Synthesis of β,β-Disubstituted Indanones via the Pd-Catalyzed

Aug 24, 2017 - Under Pd catalysis with a newly synthesized electron-deficient heterocycle, 2-(4,5-dihydroimidazol-2-yl)pyrimidine (as the ligand), the...
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Synthesis of β,β-Disubstituted Indanones via the Pd-Catalyzed Tandem Conjugate Addition/Cyclization Reaction of Arylboronic Acids with α,β-Unsaturated Esters Ang Gao,† Xiu-Yan Liu,† Hao Li,† Chang-Hua Ding,*,† and Xue-Long Hou*,†,‡ †

State Key Laboratory of Organometallic Chemistry, ‡Shanghai−Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China S Supporting Information *

ABSTRACT: Under Pd catalysis with a newly synthesized electron-deficient heterocycle, 2-(4,5-dihydroimidazol-2-yl)pyrimidine (as the ligand), the reaction of α,β-unsaturated esters with arylboronic acids afforded a wide range of 3,3-disubstituted indan-1-ones bearing a quaternary carbon in high yields. Mechanistic studies revealed that the reaction involves a tandem conjugate addition/1,4-Pd shift followed by a cyclization.

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INTRODUCTION β,β-Disubstituted indanone subunits are common in many natural products such as trigoxyphin M and (−)-taiwaniaquinol (Scheme 1).1 Several protocols for the preparation of β,β-disubstituted indanone derivatives have been reported in recent years. Hayashi developed a procedure for the synthesis of β,β-disubstituted indanones by rhodium-catalyzed addition of arylzinc reagents to aryl alkynyl ketones followed by cyclization.2 Murakami’s strategy to access β,β-disubstituted indanones was a Rh-catalyzed asymmetric intramolecular addition/ring-opening reaction of borylsubstituted cyclobutanones.3 Ichikawa and co-workers used an intramolecular Heck-type reaction followed by β-fluorine elimination to prepare indanone derivatives,4 while Liu’s work utilized a Au-catalyzed oxidative cyclization of cis-substituted 3-en-1-ynes to obtain indanones.5 Gouverneur also reported a single example of the preparation of 1-indanone by the reaction of 3-methylcrotonic acid with benzene.6 In spite of these developments, new approaches to this important building block still remain to be explored. In contrast, the palladium-catalyzed Michael addition of arylboronic reagents has become an important synthetic tool for constructing carbon−carbon bonds,7 and a variety of acyclic α,β-unsaturated ketones, aldehydes, and nitroalkanes, as well as cyclic enones, are suitable substrates.8 α,β-Unsaturated esters have also been used in this type of reaction;9 however, the addition reactions are very slow, and the oxidative Heck reaction can become favored in some cases.10 During our studies on the Pd-catalyzed reactions of boronic acids with unsaturated compounds,11 the reaction of (E)-ethyl-3-phenylbut-2-enoate (1a) with phenylboronic acid (2a) was run under Pd-catalysis. Unexpectedly, 3-methyl-3-phenyl-indanone (3a) was obtained instead of the desired conjugated addition product. Due to the importance of indanones, this interesting result inspired us to study this reaction further. Herein, we would like to report the Pd-catalyzed tandem conjugate addition/cyclization reaction of arylboronic acids with α,β-unsaturated esters to prepare indanones as well as the corresponding mechanistic study. © 2017 American Chemical Society

RESULTS AND DISCUSSION Initially, the reaction of ethyl (E)-β-methylcinnamate (1a) with phenylboronic acid (2a) in the presence of Pd(OAc)2 and 1,10-phenanthroline (L1) was examined. Surprisingly, 3-methyl3-phenyl-indanone (3a) was prepared in 22% yield (entry 1, Table 1) instead of the Michael addition product. Because of the usefulness of indanones in organic synthesis, further investigations were carried out. Studies on the influence of reaction parameters revealed that performing the reaction under an oxygen atmosphere afforded a better yield of 3a (entry 2 vs entry 1, Table 1). In contrast, trace amounts of 3a were detected when the reaction was conducted under argon, indicating the importance of the presence of oxygen (data not shown). The optimum temperature for the reaction was 80 °C (entry 2 vs entries 3 and 4, Table 1). A solvent screen showed that the reaction did not proceed in THF or toluene (entries 5 and 6, Table 1), but the reaction proceeded well in polar solvents, such as DMF and N,N-dimethylacetamide (DMAc) (entries 2 and 7, Table 1). Switching the palladium source from Pd(OAc)2 to Pd(TFA)2 slightly increased the yield (entries 8 vs entry 7, Table 1). With Pd(TFA)2 as the catalyst in DMAc, the effect of the ligands on the reaction was studied. Phosphine ligands, such as dppe and BINAP, showed no catalytic activity (data not shown). Bidentate nitrogen ligands, such as 1,10-phenanthroline-5,6-dione (L2), bisoxazoline L3, pyridineoxazolines L4 and L5, and pyrimidineoxazoline L6, were also unreactive under these conditions (Scheme 2 and entries 9−13, Table 1). However, the results of the reactions using ligands L4, L5, and L6 suggested that an electron-deficient ligand might be more effective in this reaction (entries 12 vs 11; entries 13 vs 11, Table 1). Thus, a new ligand, pyrimidineimidazoline rac-L7, was designed and synthesized by replacing the oxazoline ring of ligand L6 with an imidazoline Received: June 2, 2017 Published: August 24, 2017 9988

