Lithiated benzothiophenes and benzofurans require 2-silyl protection to avoid anion migration

Article abstract of DOI:10.1055/s-2004-825609

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.

Full text of DOI:10.1055/s-2004-825609

LETTER
1351
Lithiated Benzothiophenes and Benzofurans Require 2-Silyl Protection to
Avoid Anion Migration
Lithiated
B
enzothioph
a
enes and Be
r
nzofura
v
2
i
-Silyl
P
n
rotection M. Hansen,*a Marcella T. Clayton,a Alexander G. Godfrey,a John L. Grutsch Jr.,a Sandra S. Keast,a
Dan T. Kohlman,b Andreea R. McSpadden,a Steven W. Pedersen,a Jeffrey A. Ward,a 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
Received 5 February 2004
Dedicated to Professor Clayton H. Heathcock on the occasion of his retirement
Grignard addition to piperidone 2 has been reported to
Abstract: 2-Trimethylsilyl protection of benzothiophenes and ben-
proceed in low yield due to competing attack of the
zofurans prevents anion migration to the 2-position when lithiated
species are formed. These lithiated benzothiophenes and benzo-
furans provide superior results in additions to piperidones. De-
Grignard reagent on the Boc group.2a In our hands, addi-
tion of piperidone 2 to the Grignard reagent of bromide 33
protection is conveniently achieved under acidic conditions. Direct in THF at reflux, afforded a 2:1 ratio of tertiary alcohol 4
C-7 metalation of benzothiophene is enabled by 2-triisopropylsilyl
protection at C-2.
and quenched benzothiophene (5), but no evidence for
Boc removal (Scheme 2).4 Enolization of piperidone 2 is
the most likely explanation for these results.5 Enolization
Key words: lithiation, metalation, benzothiophene, silyl protecting
group, piperidone addition reactions
by a Grignard reagent is normally a minor side reaction
except for hindered or unusually acidic ketones.6 Piperi-
done 2 may have increased acidity due to the inductive
As key intermediates in the synthesis of the dual SSRI/ effect of the N-Boc group.7,8
5HT1A antagonist LY433221 and related compounds, we
required an efficient large-scale synthesis of 4-ben-
1) Mg, THF,
reflux
HO
zothiophene substituted tetrahydropyridine derivatives
+
Br
such as 1 (Scheme 1).1 Related 4-aryltetrahydropyridines
S
BocN
2) 2, add
over 1 min,
reflux
S
S
are of general interest due to their wide range of biological
activities.2 An ideal approach to this class of compounds
seemed to be addition of a Grignard reagent derived from
7-bromobenzothiophene (3) to 1-Boc-4-piperidone (2),
followed by acid catalyzed elimination and deprotection
(Scheme 1). We report herein that optimal implementa-
tion of the chemistry in Scheme 1 requires C-2 protection
with a trimethylsilyl (TMS) group and formation of the
7-lithio anion. An extension of this protection strategy
enables direct C-7 lithiation of 2-triisopropyl-silyl-
benzothiophene. This novel strategy allows direct access
to 7-substituted benzothiophenes.
4
5
3
ratio – 2:1
Scheme 2
Utilization of the more reactive lithium anion should
allow operation at low temperature where enolization side
reactions are normally suppressed. The 7-lithio anion was
prepared by treatment of bromide 3 in THF with n-BuLi
in hexanes at –78 °C for five minutes. Addition of piperi-
done 2 afforded the expected products 4 and 5 along with
by-product 6 in a ratio of 5:1:1 (Scheme 3). By-product 6
is derived from proton transfer from the more acidic 2-po-
sition. Formation of the 2-isomer was eliminated by add-
ing n-BuLi last to a mixture of bromide 3 and ketone 2 in
THF at –78 °C, but complete conversion of bromide 3
required 1.5 equivalents of n-BuLi due to competing
reaction with the ketone.
O
S
N
N
LY433221
O
1) n-BuLi, THF,
HO
+
–78 °C, 5 min
Br
BocN
Br
S
4 + 5 +
S
HN
S
S
BocN
2) 2, –78 °C
1
2
3
6
3
ratio – 5:1:1
Scheme 1
Scheme 3
SYNLETT 2004, No. 8, pp 1351–1354
0
1.
0
7.
2
0
0
4
Advanced online publication: 04.06.2004
DOI: 10.1055/s-2004-825609; Art ID: Y00404ST
© Georg Thieme Verlag Stuttgart · New York

