• 10.1002/anie.200500227
  • Angewandte Chemie International Edition
  • 44
  • October 2005
  • 6576-6579

Catalytic Enantioselective Friedel-Crafts Alkylation of Indoles with Nitroalkenes by Using a Simple Thiourea Organocatalyst

Good reported synthesis with room for improvement



This article describes the structure optimization and initial mechanistic understanding of a simple thiourea catalyst for the enantioselective alkylation of indoles with nitroalkenes.  The indole ring has proven to be a “privileged” structure in medicinal chemistry, therefore, providing a synthetic method which easily provides optically active indole derivatives would be extremely beneficial.   Nitroalkenes are an attractive derivatizing agent due to the strong electron-withdrawing nitro group which can be easily transformed into a variety of functional groups for further modifications.

The thiourea/urea scaffold was selected as the catalyst’s core due to its ability to activate carbonyl groups through a weak bidentate hydrogen-bonding motif.  Initially, five thiourea/urea catalysts (1a, 1b, 1c, 1d, 1e) where prepared and the addition of indole (2a) to trans-nitrostyrene (3a) was used as a test reaction to evaluate the potential catalysts.  It was shown that all prepared catalysts increased the reactivity of trans-nitrostyrene compared to the non-catalyized reaction, however, only the (1R,2S)-1-amino-2-indanol-3,5-bis(trifluoromethyl)phenyl-thiourea (1d) catalyst showed asymmetric induction as the product (4a) was obtained in 35% ee.  Optimization of the reaction conditions with 1d (solvent and temperature) increased the product ee (4a) from 35% to 85%.  The reaction scope was then investigated through a series of alkylations between various indoles and nitroalkenes.  The results show that the optimized coupling reaction is effective with moderate to high product yields and ee.  It should be noted that an electron withdrawing group on the indole and an isopropyl group on the nitroalkene reduced yields (37% and 35%, respectively), but did not dramatically decrease ee. 

The authors comment that the asymmetric induction might be due to the reversible formation of a complex in which the thiourea protons are hydrogen-bonding to the two oxygen atoms of the nitro group and the alcohol group is interacting with the indolic proton in a weak hydrogen-bonding fashion.  To investigate these interactions further, two catalysts were prepared in which the hydroxy group was protected with a trimethylsilyl group (1f) or lacking the alcohol functionality (1g) completely.  Both catalysts (1f and 1g) showed poor activity under the optimized reaction conditions in terms of yield and ee, thus, showing the necessity of a free alcohol group for asymmetric induction and catalyst activity. 

I have successful synthesized compound 1d, however, I had changed the protocol to improve on the purification method and isolated yield.

Original protocol:  (1R,2S)-cis-1-amino-2-indanol (5 mmol) was added to a stirring solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (5 mmol) in dichloromethane (10 mL) at room temperature.  The reaction continued to stir at room temperature overnight, then the solvent was evaporated under reduced pressure and the white solid purified by crystallization  (n-hexane/acetone) affording 1d as a white solid in 88% yield.

My protocol:  (1R,2S)-cis-1-amino-2-indanol (3 mmol) was dissolved in dichloromethane to which an equal volume of saturated sodium bicarbonate solution was added and the biphasic reaction was cooled to 0 deg C.  Next, the 3,5-bis(trifluoromethyl)phenyl isothiocyanate (3.1 mmol) was added dropwise and the reaction stirred at 0 deg C for 30 minutes followed by 2 hours at room temperature.  The reaction was diluted with dichloromethane and the organic layer was separated, washed with sodium bicarbonate, dried with MgSO4, and concentrated under reduced pressure to afford 1d as a white solid in 93% yield.  

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