A synthesis of 3,5-disubstituted phenols

Article abstract of DOI:10.1021/op900322u

Robust and scalable syntheses of some synthetically useful 3,5- disubstituted phenols are presented. The process involves the selective displacement of a halogen by nucleophilic aromatic substitution using a preformed mixture of potassium tert-butoxide and p-methoxybenzyl alcohol (PMB-OH), followed by deprotection of the PMB ether with acid in the presence of 1,3-dimethoxybenzene. These processes have been demonstrated on kilogramscale, providing crystalline phenols in good yield and high purity.

Full text of DOI:10.1021/op900322u

Organic Process Research & Development 2010, 14, 477–480
A Synthesis of 3,5-Disubstituted Phenols
James P. Davidson,*,† Keshab Sarma,‡ Dan Fishlock,‡ Michael H. Welch,† Sunil Sukhtankar,§ Gary M. Lee,† Michael Martin,⊥
and Gary F. Cooper¶
Chemical Synthesis, Roche Palo Alto LLC, 3431 HillView AVenue, Palo Alto, California 94304, U.S.A., Chemical Synthesis,
Hoffmann-La Roche, 340 Kingsland AVenue, Nutley, New Jersey 07110, U.S.A.
Abstract:
Robust and scalable syntheses of some synthetically useful 3,5-
disubstituted phenols are presented. The process involves the
selective displacement of a halogen by nucleophilic aromatic
substitution using a preformed mixture of potassium tert-butoxide
and p-methoxybenzyl alcohol (PMB-OH), followed by deprotec-
tion of the PMB ether with acid in the presence of 1,3-dimethoxy-
benzene. These processes have been demonstrated on kilogram
scale, providing crystalline phenols in good yield and high purity.
Figure 1. 3,5-Disubstituted phenols of interest.
Scheme 1. Early approaches to 1 and 2
Introduction
Phenols with the 3,5-substitution pattern can be synthetically
challenging and are not widely available in significant quantities
from commercial sources. As part of a research effort, we had
need of a reliable synthesis of phenols of this type. Phenols 1
and 2 were identified early on as key starting materials.1 Our
medicinal chemistry colleagues were interested in further
modifications at the 3- and 5-positions and so compounds 3
and 4 were chosen as they could easily be elaborated by taking
advantage of various chemistries known for aryl halides.
Classically, phenols of this type have been prepared accord-
ing to the method of Hodgson2 by using diazonium chemistry.
Various 1,3,5 substituted benzenes are currently available
commercially, possibly from similar Sandmeyer type processes.
Phenols 1-4 have become available from catalog vendors in
the past few months indicating an increasing interest.
Although unknown to us at the outset of this work, recent
progress in the transition metal catalyzed coupling of hydroxide
has opened up the possibility of replacing halogens directly to
access a variety of phenols and avoiding biaryl ether formation.3
A recent report describing the preparation of 3 by C-H
activation has also surfaced.4 Notwithstanding, experimental
details for larger scale syntheses, and more generally, descrip-
tions of synthetic approaches readily amenable to scale-up are
quite limited. Our requirements for phenols 1-4 ranged from
hundreds of grams to >10 kg, and at the start of our effort there
were few viable options.
* Author for correspondence. E-mail: james.davidson.jd1@roche.com.
† Chemical Synthesis, Roche Palo Alto LLC.
‡ Chemical Synthesis, Hoffmann-La Roche.
§ Chemical Research and Development, Pfizer Pharmaceutical India.
⊥ Present address: 238 Mississippi St., San Francisco, CA 94107.
¶ Present address: 16 Valley Oak St. Portola Valley, CA.
