Efficient functionalization of aromatic C-H bonds catalyzed by gold(III) under mild and solvent-free conditions

Article abstract of DOI:10.1021/jo0497353

A gold(III)-catalyzed carbon-carbon bond formation reaction between arenes and electron-deficient alkynes or alkenes is described. Electron-rich arenes can be efficiently functionalized with the alkyne or alkene substrates. This reaction can be run with neat reactants at ambient temperature. Under the solventless conditions, clean product was obtained from a reaction of equal molar amounts of arene and alkyne substrates. The mild conditions and potential tolerance to different functional groups make this method practical for arene functionalization and for constructing complicated molecules. Efficient preparation of various coumarins from aryl alkynoates was demonstrated. Preliminary mechanistic studies were performed to probe the pathway of this reaction.

Full text of DOI:10.1021/jo0497353

Efficien t F u n ction a liza tion of Ar om a tic C-H Bon d s Ca ta lyzed by
Gold (III) u n d er Mild a n d Solven t-F r ee Con d ition s
Zhangjie Shi and Chuan He*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637
chuanhe@uchicago.edu
Received February 13, 2004
A gold(III)-catalyzed carbon-carbon bond formation reaction between arenes and electron-deficient
alkynes or alkenes is described. Electron-rich arenes can be efficiently functionalized with the alkyne
or alkene substrates. This reaction can be run with neat reactants at ambient temperature. Under
the “solventless” conditions, clean product was obtained from a reaction of equal molar amounts of
arene and alkyne substrates. The mild conditions and potential tolerance to different functional
groups make this method practical for arene functionalization and for constructing complicated
molecules. Efficient preparation of various coumarins from aryl alkynoates was demonstrated.
Preliminary mechanistic studies were performed to probe the pathway of this reaction.
In tr od u ction
phenylacetylene in a stoichiometric manner with heating
to give high yields of product diphenylacetylene.3c The
mechanism of this reaction is not clear.
Catalytic functionalization of aromatic C-H bonds to
form C-C bonds, if realized under mild and environ-
mentally benign conditions, will provide the most eco-
nomic way to construct molecules containing arene
groups. Although progress has been made in recent
years,1 efficient processes that work at ambient temper-
ature in a typical organic medium or under solvent-free
conditions are very limited.
In 1931, Kharasch and Isbell demonstrated that an-
hydrous gold(III) chloride can react with neat benzene,
toluene, or other aromatic compounds to form arylgold-
(III) complexes at room temperature.2 Subsequent studies
of this chemistry led to the isolation and characterization
of several arylgold(III) species generated from the reac-
tion.3 This auration reaction was shown to proceed in an
electrophilic manner.2,3 In one case, arylgold(III) species
were shown to be stabilized by binding to 2,6-lutidine.
This lutidine-bound phenylgold(III) complex reacted with
Hashmi’s group discovered that 1 mol % of AuCl3 in
acetonitrile catalyzes formation of C-C bonds between
2-methylfuran and methyl vinyl ketone.4 It was proposed
that an arylgold(III) species was likely generated from
electrophilic metalation of the 2-methylfuran by AuCl3.
Then the arylgold(III) added to methyl vinyl ketone to
give the 1,4-addition product. At around the same time
that we were investigating these types of reactions,
another group discovered hydroarylation of alkyne sub-
strates with AuCl3 plus 2-3 equiv of silver(I) salts.5 With
1.5 mol % of AuCl3/2AgSBF6, 10 equiv of mesitylene
reacted with 1 equiv of phenylacetylene to yield 1-mesi-
tyl-1-phenylethene in 86% yield in nitromethane at 60
°C. It was thought that in this reaction gold(III) merely
works as Lewis acid to increase the electrophilicity of the
alkyne group. With electron-deficient alkynes, gold(I)
salts appeared to be better hydroarylation catalysts.
(1) (a) J ia, C. G.; Piao, D. G.; Oyamada, J . Z.; Lu, W. J .; Kitamura,
T.; Fujiwara, Y. Science 2000, 287, 1992-1995. (b) Cho, J .-Y.; Tse, M.
K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305-
308. (c) Ishiyama, T.; Takagi, J .; Ishida, K.; Miyaura, N.; Anastasi, N.
R.; Hartwig, J . F. J . Am. Chem. Soc. 2002, 124, 390-391. (d) Murai,
S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.;
Chatani, N. Nature 1993, 366, 529-531. (e) Weissman, H.; Song, X.
P.; Milstein, D. J . Am. Chem. Soc. 2001, 123, 337-338. (f) Matsumoto,
T.; Taube, D. J .; Periana, R. A.; Taube, H.; Yoshida, H. J . Am. Chem.
Soc. 2000, 122, 7414-7415. (g) Tan, K. L.; Bergman, R. G.; Ellman, J .
A. J . Am. Chem. Soc. 2001, 123, 2685-2686. (h) Yokota, T.; Tani, M.;
Sakaguchi, S.; Ishii, Y. J . Am. Chem. Soc. 2003, 125, 1476-1477. (i)
Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J . Am. Chem. Soc. 2003, 125,
7506-7507. (j) Hennessy, E.; Buchwald, S. L. J . Am. Chem. Soc. 2003,
125, 12084-12085. (k) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.;
Inoue, Y. J . Am. Chem. Soc. 2003, 125, 12102-12103. (l) Tsukada,
N.; Mitsuboshi, T.; Setoguchi, H. Inoue, Y. J . Am. Chem. Soc. 2003,
125, 12102-12103 and references therein.
Resu lts a n d Discu ssion
We report here an efficient hydroarylation reaction of
alkynes and alkenes to form C-C bonds. The reactions
are catalyzed by gold(III) complexes under mild and even
solvent-free conditions at ambient temperature (eq 1). No
excess amount of arene substrate is required for comple-
tion of the reaction. For example, reacting pentameth-
ylbenzene with HCtCCO2Et in dichloroethane or with-
(2) Kharasch, M. S.; Isbell, H. S. J . Am. Chem. Soc. 1931, 53, 3053-
3059.
(3) (a) Liddle, K. S.; Parkin, C. J . Chem. Soc., Chem. Commun. 1972,
26-28. (b) de Graaf, P. W. J .; Boersma, J .; van der Kerk, G. J . M. J .
Organomet. Chem. 1976, 105, 399-406. (c) Fuchita, Y.; Utsunomiya,
Y.; Yasutake, M. J . Chem. Soc., Dalton Trans. 2001, 2330-2334.
(4) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J .-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285-2288. (b) Dyker, G.; Muth, E.; Hashmi,
A. S. K. Adv. Synth. Catal. 2003, 345, 1247-1252.
10.1021/jo0497353 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/23/2004
J . Org. Chem. 2004, 69, 3669-3671
3669

