Cycloaddition Reaction - ACS Publications - American Chemical Society

Aug 22, 2017 - antifungal, antihypertensive, anticancer, antiviral, and antibacte- rial.1 For example (Scheme 1), Linezolid and RWJ-416457, with core ...
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Synthetic Access to Oxazolidin-4-ones via Elimination/[3+2] Cycloaddition Reaction Shengsheng Jiang, Kai Li, Jun Yan, Kuangxi Shi, Chengtao Zhao, Limin Yang,* and Guofu Zhong* College of Materials, Chemistry & Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China S Supporting Information *

ABSTRACT: Elimination/[3+2] cycloaddition reactions of simple enals and unprotected isatins with haloamides have been developed. This transformation provides rapid access to highly functionalized oxazolidin-4-ones that are represented in bioactive compounds.

O

Cycloaddition in its many manifestations represents one of the most powerful methods in organic chemistry for making cyclic structures. The aza-oxyallylic cation, easily generated in situ from α-haloamide by elimination of hydrogen halide, has been primarily discussed in the literatures and the 1,3-dipolar cycloaddition reactions of aza-oxyallylic cation dipole4 with furan, cyclopentadiene furnishs seven-membered rings by [3+4] type.5 However, aza-oxyallylic cation dipoles have also been shown to undergo dearomative [3+2] cycloaddition reactions with indole,6 2-methylfuran,7 dienes,8 and emamines.9 Nonetheless, little is known about its reactivity in cycloaddition reaction with enals and isatins. The chemistry described in this communication builds on the investigation of Jeffrey and Wu in exploring the dearomative indole [3+2] cycloaddition reactions of aza-oxyallyl cationic intermediates (Scheme 2).6 In earlier studies, these two groups

xazolidinones are important scaffolds found in numerous biorelevant nature products with a wide range of natural and biological activities, such as antidepressant, antihistaminic, antifungal, antihypertensive, anticancer, antiviral, and antibacterial.1 For example (Scheme 1), Linezolid and RWJ-416457,

Scheme 1. Examples of Biologically Active Oxazolidinones

Scheme 2. Previously Reported 1,3-Dipolar Cycloaddition Reactions of Azaoxyallyl Cations

with core structure of oxazolidin-2-one, are the first artificially synthesized antibiotics. As for oxazolidin-4-ones, lipoxazolidinones A−C, and synoxazolidinones A and B,2 which were isolated from a Guam marine sediment and the subarctic ascidian Synoicum pulmonaria, respectively, exhibit excellent antibacterial and antifungal activities. As a result, considerable resources have been expended to develop new and improved methods for synthesis of oxazolidinones. Compared to oxazolidin-2-ones, for which several synthetic strategies have been published, only a few syntheses have been reported to yield oxazolidin-4-ones,3 which clearly underlines the need to develop efficient methods for access to original oxazolidin-4one derivatives. © 2017 American Chemical Society

independently discovered that aza-oxyallyl cationic intermediate could be generated from α-haloamide via elimination reaction mediated by base. While in our report, the aza-oxyallyl cationic intermediate can be engaged in [3+2] cycloaddition reactions with enals and isatins, which facilitates the formation of new C−O and C−N bond (Scheme 2). The importance of this methodology is due to its great potential for accessing highly functionalized oxazolidin-4-one derivatives, especially Received: March 7, 2017 Published: August 22, 2017 9779

DOI: 10.1021/acs.joc.7b00547 J. Org. Chem. 2017, 82, 9779−9785

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The Journal of Organic Chemistry Table 1. Condition Optimizationa

spiro[indoline-2,2′-oxazolidine]-3,4′-diones. During the preparation of this article and the application of patent,10 studies carried out by Jeffrey, Lin, and Wang also demonstrated a similar methodology for the construction of 4-oxazolidinone using aldehyde reactants.11 For the elimination/[3+2] cycloaddition reaction of enals with haloamides to synthesis oxazolidin-4-one derivatives, we proposed the following mechanism. First, aza-oxyallyl cationic diploe 4 was generated via base mediating elimination of HBr from α-haloamide. One thing to be noted is that an electrondonating group (OBn) is essential for stabilizing the proposed dipolar species 4, which can tautomerize to the dipolar species 5 (Scheme 3, eq 1). The diploar intermediate 5 then Scheme 3. Proposed Mechanism of Elimination/[3+2] Cycloaddition Reaction

entry

base

solvent

yield (%)b

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

Et3N Et3N Et3N DIPEA DBU DMAP DABCO pyridine piperidine N-methylmorpholine TMEDA DBN diethanolamine NH4HCO3 Na2CO3 Cs2CO3 K2CO3 NaHCO3 K2CO3

DCM TFE HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

35 35 55 40 71 66 49 54 68 72 60 68 53 60 70 73 77 trace 99

a Unless otherwise specified, reaction was performed in 0.2 mmol scale in solvent (1.0 mL) at rt. bYields of isolated products. cUsed 1:2 reactant ratio of 1a and 2a.

cycloaddition reaction and HFIP was found to effectively promote the reaction (Table 1, entry 3). Next, different bases were evaluated for this reaction using HFIP as solvent. The reaction was completed by using DIPEA with a lower yield (Table 1, entry 4). When DBU or N-methylmorpholine was employed, the yield was increased obviously, albeit with a longer reaction time (Table 1, entries 5, 10). Then we turned our attention to inorganic bases. To our delight, the inorganic bases we tried, such as Na2CO3, Cs2CO3, and K2CO3, afforded comparable results to that of DBU and N-methylmorpholine with shorter reaction time (Table 1, entries 15, 16, and 17). It is inexplicable that trace desired product was obtained by using NaHCO3 as base, possibly due to the elimination of αbromoamide affording acrylamide (Table 1, entry 18). It is particularly noteworthy that almost quantitative yield was obtained when the reactant ratio of 1a:2a was changed from 1:1 to 1:2 and K2CO3 was used as base and HFIP was the solvent (Table 1, entry 19). With the optimal reaction conditions established, the scope of this elimination [3+2] cycloaddition reaction was investigated (Scheme 4). The reaction proceeded smoothly for a broad spectrum of enals with haloamides to afford the desired products in good yields. Both electron-donating and electronwithdrawing substituents on β-phenyl group were tolerated and it seems the former giving higher yield (Scheme 4, 3a−3f). Replacing β-phenyl group with heteroaryl, such as fur-2-yl, did not significantly change the reaction result in yield (Scheme 4, 3g). Even quantitative yield was obtained when replacing phenyl group with prop-1-en-1-yl group (Scheme 4, 3h). The substituents on α-position of enals were also well tolerated with α-methyl substituted enal giving the quantitative yield (Scheme

participates in the cycloaddition reaction and there were two possible mechanisms: stepwise and concerted. The preliminary experimental observation showed that it should be a stepwise type on account of diastereoisomeric ratio of cycloadducts was as low as 1:1.35 and 1:2 (Scheme 4, 3l and 3m). The following nucleophilic attack of enal delivered a zwitterion intermediate 6. An intramolecular attack of nitrogen negative ion on carbonyl carbon forms the cycloadduct product oxazolidin-4one 3 (Scheme 3, eq 2). One of the challenges of this reaction lies in the reactivity of α,β-unsaturated aldehydes, which can undergo unwanted [3+2] cycloaddition of CC with aza-oxyallylic cation dipole to generate pyrrolidin-2-one (Scheme 3, eq 3). Furthermore, the unwanted [3+4] cycloaddition of enal with aza-oxyallylic cation dipole can generate oxazepin-3-one (Scheme 3, eq 4). Besides aza-oxyllyl cationic diploe species, it is very easy to get acrylamide product by elimination of HBr from α-haloamide. To investigate this unprecedented [3+2] cycloaddition, we first surveyed the commercial available substrate cinnamaldehyde 1a and readily prepared α-bromoamide 2a in the presence of different bases and solvents. The results were summarized in Table 1. To our surprise, the reaction took place smoothly in the presence of Et3N in dichloromethane at room temperature and delivered the desired product and was accompanied by some acrylamide (Table 1, entry 1). Inspired by Jeffrey and Wu’s work, fluorosolvent was chosen as solvent for this 9780

DOI: 10.1021/acs.joc.7b00547 J. Org. Chem. 2017, 82, 9779−9785

Note

The Journal of Organic Chemistry Scheme 4. Substrate Scope of Elimination/[3+2] Cycloaddition Reaction of Haloamides with Enals

Scheme 5. Substrate Scope of Elimination/[3+2] Cycloaddition Reactions of Haloamides with Isatins

9781

DOI: 10.1021/acs.joc.7b00547 J. Org. Chem. 2017, 82, 9779−9785

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The Journal of Organic Chemistry 4, 3i, 3j, and 3k). The scope of the reaction using various αhalo-hydroxamate reactants was explored. The scope of the reaction using various haloamide substrates was also examined under optimized conditions (Scheme 4, 3l− 3u). Monosubstituent on haloamides provide the desired products as a mixture of diasteroisomers (Scheme 4, 3l, 3m, and 3n), which indicated that the elimination [3+2] cycloaddition reaction should be a stepwise cycloaddition mechanism. Besides, the difference between total yields of monoalkyl (40% yield, 3m) and monoaryl (96% yield, 3l) substituents is presumably due to the stabilizing effect that aryl groups have on the resulting dipolar species 5. Similarly, the cyclohexyl substituted haloamides were also well-tolerated, which reacted rapidly with all kinds of enals in the presence of K2CO3 and HFIP at room temperature to afford desired product in good to excellent yield (Scheme 4, 3m−3u). In an effort to expand the utilities of our reaction, this methodology was developed to elimination/cycloaddition reaction of haloamides with unprotected isatins. To our surprise, the unexpected 2′-spirocyclic oxindole adducts were obtained instead of 3′-spirocyclic oxindoles. In this reaction, spirocyclization took place on 2-positions of isatin rather than on 3-position. The targeted heterocyclic compounds contain a spiro[indoline-2,2′-oxazolidine]-3,4′-dione core, which is, to our best knowledge, unreported in literatures. The substrate scope of the reaction using various haloamides and unprotected isatins were also examined under optimized conditions. The reaction proceeded smoothly in the presence of K2CO3 and HFIP at room temperature to afford various spiro[indoline-2,2′-oxazolidine]-3,4′-diones in good yield (Scheme 5, up to 86% yield). Both strong electron-donating (methoxyl group) and strong electron-withdrawing (nitro group) substituents on isatin were tolerated and gave higher yields (Scheme 5, 8c, 8e, 8k). However, 5-Br substituted isatin reduced the reactivity and only 25% yield was obtained. It is worth mentioning that when protected isatin was used in this reaction, only trace of the desired product was observed. To determine the reaction results of the elimination/[3+2] cycloaddition reactions, the X-ray crystallographic analysis of the product 3h and 8c were performed to provide the structures of targeted heterocyclic compounds (for details please see in Supporting Information, CCDC 1501290 and CCDC 1544760). In conclusion, an elimination/[3+2] cycloaddition reaction of simple enals with haloamides have been developed. This transformation provides rapid access to highly functionalized oxazolidin-4-ones that are represented in bioactive compounds. This methodology was also applied to cycloaddition of haloamides with unprotected isatins, affording heterocyclic compounds containing a spiro[indoline-2,2′-oxazolidine]-3,4′dione core.

■

of the enal/isatin (monitored by TLC). Then the mixture was concentrated under reduced pressure. The residue was purified via flash column chromatography (petroleum ether/ethyl acetate 20:1 to 10:1) to provide the desired product. (E)-3-(Benzyloxy)-5,5-dimethyl-2-styryloxazolidin-4-one (3a). White solid (32.0 mg, 99% yield); mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 10H), 6.71 (d, J = 12.0 Hz, 1H), 5.89 (dd, J = 12.0, 8.0 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 5.02 (dd, J = 48.3, 10.6 Hz, 2H), 1.48 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 137.9, 135.1, 134.6, 129.9, 128.9, 128.7, 128.5, 127.2, 124.5, 87.9, 78.4, 77.7, 25.5, 23.1; HRMS (ESI-TOF): m/z calculated for C20H22NO3 (M+H)+: 324.1594, found: 324.1595. (E)-3-(Benzyloxy)-2-(4-methoxystyryl)-5,5-dimethyloxazolidin-4one (3b). White solid (35.0 mg, 99% yield); mp 84−85 °C; 1H NMR (400 MHz, CDCl3) δ 7.35−7.30 (m, 7H), 6.88 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 16.0 Hz, 1H), 5.74 (dd, J = 16.0, 8.0 Hz, 1H), 5.19 (d, J = 8.0 Hz, 1H), 5.02 (dd, J = 48.5, 12.0 Hz, 2H), 3.83 (s, 3H), 1.47 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 160.3, 137.6, 134.7, 129.9, 129.1, 128.6, 128.5, 127.9, 122.1, 114.1, 88.2, 78.4, 77.6, 55.3, 25.5, 23.0; HRMS (ESI-TOF): m/z calculated for C21H24NO4 (M+H)+: 354.1700, found: 354.1697. (E)-3-(Benzyloxy)-2-(2-methoxystyryl)-5,5-dimethyloxazolidin-4one (3c). Clear liquid (33.3 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.39−7.30 (m, 7H), 7.09 (d, J = 16.0 Hz, 1H), 6.91 (m, 2H), 5.98 (dd, J = 16.0, 8.0 Hz, 1H), 5.24 (d, J = 8.0 Hz, 1H), 5.02 (dd, J = 48.1, 10.4 Hz, 2H), 3.87 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 172.5, 157.3, 134.7, 133.2, 130.0, 129.9, 129.0, 128.5, 127.8, 125.0, 124.3, 120.6, 110.9, 88.4, 78.4, 77.6, 55.5, 25.5, 23.0; HRMS (ESI-TOF): m/z calculated for C21H24NO4 (M+H)+: 354.1700, found: 354.1709. (E)-3-(Benzyloxy)-2-(4-chlorostyryl)-5,5-dimethyloxazolidin-4one (3d). Clear liquid (22.0 mg, 62% yield); 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 9H), 6.63 (d, J = 16.0 Hz, 1H), 5.81 (dd, J = 16.0, 8.0 Hz, 1H), 5.17 (d, J = 8.0 Hz, 1H), 5.02 (dd, J = 48.1, 9.6 Hz, 2H), 1.47 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 136.5, 134.7, 134.6, 133.6, 129.9, 129.2, 128.9, 128.5, 128.4, 125.1, 87.6, 78.4, 77.8, 25.5, 23.1; HRMS (ESI-TOF): m/z calculated for C20H21ClNO3 (M+H)+: 358.1210, found: 358.1207. (E)-3-(Benzyloxy)-2-(4-fluorostyryl)-5,5-dimethyloxazolidin-4-one (3e). White solid (21.3 mg, 62% yield); mp 114−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.36−7.30 (m, 7H), 7.04 (m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 5.76 (dd, J = 16.0, 8.0 Hz, 1H), 5.17 (d, J = 8.0 Hz, 1H), 5.02 (dd, J = 48.3, 8.9 Hz, 2H), 1.47 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 163.1 (d, J = 248.0 Hz), 136.6, 134.7, 131.4, 129.9, 129.1, 128.8 (d, J = 8.0 Hz), 128.5, 124.2 (d, J = 2.0 Hz), 115.7 (d, J = 22.0 Hz), 87.8, 78.4, 77.7, 25.5, 23.1; HRMS (ESI-TOF): m/z calculated for C20H21FNO3 (M+H)+: 342.1500, found: 342.1502. (E)-3-(Benzyloxy)-5,5-dimethyl-2-(4-nitrostyryl)oxazolidin-4-one (3f). White solid (25.8 mg, 70% yield); mp 97−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.35−7.33 (m, 5H), 6.71 (d, J = 16.0 Hz, 1H), 5.93 (dd, J = 16.0, 8.0 Hz, 1H), 5.18 (d, J = 8.0 Hz, 1H), 5.04 (dd, J = 40.2, 12.0 Hz, 2H), 1.49 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 147.8, 141.4, 134.9, 134.7, 130.0, 129.3, 129.2, 128.6, 127.8, 124.0, 87.0, 78.3, 78.0, 25.5, 23.2; HRMS (ESI-TOF): m/z calculated for C20H21N2O5 (M+H)+: 369.1445, found: 369.1448. (E)-3-(Benzyloxy)-2-(2-(furan-2-yl)vinyl)-5,5-dimethyloxazolidin4-one (3g). Clear liquid (26.8 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 6H), 6.50 (d, J = 16.0 Hz, 1H), 641−6.37 (m, 2H), 5.87 (dd, J = 16.0, 8.0 Hz, 1H), 5.14 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 61.2, 10.6 Hz, 2H), 1.46 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 151.1, 143.1, 134.6, 129.9, 129.1, 128.5, 125.2, 122.7, 111.6, 110.7, 87.5, 78.5, 77.7, 25.5, 23.2; HRMS (ESI-TOF): m/ z calculated for C18H20NO4 (M+H)+: 314.1387, found: 314.1386. 3-(Benzyloxy)-5,5-dimethyl-2-((1E,3E)-penta-1,3-dien-1-yl)oxazolidin-4-one (3h). White solid (28.6 mg, 99% yield); mp 72−73 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 6.31 (dd, J = 16.0, 12.0 Hz, 1H), 6.05−6.04 (m, 1H), 5.88−5.83 (m, 1H), 5.30−5.24 (m, 1H), 5.07−5.03 (m, 2H), 4.93 (d, J = 12.0 Hz, 1H), 1.81−1.80 (m, 3H), 1.43 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ

EXPERIMENTAL SECTION

1

H and 13C NMR spectra were measured at 400/500 and 100/125 MHz, respectively. The solvent used for NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by an HRMS/MS instrument. Analytical grade solvents for the column chromatography were used after distillation, and commercially available reagents were used as received. General Procedure for the (3+2)-Cycloaddition of Enals/ Isatins with Haloamides. Enal/isatin (0.10 mmol) was dissolved in solvent HFIP (1.0 mL) and then α-haloamide (2.0 equiv, 0.20 mmol)) and potassium carbonate (1.0 equiv, 0.10 mmol) were added. The mixture was stirred at room temperature until complete consumption 9782

DOI: 10.1021/acs.joc.7b00547 J. Org. Chem. 2017, 82, 9779−9785

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The Journal of Organic Chemistry

134.7, 129.9, 129.8, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.2, 127.1, 124.2, 124.0, 89.7, 89.6, 78.6, 78.5, 76.7, 76.1, 24.8, 24.7, 8.9, 8.6; HRMS (ESI-TOF): m/z calculated for C20H22NO3 (M+H)+: 324.1594, found: 324.1596. (E)-3-(Benzyloxy)-2-styryl-1-oxa-3-azaspiro[4.5]decan-4-one (3o). White solid (27.9 mg, 76% yield); mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 10H), 6.71 (d, J = 16.0 Hz, 1H), 5.93−5.81 (m, 1H), 5.21 (d, J = 8.0 Hz, 1H), 5.01 (dd, J = 48.0, 8.0 Hz, 2H), 1.88−1.81 (m, 1H), 1.72−1.60 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 172.4, 137.6, 135.3, 134.7, 129.9, 129.1, 128.9, 128.7, 128.5, 127.2, 124.9, 88.1, 78.9, 78.5, 34.0, 31.0, 24.8, 21.1, 21.0; HRMS (ESI-TOF): m/z calculated for C23H26NO3 (M+H)+: 364.1907, found:364.1904. (E)-3-(Benzyloxy)-2-(4-methoxystyryl)-1-oxa-3-azaspiro[4.5]decan-4-one (3p). Clear liquid (25.1 mg, 64% yield); 1H NMR (400 MHz, CDCl3) δ 7.36−7.29 (m, 7H), 6.88 (m, 2H), 6.65 (d, J = 15.8 Hz, 1H), 5.76 (m, 1H), 5.20 (d, J = 8.0 Hz, 1H), 5.00 (dd, J = 48.0, 10.5 Hz, 2H), 3.83 (s, 3H), 1.71−1.60 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 172.5, 160.2, 137.3, 134.8, 129.9, 129.0, 128.5, 128.4, 128.0, 122.5, 114.1, 88.4, 78.8, 78.4, 55.3, 34.0, 30.9, 24.8, 21.1, 21.0; HRMS (ESI-TOF): m/z calculated for C24H28NO4 (M+H)+: 394.2013, found: 394.2014. (E)-3-(Benzyloxy)-2-(4-fluorostyryl)-1-oxa-3-azaspiro[4.5]decan4-one (3q). White solid (35.2 mg, 92% yield); mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.36−7.29 (m, 7H), 7.04 (m, 2H), 6.65 (d, J = 15.8 Hz, 1H), 5.78 (dd, J = 15.8, 7.8 Hz, 1H), 5.18 (d, J = 7.8 Hz, 1H), 5.00 (dd, J = 48.0, 10.7 Hz, 2H), 1.74−1.55 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 172.5, 163.1 (d, J = 248 Hz), 136.4, 134.8, 131.4, 129.9, 129.1, 128.8 (d, J = 8 Hz), 128.5, 124.7, 115.7 (d, J = 22 Hz), 88.0, 78.9, 78.4, 34.0, 30.9, 24.7, 21.1, 21.0; HRMS (ESI-TOF): m/z calculated for C23H25FNO3 (M+H)+: 382.1813, found: 382.1819. (E)-3-(Benzyloxy)-2-(4-chlorostyryl)-1-oxa-3-azaspiro[4.5]decan4-one (3r). White solid (31.4 mg, 80% yield); mp 103−104 °C; 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m, 9H), 6.63 (d, J = 15.8 Hz, 1H), 5.82 (m, 1H), 5.18 (d, J = 7.8 Hz, 1H), 5.00 (dd, J = 12.0, 10.7 Hz, 2H), 1.90−1.54 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 172.5, 136.2, 134.7, 134.6, 133.7, 129.9, 129.1, 128.9, 128.5, 128.4, 125.6, 87.9, 78.9, 78.4, 34.0, 30.9, 24.7, 21.1, 21.0; HRMS (ESI-TOF): m/z calculated for C23H25ClNO3 (M+H)+: 398.1517, found: 398.1511. (E)-3-(Benzyloxy)-2-(2-nitrostyryl)-1-oxa-3-azaspiro[4.5]decan-4one (3s). Clear liquid (20.4 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 1H), 7.60 (m, 1H), 7.53 (m, 1H), 7.51− 7.45 (m, 1H), 7.40 (m, 2H), 7.35−7.28 (m, 3H), 7.22 (d, J = 15.7 Hz, 1H), 5.84 (m, 1H), 5.17 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 32.0, 10.8 Hz, 2H), 1.94−1.53 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 172.1, 147.9, 134.7, 133.2, 132.5, 131.1, 130.3, 130.1, 129.2, 129.16, 129.13, 128.5, 124.7, 87.2, 79.1, 78.2, 34.0, 31.3, 24.7, 21.1, 21.0; HRMS (ESITOF): m/z calculated for C23H25N2O5 (M+H)+: 409.1758, found: 409.1768. (E)-3-(Benzyloxy)-2-(1-phenylprop-1-en-2-yl)-1-oxa-3-azaspiro[4.5]decan-4-one (3t). Clear liquid (29.9 mg, 80% yield); 1H NMR (400 MHz, CDCl3) δ 7.39−7.29 (m, 10H), 6.59 (s, 1H), 5.13 (s, 1H), 4.98 (dd, J = 88.0, 10.4 Hz, 2H), 1.84 (s, 3H), 1.82−1.51 (m, 9H), 1.42−1.25 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.5, 136.3, 134.8, 133.8, 132.8, 129.7, 129.1, 129.0, 128.5, 128.3, 127.5, 92.5, 78.8, 77.9, 33.5, 31.1, 24.8, 21.1, 20.9, 11.4; HRMS (ESI-TOF): m/z calculated for C24H28NO3 (M+H)+: 378.2064, found: 378.2073. (Z)-3-(Benzyloxy)-2-(1-bromo-2-phenylvinyl)-1-oxa-3-azaspiro[4.5]decan-4-one (3u). Clear liquid (36.2 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.74−7.72 (m, 2H), 7.46−7.31 (m, 8H), 7.12 (s, 1H), 5.17 (m, 2H), 4.96 (m, 1H), 2.02 (m, 1H), 1.94−1.81 (m, 1H), 1.78−1.57 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 171.5, 135.7, 134.7, 133.9, 129.8, 129.5, 129.3, 129.2, 128.6, 128.4, 122.7, 91.4, 79.7, 78.6, 33.1, 32.4, 24.7, 21.1, 20.9; HRMS (ESI-TOF): m/z calculated for C23H25BrNO3 (M+H)+: 442.1012, found: 442.1021. 3′-(Benzyloxy)-5′,5′-dimethylspiro[indoline-2,2′-oxazolidine]3,4′-dione (8a). Yellow oil (17.0 mg, 50% yield); 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 1H), 7.49−7.43 (m, 1H), 7.36 (m, 3H), 7.28−7.24 (m, 2H), 6.87 (m, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.03 (dd, J = 110.0, 10.9 Hz, 2H), 4.13 (s, 1H), 1.64 (s, 3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.6, 172.1, 158.2, 138.7, 134.7, 130.1, 129.2, 128.5,

172.3, 138.2, 134.7, 133.9, 129.9, 129.8, 129.1, 128.5, 124.8, 87.7, 78.4, 77.5, 25.4, 22.9, 18.1; HRMS (ESI-TOF): m/z calculated for C17H22NO3 (M+H)+: 288.1600, found: 288.1594. (E)-3-(Benzyloxy)-2-(1-bromo-2-phenylvinyl)-5,5-dimethyloxazolidin-4-one (3i). Clear liquid (30.6 mg, 76% yield); 1H NMR (400 MHz, CDCl3) δ 7.73−7.70 (m, 2H), 7.42−7.36 (m, 8H), 7.10 (s, 1H), 5.19−5.14 (m, 2H), 4.97 (m, 1H), 1.58 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 135.9, 134.7, 133.9, 129.8, 129.4, 129.3, 129.2, 128.6, 128.4, 122.4, 91.2, 78.5, 24.8, 24.5; HRMS (ESITOF): m/z calculated for C20H21BrNO3 (M+H)+: 402.0699, found: 402.0708. (E)-3-(Benzyloxy)-5,5-dimethyl-2-(1-phenylprop-1-en-2-yl)oxazolidin-4-one (3j). Clear liquid (33.5 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.38−7.33 (m, 10H), 6.57 (s, 1H), 5.12−5.09 (m, 2H), 4.88 (m, 1H), 1.83 (d, J = 1.3 Hz, 3H), 1.49 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 136.2, 134.7, 134.0, 132.5, 129.8, 129.2, 129.1, 128.6, 128.4, 127.6, 92.2, 77.9, 77.7, 24.9, 23.4, 11.4; HRMS (ESI-TOF): m/z calculated for C21H24NO3 (M +H)+: 338.1751, found: 338.1754. (E)-3-(Benzyloxy)-5,5-dimethyl-2-(1-phenyloct-1-en-2-yl)oxazolidin-4-one (3k). Clear liquid (34.0 mg, 84% yield); 1H NMR (400 MHz, CDCl3) δ 7.39−7.32 (m, 10H), 6.52 (s, 1H), 5.12−5.10 (m, 2H), 4.86 (m, 1H), 2.33−2.26 (m, 1H), 2.17−2.10 (m, 1H), 1.49 (s, 3H), 1.37 (s, 3H), 1.28−1.26 (m, 8H), 0.88−0.85 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 137.0, 136.2, 134.7, 134.3, 129.8, 129.1, 128.8, 128.6, 128.5, 127.6, 92.6, 77.8, 77.7, 31.4, 29.8, 29.1, 26.2, 24.9, 23.2, 22.6, 14.0; HRMS (ESI-TOF): m/z calculated for C26H34NO3 (M+H)+: 408.2533, found: 408. 408.2529. (E)-3-(Benzyloxy)-5-phenyl-2-styryloxazolidin-4-one (3l). Clear liquid (isolated diastereoisomer; diastereomer ratio was determined by yields of isolated diastereoisomers. dr = 1:2, 11.2 mg, 32% yield); 1 H NMR (400 MHz, CDCl3) δ 7.42−7.33 (m, 15H), 6.68 (d, J = 15.8 Hz, 1H), 6.08 (dd, J = 15.8, 7.4 Hz, 1H), 5.32 (m, 2H), 5.03 (dd, J = 32.0, 12.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.4, 137.8, 135.6, 135.1, 134.7, 130.0, 129.3, 129.0, 128.78, 128.75, 128.72, 128.6, 127.2, 126.4, 123.6, 89.8, 78.4, 76.3; HRMS (ESI-TOF): m/z calculated for C24H22NO3 (M+H)+: 372.1594, found: 372.1591. White solid (isolated diastereoisomer, dr = 1:2, 24.1 mg, 64% yield); mp 119−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.41−7.33 (m, 15H), 6.81 (d, J = 15.8 Hz, 1H), 5.92 (m, 1H), 5.43 (m, 1H), 5.19 (s, 1H), 5.03 (dd, J = 40.0, 10.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.3, 138.5, 135.5, 135.1, 134.6, 130.0, 129.1, 129.0, 128.9, 128.7, 128.6, 128.5, 127.3, 126.8, 124.0, 89.8, 78.7, 77.4; HRMS (ESI-TOF): m/z calculated for C24H22NO3 (M+H)+: 372.1594, found: 372.1591. (±)-(2R,5S)-3-(Benzyloxy)-5-methyl-2-((E)-styryl)oxazolidin-4-one and (±)-(2R,5R)-3-(Benzyloxy)-5-methyl-2-((E)-styryl)oxazolidin-4one (3m). Clear liquid (cis- and trans- diastereomers are inseparable and characterized as a mixture; diastereomer ratio was determined by the H NMR spectra. dr = 1:1.35. 12.4 mg, 40% yield); 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 10 + 6.41H), 6.73 (m, 1 + 0.66H), 5.98 (dd, J = 15.8, 7.6 Hz, 0.71H), 5.87 (dd, J = 15.8, 7.9 Hz, 1H), 5.25−5.21 (m, 1 + 0.68H), 5.09−4.94 (m, 2 + 1.44H), 4.48−4.43 (m, 0.72H), 4.33−4.28 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.43 (d, J = 6.9 Hz, 2.19H); 13C NMR (100 MHz, CDCl3) δ 171.3, 170.2, 138.2, 137.3, 135.2, 135.1, 134.7, 134.6, 129.8, 129.7, 129.2, 129.1, 129.0, 128.9, 128.7, 128.6, 128.5, 127.2, 127.1, 124.3, 123.7, 89.7, 89.0, 78.6, 78.5, 72.3, 71.5, 17.9, 17.1; HRMS (ESI-TOF): m/z calculated for C19H20NO3 (M+H)+: 310.1438, found: 310.1437. (±)-(2R,5S)-3-(Benzyloxy)-5-ethyl-2-((E)-styryl)oxazolidin-4-one and (±)-(2R,5R)-3-(Benzyloxy)- 5-ethyl-2-((E)-styryl)oxazolidin-4one (3n). Clear liquid (cis- and trans-diastereomers are inseparable and characterized as a mixture; diastereomer ratio was determined by the H NMR spectra. dr = 1:3, 22.6 mg, 70% yield); 1H NMR (400 MHz, CDCl3) δ 7.39−7.28 (m, 10 + 3.03H), 6.74 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 0.31H), 5.99 (dd, J = 15.8, 7.7 Hz, 0.32H), 5.84 (dd, J = 15.8, 8.0 Hz, 1H), 5.25 (dd, J = 8.0, 0.9 Hz, 1H), 5.21 (dd, J = 7.7, 1.6 Hz, 0.32H), 5.06 (m, 1 + 0.34H), 4.95 (dd, J = 10.5, 2.8 Hz, 1 + 0.30H), 4.33 (m, 0.31H), 4.23 (m, 1H), 1.91 (m, 1 + 0.30H), 1.84−1.75 (m, 1 + 0.29H), 1.02 (t, J = 7.4 Hz, 3 + 1H); 13C NMR (100 MHz, CDCl3) δ 170.7, 169.4, 138.1, 137.3, 135.1, 134.8, 9783

DOI: 10.1021/acs.joc.7b00547 J. Org. Chem. 2017, 82, 9779−9785

Note

The Journal of Organic Chemistry

122.4, 121.1, 117.6, 97.0, 79.5, 78.5, 26.9, 25.9, 20.5, 15.5; HRMS (ESI-TOF): m/z calculated for C21H23N2O4 (M+H)+: 367.1652, found: 367.1643. 3′-(Benzyloxy)-5″-methoxydispiro[cyclohexane-1,5′-oxazolidine2′,2″-indoline]-3″,4′-dione (8j). Yellow solid (17.7 mg, 43% yield); mp 109−111 °C; 1H NMR (500 MHz, CDCl3) δ 7.43−7.30 (m, 3H), 7.29−7.21 (m, 2H), 7.13 (m, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 5.02 (dd, J = 110.1, 10.9 Hz, 2H), 3.82 (s, 1H), 3.77 (s, 3H), 2.19−1.22 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 195.1, 171.9, 154.3, 153.7, 134.8, 130.0, 129.2, 128.5, 128.0, 118.2, 113.8, 106.2, 97.5, 80.7, 78.5, 55.8, 35.4, 33.8, 24.6, 21.2, 21.0; HRMS (ESITOF): m/z calculated for C23H25N2O5 (M+H)+: 409.1758, found: 409.1755. 3′-(Benzyloxy)-5″-methyldispiro[cyclohexane-1,5′-oxazolidine2′,2″-indoline]-3″,4′-dione (8k). Yellow liquid (33.0 mg, 84% yield); 1 H NMR (500 MHz, CDCl3) δ 7.38−7.24 (m, 7H), 6.51 (d, J = 8.2 Hz, 1H), 5.01 (dd, J = 116.8, 10.9 Hz, 2H), 3.95 (s, 1H), 2.28 (s, 3H), 2.12 (m, 1H), 1.96−1.82 (m, 2H), 1.77−1.47 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 194.8, 171.8, 156.5, 139.6, 134.8, 130.3, 130.1, 129.1, 128.5, 125.0, 118.0, 112.1, 96.9, 80.6, 78.4, 35.4, 33.8, 24.6, 21.2, 21.0, 20.5; HRMS (ESI-TOF): m/z calculated for C23H25N2O4 (M +H)+: 393.1809, found: 393.1811. 3′-(Benzyloxy)-5″,7″-dimethyldispiro[cyclohexane-1,5′-oxazolidine-2′,2″-indoline]-3″,4′-dione (8l). Yellow solid (19.5 mg, 48% yield); mp 105−107 °C; 1H NMR (500 MHz, CDCl3) δ 7.37−7.14 (m, 7H), 5.02 (dd, J = 116.3, 10.8 Hz, 2H), 4.05 (s, 1H), 2.26 (s, 3H), 2.13−2.10 (m, 1H), 2.04 (s, 3H), 1.92−1.86 (m, 2H), 1.73−1.53 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 194.1, 170.8, 154.5, 139.4, 133.7, 129.3, 128.8, 128.0, 127.4, 121.3, 120.1, 116.6, 96.1, 79.7, 77.5, 34.3, 32.9, 23.6, 20.2, 19.9, 19.5, 14.5; HRMS (ESI-TOF): m/z calculated for C24H27N2O4 (M+H)+: 407.1965, found: 407.1961.

125.4, 120.7, 117.7, 112.1, 96.3, 79.5, 78.5, 26.9, 25.8; HRMS (ESITOF): m/z calculated for C19H19N2O4 (M+H)+: 339.1339, found: 339.1345. 3′-(Benzyloxy)-5-bromo-5′,5′-dimethylspiro[indoline-2,2′-oxazolidine]-3,4′-dione (8b). Yellow solid (10.5 mg, 25% yield); mp 83−85 °C; 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 7.53 (m, 1H), 7.44− 7.39 (m, 3H), 7.36−7.26 (m, 2H), 6.45 (d, J = 8.5 Hz, 1H), 5.01 (dd, J = 115.0, 11.1 Hz, 2H), 3.98 (s, 1H), 1.62 (s, 3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.4, 171.1, 155.7, 139.9, 133.8, 129.2, 128.3, 127.6, 126.9, 118.2, 112.6, 111.7, 95.4, 78.7, 77.4, 25.9, 24.7; HRMS (ESI-TOF): m/z calculated for C19H18BrN2O4 (M+H)+: 417.0444, found: 417.0436. 3′-(Benzyloxy)-5-methoxy-5′,5′-dimethylspiro[indoline-2,2′-oxazolidine]-3,4′-dione (8c). Yellow solid (28.5 mg, 77% yield); mp 85− 87 °C; 1H NMR (500 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 7.13−7.11 (m, 1H), 6.99 (m, 1H), 6.56 (m, 1H), 5.03 (dd, J = 110.0, 8.9 Hz, 2H), 3.91 (s, 1H), 3.77 (m, 3H), 1.63 (s, 3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.9, 172.1, 154.4, 153.6, 134.8, 130.0, 129.2, 128.6, 128.1, 118.2, 113.8, 106.3, 97.3, 79.5, 78.5, 55.8, 26.9, 25.8; HRMS (ESI-TOF): m/z calculated for C20H21N2O5 (M+H)+: 369.1445, found: 369.1436. 3′-(Benzyloxy)-5,5′,5′-trimethylspiro[indoline-2,2′-oxazolidine]3,4′-dione (8d). Yellow liquid (17.7 mg, 50% yield); 1H NMR (500 MHz, CDCl3) δ 7.46−7.22 (m, 7H), 6.51 (m, 1H), 5.02 (dd, J = 115.0, 10.9 Hz, 2H), 3.99 (s, 1H), 2.28 (s, 3H), 1.63 (s, 3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.6, 171.0, 155.5, 138.7, 133.7, 129.3, 129.1, 128.2, 127.5, 124.0, 116.9, 111.1, 95.7, 78.4, 77.4, 25.9, 24.8, 19.5; HRMS (ESI-TOF): m/z calculated for C20H21N2O4 (M+H)+: 353.1496, found: 353.1493. 3′-(Benzyloxy)-5′,5′-dimethyl-5-nitrospiro[indoline-2,2′-oxazolidine]-3,4′-dione (8e). Yellow solid (33.1 mg, 86% yield); mp 100− 102 °C; 1H NMR (500 MHz, CDCl3) δ 8.37−8.34 (m, 2H), 7.49− 7.41 (m, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.29−7.22 (m, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.02 (dd, J = 115.0, 11.4 Hz, 2H), 4.54 (s, 1H), 1.64 (s, 3H), 1.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 191.8, 171.0, 159.9, 140.2, 133.8, 132.6, 129.3, 128.5, 127.7, 121.0, 115.8, 110.2, 95.4, 79.1, 77.5, 25.8, 24.7; HRMS (ESI-TOF): m/z calculated for C19H18N3O6 (M+H)+: 384.1190, found: 384.1189. 3′-(Benzyloxy)-7-chloro-5′,5′-dimethylspiro[indoline-2,2′-oxazolidine]-3,4′-dione (8f). Yellow solid (16.8 mg, Yield: 45%); mp 88−89 °C; 1H NMR (500 MHz, CDCl3) δ 7.50−7.44 (m, 2H), 7.39−7.30 (m, 3H), 7.27 (m, 2H), 6.87−6.84 (m, 1H), 5.06 (dd, J = 97.5, 10.9 Hz, 2H), 4.59 (s, 1H), 1.63 (s, 3H), 1.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.0, 171.0, 153.6, 136.6, 133.3, 128.8, 128.3, 127.6, 122.7, 120.2, 118.1, 116.2, 95.3, 78.8, 77.7, 25.8, 24.8; HRMS (ESITOF): m/z calculated for C19H18ClN2O4 (M+H)+: 373.0950, found: 373.0946. 1-(Benzyloxy)-9a-hydroxy-3,3-dimethyl-7-(trifluoromethoxy)1,9a-dihydro-9H-imidazo[1,2-a]indole-2,9(3H)-dione (8g). Yellow solid (17.4 mg, 41% yield); mp 95−97 °C; 1H NMR (500 MHz, CDCl3) δ 7.45−7.26 (m, 7H), 6.55 (d, J = 8.7 Hz, 1H), 5.03 (dd, J = 107.8, 11.1 Hz, 2H), 4.08 (s, 1H), 1.63 (s, 3H), 1.50 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.9, 171.0, 155.4, 141.6, 133.7, 130.8, 129.1, 128.3, 127.6, 119.5 (q, J = 257.0 Hz). 117.0, 116.9, 111.9, 95.8, 78.7, 77.5, 25.9, 24.7; HRMS (ESI-TOF): m/z calculated for C20H18F3N2O5 (M+H)+: 423.1162, found: 423.1146. 3′-(Benzyloxy)-5-fluoro-5′,5′-dimethylspiro[indoline-2,2′-oxazolidine]-3,4′-dione (8h). Yellow liquid (20.0 mg, 56% yield); 1H NMR (500 MHz, CDCl3) δ 7.40−7.33 (m, 3H), 7.27−7.18 (m, 4H), 6.54 (m, 1H), 5.03 (dd, J = 107.2, 11.0 Hz, 2H), 4.02 (s, 1H), 1.63 (s, 3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.4 (d, J = 2.9 Hz), 172.0, 157.1(d, J = 242.2 Hz), 154.6, 134.7, 130.1, 129.3, 128.6, 125.9 (d, J = 25.2 Hz), 118.2 (d, J = 6.3 Hz), 113.3 (d, J = 6.3 Hz), 110.9 (d, J = 22.7 Hz), 97.1, 79.6, 78.5, 26.9, 25.8; HRMS (ESI-TOF): m/z calculated for C19H18FN2O4 (M+H)+: 357.1245, found: 357.1244. 3′-(Benzyloxy)-5,5′,5′,7-tetramethylspiro[indoline-2,2′-oxazolidine]-3,4′-dione (8i). Yellow solid (19.8 mg, 54% yield); mp 91−93 °C; 1H NMR (500 MHz, CDCl3) δ 7.38−7.24 (m, 5H), 7.21 (s, 1H), 7.14 (s, 1H), 5.04 (dd, J = 119.6, 10.9 Hz, 2H), 4.03 (s, 1H), 2.26 (s, 3H), 2.03 (s, 3H), 1.64 (s, 3H), 1.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 194.9, 172.1, 155.5, 140.4, 134.7, 130.4, 129.9, 129.1, 128.5,

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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.7b00547. NMR spectra for 3a−3u and 8a−8l (PDF) X-ray crystallographic data for 3h (CIF) X-ray crystallographic data for 8c (CIF)

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AUTHOR INFORMATION

Corresponding Authors

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

Limin Yang: 0000-0003-1021-3942 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC (21302032, 21373073, and 21672048) and the PCSIRT (IRT 1231) for financial support. G.Z. appreciated a Qianjiang Scholar from Zhejiang Province in China.

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REFERENCES

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