Light triggered addition/annulation of 2-isocyanobiphenyls toward 6-trifluoromethyl-phenanthridines under photocatalyst-free conditions

Abstract

A photocatalyst-free, light promoted sequential radical addition/annulation of 2-isocyanobiphenyls to 6-trifluoromethyl phenanthridines is presented. Wide substrate scopes and scale-up experiment demonstrate the promising efficiency and utility of this strategy.

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Isonitriles are privileged motifs in organic synthesis because of their vast potentials for synthetic versatility, which have aroused intensive and continuing interest from chemists.¹ Recently, the radical addition/intramolecular homolytic aromatic substitution (HAS) reactions of 2-isocyanobiphenyls have been extensively investigated. By such a cascade procedure, a rapid assembly of 6-substituted phenanthridine frameworks is accomplished with high synthetic efficiency and atom economy. To date, various types of radical precursors including boronic acids,² halides,³ aldehydes,⁴ diphenylphosphine oxide,⁵ a-oxocarboxylic acids,⁶ silanes,⁷ peroxides,⁸ amides,⁹ ethers,¹⁰ alkanes,¹¹ hydrazines,¹² and carbazates¹³ have been gradually explored for such transformations and a myriad of phenanthridine scaffolds with diverse functional groups have been successfully produced. Due to the wide applications in pharmaceutical science and drug research of phenanthridines and their derivatives,¹⁴ the synthesis 6-trifluoromethyl phenanthridines may be of great significance, and their potential biological activities may be profoundly enhanced to some extent. Because the incorporation of trifluoromethyl group can alert the physicochemical properties of the parent compounds, such as electronegativity, hydrophobicity, metabolic stability, and bioavailability compared to their non-trifluoromethylated counterparts.¹⁵ Although various methods leading to 6-trifluoromethyl phenanthridines have emerged,¹⁶ there are only three examples involving the somophilic isocyanide insertion by the electrophilic CF₃ radical (Scheme 1). In 2013, Studer and co-workers reported a novel Bu₄NI-catalyzed formation of 6-trifluoromethyl phenanthridines by using Togni's reagent as the precursor of CF₃ radical in 1,4-dioxane at 80 °C.¹⁷ Almost simultaneously, Zhou et al. described a PhI(OAc)₂-mediated oxidative cyclization of 2-isocyanobiphenyls with CF₃SiMe₃ in combination with BQ as the additive.¹⁸ In 2014, the Studer group again made an advance on finding a NiBr₂ assisted and CF₃I participated facile synthesis of 6-trifluoromethyl phenanthridines.¹⁹ Despite of the high effectiveness for the above strategies, some disadvantages are existed, such as the use of expensive CF₃ reagents and environmentally unfriendly oxidants, the relatively high temperature, which restrict their practical applications to some extent. Therefore, the development of a mild, economic, environmentally benign and efficient alternative to realize the direct construction of 6-trifluoromethyl phenanthridines via the radical addition followed by HAS process is still an urgent need.

Scheme 1 The cascade addition/annulation of 2-isocyanobiphenyls to 6-trifluoromethyl phenanthridines.

Typically, the CF₃ radical can be generated in three ways: the reduction, oxidation and homolysis of CF₃ reagents using reducing agents, oxidizing agents and light-excitation or at high temperature or using initiators. The former two are preferred methods for the trifluoromethylation of a wide range of interesting scaffolds,²⁰ while the reactions involving the homolysis of CF₃ reagents are still limited.²¹ Recently, we have investigated the light-induced BiOBr nanosheets accelerated trifluoromethylation/arylation of N-aryl acrylamide substrates employing CF₃SO₂Cl as CF₃ source.²² It is observed that small amount of the product is still formed without the addition of BiOBr photosensitizer. We reason this result may be ascribed to the homolysis of CF₃SO₂Cl under light-excitation generating the CF₃ radical that engages this tandem transformation. This speculation inspired us to take advantage of these unexpected CF₃ radicals, produced from the direct light-irradiation of CF₃SO₂Cl, for the trifluoromethylation of organic molecules. Isonitriles are isoelectronic with carbon monoxide, which can act as well-established C-radical acceptors. Herein, we wish to disclose our recent endeavor in light-mediated sequential arylation/trifluoromethylation of 2-isocyanobiphenyls to synthesize 6-trifluoromethyl-phenanthridines. Compared with the aforementioned protocols on the synthesis of 6-trifluoromethyl-phenanthridines, this procedure own three unique features: (1) the use of easily available and high active CF₃SO₂Cl as trifluoromethylating reagent; (2) direct light-induced transformation under photocatalyst-free conditions; (3) gram-scale synthesis. This promising and green chemical transformation constitutes an important complementary to the current light-driven organic reactions.²³

