P(NMe2)3-Mediated Reductive (1 + 4) Annulation Reaction of Isatins

Sep 28, 2017 - P(NMe2)3-Mediated Reductive (1 + 4) Annulation Reaction of Isatins with Nitroalkenes: An Access to Spirooxindolyl Isoxazoline N-Oxides ...
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Article Cite This: J. Org. Chem. 2017, 82, 10997-11007

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P(NMe2)3‑Mediated Reductive (1 + 4) Annulation Reaction of Isatins with Nitroalkenes: An Access to Spirooxindolyl Isoxazoline N‑Oxides and Their Corresponding Isoxazolines Yiyi Liu,† Hengyu Li,† Xun Zhou,‡ and Zhengjie He*,† †

The State Key Laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, P. R. China ‡ School of Materials Science and Engineering, Central South University, Changsha 410083, P. R. China S Supporting Information *

ABSTRACT: The reductive (1 + 4) annulation reaction of isatins and substituted nitroalkenes mediated by a trivalent phosphorus reagent has been realized for the first time, providing easy access to spirooxindolyl isoxazoline N-oxides in moderate to excellent yields with a flexible substrate scope. This reaction presumably proceeds through a Michael addition−intramolecular substitution sequence via active in situ generated Kukhtin−Ramirez zwitterions from isatins and P(NMe2)3. It is also demonstrated that the spirooxindolyl isoxazoline N-oxides can be readily converted into the corresponding isoxazolines in good yields.

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INTRODUCTION The spirooxindole motif bearing a spiro five-membered heterocycle at the 3-position of the oxindole frame represents a ubiquitous structural feature of many biological natural products and pharmaceuticals.1,2 The development of efficient synthetic methods for this type of spirocyclic motif has accordingly attracted much interest from organic chemists, and an array of effective methods have been therefore developed by different annulation strategies.2 As a subset of the spirooxindoles, spirooxindolyl isoxazolines have recently gained considerable interest due to their potential pharmaceutical properties3 and their usefulness in organic synthesis.4 The chemical propensities of the nitrogen−oxygen bond of the isoxazoline ring enable spirooxindolyl isoxazolines to serve as valuable synthetic intermediates, particularly in the syntheses of biologically important 3-hydroxyl-3-alkyl oxindoles. 4b,c Although there are many effective methods documented in the literature for the synthesis of an isoxazoline ring,4,5 the known methods for spirooxindolyl isoxazolines are very limited.4,6 The reported syntheses of spirooxindolyl isoxazolines are unexceptionally based on the 1,3-dipolar cycloaddition reaction of 3-alkylidene oxindoles and nitrile oxides. Since this cycloaddition strategy is inherently plagued with issues such as the instability of nitrile oxides, their propensity to dimerize, and the regioselectivity of the cycloaddition reaction, its efficiency and generality in the synthesis of spirooxindolyl isoxazolines are substantially restricted.7 Therefore, new and alternative synthetic methods for structurally diverse spirooxindolyl isoxazolines remain in high demand. Recently, the classical Kukhtin−Ramirez adducts (Scheme 1), which can be readily generated from trivalent phosphorus reagents and 1,2-dicarbonyl compounds, have attracted © 2017 American Chemical Society

Scheme 1. (1 + 4) Annulation Reactions via Kukhtin− Ramirez Adducts

remarkable interest.8−11 Through their dipolar structure, the Kukhtin−Ramirez adducts exhibit rich and appealing reactivity, particularly serving as carbene surrogates or 1,1-dipoles, in a series of organic synthetic reactions including cyclopropanation,9 X−H insertion reactions (X = C, O, N),10 and others.11 Aside from the above reaction modes, our group recently reported a P(NMe2)3-mediated reductive (1 + 4) annulation reaction of isatins with enones leading to efficient synthesis of Received: August 4, 2017 Published: September 28, 2017 10997

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry spirooxindole-dihydrofurans.12 The reaction represents the first effective protocol to construct five-membered cycles through the (1 + 4) annulation mode of Kukhtin−Ramirez adducts as 1,1-dipoles (Scheme 1a). Most recently, Ashfeld and coworkers have successfully realized a formal (1 + 4) annulation of 1,2-dicarbonyls and o-quinone methides by the same protocol, providing elegant access to dihydrobenzofurans with a quaternary center at C2.13 Inspired by these preceding studies and also motivated by the fact that nitroalkenes can act as effective partners in the (1 + 4) annulation reactions with the ylide-type 1,1-dipoles,5d we envisioned that the similar (1 + 4) annulation reaction of nitroalkenes and Kukhtin−Ramirez 1,1dipoles in situ generated from isatins and P(NMe2)3 could be feasible and accordingly provide an easy access to spirooxindolyl isoxazolines (Scheme 1b). Herein we report the relevant results from such investigations.

diastereoselectivities (entries 3 and 4). Products 3ca and 3da were only obtained as an inseparable diastereomeric mixture by column chromatographic isolation. With isatin 1a and nitroalkene 2a chosen as the reactants, a couple of representative trivalent phosphorus reagents were also checked (entries 5−7). It turned out that phosphite P(OMe)3 and phosphines such as PPh3 and PBu3 were all ineffective in the reaction. This result further confirms that the Kukhtin−Ramirez adducts from P(NMe2)3 and 1,2-dicarbonyls possess superior reactivity in the insertion reactions10 and the annulation reactions.9,12,13 Furthermore, solvent screening unveiled that CH2Cl2 remained the best choice, although common solvents including THF, toluene, and ether all uneventfully gave 3aa in moderate to good yields and modest diastereoselectivities (entries 8−10). With the preferred conditions identified as entry 1 in Table 1, the generality of the P(NMe2)3-mediated (1 + 4) annulation reaction between isatins 1 and nitroalkenes 2 was then investigated (Table 2). With nitroalkene 2a employed as a representative reactant, a variety of isatins 1 bearing different X substituents at the benzene ring were further tested. Substrates 1e−n with electron-donating or -withdrawing substituent(s) all smoothly afforded their corresponding products 3 in modest to excellent yields with varied diastereoselectivities (entries 2−11). Products 3ea−3na were all obtained as a pair of diastereomers, which were separable by column chromatography with the two exceptions of 3ia and 3la. In the cases of 3ia and 3la, isomers trans-3ia and trans-3la could not be separated from their corresponding cis-isomers, although purecis-isomers, although pure cis-3ia and cis-3la products were collected by column chromatographic isolation (entries 6 and 9). It is noteworthy that, except for 1d (Table 1, entry 4) and 1n (Table 2, entry 11), all tested isatins 1 afforded isomers cis-3 as the major products (Table 1, entries 1−4, and Table 2, entries 1−11). Contrarily, isatins 1d and 1n respectively delivered their corresponding trans-3da and trans-3na as the major products in low diastereoselectivities (Table 1, entry 4, and Table 2, entry 11). The increased steric hindrance at the 1- or 4-position of isatins 1 presumably resulted in the alteration of the stereoselectivity trend of the annulation reaction. Under the standard conditions and with isatin 1a chosen as a reactant, a series of nitroalkenes 2 were also surveyed (Table 2, entries 12−27, and Scheme 2). A group of tert-butyl 2-nitro acrylates 2b−k bearing different substituted phenyls readily delivered their normal annulation products 3 in good to excellent yields and 2.3:1 to 4.4:1 cis/trans ratios (entries 12− 21). In the cases of 2b and 2i, the minor products trans-3ab and trans-3ai were not separated from their corresponding cisisomers, although pure cis-3ab and trans-3ai were collected by column chromatographic isolation (entries 12 and 19). Both 1naphthyl (2l) and 2-naphthyl (2m) substituted nitroalkenes were also effective in the annulation reactions with isatin 1a, affording their corresponding products 3al and 3am in high yields and moderate diastereoselectivities (entries 22 and 23). Product 3al was only isolated as a diastereomeric mixture with a 6:1 cis/trans ratio (entry 22). In sharp contrast, aliphatic isopropyl-substituted nitroalkene 2n bearing an ethyl ester group almost exclusively gave its trans-isomer product trans-3an in 68% yield (entry 24). Nitroalkenes 2 with ester groups other than tert-butyl ester were further tested. Both ethyl ester (2o, 2p) and benzyl ester (2q) substituted nitroalkenes readily gave their annulation products 3ao−3aq in good yields but in low diastereoselectivities (Table 2, entries 25−27). Other substituted nitroalkenes 2r−t were further tested (Scheme 2).

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RESULTS AND DISCUSSION We commenced our investigation with the substrates Nmethoxymethyl isatin 1a and tert-butyl 2-nitro-3-phenyl acrylate 2a (as an E/Z mixture) under the predetermined conditions (Table 1). Gratifyingly, an expected P(NMe2)3-mediated (1 + Table 1. A Brief Survey of the Model Reaction Conditionsa

entry

1

solvent

PR′3

yield (%)b

drc

1 2 3 4 5 6 7 8 9 10

1a 1b 1c 1d 1a 1a 1a 1a 1a 1a

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF toluene ether

P(NMe2)3 P(NMe2)3 P(NMe2)3 P(NMe2)3 P(OMe)3 PPh3 PBu3 P(NMe2)3 P(NMe2)3 P(NMe2)3

3aa, 96 3ba, 77 3ca, 60d 3da, 43d 3aa, trace 3aa, trace 3aa, trace 3aa, 52 3aa, 77 3aa, 87

3.4:1 3.6:1 1.4:1 1:1.2

2:1 2:1 2:1

a

Typical conditions: under a N2 atmosphere, to a stirred mixture of isatin 1 (0.2 mmol) and nitroalkene 2a (50 mg, 0.22 mmol) in solvent (1.5 mL) was dropwise added a solution of phosphorus agent PR′3 (0.22 mmol) in solvent (0.5 mL) at −78 °C. The resulting mixture was then warmed to rt by removing the cooling bath and stirred at rt for 24 h. bThe combined yield of two isolated diastereomers. cDetermined by 1 H NMR assay of the isolated product and referring to the ratio of cis-3 versus trans-3. dAs an inseparable diastereomeric mixture.

