Gold-catalyzed cycloisomerization of siloxy enynes to cyclohexadienes

Article abstract of DOI:10.1021/ja046112y

We have described the first Au-catalyzed cycloisomerization of 1-siloxy-5-en-1-ynes. The reaction is efficiently catalyzed by AuCl (1 mol %) to afford siloxy cyclohexadienes, which can be readily converted to the corresponding 1,2- and 1,3-cyclohexenones. The catalytic process displays a broad substrate scope and exceedingly mild reaction conditions (30 min, 20 °C). The presence of a siloxy alkyne moiety is crucial for enabling the skeletal reorganization process, which is postulated to proceed via a novel reaction mechanism involving a cascade of 1,2-alkyl migrations. Copyright

Full text of DOI:10.1021/ja046112y

Published on Web 09/03/2004
Gold-Catalyzed Cycloisomerization of Siloxy Enynes to Cyclohexadienes
Liming Zhang and Sergey A. Kozmin*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received June 30, 2004; E-mail: skozmin@uchicago.edu
Table 1. Gold-Catalyzed Cycloisomerization of Siloxy Enynes
Metal-catalyzed enyne cycloisomerizations provide rapid and
efficient access to a variety of cyclic structural motifs for a range
of synthetic applications.1 Particularly noteworthy are the latest
advances in platinum(II)2 and gold(I)3 catalysis of these transforma-
tions. In this communication, we describe our discovery and
subsequent investigation of the first Au-catalyzed skeletal reorga-
nization of 1-siloxy-5-en-1-ynes to furnish highly substituted siloxy
cyclohexadienes. Furthermore, we demonstrate that the presence
of a siloxy alkyne moiety is crucial for enabling the skeletal
reorganization process, which proceeds via a novel reaction
mechanism involving a series of alkyl migrations.
In the course of our investigation of basic reactivity of siloxy
alkynes,4 we found that treatment of siloxy enyne 1 with a catalytic
amount of AuCl resulted in efficient formation of a new product
that was identified as siloxy cyclohexadiene 2 (Scheme 1). Structural
Scheme 1
assignment of 2 was based on a series of NMR studies, including
COSY, NOESY, HMQC, and HMBC experiments. The remarkable
catalytic efficiency of this process is highlighted by the fact that
the reaction proceeded to completion within 20 min at room
temperature using only 1 mol % AuCl. While addition of phosphine
resulted in inhibition of catalytic activity, the efficiency can be
recovered using Au(PPh3)Cl in the presence of AgBF4, presumably
due to the generation of a cationic gold complex.3 In the absence
of Au(I), neither AgBF4 nor AgOTf promoted formation of 2. The
cycloisomerization can be catalyzed by PtCl2 (10 mol %); the
reaction, however, requires to be conducted at 80 °C and proceeds
with lower efficiency (66% yield). These studies revealed that AuCl
proved to be the most effective catalyst for the cycloisomerization
of siloxy enyne 1.
Our investigation of the scope of the Au-catalyzed skeletal
reorganization of siloxy enynes is summarized in Table 1. Subjec-
tion of the 3-aryl-substituted enyne 3 to the general cycloisomer-
ization protocol afforded the expected diene 4 in 73% yield (entry
1). The 5-trimethylsilylmethyl group was retained in the cyclization
product 6 despite the labile nature of this material (entry 2). 4-Alkyl
substitution of enyne 7 was well tolerated (entry 3). Cycloisomer-
izations of 5-phenyl-substituted enyne 9 afforded a 4:1 mixture of
nonconjugated and conjugated cyclohexadienes (entry 4).
A similar outcome (3:1 ratio of dienes, entry 5) was observed in
the cycloisomerization of enyne 11 containing a trisubstituted alkene
moiety. To explore the possibility of exclusive formation of
conjugated cyclohexadienes, we prepared enynes 13, 15, and 17
containing quaternary stereogenic centers at the 3-position. To our
delight, subjection of enynes 13 and 15 to the general cycloisomer-
ization conditions afforded conjugated diens 14 and 16 in 88 and
a General reaction protocol: Siloxy enyne (0.2 mmol) was dissolved in
CH2Cl2 (4 mL) and treated with AuCl (0.002 mmol). The resulting solution
was stirred at 20 °C for 30 min. After treatment of the reaction mixture
with a drop of Et3N, the solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography on silica gel.
b Refers to isolated yields of spectroscopically pure products that were fully
characterized by NMR, IR and MS. c Ratio of 1,4- to 1,3-cyclohexadienes
) 6:1. d Ratio of 1,4- to 1,3-cyclohexadienes ) 4:1. e Ratio of 1,4- to 1,3-
cyclohexadienes ) 3:1.
89% yields, respectively (entries 6 and 7). Finally, cycloisomer-
ization of dienyne 17 proceeded with complete chemoselectivity
to afford 18 as a single reaction product (entry 8). Additional studies
revealed that while both di- and trisubstituted alkenes efficiently
9
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J. AM. CHEM. SOC. 2004, 126, 11806-11807
10.1021/ja046112y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Scheme 4
in regeneration of the active catalyst and formation of two isomeric
