C-O bond formation in a microfluidic reactor: High yield SNAr substitution of heteroaryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2016.03.095

This study describes our development of a novel and efficient procedure for C-O bond formation under mild conditions, for coupling heteroaryl chlorides with phenols or primary aliphatic alcohols. We utilized a continuous-flow microfluidic reactor for C-O bond formation in electron-deficient pyrimidines and pyridines in a much more facile manner with a cleaner reaction profile, high yield, quick scalability, and without the need for the transition metal catalyst. This approach can be of general utility to make C-O bond containing intermediates of industrial importance in a continuous and safe manner.

Full text of DOI:10.1016/j.tetlet.2016.03.095

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CAO bond formation in a microfluidic reactor: high yield SNAr
substitution of heteroaryl chlorides
⇑
Mohammad Parvez Alam, Barbara Jagodzinska, Jesus Campagna, Patricia Spilman, Varghese John
Drug Discovery Laboratory, Department of Neurology, Mary S. Easton Center for Alzheimer’s Disease Research, University of California, Los Angeles, CA 90095, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This study describes our development of a novel and efficient procedure for CAO bond formation under
mild conditions, for coupling heteroaryl chlorides with phenols or primary aliphatic alcohols. We utilized
a continuous-flow microfluidic reactor for CAO bond formation in electron-deficient pyrimidines and
pyridines in a much more facile manner with a cleaner reaction profile, high yield, quick scalability,
and without the need for the transition metal catalyst. This approach can be of general utility to make
CAO bond containing intermediates of industrial importance in a continuous and safe manner.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 4 March 2016
Revised 27 March 2016
Accepted 28 March 2016
Available online xxxx
Keywords:
Flow chemistry
SNAr reaction
CAO bond
Micro-fluidic reactor
Introduction
constitutes a significant synthetic challenge. Pertinent to our hit-
to-lead optimization work, improvement of such strategies would
In both academia and industry, carbonAoxygen (CAO) bond
forming reactions are of great utility as these bonds are ubiquitous
in natural products, polymers, and biologically active molecules.1
Some examples of bioactive molecules incorporating the CAO bond
are shown in Figure 1. Puromorphamine is a Hedgehog-signaling
pathway activator, an important regulator of stem cell renewal
and cancer growth,2 BMS-777607 at therapeutic doses acts as a
facilitate synthesis of analogs for biological analysis as part of our
drug discovery efforts. Our interest is in finding an alternative,
green chemistry approach to the precious transition-metal cat-
alyzed CAO coupling reactions. To the best of our knowledge
microfluidic reactor-based, rapid and high yield CAO bond forma-
tion under mild conditions, as described in this manuscript, has not
been previously reported. Our approach, described herein, supple-
ments the traditional CAO bond-forming reactions described
above. Furthermore, it also reveals the benefits of using a continu-
ous-flow microfluidic reactor, which include the following: short
reaction times, superior mixing, efficient heat transfer, increased
pressures, and the use of less reactive reagents that result in a high
yield reaction.9–17
multi-kinase inhibitor,3 and bispyribac-sodium is used as
a
herbicide.4
Traditionally, CAO bonds are formed using nucleophilic aro-
matic substitution (SNAr). Copper-mediated Ullmann coupling
has typically been used for the synthesis of aryl ethers from aryl
bromides/iodides and phenols, but it is characterized by a harsh
reaction conditions and the need for stoichiometric amount of
metal.5 In the last decade, many groups have switched to Buchwald
methodology, which utilizes a catalytic amount of copper and var-
ious ligands to generate the aryl ethers.6 There are substantial
precedents where SNAr reactions were performed on activated aryl
halides in flow under both traditional and microwave heating.7
More recently, Charaschanya et al. have reported high-tempera-
ture and high-pressure SNAr reactions of heterocycles with various
nitrogen nucleophiles.8 Although significant advances have been
achieved in this area, the development of a more efficient, mild,
economical, and green strategies for the CAO bond formation still
Results and discussion
In conventional batch reactions, dichloropyrimidine exhibits a
low reactivity as compared to its bromo- or iodo-counterpart.18
Consequently, the CAO bond formation using this intermediate is
slow and takes many hours even under the metal catalysis.19 In
the initial phase of development of our method, we used 4,6-
dichloro-2,5-dimethylpyrimidine and 4-methoxy-2-methylphenol
to study the effects of temperature, pressure, and solvent on the
yield of CAO bond formation (Table 1) in the continuous-flow
microreactor. Traditionally, 4,6-dichloro-2,5-dimethylpyrimidine
is coupled with 4-methoxy-2-methylphenol after treatment with
sodium hydride (60% suspension in oil) in DMF for 5–10 h.20
⇑
Corresponding author. Tel.: +1 (310) 206 4345; fax: +1 (310) 794 3148.
