Facile construction of three-membered rings via benzyne-promoted Darzens-type reaction of tertiary amines

Article abstract of DOI:10.1016/j.tet.2018.11.065

A range of tertiary amines having electron-withdrawing groups were activated in situ by benzyne, generated from 2-(trimethylsilyl)phenyl triflate and a fluoride source, and participated in the Darzens-type reaction with carbonyl compounds, imines, and vinyl ketones to afford structurally diverse epoxides, aziridines, and cyclopropanes, respectively, in moderate to excellent yields with high trans-selectivity. The reaction involves in situ formation of unstrained ammonium ylides from tertiary amines and benzyne, proceeds in the absence of transition metals and strong bases, and tolerates a wide variety of functional groups.

Full text of DOI:10.1016/j.tet.2018.11.065

Accepted Manuscript
Facile construction of three-membered rings via benzyne-promoted Darzens-type
reaction of tertiary amines
Ya-Nan Xu, Shi-Kai Tian
PII:
S0040-4020(18)31455-8
https://doi.org/10.1016/j.tet.2018.11.065
TET 29976
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 October 2018
Revised Date: 28 November 2018
Accepted Date: 29 November 2018
Please cite this article as: Xu Y-N, Tian S-K, Facile construction of three-membered rings via benzyne-
promoted Darzens-type reaction of tertiary amines, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2018.11.065.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Facile construction of three-membered rings
via benzyne-promoted Darzens-type reaction
of tertiary amines
Leave this area blank for abstract info.
Ya-Nan Xu, Shi-Kai Tian
Hefei National Laboratory for Physical Sciences at the Microscale, Center for Excellence in Molecular Synthesis, and
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Facile construction of three-membered rings via benzyne-promoted Darzens-type
reaction of tertiary amines
Ya-Nan Xu, Shi-Kai Tian
Hefei National Laboratory for Physical Sciences at the Microscale, Center for Excellence in Molecular Synthesis, and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A range of tertiary amines having electron-withdrawing groups were activated in situ by
benzyne, generated from 2-(trimethylsilyl)phenyl triflate and a fluoride source, and participated
in the Darzens-type reaction with carbonyl compounds, imines, and vinyl ketones to afford
structurally diverse epoxides, aziridines, and cyclopropanes, respectively, in moderate to
excellent yields with high trans-selectivity. The reaction involves in situ formation of unstrained
ammonium ylides from tertiary amines and benzyne, proceeds in the absence of transition metals
and strong bases, and tolerates a wide variety of functional groups.
Available online
Keywords:
Amines
Ammonium ylides
Arynes
2009 Elsevier Ltd. All rights reserved
.
Darzens reaction
Three-membered rings
———
Corresponding author.
E-mail: tiansk@ustc.edu.cn (S.-K. Tian)

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
type reaction of tertiary amine 1a with aldehyde 2a in acetonitrile
under air at 60 oC and found that the use of CsF afforded epoxide
3a in the best yield (72%) with 98:2 trans/cis-selectivity (Table
1, entry 1).8-11 We also examined more solvents such as toluene
(trace), tetrahydrofuran (trace), 1,2-dimethoxyethane (32%
yield), and dimethyl sulfoxide (trace), but unfortunately, failed to
enhance the yield.
Three-membered rings are present in many biologically
relevant molecules and serve as versatile intermediates in
chemical synthesis.1 Among the general approaches for the
construction of three-membered rings, the well-known Darzens
reaction proves powerful for the synthesis of epoxides by treating
aldehydes or ketones with α-halo carbonyl compounds in the
presence of bases.2 To expand the scope of the Darzens reaction,
many efforts have been devoted to find readily accessible
surrogates of α-halo carbonyl compounds. In addition to
sulfonium ylides,3 ammonium ylides have been explored to
replace α-halo carbonyl compounds in the Darzens-type reaction
to access epoxides, despite that the substrate scope is limited to
aryl-, carbamoyl-, and cyano-stabilized ammonium ylides, which
are prepared by N-alkylation of tertiary amines followed by
treatment with bases (Scheme 1, a).4 The Darzens-type reaction
of ammonium ylides has been extended to imines and electron-
deficient alkenes, yielding the corresponding aziridines and
Table 1
Benzyne-promoted Darzens-type reaction of tertiary amines with
aldehyde 2a.a
Yield dr (trans
Entry
1
NR1R2
EWG
3
(%)b
/cis)c
cyclopropanes,
respectively.4a-c,e,i,n-p,r,s
Related
strained
1
2
1a N(Me)Ph
1b NMe2
CO2Et
CO2Et
3a 72
3a 56
98:2
aziridinium ylides, generated in situ from aziridines and arynes,
have also been reported to add to aldehydes to afford N-aryl α-
amino epoxides (Scheme 1, b).5 Herein we report a modified
Darzens-type reaction by in situ formation of unstrained
ammonium ylides from tertiary amines and benzyne in the
absence of strong bases and metals for the construction of three-
membered rings such as epoxides, aziridines, and cyclopropanes
(Scheme 1, c).
