Synthesis of Functionalized 3-Cyanoisoxazoles Using a Dianionic

of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan. J. Org. Chem. , 2017, 82 (10), pp 5409–5415. DOI: 10.1021/acs.joc...
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Synthesis of Functionalized 3‑Cyanoisoxazoles Using a Dianionic Reagent Kento Iwai,† Haruyasu Asahara,†,‡,§ and Nagatoshi Nishiwaki*,†,‡ †

School of Environmental Science and Engineering and ‡Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan § Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan S Supporting Information *

ABSTRACT: A series of 5-acylated 3-cyanoisoxazoles were efficiently synthesized by the Michael addition of dianionic cyano-aci-nitroacetate to α-chloro-α,β-unsaturated ketones followed by intramolecular nucleophilic substitution of the nitronate ion intermediate. In this process, the dianionic reagent serves as the safe synthetic equivalent of the explosive nitroacetonitrile. The 3-cyano group is sufficiently reactive toward ethanolysis and 1,3-dipolar cycloaddition with an azide to afford ethyl ester and tetrazole, respectively. A pyridine ring between the 5-acyl and the 4-aryl group was also constructed. This led to the formation of the isoxazolo[5,4-c]quinoline derivative.

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INTRODUCTION The chemical diversity of the cyano group facilitates the conversion to other functional groups such as amino, carbonyl, and acyl groups. Furthermore, nitriles also serve as precursors for heteroaromatic compounds like imidazoles and tetrazole.1,2 This chemical property exhibited by a cyano group facilitates the construction of a compound library for the development of new medicines and functional materials.2,3a From this viewpoint, 3-cyanoisoxazoles have been employed as important precursors for versatile isoxazole analogues.3 However, the starting 3-cyanoisoxazoles are not easily performed. The 1,3dipolar cycloaddition of a nitrile oxide with alkynes is often employed for constructing an isoxazole ring; however, this protocol is inefficient, leading to only a few 3-cyanoisoxazoles. This occurs because cyanonitrile oxide is not a common synthetic reagent.4 Instead, 3-cyanoisoxazoles are usually prepared by chemical conversion of the corresponding esters via the amides. Unfortunately, such a procedure suffers from restrictions like harsh reaction conditions, low reaction efficiency, and poor availability of the precursors (Scheme 1a).3,5 These disadvantages prevent the easy access to 3cyanoisoxazoles comprising an additional functional group. To

the best of our knowledge, there is only one prior report on the synthesis of acylated 3-cyanoisoxazoles by cyclization of a polyfuntionalized oxime (Scheme 1b).6 Hence, development of a facile and efficient synthetic method of functionalized 3cyanoisoxazoles is still a challenging target. We have previously reported that dianionic cyano-acinitroacetate 2 is readily generated from the pyridinium salt of nitroisoxazolone 1 with 2 equiv of 1-methylpyrrolidine.7 Dianion 2 is soluble into almost all common organic solvents and is regarded as a masked form of the explosive nitroacetonitrile (NAN). Indeed, 2 serves as a safe synthetic equivalent of NAN to afford δ-keto-α-cyanonitronate 3 via Michael addition to an α,β-unsaturated ketone (enone) and subsequent decarboxylation (Scheme 2).7a We considered a promising synthetic route wherein α-chloroenones 5 afford 3cyano-5-acylisoxazoles 7 by the intramolecular substitution of the resultant nitronate 6. In this paper, we demonstrate a onestep synthesis of 5-acylated 3-cyanoisoxazoles 7 and their chemical conversion. The procedure leads to polyfunctionalized heterocyclic compounds that are not easily available by alternative methods.

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RESULT AND DISCUSSION Several reports referring to the explosibility of NAN can be found in literature.8 Hence, thermochemical properties of pyridinium salt 1 and dianion 2 were evaluated by differential scanning calorimetry (DSC); these compounds have been used without any reported danger.9,10 Indeed, NAN rapidly decomposed in air at 109 °C, releasing 874 J/g of energy. This classifies it as an explosive material according to the UN Orange Book.11 Conversely, pyridinium salt 1 and dianion 2

Scheme 1. Synthesis of 3-Cyanoisoxazole by Conventional Methods

Received: April 6, 2017 Published: May 4, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

Article

The Journal of Organic Chemistry Scheme 2. Synthetic Strategy for 3-Cyanoisoxazole

were stable even at 140 °C, and smaller energies (163 and 250 J/g, respectively) were released, indicating that both compounds are safely treatable reagents under air (see Supporting Information). When 1-methylpyrrolidine was added to a suspension of pyridinium salt 1 in benzene, the mixture became immediately clear; this confirmed the generation of dianion 2. Although dianion 2 is stable enough to be isolated, the one-pot addition of α-chloroenone 5a to the solution proceeded without isolation of 2. After heating the resultant mixture at 60 °C for 1 day, 4-arylated 5-acetyl-3-cyanoisoxazole 7a was isolated in 37% yield by silica gel column chromatography (Scheme 3).

