Palladium-catalyzed intramolecular C−H bond functionalization of trifluoroacetimidoyl chloride derivatives: Synthesis of 6-trifluoromethyl-phenanthridines

Journal of Fluorine Chemistry 163 (2014) 23–27

Contents lists available at ScienceDirect

Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor

Palladium-catalyzed intramolecular CH bond functionalization of trifluoroacetimidoyl chloride derivatives: Synthesis of 6-trifluoromethyl-phenanthridines Mei Zhu a, Weijun Fu a,*, Guanglong Zou b, Chen Xu a, Zhiqiang Wang a a b

College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang 471022, PR China School of Chemistry and Environmental Science, Guizhou Minzu University, Guiyang 550025, PR China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 March 2014 Received in revised form 8 April 2014 Accepted 9 April 2014 Available online 21 April 2014

Highly efficient approaches to obtain 6-trifluoromethyl-phenanthridine derivatives have been realized through the palladium-catalyzed intramolecular C–H bond functionalization of trifluoroacetimidoyl chlorides. The reaction allows the direct formation of CSp2–CSp2 bonds via C–H bond functionalization and rapid access to phenanthridine ring systems in moderate to high yields with good functional group tolerance. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Palladium-catalyzed Phenanthridines Trifluoroacetimidoyl chlorides C–H functionalization

1. Introduction Phenanthridine is a ubiquitous framework found in many natural products [1–4], biologically active molecules [5–7], and optoelectronic materials [8–10]. Therefore, molecules containing this motif have attracted considerable attention in medicinal chemistry, and much effort has been focused on the synthetic methods of the phenanthridine ring system [11–17]. In particular, CF3-containing phenanthridines are of significant interest because trifluoromethyl group enhance biological and therapeutic activities of organic compounds. In 2013, Wu and co-workers reported rhodium-catalyzed [2 + 2 + 2] cycloaddition reaction between diynes and alkynes leading to CF3-containing phenanthridines [18]. Zhang and co-workers described the first example of a Pdcatalyzed tandem Suzuki/C–H arylation reaction of N-aryltrifluoroacetimidoyl chlorides with arylboronic acids [19]. More recently, another efficient strategy to build the phenanthridine scaffold was based on intermolecular radical addition/cyclization of 2-isocyanobiaryls with CF3 radicals developed by the groups of Studer and co-workers, Zhou and co-workers and Yu and co-workers, respectively [20–22].

* Corresponding author. Tel.: +81 39 69810261. E-mail address: [email protected] (W. Fu). http://dx.doi.org/10.1016/j.jfluchem.2014.04.005 0022-1139/ß 2014 Elsevier B.V. All rights reserved.

Trifluoroacetimidoyl chlorides, easily prepared from commercially available trifluoroacetic acid (TFA), amines, PPh3, and Et3N in CCl4 in a one-pot manner [23], are one kind of the most important intermediates and versatile building blocks in organic synthesis [24–26]. For example, they are widely used as one of the coupling partners in transition-metal-catalyzed carbon–carbon bond formations via cross-coupling reactions [27–31]. Meanwhile, transition-metal-catalyzed C(sp2)–Cl bonds of trifluoroacetimidoyl chlorides were inserted into multiple bond have been explored [32]. Recently, transition-metal-catalyzed C–H bond functionalization has emerged as a useful, step-economical method for the direct conversion of C–H bonds to C–C and C–heteroatom bonds [33–38]. Inspired by recent advance on transition-metal-catalyzed direct C–H bond functionalizations and in parallel with our continuing efforts to develop synthetic methods of CF3-containing heterocycles [39–42], we report here an efficient protocol for the synthesis of 6-trifluoromethyl-phenanthridines via palladiumcatalyzed intramolecular aromatic C–H bond functionalization of trifluoroacetimidoyl chlorides (Scheme 1). 2. Results and discussion Initially, we started to evaluate the reaction parameters by employing N-biaryltrifluoroacetimidoyl chloride (1a) as model substrate. To our delight, the use of 10 mol% Pd(OAc)2 as the catalyst, K2CO3 (2.0 equiv) as the base and PPh3 as the ligand in

