Enantioselective quaternization of 4-substituted oxazol-5-(4H)-ones using recoverable Cinchona-derived dimeric ammonium salts as phase-transfer organocatalysts

Article abstract of DOI:10.1016/j.tetasy.2012.01.012

Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts (5 mol %) for the enantioselective 4-alkylation of 4-substituted azlactones. The corresponding adducts bearing a new quaternary center were obtained with up to

Full text of DOI:10.1016/j.tetasy.2012.01.012

Tetrahedron: Asymmetry 23 (2012) 176–180
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Tetrahedron: Asymmetry
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Enantioselective quaternization of 4-substituted oxazol-5-(4H)-ones using
recoverable Cinchona-derived dimeric ammonium salts as phase-transfer
organocatalysts
⇑
⇑
Silvia Tarí, Angel Avila, Rafael Chinchilla , Carmen Nájera
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts
(5 mol %) for the enantioselective 4-alkylation of 4-substituted azlactones. The corresponding adducts
bearing a new quaternary center were obtained with up to 80% ee when using a dimeric ammonium salt
Received 16 January 2012
Accepted 19 January 2012
Available online 17 February 2012
derived from cinchonidine, and are precursors of
recovered almost quantitatively by precipitation in ether and reused without loss of activity.
Ó 2012 Elsevier Ltd. All rights reserved.
a,a-disubstituted a-amino acids. The catalysts can be
1. Introduction
under simple and convenient phase-transfer conditions,11 the enan-
tioselective version of this process has remained almost unexplored.
The development of strategies for the preparation of enantio-
Thus, recently, azlactones from a-substituted a-amino acids have
merically enriched non-proteinogenic
acids has received considerable attention in recent years.1 These
quaternized -amino acids show interesting properties in biologi-
cal and medicinal chemistry; the additional -substituent often
a
,
a
-disubstituted
a
-amino
been alkylated with activated alkyl halides under biphasic condi-
tions using a P-spiro chiral tetraaminophosphonium salt as a
phase-transfer organocatalyst;12 this salt has also been employed
as a catalyst for the 4-akylation of azlactones on a terminal peptide
backbone.13 Surprisingly, in spite of being very commonly em-
ployed as chiral organocatalysts, especially when dealing to
phase-transfer processes,14 Cinchona alkaloid-derived ammonium
salts have never been used in this transformation.
In the last few years, our group has developed recoverable
unsupported15–18 and supported19 Cinchona alkaloid-derived
ammonium salts for use in organocatalyzed enantioselective reac-
tions. Particularly interesting has been the preparation of a series
of dimeric anthracenyldimethyl-derived ammonium salts from Cin-
chona alkaloids, which have been employed as recoverable organo-
catalysts in enantioselective transformations such as asymmetric
alkylation15 and Michael addition16 reactions of glycinate Schiff
a
a
helps to sterically constrain free rotation of the residue’s side chain
leading to unique folding when incorporated into peptides.1d,2 In
addition, peptides containing quaternary a-amino acids present in-
creased hydrophobicity, as well as a higher stability toward both
chemical3 and metabolic4 decomposition. Moreover, quaternary
a-amino acid derivatives can be found in Nature either in their free
form, or within the structures of biologically interesting heterocy-
clic natural compounds.1c,5
Oxazol-5-(4H)-ones, also known as azlactones, are well known
starting materials suitable for the synthesis of different amino
acids due to their diverse chemistry.6 In particular, 4-substituted
oxazol-5-(4H)-ones are appropriate substrates for synthesizing
enantiomerically enriched quaternary substituted
a
-amino acids.7
bases for the enantioselective synthesis of a-amino acids under
Thus, 4-substituted oxazol-5-(4H)-ones are readily available and
configurationally labile a-amino acid derivatives due to the acidity
phase-transfer conditions. Recently, they have also been employed
in the enantioselective quaternization of cyclic b-keto esters18 and
in the enantioselective cyanoformylation of aldehydes.17 Herein
we report the use of these dimeric ammonium salts as recoverable
organocatalysts in the 4-alkylation of 4-substituted oxazol-5-(4H)-
ones for the enantioselective generation of quaternary stereocen-
of the
a
-hydrogen (pKa ꢀ 9, H2O, 25 °C),8 and have been 4-alkyl-
ated enantioselectively mainly by catalytic procedures involving
chiral transition metal complexes.7 Recently, this transformation
has also been achieved using chiral organocatalysts, after enantio-
selective addition to conjugated systems9 or Mannich reactions.10
However, although the direct 4-alkylation of 4-substituted oxa-
zol-5-(4H)-ones using alkyl halides has been shown to be feasible
ters of
a,a-disubstituted a-amino acid derivatives.
