One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

Article abstract of DOI:10.3762/bjoc.13.189

Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields.

Full text of DOI:10.3762/bjoc.13.189

One-pot multistep mechanochemical synthesis of
fluorinated pyrazolones
Joseph L. Howard, William Nicholson, Yerbol Sagatov and Duncan L. Browne*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1950–1956.
School of Chemistry, Cardiff University, Main Building, Park Place,
Cardiff, CF10 3AT, UK
doi:10.3762/bjoc.13.189
Received: 11 July 2017
Email:
Accepted: 25 August 2017
Published: 14 September 2017
Duncan L. Browne* - dlbrowne@cardiff.ac.uk
* Corresponding author
This article is part of the Thematic Series "Mechanochemistry".
Guest Editor: J. G. Hernández
Keywords:
fluorination; heterocycles; mechanochemistry; multistep; solid-state
synthesis
© 2017 Howard et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based pro-
cesses. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechano-
chemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compati-
bility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and
subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in
moderate to excellent yields.
Introduction
Mechanochemical methods are emerging as an alternative ap- nity, perhaps the most interesting examples of mechanochem-
proach to traditional solvent-based reactions for chemical syn- ical reactions are not those that are merely solventless but those
thesis. Under mechanochemical conditions reactions are per- in which different reactivity or selectivity arises, as well as
formed between neat reagents and do not require a solvent. Pro- those that are significantly shorter in reaction time than those
cessing chemical reactions in such a manner is desirable as conducted in solution. Indeed, there are several examples where
reactions are consequently less wasteful and more environmen- reactions are clearly significantly faster under mechanochem-
tally benign than the analogous solution-based approaches, ical conditions [7,8].
especially if the work-up and purification processes can also be
made solventless or solvent minimised [1,2]. As such, there is One of several challenges to be overcome for the further devel-
now a significant number of mechanochemical synthetic trans- opment of mechanochemistry as an up to date tool for synthesis
formations reported [3-6]. However, for the synthetic commu- is to gain a better insight into the ability to run multistep proce-
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Beilstein J. Org. Chem. 2017, 13, 1950–1956.
dures. One-pot multistep procedures are particularly efficient, in Having recently begun our research programme in the area of
that the same reaction vessel is used for each step, additional mechanochemistry, we were particularly intrigued by the
reagents are simply added to the reaction mixture at each stage compatibility of differing chemical forms and additives across a
with no isolation of intermediates or removal of side products two-step, one-grinding jar solventless process. To investigate
[9]. One-pot procedures require the conditions for each step to this we designed a 2-step reaction related to our recent work on
be compatible with succeeding steps. Typical problems encoun- liquid assisted grinding effects of the fluorination of 1,3-dicar-
tered when attempting to multistep reactions include solvent bonyl compounds, in which the dicarbonyl will initially form a
compatibility, or, issues with side products that can inhibit pyrazolone in the first reaction prior to undergoing difluorina-
future steps, e.g., by providing access to alternative reaction tion in the second step (Scheme 1) [17].
pathways, poisoning catalysts or altering the pH unfavourably
[9]. With regards to mechanochemistry such processing serves Notably this approach will likely require a grinding auxiliary in
to amplify the sustainability metrics by running back-to-back the first step where two liquid phases react and will be cata-
solventless reactions. Multistep mechanochemical procedures lysed by an acid to afford a solid pyrazolone material. This will
have been successfully applied to the synthesis of O-glycosides then be followed by a difluorination reaction between
[10], bioactive hydantoins [11], extended iptycenes [12] and solid–solid reactants, this reaction may perform better in the
organometallics [13] where problems can occur using solution- presence of base in the second step. In this report, we present a
based synthesis due to limited solubility. Whilst mechanochem- systematic approach to finding the optimal conditions, which
ical one-pot procedures offer the inherent ability to overcome are most compatible with both steps. Notably, fluorinated pyra-
the issue of identifying a solvent compatible with several zolones have the potential to be useful pharmaceutical or agro-
consecutive steps, we envisaged alternative hurdles not previ- chemical products, given the desirable properties that can be ob-
ously described with regard to compatibility of chemical form. tained on introduction of fluorine to a molecule [18-25]. How-
The state of reagents or chemical form is significant to reac- ever, there have been limited reports on the synthesis of fluori-
tions conducted under mechanochemical conditions, where nated pyrazoles, but fluorinated pyrazolones remain poorly
liquids and solids behave differently. For instance, when liquid studied [26-30].
