Synthesis of indenyl ethers by gold(I)-catalyzed intramolecular carboalkoxylation of alkynes

Article abstract of DOI:10.1021/ja064209+

The gold(I)-catalyzed carboalkoxylation of alkynes to form indanone derivatives from readily available ortho-acetylenic benzylic ethers is described. Importantly, the gold(I)-catalyzed rearrangement of enantioenriched benzylic ethers proceeds with chirali

Full text of DOI:10.1021/ja064209+

Published on Web 08/26/2006
Synthesis of Indenyl Ethers by Gold(I)-Catalyzed Intramolecular
Carboalkoxylation of Alkynes
Pascal Dube´ and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received June 15, 2006; E-mail: fdtoste@berkeley.edu
Recently, cationic phosphinegold(I) complexes have been re-
catalyst increased the yield (70%) of cyclized products, however,
as a mixture of enol ether 2a and ketone 3.5 Surmising that the
ketone arose from hydrolysis of the enol ether with adventitious
water, addition of activated molecular sieves produced enol ether
2a in 81% yield (Table 1, entry 1).6
With optimal conditions in hand, we examined the scope of the
gold(I)-catalyzed carboalkoxylation. We were pleased to find that
the reaction proceeded in high yields with alkyl, phenyl, and ester
substituents on the alkyne (entries 2-4). As predicted by the
proposed mechanism, the presence of electron-withdrawing groups
on the phenyl rings considerably slowed the conversion of 1 to 2
(entries 5 and 7), while functionalization of the latter with electron-
donating substituents increased the rate and the yield of the reaction
(entries 6 and 8). Additionally, allylic ethers also participated in
this gold(I)-catalyzed cyclization (entries 9-11).
ported to catalyze a variety of transformations involving alkynes.
While back-bonding from gold(I) into a cationic intermediate may
be essential to some of these transformations,1 a more conventional
reaction pathway relies on the π-acidity of cationic gold(I)
complexes to induce a trans-addition of a nucleophile generating
a vinylgold intermediate (A).2 Trapping of this intermediate with
carbon-based electrophiles is challenging, as it undergoes rapid
protonation to regenerate the cationic gold(I) catalyst. We hypoth-
esized that protonation of the vinylgold intermediate might be
circumvented through intramolecular reaction with an in situ
generated electrophile. Toward this goal, we envisioned that a
benzylic cation (B), a potent electrophile, could be generated by
cyclization-induced fragmentation of a C-X bond (eq 1).3
On the basis of the requirement for a carbocation-stabilizing
substituent at the benzylic position, we reasoned that a carboxonium
ion might also be a viable intermediate in this reaction. Accordingly,
ketal 4 reacted smoothly to furnish the protected 1-indenone adduct
5 in 84% yield (eq 2).7 Moreover, the gold(I)-catalyzed reaction
was readily extended to the formation of cyclohexene 7 in 72%
yield from acyclic benzyl ether 6 (eq 3).
On the basis of this hypothesis, the reaction of gold(I) complexes
with benzyl methyl ether 1a was examined. While no reaction was
observed on treatment with neutral Ph3PAuCl, 1a was completely
consumed on exposure to 2 mol % of Ph3PAuBF4, affording a 32%
yield of a mixture of enol ether 2a and indanone 3.4 The use of a
more electrophilic gold(I) complex, (p-CF3-C6H4)3PAuBF4,2f as a
Table 1. Scope of the Gold(I)-Catalyzed Carboalkoxylation
We envisioned two potential mechanisms for these transforma-
tions both proceeding through an intermediate carbocation (eq 4).
As hypothesized in eq 1, alkyne activation followed by C-O bond
scission would generate carbocation 8 which would be trapped by
the vinylgold(I) intermediate to give the observed indene adduct.
Alternatively, typical Lewis acid activation of the benzylic ether
generates carbocation 9 and a gold(I)-alkoxide. Trapping of the
cation with the acetylene and (concerted or stepwise) addition of
the gold(I)-alkoxide to the alkyne would afford the indenyl ether.
a Isolated yields. b Conversion by 1H NMR. c With 5 mol % of catalyst,
40 °C.
A double label crossover experiment was conducted in order to
probe these mechanistic possibilities (eq 5). The lack of observed
9
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10.1021/ja064209+ CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
crossover is consistent with a mechanism involving alkyne activa-
tion rather than ionization of the benzylic ether; however, a mechan-
ism proceeding through a tight ion pair of 9 could not be excluded.
To examine this possibility, enantioenriched 1k was subjected to
the conditions of the gold(I)-catalyzed reaction.8 At 30% conversion,
1k was recovered with identical enantiomeric excess further
disfavoring a pathway that proceeds through ionization of the
methoxy group. Furthermore, we were surprised to find that indene
2k was also isolated with excellent chirality transfer.9 A number
of allylic ethers underwent the gold(I)-catalyzed rearrangement with
only modest deterioration of enantiomeric excess (eq 6).10
References
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(2) For some recent examples of addition of nucleophiles to alkynes catalyzed
by Au(I) complexes, see: (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-
