Nucleophilic fluorination facilitated by a CsF-CaF2 packed bed reactor in continuous flow

Article abstract of DOI:10.1039/c7cc09035h

A simple to prepare, dry and handle packed bed reactor carrying CsF on CaF₂, towards nucleophilic fluorinations in continuous flow, is reported. The reactor also proved adaptable for silyl-ether deprotection and trifluoromethylations with Ruppert's reagent. The study includes reactor stability and scale-up investigations.

Full text of DOI:10.1039/c7cc09035h

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Reactivity differences of Sc
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DOI: 10.1039/C7CC09035H
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Nucleophilic Fluorination Facilitated by a CsF-CaF Packed Bed
2
Reactor in Continuous Flow.
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
M. B. Johansen and A. T. Lindhardt
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple to prepare, dry and handle packed bed reactor carrying Sanford and Yossi Zafrani have reported on soluble quaternary
6
CsF on CaF , towards nucleophilc fluorinations in continuous flow, ammonium fluorides that tolerates drying. In 2011, Noël et.
2
is reported. The reactor also proved adaptable for silyl-ether al. reported on the palladium catalysed fluorination of aryl
deprotection and trifluoromethylations with Ruppert’s reagent. triflates in continuous flow, using pre-dried CsF packed in a
7
The study includes reactor stability and scale-up investigations.
bed reactor. To obtain high reactivity and to avoid obstruction
of flow, Noël used CsF particles obtained by two-fold sieving of
CsF-powder through different mesh-nets inside a glovebox.
During our research into fluorination reactions, and inspired by
the work of Noël et. al., we became interested in the potential
The substitution of hydrogen with fluorine during the design of
pharmaceuticals and agrochemicals, has become a well-
established method, towards alteration of a compounds
1
metabolic stability and bioavailability. Given the success of
benefits of adapting nucleophilic fluorinations into
a
8
fluorinated structures several methods for fluorine
introduction have been developed. These methods are divided
into four categories, named accordingly to the character of the
fluorine being installed; being radical, electrophilic,
continuous flow setup. Besides acting as a static mixer and
heat exchanger, a packed bed reactor (PBR) will enhance the
mass transport of otherwise insoluble fluoride anions by its
inherent large surface-to-volume ratio of loaded reagents.
Importantly, a PBR loaded with a metal-fluoride will push any
halide exchange equilibriums in favour of the fluorinated
2
nucleophilic, and metal mediated. Nucleophilic fluorination
often occurs through S 2-type displacement of leaving groups,
N
3
at sp -hybridized carbon centres. Similar leaving groups, bound
9
product (See Figure 1). This effect arises as the reactor
2
directly to an electron deficient aromatic core (sp -carbon) can
simulates a setup in which expelled CsCl is removed
continuously from the reaction while being replenished with
3
also be displaced through S Ar reactions. Despite their simple
N
appearance, nucleophilic fluorinations are hampered by the
low solubility of metal fluorides, such as CsF, and the need for
perfectly dry reaction conditions. These drawbacks are
normally addressed by superstoichiometric amounts of metal
fluoride, addition of phase transfer catalysts, elevated
temperatures and long reaction times. Drying, handling and
storage of anhydrous metal fluorides is problematic and
Classical Nucleophilic Flourination with CsF
CsF TBACl
CsCl TBAF
R
R
TBACl
TBAF
(N) Cl
(N)
F
This Manuscript
4
requires the use of a glovebox. Furthermore, drying of the
R
Pump
Packed Bed Reactor
soluble fluoride source tetrabutylammonium fluoride (TBAF), is
hampered by the Hofmann elimination, leading to its
decomposition. This was circumvented by the group of
DiMagno who reported on the in situ formation of anhydrous
(N) Cl
R
CsF-CaF
2
(N)
F
Phase Transfer Catalyst
PBR - Before
=
CsF
CaF2
TBAF
by
reacting
hexafluorobenzene
with
5
tetrabutylammonium cyanide. Later, the groups of Melanie
PBR - After
CaF2
=
CsCl
CaF Particles coated
with CsF or CsCl
2
Figure 1. Nucleophilic Fluorination using CsF and the CsF-CaF
2
Packed Bed Reactor.
