Tetrahedron Letters 53 (2012) 2005–2008

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Tetrahedron Letters

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Trifluoromethylation of heterocycles via visible light photoredox catalysis

Naeem Iqbal, Sungkyu Choi, Euna Ko, Eun Jin Cho ⇑Department of Chemistry and Applied Chemistry, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, ansan, Kyeonggi-do 426-791, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 January 2012Revised 3 February 2012Accepted 7 February 2012Available online 14 February 2012

Keywords:Visible lightPhotoredox catalysisTrifluoromethylationHeterocyclesRuthenium

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⇑ Corresponding author. Tel.: +82 31 400 5496; faxE-mail address: echo@hanyang.ac.kr (E.J. Cho).

A method has been developed for the visible light-induced trifluoromethylation of heterocyclic com-pounds. A variety of electron-rich heterocycles were transformed into trifluoromethylated products byusing CF3I as the trifluoromethyl radical source and Ru(bpy)3Cl2 as the photocatalyst under mild reactionconditions. This operationally simple and eco-friendly process can introduce trifluoromethyl groupswithout prefunctionalization.

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X

R

CF3

R

Cu-or Pd-catalyzedprocesses

Trifluoromethylation of prefunctionalized aromatics

(1)

X = Cl, I, B(OH) 2

X X

CF3R RRu-catalyzed

photoredox catalysis

Trifluoromethylation of heteroaromatics

(2)

The incorporation of small and highly electronegative trifluoro-methyl group can profoundly alter the physical and chemical prop-erties1 of the heterocyclic compounds and results in their broadrange exploitation throughout pharmaceuticals, agrochemicals,dyes, and polymers.2 For example, the presence of a trifluoro-methyl (CF3) group can greatly influence the molecular activitiesof the molecule such as binding selectivity, lipophilicity, bioavail-ability, and metabolic stability.2a,2c Because fluorinated com-pounds are notably absent in the nature, the installment of thismoiety is a test for the success of organic synthesis.3

Several processes for the incorporation of trifluoromethyl groupusing nucleophilic, electrophilic, or free radical reagents have beenreported.4 Especially recent developments in transition metal-med-iated coupling processes created breakthroughs in the arena of tri-fluoromethylation chemistry (Fig. 1 (1)).5,6 These methods enabledCF3 substitution on a range of aromatics and heteroaromatics withprior fluorinating building blocks. However, substituting CF3 ontothe ideal positions of a drug entity still requires multistep synthesisusing an aryl precursor with an activating group around the aro-matic ring. Herein we report a mild, operationally simple, andeco-friendly trifluoromethylation process for heteroaromatic com-pounds using visible light photoredox catalysis (Fig. 1 (2)).7–9 Thisradical-mediated method can introduce trifluoromethyl groups atless reactive sites of heterocycles without prefunctionalization.10

Inspired by the a-trifluoromethylation of aldehydes,8b,8p we pro-posed that electrophilic trifluoromethyl radicals could be generatedfrom CF3I by visible light photoredox catalysis, and it would effec-tively combine the electron rich heteroaromatics.8h We assume that

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RuðbpyÞ32þ is excited by visible light, providing Ru ðbpyÞ32þ that isthen reductively quenched by an amine to produce RuðbpyÞ31þ

and the ammonium radical cation. The RuðbpyÞ31þ species in turnperforms a single-electron reduction of the F3C�I bond, regenerat-ing RuðbpyÞ32þ and forming a carbon-centered CF3 radical. Finallycoupling of this electron-deficient radical with an electron-rich het-erocycle and the oxidation of the resulting radical followed byrearomatization gives the trifluoromethylated product (Fig. 2).7

We commenced our studies by examining the trifluoromethyla-tion of 3-methylindole11 with several iridium and ruthenium cata-lysts (Table 1). This confirmed the feasibility of the desiredincorporation by using Ir or Ru photocatalysts with DIPEA as areductant in DMF under visible light source (24 W fluorescent

X = N, O, S X = N, O, S'visible light'

Figure 1. Trifluoromethylation of aromatics and heteroaromatics.

Table 2Optimization of trifluoromethylationa

NH

Me

NH

Me

CF3+ CF3Ibase, solvent, r.t.

