Hydroxytetraphenylenes as Chiral Ligands: Application to Asymmetric Darzens Reaction of Diazoacetamide with Aldehydes

Article abstract of DOI:10.1055/s-0036-1588880

Hydroxytetraphenylenes with rigid conformations are potential candidates for employment as chiral ligands in asymmetric synthesis. Highly diastereo- and enantioselective Darzens reactions between aldehydes and diazo-N,N-dimethylacetamide were found to be catalyzed by a chiral titanium complex formed in situ from Ti(O ⁱ Pr)₄ and chiral 1,16-dihydroxytetraphenylene, leading to the formation of cis-glycidic amides in moderate to high yields with excellent enantiomeric purities (40-99% yield, up to 99% ee).

Full text of DOI:10.1055/s-0036-1588880

SYNTHESIS
0
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1
1
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1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
G.-L. Chai et al.
Paper
Synthesis
Hydroxytetraphenylenes as Chiral Ligands: Application to Asym-
metric Darzens Reaction of Diazoacetamide with Aldehydes
(R)-DHTP/Ti(OiPr)4
O
Guo-Li Chaia
Jian-Wei Hana
Henry N. C. Wong*a,b
O
O
H
H
Ph
(10 mol%)
N
N
∗
∗
+
R
Ph
R
H
H
3 Å MS
MeCN, 0 °C
N2
O
a Shanghai-Hong Kong Joint Laboratory in Chemical
Synthesis, Shanghai Institute of Organic Chemistry,
The Chinese Academy of Sciences, 345 Ling Ling
Road, Shanghai, 200032, P. R. of China
b Department of Chemistry, The Chinese University of
Hong Kong, Shatin, New Territories, Hong Kong SAR,
P. R. of China
19 examples
40–99% yield
> 99/1 dr
up to 99% ee
OH
OH
hncwong@cuhk.edu.hk
Dedicated to Professor Dr. Dieter Enders on the occa-
sion of his 70th birthday.
(R)-DHTP
Received: 10.08.2016
Accepted after revision: 22.08.2016
Published online: 15.09.2016
gands in asymmetric hydrogenation, the α-acylaminoacry-
lates derivatives were hydrogenated in quantitative yields
with excellent enantioselectivities of 94–99% ee.4 Further-
more, tetraphenylene-based organocatalysts were also
used in [4+2] cycloaddition between anthrone and maleim-
ides by the Wong group.5
DOI: 10.1055/s-0036-1588880; Art ID: ss-2016-h0562-op
Abstract Hydroxytetraphenylenes with rigid conformations are poten-
tial candidates for employment as chiral ligands in asymmetric synthe-
sis. Highly diastereo- and enantioselective Darzens reactions between
aldehydes and diazo-N,N-dimethylacetamide were found to be cata-
lyzed by a chiral titanium complex formed in situ from Ti(OiPr)4 and chi-
ral 1,16-dihydroxytetraphenylene, leading to the formation of cis-gly-
cidic amides in moderate to high yields with excellent enantiomeric
purities (40–99% yield, up to 99% ee).
The asymmetric Darzens reaction is a powerful synthet-
ic method to realize optically pure epoxides that have wide
utilization in organic synthesis. Several elegant methods
concerning the Darzens reaction are known to produce α,β-
epoxycarbonyl compounds.6–13 Earlier catalytic systems in-
cluded phase-transfer catalysts of chiral quaternary cincho-
nium salts,6 chiral crown ethers,7 and a bis-ammonium salt
derived from BINOL.8 Chiral sulfur ylides were also em-
ployed to promote the Darzens reaction with or without
metals.9 In 2008, the research groups of Wulff and Maruoka
reported axially chiral Brønsted acids in the asymmetric
aziridination of diazoacetamides and imines, respectively.10
North and co-workers utilized salen ligands in combination
with various metals as Lewis acid catalysts to provide epoxy
esters with moderate diastereoselectivities and enantio-
selectivities.11 In 2009, Gong reported that dihydroxyl li-
gands of BINOL, in combination with titanium or zirconium
metal, catalyzed the enantioselective Darzens reaction be-
tween diazoacetamides and aldehydes with excellent re-
sults.12 Later, Sun screened various diol–Ti complexes in the
asymmetric Darzens reaction, and noted that excellent en-
antioselectivity was achieved by the (+)-pinanediol li-
gand.13
Key words asymmetric catalysis, tetraphenylene, chiral ligand,
Darzens reaction, diazoacetamide
Over past decades, the area of asymmetric catalysis has
continued to evolve at an accelerating speed.1 Numerous
chiral catalytic systems and a wide range of enantioselec-
tive transformations were developed in these endeavors.
