Modular synthesis of unsymmetrical doubly-ring-fused benzene derivatives based on a sequential ring construction strategy using oxadiazinones as a platform molecule

Article abstract of DOI:10.1246/cl.190118

An efficient benzene ring construction method using oxadiazinones as a platform molecule has been developed. Sequential reactions of oxadiazinones with cycloalkynes and arynes afforded partially reduced polyaromatics. This method enables facile preparation of various unsymmetrical doubly-ring-fused benzene derivatives including multisubstituted tetrahydroanthracenes and anthracenes.

Full text of DOI:10.1246/cl.190118

Advance Publication Cover Page
Modular Synthesis of Unsymmetrical Doubly-ring-fused Benzene Derivatives Based on a
Sequential Ring Construction Strategy Using Oxadiazinones as a Platform Molecule
Tomohiro Meguro, Shengnan Chen, Kazuya Kanemoto,
Suguru Yoshida,* and Takamitsu Hosoya*
Advance Publication on the web April 6, 2019
doi:10.1246/cl.190118
© 2019 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
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Publication manuscripts.

1
Modular Synthesis of Unsymmetrical Doubly-ring-fused Benzene Derivatives Based on a
Sequential Ring Construction Strategy Using Oxadiazinones as a Platform Molecule
Tomohiro Meguro, Shengnan Chen, Kazuya Kanemoto, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
E-mail: s-yoshida.cb@tmd.ac.jp; thosoya.cb@tmd.ac.jp
1
2
3
4
5
6
7
An efficient benzene ring construction method using
50 instead. This result clearly shows that pyrone 5 is more
51 reactive than oxadiazinone 1a in the reaction with benzyne.
52 The higher reactivity of 5 with benzyne than that of 1a was
53 supported by theoretical calculations (B3LYP/6-31G(d)) for
54 1a, 5, and benzyne, which indicated a smaller energy gap
55 between the HOMO level of 5 and the LUMO level of
56 benzyne than that between the levels of 1a and benzyne.11,12
57
oxadiazinones as a platform molecule has been developed.
Sequential reactions of oxadiazinones with cycloalkynes
and arynes afforded partially reduced polyaromatics. This
method enables facile preparation of various unsymmetrical
doubly-ring-fused
benzene
derivatives
including
multisubstituted tetrahydroanthracenes and anthracenes.
8
9
Keywords: Benzene Ring Construction, Oxadiazinone,
Strained Alkyne
A
This work
R
R
R
2
1
O
O
N
10
Various types of multiply ring-fused aromatic
1
2
1
O
N
O
O
11 compounds play significant roles in a broad range of
12 disciplines, including pharmaceutical science1 and materials
13 chemistry.2 However, the number of efficient synthetic
14 methods for multiply ring-fused aromatic compounds is still
15 limited, despite their potential importance.3,4 For example,
16 the construction of multiply ring-fused benzenes has
17 previously been achieved by methods such as transition-
18 metal catalyzed [2+2+2] cycloaddition, which usually
19 requires suitable well-designed starting materials including
20 diynes having suitable linkers synthesized by a linear route.4