>98:2
>98:2
3
1c
1d
1e
CO2Et
CO2Et
CO2Et
3a 52
3a 53
3a 28
4
>98:2
98:2
5d
6e
7
1f NHMe
CO2Et
3a 67
3b 83
3c 61
3d 44
>98:2
98:2
1g N(Me)Ph
1h N(Me)Ph
1i N(Me)Ph
CO2Bn
t
8
CO2 Bu
>98:2
90:10
9
CONHMe
10f
11
1j N(Me)Ph
3e 76
87:13
1k N(Me)Ph
1l N(Me)Ph
CN
3f 90
3g 31
50:50
>98:2
12
a
Reaction conditions:
1
(0.24 mmol), 2a (0.20 mmol), 2-
(trimethylsilyl)phenyl triflate (0.30 mmol), CsF (0.60 mmol), acetonitrile (1.2
mL), 60 oC, 24 h.
b Isolated yield.
c Determined by 1H NMR spectroscopic analysis.
d 25% ee for 3a.
e
2-(trimethylsilyl)phenyl triflate (0.60 mmol) and CsF (0.80 mmol) were
used.
f 98% de for 3e (trans).
Scheme 1. The Darzens-type reactions of ammonium ylides and
aziridinium ylides.
The benzyne-promoted Darzens-type reaction of tertiary
amines was significantly affected by the N-substituents. When
the N-methyl group and the N-phenyl group of tertiary amine 1a
were replaced with N,N-dialkyl groups, epoxide 3a was obtained
in much lower yields but still with high trans-selectivity (Table
1, entries 2-5). The introduction of an L-proline-derived N-
substituent permitted the synthesis of optically active epoxide 3a
albeit in a low yield with poor chirality transfer (Table 1, entry
5). To our delight, in situ generation of amine 1a from secondary
amine 1f also led to the formation of epoxide 3a in a good yield
(Table 1, entry 6). In addition to ester groups, we examined more
electron-withdrawing groups such as carbamoyl, cyano, and 2-
benzoxazolyl, delivering a range of functionalized epoxides in
varied yields and trans/cis-selectivity (Table 1, entries 9-12). It is
noteworthy that the reaction of substrate 1j, having a chiral
2. Results and discussion
Inspired by the previously reported nucleophilic addition of
tertiary amines to arynes generated from 2-(trimethylsilyl)aryl
triflates under mild conditions,6,7 we envisioned that the
zwitterions generated from tertiary amines, having an electron-
withdrawing group, and benzyne would undergo proton transfer
to generate quaternary ammonium ylides,6j,p,q,s,t which would
participate in nucleophic addition to aldehydes, imines, and
electron-deficient alkenes to afford epoxides, aziridines, and
cyclopropanes, respectively (Scheme 1, c).4 Using 2-
(trimethylsilyl)phenyl triflate as
a benzyne precursor, we
surveyed a few fluoride sources, such as CsF, KF, and
tetrabutylammonium fluoride (TBAF), in the model Darzens-

carbamoyl group,4o
with 98% de (Table 1, entry 10).
afforded epoxide 3e, the mAajoCr CtraEnsP-iTsoEmDer, MANUSCRIPT
A range of aromatic and heteroaromatic aldehydes were
examined in the benzyne-promoted Darzens-type reaction of
amine 1a, and in general, the corresponding functionalized
epoxides were obtained in moderate to good yields with high
trans-selectivity (Scheme 2, 3h-r). A variety of functional groups
were introduced into the epoxide products by employing the
corresponding aromatic aldehydes having such groups. The
reaction was successfully extended to a propargylic aldehyde, an
aliphatic aldehyde, and an activated ketone such as isatin
(Scheme 2, 3s-u). In these cases, the corresponding epoxides
were also obtained in good yields with high trans-selectivity.
Scheme 3. Benzyne-promoted Darzens-type reaction of amine 1a
with imines or vinyl ketones.
3. Conclusion
In summary, a modified Darzens-type reaction has been
developed to access three-membered rings through in situ
formation of unstrained ammonium ylides from tertiary amines
and benzyne. With 2-(trimethylsilyl)phenyl triflate as a benzyne
precursor, a range of tertiary amines having electron-withdrawing
groups were activated in situ to react with carbonyl compounds,
imines, and vinyl ketones to afford structurally diverse epoxides,
aziridines, and cyclopropanes, respectively, in moderate to
excellent yields with high trans-selectivity. It is noteworthy that
the reaction proceeds in the absence of transition metals and
strong bases and tolerates a wide variety of functional groups.
4. Experimental
4.1. General information
Amines 1a-i and 1k,12 imines 4,13 vinyl ketones 5,14 and
compound 84o were prepared according to literature procedures.
1H NMR and 13C NMR spectra were recorded on a Bruker AC-
400 FT spectrometer (400 MHz and 100 MHz, respectively)
using tetramethylsilane as an internal reference, and chemical
shifts (δ) and coupling constants (J) were expressed in ppm and
Hz, respectively. High resolution mass spectra (HRMS) were
recorded on a LC-TOF spectrometer (Micromass). ESI-mass data
were acquired using a Thermo LTQ Orbitrap XL instrument
equipped with an ESI source and controlled by Xcalibur
software. High pressure liquid chromatography (HPLC) analyses
were performed on a Hewlett-Packard 1200 Series instrument
equipped with anisostatic pump, using a Daicel Chiralpak
column (OD, 250 × 4.6 mm) with isopropanol/hexane as mobile
phase, and the UV detection was monitored at 254 nm.
Scheme 2. Benzyne-promoted Darzens-type reaction of amine 1a
with carbonyl compounds. a Reaction conditions: 1a (0.24
mmol), 2 (0.20 mmol), 2-(trimethylsilyl)phenyl triflate (0.30
mmol), CsF (0.60 mmol), acetonitrile (1.2 mL), 60 oC, 24 h. b
Isolated yields and dr (trans/cis) were given.
