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Radical “on water” addition to C=N bond of hydrazones: a synthesis of isoindolinone derivatives Tae Kyu Nam, and Doo Ok Jang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03193 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 2, 2018

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The Journal of Organic Chemistry

Radical “on water” addition to C=N bond of hydrazones: a synthesis of isoindolinone derivatives Tae Kyu Nam and Doo Ok Jang* Department of Chemistry, Yonsei University, Wonju 26493, Republic of Korea Supporting Information Placeholder

ABSTRACT: A radical “on water” addition to the C=N bond of hydrazones has been described. Hydrazone, diphenylsilane, alkyl iodide, and triethylborane afforded the corresponding addition products “on water” in good yields. A significant solvent effect was observed from water. The developed protocol can be applied to the synthesis of 3-substituted isoindolinone derivatives. Moreover, the process offers environmentally benign tin-free radical reaction conditions. INTRODUCTION Water is an ideal solvent from economic and environmental points of view because it is cheap, readily available, non-flammable, and non-toxic. Since the successful use of water as a solvent in organic synthesis by Breslow,1 several reactions using water as the reaction medium have been reported. As a solvent in organic synthesis, water has drawn significant attention owing to the “on water” concept reported by Sharpless,2 which refers to reactions where insoluble reactants react in an aqueous suspension with accelerated reaction rate and improved selectivity compared to reactions in organic solvents. Several reactions using on-water conditions have been reported.3 Solvent effects are in radical reactions.4 Thus, water has been generally employed as a reaction medium in radical reactions without any expectations of solvent effects.5 Research on employing water in radical reactions has been focused on increasing the solubility of the components. Towards that end, reactions employing water and organic solvents6 and/or high reaction temperatures with vigorous stirring7 have been developed. Water-soluble initiators8 and chain carriers9 have been developed to use water the reaction medium in radical reactions. Oshima and coworkers10 reported that halide atom transfer radical reactions with insoluble substrates took place “on water” at room temperature with a significantly higher reaction rate than reactions in organic solvents. Most recently, Lipshutz and coworkers11 reported the copper-catalyzed trimethylation of acrylamides “on water”. Herein, we wish to report an “on water” radical addition reaction to C=N bonds at room temperature, wherein a significant solvent effect was observed. Et3B and Ph2SiH2 were used as radical initiator and radical chain carrier, respectively, as they are stable in water. RESULTS and DISCUSSION Benzaldehyde-derived phenyl hydrazone 1 was chosen as a model substrate. A heterogeneous mixture of 1 (0.45 mmol), isopropyl iodide (5 equiv), Ph2SiH2 (1 equiv), and water (15 mL) was treated with 0.5 equiv of Et3B (1 M solution in THF) at room temperature every 3 h for 24 h. The reaction was monitored by TLC. The reaction afforded the isopropyl-added product 1a in 83% yield (Table 1, entry 1). The same reaction was performed in THF, and resulted in a 63% yield of addition product 1a along with recovered starting material 1 (20%) and a small quantity of ethyl addition product (10%) (entry 2). Similarly, reactions performed in organic solvents such as MeOH, acetone, and THF/(CH2Cl)2 (1/1, v/v) gave low yields of addition product 1a (entries 3-5). This indicated that the reaction proceeded more efficiently “on water” than in organic solvents. The reactions that were carried out in water and THF were less effective than in water only (entries 6 and 7). The reaction performed at 75 °C was not efficient, giving a 35% yield of isopropyl added product 1a with an increased amount of the Et-addition ACS Paragon Plus Environment

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product (entry 8). Sonication was not suitable for promoting the reaction, as it gave product 1a in 53% yield (entry 9). The reaction without Ph2SiH2 gave a 32% yield of the isopropyl-added product with a considerable amount of the Et-addition adduct (entry 10). The reaction was carried out “on D2O” in order to determine the hydrogen source. No D-incorporated product was obtained (entry 11), indicating that H2O and D2O do not act as hydrogen sources in the reaction.12 The reaction was also performed in the presence of Ph2SiD2, affording 1a in 73% yield with ~20% D-incorporation (entry 12). The reaction mixture of 1, Ph2SiH2, isopropyl iodide, and Et3B in H2O was analyzed by GC-MS, and the observed intermediate was converted into 1a after silica gel treatment. These observations indicate that the final step of the reaction is not a radical process, and that Ph2SiH2 is not a major hydrogen source for the reaction, although it contributes to increase the yield of the desired product. When the reaction was carried out with neat Et3B, addition products were obtained in 85% yield with an increase in the amount of the Et-addition adduct due to the high concentration of Et3B (entry 13), proving that a diluted Et3B solution is required to obtain a high yield of the desired product. The highest yield was attained with a 1 M solution of Et3B in hexanes (92%) (entry 14). The reaction that was carried out in a large volume of water (50 mL) gave a 94% yield (compared with entry 1), indicating that lower reactant concentrations increased the yield of the desired product. The reaction was performed in a suspension. After completion of the reaction, the suspension state was maintained because of the insolubility of the product. These observations reveal that as a reaction medium, water plays a significant role in accelerating the reaction rate and selectivity. The solvent effect might be attributed to reduction of reactant volumes by hydrophobic effects and/or hydrogen bonding between the substrate and free –OH of interfacial water molecules.13 Table 1. Screening reaction conditions.a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a

solvent H2O THF MeOH Acetone THF/(CH2Cl)2 (1/1, v/v) THF/H2O (7/3, v/v) THF/H2O (1/1, v/v) H2O H2O H2O D2O H2O H2O H2O

yield (%)b 83 63 (10) 35 (46) 41 (14) 46 (12) 35 (15) 48 (13) 34 (52)c 53 (32)d 32 (45)e 80f 73g 45 (40)h 92i

0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in THF) was added every 3 h until the reaction was complete. bIsolated yield. The yield of the Et-adduct is given in parenthesis. c Conducted at 75 °C. dWith sonication. eWithout Ph2SiH2. fD-incorporated product was not observed. 2 ACS Paragon Plus Environment

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g

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

With Ph2SiD2 17% D-incorporated product was observed. hNeat Et3B was used. iEt3B (1 M solution in hexanes) was used.

