Mechanism and regioselectivity of the anionic oxidative rearrangement of 1,3-diketones towards all-carbon quaternary carboxylates

Article abstract of DOI:10.1039/c9cc03331a

The oxidative rearrangement of 1,3-diketones is an underexplored alternative to enolate chemistry in the synthesis of all-carbon quaternary carboxylates. The mechanistic investigation of this reaction has resulted in a mild base mediated protocol, whose r

Full text of DOI:10.1039/c9cc03331a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C9CC03331A
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Mechanism and regioselectivity of the anionic oxidative
rearrangement of 1,3-diketones towards all-carbon quaternary
carboxylates
Received 00th January 20xx,
Accepted 00th January 20xx
Emma Bratt,b† Samuel Suárez-Pantiga,a† Magnus J. Johanssonb and Abraham Mendoza*a
DOI: 10.1039/x0xx00000x
The oxidative rearrangment of 1,3-diketones is an underexplored
alternative to enolate chemistry in the synthesis of all-carbon
quaternary carboxylates. The mechanistic investigation of this
reaction has resulted in a mild base mediated protocol, whose
regioselectivity has been studied in challenging acyclic substrates.
Carboxylic acids are widespread in natural and artificial
molecules with important functions, particularly those with an
all-carbon quaternary center next to the carboxylic function 1
(Scheme 1A). The synthesis of these congested products
requires powerful nitrile enolates 2,3 as masked carboxylate
equivalents (Scheme 1B).1-4 However, gaining control over
those processes needs cryogenic and strictly anhydrous
conditions. Alternatively, the oxidative sigmatropic
rearrangement of 1,3-diketones 4 offers a fundamental
advantage to gain a facile entry into these compounds.5-6 The
required -diketones substrates 4 can be obtained easily
through mild alkylation reactions of materials 5 with technical
solvents and reagents. The formation of the key C-C bond
through an intramolecular alkyl shift is advantageous over
intermolecular coupling, as it is less sensitive to congested
environments and can be conducted in a stereospecific
fashion.7
However, the oxidative rearrangement of 4 has been studied
and used only rarely.5 This can be explained, in part, by the
substrate-dependent character of this reaction. The diketones
4a (Scheme 2A) in which one of the migrating groups is
connected to the central carbon with a cyclic structure have
Scheme 1 - Retrosynthesis of all-carbon quaternary carboxylates and limitations
of the key oxidative sigmatropic rearrangement of 1,3-diketones.
been most successful, and produce ring- contracted carboxylic
generally less efficient and less selective and give rise to
mixtures of products 1b,b' due to the alternative
rearrangement modes of the endoperoxide intermediate 6b.7
In most reports, this rearrangement is conducted under acidic5-
acids 1a through the endoperoxide intermediate 6a.5,
In
7-12
stark contrast, unbiased acyclic substrates 4b (Scheme 2B) are
6, 10-15
or neutral7-9, 12 conditions, sometimes requiring forcing
a. Dept. of Organic Chemistry, Stockholm University,
8, 14
temperatures.5-6,
Symmetric diketone substrates are
Arrhenius laboratory, 106 91 Stockholm (Sweden)
b. Medicinal Chemistry, Early Cardiovascular, Renal and Metabolism,
R&D BioPharmaceuticals, AstraZeneca, Gothenburg
commonplace to avoid the low regioselectivities reported in
16
unsymmetrical diketones.7,
As far as we are aware, the
Pepparedsleden 1, 431 83 Mölndal (Sweden).
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
highest regioselectivity in the sigmatropic shift of carbon groups
ever recorded in this reaction is 1.6:1.16 Recently, the study of
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cyclic formyl substrates revealed that the regioselectivity is
highly dependent on the structure of the substrate despite the
conformational bias and the stereoelectronic difference
between the migrating groups.7
Table 1 - Performance of the rearrangement with literature additives (state-of-the-art)
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DOI: 10.1039/C9CC03331A
entry
additive
none
AcOH
none
t (h)
22
22
22
22
T (°C)
65
65
r.t.
r.t.
conv. (%)a
1c (%)a
80
45
13
1
1
2
3
4
97
56
76
7
AcOH
a) Determined by 1H-NMR using 1,2,4,5-tetrachloro-3-nitrobenzene as internal
standard.
17-18
the equilibrium between diketones and H2O2,12,
the
substrate 4c was deemed suitable for its symmetric structure.