diene products I and J. To further probe the effect of 1-siloxy
substitution, we subjected enyne 21 (Scheme 4) to the standard
cyclization protocol. The reaction produced cyclopropane 22 as a
single product, highlighting the crucial role of the siloxy alkyne
moiety in the outcome of the enyne cycloisomerization, presumably
due to the stabilization of cationic intermediate E.
In summary, we have developed a highly efficient Au-catalyzed
cycloisomerization of siloxy enynes that features low catalyst
loading and exceedingly mild reaction conditions. This new catalytic
process provides rapid access to highly substituted siloxy cyclo-
hexadienes and the corresponding 1,2- and 1,3-cyclohexenones.
Importantly, the siloxy alkyne moiety is uniquely responsible for a
novel reaction mechanism of the cycloisomerization, which is
proposed to involve a cascade of 1,2-alkyl shifts.
participated in the cycloisomerization process, terminal monosub-
stituted alkenes proved to be unreactive during the current catalytic
protocol.
Siloxy cyclohexadiene products of the cycloisomerizations can
be efficiently converted to 1,2- and 1,3-cyclohexenones, highlighting
the general synthetic utility of this process. Protodesilylation of
silyl enol ether 6 afforded nonconjugated enone 19 (Scheme 2).
Subjection of siloxy diene 14 to the same protocol afforded
conjugated enone 20.
Scheme 3
Acknowledgment. We thank Randy Sweis for preparation and
cycloisomerization of enyne 21. S.A.K thanks the Dreyfus Founda-
tion for a Teacher-Scholar Award and Amgen, Inc., for a New
Investigator’s Award. S.A.K. is a fellow of the Alfred P. Sloan
Foundation.
Supporting Information Available: Full characterization of new
compounds and selected experimental procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For selected reviews, see: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813. (b) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M.
Chem. Eur. J. 2003, 9, 2627. (c) Me´ndez, M.; Mamane, V.; Fu¨rstner, A.
Chemtracs: Org. Chem. 2003, 16, 397.
(2) (a) Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567.
(b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics
1996, 15, 901. (c) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.;
Seki, Y. J. Am. Chem. Soc. 1998, 120, 9104. (d) Fu¨rstner, A.; Szillat, H.;
Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305. (e) Fu¨rtsner,
A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785. (f) Trost,
B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801. (g) Fu¨rstner,
A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2001, 123, 11863. (h) Me´ndez,
M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J.
Am. Chem. Soc. 2001, 123, 10511. (i) Mainetti, E.; Mouries, V.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. Angew. Chem., Int.
Ed. 2002, 41, 2132. (j) Martin-Matute, B.; Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2003, 125, 5757. (k) Cadran, N.;
Cariou, K.; Herve, G.; Aubert, C.; Fensterbank, L.; Malacria, M.; Marco-
Contelles, J. J. Am. Chem. Soc. 2004, 126, 3408. (l) Harrak, Y.;
Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mouries, V.;
Dhimane, A. L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,
126, 8656. Also see ref 3b.
(3) (a) 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. (b)
Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004,
126, 8654.
(4) For our previous studies on reactivity and applications of siloxy alkynes,
see: (a) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem.,
Int. Ed. 2001, 40, 4274. (b) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A.
J. Am. Chem. Soc. 2004, 126, 7442. (c) Reddy, D. S.; Kozmin, S. A. J.
Org. Chem. 2004, 69, 4860. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 10204-10205.
(5) Structure C is used to illustrate the movement of electron density during
the conversion of Au-alkyne complex B to carbene D, which may proceed
directly as previously suggested in ref 3a.
Formation of the cyclohexadiene products can be rationalized
using the mechanistic analysis presented in Scheme 3. Coordination
of the π-acidic AuCl with siloxy alkyne A, followed by intramo-
lecular attack by the proximate alkene (structure B), promotes
cyclization to give cyclopropyl gold carbene D.5 Formation of
similar intermediates has been postulated in the reported Pt- and
Au-catalyzed cycloisomerizations of enynes to give [3,1,0] and
[4,1,0] bicyclic structures.2,3 The presence of the siloxy moiety,
however, dramatically alters the subsequent mechanistic scenario.
We propose that the formation of the observed cyclohexadiene
products can be explained by the subsequent 1,2-alkyl shift to give
oxocarbenium ion E, which undergoes another 1,2-shift, followed
by fragmentation of the intermediate F. Depending on the nature
of the R2 substituent at the 3-position of the enyne, the subsequent
intermediate gold carbenoid can undergo two alternative 1,2-hydride
shifts (structures G and H). Subsequent elimination of AuCl results
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