The scope and limitations of the reaction were investigated using various alkyl iodides. The results are presented in Table 2. With secondary alkyl halides, the reactions proceeded smoothly to give the addition product in high yields (Table 2, entries 1-2). The reaction with 1-adamantyl iodide, which cannot be hydrolyzed, gave a high yield of the product (entry 3). However, the reaction with tert-butyl iodide gave a poor yield of the addition product because this substrate readily hydrolyzed under the reaction conditions (entry 4). The reaction with primary radical, n-octyl radical, afforded a low yield of the addition product (entry 5). This was attributed to the competition between the primary n-octyl and ethyl radicals for the addition to the C=N bond. This problem was resolved by employing trialkylboranes that have the same alkyl group as the alkyl halide. Thus, when n-butyl iodide was used as radical source, tributylborane was employed as radical initiator, affording a high yield of the nBuadded product (entry 6). Similarly, the Et-added product was obtained in a high yield (entry 7). Table 2. Various alkyl radical additions to C=N bond “on water”.a

Et3B (equiv) c-Hexyl, 1b 3 c-Dodecyl, 1c 8 1-Adamantyl, 1d 8 t-Butyl, 1e 7 n-Octyl, 1f 6 n-Butyl, 1g 1 Ethyl, 1h 2

entry R

time (h) yield (%)b

1 2 3 4 5 6 7

18 48 48 42 36 6 12

79 68 84 34 (53) 55 (34) 92c 92

a

0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete. bIsolated yield. The yield of the Et-adduct is given in parenthesis. cBu3B (1 M solution in THF) was used. Next, we investigated the substrate generality of the reaction (Table 3). Various hydrazone derivatives were used as substrates in the presence of isopropyl iodide under the optimized “on water” conditions. Aromatic aldehyde-derived hydrazone derivatives with electron-withdrawing groups underwent the reaction smoothly to produce the corresponding addition product in higher yields (Table 3, entries 1-7) than hydrazones with electro-donating groups (entries 8-10). A heteroaromatic aldehyde-derived hydrazone afforded the addition product in moderate yield (entry 11). An aliphatic aldehyde-derived hydrazone reacted with lower efficiency than aromatic aldehyde-derived hydrazones (entry 12). A hydrazone with a long aliphatic chain gave a poor yield (entry 13), due to the hindrance caused by the folding of the long chain. Table 3. Isopropyl radical addition to various hydrazones “on water”.a

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Et3B (equiv) 4-F-C6H4, 2a 4 3-F-C6H4, 3a 5 4-Cl-C6H4, 4a 2.5 3-Cl-C6H4, 5a 6 2-Cl-C6H4, 6a 6 2-Br-C6H4, 7a 4 4-CF3-C6H4, 8a 2 4-MeO-C6H4, 9a 2 4-Et-C6H4, 10a 8 2-Me-C6H4, 11a 4 2-Furyl, 12a 6 Me, 13a 4 n-Heptyl, 14a 6

entry R

time (h) yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

24 30 15 36 36 24 12 12 48 24 36 24 36

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92 90 90 81 83 81 83 75 71 62 70 76 41

a

b

Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete. Isolated yield.

A plausible mechanism for the alkyl radical addition to the C=N bond of hydrazone is depicted in Scheme 1. The interaction of Et3B with oxygen generates an ethyl radical, which reacts with the alkyl halide to give the alkyl radical. The resulting alkyl radical adds to the C=N bond of hydrazone, resulting in the formation of radical intermediate I. This intermediate can abstract a hydrogen from Ph2SiH2 through a minor pathway (path a) to form the addition product and diphenylsilyl radical, which sustains the radical chain. Alternatively, intermediate I reacts with Et3B, via the dominant pathway, to form intermediate II, which undergoes hydrolysis on silica gel, finally affording the addition product (path b).

Scheme 1. Proposed mechanism for alkyl radical addition to C=N bond. Many biologically important heterocyclic compounds contain an isoindolinone moiety.14 The 3substituted isoindolinone skeleton has drawn considerable attention due to its wide range of therapeutic ACS Paragon Plus Environment

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activities.15 As such, the present process was applied to the synthesis of 3-substituted isoindolinone derivatives. The addition of isopropyl radical to substrate 15 was carried out under the optimized reaction conditions, resulting in 75% yield of 3-isopropyl substituted isoindolinone 15a (Table 4, entry 1). Interestingly, the reaction without Ph2SiH2 also proceeded smoothly, affording an even higher yield of the isoindolinone derivative (entry 2). Upon increasing the amount of Ph2SiH2, the yield of the product decreased (entry 3). These results indicate that the hydrogen radical source is not required for the reaction. The reaction might proceed via intermediate II in Scheme 1, which is more reactive in the intramolecular cyclization than intermediate I. The reaction with a large excess of Ph2SiH2 gave a lower yield of the product, supporting that the intermediate of the reaction is II. Table 4. Effect of amount of Ph2SiH2 on the addition reaction.a

entry Ph2SiH2 (equiv) yield (%)b 1

1

75

2

0

91

3

4

46

a

0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete. bIsolated yield. Next, the scope of the reaction was investigated with various alkyl iodides as radical precursors (Table 5). Reactions with secondary alkyl iodides gave the corresponding 3-substituted isoindolinones in high yields (Table 5, entries 1-2). The reaction with 1-adamantyl iodide exhibited high efficiency, whereas t-butyl iodide afforded the Et-added product as the major product, due to the hydrolysis of tbutyl iodide (entries 3 and 4). Moderate-to-low yields were observed in the reaction with primary alkyl iodides due to the competitive addition of the ethyl radical generated from triethylborane (entries 5 and 6). When primary alkyl halides with the same alkyl group as the trialkylborane were employed, there was no complication in the reaction, and products were obtained in excellent yields (entries 7 and 8).