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fresh CsF, as the reaction mixture moves through the column CaF to the metal fluoride dissolved in MeOH followed by slow
1
0
(
Figure 1). Finally, as the encaged metal-fluoride is sealed evaporation of the solvent (see electronic supplementary
from its surroundings, extractive in-line drying, by flushing of information (ESI) for details). Gentle grinding of the material
the PBR with superheated solvents, will remove any CsF-bound provided a MF-CaF support that, when loaded into the PBR,
water, thereby setting the stage for nucleophilic fluorinations. did not lead to the obstruction of flow or resulted in large
In this manuscript we wish to report on the development of an pressure drops. Prior to the first application of each MF-CaF
efficient CsF-CaF packed bed reactor towards nucleophilic packed bed reactor simple in-line drying was preformed by
fluorinations. The reactor material was obtained by passing acetonitrile or toluene through the column at 180 °C
evaporation of dissolved CsF onto correctly sized CaF until no more water was expelled (Table 1 A, see ESI for
2
2
2
2
particles. Efficient in-line drying was achieved by passing details). The initial experiments were centred on the
superheated acetonitrile or toluene through the reactor bed. nucleophilic fluorination of benzyl bromides and chlorides in
This “simple to handle and dry” flow setup provided reactive continuous flow (Table 1). CsF-CaF
CsF applied in nucleophilic halo-substitution reactions of both its corresponding KF-CaF , and hence, CsF was chosen as the
benzylic bromides and chloro-(hetero)aromatic derivatives. fluoride source (see ESI for reactions with KF-CaF ).
2
proved more reactive than
2
2
Reactor stability and accessibility tests proved that a total The benzyl halide (0.5 M) and tetrabutylammonium chloride
loading of only 2 equivalents of CsF was sufficient in these (TBACl – 40 mol %) were dissolved in MeCN and passed
transformations. Finally, the continuous flow setup also through the PBR with a residence time of 25 minutes at 110 °C
proved reactive in fluoride-mediated removal of silyl-based (See ESI for reactor setup). This setup afforded the desired
protection groups and trifluoromethylations of aldehydes and benzyl fluorides in isolated yields ranging
ketones with excellent isolated yields and residence times
a
down to 2 minutes.
Table 1. In-Line Drying and Nucleophilic Fluorinations
A) In-Line Drying of CsF-CaF Reactor
1000
Initial experiments using a packed bed reactor loaded with
commercial available CsF (directly from the bottle, ball-milled
or grinded in a mortar) failed. This failure can be ascribed to
the presence of small CsF particles that leads to high pressure
drops and clogging of the PBR. In order to circumvent sorting
of hygroscopic metal fluoride particles, focus was instead
turned towards the identification of a solid support upon
which CsF could be loaded. Silica gel and alumina oxide failed
as solid supports, due to the Lewis basic nature of fluoride
2
Water content [ppm]
5
00
0
0
50
100
150
200
250
Volume of flushed MeCN [mL]
B) Nucleophillic Fluorination of Benzylic Bromides and Chlorides
1
1
(
Figure 2). Next, the reactor was loaded with fluoride ion
R
Br + (Bu)
0.4 equiv
NCl
4
exchanged Amberlyst IRA-900 polymer beads. This amberlyst
system provided a reactor with apparent good conversion into
the desired nucleophilic substituted 2-fluoropyridine.
However, the mass balance was poor with the majority of
injected material being retained inside the polymeric matrix.
