The application of stop-flow microwave technology to scaling-out S NAr reactions using a soluble organic base

Article abstract of DOI:10.1039/b926537f

A model S_NAr reaction which gives a range of substituted diaryl ethers has been re-developed to function with the soluble organic base DBU in the place of insoluble potassium carbonate. Manufacture of these diaryl ethers has then been achieved by scaling-out in an automated stop-flow microwave reactor to give productivities of >0.5 kg per day. Analogous reaction partners have also been scaled up in this reactor to extend the scope of the study. Brief comparison in a scale-up batch microwave reactor is also made. Lastly, continuous 24 h processing is reported in this small microwave stop-flow reactor, which requires no manual intervention once started.

Full text of DOI:10.1039/b926537f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The application of stop-flow microwave technology to scaling-out SNAr
reactions using a soluble organic base†‡
Jameel A. Marafie and Jonathan D. Moseley*
Received 22nd December 2009, Accepted 18th February 2010
First published as an Advance Article on the web 11th March 2010
DOI: 10.1039/b926537f
A model SNAr reaction which gives a range of substituted diaryl ethers has been re-developed to
function with the soluble organic base DBU in the place of insoluble potassium carbonate.
Manufacture of these diaryl ethers has then been achieved by scaling-out in an automated stop-flow
microwave reactor to give productivities of >0.5 kg per day. Analogous reaction partners have also been
scaled up in this reactor to extend the scope of the study. Brief comparison in a scale-up batch
microwave reactor is also made. Lastly, continuous 24 h processing is reported in this small microwave
stop-flow reactor, which requires no manual intervention once started.
be tuned across a range of electronic (4-MeO vs. 4-NO2) and
steric (H vs. 4-tBu) features. Alternative nucleophiles may also
Introduction
Microwave synthesis has been widely adopted within the phar-
be used e.g. thiophenols. Most of the product diaryl ethers 3
maceutical industry at small scale, and is generally accepted in
are crystalline and can be isolated by a simple aqueous drown-
academia also.1 Scale-up of microwave synthesis however, has
out with water. Furthermore, these simple structures are not as
proven more difficult to achieve and is still a challenging area.2 We
uninteresting as might be supposed, as several are claimed as
potential agrochemicals/insecticides7 and a surprising number are
apparently novel. They are also representative of more complex
diaryl ether structural motifs8 which are found in many important
biologically active molecules, including natural products, and
potential and actual pharmaceuticals.9 Lastly, and from a purely
pragmatic point of view when working on larger scale, all of the
starting materials were cheap and available on sufficient scale.
Whilst this reaction was useful in many respects for testing het-
erogeneous reactions in large scale microwave (and conventional)
reactors, it could not be used in continuous flow or stop-flow
microwave reactors, since these require a homogeneous reaction
mixture. We have recently reported on a number of homogeneous
reactions conducted in an automated stop-flow microwave reactor
(the CEM Voyager),10 and were keen to exemplify and further
test the manufacturing capability of this reactor using this model
reaction, since it has many other desirable features, as noted
above. We therefore determined to replace insoluble K2CO3 with
a soluble organic base to obtain a homogeneous reaction mixture
which could be processed through continuous flow and stop-flow
microwave reactors.
Details of the Voyager have been discussed at length in our
previous report,10 or as presented by others.11 In brief, the Voyager
has an 80 mL Pyrex glass vessel with ~50 mL operating volume,
fed by three inlet lines and emptied by one exit line which
may be collected as product or waste. Up to three reaction
solutions/solvents may be pumped into the vessel, which is then
sealed and heated by microwaves to the set temperature. At the end
of the reaction, compressed air cooling rapidly cools the reaction
mixture, which is then pumped out. All of the lines and the vessel
may be flushed with fresh solvent if they require cleaning before the
sequence is repeated again. This process of small batch microwave
heating can be fully automated to run as many batches as required;
it is essentially only limited by material availability. The Voyager is,
thus, an interesting hybrid reactor, combining microwave heating
have reported on the scale-up of one simple thermal rearrangement
in a variety of microwave reactors,3 as well as more recently
on a wider range of reactions in a subset of these reactors.4
One such reaction which we have found particularly useful is
a model SNAr reaction (Scheme 1). This is typical of many
heterogeneous pharmaceutical reactions in that it consists of two
organic components combining in the presence of an inorganic
base (K2CO3) suspended in a polar aprotic solvent.
Scheme 1 SNAr reaction with substituted phenols. Key to compound
structures in Table 1.
This proved to be an ideal probe reaction in the evaluation of
large-scale microwave reactors5 for several reasons. The reaction
is very reliable under standard procedures; any failure in the
reaction is, therefore, normally indicative of instrumentation
issues. Reaction progress is dependent solely on the temperature
since there is no catalyst or initiation period (we assumed and
saw no evidence of a special microwave effect).6 The reaction
of 3,4-dichloronitrobenzene (DCNB, 1) is almost completely
selective at the 4-position, whilst leaving the 3-position open to
further chemical elaboration. The phenol coupling partner 2 may
AstraZeneca, PR&D, Avlon Works, Severn Road, Hallen, Bristol,
United Kingdom BS10 7ZE. E-mail: jonathan.moseley@astrazeneca.com;
Fax: +44 117 938 5081; Tel: +44 117 938 5601
† This paper is part of an Organic & Biomolecular Chemistry web theme
issue on enabling technologies for organic synthesis.
‡ Electronic supplementary information (ESI) available: HPLC spectra
to support compound purity; photograph of the Voyager stop-flow
microwave reactor. See DOI: 10.1039/b926537f
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2219–2227 | 2219
©

View Article Online
for rapid reaction, a small batch volume for rapid cooling, and
continuous flow technology for automated sequencing.
Results and discussion
Development of homogeneous reaction conditions
The standard conditions used for the heterogeneous SNAr reaction
were to heat 1.2 equivalents of phenol 2 with 1.0 equiva-
lents of DCNB (1) dissolved in N,N-dimethylacetamide (DMA)
(12.5 wt%) slurried with 1.5 equivalents of K2CO3 (-352 mesh) at
140 ◦C for 10 min. On cooling and addition of an equal volume of
water, the product diaryl ether 3 could be obtained by filtration in
up to 100% yield and 99% purity as determined by HPLC and 1H
NMR.4 The standard substrate used was 4-methoxyphenol (2a),
since this was particularly cheap, and yielded the crystalline diaryl
ether 3a in excellent yield and quality. The standard conditions
were modified slightly to 1.2 equivalents of organic base (and
1.1 equivalents of phenol 2a), because the reactions were now
homogeneous; a larger excess of K2CO3 had been used under
heterogeneous conditions to compensate for the probable phase
transfer effects involved with using an insoluble base. We identified
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) from earlier reports12
as the most likely replacement for K2CO3, but decided to screen a
range of common bases of varying pKbs (e.g. pyridine, lutidine, 1,4-
diazabicyclo[2.2.2]octane (DABCO) and triethylamine, amongst
others) for the conversion of 1 and 2a to give 3a. Reactions were
screened in 5 mL tubes on a small scale microwave reactor at 140 ◦C
for 10 min each. DBU proved far superior to all the other bases
tried, with only 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) giving
near equivalent conversions.
