Regioselective Asao-Yamamoto benzannulations of diaryl acetylenes

Article abstract of DOI:10.1021/ol502938y

Asao-Yamamoto benzannulations transform diarylalkynes into 2,3-diarylnaphthalenes, and regioselective variants of this reaction are of interest for synthesizing substituted polycyclic aromatic systems. It is shown that regioselective cycloadditions occur when one alkyne carbon preferentially stabilizes developing positive charge. Simple calculations of the relative energies of carbocations localized at each alkyne carbon of a substrate predict the regioselectivity, which is not eroded by bulky substituents, including 2,6-disubstituted aryl groups.

Full text of DOI:10.1021/ol502938y

Letter
pubs.acs.org/OrgLett
Regioselective Asao−Yamamoto Benzannulations of Diaryl
Acetylenes
Hasan Arslan, Katherine L. Walker, and William R. Dichtel*
†
‡
Department of Chemistry and Chemical Biology, Cornell University, Baker Laboratory, Ithaca, New York 14853-1301, United States
S Supporting Information
*
ABSTRACT: Asao−Yamamoto benzannulations transform diarylalkynes
into 2,3-diarylnaphthalenes, and regioselective variants of this reaction are
of interest for synthesizing substituted polycyclic aromatic systems. It is
shown that regioselective cycloadditions occur when one alkyne carbon
preferentially stabilizes developing positive charge. Simple calculations of
the relative energies of carbocations localized at each alkyne carbon of a
substrate predict the regioselectivity, which is not eroded by bulky
substituents, including 2,6-disubstituted aryl groups.
1
3
terically congested aromatic systems such as hexaarylben-
Scheme 1. C-Labeled and F-Substituted Derivatives of 1
Were Used to Probe the Regioselectivity of the Asao−
Yamamoto Benzannulation of Diarylalkynes, Which Is
1
2
S
zenes, o-arylene polymers and oligomers, and polypheny-
3
lene dendrimers exhibit desirable optoelectronic properties,
1
2
often exhibit rigid structures or specific conformations, and are
Nontrivial When Ar ≠ Ar
4
precursors of fused polycyclic aromatic hydrocarbons (PAHs)
5
and graphene nanoribbons (GNRs). These motifs are most
commonly accessed using transition metal-catalyzed cross-
5
a,b
couplings,
cycloadditions between tetraarylcyclopentadie-
1d,5c
1a−c
nones and alkynes,
or alkyne cyclotrimerizations.
Although these approaches are useful and powerful, many
structural motifs and substitution patterns remain outside their
scope. Complementary methods for the preparation of highly
substituted and congested aromatic systems are of great interest.
For example, we recently demonstrated that a benzannulation
6
evaluate the regioselectivity of the benzannulation reaction
Scheme 1) using 13C-labeled and F-substituted o-phenyl-
reaction first reported by Asao and Yamamoto converts the
(
relatively unreactive alkynes along a poly(phenylene ethynylene)
1
3
7
ethynylbenzaldehydes, 1- C and 1-F. Single regioisomers are
(
PPE) backbone into 2,3-diaryl naphthalene moieties. This
2
obtained for many diarylalkynes, including polyfunctional alkyne
substrates that serve as desirable PAH precursors. The
combinations of aryl substituents studied indicate that electronic
effects determine the regioselectivity. Hindered alkynes, such as
those bearing terphenyl or 2,6-dimethylphenyl groups, provide
regiochemical outcomes consistent with their electronic proper-
ties, such that steric hindrance does not influence the product
distribution. These findings provide a simple model to employ
the benzannulation reaction to access specific substituted
naphthalene derivatives and large functional π-electron systems.
The regioselectivity of the benzannulation reaction was first
established for 1-methoxy-4-(phenylethynyl)benzene 2 to assess
the role of the electron-donating methoxy group. We employed
process transforms easily prepared PPEs into otherwise
inaccessible, densely substituted poly(arylene)s. The reaction
also tolerates alkynes bearing both bulky ortho-substituents and
triisopropylsilyl-protected alkynes, providing new contorted
8
hexabenzocoronene derivatives and branched oligo(o-naphtha-
9
lenes).
