Aromatic borylation/amidation/oxidation: A rapid route to 5-substituted 3-amidophenols

Article abstract of DOI:10.1021/ol060207i

5-Substituted 3-amidophenols are prepared by subjecting 3-substituted halobenzenes to an Ir-catalyzed aromatic borylation, followed by a Pd-catalyzed amidation, and finally an oxidation of the boronic ester intermediate. The entire C-H activation borylation/amidation/oxidation sequence can be accomplished without isolation of any intermediate arenes. Usefully, amide partners can include lactams, carbamates, and ureas.

Full text of DOI:10.1021/ol060207i

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1411-1414
Aromatic Borylation/Amidation/
Oxidation: A Rapid Route to
5-Substituted 3-Amidophenols
Feng Shi, Milton R. Smith, III,* and Robert E. Maleczka, Jr.*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
maleczka@chemistry.msu.edu
Received January 24, 2006
ABSTRACT
5-Substituted 3-amidophenols are prepared by subjecting 3-substituted halobenzenes to an Ir-catalyzed aromatic borylation, followed by a
Pd-catalyzed amidation, and finally an oxidation of the boronic ester intermediate. The entire C H activation borylation/amidation/oxidation
−
sequence can be accomplished without isolation of any intermediate arenes. Usefully, amide partners can include lactams, carbamates, and
ureas.
5-Substituted 3-amidophenols, with the amido group includ-
ing ureas and carbamates, represent a structure motif found
in kinase inhibitors,1 growth regulators,2 and other biologi-
cally important compounds.3 Natural products containing
5-substituted 3-amidophenolic cores include the maytansi-
noids, herbimycins, trienomycins, and other ansamycin anti-
biotics,4 which are biosynthesized from 3-amino-5-hydroxy-
Figure 1. 3-Amino-5-hydroxybenzoic acid (AHBA).
benzoic acid (AHBA),5 itself a 5-substituted 3-amidophenol
(Figure 1).
are readily available. Unfortunately, this condition is rarely
The most common synthetic routes to 5-substituted 3-ami-
met because the vagaries of aromatic substitution make
dophenols involve an amidation of the functionalized aniline
selective 1,3,5-trisubstitution of benzenes an onerous task.
with carboxylic acid derivatives6 or an isocyanate.7 Such
As a result, preparations of AHBA have typically been long
and harsh.8 Likewise, many existing syntheses of 5-substi-
tuted 3-amidophenolic natural products use an inordinate
number of steps to build the aromatic moiety.9
approaches can be straightforward, if the appropriate anilines
(1) (a) Thaimattam, R.; Daga, P.; Rajjak, S. A.; Banerjee, R.; Iqbal, J.
Bioorg. Med. Chem. 2004, 12, 6415-6425. (b) Wityak, J.; Das, J.; Moquin,
R. V.; Shen, Z.; Lin, J.; Chen, P.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen,
D. R.; Fang, Q.; de Fex, H. F.; Schieven, G. L.; Kanner, S. B.; Barrish, J.
C. Bioorg. Med. Chem. Lett. 2003, 13, 4007-4010.
We had previously overcome similar electronic obstacles
impeding the preparation of a variety of 3,5-disubstituted
phenols. Specifically, we showed that sterically controlled
regioselective catalytic aromatic borylation10 of 1,3-disub-
stituted arenes, followed by an in situ oxidation of the newly
installed C-B bond constitutes an efficient one-pot synthesis
of the desired phenols (Scheme 1).11
(2) (a) Bollinger, F. G.; D’Amico, J. J. U.S. Patent 4,146,386, 1979. (b)
Kane, J. L., Jr.; Hirth, B. H.; Liang, B.; Gourlie, B. B.; Nahill, S.; Barsomian,
G. Bioorg. Med. Chem. Lett. 2003, 13, 4463-4466.
(3) Scifinder Scholar reveals ∼4700 structures in ∼600, mostly patent,
references.