24 W light bulb or blue LEDs

1 mol % Ru(bpy)3Cl2

a2a1

Entry Base (2 equiv) Solvent Yieldb (%)

1 DIPEA DMF (0.25 M) 552 TEA DMF (0.25 M) 683 TEA CH2Cl2 (0.25 M) 674 TEA CH3CN (0.25 M) 825 TEA CH3CN (0.10 M) 626 TEA CH3CN (0.50 M) 407 TMEDA DMF (0.25 M) 678 TMEDA CH3CN (0.25 M) 929 TMEDA (1 equiv) CH3CN (0.25 M) 59

a Reaction conditions: 1a (0.3 mmol), CF3I (0.9–1.2 mmol), Ru(bpy)3Cl2 (1 mol %),base, solvent, 24 W light bulb or blue LEDs, room temperature, 24 h.

b The given yield was estimated by gas chromatography with dodecane as aninternal standard.Table 1

Photocatalysts screena

NH

Me

NH

Me

CF3

1 mol % photocatalyst+ CF3I

DIPEA, DMF24 W light bulb, r.t.

a2a1

Entry Reaction conditions Yieldb (%)

1 Ir(ppy)3 202 Ir(ppy)2(dtb-bpy)PF6 213 Ru(bpy)3Cl2 554 Ru(bpy)3(PF6)2 545 No visible light 06 No photocatalyst 0

a Reaction conditions: 1a (0.3 mmol), CF3I (0.9–1.2 mmol), photocatalyst(1 mol %), DIPEA (0.6 mmol), DMF (1.2 mL), 24 W light bulb, room temperature,24 h.

b The given yield was estimated by gas chromatography with dodecane as aninternal standard.

NH

Me

CF3NH

Me

CF3

HNH

Me

*Ru(bpy)32+

Ru(bpy)32+ Ru(bpy)3+

CF3F

IFF

NH

Me

CF3

NR3

NR3

[Ox]

H+

I-

Figure 2. Proposed mechanism for the trifluoromethylation via visible lightphotoredox catalysis.

2006 N. Iqbal et al. / Tetrahedron Letters 53 (2012) 2005–2008

household bulb). Unlike with the a-trifluoromethylation of alde-hydes,8b Ru catalysts showed better reactivity than Ir for the triflu-oromethylation of heterocycles (entries 3 and 4). The removal ofthe light source from this protocol resulted in the complete lossof the catalyst activity. Alternatively, removal of the catalyst underthe light source did not allow the desired transformation. These re-sults were in complete accordance with the proposed mechanismin Figure 2.

Based on the results in Table 1, commercially available Ru(b-py)3Cl2 was used as the photocatalyst for further optimization.While screening through available bases (DIPEA, 4-methoxytriphe-nylamine, TEA, lutidine, TMEDA) and solvents (DMF, CH3CN,CH2Cl2, dioxane, ethanol, CH3NO2) (Table 2), TMEDA was foundto be the best electron donor with Ru(bpy)3Cl2 complex in CH3CN(Table 2, entry 8). In general, the use of CH3CN as the solvent gavegood results probably due to the greater solubility of the CF3I inCH3CN. A study of reaction concentrations showed that 0.25 Mconcentration in CH3CN gave the best results (entries 4–6). Usinga higher equivalent ratio of the base did not affect the reaction effi-ciency although using less base led to the lower product yield (en-try 9). Use of blue LEDs as a visible light source showed higherefficiency. In addition, the reaction required the use of at least3–4 equiv CF3I for the reproducible results.

With optimal conditions in hand, a series of heterocyclic com-pounds were then screened as suitable coupling partners for triflu-oromethylation (Table 3). A variety of heterocycles, including