Scheme 4. Plausible Mechanism for Forming 7a

Next, the reaction conditions were investigated to improve the yield of 7a (Table 1). Among several solvents tested, acetonitrile was found to be the most suitable (entries 1−4). In

Scheme 3. Synthesis of 5-Acyl-3-cyanoisoxazole 7a

Table 1. Optimization of Reaction Conditions

In the 1H NMR of enone 5a, a singlet signal of the olefinic proton was observed at 7.70 ppm; this disappeared in the 1H NMR of product 7a. The MS spectrum presented molecular ion peaks at 246 and 248 with a 3:1 ratio. This corresponds to the dehydrochlorinated form of the adduct from 5a and NAN. Moreover, in the 13C NMR spectrum, two additional signals appeared at 108.9 and 161.8 ppm. The former signal was assigned to the cyano group, confirmed by the absorption at 2252 cm−1 in the IR spectrum. Based on these spectral data, product 7a was determined as an isoxazole comprising a cyano and an acetyl group. However, the positions of these functional groups could not be secured. Finally, the structural determination was achieved by X-ray structure analysis using a single crystal of 2,4-dinitrophenylhydrazone derived from 7a.12 A plausible mechanism for the synthesis of 7a is illustrated in Scheme 4. Michael addition of cyano-aci-nitroacetate 2 to enone 5a affords adduct intermediate 6a. In the subsequent cyclization step, two reaction paths are plausible. In path a, the nitronate anion directly substitutes a chloro group to furnish 8a. In path b, the enone intermediate 9a is formed by dehydrochlorination while isoxazoline 8a is formed via the ene reaction. Dehydration of 8a easily occurs and is accompanied by aromatization, leading to isoxazole 7a (Scheme 4).

yielda (%)

recoverya (%)

entry

X

solvent

temp (°C)

Y (equiv)

7a

5a

1 2 3b 4 5c 6 7 8 9 10 11

Cl Cl Cl Cl Cl Cl Cl Cl Br Cl Br

PhH CHCl3 MeOH MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN

60 60 60 60 rt 80 100 60 60 rt rt

1 1 1 1 1 1 1 1.2 1.2 1 1

38 53 36 84 66 82 77 92 (77)d 86 43 32

60 46 27 15 34 18 23 8 4 57 52

a c

5410

Determined by 1H NMR. bEster 10 was formed in 27% yield. Reaction time: 7 days. dIsolated yield.

DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

Article

The Journal of Organic Chemistry Table 2. Synthesis of Other Isoxazoles 7

entry

R3

R4

R5

product

yield (%)

a

CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CONH2 CONH2 CN CN

4-MeOC6H4 4-MeC6H4 Ph 4-BrC6H4 4-NO2C6H4 Ph Ph Ph Ph Ph Ph 4-MeC6H4 4-(5-chloro-2-furyl) Pr H

Me Me Me Me Me 4-MeOC6H4 3-MeOC6H4 4-MeC6H4 Ph 4-ClC6H4 4-NO2C6H4 4-MeC6H4 Ph Ph Ph

7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7q 7r 7s 7t

61 68 68 64 56 85 91 quant. 94 97 90 97 47 37 53 93 82 NDc NDc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16b 17b 18b 19a a

−(CH2)3− −(CH2)2− Ph Ph

H OMe

Reaction temperature: 100 °C. bReaction temperature: rt. cNot detected.