Changing the reaction conditions was able to extend the
benzyne-promoted Darzens-type reaction to the construction of
more types of three-membered rings (Scheme 3). In the presence
of 2-(trimethylsilyl)phenyl triflate, KF, and 18-crown-6, amine
1a reacted with N-Boc aromatic imines in acetonitrile at room
temperature, delivering aziridines 5a-e in moderate to good
yields with high trans-selectivity. Simply replacing acetonitrile
with dichloromethane as the solvent, the reaction worked well
with a range of vinyl ketones to afford cyclopropanes 7a-e in
good to excellent yields with high trans-selectivity.
4.2. Preparation of amine 1j
To a solution of N-methylaniline (1.07 g, 1.08 mL, 10.0
mmol) in ethanol (20 mL) was added sodium carbonate (1.59 g,
15.0 mmol) and compound 8 (2.57 g, 8.6 mmol). The suspension
was stirred under reflux for 14 h and cooled to room temperature.
The mixture was quenched with water (50 mL) and extracted
with ethyl acetate (4 x 20 mL). The combined organic fractions
were washed with water (4 x 25 mL) and brine (20 mL), dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography,
eluting with ethyl acetate/petroleum ether (1:10 v/v), to give (R)-
1-(2,2-dimethyl-4-phenyloxazolidin-3-yl)-2-
(methyl(phenyl)amino)ethan-1-one (1j) as a yellow solid (2.56 g,
o
1
95% yield). m.p. 84-85 C; H NMR (400 MHz, CDCl3) δ 7.45-
7.39 (m, 2H), 7.38-7.32 (m, 3H), 7.15-7.09 (m, 2H), 6.67 (t, J =

4
Tetrahedron
7.2 Hz, 1H), 6.41 (d, J = 8.0 Hz, 2H), 4.97 (dd, J = 6.4, 2.4 Hz,
148.6, 137.4, 134.8, 131.8, 130.0, 128.9, 128.8, 128.7, 124.0,
ACCEPTED MANUSCRIPT
+
1H), 4.41 (dd, J = 8.8, 6.4 Hz, 1H), 3.94 (dd, J = 8.8, 2.4 Hz,
1H), 3.87 (d, J = 16.8 Hz, 1H), 3.56 (d, J = 16.8 Hz, 1H), 2.93 (s,
3H), 1.87 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.6, 149.2, 141.0, 129.3, 129.2, 128.4, 126.2, 117.1, 112.2,
97.0, 60.8, 56.2, 39.8, 25.6, 23.5; HRMS (ESI) calcd for
C20H24N2O2Na+ (M + Na)+ 347.1730, found 347.1730.
121.0, 67.9, 56.9, 56.8; HRMS (ESI) calcd for C16H14NO5 (M +
H)+ 300.0867, found 300.0858.
4.4.3. tert-Butyl trans-3-(3-nitrophenyl)oxirane-2-carboxylate
(3c)
Yellow oil (32.4 mg, 61% yield); 1H NMR (400 MHz, CDCl3)
δ 8.23-8.16 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz,
1H), 4.15 (d, J = 1.6 Hz, 1H), 3.43 (d, J = 1.6 Hz, 1H), 1.53 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 166.5, 148.6, 137.8, 131.9,
129.9, 123.9, 121.1, 83.4, 57.6, 56.5, 28.1; HRMS (ESI) calcd for
C13H15NO5Na+ (M + Na)+ 288.0842, found 288.0842.
4.3. Preparation of amine 1l
4.4.4. N-Methyl trans-3-(3-nitrophenyl)oxirane-2-carboxamide
(3d)
To a solution of N-methylaniline (214 mg, 0.21 mL, 2.0
mmol) in ethanol (10 mL) was added sodium carbonate (317 mg,
3.0 mmol) and 2-chlorobenzoxazole (335 mg, 2.0 mmol). The
suspension was stirred under reflux for 14 h, cooled to room
temperature, quenched with water (20 mL), and extracted with
ethyl acetate (4 x 10 mL). The combined organic fractions were
washed with water (4 x 10 mL) and brine (20 mL), dried over
anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography,
eluting with ethyl acetate/petroleum ether (1:10 v/v), to give N-
(benzo[d]oxazol-2-ylmethyl)-N-methylaniline (1l) as a pale yellow
oil (424 mg, 89% yield).15 1H NMR (400 MHz, CDCl3) δ 7.71-
7.66 (m, 1H), 7.49-7.44 (m, 1H), 7.32-7.27 (m, 2H), 7.25 (t, J =
8.0, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 4.74
(s, 2H), 3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0,
151.0, 148.8, 141.1, 129.4, 125.1, 124.5, 120.2, 117.9, 113.1,
110.8, 50.6, 39.4.
Obtained as a 90:10 mixture of trans- and cis-isomers. Yellow
o
1
solid (19.5 mg, 44% yield), m.p. 143-144 C; H NMR (400
MHz, CDCl3) δ 8.23-8.19 (m, 1H), 8.15 (s, 1H), 7.64-7.53 (m,
2H), 6.27 (s, br, 1H), 4.01 (d, J = 1.6 Hz, 1H), 3.54 (d, J = 1.6
1
Hz, 1H), 2.89 (d, J = 5.2 Hz, 3H); Partial H NMR for the cis-
isomer: δ 6.07 (s, br, 1H), 4.37 (d, J = 4.8 Hz, 1H), 3.88 (d, J =
4.8 Hz, 1H), 2.59 (d, J = 5.2 Hz, 3H); HRMS (ESI) calcd for
C10H10N2O4Na+ (M + Na)+ 245.0533, found 245.0533.
