Synthesis of Pinpoint-Fluorinated Polycyclic Aromatic Hydrocarbons: Benzene Ring Extension Cycle Involving Microwave-Assisted SNAr Reaction

Article abstract of DOI:10.1002/asia.201700870

Fluoroarenes bearing no electron-withdrawing groups (non-activated fluoroarenes) readily underwent nucleophilic aromatic substitution with α-cyanocarbanions under microwave irradiation. The sequence (i) formylalkylation involving the cyanoalkylation of fl

Full text of DOI:10.1002/asia.201700870

DOI: 10.1002/asia.201700870
Communication
Aromatic Substitution
Synthesis of Pinpoint-Fluorinated Polycyclic Aromatic
Hydrocarbons: Benzene Ring Extension Cycle Involving
Microwave-Assisted SNAr Reaction
Kohei Fuchibe, Hisanori Imaoka, and Junji Ichikawa*[a]
Abstract: Fluoroarenes bearing no electron-withdrawing
groups (non-activated fluoroarenes) readily underwent nu-
cleophilic aromatic substitution with a-cyanocarbanions
under microwave irradiation. The sequence (i) formylalkyla-
tion involving the cyanoalkylation of fluoroarenes, (ii) di-
fluorovinylidenation, and (iii) Friedel–Crafts-type cycliza-
tion, afforded extended fluoroarenes by one benzene ring
per cycle. Furthermore, the performance of multiple cycles
successfully provided higher-order pinpoint-fluorinated
Scheme 1. F-PAH Syntheses.
polycyclic aromatic hydrocarbons (F-PAHs).
chloro-5,6-dicyano-p-benzoquinone) dehydrogenation affords
pinpoint-fluorinated aromatic compounds (fluoroarenes).
(b) These compounds were also accessible from 1,1-difluoroal-
Pinpoint-fluorinated PAHs (regioselectively fluorinated polycyc-
lic aromatic hydrocarbons) are promising organic semiconduct-
ing materials[1] because of the unique properties of the fluorine
substituent.[2] The high electronegativity of fluorine leads to an
enhanced resistance of PAHs to aerial oxidation by lowering
the energy level of their HOMO. In addition, the repulsive inter-
action between lone pairs in the fluorine 2p orbitals and the
adjacent p electrons in the carbon 2p orbitals perturbs the
electron density of the extended p systems,[3] which would
render these compounds highly soluble in polar organic sol-
vents, leading to printable organic electronics.[4] It is also worth
mentioning the low steric impact of fluorine, whose introduc-
tion into PAH molecules should not change their molecular
shape, would not significantly affect their p–p stacking in the
solid structure.[5,6] Therefore, the effects of installing a single
fluorine substituent in PAH skeletons would lead to advanta-
geous semiconducting materials, such as THF-soluble fluorinat-
ed picenes, which exhibit p-type semiconducting behavior.[5,7]
To facilitate the efficient synthesis of pinpoint-fluorinated
PAHs, we have recently developed metal-catalyzed cyclizations
of fluoroalkenes on the basis of the following benzene ring
construction strategy (Scheme 1): (a) 1,1-difluoroallenes, readily
prepared via difluorovinylidenation of aldehydes,[8] undergo a
Friedel–Crafts-type cyclization in the presence of a catalytic
amount of indium(III) bromide.[9] Subsequent DDQ (2,3-di-
kenes via
a
cationic palladium(II)-catalyzed cyclization
(Scheme 1).[5,10,11]
As the preparation of the substrates for the indium(III)-cata-
lyzed synthesis of pinpoint-fluorinated PAHs (i.e., difluoroal-
lenes) involved fluoroarenes as starting materials, we envi-
sioned a cyclic benzene ring extension strategy that would
comprise the following steps (Scheme 2): (i) starting fluoroar-
enes would be subjected to formylalkylation via an SNAr reac-
tion to provide arylacetoaldehydes; (ii) the aldehydes would be
then subjected to difluorovinylidenation;[8] finally, (iii) the Frie-
del–Crafts-type cyclization of the obtained 1,1-difluoroallenes[9]
would furnish the benzene ring-extended fluoroarenes.
