Palladium-catalyzed, sequential, three-component cross-coupling of aryl halides, alkynes, and arynes

Article abstract of DOI:10.1002/anie.200604969

(Chemical Equation Presented) Three's a crowd? Polycyclic aromatic hydrocarbons can be synthesized efficiently and in high yield using the first palladium-catalyzed, sequential, three-component coupling of alkynes and arynes with aryl halides (see scheme). This process appears to involve the catalytic, stepwise carbopalladation of an alkyne and an aryne to generate the three-component products.

Full text of DOI:10.1002/anie.200604969

Angewandte
Chemie
DOI: 10.1002/anie.200604969
Cross-Coupling
Palladium-Catalyzed, Sequential, Three-Component Cross-Coupling of
Aryl Halides, Alkynes, and Arynes**
Zhijian Liu and Richard C. Larock*
Alkynes have been frequently used as substrates for palla-
dium-catalyzed carbopalladation by functionally substituted
[
1]
aryl and vinylic halides. Aryl halides have also been treated
with alkynes in the presence of a palladium catalyst to
[
2]
[3]
generate naphthalenes. Arynes are very reactive sub-
strates compared to ordinary alkynes. Although there are a
number of examples of stoichiometric transition-metal aryne
[
4]
complexes being employed creatively in organic synthesis,
[
5]
arynes have only recently been reported to undergo
palladium-catalyzed conversion. Thus, the cyclotrimerization
of arynes and the co-cyclotrimerization of arynes with
alkynes are catalyzed by palladium. Yamamoto and co-
workers have established that p-allylpalladium species are
very effective for the intermolecular carbopalladation of
arynes and can be employed in a three-component coupling
with alkynes to produce naphthalenes. Until the recent
demonstration that an aryne can react with benzyl bromide in
the presence of a palladium catalyst and undergo a subse-
[
6]
[
7]
pound 4a was established by X-ray crystallography. Subse-
quent work focused on optimization of this process (Table 1).
[
8]
Changing the ligand from dppf to P(o-tolyl) had little effect
3
(Table 1, entries 1 and 2). We subsequently found that the
addition of TlOAc dramatically increased the yield from 18%
[
9]
[12]
quent Heck reaction, all examples of the carbopalladation
to 79% (compare entries 2 and 3, Table 1).
No cyclo-
of arynes have involved very stable p-allylpalladium inter-
trimerization products of arynes or co-cyclotrimerization
products of arynes with alkynes were detected in these
reactions. The role of the TlOAc is unclear at this time,
although it may be involved in removing the halide from
solution. Interestingly, the yield was even higher in the
absence of the phosphine ligand. The desired product 4a can
thus be obtained in 85% yield (Table 1, entry 4). Changing
the amount of toluene in the solvent provided lower yields of
the desired product, and the starting material 1a was
recovered both when an increased and when a decreased
amount of toluene was used (Table 1, entries 5 and 6). When
only 1.2 equiv of the aryne precursor 3a were employed, the
desired coupling product 4a was isolated in 86% yield
(Table 1, entry 7). Decreasing the amount of diphenyl acet-
ylene (2a) from 2.0 to 1.5 equiv still afforded 83% yield
(Table 1, entry 8). When only 0.5 equiv of TlOAc were used in
this process, only a 68% yield of compound 4a was obtained
(Table 1, entry 9). Replacing TlOAc by AgNO3 in this
reaction proved ineffective (Table 1, entry 10). To date, the
optimal reaction conditions for this particular reaction are
those shown in entry 7 in Table 1.
The scope and limitations of this palladium-catalyzed,
three-component coupling process were next examined using
various aryl halides, acetylenes, and aryne precursors. The
results are summarized in Table 2. We first allowed ethyl 4-
iodobenzoate (1a) to react with diphenyl acetylene (2a) and
several different aryne precursors (3b–e). All of the aryne
precursors gave very high yields of the corresponding
coupling products (Table 2, entries 1–4). It is noteworthy
that aryne precursor 3e affords two isomers, 4e and 4 f, in a
1:1 ratio, clearly suggesting the intermediacy of an aryne
[
8,10]
mediates.
