Regioselective Synthesis of Polyheterohalogenated Naphthalenes via the Benzannulation of Haloalkynes

Article abstract of DOI:10.1002/chem.201503418

Independent control of halide substitution at six of the seven naphthalene positions of 2-arylnaphthalenes is achieved through the regioselective benzannulation of chloro-, bromo-, and iodoalkynes. The modularity of this approach is demonstrated through the preparation of 44 polyheterohalogenated naphthalene products, most of which are difficult to access through known naphthalene syntheses. The outstanding regioselectivity of the reaction is both predictable and proven unambiguously by single-crystal X-ray diffraction for many examples. This synthetic method enables the rapid preparation of complex aromatic systems poised for further derivatization using established cross-coupling methods. The power and versatility of this approach makes substituted naphthalenes highly attractive building blocks for new organic materials and diversity-oriented synthesis.

Full text of DOI:10.1002/chem.201503418

DOI: 10.1002/chem.201503418
Full Paper
&
Polycyclic Aromatic Hydrocarbons
Regioselective Synthesis of Polyheterohalogenated Naphthalenes
via the Benzannulation of Haloalkynes
Dan Lehnherr,[a] Joaquin M. Alzola,[a] Emil B. Lobkovsky,[b] and William R. Dichtel*[a]
Abstract: Independent control of halide substitution at six
of the seven naphthalene positions of 2-arylnaphthalenes is
achieved through the regioselective benzannulation of
chloro-, bromo-, and iodoalkynes. The modularity of this ap-
proach is demonstrated through the preparation of 44 poly-
heterohalogenated naphthalene products, most of which
are difficult to access through known naphthalene synthe-
ses. The outstanding regioselectivity of the reaction is both
predictable and proven unambiguously by single-crystal X-
ray diffraction for many examples. This synthetic method en-
ables the rapid preparation of complex aromatic systems
poised for further derivatization using established cross-cou-
pling methods. The power and versatility of this approach
makes substituted naphthalenes highly attractive building
blocks for new organic materials and diversity-oriented syn-
thesis.
compounds if X1–X5 are every combination of five substituents
{F, Cl, Br, I, H} and R and X6 are held constant. If R is allowed to
be any halogenated phenyl group, more than 5.8 million struc-
tures are possible.[8] In light of these possibilities, direct halo-
genation potentially affords complex mixtures and is limited to
substitution patterns provided by the innate reactivity of the
arene.[9] This problem has restricted the use of naphthalene
Introduction
Polycyclic aromatic compounds substituted with multiple hal-
ides, or polyhalogenated aromatics (PHAs), are desirable tar-
gets for both synthetic elaboration and end-use application.
They serve as divergent substrates for cross-coupling reactions,
representing platforms for diversity-oriented synthesis[1] by
means of converting each halide to new CÀC, CÀN, CÀO, or CÀ moieties throughout organic synthesis and motivates the de-
S bonds. Haloarenes are also important precursors of larger ar-
omatic architectures and conjugated polymers, and halide in-
corporation provides a means to tune many properties, includ-
ing redox potentials, HOMO–LUMO energies, conformational
structure, and crystal packing.[2] Finally, PHAs comprise flame-
retardants, agrochemicals, and molecular recognition sys-
tems[3,4] with functions ranging from sensing[5] to halogen-
bonding catalysis.[6]
velopment of predictable, reliable methods to prepare polyhet-
erohalogenated naphthalenes (PHHNs).
Cycloaddition strategies are useful for building carbocycles
in a convergent manner.[10,11] The Cu-catalyzed benzannulation
of acetylenes, including diarylacetylenes to provide 2,3-diaryl-
naphthalenes, was first reported by Yamamoto and co-work-
ers,[12] although the regioselectivity of this transformation was
not investigated. We recently employed a fluorobenzaldehyde
cycloaddition partner (Figure 1, middle),[13] which provided
single regioisomers for diarylacetylenes with significant elec-
tronic differences between their aryl substituents. However,
the imperfect regioselectivity for diarylacetylenes lacking this
electronic difference, combined with the poor reactivity of
diarylacetylenes bearing even weak electron-withdrawing
groups, limits the utility of this transformation. The possibility
of overcoming both of these limitations motivated the present
investigation of the benzannulation of haloalkynes.