4.4.5. ((R)-2,2-Dimethyl-4-phenyloxazolidin-3-yl)((2R,3S)-3-(3-
nitrophenyl)oxiran-2-yl)methanone (3e)4o
Obtained as an 87:13 mixture of trans- and cis-isomers. White
solid (56.0 mg, 76% yield), m.p. 119-120 C; [α]D = -40.0 (c =
0.50, CHCl3); H NMR (400 MHz, CDCl3) δ 8.07 (ddd, J = 8.0,
2.4, 0.8 Hz, 1H), 7.60-7.57 (m, 1H), 7.38-7.32 (m, 1H), 7.17-7.07
(m, 5H), 7.03-6.97 (m, 1H), 5.09 (dd, J = 6.8, 4.8 Hz, 1H), 4.42
(dd, J = 9.2, 6.8 Hz, 1H), 3.87 (dd, J = 9.2, 4.8 Hz, 1H), 3.71 (d,
J = 2.0 Hz, 1H), 3.22 (d, J = 2.0 Hz, 1H), 1.89 (s, 3H), 1.72 (s,
o
20
1
4.4. General procedure for synthesis of epoxide 3
1
A
mixture of amine 1 (46.4 mg, 0.24 mmol), 2-
3H); Partial H NMR for the cis-isomer: δ 5.20 (dd, J = 6.8, 4.8
(trimethylsilyl)phenyl triflate (89.5 mg, 0.30 mmol), CsF (91.1
mg, 0.60 mmol), and acetonitrile (0.80 mL) in a sealed tube was
heated at 60 oC (oil bath) for 10 min, and a solution of aldehyde 2
(0.20 mmol) in acetonitrile (0.40 mL) was added. The mixture
was stirred at 60 C for 24 h, cooled to room temperature, and
purified by silica gel chromatography, eluting with ethyl
Hz, 1H), 3.68 (d, J = 4.8 Hz, 1H), 2.85 (d, J = 6.0 Hz, 1H), 1.58
(s, 3H), 1.47 (s, 3H).
4.4.6. trans-3-(3-Nitrophenyl)-oxirane-2-carbonitrile (3f)16
o
Compound 3f was separated from the corresponding cis-
isomer 3f-cis on silica gel chromatography.
acetate/petroleum ether (1:10 v/v), to give epoxide 3.
o
3f: White solid (17.1 mg, 45% yield), m.p. 115-116 C. 1H
4.4.1. Ethyl trans-3-(3-nitrophenyl)oxirane-2-carboxylate (3a)
Obtained as a 98:2 mixture of trans- and cis-isomers. White
NMR (400 MHz, CDCl3) δ 8.29-8.24 (m, 1H), 8.18-8.15 (m,
1H), 7.68-7.59 (m, 2H), 4.44 (d, J = 1.6 Hz, 1H), 3.49 (d, J = 1.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 148.8, 135.2, 131.8,
130.4, 124.8, 120.9, 115.3, 57.4, 44.9.
3f-cis: White solid (17.1 mg, 45% yield), m.p. 111-112 oC. 1H
NMR (400 MHz, CDCl3) δ 8.33-8.28 (m, 2H), 7.76 (d, J = 8.0
Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 4.39 (d, J = 3.6 Hz, 1H), 3.89
(d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 148.5, 133.9,
132.0, 130.2, 124.8, 122.0, 114.4, 56.7, 45.2.
o
1
solid (34.2 mg, 72% yield), m.p. 51-52 C; H NMR (400 MHz,
CDCl3) δ 8.24-8.16 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.58 (t, J =
8.0 Hz, 1H), 4.36-4.24 (m, 2H), 4.22 (d, J = 1.6 Hz, 1H), 3.52 (d,
J = 1.6 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H); Partial 1H NMR for the
cis-isomer: δ 3.89 (d, J = 4.4 Hz, 1H), 1.07 (t, J = 7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 167.5, 148.6, 137.5, 131.8, 130.0,
124.0, 121.0, 62.3, 57.0, 56.8, 14.2; HRMS (ESI) calcd for
C11H11NO5Na+ (M + Na)+ 260.0529, found 260.0529.
4.4.7.
trans-2-(3-(3-Nitrophenyl)oxiran-2-yl)benzo[d]oxazole
Table 1, entry 5: The ee was determined to be 25% by HPLC
analysis (Chiralpak OD column, λ = 254 nm, hexane/isopropanol
= 95/5, flow rate = 1.0 mL/min): tR(major) = 24.8 min,
tR(minor) = 32.0 min. [α]D20 = -1.4 (c = 0.30, CHCl3).
(3g)
o
1
White solid (17.4 mg, 31% yield), m.p. 145-146 C; H NMR
(400 MHz, CDCl3) δ 8.29-8.23 (m, 2H), 7.79-7.72 (m, 2H), 7.65-
7.55 (m, 2H), 7.45-7.36 (m, 2H), 4.68 (d, J = 2.0 Hz, 1H), 4.21
(d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.3, 150.9,
148.8, 141.0, 137.5, 131.8, 130.1, 126.2, 125.2, 124.1, 121.0,
120.6, 111.1, 58.8, 55.3; HRMS (ESI) calcd for C15H10N2O4Na+
(M + Na)+ 305.0531, found 305.0533.
