A Silicon Linker for Direct Loading of Aromatic Compounds to Supports. Traceless Synthesis of Pyridine-Based Tricyclics

Full text of DOI:10.1021/jo9710745

6
102
J . Org. Chem. 1997, 62, 6102-6103
Sch em e 1a
A Silicon Lin k er for Dir ect Loa d in g of
Ar om a tic Com p ou n d s to Su p p or ts.
Tr a celess Syn th esis of P yr id in e-Ba sed
Tr icyclics
†
Frank X. Woolard, J onathan Paetsch, and
J onathan A. Ellman*
Department of Chemistry, University of California,
Berkeley, California 94720
Received J une 16, 1997
Two years ago we reported a silicon-based linkage
strategy to attach aromatic and heteroaromatic com-
1
pounds to solid supports. Cleavage of synthesis products
a
n-Butyllithium, THF, then allyldimethylsilyl chloride; (b)
from the support by protodesilylation leaves no residual
functionality on the product, i.e., leaves no trace that
synthesis was performed on a solid support. Subse-
quently, several additional reports appeared describing
the application of silicon-based linkers for the traceless
synthesis of aromatic compounds.2 A serious limitation
of all of the published approaches is the use of preformed
handle strategies, whereby the starting material is first
attached to the silicon linker, and then the linker is
attached to the solid support. Herein, we report the first
general method for the direct loading of aromatic com-
pounds onto a silyl-substituted support. The utility of
the approach is demonstrated by the solid-phase synthe-
sis of pyridine-based tricyclics. Members of this impor-
tant class of heterocycles have diverse therapeutic ac-
tivities. For example, nevirapine is an HIV-1 reverse
9-BBN, THF, then bromo-substituted polystyrene-1% divinyl-
benzene, Pd(PPh3)4, Na2CO3; (c) HCl, CH2Cl2.
,3
4
transcriptase inhibitor and pirenzepine is the prototypi-
cal M
1
-selective antimuscarinic for ulcer treatment.5
Frechet first reported the preparation of silyl chloride
substituted polystyrene-divinylbenzene resins by lithia-
tion of the phenyl rings followed by reaction with dial-
kyldichlorosilanes.6 These silyl-substituted resins have
since been employed by a number of researchers for the
preparation of silyl ether based linkages.7 Unfortunately,
these resins generally cannot be used to link aromatic
or heteroaromatic compounds to supports because pro-
todesilylation will result in cleavage of the silyl group
not only from the aromatic compound, but also from
the phenyl ring of the support. We have therefore
developed a linkage strategy in which the silyl group is
attached to the support through a stable aliphatic tether
(Scheme 1).
Silane 1 is isolated in quantitative yield by generation
of (4-methoxyphenyl)lithium followed by addition to
allyldimethylsilyl chloride. Hydroboration of silane 1
8
followed by in situ Suzuki coupling with bromophenyl-
6
substituted resin directly provides silyl-derivatized resin
2
.
Activation to provide silyl chloride resin 3 is ac-
†
Visiting Scientist: Zeneca Ag Products, 1200 South 47th Street,
Richmond, CA 94804.
(
(
1) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006.
2) (a) Chenera, B. C.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem.
F igu r e 1.
Soc. 1995, 117, 11999. (b) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 270. (c) Boehm, T. L.; Showalter, H. D.
H. J . Org. Chem. 1996, 61, 6498. (d) Plunkett, M. J .; Ellman, J . A. J .
Org. Chem. 1997, 62, 2885.
complished prior to use simply by brief exposure to an
HCl solution in CH Cl . Use of masked silyl resin 2 has
2 2
(3) For a recent review on linkage strategies and methods see:
Backes, B. J .; Ellman, J . A. Curr. Opin. Chem. Biol. 1997, 1, 86.
two important advantages over methods for the direct
preparation of silyl chloride resins. First, silyl resin 2 is
stable and can be stored indefinitely. We and others have
observed that support-bound silyl chlorides, particularly
support-bound dimethylsilyl chlorides, are highly water
(
4) Merluzzi, V. and co-workers. Science 1990, 250, 1411.
(5) Hirschowitz, B. I.; Hammer, R.; Giachetti, A.; Keirns, J . J .;
Levine, R. R. Trends Pharmacol. Sci. 1983, Suppl., 1.
(
(
6) Farrall, M. J .; Frechet, J . M. J . J . Org. Chem. 1976, 41, 3877.
7) (a) Chan, T. H.; Huang, W. Q. J . Chem. Soc., Chem. Commun.
1
995, 909. (b) Randolph, J . T.; McLure, K. F.; Danishefsky, S. J . J .
Am. Chem. Soc. 1995, 117, 5712.
8) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
7
a
sensitive and cannot be stored for prolonged periods.
