Application of aryloximes as solid-phase ketone linkers.

Article abstract of DOI:10.1021/ol026913a

In both solution and the solid phase, a variety of ketone oxime anions have been treated with 4-substituted-2-fluorobenzonitriles to give the corresponding nucleophilic aromatic substitution aryloxime adducts. Under aqueous acidic conditions, these adducts underwent cyclization to give the corresponding ketones. Suzuki and amide coupling reactions were also successfully performed on two resin-bound oximes followed by subsequent cyclorelease to give ketone product in good yields and purities. [reaction--see text]

Full text of DOI:10.1021/ol026913a

ORGANIC
LETTERS
2003
Vol. 5, No. 1
7-10
Application of Aryloximes as
Solid-Phase Ketone Linkers
Salvatore D. Lepore† and Michael R. Wiley*
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
wileymr@lilly.com
Received September 16, 2002
ABSTRACT
In both solution and the solid phase, a variety of ketone oxime anions have been treated with 4-substituted-2-fluorobenzonitriles to give the
corresponding nucleophilic aromatic substitution aryloxime adducts. Under aqueous acidic conditions, these adducts underwent cyclization
to give the corresponding ketones. Suzuki and amide coupling reactions were also successfully performed on two resin-bound oximes followed
by subsequent cyclorelease to give ketone product in good yields and purities.
Techniques for the solid-phase synthesis of ketones have
been limited to relatively few methods despite the presence
of this funtional group in a large variety of pharmaceutical
and natural products.1 Ketones have been generated from
the displacement of polymer-bound Weinreb amides with
carbon nucleophiles.2 More commonly, ketones have been
prepared in solution and subsequently immobilized on a solid
support through the use of a protecting group linker strategy.3
Early work in this area produced linkers based on ketals,4
thioketals,5 and imines.6 Webb’s semicarbazide linker,7
initially developed for the solid-phase synthesis of C-terminal
peptide aldehydes, has been recently extended to the
synthesis of trifluoromethyl ketones.8 The linkage of ketones
to polymer support as the hydrazone has also recently been
described by Ellman.9
We became interested in developing an oxime-based
ketone linker in the course of our investigations on the solid-
phase synthesis of 3-aminobenzisoxazoles.10,11 In this ap-
proach, based on the method of Shutske,12 a ketone oxime13
is coupled with a 2-fluorobenzonitrile to give an aryloxime
intermediate (Scheme 1). Acidic hydrolysis then leads to
cyclization of the aryloxime to produce the aromatic
heterocycle and a ketone. In our earlier work, an oxime-
† Current address: Department of Chemistry, Florida Atlantic University,
Boca Raton, FL 33431. E-mail: slepore@fau.edu.
(1) Over 100 ketone-containing drugs have been brought to market in
the last 10 years according to the MDL Drug Data Report (electronic
database).
(2) Salvino, J. M.; Mervic, M.; Mason, H. J.; Kiesow, T.; Teager, D.;
Airey, J.; Labaudiniere, R. J. Org. Chem. 1999, 64, 1823. O’Donnell, M.
J.; Drew, M. D.; Pottorf, R. S.; Scott, W. L. J. Comb. Chem. 2000, 2, 172.
(3) Backes, B. J.; Ellman, J. A. Curr. Opin. Chem. Biol. 1997, 1, 86.
(4) Leznoff, C. C.; Wong, J. Y. Can. J. Chem. 1973, 51, 3756.
(5) Huwe, C. M.; Ku¨nzer, H. Tetrahedron Lett. 1999, 40, 683.
(6) Worster, P. M.; McArthur, C. R.; Leznoff, C. C. Angew. Chem., Int.
Ed. Engl. 1979, 18, 221.
(8) Poupart, M.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem. 1999,
64, 1356. The Webb linker has also been recently used with nonfluorinated
ketones; see: Giroux, A.; Han, Y. Solid-Phase Synthesis of Biaryl Aldehydes
and Ketones Using Webb’s Semicarbazide Linker. Book of Abstracts, 217th
National Meeting of the American Chemical Society, Anaheim, CA, March
21-25, 1999; American Chemical Society: Washington, DC; 1999.
(9) Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907.
(10) Lepore, S. D.; Wiley, M. R. J. Org. Chem. 1999, 64, 4547.
(11) Lepore, S. D.; Wiley, M. R. J. Org. Chem. 2000, 65, 2924.
(12) Shutske, G. M.; Kapples, K. J. J. Heterocycl. Chem. 1989, 26, 1293.
(13) Aldehyde oximes were not studied since their corresponding
aryloxime adducts are unstable to the basic conditions used in the SNAr
reaction leading to the formation of nitriles; see: Cho, B. R.; Cho, N. S.;
Song, K. N.; Kim, Y. K. J. Org. Chem. 1998, 63, 3006 and references
therein.
(7) Murphy, A. M.; Dagnino, R.; Vallar, P. L.; Trippe, A. J.; Sherman,
S. L.; Lumpkin, R. H.; Tamura, S. Y.; Webb, T. R. J. Am. Chem. Soc.
1992, 114, 3156.
10.1021/ol026913a CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002

