A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines

Article abstract of DOI:10.1002/anie.201704529

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst-free conditions. This assembly-line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h^?1).

Full text of DOI:10.1002/anie.201704529

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Accepted Article
Title: A Unified Continuous Flow Assembly Line Synthesis of Highly
Substituted Pyrazoles and Pyrazolines
Authors: Joshua Britton and Timothy F Jamison
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704529
Angew. Chem. 10.1002/ange.201704529
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10.1002/anie.201704529
Angewandte Chemie International Edition
COMMUNICATION
A Unified Continuous Flow Assembly Line Synthesis of Highly
Substituted Pyrazoles and Pyrazolines
Joshua Britton and Timothy F. Jamison*
F
Abstract: A rapid and modular continuous flow synthesis of highly
O
F
NH
F
O
functionalized fluorinated pyrazoles and pyrazolines has been
developed. Flowing fluorinated amines through sequential reactor
coils mediates diazoalkane formation and [3+2] cycloaddition to
generate more than 30 azoles in a telescoped fashion. Pyrazole
cores are then sequentially modified through additional reactor
modules performing N-alkylation and arylation, deprotection, and
amidation to install broad molecular diversity in short order.
Continuous flow synthesis enables the safe handling of diazoalkanes
at elevated temperatures, and the use of aryl alkyne dipolarphiles
under catalyst free conditions. This assembly line synthesis provides
F
Cl
Cl
NH
F
N
H
N
N
F
O
H
Me
N
F
O
NH
F
NH
Me
Bixafen
Fungicide
Sedaxane
Fungicide
Syngenta
F
F
N
N
H
Bayer CropScience
N
H
N
F
F
Me
Me
Fluxapyroxad
Fungicide
Isopyrazam
Fungicide
Syngenta
BASF
F
F
.HCl
H
H2N
F
F
F
F
F
F
O
H
N
S
H
F
O
R3
4
R2
N
H
3
N
N
O
N
O
N
2
N
1
H2N
S
R4
5
N
O
N
Me
DPC-602
Arterial thrombosis
O
AS-136A
R1
Measles virus inhibitor
Common Pyrazole
Core
F
F
F
F
F
H
F
H
N
a
flexible approach for the synthesis of agrochemicals and
N
S
N
N
F
F
F
Me
pharmaceuticals, as demonstrated by four-step, telescoped
a
F
F
F
H
F
H
N
O
O
synthesis of measles therapeutic, AS-136A, in a total residence time
of 31.7 min (1.76 g h-1).
N
O
S
O
N
NH2
OMe
N
NH2
Cl
Mavacoxib
COX-2 inhibitor
Pfizer
Celecoxib
COX-2 inhibitor
Pfizer
Cl
OMe
Human lung
cancer suppression
SC-560
COX-1 inhibitor
In recent years, continuous flow synthesis has emerged as
an enabling technology.[1] At its core, pumps drive fluids through
reactor coils where solutions can be heated above their
atmospheric boiling points,[2] rapidly cooled,[2a,3] and effectively
irradiated.[4] Additionally, hazardous reactions can be safely
processed on scale by ensuring only small quantities of
hazardous material exist at any given time.[1d,5] With these
benefits in mind, our laboratory is interested in improving the
synthesis of active pharmaceutical ingredients (APIs),[6]
commodity chemicals[6e,7] and new materials[8] through the use of
continuous flow technology.
A large fraction of agrochemicals and pharmaceuticals
contain highly substituted pyrazole cores with CF2H or CF3
moieties at the 3-position (Figure 1). To create a rapid and
divergent synthesis of these molecules, we envisaged the use of
an assembly line synthesis.[9] In an assembly line process,
organic scaffolds are passed through sequential reactor
modules to accrue molecular complexity. In our system, a
common pyrazole core would first be synthesized, and then
modified through a series of subsequent, downstream, modules
to generate agrochemicals and pharmaceuticals. Choosing the
order, and type, of modules would govern the substitution
pattern and complexity of the final product. Herein, a multi-step
continuous flow synthesis of fluorinated pyrazole cores, and their
subsequent modification with additional modules is described.
