Ru(III)-Catalyzed Cyclization of Arene-Alkene Substrates via Intramolecular Electrophilic Hydroarylation

Article abstract of DOI:10.1021/ol036385i

(Matrix presented) We herein report that RuCl₃/AgOTf has proven to be a hydroarylation catalyst with an efficiency and scope superior to previously known methods. This catalyst demonstrated consistent performance with arene-ene substrates of diverse structural features, providing good to excellent yields of cyclization products (chromanes, tetralins, terpenoids, dihydrocoumarins).

Full text of DOI:10.1021/ol036385i

ORGANIC
LETTERS
2004
Vol. 6, No. 4
581-584
Ru(III)-Catalyzed Cyclization of
Arene-Alkene Substrates via
Intramolecular Electrophilic
Hydroarylation
,‡
So Won Youn,† Stefan J. Pastine,‡ and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, New York, New York 10027, and
Department of Chemistry, Pukyong National UniVersity, Busan, Korea
sames@chem.columbia.edu
Received December 6, 2003
ABSTRACT
We herein report that RuCl3/AgOTf has proven to be a hydroarylation catalyst with an efficiency and scope superior to previously known
methods. This catalyst demonstrated consistent performance with arene-ene substrates of diverse structural features, providing good to
excellent yields of cyclization products (chromanes, tetralins, terpenoids, dihydrocoumarins).
Intramolecular hydroarylation, a formal addition of arene
C-H bonds across multiple bonds in an intramolecular
manner, provides a direct route to valuable organic com-
pounds such as annulated arene heterocycles and carbocycles.
In contrast to the Heck reaction, a hydroarylation approach
not only eliminates the requirement for a halogen (or triflate)
substituent but also allows for multiple mechanistic pos-
sibilities, which in turn may lead to different regioisomeric
products (Figure 1). These alternative mechanistic routes
† Pukyong National University.
‡ Columbia University.
(1) For examples of non-oxidative cyclization, see: (a) Ahrendt, K. A.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2003, 5, 1301-1303. (b) Tan, K.
L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202-
3203. (c) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 9692-9693. For examples of oxidative
cyclizations, see: (d) Beccalli, E. M.; Broggini, G. Tetrahedron Lett. 2003,
44, 1919-1920. (e) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
125, 9578-9579.
(2) (a) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2001,
123, 1505-1506. (b) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992-1995.
Figure 1. Hydroarylation vs Heck reaction.
(3) For examples of alkyne activation/cyclization, see: (a) Pastine, S.
J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055-1058. (b) Pastine, S.
J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859-8868. (c)
Nishizawa, M.; Yadav, V. K.; Skwarczynski, M.; Takao, H.; Imagawa, H.;
Sugihara, T. Org. Lett. 2003, 5, 1609-1611. (d) Martin-Matute, B.; Nevado,
C.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003, 125, 5757-
5766. (e) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414-
1417. (f) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264-6267.
(g) Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org. Chem. 2000, 65,
4913-4918. (h) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem.
2000, 65, 7516-7522.
include arene metalation-Heck-type addition1 and multiple-
bond activation-electrophilic substitution.2,3
We have recently developed a new platinum-catalyzed
hydroarylation method that provides direct access to chromene,
coumarin, and dihydroquinoline scaffolds from arene-yne
substrates.3a,b We became interested in the possibility of
10.1021/ol036385i CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

