Synlett 2015; 26(01): 73-75
DOI: 10.1055/s-0034-1378936
cluster
© Georg Thieme Verlag Stuttgart · New York

Methyl 4-Pentafluorosulfanylphenyl Sulfoximines

Christine M. M. Hendriks
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092391   Email: carsten.bolm@oc.rwth-aachen.de
,
Jens Reball
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092391   Email: carsten.bolm@oc.rwth-aachen.de
,
Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092391   Email: carsten.bolm@oc.rwth-aachen.de
› Author Affiliations
Further Information

Publication History

Received: 26 September 2014

Accepted after revision: 20 October 2014

Publication Date:
20 November 2014 (online)

 


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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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]

Zoom Image
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]).

Zoom Image
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.


#

Acknowledgment

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

Supporting Information

  • References and Notes


    • For reviews, see:
    • 1a Kirsch P. Modern Fluoroorganic Chemistry . Wiley-VCH; Weinheim: 2004
    • 1b Crowley PJ, Mitchell G, Salmon R, Worthington PA. Chimia 2004; 58: 138
    • 1c Jeschke P. ChemBioChem 2004; 5: 570
    • 1d Pursur S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 1e Fluorine in Medicinal Chemistry and Chemical Biology. Ojima I. Wiley-Blackwell; Chichester: 2009
    • 1f Ojima I. J. Org. Chem. 2013; 78: 6358
    • 1g Wang J, Sánchez-Roselló M, Aceña JL, Del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
  • 3 Sheppard WA. J. Am. Chem. Soc. 1962; 84: 3064
  • 4 Sheppard WA. J. Am. Chem. Soc. 1962; 84: 3072
  • 5 Hansch C, Muir RM, Fujita T, Maloney PP, Geiger F, Streich M. J. Am. Chem. Soc. 1963; 85: 2817

    • For recent examples, see:
    • 6a Altomonte S, Baillie GL, Ross RA, Riley J, Zanda M. RSC Adv. 2014; 4: 20164
    • 6b Chia PW, Brennan SC, Slawin AM. Z, Riccardi D, O’Hagan D. Org. Biomol. Chem. 2012; 10: 7922
    • 6c Micheli F, Andreotti D, Braggio S, Checchia A. Bioorg. Med. Chem. Lett. 2010; 20: 4566
    • 6d Mo T, Mi X, Milner EE, Dow GS, Wipf P. Tetrahedron Lett. 2010; 51: 5137
    • 6e Stump B, Eberle C, Schweizer WB, Kaiser M, Brun R, Krauth-Siegel RL, Lentz D, Diederich F. ChemBioChem 2009; 10: 79
    • 6f Wipf P, Mo T, Geib SJ, Caridha D, Dow GS, Gerena L, Roncal N, Milner EE. Org. Biomol. Chem. 2009; 7: 4163
    • 6g Lim DS, Choi JS, Pak CS, Welch JT. J. Pestic. Sci. 2007; 32: 255

      For examples, see:
    • 7a Ye C, Gard GL, Winter RW, Syvret RG, Twamley B, Shreeve JM. Org. Lett. 2007; 9: 3841
    • 7b Winner SW, Winter RW, Smith JA, Gard GL, Hannah NA, Rananavare SB, Piknova B, Hall SB. Mendeleev Commun. 2006; 16: 182
    • 7c Kirsch P, Hahn A. Eur. J. Org. Chem. 2005; 3095
    • 8a Prévost S, Dupré N, Leutzsch M, Wang Q, Wakchaure V, List B. Angew. Chem. Int. Ed. 2014; 53: 8770 ; Angew. Chem. 2014, 126, 8915
    • 8b Lee J.-W, List B. J. Am. Chem. Soc. 2012; 134: 18245
    • 9a Bowden RD, Greenhall MP, Moillet JS, Thomson J. F2 Chemicals WO9705106, 1997 ; Chem. Abstr. 1997, 126, 199340.
    • 9b Umemoto T IM&T Research Inc. WO2010014665 (A1), 2010

