Nickel- vs Palladium-Catalyzed Synthesis of Protected Phenols from Aryl Halides

Article abstract of DOI:10.1021/jo970453v

We report the nickel-catalyzed formation of alkyl and silyl ethers from aryl halides in one step. These ethers can act as precursors to phenols by reaction with Bronsted or Lewis acids or with fluoride. A combination of Ni(COD)₂ and DPPF mediates the formation of tert-butyl aryl, methyl aryl, and tert-butyldimethyl silyl aryl ethers efficiently from aryl halides and sodium alkoxides or sodium siloxides under mild reaction conditions. Reactions to form the tert-butyl aryl ethers mediated by nickel complexes have lower turnover numbers than the analogous palladium-catalyzed reactions. However, reactions to form methyl aryl ethers show higher yields when catalyzed by a combination of Ni(COD)₂ and BINAP than when catalyzed by BINAP or DPPF and palladium catalyst precursors. Similarly, the formation of silyl aryl ethers occurs in higher yields and under milder conditions when catalyzed by a combination Ni(COD)₂ and DPPF than when catalyzed by palladium complexes. We also report improved yields from our previous results for the palladium-catalyzed conversion of aryl halides to tert-butyl aryl ethers.

Full text of DOI:10.1021/jo970453v

J . Org. Chem. 1997, 62, 5413-5418
5413
Nick el- vs P a lla d iu m -Ca ta lyzed Syn th esis of P r otected P h en ols
fr om Ar yl Ha lid es
Grace Mann and J ohn F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107
Received March 12, 1997X
We report the nickel-catalyzed formation of alkyl and silyl ethers from aryl halides in one step.
These ethers can act as precursors to phenols by reaction with Brønsted or Lewis acids or with
fluoride. A combination of Ni(COD)2 and DPPF mediates the formation of tert-butyl aryl, methyl
aryl, and tert-butyldimethyl silyl aryl ethers efficiently from aryl halides and sodium alkoxides or
sodium siloxides under mild reaction conditions. Reactions to form the tert-butyl aryl ethers
mediated by nickel complexes have lower turnover numbers than the analogous palladium-catalyzed
reactions. However, reactions to form methyl aryl ethers show higher yields when catalyzed by a
combination of Ni(COD)2 and BINAP than when catalyzed by BINAP or DPPF and palladium
catalyst precursors. Similarly, the formation of silyl aryl ethers occurs in higher yields and under
milder conditions when catalyzed by a combination Ni(COD)2 and DPPF than when catalyzed by
palladium complexes. We also report improved yields from our previous results for the palladium-
catalyzed conversion of aryl halides to tert-butyl aryl ethers.
In tr od u ction
Improved copper-catalyzed processes have made this
method more practical, but strongly basic conditions are
still required.9,10
Phenols are widespread in nature and are common in
synthetic chemistry. New mild methods for their syn-
thesis would, therefore, be valuable. Aryl halides would
be suitable precursors to phenols if mild methods for
nucleophilic aromatic substitution could be found.1 Reac-
tions that convert aryl halides to phenols in the absence
of a catalyst require strongly basic conditions, high
temperatures, and elevated pressures. For example, in
industry, chlorobenzene is hydrolyzed by 10-20% NaO-
H(aq) at 350-400 °C under pressure.2
The phenolic hydroxyl group is common in natural
products. Protection of the hydroxyl functionality be-
comes necessary in order to prevent reaction with oxidiz-
ing agents and electrophiles in the course of multistep
synthesis. Many methods are available for protecting
phenols, and ethers are a widely used mask.3 Thus, new
methods for the formation of phenols as readily cleavable
silyl or alkyl ethers would be valuable.
We recently reported the palladium-catalyzed inter-
molecular conversion of aryl bromides to phenols by
substitution of tert-butoxide, followed by deprotection
under acidic conditions.11,12 The formation of alkyl aryl
ether most likely occurs by reductive elimination from
the palladium alkoxide complex we had isolated. We
have investigated the scope of this chemistry using nickel
complexes as catalysts because (1) nickel alkoxide com-
plexes are known,13-16 (2) first-row transition metals are
often more reactive than second-row metals, (3) nickel
complexes are known to catalyze cross-coupling processes
through mechanisms not likely to occur with palladium
complexes,17,18 and (4) nickel is less expensive than
palladium.
