The lithiation of N-tert-butoxycarbonyl (N-Boc)-1,2,3,4-tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using n-butyllithium in THF at -50 °C for less than 5 min. The intermediate organolithium was quenched with electrophiles to give 1-substituted 1,2,3,4-tetrahydroisoquinolines. Monitoring the lithiation by IR or NMR spectroscopy showed that one rotamer reacts quickly and the barrier to rotation of the Boc group was determined by variable-temperature NMR spectroscopy and found to be about 60.8 kJ mol(-1), equating to a half-life for rotation of approximately 30 s at -50 °C. The use of (-)-sparteine as a ligand led to low levels of enantioselectivity after electrophilic quenching and the "poor man's Hoffmann test" indicated that the organolithium was configurationally unstable. The chemistry was applied to N-Boc-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine.
Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at –78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products.
Lithiation of N-Boc-1-phenyltetrahydroisoquinolines was optimized by in situ IR spectroscopy. The kinetics for rotation of the carbamate group and for the enantiomerization of the organolithium were determined. The organolithium is configurationally stable at low temperature, and the asymmetric synthesis of 1,1disubstituted tetrahydroisoquinolines can be achieved with high yields and high enantiomer ratios. The chemistry was applied to the preparation of FR115427 and provides a way to recycle the undesired enantiomer in the synthesis of solifenacin.
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...
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