Gold-catalyzed intramolecular hydroarylation of olefins. Scope evaluation and preliminary mechanistic studies

Article abstract of DOI:10.1016/j.tetlet.2011.04.122

We report a gold-catalyzed intramolecular hydroarylation of unactivated olefins using a combination of AuCl₃/AgOTf as the catalytic system affording dihydrobenzopyrans, tetralins and tetrahydroquinolines in good yields. For our preliminary mechanistic studies, we have investigated the kinetic isotope effects with deuterated arene compounds and found that this catalytic hydroarylation is consistent with an electrophilic aromatic substitution process.

Full text of DOI:10.1016/j.tetlet.2011.04.122

Tetrahedron Letters 52 (2011) 3509–3513
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed intramolecular hydroarylation of olefins. Scope evaluation
and preliminary mechanistic studies
⇑
⇑
Mickael Jean , Pierre van de Weghe
Université de Rennes 1, UMR 6226, Sciences Chimiques de Rennes, Equipe PNSCM, UFR Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof. Léon Bernard,
F-35043 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a gold-catalyzed intramolecular hydroarylation of unactivated olefins using a combination of
AuCl3/AgOTf as the catalytic system affording dihydrobenzopyrans, tetralins and tetrahydroquinolines in
good yields. For our preliminary mechanistic studies, we have investigated the kinetic isotope effects
with deuterated arene compounds and found that this catalytic hydroarylation is consistent with an elec-
trophilic aromatic substitution process.
Received 4 February 2011
Revised 29 April 2011
Accepted 29 April 2011
Available online 5 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular hydroarylation
Gold catalysis
Mechanistic studies
During the last decade, the use of homogenous gold catalysts for
organic transformations has enjoyed tremendous popularity
among chemists working in the field of catalysis and organic syn-
thesis.1 The majority of such transformations allowed a nucleo-
philic attack after gold-activation of carbon–carbon double or
triple bonds.
salts to catalyze the intramolecular hydroarylation of alkenes
and our preliminary efforts to understand the mechanism of this
reaction process.
In our initial investigation, the search for optimal reaction
conditions was conducted using homoallyl phenyl ether 1 as a
model compound by varying the catalytic system and the sol-
vent (Table 1). During our preliminary studies, whatever the gold
chloride used, it appeared that silver triflate led to better results
compared to other silver salts (AgClO4, AgSbF6, AgBF4, AgOTs,
AgPF6 and AgNTf2).4 Moreover in the absence of gold or silver
salts no reaction occurred and only the starting material 1 was
recovered.3e After some experimentations, we found that
5 mol % AuCl/AgOTf or 5 mol % AuCl3/AgOTf in dichloroethane
(DCE) at 80 °C were the best reaction conditions to obtain a
complete conversion of the starting material 1 (Table 1, entries
2, 9 and 10). While the intermolecular hydroarylation of alkenes
with indoles using the combination of PPh3AuCl/AgOTf as the
catalyst was achieved in good yields,5 we noticed in our case
that the same catalytic system slowed the reaction (Table 1, en-
In the recent years, transition metal-catalyzed inter- and intra-
molecular additions of arenes to carbon–carbon multiple bonds
(hydroarylation reactions) appeared as efficient approaches for
the functionalization of arenes through a C–C bond formation.2
In 2004, Sames described the catalytic intramolecular hydroaryla-
tion of unactivated olefins using RuCl3/AgOTf in dichloroethane. A
variety of annulated heterocycles and carbocycles were prepared
under these mild reaction conditions.3a More recently, In(OTf)3 in
dichloroethane at 90 °C showed also a good catalytic activity for
intramolecular hydroarylation of olefins to afford tetralin and
chroman derivatives in modest to good yields.3b Efficient gold
(III)-catalyzed intermolecular addition of electron-rich arenes
with alkenes was developed, best results were obtained in the
presence of AuCl3/AgSbF6 as the catalytic system in dichloroeth-
ane at 50 °C.3c Similar results were also reported by using a cat-
alytic amount of Ca(NTf2)2/Bu4NPF6 in methylene chloride at
room temperature.3d These recent results prompt us to report
our work on the use of 5 mol % of a mixture of gold and silver
try 5). To have
a complete conversion of 1 with 5 mol %
PPh3AuCl/AgOTf in DCE, it was necessary to conduct the reaction
at 80 °C for 24 h. The presence of other ligands attached to the
gold(I) chloride as a phosphite or NHC did not improve the re-
sults obtained with AuCl (Table 1, entries 6 and 7). Although
the Hashmi’s complex [Au]-II in the presence of AgOTf led to
a lower conversion after one hour of reaction than that observed
with AuCl3/AgOTf, this catalytic system also appeared interesting
since the reaction was completed after 6 h of stirring at 80 °C
(Table 1, entry 13).
