Synthesis of fused polycyclic aromatics by palladium-catalyzed annulation of arynes using 2-halobiaryls

Article abstract of DOI:10.1021/ja055781o

The Pd-catalyzed annulation of arynes by 2-halobiaryls and related vinylic halides provides a very efficient, high yielding synthesis of polycyclic aromatic and heteroaromatic hydrocarbons. This process appears to involve the catalytic, stepwise coupling

Full text of DOI:10.1021/ja055781o

Published on Web 10/22/2005
Synthesis of Fused Polycyclic Aromatics by Palladium-Catalyzed Annulation
of Arynes Using 2-Halobiaryls
Zhijian Liu, Xiaoxia Zhang, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received August 23, 2005; E-mail: larock@iastate.edu
Table 1. Optimization of the Pd-Catalyzed Annulation of Benzyne
Transition metal-catalyzed annulation processes have proven very
useful in organic synthesis.1 Alkynes have been frequently used as
substrates for Pd-catalyzed annulations with functionally substituted
aryl and vinylic halides to synthesize a wide variety of carbocycles
and heterocycles.2 Arynes are very reactive substrates compared
to ordinary alkynes, and they readily undergo cyclotrimerization
under Pd catalysis to form polycyclic aromatic hydrocarbons.3 The
Pd-catalyzed cocyclotrimerizations of arynes with alkynes,4 arynes
with allylic halides,4c,5 and arynes with alkynes and allylic halides6
have also been reported. All examples of the carbopalladation of
arynes reported so far have involved very stable π-allylpalladium
intermediates.4c,5,6 The inherent instability and high reactivity of
aryl and vinylic palladium species obtained by oxidative addition
to Pd(0) and the high reactivity and propensity of arynes to
cyclotrimerize in the presence of Pd(0) do not bode well for
annulation processes requiring these species to react with one
another. Nevertheless, we have recently found that 2-halobenzal-
dehydes react with arynes generated from o-(trimethylsilyl)aryl
triflates under Pd catalysis to generate fluoren-9-ones in high yields.7
Herein, we wish to report a very efficient, high yielding synthesis
of polycyclic aromatic hydrocarbons of potential interest as
π-conjugated functional materials,8 which involves the Pd-catalyzed
annulation of arynes by aromatic and vinylic halides.
(eq 1)a
catalyst
P(o-tolyl)3
(equiv)
2a
CsF
solvent
entry
(0.05 equiv)
(equiv)
(equiv)
(MeCN/toluene)
% 3ab
1
2
3
4
5
6
7
8
9
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd2(dba)3
Pd(PPh3)4
0.05
0.05
0.05
0.05
0.05
0.05
0.10
0.02
0.05
0
2.0
0.33
5.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1:1
1:1
1:1
1:3
1:9
0:100
1:9
1:9
1:9
1:9
38
42
30
52
92
trace
82c
87d
73
10
84c
a All reactions were run using substrate 1a (0.30 mmol), 5 mol % of the
Pd catalyst, 5 mol % of P(o-tolyl)3, and the indicated amount of CsF in 4.0
mL of MeCN plus toluene at 110 °C for 24 h unless otherwise specified.
b Isolated yield. c Approximately 5% of 1a was recovered. d Pd(dba)2 (0.02
equiv) was employed.
biphenyl (1a) to react with 2.0 equiv of 2a and 2.0 equiv of 2c
under our “optimal” reaction conditions. Indeed, we obtained a 55%
yield of 3a and only a 24% yield of 3k (eq 2).
We first allowed 2-iodo-4′-methylbiphenyl (1a) to react with 2.0
equiv of o-(trimethylsilyl)phenyl triflate (2a), 5 mol % of Pd(dba)2,
5 mol % of P(o-tolyl)3, and 3.0 equiv of CsF in 2.0 mL of MeCN
and 2.0 mL of toluene at 110 °C for 24 h. The desired annulation
product 3a was obtained in a 38% yield (eq 1; Table 1, entry 1).
Subsequent work focused on optimization of this reaction (Table
1). During this process, we found that the slow generation of
benzyne from treatment of 2a with CsF is crucial to the success of
this annulation chemistry (compare entries 1, 4, and 5). By
increasing the amount of toluene in the solvent, we can slow the
generation of benzyne and improve the yield of annulation product
to a point. However, using toluene as the only solvent provided
only a trace of arene 3a (entry 6). So far, the optimal reaction
conditions for this particular reaction are those shown in entry 5 in
Table 1.
The scope and limitations of this Pd-catalyzed aryne annulation
process were next examined using various aromatic and vinylic
