Synthesis of 2 H-Azirines via Iodine-Mediated Oxidative Cyclization of Enamines

Article abstract of DOI:10.1021/acs.joc.8b02022

A facile and practical oxidative cyclization reaction of enamines to 2H-azirines has been developed, employing molecular iodine. The features of the present synthetic approach include no use of transition metals, mild reaction conditions, and simplicity o

Full text of DOI:10.1021/acs.joc.8b02022

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Article
Synthesis of 2H-Azirines via Iodine-
Mediated Oxidative Cyclization of Enamines
Manman Wang, Jiao Hou, Wenquan Yu, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02022 • Publication Date (Web): 26 Nov 2018
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Synthesis of 2H-Azirines via Iodine-Mediated Oxidative
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Cyclization of Enamines
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Manman Wang, Jiao Hou, Wenquan Yu,* and Junbiao Chang*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan Province
450001, P. R. China
R3
R3
I2, DBU, CH2Cl2
R1
NH2
R1
R2
R2
room temperature
N
R1, R2 = aryl, alkyl or H
R3 = CN, CO2Et or COMe
24 examples, 49-99%
gram-scale
Abstract: A facile and practical oxidative cyclization reaction of enamines to
2H-azirines has been developed employing molecular iodine. The features of the present
synthetic approach include no use of transition metals, mild reaction conditions and
simplicity of operation. Under the optimal reaction conditions, a variety of 2H-azirine
derivatives were synthesized from simple and readily accessible enamine precursors in an
efficient and scalable fashion.
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. Introduction
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2H-Azirines, containing one nitrogen atom and one double bond in a three-membered
ring, are an important class of the smallest heterocyclic systems. Owing to the high
reactivity enhanced by the ring strain, they can participate in many chemical
transformations1 as nucleophiles, electrophiles, dienophiles, or dipolarophiles. As
valuable synthons, 2H-azirines have been extensively utilized to construct other
heterocyclic skeletons such as indoles,2 pyrroles,3 pyridines,4 oxazoles,5 pyrazines,6
triazoles7 and azepines.8 Moreover, this structural motif also occurs frequently in natural
products9 with diverse biological properties. For example, Azirinomycin, the first
azirine-containing natural product, exhibits broad spectrum antibiotic activity.9a
Consequently, considerable efforts have been made for the construction of the
2H-azirine framework.1a, 1b, 1d Classical synthetic strategies include Neber rearrangement
of ketoximes,10 thermolysis/photolysis of vinyl azides,11 oxidation/elimination of
aziridines,12 ring contraction of isoxazole derivatives,13 and cycloaddition of carbenes
with nitriles.14 Moreover, direct oxidative cyclization of enamine precursors is also an
attractive approach to access 2H-azirines in an atom- and step-economic fashion. Yet,
this transformation was only achieved by Du, Zhao and coworkers using hypervalent
iodine reagents.15 Inspired by our previous work on I2-mediated intramolecular C−H
amination,16 herein we describe a simple and practical methodology for the synthesis of
2H-azirines from readily accessible enamines.
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. Results and Discussion
The required enamine substrate 2a was readily prepared by a modified Thorpe procedure
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from phenylacetonitrile with benzonitrile.17 Initial solvent screening (Table 1, entries 1−6)
indicated that CH2Cl2 is the desired one for this transformation. In the presence of K2CO3
as base, I2-mediated cyclization of substrate 2a in CH2Cl2 at room temperature was
complete within 5 h producing the expected 2H-azirine 1a in 80% yield (entry 2).
Screening of various organic and inorganic bases (entries 7−15) demonstrated that DBU
is the optimal one. When DBU was utilized as the base, both the conversion rate and the
yield of 1a were significantly increased (entry 10). Further optimization of the reaction
conditions suggested that the complete consumption of enamine 2a requires at least 1.2
equiv of iodine (entry 10 vs entry 17) with 2.5 equiv of the base DBU (entry 10 vs entry
16). However, excess iodine resulted in the decreased yield of the product (entry 18).
Replacement of iodine with N-Iodosuccinimide (NIS) also afforded product 1a but in a
lower yield (entry 19). Under the optimal cyclization conditions, the synthesis of 1a was
successfully carried out on a gram scale (entry 10).
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Table 1. Reaction Condition Optimization for the Synthesis of 2H-Azirine 1a.a
CN
NC
Ph
I2, base
Ph
Ph
Ph
solvent, temp.
N
NH2
2a
1a
entry
I2/equiv
1.2
base/equiv
solvent
temp.
time
5 h
yieldb
77%
80%
68%
39%
27%
1
2
3
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5
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
toluene
CH2Cl2
rt
rt
rt
rt
rt
1.2
5 h
1.2
1,4-dioxane
CH3CN
18 h
18 h
1 h
1.2
1.2
DMSO
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1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.5
K2CO3 (2.5)
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
1 h
0%
7
NaHCO3 (2.5)
AcONa (2.5)
Cs2CO3 (2.5)
DBU (2.5)
24 h
24 h
22 h
16%
12%
77%
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0.5 h 92% (90%)c
Et3N (2.5)
5 h
24 h
24 h
24 h
24 h
3 h
0%
pyridine (2.5)
DMAP (2.5)
NMI (2.5)
trace
trace
trace
trace
80%
81%
74%
35%
imidazole (2.5)
DBU (1.2)
DBU (2.0)
3 h
DBU (3.0)
0.5 h
0.5 h
d
-
DBU (2.5)
a Optimal reaction conditions (entry 10): 2a (0.5 mmol), I2 (0.6 mmol), DBU (1.25 mmol), CH2Cl2 (5
b
c
d
mL), rt. Isolated yields. The yield of gram-scale synthesis (6 mmol). NIS (0.6 mmol) was used
instead of iodine.
With the optimized conditions in hand (Table 1, entry 10), we then examined the
substrate scope of this reaction. As shown in Scheme 1, the present synthetic
methodology is compatible with both electron-donating groups (EDGs) and
electron-withdrawing groups (EWGs) on the benzene ring at R1 position. The presence of
EDGs (Me, OMe) at the para- position favored the formation of the expected 2H-azirines
(1b−c). Introduction of EWGs (F, Cl, CF3) affected the yields of the corresponding
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products (1d−f). The steric hinderance of the ortho-methyl group could be responsible for
the decreased yield of 1h. Replacement of the aromatic R1 group with an aliphatic one
(nPr) also produced the desired 2H-azirine (1i), but in a relatively lower yield. This could
be due to the decreased stability of the imine-type intermediates caused by the alkyl
substituent (cf. compounds A and B in Scheme 4A) during the transformation.
