Studies of a diastereoselective electrophilic fluorination reaction employing a cryo-flow reactor

Article abstract of DOI:10.1055/s-0033-1338455

The application of meso-scale flow chemistry in research laboratories continues to increase. Here, we report on the use of a modular cryo-flow device as applied to a diastereoselective fluorination process. The reactor can be incorporated into existing flow chemistry setups to permit continuous processing at low temperatures without recourse to cryogenic consumables. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338455

1298▌
LETTER
lSettteur dies of a Diastereoselective Electrophilic Fluorination Reaction Employing
a Cryo-Flow Reactor
Diastereoselective Fluorination under Flow Conditions
Keiji Nakayama,a Duncan L. Browne,b Ian R. Baxendale,b,1 Steven V. Ley*b
a
Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo, Shinomiya, Hiratsuka, Kanagawa,
254-0014, Japan
b
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received: 26.03.2013; Accepted after revision: 08.04.2013
Only when both reagents were cooled and the enolate me-
Abstract: The application of meso-scale flow chemistry in research
tered into the vessel containing NFSI was high conversion
laboratories continues to increase. Here, we report on the use of a
obtained, within the range of 85–90% (HPLC assay).
modular cryo-flow device as applied to a diastereoselective fluori-
nation process. The reactor can be incorporated into existing flow
chemistry setups to permit continuous processing at low tempera-
tures without recourse to cryogenic consumables.
The reduced conversion obtained upon slow addition of a
room temperature solution of NFSI to the enolate can be
explained by a propensity for the unreacted parent enolate
to protonate by quenching with the more acidic fluorinat-
Key words: diastereoselective fluorination, flow chemistry, cryo-
flow reactor, polymer-supported reagents, chiral auxiliary
ed product. Presumably the high diastereomeric ratio ob-
tained under these conditions therefore results from
asymmetric protonation of the fluorous enolate, although
Enantioenriched molecular scaffolds containing fluorine
are an interesting class of building blocks for the prepara-
tion of new functional compounds.2 Whilst there are many
methods available for the preparation of these types of
materials,3 one approach was particularly noteworthy in
the context of an ongoing research project. Specifically,
Davis and Kasu reported that the asymmetric auxiliary
controlled addition of an enolate to a fluorine electrophile
provides the corresponding α-fluorocarbonyl derivatives
in both good yields and high diastereoselectivities
(Scheme 1).4
some induction from the direct fluorination cannot be
ruled out. The low conversion can be overcome to some
extent by fast addition of the NFSI, whereby any pseudo
first order concentration effects are minimised and thus
the rate of the desired reaction is competitive with that of
the unwanted reaction.
Overall, the scaled batch process used to obtain these ma-
terials is costly and inefficient, requiring liquid nitrogen
based temperature regulation for two large cryogenic re-
actors. Additionally, the length of time required to cool
and later warm the reactors as well as the necessity for the
slow dosing of one reagent into the other is a concern. The
ΔT values observed for the scaled batch processes without
careful control of these addition rates were typically be-
tween 20–50 °C. With these clear drawbacks for the batch
process, we opted to investigate a flow route, starting at
the meso-scale with the eventual vision of moving to a
larger, more commercially viable continuous reactor; our
findings are summarized herein.
O
O
O
O
1) NaHMDS (1.1 equiv), THF, –78 °C
2) NFSI (1.3 equiv), THF, –78 °C
Ph
Ph
N
O
N
O
F
Me
Me
Ph
NFSI = (PhSO2)2NF
Ph
enolate added to NFSI 85% yield, >95:5 dr
NFSI added to enolate 64% yield, >95:5 dr
We began by constructing a simple modular apparatus
consisting of the recently developed cryo-flow reactor5
with a Vapourtec R2 unit.6 Our initial investigations to-
wards a flow method for the diastereoselective fluorina-
tion utilized approaches developed in our previous low-
temperature borylation work.7 Specifically, one stream
containing both the electrophilic species and the latent or-
ganolithium was combined with another stream contain-
ing the base. Our reactor comprised two 5 mL reagent
loading loops, the stream-one loop was charged with a 5
mL segment of a 0.1 M solution of LiHMDS in tetrahy-
drofuran and the stream-two loop was charged with a mix-
ture of NFSI and the carbonyl auxiliary, also at 0.1 M in
tetrahydrofuran. The two streams were each pumped at
0.5 mL/min passing through a 1 mL pre-cooling coil be-
fore combining at a T-piece connector and entering the
Scheme 1 Observations made by Davis and Kasu
On scaling the process in batch several observations were
made:
Firstly, slow addition of a room temperature solution of N-
fluorobenzenesulfonimide (NFSI) to a –78 °C solution of
a lithium enolate resulted in less than 50% conversion.
