C-H activation/borylation/oxidation: A one-pot unified route to meta-substituted phenols bearing ortho-/para-directing groups

Article abstract of DOI:10.1021/ja0349857

An efficient one-pot C-H activation/borylation/oxidation protocol for the preparation of phenols is described. This method is particularly attractive for the generation of meta-substituted phenols bearing ortho-/para-directing groups, as such substrates are difficult to access by other phenol syntheses. Copyright

Full text of DOI:10.1021/ja0349857

Published on Web 06/06/2003
C-H Activation/Borylation/Oxidation: A One-Pot Unified Route To
Meta-Substituted Phenols Bearing Ortho-/Para-Directing Groups
Robert E. Maleczka, Jr.,* Feng Shi, Daniel Holmes, and Milton R. Smith, III*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received March 4, 2003; E-mail: maleczka@cem.msu.edu
Scheme 1
Phenols serve as synthetic building blocks for the construction
of compounds ranging from polymers to pharmaceuticals.1 Despite
numerous phenol syntheses,2,3 straightforward routes to 3,5-
disubstituted phenols bearing ortho-/para- directing groups are
lacking.4 Traditional approaches to such phenols are obstructed by
the fact that electronic effects typically govern regioselectivities in
aromatic substitution chemistry. Thus, the 5-position in 1,3-
disubstituted benzenes is notoriously inert when the substituents
are ortho/para directors. Illustrative of this problem is 3-bromo-5-
chlorophenol (1). To the best of our knowledge,5 the only two
descriptions of this potentially useful6 and versatile molecule date
back to 1926,7 including a synthesis by Hodgson and Wignall7a
that requires 10 steps starting from TNT!
Scheme 2
Scheme 3
Transition metal catalyzed C-H activations potentially offer
general solutions to this dilemma since steric effects often dictate
the regioselectivity of arene activation. Indeed, sterics dominate
the regioselectivities for catalytic aromatic C-H activation/bory-
lations,8 which effectively impart the chemical versatility of
arylboronic acids and esters to aromatic C-H bonds. Moreover,
we recently demonstrated that the functional group tolerance and
selectivity of Ir catalysts enable the combination of such aromatic
borylations with subsequent chemical events.8a Since it is known
that Oxone can oxidize arylboronic esters to phenols,9 we hypoth-
esized that a one-pot aromatic C-H activation/borylation/oxidation
protocol (Scheme 1) would constitute the most direct route to
numerous structurally simple phenols whose practical use is
currently limited by their accessibility.
Iridium phosphine complexes catalyze the conversion of neat
mixtures of arenes and pinacolborane (H-BPin) to arylboronic
esters, where the arene is the limiting reagent.8a Thus, we first
attempted oxidation of arylboronic esters in crude reaction mixtures
with Oxone using the literature protocol (Oxone, base, buffer, in
10-15% aqueous acetone at 2 °C).9 These attempts gave irrepro-
ducible yields. Surprisingly, a 1:1 acetone-water solution of Oxone,
where the base and buffer were omitted, gave good to excellent
yields at room temperature.10
Our typical protocol11 (Scheme 2) consists of heating an
H-BPin/arene mixture (H-BPin:arene ≈ 1.5-2.5:1) with (Ind)-
Ir(COD) (0.02 equiv vs arene) and 0.02 equiv 1,2-bis(dimeth-
ylphosphino)ethane (dmpe) at 150 °C (or 1,2-bis(diphenylphosphino)-
ethane (dppe) at 100 °C)8a until the borylation is complete by GC-
FID. After the reaction mixture has cooled to room temperature,
acetone and an aqueous solution of Oxone are added sequentially.
Within 10 minutes stirring at room temperature the oxidation is
usually complete, typically affording the phenol as the only aromatic
product. As shown in Scheme 2, 3-bromo-5-chlorophenol (1) was
prepared in 83% yield from commercially available 3-bromochlo-
robenzene. In contrast to the arduous route from TNT, our sequence
can be completed in a single flask over the course of an afternoon.
Table 1 summarizes syntheses of various other phenols using
this protocol. As previously noted,8 electron-donating substituents
retard aromatic borylations, but subsequent oxidations of the
resulting arylboronic esters and the isolated yields of the corre-
sponding phenols were not visibly perturbed by electronic effects.
That said, for electron-poor phenols, complete removal of hydrogen-
bond accepting solvents such as acetone or ether required distillation
or sublimation.11 Improvements over published routes were realized
for most of the known phenols in Table 1.11 Moreover, preparations
of phenols 7 and 14-17 are described here for the first time.5
Perhaps most noteworthy, aromatic borylation/oxidation appears
to be the first unified approach to 1-18.
Over-oxidation12 was not a problem, as quinones were not
observed. Even for substrates bearing oxidizable nitrogens, such
as the pyridine of entry 5 and the amino group of entry 16, no
N-oxides were detected in the isolated products.13 Ethers and esters
could survive the transformation (entries 3-4), but demethylation
of 2,6-dichloroanisole (entry 8) accompanied borylation.14 The small
