Streamlined synthesis of polycyclic conjugated hydrocarbons containing cyclobutadienoids via C-H activated annulation and aromatization

Article abstract of DOI:10.1021/jacs.6b12888

The juxtaposition of fused cyclobutadienoid (CBD) with benzenoid creates intriguing alternating antiaromatic and aromatic conjugation. Synthetic accessibility of such molecules, however, has been challenging and limited in scope. We report a modular and streamlined synthetic strategy to access a large variety of polycyclic conjugated hydrocarbons with fused CBD. Synthesis was achieved through efficient palladium-catalyzed C-H activated annulation between abundant aryl bromides and oxanorbornenes, followed by aromatization under acidic conditions. The influence of four-membered ring was examined using spectroscopy, crystallography, and computation. This strategy will facilitate exploration on the chemical, structural, and electronic properties of such conjugated systems containing CBD.

Full text of DOI:10.1021/jacs.6b12888

Communication
pubs.acs.org/JACS
Streamlined Synthesis of Polycyclic Conjugated Hydrocarbons
Containing Cyclobutadienoids via C−H Activated Annulation and
Aromatization
Zexin Jin, Yew Chin Teo, Nicolo G. Zulaybar, Matthew D. Smith, and Yan Xia*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
S
* Supporting Information
Scheme 1. Syntheses of Phenylene Structures
ABSTRACT: The juxtaposition of fused cyclobutadienoid
(CBD) with benzenoid creates intriguing alternating
antiaromatic and aromatic conjugation. Synthetic accessi-
bility of such molecules, however, has been challenging
and limited in scope. We report a modular and streamlined
synthetic strategy to access a large variety of polycyclic
conjugated hydrocarbons with fused CBD. Synthesis was
achieved through efficient palladium-catalyzed C−H acti-
vated annulation between abundant aryl bromides and
oxanorbornenes, followed by aromatization under acidic
conditions. The influence of four-membered ring was
examined using spectroscopy, crystallography, and compu-
tation. This strategy will facilitate exploration on the
chemical, structural, and electronic properties of such
conjugated systems containing CBD.
onbenzenoid structures with antiaromaticity have been
much less explored with limited understanding of their
N
electronic structures, chemical reactivity, and solid-state prop-
erties, compared to ubiquitous aromatic π-systems, largely due
to their challenging synthesis and limited stability.1 Opposite to
aromaticity, antiaromaticity leads to strong destabilization,
π-bond localization, and a paratropic current.2 [N]Phenylene is
an intriguing family of conjugated ladder structures with fused
antiaromatic 4π-electron cyclobutadienoid (CBD) and aromatic
6π-electron benzenoid rings, two extremes of the aromaticity
continuum.3 As a result, the benzenoids fused with CBD are
dearomatized to show significant bond alternation.3 The most-
established synthesis of [N]phenylenes was developed by
Vollhardt and co-workers via cobalt-catalyzed [2 + 2 + 2]
cycloaddition of appropriately designed phenylethynyl sub-
strates under photolysis (Scheme 1a).3,4 Their seminal work
produced almost all known [N]phenylenes in literature.
However, the cobalt-catalyzed cycloadditions form only
benzenoid, thus phenylene structures, in moderate yields, and
the synthesis of the required phenylethynyl precursors is
multistep and time-consuming. Swager and co-workers recently
extended [N]phenylene to phenylene-containing acenes
(Scheme 1b), using 3,4-bis(methylene)cyclobutene as one of
the starting materials, which is an air sensitive compound that
needs to be synthesized via flash vacuum pyrolysis.5 As a result
of challenging synthesis, conjugated molecules containing four-
membered rings remain rare but intriguing.3,5,6
investigation into the influence of their antiaromaticity and
tuning of their optoelectronic properties. Transition-metal
catalyzed C−H activation is emerging as powerful strategies for
the synthesis of extended π-systems.7 In powerful norbornene
(NBE) mediated C−H functionalization of arenes, NBE fused
benzocyclobutene may form as a byproduct following the ortho-
C−H activation step.8 We recently tuned this side reaction
pathway into highly efficient catalytic arene-NBE annulation
(CANAL) and used this chemistry to synthesize a series of
shape-persistent, nonconjugated ladder polymers.9 We envi-
sioned that if NBE is replaced with oxanorbornene (oNBE),
the CANAL chemistry may yield oNBE fused benzocyclobu-
tene structures that can then be aromatized to form CBD
subunits (Scheme 1c). Because a plethora of aryl bromides and
oNBEs are readily accessible and widely used for many
coupling reactions (especially aryl bromides are ubiquitously
used for the synthesis of almost all conjugated structures), this
strategy represents a versatile and step-economic synthesis of a
wide range of conjugated structures containing CBD circuits.
