Redox-neutral photocatalytic cyanomethylation/cyclization cascade of olefinic amides: Access to cyanomethylated benzoxazines

Article abstract of DOI:10.1016/j.tet.2019.130716

A visible-light-induced photocatalytic cyanomethyl radical addition/intramolecular cyclization cascade reaction of olefinic amides has been developed under mild conditions. This reaction provides a novel method for the synthesis of various cyanomethyl-con

Full text of DOI:10.1016/j.tet.2019.130716

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Redox-neutral photocatalytic cyanomethylation/cyclization cascade of olefinic amides:
Access to cyanomethylated benzoxazines
Liang Liu, Yan-Hong He, Zhi Guan
PII:
S0040-4020(19)31096-8
https://doi.org/10.1016/j.tet.2019.130716
TET 130716
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 August 2019
Revised Date: 16 October 2019
Accepted Date: 18 October 2019
Please cite this article as: Liu L, He Y-H, Guan Z, Redox-neutral photocatalytic cyanomethylation/
cyclization cascade of olefinic amides: Access to cyanomethylated benzoxazines, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.130716.
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Graphical Abstract

Redox-neutral photocatalytic cyanomethylation/cyclization
cascade of olefinic amides: access to cyanomethylated
benzoxazines
Liang Liu, Yan-Hong He*, and Zhi Guan*
Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education, School of Chemistry
and Chemical Engineering, Southwest University, Chongqing 400715, China
E-mails: heyh@swu.edu.cn (for Y.-H. He); guanzhi@swu.edu.cn (for Z. Guan)
Abstract: A visible-light-induced photocatalytic cyanomethyl radical addition/intramolecular
cyclization cascade reaction of olefinic amides has been developed under mild conditions. This
reaction provides a novel method for the synthesis of various cyanomethyl-containing
benzoxazines , which are useful pharmaceutical framework. The method exhibits good functional
group tolerance and a wide range of substrate scope.
Keywords: visible-light; radical addition; cyclization cascade; cyanomethyl-containing
benzoxazines
1. Introduction
Benzoxazines are a class of important compounds containing a nitrogen and oxygen
heterocyclic skeleton, which are widely found in pharmaceutical and biologically related
products.1 For example, anticonvulsant (I),2 fungicides (II),3 hypolipidemic active agent (III),4
and cetilistat (IV)5 all contain this versatile framework (Fig. 1). Moreover, benzoxazines are
also useful synthetic intermediates in organic synthesis. Thus, the study of benzoxazines has
attracted great interest. In addition, cyano group is also found in natural products, dyes and
pharmaceuticals.6 Nitriles can be converted to different types of compounds such as
carboxylic acids, amides, esters, amidines, aldehydes, ketones and tetrazoles.7 Based on the
importance of benzoxazines and nitriles, we deem that it would be intriguing to introduce the
1

versatile synthetic unit cyano group into benzoxazine to construct highly functional drug-like
molecules. Studies on the synthesis of such compounds would enrich the current benzoxazine
chemistry.
Fig. 1 Representative examples of benzoxazines.
Benzoxazines are typically synthesized by condensation of 2-aminobenzyl alcohols with
aldehydes,8 or the cyclization of acetylenic amides,9 however, these methods generally have
some disadvantages such as harsh reaction conditions and narrow substrate scope.10 A number
of strategies have been developed for the construction of various functionalized benzoxazine
derivatives based on electrophilic cyclization of olefinic amides with halonium ions and even
free radicals.11-12 Recently, visible light catalyzed free radical addition to olefinic amides
followed by intramolecular cyclization has led to the efficient synthesis of benzoxazines
under mild conditions. For example, Xiao's group reported the oxytrifluoromethylation of
olefinic amides by photocatalysis to synthesize CF3-containing benzoxazines.12a Fu's group
demonstrated visible-light-mediated oxydifluoromethylation of olefinic amides with
difluoromethyl sulfones for the synthesis CF2H-containing benzoxazines and oxazolines.13
There are very few studies on the synthesis of cyanomethylated benzoxazines. To the best
of our knowledge, only Ji's group has so far reported two examples of the synthesis of
benzoxazines. One is a copper-catalyzed reaction of olefinic amides with acetonitrile to
access cyanomethylated benzoxazines using stoichiometric peroxide at 140 °C.14 The other is
a palladium-catalyzed reaction of olefinic amides with bromoacetonitrile to form
cyanomethylated benzoxazines at a high temperature of 110 °C in the presence of a ligand
and Ag2CO3.15 Therefore, it is still highly desirable to find mild methods for the synthesis of
this type of compounds.
2