2. Results and discussion
As a model starting material for the first screening reactions, we
employed 4-benzylated oxazol-5-(4H)-one (S)-4a, available in a
⇑
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: chinchilla@ua.es (R. Chinchilla), cnajera@ua.es (C. Nájera).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.012

S. Tarí et al. / Tetrahedron: Asymmetry 23 (2012) 176–180
177
78% yield via cyclization of N-benzoyl-
L
-phenylalanine promoted
important for the enantioselectivity of the reaction. Thus, the ally-
lation of (S)-4a was carried out under the same reaction conditions
but using the commercially available Lygo’s monomeric cinchoni-
dine ammonium salt 221 (10 mol %) as the phase-transfer catalyst
(Table 1, entry 4). The resulting azlactone (S)-5aa was obtained
in a shorter reaction time, but with only 14% ee.
by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI).20 The dimeric cinchonidine-derived ammonium salt
1a15,16 was used as an organocatalyst (5 mol %) in the reaction of
(S)-4a with allyl bromide in the presence of solid K3PO4ꢁH2O
(5 equiv) as base and a mixture of toluene/chloroform (7/3 v/v),
usually effective in enantioselective phase-transfer reactions
involving dimeric ammonium salts,15 as solvent at room tempera-
ture (Table 1, entry 1). Under these conditions, the resulting 4-ally-
lated azlactone 5aa was obtained as the (S)-enantiomer in 73% ee.
The use of an O-allylated cinchonidine-derived ammonium salt
1b15,16 under the same reaction conditions caused a considerable
decrease in enantioselectivity (Table 1, entry 2), but when the O-
free quinine-derived dimeric ammonium salt 1c18 was employed
as the catalyst, the enantioselectivity for (S)-5aa increased slightly
to 33% (Table 1, entry 3).
Cl-
N
+
OH
N
2
R1
Other bases were then tested in order to improve the enantiose-
lectivity of this process. Thus, the use of K2HPO4 gave rise to a
much longer reaction time and 59% ee for (S)-5aa (Table 1, entry
5), whereas the use of K2CO3 showed an increase in the enantiose-
lectivity of the process up to 70% ee (Table 1, entry 6). The use of
other carbonates as bases, such as Na2CO2, afforded 67% ee for
(S)-5aa (Table 1, entry 7), whereas Cs2CO3 yielded only 17% ee (Ta-
ble 1, entry 8). In addition, the use of liquid–liquid phase-transfer
conditions was attempted by employing saturated aq K2CO3, but
the enantioselectivity decreased to 54% ee (Table 1, entry 9).
After solid K2CO3 was established as the most convenient base,
other solvents were tested. The use of tert-butyl methyl ether
(TBME) gave no enantioselection (Table 1, entry 10), while dichlo-
romethane gave 58% ee for (S)-5aa in a rather rapid reaction (Ta-
ble 1, entry 11).
2 X-
N
+
R1
OR2
+ N
N
R2O
1a, R1 = H, R2 = H, X = Cl
N
1b, R1 = H, R2 = allyl, X = Br
1c, R1 = OMe, R2 = H, X = Cl
Since the O-free cinchonidine-derived dimeric ammonium salt
1a proved more effective than the related quinine-derived salt
1c, we decided to clarify whether the dimeric structure of 1a was
The effect of the reaction temperature was subsequently ex-
plored using solid K2CO3 as the base and a mixture of PhMe/CHCl3
Table 1
Screening and optimization of the reaction conditions for the enantioselective allylation reaction
O
O
Ph
Br
Ph
cat., base
O
*
O
N
N
solvent, T
Ph
Ph
(S)-4a
5aa
Ent.
