Mechanistic Pathways in Amide Activation: Flexible Synthesis of Oxazoles and Imidazoles

Article abstract of DOI:10.1021/acs.orglett.7b01678

The preparation of substituted aminooxazoles and aminoimidazoles from α-arylamides and α-aminoamides through triflic anhydride-mediated amide activation is reported. These reactions proceed via the intermediacy of nitrilium adducts and feature N-oxide-promoted umpolung of the α-position of amides as well as a mechanistically intriguing sequence that results in sulfonyl migration from nitrogen to carbon. Quantum-chemical mechanistic analysis sheds light on the intricacies of the process.

Full text of DOI:10.1021/acs.orglett.7b01678

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Letter
pubs.acs.org/OrgLett
Mechanistic Pathways in Amide Activation: Flexible Synthesis of
Oxazoles and Imidazoles
Giovanni Di Mauro,†,§ Boris Maryasin,†,‡,§ Daniel Kaiser,† Saad Shaaban,† Leticia Gonzalez,‡
́
and Nuno Maulide*,†
†Institute of Organic Chemistry, Faculty of Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
̈
‡Institute of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Wahringer Straße 17, 1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: The preparation of substituted aminooxazoles
and aminoimidazoles from α-arylamides and α-aminoamides
through triflic anhydride-mediated amide activation is
reported. These reactions proceed via the intermediacy of
nitrilium adducts and feature N-oxide-promoted umpolung of
the α-position of amides as well as a mechanistically intriguing sequence that results in sulfonyl migration from nitrogen to
carbon. Quantum-chemical mechanistic analysis sheds light on the intricacies of the process.
itrogen-containing heterocycles are a nearly ubiquitous
feature in nature. In particular, both oxazoles and
Recently, our group disclosed the lutidine N-oxide (LNO)-
mediated oxidative C−C coupling of arenes and alkenes with
amides (Scheme 1a).14 Therein, the formation of a latent
N
imidazoles are core structural motifs of several pharmaceuticals
and bioactive compounds (Figure 1).1 Oxazoles are known for
Scheme 1. (a) Oxidative C−C Coupling at the α-Position of
Amides; (b) Formation of Imidazoles and Oxazoles by
Alternative Pathways
Figure 1. Pharmaceuticals and bioactive compounds containing
oxazole and imidazole motifs.
their use as nonsteroidal anti-inflammatory drugs, PPAR
modulators, hypoglycemics, and antibacterial agents,2 while
imidazoles play important therapeutic roles, for example as
antifungals, proton pump inhibitors, angiotensin inhibitors, and
kinase inhibitors.3 As a result of this central role, a vast number
of approaches and synthetic routes for the formation of both
oxazoles and imidazoles have been reported.4−6
Amide activation using triflic anhydride has shown
considerable synthetic versatility and utility in organic syn-
thesis.7 Since the pioneering work of Ghosez,8 a plethora of
synthetic methods for the functionalization of amides have been
developed.9 In particular, the preparation of heterocycles has
received a great deal of attention in recent years, with the
syntheses of pyrimidines,10 pyridines,11 lactones,12 and
tetrazoles13 at the forefront of these developments.
electrophilic enolonium species (I) enabled intramolecular
nucleophilic attack on the α-position of a selectively activated
amide, generating tetrahydroisoquinolinones.
During the exploration of this transformation, we were
intrigued by the side products obtained from premature
interception of putative reactive intermediates with nucleo-
philes other than the aromatic rings (or olefins) employed in
the bulk of the work (Scheme 1b). In the case of an α-
arylamide with lowered capability of intramolecular cyclization
(1a; Scheme 2a), we were surprised to isolate oxazole 2a as the
exclusive reaction product, as confirmed by X-ray crystallog-
Received: June 5, 2017
© XXXX American Chemical Society
A
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Letter
We thus logically attempted to widen the scope of R1 to
heteroatoms, such as protected nitrogens (1k). To our surprise,
however, reaction of 1k with benzonitrile under the standard
conditions did not lead to the expected oxazole; in the event, a
1,2,4,5-substituted imidazole (3r) was observed as the only
product (Scheme 4a). Particularly striking is the observation
Scheme 2. (a) Unexpected Oxazole Formation; (b) Putative
Reaction Mechanism
Scheme 4. Unexpected Imidazole Formation
raphy (CCDC 1537944; see the Supporting Information (SI)
for further details). Mechanistically, this reaction outcome can
be explained by the addition of LNO to the activated amide,
forming α-electrophilic intermediate I,14 followed by inter-
molecular addition of acetonitrile (Scheme 2b). Oxazole
formation is finalized via 5-endo-dig cyclization of the amide
onto the transiently formed nitrilium ion.15
Brief optimization (see the SI) identified milder conditions
that, for simple substrates, reliably afforded the desired
substituted oxazoles in moderate to good yields (Scheme 3).
that in the course of the reaction, the tosyl substituent of
substrate 1k appears to have migrated from nitrogen to carbon.
