General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams**

Article abstract of DOI:10.1002/anie.202107536

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol %) Vaska's complex (IrCl(CO)(PPh₃)₂) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of α-amino 1,3,4-oxadiazole architectures were accessed from carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Br?nsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. The high chemoselectivity of the catalytic reductive activation step allowed late-stage functionalization of 10 drug molecules, including the synthesis of heterodiazole-fused drug–drug conjugates.

Full text of DOI:10.1002/anie.202107536

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Heterocycles
Hot Paper
General a-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive
Functionalization of Tertiary Amides and Lactams**
Daniel Matheau-Raven and Darren J. Dixon*
Abstract: An iridium-catalyzed reductive three-component
coupling reaction for the synthesis of medicinally relevant a-
amino 1,3,4-oxadiazoles from abundant tertiary amides or
lactams, carboxylic acids, and (N-isocyanimino) triphenyl-
phosphorane, is described. Proceeding under mild conditions
using (< 1 mol%) Vaskaꢀs complex (IrCl(CO)(PPh3)2) and
tetramethyldisiloxane to access the key reactive iminium ion
intermediates, a broad range of a-amino 1,3,4-oxadiazole
architectures were accessed from carboxylic acid feedstock
coupling partners. Extension to a-amino heterodiazole syn-
thesis was readily achieved by exchanging the carboxylic acid
coupling partner for C-, S-, or N-centered Brønsted acids, and
provided rapid and modular access to these desirable, yet
difficult-to-access, heterocycles. The high chemoselectivity of
the catalytic reductive activation step allowed late-stage
functionalization of 10 drug molecules, including the synthesis
of heterodiazole-fused drug–drug conjugates.
Figure 1. 1,3,4-Oxadiazoles as privileged structural motifs.
T
he 1,3,4-oxadiazoles, and related heterodiazoles, are priv-
Traditional syntheses of a-amino 1,3,4-oxadiazoles are
largely based on indirect condensation approaches where the
oxadiazole unit is constructed through dehydration of a 1,2-
diacylhydrazine.[2k,4] The need for multistep synthesis, and
harsh dehydration conditions typically dictates that the
oxadiazole be introduced at an early stage in the synthetic
sequence, and thus a direct and late-stage introduction of this
motif would be both desirable and enabling.[5]
ileged heterocyclic structures in medicinal chemistry
(Figure 1). As heteroaromatic bioisosteres for esters and
amides, they conserve hydrogen bonding networks within
receptor sites, while providing hydrolytic stability and favour-
able metabolic and pharmacokinetic properties.[1] Examples
in pharmaceutical compounds include HIV anti-retroviral
Raltegravir, and clinical candidates targetting cystic fibrosis
(PTI-428) and Huntingtonꢀs disease (GSK-356278). Continu-
ing investigations into their biological activities as antimicro-
bial, anticancer, anticonvulsants, and anti-inflammatory
agents (amongst others) highlight their significant and grow-
ing impact within drug discovery programs.[2] Beyond simple
bioisosteres, a-amino 1,3,4-oxadiazoles are also universal
peptidomimetics capable of mimicking any local pair of
amino acids, in any secondary structure,[3] a feature which has
been exploited through their use as a conformation stabilising
unit within peptide macrocycles.[3b,c]
Tertiary amides, and lactams, abundant in pharmaceutical
compounds, are commonly considered inert functional
groups. However, in recent years, reports from Nagashima,[6]
Huang,[7] Chida and Sato,[8] and our group,[9] among others,[10]
have shown that tertiary amides can act efficiently as robust
and ubiquitous iminium ion, and enamine, precursors.[11] The
dormant amide can be reductively activated with exquisite
chemoselectivity by Vaskaꢀs complex (IrCl(CO)(PPh3)2), at
low catalyst loadings (typically < 1 mol%), and 1,1,3,3-
tetramethyldisiloxane (TMDS), affording an O-silylated
hemiaminal which is smoothly transformed into a reactive
iminium ion upon treatment with Brønsted or Lewis acids.
Advancing our groupꢀs program on reductive amide
functionalization, the late-stage synthesis of a-amino 1,3,4-
oxadiazoles presented an attractive and unsolved challenge.
Previous work on related Ugi-type reactions highlighted that
reductively-generated iminium ions can engage with isocya-
nide nucleophiles.[7b,9g] As such, and inspired by work from
Ramazani,[5a–c] we hypothesized that treatment of a reduc-
tively-generated O-silylated hemiaminal with the functional-
ized isocyanide (N-isocyanimino) triphenylphosphorane
(NIITP),[12] in conjunction with a carboxylic acid (or appro-
priate C-, S-, or N-centered Brønsted acid), would efficiently
afford the a-amino 1,3,4-oxadiazoles (or heterodiazole)
[*] D. Matheau-Raven, Prof. Dr. D. J. Dixon
Chemistry Research Laboratory, Department of Chemistry
University of Oxford, 12 Mansfield Road, Oxford (UK)
E-mail: Darren.dixon@chem.ox.ac.uk
[**] A previous version of this manuscript has been deposited on
a preprint server (https://doi.org/10.26434/chemrxiv.14664672.v1).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202107536.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
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.