Particularly, the benzylic protons that do not participate in the
rearrangement facilitate the monitorization (Scheme 3). Upon
mixing with H2O2, we observed the slow condensation with 4c
in neutral media over the course of several hours at room
temperature (50% conversion at 12 hours), observing traces of
the carboxylic acid product 1c. Two intermediates 6c with
symmetric structure accumulated progressively over time in a
10:1 ratio. The multiplicity of their 1H-NMR signals, and
additional 1D-NOE experiments further confirmed the cis
relationship of the hydroxyl groups in the major
diastereoisomer meso-6c, thus contradicting the previous belief
that this intermediate is trans.16 The 13C-NMR spectra displayed
a single signal in the acetal region (C =107.13 ppm), which is
Scheme 2 - State-of-the-art in the synthesis of carboxylic acids through the
oxidative rearrangement of 1,3-diketones.
This reaction has been proposed to proceed through an
13-16
endoperoxide dihemiketal intermediates 6.6-11,
The
superior performance in the presence of acidic additives5-6, 10-15
was deemed to catalyse the condensation equilibrium between
the diketones 4 and H2O2, which can lead to multiple adducts.12,
17-18
The sigmatropic rearrangement driven by the
fragmentation of the O–O bond has also been proposed to be
acid catalyzed.6, 16 However, there is no experimental evidence
that kinetically correlate any of the possible endoperoxide
intermediates12, 17-18 with the formation of the carboxylic acid
products 1. These fundamental challenges add to the known
background reactivity of diketones 4 with H2O2 through rapid
de-acylation6-9, 16-17 and Baeyer-Villiger oxidation.19-20
In line with our interest in the synthesis of ligands and polar
molecules,21-26 we aimed to clarify the mechanism of this
reaction and the fundamental role of the various additives
reported. We hoped to use this knowledge to understand the
complex dynamics of this system and to control the
regioselectivity of the alkyl shift in unbiased acyclic substrates.
Scheme 3 - Speciation of the reaction between diketone 4c and H2O2.
Preliminary scouting of the wide variety of conditions in
12
literature revealed that under forcing conditions,7-9,
the
consistent with known endoperoxide dihemiketals (C = 105-
106 ppm),12 and allow us to discard hydroperoxyketals
reaction was surprisingly most efficient in the absence of acetic
10-15
acid (entries 1, 2; Table 1).5-6,
Milder temperature
§
structures (C ~ 113 ppm).12, 2D-Heteronuclear correlation
conditions were desirable to enhance the regioselectivity on
unsymmetrical diketone substrates. However, only low yields
were observed at room temperature (entries 3, 4), despite the
intriguing high conversion observed in neutral media (entry 3).
In the presence of catalytic H2SO4, extensive decomposition
occurred.
experiments further confirmed the connectivity of the acetal
framework of the intermediate.
Brönsted acid additives are extensively used in the oxidative
rearrangement of 1,3-diketones and other condensations
17-18
between polyketones and H2O2.12,
To our surprise, we
observed complete inhibition of the reaction in the presence of
acetic acid, as opposed to the slow, yet detectable, evolution in
neutral media (Scheme 4A). We have confirmed that the
We studied the evolution of this system by in-situ NMR
spectroscopy.27 Taking into account the known complexity of
2 | J. Name., 2012, 00, 1-3
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rearrangement of an independently synthesized endoperoxide the overlay of the shifted data to account for the initial
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6c into the product 1c, occurs in acidic media at a similar slow conversion that occurred in the basic reaDctOioI:n10(.S10ch39e/mC9eC4CC03).331A
rate to that found in neutral media (see SI). The lack of All these observations point to a base-promoted sigmatropic
significant acceleration in the rearrangement of endoperoxide rearrangement via intermediate Li-6c, which is self-inhibited by
6c in acidic media, discards the acid-catalysis that has been the formation of the carboxylic acid by-product 7c (Scheme 4D).
assumed to operate earlier.16 Although base additives are rare The progress of the reaction generates carboxylic acid products
28
in the literature of this reaction,16,
and sometimes even that neutralize the basic media, decreasing the rate of the
declared to be detrimental to its efficiency,10 the inhibition in reaction into the apparent zero-order regime observed after
acidic media invited to explore their effect. Surprisingly, the the initial burst. The accumulation of the endoperoxide 6c in
presence of just 0.5 equiv. LiOH leads to a fast reaction that neutral media and its slow evolution into the carboxylate
reaches 78% conversion in 10 minutes, and then proceeds very product 1c is likely due to a lower concentration of the
slowly. However, the yield of the product 1c was only 40% endoperoxide anion Li-6c. As far as we know, these are the first
despite the high conversion of 4c. This seemed to point at the evidences of an anionic rearrangement mechanism operating in
accumulation of intermediate 6c. Speciation of the reaction this reaction. This mechanism does not rule out the
mixture over time (Scheme 4B) revealed that after the initial unimolecular evolution of the endoperoxide intermediate 6c in
burst, the concentration of the endoperoxide intermediate 6c neutral or acidic media, which is commonly proposed in the
decays slowly with apparent zero-order kinetics. This occurs at literature. However, our data strongly suggests that
a very similar rate as it does in neutral media, as evidenced by rearrangement from endoperoxide Li-6c is significantly faster.