⇑
Corresponding authors. Tel.: +33 (0)2 23 23 38 03; fax: +33 (0)2 23 23 44 25
(P.V.D.W.).
E-mail addresses: mickael.jean@univ-rennes1.fr (M. Jean), pierre.van-de-we-
ghe@univ-rennes1.fr (P. van de Weghe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.122

3510
M. Jean, P. van de Weghe / Tetrahedron Letters 52 (2011) 3509–3513
Table 1
Optimum conditions for the gold-catalyzed intramolecular hydroarylation of olefins
5 mol% [Au]
5 mol% AgOTf
O
O
Solvent, Temp
Time
1
2
Me
a
a
Entry
[Au]
Solvent
Temp (°C)
Time (h)
Conv (%)
Yield (%)
1
2
3
4
5
6
7
8
AuCl
DCE
DCE
DCE
CH3CN
DCE
DCE
rt
1
1
0.5
1
1
1
1
1
5
100
75
34
15
0
25
15
0
75
60
7
7
0
80
80
80
80
80
80
rt
Ph3PAuCl
(PhO)3PAuCl
[Au]-I
DCE
DCE
7
0
AuCl3
9
DCE
DCE
DCM
CH3CN
DCE
80
80
80
80
80
1
0.5
1
1
1
100
100
30
32
66
85
75
10
0
10
11
12
13
[Au]-II
50
a
Determined by 1H NMR using 1,4-dinitrobenzene as the internal standard.
the reason of the presence for derivative 4lc obtained from a tan-
dem sigmatropic rearrangement–intramolecular hydroaryloxyla-
tion reaction (Scheme 1 and Table 2, entry 13).
Me
Me
N
N
O
N
Cl Au
Cl
Me
Me
Me
Me
Au
Cl
[Au]-I
O
This tandem sigmatropicrearrangement–intramolecular hydro-
aryloxylation reaction was confirmed in the course of our tentative
to realize the intramolecular hydroarylation of the allyl aryl ether 5
(Scheme 2). Under our reaction conditions, only dihydrobenzopy-
rane 6 was obtained in good yield. While with a catalytic amount
of AuCl3, 5 afforded a messy mixture of product 7 and phenol 8,
product 6 was quantitatively formed in the presence of 5 mol %
of AgOTf. It seems that this tandem process takes place only under
the influence of the silver salt although it has been shown that
Au(I) catalyzes the formation of dihydrobenzofurans from allyl aryl
ethers.6
The utility of our catalytic system for the cyclization was also
evaluated for aryl ester derivatives (Scheme 3). Surprisingly, ben-
zoic 1,1-dimethylallyl ester 9 gave no cyclization product and only
the benzoic acid was obtained. Contrary to the Sames’s work,3a no
dihydrocoumarin was formed upon the combination of AuCl3/
AgOTf from the phenyl but-3-enoic ester 11. After 4 h stirring, a
complex mixture of the starting material 11 (51%), the olefin isom-
erization product 13 (E/Z 21%), the acyclic Fries substrate 14 (8%),
the cyclic ketone 15 (4%) and the phenol 12 (16%) was obtained. To
prevent the olefin isomerization, the gem-dimethyl derivative 16
was prepared and then submitted to the Au/Ag catalysis. After
4 h at 80 °C, no reaction occurred and the starting material was
recovered, suggesting that the isomerization of the double bond
plays an important role in the reaction process.