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products in a late-stage three-component coupling reaction,
following the mechanism proposed in Scheme 1. Nitrogen
heterocycles, and their saturated analogues are essential
elements of numerous pharmaceuticals;[13] and through the
reductive functionalization of lactams our strategy would
enable the synthesis of valuable a-functionalized heterocycles
in a divergent manner. Furthermore, this strategy would allow
the late-stage functionalization (LSF) of amide or lactams,
and carboxylic acid containing active pharmaceutical ingre-
dients (APIs), providing a-amino 1,3,4-oxadiazoles with
complex structural and chemical features. Herein we wish to
report our findings.
Scheme 2. Reaction discovery and optimization.
yields of the desired products. N-Boc glycine (6) could be
successfully employed affording a product with two orthog-
onally protected amines. A 1,3,4-oxadiazole functionalized
with a terminal alkyne (7) was readily synthesized by use of
propynoic acid. A trifluoromethyl 1,3,4-oxadiazole (8) was
synthesized using trifluoroacetic acid, however an excess of
amide was required for acceptable yield. Heteroaryl carbox-
ylic acids could be employed, showcasing the tolerance of the
reaction to the presence of Lewis basic functionalities,
producing 9–11. Carboxylic acids bearing electrophilic sub-
stituents including; aldehydes (12), sulfonyl fluorides (13),
trifluoromethyl alkenes (14), allyl bromides (15), and alkyl
bromides (16), acted as efficient coupling partners providing
products with additional sites for further nucleophilic func-
tionalization. Pyruvic acid (17), and an oxalic acid half ester
(18) reacted successfully affording acyl a-amino 1,3,4-oxadia-
zoles in 48% and 57% yield, respectively. The late-stage
functionalization of two carboxylic acid containing APIs (19,
20) was realized, demonstrating the potential application of
this methodology in drug discovery programmes.
Scheme 1. General reductive approach to a-amino 1,3,4-oxadiazoles,
and heterodiazoles.
As late-stage access to saturated nitrogen heterocycles
possessing an a-1,3,4-oxadiazole moiety was unprecedented,
N-benzyl lactam (1) was chosen as a model substrate.
Pleasingly, treatment of a THF solution of 1 with 0.5 mol%
Vaskaꢀs complex, and 2 equiv TMDS, followed by addition of
2 equiv of NIITP and benzoic acid, afforded, on the first
attempt, the desired a-amino 1,3,4-oxadiazole 2 in 78%
isolated yield (Scheme 2, entry 1). The formation of 3 as
a side-product, arising from the excess of NIITP and benzoic
acid in the reaction mixture, complicated purification of 2.[14]
Lowering the equivalents of NIITP and benzoic acid as well as
reducing the reaction time for the second stage from 16 h to
1 h, delivered 2 in 87% yield with no formation of 3 observed
by NMR analysis of the crude reaction product (Scheme 2,
entry 2). A solvent screen for the amide reduction subse-
quently revealed THF to be optimal (Scheme 2, entries 3 and
4).
Encouraged by these results we hypothesized that a range
of C-, S-, and N-centered Brønsted acidic reaction partners
could be suitable replacements for a carboxylic acid and
produce distinct a-amino heterodiazole scaffolds. Pleasingly,
use of thioacetic acid afforded the a-amino 1,3,4-thiadiazole
(21) thus granting access to a single-atom modification of the
parent oxadiazole.[15]
A 1,3-dicarbonyl compound (1,3-
diphenyl-1,3-propanedione) proved suitably acidic allowing
facile access to a unique a-amino 1,3,4-oxadiazepine scaffold
(22).[16] Our investigation of N-H Brønsted acids started with
use of 4-hydroxyquinazoline and gave the a-amino
[1,2,4]triazolo[4,3-c]quinazoline (23) in 33% yield.[17] Build-
ing upon this result, N-acyl sulfonamides (24) and N-acyl
carbamates (25) were reacted to afford N-functionalized a-
amino 1,2,4-triazoles.[18] Fortuitously, the product deriving
from N-acyl phosphonate ester (26) proved susceptible to
mild hydrolysis, allowing for isolation of the N-H a-amino
1,2,4-triazole (27) in a one-pot procedure. These examples
demonstrate the first use of protected amides as N-H
With optimal conditions in hand, we investigated the
scope of the reaction with respect to the carboxylic acid
component (Scheme 3). We found that acetic acid (4), and 1-
phenyl-1-cyclopropanecarboxylic acid (5) gave excellent
2
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Scheme 3. Reaction scope.
