A continuous-flow approach to 3,3,3-trifluoromethylpropenes: Bringing together grignard addition, peterson elimination, inline extraction, and solvent switching

Article abstract of DOI:10.1021/op500190j

A continuous-flow approach to the synthesis of 3,3,3-trifluoromethylpropenes involving Grignard addition of (trimethylsilyl)methylmagnesium chloride to a trifluoromethyl ketone followed by dehydrative desilylation of the α-tri fluoromethyl-β-hydroxysilyl alcohol using trimethylsilyl tri fluoromethanesulfonate is reported. An inline aqueous/organic extraction and a concomitant solvent switch were key to the success of the methodology. Transition from batch to continuous flow conditions allows for higher yields, shorter reaction times, and facile scale out.

Full text of DOI:10.1021/op500190j

Article
pubs.acs.org/OPRD
A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes:
Bringing Together Grignard Addition, Peterson Elimination, Inline
Extraction, and Solvent Switching
Trevor A. Hamlin,† Gillian M. L. Lazarus,† Christopher B. Kelly,† and Nicholas E. Leadbeater*,†,‡
†Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269-3060, United States
‡Department of Community Medicine & Health Care, University of Connecticut Health Center, The Exchange, 263 Farmington
Avenue, Farmington, Connecticut 06030, United States
S
* Supporting Information
ABSTRACT: A continuous-flow approach to the synthesis of 3,3,3-trifluoromethylpropenes involving Grignard addition of
(trimethylsilyl)methylmagnesium chloride to a trifluoromethyl ketone followed by dehydrative desilylation of the α-
trifluoromethyl-β-hydroxysilyl alcohol using trimethylsilyl trifluoromethanesulfonate is reported. An inline aqueous/organic
extraction and a concomitant solvent switch were key to the success of the methodology. Transition from batch to continuous
flow conditions allows for higher yields, shorter reaction times, and facile scale out.
yields. However, the methodology does have drawbacks. The
two-step process required isolation of the intermediate alcohol,
thus limiting the amount of material produced per unit time
and increasing waste. In an attempt to overcome these
limitations, we wanted to transition our batch process to a
continuous-flow approach. We report the results of our efforts
here.
INTRODUCTION
■
The incorporation of fluorine into organic molecules has a
profound effect on their physical and chemical properties.1
Many drugs or drug candidates now feature fluorine for this
reason. As a result, there is increasing interest in synthetic
methods for selectively incorporating fluorine atoms into
organic molecules.2 This includes not only introduction of
single fluorine atoms but also difluoromethyl and trifluor-
omethyl groups. Our group has developed a number of routes
for the preparation of trifluoromethyl ketones (TFMKs).3,4 Not
only have TFMKs been used as chemical probes to obtain
mechanistic information on biochemical pathways, but they
themselves have been found to be potent enzyme inhibitors.5
However, these fluorinated motifs can also serve as critical
intermediates in constructing trifluoromethylated heterocycles,
medicinal compounds, and fluorinated analogues of natural
products.6
To this end, we have recently used TFMKs as starting
materials for the preparation of 3,3,3-trifluoromethylpropenes.
This class of compounds is attractive to medicinal chemistry as
an isostere to certain amino acid groups,7 and to agro-
chemistry8 as key intermediates in the synthesis of potent
insecticides (or, in some cases, insecticides themselves). Our
synthetic approach involved Grignard addition of
(trimethylsilyl)methylmagnesium chloride to the TFMK
followed by dehydrative desilylation of the α-trifluoromethyl-
β-hydroxysilylalcohol using TMSOTf (Scheme 1).9 The
reaction was compatible with a range of functionalities, and
the alkene products could be obtained in good to excellent
RESULTS AND DISCUSSION
■
The use of continuous-flow processing is of increasing interest
both in academia and industry.10 Given the ubiquitous nature
of main group organometallic reagents in organic chemistry, it
comes as no surprise that there is literature precedent for their
use in flow.11 Additionally, olefination methods for preparing
nonfluorine-containing alkenes have also been adapted for
continuous flow processing.12 However, we faced a particular
challenge in our objective. The first step of our reaction is
performed in a Lewis basic solvent (diethyl ether or THF), but
these solvents have a severely detrimental effect on the
dehydrative desilylation step, which is catalytic in TMSOTf.
Therefore, we needed to perform an in-flow solvent switch, at
the same time removing as much of the THF solvent as we
could, prior to introducing TMSOTf. Before addressing this
challenge, we decided to focus attention on reducing the
reaction time of the Grignard addition step. In batch, we
performed the reaction at room temperature overnight. This is
clearly too long a time for transition to flow processing.
