Contrasting C- and O-Atom Reactivities of Neutral ... - ACS Publications

Article Cite This: J. Org. Chem. 2018, 83, 203−219

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Contrasting C- and O‑Atom Reactivities of Neutral Ketone and Enolate Forms of 3‑Sulfonyloxyimino-2-methyl-1-phenyl-1butanones Yingtang Ning, Yuko Otani, and Tomohiko Ohwada* Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku Tokyo 113-0033, Japan S Supporting Information *

ABSTRACT: The mechanisms of intramolecular cyclization of 3sulfonyloxyimino-2-methyl-1-phenyl-1-butanones (1) under basic (DABCO and t-BuOK) and acidic (AcOH and TFA) conditions were investigated by means of experimental and computational methods. The ketone, enol, and enolate forms of 1 can afford different intramolecular cyclization products (2, 3, 4), depending on the conditions. The results of the reaction of 1 under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (t-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketones, which exhibit reactivities arising from both the oxygen lone-pair electrons (O atom reactivity) and carbon σ-electrons (C atom reactivity). The neutral enol in DABCO afforded 2H-azirine 4. On the other hand, the products (isoxazole 2 and oxazole 3) generated from the ketone form and from the enolate form are the same, but the reaction mechanisms are apparently different. The results demonstrate ambident-like reactivity of neutral ketone in the 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanone system.

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Scheme 1. Ambident-like Reactions of (a) Enolate Anion, (b) Enol, and (c) Neutral Ketonea

Figure 1. Examples of different reactivities of ambident nucleophiles. (a) CN−, sulfoxides and hydrazines. (b) SCN−, phenols and enolates.

a

INTRODUCTION Ambident reactivity refers to the situation where a compound possesses two strongly interacting reactive centers, either of which may form a chemical bond, accompanied by loss of reactivity at the other site.1 Several ideas have been proposed to explain the different reaction preferences of typical ambident nucleophiles (Figure 1) under different conditions, including the hard and soft acids and bases (HSAB) theory,2 charge and orbital control of organic reactions,3 and the Marcus theory.4

lead to a preference for the C-attack product by blocking the Onucleophilicity.7 In the gas phase without a counterion, Oattack is favored because the O-nucelophilicity was not blocked by the counterions and solvent and resonance effects significantly increase the barrier for C atom reactivity.8

Among ambident reactive species, enols and enolates are of particular interest because of their importance in synthetic chemistry.5 Enolate anions generated under basic conditions can react at either the oxygen atom (O-attack) or the carbon atom (C-attack) (Scheme 1a).6 The reaction selectivity depends upon many factors, including the nature of the enolate, the electrophilic counterpart, the reaction solvent, and the counterion. For example, metal-cation coordination can © 2017 American Chemical Society

Tautomerization of ketones to corresponding enols is relatively facile.

Received: October 10, 2017 Published: November 30, 2017 203

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1a and 1b possess both a carbonyl group (CO) and hydroxyimino group (CN−OR) in a single molecule. In all reaction substrates, the oxime N−O bonds are anti-periplanar with the carbonyl groups (i.e., E-oximes). We performed the reactions of 1a and 1b under Brønsted basic conditions (Scheme 3, reactions 1 and 2) and acidic conditions (Scheme 3,

In contrast to the interest in ambident reactivity of anionic enolates and neutral enols, the closely related C atom and O atom reactivities of neutral ketones have been little studied. Neutral ketones may have potential for dual reactivities based on the oxygen lone-pair electrons (Scheme 1c, O atom reactivity) and carbon σ-electrons (C atom reactivity). OAttack reactions of ketones occur under acidic conditions.9,10 However, it is difficult to study the nucleophilic reactivity at the C atom of ketones because of the inductive effect of the proximate oxygen and the inherent difficulty of breaking an sp3 C−C or C−H bond at the α position.11 Modern synthetic chemistry generally utilizes enolate and enamine intermediates to activate the α-position of carbonyl functionalities.12 In addition, tautomerization of ketones to the corresponding enols is relatively facile under both acidic and basic conditions,13 and C-attack on the enol form predominates over C-attack on the ketone form, even if the equilibrium constant is small (Scheme 1b). Indeed, organic chemistry textbooks state that the tautomerization of ketones to enols explains why “substitution reactions [at carbon] do not occur from the carbonyl form”.14 To study the nucleophilic reactivities of the C and O atoms of ketones, we designed 3-sulfonyloxyimino-2-methyl-1-phenyl1-butanones 1a and 1b as model molecules (Scheme 2). The

Scheme 3. Reactions of 1a and 1b under Brønsted Basic (Reactions 1 and 2) and Acidic Conditions (Reactions 3 and 4)a

Scheme 2. Model Compounds 1a and 1b and the O-Attack/ C-Attack Reactivity of the Ketone Form of 1a

a

Yields in parentheses were calculated from 1H NMR signals of the crude product, using 1,2-dichloroethane as internal standard.

oxime functionality (CNOR) can undergo Beckmann rearrangement,15 which can lead to cleavage of the C−C σ bond, even in the case of the electron-deficient C−C σ bond, exemplified in p-nitroacetophenone oxime (Supporting Information, Scheme S1a).16 Oxime compounds are also able to react with a C anion,17 which is known as the Neber rearrangement (Scheme S1).18 These different reactivities of oxime compounds with C−C bonds and C anions, together with the potent reactivity of oximes with heteroatoms via 5membered ring formation (Scheme S1),19−21 make 1a and 1b suitable for the study of ambident-like reactivity of ketones. In this study, we investigated the reactivities of the C and O atoms of neutral ketone form in the specially designed 3sulfonyloxyimino-2-methyl-1-phenyl-1-butanone system, in comparison with those of the corresponding enol and anionic enolate forms, focusing on intramolecular substitution reaction with the oxime nitrogen atom. Notably, different distributions of products, and sometimes different products, were obtained. Reactivities of the ketone form and enolate (enol) form are favored under acidic and basic conditions, respectively. We also show that chemoselective synthesis of isoxazoles22 and 2Hazirines,23 which are important synthons in organic chemistry, can be achieved from the same substrate under different conditions through control of the selectivity for O-attack and C-attack.

reactions 3 and 4). High selectivity for C-attack (C−N bond formation) was observed in the reaction of 1a with a relatively mild base, 1,4-diazabicyclo[2.2.2]octane (DABCO), yielding the 2H-azirine 4a (Scheme 3, reaction 1). Previous reports24 have described the transformation of 4a into 3a by strong bases, and we found that when 1a was treated with t-BuOK, 2a and 3a were obtained in comparable yields (Scheme 3, reaction 2). Product 2a contains a new O−N bond, which indicates O atom reactivity. Our mechanistic studies (vide infra) strongly suggest that these reactions under basic conditions occurred from the enol (DABCO) and enolate (t-BuOK) forms of 1a. On the contrary, a preference for O-attack, leading to the formation of an O−N bond, was observed under acidic conditions using AcOH (Scheme 3, reaction 3). When stronger trifluoroacetic acid (TFA) was used, the reaction again gave a mixture of 2a and oxazole 3a (Scheme 3, reaction 4). The intermediacy of 2H-azirine 4a under acidic conditions was excluded, since 4a in AcOH and TFA did not produce either 2a or 3a, and 4a was recovered after aqueous workup. Under acidic conditions, 1a and 1b react preferentially as the ketone form, without tautomerizing to the corresponding enol, and provide rare examples of ambident-like reactivities of ketones. Specifically, 2a originates from intramolecular O-attack in 1a (1b), which is highly favored in AcOH. On the other hand, the formation of 4a and 3a reflects C atom reactivity, which is favored in the reaction with DABCO. Dual O- and C-reactivities, that is, formation of both 2a and 3a, occurred in the reactions with TFA and tert-BuOK. To understand what reactive species are

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RESULTS AND DISCUSSION Divergent Reactivity of 2-Methyl-3-(((methylsulfonyl)oxy)imino)-1-phenylbutan-1-one 1a and 1b. Compounds 204

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Figure 2. Mechanistic studies of Neber-type reaction of 1a.

hydrochloride salt of DABCO ([DABCO-H+]), in the presence of 2 equiv of DABCO, had the effect of slowing the reaction by about 30% at −4 °C.30 This result is as would be expected if the enol/enolate intermediate (5a/5a−) is less stable than the starting ketone (1a) and if k−1 is comparable to k2, although the cyclization step is not rate-determining (eq 1). This situation is supported by the following computational studies.

