A novel method for the generation of nitrile oxides on solid phase: Application to the synthesis of substituted benzopyranoisoxazoles

Article abstract of DOI:10.1021/ol016793r

(Equation Presented) A solid-phase synthesis of substituted benzopyranoisoxazoles is described. The six-step synthesis features a novel method of generating nitrite oxides on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a

Full text of DOI:10.1021/ol016793r

ORGANIC
LETTERS
2
002
Vol. 4, No. 3
23-326
A Novel Method for the Generation of
Nitrile Oxides on Solid Phase:
3
Application to the Synthesis of
Substituted Benzopyranoisoxazoles
Esther Y. Chao, Douglas J. Minick, Daniel D. Sternbach, Barry G. Shearer, and
Jon L. Collins*
GlaxoSmithKline, FiVe Moore DriVe, Research Triangle Park, North Carolina 27709
jlc22136@gsk.com
Received September 21, 2001
ABSTRACT
A solid-phase synthesis of substituted benzopyranoisoxazoles is described. The six-step synthesis features a novel method of generating
nitrile oxides on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne for assembly of the
benzopyranoisoxazole scaffold. Furthermore, the utilization of single-bead attenuated total reflectance Fourier transform infrared (ATR-IR)
microspectroscopy as an essential analytical tool for reaction optimization is highlighted.
Combinatorial chemistry and high throughput parallel syn-
thesis have emerged as powerful tools for the generation of
large collections of diverse compounds. The pharmaceutical
industry, in particular, has invested in and integrated numer-
ous aspects of combinatorial chemistry into the drug
discovery process with one goal being to provide novel
ligands for the plethora of biological targets derived from
the human genome.2
be successfully accomplished on solid phase and has led to
an improvement in the purities and yields of the targeted
compounds. Although numerous solid-phase chemistries have
been reported in the literature, the majority are directed
toward the solid-phase synthesis of heterocycles.4 One
strategy that has proven particularly valuable for the solid-
phase synthesis of conformationally rigid heterocycles is the
1
5
1,3-dipolar cycloaddition reaction. This strategy has been
During the past decade, the quality of solid supports and
linkers has improved significantly. This, in turn, has
expanded the number of synthetic transformations that can
successfully applied to the solid-phase synthesis of male-
3
6
imide-fused indolizinium carboxylates, tricyclic tetra-
7
8
hydroquinolines, tetrahydro-â-carbolines, and indolyl di-
9
ketopiperazine alkaloids.
(1) For reviews on solid-phase synthesis see: (a) Bunin, B. A. The
Combinatorial Index; Academic Press: New York, 1998. (b) Dolle, R. E.;
Nelson, K. H. J. Comb. Chem. 1999, 1, 235. (c) Lorsbach, B. A.; Kurth,
M. J. Chem. ReV. 1999, 99, 1549. (d) Kingsbury, C. L. Mehrman, S. J.;
Takacs, J. M. Curr. Org. Chem. 1999, 3, 497. (e) Corbett, J. W. Org. Prep.
Proced. Int. 1998, 30, 489. (f) Booth, S.; Hermken, P. H. H.; Ottenheijm,
H. C. J.; Rees, D. Tetrahedron 1998, 54, 15385. (g) Nefzi, S.; Ostresh, J.
M.; Houghten, R. A. Chem. ReV. 1997, 97, 449. (h) Hermken, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1997, 53, 5643. (i) Hermken,
P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1997, 52, 4527. (j)
Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17. (k)
Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555.
(3) For reviews on solid-phase synthesis supports and linkers see: (a)
Guiller, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (b) Hudson,
D. J. J. Comb. Chem. 1999, 1, 333. (c) Hudson, D. J. J. Comb. Chem.
1999, 1, 403.
(4) For a recent review: Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
(5) Kantorowski, E. J.; Kurth, M. J. Mol. DiVersity 1997, 2, 207-216.
(6) Bicknell, A. J.; Hird, N. W.; Readshaw, S. A. Tetrahedron Lett. 1998,
39, 5869-5872.
(7) (a) Kiselyov, A. S.; Smith, L. II.; Virgilio, A.; Armstrong, R. W.
Tetrahedron 1998, 54, 7987-7996. (b) Kiselyov, A. S.; Smith, L. II.;
Armstrong, R. W. Tetrahedron 1998, 54, 5089.
(
2) Beeley, L. J.; Duckworth, D. M.; Southan, C. Progress in Medicinal
(8) Fantauzzi, P. P.; Yager, K. M. Tetrahedron Lett. 1998, 39, 1291-
1294.
Chemistry 2000, 371.
1
0.1021/ol016793r CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

As a step toward identifying novel ligands for new
biological targets, we also investigated the synthesis of
conformationally rigid heterocyclic templates on solid phase.
Scheme 1. Solid-Phase Synthesis of Benzopyranoisoxazolesa
10
In particular, we were intrigued by a report that the phenolic
naphthoisoxazole ring system, exemplified by 1, serves as a
novel scaffold for the synthesis of estrogen receptor modula-
tors. Thus, we speculated that the benzopyranoisoxazole ring
11
system (2) may serve as a novel steroid mimetic template,
and herein we report the efficient solid-phase synthesis of
substituted benzopyranoisoxazoles. The synthesis features a
novel method of generating nitrile oxides on a polymer
support under mild conditions followed by a subsequent
intramolecular 1,3-dipolar cycloaddition with a tethered
alkyne. Furthermore, we exemplify the utilization of single-
bead attenuated total reflectance Fourier transform infrared
(
ATR-IR) microspectroscopy as an essential analytical tool
12
for reaction optimization.
a
b
Butylamine, NaHB(OAc)
3
, DCE. 3-Formyl-4-hydroxybenzoyl
c
chloride (5), 2,6-lutidine, DCM. (I) 8, propargyl alcohol, DCM;
O, THF. d
DMF. 15% TFA/DCM.
3 3
NOH‚HCl, Et N,
N, MeOH e NBS, Et
(
II) LiOH, H
2
H
2
As a starting point, we chose 3-formyl-4-hydroxybenzoic
acid as a properly functionalized starting material for the
synthesis of our benzopyranoisoxazoles. The benzoic acid
functionality would serve as a solid-phase attachment point
via an amide linkage while the salicylaldehyde functionality
contained key functionalities for elaboration of the pyrano-
isoxazole ring. Commercially available 2-(4-formyl-3-meth-
f
acid chloride (5) with thionyl chloride followed by addition
to resin 4. Fortunately, the unreacted resin-bound amine did
not interfere with the remaining synthetic steps (vide infra).
A small percentage (<5%) of ester formation was observed
between resin-bound phenol and unreacted acid chloride;
however, treatment with aqueous LiOH in 1,4-dioxane
effected saponification of the ester to the desired phenol.
With the 3-formyl-4-hydroxybenzoyl moiety successfully
loaded onto resin, our efforts focused on elaboration of the
salicylaldehyde functionality to an aldoxime containing a
phenol-tethered alkyne. Toward this end, subjection of the
1
3
oxyphenoxy)-ethyl polystyrene resin 3 was treated with
excess butylamine and sodium triacetoxyborohydride in 1,2-
dichloroethane to give the corresponding amine-functional-
ized resin 4 (Scheme 1). The absence of a residual aldehyde
following analysis by ATR-IR and magic angle spinning
1
14
(
MAS) H NMR demonstrated complete consumption of
the resin-bound aldehyde. A number of standard conditions
were evaluated for coupling of 3-formyl-4-hydroxybenzoic
acid to the amine-functionalized resin; however, no condi-
tions were identified that led to an acceptable yield or purity
of the desired amide. Successful amide formation was
realized in approximately 60% yield, as measured by differ-
ential ATR-IR, upon prior formation of the corresponding
15
resin-bound phenol to a Mitsunobu reaction by treatment
with propargyl alcohol and DEAD or DIAD provided the
propargyl ether 7. A small amount of the resin was cleaved
with 15% TFA in dichloromethane; however, several impuri-
1
ties were observed in the H NMR spectrum with the major
impurity derived from DEAD or DIAD. Variation of the
solvent, temperature, and order of addition did not improve
purity therefore alternative reagents were investigated.
Several groups have reported that sulfonamide betaine 8 is
an effective reagent for the solid-phase Mitsunobu reaction
between a resin-bound phenol and an alcohol.16 Exposure
of 6 to a solution of propargyl alcohol and 8 in dichloro-
methane provided the desired product; however, several
(9) (a) Van Levezijn, A.; van Maarseveen, J. H.; Stegman, K.; Visser,
G. M.; Kooman, G.-J. Tetrahedron. Lett. 1998, 39, 4737-4740. (b) Gong,
Y.-D.; Najdi, S.; Olmstead, M. M.; Kurth. M. J. J. Org. Chem. 1998, 63,
3
081-3086.
10) Huebner, V. D.; Lin, X.; James, I.; Chen, L.; Desai, M.; Moore, J.
C.; Krywult, B.; Navaratnam, T.; Singh, R.; Trainor, R.; Wang, L. WO
0/08001, 2000.
11) For solution-phase syntheses of the benzopyranoisoxazole skeleton
(
0
(
see: (a) Sami, M.; Izhar; Kar; Gandhi, K.; Ray, Jayanata, K. Org. Prep.
Proced. Int. 1991, 23, 186-8. (b) Fusco, R.; Garanti, L.; Zecchi, G. Chim.
Ind. 1975, 57, 16. (c) Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.;
Hishinuma, I.; Nagakawa, J.; Asada, M.; Miyamoto, N.; Hida, T.; et al.
PCT Int. Appl. WO 9414777, 1994.
impurities were present following analysis of a cleaved (15%
1
TFA/CH
2
Cl
2
) sample by LC/MS and H NMR. As before,
(
12) Yan, B.; Gremlich, H.-U.; Moss, S.; Coppola, G. M.; Sun, Q.; Liu,
(15) (a) Devraj, R, J. Org. Chem. 1996, 61, 9368-9373. (b) Hamper,
B. C.; Dukesherer, D. R.; South, M. S. Tetrahedron Lett. 1996, 37, 3671.
(16) (a) Castro, J. L.; Matassa, V. G. J. Org. Chem. 1994, 59, 2289-
2291. (b) Swayze, E. E. Tetrahedron Lett. 1997, 38, 8465-8468. (c)
Brummond, K. M.; Lu, J. J. Org. Chem. 1999, 65, 1723-1726.
L. J. Comb. Chem. 1999, 1, 46-54.
(
13) Available from Novabiochem.
(14) Luo, Y.; Ouyang, X.; Armstrong, R. W.; Murphy, M. M. J. Org.
Chem. 1998, 63, 8719-8722.
324
Org. Lett., Vol. 4, No. 3, 2002