(4) (a) Wrona, I. E.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am.
Chem. Soc. 2005, 127, 15026-15027. (b) Yu, T.-W.; Muller, R.; Muller,
M.; Zhang, X.; Draeger, G.; Kim, C.-G.; Leistner, E.; Floss, H. G. J. Biol.
Chem. 2001, 276, 12546-12555. (c) Floss, H. G. Nat. Prod. Rep. 1997,
14, 433-452 and references therein. (d) Larson, G. M.; Schaneberg, B. T.;
Sneden, A. T. J. Nat. Prod. 1999, 62, 361-363. (e) Kibby, J. J.; Rickards,
R. W. J. Antibiot. 1981, 34, 605-607.
(6) Angeles, E.; Santillan, A.; Martinez, I.; Ramirez, A.; Moreno, E.;
Salmon, M.; Martinez, R. Synth. Commun. 1994, 24, 2441-2447.
(7) Shah, M. N.; Joshi, V. Indian J. Heterocycl. Chem. 1994, 4, 59-62.
(8) Becker, A. M.; Rickards, R. W.; Brown, R. F. C. Tetrahedron 1983,
39, 4189-4192 and references therein.
(5) For a library built around AHBA, see: Dankwardt, S. M.; Phan, T.
M.; Krstenansky, J. L. Mol. DiVersity 1996, 1, 113-120.
10.1021/ol060207i CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

protocols,16 both of which are quite mild and versatile.
Carboxyamides, ureas, and carbamates have been coupled
with a variety of aryl halides and triflates. Nonetheless, to
the best of our knowledge there are no reported examples
of amides coupling with aryl halides that bear a boronic ester
group. As such, we were concerned that the C-N coupling
conditions could also promote an undesired Suzuki reaction
between the aryl halide and the boronic ester group. In fact,
we had previously demonstrated that polyphenylenes could
be efficiently generated by just such a process.10b
Scheme 1. One-Pot Aromatic Borylation/Oxidation11 and
Aromatic Borylation/Amidation13 Schemes
In the aforementioned aromatic borylation/amination se-
quence, we found that Suzuki side reactions could be
suppressed when the C-N couplings were run under dry
conditions, which were achieved, in part, through the use of
anhydrous K3PO4 as the base.13 For the proposed amidation
protocol, we hoped that Suzuki rates could be similarly
curbed despite the lower reactivity and elevated acidity of
amides relative to amines.
Given these uncertainties, our initial efforts focused solely
on the metal mediated amidation of boronic ester substituted
aryl halides. We first tried the amidation of 2a using
acetamide and Cu-catalyzed conditions,15 but this met with
little success (Scheme 3). Although control experiments
A hallmark of Ir-catalyzed aromatic borylation (the first
step of our phenol synthesis) is its tolerance of halogen
substituents.10 We have shown that these halogens can
participate in Pd-catalyzed amination reactions12 allowing
for a one-pot aromatic borylation/amination route to a variety
of amino-substituted arylboronic esters (Scheme 1).13
In the context of the one-pot protocols for aromatic
borylation/amination and aromatic borylation/oxidation, the
putative aromatic borylation/amidation/oxidation approach
to 5-substituted 3-amidophenols in Scheme 2 piqued our
Scheme 2. Proposed One-Pot Aromatic Borylation/Amidation/
Oxidation Route to 5-Substituted 3-Amidophenols
Scheme 3
curiosity. Such a method would be uniquely efficient for
preparing these types of functionalized arenes, especially if
all reactions could be telescoped into a single reaction vessel.
For the key amidation step, we looked to follow the Ir-
catalyzed aromatic borylation with an in situ C-N coupling
between the halosubstituted arylboronic ester and an added
amide. Over the past several years, Buchwald and co-workers
have developed both Pd-14 and Cu-mediated15 amidation
proceeded as described by Buchwald, the couplings failed
with aryl halides containing a boronic ester group. Copper
loadings of 1-10 mol % were tested on amidations of both
purified and crude 2a, with both acetamide and benzamide.
