Oxidative Deaminations and Deisatinylations of Ugi-Azide and Ugi-3CR Products: A Two-Step MCR-Oxidation Protocol toward Functionalized α-Ketoamides and α-Ketotetrazoles

Article abstract of DOI:10.1021/acs.orglett.7b00710

A new postcondensation multicomponent reaction (MCR) methodology, comprising oxidative deaminations enabling access to multiple privileged carbonyl-containing scaffolds in two steps, is described. These protocols allow facile access to functionalized α-ke

Full text of DOI:10.1021/acs.orglett.7b00710

Letter
pubs.acs.org/OrgLett
Oxidative Deaminations and Deisatinylations of Ugi-Azide and Ugi-
3CR Products: A Two-Step MCR-Oxidation Protocol toward
Functionalized α‑Ketoamides and α‑Ketotetrazoles
Christopher Foley,† Arthur Shaw,‡ and Christopher Hulme*,†,‡
‡
†Department of Chemistry and Biochemistry, College of Science, and Department of Pharmacology and Toxicology, College of
Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States
S
* Supporting Information
ABSTRACT: A new postcondensation multicomponent reaction
(MCR) methodology, comprising oxidative deaminations enabling access
to multiple privileged carbonyl-containing scaffolds in two steps, is
described. These protocols allow facile access to functionalized α-
ketoamide and α-ketotetrazole small-molecule peptidomimetic-like
building blocks from prototypical synthons with two points of diversity.
Incorporation of chalcone and alkynyl moieties with further ring-forming reactions enables access to additional novel heterocyclic
ring systems, including a unique and potentially highly pharmacologically relevant scaffold, a 1,2-selenazol-3(2H)-one.
α-Ketoamides are quintessential privileged motifs found in
many natural products and pharmaceuticals. Reminiscent of
endogenous peptide bonds, the α-ketoamide motif has
demonstrated significant utility as a peptidomimetic transition
state inhibitor, as exemplified by Boceprevir and Telaprevir,
agents effective against hepatitis C virus-NS3-4A serine
protease1 (Scheme 1). α-Ketoamide constructs have been
Scheme 2. Generic Routes to α-Ketoamides and α-
Ketotetrazoles
Scheme 1. Pharmaceutically Important α-Ketoamides
extensively developed as histone deacetylase,2 peptidase,3
protease,4 peptidyl proline isomerase,5 lipase,6 and hydrolase
inhibitors.7 Additionally, α-ketoamides are embedded in many
building blocks, notably the versatile isatins.
oxidative deisatinylation reaction, effectively an oxidative
deamidation reaction of a tertiary amide (isatin).
We rationalized that if an oxidative deisatinylation (deamida-
tion) reaction could occur with isatinic tertiary amides, then an
analogous transformation was likely feasible with secondary and
tertiary amines through a similar iminium ion intermediate in an
oxidative deamination. Initially, we focused our studies on using
aniline as the primary amine input in both the Ugi-azide and
Ugi-3CR,11,12 where MCR products 1 and 3 act as oxidizable
surrogates to generate ketones 2 and 4.
The methodology described herein is compatible for the
conversions of secondary and tertiary amine MCR products to
ketones. Interestingly, despite transamination methodology
being a crucial part of biological processes in the conversion
Diverse synthetic methods developed toward α-ketoamides
(Scheme 2) include examples of C1 oxidation, C2 oxidation, C1−
NHRR formation by oxidative amidation, amide coupling, and
C1−C2 coupling.8 Although many routes to α-ketoamides are
currently available, each suffers from innate methodological
limitations, such as poor general substrate diversity, lack of
commercially available starting materials, and the need for main
group and precious metals. Moreover, current synthetic
protocols that access bioisosteres of α-ketoamides, namely, α-
ketotetrazoles, are arduous with limited scope, being incompat-
ible with the demands of production scale high-throughput
library generation.9
In previous studies toward N-functionalized peptidomimetic-
Received: March 9, 2017
like isatins,10 we serendipitously discovered a sequence-ending
© XXXX American Chemical Society
A
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Letter
of amino acids to keto acids, few laboratory methods exist for
the high-throughput conversion of amines to ketones.
