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Synlett 2012(2): 285-289  
DOI: 10.1055/s-0031-1290069
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Room-Temperature Palladium-Catalyzed Coupling of Heteroaryl Amines with Aryl or Heteroaryl Bromides

Thomas A. Moss*, Matthew S. Addie, Thorsten Nowak, Michael J. Waring
AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK
e-Mail: thomas.moss@astrazeneca.com;

Further Information

Publication History

Received 6 October 2011
Publication Date:
04 January 2012 (online)

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Abstract

Heteroaryl amines readily undergo Buchwald-Hartwig amination reactions with a range of aryl and heteroaryl bromides at room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu. The pharmaceutically attractive biaryl amines are generally formed in short reaction times (0.5-16 h) and in good to excellent yields.

Key words

amination - biaryl amine - coupling - heteroaryl amine - palladium

The palladium-catalyzed amination of aryl and heteroaryl halides has quickly emerged as a valuable tool in the synthesis of natural products and pharmaceuticals. [¹] Since the pioneering studies by Buchwald and Hartwig, [²] this process has attracted widespread interest from both academic and industrial groups, with significant improvements in substrate scope being realised in recent years. [³] Despite these advancements, the coupling of heteroaryl amines with aryl and heteroaryl halides remains problematic, often requiring long reaction times and considerable tailoring of reaction conditions. [4] One notable exception was reported by Schulte, where several electron-deficient heteroaryl amines were coupled with aryl and heteroaryl halides using a Pd2(dba)3/xantphos catalyst system with sodium phenolate as base under thermal or microwave ­irradiation. [5] In this case, the authors suggested the high solubility of sodium phenolate in 1,4-dioxane was responsible for the rate acceleration and functional group tolerance observed.

Scheme 1 Readily activated palladium precatalysts

One important advancement in Pd-catalyzed amination is the development of readily activated phosphine precatalysts, which allow the monoligated Pd(0) species to be formed at or below room temperature (Scheme  [¹] ). [6] This has advantages over traditional catalyst systems; Pd2(dba)3, a stable source of Pd(0), can retard the formation of active catalyst due to the coordinating dba ligands, and Pd(OAc)2 requires in situ reduction to Pd(0). [7] As oxidative addition has been shown to occur at temperatures as low as -40 ˚C, employing a readily activated precatalyst potentially allows cross-coupling reactions to take place at low temperature. [³f] [8]

The incorporation of heterocyclic ring systems into organic molecules is of particular interest in medicinal chemistry. Five-membered amino heterocycles, such as pyrazole, imidazole, oxazole and isoxazole, are particularly desirable substructures in molecular design due to their low ­lipophilicity, metabolic susceptibility and their defined arrangement of hydrogen bonding elements. Examples of this include ATP competitive kinase inhibitors where these functionalities present an essential molecular recognition element. [9] Hence we were interested in developing a methodology that would allow facile incorporation of such substituents via an amination strategy.

Table 1 Optimisation of Conditions for the C-N Coupling of 3-­Methyl-5-aminopyrazole with Bromobenzenea

Entry Base Solvent Conditions Yield (%)b
1 NaOt-Bu dioxane r.t., 24 hc  69
2 NaOt-Bu dioxane r.t., 2 h (10) n.d.
3 NaOt-Bu dioxane 90 ˚C, 3 h (50) 28
4 Cs2CO3 dioxane 90 ˚C, 3 h (80) 59
5 LiHMDS dioxane r.t., 2 h (<10) n.d.
6 NaOt-Bu DMA r.t., 3 h (50) n.d.
7 NaOt-Bu t-BuOH r.t., 4 h  96
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), bromobenzene (1.25 equiv), base (2.1 equiv), t-BuXPhos precatalyst 1 (0.5 mol%), solvent (5 mL).
b Isolated yields. Values in parentheses refer to¹H NMR conversion.
c A higher amount of the catalyst (5 mol%) was used.

