Flexible and Chemoselective Oxidation of Amides to α-Keto Amides and α-Hydroxy Amides

Article abstract of DOI:10.1021/jacs.7b02983

A suite of flexible and chemoselective methods for the transition-metal-free oxidation of amides to α-keto amides and α-hydroxy amides is presented. These highly valuable motifs are accessed in good to excellent yields and stereoselectivities with high functional group tolerance. The utility of the method is showcased by the formal synthesis of a potent histone deacetylase inhibitor.

Full text of DOI:10.1021/jacs.7b02983

Communication
pubs.acs.org/JACS
Flexible and Chemoselective Oxidation of Amides to α‑Keto Amides
and α‑Hydroxy Amides
Aurelien de la Torre,† Daniel Kaiser,† and Nuno Maulide*
́
Institute of Organic Chemistry, Faculty of Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
̈
S
* Supporting Information
carbonyl and carboxyl derivatives), the selective oxidation of
amides to α-hydroxy amides in the presence of other carbonyl
compounds remains an unsolved challenge.
ABSTRACT: A suite of flexible and chemoselective
methods for the transition-metal-free oxidation of amides
to α-keto amides and α-hydroxy amides is presented.
These highly valuable motifs are accessed in good to
excellent yields and stereoselectivities with high functional
group tolerance. The utility of the method is showcased by
the formal synthesis of a potent histone deacetylase
inhibitor.
Triflic anhydride-mediated activation of amides is a powerful
synthetic tool to enhance the intrinsic electrophilicity of amides.8
This approach has been exploited by various research groups,
allowing amides to undergo cycloadditions and nucleophilic
additions in a chemoselective fashion.9 We recently disclosed the
use of an electrophilic enolonium species,10 based on amide
activation and trapping with an N-oxide, to trigger umpolung
reactivity at the α-position of amides.10 Precedent for this
reactivity dates back to work by Ghosez and co-workers, forming
particular α,β-unsaturated amides and α-chloroamides.11 We
posited that this intermediate might be coerced to undergo a
second attack by the N-oxide species. The resulting oxapyr-
idinium species A (Figure 1c) should be a versatile intermediate:
following basic workup, it might afford the corresponding α-keto
amide, while a reductive workup could lead to the corresponding
α-hydroxy amide (Figure 1c). Herein we report the development
of a flexible approach for the α-oxidation of amides to α-hydroxy
and α-keto amides.
After extensive optimization using amide 1f (see the
Supporting Information (SI)), we identified 2,6-lutidine-N-
oxide (LNO) as the ideal oxidant and the use of molecular sieves
(3 Å) as beneficial for achieving high conversions and
reproducible yields. The reaction is simply quenched using
aqueous NaOH to afford the corresponding keto amide 2f.
As shown in Scheme 1, several aliphatic amides could be
oxidized to the corresponding α-keto amides in good yields.
Various functional groups were tolerated under the reaction
conditions, including alkenes (2a, 2b), alkynes (2d), and halides
(2e). Moreover, the oxidation is chemoselective for amides in the
presence of esters, ketones, and nitriles (2g−i). The nitrogen
substituents could also be modified to some extent. Piperidine,
dimethyl, and morpholine amides could be oxidized in moderate
to good yields (2j−l). However, α-aryl amides proved to be
reluctant under those oxidation conditions (2m), as were
sterically hindered amides (not shown). Additionally, the α-
oxidation of secondary amides did not proceed to yield the
desired products. As previous work has shown, electrophilically
activated secondary amides form the corresponding nitrilium
ions and therefore cannot undergo the reactions described
herein.8b,9c
elective oxidation reactions are highly sought in organic
1
Schemistry. As a ubiquitous motif in bioactive molecules as
well as a uniquely reactive ambident proelectrophile and
pronucleophile, the α-keto amide function has attracted the
interest of the scientific community.2−4 Similarly, α-hydroxy
carbonyl derivatives are important and widespread motifs in
organic synthesis.5
The most straightforward approach to access an α-keto amide
motif would arguably be the direct α-oxidation of an amide
substrate. Surprisingly, methods to achieve this transformation
are scarce. Indeed, to the best of our knowledge, the oxidation of
amides to α-keto amides is limited to the specific case of α-aryl
amides (thus being effectively a benzylic oxidation) (Figure 1a).6
On the other hand, the oxidation of carbonyl compounds to α-
hydroxy carbonyl compounds is well-described, mainly using
enol or enolate chemistry, including the venerable Rubottom
oxidation (Figure 1b).5,7 However, as the amide function is the
least prone to enolate formation (lowest α-CH acidity among all
Exchanging the basic quench for reductive conditions allowed
the synthesis of the corresponding α-hydroxy amides. We
Received: March 25, 2017
Figure 1. Strategies for α-oxidation of amides.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b02983
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Journal of the American Chemical Society
Communication
Scheme 1. Scope of the Amide to α-Keto Amide Oxidation
Scheme 3. Scope of the Amide to α-OTMP Amide Oxidation
a
b
Reaction time = 12 h. brsm = based on recovered starting material.
