Gold-catalyzed synthesis of substituted tetrahydronaphthalenes

Article abstract of DOI:10.1021/ol062582g

(Diagram presented) We report a gold-catalyzed benzannulation of 3-hydroxy-1,5-enynes to generate tetrahydronaphthalenes. This mild process proves to be an effective method to synthesize various metasubstituted aromatic rings in good yields.

Full text of DOI:10.1021/ol062582g

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5905-5908
Gold-Catalyzed Synthesis of Substituted
Tetrahydronaphthalenes
Christiane M. Grise´ and Louis Barriault*
Center for Catalysis Research and InnoVation, Department of Chemistry,
10 Marie Curie, UniVersity of Ottawa, Ottawa, Canada K1N 6N5
lbarriau@uottawa.ca
Received October 19, 2006
ABSTRACT
We report a gold-catalyzed benzannulation of 3-hydroxy-1,5-enynes to generate tetrahydronaphthalenes. This mild process proves to be an
effective method to synthesize various metasubstituted aromatic rings in good yields.
1,2,3,4-Tetrahydronaphthalenes and related derivatives are
an important class of molecules which often comprise key
fragments of medicinally important molecules.1 Typically,
tetrahydronaphthalenes are obtained by hydrogenation of
naphthalenes or by Friedel-Crafts alkylations.2 These ap-
proaches are plagued by regioselectivity problems and low
yields. Owing to the importance of substituted aromatic
compounds in organic and medicinal chemistry, the develop-
ment of efficient methods to prepare aromatic rings is of
paramount importance. Transition-metal-catalyzed benz-
annulation of enynes represents an attractive alternative for
de novo synthesis of tetrahydronaphthalene frameworks.
Catalysis by Au salts/complexes provides a mild and efficient
method to activate alkynes, allenes, and alkenes. As a
consequence, numerous accounts of gold-catalyzed carbon-
carbon bond-forming reactions have been reported.3 More
specifically, cycloisomerization of 1,5-enynes and 1,6-enynes
has been investigated and reported as a method to access
various synthons.4 Yet, only a few examples of Au- and Ag-
catalyzed benzannulations have been described.5 Herein, we
present a new efficient catalytic method to access tetra-
hydronaphthalenes from 3-hydroxy-1,5-enynes.
Hydroxy-enynes are known to undergo cycloisomerization
upon treatment with Cu, Pt, or Au salts.6 Typically, the
products observed were either metathesis-type or polycyclic
compounds. In 1984, Gore et al. reported Ag(I)-mediated
(4) Cycloisomerization of enynes. For recent reviews, see: Ma, S.; Yu,
S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200. Other recent papers: (a)
Lopez, S.; Herrero-Gomez, E.; Perez-Galan, P.; Nieto-Oberhuber, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029.
(5) (a) Shibata, T.; Ueno, Y.; Kanda, K. Synlett 2006, 3, 411. (b) Asao,
N. Synlett 2006, 11, 1645. (c) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 7436. (d) Lin, M.-Y.; Das, A.; Liu, R.-S. J. Am.
Chem. Soc. 2006, 128, 9340. (e) Hashmi, A. S. K.; Weyrauch, J. P.;
Kurpejovic, E.; Frost, T. M.; Miehlich, B.; Frey, W.; Bats, J. W. Chem.-
Eur. J. 2006, 12, 5806. (f) Dankwardt, J. W. Tetrahedron Lett. 2001, 42,
5809.
(6) (a) PtCl2: Harrack, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.;
Mainetti, E.; Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M.
J. Am. Chem. Soc. 2004, 126, 8656. (b) Cu(BF4)(CH3CN)4 or PtCl2: Fehr,
C.; Farris, I.; Sommer, H. Org. Lett. 2006, 8, 1839. (c) Au salts: Gagosz,
F. Org. Lett. 2005, 7, 4129. (d) PtCl2 and Au salts: Mamane, V.; Gress,
T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (e) Pt, Cu,
and Au salts: Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901.
(f) Pt and Au salts: Fu¨rstner, A.; Hannen, P. Chem.-Eur. J. 2006, 12,
3006. (g) Au salts: Marion, N.; de Fre´mont, P.; Lemie`re, G.; Stevens, E.
D.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. Commun. 2006, 19,
2048. (h) Pt salts: Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria,
M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. (i) Pt
salts: Blaszykowski, C.; Harrak, Y.; Goncu¨alves, M.-H.; Cloarec, J.-M.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2004, 6, 3771.
(1) Selected examples: (a) Cimetiere, B.; Dubuffet, T.; Landras, C.;
Descombes, J.-J.; Simonet, S.; Verbeuren, T. J.; Lavielle, G. Bioorg. Med.
Chem. Lett. 1998, 8, 1381. (b) Stutz, A.; Georgopoulos, A.; Granitzer, W.;
Petranyi, G.; Berneyt, D. J. Med. Chem. 1986, 29, 112. (c) Dumas, M.;
Dumas, J. P.; Bardou, M.; Rochette, L.; Advenier, C.; Giudicelli, J. F. Eur.
J. Pharmacol. 1998, 348, 223.
(2) (a) Amer, I.; Amer, H.; Blum, J. J. Mol. Catal. 1986, 34, 221. (b)
Cheng, J. C.; Maioriello, J.; Larsen, J. W. Energy Fuels 1989, 3, 321. (c)
Kurteva, V. B.; Santos, A. G.; Afonso, C. A. M. Org. Biomol. Chem. 2004,
2, 514.
(3) Recent reviews on gold-catalyzed reactions: (a) Hoffmann-Ro¨der,
A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (b) Hashmi, A. S. K.
Angew. Chem., Int. Ed. 2005, 44, 6990. (c) Hashmi, A. S. K. Gold Bull.
2004, 37, 51. (d) Echavarren, A. M.; Nevado, C. Chem. Soc. ReV. 2004,
33, 431.
10.1021/ol062582g CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/10/2006

