Photoinduced Cyclizations of o-Diisocyanoarenes with Organic Diselenides and Thiols that Afford Chalcogenated Quinoxalines

Article abstract of DOI:10.1021/acs.joc.0c00647

This study describes the syntheses of 2,3-bis(selanyl)quinoxalines via the photoinduced cyclizations of o-diisocyanoarenes with diaryl or dialkyl diselenides, in addition to providing a detailed discussion of the corresponding mechanism and revealing that the developed procedure can also be applied to prepare 2-thiolated quinoxaline derivatives from o-diisocyanoarenes and thiols. The developed technique does not need the use of additives or metal catalysts and features the advantages of a high conversion, a broad substrate scope, and mild reaction conditions, thereby rendering it a valuable addition to the quinoxaline synthesis toolbox.

Full text of DOI:10.1021/acs.joc.0c00647

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Article
Photoinduced Cyclizations of o-Diisocyanoarenes with Organic
Diselenides and Thiols that Afford Chalcogenated Quinoxalines
Cong Chi Tran, Shin-ichi Kawaguchi, Fumiya Sato, Akihiro Nomoto, and Akiya Ogawa
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2020
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The Journal of Organic Chemistry
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Photoinduced Cyclizations of o-Diisocyanoarenes with Organic
Diselenides and Thiols that Afford Chalcogenated Quinoxalines
Cong Chi Tran†, Shin-ichi Kawaguchi§,*, Fumiya Sato†, Akihiro Nomoto†, and Akiya Ogawa†,*
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†Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho,
Nakaku, Sakai, Osaka 599-8531, Japan
§Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-
cho Karatsu, Saga 847-0021, Japan.
ABSTRACT: This study describes the syntheses of 2,3-bis(selanyl)quinoxalines via the photoinduced cyclizations of o-
diisocyanoarenes with diaryl or dialkyl diselenides, in addition to providing a detailed discussion of the corresponding
mechanism, and revealing that the developed procedure can also be applied to prepare 2-thiolated quinoxaline derivatives
from o-diisocyanoarenes and thiols. The developed technique avoids the use of additives or metal catalysts and features the
advantages of a high conversions, a broad substrate scope, and mild reaction conditions, thereby rendering it a valuable
addition to the quinoxaline synthesis toolbox.
reported14 (Scheme 2(c)). These reactions utilize the good
INTRODUCTION
radical acceptor properties of isocyanides.15
The Masamune–Bergman cyclization, i.e., the thermal or
Thus, we herein describe the photoinduced cyclization
photochemical cycloaromatization of an endiyne in the
reactions of o-diisocyanoarenes
1
with diorganyl
presence of a hydrogen donor such as 1,4-cyclohexadiene
(Scheme 1(a)) to afford a substituted arene,1 involves the
formation of an arene biradical as the key intermediate and
is widely used in natural products synthesis2 and in the
cleavage of DNA.3 The quinoline 2,4-biradical intermediate
formed during the photoinduced/thermal aza-Bergman
cyclization of an o-alkynylarylisocyanide can be trapped
diselenides 2 that afford 2,3-bis(selanyl)quinoxalines 3 and
the cyclization reactions of o-diisocyanoarenes 1 with thiols
4 that afford 2-thiylquinoxalines 5, respectively. This
manuscript shows that these cyclization reactions can be
carried out under mild metal- and additive-free conditions
(Scheme 3).
6
with I2,4 (PhSe)2,5 or (PhTe)2 to furnish heteroatom-
Scheme 1. Cycloaromatizations Reactions of Endiynes
and Their Analogues
substituted quinoline derivatives (Scheme 1(b)), or,
alternatively, it can be trapped with a hydrogen donor such
as a tin hydride, PhSeH, or an alkanethiol, to afford a
quinoline derivative.5
However, arenethiols, which are more acidic than
alkanethiols, prefer to undergo an ionic cyclization reaction
over aza-Bergman cyclization, especially in the presence of
a base such as triethylamine (Scheme 1(c)).5,7 Notably,
while o-alkynylarylisocyanides undergo ionic cyclization in
the presence of alcohols, amines, active methylene
compounds,8
and
hydrogen
halides,9
o-
alkenylarylisocyanides predominantly undergo radical
cyclization, as exemplified by their photoinduced 5-exo-
cyclizations with (PhS)2 in the presence of (PhTe)2 (Scheme
1(d)). 10
Recently, several examples of quinoxaline syntheses from
o-diisocyanoarenes
via
radical-mediated
perfluoroalkyliodination11,12 and hydrophosphorylation13
processes have been reported (Schemes 2(a) and 2(b)), and
the
efficient
syntheses
of
N-
(carboselenoate)benzimidazolones via the cascade
cyclization reactions of o-diisocyanides have also been
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Page 2 of 11
Masamune-Bergman Cyclization
NC
+
NC
N
N
XPh
XPh
Xenon lamp ( >300 nm)
R1
H
H
(PhX)2
1
2
3
4
5
6
7
8
R1
R2
R1
CDCl3 (0.5 mL), r.t., 9 h, Ar
h or
(a)
1a
R2
R2
Entry
1
(PhX)2
Yieldb, %
N.D
Aza-Bergman Cyclization
(PhS)2 2.0 equiv.
R1
E
R1
R1
E
(PhS)2 2.0 equiv., and (PhSe)2
2.0 equiv.
E-E
h or
2
80 (40/40)b
R
R
R
NC
N
N
H
E = ArSe,
9
3
4
(PhSe)2 2.0 equiv.
90
N.Dc
ArTe,
I
(b)
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(PhTe)2 2.0 equiv.
R1
H
E-H
R
aReaction conditions: 1a (0.1 mmol), diphenyl
dichalcogenide, CDCl3 (0.5 mL) under Ar, Pyrex tube, room
temperature, 9 h. N.D.: not detected. bA mixture of cyclic
E = Bu3Sn,
(TMS)3Si,
RS
N
Ionic Cyclization
R
thioselenide
and
diselenide,
i.e.,
[H-base]+
R1
R1
H
N
N
SePh
N
SPh
and
R1
E
E-H
N
SePh
N
SePh
was formed (1:1 ratio, as
(c)
R
R
-base
E
determined by 77Se NMR spectroscopy). cA filter ( > 400 nm)
was used.
base
NC
N
E = MeO,
Et2N,
(EtO2C)2CH
X (F, Cl, Br, I)
ArS
RESULTS AND DISCUSSION
Radical Cyclization
R1
Initially, we investigated the photoinduced reactions of o-
diisocyanobenzene (1a) with diphenyl dichalcogenides
(Table 1). In the case of diphenyl disulfide (X = S), the
desired thiolated quinoxaline was not formed (entry 1).
When equimolar amounts of diphenyl disulfide and
diphenyl diselenide (2a, X = Se) were used, a 1:1 mixture of
thioselenated and diselenated quinoxaline derivatives was
obtained (entry 2) while 2,3-bis(phenylselanyl)quinoxaline
(3a) was produced in high yield in the presence of two
equivalents of 2a alone (entry 3). In sharp contrast, no
reaction was observed when diphenyl ditelluride was used
instead of 2a (entry 4).
R1
R1
E
h, E-E
(PhTe)2
(d)
R
R
R
E
NC
N
E
N
H
E = ArS
Scheme 2. Radical Cyclization Reactions of o-
Diisocyanoarenes
NC
N
N
I
RfI
R
R
(a)
(b)
(c)
R
R
NC
Rf
Table 2. Optimization of the Photoinduced Cyclization
of o-Diisocyanobenzene with Diphenyl Diselenide
N
N
H
NC
NC
R2P(O)H
N
N
SePh
SePh
NC
lamp
P(O)R2
(PhSe)2
+
solvent, r.t., 9 h, Ar
NC
O
SeR
O
1a
2a
3a
, 0.1 mmol
NC
NC
N
PhS(O)2SeAr
R
R
Entry
1
Reaction conditions
Yield (%)
N
H
Mercury lamp, (PhSe)2 1.0 equiv., 48
0.5 mL CDCl3
Scheme 3. Photoinduced Cycloaromatization Reactions
2
3
4
5
6
7
Tungsten lamp, (PhSe)2 1.0 59
equiv., 0.5 mL CDCl3
of o-Diisocyanoarenes
N
N
SeR1
SeR1
h, (R1Se)2 (2)
Xenon lamp, (PhSe)2 1.0 equiv., 71
0.5 mL MeCN
R
R
NC
NC
Xenon lamp, (PhSe)2 1.0 equiv., 67
0.5 mL CH2Cl2
3
5
R
h, R2SH (4)
N
N
H
Xenon lamp, (PhSe)2 1.0 equiv., 81
0.5 mL CDCl3
1
SR2
Xenon lamp, (PhSe)2 2.0 90
equiv., 0.5 mL CDCl3
Table
1.