Cat. (mol %)
Base
Solvent
T (°C)
t (d)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a (5)
1b (5)
1c (5)
2 (10)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (10)
3 (5)
K3PO4ꢁH2O
K3PO4ꢁH2O
K3PO4ꢁH2O
K3PO4ꢁH2O
K2HPO4
K2CO3
Na2CO3
Cs2CO3
K2CO3 (aq)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
TBME
CH2Cl2
PhMe/CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
25
25
25
25
25
0
0
ꢂ20
ꢂ30
ꢂ20
ꢂ20
0.6
0.2
0.7
0.1
2
0.2
0.2
0.2
0.3
1
0.1
2
0.3
2
3
2
73
53
84
74
61
72
39
48
65
34
78
64
66
49
39
54
43
63 (S)
11 (S)
33 (S)
14 (S)
59 (S)
70 (S)
67 (S)
17 (S)
54 (S)
0
58 (S)
70 (S)
73 (S)
80 (S)
70 (S)
64 (S)
10 (R)
CH2Cl2
CH2Cl2
5
a
Determined by 1H NMR (300 MHz) using diphenylmethane as the internal standard.
The enantioselectivities and absolute stereochemistry were determined by chiral HPLC.12
b

178
S. Tarí et al. / Tetrahedron: Asymmetry 23 (2012) 176–180
Table 2
Enantioselective 4-alkylation of 4-substituted oxazol-5-(4H)-ones 4 organocatalyzed by cinchonidine-derived dimeric ammonium salt 1a under phase-transfer conditions
O
R1
O
R1
*
1a (5 mol%)
R2
R2Br
O
+
O
N
K2CO3 (s, 5eq)
CH2Cl2, -20 ºC
N
Ar
Ar
4
5
Entry
R1
Ar
No.
R2Br
t (d)
No.
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
Me
Ph
Ph
Ph
Ph
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
rac-4f
(S)-4g
CH2@CHCH2Br
CH2@C(Me)CH2Br
(Me)2C@CHCH2Br
HC„CCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
CH2@CHCH2Br
2
3
3
1
3
2
3
3
5
3
(S)-5aac
(S)-5ab
rac-5ac
(S)-5ad
(S)-5ba
(S)-5ca
(S)-5da
(R)-5ea
(R)-5fa
(R)-5ga
49
32
81
23
18
90
90
65
35
35
80
59
0
25
42
55
52
62
53
57
4-MeOC6H4
4-F3CC6H4
4-ClC6H4
Ph
Ph
Ph
Et
iBu
10
a
b
c
Determined by 1H NMR (300 MHz) using diphenylmethane as an internal standard.
Enantioselectivities determined by chiral HPLC.
The absolute configuration was determined by the order of elution of the enantiomers in chiral HPLC.12
(7/3 v/v) as the solvent. Lowering the temperature to 0 °C did not
increase the enantioselection for (S)-5aa compared to when room
temperature was used, but the reaction rate decreased dramati-
cally (Table 1, compare entries 6 and 12). However, when dichloro-
methane was used as the solvent, lowering the reaction
temperature to 0 °C raised the enantioselectivity for (S)-5aa up to
73% ee with a short reaction time (Table 1, entry 13). Therefore,
dichloromethane was used as the solvent when the temperature
was diminished to ꢂ20 °C, affording (S)-5aa in 80% ee (Table 1,
entry 14). Lowering the temperature down to ꢂ30 °C did not give
better results (Table 1, entry 15). In addition, an increase in the
loading of catalyst 1a up to 10 mol % at ꢂ20 °C gave a lower enan-
tioselection for (S)-5aa (Table 1, entry 16).
Initially, the behaviors of allylic bromides, other than allyl
bromide, were investigated (Table 2). Thus, when the oxazol-5-
(4H)-one from L-phenylalanine (S)-4a was reacted with methallyl
bromide, the corresponding quaternized azlactone 5ab was ob-
tained in 59% ee (Table 2, entry 2); the use of prenyl bromide gave
rise to the corresponding azlactone 5ac but as a racemic mixture
(Table 2, entry 3). When propargyl bromide was employed as an
electrophile for the alkylation of 4a, the quaternized adduct (S)-
4a was obtained in only 25% ee (Table 2, entry 4). The absolute con-
figuration of these and other alkylated azlactones was tentatively
assigned assuming the same sense in enantioselectivity was
achieved with 1a than when using substrate (S)-4a.
