Tritylamine as an ammonia surrogate in the ugi reaction provides access to unprecedented 5-sulfamido oxazoles using burgess-type reagents

Article abstract of DOI:10.1021/acs.orglett.1c01002

Starting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position. The synthetic procedure employs readily available starting materials and proceeds smoothly under mild reaction conditions with good tolerance for a variety of functional groups, coming to fill a gap in the field of oxazole compounds.

Full text of DOI:10.1021/acs.orglett.1c01002

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Letter
Tritylamine as an Ammonia Surrogate in the Ugi Reaction Provides
Access to Unprecedented 5‑Sulfamido Oxazoles Using Burgess-type
Reagents
Irene Preet Bhela, Marta Serafini,* Erika Del Grosso, Gian Cesare Tron, and Tracey Pirali
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ABSTRACT: Starting from a wide range of α-acylamino amide
substructures synthesized using tritylamine as an ammonia
surrogate in the Ugi reaction, Burgess-type reagents enable
cyclodehydration and afford unprecedented oxazole scaffolds
with four points of diversity, including a sulfamide moiety in the
5-position. The synthetic procedure employs readily available
starting materials and proceeds smoothly under mild reaction
conditions with good tolerance for a variety of functional groups, coming to fill a gap in the field of oxazole compounds.
xazoles are heterocycles extensively used by medicinal
Ochemists not only as pharmacophoric groups per se but
also as structural elements that impose a degree of conforma-
tional restriction.1 Moreover, because of the similarity in the
electronic properties, they behave as isosteres of amides,
endowed with a better chemical and metabolic stability along
with an acceptable oral bioavailability.2 Oxazoles also find wide
application in medicinal chemistry for the design of
peptidomimetic structures.3 Finally, their inclination to
undergo cycloaddition transformations as azadienes is often
exploited for generating new molecular scaffolds.4 It is
therefore not surprising that the development of efficient
methodologies for access to this high-value substructure has
drawn considerable attention over the years.
Several procedures have been reported to generate oxazoles
bearing a point of diversity in the 5-position. For example, 5-
aminooxazoles displaying a tertiary nitrogen at the 5-position
can be prepared by the multicomponent reaction (MCR)
reported by Zhu et al., among aldehydes, amines, and tertiary
α-isocyanoacetamides promoted by ammonium chloride
(Figure 1).5 The most common methodology available for
the preparation of 5-aminooxazoles bearing a secondary
nitrogen at the 5-position is represented by the trifluoroacetic
acid (TFA)/trifluoroacetic anhydride (TFAA)-mediated cyclo-
dehydration of diamide/dipeptide precursors. In this regard, 10
years after the pioneering work of Fleury and coworkers that
reported in 1973 the cyclization of α-acyl amino acids to give
5-(acetamido)oxazoles,6 Lipshutz described the cyclization of
Figure 1. Synthetic approaches to 5-substituted oxazoles.
α-acylamino amides to give 5-(trifluoroacetamido)oxazoles
(Figure 1).7 Other examples emerged from the literature, but
Received: March 23, 2021
the preparation of the substrates usually required lengthy
routes that included protection and deprotection steps.8 A step
forward was taken in 2009 by Thompson et al. that described
the preparation of the diamide precursor by an Ugi reaction in
Published: April 29, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01002
Org. Lett. 2021, 23, 3610−3614
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trifluoroethanol followed by cyclization in the presence of
TFA/TFAA to give 5-(trifluoroacetamido)-oxazoles (Figure
1).9 Further cyclization procedures have been reported,
including the rhodium-catalyzed reaction between a diazo-
compound and a protected L-leucinamide followed by an I2/
PhP3-mediated cyclization (Figure 1),3 the coupling of two
molecules of isocyanides with carboxylic acid promoted by zinc
bromide,10 the [4 + 1] cycloaddition between an isocyanide
and an N-acylimine,11 and the Cp*Co(III)-catalyzed reaction
between an N-(pivaloyloxy)amide and an ynamide (Figure
1),12 but challenges still remain with regard to limitations in
the range of applicable substrates and the reaction efficiency.