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Scheme 1. Scope of R1 Group.a
CN
NC
R1
R1
I2, DBU
Ph
Ph
N
NH2
CH2Cl2, rt
2
1
Me
OMe
NC
Ph
Ph
NC
Ph
NC
N
Ph
N
N
1a
, 92%
1b
, 99%
1c
, 99%
F
Cl
CF3
NC
Ph
NC
Ph
NC
Ph
N
N
N
1d
, 81%
1e
, 85%
1f
, 56%
NC
Ph
NC
Ph
NC
Ph
Me
N
N
N
Me
b
1g
, 86%
1h
, 50%
1i
, 49%
a Reaction conditions: 2 (0.5 mmol), I2 (0.6 mmol), DBU (1.25 mmol), CH2Cl2 (5 mL), rt. b With 32%
of the substrate 2i recovered.
To further investigate the generality of the present reaction, enamine substrates bearing
various R2 groups were subjected to the standard cyclization conditions (Scheme 2). This
synthetic process can tolerate a range of para-, meta-, ortho- and di-substituents on the
aromatic ring at the R2 position to form the corresponding products (1j−r) efficiently.
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The structure of 2H-azirine 1n was further confirmed by X-ray crystallography. This
method is also amenable to substrates bearing α-naphthyl, 2-pyridyl or alkyl moieties
(1s−t, 1v). When R2 is H, only the corresponding vinyl iodide (1u') was formed (for the
plausible mechanism see Scheme 4B). Furthermore, good functional group tolerance of
this reaction also allows for the replacement of the cyano group at the R3 position with
other EWGs such as carboxylic acid ester (1w) and methyl ketone (1x). Taking 1a as an
example, the 2H-azirine was further converted into a 3-cyano-indole (3a) in the presence
of palladium catalyst2a (Scheme 3).
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Scheme 2. Scope of R2 and R3 Groups.a
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R3
R3
R1
R1
4
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I2, DBU
R2
R2
N
CH2Cl2, rt
NH2
2
1
8
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NC
NC
NC
Ph
Ph
Ph
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N
N
N
Me
MeO
Cl
1j
1k
, 92%
1l
, 94%
, 95%
NC
Cl
Br
Ph
NC
N
NC
N
N
CF3
1o
Cl
Br
1m
, 92%
1n
, 84%
, 84%
NC
Ph
NC
NC
Ph
Ph
N
N
N
Cl
Cl
Cl
, 96%
Cl
1p
1q
, 95%
1r
, 90%
NC
CN
NC
N
Ph
Ph
Ph
I
N
N
NH2
1s
1t
, 62%
1u'
, 82%
, 80%
O
Me
NC
EtO2C
Ph
Ph
Ph
Ph
( )4
N
N
N
Br
1v
1w
1x
, 89%
, 58%
, 68%
a Reaction conditions: 2 (0.5 mmol), I2 (0.6 mmol), DBU (1.25 mmol), CH2Cl2 (5 mL), rt.
Scheme 3. Formation of 3-Cyano-indole 3a via Pd-Catalyzed Rearrangement of
2H-Azirine 1a.
CN
NC
Ph
Pd(MeCN)2Cl2
Ph
N
o-xylene, 140 °C, 65%
N
H
1a
3a
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On the basis of the experimental results along with our previous work,16 a tentative
reaction mechanism for this I2-mediated cyclization of enamines to 2H-azirines is
proposed in Scheme 4A. First, iodination of the enamine substrate 2 by iodine under the
basic conditions generates a 2-iodo imine intermediate B. The imine nitrogen atom then
attacks the iodo-substituted carbon in compound B to form a three-membered 2H-azirine
ring (C). Finally, the subsequent deprotonation by base afford the product 1. In the case
of enamine substrate 2u (R2 = H), the resulting iodide intermediate A' may directly
undergo β-deprotonation to result in the corresponding vinyl iodide (1u') (Scheme 4B).
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Scheme 4. Proposed Mechanisms for the Formation of 1H-Azirine 1a and Vinyl Iodide
1u'.
R3
R3
I
I
R3
I
R1
NH
R1
NH2
I
R2
R1
NH
R2
(A)
R2
H
base
R1
2
A
B
R3
R2
R3
R2
R1
N
H
N
base
C
1
CN
CN
I
I
CN
I
base
(B)
Ph
Ph
Ph
H
I
H
NH2
NH2
1u'
NH2
2u
A'
. Conclusion
In summary, we have developed an I2-mediated oxidative cyclization reaction for the
synthesis of 2H-azirines under transition-metal-free conditions. The required enamine
substrates were readily obtained by Thorpe reaction of benzonitrile with
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phenylacetonitrile or by condensation of ammonium formate with ketones. In the
presence of DBU as base, the enamine precursors were cyclized by the treatment with
iodine to the 2H-azirine products smoothly and efficiently. Moreover, the present
reaction can be successfully conducted on a gram scale. This practical methodology
provided an attractive alternative for 2H-azirine synthesis under mild reaction conditions.
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. Experimental Section
General Information. 1H and 13C{1H} NMR spectra were recorded on a 400 MHz (100
MHz for 13C{1H} NMR) spectrometer. Chemical shift values are given in ppm (parts per
million) with tetramethylsilane (TMS) as an internal standard. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet;
m, multiplet; dd, doublet of doublets; dt, doublet of triplets. The coupling constants (J)
are reported in Hertz (Hz). Melting points were determined on a micromelting point
apparatus without corrections. High-resolution mass spectra (HRMS) were obtained on a
Q-TOF mass spectrometer equipped with an electrospray ion source (ESI), operated in
the positive mode. Flash column chromatography was performed over silica gel 200–300
mesh. Most of the enamine substrates were synthesized as a mixture of Z/E isomers. In
the cases where only a small amount of the other isomer was formed, the substrate could
be obtained as a single Z (or E) isomer after purification. The absolute configuration was
not assigned. Substrate 2t was synthesized as the E-isomer and 2w−x as the Z-isomers
due to the existence of intramolecular hydrogen bonds.
General Procedure for the Preparation of Enamine Substrates 2a−h, 2j−u. The
synthesis was performed by a modified Thorpe procedure.17 A mixture of an aliphatic
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nitrile (5 mmol) and the corresponding benzonitrile (5 mmol) in BuOH (10 mL) was
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t
treated with BuOK (1.40 g, 12.5 mmol), and then stirred at room temperature for 3 h.
