New methodology toward α,β-unsaturated carboxylic acids from saturated acids

Article abstract of DOI:10.1021/ol500127u

A carefully designed three-step unsaturation of carboxylic acids is described. Briefly, carboxylic acids were converted to the trifluoromethyl ketone. Subsequent treatment with selenium dioxide followed by hydrolysis afforded α,β-unsaturated carboxylic acids. The mechanism of the reported transformation was investigated, which led us to propose a novel explanation featuring selenium dioxide assisted enolizaion of a trifluoromethyl ketone followed by β-deprotonation.

Full text of DOI:10.1021/ol500127u

Letter
pubs.acs.org/OrgLett
New Methodology toward α,β-Unsaturated Carboxylic Acids from
Saturated Acids
Qingjiang Li and Gregory P. Tochtrop*
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, United States
S
* Supporting Information
ABSTRACT: A carefully designed three-step unsaturation of
carboxylic acids is described. Briefly, carboxylic acids were
converted to the trifluoromethyl ketone. Subsequent treatment
with selenium dioxide followed by hydrolysis afforded α,β-
unsaturated carboxylic acids. The mechanism of the reported
transformation was investigated, which led us to propose a
novel explanation featuring selenium dioxide assisted enolizaion
of a trifluoromethyl ketone followed by β-deprotonation.
wide variety of synthetic methodologies targeting either
the construction or utilization of α,β-unsaturated carbonyl
approach. As a result, satisfactory reports on the α,β
unsaturation of carboxylic acids are rare.
A
compounds have been developed due to their ubiquitous nature
in organic chemistry. Two major approaches have been utilized
in constructing such functional groups: (1) concomitant
formation during synthetic construction of a molecule (for
example via aldol condensation or Wittig-type reactions1) or
(2) dehydrogenation of a previously established carbonyl
compound.2,3 Although the first approach is usually more
efficient, the second approach is more important, as it provides
the only option for regioselective introduction of unsaturation
to previously established carbonyl compounds. Typically, the
second approach involves deprotonation α to the carbonyl
group to generate an enolate, which is then condensed with a
variety of functional groups that can act as a leaving group in a
subsequent elimination reaction. This generalized method,
affording α,β-unsaturated carbonyl compounds is shown in
Scheme 1. Relatively recent work from Nicolaou et al.
During the course of our work on bile acids, we found that
traditional methods (Scheme 1; examples include α-selenation
and halogenation)2b,4 to produce α,β-unsaturated carboxylic
acids proved unreliable on these highly functionalized
molecules. This served as the impetus to further investigate
the transformation and identify new approaches with the goal
of identifying an efficient route with s broad scope.
A three-step unsaturation strategy was proposed (Table 1)
whereby the carboxylic acid is converted to trifluoromethyl
ketone 2, which is followed by dehydrogenation (in this case
with selenium dioxide). Subsequent treatment of the enone
under basic conditions provides the unsaturated acid 4 as the
final product. Conversion to the trifluoromethyl ketone was
chosen as the surrogate group for carboxylic acid for three
reasons. First, it can be easily generated from a parent acid5 and
readily removed under relatively mild conditions. Second, the
strong electron-withdrawing effect of trifluoromethyl groups
favors the enol form of ketone−enol equilibrium and, therefore,
facilitates dehydrogenation. Third, protection of hydroxyl
groups can be concurrently accomplished during the
conversion of acid to trifluoromethyl ketone.
Scheme 1. A General Strategy for α,β-Unsaturation
The use of selenium dioxide to generate a carbon−carbon
double bond adjacent to carbonyl functionalities6 possesses
clear advantages when compared to the traditional approaches.
