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Synlett 2009(2): 198-200  
DOI: 10.1055/s-0028-1087511
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Desulfurizing Difluorination Reaction of Benzyl Sulfides Using IF5

Tadahito Fukuhara, Shoji Hara*
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax: +81(11)7066556; e-Mail: shara@eng.hokudai.ac.jp;

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Publication History

Received 10 August 2008
Publication Date:
15 January 2009 (online)

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Abstract

A desulfurizing difluorination reaction of benzyl sulfides having a functional group such as an ester, a ketone, a nitrile, or an amide was performed by a reaction with IF5. Consequently, gem-­difluoro compounds could be obtained selectively.

Key words

fluorination - desulfurization - hypervalent iodine - oxidation - sulfide

Organofluorine compounds often exhibit unique biological activities, [¹] particularly, α,α-difluorocarbonyl compounds which are widely used in various areas of bioorganic and medicinal chemistry. [²] Several methods have been developed for the synthesis of α,α-difluorocarbonyl compounds, such as Pummerer-type fluorination of α-thiocarbonyl compounds, [³] electrophilic fluorination of carbonyl compounds, [²b] [4] deoxyfluorination of α-ketocarbonyl compounds, [5] and building-block methods. [6] Pummerer-type difluorination of α-thiocarbonyl compounds proceeds under mild conditions. However, the removal of the thio group from the products is difficult. The deoxyfluorination reaction of α-ketocarbonyl compounds with (diethylamino)sulfur trifluoride (DAST) or Deoxofluor has been frequently used for the synthesis of α,α-difluorocarbonyl compounds. However, when this method is applied to the reaction with α-diketones for the synthesis of α,α-difluoroketones, it is difficult to distinguish the two carbonyl groups in the substrate, and undesired side reactions can occur, such as the polyfluorination reaction. [5c] [d]

Previously, we reported the novel polyfluorination reaction of aryl alkyl sulfides using IF5 with concomitant migration of the arylthio group. [7] During the study of fluorination of the sulfides using IF5, we found that in the reaction of benzyl sulfides 1 with IF5, a Pummerer-type fluorination and a desulfurizing fluorination reaction occur successively to give gem-difluoro compounds 2 selectively (Scheme  [¹] ).

Scheme 1

The reaction of ethyl 2-methylthio-2-phenyl acetate (1a) with IF5 was examined (Table  [¹] ). The desulfurizing di­fluorination reaction of 1a proceeds at 0 ˚C to room temperature in hexane or CH2Cl2, and ethyl 2,2-difluoro-2-phenylacetate (2a) was obtained selectively. On the other hand, the reaction is slower in polar solvents, such as DMF or THF, and even after 18 hours, 1a remained unchanged.

Table 1 Solvent Effect in a Desulfurizing Difluorination Reactiona

Solvent Time (h) Temp (˚C) Yield (%)b
CH2Cl2  2 0 66
hexane  2 0 61
hexane  2 r.t. 73
THF  8 r.t.  0
MeCN 18 r.t. trace
a IF5 (1.5 equiv to 1a) was used.
b Isolated yield based on 1a.

The present desulfurizing difluorination reaction is applicable to various benzyl sulfides (Table  [²] ). The desulfurization reaction occurs not only in alkyl sulfides (entries 1-4 and 6-8) but also in aryl sulfides (entries 5 and 9). As aryl substituents, 1-naphthyl (entry 6) and bromophenyl group (entry 7) as well as phenyl group are effective in inducing the desulfurizing difluorination reaction. From the substrates with a functional group such as an ester (entries 1, 6, and 7), ketone (entries 2, 4, 5, and 8), nitrile (entry 3), and amide (entry 9), the corresponding gem-difluoro compounds (2a-h) were obtained in good yields.

Table 2 Desulfurizing Difluorination of Various Benzyl Sulfides with IF5 a

Entry 1 R¹ R² R³ Solvent Time (h) Product Yield (%)b
1 1a Ph CO2Et Me hexane 2 2a 73
2 1b Ph C(O)Me Me hexane 2 2b (81)
3 1c Ph CN Me hexane 2 2c (71)
4 1d Ph C(O)Ph Me CH2Cl2 0.75 2d 85
5c 1d′ Ph C(O)Ph 4-ClC6H4 CH2Cl2 1 2d 73
6d 1e 1-naphthyl CO2Et Me CH2Cl2 0.5 2e 70
7 1f BrC6H4
(o/p = 1:4) 		CO2Et Me hexane 5 2f 74
8 1g Ph C(O)(2,3-diF)C6H3 Et CH2Cl2 0.4 2g 76
9 1h Ph C(O)NEt2 Ph CH2Cl2 1 2h 78
a If not otherwise mentioned, the reaction was carried out at r.t. using 1.5 equiv of IF5.
b Isolated yields based on substrate used; NMR yields in parentheses.
c The reaction was carried out at 0 ˚C.
d The reaction was carried out at -20 ˚C.

Both the Pummerer-type fluorination [³] [8] and desulfurizing fluorination [8] [9] of the sulfide are well known, but the de­sulfurizing difluorination reaction is rare. [¹0] Consequently, two fluorine atoms can be introduced into the benzyl position, substituting for one sulfur group and one hydrogen atom.