Despite significant advances, this field still lacks privileged
chiral skeletons that highly match substrates and ligands
like those host-guest interactions in enzymes. Furthermore,
the structural features of these ligands responsible for reac-
tivity and selectivity are not immediately clear. However,
some trends can still be discerned. For instance, the 1,1′-
binaphthyl skeleton is one of the most successful platforms
in asymmetric catalysis, which could be ascribed to its
structure with C2-symmetry. In this regard, tetraphenylene
was determined to be a non-planar molecule, featuring a
distinct saddle-shaped framework.2 The saddle-shaped ge-
ometry of tetraphenylene has been proved to be very rigid
and stable, which was confirmed by the high-energy barri-
er to inversion by neutron diffraction studies as well as
thermal experiments.3 With this geometric rigidity, studies
of tetraphenylene derivatives have led to their applications
in asymmetric catalysis. In 2005, Wong reported phosphor-
amidites based on the tetraphenylene skeleton as chiral li-
In order to study the potential applications of tetra-
phenylenes, we recently reported several strategies to pro-
duce enantiopure hydroxytetraphenylenes.2 In this connec-
tion, we describe herein the synthesis of 1,16-dihydroxy-
tetraphenylenes (DHTP) as chiral ligands (Scheme 1).14 The
use of an (R)-DHTP/titanium(IV) complex as a chiral cata-
lytic system in the asymmetric Darzens reaction between
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
G.-L. Chai et al.
Paper
Synthesis
diazoacetamides and aldehydes indeed led to the formation
of epoxides in good yields with excellent enantioselectivi-
ties.
the Darzens reaction of diazo-N,N-dimethylacetamide (6)
with benzaldehyde (5a) as a model reaction in dichloro-
methane at 0 °C by using 10 mol% of the titanium complex,
which formed in situ between L1–L5 and Ti(OiPr)4. Encour-
agingly, the reaction proceeded smoothly to generate cis-
glycidic amide 7a in 79% yield with 95% ee (Table 1, entry 1)
by using a complex of L1/Ti(IV) (2:1) as the chiral catalyst. It
is worth noting that this reaction exhibited excellent dias-
tereoselectivities and the trans-diastereomer was not de-
tectable by 1H NMR spectroscopic analysis of the crude
product. Additional studies on the stoichiometry of L1 and
Ti(OiPr)4 revealed that tuning the ratio of L1/Ti(OiPr)4 from
2:1 to 1:1 led to a slightly decreased enantioselectivities
(Table 1, entries 2–4). Furthermore, we found that molecu-
lar sieves as additives had a positive effect on the yields of
the desired products (Table 1, entries 5–7). Thus, the pres-
ence of 3-Å molecular sieves led to a higher yield and with-
out obviously decreasing the enantioselectivity (Table 1,
OH
OH
OH
OH
OH
OH
(R)-BINOL
(R)-DHTP
Scheme 1 Concept and design of chiral hydroxytetraphenylenes
As shown in Scheme 2, starting from the bis-pinacol es-
ter of biphenyl-2,2′-diboronic acid (1)15 and 2,2′-diiodo-
6,6′-dimethoxybiphenyl (2),16 the construction of 1,16-di-
methoxytetraphenylene (3) was readily achieved by palla-
dium-catalyzed double Suzuki reaction according to our re-
cent report.17 Next, demethylation by boron tribromide
generated 1,16-dihydroxytetraphenylene (4) in an excellent
yield of 98%. Resolution of racemic 4 was thus efficiently
carried out by the use of a chiral stationary phase column
(Daicel Chiralpak AD-H) on a preparative scale, giving both
(R)-DHTP and (S)-DHTP in enantiomerically pure forms.
The absolute configuration of (R)-DHTP (L1) and (S)-DHTP
(L2) was determined by comparison of their optical rota-
tions with known samples.14 It is noteworthy that the syn-
thesis of chiral 1,8,9,16-tetrahydroxytetraphenylenes
[(R,R)- and (S,S)-THTP, viz. L3 and L4] was also achieved ac-
cording to our previous report (see Supporting Informa-
tion).18 Furthermore, chiral ligand L5 was prepared via a
double etherification reaction according to the literature
procedure (see Supporting Information).5
OH
OH
HO
HO
OH
OH
OH
OH
L1
L2
L3
HO
HO
OH
OH
OH
OH
O
O
L4
L5
With these hydroxytetraphenylenes L1–L5 in hand,
asymmetric Darzens reaction employing these chiral li-
gands was then assessed (Figure 1). Initially, we explored
Figure 1 Chiral hydroxytetraphenylenes employed in asymmetric
Darzens reaction
Pd(OAc)2 (20 mol%)
K2CO3 (6 equiv)
OMe
OMe
BBr3
B(pin)
B(pin)
MeO
MeO
I
I
+
CH2Cl2
DME/H2O
80 °C
3
2
1
52% yield
OH
resolution
OH
OH
OH
+
by chiral HPLC
(Daicel Chiralpak
AD-H)
OH
OH
4
L1
L2
rac-DHTP
98% yield
(R)-DHTP
45% yield
(S)-DHTP
43% yield
Scheme 2 Synthesis of (R)-DHTP and (S)-DHTP
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
G.-L. Chai et al.