Table 5. “On water” synthesis of 3-alkyl isoindolinone with various alkyl groups.a

entry R

Et3B time (h) yield (%)b (equiv)

1

c-Hexyl, 15b

4

24

84

2

c-Dodecyl, 15c

4

24

89

3

1-Adamantyl, 15d 4

24

90


5


4

t-Butyl, 15e

5

30

15 (74)

5

n-Octyl, 15f

4

24

55 (32)

6

i-Butyl, 15g

4

24

27 (60)

7

n-Butyl, 15h

4

24

95c

8

Ethyl, 15i

4

24

94

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a

0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete. bIsolated yield. The yield of the Et-adduct is given in parenthesis. cBu3B (1 M solution in THF) was used. The results of the addition of isopropyl group to various hydrazone derivatives are summarized in Table 6. Substrates with both electron-withdrawing and electron-donating groups underwent the addition reaction “on water” to afford high yields of the corresponding 3-isopropyl isoindolinone derivatives. Table 6. Synthesis of 3-isopropyl isoindolinone derivatives using on-water conditions.a

entry R1, R2

Et3B time yield (equiv) (h) (%)b

1

R1= H, R2 = Cl, 5 16a

30

78

2

R1= H, R2 = 6 OEt, 17a

36

83

3

R1, R2 = OMe, 6 18a

36

83

a

0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete. bIsolated yield. The yield of the Et-adduct is given in parenthesis. In conclusion, we have developed an “on water” radical addition reaction to the C=N bond of hydrazones. The reaction was faster “on water” than in organic solvents. The radical addition/reduction reaction shows a significant solvent effect of water. The established process is a tin-free radical reaction using non-toxic diphenyl silane as the radical chain carrier and hydrogen source. The process could be applied to the synthesis of 3-substituted isoindolinone derivatives with high efficiencies. The advantages of the present process include high yields, the use of a green solvent, tin-free conditions, and an easy work-up. EXPERIMENTAL SECTION General information. Unless otherwise specified, chemicals were purchased from Sigma-Aldrich Co. and used without further purification. Column chromatography was performed on silica gel (230–400 mesh, Merck). TLC was performed on glass sheets pre-coated with silica gel (Kieselgel 60 PF254, Merck). 1H- and 13C-NMR spectra were recorded on a Bruker 400 NMR spectrometer, which operated at 400 MHz for 1H and 100 ACS Paragon Plus Environment

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MHz for 13C nuclei and are internally referenced to residual proton solvent signals. Chemical shifts are reported in parts per million (ppm). IR spectra were recorded on a Perkin–Elmer 16 PC FTIR spectrometer. Microanalyses were performed on a CE instrument EA1110 elemental analyzer. Highresolution mass spectra (HRMS) were recorded on ThermoFisher Scientific LTQ Orbitrap XL (ESI). Typical experimental procedure. A heterogeneous mixture of hydrazone (0.45 mmol), alkyl iodide (2.23 mmol), Ph2SiH2 (82.8 µL, 0.45 mmol), and water (15 mL) was purged with argon for 10 min. Et3B (220 µL, 0.22 mmol, 1 M solution in hexanes) was added every 3 h to the suspension via syringe with the needle directly above the suspension until the reaction was complete. When the reaction was complete, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. After filtration, the residue was purified by flash column chromatography on silica gel. N'-(2-Methyl-1-phenylpropyl)benzohydrazide (1a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 92% yield (110 mg); mp 97-99 °C;; IR (KBr) ν 3235, 1633, 1604, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.72 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 1.91-2.01 (m, 1H), 3.79 (d, J = 7.3 Hz, 1H), 4.55 (brs, 1H), 7.17-7.23 (m, 1H), 7.23-7.32 (m, 6H), 7.33-7.41 (m, 1H), 7.44-7.49 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.2, 19.8, 32.6, 71.5, 127.0, 127.7, 128.5, 128.7, 128.8, 131.9, 133.0, 140.5, 167.2; HRMS (ESI-MS) calc. (m/z) for C17H19N2O (M–H) –: 267.1497, found: 267.1502. N'-(Cyclohexyl(phenyl)methyl)benzohydrazide (1b): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 79% yield (108 mg); mp 146-148 °C; IR (KBr) ν 3234, 1625, 1602, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.81-0.93 (m, 1H), 1.02-1.18 (m, 3H), 1.18-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.56-1.67 (m, 2H), 1.67-1.82 (m, 2H), 1.98-2.07 (m, 1H), 3.84 (dd, J = 7.5, 2.5 Hz, 1H), 5.27 (brs, 1H), 7.22-7.29 (m, 1H), 7.29-7.35 (m, 6H), 7.40-7.45 (m, 1H), 7.50-7.54 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 26.1 (2), 26.4, 29.3, 30.1, 42.2, 70.6, 126.9, 127.5, 128.3, 128.6, 131.7, 132.8, 140.7, 166.9; HRMS (ESI-MS) calc. (m/z) for C20H25N2O (M+H)+: 309.1967, found: 309.1958. N'-(Cyclododecyl(phenyl)methyl)benzohydrazide (1c): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). Colorless oil; 68% yield (119 mg); IR (KBr) ν 3285, 2931, 1638, 1578 cm-1; 1 H NMR (400 MHz, CDCl3) δ 1.07-1.52 (m, 23H), 4.13 (d, J = 8.3 Hz, 1H), 7.28-7.35 (m, 4H), 7.357.41 (m, 3H), 7.41-7.49 (m, 2H), 7.50-7.57 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 22.0, 23.2 (2), 23.5, 23.6, 24.8, 25.3 (2), 26.3, 39.7, 68.0, 126.9, 127.6, 128.5, 128.8 (2), 131.9, 133.2, 141.7, 167.1; HRMS (ESI-MS) calc. (m/z) for C26H35N2O (M–H)–: 391.2749, found: 391.2755. N'-(1-Adamantyl(phenyl)methyl)benzohydrazide (1d): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 84% yield (135 mg); mp 180-183 °C; IR (KBr) ν 3252, 1625, 1469, 1643 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.57-1.85 (m, 12H), 2.00 (s, 3H), 3.74 (s, 1H), 7.297.41 (m, 6H), 7.42-7.58 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 28.6, 36.4, 37.2, 39.2, 75.3, 126.9, 127.5, 128.0, 128.8, 129.7, 131.8, 133.1, 138.9, 167.0; HRMS (ESI-MS) calc. (m/z) for C24H29N2O (M+H)+: 361.2280, found: 361.2263. N'-(2,2-Dimethyl-1-phenylpropyl)benzohydrazide (1e): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 34% yield (43 mg); mp 112-114 °C; IR (KBr) ν 3218, 1622, 1576, 1451 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 9H), 3.89 (s, 1H), 7.25-7.34 (m, 6H), 7.34-7.42 (m, 3H), 7.44-7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 27.1, 34.6, 74.4, 127.0, 127.6, 128.1, 128.8, 129.5, 131.9, 133.0, 139.6, 167.1; HRMS (ESI-MS) calc. (m/z) for C18H21N2O (M–H)–: 281.1654, found: 281.1657. N'-(1-Phenylnonyl)benzohydrazide (1f): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). Yellow oil; 55% yield (83 mg); IR (KBr) ν 3282, 1635, 1603, 1455 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J = 6.9 Hz, 3H), 1.15-1.40 (m, 12H), 1.65-1.78 (m, 1H), 1.80-1.92 (m, 1H), 4.08 (dd, J = 8.3, 5.8 Hz, 1H), 7.27-7.35 (m, 1H), 7.35-7.45 (m, 6H), 7.46-7.53 (m, 1H), 7.607.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3, 22.8, 26.2, 29.4, 29.6, 29.8, 32.0, 35.4, 65.6, 127.4, 127.8, 128.1, 128.7, 128.8, 131.9, 133.1, 142.1, 167.3; HRMS (ESI-MS) calc. (m/z) for C22H31N2O (M+H)+: 339.2436, found: 339.2425. ACS Paragon Plus Environment

