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Synlett 2003(12): 1822-1825  
DOI: 10.1055/s-2003-41475
LETTER
© Georg Thieme Verlag Stuttgart · New York

The First Rapid Palladium-Catalyzed Aminations of (Azahetero)aryl Chlorides under Temperature-Controlled Microwave Heating

Bert U. W. Maes*, Kristof T. J. Loones, Guy L. F. Lemière, Roger A. Dommisse
Department of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, 2020 Antwerp, Belgium
Fax: +32(3)2180233; e-Mail: bert.maes@ua.ac.be;
Further Information

Publication History

Received 24 June 2003
Publication Date:
19 September 2003 (online)

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Abstract

Fast palladium-catalyzed aminations of activated and unactivated azaheteroaryl chlorides as well as unactivated aryl chlorides have been achieved using temperature-controlled microwave heating. Good yields (75-91%) were obtained in a reaction time of only 10 minutes.

Key words

palladium - homogeneous catalysis - Buchwald-Hartwig amination - aryl chlorides - microwave irradiation

9

Recently, an interesting article appeared dealing with fast (15 min) r.t. Pd-catalyzed aminations of activated and unactivated aryl chlorides using alkyl di-tert-butylphos-phane ligated palladium(I) dimers. Unfortunately, the scope of this exceptionally fast r.t. amination chemistry is narrow (see ref. [7j] ). Although, other catalysts have also been used to perform Buchwald-Hartwig aminations at r.t. the scope is generally broader at higher temperature. Moreover, the reaction times for couplings at r.t. are in the order of hours to 1 d (see refs. 7h, 8b) .

13

2-(Dicyclohexylphosphanyl)biphenyl is commercially available from Strem Chemicals. The effectiveness of this biphenyl based ligand is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination (see ref. [7h] ).

14

In this preliminary study no attempts were made to further reduce the catalyst loading.

15

Since primary anilines are known to give diarylation we used a larger excess of aniline (1.5 equiv instead of 1.2 equiv) to suppress the formation of such an undesired compound. MS analysis of the crude reaction mixtures of the aminations with p-toluidine revealed in every case a peak with a mass that is in accordance with the presence of diarylated p-toluidine (Table [1] , entries 4, 6, 10 and 11). Since only small amounts of diarylated p-toluidine were formed no attempts were made to isolate these side compounds.

16

The coupling of 3-chloropyridine with N-methylaniline under classical heating (110 °C) using DCPB as ligand for the palladium catalyst was also already reported by Buchwald. Similarly as for the coupling of 2-chloropyridine with morpholine we obtained a lower isolated yield (83% instead of 97%) using the same loading of Pd (1 mol%). [17] However, also in this case a tremendous increase in conversion rate was observed under microwave irradiation (speed-up factor: 132). See ref. 7h.

17

The reaction of 3-chloropyridine with N-methylaniline and 2-chloropyridine with morpholine was performed at a double concentration in comparison with the classical heating experiments reported by Buchwald due to the size limitation of the pressure vials and the high temperatures used (150 °C or 200 °C).

18

General procedure for the fast palladium-catalyzed amination of (azahetero)aryl chlorides:
A pressure vial of 10 mL was charged with (azahetero)aryl chloride (1 mmol), amine (1.2 mmol or 1.5 mmol) and t-BuONa (0.1345 g, 1.4 mmol) in air. Subsequently the vial was flushed with Ar for 1 min. Then, 1 mL of a stock solution of precatalyst {Pd/2L: Pd(OAc)2 (Acros) and DCPB [Strem Chemicals, DCPB = 2-(dicyclohexylphosphanyl)bi-phenyl] in anhyd toluene (Acros, extra anhyd < 30 ppm water)} was added via a syringe and the resulting mixture was flushed with Ar for an additional 2 min under magnetic stirring. Next, the vial was sealed with an Al crimp top with septum and heated at 150 °C or 200 °C in a CEM Discover microwave apparatus. The initial power supplied was 300 W. Once the temperature was reached (IR measurement), the power dropped and fluctuated to maintain the temperature at the desired value. The total heating time of all reactions was 10 min. A typical example of the temperature, pressure and power curves in function of the reaction time is shown in ref. 20. After the reaction vials were cooled down to r.t. using a propelled air flow, they were opened and filtered over Celite and rinsed well with 100 mL CH2Cl2 or Et2O. The filtrate was subsequently evaporated under reduced pressure and the residue purified by flash column chromatography on silica gel.

19

In control experiments all the Buchwald-Hartwig aminations studied were also performed without the use of Pd-catalyst. In all the reactions without catalyst starting material remained and in some cases a small amount of the desired coupling product could be detected as judged by MS and TLC analysis. To get an idea about the importance of the uncatalyzed SNAr pathway under the microwave conditions used, we chose to work up a reaction with an activated aryl chloride substrate since it can be expected that in such a case the SNAr reaction works the best: For the coupling of p-toluidine with 2-chloropyridine an isolated yield of only 10% of N-(2-pyridyl)-4-methylaniline was obtained, which proves that the uncatalyzed pathway is not very important under the conditions studied.

20

Temperature, pressure and power curves as function of the reaction time for the microwave-assisted coupling of 3-chloropyridine with N-methylaniline (Table [1] , entry 3) (Figure [1] ).