Practical one-pot C-H activation/borylation/oxidation: Preparation of 3-bromo-5-methylphenol on a multigram scale

Article abstract of DOI:10.1055/s-0030-1258443

A practical one-pot C-H activation/borylation/oxidation sequence for the generation of 3,5-disubstituted phenols is presented. Specifically, 3-bromo-5-methylphenol is prepared from 3-bromotoluene, without isolation of intermediates, on a multigram scale, and in high yield. The process proceeds under mild conditions and can be completed within one day. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258443

PRACTICAL SYNTHETIC PROCEDURES
857
Practical One-Pot C–H Activation/Borylation/Oxidation: Preparation of
3
-Bromo-5-methylphenol on a Multigram Scale
P
A
reparation of 3-B
.
r
omo-5-meth
M
ylphenol onica Norberg, Milton R. Smith, III * Robert E. Maleczka, Jr. *
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Fax +1(517)3531793; E-mail: maleczka@chemistry.msu.edu
PSP
Received 30 November 2010; revised 23 January 2011
No201
Abstract: A practical one-pot C–H activation/borylation/oxidation sequence for the generation of 3,5-disubstituted phenols is presented.
Specifically, 3-bromo-5-methylphenol is prepared from 3-bromotoluene, without isolation of intermediates, on a multigram scale, and in
high yield. The process proceeds under mild conditions and can be completed within one day.
Key words: phenol, C–H activation, borylation, oxidation, boronic ester
H–BPin (1.5 equiv)
BPin
H
(Ind)Ir(cod) (2 mol%)
dmpe (2 mol%)
OH
aqueous oxone
1
50 °C, N2, 6 h
acetone
25 °C, 7 min
Br
Br
open system
Br
2
1
3
1
4.1 g (82.4 mmol)
12.6 g, 81%
Scheme 1 One-pot C–H activation/borylation/oxidation for the preparation of 3 on a multigram scale
Phenols are ubiquitous motifs in organic chemistry.1 arenes is sensitive to sterics, 1,3-substituted benzenes are
Within the gamut of phenols known to the synthetic readily borylated at the meta position. Furthermore, these
chemist, 3,5-disubstituted phenols constitute an interest- borylations are highly atom economical and clean with
ing subclass that have garnered interest from the pharma- hydrogen gas being the only stoichiometric byproduct of
6
2
ceutical and fine chemical industries. Such phenols, the reaction. In lieu of this, we determined that the boryl-
especially those with ortho-/para-directing groups, are of- ation event could be followed with an Oxone oxidation7
ten difficult to access through conventional, electronically of the crude boronic ester intermediate to the correspond-
governed, aromatic substitution chemistry. Illustrative of ing phenol (Scheme 1). With this one-pot C–H activation/
such difficulties is 3-bromo-5-chlorophenol, which was borylation/oxidation sequence, we prepared a variety of
3
originally prepared by Hodgson and Wignall. Amazing- 3,5-disubstituted phenols, including those represented in
ly, for over seventy-five years, no additional syntheses of Scheme 2.5
this molecule appeared in the peer-reviewed literature!
Electron-poor and electron-neutral di- and trisubstituted
Earlier this year, a group of Hoffman-La Roche chemists arenes, including heterocyclic, proved amenable to the
lead by Davidson described the challenges of preparing chemistry and a variety of functional groups, including es-
contra-electronically substituted 3,5-disubstituted phe- ters, ethers, amines, and halides were well tolerated. Use-
2
nols on a large scale. They offered their own preparation fully, Botting and co-workers extended the scope of the
of such phenols, which involved an initial ipso-substitu- methodology to include electron-rich bis-protected resor-
8
tion of a halide by an alkoxide followed by subsequent cinols. Thus, C–H activation/borylation/oxidation con-
2
deprotection, as an elegant solution to the problem. In stitutes the most direct route to a wide variety of 3,5-
that same report, the authors noted that other recent ap- disubstituted phenols, marking a valuable advance in
proaches to such molecules suffered in terms of their op- making accessible otherwise difficult to obtain phenols.9
eration at large or even multigram scale.
2
Nonetheless, as Davidson noted, the reactions had only
Such criticism certainly applied to our own iridium-cata- been reported on 1 mmol of arene and the borylation step
4
lyzed C–H activation/borylation /oxidation sequence for was performed in a sealed air-free flask. In such a closed
the preparation of 3-bromo-5-chlorophenol and other system, both the applied heat and the hydrogen gas being
5
meta-orientated di- and trisubstituted phenols. Since the generated resulted in pressure buildups that made multi-
1
0
regioselectivity in the direct borylation chemistry of gram syntheses inherently hazardous and, thus, imprac-
tical.
