Sustainable Access to 5-Amino-Oxazoles and Thiazoles via Calcium-Catalyzed Elimination-Cyclization with Isocyanides

Article abstract of DOI:10.1002/cssc.202100225

Herein, we report a sustainable, modular, rapid and high-yielding transformation to afford densely functionalized 5-aminooxazoles and thiazoles. The reaction is tolerant to a wide range of functional groups and is typically complete in under 30 min. Furth

Full text of DOI:10.1002/cssc.202100225

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doi.org/10.1002/cssc.202100225
ChemSusChem
Sustainable Access to 5-Amino-Oxazoles and Thiazoles via
Calcium-Catalyzed Elimination-Cyclization with Isocyanides
Ashley J. Basson[a] and Mark G. McLaughlin*[a]
principles of green chemistry, including transition metal[17] and
Herein, we report a sustainable, modular, rapid and high-
photoredox catalysis[18] as well as innovative strategies utilizing
yielding transformation to afford densely functionalized 5-
main group reagents.[19]
aminooxazoles and thiazoles. The reaction is tolerant to a wide
Owing to our interest in employing group 2 metal catalysts
to generate reactive intermediates, we sought to establish a
method to produce oxazole motifs bearing multiple functional
handles, and in particular, oxazoles containing a 5-amino group.
This was borne out of the fact that although many elegant
strategies have been described for multiply functionalized
oxazoles,[20] there are limited reports whereby the oxazole is
formed directly using truly catalytic approaches (Scheme 1).
Our investigation therefore began by exploring the feasi-
bility of this strategy, using 1a as a model substrate. Upon
treating 1a with tert-butylisocyanide in the presence of catalytic
range of functional groups and is typically complete in under
30 min. Furthermore, the described transformation is inherently
green in relation to the catalyst and solvent choice as well as
producing environmentally benign alcoholic by-products.
The advent of more sustainable synthetic methodology is of
paramount importance to the future of manufacturing, health-
care and agriculture. The requirement to find reaction con-
ditions that use more environmentally benign reagents is now a
cornerstone of modern synthetic organic chemistry, with the
introduction of the Twelve Principles of Green Chemistry
cementing its importance within the community.[1] This has led
to seminal work describing the use of non-precious transition
metals and main group organometallics in synthesis,[2] as well
as the increase in the use of photo-[3] and electrochemistry[4] to
mediate important transformations. Furthermore, the use of
organocatalysis[5] and more sustainable radical initiators[6] have
been successfully employed to produce important intermedi-
ates and complex scaffolds alike.
Our enthusiasm for sustainable synthesis stems from our
interest in the use of group 2 metals in synthesis.[7] In particular,
we are interested in accessing scaffolds which hold special
interest to medicinal chemists,[8] with our current work focusing
on 5-membered heterocyclic motifs.[9] Oxazoles play an increas-
ingly important role in the discovery of new therapeutics,[10]
from antibacterial agents targeting multiple ESKAPE
pathogens[11] to novel kinase inhibitors for the treatment of
cancer.[12] Unsurprisingly, much attention has been paid to their
synthesis, including the classical Robinson-Gabriel synthesis[13]
and Van-Leusen reaction.[14] More modern approaches using
stoichiometric Lewis acids,[15] and redox strategies[16] have been
successful in producing a range of substituted oxazoles. Of
greater interest are methods employing at least one of the
[21]
°
Ca(NTf2)2/nBu4NPF6
in DCE at 80 C, we were pleased to
discover that the reaction had gone to completion within
5 min, providing the desired oxazole in 83% isolated yield
(Table 1, entry 1). Increasing the reaction time to 15 min led to
a slight increase in yield (Table 1, entry 3); however, running the
reactions over a prolonged period of time resulted in a
noticeable drop in yield and reproducibility (Table 1, entry 2). In
an effort to increase the overall sustainability of the reaction,
we proceeded to screen a range of solvents touted as being
more green.[22] Surprisingly, given the oxophilic nature of
calcium,[23] ethyl acetate turned out to be the best solvent in
terms of yield, reproducibility and reaction time. Finally, in order
to rule out acid-based catalysis, we performed the reaction in
the presence 2,6-di-tert-butylpyridine, and found no reduction
in reactivity (Table 1, entry 8).
Table 1. Reaction optimization.
°
Entry
Loading
[mol%]
T [ C]
Solvent
t
Yield
[%]
[a] A. J. Basson, Dr. M. G. McLaughlin
Department of Natural Sciences
1
2
3
4
5
6
7
8
10
1
5
5
5
5
5
5
80
80
80
80
80
80
80
80
1,2-DCE
1,2-DCE
1,2-DCE
EtOAc
EtOAc
MeCN
5 min
2 h
15 min
30 min
30 min
12 h
83
73
86
99[a]
92[b]
53[a]
0
Manchester Metropolitan University
Chester Street, Manchester, M1 5GD (United Kingdom)
E-mail: m.mclaughlin@mmu.ac.uk
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cssc.202100225
acetone
EtOAc
12 h
30 min
© 2021 The Authors. ChemSusChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
96[a,c]
[a] NMR yield. [b] Isolated yield. [c] Reaction carried out in presence of 2,6-
di-tert-butyl pyridine.