In light of the previous research, we designed a mild cascade reaction to synthesize
cyanomethylated benzoxazines, which includes photocatalytic formation of cyanomethyl
radical from bromoacetonitrile, addition of cyanomethyl radical to olefin amide, and
intramolecular cyclization. This strategy avoids stoichiometric peroxides and high
temperatures.
2. Results and discussion
The study was initiated with N-(2-(prop-1-en-2-yl)phenyl) benzamide (1a) and
bromoacetonitrile (2) as model substrates (1a/2 = 1:3, molar ratio). In the presence of
fac-Ir(ppy)3 (3% mol) as a photocatalyst and Na2CO3 (2.0 equiv) as a base in degassed dry
CH3CN under 23 W compact fluorescent lamp (CFL) irradiation for 12 h at room temperature,
the desired product 3a was isolated in 59% yield (Table 1, entry 1). When 9 W blue LEDs
were used instead of 23 W CFL, the reaction yield increased to 68% (Table 1, entry 2), so we
chose 9 W blue LEDs for subsequent experiments. In order to further improve the reaction
efficiency, the reaction conditions were optimized by studying various parameters such as
photocatalyst, solvent, base and molar ratio of substrates. Firstly, when other commonly used
photocatalysts such as [Ir(dtbbpy)(ppy)2][PF6] (E*red IrIII/IrIV = -0.89 V vs. SCE in CH3CN),16
Ru(bpy)3Cl2·6H2O (E*red RuII/RuIII = -0.81 V vs. SCE in CH3CN),16 Rose Bengal (E*red
=
-0.99 V vs. SCE in CH3CN)17 and Eosin Y (E*red = -1.06 V vs. SCE in CH3CN)18 were used,
no catalytic activity was observed for the reaction (Table 1, entries 3-6). A possible
explanation is that the reduction potentials of the excited state of these photocatalysts are
higher than the reduction potential of bromoacetonitrile 2 (Ered = -1.46 V vs. SCE in CH3CN)
( Fig. S4), so they cannot reduce 2. In contrast, excited fac-Ir(ppy)3 (E*red = -1.73 V vs. SCE
in CH3CN),16 has a lower reduction potential than bromoacetonitrile 2, so it can reduce 2 to
allow the reaction to proceed. Next, several bases such as K2CO3, K2HPO4, KOAc, Et3N,
DABCO and 2,6-Lutidine were examined (Table 1, entries 7−12). To our delight, the yield of
3a was increased to 73% by using KOAc as a base (Table 1, entry 9). Then, we investigated
other solvents such as THF, DMF, DMSO, EtOH, and acetone, but none of them is better than
acetonitrile (Table 1, entries 13–17).
3

Control experiments showed that photocatalyst and visible light irradiation are
indispensable for the reaction (Table 1, entries 18–19). Moreover, when the reaction was
performed in air instead of argon, the yield of 3a dropped to 32% (Table 1, entry 20),
indicating that the presence of oxygen is detrimental to the reaction. When the reaction was
carried out in the absence of a base, only 32% yield of 3a was isolated, and most of 1a was
recovered (Table 1, entry 21), suggesting that the addition of the base indeed promotes the
reaction. Finally, we explored the effect of the amounts of 2a, photosensitizer and base on the
reaction, and found that when their amounts were reduced to 2.0 equiv, 2 mol%, 1.5 equiv,
respectively, the reaction gave a satisfactory yield of 75% (Table 1, entry 22). Therefore, the
optimized reaction conditions include: 1a (1.0 equiv), 2 (2.0 equiv), KOAc (1.5 equiv), 2 mol%
fac-Ir(ppy)3, 9 W blue LED irradiation, and CH3CN as a solvent.
Table 1. Optimization of reaction conditions.a
Entry
1c
2
Photocatalyst
fac-Ir(ppy)3
Base
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Yieldb (%)
59
68
0
fac-Ir(ppy)3
3
[Ir(dtbbpy)(ppy)2][PF6]
Ru(bpy)3Cl2·6H2O
Rose Bengal
Eosin Y
4
0
5
0
6
0
7
fac-Ir(ppy)3
58
66
73
Trace
46
17
50
23
33
Trace
8
fac-Ir(ppy)3
K2HPO4
KOAc
9
fac-Ir(ppy)3
10
11
12
13
14
15
16
fac-Ir(ppy)3
Et3N
fac-Ir(ppy)3
DABCO
2,6-Lutidine
KOAc
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
KOAc
DMF
fac-Ir(ppy)3
KOAc
DMSO
EtOH
fac-Ir(ppy)3
KOAc
4

17
18
19d
20e
21
fac-Ir(ppy)3
None
KOAc
KOAc
KOAc
KOAc
-
Acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
0
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
0
32
32
75
22f
KOAc
aUnless otherwise noted, reaction conditions: the mixture of 1a (1.0 equiv, 0.2 mmol), 2 (3.0
equiv, 0.6 mmol), photocatalyst (3 mol%) and base (2.0 equiv, 0.4 mmol) in degassed dry
solvent (1 mL) was irradiated by 9 W blue LEDs under Ar atmosphere at RT for 12 h.
bIsolated yield after flash chromatography. cUnder 23 W CFL irradiation. dIn the dark. eUnder
air atmosphere. f2 (2.0 equiv), fac-Ir(ppy)3 (2 mol%), KOAc (1.5 equiv).
With the optimized reaction conditions in hand, we investigated the scope of olefinic
amides for this visible-light-induced photocatalytic cyanomethylation/cyclization cascade
reaction (Table 2). First, various electron-donating or electron-withdrawing groups such as
Me, Et, MeO, EtO, F, Cl, Br, I, CF3 at the para-position of the benzamide unit were tolerated,
and led to desired products in good yields (3b−3j). However, when the para- position was
substituted by strong electron-withdrawing substituent NO2, the corresponding product cannot
be obtained and the substrate was completely recovered (3k). The yield of the corresponding
product lowered due to the steric hindrance effect when the ortho- position of the benzamide
moiety was substituted (3l vs 3b). In addition, the substrate bearing a meta-substituent
showed good reactivity (3m). Both 2,4-disubstituted and 3,4-disubstituted, as well as
3,4,5-trisubstituted benzamide moiety were suitable to the reaction well, giving moderate
yields (3n-3p). Furthermore, heteroarylamides and naphthylamides such as 1q and 1r also
reacted smoothly, leading to the desired products 3q and 3r in yields of 63% and 52%,
respectively. To our delight, the aliphatic amides 1s and 1t were also transformed into the
corresponding products in 76% and 66% yields, respectively (3s and 3t). Moreover, the
olefinic amide bearing an aryl group at α position of the styrene unit also worked well, giving
the corresponding product in 66% yield (3u). Olefinic amides with alkyl substituent on the
styrene unit also participated in the reaction smoothly under the optimal conditions, and the
target products were obtained with satisfactory yields (3v-3x). Considering the bioactive
5

