Silicon- and sulfur-mediated synthesis of benzoannulated cyclooctanols

Article abstract of DOI:10.1016/j.tetlet.2009.08.092

The reaction of a silyl-substituted thioacetal with ortho-difunctionalized benzenes as biselectrophiles allows access to multifunctional cyclooctanols.

Full text of DOI:10.1016/j.tetlet.2009.08.092

Tetrahedron Letters 50 (2009) 6187–6190
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silicon- and sulfur-mediated synthesis of benzoannulated cyclooctanols
*
Florian Genrich, Ernst Schaumann
Institut für Organische Chemie, Technische Universität Clausthal, Leibnizstraße 6, 38678 Clausthal-Zellerfeld, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of a silyl-substituted thioacetal with ortho-difunctionalized benzenes as biselectrophiles
allows access to multifunctional cyclooctanols.
Received 24 June 2009
Revised 19 August 2009
Accepted 26 August 2009
Available online 1 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Biselectrophiles
Epoxides
Thioacetals
Silyl-migration
Carbocycles
Cyclooctanes
1. Introduction
which is easily available from 2-carboxy-cinnamic acid.6,11 After
protection12 of the alcohol as TBS-ether, ester 313 is reduced14 to
Recently, our group has developed a flexible domino process for
the synthesis of carbocycles.1 This is based on the one-pot reaction
of silyl-substituted thioacetal carbanions as dianion equivalents
with epoxy-tosylates. Following epoxide ring opening by the carb-
anion, a reversible C?O silyl migration (Brook rearrangement)2 is
the key step. The method has been expanded using bis-epoxides,3
vinyl-epoxides,4 epoxy-aziridines5 or multifunctional esters6–8 as
biselectrophilic reaction partners of the carbanion. Best results
are usually obtained for cyclopentane synthesis, while the seven-
membered rings are only obtained in modest yields. So the method
does not seem attractive for the synthesis of eight-membered
rings.9 Still, the synthesis of cyclooctanols would be quite interest-
ing, taking into account the limited accessibility to this ring
system. Now we reasoned that the formation of the larger ring
might be favoured by a benzene unit as backbone in the carbon
chain connecting an oxirane moiety and a leaving group as electro-
philic centres (Scheme 1). Here we report our encouraging results
which nicely complement the existing methods10 for benzocyc-
looctane synthesis.
benzyl alcohol 415 by DIBAL in high yield (Scheme 3).
The hydroxy group of compound 4 is converted16 into THP-
ether 517 by acid-catalyzed addition to 3,4-dihydro-2H-pyran.
Desilylation with TBAF provides alcohol 618 which is oxidized to
the corresponding aldehyde 719 using IBX20 in DMSO. Aldehyde 7
can alternatively be synthesized in two steps from 2-iodo-benzyl
alcohol 12.21
Me3Si
SMe
SMe
SMe
SMe
=
1
SMe
SMe
SMe
SMe
Scheme 1. A silyl-substituted thioacetal as 1,1-dianion equivalent and 1,7-
biselectrophiles as synthons for the Si-induced domino synthesis of eight-
membered carbocycles.
2. Results and discussion
O
CO2Me
Cl
For the two promising biselectrophiles 11 and 18 retro synthe-
sis leads to hydroxyester 2 as a common precursor (Scheme 2),
OH
Br
2
11
18
O
* Corresponding author. Tel.: +49 5323 72 2519; fax: +49 5323 72 2858.
E-mail address: ernst.schaumann@tu-clausthal.de (E. Schaumann).
Scheme 2. Retro synthesis of two biselectrophiles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.092

6188
F. Genrich, E. Schaumann / Tetrahedron Letters 50 (2009) 6187–6190
Scheme 3. Synthesis of biselectrophile 11. Reagents and conditions: (a) TBSCl (1.2 equiv), imidazole (1.5 equiv), CH2Cl2, room temperature, 24 h; (b) DIBAL (2.2 equiv),
toluene, À78 °C, 35 min; (c) DHP (1.5 equiv), p-TsOHÁH2O (5 mol %), CH2Cl2, room temperature, 20 h; (d) TBAFÁ3H2O (1.5 equiv), THF, room temperature, 60 min; (e) IBX
(1.1 equiv), DMSO, room temperature, 20 h; (f) MePPh3Br (1.5 equiv), NaHMDS (2 equiv), THF, 0 °C?room temperature, 18 h; (g) p-TsOHÁH2O (5 mol %), MeOH, room
temperature, overnight; (h) CCl4 (1.7 equiv), PPh3 (1.5 equiv), CH2Cl2, 0 °C?room temperature, 2.5 d; (i) m-CPBA (1.4 equiv), CH2Cl2, room temperature, 6.5 h; (j) DHP
(1.5 equiv), p-TsOHÁH2O (5 mol %), CH2Cl2, room temperature, 70 h; (k) allyl alcohol (1.5 equiv), TBAB (1 equiv), Pd(OAc)2 (2 mol %), KHCO3 (2 equiv), DMF, 90 °C, 2 h.
