Generation of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reaction of isoquinoline-N-oxide with Togni reagent

Abstract

Isoquinoline-N-oxides react with Togni reagent catalyzed by copper(II) triflate, leading to 1-(trifluoromethyl)isoquinolines in good yields. The reaction proceeds smoothly under mild conditions with high efficiency.

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1. Introduction

In the past decade, we have been interested in the generation of natural-product-like compounds with privileged scaffolds using the strategy of diversity-oriented synthesis.¹ Among the libraries of small molecules we have synthesized,² several hits of isoquinolines for the inhibition of cervical carcinoma were discovered in the subsequent biological evaluation. Prompted by this result and with an expectation of finding more active compounds, the accessibility of diverse isoquinolines is of high demand.

Recently, the synthesis of fluorinated molecules has attracted much attention within the chemical community. Different methods have been reported for the incorporation of fluoro-containing groups into organic compounds.^3,4 We are also interested in this field for the construction of fluorinated heterocycles.^5,6 It would be desirable to provide facile routes for fluorinated isoquinolines.^6,7 Xu and Liu have developed a silver-catalyzed oxidative aminofluorination of alkynes for the synthesis of 4-fluoroisoquinolines.^7a 1-((Trifluoromethyl)thio)isoquinolines A (Fig. 1) can be accessed through a silver(I)-catalyzed reaction of 2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolate in the presence of p-methoxybenzenesulfonyl chloride.^6a We have also described an efficient route to 1-(trifluoromethyl)-1,2-dihydroisoquinolines B (Fig. 1) under mild conditions via a silver(I)-catalyzed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane.^6b In order to expand the diversity of fluorinated isoquinolines, we envisioned that 1-(trifluoromethyl)isoquinolines C (Fig. 1) could be prepared as well, which would be beneficial for our specific biological assays. Therefore, we initiated a program for the method development of the construction of 1-(trifluoromethyl)isoquinolines.

Fig. 1 Fluorinated isoquinolines.

The importance of the trifluoromethyl group in many drugs or drug candidates has been recognized.⁸ Higher solubility and lipophilicity have been observed for trifluoromethyl-substituted compounds, leading to better membrane permeability and increased bioavailability. Therefore, methods for the trifluoromethylation process have been developed.⁹ On the other hand, as mentioned above, we have built up a library of isoquinolines over the past few years. Our strategy focused on tandem reactions using 2-alkynylbenzaldoximes as the starting material.¹⁰ The key intermediate of isoquinoline-N-oxide has been identified during the transformation.¹¹ In the meantime, the Togni reagent has been used widely for introduction of the trifluoromethyl group into small molecules.¹² We conceived that 1-(trifluoromethyl)isoquinolines would be constructed through reaction of isoquinoline-N-oxide with Togni reagent.¹³ The proposed synthetic route is presented in Scheme 1.

Scheme 1 A proposed synthetic route to 1-(trifluoromethyl)isoquinolines.

We hypothesized that a SET (single electron transfer) process would occur to give intermediate D in the presence of Togni reagent and copper catalyst based on the result disclosed by Bouyssi and Baudoin.^12a In the meantime, complex E would be formed when isoquinoline-N-oxide was treated with copper salt. Thus, after the addition of trifluoromethyl radical to isoquinoline-N-oxide, intermediate G would be afforded with the formation of intermediate F. The subsequent transformation would produce the expected 1-(trifluoromethyl)isoquinoline 3 and radical H. Therefore, we started to investigate the feasibility of this transformation.

2. Results and discussion

Initially, a model reaction of isoquinoline-N-oxide 1a and Togni reagent 2 was explored (Table 1). In the beginning, the reaction was performed in the presence of CuCl (10 mol%) and DMAP (2.0 equiv.) in MeCN at 40 °C. To our delight, the desired product 3a was obtained in 26% yield (Table 1, entry 1). This result encouraged us to carry out the further screening of other metal catalysts. The yield could not be improved when the catalyst was changed to CuBr or CuI (Table 1, entries 2 and 3). A lower yield was observed when FeCl₂ was used as a replacement (Table 1, entry 4). Only a trace amount of product was detected when CuSCN was employed in the transformation (Table 1, entry 5). Further examination of copper salts revealed (Table 1, entries 6–9) that the reaction worked efficiently in the presence of copper(II) triflate, giving rise to the corresponding product 3a in 51% yield (Table 1, entry 9). A control experiment indicated that no reaction occurred in the absence of metal catalyst (Table 1, entry 10). Further, a survey of bases demonstrated that no better result was obtained when other bases were utilized in the reaction process (Table 1, entries 11–16). The reaction performed in various solvents was then investigated (Table 1 entries 17–21), leading to the expected product 3a in lower yields. The yield could not be improved when the reaction temperature was changed to 60 or 80 °C (Table 1 entries 22 and 23). The yield was dramatically decreased when the reaction took place at room temperature (data not shown in Table 1). Gratifyingly, the reaction afforded the corresponding product 3a in 66% yield when the amount of DMAP was increased to 3.0 equiv. (Table 1, entry 24).

