 4.18–4.19 (m, 1H), 3.28–3.35 (dd, J = 13.5, 8.6 Hz, 1H),
2.97–3.03 (dd, J = 13.5, 5.7 Hz, 1H), 2.81–2.85 (m, 1H), 2.22–2.28
(m, 1H), 1.61 (s, 9H). 13C (75 MHz, CDCl3) d 165.6, 154.5, 140.5,
139.2, 130.7, 129.8, 129.3, 126.9, 126.6, 126.2, 126.0, 124.9, 112.7,
80.3, 76.1, 68.6, 43.5, 42.3, 28.2. HRMS-ESI (m/z): [M + Na]+
calcd for C25H27NNaO3S, 444.1607; found, 444.1612.
General procedure for the synthesis of N-aryl-b-amino alcohols
Chlorotrimethyl silane (1 equiv.) and potassium iodide (1 equiv.)
were stirred in acetonitrile at room temperature for half an hour.
To this solution, isoxazolidine (0.5 equiv.) and water (0.25 equiv.)
were added and stirred for a further 1 h at room temperature. The
reaction mixture was treated with water and stirred for another
1 h, then washed with sodium thiosulfate solution (5%) before
extraction with ethyl acetate. The organic layer was separated and
dried over anhydrous sodium sulfate. After removal of the solvent,
the residue was then purified by flash chromatography on silica
gel, eluting with 40–50% ethyl acetate–petroleum ether, to give the
product.
(
)-(3R,5R)-2-(4-Nitrophenyl)-3-(4-methylbenzyl)-5-(thiophen-
2-yl)isoxazolidine (12j). Yield 54%; 1H (300 MHz, CDCl3) d
8.18–8.21 (d, J = 9 Hz, 2H), 7.51–7.54 (d, J = 9 Hz, 1H), 7.15–7.18
(m, 3H), 7.04–7.06 (m, 3H), 6.76–6.79 (d, J = 9 Hz, 2H), 5.27–5.32
(m, 1H), 4.27–4.29 (m, 1H), 3.31–3.38 (dd, J = 13.5, 9 Hz, 1H),
3.09–3.15 (dd, J = 13.5, 4.9 Hz, 1H), 2.94–2.99 (m, 1H), 2.32–
2.35 (m, 1H), 2.25 (s, 3H). 13C (75 MHz, CDCl3) d 155.7, 141.6,
139.2, 136.2, 130.5, 127.3, 127.1, 126.9, 126.5, 125.5, 123.8, 112.5,
76.7, 67.7, 43.5, 41.7, 22.1. HRMS-ESI (m/z): [M + Na]+ calcd
for C21H20N2NaO3S, 403.1093; found, 403.1096.
( )-(1S,3S)-1,4-Diphenyl-3-(phenylamino)butan-1-ol
(13a).
Yield 98%; 1H (300 MHz, CDCl3) d 7.21–7.33 (m, 10H), 7.06–7.09
(m, 2H), 6.84–6.87 (m, 1H), 6.77–6.80 (m, 2H), 4.89–4.94 (m,
1H), 3.87–3.90 (br, 3H), 2.79–2.87 (m, 2H), 1.90–1.96 (m, 1H),
1.72–1.80 (m, 1H). 13C (75 MHz, CDCl3) d 146.5, 144.3, 137.3,
129.7, 129.5, 128.4, 128.3, 127.5, 126.5, 125.8, 119.1, 115.3,
74.4, 54.4, 42.7, 40.3. HRMS-ESI (m/z): [M + Na]+ calcd for
C22H23NNaO, 340.1675; found, 340.1678.
(
)-tert-Butyl-4-{[(3R,5R)-5-(4-cholorophenyl)-2-(4-cyano-
1
phenyl) isoxazolidin-3-yl]methyl}benzoate (12k). Yield 67%; H
(300 MHz, CDCl3) d 8.01–8.04 (d, J = 9 Hz, 2H), 7.75–7.78 (d,
J = 9 Hz, 2H), 7.32–7.48 (m, 6H), 6.73–6.76 (d, J = 9 Hz, 2H),
4.97–5.03 (m, 1H), 4.27 (m, 1H), 3.25–3.32 (dd, J = 13.5, 9 Hz,
1H), 3.07–3.13 (dd, J = 13.5, 4.8 Hz, 1H), 2.95–2.99 (m, 1H),
2.15–2.21 (m, 1H), 1.62 (s, 9H). 13C (75 MHz, CDCl3) d 161.5,
154.5, 140.3, 136.9, 135.7, 133.3, 133.2, 131.2, 131.0, 130.4, 126.5,
118.6, 113.2, 103.8, 80.6, 80.3, 68.0, 43.6, 42.5, 29.4. HRMS-ESI
(m/z): [M + Na]+ calcd for C28H27ClN2NaO3, 497.1606; found,
497.1609.
