Synthesis of 9-(C_n-1F_2n-1)-substituted acridine by the reaction of 2-(C_nF_2n+1)-substituted aniline with ortho-methyl-substituted aromatic Grignard reagent

Introduction

The chemistry of aza-ortho-xylylene (3, R^F = F, Scheme 1) has been of interest both from a theoretical point of view and as an important tool in heterocyclic synthesis. Although the intermediate product 3 can be generated by using many approaches, the anionic activation of the trifluoromethyl group in 1 (R^F = F) to give anion 2 has emerged as the most practical way.

Scheme 1

This synthetic chemistry has been reviewed extensively by us [1–4], our former student [5], and others [6, 7]. The chemistry of ionically activated higher homologs 1 (R^F = C_nF_2n+1, n ≥ 1) has been explored to a much smaller extent [8, 9]. 2-(Perfluoroalkyl)anilines 1 are readily available by a coupling reaction of 2-iodoaniline with a perfluoroalkyl bromide or iodide in the presence of copper bronze [10, 11] or by reductive perfluoroalkylation of aniline with the perfluoroalkyl halide in the presence of Zn and SO₂ [12, 13]. 2-(Trifluoromethyl)aniline is a widely available commercial product. Very recently, we have reported an unusual synthesis of 9-arylacridines by the reaction of 1 (R^F = F) with aromatic Grignard reagents substituted with a methyl or ethyl group at position 2 [14]. This synthesis is unusual in that the alkyl group is eliminated during the reaction. In this report, we describe the reactions of 1 containing a longer perfluoroalkyl chain (R^F = C_nF_2n+1, n ≥ 1) with aromatic Grignard reagents that contain a methyl group at position 2 or two methyl groups at positions 2 and 6.

Results and discussion

We have previously reported that the treatment of 2-(perfluoroethyl)aniline (Scheme 2) and 2-(perfluorobutyl)aniline (Scheme 3) with phenylmagnesium bromide furnished the respective molecular propellers 4 and 7 [9]. The treatment of the former aniline with 2,4-dimethylphenylmagnesium bromide yielded the analogous compound 5. Molecular propellers exist in chiral helical conformations in which the helicity and the correlated rotation of the planar substituents (blades) are imposed by severe steric hindrance in the molecule. Depending on the nature of the aryl groups, a single molecule may exist in a large number of conformational isomers [9]. The three fluorine atoms of the CF₃ group in 4 and 5 are anisochronous at -25°C, and they give rise to a clearly defined AA′X absorption pattern in each ¹⁹F NMR spectrum. In a similar way, the ¹⁹F NMR spectrum of 7 exhibits AB absorption for each CF₂ moiety. The observed single AA′X pattern for CF³ of 4, the single AA′X pattern for CF₃ of 5, and two AB absorptions for the CF₂CF₂ moiety of 7 are consistent with the presence of a single racemic pair in each case. This is an unusual finding because two racemic pairs, due to two different orientations of the aminophenyl moiety in 4, 5, and 7, and an additional set of orientations of the 2,4-dimethylphenyl groups in 5 relative to the perfluoroalkyl group in the molecular propeller (syn and anti) can be predicted [9]. The observed absorption patterns in the ¹⁹F NMR spectra taken at low temperature give rise to a broad singlet with increasing temperature. The coalescence temperature is 21°C, 52°C, and 81°C for 4, 5, and 7, respectively. It can be concluded that the order of steric hindrance in these molecules parallels the order of activation energy for racemization, as indicated by the coalescence temperatures.

Scheme 2

Scheme 3

Mechanistically, the formation of a molecular propeller requires addition of the Grignard reagent with the intermediate product 3 (Scheme 1) followed by elimination of fluoride from the adduct and the consecutive addition of a second molecule of the Grignard reagent with the resultant aryl-substituted analog of 3. The treatment of 2-(perfluoroethyl)aniline with the more sterically hindered mesitylmagnesium bromide produced acridine 6 instead of the expected molecular propeller. It can clearly be seen that the molecule of 6 incorporates elements of the starting aniline and the Grignard reagent without one methyl group. The formation of acridines with the unusual pattern of the loss of the ortho-methyl group from the arylmagnesium bromide was also observed for the reactions of 2-(perfluorobutyl)aniline (Scheme 3). Interestingly, the reactions with the arylmagnesium reagents substituted with the methyl group at the ortho position and containing no substituent at the second ortho position also resulted in elimination of the methyl group. This is clearly seen from Scheme 3 by the synthesis of acridines 8–11. The reaction of 2-ethylphenylmagnesium bromide also yielded acridine 8 devoid of the ethyl group. As with the synthesis of acridine 6 discussed above, the treatment of 2-(perfluorobutyl)aniline with a 2,6-disubstituted phenylmagnesium bromide furnished acridine 12 devoid of the methyl group. To better understand this unusual reaction, 2-(perfluorobutyl)aniline was allowed to react with 2-fluoro-6-methylphenylmagnesium bromide (Scheme 4). Again, the methyl group was eliminated during this high-yield reaction to give fluorine substituted acridine 13. The treatment of this aniline with 3,5-dimethylphenylmagnesium bromide (no substituents at the ortho positions) gave a complicated mixture of products, none of them major. GC-MS analysis of the crude mixture indicated the presence of <1% of a product with the molecular ion peak for the apparent acridine 14.

Scheme 4

As can be seen from Scheme 5, this novel acridine synthesis proceeds well with 2-(perfluorohexyl)aniline. As expected, the 9-(perfluoropentyl)acridines 15 and 16 are oils. Product 16 was transformed into a solid salt by treatment with hydrobromic acid and the salt was crystallized for purification.

Several syntheses reported above were also conducted with chloride analogs of the bromide Grignard reagents. In all cases, the reaction times and the yields were comparable. Isolation of the perfluoro-substituted products is considered as important information. These molecules are highly volatile and it would not be unusual to obtain low yields by concentrating solutions in relatively high-boiling solvents under reduced pressure. The use of pentanes and ether is strongly recommended. Another treatment against loss of product is to precipitate a hydrobromide salt from solution.

Scheme 5

Conclusion and final remarks

This report describes the scope and limitations of a novel synthesis of 9-(perfluoroalkyl)acridines. We have conducted detailed mechanistic studies that are summarized in Scheme 6 and will be described in our forthcoming paper. An important observation is that the final acridine product is formed during workup following quenching of the mixture with water and exposure to air. The mechanistic report will address the generation of two isomers of the intermediate product 17, their equilibration, and electrocyclization of the isomer Z-17.

Scheme 6

Experimental