responsible for these reactions, we carried out a series of mechanistic studies of these transformations. Base-Catalyzed Reactions of 2-Methyl-3(((methylsulfonyl)oxy)imino)-1-phenylbutan-1-one 1a. Reaction of 1a with DABCO: C-Attack Reaction of Enol (Reaction 1) (Scheme 3). We first studied the reaction of 1a with DABCO. This transformation from 1a to 4a is a familiar Neber-type rearrangement reaction of oxime compounds. The general mechanism of Neber rearrangement is not fully understood,18 and may depend on the nature of the substrate.25 Surprisingly few reaction kinetics data or computational results are available, despite recent advances in application of the Neber rearrangement during the construction of complex molecules.23,26 For 1a, we found that the best yield was obtained with DABCO in dichloromethane (Table S1, Supporting Information), although the reaction also proceeded smoothly with other bases including triethylamine and DBU. Therefore, mechanistic study was conducted employing DABCO in CH2Cl2. When an optically active sample of 1a (82:18 er) was treated with DABCO, the racemic form of 4a was obtained (Figure 2, a). This excludes the possibility of a concerted mechanism for the Neber rearrangement.25b,27 The reaction showed first-order kinetics for DABCO over the range from 1 to 10 equiv (Supporting Information, Figure S1). The hydrogen/deuterium kinetic isotope effect (KIE) was next studied, and a KIE of kH/kD = 5.2 was observed at −4 °C (Figure 2, b; also see the details of kinetic measurements in Supporting Information). These results suggest that C-attack probably occurred in the enol form (5a). The deprotonation should be the rate-determining step (RDS), and the enolate intermediate can react either intramolecularly to afford 4a directly or generate the enol after proton transfer. This mechanism involved the formation of the carbanion intermediate as the rate-limiting step, as in the E1cB mechanism.28 This is also in agreement with the results of 13C KIE measurement at natural abundance. Overall, it appears that bond cleavage at the C atom occurred in the RDS (KIE = 1.015, Figure 2c and Figure S2).29 When the reaction was monitored by means of 1H NMR, the enol/enolate (5a/5a−, Scheme 4) intermediate was too unstable to be observed. The addition of 0.5 equiv of

rate =

k1k 2[DABCO][1a] k −1[DABCO‐H+] + k 2[DABCO]

(1)

We also conducted DFT calculations on the putative transformation at the M06-2X/def2-TZVPP/CPCM//M062X/6-31+G(d,p)/CPCM level, which has been reported to be compatible with an E1cB-type reaction.31 This calculation method was also used in the computational studies of other reactions of 1a for the sake of consistency and comparability. In these computational studies, NH3 was used as a base instead of DABCO for simplicity. In the first step of the transformation, the 3-sulfonyloxyimino-1-ketone 1a is deprotonated by NH3 to form the intermediate NC2 in a slightly endergonic reaction (Figure 3, a, ΔG0 = +2.9 kcal/mol). This step suggests a barrier of 19.6 kcal/mol for the transition state, which is assigned as the rate-determining step (NC1 to NC2). This value was confirmed experimentally: the linear Eyring plot suggests an activation barrier of ΔGexp‡ = 19.7 kcal/mol (Figure S1, Supporting Information). The proton transfer from ammonia to the carbonyl oxygen of NC1 was observed, which occurred simultaneously with the deprotonation (i.e., direct formation of NC2 from NC1); and for the reaction with DABCO, it is more likely that the enol intermediate is formed with a stepwise mechanism (Scheme S4). The intermediate NC2 shows a strong enol character (Mayer bond order32 of C(11)−C(22) = 1.64; Figure 3b), with negative charge located predominantly on the oxygen atom (ChelpG and NPA, Table S2). The deprotonation occurs in the trans-form of 1a, and thus the hydroxyimino group (CNOMs) is located anti-periplanar to the oxygen atom in the resultant enol ((E)-enol, NC2). Further cyclization by O-attack to afford isoxazole 2a is not favored (NC2 to NO3) by the s-trans geometry, and instead, cyclization occurred in a three-membered transition state (NCT2) to give the 2H-azirine (NC2 to NC3, ΔG0 = −14.2 kcal/mol, ΔG‡ = 16.5 kcal/mol).33 The C-attack on nitrogen atom occurred in a concerted manner with cleavage of the N−O bond in the hydroxylimine group, resembling the SN2 reaction mechanism (NCT2, Figure 3c). Therefore, the Neber rearrangement reaction of 1a can be considered as the result of C-attack (C11) on the intramolecular hydroxyimino N atom after formation of the enol intermediate, reflecting the C atom reactivity of enols.

Scheme 4. Enol Intermediate Formed from Ketone

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Figure 3. Computational results for the reaction of 1a with NH3. (a) Energy profile for C-attack reaction (NC1 to NC3, major) and O-attack reaction (NO1 to NO3, minor). (b) Calculated geometry for the (E)-enol intermediate NC2. Calculated geometry for NCT2.

Under the same reaction conditions, a small amount of isoxazole product was also obtained (Scheme 3). We also studied this transformation computationally (Figure 3a, NO1 to NO3), and found that the reaction is most likely to occur through a (Z)-enol intermediate (NO2).34 The formation of NO2 is both kinetically and thermodynamically disfavored, in accordance with the experimental reaction selectivity. Reaction of 1a with t-BuOK: C-Attack and O-Attack Reactions of Enolates (Reaction 2) (Scheme 3). The reaction of 1a with t-BuOK affords a mixture of isoxazole 2a and oxazole 3a in a ratio that is close to 1:1. As regards the formation of oxazole 3a, which is attributable to C atom reactivity, a previous mechanistic study has indicated that 4a can be transformed into 3a with t-BuOK by a deprotonation-initiated mechanism (Scheme S2).24b Generally, enolate can react at both the C atom and the O atom. The reaction selectivity has been extensively studied, and it is well established that it is influenced by the counterion.7 To study whether K+ is important for the reaction selectivity, we conducted a series of reactions of 1a under basic conditions (Table 1). The reaction of 1a with t-BuOK is extremely fast and could not be monitored with NMR even at −20 °C. Changing the counterion from K+ to Na+ caused little difference in the reaction selectivity (entry 2). When the reaction was conducted in the presence of 18-crown-6,35 the reaction still gave both 2a and 3a in a similar ratio (entry 3). The presence of NEt3 and toluene enhanced the E/Z selectivity of Li+-enolate by affecting the aggregation state, which changes the anti/syn preference in aldol condensation.36 As O-attack can only occur from the Zenol (Figure 3b), one might expect that the addition of NEt3 would affect the O-attack (2a)/C-attack (3a) selectivity. However, NEt3/toluene had little influence on the reaction selectivity (entries 4 and 5). Therefore, the interaction of enolates with metal ions is probably not directly related to the

Table 1. Effect of Counterions on the Reaction Selectivity of 1a under Basic Conditionsa

a

All yields were determined based on 1H NMR signals of the crude products, with 1,2-dichloroethane as an internal standard.

difference in reaction selectivity of 1a with DABCO and tBuOK. Further scrutiny was conducted using computational methods, with MeOK as a base.37 It should be noted that the E/Z isomerization of oximes (C = N−OMs) would be possible under the reaction conditions due to the resonance in the enolate intermediates (BC2 and BO2); but this isomerization was not further studied in the current study, considering the fast transformation of 1a with tert-BuOK. The energy profiles for the transformation of 1a into 4a (BC1 to BC3) and 2a (BO1 to BO3) are shown in Scheme 5. In both reaction 206

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The Journal of Organic Chemistry Scheme 5. Energy Profile of the Reaction of 1a with MeOK, Leading to Isoxazole BO3 and 2H-Azirine BC3

cyclization reaction (O−N bond formation) could occur in either ketone or enol form. Next, it is of interest to know whether the cyclization reaction occurs concertedly with the cleavage of the oxime N−OMs bond (Scheme S1, SN2) or via an iminyl cationic intermediate (SN1).43 The experimental results indicate that the energy barrier for the reaction of 1a in AcOH/MeCN solution is ΔGexp⧧ = 24.3 kcal/mol at 298 K (Figure 4a). The Hammett relationship

pathways, the deprotonation step leads to the formation of an enolate intermediate (BC2 or BO2) prior to the cyclization step. The (E)-enolate (BC2) gives the 2H-azirine product (BC2 to BC3), which can be further transformed into oxazole, while the (Z)-enolate undergoes cyclization reaction to give the isoxazole product (BO2 to BO3). As in the case of the reaction with DABCO, the configurations of the enolates (Z and E) are directly related to the reaction selectivity, and the reaction of 1a with t-BuOK reflects both C-atom reactivity and O-atom reactivity of the enolates. For both reactions, the deprotonation to generate the enolates BC238 and BO239 is highly exothermic (−16.8 kcal/ mol and −17.7 kcal/mol), and the reactions are more favorable than those with DABCO. These low-lying intermediates may block the backward trajectory, since the barrier is greater than 19 kcal/mol (back to BC1 and BO1, respectively) compared to the low barriers needed for the extrusion of products. The Cattack cyclization and formation of 2H-azirine (BC3) follows a similar mechanism to the reaction with NH3 (Figure 3), although the energy profile is very different. The O-attack cyclization also occurs in a concerted manner (BO2 to BO3, ΔG‡ = 12.1 kcal/mol), and the construction of the isoxazole ring is thermodynamically favorable (ΔG0 = −47.7 kcal/mol). Nucleus-independent chemical shift (NICS)40 computations for the forming isoxazole ring on the corresponding transition state (BOT2, form BO2 to BO3, vide infra) suggest that a polar mechanism is favored over an electrocyclic pathway.41 The difference between the activation barriers leading to irreversible formation of BC2 (E-enolate) and BO2 (Z-enolate) is smaller than 1 kcal/mol. This energy profile can account for the similar yields of 2a and 3a obtained in the reaction of 1a with t-BuOK. Since both of these energy barriers are smaller than 3 kcal/mol, the selectivity is likely to be controlled by the diffusion process, which reduces the O-attack and C-attack selectivity.42 Acid-Catalyzed Reactions of 2-Methyl-3(((methylsulfonyl)oxy)imino)-1-phenylbutan-1-one 1a. Reaction of 1a with AcOH: O-Attack Reaction of Neutral Ketone (Reaction 3) (Scheme 3). The reaction of 1a in a solution of MeCN/AcOH shows a preference for isoxazole formation (2a, 91%), which is a result of O-atom reactivity (Table S3). The intermediacy of 2H-azirine 4a in the formation of 2a was excluded: 4a in AcOH did not produce 2a, and 4a was recovered after aqueous workup. Considering the potential for ketone-enol tautomerization under acidic conditions, the