The aldehyde is then transformed into olefin 822 by a Wittig
reaction using methyl-triphenylphosphonium bromide. Acid-cata-
lyzed deprotection of the THP-ether to benzyl alcohol 9,23 followed
by an Appel reaction, yields chloride 10,24 which is oxidized to
epoxide 1125 using m-CPBA.
For the synthesis of the second C7-building block 18 (Scheme 4),
benzyl alcohol 4 is first oxidized to benzaldehyde 1426 by IBX20 in
DMSO. The reduction of ester 3 by DIBAL cannot be stopped at the
stage of the aldehyde, so that it is necessary to prepare compound
14 in two steps.
The Wittig reaction of aldehyde 14 with methyl-triphenylphos-
phonium bromide yields styrene 1527, which is then deprotected to
alcohol 1628 by TBAF. An Appel reaction29 with carbon tetrabro-
mide and triphenylphosphine leads to compound 17,30 which is
finally transformed into the biselectrophilic bromo-epoxide 1831
by m-CPBA in high yield.
lation with an excess of TBAF (yield 4%) finally providing pure 20 in
46% yield.
Compound 20 could not be characterized by standard 200 MHz
NMR measurements in CDCl3. The multiple possible conformations
of the eight-membered ring made some methylene groups unde-
tectable in the 13C NMR spectrum. Also signals in the 1H NMR spec-
trum were indistinct broad multiplets. Finally a 400 MHz NMR
analysis in deuterated DMSO at 55 °C gave sharp signals as ring
inversion becomes sufficiently fast on the NMR time scale. So
cyclooctanol 20 could be fully characterized by 1H–13C-HSQC,
1H–1H-COSY and 1H–13C-HMBC correlation spectroscopy.
The epoxide function of the second biselectrophile, styrene
oxide 18, turned out to be less reactive (Scheme 6). Employing
the corresponding chloride or tosylate in the domino process gave
no carbocycle. Nevertheless a second cyclooctanol is prepared in
three steps. From the reaction of bromide 18 with carbanion 1 sily-
lated compound 23 is isolated in 54% yield.34 After desilylating
with TBAF, thioacetal 2435 can finally be cyclized by n-BuLi in the
presence of DMPU.36 DMPU as lithium complexing agent allows
deprotonation of the thioacetal CH-functionality at low tempera-
tures such as À78 °C so that the ring can selectively be formed
by intramolecular attack at the terminal carbon of the epoxide
ring. Cyclooctanol 25 is isolated in 36% yield along with 11% of
The reaction of benzyl chloride 11 with dianion equivalent 16,32
yields in fact the eight-membered carbocycle 19 in a one-pot dom-
ino process (Scheme 5).33 After work-up carbocycle 19 is separated
from side product 21 by flash chromatography. Compound 21 is
found in 14% yield and obviously results from substitution of the
chloride. Another contamination of silyl ether 19 by a trace of
the silylated derivative of alcohol 22 can be removed after desily-
CHO
a)
b)
OH
OTBS
OTBS
OTBS
96 %
93 %
4
14
15
c) 94 %
O
e)
d)
Br
Br
OH
90 %
87 %
18
17
16
Scheme 4. Reagents and conditions: (a) IBX (1.1 equiv), DMSO, room temperature, 21 h; (b) MePPh3Br (1.5 equiv), NaHMDS (2.0 equiv), THF, 0 °C?room temperature, 21 h;
(c) TBAFÁ3H2O (1.5 equiv), THF, room temperature, 60 min; (d) CBr4 (1.1 equiv), PPh3 (1.1 equiv), CH2Cl2, 0 °C?room temperature, 20 h; (e) m-CPBA (1.5 equiv), CH2Cl2, room
temperature, 18 h.