4.4.8. Ethyl trans-3-phenyloxirane-2-carboxylate (3h)17
Colorless oil (26.5 mg, 31% yield); 1H NMR (400 MHz,
CDCl3) δ 7.40-7.33 (m, 3H), 7.34-7.27 (m, 2H), 4.35-4.21 (m,
4.4.2. Benzyl trans-3-(3-nitrophenyl)oxirane-2-carboxylate (3b)
Obtained as a 98:2 mixture of trans- and cis-isomers. Yellow
1
oil (49.7 mg, 83% yield); H NMR (400 MHz, CDCl3) δ 8.22-
8.14 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H),
7.41-7.34 (m, 5H), 5.30 (d, J = 12.4 Hz, 1H), 5.24 (d, J = 12.4
Hz, 1H), 4.23 (d, J = 1.6 Hz, 1H), 3.56 (d, J = 1.6 Hz, 1H);
1
Partial H NMR for the cis-isomer: δ 4.33 (d, J = 4.4 Hz, 1H),
3.92 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.3,

o
1
White solid (31.3 mg, 66% yield), m.p. 64-65 C; H NMR
2H), 4.09 (d, J = 2.0 Hz, 1H), 3.51 (d, J = 2.0 AHzC, 1CHE), P1.3T3E(tD, J MANUSCRIPT
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 135.1,
(400 MHz, CDCl3) δ 8.22 (dd, J = 8.4, 1.2 Hz, 1H), 7.71 (dt, J =
7.2, 0.8 Hz, 1H), 7.64-7.60 (m, 1H), 7.58-7.51 (m, 1H), 4.69 (d, J
= 1.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.39 (d, J = 1.6 Hz, 1H),
1.36 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.7,
147.5, 134.7, 132.3, 129.5, 127.4, 125.0, 62.2, 56.3, 56.0, 14.3;
HRMS (ESI) calcd for C11H11NO5Na+ (M + Na)+ 260.0529,
found 260.0529.
129.1, 128.8, 125.9, 61.9, 58.0, 56.9, 14.2.
4.4.9. Ethyl trans-3-(4-chlorophenyl)oxirane-2-carboxylate (3i)17
Colorless oil (33.6 mg, 74% yield); 1H NMR (400 MHz,
CDCl3) δ 7.35 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 4.36-
4.21 (m, 2H), 4.07 (d, J = 1.6 Hz, 1H), 3.46 (d, J = 1.6 Hz, 1H),
1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1,
135.0, 133.7, 129.1, 127.3, 62.1, 57.4, 56.9, 14.3.
4.4.16. Ethyl trans-3-(naphthalen-2-yl)oxirane-2-carboxyate
(3p)17
4.4.10. Ethyl trans-3-(4-bromophenyl)oxirane-2-carboxylate (3j)
Obtained as a 98:2 mixture of trans- and cis-isomers. Yellow
oil (35.9 mg, 74% yield); 1H NMR (400 MHz, CDCl3) δ 7.83-7.9
(m, 4H), 7.52-7.45 (m, 2H), 7.31 (dd, J = 8.4, 1.6 Hz, 1H), 4.37-
4.22 (m, 2H), 4.26 (d, J = 1.6 Hz, 1H), 3.61 (d, J = 1.6 Hz, 1H),
Obtained as a 98:2 mixture of trans- and cis-isomers. Yellow
oil (42.3 mg, 78% yield); 1H NMR (400 MHz, CDCl3) δ 7.50 (d,
J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 4.36-4.21 (m, 2H), 4.05
(d, J = 1.6 Hz, 1H), 3.45 (d, J = 1.6 Hz, 1H), 1.33 (t, J = 7.2 Hz,
1
1.33 (t, J = 7.2 Hz, 3H); Partial H NMR for the cis-isomer: δ
3.89 (d, J = 4.4 Hz, 1H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.3, 133.7, 133.1, 132.5, 128.7, 128.0, 127.9,
126.7, 126.6, 126.1, 122.6, 61.9, 58.3, 56.9, 14.2.
1
3H); Partial H NMR for the cis-isomer: δ 3.81 (d, J = 4.4 Hz,
1H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.0, 134.2, 132.0, 127.6, 123.1, 62.0, 57.4, 56.9, 14.2; HRMS
(ESI) calcd for C11H11BrO3Na+ (M + Na)+ 292.9784, found
292.9787.
4.4.17. Ethyl trans-3-(pyridin-2-yl)oxirane-2-carboxylate (3q)19
Obtained as a 98:2 mixture of trans- and cis-isomers. Yellow
oil (26.2 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 8.60 (d,
J = 4.4 Hz, 1H), 7.72 (dt, J = 7.6, 1.6 Hz, 1H), 7.32-7.28 (m, 2H),
4.36-4.22 (m, 2H), 4.25 (d, J = 1.6 Hz, 1H), 3.72 (d, J = 1.6 Hz,
1H), 1.33 (t, J = 7.2 Hz, 3H); Partial 1H NMR for the cis-isomer:
δ 3.90 (d, J = 4.4 Hz, 1H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.0, 154.5, 149.9, 137.1, 123.9, 120.7,
62.0, 58.1, 55.8, 14.2.