Unfortunately, throughout all experiments protodeborylation
remained the major, if not exclusive, reaction during these
amidation attempts.
(9) Smith’s synthesis of trienomycin A is illustrative in this regard, as
nearly 25% of their total synthetic steps were dedicated to building the
aromatic region of the target molecule. See: Smith, A. B., III; Barbosa, J.;
Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1996, 118, 8316-8328.
(10) (a) Tse, M. K.; Cho, J.-Y.; Smith, M. R., III Org. Lett. 2001, 3,
2831-2833. (b) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.;
Smith, M. R., III Science 2002, 295, 305-308. (c) Ishiyama, T.; Takagi,
J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002, 41, 3056-
3058. (d) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.
R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390-391. (e) For a review
see: Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2003, 680, 3-11.
(11) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III J. Am.
Chem. Soc. 2003, 125, 7792-7793.
In contrast, the amidation of 2a with acetamide worked
under Pd-catalysis,14 with no more than trace Suzuki coupling
(14) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. (b)
Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048. (c)
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
(15) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421-7428.
(16) Also see: Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035-
2038.
(12) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.
(13) Holmes, D.; Chotana, G. H.; Maleczka, R. E., Jr.; Smith, M. R., III
Org. Lett. 2006, 8, 1407-1410.
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Org. Lett., Vol. 8, No. 7, 2006

or protodeborylation occurring. Furthermore, slight modifica-
tions to the literature stoichiometries and other reaction
conditions decreased amidation times of the halogenated
arylboronic ester from overnight to a few hours (Scheme
3).17 Moreover, the amidation could be carried out on crude
2a generated from the Ir-catalyzed aromatic borylation of
1a, with pinacol borane (HBPin), catalytic [Ir(OMe)(COD)]2,
and dtbpy ligand.
esters on silica gel makes for a less than ideal protocol.
Therefore we investigated if the crude aromatic borylation/
amidation product could be adequately “cleaned-up” for the
oxidation step without actually needing to isolate the ami-
doarylboronic ester. Toward this end we were gratified that
passing the crude reaction mixture through a short plug of
silica gel provided a mixture that once evaporated could be
successfully subjected to the standard oxone conditions
(Table 1).17,19
With the one-pot borylation/amidation portion of the pro-
posed sequence in hand and optimized, we undertook con-
verting the amide-substituted arylboronic ester to the ami-
dophenol. Our previously developed one-pot catalytic aro-
matic borylation/oxidation used oxone as the oxidant.11 In
those oxidations, acetone was the standard solvent and the
reactions were typically run in the absence of any base or
buffer. Nonetheless, we had also shown ethereal solvents to
be acceptable and Webb and Levy employed NaHCO3 as
buffer in their original report.18 Thus, we expected that nei-
ther the solvent nor the Cs2CO3 used in the amidation step
would interfere with our plans to conclude the one-pot pro-
cess with the oxone oxidation of the crude amidation inter-
mediate (Scheme 2). This hypothesis proved incorrect as all
attempts at a strictly one-pot catalytic aromatic borylation/
amidation/oxidation failed to give any of the desired phenol.
We were able to determine that this failure stemmed from
the catalytic milieu and not the amidation intermediates, as
isolated 3a (see Scheme 3) could be oxidized to the phenol
with oxone in 95% yield. While a one-pot aromatic boryla-
tion/amidation followed by purification and then an oxidation
would make for a fairly efficient route to 5-substituted 3-ami-
dophenols, the poor resolution of amido-substituted boronic
Since the silica gel plug removed only insoluble solids
and the most polar salts, pinacol originating from the
borylation step remained in the final reaction mixture.
Separating the pinacol from the similarly polar 5-substituted
3-amidophenols can be difficult. To avoid this problem, the
final oxidation mixture was worked up with NaIO4 to destroy
the diol. In this way the pure phenols could readily be
obtained in undiminished isolated yields.