For the desulfurizing difluorination reaction, the presence of an aryl group is critical. When butyl 2-methylthioacetate (4) was subjected to reaction with IF5, the Pummerer-type difluorination reaction occurs without desulfurization to give butyl α,α-difluoro-α-(methylthio)acetate 5 ­selectively. The aryl group must be stabilizing a carbocation generated by the elimination of the sulfur group and accelerating the desulfurizing fluorination step. [¹0] On the other hand, the presence of an electron-withdrawing group is not critical. When methyl benzyl sulfide 6 was used for the reaction with IF5, the desulfurizing difluorination reaction occured to give (difluoromethyl)benzene 7 (Scheme  [²] ).

Scheme 2

The reaction possibly proceeds as follows: (1) a fluorine atom is introduced at the α-position of the sulfur group via the Pummerer-type fluorination reaction to give a mono­fluoro sulfide 3; (2) desulfurizing fluorination occurs to give a difluoro compound 2. We tried to find the mono­fluorinated sulfide 3 in the reaction mixture, but failed. The second step, the desulfurizing fluorination, must be rapid under the conditions and it is difficult to find 3 (Scheme  [³] ).

Scheme 3

Scheme 4

In order to confirm the reaction mechanism, monofluorinated intermediate 3a was prepared by the other method. Previously, we reported the oxidative fluorination of the sulfides using IF5 in Et3N˙3HF which did not cause the desulfurizing reaction. [³c] When 1a was subjected to a reaction with IF5 in Et3N˙3HF at 0 ˚C for 35 minutes, the consumption of 1a and formation of a new product could be confirmed by GC. After workup, ¹9F NMR analysis of the crude mixture showed the formation of 3a (δ = -140.19 ppm) [¹0a] and the absence of 2a (δ = -104.5 ppm). From the crude 3a, compound 2a was obtained in 70% yield by the reaction with IF5. This result supports the view that the present desulfurizing difluorination reaction proceeds through the intermediate 3, which was formed by the Pummerer-type fluorination reaction of 1 (Scheme  [4] ).

Synthesis of Ethyl 2,2-Difluoro-2-phenylacetate (2a)

To a IF5˙5CH2Cl2 (0.975g, 1.5 mmol) in a TeflonTM PFA bottle, a hexane solution (4 mL) of ethyl 2-methylthio-2-phenylacetate (1a, 210 mg, 1.0 mmol) was added at 0 ˚C, and the mixture was stirred at r.t. for 2 h. Then, the mixture was poured into aq NaHCO3 and extracted with Et2O three times. The combined organic phase was washed with aq Na2S2O3 and dried over MgSO4. Purification by column chlomatography (SiO2, hexane-Et2O) gave 2a (144 mg) in 72% yield; liquid. IR (liquid film): 2987, 1763, 1267, 1104 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.2 Hz, 3 H), 4.30 (q, J = 7.2 Hz, 2 H), 7.44-7.52 (m, 3 H), 7.61 (d, J = 7.3 Hz, 2 H). ¹9F NMR (376 MHz, CDCl3): δ = -104.49 (s, 2 F) (lit [5a] -103.9). ¹³C NMR (100 MHz, CDCl3): δ = 13.82, 63.09, 113.36 (t, ¹ J C-F = 252.9 Hz), 125.41 (t, ³ J C-F = 6.7 Hz, 2 C), 128.61, 130.96 (t, 4 J C-F = 1.9 Hz, 2 C), 132.81 (t, ² J C-F = 25.9 Hz), 164.21 (t, ² J C-F = 35.5 Hz). HRMS (EI): m/z calcd for C10H10F2O2 [M+]: 200.0649; found: 200.0645.

2,2-Difluoro-1,2-diphenylethanone (2d)

Liquid; IR (liquid film): 1703, 1450, 1256, 1135 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.43-7.61 (m, 8 H), 8.02-8.04 (m, 2 H). ¹9F NMR (376 MHz, CDCl3): δ = -98.12 (s, 2 F) [lit. [¹¹] -98.0 (s, 2 F)]. ¹³C NMR (100 MHz, CDCl3): δ = 116.88 (t, ¹ J C-F = 253.9 Hz), 125.59 (t, ³ J C-F  = 5.8 Hz, 2 C), 128.62 (2 C), 128.81 (2 C), 130.25 (t, 4 J C-F = 2.9 Hz, 2 C), 130.91, 132.10, 133.08 (t, ² J C-F = 24.9 Hz), 134.20, 188.94 (t, ² J C-F = 30.7 Hz). HRMS (EI): m/z calcd for C14H10F2O [M+]: 232.0700; found: 232.0683.

