Merging gold catalysis, organocatalytic oxidation, and Lewis acid catalysis for chemodivergent synthesis of functionalized oxazoles from: N -propargylamides

Article abstract of DOI:10.1039/c7cc05746f

Novel catalytic systems consisting of cationic gold complexes, N-hydroxyphthalimide (NHPI), and transition-metal-based Lewis acids have been developed for the one-pot synthesis of functionalized oxazoles from N-propargylamides with excellent functional group tolerance. These transformations demonstrated the excellent compatibility of homogeneous gold catalysis with organocatalytic oxidative carbon-nitrogen bond formations using tert-butyl nitrite as the terminal oxidant. Moreover, oxazolecarbonitriles or carboxamides can be easily synthesized in a one-pot protocol according to the different synthetic requirements.

Full text of DOI:10.1039/c7cc05746f

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Merging gold catalysis, organocatalytic oxidation, and lewis acid
catalysis for chemodivergent synthesis of functionalized oxazoles
from N-propargylamides
Received 00th January 20xx,
Accepted 00th January 20xx
Shaoyu Mai,a Changqing Rao,a Ming Chen,b Jihu Su,b Jiangfeng Du,b and Qiuling Song*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Novel catalytic systems consisted of cationic gold complex, N- satisfactory unless the gold-catalyzed cyclization and the
hydroxyphthalimide (NHPI), and transition-metal-based Lewis oxidation reaction were conducted in two seperated
acids have been developed for the one-pot synthesis of operations.
functionalized oxazoles from N-propargylamides with excellent
functional group tolerance. These transformations demonstrated
the excellent compatibility of homogeneous gold catalysis with
organocatalytic oxidative carbon−nitrogen bond formations using
tert-butyl nitrite as the terminal oxidant. Moreover,
oxazolecarbonitriles or carboxamides can be easily synthesized in
a
one-pot protocol according to the different synthetic
requirements.
Oxazole derivatives are widely found in natural products and
pharmaceuticals with impressive biological properties, such as
antiviral, antibacterial, antileukemia, and antitumor activities.1
Tremendous efforts have been devoted to the development of
new methodologies and strategies to construct the oxazole
ring,2 such as condensations,2c cyclizations,2d transition-metal-
catalyzed addition of diazo compounds to nitriles,2e and
rearrangements.2f However, most of these reactions require
harsh reaction conditions, limiting the wide application of
these classical oxazole synthetic methods in organic synthesis.
Homogeneous gold catalysis provides a practical solution to
address this challenge.3−5 In 2004, Hashmi group developed a
gold-catalyzed 5-exo-dig cyclization of N-propargylamide to
synthesize functionalized 5-methyloxazoles (Scheme 1a).4a In
their pioneering work, the catalytic cycle was furnished by a
Scheme 1 Gold-catalyzed cyclizations of N-propargylamides for
functionalized oxazole synthesis.
Recently, the incompatibility between gold catalysis and
transition-metal-catalyzed oxidations has also been observed
by Shi and Jiao groups (Scheme 1c).5 For example, due to the
poor compatibility and the orthogonal reactivity of the two
catalytic systems, the carbon−nitrogen (C−N3) bond formation
can only be achieved in a two-step approach. To solve this
problem, Shi, Jiao, and co-workers5 developed an elegant
synergistic gold and iron dual catalysis6 for the synthesis of 5-
formyloxazoles (Scheme 1d). Such reaction efficiently
constructed the oxazole skeleton with an additional
carbon−oxygen double bond. To the best of our knowledge, no
other successful examples for the synthesis of valuable oxazole
derivatives have been achieved to solve the incompatibility
between gold catalysis and oxidation reactions. Therefore, it
becomes highly desirable yet very challenging to develop new
catalytic reactions by the combination of gold-catalyzed
cyclization and oxidation processes. We envisioned that
organocatalytic oxidations,7 which appear to be milder
compared to traditional oxidation processes, may be
compatible with gold catalysis, and thus may promote new
protodeauration step, leading to
a methyleneoxazoline
intermediate. Thereafter, the same group attempted to react
the in situ generated methyleneoxazoline with electrophilic
halogenating reagents4c or dioxygen4e for the formation of
carbon−halogen and carbon−oxygen bonds, respectively
(Scheme 1b). However, the reaction yield is generally not
a. Institute of Next Generation Matter Transformation, College of Chemical
Engineering, College of Material Sciences, Huaqiao University, Xiamen, Fujian
361021, China.
E-mail: qsong@hqu.edu.cn
b. CAS Key Laboratory of Microscale Magnetic Resonance, Department of Modern
Physics, University of Science and Technology of China, Hefei, Anhui 230026, China
Electronic Supplementary Information (ESI) available. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/x0xx00000x
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transformations of significant interest. Considering that metal-
based Lewis acid (LA) additives are known to improve the
efficiency of aerobic oxidations catalyzed by N-
hydroxyphthalimide (NHPI) and other organocatalysts,7 we
also expected that the introduction of Lewis acids and suitable
solvents may help to blend homogeneous gold catalysts and
redox-active organocatalysts together.