Scheme 4 - Effect of the acidic and basic additives and mechanistic proposal. Percentages are relative to the initial concentration of the limiting diketone 4c (0.05 M).
In this scenario, we should expect that the rate, and most which resulted in slightly faster conversion (see SI). Although we
importantly, the final conversion and yield of the reaction never experienced any safety issues, the diketone was added at
should increase when the basicity of the reaction media is 0°C to control possible exotherms. Upon warming to room
increased. We reasoned that at some point, the concentration temperature, we obtained the desired product 1c in 96% yield
of base should be high enough to avoid the accumulation of in less than 10 minutes, as evidenced by 1H-NMR.
endoperoxide intermediate 6c, thus achieving complete
conversion rapidly. To our delight, increasing amounts of LiOH
enabled higher conversions and higher yields of the desired
product 1c (Scheme 5A,B). In these experiments, the
conversions in the initial burst correlated with the initial
concentration of base. The following slow regimes had apparent
zero-order with similar rates, as evidenced by the overlay of the
conversion-shifted plots (Scheme 5C). This is consistent with the
expected self-neutralization of the reaction medium at different
conversions, depending on the initial concentration of base
(vide supra). With 4 equivalents of LiOH we only transiently
detected the endoperoxide intermediate 6c, thus leading to
high yields of 1c rapidly (Scheme 5D). The reaction was equally
efficient with NaOH or KOH, which indicates that lithium does
not play a major role in the rearrangement (see SI). Pre-mixing
of base and H2O2 generated the milder base LiOOH in-situ,
Scheme 5 - Effect of the initial concentration of base additive in the conversion,
yield and accumulation of endoperoxide intermediate. Percentages are relative to
the initial concentration of the limiting diketone 4c (0.05 M).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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The mild protocol developed with the guidance of intermediate
speciation, allowed to explore the intrinsic regioselectivity of
the sigmatropic rearrangement. We set out to compare the
migrating ability of different carbon groups, relative to that of
methyl, using model substrates 4c-k. Primary and secondary
alkyls, including cyclopropyl and benzyl, where deemed suitable
for the rearrangement, albeit with poor regio-discrimination
(entries 1-5, Table 2). Bearing in mind that Li-6 is reminiscent of
a semi-pinacol intermediate, it was expected that substituents
with higher s-character would be more easily outcompeted by
alkyl groups. Indeed, aryl-substituents significantly increased
the selectivity, while preserving the overall efficiency of the
process (entries 6,7). The selectivity was increased further using
electron deficient aromatics, likely due to the decreased
electron density in their shifting carbon (entries 8,9). This effect
was particularly noteworthy in the case of the p-trifluorotolyl
derivative 4k, in which the rearrangement proceeded with 31:1
selectivity (entry 9), thus surpassing the highest 1.6:1
regioselectivity reported between carbon substituents.16 While
slow aryl migration benefits the regioselective alkyl shift studied
herein, further developments are required to invert this trend
to access interesting -arylcarboxylates (Scheme 1A).
Notes and references
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DOI: 10.1039/C9CC03331A
‡ We thank Jorge Otero and Mulima Mabbanti for their
contributions, and AstraZeneca Gothenburg and Stockholm
University for unrestricted support. We are grateful to the
Wallenberg Foundation (KAW2016.0153), and the ERC (714737).
NMR raw data is available DOI: 10.5281/zenodo.3234375.
§ Fast fragmentation prevented HRMS analysis.
1
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entry
R
yield (%)a
85
Li-1c : Li-1d-k
--
1
2
3
4
5
6
7
8
9
Me (4c)
n-Bu (4d)
Bn (4e)
i-Pr (4f)
c-Pr (4g)
Ph (4h)
4-MeOPh (4i)
4-ClPh (4j)
4-CF3Ph (4k)
68
65
57
81
72
63
55
64
2.4 : 1
1.7 : 1
1.0 : 1
2.7 : 1
8.0 : 1
8.8 : 1
14.2 : 1
31.0 : 1
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a) Combined yield of the isolated products
To summarize, the characterization and speciation of
intermediates in the oxidative rearrangement of 1,3-diketones
allowed to rationalize the efficiency of a mild, efficient and
practical protocol in basic media. The identification of the self-
inhibition profile of this reaction proved key to optimize the
current conditions. The stereochemistry of the intermediate
endoperoxide dihemiketal intermediate, and its competence
relative to its anionic derivative, challenge previous proposed
mechanisms. The mild conditions of the rearrangement
promoted by LiOOH allowed to explore the relative intrinsic
regioselectivity of the migration and allowed the rational design
of a promising spectator group. These discoveries enable future
applications of this reaction in the synthesis of complex
molecules with valuable migrating groups, which we are
currently exploring.
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