The synthesis of highly substituted isoxazoles by electrophilic cyclization: An efficient synthesis of valdecoxib

Article abstract of DOI:10.1021/jo701942e

(Chemical Equation Presented) A large number of functionally substituted 2-alkyn-1-one O-methyl oximes have been cyclized under mild reaction conditions in the presence of ICl to give the corresponding 4-iodoisoxazoles in moderate to excellent yields. The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles, including valdecoxib.

Full text of DOI:10.1021/jo701942e

The Synthesis of Highly Substituted Isoxazoles by Electrophilic
Cyclization: An Efficient Synthesis of Valdecoxib
Jesse P. Waldo and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed September 4, 2007
A large number of functionally substituted 2-alkyn-1-one O-methyl oximes have been cyclized under
mild reaction conditions in the presence of ICl to give the corresponding 4-iodoisoxazoles in moderate
to excellent yields. The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield
3,4,5-trisubstituted isoxazoles, including valdecoxib.
Introduction
thalenes and 2-naphthols,14 chromones,15 isoindolin-1-ones,16
and benzo[b]selenophenes.17
We recently reported the synthesis of numerous highly
substituted isoxazoles through the cyclization of various 2-alkyn-
1-one O-methyl oximes (eq 1)18 by a variety of electrophiles.
The isoxazole skeleton has been the focus of many biological
studies in recent years.1 Our group and others have reported
that the electrophilic cyclization of functionally substituted
acetylenes is a powerful synthetic tool for constructing a diverse
assortment of ring systems, including benzo[b]thiophenes,2
isoquinolines and naphthyridines,3 isocoumarins and R-pyrones,4
benzofurans,5 furans,6 indoles,7 furopyridines,8 cyclic carbon-
ates,9 2,3-dihydropyrroles and pyrroles,10 pyrilium salts and
isochromenes,11 bicyclic â-lactams,12 2H-benzopyrans,13 naph-
(1) (a) For a brief review, see: Carlsen, L.; Do¨pp, D.; Do¨pp, H.; Duus,
F.; Hartmann, H.; Lang-Fugmann, S.; Schulze, B.; Smalley, R. K.;
Wakefield, B. J. In Houben-Weyl, Methods in Organic Chemistry; Schau-
mann, E., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 1992; Vol. E8a,
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F.; Marwood, R.; Patel, S.; Ragan, C. I. J. Med. Chem. 1996, 39, 1943. (c)
Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.; Vestergaard,
H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.;
Liljefors, T. J. Med. Chem. 2002, 45, 2454. (d) Daidone, G.; Raffa, D.;
Maggio, B.; Plescia, F.; Cutuli, V. M. C.; Mangano, N. G.; Caruso, A.
Arch. Pharm. Pharm. Med. Chem. 1999, 332, 50. (e) Tomita, K.; Takahi,
Y.; Ishizuka, R.; Kamamura, S.; Nakagawa, M.; Ando, M.; Nakanishi, T.;
Nakamura, T.; Udaira, H. Ann. Sankyo Res. Lab. 1973, 1, 25; Chem. Abstr.
1974, 80, 120808. (f) Talley, J. J. Prog. Med. Chem. 1999, 13, 201. (g)
Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.;
Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y.
Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775. (h) Giovannoni,
M. P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.; Bartolini, A.; Kal Piaz, V.
J. Med. Chem. 2003, 46, 1055. (i) Li, W.-T.; Hwang, D.-R.; Chen, C.-P.;
Shen, C.-W.; Huang, C.-L.; Chen, T.-W.; Lin, C.-H.; Chang, Y.-L.; Chang,
Y.-Y.; Lo, Y.-K.; Tseng, H.-Y.; Lin, C.-C.; Song, J.-S.; Chen, H.-C.; Chen,
S.-J.; Wu, S.-H.; Chen, C.-T. J. Med. Chem. 2003, 46, 1706.
The yields of the desired Z-O-methyl oximes from the ynones
are generally good, and these compounds are easily isolated by
column chromatography on silica gel. We now report the full
details of our work on the ICl-induced cyclization of 2-alkyn-
(4) (a) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401. (b) Yao,
T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Oliver, M. A.; Gandour,
R. D. J. Org. Chem. 1984, 49, 558. (d) Biagetti, M.; Bellina, F.; Carpita,
A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023. (e) Rossi, R.; Carpita,
A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59, 2067.
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1999, 1432. (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
10292.
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1007. (b) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (c)
Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (d)
Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (e)
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6, 1037. (d) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62.
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Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(3) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437.
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10.1021/jo701942e CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/03/2007
J. Org. Chem. 2007, 72, 9643-9647
9643

Waldo and Larock
1-one O-methyl oximes, which provides a very efficient
synthesis of 4-iodoisoxazoles. Numerous examples are reported.
The resulting 4-iodoisoxazoles are readily elaborated by con-
ventional palladium-catalyzed processes to afford highly sub-
stituted isoxazoles, including valdecoxib.
but was not observed in any other cases. Nevertheless, in the
cases when R is equal to a proton (21) or methyl (23), the
desired Z-O-methyl oxime could be isolated by utilizing a basic
alumina column, although the yields were only modest. It was
discovered that only the Z isomer cyclized when subjected to
our usual ICl cyclization conditions. Our attempts at simulta-
neous isomerization and cyclization of the E isomer were
unsuccessful. Consequently, it is essential that the Z-O-methyl
oxime isomer be employed in the cyclization process.
Results and Discussion
The requisite ynones can be easily prepared (Scheme 1) by
the palladium/copper-catalyzed Sonogashira coupling of an acid
chloride with a terminal acetylene19 or by Pd-catalyzed carbo-
nylative coupling of terminal acetylenes with aryl iodides.20 The
ynones can also be prepared by allowing a lithium acetylide to
react with an aldehyde, followed by oxidation of the resulting
secondary alcohol.21 In addition, ynones can be conveniently
prepared by the treatment of silyl acetylenes with an acid
chloride in the presence of aluminum chloride.22
With the desired Z-O-methyl oximes in hand, we studied the
scope of the cyclization methodology (Table 1). In our earlier
studies,18 we discovered that using ICl as the source of
electrophilic iodine provided the best results for the formation
of isoxazoles. I2 may also be used to induce the cyclization of
compound 1. However, the reactions are slower and higher
molar equivalents of I2 are required to achieve yields comparable
to those of ICl (Table 1, compare entries 1 and 2).
SCHEME 1
When the terminus of the alkynyl moiety was substituted with
aliphatic substituents ranging from compact to bulky, the yields
were excellent (Table 1, entries 3-5). Furthermore, the intro-
duction of substituents on the aryl group has little effect on the
yield of the reaction. The electron-withdrawing group CO2Et
(9) and the electron-donating group OMe (11), both in the para
position of the phenyl ring, did not significantly change the
reaction yields compared to the parent system (Table 1, entries
6 and 7). Furthermore, substituting the alkynyl unit with a
thiophene heterocycle (13) lowered the yield only slightly (Table
1, entry 8).
The O-methyl oximes required in our isoxazole synthesis are
readily prepared by stirring the ynone in the presence of
methoxylamine hydrochloride, pyridine, and Na2SO4 or MgSO4
at room temperature using methanol as the solvent.23 Heating
is sometimes required, especially when R1 is an aromatic ring
bearing electron-donating groups. When R1 is a bulky group
relative to the alkyne moiety, the desired Z isomer is the
predominant product. However, if R1 is significantly less bulky,
a mixture of isomers often results and the desired isomer must
be separated by column chromatography. Upon preparation of
the 2-alkyn-1-one O-methyl oximes 21 and 23, a 1:1 mixture
of E-Z O-methyl oximes, observable by 1H NMR spectroscopy,
was obtained. Our attempts at separating these isomers on a
silica gel column led to the unwanted E isomer exclusively (eq
2). The 1:1 mixture of E:Z O-methyl oximes 21 and 23
isomerized exclusively to their E isomers. This isomerization
only occurred when R was either a proton or a methyl group
The effect of changing the substituents in the 1 position of
the 2-alkyn-1-one O-methyl oxime was also studied. The para
electron-withdrawing groups in compounds 15 and 17 provided
the corresponding isoxazoles 16 and 18 in excellent yields (Table
1, entries 9 and 10). The electron-donating group NMe2 in the
para position of compound 19 required a dramatic increase in
reaction time and 2.2 mol equiv of ICl had to be used to achieve
an excellent yield of 20; 1.2 mol equival of ICl provided only
a trace of 20, and the reaction suffered from low conversion.
No further iodinated products were observed in the reaction.
Other substituents in the 1 position of the 1-alkynone were
generally quite successful. For example, compounds 21 and 23,
as the pure Z-isomers, afforded the expected product with only
a slight decrease in yields (Table 1, entries 12 and 13) using
our standard procedure, whereas compound 25 provided an
excellent yield of 26 (Table 1, entry 14). Introducing a bulky
t-Bu group (27) into the alkynone provided a quantitative yield
of the desired isoxazole 28 (Table 1, entry 15). Compounds
29 and 31 introduce steric bulk at the ortho positions of the
parent phenyl rings. This did not hinder the reaction, and
high yields of the isoxazole products 30 and 32 were obtained
using short reaction times (Table 1, entries 16 and 17). Thus,
steric effects appear to be minimal in this process. Compound
31 cyclized exclusively to the desired 5-endo dig isoxazole
product 32, and the possible 6-exo dig chromone oxime product
was not observed, even though we have successfully cyclized
closely related ketones to the corresponding chromones15
(Scheme 2).
(10) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc. Chem.
Commun. 1998, 2207.
(11) (a) Barluenga, J.; Vazque-Villa, H.; Ballesteros, A.; Gonzalez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (b) Yue, D.; Della Ca`, N.; Larock,
R. C. Org. Lett. 2004, 6, 1581. (c) Yue, D.; Della Ca`, N.; Larock, R. C. J.
Org. Chem. 2006, 71, 3381.
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Gonzalez, J.; Turos, E. J. Org. Chem. 1998, 63, 8898.
(13) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org.
Chem. 2007, 72, 1347.
(14) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
(15) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006,
71, 1626.
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(17) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307.
(18) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 23, 5203.
(19) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 777.
(20) (a) Kobayashi, T.; Tanaka, M. J. Chem. Soc. Chem. Commun. 1981,
333. (b) Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057.
(21) Lin, C.-F.; Lu, W.-D; Wang, I.-W.; Wu, M.-J. Synlett 2003, 2057.
(22) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96, 3280.
(23) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc. 1986,
108, 6016.
9644 J. Org. Chem., Vol. 72, No. 25, 2007

Efficient Synthesis of Valdecoxib
TABLE 1. Synthesis of 4-Iodoisoxazoles by Electrophilic
Cyclizationa
SCHEME 2
cyclization of compound 39 required the use of 3 equiv of ICl,
as well as an increased reaction time. Compound 41 was
synthesized to study the effect of having two sterically bulky
t-Bu substituents present in the same substrate. The reaction
required a slight increase in time. Nevertheless, isoxazole 42
was obtained in a very good yield (Table 1, entry 22). The highly
substituted aryl group of O-methyl oxime 43 also provided an
excellent yield of isoxazole 44 (Table 1, entry 23). Scaled up
reactions, including multigram preparations of compounds 2,
4, and 44, did not affect the yield or outcome of the methodol-
ogy. This is important to note in cases where one wishes to
produce a large quantity of product for use in total synthesis or
library generation.
To demonstrate the value of the 4-iodoisoxazole products
generated in this methodology, a number of reactions were
carried out utilizing the iodine handle. We reasoned that we
could approach the highly potent COX-2 inhibitor 4-(5-methyl-
3-phenyl-4-isoxazolyl)benzenesulfonamide (valdecoxib) (46)24,1g
by a Suzuki-Miyaura cross-coupling of isoxazole 4 with the
appropriate boronic acid ester.25 Using our isoxazole methodol-
ogy to prepare 4 and a Suzuki-Miyaura coupling with the
commercially available benzenesulfonamide-4-boronic acid pi-
nacol ester, we were able to develop a very efficient route to
valdecoxib (Scheme 3). Starting with ynone 45, O-methyl oxime
3 was obtained in a 92% yield. Compound 3 was subjected to
our ICl cyclization conditions to afford isoxazole 4 in nearly a
quantitative yield. After several protocols were screened, Suzuki
cross-coupling was best accomplished using 5 mol % PdCl2
catalyst, 1.4 equiv of KHCO3 in 4:1 DMF:H2O at 85 °C for 3
h to provide valdecoxib (46) in an 81% isolated yield, which
constitutes a 74% overall yield from ynone 45.
SCHEME 3
a All reactions were carried out in CH2Cl2 (10 mL/mmol) at room
temperature using 0.25 mmol of starting material unless otherwise specified.
b Isolated yields after column chromatography. c The reaction was carried
out in CH3CN.
This synthetic route to valdecoxib provides a high overall
yield and utilizes very mild reaction conditions compared to
Introduction of the oxygen-containing heterocycles 33 and
35 into the alkynone also provided isoxazoles in good yields
(Table 1, entries 18 and 19). The nitrogen-containing hetero-
cycles 37 and 39 also afforded the desired isoxazoles, although
the yields were only modest (Table 1, entries 20 and 21). The
(24) (a) Talley, J. J. (G. D. Searle & Company), U.S. Patent 5,859,257,
1999; Chem. Abstr. 1999, 130, 110269. (b) Talley, J. J. Prog. Med. Chem.
1999, 13, 201.
(25) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147 and references therein.
J. Org. Chem, Vol. 72, No. 25, 2007 9645

Waldo and Larock
those previously reported. Earlier reports on the synthesis of
valdecoxib required the use of strong bases, such as n-BuLi,1g,24,26
or the preparation of boronic acids in situ using air- and water-
sensitive triisopropyl borate (i-PrO)3B.26 These previous pro-
cesses also suffer from poor overall yields. In addition to the
aforementioned advantages of this synthesis, one may construct
many analogues of valdecoxib by choosing from the wide array
of commercially available starting materials that are appropriate
for this methodology.
Other palladium-catalyzed methodology has also proven
useful for further elaboration of these iodoisoxazoles. For
example, we were able to convert 4-iodo-3,5-diphenylisoxazole
(2) to the corresponding methyl ester by allowing 2 to react in
the presence of catalytic amounts of Pd(OAc)2 plus a ferrocene
ligand, carbon monoxide, and methanol to afford methyl ester
47 in a 51% yield (eq 3).27 Reduction of compound 2 to 3,5-
diphenylisoxazole was an observed minor side product. In
addition, we were able to convert 4-iodo-5-methyl-3-phenyl-
isoxazole (4) to the corresponding phenethylamide by a similar
approach using a modified literature procedure.28 By allowing
compound 4 to react in the presence of catalytic amounts of
PdCl2(PPh3)2, carbon monoxide, and 2-phenethyl amine, we
were able to obtain 48 cleanly in good yield (eq 4).
cyclization of Z-O-methyl oximes of 2-alkyn-1-ones. Our
methodology tolerates a wide variety of functional groups,
including heterocycles and sterically cumbersome substrates.
This process can be scaled up to provide multigram quantities
of the desired product without sacrificing the yield or outcome
of the methodology. One can construct libraries of highly
substituted isoxazoles by invoking the appropriate starting
materials in an orderly fashion. Furthermore, the iodine handle
of the products provides an opportunity for further functional-
ization, as demonstrated by the ester and amide products 47
and 48, the Sonogashira product 49, and the Heck product 50.
Experimental Section
General Procedure for the Preparation of Alkynones from
Acyl Chlorides. To a 25 mL flask were added CuI (0.05 mmol),
PdCl2(PPh3)2 (0.01 mmol), and triethylamine (5 mL). The flask
was flushed with argon, and the terminal acetylene (2.5 mmol) was
added to the stirred suspension, followed by immediate dropwise
addition of the acyl chloride (3.25 mmol, 1.3 equiv). When the
acyl chloride was a solid, it was added as a solution in THF. The
resulting mixture was allowed to stir at room temperature overnight,
water (5 mL) was added, and the aqueous layer was extracted with
ethyl acetate. The organic layers were combined, dried, and
concentrated under reduced pressure. The residue was then purified
by column chromatography on silica gel to afford the desired
alkynone.