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Upon the completion of the reaction (monitored by TLC), it was quenched with H2O (20
mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over
anhydrous Na2SO4, concentrated, and then purified through silica gel column
chromatography to afford the enamine substrate 2.
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General Procedure for the Preparation of Enamine Substrates 2i, 2v−x.15a A reaction
mixture of the corresponding ketone (5 mmol), ammonium formate (1.58 g, 25 mmol)
and molecular sieves (4 Å, 1 g) in anhydrous EtOH (20 mL) was heated to reflux until
TLC indicated the total consumption of the ketone. After cooling to room temperature, it
was filtered through a silica gel pad and the filtrate was concentrated. The resulting
residue was treated with H2O (10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layer was dried over anhydrous Na2SO4, concentrated, and then
purified through silica gel column chromatography to afford the enamine substrate 2.
3-Amino-2,3-diphenylacrylonitrile (2a).17 Eluent: EtOAc/PE 20:80; yield: 727 mg,
1
66%; yellow solid, mp 132–137 °C; H NMR (400 MHz, CDCl3) δ 7.69–7.67 (m, 2H),
7.53–7.41 (m, 7H), 7.31–7.27 (m, 1H), 4.80 (s, 2H); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H13N2 221.1073, found 221.1065.
3-Amino-2-phenyl-3-(p-tolyl)acrylonitrile (2b).17 EtOAc/PE 20:80; yield: 726 mg, 66%
(minor:major = 1:6.3); yellow solid, mp 131–133 °C; 1H NMR (400 MHz, CDCl3): major
isomer: δ 7.59 (d, J = 8.0 Hz, 2H), 7.54–7.52 (m, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.31–7.27
(m, 3H), 4.77 (s, 2H), 2.41 (s, 3H); minor isomer: δ 7.19–7.17 (m, 2H), 7.11–7.03 (m,
5H), 7.01–6.99 (m, 2H), 4.95 (s, 2H), 2.34 (s, 3H); HRMS (ESI-TOF) m/z: [M + H]+
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calcd for C16H15N2 235.1230, found 235.1231.
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3-Amino-3-(4-methoxyphenyl)-2-phenylacrylonitrile (2c). EtOAc/PE 20:80; yield: 713
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1
mg, 57% (minor:major = 1:2.3); white solid, mp 174–175 °C; H NMR (400 MHz,
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CDCl3): major isomer: δ 7.65 (d, J = 8.8 Hz, 2H), 7.53–7.51 (m, 2H), 7.43 (t, J = 8.0 Hz,
2H), 7.02–6.96 (m, 3H), 4.76 (s, 2H), 3.85 (s, 3H); minor isomer: δ 7.29 (d, J = 7.6 Hz,
2H), 7.22 (d, J = 8.8 Hz, 2H), 7.14–7.10 (m, 2H), 7.07–7.05 (m, 1H), 6.79 (d, J = 8.8 Hz,
2H), 4.95 (s, 2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): major isomer: δ 161.4,
156.8, 134.23, 129.6, 129.4, 128.6, 128.2, 125.8, 122.6, 114.2, 81.3, 55.4; minor isomer:
δ 161.0, 157.7, 134.15, 130.4, 129.1, 128.1, 127.3, 126.8, 121.1, 114.1, 80.5, 55.3;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15N2O 251.1179, found 251.1177.
3-Amino-3-(4-fluorophenyl)-2-phenylacrylonitrile (2d). EtOAc/PE 20:80; yield: 845
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mg, 71%; yellow solid, mp 135–138 °C; H NMR (400 MHz, CDCl3) δ 7.69–7.66 (m,
2H), 7.51–7.49 (m, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.32–7.28 (m, 1H), 7.14 (t, J = 8.8 Hz,
2H), 4.81 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (d, JC–F = 249.4 Hz), 156.0,
133.7, 132.0 (d, JC–F = 3.3 Hz), 130.3 (d, JC–F = 8.6 Hz), 129.5, 128.6, 127.6, 122.1, 116.0
(d, JC–F = 21.7 Hz), 82.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H12FN2
239.0979, found 239.0977.
3-Amino-3-(4-chlorophenyl)-2-phenylacrylonitrile (2e).18 EtOAc/PE 20:80; yield: 916
mg, 72%; white solid, mp 150–153 °C; 1H NMR (400 MHz, CDCl3) δ 7.64–7.60 (m, 2H),
7.51–7.49 (m, 2H), 7.46–7.42 (m, 4H), 7.30 (tt, J = 7.6, 1.2 Hz, 7H), 4.79 (m, 2H);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H11ClN2Na 277.0503, found 277.0501.
3-Amino-2-phenyl-3-(4-(trifluoromethyl)phenyl)acrylonitrile (2f). EtOAc/PE 20:80;
yield: 980 mg, 68%; white solid, mp 147–148 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (d,
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J = 8.4 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.53–7.51 (m, 2H), 7.48–7.44 (m, 2H),
7.35–7.31 (m, 1H), 4.81 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.3, 139.4, 133.3,
132.5 (q, JC–F = 32.6 Hz), 129.6, 128.7, 128.6, 127.9, 126.0 (q, JC–F = 3.7 Hz), 123.7 (q,
JC–F = 270.8 Hz), 121.5, 83.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H11F3N2Na
311.0767, found 311.0767.
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3-Amino-2-phenyl-3-(m-tolyl)acrylonitrile (2g). EtOAc/PE 20:80; yield: 872 mg, 75%;
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yellow solid, mp 131–133 °C; H NMR (400 MHz, CDCl3) δ 7.53–7.47 (m, 4H),
7.45–7.41 (m, 2H), 7.37–7.33 (m, 1H), 7.31–7.27 (m, 2H), 4.78 (s, 2H), 2.42 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 157.2, 138.7, 136.0, 134.1, 131.4, 129.4, 128.8,
128.7, 128.6, 127.4, 125.2, 122.2, 81.7, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H15N2 235.1230, found 235.1230.
3-Amino-2-phenyl-3-(o-tolyl)acrylonitrile (2h).19 EtOAc/PE 20:80; yield: 948 mg, 81%;
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yellow oil; H NMR (400 MHz, CDCl3) δ 7.54–7.48 (m, 4H), 7.44 (t, J = 7.6 Hz, 2H),
7.38–7.34 (m, 1H), 7.31–7.27 (m, 2H), 4.77 (s, 2H), 2.42 (s, 3H); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C16H15N2 235.1230, found 235.1228.