Paper
Synthesis
Table 1 Screening the Reaction Conditions for Asymmetric Darzens
yield and enantioselectivity (95% yield with 97% ee) while
tetrahydrofuran only gave an ee value of 85% (Table 2, en-
tries 5 and 6). A much lower yield of 6% with a moderate ee
of 65% was observed when methanol was used as the sol-
vent (Table 2, entry 7). Fortunately, a polar solvent, namely
acetonitrile, afforded the best yield of 95% with an excellent
enantioselectivity of 98% ee (Table 2, entry 8). Consequent-
ly, an investigation of the temperature effect on the reaction
performance was carried out in acetonitrile. It was found
that the temperature of 0 °C resulted in the highest level of
yield and enantioselectivity (Table 2, entries 8–10).
Reactiona
O
O
CHO
+
H
chiral ligand, Ti(OiPr)
CH2Cl2, 0 °C
N
H
Ph
4
Ph
P
N
H
O
N2
5a
6
7a
Entry
Ligand
Ratio ligand/Ti Additive
Yieldb (%) ee (%)c
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L3
L4
L4
L5
2.0:1
1.5:1
1.2:1
1.0:1
1.5:1
1.5:1
1.5:1
2.0:1
1.0:1
1.0:1
2.0:1
2.0:1
none
79
75
87
87
92
89
89
83
47
84
52
55
95 (S,S)
93 (S,S)
91 (S,S)
77 (S,S)
91 (S,S)
93 (S,S)
90 (S,S)
95 (S,S)
65 (S,S)
–68 (R,R)d
–57 (R,R)d
–68 (R,R)d
none
3
none
Table 2 Effect of Solvent and Temperature on the Asymmetric
Darzens Reactiona
4
none
5
4 Å MS
3 Å MS
5 Å MS
3 Å MS
none
L1 (20 mol%)
O
O
CHO
+
6
H
Ti(OiPr)4 (10 mol%)
N
H
Ph
Ph
Ph
N
7
H
3 Å MS
solvent
temperature
O
N2
8
5a
6
7a
9
10
11
12
none
Entry
Solvent
Time (h)
Temp (°C) Yieldb (%)
ee (%)c
none
1
2
CH2Cl2
CHCl3
DCE
12
10
10
25
10
20
48
1
0
0
83
89
91
64
95
93
6
95
92
95
90
97
85
65
98
98
96
none
a Reaction conditions: 5a (0.24 mmol), 6 (0.2 mmol), Ti(OiPr)4 (0.02 mmol),
CH2Cl2 (2 mL), 0 °C, 12–24 h; under an argon atmosphere.
b Isolated yield.
3
0
c The ee values were determined by HPLC analysis using a chiral column.
d Opposite configuration of 7a was obtained.
4
toluene
Et2O
0
5
0
6
THF
0
7
MeOH
MeCN
MeCN
MeCN
0
entry 1 vs entry 8). An evaluation of titanium(IV) complex-
es formed by different hydroxytetraphenylenes L3–L5
showed that the L1/Ti(IV) complex was the most efficient
catalyst, offering the highest enantioselectivity while the
complexes of L3–L5 only afforded 7a in moderate ee values.
The relative and absolute configurations of the products
were determined by both specific rotation values and high
performance liquid chromatography (HPLC) data in com-
parison with their respective literature values.12
8
0
95
92
92
9
1
25
–20
10
5
a Reaction conditions: 5a (0.24 mmol), 6 (0.2 mmol), L1 (0.04 mmol),
Ti(OiPr)4 (0.02 mmol), solvent (2 mL), 3-Å MS (200 mg); under an argon at-
mosphere.
b Isolated yield.
c The ee values were determined by HPLC analysis using a chiral column.
Subsequently, in order to enhance ee value of the de-
sired product 7a, we started to screen solvents. As shown in
Table 2, halogenated solvents such as dichloromethane,
chloroform, and 1,2-dichloroethane gave yields in the range
of 83–91% and enantioselectivities of 92–95% (Table 2, en-
tries 1–3). Non-polar solvent such as toluene provided a
sluggish reaction, although the enantioselectivity remained
at 90% ee (Table 2, entry 4). Diethyl ether increased both the
Moreover, (R,R)-7a was obtained in high yield with ex-
cellent enantioselectivity (95% yield, 99% ee) when L2 (S)-
DHTP) was used as the chiral ligand (Scheme 3).
Under the optimized reaction conditions, we then ex-
plored the substrate scope of aldehydes in Darzens reaction
(Table 3). Benzaldehyde derivatives bearing electron-with-
drawing substituents at either para or meta positions pro-
O
O
L2 (20 mol%)
O
H
Ti(OiPr)4 (10 mol%)
N
H
Ph
Ph
N
H
+
H
O
3 Å MS
MeCN, 0 °C, 1 h
N2
5a
6
(R,R)-7a
95% yield, 99% ee
Scheme 3 Synthesis of (R,R)-7a. Reagents and conditions: 5a (0.24 mmol), 6 (0.2 mmol), L2 (0.04 mmol), Ti(OiPr)4 (0.02 mmol), MeCN (2 mL), 0 °C, 3 Å
MS (200 mg) under an argon atmosphere.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
G.-L. Chai et al.