First, it is more efficient stepwise, as it circumvents the
deprotonation−substitution−elimination process and gives the
final enone in a single step. Second, it can avoid the use of a
strong base, which is required for α-deprotonation and
elimination. This, of course, improves the functional group
tolerance. The use of selenium dioxide proved ideal for our
approach, as its neutral nature was compatible with the acid and
base sensitive trifluoromethyl ketone, which proved to be
represents an important step forward for the α,β-unsaturation
of aldehydes and ketones using o-iodoxybenzoic acid (IBX), but
this work also highlights the lack of progress and the
underdeveloped nature of the unsaturation of acids.3
As evidenced by the work with IBX, dehydrogenation
approaches are generally more tractable with ketone- or
aldehyde-containing substrates as compared to carboxylic
acids. This fact is primarily derived from the low propensity
of acids to undergo enolization, a required step in almost any
Received: January 16, 2014
Published: February 19, 2014
© 2014 American Chemical Society
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With all three bile acids successfully synthesized, we studied
the scope of this methodology. As shown in Table 1,
trifluoromethyl ketone containing aryl substitution at the γ-
position (2d) was proven to be an ideal substrate, affording
high yields and facile conversion to the unsaturated acid. We
then studied the steric effect by introducing methyl groups on
different positions close to carbonyl groups starting with an β-
substituted ketone (2e). In this case, only α-hydroxylated
product 3e was isolated instead of enone. Dehydrogenation of
compounds without γ-substitution (2f−g) by selenium dioxide
did occur, but did not stop at the enone stage. Further
oxidation at the γ-position introduced a hydroxyl group, which
rapidly reacted with the trifluoromethyl ketone to afford a
stable hemiketal (3f−g). This result is noteworthy, as several
biologically relevant lipid peroxidation products contain this γ-
hydroxy, α,β-unsaturated functionality including 4-hydroxy-2-
(E)-nonenal (4-HNE),10 the corresponding acid (4-HNA),11
and the entire family of OxPCCD36 molecules.12 The method-
ology reported here is easily the most efficient route to their
synthesis.
Table 1. Yields for the Three-Step α,β-Unsaturation of
Carboxylic Acids
To this point, the hemiketal products (3f−g) are sufficiently
stable that ring-opening reactions must be combined with
further conversion of the enone to avoid recyclization during
the workup process. Two conditions were tried: (1) strong
acidic conditions in the presence of selenium dioxide resulted in
1,4-diketone 5, which can be isolated in excellent yield (Scheme
2); (2) saturated KOH EtOH in the presence of water, which
a
An alternate method was used for a better yield.5b
incompatible with the IBX methodology mentioned above.3
Further, the strong electron-withdrawing effect of trifluoro-
methyl ketone dictates the selenium reactivity we report here.
This is critical, as the dehydrogenation of linear carbonyl
compounds by selenium dioxide has been repeatedly proven
intractable.7 A careful literature search identified the proposed
mechanisms for selenium unsaturation as proceeding via the
enol of a carbonyl equilibrium.8 By activating the carbonyl
group with an electron-withdrawing group, the equilibrium
shifted toward the enol form, which we hypothesized would
drive the reaction pathway toward unsaturation. Based on this
assumption, we predicted that, with increased reactivity, the
yield of the dehydrogenation product on an acyclic mono-
ketone could be improved to the point of being a viable and
efficient route for the α, β-unsaturation of acids.
Bile acids are a diverse class of natural product amphiphiles
with multiple hydroxyl groups of various regio- and stereo-
chemistry. As shown in Table 1, when treated with trifluoro-
acetic anhydride using Reeves’ method,5a all of the hydroxyl
groups were effectively protected with concomitant conversion
of acid to trifluoromethyl ketone. As we postulated,
introduction of the electron-withdrawing group made the
dehydrogenation step tractable and the reaction of trifluoro-
methyl ketones (3a−c) with 2 equiv of selenium dioxide
proceeded smoothly to provide enones with good yields. Less
selenium dioxide resulted in the incomplete conversion of
trifluoromethyl ketone. Several solvent combinations, including
various permutations of dioxane, water, ethanol, and
isopropanol, were tried but only tert-butanol afforded the
desired products. Inconsistent with previous reports9 on
selenium reactivity, the addition of acids had no significant
accelerating effect on the reaction rate. Ultimately, α,β-
unsaturated bile acids were obtained in good yields after
being hydrolyzed in a 10% solution of KOH in EtOH/H2O at
room temperature.
Scheme 2. Dehydrogenation of Substrate with γ-Hydrogen
and Subsequent Conversions
afforded the hydrolyzed 4-HNA derivative 6. Attempts to stop
the cascade at the enone stage by adding selenium dioxide in
portions were also conducted and successful, but low yielding.
The versatility of selenium dioxide in terms of accomplishing
multiple oxidative conversions also makes its mechanistic
studies more difficult. From one substrate to multiple products,
it is hard to decipher where reaction pathways diverge from
uniformity and, consequently, whether intermediates are shared
between pathways. To date, three mechanisms have been
proposed for the dehydrogenation process by selenium dioxide:
direct β-deprotonation proposed by Speyer,13 elimination of an
α-selenated species 10 proposed by Sharpless,8 and elimination
of selenous ester 12 proposed by Corey and Schaefer9 (Scheme
3). In the first two proposed mechanisms, the enol form 8 of
the carbonyl is the active species that directly reacts with
selenium dioxide, while Corey et al. proposed enolization as
assisted by selenium dioxide, which served as a Lewis acid.