With the 3-step protocol in place, we surveyed the scope
of the sequence against a variety of haloarenes and amides
(Table 1).17 For electron-deficient arylbromides reacting with
primary amides (entries 1-7, 9, and 10), the process was
clean and relatively high yielding. Suzuki byproducts and
protodeborylation were minimal, if observed at all. A range
of electron-withdrawing groups at the 5-position was toler-
ated, including esters and chloride. Benzonitriles could also
be transformed into the desired products; however, [Ir(OMe)-
(COD)]2 and dtbpy proved the C-H activation catalyst/ligand
combination of choice for these substrates. For most other
substrates tested, the substitution of [Ir(OMe)(COD)]2 and
dtbpy for (Ind)Ir(COD) and dmpe netted little difference in
the overall process (Scheme 3 vs entry 1). That said, in the
case of methyl 3-bromobenzoate the efficiency of the overall
sequence was affected by incomplete borylation. Fortunately,
simply reacting this substrate in an open flask (nitrogen
atmosphere) under the [Ir(OMe)(COD)]2 conditions allowed
the borylation to run to full conversion (entries 5 and 6).
Presumably, inhibition of catalysis is avoided when the
hydrogen byproduct can escape.
In addition to carboxyamides, carbamates and ureas were
also suitable amide partners. Several entries from this group
of substrates merit additional comment. By employing Boc-
NH2 (entry 6) we could generate a carbamate protected AH-
BA from commercially available starting materials in compe-
titive overall yield. Additionally, entry 7 showed how a di-
substituted urea could be formed without the need to prepare
functionalized isocyanates.20 Acrylamides could also be used
in this process. However, with acrylamide itself the desired
product could only be isolated in 37% yield (entry 9),
whereas the more substituted tiglic amide was less prone to
side reactions and afforded the final product in a synthetically
useful 66% yield (entry 10).
(17) (a) See the Supporting Information for details. (b) General procedure
for one-pot C-H activation/borylation/amidation/oxidation: In a drybox,
arene (2.0 mmol), HBPin (1.5-2.0 equiv), 2 mol % of (Ind)Ir(COD) (or
1.5 mol % of [Ir(OMe)(COD)]2), and 2 mol % of dmpe (or 3 mol % of
dtbpy for reactions run with [Ir(OMe)(COD)]2) were transferred into an
air-free flask equipped with a stirrer bar. (In reactions where solvent is
needed, the reagents were dissolved in 1-6 mL of n-hexane and transferred
to the air-free flask.) The flask was sealed (unless otherwise noted), brought
out of the drybox, and placed in an oil bath preheated to 150 °C (or at
room temperature for reactions run with [Ir(OMe)(COD)]2). The reaction
was run at this temperature until judged complete by GC-FID. At that time,
the reaction was allowed to cool to room temperature. If solvent was used,
it was removed by a gentle nitrogen flow. The crude borylation mixture
was then pumped under high vacuum for several hours to remove the
excessive HBPin. The flask was then returned to the drybox and charged
with 1 mol % of Pd2dba3, 3 mol % of xantphos, amide (1.05-1.15 equiv),
Cs2CO3 (1.4 equiv), and 6 mL of THF or DME. The flask was sealed,
taken out of the box, and heated to the indicated temperature. The reaction
was stirred at this temperature until judged complete by GC-FID. At this
time, the reaction mixture (typically a yellow suspension) was then cooled
to room temperature and filtered through a silica pad (1-2 cm thick × 4.5
cm diameter; ∼12 g) eluting with acetone until the filtrate showed no UV
activity on TLC (ca. 150-200 mL). The acetone was evaporated and the
residue was dissolved back in 6 mL of acetone (or more if needed to obtain
a homogeneous solution). To that stirred solution was added dropwise an
aqueous solution of oxone (1.33 g (1.0 equiv) in 6 mL water) and the
resulting reaction was stirred for 10 min at room temperature. At that time
an aqueous suspension of NaIO4 (430 mg (1.0 equiv per pinacol mol equiv)
in 2 mL water) was added in a single portion followed by 2 mL of acetone.
