Synlett 2015; 26(01): 76-78
DOI: 10.1055/s-0034-1379501
cluster
© Georg Thieme Verlag Stuttgart · New York

Electrophilic Aromatic Trifluoromethylthiolation with the Second Generation of Trifluoromethanesulfenamide

Sébastien Alazet
a  Institute of Chemistry and Biochemistry (ICBMS, UMR CNRS 5246), Université de Lyon, Université Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Lyon, France   Email: Thierry.billard@univ-lyon1.fr
b  CERMEP, In Vivo Imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69003 Lyon, France
,
Thierry Billard*
a  Institute of Chemistry and Biochemistry (ICBMS, UMR CNRS 5246), Université de Lyon, Université Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Lyon, France   Email: Thierry.billard@univ-lyon1.fr
b  CERMEP, In Vivo Imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69003 Lyon, France
› Author Affiliations
Further Information

Publication History

Received: 29 September 2014

Accepted after revision: 03 November 2014

Publication Date:
28 November 2014 (online)

 


Abstract

Direct trifluoromethylthiolation of various aromatic and heteroaromatic compounds, variously substituted, can be performed with the second generation of trifluoromethanesulfenamide via a ‘Friedel–Crafts-like reaction’. This reaction requires mild conditions with a catalytic amount of protic or Lewis acid. Good results have been obtained, even with aromatic compounds bearing deactivating substituents.


#

Because of the intrinsic properties of the fluorine atom, fluorinated compounds have known these last years an increasing interest in a large panel of applications, from materials to life sciences.[1] In this last field, the introduction of fluorinated group generally contributes to better physicochemical properties.[2] In particular, the CF3S group, because of its high lipophilicity (Hansch parameter πR = 1.44),[3] can favor the transmembrane permeation and, consequently, increase the biodisponibility of molecules.[4]

A lot of methods have been described in literature to synthesize compounds bearing this specific group.[5] However, these methods are essentially indirect methods which could require aggressive reagents. The most efficient, and elegant, way to easily access the trifluoromethylthiolated molecules is the direct introduction of the CF3S moiety. Recently, some elegant solutions have emerged to enable one to propose an efficient toolbox to organic chemists. Thus, various reagents for nucleophilic or electrophilic reactions are now available for a large panel of reactions.[5a] [b] [6] Nevertheless, only a few classic electrophilic aromatic substitutions have been described.

If we exclude the CF3SCl chemistry, because of the high toxicity of this gaseous compound,[7] the first generation of trifluoromethanesulfenamide has been the first reagent able to perform ‘Friedel–Crafts-like reaction’.[8] However, these reactions were limited to electron-rich aromatic compounds such as indoles. Later, a trifluoromethanesulfonyl hypervalent iodonium ylide reagent was also successfully employed to trifluoromethylthiolate indoles.[9] Shen et al. have also published lately the trifluoromethylthiolation of indoles in mild conditions with their trifluoromethanesulfenate reagent.[10] Very recently, N-trifluoromethylthiosaccharin has been developed and a larger panel of aromatics could be trifluoromethylthiolated with this new reagent.[11] Nevertheless, to this day, it appears that the electrophilic aromatic trifluoromethylthiolation is still in progress and further methods are expected to extend the investigations.

Table 1 Trifluoromethylthiolation of 2a with 1a

Entry

Catalyst (equiv)

Solvent

Temp (°C)

Time (h)

3a (%)a

1

BF3·Et2O (2.5)

CH2Cl2

20

18

0

2

BF3·Et2O (2.5)

CH2Cl2

50

18

16

3

TMSCl (1)

CH2Cl2

50

18

0

4

TfOH (1)

CH2Cl2

20

18

92

5

TfOH (1)

CH2Cl2

50

18

88

6

TfOH (1)

ClCH2CH2Cl

80

18

88

7

TfOH (0.2)

CH2Cl2

20

18

25

8

TfOH (0.2)

CH2Cl2

50

18

40

9

TfOH (0.2)

ClCH2CH2Cl

80

18

90

10

TfOH (0.2)

ClCH2CH2Cl

80

5 min

22

11

TfOH (0.2)

ClCH2CH2Cl

80

1

40

12

TfOH (0.2)

ClCH2CH2Cl

80

6

68

13

TfOH (0.2)

ClCH2CH2Cl

80

36

90

14

TMSCl (1)

MeCN

80

18

90

15

TMSCl (0.2)

MeCN

80

18

86

a Crude yield was determined by 19F NMR using PhOCF3 as an internal standard.

