English

• 0.   Introduction

  Spirocyclic oxindoles are privileged structural motifs existing in a broad range of natural products and pharmaceuticals, which possess significant biological activities.^[1] It has been shown that substituents and spatial structures greatly influence the properties of those compounds.^[2] And potentially promising skeletons are those bearing a heteroatom (especially N or O) in the spiro stereocenter at the C(3) position of the oxindole.^[3] Among various spirocyclic oxindoles, tetrahydrofuran spirooxindole derivatives have also attracted much attention of organic chemists for their potential biological activities. For example, spiro[furo-2, 3'-oxindole]s could inhibit the growth of lung adenocarcinoma (A549) cells and hepatocellular carcinoma (HepG2) cells.^[4] Consequently, a lot of elegant methods for their generation have been developed.^[5]

  Among these documented methods, there are two pathways to access tetrahydrofuran spirooxindoles. One method for the synthesis of tetrahydrofuran spirooxindoles starts with isatins or 3-hydroxy-2-oxindoles containing ring A, followed by the construction of the spiro-carbon center and the formation of ring B (Pathway a, Scheme 1">Scheme 1).^[6] The other needs readily available B-ring-containing amides to construct spiro-carbon and form ring A (Pathway b, Scheme 1">Scheme 1).^[7] Only one ring is built and the other has already existed in one of the substrates in both above strategies. Meanwhile, sometimes these strategies have some inherent drawbacks, such as harsh reaction conditions, multiple operation procedures, poor compatibility of functional groups, and poor availability of the starting material to diversify the molecular structure. It is highly desirable and challenging to develop simple and integrated methods for the construction of a spiro-carbon center, ring A, and ring B in one-pot reaction.

  Scheme1

  

  Scheme1.  Construction of tetrahydrofuran spirooxindoles

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  Recently, our group has endeavored to develop the applications of metal-catalysts.^[8] And we have successfully realized some dinuclear metal-catalytic asymmetric cascade reactions for the synthesis of structurally novel and functionalized compounds, ^[9] such as Michael/hemiketali- zation to construct five- or six-membered oxygenated het-erocycles, ^[9a-9b] phospha-Michael/Michael cascade reaction for the synthesis of 1, 2, 3-trisubstituted indanes, ^[9c] Kno- evenagel/Michael/cyclization for the synthesis of dihydrofuran spirooxindoles, ^[9d] Michael/transesterification for the formation of spiro-indanone γ-butyrolactones, ^[9e] and asy- mmetric exo′-selective [3+2] cycloaddition to construct trifluoromethyl-substituted 2, 3-pyrrolidinyl dispirooxindoles.^[9f] Particularly, we recently demonstrated that β, γ-unsaturated α-ketoamides could serve as especially appropriate Michael acceptors for the enantioselective construction of dispirocyclic oxindoles through cascade Michael/cyclization/Friedel-Crafts reaction.^[9g-9h]

  As a continuation, we envisioned that the reaction of α-hydroxy aryl ketones 1 with β, γ-unsaturated α-ketoa- mides 2 may provide a straightforward approach to construct multisubstituted tetrahydrofuran spirooxindoles in one pot reaction. Herein we wish to report our progress with acceptable results in this area.^[10]

  1.   Results and discussion

  1.1   Catalyst screening and optimization

  Initially, α-hydroxy aryl ketone 1a and β, γ-unsaturated α-ketoamide 2a were chosen as model substrates for optimization studies (Table 1). Reactions were conducted in dichloromethane (DCM) at room temperature for 24 h. However, no obvious reaction occurred when ZnCl₂ (10 mol%) was used as catalyst (Table 1, Entry 1). A number of Lewis acids, such as FeCl₃, Zn(OTf)₂, Zn(OAc)₂, Cu(OTf)₂, Cu(OAc)₂, Mn(OAc)₂, La(OAc)₂, and so on, were also tested, and none of them could catalyze the model reaction (Table 1, Entries 1~7). Then, some bases were employed as catalysts in this model reaction. Fortunately, the product 3 was obtained in 49% isolated yield when NaOH was used (Table 1, Entry 8). Encouraged by this, KOH and CH₃ONa were examined subsequently, and the yields of product 3 were improved to 49% and 70%, respectively (Table 1, Entries 9 and 10). A Brø nsted base ZnEt₂ was also evaluated, and gave the product 3 in 81% yield (Table 1, Entry 11). However, no reaction occurred when Lewis base NEt₃ was used as catalyst (Table 1, Entry 12).

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Catalyst	x/mol%	Solvent	Yield/% of 3	Yield/% of 4/4' (4/4')
  1	ZnCl2	10	CH2Cl2	Trace	—
  2	FeCl3	10	CH2Cl2	NR	—
  3	Zn(OTf)2	10	CH2Cl2	NR	—
  4	Cu(OTf)2	10	CH2Cl2	NR	—
  5	La(OAc)3	10	CH2Cl2	NR	—
  6	Co(OAc)2	10	CH2Cl2	NR	—
  7	Zn(OAc)2	10	CH2Cl2	NR	—
  8	NaOH	10	CH2Cl2	45	—
  9	KOH	10	CH2Cl2	49	—
  10	CH3ONa	10	CH2Cl2	70	—
  11	ZnEt2	10	CH2Cl2	81	—
  12	NEt3	10	CH2Cl2	NR	—
  13	ZnEt2	10	THF	62	—
  14	ZnEt2	10	Toluene	64	—
  15	ZnEt2	10	Benzene	74	—
  16	ZnEt2	10	CHCl3	76	—
  17	ZnEt2	10	CH3CN	79	—
  18b	ZnEt2	5	CH2Cl2	76	—
  19c	ZnEt2	20	CH2Cl2	88	—
  20c	ZnEt2	30	CH2Cl2	88	—
  21d, e	ZnEt2	20	CH2Cl2	—	60 (32/28)
  22d, f	ZnEt2	20	CH2Cl2	—	71 (39/32)
  23d, g	ZnEt2	20	CH2Cl2	—	84 (46/38)
  a Unless otherwise noted, all the reactions were conducted with 10 mol% catalyst, 0.20 mmol of 1, and 0.21 mmol of 2 in 2 mL of solvent at 20 ℃ for 24 h. b Reaction time was 40 h. c Reaction time was 6 h. d 6 h later, acid was added at 0 ℃ and the mixture was stirred for another 1 h. e Two drops of H2SO4 was added. f 0.5 mL of HCl was added. g 0.5 mL of CF3COOH (TFA) was added.