21 Thus, facile convergent synthetic methods for multiply ring-
22 fused aromatic compounds from readily available starting
23 materials are highly sought-after. Herein, we describe a
24 modular synthesis of unsymmetrical doubly-ring-fused
25 benzene derivatives by sequential Diels–Alder reactions of
26 oxadiazinones 1 with cycloalkynes and arynes that proceed
27 with liberation of nitrogen and carbon dioxide (Figure 1A).
N
R
R’
R’
R’
R
N
O
O
1
oxadiazinone
1
2
N2
CO2
O
1
R’
R’
B
Double ring formation by Nuckolls and coworkers
Ph
Me3Si
TfO–
PhI
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
O
Ph
Ph
Ph
Bu4NF
THF
N
N
O
Ph
3 10%
Ph
1a
C
Our initial attempt for single ring formation
Me3Si
TfO
(0.10 mmol)
Bu4N[Ph3SiF2]
(0.20 mmol)
THF, 60 °C
4a
Ph
Ph
Ph
O
28
Oxadiazinones 1 are known to behave as electron-
1a
(0.20 mmol)
+
29 deficient dienes that react with electron-rich dienophiles,5
30 such as alkenes and ynamines, by the inverse-electron
31 demand Diels–Alder (IEDDA) reaction,6 followed by the
32 retro-Diels–Alder reaction7 involving the liberation of
33 nitrogen. The resulting pyrones also serve as good dienes
34 for the Diels–Alder reaction8 and are capable of reacting
35 with other dienophiles with the liberation of carbon dioxide
36 to afford benzene derivatives with two fused rings. For
37 example, synthesis of pentacene 3 was achieved in a single
38 step via the double ring formation of oxadiazinone 1a with
39 two molar amounts of naphthalyne generated from the
40 precursor 2 (Figure 1B).5d
O
Ph
5
not detected
6
35%
(based on 4a)
58
59 Figure 1. Benzene ring construction by sequential reactions using
60 oxadiazinones 1. (A) Concept of this work. (B) Pentacene synthesis by
61 the reaction between 1a and naphthalyne. (C) Our initial attempt.
62
63
Considering that highly electrophilic arynes and
64 electron-rich cycloalkynes significantly differ in reactivity
65 toward ynophiles, we turned our attention to the use of
66 cyclooctynes in reactions with oxadiazinones 1 (Figure 2).
67 In 1983, Sauer and coworkers reported the reaction of
68 oxadiazinone 1a with cyclooctyne (7) in nitrobenzene,
41
With the aim of preparing unsymmetrical doubly-ring-
42 fused benzene derivatives, we attempted to obtain mono-
43 cycloadduct 5 by the reaction of an two molar amounts of
44 oxadiazinone 1a with benzyne9,10 generated from o-
69 which afforded mono-cycloadduct
8
(Figure 2A).13
70 However, in that study, only a limited number of examples
71 using simple cyclooctyne (7) were demonstrated, and the
72 details of the results, including the yields of the products,
73 were not disclosed. Inspired by this pioneering work, we
74 examined the reaction of oxadiazinone 1a with
75 bicyclo[6.1.0]nonyne (BCN) derivative 9, which is a
45 silylphenyl
triflate
4a
upon
treatment
with
46 tetrabutylammonium difluorotriphenylsilicate (TBAT),
47 which is used as a fluoride ion source (Figure 1C).
48 Regrettably, the desired pyrone 5 was not obtained and the
49 doubly-ring-fused 9,10-diphenylanthracene (6) was formed