Since no proposed mechanism could sufficiently explain our
results, we decided to test them individually. Starting with the
direct β-hydrogen transfer mechanism, we designed an isotope
labeling experiment. Based on the logic of the proposed
mechanism, we reasoned that replacement of β-hydrogens of
the substrate with deuterium would result in a first-order
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increase of the reaction rate was observed when adding acetic
acid to the reaction mixture, the Corey−Schaefer mechanism
seemed more reasonable. To further verify this observation, 1.2
equiv of Ti(OiPr)4, a strong Lewis acid to coordinate with the
carbonyl group, was added to the trifluoromethyl ketone for 1 h
prior to selenium dioxide addition. This experiment resulted in
no reaction, which subsequently served as further evidence that
the reaction initiates with the ketone instead of the enol.
Additionally, the Sharpless mechanism cannot explain the
formation of the α-hydroxylation product (3e, Table 1)
Scheme 3. Mechanistic Studies of Dehydrogenation by
Selenium Dioxide
The major defficiency of the Corey mechanism, as pointed
out by Sharpless et al.,8 is the involvement of selenous ester 12,
which is unstable and undergoes rapid hydrolysis before
elimination can occur. After considering these arguments, we
propose a new mechanism by combining the selenium dioxide
assisted enolization with a β-deprotonation process. As shown
in Scheme 5, we propose that high valence selenium reacts with
isotope effect in the reaction rate. Consequently, a β-deuterated
fatty acid was prepared in the synthesis described below and
converted to trifluoromethyl ketone to react with selenium
dioxide. The reaction rate was monitored by NMR and
compared with that of the analogous fatty acid without
deuterium.
Scheme 5. Proposed Mechanisms of Dehydrogenation by
Selenium Dioxide
As shown in Scheme 4, 1-dodecyne 13 was cross-coupled
with ethyl diazoacetate catalyzed by copper(I) iodide14 in
Scheme 4. Synthesis of Deuterated Trifluoromethyl Myristyl
Ketone
trifluoromethyl ketone to form the enol ester 17. The enol ester
undergoes 1,4-elimination directly instead of nucleophilic attack
of the carbon−carbon double bond to form selenium ester. In
the case of an α-substituted substrate, such as compound 2e in
Table 1, 1,4-elimination is prohibited in the most energetically
stable conformation since the selenium ester is trans to the β-
hydrogens. When 1,4-elimination is restricted, nucleophilic
attack at the α-position occurs and the subsequent hydrolysis of
selenium(II) ester 18 affords alcohol as the product instead of
enone. This explains the formation of the observed α-
hydroxylation product(s).
In summary, a three-step method for the α,β-unsaturation of
carboxylic acids that features the shortest synthetic route and
most versatile substrate scope was developed. Careful thought
was given to the introduction of a trifluoromethyl ketone,
which made the utilization of this reaction possible. The
intermediates, trifluoromethyl enone and γ-hydroxyl enone, as
versatile substrates to multiple conversions,15are potentially
important as the final products, especially in the context of
medicinal chemistry as precursors of potent enzyme inhib-
itors.16 Furthermore, a very important class of lipid
peroxidation products can be easily prepared from a saturated
fatty acid in three steps utilizing this methodology featuring a
tandem γ-oxidation by selenium dioxide.
excellent yield. Subsequent deuteration in the presence of 5%
platinum on carbon, hydrolysis, and conversion to the
trifluoromethyl ketone 16 was achieved in excellent overall
yield.
The deuterated ketone was refluxed in tert-butanol with
selenium dioxide, and the reaction rate was monitored by NMR
at 24 h intervals to compare with that of the undeuterated
compound. The reaction rate was calculated by the integral of
the peaks of starting materials vs that of the product
(Supporting Figure 1). No significant difference in reaction
rates was observed, which suggested that the removal of β-
hydrogen to form a carbon−carbon double bond is not likely to
be the rate-limiting step, and we therefore excluded the β-
hydrogen transfer mechanism.
We then analyzed our results in the context of both the
Sharpless and Corey−Schaefer mechanisms. The main
disagreement between these models pertains to the reactive
species that initiates the reaction with selenium dioxide. The
Sharpless mechanism proposes a direct electrophilic attack of
selenium dioxide to the enol form based on the indirect
observation of carbon−selenium species, while Corey and
Schaefer proposed that the enolization of the ketone was
assisted by selenium dioxide as a Lewis acid (Scheme 3). When
the two mechanisms are compared, adding acid should
accelerate the Sharpless mechanism by accelerating the enol−
ketone tautomerization, as the rate limiting step is electrophilic
attack of selenium dioxide to the enol. Since no significant
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: tochtrop@case.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a National Science Foundation
Grant MCB-0844801 to G.P.T.
■
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