After significant experimentation, attention was finally turned
1
mmol
MeCN
Cl
CsF-CaF
2
BPR
R
F
F
V = 2 mL
V
void = 2.4 mL
Sample loop
110oC, r
= 25 min
T
Br
NC
tBu
towards fluorospar (CaF
the group of Clark, indicated that KF or CsF loaded onto CaF
did not impede the fluoride nucleophilicity in batch
2
) as a solid support. Early reports by
F
F
F
2
Cl
0% (65%)b - 1
7
74% (72%)b - 2
68% - 3
68% - 4
1
2
reactions. Commercially available CaF
2
with 98% of all
C) CsF Accessibility Test by Scale-out Synthesis of 2.
particles ranging in size from 0.1 μm – 60 μm was chosen for
tBu
1
further testing. The support was prepared by addition of
3
tBu
Br
+
(Bu)
4
NCl
Cs
F
-CaF
2
BPR
F
2
(5 - 0.5 M)
0
.4 equiv
V
void
o
=
2.4 mL
11,4 mmol -
Dissolved in MeCN
1
10 C, r
T
= 25 min
R
1
00
NMR Yield of 2 [%]
(
N)
Cl
Packed Bed Reactor
R
8
6
4
2
0
0
0
0
0
CsF on Support
Sample loop
(N)
F
HPLC Pump
Packed with CsF
N
F
Poor mass balance
Collection time [min]
250 300 350
See ESI for specific reaction details for each entry. The corresponding benzyl
Large pressure drop
Amberlyst 900 - Fluoride loaded
0
50
100
150
200
F
F
O
O
O
O
O
Al
O
Basic and
non-nucleophilic
materials
a
b
Si
O
Cs
Cs
chloride was used instead.
CsF on
alumina oxide
CsF on Silica gel
14,15
).
from 65 – 74% (Table 1 – B, Compounds
1
–
4
Aliphatic
Figure 2. Failed Solid Supports for CsF-Loaded Reactor.
halides did only provide trace fluorination, along with
2
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6
a
elimination products, when subjected to the flow-setup. In Table 3. CsF-CaF
order to test the fluoride accessibility of the CsF-CaF material
a scale-out experiment was performed with 1-bromomethyl-4-
tertbutylbenzene ( ) (Table 1 – C). (0.5 M) was pumped
2
Mediated Deprotection of Silyl Ethers
2
PG
R
O
F
3
C
OH
0
.1-0.5 M
5 equiv.
5
5
H
R
DMF : Toluene
: 1
CsF-CaF
120 o
= 5 min
2
BPR
O
through the PBR, under identical conditions as above, and
1
samples were collected in 20-minute intervals. The H-NMR
7
V = 2 mL
C
Sample loop
r
T
yield of
2
was determined for all samples using dimethyl
slowly
O
TBSO
O
R
3
SiO
terephthalate as internal standard. The yield of
2
EtO
H
OMe
O
decreased from 80 % – 66 % over the first 240 minutes after
which it quickly deteriorated. The combined yield of the first
MeO
Cl
Silyl Protectiong group:
8
6%c - 15
240 minutes corresponds to the formation of 11.4 mmol of
2.
TES: 93% - 14
TES: 93% - 14b
H
H
21 mmol of CsF loaded onto CaF was packed on the reactor,
2
TIPSO
TBS: 90% - 14
9
4% - 13
corresponding to more than 50 % of loaded CsF being
1
accessible, or a loading of only 2 equivalents of CsF!
7
a
The silylether (0.1 M) and trifluoroethanol (0.5 M) in DMF:toluene (7:1) at 120 °C
b
c
Next, attention was turned towards the nucleophilic with r = 5 min. TES-protected vaniline (0.5 M) with trifluoroethanol (2.5 M).