Photoinduced
Reactions
of
o-
Xenon lamp, (PhSe)2 3.0 equiv., 72
0.5 mL CDCl3
Diisocyanobenzene (1a) with Chalcogenidesa
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8a
9
In dark, (PhSe)2 2.0 equiv., 0.5 33
mL toluene
Notably, selenides bearing electron-donating or electron-
withdrawing groups were supported. When m,p-
difluorinated diaryl diselenide was employed, quinoxaline
1
2
3
4
5
6
7
a
In dark, (PhSe)2 2.0 equiv., 0.5
mL CDCl3
0
3j was isolated in good yield (78%). Owing to the steric
effect,
bis(o-chlorophenyl)
diselenide
gave
the
a80 °C.
corresponding quinoxaline 3k in a low yield. Interestingly,
the reaction of 1a with aliphatic diselenides (diethyl
diselenide and dibutyl diselenide) afforded the desired
quinoxalines (3l and 3m, respectively) in good yields.
Furthermore, we examined the o-diisocyanobenzene scope.
8
9
Table 3. Cyclization Reactions of o-Diisocyanoarenes
with Diselenides:a,b Reaction Scope
The
cyclization
of
methyl-substituted
o-
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diisocyanobenzenes with 2a successfully afforded the
corresponding products (3n and 3o) in yields of 90 and
77%, respectively. In the case of o-diisocyanobenzene
bearing an electron-withdrawing group, the desired
quinoxaline 3p was obtained in satisfactory yield (83%).
The reaction was also scalable in good yield (Table 3,
footnote c).
NC
N
N
SeR1
SeR1
Xe lamp
(R1Se)2
+
R
R
CDCl3 (0.5 mL), r.t., 9 h, Ar
NC
1
2
3
X
3a, X = H, 90%, 83%c
3f, Y = CH3, 57%
3g, Y = F, 85%
3h, Y = Cl, 65%
3i, Y = CF3,77%
3b, X = OCH3, 63%
3c, X = F, 61%
N
N
Se
N
N
Se
Se
Y
Y
Se
3d, X = Cl, 79 %
3e, X = CF3, 87%
X
Table 4. Optimization of the Photoinduced Thiolative
Cyclization of 1a with Cyclohexanethiol (4a)
F
Cl
Se
Se
Cl
Z
N
N
Se
Se
F
F
F
N
N
N
N
Se
Se
SH
NC
N
H
S
Lamp
+
Z
CDCl3 (0.5 mL), r.t.,
9 h, Ar
NC
N
3j, 78%
3k, 21%
3l,
3m,
Z
Z
= C2H5, 88%
= C4H9, 99%
1a, 0.2 mmol
4a
5a
O
Entry
Reaction conditions
Yield (%)
45%
N
N
Se
Se
N
N
Se
Se
N
N
Se
Se
O
1
2
3
4
5a
6
7
Hg lamp, cHexSH 1.0 equiv.
Xenon lamp, cHexSH 1.0 equiv.
Xenon lamp, cHexSH 2.0 equiv.
Xenon lamp, cHexSH 3.0 equiv.
In dark, cHexSH 2.0 equiv.
In dark, cHexSH 2.0 equiv.
81%
3n, 90%
3o, 77%
3p, 83%
89%
72%
aReaction conditions: o-diisocyanoarene (0.1 mmol),
diselenide (0.2 mmol), CDCl3 (0.5 mL), Xe lamp, Pyrex tube, Ar,
room temperature, 9 h. bIsolated yield. cGram-scale reaction: o-
diisocyanobenzene (1a, 1.00 g, 7.8 mmol), diphenyl diselenide
(2a, 4.9 g, 15.6 mmol) in CHCl3 (10 mL).
63%
0 %
In dark, cHexSH 2.0 equiv., Et3N 4.0 9%
equiv.
Hence, 2a was chosen for further investigations into the
photoinduced
diisocyanobenzenes 1 (entry 3, Table 1). In the next step,
we optimized the reaction of 1a with 2a (Table 2).
(cHex = cyclohexyl). a In toluene (0.5 mL), 80 °C.
cyclization
reactions
of
o-
Sulfur-containing molecules are widely used in materials
chemistry, bioscience, and organic chemistry, which makes
the development of corresponding synthetic methods a task
of high importance.17 Unfortunately, because of their lower
carbon-radical capturing abilities, organic disulfides proved
to be ineffective for the cycloaromatization of o-
diisocyanoarenes (Table 1, entry 1). Consequently, we next
examined the cycloaromatization of o-diisocyanobenzene
using thiols 4 as sulfur sources under various irradiation
conditions (Table 4).
Upon irradiation with a high-pressure Hg lamp through
Pyrex glass, cyclization with hydrothiolation afforded 2-
(cyclohexylsulfanyl)quinoxaline (5a) in moderate yield
(entry 1), and this yield was found to increase when the
light source was changed to a xenon lamp (entry 2).
Similarly, high yields of 5a were obtained at elevated thiol
loadings (entries 3 and 4). Upon heating at 80 °C in the dark,
5a was obtained in a moderate yield (entry 5), while no
reaction was observed in the dark at room temperature
(entry 6). Addition of a base, Et3N, was not effective for the
desire cyclization reaction (entry 7).
The yield of 3a significantly decreased when a high-
pressure Hg lamp was employed as the light source (entry
1), whereas a tungsten lamp proved to be more suitable for
the reaction (entry 2). When acetonitrile (MeCN) or
dichloromethane (CH2Cl2) was used as the solvent, the
desired quinoxaline 3a was obtained in good yield (71 or
67% respectively, entries 3 and 4). Irradiation with a Xe
lamp gave 3a in a yield of 81% (entry 5), which increased to
90% (entry 6) when the loading of 2a was raised to 2.0
equiv. and decreased as this loading was increased further
(entry 7). Heating at 80 °C in toluene in the dark led to a low
yield of 3a (entry 8)16, whereas no reaction was observed at
room temperature in the dark (entry 9). Hence, the
conditions of entry 6 were chosen to investigate the
substrate scope of the transformation (Table 3).
A variety of substituted diaryl diselenides was generally
tolerated. p-Substituted diaryl diselenides gave the desired
bisselenated quinoxalines 3b–3e in moderate-to-good
yields, while products from m-substituted diaryl
diselenides 3f–3i were obtained in 57–85% isolated yields.
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We considered the following two pathways for the
1
2
3
4
5
6
7
8
Table 5. Cyclization Reactions of o-Diisocyanoarenes
mechanism of the photoinduced bisselenative cyclization of
an o-diisocyanoarene with an organic diselenide (Scheme
4). o-Diisocyanobenzene absorbs in the near-UV region and
therefore can undergo an aza-Bergman-type cyclization
upon irradiation with near-UV light to generate biradical
species that are subsequently captured by organic selenides
(path a). Alternatively, selenyl radicals generated by
irradiation with near-UV or visible light18 may attack an
with Thiols:a,b Substrate Scope
NC
NC
N
N
H
Xe lamp
R
R
+
R1SH
SR1
CDCl3 (0.5 mL), r.t., 9 h, Ar
1
5
4
N
N
N
N
isocyanide group in
1 to form an imidoyl radical
9
N
S
N
S
S
intermediate that can then intramolecularly add to the
other isocyano group to afford a cyclized imidoyl radical
that is finally captured by the diselenide to afford 3 (path b).