Paper
Synthesis
vided cis-epoxides in good yields of 88–99% with excellent
enantioselectivities (95–99% ee; Table 3, entries 2–5). How-
ever, in the case of p-fluorobenzaldehyde, the product was
obtained in 78% yield with a moderate ee value of 70% (Ta-
ble 3, entry 6). Electronically rich and neutral aromatic al-
dehydes were also employed in the Darzens reaction, af-
fording the desired products 7g–l in moderate to good
yields with excellent enantioselectivities (Table 3, entries
7–12). Interestingly, the heteroaromatic aldehyde 5m was
also tolerated in this reaction with the yield of 88% and ex-
cellent ee value of 99% (Table 3, entry 13). The extension of
the substrate scope to aliphatic aldehydes including linear
and branched aliphatic aldehydes was also rather success-
ful, giving the glycidic amides 7n–s in 41–95% yields with
80–99% ee (Table 3, entries 14–19).
In conclusion, we disclose in this article an asymmetric
Darzens reaction between aldehydes and diazo-N,N-di-
methylacetamide by using a chiral Lewis acid catalyst
formed in particular from (R)-DHTP and titanium(IV) iso-
propoxide, solely giving cis-glycidic amides in good yields
with excellent enantioselectivities. This protocol tolerated a
broad range of structurally diverse aldehydes, including ar-
omatic, unsaturated, and aliphatic aldehydes. The current
protocol provides an important alternative to prepare ep-
oxy amides with high enantiomeric purity. It is believed
that the chiral hydroxytetraphenylenes will be suitable for
the preparation of more catalysts and a wide range of cata-
lytic asymmetric reactions will be discovered by using
these catalytic systems. The studies in this direction are un-
derway in our laboratories.
Table 3 Reaction Scope for Asymmetric Darzens Reactiona
All reactions were carried out under an atmosphere of argon and sol-
vents were dried according to established procedures. Schlenk tubes
were all flamed and cooled before use. All reagents were purchased
from J&K or Aldrich Co., Ltd. Benzaldehyde, butyraldehyde, and isobu-
tyraldehyde were distilled before use. Other aldehydes were used
without further purification. Flash chromatography (FC) was carried
out using Merck silica gel 60 (230–400 mesh). HPLC analysis was per-
formed on a DIONEX UltiMate 3000, NO.8074238, ThermoScientific.
Chiral HPLC data for the epoxidation products could be obtained us-
ing a Chiralcel OD or Chiralpak AD-H column. These chiral columns
were purchased from Daicel Chemical Industries, Ltd. Optical rota-
tions were measured on an Autopol I polarimeter. 1H and 13C NMR
spectra were measured with Agilent 400 (400 MHz) spectrometer
and Agilent 500 (500 MHz) (samples in CDCl3 with TMS as the inter-
nal standard). LR-MS were recorded with Agilent GC-MS 5975C, or
Agilent 1100 LC-MSD SL. All melting points were determined using a
digital melting point apparatus and are uncorrected. The starting di-
azo-N,N-dimethylacetamide was prepared according to reported pro-
cedures.13
L1 (20 mol%)
O
O
Ti(OiPr)4 (10 mol%)
O
H
H
Ph
N
N
+
R
Ph
R
H
H
N2
3 Å MS
MeCN, 0 °C
O
5
6
7
Entry
R
Product
Yieldb (%)
ee (%)c
1
2
Ph
7a
7b
7c
7d
7e
7f
95
99
88
91
87
78
83
60
40
92
75
72
88
41
92
56
95
66
94
98
99
98
95
98
70
96
74
92
97
99
98
99
80
99
98
98
98
97
4-O2NC6H4
3-O2NC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
3-MeOC6H4
2-naphthyl
1-naphthyl
pyridin-2-yl
Cy
3
4
5
6
7
7g
7h
7i
8
Asymmetric Darzens Reactions; General Procedure
9
To a 25-mL Schlenk tube equipped with a magnetic stirrer, in which
the air was replaced by argon, was added (R)-DHTP (13.4 mg, 0.04
mmol), MeCN (2 mL), and Ti(OiPr)4 (6 μL, 0.02 mmol). The mixture
was stirred at r.t. for 1 h. Then 3-Å molecular sieves (200 mg) were
added. The resulting orange solution was cooled to 0 °C, and then al-
dehyde (0.24 mmol) and diazoacetamide (0.2 mmol) were introduced
into the reaction system under an argon atmosphere. The mixture
was stirred at 0 °C. After completion of the reaction (monitored by
TLC), H2O (0.1 mL) was added to the mixture to quench the reaction.
After evaporation under reduced pressure, the residue was purified
by flash column chromatography (silica gel, hexane/EtOAc, 15:1–1:1)
to yield pure products.
10
11
12
13
14
15
16
17
18
19
7j
7k
7l
7m
7n
7o
7p
7q
7r
Pr
iPr
C(Et)=CH2
Bn
CH2CH2Ph
7s
N,3-Diphenyloxirane-2-carboxamide (7a)
a Reaction conditions: 5 (0.24 mmol), 6 (0.2 mmol), L1 (0.04 mmol),
Ti(OiPr)4 (0.02 mmol), MeCN (2 mL), 0 °C, 3 Å MS (200 mg), 1–24 h; under
an argon atmosphere.
Flash column chromatography (petroleum ether/EtOAc, 5:1); color-
less solid; yield: 46 mg (95%); mp 104–105 °C (Lit.12a 101–103 °C);
98% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 80:20, flow rate
1.0 mL/min, T = 30 °C, 214 nm): tR = 14.70 (major), 12.16 min (mi-
nor)]; [α]D27 +18.6 (c 1.00, CH2Cl2).
b Isolated yield.
c The ee values were determined by HPLC analysis using a chiral column.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
G.-L. Chai et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.49 (br s, 1 H), 7.42–7.40 (m, 2 H),
7.34–7.27 (m, 3 H), 7.23–7.14 (m, 4 H), 7.07–7.03 (m, 1 H), 4.43 (d, J =
4.8 Hz, 1 H), 3.92 (d, J = 4.8 Hz, 1 H).
LRMS (ESI): m/z = 258.1 [C15H12FNO2 + H]+.
N-Phenyl-3-p-tolyloxirane-2-carboxamide (7g)
LRMS (ESI): m/z = 240.1 [C15H13NO2 + H]+, 262.1 [C15H13NO2 + Na]+.
Flash column chromatography (petroleum ether/EtOAc, 5:1); color-
less solid; yield: 42 mg (83%); mp 130–132 °C (Lit.13 127–128 °C); 96%
ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate 0.7
mL/min, T = 30 °C, 214 nm): tR = 9.41 (major), 7.42 min (minor)];
[α]D27 +24.2 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.53 (br s, 1 H), 7.29–7.20 (m, 6 H),
7.12 (d, J = 8.0 Hz, 2 H), 7.07–7.04 (m, 1 H), 4.39 (d, J = 4.8 Hz, 1 H),
3.90 (d, J = 4.8 Hz, 1 H), 2.28 (s, 3 H).
3-(4-Nitrophenyl)-N-phenyloxirane-2-carboxamide (7b)
Flash column chromatography (petroleum ether/EtOAc, 2:1); yellow-
ish solid; yield: 56 mg (99%); mp 170–172 °C (Lit.12a 166–169 °C); 99%
ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate 0.7
mL/min, T = 30 °C, 214 nm): tR = 15.67 (major), 8.39 min (minor)];
[α]D27 +49.4 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.61–7.58 (br s,
1 H), 7.60 (d, J = 8.7 Hz, 2 H), 7.23–7.20 (m, 4 H), 7.10–7.06 (m, 1 H),
4.47 (d, J = 5.2 Hz, 1 H), 4.01 (d, J = 4.8 Hz, 1 H).
LRMS (ESI): m/z = 254.1 [C16H15NO2 + H]+, 276.1 [C16H15NO2 + Na]+.
N-Phenyl-3-m-tolyloxirane-2-carboxamide (7h)
LRMS (ESI): m/z = 285.1 [C15H12N2O4 + H]+, 307.1 [C15H12N2O4 + Na]+.
Flash column chromatography (petroleum ether/EtOAc, 5:1); color-
less solid; yield: 30 mg (60%); mp 103–106 °C; 74% ee [HPLC (Daicel
Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate 0.7 mL/min, T = 30 °C,
3-(3-Nitrophenyl)-N-phenyloxirane-2-carboxamide (7c)
27
214 nm): tR = 8.40 (major), 7.34 min (minor)]; [α]D +19.6 (c 1.00,
Flash column chromatography (petroleum ether/EtOAc, 4:1); color-
less solid; yield: 50 mg (88%); mp 152–154 °C (Lit.13 146–147 °C); 98%
ee [HPLC (Daicel Chiralpak AD-H, n-hexane/iPrOH, 60:40, flow rate =
0.7 mL/min, T = 30 °C, 214 nm): tR = 10.81 (major), 8.73 min (minor)];
[α]D27 +16.7 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H), 8.15–8.12 (m, 1 H), 7.75–
7.70 (m, 2 H), 7.53–7.49 (t, J = 8.0 Hz, 1 H), 7.25–7.20 (m, 4 H), 7.09–
7.06 (m, 1 H), 4.48 (d, J = 4.8 Hz, 1 H), 4.01 (d, J = 4.8 Hz, 1 H).
CH2Cl2).
IR (KBr): 3333, 1673, 1595, 1520, 1442, 804, 775, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (br s, 1 H), 7.24–7.16 (m, 7 H),
7.08–7.04 (m, 2 H), 4.40 (d, J = 4.8 Hz, 1 H), 3.91 (d, J = 4.8 Hz, 1 H),
2.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.6, 138.4, 136.1, 132.7, 129.6,
129.0, 128.6, 127.1, 125.0, 123.5, 120.3, 58.8, 56.7, 21.4 (two carbons
overlapped).
LRMS (ESI): m/z = 285.1 [C15H12N2O4 + H]+, 307.0 [C15H12N2O4 + Na]+.
LRMS (ESI): m/z = 254.1 [C16H15NO2 + H]+, 276.0 [C16H15NO2 + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H16O2N: 254.1176; found:
3-(4-Chlorophenyl)-N-phenyloxirane-2-carboxamide (7d)
Flash column chromatography (petroleum ether/EtOAc, 4:1); color-
less solid; yield: 50 mg (91%); mp 136–138 °C (Lit.12a 141–143 °C);
95% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 214 nm): tR = 9.94 (major), 7.24 min (minor)];
[α]D27 +23.9 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.55 (br s, 1 H), 7.35–7.21 (m, 8 H),
7.10–7.06 (m, 1 H), 4.38 (d, J = 4.8 Hz, 1 H), 3.92 (d, J = 4.8 Hz, 1 H).
254.1175.
N-Phenyl-3-o-tolyloxirane-2-carboxamide (7i)
Flash column chromatography (petroleum ether/EtOAc, 5:1); color-
less solid; yield: 20 mg (40%); mp 90–92 °C; 92% ee [HPLC (Daicel Chi-
ralpak AD-H, hexane/iPrOH, 60:40, flow rate 0.7 mL/min, T = 30 °C,
214 nm): tR = 8.57 (major), 8.09 min (minor)]; [α]D +38.0 (c 1.00,
CH2Cl2).
27
LRMS (ESI): m/z = 274.1 [C15H12ClNO2 + H]+, 296.0 [C15H12ClNO2 + Na]+.
IR (KBr): 3302, 2923, 1667, 1598, 1547, 1443, 756, 712, 691 cm–1
.
3-(4-Bromophenyl)-N-phenyloxirane-2-carboxamide (7e)
1H NMR (500 MHz, CDCl3): δ = 7.41–7.38 (m, 2 H), 7.20–7.08 (m, 7 H),
7.05–7.01 (m, 1 H), 4.37 (d, J = 4.5 Hz, 1 H), 3.99 (d, J = 4.5 Hz, 1 H),
2.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.7, 136.8, 136.0, 131.4, 130.4,
129.0, 128.7, 125.9, 125.8, 124.9, 120.4, 58.3, 56.4, 18.8.
LRMS (ESI): m/z = 254.1 [C16H15NO2 + H]+, 276.0 [C16H15NO2 + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H16O2N: 254.1176; found:
Flash column chromatography (petroleum ether/EtOAc, 3:1); color-
less solid; yield: 55 mg (87%); mp 170–172 °C (Lit.12a 167–169 °C);
98% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 254 nm): tR = 10.74 (major), 7.49 min (minor)];
[α]D27 +22.0 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.55 (br s, 1 H), 7.46 (d, J = 8.4 Hz, 2 H),
7.29–7.21 (m, 6 H), 7.10–7.06 (m, 1 H), 4.35 (d, J = 4.8 Hz, 1 H), 3.92
(d, J = 4.8 Hz, 1 H).
254.1175.
LRMS (ESI): m/z =318.0 [C15H12BrNO2 + H]+, 341.9 [C15H12BrNO2 + Na]+.
3-(3-Methoxyphenyl)-N-phenyloxirane-2-carboxamide (7j)
Flash column chromatography (petroleum ether/EtOAc, 3:1); color-
less solid; yield: 50 mg (92%); mp 100–101 °C (Lit.12a 104–108 °C);
97% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 214 nm): tR = 9.99 (major), 8.57 min (minor)];
[α]D27 +24.3 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.55 (br s, 1 H), 7.25–7.18 (m, 5 H),
7.08–7.04 (m, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 6.94 (s, 1 H), 6.81 (dd, J =
8.4, 2.4 Hz, 1 H), 4.40 (d, J = 4.8 Hz, 1 H), 3.90 (d, J = 4.8 Hz, 1 H), 3.73
(s, 3 H).
3-(4-Fluorophenyl)-N-phenyloxirane-2-carboxamide (7f)
Flash column chromatography (petroleum ether/EtOAc, 3:1); color-
less solid; yield: 40 mg (78%); mp 114–116 °C (Lit.12a 106–108 °C);
70% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 254 nm): tR = 8.83 (major), 7.02 min (minor)];
[α]D27 +9.9 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.51 (br s, 1 H), 7.37–7.35 (m, 2 H),
7.24–7.16 (m, 4 H), 7.07–6.97 (m, 3 H), 4.36 (d, J = 4.8 Hz, 1 H), 3.90
(d, J = 4.4 Hz, 1 H).
LRMS (ESI): m/z = 270.1 [C16H15NO3 + H]+, 292.0 [C16H15NO3 + Na]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
G.-L. Chai et al.