We now report a new mild method for the efficient
conversion of aryl halides to phenols protected as alkyl
or silyl aryl ethers in one step catalyzed by nickel
phosphine complexes.19 The ethers formed by this method
are tert-butyl aryl ethers, methyl aryl ethers, and tert-
butyldimethylsilyl aryl ethers that can all be conveniently
deprotected to form phenols. We have found that
Ni(COD)2 and a chelating phosphine catalyze the forma-
tion of methyl aryl ethers and silyl aryl ethers in better
The synthesis of phenols as protected alkyl aryl ethers
under mild conditions from the direct reaction between
aryl halides and alkoxides is limited to reactions of aryl
halides with strong electron-withdrawing substituents.1
Copper salts can mediate the formation of alkyl aryl
ethers from aryl halides,4-8 but these reactions usually
require prolonged heating in strongly basic solutions and
in solvents such as DMF that are difficult to remove.
(9) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007-
1010.
(10) Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Comm. 1995, 25,
2775-2780.
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
(11) Mann, G.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 13109-
(1) For
a
review of OH- and OR- as nucleophiles in aromatic
10.
substitution, see: Fyfe, C. A. In The Chemistry of the Hydroxyl Group;
Patai, S., Ed.; Wiley Interscience: New York, 1971; Vol. 1; pp 83-
127.
(2) Bunnett, J . F.; Zahler, R. E. Chem. Rev. 1951, 49, 273-412.
(3) Greene, T., W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons, Inc.: New York, 1991; pp 143-
162.
(4) Lindley, J . Tetrahedron 1984, 40, 1433-1456.
(5) Bacon, R. G. R.; Rennison, S. C. J . Chem. Soc. C 1969, 312-
315.
(12) A paper using Pd and BINAP as catalyst for the formation of
alkyl aryl ethers appeared following the publication of ref 11. Palucki,
M.; Wolfe, J . P.; Buchwald, S. J . Am. Chem. Soc. 1997, 119, 3395-
3396.
(13) Bryndza, H. E.; Tam, W. Chem. Rev. 1988, 88, 1163-1188.
(14) Bhaduri, S.; J ohnson, B., F. G.; Matheson, T. W. J . Chem. Soc.,
Dalton Trans. 1977, 561-564.
(15) Matsunaga, P. T.; Hillhouse, G. L. J . Am. Chem. Soc. 1993,
115, 2075-2077.
(16) Matsunaga, P. T.; Mavropoulous, J . C.; Hillhouse, G. L.
Polyhedron 1995, 14, 175-185.
(6) Keegstra, M. A.; Peters, T., H. A.; Brandsma, L. Tetrahedron
1992, 48, 3633-52.
(17) Yamamoto, A.; Yamamoto, T.; Komiya, S. Pure Appl. Chem.
1984, 56, 1621-34.
(7) Whitesides, G. M.; Sadowski, J . S.; Lilburn, J . J . Am. Chem. Soc.
1974, 96, 2829-2835.
(18) Tsou, T. T.; Kochi, J . K. J . Am. Chem. Soc. 1979, 101, 7547-
(8) Aalten, H. L.; Van Koten, G.; Grove, M. D.; Kuilman, T.; Riekstra,
O. G.; Lumbertus, A. H. Tetrahedron 1989, 45, 5565-5578.
7560.
(19) Cramer, R.; Coulson, R. J . Org. Chem. 1975, 40, 2267-2273.
S0022-3263(97)00453-2 CCC: $14.00 © 1997 American Chemical Society

5414 J . Org. Chem., Vol. 62, No. 16, 1997
Mann and Hartwig
Ta ble 1. F or m a tion of ter t-Bu tyl Ar yl Eth er s fr om Ar yl
Ha lid es Ca ta lyzed by 15 m ol % Ni(COD)2 a n d 30 m ol %
Liga n d
Ta ble 2. F or m a tion of t-Bu tyl Ar yl Eth er s fr om Ar yl
Ha lid es Ca ta lyzed by DP P F a n d P a lla d iu m P r eca ta lystsa
38
yields and under milder conditions than several pal-
ladium complexes (COD ) cyclooctadiene). In the context
of ether formation, a survey of nickel catalysts, a com-
parison with the Pd-catalyzed system, and a brief com-
parison between DPPF and Tol-BINAP (DPPF ) 1,1′-
bis(diphenylphosphino)ferrocene, Tol-BINAP ) 2,2′-Bis(di-
p-tolylphosphino)-1,1′-binaphthyl) ligands are presented.
electron deficient aryl halides. Less than 1% ether was
observed by GC when electron neutral or electron rich
aryl halides were used. In these reactions, the dehalo-
genated arene was the major product after prolonged
heating. In addition to aryl bromides, Ni(COD)2 and
DPPF also catalyzed the conversion of electron deficient
aryl chlorides to alkyl aryl ethers in good yields.20
We briefly invested the combination of Ni(COD)2 and
chelating ligands other than DPPF for the formation of
tert-butyl aryl ethers. Ni(COD)2 and DPPE (1,2-bis-
(diphenylphosphino)ethane) catalyzed the formation of
(4-tert-butoxyphenyl)phenylmethanone in better yield
than Ni(COD)2 and DPPF, but this catalyst system was
not effective for the arylation of alkoxides using other
aryl halides. In general, the yields for formation of tert-
butyl aryl ether were higher for reactions involving DPPF
than those involving DPPE, but the optimal metal and
ligand appears to depend on the specific substrates.
