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Nov 21, 2017 - Michelle A. Kroc, Ami Prajapati, Donald J. Wink, and Laura L. Anderson. Department of Chemistry, University of Illinois at Chicago, Chi...
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Cascade Synthesis of 3‑Functionalized Indoles from Nitrones and Their Conversion to Cycloheptanone-Fused Indoles Michelle A. Kroc, Ami Prajapati, Donald J. Wink, and Laura L. Anderson* Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States S Supporting Information *

ABSTRACT: A cascade reaction of N-aryl-α,β-unsaturated nitrones and electron-deficient allenes has been discovered that allows single-step access to 3-functionalized indoles that usually require preformation and alkylation of an indole precursor. The heterocycles prepared through the hydrogen bond donor catalyzed cascade reaction are poised to undergo a McMurry coupling to form previously synthetically elusive cycloheptanone-fused indoles. The scope of these transformations is discussed as well as mechanistic experiments describing proposed intermediates of the cascade reaction and an initial catalytic asymmetric example that generates a carbon stereocenter during the cascade process.

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INTRODUCTION

put forth in the design of catalysts to control the regio- and stereoselectivity of this process.4,5 Recently, our group has investigated the cascade reactivity of N-aryl-α,β-unsaturated ketonitrones and electron-deficient allenes (Scheme 1B). We have discovered that these transformations provide rapid access to dihydrocarbazoles and dihydropyridoindoles and that the chemo-, regio-, diastereo-, and enantioselectivity of these transformations can be controlled by hydrogen bond donor catalysts.6 We wondered if a catalyst could be identified that would allow us to selectively isolate functionalized indole 1 and disfavor dihydrocarbazole or dihydropyridoindole formation. If successful, this strategy would enable us to divert this reactive intermediate through a McMurry coupling to form mediumring heterocycles such as 5, which are known motifs in biologically active molecules, but have not successfully been prepared through indole derivatization (Scheme 1C).7−10 While initially exploring this idea, we were delighted to observe that indole 1 could be prepared from nitrone 2 and allenoate 3a in the presence of phosphoric acid catalyst 4. Herein, we discuss the optimization and scope for the preparation of functionalized indoles 1 from N-aryl-α,β-unsaturated ketonitrones and electron-deficient allenes, mechanistic insight into the cascade process, initial catalytic asymmetric conditions, and the cyclization of these functionalized heterocycles to rapidly form cycloheptanone-fused indoles 5.

Indoles are privileged heterocyclic structures that have been used in a variety of medicinal and materials applications.1 Due to the demand for broad libraries of these compounds with many different substitution patterns, new synthetic approaches toward indoles have been widely pursued with particular emphasis on functional group compatibility and addressing the regioselectivity limitations of traditional indole preparations.2 3Substituted indoles such as 1, that are attached at the β-position of a carbonyl compound, are common scaffolds and valuable synthetic precursors of indole alkaloids (Scheme 1A).3 These compounds are often prepared by the addition of an indole precursor to a Michael acceptor, and significant effort has been Scheme 1. Cascade Reactions of Nitrones and Allenes for the Synthesis of 3-Functionalized Indoles

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RESULTS AND DISCUSSION The reaction conditions for the synthesis of indoles 1 from α,βunsaturated nitrones and electron-deficient allenes were optimized using phosphoric acid catalyst 4. These products were not observed during our previous studies with less acidic thiourea and squaramide catalysts and were only observed in Received: October 17, 2017 Published: November 21, 2017 © 2017 American Chemical Society

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Table 1. Optimization of the Phosphoric Acid Catalyzed Cascade Synthesis of 3-Functionalized Indole 1a

entry

solvent

[4] (mol %)

T (°C)

time (h)

% 1aa

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

PhMe acetone DCE THF i-PrOAc DMSO EtOH THF THF THF THF THF

10 10 10 10 10 10 10 10 10 10 10 5

25 25 25 25 25 25 25 30 60 30 30 30

18 18 18 18 18 18 18 18 18 6 12 6

30 67 65 75 66 31 40 78 39 81 (74)b 78 70

Table 2. Scope of 3-Functionalized Indole Cascade Synthesis

a

Percent of 1a in the product mixture determined by 1H NMR spectroscopy using CH2Br2 as a reference. b% yield.

the presence of more acidic phosphoric acid catalysts.6,11 As shown in Table 1, entry 1, when nitrone 2a and allenoate 3a were initially mixed with 10 mol % of 4 in toluene at 25 °C, indole 1a was formed as 30% of the product mixture. Further screening showed that the choice of solvent had a considerable effect on this transformation. The synthesis of indole 1a improved significantly when the reaction was run in acetone, DCE, THF, and i-PrOAc (Table 1, entries 2−5) but remained low to moderate in DMSO or EtOH (Table 1, entries 6 and 7). The optimal reaction medium was identified as THF, and the formation of 1a was further improved by increasing the reaction temperature to 30 °C and decreasing the reaction time to 6 h (Table 1, entries 8−11). A reduction in catalyst loading gave the desired product, as a slightly reduced proportion of the product mixture (Table 1, entry 12). The conditions in Table 1, entry 10, were determined to be optimal for the synthesis of indole 1a from 2a and 3a and were used to further investigate the scope of the new method for the single-step synthesis of indoles 1 from nitrones 2 and electron-deficient allenes 3. Having identified optimal conditions for the synthesis of 1a from nitrone 2a and allenoate 3a, we decided to further explore the scope of this transformation. As shown in Table 2, a variety of N-aryl substituents are tolerated on nitrone 2, including aryl groups with ether, thioether, vinyl, acetal, halogen, and ester substituents (entries 1−8). N-Aryl groups with electrondonating substituents gave the highest yielding transformations, and the structure of 1g was verified by X-ray diffraction.12 Both aryl and heteroaryl substituents were tolerated at the R2position of the nitrone as well as a styrenyl group (Table 2, entries 9−15). Substituents at the R1-position of the nitrone tolerated both electron-rich and electron-poor aryl groups, but electron-withdrawing functionalities gave the indole product in attenuated yield (Table 2, entries 16−18). Screening of electron-deficient allenes also showed that several different allenoates and a sulfonyl-substituted allene were tolerated for the synthesis of functionalized indoles 1 (Table 2, entries 19− 21). The breadth of these reactions spanned the range of N-

a

Conditions: 2 (1 equiv), 3 (3 equiv), 4 (10 mol %), THF (0.1 M), 30 °C, 6 h. b79% yield when run on a 1 mmol scale. c5:1 mixture of regioisomers. dR = allyl.

aryl-α,β-unsaturated nitrones accessible via the Chan−Lam coupling of arylboronic acids and oximes and describes the scope of our method for the synthesis of indoles 1.13 Initially, we proposed that the synthesis of indole 1a from nitrone 2a and allenoate 3a was proceeding through 1086

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involve a challenging cyclization using the kinetic enolate of the β-ketoester fragment of 6a and preference for 7-membered ring formation over 5-membered ring formation, this proposed pathway is more consistent with our crossover experiments than proposed mechanism A. With a variety of functionalized indoles 1 prepared in a single step from N-aryl-α,β-unsaturated nitrones 2 and allene reagents 3, we wanted to explore the cyclization of these compounds to cycloheptanone-fused indoles 5.9 To the best of our knowledge, there are no reported procedures for the preparation of these heterocycles due to the challenge in accessing this particular regioisomer through Friedel−Crafts alkylation of an indole.10 As shown in Scheme 3, we observed that indoles 1 can undergo

Scheme 2. Proposed Mechanism and Mechanistic Experiments

Scheme 3. McMurry Cyclization of 3-Functionalized Indoles 1 for the Synthesis of Cycloheptanone-Fused Indoles 5

mechanism A in Scheme 2A. This proposed pathway involves the hydrolysis of an initially formed imino β-ketoester intermediate 6a to give indole 7 and Michael acceptor 8, followed by recombination via conjugate addition to give indole 1a.14 We have previously shown that 6a can be generated from a mixture of 2a and 3a in the absence of a catalyst. Generation of 6a and subsequent treatment with catalyst 4 under the optimized reaction conditions showed conversion of this intermediate to indole 1a (Scheme 2A).6 This experiment supported our hypothesis that 6a is an intermediate on the pathway to 1a. In contrast to our initially proposed mechanism, several crossover experiments indicated that fragmentation does not occur during the conversion of 6a to 1a. When nitrones 2d and 2i were simultaneously treated with 3a and catalyst 4, only 1d and 1i were observed as products (Scheme 2B). When nitrone 2i was mixed with ketone 9 under the same reaction conditions, similarly, no crossover products were observed (Scheme 2C). In light of these experiments, we have revised our proposed reaction pathway as mechanism B (Scheme 2D). This pathway similarly begins with the formation of imino βketoester intermediate 6a, which undergoes activation of the βketoester fragment with 4 and cyclization to form benzazepine 10a. Hydrolysis of 10a is then proposed to give aniline 11a, which can undergo intramolecular nucleophilic addition and condensation to form indole 1a. While mechanism B does

a McMurry coupling to form cycloheptanone-fused indoles 5.7 This transformation was shown to be optimal using a combination of TiCl3 and KC8.7b As illustrated in Scheme 3, the reductive coupling tolerates a variety of the functionalized indoles prepared in Table 2, including acetal-, thiophene-yl-, and styrenyl-substituted examples 5e, 5k, and 5p, respectively. Low to moderate diastereoselectivity was observed for these transformations, which could be due to mild kinetic selectivity for a chairlike protonation of the initially formed enol ether (Scheme 3B).15 Because this particular regioisomer of cycloheptanone-fused indole is not amenable to synthesis by traditional methods,5,10 these compounds are understudied but are known motifs in biologically active molecules.9 Designing new methods to access these structures will allow for further studies directed at expanding our understanding of their activity. Having discovered a new efficient route to functionalized indoles 1 and cycloheptanone-fused indoles 5 through a phosphoric acid catalyzed cascade reaction, we wondered if a 1087

