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<A NAME="RY00404ST-8A">8a</A> Due to cost and waste disposal issues, the classical approach using CeCl3 was not investigated, see:
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<A NAME="RY00404ST-8B">8b</A> The organotitanium reagent made from ClTi(Oi-Pr)3 was unreactive, see:
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In these cases silicon directs the initial metalation, rather than preventing a subsequent
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Tetrahydropyridine 1 was isolated as the oxalate salt to aid in purification and to provide a stable solid
for storage.
<A NAME="RY00404ST-16">16</A>
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.
2-Silyl benzofurans:
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Hart DJ.
Mannino A.
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Mohamadi F, and
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<A NAME="RY00404ST-19">19</A>
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).
<A NAME="RY00404ST-20">20</A>
p-TsOH in toluene at reflux provided higher yields than aq HCl in the deprotection
of this substrate.
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Rizzo JR,
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<A NAME="RY00404ST-22">22</A>
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.
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Kuehm-Caubere C.
Adach-Becker S.
Fort Y.
Caubere P.
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<A NAME="RY00404ST-23B">23b</A> Partial conversion to a 2,7-dianion has been reported:
Chadwick DJ.
Willbe C.
J. Chem. Soc., Perkin Trans. 1
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<A NAME="RY00404ST-24">24</A>
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.
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Bates RB.
Kroposki LM.
Potter DE.
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1972,
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560
<A NAME="RY00404ST-26">26</A>
Alcohol 20 was isolated as a 10:1 mixture containing an inseparable impurity tentatively identified
as the isomeric 4-substituted benzothiophene.