Copper-catalyzed radical reactions of 2-azido-N-arylacrylamides with 1-(trifluoromethyl)-1,2-benziodoxole and 1-azidyl-1,2-benziodoxole

Article abstract of DOI:10.1039/c6ob00226a

The reactions of 2-azido-N-arylacrylamides with trifluoromethyl radicals and azidyl radicals were investigated by using Togni's reagent and Zhdankin's reagent as the source of these radicals. Under the catalysis of CuI, Togni's reagent was firstly converted into the trifluoromethyl radical, which then reacted with 2-azido-N-arylacrylamides to afford the corresponding α-(arylaminocarbonyl)iminyl radicals. The cyclization of the iminyl radicals delivered quinoxalin-2(1H)-one products in moderate yields. A similar reaction took place between 2-azido-N-arylacrylamides and the azidyl radical. In the latter cases, the reaction produced 3-azidomethyl and 3-cyano-subsituted quinoxalin-2(1H)-ones. This study not only helps elucidate the factors influencing the cyclization of α-(arylaminocarbonyl)iminyl radicals, but also provides a new approach towards quinoxalin-2-ones.

Full text of DOI:10.1039/c6ob00226a

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DOI: 10.1039/C6OB00226A
Journal Name
ARTICLE
Copper-catalyzed radical reactions of 2-azido-N-arylacrylamides
with 1-(trifluoromethyl)-1,2-benziodoxole and 1-azidyl-1,2-
benziodoxole
Received 00th January 20xx,
Accepted 00th January 20xx
Tonghao Yang,a Haizhen Zhua and Wei Yu*a
DOI: 10.1039/x0xx00000x
The reactions of 2-azido-N-arylacrylamides with the trifluoromethyl radical and azidyl radical were investigated by using
Togni’s reagent and Zhdankin’s reagent as the source of these radicals. Under the catalysis of CuI, Togni’s reagent was
firstly converted to the trifluoromethyl radical, which then reacted with 2-azido-N-arylacrylamides to afford the
corresponding -(arylaminocarbonyl)iminyl radicals. The cyclization of the iminyl radicals delivered quinoxalin-2(1H)-one
products in moderate yields. Similar reaction took place between 2-azido-N-arylacrylamides and the azidyl radical. In the
latter cases, the reaction produced 3-azidomethyl and 3-cyano-subsituted quinoxalin-2(1H)-ones. This study not only helps
elucidate the factors influencing the cyclization of -(arylaminocarbonyl)iminyl radicals, but also provides a new approach
towards quinoxalin-2-ones.
www.rsc.org/
show that iminyl radicals can be conveniently prepared from
addition of a radical to vinyl azides followed by extrusion of a
nitrogen molecule. We envisioned that by using this strategy,
Introduction
Iminyl radicals are valuable intermediates in the synthesis of
nitrogen heterocycles.1 Recent studies by Spagnolo et al.,2
Zhang et al.3 and our own4 demonstrate that the cyclisation of
the cyclization of alkyl substituted -(arylaminocarbonyl)iminyl
radicals could be further evaluated with regard to the
substituent effect. Moreover, as both trifluoromethyl12 and
azidyl13 groups are important functional groups, a new method
for the preparation of trifluoromethyl and azidyl-functionalized
quinoxalin-2(1H)-ones will be synthetically useful. By using 1-
(trifluoromethyl)-1,2-benziodoxole (Togni’s reagent) as the
source of trifluoromethyl radical and 1-azidyl-1,2-benziodoxole
(Zhdankin’s reagent) as the source of azidyl radical, we
implemented this idea, and herein we wish to report our result.
the
-(arylaminocarbonyl)iminyl radical would deliver the
quinoxalin-2(1H)-one ring structure (Scheme 1). As quinoxalin-
2-one is an important heterocyclic skeleton that appears in
many
biologically
and
pharmaceutically
significant
compounds,5 this reaction holds promise to become a highly
useful synthetic tool. Despite these encouraging results,
however, previous investigations indicate that the efficacy of
this approach is largely influenced by the reaction conditions
and the structural features of the iminyl radical. Considering
the substituent effect adjacent to the iminyl radical center (R3),
the yields are generally high when R3 is an ethoxycarbonyl
group,4 but are much lower when it becomes an alkyl group.2
On the other hand, when an aryl group is attached to the
iminyl radical, no quinoxalin-2-one product could be
generated.4,6 In an attempt to further expand the scope of this
Scheme 1 An approach towards quinoxalin-2(1H)-one moiety via the cyclization of -
(arylaminocarbonyl)iminyl radicals
N3
reaction,
we
investigated
the
tandem
radical
N
N3
X
X
X
- N2
R1
R1
R1
addition/cyclization reaction of vinyl azides with
trifluoromethyl radical7 and azidyl radical8 (Scheme 2). Recent
studies by Chiba et al.9 Spagnolo, et al.,10 and Zhou, et al.11
N
R2
O
N
R2
N
R2
O
O
1
H
N
[O], -H+
N
X
X
R1
R1
N
R2
O
N
R2
O
X = CF3, N3
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Scheme 2 Design of this work
After some futile attempts to improve yield, we next chose
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15
Togni’s reagent as the trifluoromethylDaOtiIn: g10.a10g3e9n/Ct.6OBR0e0c2e26nAt
studies demonstrate that Togni’s reagent constitutes a reliable
source of the trifluoromethyl radical, and is applicable to a