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N'-(1-Phenylpentyl)benzohydrazide (1g): Purified by column chromatography on silica gel (hexanes/EtOAc, 7:3). Colorless oil; 92% yield (116 mg); IR (KBr) ν 3282, 1637, 1534, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.0 Hz, 3H), 1.12-1.22 (m, 1H), 1.22-1.36 (m, 3H), 1.60-1.72 (m, 1H), 1.76-1.86 (m, 1H), 4.03 (dd, J = 8.2, 5.90 Hz, 1H), 5.17 (s, 1H), 7.25-7.31 (m, 1H), 7.30-7.40 (m, 6H), 7.41-7.48 (m, 2H), 7.54-7.59 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.7, 28.1, 34.8, 65.5, 126.9, 127.7, 127.9, 128.6, 128.6, 131.8, 132.7, 141.6, 167.2; HRMS (ESI-MS) calc. (m/z) for C18H21N2O (M–H)–: 281.1654, found: 281.1658. N'-(1-Phenylpropyl)benzohydrazide (1h):16 Purified by column chromatography on silica gel (hexanes/EtOAc, 7:3). White solid; 92% yield (104 mg); mp 90-92 °C; IR (KBr) ν 3271, 1640, 1601, 1476 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 7.6 Hz, 3H), 1.64-1.80 (m, 1H), 1.80-1.95 (m, 1H), 3.99 (dd, J = 8.4, 5.6 Hz, 1H), 7.25-7.31 (m, 1H), 7.31-7.42 (m, 6H), 7.42-7.51 (m, 2H), 7.56-7.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 10.6, 28.2, 67.0, 127.0, 127.8, 128.7, 128.8, 132.0, 133.0, 141.6, 167.4; HRMS (ESI-MS) calc. (m/z) for C16H19N2O (M+H)+: 255.1497, found: 255.1490. N'-(1-(4-Fluorophenyl)-2-methylpropyl)benzohydrazide (2a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 92% yield (117 mg); mp 116-118 °C; IR (KBr) ν 3228, 1638, 1604, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.79 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 1.92-2.09 (m, 1H), 3.84 (d, J = 7.2 Hz, 1H), 3.93 (brs, 1H), 7.14-7.22 (m, 1H), 7.22-7.29 (m, 2H), 7.297.40 (m, 3H), 7.40-7.49 (m, 2H), 7.49-7.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.8, 32.8, 70.6, 115.3 (d, 2JC-F = 21.2 Hz), 126.9, 128.9, 130.1, (d, 3JC-F = 7.9 Hz), 132.0, 133.1, 136.7 (d, 4JC-F = 3.0 Hz), 162.4 (d, 1JC-F = 245.3 Hz), 167.3; Elem. Anal. Calcd for C17H19FN2O: C, 71.31; H, 6.69; N, 9.78. Found: C, 71.28; H, 6.73; N, 9.74. N'-(1-(3-Fluorophenyl)-2-methylpropyl)benzohydrazide (3a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 90% yield (115 mg); mp 117-119 °C; IR (KBr) ν 3252, 1626, 1591, 1449 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 1.96-2.07 (m, 1H), 3.87 (d, J = 7.0 Hz, 1H), 4.80 (brs, 1H), 6.93-7.02 (m, 1H), 7.07-7.15 (m, 2H), 7.25-7.32 (m, 1H), 7.33-7.40 (m, 2H), 7.44-7.50 (m, 1H), 7.56-7.62 (m, 2H), 7.64 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 19.0, 19.7, 32.7, 70.7, 114.4 (d, 2JC-F = 21.2 Hz), 115.2 (d, 2JC-F = 21.4 Hz), 124.5 (d, 4JC-F = 2.7 Hz), 127.0, 128.7, 129.7 (d, 3JC-F = 8.2 Hz), 131.9, 132.9, 143.7 (d, 3JC-F = 6.7 Hz), 163.0 (d, 1JC-F = 245.4 Hz), 167.5; HRMS (ESI-MS) calc. (m/z) for C17H20FN2O (M+H)+: 287.1560, found: 287.1552. N'-(1-(4-Chlorophenyl)-2-methylpropyl)benzohydrazide (4a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 90% yield (122 mg); mp 115-117 °C; IR (KBr) ν 3229, 1634, 1603, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.91-2.03 (m, 1H), 3.83 (d, J = 7.0 Hz, 1H), 5.24-5.33 (m, 1H), 7.22-7.32 (m, 4H), 7.35 (t, J = 15.2 Hz, 2H), 7.38-7.49 (m, 2H), 7.79-7.57 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.0, 19.8, 32.7, 70.8, 127.0, 128.7, 128.9, 130.1, 132.1, 132.8, 133.4, 139.2, 167.4; HRMS (ESI-MS) calc. (m/z) for C17H20ClN2O (M+H)+: 303.1264, found: 303.1257. N'-(1-(3-Chlorophenyl)-2-methylpropyl)benzohydrazide (5a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 81% yield (123 mg); mp 117-119 °C; IR (KBr) ν 3249, 1629, 1601, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.82 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.91-2.08 (m, 1H), 3.84 (d, J = 6.4 Hz, 1H), 5.33 (brs, 1H), 7.17-7.23 (m, 1H), 7.23-7.30 (m, 2H), 7.33-7.43 (m, 4H), 7.43-7.51 (m, 1H), 7.53-7.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.7, 32.7, 71.0, 127.0, 127.1, 127.9, 128.6, 128.9, 129.7, 132.1, 132.8, 134.4, 143.1, 167.5; HRMS (ESI-MS) calc. (m/z) for C17H20ClN2O (M+H)+: 303.1264, found: 303.1254. N'-(1-(2-Chlorophenyl)-2-methylpropyl)benzohydrazide (6a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 83% yield (112 mg); mp 118-119 °C; IR (KBr) ν 3235, 1633, 1581, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.7 Hz, 3H), 1.92-2.18 (m, 1H), 4.47 (d, J = 7.4 Hz, 1H), 5.39 (brs, 1H), 7.13-7.20 (m, 1H), 7.22-7.38 (m, 4H), 7.38-7.46 (m, 1H), 7.51-7.63 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.0, 19.5, 32.6, 66.5, 127.0, 128.4, 128.7, 129.1, 129.6, 131.7, 133.1, 134.5, 135.2, 139.2, 167.3; HRMS (ESI-MS) calc. (m/z) for C17H20ClN2O (M+H)+: 303.1264, found: 303.1251. ACS Paragon Plus Environment

