Diastereo- and enantioselective preparation of oxazolines via the base-catalysed aldol reaction of isocyanoacetates with aldehydes using cinchona alkaloids

Article abstract of DOI:10.3184/174751916X14683198156665

A diastereo- and enantioselective base-catalysed aldol reaction of t-butyl isocyanoacetate with aldehydes under phase-transfer catalytic conditions yielded 19 4,5-disubstituted oxazolines, 16 of which are novel. Key to success was the use of a free 9-OH-c

Full text of DOI:10.3184/174751916X14683198156665

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 SEPTEMBER, 521–525
RESEARCH PAPER 521
Diastereo- and enantioselective preparation of oxazolines via the base-
catalysed aldol reaction of isocyanoacetates with aldehydes using
cinchona alkaloids
Rui-Chuan Diao, Wen-Tao Zhao and Shen Li*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300354, P.R. China
A diastereo- and enantioselective base-catalysed aldol reaction of t-butyl isocyanoacetate with aldehydes under phase-transfer catalytic
conditions yielded 19 4,5-disubstituted oxazolines, 16 of which are novel. Key to success was the use of a free 9-OH-containing cinchona
alkaloid-based quaternary ammonium salt bearing bulky and electron-withdrawing aryl groups on the N-benzyl moiety. This process
tolerates both aromatic and aliphatic aldehydes, affording the corresponding chiral oxazoline products in diastereoselectivities up to 20:1
and enantioselectivities up to 78% ee.
Keywords: aldol reaction, phase-transfer catalysis, isocyanoacetate, cinchona alkaloids, oxazoline
Optically active oxazolines are among the most commonly
Table 1 Catalyst screening and reaction optimisation in the phase-
transfer catalysed aldol reaction of t-butyl isocyanoacetate with
1
used chiral ligands for metal-catalysed reactions, and are also
a
benzaldehyde (1a)
2
,3
core components present in many bioactive natural products.
O
O
N
5
mol% catalyst
conditions
Moreover, they are precursors to β-hydroxy-α-amino acids,
+
CN
COOt-Bu
Ph
which are useful building blocks for peptides and other
Ph
H
COOt-Bu
2a
4
biological compounds. Consequently, great efforts have been
1a
Chiral phase-transfer catalysts:
R2
devoted to the development of efficient methods for the synthesis
of chiral oxazolines. The aldol reaction of isocyanoacetates
with carbonyl compounds represents one of the most efficient
Ar Ar
OH
OR1
5
routes to construct the oxazoline rings. Since Ito and cowriters
N
O
N
reported the first example of an asymmetric aldol reaction of
isocyanoacetates with aldehydes catalysed by a chiral gold
Br
N
Ar
Br
OH
6
3a Ar = 9-Anthracenyl
complex, a number of transition-metal complexes, including
1
2
7
–11
12–16
17–19
18–21
R = H, R = H
b Ar = 3,5-(CF )
2
C H
3 6 3
R = H, R = H
Ar Ar
3 2
6 3
4 Ar = 3,5-(CF ) C H
those of gold,
silver,
platinum,
palladium,
and
3
2
2
cobalt, have been demonstrated to be effective for this
reaction. In sharp contrast, organocatalysts have been largely
neglected in the asymmetric aldol reaction of isocyanoacetates
with carbonyl compounds despite the explosive growth of
1
2
1
2
3
3
3
3
3
c Ar = C F , R = H, R = H
6
5
1
2
d Ar = 3,5-[3,5-(CF3)
e Ar = 3,5-[3,5-(CF
Ar = 3,5-[3,5-(CF3)
g Ar = 3,5-[3,5-(CF3)
2
2
2
2
6
C H ]
2
2
2
2
C H , R = H, R = H
3
6 3
1
2
3
)
6
C H ]
3
C H , R = allyl, R = H
6 3
2
3–25
organocatalysis in the last decade.
1
2
f
6
C H ]
C H , R = H, R = OCH
3
3
6
3
In recent years, asymmetric phase-transfer catalysis has
emerged as an area of intense interest in asymmetric synthesis
owing to its operational simplicity and transition metal-free
1
2
6
C H ]
3
6 3
C H , R = H, R = OH
Temp./ Time/
b
Yield/ ee/
c d
Entry Catalyst Base
Solvent
d.r.
2
6,27
°
C
h
%
%
reaction conditions.
Considering the acidic CH fragment in
isocyanoacetates, we envisioned that an isocyanoacetate would
be deprotonated to form a chiral ion pair in the presence of a
chiral quaternary ammonium salt under basic conditions, which
was capable of reacting with appropriate carbonyl compounds
to generate chiral oxazolines. Here we report our preliminary
results on this subject.