4) annulation reaction between 1a (0.2 mmol) and 2a (0.22 mmol) occurred, furnishing the corresponding spirooxindolyl isoxazoline N-oxides 3aa in 96% isolated yield with a 3.4:1 cis3aa/trans-3aa ratio (Table 1, entry 1). To further explore the reaction parameters, a brief survey of the model reaction was carried out (Table 1). First, different substituents R at the nitrogen atom of the indole ring in 1 were surveyed (entries 2− 4). Under the same conditions, N-methyl isatin 1b readily gave its corresponding annulation product 3ba in 77% yield and 3.6:1 diastereoselectivity (entry 2), while N-acyl (1c) and Nbenzyl (1d) substituted isatins only afforded their corresponding products 3ca and 3da in modest yields and lower 10998

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry Table 2. P(NMe2)3-Mediated Reductive (1 + 4) Annulation of Isatins 1 and Nitroalkenes 2a

entry

X in 1

R1, EWG in 2

3, yield (%)b

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

H (1a) 5-Me (1e) 5-MeO (1f) 5-F (1g) 5-Cl (1h) 5-Br (1i) 5-NO2 (1j) 6-Cl (1k) 7-Cl (1l) 7-Me-5-Br (1m) 4-Br (1n) 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a

Ph, CO2But (2a) 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a p-MeO-Ph, CO2But (2b) p-Me-Ph, CO2But (2c) p-F-Ph, CO2But (2d) p-Cl-Ph, CO2But (2e) p-Br-Ph, CO2But (2f) p-CF3−Ph, CO2But (2g) m-MeO-Ph, CO2But (2h) m-Me-Ph, CO2But (2i) m-Cl-Ph, CO2But (2j) m-Br-Ph, CO2But (2k) 1-naphthyl, CO2But (2l) 2-naphthyl, CO2But (2m) iPr, CO2Et (2n) Ph, CO2Et (2o) m-NO2-Ph, CO2Et (2p) Ph, CO2Bn (2q)

3aa, 96 3ea, 99 3fa, 99 3ga, 77 3ha, 72 3ia, 71d 3ja, 57 3ka, 88 3la, 77d 3ma, 84 3na, 63 3ab, 99d 3ac, 95 3ad, 98 3ae, 99 3af, 98 3ag, 88 3ah, 99 3ai, 99d 3aj, 65 3ak, 87 3al, 99d 3am, 99 3an, 68 3ao, 97 3ap, 79 3aq, 84

3.4:1 2.3:1 2.6:1 4.2:1 2:1 2.4:1 3.1:1 4:1 2:1 2.2:1 1:1.3 3.6:1 2.8:1 4.4:1 2.6:1 3.5:1 3.1:1 3.6:1 2.6:1 2.3:1 3.4:1 6:1 2.8:1 1:20 1.2:1 2.4:1 1.1:1

a For details, see the Experimental Section. bIsolated yield based on 1. cReferring to the ratio of cis-3/trans-3 determined by the 1H NMR assay of the isolated diastereomeric mixture or by the yields of the separated isomer products. dIsomers cis-3 and trans-3 were not completely separated.

2). Thus, the results in Tables 1 and 2 and Scheme 2 show that the P(NMe2)3-mediated (1 + 4) annulation reaction between isatins 1 and nitroalkenes 2 has a flexible substrate scope and accordingly constitutes a new and efficient synthetic method to generate important spirooxindolyl isoxazoline N-oxides. The structures of spirooxindolyl isoxazoline N-oxides 3 were determined by 1 H and 13 C NMR and HRMS (ESI) measurements and were further confirmed by X-ray crystallographic analyses for representative compounds cis-3ao and cis3ha (see the Supporting Information). The relative configuration of trans-3an was assigned with the aid of NOESY analysis. By 1 H NMR spectra, isomer cis-3 is easily distinguished from its corresponding trans-3; the chemical shift of the methine proton of the isoxazoline ring in cis-3 is about 0.4 ppm downfield relative to that of trans-3. The relative configuration of byproduct F was assigned by analogy with the analogues reported in our previous work.12 Although a precise mechanism of this (1 + 4) annulation reaction remains elusive, according to our results in this study and previous closely related reports,9d,12 a rationale about formation of the annulation product 3 is exemplified in Scheme 3. Presumably, the reaction sequence is initiated with the formation of the Kukhtin−Ramirez adduct A from P(NMe2)3 and isatin 1, like 1a. Via its dipolar form B, the Kukhtin−

Scheme 2. Annulation Reactions of Isatin 1a with Other Nitroalkenes

Under the standard conditions, benzoyl-substituted 2r readily condensed with isatin 1a, delivering the normal annulation product 3ar in 58% yield and byproduct F in 23% yield. Product 3ar was obtained as an inseparable diastereomeric mixture with 3.6:1 cis/trans ratio. Apparently, the byproduct F was competitively generated through a known (1 + 4) annulation mode with substrate 2r acting as an enone.12 However, simple nitroalkenes 2s and 2t both failed to give the desired annulation products in the reactions with 1a (Scheme 10999

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry

Table 3. Transformation of Isoxazoline N-Oxides 3 into Isoxazolines 4a

Scheme 3. Formation of the Annulation Product 3

a

Ramirez adduct then engages in a Michael addition to nitroalkene 2, like 2a, in two possible modes, generating intermediates C and C′, respectively (shown in the Newman projection). For such nitroalkenes 2 as 2a, the Michael addition in mode a is favored, delivering intermediate C as a major one, since the possible π−π stacking interaction between phenyl groups and less steric hindrance between the small hydrogen and bulky phosphonium moiety both facilitate the formation of intermediate C. In contrast, mode b is disfavored, leading to intermediate C′ as a minor product. Finally, intermediates C and C′ undergo an intramolecular substitution in a process similar to SN2 to afford the corresponding annulation products cis-3aa and trans-3aa, respectively (Scheme 3). As this plausible mechanism indicates, the stereoselectivity in the Michael addition step is critical to the diastereoselectivity of the annulation reaction. The stereoselectivity of the Michael addition between Kukhtin−Ramirez dipole B and nitroalkene 2 is primarily controlled by the steric and electronic effects of the substrates’ substituents. As shown in Tables 1 and 2 and Scheme 2, the dr values of the annulation products 3 fluctuate as the substituents of the substrates 1 and 2 vary. In most of cases, isomers cis-3 were obtained as the major products. In a few cases, this diastereoselectivity trend was even reversed; isomers trans-3 were formed as the major products (Table 1, entry 4, and Table 2, entries 11 and 24). The substrates 2 as an E/Z mixture with the E/Z ratio ranging from 1:1 to 13:1 were used in the study. The E/Z ratio of 2, however, did not consistently correlate with the diastereoselectivity of product 3. For example, nitroalkene 2d with a 13:1 E/Z ratio yielded product 3ad in a 4.4:1 cis/trans ratio (Table 2, entry 14), and nitroalkene 2n with a 2.5:1 E/Z ratio produced 3an in a 1:20 cis/trans ratio (Table 2, entry 24). Considering the basicity of P(NMe2)3 and the acidity of the methine hydrogen of the isoxazoline ring in 3, three control experiments were conducted where cis-3ba, cis-3ea, and trans-3ao were treated with equimolar amounts of P(NMe2)3 in CH2Cl2 at rt for 24 h, respectively. No isomerization into their corresponding isomer was observed for both cis- and trans-3. To further extend the utility of this annulation reaction to important spirooxindolyl isoxazolines, we also investigated the transformation of spirooxindolyl isoxazoline N-oxides 3 into the corresponding spirooxindolyl isoxazolines 4 (Table 3).

entry

3

X, R, R1 in 4

yield (%)b

1 2 3 4 5 6 7 8 9 10

cis-3aa cis-3ba trans-3ba cis-3ea cis-3fa cis-3ia cis-3ah cis-3ak cis-3al cis-3am

H, CH2OMe, Ph (cis-4aa) H, Me, Ph (cis-4ba) H, Me, Ph (trans-4ba) 5-Me, CH2OMe, Ph (cis-4ea) 5-MeO, CH2OMe, Ph (cis-4fa) 5-Br, CH2OMe, Ph (cis-4ia) H, CH2OMe, m-MeO-Ph (cis-4ah) H, CH2OMe, m-Br-Ph (cis-4ak) H, CH2OMe, 1-naphthyl (cis-4al) H, CH2OMe, 2-naphthyl (cis-4am)

80 78 80 70 77 82 74 74 65 61

For details, see the Experimental Section. bIsolated yield.

According to a reported procedure for reduction of isoxazoline N-oxide,5a 10 selected annulation products 3 with cis or trans configuration were treated with excessive P(OMe)3 under reflux for 12 h. Their corresponding spirooxindolyl isoxazolines 4 with retention of configuration were readily obtained in good yields (Table 3). Thus, the (1 + 4) annulation reaction also provides a facile and efficient access to spirooxindolyl isoxazolines.