Results and Discussion
Dichloro- and difluoro-benzonitrile 5 and 6 are commercially
available, and 6 had been reported5 to react selectively with
sodium methoxide to displace one halogen (Scheme 1). The
resulting methyl ether has been cleaved by either reaction with
lithium iodide in collidine under reflux (186 °C), or with boron
tribromide.6
This methoxide approach had a number of potential limita-
tions. Boron tribromide, or the rather forcing conditions of
lithium iodide in refluxing collidine were needed to remove the
(1) Elworthy, T. R.; Dunn, J. P.; Hogg, J. H.; Lam, G.; Saito, Y. D.;
Silva, T. M. P. C.; Stefanidis, D.; Woroniecki, W.; Zhornisky, E.;
Zhou, A. S.; Klumpp, K. Bioorg. Med. Chem. Lett. 2008, 18, 6344–
6347. Sweeney, Z. K.; Acharya, S.; Briggs, A.; Dunn, J. P.; Elworthy,
T. R.; Fretland, J.; Giannetti, A. M.; Heilek, G.; Li, Y.; Kaiser, A. C.;
Martin, M.; Saito, Y. D.; Smith, M.; Suh, J. M.; Swallow, S.; Wu, J.;
Hang, J. Q.; Zhou, A. S.; Klumpp, K. Bioorg. Med. Chem. Lett. 2008,
18, 4348–4351. Sweeney, Z. K.; Dunn, J. P.; Li, Y.; Heilek, G.;
Dunten, P.; Elworthy, T. R.; Han, X.; Harris, S. F.; Hirschfeld, D. R.;
Hogg, J. H.; Huber, W.; Kaiser, A. C.; Kertesz, D. J.; Kim, W.;
Mirzadegan, T.; Roepel, M. G.; Saito, Y. D.; Silva, T. M. P. C.;
Swallow, S.; Tracy, J. L.; Villasen˜or, A. G.; Vora, H.; Zhou, A. S.;
Klumpp, K. Bioorg. Med. Chem. Lett. 2008, 18, 4352–4354. Sweeney,
Z. K.; Harris, S. F.; Arora, N.; Javanbakht, H.; Li, Y.; Fretland, J.;
Davidson, J. P.; Billedeau, J. R.; Gleason, S. K.; Hirschfeld, D.;
Kennedy-Smith, J. J.; Mirzadegan, T.; Roetz, R.; Smith, M.; Sperry,
S.; Suh, J. M.; Wu, J.; Tsing, S.; Villasen˜or, A. G.; Paul, A.; Su, G.;
Heilek, G.; Hang, J. Q.; Zhou, A. S.; Jernelius, J. A.; Zhang, F.-J.;
Klumpp, K. J. Med. Chem. 2008, 51, 7449–7458. Sweeney, Z. K.;
Kennedy-Smith, J. J.; Wu, J.; Arora, N.; Billedeau, J. R.; Davidson,
J. P.; Fretland, J.; Hang, J. Q.; Heilek, G. M.; Harris, S. F.; Hirschfeld,
D.; Inbar, P.; Javanbakht, H.; Jernelius, J. A.; Jin, Q.; Li, Y.; Liang,
W.; Roetz, R.; Sarma, K.; Smith, M.; Stefanidis, D.; Su, G.; Suh, J. M.;
Villasen˜or, A. G.; Welch, M.; Zhang, F.-J.; Klumpp, K. ChemMed-
Chem 2009, 4, 88–99.
(3) Sergeev, G. S.; Schulz, T.; Torborg, C.; Spannenberg, A.; Neumann,
H.; Bell, M. Angew. Chem., Int. Ed. 2009, 48, 7595–7599. Tlili, A.;
Xia, N.; Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
8725–8728. Zhao, D.; Wu, N.; Ahang, S.; Xi, P.; Su, X.; Lan, J.;
You, J. Angew. Chem., Int. Ed. 2009, 48, 8729–8732.
(4) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R. J. Am. Chem.
Soc. 2003, 125, 7792–7793. Maleczka, R. E., Jr.; Smith, M. R.;
Holmes, D.; Shi, F. Chem. Abstr. 2004, 140, 163576. U.S. Pat. Appl.
2003-620122, 2004030197, 2004.
(5) Kertesz, D. J.; Martin, M.; Palmer, W. S. Chem. Abstr. 2005, 143,
405914. U.S. Pat. Appl. 2005-105990, 2005234236, 2005.
(6) Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem.
2004, 69, 8982–8983.