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11
12
13
14
15
16
17
18
19
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22
23
24
25
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27
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46
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48
49
50
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52
53
54
55
56
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58
59
60
Cl
5a, 89%
5b, 63%
5c, 62%
N
N
N
C10H21
N
S
N
S
N
S
Scheme 4. Possible Pathways for the Bisselenative
Cyclization of an o-Diisocyanoarene
5d, 87%
5e, 89%
5f, 71%
F
F
h or
2 R1Se
R1SeSeR1
N
N
N
F
N
F
S
F
F
N
S
S
N
(path a)
SeR1
SeR1
NC
N
N
N
R1SeSeR1
5g, 68%
5h, 63%
5i, 69%
h or
R
R
R
N
OMe
N
N
NC
N
1
3
N
S
S
(path b)
R1Se
-R1Se
R1SeSeR1
N
C
N
N
5j, 64%
5k, 71%
R
R
SeR1
O
N
N
N
N
SeR1
N
O
S
N
S
N
S
5n + 5n',65% (31%/34%)b
5l, 81%
Unsuccessful examples
5m + 5m',74% (44%/30%)
Scheme 5. Mechanistic Insight into the Bisselenative
Cyclization Reactions of o-Diisocyanobenzene
OH
N
N
N
N
NC
N
H
N
N
H
iPr
Si iPr
iPr
h (>300 nm)
(a)
(b)
NH2
+
PhSeH
S
N
S
N
S
NC
N
H
SePh
1, 0.1 mmol 2.5 mmol
6, not detected
7, 30% NMR yield
aReaction conditions: o-diisocyanoarene (0.2 mmol), thiol
(0.4 mmol), CDCl3 (0.5 mL), xenon lamp, Pyrex tube, argon,
room temperature, 9 h. bIsomer ratio was determined by 1H
NMR spectroscopy.
N
H
H
NC
h (>300 nm)
+
(TMS)3SiH
2.5 mmol
N
NC
1, 0.1 mmol
6, not detected
With the above results in mind, we selected the
conditions of entry 3 in Table 4 to study the substrate scope
of the thiolative o-diisocyanoarene cyclization reaction
(Table 5). When aliphatic thiols were used to cyclize 1a, the
desired cycloaromatization products 5a–5f were obtained
in moderate to high yields (62–89%). Despite steric
hindrance, tert-butanethiol successfully afforded the
corresponding quinoxaline 5f in a 71% yield. Furthermore,
a variety of aromatic thiols was tolerated, affording
quinoxaline derivatives 5g–5k in good yields (64–71%).
The substituent on the aromatic thiol had no significant
effect on the yields of the cyclization products. Moreover,
To clarify which pathway contributes to the bisselenated
cyclization of 1, we examined the photoinduced reactions of
1a with benzeneselenol and (TMS)3SiH (Scheme 5). If path
a in Scheme 4 is dominant, formation of quinoxaline (6) is
excepted. However, no quinoxaline (6) was obtained,
probably because radical cyclization follows path b in which
6 cannot be formed. This result strongly suggests that o-
diisocyanobenzene does not undergo the aza-Bergman-
type cyclization when irradiated at room temperature. In
Scheme 5(a), selenoquinoxaline adduct 7 is confirmed as a
byproduct. This result might support that pathway b is
preferred.
c
the reaction of HexSH with o-diisocyanoarenes provided
We subsequently examined the cyclization of o-
diisocyanobenzene with 2a or benzenethiol in the presence
good yields of quinoxalines 5l–5n. In the cases of 5m and
5n, a regioisomeric mixture (5m’ and 5n’, respectively) was
obtained. Unfortunately, the developed cyclization protocol
was not applicable to thiols bearing unprotected alcohol
groups (a complex mixture was formed), amines (no
product), and (iPr)3SiSH (no product). In summary, thiols
were tolerated to provide the corresponding thiolated
quinoxalines 5 in moderate to good yields.
of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as
a
radical-trapping reagent (Scheme 6). In the case of 2a, no
reaction was observed (Scheme 6(a)), which strongly
suggests that the bisselenative cyclization involves a radical
process. Similarly, thiolative cyclization reaction in the
presence of benzenethiol (4a) barely proceeded in the
presence of TEMPO (Scheme 6(b) and 6(d)). The base
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Pathway a
selected was found to have no significant effect on the
1
2
3
4
5
6
7
product yield (Scheme 6(c) and 6(d)). We therefore
consider that radical pathway is dominant in the case of
aliphatic thiol although an ionic pathway is not still
RSH
RS
excluded19,20
.
NC
N
N
C
N
N
RS
R
R
R
Scheme 6. Mechanistic Insight into the Bisselenative
Cyclization of o-Diisocyanobenzene
SR
NC
1
SR
Xe lamp
TEMPO (0.4 mmol)
8
9
H
N
RSH
NC
NC
N
SePh
SePh
R
(PhSe)2
(a)
(b)
H
+
+
CDCl3 (0.5 mL), r.t.
Ar, 9 h
- RS
2a
SR
N
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N.D.
0.1 mmol
0.2 mmol
Pathway b
RSH
RS
H
+
Xe lamp
TEMPO (0.4 mmol)
SH
NC
NC
N
N
H
CDCl3 (0.5 mL), r.t.
Ar, 9 h
ScHex
NC
N
N
C
N
N
RS
4a
0.4 mmol
R
R
R
0.2 mmol
14% NMR yield
SR
NC
Xe lamp
Et3N 200% mol (0.4 mmol) or
30% mol (0.06 mmol)
1
SR
H
N
SH
RSH
NC
NC
N
N
R
+
+
(c)
CDCl3 (0.5 mL), r.t.
Ar, 9 h
ScHex
SR
- RS
N
5
0.2 mmol
0.4 mmol
SH
91% NMR yield
Xe lamp
Et3N (0.4 mmol), TEMPO
(0.4 mmol)
NC
NC
N
N
H
CONCLUSIONS
(d)
ScHex
CDCl3 (0.5 mL), r.t.
Ar, 9 h
In summary, we developed mild and efficient
photoinduced cyclization reactions of o-diisocyanoarenes
with organic diselenides and thiols that afford
chalcogenated quinoxalines. In the case of a diselenide,
cyclization is believed to involve a radical process, while
both a radical pathway and an ionic pathway are considered
in the case of thiols. The developed protocol can be used to
establish a library of chalcogen-substituted quinoxalines
which are known to be potential oxidants with promising
bioactivities.
0.2 mmol
0.4 mmol
15% NMR yield
A possible pathway for the thiolative cyclization of an o-
diisocyanoarene is shown in Scheme 7. Thiyl radicals
generated by irradiation with near-UV or visible light may
attack an isocyano group in 1 to form an imidoyl radical
intermediate that can then intramolecularly add to the
other isocyano group to afford a cyclized imidoyl radical
that is finally captured by the thiol to afford 5 (Pathway a).
Alternatively, thiolate anion generated from the
corresponding thiol attacks an isocyano group in 1 to form
an imidoyl anion intermediate that can then
intramolecularly add to the other isocyano group to afford
the quinoxaline anion that is finally protonated by the thiol
to afford 5 (Pathway b).
EXPERIMENTAL SECTION
General Remarks
Unless otherwise stated, all starting materials and
catalysts were purchased from commercial sources and
used without further purification. All solvents were distilled
and degassed with N2 before use. Thiol, diphenyl
dichalchogenide, and diethyl diselenide 2l were purchased
from Tokyo Chemical Industry. Other diselenides 2b–k, 2m,
and o-diisocyanoarenes 1b–d were prepared according to
previously reported procedures.11,18,19 1H NMR spectra were
recorded on JEOL JNM-ECS400 (400 MHz) and JEOL JNM-
ECX400 (400 MHz) FT spectrometers in CDCl3 with Me4Si as
the internal standard. 13C NMR spectra were recorded on
JEOL JNM-ECX400 (100 MHz) FT NMR or JEOL JNM-ECS400
(100 MHz) FT NMR spectrometers in CDCl3. 19F and 77Se
NMR spectra were recorded on a JEOL JNM-ECX400 (373
MHz and 75 MHz, respectively) instrument in CDCl3 with
CFCl3 and Me2Se as external standards, respectively. IR
spectra are reported in wave numbers (cm−1). ESI and EI
mass spectra were recorded using double-focusing mass
spectrometers. High-resolution mass spectra (HRMS) were
recorded on a Bruker micrOTOF II ESI(+)/TOF instrument.