Recently, we have developed a second generation of trifluoromethanesulfenamide (1a) that is more reactive and which has been successfully used to carry out reactions that were impossible to realize with the first-generation reagent.[12] In this context, to continue the exploration of the reactivity of this new reagent and, also, to propose new tools for electrophilic aromatic trifluorometylthiolation, we decided to study ‘Friedel–Crafts-like reactions’ with 1a.

To determine the optimal conditions, m-dimethoxybenzene has been chosen as the model substrate (Table [1]).

Zoom Image
Scheme 1 Electrophilic aromatic trifluoromethylthiolation with 1a, catalyzed by TfOH. a The reaction was carried out with 0.2 equiv of TfOH. b The reaction was carried out with 1 equiv of TfOH. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).

If Lewis acids were not efficient to favor this reaction in dichloromethane (Table [1], entries 1–3), Brönsted acid, such as triflic acid, was very efficient to catalyze this reaction (Table [1], entries 4–6). With one equivalent of TfOH, no temperature effect on the yield was observed (Table [1], entries 4–6). Given the mechanism of the SEAr, the required proton amount should be catalytic. Indeed, only 0.2 equivalent of TfOH appeared to be sufficient. Nevertheless, in this case, heating to 80 °C was required to favor the kinetics (Table [1], entries 7–9). A solvent effect was observed for the TMSCl catalysis since good results were obtained in acetonitrile, with stoichiometric or catalytic amount, (Table [1], entries 14 and 15) whereas nothing happened with one equivalent in CH2Cl2. In term of kinetics, the optimal reaction time was determined to be around 18 hours (Table [1], entries 9–13).

With the optimal conditions in hand (Table [1], entry 9), various aromatic compounds were engaged in this reaction (Scheme [1]).[13] [14] [15]

The reaction gave, in general, good yields with various aromatic compounds. The trifluoromethylation of toluene remained unsatisfactory, which is certainly because it is not sufficiently electron-rich. On the contrary, mesitylene was trifluoromethylated with satisfactory yield (3g). When the trifluoromethylthiolation was difficult, the use of one equivalent of TfOH was, generally, beneficial and good yields could be then obtained, even in the case of nitro compounds (3l).

In the case of protic acid sensitive compounds, such as nitrogenated molecules, catalysis with TMSCl was considered (Scheme [2]). Good yields were then obtained. Again, the use of one equivalent of TMSCl was required to increase the obtained yields.

Zoom Image
Scheme 2 Electrophilic aromatic trifluoromethylthiolation with 1a, catalyzed by TMSCl. a The reaction was carried out with 0.2 equiv of ­TMSCl. b The reaction was carried out with 1 equiv of TMSCl. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).

Since the superior homologue of 1a is also easily available, a few examples of pentafluoroethylthiolation were also performed (Scheme [3]). Good yields were observed also for this reaction.

Zoom Image
Scheme 3 Electrophilic aromatic pentafluoroethylthiolation with 1a, catalyzed by TfOH. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).

To conclude, the second generation of trifluoromethanesulfenamide, which we have recently developed, confirms its higher reactivity, compared to its first-generation counterpart. With this new reagent, electrophilic aromatic trifluoromethylthiolations can be performed in mild conditions (catalytic amount of acid) with various aromatic compounds. For the first time, aromatics bearing alkyl or nitro compounds have been successfully trifluoromethylthiolated. Furthermore, the extension of these reactions to pentafluoroethylthiolation has been initiated. Therefore, this family of reagent confirms its effectiveness and its place into the toolbox of trifluoromethylthiolating reagents.


#

Acknowledgment

The CNRS and the French Ministry of Research are thanked for their financial supports. The French Fluorine Network is also thanked for its support.