However, SNAr reactions of fluoroarenes have been conduct-
ed on arenes activated by electron-withdrawing groups, in-
cluding halogenes and trifluoromethyl groups,[12] and the SNAr
[a] Dr. K. Fuchibe, H. Imaoka, Prof. Dr. J. Ichikawa
Division of Chemistry, Faculty of Pure and Applied Sciences
University of Tsukuba
Tsukuba, Ibaraki 305-8571 (Japan)
E-mail: junji@chem.tsukuba.ac.jp
Supporting information for this article can be found under:
https://doi.org/10.1002/asia.201700870.
Scheme 2. Benzene ring extension cycle.
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reactions of non-activated fluoroarenes have been limited to
those on benzene p systems.[13] In the course of this study, we
found that microwave irradiation[14] significantly facilitated the
desired SNAr reaction of non-activated fluoroarenes with naph-
thalene or higher-order PAH p systems (Table 1).[15] When fluo-
ronaphthalene 1a and propionitrile (4.0 equiv) were heated in
Table 2. Microwave-assisted SNAr reaction.[a]
Entry
1
1[b]
1a
R1, R2
H, H
Nitrile 2
Yield [%][c]
Table 1. Optimizations of SNAr reaction.[a]
2b
2c
2d
2e
53 (ND)
90 (10)
92 (70)
54 (ND)
2
3
4
1a
n-C8H17, H
CH3, CH3
CH3, H
Entry
Heating
Concentration of
Conditions
Yield of
2a [%]
1a [M]
1a
1
2
3
4
5
oil bath
oil bath
microwave
microwave
microwave
0.25
0.25
0.25
0.25
0.50
658C, 24 h
6
17
70
77
808C,[b] 16 h
808C,[b] 1 h
808C,[b] 1.5 h
808C,[b] 1.5 h
1b[d]
88 (82)
[a] 1H NMR yield based on an internal standard (CH2Br2). Isolated yield in
parentheses. [b] The reaction was conducted in a sealed vessel.
5
6
7
8
1c[d]
CH3, H
CH3, H
CH3, H
CH3, H
2 f
2g
2h
2i
76
93
70
89
refluxing THF using a conventional oil bath in the presence of
potassium bis(trimethylsilyl)amide (KHMDS, 4.0 equiv, entry 1),
the desired alkylated naphthalene 2a was obtained, albeit in
low yields (6–17%, Table 1, entries 1 and 2). In contrast, micro-
wave irradiation at 808C dramatically increased the yield of 2a
to 70% (entry 3). Further optimization afforded yields of up to
82% after isolation (entries 4 and 5).[16,17]
1d
1e[d]
Acetonitrile (Table 2, entry 1) reacted with 1a in a manner
similar to that of propionitrile, affording the corresponding pri-
mary nitrile 2b in 53% yield under microwave irradiation. In
contrast, 2b was not obtained when performing the SNAr reac-
tion of acetonitrile under oil bath heating (THF, reflux, 18 h).
Decanonitrile, whose C8 alkyl chain is expected to enhance the
solubility of PAHs, also afforded the corresponding naphtha-
lene 2c in 90% yield (entry 2). Thus, as well as secondary nitri-
les,[13a] acetonitrile and primary nitriles reacted with fluoro-
naphthalene under microwave irradiation. Isobutyronitrile,
which is an effective substrate for nucleophilic aromatic substi-
tution, gave 2d in 92% yield (entry 3).
1 f[d]
9
1g[e]
CH3, H
2j
92
[a] The reaction was conducted in a sealed vessel. [b] Unless otherwise
noted, the concentration of 1 was 0.50m. [c] Isolated yield. The yield ob-
tained under oil bath heating (THF, 658C) is shown in parentheses. [d] 1
1
0.25m. [e] 1g 0.008m. ND=Not detected by H NMR spectroscopy.
