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Synlett 2004(8): 1351-1354  
DOI: 10.1055/s-2004-825609
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Marvin M. Hansen*a, Marcella T. Claytona, Alexander G. Godfreya, John L. Grutsch Jr.a, Sandra S. Keasta, Dan T. Kohlmanb, Andreea R. McSpaddena, Steven W. Pedersena, Jeffrey A. Warda, Yao-Chang Xub
a Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indiananapolis, IN 46285, USA
b Discovery Chemistry, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indiananapolis, IN 46285, USA
Fax: +1(317)2764507; e-Mail: mmh@lilly.com;
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Publication History

Received 5 February 2004
Publication Date:
04 June 2004 (online)

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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

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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., 215th 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.