Scheme 7. A Possible Pathway for the Thiolative
Cyclization of an o-Diisocyanoarene
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General Procedure for the Synthesis of o- Procedure for the Gram-Scale Reaction of 1a with 2a.
Diisocyanides.10 An equimolar mixture of formic acid and
acetic anhydride (slight excess of formic acid) was stirred
for 2 h at 55–60 °C in an oil bath to form formic acetic
anhydride in situ (5.3 mL, 40.0 mmol, 4.0 equiv.). The
prepared mixture was added to a solution of aryl diamine
(10 mmol, 1.0 equiv.) in DCM (15 mL) at 0 °C. After stirring
for 2–3 h at room temperature, saturated aqueous NaHCO3
was added and the aqueous phase was extracted multiple
times with DCM and ethyl acetate (EtOAc). The combined
organic phases were dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was dissolved in a
mixture of DCM (15 mL) and trimethylamine (17 mL, 0.12
mol, 12 equiv.), and the solution was slowly charged with
POCl3 (2.7 mL, 30 mmol, 3.0 equiv.) at 0 °C. The resulting
mixture was then stirred for 2 h at this temperature, after
which saturated aqueous NaHCO3 was added slowly. After
stirring for at least 1 h at room temperature, the aqueous
phase was extracted three times with DCM. The combined
organic phases were dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The desired o-diisocyanides 1
were isolated by silica gel column chromatography
(hexane/ Et2O = 100/10 - 100/30).
o-Diisocyanobenzene 1a (1.00 g, 7.8 mmol), diphenyl
diselenide 2a (4.9 g, 15.6 mmol), and CHCl3 (10 mL) were
placed in a Pyrex tube under an argon atmosphere. The
reaction was irradiated with a xenon lamp at room
temperature for 48 h and after this time, the solvent was
evaporated and the product was purified by silica-gel
column chromatography (hexane/AcOEt = 100/1) to afford
quinoxaline 3a (83%, 3.45 g).
1
2
3
4
5
6
7
8
Spectral Data for the Products
9
2,3-Bis(phenylselanyl)quinoxaline (3a).24 The product was
purified by preparative TLC (hexane/AcOEt = 9/1). Yellow
solid, 39.8 mg, 90%, mp 90–92 °C; 1H NMR (400 MHz,
CDCl3): δ 7.85–7.63 (m, 6H), 7.55–7.47 (m, 2H), 7.45–7.33
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.4, 142.0,
135.8, 129.4, 129.0, 128.5. 127.9; 77Se NMR (75 MHz, CDCl3):
δ 466.6; IR (KBr, ν/cm−1): 585, 688, 737, 1020, 1068, 1122,
1152, 1237.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3-Bis((4-methoxyphenyl)selanyl)quinoxaline (3b). The
product was purified by preparative TLC (hexane/AcOEt =
1
9/1). Yellow solid, 31.6 mg, 63%, mp 142–144 °C; H NMR
(400 MHz, CDCl3): δ 7.30–7.67 (m, 2H), 7.64 (d, J = 8.7 Hz,
4H), 7.53–7.46 (m, 2H), 6.95 (d, J = 8.7 Hz, 4H), 3.86 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 155.8, 142.0, 137.8,
128.7, 128.4, 117.9, 115.1, 55.4; 77Se NMR (75 MHz, CDCl3):
δ 452.8; IR (KBr, ν/cm−1): 761, 816, 975, 1025, 1092, 1174,
1247, 1492, 2357; HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd.
for C22H18N2NaO2Se2 524.9596; Found 524.9595.
General Procedure for the Synthesis of Diselenides.21
Mg powder (0.48 g, 20 mmol), a stirring bar, and a small
piece of I2 were added to a 100-mL three-necked flask. The
flask was then equipped with a condenser and charged with
N2. Under a N2 atmosphere, anhydrous diethyl ether (10
mL) was injected using a syringe, after which 20 mmol of
the aryl bromide was added slowly followed by anhydrous
ether (5 mL). After the preparation of this Grignard reagent,
dried selenium powder (20 mmol, 1.6 g) was added slowly.
After stirring for 1 h, the mixture was dumped into 100 mL
of 3 M HCl solution cooled in ice to acidolyze the mixture.
The mixture was then extracted with diethyl ether (3 x 20
mL) and the combined organic layers were dried over
anhydrous Na2SO4. The solution was charged with O2 for 48
2,3-Bis((4-fluorophenyl)selanyl)quinoxaline (3c). The
product was purified by preparative TLC (hexane/AcOEt =
1
9/1). Yellow solid, 29.1 mg, 61%, mp 137–139 °C; H NMR
(400 MHz, CDCl3): δ 7.82–7.6 (m, 6H), 7.60–7.44 (m, 2H),
7.18–7.01 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.5
(d, JC–F = 249.2 Hz), 154.9, 142.0, 138.1 (d, JC–F = 7.7 Hz),
129.2, 128.4, 122.2 (d, JC–F = 2.9 Hz), 116.7 (d, JC–F = 22.0 Hz);
19F (373 MHz, CDCl3): δ −116.8; 77Se NMR (75 MHz, CDCl3):
δ 458.0; IR (KBr, ν/cm−1): 508, 757, 808, 976, 1065, 1095,
1126, 1156, 1227, 1485; HRMS (EI) m/z: [M]+ Calcd. for
C20H12F2N2Se2 477.9303; Found 477.9307.
h
during which time it turned a red-orange color.
Distillation of the solvent afforded the crude diselenide,
which was purified by column chromatography (eluent:
hexane) (the products may contain a small amount of
unisolable Ar2Se3 and starting material).22 Dibutyl diselenide
2m was prepared according to a literature report23 using 20
mmol of butyl bromide.
General Procedure for the Photoinduced Cyclization
of o-Diisocyanoarene with Organic Diselenide. o-
Diisocyanoarene 1(0.1 mmol), diselenide 2 (0.2 mmol), and
CDCl3 (0.5 mL) were placed sequentially into in a Pyrex tube
under an inert atmosphere. The reaction mixture was
irradiated with a xenon lamp at room temperature for 9 h,
after which the resulting solution was subjected to
preparative TLC (hexane/AcOEt = 9/1) to afford the desired
quinoxaline 3.
General Procedure for the Photoinduced Cyclization
of o-Diisocyanoarene with Thiols . o-Diisocyanoarene 1
(0.2 mmol), thiol 4 (0.4 mmol), and CDCl3 (0.5 mL) were
placed sequentially into a Pyrex tube under an inert
atmosphere. The reaction was irradiated with a xenon lamp
at room temperature for 9 h, after which the resulting
solution was subjected to preparative TLC (hexane/AcOEt =
9/1) to afford the desired quinoxaline 5.
2,3-Bis((4-chlorophenyl)selanyl)quinoxaline (3d). The
product was purified by preparative TLC (hexane/AcOEt =
1
9/1). Yellow solid, 40.3 mg, 79%, mp 165–167 °C; H NMR
(400 MHz, CDCl3): δ 7.77–7.69 (m, 2H), 7.63 (d, J = 8.2 Hz,
4H), 7.58–7.52 (m, 2H), 7.37 (d, J = 8.2 Hz, 4H);13C{1H} NMR
(100 MHz, CDCl3): δ 154.6, 142.0, 137.1, 135.4, 129.6, 129.4,
128.5, 125.8; 77Se NMR (75 MHz, CDCl3): δ 461.1; IR (KBr,
ν/cm−1): 758, 807, 979, 1012, 1090, 1472; HRMS (EI) m/z:
[M]+ Calcd. for C20H12Cl2N2Se2 509.8704; Found 509.8707.
