CsF-Catalyzed Transannulation Reaction of Oxazolones

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CsF-Catalyzed Transannulation Reaction of Oxazolones: Diastereoselective Synthesis of Diversified trans-N-(6-Oxo-1,4,5,6tetrahydropyrimidin-5-yl)benzamides with Arylidene Azlactones and Amidines Golnaz Parhizkar, Ahmad Reza Khosropour, Iraj MohammadpoorBaltork, Elahehnaz Parhizkar, and Hadi Amiri Rudbari ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00027 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 28, 2018

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ACS Combinatorial Science

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Title: CsF-Catalyzed Transannulation Reaction of Oxazolones: Diastereoselective Synthesis of Diversified trans-N-(6-Oxo-1,4,5,6-tetrahydropyrimidin-5-yl)benzamides with Arylidene Azlactones and Amidines Authors: Golnaz Parhizkar, Ahmad Reza Khosropour, Iraj Mohammadpoor-Baltork, Elahehnaz Parhizkar, Hadi Amiri Rudbari

ACS Paragon Plus Environment

ACS Combinatorial Science 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

CsF-Catalyzed Transannulation Reaction of Oxazolones: Diastereoselective Synthesis of Diversified trans-N-(6-Oxo-1,4,5,6tetrahydropyrimidin-5-yl)benzamides with Arylidene Azlactones and Amidines Golnaz Parhizkar,† Ahmad Reza Khosropour,*,† Iraj Mohammadpoor-Baltork,*,† Elahehnaz Parhizkar,‡ Hadi Amiri Rudbari† †

Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran

‡

Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences,

Shiraz 71468-64685, Iran *Corresponding author. Tel.: +98-31- 37932705; fax; +98-31-36689732; e-mail: [email protected]; [email protected]


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ABSTRACT: A versatile and straightforward synthetic strategy for the construction of new tetrasubstituted 1,3-diazinones is described. The procedure is based on CsF-catalyzed, microwave-assisted, ring transformation reaction of arylidene azlactones with amidines. Moreover, this technique provides diversified trans-N-(6-oxo-1,4,5,6-tetrahydropyrimidin-5yl)benzamides with a good antimicrobial activity.

KEYWORDS: Azlactone; Amidine; CsF; Transannulation Reaction; Diastereoselective INTRODUCTION The six-membered N-heterocyclic compounds, particularly pyrimidine moieties, can be found widespread in the core skeleton of some natural products as well as in pharmaceuticals.1 Among them, dihydropyrimidinones by revealing a plethora of biological and pharmacological activities such as antimicrobial,2 antitumor,2,3 antiviral,3 antimalarial,4 anti-inflammatory,5 antihypertensive agents,6 calcium channel blockers,7 α-1a-antagonism,8 neuropeptide Y (NPY) antagonism,9 and mitotic kinesin inhibitors,10 play a prominent role in medical chemistry. Moreover, some dihydropyrimidin-4-one subunits are evaluated as HIV-1 inhibitors.11 Several other ones are currently used in the modulation of psychiatric diseases.12 For instance, risperidone (Risperdal) and paliperidone (9-hydroxy-risperidone, Invega) have been developed for the treatment of schizophrenia.13

Also,

6-oxo-1,4,5,6-tetrahydropyrimidines

core

possess

pronounced

pharmacological activities. For example, Liu et al. have recently described a series of 6-oxo1,4,5,6-tetrahydropyrimidine-5-carboxylates with inhibiting neuraminidase (NA) of influenza A virus (Figure 1, I).14 They found that 5-carboxylate group, 2-acetamino group and the substituted benzene of the compounds are essential for the inhibitory activities. Also, this structural motif exists

in

some

drugs

such

as

(±)-2-(m-chlorophenyl)-3,4a,5,6,7,7a-



hexahydrocyclopenta[d]pyrimidin-4(3H)-one (CHINOIN-143) with a strong anti-inflammatory effect15 and Entecavir as an anti-hepatitis B virus drug16 (Figure 1, II and III).

Figure 1. 6-Oxo-1,4,5,6-tetrahydropyrimidine as substructure in bioactive compounds.