halides and aryne precursors. The results are summarized in Table
2. Substrates bearing both electron-donating and electron-withdraw-
ing groups efficiently undergo this aryne annulation process to
generate high yields of the corresponding polycyclic aromatics
(Table 2, entries 1, 2, and 4). When the 4-methoxy-substituted aryne
precursor 2b was allowed to react with 2-iodo-4′-methylbiphenyl
(1a), two isomers (3c and 3d) were obtained in a 1:1 ratio, clearly
suggesting the intermediacy of an aryne. Interestingly, relatively
unreactive 2-bromobiphenyl also reacts well with aryne precursor
2c to afford the corresponding annulation product in a 79% yield
(entry 7). A number of heterocycles, including an indole, a
benzofuran, and a chromone, have also successfully been employed
in this process, affording excellent yields of the corresponding
polycyclic materials (Table 2, entries 8-10). This latter chromone
substrate is particularly interesting since it has been shown
previously by us that this substrate reacts with diphenyl acetylene
in the presence of a Pd catalyst to afford a furan product arising
by alkyne insertion and attack of the resulting vinylpalladium
intermediate on the carbonyl oxygen.9 It is also particularly
noteworthy that vinylic halides, such as chromone 1h and the simple
vinylic bromide 1i, provide excellent yields of annulation products
(entries 10 and 11).
However, when the 4,5-dimethoxy- and 4,5-dimethyl-substituted
aryne precursors 2c and 2d (see Table 2 for these structures) were
employed to this annulation process, we needed to decrease the
amount of toluene in order to obtain good yields of the correspond-
ing annulation products. We believe that generation of the arynes
is significantly slower using the aryne precursors 2c and 2d. To
obtain evidence for this hypothesis, we allowed 2-iodo-4′-methyl-
9
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J. AM. CHEM. SOC. 2005, 127, 15716-15717
10.1021/ja055781o CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Annulation of Arynesa
Scheme 1
intermediates (the aryne and the arylpalladium intermediate c)
present in only very low concentrations at any one time reacting
with each other to afford excellent yields of annulation products
seems to favor the process described in cycle A, although the
successful reaction of an aryl iodide and two arynes (eq 3) suggests
that cycle B is also possible. Other mechanistic possibilities are
also under consideration.
In summary, we have developed a novel, high yielding synthesis
of fused polycyclic aromatics, which involves the Pd-catalyzed
carboannulation of arynes by aryl and vinylic halides. This
methodology provides an exceptionally efficient route to a wide
variety of substituted polycyclic aromatic and heteroaromatic
compounds from readily available starting materials. Further studies
on the reaction mechanism and the scope of the double aryne
annulation process are in progress.
Acknowledgment. We are grateful to the National Science
Foundation for partial support of this research. Thanks are also
extended to Johnson Matthey, Inc. and Kawaken Fine Chemicals
Co., Ltd. for donating the Pd salts, and Frontier Scientific Co. for
donating the arylboronic acids used to prepare the starting materials.
a All reactions were run using 0.30 mmol of organic halide, 0.6 mmol
of aryne precursor, 5 mol % of Pd(dba)2, 5 mol % of P(o-tolyl)3, and 3.0
equiv of CsF in 4.0 mL of 1:9 MeCN:toluene at 110 °C for 24 h unless
otherwise specified. b Isolated yield. c The ratio of products was determined
1
by H NMR spectral analysis. d MeCN:toluene ) 1:3.
Our success using 2-halobiaryls to annulate arynes and previous
Pd-catalyzed cyclotrimerizations suggested to us that we might also
be able to generate polycyclic aromatics by the reaction of an aryl
iodide and two arynes.10 Indeed, the reaction of ethyl 4-iodobenzoate
and 3 equiv of triflate 2d afforded a 50% yield of arene 3l alongside
22% of cyclotrimer 3m (eq 3).
Supporting Information Available: Detailed experimental pro-
cedure and characterization data for all previously unknown products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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