E-mail address: VJohn@mednet.ucla.edu (V. John).
http://dx.doi.org/10.1016/j.tetlet.2016.03.095
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alam, M. P.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.095

2
M. P. Alam et al. / Tetrahedron Letters xxx (2016) xxx–xxx
OMe
N
MeO
O
N
N
N
N
O
H
N
F
N
O
NH
N
N
O
O
ONa
O
F
O
N
N
MeO
N
N
O
N
H
N
OMe
Purmorphamine
Bispyribac-sodium
BMS-777607
Figure 1. Examples of bioactive molecules containing CAO bond.
Table 1
Effect of temperature and pressure on yield of CAO bond formation
a
c
Entry
Solvent
T (oC)
P (bar)
Flow rateb
(l
L/min)
tR (min)
Yieldd (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF–H2O
THF–H2O
THF–H2O
66
66
66
66
76
90
90
100
110
1
1
1
1
2
4
4
4
4
500
250
100
50
50
50
50
50
50
2
4
6
12
10
20
20
20
20
20
20
19 (clog)
30 (clog)
45 (clog)
55 (clog)
54
71
87
a
Synthesis of compound 3a was done under varying conditions (entries 1–9); two solutions were prepared and introduced by Pump A & B into the Asia microfluidic
reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equiv) in THF–H2O (2.5 mL, 3:2 v/v) and the other contained a mixture of phenol 2a (0.84 mmol, 1.5 equiv) and NaOH
(0.84 mmol, 1.5 equiv) in THF–H2O (2.5 mL, 3:2 v/v).
b
Flow rates of the combined solutions.
Retention time (in a 1 mL microfluidic reactor).
Yield determined by LCMS.
c
d
However, sodium hydride (60% suspension in oil) cannot be used in
a microfluidic reactor due to clogging of either the back pressure
regulator or the microfluidic reactor chip. Thus, we used THF as
the solvent and NaOH as the base to generate the required phenox-
ide. Under these conditions, using a temperature of 60 °C, and 1 bar
pressure, the expected monophenoxy derivative, 3a, was formed in
varying yields depending on residence time in the reactor. We
obtained yields of 6%, 12%, 19% and 30% with flow rates of the com-
clogging of the microfluidic reactor or back pressure regulator
was observed after a few runs, likely due to the deposition of NaCl.
To solve the clogging issue, the reaction solvent was combined
with water to remove NaCl formed as a byproduct. Switching the
solvent to THF–H2O (3:2 v/v) provided a similar yield of 54% at
90 °C, 4 bar pressure, using the combined flow rate of 50 lL/min
without any observed clogging. Further increase of temperature
while maintaining the 4 bar pressure was also evaluated to deter-
mine if there was any improvement of reaction yield. To our
delight, using the THF–H2O solvent system and the combined flow
bined solution being 500
lL/min, 250 lL/min, 100 lL/min, and
50 L/min, respectively (Table 1, entries 1–4). This corresponded
l
to residence times of 2, 4, 10, and 20 min, respectively, in the
1 mL microfluidic reactor. To improve yields we evaluated the
reaction at 76 °C and 90 °C under 2 bar and 4 bar pressure, respec-
tively. The temperature and/or pressure changes in the microreac-
tor were done easily, using the Asia chip climate controller (À10 °C
to +150 °C range) and the Asia pressure controller (1–10 bar
range). Using the higher temperature and pressure, the product
yield was shown to be increased to 45% and 55%, respectively
(Table 1, entries 5 and 6). However, under these conditions,
rate of 50 lL/min (Pump A & B at 25 lL/min each), the target cou-
pling product yield increased to 87% when reactor temperature
was maintained at 110 °C and 4 bar pressure (entry 9). Under these
conditions no clogging of the glass microfluidic reactor chip or the
back pressure regulator was observed. Additional increases in reac-
tor temperature to 120 °C and above did not improve the product
yield and, interestingly, clogging of the microfluidic reactor chip
was once again observed. Therefore, for further studies with
pyrimidine 1, temperature, pressure and combined flow rate were
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M. P. Alam et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
RO
Cl
Cl
Cl
R
OH
N
N
N
N
NaOH, THF-H2O (3:2 v/v)
3
1
Cl
O
Cl
O
O
Cl
O
Cl
N
N
N
N
N
N
O
Cl
3a, 87%
3b
3c
, 83%
, 85%
F3C
Cl
O
Cl
O
Cl
N
N
N
N
N
N
3d, 84%
3e, 87%
3f
, 84%
Scheme 1. CAO bond formation using compound 1 with different phenols and alcohols.a,b aFor synthesis of various 3 derivatives, two solutions were prepared and introduced
by Pump A & B into the Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equiv) in THF–H2O (2.5 mL, 3:2 v/v) and the other contained a mixture of
corresponding phenols (0.84 mmol, 1.5 equiv) and NaOH (0.84 mmol, 1.5 equiv) in THF–H2O (2.5 mL, 3:2 v/v). bProduct yield determined by LCMS.