Furthermore, they have been used as precursors for the synthesis of some β-amino acids such as emeriamine and cispentacin, which are key components of some pharmaceuticals.17 Despite the privilege structure of this framework in pharmacological and biological investigations, particularly in the designing of new drug candidates, only a few synthetic routes, such as aza-Wittig reaction,1 azide-alkyne cycloaddition,13,17 multi steps amidation reaction,15 and the modified Biginelli-Atwal reaction12,18 are available in the literature for the synthesis of 6oxo-1,4,5,6-tetrahydropyrimidines. However, the majority of them suffer from partial diversity and/or complexity associated with the usage of a multi-step method under harsh conditions. Therefore, the evolvement of a new and practical alternative protocol for the synthesis of diversely structured, is remarkably essential. Arising from the capability of azlactones to act as 1,3-dipole precursors, (e.g. domino cyclization reactions),19 the attractiveness of 4-arylidene-2-aryl-5(4H)-oxazolones (arylidene azlactones) makes them profitable intermediates and building blocks for preparation of miscellaneous compounds (e.g. non-natural amino acids20 and heterocycles20b,21). Using this property, we have


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recently reported the ring-opening/cyclization reaction of azlactones with DBU and DBN22 to generate pyrrolam A analogs with a high antimicrobial activity. Furthermore, our approach to developing the azlactone chemistry motivated us to introduce an atom-economical,

simple

scheme

to

furnish

polyfunctional

trans-N-(6-oxo-1,4,5,6-

tetrahydropyrimidin-5-yl)benzamides via a CsF-catalyzed, microwave-assisted, transannulation reaction of arylidene azlactones with amidines (Scheme 1).

Scheme

1.

CsF-Catalyzed

Synthesis

of

Polyfunctional

trans-N-(6-Oxo-1,4,5,6-

tetrahydropyrimidin-5-yl)benzamides

RESULTS AND DISCUSSION At the outset, we considered the reaction of (Z)-4-(4-nitrobenzylidene)-2-phenyloxazol-5(4H)one 1{1} with N-(4-chlorophenyl)benzimidamide 2{1} as a template. For this transformation, we investigated the key factors and optimized reaction conditions. To this end, first we examined the effect of catalyst. It is noteworthy that, basic catalysts play a crucial role so that no product was observed in its absence (Table 1, entry 1).



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Table 1. Optimization of the Reaction Conditionsa

Entry Base (equiv) Solvent T (°C) 1 CH3CN reflux 2 NEt3 (0.2) CH3CN reflux 3 DIPEAd (0.2) CH3CN reflux e 4 DABCO (0.2) CH3CN reflux 5 NaOAc (0.2) CH3CN reflux 6 Na2CO3 (0.2) CH3CN reflux 7 K2CO3 (0.2) CH3CN reflux 8 KF (0.2) CH3CN reflux 9 CsF (0.2) CH3CN reflux 10 CsF (0.2) DMF reflux 11 CsF (0.2) THF reflux 12 CsF (0.2) DCE reflux 13 CsF (0.15) CH3CN reflux 14 CsF (0.1) CH3CN reflux 15 CsF (0.05) CH3CN reflux 16 CsF (0.1) CH3CN MW (70 °C) 17 CsF (0.1) CH3CN MW (60 °C) 18 CsF (0.1) CH3CN MW (80 °C) a Reaction conditions: 1{1} (0.20 mmol), 2{1} (0.20 c

Determined

by

1

H

NMR

of

the

crude

t (h) Yield (%)b 3{1,1}:4{1,1}c 12 trace 6 35 10:1 4 43 10:1 6 30 9:1 6 41 10:1 3 54 9:1 3 65 10:1 2 77 12:1 2 81 >13:1 4 69 13:1 6 24 10:1 6 33 12:1 2 88 13:1 2 86 13:1 2 72 13:1 8 min 88 >13:1 8 min 83 13:1 8 min 89 13:1 mmol), solvent (1 mL). bIsolated yield.

product.

d

Diisopropylethylamine.

e

1,4-

Diazabicyclo[2.2.2]octane.

The screening of various organic and inorganic bases in this reaction illustrates that in comparison with organic ones (e.g. triethylamine, diisopropylethyl amine (DIPEA) or DABCO), inorganic catalysts (e.g. potassium fluoride or cesium fluoride) appear to be more suitable for the efficient transformation. Importantly, the yield of the adduct 3{1,1} is improved after 3 h in acetonitrile when CsF is charged rather than KF (81% and 77% yield respectively, entries 8 and 9). Overall, in contrast to other bases, the best diastereoselectivities are observed in the presence