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3d
3d
3d
3d
3d
3d
3d
3d
4
Cs CO3 Toluene
–30
–30
−30
–30
–30
–30
–30
24
24
24
24
24
24
24
24
24
24
30
24
7:1 60
8:1 67
7:1 45
8:1 57
8:1 64
8:1 61
7:1 68
8:1 59
8:1 61
8:1 97
8:1 75
7:1 63
11
13
2
2
Cs CO3 Toluene
2
Cs CO3 Toluene
2
Cs CO3 Toluene
49
14
46
19
46
15
13
64
25
72
-–
2
Cs CO3 Toluene
2
Cs CO3 Toluene
2
Cs CO3 Toluene
2
Results and discussion
Cs CO3 Mesitylene –30
2
A preliminary experiment showed that it was possible to carry
out the reaction of benzaldehyde 1a and t-butyl isocyanoacetate
in toluene at –30 °C with Cs CO as the base and cinchonine-
Cs CO3 CH Cl2
–30
–30
–30
–30
–30
–30
–40
–30
2
2
1
0
Cs CO3 Et2O
2
2
3
11
K2CO3 Toluene
derived chiral quaternary ammonium salt 3a as the catalyst
Table 1, entry 1). The desired oxazoline product 2a was obtained
in a modest yield of 60% with a high diastereoselectivity of
:1, but the enantioselectivity for the major diastereomer was
1
2
KOH
K3PO4
Toluene
Toluene
(
1
3
40 10:1 70
e
1
4
K2HPO4 Toluene
24
96 10:1 67
40 8:1 64
–
nr
7
1
5
K3PO4
K3PO4
Toluene
Toluene
70
26
disappointing (only 11% ee). We then optimised that result by
varying the base, the solvent and the catalyst and the results
are shown in Table 1. We conducted the catalyst screening
experiments with several cinchoninium bromides 3b–d under
the same conditions (entries 2–4). Gratifyingly, the ee value
was improved to 49% by employing catalyst 3d bearing bulky
and electron-withdrawing aryl groups on the N-benzyl moiety
16
a
Unless otherwise noted in Table 1, all reactions were carried out with benzaldehyde
a (0.10 mmol), t-butyl isocyanoacetate (0.12 mmol), base (0.30 mmol) and catalyst
1
(
0.005 mmol) in 1.0 mL of solvent.
b
1
Determined by H NMR analysis of the crude reaction mixture.
Isolated yield of major diastereomer.
c
d
ee of the major diastereomer. Determined by HPLC analysis using a chiral stationary
phase. The absolute configuration was assigned by comparison of the optical rotation
with literature reported data.
e
*
Correspondent. E-mail: shenli@tju.edu.cn
No reaction.

522 JOURNAL OF CHEMICAL RESEARCH 2016
(
entry 4). It is worth mentioning that the presence of a free 9-OH
Table 2 Scope of the phase-transfer catalysed aldol reaction of t-butyl
a
isocyanoacetate with various aldehydes
group in the catalysts proved to be a crucial factor in achieving
high levels of asymmetric induction, since the O-allylated
catalyst 3e gave a significantly reduced enantioselectivity
O
O
5
mol% 3d
N
+
CN
COOt-Bu
R
H
R
3
equiv. K3PO4
(entry 5). A comparable result to that with 3d was achieved by
COOt-Bu
o
toluene, –30 C
using the corresponding quinidine-derived catalyst 3f, which
indicates that the 6′-OMe group has a negligible effect on the
catalyst performance (entry 6). In sharp contrast, a free 6′-OH-
containing bifunctional catalyst 3g was found to be unsuitable
for this transformation (entry 7). Toluene proved to be the best
among the commonly used solvents for phase-transfer catalysis
1
2
b
c
d
Entry
R
C6H
Product
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Time/h
40
40
36
26
36
40
40
40
40
40
28
28
36
36
28
28
40
36
30
d.r.
Yield/% ee/%
1
2
3
4
5
6
7
8
9
10:1
7:1
8:1
8:1
8:1
6:1
8:1
8:1
8:1
8:1
5:1
7:1
17:1
20:1
6:1
20:1
13:1
10:1
12:1
72
74
76
72
72
72
65
65
65
64
80
79
66
72
73
86
69
74
80
72
50
65
75
78
40
53
71
70
66
54
44
69
77
50
60
44
52
52
5
2-OMeC6H
4
3-OMeC6H4
4-OMeC6H4
4-OBnC6H4
2-BrC6H4
3-ClC6H4
4-FC6H4
4-BrC6H4
4-CF C H
6 4
1-naphthyl
2-naphthyl
2-furyl
2-thienyl
(E)-styryl
phenethyl
n-heptyl
(entries 8−10 versus 4). Comparing a series of inorganic bases,
anhydrous K PO was the most promising one with respect to
3
4
yield, diastereoselectivity and enantioselectivity (entry 13).
Lowering the temperature to –40 °C had no beneficial effect on
enantiocontrol but did significantly decrease the reaction rate
(entry 15). Therefore, the reaction conditions as shown in Table
1
, entry 13 were selected as the optimal conditions. An attempt
1
0
3
to further improve the reaction outcome by the employment of
Maruoka’s bifunctional N-spiro quaternary ammonium salt 4
was unsuccessful (entry 16).