M. Zhu et al. / Journal of Fluorine Chemistry 163 (2014) 23–27

24 Table 1 Reactions of 1a under different conditions.a

Pd,base, ligand Cl N 1a

solvent, 120 oC

N

CF3

CF3

2a

Entry

Catalyst

Base

Ligand

Solvent

Yield (%)b

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

Pd(OAc)2 Pd(PPh3)4 Pd(PPh3)2Cl2 Pd(CH3CN)2Cl2 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K3PO4 Cs2CO3 Na2CO3 KOAc K2CO3 K2CO3 K2CO3

PPh3 PPh3 PPh3 PPh3 PCy3 P(tBu)3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3 PCy3

Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene DMF DMSO CH3CN

48 62 38 Trace 72 64 45 54 37 Trace 43 Trace Trace

a b

Reaction conditions: 1a (0.4 mmol), [Pd] (10 mol%), ligand (20 mol%), base (0.8 mmol) in solvent (4.0 mL) at 120 8C under N2 atmosphere for 12 h. Isolated yield.

toluene at 120 8C could give the corresponding 6-trifluoromethylphenanthridine 2a in 48% yield (Table 1, entry 1). Then we tried other palladium source, such as Pd(PPh3)4, Pd(PPh3)2Cl2 and Pd(CH3CN)2Cl2. The results indicated that Pd(0) was more effective than Pd(II) species and Pd(PPh3)4 displayed the highest reactivity in the model reaction (Table 1, entries 1–4). Then, we investigated the effect of ligands [PPh3, PCy3, and P(tBu)3] on the reaction and observed that the addition of PCy3 or P(tBu)3 as ligand afforded better yields of 72% and 64%, respectively (Table 1, entries 5–6). The base also plays an important role in the cyclization reaction. K2CO3 was found to be the best one among the bases investigated. Other bases such as K3PO4, Cs2CO3, and Na2CO3 were inferior and generated 2a in 37–54% yields (Table 1, entries 7–9). Only a trace amount of 2a was detected when KOAc was used as a base (Table 1, entry 10). Polar solvents such as DMF, DMSO and CH3CN were unfavorable for this transformation (Table 1, entries 11–13). With the optimized conditions in hand, we then explored the scope and generality of the present process, and the results are summarized in Table 2. As shown in Table 2, a variety of substituents (such as Me, OMe, F, Cl, and CF3) on the 40 -position of the aromatic ring were applicable, affording the cyclized products in good yields (Table 2, entries 1–7). The reaction also worked well with 20 -substituted substrate, albeit giving the products in moderate yields (Table 2, entries 8–9). As expected, 30 -substituted substrate 1k gave a mixture of two regioselective products (products 2k/2k0 ). In addition, 2-thiophenyl trifluoroacetimidoyl chloride 1l were also viable substrate to provide a thieno-[3,2c]quinoline system (2l). Subsequently, the effect of the substituents on the aromatic ring attached to trifluoroacetimidoyl

R2

chloride was screened. In all cases, substrates 1m–q proceeded smoothly to give the corresponding products 2m–q in moderate to good yields (Table 2, entries 12–16). Likewise, the perfluoroalkylated substrate 1r was also tested in this cyclization reaction, and the corresponding 6-perfluoroalkylated phenanthridine 2r was formed smoothly. The structure of 2r was unequivocally confirmed by single-crystal X-ray analysis (Fig. 1) [43]. To gain insight into the mechanism, we tried the TEMPOtrapping experiment. That is, treatment of 1a in the presence of TEMPO (1.2 equiv), Pd(PPh3)4 (10 mol%), PCy3 (20 mol%), K2CO3 (2.0 equiv) in toluene at 120 8C for 12 h afforded the cyclized product 2a in 70% yield (Scheme 2). This result indicated that radical pathway can be ruled out. A proposed reaction mechanism was shown in Scheme 3. The oxidative addition of trifluoroacetimidoyl chloride 1 to Pd(0) species afforded intermediate A. Subsequently, A underwent an intramolecular electrophilic aromatic palladation through C–H

R2

10 mol% Pd(PPh3)4 20 mol% PCy3

Cl R1

N CF3 1

2.0 equiv. K2CO3

R1

N

CF3

o

toluene,120 C

2

Scheme 1. Palladium-catalyzed intramolecular C–H bond functionalization of trifluoroacetimidoyl chlorides.

Fig. 1. X-ray crystal structure of 2r.