4.4.11. Ethyl trans-3-(4-iodophenyl)oxirane-2-carboxylate (3k)
Yellow oil (44.5 mg, 70% yield); 1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.36-4.21 (m,
2H), 4.04 (d, J = 1.6 Hz, 1H), 3.45 (d, J = 1.6 Hz, 1H), 1.33 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0, 137.9,
134.9, 127.7, 94.8, 62.1, 57.6, 56.9, 14.3; HRMS (ESI) calcd for
C11H11IO3Na (M + Na)+ 340.9645, found 340.9648.
4.4.18.
carboxylate (3r)
Ethyl
trans-3-(benzo[b]thiophen-2-yl)oxirane-2-
4.4.12. Ethyl trans-3-(4-cyanophenyl)oxirane-2-carboxylate
(3l)18
Yellow oil (39.2 mg, 79% yield); 1H NMR (400 MHz, CDCl3)
δ 7.81-7.77 (m, 1H), 7.75-7.71 (m, 1H), 7.41 (s, 1H), 7.34-7.30
(m, 2H), 4.41 (d, J = 1.2 Hz, 1H), 4.37-4.22 (m, 2H), 3.73 (d, J =
1.2 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.8, 139.5, 139.4, 139.3, 125.2, 124.8, 124.3, 123.8,
122.6, 62.2, 57.3, 55.4, 14.3; HRMS (ESI) calcd for
C13H12SO3Na+ (M + Na)+ 271.0399, found 271.0399.
Obtained as a 97:3 mixture of trans- and cis-isomers. Yellow
oil (33.0 mg, 76% yield); 1H NMR (400 MHz, CDCl3) δ 7.68 (d,
J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.37-4.23 (m, 2H), 4.15
(d, J = 1.6 Hz, 1H), 3.47 (d, J = 1.6 Hz, 1H), 1.34 (t, J = 7.2 Hz,
1
3H); Partial H NMR for the cis-isomer: δ 3.88 (d, J = 4.4 Hz,
1H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
167.5, 140.5, 132.6, 126.6, 118.5, 113.0, 62.3, 57.1, 57.0, 14.3;
HRMS (ESI) calcd for C12H11NO3Na+ (M + Na)+ 240.0631,
found 240.0632.
4.4.19. Ethyl trans-3-(phenylethynyl)oxirane-2-carboxylate (3s)
Yellow oil (28.1 mg, 65% yield); 1H NMR (400 MHz, CDCl3)
δ 7.47-7.43 (m, 2H), 7.37-7.28 (m, 3H), 4.34-4.21 (m, 2H), 3.82
(d, J = 1.6 Hz, 1H), 3.70 (d, J = 1.6 Hz, 1H), 1.33 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 132.1, 129.4, 128.5,
121.4, 84.7, 83.4, 62.2, 54.8, 45.6, 14.2; HRMS (ESI) calcd for
C13H12O3Na+ (M + Na)+ 239.0679, found 239.0679.
4.4.13. Ethyl trans-3-(4-nitrophenyl)oxirane-2-carboxylate (3m)
Obtained as a 98:2 mixture of trans- and cis-isomers. White
o
1
solid (32.3 mg, 68% yield), m.p. 65-66 C; H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 4.38-
4.24 (m, 2H), 4.21 (d, J = 1.6 Hz, 1H), 3.49 (d, J = 1.6 Hz, 1H),
1
1.35 (t, J = 7.2 Hz, 3H); Partial H NMR for the cis-isomer: δ
4.4.20. Ethyl trans-3-phenethyloxirane-2-carboxylate (3t)17
3.90 (d, J = 4.4 Hz, 1H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.4, 148.5, 142.4, 126.8, 124.1, 62.3, 57.1,
56.8, 14.3; HRMS (ESI) calcd for C11H11NO5Na+ (M + Na)+
260.0529, found 260.0530.
Obtained as an 86:14 mixture of trans- and cis-isomers.
1
Colorless oil (34.4 mg, 78% yield); H NMR (400 MHz, CDCl3)
δ 7.32-7.26 (m, 2H), 7.23-7.17 (m, 3H), 4.28-4.12 (m, 2H), 3.20
(s, 2H), 2.89-2.70 (m, 2H), 2.08-1.81 (m, 2H), 1.29 (t, J = 7.2 Hz,
4.4.14.
Ethyl
trans-3-(4-(methylsulfonyl)phenyl)oxirane-2-
1
3H); Partial H NMR for the cis-isomer: δ 3.50 (d, J = 4.4 Hz,
carboxylate (3n)
1H).
Obtained as a 98:2 mixture of trans- and cis-isomers. Yellow
4.4.21. Ethyl trans-1-methyl-2-oxospiro[indoline-3,2'-oxirane]-
o
1
solid (46.5 mg, 86% yield), m.p. 141-142 C; H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz,
2H), 4.34-4.25 (m, 2H), 4.20 (s, 1H), 3.49 (s, 1H), 3.06 (s, 3H),
3'-carboxylate (3u)20
Yellow solid (33.6 mg, 68% yield), m.p. 107-108 oC; 1H NMR
(400 MHz, CDCl3) δ 7.45 (dd, J = 7.6, 0.8 Hz, 1H), 7.41 (td, J =
8.0, 1.2 Hz, 1H), 7.07 (td, J = 8.0, 0.8 Hz, 1H), 6.92 (d, J = 8.0
Hz, 1H), 4.36-4.22 (m, 2H), 4.21 (s, 1H), 3.28 (s, 3H), 1.29 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 165.8,
145.7, 131.2, 124.8, 123.2, 119.3, 109.0, 62.3, 60.2, 59.8, 26.9,
14.2.
