J. Am. Chem. Soc. 1996, 118, 10333-10334
10333
for the coupling of tertiary alkoxides and we are aware of no
reports of intramolecular processes of this type which proceed
in good yield.8 Herein we report our efforts in effecting an
intramolecular Pd-catalyzed ipso substitution of an aryl halide
with an alcohol (eq 1).
Synthesis of Oxygen Heterocycles via a
Palladium-Catalyzed C-O Bond-Forming Reaction
Michael Palucki,‡ John P. Wolfe, and Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed July 19, 1996
Palladium-catalyzed cross coupling reactions of Ar-X (X
) I, Br, and OTf) with carbon nucleophiles (R-M, where M
) SnR′3, BR′2, or MgX) have found wide application in the
syntheses of complex organic molecules, due in part, to the mild
reaction conditions and high functional group compatibility.1
Successful extension of this class of reactions to heteroatom
nucleophiles including amines2 and thiols3 has been reported.
Recent advances in the Pd-catalyzed aryl aminations have
extended the generality of this reaction to include a wide variety
of amines.4 In contrast, the Pd-catalyzed coupling of Ar-X
with alcohols still remains an elusive goal despite its potential
application in organic synthesis. Aryl ethers, including oxygen
heterocycles, are prominent in a large number of pharmacologi-
cally important molecules and are found in numerous secondary
metabolites.5 Existing methods for the conversion of Ar-X to
aryl ethers often require harsh or restrictive conditions and/or
the presence of activating groups on the arene ring.6 For
example, the Cu(I)-catalyzed syntheses of aryl and vinyl ethers
commonly require freshly prepared sodium alkoxides in a large
excess of the corresponding alcohol to achieve reasonable yields
from the corresponding aryl halides and vinyl halides.7 Fur-
thermore, this method has not been demonstrated to be effective
Subjecting substrates 1 and 2 to reaction conditions which
were successful in the intramolecular Pd-catalyzed amination
reaction (Pd2(dba)3, 2P(o-tolyl)3, NaOt-Bu in toluene at 80 °C)
afforded no desired cyclized product.9 Conversely, the use of
ligands including (S)-(-)-2,2′-bis(di-p-tolylphosphino)-1,1′-bi-
naphthyl (Tol-BINAP), (S)-(-)-2,2,′-bis(diphenylphosphino)-
1,1′-binaphthyl (BINAP), and 1,1′-bis(diphenylphosphino)-
ferrocene (DPPF) in place of P(o-tolyl)3 effected cyclization of
the model substrates at g80 °C in toluene with either Pd2(dba)3
or Pd(OAc)2 as the Pd source and either NaOt-Bu or K2CO3 as
base.10 This observation is in accord with recent reports that
chelating bis(phosphine) ligands significantly improved the Pd-
catalyzed amination reaction.4c,d Although Pd2(dba)3 was an
effective precatalyst, Pd(OAc)2 was found to be superior. Using
the aforementioned conditions, a variety of intramolecular
substrates were examined and the results obtained are shown
in Table 1.11
As shown, five-, six-, and seven-membered heterocycles were
obtained in good yields from the corresponding aryl halide. In
addition, a number of functional groups were found to be
compatible with the reaction conditions including acetals (entry
3), silyl ethers (entry 4), and amides (entry 7). Reactions
performed using method A were significantly slower (24-36
h) than reactions performed using method B (1-6 h); however,
the reactions using method A were somewhat cleaner. It should
be noted that no reaction was observed in the absence of base.
Cyclization of the aryl iodide substrate (entry 2) was extremely
slow in toluene, but in 1,4-dioxane, complete conversion
occurred in 24-36 h. Two equivalents of ligand relative to
palladium and two equivalents of NaOt-Bu relative to substrate
were required to achieve reasonable yields in the cyclization of
substrates containing a secondary alcohol (entries 11 and 12).
Observed side products included dehalogenation of the aryl
halides and, in the case of substrates containing a secondary
alcohol, oxidation of the alcohol to the ketone. Attempts to
cyclize 2-bromophenethyl alcohol afforded only phenylacetal-
dehyde which was unstable under the reaction conditions.12
‡ National Institutes of Health Postdoctoral Fellow.