Recently, we reported that aryl and vinylic
halides can be employed in the catalytic carbopalladation of
[
11]
arynes. Our experience in aryne and alkyne chemistry led
us to consider the possibility of using palladium to catalyze
the stepwise carbopalladation of alkynes and arynes using
aryl halides. Herein, we wish to report preliminary results on
the palladium-catalyzed, three-component, sequential inter-
molecular coupling of aryl halides, alkynes, and arynes
[
Eq. (1); TMS = trimethylsilyl, OTf = OS(O) CF ].
2 3
We first allowed ethyl 4-iodobenzoate (1a) to react with
.0 equiv of diphenyl acetylene (2a), 2.0 equiv of the silylaryl
2
triflate 3a, 5 mol% of [Pd(dba) ] (dba = dibenzylidenace-
2
tone), 5 mol% of 1,1’-bis(diphenylphosphino)ferrocene
(
dppf), and 3.0 equiv of CsF in 2.0 mL of MeCN and 2.0 mL
of toluene at 908C for 24 h. Surprisingly, we obtained only
product 4a in a 22% yield, and compound 5a was not
detected [Eq. (1); Table 1, entry 1]. The structure of com-
[
*] Z. Liu, Prof. Dr. R. C. Larock
Department of Chemistry, Gilman Hall
Iowa State University
Ames, IA 50011 (USA)
Fax: (+1)515-294-0105
E-mail: larock@iastate.edu
[
**] We are grateful to the National Science Foundation and the National
Institutes of Health Kansas University Center of Excellence in
Chemical Methodologies and Library Development (P50
GM069663) for their financial support. The authors thank Dr.
Arkady Ellern for assistance with X-ray crystallography.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 2535 –2538
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Communications
[
a]
Table 1: Optimization of the palladium-catalyzed three-component cross-coupling [Eq. (1)].
(Table 2, entry 4). Ethyl 4-bromo-
benzoate (1b) also affords good
[%] results in this process, providing a
Entry
Catalyst
0.05 equiv)
Ligand
TIOAc
[equiv]
2a
[equiv]
3a
[equiv]
Solvent
(MeCN:toluene)
4a
[%]
5a
[
b]
(
7
9% yield of 4a, but only if P(o-
[
[
c]
c]
1
2
3
4
5
6
7
8
9
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
dppf
P(o-tolyl)3
P(o-tolyl)3
–
–
–
–
–
–
–
0
0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
1:1
1:1
1:1
1:1
100:0
1:3
1:1
1:1
1:1
1:1
22
18
79
85
51
61
86
83
68
40
0
0
0
0
0
0
0
0
0
0
tolyl) was added (Table 2, entry 5).
3
The reaction of ethyl 3-iodoben-
zoate (1c) gave 4g as the only
isomer (Table 2, entry 6). Other
substrates bearing both electron-
withdrawing and electron-donating
groups, such as ketone, aldehyde,
bromide, and methoxy groups, effi-
ciently undergo this coupling pro-
cess to generate good to excellent
yields of the corresponding prod-
ucts (Table 2, entries 7–11). It is
interesting to note that 4-iodoben-
zaldehyde (1e) affords a 91% yield
1.2
1.2
1.2
1.2
1.2
1.2
0.5
[
[
d]
d]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[
e]
1
0
1.2
[
a] All reactions were run using substrate 1a (0.30 mmol), 5 mol% of [Pd(dba) ], 5 mol% of the ligand,
if added, and 3.0 equiv of CsF in the solvent shown at 908C for 8 h, unless otherwise specified. The best
result is highlighted in bold. [b] Yield of isolated product. [c] The reaction was run for 1 day. [d] Some
2
starting material 1a was left. [e] AgNO was employed instead of TlOAc.
