Chemo- and Diastereoselective Michael–Michael-Acetalization

Jul 31, 2017 - A novel, organobase-catalyzed and highly chemoselective Michael–Michael-acetalization cascade is presented for the efficient synthesi...
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Chemo- and Diastereoselective Michael−Michael-Acetalization Cascade for the Synthesis of 1,3-Indandione-Fused Spiro[4.5]decan Scaffolds Shu-Mei Yang,† Yi-Ling Tsai,† Ganapuram Madhusudhan Reddy, Lennart Möhlmann, and Wenwei Lin* Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, 11677 Taiwan, R.O.C. S Supporting Information *

ABSTRACT: A novel, organobase-catalyzed and highly chemoselective Michael−Michael-acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons. Following this very simple protocol, a broad range of products was obtained in good yields with excellent diastereocontrol. The role of steric factors in the acetalization step was evaluated.

D

Scheme 1. Envisaged Chemoselective Cascade for the Synthesis of Spiro[4.5]decan Indandione Scaffolds

ue to their widespread occurrence in natural products, dyes, and biologically active compounds, spirocyclic-1,3indandione derivatives are treated as structural motifs of significant synthetic importance.1−5 Despite extensive efforts made toward synthesizing spirocyclic derivatives,6−8 the efficient construction of all-carbon spiro connections involving indandione scaffolds still persists as a topic of interest for synthetic chemists.7,8 One very elegant method for synthesis of such derivatives is the application of organocatalytic tandem processes starting from readily available 2-arylidene-1,3-indandiones. These reaction sequences generally utilize the ability of 2-arylidene1,3-indandiones to act as potent Michael acceptors which will, in the case of a 1,4-addition, be transformed into 1,3-diketone nucleophiles that can participate in additional transformations.8 The development of such tandem processes using multifunctional substrates which feature both nucleophilic as well as electrophilic properties in the same molecule has nowadays become a subject of interest in synthetic chemistry because it allows an efficient and rapid synthesis of elaborated chemical structures without isolation of intermediates.9,10 However, tuning the chemoselectivity is considered as a key factor in such cascade reactions.11−13 The course of the reaction depends on not only relative reactivity of multiple active sites but also on reaction conditions which could alter the reactivity of particular sites and the stability of intermediates/products being formed. The reaction parameters and inherent functional groups have to be tailored precisely to prevent unwanted side reactions. Motivated by this challenge, we investigated the possible chemoselective synthesis of complex spiro[4.5]decan scaffolds via a base promoted Michael−Michael-acetalization cascade using o-hydroxy-bearing 2-arylidene-1,3-indandione 1 and diketone 2 as two bifunctional substrates (Scheme 1). We © 2017 American Chemical Society

thereby envisaged the subsequent formation of three new bonds (two C−C and one C−O bond) in a single reaction step with the generation of one quaternary and three tertiary stereogenic centers. However, the fact that both substrates bear a Michael acceptor unit as well as a nucleophilic site made the outcome of this proposed transformation uncertain. Previously, few related methods have been designed for the synthesis of Received: June 8, 2017 Published: July 31, 2017 9182

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

Note

The Journal of Organic Chemistry

and longer reaction time compared to those of DABCO. Therefore, DABCO was the best choice to be used as a base for further optimization. Next, different solvents were tested for their effect on the outcome of the cascade reaction (entries 8−13). Use of solvents such as DCM, xylenes, THF, and ethyl acetate gave yields slightly lower compared to those of toluene. A slight improvement in the yield of 3aa was observed when MeOH or EtOH was used as solvent (entries 12 and 13). It is worthy to mention that the rate of reaction was enhanced in polar solvents to some extent. This was a result of keto−enol tautomerism in 2a being influenced by the solvent used. It was promising to see that the reaction proceeded smoothly even under catalytic conditions without any drop in yield of 3aa, although the reaction rate was significantly affected: use of 40 mol % DABCO required 12 h (entry 14), while 10 mol % of it took 24 h to achieve full consumption of starting material 1a (entry 15). The structure and relative configuration of 3aa was established by single-crystal X-ray analysis (see Supporting Information).15 With the optimized reaction conditions in hand, we were then interested in exploring the substrate scope of this novel cascade reaction. Therefore, we first synthesized various new 2arylidene-1,3-indandione substrates 1 bearing additional substituents at meta or para positions relative to the hydroxyl group and employed them for the cascade reaction. To our delight, all of these substrates were capable of undergoing the required transformation, albeit with varied reactivities (Table 2, entries 2 to 4). Presence of an additional hydroxyl group reduced the reactivity of substrate 1b and hence required the use of stoichiometric amount of DABCO to achieve optimal yield of the product (entry 2). In contrast, a methoxy substituent in the same position (entry 3) did not have a major influence on its reactivity, and the reaction rate was slightly lowered compared to that of unsubstituted substrate 1a. However, presence of the methoxy group at the meta position relative to existing hydroxyl group revealed a distinct steric effect, resulting in reduced reactivity and required the use of stoichiometric amount of DABCO to achieve optimal conversion (entry 4). We next tested the scope of various bifunctional substrates 2 featuring different R4 and R5 groups. Presence of an electrondonating (Table 2, entry 6) or electron-withdrawing group on the para, meta, or ortho position of the aryl group of R4 substitution (entries 7−10) resulted in corresponding products in varied reaction times. Next, the effect of varying R5 substitutions on the reaction outcome was investigated. In addition to aromatic substituents (entries 11−16), even the heteroaromatic thienyl group (entry 17) was tolerated well and resulted in the product in good yield. However, presence of an ortho substitution on aryl group of R5 (2h and 2k) resulted in double Michael addition products 4ah and 4ak,15 respectively, without further acetalization (entries 12 and 15). Likewise, even the presence of an aliphatic i-propyl substitution on R5 resulted in double Michael addition product 4an15 (entry 18), which indicated that steric factors played an important role in the acetalization step. In these three cases, double Michael addition adduct 4 existed in enolic form to reduce the steric repulsions between the arylidene group on indandione and the acyl group, thereby leaving no possibility for further acetalization. To test the significance of o-hydroxy group in initial Michael addition steps, we carried out a reaction using alkylidene indandione with hydroxy group masked (1f). The expected

indandione-fused spirocyclohexanones either via the L-prolinecatalyzed Knoevenagel/Diels−Alder/epimerization sequence of aldehydes, 1,3-indandione, and methyl vinyl ketones7f,g or the double Michael addition of 2-arylidene indandiones and curcumins.8j However, presence of an additional o-hydroxyl functionality on arylidene indandione makes the present work more challenging as it could assist in further acetalization of the initially formed cyclohexanone adducts, resulting in complex spiro[4.5]decan scaffolds. We started our investigations using 1a and 2a14 as model substrates in the presence of 1 equiv of cyclopentylamine with toluene as solvent to mimic the conditions that we used in our earlier report (Table 1, entry 1).8a However, the reaction did Table 1. Optimization of Reaction Conditionsa

entry

base

solvent

time (h)b

yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e

CpNH2 DABCO Et3N NMM DBU piperidine Na2CO3 DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO

toluene toluene toluene toluene toluene toluene toluene DCM xylenes THF EtOAc MeOH EtOH MeOH MeOH

12 12 36 12 48 48 48 3 6 7 2 2 2 12 24

0 80 55 73 0 0 71 75 71 74 76 82 82 82 82

a Unless otherwise specified, all reactions were carried out using 1a (0.1 mmol), 2a (1.1 equiv), and base (1.0 equiv) in the indicated solvent (0.5 mL) at 30 °C. bReaction time indicates the time after which no further increase in the yield of 3aa was observed. cYield of 3aa as determined by 1H NMR analysis of the crude reaction mixture using Ph3CH as internal standard. d40 mol % DABCO was used. e10 mol % DABCO was used. CpNH2 = cyclopentylamine. NMM = Nmethylmorpholine.

not proceed, and 2a was completely recovered, while 1a decomposed in the reaction. When DABCO was used, the reaction proceeded smoothly, and spiro adduct 3aa was isolated in 80% yield (entry 2) remarkably as a single diastereomer. After this promising result, further screening was performed to find optimal reaction conditions for better results. At first, other bases were tested (entries 3−7). Using the tertiary amines such as Et3N or N-methylmorpholine instead of DABCO led to reduced yields of the product (entry 3 and 4). Surprisingly, use of DBU as a base resulted in complete decomposition of substrate 1a without the formation of product (entry 5). When a secondary amine such as piperidine was used, reaction did not proceed, and starting materials were recovered after 48 h (entry 6). Interestingly, an inorganic base such as Na2CO3 could also promote the reaction (entry 7), albeit resulting in lower yield 9183