oxy-Cope reaction of various 3-hydroxy-1,5-enynes to give
the desired enone.7 However, they found that the treatment
of alcohol 1 with a stoichiometric amount of AgOTf in
THF-H2O gave a complex mixture of products from which
tetrahydronaphthalene 2 was isolated in 15% yield.7a There-
fore, we investigated a catalytic version of this unusual
benzannulation. To our delight, subjection of 1 to 1 mol %
of Au(PPh3)Cl and 1 mol % of AgOTf in dichloromethane
gave 2 in 72% yield. To optimize the reaction conditions,
other catalyst systems were explored (Table 1).
Scheme 1. Proposed Mechanism for Au(I)-Catalyzed
Benzannulation
Table 1. Au- and Ag(I)-Catalyzed Tetrahydronaphthalene
Synthesis
corresponding oxy-Cope product 8 could be envisaged.
However, no oxy-Cope or ring expansion products were
observed from the reaction mixture as only tetrahydronaph-
thalene 2 was isolated. This enyne cycloisomerization has a
unique mechanism because an aromatic compound was
generated instead of a metathesis, a polycyclic, or an oxy-
Cope product. Having the optimal reaction conditions (entry
7, Table 1) in our hands, we thus examined the scope of the
reaction (Table 2).
entry
catalysta
yieldb (%)
1
2
3
4
5
6
7
5% Au(PPh3)Cl, 5% AgBF4
5% Au(PPh3)Cl, 5% AgSbF6
2.5% AuCl3
2.5% Au(PPh3)Cl
2.5% AgOTf
42
22
22c
0
48c
45c
84
2.5% AgOTf, 2.5% PPh3
2.5% Au(PPh3)Cl, 2.5% AgOTf
Table 2. Au(I)-Catalyzed Cyclization of 3-Hydroxy-1,5-enynes
a Reactions run in DCM, 23 °C, 18 h. b Isolated yield. c NMR conversion.
Treatment of alcohol 1 with 5% of Au(PPh3)Cl and 5%
of AgBF4 (entry 1) gave 2 in 42% yield. Changing the silver
salt to AgSbF6 gave the desired product in 22% yield (entry
2). A catalytic amount of AuCl3 also catalyzed the benz-
annulation, albeit in low conversion (entry 3). A control
experiment employing 2.5% of Au(PPh3)Cl only (entry 4)
did not give any desired tetrahydronaphthalene 2. However,
2.5% of AgOTf (entry 5) or 2.5% of AgOTf and 2.5% of
PPh3 (entry 6) did promote the reaction, although with a 48
and 45% yield, respectively, after 18 h. The best catalyst
system was a combination of Au(PPh3)Cl and AgOTf. The
use of 2.5 mol % of both catalysts led to the desired product
in 84% yield. A reduction of catalyst loading to 0.1 mol %
of Au(PPh3)Cl and AgOTf, however, led to a significant loss
in yield (58%), and a longer reaction time (96 h) was
observed.
entry
R1
R2
n
yield %a
1
2
3
4
5
6
7
8
Me
H
H
H
H
Me
Ph
0
1
1
1
1
1
1
1
2a, 28
2b, 10
2c, 84
2d, 77
2e, 86
2f, 73
2g, 66
2h, 75b
Ph
Me
Me
Me
Me
Me
4-NO2C6H4
4-NHAcC6H4
9
10
11
OEt
Me
Me
H
H
Ph
1
2
2
2i, 12
2j, 51
2k, 65
a Isolated yield after column chromatography. b 1.5 equiv of PTSA was
added and 10% of Au and Ag was used.
We proposed the following mechanism depicted in Scheme
1. Cyclization of the Au(I) complex 3 can either occur in a
5-exo dig manner giving 4 or in a 6-endo dig fashion to
give 5 which exists in equilibrium with compound 6. It is
known that acyclic 3-hydroxy-1,5-enynes react via an
intermediate analogous to 6 followed by a 1,2-hydride shift
to generate polycyclic compounds.6b,c In this case, a 1,2-
hydride shift is not possible due to the tertiary alcohol. On
the other hand, a ring expansion of 5 (or 4) to give the
At first glance, we observed that the ring size affected
the yield of the reaction. Lower yields were observed when
the reaction was performed with 3-hydroxy-1,5-enynes
having five- and seven-membered rings (entries 1, 10, and
11). It was noticed that the substituents at R1 play an
important role in the reaction. When R1 was a hydrogen,
the desired product 2b was isolated in 10% yield (entry 2).
One might assume that the stability of the carbocation in 5
could favor the process. To our surprise, benzannulation of
enol ether 1i provided the desired product 2i in only 12%
yield (entry 9).8 In contrast, Au(I)-catalyzed benzannulation
(7) (a) Bluthe, N.; Malacria, M.; Gore, J. Tetrahedron Lett. 1984, 25,
2873. (b) Bluthe, N.; Malacria, M.; Gore, J. Tetrahedron 1986, 42, 1333.
5906
Org. Lett., Vol. 8, No. 25, 2006