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CONCLUSION In summary, we have successfully realized a new P(NMe2)3mediated reductive (1 + 4) annulation reaction of isatins and substituted nitroalkenes to produce important spirooxindolyl isoxazoline N-oxides in modest to excellent yields with a broad substrate scope. Mechanistically, this reaction proceeds through a tandem Michael addition−intramolecular substitution sequence with the in situ generated Kukhtin−Ramirez adduct acting as a 1,1-dipole, and accordingly, this expands the validity and scope of the Kukhtin−Ramirez adduct-based annulation strategy in the synthesis of cyclic compounds. As illustrated in this work, the annulation products spirooxindolyl isoxazoline N-oxides can be readily converted to their corresponding isoxazolines in good yields. Thus, this annulation reaction also provides an easy access to spirooxindolyl isoxazolines. It is noteworthy that this synthetic protocol represents the first synthesis of spirooxindolyl isoxazolines different from those based on the 1,3-dipolar cycloaddition of nitrile oxides.4,6 On the basis of the characteristic reactivity of Kukhtin−Ramirez adducts, more organic reactions are currently under investigation in our laboratory, and relevant results will be reported in due course.

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EXPERIMENTAL SECTION

Unless otherwise noted, all reactions were carried out in a nitrogen atmosphere. Solvents were purified prior to use according to conventional procedures. 1H and 13C NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard. HRMS spectra were acquired in ESI mode (positive ion) with the TOF mass analyzer used. Column chromatography was performed on silica gel (200−300 mesh) using a mixture of petroleum ether/ethyl acetate as 11000

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry eluent. Isatins 114 and nitroalkenes 215 were prepared according to the literature procedures. General Procedure for P(NMe2)3-Mediated Reductive (1 + 4) Annulation Reaction of Isatins 1 and Nitroalkenes 2 (Tables 1 and 2 and Scheme 2). Under a N2 atmosphere and at −78 °C, to a stirred solution of isatin 1 (0.2 mmol) and nitroalkene 2 (0.22 mmol) in CH2Cl2 (1.5 mL) was added dropwise a solution of P(NMe2)3 (0.22 mmol, 40 μL) in CH2Cl2 (0.5 mL) by means of a syringe. The resulting reaction mixture was then warmed up to rt by removing the cooling bath and stirred at the same temperature for 24 h. The TLC analysis indicated that 1 was completely consumed. The solvent was removed on a rotary evaporator under reduced pressure, and the residue was subjected to column chromatographic isolation on silica gel by gradient elution with petroleum ether (60−90 °C)/ethyl acetate (20:1−5:1) to give product 3. The diastereomeric ratio of cis-3 versus trans-3 was measured by integrating the intensity of the diagnostic methine proton signal (for the isolated 3 as a diastereomeric mixture, the signal of the cis-isomer shifts about 0.4 ppm downfield relative to that of the trans-isomer) or by comparing the yields of the isolated cisand trans-isomers. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′-phenyl4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3aa). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give the major product cis-3aa (63 mg, 74% yield) as a pale yellow solid and the minor product trans3aa (18 mg, 22% yield) as a yellow solid. For cis-3aa: mp 172−173 °C; 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.3 Hz, 1H), 7.47−7.38 (m, 1H), 7.30−7.26 (m, 1H), 7.24−7.15 (m, 3H), 7.05−6.98 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 5.28 (s, 1H), 4.85 (d, J = 11.2 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 2.53 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 156.9, 142.7, 132.0, 131.8, 128.6, 128.4, 128.2, 124.5, 124.1, 123.4, 110.3, 109.8, 83.8, 83.6, 71.3, 59.2, 55.1, 27.5; HRMS-ESI [M + NH4]+ calcd for C23H28N3O6 442.1973, found 442.1978. For trans-3aa: mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.34−7.28 (m, 3H), 7.25−7.19 (m, 1H), 7.09−7.03 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.75−6.67 (m, 1H), 6.36 (d, J = 7.2 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.88 (s, 1H), 3.38 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.2, 157.0, 142.5, 134.5, 131.3, 128.84, 128.78, 128.1, 127.1, 123.2, 112.0, 110.6, 110.1, 83.6, 81.9, 71.6, 56.5, 55.8, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H28N3O6 442.1973, found 442.1976. 3′-(tert-Butoxycarbonyl)-1-methyl-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ba). Following the general procedure, isatin 1b (32 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give the major product cis-3ba (47 mg, 60% yield) as a yellow solid and the minor product trans-3ba (13 mg, 17% yield) as a pale yellow solid. For cis-3ba: mp 182−183 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.27−7.15 (m, 4H), 7.02−6.96 (m, 2H), 6.72 (d, J = 7.8 Hz, 1H), 5.21 (s, 1H), 2.79 (s, 3H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.6, 157.0, 144.1, 132.0, 131.6, 128.33, 128.27, 128.0, 124.24, 124.18, 123.5, 109.9, 108.7, 83.4, 83.3, 59.0, 27.5, 25.8; HRMSESI [M + NH4]+ calcd for C22H26N3O5 412.1867, found 412.1870. For trans-3ba: mp 153−154 °C; 1H NMR (400 MHz, CDCl3) δ 7.33− 7.28 (m, 3H), 7.25−7.21 (m, 1H), 7.10−7.02 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.71−6.64 (m, 1H), 6.33 (dd, J = 7.6, 0.6 Hz, 1H), 4.87 (s, 1H), 3.22 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.6, 157.0, 144.2, 134.7, 131.2, 128.8, 128.6, 128.0, 126.9, 122.8, 120.4, 110.9, 108.6, 83.4, 81.7, 55.4, 27.7, 26.4; HRMS-ESI [M + NH4]+ calcd for C22H26N3O5 412.1867, found 412.1873. 1-Acetyl-3′-(tert-butoxycarbonyl)-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ca). Following the general procedure, isatin 1c (38 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give product 3ca as an inseparable diastereomeric mixture (51 mg, 60% yield, dr 1.4:1). NMR data for the major isomer cis-3ca: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34−7.21 (m, 3H), 6.93 (d, J = 7.2 Hz, 2H), 5.22 (s, 1H), 2.14 (s, 3H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 169.4, 156.7, 140.3, 131.8, 131.5, 128.9, 128.4, 128.1, 126.2,

125.0, 123.9, 116.8, 108.8, 83.9, 83.4, 60.6, 27.5, 25.4. Selected signals for the minor isomer trans-3ca: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 7.10−7.01 (m, 2H), 6.81 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.88 (s, 1H), 2.74 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.3, 170.1, 156.8, 140.3, 133.8, 131.4, 129.0, 128.9, 126.5, 123.3, 119.3, 116.5, 110.1, 83.8, 81.4, 56.1, 27.6, 26.6. HRMS-ESI [M + NH4]+ calcd for C23H26N3O6 440.1816, found 440.1818. 1-Benzyl-3′-(tert-butoxycarbonyl)-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3da). Following the general procedure, isatin 1d (47 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give product 3da as an inseparable diastereomeric mixture (40 mg, 43% yield, dr 1:1.2). NMR data for the major isomer trans-3da: 1H NMR (400 MHz, CDCl3) δ 7.31−7.27 (m, 6H), 7.09−7.05 (m, 4H), 6.67−6.62 (m, 2H), 6.44 (d, J = 7.3 Hz, 1H), 6.38 (dd, J = 7.8, 1.0 Hz, 1H), 4.96 (s, 1H), 4.95−4.85 (m, 2H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.7, 157.1, 143.3, 132.1, 131.6, 131.1, 129.0, 128.8, 128.6, 128.1, 127.2, 127.0, 123.6, 122.8, 120.7, 110.7, 109.6, 83.6, 55.8, 43.9, 27.7. Selected signals for the minor isomer cis-3da: 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.4, 0.8 Hz, 1H), 7.38−7.32 (m, 4H), 7.26−7.23 (m, 2H), 7.20−7.13 (m, 2H), 7.12−7.10 (m, 1H), 5.30 (s, 1H), 5.00 (d, J = 15.9 Hz, 1H), 4.13 (d, J = 15.9 Hz, 1H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 157.0, 143.7, 134.8, 134.6, 134.5, 128.9, 128.7, 128.5, 128.4, 128.0, 127.4, 126.5, 124.5, 123.9, 110.0, 109.9, 81.8, 59.2, 43.7, 27.6. HRMS-ESI [M + NH4]+ calcd for C28H30N3O5 488.2180, found 488.2180. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-5-methyl-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ea). Following the general procedure, isatin 1e (41 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give the major product cis-3ea (60 mg, 68% yield) as a yellow solid and the minor product trans-3ea (26 mg, 31% yield) as a pale yellow solid. For cis-3ea: mp 174−175 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.25−7.17 (m, 4H), 7.06−6.98 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.26 (s, 1H), 4.83 (d, J = 11.1 Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 157.0, 140.3, 133.9, 132.2, 128.7, 128.4, 128.2, 125.1 (2C overlapped), 123.6, 110.0, 109.8, 83.9, 83.5, 71.3, 59.2, 55.1, 27.6, 21.1; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2137. For trans-3ea: mp 143−144 °C; 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 3H), 7.09−6.98 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 6.12 (s, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.08 (d, J = 10.9 Hz, 1H), 4.87 (s, 1H), 3.37 (s, 3H), 1.98 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.2, 157.1, 139.9, 134.6, 132.9, 131.5, 128.73, 128.66, 128.1, 127.9, 119.9, 110.6, 109.7, 83.6, 82.1, 71.6, 56.5, 55.7, 27.7, 20.7; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2136. 3′-(tert-Butoxycarbonyl)-5-methoxy-1-(methoxymethyl)-2-oxo4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3fa). Following the general procedure, isatin 1f (44 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to obtain the major product cis-3fa (65 mg, 71% yield) as a pale yellow solid and the minor product trans-3fa (25 mg, 28% yield) as a yellow solid. For cis-3fa: mp 178− 179 °C; 1H NMR (400 MHz, CDCl3) δ 7.28−7.17 (m, 4H), 7.06− 7.00 (m, 2H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.25 (s, 1H), 4.82 (d, J = 11.1 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 3.88 (s, 3H), 2.51 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 156.90, 156.86, 135.8, 132.1, 128.7, 128.5, 128.2, 124.6, 116.7, 111.0, 110.9, 109.7, 84.0, 83.6, 71.4, 59.3, 55.9, 55.0, 27.5; HRMS-ESI [M + NH4]+ calcd for C24H30N3O7 472.2078, found 472.2079. For trans-3fa: mp 154−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.31 (m, 3H), 7.09 (d, J = 2.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 5.89 (d, J = 2.5 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 5.08 (d, J = 10.9 Hz, 1H), 4.87 (s, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1, 157.0, 155.9, 135.7, 134.6, 128.9, 128.8, 128.1, 120.7, 117.8, 112.3, 110.8, 110.6, 83.6, 81.9, 71.6, 56.5, 55.7, 55.5, 27.7; HRMS-ESI [M + NH4]+ calcd for C24H30N3O7 472.2078, found 472.2083. 3′-(tert-Butoxycarbonyl)-5-fluoro-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ga). Following 11001