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tetramethylsilane on the δ scale, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. IR spectra were recorded at ambient temperature using ATR sampling. High-resolution mass spectra were acquired on an LTQ FT spectrometer with a TOF detector and were obtained by peak matching. Melting points are reported uncorrected. Analytical thin-layer chromatography was performed on 0.25 mm extra hard silica gel plates with UV254 fluorescent indicator. Mediumpressure liquid chromatography was performed using force flow of the indicated solvent system down columns packed with 60 Å (40−60 μm) mesh silica gel (SiO2). Samples purified by medium-pressure liquid chromatography were dry-loaded onto Celite. Unless otherwise noted, all reagents and solvents were obtained from commercial sources and, where appropriate, purified prior to use. Unless otherwise noted, all reactions were performed under N2 using standard Schlenk techniques. Chiral HPLC analysis was done on a high-throughput system with a Daicel Chiralpack IA-3 column and a VW detector. CH2Cl2, toluene, and THF were dried by filtration through alumina according to the procedure of Grubbs.18 Nitrones 2a−d, 2f, 2g, and 2o were prepared as previously reported.6 Allenes 3a−d were prepared as previously reported.6 Catalysts 4, R-4, R-13, and 14, as well as 4(methoxyphenyl)boronic acid, 4-(methylphenyl)boronic acid, 4methoxycarbonylphenylboronic acid, and 3,4-(methylenedioxy)phenylboronic acid, were purchased from Sigma-Aldrich and used as received. Synthesis of Indoles 1a−u. General Procedure for the Synthesis of Indoles 1a−u. A 5 mL conical vial was charged with nitrone 2 (1.0 equiv) and catalyst 4 (10 mol %) and flushed with N2 using a septum and a vent needle. A solution of allene 3 (3 equiv) in THF (3.0 mL) was added to the solids via syringe. The septum was then removed and replaced with a Teflon-lined screw cap. The closed vial was then stirred at 30 °C for 6 h. At this time, the solvent was removed from the reaction mixture under vacuum, and the crude reaction mixture was purified by medium-pressure chromatography (3:7−2:3 EtOAc/ hexanes) to give 1. Indole 1a. The general procedure for the synthesis of indole 1a was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1a as an offwhite solid (0.0945 g, 74%): 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 7.89 (d, J = 5.0 Hz, 2H), 7.52−7.50 (m, 1H), 7.41−7.34 (m, 4H), 7.28−7.25 (m, 2H), 7.18−7.16 (m, 2H), 6.91−6.89 (m, 1H), 6.78−6.76 (m, 1H), 5.09−5.07 (m, 1H), 3.97−3.83 (m, 4H), 3.74 (s, 3H), 3.71 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.9, 171.2, 153.7, 143.5, 137.1, 133.0, 131.2, 128.6, 128.4, 128.3, 128.1, 127.6, 127.3, 126.1, 115.1, 111.7, 111.0, 102.3, 56.0, 52.3, 43.2, 36.3, 31.9; IR (thin film) 3388, 3017, 2962, 1732, 1682, 1596 cm−1; HRMS (ESI) m/z calcd for C27H26NO4 (M + H)+ 428.1862, found 428.1854; mp 49−51 °C. When the general procedure for the synthesis of indole 1a was run on a 1 mmol scale, the product was purified by mediumpressure chromatography (2:5, EtOAc/hexanes) to afford 1a as an offwhite solid (0.3373 g, 79%). Indole 1b. The general procedure for the synthesis of indole 1b was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1b as a light brown solid (0.1056 g, 81%): 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.89 (d, J = 5.0 Hz, 2H), 7.51 (m, 1H), 7.46−7.45 (m, 1H), 7.41−7.35 (m, 4H), 7.29−7.26 (m, 2H), 7.19−7.17 (m, 2H), 7.13− 7.11 (m, 1H), 5.11−5.08 (m, 1H), 4.00−3.86 (m, 4H), 3.71 (s, H), 2.40 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.7, 171.2, 143.3, 137.0, 134.7, 133.1, 128.6, 128.4, 128.3, 128.0, 127.5, 127.5, 127.4, 126.2, 123.6, 120.5, 115.0, 111.6, 52.4, 43.2, 36.3, 31.7, 19.0; IR (thin film) 3368, 3024, 2950, 1731, 1681, 1596 cm−1; HRMS (ESI) m/z calcd for C27H26NO3S (M + H)+ 444.1633, found 444.1625; mp 43−45 °C. Indole 1c. The general procedure for the synthesis of indole 1c was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1c as an offwhite solid (0.0891 g, 72%): 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 7.94 (d, J = 10.0 Hz, 2H), 7.55−7.52 (m, 1H), 7.44−7.39 (m, 4H), 7.31−7.28 (m, 3H), 7.22−7.18 (m, 2H), 6.97 (d, J = 10.0 Hz,

catalytic asymmetric version of this transformation was accessible. Setting the stereochemistry at a carbon atom adjacent to the 3-position of an indole is an important synthetic problem and we wanted to determine whether our method could address this challenge.16 As shown in Table 2, catalysts R-4 and R-13 gave 1a in low enantiomeric excess (Table 3, entries 1 and 2). The yield of the cascade reaction was Table 3. Catalytic Asymmetric Synthesis of 1a

entrya

cat. 1

cat. 2

solvent

% yield

% ee

1 2 3b 4b

R-4 R-13 R-4 R-13

none none 14 14

THF THF PhMe PhMe

79 40 58 59

15 2 44 67

a Conditions: 2 (1 equiv), 3 (3 equiv), cat. 1 and/or cat. 2 (10 mol %), THF or PhMe (0.1 M), 30 °C, 6 h. b25 °C.

also attenuated with bulkier catalyst R-13. Surprisingly, when R-4 and R-13 were mixed with 14, 1a was isolated in significantly higher enantiomeric excess.17 When a mixture of 2a and 3a was treated with catalyst 14 in the absence of catalyst 4 or catalyst 13, only the alternative cascade reaction products illustrated in Scheme 1B were observed in low yield. This experiment suggests that the more acidic catalysts R-4 or R-13 are required to promote the formation of indole 1a, while catalyst 14 is not acidic enough to promote the desired reactivity but has the appropriate structure to form energetically distinct transition states. These results further expand the applicability of this cascade reaction to include the synthesis of γ-indolo carbonyl compounds with defined stereochemistry at the β-position.

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CONCLUSION In summary, we have discovered that mixtures of nitrones 2 and electron-deficient allenes 3, undergo a cascade reaction for the synthesis of 3-functionalized indoles 1 in the presence of phosphoric acid catalyst 4. This transformation is noteworthy since access to functionalized indoles of this type usually requires the derivatization of a preformed indole. The heterocycles prepared from the cascade synthesis presented above also undergo a McMurry coupling to form synthetically challenging cycloheptanone-fused indoles 5. Mechanistic experiments have suggested that the cascade reaction does not proceed via fragmentation and recombination and initial screening of catalytic asymmetric conditions indicate that enantioenriched indoles can be accessed by this method.