Supporting Information

  • References and Notes

  • 3 Hansch C, Leo A, Taft RW. Chem. Rev. 1991; 91: 165
    • 5a Toulgoat F, Alazet S, Billard T. Eur. J. Org. Chem. 2014; 2415
    • 5b Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2014; in press; doi: 10.1021/cr500193b
    • 5c Boiko VN. Beilstein J. Org. Chem. 2010; 6: 880
    • 5d Leroux F, Jeschke P, Schlosser M. Chem. Rev. 2005; 105: 827
    • 6a Landelle G, Panossian A, Pazenok S, Vors J.-P, Leroux FR. Beilstein J. Org. Chem. 2013; 9: 2476
    • 6b Tlili A, Billard T. Angew. Chem. Int. Ed. 2013; 52: 6818
  • 7 Stump EC. Chem. Eng. News 1967; 45: 51, 44
  • 8 Ferry A, Billard T, Bacqué E, Langlois BR. J. Fluorine Chem. 2012; 134: 160
  • 9 Yang Y.-D, Azuma A, Tokunaga E, Yamasaki M, Shiro M, Shibata N. J. Am. Chem. Soc. 2013; 135: 8782
  • 10 Ma B, Shao X, Shen Q. J. Fluorine Chem. 2014; doi: 10.1016/j.jfluchem.2014.09.011
  • 11 Xu C, Ma B, Shen Q. Angew. Chem. Int. Ed. 2014; 53: 9316
  • 12 Alazet S, Zimmer L, Billard T. Chem. Eur. J. 2014; 20: 8589
  • 13 Typical Procedure: A 10 mL sealed tube equipped with a magnetic stirrer was charged with the arene (0.50 mmol, 1.0 equiv) and TsNMeSCF3 (1a) or TsNMeSCF2CF3 (1b; 1.2 equiv) in anhyd DCE. The reaction was stirred at r.t. for 1 min and triflic acid was added slowly (0.2 equiv) and the reaction was stirred at 80 °C for 18 h. The progress of the reaction was checked by 19F NMR with PhOCF3 as internal standard. After completion, the reaction was warmed to r.t. and the solvent was removed under vacuum and the residue was purified by flash chromatography to give the desired product.
  • 14 4-[(Trifluoromethyl)sulfanyl]benzene-1,3-diol (3b): brown solid; mp <50 °C. 1H NMR: δ = 7.41 (d, 3 J H,H = 8.6 Hz, 1 H), 6.56 (d, 3 J H,H = 2.7 Hz, 1 H), 6.85 (dd, 3 J H,H = 8.6, 2.7 Hz, 1 H), 4.50–6.10 (br, 2 H). 13C NMR: δ = 161.1, 159.5, 139.6, 128.8 (q, 1 J C,F = 315 Hz), 109.9, 103.0, 99.62 (q, 3 J C,F = 1.7 Hz). 19F NMR: δ = –44.52 (s, 3 F). Anal. Calcd for C7H5F3O2S: C, 40.00; H, 2.40; S, 15.26. Found: C, 40.12; H, 2.29; S, 15.47.
  • 15 Synthesis of 2,4-Dimethoxy-1-[(pentafluoroethyl)sulfanyl]benzene (4a): 1H NMR: δ = 7.51 (d, 3 J H,H = 8.5 Hz, 1 H), 6.50–6.52 (m, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H). 13C{19F} NMR: δ = 164.3, 162.7, 141.0, 120.0 (CF2), 118.9 (CF3), 105.7, 101.7 (t, 3 J C,F = 2 Hz), 99.3, 56.1, 55.62. 19F NMR: δ = –82.94 (t, 3 J F,F = 3.4 Hz, 3 F), –93.06 (q, 3 J F,F = 3.5 Hz, 2 F). Anal. Calcd for C10H9F5O2S: C, 41.67; H, 3.15; S, 11.12. Found: C, 41.79; H, 2.91; S, 11.4.