However, during our initial batch study we did not optimize the
reaction. We therefore investigated the effects of temperature
on the reaction. Using 4-methoxy-2,2,2-trifluoroacetophenone
(1a) as a test substrate, we performed the reaction in THF,
Scheme 1. Preparation of 3,3,3-trifluoromethylpropenes in
batch
Special Issue: Organometallic Carbanions in Practical Organic
Synthesis
Received: June 12, 2014
Published: August 6, 2014
© 2014 American Chemical Society
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employing an excess of an approximately 1.8 M solution of the
Grignard reagent. At room temperature, we obtained an 80%
conversion to the product (2a) after 30 min (Table 1, entry 1).
Performing the reaction at 40 °C increased the conversion to
95%, and complete conversion was observed when operating at
50 °C (entries 2 and 3).
a
Table 1. Optimization of the Grignard reaction
Figure 2. A schematic of the membrane-based separator employed in
this study. The pressure differential controller (shown in the schematic
with a deformed diaphragm (heavy curved line) provides a fixed
pressure difference across the membrane (short vertical lines). The
aqueous and organic phases are shown in blue and white, respectively.
[Reproduced with permission from ref 14, American Chemical
Society].
b
entry
temperature (°C)
conversion (%)
1
2
3
25
40
50
80
95
100
a
Reaction conditions unless otherwise noted: 2 mmol scale, 1a (1
equiv, 1 M in anhyd. THF), Me3SiCH2MgCl (excess, ∼1.8 M in
b
1
To achieve this, the separator integrates a porous membrane
(typically PTFE) with a high-precision pressure differential
controller to ensure that optimal operating conditions are
always maintained.
anhyd. THF), 30 min. Determined by H NMR spectroscopy.
Our attention then turned to addressing the need for a
solvent switch. We proposed to undertake this at the same time
as removing magnesium byproducts formed in the Grignard
step. We believed that by performing an inline aqueous/organic
extraction we would be able to remove the water-soluble
magnesium salts as well as partitioning the THF into the
aqueous phase with judicious choice of the new organic solvent.
There have been many reports of inline extraction in flow.13
One that particularly attracted our attention involved a newly
available membrane-based liquid−liquid separator (Figure
1).14−16 The unit has excellent chemical compatibility, allows
Before using the separator, we returned to batch chemistry to
find a suitable reaction medium for the TMSOTf-catalyzed
dehydrative desilylation step. In our original batch approach we
used dichloromethane as the solvent. However, removal of
THF from this solvent would be difficult, given its polar nature.
We tried performing the desilylation in hexane, which would be
a much more suitable solvent for removing THF by water
washing, but the limited solubility of 2a posed a problem.
Moving to a 9:1 hexane/dichloromethane mixture, we were
able to perform the desilylation of 2a in 10 min at room
temperature with complete conversion to 3a using TMSOTf
(Scheme 2).
Scheme 2. Dehydrative desilylation of 2a to yield alkene 3a
Our strategy was to perform the Grignard reaction in THF in
one flow coil, introduce a stream of dilute hydrochloric acid (to
quench the Grignard reaction) followed by 9:1 hexane/
dichloromethane, and then send this mixture into the
aqueous/organic separator. Before attaching the separator, we
wanted to test the Grignard reaction in flow, followed by the
solvent additions. We brought together THF solutions of 1a
(0.15 mL min−1) and of Grignard reagent (0.22 mL min−1),
passing the mixture through a 10 mL PFA coil heated to 50 °C.
We then introduced a stream of 10% HCl in water at a flow rate
of 3 mL min−1 and 9:1 hexane/dichloromethane at a flow rate
of 0.75 mL min−1. While the reaction was successful, we noted
that the hydrochloric acid quench led to the formation of a
precipitate which, over time, clogged the tubing. To overcome
this, we changed from hydrochloric acid to tetrafluoroboric acid
as tetrafluoroborate salts typically have higher solubility than
the corresponding halides. Using a 10% HBF4 aqueous solution
we were able to both quench the Grignard reaction and ensure
that the resulting magnesium byproducts remained in solution.
Figure 1. Membrane-based liquid−liquid separator employed in this
study.
for operation under pressure (up to 300 psi), and can operate
at flow rates up to 15 mL min−1. In addition, it has a low
separation pressure differential and therefore is suitable for the
majority of aqueous/organic solvent pairs. Finally, it does not
require any adjustments from the operator and so can be
deployed as a “plug and play” unit. It exploits surface forces to
achieve separation as shown schematically in Figure 2. When
the two phases come in contact with the membrane, the
wetting phase is prone to wet the membrane and travel through
the membrane pores while the nonwetting phase is repelled.
The membrane provides successful separation if the pressure
differential across it is tightly controlled in order to let the
wetting phase pass and not push the nonwetting phase through.
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a
Table 2. Effect of flow rate and membrane pore size on solvent composition.
entry
pore size (μm)
x (mL min−1
)
y (mL min−1
)
hexane/THF/CH2Cl2
1
2
3
4
5
6
0.5
0.5
0.5
1.0
1.0
1.0
1
2
3
1
2
3
1
2
3
1
2
3
9:5:1
9:5:1
9:3:1
9:6:1
9:6:1
9:3:1
a
1
Determined by H NMR spectroscopy.
With these conditions in hand, we placed the separator inline.
The separation was effective with alcohol 2a remaining entirely
in the organic phase. However, there was also a significant
amount of THF left in the organic phase. We hypothesized that
the increased ionic strength of our aqueous stream decreased
solubility of THF. To circumvent this issue, we decided to
introduce a flow of deionized water into the organic stream
leaving the first separator and then passed the resultant mixture
through a second separator to remove more of the THF. We
had to determine optimal flow rates for both aqueous streams
in order to remove as much THF as possible. To achieve this,
we started with a flow of THF (0.37 mL min−1), introduced
10% aq HBF4 followed by 9:1 hexane/dichloromethane (0.75
mL min−1), passed this through the first separator, intercepted
the organic output with a flow of water, and then passed this
through the second separator. Assaying the composition of the
stream with a relative molar composition of 9:3:1 of hexane,
THF, and dichloromethane, respectively.
Knowing the composition of the solvent mixture exiting the
second separator, we wanted to probe the sensitivity of the
desilylation reaction to this quantity of THF in solution. We
decided to build margin into our experiments so instead of
using a 9:3:1 molar ratio of hexane/THF/dichloromethane, we
opted to use a 9:3:1 volume ratio. This corresponds to a
scenario where significantly more THF was in solution as
§
compared to our ideal case. To this end, we performed a series
of small-scale batch tests in which we dosed different amounts
of TMSOTf into a 9:3:1 (by volume) hexane/THF/dichloro-
methane solution of 2a. Operating at our previously published
loading of 10 mol % TMSOTf we obtained a 42% conversion
after a reaction time of 10 min (Table 3, entry 1). By increasing
the catalyst loading to 30 mol %, we were able to obtain
complete conversion (Table 2, entry 4). Using a catalyst
loading of 15 mol % and extending the reaction time to 30 min
did not offer an alternative strategy (Table 3, entry 5). We
therefore opted to move forward with a TMSOTf loading of 30
mol % and a reaction time of 10 min for the desilylation in flow.
With optimized conditions in hand for both steps of the
reaction as well as for the separation/solvent swap, we
concatenated our reactors, input streams, and separators to
1
organic solvent mixture exiting this second separator by H
NMR spectroscopy as a function of flow rates of the two
aqueous streams, we found that the optimal results were
obtained when both operated at 3 mL min−1 (Table 2, entry 3).
We also probed the effect of separator membrane pore size.
There was no observable difference between a 0.5 μm (entries
1−3) and 1.0 μm (entries 4−6) pore size membrane. Under
optimal working conditions, we were able to obtain an outlet
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a
Table 3. Optimization of Lewis Acid loading and residence
time.
Table 4. Methylenation of TFMKs in flow
a
b
entry
TMSOTf (mol %)
reaction time (min)
conversion (%)
1
2
3
4
5
0.1
10
10
10
10
30
42
53
0.15
0.2
70
0.3
100
61
0.15
a
Reaction conditions unless otherwise noted: silylated intermediate,
2a (0.3 mmol scale, 1 equiv, 0.2 M in 2a), TMSOTf (loading in table),
b
solvent (1.5 mL, 9:3:1 hexane/THF/CH2Cl2 by volume). Deter-
1
mined by H NMR spectroscopy.
perform the synthesis of 3a (Figure 3). Working on the 2 mmol
scale, we obtained an 84% isolated yield of 3a.