identified three orthogonal reductive conditions leading to the
desired products (Scheme 2). For convenience of isolation, the
Scheme 2. Reductive Workup Leading to an α-Hydroxy
Amide
a
1 equiv of 2-fluoropyridine was added to the reaction mixture.
(1q) substituents on nitrogen could also be oxidized in good
yields. Sterically hindered amides were also easily oxidized, as
exemplified by isovalerylamide 1r and dibenzylamide 1s. Methyl
ethers did not affect the reaction (cf. 1t). An α-cyclopropyl
substituent was also tolerated, affording 4u in good yield without
cleavage of the cyclopropyl moiety (vide infra). Finally, an α,α-
disubstituted amide could also be oxidized to form protected
tertiary alcohol 4v in good yield.
α-hydroxy amide was directely TBS-protected. By the use of
either zinc and acetic acid, hydrogen and catalytic palladium on
carbon, or sodium borohydride, protected α-hydroxyamide 3c
was isolated in good yield (Scheme 2) in a highly flexible manner.
Aware that the limitations in the scope of our transformation
could hamper its synthetic utility, we decided to explore a
complementary approach for the cases giving low yields. In the
course of our investigations, we made the remarkable observation
that treating the amide with 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO) and triflic anhydride led to the formation of the
corresponding α-(tetramethylpiperidin-1-yl)oxyamide.12 This
intermediate product is particularly interesting because the
tetramethylpiperidine (TMP) moiety can be considered as a
protecting group for the hydroxy function,13 and we decided to
explore the scope of the formation of α-OTMP amides (Scheme
3; additional substrates are shown in the SI). To our delight, the
amides oxidized using LNO could also be oxidized using
TEMPO, affording 4a−l in good yields. In this reaction, the
chemoselectivity of the oxidation of amides was preserved, and
the reaction could be conducted in the presence of esters,
ketones, and nitriles as well as unsaturations and halides. More
importantly, phenylacetamide 1m could now be oxidized to the
corresponding α-OTMP amide 4m in excellent yield (compare
2m in Scheme 1, 37% yield with 4m in Scheme 3, 96% yield).
Other amides containing ethyl (1n, 1o), allyl (1p), and benzyl
The synthetic flexibility of these products is illustrated in
Scheme 4. A simple reductive workup using zinc and acetic acid
Scheme 4. One-Pot Synthesis of α-Hydroxy Amides and α-
Keto Amides from the α-OTMP Precursor
afforded α-hydroxy amide 5n in good yield.13d Similarly, using
magnesium monoperoxyphthalate (MMPP) hexahydrate as a
cheap and mild oxidant for the quench,14 we could perform the
oxidation of 1n to α-keto amide 2n in good yield. Remarkably, no
significant loss of yield was observed in this transformation
compared to the formation of the α-OTMP amide 4n.
We were subsequently intrigued as to whether the addition of
TEMPO to simple amides could be performed in a
diastereoselective fashion. Pleasingly, we found that exposure
of chiral amide 1w to Tf2O and TEMPO afforded the desired
B
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Journal of the American Chemical Society
Communication
product in nearly quantitative yield with an excellent
diastereomeric ratio (Scheme 5a).15 Additionally, one-pot
reduction of this product efficiently afforded the free alcohol
5w without erosion of the diastereoselectivity (Scheme 5b).