None of the aforementioned cyclodehydrations allows the
insertion of a sulfamide moiety in the 5-position of the oxazole
ring. Herein we disclose a reaction in which the use of Burgess-
type reagents13 leads to the simultaneous formation of the
oxazole ring and insertion of a sulfamide group on the
heterocyclic system.
proposed reaction mechanism, summarized in Scheme 1. The
reaction between the oxygen of the amide and the Burgess
Scheme 1. Proposed Mechanism for the Dehydration of
Diamide 5 by Means of the Burgess Reagent
In addition to being a powerful dehydrating agent, the
Burgess reagent has also been described for its ability to
mediate the synthesis of sulfamidates, epoxyalcohols, α- and β-
glycosilamines, and cyclic sulfamides. Taking inspiration from
the versatile applications of the Burgess reagent, we decided to
investigate its dual nature as both a dehydrative and a
nondehydrative reagent in a single modality, and we speculated
that the application of this reagent to a diamide substructure
could result in the formation of oxazoles bearing an N,N′-
unsimmetrical sulfamide at position 5.14 To verify our
hypothesis, we initially performed a prototype reaction of the
diamide precursor 1a (1 equiv) in the presence of an excess of
Burgess reagent (2 equiv) in dry tetrahydrofuran (THF) at
reflux. Gratifyingly, we observed the formation of 5-sulfamido
oxazole 2a, even if in moderate yield (40%, Table 1, entry 3).
reagent gives intermediate 4 (pathway A, Scheme 1), which is
then intramolecularly intercepted by the second amide oxygen
to afford intermediate 5. After an irreversible intramolecular E2
elimination, intermediate 5 restores the aromaticity of oxazole
to give the 5-aminooxazole 7. It is reasonable that a competing
mechanism, triggered by the reaction between the Burgess
reagent and the oxygen of the other amide, can take place
(pathway B, Scheme 1). It should be noted that intermediate 7
can not be isolated even if 1 equiv of Burgess reagent is used,
suggesting that once formed, it immediately attacks a second
molecule of the Burgess reagent, giving the corresponding 5-
sulfamido oxazole 2 (Scheme 1).
Table 1. Screening of Conditions for the Cyclization
Reaction
Once the optimal conditions had been established, a library
of diamide precursors was synthesized. From our experience in
the field of MCRs,15 we assumed that the simplest procedure
to afford the required diamide substructures was represented
by the Ugi 4-component reaction. However, when this MCR is
conducted in the presence of ammonia it is known that yields
are poor, especially when formaldehyde is used as an oxo
reactive partner, due to the formation of side products.16 This
limitation was evident when, during a medicinal chemistry
campaign aimed at identifying novel IDO1 inhibitors,17 two
compounds, 1o and 1p (Scheme 2), bearing a diamide
substructure were required for our structure−activity relation-
ship study. Indeed, the Ugi MCR afforded the two compounds
in poor yields, with the use of either ammonia or one of its
surrogates,18 for example, 2,5-dimethoxy benzylamine, as
described by Thompson et al. (Figure 1).9
temp
time
(h)
yield
(%)
entry
reagent
solvent
(°C)
a
1
2
3
4
5
6
7
Burgess (3 equiv)
Burgess (3 equiv)
Burgess (2 equiv)
Burgess (1 equiv)
Burgess (3 equiv)
Burgess (2 equiv)
Burgess (1 equiv)
dry THF
dry THF
dry THF
dry THF
dry CH2Cl2
dry CH2Cl2
dry CH2Cl2
66
66
66
40
40
40
40
1
5
1
1
1
1
1
34
26
40
a
a
b
trace
a
59
71
a
a
20
a
Yields based on isolated product after gravimetric chromatography
b
are given. Based on TLC.
Prompted by the challenge to expand the chemical space
around oxazoles, we further optimized the reaction conditions,
as summarized in Table 1.