van der Waals radius of fluoride makes possible the preparation of
5-bromo-2-fluorophenol (13). Furthermore, multiple hydroxyls can
be installed by adjusting the amounts of H-BPin and Oxone (entries
13-14).
Borylations can also be performed in inert solvents such as
cyclohexane (entries 5, 9-11, 13-15), which is then removed prior
to the oxidation step. The oxidation step can be performed in other
water-miscible solvents such as acetonitrile, DMF, dioxane, THF,
or diglyme. Thus, while acetone remains our solvent of choice for
the oxidation step, dimethyldioxirane is not a required intermedi-
ate.15 Oxidations in CHCl3 or CH2Cl2 failed.16
While bromide and chloride tolerance was universal, partial
deiodination of 1-bromo-3-iodobenzene occurred during borylation
9
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J. AM. CHEM. SOC. 2003, 125, 7792-7793
10.1021/ja0349857 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Phenols via One-Pot C-H
with (Ind)Ir(COD). This could be avoided by using Ishiyama and
Miyaura’s [Ir(OMe)(COD)]2-dtbpy system to borylate with B2Pin2
at room temperature (Scheme 3).17
Activation/Borylation/Oxidationa
In summary, one-pot aromatic borylation/oxidation is an efficient
protocol for preparing phenols. This method is particularly attractive
for the generation of meta-substituted phenols bearing ortho-/para-
directing groups, as such substrates are often difficult to access by
other means.
Acknowledgment. We thank the Michigan Life Sciences
Corridor, NSF (CHE-9984644 to R.E.M.), NIH (GM63188 to
M.R.S.), and the Yamanouchi USA Foundation for generous
support. We also thank Dr. Jian-Yang Cho and Mr. Ghayoor Abbas
Chotana for useful discussions and preparation of the Ir-catalysts
and Dr. Man Kin Tse for studying the borylation of 1-bromo-4-
fluorobenzene.
Supporting Information Available: Experimental procedures and
spectral data for phenols 1-18 along with comparisons to previously
described syntheses (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New York,
1996.
(2) (a) Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W.
J. Chem. Soc., Perkin Trans. 2 2002, 1135-1150. (b) George, T.; Mabon,
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Trans. 1 2000, 2529-2574. (c) Sweeney, J. B. Contemp. Org. Synth. 1997,
4, 435-453.
(3) For more recent innovative approaches, see: (a) Hoarau, C.; Pettus, T.
R. R. Synlett 2003, 127-137. (b) Guo, Z.; Schultz, A. G.; Antoulinakis,
E. G. Org. Lett. 2001, 3, 1177-1180. (c) Marchueta, I.; Olivella, S.; Sola,
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(4) For an alternative approach, see: Keil, W.; Wedemeyer, K.; Evertz, W.
Ger. Offen. DE 2344925, 1975.
(5) Per SciFinder Scholar.
(6) Ho¨ger, S.; Bonrad, K.; Mourran, A.; Beginn, U.; Mo¨ller, M. J. Am. Chem.
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(7) (a) Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926, 2077-2079. (b)
Kohn, M.; Zandman, A. Monatsh. Chem. 1926, 47, 357-377.
(8) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M.
R., III. Science 2002, 295, 305-308 and references cited therein. (b)
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J. F. J. Am. Chem. Soc. 2002, 124, 390-391 and references cited therein.
(9) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117-5118.
(10) Interestingly, Webb and Levy (ref 9) reported that oxidations above 15
°C gave lower yields.
(11) See Supporting Information (SI) for full details.
(12) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T. R.
R. Org. Lett. 2002, 4, 285-288 and references cited therein. (b) Crandall,
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(13) Preliminary spectroscopic studies suggest that transient amounts of
N-oxides are being formed during these reactions. Further analyses of
this process are ongoing and will be reported elsewhere.
(14) Demethylation of 2,6-dichloroanisole is known to be facile. See Majetich,
G.; Zhang, Y.; Wheless, K. Tetrahedron Lett. 1994, 47, 8727-8730.
(15) We have not ruled out in situ formation of DMDO when acetone is the
solvent. However, our reactions are run in the absence of base or buffer,
which are typically added to promote DMDO formation. See ref 9 and
Murray, R. W. Chem. ReV. 1989, 89, 1187-1201. Furthermore, a reaction
using DMDO in place of aq Oxone only afforded a trace of the phenol.
(16) In contrast, 3,4-dichlorophenol was obtained in 44% yield when Bu4NI
(25 mol %) was added to an oxidation of 3,4-dichlorophenylpinacolborane
run in CH2Cl2.
a Typical conditions: Arene, H-BPin, 2 mol % (Ind)Ir(COD), 2 mol %
dmpe, neat under N2; then acetone, 1 equiv (per boron) aqueous Oxone, 25
°C, 7 min (see SI for details). b Borylation time can be H-BPin batch
dependent. c Average isolated yields of two runs. d The borylation was
described in ref 8a. e See SI for slight deviation from typical conditions.
f Borylation run with dppe at 100 °C. g Borylation run in C6H12.
(17) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int.
Ed. 2002, 41, 3056-3058.
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