Despite their importance, efficient, predictable, and modular
methods to access PHAs remains challenging, particularly for
aromatic systems larger than benzene. Introducing more than
one halide type, such as through heterohalogenation process-
es,[7] increases the number of potential regioisomers. For the
common halides {F, Cl, Br, I}, there are 30 dihalo- and >400 tri-
halobenzene regioisomers. The possibilities increase dramat-
ically in larger systems. For example, the polyhalogenated
naphthalene in Figure 1 (bottom) represents more than 3000
Here we access specific PHHN regioisomers via the benzan-
nulation of haloalkynes using arylbenzaldehydes (Figure 1,
bottom). Our approach provides PHHNs in a programmable
manner, enabling the controlled incorporation of halides at six
of the eight positions of the naphthalene, along with diverse
aryl substituents at the 2 position. As such, most of the PHHNs
are unattainable by other methods, yet both the haloalkyne[14]
and 2-(phenylethynyl)benzaldehyde substrates are prepared in
one step from commercial building blocks: haloalkynes via hal-
ogenation of the corresponding terminal acetylene[14,15] or
[a] Dr. D. Lehnherr, J. M. Alzola, Prof. Dr. W. R. Dichtel
Department of Chemistry and Chemical Biology, Baker Laboratory
Cornell University, Ithaca, New York, 14853-1301 (USA)
E-mail: wdichtel@cornell.edu
[b] Dr. E. B. Lobkovsky
Department of Chemistry and Chemical Biology
X-ray Crystallography Laboratory, Cornell University
Ithaca, New York, 14853-1301 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503418.
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sensitive substrates. Substitution of the Cu(OTf)2 cata-
lyst for other transition metal Lewis acids, such as
Zn(OTf)2 (entry 5) or AgOTf (entry 6), highlight their
viability as alternate catalytic systems for the regiose-
lective benzannulation of haloalkynes, although
slightly lower yields are obtained.
Having established optimal conditions, we ex-
plored the scope and limitations of aldehydes capa-
ble of benzannulating haloalkyne 1 (Table 2). A wide
variety of aldehydes (2–15) provide polyfunc-
tionalized naphthalenes (18–31) with yields ranging
from 84–97%. Functionalization is formally trans-
ferred from the benzaldehyde to the naphthalene
with complete regiochemical control to install
a single halide (18–24) at any of the four possible po-
sitions on the naphthalene derived from the benzal-
dehyde moiety. Trifluoromethylated naphthalenes are
also accessible (25). Naphthalenes decorated with
two fluorine (26), two chlorine (27), three fluorine
(28), two methyl (30), two methoxy (31) groups or
no additional substituents (29) derived from the ben-
zaldehyde reagent are viable targets. The limitations
on the aldehyde component are illustrated by the
Figure 1. Illustration of synthetic challenge for naphthalene halogenation (top), previous
work on the regioselective benzannulation of diarylacetylenes (middle), current work on
the regioselective benzannulation of haloalkynes to access polyheterohalogenated naph-
thalenes (bottom).
TMS-protected acetylene,[16] and substituted benzaldehydes
from the corresponding 2-iodo or 2-bromobenzaldehyde.
Table 2. Benzaldehyde scope in the benzannulation of iodoalkyne 1.
Results and Discussion
We first optimized the benzannulation of iodoalkyne 1 with
fluorobenzaldehyde 2 (Table 1). Under the optimized condi-
tions (entry 1), the reaction of 1 (1 equiv, 0.05m in 1,2-DCE)
and excess 2 (1.7 equiv) in the presence of 10 mol% of
Cu(OTf)2 and CF3CO2H (5 equiv) affords naphthalene 18 in 94%
yield with excellent regioselectivity (18:19 >98:2). Entry 2 illus-
trates that Cu(OTf)2 is necessary for the formation of 18, while
the omission of CF3CO2H (entry 3) results in decreased yield
and erosion of the regioselectivity. The use of AcOH instead of
CF3CO2H (entry 4) provides 18 in only slightly diminished yield
(86%), such that this modification might prove useful for acid-
Table 1. Reaction outcomes upon deviating from the optimal condi-
tions.[a]
Entry
Change to optimal conditions
Yield of 18 [%]
Ratio 18:19
1
2
3
4
5
6
none
no Cu(OTf)2
no CF3CO2H
AcOH instead of CF3CO2H
Zn(OTf)2 instead of Cu(OTf)2
AgOTf instead of Cu(OTf)2
94
<5
19
86
81
76
>98:2
NA
83:17
>98:2
>98:2
>98:2
Reaction conditions: 0.05m of 1 in 1,2-DCE with Cu(OTf)2 (10 mol%) and
CF3CO2H (5 equiv), 1008C, 2 h. All yields are isolated yields. Reaction
scale=0.7 mmol haloalkyne, except for substrate 14 (0.6 mmol) and 15
(0.9 mmol).
[a] Data measured by 19F NMR spectroscopy with hexafluorobenzene as
an internal standard. NA=not available.