  Next, the evaluation of different solvents, including tetrahydrofuran (THF), toluene, benzene, CHCl₃, and CH₃CN indicated that CH₂Cl₂ was the optimal solvent which gave the product 3 in 81% yield (Table 1, Entries 11, 13~17). When the catalyst loading amount was lowered to 5 mol%, the yield of product 3 was decreased to 76% and the reaction time was prolonged to 48 h. Once increasing the catalyst loading amount to 20 mol%, the yield of product 3 was increased to 88% in 6 h. While the yield was not further improved when 30 mol% catalyst loading was employed, which indicated that 20 mol% of ZnEt₂ was the best choice (Table 1, Entries 18~20).

  The ¹H NMR and ¹³C NMR spectra revealed that product 3 was obtained as a mixture of the chain structure (Michael addition product) and the cyclic structure (Michael/hemi- ketalization product).^[10] There was a dynamic balance between the chain structure and the cyclic structure, which led to the difficulty to purify and characterize. It was found that this mixture could give the title compound tetrahydrofuran spirooxindole 4/4' through an intramolecular Friedel-Crafts reaction, when it was treated with H₂SO₄ (Table 1, Entry 21). Then, concentrated hydrochloric acid (HCl) and CF₃COOH (TFA) were evaluated, and TFA was the optimal choice giving product 4/4' in 84% total yields through 2 steps one-pot reaction (Table 1, Entries 22 and 23). Although the diastereoselectivity was low, the two isomers of anti-4aa and syn-4aa' could be separated by flash column chromatography on silica gel.

  Thus the optimal conditions were determined as follows (Table 1, Entry 23): 20 mol% ZnEt₂, 2 mL of CH₂Cl₂, α-hydroxy aryl ketones 1 (0.20 mmol), β, γ-unsaturated α-ketoamide 2 (0.21 mmol) at 20 ℃ for 6 h. Then 0.5 mL of TFA was dropwise added at 0 ℃ and stirred for another 1 h.

  1.2   Substrate scope

  The substrate scope of this multisubstituted tetrahydrofuran spirooxindoles forming reaction was explored under the optimal conditions. Using 1a as a model substrate, the N-protecting groups R¹ of β, γ-unsaturated-α-ketoamides 2 was first examined. The experiment results revealed that the steric bulk of the substituent at N atom in 2a~2c had an obvious influence on the yield in this reaction. When substituent R¹ was changed from Me to Et or Bn, the total yields of products 4/4' decreased to 53% and 51% (Table 2, Entries 2 and 3). The reason might owe to the larger steric hindrance of Et or Bn.

  Table 2

  

  Table 2.  Substrate scope of the reaction^a

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  Entry	Ar1	R1	Ar2	R2	Product	Yield/% (4/4')
  1	Ph	Me	Ph	H	4aa/4aa'	84 (46/38)
  2	Ph	Et	Ph	H	4ab/4ab'	53 (22/31)
  3	Ph	Bn	Ph	H	4ac/4ac'	51 (25/26)
  4	Ph	Me	Ph	F	4ad/4ad'	86 (56/30)
  5	Ph	Me	Ph	Cl	4ae/4ae'	87 (57/30)
  6	Ph	Me	Ph	Br	4af/4af'	61 (39/22)
  7	Ph	Me	Ph	Me	4ag/4ag'	74 (44/30)
  8	Ph	Me	Ph	MeO	4ah/4ah'	76 (37/39)
  9	Ph	Me	4-O2NC6H4	H	4ai/4ai'	51 (24/27)
  10	Ph	Me	4-FC6H4	H	4aj/4aj'	77 (39/38)
  11	Ph	Me	4-ClC6H4	H	4ak/4ak'	88 (44/44)
  12	Ph	Me	4-BrC6H4	H	4al/4al'	94 (61/33)
  13	Ph	Me	4-MeC6H4	H	4am/4am'	79 (41/38)
  14	Ph	Me	4-MeOC6H4	H	4an/4an'	72 (39/33)
  15	Ph	Me	3-BrC6H4	H	4ao/4ao'	72 (49/23)
  16	Ph	Me	2-BrC6H4	H	4ap/4ap'	79 (50/29)
  17	Ph	Me	1-Naphthyl	H	4aq/4aq'	75 (37/38)
  18	Ph	Me	2-Naphthyl	H	4ar/4ar'	84 (58/26)
  19	Ph	Me	2-Furyl	H	4as/4as'	85 (43/42)
  20	4-FC6H4	Me	Ph	H	4ba/4ba'	87 (47/40)
  21	4-ClC6H4	Me	Ph	H	4ca/4ca'	92 (48/44)
  22	4-BrC6H4	Me	Ph	H	4da/4da'	94 (59/36)
  23	4-MeC6H4	Me	Ph	H	4ea/4ea'	98 (46/42)
  24	4-MeOC6H4	Me	Ph	H	4fa/4fa'	91 (62/29)
  25	3-BrC6H4	Me	Ph	H	4ga/4ga'	80 (48/42)
  26	3-MeOC6H4	Me	Ph	H	4ha/4ha'	78 (41/37)
  27	2-MeOC6H4	Me	Ph	H	4ia/4ia'	71 (42/29)
  a Unless otherwise noted, all the reactions were conducted with 20 mol% catalyst, 0.20 mmol of 1, and 0.21 mmol of 2 in 2 mL of CH2Cl2 at 20 ℃. 6 h later, 0.5 mL of TFA was dropwise added at 0 ℃.

  Then a series of N-methyl β, γ-unsaturated-α-ketoamides 2 bearing various substituents attached on the phenyl ring were investigated. Substrates 2d~2h with electron-with- drawing halogen groups (F, Cl or Br) or electron-donating groups (Me or MeO) at the para-position of the N-aromatic ring reacted with 1a efficiently under the standard conditions. And the corresponding products 4/4' were ob- tained in 62%~87% total yields (Table 2, Entries 4~8).

  The effect of the para-substituent of the phenyl ring (Ar²) was also explored. Various functional groups, both the electron-withdrawing groups (NO₂, F, Cl or Br) and the electron-donating groups (Me or MeO), were well tolerated (Table 2, Entries 9~14). Meanwhile, it was also observed that nitro group of Ar² affected the yield obviously (51%, Table 2, Entry 9). Substrates 2o and 2p with Br substituent at the meta- or ortho-position of Ar² provided the corres- ponding products 4/4' in 72% and 79% total yields, respectively (Table 2, Entries 15, 16). Notably, 1-naphthyl and 2-naphthyl substituted ketoamides 2q~2r took part in this reaction successfully, giving corresponding products 4/4' in total yields of 75% and 84%, respectively. Further study showed that 2-furyl substituted ketoamide 2s was also a suitable substrate to react with 1a in 85% total yields.