T
substitution of chlorinated heteroaromatics, the results of Trifluoroethanol (0.12 M) at room temp. with r
which are depicted in Table 2. 2-Chloropyridine carrying either
T
= 20 min.
where all protected as their corresponding TES, TIPS, and TBS
silyl ethers (See Table 3). Full conversion to the alcohols were
obtained by passing the silylethers dissolved DMF:toluene
a 5-neopentyl amide or a 5-cyano as substituent afforded the
fluorinated compounds and in 68% and 59% isolated yields,
respectively. 4,7-Dichloroquinoline afforded mono 4-
fluorinated in 58% isolated yield and 64% of was secured
6
9
(
7:1) through the CsF-CaF
1
2
PBR at 120 °C with a residence time
7
8
8,19
of 5 minutes.
Trifluoroethanol functioned as the proton
after column chromatography. Next, two pyrimidine analogues
were tested affording the desired products in 66% and 65%
isolated yields (compunds 10 and 11, respectively). Finally,
nucleophilic displacement of chloride on isopropyl 2-chloro-5-
nitrobnzoate afforded 12 in a good 75% isolated yield. Full
conversion was obtained for all entries in Table 2, and besides
the fluorinated products, side-products resulting from
heteroaromatic dimerization or hydrolysis were identified.
Having established the nucleophilicity of the in-line dried CsF-
source for the deprotection. TIPS removal from 13 afforded
alcohol in a near quantitative 94% isolated yield. The TES-
ether, and the more stable TBS ether, was cleaved from
vaniline in isolated yields of 93% and 90%, respectively.
Increasing the concentration to 0.5 M of 14 did not affect the
reaction and afforded the free alcohol in an identical 93%
isolated yield. Finally, TBS-ether removal from 15 at room
temperature with a residence time of 20 minutes afforded the
free alcohol in a good 86% isolated yield.
2
CaF support, it was next decided to investigate its utility in
As the last part of this study the trifluoromethylation of
aldehydes and ketones using Ruppert’s reagent was
fluoride-mediated reactions. Three alcohols, the ethyl ester of
lithocholic acid, vaniline and the Morita-Baylis-Hillman alcohol,
prepared from 4-chlorobenzaldehyde with methyl acrylate,
1
6a,20
investigated.
room temperature, full trifluoromethylation was accomplished
using the CsF-CaF reactor (See Table 4). The crude reactions
With a residence time of only 5 minutes, at
2
Table 2. Nucleophilic Aromatic Fluorinations in Flow.
were obtained as a mixture of the alcohol and the
corresponding TMS-protected ethers, the latter that was
cleaved during acidic workup. Four aldehydes were tested,
carrying both electron donating and electron withdrawing
groups, and afforded isolated yields ranging from 70% – 83%
Cl
R
4
(Bu) NCl
+
(
N)
0
.4 equiv
0
.5 - 1 mmol
(
compounds 16, 17, 19 and 20). One heteroaromatic aldehyde
F
was tested, 1-methyl-1H-pyrrole-2-carbaldehyde, and afforded
18 in 84% isolated yield. 4-Cyanoacetophenone (22) proved
highly reactive, affording 21 in an excellent 94 % isolated yield.
Finally, compound 22 was selected for a scale-out experiment.
Additional optimization revealed that the residence time
needed to convert 22 to 21 was less than 60 seconds, even at
an increased concentration of 0.75 M for 22. However, the
reaction exotherm caused the PBR to overheat. This heat was
MeCN or
DMF
CsF-CaF
2
BPR
R
(N)
V = 2 mL
Sample loop
V
void = 2.4 mL
o
5
0-150 C, r
T
= 10-40 min
F
O
N
H
N
Br
Cl
N
N
F
F
6
8% - 6
58% - 7
64% - 8
OMe
dissipated by cooling the CSF-CaF
PBR in a water bath at room
to 120 seconds.
F
O
2
F
NC
N
temperature combined with an increase in r
T
O
N
This setup afforded a stable system and the scale-out reaction
was run for 42 minutes resulting in the isolation of 34 mmol of
21 (7.4 grams). Interestingly, catalytic behaviour of fluoride
was observed as 34 mmol of 21 was secured with only 21
mmol of CsF loaded onto the onto the packed bed reactor.