M. Zhu et al. / Journal of Fluorine Chemistry 163 (2014) 23–27 Table 2 Synthesis of 6-trifluoromethyl-phenanthridines.a Entry

Substrate

1 2 3 4 5 6 7

Ar2 Yield (%)b

Product

R

R

Cl N

CF3

N CF3

8 9

R = H, 2b, 75 R = Et, 2c, 70 R = OCH3, 2d, 67 R = F, 2e, 77 R = Cl, 2f, 69 R = CF3, 2g, 80 R = Ph, 2h, 62

Ar1

Ar2 Ar1

Cl N CF3

1

Pd(II)Cl N

Pd(0)

CF3

A

R = CH3, 2i, 58 R = OCH3, 2j, 51

R

R

25

Ar2

Ar2 Cl CF3

N

N

Ar1

CF3 10

P

OCH3

OCH3

2k + 2k0 (o:p = 3:2)c, 65

N B

CF3

Scheme 3. Plausible reaction mechanism.

CF3

activation of the aromatic hydrogen, and subsequent proton abstraction,[44,45] forming the palladacycle B, which followed by a reductive elimination to afford the desired product 2.

2l, 47

S

S

Pd(II)

CF3

N

N 11

Ar1

2

o

Cl

CF3

N

Cl N

N

CF3

3. Conclusion

CF3 12 13

R = CH3, 2m, 70 R = F, 2n, 82

R

R Cl

CF3

N

N CF3

2o, 79

14

4. Experimental

Cl F3C

N

F3C

N

CF3

4.1. General

CF3 15 16

R = CH3, 2p, 65 R = Cl, 2q, 76

R

R Cl N CF3

R

N

CF3

R 2r, 74

17

Cl N

N CF2CF3

Reaction conditions: 1a (0.4 mmol), Pd(PPh3)4 (10 mol%), PCy3 (20 mol%), K2CO3 (0.8 mmol) in toluene (4.0 mL) at 120 8C under N2 atmosphere for 12 h. b Isolated yield. c The ratio of regioisomers based on 19F NMR analysis.

Pd(PPh3)4, PCy3 Cl 1a

K2CO3, 120 oC

CF3

Solvents were purified or dried in a standard manner. Reactions were monitored by TLC on silica gel plates (GF254), and the analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica gel plates. 1H NMR spectra and 13C NMR spectra were measured in CDCl3 and recorded on a 400 or 500 MHz NMR spectrometers with TMS as an internal standard. Column chromatography over silica gel (300–400 mesh) and petroleum ether/ethyl acetate combination was used as the eluent.

CF2CF3

a

N

In conclusion, we have developed an efficient method for the synthesis of 6-trifluoromethyl-phenanthridines through palladium-catalyzed intramolecular C–H bond functionalization of trifluoroacetimidoyl chlorides. The result presented here should be of considerable interest for valuable synthetic building blocks for medicinal science.

TEMPO (1.2 equiv)

N 2a 70%

Scheme 2. TEMPO-trapping experiment.

CF3

4.2. Typical procedure for synthesis of 6-trifluoromethylphenanthridines A mixture of N-biaryltrifluoroacetimidoyl chloride 1 (0.4 mmol), Pd(PPh3)4 (0.04 mol, 10 mol%), PCy3 (0.08 mol, 20 mol%), K2CO3 (0.8 mol, 2 equiv) in toluene (4 mL) was evacuated and backfilled with nitrogen (3 cycles) and then stirred at 120 8C for 12 h. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. The resulting solution was directly filtered through a pad of silica gel using a sintered glass funnel, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give the desired 6trifluoromethyl-phenanthridines 2. 4.2.1. 6-(Trifluoromethyl)-8-methylphenanthridine (2a) [21] White solid, mp 107–109 8C; 1H NMR (400 MHz, CDCl3): d 8.36– 8.48 (m, 2H), 8.20 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.64–7.72 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): d