Results from palladium-catalyzed conversion of aryl
halides to tert-butyl aryl ethers are outlined in Table 2
for comparison with Ni-catalyzed systems (Table 1).21 Pd
catalysts mediated the conversion of aryl halides to tert-
butyl aryl ethers with higher yields than Ni catalysts.
Reactions that were complete using 3% palladium cata-
lyst required 15% nickel catalyst for complete consump-
tion of aryl halide. Reactions using 3% palladium
catalyst were complete in 5 h at 95 °C while reactions
with 10% palladium catalyst were complete in just 1 h
at the same temperature. The yields and selectivities
for reactions containing either 3% or 10% palladium
catalyst were similar to each other, and reaction yields
were independent of whether 1 or 2 equiv of DPPF ligand
per Pd were used. The yields were the same for reactions
containing either 1 or 2 equiv of alkoxide.
Resu lts a n d Discu ssion
Reactions of aryl halides and sodium alkoxides and
sodium siloxides catalyzed by a combination of nickel
catalyst precursor and chelating ligand provide alkyl aryl
ethers or silyl aryl ethers in high yields for electron
deficient aryl halides. The overall reaction is shown in
eq 1. The experimental procedure for the generation of
2–18 h
protected phenols from aryl halides by a nickel catalyst
simply involved heating a mixture of aryl halide (1 equiv),
sodium alkoxide or sodium siloxide (1.2 equiv), DPPF
ligand (15-30%), and Ni(COD)2 (10-15%) in toluene or
a mixture of methanol and toluene for 2-18 h at 95 °C.
Absorption of the crude mixture onto silica gel followed
by flash chromatography afforded the pure isolated alkyl
ethers. Isolation of the silyl ethers by column chroma-
tography on silica gel led to a small amount of depro-
tected phenol. The major side product observed in each
reaction by GC/MS was the dehalogenated arene. No
tert-butyl aryl ether or silyl aryl ether was formed in
toluene solvent in the absence of the nickel catalyst or
ligand as detected by GC analysis. Similarly, less than
5% of methyl aryl ether was detected by GC/MS when
methanol or a mixture of methanol and toluene were used
as solvent in the absence of Ni(COD)2 or DPPF.
F or m a tion of ter t-Bu tyl Ar yl Eth er s w ith Nick el
a n d P a lla d iu m Ca ta lysts. Table 1 shows our results
for the formation of tert-butyl aryl ethers from aryl
halides catalyzed by Ni(COD)2 and DPPF. Sodium
counterion proved critical. Reactions with potassium tert-
butoxide or lithium tert-butoxide, Ni(COD)2, DPPF, and
aryl halide afforded no significant amounts of ether. Like
the reactions catalyzed by DPPF-ligated palladium com-
plexes, complexes generated from the Ni(COD)2 precursor
mediated the formation of tert-butyl aryl ethers from
In addition to results presented in communication form
previously, we found that bromobenzamides underwent
formation of aryl ethers. This type of aryl halide is
important for solid phase applications, since amides
commonly link substrates to the support. Further, a
combination of DPPF and Pd(OAc)2 catalyzed the forma-
tion of tert-butyl aryl ethers with electron neutral aryl
(20) The first Pd-catalyzed amination of aryl chlorides was recently
published. Beller, M.; Riermeier, T. H.; Reisinger, C.-P.; Herrmann,
W. A. Tetrahedron Lett. 1997, 38, 2073-2079.
(21) We have previously reported the Pd-mediated formation of tert-
butyl aryl ethers, ref 11. The yields in Table 2 are higher than those
published in ref 11 simply due to improved isolation techniques.

Protected Phenols from Aryl Halides
J . Org. Chem., Vol. 62, No. 16, 1997 5415
Ta ble 3. DP P F /Ni(COD)2-Ca ta lyzed Con ver sion of Ar yl
Ha lid es to Meth yl Ar yl Eth er sa
Ta ble 4. Ni(COD)2 a n d P d (DBA)2-Ca ta lyzed F or m a tion
of ter t-Bu tyld im eth ylsilyl Eth er s fr om Ar yl Ha lid es Usin g
DP P F a s Liga n d
vent resulted in the formation of the methyl aryl ether
in 95% yield by GC after heating for 17 h at 55 °C. The
uncatalyzed arylation of alcohols and the need for
anhydrous solvents in these uncatalyzed reactions has
been discussed recently.12 Thus, the nickel-catalyzed
reactions allow for the conversion of electron deficient
aryl halides to methyl aryl ethers in volatile, nonpolar
solvents.
F or m a tion of Silyl Ar yl Eth er s. We also investi-
gated the use of sodium siloxides in the nickel-mediated
formation of silyl aryl ethers from aryl halides. Reactions
of aryl halide and sodium trimethylsiloxide, sodium
triethylsiloxide, or sodium triphenylsiloxide catalyzed by
a combination of Ni(COD)2 and DPPF did not form silyl
aryl ether. However, excellent yields of tert-butyldi-
methylsilyl aryl ether were observed by GC for the
reaction of sodium tert-butyldimethylsiloxide (NaOTB-
DMS) and electron deficient aryl halides catalyzed by
Ni(COD)2 and DPPF (Table 4). Attempts to isolate the
tert-butyldimethylsilyl aryl ethers by column chromatog-
raphy resulted in some hydrolysis of the silyl ether to
generate phenol. Thus, we report yields determined by
GC for all of the reactions of NaOTBDMS. Nevertheless,
isolated yields were high. An average isolated yield for
the reaction between NaOTBDMS and bromobenzonitrile
was 67% (12% of the deprotected phenol was also
isolated).
In addition to the combination of Ni(COD)2 and DPPF,
the combination of DPPF and Pd(DBA)2 also mediated
the formation of silyl aryl ethers. However, yields for
the reactions catalyzed by Ni(COD)2 and DPPF were
higher, and the nickel-catalyzed reactions occurred at
lower temperatures and in shorter reaction times. For
example, Ni(COD)2 and DPPF mediated the formation
of silyl aryl ethers in greater than 95% yield at 95 °C in
2 h, but less than 10% of the silyl ether was observed
under these conditions when a combination of DPPF and
Pd(DBA)2 were used as the catalyst. Instead, the pal-
ladium-catalyzed formation of silyl aryl ethers in 2 h
required heating at 120 °C. Reaction temperature proved
important to the reaction yield, since prolonged heating
of the silyl aryl ether product resulted in its slow
decomposition. Thus, nickel catalysts are not only better
than palladium catalysts for formation of methyl aryl
ethers from aryl halides but also for the analogous
formation of silyl aryl ethers.
halides at temperatures that are slightly higher than
those used for reactions of electron poor aryl halides, but
the yields were modest and slightly lower than those
obtained previously with Tol-BINAP as ligand.12 Sur-
prisingly, both Pd(DBA)2 (DBA
) dibenzylidene-
acetone) and Pd(OAc)2 catalyzed the conversion of some
aryl chlorides to aryl ethers in good yields at 95 °C.20
Control experiments with aryl chlorides performed si-
multaneously in the presence and absence of metal and
ligand showed that formation of ether required the
palladium catalyst in these solvent systems.
F or m a tion of Meth yl Ar yl Eth er s. In combination
with DPPF, the nickel catalyst precursor Ni(COD)2 was
superior to the three palladium catalyst precursors
Pd(DBA)2, Pd(OAc)2, and Pd(PPh3)4 for formation of
methyl aryl ethers from aryl halides. The results for
nickel-catalyzed formation of methyl aryl ethers are
summarized in Table 3. The nickel-catalyzed formation
of alkyl aryl ethers from NaOMe occurred in much higher
yields than those catalyzed by palladium complexes. The
yields of methyl aryl ether from reactions catalyzed by
palladium and DPPF were less than 25% when monitored
by GC, and these reactions were not pursued. The
dehalogenated arene was the major product formed in
the reactions catalyzed by DPPF and the palladium
catalyst precursors.22 As was the case for reactions that
formed tert-butyl aryl ethers, reactions catalyzed by
Ni(COD)2 and DPPF that formed methyl aryl ethers in
the presence of sodium methoxide were limited to elec-
tron deficient aryl halides. The major side product was
the dehalogenated arene.
Due to the insolubility of the sodium methoxide, these
reactions were conducted in the presence of methanol.
Reactions conducted in pure methanol or in a 1:1 mixture
of methanol and toluene gave similar yields, but reactions
with a smaller amount of methanol resulted in incom-
plete consumption of aryl halide and increased amounts
of arene product. The methanol was used directly from
a commercial source, suggesting that careful elimination
of water and air is not necessary for this chemistry to
occur.
Uncatalyzed formation of methyl aryl ethers using
4-bromobenzonitrile were studied in various solvents in
order to compare these reactions to those catalyzed by
nickel complexes in a combination of untreated methanol
and toluene. Reactions conducted in methanol solvent
in the absence of metal or ligand resulted in only 5% yield
of the methyl aryl ether when heated for 48 h at 95 °C.