The possible effect on the enantioselectivity of the process of
the presence of electron-withdrawing or electron-releasing groups
on the aryl group at the 2-position of the oxazol-5-(4H)-one was
Expecting to achieve an opposite enantioselection, we per-
formed this enantioselective allylation reaction using the cincho-
nine-derived dimeric ammonium salt 3, which can be considered
investigated by preparing
L-phenylalanine-derived azlactones
a
pseudoenantiomer of the cinchonidine-derived counterpart
4a,b,c bearing methoxylated, trifluoromethylated, and chlorinated
aryl groups respectively, and performing the alkylation reaction
with allyl bromide. Thus, the methoxylated azlactone (S)-4b gave
rise to the corresponding allylated product 5ba in 42% ee and
low yield, whereas the azlactone (S)-4c, bearing a trifluoromethyl
group, afforded the corresponding product 5ca in 55% ee and very
good yield (Table 2, entries 5 and 6), similar results being obtained
when the chlorinated oxazolone (S)-4d was allylated (Table 2,
entry 7).
1a.15 This was confirmed by the isolation of the corresponding
opposite allylated azlactone (R)-5aa, but only in poor 10% ee
(Table 1, entry 17).
2 Cl-
+
N
Other oxazol-5-(4H)-ones, obtained from
than -phenylalanine, were also prepared and employed in the
allylation with allyl bromide. Thus, oxazolone (S)-4e from -alanine
was obtained and allylated under the optimized reaction condi-
tions, affording the 4-allylated oxazolone 5ea in 62% ee (Table 2,
entry 8). The oxazolone derived from racemic 2-aminobutyric acid
gave rise to the corresponding allylated product 5fa in 53% ee, thus
discarding a possible ‘memory of chirality’ effect in the origin of
the enantioselectivities achieved in this process (Table 2, entry
a-amino acids other
L
HO
N
+
L
N
OH
N
3
9). In addition, the allylation of L-leucine-derived azlactone (S)-4g
afforded adduct 5ga in 57% ee (Table 2, entry 10).
With the most appropriate ammonium salt 1a and convenient
reaction conditions (solid K2CO3 as base, dichloromethane as sol-
vent, ꢂ20 °C reaction temperature) established, we proceeded to
extend the procedure to other 4-substituted oxazol-5-(4H)-ones,
as well as other halides (Table 2).
It is interesting to note that the ammonium salt 1a can be
recovered in 93% yield once the reaction is complete after remov-
ing the base by filtration, evaporation of the dichloromethane,
addition of ethyl ether and filtration of the precipitate. The recov-
ered ammonium salt can be reused up to three times in the model

S. Tarí et al. / Tetrahedron: Asymmetry 23 (2012) 176–180
179
reaction (Table 2, entry 1) giving rise to almost identical yields and
enantioselectivities.
4.2.3. 4-Benzyl-2-(4-chlorophenyl)oxazol-5(4H)-one 4d
White solid; mp 120 °C (CH2Cl2/Et2O). ½a D25
¼ ꢂ4:7 (c 1, MeOH);
ꢃ
IR(KBr):
m
2359, 2340, 1820, 1653, 1489, 1044, 731 cmꢂ1; 1H NMR:
d 7.85 (d, J = 8.5 Hz, 2H, Ar-Cl), 7.43 (d, J = 8.5. 2H, Ar-Cl), 7.31 (m,
5H, Ph), 4.69 (dd, J = 6.5, 5.0 Hz, 1H, PhCH2CH), 3.37 (dd, J = 13.9,
4.9 Hz, 1H, PhCHAHBCH), 3.19 (dd, J = 13.9, 6.7 Hz, 1H,
PhCHAHBCH); 13C NMR: d 177.3, 161.0, 139.2, 135.2, 132.0, 129.6,
129.3, 128.5, 127.4, 124.3, 66.6, 37.4; MS (EI, 70 eV): m/z (%) 285
(M+, 7), 91 (100); HRMS (EI): m/z calcd for C16H12ClNO2 (M+)
285.0557, found 285.0527.
3. Conclusions
It can be concluded that quaternized oxazol-5-(4H)-ones,
precursors of
enantioselectively by a direct alkylation reaction between oxazol-
5-(4H)-ones from -amino acids and activated bromides, using Cin-
a,a-disubstituted a-amino acids can be generated
a
chona-derived dimeric ammonium salts as chiral organocatalysts
under solid–liquid phase-transfer conditions. The best results were
obtained with a cinchonidine-derived dimeric species. This organo-
catalyst can be separated from the reaction medium by precipita-
tion in ether and filtration, and reused without a loss of activity.