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

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The Journal of Organic Chemistry Table 2. Substrate Scope for the Cascade Reactiona

entry

R1/R2/R3

R4/R5

time (h)

yield (%)b

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

H/H/H (1a) H/H/OH (1b) H/H/OMe (1c) H/OMe/H (1d) H/H/Br (1e) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a) H/H/H (1a)

Ph/Ph (2a) Ph/Ph (2a) Ph/Ph (2a) Ph/Ph (2a) Ph/Ph (2a) p-OMePh/Ph (2b) p-BrPh/Ph (2c) p-ClPh/Ph (2d) m-ClPh/Ph (2e) o-ClPh/Ph (2f) Ph/p-BrPh (2g) Ph/o-BrPh (2h) Ph/p-ClPh (2i) Ph/m-ClPh (2j) Ph/o-ClPh (2k) Ph/p-OMePh (2l) Ph/thienyl (2m) Ph/i-Pr (2n)

24 24 36 27 24 75.5 96 24.5 24 24 24.5 24.5 27 24.5 24.5 48 24 24

82 (3aa) 82 (3ba) 77 (3ca) 83 (3da) 82 (3ea) 72 (3ab) 72 (3ac) 67 (3ad) 72 (3ae) 72 (3af) 78 (3ag) 76 (4ah)d 82 (3ai) 73 (3aj) 77 (4ak)d 84 (3al) 71 (3am) 58 (4an)d

a

Unless otherwise specified, all the reactions were carried out using 1 (0.1 mmol), 2 (1.1 equiv), and DABCO (10 mol %) in MeOH (0.5 mL) at 30 °C. bIsolated yields. c1.0 equiv of DABCO was used. dDouble Michael addition product 4 was obtained (dr >20:1).

double Michael addition product 4fa was obtained as a single diastereomer in good yield (Scheme 2). This indicated that the free hydroxyl group in 1 would not play any role in controlling the stereochemical outcome of initial double Michael addition.

Scheme 3. Plausible Mechanism for the Formation of 3aa

Scheme 2. Double Michael Addition of 1f and 2a

A plausible mechanism for the diastereoselective formation of 3aa is presented in Scheme 3. An initial deprotonation of 2a by base would result in the enolate which would undergo Michael addition onto 1a, furnishing the intermediate I. This would subsequently result in a second Michael addition generating the intermediate II. In case of 4ah, 4ak, and 4an, intermediate II was found to be stable in the enolic form15 to minimize the steric repulsions between the adjacent aryl and acyl groups, and the reaction terminated at this stage. However, in other cases, intermediate II would transform into the more stable conformation III which, upon proton transfer, acetalization, and protonation, would result in the cascade product 3.

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CONCLUSIONS In conclusion, we developed a new Michael−Michaelacetalization cascade for the diastereoselective synthesis of highly functionalized spiro[4.5]decan scaffolds by the simultaneous formation of two C−C and one C−O bond and generation of four stereocenters. The reaction is found to be highly chemo- and diastereoselective, and formation of any 9184

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

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The Journal of Organic Chemistry

136.3, 136.2, 128.4, 124.9, 123.8, 123.7, 121.6, 117.8, 116.6, 56.1; IR (KBr) ν̃ (cm−1): 3299 (m), 3125 (w), 2959 (w), 1719 (m), 1671 (s), 1581 (s), 1498 (m), 1168 (w), 816 (w), 739 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H11O4 279.0657; found: 279.0658. 2-(2-Hydroxy-4-methoxybenzylidene)-1H-indene-1,3(2H)-dione (1d). Following the general procedure A, 1d was obtained from 2hydroxy-4-methoxybenzaldehyde in 95% yield (266.3 mg) as a yellow solid. Rf: 0.13 (ethyl acetate/hexanes: 1/3); mp: 245.6−246.3 °C; 1H NMR (400 MHz, d6-DMSO) δ 11.1 (s, 1H), 9.10 (d, J = 9.0 Hz, 1H), 8.26 (s, 1H), 7.92−7.77 (m, 4H), 6.55 (d, J = 9.0 Hz, 1H), 6.50 (s, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 190.3, 189.1, 166.3, 162.9, 141.5, 139.8, 139.1, 135.4, 135.3, 135.1, 123.7, 122.53, 122.47, 114.1, 107.0, 100.2, 55.6; IR (KBr) ν̃ (cm−1): 3434 (s), 1637 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H11O4 279.0657; found: 279.0657. 2-(5-Bromo-2-hydroxybenzylidene)-1H-indene-1,3(2H)-dione (1e). Following the general procedure A, 1e was obtained from 2hydroxy-5-bromobenzaldehyde in 77% yield (253.4 mg) as a yellow solid. Rf: 0.75 (ethyl acetate/hexanes: 1/2); mp: 227.5−227.9 °C; 1H NMR (400 MHz, d6-DMSO) δ 11.2 (s, 1H), 9.10 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 8.01−7.89 (m, 4H), 7.58 (dd, J = 8.8, 2.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 189.5, 188.9, 159.0, 141.9, 139.4, 137.8, 137.8, 135.9, 135.8, 134.7, 128.2, 123.1, 123.0, 121.6, 118.2, 110.0; IR (KBr) ν̃ (cm−1): 3167 (m), 1681 (s), 1585 (m), 1392 (m), 1352 (m), 1221 (m), 812 (w), 733 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C16H8O3Br 326.9657; found: 326.9655. General Procedure B for the Synthesis of 1f.6a A mixture of 1,3-indanedione (292 mg, 2.0 mmol, 1.0 equiv), aldehyde (100 mg, 2.2 mmol, 1.1 equiv), and L-proline (70 mg, 30 mol %) in MeOH (4.0 mL) was stirred at room temperature for 12 h. The precipitate was then filtered off, sequentially washed with MeOH (10.0 mL), and dried in vacuo to afford the condensation product 1f. 2-(2-Methoxybenzylidene)-1H-indene-1,3(2H)-dione (1f). Following the general procedure B, 1f was obtained from 2-methoxybenzaldehyde in 89% yield (470.4 mg) as a yellow solid; Rf: 0.5 (ethyl acetate/hexanes: 1/5); mp: 168.2−169.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.91 (dd, J = 7.9, 1.5 Hz, 1H), 8.52 (s, 1H), 8.04−7.97 (m, 2H), 7.84−7.78 (m, 2H), 7.54 (td, J = 7.6, 1.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.5, 189.2, 160.5, 142.3, 141.3, 140.0, 135.3, 135.1, 134.9, 133.9, 128.2, 123.12, 123.10, 122.0, 120.3, 110.6, 55.7; IR (KBr) ν̃ (cm−1): 3431 (s), 1620 (m), 1239 (w), 735 (w); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13O3 265.0865; found: 265.0867. General Procedure C for the Synthesis of Starting Material 2.18 To a stirred solution of LDA (12.5 mL, 2.0 M in THF) in anhydrous THF at −78 °C under N2 atmosphere was added a solution of corresponding ketone (10.0 mmol) dissolved in THF (10.0 mL). The mixture was stirred at −78 °C for 30 min. Then the acid chloride (1.1 equiv) was added dropwise to the reaction mixture and stirred for another 30 min. Then the solution was poured into aqueous hydrochloric acid (1N). The aqueous phase was extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were washed successively with brine and water. Following drying over anhydrous MgSO4, the volatile components were removed under reduced pressure. The residue was purified by column chromatography to give the desired product 2. (1Z,4E)-1-Hydroxy-1,5-diphenylpenta-1,4-dien-3-one (2a). Following the general procedure C, 2a was obtained from benzylacetone and benzoyl chloride in 62% yield (1.550 g) as a yellow solid. Rf: 0.61 (ethyl acetate/hexanes: 1/10); mp: 110.9−111.1 °C; 1H NMR (400 MHz, CDCl3) δ 16.20 (brs, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.67 (d, J = 15.8 Hz, 1H), 7.58−7.47 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.39−7.29 (m, 3H), 6.61 (d, J = 15.8 Hz, 1H), 6.32 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 189.2, 179.4, 139.9, 136.1, 134.9, 132.5, 129.9, 128.8, 128.5, 127.9, 127.3, 123.3, 97.6; MS (70 eV, EI) m/z (%): 250 [M]+ (50), 145 (60), 115 (35), 105 (90), 103 (40), 77 (100); IR (KBr) ν̃ (cm−1): 3436 (s), 1630 (m), 1277 (w), 977 (w), 764 (m), 692 (m), 686 (m); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H15O2 251.1072; found: 251.1073.

unexpected side products was not observed in spite of the presence of multiple reactive sites. The cascade products are obtained in good yields with a broad range of substrates by using inexpensive organic base (DABCO) as a catalyst. Spiro[4.5]decan scaffolds are found to have useful biological properties, and their functionalized derivatives could prove to be useful in drug discovery.16 Studies toward developing an enantioselective format of this reaction and evaluation of bioactivity of synthesized compounds are being carried out in our laboratory, and the results will be published in due course.