[Au]-II
Finally, the use of AuCl and AuCl3 on other 4-aryloxybut-1-enes
led us to pick out gold(III) chloride in combination with silver tri-
flate in dichloroethane at 80 °C as the best catalytic conditions for
the study of the scope of this reaction (Table 2).4 Thus a variety of
homoallyl aryl ethers (3a–o) with various functional groups such
as methoxy, chloride, nitro and free phenol, were submitted to
our reaction conditions. It was found that methoxy, chloride, and
free phenol groups were tolerated and afforded the expected prod-
ucts in good yields. The reaction worked well with the naphthyl
derivative 3k and gave an inseparable mixture of two regioisomers
4ka and 4kb in 10/1 ratio (Table 2, entry 12). We were also pleased
to observe the formation of the hydroarylated product 4m derived
from the homoallyl thymol ether 3m, a sterically hindered starting
material (Table 2, entry 14). Similarly the 5-phenylpent-1-ene 3p
led to the tetralin 4p in excellent yield (Table 2, entry 17). Lower
yield was obtained for the synthesis of tetrahydroquinoline 4q
from the aniline derivative 3q (Table 2, entry 18). As previously re-
ported, the protecting group of the amine is essential. No reaction
occurred with the free amine or when the amine was protected as
N-Me, N-Ac, N-Ts, N-Boc and N-Cbz.3a,3b
We also noticed the importance of the nature of the substituent
on the aromatic ring. While in the presence of methoxy group on
the arene, the hydroarylation worked well, starting from the sesa-
mol derivative 3o no product of reaction was observed and only
decomposition products were found in the crude reaction mixture
(Table 2, entry 16). The presence of a strong electron-withdrawing
group such as a nitro group prevented the hydroarylation reaction
and only the corresponding nitrophenol was obtained after 24 h of
stirring (Table 2, entries 4, 8, and 11). The loss of the alkyl chain
resulted in the isomerization of the terminal olefin under these
reaction conditions. This isomerization process was probably also
With these results in hand, we decided to undertake prelimin-
ary mechanistic studies. Like the gold-catalyzed hydroarylation
of alkynes as reported in the literature, the intramolecular hydro-
arylation of olefins catalyzed in the presence of AuCl3/AgOTf pro-
ceeds either via
r-aryl-gold species generated through
metallation of arenes and addition to the olefin or via a Lewis acid
activation of olefin and a Friedel–Crafts-type alkenylation of are-
nes. However, in the case of intermolecular hydroarylation of al-
kynes, the pathway via the direct auration of arenes could be
discarded since the work published by Fuchita.7 Addition of com-
plexes ArAuCl2(2,6-lutidine) with phenylacetylene afforded arylat-
ed phenylacetylenes instead of the hydroarylation products. On the

M. Jean, P. van de Weghe / Tetrahedron Letters 52 (2011) 3509–3513
3511
Table 2
Gold-catalyzed intramolecular hydroarylation of olefins
5 mol% AuCl3
5 mol% AgOTf
X
X
R1
R1
DCE, 80 ºC
2 h
Me
Entry
1
Substrate
Product
Yielda (%)
Entry
Substrate
Product
Yielda (%)
O
O
O
O
68
92
10
11
92b
60c
Cl
Cl
3i
1
4i
Me
O
Me
2
OMe
OMe
O
O
OH
O2N
O2N
4j
2
3
4
3j
3a
4a
Cl
Me
O
Cl
O
O
Me
O
4ka
O
68b
67c
12
13
82
3k
10 / 1
Me
O
4kb
3b
4b
NO2
Me
OH
4c
NO2
O
O
Me
4la
O
68d
3l
3 / 2
Me
4lb
3c
OH
O
OH
Me
Me
Me
Me
O
O
O
5
6
65
85
14
15
90
75
4m
3m
4d
3d
Me
Me
Me Me
O
MeO
O
MeO
O
O
O
O
O
Me
3 / 1
3e
4ea
Me
OMe Me 4eb
3n
4n
Me
Cl
O
Cl
O
O
O
O
O
7
8
95b
50c
16
17
Decompositione
—
3 / 2
3o
3f
4fa
4fb
Me
Me
OH
Cl
O2N
O
O2N
98
4g
3p
4p
3g
Me
O
O
Tf
N
Tf
N
9
98
18
55f
MeO
MeO
3h
4h
Me
3q
4q
Me
a
b
c
d
e
f
Isolated yield (average of two or three runs) after purification by preparative thin layer chromatography on silica gel.
Reaction time = 6 h.
Only traces of the expected product 4 detected by 1H NMR from the crude reaction mixture after 24 h stirring.