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EXPERIMENTAL SECTION

General Information. 1H and 13C NMR spectra were recorded at ambient temperature using 500 MHz spectrometers. The data are reported as follows: chemical shift in ppm from internal 1088

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1H), 8.29 (s, 1H), 7.90 (d, J = 5.0 Hz, 2H), 7.79 (d, J = 10.0 Hz, 1H), 7.52−7.49 (m, 1H), 7.40−7.35 (m, 4H), 7.29−7.25 (m, 3H), 7.19− 7.16 (m, 1H), 5.14−5.11 (m, 1H), 4.06−3.92 (m, 4H), 3.89 (s, 3H), 3.70 (s, 3H); 13C{1H} NMR (500 MHz, CDCl3) δ 198.6, 171.1, 168.2, 143.2, 138.5, 136.9, 133.1, 129.0, 128.6, 128.5, 128.0, 127.5, 126.6, 126.3, 123.0, 122.4, 121.4, 116.5, 110.7, 52.4, 51.8, 43.4, 36.3, 31.6; IR (thin film) 3339, 3021, 2951, 1749, 1687, 1597 cm−1; HRMS (ESI) m/z calcd for C28H26NO5 (M + H)+ 456.1811, found 456.1801; mp 52−53 °C. Indole 1i. The general procedure for the synthesis of indole 1i was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1i as pale orange solid (0.0914 g, 64%): 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 7.90 (d, J = 10.0 Hz, 2H), 7.52−7.49 (m, 1H), 7.40−7.37 (m, 2H), 7.14 (d, J = 10.0 Hz, 1H), 6.98−6.96 (m, 1H), 6.86−6.85 (m, 2H), 6.79−6.76 (m, 1H), 6.72 (d, J = 10.0 Hz, 1H), 5.87 (d, J = 5.0 Hz, 2H), 5.03−5.00 (m, 1H), 3.94−3.81 (m, 4H), 3.78 (s, 3H), 3.70 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.8, 171.2, 153.7, 147.8, 145.8, 137.6, 137.1, 133.1, 131.2, 128.6, 128.2, 128.0, 127.2, 119.9, 115.2, 111.7, 110.9, 108.7, 107.8, 102.4, 100.9, 56.0, 52.3, 43.3, 36.1, 31.9; IR (thin film) 3390, 3012, 2950, 1731, 1681 cm−1; HRMS (ESI) m/z calcd for C28H26NO6 (M + H)+ 472.1760, found 472.1756; mp 53−57 °C. Indole 1j. The general procedure for the synthesis of indole 1j was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1j as pale orange solid (0.0949 g, 76%): 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 7.91 (d, J = 5.0 Hz, 2H), 7.53−7.50 (m, 1H), 7.42−7.36 (m, 2H), 7.33−7.30 (m, 1H), 7.16 (d, J = 10.0 Hz, 1H), 7.00−6.98 (m, 1H), 6.80−6.78 (m, 1H), 6.30−6.29 (m, 1H), 6.08−6.07 (m, 1H), 5.10−5.07 (m, 1H), 3.99−3.82 (m, 4H), 3.80 (s, 3H), 3.72 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 198.2, 171.3, 156.5, 153.7, 141.2, 137.0, 133.1, 131.1, 128.5, 128.3, 128.1, 127.0, 112.6, 111.7, 111.1, 110.3, 105.9, 102.1, 56.0, 52.3, 42.0, 31.7, 31.2; IR (thin film) 3390, 3012, 2951, 1732, 1682, 1504 cm−1; HRMS (ESI) m/z calcd for C25H24NO5 (M + H)+ 418.1654, found 418.1643; mp 86−87 °C. Indole 1k. The general procedure for the synthesis of indole 1k was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1k as an offwhite amorphous solid (0.1042 g, 83%): 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 7.93−7.92 (m, 2H), 7.54−7.51 (m, 1H), 7.43−7.40 (m, 2H), 7.34−7.30 (m, 1H), 7.20−7.18 (m, 1H), 7.14−7.13 (m, 1H), 6.97−6.95 (m, 1H), 6.91−6.89 (m, 2H), 5.28−5.23 (m, 1H), 4.02− 3.89 (m 4H), 3.73 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.2, 171.3, 148.6, 137.0, 134.3, 133.1, 128.6, 128.3, 128.1, 127.6, 126.8, 126.6, 124.1, 123.6, 123.3, 119.3, 114.5, 110.8, 52.3, 44.9, 32.6, 31.8, 21.7; IR (thin film) 3385, 3049, 2951, 1732, 1682 cm−1; HRMS (ESI) m/z calcd for C25H23NO3SNa (M+Na)+ 440.1296, found 440.1285. Indole 1l. The general procedure for the synthesis of indole 1l was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1l as an offwhite solid (0.0975 g, 70%): 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 7.92 (d, J = 10 Hz, 2H), 7.53−7.50 (m, 1H), 7.42−7.39 (m, 2H), 7.14 (d, J = 10.0 Hz, 1H), 7.03−6.99 (m, 3H), 6.84 (s, 1H), 6.84−6.77 (m, 1H), 5.07−5.04 (m, 1H), 4.02−3.85 (m, 4H), 3.79 (s, 3H), 3.72 (s, 3H), 2.28 (s, 6H); 13C{1H} NMR (500 MHz, CDCl3) δ 199.0, 171.3, 153.6, 143.4, 137.7, 137.2, 133.0, 131.2, 128.5, 128.2, 128.1, 127.8, 127.3, 125.5, 115.3, 111.6, 111.1, 102.3, 56.0, 52.3, 43.2, 36.3, 31.9, 21.5; IR (thin film) 3391, 3012, 2949, 1732, 1682, 1597 cm−1; HRMS (ESI) m/z calcd for C29H30NO4 (M + H)+ 456.2183, found 456.2175; mp 44−46 °C. Indole 1m. The general procedure for the synthesis of indole 1m was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1m as a light brown solid (0.1106 g, 83%): 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 7.90 (d, J = 5.0 Hz, 2H), 7.53−7.50 (m, 1H), 7.41−7.38 (m, 2H), 7.33−7.30 (m, 2H), 7.15 (d, J = 10.0 Hz, 1H), 6.97−6.94 (m, 2H), 6.90−6.88 (m, 1H), 6.79−6.77 (m, 1H), 5.09- 5.06 (m, 1H), 3.96−3.81 (m, 4H), 3.76 (s, 3H), 3.70 (s, 3H); 13C{1H} NMR (125

1H), 5.16−5.13 (m, 1H), 3.99−3.84 (m, 4H), 3.70 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.9, 171.3, 143.7, 137.2, 134.3, 133.0, 128.6, 128.5, 128.4, 128.1, 127.6, 127.6, 127.1, 126.0, 123.2, 119.3, 114.9, 110.8, 52.3, 43.6, 36.3, 31.9, 21.7; IR (thin film) 3394, 3021, 2947, 1731, 1682, 1597 cm−1; HRMS (ESI) m/z calcd for C27H26NO3 (M + H)+ 412.1913, found 412.1906; mp 50−53 °C. Indole 1d. The general procedure for the synthesis of indole 1d was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1d as a light yellow solid (0.0977 g, 77%): 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 7.91 (d, J = 10.0 Hz, 2H), 7.52 (m, 1H), 7.46 (s, 1H), 7.42−7.37 (m, 4H), 7.30−7.27 (m, 3H), 7.22−7.18 (m, 2H), 6.77 (dd, J = 17.5, 10.0 Hz, 1H), 5.62 (d, J = 15.0 Hz, 1H), 5.15−5.11 (m, 2H), 4.01− 3.84 (m, 4H), 3.71 (s, 3H); 13C{1H} NMR (500 MHz, CDCl3) δ 198.8, 171.2, 143.5, 138.1, 137.1, 135.8, 133.1, 129.4, 128.6, 128.4, 128.1, 128.0, 127.6, 126.9, 126.1, 119.7, 118.3, 115.6, 111.2, 110.8, 52.3, 43.5, 36.3, 31.8; IR (thin film) 3379, 3023, 2945, 1731, 1682 cm−1; HRMS (ESI) m/z calcd for C28H26NO3 (M + H)+ 424.1913, found 424.1902; mp 50−52 °C. Indole 1e. The general procedure for the synthesis of indole 1e was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1e as a light yellow solid (0.0862 g, 62%, regioselectivity = 5:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 8.53 (s, 1H), 7.90−7.89 (m, 2H), 7.53−7.50 (m, 1H), 7.41−7.38 (m, 2H), 7.35−7.34 (m, 2H), 7.29− 7.26 (m, 2H), 7.19−7.16 (m, 1H), 6.83−6.81 (m, 1H), 6.70−6.68 (m, 1H), 5.87−5.85 (m, 2H), 5.05−5.02 (m, 1H), 3.95−3.39 (m, 4H), 3.69 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.8, 171.4, 144.4, 143.4, 142.4, 137.1, 133.0, 132.9, 130.9, 128.5, 128.3, 128.0, 127.5, 126.1, 125.9, 120.4, 100.5, 98.3, 92.2, 52.3, 43.0, 36.2, 31.7; 1H NMR (500 MHz, CDCl3) (minor isomer) δ 8.76 (s, 1H), 7.94−7.93 (m, 2H), 7.53−7.50 (m, 1H), 7.41−7.38 (m, 2H), 7.35−7.34 (m, 2H), 7.29− 7.26 (m, 2H), 7.19−7.16 (m, 1H), 7.15−7.14 (m, 1H), 6.75−6.73 (m, 1H), 5.96−5.94 (m, 2H), 4.98−4.97 (m, 1H), 4.30−4.25 (m, 1H), 3.95−3.79 (m, 3H), 3.69 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 199.1, 144.6, 132.9, 128.5, 128.3, 127.7, 126.0, 120.4, 115.5, 104.3, 103.2, 100.1, 44.9, 36.7, 31.6; IR (thin film) 3378, 3023, 2951, 1731, 1681 cm−1; HRMS (ESI) m/z calcd for C27H24NO5 (M + H)+ 442.1654, found 442.1649; mp 48−52 °C. Indole 1f. The general procedure for the synthesis of indole 1f was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1f as a white solid (0.0839 g, 66%): 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 7.91 (d, J = 5.0 Hz, 2H), 7.53−7.50 (m, 1H), 7.42−7.36 (m, 4H), 7.31−7.28 (m, 2H), 7.21−7.18 (m, 1H), 7.13−7.11 (m, 2H), 6.84− 6.80 (m, 1H), 5.11−5.08 (m, 1H), 4.01−3.89 (m, 4H), 3.72 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 198.8, 171.2, 157.5 (d, JC−F = 237.5 Hz), 143.2, 137.0, 133.1, 132.5, 129.4, 128.6, 128.5, 128.0, 127.5, 126.9 (d, JC−F = 12.5 Hz), 126.2, 115.5 (d, JC−F = 12.5 Hz), 111.8 (d, JC−F = 12.5 Hz), 109.8 (d, JC−F = 25.0 Hz), 104.5 (d, JC−F = 25.0 Hz), 52.4, 43.0, 36.2, 31.7; IR (thin film) 3367, 3025, 2951, 1731, 1681, 1596 cm−1; HRMS (ESI) m/z calcd for C26H23NO3F (M + H)+ 416.1662, found 416.1649; mp 92−93 °C. Indole 1g. The general procedure for the synthesis of indole 1g was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1g as an offwhite solid (0.0869 g, 60%); 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 7.95 (d, J = 5.0 Hz, 2H), 7.57 (s, 1H), 7.54−7.51 (m, 1H), 7.42− 7.39 (m, 2H), 7.34−7.27 (m, 4H), 7.21−7.15 (m, 2H), 7.10 (d, J = 5.0 Hz, 1H), 5.08−5.05 (m, 1H), 3.98−3.85 (m, 4H), 3.72 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 198.6, 171.2, 143.0, 136.9, 134.5, 133.1, 128.9, 128.6, 128.5, 128.4, 128.0, 127.4, 126.3, 124.4, 121.9, 114.9, 112.7, 112.5, 52.4, 43.2, 36.1, 31.6; IR (thin film) 3377, 3039, 2959, 1734, 1698, 1590 cm−1; HRMS (ESI) m/z calcd for C26H23NO3Br (M + H)+ 476.0861, found 476.0858; mp 45−50 °C. Indole 1h. The general procedure for the synthesis of indole 1h was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1h as an offwhite solid (0.0688 g, 51%): 1H NMR (500 MHz, CDCl3) δ 9.07 (s, 1089