variety of transformations.16 Copper salts are suitable catalysts
to engender the generation of the trifluoromethyl radical from
Togni’s reagent. Thus, on the basis of recent studies, we tested
some commonly used copper salts for their catalytic capacity
Results and discussion
on the reaction of 1a with Togni’s reagent (A), and the results
are summarized in Table 1.
As can be seen in Table 1, among the copper catalysts
examined, all can catalyze the desired reaction to afford 2a
Scheme 3 Reaction of 1a with CF3SO2Cl under visible light irradiation
Table 1 Screening of the reaction conditions with Togni’ reagent a
except CuCl2 and CuBrSMe2, but using CuI delivered the best
o
result when the reaction proceeded in toluene at 80 C (Table
1, entry 8). The yield of 2a reached 67% by using 4.0 equiv. of
A
(Table 1, entry 19). Lowering the reaction temperature
would extend the reaction time (Table 1, entry 16), whereas
o
raising the temperature to 100 C resulted in the decrease in
the yield of 2a (Table 1, entry 17).
The optimized reaction conditions (Table 1, entry 19) were
then applied to
variously substituted 2-azido-N-
Entry
Cat.
Equiv. of
A
Sovlent
Temp.
(oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
Yield of
2ab
30
44
24
arylacrylamides ( ), and the results are listed in Table 2. All the
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuI
CuCl
CuTc
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
4.0
2.0
2.0
2.0
2.0
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
para and meta-substituted compounds except compound 1g
were transformed to trifluoromethyl-attached quinoxalin-2-
ones
2
, while the desired reaction failed to occur to ortho-
1q (Table 2, entries 14-17). In the
CuTc
48
substituted compounds 1n
-
CuCl2
Cu(OAc)2
Cu powder
CuI
CuCl
CuBr
CuBr·SMe2
CuTc
CuCl2
Cu(OAc)2
Cu powder
CuI
N.R.c
32
latter cases, most of the substrate was recovered after 18 h,
indicating that the presence of an ortho-substituent would
32
58
36
prohibit
1 from reacting with trifluoromethyl radical. For the
reaction of 1a, the yield was a little lower on 0.5 mmol scale
than that shown in Table 1 (on 0.2 mmol scale). It is interesting
30
--d
to see that when meta-substituted 1h
substrates, different selectivities were observed: in the cases
of 1i 1j 1l and 1m, 5-substituted isomers 2-1 were obtained
-1m was used as the
25
N.R.c
23e
,
,
as the only isolable product, whereas the reaction of iodine-
substituted 1k afforded only 7-substituted isomer 2k-2. On the
other hand, both isomers were obtained when 1h was used as
the substrate. Our previous studies indicates that cyclization of
46e
57e
CuI
CuI
CuI
CuI
CuI
CuI
CuI
26d
60e
the
-(arylaminocarbonyl)iminyl radical is of ortho-selectivity,
67e
that is, the attack prefers to take place at the sterically more
48e
CH3CN
DMF
CHCl3
mixture f
mixture f
N.R.c
crowded dual ortho position. The result with 1i, 1j, 1l and 1m
is consistent with our previous observation.4 The abnormal
selectivity in the case of 1k (Table 2, entry 11) remains unclear
at this stage.
a
The reaction was carried out on a 0.2 mmol scale in 2 mL solvent under an
Unlike other substrates, compound 1g reacted to give
spirocyclohexadienones 3g rather than the corresponding
quinoxalin-2-one product (Table 2, entry 7). The formation of
compound 3g involved an azaspirocyclohexadienyl carbocation
intermediate, with an azaspirocyclohexadienyl radical being its
precursor. Similar result was also obtained in our previous
study.4
Besides the above-mentioned results, it can also be seen in
Table 2 that replacement of benzyl with aryl or other alkyl N-
substituent would cause no substantial change in quinoxalin-2-
one production (Table 2, entries 18-20).
argon atmosphere. 10 mol % of copper catalyst was used unless otherwise
b
specified. NMR yield with 1,4-dioxane as an internal standard unless otherwise
d
e
f
specified. c No reaction took place. 1a decomposed. Isolated yield. Complex
mixture was obtained. CuTc: copper(I) thiophene-2-carboxylate. DCE: 1,2-
dichloroethane.
We began our study by examining the reaction of 2-azido-N-
benzyl-N-phenylacrylamide
(1a) with the trifluoromethyl
radical. Firstly, CF3SO2Cl was used as the source of
trifluoromethyl radical, and was allowed to react with 1a
under the recently developed visible light irradiation
conditions.14 As expected, the desired reaction took place, but
the yield of quinoxalin-2-one product 2a was low (Scheme 3).
2 | J. Name., 2012, 00, 1-3
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Table 2 CuI-catalyzed reaction of 1 with Togni’s reagent a
View Article Online
DOI: 10.1039/C6OB00226A
11
12
1k
m-I
Bn
Bn
2k-2 (34)
Me
N
CF3
1l m-Me
N
O
Entry
1
Sub. R1
R2
Product(s) (Yield, %)b
Bn
2l-1 (57)
N
CF3
OMe
1a
1b
1c
H
Bn
N
O
N
Bn
CF3
2a (64)
2b (50)
2c (56)
13
1m m-OMe Bn
N
O
Bn
2m-1 (60)
F
N
N
CF3
2
3
4
p-F Bn
p-Cl Bn
p-Br Bn
O
14
15
16
17
1n o-F
1o o-Cl
Bn
Bn
N.R.d
N.R.d
N.R.d
N.R.d
Bn
1p o-Me Bn
1q o-OMe Bn
18
19
20
1r
1s
H
Me
Ph
2r (60)
2s (48)
Br
N
CF3
1d
N
O
N
CF3
Bn
2d (48)
H
N
O
O
Ph
I
N
CF3
5
1e
1f
p-I Bn
N
O
N
N
CF3
2e (38)c
Bn
1t o-(CH2)3-(N)
2t (56)