2
1
2
3
4
5
6
7
8
9
cyclopropane-fused cyclooctyne frequently used in click
chemistry (Figure 2B).14 The reaction in dichloromethane
proceeded smoothly at room temperature to afford pyrone
10a quantitatively without formation of bis-cycloadduct 11
with a second-order rate constant (k) of 0.044 M−1s−1 (Figure
2B). Frontier orbital analysis indicated that the energy gap
between the LUMO level of 1a and the HOMO level of 9 is
smaller than that between the levels of 10a and 9, showing
good agreement with the experimental results.12,15
38 generating it from 2-(trimethylsilyl)cyclohexen-1-yl triflate
39 (12) (Scheme 1).18 Treating
a mixture of 1a and
40 cyclohexyne precursor 12 with potassium fluoride and 18-
41 crown-6 in THF at 60 °C successfully afforded pyrone 13a
42 without producing bis-cycloadduct 14. Using TBAT instead
43 of potassium fluoride and 18-crown-6 also afforded the
44 mono-cycloadduct 13a in high yield.12
45
Me3Si
10
TfO
(1.0 equiv)
KF (2.1 equiv)
18-crown-6
(2.1 equiv)
12
A Pioneering work by Sauer and coworkers
Ph
Ph
Ph
Ph
Ph
Ph
O
O
N
N
O
7
+
O
O
1a
THF
60 °C
O
8
PhNO2, 20 °C
Ph
k = 0.0014 M–1s–1
Ph
Ph
1a
(1.5 equiv)
13a
85%
14
not detected
B
46
H
R
47
48
49
Scheme 1. Reaction of oxadiazinone 1a with cyclohexyne.
Ph
Ph
H
9
H
O
(1.2 equiv)
Reactions of cycloalkene-fused pyrones with arynes
1a
R +
R
R
O
CH2Cl2, rt
50 efficiently afforded unsymmetrical doubly-ring-fused
51 benzene derivatives along with the liberation of carbon
52 dioxide (Figures 3 and 4). Treatment of a mixture of
53 cyclooctene-fused pyrone 10a and o-silylphenyl triflate 4a
54 with TBAT yielded cyclooctene-fused naphthalene 15 in
55 good yield leaving the carbamate moiety untouched (Figure
56 3A). Similarly, tetrahydroanthracene 16a was obtained in
57 high yield from cyclohexene-fused pyrone 13a (Figure 3B).
58
H
Ph
10a
quant.
11
not detected
11
12 Figure 2. Reactions of oxadiazinone 1a with cyclooctynes. (A)
13 Pioneering work. (B) Our attempt. R = CH2OCONHBn.
14
15
16 efficiently prepared by the reaction of BCN derivative 9
17 with oxadiazinones 1b–1e bearing two aryl groups
18 substituted with an electron-donating or -withdrawing group
19 at the para-position of either of the aryl groups (Table 1).
20 Kinetic studies showed that the reactions of oxadiazinones
21 1c and 1e bearing an electron-deficient aryl substituent
22 proceed more than three times faster than those of electron-
23 rich group-substituted substrates 1b and 1d.12,16 This
Various cyclooctene-fused pyrones 10b–10e were
Me3Si
A
TfO
4a
(1.0 equiv)
Bu4N[Ph3SiF2]
(2.0 equiv)
Ph
H
H
10a
(1.5 equiv)
THF, 60 °C
O
O
Ph
Ph
24 substituent-effect on the reactivity of oxadiazinones also
NHBn
15
71%
25 support that the transformation involves the IEDDA reaction.
26
27
B
4a
(1.0 equiv)
Table 1. Synthesis of cyclooctene-fused pyrones
Bu4N[Ph3SiF2]
(2.0 equiv)
R
R
13a
(1.5 equiv)
9
(1.0 equiv)
H
H
O
O
THF, 60 °C
N
N
Ph
16a
78%
O
O
CH2Cl2, rt
O
O
59
R’
R’
NHBn
1
10
28
60 Figure 3. Synthesis of fused naphthalenes. (A) Reaction of
61 cyclooctene-fused pyrone 10a with benzyne. (B) Reaction of
62 cyclohexene-fused pyrone 13a with benzyne.
Entry
R
R’
1
10
Yield/%a
1
2
C6H4-p-OMe
C6H4-p-CF3
Ph
Ph
1b
1c
10b
10c
92
63
64
quant.
Various arynes participated in reactions with
pyrone 13a to afford
3b
Ph
C6H4-p-OMe
1d
10d
quant.
88
65 cyclohexene-fused
66 tetrahydroanthracenes 16b–16d (Figure 4). These include 3-
67 methylbenzyne and 4,5-dimethoxybenzyne, which reacted
68 with pyrone 13a to afford tetrahydroanthracenes 16b and
69 16c, respectively, in high yields. Furthermore,
70 tetrahydroanthracene 16d bearing a morpholino group was
71 successfully synthesized by the reaction of 13a with 3-
72 morpholinobenzyne generated from the corresponding o-
73 silylaryl triflate-type precursor,19 which was prepared from
4
Ph
C6H4-p-NO2
1e
10e
29
30
31
aIsolated yields. bBCN derivative 9 (1.1 equiv) was added.
Since theoretical analysis indicated that the HOMO
32 levels of highly strained cycloalkynes are similar to that of
33 BCN derivative 9,12,17 we expected that reactions of
34 oxadiazinones with various cycloalkynes would also afford
35 pyrones selectively without formation of the bis-
36 cycloadducts. Based on this idea, we attempted the reaction
37 of oxadiazinone 1a with short-lived cyclohexyne by
74 2-iodo-1,3-bis(triflyloxy)benzene
via
3-
75 (triflyloxy)benzyne.20