DOI: 10.1021/acs.joc.7b02638 J. Org. Chem. 2018, 83, 1085−1094

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2951, 1731, 1691, 1585 cm−1; HRMS (ESI) m/z calcd for C27H25N2O6 (M + H)+ 473.1713, found 473.1712; mp 46−51 °C. Indole 1s. The general procedure for the synthesis of indole 1s was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1s as an offwhite solid (0.0931 g, 66%): 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.93−7.92 (m, 2H), 7.53−7.50 (m, 1H), 7.42−7.40 (m, 4H), 7.31−7.27 (m, 2H), 7.21−7.15 (m, 2H), 6.94−6.92 (m, 1H), 6.79− 6.77 (m, 1H), 5.15−5.12 (m, 1H), 3.97−3.79 (m, 4H), 3.77 (s, 3H), 1.48 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.9, 170.2, 153.6, 143.6, 137.7, 133.0, 131.3, 129.2, 128.6, 128.3, 128.1, 127.6, 127.3, 126.0, 114.8, 111.6, 110.8, 102.4, 81.8, 56.0, 43.3, 36.3, 33.2, 28.1; IR (thin film) 3386, 3049, 2979, 1724, 1682,1392, 1144 cm−1; HRMS (ESI) m/z calcd for C30H32NO4(M + H)+ 470.2331, found 470.2344; mp 54−59 °C. Indole 1t. The general procedure for the synthesis of indole 1t was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1t as an offwhite amorphous solid (0.0976 g, 72%): 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 7.91−7.89 (m, 2H), 7.53−7.50 (m, 1H), 7.41−7.36 (4H), 7.29−7.26 (m, 2H), 7.19−7.15 (m, 2H), 6.91−6.87 (m, 1H), 6.78−6.76 (m, 1H), 5.93−5.85 (m, 1H), 5.32−5.22 (m, 2H), 5.12− 5.10 (m, 1H), 4.62−4.61 (m, 2H), 3.98−3.85 (m, 4H), 3.75 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 198.8, 170.5, 153.7, 143.4, 137.1, 133.0, 131.7, 131.2, 131.1, 128.5, 128.4, 128.0, 127.6, 127.2, 126.1, 118.8, 115.2, 111.6, 111.0, 102.3, 66.0, 56.0, 43.1, 36.3, 32.0; IR (thin film) 3378, 3058, 3018, 2940, 1731, 1682 cm−1; HRMS (ESI) m/z calcd for C29H28NO4 (M + H)+ 454.2018, found 454.2028. Indole 1u. The general procedure for the synthesis of indole 1u was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1u as an offwhite solid (0.1490 g, 98%): 1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 7.83−7.81 (m, 2H), 7.72−7.71 (m, 2H), 7.53−7.51 (m, 1H), 7.43−7.38 (m, 3H), 7.34−7.31 (m, 2H), 7.24−7.22 (m, 1H), 7.14− 7.12 (m, 3H), 6.95−6.94 (m, 2H), 6.83−6.81 (m, 1H), 6.74−6.70 (m, 1H), 4.81−4.74 (m, 2H), 4.59−4.56 (m, 1H), 3.83−3.75 (m, 1H), 3.69 (s, 3H), 3.46−3.41 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.4, 153.7, 142.3, 138.0, 136.8, 133.9, 133.2, 129.3, 128.6, 128.2, 128.1, 128.0, 127.4, 126.5, 126.1, 122.4, 119.0, 112.5, 112.2, 102.4, 55.8, 54.1, 42.8, 35.6; IR (thin film) 3368, 3059, 2903, 1682, 1595 cm−1; HRMS (ESI) m/z calcd for C31H28NO4S (M + H)+ 510.1739, found 510.1745; mp 74−78 °C. Synthesis of Cycloheptanone-Fused Indoles 5. General Procedure for the Synthesis of Indoles 5a, 5c−f, 5k, 5m, and 5o.7b,c A 50.0 mL three-neck flask was charged with TiCl3·AlCl3 (1.39 mmol, 6.00 equiv) and KC8 (2.78 mmol, 12.0 equiv). These solids were then combined with THF (18 mL), and the reaction flask was attached to a reflux condenser. The resulting slurry was refluxed at 66 °C for 1.5 h. While the slurry continued to reflux at 66 °C, indole 1 was added in portions (3 × 1.00 mL, 0.080 M in THF) over 10 min, and the reaction mixture was refluxed for an additional 75 min. At this time, the reaction mixture was cooled to 25 °C, filtered over Florosil, and concentrated under vacuum. The crude mixture was purified by medium-pressure column chromatography (2:5, ether/hexanes) to give 5. Indole 5a. The general procedure for the synthesis of indole 5a was run on a 0.23 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5a as an orange amorphous solid (0.0607 g, 69%, dr = 4:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.99 (s, 1H), 7.36−7.24 (m, 5H), 7.22−7.14 (m, 4H), 7.10−7.09 (m, 2H), 6.80−6.76 (m, 1H), 6.45− 6.42 (m, 1H), 4.68−4.66 (m, 1H), 4.25−4.22 (m, 1H), 3.80−3.77 (m, 1H), 3.72−3.69 (m, 1H), 3.63 (s, 3H), 3.03−2.98 (m, 1H), 2.64−2.61 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.6, 153.9, 142.6, 138.9, 131.0, 128.9, 128.7, 128.5, 128.1, 128.0, 127.7, 127.3, 127.2, 126.5, 111.7, 111.3, 101.6, 55.7, 55.1, 41.7, 40.3, 37.1; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.96 (s, 1H), 6.76− 6.74 (m, 1H), 6.36−6.34 (m, 1H), 4.45−4.42 (m, 1H), 3.95−3.92 (m, 1H), 3.58 (s, 3H), 3.56−3.53 (m, 1H), 2.98−2.90 (m, 1H), 2.45−2.42 (m, 1H); 13C NMR (125 MHz, CDCl3) (minor isomer, diagnostic

