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

Shaoyu Mai a, Changqing Rao a, Ming Chen b, Jihu Su b, Jiangfeng Du b and Qiuling Song *a
aInstitute 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
bCAS Key Laboratory of Microscale Magnetic Resonance, Department of Modern Physics, University of Science and Technology of China, Hefei, Anhui 230026, China

Received 24th July 2017 , Accepted 21st August 2017

First published on 21st August 2017


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.


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 rings,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, the group of Hashmi 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 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 satisfactory unless the gold-catalyzed cyclization and the oxidation reaction were conducted in two separate operations.


image file: c7cc05746f-s1.tif
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 the groups of Shi and Jiao (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 a 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 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.

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.

We commenced our investigations with N-propargylbenzamide (1) as the standard substrate by examining various conditions.8 It was observed that Conditions A (Table S1, entry 4, ESI) afforded 5-oxazolecarbonitrile 2 in 70% yield, whereas 5-oxazolecarboxamide 3 was obtained in 68% yield under Conditions B (Table S1, entry 14, ESI). 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 and 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 The 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 the substrate with the steric-demanding 1-adamantanyl substituent was also suitable in this transformation, generating the corresponding nitrile product 22 in 74% yield. Unfortunately, the phenoxymethyl substrate did not give the desired product 23 under the standard conditions.


image file: c7cc05746f-s2.tif
Scheme 2 5-Oxazolecarbonitrile synthesis catalyzed by an Au/NHPI/Ni ternary system.

Then we investigated the substrate scope for the synthesis of 5-oxazolecarboxamides (Scheme 3). The reaction worked well with para-substituted arylamide substrates. Alkyl (24–26), alkoxy (27 and 28), halo (29–31), trifluoromethyl (32), formyl (33), and cyano (34) groups were all compatible under the 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 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 corresponding products in reasonable yields (41–43). Gratifyingly, alkenyl- and alkylamides demonstrated good reactivity as well and the desired products were obtained in decent yields (44–48), which underscores the great potential and the broad spectrum of this novel catalytic system.


image file: c7cc05746f-s3.tif
Scheme 3 5-Oxazolecarboxamide synthesis catalyzed by an Au/NHPI/Cu ternary system.

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 2 mainly at the C5-position to demonstrate the synthetic value of our methodologies (Scheme 4). 2 can be easily converted 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 with p-TsOH·H2O (p-toluenesulfonic acid) under reflux conditions.12 Tetrazole 51 can also be easily prepared from 2 with sodium azide in 92% yield.13


image file: c7cc05746f-s4.tif
Scheme 4 Derivatizations of carbonitrile 2.

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 the group of Hashmi.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 absence of the gold catalyst (Scheme 5a). In all cases, only trace amounts 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,d 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 the groups of Lu15a and Williams,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). 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 the vinyl–Au–L complex and the gold catalyst may be involved in the catalytic cycle.17,18


image file: c7cc05746f-s5.tif
Scheme 5 Control experiments to explore the possible intermediates in our catalytic transformations.

To obtain more mechanistic information, we conducted several deuterium labeling experiments (Scheme 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 substrate 58 and subjected it to Conditions A. To our delight, the desired product ketone 59 (generating from the hydrolysis of oxime 60) was obtained in 25% isolated yield in the presence of the 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


image file: c7cc05746f-s6.tif
Scheme 6 Isotopic labeling experiments and reaction of internal alkyne 58.

According to the above-mentioned mechanistic experiments, EPR experiments (see the ESI for details) and precedent reports,5,14,17 a plausible reaction mechanism is proposed in Scheme 7. First, the cyclization of propargyl amide 1 initiated by cationic Au(I) leads to the vinyl–Au intermediate A. Based on our control experiments (Scheme 5d), we speculate that intermediate A itself could react with LAuX to give complex B, which might compete with protodeauration giving the good affinity of the π bond to the NO radical. The radical addition of complex B with NO then takes place to give intermediate C with a newly formed carbon–nitrogen bond. The subsequent hydrogen atom transfer (HAT) from the intermediate C to PINO occurs, generating NHPI and an aromatized intermediate D. Finally, this intermediate would be expected to rapidly isomerize or proton transfer to aldoxime 54, which undergoes further Lewis acid catalyzed transformations to give the final products 2 and 3 through choosing appropriate solvents. This hypothesis 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.


image file: c7cc05746f-s7.tif
Scheme 7 Plausible reaction mechanism.

In conclusion, we have disclosed a novel ternary catalytic system consisted of gold catalysts, redox-active NHPI catalysts, and transition-metal catalysts for the practical 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 the organocatalytic oxidation process is crucial in the success of our transformations. Further mechanistic studies are ongoing in our laboratory.

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 the Program of Innovative Research Team of Huaqiao University (Z14X0047) is 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.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. CCDC 1482206. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc05746f

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