1352
M. M. Hansen et al.
LETTER
The rearrangement of benzothiophene anions to the ther- product 10 and the bis-silylated product 11. These com-
modynamically favored 2-position is known.9 Although pounds could be separated by chromatography, but it was
proton transfer may be suppressed by use of a less polar more convenient to carry the mixture directly into the
solvent, metal-halogen exchange rates are slowed and an- metal-halogen exchange/addition step to afford a mixture
ion solubility issues became problematic with bromide of mono- and bis-silylated products 12 and 13 in 72%
3.10 Blocking the 2-position with a silyl group is common- yield. Both products were conveniently deprotected under
ly used to solve this problem in metalation of aryl,11 or acidic conditions to afford the 4-substituted tetrahydropy-
thiophene rings,12 but has been rarely applied to ben- ridine oxalate salt 14 in 75% yield.20 Subsequently it was
zothiophene chemistry.13 This strategy was successfully shown that the mono-silylated benzofuran 10 could be ob-
applied to 7-bromobenzothiophene (3) and related mole- tained with <1% of bis-silylated 11 by silylation with 1.3
cules as described below.
equivalents of LDA and 1.3 equivalents of TMSCl in
THF/chlorobenzene at –78 °C.
Treatment of bromide 3 with two equivalents of lithium
diisopropylamide (LDA) and two equivalents of commer- Additions to hindered N-benzylpiperidone 1621 highlight-
cial trimethylsilyl chloride (TMSCl) afforded the silyl- ed the benefit of lithio anion 15b relative to the Grignard
protected bromide 7 in quantitative yield (Scheme 4). Use
of excess reagents allowed the reaction to be driven to
completion without use of purified TMSCl. Metal-halo-
gen exchange of protected bromide 7 in THF at –60 °C
afforded a stable organolithium species. Addition of pip-
eridone 2 as a solution in THF at –60 °C afforded the de-
sired addition product 8 in 92% yield. This is a dramatic
improvement over the 40–60% yields that were typical us-
ing the Grignard chemistry. Silyl deprotection can be
achieved under basic or acidic conditions.14 As shown in
Scheme 4, deprotection occurred readily in 91% yield
with 6 N HCl and toluene at reflux, the standard condi-
tions used for Boc deprotection and alcohol dehydration.
The overall process from 7-bromobenzothiophene (3)
proceeded in 84% yield and required only one step for the
silyl protection strategy, since protiodesilylation occurred
during Boc removal/dehydration.15,16 Conversion of tet-
rahydropyridine 1 to LY433221 will be described in due
course.
reagent 15a (Scheme 5). Due to steric hindrance, enoliza-
tion by the Grignard reagent was now the major reaction.
Simple substitution of the lithium reagent 15a in this se-
quence led to a dramatically improved 66% yield of 17
over the same two steps.22
O
1)
BnN
M
2) H+
16
S
S
BnN
R
17
15a
15b
M = MgBr, R = H
M = Li, R = SiMe3
5% yield
66% yield
Scheme 5
After demonstrating that 2-silyl protection of ben-
zothiophenes allowed generation of a stable 7-lithio anion
by metal-halogen exchange, it was of interest to see if di-
rected ortho lithiation of a 2-silyl protected ben-
zothiophene could give access to the same species.
Although metalation of related dibenzothiophenes has
been achieved, the C-7 directed metalation of ben-
zothiophenes has not been reported.23 Initially ben-
zothiophene (5) was converted to the 2-TMS derivative
and treated with n-BuLi in THF at room temperature. Af-
ter addition of piperidone 2, a mixture of 7-substituted and
2-susbstituted products was obtained, indicating competi-
tion between deprotonation at C-7 and nucleophilic silyl
removal at C-2. In order to prevent attack at silicon, the
triisopropylsilyl (TIPS) derivative 18 was prepared
(Scheme 6).24 Complete metalation of TIPS protected 18
could not be achieved using n-BuLi in THF without com-
peting reaction with THF.25 Metalation using 1.5 equiva-
lents of n-BuLi and 1.5 equivalents of TMEDA in hexane
at room temperature, followed by addition of ketone 2 in
THF at –78 °C afforded a 76% yield of the desired 7-sub-
stituted benzothiophene 20.26 Tandem alcohol dehydra-
tion and deprotection using TFA occurred analogously to
the TMS derivative to provide tetrahydropyridine 1. This
novel approach to 7-substituted benzothiophenes avoids
dealing with the odiferous bromo thiophenol precursors
that lead to the bromo substituted benzothiophenes used
above. This strategy should find further application in
benzothiophene synthesis.
Z
2 equiv LDA
Y
1) n-BuLi, THF,
Y
2 equiv TMSCl
–60 °C, 5 min
THF, –70 °C
2) 2, –60 °C
Br
Br
X
X
SiMe3
7
X = S, Y = H, Z = H
3 X = S, Y = H
9 X = O, Y = F
10 X = O, Y = F, Z = H
11 X = O, Y = F, Z = TMS
Z
1) 6N HCl,
Y
Y
tol, reflux
2) oxalic acid,
EtOH
(CO2H)2
HN
HO
X
BocN
X
SiMe3
1•oxalic acid
X = S, Y = H
14•oxalic acid
X = O, Y = F
8 X = S, Y = H, Z = H
12 X = O, Y = F, Z = H
13 X = O, Y = F, Z = TMS
Scheme 4
The benzothiophene silyl protection strategy was applied
to the preparation of the related benzofuran 14
(Scheme 4).17 The 4-fluoro group complicated the robust
and simple silylation conditions described above, due to
the ortho directing ability of the fluorine.18 Treatment of
7-bromo-4-fluorobenzofuran (9)19 with excess LDA and
excess TMSCl afforded a 1:1 mixture of mono-silylated
Synlett 2004, No. 8, 1351–1354 © Thieme Stuttgart · New York