influence from the substituent on the benzoyl group. It was also possible to introduce a heterocyclic ring into the 4-position to afford isoxazole 7n in 47% yield. α-Chloroenone did not require an aromatic ring at the β-position, and 4-propylisoxazole 7o and 4-unsubstituted isoxazole 7p were afforded in moderate yields. When cyclic enones 5q and 5r were used, the respective condensed isoxazoles 7q and 7r were efficiently prepared. Hydration of the cyano group also occurred, even at room temperature. When the more reactive enal 5s was employed, the reaction mixture was complicated because of several unidentified byproducts, even at room temperature. On the other hand, the less reactive cinnamate 5t was inert, albeit after heating at 100 °C for 1 day. The cyano group of 7 exhibited high reactivity (Table 1, entry 3, and Table 2, entries 16 and 17).10 Indeed, in the presence of DBU, ethanolysis of 7m proceeded easily, even at room temperature, to afford ethyl ester 11 in 74% yield. Conversely, 3-cyano-5-phenylisoxazole required harsh reaction conditions to undergo the hydrolysis leading to 12 (Scheme 5).3 The cyano group in 7m was applied to the click construction of 4-tetrazolylisoxazole 13a by 1,3-dipolar cycloaddition with benzyl azide. This is the first example of the direct conversion of cyanoisoxazole to substituted tetrazolylisoxazole.2a Moreover, unsubstituted tetrazole-substituted isoxazole 13b was also afforded in good yield using sodium azide (Table 3). The multifunctionalities of 4-substituted 3-cyano-5-acylisoxazoles 7 are expected to facilitate various chemical conversions, enabling the construction of a new compound library. To demonstrate the synthetic potential of 7, the construction of a ring between the 5-acyl and 4-phenyl groups was attempted according to Yoshikai’s method.14 The acyl group was

the reaction in methanol, methyl ester 10 was also formed in 27% yield (entry 3). Notably, the cyano group of 7a easily undergoes methanolysis because the nitrile functional group generally withstands in heated methanol. The reaction proceeded to afford 7a in moderate yield, even at room temperature when the reaction time was prolonged (entry 5). Heating the reaction mixture at 80 °C afforded 7a in a similar yield; however, this yield decreased at higher temperatures (entries 6 and 7). Although 7a was produced in high yield under the reaction conditions in entry 8, α-chloroenone 5a was still recovered without any detectable byproducts. This indicated the competitive thermal decomposition of dianion 2. This problem was easily addressed by using small excess amounts of isoxazolone 1 to increase the yield of isoxazole 7a to 92% (entry 8). Because α-bromoenone 5a′ (X = Br) serves as a precursor for isoxazolines,13 the reactivity of 5a′ was compared with that of 5a under the same reaction conditions (entries 8−11). Bromoenone 5a′ underwent the reaction similarly; however, the yield of 7a was somewhat lower than that from 5a. From the viewpoint of stability, α-chloroenone 5a was confirmed to be a more treatable substrate for this reaction. Several other α-chloroenones 5b−t were subjected to this protocol using the optimized reaction conditions in hand. αChlorobenzalacetones 5b−f reacted with dianion 2 to afford products 7b−f, respectively; p-methoxybenzalacetone 5b required severe conditions, presumably due to the low electrophilicity of the double bond. On the other hand, reactive p-nitrobenzalacetone 5f afforded a rather complicated mixture as a result of the side reactions, from which isoxazole 7f was isolated by silica gel column chromatography. For αchlorochalcones 5g−m, the corresponding isoxazoles 7g−m were delivered in excellent yields, without any significant 5411

DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

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The Journal of Organic Chemistry