F. Genrich, E. Schaumann / Tetrahedron Letters 50 (2009) 6187–6190
6189
Scheme 5. Silicon-induced domino synthesis of cyclooctanol 20. Reagents and conditions: (a) 1 (1.3 equiv), THF, À78?À50 °C, 18 h; (b) TBAFÁ3H2O (3 equiv), THF, room
temperature, 30 min.
Scheme 6. Silicon–sulfur-mediated preparation of cyclooctanol 25. Reagents and conditions: (a) 1 (1.3 equiv), THF, À78?À30 °C, 21 h; (b) TBAF, THF; (c) n-BuLi (1.3 equiv),
DMPU (1.0 equiv), THF, 20 h at À78?0 °C + 7 h at room temperature.
7. Genrich, F. Dissertation, Technische Universität Clausthal, 2009.
8. Harms, G. Dissertation, Technische Universität Clausthal, 2001.
9. Reviews: (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881–930; (b) Petasis, N.
A.; Patane, M. A. Tetrahedron 1992, 48, 5757–5821.
10. (a) Khan, F. A.; Czerwonka, R.; Zimmer, R.; Reißig, H.-U. Synlett 1997, 995–997;
cycloheptane 26 and 36% of recovered starting material 24. For car-
bocycle 25 standard NMR analysis is possible in CDCl3 solution and
signals could be assigned by 1H–13C-HSQC, 1H–1H-COSY and
1H–13C-HMBC correlation techniques.
(b) Reißig, H.-U.; Khan, F. A.; Czerwonka, R.; Dinesh, C. U.; Shaikh, A. L.;
Zimmer, R. Eur. J. Org. Chem. 2006, 4419–4428.
3. Conclusion
11. Arth, C.; Clemens, M.; Meise, W. Liebigs Ann. Chem. 1994, 259–263.
12. Chanteau, S. H.; Tour, J. M. J. Org. Chem. 2003, 68, 8750–8766.
13. Selected data of compounds: Ester 3: Colourless liquid. 1H NMR (200 MHz,
CDCl3 = 7.26): d = 7.87–7.83 (m, 1H), 7.46–7.37 (m, 1H), 7.29–7.17 (m, 2H),
3.88 (s, 3H), 3.66 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 1.89–1.75 (m, 2H),
0.91 (s, 9H), 0.06 (s, 6H) ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 168.5,
144.4, 132.2, 131.4, 131.0, 130.0, 126.2, 63.1, 52.3, 35.0, 31.2, 26.4, 18.7, -
Applying the silicon-induced domino reaction of dianion equiv-
alent 1 to biselectrophile 11 containing an epoxide moiety and a
leaving group provides the eight-membered carbocycle 19 in a
one-pot reaction involving a [1,4]-silyl shift followed by ring clo-
sure. Cyclooctanol 25 is obtained exploiting the CH-acidity of the
thioacetal function in 24 by n-BuLi/DMPU for intramolecular cycli-
zation. Two isomeric cyclooctanols 20 and 25 are therefore avail-
able from hydroxyester 2.
4.9 ppm. IR (film):
m .
= 1726 (C@O), 1090 (OSi) cmÀ1
14. Davis, F. A.; Fanelli, D. L. J. Org. Chem. 1998, 63, 1981–1985.
15. Benzyl alcohol 4: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.38–7.34
(m, 1H), 7.25–7.15 (m, 3H), 4.70 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 7.5 Hz,
2H), 2.43 (s, 1H), 1.91–1.82 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H) ppm. 13C NMR
(50 MHz, CDCl3 = 77.4): d = 140.6, 139.2, 129.8 129.3, 128.4, 126.6, 63.6, 62.5,
34.5, 28.2, 26.3, 18.7, À4.9 ppm. IR (film):
m .
= 3346 (OH), 1100 (OSi) cmÀ1
16. Miura, K.; Hondo, T.; Okajima, S.; Nakagawa, T.; Takahashi, T.; Hosomi, A. J. Org.
Chem. 2002, 67, 6082–6090.