Ethyl Bromophenyl-2,2-difluoroacetate (2f)

Liquid (a mixture of o- and p-isomers, ratio ortho/para = 1:4). IR (liquid film): 1767, 1267, 1105 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.3 Hz, 2.4 H), 1.33 (t, J = 7.4 Hz, 0.6 H), 4.30 (q, J = 7.2 Hz, 1.6 H), 4.36 (q, J = 7.2 Hz, 0.4 H), 7.34-7.75 (m, 0.8 H), 7.48 (d, J = 8.4 Hz, 1.6 H), 7.60 (d, J = 8.5 Hz, 1.6 H). ¹9F NMR (376 MHz, CDCl3): δ = -102.51 (s, 0.4 F), -104.73 (s, 1.6 F). ¹³C NMR (100 MHz, CDCl3): δ (ortho) = 13.66, 63.28, 112.68 (t, ¹ J C-F = 253.0 Hz), 120.24 (t, ³ J C-F  = 4.8 Hz), 125.59 (t, 4 J C-F = 1.9 Hz), 127.35, 127.58 (t, ³ J C-F = 8.6 Hz), 132.11, 132.74 (t, ² J C-F = 24.0 Hz), 162.92 (t, ² J C-F = 34.5 Hz). ¹³C NMR (100 MHz, CDCl3): δ (para) = 13.71, 63.23, 112.92 (t, ¹ J C-F  = 252.6 Hz), 127.11 (t, ³ J C-F  = 5.8 Hz, 2C), 131.74 (t, ² J C-F  = 26.8 Hz), 131.85 (2 C), 133.93, 163.63 (t, ² J C-F  = 35.5 Hz). HRMS (EI): m/z calcd for C10H9BrF2O2 [M+]: 277.9754; found: 277.9757.

1-(3,4-Difluorophenyl)-2,2-difluoro-2-phenylethanone (2g)

Liquid. IR (liquid film): 1713, 1612, 1263 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.84-6.99 (m, 2 H), 7.45-7.61 (m, 5 H), 7.79-7.85 (m, 1 H). ¹9F NMR (376 MHz, CDCl3): δ = -100.12 to -100.22 (m, 1 F), -100.61 (d, J = 14.0 Hz, 2 F), -102.62 to -102.75 (m, 1 F). ¹³C NMR (100 MHz, CDCl3): δ = 105.17 (t, ² J C-F = 25.9 Hz), 111.95 (dd, ² J C-F = 22.0, ³ J C-F = 3.8 Hz), 116.10 (t, ¹ J C-F  = 253.9 Hz), 118.73 (dd, ² J C-F  = 12.5, ³ J C-F = 3.8 Hz), 125.78 (t, ³ J C-F = 6.5 Hz, 2 C), 128.66, 130.98 (t, 4 J C-F  = 1.9 Hz, 2 C), 132.00 (t,
² J C-F = 25.2 Hz), 132.96-133.16 (m), 162.24 (dd, ¹ J C-F = 264.4, ² J C-F = 12.5 Hz), 166.15 (dd, ¹ J C-F = 259.7, ² J C-F = 12.5 Hz), 187.52 (td, ² J C-F = 34.0, 4 J C-F = 2.9 Hz). HRMS (EI): m/z calcd for C14H8F4O [M+]: 268.0511; found: 268.0518.

Acknowledgment

We are grateful to Asahi Glass Co., Ltd. for their gift of IF5.

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    Search in Google Scholar
  • 1b Welch JT. Eswarakrishnan S. Fluorine in Bioorganic Chemistry   Wiley; New York: 1991. 
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    Search in Google Scholar
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    Search in Google Scholar
  • 2b Konas DW. Coward JK. Org. Lett.  1999,  1:  2105 
    Search in Google Scholar
  • 2c Dubowchik GM. Vrudhula VM. Dasgupta B. Ditta J. Chen T. Sheriff S. Sipman K. Witmer M. Tredup J. Vyas DM. Verdoorn TA. Bollini S. Vinitsky A. Org. Lett.  2001,  3:  3987 
    Search in Google Scholar
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    Search in Google Scholar
  • 3b Motherwell WB. Greaney MF. Edmunds JJ. Steed JW. J. Chem. Soc., Perkin Trans. 1  2002,  2816 
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  • As for the review, see:
  • 3d Dawood KM. Tetrahedron  2004,  60:  1435 
    Search in Google Scholar
  • 3e Fuchigami T. Tajima T. J. Fluorine Chem.  2005,  126:  181 
    Search in Google Scholar
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  • 6e Boyer N. Gloznec P. Nanteuil GD. Jubault P. Quirion J.-C. Tetrahedron  2007,  63:  12532 
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  • As for the review, see:
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    Search in Google Scholar
  • 9b Reddy VP. Alleti R. Perambuduru MK. Welz-Biermann U. Buchholz H. Prakash GKS. Chem. Commun.  2005,  654 
  • 9c Cohen O. Rozen S. Tetrahedron  2008,  64:  5362 
    Search in Google Scholar
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    Search in Google Scholar
  • 10b Furuta S. Kuroboshi M. Hiyama T. Tetrahedron Lett.  1995,  36:  8243 
    Search in Google Scholar
  • 11 Rozen S. Brand M. J. Org. Chem.  1986,  51:  222 
    CrossrefSearch in Google Scholar
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Scheme 1

Scheme 2

Scheme 3

Scheme 4