Synthesis of CMe2CF3-Containing Heteroarenes via Tandem 1, 1

Nov 23, 2018 - A tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with 3,3,3-trifluoro-2,2-dimethylpropanoic acid was developed...
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Article Cite This: J. Org. Chem. 2018, 83, 15236−15244

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Synthesis of CMe2CF3‑Containing Heteroarenes via Tandem 1,1Dimethyltrifluoroethylation and Cyclization of Isonitriles Wen-Qiang Shi,† Shuai Liu,† Chen-Ze Wang,† Yangen Huang,† Feng-Ling Qing,†,‡ and Xiu-Hua Xu*,‡ †

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Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China ‡ Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: A tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with 3,3,3-trifluoro-2,2-dimethylpropanoic acid was developed. This protocol provides the efficient synthesis of a series of previously unknown CMe2CF3-containing heteroarenes, which are potentially useful in the drug discovery process.

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INTRODUCTION The introduction of fluorinated groups into organic molecules often results in beneficial changes in their physical, chemical, and biological properties.1 Among various fluorinated groups, trifluoromethyl (CF3) has prevailed as a key structural motif of pharmaceuticals, agrochemicals, and functional materials. Consequently, the synthesis of trifluoromethylated compounds has received much attention over the past few decades.2 In this context, increasing attention has shifted spontaneously to the CF3-derived groups, such as OCF3,3 SCF3,4 SeCF3,5 CH2CF3,6 NRCF3,7 and SO2CF38 (Figure 1). Recently, substantial endeavors have been witnessed in developing efficient methods for the incorporation of these CF3-derived groups into organic compounds.

Figure 2. CMe2CF3-containing bioactive compounds.

approaches require several steps, which are neither atomeconomical nor synthetically practical. Recently, we reported the first practical synthesis of CMe2CF3-substituted heteroarenes by decarboxylative 1,1-dimethyltrifluoroethylation of heteroarenes with 3,3,3-trifluoro-2,2-dimethylpropanoic acid (TFDMPA) (Scheme 1c). 12 As an extension of the decarboxylation of TFDMPA and in continuation of our recent research interest in fluoroalkylation using fluoroalkyl carboxylic/sulfonic acid derivatives,13 we wish to disclose our recent results on tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with TFDMPA for the preparation of CMe2CF3-containing heteroarenes (Scheme 1d).

Figure 1. Trifluoromethyl (CF3) and CF3-derived groups.

As a highly lipophilic9 and bulky CF3-derived group, CMe2CF3 has begun to attract the attention of medicinal chemists and been applied in biological applications and drug design.9−11 Some representative examples of CMe2CF3containing bioactive compounds are shown in Figure 2.10 Despite the increasing importance of CMe2CF3-containing heteroarenes in medicinal chemistry,9−11 less attention has been directed toward the synthesis of these compounds. Conventional synthetic methods mainly include trifluoromethylation/methylation of (hetero)aryl methyl ketones (Scheme 1a)9a,10c,11a,d,e and aromatization from CMe2CF3-containing building blocks (Scheme 1b).9b,c,10a,b,11b,c,f However, both © 2018 American Chemical Society

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RESULTS AND DISCUSSION Recently, the isonitrile insertion reaction has emerged as a powerful strategy for the construction of various heteroarenes, especially in the preparation of trifluoromethylated14 and polyfluoroalkylated15 heteroarenes. Despite of the high Received: September 28, 2018 Published: November 23, 2018 15236

DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

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The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

Scheme 1. Methods for the Preparation of CMe2CF3Containing Heteroarenes

effectiveness for this fluoroalkylation/cyclization strategy, the reported reactions normally employ expensive or difficult-tohandle fluoroalkylating reagents to generate fluoroalkyl radicals. On the other hand, decarboxylation of alkyl carboxylic acids to generate alkyl radical has been known for a long time.16 However, the decarboxylation of fluoroalkyl carboxylic acids has been rarely reported,17 even though the cheap and stable fluoroalkyl carboxylic acids are attractive fluoroalkyl radical sources. Inspired by recent work on radical fluoroalkylation with fluoroalkyl carboxylic acids,12,13a,17 we envisioned that the tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with TFDMPA might provide new access to CMe2CF3-containing heteroarenes. These CMe2CF3containing heteroarenes are previously unknown and potentially useful in the drug discovery process. To test our hypothesis, the reaction was investigated by using 2-isocyanobiphenyl (1a) as the model substrate with (NH4)2S2O8 as the oxidant in MeCN (Table 1, entry 1). However, none of the desired phenanthridine 3a was formed. The screening of different solvents revealed that DMSO/H2O was optimal, affording 3a in 25% yield (entries 2−6). Similar to our previous decarboxylative 1,1-dimethyltrifluoroethylation of heteroarenes with TFDMPA,12 the use of inorganic bases, such as K2CO3, Cs2CO3, NaOEt, t-BuOK, K3PO4, and K2HPO4, could promote this reaction (entries 7−12) and the highest yield of 3a was achieved in the presence of K3PO4 (entry 11). Switching (NH4)2S2O8 to Na2S2O8 or K2S2O8 resulted in lower yields (entries 13 and 14). Finally, neither lower nor higher temperature could improve the reaction efficiency (entries 15 and 16). With the optimized reaction conditions in hand (Table 1, entry 11), the substrate scope of this decarboxylative 1,1dimethyltrifluoroethylation with TFDMPA was explored. As shown in Scheme 2, various 2-isocyanobiaryl compounds (1a− t) underwent this reaction smoothly to deliver CMe2CF3substituted phenanthridine derivatives (3a−t) in moderate to excellent yields. A wide range of functional groups, such as ether, thioether, fluoro, chloro, cyano, and trifluoromethyl, were well tolerated under the present conditions. Notably, isonitriles 1u and 1v having a pyridine or dibenzo[b,d]thiophene ring instead of the benzene ring were also

entry

oxidant

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

(NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 Na2S2O8 K2S2O8 (NH4)2S2O8 (NH4)2S2O8

additive

solvent

yieldb (%)

K2CO3 Cs2CO3 NaOEt t-BuOK K3PO4 K2HPO4 K3PO4 K3PO4 K3PO4 K3PO4

MeCN DMSO DMF H2O DMSO/H2O MeCN/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O DMSO/H2O

0 8 trace 4 25 16 64 36 38 71 83 51 76 73 58 63

a

Reaction conditions: 1a (0.1 mmol), 2a (0.25 mmol), oxidant (0.25 mmol), additive (0.25 mmol), solvent (1.0 mL), 85 °C, under N2, 12 h. bYields determined by 19F NMR spectroscopy using trifluoromethylbenzene as an internal standard. cCosolvent/H2O (1.0/0.5 mL). d70 °C. e100 °C.