structures shown in Fig. 1, similar substrates bearing Cl or Br on the phenyl ring of the
styrene unit were examined, and the corresponding products (3y and 3z) were obtained in
moderate yields. Moreover, besides bromoacetonitrile, we have explored bromopropionitrile,
chloroacetonitrile and trifluoromethanesulfonyl chloride as free radical precursors, but none
of them reacted with 1a to form the corresponding products.
Table 2. Scope of substrates.a,b
aReaction conditions: a mixture of 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv), KOAc
(0.3 mmol, 1.5 equiv), and fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) in degassed dry CH3CN (1.0
b
mL) was irradiated with 9 W blue LEDs under Ar atmosphere at RT for 10-24 h. Isolated
yield.
6

In order to explore the mechanism of the reaction, some control experiments were
performed (Scheme 1). To verify whether the reaction involves a free radical process, the
effects of some commonly used free radical scavengers on the reaction were investigated.
When the radical scavengers TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and BHT
(2,6-di-tert-butyl-4-methylphenol) were separately added to the reaction system, the reaction
was remarkably suppressed without obtaining the desired product. When the radical
scavenger 1,1-diphenylethene was used, the formation of 3a was completely inhibited, but 4a
was isolated in 63% yield. The above experimental results indicated that the reaction may
undergo a free radical process and involve the cyanomethyl radical. Subsequently, the light
on/off experiments were performed to investigate the effect of photo-irradiation. The results
showed that continuous irradiation of visible light is indispensable, indicating that there may
be no free radical chain propagation process (Fig. 2a). In addition, the fluorescence
quenching experiment was carried out and it was found that 2 could significantly quench the
excited state of fac-Ir(ppy)3, while the quenching effect of 1a was not obvious, indicating that
2 may be involved in the oxidation process of the excited state fac-Ir(ppy)3 (Fig. 2b-d).
Finally, as described above, the results of cyclic voltammetry measurements suggested that 2
(Ered = -1.46 V vs. SCE in CH3CN) (Fig. S4) can be reduced by excited fac-Ir(ppy)3 (E*red =
-1.73 V vs. SCE in CH3CN). This further illustrated the possibility that the reaction is initiated
by cyanomethyl radical, which is generated from 2 via its single-electron-transfer (SET)
reduction by excited photocatalyst.
Scheme 1. Control experiments.
7

Fig. 2 (a) Light on/off experiment. (b) Quenching of fac-Ir(ppy)3 fluorescence emission in the
presence of 1a. (c) Quenching of fac-Ir(ppy)3 fluorescence emission in the presence of 2. (d)
Stern-Volmer plots of fac-Ir(ppy)3 with quenchers 1a and 2.
8

Based on the above control experimental results and related literature reports,10-12
a
plausible reaction mechanism was proposed (Scheme 2). First, the [fac-Ir(III)(ppy)3] is excited
into [fac-Ir(III)(ppy)3*] under irradiation of visible light, which is quenched with
+
bromoacetonitrile 2 to [fac-Ir(IV)(ppy)3 ] complex by a SET process, while producing the
cyanomethyl radical. Subsequently, the cyanomethyl radical attacks the C-C double bond of
olefinic amide 1a to generate the radical intermediate I. Then, I is oxidized by
+
[fac-Ir(IV)(ppy)3 ] to give the carbocation II and [fac-Ir(III)(ppy)3]. Finally, the intermediate II
undergoes a cyclization reaction followed by deprotonation with the aid of a base to give the
target product 3a.
Scheme 2. Proposed reaction mechanism.
3. Conclusion
In
summary,
we
have
successfully
developed
a
visible-light-induced
cyanomethylation/cyclization tandem reaction of olefinic amides with readily available
bromoacetonitrile for the synthesis of various cyanomethyl-containing benzoxazines. This
redox-neutral photocatalytic reaction completes the synthesis of C-C and C-O bonds in one
9

pot without using any oxidizing agent. The reaction has the notable features of mild reaction
conditions, simple operation, good functional group compatibility and wide range of substrate
scope.
4. Experimental Section
4.1. General experimental details
Unless otherwise noted, materials obtained from commercial suppliers were used directly
without further purification. Flash column chromatography was performed using 200-300
1
mesh silica gel at increased pressure. All H NMR spectra and 13C NMR spectra were
respectively recorded on 600 or 400 MHz and 150 MHz or 100 NMR spectrometers using
deuterochloroform (CDCl3) as solvent at room temperature , all chemical shifts are given as δ
value (ppm) with reference to tetramethylsilane (TMS) as an internal standard. The peak
patterns are indicated as follows (s = singlet; d = doublet; t = triplet; m = multiplet; q =
quartet). The coupling constants, J, are reported in Hertz (Hz). High-resolution mass spectra
were obtained by using ESI ionization sources (Varian 7.0 T FTICR-MS). Fluorescence
emission was determined by fluorescence spectrophotometer (F-320 Gangdong, Tianjin).
Melting points were taken on a WPX-4 apparatus and were uncorrected (Yice instrument
equipment Co Ltd, Shanghai). The starting materials 1 were prepared according to the method
reported in the literature.19
4.2. General procedure for the preparation of products 3
A round bottomed flask equipped with a magnetic stirrer bar was charged with fac-Ir(ppy)3
(2 mol %), olefinic amide 1 (0.2 mmol), KOAc (0.3 mmol) and bromoacetonitrile 2 (0.4
mmol). The flask was evacuated and backfilled with Ar (three times). Then degassed dry
CH3CN (1 mL) was injected under Ar. The resultant mixture was stirred at room temperature
under irradiation of 9 W blue LEDs. The reaction was monitored by thin-layer
chromatography (TLC), and the reaction was quenched with water (5 mL) after completion of
the reaction. The resulting mixture was extracted with ethyl acetate (5 mL × 3). The organic
layer was combined, and dried with anhydrous Na2SO4. The solvent was removed in vacuo,
10