of an electron-rich aromatic ring system such as furan 9 and
aryl 11 proceeded in 57 and 76% yields, respectively (eqs 2
and 3, Scheme 2). On the other hand, the reaction proceeded
Table 3. Investigation into the Reactive Species
Scheme 2
additive
(equiv)
conversionb
(%)
run
catalysta
1
2
3
4
5
6
7
8
2.5% Au(PPh3)Cl, 2.5% AgOTf DTBMP (1.05)
2.5% Au(PPh3)Cl, 2.5% AgOTf DTBMP (0.05)
0
31-50
79
29
22
34
2.5% Au(PPh3)Cl, 2.5% TfOH
2.5% AuCl, 2.5% TfOH
2.5% AuCl
-
-
-
-
-
-
2.5% Au(PPh3)Cl, 2.5% PTSA
2.5% Au(PPh3)Cl, 2.5% TCA
2.5% Au(PPh3)Cl, 2.5% TFA
38
0
1
a Reactions run in DCM at 23 °C for 18 h. b Determined by H NMR.
Au(PPh3)Cl and PTSA (run 6), trichloroacetic acid (run 7),
or TFA (run 8) gave conversions of 34, 38, and 0%,
respectively. A comparison between AuCl and TfOH (run
4) and AuCl alone (run 5) indicated that the phosphine ligand
might have a role in the catalysis. 31P NMR studies revealed
that Au(I) cationic species were not detected when Au(PPh3)Cl
and TfOH were mixed in the presence of the substrate 1
(spectra d, Figure 1). In fact, the chemical shift (32.69 ppm)
in good yields with substrates having an internal alkyne
(entries 4-7 and 11) and cyclic olefin (eq 4). This provided
metasubstituted aromatic rings which are difficult to obtain
via cross-coupling reactions. Conversely, the cyclization of
the pyridine derivative 1h did not occur under the typical
reaction conditions and only starting material was recovered.
It was found that the addition of 1.5 equiv of PTSA was
necessary to obtain 2h in 75% yield (entry 8).
Because the reaction with substrate 1h only proceeded
when in the presence of an excess of acid, we were curious
to determine if the Bronsted acid plays a role in the other
benzannulations. One might propose that elimination of water
could be facilitated in the presence of acid (7f2, Scheme
1). Alternatively, one might suggest that the elimination of
water could occur to form a diene-yne intermediate which
undergoes a Au(I) benzannulation. To verify this, the reaction
was performed in the presence of 1.05 equiv of 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) (Table 3, run 1). In this
case, only starting material was recovered.
However, a low conversion was observed when the
reaction was performed in the presence of 5 mol % of
DTBMP (run 2). On the other hand, exposure of alcohol 1
to 5 mol % of TfOH, PTSA, or chloroacetic acid did not
give any desired product 2. Only starting material was
recovered, thereby ruling out simple Bronsted acid catalyzed
benzannulation or formation of a diene-yne intermediate.9
To further study the exact nature of the catalyst, a series
of experiments with different gold complexes were con-
ducted. A catalyst system generated from 2.5 mol % of
Au(PPh3)Cl and 2.5 mol % of TfOH gave a conversion of
79% after 18 h (run 3). Catalyst systems generated from
Figure 1. 31P NMR study at 23 °C in CDCl3 (PPh3 used as a
standard at -6.0 ppm). (a) Au(PPh3)Cl; (b) Au(PPh3)Cl (2.5 mol
%) and AgOTf (2.5 mol %) after 16 h; (c) Au(PPh3)Cl (2.5 mol
%), AgOTf (2.5 mol %), and alcohol 1 (59% conversion); (d)
Au(PPh3)Cl (5 mol %), TfOH (5 mol %), and alcohol 1 (37%
conversion).
is identical to that of Au(PPh3)Cl alone (spectra a). However,
different Au(I) complexes were generated when Au(PPh3)Cl
and AgOTf were mixed alone to form Au(PPh3)OTf (spectra
b) or in the presence of substrate 1 (spectra c). In the latter
case, one might propose the existence of a cationic gold
species such as [Au(PPh3)-Ar]+ (Ar ) tetrahydronaphtha-
lene).
(8) Besides the desired product 2i, only degradation products were
1
observed by H NMR.
(9) Exposure of 1 and 1e to 1 equiv of TfOH and PTSA, respectively,
in DCM at room temperature gave a myriad of compounds from which no
tetrahydronaphthalenes, 2, 2e, or diene-yne products were observed by 1H
NMR of the crude mixture. Compound 2 was exposed to TfOH (1 equiv)
for 2.5 h at 23 °C, and no degradation products were observed.
Org. Lett., Vol. 8, No. 25, 2006
5907

