Gold(I)-catalyzed propargyl claisen rearrangement

Article abstract of DOI:10.1021/ja044602k

Homoallenic alcohols are prepared from propargyl vinyl ethers using a trinuclear gold(I)-oxo complex, [(Ph₃PAu)₃O]BF₄, as a catalyst for propargyl Claisen rearrangement at room temperature. The gold(I)-catalyzed reaction is effective for a diverse collection of propargyl vinyl ethers, including substrates containing aryl and alkyl groups at the propargylic position, and hydrogen, aryl, and alkyl substituents at the alkyne terminus. Tertiary propargyl vinyl ethers can be employed in the reaction, at slightly elevated temperatures, to afford tetrasubstituted allenes. Importantly, the rearrangement of 1,2-disubstituted vinyl ethers proceeds with excellent diastereoselectivity, and the rearrangement of chiral nonracemic propargyl vinyl ethers proceeds with excellent chirality transfer to furnish enantioenriched allenes. Copyright

Full text of DOI:10.1021/ja044602k

Published on Web 11/18/2004
Gold(I)-Catalyzed Propargyl Claisen Rearrangement
Benjamin D. Sherry and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
Received September 6, 2004; E-mail: fdtoste@uclink.berkeley.edu
The [3,3]-sigmatropic rearrangement of allyl vinyl ethers1 is an
Table 1. Au(I)-Catalyzed Propargyl Claisen Rearrangement
indispensable tool in organic synthesis, and catalysis of this reaction
has further strengthened its impact.2 In general, Lewis acid catalysis
of the Claisen rearrangement can be divided into two classes: hard
Lewis acids, which catalyze the reaction by coordination to the
oxygen atom,3 and soft Lewis acids, in particular those based on
Hg(II) and Pd(II), which catalyze the reaction through coordination
to the π-bonds.4 The latter mode of catalysis is often limited by
binding of the electrophilic metal to the strongly nucleophilic vinyl
ether, thus preventing activation of the allylic olefin. Recent reports
of Au(I)-catalyzed additions to alkynes,5 suggest that this limitation
might be absent in a Au(I)-catalyzed acetylenic Claisen rearrange-
ment.6 Importantly, a general catalytic version of the Claisen
rearrangement of propargyl vinyl ethers has yet to be developed.7
In light of our previous success employing Ph3PAuOTf for
carbon-carbon bond formation,5a we chose this catalyst system in
preliminary studies of the acetylenic Claisen rearrangement. While
Ph3PAuOTf did afford the desired allene 2,8 a substantial amount
of the product derived from competing [1,3]-rearrangement was
also formed (eq 1). Interestingly, changing the counterion from
triflate to tetrafluoroborate addressed the problems of regiocontrol;
however, the use of Ph3PAuBF4 as a catalyst provided almost
racemic homoallenic alcohol 2 from enantioenriched propargyl vinyl
ether 1.9 Our interest in catalysis with metal-oxo complexes10 led
us to consider the gold-oxo complex, [(Ph3PAu)3O]BF4,11 as an
alternative means by which to access electrophilic Au(I) species.12
In the event, treatment of enantioenriched propargyl vinyl ether 1
with 1 mol % [(Ph3PAu)3O]BF4 afforded homoallenic alcohol 2 in
91% yield and with nearly complete chirality transfer.
a Isolated yield after column chromatography. b Run with 0.1 mol %
[(Ph3PAu)3O]BF4. c Run at 75 °C in 1,2-dichloroethane.
Scheme 1. Proposed Mechanism for the Au(I)-Catalyzed
Rearrangement
ability to perform a number of reactions with as little as 0.1 mol %
[(Ph3PAu)3O]BF4 (entries 6-8 and 11).
Our preliminary experiments directed toward catalyst optimiza-
tion revealed that [(Ph3PAu)3O]BF4 was uniquely effective at
transferring central chirality of the starting carbinol to axial chirality
in the allene product (eq 1). We have found that this reaction is
applicable to a variety of substrates providing access to enantio-
merically enriched homoallenic alcohols13 (eq 2). For example, Au-
(I)-catalyzed reaction of silylacetylene (R)-4n proceeds with
complete chirality transfer to provide allenylsilane14 (S)-5n in 98%
yield after reduction of the intermediate aldehyde.
With optimized reaction conditions in hand, we set out to define
the scope of the catalytic acetylenic Claisen rearrangement. The
Au(I)-catalyzed reaction is effective for a diverse collection of
propargyl vinyl ethers (Table 1). Specifically, substrates containing
electron-rich and electron-deficient aryl groups at the propargylic
position afforded good to excellent yields of the desired homoallenic
alcohols (entries 1-6). A range of alkyl groups can also be
incorporated at the propargylic position, including linear and
branched aliphatic moieties (entries 7-11). Substitution at the
alkyne terminus is equally tolerated, spanning hydrogen (entry 1),
aryl (entries 7 and 8), and alkyl substituents (entries 2-6 and 9-13).
Importantly, the reaction is tolerant of commonly employed
protecting groups, such as silyl ethers (entries 2 and 9) and pivolate
ester (entry 3). Furthermore, tertiary propargyl vinyl ethers can be
employed in the reaction, at slightly elevated temperatures, to afford
tetrasubstituted allenes in good to excellent yield (entries 12 and
13). Notably, the efficiency of the reaction is illustrated by the
Employing â-substituted vinyl ethers in the Claisen rearrange-
ment affords synthetically useful R-substituted carbonyl products.15
To probe the diastereoselectivity of the acetylenic Claisen rear-
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10.1021/ja044602k CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
(3) (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981,
22, 3985. (b) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J.
Am. Chem. Soc. 1990, 112, 316. (c) Trost, B. M.; Schroeder, G. M. J.