A limited range of five substrates, varying from the already
tested electron-rich 2a (4-MeO) through to the electron-poor 2k
(4-NO2) were then screened in small scale microwave tubes at
a range of temperatures from 80 to 180 ◦C (10 min each). The
results are shown in Fig. 1 (for 2a and 2k only) and confirm the
expected trend, with 2a having the highest conversions and 2k
the lowest, and the others being somewhat intermediate. From
these results, it was extrapolated that conversions would be >90%
for most substrates at ~160 ◦C, with the possible exception of those
bearing very electron-poor substituents.
Control experiments were also performed at room temperature
to determine the background rate of reaction under ambient
conditions. The highest rate was for 2a, which gave ~20%
conversion to 3a after 7 h and 40–50% after 24 h, whereas 2k
was effectively unreactive at RT up to 24 h. It was important
to establish the background rate of reaction over the planned
reaction times (3, 8 and 24 h) to determine if the two reagents
1 and 2 needed to be segregated. Although background reaction
might appear desirable, and often is chemically, it can cause other
issues. If premature precipitation of the product or other reaction
by-products occurs in the feed vessels, this can result in blockages
in the inlet lines.10 It is also desirable that all batches are processed
equally; if some reaction has already taken place before heating,
the batch may effectively be over-heated, resulting in reduced
quality from degradation products. Given that the background
reaction rate at room temperature would be significant for some
substrates, we decided to charge them from separate feed vessels
for each batch.
Fig. 1 Reaction conversion of 1 with 2a (dark/diamonds) and 2k
(light/circles).
Development of isolation procedure
Portionwise addition of an equal volume of water to the K2CO3-
mediated heterogeneous reaction mixtures had precipitated the
desired diaryl ethers 3 in excellent yields and purities in most cases.
When this was tried for several homogeneous reaction mixtures,
the products tended to be highly coloured and crystallised
with poor form or oiled out, despite the fact that they were
known to be white or pale yellow-coloured solids under the
heterogeneous reaction isolation conditions. A cursory analysis
by 1H NMR suggested that the samples were contaminated with
residual DBU. In principle, this should be removed by washing
with acid. We also rationalised that the high ionic strength
of the heterogeneous reaction conditions (due to the presence
of by-product KCl) probably aided good physical form and
crystallisation of the product ethers 3, and helped to ensure high
yields. We therefore determined to replicate in the homogeneous
reaction, as nearly as possible, the aqueous drown-out conditions
from the heterogeneous reaction.
We used diaryl ether 3j derived from 2j (4-CN), because this
appeared particularly crystalline and offered the best model for
success. A stock solution of previously prepared 3j was dissolved
in the requisite volume of DMA along with 1.2 equivalents of
DBU and 0.1 equivalents of phenol 2j (the reaction excess), and
separated into 50 mL portions, to which were added 50 mL
portions of stock solutions of either 10 or 20 wt% aqueous KCl
containing 3 equivalents of HCl. The recovered crystalline product
was then slurry washed with 2 M HCl (to remove residual DBU)
and then twice with water (to remove residual DMA and KCl). All
combinations gave essentially quantitative recovery of 3j, so the
lower strength 10 wt% solution was preferred. Quality by HPLC
1
and H NMR was excellent, as was the form, and colour was
typically pale yellow, much improved on the original process when
using only water at neutral pH.
Initial stop-flow investigations
We were now ready to begin testing the scaling out capability
of the Voyager for this SNAr reaction. Where reference samples
2220 | Org. Biomol. Chem., 2010, 8, 2219–2227
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
had not already been isolated, 20 mL scale microwave reactions
were performed and the product ethers 3 isolated by aqueous KCl
drown-out to provide spectroscopic data and analytical markers
peaks. Substitution patterns that did not give solid diaryl ethers of
good form on aqueous drown-out (Scheme 2, 3l–q) were passed
over in favour of those that did. This was purely for the convenience
of isolation in this study, since these products gave reactions of high
conversion and analytical purity, and could have been isolated on
larger scale using an extractive work-up.
Increasing the reaction temperature to 180 ◦C in the Voyager was
entirely feasible, but had a number of drawbacks. A key parameter
for scaling-out in a small vessel is the cycle time; increasing the
reaction temperature to 180 ◦C would require both longer heating
and cooling times. Furthermore, the extra 30 ◦C required the small
300 W microwave unit to work disproportionately hard to achieve
180 ◦C. This added too much time to a 10 min reaction, so we
decided to reduce the cycle time by adjusting the stoichiometry.
The initial reaction stoichiometry had been chosen to match the
efficiencies of very large scale production. Since all the materials
were cheap, we decided an increase in stoichiometry could be
used to increase the reaction rate without being economically
deleterious. The phenol charge was raised to 1.2 equivalents and
the DBU to 1.5 equivalents. The pump settings were adjusted to
accommodate the slight changes in stoichiometry and volumes,
and the three-batch proving trial showed complete reaction at
150 ◦C after 10 min. These conditions gave complete reaction for
all substrates except 2k, which required 10 min at 160 ◦C. The KCl
drown-out solution worked just as well as before, giving identical
yield and quality for all substrates.
Scaling-out stop-flow preparations
With the conditions now optimised (150 ◦C 10 min, 1.2 eq.
phenol, 1.5 eq. DBU), all the diaryl ethers 3a–k were prepared in
automated sequences of 10 or 30 batches, as shown in Table 1. For
each substrate, the pump on the Voyager was calibrated to dispense
23 mL of DCNB stock solution through line 1, and 27–31 mL
of phenol/DBU stock solution through line 2. (The variation in
volume was due to the differing molecular mass of the dissolved
phenols required to maintain equivalent stoichiometries.) The
single pump could be separately calibrated for both lines but
had to be re-calibrated for each new phenol processed. This took
only 5–10 min and once done, remained constant for all batches
processed within that method. These charges achieved the finalised
stoichiometric ratio of 1.2 eq. of phenol and 1.5 eq. of DBU, which
were charged jointly. Each batch was heated with stirring to 150 ◦C
for 10 min (160 ◦C for 3k), before being cooled to 90 ◦C and
removed from the vessel. The next batch in the sequence was then
charged automatically.
The cycle time for each individual 50 mL batch took ~16 min to
run and contained ~25 mmol. The 30 batch sequences took 8 h,
during which time ~1.5 L of reaction solution was processed to give
800 mmol of diaryl ether product (typically ~200 g). Representative
samples of product (typically 0.5 L of crude reaction solution) were
isolated by aqueous drown-out in each case to confirm yield and
quality, as shown in Table 1.
Scheme 2 Additional substituted phenols investigated but not scaled up
in the Voyager.
