Abstract
The intramolecular radical aromatic substitution of heteroaryl sulfones by tethered aryl radicals has been investigated as a source of alkyl radicals. The 1-(2-iodobenzyl)benzimidazole-2-sulfonyl system was found to be the most effective, while a tetrazole-based system did not undergo the desired radical aromatic substitution at all. Application of the benzimidazole-based system to the generation of alkyl radical and their subsequent use in radical cyclizations was demonstrated.
Ongoing projects in our laboratory required the use of alkyl radical precursors beyond the halides, chalocogenides, and thiocarbonyl derivatives traditionally employed.1,2 Nitroalkanes met many of our requirements1,2,3 but still suffered from several limitations, most notably the high acidity of the α-hydrogen. Looking for another group with powerful electron-withdrawing properties but lower acidity of the α-hydrogens, we focused our attention on the sulfones. As this group is somewhat inert to direct displacement by tributyltin hydride and its surrogates, and does not take part in intramolecular homolytic substitution reactions at sulfur1 we focused our attention on alkyl radical generation by intramolecular ipso-type substitution of alkyl aryl sulfones.
The susceptibility of aryl sulfones toward ipso intramolecular homolytic substitution is well known.2 This reaction typically involves attack of a C-centered radical upon the ipso position of an aryl-sulfone, the cyclic radical intermediate then fragments resulting in formation of a sulfonyl radical. The earliest example of this reaction involved the attack of an alkyl radical on an aryl sulfonamide resulting in the transfer of the aryl group to the alkane.2 Subsequently, this reaction has been widely employed in the synthesis of novel fused hetero-cycles and biaryls, with the focus on products derived from the aryl moiety of the initial alkyl aryl sulfone.3–6 We envisaged an alternative application of this chemistry with the emphasis on the alkylsulfonyl radical expelled in the ipso-substitution process as a precursor, via extrusion of sulfur dioxide,7 as an alkyl radical progenitor.
The general strategy foreseen here (Scheme 1) involves the synthesis of a system in which an aryl iodide trigger is tethered to an aromatic thiol; this thiol 1 can then be alkylated and subsequently oxidized to a sulfone 2. While generally stable to typical synthetic manipulations this sulfone 2 undergoes ipso substitution upon generation of the aryl radical 3 resulting in ejection of the alkyl sulfonyl radical 6, which rapidly extrudes sulfur dioxide to leave the desired alkyl radical 7.
Scheme 1.
General Strategy for the Generation of Alkyl Radicals from Arylsulfones
A series of sulfones where synthesized based on aromatic thiols containing a second heteroatom for installation of the 2-iodobenzyl “trigger.” The 2-methylnaphthalenyl radical was chosen as a model radical leaving group because of the characteristic chemical shift of methyl singlet at δ 2.48 in the product, which makes identification of a successful reaction by NMR possible. Compounds 9, 11, and 13 (Table 1) where constructed by sequential alkylations of the base compound followed by oxidation.8 A tetrazole based system 19 was constructed (Scheme 2) from the isothiocyanate 16 by way of a [3+2] cycloaddition in aqueous solution.9,10,11
Table 1.
Synthesis of Arylsulfones for Screening
| Base | Yield 3-Step Synthesis9 | Compound |
|---|---|---|
 |
77, 70, 85 |  |
 |
86, 92, 98 |  |
 |
33, 59, 51 |  |
Scheme 2.
Synthesis Tetrazole Based System 1912
Radical reactions were performed by syringe pump controlled addition of an AIBN/tributyltin hydride solution to a refluxing solution of the various alkyl aryl sulfones in order to minimize the concentration of stannane in an effort to reduce premature trapping of the aryl radical (Table 2). Not surprisingly, inspection of the reaction mixture of the 2-mercaptophenol-based system 9 by 1H NMR spectroscopy did not show evidence of successful homolytic aromatic substitution, as indicated by the absence of 2-methylnaphthalene. Rather, a complex mixture of dehalogenated starting material and biaryl compounds, presumably the result of addition of the aryl radical to solvent and possibly the 3-position of the alkoxy benzene ring, was produced. Subjecting 11 to the same conditions resulted in simple dehalogenation of the majority of the starting material. However, the formation of 2-methylnaphthalene in 10–20 % yield gave some grounds for optimism. The benzimidazole system 13 was the most successful precursor producing moderate amounts of product in the screening reaction.