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of fluoride salts (entries 8-18). Moreover, the solvent effect study shows that the reaction is slower with lower yield when it is conducted in DMF, 1,2-dichloroethane (DCE), or THF (4-6 h with 24-69% yields, Table 1, entries 10-12). On the other hand, there is a rough relation between the solvent’s polarity and the diastereoselectivity ratio. Higher diastereoselectivities are achieved in more polar solvents (entries 9-12). The optimal loading of CsF was also surveyed and realized that, the yield of 3{1,1} decreases slightly with reducing to 10 mol % after 2 h. It is noteworthy that utilizing a lower amount (5 mol%) sharply decreases the desired product to 72% (Table 1, entries 13-15). In order to diminish the reaction time and make the procedure more practical, we investigated microwave irradiation effect in this reaction with a temperature-controlled program. During irradiation the temperature was regulated by controlling the MW power with an IR sensor monitor. As illustrated in Table 1, the yield provided by the microwave-assisted reaction at 70 °C (8 min, entry 16) is better than that of conventional heating (88%, entry 16). Also, the results reveal that the product was obtained in good diastereoselectivity (13:1 dr). Notably, we had a lower yield with the same reaction at a lower temperature (60 °C, entry 17), whereas an increase in temperature (entry 18) did not improve the yield. From these results, the optimal condition (entry 16) was chosen for our sequence surveys. To the best of our knowledge, not only the protocol based on azlactone and amidine in the presence of CsF as catalyst under microwave irradiation is unprecedented, but also the structure of the tetrasubstituted 6-oxo-1,4,5,6-tetrahydropyrimidines is new. With the optimized reaction conditions in hand, we first probed the influence of substituents on the aromatic ring of the azlactone (Figure 2).



Figure 2. Diversity of reagents.

As shown in Scheme 2, substrate 1 with functionalized Ar1 underwent the titled reaction with various reactivity. For instance, substrates bearing electron-withdrawing groups such as NO2, CN or halide functionalities (e.g. Cl, Br, F) perform efficiently to deliver the desired products in high yields (3{1,1}-3{8,1}, 78-88%) and moderate to high diastereoselectivity (8:1 to ˃16:1 dr), while electron-donating ones (e.g. OCH3) exhibit slightly lower efficiency (3{9,1}, 63% yield, 11:1 dr; after 20 min).


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Scheme 2. Reaction of Azlactones with N-(4-Chlorophenyl)benzimidamide 2{1}a,b,c

a

Reaction conditions: 1 (0.20 mmol), 2{1} (0.20 mmol), CH3CN (1 mL). bYield of isolated

product. cDiastereoselectivities were determined by 1H NMR of the crude product.

Moreover, thiophene, 3{10,1}) or bulky aryl-substituents (e.g. naphthalene, 3{11,1}) not only provide a promising quantity of the corresponding products, but also moderate to high



diastereoselectivities. Looking at Scheme 2 appears that the kind of substitution on Ar2 has also impacted on the outcome of the reaction. For example, the existence of electron withdrawing groups such as NO2 (3{12,1}, 3{13,1}) or Cl (3{14,1}, 3{15,1}) on Ar2 ring slightly increases the reactivity of the azlactone substrate in the reaction as compared to electron donating ones (3{16,1}). The single crystal X-ray diffraction study of 3{3,1} (see the details in Supporting Information) unequivocally confirms the trans-isomer as dominant configuration (Figure 3).

Figure 3. X-ray structure of compound 3{3,1}.

The versatility of this procedure was further examined by using amidine derivatives with respect to bearing variable aryl or heteroaryl groups to similarly probe electronic effects (Scheme 3).


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Scheme 3. Reaction of (Z)-4-(4-Chlorobenzylidene)-2-phenyloxazol-5(4H)-one 1{3} with Amidinesa,b,c

a

Reaction conditions: 1{3} (0.20 mmol), 2 (0.20 mmol), CH3CN (1 mL). bYield of

isolated product. cDiastereoselectivities were determined by 1H NMR of the crude product.

The results demonstrate both the value and the efficiency of this procedure for the synthesis of trans-N-(6-oxo-1,4,5,6-tetrahydropyrimidin-5-yl)benzamides 3{3,2}-3{3,7}. Also, the yields and diastereoselectivities (78%-85% and dr˃8:1 respectively) show the generality of this process. In addition, the results indicate that although the electron releasing groups on the aromatic ring of Ar3 comparatively increase the rate of the reaction (3{3,3} and 3{3,4}, 83% and 85% with 10:1 and 8:1 dr, respectively), the kind of the substituents on the amidine has no significant impact on the yield of the products.



We have evaluated this protocol to synthesize more complex derivatives. To this end, bisazlactone 1{17} subjected to the reaction with two equivalents of amidine 2{1} and bisamidine 2{8} reacted with two equivalents of azlactone 1{3} via the procedure (Scheme 4).