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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The Journal of Organic Chemistry Scheme 1. Some Natural Products Bearing β,β-Disubstituted Indanone Cores

Table 1. Influence of Reaction Parameters on the Pd-Catalyzed Tandem Reaction of Ethyl (E)-βMethylcinnamate (1a) and Phenylboronic Acid (2a)a

entry

[Pd]

L

solvent

T (°C)

yield (%)b

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

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2

L1 L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L6 rac-L7 rac-L8 L9

DMF DMF DMF DMF THF toluene DMAc DMAc DMAc DMAc DMAc DMAc DMAc DMAc DMAc DMAc

80 80 60 120 80 80 80 80 80 80 80 80 80 80 80 80

22 45 36 45 NR NR 46 49 trace NR trace 10 25 68 86 40

Table 2. Substrate Scope for the Pd-Catalyzed Tandem Reaction of α,β-Unsaturated Esters 1 and Arylboronic Acids 2a

a Molar ratio 1a/2a/[Pd]/L = 100/200/5/6. bIsolated yield. cRun under aerobic conditions.

Scheme 2. Various Bidentate Nitrogen Ligands

a

Molar ratio 1/2/Pd(TFA)2/rac-L8 = 100/200/5/6, under balloon pressure of O2. bIsolated yield.

ring. Pleasingly, ligand rac-L7 significantly improved the yield of the reaction, affording indanone 3a in 68% yield (entry 14, Table 2). A further increase in yield was achieved using ligand rac-L8 with a tosyl group on the nitrogen atom, which gave 86% of 3a (entry 15, Table 1). For comparison, a lower yield was obtained using bispyrimidine L9 (entry 16, Table 1). These results indicated that the electronic properties of the ligand are important for the reaction. With the optimum conditions established, the substrate scope of this Pd-catalyzed tandem reaction was examined (Table 2). The reaction proceeded well for a variety of α,β-unsaturated

esters 1 and arylboronic acids 2, affording the corresponding β,β-disubstituted indanones in 42−95% yield. The reaction of ethyl 3-methylbut-2-enoate (1b) gave indanone 3b in 95% yield (entry 2, Table 2). The reaction tolerated the arylboronic acids 2 with either electron-donating or electron-withdrawing substituents at the para position of phenyl ring (entries 3−10, Table 2). Notably, the reaction of arylboronic acid 2h, bearing a sensitive formyl group, could be used to provide indanone 3i in 58% yield (entry 9, Table 2). The substituent at the 2-position of the phenyl ring of arylboronic acid 2j showed a limited effect on 9989

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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The Journal of Organic Chemistry the reaction (entry 11, Table 2). The cyclization step for the reaction of ester 1b and naphthalen-2-ylboronic acid (2k) occurs regioselectively at the 3-position of the naphthyl group (entry 12, Table 2). The yield of indanone decreased greatly if ethyl (E)-β-ethylcinnamate (1c) was the substrate (entry 13, Table 2). Notably, the presence of bulky groups such as isopropyl or cyclohexyl at the β-position of α,β-unsaturated esters 1 had a little influence on the reaction (entries 14 and 16, Table 2). Changing the R3 ester group of acrylate also had little effect on the reaction (entries 17 and 18 vs entry 2, Table 2). The ring formation could be occurring on either of the aryl rings in the cyclization step of the reaction of β-alkyl-β-aryl-α,βunsaturated esters with arylboronic acids. Two control experiments were performed to determine which aryl ring is involved in the cyclization step (eqs 1 and 2). The reaction of ethyl

3b and d4-3b were produced in a ratio of 1/1, and a 52% loss of deuterium at the 4-position of d4-3b was observed (eq 5). These results were consistent with eqs 3 and 4. Furthermore, ester 1i bearing an aryl group reacted with PhB(OD)2 2a-D to give a mixture of 3q-D and 3q′-D in 47% yield in a ratio of 1/2.3 (eq 6). 1H NMR spectroscopy of 3q′-D showed that 35% of the 4-position and 45% of the two o-positions of the methoxyphenyl ring were deuterated. For product 3q-D, 1H NMR spectroscopy showed that a total of 1.32 aryl protons were deuterated; deuteration should be occurring at the same position as that of 3q′-D, although the position could not be assigned. The above results provided further support of a reversible 1,4-palladium migration (vide inf ra).12 The ethyl 3-methyl-3-phenylbutanoate, a possible conjugate addition product of PhB(OH)2 to ester 1b, was subjected to the standard reaction conditions (eq 7).13 No indanone 3b was observed,

