Construction of Condensed Polycyclic Aromatic Frameworks through Intramolecular Cycloaddition Reactions Involving Arynes Bearing an Internal Alkyne Moiety

Article abstract of DOI:10.1002/chem.201704345

Facile synthetic methods for condensed polycyclic aromatic compounds via aryne intermediates are reported. The generation of arynes bearing a (3-arylpropargyl)oxy group from the corresponding o-iodoaryl triflate-type precursors efficiently afforded arene-fused oxaacenaphthene derivatives, which were formed through intramolecular [2+4] cycloaddition. Extending the method to the generation of arynes bearing a 1,3-diyne moiety led to a continuous generation of naphthalyne intermediate through the hexadehydro Diels–Alder reaction involving the aryne triple bond. This novel type of aryne-relay chemistry enabled the synthesis of a unique aminoarylated oxaacenaphthene derivative and highly ring-fused anthracene derivatives.

Full text of DOI:10.1002/chem.201704345

A Journal of
Accepted Article
Title: Construction of Condensed Polycyclic Aromatic Frameworks
through Intramolecular Cycloaddition Reactions Involving Arynes
Bearing an Internal Alkyne Moiety
Authors: Suguru Yoshida, Keita Shimizu, Keisuke Uchida, Yuki
Hazama, Kazunobu Igawa, Katsuhiko Tomooka, and
Takamitsu Hosoya
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201704345
Link to VoR: http://dx.doi.org/10.1002/chem.201704345
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10.1002/chem.201704345
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COMMUNICATION
Construction of Condensed Polycyclic Aromatic Frameworks
through Intramolecular Cycloaddition Reactions Involving Arynes
Bearing an Internal Alkyne Moiety
Suguru Yoshida,* Keita Shimizu, Keisuke Uchida, Yuki Hazama, Kazunobu Igawa, Katsuhiko Tomooka,
and Takamitsu Hosoya*
Abstract: Facile synthetic methods for condensed polycyclic
aromatic compounds via aryne intermediates are reported. The
generation of arynes bearing a (3-arylpropargyl)oxy group from the
corresponding o-iodoaryl triflate-type precursors efficiently afforded
arene-fused oxaacenaphthene derivatives, which were formed
through intramolecular [2+4] cycloaddition. Extending the method to
the generation of arynes bearing a 1,3-diyne moiety led to a
continuous generation of naphthalyne intermediate through the
hexadehydro Diels–Alder reaction involving the triple bond of aryne.
This novel type of aryne-relay chemistry enabled the synthesis of a
unique aminoarylated oxaacenaphthene derivative and highly ring-
fused anthracene derivatives.
approach enabled the facile construction of a large chemical
library that consists of a diverse range of compounds. To further
diversify the synthesizable compounds based on this modular
synthetic approach, we prepared o-iodoaryl triflate 3a bearing
(3-phenylpropargyl)oxy group and attempted the cycloaddition of
aryne generated from 3a with benzyl azide (4) (Figure 1B). As a
result, treating the mixture of 3a and 4 in THF with a silylmethyl
Grignard reagent at –78 °C afforded the desired cycloadduct 5,
from which a variety of benzotriazoles could be prepared by the
transformation of the internal alkyne moiety. From a careful
examination of the byproducts, we identified a small amount of
phenanthrene derivative, 5H-phenanthro[1,10-bc]furan (6a).[7]
The formation of tetracyclic compound 6a indicates a possibility
that two intramolecular C–C bond formations between the aryne
carbons and the phenylethynyl group has occurred.[8] We were
intrigued by this unexpected result and opted to delve into this
transformation that would enable straightforward construction of
condensed polycyclic aromatic frameworks.
Condensed polycyclic aromatic compounds, such as
phenanthrene and anthracene derivatives, are important scaffold
structures that have wide applications in broad fields including
materials science and natural product chemistry.[1] Among the
reported methods for constructing these complex skeletons,[2]
cycloaddition reactions of aryne intermediates are particularly
useful.[3–6] Nevertheless, condensed polycyclic aromatic
compounds that are synthesizable by conventional methods are
still limited. Herein, we report synthetic methods for constructing
condensed polycyclic aromatic compounds that include strained
2H-naphtho[1,8-bc]furan (oxaacenaphthene) derivatives, which
were formed through reactions involving arynes.
N
A
N
N
N3 R1
Me3SiCH2MgCl
THF, –78 °C
1.