Me
N
N
CF3
6
7
p-Me Bn
O
a Reaction conditions: A mixture of 0.5 mmol of 1, 1.0 mmol of A and 0.05 mmol
Bn
2f (41)
3g (60)
of CuI in 5 mL of anhydrous toluene was stirred at 80 oC under an argon
b
c
atmosphere for 18 h. Isolated yield. 2e was accompanied by a minor amount
of 1-benzyl-6-iodo-3-(iodomethyl)quinoxalin-2(1H)-one (yield: 9%). Similar 3-
(iodomethyl)quinoxalin-2(1H)-one by products were also detected in tiny amount
1g p-OMe Bn
d
in the reactions of other substrates. No reaction took place. Most of the
substrate was recovered.
Following our investigation on the reaction of
trifluoromethyl radical, we went on to see if azidyl radical
could react with
in the same way.17 We employed Zhdankin’s
1 with
8
1h
m-F Bn
1
reagent as the source of azidyl radical. As an analogue of
Togni’s reagent, Zhdankin’s reagent also has the merit of good
thermal stability and high reactivity, and thus has found wide
applications in the azidation of manifold organic compounds.18
Like Togni’s reagent, Zhdankin’s reagent can also be reduced
by Cu(I) to give the azidyl radical.18d,18e In our subsequent study,
we first tested some conditions for the copper-catalyzed
2h-1 (29), 2h-2 (38)
Cl
N
CF3
9
1i
1j
m-Cl
Bn
N
O
Bn
2i-1 (38)
2j-1 (53)
reaction of 1a with Zhdankin’s reagent (B), and the results are
summarized in Table 3.
Br
N
CF3
As shown in Table 3, toluene was found to be the suitable
10
m-Br Bn
o
N
O
solvent, and the optimal reaction temperature was 4060 C.
Bn
Two products, 4a and 5a, were obtained, and their ratio was
largely influenced by the catalyst used. When CuI was used as
the catalyst, both 4a and 5a were obtained, with the latter
being the major product. However, the CuTc-catalyzed
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4 and 5, whVilieew1AdrticalenOdnl1inee
reaction afforded only 4a, even after long reaction time (Table and 1f reacted to afford a mixture of
entry 17). By contrast, when the catalyst became Cu were converted thoroughly to the 3-cyano-subsituted 5d and
powder or Cu(OAc)2, only compound 5a was obtained after 24 5e at the time when the substrate was completely consumed.
h (Table 3 entries 18 and 19). Control experiment indicates The low yield for the reaction of 1f can be attributed to the
DOI: 10.1039/C6OB00226A
3
，
，
that compound 5a derived from 4a by oxidation and decomposition of the products, as compound 5f was found to
denitrogenation.19
be very unstable.20 On the other hand, no isolable product was
obtained in the case of 1g. For the meta-substituted 1h 1m
-
,
Table 3 Screening of the conditions for the reaction of 1a with Zhdankin's reagent a
the composition of the products was complicated because of
the formation of the regio-isomers. Moreover, it was also
largely influenced by the electronic nature of the substituent.
When 1l or 1m was used as the substrate, three products were
obtained for each reaction. Unfortunately, these products,
except 4l-1 and 5m-1, are very unstable; their decomposition
was observed (by color change) during the preparation of
sample for NMR measurement.20 Overall, these results of
Entry
[Cu]
Solvent
Temp.
(oC)
Time (h)
Yield of
4a and
5a (%)b
18 (4a)c,
40 (5a)c
13 (4a),
31 (5a),
23 (4a),
44 (5a)
17 (4a)c,
41 (5a)c
15 (4a)c,
29 (5a)c
15 (4a)c,
44 (5a)c
--d
indicate that the transformation from
substituent effect at the benzene ring, which also has a big
influence on the stability of and . Despite the instability of
some of these products, however, the regioselectivities of the
reactions of 1h 1l shown in Table 4 are in general consistent
4 to 5 is sensitive to the
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
toluene
methanol
toluene
40
40
40
rt
6
8
4
5
-
6
with those exhibited in the trifluoromethylation reactions
(Table 2). Besides the substituent effect illustrated above, the
current reaction is susceptible to other structural change. As
such, the reaction of 1r gave only compound 5r as the only
isolable product (which is also unstable), whereas 1t
decomposed completely under the same conditions.
toluene
24
16
4
methanol
toluene
rt
60
The CuI-catalyzed reactions of compounds
1 with Togni’s
reagent and Zhdankin’s reagent can be rationalized with a
mechanism shown in Scheme 4. The yields of the quinoxalin-2-
one products were in general moderate, but significantly
higher than those reported by Spagnolo et al.2 for cyclization
of other 1-alkyl-(arylaminocarbonyl)iminyl radicals under
reductive conditons. The instability of the products is partly
responsible for the low yield exhibited in Table 4, but in
general the current reactions reflect a demonstrable structural
influence on the cyclization step. Both the trifluoromethyl and
azidyl are electron withdrawing groups, and they can affect the
cyclization by enhancing the electrophilicity of the iminyl
radical. However, this effect is much weaker than that of
ethoxycarbonyl group in radical R-e.4 The present results, in
combination with these previous studies, corroborate that an
adjacent electron withdrawing group is beneficial to the
7
CuI
CuI
toluene
toluene
80
40
4
6
8e
˂1 (4a)c,