1
1
1
2
2
8
1
3
Having established the reaction conditions, the generality
of this aldol reaction was explored with structurally diverse
aldehydes 1a–s. As summarised in Table 2, this reaction has
proven to be general for both aromatic and aliphatic aldehydes,
affording a broad range of chiral oxazolines 2a–s in good yields
with high diastereoselectivities ranging from 6:1 to 20:1. The
enantioselectivity was strongly dependent on the structure of
the aldehydes. Generally speaking, aromatic aldehydes with
para-substituents on the phenyl ring offered higher ee values
than their ortho- or meta-substituted counterparts (entries 2, 3
versus 4 and 6 versus 9). In addition, aromatic aldehydes with
electron-donating groups exhibited better enantioselectivity
than those with electron-withdrawing substituents (entries 4, 5
versus 8–10). Accordingly, the highest enantioselectivity of 78%
ee was achieved when aldehyde 1e with a para-benzyloxy group
was employed (entry 5). The heteroaromatic aldehydes 1m
and 1n were also well-tolerated, delivering the corresponding
oxazolines 2m and 2n in 69% and 77% ee, respectively (entries
1
4
1
5
1
6
1
7
1
8
isopropyl
cyclohexyl
19
2s
a
Reaction conditions: 1 (0.10 mmol), t-butyl isocyanoacetate (0.12 mmol), anhydrous
K PO (0.30 mmol), 3d (0.005 mmol) in toluene (1.0 mL) at –30 °C for the stated time.
3
4
b
c
d
1
Determined by H NMR analysis of the crude reaction mixture.
Isolated yield of major diastereomer.
ee of the major diastereomer. Determined by HPLC analysis using a chiral stationary
phase.
with an ESI resource. Optical rotations were determined using an
Autopol IV automatic polarimeter. HPLC analyses were carried out
on a Hewlett Packard Model HP 1200 instrument. Melting points
were measured on a WRS-1A digital melting point apparatus and are
uncorrected.
1
3 and 14). Aliphatic aldehydes as exemplified by 2o–s were
Diethyl ether and toluene were distilled from sodium/benzophenone
prior to use; CH Cl was distilled from CaH . All purchased reagents
equally reactive with t-butyl isocyanoacetate under the same
reaction conditions, leading to moderate enantioselectivities
ranging from 44% to 60% ee (entries 15–19).
2
2
2
were used without further purification. Cinchona alkaloid-based
phase-transfer catalysts were synthesised according and in analogy to
2
9–31
literature-known methods.
Conclusion
Phase-transfer catalysed aldol reaction of t-butyl isocyanoacetate
with aldehydes; general procedure
In summary, we have developed a diastereo- and enantioselective
aldol reaction of t-butyl isocyanoacetate with aldehydes under
phase-transfer catalytic conditions. Key to success was the use
of a free 9-OH-containing cinchona alkaloid-based quaternary
ammonium salt bearing bulky and electron-withdrawing aryl
groups on the N-benzyl moiety. This process tolerates both
aromatic and aliphatic aldehydes, affording a broad range
of chiral oxazolines in diastereoselectivities up to 20:1 and
enantioselectivities up to 78% ee. Further investigations to
expand the scope of this transformation are ongoing in our
laboratory.
t-Butyl isocyanoacetate (16.9 mg, 0.12 mmol), catalyst (0.005 mmol),
K PO (63.6 mg, 0.30 mmol) and toluene (1 mL) were added to a 10
3
4
mL Schlenk flask equipped with a stirring bar. The mixture was cooled
to –30 °C before aldehyde 1 (0.10 mmol) was added in one portion.
The vigorous stirring was maintained until the reaction was complete
(monitored by TLC). Filtration of the resulting mixture through a
Celite pad then concentration under vacuum gave the crude product,
1
which was analysed by H NMR to determine the diastereomer ratio.
The major diastereomer was obtained after column chromatography on
silica gel using EtOAc/petroleum ether (1:4) as eluent.
14
Experimental
t-Butyl (4R,5S)-5-phenyl-4,5-dihydrooxazole-4-carboxylate (2a)
NMR spectra were recorded on a Bruker Avance III spectrometer
10:1 dr of crude product, the trans isomer was obtained as a
colourless oil after column chromatography, 72% yield (17.8 mg); the
enantioselectivity was determined by HPLC using a Chiralpak AD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 95:5, λ 220 nm,
1
13
operating at 400 MHz ( H NMR) or 101 MHz ( C NMR) in CDCl .
3
Chemical shifts were reported in ppm downfield from internal Me Si
4
(
0 ppm). Multiplicity was indicated as follows: s (singlet), d (doublet),
–1
t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets).
