General method for functionalized polyaryl synthesis via aryne intermediates

Article abstract of DOI:10.1021/ja504886x

A method for base-promoted arylation of arenes and heterocycles by aryl halides and aryl triflates is described. Additionally, in situ electrophilic trapping of ArLi intermediates generated in the reaction of benzyne with deprotonated arenes or heterocycles has been developed, providing rapid and easy access to a wide range of highly functionalized polyaryls. Base-promoted arylation methodology complements transition-metal-catalyzed direct arylation and allows access to structures that are not easily accessible via other direct arylation methods. The reactions are highly functional-group tolerant, with alkene, ether, dimethylamino, trifluoromethyl, ester, cyano, halide, hydroxyl, and silyl functionalities compatible with reaction conditions.

Full text of DOI:10.1021/ja504886x

Article
pubs.acs.org/JACS
General Method for Functionalized Polyaryl Synthesis via Aryne
Intermediates
Thanh Truong,‡ Milad Mesgar, Ky Khac Anh Le, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
ABSTRACT: A method for base-promoted arylation of
arenes and heterocycles by aryl halides and aryl triflates is
described. Additionally, in situ electrophilic trapping of ArLi
intermediates generated in the reaction of benzyne with
deprotonated arenes or heterocycles has been developed,
providing rapid and easy access to a wide range of highly
functionalized polyaryls. Base-promoted arylation method-
ology complements transition-metal-catalyzed direct arylation
and allows access to structures that are not easily accessible via other direct arylation methods. The reactions are highly
functional-group tolerant, with alkene, ether, dimethylamino, trifluoromethyl, ester, cyano, halide, hydroxyl, and silyl
functionalities compatible with reaction conditions.
Scheme 1. Mechanism of Base-Promoted Arylation of
Heterocycle and Arene C−H Bonds
1. INTRODUCTION
The biaryl structure is a central building block in a large
number of natural products, organic materials, and biologically
active compounds.1 Direct arylation through C−H bond
cleavage represents an efficient alternative to classical methods
for polyaryl preparation.2 Second-row transition metals such as
palladium, ruthenium, rhodium, and iridium have emerged as
catalysts in direct arylation reactions. Excellent regioselectivity
with respect to arene C−H bonds has been achieved for
arylation of heterocycles as well as directing-group-containing
and electron-poor arenes. In contrast, functionalization of other
arenes often suffers from unsatisfactory selectivity. More
recently, the use of inexpensive first-row metal catalysts has
attracted substantial interest. Copper, nickel, and iron have
been shown to catalyze direct arylation of sp2 C−H bonds.2d
Several reports describe processes for the assembly of biaryl
structures using aryl iodonium salts or photochemical
methods.4 Recently, direct arylation of arenes with the aid of
organocatalysts has been reported.5 Specifically, alkali metal
alkoxide bases combined with amine bases were reported to
promote formation of biaryls in the coupling of arenes with aryl
halides. Reactions proceed by a homolytic aromatic substitution
mechanism.5d However, arylation of simple compounds such as
anisole or pyridine affords isomer mixtures, and the arene
coupling component is often used in up to 100 equiv excess.
We have recently described direct base-promoted intermo-
lecular arylation of heterocycle and arene C−H bonds.6 In
these reactions, less than 2.5 equiv of C−H bond coupling
partner is used, and functionalization occurs at the most acidic
carbon−hydrogen bond. In the presence of hindered amide
bases, the (hetero)arene is deprotonated while the aryl halide
forms aryne. Addition of aryl anion to the aryne affords the o-
anionic biaryl intermediate 1, which is subsequently protonated
to form product 2 (Scheme 1). Trapping of 2 with electrophiles
other than H+ should be possible, leading to o-substituted
biaryls of type 3. Overall, the reaction product 3 can be thought
of as a result of 2-fold C−H bond functionalization: C−H/C-
Cl coupling followed by a C−H/electrophile reaction. In order
for this sequence of reactions to be successful, arylmetal
intermediate 1 has to be compatible with protonated base
formed during formation of benzyne and 1. Several examples of
aryne reactions with nucleophiles followed by trapping of aryl
metal intermediates with electrophiles have been reported.7 A
general procedure employing an accessible aryl halide or triflate
aryne precursor, C−H bond nucleophiles, and diverse trapping
reagents has not been demonstrated.