Under the same conditions, fast addition of NFSI resulted
in much greater conversion (>80%), however, an exo-
therm of up to 50 °C occurred in the reactor.
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DOI: 10.1055/s-0033-1338455; Art ID: ST-2013-D0268-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Fluorination under Flow Conditions
1299
LiHMDS (0.1 M)
THF
0.5 mL/min
cryo-flow reactor
- 1 mL pre-cooling loops
- 52 mL cooled reactor coil
O
O
5 mL
loading
loops
N
Ph
O
F
Bn
X °C
dropped into aqueous
NH4Cl
THF
0.5 mL/min
Temp
Conv.
29%
dr
NFSI (0.1 M)
Xc-carbonyl (0.1 M)
–60 °C
–40 °C
–20 °C
90:10
91:9
25%
< 20%
85:15
Scheme 2 Schematic of the flow apparatus for the in situ quench studies
main cooled reactor coil. The reactor output was collected electrophile at low temperatures gave the best results, we
directly in a flask containing a saturated aqueous solution constructed the corresponding flow setup to reflect this,
of ammonium chloride (Scheme 2). The temperature of including a third stream (Table 1). The depicted apparatus
the cryo-flow reactor was varied and the output analyzed. allowed us to assess a number of additional parameters.
Through the use of this in situ quenching (NFSI present As expected, and inline with the batch and flow observa-
during deprotonation), only low conversion into the de- tions, performing the quench part of the reaction over a
sired fluorinated product was observed at –60, –40 and range of low temperatures did not affect the diastereose-
–20 °C.
lectivity of the process (Table 1, entries 1, 2 and 3). How-
ever, the conversion into the desired fluorinated product
was markedly better when the quench temperature was
lowest (c.f. Table 1, entries 1, 2 and 3). It was found that
the setup depicted could be reliably used for reaction con-
centrations up to 0.2 M in oxazolidinone (entry 4), at 0.4
M the system was prone to occasional and unpredictable
blockages due to the small tube diameters involved
(0.8 mm i.d.).
The setup was modified to provide a sequential addition
of the electrophile; the key results are outlined in Scheme
3. It was found that, at these concentrations and flow rates,
active cooling was actually detrimental to the lithiation
step. However, when the post-reactor NFSI quench-pot
was not cooled, the resulting isolated yield was poor.
Pleasingly, the percentage conversion could be translated
into isolated yield following extraction and flash column
chromatography. Although it was noted that the extraction We employed this same experimental setup to provide a
part of this purification process was found to lead to some further three diastereoenriched fluorinated building
observed variability, attributable to losses of the corre- blocks, all of which were produced in good selectivity
sponding α-fluoro carboxylic acid to the aqueous phase, without modification of the protocol (Figure 1).8 How-
the ease of hydrolysis of α-substituted amides of this type ever, hydrolysis during the aqueous extraction of the
has previously been documented.3 However, such cleav- α-fluoro products remained an issue, as seen by compari-
age is typically accompanied by an erosion of the enantio- son of conversion values with those of the isolated yields.
meric excess in the product and so a reductive or peroxy-
To some extent this issue can be dealt with by simply re-
covering the lost material from the aqueous layer. Howev-
mediated release protocol is often preferred.2f
Having established that a sequence of room temperature er, when employing meso-scale flow systems a better
deprotonation and subsequent addition of the fluorine solution is often to use polymer-supported reagents, to
LiHMDS (0.1 M)
THF
0.5 mL/min
X = –60 °C
conv. 51%, dr 92:8
cryo-flow reactor
- 1 mL pre-cooling loops
- 52 mL reactor coil
X = r.t.
