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Synthesis 2011(15): 2383-2386  
DOI: 10.1055/s-0030-1260074
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© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Fluorohydrins through Electrophilic Fluorination of Allyl Silanes

Weibo Wang, Bo Xu*, Gerald B. Hammond*
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
Fax: +1(502)8523899; e-Mail: bo.xu@louisville.edu; e-Mail: gb.hammond@louisville.edu;

Dedicated to Professor Kenji Uneyama on the occasion of his 70th birthday


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Publication History

Received 29 April 2011
Publication Date:
17 June 2011 (online)

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Abstract

A convenient method for the efficient and regioselective monofluorination of allyl silanes to afford 1-fluoro-3-silyl-2-ols in 43-62% yields via fluorohydroxylation, using Selectfluor as the eletrophilic fluorination reagent has been developed. The regioselectivity can be rationalized by considering the stabilization of the β-carbocation intermediate by the silyl group.

Key words

allyl silanes - fluorination - fluorohydrins - regioselectivity

Extensive research has established that the chemical reactivity of fluorinated organic compounds is distinct from other halide-containing analogues. [¹] Consequently, fluorine substitution can effectively modify the physicochemical properties of a molecule. In this regard, fluorohydrins have been sought as intermediates and biological targets. [²] Typically, fluorohydrins are synthesized through epoxide ring opening using a fluorinating agent; [³] however, in many cases, the regioselectivity and yields are less than satisfactory. There are other methods that rely on fluorinated molecular building blocks, but these building blocks are often derived from potential atmospheric ozone-depleting­ agents such as CFHCl2. [4]

Selectfluor is an exceptionally stable, virtually non-hygroscopic­, crystalline, electrophilic fluorinating agent [5] that has been used in several applications, such as fluorohydroxylation of aryl substituted allenes. [6] Recently, we reported a versatile synthesis of fluoroketones through gold-catalyzed fluorination of alkynes using Selectfluor. [7] During our attempts to extend the scope of this reaction to alkenes, we conducted the fluorination of allyltriisopropylsilane (1a) in the presence of 5 mol% [AuClPPh3]; this reaction afforded the fluorohydrin product 2a in around 50% yield (Scheme  [¹] ). Further investigations revealed that no other regioisomer was formed. This reaction represented a highly regioselective intermolecular fluorohydroxylation of an alkene. Gouverneur and co-workers have reported an electrophilic fluorocyclization of allyl silanes, [8] but, to the best of our knowledge, the synthetically more useful intermolecular fluorohydroxylation of allyl silanes has not been reported before.

Further optimization of this transformation is shown in Table  [¹] . Without any gold catalyst, the fluorination of 1a in acetonitrile-water (20:1) gave 1-fluoro-3-(triisopropylsilyl)propan-2-ol (2a; Table  [¹] , entry 1) in 56%, which indicated that the reaction occurred independently of the gold catalyst. Increasing the amount of water led to a slightly increased yield (Table  [¹] , entry 2), but a further increase in the water content actually decreased the yield (Table  [¹] , entry 3). We also investigated other nucleophiles. No reaction was observed when ethanol was used as both nucleophile and solvent (Table  [¹] , entry 4), but the fluorination of 1a in acetonitrile-ethanol (10:1) afforded (2-ethoxy-3-fluoropropyl)triisopropylsilane (2b) in 61% yield (Table  [¹] , entry 5). This result indicated that the solvent (MeCN) played an important role in this transformation. The reaction of 1a with other nucleophiles, such as acetic acid, formamide and diethylamine, afforded complex mixtures (Table  [¹] , entries 6, 7). Thus, the reaction conditions presented in Table  [¹] , entry 2 was regarded as optimal for further studies.