To establish the ideal reaction conditions, an initial study was conducted with 3-methyl-5-aminopyrazole (2) and bromobenzene. We chose t-BuXPhos precatalyst 1 as the Pd source, as it is known to be a particularly effective catalyst in weakly nucleophilic heteroaryl systems. [4] Furthermore, by judicious choice of base, the precatalysts can readily form the active Pd(0) species at or below room temperature, allowing C-N coupling reactions to be performed under milder conditions and at lower catalyst loadings than under typical coupling conditions (Table  [¹] ). Using NaOt-Bu as base in 1,4-dioxane, the reaction proceeded smoothly at 5 mol% catalyst loading, affording the biaryl amine in a 69% isolated yield (entry 1). The arylation was completely selective for the exocyclic amine; no arylation of the N(H) heterocycle was observed by ¹H NMR, which is consistent with literature findings for the Pd-catalyzed amination of amino pyrazoles. [4] Unfortunately, on lowering the catalyst loading to a more practical 0.5 mol%, the product was only observed in trace amounts after two hours at room temperature (entry 2). During the course of the reaction significant amounts of solids precipitated from the initially homogenous mixture, which we hypothesized may have been the sodium salt of the pyrazole starting material. In an attempt to improve solubility, the reaction was conducted at 90 ˚C (entry 3), giving the product in a slightly improved 28% yield after three hours. Switching the base to the milder Cs2CO3 (entry 4), gave a marked improvement in yield following stirring at 90 ˚C for three hours, but the conversion was still at an unacceptable level. LiHMDS has been used as base in cases where an acidic proton is present in the starting materials, [4a] [¹0] however in our hands this gave a complex mixture of products (entry 5). Pleasingly, employing more polar solvent mixtures led to improved reactivity; t-BuOH giving the product in near quantitative yield following stirring at room temperature for four hours (entry 7). For direct comparison, the reaction was conducted under the same conditions using Pd2(dba)3 as the catalyst with t-BuXPhos as the ligand, giving only trace amounts of product (<5%) after four hours at room temperature.

Table 2 Room-Temperature Coupling of 3-Methyl-5-aminopyrazole (2) with Aryl and Heteroaryl Halides with t-BuXPhos Precatalyst 1 a

Entry Aryl halide Time (h) Product Yield (%)b
 1c

4

 96
 2

4

 88
 3

6

 89
 4

4

 88
 5

6

 57
 6

2

 93
 7

6

  0
 8

4

(92) 70
 9

6

 61
10

6

 74
11

16

(75) 48
12d

6

  0
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), aryl halide (1.25 equiv), NaOt-Bu (2.1 equiv), t-BuXPhos precatalyst 1 (1 mol%), t-BuXPhos ligand (1 mol%), t-BuOH (5 mL), r.t.
b Isolated yields. Values in parentheses refer to the ¹H NMR conversion.
c A lower amount of the precatalyst (0.5 mol%) was used, without ­additional ligand. Refer to Table  [¹] (entry 7) for details.
d 4-Bromopyridazine hydrobromide was used, with base (3.1 equiv).

We next evaluated a range of aryl bromides in order to assess the generality of the reaction (Table  [²] ). Heteroaryl halides which can coordinate with the Pd species are known to be difficult coupling partners, and thus have attracted particular attention in the literature, [¹¹] particularly in light of their prevalence in natural products and pharmaceutical agents. Pleasingly, using our optimal conditions as an initial start point, 3-methyl-5-aminopyrazole (2) was successfully coupled with a range of heteroaryl bromides including pyridines, pyrimidines, pyrazine and pyridazines at room temperature in moderate to high yields. In these cases, the catalyst loading was increased to 1 mol% and an additional 1 mol% of the t-BuXPhos ligand was added to ensure stability of the catalyst in solution. 2-, 3- and 4-Bromopyridine (entries 2, 4 and 5) were all readily coupled in moderate to good yields and in relatively short reaction times. Aryl and heteroaryl chlorides are generally more accessible than their bromo analogues, thus we were pleased to find that 2-chloropyridine reacted in a comparable time and in similar yield to 2-bromopyridine (entry 3), demonstrating that these conditions are not limited only to aryl bromides. 4-Chlorobromobenzene (entry 6) reacted smoothly and chemoselectively at the bromo position to give a single product in a 93% yield, with no discernible amounts of dimer being observed. Under the reaction conditions, bromopyrimidines (entries 7-9) were slightly less reactive than their pyridine analogues, with 2-bromopyrimidine (entry 9) in particular only giving a moderate 61% yield of the desired product. 4-Bromopyrimidine failed to give any observable product (entry 7). Further evaluation of the literature revealed that very few successful Buchwald-Hartwig aminations have been performed on 4-halopyrimidines compared to their 2- and 5-analogues. [¹²] Pyrazine could also be coupled efficiently (entry 10), however 3- and 4-bromopyridazines (entries 11 and 12) were somewhat problematic coupling partners due to the instability of halopyridazines; [¹³] only 3-bromopyridazine (entry 11) gave any observable product.

We then turned our attention to the amine component (Table  [³] ). Using our optimal conditions, a range of both unprotected and (N-)protected heteroaryl amines including pyrazoles, imidazoles, triazoles and isoxazoles were evaluated with both aryl and heteroaryl bromides. In general the reaction performed well on both unprotected (entries 1-6 and 10) and N-protected (entries 7-9 and 11-13) heterocycles, indicating that additional protection of N(H) endocyclic amines is not necessary for reactivity, or to avoid undesired heterocycle arylation. In almost all cases the biaryl amines were formed in good yield and in short reaction times (0.5-6 h) at room temperature, the exception being the 3-amino-1,2,4-triazole (entry 10), which required heating to 90 ˚C for seven hours to achieve a 40% conversion to the product.