variation of the reaction conditions did not improve product
purity. We hypothesized that exposure to TFA during the
cleavage step led to a number of decomposition pathways
due to the close proximity of the aldehyde and alkyne
moieties. Thus, single-bead ATR-IR was investigated for on-
bead reaction monitoring. In contrast to the post-cleavage
data, ATR-IR indicated successful alkyl ether formation
We next turned our attention to elaboration of 9 to a
substituted benzopyranoisoxazole. Several groups have re-
ported the generation of nitrile oxides from aldoximes on a
solid phase. Of these, we were particularly attracted to the
Huisgen method since this protocol is reported to give good
yields and purities of products. Accordingly, treatment of
resin-bound aldoxime 9 with excess commercially available
1
9
(Figure 1) in >90% yield. The shift in aldehyde CdO stretch
bleach in THF generated an intermediate nitrile oxide,
which underwent spontaneous intramolecular 1,3-dipolar
cycloaddition with the tethered alkyne to give the benzo-
pyranoisoxazole ring system. While the desired product was
1
evident by H NMR, the aqueous bleach led to hydrolysis
of the aldoxime and provided 10-15% of aldehyde 7 as a
20
byproduct. A number of other methods have been reported
for the efficient conversion of aldoximes to nitrile oxides in
21
solution including N-chlorobenzotriazole (NCBT), iodo-
2
2
23
benzene dichloride, lead tetraacetate, and dehydrohalo-
2
4
genation of hydroximinoyl halide method. We attempted
a number of these reported methods on a solid phase with
none providing an acceptable yield and purity of the desired
product. Ultimately, it was discovered that treatment of 9
with a solution of NBS and triethylamine in DMF gave rise
to the targeted benzopyranoisoxazole in 44% overall yield
and 99% purity following cleavage and analysis of the crude
Figure 1. ATR-IR spectra are shown for the conversion of resin
to resin 7.
6
1
13
product by LC/MS (Table 1, Entry 1), H NMR, and
C
from 1660 cm- in resin 6 to 1680 cm-1 in resin 7 was
consistent with loss of an intramolecular hydrogen bond
between the phenolic hydrogen and the aldehyde.1 Forma-
tion of a propargylic hemiacetal was also observed in the
IR spectrum (data not shown); however, resin washing with
dilute acetic acid affected acetal hydrolysis to give resin 7.
Reaction with hydroxylamine hydrochloride and triethyl-
1
Table 1. Overall Yields and Purities of Substituted
Benzopyranoisoxazoles 10a-i
a,b
7
1
8
amine in MeOH afforded the desired aldoxime product 9.
As before, ATR-IR was essential for reaction monitoring due
to competing hydrolysis of the aldoxime under the acidic
conditions used for cleavage. Disappearance of the aldehyde
CdO band accompanied by the appearance of bands
diagnostic for an oxime functionality indicated successful
oxime formation in >90% yield as measured by differential
ATR-IR (Figure 2).
overall yield
(%)
purity
(%)
entry
product
R2
R3
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
Me
Et
n-Pr
Ph
H
H
H
i-Pr
H
H
H
H
H
44
44
34
55
33
34
31
37
43
99
95
98
99
92
92
96
99
96
Me
C10H21
Ph
Ph
a
Yields by gravimetric analysis based on isolated material following
cleavage from a solid support. Yields were confirmed by Chemiluminescent
b
Nitrogen Detection (CLND) and are (10% of reported yields. Purities
based on LCMS analysis of cleaved samples. LCMS purity was consistent
1
with purity by H NMR.
NMR. Importantly there was no evidence of aldoxime
hydrolysis in the crude product.
Once optimal conditions were identified for the efficient
generation of the nitrile oxide on solid phase and subsequent
Figure 2. ATR-IR data are shown for (a) resin 7 and (b) resin 9.
The difference spectrum (9 minus 7) is included (see difference
spectrum c) to highlight bands diagnostic for an oxime.
-1
(
17) For comparison, salicylaldehyde CdO stretch is 1660 cm and
-1
o-anisaldehyde CdO stretch is 1685 cm
(18) Cheng, J.-F.; Mjalli, A. M. M. Tetrahedron Lett. 1998, 39, 939-
42.
.
9
Org. Lett., Vol. 4, No. 3, 2002
325

