Synthesis of CMe2CF3-Containing Heteroarenes via Tandem 1, 1

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Synthesis of CMe2CF3-Containing Heteroarenes via Tandem 1,1-Dimethyltrifluoroethylation and Cyclization of Isonitriles Wen-Qiang Shi, Shuai Liu, Chen-Ze Wang, Yangen Huang, Feng-Ling Qing, and Xiu-Hua Xu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02506 • Publication Date (Web): 23 Nov 2018 Downloaded from http://pubs.acs.org on November 24, 2018

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The Journal of Organic Chemistry

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

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 E-mail: [email protected]

Table of Graphic Contents

O

Ar + NC

Me F3C

Me

(NH4)2S2O8 K3PO4

OH DMSO/H O 2 85°C

Ar Me CF Me 3 27 examples 41-94% yields N

Abstract A tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with 3,3,3-trifluoro-2,2dimethylpropanoic acid (TFDMPA) 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 CF3derived 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.

SCF3

OCF3

SeCF3

CF3

CMe2CF3 SO2CF3

NRCF3

CH2CF3

less attention

increasing attention

much attention

Figure 1. Trifluoromethyl (CF3) and CF3-derived groups Me F3C Me H N

N S

O N N H

N H

N

O OMe

BRAFV600E inhibitor (ref 10a) OMe

N O H2N

O

F

MeO2S

PI3K inhibitor (ref 10b)

O N H

N Me Me CF3

N

O

N H

N TRPV1 antagonist (ref 10c)

Me CF Me 3

Figure 2. CMe2CF3-containing bioactive compounds

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 ACS Paragon Plus Environment

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examples of CMe2CF3-containing 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 approaches require several steps, which are neither atom-economical 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 1,1dimethyltrifluoroethylation and cyclization of isonitriles with TFDMPA for the preparation of CMe2CF3-containing heteroarenes (Scheme 1d).

Scheme 1. Methods for the Preparation of CMe2CF3-Containing Heteroarenes previous work

O Me

(Het) Ar

HO CF3 1) NaH, MsCl Me 2) AlMe3 (Het)

[-CF3]

Ar

Me CF3 Me

R

several steps (Het) Ar

O O

H (Het) Ar

+

Me F3C

OH Me

(NH4)2S2O8 K3PO4 DMSO/H2O

this work (Het) Ar

NC

Me F3C

(Het) Ar

Me CF3 Me

(b)

Me CF3 Me

(Het) Ar

(c)

(Het) Ar

O +

Me CF3 Me (a)

OH

oxidant

Me

N

Me (d) CF Me 3


3


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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 effectiveness for this fluoroalkylation/cyclization strategy, the reported reactions normally employ expensive or difficult-to-handle 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 despite 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 the new access to CMe2CF3-containing heteroarenes. These CMe2CF3-containing 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 1,1dimethyltrifluoroethylation 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 highest yield of 3a was achieved in the presence of K3PO4 (entry 11). Switching of (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).


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Table 1. Optimization of Reaction Conditionsa

NC

Me + F3C

1a

CO2H Me 2a

oxidant additive solvent, 85 oC

N 3a

Me CF Me 3

entry

oxidant

additive

solvent

yield (%)b

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

― — — — — — 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

aReaction

conditions: 1a (0.1 mmol), 2a (0.25 mmol), oxidant (0.25 mmol), additive (0.25 mmol), solvent (1.0 mL), 85 oC, under N2, 12 h. bYields determined by 19F NMR spectroscopy using trifluoromethylbenzene as an internal standard. cCo-solvent/H2O (1.0/0.5 mL). d70 oC. e100 oC. With the optimized reaction conditions in hand (Table 1, entry 11), the substrate scope of this decarboxylative 1,1-dimethyltrifluoroethylation 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 compatible in this reaction. The structure of 3v was confirmed by X-ray diffraction studies (see the supporting information). ACS Paragon Plus Environment

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Scheme 2. Substrate Scope of 1,1-Dimethyltrifluoroethylation of Isonitriles with TFDMPAa

R1

R1 Me + F3C

R2 NC 1

(NH4)2S2O8

CO2H K3PO4

R2

DMSO/H2O 85°C

Me 2a

H

N 3

t-Bu

Me

Me CF3 3a, 72% Me

Me CF3 3c, 63% Me

Me CF3 3b, 59% Me

N

N

N

Ph

OMe

Me CF3 3d, 94% Me

MeO

Me CF3 3e, 48% Me

N

N

SMe

Me CF3 3g, 49% Me N

F

Me CF3 3h, 63% Me

Me CF3 3i, 64% Me

CN

CF3

Cl

Me CF3 3j, 67% Me

Me CF3 3f, 77% Me N

OCF3

N

Me CF3 3k, 91% Me

N

Me CF Me 3

N

N

Me CF3 3l, 60% Me N

R F

Me Me CF Me 3 3m (R = H), 72%; 3n (R = Me), 57%; 3o (R = t-Bu), 41%; 3p (R = Ph), 86%; 3q (R = OMe), 51%; 3r (R = F), 64%; 3s (R = Cl), 56%