26

M. Zhu et al. / Journal of Fluorine Chemistry 163 (2014) 23–27

146.0 (q, J = 32.6 Hz), 141.3, 138.2, 133.1, 131.7, 130.9, 129.1, 128.8, 125.1, 125.0, 122.2, 122.0 (q, J = 275.2 Hz), 121.8, 21.9. 19F NMR (376 MHz, CDCl3) d 64.3 (s, 3 F). 4.2.2. 6-(Trifluoromethyl)phenanthridine (2b) [21] White solid, mp 62–64 8C; 1H NMR (500 MHz, CDCl3): d 8.59 (d, J = 8.5 Hz, 1H), 8.49–8.50 (m, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.19–8.20 (m, 1H), 7.81–7.84 (m, 1H), 7.66–7.73 (m, 3H); 13C NMR (125 MHz, CDCl3): d 146.5(q, J = 33.0 Hz), 141.8, 134.0, 131.4, 131.1, 129.3, 129.2, 128.1, 125.9 (q, J = 4.1 Hz), 125.1, 122.5, 122.1, 121.9 (q, J = 275.6 Hz), 121.8. 19F NMR (376 MHz, CDCl3) d 63.5 (s, 3 F). 4.2.3. 8-Ethyl-6-(trifluoromethyl)phenanthridine (2c) White solid, mp 102–103 8C; 1H NMR (400 MHz, CDCl3): d 8.49– 8.54 (m, 2H), 8.22–8.25 (m, 1H), 8.12 (s, 1H), 7.70–7.76 (m, 3H), 2.90 (q, J = 8.0 Hz, 2H), 1.36 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 146.3 (q, J = 32.3 Hz), 144.4, 141.4, 132.1, 131.0, 129.1, 128.9, 125.2, 124.0 (q, J = 3.5 Hz), 122.5, 122.1 (q, J = 275.2 Hz), 122.0, 121.9, 29.2, 15.5. 19F NMR (376 MHz, CDClB3B) d 63.4 (s, 3 F); EI-MS (m/z): 276 [MP + 1]+. 4.2.4. 6-(Trifluoromethyl)-8-methoxyphenanthridine (2d) [21] White solid, mp 98–101 8C; 1H NMR (400 MHz, CDCl3): d = 8.44 (d, J = 9.2 Hz, 1H), 8.37–8.39 (m, 1H), 8.19–8.21 (m, 1H), 7.66–7.70 (m, 2H), 7.59 (s, 1H), 7.42–7.45 (m, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 158.9, 145.4(q, J = 33.1 Hz), 140.9, 131.0, 129.2, 128.3, 128.26, 125.2, 124.0, 123.0, 122.4, 122.1 (q, J = 275.1 Hz), 121.5, 105.4(q, J = 3.6 Hz), 55.5. 19F NMR (376 MHz, CDCl3) d 64.1 (s, 3 F). 4.2.5. 