We report here (1) an expansion of scope of our previous
methodology that allows a general, highly regioselective
arylation of a wide range of arenes and heterocycles by aryl
halides and triflates, and (2) trapping of intermediate aryl
anions with a variety of electrophiles, resulting in ortho-
functionalized biaryls and polyaryls.
Received: July 29, 2013
© XXXX American Chemical Society
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2. RESULTS AND DISCUSSION
Article
can be used to generate arynes at −78 °C, allowing greater
functional group tolerance and simplified temperature regimes
(Table 1). The results of heterocycle and arene arylation by aryl
triflates are presented in Table 2. All reactions were carried out
at −78 °C in diethyl ether/THF mixed solvent. Dihalobenzenes
such as 1,3-dichloro-, 1,3-difluoro-, 1,2-difluoro-, and 2-chloro-
1-fluorobenzene afford products in good yields (entries 1−4).
2-Chloro-1,4-bis(trifluoromethyl)benzene is reactive, and the
arylation product was obtained in 62% yield (entry 5). These
examples show that formation of arynes from 2-lithiohaloben-
zenes (halogen = Cl, F) is slow on the time scale of benzyne
formation from phenyl triflate. 1-Methyl-1,2,4-triazole and 1-
phenylpyrazole are arylated efficiently (entries 6 and 7). 2,4,6-
Trichloropyridine can be diarylated in 54% yield (entry 8).
Triflates other than PhOTf can also be used. Interestingly,
benzothiophene arylation by 2-trimethylsilylphenyl triflate, a
common benzyne precursor,10 affords the ortho-substituted
product in good yield with the silyl group intact (entry 9). The
regioselectivity can be explained by the inductive electron
donating effect of silicon.11 2-Chlorophenyl triflate can be used
to arylate benzothiophene in 53% yield (entry 10). The product
contains a halogen functionality which can be used for further
cross-coupling reactions. It can be concluded that aryl triflates
can be used for arylation of substrates possessing DMSO pKa ’s
at or below 35.12
2.1. Benzyne Formation. We have previously used
commercially available aryl halides as benzyne sources in direct
arylation reactions.6 Formation of arynes from halobenzenes
was achieved by deprotonation affording 2-haloaryl anion
followed by elimination of halide ion. A better leaving group
than chloride would accelerate formation of benzyne, allowing
generation of benzyne at low temperatures, avoiding com-
petitive protonation by TMPH, and allowing electrophilic
trapping of intermediate aryl metals. It is known that
aryllithium protonation by tetramethylpiperidine is slow at
low temperatures.8 Aryl triflates have been used for
deprotonative benzyne generation.9 Comparison of aryl triflates
and chlorides in benzyne generation is shown in Table 1. At
a
Table 1. Optimization of Benzyne Formation
entry
1
X
base (B)
solvent
conv (%)
