Lithiated Benzothiophenes and Benzofurans Require 2-Silyl Protection to Avoid Anion Migration

Abstract

2-Trimethylsilyl protection of benzothiophenes and benzofurans prevents anion migration to the 2-position when lithiated species are formed. These lithiated benzothiophenes and benzofurans provide superior results in additions to piperidones. De­protection is conveniently achieved under acidic conditions. Direct C-7 metalation of benzothiophene is enabled by 2-triisopropylsilyl protection at C-2.

Key words

lithiation - metalation - benzothiophene - silyl protecting group - piperidone addition reactions

References

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• 9e

  See ref. [8b]

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• In these cases silicon directs the initial metalation, rather than preventing a subsequent proton transfer:
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3

Prepared by alkylation of 2-bromothiophenol with bromoacetaldehyde diethyl acetal, followed by Amberlyst-15 catalyzed Friedel-Crafts cyclization, see: Zhang, T. Y.; Allen, M. J.; Godfrey, A. G.; Vicenzi, J. T., 215^th National Meeting of the American Chemical Society, Dallas, TX, 1998, Poster ORGN 242.

4

Product ratios assigned by reverse phase high-pressure liquid chromatography (HPLC). No other products observed by HPLC.

7

Changes in solvent, addition rate or reaction temperature had little impact on the product to benzothiophene ratio. However, inverse addition of the Grignard reagent to the ketone in THF at reflux significantly increased the amount of enolization (0.3:1 ratio of 4:5).

14

See ref. [11]

15

Tetrahydropyridine 1 was isolated as the oxalate salt to aid in purification and to provide a stable solid for storage.

16

Procedures for Scheme 4: Compound 7: To 7-bromo-benzothiophene (3, 34.6 g, 0.16 mmol) in THF (346 mL) at -78 °C was added TMSCl (41.1 mL, 0.32 mmol) followed by LDA (Aldrich, 162 mL, 2 M, 0.32 mmol). After 1 h, workup with 1 N HCl and MTBE followed by plug filtration through silica gel with hexanes afforded 52.8 g (ethylbenzene corrected = 47.5 g, 100%) of 7-bromo-2-trimethylsilyl-benzothiophene(7) as an oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.76 (dd, 1 H, J = 7.7, 0.8 Hz), 7.56 (s, 1 H), 7.47 (dd, 1 H, J = 7.7, 0.8 Hz), 7.22 (t, 1 H, J = 7.7 Hz), 0.40 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 145.0, 143.5, 141.95, 131.5, 126.9, 125.4, 122.3, 115.6, -0.4). MS: m/z = 284 [M⁺]. Anal. Calcd for C₁₁H₁₃BrSSi: C, 46.31; H, 4.59. Found: C, 46.07; H, 4.65. Compound 8: To 7 (2.67 g, 9.36 mmol) in THF (15 mL) at -78 °C was added n-BuLi (2.5 M in hexanes, 4.5 mL, 11.3 mmol, 1.2 equiv). After 10 min, a solution of piperidone 2 (2.25 g, 11.3 mmol, 1.2 equiv) in THF (12 mL) was added. After 1 h, workup with 1 N HCl and toluene afforded 5.62 g of crude 8. Reslurry in 20% EtOAc/hexane afforded 2.63 g (69%) of 8 as a solid. The filtrate was chromatographed on flash silica gel to afford 0.84 g (yield = 3.47 g, 92%): mp 153-158 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.74 (dd, 1 H, J = 7.7, 1.1 Hz), 7.48 (s, 1 H), 7.32 (t, 1 H, J = 7.7, 7.4 Hz), 7.23 (dd, 1 H, J = 7.4, 1.1 Hz), 4.04 (br s, 2 H), 3.30 (br t, 2 H), 2.16 (br t, 2 H), 2.09 (s, 1 H), 1.99 (d, 2 H, J = 12.9 Hz), 1.48 (s, 9 H), 0.38 (t, 9 H, J = 3.6 Hz). ¹³C NMR (75 MHz, DMSO): δ = 154.0, 143.5, 142.1, 141.8, 139.2, 130.8, 124.2, 122.3, 120.0, 78.5, 70.9, 35.7, 28.1, 0.38. MS: m/z = 406 (M⁺). Compound 1: A solution of alcohol 8 (1.09 g, 2.68 mmol), toluene (10 mL) and 6 N HCl (10 mL) was heated at reflux for 5 h. The layers were separated and the acid layer was washed with toluene. The acid layer was made basic with 5 N NaOH (pH = 12-13) and extracted with EtOAc. The extracts were concentrated to afford 0.52 g of 1. To 1 (7.73 g, 35.9 mmol) in EtOH (65 mL) at reflux was added a solution of oxalic acid (3.23 g, 35.9 mmol) in EtOH (15 mL). The mixture was allowed to cool and product was collected and dried to afford 8.93 g (87%) of 1·oxalic acid: mp 192-193 °C (dec). ¹H NMR (300 MHz, DMSO): δ = 8.48 (br s, 3 H), 7.84 (d, 1 H, J = 7.9 Hz), 7.79 (d, 1 H, J = 5.5 Hz); 7.51 (d, 1 H, J = 5.8 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 7.32 (d, 1 H, J = 7.3 Hz), 6.29 (s, 1 H), 3.83 (s, 2 H), 3.35 (t, 2 H, J = 5.8 Hz), 2.76 (s, 2 H). ¹³C NMR (62.5 MHz, DMSO): δ = 164.9, 140.4, 136.6, 135.3, 135.2, 127.5, 124.7, 124.6, 123.3, 122.2, 120.0, 41.23, 40.13, 24.8. MS: m/z = 216 [MH⁺]. Anal. Calcd for C₁₃H₁₃BrNS·C₂H₂O₄: C, 59.00; H, 4.95; N, 4.59. Found: C, 59.04; H, 4.65; N, 4.33.