conversion to 10, several substituted propargylic alcohols
were selected to test the generality of the reaction. Nine
substituted propargylic alcohols were loaded onto 6 using
sulfonamide betaine 8 and converted to the corresponding
aldoximes 9b-9i. Subjection of each resin-bound aldoxime
pyranoisoxazoles 10 is tolerant of various substitutions, and
given the ease of synthesis of substituted and unsubstituted
propargylic alcohols, incorporation of more functionalized
monomers should proceed with ease.
In summary, we have demonstrated the efficient solid-
phase synthesis of substituted benzopyranoisoxazoles in high
yield and purity. The synthesis features very mild conditions
for the generation of nitrile oxides from aldoximes on solid
3
to NBS/Et N in DMF provided substituted benzopyrano-
isoxazoles 10b-10i in 31-55% overall yield, as determined
by gravimetric analysis and confirmed by Chemiluminescent
Nitrogen Detection (CLND). While the modest yield (60%)
of the amide formation step leads to modest overall yields,
the remaining five transformations occur in >90% average
yield and give rise to product purities ranging from 92 to
3
phase using NBS and Et N in DMF, which should be
compatible with a number of solid-phase chemistries and
monomer functionalities. We have also demonstrated the
utility of ATR-IR as an essential tool for on-bead reaction
monitoring and optimization. Given the large number of
commercially available primary amines and propargylic
alcohols, a diverse collection of substititued benzopyrano-
isoxazoles can now be synthesized using the synthetic route
described herein. Moreover, the resin-bound salicylaldehyde
derivative 6 may serve as a generic template for the solid-
phase synthesis of other steroid mimetic templates. These
results will be reported in due course.
99% (Table 1). Substitution at the propargylic carbon with
alkyl or aryl did not effect product purity, while substitution
with aryl led to a decrease in product yield (Entry 9). In
contrast, product yields were not effected by substitution with
either an alkyl or aryl substituent at the terminal alkyne
carbon. Similarly, simultaneous substitution at both the
propargylic and the terminal alkyne carbons was not
detrimental to product yield or purity. Overall, the efficient
transformation of formyl resin 4 to substituted benzo-
Acknowledgment. We thank Wendy White, Neata Bass,
and Andrea Sefler for their assistance with LCMS and MAS
NMR analysis.
(
19) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(20) In contrast see Kizer, D. E.; Miller, R. B.; Kurth, M. J. Tetrahedron
Lett. 1999, 40, 3535-3538.
(
21) Kim, J. N.; Ryu, E. K. Synth, Commun. 1990, 20, 1373-1377.
Supporting Information Available: Experimental pro-
cedures for the research described in this article. This material
is available free of charge via the Internet at http://pubs.acs.org.
(22) Radhakrishna, A. S.; Sivaprakash, K.; Singh, B. B. Synth. Commun.
1
991, 21, 625-1629.
(
23) Just, G.; Dahl, K. Tetrahedron 1968, 24, 5251.
(24) (a) Gruundmann, C.; Richer, R. J. J. Org. Chem. 1965, 30, 476. (b)
Hassner, A.; Lokanatha, R. K. M. Synthesis 1989, 57.
OL016793R
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