Figure 4. Linear energy relationship for the reaction in AcOH/MeCN. (a) Activation entropy and activation enthalpy of the reaction of 1a in AcOH/MeCN. (b) Hammett relationship (at 56 °C) for 1a and parasubstituted derivatives (1c−f). (c) Reaction rate of o-OMe-substituted 1g and p-OMe-substituted 1c. 207

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The Journal of Organic Chemistry (Figure 4b) for substituents at the para-position of the benzene ring shows a negative value of the Hammett constant (ρ= −3.1), which can be interpreted as reflecting the accumulation of positive charge during the RDS. A series of isotope-labeling experiments offers conclusive evidence for the involvement of the ketone form (Scheme S3), but not the enol form (Scheme S3) of 1a during the cyclization step. The results of isotope-labeling experiments are summarized in Figure 5. When 1a was treated with AcOD at

CNOMs groups is probably rate-limiting. Common-ion depression of the reaction rate was not observed at 56 °C, since the reaction rate was almost unchanged upon reacting 1b (NOTs) in AcOH/MeCN in the presence of 5 equiv of TsONa. Furthermore, ortho-OMe substitution (1g) increased the reaction rate, which is indicative of an SN2 reaction (Figure 4c).44 These results are all consistent with a SN2-like mechanism, in which formation of the new O−N bond occurs concertedly with cleavage of the hydroxyimino N−OMs bond. The results of the computational study also support a concerted, SN2-like reaction mechanism from the ketone form of 1a. The free energy profile for the reaction of 1a with AcOH is shown in Figure 6. The reaction is initiated by substitution of the carbonyl oxygen atom on the oximo nitrogen, forming the oxonium intermediate (SO1 to SO2). The transition state for this substitution step (SOT1) shows a strong SN2 character, and possesses an activation energy barrier of 25.1 kcal/mol, in reasonable accordance with the experimental value of 24.3 kcal/ mol; this is the RDS of the putative transformation. The following deprotonation reaction (SO2 to SO3) is relatively facile (ΔG⧧ = 6.2 kcal/mol) with the assistance of acetic acid (SOT2). The developing aromaticity in the transition state accounts for the low activation barrier of deprotonation, in both the isoxazole formation and oxazole formation reactions (vide infra).45 This is in line with the exothermic character of the reaction (ΔG0 = −17.1 kcal/mol), which generates a thermodynamically stable isoxazole product. Reaction of 1a with TFA: O-Attack and C-Attack Reactions of Neutral Ketone (Reaction 4) (Scheme 3). Compounds 1a and 1b react in TFA solution to give a mixture of isoxazole 2a and oxazole 3a.46 The intermediacy of 2Hazirine 4a in the formation of 2a and 3a was excluded: 4a in TFA did not produce 3a, and 4a was recovered after aqueous workup (vide infra). In this context, the formation of 3a under acidic conditions involves a different reaction mechanism from the case of t-BuOK-catalyzed formation of 4a. We are interested in the origin of the different reaction selectivity compared with the reaction using AcOH. Also, ketone-enol tautomerization of 1a could occur in strongly acidic TFA, and so the reaction might proceed through the enol form of 1a, as was recognized in the reaction with t-BuOK. Reaction monitoring with NMR at 18 °C indicated that the rate constants (kobs) for the formation of 2a and 3a from 1b were much smaller than the diffusion limit (Scheme 6a). While the selectivity of the reaction of 1a with t-BuOK can be

Figure 5. Isotope-labeling experiments for reaction of 1a in AcOH/ MeCN.

60 °C for 30 min, hydrogen−deuterium exchange was not observed in the recovered 1a (Figure 5a). Pre-equilibration between ketone and enol is therefore not likely to occur, and the reaction appears to proceed either in the ketone form 1a, or in the enol form 1a with enolization as the RDS. Direct measurement of hydrogen/deuterium KIE gave a KIE value of 1.12 at 56 °C (Figure 5b). These results exclude the possibility of cyclization reaction in the enol form or a concerted cyclization mechanism similar to the Paal-Knorr furan synthesis reaction (Scheme S3). Therefore, the cyclization reaction can only occur at the ketone form to generate a cationic intermediate, indicating O-atom reactivity of ketones. The nucleophilic substitution reaction on the hydroxyimino nitrogen may occur via either a concerted mechanism (SN2-like, Scheme S3) or a stepwise mechanism (SN1-like, Scheme S3). The result of 13C KIE measurement under natural abundance (at 50 °C) is shown in Figure 5c. Both the carbonyl carbon and iminyl carbon of 1a exhibit secondary 13C KIEs (1.004 and 1.007, respectively; Figure 5c and Figure S2). These KIEs suggest that the cyclization step involving both the CO and

Figure 6. Energy profiles and calculated geometries for the reaction of 1a with AcOH. SOT1: transition state for the cyclization step. SOT2: transition state for the deprotonation step. 208

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The Journal of Organic Chemistry Scheme 6. H−D KIEs for 1b and 1b-Ac in TFAa

In contrast, the rate constant for reaction of 1b-D with TFA was similar to that for 1b. A secondary deuterium KIE was measured for both the reaction leading to 2a (KIE = 1.07) and that leading to 3a (KIE = 1.19)(Scheme 6a). The deprotonation at the 2-position is therefore not involved in the rate-limiting step; pre-equilibrium of ketone−enol tautomerization is also unlikely because the reaction rates for 1b-D to afford 2a and 3a are much faster than the rate of deuterium−hydrogen exchange of 1a-Ac-D. The reaction of 2H-azirine 4a in TFA was also carried out. Compound 4a was obtained in the reaction of 1a with DABCO, reflecting the C-atom reactivity of enol (Scheme 3, reaction 1). Treating 4a in TFA for 1 h at 20 °C resulted in recovery of the azirine in 77% yield, accompanied by a small amount of decomposition. Considering the different behaviors of 4a and 1a in TFA, it seems plausible that the enol form of 1a was not involved in the reaction of 1a in TFA. It is interesting that C-attack is preferred in the ketone form, though enolization is also viable in TFA. The mechanism of oxime nitrogen insertion into the C−C σ bond at the α-position to the carbonyl moiety is essentially the same as that of Beckmann rearrangement. Intramolecular cyclization of the resultant nitrilium gives the oxazole product 3a (Scheme 8).48

a

Rate constants are shown as measured observed rate constants (kobs (s−1)) at 18 °C.

Scheme 8. Reaction Mechanism of 1a to 3a in TFA

explained in terms of the reactivity−selectivity principle and is probably diffusion-controlled, this cannot be the case for the reaction using TFA. Under basic conditions, the counterion had only a limited influence on reaction selectivity (Table 1). However, the addition of 2.0 equiv of AcOK to the reaction solution of 1b with TFA changed the reaction selectivity to preferentially afford isoxazole 2a, which is most likely to be explained by the interaction of O and N atoms with K+ (Scheme 7).39 It is therefore inferred that the ketone form selectivity is activation-controlled.

To understand the difference of reaction selectivity, the energy profiles for the reactions of 1a in TFA solution were calculated (Figure 7). The reaction from 1a to 2a in TFA (SM to AO3), resulting from O atom reactivity, shows similar behavior to the same transformation in AcOH, except that the substitution step is more facile and exothermic (ΔG⧧ = 22.6 kcal/mol, ΔG0 = −7.0 kcal/mol), probably due to the higher acidity of TFA, which activates the oxime functionality.15 A computational study of the reaction from 1a to 3a was conducted by using one molecule of TFA (Figure 7, SM to AC4). It should be noted that a detailed computational study of the Beckmann rearrangement process suggested that multiple acid molecules are required to estimate the influence of solvent,48 and thus, the implicit solvent model used in the current computational study would have influenced the energy profile. Fortunately, however, we found that using a single TFA molecule is sufficient to provide valuable insight into the reaction mechanism. A three-step reaction mechanism furnished the oxazole product (SM to AC4) (Figure 7). The first step, forming a nitrilium intermediate (AC2), proceeds via the same reaction mechanism as the Beckmann rearrangement reaction and is highly thermodynamically favored (ΔG0 = −34.2 kcal/mol). This step is recognized as the RDS of the putative transformation, and the energy barrier (ΔG⧧ = 23.0 ⧧ kcal/mol) is close to that for the reaction of 1a to 2a (ΔG = 22.6 kcal/mol). This is in line with the observed reaction selectivity, i.e., both 2a and 3a are obtained in the reaction. Then, cyclization (AC2 to AC3) and deprotonation (AC3 to AC4) occur stepwise with much lower energy barriers (9.3 and 4.0 kcal/mol, respectively). The transformation is highly thermodynamically favored (ΔG0 = −54.6 kcal/mol, from SMto AC4), generating the oxazole 3a irreversibly. Thus, the

Scheme 7. Effect of AcOK on Reaction Selectivitya

a

Yields in parentheses were calculated from 1H NMR signals of the crude product using 1,2-dichloroethane as internal standard.