The remarkable efficiency of the benzannulation reaction
warrants elaboration to functionalized benzaldehyde cyclo-
addition partners. These reactants will enable the synthesis of
PAHs with otherwise unavailable substitution patterns, yet
introduce the possibility of forming regioisomers. Excellent
regioselectivity is paramount, and as the reaction’s most desirable
attribute, its ability to modify polyfunctional alkyne substrates
would be rendered irrelevant if mixtures of regioisomers were
produced. Previously, the regioselectivity of a related AuCl3-
catalyzed benzannulation, which provides naphthyl ketone
1
3
1
- C to probe the inherent regioselectivity of o-phenyl-
2
ethynylbenzaldehyde 1, which is the prototypical cycloaddition
partner for the benzannulation reaction. Compound 2 forms a
1
3
10
single naphthalene product upon benzannulation with 1- C
products, was attributed to electronic effects. This issue has
2
not been addressed previously in the Cu(OTf) -catalyzed
2
formation of naphthalenes, and substituted o-phenylethynylben-
Received: October 4, 2014
zaldehydes had not been employed prior to this study. Here we
©
XXXX American Chemical Society
A
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Letter
Table 1. Regioselectivity and Isolated Yields Obtained for the
Benzannulations of Various Diarylacetylenes
1
Figure 1. Partial H NMR spectra (400 MHz, CDCl , 298 K) of (A) 3,
3
1
3
(
B) its corresponding single isotopomer 3a- C obtained from the
1
3
regioselective benzannulation of 2 with 1- C , (C) 5, and (D) the 49:51
2
1
3
13
mixture of 5a- C and 5b- C obtained from the nonregioselective
1
3
benzannulation of 4 with 1- C .
2
(
Figure 1). The complete regioselectivity of the reaction is
1
readily diagnosed by comparing the H NMR spectra of
1
3
13
naphthalene 3 and its C-enriched counterpart, 3a- C. In the
spectrum of 3 (Figure 1A), the hydrogens adjacent to each
phenyl substituent, H and H , respectively, resonate with
a
d
overlapping signals centered near 7.9 ppm. Only one of these
1
3
resonances is split into a doublet in the spectrum of 3a- C as a
1
13
consequence of H− C coupling, and the identity of this
1
resonance was assigned unambiguously as H by analyzing its H,
d
1
3
C, ROESY, and COSY NMR spectra (see Supporting
Information). Likewise, the benzannulation of 2 with 1-F
produced a single fluoronaphthalene product 3a-F (Table 1),
which corresponds to the same regiochemical outcome as the
isotopic labeling experiment. In contrast, a control experiment
with compound 4, which bears electronically similar 4-t-butyl
and 4′-methyl substituents, provides a nearly equal mixture of
1
regioisomers. A comparison of the H NMR spectra of the 2,3-
1
3
diarylnaphthalene 5 (Figure 1C) and mixture of 5a- C and
1
3
5
b- C (Figure 1D) indicates that both H and H peaks are
a d
13
coupled to a C nucleus. Benzannulation of 4 with 1-F also
provided nearly equal amounts of the fluoronaphthalenes 5a-F
and 5b-F. These findings suggest that differences in electron
donating ability of aryl substituents provide regioselective
benzannulation reactions.
remarkable tolerance of the benzannulation reaction to phenyl-
acetylenes bearing an ortho substituent (such as 12), but 2,6-
disubstituted phenyl moieties were previously undemonstrated.
We selected additional substrates 6, 8, 10 (Table 1) and diyne
2 (Scheme 2) to evaluate these electronic effects more
1
3
1
Nevertheless, 6 was benzannulated efficiently with 1, 1- C , and
2
thoroughly and to determine if steric factors also influence the
regioselectivity. Each substrate was benzannulated with 1 (see
Supporting Information), as well as its isotopically labeled
1-F and provided single regioisomers for the latter two
1
3
cycloaddition partners, 7a- C and 7a-F, respectively. These
products correspond to the same regiochemical outcome as the
methoxy-functionalized substrate 2, which is consistent with the
interpretation that the electron-donating property of the methyl
groups, rather than their steric demands, direct the cycloaddition.
The benzannulation of 10 provided poor regioselectivity and
proceeded to only 60% conversion (remaining 10 was the only
diarylalkyne substrate that was recoverable from the crude
reaction mixture), which we attribute to the electron-with-
13
analogue 1- C and/or fluorine-substituted 1-F. The products
2
were characterized using a full complement of 1D and 2D NMR
experiments, in addition to high-resolution mass spectrometry
and infrared spectroscopy, which allowed their structures to be
determined unambiguously. Compound 6 provides insight into
the effect of steric hindrance on the benzannulation’s efficiency
and regioselectivity. Our previous studies demonstrated the
B
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Organic Letters
Letter
1
3
Scheme 2. Benzannulation of Diyne 12 by 1- C and 1-F Provides Doubly Benzannulated Products as Single Products and
2
Excellent Isolated Yields
drawing nature of its Cl substituent. The reaction efficiency
decreases further when more powerful electron withdrawing
substituents are present, such as a p-acetyl group (5%
conversion). Dialkyne 12 preferentially forms a single
ratio. These calculations also show that the regiochemical
outcome may be predicted from the inherent electronic
properties of the alkyne substrate without considering the
energies of specific intermediates or transition states of the net [4
+ 2] cycloaddition associated with the benzannulation
mechanism, whose energies might be influenced by steric factors
associated with each substrate.