MHz, CDCl3) δ 198.7, 171.1, 161.3 (d, JC−F = 237.5), 153.7, 139.2, 137.0, 133.1, 131.2, 129.1 (d, JC−F = 12.5 Hz), 128.6, 128.5, 128.3, 128.0, 127.1, 115.1 (d, JC−F = 12.5 Hz), 111.7, 111.0, 102.3, 56.0, 52.3, 43.3, 35.6, 31.9; IR (thin film) 3397, 3012, 2951, 1732, 1677, 1506 cm−1; HRMS (ESI) m/z calcd for C27H25NO4F (M + H)+ 446.1779, found 446.1768; mp 48−51 °C. Indole 1n. The general procedure for the synthesis of indole 1n was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1n as a yellow solid (0.0979 g, 70%): 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 8.10 (d, J = 5.0 Hz, 2H), 7.91 (d, J = 5.0 Hz, 2H), 7.55−7.50 (m, 3H), 7.43−7.40 (m, 2H), 7.18 (d, J = 10.0 Hz, 1H), 6.85−6.78 (m, 2H), 5.17−5.15 (m, 1H), 3.98−3.83 (m, 4H), 3.75 (s, 3H), 3.70 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.0, 170.9, 153.9, 151.4, 146.3, 136.8, 136.7, 133.4, 131.2, 128.7, 128.5, 128.0, 126.8, 123.6, 113.8, 111.9, 111.0, 102.1, 56.0, 52.4, 42.7, 36.3, 31.9; IR (thin film) 3390, 3072, 2951, 1732, 1682, 1514 cm−1; HRMS (ESI) m/z calcd for C27H25N2O6 (M + H)+ 473.1691, found 473.1713; mp 153−156 °C. Indole 1o. The general procedure for the synthesis of indole 1o was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1o as an offwhite solid (0.1008 g, 77%): 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 7.91−7.90 (m, 2H), 7.547.51 (m, 1H), 7.47−7.46 (m, 1H), 7.43−7.40 (m, 2H), 7.33−7.31 (m, 2H), 7.28−7.25 (m, 2H), 7.23− 7.17 (m, 2H), 6.99−6.97 (m, 1H), 6.66−6.62 (m, 1H), 6.46−6.42 (m, 1H), 4.57−4.53 (m, 1H), 4.00−3.90 (m, 2H), 3.74−3.70 (m, 4H), 3.65−3.61 (m, 1H), 2.45 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.8, 171.3, 137.5, 137.1, 134.3, 133.0, 132.7, 132.1, 129.7, 128.5, 128.4, 128.1, 127.2, 127.1, 126.9, 126.3, 123.2, 119.3, 113.6, 110.8, 52.3, 43.6, 34.8, 31.9, 21.7; IR (thin film) 3388, 3052, 2949, 1732, 1679 cm−1; HRMS (ESI) m/z calcd for C29H28NO3 (M + H)+ 438.2069, found 438.2058; mp 46−48 °C. Indole 1p. The general procedure for the synthesis of indole 1p was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (3:7, EtOAc/hexanes) to afford 1p as a light brown solid (0.1016 g, 74%): 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H), 7.89 (d, J = 10.0 Hz, 2H), 7.38−7.36 (m, 2H), 7.28- 7.25 (m, 2H), 7.19−7.13 (m, 2H), 6.94−6.91 (m, 1H), 6.86 (d, J = 10.0 Hz, 2H), 6.78−6.76 (m, 1H), 5.11−5.08 (m, 1H), 3.94−3.83 (m, 4H), 3.82 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.4, 171.2, 163.4, 153.6, 143.6, 131.2, 130.3, 130.2, 130.1, 128.3, 127.6, 127.3, 126.0, 115.3, 113.7, 111.7, 111.0, 102.3, 56.0, 55.5, 52.3, 42.7, 36.4, 31.9; IR (thin film) 3375, 3014, 2951, 1732, 1671, 1598 cm−1; HRMS (ESI) m/z calcd for C28H28NO5 (M + H)+ 458.1967, found 458.1960; mp 47−51 °C. Indole 1q. The general procedure for the synthesis of indole 1q was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1q as an offwhite solid (0.1064 g, 69%): 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 7.72 (d, J = 10.0 Hz, 2H), 7.51−7.50 (m, 2H), 7.36−7.34 (m, 2H), 7.29−7.26 (m, 2H), 7.20−7.14 (m, 2H), 6.92−6.86 (m, 1H), 6.78−6.74 (m, 1H), 5.07−5.05 (m, 1H), 3.95−3.79 (m, 4H), 3.74 (s, 3H), 3.70 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.0, 171.2, 153.7, 143.2, 135.8, 131.8, 131.2, 129.6, 128.4, 128.3, 128.2, 127.5, 127.1, 126.2, 114.9, 111.7, 111.0, 102.3, 56.0, 52.3, 43.0, 36.4, 31.9; IR (thin film) 3390, 3021, 2950, 1731, 1682, 1584 cm−1; HRMS (ESI) m/z calcd for C27H25NO4Br (M + H)+ 506.0974, found 506.0967; mp 47−49 °C. Indole 1r. The general procedure for the synthesis of indole 1r was run on a 0.30 mmol scale. The product was purified by mediumpressure chromatography (2:3, EtOAc/hexanes) to afford 1r as an orange solid (0.0632 g, 45%): 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 8.17 (d, J = 5.0 Hz, 2H), 7.94 (d, J = 10.0 Hz, 2H), 7.35−7.34 (m, 2H), 7.29−7.26 (m, 2H), 7.20−7.19 (m, 1H), 7.15−7.13 (m, 1H), 6.87−6.85 (m, 1H), 6.77−6.75 (m, 1H), 5.05−5.02 (m, 1H), 4.05− 4.00 (m, 1H), 3.92−3.81 (m, 3H), 3.74 (s, 3H), 3.72 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.7, 171.0, 153.8, 150.1, 142.8, 141.4, 131.1, 128.9, 128.5, 128.4, 127.4, 127.0, 126.3, 123.7, 114.4, 111.7, 111.0, 102.4, 56.0, 52.4, 43.5, 36.6, 31.8; IR (thin film) 3400, 3020, 1090

DOI: 10.1021/acs.joc.7b02638 J. Org. Chem. 2018, 83, 1085−1094

The Journal of Organic Chemistry

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peaks) δ 204.6, 145.7, 140.3, 128.8, 127.7, 126.5, 113.2, 102.0, 57.5, 55.6, 44.7, 40.2; IR (thin film) 3395, 3063, 2937, 2843, 1704, 1589 cm−1; HRMS (ESI) m/z calcd for C26H24NO2 (M + H)+ 382.1807, found 382.1802. Indole 5c. The general procedure for the synthesis of indole 5c was run on a 0.23 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5c as an orange amorphous solid (0.0641 g, 75%, dr = 12:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.88 (s, 1H), 7.31−7.25 (m, 5H), 7.22−7.17 (m, 4H), 7.10−7.08 (m, 2H), 6.97−6.95 (m, 1H), 6.85− 6.82 (m, 1H), 4.72−4.68 (m, 1H), 4.28−4.25 (m, 1H), 3.79−3.76 (m, 1H), 3.67−3.64 (m, 1H), 3.04−2.99 (m, 1H), 2.63−2.59 (m, 1H), 2.29 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.5, 142.7, 138.9, 134.1, 128.9, 128.7, 128.5, 128.1, 128.0, 127.6, 127.3, 126.5, 126.4, 123.7, 119.3, 118.9, 110.3, 55.0, 41.6, 40.2, 37.0, 21.5; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.85 (s, 1H), 6.73− 6.72 (m, 1H), 4.49−4.45 (m, 1H), 3.93−3.90 (m, 1H), 3.58−3.55 (m, 1H), 2.26 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 205.3, 123.6, 119.3, 57.2, 44.6, 41.7, 40.5; IR (thin film) 3391, 3063, 2921, 2854, 1703, 1599 cm−1; HRMS (ESI) m/z calcd for C26H24NO (M + H)+ 366.1858, found 366.1862. Indole 5d. The general procedure for the synthesis of indole 5d was run on a 0.23 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5d as a yellow amorphous solid (0.0655 g, 74%, dr = 4:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.96 (s, 1H), 7.29−7.20 (m, 8H), 7.17−7.16 (m, 2H), 7.09−7.08 (m, 2H), 7.02−6.99 (m, 1H), 6.67−6.62 (m 1H), 5.54−5.51 (m, 1H), 5.04−5.00 (m, 1H), 4.76−4.72 (m, 1H), 4.28− 4.25 (m, 1H), 3.81−3.78 (m, 1H), 3.69−3.67 (m, 1H), 3.04−2.98 (m, 1H), 2.64−2.61 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.6, 142.6, 138.9, 137.8, 135.7, 129.7, 128.8, 128.7, 128.6, 128.1, 127.6, 127.4, 127.0, 126.6, 126.5, 120.1, 117.8, 111.0, 110.8, 55.1, 41.6, 40.2, 37.0; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.93 (s, 1H), 6.88−6.86 (m, 1H), 5.48−5.45 (m, 1H), 4.49−4.45 (m, 1H), 3.94−3.91 (m, 1H), 3.58−3.55 (m, 1H), 2.91−2.89 (m, 1H), 2.47−2.41 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 205.3, 145.7, 140.3, 135.8, 118.2, 111.0, 57.4, 44.6, 40.3; IR (thin film) 3399, 3072, 2930, 2871, 1703, 1627 cm−1; HRMS (ESI) m/z calcd for C27H24NO (M + H)+ 378.1858, found 378.1850. Indole 5e. The general procedure for the synthesis of indole 5e was run on a 0.24 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5e as a light brown amorphous solid (0.0406 g, 44%, dr = 5:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.94 (s, 1H), 7.29−7.19 (m, 6H), 7.16−7.15 (m, 2H), 7.08−7.06 (m, 2H), 6.75−6.73 (m, 1H), 6.38− 6.36 (m, 1H), 5.89−5.86 (m, 1H), 5.84−5.82 (m, 1H), 4.60−4.57 (m, 1H), 4.24−4.21 (m, 1H), 3.77−3.75 (m, 1H), 3.72−3.66 (m, 1H), 3.02−2.96 (m, 1H), 2.60−2.55 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.4, 144.8, 142.7, 138.9, 130.6, 128.8, 128.6, 128.4, 128.1, 128.0, 127.6, 127.3, 124.7, 122.3, 113.6, 100.5, 98.1, 91.9, 55.0, 41.6, 40.4, 37.0; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.91 (s, 1H), 6.70−6.69 (m, 1H), 6.31−6.30 (m, 1H), 5.60− 5.59 (m, 1H), 4.66−4.63 (m, 1H), 4.39−4.36 (m, 1H), 3.93−3.90 (m, 1H), 3.53−3.50 (m, 1H), 2.91−2.83 (m, 1H), 2.42−2.37 (m, 1H); 13 C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 204.6, 145.7, 142.9, 126.6, 104.5, 102.3, 98.5, 91.9, 57.3, 55.1, 44.7, 40.7; IR (thin film) 3400, 3108, 3060, 3024, 2959, 1699 cm−1; HRMS (ESI) m/z calcd for C26H22NO3 (M + H)+ 396.1600, found 396.1588. Indole 5f. The general procedure for the synthesis of indole 5f was run on a 0.23 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5f as a light brown amorphous solid (0.0588 g, 68%, dr = 5:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 8.21 (s, 1H), 7.36−7.21 (m, 6H), 7.18−7.13 (m, 3H), 7.08−7.07 (m, 2H), 6.87−6.85 (m, 1H), 6.57− 6.55 (m, 1H), 4.70−4.66 (m, 1H), 4.27−4.25 (m, 1H), 3.81−3.78 (m, 1H), 3.72−3.70 (m, 1H), 3.04−3.01 (m, 1H), 2.64−2.59 (m, 1H); 13 C{1H} NMR (125 MHz, CDCl3) δ 204.6, 157.8 (d, JC−F = 212.5 Hz), 142.3, 138.7, 132.4, 128.9, 128.8, 128.6, 128.3, 128.0, 127.6, 127.4, 126.8, 126.7, 111.4 (d, JC−F = 12.5 Hz), 110.3 (d, JC−F = 25.0 Hz), 104.3 (d, JC−F = 25.0 Hz), 55.0, 41.7, 40.3, 36.9; 1H NMR (500