the mixture was extracted with chloroform (3 mL × 3). The organic layer was washed with brine (10 mL × 1), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexane/acetone = 95/5, Rf = 0.21) to afford isoxazole 7a (37.4 mg, 0.15 mmol, 77%) as a pale yellow solid: mp 102−103 °C; IR (ATR/cm−1) 2252, 1703; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 2.67 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1 (C), 161.8 (C), 141.4 (C), 136.8 (C), 130.9 (CH), 129.2 (CH), 124.6 (C), 122.6 (C), 108.9 (C), 28.4 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C12H6ClN2O2 245.0123; found 245.0119. When other chloroenones 5 were employed, the reactions were conducted in a similar way. 3-Cyano-5-ethanoyl-4-(4-methoxyphenyl)isoxazole (7b): Pale yellow oil (29.5 mg, 61%); IR (ATR/cm−1) 2250, 1703; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1 (C), 161.35 (C), 161.33 (C), 141.6 (C), 131.1 (CH), 125.7 (C), 116.1 (C), 114.4 (CH), 109.3 (C), 55.4 (CH3), 28.5 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C13H9N2O3 241.0618; found 241.06258. 3-Cyano-5-ethanoyl-4-(4-methylphenyl)isoxazole (7c): Yellow solid (30.7 mg, 68%); mp 98−99 °C; IR (NaCl/cm−1) 2250, 1666; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0 (C), 161.6 (C), 141.6 (C), 140.9 (C), 129.6 (CH), 129.4 (CH), 125.8 (C), 121.2 (C), 109.2 (C), 28.5 (CH3), 21.4 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C13H9N2O2 225.0669; found 225.0664. 3-Cyano-5-ethanoyl-4-phenylisoxazole (7d): Pale yellow solid (28.8 mg, 68%); mp 69−70 °C; IR (ATR/cm−1) 2252, 1703; 1H NMR (400 MHz, CDCl3) δ 7.58−7.56 (m, 2H), 7.51−7.50 (m, 3H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.9 (C), 161.8 (C), 141.6 (C), 130.5 (CH), 129.5 (CH), 128.9 (CH), 125.7 (C), 124.2 (C), 109.1 (C), 28.5 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C12H7N2O2 211.0513; found 211.0511. 4-(4-Bromophenyl)-3-cyano-5-ethanoylisoxazole (7e): Yellow solid (37.2 mg, 64%); mp 97−98 °C; IR (NaCl/cm−1) 2252, 1714; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 2.60 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0 (C), 161.8 (C), 141.3 (C), 132.2 (CH), 131.0 (CH), 125.2 (C), 124.6 (C), 123.1 (C), 108.9 (C), 28.4 (CH3); HRMS (ESI-QTOF) m/z [M − H]− calcd for C12H6BrN2O2 288.9618; found 288.9616. 3-Cyano-5-ethanoyl-4-(4-nitrophenyl)isoxazole (7f): Yellow solid (28.8 mg, 56%); mp 105−106 °C; IR (ATR/cm−1) 2252, 1699, 1525, 1352; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 2.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0 (C), 162.3 (C), 148.8 (C), 141.1 (C), 130.8 (CH), 130.6 (C), 124.0 (CH), 123.4 (C), 108.5 (C), 28.4 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C12H6N3O4 256.0363; found 256.0360. 3-Cyano-5-(4-methoxybenzoyl)-4-phenylisoxazole (7g): Yellow oil (51.7 mg, 85%); IR (ATR/cm−1) 2253, 1659, 1263; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.8 Hz, 2H), 7.55−7.54 (m, 2H), 7.46−6.96 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.9 (C), 165.1 (C), 163.5 (C), 140.6 (C), 132.7 (CH), 130.0 (CH), 129.2 (CH), 129.0 (CH), 127.8 (C), 125.7 (C), 124.8 (C), 114.3 (CH), 109.3 (C), 55.7 (CH3); HRMS

Scheme 5. High Reactivity of the Cyano Group of Isoxazole 7m

Table 3. 1,3-Dipolar Cycloaddition of 7m with Azides

entry

azide

conditions

R

product

yield (%)

1 2

PhCH2N3 NaN3

neat, 130 °C, 20 h MeOH, 65 °C, 1 d

PhCH2 H

13a 13b

23 93

transformed to O-acyloxime 14 upon treatment with hydroxyammonium chloride and subsequent treatment with acetyl chloride. When O-acyloxime 14 was heated at 150 °C in the presence of trifluoroborane for 1 day, isoxazolo[5,4c]quinoline 15 was afforded in 36% overall yield (Scheme 6).

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CONCLUSION In summary, a variety of 5-acyl-3-cyanoisoxazoles 7 were prepared by the reaction of cyano-aci-nitroacetate 2 and αchloroenones. In this method, polyfunctionalized isoxazole, comprising acyl and cyano groups, can be synthesized in one step. The introduced functionalities enable further chemical transformations such as intramolecular annulation between vicinal substituents and esterification as well as 1,3-dipolar cycloaddition of the cyano group. The high reactivity and diverse functionalities of 7 will facilitate the construction of a compound library useful for developing new functional materials.

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EXPERIMENTAL SECTION

General Procedure for the Synthesis of 4-(4-Chlorophenyl)3-cyano-5-ethanoylisoxazole (7a). In a screw-capped tube, to the suspension of the pyridinium salt of nitroisoxazolone 1 (50.2 mg, 0.24 mmol) in MeCN (2.5 mL) was added 1-methylpyrrolidine (53 μL, 0.48 mmol), and the resultant mixture was stirred until the salt was completely dissolved. Then, 3-chloro-4-(4-chlorophenyl)-3-butene-2one (5a) (42.8 mg, 0.2 mmol) was added, and the mixture was heated at 60 °C for 1 day. After acidification with 1 M HCl (3 mL, 3 mmol),