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DOI: 10.1039/C7CC05746F
Herein, we report two novel Au/NHPI/LA ternary catalytic
systems for the practical synthesis of highly functionalized
oxazoles from easily prepared N-propargylamide substrates
(Scheme 1e). To the best of our knowledge, the one-pot
generation of these C−N bond formation products by merging
gold catalysis and catalytic oxidations has never been reported
before.
Scheme
Au/NHPI/Cu ternary system.
3
5-Oxazolecarboxamide synthesis catalyzed by
Then we investigated the substrate scope for the synthesis
of 5-oxazolecarboxamides (Scheme 3). The reaction worked
well with para-substituted arylamide substrates. Alkyl (24
alkoxy (27 and 28), halo (29 31), trifluoromethyl (32), formyl
33), and cyano (34) groups were all compatible under the
−26),
−
(
standard conditions, leading to the desired products in
moderate to good yields. Meanwhile, meta-, ortho-, and
disubstituted arylamide substrates also showed good
tolerance with the target transformation (35−40). Other
Scheme
2 5-Oxazolecarbonitrile synthesis catalyzed by
substrates with aromatic substituents, including 2-naphthyl as
well as the heteroaromatic 3-furanyl and 3-thiophenyl groups,
were also good candidates for this protocol, rendering the
Au/NHPI/Ni ternary system.
We
propargylbenzamide
examining various conditions.8 It was observed that Conditions
A (Table S1, entry 4) afforded the 5-oxazolecarbonitrile in
70% yield, whereas 5-oxazolecarboxamide was obtained in
commenced
our
investigations
with
N-
corresponding products in reasonable yields
(41−43).
(1) as the standard substrate by
Gratifyingly, alkenyl- and alkylamides demonstrated good
reactivity as well and the desired products were obtained in
2
decent yields (44
−48), which underscores the great potential
3
and the broad spectrum of this novel catalytic system.
68% yield under Conditions B (Table S1, entry 14). The
generation of 5-oxazolecarbonitriles was first tested (Scheme
2). Gratifyingly, a variety of N-propargylamide substrates
bearing aryl substituents with different electronic effects and
functional groups were well tolerated in this transformation,
affording the desired products in moderate to good yields (
2,
5−
21). Notably, the ortho substituents on the phenyl ring did
not affect the reaction yields (14 and 15). Moreover, the
structure of 14 was unambiguously confirmed by X-ray
crystallographic analysis.9 2-Naphthyl substrate was also well
tolerated under the standard conditions (19). Substrates with
heteroaromatic substituents, such as 3-furanyl and 3-
thiophenyl groups, were compatible as well, giving the desired
products 20 and 21 in 50% and 52% yields, respectively. It is
noteworthy that substrate with the steric-demanding 1-
adamantanyl substituent was also suitable in this
transformation, generating the corresponding nitrile product
22 in 74% yield. Unfortunately, phenoxylmethyl substrate did
not give the desired product 23 under the standard conditions.
Scheme 4 Derivatizations of carbonitrile 2.
Boger and co-workers have found that 5-substituted
oxazoles are potent inhibitors of fatty acid amide hydrolase.10
Therefore, we investigated the derivatizations of nitrile
mainly at the C5-position to demonstrate the synthetic value
of our methodologies (Scheme 4). can be easily converted
2
2
into either amide 311 or carboxylic acid 49 under different basic
conditions in good yields. 2-Imidazoline 50 containing two
heterocycles was prepared in 61% yield by mixing
2 and
ethylenediamine up with p-TsOH·H2O (p-toluenesulfonic acid)
2 | J. Name., 2012, 00, 1-3
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under reflux conditions.12 Tetrazole 51 can also be easily substrate 58 and subjected it to Conditions A. To our delight,
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prepared from
2
with sodium azide in 92% yield.13
the desired product ketone 59 (generatDinOgI:f1r0o.1m039h/yCd7rCoCl0y5s7is46oFf
oxime 60) was obtained in 25% isolated yield in the presence
of gold catalyst, yet only a trace amount of 59 was observed
without the cationic gold complex (Scheme 6d). This
experimental observation supported our previous hypothesis
that the σ-activation should not be the major reaction
pathway.19
Scheme 5 Control experiments to explore the possible
intermediates in our catalytic transformations
To gain insights into the reaction mechanism, we started to
explore the possible intermediates in our catalytic systems.