MHz, CDCl3) (minor isomer, diagnostic peaks) δ 8.74 (s, 1H), 7.90− 7.89 (m, 1H), 6.57−6.55 (m, 1H), 5.10−5.07 (m, 1H), 4.43−4.41 (m, 1H), 4.01−3.89 (m, 1H), 3.58−3.55 (m, 1H), 2.95−2.87 (m, 1H), 2.46−2.42 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 205.2, 145.3, 140.1, 133.2, 113.5, 104.8, 57.4, 44.6, 42.1, 36.3; IR (thin film) 3464, 3074, 2947, 2874, 1704, 1485 cm−1; HRMS (ESI) m/z calcd for C25H21NOF (M + H)+ 370.1611, found 370.1607. Indole 5k. The general procedure for the synthesis of indole 5k was run on a 0.24 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5k as an amorphous orange solid (0.0555 g, 64%, dr = 4:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 8.00 (s, 1H), 7.39−7.29 (m, 4H), 7.24−7.23 (m, 2H), 7.19−7.15 (m, 2H), 7.11−7.07 (m, 1H), 7.01− 6.99 (m, 1H), 6.91−6.90 (m, 1H), 5.01−5.00 (m, 1H), 4.16−4.14 (m, 1H), 3.91−3.88 (m, 1H), 3.74−3.71 (m, 1H), 3.04−2.98 (m, 1H), 2.70−2.65 (m, 1H), 2.39 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.7, 146.9, 139.0, 133.9, 129.1, 128.9, 128.2, 128.1, 127.4, 127.0, 126.7, 126.2, 125.3, 123.9, 123.8, 118.6, 110.5, 55.1, 41.8, 37.9, 35.6, 21.6; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.96 (s, 1H), 4.84−4.81 (m, 1H), 4.63−4.60 (m, 1H), 3.51−3.48 (m, 1H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 205.6, 150.2, 140.4, 134.2, 119.0, 113.2, 56.7, 41.7, 41.1, 39.2, 21.7; IR (thin film) 3391, 3060, 2921, 2857, 1704, 1483 cm−1; HRMS (ESI) m/z calcd for C24H22NOS (M + H)+ 372.142, found 372.1421. Indole 5m. The general procedure for the synthesis of indole 5m was run on a 0.24 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5m as an amorphous orange solid (0.0521 g, 56%, dr = 3:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.96 (s, 1H), 7.35−7.24 (m, 3H), 7.18−7.13 (m, 2H), 7.05−7.03 (m, 2H), 6.96−6.92 (m, 3H), 6.80− 6.79 (m, 1H), 6.44−6.42 (m, 1H), 4.66−4.65 (m, 1H), 4.27−4.24 (m, 1H), 3.78−3.75 (m, 1H), 3.67−3.66 (m, 1H), 3.65 (s, 3H), 3.03−2.97 (m, 1H), 2.59−2.56 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.2, 161.5 (d, JC−F = 250.0 Hz), 154.0, 138.7, 130.9, 129.8, 129.5, 129.3, 129.1, 129.0, 128.9, 128.0, 127.4, 127.3, 115.4 (d, JC−F = 12.4 Hz), 111.6 (d, JC−F = 37.5 Hz), 101.6, 55.8, 55.0, 41.6, 39.6, 37.0; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.94 (s, 1H), 6.77−6.75 (m 1H), 6.34−6.31 (m, 1H), 4.45−4.41 (m, 1H), 3.92−3.90 (m, 1H), 3.60 (s, 3H), 3.56−3.53 (m, 1H), 2.90−2.82 (m, 1H), 2.42−2.38 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 204.8, 138.2, 113.0, 102.0, 57.3, 43.9, 40.4; IR (thin film) 3394, 3059, 2939, 2830, 1703, 1624, 1588 cm−1; HRMS (ESI) m/z calcd for C26H23NO2F (M + H)+ 400.1713, found 400.1714. Indole 5o. The general procedure for the synthesis of indole 5o was run on a 0.23 mmol scale. The product was purified by mediumpressure chromatography (2:5, ether/hexanes) to afford 5o as an amorphous orange solid (0.0478 g, 52%, dr = 2:1): 1H NMR (500 MHz, CDCl3) (major isomer) δ 7.91 (s, 1H), 7.41−7.23 (m, 8H), 7.19−7.16 (m, 2H), 7.03−7.01 (m, 2H), 6.46−6.42 (m, 2H), 6.39− 6.35 (m, 1H), 4.27−4.24 (m, 1H), 4.15−4.11 (m, 2H), 3.74−3.71 (m, 1H), 2.90−2.80 (m, 1H), 2.58−2.54 (m, 1H), 2.44 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 204.7, 139.0, 137.4, 134.0, 131.3, 133.3, 130.0, 129.0, 128.9, 128.8, 128.6, 128.5, 128.1, 127.4, 127.2, 126.4, 123.6, 118.8, 110.4, 55.5, 41.6, 37.4, 35.5, 21.7; 1H NMR (500 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 7.89 (s, 1H), 6.66−6.63 (m, 1H), 4.56−4.53 (m, 1H), 4.15−4.11 (m, 1H), 3.89−3.87 (m, 1H), 3.50−3.46 (m, 1H), 2.90−2.82 (m, 1H), 2.43 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) (minor isomer, diagnostic peaks) δ 205.7, 140.6, 137.5, 134.2, 126.1, 125.7, 119.4, 112.6, 111.9, 110.5, 56.7, 41.8, 41.4, 37.5, 21.6; IR (thin film) 3390, 3060, 2920, 2837, 1704, 1494 cm−1; HRMS (ESI) m/z calcd for C28H26NO (M + H)+ 392.2014, found 392.2021. Mechanistic Experiments. Isolation of Imino-β-ketoester Intermediate and Conversion to Indole 1a (Scheme 2A). Nitrone 2a (0.0977 g, 0.296 mmol) was treated with allenoate 3a (0.088 g, 0.90 mmol) in THF (3.0 mL) for 6 h at 25 °C. At this time, the reaction mixture was concentrated under vacuum and the residue dissolved in 1091