Paper
Synthesis
3-(Naphthalen-2-yl)-N-phenyloxirane-2-carboxamide (7k)
3-Isopropyl-N-phenyloxirane-2-carboxamide (7p)12a
Flash column chromatography (petroleum ether/ EtOAc, 4:1); color-
less solid; yield: 43 mg (75%); mp 148–150 °C (Lit.12a 143–145 °C);
99% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 214 nm): tR = 12.23 (major), 9.55 min (minor)];
[α]D27 +33.5 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.80–7.76 (m, 3 H), 7.63
(br s, 1 H), 7.50–7.43 (m, 3 H), 7.15–7.08 (m, 4 H), 7.00–6.96 (m, 1 H),
4.57 (d, J = 4.8 Hz, 1 H), 4.00 (d, J = 4.8 Hz, 1 H).
Flash column chromatography (petroleum ether/EtOAc, 10:1); color-
less oil, yield: 23 mg (56%); 98% ee [HPLC (Daicel Chiralpak AD-H,
hexane/iPrOH, 80:20, flow rate 0.7 mL/min, T = 30 °C, 214 nm): tR
8.19 (major), 7.79 min (minor)]; [α]D27 +29.4 (c 1.00, CH2Cl2).
=
1H NMR (400 MHz, CDCl3): δ = 7.84 (br s, 1 H), 7.56 (d, J = 7.6 Hz, 2 H),
7.36 (t, J = 7.6 Hz, 2 H), 7.16 (t, J = 7.6 Hz, 1 H), 3.65 (d, J = 4.4 Hz, 1 H),
2.97 (dd, J = 4.8, 9.6 Hz, 1 H), 1.53–1.47 (m, 1 H), 1.16 (d, J = 6.4 Hz, 3
H), 1.01 (d, J = 6.8 Hz, 3 H).
LRMS (ESI): m/z = 290.1 [C19H15NO2 + H]+, 312.1 [C19H15NO2 + Na]+.
LRMS (ESI): m/z = 206.1 [C12H15NO2 + H]+, 228.1 [C12H15NO2 + Na]+.
3-(Naphthalen-1-yl)-N-phenyloxirane-2-carboxamide (7l)
N-Phenyl-3-(but-1-en-2-yl)oxirane-2-carboxamide (7q)
Flash column chromatography (petroleum ether/EtOAc, 5:1); color-
less solid; yield: 41 mg (72%); mp 142–145 °C (Lit.12a 153–158 °C);
98% ee [HPLC (Daicel Chiralpak AD-H, hexane/iPrOH, 60:40, flow rate
0.7 mL/min, T = 30 °C, 214 nm): tR = 11.33 (major), 8.56 min (minor)];
[α]D27 +125.4 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4
Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.61–7.50 (m, 3 H), 7.44–7.36 (m, 2
H), 7.14–7.10 (m, 2 H), 7.02–6.96 (m, 3 H), 4.80 (d, J = 4.4 Hz, 1 H),
4.16 (d, J = 4.4 Hz, 1 H).
Flash column chromatography (petroleum ether/EtOAc, 10:1); color-
less oil, yield: 41 mg (95%); 98% ee [HPLC (Daicel Chiralpak OD, hex-
ane/iPrOH, 80:20, flow rate 0.7 mL/min, T = 30 °C, 254 nm): tR = 9.99
(major), 10.99 min (minor)]; [α]D27 +11.4 (c 1.00, CH2Cl2).
IR (KBr): 3337, 2970, 1667, 1596, 1527, 1444, 1315, 950, 936, 818,
755, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.66 (br s, 1 H), 7.45 (d, J = 8.0 Hz, 2 H),
7.33 (t, J = 7.6 Hz, 2 H), 7.14 (t, J = 7.6 Hz, 1 H), 5.16 (d, J = 1.0 Hz, 1 H),
5.05 (d, J = 1.0 Hz, 1 H), 3.75 (m, 2 H), 2.17–2.10 (m, 2 H), 1.06–1.02 (t,
J = 7.2 Hz, 3 H).
LRMS (ESI): m/z = 290.1 [C19H15NO2 + H]+, 312.1 [C19H15NO2 + Na]+.
13C NMR (100 MHz, CDCl3): δ = 164.7, 143.2, 136.5, 129.1, 124.9,
119.9, 111.5, 59.8, 56.5, 26.2, 12.0.
N-Phenyl-3-(pyridin-2-yl)oxirane-2-carboxamide (7m)12a
LRMS (ESI): m/z =206.1 [C13H15NO2 + H]+, 228.1 [C13H15NO2 + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H16O2N: 218.1176; found:
Flash column chromatography (petroleum ether/EtOAc, 1:1); color-
less oil, yield: 42 mg (88%); 99% ee [HPLC (Daicel Chiralpak OD, hex-
ane/iPrOH, 80:20, flow rate 0.7 mL/min, T = 30 °C, 254 nm): tR = 17.04
(major), 24.22 min (minor)]; [α]D27 +67.3 (c 1.00, CH2Cl2).
218.1175.
1H NMR (400 MHz, CDCl3): δ = 8.76 (br s, 1 H), 8.58 (d, J = 4.8 Hz, 1 H),
7.67 (dt, J = 1.5, 7.5 Hz, 1 H), 7.45–7.41 (m, 3 H), 7.29–7.20 (m, 3 H),
7.08–7.05 (m, 1 H), 4.40 (d, J = 4.5 Hz, 1 H), 3.97 (d, J = 4.5 Hz, 1 H).