Acknowledgements
17. THP-ether 5: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.42–7.34 (m,
1H), 7.24–7.14 (m, 3H), 4.82 (d, J = 11.9 Hz, 1H), 4.76–4.70 (m, 1H), 4.52 (d,
J = 11.9 Hz, 1H), 3.98–3.87 (m, 1H), 3.67 (t, J = 6.3 Hz, 2H), 3.61–3.50 (m, 1H),
2.77–2.69 (m, 2H), 1.89–1.50 (m, 8H), 0.91 (s, 9H), 0.06 (s, 6H) ppm. 13C NMR
(50 MHz, CDCl3 = 77.4): d = 141.2, 136.3, 129.6, 129.4, 128.1, 126.3, 98.3, 67.2,
63.0, 62.5, 34.6, 31.0, 29.1, 26.4, 25.9, 19.8, 18.7, À4.9 ppm.
Support of our work by the Deutsche Forschungsgemeinschaft
(Scha 231/11) and by the Fonds der Chemischen Industrie, Frank-
furt, is gratefully acknowledged.
18. Alcohol 6: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.38–7.15 (m,
4H), 4.88 (d, J = 11.5 Hz, 1H), 4.73–4.69 (m, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.00–
3.89 (m, 1H), 3.63 (t, J = 6.0 Hz, 2H), 3.64–3.51 (m, 1H), 7.92–7.70 (m, 2H), 2.10
(s, 1H), 1.97–1.50, 8H) ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 141.2, 135.9,
130.2, 129.8, 128.6, 126.4, 98.6, 67.6, 63.1, 62.0, 34.3, 31.0, 28.3, 25.8,
References and notes
1. (a) Reviews: Schaumann, E.; Kirschning, A. Synlett 2007, 177–190. Kirschning,
A.; Kujat, C.; Luiken, S.; Schaumann, E. Eur. J. Org. Chem. 2007, 2387–2400; (b)
Fischer, M.-R.; Kirschning, A.; Michel, T.; Schaumann, E. Angew. Chem. 1994,
106, 220–221; Angew. Chem., Int. Ed. Engl. 1994, 33, 217–218.; (c) Michel, T.;
Kirschning, A.; Beier, C.; Bräuer, N.; Schaumann, E.; Adiwidjaja, G. Liebigs Ann.
Chem. 1996, 1811–1821; (d) Bräuer, N.; Michel, T.; Schaumann, E. Tetrahedron
1998, 54, 11481–11488.
20.0 ppm. IR (film):
m .
= 3417 (OH) cmÀ1
19. Aldehyde 7: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 9.84 (t,
J = 1.3 Hz, 1H), 7.39–7.14 (m, 4H), 4.83 (d, J = 11.8 Hz, 1H), 4.72–4.69 (m, 1H),
4.50 (d, J = 11.8 Hz, 1H), 3.96–3.85 (m, 1H), 3.61–3.51 (m, 1H), 3.07–2.97 (m,
2H), 2.87–2.76 (m, 2H), 1.93–1.50 (m, 6H) ppm. 13C NMR (50 MHz,
CDCl3 = 77.4): d = 202.0, 139.8, 136.2, 130.1, 129.6, 128.6, 126.9, 98.4, 67.6,
2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
m .
= 1723 (CHO) cmÀ1
3. Bräuer, N.; Dreeßen, S.; Schaumann, E. Tetrahedron Lett. 1999, 40, 2921–2924.
4. Tries, F.; Schaumann, E. Eur. J. Org. Chem. 2003, 1085–1090.
5. Harms, G.; Schaumann, E.; Adiwidjaja, G. Synthesis 2001, 577–580.
6. Genrich, F.; Harms, G.; Schaumann, E.; Gjikaj, M.; Adiwidjaja, G. Tetrahedron
2009, 65, 5577–5587.
62.7, 45.6, 31.0, 25.8, 25.2, 19.8 ppm. IR (film):
20. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537–4538.
21. Badone, D.; Bernassau, J.-M.; Cardamone, R.; Guzzi, U. Angew. Chem. 1996, 108
575–578; Angew. Chem. Int. Ed. Engl. 1996,35 535–538.

6190
F. Genrich, E. Schaumann / Tetrahedron Letters 50 (2009) 6187–6190
22. Olefin 8: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.42–7.37 (m, 1H),
7.30–7.15 (m, 3H), 6.00–5.80 (m, 1H), 5.12–4.96 (m, 2H), 4.83 (d, J = 11.9 Hz,
1H), 4.73 (t, J = 3.2 Hz, 1H), 4.51 (d, J = 11.9 Hz, 1H), 3.99–3.88 (m, 1H), 3.62–
3.52 (m, 1H), 2.81–2.74 (m, 2H), 2.42–2.31 (m, 2H), 1.95–1.51 (m, 6H) ppm. 13C
NMR (50 MHz, CDCl3 = 77.4): d = 140.9, 138.6, 136.2, 129.6, 129.5, 128.2, 126.4,
115.2, 98.3, 67.4, 62.5, 35.6, 32.2, 31.0, 25.9, 19.7 ppm.
at room temperature silica gel is added and the solvents are evaporated.