Furthermore, numerous C−N bond cleavage/insertion strat-
egies have been developed.13 However, general methodology for
the oxidative deamination of sec-secondary amines, sec-tertiary
amines, and sec-tertiary amides to ketones is seemingly
nonexistent in the literature. Examples of organo-catalyst-
mediated oxidative deamination reactions have been reported
with primary amines.14 Some related reactions of free amines
and SeO2 include nitrone formation from reaction of piperidine
and selenium dioxide15 as well as nitrosoarenes and diazo
compounds from reaction of aniline and SeO2/H2O2.16
Our preliminary investigations began with the oxidative
deisatinylation reaction, which afforded the general structures,
α-ketoamides 2 and α-ketotetrazoles 4, when aromatic
aldehydes were employed. Thiophene and furan aldehydes
(Scheme 3) were run in conjunction with o-aminoacetophenone
aniline proving compatible with benzaldehydes to give 9d (58%)
and 9e (86%). Heteroaromatic aldehydes (3-pyridylaldehyde
and 2-indole aldehyde) afforded corresponding α-ketoamides 9f
and 9g in 72 and 50% yields, respectively. Aliphatic aldehydes,
specifically propionaldehyde, proved more temperamental, with
9h not detected in a complex mixture. However, cyclo-
propylaldehyde and isobutyraldehyde afforded 9i and 9j, albeit
in moderate to poor yields (60 and 21%, respectively).
Moreover, when aniline was replaced by o-aminoacetophe-
none coupled with heating in a sandbath (3 h, 100 °C), 8k was
oxidatively deisatinylated to 9k with cleaner conversion and in
higher yield (60%). We found this result very promising as it
demonstrated the process could clearly be optimized on an
individual reaction basis for more challenging and highly
decorated Ugi-3CR reagents.
Employing phenylpropionaldehyde-derived 8l in the Ugi-
3CR/oxidative deamination sequence afforded further oxidized
conjugated product 9k (26%), as opposed to 9l, derived from an
oxidative deamination/oxidative dehydrogenation sequence.17
Conversion of 8m to ynamide derivative 9m proved stubborn,
despite changes in reaction temperature and the amine. Only
upon heating 8m prepared from o-aminoacetophenone (3 h,
sandbath, 100 °C) was a main product fraction obtained. X-ray
crystallography of the product (Figure 1) led to the discovery of
Scheme 3. Multicomponent U-3CR of Amines, Aldehydes,
and Isonitriles Proceeded by Oxidative Deamination
Figure 1. ORTEP diagram of 10a with displacement ellipsoids at 50%
probability.18
the peculiar monocyclic selenium heterocycle 10a, a 1,2-
selenazol-3(2H)-one, whose unsaturated isomer has not yet
been reported. In regard to pharmacological relevance, it must
be noted that the related bicyclic benzo[d][1,2]selenazol-
3(2H)-one system is observed in Ebselen, a potent scavenger
of H2O2, which is being investigated for a variety of indications,
including stroke and bipolar disorder.19
Mechanistically, we propose an unusual intermolecular [1,2]
addition of selenious acid (H2SeO3) to the alkyne 8m to afford
the selenite ester 11 (Scheme 4), which is followed by
a
b
c
o-Amino acetophenone used in the MCR. Dry dioxane. Aniline
d
e
used in the MCR. Dioxane, H2O 9:1. Piperidine used in the MCR.
f
g
Percent yield based on recovery of starting material. 3 h, 100 °C
(sandbath).
in the phenylphosphinic acid catalyzed Ugi-3CR to afford
condensation products 8a and 8b, which were then oxidatively
cyclized to an isatin and in the same pot deisatinylated, all by
treatment with selenium dioxide, to give 9a (57%) and 9b
(73%) in good yield. These yields compared favorably to our
previously reported example 9c (46% yield)10 and established
that this may indeed be a general transformation.
Scheme 4. Proposed N−Se Selenocyclization Mechanism
We replaced ο-aminoacetophenone 5 through an analogous
oxidative deamination with cheaper and more atom-economical
amines, thus avoiding an intermediary isatin-forming step
(Scheme 3).16 In a head-to-head comparison, 9c was prepared
in 67% yield (aniline = amine input in 3CR) and 64% yield
(piperidine = amine input in 3CR), an improvement of 20%
over the previously nominally reported deisatinylation proc-
ess.10 The scope of methodology was further explored with
B
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Letter
decomposition to ketone 12. The enol tautomer of 12 further
reacts with SeO2 to give 13, which undergoes an intramolecular
N−Se bond-forming cyclization to 14. [1,3]-Hydride shift to 15
and subsequent loss of water delivers 10a, a 1,2-selenazol-
3(2H)-one.
Analogously, we also obtained dual functionalized α-
ketotetrazole compounds in two steps using our MCR-oxidative
deamination approach with the Ugi-azide reaction (Scheme 5).
