Cyclization of Aryl Silanes with Unexpected Retention of Silicon

Article abstract of DOI:10.1021/ol026494h

(Matrix Presented) Intramolecular Friedel-Crafts cyclization of 2-O-benzyl ethers at a model pyranose acetal is activated by incorporation of a trimethylsilyl group, albeit via unexpected, presumably steric means.

Full text of DOI:10.1021/ol026494h

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3797-3798
Cyclization of Aryl Silanes with
Unexpected Retention of Silicon
Stephen Philip Fearnley* and Michael W. Tidwell
Department of Chemistry and Physics, Lamar UniVersity, P.O. Box 10022,
Beaumont, Texas 77710
fearnleysp@hal.lamar.edu
Received July 10, 2002 (Revised Manuscript Received September 17, 2002)
ABSTRACT
Intramolecular Friedel−Crafts cyclization of 2-O-benzyl ethers at a model pyranose acetal is activated by incorporation of a trimethylsilyl
group, albeit via unexpected, presumably steric means.
The intramolecular Friedel-Crafts condensation of suitably
tethered benzylic aryls at activated cyclic oxoniums, eq 1,
offers a rapid entry to isochroman targets.1 In fact, this
process is a major competing pathway during intermolecular
glycosylation.2 These side reactions have been adapted,
notably by Martin,3 yet remain subject to subtle and
unpredictable stereoelectronic control,4 especially in the
pyranose series.5 Moreover, many employ exotic anomeric
activation or require electron-rich arenes.
to enhance the process on electronic grounds (increased
nucleophilicity and augmented stability of intermediate
carbocation) as well as cater to regiocontrol in arenes with
more complex substitution patterns.
We recently considered a directly analogous arylsilane-
mediated Friedel-Crafts closure6,7 to promote the overall
desired annulation, eq 2. We expected this ortho-silyl moiety
(1) For example, the pyranonaphthoquinone antibiotics: Brimble, M. A.;
Nairn, M. R.; Prabaharan, H. Tetrahedron 2000, 56, 1937.
(2) (a) Martin, O. R. Tetrahedron Lett. 1985, 26, 2055. (b) Suzuki, K.;
Maeta, H.; Suzuki, T.; Matsumoto, T. Tetrahedron Lett. 1989, 30, 6879.
Maeta, H.; Matsumoto, T.; Suzuki, K. Carbohydr. Res. 1993, 249, 49. (c)
Bu¨rli, R.; Vasella, A. HelV. Chim. Acta 1996, 79, 1159. (d) Crich, D.; Cai,
W.; Dai, Z. J. Org. Chem. 2000, 65, 1291. (e) Araki, Y.; Kobayashi, N.;
Ishido, Y.; Nagasawa, J. Carbohydr. Res. 1987, 171, 125. (f) Miethchen,
R.; Gabriel, T. J. Fluorine Chem. 1994, 67, 11. (g) Hosoya, T.; Takashiro,
E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004. (h)
Kovensky, J.; Sinay¨, P. Eur. J. Org. Chem. 2000, 3523.
(3) (a) Martin, O. R. Carbohydr. Res. 1987, 171, 211. (b) Martin, O. R.;
Hendricks, C. A. V.; Deshpande, P. P.; Cutler, A. B.; Kane, S. A.; Rao, S.
P. Carbohydr. Res. 1990, 196, 41. (c) Rousseau, C.; Martin, O. R.
Tetrahedron: Asymmetry 2000, 11, 409. Other related studies: (d) Martin,
O. R.; Rao, S. P.; El-Shenawy, H. A.; Kurz, K. G.; Cutler, A. B. J. Org.
Chem. 1988, 53, 3287. (e) Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-
Shenawy, H. A. J. Am. Chem. Soc. 1988, 110, 8698.
We constructed a prototypical substrate via epoxidation
of dihydropyran in MeOH,8 followed by benzylation with
(5) A brief survey of unactivated benzyl substrates is illustrative. 1,6-
Anhydro-D-glucose: no tricyclic products (ref 3b). 1-O-Acetyl hexapyranoses
(manno- and gluco-): “complex mixtures” (refs 2a and 3a). R-Glucopyran-
osyl chloride: 74% yield. Verlhac, P.; Leteux, C.; Toupet, L.; Veyrie`res,
A. Carbohydr. Res. 1996, 291, 11.
(6) For reviews of arylsilanes in regiospecific electrophilic aromatic
substitutions, see: Eaborn, C. J. Organomet. Chem. 1975, 100, 43, Fleming,
I. In ComprehensiVe Organic Chemistry; Barton, D. H. R., Ollis, W. D.,
Eds.; Pergamon: Oxford, 1979; Vol. 3, Chapter 13, p 613.
(7) For specific intramolecular examples, see: (a) Miller, R. B.; Tsang,
T. Tetrahedron Lett. 1988, 29, 6715. (b) Majetich, G.; Zhang, Y.; Feltmann,
T. L.; Belfoure, V. Tetrahedron Lett. 1993, 34, 441. (c) Cho, I.-S.; Tu,
C.-L.; Mariano, P. S. J. Am. Chem. Soc. 1990, 112, 3594.
(4) For example, double C-glycosidation: Martin, O. R.; Mahnken, R.
E. J. Chem. Soc., Chem. Commun. 1986, 497. Martin, O. R.; Rao, S. P.;
Hendricks, C. A. V.; Mahnken, R. E. Carbohydr. Res. 1990, 202, 49.
(8) Sweet, F.; Brown, R. K. Can. J. Chem. 1966, 44, 1571.
10.1021/ol026494h CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/04/2002