The initial scouting work was conducted on phenol 2a. A stock
solution of DCNB (1) at 25 wt% in DMA was prepared. A similar
solution of phenol 2a (1.1 eq.) was prepared in an equal volume
of DMA with DBU added (1.2 eq.). We had established that
phenol/DBU solutions were stable at RT for several days, whereas
the DCNB/DBU solution started to degrade over this time. By
co-charging the DBU with the phenol, one potential operation was
removed from the protocol, which would help to keep the cycle
time short. Appropriate volumes (~25 mL each) of the two reaction
solutions were pumped into the reaction vessel through separate
lines to give the correct stoichiometry. The vessel was sealed and
heated by microwaves (300 W) to 150 ◦C for 10 min with stirring.
At the end of the heating time, compressed air cooled the vessel
and the reaction solution was pumped out at 90 ◦C to a receiver
vessel. The next batch could then be charged automatically.
We have found that a proving trial of three to five batches is
useful to adequately test a new method, for example by showing
that lines do not gradually block between batches.10 Air is used
to blow the internal lines clear of starting materials and reaction
products. Small line washes with fresh solvent can also be used to
clean the lines. In this case, no line or vessel washes were required
between batches. However, reaction conversions were incomplete
◦
at 150 C for 2a. This may be because the Voyager measures the
Alternative stop-flow preparations
internal temperature by fibre optic probe, whereas the scouting
reactions had been conducted in a small scale microwave reactor
using an IR pyrometer measuring the external temperature of
the glass-walled vessels. Although good and consistent results can
be obtained with these instruments using external IR pyrometers
(irrespective of manufacturer), the vessel contents may be at a
slightly higher temperature than that registered. Consequently,
repeat three-batch trials were conducted up to 180 ◦C which
showed complete reaction after 10 min with no loss in yield or
purity (due to over-reaction).
Having established the principle of scaling out in the stop-flow
microwave reactor, we then attempted to broaden the scope
of the methodology with alternative substrates to 1. Thus,
compounds 4a–f were tested under identical conditions in small
scale microwave tubes using phenol 2a as the standard nucleophile
(Scheme 3). Unsurprisingly, methyl ester 4b proved too deactivated
to react at 150 ◦C, requiring instead 180 ◦C for 60 min to give 5b,
but at this temperature, adventitious hydrolysis of the ester group
to 4a started to occur (4a had also been found not to react).
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2219–2227 | 2221
©

View Article Online
Table 1 Summary of compounds prepared in the Voyager with batch numbers, yield and purity
Nucleophile
substituent
Literature
reference
Product
Coupling partner
Nucleophile
No. of batches
Yield (%)
Purity by LC (%)
mp/◦C
3a
3b
3c
3d
3e
3f
3g
3h
3i
1
2a
2b
2c
2d
2e
2f
4-MeO
3-MeO
2-MeO
4-tBu
4-Br
4-F
30a
10
10
10
10
30
10
10
10
30
10b
10
10
10c
10d
97
86
88
85
97
91
99
84
86
96
70
83
83
45
88
100
97
100
95
98
100
95
98
99
99
81
88–89
64–66
104–105
91–93
99–100
68–69
98–104
123–124
79–80
109–110
94–98
85–86
59–60
90–92
7e, 15
n/a
7e
7e, 16
n/a
7e
n/a
17
n/a
7c
7a
n/a
18
n/a
19
1
1
1
1
1
1
2g
2h
2i
4-Ph
1
4-CO2Me
4-CHO
4-CN
4-NO2
4-MeO
4-MeO
4-CN
1
3j
1
2j
3k
5c
5f
7
1
2k
2a
2a
2j
4c
4f
6c
1
96
98
96
98
9a
8a
4-MeO
96–99
n/a: None available.a Also prepared on 90 batch scale. b Required 160 ◦C for 10 min. c Required 180 ◦C for 10 min. d Required 80 ◦C for 60 s.
be the ortho-, para- and di-substituted products. The less activated
meta-substituted 6b required 180 ◦C for 10 min for full conversion
to two products, assumed to be the mono- and di-substituted
products. Lastly, the 2,3-DCNB equivalent 6c was tested with 2j,
which also required 10 min at 180 ◦C for complete conversion
to the single isomer 7 (Table 1). Despite the slower reaction, we
persisted in this case to obtain an alternative substitution pattern,
but the product proved difficult to isolate, and after an extensive
extractive work-up (in place of the aqueous drown-out), only a
45% yield was obtained, albeit of good quality product (97%).
Alternative nucleophiles were also briefly investigated using 1
as the test-bed (Scheme 5). The thiophenol 8a (sulfur analogue
of 2a) was found to require only 1 min at 80 ◦C for complete
reaction, but with pumping the cycle time was 5.7 min per batch.
Ten batches were prepared in less than 1 h from which the product
diarylthioether 9a was isolated in only moderate purity (82%) after
the aqueous drown-out. Re-slurrying several times with methanol,
however, gave good quality product (97%) in high yield (88%)
(Table 1). Thiophenol 8k was also investigated to prepare 9k on
small scale, but the reaction was found to be so fast it was not
worth considering for microwave synthesis. Coincidentally, the
sulfur analogue (8h) of 2h would have been ideal for preparing
9h, a proposed intermediate in the potential alternative synthesis
of AZD7545, a former AstraZeneca development compound
(Scheme 6).13 Again, small scale microwave studies proved this was
a viable transformation, but the work was not scaled up (solely due
to the cost of 8h).
Scheme 3 Alternative coupling partners to 1 investigated.
Ethyl ester 4c with the additional nitro group performed very well,
however, to give diaryl ether 5c under the standard conditions. Of
the nitriles, 4d was too deactivated to react at 150 ◦C; 4e did react
but required 180 ◦C for 30 min for full conversion; but 4f reacted
cleanly under the standard conditions to give product 5f in good
yield and high purity (Table 1).
Alternative dichloro-substitution patterns to 1 retaining the
activating nitro group were also investigated (Scheme 4). So the
2,4-DCNB equivalent 6a gave complete conversion at 150 ◦C after
10 min to an unresolved mixture of three compounds, assumed to
Scheme 5 SNAr reaction with substituted thiophenols.
Several substituted anilines, including p-anisidine, were also
investigated on small scale with 1. Unsurprisingly, these failed
to react under the standard conditions, presumably due to
Scheme 4 Alternative substitution patterns to 1 investigated.
2222 | Org. Biomol. Chem., 2010, 8, 2219–2227
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Overall, this shows that a modest scale-up (~30 mmol) can be
achieved simultaneously for up to 16 related reaction products in
less than 1 h, which should be of interest to medicinal chemists.
Alternatively, a larger scale-up for one product (~0.5 mol) could
be achieved in the same time if all tubes (total volume 1.0 L) were
loaded with the same starting materials. However, this would not
be as convenient as the automated stop-flow microwave reactor
which can be left to run unattended.