2,3-Bis((4-(trifluoromethyl)phenyl)selanyl)quinoxaline
(3e). The product was purified by preparative TLC
(hexane/AcOEt = 9/1). Yellow solid, 50.3 mg, 87%, mp 171–
173 °C; 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.2 Hz, 4H),
7.79–7.73 (m, 2H), 7.64 (d, J = 8.2 Hz, 4H), 7.61–7.56 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.1, 142.1, 135.5,
132.5, 130.9 (q, JC–F = 32.6 Hz), 129.4 (d, JC–F = 123.6 Hz),
126.1 (q, JC−F = 3.8 Hz), 125.4, 122.7;19F (373 MHz, CDCl3): δ
−62.6; 77Se NMR (75 MHz, CDCl3): δ 468.5; IR (KBr, ν/cm−1):
762, 828, 973, 1013, 1060, 1077, 1328, 1601; HRMS (EI)
m/z: [M]+ Calcd. for C22H12F6N2Se2 577.9239; Found
577.9232.
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The Journal of Organic Chemistry
2,3-Bis(m-tolylselanyl)quinoxaline (3f). The product was
(m, 2H), 7.37−7.29 (m, 2H), 7.28−7.19 (m, 2H);13C{1H} NMR
(100 MHz, CDCl3): δ 154.4, 142.2, 138.0, 136.2, 130.1, 130.0,
129.6, 129.3, 128.7, 127.4; HRMS (EI) m/z: [M]+ Calcd. for
C20H12Cl2N2Se2 509.8704; Found 509.8711.
1
2
3
4
5
6
7
8
purified by preparative TLC (hexane/AcOEt = 9/1). Yellow
liquid, 26.8 mg, 57%; 1H NMR (400 MHz, CDCl3): δ 7.79–7.66
(m, 2H), 7.55 (s, 2H), 7.53–7.47 (m, 4H), 7.32–7.17 (m, 4H),
2.37 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.6, 142.0,
139.1, 136.1, 132.7, 129.6, 129.1, 128.9, 128.5, 127.7, 21.4;
77Se NMR (75 MHz, CDCl3): δ 466.5; IR (KBr, ν/cm−1): 685,
759, 974, 1091, 1161, 1246, 1472, 1512, 1642, 3462; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C22H18N2NaSe2
492.9698; Found 492.9688.
2,3-Bis(ethylselanyl)quinoxaline (3l). The product was
purified by preparative TLC (hexane/AcOEt = 9/1). Yellow
1
oil, 30.4 mg, 88%; H NMR (400 MHz, CDCl3): δ 7.94−7.82
(m, 2H), 7.63−7.53 (m, 2H), 3.36 (q, J = 7.9 Hz, 4H), 1.58 (t, J
= 7.3 Hz, 6H);13C{1H} NMR (100 MHz, CDCl3): δ 155.7, 141.4,
128.3, 127.9, 21.6, 15.3; 77Se NMR (75 MHz, CDCl3): δ 373.6;
IR (NaCl, ν/cm−1): 758, 961, 984, 1100, 1125, 1162, 123,
1371, 1511, 2863, 2921; HRMS (EI) m/z: [M]+ Calcd. for
C12H14N2Se2 345.9490; Found 345.9494.
9
2,3-Bis((3-fluorophenyl)selanyl)quinoxaline (3g). The
product was purified by preparative TLC (hexane/AcOEt =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
9/1). Yellow solid, 40.6 mg, 85%, mp 118−120 °C; H NMR
(400 MHz, CDCl3): δ 7.90−7.71 (m, 2H), 7.64−7.53 (m, 2H),
7.52−7.43 (m, 4H), 7.42−7.30 (m, 2H), 7.19−7.04 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 162.7 (d, JC−F = 250.2 Hz),
154.5, 142.1, 131.0 (d, JC−F = 2.9 Hz), 130.5 (d, JC−F = 7.7 Hz),
129.5, 129.2 (d, JC−F = 7.7 Hz), 128.5, 122.4 (d, JC−F = 22.0 Hz),
116.1 (d, JC−F = 21.1 Hz);19F (373 MHz, CDCl3): δ −111.4; 77Se
NMR (75 MHz, CDCl3): δ 471.5; IR (KBr, ν/cm−1): 674, 755,
752, 856, 978, 1093, 1125, 1160, 1210, 1424, 1470; HRMS
(EI) m/z: [M]+ Calcd. for C20H12F2N2Se2 477.9303; Found
477.9293.
2,3-Bis(butylselanyl)quinoxaline (3m). The product was
purified by preparative TLC (hexane/AcOEt = 9/1). Yellow
oil, 39.8 mg, 99%; H NMR (400 MHz, CDCl3): δ 7.95−7.82
1
(m, 2H); 7.83−7.51 (m, 2H), 3.39 (t, J = 7.3 Hz, 4H), 1.84
(quintet, J = 7.3 Hz, 4H), 1.51 (septet, J = 7.3 Hz, 4H), 0.97 (t,
J = 7.3 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.7,
144.3, 128.1, 127.8, 30.0, 27.4, 23.2, 12.7; 77Se NMR (75
MHz, CDCl3): δ 343.5; IR (KBr, ν/cm−1): 587, 758, 983, 1101,
1162, 1253, 1512, 2870, 2928, 2956; HRMS (ESI+/TOF)
m/z: [M+Na]+ Calcd. for C16H22N2NaSe2 425.0011; Found
425.0021.
6,7-Dimethyl-2,3-bis(phenylselanyl)quinoxaline (3n). The
product was purified by preparative TLC (hexane/AcOEt =
9/1). Yellow solid, 42.3 mg, 90%, 160-162 °C; 1H NMR (400
MHz, CDCl3): δ 7.80−7.62 (m, 4H), 7.47 (s, 2H), 7.43−7.31
(m, 6H), 2.33 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
153.9, 141.0, 139.5, 135.5, 129.3, 128.6, 128.5, 127.7, 20.1;
77Se NMR (75 MHz, CDCl3): δ 463.2; IR (KBr, ν/cm−1): 971,
1099, 1194, 1237, 1437, 1474, 1506, 2358; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C22H18N2NaSe2
492.9698; Found 492.9690.
2,3-Bis((3-chlorophenyl)selanyl)quinoxaline (3h). The
product was purified by preparative TLC (hexane/AcOEt =
1
9/1). Yellow solid, 33.1 mg, 65%, mp 157−159 °C; H NMR
(400 MHz, CDCl3): δ 7.88−7.70 (m, 4H), 7.65−7.51 (m, 4H),
7.45−7.28 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.4,
142.1, 135.2, 134.8, 133.6, 130.3, 129.5, 129.2, 129.1, 128.6;
77Se NMR (75 MHz, CDCl3): δ 472.2; IR (KBr, ν/cm−1):755,
773, 976, 1094, 1457, 1506; HRMS (EI) m/z: [M]+ Calcd. for
C20H12Cl2N2Se2 509.8704; Found 509.8706.
2,3-Bis((3-(trifluoromethyl)phenyl)selanyl)quinoxaline
(3i). The product was purified by preparative TLC
(hexane/AcOEt = 9/1). Yellow solid, 44.5 mg, 77%, mp
100−102 °C; 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 2H), 7.89
(d, J = 7.8 Hz, 2H), 7.80−7.65 (m, 4H), 7.63−7.47 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 153.9, 142.1, 138.8, 130.5
(q, JC−F = 3.8 Hz), 131.6 (q, JC−F = 32.6 Hz), 129.6, 128.5, 128.4,
125.8 (q, JC−F = 2.9 Hz,), 125.2, 122.4; 19F (373 MHz, CDCl3):
δ −62.5; 77Se NMR (75 MHz, CDCl3): δ 467.9; IR (KBr,
ν/cm−1): 5503, 690, 756, 789, 975, 1066, 1081, 1093, 1110,
1171, 1276, 1304, 1324, 1423; HRMS (EI) m/z: [M]+ Calcd.
for C22H12F6N2Se2 577.9239; Found 577.9233.