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry

= 8.8 Hz, 1H), 7.40−7.28 (m, 3H), 7.23 (s, 1H), 7.15−7.02 (m, 3H), 5.21 (d, J = 10.9 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 4.92 (s, 1H), 3.40 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1, 156.7, 147.6, 143.7, 133.6, 129.6, 129.4, 127.8, 127.7, 123.0, 121.4, 110.2, 109.5, 84.2, 80.7, 72.0, 56.8, 56.1, 27.8; HRMS-ESI [M + Na]+ calcd for C23H23N3NaO8 492.1377, found 492.1380. 3′-(tert-Butoxycarbonyl)-6-chloro-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ka). Following the general procedure, isatin 1k (45 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to deliver the major product cis3ka (65 mg, 71% yield) as a pale yellow solid and the minor product trans-3ka (16 mg, 17% yield) as a yellow solid. For cis-3ka: mp 187− 188 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 7.27−7.19 (m, 4H), 7.05−6.98 (m, 2H), 6.95 (d, J = 1.7 Hz, 1H), 5.24 (s, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.65 (d, J = 11.2 Hz, 1H), 2.52 (s, 3H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 156.8, 143.8, 137.9, 131.8, 128.7 (2C overlapped), 128.4, 125.6, 124.2, 121.8, 111.2, 109.5, 83.8, 83.4, 71.5, 59.2, 55.3, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1585. For trans-3ka: mp 153−154 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 3H), 7.11−7.01 (m, 2H), 6.99 (d, J = 1.8 Hz, 1H), 6.70 (dd, J = 8.2, 1.8 Hz, 1H), 6.25 (d, J = 8.2 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 5.08 (d, J = 10.9 Hz, 1H), 4.85 (s, 1H), 3.38 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 156.9, 143.6, 137.6, 134.3, 129.04, 129.0, 128.01, 127.97, 123.4, 118.3, 111.0, 110.4, 83.8, 81.4, 71.7, 56.6, 55.7, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1585. 3′-(tert-Butoxycarbonyl)-7-chloro-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3la). Following the general procedure, isatin 1l (45 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give product cis-3la as an inseparable diastereomeric mixture (71 mg, 77% yield, dr 2:1). NMR data for the major isomer cis-3la: 1H NMR (400 MHz, CDCl3) δ 7.64−7.59 (m, 1H), 7.42−7.37 (m, 1H), 7.33−7.29 (m, 1H), 7.27− 7.22 (m, 2H), 7.22−7.19 (m, 1H), 7.05−7.01 (m, 2H), 5.25 (s, 1H), 5.15 (d, J = 11.1 Hz, 1H), 5.03 (d, J = 11.1 Hz, 1H), 2.69 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.7, 156.8, 138.9, 134.1, 131.7, 128.9, 128.7, 128.6, 128.4, 124.9, 123.2, 116.8, 109.5, 83.8, 82.6, 71.5, 59.3, 55.7, 27.5. Selected signals for the minor isomer trans-3la: 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 1.0 Hz), 6.64 (t, J = 7.9 Hz), 6.31 (dd, J = 7.6, 1.0 Hz), 5.50 (d, J = 10.6 Hz), 5.42 (d, J = 10.6 Hz), 4.88 (s), 3.42 (s), 1.29 (s); 13C NMR (100 MHz, CDCl3) δ 174.9, 156.8, 138.5, 134.0, 133.5, 128.0, 126.8, 125.5, 123.9, 123.0, 116.6, 110.1, 83.7, 80.8, 72.0, 56.6, 56.0, 27.6. HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1586. 5-Bromo-3′-(tert-butoxycarbonyl)-1-(methoxymethyl)-7-methyl2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ma). Following the general procedure, isatin 1m (57 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to afford the major product cis-3ma (60 mg, 58% yield) as a pale yellow solid and the minor product trans-3ma (23 mg, 26% yield) as a yellow solid. For cis3ma: mp 184−185 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.35 (s, 1H), 7.26−7.19 (m, 3H), 7.07−7.00 (m, 2H), 5.22 (s, 1H), 4.88 (d, J = 11.5 Hz, 1H), 4.80 (d, J = 11.5 Hz, 1H), 2.60 (s, 3H), 2.40 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.7, 156.8, 139.9, 137.7, 131.9, 128.7, 128.6, 128.3, 126.5, 125.3, 124.0, 116.4, 109.4, 83.7, 82.7, 71.5, 59.4, 55.2, 27.5, 17.9; HRMS-ESI [M + NH4]+ calcd for C24H29BrN3O6 534.1234, found 534.1236. For trans-3ma: mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 3H), 7.14 (d, J = 1.3 Hz, 1H), 7.06−6.98 (m, 2H), 6.27 (d, J = 1.7 Hz, 1H), 5.22 (s, 2H), 4.85 (s, 1H), 3.39 (s, 3H), 2.45 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.0, 156.9, 139.5, 137.2, 134.0, 129.1, 129.0, 128.0, 127.8, 123.4, 122.6, 115.6, 110.1, 83.8, 80.9, 72.1, 56.4, 56.0, 27.7, 18.0; HRMS-ESI [M + NH4]+ calcd for C24H29BrN3O6 534.1234, found 534.1233. 4-Bromo-3′-(tert-butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3na). Following the general procedure, isatin 1n (54 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to deliver the major product trans-3na (36 mg, 35% yield) as a yellow solid and the minor product

the general procedure, isatin 1g (42 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to obtain the major product cis3ga (55 mg, 62% yield) as a yellow solid and the minor product trans3ga (13 mg, 15% yield) as a pale yellow solid. For cis-3ga: mp 186− 187 °C; 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 7.2, 2.2 Hz, 1H), 7.26−7.17 (m, 3H), 7.17−7.09 (m, 1H), 7.04 (d, J = 3.7 Hz, 2H), 7.07−6.99 (m, 1H), 5.25 (s, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 2.53 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 159.7 (d, J = 244.2 Hz),156.7, 138.6 (d, J = 2.1 Hz), 131.8, 128.7, 128.6, 128.3, 125.1 (d, J = 7.9 Hz), 118.4 (d, J = 23.4 Hz), 112.4 (d, J = 25.3 Hz), 111.4 (d, J = 7.9 Hz), 109.4, 83.8, 83.6, 71.5, 59.3, 55.1, 27.5; HRMS-ESI [M + NH4]+ calcd for C23H27FN3O6 460.1878, found 460.1885. For trans-3ga: mp 167−168 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.31 (m, 3H), 7.10−7.03 (m, 2H), 6.97− 6.89 (m, 2H), 6.09 (dd, J = 8.0, 1.8 Hz, 1H), 5.15 (d, J = 10.9 Hz, 1H), 5.09 (d, J = 10.9 Hz, 1H), 4.89 (s, 1H), 3.37 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 158.9 (d, J = 243.1 Hz), 156.9, 138.4, 134.1, 129.13, 129.09, 127.9, 121.7 (d, J = 8.4 Hz), 117.9 (d, J = 23.7 Hz), 114.9 (d, J = 26.1 Hz), 111.0 (d, J = 8.1 Hz), 110.2, 83.8, 81.6, 71.8, 56.5, 55.9, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H27FN3O6 460.1878, found 460.1882. 3′-(tert-Butoxycarbonyl)-5-chloro-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ha). Following the general procedure, isatin 1h (45 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to give the major product cis-3ha (44 mg, 48% yield) as a pale yellow solid and the minor product trans3ha (22 mg, 24% yield) as a yellow solid. For cis-3ha: mp 185−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.26−7.16 (m, 3H), 7.08−7.00 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 5.26 (s, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 2.53 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.8, 156.7, 141.2, 131.8 (2C overlapped), 129.5, 128.7 (2C overlapped), 128.3, 125.3, 124.9, 111.5, 109.3, 83.8, 83.3, 71.5, 59.3, 55.2, 27.5; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1589. For trans-3ha: mp 147−148 °C; 1H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 3H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.10− 7.00 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.09 (d, J = 10.9 Hz, 1H), 4.88 (s, 1H), 3.37 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.8, 156.9, 140.8, 134.0, 131.2, 129.1, 129.0, 128.8, 127.9, 127.4, 121.7, 111.2, 110.1, 83.8, 81.5, 71.7, 56.6, 55.9, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1588. 5-Bromo-3′-(tert-butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ia). Following the general procedure, isatin 1i (54 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to deliver product 3ia (71 mg, 71% yield, dr 2.4:1) as a diastereomeric mixture. The second careful separation of this mixture by column chromatography afforded the major product cis-3ia (41 mg, 40% yield) as a yellow solid: mp 184− 185 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 7.26−7.18 (m, 3H), 7.08−6.98 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.26 (s, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 2.52 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.7, 156.7, 141.7, 134.7, 131.8, 128.7 (2C), 128.3, 127.7, 125.7, 116.6, 111.9, 109.3, 83.8, 83.3, 71.4, 59.3, 55.2, 27.5; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1077. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-5-nitro-2-oxo-4′phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ja). Following the general procedure, isatin 1j (47 mg, 0.2 mmol) and nitroalkene 2a (55 mg, 0.22 mmol) were employed to deliver the major product cis3ja (40 mg, 43% yield) as a pale yellow solid and the minor product trans-3ja (13 mg, 14% yield) as a yellow solid. For cis-3ja: mp 186− 187 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 8.7, 2.2 Hz, 1H), 7.27−7.20 (m, 3H), 7.08 (d, J = 8.7 Hz, 1H), 7.06−7.00 (m, 2H), 5.36 (s, 1H), 4.89 (d, J = 11.3 Hz, 1H), 4.75 (d, J = 11.3 Hz, 1H), 2.55 (s, 3H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 156.5, 148.1, 144.4, 131.5, 128.9, 128.7, 128.5, 128.4, 124.9, 120.7, 110.5, 108.9, 84.1, 82.8, 71.8, 59.4, 55.5, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27N4O8 487.1823, found 487.1830. For trans-3ja: mp 163−164 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J 11002