Scheme 1

Table 1 Screening Conditions

Entry Nucleophile (ratio MeCN/Nu) Yield (%)
1 H2O (20:1) 56
2 H2O (10:1) 60
3 H2O (5:1) 55
4 EtOH NR
5 EtOH (10:1) 61
6 AcOH (10:1) mixture
7 HCONH2 (10:1) mixture
8 Et2NH (10:1) NR

With optimized reaction conditions in hand, we explored the scope of this transformation (Table  [²] ). The reactions of allyltriisopropylsilane (1a) with water, ethanol, isopropanol, allyl alcohol, butan-1-ol and 2-cyclohexylethanol gave good yields (Table  [²] , entries 1-6). Use of the relative more sterically hindered isopropanol substrate reduced the yield slightly (Table  [²] , entry 3). Higher temperature (60 ˚C) was needed for complete reaction of 1a with allyl alcohol, furnishing product 2d in 61% yield (Table  [²] , entry 4). Reaction of allyltriphenylsilane (1b) with acetonitrile-water (10:1) afforded 2g in 55% yield (Table  [²] , entry 7). Diallyl silanes, such as diallyldiphenylsilane (1c), were highly reactive under the standard conditions and failed to give the desired fluorinated product (Table  [²] , entry 8). The reaction of allyl silane with a non-terminal double bond, such as 1d, worked well (Table  [²] , entry 9). The good, but not excellent, yields observed in Table  [²] may be due to a competing electrophilic fluorodesilylation reaction of allyl silane 1. Gouverneur and co-workers have developed efficient syntheses of allyl and propargyl fluorides through the fluorodesilylation of allyl and allenyl silanes. [9] In those transformations, [9] allyl silanes with a smaller silyl group (e.g., TMS) were used. The bulkier silyl group (e.g., TIPS) used in our examples are more resistant to fluorodesilylation, but may not completely prevent the fluorodesilylation process. If desired, the silyl group in 2 can be removed by applying literature methods. [8]

Table 2 Scope of the Reaction

Entry 1 Nu 2 Yield (%)a
1

1a 		H2O

2a 		60
2 1a EtOH

2b 		61
3 1a

2c 		43
4b 1a

2d 		61
5 1a

2e 		60
6 1a

2f 		62
7

1b 		H2O

2g 		55
8

1c 		H2O complex mixture -
9

1d 		H2O

2h 		59
a Isolated yield.
b Reaction was conducted at 60 ˚C.

The proposed mechanism is shown in Scheme  [²] . It has been well established that the silyl group has a strong stabilizing effect on β-carbocations and radical cations. [¹0] This fact is probably the key reason for the regioselectivity observed. We propose that allyl silane reacts with Selectfluor­ to give β-carbocation A, and quenching of A by a nucleophile gives the final product 2. Single-electron transfer (SET) has been proposed in many Selectfluor-mediated reactions; [5b] it is also possible that the present reaction goes through an SET mechanism, that is, the reaction of 1 with Selectfluor would give radical cation B, which would then react with a nucleophile to give the final product 2.

Scheme 2 Proposed mechanism

In conclusion, we have developed a convenient method for the efficient monofluorination of allyl silanes using Selectfluor as the electrophilic fluorination reagent. The stabilizing effect of the silyl group on the β-carbocation is critical for the success of this reaction. The use of easy-to-handle N-F reagents is a particularly attractive feature of this reaction. Further research on the implications of this transformation, including an asymmetric version, is under way in our laboratory.

The ¹H, ¹³C and ¹9F NMR spectra were recorded at 500, 126 and 470 MHz, respectively, using CDCl3 as solvent. The chemical shifts are reported in δ (ppm) values relative to CHCl3 (δ = 7.26 ppm for ¹H NMR and δ = 77.0 ppm for ¹³C NMR) and CFCl3 (δ = 0 ppm for ¹9F NMR), multiplicities are indicated by: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), h (hextet), m (multiplet) and br (broad). Coupling constants (J) are reported in hertz. All air- and/or moisture-sensitive reactions were carried out under an argon atmosphere. All reagents and solvents were employed without further purification. The products were purified using a CombiFlash system (Teledyne ISCO) or a regular glass column. TLC was developed on Merck silica gel 60 F254 aluminum sheets. IR spectra were recorded with a Bruker IFS 25 spectrometer. High resolution ESI-MS were obtained with a MS-FTICR-MSn system (LTQ FT, Thermo Electron Corp.).