and the residue was purified by flash column chromatography (petroleum ether/EtOAc = 5:1
to 10:1, v/v) to give the desired product 3.
5. Spectral Data
5.1. 3-(4-methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3a):20
Yellow oil; Yield = 75%; 1H NMR (600MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 2H),
7.53-7.50 (m, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36-7.32 (m, 2H), 7.25-7.22 (m, 1H), 7.07 (d, J =
13
7.4 Hz, 1H), 2.53-2.44 (m, 2H), 2.41-2.32 (m, 2H), 1.70 (s, 3H) ppm; C NMR (150 MHz,
CDCl3) δ 155.9, 138.8, 132.2, 131.7, 129.3, 128.4, 127.8, 127.2, 127.1, 125.8, 122.4, 119.2,
79.6, 77.3, 77.1, 76.8, 36.7, 28.1, 12.4 ppm.
5.2. 3-(4-methyl-2-(p-tolyl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3b):
1
Yellow oil; Yield = 76%; H NMR (600MHz, CDCl3) δ 8.02 (d, J = 8.1 Hz, 2H),
7.36-7.31 (m, 2H), 7.28-7.25 (m, 2H), 7.23-7.20 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 2.51-2.44
13
(m, 2H), 2.42 (s, 3H), 2.40-2.33 (m, 2H), 1.69 (s, 3H) ppm; C NMR (150 MHz, CDCl3) δ
156.1, 142.3, 138.9, 129.4, 129.3, 129.1, 127.9, 127.2, 126.9, 125.7, 122.3, 119.2, 79.5, 77.2,
77.0, 76.8, 36.7, 28.0, 21.6, 12.4 ppm. HRMS (ESI) m/z 313.1307 (M + Na+), Cal.
C19H18N2NaO+, 313.1311.
5.3. 3-(2-(4-ethylphenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3c):20
1
Yellow oil; Yield = 67%; H NMR (600MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 2H),
7.34-7.28 (m, 4H), 7.24-7.19 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H),
13
2.52-2.42 (m, 2H), 2.42-2.31 (m, 2H), 1.69 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H) ppm; C NMR
(150 MHz, CDCl3) δ 156.1, 148.5, 139.0, 129.8, 129.2, 128.1, 128.0, 127.3, 126.9, 125.8,
122.3, 119.3, 79.4, 77.3, 77.0, 76.8, 36.8, 28.9, 28.0, 15.3, 12.4 ppm.
5.4. 3-(2-(4-methoxyphenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3d):20
1
Yellow oil;BYield = 62%; H NMR (600MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H),
7.36-7.29 (m, 2H), 7.23-7.17 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 3.87
(s, 3H), 2.53-2.42 (m, 2H), 2.42-2.31 (m, 2H), 1.68 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ 162.6, 155.8, 139.1, 129.7, 129.2, 127.2, 126.7, 125.6, 124.7, 122.3, 119.3, 113.8, 79.4, 77.2,
77.0, 76.8, 55.4, 36.7, 28.0, 12.4 ppm.
11

5.5. 3-(2-(4-ethoxyphenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3e):
1
Yellow oil; Yield = 55%; H NMR (600MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 2H),
7.33-7.31 (m, 2H), 7.21-7.18 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 4.10
(q, J = 7.0 Hz, 2H), 2.52-2.41 (m, 2H), 2.41-2.31 (m, 2H), 1.68 (s, 3H), 1.44 (t, J = 7.0 Hz,
3H) ppm; 13C NMR (150 MHz, CDCl3) δ 162.0, 155.9, 139.2, 129.7, 129.2, 127.1, 126.6,
125.5, 124.5, 122.3, 119.3, 114.2, 79.3, 77.2, 77.0, 76.8, 63.7, 36.7, 28.0, 14.7, 12.4 ppm.
+
HRMS (ESI) m/z 343.1420 (M + Na+), Cal. C20H20N2NaO2 , 343.1417.
5.6. 3-(2-(4-fluorophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3f):20
Yellow oil; Yield = 74%; 1H NMR (600MHz, CDCl3) δ 8.15-8.13 (m, 2H), 7.37-7.31 (m,
2H), 7.25-7.22 (m, 1H), 7.13 (t, J = 8.6 Hz, 2H), 7.07 (d, J = 7.7 Hz, 1H), 2.51-2.43 (m, 2H),
2.42-2.32 (m, 2H), 1.70 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 165.1 (d, J = 252.5 Hz),
155.0, 138.7, 130.1 (d, J = 8.9 Hz), 129.4, 128.5 (d, J = 2.7 Hz), 127.2, 127.1, 125.8, 122.4,
119.1, 115.5 (d, J = 21.9 Hz), 79.8, 77.2, 77.0, 76.8, 36.7, 28.2, 12.4 ppm.
5.7. 3-(2-(4-chlorophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3g):20
Yellow oil; Yield = 71%.; 1H NMR (600MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.42 (d,
J = 8.5 Hz, 2H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 2.49-2.41 (m,
2H), 2.41-2.32 (m, 2H), 1.69 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 155.1, 138.5, 138.0,
130.7, 129.4, 129.2, 128.7, 127.4, 127.1, 125.9, 122.4, 119.1, 80.0, 77.2, 77.0, 76.8, 36.7, 28.2,
12.4 ppm.
5.8. 3-(2-(4-bromophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3h):20
Yellow oil; Yield = 69%; 1H NMR (600MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H), 7.58 (d,
J = 8.5 Hz, 2H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 1H), 7.07 (d, J = 7.5 Hz, 1H), 2.50-2.42 (m,
2H), 2.42-2.31 (m, 2H), 1.69 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 155.0, 138.6, 131.6,
131.2, 129.4, 129.3, 127.4, 127.1, 126.4, 125.9, 122.4, 119.1, 79.9, 77.2, 77.0, 76.8, 36.7, 28.2,
12.4 ppm.
5.9. 3-(2-(4-iodophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3i):
Yellow oil; Yield = 68%; 1H NMR (600MHz, CDCl3) δ 7.85-7.79 (m, 4H), 7.35-7.31 (m,
2H), 7.26-7.23 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 2.50-2.42 (m, 2H), 2.41-2.31 (m, 2H), 1.69
13
(s, 3H) ppm; C NMR (150 MHz, CDCl3) δ 155.2, 138.6, 137.6, 131.8, 129.4, 129.3, 127.4,
127.2, 125.9, 122.4, 119.1, 98.8, 79.9, 77.2, 77.0, 76.8, 36.7, 28.2, 12.4 ppm. HRMS (ESI)
12