  • References and Notes

  • 3 Hansch C, Leo A, Taft RW. Chem. Rev. 1991; 91: 165
    • 5a Toulgoat F, Alazet S, Billard T. Eur. J. Org. Chem. 2014; 2415
    • 5b Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2014; in press; doi: 10.1021/cr500193b
    • 5c Boiko VN. Beilstein J. Org. Chem. 2010; 6: 880
    • 5d Leroux F, Jeschke P, Schlosser M. Chem. Rev. 2005; 105: 827
    • 6a Landelle G, Panossian A, Pazenok S, Vors J.-P, Leroux FR. Beilstein J. Org. Chem. 2013; 9: 2476
    • 6b Tlili A, Billard T. Angew. Chem. Int. Ed. 2013; 52: 6818
  • 7 Stump EC. Chem. Eng. News 1967; 45: 51, 44
  • 8 Ferry A, Billard T, Bacqué E, Langlois BR. J. Fluorine Chem. 2012; 134: 160
  • 9 Yang Y.-D, Azuma A, Tokunaga E, Yamasaki M, Shiro M, Shibata N. J. Am. Chem. Soc. 2013; 135: 8782
  • 10 Ma B, Shao X, Shen Q. J. Fluorine Chem. 2014; doi: 10.1016/j.jfluchem.2014.09.011
  • 11 Xu C, Ma B, Shen Q. Angew. Chem. Int. Ed. 2014; 53: 9316
  • 12 Alazet S, Zimmer L, Billard T. Chem. Eur. J. 2014; 20: 8589
  • 13 Typical Procedure: A 10 mL sealed tube equipped with a magnetic stirrer was charged with the arene (0.50 mmol, 1.0 equiv) and TsNMeSCF3 (1a) or TsNMeSCF2CF3 (1b; 1.2 equiv) in anhyd DCE. The reaction was stirred at r.t. for 1 min and triflic acid was added slowly (0.2 equiv) and the reaction was stirred at 80 °C for 18 h. The progress of the reaction was checked by 19F NMR with PhOCF3 as internal standard. After completion, the reaction was warmed to r.t. and the solvent was removed under vacuum and the residue was purified by flash chromatography to give the desired product.
  • 14 4-[(Trifluoromethyl)sulfanyl]benzene-1,3-diol (3b): brown solid; mp <50 °C. 1H NMR: δ = 7.41 (d, 3 J H,H = 8.6 Hz, 1 H), 6.56 (d, 3 J H,H = 2.7 Hz, 1 H), 6.85 (dd, 3 J H,H = 8.6, 2.7 Hz, 1 H), 4.50–6.10 (br, 2 H). 13C NMR: δ = 161.1, 159.5, 139.6, 128.8 (q, 1 J C,F = 315 Hz), 109.9, 103.0, 99.62 (q, 3 J C,F = 1.7 Hz). 19F NMR: δ = –44.52 (s, 3 F). Anal. Calcd for C7H5F3O2S: C, 40.00; H, 2.40; S, 15.26. Found: C, 40.12; H, 2.29; S, 15.47.
  • 15 Synthesis of 2,4-Dimethoxy-1-[(pentafluoroethyl)sulfanyl]benzene (4a): 1H NMR: δ = 7.51 (d, 3 J H,H = 8.5 Hz, 1 H), 6.50–6.52 (m, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H). 13C{19F} NMR: δ = 164.3, 162.7, 141.0, 120.0 (CF2), 118.9 (CF3), 105.7, 101.7 (t, 3 J C,F = 2 Hz), 99.3, 56.1, 55.62. 19F NMR: δ = –82.94 (t, 3 J F,F = 3.4 Hz, 3 F), –93.06 (q, 3 J F,F = 3.5 Hz, 2 F). Anal. Calcd for C10H9F5O2S: C, 41.67; H, 3.15; S, 11.12. Found: C, 41.79; H, 2.91; S, 11.4.

Zoom Image
Scheme 1 Electrophilic aromatic trifluoromethylthiolation with 1a, catalyzed by TfOH. a The reaction was carried out with 0.2 equiv of TfOH. b The reaction was carried out with 1 equiv of TfOH. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).
Zoom Image
Scheme 2 Electrophilic aromatic trifluoromethylthiolation with 1a, catalyzed by TMSCl. a The reaction was carried out with 0.2 equiv of ­TMSCl. b The reaction was carried out with 1 equiv of TMSCl. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).
Zoom Image
Scheme 3 Electrophilic aromatic pentafluoroethylthiolation with 1a, catalyzed by TfOH. Isolated yields (in parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard).