Synthesis of 4-cyanoethylated benzoxazines by visible-light-promoted radical oxycyanomethylation of olefinic amides with bromoacetonitrile

Article abstract of DOI:10.1016/j.tetlet.2019.07.017

A facile and efficient protocol for the visible-light-promoted radical oxycyanomethylation of olefinic amides with bromoacetonitrile has been developed, affording a series of 4-cyanoethylated benzoxazine derivatives in moderate to excellent yields. The re

Full text of DOI:10.1016/j.tetlet.2019.07.017

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Synthesis of 4-cyanoethylated benzoxazines by visible-light-promoted radical
oxycyanomethylation of olefinic amides with bromoacetonitrile
Song Sun, Cong Zhou, Jiang Cheng
PII:
S0040-4039(19)30663-X
https://doi.org/10.1016/j.tetlet.2019.07.017
TETL 50926
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Reference:
Tetrahedron Letters
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30 June 2019
8 July 2019
Please cite this article as: Sun, S., Zhou, C., Cheng, J., Synthesis of 4-cyanoethylated benzoxazines by visible-light-
promoted radical oxycyanomethylation of olefinic amides with bromoacetonitrile, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.07.017
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Synthesis of 4-cyanoethylated benzoxazines by
visible-light-promoted radical oxycyanomethylation of
olefinic amides with bromoacetonitrile
Song Sun*, Cong Zhou and Jiang Cheng

1
Tetrahedron Letters
Synthesis of 4-cyanoethylated benzoxazines by visible-light-promoted radical
oxycyanomethylation of olefinic amides with bromoacetonitrile
Song Sun*, Cong Zhou and Jiang Cheng
aSchool of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key Laboratory of
Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China.
†E-mail: sunsong@cczu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and efficient protocol for the visible-light-promoted radical oxycyanomethylation
of olefinic amides with bromoacetonitrile has been developed, affording a series of 4-
cyanoethylated benzoxazine derivatives in moderate to excellent yields. The reaction
featured with diverse functional group tolerance and mild reaction conditions.
Available online
Keywords:
Visible-light-promoted
Benzoxazines
Oxycyanomethylation
Olefinic amides
Figure 1. Pharmaceutical scaffolds including benzoxazines.
Cyanoalkyl moieties are important structural motifs that
widely exist in biologically active natural products and
medicines.1 Moreover, the cyano served as precursors of
carboxylic acids, esters, amides, amines, aldehydes, and
ketones.2 Therefore, considerable efforts have been paid into
the development of more efficient cyanoalkylation reactions
in recent years.3 Among the well-developed reactions,
transition-metal catalyzed C(sp3)−H bond oxidative
functionalization of alkyl nitriles are of particular interest, as
these strategies could introduce cyanoalkyl groups into the
target frameworks in a step-economical fashion, however,
excess of chemical oxidant and elevated reaction
temperature are often required in these procedures.4
Scheme 1. Synthesis of 4-Cyanoethylated Benzoxazines.
Alternatively,
visible-light-induced
photocatalytic
difunctionalization of alkenes with cyclobutanone oxime5 or
bromoacetonitrile6 represents another useful cyanoalkylation
reaction, which can avoid the use of stoichiometric redox
reagents. For example, Xiao and co-workers reported a
visible-light-driven cascade reaction of oxime esters,
styrenes, and boronic acids to generate various diversely
1,1-diarylmethane-containing alkylnitriles.7 MacMillan
group reported an enantioselective α-cyanoalkylation of
aldehydes by photoredox organocatalysis using a cheap
bromoacetonitrile as the cyanoalkyl source.8 Despite much
progress has been paid in this field, establishing more
straightforward methods as well as developing
environmentally friendly reaction conditions to generate
diverse cyano-containing compounds remains an area of
synthetic interest.
On the other hand, 4-substituted-4H-1,3-benzoxazine
scaffolds occur frequently in many pharmaceutically active
molecules, such as anticancer, antibacterial, anticonvulsant, and
HIV protease inhibitory activities (Figure 1),9 and they are also
useful synthetic intermediates in organic synthesis. As a result,
several elegant methodologies have been developed to access
such frameworks.10 Firstly, the construction of 4-substituted-4H-
1,3-benzoxazine derivatives by tandem radical addition to
olefinic amides followed by cyclization is the most common
method.11 Nevertheless, to date, the synthesis of 4-cyanoethylated