The tandem Claisen rearrangement–intramolecular hydroaryloxylation product 4lc was also formed, isolated yield = 25%, see Scheme 1.
No hydroarylation product formed, no starting material recovered.
Reaction time = 24 h.
other hand, no reaction occurred when the aryl gold(III) complex
was placed in the presence of internal alkynes or styrene. These
observations led us to believe that the reaction proceeds probably
via a Friedel–Crafts-type mechanism.
Experiments using the deuterated aromatic derivative 17 sup-
ported the mechanism via a gold-activation of the olefin and an
electrophilic aromatic substitution pathway. Indeed, when an
equimolar mixture of 3p and 17 was submitted to our hydroaryla-
tion conditions, a complete conversion of both compounds was ob-
served and the corresponding products 4p and 18 were obtained in
Me
Me
OH
Me
O
O
3l
4lc
Scheme 1. Formation of 4lc.

3512
M. Jean, P. van de Weghe / Tetrahedron Letters 52 (2011) 3509–3513
Me
Me
5 mol% AuCl3
5 mol% AgOTf
5 mol% AuCl
5 mol% AgOTf
3
MeO
MeO
+ 2 H2O
(1)
DCE, 80 ºC
1 h
Me
Me
DCE, 80 ºC, 5 h
75%
O
O
3p
4p
18
Me
5
6
MeO
Me
Me
D
D
D
D
MeO
5 mol% AuCl
3
D
D
D
D
ibidem
+
DCE, 80 ºC, 5 h
5 mol% AgOTf
DCE, 80 ºC, 5 h
OH
OH
+ 2 H2O
(2)
(3)
7
1 / 1
8
D
CH2Y
17
3p
(conversion = 100%)
6
45% deuterium incorporation :Y = D, H
ibidem
Scheme 2. Tandem sigmatropic rearrangement–intramolecular hydroaryloxylation
+ 2 D2O
reaction.
4p
CH2Y
30% deuterium incorporation :Y = D, H
O
5 mol% AuCl
5 mol% AgOTf
3
D
D
D
O
Me
Me
PhCO H
2
10
D
D
D
ibidem
DCE, 80 ºC
2 h
+ 2 D2O
(4)
9
O
O
D
D
11 + PhOH +
5 mol% AuCl
3
5 mol% AgOTf
D
CH Y
2
17
18
90% deuterium incorporation : Y = D, H
12
13
O
O
O
Me
DCE, 80 °C
4 h
OH
O
Me
Scheme 5. Hydroarylation reactions in the presence of H2O or D2O.
+
11
incorporation showed an expected kinetic isotopic effect at the final
stage of the catalytic cycle.
5 mol% AuCl
3
5 mol% AgOTf
14
15
O
O
O
No reaction
One of our fears in this study was the formation of Brönsted acid
by reaction between H2O and AgOTf or AuCl3. Indeed, as reported
in the literature but with a higher efficiency,3a compounds 1 and
3p were converted into 2 and 4p with 5 mol % TfOH in DCE at
80 °C (65% and 90% yield, respectively).3a,9,10 To avoid any suspi-
cion of TfOH catalysis, 3p has been placed with 5 mol % AgOTf,
two equivalents of H2O in DCE at 80 °C. After 2 h of stirring, only
the starting compound was present in the reaction mixture indi-
cating that the couple gold/silver salts are essential for the reac-
tion. Repeating this experience using AuCl3 instead of AgOTf led
us to the same result excluding a catalysis by the complex
[AuCl3ÁH2O] or any Brönsted acid in our typical procedure.11 Note
that the reaction also carried out with phenol 3d did not generate
TfOH in the reaction mixture (Table 2, entry 5). This was attested
by the absence of any reaction of 3d in the presence of 5 mol %
AgOTf and two equivalents of water after several hours of heating
at 80 °C in DCE, while 5 mol % TfOH allowed a complete conversion
of 3d into 4d.2a
Me
DCE, 80 ºC
4 h
Me
16
Scheme 3. Attemps of hydroarylation of ester derivatives.
5 mol% AuCl3
5 mol% AgOTf
Me
3p
0.5 equiv
4p
18
1 : 1
DCE, 80 ºC
15 min
D
D
D
D
D
D
D
D
D
CH2Y
17
0.5 equiv
Y = D, H
Scheme 4. Competitive hydroarylation.
