Annulative π-Extension of Unactivated Benzene Derivatives through Nondirected C-H Arylation

Article abstract of DOI:10.1021/acs.orglett.9b02583

Annulative π-extension chemistry provides a concise synthetic route to polycyclic arenes. Herein, we disclose a nondirected annulation approach of unactivated simple arenes. The palladium-catalyzed 2-fold C-H arylation event facilitates tandem C-C linkage relays to furnish fully benzenoid triphenylene frameworks using cyclic diaryliodonium salts. The inseparable regioisomeric mixture of 1- and 2-methyltriphenylenes is identified by the combined analysis of ion mobility-mass spectrometry, gas-phase infrared spectroscopy, and molecular simulation studies.

Full text of DOI:10.1021/acs.orglett.9b02583

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Annulative π‑Extension of Unactivated Benzene Derivatives through
Nondirected C−H Arylation
Jae Bin Lee, Min Ho Jeon, Jeong Kon Seo, Gert von Helden, Jan-Uwe Rohde,∥ Bum Suk Zhao,*,∥
†
†
‡
§
,
#
,†
Jongcheol Seo,* and Sung You Hong*
†School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil, Ulsan
4919, Korea
4
‡
§
∥
#
UNIST Central Research Facility, Ulsan 44919, Korea
Fritz-Haber-Institut der Max-Planck-Gesellschaft, Berlin 14195, Germany
Department of Chemistry, UNIST, Ulsan 44919, Korea
Department of Chemistry, POSTECH, Pohang 37673, Korea
*
S Supporting Information
ABSTRACT: Annulative π-extension chemistry provides a
concise synthetic route to polycyclic arenes. Herein, we disclose
a nondirected annulation approach of unactivated simple arenes.
The palladium-catalyzed 2-fold C−H arylation event facilitates
tandem C−C linkage relays to furnish fully benzenoid
triphenylene frameworks using cyclic diaryliodonium salts. The
inseparable regioisomeric mixture of 1- and 2-methyltripheny-
lenes is identified by the combined analysis of ion mobility-mass
spectrometry, gas-phase infrared spectroscopy, and molecular
simulation studies.
oordinating moieties on substrates guide transition-metal
aryl−aryl cross-coupling reactions. The preassembled precur-
C
catalysts to proximal C−H bonds and impart site
sors are often stitched together through Scholl oxidation
1
−4
12
selectivity and increased reactivity.
This chelation-assisted
(Scheme 1a). However, the complexity of prefunctionalized
approach promotes an effective agostic interaction between the
metal center and an inert C−H bond to form an ortho-
substrates necessitates tedious multistep procedures.
Annulative π-extension (APEX) employs one- or two-step
procedures to yield DG-free PAH templates with high atom
1
,2
2
cyclometalation intermediate. C(sp )−H activation chem-
istry has been utilized to provide access to extended aromatic
systems such as polycyclic aromatic hydrocarbons (PAHs) and
18
and step economy. In particular, edge geometrical features of
the PAH templates show intrinsic reactivity toward K- or bay
5
18−21
nanographene segments. Our group has previously reported a
region-selective APEX reactions (Scheme 1b).
However,
tandem arylation route using coordinating moiety-bearing
arenes to obtain functionalized triphenylenes as a fully
benzenoid building unit of PAHs. However, this directed
this approach has been limited in its ability to provide fully
benzenoid structures. Moreover, the substrate scaffolds
possessing these peripheral features are largely based on
fused-cyclic arenes and not simple arenes. Direct access to
triphenylene frameworks from simple arenes presents formi-
dable challenges associated with the (i) low reactivity of arenes
and (ii) poor site-selectivity of C−H activation in the absence
of DGs. Herein, we sought to devise a single-step nondirected
APEX route using simple arenes for obtaining fully benzenoid
triphenylenes (Scheme 1c).
6
annulation route, assisted by preinstalled directing groups
(
DGs), inevitably limits access to the parent framework
7
,8
structure. Despite recent progress on removable or traceless
DG strategies including decarboxylative methods,
9
−11
the
removal of nonessential DGs is typically not trivial and can
often lead to poor atom and step economy.
The symmetry, size, and structure of PAHs profoundly
Our study commenced with the nondirected approach using
influence the physicochemical properties, stability, and
22−28
1
2−16
benzene (1a),
which is underdeveloped as compared with
reactivities of these frameworks.