The light-induced isonitrile insertion reaction is initiated by treating 2-isocyanobiphenyl (1e) and CF₃SO₂Cl (2) with the addition of K₂HPO₄ in DMF under light irradiation (280–780 nm) for 6 h. As expected, this reaction indeed occurs, and 33% yield of the desired product is obtained (Table 1, entry 1). Delightedly, the yield of 3e dramatically increased to 76% when the reaction proceeds in DMAC (Table 1, entry 2). Encouraged by this exciting result, we further screen the other solvents including the polar/non-polar and protonic/non-protonic solvents, and observe that the others are inferior to DMAC, or even useless (Table 1, entries 3–10), which indicates a significant solvent effect of this radical addition/annulation of 2-isocyanobiphenyl. Additionally, examination of bases reveals that this one-pot tandem reaction proceeds more effectively in the presence of inorganic base, and K₂HPO₄ is the optimal one (Table 1, entries 11–15). However, the reaction efficiency is remarkablely decreased when K₂HPO₄ is removed from the reaction media, demonstrates that the base plays a stimulative role for the creation of trifluoromethylated phenanthridines (Table 1, entry 16). In order to identify the effective wavelength range for this reaction clearly, the UV-visible absorption test of CF₃SO₂Cl in DMAC is conducted (Fig. S1 in ESI†). From the spectrogram we can see that the optimal wavelength absorption range of CF₃SO₂Cl is approximately between 270 and 350 nm. It means that only this wavelength range is effective for the activation of CF₃SO₂Cl, and the rest section that from 350 nm to 780 nm is almost useless. Noting that, the reaction does not occur in the dark, showing that the CF₃ radical is indeed generated by light-illumination, and that is the light that triggers this cascade transformation (Table 1, entry 17).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Base	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2 CF3SO2Cl (0.6 mmol), solvent (1.0 mL), base (0.6 mmol), 300 W Xe lamp, 0 °C. b Isolated yield is reported. c No reaction. d In the dark.
1	DMF	K2HPO4	33
2	DMAC	K2HPO4	76
3	DMSO	K2HPO4	N.R.^c
4	CH3CN	K2HPO4	23
5	NMP	K2HPO4	N.R.^c
6	EtOAc	K2HPO4	43
7	CH3OH	K2HPO4	N.R.^c
8	THF	K2HPO4	N.R.^c
9	CH2Cl2	K2HPO4	Trace
10	Toluene	K2HPO4	N.R.^c
11	DMAC	K2CO3	68
12	DMAC	K3PO4	57
13	DMAC	KOH	67
14	DMAC	tBuOK	49
15	DMAC	Et3N	34
16	DMAC	—	30
17^d	DMAC	K2HPO4	N.R.^c