During the optimization process, it was clear that neither a
higher temperature nor a prolonged reaction time favors the
formation of the product. In particular, after 1 h, the starting
material has usually reacted completely, with the exception of
those reactions in which 1 equiv of Burgess reagent is used
(entries 4 and 7). Regarding the Burgess reagent, the highest
yield is achieved using 2 equiv, a result in accordance with the
To circumvent this limitation, we investigated the use of
tritylamine as an amine component in the Ugi reaction.
Despite its steric hindrance, tritylamine was reported by
̈
Domling to be an efficient and easily cleavable surrogate of
ammonia in a modified version of the Ugi tetrazole synthesis to
afford α-aminotetrazoles,19 but, surprisingly, to the best of our
knowledge, this amine had never been applied in a classical Ugi
reaction. First of all, an Ugi MCR was performed under
classical conditions, and isocyanide 10, formaldehyde 11a,
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b
c
Scheme 2. Diamide Starting Materials
Scheme 3. Synthesized 5-Sulfamido Oxazoles
a
This reaction was scaled up to 6 mmol of 10a with a yield of 80%.
Reaction conditions: (1) 10 (0.8 mmol, 1 equiv), 11 (0.8 mmol, 1
b
equiv; in the case of 11a: 1.6 mmol, 2 equiv), 12 (0.8 mmol, 1 equiv),
13 (0.8 mmol, 1 equiv), CH3OH (1.5 mL), 40 °C for 40 min, rt
overnight. (2) TFA (3.4 mL), CH2Cl2 (3.4 mL), 0 °C for 30 min, rt
for 3 h. Yields based on isolated product after gravimetric
chromatography are given.
a
tritylamine 12, and acetic acid 13o reacted together in
methanol, affording an intermediate that was next deprotected
using TFA in CH2Cl2 at 0 °C to cleave the trityl group. With
this approach, compound 1o was obtained in one pot in a yield
of 84%. Similarly, compound 1p was synthesized using benzoic
acid under the same conditions in 82% of yield.
This reaction was scaled up to 4.5 mmol of 1a with a yield of 87%.
This reaction was scaled up to 3 mmol of 1a with a yield of 68%.
b
c
Reaction conditions: 1 (0.4 mmol, 1 equiv), Burgess reagent (0.8
mmol, 2 equiv), dry CH2Cl2 (1.4 mL), 40 °C, 1 h. Yields based on
isolated product after gravimetric chromatography are given.
m, which can free the amino group under hydrogenolysis. This
is exemplified by the results reported in Scheme 4: Seven
products (14a,b, 14f, 14h, 14j−l) in the presence of H2 and
Pd/C reacted to afford the corresponding 5-sulfamido oxazoles
(15a,b, 15f, 15h, 15j−l). Compounds 15h, 15k, and 15l were
This straightforward approach was applied to different
isocyanides to investigate the scope of the reaction. As shown
in Scheme 2, primary (1a−d, 1n), secondary (1e, 1f), tertiary
(1g, 1h), aromatic (1i), and benzylic (1j−m, 1o,p) isocyanides
are well tolerated, leading to the corresponding products in
high yields. Carboxylic acids bearing different functional
groups, such as nitro (1e) and nitrile (1h), resulted in being
well tolerated, whereas the reactivity of our MCR was highly
influenced by the nature of the carbonyl components. Indeed,
linear aldehydes (1f, 1l,m) lead to good yields, but more
sterically hindered reagents, such as aromatic aldehydes or
ketones, did not provide the corresponding compounds (data
not shown).
Scheme 4. Deprotection of 5-Sulfamido Oxazoles to Afford
b
Monosubstituted 5-Sulfamido Oxazoles
With these Ugi precursors in hand, we next performed the
cyclodehydration step under the previously optimized reaction
conditions. Before setting up the cyclodehydrations, the Ugi
precursors were purified by column chromatography, as the
reaction mixture resulting from the Ugi reaction and the trityl
deprotection usually presents several byproducts. The
corresponding N,N′-disubstituted 5-sulfamido oxazoles 2a−o
were obtained in good to excellent yields (Scheme 3). Low
yields were observed when the oxazole displayed a hindered
substituent at position 4 (2f).
a
This reaction was scaled up to 1 mmol of 14a with a yield of 56%.