Extended scale-out stop-flow preparation
As a final test of robustness of the stop-flow reactor, 90 batches
of the standard reaction pair (1 and 2a) were processed in a
continuous run over 24 h with no manual intervention. This
included ~15 h of unattended operation overnight. A ten-batch
portion (530 mL) of crude product reaction mixture was submitted
to the optimised aqueous drown-out procedure which gave a 98%
yield of product 3a of >99% purity by HPLC. Overall, the total
reaction volume processed was 4.7 L containing 2.3 moles of 1
which was accomplished in just under 25 h.
Scheme 6 Potential synthesis of AZD7545.
poor nucleophilicity, but products were formed on heating to
~200 ◦C. Some of these reaction products appeared to be adducts
with DBU (as determined by 1H NMR analysis). Attempts to use
triethylamine gave limited reaction at 200 ◦C and poor quality.
The homologous benzylamine analogue 10 was investigated and
did react to give 11, but required 2 eq. of 10 (and 1.0 eq. of
DBU) for the best results (83% conversion after 10 min at 165 ◦C).
However, this was not taken into the stop-flow reactor.
Conclusions
This paper reports on the manufacture of a range of poten-
tially useful pharmaceutical and agrochemical diaryl ethers and
related compounds through scaling-out in an automated stop-
flow microwave reactor. The process is facile and requires no
manual intervention once started, such that as much product
can be prepared as required, given sufficient availability of
starting materials and time. Of particular significance in this case,
continuous 24 h processing has been achieved for the first time,
which demonstrates that this relatively small-scale microwave stop-
flow reactor is both robust and reliable. Furthermore, production
rates of >0.5 kg per day can be achieved (for this reaction),
which would meet the typical manufacturing requirements of
early clinical pharmaceutical development. The production rates
are facilitated by a combination of rapid microwave heating, fast
cooling due to small vessel size, and automated charging through
a stop-flow approach. Higher productivities could be achieved by
the use of more reactors operating in parallel.
Batch microwave scale-up preparations
As an adjunct to this study, the standard reaction set (Scheme 1)
was also trialled in an alternative microwave batch reactor, the
Anton Paar Synthos 3000.14 This is a multimode microwave
reactor which has sixteen 100 mL reaction tubes, each with
an effective working volume of ~60 mL. Each tube is stirred
magnetically and rotated slowly in the microwave cavity to ensure
a uniform microwave field over the course of the reaction.
A stock solution of 1 and DBU (1.5 eq.) in DMA (12.5 wt%
based on 1) was made up and split between fourteen tubes
(28 mmol of 1 each) to which were added 34 mmol (1.2 eq.)
of phenols 2a–k (3.8–6.0 g depending on molecular weight),
including duplicate tubes of 2a, 2j and 2k. The final two tubes were
made up in a similar manner on 28 mmol scale using 4c and 4f with
2a, respectively. The total volume in each tube was ~55–60 mL. A
single run at 150 ◦C for 10 min converted all starting material
combinations for all sixteen tubes to their respective products
(3a–k, 5c and 5f) in ~40 min (allowing for heating and cooling).
Conversions were marginally lower than in the Voyager, probably
because of the initial over-heating of the reaction samples in the
Voyager to ~160 ◦C, but there was no substantial preparative
difference. Two of the duplicated samples were combined and
isolated by aqueous drown-out to confirm yield and quality (3a
91% yield, 100% purity by HPLC; 3j 93% yield, 98% purity by
HPLC).
Experimental
General procedures
Reaction mixtures and products were analysed by reverse phase
HPLC on an Agilent 1100 series instrument according to the
following conditions: column, Varian Polaris Amide C18 3 mm,
50 ¥ 3.0 mm i.d.; eluent A, 100% purified water, 0.03% v/v
trifluoroacetic acid; eluent B, 100% acetonitrile, 0.03% v/v tri-
fluoroacetic acid; flow rate 1.25 mL min-1.; wavelength 230 nm;
temperature 45 ◦C; injection volume 2 mL; at t = 0 min, 5%
eluent B; at t = 6 min, 95% eluent B; at t = 7.5 min, 95% eluent
B; post time 1.5 min. Typical retention times (RT) are noted in
each case. Melting points were determined using a Griffin melting
point apparatus (aluminium heating block) and are uncorrected.
1H and 13C NMR spectra were recorded on a Varian Inova 400
spectrometer at 400 and 100.6 MHz respectively with chemical
shifts given in ppm relative to TMS at d = 0. High resolution mass
spectra were performed on a Micromass GCT mass spectrometer
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2219–2227 | 2223
©

View Article Online
with EI+ source. Analytical TLC was carried out on commercially
prepared plates coated with 0.25 mm of self-indicating Merck
Kieselgel 60 F254 and visualised by UV light at 254 nm. Preparative
scale silica gel flash chromatography (for purification of analytical
samples only) was carried out by standard procedures using Merck
Kieselgel 60 (230–400 mesh). Where not stated otherwise, assume
standard practices have been applied.
over 30 min with mechanical stirring to an equal volume of
crude reaction product (generally performed on ~500 mL scale,
representing a 10 batch run) during which time an exotherm of
typically 12–16 K was observed initially. In most cases, a dense
yellow precipitate formed about halfway through this addition.
The reaction mixture was cooled back to 20 ◦C and the precipitate
isolated by filtration. The product cake was slurry washed with
2 M hydrochloric acid (300 mL on 500 mL scale), followed by
two slurry washes with water (500 mL each). Larger volumes do
not affect yield and may be required to enhance quality in some
cases. The product diarylethers (3a–k, 5c, 5f, 7, 9a) were dried to
constant weight in a vacuum oven at 50 ◦C.
Small scale microwave preparations
Small scale microwave reactions were performed in sealed, thick-
walled glass tubes (5 or 20 mL) in a Biotage Initiator 300 W
focused microwave reactor with external IR temperature probe
and non-invasive pressure transducer. Stoichiometries and solvent
volumes were as noted below in the general procedures for stop-
flow preparations, and conducted on typically 2 mmol (5 mL tube)
or 9 mmol (20 mL tube) scales. The heating time is not included in
the quoted hold time for any given procedure; control studies show
that the heating time has a negligible effect on overall conversion.
Where products were isolated to provide reference markers and
analytical data, the aqueous drown-out procedure described in the
text was used if possible (for solids of good form), or alternatively
an extractive procedure with ethyl acetate or MTBE followed
by flash silica gel chromatography and/or recrystallisation from
methanol was used instead.
Stop-flow microwave preparations of diarylethers (3a–k, 5c, 5f, 7,
and 9a)
The stop-flow preparation for 3a is given in full; for other com-
pounds, only differing parameters are given, in addition to physical
and spectroscopic characterisation data. For all compounds,
typically ~0.5 L of representative crude reaction solution (10
batches) was taken from which the desired products were isolated
by aqueous drown-out with the procedure noted above. Physical
and quality data and yields are taken from samples derived by
aqueous drown-out directly from these large scale preparations,
and were not further purified, except where noted.