Additionally, intermediate Iformed by attack of LNO (see
Scheme 2b)does not appear to be involved in this
transformation. Indeed, optimization of the reaction conditions
using 1j confirmed that LNO plays no role in the formation of
the imidazole and also showed that the reaction could be run at
room temperature (Scheme 4b; see the SI for details). Further
optimization showed an added beneficial effect of using 2-
nitropyridine (2-NO2-pyr), presumably due to decreased
nucleophilicity (in comparison to 2-I-pyr) and therefore an
increased fraction of keteniminium in solution (vide infra for a
mechanistic discussion). Additionally, X-ray crystallographic
analysis unambiguously confirmed the assigned structure of 3j
as well as the tosyl migration (Scheme 4b, CCDC 1553624; see
the SI for further details).
a
Scheme 3. Formation of Oxazoles from Simple Amides
With the optimized conditions in hand, the scope of the
reaction was explored (Scheme 5). While alkylnitriles gave low
to moderate conversions throughout (3j−l), benzonitrile led to
imidazole formation in good yield (3m). Other arylnitriles were
also tolerated (3n−q), showcasing a trend where less
nucleophilic (i.e., electron-poor) nitriles afforded lower yields
(compare 3m and 3o). Simple alkyl substituents on the amide
nitrogen, as in the case of diisobutylamide 1k, also allowed the
formation of the corresponding 2-aminoimidazole (3r). Besides
the tosyl protecting group, mesyl sulfonamides were also viable
substrates (3s−u). The nosyl protecting group, however, led to
a marked decrease in product yield (3v), presumably due to the
much diminished O-nucleophilicity of the sulfonamide (vide
infra). Nitriles containing electron-withdrawing groups or
functionality that could interfere with triflic anhydride were
not viable coupling partners in this reaction (3w−y).
a
Reaction conditions: To amide 1 (0.2 mmol) and 2-I-pyr (0.4 mmol)
in R4CN (2 mL) at 0 °C was added Tf2O (0.2 mmol). After 15 min,
LNO (0.21 mmol) was added, followed by heating to 80 °C for 2 h.
Isolated yields are shown.
The imidazoles presented in Scheme 5 are products of a
mechanistically interesting net N-to-C sulfonyl migration. In
order to further elucidate the mechanism of this reaction,
quantum-chemical calculations were performed. Scheme 6
depicts the mechanism of this transformation, as calculated for
the simplified substrate S (see the SI for the computational
details). The first two steps are the activation of the starting
material S by virtue of triflic anhydride and the subsequent
reaction of the keteniminium ion S′ with acetonitrile leading to
intermediate A. Although similar steps are well-known,10,16
Varying substitution on nitrogen was tolerated, and the use of
different nitriles similarly afforded the desired compounds (2a−
h). We were additionally able to scale up the synthesis of 2b to
1.5 mmol with comparable isolated yield. It quickly became
evident, however, that the possible substituent R1 was limited to
aromatics (cf. 2i, for which R1 = Pr). We attributed this
observation to increased LUMO stabilization of intermediate I
by virtue of the aryl moiety.14
B
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Letter
Scheme 5. Scope and Limitations of Imidazole Formation
a
with Various Nitriles
Figure 2. Computed reaction pathway (ΔG298,MeCN, kcal mol−1) for
the conversion of A to E (see Scheme 6) and the optimized structures.
substantial energetic stabilization in the next step, where the S−
N bond breaks, forming intermediate C (ΔG(B−C) = −25.8
kcal mol−1). Additional thermodynamic stabilization is achieved
via the second annulation step and TSC−D. The five-membered-
ring intermediate D undergoes a strongly exergonic [2,3]-
sigmatropic rearrangement (ΔG(D−E) = −21.4 kcal mol−1),
affording intermediate E with the concerted formation of the
C−S bond and breaking of the C−O bond. Finally,
intermediate E is deprotonated by the base, generating the
final product F through aromatization.