LETTER
Lithiated Benzothiophenes and Benzofurans Require 2-Silyl Protection
1353
(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).
1.5 equiv n-BuLi,
1.5 equiv TMEDA,
hexane, r.t., 20 h
LDA, TIPSCl,
THF, r.t., 3 d
S
S
98%
Si
(i-Pr)3
18
5
(8) (a) 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.
(b) The organotitanium reagent made from ClTi(Oi-Pr)3 was
unreactive, see: Hutton, J.; Jones, A. D.; Lee, S. A.; Martin,
D. M. G.; Meyrick, B. R.; Patel, I.; Peardon, R. F.; Powell,
L. Org. Process Res. Dev. 1997, 1, 61. (c) TMEDA as an
additive was not investigated, but has been reported to
suppress enolization in a related case, see: Herrinton, P. M.;
Owen, C. E.; Gage, J. R. Org. Process Res. Dev. 2001, 5, 80.
(9) (a) Dickinson, R. P.; Iddon, B. J. Chem. Soc. C 1968, 2733.
(b) Dickinson, R. P.; Iddon, B. J. Chem. Soc. C 1971, 3447.
(c) Scrowston, R. M. Recent Advances in the Chemistry of
Benzo[b]thiophenes, In Advances in Heterocyclic
TFA,
CH2Cl2,
r.t., 3.5 h
S
Ketone 2,
THF,
HO
Li
–78 °C
S
BocN
1
Si
(i-Pr)3
63%
76%
Si
(i-Pr)3
20
19
Scheme 6
In conclusion we have shown that 2-TMS protected
benzothiophene and benzofuran substrates enable metal-
halogen exchange to provide useful lithiated intermedi-
ates. These lithiated intermediates provide superior results
in additions to ketones relative to the corresponding
Grignard reagents. 2-TIPS protection of benzothiophene
allows directed metalation at C-7, providing an expedient
route to 7-susbstituted benzothiophenes.
Chemistry, Vol 29; Katritzky, A. R., Ed.; Academic Press:
London, 1981, 171–249. (d) Rajappa, S.; Natekar, M. V.
Thiophenes and their Benzo Derivatives: Reactivity, In
Comprehensive Heterocyclic Chemistry II, Vol 2; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996, 419–606. (e) See ref.8b
(10) Wu, X.; Chen, T.; Zhu, L.; Rieke, R. D. Tetrahedron Lett.
1994, 35, 3673.
(11) Snieckus, V. Chem. Rev. 1990, 90, 879.
Acknowledgment
(12) (a) Samanta, S. S.; Ghosh, S. C.; De, A. J. Chem. Soc.,
Perkin Trans. 1 1997, 2683. (b) Sakamoto, Y.; Komatsu, S.;
Suzuki, T. J. Am. Chem. Soc. 2001, 123, 4643.
(13) In these cases silicon directs the initial metalation, rather
than preventing a subsequent proton transfer: (a) Kamila,
S.; Mukherjee, C.; Mondal, S. S.; De, A. Tetrahedron 2003,
59, 1339. (b) Ghosh, S. C.; De, A. J. Chem. Soc., Perkin
Trans. 1 1999, 3705. (c) Mandal, S. S.; Samanta, S. S.; Deb,
C.; De, A. J. Chem. Soc., Perkin Trans. 1 1998, 2559.
(14) See ref.11
We thank Dr. Vincent Rocco and Dr. Jean Takeuchi for helpful ad-
vice and the Lilly Research Laboratories Physical Chemistry group
for characterization data. We thank Eli Lilly and Company for a
Summer Intern Fellowship for A. R. McSpadden.
References
(1) Hertel, L. W.; Kohlman, D. T.; Liang, S. X.; Wong, D. T.;
Xu, Y. PCT Int. Appl., WO 00/000198, 2000.
(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
(2) (a) Wustrow, D. J.; Wise, L. D. Synthesis 1991, 993.
(b) Eastwood, P. R. Tetrahedron Lett. 2000, 41, 3705.
(c) Glase, S. A.; Akunne, H. C.; Heffner, T. G.; Jaen, J. C.;
MacKenzie, R. G.; Meltzer, L. T.; Pugsley, T. A.; Smith, S.
J.; Wise, L. D. J. Med. Chem. 1996, 39, 3179.
(d) Zimmerman, D. M.; Cantrell, B. E.; Reel, J. K.; Hemrick-
Luecke, S. K.; Fuller, R. W. J. Med. Chem. 1986, 29, 1517.
(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.
(ethylbenzene corrected = 47.5 g, 100%) of 7-bromo-2-
trimethylsilyl-benzothiophene(7) as an oil. 1H NMR (300
MHz, CDCl3): d = 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): d = 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): d = 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): d = 154.0, 143.5,
(4) Product ratios assigned by reverse phase high-pressure
liquid chromatography (HPLC). No other products observed
by HPLC.
(5) For reports of moderate yields where enolization is likely,
see: (a) 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. (b) Annoura, H.; Nakanishi, K.; Uesugi, M.;
Fukunaga, A.; Imajo, S.; Miyajima, A.; Tamura-Horikawa,
Y.; Tamura, S. Bioorg. Med. Chem. Lett. 2002, 10, 371.
(c) Sui, Z.; De Voss, J. J.; DeCamp, D. L.; Li, J.; Craik, C.
S.; Ortiz de Montellano, P. R. Synthesis 1993, 803.
(6) March, J. Advanced Organic Chemistry, Reactions
Mechanisms and Structure, 4th ed.; John Wiley and Sons:
New York, 1992, 926–927.
Synlett 2004, No. 8, 1351–1354 © Thieme Stuttgart · New York