Scheme 6. Construction of the Isoxazoloquinoline Framework from Polyfunctionalized Isoxazole 7b

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DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

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The Journal of Organic Chemistry (ESI-Q-TOF) m/z [M + AcO]− calcd for C20H15N2O5 363.0986; found 363.0992. 3-Cyano-5-(3-methoxybenzoyl)-4-phenylisoxazole (7h): Pale yellow oil (55.3 mg, 91%); IR (NaCl/cm−1) 2252, 1660; 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.2, 3.6 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.46−7.44 (m, 4H), 7.38 (dd, J = 8.0, 8.0 Hz, 1H), 7.19 (ddd, J = 8.0, 2.8, 0.8 Hz, 1H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.4 (C), 162.9 (C), 160.0 (C), 140.8 (C), 136.0 (C), 130.2 (CH), 129.9 (CH), 129.2(CH), 129.0 (CH), 126.3 (C), 124.6 (C), 123.1 (CH), 121.7 (CH), 113.7 (CH), 109.2 (C), 55.5 (CH3); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C20H15N2O5 363.0986; found 363.0995. 3-Cyano-5-(4-methylbenzoyl)-4-phenylisoxazole (7i): Yellow solid (57.7 mg, quant.); mp 98−99 °C; IR (NaCl/cm−1) 2252, 1699; 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 7.2, 3.2 Hz, 2H), 7.45−7.44 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.2 (C), 163.2 (C), 146.4 (C), 140.7 (C), 132.4 (C), 130.3 (CH), 130.1 (CH), 129.6 (CH), 129.2 (CH), 129.0 (CH), 126.0 (C), 124.7 (C), 109.3 (C), 21.8 (CH3); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C20H15N2O4 347.1037; found 347.1044. 5-Benzoyl-3-cyano-4-phenylisoxazole (7j): Pale yellow oil (51.5 mg, 94%); IR (NaCl/cm−1) 2253, 1707; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.54 (dd, J = 7.2, 2.4 Hz, 2H), 7.48 (dd, J = 7.5, 7.5 Hz, 2H), 7.46−7.43 (m, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 181.6 (C), 162.9 (C), 140.8 (C), 134.94 (C), 134.91 (CH), 130.2 (CH), 130.1 (CH), 129.2 (CH), 129.0 (CH), 128.9 (CH), 126.4 (C), 124.6 (C), 109.2 (C); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C19H13N2O4 333.0880; found 333.0886. 5-(4-Chlorobenzoyl)-3-cyano-4-phenylisoxazole (7k): White solid (59.8 mg, 97%); mp 83−84 °C; IR (NaCl/cm−1) 2252, 1668; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 2H), 7.56−7.53 (m, 2H), 7.48−7.46 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 180.2 (C), 162.4 (C), 141.7 (C), 141.0 (C), 133.2 (C), 131.4 (CH), 130.4 (CH), 129.37 (CH), 129.31 (CH), 129.1 (CH), 126.8 (C), 124.4 (C), 109.1 (C); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C19H12ClN2O4 367.0491; found 367.0498. 3-Cyano-5-(4-nitrobenzoyl)-4-phenylisoxazole (7l): Yellow solid (57.4 mg, 90%); mp 130−131 °C; IR (KBr/cm−1) 2257, 1677; 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.62−7.49 (m, 2H), 7.51−7.49 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.7 (C), 161.5 (C), 151.0 (C), 141.4 (C), 139.4 (C), 131.0 (CH), 130.7 (CH), 129.4 (CH), 129.1 (CH), 128.0 (C), 124.0 (C), 123.9 (CH), 108.8 (C); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C19H12N3O6 378.0731; found 378.0745. 3-Cyano-5-(4-methylbenzoyl)-4-(4-methylphenyl)isoxazole (7m): Yellow oil (58.6 mg, 97%); IR (NaCl/cm−1) 2252, 1668; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.2 (C), 163.0 (C), 146.3 (C), 140.8 (C), 140.4 (C), 132.5 (C), 130.3 (CH), 129.7 (CH), 129.6 (CH), 129.1 (CH), 126.2 (C), 121.7 (C), 109.4 (C), 21.8 (CH3), 21.3 (CH3); HRMS (ESI-Q-TOF) m/z [M + CN]− calcd for C20H14N3O2 328.1091; found 328.1106. 5-Benzoyl-4-(5-chloro-2-furyl)-3-cyanoisoxazole (7n): Yellow solid (28.0 mg, 47%); mp 122−123 °C; IR (NaCl/cm−1) 2254, 1660; 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.55(d, J = 3.6 Hz, 1H), 6.37 (d, J = 3.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 180.7 (C), 160.7 (C), 139.9 (C), 139.3 (C), 138.4 (C), 135.2 (C), 134.7 (CH), 130.0 (CH), 128.9 (CH), 117.7 (CH), 117.0 (C), 109.2 (CH), 108.9 (C); HRMS (ESI-Q-TOF) m/z [M + CN]− calcd for C16H7ClN3O3 324.0181; found 324.0192. 5-Benzoyl-3-cyano-4-propylisoxazole (7o): Colorless oil (17.8 mg, 37%); IR (ATR/cm−1) 2254, 1664; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.4 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.56 (dd, J = 7.4, 7.4 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 1.74 (tq, J = 7.5, 7.5 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.5 (C), 163.5 (C), 142.2 (C), 135.3 (C), 134.5 (CH), 129.9 (CH), 128.9

