A Catalytic Intermolecular Formal Ene Reaction between Ketone-Derived Silyl Enol Ethers and Alkynes

Article abstract of DOI:10.1021/jacs.6b06847

A catalytic formal ene reaction between ketone-derived silyl enol ethers and terminal alkynes is described. This transformation is uniquely capable of bimolecular assembly of 2-siloxy-1,4-dienes and can be used to access β,?-unsaturated ketones containing quaternary carbons in the α-position.

Full text of DOI:10.1021/jacs.6b06847

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Communication
A Catalytic Intermolecular Formal Ene Reaction
Between Ketone-Derived Silyl Enol Ethers and Alkynes
Stephen D. Holmbo, Nicole A. Godfrey, Joshua J Hirner, and Sergey V. Pronin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2016
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A Catalytic Intermolecular Formal Ene Reaction Between Ketone-
Derived Silyl Enol Ethers and Alkynes
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Stephen D. Holmbo,‡ Nicole A. Godfrey,‡ Joshua J. Hirner,† and Sergey V. Pronin*
Department of Chemistry, University of California, Irvine, California 92697ꢀ2025, United States
Supporting Information Placeholder
the idea of performing intermolecular alkenylations in a
catalytic fashion with retention of the silyl enol ether
functionality in the product.14 Electrophilic activation of
alkynes toward nucleophilic attack by silyl enol ethers
has found extensive application in αꢀalkenylation of
ketones. In his pioneering work, Conia described the
ABSTRACT: A catalytic formal ene reaction between
ketoneꢀderived silyl enol ethers and terminal alkynes is
described. This transformation is uniquely capable of
bimolecular assembly of 2ꢀsiloxyꢀ1,4ꢀdienes and can be
used to access β,γꢀunsaturated ketones containing quaꢀ
ternary carbons in the αꢀposition.
first, to our knowledge, examples of such reactivity.15
A
number of reports of related Al(III)ꢀmediated16 and tranꢀ
sition metalꢀcatalyzed17ꢀ22 intramolecular alkenylations
of ketoneꢀderived enoxysilanes had followed in subseꢀ
quent years, including some asymmetric variants.23
However, relevant intermolecular alkenylations of silyl
enol ethers find very little precedent13,24,25 and the only
available catalytic intermolecular process requires use of
1,3ꢀdicarbonyls as activated precursors26 (Scheme 1). In
Intermolecular alkenylation of enolates or their surroꢀ
gates offers direct and convenient access to β,γꢀ
unsaturated ketones, versatile building blocks that conꢀ
tain two orthogonal functionalization sites. Over 30
years ago, Migita reported pioneering examples of such
sp2ꢀsp3 coupling processes, which relied on Pd(0)ꢀ
catalyzed alkenylation of in situ generated triꢀnꢀbutyltin
enolates with substituted vinyl bromides.1 Subsequent
works from other laboratories further demonstrated the
power of Pd(0)ꢀ and Ni(0)ꢀcatalyzed alkenylations in the
synthesis of β,γꢀunsaturated ketones,2ꢀ8 although these
reactions are typically limited to arylꢀalkyl or alkenylꢀ
alkyl ketones. Intermolecular alkenylations of dialkyl
ketones bearing two unactivated enolizable positions are
much less represented.9,10 In this context, selective forꢀ
mation of quaternary centers poses a particular chalꢀ
lenge, and only isolated examples can be found in the
literature.7,11 It is noteworthy that analogous intramolecꢀ
ular alkenylations are much more common and have
found a number of applications in synthesis, likely owꢀ
ing to high levels of regiocontrol enforced by kinetic
selectivity during cyclization.12 Here we demonstrate a
new catalytic formal ene reaction between silyl enol
ethers and terminal alkynes that is uniquely capable of
bimolecular assembly of 2ꢀsiloxyꢀ1,4ꢀdienes and can be
used to access β,γꢀunsaturated ketones containing quaꢀ
ternary carbons in the αꢀposition.
