Dess-Martin periodinane oxidative rearrangement for preparation of α-keto thioesters

Article abstract of DOI:10.1039/c7ob02959d

A Dess-Martin Periodinane (DMP) mediated oxidative rearrangement reaction was uncovered. The reaction proceeds via oxidation of a β-hydroxy thioester to a β-keto thioester, followed by an α-hydroxylation and then further oxidation to form a vicinal thioester tricarbonyl. This product then rearranges, extruding CO₂, to form an α-keto product. The mechanism of the rearrangement was elucidated using ¹³C labelling and analysis of the intermediates as well as the products of the reaction. This efficient process allows for easy preparation of α-keto thioesters which are potential intermediates in the synthesis of pharmaceutically important heterocyclic scaffolds such as quinoxalinones.

Full text of DOI:10.1039/c7ob02959d

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Dess–Martin periodinane oxidative rearrangement
for preparation of α-keto thioesters†
Cite this: DOI: 10.1039/c7ob02959d
Randy Sanichar,
Ciaran Carroll, Ryan Kimmis, Bela Reiz and John C. Vederas
*
A Dess–Martin Periodinane (DMP) mediated oxidative rearrangement reaction was uncovered. The reac-
tion proceeds via oxidation of a β-hydroxy thioester to a β-keto thioester, followed by an α-hydroxylation
and then further oxidation to form a vicinal thioester tricarbonyl. This product then rearranges, extruding
CO2, to form an α-keto product. The mechanism of the rearrangement was elucidated using 13C labelling
and analysis of the intermediates as well as the products of the reaction. This efficient process allows for
easy preparation of α-keto thioesters which are potential intermediates in the synthesis of pharmaceuti-
cally important heterocyclic scaffolds such as quinoxalinones.
Received 30th November 2017,
Accepted 18th December 2017
DOI: 10.1039/c7ob02959d
rsc.li/obc
inconsistent behaviour of DMP were addressed when it was
shown that exposure to the atmosphere or the addition of an
Introduction
Polyvalent iodine reagents emerged in the 1980s as selective equivalent of water vastly accelerated the rate of oxidations.6
oxidants in organic chemistry.1–3 Most commonly used are A rate increase also occurred when 2 equivalents of alcohol
2-iodoxybenzoic acid (IBX)4 and 1,1,1-triacetoxy-1,1-dihydro- were added. The authors proposed that the water or alcohol
1,2-benziodoxol-3-(1H)-one, known as Dess–Martin Period- replaces one of the acetoxy groups on DMP, and that this
inane (DMP).5 DMP is one of the mildest reagents for oxi- makes the remaining iodine–alkoxy bond more labile, thereby
dation of primary and secondary alcohols.6 DMP also does accelerating the reactions.6
α-oxidations of β-keto esters and amides to form vicinal tricar-
Golec and coworkers showed that DMP may be used to
bonyl derivatives of pharmaceutical interest.6,7 In addition it transform β-diketones, β-ketoesters and β-ketoamides to
converts: allylic alcohols to α,β-unsaturated carbonyls;8 aldox- produce the corresponding vicinal tricarbonyl compounds by
imes and ketoximes to aldehydes and ketones;9 N-acyl α-oxidation in varying yields.15 Subsequently, Meyer and
hydroxylamines to acyl nitroso compounds;10 4-substituted Schreiber proposed that the α-methylene oxidation of β-keto
anilides to p-quinones;11 β-amino alcohols to α-amino alde- esters is facilitated by the acetoxyiodinane oxide reacting with
hydes without epimerization;12 and γ,δ-unsaturated aromatic the enol form of the β-keto ester product, as depicted in
amides to heterocycles.13 However, there were no reports to Fig. 1.6
show that DMP is involved in the rearrangement of β-hydroxy
thioesters to α-keto thioesters, which we now describe.
