Substituted N-tert-butoxycarbonyl (Boc)-1,2,3,4-tetrahydroisoquinolines were prepared and treated with n-butyllithium in THF at -50 °C to test the scope of the metallation and electrophilic quench. The lithiation was optimised by using in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined. The 1-lithiated intermediates could be trapped with a variety of electrophiles to give good yields of 1-substituted tetrahydroisoquinoline products. Treatment with acid or reduction with LiAlH4 allows conversion to the N-H or N-Me compound. The chemistry was applied to the efficient total syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline. IntroductionThe tetrahydroisoquinoline ring structure is present in a large number of natural and biologically active products. Derivatives with a substituent in the 1-position are particularly common and are typically prepared by Pictet-Spengler or BischlerNapieralksi reactions. 1 Other methods include addition to iminium ions or reduction of isoquinoline rings. 2 An alternative approach to such compounds makes use of the ability to deprotonate at the 1-position of the tetrahydroisoquinoline ring. This method has potential to provide access to a large range of differently substituted derivatives. Various Nsubstituents on the tetrahydroisoquinoline can be used to aid the metallation. 3 We have reported that an efficient and relatively mild method is to use the N-Boc derivative with deprotonation by using n-BuLi. 4,5 However we have so far reported only a few examples with the parent compound NBoc-tetrahydroisoquinoline 1 and with the 6,7-dimethoxy derivative 2 (Fig. 1). 4 Here we demonstrate that the chemistry is amenable to other substituted tetrahydroisoquinolines and to a variety of different electrophiles, leading to its application to the syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline.In our earlier work we showed that the Boc group in N-Boctetrahydroisoquinoline rotates slowly at -78 °C. 4 As the lithiation at the 1-position is directed by complexation of the base (n-butyllithium) with the carbonyl of the Boc group, 6 better yields can be obtained at -50 °C since the Boc rotation is faster. We wanted to test whether the same phenomenon also occurs with other derivatives and whether the lithiationsubstitution chemistry is amenable to different substituted tetrahydroisoquinolines. The lithiations of a selection of N-Boctetrahydroisoquinoline compounds (2-5) and applications of this chemistry to the preparation of some natural products are described in this article. Fig. 1Structures of some N-Boc-tetrahydroisoquinolines. Results and discussionWe selected to prepare the tetrahydroisoquinolines 2-5 (Fig. 1). These compounds provide a range of electron-donating (alkoxy) and electron-withdrawing (chloro and trifluoromethyl) groups on the tetrahydroisoquinolines used for the lithiation chemistry. For syntheses of compounds 2-5, see the Supplementary Information. The lithiation of tetrahydroisoquinoline 3 was monitored by in situ ReactIR...
Tetrahydroisoquinolines are found in many natural products and drug compounds and a convenient method to access 1‐substituted derivatives is to carry out the lithiation at C‐1 followed by trapping with an electrophile. Here we explore the feasibility of lithiation at C‐3 by using a substrate with a benzylic proton on both sides of the nitrogen atom such that lithiation with nBuLi could occur at either C‐1 or C‐3 of the tetrahydroisoquinoline. The regioselectivity in the lithiation was determined using the substrate N‐tert‐butoxycarbonyl (Boc)‐3‐phenyltetrahydroisoquinoline. The lithiation could be followed by in situ ReactIR spectroscopy and the rate of rotation of the carbamate group was determined (barrier to rotation was approximately ΔG‡ 58 kJ/mol at –50 °C). Subsequent trapping of the organolithium species with an electrophile gave a mixture of two regioisomeric products with a preference for reaction at C‐1. This led to the isolation of 1,3‐disubstituted tetrahydroisoquinolines with trans relative stereochemistry. Removal of the Boc group from the nitrogen atom gave secondary and tertiary amine products.
The intermediately formed 1‐lithiated derivatives are trapped with diverse electrophiles, thus affording 1‐functionalized tetrahydroisoquinolines in high yields.
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