(2) Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926, 2077–2079.
10.1021/op900322u  2010 American Chemical Society
Published on Web 02/04/2010
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Scheme 2. Possible byproducts formed with 3,5-dibromo
benzonitrile
Scheme 4. Scalable preparation of phenols 2-4
Scheme 3. Byproducts in reaction with
1,3,5-tribromobenzene
the approach was not pursued for further scale up, it offers a
very reasonable and rapid approach to lab scale production
of 3.
Looking back at phenol 2, alternative alkoxide nucleophiles
seemed likely to be effective and offer the benefit of a more
facile cleavage. Tertiary alcoholates did not participate in the
nucleophilic aromatic substitution, and potassium tert-butoxide
turned out to be the preferred base for subsequent investigations.
We quickly settled on 4-methoxybenzyl alcohol (PMB-OH)
(Scheme 4).8
Reaction of 6 with a preformed mixture of 4-methoxybenzyl
alcohol and potassium tert-butoxide, in a small volume of
N-methyl-pyrrolidinone (NMP) provided the corresponding
ether 17. Attempts to execute this reaction in THF resulted in
incomplete consumption of the starting benzonitrile. The nitrile
functionality appeared to be more reactive in less polar media,
and cyclotrimerization of the nitrile into 2,4,6-triazines9 was
observed by LC-MS. This behavior was sufficiently suppressed,
but not eliminated in NMP. After the reaction was complete,
the dark solution was cooled, and added to a mixture of toluene
and dilute aqueous acetic acid. The organic layer was separated
from the aqueous NMP10 to give a solution of 17 in toluene
ready for direct deprotection or isolation.
In order to access the bromo derivatives 3 and 4, 1,3-
dibromo-5-fluorobenzene (18) or 1-bromo-3-chloro-5-fluo-
robenzene (19) were used respectively. Carrying out the
displacement was straightforward. Using 4-methoxybenzyl
alcohol and potassium tert-butoxide, this time in THF at 50-60
°C, provided the corresponding ethers in good yields (>90%
isolated solid). In these cases, isolation was generally carried
out after aqueous workup, by replacing the solvent with
methanol.
methyl group, and neither option was appealing for large scale
work. The reaction of methoxide with 3,5-dibromo-benzonitrile
(9) did not result in a clean transformation (Scheme 2). In order
for methoxide to participate in a nucleophilic aromatic substitu-
tion with the more electron rich dibromide, a temperature of
50-80 °C was required. Unfortunately this temperature also
increased the susceptibility of the nitrile group to nucleophilic
attack, leading to a mixture of 10 and byproducts tentatively
identified by LC/MS as amides 11 and 12.
Also, while 1,3,5-tribromobenzene (13) did participate in the
nucleophilic aromatic substitution reaction with methoxide in
DMF at 80 °C, in our hands the reaction resulted in a mixture
of either 13 and 14, or 14 and 15 neither of which provided an
opportunity for simple purification (Scheme 3).6 Alternatively,
it was shown that 13 could be treated with isopropylmagnesium
chloride under mild conditions to give the mono-Grignard
species rapidly and selectively.7 Subsequent transmetalation with
triisopropyl borate occurred on a similarly rapid time scale, also
with a small exotherm. If the resulting aryl boronic ester
solutions were oxidized with aq. hydrogen peroxide, then 3,5-
dibromophenol was the main product. However, several other
poly brominated phenols also formed and were detected by GC/
MS as byproducts in the isolated material.
We hypothesized that the electron rich phenol would be
highly susceptible to electrophilic aromatic substitution, and that
the mixture of bromide ions and peroxide resulted in electro-
philic bromine species capable of brominating 3. We found that
removal of volatile byproducts including isopropyl bromide,
and the inorganic magnesium salts prior to the peroxide addition
allowed 3,5-dibromophenol to be synthesized in high yield and
purity without simultaneous production of poly brominated
phenols. Thus, after Grignard formation, and addition of B(i-
PrO)3, the mixture was sequentially washed with dilute sulfuric
acid, and then concentrated by distillation under reduced
pressure. Then, when the oxidative peroxide treatment and
workup was initiated, 3 was made cleanly. This process has
been demonstrated on 50-g scale, providing a near quantitative
yield of 3,5-dibromophenol with a single isolation. Although
With these protected phenols in hand, a series of deprotection
conditions were evaluated using 17 as a model because at the
(8) Other primary alcohols would be expected to participate in the
nucleophilic aromatic substitution, thus opening up the possibility of
allyl-, or 2-trimethylsilylethyl-protected phenols; however, such experi-
ments were not tested in our lab.
(9) Chen, X.; Bai, S.-D.; Wang, L.; Liu, D.-S. Heterocycles 2005, 65,
1425–1430. Cui, D.; Nishimura, M.; Hou, Z. Angew. Chem., Int. Ed.
2005, 44, 959–962. Davies, R. P.; Raithby, P. R.; Shields, G. P.; Snaith,
R.; Wheatley, A. E. H. Organometallics 1997, 16, 2223–2225. Deng,
Z.; Qiu, W.; Li, W.; Li, Y. Chin. Sci. Bull. 2004, 49, 127–130. Herrera,
A.; Martinez-Alvarez, R.; Ramiro, P.; Chioua, M.; Chioua, R. Synthesis
2004, 503–505. Xu, F.; Sun, J.-H.; Yan, H.-B.; Shen, Q. Synth.
Commun. 2000, 30, 1017–1022.
(7) Laliberte, D.; Maris, T.; Wuest, J. D. J. Org. Chem. 2004, 69, 1776–
(10) Delhaye, L.; Ceccato, A.; Jacobs, P.; Kottgen, C.; Merschaert, A. Org.
Process Res. DeV. 2007, 11, 160–164.
1787.
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Scheme 5. Byproducts were observed in the deprotection
step for the electron rich 20
Conclusion
In summary, procedures for the formation of differentially
3,5-substituted phenols from inexpensive commercially avail-
able starting materials have been developed and demonstrated
to be effective on a reasonable scale. Further improvements
could be envisioned, including the possible elimination of
intermediate ether isolations for 20 and 21, and optimizing the
final crystallization conditions, but these are unnecessary for
general practice. These processes have been demonstrated on
scales delivering between grams and kilograms of phenols as
high purity crystalline solids where the yields were generally
75-85% overall for the process.
time compound 2 was in high demand.11 In acetic acid at or
near 110 °C, deprotection was complete, but the formation of
4-methoxybenzyl acetate was problematic. Unfortunately, this
byproduct acted as a cosolvent in the isolation resulting in only
modest yields, and it was partly retained in the isolated product
after crystallization. The use of stronger acids with less
nucleophilic conjugate bases eliminated the formation of adducts
of this type, but led to a mixture of polymeric material derived
from the 4-methoxybenzyl group that coprecipitated with the
product. For the electron rich phenols such as 20, alkylated
byproducts such as 22 and 23 (Scheme 5) were detected by
LC/MS. It was clear that a cation scavenger was required.
To avoid the stench complications associated with the large
scale use of sulfur-derived additives, other electron rich aromat-
ics were explored as cation scavengers. The introduction of
excess 1,3-dimethoxybenzene proved effective, decreasing the
formation of alkylated byproducts related to the desired phenol
to nearly undetectable levels in the isolated phenols.
Ultimately, two methods were found to be highly effective
for the deprotection, each being suited to the nature of the
specific compound. For ethers 20 and 21, both of which were
isolated intermediates, catalytic (10 mol %) methanesulfonic acid
at 5 °C with 2.5 equiv of 1,3-dimethoxybenzene in a small volume
of toluene was shown to be optimal. Upon reaction completion,
the mixture was extracted with caustic to separate the phenol from
the organic byproducts and solvents, and then crystallized by
acidification resulting in yields generally of 80-85%.
In the case of 17, obtained as a solution in toluene, a
telescoped process was desired. However, the methanesulfonic
acid catalyzed deprotection method required rigorous elimina-
tion of water and residual p-methoxybenzyl alcohol as these
sequestered and/or consumed the catalytic acid. Trifluoroacetic
acid (0.5 equiv) in toluene at 70 °C was employed, again using
1,3-dimethoxybenzene as a scavenger. Due to the observation
that measurable amounts of nitrile hydrolysis could occur during
the caustic extraction of 2, an alternative purification was
developed. First, the crude phenol product was precipitated from
the toluene-TFA reaction mixture by addition of heptane. The
product was isolated by filtration, and the wet-cake was
dissolved in isopropanol. The isopropanol solution was then
treated with activated carbon and filtered. The clarified solution
was concentrated partially, and the solvent replaced with heptane
to induce crystallization, and 2 was isolated in 75% overall yield
from 6.
Experimental Section
Unless otherwise noted, solvents and reagents were reagent
grade and used without purification. All reactions involving air
or moisture-sensitive reagents were performed under an inert
atmosphere of nitrogen. Unless otherwise stated, analytical
HPLC separations were performed using an Agilent Zorbax SB-
C8, 100 mm length × 3.0 mm ID packed with 3.5 µm particles,
flow rate of 1.2 mL/min, and a linear gradient as follows:
Component A: 0.1% trifluoroacetic acid in water; Component
B: 0.1% trifluoroacetic acid in acetonitrile; elution gradient 10%
to 90% B from 0 to 3.5 min, hold 90% B for 1.5 min, temp 30
°C, UV detection at 220 nm. Mass spectra were taken using an
Agilent 6890N GC with an Agilent 5973N MS instrument using
electron impact (EI) positive ionization energy ) 70 eV [tuned
with PFTBA (perfluorotributylamine)]. The column is an
Agilent DB-5MS, 30 m length × 0.25 mm diameter, 0.25 µm
film thickness. Oven is programmed from 70 to 300 °C at
20 °C/min. Injector temp ) 250 °C.
3-Chloro-5-hydroxybenzonitrile (2). To a solution of
potassium tert-butoxide (3 kg, 26.7 mol) in NMP (12 kg) was
added 4-methoxybenzyl alcohol (4.22 kg, 30.5 mol) at <40 °C.
The resulting mixture was stirred for 1 h and then transferred
over 40 min into a premixed solution of 3,5-dichlorobenzonitrile
(4.37 kg, 25.4 mol) in NMP (5 kg) at 40-50 °C. The reaction
was stirred for 1.5 h at 40 °C, (at which point HPLC analysis
showed 17 (rt 3.76 min) and <2% of dichlorobenzonitrile) and
then cooled to 22 °C and quenched with a mixture of water
(22 L), acetic acid (5 kg) and toluene (30 kg). The mixture
was stirred vigorously and the aqueous layer removed. The
organic layer was washed with additional water (3 × 20 L)
and then concentrated by atmospheric distillation at 110 °C
(removing ∼20 kg solvent). The mixture was cooled to 50 °C,
and 1,3-dimethoxybenzene (4.1 kg, 29.7 mol) and trifluoroacetic
acid (1.5 kg, 13.2 mol) were added. The mixture was stirred at
70 °C for 2 h (HPLC analysis showed <2% 17), at which point
it was diluted with heptanes (26 kg) and then cooled to 5 °C
overnight. The precipitate was filtered and then washed with
heptanes (20 kg) and dried under N2. The damp, crude cake
(86.4% purity by HPLC/external standard) was combined with
Celite (600 g) and Calgon activated carbon (600 g) in isopro-
panol (20 kg) and the suspension stirred at 80 °C for 2 h. The
mixture was cooled to 22 °C and then filtered through a Celite
pad. The cake was rinsed with additional isopropanol (10 kg).
The combined filtrate was partially concentrated by distillation
under reduced pressure to approximately 1/2 the original volume,
(11) 3-Fluoro-5-hydroxybenzonitrile was not pursued further, and no
procedure was demonstrated. However, it is highly likely that the
developed procedure described for 3-chloro-5-hydroxybenzonitrile
would be effective.