5-Methyl-2,3-bis(phenylselanyl)quinoxaline (3o). The
product was purified by preparative TLC (hexane/AcOEt =
1
9/1). Yellow solid, 35.1 mg, 77%, 63−65 °C; H NMR (400
MHz, CDCl3): δ 7.83−7.66 (m, 4H), 7.47 (d, J = 7.3 Hz, 1H),
7.45−7.30 (m, 8H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 155.0, 153.7, 142.0, 141.1, 136.7, 136.5, 135.4,
129.34, 129.30, 129.2, 128.9, 128.7, 128.6, 127.98, 127.96,
126.2, 16.5; 77Se NMR (75 MHz, CDCl3): δ 476.4, 457.7; IR
(KBr, ν/cm−1): 687, 736, 765, 926, 1058, 1118, 1164, 1246,
1438, 1475, 1510; HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd.
for C21H16N2NaSe2 478.9542; Found 478.9544.
2,3-Bis((3,4-difluorophenyl)selanyl)quinoxaline (3j). The
product was purified by preparative TLC (hexane/AcOEt =
Methyl 2,3-bis(phenylselanyl)quinoxaline-6-carboxylate
(3p). The product was purified by preparative TLC
(hexane/AcOEt = 9/1). Yellow solid, 41.5 mg, 83%,
1
9/1). Yellow solid, 40.1 mg, 78%, mp 162−164 °C; H NMR
(400 MHz, CDCl3): δ 7.82−7.71 (m, 2H), 7.63−7.53 (m, 4H),
7.50−7.40 (m, 2H), 7.29−7.15 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 154.1, 151.2 (dd, JC−F = 24.0, 262.6 Hz), 150.4
(dd, JC−F = 16.3, 255.9 Hz), 142.1, 132.4 (dd, JC−F = 2.9, 3.8
Hz), 129.6, 128.5, 125.1 (d, JC−F = 18.2 Hz), 122.5 (t, JC−F = 4.8
Hz), 118.2 (d, JC−F = 17.2 Hz);19F (373 MHz, CDCl3): δ −135.8
(t, JF−F = 11.6, 2F), −136.1 (t, JF−F = 11.6, 2F); 77Se NMR (75
MHz, CDCl3): δ 469.0; IR (KBr, ν/cm−1): 755, 772, 1095,
1273, 1498; HRMS (EI) m/z: [M]+ Calcd. for C20H10F4N2Se2
513.9114; Found 513.9119.
2,3-Bis((2-chlorophenyl)selanyl)quinoxaline (3k). The
product was purified by preparative TLC (hexane/AcOEt =
9/1). Yellow liquid, 10.7 mg, 21%; 1H NMR (400 MHz,
CDCl3): δ 7.84−7.40 (m, 2H), 7.67−7.55 (m, 4H), 7.54−7.48
120−122 °C; 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 8.09
(d, J = 8.7 Hz, 1H), 7.82−7.63 (m, 5H), 7.52−7.35 (m, 6H),
3.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.4, 158.5,
156.7, 143.9, 141.1, 136.2, 136.1, 131.0, 130.9, 129.9, 129.5,
129.5, 129.3, 129.2, 128.6, 128.5, 127.0, 52.5; 77Se NMR (75
MHz, CDCl3): δ 476.4, 469.2; IR (KBr, ν/cm−1): 688, 738, 978,
1103, 1134, 1253, 1294, 1438, 1475, 1509, 1721, 2365;
HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd. for C22H16N2NaO2S2
522.9440; Found 522.9442.
2-(Cyclohexylthio)quinoxaline (5a). The product was
purified by preparative TLC (hexane/AcOEt = 9/1). Pale
1
yellow liquid, 43.4 mg, 89%; H NMR (400 MHz, CDCl3): δ
8.52 (s, 1H), 7.97 (dd, J = 1.4, 8.2 Hz, 1H), 7.90 (dd, J = 1.4,
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8.2 Hz, 1H), 7.70−7.63 (m, 1H), 7.62−7.55 (m, 1H), 2-((Perfluorophenyl)thio)quinoxaline (5h). The product
4.19−4.01 (m, 1H), 2.25−1.13 (m, 10H); 13C{1H} NMR (100
MHz, CDCl3): δ 156.5, 145.2, 142.9, 139.8, 130.1, 129.3,
127.95, 129.94, 42.8, 33.0, 26.0, 25.8; HRMS (ESI+/TOF)
m/z: [M+Na]+ Calcd. for C14H16N2NaS 267.0932; Found
267.0935.
2-(Benzylthio)quinoxaline (5b). The product was purified
by preparative TLC (hexane/AcOEt = 9/1). Yellow liquid,
31.5 mg, 63%; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 8.00
(dd, J = 1.4, 8.2 Hz, 1H), 7.97 (dd, J = 1.4, 8.2 Hz, 1H),
7.74−7.67 (m, 1H), 7.66−7.58 (m, 1H), 7.48 (d, J = 7.3 Hz,
2H), 7.34−7.25 (m, 3H), 4.56 (s, 2H);13C{1H} NMR (100 MHz,
CDCl3): δ 155.7, 144.6, 142.7, 140.1, 137.4, 130.3, 129.35,
129.29, 128.7, 128.2, 127.9, 127.5, 33,8; HRMS (ESI+/TOF)
m/z: [M+Na]+ Calcd. for C15H12N2NaS 275.0619; Found
275.0612.
was purified by preparative TLC (hexane/AcOEt = 9/1).
White solid, 41.3 mg, 63%, mp 70-72 °C; 1H NMR (400 MHz,
CDCl3): δ 8.73 (s, 1H), 8.12−8.01 (m, 1H), 7.82−7.64 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 151.5, 142.7, 142.6, 140.6,
130.8, 129.4, 129.3, 128.4; 19F (373 MHz, CDCl3): δ
−129.3-−129.9 (m, 2F), −148.8-−149.2 (m, 1F),
−159.7-−160.5 (m, 2F); HRMS (ESI+/TOF) m/z: [M+Na]+
Calcd. for C14H5F5N2NaS 350.9991; Found 350.9994.
2-((4-Fluorophenyl)thio)quinoxaline (5i). The product
was purified by preparative TLC (hexane/AcOEt = 9/1).
Colorless liquid, 35.3 mg, 69%; 1H NMR (400 MHz, CDCl3): δ
8.45 (s, 1H), 7.99 (dd, J = 1.6, 8.0 Hz, 1H), 7.85 (dd, J = 1.8,
7.8 Hz, 1H), 7.74−7.57 (m, 4H), 7.22-7.13 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 163.8 (d, JC−F = 250.2 Hz), 156.8,
143.2, 142.3, 140.0, 137,4 (d, JC−F = 8.6 Hz), 130.6, 129.3,
128.9, 128.3, 123.9 (d, JC−F = 2.9 Hz), 117.1 (d, JC−F = 22.0 Hz);
19F (373 MHz, CDCl3): δ −110.3; HRMS (ESI) m/z: [M+Na]+
Calcd. for C14H9FN2NaS 279.0368; Found 279.0365.
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2-((4-Chlorobenzyl)thio)quinoxaline (5c). The product
was purified by preparative TLC (hexane/AcOEt = 9/1).
1
Yellow liquid, 35.5 mg, 62%; H NMR (400 MHz, CDCl3): δ
8.57 (s, 1H), 8.01 (dd, J = 1.4, 8.2 Hz, 1H), 7.95 (dd, J = 1.4,
8.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H),
4.54 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.2, 144.6,
142.6, 140.1, 136.1, 133.3, 130.6, 130.4, 129.4, 128.8, 128.3,
127.8, 33,0; HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd. for
C15H11ClN2NaS 309.0229; Found 309.0225.
2-(Decylthio)quinoxaline (5d). The product was purified
by preparative TLC (hexane/AcOEt = 9/1). Colorless liquid,
52.6 mg, 87%; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.99
(dd, J = 1.4, 8.2 Hz, 1H), 7.91 (dd, J = 1.4, 8.2 Hz, 1H),
7.71−7.64 (m, 1H), 7.63−7.56 (m, 1H), 3.32 (t, J = 7.3 Hz, 2H),
1.90−0.80 (m, 19H);13C{1H} NMR (100 MHz, CDCl3): δ 156.6,
145.0, 142.9, 139.8, 130.1, 129.3, 127.9 (overlap), 32.0,
29.65, 29.60 (overlap), 29.4, 29.2, 29.1, 29.0, 22.8, 14.2;
HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd. for C18H26N2NaS
325.1714; Found 325.1717.