O
Cl
2a
N
N
N
N
N
O
NaOH, THF-H2O (3:2 v/v)
4 bar, 110 oC
4
6
5, 81%
2a
Cl
O
N
4 bar pressure
O
THF-H2O (3:2 v/v)
THF-H2O (3:2 v/v)
Toulene
DMF
DMSO
90 oC
7,
failed
110 oC
110 oC
140 oC
150 oC
Scheme 2. CAO bond formation using mono chloropyrimidine and pyridine.a,b,c aFor synthesis of 5 & 7, two solutions were prepared and introduced by Pump A & B into the
Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equiv) in THF–H2O (2.5 mL, 3:2 v/v) and the other contained a mixture of phenol 2a (0.84 mmol,
1.5 equiv) and NaOH (0.84 mmol, 1.5 equiv) in THF–H2O (2.5 mL, 3:2 v/v). bFor attempted synthesis of 7 Toulene, DMF and DMSO neat were also used. cYield determined by
LCMS.
N
Cl
N
OAr
Ar-OH
O2N
NaOH, THF-H2O (3:2 v/v)
O2N
9
8
N
O
N
O
N
O
O2N
O2N
O
O2N
Cl
9a, 72%
9b, 70%
9c,
72%
Scheme 3. CAO bond formation using 2-chloro-5-nitropyridine with different phenols.a,b aFor synthesis of various 9 derivatives, two solutions were prepared and introduced
by Pump A & B into the Asia microfluidic reactor; one contained the aryl halide 1 (0.56 mmol, 1.0 equiv) in THF–H2O (2.5 mL, 3:2 v/v) and the other contained a mixture of
corresponding phenols (0.84 mmol, 1.5 equiv) and NaOH (0.84 mmol, 1.5 equiv) in THF–H2O (2.5 mL, 3:2 v/v). bYield determined by LCMS.
maintained at 110 °C, 4 bar and 50
H2O (3:2 v/v) solvent system.
After optimizing reaction conditions, we investigated CAO bond
formation with different phenols and alkyl alcohols. 4-Chloro-2-
l
L/min, respectively, in THF–
methylphenol, 2-chloro-6-methylphenol, 2,4,6-trimethylphenol,
sodium 2,2,2-trifluoroethoxide and sodium methoxide all reacted
with 4,6-dichloro-2,5-dimethylpyrimidine to generate the
monophenoxy (3a–3d) or monoalkoxy compounds (3e–3f) in a
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M. P. Alam et al. / Tetrahedron Letters xxx (2016) xxx–xxx
high yields. Notably as shown in Scheme 1, the reaction proceeds
regioselectively and only a mono-isomer was formed.
microfluidic reactor. Mass Spectrometry Instrumentation was
made available through the support of Dr. Greg Khitrov at the
University of California, Los Angeles Molecular Instrumentation
Encouraged by the above results, we tried to extend the same
protocol to 2-chloropyridine and 4-chloropyrimidine. Interest-
ingly, while 4-chloro-2-methylpyrimidine reacted smoothly to
generate the CAO coupled product 5 in 81% yield; no conversion
was observed with 2-chloropyridine, even with different solvent
systems, and varying temperature and pressure conditions
(Scheme 2). Switching the solvent system to toluene or DMF did
not furnish any coupled product. Only a trace amount of coupled
product 7 was observed as detected in mass spectrometry when
DMSO was used as solvent.
Center
– Mass Spectrometry Facility in the Department of
Chemistry.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds) associated with this article can be found in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2016.03.095.
Reactions of 2-chloro-5-nitropyridine, 8, were explored with
three different phenols and done in the microfluidic reactor to fur-
nish products in good yield. Coupling with 4-methoxy-2-
methylphenol produced 9a in 72% yield whereas 4-chloro-2-
methylphenol produced 9b in 70% yield and 2,4,6-trimethylphenol
gave 72% of coupled product 9c (Scheme 3). In the pyridine series
CAO bond formation was found to be dependent on the electronic
property of the ring. The presence of an electronegative nitro group
in the pyridine ring facilitated CAO bond formation.
References and notes
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Acknowledgements
This research was supported by the Mary S. Easton Center for
Alzheimer’s Disease Research at UCLA, and NIH Grant
(AG051386). We thank Syrris for technical assistance with the
Please cite this article in press as: Alam, M. P.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.095