Cl
TMPLi
TMPLi
TMPLi
LDA
THF
THF
Et2O
Et2O
Et2O
trace
41
b
2
Cl
3
4
5
6
Cl
trace
trace
70
OTf
OTf
OTf
TMPLi
TMPLi
2.3. Heterocycle and Arene Arylation by Aryl Halides.
Aryl triflates allow for uniform C−H bond arylation conditions
at low temperature. In contrast, use of aryl chloride reagents
requires substantial optimization of reaction temperature,
solvents, and stoichiometry. In many cases, however, there
are advantages in using aryl chlorides. First, aryl chlorides are
substantially cheaper than aryl triflates. Second, aryl triflates
cannot be used for the arylation of nonacidic arenes (pKa > 35,
DMSO solvent)12 due to fast aryne formation relative to
deprotonation of ArH, resulting in low product yields. We have
previously reported aryl chloride use in heterocycle and arene
arylation.6 Additional examples are presented in Table 3
showing several other arene and heterocycle classes that are
reactive. Diphenyl ether can be arylated by chlorobenzene in
53% yield (entry 1). Aryl ethers can not be arylated by aryl
triflates in acceptable yields. Dibenzofuran arylation by 2-
bromocumene and 2-chloronaphthalene affords the m-sub-
stituted products in good yields (entries 2 and 3). 2,4-
Dimethoxybenzonitrile can be arylated in 42% yield, showing
that nitrile functionality is compatible with the reaction
conditions (entry 4). The C-arylation of NH-containing
heterocycles such as 2-methyl- and 2,3-dimethylindoles is
possible under the conditions developed for aniline arylation
(entries 5 and 6).6c Interestingly, 4- and 5-hydroxybenzofurans
are arylated at the 2-position (entries 7 and 8). The O-arylation
product was not observed in the crude reaction mixture for
entry 8. This experiment shows that heterocycle C-arylation is
compatible with a phenolic hydroxyl group, in contrast to
related copper-catalyzed reactions where O-arylation of phenols
is observed.13 Methoxypyridines can also be arylated in good
yields (entries 9 and 10). For these substances, arylation
regioselectivity is determined by the methoxy group.6a,14
Reactions are typically run at −15 to −65 °C, with the
exception of indole arylation (entries 5 and 6), which occurs at
room temperature. Most reactions give the best yields in THF/
diethyl ether mixtures (entries 1−3, 7, 8), However, more
sensitive substrates such as nitriles (entry 4) require low
Et2O/THF (50/1)
89
a
Total volume of solvent 1.5 mL, 0.25 mmol scale, PhX/base 1/2; 10
b
h; 6 h for entry 6. Temperature: −62 °C, time: 12 h.
−78 °C, chlorobenzene is unreactive in THF and diethyl ether
(entries 1 and 3). In THF, which facilitates the deprotonation/
halide elimination sequence, chlorobenzene forms benzyne at
−62 °C, albeit relatively slowly (entry 2). Thus, at least some
chloroarenes should be usable for arylation/electrophilic
quench sequences if solvent/temperature optimization is
performed. Phenyl triflate does not form appreciable amounts
of benzyne when treated with LDA in diethyl ether at −78 °C
(entry 4). However, under the same conditions, TMPLi base
was efficient (entry 5). Addition of a small amount of THF to
diethyl ether solvent increases the yield of coupling product and
decreases the reaction time (entry 6). Consequently, use of aryl
triflates to generate benzyne at low temperatures should allow
arylation of sensitive substrates. Trapping of aryl lithium
intermediates with electrophiles should be feasible. The
experiments also show that benzyne formation is most efficient
in THF solvent.
2.2. Heterocycle and Arene Arylation by Aryl Triflates.
We have reported a method for base-mediated arylation of
(hetero)arenes by aryl halides.6a The best results in arene
arylation were obtained by employing LiTMP base in a
pentane/THF solvent mixture. Arynes had to be generated at
an appreciable rate to avoid prohibitively slow reactions. The
rate of generation is highly dependent on the structure of the
aryl halide. Simultaneously, aryl anions from the C−H bond
coupling component had to be generated in appreciable
concentrations. If aryl anions were present in low concen-
trations, aryne was consumed in side reactions. Consequently,
the temperature for each reaction had to be optimized.
Compounds possessing sensitive functional groups were either
incompatible with the arylation conditions or relatively complex
temperature regimes were required. In contrast, aryl triflates
B
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a
Table 2. Arylation with Aryl Triflates
a
Conditions: ArOTf (2−4 equiv), Ar−H (1 equiv), TMPLi (4−6 equiv), Et2O/THF solvent (30−40/1), −78 °C, 18 h, 0.25 mmol scale. Yields are
b
c
isolated yields. See Supporting Information for details. Base: LDA, THF solvent. Time: 12 h in THF at −85 °C.
temperatures. Thus, THF solvent, where benzyne generation
occurs even at −65 °C, is optimal.
(Scheme 1, structure 3). In this way, structures inaccessible
by other direct arylation methods could be accessed. In essence,
a three-component coupling between ArX, ArH, and electro-
phile would be realized.
Optimization of trapping conditions is shown in Table 4.