We first attempted the CANAL reaction using bromo-p-
xylene and benzooxanorbornadiene as model substrates. Under
the same conditions that we have used to achieve quantitative
A facile synthetic method to access a wide variety of phen-
ylene or CBD containing structures will enable systematic
Received: December 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b12888
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
annulation between bromo-p-xylene and NBE, however, only
(2-naphthyl)-p-xylene was obtained and no desired annulation
product was observed (Figure S1). We rationalized that the
naphthyl substituent was formed via Pd-assisted oNBE ring-
opening followed by rapid aromatization from the aryl
bromide-oNBE cross-coupled intermediate. This observation
indicated that β-oxygen elimination of oNBE strongly com-
peted with the annulation pathway. To suppress this undesired
reaction pathway, we introduced two methyl groups to the
bridge-head positions of oNBE, using 1,4-dimethyl-benzoox-
anorbornadiene as the substrate. Simple bromobenzene, instead
of bromo-p-xylene, was used as the other coupling substrate, to
avoid the otherwise high steric hindrance of the palladacycle
intermediate. Delightfully, the selectivity was dramatically
improved with the desired annulation product A formed in
87% yield using 5 mol % Pd(OAc)2 and 10 mol % PPh3 as
ligand. Small amounts of two byproducts B and C were also
detected (Table 1). The reaction mechanism is proposed to
Scheme 2. Proposed Mechanism
Table 1. Optimization of Annulation between oNBE and
a
Aryl Bromide
the annulation is unimportant for our goal of synthesizing novel
π-systems since the fused oxanorbornyl ring will be aromatized
in the next step, but 2D NMR spectroscopy of the product
indicated that the exo-product was formed (Figure S2), in
agreement with what we previously observed using NBEs as the
substrates.9
We next explored the scope of CANAL using phenyl
bromides with variable electronic properties and extending the
conjugation to pyrenyl bromides (Scheme 3). All the electron-
rich and -neutral aryl bromides gave >80% isolated yields of the
desired products (3a−e) using 5 mol % Pd(OAc)2 and 10 mol %
JohnPhos. Electron-deficient aryl bromides gave slower reac-
tions and moderate yields (50−60%) (3f−g). We suspected
that the C−H activation step may be rate-determining and is
slowed for electron-deficient arenes. We also varied the oNBE
structures. Varying the substituents on benzo-oNBEs did not
affect the reaction efficiency or selectivity, and high yields
(>89%) were obtained (3h−i). Therefore, aryl bromide and
oNBE can be independently varied to yield precursors for a
wide range of asymmetric CBD-containing polycyclic con-
jugated hydrocarbons (PCHs), and the tolerance to a range of
functional groups allows tuning of the energy levels of PCHs
and their further manipulation using substitutions. We further
illustrated the synthetic flexibility by synthesizing a donor-
bridge-acceptor type of compound (4j), which is useful to tune
the optoelectronic properties and understand electron transfer
across the four-membered ring in the future.12 Subsequent
aromatization of all the CANAL products was achieved using
pyridinium p-toluenesulfonate (PPTS) in toluene at 120 °C to
afford the corresponding CBD-containing PCHs. Pure PCHs
were obtained in >80% isolated yields after simple aqueous
and MeOH washes of the crude products without column
chromatography. We also synthesized an acene-like molecule 6
containing two four-membered rings, using dibromo-bis-
(triisopropylsilylethynyl)-anthracene 5 and oNBE 2a, in 88%
and 80% yields for the CANAL and aromatization steps, respec-
tively (Scheme 3). Exclusive regioselectivity for C−H activation
and annulation at 3 and 7 positions of anthracene was observed.
Stronger acids, such as HCl, were required for aromatization to
produce 6. The generated antiaromaticity and increased strain
b
conv. (%)
entry
ligand
A
B
C
1
2
3
4
5
PPh3
87
62
72
88
9
6
7
9
0
4
0
0
1
0
PtBu3
P(o-Tol)3
P(2-furyl)3
Johnphos
c
97 (91 )
a
Reactions were performed using 5 mol % Pd(OAc)2, 10 mol %
ligand, 1 equiv Cs2CO3, at [substrate] = 0.25 M in THF at 130 °C for
24 h in a sealed pressure tube. Conversions were determined by
b
c
NMR spectroscopy using mesitylene as the internal standard. Isolated
yield.
start with oxidative addition of Pd(0) to aryl bromide, followed
by coupling with oNBE (Scheme 2). The ortho aryl C−H bond
is then activated to form the palladacycle, followed by reductive
elimination to give the desired product A. Competing with
C−H activation, β-oxygen elimination10 of the oNBE coupled
Pd intermediate may occur to give ring-opened product B. The
palladacycle intermediate may also undergo ortho coupling with
another equivalent of aryl bromide before annulation occurs to
give product C. To improve further the yield and the selectivity
for the CANAL product, various phosphine-based ligands were
examined. We found that bulky ligands eliminated the
formation of ortho coupled product C. Gratifyingly, Johnphos
ligand gave both high yield and high selectivity for the desired
product A with 97% conversion (91% isolated yield). The rela-
tively bulky Buchwald ligands are known to not only stabilize
the Pd intermediate but also accelerate reductive elimination,11
thus facilitating the annulation pathway. The stereochemistry of
B
DOI: 10.1021/jacs.6b12888
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Journal of the American Chemical Society
Communication
Scheme 3. Synthesis of CBD-Containing PCHs from Various Aryl Bromides and oNBEs
All yields are isolated yields. The first yield is for the CANAL step and the second yield is for the aromatization step. (a) 5 mol % Pd(OAc)2, 10 mol %
JohnPhos, 1.0 equiv. Cs2CO3, in THF at 130 °C for 24 h in a sealed pressure tube; (b) PPTS, toluene, 120 °C; (c) HCl, iPrOH/CHCl3, 80 °C.
upon aromatization may reduce the favorable aromatic stabiliza-
tion energy.