components are used it may be critical to add a solid auxiliary
that helps the transfer of energy and mass (adequate mixing) Results and Discussion
throughout the mixture. In many cases, leaving out such an Initially the mechanochemical pyrazolone formation was inves-
auxiliary material can result in a gum or a paste that does not tigated as the first step of the two step process, we opted to keep
mix well and results in low reaction conversions. Clearly the the ball size, ball number, jar size and jar and ball material as in
presence of such a material may have a knock-on effect on any our previous studies to reduce the number of variables for this
multistep process. Liquid-assisted grinding (LAG) is another analysis [17]. In the first instance, simply milling the two
phenomenon that can provide enhancement to the reaction liquids in the absence of an auxiliary material resulted in a poor
outcome and again should be considered for use in a multistep yield (Table 1, entry 1). Pleasingly, treatment of ethyl benzoyl-
format [14-16].
acetate with one equivalent of phenylhydrazine in the presence
Scheme 1: Factors to be considered regarding the physical form in the one-pot two-step mechanochemical procedure.
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Beilstein J. Org. Chem. 2017, 13, 1950–1956.
of sodium chloride afforded the desired pyrazolone product in the larger amount of liquid altering the texture of the reaction
66% yield after milling for 10 minutes (Table 1, entry 2). The mixture and thus reducing effective mixing. An alternative
addition of a grinding auxiliary could play several roles. We justification is that at higher acid equivalents in the solid state
propose that the key benefits are related to improved mixing, the ‘on–off’ protonation of the hydrazine is slow, meaning that
and aiding in energy transfer, specifically in mechanochemical the nucleophilicity is greatly retarded compared to lower acid
reactions where the reaction mixture could be described as a loadings. Nonetheless, considering that the subsequent fluori-
gum, paste or liquid. Notably, the comparable reaction under nation step should proceed optimally under basic conditions
solvent-based conditions (in toluene, under reflux) required [17], the lowest amount of acid which also provided a good
24 hours to achieve a similar yield (Table 1, entry 3).
yield was thus chosen; 30 μL (Table 1, entry 9). Finally, the
reaction time with this quantity of acid was then optimised,
whereupon the reaction was found to be complete after
40 minutes producing 92% isolated yield of pyrazolone 1
(Table 1, entry 14). For comparison, these optimal conditions
have been applied to a solution-based reaction, resulting in a
poorer yield after 24 hours at reflux in toluene (Table 1, entry
17). Having achieved optimal conditions for the first step of the
reaction, our attention turned to the second step.
Table 1: Optimisation of pyrazolone formation.
Initial investigation of the fluorination of the pyrazolone
focused on finding the optimum reaction time for the isolated
step rather than two-step, i.e., the pyrazolone material was iso-
lated from step one and purified before subjecting to this second
reaction optimisation. With no additives, the fluorination was
complete after 2 hours (Table 2, entry 4), notably an extra hour
returned no further improvement (Table 2, entry 5). The fluori-
nation reaction studied here proceeds via an enolate which is
aromatic and therefore is relatively facile (compared to the
fluorination of other heterocyclic systems). Introduction of a
mild base, such as sodium carbonate to the reaction vessel
Entry Additive (equiv)
Time [min] Yielda
1b
2
–
10
10
1440
10
10
10
10
10
10
10
20%
–
66%
3c
4
–
58%
HCl (0.5)
43%
5
tosic acid (0.5)
oxalic acid (0.5)
citric acid (0.5)
benzoic acid (0.5)
acetic acid (0.5, 30 μL)
acetic acid (0.08, 5 μL)
37%
6
22%
7
38%
8
88%
9
88%
10
11
12
13
14
15
16
17b
75%
Table 2: Optimisation of pyrazolone fluorination.
acetic acid (1.7, 100 μL) 10
acetic acid (4.2, 250 μL) 10
97%
73%
acetic acid (0.5)
acetic acid (0.5)
acetic acid (0.5)
acetic acid (0.5)
acetic acid (0.5)
20
86%
40
97% (92%d)
97%
60
120
1440
97%
80%
aDetermined by 1H NMR using mesitylene as an internal standard.
bMechanochemical reaction with no NaCl. cSolvent based reaction:
heating under reflux in toluene, no NaCl. dIsolated yield.