DOI: 10.1021/acs.joc.7b02638 J. Org. Chem. 2018, 83, 1085−1094

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CDCl3 (0.5 mL). CH2Br2 (7.0 μL, 0.10 mmol) was added to the resulting solution as a 1H NMR spectroscopy reference. 1H NMR spectroscopic analysis of the product mixture vs CH2Br2 showed 6a (65%): 1H NMR (500 MHz, CDCl3) (diagnostic peaks) δ 7.72−7.70 (m, 2H), 7.46−7.45 (m, 4H), 7.32−7.27 (m, 9H), 3.79 (s, 3H), 3.67− 3.66 (m, 2H), 3.55 (s, 3H), 3.41−3.37 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) (diagnostic peaks) δ 200.5, 167.4, 156.8, 55.4, 52.1, 48.4, 46.7; LRMS (ESI) m/z calcd for C27H25NO4 (M + H)+ 427.5, found 428.2. The crude sample of 6a was then diluted with THF (3.0 mL), treated with catalyst 4 (0.0010 g, 0.030 mmol), combined with additional allenoate (0.088 g, 0.90 mmol), and heated to 30 °C for 6 h. At this time, the reaction mixture was concentrated under vacuum and the residue dissolved in CDCl3 (0.5 mL). CH2Br2 (7.0 μL, 0.1 mmol) was added to the resulting solution as a 1H NMR spectroscopy reference. 1H NMR spectroscopic analysis of the product mixture vs CH2Br2 showed 1a (63%). Crossover Experiment (Scheme 2B). Nitrone 2d (0.0668 g, 0.205 mmol) and nitrone 2i (0.0756 g, 0.202 mmol) were treated with allenoate 3a (0.116 g, 1.18 mmol, 6 equiv) and catalyst 4 (0.0134 g, 0.0384 mmol, 20 mol %) in THF (4.0 mL) for 6 h at 30 °C. At this time, the reaction mixture was concentrated under vacuum and the residue was dissolved in CDCl3 (0.5 mL). CH2Br2 (7.0 μL, 0.1 mmol) was added to the resulting solution as a 1H NMR spectroscopy reference. 1H NMR spectroscopic analysis of the product mixture vs CH2Br2 showed 1d (78%) and 1i (76%). No other products of the cascade reaction were observed. Crossover Experiment (Scheme 2C). Nitrone 2i (0.0758 g, 0.203 mmol) and 9 (0.0470 g, 0.219 mmol) were treated with allenoate 3a (0.0588 g, 0.600 mmol, 3 equiv) and catalyst 4 (0.0067 g, 0.019 mmol 10 mol %) in THF (2.0 mL) for 6 h at 30 °C. At this time, the reaction mixture was concentrated under vacuum and the residue was dissolved in CDCl3 (0.5 mL). CH2Br2 (7.0 μL, 0.10 mmol) was added to the resulting solution as a 1H NMR spectroscopy reference. 1H NMR spectroscopic analysis of the product mixture vs CH2Br2 showed 1i (62%). No other products of the cascade reaction were observed. Catalytic Asymmetric Indole Synthesis. Synthesis of Indole 1a with Caalyst R-4. The general procedure for the synthesis of indole 1a was run on a 0.152 mmol scale with R-4 (0.0046 g, 0.012 mmol). The product was purified by medium-pressure chromatography (2:5, EtOAc/hexanes) to afford 1a as an off-white solid (0.0504 g, 79%). The product was analyzed by HPLC to determine enantiomeric excess: 15% ee for 1a (Daicel Chiralpack IA-3, 4.6 mm × 250 mmL, 1:10 IPA/hexanes, 25 °C, 1.0 mL/min, 254 nm, tR = 16.501 and 17.648 min). Synthesis of Indole 1a with Catalyst R-13. The general procedure for the synthesis of indole 1a was run on a 0.152 mmol scale with R-13 (0.0092 g, 0.012 mmol). The product was purified by mediumpressure chromatography (2:5, EtOAc/hexanes) to afford 1a as an offwhite solid (0.0256 g, 40%). The product was analyzed by HPLC to determine enantiomeric excess: 2% ee for 1a (Daicel Chiralpack IA-3, 4.6 mm × 250 mmL, 1:10 IPA/hexanes, 25 °C, 1.0 mL/min, 254 nm, tR = 16.681 and 17.878 min). Synthesis of Indole 1a with Catalyst R-4 and 14. The general procedure for the synthesis of indole 1a was run on a 0.149 mmol scale with R-4 (0.0046 g, 0.012 mmol) and 14 (0.0086 g, 0.017 mmol) in toluene at 25 °C. The product was purified by medium-pressure chromatography (2:5, EtOAc/hexanes) to afford 1a as an off-white solid (0.0371 g, 58%). The product was analyzed by HPLC to determine enantiomeric excess: 44% ee for 1a (Daicel Chiralpack IA-3, 4.6 mm × 250 mmL, 1:10 IPA/hexanes, 25 °C, 1.0 mL/min, 254 nm, tR = 16.713 and 17.882 min). Synthesis of Indole 1a with Catalyst R-13 and 14. The general procedure for the synthesis of indole 1a was run on a 0.149 mmol scale with R-13 (0.0092 g, 0.012 mmol) and 14 (0.0086 g, 0.017 mmol) in toluene at 25 °C. The product was purified by mediumpressure chromatography (2:5, EtOAc/hexanes) to afford 1a as an offwhite solid (0.0376 g, 59%). The product was analyzed by HPLC to determine enantiomeric excess: 67% ee for 1a (Daicel Chiralpack IA-3, 4.6 mm × 250 mmL, 1:10 IPA/hexanes, 25 °C, 1.0 mL/min, 254 nm, tR = 16.273 and 17.311 min).

Synthesis of N-Arylnitrones 2. General Procedure for the Synthesis of N-Arylnitrones 2.6,13 A 100 mL round-bottom flask was charged with an oxime (1.0 equiv), an arylboronic acid (3.0 equiv), Cu(OAc)2 (2 equiv), and anhydrous Na2SO4 (8−9 equiv). These solids were diluted with DCE to form a 0.1 M solution. Pyridine (10 equiv) was added to the slurry via syringe. The flask was then capped with a septum and pierced with a ventilation needle. The reaction mixture was stirred at 25 °C for 18 h open to air. The reaction mixture was then concentrated under vacuum, and the residue was purified by medium-pressure chromatography (2% NEt3, 30−40% EtOAc/ hexanes) to give 2 as a yellow solid. Nitrone 2e. Chalcone oxime6,13 (0.3322 g, 1.487 mmol) was treated with 3,4-(methylenedioxy)phenylboronic acid (0.746 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 30% EtOAc/hexane) afforded 2e as a yellow solid (0.2191 g, 43%): 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 20.0 Hz, 1H), 7.52 (d, J = 5.0 Hz, 2H), 7.23−7.29 (m, 6H), 7.19−7.18 (m, 2H), 6.87 (s, 1H), 6.70−6.66 (m, 2H), 6.54 (d, J = 5 Hz, 1H), 5.92 (s, 2H); 13 C{1H} NMR (125 MHz, CDCl3) δ 149.5, 147.6, 147.5, 141.4, 140.6, 136.3, 133.0, 130.7, 129.3, 129.0, 128.8, 128.5, 127.6, 122.2, 119.0, 107.4, 106.3, 101.8; IR (thin film) 3058, 2898, 1573, 1472, 1444 cm−1; HRMS (ESI) m/z calcd for C22H18NO3 (M + H)+ 344.1287, found 344.1275; mp 165−167 °C. Nitrone 2h. Chalcone oxime6,13 (0.3360 g, 1.500 mmol) was treated with 4-(methoxycarbonyl)phenylboronic acid (0.809 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.0 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2h as a yellow solid (0.2829 g, 53%): 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 15.0 Hz, 1 H), 7.88 (d, J = 10.0 Hz, 2H), 7.56−7.53 (m, 2H), 7.37−7.26 (m, 8H), 7.17−7.16 (m, 2H), 6.75 (d, J = 15.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.8, 165.7, 150.4, 150.3, 141.5, 136.1, 132.3, 132.1, 130.8, 130.1, 129.6, 129.4, 128.8, 128.7, 127.8, 125.0, 121.8, 121.6, 52.3; IR (thin film) 3057, 2950, 1720, 1600, 1572, 1435 cm−1; HRMS (ESI) m/z calcd for C23H20NO3 (M + H)+ 358.1443, found 358.1440; mp 133−136 °C. Nitrone 2i. (1E,2E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-phenylprop-2en-1-one oxime6b (0.4012 g, 1.501 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2i as a yellow solid (0.3410 g, 61%): 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 15.0 Hz, 1H), 7.30−7.26 (m, 3 H), 7.19−7.14 (m, 5H), 6.89 (d, J = 10.0 Hz, 1H), 6.75 (d, J = 5.0 Hz, 1H), 6.67 (d, J = 10.0 Hz, 2H), 6.60 (d, J = 15.0 Hz, 1H), 5.98 (s, 2H), 3.72 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.3, 149.3, 148.7, 148.3, 140.5, 140.0, 133.2, 131.1, 130.7, 128.8, 128.4, 126.2, 123.5, 120.7, 113.5, 108.4, 106.2, 101.4, 55.4; IR (thin film) 3072, 3035, 2961, 2836, 1476 cm−1; HRMS (ESI) m/z calcd C23H20NO4 (M + H)+ 374.1392, found 374.1387; mp 184−186 °C. Nitrone 2j. (1E,2E)-3-(Furan-2-yl)-1-phenylprop-2-en-1-one oxime 6,13 (0.3192 g, 1.497 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2j as a yellow solid (0.2361 g, 49%): 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 15.0 Hz, 1H), 7.46−7.44 (m, 1H), 7.28−7.26 (m, 3H), 7.19 (d, J = 5.0 Hz, 2H), 7.15−7.14 (m, 2H), 6.67 (d, J = 5.0 Hz, 2H), 6.54 (d, J = 20.0 Hz, 1H), 6.46−6.42 (m, 2H), 3.72 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.3, 153.0, 148.6, 144.0, 140.5, 133.1, 130.6, 128.8, 128.5, 126.4, 126.2, 120.5, 113.5, 112.3, 112.2, 55.4; IR (thin film) 3057, 2961, 2837, 1606, 1481 cm−1; HRMS (ESI) m/z calcd for C20H18NO3 (M + H)+ 320.1287, found 320.1285; mp 155−157 °C. Nitrone 2k. (1E,2E)-1-Phenyl-3-(thiophene-2-yl)prop-2-en-1-one oxime19 (0.5260 g, 2.290 mmol) was treated with 4-(methylphenyl)boronic acid (0.9330 g, 4.50 mmol), Cu(OAc)2 (0.816 g, 3.00 mmol), Na2SO4 (2.74 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (23.0 mL). Chromatography (2% NEt3, 50% EtOAc/hexane) 1092

