Sequential amination of heteroaromatic halides with aminopyridine 1 - oxides and their N-protected derivatives based on novel aza-Smiles rearrangement

Introduction

N-Arylation of heteroaromatic amines with aryl and (hetero)aryl halides via aromatic nucleophilic substitution or mediated by transition metals have acquired importance due to the versatility of products that are prevalent in compounds of biological, pharmaceutical, and materials interest (Hartwig et al., 2007). In the course of our research efforts, we required an access to a number of N-arylated and N-(hetero)arylated 3-amino-1,2,4-triazines for their application in asymmetric bifunctional catalysis (Ma and Cahard, 2004; Denmark and Beutner, 2008). The former compounds bearing chiral oxazoline ring (Figure 1) were prepared via a two-step synthesis, with the key step being a palladium-catalyzed aryl amination between 2-(2′-aminophenyl)oxazolines and corresponding 3-halogeno-1,2,4-triazines in the presence of chelating bisphosphine ligand (Karczmarzyk et al., 2011).

Figure 1

Chiral oxazoline ligands for asymmetric catalysis.

Although clearly effective, such approach is not always well suited for the N-(hetero)arylation of electron-poor heteroaromatic amines. In particular, such amines require their own optimized catalyst or ligand system, and minor structural variations within the substrate may dramatically change the outcome of the catalytic process (Garnier et al., 2004). An alternative approach to the synthesis of the aforementioned systems may involve the nucleophilic aromatic substitution of the 1,2,4-triazine substrate by appropriately modified heteroaromatic amines. Unlike aminopyridines, their N-oxides have lower basicity (Andreev, 2009) and as bifunctional nucleophiles can react with electrophiles at either oxygen or amino nitrogen atoms (Rykowski and Pucko, 1998). The use of 2-aminopyridine 1-oxides in the amination reaction of electrophilic chloronitropyridines has recently been shown to be an effective and operationally simple route for the synthesis of nitro-substituted 2,2′-dipyridylamine 1-oxides (Wolińska and Pucko, 2012). Moreover, their formamidine-protected derivatives were also reacted with chloronitropyridines, giving rise to intermediary 1-pyridyloxypyridinium salts that easily underwent base-catalyzed rearrangement into nitro derivatives of 2,2′-dipyridylamine N-oxides in good yield (Wolińska and Pucko, 2012). On the basis of the latter studies, we became interested in determining whether this protocol would be applicable to the less electrophilic heteroaromatic halides without an electron withdrawing group. In view of the importance of pyridine N-oxides in coordination and medicinal chemistry (Balzarini et al., 2006) as well as their facile deoxygenation and transformation into a wide range of other functional groups (Leclerc and Fagnou, 2006), such cross-coupling reactions involving various aminopyridine 1-oxides have been a challenging target. Here we report the results of our initial investigations on S_NAr vs. Pd-catalyzed aminations of chloro derivatives of azines, diazines, and triazines using as nucleophiles 2-aminopyridine 1-oxides and/or their N-protected derivatives.

Results and discussion

Initial experiments were performed with a readily available 3-chloro-5,6-diphenyl-1,2,4-triazine (1) as the model substrate. The reaction of 2-aminopyridine 1-oxide (2a) with 1 in DMF at 100°C for 5 h led to the exclusive formation of an expected S_NAr product 3 (75%) (Scheme 1, Table 1). When increasing the temperature to 150°C, a complete conversion of 1 was observed within 2 h; however, the reaction was not selective and provided a mixture of the desired compound 3 (68%) and deoxygenated product 5 (13%). To circumvent the formation of 5, we proceeded to optimize the reaction with respect to the temperature and solvent. As can be seen from Table 1, the reaction of 2a with 3-chloro-5,6-diphenyl-1,2,4-triazine (1) in dioxane at 80°C in the presence of dry potassium carbonate was completed within 5 h, providing direct access to compound 3 in 88% yield. For a comparison, we tried to couple 1 with 2-aminopyridine (4) under the conditions mentioned above. However, even traces of the amination product 5 could not be detected in the reaction mixture. This last result reflects an important role of the N-oxide functionality in 2-aminopyridine 1-oxides during N-(hetero)arylation reaction.