MeO
N
F
N
F
N
Ph
N
5
9% - 9
66% - 10
65% - 11
O
O
75% - 12
a
See ESI for specific reaction details for each entry.
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Table 4. CsF-CaF
O
2
Mediated Trifluoromethylations.
1
2
(a) T. Furuya, A. S. Kamlet, T. Ritter, Nature, 2011, 473, 470;
(b) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson,
S. L. Buchwald, Science, 2010, 328, 1679; (c) T. Liang, C. N.
Neumann, T. Ritter, Angew. Chem. Int. Ed., 2013, 52, 8214;
(d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev., 2008, 37, 320.
For references and citations therein, see: (a) C. C. Sazepin, R.
H/R
F3CSiMe3
R
+
1
mmol
(2 equiv)
OH
CF
3
H/R
DMF
CsF-CaF
2
BPR
R
Hemelaere, J.-F., Paquin, G. M. Sammis. Synthesis, 2015, 47
2554; (b) Q. Lefebvre, Synlett, 2017, 28, 19. (c) N. Shibata, A.
Matsnev, D. Cahard. Beilstein J. Org. Chem., 2010, , 65. (d)
,
V = 2 mL
Sample loop
Vvoid = 2.4 mL
After acidic workup
rt, r
T
= 5 min
6
OH
OH
CF
OH
C. N. Neumann, T. Ritter. Acc. Chem. Res., 2017, 50, 2822; (e)
X. Liu, C. Xu, M. Wang, Q. Liu. Chem. Rev., 2015, 15, 683. (f)
D. A. Watson, M. Su, G. Tevorovskiy, Y. Zhang, J. García-
Fortanet, T. Kinzel, S. L. Buchwald. Science, 2009, 325, 1661.
(a) D. J. Adams, J. H. Clark, Chem. Soc. Rev. 1999, 28, 225.; (b)
P. Richardson, Expert Opin. Drug. Discov. 2016, 11:10, 983.;
(c) D. E. Yerien, S. Bonesi, A. Postigo, Org. Biomol. Chem.
CF
3
3
3
CF
3
H
H
H
NMe
84% - 18
OH
Br
MeO
83% - 16
77% - 17
3
OH
OH
CF
3
CF
CF
3
MeO
MeO
H
H
2
016, 14, 8398
J. H. Clark. Chem. Rev., 1980, 80, 429.
(a) H. Sun, S. G. DiMagno, J. Am. Chem. Soc., 2005, 127
TsO
N
4
5
OMe
OMe
,
70% - 19
68% - 20
94% - 21
2
4
050; (b) H. Sun, S. G. DiMagno, Angew. Chem. Int. Ed. 2006,
, 2720.
O
5
Scale-out Synthesis of 21
6
(a) S. D. Schimler, S. J. Ryan, D. C. Bland, J. E. Anderson, M. S.
Sandford. J. Org. Chem., 2015, 80, 12137; (b) M. A, Cismesia,
S. J. Ryan, D. C. Bland, M. S. Sandford. J. Org. Chem. 2017, 82
5020; (c) S. Elias, N. Karton-Lifshin, L. Yehezkel, N. Ashkenazi,
I. Columbus, Y. Zafrani. Org. Lett., 2017, 19, 3039.
OH
CF
3
NC
,
CsF-CaF
2
BPR
0
.75 M - 22
+
V
void = 2.4 mL
rt, r = 2 min
2 minutes runtime
NC
F
3
CSiMe
2 equiv)
3
T
34 mmol, 94% - 21
(
7,4 grams
7
8
T. Noël, T. J. Maimone, S. L. Buchwald. Angew. Chem. Int. Ed.
2
4
011, 50, 8900.
(a) R. L. Hartman, J. P. McMullan, K. F. Jensen. Angew. Chem.
Int. Ed., 2011, 50, 7502; (b) J. Britton, C. L. Raston. Chem. Soc.
Rev., 2017, 46, 1250.