8-Fluoro-6-(trifluoromethyl)phenanthridine (2e) White solid, mp 87–89 8C; 1H NMR (400 MHz, CDCl3): d = 8.56– 8.60 (m, 1H), 8.42–8.44 (m, 1H), 8.21–8.23 (m, 1H), 7.93–7.95 (m, 1H), 7.72–7.77 (m, 2H), 7.58–7.63 (m, 1H); 13C NMR (100 MHz, CDCl3): d = 161.4 (d, J = 248.9 Hz), 145.6(q, J = 29.4 Hz), 141.3, 131.2, 130.6(d, J = 1.9 Hz), 129.6, 129.2, 125.1(d, J = 9.0 Hz), 124.6, 122.7(d, J = 8.8 Hz), 121.8, 121.7(q, J = 275.1 Hz), 120.8 (d, J = 23.8 Hz), 110.7 (dq, J = 23.2 Hz, J = 3.4 Hz).19F NMR (376 MHz, CDCl3) d 63.99 (s, 3 F), 109.92 (s, 1 F). 4.2.6. 4.2.6. 8-Chloro-6-(trifluoromethyl)phenanthridine (2f) [21] White solid, mp 114–116 8C; 1H NMR (400 MHz, CDCl3): d = 8.48 (d, J = 8.8 Hz, 1H), 8.41–8.43 (m, 1H), 8.25–8.27 (m, 1H), 8.19–8.22 (m, 1H), 7.71–7.79 (m, 3H); 13C NMR (100 MHz, CDCl3): d = 145.6(q, J = 33.1 Hz), 141.6, 134.2, 132.2, 132.0, 131.2, 129.67, 129.66, 125.1 (q, J = 3.0 Hz), 124.4, 124.1, 122.4, 121.9, 121.6 (q, J = 274.6 Hz). 19F NMR (376 MHz, CDCl3) d 63.6 (s, 3 F). 4.2.7. 6,8-Bis(trifluoromethyl)phenanthridine (2g) [21] White solid, mp 106–108 8C; 1H NMR (500 MHz, CDCl3): d = 8.80 (t, J = 8.5 Hz, 1H), 8.60–8.63 (m, 2H), 8.31–8.32 (m, 1H), 8.10–8.11 (m, 1H), 7.83–7.90 (m, 2H); 13C NMR (125 MHz, CDCl3): d = 146.3 (q, J = 33.5 Hz), 142.4, 136.0, 131.4, 130.6, 130.1, 129.9, 129.8 (q, J = 4.1 Hz), 127.3, 124.2, 123.8, 123.6 (q, J = 270.9 Hz), 122.4, 121.6 (q, J = 275.3 Hz), 121.0. 19F NMR (376 MHz, CDCl3) d 62.6 (s, 3 F), 63.3 (s, 3 F). 4.2.8. 6-(Trifluoromethyl)-8-phenylphenanthridine (2h) [21] White solid, mp 126–127 8C; 1H NMR (400 MHz, CDCl3): d = 8.70 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.55–8.58 (m, 1H), 8.53 (s, 1H), 8.26–8.28 (m, 1H), 8.10–8.13 (m, 1H), 7.71–7.79 (m, 4H), 7.51–7.55 (m, 2H), 7.44–7.46 (m, 1H); 13C NMR (100 MHz, CDCl3): d = 146.6 (q, J = 32.7 Hz), 141.7, 140.9, 139.8, 132.9, 131.2, 130.7, 129.4, 129.3, 129.2, 128.3, 127.5, 125.0, 123.8 (q, J = 3.3 Hz), 123.1, 122.2, 122.1, 122.0 (q, J = 275.4 Hz). 19F NMR (376 MHz, CDCl3) d 63.3 (s, 3 F).