3-Amino-2-phenylhex-2-enenitrile (2i). EtOAc/PE 10:90; yield: 717 mg, 77% (with a
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small amount of the other isomer); white solid, mp 58–59 °C; H NMR (400 MHz,
CDCl3) δ 7.39–7.37 (m, 4H), 7.25–7.22 (m, 1H), 4.67 (s, 2H), 2.54 (t, J = 7.8 Hz, 2H),
1.73 (sext, J = 7.6 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
158.8, 133.7, 129.3, 128.6, 127.1, 122.0, 80.9, 36.7, 21.6, 13.5; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C12H15N2 187.1230, found 187.1228.
3-Amino-3-phenyl-2-(p-tolyl)acrylonitrile (2j). CH2Cl2/PE 60:40; yield: 878 mg, 75%;
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white solid, mp 150–152 °C; H NMR (400 MHz, CDCl3) δ 7.70–7.68 (m, 2H),
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7.49–7.46 (m, 3H), 7.43–7.41 (m, 2H), 7.26–7.24 (m, 2H, overlapped with the peak of
chloroform), 4.74 (s, 2H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.6, 137.4,
136.1, 130.9, 130.5, 130.1, 128.9, 128.5, 128.0, 122.2, 82.0, 21.2; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C16H15N2 235.1230, found 235.1222.
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3-Amino-2-(4-methoxyphenyl)-3-phenylacrylonitrile (2k). CH2Cl2/PE 60:40; yield:
901 mg, 72% (minor:major = 1:7.1); yellow solid, mp 170–173 °C; 1H NMR (400 MHz,
CDCl3): major isomer: δ 7.70–7.67 (m, 2H), 7.48–7.43 (m, 5H), 6.99–6.95 (m, 2H), 4.68
(s, 2H), 3.83 (s, 3H); minor isomer: δ 7.36–7.33 (m, 1H), 7.28 (d, J = 4.4 Hz, 4H),
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6.92–6.88 (m, 2H), 6.66–6.64 (m, 2H), 4.89 (s, 2H), 3.72 (s, 3H); C{1H} NMR (100
MHz, CDCl3): major isomer: δ 158.9, 156.5, 136.0, 130.5, 130.1, 128.9, 128.0, 126.0,
122.3, 114.8, 81.6, 55.4; minor isomer: δ 157.9, 157.0, 135.1, 130.4, 130.0, 128.7, 126.1,
120.9, 113.7, 80.9, 55.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15N2O
251.1179, found 251.1177.
3-Amino-2-(4-chlorophenyl)-3-phenylacrylonitrile (2l). CH2Cl2/PE 60:40; yield: 840
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mg, 66% (with a small amount of the other isomer); yellow solid, mp 165–167 °C; H
NMR (400 MHz, CDCl3) δ 7.69–7.67 (m, 2H), 7.51–7.46 (m, 5H), 7.43–7.40 (m, 2H),
4.78 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.2, 135.7, 133.2, 132.5, 130.8,
130.0, 129.6, 129.0, 128.0, 121.7, 81.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H11ClN2Na 277.0503, found 277.0501.
3-Amino-2,3-bis(4-chlorophenyl)acrylonitrile (2m).15a EtOAc/PE 10:90; yield: 751 mg,
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52% (with a small amount of the other isomer); white solid, mp 179–183 °C; H NMR
(400 MHz, CDCl3) δ 7.64–7.61 (m, 2H), 7.47–7.41 (m, 6H), 4.78 (s, 2H); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H11Cl2N2 289.0294, found 289.0292.
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3-Amino-2,3-bis(4-bromophenyl)acrylonitrile (2n). EtOAc/PE 10:90; yield: 1474 mg,
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78%; yellow solid, mp 185–186 °C; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz,
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2H), 7.59–7.55 (m, 4H), 7.40 (d, J = 8.4 Hz, 2H), 4.76 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 156.0, 134.5, 132.7, 132.6, 132.3, 130.3, 129.6, 125.3, 121.5, 121.3, 81.6;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H11Br2N2 378.9263, found 378.9262.
3-Amino-3-phenyl-2-(3-(trifluoromethyl)phenyl)acrylonitrile (2o). CH2Cl2/PE 50:50;
yield: 850 mg, 59% (with a small amount of the other isomer); white solid, mp
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100–104 °C; H NMR (400 MHz, CDCl3): δ 7.44–7.39 (m, 1H), 7.35–7.31 (m, 2H),
7.29–7.26 (m, 3H, overlapped with the peak of chloroform), 7.21 (t, J = 7.6 Hz, 1H),
7.18–7.15 (m, 2H), 5.16 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): major isomer: δ
159.3, 134.8, 134.2, 132.0, 130.7, 130.5 (q, JC–F = 32.0 Hz), 129.1, 128.7, 128.6, 125.6 (q,
JC–F = 3.8 Hz), 123.8 (q, JC–F = 270.9 Hz), 122.4 (q, JC–F = 3.8 Hz), 120.1, 79.9; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C16H11F3N2Na 311.0767, found 311.0761.
3-Amino-2-(3-chlorophenyl)-3-phenylacrylonitrile (2p).20 EtOAc/PE 10:90; yield: 891
mg, 70% (minor:major = 1:12.6); yellow oil; 1H NMR (400 MHz, CDCl3): major isomer:
δ 7.66–7.63 (m, 2H), 7.53–7.51 (m, 2H), 7.48–7.43 (m, 4H), 7.34–7.30 (m, 1H), 4.76 (s,
2H); minor isomer: δ 7.28–7.22 (m, 4H, overlapped with the peak of chloroform),
7.16–7.07 (m, 3H), 7.00–7.6.98 (m, 2H), 4.94 (s, 2H); HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C15H11ClN2Na 277.0503, found 277.0501.
3-Amino-2-(2-chlorophenyl)-3-phenylacrylonitrile (2q). EtOAc/PE 10:90; yield: 967
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mg, 76% (minor:major = 1:5.5); white solid, mp 117–122 °C; H NMR (400 MHz,
CDCl3): major isomer: δ 7.74–7.72 (m, 2H), 7.52–7.45 (m, 5H), 7.37–7.30 (m, 2H), 4.50
(s, 2H); minor isomer: δ 7.29–7.28 (m, 2H), 7.23–7.18 (m, 4H), 7.09 (td, J = 7.2, 1.6 Hz,
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1H), 6.96 (td, J = 7.6, 0.8 Hz, 1H), 6.91–6.89 (m, 1H), 5.07 (s, 2H); 13C{1H} NMR (100
MHz, CDCl3): major isomer: δ 158.4, 135.2, 135.0, 132.55, 131.6, 130.8, 130.6, 130.0,
128.9, 128.1, 127.8, 121.1, 79.1; minor isomer: δ 159.9, 134.6, 133.7, 132.50, 130.2,
129.7, 128.7, 128.5, 128.4, 126.6, 78.5; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H11ClN2Na 277.0503, found 277.0501.