While the formation of intermediate A was to be expected,
informed by similar attacks of nitriles on activated amides,10,15
the subsequent 7-endo-dig cyclization was initially less obvious.
The experimental observation that electron-poor sulfonamides
do not allow the transformation to take place, however, is in
good agreement with the O-nucleophilicity necessary for going
from A to B.
a
Reaction conditions: To amide 1 (0.2 mmol) and 2-NO2-pyr (0.4
mmol) in R3CN (2 mL) at 0 °C was added Tf2O (0.4 mmol). After 15
min, the reaction mixture was warmed to 23 °C for 2 h. Isolated yields
are shown.
Scheme 6. Mechanism of the Formation of Tetrasubstituted
Imidazoles
Following the cleavage of B to give sulfinate C and
subsequent cyclization to form D, a [2,3]-sigmatropic
rearrangementreminiscent of a retro-Mislow−Evans-type
reactionconstitutes the final peculiarity of this mechanism,
driven to completion by final aromatization from E to F. This
last step is evident and does not require a theoretical
explanation; accordingly, it was excluded from the computa-
tional study. Although a mechanism involving addition of the
sulfonamide nitrogen to nitrilium ion A might seem plausible at
first glance, our computations argue against it, as the necessary
intermediates could not be found using two different quantum-
chemical approaches: density functional theory (DFT) and an
even higher level, second-order Møller−Plesset perturbation
theory (MP2).
In summary, we have herein reported the facile syntheses of
fully substituted 5-aminooxazoles and 4-aminoimidazoles. The
title products are formed upon electrophilic activation of simple
amides with triflic anhydride in the presence of nitriles.
Computational studies shed light on the unusual mechanistic
pathway of imidazole formation, showcasing an intriguing N-to-
C sulfonyl migration via a [2,3]-sigmatropic rearrangement of a
sulfinate intermediate.
initially it was not clear how A could be converted into the final
product, imidazole F. Scheme 6 and Figure 2 present the
structures of the computed intermediates (A−F) and the
corresponding transition states as well as the reaction profile.
Intermediate A forms the seven-membered intermediate B
via O-nucleophilic attack of the sulfonamide on the nitrilium
(7-endo-dig), forming a new C−O bond. Although this step is
endergonic (ΔG(A−B) = +14 kcal mol−1), it predetermines a
C
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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/acs.or-
glett.7b01678.
■
S
Crystallographic data for 3j (CIF)
Crystallographic data for 2a (CIF)
Experimental procedures, characterization data for all
new compounds, and computational details (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*nuno.maulide@univie.ac.at
ORCID
Leticia Gonzalez: 0000-0001-5112-794X
́
Nuno Maulide: 0000-0003-3643-0718
Author Contributions
§G.D.M. and B.M. contributed equally.
Notes
(8) (a) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L.
The authors declare no competing financial interest.
́
Angew. Chem., Int. Ed. Engl. 1981, 20, 879. (b) Marko, I.; Ronsmans,
B.; Hesbain-Frisque, A.-M.; Dumas, S.; Ghosez, L.; Ernst, B.; Greuter,
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(9) Selected examples: (a) Charette, A. B.; Grenon, M. Can. J. Chem.
2001, 79, 1694. (b) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008,
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Soc. 2010, 132, 12817. (d) Bechara, W. S.; Pelletier, G.; Charette, A. B.
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Angew. Chem., Int. Ed. 2012, 51, 8314. (f) Peng, B.; Geerdink, D.;
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ACKNOWLEDGMENTS
We thank the ERASMUS Program for a studentship to G.D.M.,
Dipl. Ing. (FH) A. Roller (U. Vienna) for X-ray analysis and Dr.
■
H. Kahlig (U. Vienna) for expert NMR analysis. This research
̈
was supported by the ERC (CoG VINCAT 682002), the FWF
(P30226), and the University of Vienna. Calculations were
partially performed at the Vienna Scientific Cluster (VSC).
D.K. is a recipient of a DOC fellowship of the Austrian
Academy of Sciences.
̀
Geerdink, D.; Fares, C.; Maulide, N. Angew. Chem., Int. Ed. 2014, 53,
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Soc. 2016, 138, 11383. (j) Kolleth, A.; Lumbroso, A.; Tanriver, G.;
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