4.2.9. 6-(Trifluoromethyl)-10-methylphenanthridine (2i) [21] White solid, mp 76–78 8C; 1H NMR (400 MHz, CDCl3): d 8.85– 8.87 (m, 1H), 8.30–8.34 (m, 2H), 7.75–7.83 (m, 3H), 7.66–7.69 (m, 1H), 3.15(s, 3H); 13C NMR (100 MHz, CDCl3): d 147.1(q, J = 32.2 Hz), 142.8, 135.8, 135.6, 133.5, 131.5, 128.5, 128.4, 127.4, 126.6, 126.5, 124.3 (q, J = 3.6 Hz), 123.2, 122.1 (q, J = 275.6 Hz), 27.1. 19F NMR (376 MHz, CDCl3) d 63.0 (s, 3 F). 4.2.10. 6-(Trifluoromethyl)-10-methoxyphenanthridine(2j) [21] White solid, mp 101–103 8C; 1H NMR (500 MHz, CDCl3): d 9.56–9.59 (m, 1H), 8.29–8.32 (m, 1H), 8.03–8.05 (m, 1H), 7.72– 7.82 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 4.19 (s, 3H); 13C NMR (125 MHz, CDCl3): d 158.3, 146.2 (q, J = 33.5 Hz), 142.3, 130.9, 129.1, 128.6, 128.2, 128.0, 125.0, 124.6, 123.8, 122.1 (q, J = 275.4 Hz), 118.0, 112.2, 55.9. 19F NMR (376 MHz, CDCl3) d 63.4 (s, 3 F). 4.2.11. 6-(Trifluoromethyl)-7-methoxyphenanthridine (2k) and 6(trifluoromethyl)-9-methoxyphenanthridine (2k0 ) [19] White solid, 1H NMR (400 MHz, CDCl3): d 8.39 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.4 Hz, 0.69H), 8.16–7.20 (m, 2.2H), 8.07 (d, J = 8.0 Hz, 1H), 7.74–7.80 (m, 0.67H), 7.64–7.73 (m, 4.32H), 7.21–7.24 (m, 0.63H), 7.03 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.97 (s, 2H); 13C NMR (100 MHz, CDCl3): d 161.6, 156.6, 146.0 (q, J = 32.5 Hz), 144.5 (q, J = 35.0 Hz), 142.0, 141.4, 136.2, 136.1, 131.9, 130.9, 130.8, 129.3, 129.28, 129.0, 128.5, 127.6 (q, J = 3.0 Hz), 124.7, 124.5, 122.4, 122.0, 122.0 (q, J = 273.2 Hz), 122.0 (q, J = 275.2 Hz), 118.4, 116.5, 114.4, 114.1, 109.1, 102.9, 56.0, 55.5. 19F NMR (376 MHz, CDCl3) d 63.23 (s, 2 F), 63.55 (s, 3 F). 4.2.12. 4-(Trifluoromethyl)thieno[2,3-c]quinoline (2l) [21] White solid, mp 58–60 8C; 1H NMR (400 MHz, CDCl3): d 8.33 (d, J = 8.0 Hz, 1H), 8.17–7.20 (m, 1H), 7.69–7.82 (m, 4H); 13C NMR (125 MHz, CDCl3): d 147.9, 142.9 (q, J = 34.6 Hz), 141.9, 131.0, 129.4, 129.1, 128.9, 127.5, 125.1, 123.3, 123.1 (q, J = 3.0 Hz), 121.8 (q, J = 274.9 Hz). 19F NMR (376 MHz, CDCl3) d 65.8 (s, 3 F). 4.2.13. 6-(Trifluoromethyl)-2-methylphenanthridine (2m) [22] White solid, mp 104–105 8C; 1H NMR (400 MHz, CDCl3): d 8.53 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.78–7.82 (m, 1H), 7.65–7.69 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3): d 145.0(q, J = 32.5 Hz), 140.0, 139.5, 133.5, 131.05, 131.04, 130.7, 127.8, 125.7 (q, J = 3.0 Hz), 124.9, 122.4, 122.1 (q, J = 276.2 Hz), 121.8, 121.6, 22.1. 19F NMR (376 MHz, CDCl3) d 63.3 (s, 3 F). 4.2.14. 2-Fluoro-6-(trifluoromethyl)phenanthridine (2n) [20] White solid, mp 104–106 8C; 1H NMR (400 MHz, CDCl3): d 8.44 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.20–8.24 (m, 1H), 8.06– 8.09 (m, 1H), 7.84–7.88 (m, 1H), 7.73–7.77 (m, 1H), 7.46–7.51 (m, 1H); 13C NMR (100 MHz, CDCl3): d 162.6 (d, J = 249.0 Hz), 145.8 (dq, J = 33.0, 2.8 Hz), 138.5, 133.5 (d, J = 9.5 Hz), 133.2 (d, J = 4.4 Hz), 131.4, 128.7, 126.7 (d, J = 9.6 Hz), 125.9 (q, J = 3.5 Hz), 122.6, 121.9 (q, J = 276.1 Hz), 121.7, 118.4 (d, J = 25.4 Hz), 107.1 (d, J = 23.7 Hz). 19F NMR (376 MHz, CDCl3) d 63.5 (s, 3 F), 108.7 (s, 1 F). 4.2.15. 3,6-Bis(trifluoromethyl)phenanthridine (2o) [22] White solid, mp 105–107 8C; 1H NMR (500 MHz, CDCl3): d 8.63 (t, J = 8.5 Hz, 2H), 8.61 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.92–7.98 (m, 2H), 7.82–7.85 (m, 1H); 13C NMR (125 MHz, CDCl3): d 147.9 (q, J = 33.4 Hz), 140.9, 133.1, 132.0, 131.2 (q, J = 33.2 Hz), 129.2, 128.6 (q, J = 3.4 Hz), 127.2, 126.1 (q, J = 3.4 Hz), 124.9 (q, J = 3.3 Hz), 123.7 (q, J = 270.9 Hz), 123.1, 122.8, 122.2, 121.6 (q, J = 275.1 Hz). 19F NMR (376 MHz, CDCl3) d 62.5 (s, 3 F), 63.7 (s, 3 F).