DOI: 10.1021/acs.joc.7b02638 J. Org. Chem. 2018, 83, 1085−1094

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afforded 2k as a yellow solid (0.3546 g, 49%): 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 15.0 Hz, 1H), 7.31−7.26 (m, 4H), 7.16−7.12 (m, 4H), 7.07−7.04 (m, 1H), 6.99−6.96 (m, 3H), 6.83 (d, J = 20.0 Hz, 1H), 2.24 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.0, 148.9, 144.8, 142.3, 138.7, 132.9, 132.8, 130.7, 129.1, 128.9, 128.5, 128.0, 127.4, 124.7, 121.5, 21.1; IR (thin film) 3103, 3079, 2922, 1587, 1505 cm−1; HRMS (ESI) m/z calcd C20H18NOS (M + H)+ 320.1109, found 320.1110; mp 160−164 °C. Nitrone 2l. (1E,2E)-3-(3,5-Dimethylphenyl)-1-phenylprop-2-en-1one oxime6,13 (0.3678 g, 1.463 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 30% EtOAc/hexane) afforded 2l as a yellow solid (0.3518 g, 66%): 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 15.0 Hz, 1H), 7.28−7.26 (m, 3H), 7.20−7.15 (m, 6H), 7.00−7.94 (m, 1H), 6.68− 6.81 (m, 3H), 3.71 (s, 3H), 2.29 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.3, 149.4, 140.7, 140.5, 138.2, 136.3, 133.4, 133.2, 131.1, 128.8, 128.4, 126.2, 125.6, 121.9, 113.5, 55.4, 21.2; IR (thin film) 3060, 3018, 2953, 2836, 1591, 1500, 1463 cm−1; HRMS (ESI) m/z calcd C24H24NO2 (M + H)+ 358.1807, found 358.1811; mp 136−138 °C. Nitrone 2m. (1E,2E)-3-(4-Fluorophenyl)-1-phenylprop-2-en-1-one oxime 6,13 (0.3604 g, 1.493 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2m as a yellow solid (0.2222 g, 43%): 1H NMR (500 MHz, CDCl3) δ 8.08−8.04 (d, J = 20.0 Hz, 1H), 7.51−7.48 (m, 2H), 7.30−7.29 (m, 3H), 7.20−7.15 (m, 4H), 7.04− 7.01 (m, 2H), 6.69−6.63 (m 3H), 3.73 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 163.2 (d, JC−F = 250.0 Hz), 159.4, 149.1, 140.4, 138.8, 133.1, 132.7, 130.7, 129.3 (d, JC−F = 12.5 Hz), 128.9, 128.5, 126.2, 122.1, 115.9 (d, JC−F = 25.0 Hz), 113.6, 55.4; IR (thin film) 3055, 3012, 2939, 2837, 1597, 1506 cm−1; HRMS (ESI) m/z calcd for C22H19NO2F (M + H)+ 348.1400, found 348.1402; mp 160−161 °C. Nitrone 2n. (1E,2E)-3-(4-Nitrophenyl)-1-phenylprop-2-en-1-one oxime 6,13 (0.4056 g, 1.512 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 60% EtOAc/hexane) afforded 2n as a yellow solid (0.2476 g, 44%): 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 20.0 Hz, 1H), 8.18 (d, J = 10.0 Hz, 2H), 7.64−7.63 (m, 2H), 7.32−7.31 (m, 3H), 7.21− 7.17 (m, 4H), 6.74−6.68 (m, 3H), 3.73 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.7, 148.4, 147.5, 142.8, 140.4, 136.6, 132.7, 130.7, 129.1, 128.7, 127.9, 126.4, 126.1, 124.1, 113.6, 55.5; IR (thin film) 3058, 3015, 2947, 2838, 1590 cm−1; HRMS (ESI) m/z calcd C22H19N2O4 (M + H)+ 375.1345, found 375.1334; mp 161−164 °C. Nitrone 2p. (1E,2E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1one oxime6,13 (0.3579 g, 1.413 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2p as a yellow solid (0.3813 g, 63%): 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 15.0 Hz, 1H), 7.51−7.50 (m, 2H), 7.33−7.27 (m, 3H), 7.19 (d, J = 10.0 Hz, 2H), 7.07 (d, J = 5.0 Hz, 2H), 6.79 (d, J = 5.0 Hz, 2H), 6.71−6.67 (m, 3H), 3.76 (s, 3H), 3.71 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.7, 159.2, 149.0, 140.6, 140.2, 136.5, 132.1, 129.1, 128.8, 127.6, 126.2, 125.2, 122.6, 114.0, 113.6, 55.4, 55.2; IR (thin film) 2959, 2837, 1605, 1573, 1517, 1463 cm−1; HRMS (ESI) m/z calcd C23H22NO3 (M + H)+ 360.1600, found 360.1613; mp 123−125 °C. Nitrone 2q. (1E,2E)-1-(4-Bromophenyl)-3-phenylprop-2-en-1-one oxime 6,13 (0.4585 g, 1.517 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 40% EtOAc/hexane) afforded 2q as a yellow solid (0.3813 g, 63%): 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 10.0 Hz, 1H), 7.52−7.51 (m, 2H), 7.43 (d, J = 5.0 Hz, 2H), 7.35−7.31 (m, 3H), 7.19

(d, J = 5.0 Hz, 2H), 7.04 (d, J = 10.0 Hz, 2H), 6.71 (d, J = 10.0 Hz, 2H), 6.66 (d, J = 15.0 Hz, 1H), 3.75 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.6, 148.1, 140.2, 140.1, 136.2, 132.3, 132.1, 131.8, 129.4, 128.8, 127.6, 126.2, 123.3, 122.1, 113.8, 55.5; IR (thin film) 3072, 3021, 2964, 1605, 1505 cm−1; HRMS (ESI) m/z calcd C22H19NO2Br (M + H)+ 408.0599, found 408.0609; mp 167−171 °C. Nitrone 2r. (1E,2E)-1-(4-Nitrophenyl)-3-phenylprop-2-en-1-one oxime 6,13 (0.3997 g, 1.489 mmol) was treated with 4(methoxyphenyl)boronic acid (0.683 g, 4.50 mmol), Cu(OAc)2 (0.545 g, 3.00 mmol), Na2SO4 (1.70 g, 12.8 mmol), and pyridine (1.25 mL, 15.0 mmol) in DCE (15.0 mL). Chromatography (2% NEt3, 50% EtOAc/hexane) afforded 2r as a yellow solid (0.2916 g, 51%): 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 10.0 Hz, 2H), 8.08 (d, J = 20.0 Hz, 1H), 7.51−7.50 (m, 2H), 7.38−7.33 (m, 5H), 7.19− 7.17 (m, 2H), 6.71 (d, J = 5.0 Hz, 2H), 6.63 (d, J = 15.0 Hz, 1H), 3.74 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.0, 147.5, 147.0, 146.8, 140.0, 139.9, 139.8, 135.9, 131.9, 129.6, 127.6, 126.2, 123.7, 121.7, 113.9, 55.5; IR (thin film) 3051, 3026, 2967, 2947, 2838, 1598 cm−1; HRMS (ESI) m/z calcd C22H19N2O4 (M + H)+ 375.1347, found 375.1345; mp 162−164 °C.

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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.7b02638. Additional characterization data for all new compounds (PDF) Crystallographic data for compound 1g (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Laura L. Anderson: 0000-0002-8764-7522 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Science Foundation for their generous financial support (NSF-CHE 1464115). We thank Prof. Justin T. Mohr (UIC) for helpful discussions. We thank Mr. Furong Sun (UIUC) for high-resolution mass spectrometry data.

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REFERENCES

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