(1) For a review of Stille couplings see: (a) Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508. (b) Mitchell, T. N. Synthesis 1992, 803. For
a review of Suzuki couplings see: (c) Martin, A. R.; Yang, Y. Acta Chem.
Scand. 1993, 47, 221. (d) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. For a review of Kumada couplings see: (e) Knight, D. W. In
ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I.; Schreiber, S.
L., Eds.; Pergamon Press: New York, 1991; Vol. 3, Chapter 2.3.
(2) (a) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
(b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. (c)
Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. (d)
Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(3) (a) Kosugi, M.; Shimizu, T.; Migita, T. Chem. Lett. 1978, 13. (b)
Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-I.; Kato, Y.; Kosugi, M.
Bull. Chem. Soc. Jpn. 1980, 53, 1385. (c) Baran˜ano, D.; Hartwig, J. F. J.
Am. Chem. Soc. 1995, 117, 2937. (d) Arnould, J. C.; Didelot, M.; Cadilhac,
C.; Pasquet, M. J. Tetrahedron Lett. 1996, 37, 4523.
(4) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133. (b)
Zhao, S.-H.; Miller, A. K.; Berger, J.; Flippin, L. A. Tetrahedron Lett. 1996,
37, 4463. (c) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (d) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217.
(5) (a) Ellis, G. P. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; John Wiley & Sons: New York, 1977;
Vol. 31. (b) Mustafa, A. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; John Wiley & Sons: New York, 1974;
Vol. 29.
The mechanism of the Pd-catalyzed synthesis of aryl ethers
most likely proceeds via a pathway roughly similar to that
suggested for the Pd-catalyzed aryl amination reaction.9a,13 As
shown in Scheme 1, oxidative addition of the Pd(0)Ln with the
(6) For a review of alkenyl and aryl C-O bond forming reactions see:
(a) Chiuy, C. K.-F. In ComprehensiVe Organic Functional Group Trans-
formations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon
Press: New York, 1995; Vol. 2, Chapter 2.13. For the synthesis and
application of benzopyrans see: (b) Hepworth, J. D. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: New York, 1984; Vol. 3, Chapter 2.24. For the synthesis and
application of benzofurans see: (c) Donnelly, D. M. X.; Meegan, M. J. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon Press: New York, 1984; Vol. 4, Chapter 3.12. For examples of
nickel catalyzed synthesis of aryl ethers see: (d) Cramer, R.; Coulson, D.
R. J. Org. Chem. 1975, 40, 2267. (e) Cristau, H.-J.; Desmurs, J.-R. Ind.
Chem. Libr. 1995, 7, 240.
(7) (a) Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Commun. 1995, 25,
2775. (b) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007.
(c) Keegstra, M. A.; Peters, T. H.; Brandsma, L. Tetrahedron 1992, 48,
3633. (d) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63. (e) Aalten, H.
L.; Van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof,
L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
(8) For a review on copper catalyzed aromatic nucleophilic substitutions
see: Lindley, J. Tetrahedron 1984, 40, 1433.
(9) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348. (b) Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 52, 7525.
(10) In addition to tri-o-tolylphosphine, the following ligands were
screened for the cyclization of substrate 1 and found to be ineffective: 1,-
10-phenanthroline, 2,2′-dipyridyl, tris(2,4,6-trimethoxyphenyl)phosphine,
1,2-bis(diphenylphosophino)benzene, and 1,2-bis(diphenylphosphino)ethane.
(11) No reaction was observed under the reaction conditions employed
in the absence of Pd(OAc)2 for any of the entries listed in Table 1.
(12) It has been reported that treatment of trans-[PdBr(C6H5)(PPh3)2]
with a solution of NaOMe in toluene at 35 °C afforded benzene (80% yield),
HCHO (20% yield), and anisole (trace). (a) Yoshida, T.; Okano, T.; Otsuka,
S. J. Chem. Soc., Dalton Trans. 1976, 993. Treatment of aryl halides with
a solution of NaOMe and catalytic amounts of Pd(PPh3)4 in toluene affords
upon heating the dehalogenated product and formaldehyde in high yields.
(b) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619.
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