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Synlett 2002(12): 1995-1998
DOI: 10.1055/s-2002-35579
LETTER
© Georg Thieme Verlag Stuttgart · New York

Selective Palladium-Catalyzed Aminations on 2-Chloro-3-iodo- and 2-Chloro-5-iodopyridine

Bert U. W. Maes*a, Kristof T. J. Loonesa, Tim H. M. Jonckersa, Guy L. F. Lemièrea, Roger A. Dommissea, Achiel Haemersb
a Department of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, 2020 Antwerp, Belgium
Fax: +32(3)2180233; e-Mail: bert.maes@ua.ac.be;
b Department of Medicinal Chemistry, University of Antwerp (UIA), Universiteitsplein 1, 2610 Antwerp, Belgium
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Publication History

Received 13 August 2002
Publication Date:
20 November 2002 (online)

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Abstract

Regioselective palladium-catalyzed aminations with anilines on 2-chloro-3-iodo- and 2-chloro-5-iodopyridine have been performed with excellent yields and good selectivity. The use of a large excess of Cs2CO3 in combination with Pd-BINAP catalyst was essential to obtain sufficiently fast reactions. The mild conditions permit the presence of base sensitive functional groups. Moreover, the catalytic system developed also allows the arylamination of aryl iodides.

Key words

palladium - aminations - chloro-iodopyridines - iodobenzenes - diarylamines

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The reactions were followed with GC using diphenyl ether as internal standard. Aliquots of the reaction mixtures were monitored after 4, 8, 24 and 48 hours. Reactions were considered as finished if less than 5% of starting material was present: K2CO3 (48 hours), K3PO4 (24 hours) and Cs2CO3 (8 hours).

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Buchwald originally used a double amount of XANTPHOS (Pd/2L instead of Pd/L)

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General procedure for the selective Pd-catalyzed aminations on 2-chloro-3-iodopyridine and 2-chloro-5-iodopyridine using Pd(OAc)2-BINAP:
A round bottom flask was charged with Pd(OAc)2 (Acros, 0.03 mmol or 0.045 mmol), (±)-BINAP (Strem Chemicals, 0.03 mmol or 0.045 mmol) and toluene (Acros, 99%, 5 mL). The mixture was flushed with nitrogen for 10 minutes under magnetic stirring. In another round bottom flask chloro-iodopyridine (0.359 g, 1.5 mmol), aniline (1.8 mmol) and Cs2CO3 (Acros, 99.5%, 2.444 g, 7.5 mmol) were weighed. Then, the Pd(OAc)2-BINAP solution was added, and the flask was rinsed well with an additional amount of toluene (10 mL). The resulting mixture was flushed with nitrogen for 5 minutes under magnetic stirring and subsequently heated in an oil bath under vigorous magnetic stirring (oil bath temperature 120 °C, N2 atmosphere). After overnight reflux the mixture was cooled down to room temperature. The solid material was filtered off and washed well with CH2Cl2 (200 mL). The filtrate was evaporated and the resulting crude product was purified by flash column chromatography.

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General procedure for the selective Pd-catalyzed aminations on 2-chloro-3-iodopyridine and 2-chloro-5-iodopyridine using Pd2(dba)3-XANTPHOS:
A round bottom flask was charged with Pd2(dba)3 (Acros, 0.015 mmol), XANTPHOS (Strem Chemicals, 0.03 mmol or 0.06 mmol) and freshly distilled dioxane (Acros, stabilized 99+%; dried over sodium/benzophenone, 3 mL). The mixture was flushed with nitrogen for 10 minutes under magnetic stirring. In another round bottom flask chloro-iodopyridine (0.359 g, 1.5 mmol), aniline (1.8 mmol) and Cs2CO3 (Acros, 99.5%, 2.1 mmol or 7.5 mmol) were weighed. Then, the Pd2(dba)3-XANTPHOS solution was added, and the flask was rinsed well with triethylamine (Aldrich, 99%; stored over K2CO3, 1.5 mL). The resulting mixture was flushed with nitrogen for 5 minutes under magnetic stirring and subsequently heated in an oil bath under vigorous magnetic stirring (oil bath temperature 100 °C, N2 atmosphere). After overnight reflux the mixture was cooled down to room temperature. The solid material was filtered off and washed well with CH2Cl2 (200 mL). The filtrate was evaporated and the resulting crude product was purified by flash column chromatography.

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Spectroscopic data of selected compounds:
2-Chloro-3-(4-methylphenylamino)pyridine (Table 1, entries 1-3): δH (400 MHz, CDCl3): 7.78 (dd, J = 4.6, 1.7 Hz, 1 H, H-6), 7.34 (dd, J = 8.1, 1.7 Hz, 1 H, H-4), 7.14 (d, J = 8.1 Hz, 2 H, H-3′,5′), 7.03 (d, J = 8.1 Hz, 2 H, H-2′,6′), 7.00 (dd, J = 8.1 Hz, 4.6 Hz, 1 H, H-5), 6.08 (br s, 1 H, NH), 2.32 (s, 3 H, CH3); δC (400 MHz, CDCl3): 138.5, 138.3, 138.0, 137.6, 133.7, 130.0, 122.9, 121.9, 120.4, 20.6.
2-Chloro-5-(4-methylphenylamino)pyridine (Table 2, entries 1-4): δH (400 MHz, CDCl3): 8.13 (dd, J = 3.1 Hz, 0.5 Hz, 1 H, H-6), 7.35 (dd, J = 8.5 Hz, 3.1 Hz, 1 H, H-4), 7.20 (dd, J = 8.5 Hz, 0.5 Hz, 1 H, H-3), 7.19 (d, J = 8.4 Hz, 2 H, H-3′,5′), 7.04 (d, J = 8.4 Hz, 2 H, H-2′,6′), 5.74 (br s, 1 H, NH), 2.39 (s, 3 H, CH3); δC (400 MHz, CDCl3): 141.5, 140.1, 138.7, 138.3, 132.8, 130.2, 125.7, 124.2, 119.9, 20.7.

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General procedure for the synthesis of diarylamines via Pd-catalyzed aminations on iodobenzenes:
A round bottom flask was charged with Pd(OAc)2 (Acros, 0.0034 g, 0.015 mmol), (±)-BINAP (Strem Chemicals, 0.0094 g, 0.015 mmol) and toluene (Acros, 99%, 5 mL). The mixture was flushed with nitrogen for 10 minutes under magnetic stirring. In another round bottom flask aryl iodide (1.5 mmol), aniline (1.8 mmol) and Cs2CO3 (Acros, 99.5%, 2.444 g, 7.5 mmol) were weighed. Then, the Pd(OAc)2-BINAP solution was added, and the flask was rinsed well with an additional amount of toluene (10 mL). The resulting mixture was flushed with nitrogen for 5 minutes under magnetic stirring and subsequently heated in an oil bath under vigorous magnetic stirring (oil bath temperature 120 °C, N2 atmosphere). After overnight reflux the mixture was cooled down to room temperature. The solid material was filtered off and washed well with CH2Cl2 (200 mL). The filtrate was evaporated and the resulting crude product was purified by flash column chromatography. The characterization data of N-(3-carbethoxyphenyl)-N-methylaniline, N-(4-carbethoxyphenyl)-N-methylaniline and 3-cyano-2′-carbethoxydiphenylamine were identical with those reported in the literature. [10]