Preparation of reaction solutions
2-Chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (3a). DCNB
(1) (160 g, 0.83 mole) was dissolved in DMA (640 mL, 25 wt%) and
charged to a 1 L bottle. In a separate 1 L bottle, 4-methoxyphenol
(2a) (124 g, 0.99 mole, 1.20 eq.) was dissolved in DMA (640 mL)
and DBU (186 mL, 1.24 mole, 1.50 eq.) added and the contents
stirred until homogeneous. One input line (SM1) was placed in
the bottle containing 1 and the other input line (SM2) placed in
the bottle containing 2a/DBU. The materials were processed in a
CEM Voyager microwave reactor in 30 continuous cycles to give
1560 mL of dark reaction mixture. Each batch consisted of 23 mL
of 1 (~28 mmol) and 29 mL of 2a (~33 mmol), took ~16.5 min to
run and gave 52 mL of crude product mixture. In order to make the
work-up more manageable (in the lab), the crude reaction mixture
was split into three 520 mL portions, of which one was chosen
at random to isolate representative product by the method noted
above. The title compound was prepared as a pale yellow solid
(69.2 g, 97% on 10 batch scale). HPLC (RT 4.87 min, 99.7%); mp
88-89 ◦C (lit.15 86-90 ◦C); 1H NMR (400 MHz, CDCl3) d 8.36 (1H,
d, J = 2.8 Hz), 8.02 (1H, dd, J = 9.2 Hz, J = 2.8 Hz), 7.06-7.02
(2H, m), 6.98-6.94 (2H, m), 6.79 (1H, d, J = 5.2 Hz), 3.84 (3H, s);
13C NMR (100.6 MHz, CDCl3) d 160.00, 157.52, 147.63, 142.26,
126.53, 123.95, 123.69, 121.77, 115.65, 115.48, 55.78; HRMS (EI+)
(Found: M+, 279.0281. C13H10ClNO4 requires M, 279.0298).
The first reaction solution (SM1) consisted of the limiting reagent
(1, 4c, 4f or 6c) dissolved in DMA at 25 wt%. The second reaction
solution (SM2) consisted of the nucleophile (2a–k or 8a, 1.2 eq.)
and DBU (1.5 eq.) dissolved in an equal volume of DMA (25 wt%
based on SM1). The volume of these homogeneous reaction
solutions was then measured and the volume of SM2 required
to maintain the correct stoichiometry relative to SM1 calculated.
General procedure for stop-flow preparations (Voyager)
In a CEM Voyager 300 W microwave reactor, limiting reagent
(SM1) was charged through the first input line (23 mL for 1,
~28 mmol) followed by the nucleophile/DBU solution (SM2)
through the second line (typically 27–31 mL depending on the
mass of the nucleophile) into the 80 mL reaction vessel (50 mL
working volume). The combined reaction mixture (~ 50 mL) was
heated by microwaves to 150 ◦C (overshoots initially to ~160 ◦C)
and held for 10 min with magnetic stirring. The reaction mixture
was then cooled to 90 ◦C with compressed air and pumped
out through the product line and collected. This cycle was then
repeated automatically, with the number of cycles depending on
the volume of the stock solutions used. To ensure that there were
sufficient materials for the desired number of cycles and practice
runs, stock solutions were made up to run a few more cycles than
planned, therefore yields quoted are based on the number of moles
that were processed by the Voyager and chosen for work up.
2-Chloro-1-(3-methoxyphenoxy)-4-nitrobenzene
(3b). Pre-
pared on 0.31 mole scale of 1 (10 batches) with 3-methoxyphenol
(2b) (45.9 g, 0.37 mole, 1.20 eq.), to yield the title compound as
a beige solid (63.4 g, 86%). HPLC (RT 4.89 min, 96.6%); mp
64-66 ◦C; 1H NMR (400 MHz, CDCl3) d 8.38 (1H, d, J = 2.5 Hz),
8.05 (1H, dd, J = 9.1 Hz, J = 2.7 Hz), 7.33 (1H, t, J = 8.0 Hz),
6.92 (1H, d, J = 8.7 Hz, 6.83-6.80 (1H, m), 6.67-6.64 (2H, m), 3.82
(3H, s); 13C NMR (100.6 MHz, CDCl3) d 161.44, 158.99, 155.65,
142.77, 130.89, 126.58, 124.76, 123.70, 117.12, 112.11, 111.43,
Aqueous drown-out isolation procedure
Hydrochloric acid (36 wt%, 127 mL) was added to a stock solution
of potassium chloride (100 g, 10 wt%) dissolved in 1 L of water.
An equal volume of this stock solution was added dropwise
2224 | Org. Biomol. Chem., 2010, 8, 2219–2227
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
106.27, 55.62; HRMS (EI+) (Found: M+, 279.0284. C13H10ClNO4
requires M, 279.0298).
1-(4-Carbomethoxyphenoxy)-2-chloro-4-nitrobenzene
(3h).
Prepared on 0.31 mole scale of 1 (10 batches) with methylparaben
(2h) (57.1 g, 0.37 mole, 1.20 eq.), to yield the title compound
as a bright orange solid (65.8 g, 84%). HPLC (RT 4.53 min,
98.3%); mp 123-124 ◦C; 1H NMR (400 MHz, CDCl3) d 8.41
(1H, d, J = 2.6 Hz), 8.13-8.10 (3H, m), 7.08 (2H, d, J = 8.7 Hz),
7.04 (1H, d, J = 9.2 Hz), 3.93 (3H, s); 13C NMR (100.6 MHz,
CDCl3) d 166.17, 158.87, 157.54, 143.79, 132.21, 127.05, 126.83,
126.16, 123.80, 119.10, 118.81, 52.36; HRMS (EI+) (Found: M+,
307.0273. C14H10ClNO5 requires M, 307.0248).
2-Chloro-1-(2-methoxyphenoxy)-4-nitrobenzene
(3c). Pre-
pared on 0.31 mole scale of 1 (10 batches) with 2-methoxyphenol
(2c) (45.9 g, 0.37 mole, 1.20 eq.), to yield the title compound as
a pale yellow solid (63.5 g, 88%). HPLC (RT 4.79 min, 100%);
mp 104-105 ◦C; 1H NMR (400 MHz, CDCl3) d 8.36 (1H, d, J =
2.8 Hz), 7.99 (1H, dd, J = 9.1 Hz, J = 2.7 Hz), 7.31-7.27 (1H,
m), 7.15-7.00 (3H, m), 6.66 (1H, d, J = 9.2 Hz), 3.78 (3H, s);
13C NMR (100.6 MHz, CDCl3) d 159.40, 151.36, 142.35, 142.22,
127.35, 126.38, 123.57, 123.31, 122.58, 121.60, 114.91, 113.32,
56.00; HRMS (EI+) (Found: M+, 279.0213. C13H10ClNO4 requires
M, 279.0298).