To study the enolization process of the 3-sulfonyloxyimino1-ketone derivatives in TFA solution, we synthesized 1a-Ac, which undergoes hydrogen−deuterium exchange in TFA-d solution but does not afford 2a or 3a (Scheme 6, b). The rate constant for enolization of 1a-Ac at 18 °C (kobs= 5.21 × 10−4 s−1) is smaller than that of the reaction of 1a with TFA (13.64 × 10−4 s−1). We also observed a primary deuterium KIE of kH/ kD = 4.87 for the hydrogen−deuterium exchange at the 2position of 1a-Ac, and the enolization of 1a-Ac-D was much slower (1.07 × 10−4 s−1).13,47 209

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Figure 7. Energy profiles for the reaction of 1a in TFA. AOT1: transition state for the O-attack reaction. ACT1: transition state for the C-attack reaction.

different selectivities of 1a in AcOH (only 2a) and in TFA (both 2a and 3a) were well interpreted by computational studies.49 Similarity of the Transition-State Geometries of Ketone and Enolate Reactions. The O-attack and C-attack reactivities lead to formation of 3-membered (4a) and 5membered (2a) rings, respectively (Scheme 3). The selectivity in cyclization reactions generating rings of various sizes has been extensively studied and is summarized by Baldwin’s rule.50 While the relatively common 5-endo-dig cyclization trajectory occurs during the formation of oxazoles in TFA (7a to 8a, Scheme 8),51a other trajectories, including SN2-type substitution on the hydroxyimino nitrogen atom, have not been extensively discussed in terms of Baldwin’s classification. SN2-type reactions on an sp2 electrophilic center are not rare,52 and both radical and polar mechanisms are possible for substitution at a sulfonyloxyimino nitrogen atom.53 Our experimental observations (Table 2)54 and computational studies suggest that a polar mechanism is most likely for our reactions, without involvement of radical intermediates.55 According to Baldwin’s classification, the ring-closure reactions of C-attack (basic conditions) and O-attack (acidic and basic conditions) should be categorized as 3-trig-exo and 5-trig-exo trajectories, though the breaking bonds are hydroxyimino O−N σ-bonds, not the common π-bonds (Figure 8). The reaction trajectories are summarized in Figure 9a. During the cyclization reactions, the CN bond of the electrophilic hydroxyimino group remains inside the forming rings. It has been proposed that the cyclization reactions from an acute attack angle with a π-bond inside the ring system are unfavorable, due to the symmetry mismatch between the n orbital of nucleophiles and the π* orbital of electrophiles51 (Figure 8) and the difficulty in meeting the stereoelectronic requirement (Bürgi−Dunitz attack angle).56 However, this kind

Table 2. Examination of Possible Involvement of Radical Intermediate in the Reaction

Figure 8. (a) Common trajectories of 3-trig-exo and 5-trig-exo cyclization. (b) Cyclization on oxime N atom. (c) Electrophilepromoted cyclization (lso see ref 51b).

of cyclization trajectory becomes feasible for an electrophilepromoted cyclization, which changes the alkyne LUMO symmetry via coordination (Figure 8c),51b and the situation is similar for the cyclization reactions of 1a. The C-attack reaction from both the enolate form (cyclization reaction) and ketone form (Beckmann rearrangement) involves an acute ∠C--NC angle (around 55°, Figure 9). For the enolate cyclization, the π orbitals of CN bond and CC bond are orthogonal (Figure 8).57 This spatial 210

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CC−O− of enolate) and C = N functionalities stay in the same plane, in order to avoid the symmetry mismatch between nO and π*C=N orbitals (Figure 8). The values of ∠O--N−O are both around 160°, which ensures efficient overlap of nO and σ*N‑OMs orbitals and little repulsion between the lone pairs of attacking O atoms and imino N atoms (Figure 8). Difference between O-Attack Reactions from Ketone and Enolate. On the other hand, the aromaticity properties are quite different between the O-attack reactions from the enolate form and ketone form. We evaluated the NICS(0)ZZ tensor along the intrinsic reaction coordinate (IRC) at the center of the forming five-membered ring; the NICSZZ value represents the contribution perpendicular to the delocalized ring of electrons. For the enolate-form O-attack cyclization, the NICSZZ value steadily decreases along the IRC (Figure 10a, left), and this is consistent with a polar cyclization mechanism.41 The NICS(0)ZZ value of ketone-form cyclization is positive because of the participation of 4π electrons (CN and CO), but a minimum value of NICS(0)ZZ = 10.9 ppm appears at the transition state (Figure 10a, right).41c Alabugin et al.41b rationalized a similar trend of aromaticity during 5-endotrig cyclization as a result of orbital interaction between the n orbital of O atom (lone pair) and adjacent C−C σ* orbital. This was confirmed by natural bond orbital (NBO) analysis58 of the transition state (Figure 10b) and the O-attack of the ketone form features a stronger interaction (13.9 kcal/mol) than the enolate form (9.45 kcal/mol). A similar trend of inplane σCb−Cc−σ*N−OMs interaction was also observed. These interactions are significant in the transition state, but are gradually diminished after the transition state of ketone form O-attack reactions and are responsible for the stabilizing effect in the transition state of ketone form reactions.

Figure 9. Geometries of TS (a) and the orbital interactions (b, isovalue = 0.08) in the cyclization steps.

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orthogonality can minimize the symmetry mismatch, and the πCC−π*CN interaction, which makes the endo cyclization unfavorable, is negligible. The σ*N−OMs orbital is more diffused than the nN orbital (Figure 8), and the acute attack angle also ensures the best overlap of πC=C−σ*N−OMs (enolate) and σC−C−σ*N−OMs (ketone, Figure 9b). For the O-attack 5-trig reactions from the ketone form and enolate form, there is little difference in the geometry of the transition states. In both cases, the attack angles ∠O--NC are around 95° and there is a large deviation from Bürgi−Dunitz attack. In the transition state, the C−CO group of ketone (or

CONCLUSION Experimental and computational studies demonstrated that the ketone, enol, and enolate forms of 3-sulfonyloxyimino-2methyl-1-phenyl-1-butanone 1a can afford different intramolecular cyclization products (2a, 3a, 4a), depending on the conditions. The results of the reaction under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (t-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketone. The products (2a and 3a) generated from the ketone

Figure 10. (a) NICS(0)ZZ tensor along the intrinsic reaction coordinate (IRC) at the center of the forming five-membered ring. (b) Interaction energy in the transition state of O-attack. LP(2): in-plane lone pair of oxygen atom that participates in the cyclization reaction. 211

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6.8 Hz), 3.09 (3H, s), 2.03 (3H, s), 1.51 (3H, d, 7.2 Hz). 13C NMR (CDCl3): δ 197.2, 167.6, 135.6, 133.7, 128.8, 128.6, 47.6, 36.4, 14.1, 13.6. HRMS (ESI-TOF, [M + Na]+): calcd for C12H15NNaO4S+ 292.0614, found 292.0616. Anal. Calcd for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.31; H, 5.65; N, 5.19.

form and from the enolate form are the same, but the reaction mechanisms are apparently different. Our study on the mechanism of Neber rearrangement of 1a suggested that deprotonation is the rate-determining step, and 4a arises from the enol form via C-attack. The formation of C-attack (3a) and O-attack (2a) products from enolate in the reaction of 1a with t-BuOK can be explained by the reactivity−selectivity principle. The reactions of 1a under acidic conditions provide unprecedented examples of ambident-like reactivity of ketones. The reactions in AcOH and TFA are activation-controlled, and the selectivity can be rationalized in terms of the Marcus theory. The C atom of ketone can react as a nucleophilic site without tautomerization to the corresponding enol, even though the enolization is a possible alternative in TFA. Reactions from the ketone form are similar to the corresponding enolate-form reactions in terms of transitionstate geometry, but the aromaticity index of the O-attack reaction is different because of the stronger in-plane interactions from C−C σ bonds. While further aspects of the reactions, such as the role of aggregation of t-BuOK59 and the resulting enolates,60 the possibility of an intimate ion pair mechanism,61 and the participation of multiple acid molecules48 remain to be investigated, our results suggest generally preferred trajectories for the 5-trig and 3-trig cyclization reactions with an oxime functionality. The synthetic potential of these trajectories is demonstrated by the selective syntheses of isoxazole (2) and azirine (4) from the same starting material (1).62

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1b: To a solution of the oxime 3-(hydroxyimino)-2-methyl-1phenylbutan-1-one (2.30 g, 12.01 mmol) in 45 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (1.62 g, 14.42 mmol) at 0 °C followed by addition of a solution of TsCl (2.75 g, 14.42 mmol) in 15 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by recrystallization from hexane/dichloromethane to afford 2-methyl-1phenyl-3-((tosyloxy)imino)butan-1-one 1b (white solid, 2.89 g, 70%). Mp: 90−91 °C. 1H NMR (CDCl3): δ 7.85−7.81 (4H, m), 7.55−7.51 (1H, m), 7.35−7.26 (4H, m), 4.41 (1H, q, J = 6.8 Hz), 2.45 (3H, s), 1.89 (3H, s), 1.37 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 196.9, 166.9, 144.9, 135.5, 133.5, 132.8, 129.6, 128.8, 128.7, 128.7, 47.4, 21.7, 14.2, 13.0. HRMS (ESI-TOF, [M + Na]+): calcd for C18H19NNaO4S+ 368.0927, found 368.0932. Anal. Calcd for C18H19NO4S: C, 62.59; H, 5.54; N, 4.06. Found: C, 62.27; H, 5.64; N, 4.10.