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unsuccessful attempt to form tetrahydronaphthalene deriva-
tive 32 by using cyclohexene-al 16, which decomposes under
the reaction conditions. Attempts at using 2-formylbenzothio-
phene 17 resulted in significant recovery of unreacted alde-
hyde and no appreciable formation of 33.
The scope of haloalkynes compatible with the benzannula-
tion using aldehydes 2–15 is demonstrated in Table 3. Nine-
teen iodo-, bromo-, and chloroalkynes (34–51) derived from
substituted phenylacetylenes were successfully utilized, and
each reliably provided only one observable naphthalene regio-
isomer with no deviation from our predictive model (vide
infra). Single-crystal X-ray crystallography of eight naphthalene
products (23, 56, 60, 64, 68, 71, 78, and 97, Figure 2) proves
the regiochemical outcome unambiguously, which is fully con-
sistent with structural characterization using 2D NMR analy-
sis.[17,18]
The reaction tolerates a wide range of substituents on the
haloalkyne. In stark contrast to the benzannulation of diaryl-
alkynes, which only tolerates electron-rich arenes,[13] haloal-
kynes attached to electron-deficient arenes are excellent sub-
strates. Haloalkynes based on arenes substituted with a halide,
an ester, an alkyne, or a nitrile form naphthalene products in
excellent yields. Electron-rich arenes, such as the 4-methoxy-
phenyl-substituted bromoalkyne (40), afford the naphthalene
product in a diminished yield, perhaps due to their decreased
thermal stability. Haloalkynes lacking an arene (52–54) were
poor substrates. The two-fold benzannulation of bis(haloal-
kynes) substrates (49–51) demonstrates the ability to prepare
bis(naphthalenes) with useful halogenation patterns of interest
for polymerization or the on-surface synthesis of carbon nano-
structures.[19] Furthermore, bis(hetero-haloalkyne) 50 provides
Table 3. Substrate scope for haloalkyne benzannulation.
Reaction conditions: 0.05m in haloalkyne substrate (0.5–1.2 mmol scale) in 1,2-DCE with Cu(OTf)2 (10 mol%) and CF3CO2H (5 equiv), 1008C, 2 h. All yields
are isolated yields.
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Figure 2. Single-crystal X-ray structures of naphthalene products 23, 56, 60,
64, 68, 71, 78, 97, and ketal 91 (thermal ellipsoids shown at the 50% proba-
bility level). Element coloring scheme: C=silver, O=light red, F=light
green, Cl=dark green, Br=dark red, I=purple.
Scheme 1. Top: Proposed mechanistic scenarios: Route A: Benzopyrylium
formation, formal [4+2] followed by protonation/retro [4+2]. Route B: Ben-
zopyrylium formation, protonation of Cu-intermediate followed by formal
[4+2], then retro [4+2]. Bottom: Cu-free regioselective benzannulation of
haloalkynes 1 using ketal 91, demonstrating the viability for Route B.
a desymmetrized building block for the synthesis of unsym-
metrical structures or oligomeric materials.
(Scheme 1, bottom), the same isomer obtained via the
Cu(OTf)2 catalysis conditions with 3 instead of 91. This result is
consistent with the regioselectivity of the benzannulation
being governed by the electronic nature of the substituents
on the acetylene, for which we developed a DFT model to pre-
dict the regioselectivity outcome by calculating relative stabili-
ties of a carbocation derived from the acetylene used in the re-
action (see Supporting Information Figure S223).[17]
Two mechanistic pathways are consistent with the observed
reaction outcomes (Scheme 1), one of which (Route A) was
proposed by Yamamoto and co-workers[12] for the benzannula-
tion of diarylacetylenes and the other (Route B) is proposed
here for the first time. In each route, Cu(OTf)2 is proposed to
complex to the alkyne of the benzaldehyde (82), providing 83
which cyclizes to a copper-bound benzopyrylium (84) that is
the divergent point for two mechanistic pathways. In route A,
CÀC bond formation between the benzopyrylium and the
haloalkyne precedes protonation of the CuÀC bond, whereas
protonation occurs prior to CÀC bond formation in route B. In
route A, the formal [4+2] occurs while the copper is still
bound to the benzopyrylium, followed by protonation of inter-
mediate 86 and finally retro-[4+2] along with formation of
mixed anhydride 88 provides naphthalene 87. In route B, pro-
tonation of Cu-intermediate 84 occurs first, followed by the
formal [4+2] cycloaddition of benzopyrylium 89 with the halo-
alkyne, and finally a retro[4+2] from adduct 90 to the naphtha-
lene product (87) and anhydride 88. To gain insight into the vi-
ability of route B, we reacted 1 equiv of ketal dimer 91 with
1 equiv of iodoalkyne 1 (0.05m in 1,2-DCE) in the presence of
5 equiv of CF3CO2H at 1008C for 2 h, which afforded halogen-
ated naphthalene 19 in 95% yield as a single regioisomer
DFT calculations identified regioisomeric transition states as-
sociated with the first CÀC bond forming step between the
haloalkyne and benzopyrylium intermediates associated with
both route A and route B (Figure 2).[17] The electronic energy
difference between the proposed regioselectivity-determining
transition states correctly predicts the experimentally observed
regiochemical outcome. In route A, DFT predicts the major
transition state is 5.6 kcalmolÀ1 lower in energy than the minor
transition state (Figure 3), consistent with the exclusive forma-
tion of the observed regioisomer. As for route B (via the Cu-
free benzopyrylium), DFT calculations of the regioisomeric tran-
sition states associated with the first CÀC bond forming step
predicts the major transition state being favored by 10.4 kcal
molÀ1 relative to the transition state corresponding to the un-
observed regioisomer.[20] While we cannot conclusively rule out
either route A or B, there is strong evidence for the viability of
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Table 4. Concomitant regioselective benzannulation of haloalkynes (0.7–
0.9 mmol scale) and halogenation using CuX2. All yields are isolated
yields.