Shi and He
TABLE 1. Gold -Ca ta lyzed In ter m olecu la r Ad d ition
Rea ction sf
F IGURE 1. Photographs of the gold(III)-catalyzed addition
of pentamethylbenzene to ethyl propiolate in the absence of
solvents. (a) Equal molar amounts of pentamethylbenzene and
ethyl propiolate (2 mmol). (b) The mixture color changed to
dark red brown after addition of gold(III) catalyst. (c) Solid
product formed after 1 h of reaction at room temperature.
TABLE 2. Gold -Ca ta lyzed In tr a m olecu la r Ad d ition
Rea ction sa
a
b
The isolated yields are reported here. Reaction was also
performed with neat reactants (2 mmol each) with 2.5 mol % of
catalyst; the yield and reaction time are reported in the paren-
a
d
theses. c Catalyst loading was 0.5 mol %. A portion of 2:1 arene/
All reactions were conducted with 0.5 mmol of ester in 2 mL
alkyne adduct was also formed. e The reaction was run with neat
reactants. f Reactions were typically conducted with 1 mmol of
arene, 0.5 mmol of alkyne, and 5 mol % of AuCl3/3AgOTf in
dichloroethane.
of dichloroethane at 50 °C (reactions for 5 and 6 were run at 70
°C). Isolated yields are reported here.
1b). A solid product (99% yield) formed after 1 h of
reaction at room temperature (Figure 1c). No impurity
peaks were observed from the crude H NMR spectrum
1
out any solvent yielded a cis-arylalkene product in the
presence of AuCl3 pretreated with 3 equiv of AgOTf at
room temperature (entry 1 in Table 1). The reaction is
quantitative under these conditions and the catalyst
loading can be lowered to 0.5 mol % (entry 2 in Table 1).
AuCl3 can also catalyze the reaction but gave the product
in a lower yield (25%). In the absence of gold, no product
was generated. The reaction also works for the alkynes
conjugated to CO2H and COMe (entries 3 and 4 in Table
1). A range of arenes can be activated and converted into
products at ambient temperature under air atmosphere
in good to excellent yields (Table 1). trans-Arylalkene
products were obtained in some reactions. Less electron-
rich arenes require heating to 50 °C for the completion
of the reaction.
The intermolecular addition of arenes to alkynes
catalyzed by gold(III) also proceeds under solvent-free
conditions. In fact, the reaction proceeds faster under
solvent-free conditions. For instance, 2.0 mmol of solid
pentamethylbenzene was added into 2.0 mmol of liquid
HCtCCO2Et at room temperature to give a pale yellow
solution (Figure 1a). Upon addition of 2.5 mol % of gold-
(III) catalyst, the solution became dark red brown (Figure
of this solid (Figure S1, Supporting Information). Excel-
lent yields were obtained for several substrates that were
tested under the solvent-free conditions (Table 1). In
several cases, good yields could be obtained only when
the reactions were run with neat reactants (entries
10-12 in Table 1). Under such conditions, electron-rich
arene substrates can be activated to add to even alkenes
in high yields; two examples are shown in Table 1 (entries
11 and 12).
This method can be used to construct molecules such
as coumarins (eq 2 in Table 2). Various coumarins were
prepared from aryl alkynoates in good to excellent yields.
The reaction worked for aryl alkynoates that bear dif-
ferent substituted groups including an electron-with-
drawing group (4 in Table 2), although a higher reaction
temperature (70 °C) was required for some of these re-
actions. It should be noted that similar reactions cata-
lyzed by palladium(II), platinum(II), platinum(IV), and
ruthenium(II) have been reported, which may go through
different mechanisms.1a,6
(6) (a) Fu¨rstner, A.; Mamane, V. J . Org. Chem. 2002, 67, 6264-
6267. (b) Pastine, S. J .; Youn, S. W.; Sames, D. Org. Lett. 2003, 5,
1055-1058. (c) Youn, S. W.; Pastine, S. J .; Sames, D. Org. Lett. 2004,
6, 581-584 and references therein.
(5) Reetz, M. T.; Sommer, K. Eur. J . Org. Chem. 2003, 3485-3496.
3670 J . Org. Chem., Vol. 69, No. 11, 2004