Table 1 Initial studies for the reaction of isoquinoline-N-oxide 1a and Togni reagent 2a^a

Entry	[M]	Base	Solvent	Yield^b (%)
a Reaction conditions: isoquinoline-N-oxide 1a (0.5 mmol), Togni reagent 2 (0.6 mmol), metal catalyst (10 mol%), base (2.0 equiv.), solvent (2.0 mL), 40 °C. b Isolated yield based on isoquinoline-N-oxide 1a. c The reaction occurred at 60 °C. d The reaction was performed at 80 °C. e In the presence of 3.0 equiv. of DMAP.
1	CuCl	DMAP	MeCN	26
2	CuBr	DMAP	MeCN	20
3	CuI	DMAP	MeCN	18
4	FeCl2	DMAP	MeCN	15
5	CuSCN	DMAP	MeCN	Trace
6	CuBr2	DMAP	MeCN	11
7	CuCl2	DMAP	MeCN	14
8	Cu(OAc)2	DMAP	MeCN	27
9	Cu(OTf)2	DMAP	MeCN	51
10	—	DMAP	MeCN	nr
11	Cu(OTf)2	Cs2CO3	MeCN	45
12	Cu(OTf)2	NaOH	MeCN	42
13	Cu(OTf)2	t-BuOK	MeCN	24
14	Cu(OTf)2	DBU	MeCN	39
15	Cu(OTf)2	Et3N	MeCN	35
16	Cu(OTf)2	K2CO3	MeCN	46
17	Cu(OTf)2	DMAP	DCE	23
18	Cu(OTf)2	DMAP	Toluene	16
19	Cu(OTf)2	DMAP	DMF	22
20	Cu(OTf)2	DMAP	THF	15
21	Cu(OTf)2	DMAP	1,4-Dioxane	13
22^c	Cu(OTf)2	DMAP	MeCN	45
23^d	Cu(OTf)2	DMAP	MeCN	49
24^e	Cu(OTf)2	DMAP	MeCN	66

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The scope of this copper(II)-catalyzed reaction of isoquinoline-N-oxides 1 with Togni reagent 2 was then explored under the above optimized conditions (10 mol% of Cu(OTf)₂, DMAP, MeCN, 40 °C). The results are summarized in Table 2. All the reactions worked well to afford the expected products 3 in moderate to good yields. Reactions of isoquinoline-N-oxides 1 with an electron-donating group attached on the aromatic ring gave rise to the corresponding products in higher yields, compared with the results obtained from isoquinoline-N-oxides 1 with an electron-withdrawing group attached to the aromatic ring. For example, the methoxy-substituted compound 3b was produced in 86% yield, whereas the chloro-substituted product 3c was generated in 50% yield. Additionally, the reactions of isoquinoline-N-oxides 1 with different groups at the R² position were examined. As expected, all transformations proceeded smoothly under the standard conditions, leading to the desired 1-(trifluoromethyl)isoquinolines in reasonable yields. During the process, not only aromatic groups but also alkyl groups were all compatible.

Table 2 Synthesis of 1-(trifluoromethyl)isoquinolines 3via a copper(II)-catalyzed reaction of isoquinoline-N-oxides 1 with Togni reagent 2^a

a Isolated yield based on isoquinoline-N-oxide 1.

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3. Conclusion

In conclusion, we have described a copper(II)-catalyzed reaction of isoquinoline-N-oxides with Togni reagent, leading to 1-(trifluoromethyl)isoquinolines in good yields. The trifluoromethyl group could be easily introduced at the 1-position of isoquinoline under mild conditions. The reaction scope has been demonstrated. Currently, incorporation of the trifluoromethyl group into other heterocycles is ongoing in our laboratory.

4. Experimental section

The general experimental procedure for the synthesis of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reaction of isoquinoline-N-oxide with Togni reagent is as follows: Isoquinoline N-oxide 1 (0.2 mmol) was added to a solution of 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent) (0.24 mmol), DMAP (0.6 mmol), and Cu(OTf)₂ (0.02 mmol) in CH₃CN (2.0 mL) under N₂ atmosphere. The mixture was stirred at 40 °C for 8–12 h. After completion of the reaction as indicated by TLC, the solvent was evaporated and the residue was purified by column chromatography on silica gel to provide the product 3.