Scheme 4. Reaction of bis-Azlactone 1{17} with Amidine 2{1} and bis-Amidine 2{8} with Azlactone 1{3}a,b,c

a

Reaction conditions: 1{17} and 2{8} (0.20 mmol), 2{1} and 1{3} (0.40 mmol), CH3CN

(2 mL). bYield of isolated product. cDiastereoselectivities were determined by 1H NMR of the crude product.


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Surprisingly, both parts of bis-azlactone and bis-amidine participated in the reaction efficiently and provided meso forms of trans,trans-3{17,1} and trans,trans-3{3,8} stereoselectively (71% and 68% yield; 16:1 and 19:1 dr, respectively). On the other hand, this procedure is adaptable to scale-up synthesis. For instance, while this reaction was performed under the reaction condition on a 50 mmol (1{11} and 2{1}) scale in the presence of 10 mol% CsF, it completed after 10 min and the product (3{11, 1}) obtained with the same yield as the smaller scale reaction (19.6 g). All of those achievements confirm that this protocol is a straightforward, robust, expeditious and viable way to produce a unique diversity of trans-N-(6-oxo-1,4,5,6tetrahydropyrimidin-5-yl)benzamides. Moreover, the reaction is regiospecific and irrespective of the substitutes nature, one regioisomer was obtained exclusively. Accordingly, a plausible mechanism proposed for this reaction is depicted in Scheme 5. It was suggested that the nucleophilic conjugate addition of amidine at the β-carbon of azlactone initiated after the deprotonation of amidine nitrogen by fluoride ion as a base. At this stage, the final product was obtained via deprotonation and further undergoes cascade reaction of the intermediate A (i.e. 6 endo-dig cyclization/ring-opening reaction). The diastereoselectivity of the trans-isomer is attributed to the electronic repulsion and steric hindrance effect between Ar1 and Ar2.



Scheme 5. Proposed Mechanism

To study the antimicrobial features, the activity of synthesized derivatives was evaluated against selected microorganisms.23 The results demonstrate that these compounds have higher activity than fungi against bacteria. Among bacteria, more efficacy is observed on Gram-positive ones. The compounds containing more Cl substituents possess larger inhibition zones and less MIC values and are more effective antimicrobial agents (see the details in Supporting Information).

CONCLUSION In this research, we have developed an efficient, practical, scalable and expeditious strategy for the synthesis of a wide range of novel trans-N-(6-oxo-1,4,5,6-tetrahydropyrimidin-5yl)benzamides promoted by CsF under microwave irradiation. The reaction of various arylidene azlactones and amidines afforded the trans-isomer product nearly as sole diasteromer. In addition, since aforementioned products exhibit antifungal and particularly antibacterial


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activities,

this

protocol

makes

a

promising

approach

to

attain

bioactive

new

dihydropyrimidinones.

EXPERIMENTAL PROCEDURES General Information. Chemicals were purchased from Fluka and Merck chemical companies. The azlactone24 and amidine25 skeletons were accessed following literature protocols. The microwave system used in these experiments includes the following items: Micro-SYNTH labstation, equipped with a glass door, a dual magnetron system with pyramid shaped diffuser, 1000 W delivered power, exhaust system, magnetic stirrer, ‘quality pressure’ sensor for flammable organic solvents, and a ATCFO fiber optic system for automatic temperature control. The progress of the reactions was monitored by thin layer chromatography (TLC) using 0.25 mm pre-coated silica gel HF254 plates. Silica gel (230-400 mesh, silicscycle) was used for column chromatography. Melting points were determined using Stuart Scientific SMP2 apparatus. FT-IR spectra were recorded on a Nicolet-Impact 400D instrument in the range of 400-4000 cm-1. 1H and

13

C NMR spectra were recorded on a Bruker Avance 400 MHz Fourier-transform

spectrometer. Coupling constants were reported in hertz. Elemental analysis was performed on a LECO, CHNS-932 analyzer. High resolution mass spectrometry (HRMS) spectra were recorded using electrospray ionization with a time-of-flight mass analyzer (ESI-TOF). General Procedure for the Preparation of Compounds 3{1,1}-3{16,1}: The reaction mixture of azlactones 1{1}-1{16} (0.20 mmol), N-(4-chlorophenyl)benzimidamide (2{1}, 0.046 g, 0.20 mmol), CsF (0.003 g, 0.10 equivalent), and CH3CN (1 mL) was subjected to MW irradiation (200 W, 70 °C) for the appropriate time according to Scheme 2. After completion of the reaction as monitored by TLC (eluent: petroleum ether/ethyl acetate, 5:2), the solvent evaporated under