NMR spectroscopy of the resulting compounds showed
shielding of arene protons adjacent to four-membered ring.
This indicated reduced diatropicity in the arenes or the
presence of paratropicity from the CBD or both. Upon aromati-
zation, the NMR signals of the protons on the benzenoids
adjacent to four-membered ring shifted upfield. For instance,
the α-proton of the benzenoid in 4a had shifted upfield to
Figure 1. NICS-XY scans (NICSπ,ZZ (σ-only)) of 6. Dashed line on
molecular structure indicates the trajectory of NICS scan.
6.93 ppm from 7.25 ppm in 3a; anthracenoid in 6 has upfield
shifted to 8.02 ppm from 8.43 ppm in the CANAL product
(all δ in CDCl3). The same trend of upfield shifting was
observed in all the compounds regardless of the electronic
properties of the substituents and conjugation length, revealing
the universal paratropicity from fused CBD.
fer. Electron delocalization was also illustrated by the electronic
structures calculated using density functional theory (DFT) at
the B3LYP/6-311+G* level of theory, which showed that the
HOMO and LUMO occupy the entire conjugated structures
across four-membered rings (Figure S5). All the synthesized
PCHs were stable under ambient conditions with no change in
absorption after 10 days in solution under air.
Single-crystal X-ray crystallography and bond-distance
analysis also revealed the influence of antiaromaticity on the
bonding structures. Crystal structure of 6 showed its nearly
planar geometry with small torsion angles along phenylene
linkage (1.69°). The four-membered ring has a slightly rect-
angular geometry with long edge of 1.50 Å and short edge of
1.44 Å (Scheme 3 inset). The adjacent benzenoids exhibit
alternating short bonds of 1.35 Å and long bonds of 1.44 Å,
revealing increased π-bond localization in order to minimize the
paratropicity of CBD. The peripheral and central benzenoid
rings that are not directly fused with four-membered rings are
less affected and have more delocalized π-bonds. The packing
of 6 (Figure 2) reveals face-to-face slipped π stacking in two
sets of columns, with an intersect angle of 67.3°, close inter-
π-planar spacing of 3.40 Å, and 0.41 Å short-axis slip of the
The same magnetic features can be captured from nucleus
independent chemical shifts (NICS) calculation,13 which com-
putes the magnetic shielding in a space of interest of a molecule
as a means to determine diatropicity and paratropicity. Negative
NICS values denote aromatic rings and positive values denote
antiaromatic rings. NICS-XY scan of 6 at the GIAO-B3LYP/
6-311+G* level of theory showed small positive NICS
values for the four-membered rings, indicating the presence
of antiaromaticity (Figure 1). Their neighboring fused rings
have significantly reduced aromaticity, indicated by the small
negative NICS values; while the benzenoids that are not
directly fused with CBDs are not as affected by the para-
tropicity, indicated by the large negative NICS values, similar to
that of normal benzenoids.
All the PCHs exhibited bathochromic shifts in their UV−vis
absorption upon aromatization, supporting the electron delo-
calization across four-membered rings (Figure S4). A strongly
electron-withdrawing nitro substituent led to broad and more
red-shifted absorption as a result of intramolecular charge trans-
C
DOI: 10.1021/jacs.6b12888
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
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Experimental and computational details, UV−vis spectra,
1H and 13C NMR spectra (PDF)
Data for C60H66Si2 (CIF)
AUTHOR INFORMATION
Corresponding Author
*yanx@stanford.edu
ORCID
Zexin Jin: 0000-0002-4971-3656
Yan Xia: 0000-0002-5298-748X
Author Contributions
Z.J. and Y.C.T. contributed equally.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Stanford University start-up
funding. We thank C. J. Galvin for setting up the aroma
package, Dr. S. Liu for preliminary exploration, and Prof. H. I.
Karunadasa for assistance with single-crystal data collection.
Y.C.T. is supported by an A*STAR graduate fellowship.
MDS is supported by a NSF graduate fellowship. Single-crystal
X-ray diffraction experiments were performed at beamline
11.3.1 at the Advanced Light Source (ALS). The ALS is sup-
ported by the Director, Office of Science, Office of Basic
Energy Sciences, of the U.S. Department of Energy under
contract no. DE-AC02-05CH11231.
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DOI: 10.1021/jacs.6b12888
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX