Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward Vicinal Tricarbonyl Amides: Two-Step MCR-Oxidation Methodology Accessing Functionalized α,β-Diketoamides and α,β-Diketotetrazoles

Article abstract of DOI:10.1021/acs.orglett.7b03977

Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily affords vicinal tricarbonyls (α,β-diketoamides) and α,β-diketotetrazoles with two diversity elements. This significant extension of our previously described multicomponent reaction-oxidative deamination methodology is proposed to proceed through a mechanistically distinct SeO₂-mediated C-N oxidation derived from an active enol of α-amino-β-ketone systems, effectively an aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide building blocks in a mere two steps.

Full text of DOI:10.1021/acs.orglett.7b03977

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward
Vicinal Tricarbonyl Amides: Two-Step MCR-Oxidation Methodology
Accessing Functionalized α,β-Diketoamides and α,β-Diketotetrazoles
Christopher Foley,† Arthur Shaw,‡ and Christopher Hulme*,†,‡
‡
†Department of Chemistry & Biochemistry, College of Science, and Division of Drug Discovery & Development, College of
Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
S
* Supporting Information
ABSTRACT: Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily
affords vicinal tricarbonyls (α,β-diketoamides) and α,β-diketotetrazoles with two diversity elements. This significant extension of
our previously described multicomponent reaction−oxidative deamination methodology is proposed to proceed through a
mechanistically distinct SeO2-mediated C−N oxidation derived from an active enol of α-amino-β-ketone systems, effectively an
aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide
building blocks in a mere two steps.
icinal tricarbonyls (VTCs) are structures of paramount
importance as building blocks and often behave as unusual
trione) and acyclic VTCs have been used as carbonyl sources in
multicomponent reactions (MCRs).16−18 Two approaches
toward vicinal tricarbonyls predominate: direct or indirect
oxidation of β-diketones. The most common is indirect
oxidation of β-diketones by Regitz diazo transfer/oxidation
with t-BuOCl or DMDO.19 One step direct oxidation is more
attractive, of which previous methods involving organoiodine-
chemistry have recently been improved upon.20,21
Ultimately, these protocols rely on an oxidative reaction
involving a (modified) central C2 methylene of a β-diketone,
typically in the form of β-ketoesters and β-ketoamides (Scheme
2). The former are readily prepared by the Claisen reaction.22
However, diverse sets of β-ketoamides are difficult to prepare,
V
turn-promoting structural elements in macrolide natural
products.1 Particularly noteworthy are vicinal tricarbonyl
amides (VTAs, α,β-diketoamides) found in the biologically
active natural product macrolides YM47141-2,2 FK-506,3 FR-
900525,4 and rapamycin.5,6 Rapamycin and tacrolimus (FK-
506) are venerable FDA-approved immunosuppressive agents
that exist in a hemiketal form (Scheme 1). Additionally, the
Scheme 1. Natural Product Macrolides Embedded with
Vicinal Tricarbonyl Amides
Scheme 2. Routes to Vicinal Tricarbonyls
electrophilic polycarbonyl framework can be seen foundation-
ally embedded in many heterocyclic structures, accessible
through nucleophilic additions to the VTC system. Privileged
heterocycles7 accessible through such additions are exemplified
by pyrroles, imidazoles, isoquinolines, quinoxalines, and
furans.8−11
Notable examples of VTCs as building blocks in the total
synthesis of natural products12 include cladoniamide F/G,13
papaveraldine, polstatin, prodigiosin,14 and vasicine.15 Perhaps
even more interesting, cyclic VTC ninhydrin (indane-1,2,3-
Received: December 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03977
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Letter
with recent methodology offering some improvement.23
Unfortunately, in both cases β-diketone syntheses require
catalysts or metal reagents and are restricted by a lack of
diversity elements.
°C for 0.5 h in EtOH/AcOH (ratio 9:0.5 v/v) under
microwave irradiation (Scheme 4) (61−81% yield).
Scheme 4. Condensations of Vicinal Tricarbonyls
As such, we rationalized that our previous postcondensation
oxidative deamination methodology,24 which employed alde-
hydes, could be utilized analogously on glyoxal derived α-
amino-β-ketoamides 1 and α-amino-β-ketotetrazoles 3, afford-
ing α,β-diketoamides 2 and α,β-diketotetrazoles 4 (Scheme 2).
Fundamentally, the key C2 center is derived from the
terminal aldehydic carbon of the glyoxal, and the C3 carbonyl is
generated as a functionalized secondary amide, derived from
the isocyanide diversity reagent. Interestingly, to the best of our
knowledge, MCR products have never been rationally utilized
as pro-VTC β-diketone synthons. As such, this work provides a
substantial improvement on current direct oxidation method-
ology of β-keto-amides as the challenges associated with their
syntheses and the restriction in diversity elements are negated
due to the wide availability of diverse glyoxals and isocyanides;
notably, the latter have high compatibility with MCR
methodology.25
Satisfied with these results, further study of the oxidative
deamination methodology was directed toward unreported α,β-
diketotetrazoles. Containing a 1,5-disubstituted tetrazole, these
VTC analogues were proposed to be potential cis-amide
bioisosteres27 of α,β-diketoamides and, thus, potentially
valuable electrophilic tetrazole building blocks.28
The Ugi-azide reaction proceeded smoothly with the amine
5, glyoxal 6, and isocyanide 7 (stoichiometry 1:1:1) to afford
the α-amino-β-ketotetrazole 12 (Scheme 5). Interestingly,
A collection of secondary-amide-containing α,β-diketoamide
building blocks (9, Scheme 3) was produced by direct oxidative
Scheme 3. Ugi-3CR of Amines, Glyoxals, and Isonitriles by
Oxidative Deamination
Scheme 5. Ugi-Azide Reaction of Amines, Glyoxals, and
Isonitriles Proceded by Oxidative Deamination
initial oxidative deamination attempts on 12 under similar
conditions to those employed to generate α,β-diketoamides 9
(60 min, 160 °C, MW) produced none of the desired α,β-
diketotetrazole 13. However, reducing the reaction time from 1
h to 1 min afforded the desired product 13 (20% yield) and its
imine congener 14 (40% yield). Attempts to convert the imine
14 to 13 in situ with addition of 3 M aqueous HCl to the
reaction mixture failed to garner 13 yet surprisingly afforded 1-
(4-bromophenyl)tetrazole 15 (48%, yield) and an unidentifi-
able side product (Scheme 5).
To circumvent formation of the stable imine 14, N-
methylaniline and piperidine were used as 2° amine inputs
16 in the Ugi-azide MCR. Subsequently, optimization of the
temperature and reaction time of the oxidative deamination
step on the 3° amine 17 (140 or 150 °C, 5 min) afforded a
collection of α,β-diketotetrazoles 18a−h (Scheme 6) with good
reaction scope and yields. Products were prepared from a
variety of isocyanides and aryl glyoxals 18a−g (30−74% yield)
or ethyl glyoxylate 18h (78% yield).
a
b
Aniline used in the initial MCR. Anhydrous dioxane used.
deamination of α-amino-β-ketoamide products 8 of the Ugi-
3CR18 derived from the phenylphosphinic acid catalyzed
condensation of aniline, 5, glyoxals 6, and isocyanides 7. The
oxidative deamination of the corresponding Ugi-3CR products
8a−f [2 equiv of SeO2, dioxane/H2O (9:1), microwave 160 °C,
5 min to 1 h] ultimately afforded products with a variety of aryl
groups 9a−c, a naphthalene 9d, and 3,4-(methylenedioxy)-
benzene 9e, coupled with examples of aromatic and aliphatic
functionality at R2 in good yield (49−78%). The related
formation of oxomalonamide 9f was also feasible (53%).
Attempts to optimize yields by replacement of aniline 5 with
piperidine, pyrrolidine, or o-aminoacetophenone in the MCR
proved detrimental, and that process was not investigated
further. Note that the purified α,β-diketoamides 9a−f were
characterized as a mixture of the tricarbonyl ketone and hydrate
(i.e., a gem-diol), as is commonly observed with this functional
group. To show utility as building blocks to access further
diversity,26 pyrazines 11a−c and quinoxaline 11d were
produced by condensation of ethylenediamines 10 (2 equiv)
with the corresponding α,β-diketoamides 9 by heating at 120
Encouragingly, the protocol was amenable to convertible
isocyanides, which feasibly will allow access to free tetrazoles
upon cleavage of the isocyanide substituent.25 A noteworthy
example is the α,β-diketotetrazole 18h, which may be viewed as
the tetrazole isologue of ethyl benzoyl formate and cis-amide
bioisostere of oxomalonamide. Unfortunately, access to the
pyruvaldehyde-derived 18i proved incompatible with these
B
DOI: 10.1021/acs.orglett.7b03977
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Letter
hydrolyzed to α,β-diketoamide 23. In the case of α,β-
diketotetrazole congeners of 23 (18a−18h), upon prolonged
heating we have also observed the benzilic acid rearrangement31
with loss of formic acid to form α-ketotetrazoles 24. The
previous observation of 1-(4-bromophenyl)tetrazole 15, likely
originates from a nonspecific addition−elimination pathway
due to the stability of the substituted tetrazole nucleus as a
leaving group. These are observed as common major side
products upon prolonged heating. X-ray crystallography of 18f
(see the Supporting Information) supports our claims regarding
the unstable nature of the α,β-diketotetrazole systems under
the conditions employed. The O3−C8−C9−O4 torsion angle is
∼90ο (92.09ο), while the bond angles at C8 and C9 are close to
those typical for sp2 hybridization.
Scheme 6. Ugi-Azide Reaction of Amines, Glyoxals, and
Isonitriles by Oxidative Deamination
Hence, the π-system between C8 and C9 is broken, leading to
an elongated C8−C9 bond (1.543 Å). Indeed, the torsion
angles, bond lengths, and perpendicularity of both halves of
each carbonyl system are nearly identical to that seen in the 1,2-
diketone benzil.32 Such 1,2-diketone character might further
support our proposed mechanisms of rapid conversion to
observed decomposition side-products.
Indeed, in comparison to X-ray structures of other α,β-
diketoamides,1,21 the α,β-diketotetrazoles do not appear to
show exact structural bioisosterism. However, α,β-diketote-
trazoles do appear to behave analogously to α,β-diketoamides
in carbonyl addition reactions and ultimately produce
bioisosteric products, although they are much more reactive
than the corresponding α,β-diketoamides in both their
synthetic procurement and synthetic utilization.
a
b
c
5 min, 150 °C, N-Methylaniline used in the initial MCR. Piperidine
d
e
used in the initial MCR. 5 min, 140 °C. Percent yield based on
recovery of starting material. 1 min, 140 °C.
f
reaction conditions. No starting material was recovered, and the
only identified product was the N1-benzyl tetrazole analogue of
15.
Mechanistically, we propose the reactivity of these α-amino-
β-ketoamide systems with SeO2 at elevated temperatures
follows what could be called an aza-Riley oxidation. In previous
work, we described oxidative deamination of α-amino amides
mediated by [2,3]-sigmatropic rearrangement of a penultimate
N-selenamidate.24 Indeed, early studies of SeO2 mediated α-
oxidations of carbonyls,29 alongside a pKa analysis of the α-
hydrogens of these respective systems indicates that α-amino-β-
ketoamides and α-amino-β-ketotetrazoles 19 can form enol 20
and then react which SeO2, generating selenohemiaminal 21
(Scheme 7). Note that 2 equiv of SeO2 are required as
incomplete conversion and isolation of imines are observed
when 1 equiv is used.
To demonstrate utility, we employed straightforward 1,2-
dicarbonyl chemistry (Scheme 8). Thus, condensation of 18c
Scheme 8. Condensations of α,β-Diketotetrazoles
Scheme 7. Proposed Mechanism for Aza-Riley Oxidation of
α-Amino β-Ketones
with 4,5-dimethylphenylenediamine 25 in methanol/acetic acid
promoted by microwave irradiation followed by direct
crystallization from the reaction mixture produced 2-
tetrazoylquinoxaline 26 (31% yield). However, condensation
of 18c with 1,2-ethylenediamine 27 afforded the 2-tetrazo-
lylpyrazine 28 (37%) and the α-ketoamide 29 (50%),
respectively, demonstrating that α,β-diketotetrazoles can
function as acylating agents analogous to ethyl benzoyl formate
in the synthesis of α-ketoamides. Although not directly
competitive with many of the methods to synthesize α-
ketoamides,24,33 optimization of conditions will allow for the
synthesis of other challenging N-bifunctional α-ketoamide
analogues of 29.