O
O
O
R2
I
N
N
N
2. N3 R2
cat. Cu, cat. TBTA
CH2Cl2, rt
OTf
I
R1
2
1
B
N3 Bn
(1.2 equiv)
4
O
O
O
We previously reported a modular synthetic method for
Me3SiCH2MgCl
Ph
(1.5 equiv)
I
Ph
N
preparation
of
bis-
and
tris-1,2,3-triazoles
via
3-
+
N
THF
–78 °C, 1.5 h
N
(propargyloxy)benzyne (I) generated from o-iodoaryl triflate-type
aryne precursor 1 by using (trimethylsilyl)methylmagnesium
chloride as an activator (Figure 1A).[5a] The cycloaddition of
aryne I with azides and the subsequent copper-catalyzed
cycloaddition of the remaining terminal alkyne moiety with
another azides afforded diverse bis-1,2,3-triazoles. This
OTf
5
81%
Bn
6a
1%
3a
Figure 1. Cycloaddition of arynes bearing an alkyne moiety with azides. (A)
Bis-1,2,3-triazole synthesis via 3-(propargyloxy)benzyne (I). (B) Reaction of
aryne, generated from o-iodoaryl triflate 3a by using a silylmethyl Grignard
reagent, in the presence of azide 4.
[*]
Dr. S. Yoshida, Mr. K. Shimizu, Mr. K. Uchida, Ms. Y. Hazama, Prof.
Dr. T. 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 (Japan)
E-mail: s-yoshida.cb@tmd.ac.jp; thosoya.cb@tmd.ac.jp
To achieve an efficient transformation from 3a to 6a, we
screened the conditions by performing the reaction in the
absence of an arynophile (Table 1). Although only a low yield of
the desired 6a was obtained when the reaction was conducted
at –78 °C (entry 1), remarkable improvements were observed
when the reaction was conducted at higher temperatures
(entries 2 and 3). The best result was obtained when the
reaction was conducted at room temperature with diethyl ether
as the solvent (entry 4). Using more nucleophilic activators
instead of (trimethylsilyl)methylmagnesium chloride[5] decreased
the yield of 6a (entries 5–7).
Dr. K. Igawa, Prof. Dr. K. Tomooka
Institute for Materials Chemistry and Engineering, Kyushu
University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
Supporting information for this article can be found under:
http ://dx.doi.org/10.1002/anie.xxxxxxxxx.
Experimental procedures and characterization for new compounds
including copies of NMR spectra (PDF). X-ray crystallographic data
for 6c (CCDC 1566709) (CIF).
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10.1002/chem.201704345
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structure.[10] Natural bond orbital analysis[10] supports the
contribution of the polarized resonance structure IV’, from which
aromatization that involves proton transfer to the anionic carbon
occurs to afford the phenanthrene derivative 6a.
Table 1: Optimization of the Reaction Conditions.
O
O
R–Mtl
Ph
(2.0 equiv)
I
Solvent
Temp., 1 h
OTf
6a
3a
O
n
O
n
Me3SiCH2MgCl
(2.0 equiv)
I
Ar
O
Entry
R–Mtl
Solvent
THF
Temp.
Yield [%][a]
Et2O
rt, 1 h
R
R
OTf
Ar
O
6
3
1
2
3
4
5
6
7
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
n-BuLi
–78 °C
20
O
O
THF
–40 °C
51
THF
rt
rt
rt
rt
rt
59
83 (82)[b]
35
S
Et2O
Et2O
Et2O
Et2O
6b
75%
6c
86%
6d
62%
6e
71%
Cl
OMe
O
CO2Me
O
O
i-PrMgCl·LiCl
PhMgBr
43
MeO2C
Br
26
6f
61%
6g
76%
6h
9%
[a] Yields based on 1H NMR analysis, unless otherwise noted. [b] Isolated
yield in the parentheses.
Figure 2. Synthesis of various tetracyclic aromatics.
Using the optimized conditions, various tetracyclic
oxaacenaphthene derivatives 6b–g were prepared from the
O
corresponding
arylpropargyl)oxy group, which were easily prepared from the
corresponding 3-hydroxy-2-iodoaryl triflates and
propargylalcohols by the Mitsunobu reaction[9,10] (Figure 2).
Substrates with 4-methoxy-, 4-chloro-, and 4-
o-iodoaryl
triflates
bearing
an
(3-
Cl
(methoxycarbonyl)phenyl groups on the alkyne moiety were
transformed to condensed phenanthrene derivatives 6b–d,
leaving these groups untouched. The structure of chloro-
substituted product 6c was confirmed from the X-ray
crystallographic analysis (Figure 3). Similarly, thiophene-fused
oxaacenaphthene 6e was obtained from 2-iodo-3-((3-(3-
Figure 3. X-ray crystal structure of 6c.
O
Me3SiCH2MgCl
(2.0 equiv)
O
Ph
I
Et2O
rt, 1 h
OTf
thienyl)propargyl)oxy)phenyl
triflate.