The mixture was further stirred for 1-2 h before being twice extracted
with EtOAc. To the aqueous layer was then added solid NaHSO3, and the
mixture was swirled until color appeared and then diminished. The aqueous
phase was then back extracted once or twice with EtOAc. The combined
organics were washed with brine, dried over MgSO4, and concentrated.
The residue was purified on silica gel chromatography (3.5 cm wide, 25-
30 cm long), using CH2Cl2/EtOAc or CH2Cl2/acetone eluent. Evaporation
followed by drying under high vacuum afforded the final product.
Reactions of aryl bromides with electron-releasing or
neutral groups and reactions that employ secondary amides
(including lactams) tended to afford the products in lower
(19) The composition of the offending species removed by the silica gel
plug is uncertain at this time.
(20) Note: Reaction of the same substrate with PMBNH(CO)NH2
afforded the corresponding urea substituted phenol in only 19% yield along
with adventitious Suzuki products.
(18) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117-5118.
Org. Lett., Vol. 8, No. 7, 2006
1413

Table 1. Catalytic Aromatic Borylation/Amidation/Oxidation of 3-Substituted Halobenzenesa
a Reagents and conditions: (i) arene (2 mmol scale), H-Bpin, 2 mol % of (Ind)Ir(COD)-dmpe, 150 °C, neat or hexane, sealed tube under N2; evaporate
(0.5-1.0 mmHg); (ii) H-Bpin, 1.5 mol % of [Ir(OMe)(COD)]2, 3 mol % of dtbpy, neat or hexane, rt; evaporate (0.5-1.0 mmHg); (ii) ∼1.10 equiv of amide,
1 mol % of Pd2dba3, 3 mol % of xantphos, 1.4 equiv of Cs2CO3, 0.33 M in THF or DME, 80-120 °C; upon completion filter through a 4.5 cm diameter
× 1-2 cm thick silica gel plug and evaporate; (iv) oxone, acetone, rt, 10 min; then 1 equiv of NaIO4 1-2 h. b Average isolated yield over three steps for
two runs. c Run open to a nitrogen manifold vs a sealed flask. d Suzuki byproducts were also observed. e NaIO4 workup was omitted. f Protodeborylation
was also observed.
In conclusion, the three-step sequence of aromatic boryl-
ation/amidation/oxidation on 3-substituted halobenzenes af-
fords 5-substituted 3-amidophenols in good overall yields
and without intermediate isolation. This chemistry further
expands the utility of the catalytic aromatic C-H activation
borylation reaction and provides an alternative route to these
important compounds. We are presently applying this process
in the theater of total synthesis.
yields (entries 8, 11, and 12). In cases of secondary amides
and lactams, Suzuki oligomerization becomes intrusive in
the amidation step. Disappointingly, the Suzuki byproducts
were not suppressed by using excess amide. With deactivated
aryl bromides, side reactions increased. Suzuki oligomer-
ization, phenyl transfer from the xantphos ligand, and
protodeborylation were all observed. Moreover, the electron-
rich aromatics did not respond well to the NaIO4 workup.
Thus for these products recrystallization or HPLC separation
was required to eliminate pinacol contamination. Finally, a
longer reaction time and higher temperature were required
when an aryl chloride was the amidation partner (entry 13).
This substrate also gave more protodeborylation; however,
Suzuki oligomerization was largely suppressed, presumably
due to the lower reactivity of the chloride.
Acknowledgment. We thank the Michigan Technology
Tricorridor Fund and the Astellas USA Foundation for gener-
ous support and BASF for their kind gift of pinacolborane.
Supporting Information Available: Experimental details
and product characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL060207I
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