Practical and efficient synthesis of chiral 2,4-disubstituted oxazolines from β-phosphonoamides

Article abstract of DOI:10.1016/j.tetasy.2013.12.003

Herein we report a practical and efficient method for the synthesis of optically active 2,4-disubstituted oxazolines (S)-1a-h in good to excellent yields. The target compounds were prepared in good yield through the Horner-Wadsworth-Emmons reaction of β-phosphonoamide 3 bearing l-phenylalaninol with commercially available aryl aldehydes followed by the cyclodehydration of the corresponding N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a-h. Additionally, the cyclodehydration of β- phosphonoamide (S)-3 followed by the Horner-Wadsworth-Emmons reaction of β-phosphono-oxazoline (S)-4 with aryl aldehydes also gave the 2,4-disubstituted oxazolines (S)-1a-h.

Full text of DOI:10.1016/j.tetasy.2013.12.003

Tetrahedron: Asymmetry 25 (2014) 156–162
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Practical and efficient synthesis of chiral 2,4-disubstituted oxazolines
from b-phosphonoamides
a
Francisco G. Avalos-Alanís a, Eugenio Hernández-Fernández a, , Rocio Hernández-Romero ,
⇑
Susana López-Cortina a, Mario Ordóñez b, , Oscar García-Barradas c, Selene Lagunas-Rivera b,
⇑
a Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Pedro de Alba S/N, Ciudad Universitaria, 66400 San Nicolás de los Garza, Nuevo León, Mexico
b Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
c Unidad de Servicios de Apoyo en Resolución Analítica de la Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala S/N, 91190 Xalapa, Veracruz, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2013
Accepted 4 December 2013
Herein we report a practical and efficient method for the synthesis of optically active 2,4-disubstituted
oxazolines (S)-1a–h in good to excellent yields. The target compounds were prepared in good yield
through the Horner–Wadsworth–Emmons reaction of b-phosphonoamide 3 bearing L-phenylalaninol
with commercially available aryl aldehydes followed by the cyclodehydration of the corresponding N-
(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–h. Additionally, the cyclodehydration of b-phospho-
noamide (S)-3 followed by the Horner–Wadsworth–Emmons reaction of b-phosphono-oxazoline (S)-4
with aryl aldehydes also gave the 2,4-disubstituted oxazolines (S)-1a–h.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
vance, much effort has been dedicated to the preparation of
oxazolines and their derivatives, including the cyclodehydration
For more than a century, heterocyclic compounds have consti-
tuted as one of the largest areas of research in organic chemistry.
They have contributed to the development of society from a bio-
logical and industrial point of view, as well as to the understanding
of life processes and to efforts to improve quality of life.1 The pres-
ence of heterocycles in many types of organic compounds of inter-
est in electronics, medicinal chemistry, and material science is very
well known. Five-membered heterocyclic compounds containing
nitrogen are privileged structures that are useful in synthetic and
of b-hydroxyamides,11 Passerini-Zhu/Staudinger-Aza-Wittig reac-
tion,12 and from nitriles,13 carboxylic acids,14 and aldehydes.15
However, in spite of their potential utility, these methods typically
suffer from one or more disadvantages such as harsh reaction con-
ditions or tedious synthetic procedures. Due to the high value of
these compounds in connection with our current research interest
in the development of efficient and practical synthetic methods,
we herein report a practical and efficient method for the synthesis
of several new chiral 2,4-disubstituted oxazolines (S)-1a–h, with
good to high yields from b-phosphonoamide (S)-3.
medicinal chemistry.2,3 Among these,
a,b-unsaturated oxazolines
with five-membered rings containing nitrogen and oxygen, have
received considerable attention in recent years, because these
compounds are part of several natural products,4 and also because
they exhibit a wide range of biological and pharmacological activ-
ities such as antibacterial,4c antituberculosis,5 antimalarial,6 and
2. Results and discussion
For the synthesis of the target chiral 2,4-disubstituted oxazo-
lines (S)-1a–h, two synthetic procedures were considered: (1)
through the cyclodehydration of N-(cinnamoyl)-(S)-phenylalaninol
derivatives (S)-2, which are readily obtained from the Horner–
Wadsworth–Emmons reaction of b-phosphonoamide (S)-3 with
commercially available aryl aldehydes; and (2) by means of the
Horner–Wadsworth–Emmons reaction of b-phosphono-oxazoline
(S)-4, also obtained from b-phosphonoamide (S)-3 (Scheme 1).
The synthetic sequence established in route A began with the
preparation of b-phosphonoamide (S)-3, which was easily obtained
using the recently described procedure in Ref. 16 Thus, the reaction
anticancer.7 Furthermore,
a,b-oxazolines can be used as Michael
acceptors for carbon-carbon bond formations, and can be trans-
formed into alcohols, aldehydes, carboxylic acids, oxazole deriva-
tives and used in the preparation of more complex compounds.8
Additionally, chiral oxazolines have been widely used in asymmet-
ric synthesis as both auxiliaries and ligands.9,10 Due to their rele-
⇑
Corresponding authors. Tel./fax: +52 818 329 40 00 (E.H.-F.); tel./fax: +52 777
329 79 00 (M.O.).
E-mail addresses: eugenio.hernandezfr@uanl.edu.mx (E. Hernández-Fernández),
palacios@uaem.mx (M. Ordóñez).
Present address: Facultad de Estudios Superiores Cuautitlán, Av. 1 de Mayo S/N,
54740 Cuautitlán Izcalli, Estado de México, Mexico.
of 2-diethyl-phosphonoacetic acid with L-phenylalaninol in the
presence of dicyclohexylcarbodiimide (DCC) and catalytic amounts
of 4-(dimethylamino)pyridine (DMAP) in dry dichloromethane at
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.003

F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
157
Table 2
OH
Bn
O
O
Preparation of chiral 2,4-disubstituted oxazolines (S)-1a–h
route A
Ar
N
Bn
Ar
N
H
OH
O
O
(S)-1
SOCl2, K2CO3
(S)-2
Ar
Ar
N
Bn
N
Bn
NaBr, MeCN, Δ
route B
H
(S)-(E)-1a-h
2a-h
(S)-(E)-
OH
O
O
O
O
(EtO)2P
(EtO)2P
N
Bn
N
H
Bn
Entry
Product
Yielda (%)
(S)-4
(S)-3
1
2
3
4
5
6
7
8
1a; Ar = C6H5
60
30
32
64
85
64
65
69
1b; Ar = 4-FC6H4
1c; Ar = 4-ClC6H4
1d; Ar = 4-BrC6H4
1e; Ar = 4-MeOC6H4
1f; Ar = 4-BnOC6H4
1g; Ar = 4-MeO2CC6H4
1h; Ar = 2-furfuryl
Scheme 1. b-Phosphonoamide (S)-3 as the starting material for the synthesis of (S)-
1a–h.
room temperature, afforded the b-phosphonoamide (S)-3 in 94%
yield. With compound 3 in hand and following a well-established
protocol for the synthesis of a,b-unsaturated amides under Horn-
er–Wadsworth–Emmons reaction conditions,16,17 we decided to
carry out the reaction of b-phosphonoamide (S)-3 with benzalde-
hyde, using 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base
in the presence of LiCl in dry THF at room temperature, to obtain
the corresponding N-(cinnamoyl)-(S)-phenylalaninol (S)-2a in
96% yield and a >98:2 ratio of E:Z (Table 1, entry 1). Similar results
were obtained in the reaction of (S)-3 with 4-fluorobenzaldehyde,
4-chlorobenzaldehyde, and 4-methoxybenzaldehyde (Table 1, en-
tries, 2, 3 and 5), and a moderate yield and excellent E:Z ratio were
obtained in the reaction of compound (S)-3 with 4-bromobenzal-
dehyde, 4-(benzyloxy)benzaldehyde, methyl 4-formylbenzoate,
and 2-furaldehyde (Table 1, entries 4, 6-8). The E:Z ratio was deter-
mined by 1H NMR spectroscopy on the crude product on the basis
of the olefinic protons.
a
Isolated after purification by column chromatography.