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N'-(1-(2-Bromophenyl)-2-methylpropyl)benzohydrazide (7a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). Pale yellow solid; 81% yield (126 mg); mp 97-100 °C; IR (KBr) ν 3286, 1634, 1603, 1467 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.7 Hz, 3H), 1.96-2.10 (m, 1H), 4.42 (d, J = 7.4 Hz, 1H), 7.01-7.12 (m, 1H), 7.28-7.39 (m, 4H), 7.39-7.45 (m, 1H), 7.49-7.55 (m, 3H), 7.55-7.60 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 18.9, 19.7, 32.7, 69.0, 125.9, 127.0, 127.6, 128.7 (2), 129.3, 131.7, 132.9, 133.1, 140.8, 167.3; HRMS (ESI-MS) calc. (m/z) for C17H20BrN2O (M+H)+: 347.0759, found: 347.0745. N'-(2-Methyl-1-(4-(trifluoromethyl)phenyl)propyl)benzohydrazide (8a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 83% yield (125 mg); mp 120-123 °C; IR (KBr) ν 3244, 1624, 1544, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H), 1.95-2.11 (m, 1H), 3.94 (d, J = 7.0 Hz, 1H), 5.27 (brs, 1H), 7.29-7.36 (m, 2H), 7.417.47 (m, 3H), 7.51-7.59 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 18.9, 19.6, 32.7, 70.8, 124.4 (q, 1JC-F = 272.0 Hz), 125.2 (q, 3JC-F = 3.7 Hz), 127.0, 128.8, 129.0, 129.7 (q, 2JC-F = 32.2 Hz), 132.0, 132.7, 145.1, 167.6; HRMS (ESI-MS) calc. (m/z) for C18H20F3N2O (M+H)+: 337.1528, found: 337.1519. N'-(1-(4-Methoxyphenyl)-2-methylpropyl)benzohydrazide (9a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 75% yield (100 mg); mp 130-134 °C; IR (KBr) ν 3235, 1633, 1581, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H), 1.97-2.09 (m, 1H), 3.81 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 6.90 (d, J = 8.6 Hz, 2H), 7.25-7.31 (m, 2H), 7.34-7.42 (m, 2H), 7.44-7.51 (m, 1H), 7.54-7.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.2, 19.9, 32.7, 55.4, 70.9, 113.8, 127.0, 128.8, 129.7, 131.9, 132.7, 133.1, 159.2, 167.1; HRMS (ESI-MS) calc. (m/z) for C18H21N2O2 (M–H)–: 297.1603, found: 297.1607. N'-(1-(4-Ethylphenyl)-2-methylpropyl)benzohydrazide (10a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 71% yield (94 mg); mp 125-127 °C; IR (KBr) ν 3284, 1637, 1601, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 1.93-2.07 (m, 1H), 2.63 (q, J = 7.6 Hz, 2H), 3.79 (d, J = 7.3 Hz, 1H), 4.25 (brs, 1H), 7.12-7.18 (m, 2H), 7.20-7.26 (m, 2H), 7.30-7.37 (m, 2H), 7.41-7.47 (m, 1H), 7.50-7.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 15.7, 19.3, 19.8, 28.7, 32.7, 71.2, 127.0, 127.9, 128.6, 128.8, 131.9, 133.1, 137.8, 143.6, 167.1; HRMS (ESI-MS) calc. (m/z) for C19H25N2O (M+H)+: 297.1967, found: 297.1960. N'-(2-Methyl-1-o-tolylpropyl)benzohydrazide (11a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 62% yield (78 mg); mp 123-126 °C; IR (KBr) ν 3285, 2962, 1638, 1532, 1464 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.80 (d, J = 6.9 Hz, 3H), 1.6 (d, J = 6.6 Hz, 3H), 1.95-2.06 (m, 1H), 2.25 (s, 3H), 4.18 (d, J = 7.9 Hz, 1H), 4.90 (brs, 1H), 7.08-7.17 (m, 2H), 7.18-7.24 (m, 1H), 7.29-7.36 (m, 2H), 7.40-7.46 (m, 1H), 7.46-7.55 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 19.5, 19.7, 20.0, 33.2, 66.0, 126.3, 126.9, 127.0, 127.3, 128.7, 130.5, 131.8, 133.1, 137.4, 139.7, 167.3; HRMS (ESI-MS) calc. (m/z) for C18H23N2O (M+H)+: 283.1810, found: 283.1808. N'-(1-(Furan-2-yl)-2-methylpropyl)benzohydrazide (12a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). Yellow oil; 70% yield (81 mg); IR (KBr) ν 3302, 2873, 1646, 1544 cm– 1 1 ; H NMR (400 MHz, CDCl3) δ 0.85 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 2.07-2.17 (m, 1H), 3.91 (dd, J = 7.2, 2.8 Hz, 1H), 5.16-5.23 (m, 1H), 6.20-6.23 (m,1H), 6.31 (dd, J = 3.0, 1.8 Hz, 1H), 7.35-7.41 (m, 3H), 7.44-7.52 (m, 2H), 7.61 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.8, 30.9, 65.1, 109.2, 110.3, 127.1, 128.9, 132.2, 132.6, 142.4, 153.3, 167.2; HRMS (ESI-MS) calc. (m/z) for C15H19N2O2 (M+H)+: 259.1447, found: 259.1430. N'-(3-Methylbutan-2-yl)benzohydrazide (13a):16 Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 76% yield (70 mg); mp 80-83 °C; IR (KBr) ν 3282, 1634, 1539, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 1.72-1.89 (m, 1H), 2.90-2.98 (m, 1H), 5.77 (brs, 1H), 7.37-7.45 (m, 2H), 7.45-7.57 (m, 1H), 7.72-7.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3, 17.2, 19.5, 31.0, 61.1, 127.1, 128.8, 132.0, 133.1, 167.5; HRMS (ESI-MS) calc. (m/z) for C12H19N2O (M+H)+: 207.1497, found: 207.1490. N'-(2-Methyldecan-3-yl)benzohydrazide (14a): Purified by column chromatography on silica gel (hexanes/EtOAc, 9:1). Yellow oil; 41% yield (52 mg); IR (KBr) ν 3284, 1637, 1601, 1459 cm–1; 1H ACS Paragon Plus Environment