H2O at -40 °C revealed a significant rate difference. Under
these conditions, adduct 3 underwent rapid cyclization to give
the corresponding ketone (t1/2 ) 2 min) and 3-aminoben-
zisoxazole 5 (Scheme 2). In the case of the electron-deficient
N,N-dimethylamido-benzonitrile adduct 4, these conditions
led to a significantly slower cyclization reaction (t1/2 ) 52
min).
Scheme 1
Several additional ketone oximes16 were reacted with
arylnitrile 1 to give the corresponding aryloxime intermedi-
ates. Following solvent removal and aqueous workup, the
aryloxime intermediates were then subjected to cyclization
conditions followed by SCX purification.17 The SCX column
effectively removed 5 to give the corresponding ketones in
>96% purity (Table 1). Ketones containing electron-donating
containing resin14 was employed so that this reaction
sequence led to the cyclorelease of 3-aminobenzisoxazoles
into solution. In our studies of this system, we observed that
the rate of cyclization of the resin-bound aryloxime inter-
mediate was very sensitive to the presence of electron-
donating/withdrawing groups para to the nitrile. For example,
in one case, an electron-donating group such as a p-methoxy
accelerated the rate of cyclorelease by a factor of 100 relative
to a p-bromo.10 This observation presented an opportunity
to address the major limitation to the use of oximes as latent
ketone functional groups, namely, the forcing conditions
required for oxime hydrolysis.15 Thus, we envisioned at-
taching the arylnitrile component to polymer leading to a
new resin-bound aryloxime intermediate. Treatment of this
intermediate with aqueous acidic conditions would then
liberate a ketone into solution leaving the 3-aminobenzisox-
azole attached to the resin.
Table 1. Cyclization Yield of a Variety of Ketones Formed by
the Aqueous Acidic Treatment of Their Precursor Aryloxime
Adducts with 1 and Resins 7 and 10
To further characterize the electronic dependence of the
cyclization reaction in the solution-phase, compounds 3 and
4 were targeted. In addition to representing electron-donating
and electron-withdrawing characteristics, we envisioned that
solid-phase analogues of 3 and 4 could be readily synthesized
for direct comparison with our solution-phase study. Thus,
aryloximes 3 and 4 were prepared in near-quantitative
yields12 using 4-methoxy-2-fluorobenzonitrile (1) and 4-(dim-
ethyl-aminocarbonyl)-2-fluorobenzonitrile (2) (Scheme 2).
a All yields are after chromatography. For reactions with 1, yields are
for the two steps. For reactions with resins 7 and 10, yields are based on
loading, and the crude purities of the cyclorelease products are based on
HPLC analysis and are >96% unless otherwise indicated. b Oximes were
treated with KOtBu at room temperature in DMF followed by the addition
of arylnitrile 1 and isolated by aqueous workup. Cyclization was performed
at room temperature in 8:4:1 CH2Cl2/TFA/H2O except in the case of entry
d. c Oximes were treated with KOtBu at room temperature in DMSO and
added to resin 7 or 10 suspended in THF and reacted for 4 h at 55 °C.
Cyclorelease was performed at 55 °C in 4:1 TFA/H2O for 1 h except in the
case of entry d. d Cyclization was performed at 55 °C in 4:1 TFA/H2O for
4 h. e Arylnitrile debenzylation of the resin gave the major side product.
f Cyclorelease was performed at 55 °C in 4:1 TFA/H2O for 12 h. g Only
starting material was recovered.
Scheme 2
and withdrawing groups (entries a and b) were obtained in
good yields by treatment of the precursor aryloximes with
Initially, adducts 3 and 4 were treated with 4:1 TFA/H2O
at room temperature leading to complete cyclization to give
4-phenylcyclohexanone and 3-aminobenzisoxazoles 5 and 6
in less than 1 min. However, the use of 8:4:1 CH2Cl2/TFA/
(16) All oximes were prepared in near quantitative yields from the
corresponding ketones by treatment with hydroxylamine hydrochloride (1.2
equiv) and pyridine (2.0 equiv) in refluxing ethanol.
(17) Aminobenisoxazole 5 was conveniently removed from the crude
product mixture by filtration through an acidified SCX column. Interestingly,
heterocycle 6 was not retained on the column. Presumably, the electron-
donating character of the methoxy group in 5 increases the basicity of the
3-amine relative to 6, allowing it to ionize on the SCX column.
(14) Degrado, W. F.; Kaiser, E. T. J. Org. Chem. 1980, 45, 1295.
(15) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1998; p 355.
8
Org. Lett., Vol. 5, No. 1, 2003