Purification by flash chromatography (SiO2, petroleum ether/EtOAc = 15:1, 6:1)
yields cyclooctanol 20 (156 mg, 46%). Colourless solid. Mp 101–103 °C; 1H
NMR (400 MHz, 55 °C, DMSO-d6 = 2.54): d = 7.25–7.12 (m, 4H), 4.45 (s, 1H),
3.92 (s, 1H), 2.99 (s, 2H), 2.83–2.71 (m, 2H), 2.16 (s, 3H), 2.13–2.06 (m, 1H),
2.11 (s, 3H), 1.81 (d, J = 14.6 Hz, 1H), 1.58–1.49 (m, 2H) ppm. 13C NMR
(100 MHz, 55 °C, DMSO-d6 = 40.4): d = 141.9, 134.8, 132.3, 129.8, 127.9, 126.0,
23. Ozaki, S.; Adachi, M.; Sekiya, S.; Kamikawa, R. J. Org. Chem. 2003, 68, 4586–
4589.
67.9, 63.5, 46.0, 41.2, 40.8, 30.5, 12.0, 11.5 ppm. IR (KBr):
m .
= 3362 (OH) cmÀ1
24. Wu, G. Z.; Lamaty, F.; Negishi, E. J. Org. Chem. 1989, 54, 2507–2508.
25. Biselectrophile 11: Colourless liquid. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.38–
7.17 (m, 4H), 4.65 (s, 2H), 3.04–2.83 (m, 3H), 2.79 (dd, J = 5.0, 4.0 Hz, 1H), 2.52
(dd, J = 5.0, 2.7 Hz, 1H), 2.06–1.74 (m, 2H) ppm. 13C NMR (50 MHz,
CDCl3 = 77.4): d = 140.5, 135.6, 130.9, 130.1, 129.5, 127.1, 52.1, 47.6, 44.6,
MS (ESI+): m/z = 307 [M+K]+, 291 [M+Na]+. HRMS (ESI+): [M+Na]+ found
291.0857, calcd 291.0853.
34. Silyl thioacetal 23: Carbanion 1 [obtained using bis(methylthio)trimethyl-
silylmethane (290 mg, 1.61 mmol, 1.3 equiv), abs THF (3.5 mL), n-BuLi (2.4 M
in hexane, 0.73 mL, 1.74 mmol, 1.4 equiv)] is added to a solution of bromide 18
(300 mg, 1.24 mmol, 1.0 equiv) in abs THF (5 mL) at À78 °C. The mixture is
stirred overnight at À78 °C to À30 °C, quenched with water after 21 h and
extracted with CH2Cl2. The combined organic layers are dried (Na2SO4) and the
solvents are evaporated. Purification of the residue by flash chromatography
(SiO2, petroleum ether/EtOAc = 300:1, 200:1, 100:1) yields 230 mg (54%) of a
colourless oil. 1H NMR (400 MHz, CDCl3 = 7.26): d = 7.25–7.15 (m, 4H), 4.03
(dd, J = 4.1, 2.7 Hz, 1H), 3.17 (dd, J = 5.7, 4.1 Hz, 1H), 2.83–2.66 (m, 2H), 2.69
(dd, J = 5.7, 2.7 Hz, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.89–1.79 (m, 4H), 0.15 (s, 9H)
ppm. 13C NMR (100 MHz, CDCl3 = 77.4): d = 140.5, 135.7, 129.5, 128.2, 126.9,
124.6, 50.9, 50.6, 47.6, 37.8, 33.5, 28.2, 11.5, 11.4, À0.6 ppm.
34.2, 28.9 ppm. IR (film): mmax = 2982, 2922, 1492, 1455, 1265, 916, 837, 767,
739, 671 cmÀ1. MS (ESI+): m/z = 219 [M+Na]+. HRMS (ESI+): [M+Na]+ found
219.0553, calcd 219.0553.