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EXPERIMENTAL SECTION

General Experimental Methods. Analytical TLC was performed on precoated, alumina-backed silica gel plates (Merck 60 F254, 0.2 mm thickness) which were developed using UV irradiation at 254 nm. Flash column chromatography was performed using silica gel (SiliCycle SiliaFlash P60, 230−400 mesh). Melting points were measured on a Fargo melting point apparatus and are uncorrected. IR spectra were recorded on a PerkinElmer 500 spectrometer, and only selected peaks are mentioned. 1H NMR spectra were recorded on either a Bruker AV-400 spectrometer or a Bruker AV-III HD-400 spectrometer. Chemical shifts are reported in δ ppm referenced to an internal TMS standard (δ = 0.0 ppm) for 1H NMR and chloroform-d (δ = 77.00 ppm) for 13C NMR. The following abbreviations (or combinations thereof) were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, td = triplet of doublet, tt = triplet of triplet, qd = quartet of doublet, b = broad, p = pseudo. High resolution mass spectra were recorded on JEOL MStation JMS-700 (2) using EI (magnetic sector analyzer) or on Waters Xevo G2-S Tof using ESI (TOF analyzer). The X-ray diffraction measurements were carried out at 200 K on a Bruker KAPPA APEX II CCD area detector system equipped with a graphite monochromator and a Mo Kα fine-focus sealed tube (k = 0.71073 Å). General Procedure A for the Synthesis of Starting Material 1. A suspension of 1.1 mmol of aldehyde (finely powdered in case of solid aldehyde) in 18 mL of water was rapidly stirred at 30 °C for 15 min. Then, 1.0 mmol of finely powdered indan-1,3-dione was added in one portion. The mixture was stirred at this temperature for 16 h and then heated in an oil bath maintained at 80 °C for 4 h. The reaction mixture was then cooled and filtered. The filter cake was washed with EtOH until it was clear of any residual starting materials (determined by 1H NMR analysis) and dried under vacuum to give the pure product 1. 2-(2-Hydroxybenzylidene)-1H-indene-1,3(2H)-dione (1a).17 Following the general procedure A, 1a was obtained from 2hydroxybenzaldehyde in 83% yield (207.7 mg) as an orange solid. Mp: 198.6−199.3 °C; 1H NMR (400 MHz, CDCl3) δ 9.63 (brs, 1H), 8.11−8.01 (m, 3H), 7.93−7.81 (m, 3H), 7.49 (td, J = 7.7, 1.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H). 2-(2,5-Dihydroxybenzylidene)-1H-indene-1,3(2H)-dione (1b). Following the general procedure A, 1b was obtained from 2,5dihydroxybenzaldehyde in 42% yield (118.8 mg) as an orange solid. Rf: 0.08 (ethyl acetate/hexanes: 1/3); mp: 242.8−243.2 °C; 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 9.13 (s, 1H), 8.40 (d, J = 3.0 Hz, 1H), 8.29 (s, 1H), 8.00−7.88 (m, 4H), 6.97 (dd, J = 8.8, 3.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 190.0, 188.9, 153.7, 149.3, 141.8, 140.2, 139.3, 135.7, 135.5, 126.6, 124.7, 122.8, 120.2, 117.6, 116.6; IR (KBr) ν̃ (cm−1): 3432 (s), 1637 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C16H9O4 265.0501; found: 265.0500. 2-(2-Hydroxy-5-methoxybenzylidene)-1H-indene-1,3(2H)-dione (1c). Following the general procedure A, 1c was obtained from 2hydroxy-5-methoxybenzaldehyde in 96% yield (269.1 mg) as an orange solid. Rf: 0.23 (ethyl acetate/hexanes: 1/3); mp: 219.7−220.5 °C; 1H NMR (400 MHz, d-acetone, 25 °C) δ 9.27 (s, 1H), 8.86 (d, J = 3.1 Hz, 1H), 8.51 (s, 1H), 8.08−7.92 (m, 4H), 7.10 (dd, J = 8.9, 3.1 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, d-acetone, 25 °C) δ 190.7, 190.2, 155.2, 153.5, 143.4, 141.1, 140.9, 9185

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

Note

The Journal of Organic Chemistry (1Z,4E)-1-Hydroxy-5-(4-methoxyphenyl)-1-phenylpenta-1,4dien-3-one (2b). Following the general procedure C, 2b was obtained from (E)-4-(4-methoxyphenyl)but-3-en-2-one and benzoyl chloride in 45% yield (1.260 g) as a yellow solid. Rf: 0.46 (ethyl acetate/hexanes: 1/10); mp: 122.5−123.4 °C; 1H NMR (400 MHz, CDCl3) δ 16.30 (brs, 1H), 7.94 (dd, J = 8.5, 1.1 Hz, 2H), 7.65 (d, J = 15.8 Hz, 1H), 7.58−7.41 (m, 5H), 6.92 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 15.8 Hz, 1H), 6.31 (s, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.4, 180.5, 161.2, 139.9, 136.2, 132.3, 129.7, 128.6, 127.7, 127.2, 121.0, 114.4, 97.2, 55.3; MS (70 eV, EI) m/z (%): 280 [M]+ (30), 203 (3), 185 (10), 175 (100), 161 (30), 105 (50), 77 (52), 69 (25); IR (KBr) ν̃ (cm−1): 3448 (m), 3055 (w), 2930 (w), 1623 (s), 1601 (s), 1524 (s), 1262 (s), 822 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17O3 281.1178; found: 281.1178. (1Z,4E)-5-(4-Bromophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3one (2c). Following the general procedure C, 2c was obtained from (E)-4-(4-bromophenyl)but-3-en-2-one and benzoyl chloride in 30% yield (0.982 g) as a yellow solid. Rf: 0.73 (ethyl acetate/hexanes: 1/ 10); mp: 162.0−163.0 °C; 1H NMR (400 MHz, CDCl3) δ 16.09 (brs, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 15.8 Hz, 1H), 7.58−7.45 (m, 5H), 7.41 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H), 6.34 (s 1H); 13C NMR (100 MHz, CDCl3) δ 189.7, 178.7, 138.5, 136.2, 134.0, 132.7, 132.1, 129.3, 128.7, 127.4, 124.1, 124.0, 97.9; MS (70 eV, EI) m/z (%): 328 [M]+ (30), 330 [M+2]+ (30), 173 (20), 144 (70), 105 (100), 77 (45); IR (KBr) ν̃ (cm−1): 3448 (w), 3048 (w), 1631 (s), 1546 (s), 1402 (m), 1278 (m), 1072 (m), 822 (s); HRMS (EI-MS) m/z: [M]+ calcd for C17H13O2Br 328.0099; found: 328.0099. (1Z,4E)-5-(4-Chlorophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3one (2d). Following the general procedure C, 2d was obtained from (E)-4-(4-chlorophenyl)but-3-en-2-one and benzoyl chloride in 41% yield (1.171 g) as a yellow solid. Rf: 0.73 (ethyl acetate/hexanes: 1/ 10); mp: 157.8−158.5 °C; 1H NMR (400 MHz, CDCl3) δ 16.09 (brs, 1H), 7.95 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 15.8 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.53−7.46 (m, 4H), 7.37 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H), 6.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 189.6, 178.8, 138.5, 136.2, 135.8, 133.6, 132.7, 129.2, 129.1, 128.7, 127.4, 123.9, 97.9; MS (70 eV, EI) m/z (%): 284 [M]+ (50), 286 [M]+ (25),179 (50), 165 (52), 144 (40), 105 (100), 77 (50), 69 (46); IR (KBr) ν̃ (cm−1): 3449 (s), 3048 (w), 1635 (s), 1587 (s), 1274 (m), 1083 (m), 758 (m); HRMS (ESI-TOF) m/z: [M − H]+ calcd for C17H12O2Cl 283.0526; found: 283.0520. (1Z,4E)-5-(3-Chlorophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3one (2e). Following the general procedure C, 2e was obtained from (E)-4-(3-chlorophenyl)but-3-en-2-one and benzoyl chloride in 55% yield (1.813 g) as a yellow solid. Rf: 0.65 (ethyl acetate/hexanes: 1/ 10); mp: 125.6−126.3 °C; 1H NMR (400 MHz, CDCl3) δ 16.05 (brs, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 15.8 Hz, 1H), 7.58−7.53 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.45−7.39 (m, 1H), 7.36−7.31 (m, 2H), 6.64 (d, J = 15.8 Hz, 1H), 6.35 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 190.0, 178.3, 138.1, 137.0, 136.2, 134.9, 132.7, 130.1, 129.7, 128.6, 127.5, 127.4, 126.2, 124.6, 98.0; IR (KBr) ν̃ (cm−1): 3442 (s), 1638 (m), 691 (w); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H1235ClO2 283.0526; found: 283.0527 and m/z: [M − H]− calcd for C17H1237ClO2 285.0496; found: 285.0504. (1Z,4E)-5-(2-Chlorophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3one (2f). Following the general procedure C, 2f was obtained from (E)-4-(2-chlorophenyl)but-3-en-2-one and benzoyl chloride in 11% yield (0.360 g) as a yellow solid. Rf: 0.59 (ethyl acetate/hexanes: 1/ 10); mp: 99.8−100.1 °C; 1H NMR (400 MHz, CDCl3) δ 16.03 (brs, 1H), 8.09 (d, J = 15.8 Hz, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.70−7.64 (m, 1H), 7.56 (t, J = 7.2 Hz,1H), 7.49 (t, J = 7.7 Hz, 2H), 7.46−7.41 (m, 1H), 7.33−7.27 (m, 2H), 6.65 (d, J = 15.8 Hz, 1H), 6.38 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 190.0, 178.4, 136.2, 135.6, 135.0, 133.3, 132.7, 130.6, 130.2, 128.6, 127.4, 127.0, 125.8, 97.9; IR (KBr) ν̃ (cm−1): 3460 (s), 1634 (s), 764 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H1235ClO2 283.0526; found: 283.0525 and m/z: [M − H]− calcd for C17H1237ClO2 285.0496; found: 285.0497. (1Z,4E)-1-(4-Bromophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3one (2g). Following the general procedure C, 2g was obtained from benzylacetone and 4-bromobenzoyl chloride in 41% yield (1.354 g) as