(E)-β-methylcinnamate (1a) and (4-methoxyphenyl)boronic acid (2c) gave the mixture of 3q and 3q′ in a ratio of 2.7/1 (eq 1). In contrast, the reaction of ester 1i with phenylboronic acid (2a) afforded the mixture of 3q and 3q′ in a ratio of 1/2.7 (eq 2). These results indicate that cyclization mainly occurred on the aryl ring of the boronic acid, and no common intermediate was involved in this step. Some experiments were carried out using deuterium-labeled phenylboronic acid (2a) to gain insight into the plausible reaction mechanism. Treatment of PhB(OD)2 2a-D with the ester 1b in the presence of Pd(TFA)2/rac-L8 gave the deuterated indanone 3b-D in 95% yield (eq 3). 1H NMR spectroscopy of 3b-D showed that 40% of the α-position of the carbonyl group and 40% of the 4-position were deuterated. The deuteration at the 4-position of the indanone was unexpected and was proposed to be produced through a reversible 1,4-palladium migration (vide inf ra).12 The employment of phenyl deuterated boronic acid d5-2a led to indanone d4-3b, in which there was 15% deuteration at the α-position of the carbonyl group and 47% deuterium incorporation at the 4-position (eq 4). In addition, boronic acid d5-2a was recovered in 20% yield without loss of deuterium. A competitive reaction was performed using equivalent amounts of boronic acid 2a and d5-2a; indanones

which suggests the indanone was not produced from the conjugate addition product. Based on the above observations and literature precedent, a plausible reaction mechanism was proposed (Scheme 3). The transmetalation of the Pd catalyst and phenylboronic acid generate Ph-Pd-Ln species A, which undergoes conjugate addition to α,β-unsaturated ester 1 to form intermediate B. A 1,4-palladium migration in B produces the aryl palladium intermediate C.12 Intramolecular cyclization of intermediate C provides indanone 3 as the final product, it is worth noting that the reaction may proceed through a Pd(II) catalysis, but the presence of O2 should be important. It seems that the role of O2 should oxidize the Pd(0) species formed in some side 9990

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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at 400 MHz. Chemical shifts for 1H NMR are reported in parts per million with the solvent resonance as the internal standard (7.26 ppm for CHCl3). The data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sep = septet, bs = broad singlet, m = multiplet), coupling constants (Hz), and integration. 13C NMR spectra were recorded on an NMR instrument operating at 100 MHz with complete proton decoupling. Chemical shifts were reported in parts per million with the solvent resonance as the internal standard (77.1 ppm for CDCl3). MS and HRMS were measured in EI or ESI mode, and the mass analysis mode of the HRMS was TOF. Infrared spectra were recorded from thin films of pure samples. Melting points were measured on an XT-4 micromelting point apparatus. Thin layer chromatography was performed on precoated glass-backed plates and visualized with UV light at 254 nm. Enantiomeric ratios were determined by chiral HPLC analysis in comparison with authentic racemic materials. General Experimental Procedure for the Synthesis of β,β-Disubstituted Indanones. Pd(OOCCF3) (0.01 mmol, 3.4 mg), rac-L8 (0.012 mmol, 5.5 mg), and DMAc (1.0 mL) were added to a Schlenk tube that contained a stir bar. The resulting solution was stirred for 1 h at room temperature. α,β-Unsaturated ester 1 (0.2 mmol) and arylboronic acid 2 (0.4 mmol) were then added sequentially. The reaction atmosphere was carefully exchanged with oxygen three times. Then, an oxygen balloon was installed in the reaction tube, and the mixture was stirred for 24 h at 80 °C. The reaction mixture was cooled to room temperature and ethyl acetate (15.0 mL), and water (5.0 mL) were added. The organic phase was washed with water (5.0 mL × 3) and brine (5.0 mL). The combined water phase was re-extracted with ethyl acetate (5.0 mL). The combined organic phase was dried over anhydrous Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (hexane/EA) to give β,β-disubstituted indanone 3. 3-Methyl-3-phenyl-2,3-dihydro-1H-inden-1-one (3a).15 Colorless oil, 86% yield (38.2 mg); 1H NMR (400 MHz, CDCl3): δ 1.85 (s, 3H), 2.86 (d, J = 19.0 Hz, 1H), 2.98 (d, J = 19.5 Hz, 1H), 7.17−7.23 (m, 3H), 7.26−7.31 (m, 3H), 7.40−7.45 (m, 1H), 7.58−7.62 (m, 1H), 7.77−7.81 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 28.3, 46.0, 55.8, 123.4, 125.6, 126.2, 126.4, 127.8, 128.5, 135.2, 135.8, 147.3, 162.8, 205.8; MS (EI): 207 (100), 222 (41), 178 (27), 208 (16), 115 (14). 3,3-Dimethyl-2,3-dihydro-1H-inden-1-one (3b).15 Colorless oil, 95% yield (30.4 mg); 1H NMR (400 MHz, CDCl3): δ 1.41 (s, 6H), 2.58 (s, 2H), 7.34−7.38 (m, 1H), 7.48−7.51 (m, 1H), 7.59−7.63 (m, 1H), 7.68−7.71 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 29.9, 38.5, 52.9, 123.2, 123.5, 127.3, 134.9, 135.2, 163.8, 205.8; MS (EI): 145 (100), 115 (44), 160 (42), 117 (40), 91 (20). 3,3,6-Trimethyl-2,3-dihydro-1H-inden-1-one (3c).15 Colorless oil, 85% yield (29.6 mg); 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 6H), 2.39 (s, 3H), 2.57 (s, 2H), 7.37−7.40 (m, 1H), 7.42−7.45 (m, 1H), 7.49−7.51 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 21.0, 30.0, 38.2, 53.2, 123.2 (2C), 135.4, 136.1, 137.3, 161.3, 206.0; MS (EI): 159 (100), 174 (39), 131 (35), 91 (26), 115 (26). 6-Methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (3d).16 Colorless oil, 83% yield (31.5 mg); 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 6H), 2.59 (s, 2H), 3.81 (s, 3H), 7.10 (d, J = 4.0 Hz, 1H), 7.20 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 7.38 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 30.0, 37.9, 53.4, 55.5, 104.4, 124.1, 124.3, 136.4, 156.7, 159.3, 205.6; MS (EI): 175 (100), 190 (34), 91 (23), 115 (15), 176 (12). Methyl 1,1-Dimethyl-3-oxo-2,3-dihydro-1H-indene-5-carboxylate (3e).17 Colorless oil, 70% yield (30.5 mg); 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 6H), 2.63 (s, 2H), 3.92 (s, 3H), 7.55 (dd, J = 8.1 Hz, 1H), 8.29 (dd, J = 1.6, 8.1 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 29.8, 38.9, 52.3, 53.0, 123.7, 125.0, 129.9, 135.5, 135.8, 166.2, 168.0, 204.8; MS (EI): 203 (100), 115 (38), 218 (34), 116 (20), 91 (19). 6-Fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (3f).17 Colorless oil, 75% yield (26.7 mg); 1H NMR (400 MHz, CDCl3): δ 1.41 (s, 6 H), 2.62 (s, 2 H), 7.30−7.35 (m, 2 H), 7.45−7.49 (m, 1 H); 19F NMR (376 MHz, CDCl3): δ −114.8; 13C NMR (100 MHz, CDCl3): δ 30.0, 38.2, 53.3, 108.9 (d, J = 21.7 Hz), 122.5 (d, J = 23.7 Hz), 125.1 (d, J = 8.1 Hz), 137.1 (d, J = 7.2 Hz), 159.3 (d, J = 2.1), 162.3