Analogous reactions conducted in anhydrous NMP sol-
Su r vey of Nick el P r ecu r sor s. A survey of several
potential nickel catalyst precursors showed that Ni(COD)2
was superior to other Ni(0) sources and to L2Ni(II)
complexes. Three Ni(0) catalyst precursors, Ni(COD)2,
Ni(CO)2(PPh3)2, and Ni(PPh3)4, were heated in the pres-
ence of DPPF, sodium alkoxide, and aryl halide. The
(22) Helquist, P.; Zask, A. J . Org. Chem. 1978, 1978, 1619-20.

5416 J . Org. Chem., Vol. 62, No. 16, 1997
Mann and Hartwig
Ta ble 5. Com p a r ison of Tol-BINAP a n d DP P F w ith
Ni(COD)2 a n d P d (DBA)2 Ca ta lyzed F or m a tion of Alk yl
a n d Silyl Eth er s
involving Tol-BINAP. Thus, the optimal nickel-contain-
ing catalyst at this time for formation of tert-butyl aryl
ethers is a combination of DPPF and Ni(COD)2. How-
ever, turnover numbers in the nickel-catalyzed formation
of tert-butyl aryl ethers are lower than those for analo-
gous reactions catalyzed by palladium complexes. Thus,
palladium complexes are preferred over nickel systems
for formation of tert-butyl aryl ethers.
As stated above, the formation of methyl and silyl aryl
ethers occurs in higher yields for nickel catalysts than
for palladium catalysts. The formation of methyl aryl
ethers occurred in higher yields when catalyzed by the
combination of Ni(COD)2 and Tol-BINAP than when
catalyzed by the combination of DPPF and Ni(COD)2.
Thus, the most effective group 8 catalyst for formation
of methyl aryl ethers from aryl halides at this time is a
combination of BINAP and Ni(COD)2.
At this time, the most effective catalyst for formation
of tert-butyldimethyl silyl ethers from aryl halides is
DPPF and Ni(COD)2. The more hindered NaOTBDMS
appeared to require a sterically less demanding ligand.
Reactions between aryl halides and this siloxide cata-
lyzed by Ni(COD)2 and Tol-BINAP required longer reac-
tion times and afforded lower yields of tert-butyldimeth-
ylsilyl ether than did reactions with Ni(COD)2 and DPPF.
Similar rates and yields for the formation of silyl aryl
ether were observed in reactions with Tol-BINAP or
DPPF and Pd(DBA)2, but these reactions occurred in
lower yields than those catalyzed by DPPF and Ni(COD)2.
reaction containing Ni(COD)2 showed the fastest rate and
best selectivity for converting 4-bromobenzophenone to
(4-tert-butoxyphenyl)phenylmethanone. In 12 h at 95 °C,
the ratio of aryl halide:arene:ether determined by GC
were 0:1:11 for reactions involving Ni(COD)2, 2:1:3 for
those involving Ni(CO)2(PPh3)2, and 13:3:1 for those
involving Ni(PPh3)4.
A combination of the five Ni(II) catalyst precursors,
Ni(PPh3)2Cl2, Ni(DPPF)Cl2, Ni(DPPP)Cl2 (DPPP ) 1,3-
bis(diphenylphosphino)propane)), Ni(acac)2‚10H2O, and
Ni(OAc)2‚4H2O, and DPPF (or DPPP in the case of
Ni(DPPP)Cl2), were tested in similar fashion for reaction
of 4-bromobenzophenone with NaO-t-Bu. Reactions in-
volving Ni(DPPF)Cl2, Ni(DPPP)Cl2, Ni(acac)2‚10H2O, and
Ni(OAc)2‚4H2O produced less than 5% aryl ether, as
determined by GC, and left a majority of the starting aryl
halide unreacted after the solution was heated for 12 h
at 95 °C. A combination of 15% Ni(PPh3)2Cl2 and 30%
DPPF converted half of the aryl halide to ether after the
solution was heated for 2 h at 95 °C, and no further
reaction occurred after an additional 12 h. Reactions
employing 5% Ni(COD)2 and 10% ligand did not com-
pletely consume the aryl halide after 20 h at 95 °C. There
was no significant difference in selectivity or yield in
reactions containing 10% or 15% nickel precatalyst
although the reactions with 15% Ni(COD)2 were faster.