Coupling constants (J) were reported in Hertz (Hz). High resolution
mass spectra (HRMS) were recorded on a VG ZAB-HS spectrometer
1.0 mL min flow rate] t = 9.89 min (major) and 11.82 min (minor)
R
2
5
25
as 72% ee; [α]D = −46.5 (c 1.0, CH Cl ), [ref: [α] = +99.6 (c 0.64,
CH Cl ) for (4S,5R)-configuration, 96% ee]; H NMR (400 MHz,
2
2
D
1
2
2

JOURNAL OF CHEMICAL RESEARCH 2016 523
CDCl ): δ 7.33–7.24 (m, 5H, ArH), 7.02 (d, J = 4.0 Hz, 1H, N=CH),
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
3
–1
5
.54 (d, J = 7.8 Hz, 1H, CH), 4.44 (dd, J = 7.8, 2.1 Hz, 1H, CH), 1.45 (s,
1.0 mL min flow rate] t = 6.32 min (minor) and 10.55 min (major) as
R
2
5
1
9
H, CH ).
40% ee; [α]D = –30 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ): δ
2 2 3
.58 (d, J = 7.9 Hz, 1H, ArH), 7.34 (t, J = 7.2 Hz, 1H, ArH), 7.30–7.27 (m,
3
7
t-Butyl (4R,5S)-5-(2-methoxyphenyl)-4,5-dihydrooxazole-4-carboxy-
late (2b)
1
6
9
H, ArH), 7.20 (t, J = 6.7 Hz, 1H, ArH), 7.14 (d, J = 1.8 Hz, 1H, N=CH),
.01 (d, J = 6.5 Hz, 1H, CH), 4.40 (dd, J = 6.5, 2.0 Hz, 1H, CH), 1.53 (s,
7:1 dr of crude product, the trans isomer was obtained as a
13
H, CH ); C NMR (101 MHz, CDCl ): δ 169.26, 156.01, 138.54, 133.09,
3
3
colourless oil after column chromatography, 74% yield (20.5 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10,
129.86, 127.87, 126.65, 121.03, 82.46, 81.38, 76.15, 27.91; HRMS (ESI)
+
for C H BrNO calcd 326.0386; found: 326.0387.
14
17
3
–1
t-Butyl (4R,5S)-5-(3-chlorophenyl)-4,5-dihydrooxazole-4-carboxylate
(2g)
λ 220 nm, 1.0 mL min flow rate] t = 7.87 min (minor) and 11.37 min
R
2
5
1
(
major) as 50% ee; [α]D = −47.3 (c 1.0, CH Cl ); H NMR (400 MHz,
2 2
CDCl ): δ 7.34–7.25 (m, 2H, ArH), 7.06 (d, J = 1.9 Hz, 1H, N=CH),
8:1 dr of crude product, the trans isomer was obtained as a colourless
oil after column chromatography, 65% yield (18.3 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220
3
6
.97 (t, J = 7.5 Hz, 1H, ArH), 6.91 (d, J = 8.2 Hz, 1H, ArH), 5.88 (d,
J = 7.6 Hz, 1H, CH), 4.40 (dd, J = 7.6, 2.0 Hz, 1H, CH), 3.82 (s, 3H,
13
OCH ), 1.54 (s, 9H, CH ); C NMR (101 MHz, CDCl ): δ 170.02,
3
3
3
–1
1
56.17, 155.87, 129.47, 127.44, 126.07, 120.64, 110.55, 81.80, 79.17,
nm, 1.0 mL min flow rate] t = 6.59 min (minor) and 8.61 min (major)
R
+
25
1
75.63, 55.26, 27.99; HRMS (ESI) for C H NO calcd 278.1387;
as 53% ee; [α]D = –36.8 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ):
2 2 3
15
20
4
found: 278.1399.
δ 7.30–7.36 (m, 3H, ArH), 7.24–7.18 (m, 1H, ArH), 7.09 (d, J = 2.0 Hz,
H, N=CH), 5.59 (d, J = 7.8 Hz, 1H, CH), 4.49 (dd, J = 7.8, 2.1 Hz, 1H,
1
t-Butyl (4R,5S)-5-(3-methoxyphenyl)-4,5-dihydrooxazole-4-carboxy-
late (2c)
1
3
CH), 1.54 (s, 9H, CH ); C NMR (101 MHz, CDCl ): δ 169.17, 155.85,
3
3
141.30, 134.90, 130.25, 128.78, 125.69, 123.57, 82.84, 81.39, 76.25,
8
:1 dr of crude product, the trans isomer was obtained as a
+
2
8.00; HRMS ESI for C H ClNO calcd 282.0891; found: 282.0894.