consistently resistant to ring closure despite considerable
effort. We therefore believe the TMS is playing an auxiliary
steric role, due to crowded ortho substitution, as evidenced
by modeling.16 First, the Si-CdC-CH2 dihedral angle is
torqued (3.43°); this deviation may enhance initial electro-
philic attack, reminiscent of the elusive Mills-Nixon effect.17
In addition, whereas the benzyl group of 7 aligns perpen-
dicular to the reactive site, the steric demands of the TMS
group in 3a force the tether to present its π-system in parallel
as required.
Scheme 1
These findings have since been developed into a practical
two-step protocol. Cyclization followed by desilylation of
the initial crude product mixture affords the cis-fused tricycle
4 exclusively and in good overall yield, Scheme 3.
the requisite bromide 2,9 Scheme 1. A survey of Lewis acids
ensued. Eventually, after some optimization,10 exposure to
BF3‚OEt2 (2 equiv) in CH2Cl2 at high dilution effected ring
closure in good overall yields, albeit in a somewhat
unexpected fashion.
Scheme 3
To our surprise, two products were obtained: the antici-
pated tricycle 4, arising from ipso substitution, and the
curiously meta-substituted 5, in which the silyl group had
apparently failed to participate. Cis stereochemistry was
3
confirmed by zero Hz J interactions across each new ring
junction, in agreement with previously reported values.2d,3b
No corresponding trans products were identified.
This direct contrast with unreactive nor-silyl precursor 7
highlights the effectiveness of the silicon moiety in attaining
the cis-fused pyranoisochroman framework and thus may
present a solution to this aberrant reaction.
This contradictory role of TMS suggested two separate
yet competing reactions. To discount other pathways (e.g.,
protodesilylation of 5) we resorted to isotopic labeling, para
to the silyl moiety. Regiospecific palladium-mediated stannyl
deuteration11 of a corresponding aryl triflate 612 allowed
synthesis of the labeled benzyl precursor. Annulation pro-
ceeded with complete regiospecific retention of deuterium
in each product as appropriate, Scheme 2.13
Acknowledgment. We thank The Robert A. Welch
Foundation for generous support of this work (V-1450).
S.P.F. is also grateful to the Gill Foundation for a Science
Faculty Development Award. We thank Professors Shawn
Allin (Spring Hill College) and Matt McIntosh (University
of Arkansas) for insightful discussions.
Supporting Information Available: Experimental pro-
Scheme 2
1
cedures and full data for 3, 4 and 5, including H and 13C
NMR spectra; details of deuterium labeling studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026494H
(9) Severson, R. G.; Rosscup, R. J.; Lindberg, D. R.; Engberg, R. D. J.
Am. Chem. Soc. 1957, 79, 6540.
(10) Overall yield was highly susceptible to concentration, e.g., at
reflux: 0.276 M, 19%; 0.036 M, 45%; 0.004 M, 72%.
(11) Dupre´, B.; Meyers, A. I. J. Org. Chem. 1991, 56, 3197.
(12) Prepared from the known phenol: Speier, J. L. J. Am. Chem. Soc.
1952, 74, 1003. See Supporting Information for details.
(13) This also discounted a 1,5-silylatropic shift in the intermediate cation
and electrophilic aromatic substitutions by opportunistic TMS-X species.
(14) For example, see: Ishibashi, H.; Sakashita, H.; Ikeda, M. J. Chem.
Soc., Perkin Trans. 1 1992, 1953 and references therein.
(15) Cox, P.; Lister, S.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1
1990, 11, 3151.
We presumed that 5 arose from simple minimization of
steric interactions, with the TMS held distal in the developing
transition state. Similar observations have been made during
related intermolecular Friedel-Crafts-type reactions, with
non-ipso substitution competitive in hindered cases.14 How-
ever, intriguingly, nor-silyl analogue 715 proved to be
(16) PC Spartan Pro, AM1 parametrization.
(17) Mills, W. H.; Nixon, I. G. J. Chem. Soc. 1930, 2510. For a discussion
correctly refuting this phenomenon, see: Siegel, J. S. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1721.
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Org. Lett., Vol. 4, No. 22, 2002