On the basis of this, we suggest that in the case of the
benzannulation of 1 catalyzed by gold and acid the active
catalyst may exist as an equilibrium with Au(PPh3)Cl and
TfOH. To the best of our knowledge, there are no reports of
an active catalyst generated from Au(PPh3)Cl and an acid.10
Further investigations on the exact nature of the active
catalyst are ongoing and will be reported in due course.
In summary, we reported a gold-catalyzed benzannulation
of 3-hydroxy-1,5-enynes to generate tetrahydronaphthalenes.
This process has proven to be an effective method to
synthesize various metasubstituted aromatic rings.
Acknowledgment. We thank the NSERC, Merck Frosst
Canada, Merck and Co., Boehringer Ingelheim, PREA, CFI,
OIT, Center for Catalysis Research and Innovation, and the
University of Ottawa for generous funding. C.M.G. thanks
NSERC for a postgraduate scholarship (CGS-D). The authors
thank Profs. Keith Fagnou and Darrin Richeson from the
University of Ottawa for helpful discussions.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) It was reported that cationic gold species are generated when
Au(PPh3)Me is treated with an acid. See: Teles, J. H.; Brode, S.; Chabanas,
M. Angew. Chem., Int. Ed. 1998, 37, 1415.
OL062582G
5908
Org. Lett., Vol. 8, No. 25, 2006