Development of a novel silyl ether linker for solid-phase organic synthesis

Full text of DOI:10.1021/jo961242d

6498
J . Org. Chem. 1996, 61, 6498-6499
of a functionalized arylchlorosilane with a solid support
containing a hydroxyl functionality to provide a resin-
bound arylsilyl ether. Further functionalization of the
aromatic moiety followed by reaction conditions in which
either the silicon-carbon or the silicon-oxygen bond
could be cleaved selectively would lead to elaborated
arenes or arenesilanols, respectively.
Develop m en t of a Novel Silyl Eth er Lin k er
for Solid -P h a se Or ga n ic Syn th esis1
Terri L. Boehm† and H. D. Hollis Showalter*
Chemistry Department, Parke-Davis Pharmaceutical
Research, Division of Warner-Lambert Company, Ann
Arbor, Michigan 48105
In order to determine the feasibility of such a linker,
we first wished to establish if an aryl moiety attached to
a silane ether could be further derivatized9 and, if so, if
the aromatic silicon-carbon bond could then be cleaved
under mild conditions in preference to the silicon-oxygen
bond. Toward this end, a solution-phase model study was
initiated for the synthesis of the 3-arylbenzofuran 11
(Scheme 1), representative of a venerable ring system in
natural products and synthetic chemistry with broad
pharmacological activity.10 Thus, the known MOM-
protected p-bromophenol 111 was subjected to lithium-
halogen exchange to generate the protected p-lithioben-
zene derivative that was then quenched with dichloro-
diisoproplysilane to provide the arylchlorosilane 2. The
bulky diisopropylsilane was chosen to impart added
stability to the silyl ether. Benzyl alcohol served as a
surrogate for polystyrene hydroxymethyl resin. Forma-
tion of the silyl ether 4 was then completed under
standard conditions.7 Functionalization of silyl ether 4
to pivotal intermediate 5 was achieved by an ortho-
directed metalation.12 Thus, lithiation of 4 with n-BuLi
in Et2O/TMEDA followed by quenching with DMF gave
the aromatic aldehyde 5 in 61% yield. As the addition
of nucleophiles to aldehyde 5 would create a site of
diversity in the molecule, we explored this reaction by
the addition of p-lithioanisole anion (p-bromoanisole,
n-BuLi, THF, -78 °C) to an ice-cold solution of aldehyde
5 to give the benzhydrol derivative 6 in excellent yield.
Alternatively, 6 could be made in high yield by reaction
of ortho-lithiated 4 with p-anisaldehyde. Alcohol 6 was
then oxidized to the ketone 7 using the highly versatile
Dess-Martin-type reagent, 1-hydroxy-1,2-benziodoxol-
3(1H)-one (IBX),13 which is easily prepared and tolerant
of air and moisture.
Received J uly 2, 1996
There is a burgeoning expectation that solution- and
solid-phase combinatorial chemistries will markedly ac-
celerate the drug discovery process. This is due in part
to the successful generation of large libraries of linear
biopolymers (principally peptides and oligonucleotides)
using solid-phase techniques. While the experimental
protocols for making these biopolymers are now well
established,2 such is not the case for the solid-phase
synthesis of small “drug-like” molecules. Early work in
the solid-phase synthesis of small molecules has relied
heavily on these methods,3 which have severely restricted
the types of chemistries that can be carried out and,
hence, the diversity of available compound targets.
Much of the current effort in solid-phase organic
synthesis is being focused on the development of new
types of linking strategies.4 This has resulted in the
construction of a wider range of compound classes due
to improved methods for linking and cleaving substrates
on solid-supports. In this vein, one recent development
is the introduction of “traceless linkers”, which allow for
the attachment of a substrate to a solid support at an
inert site within the molecule. Upon cleavage from the
resin, products are formed that show no trace or “memory”
of attachment to the solid support. Examples of this
include the preparation of p-tolyl derivatives by reductive
cleavage of benzyl thioesters5 and several silicon-based
traceless linkers that allow for the preparation of vari-
ously substituted aromatic compounds by ipsodesilylative
(via proton or other common electrophiles) or fluoride-
mediated cleavage of a resin-bound arylsilane.6 Herein,
we report the development and application of a novel
strategy for a silicon-based linker in which the arylsilane
is linked to a solid support via a silyl ether bond, in
contrast to prior strategies utilizing linkage via an
alkylsilane bond. Mild fluoride-mediated desilylation of
our resin-bound intermediates produces aromatic com-
pounds in generally excellent yield and purity.