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry

δ 174.1, 162.7 (d, J = 248.7 Hz), 156.9, 142.5, 131.5, 130.4 (d, J = 3.3 Hz), 129.8 (d, J = 8.3 Hz), 126.9, 123.4, 119.8, 115.9 (d, J = 21.8 Hz), 110.4, 110.2, 83.8, 81.8, 71.6, 56.6, 55.0, 27.8; HRMS-ESI [M + NH4]+ calcd for C23H27FN3O6 460.1878, found 460.1881. 3′-(tert-Butoxycarbonyl)-4′-(4-chlorophenyl)-1-(methoxymethyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ae). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2e (62 mg, 0.22 mmol) were employed to give the major product cis-3ae (66 mg, 72% yield) as a pale yellow solid and the minor product trans-3ae (25 mg, 27% yield) as a pale yellow solid. For cis-3ae: mp 184−185 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.30−7.26 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.00−6.93 (m, 3H), 5.25 (s, 1H), 4.86 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 156.8, 142.6, 134.5, 132.0, 130.7, 130.0, 128.4, 124.5, 124.2, 123.2, 110.4, 109.3, 83.9, 83.4, 71.4, 58.5, 55.3, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1587. For trans-3ae: mp 141−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.32−7.26 (m, 3H), 7.04−6.95 (m, 3H), 6.79 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.86 (s, 1H), 3.38 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 156.9, 142.5, 134.7, 133.1, 131.5, 129.4, 129.1, 126.9, 123.5, 119.7, 110.27, 110.24, 83.9, 81.7, 71.6, 56.6, 55.2, 27.8; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1589. 4′-(4-Bromophenyl)-3′-(tert-butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3af). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2f (72 mg, 0.22 mmol) were employed to give the major product cis-3af (77 mg, 76% yield) as a white solid and the minor product trans-3af (22 mg, 22% yield) as a pale yellow solid. For cis-3af: mp 179−180 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.29− 7.23 (m, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 8.1 Hz, 2H), 5.24 (s, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.70 (d, J = 11.2 Hz, 1H), 2.66 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 156.8, 142.6, 132.0, 131.3, 131.2, 130.3, 124.6, 124.2, 123.1, 122.6, 110.4, 109.2, 83.9, 83.4, 71.3, 58.5, 55.3, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1082. For trans-3af: mp 146− 147 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 7.31−7.22 (m, 1H), 7.02−6.91 (m, 3H), 6.84−6.76 (m, 1H), 6.40 (d, J = 7.1 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.84 (s, 1H), 3.38 (s, 3H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 156.9, 142.5, 133.6, 132.1, 131.6, 129.7, 126.9, 123.5, 122.8, 119.7, 110.3, 110.2, 83.9, 81.7, 71.6, 56.6, 55.2, 27.8; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1077. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′-(4(trifluoromethyl)phenyl)-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ag). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2g (70 mg, 0.22 mmol) were employed to give the major product cis-3ag (65 mg, 66% yield) as a pale yellow solid and the minor product trans-3ag (22 mg, 22% yield) as a pale yellow solid. For cis-3ag: mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 6.2 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 7.9 Hz, 1H), 5.35 (s, 1H), 4.85 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 2.54 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 156.7, 142.7, 136.4, 132.2, 130.8 (q, J = 32.4 Hz), 129.2, 125.1 (q, J = 3.4 Hz), 124.6, 124.4, 123.6 (q, J = 272.1 Hz), 122.9, 110.5, 109.1, 84.0, 83.4, 71.4, 58.7, 55.1, 27.6; HRMS-ESI [M + NH4]+ calcd for C24H27F3N3O6 510.1846, found 510.1854. For trans-3ag: mp 153−154 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 7.26− 7.23 (m, 1H), 7.20 (d, J = 7.7 Hz, 2H), 6.99 (d, J = 7.9 Hz, 1H), 6.81− 6.69 (m, 1H), 6.33 (d, J = 7.3 Hz, 1H), 5.17 (d, J = 10.9 Hz, 1H), 5.11 (d, J = 10.9 Hz, 1H), 4.96 (s, 1H), 3.39 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 156.8, 142.5, 138.7, 131.7, 131.1 (q, J = 32.8 Hz), 128.5, 126.7, 125.8 (q, J = 3.6 Hz), 123.6 (q, J = 272.0 Hz), 123.4, 119.6, 110.4, 109.9, 84.1, 81.6, 71.7, 56.6, 55.4, 27.8; HRMS-ESI [M + NH4]+ calcd for C24H27F3N3O6 510.1846, found 510.1854.

cis-3na (28 mg, 28% yield) as a yellow solid. For trans-3na: mp 133− 134 °C; 1H NMR (400 MHz, CDCl3) δ 7.18−7.10 (m, 5H), 7.07− 7.00 (m, 2H), 6.82 (dd, J = 7.4, 1.2 Hz, 1H), 5.47 (s, 1H), 5.18 (d, J = 11.0 Hz, 1H), 5.05 (d, J = 11.0 Hz, 1H), 3.37 (s, 3H), 1.26 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 173.8, 156.9, 143.2, 132.5, 132.0, 128.4, 128.1, 128.0, 127.8, 123.6, 120.7, 110.4, 109.1, 84.1, 83.7, 72.2, 58.7, 56.7, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1072. For cis-3na: mp 180−181 °C; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25−7.20 (m, 3H), 7.06 (br s, 2H), 6.91 (d, J = 7.8 Hz, 1H), 5.70 (s, 1H), 4.82 (d, J = 11.2 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 2.56 (s, 3H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.5, 157.0, 144.5, 133.0, 132.7, 128.9, 128.6, 128.3, 128.0, 122.5, 119.8, 109.4 (2C overlapped), 83.9, 83.7, 71.6, 55.6, 55.5, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1074. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-4′-(4-methoxyphenyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ab). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2b (61 mg, 0.22 mmol) were employed to afford product 3ab (90 mg, 99% yield, dr 3.6:1) as a diastereomeric mixture. The second careful separation of this mixture by column chromatography afforded the major product cis-3ab (55 mg, 62% yield) as a yellow solid: mp 165−166 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.28−7.23 (m, 1H), 6.99−6.89 (m, 3H), 6.73 (d, J = 8.7 Hz, 2H), 5.23 (s, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.70 (d, J = 11.2 Hz, 1H), 3.72 (s, 3H), 2.63 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.4, 159.7, 157.0, 142.7, 131.8, 129.8, 124.5, 124.1, 123.9, 123.7, 113.6, 110.3, 109.9, 83.8, 83.6, 71.3, 58.6, 55.23, 55.21, 27.6; HRMS-ESI [M + NH4]+ calcd for C24H30N3O7 472.2078, found 472.2084. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′-(p-tolyl)4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ac). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2c (58 mg, 0.22 mmol) were reacted to give the major product cis-3ac (61 mg, 70% yield) as a pale yellow solid and the minor product trans3ac (22 mg, 25% yield) as a yellow solid. For cis-3ac: mp 182−183 °C; 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz, 1H), 7.46−7.37 (m, 1H), 7.27−7.21 (m, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 7.8 Hz, 2H), 5.24 (s, 1H), 4.86 (d, J = 11.2 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 2.57 (s, 3H), 2.24 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.3, 157.1, 142.7, 138.3, 131.8, 128.9, 128.8, 128.5, 124.5, 124.1, 123.6, 110.2, 109.9, 83.8, 83.6, 71.3, 58.9, 55.1, 27.6, 20.9; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2131. For trans-3ac: mp 136−137 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.00−6.89 (m, 3H), 6.74 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.84 (s, 1H), 3.38 (s, 3H), 2.33 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.3, 157.1, 142.5, 138.6, 131.29, 131.25, 129.5, 127.9, 127.2, 123.3, 120.0, 110.9, 110.0, 83.5, 81.9, 71.6, 56.5, 55.4, 27.7, 21.2; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2129. 3′-(tert-Butoxycarbonyl)-4′-(4-fluorophenyl)-1-(methoxymethyl)2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ad). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2d (59 mg, 0.22 mmol) were employed to afford the major product cis3ad (71 mg, 81% yield) as a pale yellow solid and the minor product trans-3ad (16 mg, 17% yield) as a pale yellow solid. For cis-3ad: mp 185−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.30−7.27 (m, 1H), 7.06−6.98 (m, 2H), 6.97−6.89 (m, 3H), 5.27 (s, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 2.67 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 162.6 (d, J = 248.3 Hz), 156.8, 142.6, 132.0, 130.4 (d, J = 8.3 Hz), 127.9 (d, J = 3.3 Hz), 124.5, 124.2, 123.2, 115.19 (d, J = 21.8 Hz), 110.4, 109.5, 83.8, 83.5, 71.3, 58.3, 55.3, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27FN3O6 460.1878, found 460.1886. For trans-3ad: mp 149−150 °C; 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.3 Hz, 1H), 7.08−6.95 (m, 5H), 6.78 (t, J = 7.6 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.87 (s, 1H), 3.38 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) 11003