Scheme 3. Proposed Catalytic Cycle of the Pd-Catalyzed Tandem Reaction of α,β-Unsaturated Ester 1 and Arylboronic Acid 2a

reactions such as the homocoupling of arylboronic acids in the presence of Pd(II) species.14 During the studies of the impact of ligands on the reaction, some chiral ligands were used. A 65% ee of 3n was obtained using chiral ligand L10, while 56% ee and 63% ee were observed using ligands (R,R)-L7 and (R,R)-L8, respectively (eq 8). Thus, some other chiral ligands (L11L13) were tested.

However, lower ee percentages for 3n were observed in all cases. Methods for improving the enantioselectivity of this reaction should be investigated further.

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CONCLUSION We have developed a new Pd-catalyzed reaction of β,β-disubstituted α,β-unsaturated esters with aryl boronic acids to synthesize 1-indanone derivatives. The use of a newly synthesized electrondeficient ligand improved the efficiency of the reaction significantly. A plausible mechanism involves a tandem conjugate addition/1,4-Pd shift/intramolecular cyclization process. Investigations regarding why the cyclization step mainly occurs at the aryl ring of the boronic acid and regarding a detailed mechanism as well as optimization of the asymmetric variant of the reaction are currently underway.

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EXPERIMENTAL SECTION

General Methods. Commercially available reagents were used without further purification. Solvents were purified prior to use according to the standard methods. Column chromatography was performed on silica gel (300−400 mesh) using a forced flow of eluent. NMR spectra were recorded at room temperature on an NMR instrument operating 9991

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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The Journal of Organic Chemistry