In particular, fully
the well-established directed syntheses. Cyclic diphenyliodo-
benzenoid frameworks (e.g., triphenylene, dibenzo[fg,op]-
tetracene, and hexa-peri-hexabenzocoronene) composed of
6
,29−31
nium salt (2a) was employed as an aryl appending agent.
Received: July 24, 2019
17
Clar’s aromatic sextets possess high thermodynamic stability.
The precursors are commonly prepared by the [2 + 2 + 2]
cyclotrimerization of arynes, Diels−Alder cycloaddition, or
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02583
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
2,33
Scheme 1. Approaches for Polycyclic Arenes
event.
Replacement of Pd(TFA) by Pd(OAc) resulted
2
2
in a lower yield (entry 5). The catalytic activity of Pd (dba)
2
3
(
entry 6) is presumably associated with its oxidation by
34
hypervalent iodine reagent 2a. Palladium complex Pd-
MeCN) (BF ) was not as efficient as Pd(TFA) (entry 7).
(
4
4 2
2
The cosolvent system of benzene and ODCB resulted in a
slightly diminished yield (entry 8). The absence of molecular
sieves as a drying agent led to a significantly diminished yield
(
entry 9), suggesting that moisture hampers the catalytic cycle.
There was no significant change between air and N conditions
2
(
entry 10), while both reduced and elevated reaction
temperatures (entries 11 and 12) lowered the reaction yield.
II
Given the existing literature on Pd -catalyzed C−H arylation
35
with hypervalent iodonium salts, it is conceivable that the
reaction of 1a with 2a initially affords the iodoarene
intermediate shown in Scheme 2. Accordingly, the noncyclic
Scheme 2. Double C−H Arylation Event
After extensive screening of palladium catalysts and reagents
(
see also the SI, section III), reaction conditions for the Pd-
catalyzed 2-fold C−H activation relay were established to give
aa in 65% yield (Table 1, entry 1) under acidic conditions. In
the absence of Pd(TFA) , TFA, or AgSbF , the triphenylene
3
2
6
scaffold was not produced (entries 2−4), indicating that this
diphenyliodonium salt 2a′ produced biphenyl (BP) under the
same reaction conditions (SI section III, 88% yield). In case of
cyclic 2a, the hypothetical iodoarene intermediate may then
nondirected APEX involves an electrophilic palladation
a
Table 1. Optimization of Reaction Conditions
II
undergo oxidative addition to Pd and intramolecular C−H
activation to initiate the second arylation event yielding 3aa.
Having established the optimized reaction conditions, we
next focused on the substrate scope of our APEX approach
(
Scheme 3). Gratifyingly, substituted nonfused simple arenes
b
bearing electron-donating alkyl groups were found to be
compatible with the optimized conditions, affording the
desired triphenylene products in good yields (3ba−3ha). In
particular, sterically hindered isopropyl-, tert-butyl-, and
cyclohexyl- substituted arenes exclusively afforded the (β +
γ) arylated products (3ea−3ga), which are inaccessible by the
chelating-group assisted approach. Compared with partially
saturated tetralin 1j, naphthalene 1k was found to be more
entry
change from the standard conditions
none
no Pd(TFA)2
no TFA
yield (%)
c
1
2
3
4
5
6
7
8
9
65 (68)
0
0
0
no AgSbF6
Pd(OAc) instead of Pd(TFA)
43
21
23
58
15
64
23
38
2
2
Pd (dba) instead of Pd(TFA)
2
2
3
Pd(MeCN) (BF ) instead of Pd(TFA)
2
4
4
2
reactive in this transformation, presumably due to its π-
benzene (1.5 mL) + ODCB (1.0 mL)
without 3 Å MS
36,37
coordination to the active Pd species.
Electron-rich indole
1
l also underwent the annulation, even without the aid of TFA.
10
11
12
N atmosphere
2
The electron-rich ethoxy and methoxy groups were also
tolerated under the reaction conditions, providing the desired
triphenylene products (3ma−3oa). However, the electron-
deficient arenes (1p−1r) showed low or no reactivity, which
endorses the involvement of an electrophilic reaction pathway.