3-Phenyl-1-(trifluoromethyl)isoquinoline 3a

¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 6.4, 2.8 Hz, 2H), 7.72–7.65 (m, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.53–7.44 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.9, 148.0, 131.7, 130.5, 129.9, 129.8, 128.6, 128.4 128.2, 127.9, 127.5, 125.8 (q, ¹J_CF = 286.1 Hz), 122.2; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.05; HRMS (ESI) calcd for C₁₆H₁₁F₃N: 274.0838 (M + H⁺), found: 274.0832.

6,7-Dimethoxy-3-phenyl-1-(trifluoromethyl)isoquinoline 3b

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.29–7.24 (m, 1H), 6.74 (d, J = 10.9 Hz, 2H), 6.41 (s, 1H), 3.91 (s, 3H), 3.91 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 154.2, 152.4, 149.5, 148.3, 143.3, 130.9, 128.8, 128.1, 127.4, 127.0, 125.3 (q, ¹J_CF = 283.8 Hz), 124.1, 119.0, 110.6, 107.7, 56.4, 55.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −63.95; HRMS (ESI) calcd for C₁₈H₁₅F₃NO₂: 334.1049 (M + H⁺), found: 334.1066.

7-Chloro-3-phenyl-1-(trifluoromethyl)isoquinoline 3c

¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 6.5, 2.9 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.52–7.46 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.0, 149.3, 137.1, 131.3, 130.5, 130.0, 129.8, 129.3, 129.2, 128.7, 128.3, 127.6, 125.3 (q, ¹J_CF = 283.3 Hz), 125.7, 121.2; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.32; HRMS (ESI) calcd for C₁₆H₁₀ClF₃N: 308.0448 (M + H⁺), found: 308.0432.

7-Methyl-3-phenyl-1-(trifluoromethyl)isoquinoline 3d

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.87 (s, 1H), 7.78–7.68 (m, 3H), 7.46 (m, 4H), 2.57 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.5, 147.2, 141.1, 131.9, 130.5, 129.9, 129.6, 128.2, 127.7, 127.1, 126.7, 125.2 (q, ¹J_CF = 284.8 Hz), 121.2, 22.6; ¹⁹F NMR (378 MHz, CDCl₃) δ −61.77; HRMS (ESI) calcd for C₁₇H₁₃F₃N: 288.0995 (M + H⁺), found: 288.1004.

3-(tert-Butyl)-1-(trifluoromethyl)isoquinoline 3e

¹H NMR (400 MHz, CDCl₃) δ 8.21 (t, J = 10.4 Hz, 1H), 7.82–7.72 (m, 2H), 7.62–7.56 (m, 1H), 7.52 (t, J = 7.3 Hz, 1H), 1.58 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 156.1, 151.6, 133.4, 129.9, 127.8, 126.6, 126.4, 125.4 (q, ¹J_CF = 286.1 Hz), 124.1, 121.5, 30.2, 27.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.28; HRMS (ESI) calcd for C₁₄H₁₅F₃N: 254.1151 (M + H⁺), found: 254.1124.

3-Cyclopropyl-1-(trifluoromethyl)isoquinoline 3f

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.64–7.58 (m, 1H), 7.55 (d, J = 14.7 Hz, 1H), 7.45 (s, 1H), 2.63–2.69 (m, 1H), 1.17–1.28 (m, 2H), 0.79–0.87 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 151.7, 150.3, 132.7, 129.8, 128.4, 128.0, 127.3, 127.2, 125.3 (q, ¹J_CF = 282.3 Hz) 122.1, 15.4, 7.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.13; HRMS (ESI) calcd for C₁₃H₁₁F₃N: 238.0838 (M + H⁺), found: 238.0837.

7-Fluoro-3-phenyl-1-(trifluoromethyl)isoquinoline 3g

¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J = 10.6, 8.7 Hz, 2H), 7.83 (dd, J = 8.9, 5.8 Hz, 1H), 7.72 (dd, J = 6.6, 3.0 Hz, 2H), 7.53–7.45 (m, 3H), 7.41–7.34 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 163.3 (d, ¹J_CF = 250.4 Hz), 152.5, 148.8, 131.4, 130.6, 130.5, 129.9, 129.8, 128.3, 127.2, 125.2 (q, ¹J_CF = 278.3 Hz), 118.7, 107.2; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.54, −105.61; HRMS (ESI) calcd for C₁₆H₁₀F₄N: 292.0744 (M + H⁺), found: 292.0748.