26. Benzaldehyde 14: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 10.31 (s,
1H), 7.84 (dd, J = 7.5, 1.5 Hz, 1H), 7.50 (ddd, J = 7.5, 1.6 Hz, 1H), 7.40–7.27 (m,
2H), 3.66 (t, J = 6.2 Hz, 2H), 3.14–3.06 (m, 2H), 1.90–1.76 (m, 2H), 0.91 (s, 9H),
0.06 (s, 6H) ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 192.8, 145.6, 134.2,
131.8, 131.5, 126.9, 62.5, 35.5, 29.1, 26.3, 18.7, À4.9 ppm. IR (film):
m = 1699
(C@O), 1100 (OSi) cmÀ1
.
27. Styrene 15: Colourless oil. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.53–7.45 (m,
1H), 7.24–7.12 (m, 3H), 7.02 (dd, J = 17.4, 10.9 Hz, 1H), 5.65 (dd, J = 17.4, 1.5 Hz,
1H), 5.28 (dd, J = 10.9, 1.5 Hz, 1H), 3.64 (t, J = 6.2 Hz, 2H), 2.79–2.71 (m, 2 H),
1.85–1.71 (m, 2H), 0.92 (s, 9H), 0.06 (s, 6H) ppm. 13C NMR (50 MHz,
CDCl3 = 77.4): d = 140.1, 136.8, 135.0, 130.0, 128.1, 126.6, 126.0, 115.6, 62.8,
34.5, 29.9, 26.3, 18.7, À4.9 ppm.
35. Thioacetal 24: 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.28–7.14 (m, 4H), 4.05
(dd, J = 4.0, 2.7 Hz, 1H), 3.70–3.64 (m, 1H), 3.17 (dd, J = 5.8, 4.0 Hz, 1H), 2.85–
2.65 (m, 2H), 2.70 (dd, J = 5.8, 2.7 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 1.93–1.79
(m, 4H) ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 140.5, 135.8, 129.4, 128.2,
126.8, 124.6, 54.5, 50.9, 50.5, 34.6, 32.5, 29.1, 12.9, 12.8 ppm.
28. Cesati, R. R., III; de Armas, J.; Hoveyda, A. H. Org. Lett. 2002, 4, 395–398.
29. Baughman, T. W.; Sworen, J. C.; Wagener, K. B. Tetrahedron 2004, 60, 10943–
10948.
36. 7,7-Bis(methylthio)benzocyclooctan-5-ol (25) and 6,6-bis(methylthio)-5-hydroxy-
methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene (26): To a solution of thioacetal
24 (110 mg, 0.41 mmol, 1.0 equiv) in abs THF at À78 °C are added n-BuLi
(2.4 M in hexane, 0.22 mL, 0.53 mmol, 1.3 equiv) and DMPU (0.05 mL,
0.41 mmol, 1.0 equiv). The orange mixture is slowly warmed to 0 °C in 20 h
and is stirred for 7 h at room temperature Water is added and the mixture is
extracted with CH2Cl2. The combined organic layers are dried (Na2SO4) and the
solvents are removed. The residue is purified by flash chromatography (SiO2,
petroleum ether/EtOAc = 15:1). Cyclooctanol 25: 40 mg (36%) yellowish oil. 1H
NMR (400 MHz, CDCl3, TMS = 0.00): d = 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.27 (ddd,
J = 7.5, 1.5 Hz, 1H), 7.22 (ddd, J = 7.3, 1.5 Hz), 7.05 (dd, J = 7.3, 1.4 Hz, 1H), 5.24
(dd, J = 10.4, 2.8 Hz, 1H), 3.05 (ddd, J = 13.7, 10.6, 6.3 Hz, 1H), 2.76 (ddd,
J = 13.7, 6.4, 3.0 Hz, 1H), 2.50 (dd, J = 14.0, 2.7 Hz, 1H), 2.11 (dd, J = 14.0,
10.5 Hz, 1H), 2.09 (s, 3H), 1.99 (s, 3H), 2.01–1.91 (m, 2H), 1.72–1.61 (m, 2H),
1.44–1.37 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3 = 77.4): d = 144.1, 138.0,
129.5, 128.0, 127.2, 125.3, 69.0, 61.5, 50.4, 34.2, 31.2, 28.3, 12.3, 11.9 ppm. IR
30. Bromide 17: Colourless liquid. 1H NMR (200 MHz, CDCl3 = 7.26): d = 7.61–7.53
(m, 1H), 7.32–7.20 (m, 3H), 7.06 (dd, J = 17.3, 10.9 Hz, 1H), 5.72 (dd, J = 17.3,
1.4 Hz, 1H), 5.38 (dd, J = 10.9, 1.4 Hz, 1H), 3.48 (t, J = 6.5 Hz, 2H), 2.95–2.88 (m,
2H), 2.25–2.11 (m, 2H) ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 138.3, 136.9,
134.7, 130.1, 128.2, 127.1, 126.3, 116.2, 34.0, 33.7, 31.9 ppm.