We next tested the substrate scope of the reaction, screening
four additional TFMK starting materials. In each case, we
obtained excellent isolated yields of the desired alkene products
(Table 4, entries 1−5). The protocol works not only for
TFMKs but also for a representative difluoromethyl analogue
(entry 6). We also scaled up one example, processing 10 mmol
of 1a and obtaining a 90% isolated yield of 3a (entry 1). A
comparison of yields obtained by the original batch and current
flow methods is also shown in Table 4. Of note is that our flow
approach is not only faster but also higher yielding than the
corresponding batch methodology. This is because, in flow,
there is no need for a workup step to isolate the alcohol
intermediate. In addition, using the in-flow separator, we were
able to obtain an improved separation during the extraction
steps.
a
Reaction conditions unless otherwise noted: TFMK (2 mmol scale, 1
equiv, 1 M in anhyd THF), Me3SiCH2MgCl (excess, ∼1.8 M in anhyd.
THF), TMSOTf (0.3 equiv, 0.33 M in hexane). Isolated yield. From
ref 9. Value in parentheses indicates isolated yield of alkene on 10
mmol scale.
b
c
d
flow conditions allowed for higher yields, shorter reaction
times, and facile scale out, allowing us to process ∼14 g of
TFMK per day. The process incorporates a solvent swap using
a proprietary liquid−liquid extractor. This facilitates the two-
step reaction sequence without isolation of the intermediate α-
trifluoromethyl-β-hydroxysilyl alcohol. A range of substrates
have been screened and, in each case, the reaction proceeded
smoothly.
CONCLUSIONS
■
We have developed a continuous flow process for the synthesis
of perfluoroalkyl alkenes. Transition from batch to continuous
Figure 3. Flow configuration used for the methylenation of TFMKs.
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EXPERIMENTAL SECTION
REPRESENTATIVE PROCEDURE FOR ALKENE
SYNTHESIS
1-Methoxy-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene
■
■
General Information. All reactions requiring inert (N2)
conditions were performed using Schlenk line techniques with a
four-port dual-bank manifold. NMR spectra (1H, 13C, 19F) were
(3a). To a 15 mL conical flask was added 2,2,2-trifluoro-1-(4-
methoxyphenyl)ethanone (0.500 g, 2.4 mmol, 1 equiv) and
anhyd. THF (2.4 mL, 1 M in the TFMK). This solution was
kept under an N2 atmosphere via an inlet needle. Another 15
mL conical flask was charged with a previously prepared ∼1.8
M solution of (trimethylsilyl)methyl)magnesium chloride in
anhyd THF (∼5 mL) and kept under an N2 atmosphere via an
inlet needle. To prepare a stock solution of trimethylsilyl
trifluoromethanesulfonate, TMSOTf (0.733 g, mmol) and
hexane (30 mL, 0.1 M in the TMSOTf) were charged to a
conical flask. The system was readied as outlined above. Then
the TFMK was loaded into the reactor coil at a flow rate (P1,
blue) of 0.15 mL min−1, and the Grignard solution was set to
flow (P2, blue) at a rate of 0.22 mL min−1. At this same time
the aq HBF4 stream (P3) was set to a flow rate of 3 mL min−1,
the 9:1 hexane/dichloromethane stream (P4) to 0.75 mL
min−1, the water stream (P5) to 3 mL min−1, and the TMSOTf
stream (P6, red) to 0.31 mL min−1. Once the TFMK was
completely loaded (∼30 min), the system was set to pump
anhyd THF through both P1 and P2. When the product
mixture was judged to have completely exited the system, all
pumps were stopped. The resulting reaction mixture was
transferred from the collection flask to a separatory funnel. The
layers were separated, and the aqueous layer was extracted with
hexane (3 × 75 mL). The combined organic layers were
washed with brine (∼150 mL) and dried with Na2SO4. The
solvent was removed in vacuo by rotary evaporation. The crude
product was gently added atop a silica gel plug and eluted with
hexane (2−3 column volumes). The solvent was removed in
vacuo by rotary evaporation affording the pure alkene 3a
1
performed at 298 K on a Bruker DRX-400 MHz NMR. H
̈
NMR spectra obtained in CDCl3 were referenced to residual
nondeuterated chloroform (7.26 ppm) in the deuterated
solvent. 13C NMR spectra obtained in CDCl3 were referenced
to chloroform (77.3 ppm). 19F NMR spectra were referenced
to hexafluorobenzene (−164.9 ppm).17 Reactions were
1
monitored by H NMR and/or by TLC on silica gel plates
(60 Å porosity, 250 μm thickness). TLC analysis was
performed using Hex/EtOAc as the eluent and visualized
using permanganate stain, p-anisaldehyde stain, Seebach’s Stain,
and/or UV light. Silica plugs utilized Dynamic Adsorbants Inc.
flash silica gel (60 Å porosity, 32−63 μm).