SYNTHESIS 2011, No. 6, pp 0857–0859
x
x
.
x
x
.2
0
1
1
Herein, we report a revised C–H activation/borylation/
oxidation protocol whereby the borylation step is con-
ducted in a standard three-necked round-bottom flask that
Advanced online publication: 18.02.2011
DOI: 10.1055/s-0030-1258443; Art ID: M08010SS
Georg Thieme Verlag Stuttgart · New York
©

8
58
A. M. Norberg et al.
PRACTICAL SYNTHETIC PROCEDURES
is fitted with a condenser and open to the atmosphere (al- Pinacolborane (H–BPin) stabilized with 1% Et N was obtained
3
from BASF, acetone and CH Cl were both obtained from
beit a nitrogen atmosphere). Of practical importance, the
reagents and solvents employed in both steps were used as
purchased and without additional purification, while the
final product isolation consisted of extraction and short
column chromatography with silica gel.
2
2
Mallinckrodt Chemicals, and 1,2-bis(dimethylphosphino)ethane
(dmpe) from Strem; they were all used as received. Oxone was pur-
chased from Aldrich as 2 KHSO ·KHSO ·K SO and used as re-
1
1
5
4
2
4
ceived. (Ind)Ir(cod) was prepared according to a literature
12
procedure. Silica gel was purchased from Silicycle (60 Å porosity
and 230–400 mesh particle size). The borylation reaction was mon-
itored by Varian CP-3800 GC-FID. H and C NMR spectra were
1
13
H
OH
H–BPin (1.5–2.5 equiv)
recorded on a VXR-500 MHz instrument in CDCl , with chemical
(
Ind)Ir(cod) (2 mol%)
dmpe (2 mol%)
3
shifts reported relative to the residue peak of solvent CHCl (d =
3
150 °C (sealed tube)
1
13
7
.24 for H and d = 77.0 for C). Melting point was measured on a
R1
R3
R1
R3
then
Thomas-Hoover capillary melting point apparatus and is uncorrect-
ed.
R2
R2
aqueous oxone
acetone, 25 °C, 7 min
4
5
(
1.0 mmol)
3
-Bromo-5-methylphenol (3)
1
3
Borylation step: Under an N atmosphere, an oven-dried, 500-mL,
2
OH
OH
OH
three-neck round-bottom flask equipped with a magnetic stir bar
was charged with (Ind)Ir(cod) (685 mg, 1.65 mmol) and H–BPin
(
18.0 mL, 124.0 mmol), followed by dmpe (275 mL, 1.65 mmol)
11
Br
Cl
Br
Cl
Cl
Cl
Cl
CO2Me
and 3-bromotoluene (1, 10.0 mL, 82.4 mmol). The flask was fitted
with a reflux condenser and the reaction (still under N ) was heated
(
81%)
OH
(83%)
OH
(70%)
OH
2
in an oil bath (150 °C) for 6 h. After being allowed to cool to r.t., the
mixture was transferred with CH Cl to a 1-L one-neck round-
2
2
bottom flask and the volatiles were removed under reduced pressure
with a rotary evaporator.
Me2N
F3C
OMe
Oxidation step: To the 1-L one-neck round-bottom flask containing
crude boronic ester 2, acetone (264 mL) was added. To the resulting
(
80%)
OH
(
79%)
OH
(79%)
OH
solution, aq Oxone solution [50.7 g, 824 mmol dissolved in H O
2
1
4
(
264 mL)] was added over 25 min. The resulting grey slurry was
stirred, open to air, at r.t. for an additional 7 min, and then quenched
with sat. aq NaHSO (100 mL).
3
Workup and purification: The reaction slurry was transferred to a
separatory funnel and the layers were separated. The aqueous layer
was extracted with CH Cl (3 × 200 mL). The combined organic
Cl
Cl
Cl
Cl
Cl
N
Cl
Br
2
2
(
80%)
(88%)
(64%)
layers were washed with brine, followed by H O, and concentrated
2
with a rotary evaporator to afford 25.9 g of a dark orange oil. The
oil was dissolved in CH Cl and then passed through a short silica
Scheme 2 Representative products originally prepared at 1.0-mmol
scale by the one-pot C–H activation/borylation/oxidation of substitu-
ted arenes5
2
2
gel column [silica gel (300 mL), 100% CH Cl ]. The product con-
2
2
taining fractions were combined and evaporated to dryness. Hex-
anes (100 mL) were added to flask. The resulting slurry was stirred
and then filtered through a Büchner funnel to provide pure 3-bromo-
In selecting a substrate for scale-up, we chose 3-bromotol-
5
-methylphenol (3) (12.6 g, 67.2 mmol, 81%) as an off-white solid;
5
uene (1) as it represents a commercially available arene of mp 56–57 °C (Lit. 55–57 °C); TLC analysis: R = 0.39 (silica gel,
f
midlevel reactivity. Thus following our modified proto- CH Cl ).