The microwave-assisted SNAr reaction was applicable to a
wide variety of fluoroarenes (Figure 1). Thus, 3-fluoropyridine
(1b) afforded the corresponding product 2e in 54% yield
(Table 2, entry 4). Substitution of fluorophenanthrenes 1c and
1d also worked well to afford the corresponding 2 f and 2g in
76 and 93% yields, respectively (entries 5 and 6). Fluorochry-
sene ([4]phenacene) 1e and fluoro[4]helicene 1 f were success-
fully transformed into 2h and 2i in 70 and 89% yield, respec-
Figure 1. List of fluoroarenes with extended p systems.
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tively (entries 7 and 8), proving that substitution proceeded
smoothly even at the bay region of the phenanthrene sub-
structure of 1e. Finally, fluoropicene ([5]phenacene) 1g under-
went substitution under identical conditions to give 2j in 92%
yield (entry 9). Thus, the scope of the microwave-assisted SNAr
reaction was expanded to include non-activated fluoroarenes
with extended p systems.
[a,b]
Table 3. Benzene ring extension of fluoroarenes (2nd and 3rd cycles)
With the microwave-assisted alkylation method in hand, we
sought to explore its application to the planned benzene-ring
extension (Scheme 3). Nitrile 2a, obtained as detailed above
Entry
Cycle
Starting
Compd
Yield [%]
Step 1)
Step 2)
Steps 3,4)[c]
Step 5)
1
2
2nd
3rd
1h
1j
71[d]
64[e]
85
79
64
36
87, 1j
79, 1k
[a] Isolated yield. [b] For steps 1) to 5), see Scheme 3. [c] Two-step yield.
[d] 1h 0.5m. [e] 1j 0.25m.
Scheme 3. Benzene ring extension of 1-fluoronaphthalene (1st cycle).
from 1a (Table 1, entry 5: step 1, 82% yield), was subjected to
half reduction with diisobutylaluminium hydride (DIBAL) to
afford aldehyde 3a in 81% yield (step 2). Difluorovinylidena-
tion of 3a afforded 1,1-difluoroallene 4a in 73% yield over
two steps (steps 3 and 4). Then, 4a underwent Friedel–Crafts-
type cyclization under indium(III) catalysis to provide fluoro-
phenanthrene 1h in 94% yield (step 5), thus completing the
first cycle. In a similar manner, the benzene ring extension
starting from 2c afforded the corresponding 1i in good yield.
By repeating the same protocol with fluoroarene 1h, higher-
order pinpoint-fluorinated PAHs were synthesized (Table 3).
Thus, 1h was subjected to the second ring extension to afford
pinpoint-fluorinated chrysene 1j (entry 1). The third ring exten-
sion of 1j was performed to afford pinpoint-fluorinated picene
1k (entry 2).
The benzene ring extension was successfully applied to not
only terminal fluoroarenes but also internal ones (Scheme 4).
Pinpoint-fluorinated triphenylene 1l (top) was successfully syn-
thesized from fluorophenanthrene 1c via nitrile 2 f, whereas
pinpoint-fluorinated triphenylene 1m (bottom) was similarly
obtained from fluorohelicene 1 f via 2i.[18]
It is worth noting that the benzene ring extension using pri-
mary nitriles facilitated the synthesis of PAHs bearing a sub-
stituent in the bay region (Scheme 3, Scheme 4 and Table 3).
Scheme 4. Benzene ring extension of internal fluoroarenes.
Although effects of bay substitution are of importance not
only from the viewpoint of organic devices but also from that
of cancer research,[19] synthetic methods applicable to the mol-
ecules have been rare.[20] The benzene ring extension thus con-
tributes to a wide range of research areas by providing the
bay-substituted PAHs.
In summary, we have achieved a microwave-assisted SNAr re-
action of non-activated fluoroarenes with extended p systems.
This SNAr reaction along with difluorovinylidenation and cat-
ionic cyclization facilitated a benzene-ring-extension cycle, by
which terminal and internal fluoroarenes were converted to
the corresponding extended fluoroarenes in good yields. Thus,
the cycle increases the variety of pinpoint-fluorinated PAHs.