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3-Amino-2-(2,4-dichlorophenyl)-3-phenylacrylonitrile (2r). CH2Cl2/PE 40:60; yield:
1156 mg, 81% (minor:major = 1:1.8); white solid, mp 130–133 °C; 1H NMR (400 MHz,
CDCl3): major isomer: δ 7.36–7.31 (m, 2H, peaks of two isomers overlapped), 7.27–7.23
(m, 2H, overlapped with the peak of chloroform), 7.20–7.18 (m, 2H), 6.95 (dd, J = 8.4,
2.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.13 (s, 2H); minor isomer: δ 7.74–7.71 (m, 2H,),
7.55–7.44 (m, 5H), 7.36–7.31 (m, 1H, peaks of two isomers overlapped) 4.52 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3): major isomer: δ 160.3, 134.3, 133.8, 133.4, 131.0,
130.46, 129.5, 128.7, 128.3, 128.2, 127.0, 118.9, 78.0; minor isomer: δ 158.7, 135.9,
135.2, 135.0, 131.2, 130.49, 130.2, 129.0, 128.1, 120.7, 78.6; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C15H11Cl2N2 289.0294, found 289.0292.
3-Amino-2-(naphthalen-1-yl)-3-phenylacrylonitrile (2s). CH2Cl2/PE 50:50; yield: 838
mg, 58%; white solid, mp 188–190 °C; 1H NMR (400 MHz, CDCl3) δ 8.11–8.09 (m, 1H),
7.93–7.88 (m, 2H), 7.83–7.80 (m, 2H), 7.66–7.64 (m, 1H), 7.59–7.48 (m, 6H), 4.39 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.3, 135.5, 134.3, 131.1, 130.8, 130.2, 129.2,
129.1, 129.0, 128.8, 128.1, 127.0, 126.5, 126.1, 125.0, 122.1, 78.9; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C19H15N2 271.1230, found 271.1230.
(E)-3-Amino-3-phenyl-2-(pyridin-2-yl)acrylonitrile (2t). MeOH/CH2Cl2 2:98; yield:
796 mg, 72%; white solid, mp 112–115 °C; 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H),
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8.47–8.45 (m, 1H), 7.72–7.63 (m, 4H), 7.52–7.46 (m, 3H), 7.06–7.02 (m, 1H), 5.38 (s,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.2, 156.6, 146.7, 137.1, 136.8, 130.6, 128.8,
127.9, 121.7, 120.6, 119.0, 78.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H12N3
222.1026, found 222.1024.
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3-Amino-3-phenylacrylonitrile (2u).18 EtOAc/PE 30:70; yield: 375 mg, 52% (with a
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small amount of the other isomer); yellow solid, mp 81–84 °C; H NMR (400 MHz,
CDCl3) δ 7.52–7.40 (m, 5H), 5.00 (s, 2H), 4.24 (s, 1H); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C9H9N2 145.0760, found 145.0759.
2-(Amino(phenyl)methylene)octanenitrile (2v). Eluent: EtOAc/PE 5:95; yield: 672 mg,
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59% (minor:major = 1:1.8); yellow oil; H NMR (400 MHz, CDCl3): major isomer: δ
7.57–7.53 (m, 1H), 7.43–7.38 (m, 4H, peaks of two isomers overlapped), 4.53 (s, 2H),
1.97 (t, J = 7.6 Hz, 2H), 1.35–1.30 (m, 2H), 1.28–1.11 (m, 6H), 0.83 (t, J = 7.2 Hz, 3H);
minor isomer: δ 7.43–7.38 (m, 1H, peaks of two isomers overlapped), 7.35–7.31 (m, 4H),
4.39 (s, 2H), 2.15 (t, J = 7.6 Hz, 2H), 1.67–1.59 (m, 2H), 1.48–1.38 (m, 6H), 0.91 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): major isomer: δ 157.3, 135.5, 129.7,
128.68, 127.96, 121.1, 79.3, 31.5, 29.7, 28.4, 28.1, 22.56, 14.06; minor isomer: δ 156.1,
136.5, 130.0, 128.65, 128.01, 122.8, 80.3, 31.7, 29.0, 27.9, 27.8, 22.64, 14.12; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H20N2Na 251.1519, found 251.1519.
Ethyl (Z)-3-amino-2,3-diphenylacrylate (2w).21 EtOAc/PE 5:95; yield: 655 mg, 49%;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.19–7.11 (m, 5H), 7.06–7.97 (m, 5H), 4.17 (q,
J = 6.8 Hz, 2H), 1.21 (t, J = 6.8 Hz, 3H); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H18NO2 268.1332, found 268.1333.
(Z)-4-Amino-3-(2-bromophenyl)-4-phenylbut-3-en-2-one (2x). EtOAc/PE 5:95; yield:
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550 mg, 58%; yellow solid, mp 190–192 °C; 1H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H),
7.49 (d, J = 8.0 Hz, 1H), 7.20–7.18 (m, 2H), 7.16–7.06 (m, 5H), 7.03–6.98 (m, 1H), 5.56
(s, 1H), 1.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.0, 163.2, 142.4, 140.5,
134.8, 132.5, 128.6, 128.4, 127.3, 127.2, 109.1, 22.3; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H15BrNO 316.0332, found 316.0330.
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General Procedure for the Synthesis of Products 1. A solution of the enamine
substrate 2 (0.5 mmol) in CH2Cl2 (5 mL) was treated with iodine (152 mg, 0.6 mmol) and
DBU (190 mg, 1.25 mmol) in sequence, and then stirred at room temperature until the
disappearance of the substrate (monitored by TLC). Upon the completion of the reaction,
it was quenched with 5% Na2S2O3 (8 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic layer was dried over anhydrous Na2SO4, concentrated, and then
purified through silica gel column chromatography to afford the product 1.
2,3-Diphenyl-2H-azirine-2-carbonitrile (1a). 0.5 h; eluent: EtOAc/PE 10:90; yield: 100
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mg, 92% (0.5 mmol scale); 1.18 g, 90% (6 mmol scale); white solid, mp 42–43 °C; H
NMR (400 MHz, CDCl3) δ 7.95–7.93 (m, 2H), 7.74–7.71 (m, 1H), 7.64–7.61 (m, 2H),
7.40–7.32 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.1, 135.1, 134.2, 130.9, 129.9,
128.9, 128.7, 125.8, 119.9, 119.1, 29.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H10N2Na 241.0736, found 241.0745.