14 17 3
colourless oil after column chromatography, 76% yield (21.1 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10,
t-Butyl (4R,5S)-5-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxy-
14
late (2h)
–1
λ 220 nm, 1.0 mL min flow rate] t = 8.77 min (minor) and 10.34
8:1 dr of crude product, the trans isomer was obtained as a
colourless oil after column chromatography, 65% yield (17.3 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10,
R
2
5
1
min (major) as 65% ee; [α]D = −53.4 (c 1.0, CH Cl ); H NMR (400
2
2
MHz, CDCl ): δ 7.32 (t, J = 7.9 Hz, 1H, ArH), 7.09 (d, J = 2.0 Hz,
3
1
H, N=CH), 6.89 (m, 3H, ArH), 5.60 (d, J = 7.8 Hz, 1H, CH), 4.52
–1
(
dd, J = 7.8, 2.1 Hz, 1H, CH), 3.83 (s, 3H, OCH ), 1.54 (s, 9H, CH );
λ 230 nm, 1.0 mL min flow rate] t = 6.39 min (minor) and 7.82 min
R
25 25
3
3
13
C NMR (101 MHz, CDCl ): δ 169.49, 160.03, 155.98, 140.85, 130.05,
(major) as 71% ee; [α]D = –88.1 (c 1.0, CH Cl ), [ref: [α] = +248.4
2 2 D
1
3
1
17.69, 114.10, 111.05, 82.55, 82.14, 76.23, 55.29, 28.01; HRMS (ESI)
(c 1.5, CH Cl ) for (4S,5R)-configuration, 92% ee]; H NMR (400
2 2
+
for C H NO calcd 278.1387; found: 278.1391.
MHz, CDCl ): δ 7.31 (m, 5.2 Hz, 2H, ArH), 7.15–7.06 (m, 3H, ArH and
15
20
4
3
N=CH), 5.61 (d, J = 7.8 Hz, 1H, CH), 4.50 (dd, J = 7.8, 2.0 Hz, 1H,
t-Butyl (4R,5S)-5-(4-methoxyphenyl)-4,5-dihydrooxazole-4-carboxy-
CH), 1.54 (s, 9H, CH ).
14
3
late (2d)
8
:1 dr of crude product, the trans isomer was obtained as a
t-Butyl (4R,5S)-5-(4-bromophenyl)-4,5-dihydrooxazole-4-carboxylate
(2i)
colourless oil after column chromatography, 72% yield (20.0 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10,
8:1 dr of crude product, the trans isomer was obtained as a colourless
oil after column chromatography, 65% yield (21.2 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
–1
λ 230 nm, 1.0 mL min flow rate] t = 8.64 min (minor) and 9.94 min
R
2
5
25
(
major) as 75% ee; [α]D = −78.6 (c 1.0, CH Cl ), [ref: [α] = +118.4
2 2 D
1
–1
(c 0.25, CH Cl ) for (4S,5R)-configuration, 89% ee]; H NMR (400
1.0 mL min flow rate] t = 6.77 min (minor) and 8.37 min (major) as
2
2
R
2
5
1
MHz, CDCl ): δ 7.25 (d, J = 8.7 Hz, 2H, ArH), 7.07 (d, J = 1.9 Hz, 1H,
N=CH), 6.93 (d, J = 8.7 Hz, 2H, ArH), 5.57 (d, J = 7.8 Hz, 1H, CH),
70% ee; [α]D = –68.3 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ): δ
3
2
2
3
7.53 (d, J = 8.4 Hz, 2H, ArH), 7.20 (d, J = 8.4 Hz, 2H, ArH), 7.08 (d,
J = 2.0 Hz, 1H, N=CH), 5.58 (d, J = 7.9 Hz, 1H, CH), 4.47 (dd, J = 7.9, 2.1
4.51 (dd, J = 7.8, 2.0 Hz, 1H, CH), 3.83 (s, 3H, O–CH ), 1.53 (s, 9H,
3
13
CH ).
Hz, 1H, CH), 1.53 (s, 9H, CH ); C NMR (101 MHz, CDCl ): δ 169.23,
3
3
3
1
55.88, 138.30, 132.08, 127.23, 122.68, 82.78, 81.60, 76.24, 28.00;
t-Butyl (4R,5S)-5-(4-(benzyloxy)phenyl)-4,5-dihydrooxazole-4-carboxy-
late (2e)
+
HRMS (ESI) for C H BrNO calcd 326.0386; found: 326.0383.
1
4
17
3
8
:1 dr of crude product, the trans isomer was obtained as a white solid
t-Butyl (4R,5S)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole-
4-carboxylate (2j)
after column chromatography, 72% yield (25.4 mg); m.p.: 65−66 °C;
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ
8:1 dr of crude product, the trans isomer was obtained as a
colourless oil after column chromatography, 64% yield (20.2 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10,
–1
220 nm, 1.0 mL min flow rate] t = 15.94 min (minor) and 21.58 min
R
2
5
1
(
major) as 78% ee; [α]D = −172 (c 1.0, CH Cl ): H NMR (400 MHz,
2 2
–1
CDCl ); δ 7.41 (m, 5H, ArH), 7.26 (d, J = 8.6 Hz, 2H, ArH), 7.08 (d,
J = 1.8 Hz, 1H, N=CH), 7.01 (d, J = 8.7 Hz, 2H, ArH), 5.58 (d, J = 7.8
λ 220 nm, 1.0 mL min flow rate] t = 7.25 min (minor) and 9.01
R
25 1
3
min (major) as 66% ee; [α]D = –38.4 (c 1.0, CH Cl ); H NMR (400
2 2
Hz, 1H, CH), 5.10 (s, 2H, CH ), 4.53 (dd, J = 7.8, 2.0 Hz, 1H, CH), 1.53
MHz, CDCl ): δ 7.66 (d, J = 8.2 Hz, 2H, ArH), 7.45 (d, J = 8.2 Hz, 2H,
2
3
13
(
1
s, 9H, CH ); C NMR (101 MHz, CDCl ): δ 169.60, 159.15, 156.03,
ArH), 7.11 (d, J = 2.1 Hz, 1H, N=CH), 5.67 (d, J = 7.9 Hz, 1H, CH),
3
3
13
36.72, 131.49, 128.63, 128.07, 127.43, 127.28, 115.25, 82.46, 82.29,
4.48 (dd, J = 7.9, 2.1 Hz, 1H, CH), 1.54 (s, 9H, CH ); C NMR (101
3
+
76.05, 70.10, 28.01; HRMS (ESI) for C H NO calcd 354.1700;
MHz, CDCl ): δ 169.12, 155.89, 143.24, 130.85 (q, J = 32.4), 125.95
21
24
4
3
found: 354.1710.