Interestingly there were no reports of analogous transform-
ations with β-keto thioesters. Moreover, our group had oxi-
DMP was first prepared by Dess and Martin in 1983 by reac- dized β-hydroxy thioesters to β-keto thioesters with DMP in
tion of 2-iodobenzoic acid with KBrO3 in H2SO4 to give IBX, good yields (>75%) without detecting significant over-
which was further treated with a mixture of acetic anhydride
and acetic acid to yield the reagent in 87% overall yield.5 As
IBX is insoluble in many organic solvents, its applications
were limited, and DMP offered considerable advantages. This
preparation was further improved by Ireland and Liu in 1993,
who addressed inconsistencies in the synthetic outcome by
replacing acetic acid with catalytic p-toluenesulfonic acid in
the second step.14 This allowed reproducible formation of
DMP with significantly higher yields.14 Issues regarding the
Department of Chemistry, University of Alberta, Edmonton, Alberta,
Canada T6G-2G2. E-mail: john.vederas@ualberta.ca
†Electronic supplementary information (ESI) available: LC-MS assays, experi-
Fig. 1 The proposed mechanism for the oxidation of β-OH esters to
mental procedures, and spectral data. See DOI: 10.1039/c7ob02959d
vicinal tri-carbonyl compounds.6
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oxidation.16–19 In the present work we show that excess DMP
can form vicinal tricarbonyl thioesters, but under the con-
ditions, these are susceptible to an unexpected rearrangement
reaction to form α-keto thioesters. α-Keto carbonyl compounds
are intermediates in the preparation of heterocyclic deriva-
tives.20 Although the use of α-keto acids to form heterocycles is
quite common, the conditions required for transformation
tend to be harsh.21 However, as described below, reaction of
α-keto thioesters with diamines proceeds under very mild con-
ditions to give quinoxalinones. The quinoxalinone moiety is
considered a privileged structure, and is often used as a core
scaffold for a combinatorial library synthesis.22
Table 1 The effect of DMP equivalents on the relative distribution of
products (total equivalents of 7–11 set to 100%)
Equiv. of DMP
% 7
% 8
% 9
% 10
% 11
1.1
2.2
3.3
5.5
0
0
0
0
73
10
1
1
0
0
0
1
7
8
1
25
82
91
99
0
Results and discussion
Although oxidation of α-methyl β-hydroxy thioester 1 with
excess DMP gives the expected product 2,16 identical con-
ditions transform 3 to α-keto thioester 4 rather than the
expected β-keto derivative. This compound contains one less
carbon, and its formation was accompanied by the production
of a gas (Scheme 1). We did not find literature precedent for
this transformation. However, DMP oxidations of β-hydroxy
thioesters to β-keto thioesters can sometimes result in low
yields,16–19 whereas the same reaction on β-hydroxy esters or
amides have been reported with higher yields.15 N-Acetyl-
cysteamine (SNAC) thioesters were used in this work due to
their utility for studies with polyketide synthases,17,19 but the
reaction works similarly with other thioesters as shown in
Scheme 1. Since DMP is already known to convert β-hydroxy
esters and amides to the vicinal tricarbonyl compounds,15 it
seemed likely that the β-keto thioester was further oxidized the
vicinal tricarbonyl, which was then transformed to the α-keto
thioester.
mediates were confirmed by retention time and high resolu-
tion liquid chromatography coupled to mass spectrometry
(LCMS) with matching to synthesized standards. Complete
rearrangement starting from 7 requires 5 equivalents of DMP.
Product ratios resulting from use of less DMP suggest that 9
and 10 are rapidly transformed to subsequent products if
additional oxidizing agent is present. To confirm that the
species observed in the reaction were true intermediates, each
was reacted with the requisite equivalents of DMP. It was
observed that all of the proposed intermediates were trans-
formed to the α-keto thioester product as shown in Table 2.
Under the same conditions, the vicinal tricarbonyl compound
10 was treated with 1-acetoxybenziodoxol-3-one, the by-product
from the DMP reagent, but this did not give any rearrange-
ment. Similarly, nucleophiles with heteroatom bonds such as
hydrogen peroxide or N-hydroxyphthalimide did not rearrange
the vicinal tricarbonyl compound 10. With the intermediate
species in the rearrangement established, the mechanism of
transformation of the vicinal tricarbonyl to the α-keto thioester
was examined.
To test this, we investigated conversion of 7 to 11 by syn-
thesis of proposed intermediates 8–10 and examination of the
effect of varying equivalents of DMP (10% excess was used to
account for the purity of the reagent supplied, 95% purity) on
the product distribution (Table 1). The identities of the inter-
Substrates labelled with 13C at the β-carbon or at the thio-
ester carbonyl (Scheme 2) were made to ascertain which
Table 2 Showing the rearrangement of proposed intermediates to the
α-keto thioester product using DMP
Substrate
Equiv. of DMP
5.5
Product
4.4
2.2
1.1
Scheme 1 Showing the transformation of β-hydroxy thioesters to
different products under the same conditions.
