An efficient intermolecular palladium-catalyzed synthesis of aryl ethers [17]

Full text of DOI:10.1021/ja016863p

10770
J. Am. Chem. Soc. 2001, 123, 10770-10771
Scheme 1
An Efficient Intermolecular Palladium-Catalyzed
Synthesis of Aryl Ethers
Karen E. Torraca, Xiaohua Huang, Cynthia A. Parrish, and
Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed August 16, 2001
Aromatic ethers are structural motifs in many naturally
occurring1 and medicinal compounds.2 Although there are numer-
ous methods for their synthesis,3,4 a mild general method remains
to be developed. While Pd-catalyzed C-O bond forming pro-
cesses hold promise, success has been limited in intermolecular
processes to reactions of activated aryl halides and alcohols
lacking â-hydrogens.5 To generalize the method, â-hydride elim-
ination from A (Scheme 1), which competes with reductive
elimination, needs to be minimized.6
Table 1. Coupling Reactions of Ortho-Substituted Aryl Halides7
Herein we describe the Pd-catalyzed intermolecular coupling
of primary alcohols and aryl halides. The method works well for
electron-deficient and -neutral aryl halides and for electron-rich
aryl halides with an ortho alkyl substituent.
Initial studies of the reaction of 2-chloro-m-xylene with n-buta-
nol indicated that using 2 mol % Pd(OAc)2 in toluene with
Cs2CO3 as base and di-tert-butyl phosphine ligand 15e at 70 °C
gave good selectivity (10:1) for the formation of ether:arene. The
reaction could be carried out at room temperature (45 h), in-
creasing the selectivity to 20:1. These conditions worked for
joining 2-chloro-m-xylene and 1-halonaphthalenes with various
primary alcohols.7a Applying these conditions to less hindered
aryl halides was less successful. For example, with 2-chloro-p-
xylene, the ether:arene ratio was 0.3:1. Ultimately, we found that
28 provided excellent generality. Many ortho-substituted substrates
were effectively coupled with n-BuOH in 84-99% yield (Table
1).7b Transformations involving 2-piperidinoethanol or 2-bromobi-
phenyl were slightly less successful. Electron-donating alkoxy
groups at the ortho position led to very low yields of the desired
product.
the n-butyl ethers in moderate yield. For substrates with electron-
withdrawing substituents such as OMe, Ph, CO2Me, CF3, Ac, or
NO2, the yields increased to 80-90%. Thus, the inductive effects
of meta substituents are important in the efficiency of these
transformations.
As expected, aryl bromides and chlorides with electron-with-
drawing para substituents are efficiently transformed using the
conditions established above (Figure 1).10a Ketones, esters, nitriles,
and heterocycles are tolerated in this chemistry.
Since we had seen that o-bromoanisole was a poor substrate
and that ortho substitution was beneficial to coupling efficiency
(Table 1), we prepared a series of substituted p-bromoanisoles to
study the interplay between steric and electronic effects. While
the reaction of 4-bromoanisole with n-butanol is inefficient (Table
3),10b the selectivity for ether formation increases dramatically
with the addition of an ortho alkyl group. Little difference is seen
on changing the substituent from methyl to Et or iPr. Increasing
the length of the alkyl chain to nPr resulted in more than a 10%
decrease in yield. Reaction of 2-tert-butyl-4-bromoanisole was
extremely slow and gave ether:arene in a ratio of 0.4:1. Thus,
the inclusion of a methyl group ortho to the bromide can alter
the product:arene ratio from 0.24:1 to 2:1. 4-Br-3-phenylanisole
reacts with yields similar to 4-bromoanisole.
We next examined the coupling of meta-substituted aryl halides
whose reactions would not be facilitated by the increased rate of
reductive elimination from A due to ortho substitution.9 This study
would also allow an estimation of meta substituent inductive
effects on reaction efficiency. As shown in Table 2, aryl bro-
mides with one or two m-alkyl substituents were converted to
(1) For leading references, see: Buckingham, J. Dictionary of Natural
Products; University Press: Cambridge, MA, 1994.
(2) Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112.
(3) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.; Wiley-
VCH: New York, 1999.
(4) (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b) Keegstra, M.
A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992, 48, 3633-3652. (c)
Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007-1010. (d) Lee,
S.; Frescas, S. P.; Nichols, D. E. Synth. Commun. 1995, 25, 2775-2780. (e)
Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc.
2000, 122, 5043-5051.
(5) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333. (b) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(c) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999, 40, 8837.
(d) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc.
2000, 122, 10718. (e) Torraca, K. E.; Kuwabe, S.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 12907. (f) Parrish, C. A.; Buchwald, S. L. J. Org.
Chem. 2001, 66, 2498 and references therein.
(6) Han, R. Y.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135.
(7) Reaction conditions: 2 mol % Pd(OAc)2, 2.5 mol % L, 1 equiv of
Ar-X, 2.5 equiv of Cs2CO3, 2 equiv of ROH, toluene, [ArX] ) 0.5 M. (a) L
) 1, 23 °C. (b) L ) 2, 70 °C.