      For overviews, see:
    • 10a Johnson CR. Acc. Chem. Res. 1973; 6: 341
    • 10b Reggelin M, Zur C. Synthesis 2000; 1
    • 10c Harmata M. Chemtracts 2003; 16: 660
    • 10d Okamura H, Bolm C. Chem. Lett. 2004; 33: 482
    • 10e Gais H.-J. Heteroat. Chem. 2007; 18: 472
    • 10f Worch C, Mayer AC, Bolm C In Organosulfur Chemistry in Asymmetric Synthesis . Torru T, Bolm C. Wiley-VCH; Weinheim: 2008: 209
    • 10g Bolm C. Latv. J. Chem. 2012; 49
  • 11 For a recent review on sulfoximines in medicinal chemistry, see: Lücking U. Angew. Chem. Int. Ed. 2013; 52: 9399 ; Angew. Chem. 2013, 125, 9570
  • 12 For a recent review on sulfoxaflor and sulfoximines used as insecticides, see: Sparks TC, Watson GB, Loso MR, Geng C, Babcock JM, Thomas JD. Pestic. Biochem. Physiol. 2013; 107: 1
    • 13a Goldberg FW, Kettle JG, Xiong J, Lin D. Tetrahedron 2014; 70: 6613
    • 13b Lücking U, Jautelat R, Krüger M, Brumby T, Lienau P, Schäfer M, Briem H, Schulze J, Hillisch A, Reichel A, Wengner AM, Siemeister G. ChemMedChem 2013; 8: 1067

      For overviews on fluorinated sulfoximines, see:
    • 14a Bizet V, Kowalczyk R, Bolm C. Chem. Soc. Rev. 2014; 43: 2426
    • 14b Shen X, Hu J. Eur. J. Org. Chem. 2014; 4437

      For examples of bioactive 4-fluoroaryl sulfoximines, see:
    • 15a Shetty SJ, Patel GD, Lohray BB, Chakrabarti G, Chatterjee A, Jain MR, Patel PR. Cadila Healthcare WO2007077574 (A2), 2007
    • 15b Kahraman M, Sinishtaj S, Dolan PM, Kensler TW, Peleg S, Saha U, Chuang SS, Bernstein G, Korczak B, Posner GH. J. Med. Chem. 2004; 47: 6854

      For other selected contributions including 4-fluoro and 4-trifluoromethylaryl sulfoximines, see:
    • 16a Kowalczyk R, Edmunds AJ. F, Hall RG, Bolm C. Org. Lett. 2011; 13: 768
    • 16b Barry N, Brondel N, Lawrence SE, Maguire AR. Tetrahedron 2009; 65: 10660
    • 16c Terrier F, Magnier E, Kizilian E, Wakselman C, Buncel E. J. Am. Chem. Soc. 2005; 127: 5563
    • 16d Reggelin M, Gerlach M, Vogt M. Eur. J. Org. Chem. 1999; 1011
  • 17 For the synthesis of 1 starting from 4-nitrophenyl sulfurpentafluoride, see: Beier P, Pastýříková T, Vida N, Iakobson G. Org. Lett. 2011; 13: 1466
  • 18 García Mancheño O, Bistri O, Bolm C. Org. Lett. 2007; 9: 3809
  • 19 Stoss P, Satzinger G. Tetrahedron Lett. 1973; 267
  • 20 Synthesis of NH-Sulfoximine 4 from Sulfide 1; General Procedure: Step 1: To a solution of 1 (1.0 mmol) in MeOH (6 mL), was added NH2CN (76 mg, 1.8 mmol), t-BuOK (191 mg, 1.7 mmol) and NBS (356 mg, 2.0 mmol). The reaction was stirred at room temperature until the starting material was consumed (reaction monitored by TLC). After removing the solvent under reduced pressure, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided N-cyanosulfilimine 2. Step 2: To a solution of 2 (0.3 mmol) in EtOH (2.7 mL) was added m-CPBA (ca. 70%, 101 mg, 0.45 mmol). The reaction mixture was stirred at room temperature until the starting material was consumed (reaction monitored by TLC). After removing the solvent under reduced pressure, H2O (5 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided N-cyanosulfoximine 3. Step 3: A solution of 3 (0.23 mmol) in 50% aq H2SO4 (2.3 mL) was stirred at 110 °C for 2 h. After cooling to room temperature and adjusting the pH to 9 by addition of aq. sat NaHCO3 and aq. sat NaOH solution, the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided NH-sulfoximine 4.
  • 21 For HPLC analytical data, see the Supporting Information.
  • 22 For a recent illustrative example, see: Frings M, Thomé I, Schiffers I, Pan FF, Bolm C. Chem. Eur. J. 2014; 20: 1691
    • 23a Sedelmeier J, Bolm C. J. Org. Chem. 2005; 70: 6904
    • 23b For a recent observation, see: Frings M, Atodiresei I, Bolm C. Molbank 2014; M834
  • 24 Schmidbaur H, Kammel G. Chem. Ber. 1971; 104: 3234
  • 25 For a recent study on sulfoximine N-alkylations under strongly basic conditions (with KOH in DMSO), see: Hendriks CM. M, Bohmann RA, Bohlem M, Bolm C. Adv. Synth. Catal. 2014; 356: 1847
  • 26 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  • 27 For early examples, see: García Mancheño O, Bolm C. Org. Lett. 2007; 9: 2951