19

Prepared by alkylation of 2-bromo-5-fluorophenol with bromoacetaldehyde diethylacetal, followed by Amberlyst-15 catalyzed cyclization, see ref. [3] Compound 9: ¹H NMR (300 MHz, DMSO): δ = 8.18 (d, 1 H, J = 2 Hz), 7.56 (dd, 1 H, J = 9, 5 Hz), 7.21 (d, 1 H, J = 2 Hz), 7.10 (dd, 1 H, J = 9, 9 Hz). ¹³C NMR (75 MHz, DMSO): δ = 156.3, 153.0, 147.3, 127.6, 127.5, 117.5, 117.2, 110.4, 110.2, 103.8, 98.4, 98.3. MS: m/z = 214, 216 (M⁺ for two Br isotopes).

20

p-TsOH in toluene at reflux provided higher yields than aq HCl in the deprotection of this substrate.

22

The silyl protection strategy was also applied to the synthesis of reduced piperidine iii shown below (Scheme [7] ). The ionic reduction conditions were optimized to avoid elimination to the alkene or premature removal of the Boc group: To alcohol ii (458 g, 1.09 mol) and Et₃SiH (871 mL, 5.46 mol, 5 equiv), in CH₂Cl₂ (4.6 L) at -30 °C was added TFA (420 mL, 5.45 mol, 5 equiv) over 35 min. After warming to 13 °C over 2.5 h, 420 mL of TFA was added. After 3.5 h at r.t., a mixture of ice (6 L), H₂O (5 L), and 12 M NaOH (628 mL) was added. The layers were separated and the aqueous layer was extracted with CH₂Cl₂. The organic layers were dried (Na₂SO₄) and concentrated. The oil was dissolved in 4 L of Et₂O and HCl/EtOAc was added until the pH measured 2-3. The solid was collected and dried to afford 271 g (93%) of iii·HCl: ¹H NMR (500 MHz, DMSO): δ = 2.10-2.20 (m, 2 H), 2.30 (m, 2 H), 2.42 (s, 3 H), 2.93 (m, 1 H), 3.00-3.10 (m, 2 H), 3.69 (m, 2 H), 7.09 (s, 1 H), 7.25 (d, 1 H, J = 6 Hz), 7.57 (s, 1 H), 7.80 (d, 1 H, J = 6 Hz), 9.62 (br s, 1 H), 9.88 (br s, 1 H). ¹³C NMR (62.5 MHz, DMSO): δ = 13.5, 29.6, 38.9, 43.4, 119.3, 122.7, 12.9, 123.2, 131.5, 137.7, 139.6, 140.9. MS: m/z = 231 [M⁺]. Anal. Calcd for C₁₄H₁₈ClNS: C, 62.79; H, 6.77; N, 5.23. Found: C, 62.66; H, 6.65; N, 5.24.

24

Compound 18 is the first reported 2-TIPS benzothiophene. ¹H NMR (500 MHz, CDCl₃): δ = 1.22 (d, 18 H, J = 7 Hz), 1.49 (septet, 3 H, J = 7 Hz), 7.39 (m, 2 H), 7.57 (m, 1 H), 7.90 (m, 1 H), 7.96 (d, 1 H, J = 12 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 143.6, 141.0, 136.7, 132.6, 124.0, 123.8, 123.4, 122.0, 18.7, 11.9. MS: m/z = 290 [M⁺]. Anal. Calcd for C₁₇H₂₆SSi: C, 70.28; H, 9.02. Found: C, 70.06; H, 9.16.

26

Alcohol 20 was isolated as a 10:1 mixture containing an inseparable impurity tentatively identified as the isomeric 4-substituted benzothiophene.