( )-(1S,3S)-1-Phenyl-3-(phenylamino)-4-(p-cyanophenyl)butan-
1-ol (13b). Yield 97%; 1H (300 MHz, CDCl3) d 7.53–7.56 (d, J =
9 Hz, 2H), 7.16–7.31 (m, 9H), 6.81 (m, 1H), 6.67–6.71 (m, 2H),
4.89–4.90 (m, 1H), 4.11–4.13 (m, 1H), 3.86 (br, 2H), 2.87–2.91
(m, 2H), 1.77–1.86 (m, 2H). 13C (75 MHz, CDCl3) d 146.6, 144.5,
142.7, 131.6, 129.6, 129.5, 128.3, 128.2, 125.9, 119.3, 116.4, 115.1,
110.2, 74.3, 54.5, 42.6, 40.2. HRMS-ESI (m/z): [M + Na]+ calcd
for C23H22N2NaO, 365.1632; found, 365.1637.
( )-(3R,5R)-2-Phenyl-3-(4-methylbenzyl)-5-(4-methoxyphenyl)-
1
isoxazolidine (12l). Yield 57%; H (300 MHz, CDCl3) d 7.56–
7.59 (d, J = 9 Hz, 2H), 7.23–7.45 (m, 6H), 7.04–7.07 (d, J =
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( )-(1S,3S)-3-(Phenylamino)-4-(pyridine-2-yl)-1-p-tolylbutan-
1-ol (13c). Yield 98%; H (300 MHz, CDCl3) d 8.52–8.54 (m,
B. Y. Tay, Tetrahedron Lett., 2006, 47, 927; (e) R. W. Bates and K.
Sa-Ei, Org. Lett., 2002, 4, 4225; (f) K. G. Dongol, B. Y. Tay and K.
Xiang, Synth. Commun., 2006, 36, 1247; (g) M. Lombardo, G. Rispoli,
S. Licciulli, C. Trombini and D. D. Dhavale, Tetrahedron Lett., 2005,
46, 3789.
1
1H), 7.55–7.56 (m, 1H), 7.05–7.24 (m, 8H), 6.73–6.77 (m, 3H),
4.94–4.98 (m, 1H), 4.20–4.90 (br, 2H), 4.03–4.11 (m, 1H), 3.05–
3.06 (m, 2H), 2.33 (s, 3H), 1.86–2.05 (m, 2H). 13C (75 MHz,
CDCl3) d 158.8, 149.0, 146.9, 141.7, 136.8, 136.5, 129.3, 128.9,
125.6, 124.3, 121.4, 118.6, 115.1, 73.1, 53.3, 42.9, 41.9, 21.1.
HRMS-ESI (m/z): [M + Na]+ calcd for C22H24N2NaO, 355.1785;
found, 355.1787.
4 (a) J. A. Fritz, J. S. Nakhla and J. P. Wolfe, Org. Lett., 2006, 8, 2531;
(b) J. S. Nakhla, J. W. Kampf and J. P. Wolfe, J. Am. Chem. Soc., 2006,
128, 2893; (c) J. E. Ney and J. P. Wolfe, J. Am. Chem. Soc., 2005, 127,
8644; (d) Q. Yang, J. E. Ney and J. P. Wolfe, Org. Lett., 2005, 7, 2575;
(e) J. E. Ney and J. P. Wolfe, Angew. Chem., Int. Ed., 2004, 43, 3605;
(f) R. Lira and J. P. Wolfe, J. Am. Chem. Soc., 2004, 126, 13906.
5 Xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene; DPE-
phos = bis(2-diphenylphosphinophenyl)ether.