a brown colored solid. Rf: 0.63 (ethyl acetate/hexanes: 1/10); mp: 153.5−154.1 °C; 1H NMR (400 MHz, CDCl3) δ 16.08 (brs, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 15.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 7.5, 1.5 Hz, 2H), 7.47−7.37 (m, 3H), 6.67 (d, J = 15.8 Hz, 1H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 188.0, 179.8, 140.5, 135.2, 135.0, 131.9, 130.1, 128.9, 128.8, 128.1, 127.4, 123.2, 128.29, 97.4; MS (70 eV, EI) m/z (%): 328 [M]+ (30), 330 [M +2]+ (30), 251 (20), 185 (60), 145 (100), 115 (70), 77 (90); IR (KBr) ν̃ (cm−1): 3448 (m), 3055 (w), 1588 (s), 1447 (s), 1280 (m), 781 (s); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H12O2Br 327.0021; found: 327.0017. (1Z,4E)-1-(2-Bromophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3one (2h). Following the general procedure C, 2h was obtained from benzylacetone and 2-bromobenzoyl chloride in 16% yield (526.7 mg) as a yellow solid. Rf: 0.61 (ethyl acetate/hexanes: 1/10); mp: 80.6− 81.2 °C; 1H NMR (400 MHz, CDCl3) δ 15.41 (brs, 1H), 7.70 (d, J = 15.8 Hz, 1H), 7.65 (dd, J = 7.9, 0.9 Hz, 1H), 7.58−7.52 (m, 3H), 7.44−7.35 (m, 4H), 7.30 (td, J = 7.7, 1.7 Hz, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.12 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 192.4, 177.9, 140.6, 139.3, 134.9, 133.8, 131.6, 130.1, 129.7, 129.0, 128.1, 127.4, 122.7, 119.8, 102.2; IR (KBr) ν̃ (cm−1): 3698 (w), 1635 (s), 1582 (s), 660 (w); HRMS (EI-MS) m/z: [M]+ calcd for C17H1379BrO2 328.0099; found: 328.0098 and m/z: [M]+ calcd for C17H1381BrO2 330.0078; found: 330.0079. (1Z,4E)-1-(4-Chlorophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3one (2i). Following the general procedure C, 2i was obtained from benzylacetone and 4-chlorobenzoyl chloride in 40% yield (1.141 g) as a yellow solid. Rf: 0.69 (ethyl acetate/hexanes: 1/10); mp: 139.0− 139.8 °C; 1H NMR (400 MHz, CDCl3) δ 16.08 (brs, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 15.8 Hz, 1H), 7.56−7.50 (m, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.40−7.31 (m, 3H), 6.61 (d, J = 15.8 Hz, 1H), 6.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 188.0, 180.6, 140.4, 138.8, 135.0, 134.7, 130.1, 128.9, 128.7, 128.0, 123.1, 97.4; MS (70 eV, EI) m/z (%): 284 [M]+ (60), 145 (100), 131 (60), 77 (90), 69 (55); IR (KBr) ν̃ (cm−1): 3430 (w), 3048 (w), 1638 (s), 1584 (s), 1447 (s), 1278 (m), 1076 (m), 780 (s); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H12O2Cl 283.0526; found: 283.0521. (1Z,4E)-1-(3-Chlorophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3one (2j). Following the general procedure C, 2j was obtained from benzylacetone and 3-chlorobenzoyl chloride in 41% yield (1.172 g) as a yellow solid. Rf: 0.66 (ethyl acetate/hexanes: 1/10); mp: 120.1− 121.3 °C; 1H NMR (400 MHz, CDCl3) δ 16.01 (brs, 1H), 7.93 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 15.8 Hz, 1H), 7.61−7.54 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.46−7.36 (m, 4H), 6.65 (d, J = 15.8 Hz, 1H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 187.6, 179.8, 140.6, 138.0, 134.8, 132.3, 130.1, 129.8, 128.9, 128.0, 127.4, 125.3, 123.0, 97.6; IR (KBr) ν̃ (cm−1): 3609 (w), 1634 (s), 1582 (s), 766 (m); HRMS (ESI-TOF) m/z: [M − H]− calcd for C17H1235ClO2 283.0526; found: 283.0526 and m/z: [M − H]− calcd for C17H1237ClO2 285.0496; found: 285.0500. (1Z,4E)-1-(2-Chlorophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3one (2k). Following the general procedure C, 2k was obtained from benzylacetone and 2-chlorobenzoyl chloride in 40% yield (1.142 g) as a yellow solid. Rf: 0.63 (ethyl acetate/hexanes: 1/10); mp: 74.5−75.3 °C; 1H NMR (400 MHz, CDCl3) δ 15.55 (s, 1H), 7.70 (d, J = 15.8 Hz, 1H), 7.62 (dd, J = 7.3, 1.9 Hz, 1H), 7.56 (dd, J = 7.8, 2.3 Hz, 2H), 7.48−7.32 (m, 6H), 6.6 (d, J = 15.8 Hz, 1H), 6.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 191.0, 178.4, 140.6, 137.1, 135.0, 131.7, 131.6, 130.7, 130.1, 130.0, 129.0, 128.1, 127.0, 122.9, 102.4; IR (KBr) ν̃ (cm−1): 3696 (w), 1634 (s), 1580 (s), 766 (m); HRMS (EI-MS) m/z: [M]+ calcd for C17H1335ClO2 284.0604; found: 284.0605 and m/z: [M]+ calcd for C17H1337ClO2 286.0575; found: 286.0586. (1Z,4E)-1-Hydroxy-1-(4-methoxyphenyl)-5-phenylpenta-1,4dien-3-one (2l). Following the general procedure C, 2l was obtained from benzylacetone and 4-methoxybenzoyl chloride in 43% yield (1.211 g) as a yellow solid. Rf: 0.39 (ethyl acetate/hexanes: 1/10); mp: 120.0−120.9 °C; 1H NMR (400 MHz, CDCl3) δ 16.23 (brs, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 15.8 Hz, 1H), 7.58 (d, J = 6.7 Hz, 2H), 7.48−7.35 (m, 3H) 6.99 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 15.8 Hz, 1H), 6.31 (s, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 9186