  The reaction of ketoamide 2a with various nucleophiles was next investigated. A series of nucleophiles 1b~1i bearing either electron-withdrawing groups (F, Cl and Br) or electron-donating groups (Me and MeO) at aromatic ring Ar¹ underwent the reaction efficiently, giving 71%~95% total yields (Table 2, Entries 20~27).

  To determine the relative configuration of the products, product 4al' was treated with hydroxylamine hydrochloride and NaOAc in CH₃OH, which led to the corresponding product of oxime 5' in 96% yield (Scheme 2">Scheme 2). A single crystal of compound 5' was obtained for X-ray crystallographic analysis (Figure 1).^[11] Thus, the relative stereochemistry of 4al' could be deduced.

  Scheme2

  

  Scheme2.  Derivatization of product 4al'

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  Figure 1

  

  Figure 1.  X-ray structure of compound 5'

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  2.   Conclusions

  In conclusion, we have developed an efficient method for the direct formation of tetrahydrofuran spirooxindoles, including the constructions of a spiro-carbon center, an oxindole ring, and a tetrahydrofuran ring in one-pot reaction. This chemistry is based on Michael/hemiketalization and Fridel-Crafts reaction of α-hydroxy aryl ketones and β, γ-unsaturated α-ketoamides. Using ZnEt₂ and TFA as catalysts, the one-pot reaction proceeded efficiently and delivered a wide range of tetrahydrofuran spirooxindoles in moderate to good yields. We expect that this novel protocol would provide a convenient and versatile synthetic approach toward structurally diverse tetrahydrofuran spirooxindoles using simple chain substrates.

  3.   Experimental section

  3.1   General procedures

  The melting point (m.p.) was determined on an electrothermal digital melting point apparatus and uncorrected. NMR spectra were recorded on an NMR spectrometer using CDCl₃ or DMSO as the solvents and TMS as an internal standard (400 MHz for ¹H NMR, 100 MHz for ¹³C NMR). HRMS was performed on a Q-TOF Micro LC/MS System ESI spectrometer.

  3.2   General procedure for the catalytic reaction

  In a flame-dried Schlenk tube, a solution of diethylzinc (0.04 mL, 1.0 mol/L in hexane, 0.04 mmol) was added to a solution of compound 1 (0.2 mmol) and substrate 2 (0.21 mmol) in dry CH₂Cl₂ (2 mL) under nitrogen at 20 ℃. The mixture was stirred for 6 h to complete the Michael/ hemiketalization reaction (step 1, detected by TLC). Then, 0.5 mL of TFA was added dropwise to the mixture at 0 ℃, and stirred for another 1 h at room temperature. Finally, the solution was diluted with a saturated solution of Na₂CO₃ and extracted with CH₂Cl₂ (10 mL×3). The combined organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give products 4aa^[10] and 4aa', respectively.

  5-Benzoyl-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro- [furan-2, 3'-indolin]-2'-one (4aa'): White solid (38% yield), m.p. 209~211 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (d, J＝7.6 Hz, 2H), 7.51 (d, J＝7.3 Hz, 1H), 7.45~7.25 (m, 6H), 7.18~7.00 (m, 4H), 6.86 (d, J＝7.8 Hz, 1H), 5.97 (d, J＝8.2 Hz, 1H), 4.38 (q, J＝8.3 Hz, 1H), 3.23 (s, 3H), 3.08 (dd, J＝13.0, 8.7 Hz, 1H), 2.69 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 174.7, 143.55, 138.6, 136.5, 132.8, 131.5, 130.1, 128.7, 128.4, 128.3, 128.2, 127.1, 123.4, 123.0, 108.7, 85.2, 83.6, 49.0, 41.9, 26.5; HRMS (ESI) calcd for C₂₅H₂₂NO₃ [M+H]⁺ 384.1594, found 384.1596.

  5-Benzoyl-1'-ethyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ab'): White solid (31% yield), m.p. 200~202 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝7.7 Hz, 2H), 7.52 (d, J＝7.3 Hz, 1H), 7.45~7.22 (m, 6H), 7.17~6.97 (m, 4H), 6.87 (d, J＝7.8 Hz, 1H), 5.98 (d, J＝8.2 Hz, 1H), 4.37 (q, J＝8.3 Hz, 1H), 3.78 (q, J＝7.1 Hz, 2H), 3.08 (dd, J＝12.8, 8.7 Hz, 1H), 2.68 (dd, J＝12.9, 8.3 Hz, 1H), 1.29 (t, J＝7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.3, 174.7, 143.0, 138.9, 137.0, 133.1, 132.2, 130.3, 129.0, 128.8, 128.6, 128.6, 127.4, 123.9, 123.2, 109.2, 85.6, 84.0, 49.3, 42.5, 35.5, 13.0; HRMS (ESI) calcd for C₂₆H₂₄NO₃ [M+H]⁺ 398.1751, found 398.1754.

  5-Benzoyl-1'-benzyl-4-phenyl-4, 5-dihydro-3H-spiro-[furan-2, 3'-indolin]-2'-one (4ac'): White solid (26% yield), m.p. 175~177 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J＝7.6 Hz, 2H), 7.54 (d, J＝7.2 Hz, 1H), 7.48~7.41 (m, 1H), 7.38~7.21 (m, 10H), 7.19~7.04 (m, 4H), 6.77 (d, J＝7.8 Hz, 1H), 6.03 (d, J＝8.3 Hz, 1H), 4.95 (dd, J＝54.7, 15.7 Hz, 2H), 4.43 (q, J＝8.4 Hz, 1H), 3.19 (dd, J＝12.8, 9.0 Hz, 1H), 2.74 (dd, J＝12.8, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.3, 175.4, 142.9, 138.7, 136.9, 135.9, 133.1, 131.9, 130.3, 129.2, 129.0, 128.8, 128.6, 128.5, 128.1, 127.8, 127.5, 123.8, 123.4, 110.1, 85.5, 84.1, 49.4, 44.5, 42.4; HRMS (ESI) calcd for C₃₁H₂₆NO₃ [M+H]⁺ 460.1907, found 460.1909.

  5-Benzoyl-5'-fluoro-1'-methyl-4-phenyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ad'): White solid (30% yield), m.p. 196~198 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67 (d, J＝7.7 Hz, 2H), 7.50~7.36 (m, 1H), 7.35~7.21 (m, 5H), 7.19~7.01 (m, 4H), 6.88~6.71 (m, 1H), 5.94 (d, J＝8.3 Hz, 1H), 4.33 (dd, J＝16.8, 8.4 Hz, 1H), 3.21 (s, 3H), 3.10 (dd, J＝12.8, 9.1 Hz, 1H), 2.65 (dd, J＝12.9, 8.1 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.6, 174.5, 159.3 (d, J＝240.3 Hz), 139.48 (d, J＝1.9 Hz), 138.0, 136.5, 132.8, 128.6, 128.4, 128.3, 128.2, 127.2, 116.1, (d, J＝23.2 Hz), 111.7 (d, J＝24.7 Hz), 109.2 (d, J＝7.87 Hz), 84.98, 83.7, 48.9, 41.8, 26.6; HRMS (ESI) calcd for C₂₅H₂₁FNO₃ [M+H]⁺ 402.1500, found 402.1503.