2-Chloro-1-(4-formylphenoxy)-4-nitrobenzene (3i). Prepared
on 0.31 mole scale of 1 (10 batches) with 4-hydroxybenzaldehyde
(2i) (45.8 g, 0.37 mole, 1.20 eq.), to yield the title compound
as a beige solid (61.6 g, 86%). HPLC (RT 4.46 min, 99.3%);
mp 79-80 ◦C; 1H NMR (400 MHz, CDCl3) d 10.00 (1H, s),
8.43 (1H, d, J = 2.8 Hz), 8.16 (1H, dd, J = 9.2 Hz, J =
2.4 Hz), 7.97-7.94 (2H, m), 7.17-7.14 (2H, m), 7.12 (1H, d, J =
8.9 Hz); 13C NMR (100.6 MHz, CDCl3) d 190.54, 160.22, 156.92,
144.22, 133.17, 132.27, 126.91, 126.70, 123.89, 120.05, 118.95;
HRMS (EI+) (Found: M+, 277.0141. C13H8ClNO4 requires M,
277.0142).
1-(4-t-Butylphenoxy)-2-chloro-4-nitrobenzene (3d). Prepared
on 0.31 mole scale of 1 (10 batches) with 4-tert-butylphenol (2d)
(56.3 g, 0.37 mole, 1.20 eq.), to yield the title compound as a pale
bei◦ge solid (69.2 g, ◦85%). HPLC (RT 5.72 min, 95.2%); mp 91-
93 C (lit.16 104-107 C); 1H NMR (400 MHz, CDCl3) d 8.36 (1H,
d, J = 2.5 Hz), 8.03 (1H, dd, J = 9.0 Hz, J = 2.6 Hz), 7.47-7.43
(2H, m), 7.03-7.00 (2H, m), 6.87 (1H, d, J = 9.2 Hz); 13C NMR
(100.6 MHz, CDCl3) d 159.51, 152.09, 148.94, 142.46, 127.34,
126.54, 124.44, 123.66, 119.83, 116.48, 34.66, 31.51; HRMS (EI+)
(Found: M+, 305.0784. C16H16ClNO3 requires M, 305.0819).
2-Chloro-1-(4-cyanophenoxy)-4-nitrobenzene (3j). Prepared
on 0.83 mole scale of 1 (30 batches) with 4-cyanophenol (2j)
(119 g, 0.99 mole, 1.20 eq.), to yield the title compound as a
pale orange solid (67.0 g, 96%). HPLC (RT 4.53 min, 99.2%);
mp 109-110 ◦C; 1H NMR (400 MHz, CDCl3) d 8.43 (1H, d,
J = 2.6 Hz), 8.17 (1H, dd, J = 9.0 Hz, J = 2.8 Hz), 7.73-7.70
(2H, m), 7.14-7.08 (3H, m); 13C NMR (100.6 MHz, CDCl3) d
158.90, 156.45, 144.48, 134.69, 126.98, 126.93, 123.95, 120.38,
119.11, 118.19, 108.53; HRMS (EI+) (Found: M+, 274.0139.
C13H7ClN2O3 requires M, 274.0145).
1-(4-Bromophenoxy)-2-chloro-4-nitrobenzene (3e). Prepared
on 0.31 mole scale of 1 (10 batches) with 4-bromophenol (2e)
(64.9 g, 0.37 mole, 1.20 eq.), to yield the title compound as
a beige solid (81.1 g, 97%). HPLC (RT 5.19 min, 97.9%); mp
99-100 ◦C; 1H NMR (400 MHz, CDCl3) d 8.38 (1H, d, J =
2.8 Hz), 8.08 (1H, dd, J = 9.1 Hz, J = 2.7 Hz), 7.57-7.54 (2H,
m), 6.99-6.96 (2H, m), 6.91 (1H, d, J = 9.3 Hz); 13C NMR
(100.6 MHz, CDCl3) d 158.46, 153.88, 143.17, 133.53, 126.75,
125.18, 123.75, 121.73, 118.54, 117.35; HRMS (EI+) (Found: M+,
326.9285. C12H7BrClNO3 requires M, 326.9298).
2-Chloro-1-(4-nitrophenoxy)-4-nitrobenzene (3k). Prepared on
0.31 mole scale of 1 (10 batches) with 4-nitrophenol (2k) (51.7 g,
0.37 mole, 1.20 eq.) and heated to 160 ◦C for 10 min, to yield the title
compound as a brown solid (65.6 g, 70%). HPLC (RT 4.69 min,
2-Chloro-1-(4-fluorophenoxy)-4-nitrobenzene (3f). Prepared
on 0.83 mole scale of 1 (30 batches) according with 4-fluorophenol
(2f) (41.8 g, 0.99 mole, 1.20 eq.), to yield the title compound
as a beige solid (62.2 g, 91%). HPLC (RT 4.84 min, 100%);
◦
1
80.7%); mp 94-98 C; H NMR (400 MHz, CDCl3) d 8.45 (1H,
d, J = 2.8 Hz), 8.32-8.28 (2H, m), 8.20 (1H, dd, J = 9.0 Hz, J =
2.8 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.12-7.08 (2H, m); 13C NMR
(100.6 MHz, CDCl3) d 160.51, 156.20, 144.78, 144.30, 127.24,
127.06, 126.37, 124.00, 120.90, 118.29; HRMS (EI+) (Found: M+,
293.9987. C12H7ClN2O5 requires M, 294.0043).
◦
1
mp 68-69 C; H NMR (400 MHz, CDCl3) d 8.38 (1H, d, J =
2.6 Hz), 8.05 (1H, dd, J = 9.1 Hz, J = 2.7 Hz), 7.17-7.12 (2H,
m), 7.10-7.05 (2H, m), 6.84 (1H, d, J = 9.0 Hz); 13C NMR
(100.6 MHz, CDCl3) d 161.41, 159.20 and 158.97 (1C, d, J =
23.0 Hz), 150.37 and 150.33 (1C, d, J = 3.0 Hz), 142.77, 126.68,
124.58, 123.73, 121.96 and 121.88 (1C, d, J = 8.4 Hz), 117.35 and
117.11 (1C, d, J = 23.8 Hz), 116.38; HRMS (EI+) (Found: M+,
267.0073. C12H7ClFNO3 requires M, 267.0098).
Ethyl 4-(4-methoxyphenoxy)-3-nitrobenzoate (5c). Prepared
on 0.25 mole scale of 4c (10 batches) with 4-methoxyphenol (2a)
(38.1 g, 0.30 mole, 1.20 eq.), to yield the title compound as a
pale beige◦ solid (59.0 g, 83%). HPLC (RT 4.77 min, 96.3%);
1
mp 85-86 C; H NMR (400 MHz, CDCl3) d 8.58 (1H, d, J =
2-Chloro-1-(4-phenylphenoxy)-4-nitrobenzene (3g). Prepared
on 0.31 mole scale of 1 (10 batches) with 4-phenylphenol (2g)
(65.1 g, 0.37 mole, 1.20 eq.), to yield the title compound as a pale
beige solid (86.4 g, 99%). HPLC (RT 5.58 min, 94.7%); mp 98-
104 ◦C; 1H NMR (400 MHz, CDCl3) d 8.40 (1H, d, J = 2.8 Hz),
8.08 (1H, dd, J = 9.1 Hz, J = 2.7 Hz), 7.67-7.57 (4H, m), 7.49-
7.44 (2H, m), 7.41-7.37 (1H, m), 7.18-7.14 (2H, m), 6.97 (1H, d,
J = 9.2 Hz); 13C NMR (100.6 MHz, CDCl3) d 159.09, 154.07,
142.82, 140.00, 138.93, 129.14, 129.04, 127.70, 127.12, 126.67,
124.87, 123.76, 120.49, 117.0; HRMS (EI+) (Found: M+, 325.0511.