Three major products were formedthe desired iodophenyl-
benzothiophene 4, 2-phenylbenzothiophene 5, and bipheny-
lated compound 6 formed in the reaction of 2-lithiobenzothio-
phene with 2 equiv of benzyne. Slow generation of benzyne
from chlorobenzene was observed in THF at −65 °C when
2.4. (Hetero)Arene Arylation with Subsequent Aryl
Lithium Intermediate Trapping. 2.4.1. Considerations and
Reaction Optimization. The synthesis of highly functionalized
polyaryls has been extensively investigated due to their
widespread applications.1 Additional complexity could be
introduced in hetero(arene) arylation products if the
intermediate aryllithium reagent, formed in the reaction of
arylmetal with benzyne, was trapped by an electrophile
C
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a
Table 3. Arylation with Aryl Halides
a
Conditions: arene (0.25 mmol), ArX (0.375−0.75 mmol), TMPLi (1−1.25 mmol), Et2O/THF, pentane/THF, THF, or Et2O solvent, −65 to −15
b
°C. Yields are isolated yields. See Supporting Information for details. Heterocycle (1 mmol), PhCl (0.5 mmol), TMPLi (1.8 mmol), cyclohexane/
Et2O solvent, 23 °C.
TMPLi was used. Attempts to trap o-anionic biaryl
intermediates with I2 at this temperature failed to give a good
yield of 4 (entry 1). Instead, 5 and 6 were formed
predominately, showing that ArLi protonation by TMPH is
relatively fast under those conditions. Changing solvent from
THF to diethyl ether gave an improved 15/1 ratio of 4/(5 + 6).
However, only 5% conversion was observed, showing inefficient
formation of benzyne under these conditions (entry 2). At −20
°C in diethyl ether, 75% conversion was observed, but the
iodinated 4 was formed as a minor product due to aryllithium
protonation by TMPH (entry 3). Reaction at −45 °C resulted
in slow benzyne formation, but good selectivity for 2-
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a
Table 4. Reaction Optimization
Table 5. 2-(2-Lithiophenyl)benzothiophene Trapping with
Electrophiles
a
entry
PhX
solvent
T (°C) yield (%) 4/(5 + 6)
1
2
3
4
5
PhCl
PhCl
PhCl
PhCl
PhCl
PhOTf
THF
Et2O
Et2O
Et2O
−65
−65
−20
−45
−45
−78
78
5
1/2
15/1
1/22
16/1
10/1
12/1
74
10
87
91
Et2O/THF (9/1)
Et2O/THF (50/1)
b
6
a
PhX/benzothiophene 1.8/1; 24 h, 0.25 mmol scale. Yields
b
determined by GC analysis. Reaction time: 10 h.
iodobenzothiophene 4 was observed (entry 4). As expected,
addition of THF facilitated benzyne formation and 4 was
obtained in 80% yield when reaction was performed at -45 °C
in a 9/1 Et2O/THF mixture. Use of PhOTf under the
conditions employed in Table 2 afforded an excellent yield of 4
in short reaction times (entry 6). Thus, two sets of conditions
can be applied for arylation with subsequent electrophilic
trapping of aryl lithium intermediates. The first set of
conditions involves the use of aryl chlorides in a Et2O/THF
mixture at about −45 °C. The second set involves the use of
aryl triflates in a Et2O/THF mixture at −78 °C. The latter set
of conditions is beneficial for sensitive substrates.
2.4.2. Scope of Aryllithium Intermediate Trapping.
Arylation of benzothiophene followed by electrophilic trapping
is presented in Table 5. Trapping by I2, CBr4, CCl4, and N-
fluorobenzenesulfonimide afforded the corresponding 2-(2-
halophenyl)benzothiophenes in good to excellent yields
(entries 1−4). These products can be further functionalized
by cross-coupling reactions.15 When DMF was used as
electrophile, aldehyde was obtained in 65% yield (entry 5).
Reaction with pivaldehyde yielded a secondary alcohol (entry
6). Trapping of reaction mixture with methyl chloroformate or
CO2 followed by MeI/NaH afforded carboxylate ester in good
yield (entry 7). Both TMSCl and 4-chlorobenzoyl chloride are
reactive, and functionalized products were obtained in
reasonable yields (entries 8 and 9). Treating the reaction
mixture with chlorodiphenylphosphine generates correspond-
ing triarylphosphine in good yield (entry 10). The reaction
could be used for efficient preparation of arylphosphine ligands.
Other electrophiles such as PhSSPh can be used (entry 11).