1a-Ac. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1phenylbutan-1-one (400.0 mg, 2.092 mmol) in 10 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (260.0 mg, 2.319 mmol) at 0 °C followed by addition of a solution of AcCl (180.6 mg, 2.300 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc= 4:1) to afford 1a-Ac (colorless oil, 405.6 mg, 83%). 1H NMR (CDCl3): δ 8.04 (2H, dd, J = 0.8, 8.0 Hz), 7.58−7.54 (1H, m), 7.47−7.44 (2H, m), 4.63 (1H, q, J = 6.8 Hz), 2.15 (3H, s), 1.91 (3H, s), 1.44 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 197.9, 168.5, 165.9, 135.7, 133.7, 128.9, 128.8, 47.7, 19.6, 14.6, 12.8. HRMS (ESI-TOF, [M + Na]+): calcd for C13H15NNaO3+, 256.0944, found 256.0942. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.83; H, 6.63; N, 5.95.

EXPERIMENTAL SECTION

General Methods. All reactions were carried out under argon atmosphere in oven-dried glassware. All commercially available compounds and solvents were used as received unless otherwise mentioned. Open column chromatography was carried out using Kanto chemical silica gel (silica gel 60 N (100−210 μm)). Melting points were determined with a Yanaco micro melting point apparatus without correction. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker Avance 400. Chemical shifts were calibrated with tetramethylsilane and solvent as an internal standard or with the solvent peak, and are shown in ppm (δ) values, and coupling constants are shown in hertz (Hz). The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, dt = double triplet, dq = double quartet, h = hextet, m = multiplet, brs = broad singlet, br = broad signal. The temperature in the NMR experiments was calibrated using signals of methanol according to the reported method. Electron spray ionization time-of-flight mass spectra (ESI-TOF MS) were recorded on a Bruker micrOTOF-05 to give high-resolution mass spectra (HRMS). The combustion analyses were carried out in the microanalytical laboratory of this department. Synthesis of Compound 1.24c

1c. To a solution of the oxime 3-(hydroxyimino)-1-(4-methoxyphenyl)-2-methylbutan-1-one (450.0 mg, 2.034 mmol) in 7.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 240.0 mg, 2.140 mmol) at 0 °C followed by addition of a solution of MsCl (240.0 mg, 2.095 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 1c (colorless oil, 523.7 mg, 86%). 1H NMR (CDCl3): δ 8.03 (2H, d, J = 8.8 Hz), 6.70 (2H, d, J = 9.2 Hz), 4.55 (1H, q, J = 7.2 Hz), 3.91 (3H, s), 3.13 (3H, s), 2.00 (3H, s), 1.48 (3H, d, J = 7.2 Hz). 13 C NMR (CDCl3): δ 195.4, 167.9, 164.1, 131.0, 128.5, 113.9, 55.6, 47.1, 36.5, 14.2, 13.4. HRMS (ESI-TOF, [M + Na]+): calcd for C13H17NNaO5S+ 322.0720, found 322.0722.

1a: To a solution of the oxime 3-(hydroxyimino)-2-methyl-1phenylbutan-1-one (1.00 g, 5.23 mmol) in 15 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (0.59 g, 5.26 mmol) at 0 °C followed by addition of a solution of MsCl (0.60 g, 5.23 mmol) in 10 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 2-methyl-3(((methylsulfonyl)oxy)imino)-1-phenylbutan-1-one 1a (white solid, 1.29 g, 92%). Mp: 65−67 °C. 1H NMR (CDCl3): δ 8.03 (2H, dd, J = 0.8, 8.0 Hz), 7.67−7.63 (1H, m), 7.56−7.52 (2H, m), 4.58 (1H, q, J =

1d. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-(ptolyl)butan-1-one (410.0 mg, 1.996 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 240.0 mg, 2.140 212

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The Journal of Organic Chemistry mmol) at 0 °C followed by addition of a solution of MsCl (240.0 mg, 2.095 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 1d (white solid, 513.3 mg, 91%). Mp: 71−72 °C. 1H NMR (CD2Cl2): δ 7.93 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 4.56 (1H, q, J = 7.2 Hz), 3.11 (3H, s), 2.45 (3H, s), 2.01 (3H, s), 1.49 (3H, d, J = 7.2 Hz). 13C NMR (CD2Cl2): δ 197.1, 168.1, 145.3, 133.5, 129.9, 129.1, 47.8, 36.9, 21.8, 14.6, 13.9. HRMS (ESI-TOF, [M + Na]+): calcd for C13H17NNaO4S+ 306.0770, found 306.0779. Anal. Calcd for C13H17NO4S: C, 55.11; H, 6.05; N, 4.94. Found: C, 54.76; H, 5.99; N, 5.01.

1.41 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 199.5, 168.0, 158.0, 134.1, 130.7, 126.9, 121.0, 111.5, 55.6, 52.0, 36.4, 14.7, 14.0. HRMS (ESI-TOF, [M + Na]+): calcd for C13H17NNaO5S+ 322.0720, found 322.0741

1h: To a solution of the oxime 2-(1-(hydroxyimino)ethyl)-1phenylpent-4-en-1-one (670.6 mg, 3.086 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 380.0 mg, 3.388 mmol) at 0 °C followed by addition of a solution of TsCl (650.0 mg, 1.222 mmol) in 10.0 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford 1h (white solid, 942.9 mg, 83%). Mp: 82−84 °C. 1H NMR (CD2Cl2): δ 7.89−7.86 (2H, m), 7.82−7.79 (2H, m), 7.62−7.58 (1H, m), 7.42−7.38 (2H, m), 7.34 (2H, d, J = 8.0 Hz), 5.69−5.59 (1H, m), 5.09−5.04 (1H, m), 4.99−4.96 (1H, m), 4.45 (1H, dd, J = 6.8, 8.0 Hz), 2.76−2.69 (1H, m), 2.56−2.43 (4H, m), 1.91 (3H, s). 13C NMR (CD2Cl2): δ 196.7, 165.6, 145.2, 135.8, 133.9, 133.5, 132.6, 19.6, 128.7, 128.59, 128.57, 117.4, 52.4, 32.8, 21.4, 12.9. HRMS (ESI-TOF, [M + Na]+): calcd for C20H21NNaO4S+ 394.1083, found 394.1086. Anal. Calcd for C20H21NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.54; H, 5.76; N, 3.49.

1e: To a solution of the oxime 1-(4-chlorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (572.3 mg, 2.536 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 310.0 mg, 2.764 mmol) at 0 °C followed by addition of a solution of MsCl (310.0 mg, 2.706 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 1e (white solid, 694.4 mg, 90%). Mp: 84−85 °C. 1H NMR (CDCl3): δ 7.94 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.8 Hz), 4.48 (1H, q, J = 7.2 Hz), 3.11 (3H, s), 1.97 (3H, s), 1.47 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 195.9, 167.5, 140.5, 133.7, 130.2, 129.3, 47.5, 36.6, 14.3, 13.5. HRMS (ESI-TOF, [M + Na]+): calcd for C12H14ClNNaO4S+ 326.0224, found 326.0227. Anal. Calcd for C12H14ClNO4S: C, 47.45; H, 4.65; N, 4.61. Found: C, 47.05; H, 4.59; N, 4.48.

1i: To a solution of the oxime 2-(cyclopropylmethyl)-3(hydroxyimino)-1-phenylbutan-1-one (489.8 mg, 2.118 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 260.0 mg, 2.318 mmol) at 0 °C followed by addition of a solution of TsCl (444.0 mg, 2.329 mmol) in 10.0 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford 1i (white solid, 744.8 mg, 91%). Mp: 85−86 °C. 1H NMR (CD2Cl2): δ 7.91−7.82 (2H, m), 7.83−7.80 (2H, m), 7.63−7.58 (1H, m), 7.44−7.39 (2H, m), 7.34−7.32 (2H, m), 4.48 (1H, dd, J = 6.8, 7.6 Hz), 2.46 (3H, s), 1.93 (3H, s), 1.89−1.82 (1H, m), 1.72−1.65 (1H, m), 0.56−0.49 (1H, m), 0.41−0.32 (2H, m), 0.07−0.05 (2H, m). 13 C NMR (CD2Cl2): δ 197.0, 166.6, 145.5, 136.5, 133.8, 133.1, 129.9, 129.02, 128.99, 128.9, 34.3, 21.8, 13.5, 9.2, 4.9, 4.8. HRMS (ESI-TOF, [M + Na]+): calcd for C21H23NNaO4S+ 408.1240, found 408.1230.

1f: To a solution of the oxime methyl 4-(3-(hydroxyimino)-2methylbutanoyl)benzoate (277.2 mg, 1.113 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 140.0 mg, 1.248 mmol) at 0 °C followed by addition of a solution of MsCl (140.0 mg, 1.222 mmol) in 5.0 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 3:1) to afford 1f (white solid, 308.1 mg, 85%). Mp: 80−81 °C. 1H NMR (CDCl3): δ 8.14 (2H, d, J = 8.8 Hz), 8.05 (2H, d, J = 8.8 Hz), 4.54 (1H, q, J = 6.8 Hz), 3.96 (3H, s), 3.11 (3H, s), 2.00 (3H, s), 1.50 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 196.7, 167.3, 165.9, 138.6, 134.5, 130.1, 128.6, 52.6, 47.9, 36.6, 14.3, 13.6. HRMS (ESI-TOF, [M + Na]+): calcd for C14H17NNaO6S+ 350.0669, found 350.0662. Anal. Calcd for C14H17NO6S: C, 51.37; H, 5.23; N, 4.28. Found: C, 51.13; H, 5.06; N, 4.28.