This procedure provided the target chiral 2,4-disubstituted
oxazolines (S)-1a–h, although with only moderate yields. Conse-
quently, route B was explored in order to obtain better results. In
this context, and considering that the dehydrative cyclization of
b-hydroxy amides is a conceptually simple and synthetically
versatile approach for the synthesis of oxazolines, the reaction of
b-phosphonoamide (S)-3 with bis(2-methoxyethyl)amino-sulfur
trifluoride (Deoxo-Fluor) as the cyclo dehydrating agent was car-
ried out in the presence of K2CO3 with CH2Cl2 as the solvent at
À20 °C, to obtain the desired b-phosphono-oxazoline (S)-4 in 32%
yield. After several attempts under different reaction conditions
(varying the reaction times, temperatures, and equivalents of re-
agents), only a complex mixture of unidentified products was ob-
tained. The low yield suggested the ineffectiveness of this
strategy. For this reason, we decided to react b-phosphonoamide
(S)-3 with SOCl2, NaBr, and Et3N in CH2Cl2 at reflux, to give the
b-bromo amide (S)-5 in 80% yield, which upon the treatment with
NaH in dry THF at room temperature, provided the desired b-phos-
phono-oxazoline (S)-4 in 83% yield (Scheme 2).
Once the N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–
h were synthesized, the scope of the cyclodehydration reaction
was explored in order to obtain the target compounds (S)-1a–h.
Initially, the reaction of compound (S)-2a with SOCl2 was carried
out in acetonitrile at reflux for 4 h in the presence of NaBr and
K2CO3, to obtain the (4S)-4-benzyl-2-cinnamoyl-2-oxazoline (S)-
1a in 60% yield (Table 2, entry 1). Similar results were obtained
in the reaction of (S)-2d, and (S)-2f–h (Table 2, entries 4, 6–8),
whereas the reaction of (S)-2b and (S)-2c under the same condi-
tions afforded the 2,4-disubstituted oxazolines (S)-1b and (S)-1c,
respectively, in low yields (Table 2, entries 2 and 3). Finally, the
reaction of (S)-2e gave (S)-1e in 85% yield (Table 2, entry 5).
After preparation of phosphono-oxazoline (S)-4, the next step
was to explore the scope of the Horner–Wadsworth–Emmons reac-
tion in order to obtain chiral 2,4-disubstituted oxazolines (S)-1. In
this context, we carried out the reaction of (S)-4 with
Table 1
Preparation of N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–h
OH
OH
Bn
OH
Bn
O
O
O
O
O
H2N
Bn
(S)
ArCHO
(EtO)2P
(EtO)2P
Ar
N
H
OH
DBU, LiCl
THF, r.t.
N
H
DCC, DMAP
CH2Cl2, r. t.
3
(S)-
2a-h
(S)-(E)-
94%
Entry
Product
2a; Ar = C6H5
2b; Ar = 4-FC6H4
2c; Ar = 4-ClC6H4
2d; Ar = 4-BrC6H4
2e; Ar = 4-MeOC6H4
2f; Ar = 4-BnOC6H4
Yielda (%)
1
2
3
4
5
6
7
8
96
96
98
80
95
64
54
71
2g; Ar = 4-MeO2CC6H4
2h; Ar = 2-furfuryl
a
Isolated after purification by column chromatography.

158
F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
OH
Bn
phosphono-oxazoline (S)-4 appeared to be unstable for long reac-
tion times and gave unidentified compounds.
O
O
O
O
Deoxo-Fluor
(EtO)2P
(EtO)2P
N
Bn
After these results, we next turned our attention to the sequen-
tial cyclo dehydrohalogenation and Horner–Wadsworth–Emmons
reaction. For this purpose, the procedure reported by Shukla et al.18
was followed. Thus, the reaction of b-bromo amide (S)-5 was car-
ried out in the presence of K2CO3 as the base in dimethylformam-
ide (DMF) at reflux to afford the phosphono-oxazoline (S)-4, which
without additional purification, was treated with benzaldehyde
and refluxed for 2 h to obtain the 2,4-disubstituted oxazoline (S)-
1a in 93% yield (Table 4, entry 1). Similar results were obtained
in the reaction of (S)-5 with 4-fluorobenzaldehyde, 4-chlorobenz-
aldehyde, methyl 4-formylbenzoate, and 2-furaldehyde (Table 4,
entries 2, 3, 7 and 8). Moderate yields were obtained in the reaction
of (S)-5 with 4-bromobenzaldehyde, 4-methoxybenzaldehyde, and
4-(benzyloxy)benzaldehyde (Table 4, entries 4–6).
N
H
K2CO3
-20 ºC, CH2Cl2
32%
4
(S)-
(S)-3
SOCl2, K2CO3
80%
NaBr, MeCN, Δ
Br
O
O
NaH
(EtO)2P
N
H
THF, r. t.
83%
Bn
(S)-5
Scheme 2.
As can be seen in Table 4, a significant improvement in chemical
yields was found when applying this methodology to obtain the
target compounds (S)-1a–h. Additionally, no loss in the enantio-
meric purity of chiral 2,4-disubstituted oxazolines (S)-1a–h was
found in this process, in which the specific rotations were com-
pared with those obtained in the above experiments.
benzaldehyde, DBU, and LiCl in THF at room temperature.
However, after 4 h, only a small amount of the 2,4-disubstituted
oxazoline (S)-1a was obtained, along with the starting material.
In view of the unsatisfactory results for the synthesis of the 2,4-
disubstituted oxazoline (S)-1a under these conditions, the Horner–
Wadsworth–Emmons reaction of the phosphono-oxazoline (S)-4
was performed with benzaldehyde using NaH as the base in THF
at room temperature for 4 h, to give the 2,4-disubstituted
oxazoline (S)-1a in 30% yield. Similar results were obtained in
the reaction of (S)-4 with 4-fluorobenzaldehyde, 4-chlorobenzalde-
hyde, 4-methoxybenzaldehyde, and methyl 4-formylbenzoate,
(Table 3, entries 2–5). It was noted that when the reaction was
carried out at temperatures above 35 °C, several unidentified
products were formed. Additionally, we found that the
3. Conclusion
In conclusion, we have established a practical and efficient
methodology for the synthesis of chiral 2,4-disubstituted oxazo-
lines (S)-1a–h through the Horner–Wadsworth–Emmons reaction
of b-phosphonoamide (S)-3 bearing L-phenylalaninol with several
aryl aldehydes, followed by the cyclodehydration of the N-(cin-
namoyl)-(S)-phenylalaninol derivatives (S)-2a–h, and by sequen-
tial cyclodehydro-halogenation and Horner–Wadsworth–Emmons
reaction of (S)-5. This report represents an easy access to chiral
2,4-disubstituted oxazolines (S)-1a–h. Studies on the biological
activity of these oxazolines are currently in progress.