Scheme 3
Scheme 4
the corresponding piperazine amide. This amide was then
treated with 1 N HCl in dioxane to give 9 as the HCl salt in
83% yield (three steps). Amine 9 was then coupled to
carboxypolystyrene (1% cross-linked) to provide resin 10
in a near-quantitative loading yield (1.57 mmol/g) based on
weight.20
8:4:1 CH2Cl2/TFA/H2O for several hours at room tempera-
ture. Aliphatic ketones were also readily obtained under these
conditions. For example, aryloxime 3 cyclized in less than
5 min to give 4-phenylcyclohexanone in 89% yield and
>96% purity after SCX purification (entry c). To obtain
trifluoromethyl ketone in reasonable yields (74%, two steps)
from its corresponding aryloxime adduct, warming to 55 °C
in 4:1 TFA/H2O for 4 h was required (entry d). No
deprotection was observed in the case of aryloxime-protected
2-acetylpyridine (entry e) even under forcing conditions of
heat and concentrated aqueous TFA. For these reactions,
starting material was recovered even after extended reaction
times. The same was also true for both 3- and 4-acetylpy-
ridine (not shown).
We then proceeded to prepare arylfluoride resins that were
electronically similar to 1 and 2. Arylfluoride resin 7 was
prepared in one step by coupling Merrifield’s resin18 with
2-fluoro-4-hydroxy-benzonitrile. Both reagents are com-
mercially available and relatively inexpensive.
Following the method of Hollinshead19 (cesium carbonate
and potassium iodide in DMF), the coupling reaction gave
resin 7 in a 93% loading yield (0.96 mmol/g) (Scheme 3).20
Electron-deficient arylnitrile resin 10 was prepared in four
steps starting from 4-methoxycarbonyl-2-fluorobenzonitrile
(8).21 Methylester 8 was hydrolyzed to the corresponding
acid by treatment with LiOH, in 10:1:1 THF/MeOH/H2O at
room temperature for 12 h (Scheme 3). The crude acid
intermediate was then coupled to N-tert-butoxycarbonyl-
piperazine using carbodiimide coupling conditions to give
Resins 7 and 10 were then treated with a variety of ketone
oximes to give the resin-bound aryloxime intermediates in
loading yields ranging from 50 to 80%. Interestingly, in the
case of the 4-phenylcyclohexanone adduct with resins 7 and
10 (Table 1, entry c), treatment with 4:1 TFA/H2O at room
temperature led to very similar cyclorelease rates (t1/2 ≈ 45
min).22 At 55 °C under the same conditions, both aromatic
and aliphatic ketones were recovered in reasonable yields
and excellent purities after 1 h (Table 1, entries a-c) for
both resins 7 and 10. However, in the case of trifluoromethyl
ketone (entry d), an extended reaction time of 12 h was
necessary to effect the cyclorelease of the ketone from both
resins. These more forcing conditions led to extensive
cleavage of the arylnitrile moiety from the resin by a
debenzylation reaction in resin 7, whereas the more hydro-
lytically stable23 resin 10 furnished the desired trifluoromethyl
ketone product in 63% yield (based on loading) and >96%
purity. Longer reaction times gave slightly improved yields
but also led to decomposition products.
Having identified acceptable conditions for loading and
cyclitive removal of a variety of substrates with resins 7 and
10, we moved on to confirm the compatibility of the
aryloxime linker with two widely used bond-forming reac-
tions. Thus, aryliodide resin 11 was treated with phenylbo-
ronic acid under aqueous basic Suzuki coupling conditions24
followed by cyclorelease to give the desired biaryl ketone
12 in 86% isolated yield (>96% purity) based on loading
(Scheme 4).
(18) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(19) Hollinshead, S. P. Tetrahedron Lett. 1996, 37, 9157.
Also, BOC-protected resin 13 was treated with 25% TFA/
CH2Cl2 (1 h) followed by coupling to 4-chlorobenzoic acid
(20) Resin loading was based on weight. The near quantitative loading
yield of resin 7 is also supported by yields based on elemental fluorine
(98%) and nitrogen analysis (89%) (n ) 8 in each case). For resin 10,
fluorine and nitrogen analysis gave 91% and 107% respectively. For resin
7, a nitrile absorption at 2231 cm-1 is observed in the IR, and for resin 10,
(22) For a discussion of differences in the kinetics of solid- versus
solution-phase reactions, see: Wang, S.; Foutch, G. L. Biotechnol. Prog.
1991, 7, 111. Chen, W. Y.; Foutch, G. L. Chem. Eng. Sci. 1989, 44, 2760.
(23) The treatment of resin 10 with TFA/H2O at 55 °C for 24 h led to
no appreciable decomposition.
this absorption occurs at 2237 cm-1
.
(21) Prepared in high yield from 4-bromo-2-fluorobenzonitrile by pal-
ladium-mediated methoxy carbonylation. Dufaud, V.; Thivolle-Cazat, J.;
Basset, J. M. J. Chem. Soc., Chem. Commun. 1990, 426.
(24) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177.
Org. Lett., Vol. 5, No. 1, 2003
9