4.3. Preparation of the oxazol-5-(4H)-ones 4e–g
4.3.1. General procedure26
A solution of the N-benzoyl-
fluoroacetic anhydride (2.5 mmol, 348
a
-amino acid22 (2.5 mmol) and tri-
L) in anhydrous CH2Cl2
l
4. Experimental
4.1. General
(125 mL) was stirred at room temperature overnight under an ar-
gon atmosphere. The mixture was washed with a saturated solu-
tion of NaHCO3 (65 mL) and a saturated solution of NaCl (65 mL).
The organic phase was dried (MgSO4) and evaporated (15 Torr).
The synthesis of oxazol-5-(4H)-ones 4e–g has already been
described.25
All reagents and solvents employed were of the best grade avail-
able and were used without further purification. Melting points are
uncorrected. Specific rotations were measured using a Perkin-Elmer
341 polarimeter. IR data were collected on a Nicolet Impact 400D-FT
spectrometer. The 1H and 13C NMR spectra were recorded at 25 °C
on a Bruker AC-300 at 300 MHz and 75 MHz, respectively, using
CDCl3 as the solvent and TMS as the internal standard. MS (EI,
70 eV) were performed on a HP MS-GC-5973A. HRMS analyses were
carried out on a Finnigan MAT 95S. Enantioselectivities were deter-
mined by chiral HPLC using Chiralcel columns and n-hexane/2-pro-
panol mixtures as eluent. Ammonium salts 1a,17b 1b,15a 1c18 and 318
have been prepared following reported procedures. The absolute
configuration of adduct 5aa was determined according to the
described order of elution of their enantiomers in chiral HPLC.12
The absolute configuration of the other adducts was assigned by
analogy. Reference racemic samples of adducts 5 were obtained
by performing the enantioselective reaction using tetra-n-butylam-
monium bromide as the phase-transfer organocatalyst.
4.4. Enantioselective alkylation reaction
4.4.1. Typical procedure
To
a
solution of 1a (0.05 mmol, 43 mg), (S)-4a (1 mmol,
L) in CH2Cl2 (6 mL)
251 mg) and allyl bromide (1.2 mmol, 104
l
was added solid K2CO3 (5 mmol, 691 mg) at ꢂ20 °C. The reaction
mixture was stirred vigorously at ꢂ20 °C for 2 d (TLC), and the
base was filtered. The filtrate was evaporated (15 Torr) and Et2O
(6 mL) was added, recovering the precipitated catalyst 1a by fil-
tration (40 mg, 93%). The filtrate was diluted with water
(20 mL) and extracted with AcOEt (3 ꢄ 5 mL). The organics were
dried (MgSO4), filtered and evaporated (15 Torr), leading to ad-
duct 5aa.
The synthesis of the adducts 5aa,12 5ab,20 5ac,27 5ad,12 5ea11
and 5ga12 have already been described. Retention times observed
in chiral HPLC for both enantiomers and chromatographic separa-
tion conditions for all adducts described, as well as full analytical
and spectroscopic data for the newly prepared compounds 5ba,ca,-
da,fa are as follows.
4.2. Preparation of the oxazol-5-(4H)-ones 4a–d
4.2.1. General procedure20
A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (5.5 mmol, 1.05 g) in dry CH2Cl2 (10 mL) was added
4.4.2. (S)-4-Allyl-4-benzyl-2-phenyloxazol-5(4H)-one 5aa
HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol,
1000:1, 0.5 mL/min, tr (minor) = 36.3 min, tr (major) = 39.1 min.
to a solution of the corresponding N-aroyl-a
-amino acid22 in dry
CH2Cl2 (40 mL). The mixture was stirred for 1 h at 0 °C, diluted
with CH2Cl2 (50 mL) and washed with water (25 mL), saturated
NaHCO3 (25 mL) and water (25 mL). The organic phase was dried
(MgSO4), filtered and concentrated in vacuo (15 Torr).
The synthesis of oxazol-5-(4H)-ones 4a23 and 4b24 has already
been described. New compounds 4c and 4d were obtained in 72%
and 28% yields, respectively, and their analytical and spectroscopic
data are as follows.
4.4.3. (S)-4-Benzyl-4-(2-methylallyl)-2-phenyloxazol-5(4H)-one
5ab
HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 999:1,
1 mL/min, tr (minor) = 14.1 min, tr (major) = 29.6 min.