Scheme 1. Comparison of relevant intermolecular
alkenylations with current work
the latter example, facile enolization of the substrates
enables the eneꢀlike reaction with alkynes. A similar
process between ketoneꢀderived silyl enol ethers and
alkynes is considerably more challenging as it requires a
net proton transfer from the allylic position of the
enoxysilane to the former alkyne fragment that has never
been observed in a bimolecular setting.27 Furthermore,
the propensity of silyl enol ethers derived from unsymꢀ
During our work on the synthesis of paxilline indole
diterpenes, we identified an indium(III) bromideꢀ
mediated alkenylation of a silyl enol ether with a termiꢀ
nal alkyne as suitable means for assembly of the requiꢀ
site β,γꢀunsaturated ketone.13 We became intrigued by
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metrical dialkyl ketones to isomerize under acidic condiꢀ were less efficient (entries 6 and 7). Catalytic alkenylaꢀ
tions28,29 poses a potential issue of site selectivity. Finalꢀ
ly, the product of the alkenylation, a 2ꢀsiloxyꢀ1,4ꢀdiene,
would itself represent a substrate for the reaction, posing
an inherent issue of chemoselectivity. In particular, apꢀ
plication of such a reaction to selective construction of
quaternary centers would require preferential alkenylaꢀ
tion of fully substituted enoxysilane starting materials in
the presence of less substituted enoxysilane products.
tion in the presence of indium(III) bromide could be
performed at temperatures as low as 50 °C, which deꢀ
creased the content of allene 4 and regioisomer 5 (entry
8). Attempted alkenylation in the presence of catalytic
amounts of hydrogen bromide (generated in situ, entry
9) as well as triflic acid (entry 10) did not lead to prodꢀ
uct formation, confirming the catalytic role of the metal
derivative. The robust TIPSꢀenol ethers31 performed betꢀ
ter than more labile TMSꢀ and TBSꢀderivatives. Interestꢀ
ingly, attempted alkenylation of isomeric silyl enol ether
6 afforded siloxydiene 2 as a major product, suggesting
isomerization of 6 to 1 under the reaction conditions.
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With these considerations in mind, we set out to invesꢀ
tigate the catalytic formal ene reaction between silyl
enol ether 1 and 1ꢀoctyne (Table 1, see Supporting Inforꢀ
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Table 1. Development of the catalytic formal ene reaction
It is important to note that the product of double
alkenylation was not observed during these studies.
Alkenylation of the fully substituted enoxysilane 1 must
therefore proceed considerably faster under our condiꢀ
tions than alkenylation of product 2. Although speculaꢀ
tively, we attribute the observed selectivity to the differꢀ
ence in the conformational preferences of the bulky siꢀ
loxy group.32 To demonstrate the application of such
unusual selectivity, the synthesis of diketone 9 was unꢀ
dertaken (Scheme 2). Starting diketone 8 contains three
Scheme 2. Synthesis of diketone 9
reactive αꢀpositions, C1, C8 and C10, and selective
alkenylation at C8 represents a considerable challenge.
To our delight, subjection of the bisꢀsilyl enol ether deꢀ
rived from diketone 8 to our alkenylation conditions
resulted in selective reaction of the fully substituted siꢀ
loxyalkene fragment, delivering monoalkenylated prodꢀ
uct 9 after mild hydrolytic workꢀup.
a0.25ꢀ0.5 mmol of 1, 1.5 equiv. of alkyne, 0.25ꢀ0.5 mL
b
With a functional set of conditions in hand, we invesꢀ
tigated the preliminary scope of this catalytic formal ene
reaction. We found that alkyl acetylenes with aromatic,
halide, and ether functionalities as well as conjugated
alkynes successfully participate in the alkenylation proꢀ
cess (dienes 10ꢀ14 in Table 2, next page). The reaction
also tolerated a Lewis basic ester group (diene 15), altꢀ
hough more forcing conditions were required in this
case.33 Trimethylsilylacetylene and internal alkynes did
not participate in the alkenylation. The formal ene reacꢀ
tion was effective at forming quaternary centers containꢀ
ing four nonꢀmethyl substituents (dienes 16 and 17) and
various substitution patterns of the cyclopentene ring
were tolerated (dienes 18ꢀ21). Synthesis of dienes 19ꢀ21
demonstrates a convenient approach to diastereoselecꢀ
tive vicinal difunctionalization of a simple alkenone34
and can be useful in the context of natural product synꢀ
thesis.13 Cyclohexanoneꢀderived silyl enol ethers also
underwent successful alkenylation and corresponding
of (CH2Cl)2, 20ꢀ28 h. Based on internal standard and deꢀ
termined by 1H NMR. cd. r. 1:1. d65% isolated yield of 2.