indoles (1a–1e), pyrroles (1f–1h), thiophenes (1i), and furans(1j), were used in the reaction and resulted in the formation of tri-fluoromethylated heterocycles in good to excellent yields. Underthe optimized conditions, we did not observe the formation of sig-nificant amounts of any side products. Benzothiazoles and benzo-furans also worked for the reaction, but did not go to completion,giving low yields of the products. In addition, electron-deficientheterocycles and unactivated aromatic compounds were not reac-tive under the reaction conditions. Several functional groups weretolerant under the reaction conditions including bromide (1e),aldehydes (1g), esters (1c, 1h, and 1i), and amines (1i). Thus theprocess should be applicable to the late-stage modifications of ad-vanced intermediates in the synthesis of complicated molecules.Regarding the regioselectivity, however, a mixture of regioisomerswas obtained from the reactions of 1d and 1e (entries 4 and 5).Substitution at the 2-position of indole was preferred over the3-position due to the formation of more stable benzylic radicalas an intermediate. In addition, the use of more than 5 equiv ofCF3I resulted in the formation multi-trifluoromethylated side prod-ucts. For example, with 5 equivalent of CF3I we obtained a 10%yield of 2,5-disubstituted product along with 2-trifluoromethylat-ed N-methylpyrrole (2f) in the reaction of N-methylpyrrole (1f).

In conclusion, we have developed a visible light-induced triflu-oromethylation of electron-rich heterocycles, providing a directmethod to access trifluoromethylated heteroaromatics withoutprefunctionalization. A variety of trifluoromethylated heterocycleswere generated under mild reaction conditions in good to excellentyields. This operationally simple and eco-friendly process toleratesvarious functional groups. Thus we believe it can be one of themost efficient methods to introduce trifluoromethyl groups atthe late-stage modifications of advanced intermediates in the syn-thesis of complicated compounds.

General information

Trifluoromethylated products were, in most instances, charac-terized by 1H NMR, 13C NMR, 19F NMR, IR spectroscopy, and high-resolution mass spectrometry. Nuclear Magnetic Resonance spectrawere recorded on a Bruker 400 MHz instrument (400 MHz for 1HNMR, 101 MHz for 13C NMR, and 377 MHz for 19F NMR). All 1HNMR experiments are reported in d units, parts per million (ppm),and were measured relative to residual chloroform (7.26 ppm) inthe deuterated solvent. All 13C NMR spectra are reported in ppm rel-ative to deuterochloroform (77.23 ppm), and all were obtained with

Table 3Scope of the visible light-induced trifluoromethylationa

X

X = N, O, S

X

CF3

X = N, O, S

1 mol % Ru(bpy)3Cl2

TMEDA, CH3CNvisible light, r.t.

R R

1 2

+ CF3I

Entry Substrate Product Yieldb (%)

1NH

Me

1a

NH

Me

CF3

2a

90

2N

Me

Me

1b

NMe

2b

CF3

Me

94c

3NH

O

OEt

1c

NH

O

OEtCF3

2c

81

4 N

Me1d

N

2d

CF3

Me

*

95 (1.5:1⁄)d

5 NMe

1e

Br

N

2e

CF3

Me

*Br

86 (1.3:1⁄)d

6N

Me

1f

N

Me

CF3

2f

95d

7 NHO

H

1g

NHO

HCF3

2g

71

8 NHO

MeO

1h

NHO

MeOCF3

2h

80

9S

H2N

MeO2C

1i

SH2N

MeO2C

CF3

2i

92

10 O

1j

O CF3

2j

92d

a Reaction conditions: 1 (0.3 or 1.0 mmol), CF3I (3–4 equiv), Ru(bpy)3Cl2

(1 mol %), TMEDA (2 equiv), CH3CN (0.25 M), 24 W light bulb or blue LEDs, roomtemperature,15–24 h.

b The given yields are isolated and based on an average of two runs.c Its regioisomers (5–10%) from the substitution at six-membered ring were also

obtained.d The yield was determined by 19F NMR spectroscopy with 4-fluorotoluene as an

internal standard due to their volatility.

N. Iqbal et al. / Tetrahedron Letters 53 (2012) 2005–2008 2007

1H decoupling. All coupling constants were reported in Hz. Infraredspectra were recorded on a Bruker Alpha FT-IR spectrometer using

KBr plates. Mass spectral data were obtained from the Korea BasicScience Institute (Daegu) on a Jeol JMS 700 high resolution massspectrometer. Flash column chromatography was performed usingMerck silica gel 60 (70–230 mesh) under positive pressure.