(q, J = 3.8 Hz), 125.79, 123.88 (q, J =270.5), 83.00, 81.37, 76.33, 28.01;
+
HRMS (ESI) C H F NO calcd 316.1161; found: 316.1167.
15
17
3
3
t-Butyl (4R,5S)-5-(2-bromophenyl)-4,5-dihydrooxazole-4-carboxylate
2f)
:1 dr of crude product, the trans isomer was obtained as a colourless
(
t-Butyl (4R,5S)-5-(naphthalen-1-yl)-4,5-dihydrooxazole-4-carboxy-
late (2k)
6
oil after column chromatography, 72% yield (23.5 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
5:1 dr of crude product, the trans isomer was obtained as a white solid
after column chromatography, 80% yield (23.8 mg); m.p.: 87–89 °C;

524 JOURNAL OF CHEMICAL RESEARCH 2016
+
the enantioselectivity was determined by HPLC using a Chiralpak
126.78, 125.49, 82.48, 82.00, 73.89, 28.00; HRMS (ESI) for C H NO
16 20 3
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ
calcd 274.1438; found: 274.1444.
t-Butyl (4R,5S)-5-phenethyl-4,5-dihydrooxazole-4-carboxylate (2p)
0:1 dr of crude product, the trans isomer was obtained as a
colourless oil after column chromatography, 86% yield (23.7 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
–1
2
20 nm, 1.0 mL min flow rate] t = 11.78 min (minor) and 17.53 min
R
2
5
1
(major) as 54% ee; [α]D = –28.3 (c 1.0, CH Cl ); H NMR (400 MHz,
2 2
2
CDCl ): δ 7.98–7.90 (m, 2H, ArH), 7.85–7.88 (m, 1H, ArH), 7.60–7.52
3
(m, 2H, ArH), 7.52–7.44 (m, 2H, ArH), 7.24 (d, J = 1.9 Hz, 1H, N=CH),
6
.45 (d, J = 7.2 Hz, 1H, CH), 4.59 (dd, J = 7.2, 2.0 Hz, 1H, CH), 1.58
13
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
(s, 9H, CH ); C NMR (101 MHz, CDCl ): δ 169.79, 156.22, 134.43,
3
3
–1
1
6
7
1
.0 mL min flow rate] t = 10.43 min (major) and 12.23 min (minor) as
1
8
2
33.94, 129.83, 129.13, 126.64, 126.05, 125.37, 123.01, 122.76, 82.70,
R
2
5
1
0% ee; [α]D = –15.9 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ): δ
+
2
2
3
0.29, 75.79, 27.98; HRMS (ESI) for C H NO calcd 298.1443; found:
18
20
3
.34–7.29 (m, 2H, ArH), 7.22 (t, J = 6.8 Hz, 3H, ArH), 6.94 (d, J = 1.5 Hz,
H, N=CH), 4.61 (q, J = 7.2, 1H, CH), 4.25 (dd, J = 7.4, 1.9 Hz, 1H,
CH), 2.82–2.72 (m, 2H, CH ), 2.05–1.99 (m, 2H, CH ), 1.49 (s, 9H,
98.1458.
t-Butyl (4R,5S)-5-(naphthalen-2-yl)-4,5-dihydrooxazole-4-carboxy-
late (2l)
2
2
13
CH ); C NMR (101 MHz, CDCl ): δ 169.76, 156.34, 140.54, 128.55,
128.38, 126.23, 82.22, 80.92, 73.07, 36.82, 31.21, 27.95; HRMS (ESI) for
C H NO calcd 276.1594; found: 276.1604.