compatible in this reaction. The structure of 3v was confirmed by X-ray diffraction studies (see the Supporting Information). We also extended this methodology to the introduction of other CF3-derived groups to phenanthridines using the corresponding carboxylic acids. To our delight, CF3-containing tertiary carboxylic acids 2b−d underwent decarboxylative fluoroalkylation/cyclization smoothly, affording products 4a− c bearing different CF3-substituted cycloalkyl moieties in good yields (Scheme 3). However, decarboxylative fluoroalkylation of 1a with 1-(trifluoromethyl)cyclopropanecarboxylic acid failed to give the desired product, and no conversion of 1a was observed. Probably the generation and subsequent addition reactions of 1-(trifluoromethyl)cyclopropyl radical18 are more challenging than those of other 1-(trifluoromethyl)cycloalkyl radicals. Gratifyingly, tandem 1,1-dimethyltrifluoroethylation and cyclization of other types of isonitriles were also successful (Scheme 4). For instance, a series of vinyl isonitrile 5a−d were subjected to the standard reaction conditions to furnish CMe2CF3-substituted isoquinolines 6a−d in high yields. Furthermore, 1,1-dimethyltrifluoroethylation of 1-azido-2isocyanoarene 7 with TFDMPA gave benzoimidazole derivative 8 in 87% yield. To gain insight into the reaction mechanism, a well-known free-radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), was added to the standard reaction conditions of 1a, and the formation of product 3a was totally inhibited. This result indicated that a radical pathway was probably involved in this reaction. On the basis of this result and the previous reports,14,15,19 a plausible reaction pathway is proposed in Scheme 5. Initially, the oxidative decarboxylation of TFDMPA with (NH4)2S2O8 generates CMe2CF3 radical. Then the addition of CMe2CF3 radical to isonitriles affords imidoyl 15237

DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

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The Journal of Organic Chemistry Scheme 2. Substrate Scope of 1,1Dimethyltrifluoroethylation of Isonitriles with TFDMPAa

Scheme 4. Decarboxylative 1,1-Dimethyltrifluoroethylation of Isonitriles 5 and 7 with 2a

Scheme 5. Mechanistic Experiments

radical A, which subsequently undergoes intramolecular cyclization to provide radical intermediate B. Finally, the oxidative aromatization of B with (NH4)2S2O8 delivers the desired CMe2CF3-containing heteroarene. Obviously, the presence of a base would accelerate the aromatization step, thus leading to higher yields (Table 1, entries 7−12).

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a

Reaction conditions: 1 (0.2 mmol), 2a (0.5 mmol), (NH4)2S2O8 (0.5 mmol), K3PO4 (0.5 mmol), DMSO/H2O (2.0/1.0 mL), N2, 85 °C, 12 h, isolated yields.

CONCLUSION We have developed an efficient method for the direct introduction of CMe2CF3 into heteroarenes by tandem 1,1dimethyltrifluoroethylation and cyclization of isonitriles with TFDMPA. This work represents a new and practical synthesis of CMe2CF3-containing heteroarenes by cascade radical cyclization reactions. Given the increasing prevalence of CMe2CF3 in medicinally relevant compounds, we believe that this approach will extend the potential application of CMe2CF3-containing compounds in pharmaceutical chemistry. Further investigations of the other cascade cyclization reactions for the preparation of fluorinated compounds are underway in our laboratory.

Scheme 3. Decarboxylative Fluoroalkylation of 1a with CF3Containing Tertiary Carboxylic Acids 2b−da

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EXPERIMENTAL SECTION

General Experimental Methods. 1H NMR (TMS as the internal standard) and 19F NMR spectra (CFCl3 as the outside standard and low field is positive) were recorded on a 400 MHz spectrometer. 13 C{1H} NMR was recorded on 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. HRMS data were obtained on a GC-TOF mass

a

Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), (NH4)2S2O8 (0.5 mmol), K3PO4 (0.5 mmol), DMSO/H2O (2.0/1.0 mL), N2, 85 °C, 12 h, isolated yields.

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DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

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The Journal of Organic Chemistry