reduced pressure and the mixture was extracted with ethyl acetate (3×5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate in petroleum ether) afforded the products 3{1,1}-3{16,1}. General Procedure for the Preparation of Compounds 3{3,2}-3{3,7}: The reaction mixture of (Z)-4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (1{3}, 0.056 g, 0.20 mmol), amidines 2{2}-2{7} (0.20 mmol), CsF (0.003 g, 0.10 equivalent), and CH3CN (1 mL) was subjected to MW irradiation (200 W, 70 °C) for the appropriate time according to Scheme 3. After completion of the reaction as monitored by TLC (eluent: petroleum ether/ethyl acetate, 5:2), the solvent evaporated under reduced pressure and the mixture was extracted with ethyl acetate (3×5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate in petroleum ether) afforded the products 3{3,2}-3{3,7}. General Procedure for the Preparation of Compound 3{17,1}: The reaction mixture of (4Z,4'Z)-4,4'-(1,4-phenylenebis(methanylylidene))bis(2-phenyloxazol-5(4H)-one) (1{17}, 0.084 g, 0.20 mmol), N-(4-chlorophenyl)benzimidamide (2{1}, 0.092 g, 0.40 mmol), CsF (0.006 g, 0.20 equivalent), and CH3CN (2 mL) was subjected to MW irradiation (200 W, 70 °C) for the appropriate time according to Scheme 4. After completion of the reaction as monitored by TLC (eluent: petroleum ether/ethyl acetate, 5:2), the solvent evaporated under reduced pressure and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate in petroleum ether) afforded the product 3{17,1}.


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General Procedure for the Preparation of Compound 3{3,8}: The reaction mixture of (Z)-4(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one (1{3}, 0.113 g, 0.40 mmol), N-phenyl-4((phenylamino)methyl)benzimidamide (2{8}, 0.060 g, 0.20 mmol), CsF (0.006 g, 0.20 equivalent), and CH3CN (2 mL) was subjected to MW irradiation (200 W, 70 °C) for the appropriate time according to Scheme 4. After completion of the reaction as monitored by TLC (eluent: petroleum ether/ethyl acetate, 5:2), the solvent evaporated under reduced pressure and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate in petroleum ether) afforded the product 3{3,8}. Antimicrobial Assay: The in vitro antibacterial activities of the samples were determined by agar disc diffusion method. American Type Culture Collection (ATCC) strains of Escherichia coli (ATCC 25922) as Gram-negative and Bacillus subtilis (ATCC 11778) and clinical isolates of Staphylococcus aureus as Gram-positive bacteria (standard inoculums concentration was 1-1.5 × 108 c.f.u./mL) were grown on nutrient broth medium and incubated at 37 °C for 24 h. Microorganisms were seeded over sterilized culture medium plates and growth inhibition zones were measured in mm using streptomycin, penicillin, and tetracycline as references antibiotics (positive control). All compounds were dissolved in DMSO in the concentration of 100 µg/mL with DMSO as negative control. Minimum Inhibitory Concentration (MIC) assay was determined applying broth dilution method. This assay shows the minimum concentration that inhibits the growth of bacteria completely. The compounds (with the concentrations of 200, 100, 50, 25, 12.5 and 6.25 µg/mL) were two fold diluted into nutrient broth medium containing approximately 5 × 106 c.f.u./mL of bacteria



cells. Samples incubated at 37 °C for 24 h and the lowest concentration (highest dilution) was considered as MIC. The antifungal activity also performed by disk diffusion method on potato dextrose agar medium. Strains of fungi Candida albicans (ATCC 10261) and clinical isolates of Aspergillus flavus (2-5 × 106 spores/mL) were incubated 5 days at 35 °C. Synthesized compounds with the concentration of 100 µg/mL were mixed with agar and allowed to solidify. Fluconazole and nystatin as two antifungal drugs were selected as positive control samples. MIC of fungi was performed as the mentioned method for bacteria with differences in fungal concentration and incubation time. The nutrient broth inoculated with 2-5 × 104 spores/mL and incubated for 5 days at 35 °C. ASSOCIATED CONTENT Supporting Information Typical experimental procedures, antimicrobial assay and characterization data, including 1H and 13

C spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *Fax: +98(31)36689732. Phone: +98(31) 37932705. E-mail: [email protected] (A.R.K.), [email protected] (I.M.-B.) Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS The authors are grateful to the Center of Excellence of Chemistry and the Research Council of the University of Isfahan for financial support of this work.


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1

H NMR evaluation of a 96-member 1,2,4-trisubstituted-pyrimidin-6-one-5-

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CsF-Catalyzed Transannulation Reaction of Oxazolones

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