1
1.35 (t, J = 7.2 Hz, 3H); Partial H NMR for the cis-isomer: δ
3.90 (d, J = 4.8 Hz, 1H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.5, 141.4, 141.1, 127.9, 126.9, 62.2, 57.0,
56.9, 44.6, 14.2; HRMS (ESI) calcd for C12H14O5SNa+ (M + Na)+
293.0454, found 293.0455.
4.4.15. Ethyl trans-3-(2-nitrophenyl)oxirane-2-carboxylate (3o)

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.5. General procedure for synthesis of aziridine 5
triflate (89.5 mg, 0.30 mmol) and vinyl ketone 6 (0.20 mmol).
The mixture was stirred at room temperature for 4 h, and
To a reaction tube equipped with a magnetic stir bar was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography, eluting with ethyl acetate/petroleum
ether (1:10 v/v), to give cyclopropane 7.
charged with benzaldimine 4 (0.20 mmol), KF (34.9 mg, 0.60
mmol), and 18-crown-6 (159 mg, 0.60 mmol). The tube was
sealed with a septum, evacuated and backfilled with nitrogen
4.6.1. Ethyl trans-2-benzoylcyclopropane-1-carboxylate (7a)22
three times. Amine
1
(46.4 mg, 0.24 mmol), 2-
(trimethylsilyl)phenyl triflate (89.5 mg, 0.30 mmol), and
acetonitrile (1.2 mL) were added via syringe under nitrogen
atmosphere. The mixture was stirred at room temperature for 24
h, and purified by silica gel chromatography, eluting with ethyl
acetate/petroleum ether (1:10 v/v), to give aziridine 5.
Colorless oil (42.8 mg, 98% yield); 1H NMR (400 MHz,
CDCl3) δ 8.04-7.99 (m, 2H), 7.62-7.55 (m, 1H), 7.50-7.45 (m,
2H), 4.18 (q, J = 7.2 Hz, 2H), 3.19 (ddd, J = 8.4, 5.6, 3.6 Hz,
1H), 2.38 (ddd, J = 8.4, 5.6, 3.6 Hz, 1H), 1.66-1.56 (m, 2H), 1.29
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.1, 172.4,
137.1, 133.4, 128.7, 128.4, 61.2, 26.0, 24.7, 17.9, 14.3; HRMS
(ESI) calcd for C13H14O3Na+ (M + Na)+ 241.0835, found
241.0834.
4.5.1.
1-(tert-Butyl)
2-ethyl
trans-3-phenylaziridine-1,2-
dicarboxylate (5a)21
Yellow oil (45.4 mg, 78% yield); 1H NMR (400 MHz, CDCl3)
δ 7.34-7.29 (m, 5H), 4.34-4.19 (m, 2H), 3.81 (d, J = 2.4 Hz, 1H),
3.09 (d, J = 2.4 Hz, 1H), 1.46 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 167.6, 158.5, 135.5, 128.7, 128.5,
126.6, 82.3, 62.0, 45.1, 44.2, 28.1, 14.4.
4.6.2.
Ethyl
trans-2-(4-methoxybenzoyl)cyclopropane-1-
carboxylate (7b)
Colorless oil (42.2 mg, 85% yield); 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 4.18
(q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.14 (ddd, J = 8.8, 6.0, 4.0 Hz,
1H), 2.35 (ddd, J = 8.8, 6.0, 4.0 Hz, 1H), 1.63-1.52 (m, 2H), 1.29
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 172.7,
163.9, 130.7, 130.2, 113.9, 61.2, 55.7, 25.8, 24.5, 17.8, 14.3;
HRMS (ESI) calcd for C14H16O4Na+ (M + Na)+ 271.0941, found
271.0941.
4.5.2. 1-(tert-Butyl) 2-ethyl trans-3-(p-tolyl)aziridine-1,2-
dicarboxylate (5b)
Yellow oil (48.8 mg, 80% yield); 1H NMR (400 MHz, CDCl3)
δ 7.30 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 4.05-3.93 (m,
2H), 3.79 (d, J = 6.8 Hz, 1H), 3.39 (d, J = 6.8 Hz, 1H), 2.32 (s,
3H), 1.48 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.4, 160.8, 138.0, 130.2, 128.9, 127.6, 82.5, 61.3,
44.6, 42.8, 28.0, 21.3, 14.0; HRMS (ESI) calcd for
C17H23NO4Na+ (M + Na)+ 328.1519, found 328.1519.
4.6.3.
Ethyl
trans-2-(4-chlorobenzoyl)cyclopropane1-1-
carboxylate (7c)
Colorless oil (43.0 mg, 85% yield); 1H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.19
(q, J = 7.2 Hz, 2H), 3.13 (ddd, J = 9.2, 5.6, 3.6 Hz, 1H), 2.39
(ddd, J = 9.2, 5.6, 3.6 Hz, 1H), 1.65-1.56 (m, 2H), 1.29 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 196.0, 172.3, 140.0,
135.4, 129.8, 129.1, 61.4, 26.0, 24.9, 18.2, 14.3; HRMS (ESI)
calcd for C13H13O3ClNa+ (M + Na)+ 275.0447, found 275.0445.