5 mL
loading
loops
conv. 88%, dr 93:7
(70% isolated yield)
O
O
X °C
N
Ph
O
NFSI
–78 °C
THF
0.5 mL/min
F
Bn
Xc-carbonyl (0.1 M)
Scheme 3 Schematic of the flow apparatus for the preliminary assessment of a sequential addition quench protocol
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1298–1302

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K. Nakayama et al.
LETTER
Table 1 Assessment of the Flow Apparatus for the Two-Part Diastereoselective Fluorination Protocol
LiHMDS
r.t.
10 mL
THF
reactor coil
0.5 mL/min
5 mL
loading
loops
cryo-flow reactor
- 1 mL pre-cooling loops
- 52 mL reactor coil
O
O
THF
0.5 mL/min
N
Ph
O
10 mL
loading
loop
F
Xc-carbonyl
Bn
X °C
THF
1.0 mL/min
NFSI
Entry
[LiHMDS] (M)
[Xc-Carbonyl] (M)
[NFSI] (M)
Temp (°C)
Conv. (%)a
dr
1
2
3
4
0.11
0.11
0.11
0.22
0.1 M
0.1 M
0.1 M
0.2 M
0.055 M
0.055 M
0.055 M
0.2 M
–60
–40
–20
–60
84 (60)
66
92:8
91:9
93:7
96:4
31
88 (62)
a Numbers in parentheses represent the isolated yield.
boxylate, the anion of the sulfonimide byproduct derived
from NFSI was also caught. At this point the input feed
was switched to an aqueous acid reservoir to release the
product (see operation B: release; Scheme 4).
O
O
O
O
N
N
O
O
F
F
Bn
Bn
conv. = 88%
yield = 62%
dr = 96:4
conv. = 87%
yield = 55%
dr = 93:7
Pleasingly, with a greatly simplified product mixture, we
were able to perform a series of traditional batch process-
es (C; Scheme 4) in order to provide a crystalline salt of
the product, as a single enantiomer.9 Importantly for the
prospect of scale-up, the method did not require column
chromatography. The off-line workup consisted of an or-
ganic extraction and aqueous wash to remove the amine
byproduct, concentration of the organics, and addition of
cyclohexylamine, which permitted crystallization and
precipitation of the product in salt form. For longer runs,
many of these batch manipulations could be translated
into their flow equivalents to further reduce the manual
intervention required.10
O
O
O
O
N
N
O
O
F
F
Bn
Bn
conv. = 72%
yield = 52%
dr = 91:9
conv. = 75%
yield = 56%
dr = 94:6
Figure 1 Examples run in this process
avoid any losses and, in this case promote the saponifica-
tion in-line through downstream processing. We therefore
investigated this idea by passing the output stream from
the first reaction in the cryo reactor into an aqueous
quench pot and then re-pumping this mixture through a
column pre-loaded with an ammonium hydroxide resin.
Pleasingly, the resin did serve to hydrolyse, deprotonate
and catch the resulting α-fluoro carboxylate material on
the solid support (see operation A: hydrolysis and catch;
Scheme 4). The liquid output from this initial pass of the
crude material through the hydroxide cartridge was found
to contain both unreacted starting carbonyl-auxiliary and
the cleaved auxiliary fragment. We presume, based on
these observations, that only the fluorinated product was
saponified under these conditions and subsequently
bound to the polymeric ammonium resin as the carboxyl-
ate ion. In addition to the sequestering of the fluorous car-
In conclusion, we have reported studies toward the devel-
opment of a diastereoselective fluorination process under
meso-scale flow conditions. These studies include prelim-
inary findings on the configuration of equipment that may
be required and the development of a streamlined workup
that leads to the isolation of the product in a convenient
salt form. Whereas in batch mode the reaction necessitates
two cooled reactors and slow reagent addition to ensure
good conversion into product, the findings in meso-flow
suggest that cooling of the lithiation is not necessary be-
cause of the surface area to volume ratios and mixing dy-
namics involved. Furthermore, the work has highlighted
the necessity to ensure that the electrophilic quench is
kept cold in order to deliver good conversion into the
Synlett 2013, 24, 1298–1302
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Fluorination under Flow Conditions
1301
polymer supported
down-stream processing
flow reaction
product
A hydrolyse and catch
B release
C precipitate and filter
output from
cryo-flow reactor
crystalline salt
64% yield, single isomer
collection
pot
caught
aqueous
quench pot
at t = 0, X– = OH–
PS-Me3N+ X–
X– = –N(SO2Ph)2
+
–O2C-F-product
A - hydrolysis
and
catch mode
removed to waste
Xc-carbonyl, Xc-H
waste
pot
1M HCl (aq)
aqueous
quench pot
collection
pot
released
HN(SO2Ph)2 + HO2C-F-product
PS-Me3N+ X–
B - release
waste
pot
1M HCl (aq)
O
+
NH3
–O
Ph
C - batch manipulation
of flow output
collection
pot
conc.