extending intramolecular hydroarylation to arene-alkene
substrates. In contrast to the intermolecular versions,4 only
a handful of examples have surfaced regarding transition
metal-catalyzed intramolecular hydroarylation of alkenes.1a-c,2
These methods have been limited to specific substrate classes;
a general hydroarylation method has not emerged for arene-
ene substrates. Herein we report our results from a thorough
screen, which identified RuCl3/AgOTf as a mild and efficient
catalyst for the intramolecular hydroarylation of a broad
range of arene-ene substrates.
Table 1. Selected Data from a Systematic Screening
entry
catalyst
additive
yields (%)a
1
2
3
4
5
PtCl4
15
5
20
4
23
4
40
56
18
25
0
20
83
0
0
80
6
0
0
2
40
45
AgSbF6
AgOTf
AgOTf
AgOTf
We focused our initial efforts in this area on the cyclization
of homoallylic aryl ether 1, which was selected as the first
substrate for screening of a broad spectrum of metal salts
and complexes. Transition metal complexes were chosen
from nearly all regions of the periodic table, and we assured
that reagents and catalysts, reported previously to either
promote reactivity of alkenes and alkynes toward nucleo-
philes or facilitate electrophillic metalation of arenes, were
included in the screen. A total of 67 metal salts and
complexes were evaluated under 233 reaction conditions
(Table 1, for complete data, see Supporting Information).
Metal complexes were examined in a variety of solvents,
and the effects of silver salt additives were determined.
Careful analysis of the crude reaction mixtures by 1H NMR
during the early screening period reaffirmed our initial
worries that olefin isomerization would be problematic. In
fact, nearly all of the complexes tested induced some degree
of olefin isomerization in 1, with the cases of Pd, Rh, and
Ru being particularly extensive. To further complicate
matters, multiple products were formed; in addition to 2,
seven compounds were identifed. With the exception of
PtCl4, [PtCl2(CH2CH2)]2, Cu(OTf)2, Sc(OTf)3, and HfCl4,
none of the metal complexes examined showed the ability
to produce the desired product 2.
PtCl2
Pt(2,2′-Bipy)Cl2
[PtCl2(CH2CH2)]2
Cu(OTf)2
b
6
7
8
Sc(OTf)3
9
HfCl4
10
11
12
13
14
15
16
17
18
19
20
21
22
AgOTf
RuCl3‚xH2O
AgSbF6
AgOTf
AgBF4
AgPF6
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
RuCl3
RuCl2(COD)
RuCl2(PPh3)3
Ru3(CO)12
[RuCl2(C6H6)]2
RhCl3‚xH2O
IrCl4‚xH2O
b
a Determined by 1H NMR using trichloroethylene as an internal standard.
b Using 2.5 mol % of the dimeric complex.
2 in combination with AgOTf, albeit in a lower yield.
Interestingly, neither of the three metal chlorides were able
to promote the formation of 2 without the silver additive.
Additionaly, it was found that AgOTf was not responsible
for product formation. We suspected that trace amounts of
TfOH, formed in situ, might catalyze the coupling reaction.
However, substituting anhydrous RuCl3 for the hydrate
resulted in similar yields of 2 (Table 1). A catalytic amount
of TfOH (5 mol %) did result in the production of 2, albeit
only in 16% yield. These results suggest that ruthenium plays
an important role in the hydroarylation process, and prompted
us to explore both the efficiency and scope of this Ru(III)
catalyst in the hydroarylation of arene-ene substrates.
The utility of RuCl3/AgOTf for the cyclization of a variety
of arene-ene substrates is shown in Table 2. This method
demonstrated good compatibility with various functional
groups, including halide, methoxy, free phenol, and protected
amines (Table 2). In addition to the desired chromane
products, homoallylic aryl ether substrates produced small
quantities of dihydrobenzofuran products, which likely form
through a sequential isomerization, Clasien rearrangement,
In an attempt to increase the electrophilicity at the metal
centers, reactions were run in the presence of silver salt
additives (AgX, where X ) SbF6, OTf, BF4). As a general
trend, it was found that the conversion of 1 increased upon
the addition of silver salts, implying that more reactive
catalysts were generated in situ. However, the increased
reactivity of the metal did not always translate into better
yields of the desired product 2 but rather to increased
amounts of undesired products (see Supporting Information).
In the case of PtCl4 and HfCl4, the addition of AgOTf had
only a marginal effect, resulting in 2 and 5% increases in
the yield of 2, respectively (Table 1).
We were delighted to identify an exciting lead, which
unambiguously stood out in the array of experiments.
Remarkably, the combination of RuCl3‚xH2O/AgOTf pro-
duced 2 in 83% yield.5 In addition to RuCl3, the hydrates of
IrCl4 and RhCl3 were also able to promote the formation of
(4) For representative examples, see: (a) Lail, M.; Arrowood, B. N.;
Gunnoe, T. B. J. Am. Chem. Soc. 2003, 125, 7506-7507. (b) Matsumoto,
T.; Periana, R. A.; Taube, D. J.; Yoshida, H. J. Mol. Catal. A 2002, 180,
1-18. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731-
1769 and references therein. (d) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 7894-7895 and references therein. (e) Jensen, K.
B.; Thorhauge, J.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2001, 40, 160-163.
(5) For some examples of C-C bond formation reactions involving
RuCl3, see: (a) Fu¨rstner, A.; Voigtla¨nder, D.; Schrader, W.; Giebel, D.;
Reetz, M. T. Org. Lett. 2001, 3, 417-420. (b) Weissman, H.; Sing, X.;
Milstein, D. J. J. Am. Chem. Soc. 2001, 123, 337-338. (c) Tsou, D. T.;
Burrington, J. D.; Maher, E. A.; Grasselli, R. K. J. Mol. Catal. 1985, 30,
219-222. (d) Rhone-Poulenc. Netherlands Patent 6603115/1966.
582
Org. Lett., Vol. 6, No. 4, 2004