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With the optimized reaction conditions in hand, the substrate scope is evaluated to test the universality, as listed in Table 2. Firstly, we investigate the influence of R² on the nonisonitriles phenyl ring on the reaction efficiency. The substrates bearing the electron-rich or electron-deficient groups at para-position could all work smoothly to deliver the corresponding products in middle to good yields (Table 2, 3a–i). Noting that, even the potentially sensitive functional groups acetyl and cyano are both tolerated, and 59% and 58% yields of the phenanthridine derivatives are obtained (Table, 3h and 3i). The existence of acetyl and cyano gives an opportunity for further transformations by transition-metal catalyzed strategies or other technologies. In contrast, the ortho- and meta-substituted 2-isocyanobiphenyls suppress the reaction and a relatively low yields of the products are formed (Table 2, 3j–m). When meta-methyl substituted substrate is used, two regioisomers 3k and 3k′ are formed with a ratio of 1.5 : 1. The dioxy heterocyclic group functionalized isocyanide is also a good candidate, and under the present reaction conditions we mainly get one isomer compound as the final product with the isolated yield of 71% (Table 2, 3n). The obtained molecule 3n containing a trisphaeridine framework, which can function as DNA intercalator.^14a,c According to the significant characteristics of the trifluoromethyl-containing compounds, the biological activity of the synthesized trifluoromethylated trisphaeridine may be obviously improved. When the aromatic ring is replaced with 2-naphthyl, 9-phenanthrene and electron-deficient 2-thienyl moiety, radical addition/cyclization reactions still occur, giving rise to the desired products 3o–q in acceptable yields. Next, the substrate with a methyl group on the aromatic ring of the isocyano group is amenable to the selected reaction conditions, and 75% yield of the corresponding product is fabricated (Table 2, 3r).

Table 2 Substrate scope of the light triggered direct arylation/trifluoromethylation of 2-isocyanobiphenyls^a

a Reaction conditions: 1a (0.2 mmol), 2 CF₃SO₂Cl (0.6 mmol), DMAC (1.0 mL), K₂HPO₄ (0.6 mmol), 300 W Xe arclamp, 0 °C.

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To highlight the utility of this photochemical protocol, an amplifying reaction of 1.2 mmol of 1g with 3.6 mmol CF₃SO₂Cl is conducted under the standard conditions (Scheme 2). A comparable yield of the product 3g with that of 0.2 mmol scale experiment is afforded, hints the potential applicability of our method.

Scheme 2 Scaled-up experiment.

To confirm that this tandem transformation is originated from the addition of CF₃ radical to the terminal carbon of 2-isocyanobiphenyl, the control experiment is carried out. Adding radical trapping agent, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), to the reaction system under otherwise identical conditions leads to no desired product, which supports that a radical pathway is involved in this radical addition/annulation of 2-isocyanobiphenyl (Scheme 3). This process is distinguished from Yu's work that discloses a concise and efficient synthetic approach to 6-(trifluoromethyl)phenanthridine through the ionic isocyanide insertion with no use of catalyst.²⁴

Scheme 3 Control experiment.

Based on the above observations and the previous reports,^2–13 a plausible mechanism is presented (Scheme 4). Homolysis of CF₃SO₂Cl by photoexcitation generates CF₃ radical with the release of SO₂ and Cl radical. Subsequent addition of CF₃ radical to the terminal carbon of isocyanide affords the imidoyl radical I, which experiences a intramolecular homolytic aromatic substitution to give the cyclized radical intermediate II. The product is finally created with the leave of H radical, which is abstracted by Cl radical to get HCl. The formed HCl can be neutralized by K₂HPO₄ at the end.

Scheme 4 Proposed mechanism for the radical isocyanide insertion of 2-isocyanobiphenyl with CF₃SO₂Cl.

In conclusion, we have developed a direct light-initiated one-pot consecutive radical addition/annulation of 2-isocyanobiphenyls using cheap and high active CF₃SO₂Cl as the precursor of CF₃ radical under photocatalysts-free conditions. With this method, a variety of the corresponding 6-trifluoromethyl-phenanthridines derivatives bear diverse functional groups are constructed in acceptable to good yields. The scale-up experiment illustrates the potential applicability of our methodology. The simple, economic and environmentally friendly procedure may be applied to the future industrial processes. Further mechanistic researches and more light-induced cascade reactions for molecules with structural complexity are underway in our lab.

Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (No. 21422104).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and full spectroscopic data for all compounds. See DOI: 10.1039/c5ra16645d

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