A second site of diversity was generated by treating
ketone 7 with 5% TFA in CH2Cl2 at 0 °C to provide phenol
8. This was then alkylated with tert-butyl R-bromo
ketone at 80 °C in NMP catalyzed by Hunig’s base to give
the diketone 9. Cyclization to the benzofuran 10 was
carried out with DBU in NMP at 80 °C. When benzo-
furan 10 was subjected to standard proto-ipsodesilylation
conditions (TFA),14 the corresponding silanol was isolated
resulting from cleavage of the silicon-oxygen bond,
indicating that these conditions were not suitable to
cleave the aryl silicon-carbon bond. However, the ap-
Silyl ethers have found widespread application in
organic synthesis because of their increased stability over
trialkylsilyl ethers.7 Recently, Danishefsky has described
the use of a silyl ether linker in the solid-phase synthesis
of oligosaccharides by reacting a hydroxyl group of a
carbohydrate with a chlorosilylated resin.8 We reasoned
that a similar approach could be applied to the reaction
(7) Protecting Groups in Organic Synthesis, 2nd ed.; Greene, T. W.,
Wuts, P. G. M., Eds.; Wiley: New York, 1991.
(8) Randolph, J . T.; McClure, K. F.; Danishefsky, S. J . J . Am. Chem.
Soc. 1995, 117, 5712-5719.
(9) For an example, see; Mullen, D. G.; Barany, G. J . Org. Chem.
1988, 53, 5240-5248.
† Present address: G.D. Searle-Monsanto, St. Louis, MO.
* To whom correspondence should be addressed. Phone: (313)996-
7028. Fax: (313)996-7879. E-mail: Showalh@aa.wl.com.
(1) A preliminary account of this work was presented at the 211th
American Chemical Society National Meeting, New Orleans, LA,
March 1996; Abstract BIOT 0121.
(10) (a) Cagniant, P.; Cagniant, D. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic: New York,
1975; Vol. 18, pp 337-482. (b) Mustafa, A. In Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York,
1974; Vol. 29, pp 1-514.
(2) Merrifield, R. B. Chem. Scr. 1985, 25, 121-141. Merrifield, R.
B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
(3) Gordon, E. M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gallop, M. A. J . Med. Chem. 1994, 37, 1385-1401.
(11) Hatanaka, Y.: Yoshida, E.; Nakayama, H.; Kanaoka, Y. Bioorg.
Chem. 1989, 17, 482-485.
(4) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-600.
(5) Sucholeiki, I. Tetrahedron Lett. 1994, 35, 7307.
(12) Harvey, R. G.; Hahn, J .-T.; Bukowska, M.; J ackson, H. J . Org.
Chem. 1990, 55, 6161-6166.
(6) (a) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-
6007. (b) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem.
Soc. 1995, 117, 11999-12000. (c) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703-2706.
(13) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J .
Org. Chem. 1995, 60, 7272-7276.
(14) Funk, R. L.; Vollhart, K. P. C. J . Am. Chem. Soc. 1980, 102,
5253-5261.
S0022-3263(96)01242-X CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 19, 1996 6499
Ta ble 1. Syn th esized Ben zofu r a n sa
Sch em e 1a
compd
17 (mg)
Y
yield (mg)
11
209
100
100
100
100
100
100
100
C(CH3)3
C6H5
24
20bb
20cb
20d b
20eb
20fb
20gb
20h b
4.0
0.0
4.0
6.0
4.0
0.0
8.0
C6H4(o-OMe)
C6H4(m-OMe)
C6H4(p-OMe)
C6H4(p-Cl)
C6H4(p-CN)
C6H4(p-CF3)
a
b
Yields are for unpurified products. Reactions were carried
out in a Diversomer 8-pin synthesizer. Phenol 17 was reacted with
R-bromo ketones (3.0 mmol) and Hunig’s base (3.5 mmol). The
resulting diketones 18a -h were cyclized with DBU (3.0 mmol),
and the resin-bound benzofurans were cleaved using TBAF (1.0
mmol) in DMF.
14. p-Lithioanisole, generated as in the solution studies,
was added to a suspension of resin 14 at 0 °C to give
resin-bound benzhydrol 15. Oxidation of this with IBX
in DMSO/THF provided resin-bound MOM-ether 16,
which was cleaved with 5% TFA in CH2Cl2 to give the
resin-bound phenol 17. A number of resin-bound dike-
tones 18a -h were synthesized by treating this phenol
with a variety of R-bromoketones in the presence of
Hunig’s base in NMP at 80 °C. These were then cyclized
to the resin-bound benzofurans 19a -h by reaction with
DBU in NMP at 80 °C for 1 h. The resin-bound
benzofurans were cleaved from the solid support by
reaction with TBAF in DMF at 65 °C for 1 h. Following
an aqueous workup and filtration through a plug of basic
Al2O3, the benzofurans 11 and 20b-h (except 20c and
g) were isolated in good yields and high purity (Table 1).