Second, the loading level of the resin 2 can rapidly be
(
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Communications
J . Org. Chem., Vol. 62, No. 18, 1997 6103
Sch em e 2
a
(a) KH (1 equiv) in THF, then t-BuLi (2 equiv), then silyl resin 3; (b) 85% trifluoroacetic acid in CH2Cl2; (c) 2-azidobenzoyl chloride
in 9:1 CH2Cl2/pyridine; (d) lithiated acetanilide in THF, then R2X; (e) SnCl2/PhSH/Et3N (1:4:5) in CH2Cl2; (f) 7:2:1 DMF/TFA/HO; (g)
lithiated N-tert-butylbenzamide in THF, then R3X or (R3CO)2O; (h) chloroacetyl chloride, Et3N in dioxane, then N-methylpyrazine, CH2Cl2;
(i) Bu4NF in THF.
determined simply by treating a sample of the resin with
Br in CH Cl followed by filtration, concentration, and
mass balance of the 4-bromoanisole product. To test the
linkage strategy, 6-methoxy-2-naphthyllithium was added
to activated silyl resin 3. Cleavage from support with
tricyclic 9. Use of lithiated acetanilide as base did not
result in complete alkylation at this site. We therefore
employed the more basic lithiated N-tert-butylbenzamide.
Addition of alkylating agents or symmetric anhydrides
then provides the fully derivatized tricyclic 10. Tricyclic
9 could also be acylated under milder conditions without
the use of base by treatment with acid chlorides with
heating. For example, acylation with chloroacetyl chlo-
ride followed by chloride displacement with N-methylpip-
erazine provides access to derivatives that incorporate
the key piperazine pharmacophore of pirenzepine (see
11e and 11f in Figure 1). Cleavage from support is
2
2
2
9
2 2
HCl in CH Cl provided the expected 6-methoxynaph-
thalene product in pure form. The efficiency of loading
was 86% based upon the initial bromine substitution level
of the resin.
The utility of the silyl linkage strategy was demon-
strated by the preparation of pyridine-based tricyclics 11
(
Scheme 2). Synthesis is initiated by deprotonation of
1
0
the N-Boc 3-amino-2-chloropyridine 4 with KH followed
by halogen metal exchange and addition to silyl resin 3.
Treatment of support-bound pyridine 5 with trifluoro-
acetic acid results in removal of the Boc group without
any protodetachment of the electron deficient pyridine
intermediate. Addition of 2-azidobenzoyl chlorides in the
presence of pyridine then provides the amide product 6.
Alkylation of the amide is performed using lithiated
acetanilide as the base followed by addition of the
alkylation agent. As previously reported,11 lithiated
acetanilide is sufficiently mild that esters, secondary
amides, and secondary carbamates are not deprotonated
and alkylated. We also evaluated DBU and Schwesinger
phosphazene bases,12 but incomplete alkylation was
observed.
accomplished by treatment with Bu
4
NF in THF at room
temperature for 2 h. The yields for representative
compounds prepared according to this synthesis sequence
are provided in Figure 1.
In conclusion, a silyl linker for the direct loading of
aromatic and heteroaromatic compounds onto support
has been developed. As demonstrated for the therapeuti-
cally important class of pyridine-based tricyclics, the
linker should have broad utility for the traceless solid-
phase synthesis of many different compound classes.
Ack n ow led gm en t. Financial support for this work
was provided by Zeneca Ag Products and NIH
(
GM50353). We also thank Don Bowler, Betty Fitzger-
ald, Brenda Munson, Les Partridge, Remey Pucan, and
Ernie Yap of the WRC Analytical Department for
spectral determinations. F.X.W. wishes to thank Drs.
J ohn Kobzina and David Thompson for making possible
a most rewarding sabbatical year.
Reduction of the azide with a cocktail of thiophenol/
SnCl
2 3
/Et N (4:1:5) according to the conditions of Bartra
1
3
and Vilarrasa provides the 2-chlorooxazolidine inter-
mediate 8,1
4,15
which upon exposure to acid rearranges
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis and characterization of all compounds
to the pyridine-based tricyclic 9. The final element of
diversity is then introduced by alkylation or acylation of
(7 pages).
(
9) The loading efficiency of 2 ranges from 85-95% based upon the
bromine substitution level of the starting resin.
10) Prepared in three steps from commercially available 2-amino-
-bromo-3-nitropyridine (see Supporting Information).
11) Boojamra, C. G.; Burow, K. M.; Ellman, J . A. J . Org. Chem.
995, 60, 5742.
12) Schwesinger, R.; Willaredt, J .; Schlemper, H.; Keller, M.;
Schmidt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435.
13) Bartra, M. Romea, P.; Urpi, F.; Vilarrasa, J . Tetrahedron 1990,
6, 587.
J O9710745
(
(14) 2-Chloro-substituted oxazolidines previously have been reported
in the literature. (a) Falck, J . R.; Manna, S.; Mioskowski, C. J . Org.
Chem. 1981, 46, 3742. (b) Larsen, R. D.; Reamer, R. A.; Corley, E. G.;
Davis, P.; Grabowski, E. J . J .; Reider, P. J .; Shinkai, I. J . Org. Chem.
1991, 56, 6034.
(15) The 2-chlorooxazolidine intermediate can be isolated by treat-
ment of 8 with Bu
5
(
1
(
(
4
NF. The corresponding solution-phase azide
4
reduction also provides 2-chlorooxazolidine intermediates.