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Scheme 3 Showing the results of the crossover experiment, between
doubly labelled and unlabelled substrates (ratio of 14/15 = 1 : 1, and
16/17 = 1 : 1).
Scheme 2 Showing the products formed from the labelled substrates.
* represents 13C label.
carbon was being removed and to determine the identity of
the species being extruded. Reaction of β-hydroxy thioester 12,
bearing the 13C label at the β-carbon gave 13C-labelled α-keto
thioester 13 and m/z 44.1 was observed for unlabelled CO2 in
the headspace gas. This was confirmed by the gas phase IR
spectra (Fig. 2). The reaction of β-hydroxy thioester 14 bearing
the 13C label at the thioester carbonyl produced unlabelled 15
and m/z 45.1 was observed for the 13CO2. The corresponding
shift in the IR spectra of the resulting 13CO2 gas produced in
the reaction vessel headspace is shown in Fig. 2. These results
show that the thioester carbonyl carbon is extruded in the
form of CO2 gas.
Fig. 3 Showing the proposed mechanism for the DMP oxidative
rearrangement of β-hydroxy thioesters.
A crossover experiment was used to determine whether the
reaction was intermolecular or intramolecular. Equal amounts
of unlabelled 17 and doubly 13C-labelled 16 substrates were
mixed and then oxidized. An intramolecular process would
give α-keto thioester products that are either completely
unlabelled or doubly labelled, whereas an intermolecular reac-
tion would generate a mixture of unlabelled, singly labelled,
and doubly labelled products. High resolution LCMS analysis
showed only unlabelled 19 and doubly labelled 18 as products,
thereby demonstrating intramolecular conversion (Scheme 3).
The rearrangement mechanism of the vicinal tricarbonyl thio-
ester to the corresponding α-keto thioester may occur as out-
lined in Fig. 3.
vicinal tricarbonyl thioester. This vicinal tricarbonyl then
undergoes an intramolecular rearrangement using a molecule
of acetoxyiodinane oxide to release CO2 and the α-keto thio-
ester product.
The substrate scope was briefly explored with variations at
the γ–carbon of the thioesters. The reaction does not seem to
be affected by steric bulk at the γ-position, but a methyl substi-
tuent at the α-position does prevent the rearrangement. It
appears that very little racemization (if any) occurs at the
γ-position relative to the thioester carbonyl during transform-
ation of 24 and 26 to 25 and 27, respectively (Table 3). This
Table 3 Showing a summary of the substrates tested and their corres-
ponding products
Overall the transformation proceeds by oxidation of the
β-hydroxy thioester to a β-keto thioester, which then undergoes
an α-hydroxylation followed by another oxidation to form the
Substrate
Yield %
74
Product
66
63
60
62
Fig. 2 Showing the overlaid results of the gas phase IR for 12CO2 (red
trace) vs. 13CO2 (blue trace). Residual unlabelled CO2 in the latter is
background from air.
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Table 4 Relative distribution of products (total equivalents of starting
material-product set to 100%) for thioesters, esters and amides using
LC-MS analysis
X
Starting material β-Keto α-OH-β-keto Tri-carbonyl Product
Scheme 4 Preparation of quinoxalinones from α-keto thioesters.
S
O
N
0.0
0.0
2.3
0.0
2.0
0.0
0.0
34
1.9
0.7
52
95
99
11
0.7
was determined by direct comparison of the optical rotations
of enantiomeric compounds, both after rearrangement and
also after transformatiuon to 32 and 33, respectively (see
below, Scheme 4). The rotation values were observed to be
quite similar but in the opposite direction. While full conver-
sion of the starting material is always observed, the average
isolated yield is 65%. This is due to the polar nature of the pro-
ducts, making them harder to separate from the 2-iodobenzoic
acid formed in the work-up of the reaction. We found that
increasing the number of sodium bicarbonate washes aids in
the removal of much of this impurity, but at the cost of a lower
yield. However, if a stronger, more nucleophilic base is used,
the targeted α-keto thioesters are destroyed. Other attempts
were made to further improve the overall yield of the reaction.