Table 2. Catalytic Cyclization of Selected Substrates
All reactions were performed with 5 mol % RuCl3‚xH2O and 10 mol % AgOTf in ClCH2CH2Cl at 60 °C, unless otherwise noted. a Isolated yields.
b Performed with 20 mol % RuCl3 and 40 mol % AgOTf at 80 °C. c Performed with 1 mol % RuCl3‚xH2O and 2 mol % AgOTf at 60 °C. d Cis:trans )
82:18. e Performed with 2 mol % RuCl3‚xH2O and 4 mol % AgOTf at 60 °C. f Performed with 10 mol % RuCl3‚xH2O and 20 mol % AgOTf at 70 °C.
g Performed with 20 mol % RuCl3‚xH2O and 40 mol % AgOTf at 70 °C.
and cyclization pathway (Table 2, entries 1-5). 3,4-Dihy-
drocoumarin products could be successfully produced from
their corresponding acyclic precursors; however, higher
catalyst loading and temperatures were required (Table 2,
entry 6). Carbon-based tethers of mono-, di-, and trisubsti-
tuted olefins produced tetralin products in good to excellent
yields, with cyclization proceeding exclusively through the
6-exo mode. In contrast, substrate 19 with a shorter carbon
tether cyclized preferentially through the 6-endo mode (Table
2, entry 10). Cyclization of carbon-tethered substrates was
induced with significantly lower catalyst loadings (1 mol %)
relative to oxygen-tethered substrates (5 mol %). This is
notable because carbon-tethered substrates are inherently less
electron rich than those derived from phenols. In the case
of nitrogen-tethered substrates, the N-triflate protecting group
proved to be essential, with free N-H, N-alkyl, N-Ac, or
N-Boc substrates being unreactive (Table 2, entry 14).
Finally, C(3)-substituted indole derivatives participated in
this intramolecular hydroarylation reaction.6 Both free N-H
and N-methyl derivatives could be utilized; however, the
Org. Lett., Vol. 6, No. 4, 2004
583

N-methyl derivatives provided the tricyclic products in higher
yields (Table 2, entries 15 and 16). Noteworthy is the fact
that the regiochemistry of cyclization for indole substrates
33 and 35 (5-exo) differs from the phenyl substrate 19 with
the same carbon tether (6-endo).
find that chiral ether 41 afforded chromane 42 in 83% yield
(cis:trans ) 4:1), while no racemization was observed
(Scheme 2). This finding rules out reversible alkene migra-
Scheme 2
In the next stage of the project, we set out to address the
question of whether the hydroarylation protocol would be
applicable to substrates of higher complexity. Acid-catalyzed
polyene cyclization is one of the most widely used methods
for the synthesis of polycyclic terpenoids.7
We were interested to see if our RuCl3/AgOTf hydro-
arylation protocol could provide a mild alternative to
traditional methods. Accordingly, polyenes 37 and 39 were
prepared and subjected to the hydroarylation protocol. We
found that very mild conditions, namely, 1 mol % RuCl3
and 2 mol % AgOTf, smoothly cyclized the polyenes to the
tricyclic terpenoids 38 and 40 in nearly quantitative yields
with high stereoselectivities (trans:cis ) 99:1∼98:2). Diter-
penoid 40 is a valuable synthetic intermediate, having been
converted to the natural product ferruginol by King8 and
Ghatak.9
tion and significantly expands the scope of this hydroary-
lation methodology.
In summary, an extensive and systematic study identified
RuCl3/AgOTf as an intramolecular hydroarylation catalyst
of arene-ene substrates. A variety of annulated arene
heterocycles and carbocycles are accessible under mild
conditions using this method, including chromane, tetralin,
terpenoid, dihydrocoumarin, tetrahydroquinoline, and indolo-
cyclohexane and cyclopentane systems. It is likely that this
reaction proceeds via an electrophilic pathway involving
alkene activation, C-C bond formation, and the protonation
of a C-Ru intermediate. The contrast between the reactivity
of arene-yne3 and arene-ene substrates raises interesting
questions regarding the role of the metal catalyst on these
seemingly related pathways. Better understanding of these
issues will facilitate the development of an asymmetric
version of hydroarylation cyclizations.
Scheme 1
Acknowledgment. Generous support for this work was
provided by GlaxoSmithKline, Johnson & Johnson Focused
Giving Grant. D.S. is a recipient of the Alfred P. Sloan
Fellowship and the Camille Dreyfus Teacher-Scholar
Award.
Last, we addressed an important question of whether a
stereogenic center in chiral homoallylic ethers would be
compromised during the cyclization. We were delighted to
(6) The Widenhoefer laboratory at Duke University has recently identified
a platinum-catalyzed method for intramolecular hydroarylation of indole
substrates. Wang, X.; Widenhoefer, R. Personal communication.
(7) Bartlett, P. A. In Aymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, Part B, pp 341-409.
(8) King, F. E.; King, T. J.; Topliss, J. G. J. Chem. Soc. 1957, 573-
577.
Supporting Information Available: Complete Experi-
mental Section, complete data for the systematic screening,
experimental details, and compound spectral characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Banik, B. K.; Chakraborti, A. K.; Ghatak, U. R. J. Chem. Res., Synop.
1986, 406-407.
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