N

N

3t, 44%

Me CF Me 3

N

S

Me CF Me 3 3v, 69% N

N 3u, 69%

Me CF Me 3

aReaction

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 oC, 12 h, isolated yields.


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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-substitued 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 is more challenge than other 1(trifluoromethyl)cycloalkyl radicals.

Scheme 3. Decarboxylative Fluoroalkylation of 1a with CF3-Containing Tertiary Carboxylic Acids 2b-da

NC 1a

N F3C 4a, 77%

R + F3C

(NH4)2S2O8

CO2H K3PO4

DMSO/H2O 85°C

R 2

N F3C 4b, 65%

N 4

R

R CF3

N F3C 4c, 66%

aReaction

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 oC, 12 h, isolated yields.

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 furnishing CMe2CF3-substituted isoquinolines 6a-d in high yields. Furthermore, 1,1dimethyltrifluoroethylation of 1-azido-2-isocyanoarene 7 with TFDMPA gave benzoimidazole derivative 8 in 87% yield.


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

R

CO2Et NC

Me + F3C

CO2H Me

R 5a (R = H); 5b (R = Me); 5c (R = OMe); 5d (R = F) N3 + NC

(NH4)2S2O8 K3PO4

CO2Et

DMSO/H2O 85°C

N Me Me CF3 R 6a (R = H), 76%; 6b (R = Me), 70%; 6c (R = OMe), 75%; 6d (R = F), 86%

2a

Me F3C

7

CO2H Me 2a

(NH4)2S2O8 K3PO4 DMSO/H2O 85°C

H N

Me CF3 N Me 8, 87%

In order to gain insight into the reaction mechanism, a well-known free radical scavenge, 2,2,6,6tetramethyl-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 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).

Scheme 5. Mechanistic Experiments


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O + NC

Me F3C

OH

(NH4)2S2O8 K3PO4

N

Me (NH4)2S2O8

Me F3C

N A

Me

(NH4)2S2O8 K3PO4

Me CF Me 3

Me CF Me 3 H+

H

N B

Me CF Me 3

Conclusion We have developed an efficient method for the direct introduction of CMe2CF3 into heteroarenes by tandem 1,1-dimethyltrifluoroethylation 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.

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. 13C{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 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 ACS Paragon Plus Environment

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To a mixture of isocyanide (0.2 mmol, 1.0 equiv), CF3-containing tertiary carboxylic acid (0.5 mmol, 2.5 equiv) in DMSO/H2O (2.0/1.0 mL) was added K3PO4 (106.0 mg, 0.5 mmol, 2.5 equiv) and (NH4)2S2O8 (114.1 mg, 0.5 mmol, 2.5 equiv). The reaction mixture was stirred at 85 oC under nitrogen atmosphere for 12 h. After the reaction was complete, saturated NaHCO3 solution was added. The resulting mixture was extracted with EtOAc for 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 oC. 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), 7.807.70 (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 Calculated 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 oC. 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 (ESI-TOF): m/z Calculated for C18H17F3N [M+H]+: 304.1308; Found: 304.1306. 8-Tert-butyl-6-(1,1,1-trifluoro-2-methylpropan-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 7880 oC. 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 Calculated 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 oC. 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), 8.11ACS Paragon Plus Environment

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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 Calculated 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 chromatography. Mp 69-71 oC. 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 Calculated for C18H17F3NO [M+H]+: 320.1257; Found: 320.1256. 10-Methoxy-6-(1,1,1-trifluoro-2-methylpropan-2-yl)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 120122 oC. 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 Calculated 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 Calculated 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 oC. 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, ACS Paragon Plus Environment

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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 Calculated 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 oC. 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 Calculated 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 oC. 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); 13C{1H} NMR (100 MHz, CDCl3) δ ppm 155.4, 141.3, 131.6, 131.5, 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;

19F

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 Calculated 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 oC. 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 Calculated 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 oC. 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} ACS Paragon Plus Environment

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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; 19F 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 (ESITOF): m/z Calculated 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 oC. 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 Calculated 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 Calculated 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 oC. 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 cm-1; MS (ESI): m/z 360 [M+H]+; HRMS (ESI-TOF): m/z Calculated 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 oC. 1H NMR (400 MHz, CDCl3) δ ppm 8.74-8.65 (m, 2H), 8.28 (s, 1H), 8.04-7.93 (m, 2H), ACS Paragon Plus Environment

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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 (ESI-TOF): m/z Calculated 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 oC. 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 Calculated 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 oC. 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 Calculated 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 oC. 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 Calculated for C18H16ClF3N [M+H]+: 338.0918; Found: 338.0915.


