Michael additions of highly basic enolates to ortho -quinone methides

Article abstract of DOI:10.1021/acs.orglett.5b00972

A protocol by which ketone or ester enolates and ortho-quinone methides (o-QMs) are generated in situ in a single reaction flask from silylated precursors under the action of anhydrous fluoride is reported. The reaction partners are joined to give a variety of β-(2-hydroxyphenyl)-carbonyl compounds in 32-94% yield in a single laboratory operation. The intermediacy of o-QMs is supported by control experiments utilizing enolate precursors and conventional alkyl halides as competitive alkylating agents and the isolation of 1,5-dicarbonyl products resulting from conjugate additions that do not restore the aromatic system.

Full text of DOI:10.1021/acs.orglett.5b00972

Letter
pubs.acs.org/OrgLett
Michael Additions of Highly Basic Enolates to ortho-Quinone
Methides
Robert S. Lewis,† Christopher J. Garza,† Ann T. Dang,† Te Kie A. Pedro,† and William J. Chain*,†,‡
†Department of Chemistry, University of Hawaii at Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 96822, United States
‡The University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, United States
S
* Supporting Information
ABSTRACT: A protocol by which ketone or ester enolates
and ortho-quinone methides (o-QMs) are generated in situ in a
single reaction flask from silylated precursors under the action
of anhydrous fluoride is reported. The reaction partners are
joined to give a variety of β-(2-hydroxyphenyl)-carbonyl
compounds in 32−94% yield in a single laboratory operation.
The intermediacy of o-QMs is supported by control
experiments utilizing enolate precursors and conventional
alkyl halides as competitive alkylating agents and the isolation
of 1,5-dicarbonyl products resulting from conjugate additions
that do not restore the aromatic system.
ortho-Quinone methides (o-QMs, 4), or o-methylene cyclo-
hexadienones, are highly reactive species that participate in a
variety of organic reactions.1 The o-QM has been known in
chemical literature for over a century,2 yet their great synthetic
utility has not been fully harnessed; their high reactivity is often
a liability that necessitates the generation and consumption of
o-QMs in situ. The scope of enolates that are commonly joined
with o-QMs has heretofore been limited owing to the tendency
of the reagents employed or the byproducts produced in the
course of generating enolates to unproductively engage the o-
QM. For example, common alkoxide and amide bases and their
conjugate acids are competent nucleophiles that readily attack
o-QMs in a variety of contexts. Such behavior is the basis for
the biological activity of a host of natural products.3 Thus, there
are few examples of the controlled addition of highly basic
enolates to o-QMs, and to date, reactions have typically
employed reversible formation of o-QMs,4 malonic esters,5,6b
and/or highly Lewis acidic conditions6 or bench-stable
electron-rich o-QM equivalents7 (Scheme 1a, eqs 1−3).
Asymmetric methods have also been described in these
contexts,7,8 but the utility of these important structural motifs
is still limited.
with anhydrous fluoride (Scheme 2).10 This strategy has been
elegantly exploited by Scheidt and co-workers in several studies
exploring the union of N-heterocyclic carbene- and thiazolium-
bound carbonyl anion equivalents and o-QMs under the action
of anhydrous fluoride sources such as tetramethylammonium
fluoride (TMAF) and cesium fluoride in the presence of crown
ethers.11 The same group has described chemistry utilizing a
nitrogen equivalent that gives a putative aza-ortho-xylylene
reaction partner.12 Varvounis and co-workers showed that an o-
QM could be released from a silylated nitrate ester under the
action of fluoride and joined with nucleophiles including an
exogenously generated malonic ester enolate.5 We therefore
reasoned that a highly basic enolate and an o-QM could be
generated in a similar manner; treatment of a mixture of a silyl
enol ether or silyl ketene acetal (1) and an O-silylated phenoxy
benzyl halide (2) with anhydrous fluoride was expected to
result in the generation and coupling of both the nucleophilic
and electrophilic reaction partners in a single flask (Scheme
1b).13 Moreover, we expected the highly reactive nature of the
o-QMs to facilitate formation of congested carbon−carbon
bonds that are difficult or impossible to realize using
conventional enolate alkylation chemistry.
We report herein a protocol by which ketone or ester
enolates (3) and o-QMs (4) are generated in situ in a single
reaction flask and joined to give a variety of β-(2-
hydroxyphenyl)-carbonyl compounds (5) in one laboratory
operation (Scheme 1b). Our work greatly expands the scope of
conveniently available functionalized phenols, important
building blocks, and structure types in the context of natural
product synthesis.9
The preparation of substrates 2 from simple salicylaldehydes
is straightforward (see Supporting Information). Protection of
the phenol functions as the corresponding tert-butyldimethyl-
silyl ethers was achieved under standard conditions. Subsequent
reduction of the aldehyde function with hydride or addition of
an organolithium or Grignard reagent and conversion of the
resultant alcohol to the corresponding chloride or bromide
We were inspired by several reports from Rokita and co-
workers wherein O-silylated phenolic benzyl halides and
acetates can produce ortho-quinone methides upon treatment
Received: April 3, 2015
Published: April 23, 2015
© 2015 American Chemical Society
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Letter
treatment with acetic acid prior to warming), we are able to
routinely isolate the desired products 5 cleanly in 32−94% yield
(Scheme 3).