chromatography: mp 69−71 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 9.1 Hz, 1H), 8.42−8.33 (m, 1H), 8.09−7.99 (m, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.63−7.50 (m, 2H), 7.39−7.36 (m, 1H), 3.90 (s, 3H), 1.90 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.7, 155.5, 140.6, 129.6, 127.9 (q, J = 284.8 Hz), 127.5, 126.59, 126.56, 124.9, 123.3, 122.7, 120.1, 118.9, 108.0 (q, J = 4.0 Hz), 54.4, 49.2 (q, J = 25.3 Hz), 23.24, 23.22; 19F NMR (377 MHz, CDCl3) δ −71.22 (s, 3F); IR (thin film) ν 1463, 1216, 1188, 1132, 1100, 1003, 888 cm−1; MS (ESI) m/z 320 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H17F3NO [M + H]+ 320.1257, found 320.1256. 10-Methoxy-6-(1,1,1-tri flu o r o- 2 -me th yl p r op a n -2 -y l ) phenanthridine (3f). Compound 3f was obtained as a white solid (49.3 mg, 77%), hexane/EA = 100:1 as eluent for the column chromatography: mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 9.40 (d, J = 8.4 Hz, 1H), 8.13−8.07 (m, 2H), 7.66−7.46 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H), 1.88 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.7, 157.3, 142.9, 130.5, 128.9 (q, J = 284.8 Hz), 128.0, 127.7, 127.3, 126.6, 126.4, 125.0, 123.2, 120.0 (q, J = 4.0 Hz), 110.9, 55.8, 50.5 (q, J = 25.3 Hz), 24.49, 24.47; 19F NMR (377 MHz, CDCl3) δ −71.35 (s, 3F); IR (thin film) ν 1446, 1307, 1187, 1084, 1012, 817, 763, 709 cm−1; MS (ESI) m/z 320 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H17F3NO [M + H]+ 320.1257, found 320.1259. 8-(Methylthio)-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3g). Compound 3g was obtained as a colorless oil (32.9 mg, 49%), hexane/EA = 100:1 as eluent for the column chromatography: 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.7 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.63−7.56 (m, 3H), 2.55 (s, 3H), 1.89 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 155.5, 141.0, 136.5, 130.6, 129.7, 127.7 (q, J = 284.8 Hz), 127.7, 127.3, 126.7, 124.1, 122.8 (q, J = 4.0 Hz), 122.5, 122.2, 120.3, 49.2 (q, J = 24.2 Hz), 23.39, 23.36, 14.7; 19F NMR (377 MHz, CDCl3) δ −71.29 (s, 3F); IR (thin film) ν 1473, 1459, 1280, 1185, 1144, 1094, 1000, 836, 758, 696, 681 cm−1; MS (ESI) m/z 336 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H17F3NS [M + H]+ 336.1028, found 336.1027. 6-(1,1,1-Trifluoro-2-methylpropan-2-yl)-8-(trifluoromethoxy)phenanthridine (3h). Compound 3h was obtained as a white solid (47.0 mg, 63%), hexane/EA = 100:1 as eluent for the column chromatography: mp 54−56 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (d, J = 9.1 Hz, 1H), 8.45−8.43 (m, 1H), 8.37 (s, 1H), 8.12−8.09 (m, 1H), 7.71−7.90 (m, 3H), 1.89 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 155.8, 146.0, 141.4, 131.7, 129.9, 128.1, 127.5 (q, J = 284.8 Hz), 127.1, 124.3, 123.9, 122.2, 121.9, 120.9, 120.6, 118.4 (q, J = 4.0 Hz), 49.2 (q, J = 25.3 Hz), 23.31, 23.28; 19F NMR (376 MHz, CDCl3) δ ppm −57.89 (s, 3F), −71.64 (s, 3F); IR (thin film) ν 1256, 1187, 1144, 1100, 827, 762 cm−1; MS (ESI) m/z 374 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H14F6NO [M + H]+ 374.0974, found 374.0973. 8-Fluoro-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3i). Compound 3i was obtained as a white solid (39.3 mg, 64%), hexane/EA = 100:1 as eluent for the column chromatography: mp 70−72 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.64−8.60 (m, 1H), 8.42−8.40 (m, 1H), 8.16−8.13 (m, 2H), 7.67−7.58 (m, 2H), 7.52− 7.48 (m, 1H), 1.89 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 159.5 (d, J = 247.5 Hz), 155.6, 141.0, 129.9 (d, J = 1.0 Hz), 129.8, 127.6 (q, J = 284.8 Hz), 127.5, 126.9, 124.8 (d, J = 7.1 Hz), 124.2 (d, J = 8.1 Hz), 122.2, 120.4, 117.9 (d, J = 24.3 Hz), 111.9 (q, J = 4.0 Hz), 49.2 (q, J = 25.3 Hz), 23.21, 23.19; 19F NMR (376 MHz, CDCl3) δ ppm −71.61 (s, 3F), −111.87 to −111.94 (m, 1F); IR (thin film) ν 1227, 1146, 1114, 1003, 777, 763 cm−1; MS (ESI) m/z 308 [M + H]+; HRMS (ESI-TOF) m/z calcd for C17H14F4N [M + H]+ 308.1057, found 308.1055. 8-Chloro-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3j). Compound 3j was obtained as a yellow solid (43.4 mg, 67%), hexane/EA = 100:1 as eluent for the column chromatography: mp 84−86 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J = 8.9 Hz, 1H), 8.48 (d, J = 1.4 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.10−8.08 (m, 1H), 7.73−7.64 (m, 2H), 7.64−7.58 (m, 1H), 1.89 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ ppm 155.4, 141.3, 131.6, 131.5,

spectrometer. Unless otherwise noted, all reagents were obtained commercially and used without further purification. Substrates were purchased from commercial sources or were prepared according to literature procedures.14a,d,j,15f General Procedure for 1,1-Dimethyltrifluoroethylation of Isonitriles. To a mixture of isocyanide (0.2 mmol, 1.0 equiv), CF3containing tertiary carboxylic acid (0.5 mmol, 2.5 equiv), and K3PO4 (106.0 mg, 0.5 mmol, 2.5 equiv) in DMSO/H2O (2.0/1.0 mL) was added (NH4)2S2O8 (114.1 mg, 0.5 mmol, 2.5 equiv). The reaction mixture was stirred at 85 °C under nitrogen atmosphere for 12 h. After the reaction was complete, saturated NaHCO3 solution was added. The resulting mixture was extracted with EtOAc three times. The combined organic layer was washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography to give the desired product. 6-(1,1,1-Trifluoro-2-methylpropan-2-yl)phenanthridine (3a). Compound 3a was obtained as a white solid (41.7 mg, 72%), hexane/EA = 100:1 as eluent for the column chromatography: mp 50−52 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (d, J = 8.3 Hz, 1H), 8.52−8.47 (m, 2H), 8.10−8.08 (m, 1H), 7.80−7.70 (m, 1H), 7.67−7.58 (m, 3H), 1.91 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.5, 141.3, 133.2, 129.7, 128.6, 127.7 (q, J = 284.8 Hz), 127.6, 126.8 (q, J = 3.8 Hz), 126.5, 125.4, 123.6, 122.6, 121.9, 120.6, 49.2 (q, J = 24.6 Hz), 23.3; 19F NMR (376 MHz, CDCl3) δ ppm −71.52 (s, 3F); IR (thin film) ν 1281, 1184, 1140, 1116, 758, 728 cm−1; MS (ESI) m/z 290 [M + H]+; HRMS (ESI-TOF) m/z calcd for C17H15F3N [M + H]+ 290.1151, found 290.1149. 8-Methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3b). Compound 3b was obtained as a white solid (35.8 mg, 59%), hexane/EA = 100:1 as eluent for the column chromatography: mp 64−66 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (d, J = 8.5 Hz, 1H), 8.45−8.42 (m, 1H), 8.28 (s, 1H), 8.14−7.97 (m, 1H), 7.71− 7.45 (m, 3H), 2.54 (s, 3H), 1.90 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.2, 141.0, 135.2, 131.1, 130.3, 129.6, 127.8 (q, J = 284.8 Hz), 127.1, 126.41 (q, J = 3.0 Hz), 126.40, 123.8, 122.7, 121.8, 120.4, 49.3 (q, J = 25.3 Hz), 23.33, 23.31, 21.1; 19F NMR (376 MHz, CDCl3) δ ppm −71.52 (s, 3F); IR (thin film) ν 1281, 1183, 1117, 1026, 822, 756 cm−1; MS (ESI) m/z 304 [M + H]+; HRMS (ESITOF) m/z calcd for C18H17F3N [M + H]+ 304.1308, found 304.1306. 8 - t er t - B u t y l - 6 - ( 1 , 1 , 1 - t r ifl uoro-2-methylpr op an-2-yl)phenanthridine (3c). Compound 3c was obtained as a white solid (43.6 mg, 63%), hexane/EA = 100:1 as eluent for the column chromatography: mp 78−80 °C. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J = 8.8 Hz, 1H), 8.51 (s, 1H), 8.45−8.43 (m, 1H), 8.07−8.05 (m, 1H), 7.83−7.80 (m, 1H), 7.64−7.55 (m, 2H), 1.92 (s, 6H), 1.39 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.5, 148.2, 141.2, 130.9, 129.6, 127.8 (q, J = 284.8 Hz), 127.1, 126.9, 126.4, 123.6, 122.9 (q, J = 4.0 Hz), 122.6, 121.5, 120.5, 49.2 (q, J = 25.3 Hz), 34.2, 30.3, 23.43, 23.41; 19F NMR (376 MHz, CDCl3) δ ppm −71.37 (s, 3F); IR (thin film) ν 1479, 1281, 1186, 1099, 835, 759 cm−1; MS (ESI) m/z 346 [M + H]+; HRMS (ESI-TOF) m/z calcd for C21H23F3N [M + H]+ 346.1777, found 346.1776. 8-Phenyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3d). Compound 3d was obtained as a white solid (68.1 mg, 94%), hexane/EA = 100:1 as eluent for the column chromatography: mp 99−101 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.50−8.48 (m, 1H), 8.11−8.09 (m, 1H), 8.00− 7.97 (m, 1H), 7.70−7.64 (m, 3H), 7.62−7.58 (m, 1H), 7.48−7.45 (m, 2H), 7.39−7.33 (m, 1H), 1.95 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.6, 141.3, 139.6, 138.2, 132.2, 129.7, 128.2, 127.9, 127.62 (q, J = 287.9 Hz), 127.60, 126.8, 126.6, 126.4, 125.2 (q, J = 4.0 Hz), 124.0, 122.5, 122.4, 120.6, 49.3 (q, J = 25.3 Hz), 23.52, 23.50; 19F NMR (376 MHz, CDCl3) δ ppm −71.34 (s, 3F); IR (thin film) ν 1474, 1286, 1144, 1102, 841, 757 cm−1; MS (ESI) m/z 366 [M + H]+; HRMS (ESI-TOF) m/z calcd for C23H19F3N [M + H]+ 366.1464, found 366.1461. 8-Methoxy-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3e). Compound 3e was obtained as a white solid (30.7 mg, 48%), hexane/EA = 100:1 as eluent for the column 15239

DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

Article

The Journal of Organic Chemistry

cm−1; MS (ESI) m/z 360 [M + H]+; HRMS (ESI-TOF) m/z calcd for C22H25F3N [M + H]+ 360.1934, found 360.1936. 2-Methyl-8-phenyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3p). Compound 3p was obtained as a white solid (65.3 mg, 86%), hexane/EA = 100:1 as eluent for the column chromatography: mp 113−115 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.74−8.65 (m, 2H), 8.28 (s, 1H), 8.04−7.93 (m, 2H), 7.71− 7.61 (m, 2H), 7.53−7.42 (m, 3H), 7.36 (t, J = 7.4 Hz, 1H), 2.57 (s, 3H), 1.94 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 155.5, 139.7, 138.0, 136.6, 132.0, 129.4, 129.3, 128.1, 127.9 (q, J = 284.8 Hz), 127.6, 126.8, 126.4, 125.2 (q, J = 4.0 Hz), 124.1, 122.4, 122.3, 120.2, 49.2 (q, J = 24.2 Hz), 23.53, 23.51, 21.1; 19F NMR (376 MHz, CDCl3) δ ppm −71.36 (s, 3F); IR (thin film) ν 1488, 1282, 1183, 1107, 832, 761 cm−1; MS (ESI) m/z 380 [M + H]+; HRMS (ESITOF) m/z calcd for C24H21F3N [M + H]+ 380.1621, found 380.1618. 8-Methoxy-2-methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3q). Compound 3q was obtained as a white solid (34.0 mg, 51%), hexane/EA = 100:1 as eluent for the column chromatography: mp 124−126 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (d, J = 9.1 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.38−7.35 (m, 1H), 3.91 (s, 3H), 2.54 (s, 3H), 1.90 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.5, 154.5, 139.0, 136.5, 129.4, 128.4, 127.9 (q, J = 284.8 Hz), 127.3, 125.0, 123.3, 122.6, 119.7, 118.7, 107.9 (q, J = 4.0 Hz), 54.4, 49.5 (q, J = 24.2 Hz), 23.30, 23.28, 21.1; 19F NMR (376 MHz, CDCl3) δ ppm −71.25 (s, 3F); IR (thin film) ν 1618, 1468, 1350, 1180, 1124, 1044, 1017, 822 cm−1; MS (ESI) m/z 334 [M + H]+; HRMS (ESI-TOF) m/z calcd for C19H19F3NO [M + H]+: 334.1413, found 334.1416. 8-Fluoro-2-methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3r). Compound 3r was obtained as a white solid (41.1 mg, 64%), hexane/EA = 100:1 as eluent for the column chromatography: mp 92−94 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.61−8.57 (m, 1H), 8.18 (s, 1H), 8.14−8.10 (m, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.49−7.45 (m, 2H), 2.54 (s, 3H), 1.88 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 159.4 (d, J = 247.5 Hz), 154.6 (d, J = 4.0 Hz), 139.4, 136.9, 129.7 (d, J = 2.0 Hz), 129.5, 129.2, 127.7 (q, J = 284.8 Hz), 124.8 (d, J = 7.1 Hz), 124.1 (d, J = 7.1 Hz), 122.0, 120.0, 117.6 (d, J = 23.2 Hz), 111.7 (dq, J = 23.2, 4.0 Hz), 49.5 (q, J = 25.3 Hz), 23.24, 23.21, 21.1; 19F NMR (376 MHz, CDCl3) δ ppm −71.63 (s, 3F), −112.22 to −112.28 (m, 1F); IR (thin film) ν 1284, 1147, 1102, 1010, 904, 869 cm−1; MS (ESI) m/z 322 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H16F4N [M + H]+ 322.1213, found 322.1214. 8-Chloro-2-methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3s). Compound 3s was obtained as a white solid (37.8 mg, 56%), hexane/EA = 100:1 as eluent for the column chromatography: mp 116−118 °C;. 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (d, J = 8.9 Hz, 1H), 8.46 (d, J = 1.3 Hz, 1H), 8.20 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.68−7.65 (m, 1H), 7.50−7.48 (m, 1H), 2.55 (s, 3H), 1.88 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 154.4, 139.6, 137.0, 131.4, 131.3, 129.7, 129.5, 129.0, 127.6 (q, J = 285.8 Hz), 126.2 (q, J = 4.0 Hz), 124.6, 123.5, 121.9, 120.1, 49.6 (q, J = 25.3 Hz), 23.36, 23.33, 21.1; 19F NMR (376 MHz, CDCl3) δ ppm −71.66 (s, 3F); IR (thin film) ν 1399, 1279, 1120, 1001, 843, 780 cm−1; MS (ESI) m/z 338 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H16ClF3N [M + H]+ 338.0918, found 338.0915. 2-Fluoro-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3t). Compound 3t was obtained as a white solid (27.1 mg, 44%), hexane/EA = 100:1 as eluent for the column chromatography: mp 59−61 °C; 1H NMR (400 MHz, CDCl3) δ 8.56−8.44 (m, 2H), 8.14−7.98 (m, 2H), 7.81−7.71 (m, 1H), 7.63 (s, 1H), 7.46−7.32 (m, 1H), 1.89 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.7 (d, J = 248.5 Hz), 155.8, 138.2, 132.7 (d, J = 4.0 Hz), 132.0 (d, J = 9.1 Hz), 128.7, 127.7 (q, J = 284.8 Hz), 126.9 (q, J = 4.0 Hz), 126.1, 124.0 (d, J = 10.1 Hz), 123.7, 122.1, 116.6 (d, J = 25.3 Hz), 105.5 (d, J = 23.2 Hz), 49.2 (q, J = 25.3 Hz), 23.29, 23.27; 19F NMR (377 MHz, CDCl3) δ −71.67 (s, 3F), −112.04 to −112.12 (m, 1F); IR (thin film) ν 1495, 1178, 1145, 1126, 1111, 1098, 908, 826, 761, 666 cm−1;