During the optimization studies of the hydroarylation reaction
of 3p in the combination Au/Ag, we also noticed the formation of
product 19 after 2–3 min of stirring at 80 °C in DCE which com-
pletely disappeared after 15 min of heating in favor of the forma-
tion of the hydroarylation product 4p. We have independently
prepared and placed 19 under our catalysis conditions. After
15 min of heating, we found a complete conversion and 4p was iso-
lated in very good yield (Scheme 6).
The overall results of these preliminary experiments lead us to
propose the following catalytic cycle (Scheme 7) which has simi-
lar features to that reported by Tunge for the Fujiwara hydroary-
lation reaction catalyzed by Pd(OAc)2/TFA.12 The cationic gold
species3e could coordinate with the olefin and activate it allowing
an equimolar ratio (Scheme 4). The lack of a kinetic isotopic effect
in the cyclization process is in favor of a Friedel–Crafts-type mech-
anism rather than a C–H activation one allowing to rule out the for-
mation of
r
-aryl-gold species.8 The partial deuteration of
compound 18 is probably due to the traces of water.
To understand the role of water during the reaction process, we
performed the following experiments (Scheme 5). The hydroaryla-
tion reactions of compounds 3p and 17 were accomplished in the
presence of two equivalents of water and then with two equivalents
of D2O. In each case, we obtained a complete conversion of the
starting material after heating for 1 h. The water added into the
reaction mixture did not alter the efficiency of the catalytic system.
The lack of incorporation of deuterium in the methyl group of 18
when the hydroarylation of 17 was performed in the presence of
H2O (Scheme 5, equation 2) indicates clearly that the catalytic pro-
cess finishes by a protodeauration step. When the hydroarylation
reaction was accomplished in the presence of D2O, an incorporation
or an increase of deuterium in the methyl group was observed,
confirming the exchange Au ? H (Scheme 5, equations 3 and 4).
These various experiments and the variation of the deuterium
5 mol% AuCl3
5 mol% AgOTf
DCE, 80 ºC
15 min
Me
Me
4p
93% yield
19
Scheme 6. Hydroarylation of 19.

M. Jean, P. van de Weghe / Tetrahedron Letters 52 (2011) 3509–3513
3513
X
[Au]
X
Me
limiting step
X
X
X
(isotopic effect)
[Au]
A
B
C
Me
[Au]
X
[Au]
+
H
X = CH2, O, N-Tf
E
[Au]
X
H
D
[Au]
Scheme 7. Proposed catalytic cycle.
a nucleophilic attack of the aromatic ring. Rearomatization of D
would lead to the organoaurated intermediate E. The last step
of the catalytic cycle, the protic cleavage of the carbon-gold bond,
would be rate limiting and give the hydroarylation product and
[Au]+. In the light of our observations, the carbocation B appears
to be a plausible intermediate species, justifying the regioselectiv-
ity of the hydroarylation and the olefin migration observed during
the reaction.
In conclusion we have described a gold-catalyzed intramolec-
ular hydroarylation. A variety of functionalized arene derivatives
was converted into the desired dihydrobenzopyrans, tetralins,
and tetrahydroquinolines in good yields. Additionally, prelimin-
ary mechanistic investigations including hydrogen/deuterium
isotopic effects were undertaken. We showed that the mecha-
nism involves an electrophilic aromatic substitution and the lim-
iting step is the protodeauration process. A better understanding
of this mechanism will help the development of an asymmetric
version of this intramolecular hydroarylation reaction and also
the study of a carbodeauration step instead of the simplest
protodeauration.
References and notes
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preparation of this manuscript, a gold-catalyzed rearrangement of substituted
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Extension of the substrate scope and further developments are
in progress and will be reported in due course.
Acknowledgments
10. Under same conditions (loading, time, temperature), the catalytic system
AuCl3/AgOTf has always showed a slight more efficiency compared to TfOH
catalysis: for example, 1, 3k, 3p and 19 were converted to 2, 3ka/b and 4p in
68%, 82%, 98% and 93% using the gold/silver system compared to 65%, 79%, 90%
and 82% using TfOH.
This work was supported by the Université de Rennes 1, the
Région Bretagne and Rennes Metropole.
Supplementary data
11. Robb, W. Inorg. Chem. 1967, 6, 382–386.
12. Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440–6444.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.122.