Interestingly, unprotected benzoic acid (1q) provided the
parent triphenylene (3aa) via a decarboxylative C−H arylation
at 110 °C
at 150 °C
a
Standard conditions: 2a (0.20 mmol, 1.0 equiv), Pd(TFA) (10 mol
2
%
(
), AgSbF (0.20 mmol, 1.0 equiv), TFA (2.0 mmol, 10 equiv), 1a
6
b
2.5 mL), 130 °C, 24 h, activated 3 Å molecular sieves (MS). GC
c
yield using n-dodecane as an internal standard. Isolated yield. ODCB
o-dichlorobenzene.
1
0,11
=
pathway.
In addition, the competition experiments
B
DOI: 10.1021/acs.orglett.9b02583
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 3. Substrate Scope
The generation of regioisomers of triphenylenes 3ba, 3ca,
ha, 3na, and 3pa is associated with a small discrepancy in the
3
reactivity pattern of simple arenes. Identification of an
inseparable isomeric mixture of PAHs has been an arduous
40
task. Recently, the Seeberger, Pagel, and von Helden groups
demonstrated comprehensive structural analyses of small
organic molecules such as a benzocaine, oligosaccharide
isomers, and protein structures by using ion mobility-mass
spectrometry (IM-MS) and infrared (IR) spectroscopy in the
41−45
gas phase.
IM-MS separates molecular ions based on their
collision cross sections (CCSs), enabling the differentiation of
isomers with varying geometrical sizes. In this regard, we
speculated that combined with molecular modeling, gas-phase
IR spectroscopy of mass- and ion mobility-selected ions can
allow one to confirm the structures of the triphenylene
regioisomers. Thus, this combination of analytical techniques
was used to identify the regioisomeric mixture in the present
work. Owing to their fixed geometrical sizes, (α+β) 3ba (1-
methyltriphenylene (1-MeTPh)) and (β+γ) 3ba (2-methyl-
triphenylene (2-MeTPh)) were selected as model re-
gioisomers.
Experimental details of IM-MS and gas-phase IR spectros-
copy utilized in the present work are given in the SI, section
VII. The electrospray ionization (ESI) mass spectrum of a
sample solution of the model regioisomer mixture (1- and 2-
MeTPh) in the presence of sodium cations is shown in Figure
a
Reaction conditions: 2 (0.20 mmol, 1.0 equiv), Pd(TFA) (10 mol
), AgSbF (0.20 mmol, 1.0 equiv), TFA (2.0 mmol, 10 equiv), 1
6
b
2
%
+
S2a. Sodiated MeTPh monomer [MeTPh + Na] (m/z 265)
(
2.5 mL), 130 °C, 24 h, activated 3 Å MS. Isolated yields.
+
c
1
and its water adduct [MeTPh + Na + H O] (m/z 283) were
Inseparable regioisomeric ratios are determined by H NMR
2
d
spectroscopy. 20.0 equiv of corresponding substrate in ODCB (2.5
mL). 30.0 equiv of corresponding substrate in ODCB (2.5 mL). No
TFA.
observed at high abundance. Their arrival time distributions
measured by IM-MS have nonsymmetric shapes, which can be
fit to two overlapping Gaussian curves (Figure S2b, red and
blue lines). This suggests the presence of two isomers which
slightly differ in CCS but are not clearly resolved by our
instrumental conditions. Nonetheless, CCS values of the two
e
f
between 1n and 1a or 1p, respectively, support the
involvement of an electrophilic event (SI section IV).
2
2
Encouraged by this achievement, we next explored the
versatility of a series of iodonium salts 2 for the 2-fold aryl-
transfer reactions. The electronic nature of cyclic iodonium
salts seemed to have only a marginal effect on the yields.
Symmetrical and unsymmetrical 2 are applicable to produce
substituted triphenylenes (3ab−3ag) in moderate yields.
Undesired dimerization of 2b was also observed to give 4b
isomers could be determined: 95 ± 2 Å and 97 ± 2 Å for
+ 2 2
[MeTPh + Na] and 104 ± 2 Å and 106 ± 2 Å for [MeTPh
+ Na + H O] . Theoretical CCSs predicted from the
+
2
optimized structures of sodiated 1- and 2-MeTPh species
(see Table S5 and ) suggest that the smaller and larger CCS
values correspond to 1-MeTPh and 2-MeTPh, respectively.