The [3+2] cycloaddition of diazomethane with acetylene
yielding pyrazole was first reported in 1898.[10] More recently,
2,2-difluoromethyl diazomethane and 2,2,2-trifluoromethyl
diazomethane (1 and 2, Figure 2) have become common
synthons in organic synthesis.[11] Highly substituted pyrazoles
and pyrazolines can be obtained in a single step through a
Figure 1 Pharmaceuticals and agrochemicals containing common 3-
fluoromethyl pyrazole cores. Colours indicate structural similarities.
reaction of 1 and 2 with alkynes and alkenes.[11a,12] In this
respect, the use of 1 and 2 would provide a cost effective
approach to the construction of common pyrazole cores.
However, several advancements were required to realize this
goal.
Generally, [3+2] cycloadditions between alkynes and 1
require several hours to days,[11a, 3] while the use of 2 requires
several hours and super stoichiometric amounts of Ag2O and
NaOAc.[12b] Interestingly, 1 and 2 have been synthesized in
continuous flow before,[13-14] however, in the case of 1, all
reactants were placed into a syringe prior to entering the
continuous flow system, posing
diazoalkane can be formed in the syringe.[13] Furthermore,
although was generated in continuous flow, the [3+2]
a safety concern as the
1
cycloaddition was performed at room temperature in a round
bottom flask. Our control reactions indicated that generating 1 in
continuous flow is inconsequential if the [3+2] cycloaddition is
performed at room temperature (Supplementary Information). To
enable the safe and beneficial use of 1 and 2 in our continuous
flow system, the reactive components must be separated prior to
entry, the [3+2] cycloaddition should be rapid for immediate
diazoalkane consumption (removing a safety concern), and if
possible, transformations should be catalyst free.
Our investigation began by optimizing the formation of 1 in
the first module, and its subsequent consumption in
a
telescoped [3+2] cycloaddition with ethyl propiolate in the
second module (Figure 2). To our surprise, the formation of 1
required only five min at 60 °C, and the telescoped [3+2]
cycloaddition only 10 min at 90 °C to give 3 in an excellent 92%
yield (Table S1). The ability to synthesize 1 in the first module,
and feed it into the second enhances reaction efficiency; passing
all reagents through a single reactor coil yielded only 57%. Here,
a lower yield results due to diazoalkane decomposition at
elevated temperatures, further highlighting the benefit of reaction
isolation during multi-step synthesis.
[*]
Dr. J. Britton and Prof. Dr. T. F. Jamison
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, MA 02139 (USA)
E-mail: tfj@mit.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201704529
Angewandte Chemie International Edition
COMMUNICATION
Figure 2 Module 1 and 2 for the synthesis of highly substituted pyrazole and pyrazoline cores. Unless otherwise indicated, the system used the following
t
three solutions: a solution of CF2RCH2NH2 (2.0 equiv) and AcOH (0.4 equiv) dissolved in DCM, a second solution of BuONO (2.4 equiv) in DCM, and a third
solution of the alkyne or alkene (0.79 M, 1.0 equiv) in DCM. [a] CF3CH2NH2 (4.0 equiv), tBuONO (4.0 equiv), ACOH (0.15 equiv) and alkyne (0.79 M, 1.0 equiv).
t
t
[b] CF2HCH2NH2 (0.5 equiv), BuONO (0.8 equiv), AcOH (0.1 equiv) and alkyne (0. 79 M, 1.0 equiv). [c] CF3CH2NH2 (4.0 equiv) and BuONO (4.8 equiv) and
ACOH (0.8 equiv) and the alkyne (0.60 M, 1.0 equiv) with a 28 min residence time in module 2 at 132 °C and a back pressure of 325 psi. [d]. CF2RCH2NH2 (2.0
t
t
equiv), BuONO (2.0 equiv), AcOH (0.4 equiv) and alkyne (0.79 M, 1.0 equiv). [e] CF2RCH2NH2 (2.0 equiv), BuONO (4.0 equiv), AcOH (0.5 equiv) and alkyne
(0.79 M, 1.0 equiv). [f] Relative stereochemistry. The number indicated in the parentheses under compounds 25-33 indicates product selectivity for pyrazoline vs.
n-nitroso pyrazoline respectively. For additional details on the reactor set-up see the supporting information.
The optimized system was then used to generate 2 for
subsequent cycloaddition with ethyl propiolate to afford 4 in 99%
yield, demonstrating this reactor set up can generate high yields
of 3-trifluoromethyl pyrazoles.