Table 3 Coupling of Various Protected and Unprotected Heteroaryl Amines with Aryl and Heteroaryl Bromidesa (continued)
Entry Amine Aryl bromide Time (h) Product Yield (%)b
 1

 4

 92
 2

 4

 82
 3

 6

 70
 4

 4

 74
 5

 4

 79
 6

 6

 74
 7

 4

 83
 8

16

 80
 9

16

 97
10

 7c

(40) 34
11

 0.5

 93
12

 1

 93
13

2

 77
14

2

 97
15

4

(75) 65
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), aryl bromide (1.25 equiv), NaOt-Bu (2.1 equiv), t-BuXPhos precatalyst 1 (1 mol%), t-BuXPhos ligand (1 mol%), t-BuOH (5 mL), r.t.
b Isolated yields. Values in parentheses refer to ¹H NMR conversion.
c Reaction was performed at 90 ˚C.

In conclusion, we have developed a general set of conditions which allows five-membered heteroaryl amines to be coupled at room temperature to aryl and heteroaryl bromides and chlorides. [¹4] The transformation generally proceeds in relatively short reaction times and in good yields, giving a diverse range of pharmaceutically attractive biaryl amines. The use of t-BuXPhos precatalyst 1 allows this challenging coupling reaction to proceed at much lower temperatures than normally possible for heteroaryl amines and without the requirement for protection of the heterocyclic NH, making this method attractive in future medicinal chemistry campaigns.

14

Representative General Procedure; Coupling of Pyrazole 2 and 2-Bromopyridine: 3-Methylpyrazol-
5-amine (2; 1.50 mmol, 146 mg), t-BuXPhos Pd(II) phenethylamine chloride 1 (0.015 mmol, 10.3 mg), t-BuXPhos (0.015 mmol, 6.4 mg) and NaOt-Bu (3.15 mmol, 303 mg) were charged into a round-bottom flask which was evacuated and back-filled with nitrogen (3 ×), then purged with a stream of nitrogen for 10 min. t-BuOH (5 mL) and
2-bromopyridine (1.88 mmol, 296 mg) were added via syringe and the reaction was stirred at r.t. for 4 h. The solvent was removed then H2O, sat. aq NH4Cl and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc-MeOH, 9:1) to give the biaryl amine as a white solid (229.5 mg, 88%); mp 177-179 ˚C. IR: 3521 (br), 2995 (m), 1525 (s), 1503 (m), 1495 (m), 1420 (s), 1281 (m) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.19 (s, 3 H, Me), 6.04 (s, 1 H, CHpyrazole), 6.68 (m, 1 H, CHAr), 7.22 (m, 1 H, CHAr), 7.52 (dd, 1 H, J = 7.2, 7.0 Hz, CHAr), 8.09 (d, 1 H, J = 4.1 Hz, CHAr), 9.00 (s, 1 H, NH), 11.73 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 10.95, 94.12, 109.22, 113.60, 137.12, 138.87, 147.40, 149.06, 155.39. MS (ES): m/z (%) = 175 [M + H]+(100), 158 (100), 134 (80), 107 (25). HRMS: m/z [M + H]+ calcd for C9H11N4: 175.09782; found: 175.09778.

14

Representative General Procedure; Coupling of Pyrazole 2 and 2-Bromopyridine: 3-Methylpyrazol-
5-amine (2; 1.50 mmol, 146 mg), t-BuXPhos Pd(II) phenethylamine chloride 1 (0.015 mmol, 10.3 mg), t-BuXPhos (0.015 mmol, 6.4 mg) and NaOt-Bu (3.15 mmol, 303 mg) were charged into a round-bottom flask which was evacuated and back-filled with nitrogen (3 ×), then purged with a stream of nitrogen for 10 min. t-BuOH (5 mL) and
2-bromopyridine (1.88 mmol, 296 mg) were added via syringe and the reaction was stirred at r.t. for 4 h. The solvent was removed then H2O, sat. aq NH4Cl and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc-MeOH, 9:1) to give the biaryl amine as a white solid (229.5 mg, 88%); mp 177-179 ˚C. IR: 3521 (br), 2995 (m), 1525 (s), 1503 (m), 1495 (m), 1420 (s), 1281 (m) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.19 (s, 3 H, Me), 6.04 (s, 1 H, CHpyrazole), 6.68 (m, 1 H, CHAr), 7.22 (m, 1 H, CHAr), 7.52 (dd, 1 H, J = 7.2, 7.0 Hz, CHAr), 8.09 (d, 1 H, J = 4.1 Hz, CHAr), 9.00 (s, 1 H, NH), 11.73 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 10.95, 94.12, 109.22, 113.60, 137.12, 138.87, 147.40, 149.06, 155.39. MS (ES): m/z (%) = 175 [M + H]+(100), 158 (100), 134 (80), 107 (25). HRMS: m/z [M + H]+ calcd for C9H11N4: 175.09782; found: 175.09778.

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Scheme 1 Readily activated palladium precatalysts