Elsevier

Journal of Fluorine Chemistry

Volume 140, August 2012, Pages 88-94
Journal of Fluorine Chemistry

Selective trifluoromethylation and alkynylation of tetrahydroisoquinolines using visible light irradiation by Rose Bengal

https://doi.org/10.1016/j.jfluchem.2012.05.009Get rights and content

Abstract

A convenient and efficient method for oxidative coupling of tetrahydroisoquinoline derivatives with trimethyl(trifluoromethyl)silane and terminal alkynes to 1-trifluoromethylated or 1-alkynylated tetrahydroisoquinolines via Csingle bondH activation was developed using visible light irradiation. The protocol uses Rose Bengal as the catalyst, air as terminal oxidant, and the trifluoromethylation or alkynylation was selectively performed at the α-position of nitrogen under extremely mild conditions.

Graphical abstract

A convenient and efficient method for oxidative coupling of tetrahydroisoquinoline derivatives with trimethyl(trifluoromethyl)silane and terminal alkynes to 1-trifluoromethylated or 1-alkynylated tetrahydroisoquinolines via Csingle bondH activation was developed using visible light irradiation. The protocol uses Rose Bengal as the catalyst, air as terminal oxidant, and the trifluoromethylation or alkynylation was selectively performed at the α-position of nitrogen under extremely mild conditions.

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Highlights

► Rose Bengal catalyzed α-trifluoromethylation and α-alkynylation of tetrahydroisoquinolines under visible light irradiation. ► The reaction via Csingle bondH activation. ► The reaction uses air as terminal oxidant under transition-metal-free reaction conditions.

Introduction

Considering the importance of amines containing trifluoromethyl group at the Csingle bondα atom and alkaloids in industry as pharmaceutical and agrochemical drugs [1], [2], [3], straightforward and eco-friendly preparation of these compounds still represents a challenging task for chemists. The traditional methods for synthesizing such compounds include nucleophilic addition and 1,3-proton shift reactions involving imines of trifluoroacetic aldehyde [4], [5], [6], as well as addition reactions of trifluoromethyl carbanion at the Cdouble bondN bond of azomethine substrates and iminium cations [7], [8], [9], [10], [11]. Recently, transition metal-catalyzed Csingle bondH bond activation directly to form Csingle bondC bond has attracted great attention and a number of excellent results have been obtained because it avoids the preparation of functional groups and makes synthetic schemes shorter and more efficient [12], [13], [14], [15], [16], [17]. Among these reactions, oxidation of an sp3 Csingle bondH bond adjacent to a nitrogen atom in a tertiary amine, followed by attack of a carbon nucleophile, is a powerful strategy for Csingle bondC bond formation [18], [19], [20]. This method resides in the generation of an iminium ion intermediate in the presence of metal catalysts such as CuI, VIV, FeIII, FeII, or RuII and oxidants such as hydrogen peroxide, oxygen, and tert-butylhydroperoxide [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. For example, Li and co-workers developed an efficient copper-catalyzed trifluoromethylation of N-aryl-tetrahydroisoquinolines with TMSCF3 via oxidative sp3 Csingle bondH activation at the α-position of nitrogen using DDQ as terminal oxidant [35]. Qing and co-workers reported that benzoyl peroxide (BPO)-promoted oxidative trifluoromethylation of tertiary amines proceeded successfully under transition-metal-free reaction conditions [36]. Despite this extensive progress, the search for an efficient and practical catalytic system for trifluoromethylation of tertiary amines remains a challenge.

With the emergence of the concept of “green chemistry”, photoredox catalyzed organic transformations have been attracting much attention in recent years, not only because these transformations exhibit some particular or unexpected reactivities in some cases but also because they are significantly useful for green chemistry [37], [38], [39], [40]. Over the past 5 years, a variety of metal-based and organic dyes-based photosensitizers, as photoredox catalysts for organic transformations under visible light irradiation have been developed [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54]. Among these transformations, the oxidative cross-dehydrogenative coupling (CDC) reaction is an attractive strategy. In this case, generation of iminium ion intermediates by using visible-light photoredox catalysis followed by reactions with carbon pronucleophiles would give α-substituted products [55], [56], [57], [58], [59], [60].

α-Trifluoromethylation of tetrahydroisoquinolines is a powerful transformation in organic synthesis because 1-trifluoromethyltetrahydroisoquinoline derivatives are highly important bioactive compounds [61], [62]. Combining all the above principles and as a continuation of our interest in the design and discovery of new reactions for the synthesis of fluorinated heterocycles [63], [64], herein, we report a visible-light-induced oxidative α-trifluoromethylation and α-alkynylation of tetrahydroisoquinolines using Rose Bengal as visible light photocatalyst under transition-metal-free reaction conditions (Scheme 1).

Section snippets

Results and discussion

Our initial investigation focused on the oxidative trifluoromethylation of 2-phenyl-1,2,3,4-tetrahydroisoquinoline 1a as an example for the optimization of the reaction conditions. We found that treatment 1a with Rose Bengal (RB, 5 mol%), TMSCF3 (3.0 equiv.) and KF (3.0 equiv.) in CH3CN under irradiation by visible light afforded α-trifluoromethylation product 2a in 45% yield after 48 h (Table 1, entry 1). With this encouraging result, we first examined the influence of organic dyes on the

Conclusion

In conclusion, we have developed a simple and effective aerobic, metal-free catalytic reaction for the direct oxidative α-trifluoromethylation and α-alkynylation of N-aryl tetrahydroisoquinolines by means of visible-light irradiation. The process showed considerable synthetic advantages in terms of product diversity and the operational simplicity, practicability as well as the mild reaction conditions using visible light as the energy source.

General

Chemicals used were obtained from commercial suppliers and used without further purifications. 1H NMR spectra and 13C NMR spectra were measured in CDCl3 and recorded on Bruker Avance-400 spectrometer (400 MHz for 1H NMR, 100 MHz for 13C NMR) with TMS as an internal standard. EIMS were determined with a HP5989B mass spectrometer. Elemental analyses were performed on an EA-1110 instrument.

Typical procedure for trifluoromethylation of tetrahydroisoquinolines

RB (0.015 mmol, 5 mol%) was added to a mixture of 2-phenyl-1,2,3,4-tetrahydroisoquinoline 1a (0.3 mmol), potassium

Acknowledgments

We are grateful to the National Natural Science Foundation of China (Project Nos. 20902042 and 20902043) and Foundation of He’nan Educational Committee (No. 2010B150020).

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