Ammonium anion affinity is higher for chloride and bromide
than for fluoride, see: S. D. Alexandratos. Ind. Eng. Chem.
Res., 2009, 48, 388.
a
See ESI for specific reaction details for each entry.
In conclusion, a simple to prepare, store and handle
continuous flow packed bed reactor carrying cesium fluoride
loaded onto a calcium fluoride support has been developed.
9
Efficient in-line water removal from the CsF-CaF
2
support was 10 A Similar concept has been utilized in the Finkelstein
reaction, see: M. Chen, S. Ichikawa, S. L. Buchwald. Angew.
Chem. Int. Ed., 2015, 54, 263.
accomplished by passing superheated solvents through the
reactor, thereby avoiding the need for glovebox handling of
hygroscopic metal fluoride salts. As the reaction mixture is
continuously passed on to sections with higher fluoride
concentrations any unfavourable halide exchange equilibriums
are eliminated. The reactor was applied in nucleophilic fluoride
substitution reactions of benzylic bromides and the more
1
1
1 (a) J-M. Clacens, D. Genuit, B. Veldurthy, G. Bergeret, L.
Delmotte, A. Garcia-Ruiz, F. Figueras. Appl. Catal., B, 2004,
53, 95; (b) T. Ando, J. Yamawaki, T. Kawate, S. Sumi, T.
Hanafusa. Bull. Chem. Soc. Jpn., 1982, 55, 2504.
2 (a) J. H. Clark, Hyde, A. J. Hyde, Smith, D. K. J. Chem. Soc.
Chem. Commun. 1986, 791; (b) J. H. Clark, E. M. Goodman, D.
K. Smith, S. J. Brown, J. M. Miller. J. Chem. Soc., Chem.
Commun., 1986, 657.
challenging
nucleophilic
aromatic
substitution
of
chloro(hetero)aromates. Fluoride accessibility was determined 13 We thank Solvay for the gift of the CaF used in this study.
2
by a scale-out experiment and only a loading of 2 equivalents 14 Leaching of fluoride from the PBR is expected to occur in
correlation to the solubility of CsF in specific solvents and
2
of CsF is required. The CsF-CaF packed bed reactor also
due to the presence of the TBACl phase transfer catalyst.
5 When performing these reactions using a PBR packed with
pure CaF only trace fluorination is observed (<2%).
2
proved highly adaptable towards classical deprotection of silyl
ethers with residence times down to 5 minutes. Finally, CsF-
1
CaF
were performed with excellent isolated yields. Scale-out of the
trifluoromethylation of 4-cyanoacetophenone, with
2
mediated trifluoromethylation of aldehydes and ketones 16 (a) M. Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley.
Tetrahedron, 2009, 65, 6611; (b) T. Gustafsson, R. Gilmour, P.
H. Seeberger, Chem. Commun. 2008, 3022; (c) M. Baumann,
I. R. Baxendale, S. V. Ley. Synlett, 2008, 14, 2111.
a
residence time of 2 minutes at room temperature, afforded
more than 7 grams of the desired product in only 42 minutes.
1
2
7 In-line regeneration of the CsF-CaF PBR has not been
attempted, but could potentially be performed by passing a
saturated solution of TBAF thorough the reactor.
8 M. O´Brien, L. Konings, M. Martin, J. Heap. Tetrahedron Lett.
2017, 58, 2409.
9 T. Saito, S. M. Morimoto, C. Akiyama, T. Ochiai, K. Takeuchi,
T. Matsumoto, K. Suzuki. J. Am. Chem. Soc. 1998, 120, 11633.
0 For a few examples on trifluoromethylations using Ruppert’s
reagent in flow, see: S. Okusu, K. Hirano, Y. Yasuda, E.
1
1
2
Conflicts of interest
There are no conflicts to declare.
Tokunaga, N. Shibata. RSC. Adv., 2016, 6, 82716.; M.
Baumann, I. R. Baxendale. Synlett, 2016, 27, 159.
Notes and references
4
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