Figure 2. ORTEP diagram of 17m with displacement ellipsoids at 50%
Scheme 5. Ugi-Azide Reaction of Amines, Aldehydes, and
Isonitriles Proceeded by Oxidative Deamination
probability.22
Scheme 6. Applications of Tetrazole Chalcones To Produce
Diverse C5 Arylated Tetrazole Chemotypes
electrophilic aromatic substitution cascade24 of 17m and 18.
Benzimidazolopyridine 21 (56% yield) was produced via 1,4-
addition/imine condensation of 20 and 17m.25 4,5-Dihydropyr-
azole 23 (33% yield) was also accessible by condensing pyridinyl
hydrazine 22 with 17l.26 In addition, an analogous 3-acyl
pyrrole, 25, was prepared through a Tosmic [3 + 2]
cycloaddition27 (48% yield) through reaction of 17l and 4-
toluenesulfonylmethylisocyanide 24, which may be viewed as a
disconnected “union” of both the Ugi-azide reaction and Van
Leusen’s pyrrole synthesis. Chemical manipulation of these
tetrazole chalcone synthons represents a path toward multiple
privileged nitrogen-containing heterocyclic compounds with an
embedded cis-amide isostere.
a
b
c
Mechanistically, oxidative deamination seems to occur when
R1 is aryl, arylallyl, or dialkyl (Scheme 7). Conversion of 26 to
Aniline used in the MCR. Dioxane, H2O 9:1. Percent yield based
d
e
on recovery of starting material. Dry dioxane. o-Aminoacetophenone
used in the MCR. Benzylamine used in the MCR.
f
Scheme 7. Proposed Mechanistic Pathway
As 1,5-disubstituted tetrazole products are cis-amide isosteres,20
acyl tetrazoles have been utilized in many discovery campaigns
as building blocks for small-molecule library generation.21
From the aniline-derived MCR products 16a−16d that
utilized aromatic aldehydes in the Ugi-azide reaction, 17a−17d
were produced in moderate yields (27−68%). Other hetero-
cyclic variants, indole 17e, pyridine 17f, benzofuran 17g, and
thiophene 17h, performed moderately well (25−77% yield).
Cyclopropyl variant 17i was accessible in only moderate yield
(28%), and propionaldehyde and phenylpropionaldehyde
congeners (17j,k) proved inaccessible.
Fortunately, trans-cinnamaldehyde-derived tetrazole chal-
cones 17l−17o were readily produced through the use of either
aniline, o-aminoacetophenone, or benzylamine in moderate
yields (42−63%). The latter work showcases the first synthesis
of the tetrazole chalcone moiety (definitively confirmed by X-
ray crystallography, Figure 2), which proves to be an extremely
valuable building block for further elaboration (Scheme 6).
Tetrazole building blocks 17l and 17m were employed in
various chalcone reactions23 (Scheme 6). Compounds 19, 21,
and 23 were produced through 1,4-conjugate addition
cyclizations of chalcones 17l and 17m. 1H-Pyrazolo[3,4-
b]pyridine 19 (52% yield) proceeded through a 1,4-addition/
27 proceeds through N-selenyation followed by a [2,3]-
sigmatropic rearrangement of 27 to form imine 28, which
hydrolyzes to form carbonyl 29. However, when the R1
substituent of tetrazole congener 26 is a linear alkane, lack of
electron density favors other pathways over C−N oxidation to
the imine.
In summary, routes to α-ketoamides and α-ketotetrazoles are
completed in two steps from MCR-oxidation methodology, the
latter driven by selenium dioxide. In exploring the scope of these
succinct chemistries, green shoots have been unearthed
delivering undocumented access to 1,2-selenazol-3(2H)-ones,
the subject matter of ongoing studies. Furthermore, the utility of
undocumented chalcone tetrazoles and their affiliated chemistry
reveals rich new veins of accessible molecular diversity.
C
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Letter
to Multicomponent Reactions. In Science of Synthesis, Multicomponent
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00710.
■
Reactions I; Muller, T. J. J., Ed.; Georg Thieme: New York, 2014; Vol. 1,
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Experimental procedures, characterization data, H, 13C
NMR spectra for new α-ketoamide and α-ketotetrazole
compounds (PDF)
X-ray data for 10a (CIF)
X-ray data for 17m (CIF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hulme@pharmacy.arizona.edu.
ORCID
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Christopher Foley: 0000-0002-9028-5841
Christopher Hulme: 0000-0001-6602-9613
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the X-ray Crystallography Facility and the Mass
Spectrometry Facility at the University of Arizona.
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