39 (5a)c
23 (4a),
˂1 (5a)
19 (4a),
˂1 (5a)
mixturef
mixturef
N. R.g
9
CuI
CuI
DCE
40
40
6
6
10
DMSO
11
12
13
14
15
16
17
CuI
CuI
CuI
DMF
CH3CN
CHCl3
40
40
40
40
40
40
40
2
6
6
CuI
THF
6
N. R.g
Cu(CN)4PF6
Cu(CN)4PF6
CuTc
methanol
toluene
toluene
24
24
24
mixture f
N. R. g
43 (4a),
˂1 (5a)
˂ 1 (4a),
29 (5a)
˂1(4a),
38 (5a)
18
19
Cu powder
Cu(OAc)2
toluene
toluene
40
40
24
24
cyclization
of
-(arylaminocarbonyl)iminyl
radicals.
Furthermore, in the current cases steric hindrance by
trifluorethyl and azidomethyl substituent possibly caused
some negative influence on the cyclization of corresponding
iminyl radicals. In fact, previous studies suggest that
a The reaction was carried out on a 0.2 mmol scale in 2 mL solvent. 2.0 Equiv. of B
was used unless otherwise specified, b NMR yield with 1,4-dioxane as an internal
standard. c Isolated yield. 1a Decomposed. e 3.0 Equiv. of B was used. Complex
d
f
quinoxalin-2-one-forming
cyclization
of
-
mixture was obtained. g No Reaction took place.
(arylaminocarbonyl)iminyl radicals could be (notably)
depressed in the presence of an adjacent alkyl or aryl group.2-4
The addition of trifluoromethyl or azidyl radicals on the
The CuI-mediated reaction conditions (Table 3, entry 6) were
then applied to other substrates
illustrated in Table 4. Like the reactions with Togni’s reagent,
most of the para and meta substituted substrates reacted to
deliver quinoxalin-2-one products, but the ortho-substituted
compounds failed to react under the same conditions. Among
1, and the results were
carbon-carbon double bond in 1, on the other hand, should be
an efficient process, as these radicals can add facilely to
various functionalized olefins, including N-arylacrylamides.17b-d,
21
the para-substituted substrates (Table 4, entries 2-7), 1b, 1c
4 | J. Name., 2012, 00, 1-3
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Table 4 CuI-catalyzed reaction of 1 with Zhdankin’s reagent a
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Cl
DOI: 10.1039/C6OB00226A
CN
N
N
N3
+
N
O
Cl
N
O
9
1i
1j
10
12
18
Bn
Bn
4i-1 + 5i-2 (3:2,d 46)
Time
Entry
1
Sub.
Products (Yield, %)b
(h)c
10
11
1a
6
4j-1 + 5j-1 (3:1,e 34)
4a (12), 5a (44)
CN
O
N
F
N
F
N3
+
N
O
N
1k
2
3
1b
1c
6
Bn
Bn
4k-2 + 5k-1 (5:1,e 47)
4b (15), 5b (19)
CN
O
N
N
Cl
N
N
Cl
N3
+
O
10
Bn
Bn
4l-1 (40)
4c (15), 5c (44)
12
1l
4
CN
O
Br
N
4
5
1d
1e
12
18
N
Bn
5d (42)
5l-1 + 5l-2 (10:9,e 32)c
CN
O
I
N
N
Bn
5e (48)
4m-2 (15)c
12
1m
3.5
6
7
1f
4
4
4f (9) , 5f (22)c
5m-1 (34), 5m-2 (12)c
--d
1g
13
14
1n
1o
12
12
N.R.f
N.R.f
15
1r
6
5r (30)c
4h-1 + 4h-2 (2:5,e 17)
8
1h
6
--d
CN
N
16
1t
6
N
O
F
a Reaction conditions: A mixture of 0.5 mmol of 1, 1.0 mmol of B and 0.05 mmol
of CuI in 5 mL of anhydrous toluene was stirred at 80 oC under an argon
atmosphere. The reaction was quenched when 1 was consumed completely
(indicated by TLC). b Isolated yield. c This compound is unstable.20 d 1 decomposed.
Bn
5h-2 (16)
f
e The ratio of the products was determined by 1HNMR. No reaction took place.
Most of the substrate was recovered.
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Scheme 4 Plausible mechanism for the reactions of 1 with Tongi’s reagent and Zhdankin’s reagent.
A solution of thus prepared 2,3-dibromo-N-aryllpropanamide
(10 mmol ) and NaN3 (12 mmol, 0.78 g) in DMSO (50 mL) was
stirred overnight at room temperature under an argon
atmosphere. Then to the solution was injected with a syringe
1.5 mL of water containing 0.60 g of NaOH (15 mmol). 24 h
later, the mixture was poured into a saturated aqueous
NaHCO3 solution (50 mL), and was extracted with ethyl acetate
(3× 50 mL). The combined organic phases were washed with
brine (6× 100 mL), dried over Na2SO4, and concentrated under
reduced pressure on a rotary evaporator. The thus obtained
residual was treated with silica gel column chromatography
(with petroleum ether and ethyl acetate (15:1) as effluent) to
Conclusions
In summary, we have demonstrated that 2-azido-N-
arylacrylamides can react with trifluoromethyl radical via a
tandem addition/cyclization process to afford trifluoromethyl-
functionalized quinoxalin-2-ones. Togni’s reagent was used
herein as the source of trifluoromethyl radical. Similar reaction
took place between 2-azido-N-arylacrylamides and Zhdankin’s
reagent. In the latter cases, the reaction would produce 3-
azidomethyl and/or 3-cyano-subsituted quinoxalin-2(1H)-ones.
Both reactions involve -(arylaminocarbonyl) iminyl radicals as
give 1 23
.
key intermediates, from which quinoxalin-2-one products are
formed via cyclization. The yields of these reactions are in
general moderate, which can be ascribed to influences of both
the electronic effect and steric effect around the iminyl radical
center. Besides the mechanistic implications, the current study
provides a new approach to gain access to functionalized
quinoxalin-2-ones.
General procedure for the reaction of compounds 1 with Togni’s
reagent
A mixture of
and CuI (0.05 mmol, 9.5 mg) in 5 mL toluene was stirred at 80
C (in an oil bath) under an argon atmosphere for 16 h. The
1 (0.5 mmol), Togni’s reagent (2.0 mmol, 632 mg)