Table 3
Synthesis of chiral 2,4-disubstituted oxazolines (S)-1 from (S)-4
O
O
O
NaH, ArCHO
THF, r. t., 4 h
4. Experimental
4.1. General
(EtO)2P
N
Bn
Ar
N
Bn
(S)-4
(S)-(E)-1a-c,e,g
All commercial materials were used as received unless noted
otherwise. Anhydrous solvents (ethers) were obtained by distilla-
tion from benzophenone ketyl. Melting points were registered
using an Electrothermal II apparatus and are uncorrected. Flash
chromatography was performed using 230–400 mesh Silica Flash
60Ò silica gel. Thin layer chromatography was carried out on pre-
coated TLC sheets of silica gel 60 F254 (E. Merck). NMR spectra
Entry
Product
Yielda (%)
1
2
3
4
5
1a; Ar = C6H5
30
15
32
34
47
1b; Ar = 4-FC6H4
1c; Ar = 4-ClC6H4
1e; Ar = 4-MeOC6H4
1g; Ar = 4-MeO2CC6H4
a
Isolated after purification by column chromatography.
Table 4
Synthesis of chiral 2,4-disubstituted oxazolines (S)-1a–h from (S)-5
Br
O
O
O
O
O
K2CO3
RCHO
(EtO)2P
(EtO)2P
N
DMF, Δ
Bn
Ar
DMF, Δ
N
Bn
N
H
Bn
53-94%
5
1a-h
(S)-(E)-
(S)-
4
(S)-
Entry
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a; Ar = C6H5
1b; Ar = 4-FC6H4
1c; Ar = 4-ClC6H4
1d; Ar = 4-BrC6H4
1e; Ar = 4-MeOC6H4
1f; Ar = 4-BnOC6H4
1g; Ar = 4-MeO2CC6H4
1h; Ar = 2-furfuryl
93
93
94
80
68
53
89
94
a
Isolated after purification by column chromatography and only the E isomer was detected by 1H NMR.

F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
159
were recorded on two Varian System instruments (400 MHz for 1H,
161 MHz for 31P and 100 MHz for 13C, and 300 MHz for 1H, 121 for
31P and 75 MHz for 13C), as well as on a Mercury instrument
(200 MHz for 1H and 81 for 31P). The spectra were obtained in
CDCl3 and DMSO-d6 solution using TMS as an internal reference.
Chemical shifts (d) are reported in parts per million. Multiplicities
are recorded as follows: s = singlet, d = doublet, t = triplet,
dd = doublet of doublets, td = triplet of doublets, bs = broad signal,
q = quartet and m = multiplet. Coupling constants (J) are given in
Hz. High resolution FAB+ mass experiments were done on a JEOL
HRMStation JHRMS-700. Optical rotations were measured at
28 °C on an Anton-Paar MCP 300 polarimeter in a 2.5 mm cell.
room temperature for 30 min, prior to the addition of the corre-
sponding aldehyde (1.0 equiv), after which it was stirred at room
temperature for 4 h. The reaction was quenched by the addition
of a saturated NH4Cl solution (10 mL), and extracted with AcOEt
(3 Â 30 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by column chromatography using
Hex-AcOEt (7:3) and ethyl acetate-hexane-methanol (5:4:1).
4.4.1. N-(Cinnamoyl)-(S)-phenylalaninol (S)-2a
(300 mg, 96%) as a white solid, mp 144–146 °C, [
a
]
D = À100.0 (c
1.0, MeOH). 1H and 13C NMR data are identical with those de-
scribed in the literature.11c HRMS (FAB+): calculated for
C
18H20NO2 [M+H]+, m/z 282.1494; found for [M+H]+, m/z 282.1506.
4.2. (S)-2-(2-Diethoxyphosphoryl)acetamide-3-phenyl-propanol
(S)-3
4.4.2. N-(p-Fluorocinnamoyl)-(S)-phenylalaninol (S)-2b
(470 mg, 96%) as a solid, mp 75–77 °C, [
A solution of dicyclohexylcarbodiimide (4.15 g, 20.2 mol) and
4-(dimethylamino)pyridine (490 mg, 4.02 mmol) in 100 mL of
dry dichloromethane was slowly added at room temperature to a
solution of 2-diethyl-phosphonoacetic acid (4.37 g, 22.3 mmol)
and (S)-2-amino-3-phenyl-1-propanol (3.1 g, 20.2 mmol) in
100 mL of anhydrous CH2Cl2 under an inert atmosphere. The reac-
tion mixture was stirred at room temperature for 12 h, filtered, and
washed with AcOEt (20 mL). The organic extracts were dried over
anhydrous Na2SO4, filtered, and evaporated under reduced pres-
sure. The crude product was purified by flash chromatography on
silica gel AcOEt–Hex–MeOH (5:4:1), to obtain compound (S)-3
a]
D = À88.3 (c 1.6,
MeOH). 1H NMR (400 MHz, CDCl3): d 2.92 (d, J = 7.2 Hz, 2H, CH2Ph),
3.62 (dd, J = 11.2, 5.2 Hz, 1H, CH2OH), 3.72 (dd, J = 11.2, 3.8 Hz, 1H,
CH2OH), 4.31 (m, 1H, CHBn), 6.28 (d, Jtrans = 15.6 Hz, 1H, CHC@O),
6.38 (d, J = 7.6 Hz, 1H, NH), 6.9 (dd, J = 8.8, 7.2 Hz, 2H, Harom),
7.20–7.29 (m, 5H, Harom), 7.37 (dd, J = 8.4, 5.2 Hz, 2H, Harom), 7.50
(d, Jtrans = 15.6 Hz, 1H, CH(p-FC6H4)). 13C NMR (100 MHz, CDCl3):
d 37.2 (CH2Ph), 53.2 (CHBn), 64.0 (CH2OH), 116.0, 120.37 (CH),
126.8, 128.8, 129.4, 129.8, 131.0, 137.8, 140.4 (CH), 163.7, 166.6
(C@O). HRMS (FAB+): calculated for C18H19NO2F [M+H]+, m/z
300.1400; found for [M+H]+, m/z 300.1402.
(6.6 g, 94% yield) as a viscous oil, [
a
]
D = À16.5 (c 1.7, MeOH). 1H
and 13C NMR data are identical with those described in the litera-
ture.19 HRMS (FAB+): calculated for C15H25NO5P [M+H]+, m/z
330.1470; found for [M+H]+, m/z 330.1467.
4.4.3. N-(p-Chlorocinnamoyl)-(S)-phenylalaninol (S)-2c
(260 mg, 98%) as a solid, mp 132–134 °C, [
a
]
D = À1.3 (c 3.0,
MeOH). 1H NMR (400 MHz, CDCl3): d 2.88 (dd, J = 13.9, 7.2 Hz,
1H, CH2Ph), 2.94 (dd, J = 13.9, 7.3 Hz, 1H, CH2Ph), 3.56 (dd,
J = 11.3, 5.2 Hz, 1H, CH2OH), 3.64 (dd, J = 11.3, 4.2 Hz, 1H, CH2OH),
4.19–4.34 (m, 1H, CHBn), 6.46 (d, Jtrans = 15.7 Hz, 1H, CHC@O),
7.15–7.44 (m, 10H, Harom and NH), 7.49 (d, Jtrans = 15.7 Hz, 1H,
CH(p-ClC6H4)). 13C NMR (100 MHz, CDCl3): d 36.9 (CH2Ph), 52.8
(CHBn), 63.0 (CH2OH), 121.2, 126.4, 128.4, 129.0 (2), 129.2,
133.4, 135.5, 137.9, 139.6, 166.6 (C@O). HRMS (FAB+): calculated
for C18H19NO2Cl [M+H]+, m/z 316.1104; found for [M+H]+, m/z
316.1105.