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479

and then the solvent was replaced with heptane (∼35 kg total) to
maintain this volume until an atmospheric pressure distillation pot
temperature of ∼93-96 °C was observed. The mixture was slowly
cooled to 0 °C over 18 h, the thick suspension was filtered, the
cake washed with additional heptane (10 kg), and dried at 60 °C
for ∼6 h (a sample showed 0.49% LOD). 3-Chloro-5-hydroxy-
benzonitrile was isolated as 2.94 kg (75.1% yield) of an off-white
solid: mp 165-166 °C; 1H NMR (300 MHz, DMSO-d6) δ ppm
7.23 - 7.22 (m,. 1H), 7.10 - 7.09 (m, 1H), 7.03 - 7.01 (m, 1H),
5.36 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) δ (ppm) 159.25,
135.02, 122.53, 120.93, 118.12, 113.83; mass spectrum (EI) m/z
153 (M+ base), 155. AN HPLC retention time 2.66 min, purity
of 96 wt % (external standard).
extraction process was repeated three times and the combined
aqueous fractions washed with toluene (80 mL) and then filtered
through cotton. Acidification at ambient temperature to a pH
of ∼1.5 produced a slurry that was aged for 30 min, filtered,
and washed with water. Air drying followed by vacuum oven
drying at 50 °C produced 85.5 g (84% yield based on ether 20,
and 78% overall) of 3,5-dibromophenol12 as a white solid,
HPLC retention time 3.70 min, AN HPLC purity of 99.65%.
Alternative 3,5-Dibromophenol Synthesis (3). To a de-
gassed, stirring solution of 1,3,5-tribromobenzene (50 g, 159
mmol) in toluene (250 mL) at 20 °C, was added i-PrMgCl (103
mL, 206 mmol, 2 M in THF) over 5 min with the use of an ice
bath to keep the temperature of the mixture below 25 °C. After
reaction was complete, the mixture was stirred for 10 min at
20 °C, then, tri-isopropyl borate (39 g, 48 mL, 206 mmol) was
added over 10 min at <30 °C. After the addition was complete
the mixture was stirred for 10 min and aqueous sulfuric acid
(170 mL, 10 wt %) was added slowly at <40 °C. The aqueous
layer was separated, and the organic layer was washed with
water (50 mL). The toluene solution was cooled to 5-10 °C
and concentrated by distillation under reduced pressure (30-50
Torr), until the volume of the solution decreased by about half.
Foaming and bumping during the distillation was noted and a
nitrogen inlet was used in the early part of the distillation to
minimize the foam. After distillation, the concentrated solution
was stirred and aqueous hydrogen peroxide (22 g, 30% H2O2
in water) was added slowly at <50 °C. The beginning of this
addition was very exothermic. After the addition was complete,
water (200 mL) was added and the mixture stirred vigorously.
The phase separation took 10-15 min, and the aqueous phase
resided on top of the mixture. The organic layer was washed
with an additional 50 mL water, and the combined aqueous
mixtures were extracted with toluene (50 mL). The combined
toluene solution was then concentrated to an oil under reduced
pressure and distilled using a Kugelrohr apparatus, temperature
160-170 °C, 20-25 Torr, to give 40 g of 312 which solidified
in the receiver flask.
3-chloro-5-(4-methoxy-benzyloxy)benzonitrile 17. A small
portion of the toluene extract from above was concentrated to
a glass under reduced pressure, then dissolved in refluxing
ethanol, filtered and cooled to 5 °C to give 17 as a white solid:
mp 85-86 °C; 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (d, J
) 9.0 Hz, 2 H) 7.08 - 7.11 (m, 1 H) 7.01 (dd, J ) 2.3, 1.5
Hz, 1 H) 6.88 - 6.94 (m, 3 H) 4.93 (s, 2 H) 3.81 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ (ppm) 159.90, 159.76, 135.55,
129.30, 127.80, 123.93, 122.85, 116.88, 114.49, 114.14, 70.38,
55.32; mass spectrum (EI) m/z 273 (M+), 153, 121 (base).