Tetrahedron
4
With the optimized reaction conditions in hand, the scope and
limitation of substrates was investigated, as shown in Scheme 2.
Generally, the reaction tolerated olefinic amides bearing both
electron-donating and electron-withdrawing groups. However,
the substrates bearing electron-withdrawing groups gave inferior
results than those bearing electron-donating groups. For example,
methyl, methoxyl substituted olefinic amides could afford the
desired products 3a-3e in good yields (60%-78%). However, the
analogues bearing electron-withdrawing groups could generate
the desired products 3f-3n in only 33%-57% yields. It was found
that 2,6-dichloro-N-(2-(prop-1-en-2-yl)phenyl)benzamide 1j only
could afford the desired product 3j in only 33% yield, which
would be attributed to the steric hindrance effect. Notably, some
functional groups such as, chloro, bromo, iodo, nitro, esterand
cyano groups, which were suitable for potentially further
functionalization, survived in these reactions. Moreover, aliphatic
substrates 1q-1s also could react smoothly with
bromoacetonitrile to give the desired products 3q-3s in good
yields (60%-64%).
benzoxazines requires stoichiometric oxidants and high
temperature12 (Scheme 1 eq. 1). Herein, we envisioned that the
construction of these compounds from olefinic amides and
commercial available bromoacetonitrile through a visible-light-
driven domino radical addition/ oxidation/ cyclization cascade
reactions (Scheme 1 eq. 2). This novel reaction featured with
diverse functional group tolerance and mild reaction conditions.
Table 1. Selected results for screening the optimized reaction
conditions.a
yieldb
(%)
entry
catalyst
base
solvent
1
2
fac-Ir(ppy)3
[Ir(ppy)2(dtbbpy)]PF6
Ru(bpy)3Cl2.6H2O
eosin Y
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
DABCO
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
--
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
43
N.R.
12
Importantly, the diversity of the product was further increased
as this procedure allow to access 2-(1-naphthyl) (3o, 43%), 2-
thienyl (3p, 51%), 2-cinnamenyl (3t, 32%) of 4H-1,3-
benzoxazines in moderate yields. Subsequently, α-aryl olefinic
amide 2u also could react smoothly under the standard conditions
to generate 3u in 53% yield.
3
4
N.R.
N.R.
46
5
4CzIPN
6
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
7
53
8
20
9
78
10
11
12
13
14
15
63
DCE
51
DMSO
MeCN
MeCN
MeCN
32
0c
0
K3PO4
36d 72e
a
Reaction conditions: 1a (0.1 mmol), bromoacetonitrile (0.15
mmol), photocatalyst (0.002 mmol, 2 mol%), base (0.2 mmol)
in indicated solvent (1.0 mL) was irradiated with a 16 W white
b
LED for 24 h in a sealed Schlenk tube, unless otherwise noted.
c
d
Isolated yield.
without photocatalyst or in dark.
bromoacetonitrile (0.1 mmol), e bromoacetonitrile (0.2 mmol).
Initially, we selected N-(2-(prop-1-en-2-yl)phenyl)benzamide
1a and bromoacetonitrile 2 as model substrates to optimize the
reaction conditions. As anticipated, the reaction indeed took
place in the presence of 2 mol % fac-Ir(ppy)3 as the photocatalyst
and 2 equiv. of K2CO3 as a base under 16 W white light-emitting
diode (LED) strip irradiation in CH3CN at room temperature and
gave the oxycyanomethylation product 3a in 43% yield (Table 1,
entry 1). Then, other photocatalyst such as [Ir(ppy)2(dtbbpy)]PF6,
Ru(bpy)3Cl2.6H2O, eosin Y, 4CzIPN were tested, however, all
gave inferior results than that of fac-Ir(ppy)3 (Table 1, entries 1-
5). Subsequently, other bases such as Na2CO3, NaHCO3,
DABCO, K3PO4 were tested to further increase the efficiency of
this reaction, and K3PO4 was the best, the desired product could
be isolated in 78% yield in the presence of 2 equivalents of
K3PO4 (Table 1, entries 1, 6-9). Among the solvents tested,
MeCN was the best choice (Table 1, entries 9-12). Under the
control experiments, it was found that this reaction did not work
in the absence of each reaction parameters (Table 1, entries 13-
14). Additionally, decrease or improve the amount of
bromoacetonitrile used all gave inferior results (Table 1, entry
15).
Figure 2. The substrate scope of olefinic amides a Reaction conditions: 1
(0.1 mmol), bromoacetonitrile 2 (0.15 mmol,), photocatalyst (0.002 mmol, 2
mol%), K3PO4 (0.2 mmol) in CH3CN (1.0 mL) was irradiated with a 16 W
white LED for 24 h in a sealed Schlenk tube, unless otherwise noted

3
Some control experiments were conducted to get some insights
into this transformation. Firstly, when 3 equivalents of radical
scavenge 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added, the reaction was totally inhibited, which suggested that
the reaction probably proceeded via a radical pathway (Scheme 3,
eq. 1). To further confirm the involvement of radical in this
transformation, another radical scavenge 1,1-diphenylethenewas
used to trap the cyanomethyl radical. As expected, the formation
of product 3a was suppressed, and the coupling product 4,4-
diphenylbut-3-enenitrile (4) was obtained (Scheme 3, eq. 2).
(15KJA150001), Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology (BM2012110) and Advanced
Catalysis and Green Manufacturing Collaborative Innovation
Center for financial supports.
References and notes
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On basis of the above discussion and some relative previous
works, a tentative mechanism13 is outlined in Scheme 4. First, the
excited state [fac-Ir(III)(ppy)3*] is formed under light irradiation,
which is next oxidized by bromoacetonitrile 2 to generate a [fac-
Ir(IV)(ppy)3]+ complex and a CH2CN radical species A. The
difluoromethyl radical attacks the C–C double bond of olefinic
amides 1 to generate the radical intermediate B. The radical
intermediate B is then oxidized by [fac-Ir(IV)(ppy)3]+ to form the
carbocation intermediate C with the concurrent regeneration of
3
4
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[fac-Ir(III)(ppy)3].
Subsequent
cyclization
reaction
of
intermediate C followed by deprotonation assisted by a base give
the difluoromethylated product 3.
Scheme 3. A Tentative mechanism
5
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In conclusion, we have developed a facile and efficient
protocol
for
the
visible-light-promoted
radical
oxycyanomethylation of olefinic amides with bromoacetonitrile
has been developed, affording a series of benzoxazine derivatives
in moderate to excellent yields. The reaction featured with
diverse functional group tolerance and mild reaction conditions.
Acknowledgments
6
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We thank the National Natural Science Foundation of China
(nos. 21602019 and 21572025), “Innovation & Entrepreneurship
Talents” Introduction Plan of Jiangsu Province, Natural Science
Foundation of Jiangsu Province (BK20171193), the Key
University Science Research Project of Jiangsu Province

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5
1. Visible-light-promoted reaction of olefinic amides
with bromoacetonitrile
2. Simple bromoacetonitrile used as cyanoalkyl source
3. The reaction featured with diverse functional group
tolerance.