Again, the reaction yields for formation of tert-butyl and
silyl aryl ethers were not dependent on whether a 1:1 or
2:1 ratio of ligand to catalyst was used. However, a 2:1
ratio of ligand to Ni(COD)2 gave higher yields than a 1:1
ratio for formation of methyl aryl ethers.23
Com p a r ison of DP P F a n d Tol-BINAP : Op tim ized
Ca ta lysts for F or m a tion of ter t-Bu tyl, Meth yl, a n d
Silyl Ar yl Eth er s. Table 5 shows the results for a brief
comparison of the reactions involving Tol-BINAP and
DPPF in conjunction with Ni(COD)2 as catalyst for
formation of alkyl and silyl ethers. Buchwald recently
published the use of Tol-BINAP or BINAP and Pd2(DBA)3
for the synthesis of aryl ethers,12 oxygen-containing
heterocycles,24 aminopyridines,25 and aryl amines.26 For
the nickel-catalyzed formation of tert-butyl aryl ethers,
reactions involving a combination of Ni(COD)2 and DPPF
gave higher yields of tert-butyl ether than did reactions
Con clu sion
In short, we have shown that Ni(COD)2 can catalyze
the formation of both alkyl and silyl aryl ethers with
electron deficient aryl halides in arene solvents or a
mixture of arene and alcohol. For the formation of
methyl and silyl aryl ethers, the yields of the nickel-
catalyzed chemistry are higher than those for analogous
reactions catalyzed by DPPF and Tol-BINAP-ligated
palladium. Our results show that the selection of cata-
lyst for a specific set of reagents may require one to test
a variety of metal ligand systems until the mechanistic
aspects of both palladium- and nickel-catalyzed ether-
ations is better understood. We plan to pursue mecha-
nistic studies as a means to address these issues of
catalyst choice.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents were weighed in a drybox
under N2. Reagent weights have errors of (0.2 mg using a
microbalance and antistatic bar. Unless otherwise stated, all
solvents were dried with sodium metal and benzophenone prior
to use. Aryl halides and sodium alkoxides were used as
obtained from commercial suppliers without further purifica-
tion. GC yields were calculated with respect to the response
factors of trimethoxybenzene or naphthalene as internal
standards.
Gen er a l P r oced u r e for th e Isola tion of Alk yl a n d Silyl
Ar yl Eth er s: (4-ter t-Bu toxyp h en yl)p h en ylm eth a n on e (1)
fr om 4-Br om oben zop h en on e (2) Ca ta lyzed by Ni(COD)2
a n d DP P F . To a screw capped vial were added 17.0 mg of
Ni(COD)2 (0.0618 mmol), 68.5 mg of DPPF (0.124 mmol), 44.0
mg of sodium tert-butoxide (0.458 mmol), and 100.3 mg of
4-bromobenzophenone (0.3843 mmol). To this solid mixture
was added 4 mL of toluene. The vial was capped under N2
and heated in an oil bath at 95 °C for 18 h. After being cooled
to room temperature, the crude mixture was adsorbed onto
silica gel and the product was isolated in 67% yield by column
chromatography eluting with 30:1 hexanes/ethyl ether to
(23) The yields in Tables 1-2 and 4-5 were conducted using a 2:1
ratio of ligand to catalyst but it was discovered later that a 1:1 ratio
of ligand to catalyst gave similar yields by GC.
(24) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 10333-10334.
(25) Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1996, 61, 7240-
7241.
(26) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215-7216.

Protected Phenols from Aryl Halides
J . Org. Chem., Vol. 62, No. 16, 1997 5417
produce a pale yellow liquid: 1H NMR (CDCl3) δ 1.44 (s, 9H),
7.05 (d, J ) 8.6 Hz, 2H), 7.52 (m, 3H), 7.77 (d, J ) 8.6 Hz,
4H); 13C NMR (CDCl3) δ 28.9, 79.6, 122.2, 128.2, 129.8, 131.69,
131.72, 132.0, 138.1, 160.0, 195.8; MS m/ z 254; HRMS calcd
for C17H18O2 254.1307, found 254.1307.
(4-ter t-Bu t oxyp h en yl)p h en ylm et h a n on e (1) fr om
4-Ch lor oben zop h en on e (3) Ca ta lyzed by Ni(COD)2 a n d
DP P F . Reaction at 95 °C for 10 h gave a 69% yield of the
product after silica gel chromatography eluting with 30:1
pentane/ethyl ether.
1 fr om 2 Ca ta lyzed by Ni(COD)2 a n d DP P E. Reaction
at 95 °C for 14 h gave 93% yield of the product after silica gel
chromatography eluting with 30:1 hexanes/ethyl ether.
4-Meth oxyben zop h en on e (4) fr om 2 Ca ta lyzed by
Ni(COD)2 a n d DP P F . Reaction at 80 °C for 16 h gave 76%
yield of the product after silica gel chromatography eluting
with 30:1 pentane/ethyl ether. The spectroscopic data of the
product were identical to those of commercial material (Ald-
rich).