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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 oC. 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; MS (ESI): m/z 308 [M+H]+; HRMS (ESI-TOF): m/z Calculated 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 oC. 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 (ESI-TOF): m/z Calculated 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 oC. 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), 7.527.42 (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 Calculated 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 oC. 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);

13C{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


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(ESI): m/z 302 [M+H]+; HRMS (ESI-TOF): m/z Calculated 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 oC. 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 Calculated 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 oC. 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 Calculated 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 oC. 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 (ESI-TOF): m/z Calculated for C22H21F3NO2 [M+H]+: 388.1519; Found: 388.1520. Ethyl

7-methyl-4-(p-tolyl)-1-(1,1,1-trifluoro-2-methylpropan-2-yl)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 oC. 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);

13C{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, ACS Paragon Plus Environment

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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 Calculated 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 oC. 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); 13C{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 Calculated 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 oC. 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 = 25.3Hz), 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 Calculated 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, DMSO-d6) 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 Calculated for C11H12F3N2 [M+H]+: 229.0947; Found: 229.0946.


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Supporting Information Available: Copies of NMR spectra of all compounds and X-ray crystallography data of 3v. These material are available free of charge via the Internet at http://pubs.acs.org. Acknowledgment 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). References (1) (a) Purser, S.; Moore, P. R.; Swallow, S. Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320-330. (b) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati, G. The Fluorous Effect in Biomolecular Applications. Chem. Soc. Rev. 2012, 41, 31-42. (c) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C. A.; Sorochinsky, E.; Fustero, S. V.; Soloshonok, A.; Liu, H. Fluorine in Pharmaceutical Industry. Chem. Rev. 2014, 114, 2432-2506. (d) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822-5880. (2) For selected reviews, see: (a) Tomashenko, O. A; Grushin, V. V. Aromatic Trifluoromethylation with Metal Complexes. Chem. Rev. 2011, 111, 4475-4521. (b) Studer, A. A “Renaissance” in Radical Trifluoromethylation. Angew. Chem. Int. Ed. 2012, 51, 8950-8958. (c) Chu, L; Qing, F.-L. Oxidative Trifluoromethylation and Trifluoromethylthiolation Reactions Using (Trifluoromethyl)trimethylsilane as a Nucleophilic CF3 Source. Acc. Chem. Res. 2014, 47, 15131522. (d) Charpentier, J.; Früh, N.; Togni, A. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev. 2015, 115, 650-682. (e) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Trifluoromethyltrimethylsilane. Chem. Rev. 2015, 115, 683-730. (f) Alonso, C.; de Marigorta, E. M.; Rubiales, G.; Palacios, F. Carbon Trifluoromethylation Reactions of Hydrocarbon Derivatives and Heteroarenes. Chem. Rev. 2015, 115, 1847-1935. (3) For selected examples, see: (a) Huang, C.; Liang, T.; Harada, S.; Lee, E.; Ritter, T. Silver-Mediated Trifluoromethoxylation of Aryl Stannanes and Arylboronic Acids. J. Am. Chem. Soc. 2011, 133, 13308-13310. (b) Liu, J. B.; Chen, C.; Chu, L.; Chen, Z. H.; Xu, X. H.; Qing, F. L. Silver-Mediated Oxidative Trifluoromethylation of Phenols. Angew. Chem. Int. Ed. 2015, 54, 11839-11842. (c) Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. Asymmetric Silver-Catalysed Intermolecular Bromotrifluoromethoxylation of Alkenes with a New Trifluoromethoxylation Reagent. Nat. Chem. 2017, 9, 546-551. (d) Jiang, X.; Deng, Z.; Tang, P. Direct Dehydroxytrifluoromethoxylation of Alcohols. Angew. Chem. Int. Ed. 2018, 57, 292-295. (e) Zheng, W.; Morales-Rivera, C. A.; Lee, J, W.; Liu, P.; Ngai, M.-Y. Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes. Angew.


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Synthesis of CMe2CF3-Containing Heteroarenes via Tandem 1, 1

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