Scheme 1

To investigate further the scope of this new coupling protocol, we examined the reaction of 2-aminopyridine 1-oxides 2a,b with 2,4-dichloropyrimidine (6) (Scheme 2). The coupling of 6 with 2a,b in DMF at room temperature led to monoaminated products 11a,b as colorless precipitates in moderate yield. Less reactive 2-chloropyrimidine (7) did not react under these conditions. The insolubility of substrates 6 and 2a,b in dioxane at room temperature excluded the use of this solvent as reaction medium. Attempts to improve the yield of compounds 11a,b by increasing the reaction temperature to 80°C or 100°C failed because the reaction was not selective; a complicated mixture of products was obtained under such conditions. The yield of products 11a,b was improved by a parallel synthesis. We found that the reaction of 6 with an equimolar amount of formamidine protected 2-aminopyridine 1-oxide 8a in DMF at room temperature afforded intermediary 1-(2-chloropyrimidin-4-yloxy)pyridinium salt 9a in 80% yield. Likewise, the reaction of formamidine protected 2-amino-5-methylpyridine 1-oxide 8b with 6 in DMF at 0°C gave the expected pyridinium salt 9b. These results clearly demonstrate the high nucleophilicity of oxygen in formamidine-protected 2-aminopyridine 1-oxides. The salts thus obtained are sufficiently stable to be isolated in the pure state and characterized by spectroscopic methods and elemental analysis (see Experimental section). The deprotection of the amino groups in 9a and 9b upon treatment with aqueous ammonia results in the formation of the rearrangement products 11a,b within a few minutes. The fast rate of this reaction suggests that it is intramolecular in nature. It seems reasonable to assume that the base-induced hydrolysis of the carbon-nitrogen double bonds in 9a,b leads to unprotected intermediates 10a,b, which, through the intramolecular nucleophilic attack of the imino group on C-4 carbon of pyrimidine ring, yield the corresponding N-arylated products 11a,b (Scheme 2).

Scheme 2

To confirm that the intramolecular attack of amine nitrogen in 10a,b plays primary role in the amination reaction, we carried out a crossover experiment in which 1 equivalent of 9b and 1 equivalent of 9c, readily obtained from 8a and 2-chloro-5-nitropyridine (Wolińska and Pucko, 2012), were dissolved in ethanol and treated with aqueous ammonia (Eq. 1). In the reaction products obtained, we could identify only compounds 11b and 12, and no traces of other products were detected in the mixture. This result clearly shows that only intramolecular amination takes place during the reaction of compounds 9b and 9c with aqueous ammonia and strongly suggests that the nucleophilic substitution of halogen in electrophilic heteroaromatic halides by unprotected 2-aminopyridine 1-oxides may also proceed via an intramolecular rearrangement.

The transformation of the intermediates 10a,b to 11a,b is mechanistically similar to the well-known Smiles rearrangement (Plesniak et al., 2007). However, the major difference between these processes is in the structure of the substrates. Because the imino group in 10a,b responsible for nucleophilic attack is connected to a moiety containing a nitrogen atom instead of an alkyl-chain linker, the observed conversion can be called aza-Smiles rearrangement.

With the first coupling in hand, the next question was what conditions would be required for the second coupling, particularly in the one-pot fashion. It was expected that somewhat more forcing conditions would be required because the C-2 position in the pyrimidine ring is significantly less reactive than the C-4 position toward nucleophilic displacement. However, after a more thorough literature investigation, we found an acid-mediated approach to synthesize substituted 2-anilinopyrimidines (Hattinger et al., 2002). Fortunately, these conditions were effective for the one-pot double-coupling reaction of 2,4-dichloropyrimidine (6) with 2-aminopyridine 1-oxide (2a). Treatment of 6 with 2.2 equivalent of 2-aminopyridine 1-oxide (2a) in DMF at 100°C in the presence of 1 equivalent of TsOH afforded disubstituted product 13 in 50% yield. The same reaction conditions proved to be effective for 2-chloropyrimidine (7), 2-(1-oxidopyridin-2-yl)aminopyrimidine (14) being obtained in 64% yield (Scheme 3). When 2-aminopyridine 1-oxide (2a) was subjected to the reaction with an equimolar amount of 6 in DMF at 100°C in the presence of TsOH, monosubstituted (11a) and disubstituted (13) products were formed in low yields.

Scheme 3

In contrast to the results obtained with 6 or 7, the reaction of 2-chloropyridine (15) with 2a in DMF under acid-mediated conditions proceeds in very low yield. Further investigations revealed that the poor outcomes associated with the low reactivity of 15 may be overcome using the Buchwald-Hartwig amination (Hartwig et al., 2007). The reaction of 15 (1 equivalent) with 2a (1 equivalent) using our previously reported procedure (Karczmarzyk et al., 2011) (Pd₂dba₃, Xantphos, Cs₂CO₃, dioxane, 105°C) afforded 2-(pyridin-2-yl)aminopyridine 1-oxide (16) in 65% yield (Scheme 3). This approach may give an easy access to a variety of biheteroaromatic amine 1-oxides and is currently under investigation in our laboratory.

If desired, the amination products 11a, 13, 14, and 16 can be easily deoxygenated. The treatment of these compounds with ammonium formate and palladium/carbon in methanol under reflux conditions (Kaczmarek et al., 1990) gave the corresponding free bases 11a′, 13′, 14′, and 16′ in a quantitative yield (Scheme 3).

Conclusions

2-Aminopyridine 1-oxides and their N-protected derivatives are reactive species that smoothly undergo N-(hetero)arylation with activated heteroaromatic halides in the absence of a catalyst. Products may be easily deoxygenated with ammonium formate and palladium/carbon in excellent yield. It was also demonstrated that the use of aminoazine N-oxides in Buchwald-Hartwig amination extends the scope of the method to unactivated heteroaromatic halides as well.

Experimental