  5-Benzoyl-5'-chloro-1'-methyl-4-phenyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ae'): White solid (30% yield), m.p. 180~182 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.71~7.70 (m, 2H), 7.56 (d, J＝7.7 Hz, 2H), 7.41~7.34 (m, 2H), 7.31~7.26 (m, 3H), 7.21~7.12 (m, 2H), 6.96~6.82 (m, 2H), 6.16 (d, J＝8.5 Hz, 1H), 4.89 (dt, J＝10.5, 8.2 Hz, 1H), 3.23 (s, 3H), 3.16 (dd, J＝20.6, 8.3 Hz, 2H), 2.52 (dd, J＝12.4, 7.3 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ: 196.4, 174.7, 143.4, 136.7, 136.2, 132.8, 132.3, 131.2, 130.0, 129.7, 128.7, 128.3, 128.2, 127.7, 125.3, 123.4, 123.1, 108.6, 83.4, 81.9, 47.4, 40.6, 29.7, 26.5; HRMS (ESI) calcd for C₂₅H₂₁ClNO₃ [M+H]⁺ 418.1204, found 418.1205.

  5-Benzoyl-5'-bromo-1'-methyl-4-phenyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4af'): White solid (23% yield), m.p. 203~205 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.57~7.40 (m, 3H), 7.36~7.28 (m, 1H), 7.28~7.18 (m, 1H), 7.17~7.03 (m, 4H), 6.95~6.80 (m, 3H), 6.62 (d, J＝8.3 Hz, 1H), 5.84 (d, J＝8.4 Hz, 1H), 4.31~4.16 (m, 1H), 3.03 (s, 3H), 2.85 (dd, J＝12.9, 9.1 Hz, 1H), 2.49 (dd, J＝13.0, 8.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.2, 174.5, 142.2, 137.97, 136.3, 133.3, 132.7, 132.6, 128.4, 128.1, 127.97, 127.95, 126.9, 126.5, 115.5, 110.1, 84.8, 83.5, 48.6, 41.9, 26.1; HRMS (ESI) calcd for C₂₅H₂₁BrN- O₃ [M+H]⁺ 462.0699, found 462.0700.

  5-Benzoyl-1', 5'-dimethyl-4-phenyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ag'): White solid (30% yield), m.p. 201~203 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (d, J＝7.6 Hz, 2H), 7.47~7.36 (m, 1H), 7.35~7.22 (m, 5H), 7.20~7.02 (m, 4H), 6.73 (d, J＝7.9 Hz, 1H), 5.95 (d, J＝8.2 Hz, 1H), 4.38 (q, J＝8.4 Hz, 1H), 3.19 (s, 3H), 3.07 (dd, J＝12.9, 8.7 Hz, 1H), 2.67 (dd, J＝12.9, 8.3 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.98, 174.7, 141.2, 138.6, 136.6, 132.7, 132.6, 131.5, 130.2, 128.7, 128.5, 128.2, 128.2, 127.0, 124.2, 108.4, 85.3, 83.8, 48.99, 41.9, 26.5, 21.2; HRMS (ESI) calcd for C₂₆H₂₄NO₃ [M+H]⁺ 398.1751, found 398.1753.

  5-Benzoyl-5'-methoxy-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ah'): White solid (39% yield), m.p. 215~217 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝7.6 Hz, 2H), 7.45~7.35 (m, 1H), 7.34~7.22 (m, 4H), 7.16~6.99 (m, 4H), 6.91~6.78 (m, 1H), 6.79~6.70 (m, 1H), 5.93 (d, J＝8.3 Hz, 1H), 4.34 (q, J＝8.4 Hz, 1H), 3.82 (s, 3H), 3.18 (s, 3H), 3.07 (dd, J＝12.9, 8.7 Hz, 1H), 2.66 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.8, 174.4, 156.3, 138.5, 136.99, 136.5, 132.7, 128.6, 128.4, 128.2, 128.2, 127.0, 113.2, 111.8, 108.9, 85.2, 83.9, 56.1, 48.9, 41.9, 26.6; HRMS (ESI) calcd for C₂₆H₂₄NO₄ [M+H]⁺ 414.1700, found 414.1701.

  5-Benzoyl-1'-methyl-4-(4-nitrophenyl)-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ai'): Yellow solid (27% yield), m.p. 135~137 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.89~7.87 (m, 2H), 7.47~7.44 (m, 2H), 7.36~7.33 (m, 3H), 7.29~7.27 (m, 1H), 7.12~7.08 (m, 1H), 7.04~7.03 (m, 1H), 6.84 (d, J＝7.8 Hz, 1H), 6.26 (d, J＝3.3 Hz, 1H), 6.11~6.10 (m, 1H), 5.87 (d, J＝8.5 Hz, 1H), 4.56~4.49 (m, 1H), 3.22 (s, 3H), 3.09 (dd, J＝12.9, 8.7 Hz, 1H), 2.52 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.1, 174.4, 150.7, 143.4 141.5, 135.8, 132.8, 130.99, 130.1, 129.4, 128.9, 128.7, 128.6, 128.1, 125.8, 123.2, 123.0, 110.5, 108.6, 107.9, 83.6, 83.1, 42.7, 39.5, 26.5; HRMS (ESI) calcd for C₂₅H₂₁N₂O₅ [M+H]⁺ 429.1445, found 429.1445.

  5-Benzoyl-4-(4-fluorophenyl)-1'-methyl-4, 5-dihydro- 3H-spiro[furan-2, 3'-indolin]-2'-one (4aj'): White solid (38% yield), m.p. 220~222 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J＝7.7 Hz, 2H), 7.52~7.42 (m, 4H), 7.39~7.26 (m, 3H), 7.08 (t, J＝7.5 Hz, 1H), 7.00 (t, J＝8.5 Hz, 2H), 6.80 (d, J＝7.8 Hz, 1H), 5.71 (d, J＝9.6 Hz, 1H), 4.31 (dd, J＝20.0, 9.5 Hz, 1H), 3.21 (s, 3H), 2.89~2.79 (m, 1H), 2.66 (dd, J＝12.8, 8.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.2, 177.1, 162.1 (d, J＝244.3 Hz), 143.4, 135.5, 134.2 (d, J＝3.2 Hz), 133.7, 130.1, 130.0, 129.9, 129.8, 129.5, 128.6, 124.3, 123.5, 115.7 (d, J＝21.2 Hz), 108.6, 86.6, 83.9, 46.6, 43.96, 26.4; HRMS (ESI) calcd for C₂₅H₂₁FNO₃ [M+H]⁺ 402.1500, found 402.1503.