m/z 425.0118 (M + Na+), Cal. C18H15IN2NaO+, 425.0121.
5.10. 3-(4-methyl-2-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile
(3j):
Yellow oil; Yield = 63%; 1H NMR (600MHz, CDCl3) δ 8.25 (d, J = 8.2 Hz, 2H), 7.71 (d,
J = 8.3 Hz, 2H), 7.36 (d, J = 4.0 Hz, 2H), 7.28-7.26 (m, 1H), 7.09 (d, J = 7.5 Hz, 1H),
2.51-2.45 (m, 2H), 2.43-2.35 (m, 2H), 1.72 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ
154.5, 138.4, 135.7, 133.2 (q, J = 32.5 Hz), 129.5, 128.1, 127.8, 127.2, 126.2, 125.3 (q, J =
3.7 Hz), 123.9 (q, J = 272.6 Hz) 122.5, 119.0, 80.2, 77.3, 77.0, 76.8, 36.8, 28.3, 12.5 ppm.
HRMS (ESI) m/z 367.1030 (M + Na+), Cal. C19H15F3N2NaO+, 367.1029.
5.11. 3-(4-methyl-2-(o-tolyl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3l):
1
Yellow oil; Yield = 64%; H NMR (600MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 1H),
7.37-7.31 (m, 3H), 7.28-7.24 (m, 3H), 7.07 (d, J = 7.4 Hz, 1H), 2.63 (s, 3H), 2.53-2.44 (m,
2H), 2.44-2.33 (m, 2H), 1.73 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 157.8, 138.7, 138.2,
132.1, 131.5, 130.6, 129.5, 129.3, 127.3, 126.6, 125.9, 125.8, 122.3, 119.1, 80.0, 77.3, 77.0,
76.8, 36.7, 28.5, 21.7, 12.5 ppm. HRMS (ESI) m/z 313.1312 (M + Na+), Cal. C19H18N2NaO+,
313.1311.
5.12. 3-(2-(3-chlorophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3m):
Yellow oil; Yield = 67%; 1H NMR (600MHz, CDCl3) δ 8.10 (s, 1H), 8.02 (d, J = 7.8 Hz,
1H), 7.48 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.36-7.30 (m, 2H), 7.27-7.24 (m, 1H),
7.08 (d, J = 7.7 Hz, 1H), 2.63 (s, 3H), 2.50-2.44 (m, 2H), 2.42-2.32 (m, 2H), 1.70 (s, 3H) ppm;
13C NMR (150 MHz, CDCl3) δ 154.6, 138.5, 134.5, 134.1, 131.6, 129.6, 129.4, 127.8, 127.5,
127.1, 126.0, 125.9, 122.4, 119.1, 80.1, 77.2, 77.0, 76.8, 36.7, 28.2, 12.4 ppm. HRMS (ESI)
m/z 333.0759 (M + Na+), Cal. C18H15ClN2NaO+, 333.0765.
5.13. 3-(2-(2,4-dimethylphenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3n):
Yellow oil; Yield = 57%; 1H NMR (600MHz, CDCl3) δ 7.71 (d, J = 8.3Hz, 1H), 7.33 (d,
J = 4.1Hz, 2H), 7.25-7.22 (m, 1H), 7.09-7.06 (m, 3H), 2.61 (s, 3H), 2.52-2.46 (m, 2H),
2.44-2.32 (m, 6H), 1.71 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 157.9, 141.1, 138.8,
138.3, 132.4, 129.7, 129.3, 129.0, 127.1, 126.6, 126.6, 125.7, 122.3, 119.2, 79.9, 77.2, 77.0,
76.8, 36.6, 28.4, 21.8, 21.3, 12.5 ppm. HRMS (ESI) m/z 327.1470 (M + Na+), Cal.
C20H20N2NaO+, 327.1468.
13