Synthesis of 2; General Procedure

To a solution of 1a (99 mg, 0.5 mmol) in MeCN-H2O (10:1, 3 mL) was added Selectfluor (266 mg, 0.75 mmol). The reaction mixture was stirred at r.t. for 24-36 h and the progress of reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with sat. aq NH4Cl (10 mL), extracted with hexane or Et2O (2 × 15 mL) and the combined organic layers were dried over MgSO4. After evaporation, the residue was subjected to flash silica gel column chromatography (hexane to hexane-CH2Cl2, 1:1), affording 2a.

1-Fluoro-3-(triisopropylsilyl)propan-2-ol (2a)

Yield: 70 mg (60%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.68-0.74 (m, 1 H), 0.78-0.86 (m, 1 H), 1.02-1.17 (m, 21 H), 2.17 (s, 1 H), 4.10-4.27 (m, 2 H), 4.31-4.44 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.6, 12.2 (d, J = 4 Hz), 19.0 (d, J = 2 Hz), 68.2 (d, J = 18 Hz), 89.2 (d, J = 170 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.8 to -220.5 (m).

GC/MS (EI): m/z = 172, 103, 41.

HRMS (ESI): m/z [M + Na]+ calcd for C12H27FNaOSi+: 257.1713; found: 257.1712.

(2-Ethoxy-3-fluoropropyl)triisopropylsilane (2b)

Yield: 80 mg (61%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.73-0.77 (m, 1 H), 0.89-0.94 (m, 1 H), 1.04-1.09 (m, 21 H), 1.20 (t, J = 7 Hz, 3 H), 3.47-3.53 (m, 1 H), 3.71-3.78 (m, 2 H), 4.29-4.36 (m, 1 H), 4.39-4.46 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.7, 11.8 (d, J = 5 Hz), 15.9, 19.0, 65.5, 75.9 (d, J = 18 Hz), 87.9 (d, J = 174 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.3 to -220.1 (m).

GC/MS (EI): m/z = 243, 202, 147, 121, 41.

HRMS (ESI): m/z [M + Na]+ calcd for C14H31FNaOSi+: 285.2026; found: 285.2026.

(3-Fluoro-2-isopropoxypropyl)triisopropylsilane (2c)

Yield: 59 mg (43%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.76-0.83 (m, 2 H), 0.96-1.03 (m, 21 H), 1.09 (d, J = 7.5 Hz, 6 H), 3.71-3.81 (m, 2 H), 4.16-4.38 (m, 2 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.5, 12.5 (d, J = 7.5 Hz), 18.8 (d, J = 5 Hz), 22.3, 23.2, 69.8 (d, J = 2 Hz), 72.8 (d, J = 22 Hz), 87.4 (d, J = 216 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.4 to -220.1.

GC/MS (EI): m/z = 216, 192, 172, 103.

HRMS (ESI+): m/z [M + Na]+ calcd for C15H33FNaOSi+: 299.2182; found: 299.2184.

[2-(Allyloxy)-3-fluoropropyl]triisopropylsilane (2d)

Yield: 84 mg (61%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.67-0.71 (m, 2 H), 0.77-1.03 (m, 21 H), 3.70-3.78 (m, 1 H), 3.94-3.98 (m, 1 H), 4.10-4.15 (m, 1 H), 4.22-4.29 (m, 1 H), 4.34-4.30 (m, 1 H), 5.05-5.09 (m, 1 H), 5.17-5.21 (m, 1 H), 5.80-5.89 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.4, 18.8, 71.0 (d, J = 3 Hz), 75.6 (d, J = 22 Hz), 88.7 (d, J = 217 Hz), 116.5, 135.1.

¹9F NMR (470 MHz, CDCl3): δ = -219.5 to -219.2 (m).

GC/MS (EI): m/z = 213, 189, 171, 81.

HRMS (ESI): m/z [M + Na]+ calcd for C15H31FNaOSi+: 297.2026; found: 297.2026.