  5-Benzoyl-4-(4-chlorophenyl)-1'-methyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ak'): White solid (44% yield), m.p. 221~223 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.72~7.71 (m, 2H), 7.50~7.44 (m, 2H), 7.38~7.26 (m, 5H), 7.14~7.08 (m, 3H), 6.86 (d, J＝7.8 Hz, 1H), 5.94 (d, J＝7.9 Hz, 1H), 4.31 (q, J＝7.9 Hz, 1H), 3.23 (s, 3H), 2.98 (dd, J＝13.2, 7.5 Hz, 1H), 2.74 (dd, J＝13.2, 8.5 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.5, 174.6, 143.5, 137.5, 136.4, 132.96, 132.9, 131.4, 130.1, 130.0, 128.4, 128.3, 123.3, 123.1, 108.7, 85.5, 83.5, 48.3, 42.1, 26.5; HRMS (ESI) calcd for C₂₅H₂₁ClNO₃ [M+H]⁺ 418.1204, found 418.1205.

  5-Benzoyl-4-(4-bromophenyl)-1'-methyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4al'): White solid (33% yield), m.p. 180~182 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝7.0 Hz, 2H), 7.49~7.44 (m, 2H), 7.38~7.30 (m, 3H), 7.24~7.20 (m, 4H), 7.14~7.10 (m, 1H), 6.86 (d, J＝7.6 Hz, 1H), 5.96 (d, J＝7.7 Hz, 1H), 4.31 (dd, J＝14.8, 7.2 Hz, 1H), 3.22 (m, 3H), 3.00~2.95 (m, 1H), 2.71 (dd, J＝12.2, 8.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 174.9, 143.4, 137.7, 136.2, 133.1, 131.3, 130.3, 130.2, 128.4, 128.3, 123.3, 123.2, 121.1, 108.8, 85.2, 83.6, 48.4, 42.0, 26.5; HRMS (ESI) calcd for C₂₅H₂₁BrNO₃ [M+H]⁺ 462.0699, found 462.0700.

  5-Benzoyl-1'-methyl-4-(p-tolyl)-4, 5-dihydro-3H-spiro- [furan-2, 3'-indolin]-2'-one (4am'): White solid (38% yield), m.p. 197~199 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.72 (d, J＝7.7 Hz, 2H), 7.50 (d, J＝7.3 Hz, 1H), 7.45~7.38 (m, 1H), 7.38~7.32 (m, 1H), 7.31~7.26 (m, 2H), 7.22~7.15 (m, 2H), 7.14~7.07 (m, 1H), 6.88 (dd, J＝28.0, 7.8 Hz, 3H), 5.93 (d, J＝8.3 Hz, 1H), 4.36 (q, J＝8.4 Hz, 1H), 3.22 (s, 3H), 3.07 (dd, J＝12.8, 9.0 Hz, 1H), 2.65 (dd, J＝12.9, 8.1 Hz, 1H), 2.19 (s, 3H); ¹³C NMR (101 MHz, CDCl₃)δ: 196.3, 175.1, 143.97, 137.2, 136.9, 135.7, 132.8, 132.0, 130.3, 129.2, 128.9, 128.9, 128.4, 123.7, 123.3, 108.9, 85.7, 84.0, 49.1, 42.3, 26.7, 21.2; HRMS (ESI) calcd for C₂₆H₂₄- NO₃ [M+H]⁺ 398.1751, found 398.1753.

  5-Benzoyl-4-(4-methoxyphenyl)-1'-methyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4an'): White solid (33% yield), m.p. 189~191 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.70 (d, J＝7.4 Hz, 2H), 7.50 (d, J＝7.1 Hz, 1H), 7.45~7.39 (m, 1H), 7.37~7.32 (m, 1H), 7.32~7.27 (m, 2H), 7.25~7.20 (m, 2H), 7.11 (t, J＝7.5 Hz, 1H), 6.85 (d, J＝7.7 Hz, 1H), 6.65 (d, J＝8.6 Hz, 2H), 5.93 (d, J＝8.3 Hz, 1H), 4.34 (q, J＝8.3 Hz, 1H), 3.69 (s, 3H), 3.23 (s, 3H), 3.03 (dd, J＝12.9, 8.5 Hz, 1H), 2.67 (dd, J＝13.0, 8.4 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ: 196.1, 174.8, 158.5, 143.5, 136.6, 132.7, 131.6, 130.5, 129.97, 129.7, 128.4, 128.1, 123.3, 122.97, 113.6, 108.6, 85.3, 83.5, 55.2, 48.3, 42.2, 26.5; HRMS (ESI) calcd for C₂₆H₂₄NO₄ [M+H]⁺ 414.1700, found 414.1701.

  5-Benzoyl-4-(3-bromophenyl)-1'-methyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ao'): White solid (23% yield), m.p. 206~208 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.71 (d, J＝7.4 Hz, 2H), 7.51~7.43 (m, 2H), 7.41~7.29 (m, 5H), 7.20 (d, J＝7.8 Hz, 1H), 7.11 (t, J＝7.3 Hz, 1H), 7.02 (t, J＝7.8 Hz, 1H), 6.85 (d, J＝7.7 Hz, 1H), 5.94 (d, J＝7.9 Hz, 1H), 4.28 (q, J＝8.0 Hz, 1H), 3.22 (s, 3H), 3.01 (dd, J＝13.0, 8.1 Hz, 1H), 2.70 (dd, J＝13.1, 8.3 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ: 195.5, 174.6, 143.5, 141.1, 136.4, 132.98, 131.8, 131.3, 130.1, 130.1, 129.9, 128.4, 128.3, 127.2, 123.3, 123.1, 122.1, 108.7, 85.3, 83.5, 48.5, 41.6, 26.5; HRMS (ESI) calcd for C₂₅H₂₁BrNO₃ [M+H]⁺ 462.0699, found 462.0700.