Spiro[cyclohexane-1,1′-inden]-3′(2′H)-one (3p).20 Colorless oil, 81% yield (32.4 mg); 1H NMR (400 MHz, CDCl3): δ 1.26−1.53 (m, 5H), 1.70−1.78 (m, 5H), 2.57 (s, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 23.8, 25.5, 38.4, 43.1, 48.4, 123.4, 124.0, 127.5, 134.8, 135.5, 164.2, 206.2; MS (EI): 144 (100), 200 (38), 115 (34), 145 (33), 129 (32). 6-Methoxy-3-methyl-3-phenyl-2,3-dihydro-1H-inden-1-one (3q). Colorless oil, 56% yield mixed with 3q′ (28.2 mg); The pure sample of 3q was obtained by preparative HPLC separation. 1H NMR (400 MHz, CDCl3): δ 1.80 (s, 3H), 2.90 (dd, J = 20.0, 44.0 Hz, 2H), 3.85 (s, 3H), 7.16−7.29 (m, 8H); 13C NMR (100 MHz, CDCl3): δ 28.4, 45.4, 55.6, 56.3, 104.3, 124.6, 126.1, 126.3, 126.4, 128.4, 137.0, 147.5, 155.7, 159.6, 205.7; IR (KBr, film): 2962, 2835, 1706, 1486, 1328, 1277, 1244, 1088, 1066, 1030, 740, 699; MS (EI): 237 (100), 252 (39), 237 (18), 165 (16), 115 (9); HRMS (ESI) Calcd for C17H17O2 [M+H]+: 253.1223, found: 253.1225. 3-(4-Methoxyphenyl)-3-methyl-2,3-dihydro-1H-inden-1-one (3q′).21 Colorless oil, 56% yield mixed with 3q (28.2 mg); The pure sample of 3q′ was obtained by preparative HPLC separation. 1H NMR (400 MHz, CDCl3): δ 1.79 (s, 3H), 2.86 (dd, J = 20.0, 44.0 Hz, 2H), 3.76 (s, 3H), 6.79 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8 Hz, 2H), 7.25−7.28 (m, 1 H), 7.39 (t, J = 8.0 Hz. 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 28.5, 45.4, 55.2, 55.8, 113.7, 123.3, 125.5, 127.3, 127.7, 135.2, 135.6, 139.4, 157.9, 163.1, 206.0; MS (EI): 237 (100), 252 (39), 237 (18), 165 (15), 115 (9). Procedure for the Reaction of Ester 1b and Boronic Acid 2a-D (Eq 3). The reaction was performed according to general experimental procedure for the synthesis of β,β-disubstituted indanones using ester 1b (25.6 mg, 0.2 mmol) and boronic acid 2a-D (49.6 mg, 0.4 mmol). 3,3-Dimethyl-2,3-dihydro-1H-inden-1-one-2,4-d2 (3b-D) was obtained as a colorless oil in 95% yield (30.4 mg). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 6H), 2.57 (m, 1.6H), 7.34−7.38 (m, 1H), 7.48−7.51 (m, 0.6H), 7.59−7.63 (m, 1H), 7.68−7.71 (m, 1H); 13C NMR (100 MHz, CDCl3): δ major component: 29.9, 38.5, 52.9, 123.3, 123.5, 127.4, 134.9, 135.3, 163.8, 206.0; observable signals of the minor component: 38.4, 52.6 (t, J = 19.0 Hz), 134.8, 163.8 (t, J = 4.0 Hz), 206.0; MS (EI): 145 (36), 146 (42), 147 (20), 115 (21), 116 (17), 117 (18), 160 (C11H12O [M]+, 16), 161 (C11H11DO [M]+, 20), 162 (C11H10D2O [M]+, 7); HRMS (EI) Calcd for C11H10D2O [M]+: 162.1014, found: 162.1011. Procedure for the Reaction of Ester 1b and Boronic Acid d5-2a (Eq 4). The reaction was performed according to general experimental procedure for the synthesis of β,β-disubstituted indanones using ester 1b (25.6 mg, 0.2 mmol) and boronic acid d5-2a (50.8 mg, 0.4 mmol). 3,3-Dimethyl-2,3-dihydro-1H-inden-1one-2,4,5,6,7-d5 (d4-3b) was obtained as a colorless oil in 82% yield (26.7 mg). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 6H), 2.57, (s, 1.85H), 7.48 (s, 0.53H); 13C NMR (100 MHz, CDCl3): δ 30.0, 38.5, 52.9, 122.9 (t, J = 24.9 Hz), 123.4, 126.9 (t, J = 24.9 Hz), 134.4 (t, J = 24.2 Hz), 135.2, 163.7, 205.9; MS (EI): 149 (100), 148 (77), 118 (26), 119 (15), 120 (24), 121 (19), 163 (C11H9D3O [M]+, 33), 164 (C11H8D4O [M]+, 27), 165 (C11H7D5O [M]+, 6); HRMS (EI) Calcd for C11H7D5O [M]+: 165.1202, found: 165.1201. Procedure for the Reaction of Ester 1b, Boronic Acid 2a, and Boronic Acid d5-2a (Eq 5). The reaction was performed according to general experimental procedure for the synthesis of β,β-disubstituted indanones using ester 1b (25.6 mg, 0.2 mmol), boronic acid 2a (24.4 mg, 0.2 mmol), and boronic acid d5-2a (25.4 mg, 0.2 mmol). The mixture of 3b and d4-3b (1/1 ratio) was obtained as a colorless oil in 82% yield (26.5 mg). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 6H), 2.57 (s, 2H), 7.32−7.36 (m, 0.5H), 7.47−7.49 (m, 0.76H), 7.57−7.61 (m, 0.5H), 7.66−7.68 (m, 0.5H). Procedure for the Reaction of Ester 1i and Boronic Acid 2a-D (Eq 6). The reaction was performed according to general experimental procedure for the synthesis of β,β-disubstituted indanones using ester 1i (44.0 mg, 0.2 mmol) and boronic acid 2a-D (49.6 mg, 0.4 mmol). The mixture of 3q-D and 3q′-D (1/2.3 ratio) was obtained as a colorless oil in 47% yield (23.7 mg).