Scheme 1. (a) Selected Prior Examples of Reactions
Involving o-QMs and Enolates; (b) Nucleophilic Alkylation
a
of o-QMs by Discrete Enolates
a
Scheme 3. Michael Additions of Enolates to o-QMs
a
TBS = tert-butyldimethylsilyl, TMS = trimethylsilyl, TMAF =
tetramethylammonium fluoride, Np = 2-naphthyl, PMP = para-
methoxyphenyl, NR4F = cinchona alkaloid salt.
Scheme 2. Conversion of O-Silylated Phenolic Benzyl
Halides to ortho-Quinone Methides as Described by Rokita
and Co-workers
leaving group gave a variety of substrates 2 in good yields with
little difficulty.
a
Yields of isolated products; reactions were performed on a 1.0 mmol
b
We screened a number of conditions under which we might
join o-QM and enolate precursors, examining several fluoride
sources and ultimately we found temperature and fluoride
solubility to be critical. Reaction conditions employing TMAF
in dichloromethane routinely delivered the desired adducts 5,
but often accompanied by several decomposition products that
complicated rigorous purification. Our results and observations
suggested that the release of the enolates 3 from the silyl
precursors 1 was rapid at low temperature while the release of
the o-QMs 4 from the precursors 2 was slower, particularly for
large substituents at the R1 position (e.g., tert-butyl or phenyl),
but capture of the o-QM was rapid. Release of o-QMs can be
accelerated by warming, but at the cost of decomposition. We
addressed this issue by maintaining the temperature after the
addition of fluoride; using our optimized procedures (addition
of solutions of TMAF in dichloromethane to premixed
solutions of components 1 and 2 in dichloromethane at −78
°C, incubation at that temperature for 1 h, followed by
scale (TMAF). Product was isolated as a mixture of cyclic hemiacetal
diastereomers. Yield based on recovered starting material. Product
was isolated as a mixture of diastereomers (1.1:1 mixture with respect
to the benzylic stereogenic center). Product characterized as the
c
d
e
corresponding methyl ether.
O-Silylated phenoxy benzyl bromides and chlorides are both
effective o-QM precursors; however, the chlorides are more
bench-stable and undergo the o-QM-enolate union much more
cleanly. Our reaction conditions are amenable to the use of silyl
enol ethers, silyl ketene acetals, and silyloxydienes, though
some care must be taken when the corresponding enolates are
not thermally stable (i.e., ketene acetals).
The characterization of products 5f, 5j, 5l, and 5o required
special attention due to the formation of multiple stereogenic
centers during the course of the o-QM-enolate reaction.
Traditional NMR-based methods for the assignment of relative
stereochemistry proved inadequate in this context; for example,
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methods based on derivatization, evaluation of coupling
constants, or NOE analysis provided little insight. However,
computational analysis methods proved quite useful in this
context. Utilizing the methods described by Tantillo and co-
workers,14 we were able to assign the relative stereochemistry of
5f, 5j, 5l, and 5o with no ambiguity (see Supporting
Information). These computational methods have been power-
fully enabling in the stereochemical assignment of natural
products,14a,15 and moreover, we were able to perform these
calculations with freely available open-source programs (see
Supporting Information). As a testament to the maturity and
power of these methods, we were able to later confirm our
assignments by single crystal X-ray diffraction of 5f and one
diastereomer of 5o (Figure 1). We found that these products
example, 2-(trimethylsilyloxy)-propene 1a and 2-(trimethyl-
silyloxy)-cyclohexa-1,3-diene 1b both join smoothly with the
tert-butyl-substituted o-QM precursor 2b under the action of
fluoride to give the alkylated product (5k, 5l); however, we
were unable to productively engage 2b with conventionally
generated metal enolates derived from acetone or 2-cyclohexen-
1-one.
As further evidence of the participation of o-QM
intermediates in these reactions, we conducted control
experiments in which mixtures otherwise identical to those
described in Scheme 3 were doped with conventional alkyl
chlorides prior to the addition of TMAF and observed that the
o-QM precursors were consumed preferentially (Scheme 4a).
Scheme 4. Evidence for the Intermediacy of o-QMs: (a)
Control Experiment with Conventional Alkyl Halide; (b)
Unexpected Michael Addition Regiochemistry
Figure 1. X-ray crystallographic structures for o-QM-enolate products.