129.8, 129.2, 127.9, 127.5 (q, J = 284.8 Hz), 127.0, 126.3 (q, J = 4.2 Hz), 124.5, 123.5, 122.0, 120.5, 49.2 (q, J = 24.8 Hz), 23.33, 23.30; 19 F NMR (376 MHz, CDCl3) δ ppm −71.63 (s, 3F); IR (thin film) ν 1474, 1282, 1144, 1097, 826, 758 cm−1; MS (ESI) m/z 324 [M + H]+; HRMS (ESI-TOF) m/z calcd for C17H14ClF3N [M + H]+ 324.0761, found 324.0758. 6-(1,1,1-Trifluoro-2-methylpropan-2-yl)phenanthridine-8-carbonitrile (3k). Compound 3k was obtained as a white solid (57.2 mg, 91%), hexane/EA = 100:1 as eluent for the column chromatography: mp 154−156 °C. 1H NMR (400 MHz, CDCl3) δ ppm 8.85 (s, 1H), 8.71 (d, J = 8.6 Hz, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.15−8.12 (m, 1H), 7.93−7.91 (m, 1H), 7.80−7.73 (m, 1H), 7.68−7.66 (m, 1H), 1.91 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 155.8, 142.2, 135.9, 132.2 (q, J = 4.0 Hz), 130.0, 129.9, 129.4, 127.5 (q, J = 284.8 Hz), 127.5, 123.2, 123.1, 121.4, 121.1, 117.7, 109.2, 49.3 (q, J = 25.3 Hz), 23.51, 23.49; 19F NMR (376 MHz, CDCl3) δ ppm −71.64 (s, 3F); IR (thin film) ν 1473, 1280, 1185, 1117, 1000, 836 cm−1; MS (ESI) m/z 315 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H14F3N2 [M + H]+ 315.1104, found 315.1101. 6-(1,1,1-Trifluoro-2-methylpropan-2-yl)-8-(trifluoromethyl)phenanthridine (3l). Compound 3l was obtained as a white solid (42.9 mg, 60%), hexane/EA = 100:1 as eluent for the column chromatography: mp 75−77 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (s, 1H), 8.74 (d, J = 8.7 Hz, 1H), 8.55−8.42 (m, 1H), 8.14−8.12 (m, 1H), 7.95−7.92 (m, 1H), 7.76−7.72 (m, 1H), 7.68−7.64 (m, 1H), 1.92 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.4, 142.0, 135.4, 129.9, 128.8, 127.2 (q, J = 33.8 Hz), 128.0 (q, J = 128.3 Hz), 127.2, 124.6 (q, J = 3.0 Hz), 124.4 (q, J = 4.0 Hz), 123.1 (q, J = 272.7 Hz), 123.0, 122.9, 121.0, 49.3 (q, J = 24.2 Hz), 23.47, 23.45; 19 F NMR (376 MHz, CDCl3) δ ppm −62.37 (s, 3F), −71.65 (s, 3F); IR (thin film) ν 1474, 1286, 1144, 1102, 841, 757 cm−1; MS (ESI) m/ z 358 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H14F6N [M + H]+ 358.1025, found 358.1022. 2-Methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3m). Compound 3m was obtained as a white solid (43.7 mg, 72%), hexane/EA = 100:1 as eluent for the column chromatography: mp 58−60 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.73−7.68 (m, 1H), 7.59−7.54 (m, 1H), 7.48−7.46 (m, 1H), 2.55 (s, 3H), 1.89 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 155.4, 139.7, 136.4, 133.0, 129.4, 129.3, 128.4, 127.8 (q, J = 284.8 Hz), 126.8 (q, J = 4.0 Hz), 125.2, 123.7, 122.4, 121.8, 120.2, 49.6 (q, J = 25.3 Hz), 23.34, 23.32, 21.0; 19F NMR (376 MHz, CDCl3) δ ppm −71.59 (s, 3F); IR (thin film) ν 1443, 1281, 1139, 1050, 999, 822 cm−1; MS (ESI) m/z 304 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H17F3N [M + H]+ 304.1308, found 304.1307. 2,8-Dimethyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3n). Compound 3n was obtained as a colorless oil (36.2 mg, 57%), hexane/EA = 100:1 as eluent for the column chromatography: 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 18.7 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 2.54 (s, 3H), 2.53 (s, 3H), 1.89 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 155.1, 139.4, 136.3, 135.0, 130.8, 130.1, 129.3, 128.9, 127.8 (q, J = 284.8 Hz), 126.4 (q, J = 3.0 Hz), 123.8, 122.5, 121.7, 120.0, 49.1 (q, J = 25.3 Hz), 23.35, 23.33, 21.12, 21.04; 19F NMR (377 MHz, CDCl3) δ −71.53 (s, 3F); IR (thin film) ν 1342, 1184, 1088, 993, 822, 788 cm−1; MS (ESI) m/z 318 [M + H]+; HRMS (ESI-TOF) m/z calcd for C19H19F3N [M + H]+ 318.1464, found 318.1464. 8-tert-Butyl-2-methyl-6-(1,1,1-trifluoro-2-methylpropan-2-yl)phenanthridine (3o). Compound 3o was obtained as a white solid (29.5 mg, 41%), hexane/EA = 100:1 as eluent for the column chromatography: mp 121−122 °C; 1H NMR (400 MHz, CDCl3) δ 8.63−8.46 (m, 2H), 8.22 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 2.54 (s, 3H), 1.91 (s, 6H), 1.39 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 155.5, 148.0, 139.5, 136.3, 130.7, 129.3, 128.9, 127.6 (q, J = 284.8 Hz), 126.7, 125.8 (q, J = 4.0 Hz), 123.6, 122.4, 121.5, 120.0, 49.5 (q, J = 25.3 Hz), 34.2, 30.3, 23.48, 23.46, 21.1; 19F NMR (377 MHz, CDCl3) δ −71.38 (s, 3F); IR (thin film) ν 1281, 1145, 1016, 834, 823, 794 15240

DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

Article

The Journal of Organic Chemistry MS (ESI) m/z 308 [M + H]+; HRMS (ESI-TOF) m/z calcd for C17H14F4N [M + H]+ 308.1057, found 308.1058. 5-(1,1,1-Trifluoro-2-methylpropan-2-yl)benzo[c][2,7]naphthyridine (3u). Compound 3u was obtained as a white solid (40.1 mg, 69%), hexane/EA = 30:1 as eluent for the column chromatography: mp 74−76 °C; 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (s, 1H), 8.82 (d, J = 5.5 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.82−7.78 (m, 1H), 7.68 (t, J = 7.6 Hz, 1H), 1.94 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.2, 150.0 (q, J = 4.0 Hz), 145.9, 142.6, 138.4, 130.0, 129.9, 127.3 (q, J = 284.8 Hz), 127.3, 121.1, 120.5, 119.1, 115.2, 49.2 (q, J = 25.2 Hz), 23.42, 23.40; 19F NMR (376 MHz, CDCl3) δ ppm −72.00 (s, 3F); IR (thin film) ν 1601, 1283, 1110, 1033, 990, 830 cm−1; MS (ESI) m/z 290 [M + H]+; HRMS (ESITOF) m/z calcd for C16H14F3N2 [M + H]+ 290.1104, found 290.1101. 6-(1,1,1-Trifluoro-2-methylpropan-2-yl)benzo[4,5]thieno[3,2-k]phenanthridine (3v). Compound 3v was obtained as a white solid (54.6 mg, 69%), hexane/EA = 50:1 as eluent for the column chromatography: mp 171−173 °C;. 1H NMR (400 MHz, CDCl3) δ ppm 9.12−9.04 (m, 1H), 8.65 (d, J = 9.0 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.26−8.17 (m, 2H), 7.98−7.87 (m, 1H), 7.81−7.70 (m, 2H), 7.52−7.42 (m, 2H), 1.97 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 156.8, 142.2, 139.2, 135.7, 133.7, 133.2, 130.1, 130.0, 127.8 (q, J = 284.8 Hz), 127.5, 126.6, 126.5, 124.02, 123.98, 123.4 (q, J = 4.0 Hz), 123.3, 122.2, 121.2, 121.0, 118.8, 49.5 (q, J = 25.3 Hz), 23.75, 23.72; 19F NMR (376 MHz, CDCl3) δ ppm −71.22 (s, 3F); IR (thin film) ν 1280, 1140, 1113, 1099, 818, 746 cm−1; MS (ESI) m/z 396 [M + H]+; HRMS (ESI-TOF) m/z calcd for C23H17F3NS [M + H]+ 396.1028, found 396.1028. 6-(1-(Trifluoromethyl)cyclobutyl)phenanthridine (4a). Compound 4a was obtained as a white solid (46.4 mg, 77%), hexane/ EA = 100:1 as eluent for the column chromatography: mp 126−128 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.5 Hz, 2H), 8.46 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.73−7.51 (m, 4H), 3.30 (d, J = 12.1 Hz, 2H), 1.90−1.83 (m, 2H), 1.54 (d, J = 13.4 Hz, 2H); 13 C{1H} NMR (101 MHz, CDCl3) δ 154.3, 142.7, 134.2, 130.6, 129.6, 128.5, 128.4 (q, J = 284.8 Hz), 127.6, 127.5 (q, J = 4.0 Hz), 126.6, 126.3, 123.6, 122.8, 121.7, 54.7 (q, J = 23.2 Hz), 31.6, 25.8, 21.7; 19F NMR (377 MHz, CDCl3) δ −71.35 (s, 3F); IR (thin film) ν 1355, 1227, 1118, 1054, 979, 755 cm−1 MS (ESI) m/z 302 [M + H]+; HRMS (ESI-TOF) m/z calcd for C18H15F3N [M + H]+ 302.1151, found 302.1153. 6-(1-(Trifluoromethyl)cyclopentyl)phenanthridine (4b). Compound 4b was obtained as a white solid (41.0 mg, 65%), hexane/ EA = 100:1 as eluent for the column chromatography: mp 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.3 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.79−7.51 (m, 4H), 3.08−3.02 (m, 2H), 2.63−2.56 (m, 2H), 1.84− 1.73 (m, 2H), 1.58 (d, J = 6.4 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.3, 142.5, 134.4, 130.7, 129.8, 129.1 (q, J = 283.8 Hz), 128.7 (q, J = 4.0 Hz), 128.6, 127.5, 126.3, 125.1, 123.8, 122.6, 121.7, 61.0 (q, J = 23.2 Hz), 35.4, 26.4; 19F NMR (377 MHz, CDCl3) δ −69.04 (s, 3F); IR (thin film) ν 1442, 1302, 1216, 1130, 1039, 923 cm−1; MS (ESI) m/z 316 [M + H]+; HRMS (ESI-TOF) m/z calcd for C19H17F3N [M + H]+ 316.1308, found 316.1307. 6-(1-(Trifluoromethyl)cyclohexyl)phenanthridine (4c). Compound 4c was obtained as a white solid (43.5 mg, 66%), hexane/ EA = 100:1 as eluent for the column chromatography: mp 122−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.5 Hz, 2H), 8.46 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.77−7.45 (m, 4H), 3.30 (d, J = 12.1 Hz, 2H), 1.90−1.83 (m, 2H), 1.54 (d, J = 13.4 Hz, 2H), 1.32−1.17 (m, 2H), 1.13−1.00 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.3, 142.7, 134.2, 130.6, 129.6, 128.5, 128.4 (q, J = 283.8 Hz), 127.6, 127.5 (q, J = 4.0 Hz), 126.6, 126.3, 123.6, 122.8, 121.7, 54.7 (q, J = 23.2 Hz), 31.6, 31.5, 25.8, 21.7; 19F NMR (377 MHz, CDCl3) δ −71.35 (s, 3F); IR (thin film) ν 1460, 1278, 1162, 1056, 895, 756 cm−1; MS (ESI) m/z 330 [M + H]+; HRMS (ESI-TOF) m/ z calcd for C20H19F3N [M + H]+ 330.1464, found 330.1465.