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NMR (400 MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.17-1.35 (m, 8H), 1.35-1.52 (m, 3H), 1.79-1.92 (m, 1H), 2.70-2.75 (m, 1H), 4.90 (brs, 1H), 7.38-7.44 (m, 2H), 7.46-7.52 (m, 1H), 7.57 (brs, 1H), 7.69-7.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3, 17.9, 18.7, 22.9, 26.8, 29.0, 29.5 (2), 30.2, 32.1, 65.9, 127.0, 128.9, 131.9, 133.3, 167.3; Elem. Anal. Calcd for C18H30N2O: C, 74.44; H, 10.41; N, 9.65. Found: C, 74.40; H, 10.44; N, 9.61. N-(1-Isopropyl-3-oxoisoindolin-2-yl)benzamide (15a):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; yield 91% (119 mg); mp 217-218 °C; IR (KBr) ν 3222, 2961, 1722, 1659, 1296 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.71 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 7.1 Hz, 3H), 2.44-2.54 (m, 1H), 4.99 (d, J= 2.6 Hz, 1H), 7.21-7.27 (m, 2H), 7.34-7.40 (m, 1H), 7.42-7.48 (m, 2H), 7.53-7.59 (m, 1H), 7.81-7.87 (m, 3H), 10.87 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.7, 18.1, 29.6, 66.6, 123.3, 124.2, 127.7, 128.3, 128.6, 130.7, 131.1, 132.2, 132.4, 143.8, 166.4, 168.8; HRMS (ESI-MS) calc. (m/z) for C18H19N2O2 (M+H)+: 295.1447, found: 295.1437. N-(1-Cyclohexyl-3-oxoisoindolin-2-yl)benzamide (15b):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 84% yield (125 mg); mp 171-173 °C; IR (KBr) ν 3205, 2931, 1710, 1673, 1529, 1296 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.64-0.79 (m, 1H), 1.04-1.18 (m, 1H), 1.18-1.34 (m, 2H), 1.34-1.44 (m, 2H), 1.48-1.61 (m, 2H), 1.61-1.75 (m, 2H), 2.08 (td, J = 12.1, 2.6 Hz, 1H), 4.90 (d, J = 2.1 Hz, 1H), 7.17-7.23 (m, 2H), 7.29-7.35 (m, 1H), 7.40-7.46 (m, 2H), 7.50-7.57 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.84-7.90 (m, 2H), 11.03 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.0, 26.4 (2), 26.7, 27.3, 28.5, 39.8, 66.3, 123.1, 124.0, 127.6, 127.9, 128.4, 130.3, 131.0, 132.0, 132.3, 143.9, 166.2, 168.8; HRMS (ESI-MS) calc. (m/z) for C21H23N2O2 (M+H)+: 335.1760, found: 335.1747. N-(1-Cyclododecyl-3-oxoisoindolin-2-yl)benzamide (15c): Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). Colorless oil; 89% yield (166 mg); IR (KBr) ν 3286, 2862, 1705, 1683 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.98-1.45 (m, 23H), 5.11 (s, 1H), 7.22-7.28 (m, 2H), 7.33-7.40 (m, 1H), 7.42-7.49 (m, 2H), 7.52-7.59 (m, 1H), 7.81 (d, J = 7.40 Hz, 3H), 10.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.8, 23.2, 23.3, 23.6, 23.7, 24.0, 24.1, 25.7, 26.4, 35.1, 64.3, 123.1, 124.3, 127.7, 128.1, 128.6, 130.5, 130.5, 131.3, 132.2, 132.5, 145.0, 166.5, 169.2; HRMS (ESI-MS) calc. (m/z) for C27H35N2O2 (M+H)+: 419.2699, found: 419.2687. N-(1-Adamantyl-3-oxoisoindolin-2-yl)benzamide (15d):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 90% yield (155 mg); mp 239-241 °C; IR (KBr) ν 3237, 2905, 1700, 1668, 1528, 1292, 757 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.46-1.73 (m, 9H), 1.74-1.91 (m, 3H), 1.91-2.09 (m, 3H), 4.60 (s, 1H), 7.19-7.34 (m, 2H), 7.34-7.43 (m, 1H), 7.43-7.53 (m, 1H), 7.53-7.71 (m, 2H), 7.80-7.85 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 10.39 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 36.6, 38.0, 38.6, 71.0, 76.6, 76.9, 77.1, 77.2, 124.1, 124.9, 127.4, 127.9, 128.3, 130.4, 131.2, 131.7, 131.9, 143.7, 165.7, 170.6; HRMS (ESI-MS) calc. (m/z) for C25H25N2O2 (M–H)–: 385.1916, found: 385.1921. N-(1-tert-Butyl-3-oxoisoindolin-2-yl)benzamide (15e):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 15% yield (21 mg); mp 230-233 °C; IR (KBr) ν 3268, 2970, 1723, 1650, 1293 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H), 4.76 (s, 1H), 7.18-7.24 (m, 2H), 7.30-7.36 (m, 1H), 7.41-7.48 (m, 1H), 7.49-7.57 (m, 2H), 7.76-7.83 (m, 2H), 7.84-7.88 (m, 1H), 10.71 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.2, 36.0, 70.7, 124.4, 124.8, 127.7, 128.2, 128.6, 130.6, 131.4, 132.1, 132.2, 144.7, 166.1, 170.5; Elem. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.04; H, 6.50; N, 9.04. N-(1-Octyl-3-oxoisoindolin-2-yl)benzamide (15f):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). Yellow oil; 55% yield (90 mg); IR (KBr) ν 3235, 2927, 1708, 1664, 1293 cm–1; 1 H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.1 Hz, 3H), 0.86-0.96 (m, 1H), 0.98-1.09 (m, 2H) 1.09-1.30 (m, 9H), 1.89-2.00 (m, 2H), 5.05 (t, J = 4.6 Hz, 1H), 7.20-7.28 (m, 2H), 7.34-7.47 (m, 3H), 7.53-7.60 (m, 1H), 7.79-7.87 (m, 3H), 10.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 22.8, 23.5, 29.4, 29.6, 29.9, 30.7, 32.0, 61.6, 122.7, 124.2, 127.8, 128.2, 128.6, 130.2, 131.1, 132.2, 132.6, 145.2, 166.5, 168.7; HRMS (ESI-MS) calc. (m/z) for C23H27N2O2 (M-H)-: 363.2073, found: 363.2079. N-(1-Isobutyl-3-oxoisoindolin-2-yl)benzamide (15g): Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 27% yield (37 mg); mp 131-133 °C; IR (KBr) ν 3236, 2958, ACS Paragon Plus Environment