C18H12ClNO3 requires M, 325.0506).
2.0 Hz), 8.08 (1H, dd, J = 8.8 Hz, J = 2.2 Hz), 7.08-7.04 (2H,
m), 6.97-6.93 (2H, m), 6.90 (1H, d, J = 8.7 Hz), 4.40 (2H, q,
J = 7.1 Hz), 3.84 (3H, s), 1.40 (3H, t, J = 7.1 Hz); 13C NMR
(100.6 MHz, CDCl3) d 164.36, 157.51, 155.57, 147.47, 139.87,
134.97, 127.37, 124.45, 121.77, 117.61, 115.44, 61.73, 55.77, 14.37;
HRMS (EI+) (Found: M+, 317.0889. C16H15NO6 requires M,
317.0899).
2-Fluoro-1-(4-methoxyphenoxy)-4-cyanobenzene
(5f). Pre-
pared on a 0.42 mole scale of 4f (10 batches) with 4-methoxyphenol
(2a) (63.6 g, 0.51 mole, 1.20 eq.), to yield the title compound as
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2219–2227 | 2225
©

View Article Online
a yellow solid (69.6 g, 8◦3%). HPLC (RT 4.41 min, 98.4%); mp
59-60 ◦C (lit.18 68.3-70.5 C); 1H NMR (400 MHz, CDCl3) d 7.45
(1H, dd, J = 10.3 Hz, J = 1.8 Hz), 7.33 (1H, dt, J = 8.5 Hz, J =
1.8 Hz), 7.04-6.99 (2H, m), 6.95-6.91 (2H, m), 6.86 (1H, t, J =
8.2 Hz), 3.83 (3H, s); 13C NMR (100.6 MHz, CDCl3) d 157.21,
153.62 and 151.11 (1C, d, J = 251.7 Hz), 150.98 and 150.88 (1C,
d, J = 10.0 Hz), 147.84, 129.45 and 129.40 (1C, d, J = 4.6 Hz),
121.25, 120.68 and 120.48 (1C, d, J = 20.6 Hz), 118.32 and 118.30
(1C, d, J = 1.6 Hz), 117.82 and 117.80 (1C, d, J = 2.3 Hz),
115.35, 105.88 and 105.80 (1C, d, J = 8.4 Hz), 55.76; HRMS
(EI+) (Found: M+, 243.0672. C14H10FNO2 requires M, 243.0696).
volume ~110–115 mL each) and isolated by aqueous drown-out
according to the procedure described above to confirm yield and
quality (3a 14.4 g cream solid, 91% yield, 100% purity by HPLC;
3j 14.4 g brown solid, 93% yield, 98% purity by HPLC).
Acknowledgements
We thank Sam Whitmarsh (AstraZeneca, Avlon) for HRMS data.
Notes and references
6-Chloro-1-(4-cyanophenoxy)-2-nitrobenzene (7). Prepared on
0.31 mole scale of 6c (10 batches) with 4-cyanophenol (2j) (45 g,
0.37 mole, 1.20 eq.), and heated to 180 ◦C for 10 min, to yield, after
an extensive extractive work-up with MTBE and washing with
NaOH solution, the title compound as a crimson solid (44.5 g,
45%). HPLC (RT 4.14 min, 96.2%); mp 90-92 ◦C; 1H NMR
(400 MHz, CDCl3) d 7.96 (1H, dd, J = 8.0, 1.6 Hz), 7.87 (1H,
dd, J = 8.4, 1.8 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.43 (1H, t, J =
8.2 Hz), 6.93 (2H, d, J = 8.8 H z); 13C NMR (100.6 MHz, CDCl3)
d 159.99, 143.28, 135.63, 134.34, 130.97, 126.98, 124.38, 118.56,
16.26, 107.01; HRMS (EI+) (Found: M+, 274.0118. C13H7ClN2O3
requires M, 274.0145).
1 (a) Microwaves in Organic Synthesis, ed. A. Loupy, Wiley-VCH,
Weinheim, 2nd edn, 2006; (b) C. O. Kappe and A. Stadler, Microwaves
in Organic and Medicinal Chemistry, Wiley-VCH, Weinheim, 2005;
(c) Microwave Assisted Organic Synthesis, ed. J. P. Tierney and P. Lid-
stro¨m, Blackwell, Oxford, 2005; (d) S. Caddick and R. Fitzmaurice,
Tetrahedron, 2009, 65, 3325–3355; (e) C. O. Kappe and D. Dallinger,
Mol. Diversity, 2009, 13, 71–193; (f) C. O. Kappe, Chem. Soc. Rev.,
2008, 37, 1127–1139; (g) C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43,
6250–6284; (h) B. L. Hayes, Aldrichimica Acta, 2004, 37, 66–76; (i) M.
Nu¨chter, B. Ondruschka, W. Bonrath and A. Gum, Green Chem., 2004,
6, 128–141.
2 (a) C. R. Strauss, Org. Process Res. Dev., 2009, 13, 915–923; (b) J. M.
Kremsner, A. Stadler and C. O. Kappe, Top. Curr. Chem., 2006, 266,
233–278; (c) B. Ondruschka, W. Bonrath and D. Stuerga, in Microwaves
in Organic Synthesis, ed. A. Loupy, Wiley-VCH, Weinheim, 2nd edn,
2006.
3 J. D. Moseley, P. Lenden, M. Lockwood, K. Ruda, J.-P. Sherlock, A. D.
Thomson and J. P. Gilday, Org. Process Res. Dev., 2008, 12, 30–40.
4 J. D. Moseley and E. K. Woodman, Energy Fuels, 2009, 23, 5438–5447.
5 For examples of the preparation of diaryl ethers by microwave-assisted
SNAr reaction on small scale, see: (a) Y.-J. Cherng, Tetrahedron, 2002,
58, 4931–4935; (b) F. Li, Q. Wang, Z. Ding and F. Tao, Org. Lett.,
2003, 5, 2169–2171; (c) G. L. Rebeiro and B. M. Khadilkar, Synth.
Commun., 2003, 33, 1405–1410; (d) F. Li, Q. Meng, H. Chen, Z. Li, Q.
Wang and F. Tao, Synthesis, 2005, 1305–1313; (e) H. Xu and Y. Chen,
Synth. Commun., 2007, 37, 2411–2420.