5.14. 3-(2-(3,4-dichlorophenyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3o):
1
Yellow oil; Yield = 67%; H NMR (600MHz, CDCl3) δ 8.20 (d, J = 2.0 Hz, 1H), 7.97
(dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37-7.32 (m, 2H), 7.27-7.25 (m, 1H), 7.07
13
(d, J = 7.7 Hz, 1H), 2.49-2.43 (m, 2H), 2.42-2.33 (m, 2H), 1.70 (s, 3H) ppm; C NMR (150
MHz, CDCl3) δ 153.8, 138.3, 135.9, 132.8, 132.3, 130.4, 129.6, 129.5, 127.7, 127.0, 126.9,
126.1, 122.4, 119.0, 80.3, 77.2, 77.0, 76.8, 36.7, 28.3, 12.4 ppm. HRMS (ESI) m/z 367.0376
(M + Na+), Cal. C18H14Cl2N2NaO+, 367.0375.
5.15. 3-(4-methyl-2-(3,4,5-trimethoxyphenyl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile
(3p):
Yellow oil; Yield = 52%; 1H NMR (600MHz, CDCl3) δ 7.42 (s, 2H), 7.39-7.34 (m, 2H),
7.24 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 3.97 (s, 6H), 3.92 (s, 3H), 2.53-2.45 (m, 2H),
2.43-2.34 (m, 2H), 1.71 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 155.6, 153.1, 141.6,
138.9, 129.3, 127.5, 127.1, 127.0, 125.7, 122.3, 119.2, 105.4, 79.8, 77.2, 77.0, 76.8, 60.9, 56.4,
+
36.6, 28.1, 12.4 ppm. HRMS (ESI) m/z 389.1472 (M + Na+), Cal. C21H22N2NaO4 , 389.1472.
5.16. 3-(4-methyl-2-(thiophen-2-yl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3q):20
Yellow oil; Yield = 63%; 1H NMR (600MHz, CDCl3) δ 7.77 (s, 1H), 7.51 (d, J = 4.9Hz,
1H), 7.34-7.32 (m, 2H), 7.23-7.21 (m, 1H), 7.12 (t, J = 4.0 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H),
2.53-2.42 (m, 2H), 2.42-2.34 (m, 2H), 1.70 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ
152.7, 138.6, 136.5, 130.7, 130.1, 129.3, 127.9, 127.2, 127.0, 125.5, 122.4, 119.2, 80.1, 77.2,
77.0, 76.8, 36.6, 27.8, 12.3 ppm.
5.17. 3-(4-methyl-2-(naphthalen-2-yl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3r):20
Yellow oil; Yield = 52%; 1H NMR (600MHz, CDCl3) δ 8.60 (s, 1H), 8.25 (d, J = 8.5 Hz,
1H), 7.98-7.97 (m, 1H), 7.91-7.87 (m, 2H), 7.58-7.53 (m, 2H), 7.41-7.35 (m, 2H), 7.27-7.24
(m, 1H), 7.11-7.10 (m, 1H), 2.57-2.49 (m, 2H), 2.48-2.36 (m, 2H), 1.76 (s, 3H) ppm; 13C
NMR (150 MHz, CDCl3) δ 156.0, 138.9, 135.0, 132.8, 129.5, 129.4, 129.1, 128.4, 128.1,
127.8, 127.7, 127.3, 127.2, 126.6, 125.9, 124.4, 122.4, 119.2, 79.8, 77.2, 77.0, 76.8, 36.8, 28.2,
12.5 ppm.
5.18. 3-(2-(tert-butyl)-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3s):20
o
1
Yellow solid ; Yield = 76%; M.p. 71.3-72.7 C. H NMR (600MHz, CDCl3) δ
7.29-7.26 (m, 1H), 7.22-7.17 (m, 2H), 6.99 (d, J = 7.5 Hz, 1H), 2.45-2.36 (m, 2H), 2.35-2.25
14