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

Note

The Journal of Organic Chemistry

199.0, 151.0, 150.6, 142.5, 141.5, 139.4, 137.3, 136.9, 133.9, 129.8, 129.6, 129.0, 128.8, 128.1, 124.0, 123.8, 118.5, 118.1, 117.4, 116.2, 99.0, 61.5, 45.4, 45.0, 43.9, 42.2; IR (KBr) ν̃ (cm−1): 3398 (s), 2930 (w), 1699 (s), 1219 (s), 1051 (w), 707 (m), 492 (w); HRMS (ESITOF) m/z: [M + Na]+ calcd for C33H24O6Na 539.1471; found: 539.1476. 11-Benzoyl-2-hydroxy-8-methoxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ca). Following the general procedure D, 3ca was obtained from 1c and 2a in 77% yield (40.8 mg) as a yellow solid. Rf: 0.13 (ethyl acetate/ hexanes: 1/3); mp: 195.7−196.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.5 Hz, 1H), 7.77−7.68 (m, 3H), 7.57 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.02−6.96 (m, 6H), 6.87 (dd, J = 8.8, 2.9 Hz, 1H), 5.85 (d, J = 2.9 Hz, 1H), 5.37−5.16 (m, 2H), 3.65−3.58 (m, 4H), 3.29 (d, J = 2.2 Hz, 1H), 3.20 (t, J = 13.7 Hz, 1H), 2.42 (dd, J = 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.4, 200.6, 197.9, 152.4, 150.5, 141.4, 140.4, 137.7, 136.1, 135.8, 135.7, 133.2, 128.9, 128.8, 128.2, 127.9, 127.3, 123.3, 123.1, 116.8, 116.2, 115.9, 115.6, 98.7, 60.5, 55.7, 45.1, 44.7, 41.6, 41.3; IR (KBr) ν̃ (cm−1): 3458 (s), 2932 (w), 1686 (m), 1222 (m), 1052 (w), 699 (w), 494 (w); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H26O6Na 553.1627; found: 553.1626. 11-Benzoyl-2-hydroxy-9-methoxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3da). Following the general procedure D, 3da was obtained from 1d and 2a in 83% yield (44.0 mg) as a brown solid; Rf: 0.2 (ethyl acetate/ hexanes: 1/3); mp: 203.3−204.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.4 Hz, 1H), 7.79−7.67 (m, 3H), 7.56 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.05−6.94 (m, 5H), 6.60 (d, J = 2.4 Hz, 1H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 5.34 (brs, 1H), 5.19 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.29 (t, J = 2.2 Hz, 1H), 2.42 (d, J = 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.4, 200.6, 197.9, 152.4, 150.5, 141.4, 140.4, 137.7, 136.1, 135.8, 135.7, 133.2, 128.9, 128.8, 128.2, 127.9, 127.3, 123.2, 123.1, 116.8, 116.2, 115.9, 115.6, 98.7, 60.5, 55.7, 45.0, 44.7, 41.6; IR (KBr) ν̃ (cm−1): 3465 (s), 2930 (w), 1696 (s), 1619 (s), 1197 (m), 1108 (m), 1036 (m), 700 (m), 576 (m), 500 (w); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H26O6Na 553.1627; found: 553.1622. 11-Benzoyl-8-bromo-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ea). Following the general procedure D, 3ea was obtained from 1e and 2a in 82% yield (47.5 mg) as a white solid; Rf: 0.75 (ethyl acetate/ hexanes: 1/2); mp: 230.6−231.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.9 Hz, 1H), 7.78−7.66 (m, 3H), 7.59 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 3H), 7.03−6.90 (m, 6H), 6.47 (s, 1H), 5.30 (s, 1H), 5.25 (s, 1H), 3.54 (dd, J = 13.6, 3.9 Hz, 1H), 3.31 (s, 1H), 3.20 (t, J = 13.8 Hz, 1H), 2.43 (dd, J = 13.8, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ203.2, 200.3, 197.8, 155.4, 141.3, 140.4, 137.2, 136.3, 135.9, 135.3, 133.5, 132.91, 132.87, 128.9, 128.8, 128.3, 128.0, 127.5, 123.4, 123.1, 118.4, 117.7, 111.5, 99.1, 60.1, 44.6, 43.9, 41.4, 41.3; IR (KBr) ν̃ (cm−1): 3482 (m), 1698 (s), 1668 (m), 1265 (m), 1237 (m), 704 (m), 593 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23O5BrNa 601.0627; found: 601.0621. 11-Benzoyl-2-hydroxy-4-(4-methoxyphenyl)-2,3,4,6tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′dione (3ab). Following the general procedure D, 3ab was obtained from 1a and 2b in 72% yield (38.2 mg) as a yellow solid. Rf: 0.33 (ethyl acetate/hexanes: 1/3); mp: 210.7−211.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 1H), 7.80−7.68 (m, 3H), 7.55 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.37−7.26 (m, 3H), 7.04 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 8.7 Hz,2H), 6.74 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 8.7 Hz, 2H), 6.31 (dd, J = 7.6, 1.0 Hz, 1H), 5.30 (s, 1H), 5.22 (d, J = 2.4 Hz, 1H), 3.61 (s, 3H), 3.54 (dd, J = 13.7, 4.6 Hz, 1H), 3.31 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.41 (dd, J = 13.7, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.5, 200.7, 198.2, 158.5, 156.3, 141.4, 140.5, 136.1, 135.8, 135.7, 133.2, 130.6, 130.0, 129.9, 129.7, 128.8, 127.9, 123.3, 123.1, 119.5, 116.2, 115.9, 113.6, 98.9, 60.8, 55.0, 45.0, 44.5, 41.9, 40.2; IR (KBr) ν̃ (cm−1): 3505 (s), 2932 (m), 1698 (s), 1595 (m), 1273 (s), 1253 (s), 1051 (s), 1036 (m), 752 (s),

