B.2. Result and discussions

The newly reported chemical approach to the synthesis of long chain diketo halo nitrile from cyclohexene fused isoxazoline N-oxide derivatives by C-C bond cleavage encouraged us to apply this electrophilic method for introducing fluorine into a large variety of organic compounds.⁶ In order to achieve this objective, we used cyclohexene fused isoxazoline N-oxide (1a) as model substrate as it is easy to prepare. Firstly, N-fluorobenzenesulfonimide (A) was used as the fluorinating agent and a long chain diketo fluoro nitrile was formed from isoxazoline N-oxide for 30 hours of reaction, but the product yield was only 46 % (Table 1 entry 1). In order to increase the product yield as well as to decrease the reaction time, we tested the reaction with various other fluorinating reagents such as Selectfluor (B), Selectfluor II (C), and 1-fluoropyridinium tetrafluoroborate (D) (Table 1, entries 12 and 13). Interestingly, when Selectfluor (B) was used as the fluorinating agent, the starting material was completely consumed in 5 minutes and the desired product 1awas formed in excellent yield (99%) at room temperature (Table 1, entry 11). The structure of the product was confirmed by ¹H NMR, ¹³C NMR,¹⁹F NMR, LRMS, HRMS and Single crystal X-ray analysis (Figure I.B.2.1).

Figure I.B.2.1 Crystal structure of compound 1a¹²

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Table I.B.2.1.Optimization of the reaction with various solvents and reagents

entry^a reagent solvent time yield (%)^b yields (CH2Br2 as internal standard).

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With this preliminary observation in hand, we conducted this reaction in various solvents as shown in Table 1. While using acetonitrile as solvent at room temperature, the reaction proceeded fast and the desired product 1awas formed in excellent yields. With other solvents, the reaction time was longer and the yields were less. Thus, we selected acetonitrile as a suitable solvent for this reaction (Table 1, entry 11).

Selectfluor (B) is F⁺ active fluorinating agent. In acetonitrile, it releases F⁺ ion which aids for fluorination and C–C bond cleavage. We assume, in this reaction a fluorocarbocationic intermediate (I) was generated upon the electrophillic addition of selectfluor to the cyclohexene ring.¹¹ It leads to loss of proton(H^a) to produce the nitric oxide intermediate (II) in the presence of base that was formed from the selectfluor. This intermediate (II) was isolated and confirmed by ¹H NMR and ¹³C NMR spectra. The intermediate (II) undergoes1,4 addition of water to afford Eschenmoser-Tanabe type of intermediate (III) and the final product (10a) was formed via C-C cleavage of the resulting cyclohexane ring.

Scheme I.B.2.1. Plausible mechanism for the Selectfluor mediated fluorination and ring cleavage of cyclohexene fused isoxazoline N-oxide

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Table I.B.2.2.Selectfluor mediatedfluorinationand ring cleavage of sterically hindered isoxazoline N-oxides

aAll the reactions were performed on 0.5mmol scale by using 1.1 equiv of reagent.^bIsolated yields.

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After the optimization of reaction condition, we aimed to explore the scope of our methodology. We primarily focused on the study of the effects of steric and electronic factors of the phenyl substituent towards Selectfluor mediated ring cleavage. Accordingly, the isoxazoline N-oxide derivative containing aphenyl ring with o-substitution was first examined;

the treatment of Selectflour with o-derivative produced the desired product in excellent yield (Table 2, entry 1). In the same way, the product yields were significantly high in case of 2-nitro-5-fluoro, 2-chloro, 2-bromo and 2,4-dichloro derivatives (Table 2, entries 2, 4, 5 and 6).

Furthermore, 2-fluoro and 2-nitro- 4, 5-dimethoxy derivatives conferred moderate to good yields of the desired product (Table 2, entries 3 and 7).

Subsequently, we tested a number of m- and p-substituted, un-substituted phenyl derivatives with Selectfluor at room temperature (Table 3 When isoxazoline N-oxide with p-NO2

substitution at the phenyl ring (10) treated with Selectfluor, nitric oxide intermediate (II) was formed immediately. This intermediate was isolated as green solid and confirmed by ¹H NMR and ¹³C NMR spectra. The ¹H NMR spectra showed a doublet of tripletat 5.97 ppm with J values of 46.4, 4.9 Hz. This doublet of tripletis due to the H^b proton of the intermediate.

Figure I.B.2.2 .The doublet of tripletof H^b proton of the nitroso intermediate

This intermediate was stable at room temperature and produced its corresponding ring cleaved product (10a) little longer time compared to other substrates. Hence, ¹H NMR experiments

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were done to observe the product formation from the intermediate. After isolation by column chromatography, the intermediate was placed in NMR tube with CDCl3 and continuously observed the spectra with an interval of one hour. The half life for the conversion of intermediate into product was found to be 6 hours and 35 minutes at room temperature (Supporting information). But at 50^oC, the intermediate was converted into product in 30 minutes. In order to confirm the rapid formation of intermediate (II), anotherexperiment was conducted in CD₃CN. The substrate and reagent were placed in a NMR tube and observed the

1H NMR spectra in every 2 minutes. From this experiment it is confirmed that the formation of intermediate is very fast (5 min.) in CD₃CN.

Figure I.B.2.3.¹H NMR experiments for half-life study

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Table I.B.2.3..Selectfluor mediated fluorinationand ring cleavage of isoxazoline N-oxides with m- or p-substituted and un-substituted phenyl ring

aAll the reactions were performed on 0.5 mmol scale by using 1.1 equiv of reagent.^bIsolated yields.

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While m-substituted substrates such as 3-bromo and 3-nitro isoxazoline N-oxides were tested, the yield was excellent for the former one (Table 3, entry 1) and moderate for the later one (Table 3, entry 2). Subsequently, the p-substituted substrates (4-nitro and 4-cyano isoxazoline N-oxides) furnished only moderate yields (Table 3, entries 3 and 4). Next, our study focused on the synthesis of isoxazoline N-oxides with electron donating groups (methyl and methoxy), which are unreported perhaps due to the setback in preparation and isolation. Interestingly, we successfully synthesized 4-methyl and 4-methoxy isoxazoline N-oxides. When these substrates were then treated with Selectfluor, the desired product was formed in moderate to good yields(Table 3, entries 5 and 6). Finally, the un-substituted isoxazoline N-oxide was experimented and the yield was moderate (Table 3, entry 7).

Scheme I.B.2.2.Selectfluor mediated fluorination and ring cleavage of 4,4-dimethyl