under typical benzotriazole activated-ester conditions to give
the resin-bound amide (Scheme 4). The treatment of this resin
intermediate with cyclorelease conditions led to an 85%
isolated yield (>96% purity) of ketone 14. The successful
execution of both the Suzuki and amide coupling chemistry
involving resins 11 and 13 is in agreement with our studies
of a related system where we demonstrated that the aryloxime
linker was compatible with a wide variety of bond-forming
reaction conditions.11
In conclusion, we have developed a new solid-phase
ketone linker based on the aryloxime functional group. Our
model studies in the solution-phase have established that
aryloxime groups such as 3 that contain electron-donating
groups are more rapidly hydrolyzed to reveal the ketone than
electron-deficient systems such as 4. These solution-phase
studies inspired the synthesis of analogous electron-rich and
electron-deficient aryl oxime resins (oxime adducts of 7 and
10). A variety of ketones including trifluoromethyl ketones
were attached to both resins 7 and 10 via an aryloxime
linkage. The ketones were then recovered in good yields and
excellent purities (>96%). Suzuki and amide coupling
reactions were also successfully performed on resin-bound
ketones. On the basis of our findings, the aryloxime linker
approach described in this report should find useful applica-
tions in the solid-phase synthesis of small-molecule ketone
libraries.
Acknowledgment. The authors thank Prof. William
Roush for helpful discussions and Ms. Jolyn Smith for the
preparation of various intermediates used in this work.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 9, 12, and
14 and resins 7 and 10 and a representative procedure for
the addition of aryloximes to resins 7 or 10 followed by
subsequent cyclorelease. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL026913A
10
Org. Lett., Vol. 5, No. 1, 2003