Scheme 7. Mechanistic Experiments and Proposed
Mechanism
Scheme 5. Diastereoselective Synthesis of Both an α-OTMP
Amide and an α-Hydroxy Amide
The synthetic utility was further demonstrated by targeting α-
keto amide 6, a potent histone deacetylase inhibitor that has been
found to have significant anticancer activity in an in vivo tumor
model.16 Application of our oxidation conditions to the simple
azelaic acid-derived amide 7 smoothly led to the formation of
keto amide 8 (Scheme 6).17 Subsequent acid-mediated cleavage
Scheme 6. Synthesis of Bioactive Compound 6
second half of the reaction mechanism, isotopic labeling studies
were additionally performed (Scheme 7b, eqs 1−3; see the SI for
further details). Neither the use of 18O-labeled 1c (Scheme 7b, eq
1) nor quenching the reaction with H218O (Scheme 7b, eq 2) led
to incorporation of the label in the final product. On the other
hand, the use of 18O-labeled TEMPO afforded the pivotal
18O/18O product 4c (Scheme 7b, eq 3). We are therefore
inclined to propose initial electrophilic amide activation and
formation of I with concomitant reduction of TEMPO to anionic
TEMPO−. Nucleophilic substitution of TEMPO−, replacing
TfO−, leads to the formation of intermediate II (Scheme 7c).19
Homolytic fragmentation of this intermediateconsistent with
incorporation of the TEMPO oxygen into the amide carbonyl
subsequently affords the α-oxidation product 4. This preliminary
rationale effectively constitutes a polar-radical crossover that is
unprecedented in the field of amide activation.
In conclusion, we have described a novel flexible and
chemoselective approach for the oxidation of amides to α-keto
and α-hydroxy amides. Notably, this is the first example of a
synthetically useful and general direct oxidation of aliphatic
amides to the corresponding α-keto amides. Our strategy relies
on chemoselective amide activation using triflic anhydride along
with the use of an oxidant. In the case of nonhindered aliphatic
amides, the use of LNO as the oxidant led to the formation of
various keto amides. α-Hydroxy amides could also be synthesized
by quenching the reaction with a reductant. The scope of the
reaction could be extended to virtually any kind of amide by
switching to TEMPO as the oxidant. A wide range of α-OTMP
amides could be synthesized, and it was shown that the latter
could be converted to the corresponding α-keto and α-hydroxy
amides by quenching the reaction under oxidative and reductive
of the p-methoxybenzyl (PMB) protecting group led to the
formation of secondary keto amide 9, an intermediate in the
previous synthesis of 6. This application showcases the synthetic
utility of our methodology by shortening the eight-step synthesis
of 6 by two synthetic steps (see the SI for the synthesis of 7).
Although the mechanism of the reaction of activated amides
with LNO (serving as the oxidant and oxygen donor) could be
easily understood on the basis of previous work,10 the reactivity
of TEMPO was much less obvious to us. In particular, the
formation of 4u without opening of the cyclopropyl ring (see
Scheme 3) strongly argues against the possible intermediacy of
an α-carbonyl radical species.
Performing the reaction of 1c with only 1 equiv of TEMPO led
to full recovery of the starting material and no observable
oxidation product (Scheme 7a).18 While amide activation is
undisputable, despite several additional experiments (see the SI
for details) it remains unclear which reactions precede or effect it.
Possibilities include (a) the formation of an intermediate species
derived from the reaction of TEMPO and triflic anhydride, itself
capable of activating the amide, (b) a pre-equilibrium between a
nonreactive species formed by the reaction of TEMPO with
triflic anhydride and the reagents, and (c) direct activation of the
amide with triflic anhydride. In order to shed light onto the
C
DOI: 10.1021/jacs.7b02983
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Journal of the American Chemical Society
Communication
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conditions, respectively. The reaction could also be performed in
a diastereoselective fashion using a chiral auxiliary, leading to the
formation of the product with excellent diastereocontrol. Our
reaction could be applied to the formal synthesis of a potent
histone deacetylase inhibitor. Preliminary mechanistic observa-
tions led us to propose a polar-radical crossover, which is
unprecedented in the field of amide activation.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b02983.
■
S
Experimental procedures and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*nuno.maulide@univie.ac.at.
■
U.; Catak, S.; Sulzer-Mosse,
2015, 56, 6541. (n) Kolleth, A.; Lumbroso, A.; Tanriver, G.; Catak, S.;
Sulzer-Mosse, S.; De Mesmaeker, A. Tetrahedron Lett. 2016, 57, 2697.