reaction mixture was then cooled to room temperature, and
was poured into a saturated aqueous K2CO3 solution (10 mL).
The aqueous phase was extracted with ethyl acetate (3× 10
mL), and the combined organic layers were washed
sequentially with saturated aqueous K2CO3 solution (10 mL)
and brine, and then dried over Na2SO4. The solvent was
evaporated under reduced pressure on a rotary evaporator,
Experimental
General procedure for the preparation of 2-azido-N-
arylacrylamides (1)
2-Azido-N-arylacrylamides were prepared from arylamines in and the residual was treated with silica gel column
two steps following the procedure given below. chromatography (with petroleum ether and ethyl acetate (10:1)
To a stirred solution of the arylamine (15 mmol ) in 30 mL CCl4 as effluent unless otherwise specified) to give product
was added a solution of 2,3-dibromopropanoyl chloride (15 General procedure for the reaction of compounds 1 with
mmol, 3.75 g) in 10 mL CCl4 over 30 min at ice-salt baths. The Zhdankin’s reagent
2 (or 3g).
mixture was stirred at room temperature for 12 h. After that,
A mixture of
mg) and CuI (0.05 mmol, 9.5 mg) in 5 mL toluene was stirred at
60 C (in an oil bath) under an argon atmosphere until was
consumed completely as indicated by TLC ( 4-16 h). The
reaction mixture was then cooled to room temperature, and
was poured into a saturated aqueous K2CO3 solution (10 mL).
The aqueous phase was extracted with ethyl acetate (3× 10
mL), and the combined organic layers were washed
sequentially with saturated aqueous K2CO3 solution (10 mL)
and brine, and then dried over Na2SO4. The solvent was
1 (0.5 mmol), Zhdankin’s reagent (1.0 mmol, 289
the mixture was poured into a saturated aqueous NaHCO3
solution (50 mL), and the aqueous phase was extracted with
CH2Cl2 (3× 30 mL). The combined organic phases were then
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure on a rotary evaporator. The thus obtained
crude product was purified by column chromatography on
silica gel (with petroleum ether and ethyl acetate (15:1) as
effluent unless otherwise specified) to give 2,3-dibromo-N-
aryllpropanamide.22