These included addition of a base (DBU, K2CO3, CsCO3) to the
reaction, and increasing of the reaction temperature (room
temperature to 50 °C). However, these attempts provided no
improvements to the yield. The elevated temperatures led to
the decomposition of the product, and the addition of base
resulted in lowered yields.
Conclusions
A
new Dess–Martin Periodinane (DMP) mediated intra-
molecular rearrangement reaction was uncovered. Through a
series of 13C labelling studies and intermediate testing, it was
found that the reaction converts β-hydroxy thioesters to α-keto
thioesters, extruding the starting thioester carbon as CO2 in
the process. The attachment of the thiol functionality to the
α-carbonyl was determined to be a 1,2 migration. This mild
and efficient reaction allows for easy preparation of α-keto
thioesters, which can be used to prepare valuable intermedi-
ates for the synthesis of pharmaceutically important hetero-
cyclic compounds.
Experimental
General method for preparation of β-hydroxy thioesters
The reactivities of thioester, ester and amide functionalities
Step 1: Aldol condensation. In a flame dried round bottom
for the rearrangement were compared. As expected, the thio- flask 3-acetylthiazolidene-2-thione was dissolved in dry CH2Cl2
ester functionality is the most susceptible to the rearrange- under an argon atmosphere and cooled to 0 °C. To this solu-
ment of the three (Table 4). Under the conditions used, the tion was added 1.1 equiv. of TiCl4 and the mixture was stirred
rearrangement does not occur to a significant extent during for 10 min before further cooling to −78 °C. Then 1.1 equiv. of
oxidation of β-hydroxy amides. However, it does proceed with diisopropylethylamine (DIPEA) were added and stirring was
oxygen esters to some extent. These results may offer an expla- continued at −78 °C for 1 h. Next 1.2 equiv. of aldehyde was
nation as to why this reaction was not previously observed, as added, and the mixture stirred for 1.5 h at −78 °C. The
there are reports of the use of DMP to oxidise β-hydroxy esters mixture was warmed to 20 °C and the reaction was quenched
and amides to their corresponding β-keto and vicinal tricarbo- by the addition of 10 mL saturated NH4Cl. The phases were
nyl compounds.6,15
separated, and the aqueous layer was extracted with CH2Cl2
The reactivity of α-keto thioesters with diamines was briefly (3 × 20 mL). The combined organic layers were washed with
examined. They react readily at room temperature to form the brine (2 × 10 mL) then dried over MgSO4. The solvent was
corresponding quinoxalinones in good yields (Scheme 4). One removed under vacuum and the residue was purified by flash
of the most common approaches to prepare quinoxalinones, is column chromatography.
the treatment of α-keto acids with diamines under harsh con-
Step 2: Conversion of acyl thiazolidene-2-thiones to thio-
ditions.20 However, our results show that α-keto thioesters may esters. To a flame dried round bottom flask containing dry
be used effectively in place of α-keto acids, thereby reducing acetonitrile was added the aldol product from Step 1. This was
the reaction time and temperatures, while being compatible followed by 5.0 equiv. of K2CO3, then 1.3 equiv. of
with thermo labile functionalities.
N-acetylcysteamine (HSNAC; this is a non-volatile thiol that
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has no stench. However, other thiols may be used). The
mixture was stirred at 20 °C until the colour disappeared
(15–45 min). The solvent was removed under vacuum, and
EtOAc (20 mL) and water (20 mL) were added. The phases were
then separated, and the aqueous layer was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (2 × 10 mL), then dried over Na2SO4, and concen-
trated under vacuum. Purification of the resulting residue by
flash column chromatography yielded the β-hydroxy thioester.
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General method for DMP oxidative rearrangement of β-hydroxy
thioesters
In a 100 ml round bottom flask, the β-hydroxy thioester was
dissolved in CH2Cl2 and 5.5 equiv. of Dess–Martin periodinane
(DMP) were added. The mixture was stirred (open to air) at 10 N. E. Jenkins, R. W. Ware, R. N. Atkinson and S. B. King,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank Mark Miskolzie of the University of Alberta (UA)
NMR Facility, Wayne Moffat of the UA Analytical Services, and
Jing Zheng of the UA Mass Spectrometry Department for their
assistance in data acquisition. This work was supported by the
Natural Sciences and Engineering Research Council of Canada
(NSERC).
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J. C. Vederas, J. Am. Chem. Soc., 2013, 135, 1735–1738.
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