  5-Benzoyl-4-(2-bromophenyl)-1'-methyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ap'): White solid (29% yield), m.p. 203~205 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.71 (d, J＝7.5 Hz, 2H), 7.56 (d, J＝7.6 Hz, 2H), 7.43~7.34 (m, 2H), 7.30~7.26 (m, 3H), 7.22~7.11 (m, 2H), 6.96~6.90 (m, 1H), 6.86 (d, J＝7.7 Hz, 1H), 6.16 (d, J＝8.5 Hz, 1H), 4.89 (dd, J＝18.4, 8.1 Hz, 1H), 3.23 (s, 3H), 3.19~3.13 (m, 1H), 2.52 (dd, J＝12.4, 7.3 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ: 196.3, 174.7, 143.4, 136.7, 136.2, 132.8, 132.3, 131.2, 130.1, 129.7, 128.7, 128.3, 128.2, 127.7, 125.3, 123.4, 123.1, 108.6, 83.4, 81.9, 47.4, 40.7, 26.5; HRMS (ESI) calcd for C₂₅H₂₁BrNO₃ [M+H]⁺ 462.0699, found 462.0700.

  5-Benzoyl-1'-methyl-4-(naphthalen-1-yl)-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4aq'): White solid (38% yield), m.p. 197~199 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71~7.60 (m, 6H), 7.54~7.39 (m, 2H), 7.35~7.34 (m, 4H), 7.21~7.12 (m, 3H), 6.87 (d, J＝7.8 Hz, 1H), 6.04 (d, J＝8.2 Hz, 1H), 4.54 (q, J＝8.3 Hz, 1H), 3.25 (s, 3H), 3.20 (dd, J＝12.9, 8.7 Hz, 1H), 2.76 (dd, J＝13.0, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 174.8, 143.5, 136.5, 135.97, 133.1, 132.6, 132.4, 131.5, 130.0, 128.4, 128.1, 127.97, 127.8, 127.5, 126.6, 125.9, 125.7, 123.3, 123.0, 108.7, 85.3, 83.7, 49.1, 41.9, 26.5; HRMS (ESI) calcd for C₂₉H₂₄NO₃ [M+H]⁺434.1751, found 434.1753.

  5-Benzoyl-1'-methyl-4-(naphthalen-2-yl)-4, 5-dihydro-3-H-spiro[furan-2, 3'-indolin]-2'-one (4ar'): White solid (26% yield), m.p. 233~235 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71~7.60 (m, 6H), 7.56~7.49 (m, 2H), 7.38~7.31 (m, 4H), 7.21~7.11 (m, 3H), 6.87 (d, J＝7.8 Hz, 1H), 6.04 (d, J＝8.2 Hz, 1H), 4.54 (q, J＝8.4 Hz, 1H), 3.25 (s, 3H), 3.20 (dd, J＝12.9, 8.7 Hz, 1H), 2.76 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 174.8, 143.5, 136.5, 135.99, 133.1, 132.6, 132.4, 131.5, 130.0, 128.4, 128.1, 127.96, 127.8, 127.5, 126.6, 125.9, 125.7, 123.3, 123.0, 108.7, 85.3, 83.7, 49.1, 41.9, 26.5; HRMS (ESI) calcd for C₂₉H₂₄NO₃ [M+H]⁺ 434.1751, found 434.1753.

  5-Benzoyl-4-(furan-2-yl)-1'-methyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4as'): White solid (42% yield), m.p. 207~209 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.02~8.00 (m, 2H), 7.75 (dd, J＝8.3, 1.1 Hz, 2H), 7.58~7.56 (m, 2H), 7.50~7.47 (m, 2H), 7.41~7.32 (m, 3H), 7.15~7.11 (m, 1H), 6.88 (d, J＝7.8 Hz, 1H), 5.98 (d, J＝7.4 Hz, 1H), 4.39 (dd, J＝15.6, 7.1 Hz, 1H), 3.23 (s, 3H), 2.99 (dd, J＝13.3, 6.7 Hz, 1H), 2.85 (dd, J＝13.3, 8.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 194.8, 174.6, 147.3, 146.8, 143.6, 135.96, 133.4, 131.1, 130.4, 129.6, 128.51, 128.45, 123.4, 123.3, 123.2, 108.9, 85.8, 83.5, 48.5, 41.9, 26.5; HRMS (ESI) calcd for C₂₃H₂₀NO₄ [M+H]⁺ 374.1387, found 374.1388.

  5-(4-Fluorobenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H- spiro[furan-2, 3'-indolin]-2'-one (4ba'): White solid (40% yield), m.p. 197~199 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.81~7.77 (m, 2H), 7.50 (d, J＝7.2 Hz, 1H), 7.38~7.31 (m, 3H), 7.15~7.06 (m, 4H), 6.97~6.92 (m, 2H), 6.86 (d, J＝7.8 Hz, 1H), 5.88 (d, J＝8.3 Hz, 1H), 4.38 (q, J＝8.4 Hz, 1H), 3.23 (s, 3H), 3.09 (dd, J＝12.9, 8.9 Hz, 1H), 2.73~2.61 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 194.7, 174.8, 165.4 (d, J＝253.2 Hz), 143.5, 138.2, 132.93 (d, J＝3.1 Hz), 131.3 (d, J＝9.3 Hz), 131.33, 130.1, 128.6, 128.3, 127.1, 123.3, 123.1, 115.2 (d, J＝21.8 Hz), 108.7, 85.5, 83.8, 48.97, 41.5, 26.5; HRMS (ESI) calcd for C₂₅H₂₁FN- O₃ [M+H]⁺ 402.1500, found 402.1503.

  5-(4-chlorobenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ca'): White solid (44% yield), m.p. 178~180 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (d, J＝8.6 Hz, 2H), 7.51~7.48 (m, 1H), 7.39~7.30 (m, 3H), 7.27~7.23 (m, 2H), 7.17~7.08 (m, 4H), 6.86 (d, J＝7.8 Hz, 1H), 5.87 (t, J＝6.8 Hz, 1H), 4.49~4.27 (m, 1H), 3.23 (s, 3H), 3.08 (dd, J＝12.9, 9.0 Hz, 1H), 2.67 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.2, 174.8, 143.4, 139.1, 138.1, 134.8, 131.3, 130.1, 130.0, 129.8, 129.6, 129.4, 129.1, 128.6, 128.4, 128.3, 127.2, 123.3, 123.1, 108.7, 85.5, 83.8, 48.95, 41.5, 26.5; HRMS (ESI) calcd for C₂₅H₂₁ClNO₃ [M+H]⁺ 418.1204, found 418.1205.