To further confirm the separation of the two regioisomers by
(
see also the SI).
IM-MS, two small fractions of the ion mobility-separated
+
[
MeTPh + Na + H O] ions (I and II in Figure S2b) were
2
isolated and further investigated by gas-phase IR spectroscopy.
As shown in Figure S2c, the IR spectra of fractions I and II are
different from each other and fit well theoretical IR spectra of
+
+
[
1-MeTPh + Na + H O] and [2-MeTPh + Na + H O] ,
2
2
respectively. As shown in the inset of Figure S2c, rings of the
sodiated 1-MeTPh isomer are distorted due to steric
hindrance, whereas the sodiated 2-MeTPh isomer has a flat
geometry. This results in noticeable differences between the
peaks corresponding to out-of-plane C−H bending vibrations
To further investigate the synthetic utility of this direct
APEX protocol, we sought to apply our methodology to
phenylethyl resorcinol, a commercial skin-lightening agent
38,39
−1
found in cosmetics,
due to its simple arene-based structure.
in the range 700−850 cm . Detailed IR peak assignments are
To our delight, the annulated derivative 6 was exclusively
obtained from methyl protected 5 in 44% isolated yield
through steric control. The access to 6 by alternative/directed
C−H arylation is limited.
given in Table S6. These results demonstrate that the
regioisomeric mixture of 1-MeTPh and 2-MeTPh can be
discriminated and identified by IM-MS, although our current
instrumental setup is not sufficient to fully resolve these
isomers.
In conclusion, we have developed the first nondirected Pd-
catalyzed aromatic extension approach to construct tripheny-
lene frameworks from simple arenes. The primary synthetic
challenge associated with C−H arylation of benzene and its
derivatives is the low reactivity and site-selectivity. This study
C
DOI: 10.1021/acs.orglett.9b02583
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
provides the straightforward APEX route via Pd-catalytic relay
involving 2-fold C−H arylation in the absence of a chelating
moiety, which efficiently circumvented lengthy multistep
reactions. Furthermore, we demonstrate the discrimination
and identification of inseparable regioisomers using a gas-phase
analytical approach based on IM-MS and molecular-ion IR
spectroscopy.
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
*
(
̈
E-mail: syhong@unist.ac.kr.
E-mail: zhao@unist.ac.kr.
E-mail: jongcheol.seo@postech.ac.kr.
2
(
̈
llen, K. Graphenes as Potential Material
ORCID
(
Gert von Helden: 0000-0001-7611-8740
Jan-Uwe Rohde: 0000-0002-0691-6699
Jongcheol Seo: 0000-0001-5844-4585
Sung You Hong: 0000-0002-5785-4475
Funding
Mauri, F. Clar’s Theory, π-Electron Distribution, and Geometry of
Graphene Nanoribbons. J. Am. Chem. Soc. 2010, 132, 3440−3451.
(
18) Ito, H.; Segawa, Y.; Murakami, K.; Itami, K. Polycyclic Arene
Synthesis by Annulative π-Extension. J. Am. Chem. Soc. 2019, 141, 3−
1
0.
(19) Ito, H.; Ozaki, K.; Itami, K. Annulative π-Extension (APEX):
Rapid Access to Fused Arenes, Heteroarenes, and Nanographenes.
Angew. Chem., Int. Ed. 2017, 56, 11144−11164.
This work was supported by the UNIST research fund
(
1.190118.01). J.S. is grateful for support from the POSCO TJ
(
20) Matsuoka, W.; Ito, H.; Itami, K. Rapid Access to Nano-
Park Science Fellowship.
graphenes and Fused Heteroaromatics by Palladium-Catalyzed
Annulative π-Extension Reaction of Unfunctionalized Aromatics
with Diiodobiaryls. Angew. Chem., Int. Ed. 2017, 56, 12224−12228.
Notes
The authors declare no competing financial interest.
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Shot K-Region-Selective Annulative π-Extension for Nanographene
Synthesis and Functionalization. Nat. Commun. 2015, 6, 6251.
ACKNOWLEDGMENTS
We are grateful for the expert technical support from the staff
of the Fritz Haber Institute free electron laser (FHI FEL),
■
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Ligand-Enabled Nondirected C−H Cyanation of Arenes. ACS Catal.
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