4.3. (S)-2-(2-Diethoxyphosphoryl)acetamide-3-phenyl-
bromoprapane (S)-5
Thionyl chloride (0.88 mL, 12.3 mmol) was added dropwise to a
solution of (S)-3 (2.02 g, 6.1 mmol) and Et3N (0.85 mL, 6.1 mmol)
in anhydrous CH2Cl2 (30 mL). The reaction mixture was stirred
for 15 min at reflux followed by the addition of NaBr (940 mg,
9.2 mmol). The reaction mixture was then stirred at reflux for
3 h. After this time, the reaction was quenched by the addition of
a saturated NH4Cl solution (10 mL), and extracted with AcOEt
(3 Â 30 mL). The organic extracts were dried over anhydrous Na2-
SO4, filtered, and evaporated under reduced pressure. The crude
product was purified by flash chromatography AcOEt–Hex–MeOH
(5:4:1), to obtain compound (S)-5 (1.91 g, 80% yield) as a white so-
4.4.4. N-(p-Bromocinnamoyl)-(S)-phenylalaninol (S)-2d
(990 mg, 80%) as a solid, mp 168–169 °C, [
a
]
D = À110.8 (c 1.0,
MeOH). 1H NMR (400 MHz, CDCl3): d 2.89 (dd, J = 7.2, 2.8 Hz, 1H,
CH2Ph), 2.91 (dd, J = 7.2, 2.8 Hz, 1H, CH2Ph), 3.56 (dd, J = 11.2,
5.2 Hz, 1H, CH2OH), 3.66 (dd, J = 11.2, 4.0 Hz, 1H, CH2OH), 4.27
(m, 1H, CHBn), 6.40 (d, Jtrans = 15.6 Hz, 1H, CHC@O), 6.94 (d,
J = 8.0 Hz, 1H, NH), 7.18–7.31 (m, 7H, Harom), 7.43-7.48 (m, 3H,
Harom and CH(p-BrC6H4)). 13C NMR (100 MHz, CDCl3): d 37.0 (CH2-
Ph), 52.8 (CHBn), 63.2 (CH2OH), 121.3 (CH), 121.4, 123.9, 126.6,
128.6, 129.2, 132.0, 133.7, 137.9, 139.8 (CH), 166.5 (C@O). HRMS
(FAB+): calculated for C18H19NO2Br [M+H]+, m/z 360.0599; found
for [M+H]+, m/z 360.0590.
lid, mp 89–91 °C, [
a
]
D = À12.9 (c 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): d 1.30 (t, J = 7.2 Hz, 3H, (CH3CH2O)2P), 1.34 (t, J = 7.2 Hz,
3H, (CH3CH2O)2P), 2.82 (dd, JH/P = 17.8, Jgem = 15.5 Hz, 1H, CH2P),
2.87 (dd, JH/P = 17.8, Jgem = 15.5 Hz, 1H, CH2P), 2.94 (d, J = 7.8 Hz,
2H, CH2Ph), 3.51 (dd, J = 11.3, 3.5 Hz, 1H, CH2Br), 3.64 (dd,
J = 11.3, 4.1 Hz, 1H, CH2Br), 4.06 (dq, J = 14.2, 7.1 Hz, 2H, CH2OP),
4.15 (dq, J = 14.2, 7.1 Hz, 2H, CH2OP), 4.42–4.50 (m, 1H, CHBn),
7.10 (d, J = 8.0 Hz, 1H, NH), 7.21–7.33 (m, 5H, Harom). 13C NMR
(100 MHz, CDCl3) d: 16.4 ((CH3CH2O)2P), 16.5 ((CH3CH2O)2P),
35.2 (d, J = 131.0 Hz, CH2P), 37.5 (CH2Ph), 46.5 (CH2Br), 51.5
(CHBn), 62.9 (d, J = 3.7 Hz, CH2OP), 63.0 (d, J = 3.7 Hz, CH2OP),
127.0, 128.9, 129.4, 137.0, 163.9 (C@O). 31P NMR (161 MHz,
CDCl3): d 22.46.
4.4.5. N-(p-Methoxycinnamoyl)-(S)-phenylalaninol (S)-2e
(300 mg, 95%) as a solid, mp 128–130 °C, [
a
]
D = À95.7 (c 1.0,
MeOH). 1H NMR (300 MHz, CDCl3): d 2.91 (dd, J = 14.1, 7.6 Hz,
1H, CH2Ph), 2.98 (dd, J = 14.1, 7.6 Hz, 1H, CH2Ph), 3.60 (dd,
J = 11.2, 5.1 Hz, 1H, CH2OH), 3.67 (dd, J = 11.2, 4.3 Hz, 1H, CH2OH),
3.78 (s, 3H, CH3O), 4.26–4.34 (m, 2H, CHBn and NH), 6.40 (d,
Jtrans = 15.7 Hz, 1H, CHC@O), 6.85 (d, J = 8.7 Hz, 2H, Harom), 7.31–
7.13 (m, 5H, Harom), 7.42 (d, J = 8.7 Hz, 2H, Harom), 7.51 (d,
Jtrans = 15.7 Hz, 1H, CH(p-CH3OC6H4)). 13C NMR (75 MHz, CDCl3): d
36.6 (CH2Ph), 52.5 (CHBn), 54.8 (CH3OC6H4), 62.6 (CH2OH), 113.7,
117.7, 125.8, 126.9, 127.8, 128.7, 128.8, 137.6, 140.0, 160.3, 166.7
4.4. General procedure for the preparation of N-(cinnamoyl)-
(S)-phenylalaninol derivatives (S)-2a–h
A solution of b-phosphonoamide (S)-3 (1.0 equiv) in dry THF
(30 mL) was treated under a nitrogen atmosphere with 8-diazabi-
cyclo[5.4.0]undec-7-ene (3.0 equiv). The mixture was stirred at

160
F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
(C@O). HRMS (FAB+): calculated for C19H22NO3 [M+H]+, m/z
312.1600; found for [M+H]+, m/z 312.1587.
126.7, 128.6, 129.2, 137.8, 160.4 (d, J = 8.9 Hz, C@N). 31P NMR
(161 MHz, CDCl3) d: 21.13. HRMS (FAB+): calculated for C15H23NO4-
P [M+H]+, m/z 312.1365; found for [M+H]+, m/z 312.1363.
4.4.6. N-(p-Benzyloxycinnamoyl)-(S)-phenylalaninol (S)-2f
(380 mg, 64%) as a solid, mp 171-173 °C, [
a
]
D = À83.35 (c 1.0,
4.6. General procedure for the preparation of chiral 2,4-disub-
stituted oxazolines (S)-1a–h from (S)-2a–h
DMSO). 1H NMR (400 MHz, DMSO-d6): d 2.69 (dd, J = 13.7, 8.5 Hz,
1H, CH2Ph), 2.90 (dd, J = 13.7, 5.6 Hz, 1H, CH2Ph), 3.36 (dd,
J = 10.7, 5.6 Hz, 1H, CH2OH), 3.42 (dd, J = 10.8, 4.9 Hz, 1H, CH2OH),
3.94–4.12 (m, 1H, CHBn), 5.13 (s, 2H, OCH2Ph), 6.52 (d, Jtrans = 15.9,
1H, CHC@O), 7.04 (d, J = 8.7, 2H, Harom), 7.31 (d, Jtrans = 15.9, 1H,
CH(p-BnOC6H4), 7.12–7.53 (m, 10H, Harom), 7.48 (d, J = 8.8 Hz, 2H,
A solution of N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-
2a–h in CH3CN (30 mL) was treated with SOCl2 (1.1 equiv), K2CO3
(2.2 equiv), and NaBr (1.0 equiv). The reaction mixture was stirred
at reflux for 4 h. After this time, the reaction mixture was quenched
by the addition of a saturated NH4Cl solution (15 mL). The solvent
was evaporated under reduced pressure and the remaining resi-
dues were dissolved in water (30 mL) and extracted with AcOEt
(3 Â 30 mL). The organic extracts were combined, dried over anhy-
drous Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by column chromatography using
Hex–AcOEt (7:3).