6 (a) A. de la Hoz, A. Diaz-Ortez and A. Moreno, Chem. Soc. Rev., 2005,
34, 164–178; (b) L. Perreux and A. Loupy, in Microwaves in Organic
Synthesis, ed. A. Loupy, Wiley-VCH, Weinheim, 2nd edn, 2006; (c) D.
Obermayer, B. Gutmann and C. O. Kappe, Angew. Chem., Int. Ed.,
2009, 48, 8321–8324.
7 (a) A. Creuzburg, H. J. Zschiegner, W. Kochmann, W. Kramer, R.
Fritzsche, O. Sass and K. Naumann, East Ger. Pat., DD 106542, 1974;
(b) H. Debne and L. M. Seusse, East Ger. Pat., DD 110651, 1974;
(c) W. Sirrenberg, E. Klauke, J. Schramm, I. Hammann and W. Stendel,
Ger. Offen., DE 2638233, 1978; (d) J.-Z. Liu, L. Fan, M.-L. Ma, Y.-L.
Zhang, Y.-L Wang, G.-F. Liu and S.-H. Chen, Sichuan Daxue Xuebao
Zian Kexueban, 2002, 39, 161–163; (e) Z.-X. Yang, H. Chen, Y.-Z. Bi,
Y. Zou, T.-P. Hou and Y.-L. Wang, Youji Huaxue, 2008, 28, 432–435.
8 For recent reviews on the preparation of diaryl ethers by various
methods, including SNAr reaction, see: (a) A. W. Thomas, Science of
Synthesis, 2007, 31a, 469–543; (b) R. Frlan and D. Kikelj, Synthesis,
2006, 2271–2285; (c) J. S. Sawyer, Tetrahedron, 2000, 56, 5045–5065.
9 (a) O. N. Tolkachev, Khimiya Prirodnykh Soedinenii, 1981, 263–283;
(b) J. S. Sawyer, Drugs Future, 1996, 21, 610–614; (c) J. S. Sawyer, E. A.
Schmittling, J. A. Palkowitz and W. J. Smith III, J. Org. Chem., 1998,
63, 6338–6343; (d) For the naturally-occuring, medically important
compounds thyrozine and vancomycin, see: The Merck Index, ed.
M. J. O’Neil, Merck and Co. Inc., Whitehouse Station NJ, 14th edn,
2006.
2-Chloro-1-[(4-methoxyphenyl)thio]-4-nitrobenzene (9a). Pre-
pared on 0.31 mole scale of
1 (10 batches) with 4-
methoxythiophenol (8a) (52.1 g, 0.37 mole, 1.20 eq.) and heated to
80 ◦C for 1 min, to yield the crude product (88.5 g of 82% purity
by HPLC, 89% yield overall). Five slurry washes with methanol
(100 mL each) yielded the title compound as light brow◦n solid
1
(74.2 g, 88%). HPLC (RT 5.35 min, 97.9%); mp 96-99 C; H
NMR (400 MHz, CDCl3) d 8.19 (1H, d, J = 2.4 Hz), 7.86 (1H, dd,
J = 8.4, 2.4 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 6.8 Hz)
6.68 (1H, d, J = 9.2 Hz), 3.88 (3H, s); 13C NMR (100.6 MHz,
CDCl3) d 161.61, 149.62, 145.02, 137.71, 129.97, 125.86, 124.44,
121.91, 118.98, 116.09, 55.60; HRMS (EI+) (Found: M+, 295.0029.
C13H10ClNO3S requires M, 295.0043).
General procedure for batch microwave preparations (Synthos
3000)
DCNB (1) (77.0 g, 0.40 mole) was dissolved in DMA (616 mL,
12.5 wt%) with DBU (91 mL, 0.60 mole, 1.50 eq.) and the contents
well mixed to give a total volume of 750 mL. A 54 mL aliquot of
this solution (28.6 mmol of 1) was charged to each of fourteen
Anton Paar HF-100 PTFE tubes. The requisite mass of each
phenol 2a–k was added to each tube to maintain a stoichiometry
of 1.20 eq. (typically 3.8–6.0 g, 34.3 mmol) in one portion, with
2a, 2j and 2k prepared in duplicate. In the final pair of tubes, 4c
and 4f were charged at the same scale (28.6 mmol) in combination
with 2a. A magnetic stirrer bar was added to each PTFE tube
which was sealed in a ceramic case inside a 16-position rotor and
placed in the cavity of an Anton Paar Synthos 3000 microwave
reactor. One tube (containing 1 and 2a) was fitted with a gas-
bulb thermometer; the temperature in the others was monitored
by external IR probe. The reaction mixtures were heated with
magnetic stirring to 150 ◦C over 10 min with 1400 W available
power, held at 150 ◦C for 10 min, then cooled by fan air to ~50 ◦C
over ~20 min. Two of the duplicated samples were combined (total
10 J. D. Moseley and E. K. Woodman, Org. Process Res. Dev., 2008, 12,
967–981.
11 (a) www.cem.com; (b) K. T. J. Loones, B. U. W. Maes, G. Rombouts,
S. Hostyn and G. Diels, Tetrahedron, 2005, 61, 10338–10348; (c) M. R.
Pitts, P. McCormack and J. Whittall, Tetrahedron, 2006, 62, 4705–4708.
12 (a) W.-C. Shieh, M. Lozanov, M. Loo, O. Repic and T. J. Blacklock,
Tetrahedron Lett., 2003, 44, 4563–4565; (b) S. Chen, H. Huang, X.
Liu, J. Shen, H. Jiang and H. Liu, J. Comb. Chem., 2008, 10, 358–360;
(c) M. Iannelli, F. Bergamelli, C. M. Kormos, S. Paravisi and N. E.
Leadbeater, Org. Process Res. Dev., 2009, 13, 634–637.
2226 | Org. Biomol. Chem., 2010, 8, 2219–2227
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
13 J. D. Moseley, D. Brown, C. R. Firkin, S. L. Jenkin, B. Patel and E. W.
Snape, Org. Process Res. Dev., 2008, 12, 1044–1059.
14 (a) www.anton-paar.com; (b) A. Stadler, B. H. Yousefi, D. Dallinger,
P. Walla, E. Van Der Eycken, N. Kaval and C. O. Kappe, Org. Process
Res. Dev., 2003, 7, 707–716.
15 Ch. S. Frankovskii, E. S. El’kis and L. D. Borodkina, Zhurnal
Organicheskoi Khimii, 1970, 6, 2305–2309.
16 G. Neubauer, S. B. Cilianu, V. Tamas, C. I. Ionescu, G. Funieru, and
A. Carstea, Rom. Pat., RO 74124, 1981.
17 M. Seto and T. Ohashi, PCT Int. Appl., WO 2007097470, 2007.
18 X.-M. Yan, B.-K. Ning and L.-P. Wang, Yingyong Huagong, 2007, 36,
273–276.
19 Ch. S. Frankovskii and E. Z. Katsnel’son, Zhurnal Organicheskoi
Khimii, 1968, 4, 490–493.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2219–2227 | 2227
©