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Synlett 2007(17): 2675-2678  
DOI: 10.1055/s-2007-991060
LETTER
© Georg Thieme Verlag Stuttgart · New York

Hf(OTf)4-Doped Me3SiCl-Catalyzed Aminomethylation of Arenes with N,O-Acetals: Facile Approach to Non-Natural Aromatic Amino Acid Precursors

Norio Sakai*, Junichi Asano, Yuta Shimano, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
e-Mail: sakachem@rs.noda.tus.ac.jp;
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Publication History

Received 7 August 2007
Publication Date:
25 September 2007 (online)

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Abstract

The authors demonstrated a Hf(OTf)4-Me3SiCl-system-catalyzed aminomethylation of an aromatic compound, such as a heterocycle or an electron-rich arene, with several new types of N,O-acetals having both a cyano group and a cyclic amino moiety. This method permits the facile synthesis of artificial aromatic amino acid precursors.

Key words

N,O-acetal - aminomethylation - amino acid - hafnium

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General Procedure for the Hf(OTf) 4 -Catalyzed Aminomethylation of Aromatics with an N , O- Acetal
To a CH2Cl2 solution (2 mL) was successively added N,O-acetal 2a (92.5 mg, 0.600 mmol), 1-methylindole (65.5 mg, 0.500 mmol), and freshly distilled trimethylchlorosilane (65.7 mg, 0.600 mmol) under nitrogen atmosphere. After 1 min, Hf(OTf)4 (38.8 mg, 0.0500 mmol) was added to the solution, and the thick suspension was vigorously stirred until the reaction reached completion, as shown by TLC (hexane-EtOAc, 6:4). The reaction was quenched with a sat. aq solution of NaHCO3. The combined organic layer was dried over Na2CO3 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane-EtOAc) to afford the product 3a in 92% (119.2 mg) yield. All new compounds were fully characterized by their spectral analyses. Spectral data for (1-methyl-1H-indol-3-yl)piperidin-1-yl-acetonitrile (3a): colorless crystals; mp 143-144 °C. 1H NMR (500 MHz, CDCl3): δ = 1.40-1.60 (m, 6 H), 2.50-2.60 (m, 4 H), 3.79 (s, 3 H), 5.06 (s, 1 H), 7.14 (t, 1 H, J = 7.5 Hz), 7.26 (s, 1 H), 7.27 (t, 1 H, J = 7.5 Hz), 7.31 (d, 1 H, J = 7.5 Hz), 7.82 (d, 1 H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3): δ = 24.2, 25.9, 32.9, 50.7, 56.3, 107.9, 109.4, 116.3, 119.6, 120.1, 122.4, 126.3, 128.5, 137.5. MS-FAB: m/z 254 [M+ + H]. Anal. Calcd for C16H19N3: C, 75.85; H, 7.56; N, 16.71. Found: C, 75.77; H, 7.37; N, 16.71.
(1-Methyl-1H-pyrrol-2-yl)piperidin-1-yl-acetonitrile (6b): colorless crystals; mp 127-128 °C. 1H NMR (500 MHz, CDCl3): δ = 1.40-1.60 (m, 6 H), 2.40-2.50 (m, 4 H), 3.61 (s, 3 H), 4.71 (s, 1 H), 6.04 (t, 1 H, J = 3.5 Hz), 6.33 (d, 1 H, J = 3.5 Hz), 6.62 (d, 1 H, J = 3.5 Hz). 13C NMR (125 MHz, CDCl3): δ = 24.1, 25.8, 33.9, 50.3, 56.4, 106.6, 110.8, 114.8, 123.7, 124.4. MS-FAB: m/z = 203 [M+ + H]. Anal. Calcd for C12H17N3: C, 70.90; H, 8.43; N, 20.67. Found: C, 71.12; H, 8.16; N, 20.91.
(1-Furan-2-yl-methyl-1H-pyrrol-2-yl)piperidin-1-yl-acetonitrile (8a): colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.47 (m, 2 H), 1.59 (m, 4 H), 2.52 (m, 4 H), 4.83 (s, 1 H), 4.95 (d, 1 H, J = 10.0 Hz), 5.38 (d, 1 H, J = 10.0 Hz), 6.08 (t, 1 H, J = 5.0 Hz), 6.15 (d, 1 H, J = 5.0 Hz), 6.31 (t, 1 H, J = 5.0 Hz), 6.37 (s, 1 H), 6.73 (s, 1 H), 7.35 (s, 1 H), 13C NMR (75 MHz, CDCl3): δ = 24.0, 25.7, 43.6, 50.2, 56.3, 107.1, 107.8, 110.4, 111.2, 114.5, 123.2, 123.9, 142.6, 150.6. MS-FAB: m/z = 269, 243, 185. HRMS-FAB: m/z calcd for C16H19N3O: 269.1528; found: 269.1529.
[4-(Dimethylamino)phenyl]piperidin-1-yl-acetonitrile (9a): colorless crystals; mp 148-149 °C. 1H NMR (300 MHz, CDCl3): δ = 1.40-1.50 (m, 2 H), 1.50-1.60 (m, 4 H), 2.40-2.60 (m, 4 H), 2.96 (s, 6 H), 4.72 (s, 1 H), 6.69 (d, 2 H, J = 8.5 Hz), 7.33 (d, 2 H, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3): δ = 24.0, 25.8, 40.4, 50.7, 62.5, 112.0, 116.2, 120.7, 128.8, 150.6. MS-FAB: m/z = 244 [M+ + H]. Anal. Calcd for C15H21N3: C, 74.03; H, 8.70; N, 17.27. Found: C, 74.26; H, 8.79; N, 17.59.
Amino(1-methyl-1H-indol-3-yl)acetic acid (11): colorless solids; mp 173-174 °C. 1H NMR (300 MHz, DMSO): δ = 3.79 (s, 3 H), 5.27 (s, 1 H), 7.11 (t, 1 H, J = 7.8 Hz), 7.21 (t, 1 H, J = 7.8 Hz), 7.46 (d, 1 H, J = 7.8 Hz), 7.53 (s, 1 H), 7.68 (d, 1 H, J = 7.8 Hz), 8.78 (br s, 3 H). 13C NMR (75 MHz, DMSO): δ = 32.6, 48.6, 105.7, 110.1, 119.0, 119.5, 121.9, 125.5, 129.8, 136.5, 170.1. MS-FAB: m/z (%) = 205 (5) [M+ + H], 188 (100) [M+ - NH2], 159 (52) [M+ - CO2H]. HRMS-FAB: m/z calcd for C11H13N2O2: 205.0977; found: 205.0980 [M+ + H].
Amino(5-methylfuran-2-yl)acetic acid (12): pale yellow solids; mp 92-93 °C. 1H NMR (300 MHz, DMSO): δ = 2.18 (s, 3 H), 5.17 (s, 1 H), 6.12 (d, 1 H, J = 5.0 Hz), 6.49 (d, 1 H, J = 5.0 Hz), 8.80 (br s, 3 H). 13C NMR (75 MHz, DMSO): δ = 9.1, 47.0, 112.3, 121.4, 174.6, 180.1, 190.9. MS-FAB: m/z (%) = 156 (80) [M+ + H], 139 (100) [M+ - NH2]. HRMS-FAB: m/z calcd for C7H10NO3: 156.0661; found: 156.0665 [M+ + H].

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When the reaction was examined with an N,O-acetal having another type of a nitrogen-containing ring, such as pyrrole, the desired amino acid precursor was not obtained, resulting in the production of the unknown product.