3,5-dibromophenol (3). 4-Methoxybenzyl alcohol (86.5 g,
626.23 mmol) was warmed to liquefy (26 °C) and added over
20 min to a slurry of potassium tert-butoxide (69.6 g, 620.32
mmol) in THF (525 mL, 3.5 volumes) at ambient temperature,
the resulting exotherm raised the reaction temperature to ∼ 40
°C The mixture was stirred for 30 min at 40 °C and then
dibromofluorobenzene (150 g, 591 mmol) was added over 20
min. An exotherm up to ∼60 °C was observed and the mixture
was stirred at 60 °C for 2 h (at which point HPLC analysis
showed <3% dibromofluorobenzene). The mixture was cooled
to ambient temperature and allowed to stand overnight. It was
then diluted with water (200 mL) and acetic acid (4.5 g) and
the layers separated. The aqueous layer was washed with ethyl
acetate (100 mL) and the combined organic fraction was washed
with 50% saturated brine and concentrated under vacuum to
an oil. The crude oil was slurried with vigorous stirring in
methanol (300 mL) at 50 °C and then cooled to ambient
temperature overnight. The precipitate was filtered and washed
with methanol (2 × 50 mL), air-dried and then vacuum oven-
dried at 50 °C. Ether 20 was obtained as 204.1 g (93% yield)
of white solid, HPLC retention time 4.15 min, with AN HPLC
purity of 97.8%: mp 58-60 °C, 1H NMR (300 MHz, CDCl3))
δ ppm 7.31 (d, J ) 8.7 Hz, 2 H) 7.22 - 7.27 (m, 1 H) 7.05 (d,
J ) 1.5 Hz, 2 H) 6.91 (d, J ) 8.7 Hz, 2 H) 4.93 (s, 2 H) 3.81
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ ppm 159.98, 159.76,
129.32, 127.77, 126.60, 123.10, 117.35, 114.14, 70.38, 55.32;
mass spectrum (EI) m/z 372 (M+), 252, 121 (base).. Ether (20)
(150 g, 403.16 mmol) was dissolved in toluene (150 mL, 1
vol) and 1,3-dimethoxybenzene (150 mL, 1 vol) and cooled to
5 °C. Methanesulfonic acid (3.87 g, 40.32 mmol) was added
over 15 min at <10 °C. After stirring for an additional 5 min
the reaction was deemed complete by AN HPLC analysis (<1%
20 detected). The mixture was diluted with water (120 mL)
and the pH was adjusted to ∼11-11.5 with 50% KOH solution
and the layers separated after vigorous stirring. This caustic
3-Chloro-5-(4-methoxy-benzyloxy)bromobenzene (21). Pre-
pared in 93% as described for 20, starting from 3-chloro-5-
fluoro-bromobenzene, and isolated as a white solid from
1
methanol, HPLC retention time 4.11 min, mp 49-50 °C: H
NMR (300 MHz, CDCl3) δ (ppm) 7.32 (d, J ) 9.0 Hz, 2 H)
7.21 - 7.24 (m, 6 H) 7.18 (t, J ) 2.1 Hz, 1 H) 7.09 - 7.11
(m, 1 H) 6.93 (d, J ) 9.0 Hz, 2 H) 5.00 (s, 2 H) 3.83 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ (ppm) 159.93, 159.60, 136.03,
129.33, 127.21, 124.31, 120.44, 117.47, 116.75, 114.27, 70.67,
55.34; mass spectrum (EI) m/z 326 (M+), 328, 121 (base).
3-Bromo-5-chloro Phenol (4). prepared in 81% yield
according to the procedure for 3, giving an off white solid,
HPLC retention time 3.10 min, mp 68-69 °C,13 in 75% overall
yield from 3-chloro-5-fluoro-bromobenzene.
Acknowledgment
Significant analytical support for this work was provided by
Frida Dobrouskin, Tim Lane, Ashraf Abdallah, and Tina
Nguyen, and we thank them for their efforts.
Received for review December 10, 2009.
OP900322U
(12) Product matched the spectral properties given in ref 4.
(13) Product matched the spectral properties given in ref 4.
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