H
arom), 8.03 (d, J = 8.3 Hz, 1H, NH). 13C NMR (75 MHz, CD3OD): d
36.7 (CH2Ph), 52.5 (CHBn), 62.8 (CH2OH), 69.9 (OCH2Ph), 114.9,
118.0, 126.2, 127.3, 127.5, 127.8, 128.2, 128.4, 129.0, 129.1,
136.3, 137.8, 140.5, 159.9, 167.1 (C@O). HRMS (FAB+): calculated
for C25H26NO3 [M+H]+, m/z 388.1913; found for [M+H]+, m/z
388.1910.
4.4.7. N-(p-Carbomethoxycinnamoyl)-(S)-phenylalaninol (S)-2g
(580 mg, 54%) as a solid, mp 161–163 °C, [
a
]
D = À116.0 (c 1.0,
4.7. General procedure for the preparation of chiral 2,4-disub-
stituted oxazolines (S)-1a–c,e,h from (S)-4a–c,e,h using NaH as a
base
MeOH). 1H NMR (400 MHz, CDCl3): d 2.91 (dd, J = 13.6, 7.0 Hz,
1H, CH2Ph), 2.95 (dd, J = 13.6, 7.2 Hz, 1H, CH2Ph), 3.57 (dd,
J = 11.2, 5.2 Hz, 1H, CH2OH), 3.67 (dd, J = 11.2, 4.0 Hz, 1H, CH2OH),
3.91 (s, 3H, CH3O), 4.28 (m, 1H, CHBn), 6.52 (d, Jtrans = 15.6 Hz, 1H,
CHC@O), 7.08 (d, J = 8.0 Hz, 1H, NH), 7.18–7.31 (m, 5H, Harom), 7.49
(d, J = 8.4 Hz, 2H, Harom). 7.55 (d, Jtrans = 15.6 Hz 1H, CH(p-CH3O2-
CC6H4)), 7.98 (d, J = 8.4 Hz, 2H, Harom), 13C NMR (100 MHz, CDCl3):
d 37.0 (CH2Ph), 52.3 (CH3O), 52.9 (CHBn), 63.2 (CH2OH), 123.2
(CH), 126.6, 127.7, 128.6, 129.3, 130.1, 130.7, 137.9, 139.3, 139.7
(CH), 166.3 (C@O), 166.9 (C@O). HRMS (FAB+): calculated for
A suspension of NaH (2.2 equiv) in anhydrous THF (25 mL) was
added dropwise to a solution of (S)-4 (1.0 equiv) in dry THF
(15 mL). The mixture was stirred under an inert atmosphere at
room temperature for 30 min, prior to the addition of the corre-
sponding aldehyde (1.0 equiv). The resulting mixture was stirred
at room temperature for 4 h. After this time, the reaction was
quenched by the addition of a saturated NH4Cl solution (10 mL),
and extracted with AcOEt (3 Â 30 mL). The organic extracts were
combined, dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. The crude product was purified by column
chromatography using Hex-AcOEt (7:3).
C
20H22NO4 [M+H]+, m/z 340.1549; found for [M+H]+, m/z 340.1556.
4.4.8. N-(Furan-2-yl-acryloyl)-(S)-phenylalaninol (S)-2h
(380 mg, 71%) as a solid, mp 111–113 °C, [
a]
D = À116.0 (c 1.0,
MeOH). 1H NMR (400 MHz, CDCl3): d 2.91 (d, J = 7.3 Hz, 2H, CH2Ph),
3.60 (dd, J = 11.2, 5.3 Hz, 1H, CH2OH), 3.70 (dd, J = 11.2, 3.8 Hz, 1H,
CH2OH), 4.29 (m, 1H, CHBn), 6.28 (d, Jtrans = 15.3 Hz, 1H, CHC@O),
6.37 (d, J = 8.0, 1H, NH), 6.39 (dd, J = 3.4, 1.8 Hz, 1H, CH@CHAO),
6.49 (d, J = 3.4 Hz, 1H, CH@C), 7.34 (d, Jtrans = 15.3 Hz, 1H, CH-furyl),
7.14–7.37 (m, 6H, Harom and CH-O). 13C NMR (100 MHz, CDCl3): d
37.2 (CH2Ph), 53.2 (CHBn), 64.0 (CH2OH), 112.3, 114.2, 118.3,
126.8, 128.4, 128.7, 129.4, 137.8, 144.3, 151.3, 166.7 (C@O). HRMS
(FAB+): calculated for C16H18NO3 [M+H]+, m/z 272.1287; found for
[M+H]+, m/z 272.1282.
4.8. General procedure for the preparation of chiral 2,4-disub-
stituted oxazolines (S)-1a–h from (S)-5 using K2CO3 as a base
A mixture of (S)-5 (1.0 equiv) and K2CO3 (2.0 equiv) in dry DMF
(5 mL) was stirred at reflux for 2 h prior to the addition of the cor-
responding aldehyde (1.0 equiv), and then stirred at reflux for an
additional 2 h. The reaction mixture was quenched by the addition
of a saturated NH4Cl solution (15 mL) and extracted with AcOEt
(3 Â 30 mL). The organic extracts were combined, dried over anhy-
drous Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by column chromatography using
Hex–AcOEt (7:3).
4.5. (S)-Diethyl ((4-benzyl-4,5-dihydrooxazol-2-yl)methyl)phos-
phonate (S)-4
A suspension of NaH (130 mg, 5.6 mmol) in anhydrous THF
(25 mL) was added to a solution of (S)-5 (1.0 g, 2.5 mmol) in dry
THF (15 mL). The reaction mixture was stirred at room tempera-
ture under an inert atmosphere for 12 h. After this time, the reac-
tion mixture was quenched by the addition of a saturated NH4Cl
solution (10 mL), and extracted with AcOEt (3 Â 30 mL). The or-
ganic extracts were dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. The crude product was puri-
fied by flash chromatography AcOEt-Hex-MeOH (5:4:1), to obtain
4.8.1. (4S)-4-Benzyl-2-cinnamoyl-2-oxazoline (S)-1a
(273 mg, 93%) as a white solid, mp 71-73 °C, [
a]
D = À10.0 (c 1.0,
MeOH). 1H and 13C NMR data are identical with those described in
the literature.11c HRMS (FAB+): calculated for C18H18NO [M+H]+, m/
z 264.1388; found for [M+H]+, m/z 264.1400.