4 fr om 3 Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction
in a mixture of methanol/toluene (2 mL/2 mL) at 105 °C for
12 h gave an 81% yield of the product after silica gel
chromatography eluting with 30:1 pentane/ethyl ether.
p-An isa ld eh yd e (5) fr om 4-Br om oben za ld eh yd e (6)
Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction in a mixture
of methanol/toluene (1 mL/3 mL) at 70 °C for 2 h gave a 61%
yield of the product after silica gel chromatography eluting
with 30:1 hexanes/ethyl acetate. The spectroscopic data of the
product were identical to commercial material (Aldrich).
respect to the trimethoxybenzene internal standard. The
response factor was obtained from isolated, purified product.
All GC yields reported in the tables are an average of two or
more runs.
9 fr om 4-Ch lor ob en zon it r ile (10) Ca t a lyzed b y Ni-
(COD)2 a n d DP P F . Reaction at 95 °C for 17 h gave the
product in 72% yield as determined by GC analysis.
4-Met h oxyb en zon it r ile (11) fr om
8 Ca t a lyzed b y
Ni(COD)2 a n d DP P F . Reaction at 95 °C for 1.7 h gave the
product in 59% yield and benzonitrile in a 40% yield as
determined by GC analysis. The response factor of the product
was determined from material obtained from Aldrich.
11 fr om 10 Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction
in methanol at 95 °C for 2 h gave the product in 48% yield
determined by GC analysis.
4-(ter t-Bu tyld im eth ylsiloxy)ben za ld eh yd e (12) fr om 6
Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction at 95 °C for
2.8 h gave the product in a 100% yield by GC analysis. The
response factor of the product was obtained from the isolated
material. The spectroscopic data of the product were identical
to that reported previously.28
7 fr om 8 Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction
at 95 °C for 2.7 h gave the product in 97% yield as determined
by GC analysis.
12 fr om 6 Ca ta lyzed by P d (DBA)2 a n d DP P F . Reaction
at 120 °C for 2.3 h gave the product in 79% yield as determined
by GC analysis.
7 fr om 8 Ca ta lyzed by P d (DBA)2 a n d DP P F . Reaction
at 120 °C for 2 h gave the product in a 47% yield with 13% of
the aryl halide remaining as determined by GC analysis.
Complete reaction occurred after the solution was heated for
5 h, and the yield of the product after this time was 59% as
determined by GC analysis.
9 fr om 8 Ca ta lyzed by P d (P P h 3)4 a n d DP P F . Reaction
at 95 °C for 2 h gave the product in 91% yield as determined
by GC analysis.
9 fr om 8 Ca ta lyzed by P d (DBA)2 a n d DP P F . Reaction
at 95 °C for 2 h gave the product in 98% yield as determined
by GC analysis.
9 fr om 8 Ca ta lyzed by P d (OAc)2 a n d DP P F . Reaction
at 95 °C for 2 h gave the product in 100% yield as determined
by GC analysis.
4-(ter t-Bu tyld im eth ylsiloxy)ben zon itr ile (7) fr om
8
Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction at 95 °C for
2 h gave a 69% yield of the product27 after silica gel chroma-
tography eluting with 30:1 hexanes/ethyl ether: 1H NMR
(CDCl3) δ 0.20 (s, 6H), 0.95 (s, 9H), 6.86 (d, J ) 8.5 Hz, 2H),
7.51 (d, J ) 8.6 Hz, 2H); 13C NMR (CDCl3) δ -0.43, 18.3, 25.6,
104.7, 119.3, 121.0, 124.1, 159.8. After subsequent elution
with 1:1 hexanes/ether, 4-cyanophenol was isolated in 12%
yield.
4-ter t-Bu toxyben zon itr ile (9) fr om 4-Br om oben zon i-
tr ile (8) Ca ta lyzed by Ni(COD)2 a n d DP P F . Reaction at
100 °C for 17 h gave 59% yield of the product after silica gel
chromatography eluting with 20:1 hexanes/ethyl acetate.
9 fr om 8 Ca ta lyzed by P d (OAc)2 a n d DP P F . Reaction
at 120 °C for 12 h gave a 94% yield of the light yellow product
after silica gel chromatography eluting with 30:1 hexanes/ethyl
ether: 1H NMR (CDCl3) δ 1.41 (s, 9H), 7.03 (d, J ) 8.6 Hz,
2H), 7.56 (d, J ) 8.6 Hz, 2H); 13C NMR (CDCl3) δ 28.8, 80.2,
105.7, 119.1, 123.0, 133.4, 159.9; MS m/ z 175; HRMS calcd
for C11H13NO 175.0997, found 175.0998.
1 fr om 3 Ca ta lyzed by P d (OAc)2 a n d DP P F . Reaction
at 95 °C for 12 h gave an 89% yield of the product after silica
gel chromatography eluting with 30:1 hexanes/ethyl ether.