2-Phenyl-3-(p-tolyl)-2H-azirine-2-carbonitrile (1b). 0.5 h; eluent: EtOAc/PE 10:90;
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yield: 115 mg, 99%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.83–7.81 (m, 2H),
7.43–7.41 (m, 2H), 7.39–7.31 (m, 5H), 2.49 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
157.5, 146.5, 134.5, 130.9, 130.6, 128.8, 128.6, 125.8, 119.2, 117.0, 29.0, 22.1; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2Na 255.0893, found 255.0894.
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3-(4-Methoxyphenyl)-2-phenyl-2H-azirine-2-carbonitrile (1c). 0.5 h; eluent:
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EtOAc/PE 10:90; yield: 123 mg, 99%; white solid, mp 68–69 °C; H NMR (400 MHz,
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CDCl3) δ 7.88–7.86 (m, 2H), 7.38–7.31 (m, 5H), 7.10–7.08 (m, 2H), 3.91 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 164.9, 156.5, 134.6, 133.0, 128.7, 128.5, 125.7, 119.4, 115.4,
111.8, 55.8, 28.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2NaO 271.0842,
found 271.0839.
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3-(4-Fluorophenyl)-2-phenyl-2H-azirine-2-carbonitrile (1d). 0.5 h; eluent: EtOAc/PE
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10:90; yield: 95 mg, 81%; white solid, mp 58–59 °C; H NMR (400 MHz, CDCl3) δ
7.99–7.96 (m, 2H), 7.40–7.31 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.6 (d,
JC–F = 257.7 Hz), 157.1, 133.9, 133.4 (d, JC–F = 9.7 Hz), 128.9, 128.8, 125.7, 118.9, 117.6
(d, JC–F = 22.5 Hz), 116.2 (d, JC–F = 3.2 Hz), 29.3; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C15H9FN2Na 259.0642, found 259.0645.
3-(4-Chlorophenyl)-2-phenyl-2H-azirine-2-carbonitrile (1e). 0.5 h; eluent: EtOAc/PE
1
10:90; yield: 107 mg, 85%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.90–7.87 (m,
2H), 7.63–7.60 (m, 2H), 7.40–7.36 (m, 3H), 7.33–7.30 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 157.5, 141.8, 133.9, 131.9, 130.4, 128.92, 128.89, 125.8, 118.8, 118.4,
29.5; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H9ClN2Na 275.0346, found
275.0342.
2-Phenyl-3-(4-(trifluoromethyl)phenyl)-2H-azirine-2-carbonitrile (1f). 0.5 h; eluent:
1
EtOAc/PE 10:90; yield: 80 mg, 56%; colorless oil; H NMR (400 MHz, CDCl3) δ
13
8.10–8.08 (m, 2H), 7.91–7.89 (m, 2H), 7.41–7.38 (m, 3H), 7.33–7.31 (m, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 158.2, 136.3 (q, JC–F = 33.0 Hz), 133.5, 131.1, 129.1, 129.0,
126.8 (q, JC–F = 3.7 Hz), 125.8, 123.4, 123.1(q, JC–F = 271.5 Hz), 118.5, 29.9; HRMS
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(ESI-TOF) m/z: [M + H]+ calcd for C16H10F3N2 287.0791, found 287.0799.
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2-Phenyl-3-(m-tolyl)-2H-azirine-2-carbonitrile (1g). 1 h; eluent: EtOAc/PE 10:90;
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8
9
1
yield: 100 mg, 86%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.76–7.73 (m, 2H),
13
7.54–7.49 (m, 2H), 7.40–7.32 (m, 5H), 2.46 (m, 3H); C{1H} NMR (100 MHz, CDCl3)
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δ 158.0, 140.0, 135.9, 134.3, 131.2, 129.7, 128.8, 128.6, 128.0, 125.8, 119.7, 119.1, 29.1,
21.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2Na 255.0893, found
255.0896.
2-Phenyl-3-(o-tolyl)-2H-azirine-2-carbonitrile (1h). 1 h; eluent: EtOAc/PE 10:90; yield:
1
58 mg, 50%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.74–7.72 (m, 1H), 7.61–7.57
(m, 1H), 7.45–7.31 (m, 7H), 2.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.2,
142.5, 134.7, 134.6, 132.5, 131.6, 128.9, 128.6, 126.9, 125.7, 119.4, 118.7, 27.8, 20.1;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2Na 255.0893, found 255.0898.
2-Phenyl-3-propyl-2H-azirine-2-carbonitrile (1i). 2 h; eluent: EtOAc/PE 10:90; yield:
1
45 mg, 49%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.41–7.35 (m, 3H), 7.25–7.22
(m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 1.86 (sext, J = 7.6 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 134.5, 128.8, 128.4, 125.2, 119.3, 27.9, 27.5,
17.9, 13.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H12N2Na 207.0893, found
207.0899.
3-Phenyl-2-(p-tolyl)-2H-azirine-2-carbonitrile (1j). 0.5 h; eluent: EtOAc/PE 10:90;
1
yield: 109 mg, 94%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.94–7.92 (m, 2H),
7.73–7.69 (m, 1H), 7.64–7.60 (m, 2H), 7.23–7.16 (m, 4H), 2.35 (s, 3H); C{1H} NMR
13
(100 MHz, CDCl3) δ 158.3, 138.8, 134.9, 131.2, 130.7, 129.8, 129.5, 125.7, 120.1, 119.2,
29.1, 21.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2Na 255.0893, found
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255.0901.
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2-(4-Methoxyphenyl)-3-phenyl-2H-azirine-2-carbonitrile (1k). 0.5 h; eluent:
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8
9
1
EtOAc/PE 10:90; yield: 114 mg, 92%; colorless oil; H NMR (400 MHz, CDCl3) δ
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7.95–7.93 (m, 2H), 7.74–7.70 (m, 1H), 7.64–7.60 (m, 2H), 7.27–7.23 (m, 2H, overlapped
with the peak of chloroform), 6.91–6.87 (m, 2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.1, 158.7, 134.9, 130.7, 129.8, 127.2, 126.1, 120.3, 119.3, 114.3, 55.4, 29.0;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12N2NaO 271.0842, found 271.0848.