3
3
7:1 dr of crude product, the trans isomer was obtained as a white solid
+
after column chromatography, 79% yield (23.5 mg); m.p.: 82–83 °C;
the enantioselectivity was determined by HPLC using a Chiralpak
AD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 95:5, λ
16 22
3
t-Butyl (4R,5S)-5-heptyl-4,5-dihydrooxazole-4-carboxylate (2q)
3:1 dr of crude product, the trans isomer was obtained as a
1
–
1
2
(
20 nm, 1.0 mL min flow rate] t = 13.16 min (major) and 16.00 min
R
colourless oil after column chromatography, 69% yield (18.6 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
2
5
1
minor) as 44% ee; [α]D = –34.1 (c 1.0, CH Cl ); H NMR (400 MHz,
2 2
CDCl ): δ 7.91 (d, J = 8.6 Hz, 1H, ArH), 7.88–7.84 (m, 2H, ArH), 7.82 (s,
3
1H, ArH), 7.57–7.50 (m, 2H, ArH), 7.41 (dd, J = 8.5, 1.6 Hz, 1H, ArH),
–
1
1
4
.0 mL min flow rate] t = 4.66 min (minor) and 5.58 min (major) as
R
7
.17 (d, J = 2.0 Hz, 1H, N=CH), 5.81 (d, J = 7.8 Hz, 1H, CH), 4.62 (dd,
2
5
1
4% ee; [α]D = –28.9 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ):
2 2 3
13
J = 7.8, 2.1 Hz, 1H, CH), 1.56 (s, 9H, CH ); C NMR (101 MHz, CDCl ):
3
3
δ 6.90 (d, J = 1.6 Hz, 1H, N=CH), 4.58 (q, J = 7.2 Hz, 1H, CH), 4.18
dd, J = 7.4, 1.9 Hz, 1H, CH), 1.74–1.60 (m, 2H, CH ), 1.50 (s, 9H, CH ),
δ 169.54, 156.13, 136.42, 133.33, 133.09, 129.12, 128.07, 127.79, 126.66,
26.56, 125.05, 122.86, 82.62, 82.55, 76.23, 28.04; HRMS (ESI) for
(
1
2
3
1
13
.42–1.25 (m, 10H, CH ), 0.89 (t, J = 6.8 Hz, 3H, CH ); C NMR (101
+
2
3
C H NO calcd 298.1443; found: 298.1435.
18
20
3
MHz, CDCl ): δ 170.04, 156.32, 82.0, 81.79, 73.07, 35.05, 31.70, 29.16,
3
+
t-Butyl (4R,5S)-5-(furan-2-yl)-4,5-dihydrooxazole-4-carboxylate (2m)
7:1 dr of crude product, the trans isomer was obtained as a
29.08, 27.96, 24.75, 22.59, 14.04; HRMS (ESI) for C15
70.2064; found: 270.2074.
H
28NO
3
calcd
2
1
colourless oil after column chromatography, 66% yield (15.6 mg); the
enantioselectivity was determined by HPLC using a Chiralpak AD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 95:5, λ 220 nm,
t-Butyl (4R,5S)-5-isopropyl-4,5-dihydrooxazole-4-carboxylate (2r)
0:1 dr of crude product, the trans isomer was obtained as a
colourless oil after column chromatography, 74% yield (15.8 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
1
–1
1
.0 mL min flow rate] t = 13.26 min (major) and 14.95 min (minor) as
R
2
5
1
69% ee; [α]D = –136.3 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ):
2
2
3
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
δ 7.46 (d, J = 1.1 Hz, 1H, ArH), 6.96 (d, J = 2.0 Hz, 1H, N=CH), 6.46
d, J = 3.2 Hz, 1H, ArH), 6.39 (dd, J = 3.3, 1.8 Hz, 1H, ArH), 5.66 (d,
J = 7.7 Hz, 1H, CH), 4.80 (dd, J = 7.7, 2.1 Hz, 1H, CH), 1.50 (s, 9H, CH );
–1
1
5
.0 mL min flow rate] t = 5.10 min (minor) and 5.81 min (major) as
R
(
25
1
2% ee; [α]D = –28.2 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ): δ
2
2
3
3
6.90 (d, J = 1.5 Hz, 1H, N=CH), 4.34 (t, J = 6.9 Hz, 1H, CH), 4.22 (dd,
1
3
C NMR (101 MHz, CDCl ): δ 169.03, 155.65, 150.12, 143.85, 110.65,
09.97, 82.69, 75.25, 72.25, 27.93; HRMS (ESI) for C H NNaO calcd
3
J = 7.4, 1.7 Hz, 1H, CH), 1.88–1.76 (m, 1H, CH), 1.47 (s, 9H, CH ), 0.94
3
+
1
13
12
15
4
(dd, J = 12.6, 6.8 Hz, 6H, CH ); C NMR (101 MHz, CDCl ): δ 170.27,
56.42, 86.53, 81.96, 70.65, 32.06, 27.90, 17.31, 17.16; HRMS (ESI) for
3
3
260.0893; found: 260.0902.
