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

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.

palladium - aminations - chloro-iodopyridines - iodobenzenes - diarylamines

References

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1b Louie J. Hartwig JF. Tetrahedron Lett.  1995,  36:  3609 

For recent reviews on Pd-catalyzed amination see:

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2b Frost CG. Mendonça P. J. Chem. Soc., Perkin Trans. 1  1998,  2615 

2c Hartwig JF. Angew. Chem. Int. Ed.  1998,  37:  2046 

2d Muci AR. Buchwald SL. Top. Curr. Chem.  2002,  219:  131 

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3b Ariëns EJ. Beld AJ. Rodrigues de Miranda JF. Simonis AM. In The Receptors a Comprehensive Treatise   O’Brien RD. Plenum Press; New York: 1979. 

4 Jonckers THM. Maes BUW. Lemière GLF. Dommisse R. Tetrahedron  2001,  57:  7027 

5 2-Chloro-3-iodo- and 2-chloro-5-iodopyridine were prepared from the corresponding commercially available amino derivatives via diazotization and subsequent reaction with KI: Sakamoto T. Kondo Y. Yamanaka H. Chem. Pharm. Bull.  1985,  33:  4764 

Examples of chemoselective palladium-catalyzed C-C cross-coupling reactions on chloro-iodopyridines:

6a Mello JV. Finney NS. Org. Lett.  2001,  3:  4263 

6b Baxter P. N. W.; J. Org. Chem.; 2000, 65: 1257

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7 Just before submitting this manuscript an article appeared dealing with Pd-catalyzed aminations on 3-iodo-6-arylpyridazines. PdCl₂(dppf) catalyst in combination with t-BuONa was used in the reported amination reactions (Hartwig conditions). These conditions do not allow a large functional group compatibility on both coupling partners: Parrot I. Ritter G. Wermuth CG. Hibert M. Synlett  2002,  1123 

8 For Pd-BINAP-catalyzed aminations of aryl bromides with Cs₂CO₃ as base see: Wolfe JP. Buchwald SL. J. Org. Chem.  2000,  65:  1144 

9 Wolfe JP. Tomori H. Sadighi JP. Yin J. Buchwald SL. J. Org. Chem.  2000,  65:  1158 

10 Ali MH. Buchwald SL. J. Org. Chem.  2001,  66:  2560 

11 Komrlj J. Maes BUW. Lemière GLF. Haemers A. Synlett  2000,  1581 

12

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).

13 Wolfe JP. Buchwald SL. J. Org. Chem.  1997,  62:  6066 

14 For the palladium-catalyzed N-arylation of sulfoximines, the use of aryl iodides with Pd-BINAP as catalyst in combination with a mild carbonate base has been reported. To ensure product formation in acceptable yields the use of additives (LiBr, LiCl, AgOTf) was essential: Bolm C. Hildebrand JP. J. Org. Chem.  2000,  65:  169 

15 Wolfe JP. Buchwald SL. J. Org. Chem.  1996,  61:  1133 

16 Driver MS. Hartwig JF. J. Am. Chem. Soc.  1996,  118:  7217 

17 Hamann BC. Hartwig JF. J. Am. Chem. Soc.  1998,  120:  7369 

18 Huang J. Grasa G. Nolan SP. Org. Lett.  1999,  1:  1307 

19

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

20

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.

21

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.

22

Spectroscopic data of selected compounds:
2-Chloro-3-(4-methylphenylamino)pyridine (Table 1, entries 1-3): δ_H (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); δ_C (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): δ_H (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); δ_C (400 MHz, CDCl₃): 141.5, 140.1, 138.7, 138.3, 132.8, 130.2, 125.7, 124.2, 119.9, 20.7.

23

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]