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(b) Sugiura, M.; Yanagisawa, M.; Nakai, T. Synlett 1995, 447. For a
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(5) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526. (b) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.;
Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed.
2004, 43, 2402. (c) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J.
Am. Chem. Soc. 2004, 126, 8654. (d) Luzung, M. R.; Markham, J. P.;
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Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350.
(f) See also a Au(III)-catalyzed intramolecular cyclization of enol ethers
and alkynes: Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.s
Eur. J. 2003, 9, 2627. (g) For an excellent review of homogeneous gold-
catalyzed reactions, see: Hashmi, A. S. K. Gold Bull. 2004, 37, 51.
(6) (a) Black, D. K.; Landor, S. R. J. Chem. Soc. 1965, 6784. (b) Saucy, G.;
Marbet, R. HelV. Chim. Acta 1967, 50, 1158. (c) Saucy, G.; Cohen, N.;
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J. W.; Kilingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem. 1997,
62, 603.
rangement, (E)-enol ether 6 was subjected to the Au(I)-catalyzed
and thermal conditions. The catalytic reaction proceeds smoothly
at 40 °C to afford a single diastereomer of 7, while the thermal
reaction required heating to 170 °C and produced a 1:1.5 mixture
of diastereomers in favor of the opposite diastereomer (eq 3).16
Additionally, allene 9 can be prepared enantio- and diastereose-
lectively from the rearrangement of vinyl ether 8 (eq 4).
A mechanistic hypothesis based on a cyclization-induced rear-
rangement4c catalyzed by Au(I) is shown in Scheme 1. A 6-endo-
dig addition of the enol ether onto gold(I)-alkyne complex 10 re-
sults in the formation of intermediate 11. The diastereoselectivity
of the rearrangement can be accounted for by considering the half-
chair transition state17 leading to 11. The vinyl substituent (R′) oc-
cupies a pseudoequatorial position, and the propargylic group (R)
adopts a pseudoaxial orientation in order to avoid A1,2-strain with
the vinyl gold substituent. Grob-type fragmentation of 11 affords
the â-allenic aldehyde and regenerates the cationic Au(I) catalyst.
In accord with a mechanism involving alkyne activation, the
Au(I)-catalyzed reaction of vinyl ether 12 shows a high degree of
selectivity for the acetylenic Claisen over the allylic Claisen pathway
(eq 5). This is in sharp contrast to reported hard Lewis acid-
catalyzed3b and thermal rearrangements18 that are selective for the
allyl vinyl rearrangement.
(8) Attempts to isolate the aldehyde met with substantial decomposition;
therefore, intermediate aldehydes were reduced in situ to allow for product
purification.
(9) We found that the poor chirality transfer is most likely a result of rapid
(5 min) racemization of the allene catalyzed by Ph3PAuBF4. On the other
hand, even after 1 h, a substantial amount of the allene’s enantiomeric
excess is retained in the presence of [(Ph3PAu)3O]BF4.
(10) (a) Kennedy-Smith, J. J.; Nolin, K. A.; Gunterman, H. P.; Toste, F. D. J.
Am. Chem. Soc. 2003, 125, 4056. (b) Sherry, B. D.; Radosevich, A. T.;
Toste, F. D. J. Am. Chem. Soc. 2003, 125, 6076. (c) Luzung, M. R.; Toste,
F. D. J. Am. Chem. Soc. 2003, 125, 15760. (d) Sherry, B. D.; Loy, R. N.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4510.
(11) (a) Yang, Y.; Ramamoorthy, V.; Sharp, P. R. Inorg. Chem. 1993, 32,
1946. (b) Nesmeyanov, A. N.; Perevalova, E. G.; Struchkov, Y. T.;
Antipin, M. Y.; Grandberg, K. I.; Dyadchenko, V. P. J. Organomet. Chem.
1980, 201, 343. (c) For a review of late transition metal-oxo complexes,
see: Sharp, P. R. J. Chem. Soc., Dalton Trans. 2000, 2647.
(12) The nature of the catalytically active Au(I) species is not known at this
time. Both (Ph3P)2AuBF4 and Ph3PAuCH2CHO are generated under the
reaction conditions and were prepared independently. The former catalyzes
the reaction at a much slower rate than does [(Ph3PAu)3O]BF4, and the
latter is not a competent catalyst.
In conclusion, we have developed an air- and moisture-tolerant
Au(I) catalyst for the acetylenic Claisen rearrangement. The gold-
catalyzed reaction provides access to a variety of homoallenic
alcohols, which can be prepared enantioenriched when employing
a nonracemic propargyl vinyl ether. The reaction is highly stereo-
selective and proceeds under mild conditions with low catalyst
loading. Efforts aimed at utilizing Au(I) complexes as catalysts for
other rearrangements and understanding the unique role of the
trinuclear gold catalyst are ongoing in our laboratories.
(13) The allene absolute stereochemistry was assigned by comparison of the
optical rotation of 15: Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000,
122, 10470.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, and Merck Research Laboratories for
financial support. B.D.S. thanks Eli Lilly & Co. for a graduate
fellowship. The Center for New Directions in Organic Synthesis is
supported by Bristol-Myers Squibb as a Sponsoring Member, and
(14) For a review on the reactions of allenylsilanes, see: Masse, C. E.; Panek,
J. S. Chem. ReV. 1995, 95, 1293.
(15) (a) Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736.
(b) Frederick, M. O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J. A.; Tracey,
M. R. Org. Lett. 2003, 5, 2663.
Novartis Pharma as a Supporting Member.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) The relative stereochemistry was determined by nOe measurements (see
Supporting Information) on pyran 16, obtained from the silver-catalyzed13
cyclization of 7.
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