1
+
C H NO calcd 214.1438; found: 214.1448.
t-Butyl (4R,5S)-5-(thiophen-2-yl)-4,5-dihydrooxazole-4-carboxylate
11 20
3
(
2n)
t-Butyl (4R,5S)-5-cyclohexyl-4,5-dihydrooxazole-4-carboxylate (2s)
2:1 dr of crude product, the trans isomer was obtained as a colourless oil
2
0:1 dr of crude product, the trans isomer was obtained as a
1
colourless oil after column chromatography, 72% yield (18.2 mg);
the enantioselectivity was determined by HPLC using a Chiralpak
OD-H column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 95:5, λ
after column chromatography, 80% yield (11.2 mg); the enantioselectivity
was determined by HPLC using a Chiralpak OD-H column (25 cm ×
–1
0
.46 cm ID), [hexane/iso-propanol = 95:5, λ 220 nm, 1.0 mL min flow
–1
2
20 nm, 0.8 mL min flow rate] t = 12.90 min (minor) and 14.23 min
25
R
rate] t = 6.91 min (minor) and 8.02 min (major) as 52% ee; [α] = –18.2
(c 1.0, CH Cl ); H NMR (400 MHz, CDCl ) δ 6.89 (d, J = 1.7 Hz, 1H,
R
D
2
5
1
(major) as 77% ee; [α]D = –110.1 (c 1.0, CH Cl ); H NMR (400 MHz,
1
2
2
2
2
3
CDCl ): δ 7.33 (dd, J = 5.0, 0.9 Hz, 1H, ArH), 7.09 (d, J = 3.4 Hz, 1H,
3
N=CH), 4.35 (t, J = 7.1 Hz, 1H, CH), 4.26 (dd, J = 7.5, 1.9 Hz, 1H, CH),
.82–1.73 (m, 3H, CH and CH ), 1.71–1.63 (m, 2H, CH ), 1.47 (s, 9H, CH ),
N=CH), 7.02–6.97 (m, 2H, ArH), 5.85 (d, J = 7.6 Hz, 1H, CH), 4.64
1
2
2
3
13
(
dd, J = 7.6, 2.1 Hz, 1H, CH), 1.50 (s, 9H, CH ); C NMR (101 MHz,
13
3
1.28–0.96 (m, 6H, CH ); C NMR (101 MHz, CDCl ) δ 170.31, 156.37,
85.77, 81.95, 70.77, 41.77, 27.92, 27.90, 27.70, 26.19, 25.61, 25.46; HRMS
(ESI) for C H NO calcd 254.1751; found: 254.1760.
2
3
CDCl ): δ 168.96, 155.55, 141.52, 127.13, 126.44, 125.90, 82.72, 78.31,
3
+
7
6.05, 27.96; HRMS (ESI) for C H NNaO S calcd 276.0665; found:
+
12
15
3
14
24
3
276.0673.
This work was supported by the National Natural Science
Foundation of China (no. 21302137), the Specialized Research
Fund for the Doctoral Program of Higher Education of China (no.
t-Butyl (4R,5S)-5-((E)-styryl)-4,5-dihydrooxazole-4-carboxylate (2o)
:1 dr of crude product, the trans isomer was obtained as a colourless
6
oil after column chromatography, 73% yield (20.0 mg); the
enantioselectivity was determined by HPLC using a Chiralpak OD-H
column (25 cm × 0.46 cm ID), [hexane/iso-propanol = 90:10, λ 220 nm,
20130032120071), the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry
and the Elite Scholar Program of Tianjin University.
–
1
1
5
.0 mL min flow rate] t = 10.63 min (major) and 13.39 min (minor) as
R
2
5
1
0% ee; [α]D = –30.6 (c 1.0, CH Cl ); H NMR (400 MHz, CDCl ): δ
2
2
3
Electronic Supplementary Information
7
(
.41 (d, J = 7.0 Hz, 2H, ArH), 7.36 (d, J = 7.0 Hz, 1H, ArH), 7.34–7.29
m, 2H, ArH), 7.00 (d, J = 1.9 Hz, 1H, N=CH), 6.72 (d, J = 15.8 Hz, 1H,
CH=CH), 6.19 (dd, J = 15.8, 7.4 Hz, 1H, CH=CH), 5.26 (t, J = 7.6 Hz,
1
13
The H NMR and C NMR spectra of new oxazoline products,
and HPLC charts of chiral oxazoline products are available
through:
13
1H, CH), 4.42 (dd, J = 7.8, 2.0 Hz, 1H, CH), 1.53 (s, 9H, CH ); C NMR
3
(
101 MHz, CDCl ): δ 169.40, 156.14, 135.59, 133.89, 128.70, 128.49,
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
3

JOURNAL OF CHEMICAL RESEARCH 2016 525
1
6
Y. Lu, M. Wang, X. Zhao, X. Liu, L. Lin and X. Feng, Synlett, 2015, 26,
Received 30 April 2016; accepted 18 June 2016
Paper 1604079 doi: 10.3184/174751916X14683198156665
Published online: 6 September 2016
1545.
17
F. Gorla, A. Togni, L.M. Venanzi, A. Albinati and F. Lianza,
Organometallics, 1994, 13, 1607.
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19
8
J.M. Longmire, X. Zhang and M. Shang, Organometallics, 1998, 17, 4374.
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Lutz, A.L. Spek, G. van Koten and R.J.M. Klein Gebbink, Tetrahedron:
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