H2O
EtOAc
F
crystalline salt
64% yield, single isomer
precipitate
+
filter
extract
3 x wash
HN(SO2Ph)2
waste
cyclohexyl-
amine
Scheme 4 Assisted workup by downstream processing with polymer support
6655. (d) Less, S. L.; Handa, S.; Millburn, K.; Leadlay, P. F.;
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fluorinated product and prevent unwanted side reactions.
We believe that further studies on scaling this continuous
approach will provide a favourable alternative to the in-
consistent batch pilot runs.
Acknowledgment
We are grateful to the following for financial support: Daiichi San-
kyo (K.N.) the EPSRC (EP/F069658/1, DLB), the Royal Society
(I.R.B.) and the BP 1702 Professorship (S.V.L.).
(4) Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39,
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References and Notes
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(1) Now at Department of Chemistry, Durham University,
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(8) Typical procedure for the flow synthesis of α-
fluoroamides [collection inclusive of slug diffusion (Table
1 and Figure 1)]: The cryo-flow reactor was set at –60 °C,
which took approximately 45 minutes to reach this target
from ambient temperature (ca. 22 °C). This process was only
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1298–1302

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K. Nakayama et al.
LETTER
required for the first use, the reactor could then be left at the
desired temperature for subsequent processes. The loops
were loaded with the corresponding starting materials, at the
depicted concentrations, and pumping was initiated at 0.5
mL/min for channels A and B before switching the loaded
loops in-line. After 10.5 min, the pump for channel C was
turned on and the loaded loop was switched in line. The
collected material was quenched directly into a saturated
aqueous solution of NH4Cl, following the end of the run
(typically around 45 min) and extracted with EtOAc (3 × 50 mL).
The combined organics were dried (MgSO4) and
(b) Atallah, R. H.; Ruzicka, J.; Christian, G. D. Anal. Chem.
1987, 59, 2909. (c) Castell, O. K.; Allender, C. J.; Barrow,
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Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Org. Process
Res. Dev. 2007, 11, 399. (f) Sahoo, H. R.; Kralj, J. G.;
Jensen, K. F. Angew. Chem. Int. Ed. 2007, 46, 5704.
(g) O’Brien, M.; Koos, P.; Browne, D. L.; Ley, S. V. Org.
Biomol. Chem. 2012, 10, 7031. (h) Hu, D. X.; O’Brien, M.;
Ley, S. V. Org. Lett. 2012, 14, 4246. (i) Bourne, S. L.;
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B. C.; Jensen, K. F. Lab Chip 2009, 9, 1843. (l) Lam, K. F.;
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concentrated in vacuo. The residue was purified by column
chromatography on silica gel (gradient mixture of hexane–
EtOAc) to provide the desired products. Complete
hydrolysis of these amides can be achieved by using LiOH.
(9) The enantiomeric excess was determined by a HPLC assay,
see the Supporting Information in: Yang, X.; Birman, B. V.
Chem. Eur. J. 2011, 17, 11296.
(10) For examples of continuous liquid–liquid extraction,
separation and/or washing processes, see: (a) Kralj, J. G.;
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Synlett 2013, 24, 1298–1302
© Georg Thieme Verlag Stuttgart · New York