Originally posted in the Russian HyperLab, see
Post 431183 (missing)
(Fomalhaut: "Õèòðûé ñèíòåç õèòðûõ êàòèíîíîâ", Russian HyperLab)
Friedel-Crafts alpha-Aminoacylation of Alkylbenzene with a Chiral N-Carboxy-alpha-amino Acid Anhydride without Loss of ChiralityJ. Org. Chem. 1992, 57, 7334-7338
1: R = Me, R2 = 4-Me
2: R = i-Pr, R2 = 4-Me
3: R = sec-Bu, R2 = 4-Me
4: R = i-Bu, R2 = 4-Me
5: R = PhCH2-, R2 = 4-Me
6: R = i-Pr, R2 = 3,4-Me
7: R = i-Pr, R2 = 2,4-Me
8: R = i-Pr, R2 = 2,5-Me
9: R = i-Pr, R2 = 2,4,6-Me
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The Reaction of NCAs with Alkylbenzene in the Presence of AlCl3. The Friedel-Crafts reaction of NCAs with alkylbenzenes in the presence of AlCl3 gave the corresponding
alpha-aminoalkyl aryl ketones (F-Bs) in moderate yields. The ketones were also isolated as their hydrochlorides (F-B-HCl) after treatment with ethanol-HCl. Detailed studies of the reaction of Val-NCA (NCA of L-valine) under various conditions revealed that, in order to obtain the best yields of
alpha-aminoalkyl aryl ketones, the reaction should be carried out below 10C with a AlCl3 to NCAs ratio of 2-3:1 in alkylbenzene itself as the solvent. When CH2Cl2 was used as the solvent, the axpected reaction occured only a small amount. When CH3NO2 was used as the solvent, the expected reaction did not occur. Lewis acids such as FeCl3, TiCl4, and BF3*Et2O did not work as catalysts in this reaction. (
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Several examples of reactions of Val-NCA with toluene in the presence of AlCl3 are shown in Table 1. The only product was only a para-substituted compound, which was isolated and identified as 3-methyl-2-amino-1-(
p-methylphenyl)-1-butanone (2) or 2-HCl. As shown in Table 1, the ratio of Val-NCA to AlCl3 strongly affected the product yield. The optimum ratio of the reactants seemed to be Val-NCA:AlCl3:toluene = 1:2-3:5. The amount of toluene did not affect the yield.
Table 1. The Effect of the Reactant Ratio upon the Product Yield in the Reaction of Val-NCA with Toluene
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run NCA AlCl3 toluene yield T
no. (mmol) (mmol) (mmol) (%) (0C)
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1 20 43 470 54 23
2 20 20 470 25
3 112 247 560 57 24
4 51 151 253 56 23
5 20 61 100 65 23
6 20 62 100 69 18
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The reaction was normally carried out follows. To a suspension of Val-NCA (20 mmol) in toluene (9.2 g, ca. 11 ml, 100 mmol) was added 2-3 equiv of solid AlCl3 (8.0 g, 60 mmol) carefully, keeping the temperature under 10C. After all of AlCl3 was added over a period of 0.5-1.0 h, the mixture was kept stirring at room temperature for 4-5 h. The reaction mixture was not homogeneous at the first stage, but at the end of the reaction it had became a dark brown, homogeneous oil. Then the mixture was treated with ice and dilute HCl, and the organic phase and/or a solid, if there was one, were separated. The aqueous layer was concentrated as much as possible by means of a rotary evaporator to give a solid residue, which was filtered and dried. The solid was dissolved in a small amount of water and neutralized with an aqueous 1 N Na2CO3 solution. Ether or CH2Cl2 extraction of the neutral or slightly basic solution and evaporation of the solvent left a pale yellow oil which was almost chemically as well as optically pure alpha-aminoalkyl aryl ketone. Reverse addition (run 6), that is, the addition of Val-NCA to a mixture of AlCl3 and toluene, gave a result similar to that of run 5.
Unlike the reaction of Val-NCA with toluene, the reaction of Leu-NCA with toluene gave a mixture of 2-amino-4-methyl-1-(p-methylphenyl)-1-pentanone (4) (more than 97%) and the ortho-substituted product (less than 3%) as determined by 1H NMR analysis. In the case of Ala-NCA, it is possible that the product, obtained in 12.5% yield, was also a mixture of ortho- and para-isomers.
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In the reaction of Val-, Ile-, and Phe-NCA with toluene, only para-substituted products 2,3, and 5 were obtained.
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This alpha-aminoacylation was applied to the other alkylbenzenes. o-, m- and p-xylene and mesitylene also reacted with Val-NCA to form the expected products 6-9, respectively.
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Table 2. Preparation of alpha-Aminoalkyl Aryl Ketones, F-B 2-9.
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product yield (%) T (0C) ee (%)
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2 54.4 23 98
2 69.1 18
3 55.4 17 65 (96)
4 74.8 18 - (96)
5 64.9 29 95
6 52.5 28 96
6 62.1 23
7 55.0 27 94
8 17.7 26
9 79.2 21 98
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Experimental Section. (Partially)
(S)-2-Amino-3-methyl-1-(p-methylphenyl)-1-butanone (2).
To a cooled mixture of AlCl3 (8.3 g, 62 mmol) and toluene (9.5 g, 100 mmol) was added Val-NCA (2.91 g, 20.3 mmol) portion by portion over a period of 1 h at under 10C. The reaction mixture was kept stirring at room temperature for 5 h and then added onto ice (100 g). A white solid (0.97 g), designated as A, was isolated and washed with 40 ml of ether. The aqueous solution was concentrated to about 15 ml. A white solid (4.15 g), designated as B, was separated, and was filtered and washed with 40 ml of ether. A portion af solid B (2.28 g) was dissolved in H2O (10 ml) and ether (40 ml), and then an aqueous 1 N NaHCO3 solution (8 ml) was added. Extraction with ether (40 ml x 2) gave 0.43 g (2.27 mmol) of a yellow solid. Then 5 ml of an aqueous 1 N NaHCO3 solution was added to the above aqueous solution. A second extraction afforded 0.72 g (3.76 mmol) of a yellow solid, and the third one afforded 29 mg. The total amount of 2 obtained was 1.18 g (6.17 mmol, yield 69.1%, 99% ee).
(S)-2-Amino-3-methyl-1-(p-methylphenyl)-1-pentanone (3).
To a cooled mixture of Ile-NCA (3.23 g, 20.5 mmol) and toluene (9.8 g, 110 mmol) was added AlCl3 (8.0 g, 60 mmol) portionwise over a period of 1 h at 10C. Solids A and B were obtained in amounts of 2.11 and 2.83 g, respectively. The workup used for 2 gave 3 (55.4% yield, 65% ee).
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