4.8.2. (4S)-4-Benzyl-2-(p-fluorocinnamoyl)-2-oxazoline (S)-1b
(279 mg, 93%) as a white solid, mp 93–95 °C, [a]D = +17.7 (c 1.0,
compound (S)-4 (670 mg. 83% yield) as a yellow oil, [
a
]
D = À42.9
MeOH). 1H NMR (300 MHz, CDCl3): d 2.91 (dd, J = 13.7, 8.5 Hz, 1H,
CH2Ph), 3.35 (dd, J = 13.7, 8.5 Hz, 1H, CH2Ph), 4.25 (t, J = 7.4 Hz, 1H,
CH2O), 4.49 (t, J = 8.4 Hz, 1H, CH2O), 4.72 (m, 1H, CHBn), 6.75 (d,
Jtrans = 16.2 Hz, 1H, CHC@N), 7.20–7.24 (m, 1H, Harom), 7.32 (d,
Jtrans = 16.2 Hz, 1H, CH(p-FC6H4)), 7.45–7.65 (m, 7H, Harom), 7.67–
7.68 (m, 1H, Harom). 13C NMR (75 MHz, CDCl3): d 41.8 (CH2Ph),
67.8 (CHBn), 71.6 (CH2O), 114.9 (CH), 115.8 (CH), 116.0 (CH),
126.5, 128.6, 129.2, 131.4, 137.9, 138.7, 163.0, 163.6 (C@N). HRMS
(c 4.7, MeOH). 1H NMR (400 MHz, CDCl3) d: 1.35 (t, J = 6.8 Hz, 6H,
(CH3CH2O)2P), 2.93 (d, J = 21.5 Hz, 2H, CH2P), 2.66 (dd, J = 13.8,
8.5 Hz, 1H, CH2Ph), 3.10 (dd, J = 13.8, 5.5 Hz, 1H, CH2Ph), 4.02
(dd, J = 8.3, 7.5 Hz, 1H, CH2O), 4.24 (dd, J = 9.1, 8.8 Hz, 1H, CH2O),
4.17 (dq, J = 14.4, 7.1 Hz, 4H, CH2OP), 4.37–4.46 (m, 1H, CHBn),
7.19–7.32 (m, 5H, Harom). 13C NMR (100 MHz, CDCl3) d: 16.4 ((CH3-
CH2O)2P), 16.4 ((CH3CH2O)2P), 27.4 (d, J = 138.6 Hz, CH2P), 41.6
(CH2Ph), 62.7 (d, J = 5.3 Hz, CH2OP), 67.6 (CHBn), 72.4 (CH2O),

F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
161
(FAB+): calculated for C18H17NOF [M+H]+, m/z 282.1294; found for
[M+H]+, m/z 282.1304.
138.7, 139.5 (CH), 163.3 (C@N), 166.6 (C@O). HRMS (FAB+): calcu-
lated for C20H20NO3 [M+H]+, m/z 322.1443; found for [M+H]+, m/z
322.1430.
4.8.3. (4S)-4-Benzyl-2-(p-chlorocinnamoyl)-2-oxazoline (S)-1c
(240 mg, 94%) as a white solid, mp 81–83 °C, [
a
]
D = +4.0 (c 1.0,
4.8.8. (4S)-4-Benzyl-2-(furan-2-yl-vinyl)-2-oxazoline (S)-1h
MeOH). 1H NMR (300 MHz, CDCl3): d 2.70 (dd, J = 13.8, 8.4 Hz,
1H, CH2Ph), 3.14 (dd, J = 13.8, 5.4 Hz, 1H, CH2Ph), 4.04 (dd, J = 8.4,
7.8 Hz, 1H, CH2O), 4.27 (dd, J = 9.0, 8.4 Hz, 1H, CH2O), 4.48 (m,
1H, CHBn), 6.63 (d, Jtrans = 16.2, 1H, CHC@N), 7.21-7.51 (m, 10H,
(180 mg, 94%) as a brown solid, mp 72–74 °C, [a]D = +16.0 (c 1.0,
MeOH). 1H NMR (300 MHz, CDCl3): d (dd, J = 13.8, 8.4 Hz, 1H, CH2-
Ph), 3.16 (dd, J = 13.8, 5.2 Hz, 1H, CH2Ph), 4.01 (dd, J = 8.5, 7.5 Hz,
1H, CH2O), 4.24 (dd, J = 9.0, 8.5 Hz, 1H, CH2O), 4.49 (m, 1H, CHBn),
6.42-6.44 (m, 1H, Harom) 6.48–6.57 (m, 2H, Harom and CHC@N),
7.07–7.45 (m, 7H, Harom and CH-furfuryl). 13C NMR (75 MHz,
CDCl3): d 41.6 (CH2Ph), 67.6 (CHBn), 71.4 (CH2O), 112.0, 112.7,
112.8, 126.4, 127.0, 128.5, 129.1, 137.8, 144.0, 151.3, 163.6
(C@N). HRMS (FAB+): calculated for C16H16NO2 [M+H]+, m/z
254.1181; found for [M+H]+, m/z 254.1187.
H
arom and CH(p-ClC6H4)). 13C NMR (75 MHz, CDCl3):d 41.7 (CH2Ph),
67.7 (CHBn), 71.6 (CH2O), 115.8 (CH), 123.6, 126.5, 128.6, 128.8,
129.1, 132.0, 134.1, 137.8, 138.7 (CH), 163.4 (C@N). HRMS
(FAB+): calculated for C18H17NOCl [M+H]+, m/z 298.0999; found
for [M+H]+, m/z 298.1002.
4.8.4. (4S)-4-Benzyl-2-(p-bromocinnamoyl)-2-oxazoline (S)-1d
(250 mg, 80%) as a white solid, mp 98–99 °C, [a]D = +8.0 (c 1.0,
Acknowledgments
MeOH). 1H NMR (300 MHz, CDCl3): d 2.70 (dd, J = 13.8, 8.4 Hz,
1H, CH2Ph), 3.14 (dd, J = 13.8, 5.7 Hz, 1H, CH2Ph), 4.03 (dd, J = 8.2,
7.8 Hz, 1H, CH2O), 4.26 (dd, J = 9.0, 8.2 Hz, 1H, CH2O), 4.50 (m,
1H, CHBn), 6.60 (d, Jtrans = 16.2 Hz, 1H, CHC@N), 7.21–7.42 (m,
10H, Harom and CH(p-BrC6H4)). 13C NMR (75 MHz, CDCl3): d 41.7
(CH2Ph), 67.7 (CHBn), 71.6 (CH2O), 115.7 (CH), 126.5, 128.3,
128.7, 128.8, 129.1, 133.6, 135.3, 137.8, 138.6 (CH), 163.5 (C@N).
HRMS (FAB+): calculated for C18H17NOBr [M+H]+, m/z 342.0494;
found for [M+H]+, m/z 342.0489.
The authors thank CONACYT of México, for their financial sup-
port via projects 181816 and 101898. We thank V. Labastida-Gal-
ván for the determination of mass spectra. F.G.A.A. also thanks
the CONACYT for Graduate Scholarships.
References
1. (a) Saini, M. S.; Kumar, A.; Dwivedi, J.; Singh, R. Int. J. Pharm. Sci. Res. 2013, 4,
66–77; (b) Lashgari, N.; Ziarani, G. M. ARKIVOC 2012, i, 277–320; (c) Dua, R.;
Shrivastava, S.; Sonwane, S. K.; Shrivastava, S. K. Adv. Biol. Res. 2011, 5, 120–
144; (d) Kashyap, S. J.; Sharma, P. K.; Garg, V. K.; Dudhe, R.; Kumar, N. J. Adv. Sci.
Res. 2011, 2, 18–24.
4.8.5. (4S)-4-Benzyl-2-(p-methoxycinnamoyl)-2-oxazoline (S)-
1e
(200 mg, 68%) as a white solid, mp 68–70 °C, [a]D = +16.3 (c 1.0,
2. Asymmetry Synthesis of Nitrogen Heterocycles; Royer, J., Ed.; Wiley-VCH:
Weinheim, 2009.