2-(4-Chlorophenyl)-3-phenyl-2H-azirine-2-carbonitrile (1l). 0.5 h; eluent: EtOAc/PE
1
10:90; yield: 120 mg, 95%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.94–7.92 (m,
2H), 7.76–7.72 (m, 1H), 7.66–7.62 (m, 2H), 7.36–7.33 (m, 2H), 7.28–7.24 (m, 3H,
overlapped with the peak of chloroform); 13C{1H} NMR (100 MHz, CDCl3) δ 158.0,
135.3, 134.9, 132.9, 130.9, 129.9, 129.1, 127.1, 119.6, 118.7, 28.7; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C15H9ClN2Na 275.0346, found 275.0348.
2,3-Bis(4-chlorophenyl)-2H-azirine-2-carbonitrile (1m).15a 0.5 h; eluent: EtOAc/PE
1
10:90; yield: 132 mg, 92%; white solid, mp 126–127 °C; H NMR (400 MHz, CDCl3) δ
13
7.89–7.86 (m, 2H), 7.64–7.61 (m, 2H), 7.37–7.34 (m, 2H), 7.26–7.22 (m, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 157.4, 142.0, 135.0, 132.5, 131.9, 130.5, 129.1, 127.0, 118.4,
118.0, 28.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H8Cl2N2Na 308.9957, found
308.9968.
2,3-Bis(4-bromophenyl)-2H-azirine-2-carbonitrile (1n). 0.5 h; eluent: EtOAc/PE 10:90;
yield: 158 mg, 84%; white solid, mp 140–141 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s,
13
4H), 7.52–7.49 (m, 2H), 7.19–7.16 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 157.6,
133.5, 133.1, 132.1, 132.0, 130.8, 127.3, 123.2, 118.4, 29.0; HRMS (ESI-TOF) m/z: [M
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+ Na]+ calcd for C15H8Br2N2Na 398.8926, found 398.8926.
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3-Phenyl-2-(3-(trifluoromethyl)phenyl)-2H-azirine-2-carbonitrile (1o). 0.5 h; eluent:
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1
EtOAc/PE 10:90; yield: 120 mg, 84%; white solid, mp 29–30 °C; H NMR (400 MHz,
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CDCl3) δ 7.96–7.94 (m, 2H), 7.78–7.74 (m, 1H), 7.67–7.62 (m, 3H), 7.57–7.50 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 135.6, 135.5, 131.5 (q, JC–F = 32.6 Hz), 131.0,
130.0, 129.5, 129.0, 125.5 (q, JC–F = 3.7 Hz), 123.6 (q, JC–F = 270.9 Hz), 122.4 (q, JC–F
=
3.8 Hz), 119.3, 118.4, 28.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H9F3N2Na
309.0610, found 309.0607.
2-(3-Chlorophenyl)-3-phenyl-2H-azirine-2-carbonitrile (1p). 0.5 h; eluent: EtOAc/PE
1
10:90; yield: 114 mg, 90%; colorless oil; H NMR (400 MHz, CDCl3) δ 7.95–7.92 (m,
2H), 7.77–7.73 (m, 1H), 7.66–7.63 (m, 2H), 7.34–7.31 (m, 2H), 7.30–7.24 (m, 2H,
overlapped with the peak of chloroform); 13C{1H} NMR (100 MHz, CDCl3) δ 157.8,
136.5, 135.3, 135.1, 131.0, 130.1, 130.0, 129.0, 125.8, 124.0, 119.4, 118.6, 28.7; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H9ClN2Na 275.0346, found 275.0350.
2-(2-Chlorophenyl)-3-phenyl-2H-azirine-2-carbonitrile (1q). 0.5 h; eluent: EtOAc/PE
1
10:90; yield: 119 mg, 95%; white solid, mp 71–72 °C; H NMR (400 MHz, CDCl3) δ
8.11–8.09 (m, 2H), 7.74–7.70 (m, 1H), 7.65–7.61 (m, 2H), 7.46–7.42 (m, 2H), 7.35–7.27
13
(m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 164.4, 135.1, 133.7, 132.0, 130.8, 130.6,
130.1, 129.7, 128.5, 127.5, 120.5, 119.2, 27.3; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C15H9ClN2Na 275.0346, found 275.0352.
2-(2,4-Dichlorophenyl)-3-phenyl-2H-azirine-2-carbonitrile (1r). 0.5 h; eluent:
1
EtOAc/PE 10:90; yield: 137 mg, 96%; white solid, mp 69–70 °C; H NMR (400 MHz,
CDCl3) δ 8.09–8.06 (m, 2H), 7.76–7.72 (m, 1H), 7.66–7.63 (m, 2H), 7.47 (d, J = 2.0 Hz,
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1H), 7.37–7.35 (m, 1H), 7.28–7.25 (m, 1H, overlapped with the peak of chloroform);
13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 136.0, 135.3, 134.4, 130.9, 130.7, 129.9,
129.8, 129.4, 127.9, 120.1, 118.8, 26.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H8Cl2N2Na 308.9957, found 308.9945.
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2-(Naphthalen-1-yl)-3-phenyl-2H-azirine-2-carbonitrile (1s). 0.5 h; eluent: EtOAc/PE
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10:90; yield: 110 mg, 82%; white solid, mp 150–151 °C; H NMR (400 MHz, CDCl3) δ
8.79 (d, J = 8.4 Hz, 1H), 8.08–8.06 (m, 2H), 7.93–7.87 (m, 2H), 7.78–7.70 (m, 2H),
7.66–7.59 (m, 3H), 7.50–7.48 (m, 1H), 7.40–7.37 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 163.9, 134.9, 133.9, 131.3, 130.5, 130.3, 130.1, 129.8, 129.0, 127.4, 126.6,
125.7, 125.2, 123.9, 121.1, 120.5, 27.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H12N2Na 291.0893, found 291.0893.
3-Phenyl-2-(pyridin-2-yl)-2H-azirine-2-carbonitrile (1t). 0.5 h; eluent: CH2Cl2/PE
65:35; yield: 68 mg, 62%; colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.56–8.55 (m, 1H),
7.97–7.94 (m, 2H), 7.75–7.70 (m, 2H), 7.64–6.60 (m, 2H), 7.51–7.49 (m, 1H), 7.28–7.25
13
(m, 1H, overlapped with the peak of chloroform); C{1H} NMR (100 MHz, CDCl3) δ
157.1, 153.6, 149.8, 136.9, 135.0, 131.1, 129.7, 123.3, 120.8, 119.8, 118.8, 30.9; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H10N3 220.0869, found 220.0866.