1
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name ARTICLE
evaporated under reduced pressure on a rotary evaporator, NMR (CDCl3, 377 MHz,
and the residual was purified by silica gel column 118.03
-118.08 (m, 1F); ESI-HRMDS:OI: 1m0.1/0z39/Cc6aOlcBd0022f6oAr
chromatography (with petroleum ether and ethyl acetate (5:1) C17H12F4N2O+H = 337.0964, found 337.0956.
 ppm): -62.81 (t, J = 10.0 Hz, 3F), -
View Article Online

as effluent) to give product
4
and
5
.
1-Benzyl-6-chloro-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-
Representative characterization data
one (2c)
2-Azido-N-benzyl-N-phenylacrylamide (1a)
Yellow solid: m.p. = 149

151 °C (recrystallized from petroleum
ppm): 7.90 (d, J
6.99 = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 0.05H), 7.41 (dd, J = 2.4 Hz, J =
(m, 2H), 4.97 (s, 2H), 4.92 (d, J = 2.0 Hz, 1H), 4.88 (d, J = 2.0 Hz, 8.8 Hz, 1 H), 7.34 7.26 (m, 3H), 7.20 7.19 (m, 3H), 5.47 (s, 2H),
1H); 13C NMR (CDCl3, 75 MHz, ppm CDCl3): 164.0, 141.9, 4.67 (s, 0.10H), 3.89 (q, J = 10.4 Hz, 2H); 13C NMR (CDCl3, 100
140.0, 136.4, 129.1, 128.4, 128.3, 127.5, 127.4, 126.9, 106.4, MHz, ppm): 154.2, 152.1, 134.5, 133.1, 131.4, 131.1, 130.0,
53.4; FT-IR (KBr, cm-1): 2107, 1652.5; HRMS (ESI): calcd. for 129.4, 129.0, 128.0, 126.7, 126.3, 123.6, 115.7, 46.3, 37.6 (q, J
1
Yellow oil: Rf = 0.45 (petroleum ether : ethyl acetate = 5:1); 1H ether and CH2Cl2); H NMR (CDCl3, 400 MHz,

NMR (CDCl3, 400 MHz,
 ppm): 7.307.20 (m, 8H), 7.01




C16H14N4O+H = 279.1248, found 279.1245.
= 30 Hz); 19F NMR (CDCl3, 377 MHz,
 ppm): -62.81 (t, J = 12.0
2-Azido-N-benzyl-N-(4-fluorophenyl)acrylamide (1b)
Hz); ESI-HRMS: m/z calcd for C17H12ClF3N2O+H = 353.0669,
found 353.0659.
Yellow solid: m.p. = 41
ppm): 7.27 7.24 (m, 3H) , 7.20
4H), 4.97 (s, 1H), 4.93 (s, 2H), 4.92 (d, J = 2.0 Hz, 1H) ; 13C NMR one (2d)
(CDCl3, 100 MHz, ppm): 164.0, 161.4 (d, J = 247 Hz), 139.9, White solid: m.p. = 118
137.7, 136.1, 128.9, 128.8, 128.6, 128.5, 128.4, 127.7, 116.1, ether and CH2Cl2); H NMR (CDCl3, 400 MHz,
115.9, 106.4, 53.5; FT-IR (KBr, cm-1): 2108.8, 1642.4; ESI-HRMS: = 2.0 Hz, 1H), 7.54 (dd, J = 2.0 Hz, 9.2 Hz, 1H), 7.30 (m, 3H),
 
42 °C; 1H NMR (CDCl3, 400 MHz,

7.18 (m, 2H), 6.96 (d, J = 6.4 Hz, 1-Benzyl-6-bromo-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-


121 °C (recrystallized from petroleum
ppm): 8.06 (d, J
1

m/z calcd for C16H13FN4O+H = 297.1152, found 297.1143.
2-Azido-N-benzyl-N-(4-chlorophenyl)acrylamide (1c)
7.20

7.19 (m, 2H), 7.14 (d, J = 8.8 Hz, 1H), 5.47 (s, 2H), 3.90 (q,
ppm): 154.2,
J = 10.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz,