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A. M. Angew. Chem., Int. Ed. 2006, 45, 1105.
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catalyzed: (a) Fu¨rstner, A.; Szillat, H. Stelzer, F. J. Am. Chem. Soc. 2000,
122, 6785. (b) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc.
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Monterio, N.; Balme, G. Synlett 1998, 746. (g) Cacchi, S.; Fabrizi, G.;
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Tetrahedron Lett. 1998, 39, 5101. (i) Cacchi, S.; Fabrizi, G.; Pace, P. J.
Org. Chem. 1998, 63, 1001. (j) Nakamura, I.; Bajracharya, G. B.;
Mizushima, Y.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 4328.
(4) Reaction of 1a with 5% PtCl2/CO3e (1 atm) at 80 °C in toluene afforded
2a in 91% yield; however, under identical conditions, a complex mixture
was formed in the reaction of 1k. For additional catalysts examined, see
Supporting Information.
Given these results, a proposed mechanism is outlined in eq 7.
Gold(I)-promoted intramolecular nucleophilic addition of the ben-
zylic ether generates cationic intermediate 10. Ionization of the C-O
proceeds through a transition state (11) that maximizes overlap of
the forming carbocation with the aromatic π-system and avoids
interaction of the benzylic substituent (R′) with the forming enol
ether. This pathway allows for the central chirality of the C-O
bond to be retained in the axial chirality of carbocation intermediate
12. Intramolecular addition of the vinylgold(I) moiety to the
carbocation, via transition state 13, transfers the axial chirality to
the C-C bond central chirality of the product indene with overall
inversion of the stereocenter.11
(5) Other solvents produced lower yields of cyclized products: toluene, 22%;
THF, 0%; acetonitrile, 21%; nitromethane, 6%.
(6) For recent metal-catalyzed synthesis of indanone derivatives, see: (a)
Marion, N.; Diez-Gonza´lez, S.; de Fre´mont, P.; Noble, A. R.; Nolan, S.
P. Angew. Chem., Int. Ed. 2006, 45, 3647. (b) Shintani, R.; Yashio, K.;
Nakamura, T.; Okamoto, K.; Shimada, T.; Hayashi, T. J. Am. Chem. Soc.
2006, 128, 2772. (c) Shintani, R.; Okamoto, K.; Hayashi, T. J. Am. Chem.
Soc. 2005, 127, 2872. (d) Yamabe, H.; Mizuno, A.; Kusama, H.; Iwasawa,
N. J. Am. Chem. Soc. 2005, 127, 3248. (e) Kuninobu, Y.; Kawat, A.;
Takai, K. J. Am. Chem. Soc. 2005, 127, 13498. (f) Kundu, K.; McCullagh,
J. V.; Morehead, A. T., Jr. J. Am. Chem. Soc. 2005, 127, 16043.
(7) (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima, Y.;
Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423. (b)
Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 9844.
(8) Enantioenriched ethers were prepared from the corresponding alcohols
prepared according to 1k and 1l: (a) Frantz, D. E.; Fa¨ssler, R.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 1806. (b) Boyall, D.; Frantz, D. E.;
Carreira, E. M. Org. Lett. 2002, 4, 2605. 1i: (c) Tomita, D.; Wada, R.;
Kanai, M. Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 4138.
(9) The absolute configuration of 2l was assigned using the mandelate ester
method on alcohol 15 (see Supporting Information).
In conclusion, we have reported a gold-catalyzed process ending
with the capture of the vinylgold intermediate by a carbon-based
electrophile.12 The gold(I)-catalyzed carboalkoxylation of alkynes
proceeds with chirality transfer, providing a rapid entry into func-
tionalized enantioenriched indenyl ethers from readily available ben-
zylic ethers.13 The resulting enol ethers are well suited for further
manipulation, as demonstrated by the diastereoselective formation
of a quaternary carbon center via a gold(I)-catalyzed carboalkoxyla-
tion/Claisen rearrangement sequence.9 Further applications and studies
on the mechanism of the gold(I)-catalyzed carboalkoxylation reac-
tion are ongoing in our laboratories and will be reported in due course.
(10) Reaction of enantioenriched ether 1c (89% ee) gave nearly racemic indenyl
ether 2c (9% ee). Similarly, almost racemic 2c was observed at 50%
conversion, while 1c was recovered without substantial racemization.
(11) A mechanism involving anti-addition of an alkyne nucleophile to an allyl
or arene-gold(I) complex (as proposed for Pd in ref 7b) would also
account for the observed overall inversion. However, this mechanism is
not consistent with the observation that, under identical conditions, styrene
16 was recovered unreacted.
Acknowledgment. We gratefully acknowledge the University of
California, Berkeley, NIHGMS (R01 GM073932-01), Merck Research
Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont, GlaxoSmith-
Kline, Eli Lilly & Co., Pfizer, AstraZeneca, Abbott, and Roche for
financial support.
(12) For alkylation of a vinylgold(I) species in a gold(I)-catalyzed carbothi-
olation of alkynes, see: Nakamura, I.; Sato, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 4473.
(13) For a review of “memory of chirality”, see: (a) Zhao, H.; Hsu, D. C.;
Carlier, P. R. Synthesis 2005, 1. For recent examples involving Au(I),
see: (b) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
5802. (c) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901.
Supporting Information Available: Catalyst screen, experimental
procedures, and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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