4.4.4. rac-4-Benzyl-4-(3-methylbut-2-en-1-yl)-2-phenyloxazol-
5(4H)-one 5ac
HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 97:3,
1.0 mL/min, tr1 = 5.5 min, tr2 = 7.2 min.
4.2.2. (S)-4-Benzyl-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-
one 4c
White solid; mp 84 °C (CH2Cl2/Et2O). ½a D25
¼ ꢂ0:5 (c 1, MeOH);
ꢃ
IR (KBr):
694 cmꢂ1
m 2931, 2855, 1830, 1786, 1647, 1325, 1065, 863,
4.4.5. (S)-4-Benzyl-2-phenyl-4-(prop-2-yn-1-yl)oxazol-5(4H)-
one 5ad
;
1H NMR: d 8.03 (d, J = 8.2 Hz, 2H, Ar-CF3), 7.71 (d,
J = 8.3 Hz, 2H, Ar-CF3), 7.32–7.17 (m, 5H, Ph), 4.74 (dd, J = 6.3,
5.1 Hz, 1H, PhCH2CH), 3.40 (dd, J = 14.0, 4.9 Hz, 1H, PhCHAHBCH),
3.21 (dd, J = 14.0, 6.6 Hz, 1H, PhCHAHBCH); 13C NMR: d 176.9,
160.7, 134.9, 130.9, 130.6, 129.5, 128.5, 128.3, 127.4, 125.8,
125.7, 66.6, 37.2; MS (EI, 70 eV): m/z (%) 319 (M+, 2), 91 (100);
HRMS (EI): m/z calcd for C17H12F3NO2 (M+) 319.0820, found
319.0826.
HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 98:2,
0.5 mL/min, tr (minor) = 18.9 min, tr (major) = 20.3 min.
4.4.6. (S)-4-Allyl-4-benzyl-2-(4-methoxyphenyl)oxazol-5(4H)-
one 5ba
Colorless oil; IR (film):
m
2922, 1814, 1652, 1608, 1512, 1456,
1H NMR:
1305, 1258, 1171, 1090, 1030, 977, 890, 840, 700 cmꢂ1
;

180
S. Tarí et al. / Tetrahedron: Asymmetry 23 (2012) 176–180
d
7.79 (d, J = 8.8 Hz, 2H, Ar-OMe), 7.17 (m,
5
H, Ph), 6.91
4.4.11. (R)-4-Allyl-4-isobutyl-2-phenyloxazol-5(4H)-one 5ga
HPLC: Chiralcel OD-H, k = 210 nm, n-hexane, 0.5 mL/min, tr
(minor) = 18.4 min, tr (major) = 19.9 min.
(d, J = 8.8 Hz, 2H, Ar-OCH3), 5.75–5.60 (m, 1H, CH2CH@CH2), 5.20
(dd, J = 16.8, 1.1 Hz, 1H, CH2CH@CHAHB), 5.11 (dd, J = 9.9, 1.1 Hz,
1H, CH2CH=CHACHB), 3.85 (s, 3H, OCH3), 3.21 (d, J = 13.4 Hz, 1H,
CHACHBPh), 3.14 (d, J = 13.3 Hz, 1H, CHAHBPh), 2.79–2.64 (m, 2H,
CH2CH=CH2); 13C NMR: d 179.4, 163.2, 159.7, 134.6, 130.4, 130.0,
129.3, 128.6, 127.9, 126.9, 117.9, 113.6, 74.9, 55.2, 43.4, 41.8; MS
(EI, 70 eV): m/z (%) 321 (M+, 1), 135 (100); HRMS (EI): m/z calcd
for C20H19NO3 (M+) 321.1365, found 321.1364; HPLC: Chiralcel
OJ, k = 210 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min, tr (min-
or) = 8.0 min, tr (major) = 11.7 min.
Acknowledgments
We thank the financial support from the Spanish Ministerio de
Ciencia e Innovación (projects CTQ2007-62771/BQU, CTQ2010-
20387 and Consolider Ingenio 2010, CSD2007-00006), FEDER, the
Generalitat Valenciana (Prometeo/2009/039), and the University
of Alicante. S.T. thanks the Generalitat Valenciana for a pre-doc-
toral fellowship.