MeOH). 1H NMR (300 MHz, CDCl3): d (dd, J = 13.8, 8.7 Hz, 1H, CH2-
Ph), 3.16 (dd, J = 13.8, 4.8 Hz, 1H, CH2Ph), 3.80 (s, 3H, CH3O), 4.03
(dd, J = 8.1, 7.5 Hz, 1H, CH2O), 4.26 (dd, J = 8.7, 8.1 Hz, 1H, CH2O),
4.50 (m, 1H, CHBn), 6.52 (d, Jtrans = 16.2 Hz, 1H, CHC@N), 7.32 (d,
J = 6.9 Hz, 2H, Harom), 7.22-7.43 (m, 8H, Harom and CH(p-CH3OC6-
H4)). 13C NMR (75 MHz, CDCl3): d 41.8 (CH2Ph), 55.3 (CH3O), 67.6
(CHBn), 71.5 (CH2O), 112.7 (CH), 114.2, 126.5, 127.9, 128.5,
128.9, 129.1, 138.0, 139.7 (CH), 160.7, 164.0 (C@N). HRMS
(FAB+): calculated for C19H20NO2 [M+H]+, m/z 294.1494; found
for [M+H]+, m/z 294.1490.
3. (a) Rudrapal, M.; De, B. Int. Res. J. Pure Appl. Chem. 2013, 3, 232–249; (b)
Kushwaha, N.; Kushwaha, S. K. S.; Rai, A. K. Int. J. Chem. Technol. Res. 2012, 4,
517–531; (c) de Oliveira, C. S.; Lira, B. F.; Barbosa-Filho, J. M.; Fernandez-
Lorenzo, J. G.; de Athayde-Filho, P. F. Molecules 2012, 17, 10192–10231; (d)
Singh, A. K.; Mishra, G.; Jyoti, K. J. Appl. Pharm. Sci. 2011, 1, 44–49; (e) Yadav, P.
S.; Devprakash, S. G. P. Int. J. Pharm. Sci. Drug Res. 2011, 3, 1–7; (f) Siddiquia, N.;
Ahsana, W.; Alama, M. S.; Alia, R.; Jainb, S.; Azada, B.; Akhtara, J. Int. J. Pharm.
Sci. Rev. Res. 2011, 8, 161–169; (g) Kumar, J. R. Pharmacophore 2010, 1, 167–
177; (h) Shalini, K.; Sharma, K. M.; Kumar, N. Der Chem. Sinica 2010, 1, 36–47.
4. (a) McIntosh, J. A.; Donia, M. S.; Schmidt, E. W. J. Am. Chem. Soc. 2010, 132,
4089–4091; (b) Pfeiffer, B.; Hauenstein, K.; Merz, P.; Gertsch, J.; Altmann, K.-H.
Bioorg. Med. Chem. Lett. 2009, 19, 3760–3763; (c) Faizi, S.; Farooqi, F.; Zikr-Ur-
Rehman, S.; Naz, A.; Noor, F.; Ansari, F.; Ahmad, A.; Khan, S. A. Tetrahedron
2009, 65, 998–1004; (d) Bergeron, R. J.; Bharti, N.; Singh, S.; McManis, J. S.;
Wiegand, J.; Green, L. G. J. Med. Chem. 2009, 52, 3801–3813; (e) Portmann, C.;
Blom, J. F.; Kaiser, M.; Brun, R.; Jüttner, F.; Gademann, K. J. Nat. Prod. 2008, 71,
1891–1896; (f) García-Reynaga, P.; VanNieuwenhze, M. S. Org. Lett. 2008, 10,
4621–4623; (g) Nicolaou, K. C.; Lizos, D. E.; Kim, D. W.; Schlawe, D.; de
Noronha, R. G.; Longbottom, D. A.; Rodriquez, M.; Bucci, M.; Cirino, G. J. Am.
Chem. Soc. 2006, 128, 4460–4470; (h) Prinsep, M. R.; Moore, R. E.; Levine, I. A.;
Patterson, G. M. L. J. Nat. Prod. 1992, 55, 140–142; (i) Ireland, C. M.; Durso, A. R.,
Jr.; Newman, R. A.; Hacker, M. P. J. Org. Chem. 1982, 47, 1807–1811.
5. Moraski, G. C.; Markley, L. D.; Chang, M.; Cho, S.; Franzblau, S. G.; Hwang, C. H.;
Boshoff, H.; Miller, M. J. Bioorg. Med. Chem. 2012, 20, 2214–2220.
4.8.6. (4S)-4-Benzyl-2-(p-benzyloxycinnamoyl)-2-oxazoline (S)-
1f
(140 mg, 53%) as a white solid, mp 141–143 °C, [a]D = +23.4 (c
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d (dd, J = 13.8, 9.0 Hz, 1H,
CH2Ph), 3.16 (dd, J = 13.5, 5.1 Hz, 1H, CH2Ph), 4.03 (dd, J = 8.2,
7.5 Hz, 1H, CH2O), 4.27 (dd, J = 9.3, 8.2 Hz, 1H, CH2O), 4.49 (m,
1H, CHBn), 5.08 (s, 2H, CH2O), 6.51 (d, Jtrans = 16.2 Hz, 1H, CHC@N),
6.97 (d, J = 8.4 Hz, 2H, Harom), 7.22–7.43 (m, 13H, Harom and CH(p-
BnOC6H4)). 13C NMR (75 MHz, CDCl3): d 41.8 (CH2Ph), 67.7 (CHBn),
70.0 (CH2Ph), 71.5 (CH2O), 112.9 (CH), 115.1, 126.5, 127.4, 128.1,
128.5, 128.6, 129.0 (2), 129.1, 136.5, 138.0, 139.6 (CH), 159.9,
164.0 (C@N). HRMS (FAB+): calculated for C25H24NO2 [M+H]+, m/z
370.1807; found for [M+H]+, m/z 370.1820.
6. (a) Peña, S.; Scarone, L.; Manta, E.; Serra, G. Tetrahedron Lett. 2013, 54, 2806–
2808; (b) Gordey, E. E.; Yadav, P. N.; Merrin, M. P.; Davies, J.; Ward, S. A.;
Woodman, G. M.; Sadowy, A. L.; Smith, T. G.; Gossage, R. A. Bioorg. Med. Chem.
Lett. 2011, 21, 4512–4515.
7. (a) Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, S. L., II.; Barr, K. J.; Liu, G.;
Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.; Warner, R. B.; Kovar, P.; Nukkala, M.
A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.; Ng,
S.-C.; Rosenberg, S.; Sham, H. L. Bioorg. Med. Chem. Lett. 2012, 12, 465–469; (b)
Djurendic´, E.; Vujakovic´, S. D.; Sakac´, M.; Ajdukovic´, J.; Gakovic´, A.; Kojic´, V.;
4.8.7. (4S)-4-Benzyl-2-(p-carbomethoxycinnamoyl)-2-oxazoline
(S)-1g
´
´
Bogdanovic, G.; Klisuric, O.; Gaši, K. P. ARKIVOC 2011, ii, 83–102; (c) Ondré, D.;
Wölfling, J.; Tóth, I.; Szecsi, M.; Julesz, J.; Schneider, G. Steroids 2009, 74, 1025–
1032.