6 For recent reviews on Pd-catalyzed N-arylation reactions, see: (a) A.
Zapf, M. Beller and T. H. Riermeier, in Transition Metals for Organic
Synthesis, ed. M. Beller and C. Bolm, Wiley-VCH, Weinheim, 2004, vol.
1, p. 231; (b) A. R. Muci and S. L. Buchwald, Top. Curr. Chem., 2002,
219, 133; (c) J. F. Hartwig, in Mordern Arene Chemistry, ed. A. Didier,
Wiley-VCH, Weinheim, 2002, p. 107; (d) B. Schlummer and U. Scholz,
Adv. Synth. Catal., 2004, 346, 1599.
Acknowledgements
We are grateful for financial support from the 100 talents program
of the Chinese Academy of Sciences and the Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences.
7 The stereochemistry of 12a was confirmed to be cis by NOESY. See
supplementary material for further details†.
8 For selected examples to prepare b-amino alcohols, see: (a) P. Aschwan-
den, R. W. Geisser and E. M. Carreira, Org. Lett., 2005, 7, 5741;
(b) R. A. Pilli and D. Russowsky, J. Chem. Soc., Chem. Commun., 1987,
1053; (c) R. A. Pilli, D. Russowsky and L. C. Dias, J. Chem. Soc., Perkin
Trans. 1, 1990, 1213; (d) J. Barluenga, E. Aguilar, S. Fustero, B. Olano
and A. L. Viado, J. Org. Chem., 1992, 57, 1219; (e) G. E. Keck and A. P.
Truong, Org. Lett., 2002, 4, 3131.
9 (a) For a review, see: J. P. Freeman, Chem. Rev., 1983, 83, 241; (b) T.
Adachi, K. Harada, R. Miyazaki and H. Kano, Chem. Pharm. Bull.,
1974, 22, 61; (c) D. P. Curran, J. Am. Chem. Soc., 1983, 105, 5826;
(d) D. P. Curran, S. A. Scanga and C. J. Fenk, J. Org. Chem., 1984,
49, 3474; (e) D. Muri, N. Lohse-Fraefel and E. M. Carreira, Angew.
Chem., Int. Ed., 2005, 44, 4036; (f) J. W. Bode, N. Fraefel, D. Muri and
E. M. Carreira, Angew. Chem., Int. Ed., 2001, 40, 2082; (g) J. W. Bode,
D. Muri and E. M. Carreira, Org. Lett., 2001, 3, 1587; (h) J. W. Bode,
D. Muri and E. M. Carreira, J. Am. Chem. Soc., 2001, 123, 3611.
10 M. Boruah and D. Konwar, J. Chem. Res., 2002, 601.
Notes and references
1 For a review on the utility of amino-oxy synthons, see: M. Fredrickson,
Tetrahedron, 1997, 53, 403.
2 (a) For recent reviews, see: J. N. Matin and R. C. F. Jones, in
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products, ed. A. Padwa and W. H. Pearson,
Wiley and Sons, Hoboken, NJ, 2003, ch. 1, p. 1; (b) K. V. Gothelf
and K. A. Jørgensen, Chem. Rev., 1998, 98, 863; (c) K. V. Gothelf
and K. A. Jørgensen, Chem. Commun., 2000, 1449; (d) K. V. Gothelf,
in Cycloaddition Reactions in Organic Synthesis, ed. S. Kobayashi and
K. A. Jørgensen, Wiley-VCH, Weinheim, Germany, 2002, ch. 6, p. 211;
(e) S. Kanemasa, in Cycloaddition Reactions in Organic Synthesis, ed.
S. Kobayashi and K. A. Jørgensen, Wiley-VCH, Weinheim, Germany,
2002, ch. 7, p. 249.
3 (a) T. Ishikawa, K. Nagai, T. Kudoh and S. Saito, Synlett, 1995, 1171;
(b) T. Ishikawa, K. Nagai, M. Senzaki, A. Tatsukawa and S. Saito,
Tetrahedron, 1998, 54, 2433; (c) H.-S. Lee, J.-S. Park, B. M. Kim and
S. H. Gellman, J. Org. Chem., 2003, 68, 1575; (d) K. G. Dongol and
11 The stereochemistry of b-amino alcohols was confirmed to be cis by
NOESY. See supplementary material for further details†.
1396 | Org. Biomol. Chem., 2007, 5, 1391–1396
This journal is
The Royal Society of Chemistry 2007
©