Chemicals. Deuterated NMR solvents (CDCl3) were
purchased from Cambridge Isotope Laboratories. CDCl3 stored
over 4 Å molecular sieves and K2CO3. Sodium sulfate, sodium
carbonate, THF (reagent grade), hexane (reagent grade) were
purchased from Sigma-Aldrich. Chloromethyltrimethylsilane,
trifluoromethyl trifluoromethanesulfonate, and hexafluoroben-
zene were purchased from Synquest Laboratories and/or
Oakwood Chemicals. Trifluoromethyl ketone (TFMK) sub-
strates 1a−b, 1d were prepared as in our previously published
protocol.4b TFMK substrates 1c, 1e−f were prepared as in our
previously published protocol.9 Procedures for the preparation
of all other TFMKs are included in the Supporting Information.
The oxoammonium salt 4-acetamido-2,2,6,6-tetramethyl-1-
oxopiperidin-1-ium tetrafluoroborate was prepared according
to our recently published protocol.18
Flow Configuration. Reactions were performed using a
Vapourtec E series, (pumps P1 (blue), P2 (blue), P6 (red)),
Uniqsis FlowSyn (pumps P3, P5), and an Agilent 1100 series
HPLC pump G1312A paired with a degasser G1379A (P4).
Standard PTFE tubing (i.d. 1.0 mm, o.d. 1.8 mm) was utilized.
The two reactor coils used were made of PFA, had an internal
volume of 10 mL, and are available from Vapourtec Ltd. PEEK
Tee-mixers (Tee-connector, 0.02-in. through-hole) were
purchased from Upchurch Scientific (part # P-712) and
modified to have 0.04-in. through-hole. The liquid−liquid
separators, equipped with 1 μm porosity membranes, are
available from Zaiput Flow Technologies. The configuration
shown in Scheme 2 was assembled using the aforementioned
equipment. The anhyd THF was freshly distilled over sodium
metal and benzophenone prior to use. Prior to running an
experiment, the system was primed and flushed with the
respective solvents (THF through P1 and P2, aq deionized
water through P3 and P5, 9:1 hexane/dichloromethane through
P4, and hexane through P6. Prior to commencing the run, the
Grignard reagent solution was set to flow at a rate of 0.5 mL
min−1 so as to purge any residual water in the system. After an
initial slug of 1 mL, the system was returned to solvent for all
pumps. With the reaction coils and separators completely filled
with their respective solutions, the first and second coils were
heated to 50 and 25 °C, respectively. No back pressure
regulators were needed because the solvents were not heated
above their respective boiling points. The product exit stream
was collected in a flask containing excess sat. sodium
bicarbonate to quench the elimination reaction.
1
(0.4160 g, 84%) as a clear, pale-yellow oil. H NMR (CDCl3,
400 MHz) δ ppm 3.83 (s, 3 H) 5.70 (q, J = 1.71 Hz, 1 H) 5.87
(q, J = 1.22 Hz, 1 H) 6.88−6.93 (m, 2 H) 7.40 (d, J = 8.31 Hz,
2 H). 13C NMR (CDCl3, 125 MHz) δ ppm 55.51 (CH3)
114.24 (CH) 119.08 (q, JC−C−C−F = 5.62 Hz, CH2) 123.79 (q,
JC−F = 273.60 Hz, CF3) 126.3 (CH) 128.91 (C) 138.66 (q,
JC−C−F = 30.10 Hz, C) 160.47 (C). 19F NMR (CDCl3, 377
MHz) δ ppm −67.85. GC−MS (EI) 202 ([M]+, 100%) 187
(5%) 183 (4%) 159 (7%) 151 (5%) 133 (90%) 118 (11%) 109
(27%) 103 (9%) 89 (14%) 77 (7%) 63 (13%).
ASSOCIATED CONTENT
* Supporting Information
Key to abbreviated terms; experimental details for flow
■
S
1
reactions; general Grignard and elimination procedure; H,
13C, and 19F NMR spectra of synthesized compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nicholas.leadbeater@uconn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Vapourtec Ltd, Uniqsis Ltd, and Zaiput Flow Technologies are
thanked for equipment support. We thank the University of
Connecticut and the National Science Foundation (CAREER
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̈
ADDITIONAL NOTE
■
§
A 9:3:1 molar ratio of hexane/THF/dichloromethane
corresponds to a 79:16:5 volume ratio.
(13) See, for example: (a) Newby, J. A.; Huck, L.; Blaylock, D. W.;
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̈
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