Iptycenes with an acridinone motif developed through [4+2] cycloaddition of tethered naphthalene and iminoquinone: Via a radical reaction

Article abstract of DOI:10.1039/c7cc03030d

A new class of iptycenes was developed by combining 2-(naphthalen-1-yl)anilines and p-benzoquinones through copper(ii)-mediated radical cyclisation. This unusual cyclisation reaction resulted in the robust and efficient syntheses of iptycenes with an acridinone motif. These iptycenes can be further transformed into planar acridinone heterocyclics through the Diels-Alder reaction.

Full text of DOI:10.1039/c7cc03030d

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Iptycenes with acridinone motif developed through [4 + 2]
cycloaddition of tethered naphthalene and iminoquinone via
radical reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Selvam Raju,a Pratheepkumar Annamalai,a Pei-Ling Chen,b Yi-Hung Liuc and Shih-Ching Chuang a,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
new class of iptycene was developed by combining 2-
examples of alkyl-substituted naphthalenes and provided an
yield of up to 64% (Scheme 1a).15 Ma reported a Lewis acid
(naphthalen-1-yl)anilines and p-benzoquinones through copper
(II)-mediated radical cyclisation. This unusual cyclisation reaction
resulted in the robust and efficient syntheses of iptycenes with an
acridinone motif. These iptycenes can be further transformed to
planar acridinone heterocyclics through the Diels–Alder reaction.
(AlCl3)-assisted
Diels–Alder
reaction
of
N-2,6-
difluorophenylmaleimde and substituted naphthalenes in
CHCl3 at room temperature, yielding excellent yields of two
isomeric anti adducts (Scheme 1b).16 However, the reaction
scope was limited to parent naphthalene or with bromo- or
chloro substitution.
Iptycene, a family with various units of arenes annealed on the
alkenyl moiety of the barrelene framework,1 has been
reported to have numerous applications in polymer
chemistry,2 ligand design,3 supramolecular complexes,4
sensors,5 rapidly evolving separation technology,6 molecular
machines,7 materials science,4b, 8 biological studies,9 and host–
guest chemistry.10 Bartlett demonstrated the first synthesis of
triptycene through the Diels–Alder reaction of anthracene and
benzoquinone.11 Plenio et al further developed triptycene-
based chiral and meso-N-heterocyclic ligands and their
derived metal complexes.12 In another context, acridinone
moiety has vital functions in many therapeutic agents and is a
crucial component in anion receptors, organic light-emitting
diode devices, and sensors.13
Naphthalenes are less-reactive dienes and are therefore not
often considered as enophiles in the Diels–Alder reaction in
synthetic applications. A naphthalene ring can be induced in a
Diels–Alder reaction typically through an electronic
modulation on reactants or by performing the reactions under
harsh conditions.14 Fujita et al performed the [4 + 2]
cycloaddition of 2,3-disubstituted napthalenes with N-
cyclohexylmaleimide in a self-assembled molecular cage at
100 °C for 8 h. However, this method was limited to only a few
Scheme 1. Chemical reactivity of naphthalenes in [4
cycloaddition.
+ 2]
The copper-catalysed17 domino radical cation reaction is an
intriguing method in synthetic organometallic chemistry.
Typically, it involves one-electron oxidation and the formation
of radical cations to induce intramolecular cyclisation. We
herein propose a new class of iptycene by combining 2-
(naphthalen-1-yl)anilines (1a) and substituted benzoquinone
through copper-mediated domino radical cyclisation (Scheme
1c). We also have proved that the condensed intermediates
having a tethered iminoquinone (IQ) moiety undergo [4 + 2]
cycloaddition through the domino radical cation reaction. This
reaction resulted in the robust and efficient syntheses of
iptycenes with an acridinone motif. These iptycenes can be
a.Department of Applied Chemistry
National Chiao Tung University
1001 Ta-Hsueh Road, Hsinchu, Taiwan 30010
b.Department of Chemistry
National Tsing Hua University, Hsinchu, Taiwan 30013
c. Instrumentation Center
National Taiwan University, Taipei, Taiwan 30010
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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further transformed to planar acridinone heterocyclics containing heterocycles were newly developed, in which the
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DOI: 10.1039/C7CC03030D
through the Diels–Alder reaction.