1j: To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (366.2 mg, 1.750 mmol) in 3.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 220.0 mg, 1.960 mmol) at 0 °C followed by addition of a solution of MsCl (220.0 mg, 1.927 mmol) in 2 mL of CH2Cl2. The whole was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/ EtOAc = 4:1) to afford 1j (white solid, 391.6 mg, 78%). Mp: 84−86 °C. 1H NMR (CDCl3): δ 8.16−8.12 (2H, m), 7.32−7.27 (2H, m), 4.72 (1H, q, J = 7.2 Hz), 3.09 (3H, s), 2.01 (3H, s), 1.44 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 196.6, 168.3, 166.7 (d, JC, F=251.5 Hz), 133.5 (d, JC, F=3.0 Hz), 132.5 (d, JC, F=9.5 Hz), 116.6 (d, JC, F=22.2 Hz), 48.4, 36.7, 14.5, 14.1. HRMS (ESI-TOF, [M + Na]+): calcd for C12H14FNNaO4S+ 310.0520, found 310.0535. Anal. Calcd for

1g: To a solution of the oxime 3-(hydroxyimino)-1-(2-methoxyphenyl)-2-methylbutan-1-one (266.8 mg, 1.206 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 150.0 mg, 1.337 mmol) at 0 °C followed by addition of a solution of MsCl (150.0 mg, 1.309 mmol) in 5.0 mL of CH2Cl2. The whole was stirred at 0 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 1g (colorless oil, 342.1 mg, 95%). 1H NMR (CDCl3): δ 7.66 (1H, dd, J = 1.6, 7.6 Hz), 7.51−7.47 (1H, m), 7.04−6.96 (2H, m), 4.50 (1H, q, J = 6.8 Hz), 3.92 (3H, s), 2.97 (3H, s), 2.04 (3H, s), 213

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room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/ EtOAc = 4:1) to afford 1n (white solid, 479.8 mg, 92%). Mp: 102− 104 °C. 1H NMR (CD2Cl2): δ 7.88−7.86 (2H, m), 7.83−7.80 (2H, m), 7.61−7.57 (1H, m), 7.42−7.38 (2H, m), 7.35 (2H, d, J = 8.0 Hz), 4.25 (1H, t, J = 6.8 Hz), 2.48 (3H, s), 2.45−2.36 (1H, m), 2.31−2.22 (1H, m), 2.06−1.97 (1H, m), 1.84−1.77 (1H, m), 0.96 (3H, t, J = 7.6 Hz), 0.86 (3H, t, J = 7.6 Hz). 13C NMR (CD2Cl2): δ 196.3, 169.9, 145.1, 136.3, 133.4, 132.7, 129.5, 128.61, 128.56, 128.4, 52.9, 22.1, 21.4, 21.2, 11.5, 10.5. HRMS (ESI-TOF, [M + Na]+): calcd for C20H23NNaO4S+ 396.1240, found 396.1220. Synthesis of Compound 4 (Reaction 1).

C12H14FNO4S: C, 50.17; H, 4.91; N, 4.88. Found: C, 49.97; H, 4.82; N, 4.63.

1k: To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (488.0 mg, 2.022 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 250.0 mg, 2.224 mmol) at 0 °C followed by addition of a solution of TsCl (424.0 mg, 2.224 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 1k (white solid, 673.9 mg, 84%). Mp: 121−122 °C. 1H NMR (CDCl3): δ 8.43 (1H, s), 7.90−7.76 (6H, m), 7.62−7.51 (2H, m), 7.16 (2H, d, J = 8.0 Hz), 4.57 (1H, q, J = 7.2 Hz), 2.34 (3H, s), 1.91 (3H, s), 1.41 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3): δ 196.7, 167.2, 144.8, 135.7, 132.8, 132.4, 131.0, 129.9, 129.5, 129.0, 128.7, 128.6, 127.7, 126.9, 124.0, 47.4, 21.6, 14.3, 13.0. HRMS (ESI-TOF, [M + Na]+): calcd for C22H21NNaO4S+ 418.1083, found 418.1102.

4a: To a solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4a (colorless oil, 76.3 mg, 88%). 1H NMR (CDCl3): δ 7.63−7.61 (2H, m), 7.48−7.44 (1H, m), 7.40−7.36 (2H, m), 2.47 (3H, s), 1.55 (3H, s). 13C NMR (CDCl3): δ 202.2, 166.7, 137.4, 131.5, 128.2, 128.2, 42.0, 19.0, 12.9. The NMR spectral are consistent with the previous reports.24c

1l: To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (433.1 mg, 1.738 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 210.0 mg, 1.873 mmol) at 0 °C followed by addition of a solution of MsCl (210.0 mg, 1.839 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/ EtOAc = 3:1) to afford 1l (colorless oil, 374.4 mg, 66%). 1H NMR (CD2Cl2): δ 8.08 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 4.56 (1H, q, J = 6.8 Hz), 3.10 (3H, s), 2.34 (3H, s), 2.03 (3H, s), 1.50 (3H, d, J = 7.2 Hz). 13C NMR (CD2Cl2): δ 195.9, 158.7, 167.5, 154.9, 133.1, 130.3, 122.1, 47.6, 36.5, 20.9, 14.1, 13.5. HRMS (ESI-TOF, [M + Na]+): calcd for C14H17NNaO6S+ 350.0669, found 350.0680. Note: 1l was unstable and gradually decomposed into isoxazole 2l.

4c: To a solution of 1c (149.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4c (colorless oil, 94.2 mg, 93%). 1H NMR (CDCl3): δ 7.65 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.4 Hz), 3.85 (3H, s), 2.49 (3H, s), 1.56 (3H, s). 13C NMR (CDCl3): δ 199.8, 167.4, 162.6, 131.0, 129.4, 113.5, 55.4, 41.6, 19.6, 12.9. The NMR spectra are consistent with the previous reports.24c

1m: To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (706.9 mg, 3.478 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 430.0 mg, 3.833 mmol) at 0 °C followed by addition of a solution of MsCl (430.0 mg, 3.766 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/ EtOAc = 6:1) to afford 1m (white solid, 863.0 mg, 88%). Mp: 111 °C dec. 1H NMR (CD2Cl2): δ 8.04 (1H, dd, J = 1.2, 8.0 Hz), 7.60−7.56 (1H, m), 7.41−7.35 (2H, m), 3.72-.368 (1H, m), 3.22−3.11 (5H, m), 2.47−2.33 (2H, m), 2.10 (3H, s). 13C NMR (CD2Cl3): δ 194.8, 167.0, 143.9, 134.1, 131.9, 129.0, 127.2, 126.9, 54.4, 36.5, 28.5, 27.2, 14.2. HRMS (ESI-TOF, [M + Na]+): calcd for C13H15NNaO4S+, 304.0614· Found: 304.0622. Anal. Calcd for C13H15NO4S: C, 55.50; H, 5.37; N, 4.98. Found C, 55.55; H, 5.37; N, 5.03;

4d: To a solution of 1d (141.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4d (colorless oil, 88.1 mg, 94%). 1H NMR (CDCl3): δ 7.59 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 7.6 Hz), 2.49 (3H, s), 2.39 (3H, s), 1.56 (3H, s). 13C NMR (CDCl3): δ 201.6, 166.9, 142.3, 134.4, 128.9, 128.5, 41.8, 21.6, 19.2, 12.9. The NMR spectral are consistent with the previous reports.24c

4e: To a solution of 1e (151.9 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4e (colorless oil, 95.9 mg, 92%). 1H NMR (CDCl3): δ 7.59 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 2.46 (3H, s), 1.54 (3H, s). 13C NMR (CDCl3): δ

1n To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (307.3 mg, 1.401 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 170.0 mg, 1.516 mmol) at 0 °C followed by addition of a solution of MsCl (170.0 mg, 1.489 mmol) in 5 mL of CH2Cl2. The whole was stirred at 214

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The Journal of Organic Chemistry 200.8, 166.9, 138.0, 135.4, 129.9, 128.5, 42.1, 18.8, 12.9. The NMR spectral are consistent with the previous reports.24c

4k: To a solution of 1k (197.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4k (colorless oil, 103.9 mg, 93%). 1H NMR (CDCl3): δ 8.21 (1H, s), 7.93 (1H, d, J = 8.0 Hz), 7.88−7.86 (2H, m), 7.74 (1H, dd, J = 1.6, 8.4 Hz), 7.61−7.53 (2H, m), 2.51 (3H, s), 1.63 (3H, s). 13C NMR (CDCl3): δ 201.9, 167.0, 134.7, 134.5, 132.3, 129.4, 129.3, 128.1, 128.0, 127.7, 126.7, 124.6, 42.1, 19.2, 12.9. The NMR spectral are consistent with the previous reports.24c

4f: To a solution of 1f (163.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 2:1) to afford 4f (colorless oil, 106.3 mg, 92%). 1H NMR (CDCl3): δ 8.05 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 3.95 (3H, s), 2.47 (3H, s), 1.56 (3H, s). 13C NMR (CDCl3): δ 202.1, 166.4, 166.3, 141.4, 132.3, 129.4, 127.9, 52.4, 42.4, 18.4, 12.9. The NMR spectral are consistent with the previous reports.24c

4l: To a solution of 1l (163.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4l (colorless oil, 87.5 mg, 76%). 1H NMR (CDCl3): δ 7.74 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.88−7.86 (2H, m), 2.49 (3H, s), 2.33 (3H, s), 1.56 (3H, s). 13C NMR (CDCl3): δ 200.6, 168.9, 167.0, 153.2, 134.5, 130.1, 121.4, 42.0, 21.2, 19.1, 12.9. HRMS (ESI-TOF, [M + H]+): C13H14NO3+ 232.0968, found 232.0972.

