Methyl 4-Pentafluorosulfanylphenyl Sulfoximines

Abstract

A low-cost and high-yielding synthetic route towards methyl 4-pentafluorosulfanylphenyl sulfoximines from the corresponding sulfide has been developed. The intermediate N-cyano sulfoximine was converted into the corresponding N-(1H)-tetrazole, and the NH-sulfoximine was modified by N-arylation and N-alkylation reactions.

 

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Key words

building blocks - pentafluorosulfanyl group - sulfoximine - organofluorine compounds - sulfilimine

Fluorine-containing compounds exhibit unique physicochemical properties and, consequently, they are of interest in medicinal chemistry, crop protection, and material sciences.[1] In this context, the pentafluorosulfanyl group (SF₅), also known as ‘super-trifluoromethyl’ group, plays a very special role.[1] [2] Noteworthy are, for example, the high thermal stability of aryl sulfurpentafluorides and the chemical inertness of the SF₅ group towards hydrolysis.[3] Compared with a trifluoromethyl substituent, the SF₅ group has a higher electronegativity[4] and polarity, and the respective molecules show improved lipophilicity.[5] As a result, the SF₅ group has become an attractive structural motif in the design of biologically active compounds,[2b] [c] [6] functional materials,[7] and, as recently reported, in Brønsted acid catalysts.[8]

Due to the fact that only a few efficient synthetic methods for the introduction of the SF₅ group exist,[3] [9] commercially available SF₅-containing building blocks are rare and most of them are expensive. Therefore, the development of new scaffolds with SF₅ groups appears to be desirable.

Sulfoximines, the mono-aza analogues of sulfones, are widely used in asymmetric synthesis and catalysis.[10] Especially in the last years, such compounds have also attracted attention as drugs[11] and crop protection agents.[12] Advantageously, in contrast to sulfones, they are modifiable at the sulfoximine nitrogen, which can lead to beneficial effects on the solubility of the respective molecules.[13] Fluorine-containing sulfoximines[11] [12] ^, [14] [15] [16] are of particular interest because they combine the advantages of the sulfoximidoyl moiety with the favorable electronic and steric properties induced by, for example, a fluoro or a trifluoromethyl substituent. However, to our knowledge, sulfoximines bearing SF₅ groups are unprecedented. Here, we fill this synthetic gap and report on preparative routes towards a range of key compounds with sulfoximidoyl cores and SF₅ substituents.

For the preparation of the first target molecule (NH-sulfoximine 4), methyl 4-pentafluorosulfanylphenyl sulfide (1) was regarded as a promising starting material.[17] Fulfilling our expectations, the imination of 1 with cyanamide and N-bromosuccinimide (NBS)[18] proceeded smoothly, affording the corresponding N-cyano sulfilimine 2 in 96% yield (Scheme [1]). Subsequent oxidation with m-CPBA[18] led to N-cyano sulfoximine 3 in 81% yield. Finally, the CN-group was cleaved upon treatment with 50% aq. H₂SO₄ at 110 °C,[19] providing the desired NH-sulfoximine 4 in 71% yield.[20] Both enantiomers of the racemic mixture could be separated on analytical CSP HPLC, which allowed 4 to be obtained in non-racemic form by preparative HPLC separation.[21]

Scheme 1 Synthesis of methyl 4-pentafluorosulfanylphenyl sulfoximine 4

Considering that N-arylated sulfoximines can be highly selective ligands in asymmetric metal catalysis,[10] [22] we first investigated the application of a representative N-phenylation protocol allowing the conversion of 4-pentafluorosulfanylphenyl sulfoximine (4) into N-arylated sulfoximine 5 under copper catalysis.[23] To our delight, this approach was highly efficient, providing N-phenyl sulfoximine 5 in 93% yield starting from 4 and iodobenzene as aryl source (Scheme [2]).

Scheme 2 Derivatizations of NH-sulfoximine 4 and conversion of N-cyano sulfoximine 3

We then focused on the N-methylation of 4 to give 6. This transformation was regarded as particularly important because it was recently demonstrated that several N-methyl sulfoximines showed a significantly higher solubility compared with their isolipophilic counterparts in the sulfone series,[13a] leading to beneficial effects in their respective bioactivity studies. Here, the N-methylation of 4 was successfully performed under Eschweiler–Clark conditions,[24] [25] affording N-methylated sulfoximine 6 in 78% yield (Scheme [2]).

Considering that tetrazoles are carboxylic acid bioisosteres that often exhibit high bioactivities,[26] the conversion of N-cyano sulfoximine 3 into tetrazole 7 was studied.[27]

By using a combination of NaN₃ and ZnBr₂ in methanol–water, formation of the heterocycle proceeded smoothly, leading to N-(1H)-tetrazole methyl 4-pentafluorosulfanylphenyl sulfoximine (7) in 62% yield (Scheme [2]).

The three representative synthetic transformations depicted in Scheme [2] allow us to draw two significant conclusions: first, compounds such as 4 are readily available; and second, standard protocols can be used for modifications of sulfoximines with 4-pentafluorosulfanyl substituents providing interesting new building blocks for future synthetic and biological applications.

 

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Acknowledgment

We thank Melissa Plag for various synthetic contributions and Prof. Dr. P. Kirsch, Merck KGaA, for highly stimulating discussions.

• References and Notes


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