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Preparation of 4-(9-Anthracenyl)butyl amine hydrochloride; 4-Aryl-butylamine Fluorescent Probe

SyntheticPage 207 (2002)
Submitted 4th Nov 2002, published 4th Nov 2002

Carlos Afonso (cma@dq.fct.unl.pt),
A contribution from the Afonso / Lukanova Group, REQUIMTE/CQFB, Chemistry Department, New University of Lisbon, Portugal


Reaction Scheme

Chemicals Used
n-butyllithium (Aldrich), 9-bromoanthracene (Aldrich), 1,4-dibromobutane (Aldrich), dimethyl sulfoxide (Merck), sodium azide (Merck), Pd/C (10 %) (Merck), Ethanol (Pronalabo), anhydrous diethyl ether (pre-dried over sodium wire and distilled from sodium/benzophenone under a nitrogen atmosphere), hydrogen chloride (prepared from sulfuric acid / hydrochloric acid, following the method described in Vogelís Textbook of Practical Organic Chemistry).

Procedure
Preparation of 4-(9-anthracenyl)butyl bromide (2): To a stirred solution of 9-bromoanthracene (1) (3.084 g, 11.99 mmol) in anhydrous diethyl ether (20 ml) under argon at 0 oC was added dropwise (4 min) n-butyllithium (7.5 ml, 2.4 M in hexanes, 1.5 equiv) and stirred at r.t. for 75 min. 1,4-Dibromobutane (5.8 ml, 4.0 mol equiv) was added at once to this mixture and refluxed for 2 h. The reaction mixture was allowed to cool to room temperature, partioned between dichloromethane (70 ml) and water (70 ml). The aqueous phase was extracted with dichloromethane (2 x 70 ml), the combined organic phase was dried with MgSO4 and the solvent remover under reduced pressure to give a yellow liquid residue. n-Hexane (80 ml) was added leading to the slow formation of a pale yellow solid (2) (1.772 g, 47 %; Rf = 0.38 (n-hexane), m.p. 113-114.5 oC, m.p. 115-116 oC (EtOH, white needles). Preparation of 4-(9-anthracenyl)butyl azide (3): The 4-aryl-butylbromide (2) (1.546 g, 4.93 mmol) was added to a stirred solution of sodium azide (0.356 g, 1.1 equiv) in dimethyl sulfoxide (11 ml) at room temperature (water bath, 20 oC). After 19 h, water (22 ml) was added (CARE: exothermic) and the precipitate was filtered to give (3) (1.352, quant) as a yellow powder, Rf = 0.22 (n-hexane : dichloromethane 9.5:0.5); m.p. 78.5-79 oC (n-hexane, white small needles, complete decomposition when (3) is dissolved in refluxing ethyl acetate). Preparation of 4-(9-anthracenyl)butyl amine (4): A mixture of 4-aryl-butylazide (3) (1.186 g, 4.31 mmol) and Pd/C (10%, 0.0436 g) in absolute ethanol (80 ml) under hydrogen atmosphere (balloon) was strong stirred for 2.5 days at room temperature. The mixture was filtered, the filtrate washed with dichloromethane (20 ml), concentrated in vacuo to give (4) (1.068 g, 99 %) as a brown viscous liquid. To the above residue, dissolved in anhydrous dichloromethane (20 ml, was bubbled excess HCl. The solvent was evaporated and diethyl ether (30 ml) was added leading to the formation of solid which was filtered to give 4-(9-anthracenyl)butylamine hydrochloride (5) (0.927 g, 75 %) as a slightly yellow powder solid, m.p. 120 oC (dec), 204-208 oC.

Author's Comments
The use of fluorescent compounds as probes is an important issue in several fields, including chromatography, combinatorial chemistry, molecular biology and medicine, as chemosensors, and in material science. Although many fluorescent probes are commercially available (e.g. Molecular Probes, Inc), in some cases it is important that the fluorescent probe is attached to a substrate of interest by a long enough alkyl chain to avoid interaction between the fluorescent probe and the other functionalities within the substrate. Usually, such probes have to be tailor-made to meet the required specifications. In this page we describe a simple protocol that starts from a readily available commercial compound containing anthracene unit, 9-bromoanthracene (1). This procedure allows the preparation of 4-aryl-butylamine as a fluorescent probe containing an amine linker group and a butyl group spacer. The above methodology was also applied to the preparation of the 4-(9-phenanthrenyl)butyl amine hydrochloride (6) starting from 9-bromophenanthrene: step 1, preparation of 4-(9-phenanthrenyl)butyl bromide (48 %); step 2, preparation of 4-(9-phenanthrenyl)butyl azide (quantitative); step 3, preparation of 4-(9-phenanthrenyl)butyl amine (99 %); step 4 preparation of 4-(9-phenanthrenyl)butyl amine hydrochloride (85 %). This simple and short method (4 steps) allowed the preparation of (5) and (6) with an overall yield of 35 % and 41 % respectively and without the need of chromatographic purification. The conditions used for the first step were also applied to the preparation of the following arylbromoalkanes (10-12 mmol scale): 1-bromo-4-phenylbutane (42 %), 1-bromo-4-(1-naphthyl)butane (39 %), 1-bromo-1-methyl-4-(9-phenanthrenyl)butane (47 %), 1-bromo-3-(9-phenanthrenyl)propane (22 %), 1-bromo-5-(9-phenanthrenyl)pentane (43 %), 1-bromo-4-(1-pyrenyl)butane (28 %), 1-bromo-4-(2-biphenyl)butane (22 %). In these cases the dibromides were added dropwise (5 min), because of the observation of initial exothermic reaction, due to the presence of some excess n-butyllithium.