Attempting a catalyst free transformation in our continuous flow
setup initially yielded no product. However, increasing the
temperature and residence time (28 min) of module 2 yielded
19-24 as single regioisomers in good to excellent yields (53-
93%). This continuous flow approach has several important
advancements. First, requirements for super stoichiometric Ag2O
and NaOAc have been removed. Second, the reaction time has
been reduced to ~30 min. Third, the transformation is now
scalable, and finally, 19 was obtained in improved yields.
This high temperature transformation again draws on a
benefit of continuous flow synthesis. Operating a back pressure
of 325 psi allows DCM (bp 40 °C) and 2 (bp ~13 °C)[11b] to be
super heated without vaporization; such conditions are not
amenable to round bottom flasks. Furthermore, heating
diazoalkanes at high temperatures in a round bottom flask would
be highly dangerous. Interestingly, the use of 1 under these
conditions yielded <30% of the desired difluoro analogue. The
higher temperatures required for a catalyst free approach most
likely degrades 1 as gas evolution in the reactor was observed.
The use of 2 under these conditions opens up the possibility for
synthesizing Celecoxib, Mavacoxib, SC-560 and the human lung
cancer suppression candidate (Figure 1) in a rapid, catalyst free,
and scalable environment.
With optimized conditions in hand, a range of alkynes were
reacted with both 1 and 2 to yield 5-17 in moderate to excellent
yields (48-99%). Importantly, the system accommodated
sterically demanding alkynes 7-9 and 14-18, and larger
fluoroamines to generate 18. As 3-6 house an ester moiety at
the 5-position, it would be possible to access DPC-602 and AS-
136A (Figure 1). Other targets, however, required a synthetic
handle at the 4-position. Conceivably, additional modification to
3-6 would achieve this, but forcing the electronically disfavored
isomer with a malleable functional group at the 4-position would
be more efficient.
Using TMS-protected alkynes drives formation of the
electronically disfavored isomers 14-17 due to steric interactions
between the TMS and CF2R (R=F or H) moieties.[11a,15] Prior to
this work, three days reactivity and five equivalents of 1 yielded
14 in only 41%.[11a] Here, reducing the concentration of AcOH to
15% to avoid TMS deprotection before cycloaddition while
increasing both the concentration of difluoroethylamine and
tBuONO yielded 14-17 in good yield (59-72%) for a 15 min
residence time. Controlling the regiochemical outcome of the
[3+2] cycloaddition generates the pyrazole core for Bixafen,
Alkenes were also explored for the synthesis of
pyrazolines. From a versatility and cost standpoint, alkenes
Fluxapyroxad, Sedaxane and Isopyrazam (Figure 1). Importantly, typically have greater commercial availability, and are often
novel pyrazoles 16 and 17 have the correct oxidation state for
directly achieving the target compounds.
Next, cycloaddition of 2 with terminal aryl alkynes was
explored. Previous reports require stoichiometric Ag2O and
NaOAc for 5 h, or two weeks in a sealed tube devoid of light.[16]
more affordable. Furthermore, oxidation of certain pyrazolines
can afford pyrazoles in a single step.[13,17] Pyrazolines 25-30
were obtained in good to excellent yields (59-82%) over a 15
min residence time, improving upon previous conditions
requiring 14 h.[13]
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10.1002/anie.201704529
Angewandte Chemie International Edition
COMMUNICATION
F
state. For 31 however, a strong hydrogen bond is present that
could drive the higher yields (46-92%) experimentally observed.
With an assembly line synthesis in mind, modules 1 and 2
were scaled up (2.25 mL and 7.75 mL coils respectively) and
combined with Syrris® pumping modules (total flow rate of 750
µL min-1) to produce 4 at 2.16 g h-1 (87% yield). Next, additional
modules to facilitate a range of transformations were explored.
We envisaged that N-arylation of 21-24 would yield Celecoxib,
Mavacoxib, SC-560 and the human lung cancer suppression
candidate. Both DPC-602 and AS-136A could be accessed
through N-methylation or arylation of 4 or 6, and subsequent
amidation. Finally, Bixafen, Fluxapyroxad, Sedaxane and
Isopyrazam could be achieved through TMS cleavage of 17,
followed by N-methylation, and then amidation (Figure 3C). As a
proof of concept, individual modules were used to create highly
substituted pyrazoles on route to pharmaceuticals and
agrochemicals (Figure 3).