The general efficiency of the solid-phase synthesis is
attested to by a comparison of the overall yield of 11 (40%
and 57%, respectively) derived from a common solution
or resin-bound intermediate (4 and 13, respectively).
Little or no product was isolated when phenol resin 17
was treated with R-bromo o-methoxyphenyl ketone or
R-bromo p-cyanophenyl ketone.
a
Key: (a) (i) n-BuLi, THF, -78 °C, (ii) (Cl)2Si(i-Pr)2, -78 °C to
rt, 71%; (b) benzyl alcohol, imidazole, DMF, rt, 91%; (c) (i) n-BuLi,
TMEDA, Et2O, 0 °C, (ii) anhydrous DMF, 0 °C, 61%; (d) 4-bro-
moanisole, n-BuLi, THF, -78 °C, 90%; (e) 1-hydroxy-1,2-benzio-
doxol-3(1H)-one, DMSO/THF, rt, 93%; (f) 5% TFA in CH2Cl2, 0
°C, 88%; (g) BrCH2COC(CH3)3, (i-Pr)2NEt, NMP, 80 °C, 88%; (h)
DBU, NMP, 80 °C, 90%; (i) TBAF, DMF, 65 °C, 92%.
Sch em e 2a
In conclusion, we have developed a simple, silicon-
based solid-phase traceless linker that is readily formed
from commercially available starting materials and that
is stable to a variety of reaction conditions. In addition,
the silicon-carbon or silicon-oxygen bonds can be se-
lectively cleaved to their respective products under mild
reaction conditions. We currently are expanding this
chemistry to include the synthesis of heteroarylsilane
ether linkers and to cleave the linker silicon-carbon bond
with a range of common electrophiles.17
a
Key: (a) 2, imidazole, DMF, rt; (b) (i) n-BuLi, TMEDA, Et2O,
0 °C, (ii) anhydrous DMF, 0 °C; (c) 4-bromoanisole, n-BuLi, THF,
-78 °C; (d) 1-hydroxy-1,2-benziodoxol-3(1H)-one, DMSO/THF, rt;
(e) 5% TFA in CH2Cl2, 0 °C; (f) BrCH2COY, (i-Pr)2NEt, NMP, 80
°C; (g) DBU, NMP, 80 °C; (h) TBAF, DMF, 65 °C.
Ack n ow led gm en t. We thank Drs. A. M. Doherty
and J . C. Hodges and Prof. A. G. M. Barrett for
stimulating discussions and administrative support.
plication of Stork’s method15 of fluoride-induced hydrode-
silylation of a siloxane (TBAF in DMF at 60 °C) to silyl
ether 10 provided the desired derivative 11 in excellent
yield.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization are available for all compounds (34
pages).
The established solution-phase protocols were then
applied to the solid phase (Scheme 2). Polystyrene
hydroxymethyl resin 12 was treated with chlorosilane 2
and imidazole in DMF to give resin-bound silyl ether 13.
Resin 13 was resubjected to the above reaction conditions
in order to maximize the loading.16 Resin-bound silyl
ether 13 was then subjected to ortho-lithiation followed
by quenching with DMF to give the resin-bound aldehyde
J O961242D
(16) The substitution level was determined by treating the solid
support with TBAF in THF at room temperature for 24 h, which
resulted in cleavage of the silicon-oxygen bond. On the basis of the
mass of the recovered silanol 3, the resin loading was determined to
be 0.72 mmol/g.
(17) Treatment of 10 with excess Br2 in CH2Cl2 at 0 °C provided a
76% yield of a 1:1 mixture of the desired compound, 1-[5-bromo-3-(4-
methoxyphenyl)benzofuran-2-yl]-2,2-dimethylpropan-1-one, as well as
1-[5-bromo-3-(3-bromo-4-methoxyphenyl)benzofuran-2-yl]-2,2-dimeth-
ylpropan-1-one resulting from a second bromination of the 3-aryl
substituent.
(15) Stork, G.; Chan, T. Y.; Breault, G. J . Am. Chem. Soc. 1992,
114, 7578-7579.