Data
4-(9-Anthracenyl)butyl bromide (2): IR (film) n = 3079, 3052, 2948, 2924, 2888, 2868, 1622, 1445, 1352, 1224, 885, 732 cm-1; dH (400 MHz; CDCl3) 1.96-2.03 (m, 2H, ArCH2(CH2)2CH2Br), 2.10-2.19 (m, 2H, ArCH2(CH2)2CH2Br), 3.50 (t, 2H, J=6.8 Hz, ArCH2), 3.64 (t, 2H, J=8.0 Hz, CH2Br), 7.47-7.57 (m, 4H, Ar), 8.03 (d, 2H, J=8.0 Hz, Ar), 8.27 (d, 2H, J=8.8 Hz, Ar), 8.37 (s, 1H, Ar); dC (100 MHz; CDCl3) 26.90, 29.60, 32.98, 33.46, 124.17, 124.79, 125.55, 125.84, 129.23, 129.50, 131.56, 134.13; Anal. calcd. for C18H17Br: C 69.02%; H 5.47%. Found: C 69.05%; H 5.50%. 4-(9-Anthracenyl)butyl azide (3): IR (film) n = 3081, 3053, 2941, 2862, 2094 (N3), 1623, 1445, 1349, 1263, 884, 839, 731 cm-1; dH (400 MHz; CDCl3) 1.82-1.96 (m, 4H, ArCH2(CH2)2CH2N3), 3.35 (t, 2H, J=6.4 Hz, CH2N3), 3.65 (t, 2H, J=8.4 Hz, ArCH2), 7.47-7.60 (m, 4H, Ar), 8.03 (d, 2H, J=8.0 Hz, Ar), 6.26 (d, 2H, J=8.8 Hz, Ar), 8.36 (s, 1H, Ar); dC (100 MHz; CDCl3) 27.26, 28.25, 29.20, 51.30, 124.12, 124.77, 125.54, 125.82, 129.22, 129.48, 131.55, 134.15; Anal. calcd. for : C18H17N3: C 78.52%; H 6.22%; N 15.26%. Found: C 78.49%; H 6.28%; N 15.13%. 4-(9-Anthracenyl)butyl amine (4): IR (film) n = 3368 (NH), 3299 (NH), 3081, 3052, 2928, 2857, 1623, 1469, 1445, 1350, 1158, 1012, 883, 840, 789, 732, 634, 602 cm-1; dH (400 MHz; CDCl3) 1.52 (br, 2H, NH2), 1.69 (br, 4H, ArCH2(CH2)2CH2NH2), 2.57 (br, 2H, CH2NH2), 3.48 (br, 2H, ArCH2), 7.40-7.48 (m, 4H, Ar), 7.88 (d, 2H, J=7.6 Hz, Ar), 8.18 (s, 1H, Ar), 8.21 (d, 2H, J=8.8 Hz, Ar); dC (100 MHz; CDCl3) 25.72, 27.89, 33.13, 41.22, 123.68, 124.09, 124.76, 124.99, 128.56, 128.86, 130.92, 134.24. 4-(9-Anthracenyl)butyl amine hydrochloride (5): IR (nujol) n = 3395 (NH), 2724, 1621, 1519, 1158, 1021, 883, 741, 728 cm-1; dH (400 MHz; CD3OD) 1.90 (br, 4H, ArCH2(CH2CH2NH2HCl), 2.96 (br, 2H, CH2NH2HCl), 3.71 (br, 2H, ArCH2), 7.48 (t, 2H, J=7.2 Hz, Ar), 7.55 (td, 2H, J=8.8, 1.2 Hz, Ar), 8.03 (d, 2H, J=8.0 Hz, Ar), 8.33 (d, 2H, J=8.8 Hz, Ar), 8.38 (s, 1H, Ar); dC (100 MHz; CD3OD) 27.90, 28.81, 29.23, 40.79, 125.26, 125.90, 126.74, 126.96, 130.29, 130.92, 133.09, 134.94; m/z (FAB) 250 (MH+), 233, 191; HRMS calcd. for C18H20N: 250.15957 , found: 250.15876.


Lead Reference
Carlos A. M. Afonso, J. P. S. Farinha, J. Chem. Res. (Accepted for publication)

Other References
For a general and useful source of fluorescence probes see: R. P. Haugland, Handbook of Fluorescent Probes and Research Chemicals , Molecular Probes, Inc, 1996. The experimental conditions used for the preparation of arylbromoalkanes were based on the following described procedure: H. Cao, Y. Fujiwara, T. Haino, Y. Fukazawa, C.-H. Tung, Y. Tanimoto, Bull. Chem. Soc. Jpn. 1996, 69, 2801. For the azide preparation were used the following general reported method: S. G. Alvarez, M. T. Alvarez, Synthesis 1997, 413.

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