2-((4-Methoxyphenyl)thio)quinoxaline (5j). The product
was purified by preparative TLC (hexane/AcOEt = 9/1).
White solid, 34.3 mg, 64%, mp 53−55 °C; 1H NMR (400 MHz,
CDCl3): δ 8.38 (s, 1H), 7.97 (dd, J = 1.4, 8.2 Hz, 1H), 7.89 (dd,
J = 1.4, 8.2 Hz, 1H), 7.72−7.55 (m, 4H), 7.04−6.97 (m, 2H),
3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.1, 158.2,
143.0, 142.2, 139.8, 137.2, 130.5, 129.2, 128.6, 128.3, 119.0,
115.5, 55.5; HRMS (ESI/TOF) m/z: [M+Na]+ Calcd. for
C15H12N2NaOS 291.0568; Found 291.0550.
2-(Naphthalen-1-ylthio)quinoxaline (5k). The product
was purified by preparative TLC (hexane/AcOEt = 9/1).
Colorless liquid, 40.9 mg, 71%; 1H NMR (400 MHz, CDCl3): δ
8.37 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.02 (t, J = 6.6 Hz, 2H),
7.93 (d, J = 8.2 Hz, 2H), 7.87 (dd, J = 1.1, 8.4 Hz, 1H),
7.72−7.46 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.6,
142.9, 142.2, 139.8, 135.9, 134.7, 134.6, 131.5, 130.5, 129.2,
128.9, 128.7, 128.3, 127.8, 126.9, 126.1, 125.8, 125.7; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C18H12N2NaS 311.0619;
Found 311.0616.
2-(Cyclohexylthio)-6,7-dimethylquinoxaline (5l). The
product was purified by preparative TLC (hexane/AcOEt =
9/1). White solid, 40.9 mg, 81%, mp 55−57 °C; 1H NMR (400
MHz, CDCl3): δ 8.45 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 4.15-
4.00 (m, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.25−1.25 (m, 10H);
13C{1H} NMR (100 MHz, CDCl3): δ 155.1, 144.3, 141.8, 140.4,
138.7, 138.1, 128.4, 127.3, 42.8, 33.1, 26.1, 25.9, 20.3, 20.2;
HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd. for C16H20N2NaS
295.1245; Found 295.1246.
2-(Sec-butylthio)quinoxaline (5e). The product was
purified by preparative TLC (hexane/AcOEt
= 9/1).
Colorless liquid, 38.8 mg, 89%; 1H NMR (400 MHz, CDCl3): δ
8.55 (s, 1H), 7.99 (dd, J = 1.6, 8.0 Hz, 1H), 7.90 (dd, J = 0.9,
8.2 Hz, 1H), 7.71−7.64 (m, 1H), 7.63−7.56 (m, 1H), 4.12
(quintet, J = 6.9 Hz, 1H), 1.91−1.70 (m, 2H), 1.48 (d, J = 6.9
Hz, 3H), 1.07 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.8, 145.2, 142.9, 139.7, 130.1, 129.3, 127.9
(overlap), 41.4, 29.5, 20.6, 11.5; HRMS (ESI+/TOF) m/z:
[M+Na]+ Calcd. for C12H14N2NaS 241.0775; Found 241.0771.
2-(Tert-butylthio)quinoxaline (5f). The product was
purified by preparative TLC (hexane/AcOEt
= 9/1).
Colorless liquid, 31.0 mg, 71%; 1H NMR (400 MHz, CDCl3): δ
8.54 (s, 1H), 7.99 (dd, J = 1.4, 8.2 Hz, 1H), 7.95 (dd, J = 1.4,
8.2 Hz, 1H), 7.72−7.65 (m, 1H), 7.65−7.59 (m, 1H), 1.69 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.3, 146.1, 142.6,
139.6, 130.0, 129.3, 128.2 (overlap), 49.1, 30.4; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C12H14N2NaS 241.0775;
Found 241.0778.
2-(Cyclohexylthio)-8-methylquinoxaline
(5m).
The
product was purified by preparative TLC (hexane/AcOEt =
9/1). White solid, 22.7 mg, 44%; 1H NMR (400 MHz, CDCl3):
δ 8.54 (s, 1H), 7.84 (dd, J = 1.6, 8.0 Hz, 1H), 7.58−7.45 (m,
2H), 4.20−4.00 (m, 1H), 2.74 (s, 3H), 2.40−1.30 (m, 10H);
13C{1H} NMR (100 MHz, CDCl3): δ 155.1, 144.7, 141.8, 139.7,
136.1, 130.2, 127.6, 127.0, 43.4, 32.8, 26.3, 25.9, 16.9; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C15H18N2NaS 281.1088;
Found 281.1086.
2-(Phenylthio)quinoxaline (5g).25 The product was
purified by preparative TLC (hexane/AcOEt
= 9/1).
Colorless liquid, 32.4 mg, 68%; 1H NMR (400 MHz, CDCl3): δ
8.43 (s, 1H), 7.98 (dd, J = 1.4, 8.2 Hz, 1H), 7.89 (dd, J = 1.4,
8.2 Hz, 1H), 7.72−7.60 (m, 4H), 7.49−7.44 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 157.3, 143.5, 142.2, 139.9, 135.1,
130.5, 129.9, 129.7, 129.2, 129.0, 128.8, 128.4.
2-(Cyclohexylthio)-5-methylquinoxaline
(5m’).
The
product was purified by preparative TLC (hexane/AcOEt =
9/1). White solid, 15.5 mg, 30%; 1H NMR (400 MHz, CDCl3):
δ 8.54 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H),
7.43 (d, J = 6.9 Hz, 1H), 4.20−4.00 (m, 1H), 2.74 (s, 3H),
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2.30−1.11 (m, 10H);13C{1H} NMR (100 MHz, CDCl3): δ 155.9,
Bergman, R. G. Reactive 1,4-Dehydroaromatics. Acc. Chem. Res.
1973, 6, 25-31. (d) Grissom, J. W.; Calkins, T. L.; Huang, D.;
McMillen, H. High Temperature Radical Cyclization Anomalies in
the Tandem Enediyne-bis-radical Cyclization. Tetrahedron 1994,
50, 4635-4650. (e) Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J.
L.; Anthony, J. E. the Bergman Reaction as a Synthetic Tool;
Advantages and Restrictions. Tetrahedron 2001, 57, 3753-3760.
(f) Basak, A.; Mandal, S.; Bag, S. S. Chelation-Controlled Bergman
Cyclization: Synthesis and Reactivity of Enediynyl Ligands. Chem.
Rev. 2003, 103, 4077-4094.
(2) (a) De Voss, J. J.; Hangeland, J. J.; Townsend, C. A.
Characterization of the In Vitro Cyclization Chemistry of
Calicheamicin and Its Relation to DNA Cleavage. J. Am. Chem. Soc.
1990, 112, 4554-4556. (b) Nicolaou, K. C.; Dai, W.-M. Molecular
Design and Chemical Synthesis of Potent Enediynes. 2. Dynemicin
Model Systems Equipped with C-3 Triggering Devices and
Evidence for Quinone Methide Formation in the Mechanism of
Action of Dynemicin A. J. Am. Chem. Soc. 1992, 114, 8908-8921.
(3) (a) Basak, A.; Mitra, D.; Kar, M.; Biradha, K. Design, Synthesis
and DNA-cleaving Efficiency of Photoswitchable dimeric
Azobenzene-based C2-Symmetric Enediynes. Chem. Commun.