189.2, 178.0, 163.4, 139.3, 135.3, 129.8, 129.5, 129.1, 128.9, 127.9, 123.5, 114.0, 97.2, 55.5; MS (70 eV, EI) m/z (%): 280 [M]+ (10), 135 (100), 121 (40), 103 (45), 77 (75), 69 (30); IR (KBr) ν̃ (cm−1): 3412 (s), 2959 (w), 1627 (s), 1602 (s), 1447 (m), 1260 (s), 792 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17O3 281.1178; found: 281.1180. (1Z,4E)-1-Hydroxy-5-phenyl-1-(thiophen-2-yl)penta-1,4-dien-3one (2m). Following the general procedure C, 2m was obtained from benzylacetone and 2-thiophenecarbonyl chloride in 39% yield (0.991 g) as a yellow solid. Rf: 0.48 (ethyl acetate/hexanes: 1/10); mp: 110.2−112.1 °C; 1H NMR (400 MHz, CDCl3) δ 15.34 (brs, 1H), 7.74 (d, J = 3.6 Hz, 1H), 7.66−7.59 (m, 2H), 7.54 (d, J = 6.6 Hz, 2H), 7.44−7.32 (m, 3H), 7.14 (t, J = 4.2 Hz, 1H), 6.58 (d, J = 15.8 Hz, 1H), 6.17 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 184.9, 175.5, 143.1, 139.4, 135.1, 132.9, 130.4, 129.9, 128.9, 128.3, 127.9, 122.4, 97.9; MS (70 eV, EI) m/z (%): 256 [M]+ (60), 153 (8), 145 (40), 131 (35), 111 (100), 84 (45), 77 (70), 69 (50), 51 (20); IR (KBr) ν̃ (cm−1): 3436 (m), 3077 (m), 1630 (s), 1580 (s), 1438 (s), 1281 (s), 694 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H13O2S 257.0636; found: 257.0630. (1E,4Z)-5-Hydroxy-6-methyl-1-phenylhepta-1,4-dien-3-one (2n). Following the general procedure C, 2n was obtained from benzylacetone and isobutyryl chloride in 20% yield (432.5 mg) as an orange colored sticky semisolid. Rf: 0.72 (ethyl acetate/hexanes: 1/ 10); 1H NMR (400 MHz, CDCl3) δ 15.46 (brs, 1H), 7.58 (d, J = 15.8 Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 2H), 7.40−7.30 (m, 3H), 6.49 (d, J = 15.8 Hz, 1H), 5.66 (s, 1H), 2.57 (sept, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 205.0, 177.2, 139.3, 135.0, 129.7, 128.8, 127.8, 122.9, 98.8, 38.3, 19.1; MS (70 eV, EI) m/z (%): 216 [M]+ (40), 173 (100), 155 (10), 131 (30), 91 (6), 77 (17), 69 (5); IR (KBr) ν̃ (cm−1): 3702 (w), 2969 (s), 1585 (s), 1440 (s), 1128 (s), 693 (m); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H17O2 217.1229; found: 217.1225. General Procedure D for the Synthesis of Michael−Michael Cascade Products 4 and Michael−Michael-Acetalization Cascade Products 3. To a solution of DABCO (1.1 mg, 0.01 mmol) and 2-arylideneindane-1,3-dione 1 (0.1 mmol) in 0.5 mL of methanol was added α,β-unsaturated-1,3-diketone 2 (0.11 mmol) at 30 °C, and the resulting mixture was stirred at this temperature until completion of the reaction (monitored by 1H NMR). Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the desired product 3. 11-Benzoyl-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3aa). Following the general procedure D, 3aa was obtained from 1a and 2a in 82% yield (41.0 mg) as a yellow solid. Rf: 0.18 (ethyl acetate/hexanes: 1/5); mp: 210.6−211.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.5 Hz, 1H), 7.78−7.67 (m, 3H), 7.56 (dd, J = 8.3, 1.2 Hz, 2H), 7.47 (tt, J = 7.4, 1.2 Hz, 1H), 7.37−7.27 (m, 3H), 7.07−6.93 (m, 6H), 6.74 (td, J = 7.4, 1.0 Hz, 1H), 6.31 (dd, J = 7.6, 1.5 Hz, 1H), 5.31 (1, 1H), 5.25 (d, J = 2.5 Hz, 1H), 3.59 (dd, J = 13.7, 4.6 Hz, 1H), 3.34 (d, J = 2.5 Hz, 1H), 3.22 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.4, 200.7, 198.0, 156.3, 141.4, 140.5, 137.6, 136.1, 135.8, 135.7, 133.2, 130.6, 130.1, 128.9, 128.8, 128.2, 127.9, 127.3, 123.3, 123.1, 119.6, 116.2, 115.9, 98.9, 60.6, 45.1, 44.6, 41.6, 41.2; MS (70 eV, EI) m/z (%): 500 [M]+ (15), 248 (45), 105 (100), 77 (55); IR (KBr) ν̃ (cm−1): 3474 (s), 3055 (w), 1700 (s), 1228 (s), 753 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H24O5Na 523.1521; found: 523.1517. 11-Benzoyl-2,8-dihydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ba). Following the general procedure D, 3ba was obtained from 1b and 2a in 82% yield (42.4 mg) as a brown solid; Rf: 0.58 (ethyl acetate/hexanes: 1/ 3); mp: 211.4−212.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.4 Hz, 1H), 7.79−7.67 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.04−6.94 (m, 5H), 6.92 (d, J = 8.7 Hz, 1H), 6.78 (dd, J = 8.8, 2.8 Hz, 1H), 5.82 (d, J = 2.6 Hz, 1H), 5.26 (brs, 1H), 5.88 (d, J = 1.8 Hz, 1H), 4.48 (s, 1H), 3.60 (dd, J = 13.7, 4.5 Hz, 1H), 3.26 (s, 1H), 3.19 (t, J = 13.7 Hz, 1H), 2.41 (dd, J = 13.5, 4.5 Hz, 1H); 13C NMR (125 MHz, d-acetone) δ 204.4, 199.4, 9187

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

Note

The Journal of Organic Chemistry 576 (m); HRMS (EI-MS) m/z: [M]+ calcd for C34H26O6 530.1729; found: 530.1727. 11-Benzoyl-4-(4-bromophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ac). Following the general procedure D, 3ac was obtained from 1a and 2c in 72% yield (41.7 mg) as a yellow solid. Rf: 0.2 (ethyl acetate/ hexanes: 1/5); mp: 196.9−198.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 1H), 7.84−7.73 (m, 3H), 7.54 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.37−7.26 (m, 3H), 7.15 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.28 (brs, 1H), 5.16 (d, J = 2.3 Hz, 1H), 3.54 (dd, J = 13.7, 4.5 Hz, 1H), 3.32 (d, J = 2.0 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.40 (dd, J = 13.7, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.1, 200.4, 197.7, 156.2, 141.2, 140.2, 136.8, 136.4, 136.1, 135.5, 133.3, 131.4, 130.7, 130.6, 130.2, 128.8, 127.8, 123.5, 123.3, 121.4, 119.7, 115.9, 98.6, 60.6, 44.9, 44.7, 41.5, 40.2; IR (KBr) ν̃ (cm−1): 3462 (s), 2927 (w), 1699 (s), 1597 (m), 1231 (s), 1053 (m), 754 (m), 576 (w); HRMS (EI-MS) m/z: [M]+ calcd for C33H23BrO5 578.0729; found: 578.0735. 11-Benzoyl-4-(4-chlorophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ad). Following the general procedure D, 3ad was obtained from 1a and 2d in 67% yield (35.8 mg) as a yellow solid. Rf: 0.25 (ethyl acetate/ hexanes: 1/3); mp: 206.0−207.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.4 Hz, 1H), 7.83−7.73 (m, 3H), 7.54 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.36−7.26 (m, 3H), 7.06−6.94 (m, 5H), 6.74 (t, J = 7.4 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.30 (s, 1H), 5.17 (d, J = 1.8 Hz, 1H), 3.56 (dd, J = 13.8, 4.5 Hz, 1H), 3.32 (s, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.41 (dd, J = 13.5, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.1, 200.5, 197.7, 156.2, 141.26, 141.29, 136.4, 136.3, 136.1, 135.6, 133.3, 133.2, 130.6, 130.4, 130.2, 128.8, 128.4, 127.9, 123.4, 123.3, 119.7, 116.0, 115.9, 98.7, 60.7, 45.0, 44.7, 41.6, 40.2; IR (KBr) ν̃ (cm−1): 3504 (s), 2928 (w), 1699 (s), 1270 (m), 1231 (s), 1053 (m), 746 (m), 576 (m); HRMS (EI-MS) m/z: [M]+ calcd for C33H23ClO5 534.1234; found: 534.1235. 11-Benzoyl-4-(3-chlorophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ae). Following the general procedure D, 3ae was obtained from 1a and 2e in 72% yield (38.5 mg) as a white solid. Rf: 0.13 (ethyl acetate/ hexanes: 1/5); mp: 184.2−185.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 1H), 7.74−7.65 (m, 3H), 7.55 (d, J = 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.28−7.18 (m, 3H), 7.04 (d, J = 8.6 Hz, 2H), 6.97−6.84 (m, 3H), 6.75 (t, J = 7.4 Hz, 1H), 6.31 (d, J = 7.4 Hz, 1H), 5.29 (s, 1H), 5.19 (d, J = 2.2 Hz, 1H), 3.55 (dd, J = 13.7, 4.6 Hz, 1H), 3.34 (s, 1H), 3.17 (t, J = 13.7 Hz, 1H), 2.42 (dd, J = 13.7, 4.6 Hz d, 1H); 13C NMR (125 MHz, CDCl3) δ 202.9, 200.5, 197.6, 156.2, 141.2, 140.3, 139.8, 136.4, 136.0, 135.6, 134.0, 133.3, 130.6, 130.2, 129.5, 129.2, 128.8, 127.9, 127.6, 127.1, 123.4, 123.3, 119.7, 115.9, 98.6, 60.5, 44.9, 44.6, 41.5, 40.6; IR (KBr) ν̃ (cm−1): 3448 (s), 2926 (w), 1677 (m), 1232 (m), 756 (w); HRMS (EI-MS) m/z: [M]+ calcd for C33H23ClO5 534.1234; found: 534.1230. 11-Benzoyl-4-(2-chlorophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3af). Following the general procedure D, 3af was obtained from 1a and 2f in 72% yield (38.5 mg) as a white solid. Rf: 0.28 (ethyl acetate/ hexanes: 1/3); mp: 219.3−220.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 7.7, 0.7 Hz, 1H), 7.86−7.60 (m, 1H), 7.78−7.72 (m, 2H), 7.56 (dd, J = 8.1, 1.0 Hz, 2H), 7.48 (tt, J = 7.4, 1.2 Hz, 1H), 7.37−7.26 (m, 3H), 7.21−7.13 (m, 2H), 7.07 (dd, J = 8.3, 0.7 Hz, 1H), 6.96−6.89 (m, 2H), 6.74 (dt, J = 7.4, 1.0 Hz, 1H), 6.29 (dd, J = 7.6, 1.5 Hz, 1H), 5.28−5.25 (m, 2H), 4.38 (dd, J = 13.6, 4.5 Hz, 1H), 3.35 (d, J = 2.3 Hz, 1H), 2.98 (t, J = 13.6 Hz, 1H), 2.40 (dd, J = 13.6, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 204.3, 200.7, 196.4, 156.4, 141.2, 140.6, 136.4, 136.1, 135.9, 135.6, 134.4, 133.2, 130.5, 130.3, 130.2, 128.8, 128.6, 128.3, 127.9, 126.7, 123.5, 123.3, 119.7, 115.74, 115.69, 98.5, 59.8, 45.2, 44.9, 42.6, 36.6; IR (KBr) ν̃ (cm−1): 3449 (s), 2932 (w), 1684 (s), 1228 (s), 1107 (m), 1054 (m), 754 (m), 583 (w); HRMS (EI-MS) m/z: [M]+ calcd for C33H23ClO5 534.1234; found: 534.1230.

