9
594
J . Org. Chem. 1998, 63, 9594-9596
A Sim p le a n d Efficien t Meth od for th e
Ch a r t 1
P r ep a r a tion of Hin d er ed Alk yl-Ar yl Eth er s
Thomas F. Woiwode, Christoph Rose, and
Thomas J . Wandless*
Department of Chemistry, Stanford University,
Stanford, California 94305-5080
Received August 13, 1998
Antimitotic natural products that bind to cellular
microtubules can be used as anticancer agents, and we
are studying the cellular mechanisms of these com-
activated aryl halides with phenoxide and primary alkox-
ide nucleophiles has been shown to be an effective
strategy for ether synthesis.8 However, there are far
fewer examples of sterically hindered alkoxides being
utilized as nucleophiles in this reaction, with most reports
describing forcing conditions and moderate-to-low iso-
1
pounds. The fungal metabolite phomopsin A is a key
structure in these studies, and we are currently pursuing
2
its synthesis. Our retrosynthetic analysis of phomopsin
9
A targeted the chiral tertiary alkyl-aryl ether as a key
disconnection within the molecule. Accordingly, we have
investigated nucleophilic aromatic substitution (S Ar) as
N
lated yields of the desired ethers. Our studies demon-
strate that tertiary alkoxides react quickly and efficiently
with activated aryl halides to provide the desired tertiary
alkyl-aryl ethers under mild conditions and in good
yield.
a mild method to synthesize tertiary alkyl-aryl ethers.
In general, alkoxides can serve as bases or nucleophiles,
and alkoxides have also been shown to engage in single
electron transfer (SET) processes.3 Increasing steric
congestion close to oxygen generally decreases nucleo-
philicity, leading to an increase in basic or SET mecha-
nistic manifolds. Tertiary alkoxides are rarely used as
nucleophiles and are more often utilized as nonnucleo-
philic bases. Nevertheless, we have recently observed
that hindered tertiary alkoxides are effective nucleophiles
Initial experiments explored the reaction between
potassium tert-butoxide and a variety of aryl halide
electrophiles (Table 1). Treatment of 1-fluoro-2-nitroben-
zene with potassium tert-butoxide at 0 °C using THF, 1,4-
dioxane, or toluene as the solvent led to complete
conversion within 5 min (entry 1).10 The isolated yield
was highest using THF, and subsequent experiments
used THF as the solvent. We next investigated alterna-
tive methods for generating potassium alkoxides. Gen-
eration of the alkoxide in THF from tert-butyl alcohol and
a solution of potassium bis(trimethylsilyl)amide (KH-
MDS) worked well. With the majority of substrates, the
alcohol and aryl fluoride are dissolved in THF, and the
alkoxide is generated in situ by treatment with KHMDS.
With tert-butyl alcohol, this protocol provides results
identical to those obtained using commercially available
KOtBu.
in S
philes.
A number of methods exist for the synthesis of alkyl-
N
Ar reactions with activated aryl fluoride electro-
aryl ethers. Our initial search of the literature suggested
that copper-mediated displacements of aryl halides with
alkoxides might be promising.4 Preliminary reactions
using potassium tert-butoxide were successful; however,
attempts with more complex alkoxides proved to be low-
N
yielding. We also investigated S Ar reactions between
alkoxides and aryl halides complexed with either chro-
As anticipated from previous reports, aryl fluorides are
significantly more reactive in S Ar reactions than either
N
5
mium tricarbonyl or cationic cyclopentadienyl ruthe-
nium,6 as well as the recently reported palladium-
catalyzed cross-coupling reactions with alkoxides as
aryl chlorides or aryl bromides, and good levels of
selectivity are observed when reacting aromatic sub-
strates containing several potential halogen leaving
groups (entry 2). Para-substituted aryl fluorides serve as
good electrophiles (entry 3), and meta-substituted aryl
fluorides, as expected, do not produce the desired ether
(entry 4). The presence of an electron donating group on
the electrophile is tolerated (entry 5), and nitrile-
7
nucleophiles. None of these methodologies proved to be
suitable for synthesizing the ether linkage found in
phomopsin A. Nucleophilic aromatic substitution of nitro-
*
To whom correspondence should be addressed. Phone: (650) 723-
005. Fax: (650) 725-0259. Email: wandless@chem.stanford.edu.
1) (a) Hamel, E. Med. Res. Rev. 1996, 16, 207. (b) Wilson, L.; J ordan,
M. Chem. Biol. 1995, 2, 569.
2) (a) Culvenor, C. C. J .; Edgar, J . A.; Mackay, M. F.; Tetrahedron
989, 45, 2351. (b) Lacey, E.; Edgar, J . A.; Culvenor, C. C. J .; Biochem.
Pharm. 1987, 36, 2133.
3) (a) Guthrie, R. D.; Nutter, D. E.; J . Am. Chem. Soc. 1982, 104,
478. (b) Buncel, E.; Menon, B. C. J . Am. Chem. Soc. 1980, 102, 3499.
4) (a) Whitesides, G. M.; Sadowski, J . S.; Lilburn J . J . Am. Chem.
4
(
(
(7) (a) Mann, G.; Hartwig, J . F. J . Org. Chem. 1997, 62, 5413. (b)
Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 3395. (c) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J .
Am. Chem. Soc. 1997, 119, 6787.
(8) (a) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet,
J .; Zhu, J . J . Org. Chem., 1994, 59, 5535. (b) Evans, D. A.; Watson, P.
S. Tetrahedron Lett. 1996, 37, 3251. (c) Boger, D. L.; Borzilleri, R. M.;
Nukui, S.; Beresis, R. T. J . Org. Chem. 1997, 62, 4721. (d) Zhu, J .;
Laib, T.; Chastanet, J .; Beugelmans, R.; Angew. Chem., Int. Ed. Engl.
1996, 35, 2517.
1
(
7
(
Soc. 1974, 96, 2829. (b) Lindley, J . Tetrahedron 1984, 40, 1433. (c)
Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O.
G.; Hulshof, L. A.; Sheldon, R. A.; Tetrahedron 1989, 45, 5565. (d)
Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992, 48,
3
633.
5) (a) Hamilton, J .; Mahaffy, C. A. L. Synth. React. Inorg. Met. Org.
(9) (a) Day, C. E.; Schurr, P. E.; Emmert, D. E.; TenBrink, R. E.;
Lednicer, D. J . Med. Chem. 1975, 18, 1065. (b) DeVries, V. G.; Moran,
D. B.; Allen, G. R.; Riggi, S. J .; J . Med. Chem. 1976, 19, 946. (c)
Lednicer, D.; Heyd, W. E.; Emmert, D. E.; TenBrink, R. E.; Schurr, P.
E.; Day, C. E. J . Med. Chem. 1979, 22, 69. (d) Masada, H.; Oishi, Y.
Chem. Lett. 1978, 57-58.
(
Chem. 1986, 16, 1363. (b) Fukui, M.; Endo, Y.; Oishi, T.; Chem. Pharm.
Bull. 1980, 28, 3639.
(6) (a) Pearson, A. J .; Park, J . G. J . Org. Chem. 1992, 57, 1744. (b)
Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah, M. J . Org. Chem., 1996,
6
1
1, 3940. (c) J anetka, J . W.; Rich, D. H. J . Am. Chem. Soc. 1995, 117,
0585.
(10) All new compounds were fully characterized by spectroscopic
and analytical methods.
1
0.1021/jo981647t CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/19/1998