Subscribe to RSS
DOI: 10.1055/s-2004-825609
Lithiated Benzothiophenes and Benzofurans Require 2-Silyl Protection to Avoid Anion Migration
Publication History
Publication Date:
04 June 2004 (online)
![](https://www.thieme-connect.de/media/synlett/200408/lookinside/thumbnails/10.1055-s-2004-825609-1.jpg)
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
- 1
Hertel LW,Kohlman DT,Liang SX,Wong DT, andXu Y. inventors; PCT Int. Appl., WO 00/000198. -
2a
Wustrow DJ.Wise LD. Synthesis 1991, 993 -
2b
Eastwood PR. Tetrahedron Lett. 2000, 41: 3705 -
2c
Glase SA.Akunne HC.Heffner TG.Jaen JC.MacKenzie RG.Meltzer LT.Pugsley TA.Smith SJ.Wise LD. J. Med. Chem. 1996, 39: 3179 -
2d
Zimmerman DM.Cantrell BE.Reel JK.Hemrick-Luecke SK.Fuller RW. J. Med. Chem. 1986, 29: 1517 - For reports of moderate yields where enolization is likely, see:
-
5a
Merschaert A.Delhaye L.Kestemont J.Brione W.Delbeke P.Mancuso V.Napora F.Diker K.Giraud D.Vanmarsenille M. Tetrahedron Lett. 2003, 44: 4531 -
5b
Annoura H.Nakanishi K.Uesugi M.Fukunaga A.Imajo S.Miyajima A.Tamura-Horikawa Y.Tamura S. Bioorg. Med. Chem. Lett. 2002, 10: 371 -
5c
Sui Z.De Voss JJ.DeCamp DL.Li J.Craik CS.Ortiz de Montellano PR. Synthesis 1993, 803 - 6
March J. Advanced Organic Chemistry, Reactions Mechanisms and Structure 4th ed.: John Wiley and Sons; New York: 1992. p.926-927 -
8a Due to cost and waste disposal issues, the classical approach using CeCl3 was not investigated, see:
Liu H.Shia K.Shang X.Zhu B. Tetrahedron 1999, 55: 3803 -
8b The organotitanium reagent made from ClTi(Oi-Pr)3 was unreactive, see:
Hutton J.Jones AD.Lee SA.Martin DMG.Meyrick BR.Patel I.Peardon RF.Powell L. Org. Process Res. Dev. 1997, 1: 61 -
8c TMEDA as an additive was not investigated, but has been reported to suppress enolization in a related case, see:
Herrinton PM.Owen CE.Gage JR. Org. Process Res. Dev. 2001, 5: 80 -
9a
Dickinson RP.Iddon B. J. Chem. Soc. C 1968, 2733 -
9b
Dickinson RP.Iddon B. J. Chem. Soc. C 1971, 3447 -
9c
Scrowston RM. Recent Advances in the Chemistry of Benzo[b]thiophenes, In Advances in Heterocyclic Chemistry Vol 29:Katritzky AR. Academic Press; London: 1981. p.171-249 -
9d
Rajappa S.Natekar MV. Thiophenes and their Benzo Derivatives: Reactivity, In Comprehensive Heterocyclic Chemistry II Vol 2:Katritzky AR.Rees CW.Scriven EFV. Pergamon; Oxford: 1996. p.419-606 -
9e
See ref. [8b]
- 10
Wu X.Chen T.Zhu L.Rieke RD. Tetrahedron Lett. 1994, 35: 3673 - 11
Snieckus V. Chem. Rev. 1990, 90: 879 -
12a
Samanta SS.Ghosh SC.De A. J. Chem. Soc., Perkin Trans. 1 1997, 2683 -
12b
Sakamoto Y.Komatsu S.Suzuki T. J. Am. Chem. Soc. 2001, 123: 4643 - In these cases silicon directs the initial metalation, rather than preventing a subsequent proton transfer:
-
13a
Kamila S.Mukherjee C.Mondal SS.De A. Tetrahedron 2003, 59: 1339 -
13b
Ghosh SC.De A. J. Chem. Soc., Perkin Trans. 1 1999, 3705 -
13c
Mandal SS.Samanta SS.Deb C.De A. J. Chem. Soc., Perkin Trans. 1 1998, 2559 - 2-Silyl benzofurans:
-
17a
Hart DJ.Mannino A. Tetrahedron 1996, 52: 3841 -
17b
Mohamadi F, andSpees M. inventors; US 5,169,860. -
17c 2-Silyl furans:
Keay G. Chem. Soc. Rev. 1999, 28: 209 -
18a
Black WC.Guay G.Scheuermeyer F. J. Org. Chem. 1997, 62: 758 -
18b
Moyroud J.Guesnet J.Bennetau B.Mortier J. Tetrahedron Lett. 1995, 36: 881 - 21
Rizzo JR,Staszak MA, andZhang TY. inventors; PCT Int. Appl., WO 01/00577. -
23a
Kuehm-Caubere C.Adach-Becker S.Fort Y.Caubere P. Tetrahedron 1996, 52: 9087 -
23b Partial conversion to a 2,7-dianion has been reported:
Chadwick DJ.Willbe C. J. Chem. Soc., Perkin Trans. 1 1977, 887 - 25
Bates RB.Kroposki LM.Potter DE. J. Org. Chem. 1972, 37: 560
References
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.
4Product ratios assigned by reverse phase high-pressure liquid chromatography (HPLC). No other products observed by HPLC.
7Changes 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).
14See ref. [11]
15Tetrahydropyridine 1 was isolated as the oxalate salt to aid in purification and to provide a stable solid for storage.
16Procedures 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.
19Prepared 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).
20p-TsOH in toluene at reflux provided higher yields than aq HCl in the deprotection of this substrate.
22The 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.
24Compound 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.
26Alcohol 20 was isolated as a 10:1 mixture containing an inseparable impurity tentatively identified as the isomeric 4-substituted benzothiophene.