mation for additional details). Gold(I) complexes19
proved to be poor catalysts for the desired transforꢀ
mation with the bestꢀperforming combination of a NHCꢀ
derived precatalyst and a halideꢀscavenging additive
providing only small amounts of diene 2 and the hydroꢀ
lyzed product 3 (entry 1). Application of zinc(II) broꢀ
mide22 was unsuccessful (entry 2). Conditions similar to
those previously employed by Nakamura26 afforded only
traces of enoxysilane 2 (entry 3). However, changing the
counteranion in the indium(III)ꢀbased catalyst produced
instructive trends. While chloride (entry 4) offered only
marginal improvement over triflate, bromide (entry 5)
allowed for the efficient alkenylation of substrate 1 and
only small amounts of ketone 3, allene 4,30 and regioiꢀ
somer 5 were observed. Application of indium(III) ioꢀ
dide and introduction of halideꢀscavenging additives
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Table 2. Preliminary substrate scope of the alkenylationa
We propose that the mechanism of this catalytic forꢀ
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mal ene reaction involves initial nucleophilic attack of
enoxysilane 1 on alkyneꢀindium(III) bromide complex36
to form alkenylindium 31 (or the corresponding divinylꢀ
indium derivative; Scheme 3).37 The formation and steꢀ
Scheme 3. Proposed mechanism of the alkenylation
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reochemistry of intermediate 31 or related species is
supported by observation of deuterated ketone 34 upon
treatment of the reaction mixture with CD3OD.34 Similar
alkenylindium derivatives have been previously isolated
and characterized by Baba.24 Intermediate 31 can underꢀ
go protodemetallation with indium(III) bromideꢀketone
complex 32 to produce ketone 3 and enolate 33, respecꢀ
tively.26,38 Participation of ketone 3, which is formed
early and whose concentration remains constant during
the reaction,39 is supported by the observation that an
additive of ketone 35 undergoes silylation in situ to form
enoxysilane 36.34 Subsequent silylation of enolate 33 is
expected to afford the desired siloxydiene 2.
aTypically, starting silyl enol ethers were mixtures of
isomers, see Supporting Information for details. 1 equiv. of
silyl enol ether, 1.5 equiv. of alkyne, 10 mol% of InBr3,
(CH2Cl)2 (1 M in enoxysilane), 65 °C, ca. 24 h; r. r. ≥10:1
(except 15: r. r. 9:1; 24: r. r. 7:1). Siloxydienes (except 13ꢀ
14 and 24) contained ca. 5 mol% of inseparable allenes.
In summary, we disclose a new catalytic intermolecuꢀ
lar ene reaction between ketoneꢀderived silyl enol ethers
and terminal alkynes. Among the features of this
alkenylation are selective formation of highly sterically
encumbered quaternary centers and direct access to 2ꢀ
siloxyꢀ1,4ꢀdienes and corresponding β,γꢀunsaturated
ketones with synthetically challenging substitution patꢀ
terns. The reaction has its limitations and future work
will focus on expanding the substrate scope and further
improving the efficiency of the process. However, this
transformation has no alternatives among the current
methods and can be expected to find broad application
in natural product synthesis.
c
d
bHeated to 50 °C. Heated to 80 °C. 5 mol% of InBr3.
eNeat. f5 M in silyl enol ether. gHeated for ca. 72 h. hHeated
for ca. 48 h. iAfter hydrolysis.
ketones 22 and 23 could be readily isolated after mild
hydrolytic workꢀup.35 Furthermore, acyclic silyl enol
ethers were suitable substrates for this formal ene reacꢀ
tion (e.g., see diene 24). Because the resulting 2ꢀsiloxyꢀ
1,4ꢀdienes often proved hydrolytically unstable relative
to their cyclic counterparts, the reaction mixtures were
subjected to mild hydrolytic workꢀup, delivering the
corresponding β,γꢀunsaturated ketones (products 25ꢀ30).