  • References and Notes


    • For reviews, see:
    • 1a Kirsch P. Modern Fluoroorganic Chemistry . Wiley-VCH; Weinheim: 2004
    • 1b Crowley PJ, Mitchell G, Salmon R, Worthington PA. Chimia 2004; 58: 138
    • 1c Jeschke P. ChemBioChem 2004; 5: 570
    • 1d Pursur S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 1e Fluorine in Medicinal Chemistry and Chemical Biology. Ojima I. Wiley-Blackwell; Chichester: 2009
    • 1f Ojima I. J. Org. Chem. 2013; 78: 6358
    • 1g Wang J, Sánchez-Roselló M, Aceña JL, Del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
  • 3 Sheppard WA. J. Am. Chem. Soc. 1962; 84: 3064
  • 4 Sheppard WA. J. Am. Chem. Soc. 1962; 84: 3072
  • 5 Hansch C, Muir RM, Fujita T, Maloney PP, Geiger F, Streich M. J. Am. Chem. Soc. 1963; 85: 2817

    • For recent examples, see:
    • 6a Altomonte S, Baillie GL, Ross RA, Riley J, Zanda M. RSC Adv. 2014; 4: 20164
    • 6b Chia PW, Brennan SC, Slawin AM. Z, Riccardi D, O’Hagan D. Org. Biomol. Chem. 2012; 10: 7922
    • 6c Micheli F, Andreotti D, Braggio S, Checchia A. Bioorg. Med. Chem. Lett. 2010; 20: 4566
    • 6d Mo T, Mi X, Milner EE, Dow GS, Wipf P. Tetrahedron Lett. 2010; 51: 5137
    • 6e Stump B, Eberle C, Schweizer WB, Kaiser M, Brun R, Krauth-Siegel RL, Lentz D, Diederich F. ChemBioChem 2009; 10: 79
    • 6f Wipf P, Mo T, Geib SJ, Caridha D, Dow GS, Gerena L, Roncal N, Milner EE. Org. Biomol. Chem. 2009; 7: 4163
    • 6g Lim DS, Choi JS, Pak CS, Welch JT. J. Pestic. Sci. 2007; 32: 255

      For examples, see:
    • 7a Ye C, Gard GL, Winter RW, Syvret RG, Twamley B, Shreeve JM. Org. Lett. 2007; 9: 3841
    • 7b Winner SW, Winter RW, Smith JA, Gard GL, Hannah NA, Rananavare SB, Piknova B, Hall SB. Mendeleev Commun. 2006; 16: 182
    • 7c Kirsch P, Hahn A. Eur. J. Org. Chem. 2005; 3095
    • 8a Prévost S, Dupré N, Leutzsch M, Wang Q, Wakchaure V, List B. Angew. Chem. Int. Ed. 2014; 53: 8770 ; Angew. Chem. 2014, 126, 8915
    • 8b Lee J.-W, List B. J. Am. Chem. Soc. 2012; 134: 18245
    • 9a Bowden RD, Greenhall MP, Moillet JS, Thomson J. F2 Chemicals WO9705106, 1997 ; Chem. Abstr. 1997, 126, 199340.
    • 9b Umemoto T IM&T Research Inc. WO2010014665 (A1), 2010

      For overviews, see:
    • 10a Johnson CR. Acc. Chem. Res. 1973; 6: 341
    • 10b Reggelin M, Zur C. Synthesis 2000; 1
    • 10c Harmata M. Chemtracts 2003; 16: 660
    • 10d Okamura H, Bolm C. Chem. Lett. 2004; 33: 482
    • 10e Gais H.-J. Heteroat. Chem. 2007; 18: 472
    • 10f Worch C, Mayer AC, Bolm C In Organosulfur Chemistry in Asymmetric Synthesis . Torru T, Bolm C. Wiley-VCH; Weinheim: 2008: 209
    • 10g Bolm C. Latv. J. Chem. 2012; 49
  • 11 For a recent review on sulfoximines in medicinal chemistry, see: Lücking U. Angew. Chem. Int. Ed. 2013; 52: 9399 ; Angew. Chem. 2013, 125, 9570
  • 12 For a recent review on sulfoxaflor and sulfoximines used as insecticides, see: Sparks TC, Watson GB, Loso MR, Geng C, Babcock JM, Thomas JD. Pestic. Biochem. Physiol. 2013; 107: 1
    • 13a Goldberg FW, Kettle JG, Xiong J, Lin D. Tetrahedron 2014; 70: 6613
    • 13b Lücking U, Jautelat R, Krüger M, Brumby T, Lienau P, Schäfer M, Briem H, Schulze J, Hillisch A, Reichel A, Wengner AM, Siemeister G. ChemMedChem 2013; 8: 1067