(8) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
We undertook a study of a number of biaryl ligands to
determine what structural features were important in contributing
to their efficacy in C-O bond formation. As seen for the reaction
of nBuOH with 2-chloro-p-xylene (Table 4), binaphthyl ligands
are more effective than biphenyl ligands 3.
(9) (a) Jones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991, 30, 2615. (b)
Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc. 1996,
118, 3626.
(10) (a) Reactions of aryl halides with ortho electron-withdrawing substit-
uents were inefficient. (b) Under similar conditions, the reaction of 4-t-Bu-
(C6H4)Br and n-BuOH proceeded in moderate yield (52%).
10.1021/ja016863p CCC: $20.00 © 2001 American Chemical Society
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Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10771
Table 2. Coupling of Meta-Substituted Aryl Halides7b
Table 4. Ligand Effects in Pd-Catalyzed C-O Coupling Reaction
these results, we can make several generalizations concerning in-
termolecular Pd-catalyzed C-O bond formation between aryl
bromides and chlorides and primary alcohols: (1) Binaphthyl lig-
ands are superior to biphenyl ligands. (2) It is beneficial to have
a moderately large substituent at the 2′ position of the distal naph-
thyl group. Increasing the dihedral angle between the two aromatic
rings, which increases the effective size of the ligand, may be
beneficial.12 If R′ is too large, the ligand gives inferior results.
(3) Generally, the presence of a Me2N group is not more effective
than a similarly sized alkyl group.13 (4) Binaphthyl ligands are
more effective than their octahydro analogues. The distal naph-
thalene ring may be a better ligand for Pd.13,14 Additionally, the
electron-donating ability of 8 is increased relative to that of 2,
which may effect the partitioning of A between reductive
elimination and â-H elimination.15,16 Alternatively, the dihedral
angle between octahydrobinaphthyl rings may be larger than ideal,
reducing ligand efficacy. These results indicate that there is a
subtle interplay of both sterics and electronics that determine
whether a ligand of this class is generally successful for a difficult
transformation such as intermolecular C-O bond formation.
In summary, we have developed an efficient catalyst for the
Pd-catalyzed intermolecular coupling of aryl bromides and
chlorides and primary alcohols. While still far from ideal, it greatly
expands the scope possible for this important transformation.
Additionally, we have been able to ascertain the inductive effects
of meta substituents on the efficiency of these transformations
and on the relative importance of steric and electronic effects for
electron-rich substrates. Little information of either type has previ-
ously been available. Finally, we have presented a detailed study
on the effect of ligand variation that allows a determination of
which structural features in biaryl ligands are important for their
success in C-O bond formation. This information will form the
basis for our search for improved ligands of use to the synthetic
chemist.
Also examined were three biphenyl ligands with naphthyl or
anthracenyl groups at the ortho position of a di-tert-butyl-phos-
phinophenyl moiety (4-6). While neither 4 nor 5 are very
effective, the addition of an i-Pr group has a significant effect.
This is similar to trends seen in the biphenyl ligands for ketone
arylation and C-N bond formation.11 Interestingly, neither the
parent ligand 1 (R′ ) H) nor the derivative where R′ ) TMS
gave good results. Catalysts based on 2 proved to be of excellent
Figure 1. Pd-catalyzed coupling of electron-deficient substrates.7a
Table 3. Effect of Ortho Substitution on Reactions of
4-Bromoanisoles7b
Acknowledgment. We thank the National Institutes of Health (GM
58160), Pfizer, and Merck for support of this work. K.E.T. thanks the
NIH for a Postdoctoral Fellowship. C.A.P. was a trainee of National
Cancer Institute (CA 09112).
Supporting Information Available: Experimental procedures and
characterization of products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
generality. To probe whether the efficiency of this ligand was
due to coordination of the Me2N group, we prepared derivatives
where R′ ) Ph or Cy. While the former worked fairly well, the
cyclohexyl derivative gave the best results to date. Unfortunately,
we presently do not have a synthetically viable route to this ligand.
As we hypothesized that coordination of a portion of the distal
naphthalene ring enhances the efficacy or lifetime of the cata-
lysts,11b we prepared tetrahydro ligand 8. It gave similar results
to 6, being less effective than the three ligands of type 2. With
JA016863P
(12) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett
2001, 1050.
(13) Kocovsky, P.; Vyskocil, S.; Cisarova, I.; Sejbal, J.; Tislerova, I.;
Smrcina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray, M.;
Langer, V. J. Am. Chem. Soc. 1999, 121, 7714.
(14) Hayashi, T.; Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi, Y.;
Miki, M.; Yanagi, K. J. Am. Chem. Soc. 1994, 116, 775.
(15) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science:
Mill Valley, CA, 1987; pp 322-353.
(16) For an excellent review of seminal work on C-X reductive elimination,
see: Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
(11) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.