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-4′-(3-methoxyphenyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ah). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2h (61 mg, 0.22 mmol) were employed to give the major product cis-3ah (70 mg, 77% yield) as a pale yellow solid and the minor product trans-3ah (19 mg, 22% yield) as a pale yellow solid. For cis-3ah: mp 161−162 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.57 (br s, 2H), 5.24 (s, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.70 (d, J = 11.1 Hz, 1H), 3.67 (s, 3H), 2.61 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.4, 157.0, 142.7, 133.4, 131.8, 129.2, 124.5, 124.1, 123.6, 120.9, 114.5, 113.7, 110.3, 109.8, 83.7, 83.6, 71.3, 59.2, 55.2, 55.2, 27.6; HRMS-ESI [M + NH4]+ calcd for C24H30N3O7 472.2078, found 472.2083. For trans-3ah: mp 164−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.54 (s, 1H), 6.45 (d, J = 7.5 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.84 (s, 1H), 3.72 (s, 3H), 3.38 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.2, 159.9, 157.0, 142.4, 135.9, 131.4, 129.9, 127.0, 123.3, 120.3, 119.9, 114.0, 113.9, 110.6, 110.1, 83.6, 81.9, 71.6, 56.5, 55.7, 55.3, 27.8; HRMS-ESI [M + NH4]+ calcd for C24H30N3O7 472.2078, found 472.2082. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′-(m-tolyl)4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ai). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2i (58 mg, 0.22 mmol) were employed to give product 3ai (87 mg, 99% yield, dr 2.6:1) as a diastereomeric mixture. The second careful separation of this mixture by column chromatography afforded the major product cis-3ai (50 mg, 58% yield) as a pale yellow solid: mp 177−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.4 Hz, 1H), 7.45−7.38 (m, 2H), 7.25 (t, J = 7.7 Hz, 1H), 7.17−7.05 (m, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.58 (s, 1H), 4.90 (d, J = 11.2 Hz, 1H), 4.70 (d, J = 11.2 Hz, 1H), 2.56 (s, 3H), 1.70 (s, 3H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.3, 156.8, 142.4, 136.1, 131.7, 130.9, 130.3, 130.2, 128.3, 126.0, 124.6, 124.5, 124.1, 110.5, 110.3, 83.5, 83.4, 71.4, 55.2, 55.1, 27.5, 19.0; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2129. 3′-(tert-Butoxycarbonyl)-4′-(3-chlorophenyl)-1-(methoxymethyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3aj). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2j (62 mg, 0.22 mmol) were employed to deliver the major product cis-3aj (42 mg, 46% yield) as a pale yellow solid and the minor product trans-3aj (18 mg, 19% yield) as a yellow solid. For cis3aj: mp 167−168 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 5.24 (s, 1H), 4.90 (d, J = 11.1 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 2.67 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.9, 156.7, 142.6, 134.3, 134.2, 132.1, 129.5, 128.8, 128.6, 126.9, 124.5, 124.3, 123.2, 110.5, 109.2, 83.9, 83.4, 71.4, 58.5, 55.3, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27ClN3O6 476.1583, found 476.1588. For trans-3aj: mp 160−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.34−7.20 (m, 3H), 7.06 (s, 1H), 7.34−7.20 (m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.86 (s, 1H), 3.39 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 156.8, 142.5, 136.6, 134.9, 131.6, 130.1, 129.0, 128.2, 126.9, 126.2, 123.4, 119.7, 110.3, 110.1, 84.0, 81.7, 71.7, 56.6, 55.4, 27.8; HRMS-ESI [M + NH 4 ] + calcd for C23H27ClN3O6 476.1583, found 476.1590. 4′-(3-Bromophenyl)-3′-(tert-butoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ak). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2k (72 mg, 0.22 mmol) were employed to deliver the major product cis-3ak (68 mg, 67% yield) as a pale yellow solid and the minor product trans-3ak (20 mg, 20% yield) as a yellow solid. For cis-3ak: mp 177−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.2 Hz, 1H), 7.47−7.41 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 6.5 Hz, 1H), 7.22 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.99−6.92 (m,

2H), 5.23 (s, 1H), 4.90 (d, J = 11.2 Hz, 1H), 4.72 (d, J = 11.2 Hz, 1H), 2.66 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.9, 156.7, 142.6, 134.5, 132.1, 131.7, 131.5, 129.7, 127.3, 124.5, 124.3, 123.1, 122.2, 110.4, 109.2, 83.9, 83.4, 71.4, 58.4, 55.2, 27.6; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1082. For trans-3ak: mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 1H), 7.32−7.27 (m, 1H), 7.24−7.14 (m, 2H), 7.05−6.95 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.86 (s, 1H), 3.39 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 156.8, 142.5, 136.8, 131.9, 131.6, 131.1, 130.3, 126.9, 126.7, 123.4, 122.9, 119.7, 110.3, 110.0, 84.0, 81.8, 71.7, 56.6, 55.4, 27.8; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O6 520.1078, found 520.1072. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-4′-(naphthalen-1yl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ai). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2l (66 mg, 0.22 mmol) were employed to give product 3al as an inseparable diastereomeric mixture (94 mg, 99% yield, dr 6:1), as a yellow solid. NMR data for the major isomer cis-3al: 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 7.2 Hz, 1H), 7.49−7.38 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.15−7.06 (m, 2H), 7.15−7.06 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.63 (d, J = 11.2 Hz, 1H), 4.49 (d, J = 11.2 Hz, 1H), 2.18 (s, 3H), 1.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.6, 157.0, 142.4, 133.5, 131.7, 131.0, 128.9, 128.7, 128.6, 127.7, 126.2, 125.6, 125.2, 124.9, 124.2, 124.1, 121.5, 110.4, 110.0, 83.6, 83.0, 71.3, 54.9, 54.4, 27.5. Selected signals for the minor isomer trans-3al: 1H NMR (400 MHz, CDCl3) δ 5.81 (s), 5.23 (d, J = 10.9 Hz), 5.13 (d, J = 10.9 Hz), 3.42 (s), 1.22 (s); 13C NMR (100 MHz, CDCl3) δ 142.2, 131.2, 130.5, 129.7, 129.3, 126.4, 125.7, 124.7, 122.7, 121.3, 109.8, 71.6, 56.5, 50.5, 27.6. HRMS-ESI [M + NH4]+ calcd for C27H30N3O6 492.2129, found 492.2131. 3′-(tert-Butoxycarbonyl)-1-(methoxymethyl)-4′-(naphthalen-2yl)-2-oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3am). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2m (66 mg, 0.22 mmol) were employed to give the major product cis-3am (69 mg, 73% yield) as a yellow solid and the minor product trans-3am (25 mg, 26% yield) as a pale yellow solid. For cis-3am: mp 186−187 °C; 1H NMR (400 MHz, CDCl3) δ 7.78− 7.68 (m, 3H), 7.65 (d, J = 7.4 Hz, 1H), 7.48−7.38 (m, 4H), 7.34−7.25 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.46 (s, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 11.2 Hz, 1H), 2.20 (s, 3H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 157.0, 142.7, 133.0, 132.7, 131.9, 129.5, 127.9, 127.8, 127.7, 127.4, 126.4, 126.3, 126.0, 124.6, 124.2, 123.6, 110.3, 109.8, 83.8, 83.7, 71.2, 59.3, 54.8, 27.5; HRMS-ESI [M + NH4]+ calcd for C27H30N3O6 492.2129, found 492.2134. For trans-3am: mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.80 (m, 1H), 7.79−7.72 (m, 2H), 7.60 (s, 1H), 7.54−7.48 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 10.9 Hz, 1H), 5.04 (s, 1H), 3.40 (s, 3H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.2, 157.1, 142.5, 133.1, 133.0, 131.9, 131.3, 128.7, 127.9, 127.7, 127.2, 127.0, 126.7, 126.6, 125.7, 123.3, 119.8, 110.8, 110.1, 83.7, 81.9, 71.6, 56.6, 55.8, 27.7; HRMS-ESI [M + NH4]+ calcd for C27H30N3O6 492.2129, found 492.2132. 3′-(Ethoxycarbonyl)-4′-isopropyl-1-(methoxymethyl)-2-oxo-4′Hspiro[indoline-3,5′-isoxazole] 2′-Oxide (3an). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2n (42 mg, 0.22 mmol) were employed to exclusively deliver the major product trans-3an (49 mg, 68% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.06 (d, J = 10.9 Hz, 1H), 4.45−4.30 (m, 2H), 3.62 (d, J = 4.4 Hz, 1H), 3.35 (s, 3H), 2.41−2.27 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.12 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.4, 159.1, 142.9, 131.8, 127.0, 123.6, 120.0, 110.7, 110.4, 83.5, 71.5, 62.1, 56.5, 54.9, 28.9, 22.3, 19.1, 14.0; HRMS-ESI [M + NH4]+ calcd for C18H26N3O6 380.1816, found 380.1819. 11004

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry 3′-(Ethoxycarbonyl)-1-(methoxymethyl)-2-oxo-4′-phenyl-4′Hspiro[indoline-3,5′-isoxazole] 2′-Oxide (3ao). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2o (49 mg, 0.22 mmol) were employed to give the major product cis-3ao (42 mg, 53% yield) as a pale yellow solid and the minor product trans-3ao (35 mg, 44% yield) as a yellow solid. For cis-3ao: mp 174−175 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.4 Hz, 1H), 7.47−7.39 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.23−7.16 (m, 3H), 7.03−6.97 (m, 2H), 6.94 (d, J = 7.9 Hz, 1H), 5.34 (s, 1H), 4.85 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.26 (dq, J = 10.9, 7.1 Hz, 1H), 4.15 (dq, J = 10.9, 7.1 Hz, 1H), 2.56 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 158.2, 142.7, 132.0, 131.6, 128.6, 128.5, 128.4, 124.6, 124.2, 123.4, 110.4, 109.3, 84.0, 71.4, 61.9, 58.8, 55.3, 13.8; HRMS-ESI [M + NH4]+ calcd for C21H24N3O6 414.1660, found 414.1663. For trans-3ao: mp 141−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.36−7.28 (m, 3H), 7.26−7.20 (m, 1H), 7.13−7.02 (m, 2H), 6.97 (t, J = 9.0 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.9 Hz, 1H), 5.10 (d, J = 10.9 Hz, 1H), 4.88 (s, 1H), 4.32−4.10 (m, 2H), 3.39 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.1, 158.2, 142.5, 134.1, 131.5, 129.0, 128.1, 127.1, 123.3 (2C overlapped), 119.4, 110.2, 110.1, 82.3, 71.6, 62.0, 56.5, 55.2, 13.9; HRMS-ESI [M + NH4]+ calcd for C21H24N3O6 414.1660, found 414.1667. 3′-(Ethoxycarbonyl)-1-(methoxymethyl)-4′-(3-nitrophenyl)-2oxo-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ap). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2p (59 mg, 0.22 mmol) were employed to deliver the major product cis-3ap (49 mg, 56% yield) as a yellow solid and the minor product trans-3ap (20 mg, 23% yield) as a yellow solid. For cis-3ap: mp 165−166 °C; 1H NMR (400 MHz, CDCl3) δ 8.18−8.08 (m, 1H), 7.85 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.52−7.41 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 5.43 (s, 1H), 4.84 (d, J = 11.1 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.33−4.12 (m, 3H), 2.73 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 157.9, 147.9, 142.3, 134.7, 134.2, 132.4, 129.4, 124.6, 124.5, 123.6, 123.4, 123.0, 110.7, 108.2, 83.2, 71.4, 62.2, 57.9, 55.6, 13.8; HRMS-ESI [M + Na]+ calcd for C21H19N3NaO8 464.1064, found 464.1068. For trans-3ap: mp 78− 79 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.52−7.44 (m, 1H), 7.30−7.24 (m, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.74 (t, J = 7.7 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 5.18 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 10.9 Hz, 1H), 5.04 (s, 1H), 4.31−4.19 (m, 2H), 3.40 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 157.9, 148.4, 142.6, 136.5, 133.9, 132.0, 130.0, 126.6, 123.9, 123.5, 123.2, 119.0, 110.7, 109.1, 82.0, 71.8, 62.4, 56.7, 54.9, 14.0; HRMS-ESI [M + Na]+ calcd for C21H19N3NaO8 464.1064, found 464.1070. 3′-((Benzyloxy)carbonyl)-1-(methoxymethyl)-2-oxo-4′-phenyl4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3aq). Following the general procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2q (62 mg, 0.22 mmol) were employed to obtain the major product cis3aq (40 mg, 43% yield) as a yellow solid and the minor product trans3aq (37 mg, 41% yield) as a pale yellow solid. For cis-3aq: mp 175− 176 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.28−7.13 (m, 7H), 6.98 (d, J = 7.3 Hz, 2H), 6.93 (d, J = 7.7 Hz, 3H), 5.34 (s, 1H), 5.23 (d, J = 12.5 Hz, 1H), 5.07 (d, J = 12.5 Hz, 1H), 4.83 (d, J = 11.1 Hz, 1H), 4.66 (d, J = 11.1 Hz, 1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 158.0, 142.7, 134.4, 132.0, 131.5, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 124.6, 124.2, 123.2, 110.3, 109.2, 84.0, 71.3, 67.3, 58.6, 55.2; HRMS-ESI [M + NH4]+ calcd for C26H26N3O6 476.1816, found 476.1809. For trans3aq: mp 168−169 °C; 1H NMR (400 MHz, CDCl3) δ 7.38−7.28 (m, 3H), 7.25−7.16 (m, 4H), 7.12−7.01 (m, 2H), 7.00−6.96 (m, 3H), 6.70 (t, J = 7.7 Hz, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.28 (d, J = 12.7 Hz, 1H), 5.15−5.07 (m, 3H), 4.92 (s, 1H), 3.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0, 157.9, 142.5, 134.7, 134.0, 131.5, 129.03, 128.97, 128.4, 128.2, 128.1, 127.5, 127.1, 123.3, 119.4, 110.13, 110.06, 82.3, 71.5, 67.1, 56.5, 55.1; HRMS-ESI [M + NH4]+ calcd for C26H26N3O6 476.1816, found 476.1818. 3′-(Benzoyl)-1-(methoxymethyl)-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole] 2′-Oxide (3ar). Following the general

procedure, isatin 1a (38 mg, 0.2 mmol) and nitroalkene 2r (56 mg, 0.22 mmol) were employed to give product 3ar as an inseparable diastereomeric mixture (50 mg, 58% yield, dr 3.6:1) and byproduct F (20 mg, 23% yield). NMR data for the major isomer cis-3ar: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 7.3 Hz, 1H), 7.67 (t, J = 7.0 Hz, 1H), 7.61−7.53 (m, 2H), 7.44 (t, J = 7.7 Hz, 1H), 7.32−7.23 (m, 2H), 7.17−7.06 (m, 3H), 6.94 (d, J = 7.4 Hz, 2H), 5.69 (s, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.4, 171.8, 143.0, 134.6, 134.3, 132.1, 130.3, 130.2, 129.6, 128.9, 128.7, 128.3, 127.0, 124.9, 124.3, 116.1, 110.5, 85.3, 71.3, 59.4, 55.2. Selected signals for the minor isomer trans-3ar: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz), 7.50 (t, J = 7.4 Hz), 6.69 (t, J = 7.6 Hz), 6.36 (t, J = 13.4 Hz), 5.20 (d, J = 10.2 Hz), 5.11 (d, J = 10.2 Hz), 3.42 (s); 13C NMR (100 MHz, CDCl3) δ173.9, 142.3, 135.0, 132.5, 131.2, 128.8, 128.4, 128.1, 127.8, 127.0, 123.1, 122.0, 121.7, 109.9, 88.2, 71.6, 56.5, 54.7. HRMS-ESI [M + Na]+ calcd for C25H20N2NaO5 451.1264, found 451.1270. cis-1′-(Methoxymethyl)-4-nitro-3,5-diphenyl-3H-spiro[furan-2,3′indolin]-2′-one (F). The title compound was collected from the reaction of 1a and 2r as a yellow solid in 23% yield: mp 150−151 °C; 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.60−7.53 (m, 1H), 7.52−7.42 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.25−7.17 (m, 3H), 7.11−7.04 (m, 2H), 6.99 (d, J = 7.8 Hz, 1H), 5.43 (s, 1H), 4.86 (d, J = 11.1 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 164.6, 142.5, 132.9, 132.4, 131.9, 129.9, 128.5, 128.3, 128.2, 128.1, 127.1, 126.2, 124.5, 124.3, 110.3(2C), 89.2, 71.5, 58.5, 55.5; HRMS-ESI [M + Na]+ calcd for C25H20N2NaO5 451.1264, found 451.1268. General Procedure for Transformation of Isoxazoline NOxides 3 to the Corresponding Isoxazolines 4 (Table 3). The spirooxindolyl isoxazoline N-oxide 3 (0.15 mmol) was dissolved in trimethyl phosphite (1.0 mL) in a flask equipped with a condenser. The solution was well degassed and heated at reflux under N2 for 12 h. The TLC analysis (petroleum ether/ethyl acetate 5:1) revealed that the starting material was consumed. The reaction mixture was then cooled to 0 °C and diethyl ether (10 mL) was added to it, and the resulting mixture was washed with 1 N HCl (2.0 mL × 3) and water (10 mL). The organic layer was dried over Na2SO4. After filtration and concentration under reduced pressure, the crude product was further purified by column chromatography on silica gel (petroleum ether/ ethyl acetate 5:1 as eluent) to give the corresponding spirooxindolyl isoxazoline 4. cis-tert-Butyl 1-(Methoxymethyl)-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4aa). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3aa (64 mg, 0.15 mmol) was employed to give the product cis-4aa (49 mg, 80% yield) as a pale yellow solid: mp 137−138 °C; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.25−7.17 (m, 4H), 7.05−6.98 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 5.15 (s, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 2.63 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 158.4, 154.1, 142.5, 131.6, 131.3, 128.8, 128.4 (2C overlapped), 126.3, 124.2, 124.1, 110.0, 91.4, 84.0, 71.2, 63.7, 55.3, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H28N3O5 426.2023, found 426.2022. cis-tert-Butyl 1-Methyl-2-oxo-4′-phenyl-4′H-spiro[indoline-3,5′isoxazole]-3′-carboxylate (cis-4ba). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3ba (59 mg, 0.15 mmol) was employed to give product cis-4ba (44 mg, 78% yield) as a yellow solid: mp 167−169 °C; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.27−7.22 (m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.04−6.98 (m, 2H), 6.75 (d, J = 7.8 Hz, 1H), 5.10 (s, 1H), 2.87 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.5, 158.5, 154.0, 144.0, 131.7, 131.1, 128.6, 128.4, 128.3, 127.4, 123.9, 123.5, 108.6, 90.7, 83.9, 63.2, 27.8, 26.1; HRMS-ESI [M + NH4]+ calcd for C22H26N3O4 396.1918, found 396.1920. trans-tert-Butyl 1-Methyl-2-oxo-4′-phenyl-4′H-spiro[indoline3,5′-isoxazole]-3′-carboxylate (trans-4ba). Following the general procedure, spirooxindolyl isoxazoline N-oxide trans-3ba (59 mg, 0.15 mmol) was employed to afford product trans-4ba (45 mg, 80% yield) 11005

DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

Article

The Journal of Organic Chemistry as a pale yellow solid: mp 175−176 °C; 1H NMR (400 MHz, CDCl3) δ 7.32−7.25 (m, 3H), 7.24−7.14 (m, 1H), 7.04−6.97 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 4.95 (s, 1H), 3.21 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1, 158.1, 154.8, 144.5, 133.3, 130.8, 128.8, 128.4, 128.3, 127.0, 122.7, 121.8, 108.4, 90.0, 83.7, 59.0, 27.8, 26.4; HRMS-ESI [M + NH4]+ calcd for C22H26N3O4 396.1918, found 396.1923. cis-tert-Butyl 1-(Methoxymethyl)-5-methyl-2-oxo-4′-phenyl-4′Hspiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4ea). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3ea (66 mg, 0.15 mmol) was employed to obtain product cis-4ea (44 mg, 70% yield) as a yellow solid: mp 148−149 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.25−7.21 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 7.06−6.99 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 5.15 (s, 1H), 4.85 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.1 Hz, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 158.4, 154.0, 140.0, 133.8, 131.7, 131.6, 128.8, 128.3 (2C overlapped), 126.3, 124.7, 109.8, 91.6, 83.9, 71.2, 63.6, 55.3, 27.7, 21.1; HRMS-ESI [M + NH4]+ calcd for C24H30N3O5 440.2180, found 440.2184. cis-tert-Butyl 5-Methoxy-1-(methoxymethyl)-2-oxo-4′-phenyl4′H-spiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4fa). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3fa (68 mg, 0.15 mmol) was employed to obtain product cis-4fa (51 mg, 77% yield) as a pale yellow solid: mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 7.25−7.20 (m, 3H), 7.15 (d, J = 2.5 Hz, 1H), 7.06− 7.00 (m, 2H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.14 (s, 1H), 4.85 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 3.86 (s, 3H), 2.62 (s, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 158.4, 156.9, 154.1, 135.7, 131.6, 128.8, 128.42, 128.38, 127.4, 116.3, 110.8, 110.6, 91.8, 84.1, 71.4, 63.9, 55.9, 55.3, 27.8; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2128. cis-tert-Butyl 5-Bromo-1-(methoxymethyl)-2-oxo-4′-phenyl-4′Hspiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4ia). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3ia (76 mg, 0.15 mmol) was employed to obtain product cis-4ia (60 mg, 82% yield) as a yellow solid: mp 172−173 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 1.8 Hz, 1H), 7.52 (dd, J = 8.3, 1.8 Hz, 1H), 7.26−7.20 (m, 3H), 7.07−6.99 (m, 2H), 6.85 (d, J = 8.3 Hz, 1H), 5.14 (s, 1H), 4.85 (d, J = 11.2 Hz, 1H), 4.69 (d, J = 11.2 Hz, 1H), 2.62 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.6, 158.1, 154.0, 141.4, 134.2, 131.3, 128.8, 128.6, 128.5, 128.3, 127.4, 116.6, 111.7, 91.0, 84.2, 71.3, 63.9, 55.4, 27.7; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O5 504.1129, found 504.1134. cis-tert-Butyl 1-(Methoxymethyl)-4′-(3-methoxyphenyl)-2-oxo4′H-spiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4ah). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3ah (68 mg, 0.15 mmol) was employed to obtain product cis-4ah (49 mg, 74% yield) as a pale yellow solid: mp 128−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.77 (dd, J = 8.3, 2.4 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 5.13 (s, 1H), 4.90 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.2 Hz, 1H), 3.69 (s, 3H), 2.71 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.5, 158.5, 154.0, 142.5, 133.0, 131.3 (2C overlapped), 129.4, 126.4, 124.13, 124.07, 121.1, 114.1, 110.0, 91.4, 84.0, 71.3, 63.6, 55.4, 55.2, 27.8; HRMS-ESI [M + NH4]+ calcd for C24H30N3O6 456.2129, found 456.2135. cis-tert-Butyl 4′-(3-Bromophenyl)-1-(methoxymethyl)-2-oxo-4′Hspiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4ak). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3ak (76 mg, 0.15 mmol) was employed to obtain product cis-4ak (54 mg, 74% yield) as a pale yellow solid: mp 158−159 °C; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.4 Hz, 1H), 7.45−7.35 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.14 (t, J = 8.3 Hz, 1H), 6.99 (t, J = 6.5 Hz, 2H), 5.09 (s, 1H), 4.91 (d, J = 11.1 Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 2.78 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.8, 158.2, 153.4, 142.3, 134.1, 131.7, 131.54, 131.51, 129.8, 127.5, 126.1, 124.2, 124.1, 122.3, 110.2, 91.2, 84.3, 71.3, 62.8, 55.5, 27.8; HRMS-ESI [M + NH4]+ calcd for C23H27BrN3O5 504.1129, found 504.1131.

cis-tert-Butyl 1-(Methoxymethyl)-4′-(naphthalen-1-yl)-2-oxo4′H-spiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4al). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3al (71 mg, 0.15 mmol) was employed to obtain product cis-4al (45 mg, 65% yield) as a pale yellow solid: mp 164−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.50−7.45 (m, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.37−7.33 (m, 1H), 7.31 (t, J = 6.4 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.97 (s, 1H), 4.65 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 2.18 (s, 3H), 1.41 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.2, 158.5, 154.0, 142.4, 133.0, 132.9, 131.4, 129.2, 128.1, 128.0, 127.8, 127.5, 126.5, 126.4, 126.3, 126.2, 124.20, 124.17, 110.1, 91.5, 84.1, 71.2, 63.8, 55.2, 27.8 ppm; HRMS-ESI [M + NH4]+ calcd for C27H30N3O5 476.2180, found 476.2186. cis-tert-Butyl 1-(Methoxymethyl)-4′-(naphthalen-2-yl)-2-oxo4′H-spiro[indoline-3,5′-isoxazole]-3′-carboxylate (cis-4am). Following the general procedure, spirooxindolyl isoxazoline N-oxide cis-3am (71 mg, 0.15 mmol) was employed to obtain product cis-4am (42 mg, 61% yield) as a pale yellow solid: mp 146−147 °C; 1H NMR (400 MHz, CDCl3) δ 7.78−7.71 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.49−7.38 (m, 4H), 7.30−7.23 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 5.33 (s, 1H), 4.78 (d, J = 11.2 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 2.40 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.2, 158.5, 154.0, 142.4, 133.0, 132.9, 131.4, 129.2, 128.1, 128.0, 127.8, 127.5, 126.5, 126.4, 126.3, 126.2, 124.2, 124.2, 110.1, 91.5, 84.1, 71.2, 63.8, 55.2, 27.8; HRMS-ESI [M + NH4]+ calcd for C27H30N3O5 476.2180, found 476.2185.

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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.7b01962. Crystal data, structure refinement, and ORTEP representations of compounds cis-3ha and cis-3ao and copies of NMR (1H, 13C) spectra of new compounds 3, F, and 4 (PDF) X-ray crystallographic data (CIF files) for compound cis3ha (CIF) X-ray crystallographic data (CIF files) for compound cis3ao (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhengjie He: 0000-0002-7891-0245 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from National Natural Science Foundation of China (Grant no. 21472096; J1103306) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007

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DOI: 10.1021/acs.joc.7b01962 J. Org. Chem. 2017, 82, 10997−11007