1
3
regioisomer when reacted with both 1- C and 1-F (Scheme
2
2). These observations indicate that the reactive intermediates
derived from o-phenylethynylbenzaldehydes perfectly differ-
entiate between the terphenyl- and phenyl-substituted alkyne
carbons. We previously oxidized products similar to 13-F to
2
8
contorted hexabenzocoronene derivatives; these results dem-
onstrate that functionalized cycloaddition partners will provide
access to these derivatives with controlled substitution of their
peripheries. Overall, these observations of the regiochemical
outcome and reaction efficiency form the basis of an intuitive
model for predicting the products of benzannulation reactions
and designing syntheses that are likely to provide naphthalene-
containing systems as single regioisomers (see below).
The Cu(OTf) -catalyzed benzannulation is thought to
2
proceed through a Cu-bound pyrylium ion intermediate (Figure
6
2
A), which undergoes a formal [4 + 2] cycloaddition with the
diaryl alkyne that determines the regiochemical outcome. This
study suggests that the cycloaddition proceeds either asyn-
chronously or through a cationic intermediate, which involves
positive charge developing on one of the alkyne carbons. Step-
wise bond formation is also consistent with an established
reactivity pattern of 1 with nucleophiles in the presence of
transition metals or Lewis acids to provide substituted 1H-
1
1
isochromenes. The aryne substituent that stabilizes this
positive charge more effectively reacts with the Cu-bound
carbon atom, thus determining the naphthalene regioisomer that
will be formed (Figure 2B). Complete regioselectivity is expected
from diaryl alkyne substrates that preferentially stabilize positive
charge on one alkyne carbon relative to the other.
6
Figure 2. (A) Proposed mechanism of the Yamamoto benzannulation.
DFT calculations (utilizing the B3LYP/6-31g(d) basis set, see
Supporting Information) further support this interpretation. A
comparison of the relative energies of the vinyl carbocations
derived from both 2 and 6 indicate a strong preference (6.7−9.2
kcal/mol) for localizing positive charge at the alkyne carbon
adjacent to the substituted aromatic ring, which is consistent with
the formation of the observed regioisomers. In contrast, the two
vinyl carbocations derived from diaryl acetylene 8, which
contains both 4-methoxyphenyl and 2,6-dimethylphenyl groups,
are much closer in energy (1.3 kcal/mol in favor of the 4-MeOPh
substituent). The benzannulation of 8 with 1-F mirrors this
trend: the regioisomers 9a-F and 9b-F are formed in a 32:68
(B) Observed regioselectivity, shown here for reactions utilizing 1-F, is
consistent with asynchronous or sequential bond formation, during
which positive charge develops on the distal alkyne carbon.
In conclusion, we have demonstrated that diaryl acetylenes
that stabilize developing positive charge preferentially at one
alkyne carbon undergo regioselective Asao−Yamamoto benzan-
nulations. This reaction outcome may be predicted without
considering steric factors, suggesting that they play a minor role
in determining regioselectivity. These studies also confirm that
the benzannulation reaction is remarkably tolerant of sterically
demanding substituents, yet is inefficient for alkyne substrates
C
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Organic Letters
Letter
bearing electron-poor aryl groups. Straightforward DFT
calculations predict the nature and degree of the regioselectivity
for diarylalkyne substrates. Regioselective cycloadditions provide
rapid access to precursors of novel polycyclic aromatic
hydrocarbons with predetermined substitution patterns and
eliminate the need for symmetric substrates in planning complex
syntheses. Overall, the remarkable efficiency, tolerance of bulky
substituents, and regioselectivity of the benzannulation reaction
make it a very attractive method for preparing elaborate aromatic
architectures and carbon-based nanostructures.
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: wdichtel@cornell.edu.
Present Addresses
(
†Department of Chemistry, Northwestern University, 2145
Sheridan Road, Evanston, Illinois 60208, United States.
2013, 4, 3973−3978.
(9) Hein, S. J.; Arslan, H.; Keresztes, I.; Dichtel, W. R. Org. Lett. 2014,
16, 4416−4419.
‡
Department of Chemistry, Stanford University, 337 Campus
(10) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J.
Drive, Stanford, California 94305, United States.
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Author Contributions
(
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The manuscript was written through contributions of all authors.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the Beckman Young Investigator
Program of the Arnold and Mabel Beckman Foundation, the
NSF (CHE-1124754), the Doctoral New Investigator Program
of the ACS Petroleum Research Fund (52019-DNI7), a Sloan
Research Fellowship from the Alfred P. Sloan Foundation, and a
Camille Dreyfus Teacher-Scholar Award from the Camille and
Henry Dreyfus Foundation.
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