  5-(4-Bromobenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4da'): White solid (36% yield), m.p. 218~220 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.60 (t, J＝5.4 Hz, 2H), 7.49 (d, J＝7.2 Hz, 1H), 7.45~7.28 (m, 5H), 7.19~7.04 (m, 4H), 6.86 (d, J＝7.8 Hz, 1H), 5.86 (d, J＝8.3 Hz, 1H), 4.38 (q, J＝8.4 Hz, 1H), 3.23 (s, 3H), 3.08 (dd, J＝12.9, 9.0 Hz, 1H), 2.67 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.4, 174.7, 143.5, 138.1, 135.2, 132.6, 131.4, 131.3, 130.1, 130.1, 129.8, 128.6, 128.3, 127.9, 127.2, 123.3, 123.1, 108.7, 85.5, 83.8, 48.9, 41.5, 26.5; HRMS (ESI) calcd for C₂₅H₂₁BrNO₃ [M+H]⁺ 462.0699, found 462.0700.

  1'-Methyl-5-(4-methylbenzoyl)-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ea'): White solid (42% yield), m.p. 240~242 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J＝8.2 Hz, 2H), 7.54~7.46 (m, 1H), 7.38~7.30 (m, 3H), 7.16~7.03 (m, 6H), 6.85 (d, J＝7.8 Hz, 1H), 5.93 (d, J＝8.2 Hz, 1H), 4.37 (q, J＝8.4 Hz, 1H), 3.23 (s, 3H), 3.14~3.03 (m, 1H), 2.68 (dt, J＝23.0, 11.5 Hz, 1H), 2.32 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.4, 174.7, 143.5, 143.5, 138.6, 133.99, 131.5, 129.97, 128.9, 128.6, 128.6, 128.2, 126.99, 123.3, 122.96, 108.6, 85.1, 83.5, 48.99, 41.96, 26.5, 21.6; HRMS (ESI) calcd for C₂₆H₂₄NO₃ [M+H]⁺ 398.1751, found 398.1753.

  5-(4-Methoxybenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4fa'): White solid (29% yield), m.p. 205~207 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74~7.68 (m, 2H), 7.50 (d, J＝6.9 Hz, 1H), 7.45~7.39 (m, 1H), 7.38~7.32 (m, 1H), 7.32~7.26 (m, 2H), 7.25~7.21 (m, 2H), 7.11 (dd, J＝11.0, 4.0 Hz, 1H), 6.85 (d, J＝7.8 Hz, 1H), 6.68~6.60 (m, 2H), 5.93 (d, J＝8.2 Hz, 1H), 4.34 (q, J＝8.3 Hz, 1H), 3.68 (s, 3H), 3.23 (s, 3H), 3.02 (dd, J＝13.0, 8.4 Hz, 1H), 2.68 (dd, J＝13.0, 8.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.1, 174.7, 158.5, 143.5, 136.5, 132.7, 131.5, 130.5, 129.98, 129.7, 128.4, 128.2, 123.3, 122.98, 113.6, 108.6, 85.3, 83.5, 55.2, 48.3, 42.2, 26.5; HRMS (ESI) calcd for C₂₆H₂₄NO₄ [M+H]⁺ 414.1700, found 414.1701.

  5-(3-Bromobenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ga'): White solid (42% yield), m.p. 219~221 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77~7.72 (m, 1H), 7.67 (d, J＝7.8 Hz, 1H), 7.55~7.47 (m, 2H), 7.39~7.33 (m, 1H), 7.32~7.27 (m, 2H), 7.19~7.06 (m, 5H), 6.86 (d, J＝7.8 Hz, 1H), 5.88 (d, J＝8.3 Hz, 1H), 4.45~4.32 (m, 1H), 3.23 (s, 3H), 3.08 (dt, J＝13.0, 6.5 Hz, 1H), 2.66 (dd, J＝12.9, 8.1 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 194.9, 174.7, 143.4, 138.2, 137.9, 135.5, 131.4, 131.2, 130.1, 129.7, 128.5, 128.4, 127.3, 127.0, 123.3, 123.1, 122.4, 108.7, 85.1, 83.8, 48.9, 41.4, 26.5; HRMS (ESI) calcd for C₂₅H₂₁BrNO₃ [M+H]⁺ 462.0699, found 462.0700.

  5-(3-Methoxybenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ha'): White solid (37% yield), m.p. 170~172 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.53~7.47 (m, 1H), 7.40~7.28 (m, 4H), 7.25~7.04 (m, 6H), 7.03~6.93 (m, 1H), 6.91~6.78 (m, 1H), 5.84 (dd, J＝87.2, 8.9 Hz, 1H), 4.44~4.23 (m, 1H), 3.74 (d, J＝6.7 Hz, 3H), 3.23 (s, 3H), 3.09 (dd, J＝12.9, 8.7 Hz, 1H), 2.69 (dd, J＝12.9, 8.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.8, 174.7, 159.4, 143.5, 138.5, 137.9, 131.4, 130.0, 129.1, 128.8, 128.7, 128.2, 127.0, 123.3, 123.0, 120.9, 119.6, 112.4, 108.7, 85.2, 83.6, 55.4, 48.99, 41.8, 26.5; HRMS (ESI) calcd for C₂₆H₂₄NO₄ [M+H]⁺ 414.1700, found 414.1701.

  5-(2-Methoxybenzoyl)-1'-methyl-4-phenyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (4ia'): White solid (29% yield), m.p. 158~160 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.47 (d, J＝7.1 Hz, 1H), 7.38~7.23 (m, 4H), 7.15~6.99 (m, 5H), 6.89~6.76 (m, 2H), 6.76~6.68 (m, 1H), 6.16 (d, J＝8.2 Hz, 1H), 4.27 (q, J＝8.2 Hz, 1H), 3.90 (d, J＝8.9 Hz, 3H), 3.23 (s, 3H), 2.94 (dd, J＝13.0, 7.9 Hz, 1H), 2.67 (dd, J＝13.0, 8.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.9, 174.7, 157.3, 143.6, 139.9, 133.3, 131.8, 130.8, 129.8, 128.5, 128.0, 127.2, 126.8, 123.3, 122.8, 120.8, 110.8, 108.6, 88.1, 82.8, 55.7, 47.8, 42.9, 26.4; HRMS (ESI) calcd for C₂₆H₂₄NO₄ [M+H]⁺ 414.1700, found 414.1701.

  3.3   General procedure for the synthesis of 5'

  Hydroxylamine hydrochloride (106 mg, 1.5 mmol) and sodium acetate (100 mg, 1.2 mmol) were added to a solution of 4al' (92 mg, 0.20 mmol) in methanol (5 mL). Then, the reaction mixture was refluxed in a heating mantle for 10 h. After cooling to room temperature, water (3 mL) was added to quench the reaction. The solution was extracted with CH₂Cl₂ (10 mL×3). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude reaction mixture was purified via column chromatography on silica gel to afford pure product 5' as colorless solid in 96% yield.