Table 2.
Screening of Arylsulfones for SHi
| Arylsulfone | NMR Yield 2-Methylnaphthalene | Other Products |
|---|---|---|
| 9 | 0 % | mixture of dehalogenated and cyclized products |
| 11 | 10–20 % |  |
| 13 | 40–50 % |  |
| 19 | 0 % |  |
Two aspects of the tetrazole-based system 19 make it quite interesting in the context of aromatic homolytic substitution. First, this system is the most electron deficient of the systems studied making it highly susceptible to nucleophilic aromatic substitution, as exemplified by its widespread application in the Kocienski modification of the Julia benzothiazole-based olefination.12 Secondly, the use of the tetrazole ring eliminates the possibility of the initial aryl radical being trapped via an intramolecular 1,5-hydrogen transfer13–15 a process, which could play a role in the poor conversion of imidazole base system 11. Unfortunately, the propensity of this system toward nucleophilic aromatic substitution does not extend to radical aromatic substitution, and the only reaction observed with 19 was its clean conversion to the dehalogenated starting material 22; there was no evidence for the formation of 2-methylnaphthalene in this reaction.
Having established the supremacy of the benzimidazole nucleus in the desired radical aromatic substitution a 1(2-iodobenzyl)benzimidazole–2-thiol, which can be easily incorporated into substrates as an alkyl radical precursor, was synthesized. Thus, commercially available 2-chlorobenzimidazole 23 was treated with base and alkylated with 2-iodobenzyl bromide 14. The resulting chlorobenzimidazole 24 was converted to the thione, 25 by nucleophilic displacement of the chloride 24 with KSAc.16 This synthesis of 25 was practical and scalable for the efficient preparation of larger quantities. For the purpose of this investigation, the challenge of the generation of a primary alkyl radical was chosen. Introduction of 2517 into an alkyl compound from the alkyl halide was completed in an efficient 2-step sequence (Scheme 3).
Scheme 3.
Synthesis and Incorporation of Precursor 25
Syringe pump controlled treatment of the alkyl arylsulfone 2818 in refluxing toluene with a solution of AIBN and tributyltin hydride over 5 h (Scheme 4); resulted in successful generation of the cyclized product 3619 in 44% yield along with 28% of the dehalogenated starting material 30. Attempts to further suppress premature trapping of the aryl radical by varying the addition time proved unsuccessful (Table 3). Use of tris(trimethylsilyl) silane as propagating agent resulted in either complete dehalogenation of the aryl iodide or failure of the reaction to propagate.
Scheme 4.
Generation of Alkyl radical 34 from Sulfone 28
Table 3.
Generation and Cyclization of Alkyl Radical 34 from Sulfone 28
| Propagating Reagent | Solvent | Addition Time | Yield of 36 |
|---|---|---|---|
| Bu3SnH | Toluene | 3 h | 36% |
| Bu3SnH | Toluene | 5 h | 44% |
| Bu3SnH | Benzene | 8 h | 35% |
| TTMSH | Benzene | Immediate | 30 |
| TTMSH | Benzene | 5 h | A |
a: Starting material 28 was recovered unchanged from this reaction
A second example involves a sulfonamide 37.20 Again, the precursor 25 was incorporated smoothly into the alkyl system, resulting in a yield of 92% over two steps (Scheme 5). The methyl-pyrrolidine 3921 product of the 5-exo-cyclization of the alkyl radical was recovered in moderate yield on treatment of 38 with tributyltin hydride.
Scheme 5.
Alkyl Radical Generation via Sulfone 38
In conclusion, a system has been designed which can be effectively used as a precursor for alkyl radicals from sulfones. The 2-thiobenzimidazole 25 can be incorporated into an alkyl system in a facile 2-step sequence. The resulting sulfone can then be used to generate the corresponding alkyl radical under typical AIBN/tributyltin hydride mediated conditions.
Footnotes
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References
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