Arylation of various (hetero)arenes by aryl halides and
triflates with subsequent trapping of aryl lithium intermediates
is presented in Table 6. Arylation of benzothiophene by 2-
bromocumene followed by quenching with I2 reagent afforded
o-iodinated product in good yield (entry 1). When 9-
bromophenanthrene was used and reaction mixture was
quenched with pivaldehyde, 1-aryl-2,2-dimethylpropanol was
obtained in 77% yield (entry 2). Arylation of benzothiophene
by o-TMSC6H4OTf followed by addition of CCl4 afforded
chlorobiaryl product (entry 3). Interestingly, increasing the
amount of o-TMSC6H4OTf from 1.25 to 2.4 equiv relative to
benzothiophene allows trapping the first aryne addition product
with a molecule of another aryne, affording triaryl in a good
yield (entry 4). This reaction was repeated on 2.5 mmol scale,
and product was isolated in 69% yield. Trapping of double-
a
Benzothiophene (0.25 mmol), PhOTf (0.5 mmol), TMPLi (1.0
mmol), Et2O/THF, −78 °C, 12 h; then electrophile. Yields are
isolated yields. Please see Supporting Information for details.
addition product with CCl4 is also possible, affording a highly
functionalized triaryl in 74% yield (entry 5). Similarly, double
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a
Table 6. Arylation of (Hetero)arenes and Trapping of Aryllithium Intermediates
a
Hetero(arene) (0.25 mmol), ArX (0.3−1.0 mmol), TMPLi (1.0−1.75 mmol), THF/Et2O or THF solvent, −35 to −78 °C, 12−39 h; then quench
b
with an electrophile. Yields are isolated yields. Please see Supporting Information for details. Scale: 2.5 mmol.
addition of benzyne to benzothiophene followed by trapping
with TMSCl is successful if a 1/3 ratio of benzothiophene/
PhOTf is employed (entry 6). These examples allow efficient
syntheses of highly functionalized polyaryls which cannot be
easily made by any other means. Other arenes can also be used
for the arylation/electrophilic trapping sequence. Thus,
arylation of benzofuran followed by trapping with DMF gives
2-(benzofuran-2-yl)benzaldehyde in a yield comparable to the
one obtained for benzothiophene (entry 7). Six-memebered
ring heterocycles are reactive. 3-Methoxypyridine was treated
with chlorobenzene followed by trapping with iodine, and 4-(2-
iodophenyl)-3-methoxypyridine was obtained in acceptable
yield (entry 8). Simple arenes can be used in both inter- and
intramolecular trapping reactions. Thus, 3-methoxybenzonitrile
was reacted with benzyne generated from chlorobenzene.
Intermediate aryllithium was trapped by a cyano group, forming
4-methoxy-9-fluorenone after hydrolysis (entry 9). 2-Chlor-
oanisole can also be used as an aryne source (entry 10). 1,3-
Dimethoxybenzene is reactive, and 2′,6′-dimethoxybiphenyl-2-
carbaldehyde was prepared in 64% yield by reaction with
benzyne followed by trapping with DMF (entry 11). A
polysubstituted biaryl was produced in the reaction between
dimethoxybenzene and aryne derived from 2-bromocumene
followed by quench with iodine (entry 12).
Scheme 2. Buchwald’s SPhos Ligand Synthesis
starting materials, it requires 1,2-dihalobenzene reactants that
might be less available if SPhos analogues are prepared.16
An important use of organolithium reagents is in the
preparation of other organometallic complexes through trans-
metalation. Among those, organocopper complexes have found
wide use in synthetic organic chemistry. Thus, transmetalation
of biaryl lithium intermediates to aryl copper reagents and their
further reactivity was investigated (Table 7). Biaryl lithium was
generated by reaction of benzothiophene, phenyl triflate, and
TMPLi. Transmetalation of the reaction mixture with CuCN·
2LiCl followed by addition of electrophiles results in function-
alized arylation products. Thus, reaction with MeI electrophile
afforded 2-o-tolylbenzothiophene in excellent yield (entry 1).
Allyl bromide is reactive (entry 2). Bromomethyl acrylate ester
can be used, and product was obtained in good yield (entry 3)
showing compatibility of the reaction conditions with ester
functionality. Epoxide opening is possible, and substitution
takes place at the less hindered position (entry 4). Reactions
without added CuCN·2LiCl gave substantially lower yields of
products. We have previously reported a method for copper-
catalyzed deprotonative arene dimerization.17 When oxygen is
The methodology allows for an efficient synthesis of
Buchwald’s SPhos ligand in a one-pot reaction from simple
and readily accessible starting materials (Scheme 2). While the
current synthesis of SPhos is highly efficient and uses cheap
F
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a
Table 7. Transmetallation/Cross-Coupling Reactions
a
Hetero(arene) (0.25 mmol), PhOTf (0.5 mmol), TMPLi (1.0 mmol), −78 °C, 12 h; then CuCN·2LiCl followed by electrophile or O2. Yields are
b
c
isolated yields. Please see Supporting Information for details. 1,3-C6H4Cl2/PhOTf = 4; 4.8/1 ratio of product/2,2′,6,6′-tetrachlorobiphenyl. PhCl
as benzyne source; n-butylthiophene/PhCl = 1/1; 4.3/1 ratio of product/butylthiophene dimer.