  4-(4-Bromophenyl)-5-((E)-(hydroxyimino)(phenyl)me-thyl)-1'-methyl-4, 5-dihydro-3H-spiro[furan-2, 3'-indolin]-2'-one (5'): White solid (96% yield), m.p. 183~184 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (s, 1H), 7.65 (d, J＝7.2 Hz, 1H), 7.52 (d, J＝8.5 Hz, 2H), 7.41~7.36 (m, 3H), 7.26~7.22 (m, 1H), 7.17~7.11 (m, 5H), 7.07 (d, J＝7.8 Hz, 1H), 5.92 (d, J＝7.2 Hz, 1H), 4.54~4.49 (m, 1H), 3.17 (s, 3H), 2.82 (dd, J＝13.7, 9.6 Hz, 1H), 2.58 (dd, J＝13.7, 4.7 Hz, 1H), 2.03~1.96 (m, 1H); ¹³C NMR (101 MHz, DMSO) δ: 174.8, 156.4, 143.5, 141.7, 134.5, 131.95, 131.5, 130.8, 130.3, 130.1, 129.0, 128.6, 127.6, 124.3, 123.5, 120.2, 109.6, 82.6, 81.4, 46.5, 41.96, 26.7; HRMS (ESI) calcd for C₂₅H₂₂BrN₂O₃ [M+H]⁺ 477.0808, found 477.0809.

  Supporting information     ¹H NMR and ¹³C NMR spectra of 4' and 5'. The Supporting Information is available free of charge via the internet at http://sioc-journal.cn/.

  (Li, L.; Fan, Y.)

  
  
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• 

  Scheme1  Construction of tetrahydrofuran spirooxindoles

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  Scheme2  Derivatization of product 4al'

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  Figure 1  X-ray structure of compound 5'

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  Table 1.  Optimization of the reaction conditions^a

  Entry	Catalyst	x/mol%	Solvent	Yield/% of 3	Yield/% of 4/4' (4/4')
  1	ZnCl2	10	CH2Cl2	Trace	—
  2	FeCl3	10	CH2Cl2	NR	—
  3	Zn(OTf)2	10	CH2Cl2	NR	—
  4	Cu(OTf)2	10	CH2Cl2	NR	—
  5	La(OAc)3	10	CH2Cl2	NR	—
  6	Co(OAc)2	10	CH2Cl2	NR	—
  7	Zn(OAc)2	10	CH2Cl2	NR	—
  8	NaOH	10	CH2Cl2	45	—
  9	KOH	10	CH2Cl2	49	—
  10	CH3ONa	10	CH2Cl2	70	—
  11	ZnEt2	10	CH2Cl2	81	—
  12	NEt3	10	CH2Cl2	NR	—
  13	ZnEt2	10	THF	62	—
  14	ZnEt2	10	Toluene	64	—
  15	ZnEt2	10	Benzene	74	—
  16	ZnEt2	10	CHCl3	76	—
  17	ZnEt2	10	CH3CN	79	—
  18b	ZnEt2	5	CH2Cl2	76	—
  19c	ZnEt2	20	CH2Cl2	88	—
  20c	ZnEt2	30	CH2Cl2	88	—
  21d, e	ZnEt2	20	CH2Cl2	—	60 (32/28)
  22d, f	ZnEt2	20	CH2Cl2	—	71 (39/32)
  23d, g	ZnEt2	20	CH2Cl2	—	84 (46/38)
  a Unless otherwise noted, all the reactions were conducted with 10 mol% catalyst, 0.20 mmol of 1, and 0.21 mmol of 2 in 2 mL of solvent at 20 ℃ for 24 h. b Reaction time was 40 h. c Reaction time was 6 h. d 6 h later, acid was added at 0 ℃ and the mixture was stirred for another 1 h. e Two drops of H2SO4 was added. f 0.5 mL of HCl was added. g 0.5 mL of CF3COOH (TFA) was added.

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  Table 2.  Substrate scope of the reaction^a

  Entry	Ar1	R1	Ar2	R2	Product	Yield/% (4/4')
  1	Ph	Me	Ph	H	4aa/4aa'	84 (46/38)
  2	Ph	Et	Ph	H	4ab/4ab'	53 (22/31)
  3	Ph	Bn	Ph	H	4ac/4ac'	51 (25/26)
  4	Ph	Me	Ph	F	4ad/4ad'	86 (56/30)
  5	Ph	Me	Ph	Cl	4ae/4ae'	87 (57/30)
  6	Ph	Me	Ph	Br	4af/4af'	61 (39/22)
  7	Ph	Me	Ph	Me	4ag/4ag'	74 (44/30)
  8	Ph	Me	Ph	MeO	4ah/4ah'	76 (37/39)
  9	Ph	Me	4-O2NC6H4	H	4ai/4ai'	51 (24/27)
  10	Ph	Me	4-FC6H4	H	4aj/4aj'	77 (39/38)
  11	Ph	Me	4-ClC6H4	H	4ak/4ak'	88 (44/44)
  12	Ph	Me	4-BrC6H4	H	4al/4al'	94 (61/33)
  13	Ph	Me	4-MeC6H4	H	4am/4am'	79 (41/38)
  14	Ph	Me	4-MeOC6H4	H	4an/4an'	72 (39/33)
  15	Ph	Me	3-BrC6H4	H	4ao/4ao'	72 (49/23)
  16	Ph	Me	2-BrC6H4	H	4ap/4ap'	79 (50/29)
  17	Ph	Me	1-Naphthyl	H	4aq/4aq'	75 (37/38)
  18	Ph	Me	2-Naphthyl	H	4ar/4ar'	84 (58/26)
  19	Ph	Me	2-Furyl	H	4as/4as'	85 (43/42)
  20	4-FC6H4	Me	Ph	H	4ba/4ba'	87 (47/40)
  21	4-ClC6H4	Me	Ph	H	4ca/4ca'	92 (48/44)
  22	4-BrC6H4	Me	Ph	H	4da/4da'	94 (59/36)
  23	4-MeC6H4	Me	Ph	H	4ea/4ea'	98 (46/42)
  24	4-MeOC6H4	Me	Ph	H	4fa/4fa'	91 (62/29)
  25	3-BrC6H4	Me	Ph	H	4ga/4ga'	80 (48/42)
  26	3-MeOC6H4	Me	Ph	H	4ha/4ha'	78 (41/37)
  27	2-MeOC6H4	Me	Ph	H	4ia/4ia'	71 (42/29)
  a Unless otherwise noted, all the reactions were conducted with 20 mol% catalyst, 0.20 mmol of 1, and 0.21 mmol of 2 in 2 mL of CH2Cl2 at 20 ℃. 6 h later, 0.5 mL of TFA was dropwise added at 0 ℃.

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•