Module 3 mediates Chan-Lam-Evans C-N arylation (Figure
3C). Although notable examples of azole Chan-Lam-Evans
couplings exist, these were performed with less demanding
substrates.[18] Initially, 22% of the desired product was achieved
with Ph-B(OH)2 after 16 h at 40 °C in a round bottom flask.
Removing Et3N and translating to continuous flow with a reactor
temperature of 90 °C provided a satisfactory 66% yield. Once
again, the use of DCM at 90 °C is well suited for continuous
flow; this temperature would be difficult to achieve in a round
bottom flask. Module 4 mediates N-methylation (Figure 3A and
B). Here, the sensitivity of the CF2H group became apparent.
F
F
I
H
F
H
CH3
NH2
N
N
N
4
79%
5
93%
F
O
Me
73% overall yield
F
26 min reaction time
F
A
F
O
NH
F
I
F
F
R
R
R
TBAF
CH3
NH2
N
F
F
H
N
B
1
2
6
96%
4
5
N
Me
R
N
NH2
67-99%
42%
86%
25% overall yield
56 min reaction time
H
F
F
F
H
F
C
H
N
N
N
F
NH2
B(OH)2
O
5
86%
3
66%
56% overall yield
46 min reaction time
Legend
Diazo Formation – 5 min
Cycloaddition – 10 min
C-N Methylation- 10 min
Amidation - 1 min
1
2
3
4
5
6
TMS Removal – 30 min
C-N Arylation – 60 min
Telescoped sequence
Intermediate isolation before next module
Figure
3
Individual continuous flow modules for the generation of
agrochemical and pharmaceutical like targets. Module 3; pyrazole (0.12 M
in DCM, 2.0 equiv), Cu(OAc)2 (1.5 equiv in DCM), pyridine (2.0 equiv in DCM)
and phenylboronic acid (1.0 equiv in DCM) at 90°C. Module 4; pyrazole (0.26
M in DMF, 1.0 equiv), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 4.0 equiv in
DMF), iodomethane (MeI, 4.0 equiv in DMF) at 120 °C. Module 5; Pyrazole
(0.30 M in DMF, 1.0 equiv), 4-fluoroaniline (1.3 equiv in DMF) and lithium
bis(trimethylsilyl)amide (3.3 equiv in THF) at 40 °C. Module 6; Pyrazole (0.25
M in THF, 1.0 equiv), TBAF (1.75 equiv in THF) and AcOH (1.75 equiv in THF)
at 70 °C. For additional details on reactor set-up, see the supporting
information
While
4
can be readily methylated with MeI and
tetramethylpiperidine (1 min, microwave, 120 °C, DMF, 99%
yield), immediate decomposition of the CF2H analogues was
observed. Further optimization revealed that DBU and MeI at
120 °C for 10 mins in continuous flow provides suitable
conditions to methylate both the di, and tri-fluorinated pyrazoles
in good yield. Module 5 performs direct amidation of pyrazole
esters; combining solutions of 1M LiHMDS with the pyrazole and
amide at 40 °C for 1 min gave the corresponding amides in
excellent yields (86-96%, Figure 3A-C). Finally, module 6
performs TMS removal (Figure 3B). Although KOH at elevated
temperatures proved effective for 17 (2 equi. KOH in EtOH,
150 °C, 30 min, microwave), immediate decomposition was
observed for 16. Pleasingly, TBAF (buffered with AcOH) at
70 °C with a 30 min residence time afforded the desired product
in 96% yield.
A
novel n-nitrosopyrazoline byproduct was also observed
through a second condensation with tBuONO. Interestingly,
pyrazolines 25-30, or their n-nitroso counterparts 31-33 could be
selectively synthesized by simply changing the concentration of
tBuONO and AcOH entering the system. For example,
pyrazoline 28 was achieved in 75% yield and 97% selectivity
through standard conditions (CF2HCH2NH2 (2 equiv), tBuONO (2
equiv), AcOH (0.4 equiv)). Then, increasing the concentration of
tBuONO (4 equiv) and AcOH (0.5 equiv) generated the n-nitroso
analogue 31 in 98% yield and 94% selectivity.