(d, J = 246.5 Hz), 204.5 (d, J = 2.9 Hz); MS (EI): 163 (100), 135 (43), 178 (35), 133 (30), 115 (27). 6-Chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (3g).15 Colorless oil, 77% yield (29.9 mg); 1H NMR (400 MHz, CDCl3): δ 1.41 (s, 6H), 2.61 (s, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.0, 2.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 29.9, 38.4, 53.0, 123.1, 124.9, 133.8, 134.9, 136.8, 161.9, 204.4; MS (EI): 179 (100), 115 (58), 116 (39), 194 (37), 181 (32). 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (3h).18 Colorless oil, 70% yield (33.5 mg); 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 6H), 2.59 (s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 4.0, 8.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 29.8, 38.5, 52.9, 121.7, 125.3, 126.3, 137.2, 137.7, 162.3, 204.3; MS (EI): 116 (100), 222 (95), 224 (88), 115 (64), 237 (33), 239 (31). 1,1-Dimethyl-3-oxo-2,3-dihydro-1H-indene-5-carbaldehyde (3i). White solid, 58% yield (21.8 mg), mp 97−98 °C; 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 6H), 2.66 (s, 2H), 7.64 (d, J = 8.0 Hz, 1H), 8.14−8.16 (m, 2H), 10.05 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.7, 39.1, 52.9, 124.5, 126.2, 134.5, 136.0, 136.0, 169.5, 191.1, 204.6; IR (KBr, film): 2961, 2932, 2850, 2748, 1696, 1607, 1163, 1121, 1100, 837, 722; MS (EI): 173 (100), 115 (50), 188 (49), 117 (37), 91 (22); HRMS (ESI) Calcd for C12H13O2 [M+H]+ = 189.0910, found 189.0911. 6-Hydroxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (3j).17 Colorless oil, 82% yield (28.9 mg); 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 6H), 2.60 (s, 2H), 7.19−7.22 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.97 (brs, 1H); 13C NMR (100 MHz, CDCl3): δ 30.0, 38.2, 53.5, 108.4, 124.4, 124.6, 136.2, 156.3, 157.7, 207.9; MS (EI): 161 (100), 176 (38), 105 (28), 133 (21), 77 (15). 3,3,4-Trimethyl-2,3-dihydro-1H-inden-1-one (3k).15 Colorless oil, 82% yield (25.8 mg); 1H NMR (400 MHz, CDCl3): δ 1.51 (s, 6H), 2.52 (s, 3H), 2.61 (s, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 19.6, 28.0, 39.9, 54.7, 121.4, 127.7, 135.4, 136.3, 137.7, 159.9, 206.3; MS (EI): 159 (100), 174 (38), 131 (36), 91 (26), 115 (22). 3,3-Dimethyl-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (3l). Colorless oil, 78% yield (32.8 mg); 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 6H), 2.70 (s, 2H), 7.47−7.60 (m, 2H), 7.88−7.99 (m, 3H), 8.28 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 30.7, 38.4, 53.7, 121.9, 124.2, 126.1, 128.0, 128.5, 130.4, 132.4, 133.5, 137.4, 157.2, 206.3; IR (KBr, film): 3055, 2957, 1711, 1628, 1602, 1240, 1162, 1128, 1089, 857, 781; MS (EI): 195 (100), 210 (50), 167 (35), 165 (30), 152 (25); HRMS (ESI) Calcd for C15H15O [M+H]+: 211.1117, found: 211.1118. 3-Ethyl-3-phenyl-2,3-dihydro-1H-inden-1-one (3m). Colorless oil, 42% yield (19.9 mg); 1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 8.0 Hz, 3H), 2.17−2.39 (m, 2H), 2.92 (d, J = 8.0 Hz, 2H), 7.18−7.34 (m, 6H), 7.42 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 9.3, 32.5, 50.3, 52.4, 123.3, 126.2, 126.4, 126.5, 127.8, 128.5, 134.9, 136.9, 146.8, 160.4, 205.9; IR (KBr, film): 2967, 1711, 1600, 1460, 1323, 758, 699; MS (EI): 207 (100), 178 (26), 208 (17), 179 (8); HRMS (ESI) Calcd for C17H17O [M+H]+: 237.1274, found: 237.1277. 3-Isopropyl-3-methyl-2,3-dihydro-1H-inden-1-one (3n).3 Colorless oil, 89% yield (33.5 mg); 1H NMR (400 MHz, CDCl3): δ 0.56 (d, J = 4.0 Hz, 3H), 0.92 (d, J = 4.0 Hz, 3H), 1.95−2.03 (m, 1H), 2.25 (d, J = 20.0 Hz, 1H), 2.69 (d, J = 20.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 18.1, 18.3, 27.3, 36.6, 45.5, 46.4, 123.2, 124.1, 127.3, 134.7, 136.2, 162.7, 206.4; MS (EI): 115 (100), 146 (91), 144 (68), 188 (36). 3-Cyclohexyl-3-methyl-2,3-dihydro-1H-inden-1-one (3o)19. Colorless oil, 75% yield (34.2 mg); 1H NMR (400 MHz, CDCl3): δ 0.71−0.88 (m, 2H), 0.97−1.28 (m, 4H), 1.40 (s, 3 H), 1.59−1.63 (m, 3H), 1.75−1.80 (m, 1H), 1.89−1.93 (m, 1H), 2.23 (d, J = 20.0 Hz, 1H), 2.71 (d, J = 20.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 26.3, 26.5, 26.7, 26.8, 27.8, 28.3, 45.4, 47.0, 47.6, 123.1, 124.2, 127.3, 134.7, 136.3, 162.7, 206.5; MS (EI): 146 (100), 131 (30), 145 (22), 115 (22), 228 (8). 9992