Ethyl 4-Phenyl-1-(1,1,1-trifluoro-2-methylpropan-2-yl)isoquinoline-3-carboxylate (6a). Compound 6a was obtained as a white solid (58.9 mg, 76%), hexane/EA = 20:1 as eluent for the column chromatography: mp 80−82 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (d, J = 8.7 Hz, 1H), 7.72−7.48 (m, 3H), 7.45− 7.35 (m, 3H), 7.32−7.22 (m, 2H), 4.04 (q, J = 7.1 Hz, 2H), 1.89 (s, 6H), 0.92 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 166.2, 156.0, 139.3, 136.3, 135.1, 132.1, 128.9, 128.6, 127.6 (q, J = 284.8 Hz), 127.2, 127.0, 126.7, 126.6, 126.5, 125.8 (q, J = 4.0 Hz), 60.1, 49.5 (q, J = 25.3 Hz), 23.38, 23.35, 12.6; 19F NMR (376 MHz, CDCl3) δ ppm −71.74 (s, 3F); IR (thin film) ν 1724, 1227, 1146, 1114, 1013, 777 cm−1; MS (ESI) m/z 388 [M + H]+; HRMS (ESITOF) m/z calcd for C22H21F3NO2 [M + H]+ 388.1519, found 388.1520. Ethyl 7-Methyl-4-(p-tolyl)-1-(1,1,1-trifluoro-2-methylpropan-2yl)isoquinoline-3-carboxylate (6b). Compound 6b was obtained as a white solid (58.9 mg, 70%), hexane/EA = 20:1 as eluent for the column chromatography: mp 83−85 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.37−7.32 (m, 1H), 7.23−7.19 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 2.50 (s, 3H), 2.38 (s, 3H), 1.88 (s, 6H), 0.97 (t, J = 8.0 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 166.4, 154.9, 138.5, 136.6, 134.6, 132.3, 132.2, 130.6, 128.7, 127.8, 127.7 (q, J = 284.8 Hz), 126.7, 126.6, 124.8 (q, J = 4.0 Hz), 114.5, 114.3, 60.0, 48.9 (q, J = 24.2 Hz), 23.34, 23.32, 21.33, 20.33, 12.7; 19F NMR (377 MHz, CDCl3) δ −71.72 (s, 3F); IR (thin film) ν 1735, 1519, 1416, 1198, 1110, 842 cm−1; MS (ESI) m/z 416 [M + H]+; HRMS (ESI-TOF) m/z calcd for C24H25F3NO2 [M + H]+ 416.1832, found 416.1831. Ethyl 7-Methoxy-4-(4-methoxyphenyl)-1-(1,1,1-trifluoro-2-methylpropan-2-yl)isoquinoline-3-carboxylate (6c). Compound 6c was obtained as a white solid (67.1 mg, 75%), hexane/EA = 20:1 as eluent for the column chromatography: mp 106−108 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.23−7.11 (m, 3H), 7.00−6.89 (m, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 1.88 (s, 6H), 0.99 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 166.5, 158.4, 157.3, 153.8, 137.8, 132.2, 131.8, 131.2, 130.0, 128.2, 128.0, 127.9 (q, J = 284.8 Hz), 127.3, 120.8, 112.6, 104.7 (q, J = 4.0 Hz), 59.9, 54.4, 54.3, 48.8 (q, J = 25.3 Hz), 23.14, 23.12, 12.8; 19F NMR (377 MHz, CDCl3) δ −71.37 (s, 3F); IR (thin film) ν 1722, 1518, 1407, 1289, 1108, 1013, 834 cm−1; MS (ESI) m/z 448 [M + H]+; HRMS (ESI-TOF) m/z calcd for C24H25F3NO4 [M + H]+ 448.1730, found 448.1726. Ethyl 7-Fluoro-4-(4-fluorophenyl)-1-(1,1,1-trifluoro-2-methylpropan-2-yl)isoquinoline-3-carboxylate (6d). Compound 6d was obtained as a white solid (72.8 mg, 86%), hexane/EA = 20:1 as eluent for the column chromatography: mp 87−89 °C; 1H NMR (400 MHz, CDCl3) δ 8.15−8.12 (m, 1H), 7.62−7.58 (m, 1H), 7.36−7.32 (m, 1H), 7.28−7.19 (m, 2H), 7.18−7.08 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 1.87 (s, 6H), 1.00 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.8, 161.7 (d, J = 249.5 Hz), 159.9 (d, J = 251.5 Hz), 155.6 (d, J = 6.1 Hz), 139.0, 133.4, 131.2, 130.6, 130.55, 130.47, 129.2 (d, J = 9.1 Hz), 127.6, 127.51, 127.48 (q, J = 284.8 Hz), 119.3 (d, J = 25.3 Hz), 114.5 (d, J = 22.2 Hz), 110.1 (dq, J = 23.7, 4.0 Hz), 60.3, 49.0 (q, J = 25.3 Hz), 23.18, 23.16, 12.8; 19F NMR (377 MHz, CDCl3) δ −71.80 (s, 3F), −108.40 to −108.46 (m, 1F), −113.39 to −113.45 (m, 1F); IR (thin film) ν 1735, 1519, 1416, 1198, 842, 793 cm−1; MS (ESI) m/z 424 [M + H]+; HRMS (ESI-TOF) m/z calcd for C22H19F5NO2 [M + H]+ 424.1330, found 424.1331. 2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-1H-benzo[d]imidazole (8). Compound 8 was obtained as a white solid (40.0 mg, 87%), hexane/EA = 10:1 as eluent for the column chromatography. This compound is easily sublimed: 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.25−7.16 (m, 2H), 1.68 (s, 6H); 13C{1H} NMR (101 MHz, DMSOd6) δ 151.7, 142.3, 134.8, 127.5 (q, J = 284.8 Hz), 122.6, 121.4, 119.0, 111.4, 42.6 (q, J = 26.3 Hz), 20.59, 20.58; 19F NMR (377 MHz, DMSO-d6) δ −74.76 (s, 3F); IR (thin film) ν 2996, 1415, 1279, 1128, 992, 741 cm−1; MS (ESI) m/z 229 [M + H]+; HRMS (ESI-TOF) m/ z calcd for C11H12F3N2 [M + H]+ 229.0947, found 229.0946. 15241

DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

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The Journal of Organic Chemistry

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(4) For recent reviews, see: (a) Toulgoat, F.; Alazet, S.; Billard, T. Direct Trifluoromethylthiolation Reactions. Eur. J. Org. Chem. 2014, 2014, 2415−2428. (b) Shao, X.; Xu, C.; Lu, L.; Shen, Q. Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation. Acc. Chem. Res. 2015, 48, 1227−1236. (c) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Synthetic Methods for Compounds Having CF3−S Units on Carbon by Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related Reactions. Chem. Rev. 2015, 115, 731−764. (d) Chachignon, H.; Cahard, D. State-of-the-Art in Electrophilic Trifluoromethylthiolation Reagents. Chin. J. Chem. 2016, 34, 445−454. (e) BarataVallejo, S.; Bonesi, S.; Postigo, A. Late Stage Trifluoromethylthiolation Strategies for Organic Compounds. Org. Biomol. Chem. 2016, 14, 7150−7182. (f) Zheng, H.; Huang, Y.; Weng, Z. Recent Advances in Trifluoromethylthiolation Using Nucleophilic Trifluoromethylthiolating Reagents. Tetrahedron Lett. 2016, 57, 1397−1409. (5) For selected examples, see: (a) Chen, C.; Ouyang, L.; Lin, Q.; Liu, Y.; Hou, C.; Yuan, Y.; Weng, Z. Synthesis of CuI Trifluoromethylselenates for Trifluoromethylselenolation of Aryl and Alkyl Halides. Chem. - Eur. J. 2014, 20, 657−661. (b) Aufiero, M.; Sperger, T.; Tsang, A. S. K.; Schoenebeck, F. Highly Efficient CSeCF3 Coupling of Aryl Iodides Enabled by an Air-Stable Dinuclear PdI Catalyst. Angew. Chem., Int. Ed. 2015, 54, 10322−10326. (c) Lefebvre, Q.; Pluta, R.; Rueping, M. Copper Catalyzed Oxidative Coupling Reactions for Trifluoromethylselenolations-Synthesis of RSeCF3 Compounds Using Air Stable Tetramethylammonium Trifluoromethylselenate. Chem. Commun. 2015, 51, 4394−4397. (d) Matheis, C.; Wagner, V.; Goossen, L. J. Sandmeyer-Type Trifluoromethylthiolation and Trifluoromethylselenolation of (Hetero)Aromatic Amines Catalyzed by Copper. Chem. - Eur. J. 2016, 22, 79−82. (e) Dürr, A. B.; Fisher, H. C.; Kalvet, I.; Truong, K.N.; Schoenebeck, F. Divergent Reactivity of a Dinuclear (NHC)Nickel(I) Catalyst versus Nickel(0) Enables Chemoselective Trifluoromethylselenolation. Angew. Chem., Int. Ed. 2017, 56, 13431− 13435. (f) Zhang, B.-S.; Gao, L.-Y.; Zhang, Z.; Wen, Y.-H.; Liang, Y.M. Three-Component Difluoroalkylation and Trifluoromethylthiolation/trifluoromethylselenolation of π-Bonds. Chem. Commun. 2018, 54, 1185−1188. (6) For selected examples, see: (a) Zhao, Y.; Hu, J. PalladiumCatalyzed 2,2,2-Trifluoroethylation of Organoboronic Acids and Esters. Angew. Chem., Int. Ed. 2012, 51, 1033−1036. (b) Zhang, H.; Chen, P.-H.; Liu, G.-S. Palladium-Catalyzed Cascade C-H Trifluoroethylation of Aryl Iodides and Heck Reaction. Angew. Chem., Int. Ed. 2014, 53, 10174−10178. (c) Luo, H.; Wu, G.; Zhang, Y.; Wang, J. Silver(I)-Catalyzed N-Trifluoroethylation of Anilines and O-Trifluoroethylation of Amides with 2,2,2-Trifluorodiazoethane. Angew. Chem., Int. Ed. 2015, 54, 14503−14507. (d) Yu, X.; Cohen, S. M. Photocatalytic Metal−Organic Frameworks for Selective 2,2,2Trifluoroethylation of Styrenes. J. Am. Chem. Soc. 2016, 138, 12320−12323. (7) For selected examples, see: (a) Niedermann, K.; Früh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A. Direct Electrophilic NTrifluoromethylation of Azoles by a Hypervalent Iodine Reagent. Angew. Chem., Int. Ed. 2012, 51, 6511−6515. (b) Teng, F.; Cheng, J.; Bolm, C. Silver-Mediated N-Trifluoromethylation of Sulfoximines. Org. Lett. 2015, 17, 3166−3169. (c) Scattolin, T.; Deckers, K.; Schoenebeck, F. Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench-Stable Precursor (Me4N)SCF3. Angew. Chem., Int. Ed. 2017, 56, 221−224. (d) Yu, J.; Lin, J.-H.; Xiao, J.-C. Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines. Angew. Chem., Int. Ed. 2017, 56, 16669−16673. (8) For selected examples, see: (a) Xu, X.-H.; Taniguchi, M.; Wang, X.; Tokunaga, E.; Ozawa, T.; Masuda, H.; Shibata, N. Stereoselective Synthesis of Vinyl Triflones and Heteroaryl Triflones through Anionic O→Cvinyl and N→Cvinyl Trifluoromethanesulfonyl Migration Reactions. Angew. Chem., Int. Ed. 2013, 52, 12628−12631. (b) Xie, F.; Zhang, Z.; Yu, X.; Tang, G.; Li, X. Diaryliodoniums by Rhodium(III)Catalyzed C−H Activation. Angew. Chem., Int. Ed. 2015, 54, 7405− 7409. (c) Zhang, K.; Xu, X.-H.; Qing, F. L. Copper-Promoted

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02506.

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X-ray crystallographic data for 3v (CIF) NMR spectra of all compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Feng-Ling Qing: 0000-0002-7082-756X Xiu-Hua Xu: 0000-0002-0759-2286 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21502215, 21421002, 21332010), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), and Youth Innovation Promotion Association CAS (2016234).

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REFERENCES

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DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244

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DOI: 10.1021/acs.joc.8b02506 J. Org. Chem. 2018, 83, 15236−15244