M. Zhu et al. / Journal of Fluorine Chemistry 163 (2014) 23–27

4.2.16. 6-(Trifluoromethyl)-2,4-dimethylphenanthridine (2p) [20] White solid, mp 114–116 8C; 1H NMR (400 MHz, CDCl3): d 8.59 (d, J = 8.4 Hz, 1H), 8.31–8.33 (m, 1H), 8.13 (s, 1H), 7.79–7.84 (m, 1H), 7.67–7.71 (m, 1H), 7.43 (s, 1H), 2.81 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3): d 143.8 (q, J = 33.0 Hz), 138.96, 138.91, 138.86, 133.9, 131.7, 130.7, 127.6, 125.6 (q, J = 3.4 Hz), 124.9, 122.7, 122.2 (q, J = 275.1 Hz), 121.6, 119.4, 22.2, 17.9. 19F NMR (376 MHz, CDCl3) d 63.3 (s, 3 F). 4.2.17. 2,4-Dichloro-6-(trifluoromethyl)phenanthridine (2q) [21] White solid, mp 120–122 8C; 1H NMR (500 MHz, CDCl3): d 8.36 (d, J = 8.5 Hz, 1H), 8.29–8.31 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.84– 7.87 (m, 1H), 7.74–7.77 (m, 1H), 7.73 (d, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 146.7 (q, J = 33.6 Hz), 136.6, 136.5, 134.7, 132.5, 131.9, 129.9, 129.3, 127.0, 125.9 (q, J = 4.0 Hz), 122.6, 121.8, 121.6 (q, J = 270.3 Hz), 120.4. 19F NMR (376 MHz, CDCl3) d 63.7 (s, 3 F). 4.2.18. 6-(Perfluoroethyl)phenanthridine (2r) White solid, mp 99–101 8C; 1H NMR (400 MHz, CDCl3): d 8.55 (d, J = 8.0 Hz, 1H), 8.39–8.45 (m, 2H), 8.16–8.18 (m, 1H), 7.78–7.82 (m, 1H), 7.65–7.73 (m, 3H); 13C NMR (100 MHz, CDCl3): d 146.5(t, J = 26.3 Hz), 141.5, 133.8, 131.2, 131.1, 129.3, 129.2, 127.9, 125.9 (t, J = 6.8 Hz), 124.7, 122.5, 122.4, 121.9. 19F NMR (376 MHz, CDCl3) d 80.16 (s, 2 F), 106.80 (s, 3 F). Acknowledgment We are grateful to the National Natural Science Foundation of China (Project Nos. U1204205; 21202078; 21272110). References [1] A.A. Ali, H.M. El Sayed, O.M. Abdallah, W. Steglich, Phytochemistry 25 (1986) 2399–2401. [2] B.D. Krane, M.O. Fagbule, M. Shamma, J. Nat. Prod. 47 (1984) 1–43. [3] T. Nakanishi, M. Suzuki, A. Saimoto, T. Kabasawa, J. Nat. Prod. 62 (1999) 864–867. [4] T. Nakanishi, M. Suzuki, Org. Lett. 1 (1999) 985–988. [5] P.H. Bernardo, K.-F. Wan, T. Sivaraman, J. Xu, F.K. Moore, A.W. Hung, H.Y.K. Mok, V.C. Yu, C.L.L. Chai, J. Med. Chem. 51 (2008) 6699–6710. [6] W.G. Lewis, L.G. Green, F. Grynszpan, Z. Radic, P.R. Carlier, P. Taylor, M.G. Finn, K.B. Sharpless, Angew. Chem., Int. Ed. 41 (2002) 1053–1057. [7] E. Dubost, N. Dumas, C. Fossey, R. Magnelli, S. Butt-Gueulle, C. Balladonne, D.H. Caignard, F. Dulin, J.S.d.-O. Santos, P. Millet, Y. Charnay, S. Rault, T. Cailly, F. Fabis, J. Med. Chem. 55 (2012) 9693–9707.

27

[8] J. Zhang, J.R. Lakowicz, J. Phys. Chem. B 109 (2005) 8701–8706. [9] S.L. Bondarev, V.N. Knyukshto, S.A. Tikhomirov, A.N. Pyrko, Opt. Spectrosc. 100 (2006) 386–393. [10] N. Stevens, N. O’Connor, H. Vishwasrao, D. Samaroo, E.R. Kandel, D.L. Akins, C.M. Drain, N.J. Turro, J. Am. Chem. Soc. 130 (2008) 7182–7183. [11] A.M. Linsenmeier, C.M. Williams, S. Brase, J. Org. Chem. 76 (2011) 9127–9132. [12] J. Peng, T. Chen, C. Chen, B. Li, J. Org. Chem. 76 (2011) 9507–9513. [13] L. Zhang, G.Y. Ang, S. Chiba, Org. Lett. 12 (2010) 3682–3685. [14] Y. Wu, S.M. Wong, F. Mao, T.L. Chan, F.Y. Kwong, Org. Lett. 14 (2012) 5306–5309. [15] D. Intrieri, M. Mariani, A. Caselli, F. Ragaini, E. Gallo, Chem. Eur. J. 18 (2012) 10487–10490. [16] D.A. Candito, M. Lautens, Angew. Chem., Int. Ed. 48 (2009) 6713–6716. [17] F. Portela-Cubillo, E.M. Scanlan, J.S. Scott, J.C. Walton, Chem. Commun. 35 (2008) 4189–4191. [18] Y. Li, J. Zhu, L. Zhang, Y. Wu, Y. Gong, Chem. Eur. J. 19 (2013) 8294–8299. [19] W.-Y. Wang, X. Feng, B.-L. Hu, C.-L. Deng, X.-G. Zhang, J. Org. Chem. 78 (2013) 6025–6030. [20] B. Zhang, C. Mu¨ck-Lichtenfeld, C.G. Daniliuc, A. Studer, Angew. Chem., Int. Ed. 52 (2013) 10792–10795. [21] Q. Wang, X. Dong, T. Xiao, L. Zhou, Org. Lett. 15 (2013) 4846–4849. [22] Y. Cheng, H. Jiang, Y. Zhang, S. Yu, Org. Lett. 15 (2013) 5520–5523. [23] K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 58 (1993) 32–35. [24] K. Uneyama, J. Fluorine Chem. 97 (1999) 11–25. [25] K. Uneyama, H. Amii, T. Katagiri, T. Kobayashi, T. Hosokawa, J. Fluorine Chem. 126 (2005) 165–171. [26] X. Dong, Y. Xu, J. Liu, Y. Hu, T. Xiao, L. Zhou, Chem. Eur. J. 19 (2013) 16928–16933. [27] K. Uneyama, H. Watanabe, Tetrahedron Lett. 32 (1991) 1459–1462. [28] H. Amii, M. Kohda, M. Seo, K. Uneyama, Chem. Commun. (2003) 1752–1753. [29] C.-L. Li, M.-W. Chen, X.-G. Zhang, J. Fluorine Chem. 131 (2010) 856–860. [30] H. Amii, Y. Kishikawa, K. Kageyama, K. Uneyama, J. Org. Chem. 65 (2000) 3404– 3408. [31] H. Amii, K. Kageyama, Y. Kishikawa, T. Hosokawa, R. Morioka, T. Katagir, K. Uneyama, Organometallics 31 (2012) 1281–1286. [32] A. Isobe, J. Takagi, T. Katagiri, K. Uneyama, Org. Lett. 10 (2008) 2657–2659. [33] D. Alberico, M.E. Scott, M. Lautens, Chem. Rev. 107 (2007) 174–238. [34] E.M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 107 (2007) 5318–5365. [35] O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 42 (2009) 1074–1086. [36] B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 41 (2012) 5588–5598. [37] S.H. Cho, J.Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 40 (2011) 5068–5083. [38] S.R. Neufeldt, M.S. Sanford, Acc. Chem. Res. 45 (2012) 936–946. [39] W. Fu, F. Xu, Y. Fu, C. Xu, S. Li, D. Zou, Eur. J. Org. Chem. 2014 (2014) 709–712. [40] M. Zhu, Z. Wang, F. Xu, J. Yu, W. Fu, J. Fluorine Chem. 156 (2013) 21–25. [41] M. Zhu, W. Fu, G. Zou, C. Xu, D. Deng, B. Ji, J. Fluorine Chem. 135 (2012) 195–199. [42] W. Fu, F. Xu, Y. Fu, M. Zhu, J. Yu, C. Xu, D. Zou, J. Org. Chem. 78 (2013) 12202– 12206. [43] The atomic coordinates for 2r have been deposited at the Cambridge Crystallographic Data Centre. CCDC ID: 986031 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/ cif. [44] C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 34 (2001) 633–664. [45] H. Amii, Y. Kishikawa, K. Uneyama, Org. Lett. 3 (2001) 1109–1112.