The intermediacy of methyleneoxazoline 52 has been
previously proposed by Hashmi group.4a To verify whether the
same intermediate exists in our reactions, we synthesized 52
and subjected it to both Conditions A and B in the presence or Scheme 6 Isotopic labeling experiments and reaction of
absence of the gold catalyst (Scheme 5a). In all cases, only internal alkyne 58
traces amount of the desired products were detected,
suggesting that 52 should not be an intermediate in our
transformations. Similar results were found when 5-methyl-2-
.
phenyloxazole 53 and aldehyde
4 were employed (Scheme 5b),
indicating that 53 and 4 may also not be involved in the
catalytic cycle. Inspired by previous work,14a, 14d we prepared
aldoxime 54 and treated it under both Conditions A and B
(Scheme 5c). To our delight, the desired products
2 and 3 were
obtained in reasonable yields. These results are consistent
with the previous reports by Lu15a and Williams groups,15b
showing that nickel and copper complexes are efficient
catalysts for aldoxime dehydration and rearrangement,
respectively. These control experiments indicated that
aldoxime 54 may indeed be the key intermediate in our
Au/NHPI/LA ternary catalytic system. Moreover, to further
explore possible gold-containing intermediates, we prepared a
stable vinyl−Au−IPr complex 55 according to the literature16
and subjected it to the NHPI/Ni catalytic system (Scheme 5d).
Scheme 7 Plausible reaction mechanism.
According to the above-mentioned mechanistic experiments
EPR experiments (see ESI for details) and precedented
reports,5, 14, 17 a plausible reaction mechanism is proposed in
Scheme 7. First, cyclization of propargyl amide
cationic Au(I) leads to the vinyl-Au intermediate
our control experiments (Scheme 5d), we speculate that
intermediate itself could react with LAuX to give complex
which might compete with protodeauration giving the good
affinity of π bond to NO radical. Radical addition of complex
with NO then takes place to give intermediate with a newly
formed carbon–nitrogen bond. The subsequent hydrogen
atom transfer (HAT) from the intermediate to PINO occurs,
generating NHPI and an aromatized intermediate . Finally,
1
initiated by
A
. Based on
Surprisingly, the corresponding product
2 was not formed in
the absence of Au, however, it was obtained in 20% yield
under Conditions A (with Au catalyst). We speculate that
another active complex generated from vinyl−Au−L complex
and gold catalyst maybe involved in the catalytic cycle.17, 18
To obtain more mechanistic information, we conducted
several deuterium labeling experiments (Schemes 6a-c). These
control experiments indicated that the σ-activation should not
be the major reaction pathway. Furthermore, these results
have also excluded the involvement of protodeauration steps
in our reaction systems, otherwise a certain amount of
deuterium incorporation should be observed when excess D2O
was added (Scheme 6c). Then, we prepared an internal alkyne
A
B,
B
C
C
D
this intermediate would be expected to rapidly isomerize or
proton transfer to aldoxime 54, which undergoes further Lewis
acids catalyzed transformations to give the final products
2
and 3 by choosing appropriate solvents. This hypothesis
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Hengst, S. Schetter, A. Littmann, M. Rudolph, VMiew. AHrtaicmlezOincl,ineJ.
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combines radical reactions, gold catalysis and Lewis acid
catalysis which are unusual in homogeneous gold catalyzed
reactions.5-7 Further detailed studies are underway to clarify
this intriguing point.
In conclusion, we have disclosed a novel ternary catalytic
system consisted of gold catalyst, redox-active NHPI catalyst,
and transition-metal catalysts for the pratical and
chemodivergent synthesis of functionalized 2,5-disubstituted
oxazoles in a one-pot fashion. This protocol is an efficient and
robust method to construct oxazole scaffolds with excellent
functionality tolerance. Tert-butyl nitrite was used as the
terminal oxidant and the nitrogen source, leading to C−N bond
formation products in good yields. The excellent compatibility
of homogeneous gold catalysis with organocatalytic oxidation
process is crucial in the success of our transformations. Further
mechanistic studies are ongoing in our laboratory.
5
6
H. Peng, N. G. Akhmedov, Y.-F. Liang, N. Jiao, and X. Shi, J.
Am. Chem. Soc., 2015, 137, 8912.
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7
Financial support from the Recruitment Program of Global
Experts (1000 Talents Plan), the Natural Science Foundation of
Fujian Province (2016J01064), the National Key Basic Research
Program of China (973 Program, 2013CB921802), Fujian
Hundred Talents Plan, and Program of Innovative Research
Team of Huaqiao University (Z14X0047) are gratefully
acknowledged. We also thank Instrumental Analysis Center of
Huaqiao University for analysis support. S.M. thanks the
Subsidized Project for Cultivating Postgraduates’ Innovative
Ability in Scientific Research of Huaqiao University.
Melone and C. Punta, Beilstein J. Org. Chem., 2013, 9, 1296;
(f) K. Chen, P. Zhang, Y. Wang and H. Li, Green Chem., 2014,
16, 2344.
See Electronic Supplementary Information for details.
8
9
CCDC 1482206
(14
)
contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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18 According to the 31P NMR data, we speculate another
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,
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