4h: To a solution of 1h (185.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4h (pale yellow oil, 88.9 mg, 89%). 1H NMR (CDCl3): δ 7.65−7.62 (2H, m), 7.49−7.45 (1H, m), 7.41−7.38 (2H, m), 5.76−5.66 (1H, m), 5.11−5.06 (2H, m), 2.90−2.84 (1H, m), 2.76−2.71 (1H, m), 2.48 (3H, s). 13C NMR (CDCl3): δ 201.4, 166.4, 137.2, 133.4, 131.6, 128.2, 128.2, 118.0, 45.2, 36.3, 13.7. The NMR spectral are consistent with the previous reports.24c

4m: To a solution of 1m (140.6 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4m (colorless oil, 83.5 mg, 90%). 1H NMR (CDCl3): δ 8.02 (1H, d, J = 8.0 Hz), 7.55− 7.51 (1H, m), 7.38−7.32 (2H, m), 3.30−3.13 (1H, m), 3.13−3.05 (1H, m), 2.54 (3H, s), 2.22−2.09 (2H, m). 13C NMR (CDCl3): δ 197.1, 162.3, 143.8, 133.8, 133.6, 128.5, 127.2, 126.8, 41.3, 30.2, 28.6, 12.3. The NMR spectral are consistent with the previous reports.2

4i: To a solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4i (colorless oil, 93.9 mg, 88%). 1H NMR (CDCl3): δ 7.67 (2H, dd, J = 1.2, 8.4 Hz), 7.51− 7.47 (1H, m), 7.43−7.39 (2H, m), 2.55 (3H, s), 2.08 (1H, dd, J = 8.0, 15.2 Hz), 1.98 (1H, dd, J = 6.8, 15.2 Hz) 0.62−0.55 (1H, m), 0.50− 0.40 (2H, m), 0.10−0.04 (2H, m). 13C NMR (CDCl3): δ 202.1, 166.5, 137.3, 131.6, 128.24, 128.22, 46.3, 36.4, 14.0, 7.7, 4.8, 4.6. The NMR spectral are consistent with the previous reports.2

4n: To a solution of 1n (186.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4n (colorless oil, 90.2 mg, 90%). 1H NMR (CDCl3): δ 7.67 (2H, d, J = 8.0 Hz), 7.50− 7.46 (1H, m), 7.42−7.38 (2H, m), 2.84−2.77 (2H, m), 2.24−2.17 (1H, m), 2.01−1.92 (1H, m), 1.26 (3H, t, J = 7.2 Hz), 0.87 (3H, t, J = 7.2 Hz). 13C NMR (CDCl3): δ 201.9, 170.4, 137.4, 131.5, 128.3, 128.2, 47.8, 24.7, 21.7, 10.1, 8.7. The NMR spectral are consistent with the previous reports.24c Synthesis of Compound 2 (Reaction 3).

4j: To a solution of 1j (143.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 1 h. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford 4j (colorless oil, 86.8 mg, 91%). 1H NMR (CDCl3): δ 7.74−7.71 (2H, m), 7.10−7.06 (2H, m), 2.49 (3H, s), 1.56 (3H, s). 13C NMR (CDCl3): δ 200.3, 167.1, 164.7 (d, JC, F=251.7 Hz), 133.2 (d, JC, F=3.5 Hz), 131.1 (d, JC, F=8.9 Hz), 115.3 (d, JC, F=21.7 Hz), 42.0, 19.0, 12.9. The NMR spectral are consistent with the previous reports.24c

2a: A solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 8 h. The reaction was 215

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The Journal of Organic Chemistry

°C. 1H NMR (CDCl3): δ 7.16 (2H, d, J = 8.8 Hz), 7.80 (2H, d, J = 8.4 Hz), 3.97 (3H, s), 2.32 (3H, s), 2.23 (3H, s). 13C NMR (CDCl3): δ 166.5, 163.0, 161.2, 132.6, 130.5, 130.1, 126.4, 110.8, 52.3, 10.2, 8.3. HRMS (ESI-TOF, [M + Na]+): calcd for C13H13NNaO3+ 254.0788, found 254.0792. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.70; H, 6.04; N, 5.79

diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 9:1) to afford isoxazole 2a (white solid, 78.6 mg, 91%). Mp: 46−48 °C. 1H NMR (CDCl3): δ 7.70 (2H, dd, J = 1.6, 7.6 Hz), 7.50−7.26 (3H, m), 2.29 (3H, s), 2.17 (3H, s). 13C NMR (CDCl3): δ 164.2, 161.0, 129.3, 128.79, 128.75, 126.7, 109.2, 10.2, 8.2. HRMS (ESI-TOF, [M + Na]+): calcd for C11H11NNaO+ 196.0733, found 196.0723. Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.20; H, 6.46; N, 8.09.

2g: A solution of 1g (149.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2g (colorless oil, 91.7 mg, 90%). 1H NMR (CDCl3): δ 7.45−7.42 (2H, m), 7.07−6.99 (2H, m), 3.86 (3H, s), 2.29 (3H, s), 1.95 (3H, s). 13C NMR (CDCl3): δ 160.4, 156.8, 131.2, 130.7, 120.6, 117.8, 111.5, 111.4, 100.0, 55.5, 10.3, 7.9. HRMS (ESITOF, [M + Na]+): calcd for C12H13NNaO2+ 226.0838, found 226.0831.

2c. A solution of 1c (149.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2a (white solid, 92.8 mg, 91%). Mp: 73−75 °C. 1H NMR (CDCl3): δ 7.64 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 9.2 Hz), 3.85 (3H, s), 2.26 (3H, s), 2.13 (3H, s). 13C NMR (CDCl3): δ 165.2, 160.9, 160.3, 128.1, 121.5, 114.2, 107.9, 55.4, 10.2, 8.2. HRMS (ESI-TOF, [M + Na]+): calcd for C12H13NNaO2+, 226.0838, found 226.0828. Anal. Calcd for C12H13NO2 C, 70.92; H, 6.45; N, 6.89. Found: C, 70.77; H, 6.53; N, 6.85.

2h: A solution of 1h (185.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2h (colorless oil, 82.9 mg, 83%). 1H NMR (CDCl3): δ 7.68−7.65 (2H, m), 7.48−7.42 (3H, m), 6.02−5.93 (1H, m), 5.14 (1H, dd, J = 1.6, 10.0 Hz), 5.02 (1H, dd, 1.6, 17.2 Hz), 3.32− 3.30 (2H, m), 2.27 (3H, s). 13C NMR (CDCl3): δ 165.4, 161.0, 134.4, 129.6, 128.8, 128.3, 126.8, 116.2, 110.9, 26.8, 10.1. HRMS (ESI-TOF, [M + Na]+): calcd for C13H13NNaO+ 222.0889, found 222.0867. Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.12; H, 6.72; N, 6.98.

2d: A solution of 1d (141.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v = 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2d (white solid, 80.7 mg, 86%). Mp: 77−79 °C 1 H NMR (CDCl3): δ 7.59 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 2.40 (3H, s), 2.27 (3H, s), 2.14 (3H, s). 13C NMR (CDCl3): δ 164.3, 160.9, 139.4, 129.5, 126.5, 126.0, 108.7, 21.4, 10.2, 8.2. HRMS (ESI-TOF, [M + Na]+): calcd for C12H13NNaO+, 210.0889, found 210.0894. Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.37; H, 7.11; N, 7.39.

2i: A solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2i (colorless oil, 96.9 mg, 91%). 1H NMR (CDCl3): δ 7.73−7.71 (2H, m), 7.49−7.40 (3H, m), 2.57 (1H, d, J = 6.4 Hz), 2.33 (3H, s), 0.98−0.88 (1H, m), 0.51−0.47 (2H, m), 0.16− 0.12 (2H, m). 13C NMR (CDCl3): δ 164.8, 160.8, 129.4, 128.8, 128.7, 126.9, 113.5, 26.8, 10.8, 10.6, 4.6. HRMS (ESI-TOF, [M + Na]+): calcd for C14H15NNaO+ 236.1046, found 236.1039.

2e: A solution of 1e (151.9 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 8 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2e (colorless oil, 92.3 mg, 89%). Mp: 89−90 °C. 1H NMR (CDCl3): δ 7.67 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.4 Hz), 2.31 (3H, s), 2.18 (3H, s). 13C NMR (CDCl3): δ 163.1, 161.1, 135.3, 129.1, 127.8, 127.2, 109.6, 10.2, 8.2. HRMS (ESI-TOF, [M + Na]+): calcd for C11H10ClNNaO+ 230.0343, found 230.0342. Anal. Calcd for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C, 63.67; H, 5.05; N, 6.52.

2j: A solution of 1j (143.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 8 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2j (off-white solid, 88.3 mg, 92%). Mp: 48−50 °C. 1H NMR (CDCl3): δ 7.70−7.65 (2H, m), 7.18−7.14 (2H, m), 2.28 (3H, s), 2.14 (3H, s). 13C NMR (CDCl3): δ 163.3, 163.1 (d, JC, F=248.5 Hz), 161.0, 128.6 (d, JC, F=8.2 Hz), 125.4 (d, JC, F=3.4 Hz),

2f: A solution of 1f (163.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 12 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford isoxazole 2f (white solid, 96.5 mg, 83%). Mp: 113−114 216

DOI: 10.1021/acs.joc.7b02573 J. Org. Chem. 2018, 83, 203−219

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The Journal of Organic Chemistry 115.7 (d, JC, F=21.8 Hz), 109.0,10.2, 8.1. HRMS (ESI-TOF, [M + Na]+): calcd for C11H10FNNaO+ 214.0639, found 214.0657.

saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc = 6:1 to 2:1) to afford isoxazole 2a (colorless oil, 32.2 mg, 37%) and oxazoe 3a (white solid, 35.7 mg, 41%).