6-Fluoro-3-phenyl-1-(trifluoromethyl)isoquinoline 3h

¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J = 10.3, 5.0 Hz, 1H), 7.86 (s, 1H), 7.78–7.70 (m, 2H), 7.53–7.42 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 161.5 (d, ¹J_CF = 252.3 Hz), 151.2, 149.1, 131.3, 130.1, 129.9, 128.3, 126.6, 126.5, 124.8 (q, ¹J_CF = 273.3 Hz), 120.9, 111.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.08, −109.13; HRMS (ESI) calcd for C₁₆H₁₀F₄N: 292.0744 (M + H⁺), found: 292.0752.

3-(4-Methoxyphenyl)-1-(trifluoromethyl)isoquinoline 3i

¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H), 8.02–7.94 (d, J = 8.2 Hz, 2H), 7.68 (t, J = 7.3 Hz, 1H), 7.58–7.53 (m, 1H), 7.04 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.3, 148.4, 131.4, 130.4, 128.2, 127.6, 127.5, 126.8, 126.7, 124.4 (q, ¹J_CF = 275.4 Hz), 115.4, 114.2, 55.4; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.07; HRMS (ESI) calcd for C₁₇H₁₃F₃NO: 304.0944 (M + H⁺), found: 304.0941.

3-(4-Chlorophenyl)-1-(trifluoromethyl)isoquinoline 3j

¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.75–7.66 (m, 3H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 151.1, 146.9, 136.0, 131.2, 130.7, 130.1, 130.0, 128.8, 128.5, 127.9, 127.4, 127.1, 125.3 (q, ¹J_CF = 288.3 Hz), 122.3; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.08; HRMS (ESI) calcd for C₁₆H₁₀ClF₃N: 308.0448 (M + H⁺), found: 308.0456.

5-Methoxy-3-phenyl-1-(trifluoromethyl)isoquinoline 3k

¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 7.1 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.23–7.28 (m, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.6 Hz, 2H), 6.78 (s, 1H), 4.93 (t, J = 8.4 Hz, 1H), 3.87 (s, 3H), 1.00 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 155.2, 148.6, 138.1, 133.0, 131.1, 128.9, 128.8, 128.5, 127.0, 125.8 (q, ¹J_CF = 287.5 Hz), 125.6, 116.4, 114.1, 55.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −63.55; HRMS (ESI) calcd for C₁₇H₁₃F₃NO: 304.0944 (M + H⁺), found: 304.0938.

3-Cyclopropyl-7-fluoro-1-(trifluoromethyl)isoquinoline 3l

¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 2.04 (m, 1H), 1.23–1.27 (m, 2H), 0.83–0.88 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.1 (d, ¹J_CF = 252.6 Hz), 152.7, 148.5, 133.0, 130.9, 128.9, 128.0, 126.0, 125.1 (q, ¹J_CF = 276.7 Hz), 106.9, 14.2, 8.9; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.17, −107.01; HRMS (ESI) calcd for C₁₃H₁₀F₄N: 256.0744 (M + H⁺), found: 256.0739.

3-Butyl-7-chloro-1-(trifluoromethyl)isoquinoline 3m

¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 11.6 Hz, 1H), 7.77 (dd, J = 8.9, 5.9 Hz, 1H), 7.71 (s, 1H), 7.34 (t, J = 8.3 Hz, 1H), 3.03–2.94 (m, 2H), 1.75 (dt, J = 15.4, 7.6 Hz, 2H), 1.49 (dt, J = 14.5, 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.1, 150.4, 133.0, 129.9, 129.8, 127.3, 127.2, 125.3, 125.2 (q, ¹J_CF = 286.9 Hz), 124.8, 36.8, 28.5, 22.5, 13.8; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.64; HRMS (ESI) calcd for C₁₄H₁₄ClF₃N: 288.0761 (M + H⁺), found: 288.0772.

7-Chloro-3-cyclopropyl-1-(trifluoromethyl)isoquinoline 3n

¹H NMR (400 MHz, CDCl₃) δ 7.26–7.04 (m, 4H), 2.04 (s, 1H), 1.19–1.29 (m, 2H), 1.00–0.90 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 150.4, 150.2, 133.8, 132.8, 128.9, 125.2, 125.1, 125.0 (q, ¹J_CF = 280.6 Hz), 124.7, 28.5, 19.1, 8.1; ¹⁹F NMR (378 MHz, CDCl₃) δ −62.09; HRMS (ESI) calcd for C₁₃H₁₀ClF₃N: 272.0448 (M + H⁺), found: 272.0469.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 21032007, 21372046) is gratefully acknowledged.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of compounds 3. See DOI: 10.1039/c4qo00173g

‡ C. Fan and J. Song contributed equally.

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