4.4.7. (S)-4-Allyl-4-benzyl-2-(4-(trifluoromethyl)phenyl)oxazol-
5(4H)-one 5ca
References
Colorless oil; IR (film):
m
;
2358, 1820, 1652, 1416, 1324, 1175,
1132, 1066, 698, 619 cmꢂ1
1H NMR: d 7.96 (d, J = 8.2Hz, 2H, Ar-
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for C20H16NO2F3 (M+) 359.1133, found 359.1129; HPLC: Chiralcel
OJ, k = 210 nm, n-hexane/2-propanol, 97:3, 1.0 mL/min, tr (min-
or) = 7.3 min, tr (major) = 8.6 min.
4.4.8. (S)-4-Allyl-4-benzyl-2-(4-chlorophenyl)oxazol-5(4H)-one
5da
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2922, 2852, 2359, 2341, 1816, 1652,
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1598, 1489, 1310, 1294, 1088, 972, 699 cmꢂ1
;
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J = 8.5 Hz, 2H, Ar-Cl), 7.41 (d, J = 8.5 Hz, 2H, Ar-Cl), 7.16 (m, 5H,
Ph), 5.68 (m, 1H, CH2CH@CH2), 5.21 (dd, J = 16.1, 1.0 Hz, 1H,
CH2CH@CHAHB), 5.13 (dd, J = 10.1, 1.0 Hz, 1H, CH2CH@CHAHB),
3.22 (d, J = 13.4 Hz, 1H, CHACHBPh), 3.16 (d, J = 13.4 Hz, 1H,
CHACHBPh), 2.81–2.64 (m, 2H, CH2CH=CH2); 13C NMR: d 178.9,
159.2, 139.0, 134.3, 130.7, 130.2, 129.2, 128.5, 128.3, 127.4,
124.2, 120.8, 75.1, 43.3, 41.5; MS (EI, 70 eV): m/z (%) 325 (M+,
12), 139 (100); HRMS (EI): m/z calcd for C19H16NClO2 (M+)
325.0870, found 325.0860; HPLC: Chiralcel OJ, k = 254 nm,
n-hexane/2-propanol, 90:10, 1.0 mL/min, tr (minor) = 5.9 min, tr
(major) = 8.5 min.
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4.4.9. (R)-4-Allyl-4-methyl-2-phenyloxazol-5(4H)-one 5ea
HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 99:1,
1.0 mL/min, tr (major) = 5.0 min, tr (minor) = 6.2 min.
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(b) Tarí, S.; Chinchilla, R.; Nájera, C. Tetrahedron: Asymmetry 2010, 21, 2872–2878;
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3281; (b) Chinchilla, R.; Mazón, P.; Nájera, C. Molecules 2004, 9, 349–364; (c)
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4.4.10. (R)-4-Allyl-4-ethyl-2-phenyloxazol-5(4H)-one 5fa
Colorless oil; IR (film): m2924, 1818, 1655, 1451, 1322, 1290, 1260,
1036, 1019, 887, 799, 699 cmꢂ1; 1H NMR: d 8.01 (d, J = 7.1 Hz, 2H, Ph),
7.58 (t, J = 7.4 Hz, 1H, Ph), 7.49 (t, J = 7.7 Hz, 2H, Ph), 5.65 (m, 1H,
CH2CH=CH2), 5.17 (dd, J = 17.1, 1.4 Hz, 1H, CH2CH@CHAHB), 5.10
(dd, J = 10.2, 0.9 Hz, 1H, CH2CH@CHACHB), 2.69–2.64 (m, 1H,
CHAHBCH@CH2), 2.61–2.55 (m, 1H, CHAHBCH@CH2), 1.96 (q,
J = 7.3 Hz, 2H, CH2CH3), 0.86 (t, J = 7.4 Hz, 3H, CH2CH3); 13C NMR: d
180.0, 160.2, 132.8, 131.0, 128.9, 128.1, 125.9, 120.5, 74.3, 41.5,
30.3, 8.3; MS (EI, 70 eV): m/z (%) 229 (M+, 1), 105 (100); HRMS (EI):
m/z calcd for C14H15NO2 (M+) 229.1103, found 229.1131; HPLC: Chi-
ralcel OD-H, k = 210 nm, n-hexane/2-propanol, 995:5, 1.0 mL/min, tr
(major) = 7.8 min, tr (minor) = 12.4 min.