1 fr om 3 Ca ta lyzed by P d (DBA)2 a n d DP P F . Reaction
at 110 °C for 36 h gave an 84% yield of the product after silica
gel chromatography eluting with 30:1 pentane/ethyl ether.
N1,N1-Dieth yl-4-ter t-bu toxyben za m id e fr om N1,N1-
Dieth yl-4-br om oben za m id e Ca ta lyzed by P d (DBA)2 a n d
DP P F . Reaction at 120 °C for 13 h gave a 56% yield of the
product after silica gel chromatography eluting with 3:5
hexanes/ethyl acetate. Anal. Calcd for C15H23O2N: C, 72.25;
H, 9.30; N, 5.62. Found: C, 72.45; H, 9.22; N, 5.48.
Gen er a l P r oced u r e for Obta in in g th e GC Yield for th e
F or m a tion of Alk yl a n d Silyl Ar yl Eth er s. 1 fr om 2
Ca ta lyzed by Ni(COD)2 a n d DP P F . To a screw capped vial
were added 2.2 mg of Ni(COD)2 (0.0080 mmol), 9.6 mg of DPPF
(0.017 mmol), 8.0 mg of sodium tert-butoxide (0.083 mmol),
10.0 mg of 4-bromobenzophenone (0.038 mmol), and 9.3 mg
(0.055 mmol) of trimethoxybenzene. To this solid mixture was
added 1.6 mL of toluene. The vial was capped under N2 and
heated in an oil bath at 95 °C for 2 h. After the solution was
cooled to room temperature, 0.5 µL of the crude reaction was
injected into the GC. The GC yield of the product was 89%
after correcting for the response factor of the product with
13 fr om 14 Ca ta lyzed by P d (OAc)2 a n d DP P F . Reaction
at 100 °C for 35 h gave the product in 38% yield as determined
by GC analysis.
9 fr om 10 Ca ta lyzed by P d (DBA)2 a n d DP P F . Reaction
at 95 °C for 17 h gave the product in 82% yield by GC analysis.
9 fr om 8 Ca ta lyzed by Ni(COD)2 a n d Tol-BINAP .
Reaction at 95 °C for 2 h gave the product in 40% yield as
determined by GC analysis with 31% of the starting aryl halide
remaining. After being heated for 5 h, the reaction gave the
product in 47% yield by GC analysis with 17% of the starting
aryl halide remaining.
11 fr om 8 Ca ta lyzed by Ni(COD)2 a n d Tol-BINAP .
Reaction at 95 °C for 2 h gave the product in 91% yield as
determined by GC analysis.
7 fr om 8 Ca ta lyzed by Ni(COD)2 a n d Tol-BINAP .
Reaction at 95 °C for 2 h gave the product in 76% yield
determined by GC with 17% of the starting halide remaining.
After being heated for 5 h, the reaction gave the product in
59% yield by GC analysis with 6% of the starting aryl halide
remaining. The decrease in yield is due to decomposition of
the product upon prolonged heating.
7 fr om 8 Ca ta lyzed by P d (DBA)2 a n d Tol-BINAP .
Reaction at 120 °C for 2 h gave the product in 85% yield as
determined by GC analysis.
Gen er a l P r oced u r e for t h e F or m a t ion of Sod iu m
Siloxid es. A slight excess of silanol was added dropwise to a
pentane solution of freshly cut sodium metal. The reaction
was stirred for 12 h at room temperature at which time all
the sodium metal was consumed. The remaining pentane
mixture was evaporated to dryness, and the resultant white
(28) Swenton, J . S.; Carpenter, K.; Chen, Y.; Kerns, M. L. J . Org.
Chem. 1993, 58, 3308-3316.
(27) Saunders, D. G. Synthesis 1988, 5, 377-379.

5418 J . Org. Chem., Vol. 62, No. 16, 1997
Mann and Hartwig
product was rinsed twice with pentane to remove the excess
silanol. The white product was dried under vacuum for 12 h.
Note Ad d ed in P r oof: Concurrent work on nickel-
catalyzed amination recently appeared: Wolf, J . P.;
Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 6054-
6058.
Ack n ow led gm en t. This work was generously sup-
ported by the National Institutes of Health, Institute
of General Medical Sciences. We also gratefully ac-
knowledge a DuPont Young Professor Award, a National
Science Foundation Young Investigator Award, the
Exxon Education Foundation, and a Dreyfus Founda-
tion New Faculty Award for support for this work.
J .F.H. is a fellow of the Alfred P. Sloan Foundation. We
thank J ohnson-Matthey Alpha/Aesar for the donation
of palladium chloride.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details with quantities of reagents employed (8 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O970453V