Through a combination of modules 1-6, it is theoretically
possible to synthesize
a
large number of APIs and
agrochemicals. To demonstrate this opportunity, measles
therapeutic AS-136A was synthesized. Using modules 1 and 2
in a telescoped fashion, and then modules 4 and 5 individually
yielded AS-136A (75% yield, 99% purity) for a 26 min total
reaction time. Next, all of the required modules (1, 2, 4 and 5)
were telescoped into a single multi-step continuous flow system
to produce AS-136A (34% isolated yield, 72% purity) at a rate of
1.73 g h-1 (Figure 4). Additionally, module 4 not only drives rapid
methylation (120 °C, 10-16 min), but controlled gas formation
was observed; presumably excess diazoalkane is destroyed
releasing N2. Furthermore, this telescoped synthesis uses
LiHMDS directly from the supplier’s bottle removing the need to
handle this toxic and flammable substance.
Scheme 1. Crystal structures for the tri- and di-fluoro n-nitroso
pyrazolines. Highlighted are bond distances from the oxygen of the n-nitroso
group to the CF3 or CF2H moiety.
Subjecting 2 to optimized conditions for n-nitrosopyrazoline
formation yielded <20% in all cases. Single crystal X-ray
analysis of 31* revealed that the van der Waals radii of the
fluorine atom (147 pm) overlapped with the oxygen atom (152
pm) of the n-nitroso group, suggesting interaction in the solid
The lower yield observed in the telescoped transformation
is due to at least two factors. First, telescoping large sequences
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10.1002/anie.201704529
Angewandte Chemie International Edition
COMMUNICATION
Figure 4 Continuous flow synthesis of AS-136A. A continuous flow telescoped synthesis with modules 1,2,4 and 5 to yield measles therapeutic AS-136A in a
34% isolated yield at a rate of 1.73 g h-1. Using modules individually yields AS-136A in a 75% yield. See the supporting information for additional details.
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reagent in each step could aid the telescoped process. However,
when experimentally tested, modules 1, 2 and 3 resulted in
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t
ethyl propiolate: 2,2-difluoroethylamine: BuONO resulted in only
37% yield compared to 70% when using a 1:2:2.4 ratio.
Furthermore, using only two equivalents of MeI in module 3
resulted in 39% yield, compared 100% when using eight (Table
S2). Second, using Syrris® pumps decreased the efficiency of
module 1 and 2 (75-87% compared to 99%) as uneven fluid
delivery is observed at high back pressures (~22-24 bar).
In conclusion, a continuous flow platform for the synthesis
of valuable, highly functionalized pyrazoles and pyrazolines has
been developed. Generating common pyrazole cores for
subsequent modification in a range of modules allows a wide
breadth of chemical space to be readily and efficiently accessed.
Importantly, modules mediate rapid continuous flow chemistry
(1–60 min) by operating solvents above their atmospheric boiling
points for improved kinetics. This effect removed the need for
stoichiometric Ag2O and base for terminal aryl alkynes
dipolarphiles to participate in [3+2] cycloaddition with 2. To
demonstrate the capabilities of this system, AS-136A was
synthesized in 75% yield (99% purity) using three sets of
individual modules, or through a telescoped continuous flow
multi-step process yielding 1.73 g h-1 (34% yield, 72% purity) of
isolated product. This approach builds upon previous syntheses
of this molecule requiring several additional steps and multiple
intermediate isolations.[12b,19]
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Acknowledgements
We thank the Bill and Melinda Gates Foundation (“Medicines for
All” initiative) for financial support.
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Keywords: Multi-Step Continuous Flow Synthesis • Pyrazoles •
Assembly Line Synthesis • Active Pharmaceutical Ingredients •
Agrochemicals
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COMMUNICATION
COMMUNICATION
Reaction Modularity
Meets Flow: Assembly
lines have been used to
synthesize highly
Dr. Joshua Britton and
Prof. Dr. Timothy F.
Jamison*
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Page No. – Page No.
Measles therapeutic AS-136A
functionalized pyrazoles
and pyrazolines on route
to agrochemicals and
pharmaceuticals through
multi-step, continuous
flow synthesis.
Safe Generation
and Rapid
Consumption
5 min
Cycloaddition Methylation
10 min
10 min
Amidation
1 min
Multi-Step Continuous Flow
Assembly lines
A Unified Continuous
Flow Assembly Line
Synthesis of Highly
Substituted Pyrazoles
and Pyrazolines
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