Substrates
with
a
7
8
51%
methoxycarbonyl and bromo groups on the benzene ring at the
aryne-generating side also participated in this reaction to afford
6f and 6g, respectively. In contrast, the reaction of a substrate
with one carbon-homologated tether afforded only a low yield of
the desired phenanthrene 6h fused with a 6-membered ring,
suggesting the importance of the relative configuration of
arylethynyl moiety to the triple bond of aryne. In addition, the
reaction of o-iodoaryl triflate 7, wherein the alkyne moiety of 3a
was changed to trans-olefin, proceeded to afford tetracyclic
9,10-dihydrophenanthrene derivative 8 (Scheme 1).
Scheme 1. Reaction from 3-(Cinnamyloxy)benzyne Precursor 7.
‡
Me3SiCH2MgCl
O
O
O
I
Ph
OTf
Me3SiCH2I
+
TfOMgCl
3a
II
III
A plausible reaction mechanism is shown in Scheme 2. The
formation of benzotriazole 5 from the reaction in the presence of
azide 4 clearly indicates the generation of aryne II from o-
iodoaryl triflate 3a. Subsequent intramolecular [2+4]
cycloaddition between the triple bond of aryne and the
phenylethynyl group via distorted transition state III would
provide allenic intermediate IV, which is a resonance form of
zwitterionic intermediate IV’. Theoretical calculations (B3LYP/6-
311+G(d,p)) indicate that the strained allenic intermediate IV is
31.9 kcal/mol more stable than the aryne intermediate II,
suggesting that allene IV is justifiable as an intermediate
O
O
O
C
proton
transfer
H
H
6a
IV’
IV
Scheme 2. Plausible Reaction Mechanism.
On the basis of the plausible reaction mechanism depicted in
Scheme 2 and the reported hexadehydro Diels–Alder reaction,[6]
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10.1002/chem.201704345
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PhNMe2 13
(5.0 equiv)
we conceived the idea of generating a strained naphthalyne VII’
through a similar type of intramolecular [2+4] cycloaddition
reaction between the triple bond of aryne and the 1,3-diyne
moiety of V (Scheme 3). To test our hypothesis, we prepared o-
iodoaryl triflate 9 bearing a 1,3-diyne moiety and treated it with a
silylmethyl Grignard reagent in the presence of furan (10) at
room temperature. As expected, anthracene derivative 11 was
obtained as a major product along with a small amount of
cycloadduct 12, which was formed by the direct reaction
between the initial aryne intermediate V and furan (10). This
result demonstrates that naphthalyne VII’ was successfully
generated as the second aryne species and trapped by furan
(10) to afford an anthracene derivative 11, suggesting that the
intramolecular [2+4] cycloaddition proceeded faster than the
intermolecular cycloaddition.[11]
O
O
O
Me3SiCH2MgCl
(2.0 equiv)
Ph
H
N
I
X–
Ph
+
Ph
Et2O
rt, 1 h
NMe2
OTf
9
Me Me
Ph
Ph
Ph
15
not
14
81%
N
O
O
O
detected
Me
Me
N
Me
Ph
Ph
Me
IX
VII’
VIII
Scheme 4. Aminoarylation of Strained Naphthalyne VII’.
PhNMe2 13
(5.1 equiv)
Me3SiCH2MgCl
(2.0 equiv)
I
Ph
H
OTf–
Ph
+
O
10
Et2O
rt, 1 h
OTf
NMe2
N
(1.5 equiv)
O
O
O
16
Me Me
17
not
detected
18
32%
Me3SiCH2MgCl
(2.0 equiv)
I
O
+
O
Ph
Ph
Et2O
rt, 1 h
OTf
9
11
56%
12
9%
Ph
Scheme 5. Reaction with Unstrained Naphthalyne.
‡
O
O
O
O
O
Me3SiCH2MgCl
(3.0 equiv)
Ph
O
O
O
V
I
Ph
Ph
Ph
VII’
NTs
THF
rt, 1 h
VII
VI
20
71%
OTf
N
19
Ts
Scheme 3. Generation of Strained Naphthalyne VII’.
Scheme 6. Synthesis of Hexacyclic Anthracene Derivative 20.