In almost all cases, the desired 1,1ꢀdisubstituted alkenes
were produced in a highly regioselective manner and
only small quantities of corresponding 1,2ꢀdisubstituted
isomers were observed.
ASSOCIATED CONTENT
Detailed experimental procedures and characterization data
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
spronin@uci.edu
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(14) The utility of silyl enol ethers in modification of correspondꢀ
ing ketones has been appreciated for a long time: Brownbridge, P.
Synthesis 1983, 1ꢀ28.
Present Addresses
1
†Honeywell UOP, Des Plaines, IL 60016, United States.
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9
(15) (a) Drouin, J.; Boaventura, M.ꢀA.; Conia, J.ꢀM. J. Am. Chem.
Soc. 1985, 107, 1726ꢀ1729. Also see: (b) Drouin, J.; Boaventura, M.
A. Tetrahedron Lett. 1987, 28, 3923ꢀ3926. For application in syntheꢀ
sis see: (c) Forsyth, C. J.; Clardy, J. J. Am. Chem. Soc. 1990, 112,
3497ꢀ3505; (d) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60,
2773ꢀ2779; (e) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60,
5746ꢀ5747.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(16) Imamura, K.; Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4081ꢀ4084.
Funding from the School of Physical Sciences at the
University of California Irvine, Chao Family Comprehenꢀ
sive Cancer Center, and the National Science Foundation
(DGEꢀ1321846; to N.A.G.) is gratefully acknowledged. We
thank Professors Larry Overman, Chris Vanderwal, and
Suzanne Blum for providing access to their instrumentation
and helpful discussions.
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(27) For intramolecular examples see references 17c, 17d, and 18.
(28) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462ꢀ
4464.
(29) Formation of trace quantities of strong Brønsted acids can be
associated with processes catalyzed by metal salts: Wabnitz, T. C.;
Yu, J.ꢀQ.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484ꢀ493.
(30) Formation of 4 likely involves a regioisomeric carbometallaꢀ
tion of alkyne followed by an intramolecular hydride migration. For
relevant observations see: Harrak, Y.; Simonneau, A.; Malacria, M.;
Gandon, V.; Fensterbank, L. Chem. Commun. 2010, 46, 865ꢀ867.
(31) TIPSꢀenol ether precursors are readily available from correꢀ
sponding ketones. See Supporting Information for preparation.
(32) Such selectivity for fully substituted silyl enol ethers is not exꢀ
clusive. See Supporting Information for a detailed discussion.
(33) Application to aldehydeꢀ, ketoneꢀ, nitrileꢀ, and amideꢀ
containing alkynes was unsuccessful thus far.
(13) George, D. T.; Kuenstner, E. J.; Pronin, S. V. J. Am. Chem.
Soc. 2015, 137, 15410ꢀ15413.
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(34) See Supporting Information for details.
(35) Attempted purification of corresponding siloxydienes was unꢀ
successful.
(38) Indium(III) bromideꢀketone complex 32 can be expected to be
a strong Brønsted acid: Ren, J.; Cramer, C. J.; Squires, R. R. J. Am.
Chem. Soc. 1999, 121, 2633ꢀ2634.
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(36) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2014, 136,
10918ꢀ10920.
(37) For a review of organoindium compounds see: Shen, Z.ꢀL.;
Wang, S.ꢀY.; Chok, Y.ꢀK.; Xu, Y.ꢀH.; Loh, T.ꢀP. Chem. Rev. 2013,
113, 271ꢀ401.
(39) Protodemetallation of intermediate 10 or related species with
alkyneꢀindium(III) bromide complex can be responsible for initial
generation of ketone 3, which cannot be accounted for by the presꢀ
ence of residual TIPSOH or adventitious moisture.
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