(290 mg, 89%) as a white solid, mp 114–115 °C, [a]D = +4.0 (c
1.0, MeOH). 1H NMR (300 MHz, CDCl3): d (dd, J = 13.8, 8.7 Hz, 1H,
CH2Ph), 3.16 (dd, J = 13.8, 5.7 Hz, 1H, CH2Ph), 3.92 (s, 3H, CH3O),
4.06 (dd, J = 8.5, 7.5 Hz, 1H, CH2O), 4.30 (dd, J = 9.3, 8.5 Hz, 1H,
CH2O), 4.52 (m, 1H, CHBn), 6.72 (d, Jtrans = 16.2, 1H, CHC@N),
7.21–7.38 (m, 6H, Harom and CH(p-CH3O2CC6H4)), 7.52 (d,
J = 8.1 Hz, 2H, Harom), 8.03 (d, J = 8.1 Hz, 2H, Harom). 13C NMR
(75 MHz, CDCl3): d 41.7 (CH2Ph), 52.2 (CH3O), 67.8 (CHBn), 71.6
(CH2O), 117.6, 126.5, 127.3, 128.6, 129.1, 130.0, 130.6, 137.8,
8. (a) Jiang, H.; Yan, L.; Xu, M.; Lu, W.; Cai, Y.; Wan, W.; Yao, J.; Wu, S.; Zhu, S.;
Hao, J. J. Org. Chem. 2013, 78, 4261–4269; (b) Harvey, R. A.; Karlubíková, O.;
Parris, S.; Clayden, J. Tetrahedron Lett. 2013, 54, 4064–4066; (c) Shinada, T.; Oe,
K.; Ohfune, Y. Tetrahedron Lett. 2012, 53, 3250–3253; (d) Sen, S.; Kammaa, S. R.;
Potti, V. P.; Murthy, Y. L. N.; Chaudhary, A. V. Tetrahedron Lett. 2011, 52, 5585–
5588; (e) Pigza, J. A.; Quach, T.; Molinski, T. F. J. Org. Chem. 2009, 74, 5510–
5515; (f) Kanizsai, I.; Szakonyi, Z.; Sillanpää, R.; D’hooghe, M.; De Kimpe, N.;
Fülöp, F. Tetrahedron: Asymmetry 2006, 17, 2857–2863.
9. (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505–2550; (b) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561–3651.

162
F. G. Avalos-Alanís et al. / Tetrahedron: Asymmetry 25 (2014) 156–162
10. (a) Wolin´ ska, E. Tetrahedron 2013, 69, 7269–7278; (b) Glen, P. E.; O’Neill, J. A.
T.; Lee, A.-L. Tetrahedron 2013, 69, 57–68; (c) Aydin, A. E.; Yuksekdanaci, S.
Tetrahedron: Asymmetry 2013, 24, 14–22; (d) Saiyed, A. S.; Bedekar, A. V.
Tetrahedron: Asymmetry 2013, 24, 1035–1041; (e) Lebel, H.; Parmentier, M.;
Leogane, O.; Ross, K.; Spitz, C. Tetrahedron 2012, 68, 3396–3409; (f) Moreau, M.;
Alberico, D.; Lindsay, V. N. G.; Charette, A. B. Tetrahedron 2012, 68, 3487–3496;
(g) Maurer, F.; Huch, V.; Ullrich, A.; Kazmaier, U. J. Org. Chem. 2012, 77, 5139–
5143; (h) Carreiro, E. P.; Ramalho, J. P. P.; Burke, A. J. Tetrahedron 2011, 67,
4640–4648; (i) Castillo, M. R.; Castillón, S.; Claver, C.; Fraile, J. M.; Gual, A.;
Martín, M.; Mayoral, J. A.; Sola, E. Tetrahedron 2011, 67, 5402–5408; (j) Hager,
M.; Wittmann, S.; Schätz, A.; Pein, F.; Kreitmeier, P.; Reiser, O. Tetrahedron:
Asymmetry 2010, 21, 1194–1198; (k) Dentel, H.; Chataigner, I.; Le Cavelier, F.;
Gulea, M. Tetrahedron Lett. 2010, 51, 6014–6017.
13. (a) Aspinall, H. C.; Beckingham, O.; Farrar, M. D.; Greeves, N.; Thomas, C. D.
Tetrahedron Lett. 2011, 52, 5120–5123; (b) Bazgir, A.; Amini, M. M.; Fazaeli, Y.
Open Cat. J. 2009, 2, 163–165; (c) Mei, L.; Hai, Z. J.; Jie, S.; Ming, Z. S.; Hao, Y.;
Liang, H. K. J. Comb. Chem. 2009, 11, 220–227.
14. (a) Jiang, H.; Lu, W.; Cai, Y.; Wan, W.; Wu, S.; Zhu, S.; Hao, J. Tetrahedron 2013,
ˇ
ˇ
69, 2150–2156; (b) Kronek, J.; Nedelcev, T.; Mikulec, M.; Kleinová, A.; Luston, J.
Chem. Pap. 2013, 67, 1424–1432; (c) Miller, J. J.; Rajaram, S.; Pfaffenroth, C.;
Sigman, M. S. Tetrahedron 2009, 65, 3110–3119; (d) Kangani, C. O.; Day, B. W.
Tetrahedron Lett. 2009, 50, 5332–5335; (e) Sharma, R.; Vadivel, S. K.; Duclos, R.
I., Jr.; Makriyannis, A. Tetrahedron Lett. 2009, 50, 5780–5782.
15. (a) Kim, H. Y.; Oh, K. Org. Lett. 2011, 13, 1306–1309; (b) Murai, K.; Takahara, Y.;
Matsushita, T.; Komatsu, H.; Fujioka, H. Org. Lett. 2010, 12, 3456–3459; (c)
Takahashi, S.; Togo, H. Synthesis 2009, 2329–2332.
11. (a) Suresh, R.; Muthusubramanian, S.; Boominathan, M.; Manickam, G.
Tetrahedron Lett. 2013, 54, 2315–2320; (b) Moon, N. G.; Harned, A. M.
Tetrahedron Lett. 2013, 54, 2960–2963; (c) Pouliot, M.-F.; Angers, L.; Hamel,
J.-D.; Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121–4123; (d) Mamaghani, M.;
Mahmoodi, N. O.; Ghasemi, S. F. J. Iran. Chem. Soc. 2010, 7, 972–977; (e) Ilkgul,
B.; Gunes, D.; Sirkecioglu, O.; Bicak, N. Tetrahedron Lett. 2010, 51, 5313–5315;
(f) Sakakura, A.; Kondo, R.; Umemura, S.; Ishihara, K. Tetrahedron 2009, 65,
2102–2109.
16. Ordoñez, M.; Hernández-Fernández, E.; Montiel-Pérez, M.; Bautista, R.; Bustos,
P.; Rojas-Cabrera, H.; Fernández-Zertuche, M.; García Barradas, O. Tetrahedron:
Asymmetry 2007, 18, 2427–2436.
17. Hernández-Fernández, E.; Fernández-Zertuche, M.; García Barradas, O.;
Muñoz-Muñiz, O.; Ordóñez, M. Synlett 2006, 440–444.
18. Parab, Y. S.; Shah, R. V.; Shukla, S. R. Curr. Chem. Lett. 2012, 1, 81–90.
19. Guezane-Lakoud, S.; Berredjem, M.; Aouf, N.-E. Phosphorus, Sulfur Silicon 2012,
187, 762–768.
12. De Moliner, F.; Crosignani, S.; Banfi, L.; Riva, R.; Basso, A. J. Comb. Chem. 2010,
12, 613–616.