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Journal of Nature and Science (JNSCI), Vol.1, No.8, e169, 2015
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Synthesis of Indole-Derived Fluorine-Containing Amino Acids


Hannah C. Cade, Mark Blocker, and Abid Shaikh*


Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA 30460-8064, USA

A Brønsted acid promoted direct aminoalkylation of various indoles with trifluoromethyl oxazolidine is described. A catalytic amount of triflic acid provided straightforward access to the corresponding trifluoromethyled amino esters under mild reaction conditions and a short reaction time of 4 h. On further hydrogenolysis and hydrolysis of ester, the synthesis of indole derived unnatural trifluoromethylated amino acids was achieved. Journal of Nature and Science, 1(8):e169, 2015


Brønsted acid | Aminoalkylation | Triflic acid | Indoles | Amino acid



Organofluorine chemistry has received extensive attention especially in the pharmaceutical industry and in materials science due to the unique properties of fluorinated compounds [1]. Trifluoromethylated compounds are of particular interest as the strong electron-withdrawing effect of -CF3 group contributes to a number of biologically important molecular properties [2]. For example, it results in a significant increase in lipophilicity of the molecule, which is a very important feature for drug delivery [3]. The increased lipophilicity, and a superior metabolic stability compared to that of the methyl analogues, often accounts for an improved activity profile [4]. The different medicinal applications of fluorinated organic molecules are widespread. Some of the most well-known drugs are Prozac® (anti-depressant), Diflucan® (anti-fungal agent), Casodex® (anti-cancer agent) and Desflurane (inhalation anesthetic) [5]. Recent applications of organofluorine compounds include, potential therapeutics for HIV, cancer and Alzheimer’s disease [6]. Accordingly, the synthesis of these molecules is in great demand and the search for new biologically active fluorinated compounds is in the forefront of organic and medicinal chemistry research. Fluorine-containing amino acids in particular, a-trifluoromethyl amino acids are of special interest [7]. Incorporation of a C-F bond on amino acids results in conformationally and proteolytically stable peptides with enhanced lipophilicity [8]. The modified amino acids possess different properties such as lipophilicity, bioavailability and reactivity resulting from an increase in the electronegativity of the trifluoromethyl group [9]. They can be used as peptidomimetics and therapeutic agents and thus are interesting subjects in current medical investigations [10].   

The electrophilic aminoalkylation of aromatic compounds is a type of well-known Friedel-Craft’s reaction and a valuable tool in C–C bond formation [11]. Recent investigations demonstrated the role of a Lewis acid catalyst in allylation of oxazolidine [12], herein, we report an extension of this strategy in Friedel-Craft’s aminoalkylation of various substituted indoles with -CF3 oxazolidine derived from ethyl trifluoropyruvate and phenylglycinol. A Brønsted acid catalyst (triflic acid, TfOH) was used a catalyst.


Results and discussion:

The starting oxazolidine (2) was conveniently synthesized from ethyl trifluoropyruvate and (R)-phenylglycinol as reported in the literature [12]. As a key step, we further investigated the role of various Lewis acids and Brønsted acid catalysts for the Friedel-Crafts aminoalkylation of various indoles (1a-h) with oxazolidine (2). In order to prove the idea, 6-isopropyl indole 1d was initially used as a model substrate. Although Lewis acid catalysis could be achieved, the reactions turned out to be sluggish and no product formation was observed. On the other hand, Brønsted acid catalysts such as triflic acid provided the expected product in good yield and in short reaction time of 4 h. 

After optimizing the reaction conditions for temperature, time and catalyst the substrate scope of this reaction was investigated by treating various substituted indoles 1a–h with trifluoromethyl oxazolidine 2. The results are summarized in Figure 1. All the reactions proceeded in good yields ranging from 55% to 76% and no by-product formation was observed. Relatively higher yields were obtained when indole bearing electron-withdrawing groups such as 5-bromo 3f and 5-fluoro 3h were used. On the other hand, the presence of an electron-donating group such as alkyl groups resulted in relatively lower yields of 3c, 3d and 3e. An important observation worth mentioning is that the reactions with halogenated indoles provided the expected products without the loss of halogens. In all the cases, diastereomeric mixture of products were obtained.


Figure 1. Triflic acid-promoted nucleophilic addition of indoles 1a-h with trifluoromethyl oxazolidine 2.


Figure 2. 1H-NMR spectrum of product 3d highlighting characteristic signals


Scheme 1. Synthesis of fluorine-containing amino acid via hydrogenolysis and hydrolysis reaction sequence.


Detailed 1H-NMR analysis of product 3d revealed the characteristic splitting pattern. Deshielded Ha signal was observed as overlapping doublets at 5.10 ppm, Hb and Hc were observed as double doublet (dd) at 3.30 and 3.06 ppm respectively.

In order to extend this approach, synthesis of unusual fluorine containing amino acid was carried out using hydrogenolysis and the base promoted hydrolysis of ester 3d. Corresponding trifluoromethyl amino acid 4 was obtained as white solid in 32-48% yield (scheme 1).