      For overviews on fluorinated sulfoximines, see:
    • 14a Bizet V, Kowalczyk R, Bolm C. Chem. Soc. Rev. 2014; 43: 2426
    • 14b Shen X, Hu J. Eur. J. Org. Chem. 2014; 4437

      For examples of bioactive 4-fluoroaryl sulfoximines, see:
    • 15a Shetty SJ, Patel GD, Lohray BB, Chakrabarti G, Chatterjee A, Jain MR, Patel PR. Cadila Healthcare WO2007077574 (A2), 2007
    • 15b Kahraman M, Sinishtaj S, Dolan PM, Kensler TW, Peleg S, Saha U, Chuang SS, Bernstein G, Korczak B, Posner GH. J. Med. Chem. 2004; 47: 6854

      For other selected contributions including 4-fluoro and 4-trifluoromethylaryl sulfoximines, see:
    • 16a Kowalczyk R, Edmunds AJ. F, Hall RG, Bolm C. Org. Lett. 2011; 13: 768
    • 16b Barry N, Brondel N, Lawrence SE, Maguire AR. Tetrahedron 2009; 65: 10660
    • 16c Terrier F, Magnier E, Kizilian E, Wakselman C, Buncel E. J. Am. Chem. Soc. 2005; 127: 5563
    • 16d Reggelin M, Gerlach M, Vogt M. Eur. J. Org. Chem. 1999; 1011
  • 17 For the synthesis of 1 starting from 4-nitrophenyl sulfurpentafluoride, see: Beier P, Pastýříková T, Vida N, Iakobson G. Org. Lett. 2011; 13: 1466
  • 18 García Mancheño O, Bistri O, Bolm C. Org. Lett. 2007; 9: 3809
  • 19 Stoss P, Satzinger G. Tetrahedron Lett. 1973; 267
  • 20 Synthesis of NH-Sulfoximine 4 from Sulfide 1; General Procedure: Step 1: To a solution of 1 (1.0 mmol) in MeOH (6 mL), was added NH2CN (76 mg, 1.8 mmol), t-BuOK (191 mg, 1.7 mmol) and NBS (356 mg, 2.0 mmol). The reaction was stirred at room temperature until the starting material was consumed (reaction monitored by TLC). After removing the solvent under reduced pressure, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided N-cyanosulfilimine 2. Step 2: To a solution of 2 (0.3 mmol) in EtOH (2.7 mL) was added m-CPBA (ca. 70%, 101 mg, 0.45 mmol). The reaction mixture was stirred at room temperature until the starting material was consumed (reaction monitored by TLC). After removing the solvent under reduced pressure, H2O (5 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided N-cyanosulfoximine 3. Step 3: A solution of 3 (0.23 mmol) in 50% aq H2SO4 (2.3 mL) was stirred at 110 °C for 2 h. After cooling to room temperature and adjusting the pH to 9 by addition of aq. sat NaHCO3 and aq. sat NaOH solution, the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvents were removed under reduced pressure. Purification by flash column chromatography provided NH-sulfoximine 4.
  • 21 For HPLC analytical data, see the Supporting Information.
  • 22 For a recent illustrative example, see: Frings M, Thomé I, Schiffers I, Pan FF, Bolm C. Chem. Eur. J. 2014; 20: 1691
    • 23a Sedelmeier J, Bolm C. J. Org. Chem. 2005; 70: 6904
    • 23b For a recent observation, see: Frings M, Atodiresei I, Bolm C. Molbank 2014; M834
  • 24 Schmidbaur H, Kammel G. Chem. Ber. 1971; 104: 3234
  • 25 For a recent study on sulfoximine N-alkylations under strongly basic conditions (with KOH in DMSO), see: Hendriks CM. M, Bohmann RA, Bohlem M, Bolm C. Adv. Synth. Catal. 2014; 356: 1847
  • 26 Meanwell NA. J. Med. Chem. 2011; 54: 2529
  • 27 For early examples, see: García Mancheño O, Bolm C. Org. Lett. 2007; 9: 2951

Zoom Image
Scheme 1 Synthesis of methyl 4-pentafluorosulfanylphenyl sulfoximine 4
Zoom Image
Scheme 2 Derivatizations of NH-sulfoximine 4 and conversion of N-cyano sulfoximine 3