General experimental procedure

An oven-dried resealable test tube equipped with a magneticstir bar was charged with a heterocycle (0.3 mmol) and Ru(b-py)3Cl2�6H2O (1 mol %, 0.003 mmol), and sealed with a screw-cap.Acetonitrile (1.2 mL, 0.25 M) and N,N,N,N-tetramethylethylenedi-amine (0.6 mmol) were added to it under argon. CF3I (0.9–1.2 mmol) was then bubbled into the reaction mixture by using agastight syringe. The test tube was placed under 24 W householdlight bulb or blue LEDs at room temperature. The reaction was al-lowed to proceed for 10–24 h while its progress was checked byTLC. The reaction mixture was then diluted with diethylether, fil-tered through a plug of silica gel to remove all solids, concentratedin vacuo, and purified by flash column chromatography to give thetrifluoromethylated compound.12

Acknowledgments

This research was supported by the National Research Founda-tion of Korea (NRF) under Grant NRF-2011-0013118.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2012.02.032.

References and notes

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K. J. Med. Chem. 2008, 51, 4359; (c) Purser, S.; Moore, P. R.; Swallow, S.;Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (d)Fluorine in Medicinal Chemistryand Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: Chichester, 2009.

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5. Some examples of Cu-mediated trifluoromethylation: (a) Dubinina, G. G.;Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600; (b) Oishi, M.; Kondo,H.; Amii, H. Chem. Commun. 1909, 2009; (c) Chu, L.; Qing, F. L. Org. Lett. 2010, 12,5060; (d) Hafner, A.; Bräse, S. Adv. Synth. Catal. 2011, 353, 3044; (e) Kondo, H.;Oishi, M.; Fujikawa, K.; Amii, H. Adv. Synth. Catal. 2011, 353, 1247; (f) Senecal, T.D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174; (g) Knauber, T.;Arikan, F.; Röschenthaler, G. V.; Goossen, L. J. Chem. Eur. J. 2011, 17, 2689; (h)Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342; (i) Zhang, C. P.; Cai, J.; Zhou, C. B.;Wang, X. P.; Zheng, X.; Gu, Y. C.; Xiao, J. C. Chem. Commun. 2011, 47, 9516; (j)Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.2011, 50, 3793; (k) Tomashenko, O. A.; Escudero-Adán, E. C.; Belmonte, M. M.;Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655.

6. Some examples of Pd-mediated trifluoromethylation: (a) Grushin, V. V.;Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644; (b) Wang, X.; Truesdale,L.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 3648; (c) Cho, E. J.; Senecal, T. D.; Kinzel,T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679; (d) Ball, N.D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878; (e) Cho, E. J.;Buchwald, S. L. Org. Lett. 2011, 13, 6552; (f) Mu, X.; Chen, S.; Zhen, X.; Liu, G.Chem. Eur. J. 2011, 17, 6039.

7. Reviews: (a) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785; (b) Yoon, T. P.;Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527; (c) Narayanam, J. M. R.;Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102.

8. Examples in visible light photocatalysis: (a) Ischay, M. A.; Anzovino, M. E.; Du,J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886; (b) Nagib, D. A.; Scott, M. E.;MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875; (c) Narayanam, J. M. R.;Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756; (d) Koike, T.;Akita, M. Chem. Lett. 2009, 38, 166; (e) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am.Chem. Soc. 2010, 132, 8572; (f) Andrews, S. R.; Becker, J. J.; Gagne, M. R. Angew.Chem. 2010, 122, 7432; (g) Tucker, J. W.; Narayanam, J. M. R.; Krabbe, S. W.;Stephenson, C. R. J. Org. Lett. 2010, 12, 368; (h) Condie, A. G.; González-Gómez,J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464; (i) Tucker, J. W.;

2008 N. Iqbal et al. / Tetrahedron Letters 53 (2012) 2005–2008

Nguyen, J. D.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C. R. J. Chem.Commun. 2010, 46, 4985; (j) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.;Tucker, J. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 3104; (k) Neumann, M.;Füldner, S.; König, B.; Zeitler, K. Angew. Chem. 2011, 123, 981; (l) Lu, Z.; Shen,M.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162; (m) Dai, C.; Narayanam, J. M.R.; Stephenson, C. R. J. Nat. Chem. 2011, 3, 140; (n) Rueping, M.; Vila, C.;Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47, 2360; (o)Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. J. Am.Chem. Soc. 2011, 133, 4160; (p) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C.Angew. Chem., Int. Ed. 2011, 50, 6119.

9. During our preparation of this manuscript, the MacMillan’s group has reportedthe first visible light-induced trifluoromethylation of aromatics andheteroaromatics, see: Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.

10. (a) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.;Yamakawa, T. J. Fluorine Chem. 2010, 131, 98; (b) Ji, Y. N.; Brueckl, T.; Baxter, R.D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl.Acad. Sci. U.S.A. 2011, 108, 14411.

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12. Analytical data of unknown compounds: (1) 2a (white solid) 1H NMR (400 MHz,CDCl3) d 8.17 (bs, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.34 (dd,J = 8.0, 7.7 Hz, 1H), 7.21 (dd, J = 8.0, 7.7 Hz, 1H), 2.45 (q, J = 1.8 Hz, 3H); 13CNMR (101 MHz, CDCl3) d 150.32, 128.23, 124.96, 122.30 (q, J = 269.6 Hz),121.70 (q, J = 36.8 Hz), 120.57, 120.30, 114.26 (q, J = 3.0 Hz), 111.76, 8.55; 19F

NMR (377 MHz, CDCl3) d �58.59; IR (neat): mmax = 3393, 1453, 1113 cm�1;HRMS m/z (EI) Calcd for C10H8F3N [M+] 199.0609, Found 199.0606. (2) 2c(white solid) 1H NMR (400 MHz, CDCl3) d 9.96 (bs, 1H), 7.93 (d, J = 8.3 Hz, 1H),7.48 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.3, 8.2 Hz, 1H), 7.27 (d, J = 8.3, 8.2 Hz, 1H),4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) d160.95, 134.86, 126.24, 125.96 (q, J = 3.9 Hz), 125.09 (q, J = 1.8 Hz), 124.07 (q,J = 269.3 Hz), 122.81, 122.06 (q, J = 3.1 Hz), 112.39, 110.04 (q, J = 37.6 Hz),62.49, 14.12; 19F NMR (377 MHz, CDCl3) d �53.60;. IR (neat): mmax = 3308,2959, 1689, 1544, 1119 cm�1; HRMS m/z (EI) Calcd for C12H10F3NO2 [M+]257.0664, Found 257.0662. (3) 2g (white solid) 1H NMR (400 MHz, CDCl3) d10.19 (bs, 1H), 9.66 (s,1H), 6.99 (d, J = 3.9 Hz, 1H), 6.68 (d, J = 3.9 Hz, 1H); 13CNMR (101 MHz, CDCl3) d 180.73, 133.99, 127.46 (q, J = 40.3 Hz), 120.42 (q,J = 269.1 Hz), 120.19, 111.56 (q, J = 2.8 Hz); 19F NMR (377 MHz, CDCl3) d�60.89; IR (neat): mmax = 3182, 2925, 1677, 1572 cm�1; HRMS m/z (EI) Calcd forC6H4F3NO [M+] 163.0245, Found 163.0246. (4) 2h (white solid) 1H NMR(400 MHz, CDCl3) d 10.83 (bs, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz,1H), 3.05 (s, 3H); 13C NMR (101 MHz, CDCl3) d 161.95, 125.28 (q, J = 40.3 Hz),125.14, 120.67 (q, J = 268.7 Hz), 115.18, 111.05, 52.39; 19F NMR (377 MHz,CDCl3) d �60.43; IR (neat): mmax = 3265, 1715, 1287, 1108 cm�1; HRMS m/z (EI)Calcd for C7H6F3NO2 [M+] 193.0351, Found 193.0351. (5) 2i (white solid) 1HNMR (400 MHz, CDCl3) d 7.34 (q, JH–F = 0.9 Hz, 1H), 6.33 (bs, 2H), 3.81 (s, 3H);13C NMR (101 MHz, CDCl3) d 165.57, 164.60, 126.49, 122.50 (q, J = 268.2 Hz),111.12 (q, J = 39.8 Hz), 105.92, 51.51; 19F NMR (377 MHz, CDCl3) d �55.79; IR(neat): mmax = 3424, 3311, 1669, 1566, 1271, 1102 cm�1; HRMS m/z (EI) Calcdfor C7H6F3NO2S [M+] 225.0071, Found 225.0072; mp 80–82 �C.