3-Benzyl-N-phenyloxirane-2-carboxamide (7r)
Flash column chromatography (petroleum ether/EtOAc, 8:1); color-
less solid; yield: 33 mg (66%); mp 85–86 °C (Lit.12a 81–82 °C); 98% ee
[HPLC (Daicel Chiralpak OD, hexane/iPrOH, 80:20, flow rate 0.7
mL/min, T = 30 °C, 254 nm): tR = 13.82 (major), 20.16 min (minor)];
[α]D26 +31.6 (c 1.00, CH2Cl2).
LRMS (ESI): m/z = 241.1 [C14H12N2O2 + H]+.
3-Cyclohexyl-N-phenyloxirane-2-carboxamide (7n)12a
1H NMR (400 MHz, CDCl3): δ = 7.97 (br s, 1 H), 7.59 (d, J = 8.0 Hz, 2 H),
7.38–7.31 (m, 4 H), 7.27–7.25 (m, 3 H), 7.17–7.14 (m, 1 H), 3.72 (d, J =
4.8 Hz, 1 H), 3.48 (dd, J = 6.9, 5.2 Hz, 1 H), 2.96 (d, J = 6.0 Hz, 2 H).
Flash column chromatography (petroleum ether/EtOAc, 20:1); color-
less oil, yield: 20 mg (41%); 80% ee [HPLC (Daicel Chiralpak AD-H,
hexane/iPrOH, 90:10, flow rate 0.7 mL/min, T = 30 °C, 214 nm): tR
16.56 (major), 13.50 min (minor)]; [α]D27 +19.5 (c 1.00, CH2Cl2).
=
LRMS (ESI): m/z = 254.1 [C16H15NO2 + H]+, 276.0 [C16H15NO2 + Na]+.
1H NMR (500 MHz, CDCl3): δ = 7.86 (br s, 1 H), 7.55 (d, J = 8.5 Hz, 2 H),
7.35 (t, J = 7.5 Hz, 2 H), 7.15 (t, J = 7.5 Hz, 1 H), 3.64 (d, J = 4.5 Hz, 1 H),
3.00 (dd, J = 4.5, 9.0 Hz, 1 H), 1.99–1.96 (m, 1 H), 1.75–1.63 (m, 4 H),
1.25–1.11 (m, 6 H).
3-Phenethyl-N-phenyloxirane-2-carboxamide (7s)12a
Flash column chromatography (petroleum ether/EtOAc, 8:1); color-
less oil, yield: 50 mg (94%); 97% ee [HPLC (Daicel Chiralpak OD, hex-
ane/iPrOH, 80:20, flow rate 0.7 mL/min, T = 30 °C, 254 nm): tR = 13.35
(major), 19.26 min (minor)]; [α]D26 +35.4 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.83 (br s, 1 H), 7.54 (d, J = 8.8 Hz, 2 H),
7.36–7.33 (m, 2 H), 7.29–7.25 (m, 2 H), 7.21–7.12 (m, 4 H), 3.64 (d, J =
4.4 Hz, 1 H), 3.29–3.28 (m, 1 H), 2.84 (t, J = 7.6 Hz, 2 H), 1.98–1.87 (m,
2 H).
LRMS (ESI): m/z = 246.1 [C15H19NO2 + H]+, 268.1 [C15H19NO2 + Na]+.
N-Phenyl-3-propyloxirane-2-carboxamide (7o)12a
Flash column chromatography (petroleum ether/EtOAc, 10:1); color-
less oil, yield: 38 mg (92%); 99% ee [HPLC (Daicel Chiralpak OD, hex-
ane/iPrOH, 80:20, flow rate 0.7 mL/min, T = 30 °C, 254 nm): tR = 8.81
(major), 15.29 min (minor)]; [α]D27 +35.6 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.84 (br s, 1 H), 7.55 (d, J = 7.6 Hz, 2 H),
7.36 (t, J = 7.6 Hz, 2 H), 7.16 (t, J = 7.6 Hz, 1 H), 3.63 (d, J = 4.4 Hz, 1 H),
3.29 (dt, J = 5.2, 6.0 Hz, 1 H), 1.62–1.58 (m, 4 H), 0.99–0.95 (m, 3 H).
LRMS (ESI): m/z = 268.1 [C17H17NO2 + H]+, 290.1 [C17H17NO2 + Na]+.
Acknowledgment
LRMS (ESI): m/z = 206.1 [C12H15NO2 + H]+, 228.1 [C12H15NO2 + Na]+.
This work was supported by grants from the National Natural Science
Foundation of China (NSFC No. 21202186, 21272199, and 21472213),
as well as by the Croucher Foundation (Hong Kong) in the form of a
CAS-Croucher Foundation Joint Laboratory Grant.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
G.-L. Chai et al.
Paper
Synthesis
Supporting Information
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G