Figure 3. DFT calculated transition-states using B3LYP/6-31G(d) potentially
responsible for the regioselectivity outcome in the benzannulation of halo-
alkynes: top: Route A, bottom: Route B (see Scheme 1). Element coloring
scheme: C=silver, H=white, O=light red, F=light green, S=yellow,
Br=dark red, Cu=bronze.
route B based on three observations: 1) the regioselective for-
mation of 19 via a Cu-free route based on ketal dimer 91;
2) the regiochemical outcome under Cu(OTf)2 catalysis is de-
pendent on the amount of CF3CO2H used (entry 3, Table 1);
3) DFT calculations of regioisomeric transition-states derived
from a Cu-free benzopyrylium predict the correct regioisomer
observed experimentally.
Based on the premise that the reaction proceeds via a Cu-
bound benzopyrylium (84), regardless of whether protonation
precedes the CÀC bond formation with the haloalkyne, Cu-in-
termediate 84 provides a means to install an additional halide
via functionalization of the CuÀC bond. In Table 4, we demon-
strate this strategy based on using stoichiometric amounts of
CuX2, which both promotes the formation of the putative ben-
zopyrylium and serves as the halide source. Although the reac-
tion is regioselective, it is slower relative to the Cu(OTf)2/
CF3CO2H conditions, requiring approximately 12 h for complete
haloalkyne consumption. Nevertheless, chloro-, bromo-, and io-
doalkynes are all benzannulated to provide specific naphtha-
lene products 93–99, which contain up to four types of halo-
gens. These reactions are sometimes accompanied by a naph-
thalene product formally derived from protolysis of the CuÀC
bond in intermediate 84, which may arise from adventitious
water and was separable from the desired halogenated prod-
uct in all cases except for the ester-containing 2-aryl naphtha-
lene 97. These results demonstrate predictable access to poly-
heterohalogenated naphthalenes with independent control of
seven of the eight naphthalene positions.
ated benzaldehydes. The high efficiency, complete regioselec-
tivity, and demonstrated modularity of this approach will
enable substituted naphthalenes to be used as synthetic inter-
mediates in many new contexts. Insight into the reaction
mechanism and the origin of the regioselectivity in these benz-
annulations was obtained from experimental and computa-
tional studies using DFT calculations, including those of transi-
tion states. As a result, a sound understanding of the reaction
has emerged, including a model to predict the regiochemical
outcome of this haloalkyne benzannulation. This method ulti-
mately provides access to polyheterohalogenated naphtha-
lenes with independent control of seven of the eight naphtha-
lene positions. We are now using this transformation to pre-
pare larger polycyclic aromatic hydrocarbon architectures with
complex substitution patterns and employing these products
as building blocks for the in-solution and on-surface synthesis
of carbon nanostructures.
Acknowledgements
This work was supported by the Beckman Young Investigator
Program of the Arnold and Mabel Beckman Foundation, the
NSF (CHE-1124754), and the Doctoral New Investigator Pro-
gram of the ACS Petroleum Research Fund (52019-DNI7).
Conclusion
We demonstrated a strategy to form complex PHHNs via
a benzannulation reaction between haloalkynes and halogen-
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Keywords: benzannulation · cycloaddition · halogenation ·
polycyclic aromatic hydrocarbons · reaction mechanisms
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Received: August 28, 2015
Published online on October 30, 2015
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