11-(4-Bromobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′dione (3ag). Following the general procedure D, 3ag was obtained from 1a and 2g in 78% yield (45.2 mg) as a yellow solid. Rf: 0.2 (ethyl acetate/hexanes: 1/12); mp: 185.8−186.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5 Hz, 1H), 7.77−7.69 (m, 3H), 7.49−7.41 (m, 4H), 7.32−7.26 (m, 1H), 7.05−6.94 (m, 6H), 6.75 (td, J = 7.4, 1.0 Hz, 1H), 6.33 (dd, J = 7.5, 1.8 Hz, 1H), 5.36−5.01 (m, 2H), 3.61−3.54 (m, 1H), 3.27 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.43 (dd, J = 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.6, 199.6, 197.9, 156.2, 141.4, 140.4, 137.5, 136.2, 135.8, 134.4, 132.2, 130.6, 130.2, 129.4, 128.9, 128.5, 128.3, 127.4, 123.3, 123.1, 119.7, 116.0. 115.9, 98.7, 60.4, 45.1, 44.5, 41.6, 41.2; MS (70 eV, EI) m/z (%): 580 [M+1]+ (50), 578 [M−1]+ (50), 499 (2), 395 (10), 328 (98), 248 (55), 183 (100), 77 (18); IR (KBr) ν̃ (cm−1): 3464 (s), 2926 (s), 1696 (s), 1228 (m), 1050 (m), 581 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23BrO5Na 601.0627; found: 601.0624. 6′-(2-Bromobenzoyl)-5′-hydroxy-1′-(2-hydroxyphenyl)-3′phenylspiro[cyclohex[5′]ene-2′,2′-indene]-1′,3′-dione (4ah). Following the general procedure D, 4ah was obtained from 1a and 2h in 76% yield (44.0 mg) as a white solid. Rf: 0.55 (ethyl acetate/ hexanes: 1/1); mp: 177.6−179.3 °C; 1H NMR (400 MHz, d-acetone) δ 16.07 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.74 (td, J = 7.4 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.11−6.96 (m, 7H), 6.90 (t, J = 7.4 Hz, 2H), 6.41 (d, J = 7.9 Hz, 1H), 4.27 (s, 1H), 3.84 (dd, J = 12.2, 7.0 Hz, 1H), 3.51 (dd, J = 19.4, 12.2 Hz, 1H), 3.10 (dd, J = 19.4, 7.0 Hz, 1H); 13C NMR (125 MHz, d-acetone) δ 202.0, 197.7, 196.8, 185.9, 155.9, 143.6, 141.7, 140.6, 139.6, 136.4, 136.0, 132.8, 131.6, 131.0, 129.8, 129.1, 128.9, 128.2, 127.9, 127.5, 123.7, 123.4, 119.9, 114.9, 109.5; IR (KBr) ν̃ (cm−1): 3448 (s), 3033 (w), 2366 (w), 1701 (s), 1598 (s), 1253 (s), 761 (m), 573 (w); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23BrO5Na 601.0627; found: 601.0620. 11-(4-Chlorobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3ai). Following the general procedure D, 3ai was obtained from 1a and 2i in 82% yield (43.9 mg) as a white solid. Rf: 0.3 (ethyl acetate/ hexanes: 1/5); mp: 212.2−213.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.3 Hz, 1H), 7.80−7.68 (m, 3H), 7.51 (d, J = 8.6 Hz, 2H), 7.35−7.26 (m, 3H), 7.07−6.94 (m, 6H), 6.76 (t, J = 7.4 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H),5.23 (d, J = 2.2 Hz, 1H), 5.17 (brs, 1H), 3.58 (dd, J = 13.8, 4.6 Hz, 1H), 3.28 (d, J = 1.9 Hz, 1H), 3.19 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.6, 199.4, 197.9, 156.2, 141.3, 140.4, 139.8, 137.5, 136.2, 135.9, 133.9, 130.6, 130.1, 129.3, 129.2, 128.9, 128.2, 127.4, 123.3, 123.1, 119.7, 116.0, 115.9, 98.7, 60.4, 45.0, 44.5, 41.6, 41.2; IR (KBr) ν̃ (cm−1): 3468 (s), 2934 (w), 1693 (s), 1592 (m), 1401 (m), 1226 (s), 1049 (m), 753 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23ClO5Na 557.1132; found: 557.1127. 11-(3-Chlorobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3aj). Following the general procedure D, 3aj was obtained from 1a and 2j in 73% yield (42.3 mg) as a white solid. Rf: 0.38 (ethyl acetate/ hexanes: 1/3); mp: 215.4−216.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.4 Hz, 1H), 7.80−7.68 (m, 3H), 7.54 (s, 1H), 7.50−7.42 (m, 2H), 7.34−7.27 (m, 2H), 7.07−6.94 (m, 6H), 6.78 (td, J = 7.5 Hz, 1H), 6.35 (d, J = 7.4 Hz, 1H), 5.23 (d, J = 1.8 Hz, 1H), 5.07 (brs, 1H), 3.58 (dd, J = 13.7, 4.6 Hz, 1H), 3.30 (s, 1H), 3.21 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.4, 199.0, 197.8, 156.2, 141.3, 140.4, 137.6, 137.1, 136.2, 135.9, 135.2, 133.3, 130.6, 130.20, 130.15, 128.9, 128.3, 128.2, 127.4, 125.9, 123.3, 123.2, 119.8, 115.92, 115.88, 98.6, 60.6, 45.2, 44.6, 41.7, 41.0; IR (KBr) ν̃ (cm−1): 3456 (s), 3068 (w), 1702 (s), 1599 (m), 1245 (m), 1159 (m), 754 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23ClO5Na 557.1132; found: 557.1138. 6′-(2-Chlorobenzoyl)-5′-hydroxy-1′-(2-hydroxyphenyl)-3′phenylspiro[cyclohex[5′]ene-2′,2′-indene]-1′,3′-dione (4ak). Following the general procedure D, 4ak was obtained from 1a and 2k in 77% yield (41.2 mg) as a white solid. Rf: 0.55 (ethyl acetate/ hexanes: 1/1); mp: 184.7−186.0 °C; 1H NMR (400 MHz, CDCl3) δ 9188