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1710, 1674, 1292 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.87 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.57-1.70 (m, 1H), 1.74-1.89 (m, 1H), 1.89-2.06 (m, 1H), 5.02 (t, J = 6.2 Hz, 1H), 7.25-.734 (m, 2H), 7.36-7.49 (m, 3H), 7.53-7.60 (m, 1H), 7.80-7.91 (m, 3H), 10.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.1, 23.2, 25.1, 41.6, 60.2, 123.0, 124.3, 127.8, 128.2, 128.7, 129.8, 131.3, 132.3, 132.6, 146.0, 166.6, 168.6; HRMS (ESI-MS) calc. (m/z) for C19H19N2O2 (M–H)–: 307.1447, found: 307.1451. N-(1-Butyl-3-oxoisoindolin-2-yl)benzamide (15h):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 95% yield (131 mg); mp 131-133 °C; IR (KBr) ν 3236, 2958, 1710, 1674, 1292 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.73 (t, J = 7.1 Hz, 3H), 0.80-0.95 (m, 1H), 1.15-1.35 (m, 3H), 1.91-2.00 (m, 2H), 5.09 (t, J = 4.6 Hz, 1H), 7.25-7.31 (m, 2H), 7.38-7.50 (m, 3H), 7.57-7.62 (m, 1H), 7.81-7.90 (m, 3H), 10.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.9, 25.5, 30.4, 61.6, 122.7, 124.3, 127.8, 128.2, 128.6, 130.3, 131.2, 132.2, 132.7, 145.2, 166.6, 168.7; HRMS (ESI-MS) calc. (m/z) for C19H19N2O2 (M–H)–: 307.1447, found: 307.1449. N-(1-Ethyl-3-oxoisoindolin-2-yl)benzamide (15i):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 94% yield (118 mg); mp 137-140 °C; IR (KBr) ν 3235, 2970, 1707, 1673, 1526, 1293, 754 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.58 (t, J = 7.3 Hz, 3H), 1.89-2.07 (m, 2H), 5.03 (t, J = 4.2 Hz, 1H), 7.12-7.24 (m, 2H), 7.25-7.45 (m, 3H), 7.45-7.55 (m, 1H), 7.71-7.86 (m, 3H), 10.84 (s, 1H); 13C NMR (100 MHz, CD3CN) δ 7.9, 24.1, 63.0, 124.1, 124.4, 128.5, 129.3, 129.8, 131.5, 133.2, 133.4, 133.6, 145.5, 167.5, 168.1; HRMS (ESI-MS) calc. (m/z) for C17H15N2O2 (M–H)–: 279.1134, found: 279.1137. N-(5-Chloro-1-isopropyl-3-oxoisoindolin-2-yl)benzamide (16a):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 78% yield (114 mg); mp 172-173 °C; IR (KBr) ν 3241, 2966, 1712, 1673, 1293, 755 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.64 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 7.1 Hz, 3H), 2.33-2.46 (m, 1H), 4.91 (d, J = 2.6 Hz, 1H), 7.15 (t, J = 7.7 Hz, 2H), 7.287.38 (m, 2H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.68-7.74 (m, 3H), 10.97 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.5, 18.0, 29.5, 66.4, 124.2, 124.6, 127.7, 128.5, 130.8, 132.3, 132.4, 132.6, 134.6, 141.8, 166.2, 167.6; HRMS (ESI-MS) calc. (m/z) for C18H18ClN2O2 (M+H)+: 329.1057, found: 329.1046. N-(5-Ethoxy-1-isopropyl-3-oxoisoindolin-2-yl)benzamide (17a): Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). Pale yellow solid; yield 83% (126 mg); mp 162-164 °C; IR (KBr) ν 3239, 2915, 1707, 1674, 1493, 1258 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.65 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 1.40 (t, J = 6.9 Hz, 3H), 2.36-2.48 (m, 1H), 4.04 (q, J = 6.9 Hz, 2H), 4.88 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.17-7.23 (m, 2H), 7.26-7.37 (m, 3H), 7.81 (d, J = 7.6 Hz, 2H), 10.88 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.9, 16.5, 18.3, 29.5, 64.1, 66.3, 107.6, 121.1, 124.2, 127.7, 128.5, 131.1, 131.8, 132.1, 135.8, 159.3, 166.3, 166.3, 169.0; Elem. Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C, 70.96; H, 6.53; N, 8.32. N-(1-Isopropyl-4,5-dimethoxy-3-oxoisoindolin-2-yl)benzamide (18a):6b Purified by column chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 83% yield (131 mg); mp 194-195 °C; IR (KBr) ν 3256, 2954, 1733, 1645, 1219 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.71 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 2.28-2.37 (m, 1H), 3.82 (s, 3H), 3.98 (s, 3H), 4.83 (d, J = 2.6 Hz, 1H), 7.017.05 (m, 2H), 7.13-7.20 (m, 2H), 7.27-7.34 (m, 1H), 7.73 (d, J = 7.8 Hz, 2H), 10.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.8, 17.7, 30.0, 56.7, 62.6, 65.2, 117.1, 118.3, 122.9, 127.7, 128.4, 131.1, 132.0, 137.0, 147.7, 152.3, 166.1, 167.2; HRMS (ESI-MS) calc. (m/z) for C20H23N2O4 (M+H)+: 355.1658, found: 355.1645. ASSOCIATED CONTENT Supporting Information The Supporting Information for copies of 1H and charge on the ACS Publications website.