(CH), 128.8 (C), 109.1 (C), 24.5 (CH2), 22.6 (CH2), 13.6 (CH3); HRMS (ESI-Q-TOF) m/z [M + CN]− calcd for C16H7ClN3O3 324.0181; found 324.0192. 5-Benzoyl-3-cyanoisoxazole (7p): Pale yellow solid (21.0 mg, 53%); mp 51−52 °C; IR (ATR/cm−1) 2257, 1668; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.2 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.58 (dd, J = 7.2, 7.2 Hz, 2H), 7.32 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.4 (C), 168.9 (C), 140.1 (C), 135.0 (CH), 134.4 (C), 130.0 (CH), 129.1 (CH), 111.6 (CH), 109.0 (C); HRMS (ESI-QTOF) m/z [M − H]− calcd for C11H5N2O2 197.0356; found 197.0349. 7-Oxocyclohexa[d]isoxazole-3-carboxamide (7q): Pale yellow solid (33.5 mg, 93%); mp 91−92 °C (dec.); IR (NaCl/cm−1) 3276, 1668; 1H NMR (400 MHz, DMSO-d6) δ 13.7 (s, 1H), 9.59 (s, 1H), 2.57 (t, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H), 1.92 (dt, J = 8.0, 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 194.6 (C), 146.6 (C), 130.1 (C), 118.1 (C), 109.9 (C), 36.6 (CH2), 24.1 (CH2), 21.3 (CH2); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C8H7N2O3 179.0462; found 179.0456. 6-Oxocyclopenta[d]isoxazole-3-carboxamide (7r): Pale brown solid (27.2 mg, 82%); mp 136−141 °C (dec.); IR (NaCl/cm−1) 3185, 1684; 1H NMR (400 MHz, DMSO-d6) δ 2.59−2.61 (m, 2H), 2.42− 2.40 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 202.3 (C), 152.0 (C), 128.2 (C), 127.9 (C), 109.2 (C), 31.0 (CH2), 21.2 (CH2); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C7H5N2O3 165.0305; found 165.0298. Methyl 4-(4-chlorophenyl)-5-ethanoylisoxazole-3-carboxylate (10): Colorless oil (15.0 mg, 27%); IR (ATR/cm−1) 1743, 1705; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.58 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.5 (C), 162.4 (C), 159.5 (C), 155.2 (C), 135.5 (C), 131.3 (CH), 128.4 (CH), 124.9 (C), 122.8 (C), 53.0 (CH3), 28.4 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C13H9ClNO4 278.0214; found 278.0205. Synthesis of Ethyl 5-(4-Methylbenzoyl)-4-(4-methylphenyl)isoxazole-3-carboxylate (11). To a solution of isoxazole 7j (60.5 mg, 0.2 mmol) in EtOH (2 mL) was added DBU (30 μL, 0.2 mmol), and the resultant mixture was stirred at room temperature for 3 h. After acidification with 1 M HCl (2 mL, 2 mmol), the reaction mixture was extracted with CH2Cl2 (2 mL × 3) and dried over MgSO4. After removal of solvents under reduced pressure, the residue was subjected to column chromatography on silica gel to afford ethyl ester 11 (eluted with hexane/ethyl acetate = 98/2, 49.6 mg, 0.15 mmol, 74%) as a pale yellow oil: IR (NaCl/cm−1) 1739, 1663; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.0 (C), 163.4 (C), 159.5 (C), 155.1 (C), 145.6 (C), 138.8 (C), 133.0 (C), 130.2 (CH), 129.9 (CH), 129.4 (CH), 128.8 (CH), 124.5 (C), 123.7 (C), 62.4 (CH2) 21.8 (CH3), 21.3 (CH3), 13.9 (CH3); HRMS (ESI-Q-TOF) m/z [M + AcO]− calcd for C23H22NO6 408.1441; found 408.1441. Synthesis of 3-(1-Benzyl-5-tetrazolyl)-5-(4-methylbenzoyl)4-(4-methylphenyl)isoxazole (13a). In a sealed tube, a mixture of benzyl azide (26.6 mg, 0.2 mmol) and isoxazole 7j (303 mg, 1.0 mmol) was heated without solvent at 130 °C for 1 day. The resultant mixture was subject to column chromatography on silica gel to afford cycloadduct 13a (eluted with hexane/Et2O = 9/1, 20.0 mg, 0.046 mmol, 23%) as a pale yellow oil: IR (NaCl/cm−1) 1668; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.30−7.27 (m, 5H), 7.21−7.19 (m, 2H), 7.08 (s, 4H), 5.78 (s, 2H), 2.42 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.9 (C), 163.5 (C), 150.2 (C), 145.9 (C), 144.9 (C), 139.4 (C), 133.1 (C), 132.7 (C), 130.2 (CH), 129.9 (CH), 129.5 (CH), 129.1 (CH), 129.03 (CH), 129.00 (CH), 128.2 (CH), 124.6 (C), 122.5 (C), 52.3 (CH2), 21.8 (CH3), 21.3 (CH3); HRMS (ESI-Q-TOF) m/z [M + Na]+ calcd for C26H21N5O2Na 458.1587; found 458.1589. Synthesis of 5-(4-Methylbenzoyl)-4-(4-methylphenyl)-3-(5tetrazolyl)isoxazole (13b). To a solution of ammonium acetate (90.2 mg, 1.17 mmol) in a mixed soluvemt (MeOH/H2O = 19/1 (v/ 5413

DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

Article

The Journal of Organic Chemistry

2,4-Dinitrophenylhydrazonation of Isoxazole 7a. To a solution of isoxazole 7a (123.0 mg, 0.5 mmol) in THF (10 mL) were added 2,4-dinitrophenylhydrazine (198.2 mg, 0.5 mmol) and a drop of 12 M HCl, and the resultant solution was heated under reflux for 1 h. After the mixture was cooled to 0 °C in an ice-bath, hexane (10 mL) was dropwise over 5 min. Orange precipitates were collected by filtration and washed with a mixed solvent (hexane/THF = 8/2 (v/v), 5 mL). After being dried under reduced pressure, 3-cyano-4-(4chlorophenyl)-5-[1-(2,4-dinitrophenylhydrazino)ethyl]isoxazole (215.7 mg, 0.5 mmol, quant.) was afforded as an orange powder. Further purification was performed by recrystallization from EtOAc: orange plates; mp 202−203 °C; IR (NaCl/cm−1) 3305, 1614, 1504, 1336; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 9.2, 1.6 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 1H), 2.44 (s, 3H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ 164.8 (C), 143.2 (C), 141.1 (C), 140.8 (C), 138.8 (C), 134.4 (C), 131.5 (CH), 131.2 (C), 129.4 (CH), 129.0 (CH), 125.6 (C), 122.7 (CH), 119.0 (C), 116.0 (CH), 109.7 (C), 13.0 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C18H10ClN6O5 425.0406; found 425.0426.