Colorless oil: Rf = 0.45 (petroleum ether : ethyl acetate = 5:1); 152.1, 152.0, 134.4, 134.8, 133.4, 133.0, 131.8, 129.1, 128.6,
1H NMR (CDCl3, 400 MHz,
ppm): 7.29 7.24 (m, 5H), 128.5, 128.0, 126.7, 126.3, 123.5, 116.6, 116.0, 46.3, 37.4 (q, J
7.20 ppm): -63.53 (t, J = 12.4
7.18 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.00 (d, J = 2.0 Hz, = 30 Hz); 19F NMR (CDCl3, 282 MHz,
1H), 4.94 (s, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): 164.0, Hz); ESI-HRMS: m/z calcd for C17H12F3IN2O+H = 445.0025,





140.5, 140.0, 136.2, 133.4, 129.4, 128.6, 128.5, 128.4, 127.7, found 445.0021.
106.6, 53.5; FT-IR (KBr, cm-1): 2107.8, 1652.4; ESI-HRMS: m/z 3-(Azidomethyl)-1-benzylquinoxalin-2(1H)-one (4a)
calcd for C16H13ClN4O+H = 313.0856, found 313.0849.
2-Azido-N-benzyl-N-(4-bromophenyl)acrylamide (1d)
White solid:m.p. = 61
7.96 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 7.48 (dt, J = 2.0 Hz, J = 8.0
7.27 (m, 5H), 7.25 7.23 (m, 2H), 5.52 (s, 2H),
ppm): 7.38 (d, J = 8.4 Hz, 2H), 4.67 (s, 2H); 13C NMR (CDCl3, 100 MHz, δ ppm): 154.2, 134.8,
7.16 (m, 2H), 6.87 (d, J = 8.8 Hz, 2 ), 132.7, 130.8, 130.6, 129.0, 127.8, 126.8, 124.0, 114.5, 51.8,
5.01 (d, J = 2.4 Hz, 1H), 4.95 (d, J = 2.0 Hz, 1H), 4.94 (s, 2H); 13
45.9; ESI-HRMS: m/z calcd for C16H13N5O+Na = 314.1012,
NMR (CDCl3, 75 MHz, ppm): 152.7, 137.2, 135.0, 134.0, 133.7, found: 314.1007.
133.6, 132.5, 129.3, 128.4, 126.9, 117.7, 116.4, 113.6, 46.7; FT- 4-Benzyl-3-oxo-3,4-dihydroquinoxaline-2-carbonitrile (5a)
  ppm):
63 °C; 1H NMR (CDCl3, 400 MHz,
Colorless oil: Rf = 0.53 (petroleum ether : ethyl acetate = 5:1); Hz, 1H), 7.37
1H NMR (CDCl3, 400 MHz,
7.25 7.18 (m, 3H), 7.18





Ｈ
C

IR (KBr, cm-1): 2109.8, 1646.4; ESI-HRMS: m/z calcd for Brown solid: m.p. = 175
C16H13BrN4O+H = 357.0351, found 357.0344.

178 °C; H NMR (CDCl3, 300 MHz,
ppm): 7.96 (d, J = 10.0 Hz, 1H), 7.66 (t, J = 10.0 Hz, 1H),
7.45
7.25 (m, 7H), 5.53 (s, 2H); 13C NMR (CDCl3, 75 MHz, δ

1
1-Benzyl-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (2a)

White solid: m.p. = 109

112 °C (recrystallized from petroleum ppm): 153.1, 134.6, 133.9, 133.7, 133.4, 133.1, 131.9, 129.1,
ether and CH2Cl2); H NMR (CDCl3, 400 MHz, ppm): 7.90 (dd, 128.2, 127.0, 125.0, 115.0, 114.0, 46.5; HRMS (ESI): calcd. for
J = 8.0 Hz, 1.6 Hz, 1H), 7.47 (dt, J = 1.6 Hz, 8.0 Hz, 1H) C16H11N3O+Na = 284.0794, found: 284.0798.
7.33
7.22 (m, 7H), 5.51 (s, 2H), 3.90 (q, J = 10.4 Hz, 2H); 13C 3-(Azidomethyl)-1-benzyl-6-fluoroquinoxalin-2(1H)-one (4b)
NMR (CDCl3, 100 MHz,
132.7, 131.2, 130.7, 129.0, 127.8, 126.8, 125.1, 124.0, 114.5, NMR (CDCl3, 400 MHz,
46.2, 37.4 (q, J = 30 Hz); 19F NMR (CDCl3, 282 MHz,
ppm): - 1H), 7.35 7.28 (m , 3H), 7.24
63.66 (dt, J= 3.0, 12.0 Hz); ESI-HRMS: m/z calcd for 2H); 13C NMR (CDCl3, 100 MHz,
C17H13F3N2O+H = 319.1058, found 319.1051. 155.8, 153.8, 134.5, 133.3, 133.1, 129.2, 129.1, 129.0, 128.0,
1-Benzyl-6-fluoro-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one 126.7, 118.8, 116.1, 115.8, 115.8, 115.7, 51.7, 46.1; HRMS (ESI):
1