1354
M. M. Hansen et al.
LETTER
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): d = 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): d = 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.
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): d = 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): d = 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.
1) TMSCl, LDA
2) n-BuLi
3) 2
Me
BocN
Me
OH
Br
SiMe3
79%
S
S
i
(17) 2-Silyl benzofurans: (a) Hart, D. J.; Mannino, A.
Tetrahedron 1996, 52, 3841. (b) Mohamadi, F.; Spees, M.
US 5,169,860, 1992. (c) 2-Silyl furans: Keay, G. Chem. Soc.
Rev. 1999, 28, 209.
(18) (a) Black, W. C.; Guay, G.; Scheuermeyer, F. J. Org. Chem.
1997, 62, 758. (b) Moyroud, J.; Guesnet, J.; Bennetau, B.;
Mortier, J. Tetrahedron Lett. 1995, 36, 881.
ii
1) 5 equiv TFA, 5 equiv Et3SiH,
CH2Cl2, –30 °C
2) 5 equiv TFA, r.t.
3) HCl
HCl·HN
Me
S
93%
iii•HCl
(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): d = 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): d = 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.
(21) Rizzo, J. R.; Staszak, M. A.; Zhang, T. Y. PCT Int. Appl.,
WO 01/00577, 2001.
(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
Scheme 7
(23) (a) Kuehm-Caubere, C.; Adach-Becker, S.; Fort, Y.;
Caubere, P. Tetrahedron 1996, 52, 9087. (b) Partial
conversion to a 2,7-dianion has been reported: Chadwick, D.
J.; Willbe, C. J. Chem. Soc., Perkin Trans. 1 1977, 887.
(24) Compound 18 is the first reported 2-TIPS benzothiophene.
1H NMR (500 MHz, CDCl3): d = 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): d = 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.
(25) Bates, R. B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem.
1972, 37, 560.
(26) Alcohol 20 was isolated as a 10:1 mixture containing an
inseparable impurity tentatively identified as the isomeric 4-
substituted benzothiophene.
Synlett 2004, No. 8, 1351–1354 © Thieme Stuttgart · New York