In conclusion, we have developed an efficient and simple protocol for the Friedel-Crafts aminoalkylation of indoles with trifluoromethyl oxazolidine. Triflic acid was used as a catalyst for this transformation to provide the corresponding trifluoromethyl amino cyclic esters in good yields. In all the cases, we observed a mixture of diastereomers. To broaden the scope of this methodology, amino ester product was subjected to hydrogenolysis and hydrolysis reaction sequence to obtain the corresponding trifluomethylated amino acid. In all cases, the products were obtained as racemic mixture and our current efforts are directed towards developing an enantioselective synthesis for these compounds. 


Experimental Section:

All the indoles were purchased from Sigma and used without further purification. Ethyl 3,3,3-trifluoropyruvate and (R)-phenylglycinol were also obtained from Sigma. Triflic acid used as Brønsted acid-catalyst was also obtained from Sigma. Other solvents used in synthesis with minimum purity of 99.5% were Aldrich products. CDCl3 used as a solvent (99.8%) for the NMR studies CFCl3 used as reference for 19F NMR were purchased from Aldrich. The 1H, 13C and 19F NMR were obtained on a 400 MHz Agilent NMR spectrometer. Residual solvent signal was used a reference in case of 1H and13C NMR. The mass spectrometric identification of the products have been carried out on a Bruker Daltronics Microflex LRF MALDI-ToF system.

General procedure for triflic acid-catalyzed addition of indoles to a-trifluoromethyl oxazolidine: Trifluoromethyl oxazolidine 2 (300 mg, 1 mmol) and 1-methylindole (158 mg, 1.2 mmol) were placed in a Schlenk flask with 10 mL dichloromethane. The mixture was flushed with argon and stirred for 2 min at room temperature. This mixture was then cooled to -20 oC and triflic acid (4 µL, 20 mol%) was added with constant stirring. After 4 h, maximum conversion was observed on TLC. The reaction was quenched with 10 mL of water and slowly warmed to RT. The resulting reaction mixture was then extracted with dichloromethane and washed with water. Concentration under reduced pressure provided a light red liquid that was further subjected to column chromatography (hexane/ethyl acetate 90:10 to 50:50) to obtain a white solid of product 3b in 68% isolated yield as a viscous liquid. 1H-NMR, d (ppm) 7.80 (bs, 1H), 7.39 (d, J = 8.50 Hz, 1H), 6.98-6.96 (m, 2H), 6.92-6.87 (m, 3H), 6.56 (d, J = 8.50 Hz, 1H), 6.48 (s, 1H), 5.10 (dt, J = 8.80, 1.12 Hz, 1H), 3.87 (bs, 1H), 3.30 (dd, J = 8.80, 9.0 Hz, 1H), 3.06 (dd, J = 8.80, 9.0 Hz, 1H), 2.89 (sept. J = 6.51 Hz, 1H), 2.75 (sept. J = 7.08 Hz, 1H), 1.19 (d, J = 6.51 Hz, 6H), 1.15 (d, J = 7.08 Hz, 6H). 13C-NMR, d (ppm) 150.7, 148.7, 143.5, 137.1, 126.7, 124.3, 120.9, 119.2, 118.9, 117.2, 108.5, 107.8, 56.8, 37.3, 34.2, 24.7, 19F-NMR, -77.1 (-CF3), MS-C22H21F3N2O2 (402), found 402.23   

General procedure for hydrogenolysis and base-promoted hydrolysis: Product 3a (100 mg) was placed in a 25 mL round bottom flak along with 10 mL ethanol and flushed with argon. Pd(OH)2 (100 mg) was then added and the reaction mixture and stirred under hydrogen for 12 h. The reaction mixture was filtered on celite and resulting filterate was concentrated under vacuum to obtain an oily product. To this crude mixture was added 10 mL ethanol and 0.2 mL of 1M NaOH and then refluxed for 2 h. A white solid was observed at the bottom of the flask which was then filtered through Buchner funnel. This white solid was washed successively with water and ethanol to obtain the pure acid in 55% isolated yield as a white solid. mp 121-123.6 oC, 1H-NMR, d (ppm) 8.46 (bs, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J = 8.40, 1.8 Hz, 1H), 2.96 (sept. J = 6.60 Hz, 1H), 2.44 (bs, 2H), 1.26 (d, J = 6.60 Hz, 6H), 13C-NMR, d (ppm) 169.3, 143.7, 136.6, 126.8, 123.7, 123.0, 122.8, 119.7, 109.7, 64.7, 62.8, 24.6, 13.8, 19F-NMR, -74.8 (-CF3), MS-C14H15F3N2O2 (300), found 300.11   



Financial support provided by Georgia Southern University, College Office of Undergraduate Research (COUR) award to HCC, Faculty Research Committee- Scholarly Pursuit Grant to AS are gratefully acknowledged.


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Conflict of interest: No conflicts declared.

*Corresponding Author. Tel.: +1-912-478-0973; Fax: +1-912-478-0699. Email: malnu@georgiasouthern.edu

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