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Scheme 1. Previous closely related catalytic examples. DCE=1,2-dichloroethane, DBN=1,5-Diazabicyclonon-5-ene, DMSO=Dimethyl sulfoxide, Tf=Triflate
With these conditions now in hand, we wanted to explore
applicability and limitations of the reaction. We started by
examining the substitution on the hemiaminal itself, as this is
often less explored in the literature. As shown (Scheme 2), the
reaction is tolerant a wide range of electronically diverse
substrates. Electron-withdrawing groups (1b–1g) worked well,
providing the desired oxazole in good-to-excellent yields.
Electron-donating groups were also tolerated (1h–1j), once
again affording the corresponding 5-aminooxazole in low (1j)
to very high yields. Furthermore, thiophene (1k) and naphthyl
derivatives gave the desired product in useful yields. Unfortu-
nately all attempts employing saturated derivatives failed under
our reaction conditions. Analysis provided some insight, and in
most cases, the major product was the bisamide derived from
two equivalents of 1a. We are currently investigating this
limitation in reactivity, and will report our findings in due
course.
We then turned our attention to assessing how derivatiza-
tion of the amide portion of the starting materials affected the
reaction (Scheme 3). This proved very successful, with the
reaction providing the oxazole routinely in high yield, regard-
less of electronics (3a–3f). Heterocyclic substrates were also
well tolerated (3g–3h), affording bidentate scaffolds in ex-
cellent yield.
To ensure that the methodology is fully modular, we then
focused on varying the isocyanides used in the reaction.
Employing 1a as a model substrate, we assessed a range of
isocyanides (Scheme 4), including electron withdrawing (4a–
Scheme 2. Substrate scope of functionalized hemiaminals.
Scheme 3. Substrate scope of functionalized amides.
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Scheme 5. Thiazole Synthesis
have shown promise as a versatile building block in drug
discovery and materials chemistry. The synthesis of 2-amino-
thiazoles is well established, however their 5-amino counter-
parts remain underexplored,[24] with limited modular synthesis
of these scaffolds reported. Moreover, the routes towards the
structures are plagued with issues relating to sustainability,
with toxic or environmentally harmful by-products formed. To
this end, we subjected a series of thioamide derivatives to our
optimized conditions, which afforded the desired thiazoles in
good to excellent yields (Scheme 5)
Scheme 4. Varying the isocyanide.
4c), electron donating (4d), mixed electronic (4e), benzyl (4f)
and cyclohexyl (4g). This also proved fruitful, with a range of
structurally diverse oxazoles being formed in good to excellent
yields.
Finally, we wanted to explore the possibility of extending
this methodology to the synthesis of 5-aminothiazoles, which
Although the catalyst system is not recyclable in the
traditional sense, we wanted to explore whether the system
could be used in a sequential manner. We therefore decided to
Scheme 6. Plausible reaction mechanism.
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run the reaction to completion, followed by recharging the flask
with more starting material. We observed minimal reduction in
reactivity in the first three recharges; however, the reaction
quickly plateaus after this. We reason that this could be due to
catalyst poisoning because of increased concentration of amine
nucleophile from the oxazole or production of catalytically
inactive calcium bisalkoxides, derived from loss of iPrOH.
Keywords: calcium catalysis
oxazoles · thiazoles
· cyclisation · isocyanides ·
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A
plausible reaction mechanism is provided below.
(Scheme 6). It is now well established that the active catalyst
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Experimental Section
General procedure for the calcium-catalyzed synthesis of
5-aminooxazoles
To a 4 mL vial was added the corresponding N-acyl-N,O-acetal 1
(1.0 equiv.) and isocyanide (1.2 equiv) in EtOAc (1 mL). nBu4NPF6
(5 mol%) and Ca(NTf2)2 (5 mol%) was added, and the mixture was
°
stirred at 80 C until TLC analysis indicated complete conversion to
the product. The mixture was concentrated and purified by flash
column chromatography (EtOAc/hexane, 1% NEt3) to afford the
pure product.
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General procedure for the calcium-catalyzed synthesis of
5-aminothiazoles
To a 4 mL vial was added the corresponding N-thioacyl-N,O-acetal 5
(1.0 equiv) and isocyanide (1.2 equiv) in EtOAc (1 mL). nBu4NPF6
(10 mol%) and Ca(NTf2)2 (10 mol%) was added and the mixture was
°
stirred at 100 C until TLC analysis indicated complete conversion to
the product. The mixture was concentrated and purified by flash
column chromatography (EtOAc/hexane, 1% NEt3) to afford the
pure product.
Acknowledgements
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We thank Manchester Metropolitan University for start-up funding
and infrastructural support.
Manuscript received: January 28, 2021
Conflict of Interest
Revised manuscript received: February 18, 2021
Accepted manuscript online: February 19, 2021
Version of record online: March 3, 2021
The authors declare no conflict of interest.
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