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Cite This: J. Org. Chem. 2018, 83, 2948−2953

Solvent-Minimized, Chromatography-Free, Diastereoselective Synthesis of Oxazolidine-Dispirooxindoles via oxa-1,3-Dipolar Cycloaddition of 3‑Oxindole Peng-Ju Xia,† Jun Li,† Yu-Lun Qian,† Qing-Lan Zhao,† Hao-Yue Xiang,*,† Jun-An Xiao,‡ Xiao-Qing Chen,*,† and Hua Yang*,† †

College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning 530001, Guangxi, P. R. China

‡

S Supporting Information *

ABSTRACT: An efficient and diastereoselective decarboxylative oxa-1,3-dipolar cycloaddition between 3-oxindoles and diverse amino acids is developed to access novel oxazolidine-dispirooxindole skeletons bearing vicinal quaternary carbon centers. This protocol features operational simplicity, a broad substrate scope, and good to excellent chemical yields and diastereoselectivities. In particular, minimal solvent (1 mL/10 mmol) and chromatographyfree purification render this synthetic process more efficient and environmentally benign in the context of green chemistry.

S

Scheme 1. Representative Synthetic Profiles of Dispirooxindoles

pirooxindoles, frequently found in a variety of natural products and pharmaceuticals with a range of biological activities, such as antidiabetic,1 anticancer,2 antitubercular,3 antibacterial,4 and antimicrobial5 activities, have gained considerable attention. Consequently, a plethora of synthetic strategies have been developed to access a wide array of analogues possessing spirooxindole motifs.6 Specifically, dispirooxindoles are a class of attractive subgroup members, owing to the potentially pronounced bioactivity by incorporating two spirooxindole units.7 However, the intimidating issues caused by the demanding steric effect of quaternary center hinder the advance of efficient assembly of dispirooxindoles to some degree. In this respect, it is persistently necessary and fundamental to exploit efficient protocols to install dispirooxindoles with broader structural diversity. Azomethine ylides, in situ generated from 3-oxindole with various primary or secondary amines, serve as versatile synthetic intermediates in a range of cycloadditions, especially in 1,3dipolar cycloaddition.8 It can be rationalized that 1,3-dipolar reactions involving 3-oxindole-derived azomethine ylides and dipolarophiles offer the most step-/atom-economical and straightforward synthetic pathways for rapid assembly of dispirooxindoles. In 2015, Tu and co-workers9 reported a 1,3dipolar cycloaddition (1,3-DC) of 3-oxindole-derived azomethine ylide with methyleneindolinone to construct a 3,3′pyrrolidine-dispirooxindole framework (Scheme 1, a). In the same year, Pang’s research group11a documented a diastereoselective construction of imidazolidine-dispirooxindoles via three-component [3 + 2] cycloadditions of isatins, 2(aminomethyl)pyridine, and 3-oxindole-based imines. Recently, © 2018 American Chemical Society

Yang et al.11b disclosed a self-1,3-dipolar [3 + 2]-cycloaddition of imines derived from 3-oxindoles and benzylamine to form imidazolidine-dispirooxindole (Scheme 1, b). Regardless of these encouraging advances in the construction of dispirooxindoles, all previous work focused on the CC10 and CN11 at the C3 position of 3-oxindole. Yet, the 1,3-DC directly involved with the CO of isatin, leading to the formation of oxazolidinedispirooxindole, has never been harnessed (Scheme 1, c). Received: November 12, 2017 Published: February 6, 2018 2948

DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953

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The Journal of Organic Chemistry

Table 1. Optimization of oxa-1,3-Dipolar Cycloaddition Reactiona

As a privileged structural scaffold, oxazolidine widely exists in many bioactive compounds.12 It holds great potential as the merging of dispirooxindole with oxazolidine offers a novel class of heterocycles with new biological profiles. However, to the best of our knowledge, oxazolidine-dispirooxindole still remains elusive in the compound library of dispirooxindoles. Certainly, the gap needs to be filled, which would be of significant interest in both synthetic and medicinal settings. Presumably, 1,3-DC of 3oxindole-derived azomethine ylide with 3-oxindole is still the superior choice for this demanding task. To this end, the top challenge we are facing is how to override the undesired self-1,3dipolar cyclization of ketimines derived from 3-oxindoles and amines, giving imidazolidine-dispirooxindole rather than oxazolidine-dispirooxindole. Moreover, the intrinsic instability of the oxazolidine moiety possibly hinders clear identification of oxazolidine-dispirooxindole.13 We noticed that amino acids, especially primary amino acids, are abundant and environmentally benign building blocks for synthetic chemistry.14 Unlike wide utilization of proline in 1,3-DC,15 primary amino acids received much less attention due to their relatively sluggish decarboxylation in the formation of azomethine ylide.16 We envisaged that readily tunable steric and electronic effects of primary amino acid might help us to circumvent the hurdle of self-1,3-DC, which directs the reaction pathway more precisely to oxa-1,3-DC as expected. In addition, broad structural variation of primary amino acids would enable the diversity-oriented synthesis for this type of ring system. Herein, we disclose our success in the preparation of the unprecedented oxazolidinedispirooxindole via oxa-1,3-DC of azomethine ylides derived from 3-oxindole and amino acids with 3-oxindole. Prominently, minimized solvent usage, chromatography-free purification, and easy scale-up of this developed protocol exemplified green preparation of complex heterocycles (Scheme 1, d). We initiated our studies by testing the model reaction between N-benzyl-3-oxindole (1a) and leucine (2a) to optimize reaction parameters (Table 1). To our delight, running the reaction in MeOH successfully delivered the desired cyclo-adduct 3a in modest chemical yield (32%) and excellent diastereoselectivity; a single diastereoisomer was obtained (Table 1, entry 1). Subsequently, addition of 3,5-dinitrobenzoic acid (3,5-DNBA), trifluoroacetic acid (TFA), N,N-diisopropylethylamine (DIPEA), and K2CO3 markedly reduced the chemical yield respectively and only a trace amount of product was obtained (Table 1, entries 2−5). Surprisingly, no reaction was observed in such solvents as CH2Cl2, MeCN, H2O, toluene, DMF, and NMP at room temperature (Table 1, entries 6−11). Upon using DMSO as the solvent, the yield of 3a was improved to 58% and excellent diastereoselectivity was also obtained. Considering the significant impact of minimal solvent usage in terms of green chemistry, we further cut down the usage of DMSO to 100 μL. Interestingly, the desired product 3a was unexpectedly improved to 73% yield with a shorter reaction duration (Table 1, entries 12−13). It is worth mentioning that drastic decomposition of 3a frequently occurred upon being purified through a silica gel column, though 3a is bench-stable as solid-state. To evaluate the stability of cycloadduct 3a, several specific 1H NMR studies were carried out (please see Supporting Information). After being mixed with silica gel for 1 h, about 44% of cycloadduct 3a decomposed to go back to starting material 1a. Given the intrinsic issue of stability, we planned to modulate the purification process, to avoid the unpleasant decomposition of 3a, in a greener manner. Delightedly, pure 3a was readily achieved by simply washing with water. Simultaneously, the yield

entry

solvent

additive (0.2 equiv)

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13d

MeOH MeOH MeOH MeOH MeOH CHCl3 MeCN H2O PhMe NMP DMF DMSO DMSO

_ 3,5-DNBA TFA K2CO3 DIPEA _ _ _ _ _ _ _ _

12 12 12 12 12 12 12 12 12 12 12 12 6

32c trace trace trace trace NR NR NR NR NR NR 58c 73c/92e

a

Unless otherwise noted, the reaction was carried out in a reaction vial with 1a (0.5 mmol) and 2a (0.5 mmol) in the corresponding solvent (2 mL) at rt. bIsolated yield calculated on 0.25 mmol of 1a. cPurified through column chromatography. dThe reaction was carried out in 100 μL of DMSO. ePurified by washing with water.

of 3a was also improved to 92%. Importantly, the minimized solvent usage and chromatography-free purification process as well as the excellent yield endow this developed protocol with salient features of eco- and industrial friendliness. Moreover, the reaction progress can be easily visualized and monitored as the color of the reaction mixture gradually changes from deep red to light yellow as the reaction proceeds. Accordingly, the optimized reaction conditions were fixed as follows: mixing 1a and 2a (1a/ 2a = 1:1, 0.5 mmol scale) in DMSO (100 μL) at room temperature. To further explore the versatility of this developed protocol, a series of substituted 3-oxindoles were then evaluated and the corresponding results are summarized in Table 2. Generally speaking, various substituents, such as Cl, Br, and Me, at the C5 position of 3-oxindoles were well tolerated, giving the corresponding cycloadducts in excellent yields (Scheme 2, 3b− 3d). Pleasingly, 7-fluoroinated adduct 3e was also obtained in 91% yield and good diastereoselectivity (17:1). Subsequently, different protecting groups on 3-oxindoles were also examined, where methyl and MOM-protected 3-oxindoles proceeded smoothly to give the corresponding cycloadduct 3f and 3g in excellent yields and diastereoselectivity. However, N-acetyl-3oxindole as well as straight 3-oxindole failed to give the desired product 3h and 3i. Encouraged by the above exciting results, we next turned our attention to varying the structures of amino acids. As shown in Table 2, the reaction of N-benzyl-3-oxindole with a wide array of primary amino acids could be completed within 6 h, giving the corresponding oxazolidine-dispirooxindole 4a−4l in good yields. It can be observed that the increase of steric effect is deleterious to the diasteroselectivity. The diastereoselectivity of 4f was reduced to 5:1 due to the presence of the sterically demanding tert-butyl group. Attachment of thioether also affected the 2949

DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953

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The Journal of Organic Chemistry Table 2. Scope of Amino Acidsa

eoselectivity (99%) in 4 h, which could greatly broaden the versatility for this protocol in drug discovery. Aiming to developing a green and practical pathway for the preparation of oxazolidine-dispirooxindoles, we were devoted to exploiting the scalability of this protocol. Thus, the reaction for 3oxindole 1a and valine 2d was performed at 10 mmol scale in a 25 mL flask mediated by 1 mL of DMSO. As the reaction advanced, the color change from red to light yellow can be easily observed, which serves as an indicator for reaction progress (Scheme 3, Scheme 3. Large-Scale Reaction and Color Change in the Progress of Reaction

a

Unless otherwise noted, the reaction was carried out in a reaction vial with 1a (0.5 mmol) and 2a (0.5 mmol) in DMSO (0.1 mL) at room temperature.

bottom). Pleasingly, a good yield (86%) and an excellent dr (>20:1) for 4d were achieved after washing the crude reaction mixture with water (200 mL). Ultimately, the chemical structure and relative configuration of 4d were unequivocally established by X-ray crystallographic analysis of a single crystal (Scheme 3, top).17 In summary, an unprecedented oxa-1,3-dipolar cycloaddition between 3-oxindole-derived azomethine ylide and 3-oxindole was successfully realized under extremely mild conditions and a variety of oxazolidine-dispirooxindoles bearing two adjacent quaternary carbons were prepared in excellent yield (up to 99%) and good diastereoselectivity (up to >20:1 dr). This developed protocol is of great value owing to its desirable features including simplified operation, mild conditions, minimized solvent usage, and chromatography-free purification. More importantly, it might offer an innovative pathway to access other challenging and inherently unstable heterocycles.

Scheme 2. Substrate Scope of Isatins in Self-[3 + 3] Cycloadditiona

■

EXPERIMENTAL SECTION

General Experimental Methods. Unless otherwise noted, all the reagents were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded at 400 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical shifts were reported in ppm from the tetramethylsilane with the solvent resonance as the internal standard. Infrared spectra (IR) were measured by an FT-IR apparatus. High resolution mass spectroscopy (HRMS) was recorded on a TOF MS ES+ mass spectrometer, and acetonitrile was used to dissolve the sample. Column chromatography was carried out on silica gel (200−300 mesh). General Procedures and Characterization Data of Compound 3a−3g and 4a−4m. N-substituted isatin (0.50 mmol), amino acid (0.50 mmol, 2 equiv), and DMSO (0.1 mL) were well mixed and stirred at room temperature. After the reaction was complete (monitored by

a

Unless otherwise noted, the reaction was carried out in a reaction vial with 1a (0.5 mmol) and 2a (0.5 mmol) in DMSO (0.1 mL) at room temperature.

diastereoselectivity (4g, 6:1 dr), though an excellent yield was well maintained. The introduction of cyclohexyl groups led to a relatively sluggish reaction, and an excellent chemical yield and dr for 4i were obtained with a prolonged reaction time (48 h). Not surprisingly, the presence of a phenyl group also caused the eroded dr for 4k and 4l, albeit with excellent yields. Moreover, the secondary amino acid sarcosine was also able to give the desired cycloadduct 4k quantitatively with excellent diaster2950

DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953

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The Journal of Organic Chemistry

7.87 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.36 (dd, J = 7.8, 1.0 Hz, 1H), 7.33 (dd, J = 7.8, 1.1 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 4.48 (t, J = 8.8 Hz, 1H), 3.53−3.41 (m, 1H), 3.21 (s, 3H), 3.20 (s, 3H), 1.57− 1.67 (m, 1H), 1.41−1.48 (m, 1H), 1.01−1.09 (m, 1H), 0.82 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 176.5, 174.9, 144.2, 144.1, 131.1, 129.9, 126.6, 125.8, 125.1, 125.0, 123.6, 123.4, 108.3, 108.2, 94.6, 84.1, 65.6, 36.7, 26.1, 26.0, 23.2, 21.9; HRMS (TOFES+) m/z: [M]+ calcd for C23H25N3O3 391.1896, found 391.1891. Dispirooxindole-oxazolidine 3g. Pale yellow solid (129 mg, 0.223 mmol, yield 89%, >20:1 dr); mp 147−148 °C; IR (KBr) ν 1721, 1616, 1470, 1351, 1294, 1092, 916, 754 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.32−7.39 (m, 2H), 7.15−7.20 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 5.19 (d, J = 10.8 Hz, 1H), 5.13 (d, J = 10.8 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.44−4.51 (m, 1H), 3.37 (s, 6H), 1.56−1.66 (m, 1H), 1.44−1.51 (m, 1H), 1.12−1.19 (m, 1H), 0.80−0.82 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 177.2, 175.5, 142.5, 142.4, 131.3, 130.1, 130.1, 126.0, 125.3, 125.22, 125.20, 124.1, 124.0, 109.8, 109.7, 95.0, 84.4, 71.6, 71.5, 65.9, 56.43, 56.36, 37.0, 26.0, 23.0, 22.0; HRMS (TOF-ES+) m/z: [M + H]+ calcd for C25H30N3O5 452.2185, found 452.2185. Dispirooxindole-oxazolidine 4a. Pale yellow solid (107 mg, 0.213 mmol, yield 85%, >20:1 dr); mp 153−155 °C; IR (KBr) ν 1710, 1617, 1491, 1361, 891, 753, 624 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.26−7.33 (m, 10H), 7.21− 7.25 (m, 2H), 7.01−7.14 (m, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.10 (d, J = 15.6 Hz, 1H), 4.85−4.98 (m, 4H), 4.75 (d, J = 15.6 Hz, 1H), 4.53−4.60 (m, 1H), 3.64 (d, J = 13.2 Hz, 1H), 1.21 (d, J = 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 176.4, 175.1, 143.4, 143.3, 135.6, 135.4, 131.1, 129.9, 128.9, 127.8, 127.7, 127.3, 127.1, 126.3, 125.8, 125.3, 123.62, 123.57, 109.4, 109.2, 94.7, 84.6, 63.1, 43.9, 43.7, 12.8; HRMS (TOF-ES+) m/z: [M]+ calcd for C32H27N3O3 501.2052, found 501.2059. Dispirooxindole-oxazolidine 4b. Pale yellow solid (117 mg, 0.230 mmol, yield 92%, 10:1 dr); mp 166−168 °C; IR (KBr) ν 1704, 1615, 1489, 1368, 1117, 1028, 910, 754 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.57 (dd, J = 7.6, 0.8 Hz, 1H), 7.42 (dd, J = 7.6, 0.4 Hz, 1H), 7.01−7.19 (m, 8H), 6.83−6.92 (m, 2H), 6.79−6.81 (m, 4H), 6.40−6.43 (m, 2H), 5.90−5.96 (m, 1H), 5.08 (d, J = 16.1 Hz, 1H), 5.01 (d, J = 16.0 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1H), 2.01−2.23 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H); 13 C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.2, 173.9, 143.9, 143.8, 134.9, 134.8, 130.2, 130.0, 128.63, 128.58, 127.34, 127.31, 126.8, 126.7, 126.4, 124.8, 124.0, 123.4, 123.0, 122.0, 109.5, 97.0, 84.3, 74.7, 43.8, 28.3, 10.1; HRMS (TOF-ES+) m/z: [M]+ calcd for C33H29N3O3 515.2209, found 515.2204. Dispirooxindole-oxazolidine 4c. Pale yellow solid (130 mg, 0.245 mmol, yield 98%, 14:1 dr); mp 178−180 °C; IR (KBr) ν 1634, 1618, 1459, 1381, 1118, 1134, 623 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.57 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.07− 7.18 (m, 8H), 6.83−6.90 (m, 2H), 6.78−6.80 (m, 4H), 6.41 (dd, J = 7.8, 4.2 Hz, 2H), 5.97−6.02 (m, 1H), 5.09 (d, J = 16.0 Hz, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H), 3.82 (d, J = 11.6 Hz, 1H), 2.10−2.19 (m, 1H), 1.96−2.05 (m, 1H), 1.55−1.72 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 172.2, 173.8, 143.9, 143.8, 134.9, 134.8, 130.2, 130.0, 128.7, 127.4, 127.3, 126.79, 126.75, 126.4, 124.8, 124.0, 123.4, 123.0, 122.0, 109.51, 109.49, 95.7, 84.2, 74.7, 43.8, 43.4, 37.3, 19.2, 14.2; HRMS (TOF-ES+) m/z: [M]+ calcd for C34H31N3O3 529.2365, found 529.2373. Dispirooxindole-oxazolidine 4d. Pale yellow solid (126 mg, 0.237 mmol, yield 95%, 10:1 dr); mp 171−173 °C; IR (KBr) ν 1713, 1615, 1490, 1464, 1365, 1124, 925, 755 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.58 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.11−7.16 (m, 8H), 6.81−6.94 (m, 2H), 6.75−6.80 (m, 4H), 6.41 (d, J = 7.6 Hz, 2H), 5.66 (t, J = 7.6 Hz, 1H), 5.13 (d, J = 16.0 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.39 (d, J = 16.0 Hz, 1H), 3.80 (d, J = 9.6 Hz, 1H), 2.26−2.34 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.2, 173.9, 143.7, 134.9, 134.8, 129.9, 128.6, 127.31, 127.29, 126.8,

TLC), the mixture was washed with water (50 mL) and air-dried to afford the corresponding product. Dispirooxindole-piperazine 3a. White solid (92.3 mg, 0.13 mmol, yield 77%); mp 238 °C (decomposed); IR (KBr) ν 3406, 2824, 1612, 1465, 1344, 1033, 930 cm−1; 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J = 6.2 Hz, 2H), 7.31−7.48 (m, 10H), 6.64−7.04 (m, 14H), 6.00 (s, 2H), 5.09 (d, J = 15.2 Hz, 2H), 4.78 (d, J = 15.2 Hz, 2H), 2.65−2.68 (m, 2H), 2.31−2.51 (m, 6H); 13C NMR (DMSO-d6,100 MHz) δ 177.3, 143.2, 136.7, 136.1, 133.1, 129.3, 129.2, 129.1, 128.8, 128.6, 128.0, 126.7, 125.8, 125.1, 124.3, 122.8, 108.9, 73.5, 59.4, 43.4, 42.5, 30.6; HRMS (TOF-ES +) m/z: [M + H]+ calcd for C48H41N4O2 705.3230, found 705.3255. Dispirooxindole-oxazolidine 3b. Pale yellow solid (144 mg, 0.235 mmol, yield 94%, 13:1 dr); mp 103−105 °C; IR (KBr) ν 1726, 1616, 1482, 1344, 1175, 947, 740, 698 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.90 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.32−7.35 (m, 4H), 7.26−7.30 (m, 5H), 7.21 (dt, J = 8.4, 2.0 Hz, 3H), 6.68 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.93 (d, J = 15.9 Hz, 1H), 4.87 (d, J = 15.9 Hz, 1H), 4.70 (d, J = 15.6 Hz, 1H), 4.44−4.51 (m, 1H), 3.48 (d, J = 13.2 Hz, 1H), 1.55−1.65 (m, 1H), 1.42−1.51 (m, 1H), 1.08−1.15 (m, 1H), 0.80−0.84 (m, 6H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 176.1, 174.5, 141.9, 141.8, 135.2, 134.9, 131.1, 130.0, 129.2, 128.96, 128.95, 128.20, 128.0, 127.9, 127.4, 127.3, 127.1, 126.8, 125.8, 125.6, 110.6, 110.4, 94.7, 84.0, 66.3, 44.1, 43.8, 37.0, 26.1, 23.0, 22.0; HRMS (TOF-ES+) m/z: [M]+ calcd for C35H31N3O3Cl2 611.1742, found 611.1749. Dispirooxindole-oxazolidine 3c. Pale yellow solid (168 mg, 0.240 mmol, yield 74%, 18:1 dr); mp 185−186 °C; IR (KBr) ν 1726, 1615, 1480, 1347, 1133, 947, 732, 696 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 8.02 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.31−7.38 (m, 9H), 7.22−7.28 (m, 3H), 6.63 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.85−4.94 (m, J = 15.6 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.86 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 4.46 (ddd, J = 12.9, 9.7, 3.2 Hz, 1H), 3.48 (d, J = 13.2 Hz, 1H), 1.55−1.65 (m, 1H), 1.43−1.50 (m, 1H), 1.08−1.15 (m, 1H), 0.80−0.84 (m, 6H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 175.9, 174.3, 142.5, 142.3, 135.1, 134.8, 134.0, 132.9, 128.97, 128.95, 128.5, 128.3, 128.0, 127.9, 127.6, 127.4, 127.1,126.8, 116.5, 116.2, 111.1, 110.8, 94.6, 84.0, 66.3, 44.0, 43.8, 37.0, 26.1, 23.0, 22.1; HRMS (TOF-ES+) m/z: [M + H]+ calcd for C35H32N3O3Br2 700.0810, found 700.0801. Dispirooxindole-oxazolidine 3d. Pale yellow solid (140 mg, 0.245 mmol, yield 98%, 15:1 dr); mp 125−127 °C; IR (KBr) ν 1718, 1621, 1497, 1368, 1167, 1053, 951, 699 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.73 (s, 1H), 7.60 (s, 1H), 7.24−7.41 (m, 10H), 7.02 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 4.85−4.94 (m, 2H), 4.67 (d, J = 15.6 Hz, 1H), 4.49−4.55 (m, 1H), 3.51 (d, J = 12.8 Hz, 1H), 2.33 (d, J = 3.6 Hz, 6H), 1.56−1.65 (m, 1H), 1.45−1.53 (m, 1H), 1.11−1.18 (m, 1H), 0.79−0.83 (m, 6H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 176.6, 175.0, 140.9, 140.8, 135.8, 135.5, 133.4, 133.3, 131.2, 130.1, 128.79, 128.78, 127.7, 127.6, 127.4, 127.1, 126.7, 125.91, 125.87, 125.8, 109.2, 108.9, 95.1, 84.3, 66.0, 43.9, 43.7, 37.2, 26.1, 23.0, 22.1, 21.1; HRMS (TOF-ES+) m/z: [M]+ calcd for C37H37N3O3 571.2835, found 571.2831. Dispirooxindole-oxazolidine 3e. Pale yellow solid (132 mg, 0.228 mmol, yield 91%, 15:1 dr); mp 143−145 °C; IR (KBr) ν 1736, 1630, 1490, 1346, 1166, 951, 740, 623 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.73 (dd, J = 6.8, 1.2 Hz, 1H), 7.59 (dd, J = 6.8, 0.4 Hz, 1H), 7.31−7.39 (m, 6H), 7.25−7.29 (m, 3H), 7.00−7.11 (m, 5H), 4.90−5.15 (m, 4H), 4.46 (ddd, J = 13.4, 9.9, 4.0 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 1.50−1.60 (m, 1H), 1.36−1.44 (m, 1H), 1.03−1.09 (m, 1H), 0.76 (m, 6H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 176.4, 174.8, 147.29 (d, 1JC−F = 243 Hz), 147.26 (d, 1JC−F = 243 Hz), 136.7, 136.6, 129.9 (d, 3JC−F = 9 Hz), 129.6, 129.5, 128.7, 128.5, 127.80, 127.71, 127.70, 127.6, 127.3, 124.5 (d, 3JC−F = 4 Hz), 124.4 (d, 3JC−F = 4 Hz), 121.3, 119.4 (d, 2JC−F = 20 Hz), 118.2 (d, 2JC−F = 19 Hz), 94.7, 84.0, 66.4, 45.6, 45.4, 36.9, 26.0, 22.9, 22.0; HRMS (TOF-ES+) m/z: [M]+ calcd for C35H31N3O3F2 579.2333, found 579.2329. Dispirooxindole-oxazolidine 3f. Pale yellow solid (92 mg, 0.235 mmol, yield 94%, >20:1 dr); mp 196−197 °C; IR (KBr) ν 1720, 1615, 1495, 1373, 1118, 1014, 758, 538 cm−1; 1H NMR (CDCl3, 400 MHz) δ 2951

DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953

Note

The Journal of Organic Chemistry

Dispirooxindole-oxazolidine 4j. Pale yellow solid (112 mg, 0.190 mmol, yield 76%, >20:1 dr); mp 171−172 °C; IR (KBr) ν 1726, 1616, 1482, 1344, 1175, 947, 698 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.27−7.33 (m, 8H), 7.09− 7.25 (m, 9H), 6.99 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 15.2 Hz, 1H), 4.92 (s, 2H), 4.73 (d, J = 15.6 Hz, 1H), 4.51−4.57 (m, 1H), 3.65 (d, J = 12.8 Hz, 1H), 2.70−2.77 (m, 1H), 2.48−2.56 (m, 1H), 1.85−1.95 (m, 1H), 1.64−1.73 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 176.5, 175.0, 143.4, 143.2, 141.1, 135.6, 135.4, 131.1, 130.0, 128.9, 128.8, 128.3, 128.2, 127.8, 127.7, 127.4, 127.2, 126.6, 126.0, 125.8, 125.5, 125.3, 123.7, 123.6, 109.4, 109.2, 94.9, 84.1, 67.6, 43.9, 43.7, 33.5, 30.3; HRMS (TOF-ES+) m/z: [M]+ calcd for C39H33N3O3 591.2522, found 591.2528. Dispirooxindole-oxazolidine 4k. Pale yellow solid (127 mg, 0.225 mmol, yield 90%, >20:1 dr); mp 100−101 °C; IR (KBr) ν 1703, 1619, 1465, 1367, 1113, 762, 621 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.42 (t, J = 7.4 Hz, 3H), 7.36 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.17 (m, 7H), 7.10−7.05 (m, 2H), 6.93 (d, J = 6.7 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 6.82 (td, J = 7.6, 2.0 Hz, 2H), 6.44 (t, J = 8.0 Hz, 2H), 5.42 (t, J = 6.4 Hz, 1H), 5.04 (t, J = 16.4 Hz, 2H), 4.57 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 16.4 Hz, 1H), 3.65 (br s, 1H), 3.35 (m, 2H); 13 C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.7, 174.9, 143.9, 143.7, 138.8, 135.0, 134.9, 129.7, 129.6, 129.5, 128.7, 128.6, 128.4, 127.4, 126.94, 129.88, 126.3, 124.6, 124.4, 124.3, 123.2, 123.0, 109.44, 109.39, 74.6, 71.9, 43.7, 43.4, 42.3; HRMS (TOF-ES+) m/z: [M]+ calcd for C38H31N3O3 577.2365, found 577.2372. Dispirooxindole-oxazolidine 4l. Pale yellow solid (133 mg, 0.230 mmol, yield 92%, 6:1 dr); mp 153−155 °C; IR (KBr) ν 1720, 1615, 1491, 1465, 1366, 789, 756 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.54 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.04−7.21 (m, 11H), 6.78−6.89 (m, 5H), 6.41 (t, J = 8.8 Hz, 2H), 6.19−6.21 (m, 1H), 5.04 (dd, J = 16.0, 11.6 Hz, 2H), 4.51 (d, J = 16.0 Hz, 1H), 4.39 (d, J = 16.0, 1H), 3.91 (d, J = 8.8 Hz, 1H), 3.51 (dd, J = 14.0, 6.0 Hz, 1H), 3.30 (dd, J = 14.0, 6.4 Hz, 1H), 2.30 (s, 3H); 13 C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.2, 173.7, 144.0, 143.8, 136.1, 134.9, 134.8, 133.7, 130.2, 130.0, 129.3, 129.2, 128.7, 127.42, 127.35, 126.83, 126.79, 126.5, 124.8, 123.8, 123.4, 123.0, 121.9, 109.53, 109.47, 95.9, 84.5, 74.6, 43.8, 43.4, 41.3, 21.1; HRMS (TOF-ES +) m/z: [M]+ calcd for C39H33N3O3 591.2522, found 591.2529. Dispirooxindole-oxazolidine 4m. Pale yellow solid (124 mg, 0.248 mmol, yield 99%, >20:1 dr); mp 191−192 °C; IR (KBr) ν 1725, 1613, 1487, 1351, 1170, 757, 700 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.33−7.37 (m, 9H), 7.27− 7.31 (m, 3H), 7.16 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.85−5.01 (m, 4H), 3.81 (d, J = 10.0 Hz, 1H), 3.72 (d, J = 10.0 Hz, 1H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 176.4, 174.8, 143.9, 143.1, 135.7, 135.6, 131.1, 130.2, 128.9, 128.8, 127.7, 127.4, 127.34, 127.32, 127.2, 126.5, 124.8, 123.8, 123.5, 109.2, 109.0, 96.1, 81.8, 60.5, 43.9, 43.7, 34.5; HRMS (TOF-ES+) m/z: [M + H]+ calcd for C32H28N3O3 502.2131, found 502.2129.

126.7, 126.6, 124.9, 124.2, 123.4, 123.0, 122.2, 109.4, 100.6, 84.3, 74.9, 43.7, 43.4, 33.9, 19.5, 18.7; HRMS (TOF-ES+) m/z: [M]+ calcd for C34H31N3O3 529.2365, found 529.2369. Dispirooxindole-oxazolidine 4e. Pale yellow solid (131 mg, 0.240 mmol, yield 96%, 6:1 dr); mp 149−152 °C; IR (KBr) ν 1707, 1618, 1462, 1380, 1125, 623 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.58 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 6.73− 7.15 (m, 13H), 6.57 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 2H), 5.74− 5.80 (m, 1H), 5.00−5.16 (m, 2H), 4.34−4.49 (m, 2H), 3.81 (d, J = 11.6 Hz, 1H), 2.05−2.17 (m, 1H), 1.27−1.45 (m, 1H), 1.21 (d, J = 6.3 Hz, 1H), 1.14 (m, 3H), 1.01 (m, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer; two rotamers present) δ 177.2, 177.1, 143.9, 143.7, 134.9, 134.8, 130.1, 129.9, 128.6, 127.29, 127.28, 126.7, 126.6, 124.9, 123.4, 123.0, 122.2, 109.43, 109.42, 99.6, 99.5, 84.2, 84.1, 74.9, 74.8, 43.7, 43.4, 26.1, 25.5, 15.6, 14.7, 11.12, 11.07; HRMS (TOF-ES+) m/z: [M]+ calcd for C35H33N3O3 543.2522, found 543.2523. Dispirooxindole-oxazolidine 4f. Pale yellow solid (132 mg, 0.243 mmol, yield 97%, 5:1 dr); mp 180−184 °C; IR (KBr) ν 1719, 1616, 1489, 1360, 1129, 926, 750, 622 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.64 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.07−7.13 (m, 4H), 6.98−7.03 (m, 4H), 6.84−6.96 (m, 2H), 6.58 (t, J = 7.2 Hz, 4H), 6.32−6.39 (m, 2H), 5.90 (d, J = 12.8 Hz, 1H), 5.19 (d, J = 16.0 Hz, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.32 (d, J = 16.1 Hz, 1H), 4.26 (d, J = 16.1 Hz, 1H), 3.74 (d, J = 12.8 Hz, 1H), 1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 176.8, 174.1, 143.8, 143.5, 134.9, 134.7, 130.2, 129.8, 128.62, 128.58, 127.2, 127.1, 126.9, 126.5, 126.3, 125.3, 123.3, 123.1, 122.7, 109.4, 109.3, 102.2, 84.8, 75.5, 43.5, 43.3, 33.9, 25.9; HRMS (TOF-ES+) m/z: [M]+ calcd for C35H33N3O3 543.2522, found 543.2516. Dispirooxindole-oxazolidine 4g. Pale yellow solid (133 mg, 0.238 mmol, yield 95%, 6:1 dr); mp 146−149 °C; IR (KBr) ν 1720, 1618, 1460, 1379, 1180, 1138, 947, 852 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.56 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.05−7.16 (m, 8H), 6.84−6.91 (m, 2H), 6.19−6.80 (m, 4H), 6.41 (d, J = 8.0 Hz, 2H), 6.05−6.10 (m, 1H), 5.07 (d, J = 16.2 Hz, 1H), 5.01 (d, J = 16.0 Hz, 1H), 4.47 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 3.99 (d, J = 11.6 Hz, 1H), 2.83−2.90 (m, 1H), 2.72−2.79 (m, 1H), 2.42−2.51 (m, 1H), 2.31−2.36 (m, 1H), 2.17 (s, 3H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.0, 173.7, 143.9, 143.8, 134.80, 134.78, 130.3, 130.1, 128.7, 127.40, 127.37, 126.78, 126.76, 126.7, 126.6, 126.4, 124.8, 123.7, 123.4, 123.1, 121.8, 109.6, 94.5, 84.3, 74.7, 43.8, 43.4, 34.5, 30.0, 15.7; HRMS (TOF-ES+) m/z: [M]+ calcd for C34H31N3O3S 561.2086, found 561.2089. Dispirooxindole-oxazolidine 4h. Pale yellow solid (140 mg, 0.240 mmol, yield 96%, >20:1 dr); mp 133−134 °C; IR (KBr) ν 1715, 1618, 1464, 1356, 1132, 755, 624, 487 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.26−7.35 (m, 10H), 7.19−7.23 (m, 2H), 7.12 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.96 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.70 (d, J = 15.2 Hz, 1H), 4.55−4.62 (m, 1H), 3.54 (d, J = 13.2 Hz, 1H), 1.46−1.50 (m, 5H), 1.15−1.30 (m, 2H), 0.86−1.10 (m, 4H), 0.66−0.87 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 176.7, 175.1, 143.4, 143.3, 135.7, 135.4, 131.0, 129.8, 128.8, 127.8, 127.6, 127.4, 127.2, 126.7, 125.9, 125.3, 125.2, 123.6, 123.5, 109.4, 109.1, 94.8, 84.1, 65.3, 43.9, 43.7, 35.8, 35.2, 33.7, 32.7, 26.4, 26.1, 26.0; HRMS (TOF-ES+) m/z: [M]+ calcd for C38H37N3O3 583.2835, found 583.2843. Dispirooxindole-oxazolidine 4i. Pale yellow solid (140 mg, 0.245 mmol, yield 98%, 5:1 dr); mp 179−181 °C; IR (KBr) ν 1713, 1613, 1491, 1362, 1182, 1125, 938, 696 cm−1; 1H NMR (CDCl3, 400 MHz, major diastereomer) δ 7.57 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.07−7.16 (m, 8H), 6.76−6.90 (m, 6H), 6.40 (d, J = 8.0 Hz, 2H), 5.71 (d, J = 7.0 Hz, 1H), 5.01−5.16 (m, 2H), 4.35−4.45 (m, 2H), 3.80 (s, 1H), 2.14−2.21 (m, 1H), 1.92−1.21 (m, 2H), 1.71 (d, J = 12.0 Hz, 1H), 1.45−1.41 (m, 7H); 13C NMR (CDCl3, 100 MHz, major diastereomer) δ 177.2, 173.8, 144.0, 143.7, 134.9, 134.8, 130.1, 129.9, 128.61, 128.56, 127.30, 127.27, 126.93, 126.88, 126.74, 126.72, 126.6, 124.9, 124.2, 123.4, 123.0, 121.2, 109.44, 109.41, 99.5, 84.0, 74.8, 43.7, 43.4, 43.1, 29.6, 28.9, 26.3, 25.7, 25.6; HRMS (TOF-ES+) m/z: [M]+ calcd for C37H35N3O3 569.2678, found 569.2685.

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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.7b02865. 1 H NMR and 13C NMR spectra for compounds 3a−3g, 4a−4m; X-ray structure of dispirooxindole−piperazine 4d (PDF) Crystallographic data for 4d (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hao-Yue Xiang: 0000-0002-7404-4247 2952

DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953

Note

The Journal of Organic Chemistry

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Xiao-Qing Chen: 0000-0002-8768-8965 Hua Yang: 0000-0002-5518-5255 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21576296, 21676302, 21776318, and 81703365), China Postdoctoral Science Foundation (2017M610504), and Central South University.

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DOI: 10.1021/acs.joc.7b02865 J. Org. Chem. 2018, 83, 2948−2953