iminoquinone and naphthyl moiety underwent [4 + 2]
cycloaddition. The reaction could not proceed without
Cu(OAc)2 and yielded only 19% of 3a without AcOH (entries 2
and 3). The reaction showed a poor yield (22%) when ODCB
was replaced with CB (entry 4), and the reactions performed
in N,N-dimethylformamide and dimethyl sulfoxide did not
yield the desired product (entries 5 and 6). We observed that
the concentration of Cu(OAc)2 was important because a
reaction with 1 equiv of Cu(OAc)2 increased the yield to 43%
(entry 7). However, with other oxidants, such as CuCl, CuI,
Table 1. Optimization of reaction conditions.a
Entry 2 (equiv) Reagent (equiv)
Solvent (mL)
ODCB (1.5)
ODCB (1.5)
ODCB (1.5)
CB (1.5)
Yield (%) 3ai
39
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.3
1.5
1.7
1.9
1.7
1.7
1.7
1.7
1.7
1.7
Cu(OAc)2 (0.5)
-
Co(OAc)2 ·4H2O, and CuCl2, the reaction conversion rate
2
NDj
19
decreased to 27%, trace, 25%, and 0%, respectively (entries
8–11). We further increased the concentration of Cu(OAc)2 (2
equiv) and adjusted the solution concentration (ODCB: 1 and
2 mL). The product 3a was formed with yields of 41% and 68%,
respectively (entries 12 and 13). We further optimised the
equivalence of 2a to 1.3, 1.5, 1.7, and 1.9 equiv, and the
reaction conversion rate increased to 50%, 70%, 78%, and
74% of 3a, respectively (entries 14–17). The adjustment of the
acid additive AcOH at 3.6 and 5.4 equiv (entries 18 and 19)
and prolonged reaction time (entries 20 and 21) did not result
in higher yields. We used only catalytic amount of Cu(OAc)2
(20 mol%) and flushed oxygen as the oxidant; however, the
yield was not satisfactory. The presence of excessive oxygen
seemed to hamper the reaction process. One control
experiment showed that reactions cannot proceed well under
nitrogen (entry 23), indicating that oxygen was demanded in
adequate amount.
3b
4
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (1)
CuCl (1)
22
5
DMF (1.5)
DMSO (1.5)
ODCB (1.5)
ODCB (1.5)
ODCB (1.5)
ODCB (1.5)
ODCB (1.5)
ODCB (1)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ODCB (2)
ND
ND
43
6
7
8
27
9
CuI (1)
trace
25
.
10
11
12
13
14
15
16
17
18c
19d
20e
21f
22g
Co(OAc)2 4H2O (1)
CuCl2 (1)
ND
41
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (0.2)/O2
Cu(OAc)2 (2)
68
Based on the aforementioned optimised condition, we
50
evaluated the scope of differently substituted
2 and variously
70
substituted 2-naphthyl anilines (Table 2). By using this
1
78
developed method, moderate to good yields of polycyclic
aromatic hydrocarbons were obtained from almost all
substrates. An initial study with 2-methyl, 2-tert-butyl, and 2-
chloro-substituted quinones provided moderate yields (37%–
67%; 3b–d). The reaction with 2-chloro-substituted quinone
resulted in a poor yield because of its electron-withdrawing
74
73
56
66
ability. Next, we investigated the chemical reactivity of
1 with
an electron-donating group (EDG) and electron-withdrawing
group (EWG) towards 2a. The EDGs, 4-methyl and 5-methyl
biaryl amines, reacted with 2a to yield products 3e and 3f
(yields: 73% and 51%, respectively). Furthermore, the EWGs,
such as 4-fluoro, 5-fluoro, 4-chloro, and 4-trifluoromethoxy,
reacted with 2a to yield the desired products 3g–j (yield: 52%–
79%). Notably, 5-substituted 2-naphthyl anilines, either with
an EDG or EWG, showed relatively poor yields compared with
those with 4-substituted 2-naphthyl anilines, likely because of
the steric effect. Additional reactivity studies were conducted
for investigating the variations in the functionality on the
aniline ring with 2-methyl p-benzoquinone; these resulted in
the formation of the desired products 3k–o (yield: 42%–61%).
The reaction with a paramethyl moiety on the naphthyl ring
also yielded iptycenes (3p–r) in moderate to good yields (yield:
50%–72%). This methodology can be extended not only to
cyclisation with an anthracenyl moiety, yielding 76% of 3s but
52
35
23h
17
a
All the reactions were performed with 1a (21.9 mg, 0.1 mmol), 2a, and AcOH (1.8
b
c
d
equiv) at 140 °C under air. Without AcOH. Reaction with a 3.6 equiv of AcOH.
Reaction with a 5.4 equiv of AcOH. Reaction for 30 h. Reaction for 34 h. The
e
f
g
h
i
reaction tube was flushed pure oxygen for 5 min. Reaction carried out under N2.
Yields were determined through proton nuclear magnetic resonance spectroscopy by
using mesitylene as the internal standard. j ND denoted not detected.
First, we studied the reaction between 1a and p-
benzoquinone (2a) in a molar ratio of 1:1.1 with AcOH and
Cu(OAc)2 as the additive and oxidant, respectively, at 140 °C in
o-dichlorobenzene (ODCB) for 24 h under air (Table 1, entry 1).