́
S.; De Mesmaeker, A. Tetrahedron Lett.
́
(o) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J. J. Org. Chem. 2016, 81, 9020.
ORCID
(p) Kaiser, D.; Maulide, N. J. Org. Chem. 2016, 81, 4421. (q) Tona, V.;
Nuno Maulide: 0000-0003-3643-0718
de la Torre, A.; Padmanaban, M.; Ruider, S.; Gonzal
Am. Chem. Soc. 2016, 138, 8348.
́
ez, L.; Maulide, N. J.
Author Contributions
†A.d.l.T. and D.K. contributed equally.
(10) (a) Patil, D. V.; Kim, S. W.; Nguyen, Q. H.; Kim, H.; Wang, S.;
Hoang, T.; Shin, S. Angew. Chem., Int. Ed. 2017, 56, 3670. (b) Kaiser, D.;
de la Torre, A.; Shaaban, S.; Maulide, N. Angew. Chem., Int. Ed. 2017,
DOI: 10.1002/anie.201701538. (c) Chen, X.; Ruider, S. A.; Hartmann,
Notes
The authors declare no competing financial interest.
́
R. W.; Gonzalez, L.; Maulide, N. Angew. Chem., Int. Ed. 2016, 55, 15424.
ACKNOWLEDGMENTS
■
(11) Da Costa, R.; Gillard, M.; Falmagne, J. B.; Ghosez, L. J. Am. Chem.
Soc. 1979, 101, 4381.
We thank the University of Vienna for continued support of our
research program. Support of this research by the ERC (StG
FLATOUT and CoG VINCAT) and the DFG (Grants MA-
4861/4-1 and 4-2) is acknowledged. D.K. is the recipient of a
DOC Fellowship of the Austrian Academy of Sciences.
(12) This reaction could be accelerated by using 1 equiv of 2-
fluoropyridine. However, in most cases similar results were obtained
without this additive.
(13) (a) Inokuchi, T.; Kawafuchi, H. Tetrahedron 2004, 60, 11969.
(b) Jahn, U.; Dinca, E. Chem. - Eur. J. 2009, 15, 58. (c) Jahn, U.; Dinca, E.
J. Org. Chem. 2010, 75, 4480. (d) Dinca, E.; Hartmann, P.; Smrcek, J.;
Dix, I.; Jones, P. G.; Jahn, U. Eur. J. Org. Chem. 2012, 2012, 4461.
(14) Hayashi, M.; Shibuya, M.; Iwabuchi, Y. Synlett 2012, 23, 1025.
(15) Reducing the size of the chiral auxiliary to a 2-methylpyrrolidine
produced the desired product in 96% yield with a d.r. of 4.6/1 (see the
SI).
(16) (a) Curtin, M. L.; Dai, Y.; Davidsen, S. K.; Frey, R. R.; Guo, Y.;
Heyman, H. R.; Holms, J. H.; Ji, Z.; Michaelides, M. R.; Vasudevan, A.;
Wada, C. K. Inhibitors of histone deacetylase and their therapeutic use.
U.S. Patent 0,177,594, Nov 28, 2002. (b) Wada, C. K.; Frey, R. R.; Ji, Z.;
Curtin, M. L.; Garland, R. B.; Holms, J. H.; Li, J.; Pease, L. J.; Guo, J.;
Glaser, K. B.; Marcotte, P. A.; Richardson, P. L.; Murphy, S. S.; Bouska, J.
J.; Tapang, P.; Magoc, T. J.; Albert, D. H.; Davidsen, S. K.; Michaelides,
M. R. Bioorg. Med. Chem. Lett. 2003, 13, 3331.
(17) Because of the increased steric demand of the PMB substituent on
nitrogen, the TEMPO conditions had to be used in lieu of LNO
oxidation.
(18) In separate experiments, a reaction between TEMPO and triflic
anhydride could be observed and substantiated by changes in the 1H and
19F NMR spectra. However, characterization and identification of the
resulting species were inconclusive. See the SI for further details.
(19) The substitution of I leading to II could also conceivably result
from attack of TEMPO• and release of TfO•. However, this type of
reaction is mechanistically unprecedented in amide activation.
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DOI: 10.1021/jacs.7b02983
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