We believe that this enolization-mediated oxidation pathway
does not seem to occur with α-amino amides as previously
reported due to their lack of acidic α-hydrogens.
Selenohemiaminal 21 is then unable to undergo the
traditional Riley oxidation pathway via a Pummerer-like
rearrangement30 to the corresponding ketone due to a lack of
available ipso hydrogens. Instead, 21 is oxidized to iminium
species 22 via elimination of selanediol, which is then
In summary, we have revealed an appealing and highly
concise route to vicinal tricarbonyl amides containing two
points of embedded diversity. The method improves upon
existing routes in its simplicity while offering the ability to
rapidly assemble collections of a fundamental key building
C
DOI: 10.1021/acs.orglett.7b03977
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Organic Letters
Letter
(17) Hulme, C.; Ayaz, M.; Martinez-Ariza, G.; Medda, F.; Shaw, A. in
Recent Advances in Multicomponent Reaction Chemistry. In Small
Molecule Medicinal Chemistry: Strategies and Technologies; Czechtizky,
W., Hamley, P., Eds.; Wiley & Sons, Inc.: Hoboken, NJ, 2015; Chapter
6, pp 1−43.
block for further diversification. Moreover, we have reported
the first route to unique VTA pro-bioisosteric building blocks,
α,β-diketotetrazoles, which display interesting geometry and
reactivity, worthy of further investigation.
(18) Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47, 3622.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(20) (a) Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.; Hedgecock,
C. J. R. Tetrahedron Lett. 1993, 34, 167. (b) Santos, M. S.; Coelho, F.
RSC Adv. 2012, 2, 3237.
(21) (a) Cui, J.; Duan, Y.-N.; Yu, J.; Zhang, C. Org. Chem. Front.
2016, 3, 1686. (b) Liu, Y.; Zhang, Z.; Wan, Y.; Zhang, G.; Li, Z.; Bi, J.;
Ma, N.; Liu, T.; Liu, Q. J. Org. Chem. 2017, 82, 3901.
(22) Sprague, J. M.; Beckham, L. J.; Adkins, H. J. Am. Chem. Soc.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03977.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for new compounds (PDF)
Accession Codes
(23) Vandavasi, J. K.; Hsiao, C. T.; Hu, W. P.; Boominathan, S. S. K.;
Wang, J. J. Eur. J. Org. Chem. 2015, 2015, 3171.
CCDC 1554390 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(24) (a) Foley, C.; Shaw, A.; Hulme, C. Org. Lett. 2016, 18, 4904.
(b) Foley, C.; Shaw, A.; Hulme, C. Org. Lett. 2017, 19, 2238. (c) Shaw,
A. Y.; Denning, C. R.; Hulme, C. Tetrahedron Lett. 2012, 53, 4151.
(25) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.;
Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295.
(26) Hulme, C.; Bienayme, H.; Nixey, T.; Chenera, B.; Jones, W.;
Tempest, P.; Smith, A. L. Methods Enzymol. 2003, 369, 469.
(27) Gunawan, S.; Petit, J.; Hulme, C. ACS Comb. Sci. 2012, 14, 160.
(28) Moderhack, D. Heterocycles 2017, 94, 195.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hulme@pharmacy.arizona.edu.
ORCID
(29) Riley, H. L.; Morley, J. F.; Friend, N. A. C. J. Chem. Soc. 1932,
1875.
(30) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Org. Chem. 1974, 39,
2133.
(31) Askin, D.; Reamer, R. A.; Jones, T. K.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1989, 30, 671.
(32) Brown, C. J.; Sadanaga, R. Acta Crystallogr. 1965, 18, 158.
(33) Shaw, A. Y.; Denning, C. R.; Hulme, C. Synthesis 2013, 45, 459.
Christopher Foley: 0000-0002-9028-5841
Christopher Hulme: 0000-0001-6602-9613
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank The University of Arizona Chemistry & Biochemistry
for NIH training grant T32 GM008804.
■
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DOI: 10.1021/acs.orglett.7b03977
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