13
(m, 1H), 1.55 (s, 3H), 1.27 (s, 9H) ppm; C NMR (150 MHz, CDCl3) δ 167.1, 138.7, 129.1,
127.1, 126.8, 125.6, 122.1, 119.3, 78.6, 77.2, 77.0, 76.8, 37.3, 36.3, 28.1, 27.4, 12.4 ppm.
5.19. 3-(2-cyclopropyl-4-methyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3t):
Yellow oil; Yield = 66%; 1H NMR (600MHz, CDCl3) δ 7.29-7.26 (m, 1H), 7.17-7.14 (m,
2H), 6.98-6.96 (m, 1H), 2.41-2.33 (m, 2H), 2.30-2.22 (m, 2H) 1.76-1.72 (m, 1H), 1.55 (s, 3H),
1.11-1.08 (m, 1H), 1.03-0.99 (m, 1H), 0.93-0.87 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ
162.8, 138.5, 129.3, 126.5, 126.4, 124.5, 122.3, 119.2, 79.4, 77.2, 77.0, 76.8, 36.5, 28.1, 14.6,
12.3, 7.3, 6.7 ppm. HRMS (ESI) m/z 241.1337 (M + H+), Cal. C15H17N2O+, 241.1335.
5.20. 3-(2,4-diphenyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3u):20
Yellow solid; Yield = 66%; M.p. 108.5-109.9 oC. 1H NMR (600MHz, CDCl3) δ 8.24 (d,
J = 7.5 Hz, 2H), 7.55-7.53 (m, 1H), 7.50-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.34-7.24 (m, 7H),
2.86-2.78 (m, 2H), 2.62-2.52 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 156.1, 141.8,
139.4, 132.0, 131.9, 129.7, 128.7, 128.5, 128.5, 127.9, 127.0, 126.0, 125.7, 125.4, 123.9,
119.2, 82.8, 77.2, 77.0, 76.8, 36.3, 12.9 ppm.
5.21. 3-(4,7-dimethyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3v):
1
Yellow oil; Yield = 75%; H NMR (600MHz, CDCl3) δ 8.13 (d, J =7.4 Hz, 2H), 7.51 (t,
J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.18 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.95 (d, J =
13
7.7 Hz, 1H), 2.51-2.41 (m, 2H), 2.41-2.33 (m, 5H), 1.68 (s, 3H) ppm; C NMR (150 MHz,
CDCl3) δ 156.0, 139.3, 138.6, 132.3, 131.6, 128.3, 127.8, 127.8, 126.3, 124.2, 122.2, 119.3,
79.7, 77.2, 77.0, 76.8, 36.8, 28.2, 21.1, 12.4 ppm. HRMS (ESI) m/z 313.1310 (M + Na+), Cal.
C19H18N2NaO+, 313.1311.
5.22. 3-(4,7-dimethyl-2-(p-tolyl)-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3w):
Yellow oil; Yield = 72%; 1H NMR (600MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz, 2H), 7.25 (d,
J = 7.8 Hz, 2H), 7.17 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 2.48-2.39 (m,
5H), 2.39-2.32 (m, 5H), 1.67 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 156.2, 139.2, 138.7,
129.5, 129.1, 127.8, 127.6, 126.2, 124.2, 122.2, 119.3, 79.6, 77.2, 77.0, 76.8, 36.8, 28.2, 21.6,
21.1, 12.4 ppm. HRMS (ESI) m/z 327.1470 (M + Na+), Cal. C20H20N2NaO+, 327.1468.
5.23. 3-(2-(4-chlorophenyl)-4,7-dimethyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3x):
Yellow oil; Yield = 57%; 1H NMR (600MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.42 (d,
J = 8.5 Hz, 2H), 7.18 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 2.48-2.41 (m,
15

2H), 2.40-2.31 (m, 5H), 1.68 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 155.2, 139.4, 138.2,
137.9, 130.7, 129.2, 128.6, 128.1, 126.3, 124.0, 122.3, 119.2, 80.1, 77.2, 77.0, 76.8, 36.7, 28.3,
21.1, 12.4 ppm. HRMS (ESI) m/z 347.0924 (M + Na+), Cal. C19H17ClN2NaO+, 347.0922.
5.24. 3-(6-chloro-2,4-diphenyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3y):
Yellow oli; Yield = 55%; 1H NMR (400MHz, CDCl3) δ 8.21 (d, J = 7.1 Hz, 2H),
7.57-7.47 (m, 3H), 7.37-7.27 (m, 7H), 7.20 (d, J = 2.1 Hz, 1H), 2.85-2.71 (m, 2H), 2.62-2.51
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.2, 140.9, 138.0, 132.1, 131.5, 129.8, 128.9,
128.7, 128.6, 127.9, 127.5, 127.3, 125.3, 123.9, 118.9, 82.4, 77.3, 77.0, 76.7, 36.1, 12.8 ppm.
HRMS (ESI) m/z 373.1104 (M + H+), Cal. C23H18ClN2O+, 373.1102.
5.25. 3-(6-bromo-2,4-diphenyl-4H-benzo[d][1,3]oxazin-4-yl)propanenitrile (3z):
Yellow oli; Yield = 52%; 1H NMR (400MHz, CDCl3) δ 8.21 (d, J = 7.3 Hz, 2H),
7.57-7.46 (m, 4H), 7.34-7.28 (m, 6H), 7.25-7.21 (m, 1H), 2.84-2.72 (m, 2H), 2.61-2.49 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.3, 141.0, 138.6, 132.8, 132.1, 131.6, 128.9,
128.8, 128.6, 127.9, 127.7, 126.8, 125.3, 119.8, 119.0, 82.3, 77.4, 77.1, 76.7, 36.1, 12.9 ppm.
HRMS (ESI) m/z 417.0597 (M + H+), Cal. C23H18BrN2O+, 417.0597.
5.26. 4,4-diphenylbut-3-enenitrile (4a):21
o
1
White solid; Yield = 67%; M.p. 97.7-98.9 C. H NMR (600MHz, CDCl3) δ 7.44-7.37
(m, 3H), 7.30-7.29 (m, 3H), 7.23-7.22 (m, 2H), 7.18 (d, J = 7.0 Hz, 2H), 6.04 (t, J = 7.4 Hz,
1H), 3.15 (d, J = 7.4 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 147.6, 140.7, 138.0, 129.4,
128.8, 128.4, 128.2, 128.1, 127.4, 118.1, 115.5, 77.2, 77.0, 76.8, 18.4 ppm.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China
(Nos. 21672174 and 21977084), and the Natural Science Foundation of Chongqing (No.
cstc2019jcyj-msxmX0297).
References
1. (a) A. Krantz, R. W. Spencer, T. F. Tam, T. J. Liak, L. J. Copp, E. M. Thomas and S. P.
Rafferty, J. Med. Chem. 33 (1990) 464-479;
16