For example, a mixture of 2-(trimethylsilyloxy)-propene 1a, o-
QM precursor 2b, and 1-(1-chloro-2,2-dimethylpropyl)-2-
methoxybenzene (6)17 was treated with TMAF in dichloro-
methane as described in Scheme 3, and analysis of the crude
reaction mixture by 1H NMR showed two products: the
ketophenol 5k and 1-(1-chloro-2,2-dimethylpropyl)-2-
methoxybenzene (6) unchanged.
form a homologous series and that the reaction is highly
diastereoselective, with the exception of product 5o (formed as
a 1:1 mixture of diastereomers with respect to the benzylic
stereogenic center). The diastereochemical outcome of these
reactions is consistent with an open transition state model in
which the dipoles associated with the C−O bonds oppose one
another and there is no ion bridging between the reaction
components (Figure 2).16 The proposed model is also
Moreover, we were surprised to observe distinctly different
products in some reactions that would not be possible without
the intermediacy of the o-QMthose which result when both
coupling partners are especially sterically hindered (e.g.,
electrophiles 2b and 2c, and methyl trimethylsilyl dimethylke-
tene acetal 1b). For example, we have found that when reaction
mixtures containing 2b and 2c are treated with TMAF, the
dominant product is not a β-(2-hydroxyphenyl)-carbonyl, but
1,5-dicarbonyls (7a, 7b) instead. The 1,5-dicarbonyl products
7a and 7b were routinely isolated as the (E)-olefin geometrical
isomer, which is consistent with the observed stereochemical
outcome of the reactions described in Scheme 3.18 Such
products would only be possible if the enolate were to add to
an o-QM via the latent aromatic ring rather than via the
exocyclic enone function. These products were unexpected and
unusual in that the alkylation event does not restore the
aromatic system in its wake. These versatile and complex 1,5-
dicarbonyl-containing products have become the subject of
ongoing research in our laboratories and are the focus of
upcoming communications, though they are prone to
unproductive oligimerization reactions.
Figure 2. An open transition state model for the union of (E)-o-QMs
and enolates with no ion bridging between reaction partners.
consistent with tert-butyl- and phenyl-bearing o-QM inter-
mediates forming with (E)-olefin geometry (R1 = t-Bu or Ph);
we presume the diastereochemical outcome in product 5o is a
consequence of poor olefin geometry control when the o-QM
contains a less sterically demanding group (R1 = n-butyl).
Although we have not directly observed any o-QM
intermediates thus far in our studies, we have gathered evidence
that these reactions do indeed proceed via o-QMs and not via
simple substitutive alkylation chemistry. The exceptional
reactivity of the o-QM allows for the construction of highly
congested carbon−carbon bonds that would normally not be
possible via conventional enolate alkylation chemistry; for
We have developed a protocol by which ketone or ester
enolates and o-QMs are generated in situ in a single reaction
flask from silylated precursors under the action of anhydrous
fluoride. The reaction partners are joined to give a variety of β-
(2-hydroxyphenyl)-carbonyl compounds that are not conven-
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iently available by conventional carbonyl-based akylation
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enolate coupling reactions.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
spectra for all new compounds. Computational data and
stereochemical analysis data for compounds 5f, 5j, 5l, and 5o.
Crystallographic data for compounds 5f and 5o. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
4508−4509. (b) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem.
Soc. 2013, 135, 10634−10637. (c) Lee, A.; Younai, A.; Price, C. K.;
Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc. 2014, 136,
10589−10592.
(12) For a general review regarding aza-ortho-xylylenes, see:
Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587−3605.
(13) For a discussion of fluoride-induced formation of enolates from
silyl enolethers and silylketene acetals, see: (a) Noyori, R.; Nishida, I.;
Sakata, J.; Nishizawa, M. J. Am. Chem. Soc. 1980, 102, 1223−1225.
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Williams, D. E.; Andersen, R. J.; Miller, S. J.; Tantillo, D. J.; Berlinck,
R. G.; Sarpong, R. Nature 2014, 509, 318−324.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chain@hawaii.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Institutes of Health
(R01CA163287), the University of Hawaii, the University of
Hawaii Cancer Center, the Achievement Rewards for College
Scientists Foundation (R.S.L.), and the McNair Student
Achievement Program (A.T.D. and T.A.P.) is gratefully
acknowledged. We thank W. Yoshida (UH) for assistance
with NMR data collection, and we thank Dr. J. Greaves (UC
Irvine Mass Spectrometry Facility) for accurate mass measure-
ments.
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reactions as influenced by chelation, see: (c) Kwan, E. E.; Evans, D. A.
Org. Lett. 2010, 12, 5124−5127.
(17) See Supporting Information for details.
(18) The enone geometrical configuration in 7a and 7b was
established by 1H NMR and NOE analysis. See Supporting
Information for details.
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