2008, 38, 3067-3069. (b) Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.;
Alabugin, I. V. Hybrids of Amino Acids and Acetylenic DNA-
photocleavers: Optimising Efficiency and Selectivity for Cancer
Phototherapy. Org. Biomol. Chem. 2012, 20, 3974-3987. (c) Chen,
G. J.; Wang, Z. G.; Qiao, X.; Xu, J. Y.; Tian, J. L.; Yan, S. P. Synthesis,
DNA Binding, Photo-induced DNA Cleavage, Cytotoxicity Studies of
a Family of Heavy Rare Earth Complexes. J. Inorg. Biochem. 2013,
127, 39-45.
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143.9, 143.0, 138.9, 137.5, 129.8, 128.3, 125.9, 42.8, 33.0,
26.1, 25.9, 17.4; HRMS (ESI+/TOF) m/z: [M+Na]+ Calcd. for
C15H18N2NaS 281.1088; Found 281.1086.
Methyl 3-(cyclohexylthio)quinoxaline-6-carboxylate and
methyl 2-(cyclohexylthio)quinoxaline-6-carboxylate (5n +
5n’). The product was purified by preparative TLC
(hexane/AcOEt = 9/1). Pale yellow oil, 39.3 mg, 65%;
obtained as a mixture of 5n/5n’ (48/52); the two isomers
were difficult to separate.
9
Isomer 5n. Pale yellow oil, 31% 1H NMR (400 MHz,
CDCl3): δ 8.61 (d, J = 1.8 Hz, 1H), 8.57 (s, 1H), 8.19 (dd, J =
1.8, 8.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 4.18−4.04 (m, 1H),
4.01 (s, 3H), 2.30−1.12 (m, 10H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.5, 157.9, 147.0, 145.0, 142.2, 131.3, 130.4,
129.2, 127.5, 52.7, 43.06, 29.8, 26.1, 25.83; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C16H18N2NaO2S
325.0987; Found 325.0985.
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Isomer 5n’. Pale yellow oil, 34% 1H NMR (400 MHz,
CDCl3): δ 8.69 (d, J = 1.8 Hz, 1H), 8.57 (s, 1H), 8.28 (dd, J =
1.8, 8.4 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 4.18−4.04 (m, 1H),
3.99 (s, 3H), 2.30−1.12 (m, 10H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.5, 159.2, 146.2, 141.9, 138.9, 131.9, 129.9,
129.5, 128.1, 52.6, 43.00, 32.9, 26.0, 25.81; HRMS
(ESI+/TOF) m/z: [M+Na]+ Calcd. for C16H18N2NaO2S
325.0987; Found 325.0985.
(4) Mitamura, T.; Ogawa, A. Synthesis of 2,4-Diiodoquinolines via the
Photochemical Cyclization of o-Alkynylaryl Isocyanides with Iodine. J.
Org. Chem. 2011, 76, 1163-1166.
(5) Mitamura, T.; Iwata, K.; Nomoto, A.; Ogawa, A. Photochemical
Intramolecular Cyclization of o-Alkynylaryl Isocyanides with Organic
Dichacogenides Leading to 2,4-Bischalcogenated Quinolines. Org.
Biomol. Chem. 2011, 9, 3768-3775.
(6) Mitamura, T.; Iwata, K.; Ogawa, A. (PhTe)2-Mediated
Intramolecular Radical Cyclization of o-Ethynylaryl Isocyanides
Leading to Bistellurated Quinolines upon Visible-Light Irradiation. Org.
Lett. 2009, 11, 3422-3424.
ASSOCIATED CONTENT
Supporting Information
Copy of 1H NMR ,13C NMR spectra.
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Authors
(7) For the cyclization reactions using thiols and isocyanides, see: (a)
Yang, Z.; Song, X.; Wei, Z.; Cao, J.; Liang, D.; Duan, H.; Lin, Y. Metal-free
oxidative cascade cyclization of isocyanides with thiols: a new pathway
for constructing 6-aryl(alkyl)thiophenanthridines. Tetrahedron Lett.
2016, 57, 2410-2413 (b) Rainier, J. D.; Kennedy, A. R. Cascades to
Substituted Indoles. J. Org. Chem. 2000, 65, 6213-6216. (c) Fujiwara, S.;
Asanuma, Y.; Shin-ike, T.; Kambe, N. Copper(I)-Catalyzed Highly
Efficient Synthesis of Benzoselenazoles and Benzotellurazoles. J. Org.
Chem. 2007, 72, 8087–8090. (d) Dumonteil, G.; Hiebel, M.-A.;
Scherrmann, M.-C.; Berteina-Raboin, S. Iodine-Catalyzed Formation of
Substituted 2-Aminobenzothiazole Derivatives in PEG400. RSC Adv.
2016, 6, 73517–73521. (e) Li, D.; Lei, J. Thio Radical-Induced
Denitrogenative Annulation of 1-Azido-2-Isocyanoarenes to Construct
2-Thiolated Benzimidazoles. Org. Biomol. Chem. 2019, 17, 9666–9671.
(8) (a) Zhao, J.; Peng, C.; Liu, L.; Wang, Y.; Zhu, Q. Synthesis of 2-
Alkoxy(aroxy)-3-substituted Quinolines by DABCO-Promoted
Cyclization of o-Alkynylaryl Isocyanides. J. Org. Chem. 2010, 75, 7502-
7504.
(9) Mitamura, T.; Nomoto, A.; Sonoda, M.; Ogawa, A. Synthesis of 2-
Halogenated Quinolines byHalide-Mediated Intramolecular Cyclization
of o-Alkynylaryl Isocyanides. Bull. Chem. Soc. Jpn. 2010, 83, 822-824.
(10) (a) Mitamura, T.; Iwata, K.; Ogawa, A. Photoinduced
Intramolecular Cyclization of o-Ethenylaryl Isocyanides with Organic
Disulfides Mediated by Diphenyl Ditelluride. J. Org. Chem. 2011, 76,
3880-3887. (b) Recently a synthesis method of quinoline derivatives
from o-alkenylarylisocyanides was reported. See, Liu, Y.; Li, S.-J.;
Chen, X.-L.; Fan, L.-L.; Li, X.-Y.; Zhu, S.-S.; Qu, L.-B.; Yu, B.
Mn(III)-Mediated Regioselective 6-Endo-Trig Radical Cyclization of
* Akiya Ogawa: ogawa@chem.osakafu-u.ac.jp; Shin-ichi
Kawaguchi: skawa@cc.saga-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Tran C. C. thanks the Graduate Course for System-inspired
Leaders in Material Science (SiMS) Scholarship Program. This
work was supported by Grants-in-Aid for Scientific Research
on Scientific Research (19K17746; B, 16H04138) and
Exploratory Research (16K14049) from The Japan Society for
the Promotion of Science (JSPS), and was also supported by the
Nanotechnology Platform Program of the Nara Institute of
Science and Technology (NAIST). Tran C. C also thanks Nguyen
Minh Hoang for the construction of the supplementary journal
cover of this article.
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Addition of Diaryl Diselenide to Acetylenes. Chem. Lett. 1991, 20,
2241-2242.
(17) (a) Richter, M. Functional Diversity of Organic Molecule Enzyme
Cofactors. Nat. Prod. Rep. 2013, 30, 1324-1345. (b) Cipollone, R.;
Ascenzi, P.; Tomao, P.; Imperi, F.; Visca, P. Enzymatic Detoxification of
Cyanide: Clues from Pseudomonas Aeruginosa Rhodanese. J. Mol.
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(24) Sreedhar, B.; Reddy, P. S.; Reddy M. A. Catalyst-Free and Base-
Free Water-Promoted SNAr Reaction of Heteroaryl Halides with Thiols.
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(25) Oae, S. Reactions of Mercaptans. Synth. Org. Chem., Jpn. 1968, 26,
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The Journal of Organic Chemistry
For Table of Contents use Only
1
2
3
N
SeR1
(R1Se)2
R
N
SeR1
4
5
6
Up to 99% Yield
16 Examples
NC
NC
Photo-
irradiation
-High conversion
-Wide substrate scope
-Metal-free, additive-free
R1 = aryl, alkyl
R
7
8
R2SH
N
N
H
R
SR2
9
R2 = aryl, alkyl
Up to 89% Yield
14 Examples
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