Entry Additive (equiv)
Time [min] Yielda
1
2
3
4
5
6
7
8
9
–
10
11%
41%
83%
95%
94%
100%
68%
75%
100%
–
30
As pyrazolone formation can be catalysed by acid, a screen of
both solid and liquid acids was next performed (Table 1, entries
4–9). In general, the weaker carboxylate acids performed better
than mineral acids, with the highest yield obtained using acetic
acid (Table 1, entry 9). The quantity of acid used was then
varied. In general, the yield increased with an increase in the
amount of acid used (Table 1, entries 9–12), this was with the
exception of 250 μL or 4.2 equivalents (Table 1, entry 12),
where the yield dropped. The latter observation may be due to
–
60
–
120
180
60
–
Na2CO3 (1.0)
NaCl (6.0)b
120
120
60
acetic acid (0.5)
NaCl (6.0)b, Na2CO3 (1.0)
aDetermined by 19F NMR. bMass equivalents NaCl.
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Beilstein J. Org. Chem. 2017, 13, 1950–1956.
served to enhance the rate of reaction, providing complete Pleasingly a combination of sodium carbonate with the sodium
conversion after 1 hour (Table 2, entry 6).
chloride grinding auxiliary resulted in complete reaction after
one hour (Table 2, entry 9). The only compatibility issue
With an understanding of the second step we then assessed the remaining was the acid present from the first step. However, as
reaction whilst mimicking aspects of the first reaction in order a base improved the reactivity of the fluorination, the final
to look for compatibility of a two-step one-jar process. The conditions make use of enough sodium carbonate both to
most important difference between the two steps is the physical neutralise the remaining acid and accelerate the second step. By
state of the reactants. For the first step (Table 1), both reagents applying these compatible conditions to the one-pot procedure,
are liquids, and a grinding auxiliary was required to aid mixing the desired fluorinated pyrazolone was isolated in 75% yield
and energy transfer. However, for the second step (Table 2), the (Scheme 2). Scheme 2 also shows the physical state descriptors
reagents are solids, and the presence of a grinding agent could and photographs of the practical experiment.
have a diluting effect. Indeed, addition of sodium chloride does
slow down the fluorination, giving a poorer yield (Table 2, With suitable conditions in hand, the scope of this one-pot
entry 7). Another factor to be explored was the effect of acetic mechanochemical process was explored (Scheme 3). Initially,
acid on the second step. Again, this resulted in a decrease in the scope of β-ketoesters was assessed and the procedure was
yield of the fluorination reaction achievable within a two hour found to be compatible with both the electron-withdrawing and
reaction time (Table 2, entry 8).
electron-donating groups. However, a poorer yield was ob-
Scheme 2: Optimised conditions for the one-pot synthesis.
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Beilstein J. Org. Chem. 2017, 13, 1950–1956.
Scheme 3: Substrate scope of the one-pot, 2 step mechanochemical synthesis (isolated yields). a1 equiv Selectfluor used.
tained for the electron-withdrawing trifluoromethyl substituent Selectfluor to prepare pyrazolone 13, also in moderate yield. In
(5). The scope of phenylhydrazines was also briefly investigat- general the optimised approach seems to apply to a small range
ed, with several examples demonstrating good isolated yields, of compounds.
again an electron-withdrawing trifluoromethyl substituent was
an exception to this (7) [31]. For this case, crude 19F NMR after Conclusion
the first step shows a 41% conversion, suggesting that the pyra- In summary, we have developed a one-pot, two-step mechano-
zolone formation is the limiting factor in this example. An alkyl chemical synthesis of fluorinated pyrazolones. The experiments
β-ketoester (ethyl acetoacetate) was also used, affording methyl provide a logical approach to multistep solventless synthesis
substituted difluoropyrazolone 12 in modest yield. Finally, an under milling conditions and more broadly will assist in the
α-substituted β-ketoester was successfully converted to the conversion of other processes to such a system. After careful
pyrazolone before monofluorination using one equivalent of consideration of physical form and additive compatibility the
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