Experimental Section
Microwave-assisted SNAr reaction of non-activated fluoroarenes
(step 1): The synthesis of nitrile 2a is described as a typical proce-
dure. To a THF solution (2.4 mL) of KHMDS (1.03 g, 4.80 mmol) was
added 1-fluoronaphthalene (1a, 155 mL, 1.20 mmol) at room tem-
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perature. After propionitrile (340 mL, 4.75 mmol) was added, the
vessel was sealed and was irradiated using a microwave (65 W) at
808C for 90 min. The reaction mixture was poured into aqueous
hydrochloric acid (2m, 5 mL) at room temperature. Organic materi-
als were extracted with EtOAc (3ꢁ4 mL). The combined extracts
were washed with brine and dried over anhydrous sodium sulfate.
phosphate buffer (7 mL). The organic materials were extracted
with CH2Cl2 (3ꢁ4 mL). The combined extracts were washed with
brine and dried over anhydrous sodium sulfate. After removal of
the solvent under reduced pressure, the residue was purified by
column chromatography on silica gel (n-hexane) to give fluoroar-
ene 1h (103 mg, 94% yield) as colorless crystals.
To the residue (396 mg) were added dibromomethane (109 mg)
and a,a,a-trifluorotoluene (24 mg) as internal standards. Analysis
by NMR spectroscopy indicated that nitrile 2a was generated in
Acknowledgements
1
88% yield (by H NMR based on CH2Br2) and fluoronaphthalene 1a
was consumed completely (by 19F NMR based on CF3Ph). The resi-
due was purified by column chromatography on silica gel (n-
hexane/EtOAc, 10:1) to give nitrile 2a (178 mg, 82% yield) as a col-
orless liquid.
This research was supported by JSPS KAKENHI grant number
JP16H04105 (J.I.), MEXT KAKENHI Grant Number JP16H01002
(J.I.), and JSPS KAKENHI grant number JP15K05414 (K.F.). Tosoh
F-Tech, Inc. is acknowledged for the generous gift of 1,1,1-tri-
fluoro-2-iodoethane.
Half-reduction of nitriles (step 2): The preparation of aldehyde 3a
is described as a typical procedure. To a toluene solution (150 mL)
of nitrile 2a (28.2 g, 156 mmol) was added a toluene solution of
diisobutylaluminium hydride (DIBAL-H, 1.00m, 184 mL, 184 mmol)
at À788C. After being stirred for 3 h at À788C, aqueous hydrochlo-
ric acid (6m, 300 mL) was added and the mixture was allowed to
warm to 08C. The mixture was filtered through a pad of celite
using EtOAc as the eluent. The organic materials were extracted
with EtOAc (3ꢁ50 mL). The combined extracts were washed with
brine and dried over anhydrous sodium sulfate. After removal of
the solvent under reduced pressure, the residue was subjected to
column chromatography on silica gel (n-hexane/ethyl acetate, 4:1)
to give aldehyde 3a (19.9 g, 81% yield) as a yellow liquid.
Keywords: aromatic substitution
microwave chemistry · ring extension
·
fluorine
·
indium
·
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Manuscript received: June 14, 2017
Revised manuscript received: June 30, 2017
Accepted manuscript online: June 30, 2017
Version of record online: && &&, 0000
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COMMUNICATION
Aromatic Substitution
Kohei Fuchibe, Hisanori Imaoka,
Junji Ichikawa*
&& – &&
Lords of the rings: Fluoroarenes bear-
ing no electron-withdrawing groups
(non-activated fluoroarenes) readily un-
derwent nucleophilic aromatic substitu-
tion with a-cyanocarbanions under mi-
crowave irradiation. The sequence (i) for-
mylalkylation involving cyanoalkylation
of fluoroarenes, (ii) difluorovinylidena-
tion, and (iii) Friedel–Crafts-type cycliza-
tion, afforded extended fluoroarenes by
one benzene ring per cycle. Further-
more, the performance of multiple
cycles successfully provided higher-
order pinpoint-fluorinated polycyclic ar-
omatic hydrocarbons (F-PAHs).
Synthesis of Pinpoint-Fluorinated
Polycyclic Aromatic Hydrocarbons:
Benzene Ring Extension Cycle
Involving Microwave-Assisted SNAr
Reaction
&
&
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