1,3-Diphenylprop-2-yn-1-one. Purification by flash chroma-
tography (hexanes/EtOAc) afforded 433 mg (84%) of the product
as a yellow liquid with spectral properties identical to those
previously reported.19
General Procedure for Preparation of the O-Methyl Oximes.
The alkynone (3.5 mmol), methoxylamine hydrochloride (7.0 mmol,
579 mg), Na2SO4 (7.0 mmol, 994 mg), and pyridine (1 mL) in
methanol (10 mL) were stirred at room temperature. The reaction
was monitored by TLC until the reaction was complete. The mixture
was diluted with water (25 mL) and extracted with EtOAc (3 × 5
mL). The organic layer was washed with brine, dried, and
evaporated. The residue was then purified by column chromatog-
raphy on silica gel to afford the desired O-methyl oxime.
(Z)-1,3-Diphenylprop-2-yn-1-one O-Methyl Oxime (1). Puri-
fication by flash chromatography (40:1 hexanes/EtOAc) afforded
617 mg (75%) of the product as an off-white solid: mp
Additionally, we were able to affect Heck and Sonogashira
cross-couplings on 4-iodo-5-methyl-3-phenylisoxazole (4)
(Scheme 4). By allowing compound 4 to react under standard
Sonogashira29 conditions in the presence of 1.2 equiv of phenyl
acetylene, alkyne 49 was obtained in a good yield. Also,
allowing compound 4 to react under Heck30 reaction conditions
in the presence of N-acryloylmorpholine provided the desired
R,â-unsaturated amide 50 in excellent yield.
1
40-42 °C; H NMR (CDCl3) δ 4.14 (s, 3H), 7.37-7.40 (m, 6H),
7.60-7.63 (m, 2H), 7.90-7.93 (m, 2H); 13C NMR (CDCl3) δ 63.4,
79.7, 101.4, 122.0, 126.8, 128.6, 128.7, 129.8, 129.9, 132.4, 133.8,
140.2; IR (neat, cm-1) 3052, 2935, 1598; HRMS Calcd for C16H13-
NO: 235.0997. Found: 235.1000.
Unfortunately, the palladium-catalyzed carbonylative cycliza-
tion31 of isoxazole 4 failed, and reduction of the starting material
was the only observed product (eq 5).
General Procedure for Iodocyclization using ICl. To a stirred
solution of the appropriate O-methyl oxime (0.25 mmol) in CH2-
Cl2 (2.5 mL) was added ICl (1 M in CH2Cl2, 1.2 equiv) dropwise,
and the solution was allowed to stir at room temperature. The
reaction was monitored by TLC to establish completion. The excess
ICl was removed by washing with a saturated aqueous solution of
Na2S2O3. The aqueous solution was then extracted with CH2Cl2 (3
× 5 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated under a vacuum to yield the crude product,
which was purified by flash chromatography on silica gel using
hexanes/EtOAc as the eluent.
Conclusions
3,4,5-Trisubstituted isoxazoles have been generated in high
yields under mild reaction conditions by the electrophilic
SCHEME 4
9646 J. Org. Chem., Vol. 72, No. 25, 2007

Efficient Synthesis of Valdecoxib
Procedure for Iodocyclization using I2. To a stirred solution
of the O-methyl oxime (0.25 mmol) in CH3CN (2.5 mL) was added
I2 (0.75 mmol, 191 mg), and the solution was allowed to stir at
room temperature for 1 h. The excess I2 was removed by washing
with a saturated aqueous solution of Na2S2O3. The aqueous solution
was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated under
reduced pressure to yield the crude product. Purification by flash
chromatography afforded the product.
lence (P50 GM069663) for support of this research; Johnson
Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for
donations of palladium catalysts; and Frontier Scientific and
Synthonix for donations of the phenylboronic acid.
Supporting Information Available: General experimental
procedures and spectral data for all previously unreported starting
materials and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
3,5-Diphenyl-4-iodoisoxazole (2). The product was obtained as
a colorless solid: mp 176-178 °C (lit.32 mp 176.5-177.5 °C). The
spectral properties were identical to those previously reported.32
JO701942E
Acknowledgment. We thank the National Institute of
General Medical Sciences (R01 GM070620 and R01 GM079593)
and the National Institutes of Health Kansas University Chemi-
cal Methodologies and Library Development Center of Excel-
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