An unusual reaction occurred to yield iptycene 3a with an
acridinone motif (yield: 39%). Thus, iptycene-based nitrogen-
2 | J. Name., 2012, 00, 1-3
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also to a naphthyl moiety with a tetraphenyl substitution, We proposed that the initial condensation between 2-
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DOI: 10.1039/C7CC03030D
yielding 70% of 3t. These iptycenes were characterised by naphthyl biarylamine and
2 that yielded naphthyl 2-
through proton nuclear magnetic resonance (NMR) and 13C iminoquinone was mediated by acetic acid and copper acetate,
NMR spectroscopy as well as single-crystal X-ray diffraction evidenced by excessive amount of added Cu(OAc)2. Scheme 3
analysis.18
shows the proposed radical cation addition and cyclisation
mechanism. Cu(OAc)2 and AcOH were first implicated in the
formation of iminoquinone. Subsequent Cu(II) chelation20 with
a nitrogen atom followed by one electron oxidation generated
a radical cation intermediate IIa and its resonated forms IIb
Table 2. Substrate scope study.a
and III 21
After one electron oxidation and losing a proton from IV, a
cationic species was formed. Further electrophilic
substitution and loss of a proton from VI 3a was generated.
. Cyclisation took place to generate a radical cation IV.
V
,
We believe that the reaction proceeded through a different
reaction pathway compared with previous approaches for the
synthesis of triptycenes through the Diels–Alder reaction.
Scheme 2. Control experiments
a
All the reactions were performed using 1 (21.9 mg, 0.1 mmol), 2a (0.17
mmol), Cu(OAc)2 (36.2 mg, 2 equiv), and AcOH (1.8 equiv) at 140 °C under
air.
The control experiments revealed no [4 + 2] cycloaddition
when the N-allyl-2-(naphthalen-1-yl)aniline was exposed to
identical reaction conditions (Scheme 2a). Furthermore, no
cycloaddition occurred when cyclohex-2-enone (Scheme 2b)
and hydroquinone (Scheme 2c) were subjected to the
standard reaction condition. In these two cases, unreacted
cyclohex-2-enone and hydroquinone were recovered. This
suggested that the condensation of aniline and 2a must occur
effectively before the occurrence of [4 + 2] cycloaddition.
Notably, the production of 3a decreased to 24% when a
typical radical scavenger, 2,2,6,6-tetramethylpiperidine 1-oxyl,
was added.19 This evidence corroborated that the explored
coupling of tethered iminoquinone and nathpthyl moieties
proceeded through a radical mechanism.
Scheme 3. Proposed mechanism.
The prepared iptycenes can be transformed to other planar
heterocyclics. First, the inverse electron-demand Diels–Alder
reactions between 3,6-di-pyridin-2-yl-[1,2,4,5]tetrazine and 3a
yielded 8H-naphtho[3,2,1-kl]acridin-8-one (4a; Scheme 4a).
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We attempted to reduce the imine moiety by the NiCl2·6H2O–
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DOI: 10.1039/C7CC03030D
NaBH4–CH3OH reagent, but the bridging ethylene moiety was
reduced to produce 4b instead (Scheme 4b). The Diels–Alder
cycloaddition of 3a and 1,3-diphenylisobenzofuran, followed
by subsequent aromatisation under the catalysis of p-
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compound 4c (Scheme 4c). Finally, we performed
a
competition experiment between methyl acrylate and
iminoquinone moiety towards [4 + 2] cycloaddition by using 4-
5.
6.
((2-(furan-2-yl)phenyl)imino)cyclohexa-2,5-dienone
and
methyl acrylate with 10 mol % Pd(OAc)2 and Cu(OAc)2/O2 as
the catalyst and oxidant, respectively, in 2,2,2,-
trifluoroethanol. However, the ortho C–H activation and
insertion of methyl acrylate at 3-position of the furan moiety
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iminiquinone and the furan moiety and deoxygenation,
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Scheme 4. a)–c) Transformation of iptycenes with an acridinone
motif to other planar heterocyclics and competition experiment.
In summary, we developed a new class of iptycenes by
combining
1 and 2 through copper (II)-mediated radical
18.
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cyclisation. This reaction yielded the robust and efficient
syntheses of iptycenes with an acridinone motif. These
iptycenes can be further transformed to planar acridinone
heterocyclics through the Diels–Alder reaction. We are
currently focusing on applying this new iptycene–acridinone
motif for constructing molecular rotors in our laboratory.
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Notes and references
1.
C.-F. Chen and Y.-X. Ma, Iptycenes Chemistry, Springer
Heidelberg Dordrecht London NewYork, 2013.
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