DOI: 10.1021/acs.joc.7b01415 J. Org. Chem. 2017, 82, 9182−9190

Note

The Journal of Organic Chemistry

7.6 Hz, 1H), 7.30−7.21 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.08−6.95 (m, 8H), 6.84 (d, J = 7.4 Hz, 2H), 6.59 (d, J = 8.1 Hz, 1H), 4.39 (s, 1H), 3.68 (dd, J = 12.2, 6.5 Hz, 1H), 3.56 (dd, J = 19.1, 12.2 Hz, 1H), 3.11 (s, 3H), 3.01 (dd, J = 19.1, 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 202.1, 197.6, 195.4, 186.9, 156.2, 142.6, 140.5, 138.9, 137.4, 135.3, 134.9, 130.4, 129.3, 129.2, 129.0, 128.8, 128.2, 127.5, 127.1, 126.1, 123.2, 122.3, 120.4, 109.6, 107.5, 59.2, 53.9, 39.7, 38.8, 36.3; IR (KBr) ν̃ (cm−1): 3426 (s), 1703 (w), 1629 (w), 1242 (w), 700 (w); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H27O5 515.1858; found:515.1857.

15.9 (brs, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.13−6.95 (m, 9H), 6.79 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 6.17 (s, 1H), 4.20 (s, 1H), 4.02 (s, 1H), 3.72 (dd, J = 12.1, 6.0 Hz, 1H), 3.61 (dd, J = 19.5, 13.0 Hz, 1H), 3.01 (dd, J = 19.2, 6.1 Hz, 1H); 13C NMR (125 MHz, d-acetone) δ 206.32, 206.26, 205.9, 202.2, 197.8, 196.0, 185.8, 155.8, 143.6, 141.6, 140.5, 137.5, 136.4, 135.9, 131.4, 130.9, 129.8, 129.7, 129.0, 128.8, 128.1, 127.9, 127.0, 123.6, 123.3, 119.8, 114.9, 109.8, 59.9, 39.9, 39.2, 36.6; MS (70 eV, EI) m/z (%): 534 [M]+ (23), 395 (20), 247 (100), 139 (40); IR (KBr) ν̃ (cm−1): 3448 (s), 3063 (m), 1702 (s), 1598 (s), 1458 (m), 1255 (s), 1092 (m), 756 (s), 703 (s); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C33H23ClO5Na 557.1132; found: 557.1127. 2-Hydroxy-11-(4-methoxybenzoyl)-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3al). Following the general procedure D, 3al was obtained from 1a and 2l in 84% yield (44.6 mg) as a yellow solid. Rf: 0.15 (ethyl acetate/ hexanes: 1/2); mp: 219.4−220.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.4 Hz, 1H), 7.78−7.67 (m, 3H), 7.59 (d, J = 8.8 Hz, 2H), 7.31−7.26 (m, 1H), 7.05−6.94(m, 6H), 6.81(d, J = 8.8 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 5.27 (s, 1H), 5.21 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.59 (dd, J = 13.6, 4.6 Hz, 1H), 3.36 (d, J = 1.8 Hz, 1H), 3.20 (t, J = 13.7 Hz, 1H), 2.43 (dd, J = 13.6, 4.6 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 203.4, 198.6, 198.0, 163.7, 156.3, 141.4, 140.5, 137.7, 136.1, 135.7, 130.6, 130.4, 130.0, 128.9, 128.3, 128.2, 127.3, 123.3, 123.1, 119.5, 116.3, 115.8, 114.0, 98.8, 60.8, 55.4, 45.0, 44.6, 41.6, 41.1; MS (70 eV, EI) m/z (%): 530 [M]+ (35), 395 (17), 135 (100); IR (KBr) ν̃ (cm−1): 3448 (s), 2926 (w), 1702 (s), 1601 (s), 1266 (s), 1180 (s), 1081 (m), 762 (m), 606(w); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C34H26O6Na 553.1627; found: 553.1630. 2-Hydroxy-4-phenyl-11-(thiophene-2-carbonyl)-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2′-indene]-1′,3′-dione (3am). Following the general procedure D, 3am was obtained from 1a and 2m in 71% yield (36.0 mg) as a white solid. Rf: 0.1 (ethyl acetate/ hexanes: 1/5); mp: 232.6−233.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 1H), 7.81−7.68 (m, 3H), 7.62−7.54 (m, 2H), 7.30 (td, J = 8.5, 1.6 Hz, 1H), 7.09−6.93 (m, 7H), 6.80 (td, J = 7.3, 1.0 Hz, 1H), 6.47 (dd, J = 7.5, 1.3 Hz, 1H), 5.22 (d, J = 2.4 Hz, 1H), 3.60 (dd, J = 13.7, 4.6 Hz, 1H), 3.53 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.42 (dd, J = 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 203.4, 197.9, 191.5, 156.1, 142.2, 141.3, 140.4, 137.6, 136.2, 135.8, 134.6, 132.6, 130.7, 130.1, 129.0, 128.3, 127.4, 123.3, 123.2, 119.7, 116.2, 115.8, 98.3, 60.8, 46.0, 45.6, 41.7, 41.1; MS (70 eV, EI) m/z (%): 506 [M]+ (35), 111 (100); IR (KBr) ν̃ (cm−1): 3490 (s), 2950 (w), 1699 (s), 1652 (m), 1487 (w), 1238 (s), 1050 (m), 747 (s), 579 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H22O5SNa 529.1086; found: 529.1083. 5′-Hydroxy-1′-(2-hydroxyphenyl)-6′-isobutyryl-3′-phenylspiro[cyclohex[5′]ene-2′,2′-indene]-1′,3′-dione (4an). Following the general procedure D, 4an was obtained from 1a and 2n in 58% yield (27.1 mg) as a white solid. Rf: 0.08 (ethyl acetate/hexanes: 1/5); mp: 225.7−227.4 °C; 1H NMR (400 MHz, CDCl3) δ 16.8 (brs, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 6.10 Hz, 1H), 7.64−7.56 (m, 2H), 7.24−7.16 (m, 2H), 7.06−6.95 (m, 6H), 6.66 (d, J = 7.8 Hz, 1H), 4.90 (brs, 1H), 4.53 (s, 1H), 3.67−3.63 (m, 1H), 3.47 (dd, J = 19.3, 12.4 Hz, 1H), 2.90 (dd, J = 19.3, 6.6 Hz, 1H), 2.45−2.32 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.53 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 206.0, 201.8, 199.1, 183.5, 152.9, 142.3, 140.8, 138.6, 135.4, 135.1, 130.8, 129.0, 128.8, 128.2, 127.2, 123.2, 122.8, 120.8, 115.0, 106.2, 59.2, 38.8, 38.5, 35.6, 32.9, 19.8, 18.1; IR (KBr) ν̃ (cm−1): 3403 (s), 2966 (m), 1702 (s), 1583 (s), 1459 (s), 1342 (s), 1253 (s), 1086 (m), 752 (m); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C30H26O5Na 489.1678; found: 489.1686. (1′S,3′R)-6′-Benzoyl-5′-hydroxy-1′-(2-methoxyphenyl)-3′phenylspiro[cyclohex[5′]ene-2′,2′-indene]-1′,3′-dione (4fa). Following the general procedure D, 4fa was obtained from 1f and 2a in 76% yield (39.1 mg) as a white solid. Rf: 0.25 (ethyl acetate/hexanes: 1/5); mp:191.3−192.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.54 (d, J =

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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.7b01415. Copies of 1H, 13C NMR spectra of all compounds (PDF) X-ray crystallographic data of compound 3aa (CIF) X-ray crystallographic data of compound 4ak (CIF) X-ray crystallographic data of compound 4an (CIF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +886-2-77346131; E-mail: [email protected]. ORCID

Ganapuram Madhusudhan Reddy: 0000-0002-8803-121X Wenwei Lin: 0000-0002-1121-072X Author Contributions †

S.-M.Y. and Y.-L.T. made equal contributions to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Ministry of Science and Technology of the Republic of China (MOST 104-2113-M-003-002-MY3) for financial support.

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REFERENCES

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