2k: A solution of 1k (197.8 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 8 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford isoxazole 2k (white solid, 106.5 mg, 95%). Mp: 105− 108 °C. 1H NMR (CDCl3): δ 8.19 (1H, s), 7.97−7.84 (4H, m), 7.58− 7.55 (2H, m), 2.35 (3H, s), 2.28 (3H, s). 13C NMR (CDCl3): δ 164.2, 161.1, 133.4, 133.1, 128.6, 128.5, 127.8, 127.1, 126.7, 126.3, 126.1, 123.8, 109.6, 10.3, 8.4. HRMS (ESI-TOF, [M + Na]+): calcd for C15H13NNaO+ 246.0889, found 246.0878. Anal. Calcd for C15H13NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.92; H, 6.02; N, 6.29.

3a: To a solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of THF was added t-BuOK (224.4 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 15 min. The reaction was quenched with 0.5 mL of AcOH and diluted with ethyl acetate. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 9:1 to 4:1) to afford isoxazole 2i (colorless oil, 38.6 mg, 36%) and oxazoe 3i (colorless oil, 46.0 mg, 43%). Mp: 44−45 °C. 1H NMR (CDCl3): δ 7.59 (2H, dd, J = 1.6, 8.0 Hz), 7.46−7.42 (2H, m), 7.33−7.28 (1H, m), 2.50 (3H, s), 2.40 (3H, s). 13C NMR (CDCl3): δ 159.4, 145.1, 131.6, 129.3, 128.7, 127.3, 125.1, 13.9, 13.2. HRMS (ESI-TOF, [M + Na]+): calcd for C11H11NNaO+ 196.0733, found 196.0714.

2l: A solution of 1l (163.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 8 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 4:1) to afford isoxazole 2l (white solid, 103.8 mg, 90%). Mp: 82−84 °C. 1H NMR (CDCl3): δ 7.71 (2H, d, J = 8.4 Hz), 7.21 (2H, d, 8.8 Hz), 2.33 (3H, s), 2.28 (3H, s), 2.16 (3H, s). 13C NMR (CDCl3): δ 169.2, 163.4, 161.0, 151.2, 127.8, 126.4, 122.1, 109.3, 21.1, 10.2, 8.1. HRMS (ESI-TOF, [M + Na]+): calcd for C13H13NNaO3+ 254.0788, found 254.0795.

3i: 1H NMR (CDCl3): δ 7.61−7.59 (2H, m), 7.45−7.42 (2H, m), 7.34−7.30 (1H, m), 2.71 (2H, d, J = 6.8 Hz), 2.53 (3H, s), 1.19−1.12 (1H, m), 0.56−0.51 (2H, m), 0.29−0.26 (2H, m). 13C NMR (CDCl3): δ 159.6, 145.2, 135.4, 129.2, 128.7, 127.5, 125.4, 31.2, 14.1, 10.1, 4.3. HRMS (ESI-TOF, [M + Na]+): HRMS (ESI-TOF, [M + Na]+): calcd for C14H15NNaO+ 236.1046, found 236.1042. Reaction of 1 with TFA (Reaction 4). (1) 1a (134.7 mg, 0.500 mmol) was added to 5.0 mL of TFA at 20 °C. The whole was stirred at 20 °C for 1 h and diluted dichloromethane. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1 to 2:1) to afford isoxazole 2a (colorless oil, 56.0 mg, 65%) and oxazoe 3a (white solid, 20.1 mg, 23%). (2) 1h (185.7 mg, 0.500 mmol) was added to 5.0 mL of TFA at 20 °C. The whole was stirred at 20 °C for 1 h and diluted dichloromethane. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 8:1 to 2:1) to afford isoxazole 2h (colorless oil, 45.4 mg, 46%) and oxazoe 3h (white solid, 43.2 mg, 43%).

2m: A solution of 1m (140.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2m (pale yellow oil, 61.7 mg, 66%). 1H NMR (CDCl3): δ 7.68−7.66 (1H, m), 7.32−7.29 (3H, m), 3.06 (2H, t, J = 7.2 Hz), 2.70 (2H, t, J = 8.0 Hz), 2.32 (3H, s). 13C NMR (CDCl3): δ 165.0, 157.9, 136.4, 129.4, 128.3, 127.0, 125.4, 121.9, 112.4, 29.0, 17.9, 10.0. HRMS (ESI-TOF, [M + Na]+): calcd for C12H11NNaO+, 208.0733, found 208.0735.

2n: A solution of 1j (186.7 mg, 0.500 mmol) in 5.0 mL of AcOH/ MeCN (v/v= 1:1) was stirred at 50 °C for 4 h. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution, and brine. The solvent was evaporated and the residue was purified by column chromatography (hexane/EtOAc = 6:1) to afford isoxazole 2j (colorless oil, 85.4 mg, 85%). 1H NMR (CDCl3): δ 7.72−7.70 (2H, m), 7.51−7.42 (3H, m), 2.73 (2H, q, J = 7.2 Hz), 2.63 (2H, q, J = 7.6 Hz), 1.39 (3H, t, J = 7.6 Hz), 1.24 (3H, t, J = 7.6 Hz). 13C NMR (CDCl3): δ 165.2, 164.2, 129.3, 128.8, 128.1, 126.7, 115.1, 18.7, 15.9, 14.4, 12.2. HRMS (ESI-TOF, [M + Na]+): calcd for C13H15NNaO+ 224.1046, found 224.1050. Reaction of 1 with t-BuOK (Reaction 2). (1) To a solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of THF was added t-BuOK (224.4 mg, 4.0 equiv) at 20 °C. The whole was stirred at 20 °C for 15 min. The reaction was quenched with 0.5 mL of AcOH and diluted with ethyl acetate. The reaction mixture was and washed with water,

3h. 1H NMR (CDCl3): δ 7.56 (2H, dd, J = 1.2, 8.0 Hz), 7.44−7.41 (2H, m), 7.34−7.30 (1H, m), 6.09−5.99 (1H, m), 5.19−5.14 (2H, m), 3.50−3.48 (2H, m), 2.50 (3H, s). 13C NMR (CDCl3): δ 159.9, 145.8, 134.5, 133.5, 128.9, 128.8, 127.7, 125.4, 116.5, 31.5, 14.0. HRMS (ESITOF, [M + Na]+): calcd for C13H13NNaO+ 222.0889, found 222.0881.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02573. Kinetic measurements, DFT calculation data, and NMR spectral for 1, isoxazole 2, oxazole 3, and 2H-azirine 4 (PDF) 217

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yuko Otani: 0000-0002-8104-283X Tomohiko Ohwada: 0000-0001-5390-0203 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K14927) to T.O. The computations were performed at the Research Center for Computational Science, Okazaki, Japan. We thank the computational facility for generous allotments of computer time.

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DOI: 10.1021/acs.joc.7b02573 J. Org. Chem. 2018, 83, 203−219

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Rappoport, Z. Acc. Chem. Res. 2009, 42, 993−1003. (e) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937−2980. (f) Fernández, I.; Bickelhaupt, F. M.; Uggerud, E. J. Org. Chem. 2013, 78, 8574−8784. (g) Ochiai, M.; Okubo, T.; Miyamoto, K. J. Am. Chem. Soc. 2011, 133, 3342−3344. (53) (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 2005, 4505−4519. (b) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155−1171. (c) Li, J.; Hu, Y.; Zhang, D.; Liu, Q.; Dong, Y.; Liu, H. Adv. Synth. Catal. 2017, 359, 710−771. (54) Reaction of 1g with t-BuOK was complex, due to migration of the double bond, which generated a mixture of E- and Z- isomers. Also see ref 24b. (55) (a) Bodineau, N.; Mattalia, J.-M.; Thimokhin, V.; Handoo, K.; Négrel, J.-C.; Chanon, M. Org. Lett. 2000, 2, 2303−2306. (b) Tanko, J. M.; Li, X.; Chahma, M.; Jackson, W. F.; Spencer, J. N. J. Am. Chem. Soc. 2007, 129, 4181−4192. (c) Otte, D. A. L.; Woerpel, K. A. Org. Lett. 2015, 17, 3906−3909. (56) (a) Bürgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153− 161. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925−3941. (57) Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78, 7777−7784. (58) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. J. Comput. Chem.; University of Wisconsin: Madison, WI.201334213410.1002/jcc.23366 (59) Chisholm, M. H.; Drake, S. R.; Naiini, A. A.; Streib, W. E. Polyhedron 1991, 10, 337−345. (60) Algera, R. F.; Gupta, L.; Hoepker, A. C.; Liang, J.; Ma, Y.; Singh, K. J.; Collum, D. B. J. Org. Chem. 2017, 82, 4513−4532. (61) Winstein, S.; Clippinger, E.; Fainberg, A. H.; Heck, R.; Robinson, G. C. J. Am. Chem. Soc. 1956, 78, 328−335. (62) Reaction generality of 1 with DABCO and AcOH is summarized in Table S5. Further studies are continuing on reaction generality.

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DOI: 10.1021/acs.joc.7b02573 J. Org. Chem. 2018, 83, 203−219