(b) S. J. Hays, B. W. Caprathe, J. L. Gilmore, N. Amin, M. R. Emmerling, W. Michael, R.
Nadimpalli, R. Nath, K. J. Raser, D. Stafford, D. Watson, K. Wang and J. C. Jaen, J. Med.
Chem. 41 (1998) 1060-1067;
(c) P. Zhang, T. A. Terefenko, A. Fensome, Z. Zhang, Y. Zhu, J. Cohen, R. Winneker, J.
Wrobel and J. Yardley, Bioorg. Med. Chem. Lett. 12 (2002) 787-790.
2. H. Kuch, K. Schmitt, G. Seidl and I. Hoffmann, US 3725404, 1973.
3. H. Sugiyama, K. Hosoda, Y. Kumagai, M. Takeuchi and M. Okada, US 4596801, 1986.
4. G. Fenton, C. G. Newto, B. M. Wyman, P. Bagge, D. I. Dron, D. Riddell and G. D. Jones,
J. Med. Chem. 32 (1989) 265-272.
5. (a) P. Kopelman, A. Bryson, R. Hickling, A. Rissanen, S. Rossner, S. Toubro and P.
Valensi, Int. J. Obes. 31 (2007) 494-499;
(b) R. Padwal, Curr. Opin. Invest. Drugs. 9 (2008) 414-421;
(c) Y. Yamada, T. Kato, H. Ogino, S. Ashina and K. Kato, Horm. Metab. Res. 40 (2008)
539-543;
(d) J. Gras, Drugs Today. 49 (2013) 755-759.
6. (a) S. Krautwald and E. M. Carreira, in Comprehensive Organic Transformations: a
Guide to Functional Group Preparations, ed. C. R. Larock, Wiley-VCH, Weinheim, 1989,
p. 819;
(b) A. Kleemann, J. Engel, B. Kutscher and D. Reichert, Pharmaceutical Substance:
Synthesis Patents, Applications, Georg Thieme Verlag, Stuttgart, 4th edn, 2001.
7. (a) A. J. Fatiadi, in Preparation and Synthetic Applications of Cyano Compounds, ed. S.
Patai and Z. Rappoport, WileyVCH, New York, 1983;
(b) E. N. Bess and M. S. Sigman, in Linear free energy relationships (LFERs) in
asymmetric catalysis. Asymmetric Synthesis II: More Methods and Applications, ed. M.
Christmann and S. Bräse, Wiley-VCH, Weinheim, Germany, 2012, p. 363;
(c) Z. Rappoport, in Chemistry of the Cyano Group, John Wiley & Sons, London, 1970, p.
121;
(d) W. Zhang, C. Yang, Y.-L. Pan, X. Li and J.-P. Cheng, Org. Biomol. Chem. 16 (2018)
5788-5792.
8. (a) B. Han, X.-L. Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen, and W. Yu, J. Org. Chem.
17

77 (2012) 1136-1142;
(b) J. Ma, Y. Wan, C. Hong, M. Li, X. Hu, W. Mo, B. Hu, N. Sun, L. Jin, and Z. Shen, Eur.
J. Org. Chem. 2017, 3335-3342.
9. (a) T. Saito, S. Ogawa, N. Takei, N. Kutsumura, and T. Otani, Org. Lett. 13 (2011)
1098-1101;
(b) Z.-J. Cai, F.-H. Li, S.-Y. Wang, and S.-J. Ji, Org. Lett. 18 (2016) 4810-4813.
10. M. Chaitanya and P. Anbarasan. Org. Lett. 20 (2018) 1183-1186.
11. (a) K. Okuma, T. Yasuda, I. Takeshita, K. Shioji and Y. Yokomori, Tetrahedron. 63
(2007) 8250-8254;
(b) A. Jaganathan, A. Garzan, D. C. Whitehead, R. J. Staples and B. Borhan, Angew.
Chem., Int. Ed. 50 (2011) 2593-2596;
(c) Q. Yin and S.-L. You, Org. Lett. 16 (2014) 2426-2429.
12. (a) Q.-H. Deng, J.-R. Chen, Q. Wei, Q.-Q. Zhao, L.-Q. Lu and W.-J. Xiao, Chem.
Commun. 51 (2015) 3537-3540;
(b) H. Yang, X.-H. Duan, J.-F. Zhao and L.-N. Guo, Org. Lett. 17 (2015) 1998-2001.
13. W. Fu, X. Han, M. Zhu, C. Xu, Z. Wang, B. Ji, X.-Q. Hao and M.-P. Song, Chem.
Commun. 52 (2016) 13413-13416.
14. X.-Q. Chu, X.-P. Xu, H. Meng and S.-J. Ji, RSC Adv. 5 (2015) 67829-67832.
15. X.-Q. Chu, D. Liu, Z.-H. Xing, X.-P. Xu and S.-J. Ji, Org. Lett . 18 (2016) 776-779
16. C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev. 113 (2013) 5322-5363.
17. C. R. Lambert and I. E. Kochevar, Photochem. Photobiol. 66 (1997) 15-25.
18. D. P. Hari and B. König, Chem. Commun. 50 (2014) 6688-6699.
19. S. Jana, A. Ashokan, S. Kumar, A. Verma and S. Kumar, Org. Biomol. Chem. 13 (2015)
8411-8415.
20. X.-Q. Chu, X.-P. Xu, H. Meng and S.-J. Ji, RSC Adv. 5 (2015) 67829-67832.
21. S. Tang, C. Liu and A. Lei, Chem. Commun. 49 (2013) 2442-2444.
18

Highlights
ꢀ We first reported a novel method for the synthesis of cyanomethylated
benzoxazines via visible-light catalyzed radical cascade cyclization.
ꢀ This redox-neutral photocatalytic reaction completes the synthesis of
C-C and C-O bonds in one pot without using any oxidizing agent.
ꢀ The reaction has the notable features of mild reaction conditions,
simple operation, good functional group compatibility and wide range
of substrate scope.

Conflicts of interest
There are no conflicts to declare.