3
37 fused pyrone 13a and aryne precursor 2225 with potassium
38 fluoride and 18-crown-6.
SiMe3
OTf
FG
4
39
(1.0 equiv)
Bu4N[Ph3SiF2]
(2.0 equiv)
Ph
Ph
A
MeO
MeO
SiMe3
OTf
Me3Si
TfO
13a
S
S
S
THF, 60 °C
4c
(1.5 equiv)
12
FG
MeO
MeO
O
O
Bu4N[Ph3SiF2]
Bu4N[Ph3SiF2]
16
N
N
O
O
THF
60 °C
THF
60 °C
O
S
S
S
Ph
Ph
Ph
MeO
MeO
N
Ph
Ph
1f
20
91%
21
82%
B
Me Ph
OTf
16b
71%
16c
77%
Me3Si
16d
51%
1
13a
KF
18-crown-6
2
3
4
5
6
7
8
9
Figure 4. Synthesis of tetrahydroanthracenes 16b–16d.
THF
60 °C
SiMe3
OTf
Another type of aryne precursor21 was also applicable
to this transformation. A thienobenzyne21e generated from o-
iodoaryl triflate-type precursor 17 by treatment of
(trimethylsilyl)methylmagnesium chloride reacted with
cyclohexene-fused pyrone 13a at −78 °C to afford
thienoanthracene derivative 18 (Scheme 2). Although
TfO
SiMe3
22
23
64%
40
41 Figure 5. Synthesis of tetrahydroanthracenes 21 and 23. (A) Sequential
42 benzene ring construction from 1f. (B) Synthesis of 1,3,5-
43 tri(anthracenyl)benzene derivative 23.
10 further improvement of the yield by optimizing the reaction
11 conditions is needed, the available modules were increased,
12 expanding the scope of synthesizable products.
13
44
45
46 benzene ring construction method using oxadiazinones as a
47 platform Sequential reactions of
molecule.26,27
In summary, we have developed an efficient two-step
Ph
OTf
Me3SiCH2MgCl
(1.6 equiv)
48 oxadiazinones with cycloalkynes and arynes enabled to
49 prepare partially reduced polyaromatics in a modular
50 synthetic manner. Since the synthesis of partially reduced
51 polyaromatics by selective reduction or oxidation is not easy,
52 our method would be beneficial for preparing such
53 compounds useful in materials chemistry and
54 pharmaceutical science. Further studies to expand the scope
55 and applying the method for the synthesis of structurally
56 more complex hydrocarbons are currently underway in our
57 laboratory.
+
Bu
I
13a
(2.0 equiv)
THF, –78 °C
Bu
S
18
33%
S
Ph
Bu
17
Bu
14
15
16
17
Scheme 2. Reaction of pyrone 13a with a thienobenzyne generated
from an o-iodoaryl triflate-type precursor.
18
Oxidative aromatization of tetrahydroanthracene 16c
19 using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)22
20 efficiently afforded 2,3-dimethoxy-9,10-diphenylanthracene
21 (19) in good yield (Scheme 3). This result indicates that the
22 sequential ring construction approach also renders
23 unsymmetrical multisubstituted anthracenes easily available,
24 further expanding the synthetic utility of the method.
25
58
59
This work was supported by AMED under Grant
60 Number JP18am0101098 (Platform Project for Supporting
61 Drug Discovery and Life Science Research, BINDS); JSPS
62 KAKENHI Grant Numbers JP15H03118 and JP18H02104
63 (B; T.H.), JP16H01133 and JP18H04386 (Middle Molecular
64 Strategy; T.H.), JP26350971 (C; S.Y.), JP18J11113 (JSPS
65 Research Fellow; T.M.); Suntory Foundation for Life
66 Sciences (S.Y.); and Naito Foundation (S.Y.). We thank Dr.
67 Takashi Niwa (RIKEN BDR) and Dr. Hiroyuki Masuno
68 (IBB, TMDU) for HRMS measurements.
Ph
Ph
DDQ
(2.2 equiv)
MeO
MeO
MeO
MeO
toluene
85 °C
Ph
Ph
16c
19
86%
26
27
28
29
Scheme 3. Aromatization of tetrahydroanthracene.
69
70
Supporting
Information
is
available
on
Synthesis of a wide range of partially reduced
30 polyaromatics23 was achieved by the sequential benzene
31 ring construction strategy (Figure 5). For example, 9,10-
32 di(2-thienyl)anthracene derivative 21 was efficiently
33 prepared from oxadiazinone 1f by sequential reactions with
34 cyclohexyne and 4,5-dimethoxybenzyne (Figure 5A).24
35 Furthermore, 1,3,5-tri(anthracenyl)benzene derivative 23
36 was easily prepared by treating a mixture of cyclohexene-
71 http://dx.doi.org/10.1246/cl.xxxxxx.
72 References and Notes
73
74
75
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4
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75 15
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Energy levels of BCN derivative 9 (HOMO −6.5 eV, LUMO
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were obtained by DFT calculation (B3LYP/6-31G(d)).
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6
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77
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80
81
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.
82 17
83
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During preparation of this manuscript, synthesis of heteroatom-
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