31. Biselectrophile 18: Colourless oil. 1H NMR (200 MHz, TMS = 0.00): d = 7.30–7.16
(m, 4H), 4.06 (dd, J = 4.1, 2.7 Hz, 1H), 3.45 (t, J = 6.4 Hz, 2H), 3.18 (dd, J = 5.7,
4.1 Hz, 1H), 3.05–2.82 (m, 2H), 2.71 (dd, J = 5.7, 2.7 Hz, 1H), 2.26–2.12 (m, 2H)
ppm. 13C NMR (50 MHz, CDCl3 = 77.4): d = 139.3, 135.9, 129.6, 128.3, 127.1,
125.0, 50.8, 50.5, 34.1, 33.5, 31.2 ppm. IR (film): mmax = 2961, 1492, 1452, 1385,
1241, 1211, 986, 882, 760 cmÀ1. MS (EI, DCP, 70 eV): m/z = 242 [8%, M+], 240
[5%, M+], 129 [41%], 117 [34%], 91 [85%], 77 [100%]. HRMS (EI): [M+] found
240.0151, calcd 240.0150.
32. Seebach, D.; Kolb, M.; Gröbel, B.-. T. Chem. Ber. 1973, 106, 2277–2290.
(film): m .
= 3406 (OH) cmÀ1 MS (ESI+): m/z = 291 [M+Na]+. HRMS (ESI+):
33. 9,9-Bis(methylthio)benzocyclooctan-7-ol (20): Carbanion
1
[obtained using
[M+Na]+ found 291.0847, calcd 291.0853. Cycloheptane 26: 12 mg (11%)
colourless solid. Mp 132–134 °C. 1H NMR (400 MHz, CDCl3,TMS = 0.00):
d = 7.22–7.08 (m, 4H), 4.53 (dd, J = 11.2, 5.7 Hz, 1H), 4.02 (dd, J = 10.3, 8.0 Hz,
1H), 3.16 (t, J = 6.3 Hz, 1H), 3.00–2.94 (m, 1H), 2.73 (dd, J = 14.9, 5.7 Hz, 1H),
2.19 (s, 3H), 2.17–1.98 (m, 4H), 1.87 (s, 3H), 1.87–1.79 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3 = 77.4): d = 141.2, 138.3, 132.4, 131.1, 128.2, 126.5, 64.8, 62.7,
bis(methylthio)trimethylsilylmethane (298 mg, 1.65 mmol, 1.3 equiv), abs
THF (4 mL), n-BuLi (2.4 M in hexane, 0.74 mL, 1.78 mmol, 1.4 equiv)] is added
to a solution of biselectrophile 11 (250 mg, 1.27 mmol, 1.0 equiv) in abs THF
(5 mL) at À78 °C. The mixture is stirred overnight at À78 °C to À50 °C. After
18 h water is added in the cold, the mixture is extracted with Et2O, the extracts
are dried (Na2SO4), the solvents are removed and the residue is purified by
flash chromatography (SiO2, petroleum ether / EtOAc = 100:0, 500:1, 100:1). To
the resulting mixture containing carbocycle 19 (260 mg, <0.76 mmol, 1 equiv)
in THF (15 mL) TBAFÁ3H2O (723 mg, 2.29 mmol, 3 equiv) is added. After 30 min
57.8, 36.2, 35.8, 24.3, 12.4, 11.1 ppm. IR (film):
m
= 3299 (OH) cmÀ1. MS (EI,
DCP, 70 eV): m/z = 268 [7%, M+], 221 [100%, M+ÀSCH3], 203 [11%], 191 [28%],
173 [20%], 155 [33%], 145 [20%], 143 [69%], 128 [63%], 115 [46%], 91 [22%], 77
[15%]. HRMS (EI): [M+] found 268.0958, calcd 268.0956.