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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(35), 89 (33), 91 (32); HRMS (ESI) Calcd for C26H23N4O2S [M+H]+: 455.1536, found: 455.1537. Synthesis of Deuterated Phenylboronic Acid (2a-D). D2O (20 mL) was heated to 75 °C in a 50 mL round-bottomed flask. Triphenyl boroxine was added until the solution was saturated. The resulting solution was stirred at this temperature for 3 h. The solution was filtered while it was still hot. The filtrate was cooled to room temperature, and deuterated phenylboronic acid was obtained as a white solid. After filtration, the white solid was dried in an infrared drying oven under vacuum for 3 h (note: drying for a long period will lead to decomposition back to triphenyl boroxine). Deuterated phenylboronic acid (2a-D) (>90% D) containing 30 mol% triphenyl boroxine was obtained. 1H NMR (400 MHz, d6-dmso): δ 7.30−7.40 (m, 3H), 7.77−7.79 (m, 2H), 8.07 (s, 0.06H). (δ 7.87−7.89 are signals of triphenyl boroxine). Pd-Catalyzed Tandem Reaction of (E)-Ethyl 3,4-dimethylpent-2-enoate (1d) and Phenylboronic Acid (2a) Using Chiral Ligand L10. Pd(OOCCF3) (0.01 mmol, 3.4 mg), L10 (0.012 mmol, 3.3 mg), and DMAc (1.0 mL) were added to a Schlenk tube that contained a stir bar. The resulting solution was stirred for 1 h at room temperature. Then, (E)-ethyl 3,4-dimethylpent-2-enoate (1d) (31.2 mg, 0.2 mmol) and phenylboronic acid (2a) (48.8 mg, 0.4 mmol) were added sequentially. The reaction atmosphere was carefully exchanged with oxygen three times. Then, an oxygen balloon was installed in the reaction tube, and the mixture was stirred for 24 h at 80 °C. The reaction mixture was cooled to room temperature, and ethyl acetate (15.0 mL) and water (5.0 mL) were added. The organic phase was washed with water (5.0 mL × 3) and brine (5.0 mL). The combined water phase was re-extracted with ethyl acetate (5.0 mL). The combined organic phase was dried with anhydrous Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (hexane/EA = 20/1) to give 2,3-dihydro-1H-inden-1-one 3n (30.8 mg, 82% yield, 65% ee). Chiral HPLC (Chiralcel IC, 0.46 cm × 250 mm, n-hexane/2-propanol 99.4/0.6, flow rate 0.5 mL/min, UV 214 nm): tR = 36.7 min (major), 38.4 min (minor).

