Bronsted acid-promoted cyclizations of siloxyalkynes with arenes and alkenes

Article abstract of DOI:10.1021/ja046586x

We have described the first Bronsted acid-mediated cyclizations of siloxyalkynes with simple arenes and alkenes to afford substituted tetralone and cyclohexenone derivatives. The most notable aspect of the carbocyclizations involving siloxyalkynes is the ability to employ a range of substrates that are not restricted to those containing electron-rich arenes and alkenes. The key mechanistic feature of the reaction is the generation of a highly reactive ketenium ion upon protonation of siloxyalkyne. We believe that the low nucleophilicty of the counteranion is crucial for enabling the formation and effective interception of this highly reactive intermediate. Copyright

Full text of DOI:10.1021/ja046586x

Published on Web 08/03/2004
Brønsted Acid-Promoted Cyclizations of Siloxyalkynes with Arenes and
Alkenes
Liming Zhang and Sergey A. Kozmin*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received June 10, 2004; E-mail: skozmin@uchicago.edu
Table 1. Effect of Lewis and Brønsted Acids on the
Carbocyclization of Siloxyalkyne 7
Catalysis of carbocyclizations of alkynes with arenes and alkenes
has emerged as an important strategy for the assembly of carbocy-
clic and heterocyclic compounds.1,2 In this communication, we re-
port the first Brønsted acid-mediated cyclizations of siloxyalkynes3,4
with simple arenes and alkenes to afford substituted tetralone and
cyclohexenone derivatives. Our approach is based on generation
of highly electrophilic ketenium ion 2 from siloxyalkyne 1, followed
by intramolecular trapping of this reactive intermediate by an appro-
priately positioned nucleophile (Scheme 1). While ketenes have
entry
catalyst (mol %)
reaction time
product
yield (%)
1
2
3
4
5
6
7
8
Hg(OTf)2(TMU)2 (10)
HfCl4 (10)
GaCl3 (10)
24 h
<2a
<2a
<2b
<2b
65c
10 min
10 min
10 min
10 min
10 min
24 h
Scheme 1
AuCl3 (10)
AgNTf2 (20)
Tf2NH (10)
AgOTf (20)
TfOH (20)
8
8
9
9
86c
15d
25d
24 h
a No reaction was observed under these conditions. b Complex product
mixture was produced. c Isolated yield of spectroscopically pure product.
1
d Yield estimated from by H NMR of the reaction mixture.
Table 2. Arene-Siloxyalkyne Carbocyclizations Catalyzed by
HNTf2
been widely exploited in organic synthesis, ketenium ions have been
rarely implicated as reactive intermediates.5 Indeed, electrophilic
attack on ketenes occurs preferentially at the â-carbon leading to
the acyl cation 5.6 Siloxyalkynes, on the other hand, represent a
unique platform for generation of ketenium ions via addition of an
appropriate electrophile at the â-carbon. The resulting highly reac-
tive ketenium ion 2 is poised for subsequent interception with a
range of nucleophiles. To our knowledge, this important and broadly
useful aspect of reactivity of siloxyalkynes has not been exploited.7
In search for an effective catalyst for carbocyclization of
siloxyalkyne 7,8 we examined various Lewis-acidic additives
depicted in Table 1. Unfortunately, a range of metal salts known
to promote alkyne carbocyclizations,1 including GaCl3, HfCl4, and
Hg(OTf)2, failed to catalyze the reaction. Prompted by our recent
success in the development of [2 + 2] cycloadditions of
siloxyalkynes,3b we examined several silver-based catalysts and
discovered that AgNTf2 (20 mol %) resulted in formation of silyl
enol ether 8 with good efficiency (entry 5). Our subsequent studies
revealed that the active catalyst of this process was the conjugate
acid produced during the rearomatization step. Indeed, subjection
of alkyne 7 to 10 mol % HNTf2 afforded enol ether 8 in 86%
isolated yield (entry 6).9 Importantly, the efficiency of the reaction
was diminished significantly using other silver salts and Brønsted
acids, highlighting the importance of the trifluoromethanesulfon-
imide anion.10
Investigation of the scope of HNTf2-catalyzed siloxyalkyne arene
cyclization revealed that a range of unactivated aromatic precursors
can efficiently participate in this process (Table 2), distinguishing
this reaction uniquely from the metal-mediated carbocyclizations
of alkynes that generally require electron-rich arenes and alkenes.1
To probe the reaction mechanism, we prepared alkyne 13 in highly
enantiomerically enriched form (entry 4, Table 2).11 Subjection of
a Refers to isolated yields of products that were fully characterized by
NMR, IR, and MS. b Reaction afforded a 75:25 ratio of para-/ortho-
substituted products.
13 to the cyclization conditions afforded enol ether 19 without any
detectable loss of enantiomeric purity. This result supports an
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10.1021/ja046586x CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
25 to HNTf2 gave the expected cyclohexenones 29 and 23 in good
yields (entries 1 and 2). Cyclizations of trisubstituted and mono-
substituted alkenes were promoted more efficiently using MsOH
(entries 3-5). We are continuing our search for a catalytic protocol
to promote the siloxy enyne cyclizations.
In closing, we have developed efficient acid-promoted carbo-
cyclizations of siloxyalkynes to give a range of substituted
tetralones and cyclohexenones. The most notable aspect of this
process is the ability to efficiently generate highly reactive ke-
tenium ions that are readily intercepted by nucleophiles that are
not restricted to those containing electron-rich arenes and allyl
silanes.
electrophilic aromatic substitution mechanism (Scheme 2). An
alternative mechanism involving a [3,3]-sigmatropic rearrangement
of intermediate A, followed by 6π-electrocyclic ring closure, would
result in formation of racemic 19. The key feature of the reaction
is generation of a highly reactive ketenium ion A upon protonation
of siloxyalkyne. We believe that the low nucleophilicity of the
Acknowledgment. We thank Randy Sweis and Michael Schramm
for their initial contributions to this investigation. S.A.K. is a fellow
of the Alfred P. Sloan Foundation. S.A.K. thanks the Dreyfus
Foundation for the Teacher-Scholar Award and Amgen, Inc., for
the New Investigator’s Award.
-
NTf2 anion is crucial for enabling the formation and effective
interception of A to give a σ-complex B, which affords the final
product with concomitant regeneration of the acid catalyst.
Encouraged by the ability of HNTf2 to promote efficient arene-
siloxyalkyne carbocyclizations, we next examined the corresponding
enyne cyclizations. Indeed, subjection of siloxy enyne 22 to HNTf2
afforded enone 23 (Scheme 3). Our systematic studies revealed that
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.
Scheme 3
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a stoichiometric amount of acid is required for efficient carbocy-
clization of 22. Under optimized conditions, cyclohexenone 23 was
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(11) For complete details, see Supporting Information.
a Method A: HNTf2 (120 mol %), CH2Cl2, 20 °C, 2 h. b Method B:
MsOH (4 equiv), CH2Cl2, 20 °C, 2 h. c Yield was determined by 1H NMR
using 1,2-dibromobenzene as an internal standard.
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