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Corresponding Author *E-mail address: [email protected] ACKNOWLEDGMENT This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A3B03932348). REFERENCES (1) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816. (2) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44, 3275. (3) (a) Dilauro, G.; Dell'Aera, M.; Vitale, P.; Capriati, V.; Perna, F. M. Angew. Chem. Int. Ed. 2017, 56, 10200; (b) Hajra, S.; Singha Roy, S.; Aziz, S. M.; Das, D. Org. Lett. 2017, 19, 4082; (c) Czerwiński, P.; Michalak, M. J. Org. Chem. 2017, 82, 7980; (d) Gawande, M. B. Organic Chem. Curr. Res. 2014, 3:2; (e) Gawande, M. B.; Bonifácio, V. D. B.; Luque, R.; Branco, P. S.; Varma, R. S. Chem. Soc. Rev. 2013, 42, 5522; (f) Bulter, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302; (g) Chanda, A.; Fokin, V. Chem. Rev. 2009, 109, 725. (4) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996; (b) Giese, B.; Kopping, B.; Göbel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301. (5) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1; (b) Postogo, A. RSC Adv. 2011, 1, 14; (c) Campaña, A. G.; Estévez, R. E.; Fuentes, N.; Robles, R.; Cuerva, J. M.; Buñuel, E.; Cárdenas, D. J.; Oltra, J. E. Org. Lett. 2007, 9, 2195; (d) Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971; (e) Suárez, R. M.; Sestelo, J. P.; Sarandeses, L. A. Chem. Eur. J. 2003, 9, 4179; (f) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674. (6) (a) Shen, H.; Liu, Z.; Zhang, P.; Tan, X.; Zhang, Z.; Li, C. J. Am. Chem. Soc. 2017, 139, 9843; (b) Zhang, L.; Kim, J. B.; Jang, D. O. Tetrahedron Lett. 2014, 55, 2654; (c) Cho, D. H.; Jang, D. O. Chem. Comm. 2006, 48, 5045; (d) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324; (e) Miyabe, H.; Naito, T. Org. Biomol. Chem. 2004, 2, 1267; (f) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131; (g) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65, 5043. (7) (a) Postigo, A.; Kopsov, S.; Ferreri, C.; Chatgilialoglu, C. Org. Lett. 2007, 9, 5159; (b) Postigo, A.; Ferreri, C.; Navacchia, M. L.; Chatgilialoglu, C. Synlett 2005, 2854. (8) (a) Cho, D. H.; Jang, D. O. Tetrahedron Lett. 2005, 46, 1799; (b) Cho, D. H.; Jang, D. O. Synlett 2005, 59; (c) Nambu, H.; Anilkumar, G.; Matsugi, M.; Kita, Y.; Nambu, H. Tetrahedron 2003, 59, 77; (d) Jang, D. O.; Cho, D. H. Tetrahedron Lett. 2002, 43, 5921; (e) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi, M. Org. Lett. 2001, 3, 1157; (f) Yorimitsu, H.; Wakabayashi, K.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1999, 40, 519. (9) (a) Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc. Jpn. 1997, 70, 2519; (b) Jang, D. O. Tetrahedron Lett. 1996, 37, 5367; (c) Light, J.; Breslow, R. Tetrahedron Lett. 1990, 31, 2957. (10) (a) Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. J. Org. Chem. 2001, 66, 7776; (b) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041; (c) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 8604. (11) Yang, F.; Klumphu, P.; Liang, Y.-M.; Lipshutz, B. H. Chem. Comm. 2014, 50, 936. (12) (a) Medeiros, M. W.; Schacherer, L. N.; Spiegel, D. A.; Wood, J. L. Org. Lett. 2007, 9, 4427; (b) Cuerva, J. M.; Campaña, A. G.; Justicia, J.; Rosales, A.; Oller-López, J. L.; Robles, R.; Cárdenas, D. J.; Buñuel, E.; Oltra, J. E. Angew. Chem. Int. Ed. 2006, 45, 5522. (13) Jung, Y. S.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492. ACS Paragon Plus Environment

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