After conducting an extensive survey on the reactivity of
naphthalyne VII’, we found that it reacted with N,N-
dimethylaniline (13) in a unique fashion (Scheme 4). Treating
aryne precursor 9 with a silylmethyl Grignard reagent in the
presence of 13 at room temperature afforded an unexpected two
ortho-phenyl groups-substituted (dimethylamino)naphthalene
derivative 14 in high yield without the formation of anticipated
ammonium salt 15. The product 14 could be obtained through
the addition of 13 to naphthalyne VII’ to form a zwitterionic
intermediate VIII, followed by migratory C-phenylation via
Meisenheimer complex IX. Because the reaction of simple 2,3-
naphthalyne with 13 afforded only ammonium salt 18,[12] and the
formation of phenyl-migrated product 17 was not observed
(Scheme 5), the formation of 14 through the migratory C-
phenylation of VIII[13] is likely to be facilitated by the highly
strained five-membered ring-fused structure. Although the
details on this unique aminoarylation of aryne is yet to be
investigated, this approach would allow for the facile synthesis of
highly functionalized sterically hindered aminonaphthalenes,
which are difficult to prepare by conventional method.
In summary, we have developed facile methods for
constructing condensed polycyclic aromatic frameworks through
the generation of arynes from o-iodoaryl triflates bearing an
arylethynyl group or a 1,3-diyne moiety. In the case of arynes
bearing a 1,3-diyne moiety, a naphthalyne intermediate was
generated through a novel type of aryne-relay chemistry, which
is the first example of hexadehydro Diels–Alder reaction
involving the triple bond of aryne. Since various 3-
(propargyloxy)aryne precursors are easily synthesizable,
a
diverse range of highly condensed aromatic compounds could
be prepared from simple modules using this method. Further
studies, including the theoretical analysis of the intramolecular
cycloaddition between the triple bond of aryne and an
arylethynyl group or a 1,3-diyne moiety, are currently underway.
Acknowledgements
The authors thank Central Glass Co., Ltd. for providing Tf2O.
This work was supported by the Platform Project for Supporting
Drug Discovery and Life Science Research funded by Japan
Agency for Medical Research and Development (AMED); the
Cooperative Research Project of Research Center for
Biomedical Engineering; the Cooperative Research Program of
"Network Joint Research Center for Materials and Devices";
The generation of a naphthalyne intermediate from a 1,3-
diyne-armed aryne precursor bearing an additional arynophilic
moiety resulted in the formation of a highly condensed polycyclic
aromatic compound. For example, the sequential generation of
two types of arynes from precursor 19 with an intramolecular
furan moiety afforded a highly ring-fused hexacyclic anthracene
derivative 20 in high yield (Scheme 6).
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10.1002/chem.201704345
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COMMUNICATION
[5]
For our reports on synthetic chemistry using a silylmethyl Grignard
reagent, see: a) S. Yoshida, T. Nonaka, T. Morita, T. Hosoya, Org.
Biomol. Chem. 2014, 12, 7489; b) S. Yoshida, K. Uchida, K. Igawa, K.
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Hosoya, Chem. Lett. 2017, 46, 858.
JSPS KAKENHI Grant Numbers 15H03118 (B; T.H.), 16H01133
(Middle Molecular Strategy; T.H.), 26350971 (C; S.Y.);
17J08217 (JSPS Research Fellow; K.U.); Naito Foundation
(S.Y.).
Keywords: aryne • hexadehydro Diels–Alder reaction •
naphthalyne • oxaacenaphthene • aminoarylation
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[9]
a) O. Mitsunobu, M. Yamada, T. Mukaiyama, Bull. Chem. Soc. Jpn.
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[10] See Supporting Information for details.
[11] Treatment of a mixture of o-iodoaryl triflate 9 with furan (10, 5.0 equiv)
with Me3SiCH2MgCl (2.0 equiv) at room temperature afforded only 22%
yield of 11 along with 12 (23%).
[12] M. Hirsch, S. Dhara, C. E. Diesendruck, Org. Lett. 2016, 18, 980.
[13] For the pioneering study on the reaction between benzyne and N,N-
dialkylanilines, see: A. R. Lepley, A. G. Giumanini, A. B. Giumanini, W.
A. Khan, J. Org. Chem. 1966, 31, 2051.
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10.1002/chem.201704345
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
S. Yoshida,* K. Shimizu, K. Uchida, Y.
Hazama, K. Igawa, K. Tomooka, T.
Hosoya*
Page No. – Page No.
Construction of Condensed
Polycyclic Aromatic Frameworks
through Intramolecular Cycloaddition
Reactions Involving Arynes Bearing
an Internal Alkyne Moiety
Facile synthetic methods for condensed polycyclic aromatic
compounds via aryne intermediates bearing an alkyne moiety are
reported. In particular, the generation of arynes bearing a 1,3-diyne
moiety led to a continuous generation of naphthalyne intermediate
through the hexadehydro Diels–Alder reaction involving the triple bond
of aryne.
This article is protected by copyright. All rights reserved.