3
[
a]
Table 2: Palladium-catalyzed three-component cross-coupling.
[
b]
Entry
Substrate
Acetylene
Aryne precursor
Product(s)
Yield [%]
85
1
2
3
1a
1a
2a
2a
85
81
8
0
4
1a
2a
(1:1)
[
c]
5
6
2a
2a
3b
3b
4b
79
76
7
8
9
2a
2a
2a
2a
3a
3b
3a
3a
91
91
78
75
1
0
2
536
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Angewandte
Chemie
Table 1: (Continued)
Entry Substrate
[
b]
Acetylene
Aryne precursor
Product(s)
Yield [%]
49
1
1
2
2a
3a
1
1a
3a
56
8
0
1
1
3
4
3b
3b
(1:6)
1g
1g
81
79
1
1
5
6
3b
3b
1g
89
[
a] All reactions were run using 0.30 mmol of organic halide, 0.60 mmol of alkyne, 0.36 mmol of aryne precursor, 5 mol% of [Pd(dba) ], 0.36 mmol of
2
TlOAc, and 3.0 equiv of CsF in 2.0 mL of MeCN and 2.0 mL of toluene at 908C for 8 h, unless otherwise specified. [b] Isolated yield. [c] 5 mol% of P(o-
tolyl) was added.
3
of the desired compound 4i (Table 2, entry 8), because
Based on work on the palladium-catalyzed carbopallada-
[
1]
benzaldehyde can react with arynes directly under mild
tion of alkynes, we propose the mechanism illustrated in
Scheme 1 for this process, which consists of the following key
[
13]
reaction conditions. The presence of a bromide in the aryl
iodide is readily tolerated under our reaction conditions,
affording the corresponding cross-coupled product in 78%
yield (Table 2, entry 9). Unsymmetrical acetylenes can also be
employed in this process (Table 2, entries 12–16). When ethyl
0
steps: oxidative addition of the aryl halide to Pd and
subsequent carbopalladation of the internal alkyne to gen-
erate intermediate C or a five-membered ring palladacycle,
which can either undergo carbopalladation of another alkyne
4
-iodobenzoate (1a) was allowed to
react with 1-phenylpropyne (2b) and
aryne precursor 3a, only one isomeric
phenanthrene was obtained in 56%
yield (Table 2, entry 12). Similar
regioselectivity for this alkyne has
[
14]
been observed in our earlier work.
Ethyl 3-phenylpropiolate (2c)
afforded two isomers, 4n and 4o, in
a 1:6 ratio (Table 2, entry 13). When
phenylpropynal diethyl acetal (2d)
was employed, the corresponding
aldehyde was obtained in an 81%
yield
after
work-up
(Table 2,
entry 14). Diphenyl acetylenes bear-
ing either a methoxy (2e) or a nitro
(2 f) group also gives excellent results
in this three-component coupling
process, affording the corresponding
products 4q and 4s in very high yields
Scheme 1. Possible mechanism of the palladium-catalyzed three-component cross-coupling (see
(
Table 2, entries 15 and 16).
text for details).
Angew. Chem. Int. Ed. 2007, 46, 2535 –2538
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2537

Communications
[
2]
to generate intermediate E or carbopalladation of the aryne
to generate intermediate H. Considering the steric hindrance
created when placing two phenyl groups next to each other in
intermediate D, it seems reasonable that intermediate C
would preferentially undergo carbopalladation of the less
hindered aryne to generate H, which undergoes cyclization
combined CH Cl fractions were dried over Na SO and concentrated
2 2 2 4
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel to afford the desired product.