used as oxidant, a variety of arene and heterocycles can be
efficiently dimerized. By employing this methodology, dimeri-
zation of aryl copper reagents was achieved in good yields.
Dichlorobenzene was reacted with phenyl triflate in the
presence of TMPLi to afford 2-arylphenyllithium reagent.
Following lithium-to-copper transmetalation, oxygen was
introduced into the reaction mixture and tetraaryl product
was isolated in 44% yield (entry 5). Interestingly, when C−H
bond coupling component is used in excess, cross-dimerization
between biaryl copper and starting aryl copper species can be
achieved. For example, if excess of 1,3-dichlorobenzene is used
under the conditions of entry 5, cross-dimerization product was
obtained in moderate yield (entry 6). About 4.8/1 ratio of
cross- to homodimerization was observed. Similarly, n-
butylthiophene can be reacted with PhCl in the presence of
TMPLi followed by cross-dimerization affording a 1,2-
G
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difunctionalized arene (entry 7). In this case, a 4.3/1 ratio of
cross- vs homocoupling was observed. Essentially, this method
allows for 1,2-diarylation of aryl triflates.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
2.5. Heterocyclic Arynes. Benzyne and its derivatives have
been well-explored.18 In contrast, relatively few heterocyclic
arynes have been investigated. Pyridynes and indolynes have
been employed in the synthesis of complex natural products.19
Several attempts were made to investigate the formation and
reactivity of heterocyclic arynes. The reaction of benzothio-
phene with 2-bromopyridine in the presence of TMPLi
afforded 42% of coupling product (Scheme 3). The
AUTHOR INFORMATION
Corresponding Author
■
olafs@uh.edu
Present Address
‡Department of Chemical Engineering, HCMC University of
Technology, VNU-HCM, Ho Chi Minh City, Vietnam.
Scheme 3. Reactions of Heterocyclic Arynes
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Grant No. E-1571), the
National Institute of General Medical Science (Grant No.
R01GM077635), and the Camille and Henry Dreyfus
Foundation for supporting this research.
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regioselectivity of the reaction is consistent with the one
reported previously for 2,3-pyridynes.20 Formation of arynes
from five-membered ring heterocycles is difficult, and use of
five-membered ring arynes for synthetic purposes is exceedingly
rare.21 The challenging thiophyne generation requires use of a
triflate leaving group, as 2,5-dilithiodichlorothiophene has been
described as a free-flowing, white powder that decomposes
slowly at 115−120 °C.22 Reaction of 2-butylthiophenyl triflate
with benzothiophene afforded a single product in 21% yield
(Scheme 3). Analysis of product indicates that substitution
occurred at the C3 position of thiophene. Functionalization of
thiophene C−H bonds at the 3-position is challenging.23
3. SUMMARY
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We describe here a method for base-promoted arylation of
arenes and heterocycles by aryl halides and aryl triflates.
Despite the use of lithium amide bases, the reaction is highly
functional-group tolerant, with alkene, ether, dimethylamino,
trifluoromethyl, ester, cyano, halide, hydroxyl, and silyl
functionalities compatible with reaction conditions. Moreover,
NH-containing indole arylation at the 3-position by aryl
chlorides was achieved. Additionally, we describe a general
method for electrophilic trapping of ArLi intermediates that are
generated in the reaction of benzyne with deprotonated arenes
or heterocycles. The trapping provides rapid and easy access to
a wide range of highly functionalized polyaryls from readily
available starting materials. Furthermore, generation and use of
thiophyne is disclosed. The base-promoted arylation method-
ology complements conventional direct arylation processes,
possesses high functional group tolerance, and allows access to
structures that are not easily accessible via other direct arylation
methods.
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