v), 10 mL) were added sodium azide (76.1 mg, 1.17 mmol) and isoxazole 7j (235.6 mg, 0.78 mmol), and the resultant mixture was heated under reflux for 1 day. After removal of the solvent under reduced pressure, the residue was dissolved in CH2Cl2 (10 mL) and washed with 1 M HCl (10 mL × 1), and the aqueous layer was extracted with CH2Cl2 (2 mL × 2). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure to afford 5(4-methylbenzoyl)-4-(4-methylphenyl)-3-(5-tetrazolyl)isoxazole 13b (249.6 mg, 0.45 mmol, 93%) as a yellow oil: IR (NaCl/cm−1) 1668; 1 H NMR (400 MHz, CDCl3) δ 13.15 (br s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.20 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.2 (C), 163.5 (C), 150.7 (C), 148.8 (C), 145.9 (C), 139.4 (C), 132.7 (C), 130.3 (CH), 130.0 (CH), 129.5 (CH), 129.1 (CH), 124.1 (C), 122.8 (C), 21.8 (CH3), 21.2 (CH3); HRMS (ESI-QTOF) m/z [M − H]− calcd for C19H14N5O2 344.1153; found 344.1143. Synthesis of 3-Cyano-5-[1-(ethanoyloxyimino)ethyl]-4-(4methoxyphenyl)isoxazole (14). To a solution of isoxazole 7b (121.0 mg, 0.5 mmol) in MeOH (5 mL) was added hydroxyammonium chloride (173.8 mg, 2.5 mmol), and the resultant mixture was heated at 60 °C for 5 h. After removal of the solvent under reduced pressure, the residue was subjected to short silica gel column chromatography to afford the oxime intermediate (eluted with EtOAc, 129.8 mg, 0.5 mmol, quant.) as a yellow solid. To a cooled solution of oxime (129.8 mg, 0.5 mmol) in CH2Cl2 (5 mL) in an ice-bath were added dropwise NEt3 (83 μL, 0.6 mmol) and acetyl chloride (43 μL, 0.6 mmol). The mixture was stirred at room temperature for further 0.5 h. After H2O (3 mL) was added, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 mL × 2). Combined organic layer was dried over MgSO4 and concentrated under reduced pressure to afford 3-cyano-5-[1(ethanoylimino)ethyl]-4-(4-methoxyphenyl)isoxazole 14 (143.8 mg, 0.48 mmol, 96%) as a yellow oil. 3-Cyano-5-[(1-(hydroxyimino)ethyl)]-4-(4-methoxyphenyl)isoxazole: Yellow solid; mp 121−122 °C; IR (NaCl/cm−1) 2253, 1516; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9 (C), 160.5 (C), 146.8 (C), 141.2 (C), 130.7 (CH), 120.6 (C), 117.6 (C), 114.4 (CH), 109.6 (C), 55.3 (CH3), 11.9 (CH3); HRMS (ESI-Q-TOF) m/z [M − H]− calcd for C13H10N3O3 256.0717; found 256.0725. 3-Cyano-5-[(1-ethanoyloxyimino)ethyl]-4-(4methoxyphenyl)isoxazole (14): Yellow oil; IR (NaCl/cm−1) 2252, 1783, 1516; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 167.8 (C), 161.4 (C), 160.9 (C), 152.1 (C), 141.5 (C), 131.4 (CH), 122.6 (C), 116.8 (C), 114.3 (CH), 109.5 (C), 55.4 (CH3), 19.5 (CH3), 14.2 (CH3); HRMS (ESI-QTOF) m/z [M − H]− calcd for C15H12N3O4 298.0833; found 298.0838. Synthesis of 1-Cyano-7-methoxy-4-methylisoxazolo[5,4-c]quinoline (15). To a solution of isoxazole 14 (60.0 mg, 0.2 mmol) in PhMe (2 mL) was added BF3−OEt2 (25 μL, 0.2 mmol), and the mixture was heated in a sealed tube at 150 °C for 1 day. After the reaction mixture was washed with saturated aqueous NaHCO3 (2 mL × 1), the aqueous layer was extracted with EtOAc (3 mL × 2). Combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel to afford 1-cyano-7-methoxy-4methylisoxazolo[5,4-c]quinoline 15 (eluted with hexane/acetone = 9/1, 17.1 mg, 0.072 mmol, 36%) as a pale yellow solid: mp 136−137 °C; IR (NaCl/cm−1) 2306; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 3.98 (s, 3H), 3.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8 (C), 158.1 (C), 146.6 (C), 145.0 (C), 134.7 (C), 122.9 (CH), 121.1 (C), 120.7 (CH), 113.0 (C), 110.0 (C), 109.3 (CH), 55.6 (CH3), 19.9 (CH3); HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C13H10N3O2 240.0767; found 240.0759.

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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.7b00811. DSC measurement, 1H and 13C NMR spectra for compounds 7a−r and 10−14, and ORTEP view of 2,4dinitrophenylhydrazine of 7a (PDF) X-ray data for 7a (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +81-88757-2517. Fax: +81-887-57-2520. ORCID

Haruyasu Asahara: 0000-0002-1808-7373 Nagatoshi Nishiwaki: 0000-0002-6052-8697 Notes

The authors declare no competing financial interest.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415

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DOI: 10.1021/acs.joc.7b00811 J. Org. Chem. 2017, 82, 5409−5415