2
2
col, 3-bromotoluene (1, 14 g, 82 mmol) was borylated
1
H NMR (500 MHz, CDCl ): d = 6.90 (m, 1 H), 6.80 (m, 1 H), 6.56
3
neat in an open system. Once GC-FID indicated that the (m, 1 H), 4.78 (bs, 1 H), 2.26 (s, 3 H).
starting material was fully consumed, the volatiles were
removed under reduced pressure, and then the corre-
sponding crude boronic ester 2 (without any purification)
was subjected to oxidation with Oxone. After liquid–
liquid extraction, passing the crude phenol through a short
13
C NMR (126 MHz, CDCl ): d = 155.9, 141.4, 124.8, 122.4, 115.8,
3
1
15.0, 21.1.
Acknowledgment
silica gel column, evaporation, and filtration of the hexane We thank the Michigan Economic Development Corp. 21st Century
slurry, pure phenol 3 (12.6 g, 81% isolated yield) was ob- Jobs Fund, the NIH (GM63188 to M.R.S.), the ACS/GCI Pharma-
ceutical Roundtable, Pfizer, and the Astellas USA Foundation for
tained. The yield and purity of the final product were iden-
generous support.
tical to those observed on a 1-mmol scale. Therefore, the
ability to produce multigram quantities of 3,5-disubstitut-
ed phenols via a practical one-pot catalytic C–H activa- References
tion/borylation/oxidation protocol has been demonstrated.
(
(
1) Tyman, J. P. Synthetic and Natural Phenols; Elsevier: New
York, 1996.
2) Davidson, J. P.; Sarma, K.; Fishlock, D.; Welch, M. H.;
Sukhtankar, S.; Lee, G. M.; Martin, M.; Cooper, G. F. Org.
Process Res. Dev. 2010, 477.
We anticipate that this report will find immediate applica-
tion for the straightforward generation and use of such
phenols in academia as well as industry.
Synthesis 2011, No. 6, 857–859 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Preparation of 3-Bromo-5-methylphenol
859
(
3) (a) Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926, 2077.
b) Also see: Kohn, M.; Zandman, A. Montsh. Chem. 1926,
7, 357.
(10) For a multigram borylation of 1-chloro-3-iodobenzene with
[Ir(OMe)(cod)] -dtbpy and B pin see: Ishiyama, T.; Takagi,
(
4
2
2
2
J.; Nobuta, Y.; Miyaura, N. Org. Synth. 2005, 82, 126.
(
4) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E. Jr.;
Smith, M. R. III. Science 2002, 295, 305. (b) Boller, T. M.;
Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263. (c) For
a review see: Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
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J. Am. Chem. Soc. 2003, 125, 7792.
6) C–H Acidities can also influence regiochemical outcomes,
see: Vanchura, B. A. II.; Preshlock, S. M.; Roosen, P. C.;
Kallepalli, V. A.; Staples, R. J.; Maleczka, R. E. Jr.;
Singleton, D. A.; Smith, M. R. III. Chem. Commun. 2010,
(11) So as to establish a benchmark yield herein, the starting
3-bromotoluene was distilled over CaH under reduced
2
pressure and degassed before use. In most cases the starting
arene can be used as received, but yields are dependent on
starting material quality, which can vary by vendor and
batch. A use test prior to scale up is recommended.
(12) Merola, J. S.; Kacmarcik, R. T. Organometallics 1989, 8,
778.
(
(
(13) (a) Whereas (Ind)Ir(cod) and H–BPin are relatively air
1
3b
stable, dmpe is ‘moderately sensitive to air’ and should be
handled under an inert atmosphere. Herein, the flask into
which the initial set of reagents was charged was in a
glovebox. Once charged, the flask was moved to a fume
hood where the actual reaction was run (b) Burt, R. J.;
Chatt, J.; Hussain, W.; Leigh, G. J. J. Organomet. Chem.
1979, 182, 203.
46, 7724.
(
(
7) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
8) Marshall, L. J.; Cable, K. M.; Botting, N. P. Tetrahedron
Lett. 2010, 51, 2690.
(
9) For a Pd-catalyzed borylation/oxidation approach to similar
phenols see: Lee, Y.; Kelly, M. J. Tetrahedron Lett. 2006,
(14) WARNING: As with any oxidation of this type, one should
be watchful for exotherms and control the rate of addition
accordingly.
47, 4897.
Synthesis 2011, No. 6, 857–859 © Thieme Stuttgart · New York