Functionalization of Aromatic C-H Bonds Catalyzed by Gold(III)
substrate. A reaction with a mixture of two different
substrates (Figure 2B), one deuterium-labeled and the
other proton-substituted, was also performed. Incorpora-
tion of nearly equal amounts of H and D into both
products was observed after the two independent in-
tramolecular reactions were completed in the same
solution. This result suggests that proton generated from
the reaction is liberated into the solution before it is
incorporated into the final product.
The results observed so far seem to support the
involvement of a direct metalation of electron-rich arene
groups by gold(III) species to form arylgold(III) and 1
equiv of acid. Silver salt might help generate a more
electrophilic gold(III) species from AuCl3. AuCl3 also
worked but gave low yield product. The formed arylgold-
(III) species could add to electron-deficient alkynes and
alkenes to give the final products. This step could be
aided by Lewis acid activation of the alkynes and alkenes
by metal ions or acid present in the reaction solution.
Although we favor this mechanism we cannot exclude the
possibility of gold(III) simply works as Lewis acid to
activate alkynes and alkenes in the reactions reported
here.
F IGURE 2. Isotope experiments under the conditions of 5 mol
% AuCl3/3AgOTf in dichloroethane at room temperature.
To probe the mechanism, we mixed stoichiometric
amounts of gold(III) catalyst with pentamethylbenzene.
Immediate darkening of the solution color was observed,
accompanied by a disappearance of the aromatic proton
Con clu sion s
1
signal in the H NMR spectrum (Figure S2, Supporting
In summary, an efficient hydroarylation reaction of
electron-deficient alkynes and alkenes is described here.
More research efforts are required to fully elucidate the
mechanism of these reactions and expand the scope of
this chemistry. Nevertheless, the gold(III)-catalyzed reac-
tion presented here offers several advantages; it is atom
economic as it can be run with neat reactants and gives
clean product, the reaction proceeds efficiently at ambient
temperature under air atmosphere, and potentially dif-
ferent functional groups can be tolerated. These features
make it a favorable method for constructing complicated
molecules in one step. Further exploration of this chem-
istry by using other electrophiles is in progress.
Information). No immediate change was observed when
mixing the gold catalyst with alkyne or alkene substrates.
This result may suggest that direct metalation of arene
ring might be the first step of the reaction, which was
followed by addition of the arylgold(III) to the electron-
deficient alkyne substrate. More careful studies are
required to fully elucidate the mechanism. It is possible
that gold(III) works merely as a Lewis acid in these
reactions to activate the alkyne or alkene substrates.
Even if an arylgold(III) species was produced as an
intermediate in the reaction, the carbon-carbon bond
formation reaction could still be aided by Lewis acid-
activation of the alkyne or alkene; the metal ions (gold
or silver) or the acid released from the auration reaction
Ack n ow led gm en t. This research was supported by
the University of Chicago.
can serve as the Lewis acid.
To gain further insight of the mechanism, an isotope
experiment was performed on the reaction of the deute-
rium-labeled mesitylene with HCtCCO2Et (Figure 2A).
The result showed that the D (H) incorporated into the
vinyl part of the product comes mainly from the aromatic
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails; Figures S1 and S2. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0497353
J . Org. Chem, Vol. 69, No. 11, 2004 3671