(Z)-3-Amino-2-iodo-3-phenylacrylonitrile (1u'). 0.5 h; eluent: EtOAc/PE 20:80; yield:
107 mg, 80%; white solid, mp 112–113 °C; 1H NMR (400 MHz, CDCl3) δ 7.58–7.54 (m,
13
2H), 7.51–7.42 (m, 3H), 5.19 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 161.2, 133.0,
131.1, 129.0, 127.9, 120.5, 24.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C9H7IN2Na
292.9546, found 292.9549.
2-Hexyl-3-phenyl-2H-azirine-2-carbonitrile (1v). Eluent: EtOAc/PE 5:95; yield: 66 mg,
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58%; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.91–7.89 (m, 2H), 7.73–7.69 (m, 1H),
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7.65–7.61 (m, 2H), 1.96–1.82 (m, 2H), 1.58–1.46 (m, 2H), 1.40–1.33 (m, 2H), 1.32–1.22
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(m, 4H), 0.89–0.86 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 164.7, 134.6, 130.2,
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129.7, 121.6, 120.8, 33.7, 31.5, 28.7, 26.8, 26.2, 22.5, 14.0; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C15H18N2Na 249.1362, found 249.1342.
Ethyl 2,3-diphenyl-2H-azirine-2-carboxylate (1w). 0.5 h; eluent: EtOAc/PE 10:90;
1
yield: 90 mg, 68%; white solid, mp 42–43 °C; H NMR (400 MHz, CDCl3) δ 7.97–7.95
(m, 2H), 7.66–7.64 (m, 1H), 7.62–7.58 (m, 2H), 7.53–7.51 (m, 2H), 7.37–7.30 (m, 3H),
13
4.26 (q, J = 6.8 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ
171.2, 160.8, 136.4, 133.9, 130.4, 129.5, 128.2, 127.7, 122.1, 61.7, 41.2, 14.2; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H15NNaO2 288.0995, found 288.1003.
1-(2-(2-Bromophenyl)-3-phenyl-2H-azirin-2-yl)ethan-1-one (1x). 0.5 h; eluent:
1
EtOAc/PE 7:93; yield: 140 mg, 89%; white solid, mp 85–86 °C; H NMR (400 MHz,
CDCl3) δ 7.67–7.65 (m, 2H), 7.54–7.52 (m, 1H), 7.45–7.36 (m, 3H), 7.32–7.28 (m, 2H,
overlapped with the peak of chloroform), 7.19–7.15 (m, 1H), 2.69 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 200.2, 165.9, 139.0, 137.6, 132.7, 131.9, 129.63, 129.62, 128.7,
128.0, 127.9, 124.6, 46.8, 12.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C16H12BrNNaO 335.9994, found 335.9990.
Preparation of 2-Phenyl-1H-indole-3-carbonitrile (3a).2a A reaction mixture of
compound 1a (109 mg, 0.5 mmol) and Pd(MeCN)2Cl2 (26 mg, 0.1 mmol) in o-xylene (5
mL) in a dry sealed tube was heated to 140 °C under a nitrogen atmosphere for 2 h. After
cooling to room temperature, it was quenched with H2O (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4,
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concentrated, and then purified through silica gel column chromatography to afford
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1H-indole 3a. Eluent: EtOAc/PE 20:80; yield: 71 mg, 65%; white solid, mp 247–248 °C
7
8
9
1
(lit.22 mp 248-249 ºC); H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.91–7.88 (m, 2H),
7.79–7.77 (m, 1H), 7.57–7.46 (m, 4H), 7.36–7.29 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 144.8, 135.0, 130.1, 129.5, 129.4, 128.9, 126.9, 124.4, 122.5, 119.6, 116.9,
111.7, 84.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H10N2Na 241.0736, found
241.0732.
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. Associated Content
Supporting Information
Copies of NMR spectra of compounds 1, 2 and 3a (PDF), and X-ray structure and data of
compound 1n (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
. Author Information
Corresponding Authors
*E-mail: wenquan_yu@zzu.edu.cn
*E-mail: changjunbiao@zzu.edu.cn
Notes
The authors declare no competing financial interest.
. Acknowledgements
We thank the National Natural Science Foundation of China (No. 81773570 and
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81330075) and the Outstanding Young Talent Research Fund of Zhengzhou University
(No. 1521316004) for financial support.
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. References
1. (a) Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.; de los Santos, J. M.
2H-Azirines as Synthetic Tools in Organic Chemistry. Eur. J. Org. Chem. 2001,
2401-2414; (b) Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.; de los Santos, J.
M. Preparation, Properties and Synthetic Applications of 2H-Azirines a Review. J. Org.
Prep. Proc. Int. 2002, 34, 219-269; (c) Padwa, A. Cycloaddition and Cyclization
Chemistry of 2H-Azirines. Adv. Heterocycl. Chem. 2010, 99, 1-31; (d) Khlebnikov, A. F.;
Novikov, M. S. Recent Advances in 2H-Azirine Chemistry. Tetrahedron 2013, 69,
3363-3401, and references cited therein.
2. (a) Isomura, K.; Uto, K.; Taniguchi, H. Palladium(II)-catalysed Formation of Indoles
from 2,2-Diphenyl-2H-azirine. J. Chem. Soc., Chem. Commun. 1977, 664-665; (b) Chiba,
S.; Hattori, G.; Narasaka, K. Rh(II)-Catalyzed Isomerization of 2-Aryl-2H-Azirines to
2,3-Disubstituted Indoles. Chem. Lett. 2007, 36, 52-53; (c) Jana, S.; Clements, M. D.;
Sharp, B. K.; Zheng, N. Fe(II)-Catalyzed Amination of Aromatic C-H Bonds via Ring
Opening of 2H-Azirines: Synthesis of 2,3-Disubstituted Indoles. Org. Lett. 2010, 12,
3736-3739; (d) Novikov, M. S.; Khlebnikov, A. F.; Rostovskii, N. V.; Tcyrulnikov, S.;
Suhanova, A. A.; Zavyalov, K. V.; Yufit, D. S. Pseudopericyclic 1,5- versus Pericyclic
1,4- and 1,6-Electrocyclization in Electron-Poor 4-Aryl-2-azabuta-1,3-dienes: Indole
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Synthesis from 2H-Azirines and Diazo Compounds. J. Org. Chem. 2015, 80, 18-29; (e)
Thangaraj, M.; Bhojgude, S. S.; Jain, S.; Gonnade, R. G.; Biju, A. T. Selective Synthesis
of N-Unsubstituted and N-Arylindoles by the Reaction of Arynes with Azirines. J. Org.
Chem. 2016, 81, 8604-8611.
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