Reaction conditions: 14 (0.10 mmol, 1 equiv), Pd/C 5% (18 mg),
b
Finally, we envisaged the opportunity of using a modified
version of the Burgess reagent14,20 bearing a benzyl group: The
cyclization under the same conditions yielded products 14a−
MeOH (0.6 mL), rt, 1 h. Yields based on isolated product after
gravimetric chromatography are given.
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afforded in only low yields due to the decomposition of the
corresponding starting materials. In particular, the depro-
tection of compounds 15k and 15l leads to the formation of a
byproduct corresponding to the monosubstituted 5-sulfamido
oxazole in which the second nitrogen bound to the oxazole
ring loses the benzyl group.
ChemICare S.r.l., Enne3, Novara 28100, Italy; orcid.org/
0000-0003-3936-4787
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01002
Notes
In summary, the Ugi reaction mediated by tritylamine as a
convenient ammonia surrogate leads to diamide products that,
through cyclodehydration triggered by Burgess-type reagents,
are transformed into unprecedented oxazoles bearing N,N′-
disubstituted sulfamides at the 5-position. When displaying the
benzyl group, the obtained products undergo hydrogenolysis,
yielding monosubstitued 5-sulfamido oxazoles. Overall, the
sequential synthesis proceeds smoothly and cleanly under mild
reaction conditions, is scalable up to 1 mmol, provides high
yields, and displays good tolerance to a variety of functional
groups, coming to fill a gap in the preparation of both Ugi
products and oxazoles.
The reported methodology provides a means for making
unique heterocyclic sulfamides. The sulfamide moiety has
recently drawn attention21 and received increasing acceptance
in medicinal chemistry due to its potential to form polar
interactions with proteins of interest22 and due to the
tetrahedral nature of the sulfur atom, which provides an
additional dimension for target recognition. Because it is still
fairly under-represented, the sulfamide is an attractive means of
decorating biologically active compounds while conferring
novelty from a patent perspective. Furthermore, it is a
bioisostere of urea, carbamate, and sulfonamide that has
found wide application in the field of antibacterial agents, as
exemplified by doripenem,23 a carbapenem approved by the
United States Food and Drug Administration (FDA) in 2007,
in the endothelin receptor antagonist macitentan,24 approved
in 2013 for the treatment of pulmonary arterial hypertension,
and in the IDO1 inhibitor epacadostat.25 We therefore foresee
that the reported sequence will find wide application in drug
discovery campaigns in the near future.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.S. is supported by a Fondazione AIRC (Associazione
Italiana per la Ricerca sul Cancro) fellowship for Abroad (Rif.
25278). T.P. acknowledge the Ministero dell’Istruzione,
̀
dell’Universita e della Ricerca (MIUR) for financial support
(PRIN 2017 no. 2017WJZ9W9).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01002.
General experimental procedures, characterization data,
1
and copies of H NMR and 13C NMR spectra(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Marta Serafini − Dipartimento di Scienze del Farmaco,
̀
Universita del Piemonte Orientale, Novara 28100, Italy;
orcid.org/0000-0002-5305-8359; Phone: +39
3495338810; Email: marta.serafini@uniupo.it
Authors
Irene Preet Bhela − Dipartimento di Scienze del Farmaco,
̀
Universita del Piemonte Orientale, Novara 28100, Italy
Erika Del Grosso − Dipartimento di Scienze del Farmaco,
̀
Universita del Piemonte Orientale, Novara 28100, Italy
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bromide promoted coupling of isonitriles with carboxylic acids to
Gian Cesare Tron − Dipartimento di Scienze del Farmaco,
̀
Universita del Piemonte Orientale, Novara 28100, Italy
Tracey Pirali − Dipartimento di Scienze del Farmaco,
̀
Universita del Piemonte Orientale, Novara 28100, Italy;
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