4.5.3. 1-(tert-Butyl) 2-ethyl trans-3-(4-chlorophenyl)aziridine-
1,2-dicarboxylate (5c)
Yellow oil (39.1 mg, 60% yield); 1H NMR (400 MHz, CDCl3)
δ 7.31 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.36-4.17 (m,
2H), 3.78 (d, J = 2.4 Hz, 1H), 3.03 (d, J = 2.4 Hz, 1H), 1.47 (s,
9H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
167.4, 158.3, 134.3, 134.2, 128.9, 128.0, 82.5, 62.2, 44.4, 44.3,
28.1, 14.3; HRMS (ESI) calcd for C16H20ClNO4Na+ (M + Na)+
348.0973, found 348.0975.
4.6.4. Ethyl trans-2-(2-naphthoyl)cyclopropane-1-carboxylate
(7d)22
Colorless oil (51.0 mg, 95% yield); 1H NMR (400 MHz,
CDCl3) δ 8.58 (s, 1H), 8.05 (dd, J = 8.4, 1.6 Hz, 1H), 7.99 (d, J =
8.0 Hz, 1H), 7.93-7.86 (m, 2H), 7.64-7.53 (m, 2H), 4.21 (q, J =
7.2 Hz, 2H), 3.36 (ddd, J = 8.4, 5.6, 3.6 Hz, 1H), 2.45 (ddd, J =
8.4, 5.6, 3.6 Hz, 1H), 1.70-1.62 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 197.0, 172.6, 135.8, 134.5, 132.6,
130.4, 129. 8, 128.8, 128.7, 127.9, 127.0, 124.0, 61.3, 26.2, 24.8,
18.2, 14.3.
4.5.4. 1-(tert-Butyl) 2-ethyl trans-3-(4-nitrophenyl)aziridine-1,2-
dicarboxylate (5d)
Yellow oil (44.4 mg, 66% yield); 1H NMR (400 MHz, CDCl3)
δ 8.21 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.37-4.19 (m,
2H), 3.90 (d, J = 2.0 Hz, 1H), 3.06 (d, J = 2.0 Hz, 1H), 1.49 (s,
9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.9, 157.9, 148.0, 143.0, 127.5, 124.0, 82.9, 62.4, 44.8, 43.8,
28.0, 14.3; HRMS (ESI) calcd for C16H20N2O6Na+ (M + Na)+
359.1213, found 359.1214.
4.6.5.
Ethyl
trans-2-(furan-2-carbonyl)cyclopropane-1-
carboxylate (7e)
Colorless oil (25.0 mg, 60% yield) as a colorless oil; 1H NMR
(400 MHz, CDCl3) δ 7.64 (dd, J = 1.6, 0.8 Hz, 1H), 7.29 (dd, J =
3.6, 0.8 Hz, 1H), 6.58 (dd, J = 3.6, 1.6 Hz, 1H), 4.18 (q, J = 7.2
Hz, 2H), 3.08 (ddd, J = 8.4, 6.4, 3.6 Hz, 1H), 2.36 (ddd, J = 8.4,
6.4, 3.6 Hz, 1H), 1.63-1.53 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 185.7, 172.3, 152.8, 147.1, 118.0,
112.6, 61.3, 26.2, 24.5, 17.5, 14.3; HRMS (ESI) calcd for
C11H12O4Na+ (M + Na)+ 231.0628, found 231.0627.
4.5.5. 1-(tert-Butyl) 2-ethyl trans-3-(naphthalen-2-yl)aziridine-
1,2-dicarboxylate (5e)
Yellow oil (27.3 mg, 40% yield); 1H NMR (400 MHz, CDCl3)
δ 7.83-7.79 (m, 4H), 7.49-7.45 (m, 2H), 7.39-7.35 (m, 1H), 4.36-
4.21 (m, 2H), 3.98 (d, J = 2.0 Hz, 1H), 3.17 (d, J = 2.0 Hz, 1H),
1.48 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.6, 158.5, 133.4, 133.2, 133.0, 128.5, 128.0, 127.9,
126.6, 126.4, 126.2, 123.8, 82.4, 62.1, 45.3, 44.4, 28.1, 14.4;
HRMS (ESI) calcd for C20H23NO4Na+ (M + Na)+ 364.1519,
found 364.1515.
Acknowledgments
Dedicated to the memory of Prof. Wei-Shan Zhou. We are
grateful for the financial support from the National Natural
Science Foundation of China (21772182 and 21472178) and the
4.6. General procedure for synthesis of cyclopropane 7
To a mixture of amine 1 (46.4 mg, 0.24 mmol), KF (34.9 mg,
0.60 mmol), and 18-crown-6 (159 mg, 0.60 mmol) in
dichloromethane (1.2 mL) was added 2-(trimethylsilyl)aryl

(f) A. V. Varlamov, N. I. Guranova, T. N. Borisova, F. A. A. Toze, M. V.
Strategic Priority Research Program of the ChAineCseCAEcaPdeTmEyDof MANUSCRIPT
Ovcharov, S. Kristancho, L. G. Voskressensky, Tetrahedron 71 (2015)
1175−1181;
Sciences (XDB20000000).
(g) T. Roy, D. R. Baviskar, A.T. Biju, J. Org. Chem. 80 (2015)
11131−11137;
Supplementary Material
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17 (2015) 6270−6273;
(i) M. Hirsch, S. Dhara, C. E. Diesendruck, Org. Lett. 18 (2016)
980−983;
(j) J. Zhang, Z.-X. Chen, T. Du, B. Li, Y. Gu, S.-K. Tian, Org. Lett. 18
(2016) 4872−4875;
Copies of 1H NMR and 13C NMR spectra and HPLC traces.
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