，

1

ppm): 154.6, 150.7, 134.8, 132.7, Yellow oil: Rf = 0.37 (petroleum ether : ethyl acetate = 3:1); H
ppm): 7.65 (dd, J = 2.4 Hz, J = 8.4 Hz,
7.21 (m, 4H), 5.50 (s, 2H), 4.66 (s,
ppm): 158.7 (d, J = 244 Hz),





(2b)
calcd. for C16H12FN5O+Na = 332.0918, found 332.0923.
White solid: m.p. = 108

110 °C (recrystallized from petroleum 4-Benzyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-2-
ether and CH2Cl2); 1H NMR (CDCl3, 400 MHz,

ppm): 7.61
7.20 (m, 4H), 5.50 (s, 2H), Light yellow solid: m.p. = 205
3.91 (q, J = 10.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz,
ppm): ppm): 7.65 (dd, J = 2.4 Hz, J = 8.0 Hz, 1H), 7.42
158.7 (d, J = 253 Hz), 154.3, 152.3, 152.2, 134.6, 133.2, 133.1, 7.31
7.21 (m, 2H), 5.52 (s, 2H) ; 13C NMR (CDCl3, 100 MHz,
7.59 carbonitrile (5b)
(m, 1H), 7.34

7.27 (m, 3H), 7.24


208 °C; 1H NMR (CDCl3, 400 MHz,
7.33 (m , 5H),





129.4, 129.3, 129.1, 128.0, 126.8, 126.7, 126.3, 123.6, 119.0, ppm): 158.9 (d, J = 246 Hz), 152.7, 135.3, 133.7, 133.6, 133.5,
118.9, 116.1, 115.9, 115.8, 115.7, 46.4, 37.5 (q, J = 30 Hz); 19F 130.2, 129.3, 129.1, 128.4, 126.9, 126.8, 122.9, 122.6, 117.0,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
Chimica, 2012, 42, 1417–1427; (c) A. Studer, Angew. Chem.
Int. Ed., 2012, 51, 8950–8958; (d) S.DOBaI:r1a0t.a10-V39a/lCle6jOoBa0n02d26AA.
Postigo, Coord. Chem. Rev., 2013, 257, 3051–3069.
116.7, 116.4, 116.4, 113.7, 46.8; HRMS (ESI): calcd. for
C16H10FN3O+Na = 302.0700, found 302.0702.
View Article Online
3-(Azidomethyl)-1-benzyl-6-chloroquinoxalin-2(1H)-one (4c)
8
9
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1
White solid: m.p. = 128

130 °C; H NMR (CDCl3, 400 MHz,

ppm): 8.13 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 2.4 Hz, J = 8.8 Hz,
1H), 7.34 7.26 (m , 3H), 7.22 7.20 (m, 3H), 5.48 (s, 2H), 4.64 (s,
2H); 13C NMR (CDCl3, 100 MHz,
ppm): 155.7, 153.8, 134.4,



133.1, 131.2, 130.8, 129.8, 129.4, 129.1, 128.0, 126.7, 115.7,
57.6, 46.0; HRMS (ESI): calcd. for C16H12ClN5O+Na = 348.0623,
found 348.0626.
4-Benzyl-7-chloro-3-oxo-3,4-dihydroquinoxaline-2-
carbonitrile (5c)
Yellow solid: m.p. = 195
1

198 °C; H NMR (CDCl3, 400 MHz,

ppm): 7.95 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 2.4 Hz, J = 9.2 Hz,
1H), 7.37 7.30 (m, 4H), 7.25
7.23 (m, 2H), 5.50 (s, 2H); 13C
NMR (CDCl3, 100 MHz, ppm): 152.7, 135.1, 134.5, 133.6,



133.4, 132.0, 130.9, 130.6, 129.3, 128.4, 126.9, 116.2, 113.7,
46.8; HRMS (ESI): calcd. for C16H10ClN3O+Na = 318.0405, found
318.0413.
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11 Q Wang, J. Huang and L. Zhou, Adv. Synth. Catal., 2015, 11
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,
carbonitrile (5d)
Yellow solid: m.p. = 197
1

200 °C; H NMR (CDCl3, 400 MHz,

12 (a) T. Hiyama, Organofluorine Compounds: Chemistry and
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1H), 7.36 7.30 (m, 3H), 7.27


7.23 (m, 3H), 5.50 (s, 2H); 13C
NMR (CDCl3, 100 MHz, δ ppm): 152.7, 137.2, 135.0, 134.0,
133.7, 133.6, 132.5, 129.3, 128.4, 126.9, 117.7, 116.4, 113.6,
46.7; HRMS (ESI): calcd. for C16H10BrN3O+Na = 363.9879, found
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,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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18 For examples of azidation reactions using Zhdankin’s reagent,
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20 Compounds 5f 5l-1 5l-2 4m-2 5m-2 and 5r are unstable;
,
,
,
,
they began to decompose when samples were prepared for
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23 N. Jiang, J. Fan, T. Liu, J. Cao, B. Qiao, J. Wang, P. Gao and X.
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