3q-D. The pure sample of 3q-D was obtained by preparative HPLC separation. 1H NMR (400 MHz, CD3COCD3): δ 1.83 (s, 3H), 2.88 (s, 2H), 3.89 (s, 3H), 7.14−7.31 (m, 6.68); 13C NMR (100 MHz, CDCl3): δ 28.3, 45.4, 55.6, 56.3, 104.3, 124.6, 126.1, 126.3, 126.4, 128.4, 137.0, 147.4 (t, J = 7.3 Hz), 155.7, 159.6, 205.7; observable signals of the minor component: 128.3, 155.8, 205.8; MS (EI): 237 (19), 238 (30), 239 (30), 240 (12), 252 (C17H16O2 [M]+, 6), 253 (C17H15DO2 [M]+, 10), 254 (C17H14D2O2 [M]+, 7), 255 (C17H13D3O2 [M]+, 4); HRMS (EI) Calcd for C17H16O2 [M]+: 252.1150, found: 252.1160. 3q′-D. The pure sample of 3q′-D was obtained by preparative HPLC separation. 1H NMR (400 MHz, CD3COCD3): δ 1.83 (s, 3H), 2.86 (s, 2H), 3.75 (s, 3H), 6.85 (d, J = 3.6 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1.1H), 7.37 (d, J = 7.6 Hz. 0.65H), 7.47 (t, J = 7.6 Hz, 1H), 7.65−7.69 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 28.5, 45.4, 55.2, 55.8, 113.7, 123.3, 125.5, 127.3, 127.7, 135.2, 135.7, 139.4 (t, J = 7.7 Hz), 157.9, 163.1, 206.0; observable signals of the minor component: 113.8, 127.2, 135.1, 163.0; MS (EI): 237 (45), 238 (99), 239 (100), 240 (55), 252 (C17H16O2 [M]+, 18), 253 (C17H15DO2 [M]+, 36), 254 (C17H14D2O2 [M]+, 37), 255 (C17H13D3O2 [M]+, 21); HRMS (EI) Calcd for C17H13D3O2 [M]+: 255.1339, found: 255.1332. Synthesis of Ligands (R,R)-L7 and (R,R)-L8. The ligands (R,R)-L7 and (R,R)-L8 were prepared according to methods in the literature with minor modifications.22,23 2-Cyanopyrimidine (1.32 g, 12.5 mmol) was added to a 50 mL flame-dried Schlenk flask that contained a stir bar. Then, CH3OH (25 mL) and sodium methoxide (67.5 mg, 0.1 equiv) were added at 0 °C. The resulting mixture was stirred for 10 min at 0 °C, and then the reaction mixture was stirred at room temperature for 24 h until the solution turned wine red. The volatiles were removed in vacuo to give pyrimidine-2-carboximidate as a red liquid, which was used in the next step without purification. In a flame-dried sealed tube, a mixture of the above pyrimidine-2carboximidate (571 mg, 4.0 mmol), (1R,2R)-1,2-diphenylethylenediamine (471 mg, 2.22 mmol) and CH2Cl2 (10 mL) was stirred at 50 °C for 48 h. The resulting red solution was added to 30 mL CH2Cl2 and then washed with water (10.0 mL × 3). The aqueous layers were extracted with CH2Cl2 (10.0 mL). The combined organic layers were acidified with 1 M HCl (aq.) until the solution reached a pH of 1.0. Water was added to dissolve the solid precipitate. After separation, the aqueous phase was basified with 1 M NaOH (aq.) until the pH was 14. CH2Cl2 was added to dissolve the solid precipitate. The oil layer was separated and dried with anhydrous Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (CH2Cl2/MeOH = 20:1, Rf = 0.2) to obtain 2-((4R,5R)-4,5diphenyl-4,5-dihydro-1H-imidazol-2-yl) pyrimidine (L7): white/yellow solid, 25% yield (157 mg), mp 233−234 °C (decomposed). [α]D25 = 82.74 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.10 (s, 2H), 7.32−7.37 (m, 10H), 7.43 (t, J = 4.0 Hz, 1H), 8.88 (d, J = 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 121.9, 126.8, 127.5, 128.6, 142.9, 157.1, 157.4, 161.1; IR (KBr, film): 3056, 3020, 2906, 1559, 1492, 1451, 1411, 696; MS (EI): 195 (100), 300 (43), 89 (26), 90 (19), 196 (15); HRMS (ESI) Calcd for C19H17N4 [M+H]+: 301.1448, found: 301.1451. A solution of p-toluenesulfonyl chloride (75.7 mg, 0.4 mmol) was added dropwise to a solution of (R,R)-L7 (100 mg, 0.33 mmol) and 4-(dimethylamino) pyridine (73.1 mg, 0.6 mmol) in dichloromethane (3.0 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 12 h. Evaporation of the volatile components gave a yellow solid that was purified by column chromatography on silica gel (CH2Cl2/MeOH = 20:1, Rf = 0.7) to obtain 2-((4R,5R)-4,5-diphenyl-1-tosyl-4,5-dihydro-1H-imidazol-2-yl)pyrimidine (L8): white solid, 70% yield (101 mg); mp 249−252 °C (decomposed). [α]D25 = 4.20 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 5.13−5.18 (m, 2H), 7.05−7.14 (m, 4H), 7.25−7.35 (m, 8H), 7.45 (t, J = 4.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 8.92 (d, J = 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.6, 71.5, 79.6, 121.6, 126.4, 126.6, 127.8, 128.0, 128.2, 128.8, 129.0, 129.3, 135.0, 135.4, 140.6, 140.6, 144.2, 156.4, 157.1, 159.4; IR (KBr, film): 2925, 2853, 1562, 1158, 695, 665; MS (EI): 195 (100), 300 (52), 454

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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.7b01364.

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The spectra of compounds 3a−3q, (R,R)-L7, and (R,R)-L8 (PDF)

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Xue-Long Hou: 0000-0003-4396-3184 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This article is dedicated to Professor Yang Jie Wu on the occasion of his 90th birthday. Financial support by National Natural Science Foundation of China (NSFC) (21472214, 21372242, 21532010, 21421091), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20030100), the NSFC and the Research Grants Council of Hong Kong Joint Research Scheme (21361162001), the Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong. 9993

DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994

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DOI: 10.1021/acs.joc.7b01364 J. Org. Chem. 2017, 82, 9988−9994