Brønsted acids for the assembly of desirable a-amino
triazoles using NIITP. N-Acyl sulfonamides are a valued
motif in the pharmaceutical industry, and successful function-
alization of saccharin (28) and sulfacetamide (29) demon-
strates, to our knowledge, the first use of this functional group
for LSF.[19] Notably, compounds such as benzamide, glutari-
mide, and N-hydroxy benzamide gave complex reaction
mixtures and failed to yield the desired heterodiazole,
highlighting that acidification of the acyl N-H by an appro-
priate electron-withdrawing group is essential.
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Next studied was the scope with respect to the amide
component. Lactams with ring sizes from 5–8 (2, 30–33) gave
good yields of the desired products and showed excellent
chemoselectivity for tertiary amide activation in the presence
of terminal alkynes (32) and alkenes (33). The reactivity of
simple anilides was assessed using derivatives of N-methyl-
aniline, and indoline, and successfully delivered N-arylated a-
amino 1,3,4-oxadiazoles (34–36). Complex, and functional-
ized, a-amino 1,3,4-oxadiazole structures containing anilines
were synthesized by coupling of N-methyl-N-phenylforma-
mide with the anti-inflammatory drug indomethacin (37), and
chemoselective reductive functionalization of an a,b-unsatu-
rated ester-containing anilide (38). The chemoselectivity of
the method was further explored with amides bearing
reactive, and reducible, functional groups such as aryl iodides
and carbamates (39), nitro groups (40), boronic esters (41),
pleasingly, drug-drug conjugates featuring heterodiazoles (54,
55) were readily constructed using our standard conditions in
combination with N-tosyl probenecid (56), and thio-probe-
necid (57), which were each readily available in high yield
from the parent carboxylic acid.
A new broad scope iridium-catalyzed reductive three-
component coupling reaction for the synthesis of medicinally
relevant a-amino 1,3,4-oxadiazoles from tertiary amides or
lactams, carboxylic acids, and (N-isocyanimino) triphenyl-
phosphorane, has been developed. The reaction exhibits
excellent chemoselectivity, and functional group tolerance for
structurally diverse carboxylic acid and amide (or lactam)
coupling partners, demonstrated by the LSF of 10 drug
molecules. Furthermore, a subtle change of reaction con-
ditions allowed ready extension to a-amino heterodiazole
synthesis, and rapid production of heterodiazole-fused drug–
drug conjugates.
N O bonds (42),[8a] and ketones (43) providing the desired a-
À
amino 1,3,4-oxadiazoles without any observable reduction of
these potentially sensitive functionalities. An aliphatic ter-
tiary amide was successfully engaged (44), without complica-
tions arising from possible enamine reaction intermediates.
Commercially available formamides were functionalized into
a range of valorized products including; an enantiopure a-
amino 1,3,4-oxadiazole (45), a tertiary amide (46) and
a symmetric triamine (47) from coupling with benzene-
1,3,5-tricarboxylic acid. The method was also applied to the
LSF of five tertiary amide containing pharmaceutical mole-
cules: a benzodiazepine scaffold (48), naproamide (49), CX-
546 (50), a derivative of nortiptyline (51), and fipexide (52)
demonstrating excellent selectivity for tertiary amides, and
efficient reactivity, in the presence of intricate chemical
functionality.
Acknowledgements
D.M.-R. is grateful to the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine (EP/L015838/
1) for a studentship, generously supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis,
Pfizer, Syngenta, Takeda, UCB, and Vertex. Pablo Gabriel,
Tatiana Rogova, and Daniel Rozsar, as well as previous group
members are thanked for useful discussions, insight, and
amide starting material synthesis.
The practicality of our chemistry was demonstrated by
subjecting drug candidate CX-546 and API probenecid to the
standard reaction conditions on gram scale, affording the
oxadiazole-fused drug-drug conjugate (53) in 80% yield
(Scheme 4). Investigation of structure–activity relationships
(SAR) and synthesis of analogues is a critical process in drug
discovery. As such, the capability of our method for the rapid
production of heterodiazole analogues of 53 was examined;
Conflict of Interest
The authors declare no conflict of interest.
À
Keywords: carboxylic acids · C C coupling · heterodiazoles ·
iridium · tertiary amides
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Manuscript received: June 6, 2021
Accepted manuscript online: June 30, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heterocycles
D. Matheau-Raven,
D. J. Dixon*
&&&& — &&&&
General a-Amino 1,3,4-Oxadiazole
Synthesis via Late-Stage Reductive
Functionalization of Tertiary Amides and
Lactams
An iridium-catalyzed reductive three-
component coupling reaction for the
synthesis of medicinally relevant and
structurally complex a-amino 1,3,4-oxa-
diazoles, from tertiary amides, carboxylic
acids, and (N-isocyanimino) triphenyl-
phosphorane, is described. Extension to
heterodiazole synthesis was readily ach-
ieved as was application to the late-stage
functionalization of 10 APIs.
6
www.angewandte.org
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!