Received: December 7, 2006
Published online: February 27, 2007
0
and reductive elimination to regenerate Pd and the phenan-
Keywords: alkynes · arynes · cross-coupling · palladium ·
.
threne product K.
polycycles
To obtain further evidence for this mechanism, we
allowed vinylic halide 1j to react with 1.2 equiv of diphenyl
acetylene and 1.2 equiv of 3a under our usual reaction
conditions. Indeed, we obtained a 95% yield of the product of
carbopalladation of the aryne, 4k, and only a trace amount of
the product expected from carbopalladation of the diphenyl
[
1] a) R. C. Larock, Pure Appl. Chem. 1999, 71, 1435; b) R. C.
Larock in Topics in Organometalic Chemistry, Springer, Berlin,
2005, p. 147.
[
2] a) S. Kawasaki, T. Satoh, M. Miura, M. Nomura, J. Org. Chem.
2003, 68, 6836; b) G. Wu, A. L. Rheingold, S. L. Geib, R. F.
Heck, Organometallics 1987, 6, 1941.
[
15]
acetylene, 4t [Eq. (2)].
[
3] S. V. Kessar in Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Flemming), Pergamon, Oxford, 1991, p. 483.
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Soc. 1999, 121, 9469.
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[
5] For reviews on arynes, see: a) H. Pellissier, M. Santelli,
Tetrahedron 2003, 59, 701; b) S. Saito, Y. Yamamoto, Chem.
Rev. 2000, 100, 2901.
[
6] a) D. Peæa, S. Escudero, D. PØrez, E. Guitiµn, L. Castedo,
Angew. Chem. 1998, 110, 2804; Angew. Chem. Int. Ed. 1998, 37,
2659; b) D. Peæa, A. Cobas, D. PØrez, E. Guitiµn, L. Castedo,
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7] a) D. Peæa, D. PØrez, E. Guitiµn, L. Castedo, J. Am. Chem. Soc.
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Org. Chem. 2000, 65, 6944; c) E. Yoshikawa, K. V. Radhak-
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dron Lett. 1999, 40, 7533.
In summary, we have developed a novel, palladium-
catalyzed, sequential, three-component cross-coupling of aryl
halides with acetylenes and arynes, which affords excellent
yields of substituted phenanthrenes. This process appears to
involve the stepwise regio- and chemoselective palladium-
catalyzed carbopalladation of an internal alkyne and subse-
quent carbopalladation of the aryne. This methodology
provides an exceptionally efficient route to a wide variety of
substituted polycyclic aromatic compounds from readily
available starting materials. Further studies on the reaction
mechanism and the scope of this synthesis of polycyclic
aromatic hydrocarbons with regard to the use of various
alkynes, alkenes and arynes are in progress.
[8] a) E. Yoshikawa, Y. Yamamoto, Angew. Chem. 2000, 112, 185;
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Liu, R. C. Larock, J. Org. Chem. 2007, 72, 223.
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yields in the palladium-catalyzed double annulation of arynes,
see: T. T. Jayanth, C.-H. Cheng, Chem. Commun. 2006, 894.
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[
[
[
[
[
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4963.
Experimental Section
General procedure for the palladium-catalyzed, three-component
cross-coupling: CsF (0.9 mmol) was added to a mixture of the
haloarene (0.3mmol), the alkyne (0.60 mmol), [Pd(dba) 2]
[15] We cannot completely rule out the possibility that the product
4k results from a Diels–Alder reaction of the aryne from silyl
triflate 3a and vinylic halide 1j, and elimination of HI, although
this seems quite unlikely at the temperatures employed, see:
a) H. Kotsuki, T. Yamaguchi, K. Ohno, Y. Ichikawa, M. Ochi,
Bull. Chem. Soc. Jpn. 1994, 67, 599; b) T. Wagner-Jauregg,
Synthesis 1980, 769.
(0.015 mmol), TlOAc (0.36 mmol), and silylaryl triflate (0.36 mmol)
in MeCN (2 mL) and toluene (2 mL). The reaction mixture was
stirred at 908C for 8 h. The resulting reaction mixture was washed
with brine (20 mL) and extracted with CH Cl (20 mL) twice. The
2
2
2
538
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