(2-Butoxy-3-fluoropropyl)triisopropylsilane (2e)

Yield: 87 mg (60%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.74-0.78 (m, 2 H), 0.90-0.95 (m, 3 H), 1.05-1.10 (m, 21 H), 1.36-1.40 (m, 2 H), 1.53-1.60 (m, 2 H), 3.43-3.47 (m, 1 H), 3.62-3.67 (m, 1 H), 3.69-3.77 (m, 1 H), 4.29-4.36 (m, 1 H), 4.39-4.46 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.7, 11.8, 14.1, 19.1, 19.6, 32.6, 70.0, 76.0 (d, J = 17 Hz), 87.8 (d, J = 174 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.5 to -220.2 (m).

GC/MS (EI): m/z = 275, 231, 174, 100.

HRMS (ESI+): m/z [M + Na]+ calcd for C16H35FNaOSi+: 313.2339; found: 313.2339.

[2-(2-Cyclohexylethoxy)-3-fluoropropyl]triisopropylsilane (2f)

Yield: 103 mg (60%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.64-0.90 (m, 2 H), 0.81-0.87 (m, 3 H), 0.92-1.04 (m, 21 H), 1.05-1.19 (m, 4 H), 1.30-1.41 (m, 2 H), 1.51-1.63 (m, 4 H), 3.34-3.40 (m, 1 H), 3.58-3.68 (m, 2 H), 4.19-4.26 (m, 1 H), 4.33-4.38 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.7, 11.8, 18.3, 19.1 (d, J = 3 Hz), 26.7 (d, J = 37 Hz), 33.6 (d, J = 23 Hz), 34.7, 38.0, 68.1, 76.0 (d, J = 18 Hz), 87.9 (d, J = 174 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.0 to -219.7 (m).

GC/MS (EI): m/z = 283, 214, 172, 158, 69.

HRMS (ESI+): m/z [M + Na]+ calcd for C20H41FNaOSi+: 367.2808; found: 367.2808.

1-Fluoro-3-(triphenylsilyl)propan-2-ol (2g)

Yield: 86 mg (55%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.64-0.90 (m, 2 H), 0.81-0.87 (m, 3 H), 0.92-1.04 (m, 21 H), 1.05-1.19 (m, 4 H), 1.30-1.41 (m, 2 H), 1.51-1.63 (m, 4 H), 3.34-3.40 (m, 1 H), 3.58-3.68 (m, 2 H), 4.19-4.26 (m, 1 H), 4.33-4.38 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.7, 11.8, 18.3, 19.1 (d, J = 3 Hz), 26.7 (d, J = 37 Hz), 33.6 (d, J = 23 Hz), 34.7, 38.0, 68.1, 76.0 (d, J = 18 Hz), 87.9 (d, J = 174 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -220.0 to -219.7 (m).

GC/MS (EI): m/z = 283, 214, 172, 158, 69.

2-Fluoro-3-hydroxy-4-(triisopropylsilyl)butyl Acetate (2h)

Yield: 92 mg (59%); colorless oil.

¹H NMR (500 MHz, CDCl3): δ = 0.79-0.82 (m, 1 H), 0.91-0.96 (m, 1 H), 1.06-1.14 (m, 21 H), 1.99 (d, J = 5 Hz, 1 H), 2.11-2.13 (m, 3 H), 3.98-4.04 (m, 1 H), 4.25-4.35 (m, 1 H), 4.37-4.43 (m, 1 H), 4.48-4.51 (m, 1 H).

¹³C NMR (125 MHz, CDCl3): δ = 11.6 (d, J = 9 Hz), 13.5, 19.0, 21.0, 63.7 (d, J = 23 Hz), 68.5 (d, J = 20 Hz), 95.8 (d, J = 175 Hz).

¹9F NMR (470 MHz, CDCl3): δ = -198.2 to -197.9 (m).

GC/MS (EI): m/z = 285, 225, 181, 112, 43.

HRMS (ESI): m/z [M + Na]+ calcd for C15H31FNaO3Si+: 329.1924; found: 329.1924.

Acknowledgment

We are grateful to the National Science Foundation for financial support (CHE-0809683 and CHE-1111316), and acknowledge the support provided by the CREAM Mass Spectrometry Facility (University of Louisville) funded by NSF/EPSCoR (EPS-0447479).

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Scheme 1

Scheme 2 Proposed mechanism