Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2H in Continuous Flow

Article abstract of DOI:10.1002/anie.202004260

The deuteriodifluoromethyl group (CF₂D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF₂H) gas in t

Full text of DOI:10.1002/anie.202004260

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How to cite:
International Edition: doi.org/10.1002/anie.202004260
German Edition: doi.org/10.1002/ange.202004260
Difluoromethylation
Deuteriodifluoromethylation and gem-Difluoroalkenylation of
Aldehydes Using ClCF H in Continuous Flow
2
Wai Chung Fu and Timothy F. Jamison*
Abstract: The deuteriodifluoromethyl group (CF D) repre-
sents a challenging functional group due to difficult deuterium
incorporation and unavailability of precursor reagents. Herein,
In general, difluoromethylating reagents have limited
2
[11,12]
accessibility and efficiency (Figure 1c).
Some of these
precursors are toxic, expensive, have low atom economies or
require multiple synthetic steps to prepare. Chlorodifluoro-
we report the use of chlorodifluoromethane (ClCF H) gas in
2
the continuous flow deuteriodifluoromethylation and gem-
difluoroalkenylation of aldehydes. Mechanistic studies re-
vealed that the difluorinated oxaphosphetane (OPA) inter-
mediate can proceed via alkaline hydrolysis in the presence of
methane (ClCF H) is an inexpensive industrial chemical used
2
[13]
for the production of fluorinated polymers such as Teflon.
It is regulated as an ozone depleting substance under the
[
14]
Montreal Protocol, but exemptions were given for research
and development purposes, including its use as a reaction
feedstock. We envisioned this fluorinated gas as a potential
atom-efficient reagent for difluoromethylation. Although it
has been demonstrated as an effective difluorocarbene
D O to provide a-deuteriodifluoromethylated benzyl alcohols
2
or undergo a retro [2+2] cycloaddition under thermal
conditions to provide the gem-difluoroalkenylated product.
[
15]
Introduction
source, there are many challenges associated with the use
of this gaseous compound under batch conditions, namely (1)
The incorporation of fluorine or fluorocarbon groups into
molecules is an important tactic in medicinal chemistry to
enhance biological properties such as the bioavailability,
[
1]
binding selectivity and metabolic stability. In particular, the
difluoromethyl group (CF H) is a lipophilic hydrogen bond
2
donor that can serve as a metabolically stable bioisostere for
[2]
thiols, alcohols and amines. Deuteration is also an efficient
[
1a,3]
tool to optimize drug pharmacokinetics,
and has wide-
[
4]
spread applications in organic synthesis, structure determi-
[
5]
[6]
nation, mechanistic investigations, and quantitative anal-
[
7]
yses. Deutetrabenazine (Austedo) is the first deuterated
drug to be approved by the U.S. Food and Drug Admin-
istration (FDA) in 2017 to treat both tardive dyskinesia and
[
8]
Huntingtonꢀs disease chorea (Figure 1a). Given the utility
of both deuterated and fluorinated molecules, we became
interested in the largely underexplored deuteriodifluoro-
methyl group (CF D).
2
[
9,10]
A review of the literature
revealed there are few
methods to access the CF D group, and that useful levels of
2
deuterium incorporation to generate this moiety can be
a significant challenge. An example of an exception to this, is
the work by Colbyꢀs research group, in which deuteriodi-
fluoromethyl ketones and sulfones were synthesized with
[9]
deuterium incorporation levels in the range of 96–99%. As
shown in Figure 1b, their approach relied on the release of
trifluoroacetate from a highly fluorinated diol. The resulting
carbanion was then quenched by D O to yield the CF D
2
2
functionalized molecules.
[
*] Dr. W. C. Fu, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
7 Massachusetts Avenue, Cambridge, MA 02139 (USA)
7
Figure 1. a) Examples of deuterated and fluorinated molecules in
medicinal chemistry. b) Colby’s work on the synthesis of deuteriodi-
fluoromethyl ketones. c) Difluoromethylating reagents. d) This work:
deuteriodifluoromethylation and gem-difluoroalkenylation using chlor-
odifluoromethane gas.
E-mail: tfj@mit.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202004260.
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the need for prolonged bubbling into a solvent for saturation;
2) the choice of reaction solvent is limited by the gas
Table 1: Selected entries for optimization studies toward continuous
flow gem-difluoroalkenylation.
[
a]
(
solubility; (3) the release of gas into the system headspace
during the reaction; (4) the lengthened reaction time caused
by insufficient gas-liquid interfacial contact or continuous
bubbling into the mixture, and (5) safety concerns and
scalability issues. With our continuing interest in flow
[
16]
methodology development, we were intrigued to address
these limitations by using mircoflow technology. Flow proc-
essing provides many advantages relative to batch tech-
Entry
LiOt-Bu
[equiv]
ClCF H
[equiv]
T
[8C]
Solvent
tR
[min]
Yield
[%]
2
[16,17]
[
b]
niques
including the enhanced reactivity through im-
proved heat and mass transfer, steady-state small scale
generation with immediate consumption of unstable/hazard-
ous reagents, and facile pressurization for significantly
increased gas-liquid interfacial contact.
Herein, we report a modular continuous flow platform for
both deuteriodifluoromethylation and gem-difluoroalkenyla-
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
2.0
2.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.0
3.0
3.0
60
40
20
0
0
0
0
0
0
0
THF
THF
THF
THF
THF
2-MeTHF
CPME
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
15.0
15.0
15.0
15.0
7.5
7.5
7.5
7.7
7.7
47
57
70
80
74
76
61
74
68
79
82
tion of aldehydes using the ClCF H gas (Figure 1d). Different
2
downstream processing modules in the flow system diverts the
fate of the difluorinated oxaphosphetane (OPA) intermediate
to give desired products. The method is rapid, scalable and
exhibits a broad substrate scope.
1
11
0
7.5
12.0
0
[
[
a] Please see Supporting Information for detailed optimization tables.
b] GC-FID yields were reported.
Results and Discussion
literature precedents on the Wittig gem-difluoroalkenylation
[22c–e]
employed high reaction temperatures,
we postulated that
We initiated our study by investigating the use of ClCF H
the enhanced heat transfer might also accelerate the disso-
ciation of the ylide as well as dimerization of difluorocarbene
2
gas for the gem-difluoroalkenylation of aldehydes in flow.
gem-Difluoroalkenes are valuable synthetic intermediates
towards functional organic materials and pharmaceutically
[
23]
to form tetrafluoroethylene. We found that a decrease in
temperature improved the reaction yields with 08C being the
optimal (Table 1, entry 1–5). This is presumably due to the
stabilization of the transient ylide. The use of subzero
temperatures (À208C) led to reactor clogging. Screening of
organic co-solvents further revealed an increase in yield by
conducting the reaction with 2-MeTHF at 08C (Table 1,
entry 5–7, Table S3). The stoichiometry of reagents was also
optimized as shown in Table 1 (entry 8–10) and Table S4. Two
[18]
relevant compounds.
Although different methods have
been reported for the synthesis of gem-difluoroalkenes,
[
19]
[20]
including Suzuki coupling, Negishi coupling, and Julia–
[
21]
Kocienski olefination, the Wittig-type reaction has received
considerable attention recently due to its straightforward
[
15a,22]
synthetic protocol.
ClCF H releases singlet difluorocar-
2
benes (DCF ) in the presence of base through deprotonation
2
[15b]
and a-elimination,
in which it is expected to be subse-
equiv of LiOt-Bu and 3 equiv of ClCF H was found to provide
2
quently trapped by triphenylphosphine to form a difluoro-
the best GC-FID yield of 82% at t (residence time) = 12 min
R
methyl triphenylphosphonium ylide (Ph P=CF ) for the
Wittig reaction with aldehydes. A model flow system for
(Table 1, entry 11). However, 1 was isolated in only 20% yield
3
2
[22]
after column chromatography while addition of water or D O
2
optimization was established as depicted in Table 1. ClCF H
to the crude reaction mixture would afford the corresponding
hydration products 2 and 3 (Scheme 1).
2
was infused into the system through an MFC (mass flow
controller) and piperonal was chosen as a benchmarking
substrate. We envisioned that LiOt-Bu (1m in THF) would be
a suitable base as it generates LiCl upon deprotonation and a-
elimination of the chlorodifluoromethyl anion, thus ensuring
a homogeneous mixture in THF. A BPR (back pressure
regulator) set at 50 psi effectively pressurized the system and
In the presence of stoichiometric amounts of triphenyl-
phosphine, we initially postulated a phosphine-catalyzed
hydration of the gem-difluoroalkenes which would resemble
the hydration of activated olefins reported by Bergman and
[
24]
Toste. Nonetheless, control experiments in which pure gem-
difluoroalkene 4 was treated with PPh under similar basic
3
enabled complete dissolution of ClCF H in the mixture.
Initial solvent screening showed that THF was a promising
candidate (Table S1), giving the gem-difluoroalkene product
conditions gave no hydration products (Table S5). Additional
experiments also excluded the possibility of side products in
this reaction serving as the active catalyst. We further carried
out a crossover experiment whereby gem-difluoroalkene 4
was subjected to the fresh crude mixture A from the flow
reaction and subsequently quenched with water (Scheme 2a).
Interestingly, only compound 2 was provided in 72% yield
while gem-difluoroalkene 4 did not undergo the hydration.
These results indicated that the former reaction halted at an
intermediate state which reacted with water to afford the a-
2
1
in 47% GC-FID yield (Table 1, entry 1). LiOMe in MeOH
was not compatible with the reaction (Table S1, entry 10)
while the use of KOt-Bu immediately clogged the micro-
reactor and mixers due to undissolved KCl (Table S1,
entry 11). The ylide (Ph P=CF ) was reported to be a transient
3
2
species in an interconversion between the ylide and difluor-
[22b,d]
ocarbene due to its low dissociation energy barrier.
While
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forming a difluorocarbanion which would then be protonated
to yield the difluoromethyl group. Substituting water with
1
8
OH gave the isotopically labelled phosphine oxide (Sche-
2
me 2b, characterized by HRMS), supporting the proposed
alkaline hydrolysis of the OPA.
Recently, Byrne and co-workers reported the first obser-
vation of P-hydroxytetraorganophosphoranes as the inter-
[
26]
mediate in phosphonium salt alkaline hydrolysis, but the
same mechanism for an OPA has not been demonstrated.
Although NMR observation of oxaphosphetanes was only
Scheme 1. Formation of hydration product from crude mixture A.
[
25]
known to be possible at low temperatures, the difluorinated
OPA in our reaction is relatively stable at room temperature
and undergoes the retro [2+2] cycloaddition to give gem-
difluoroalkenes overnight in the absence of water (Figure S1–
S4). We anticipated that the Wittig pathway of OPA B is
thermodynamically controlled and heating the crude mixture
at 1008C for 5 minutes successfully gave gem-difluoroalkene 4
in 72% isolated yield (Scheme 2b), aligning with the high
yields observed by GC-FID analyses.
With an understanding of the mechanism and the
optimized flow system for generating difluorinated OPAs,
we set out to develop different downstream processing
modules to guide the outcome of the reaction. We first
focused on the hydrolysis-deuteration module (Scheme 3) to
provide a-deuteriodifluoromethylated benzyl alcohols via in
situ hydrolysis of the intermediate OPAusing D O. The use of
2
À1
1
20 equiv of D O (39 mLmin ) was found to provide the
2
highest product yield while adding LiOH in the D O to
2
increase the basicity gave no positive effect. Due to the low
solubility of phosphine oxide in the 2-MeTHF/D O mixture,
2
THF was used as the organic co-solvent to ensure homoge-
neity. Next, the generality of our continuous flow deuteriodi-
fluoromethylation was explored. Both electron-rich (3, 6b,
6
h) and electron-deficient aryl aldehydes (6c, 6j) were
converted to the corresponding products in good yields
within a residence time of 15 minutes. A diverse range of
functional groups were tolerated, including trifluoromethoxy
(
(
6c), thiomethyl (6d), halide (6e, 6 f, 6k), extended p-system
6i) and trifluoromethyl groups (6j). a,b-Unsaturated (6l–
6
m) and heteroaryl aldehydes (6n–6p) successfully under-
went the deuteriodifluoromethylation process in moderate to
good yields. In the case of isophthalaldehyde, halving the
substrate concentration provided product 6q in 65% yield
and 97% deuterium incorporation. It is notable that selec-
Scheme 2. Mechanistic studies.
tively deuterated fluorocarbon moiety (CDCF D) could be
2
generated when C1-deuterated aldehyde was used (6r). We
also successfully derived adapalene (6s), and ataluren (6t)
which are pharmaceuticals used for the treatment of acne and
Duchenne muscular dystrophy, respectively. In general, high
to excellent deuterium incorporation levels have been
obtained for all cases (95–97%). Enolizable aldehydes were
not applicable under the standard reaction conditions, and
efforts to switch the addition/mixing sequence of substrates
and reagents proved to be futile. We have observed by NMR
analysis that approximately 0.5 to 1 equivalent of chlorodi-
fluoromethane remained in the crude mixture after the course
of reaction, and we believe that further development using in-
line IR or NMR techniques would enable more efficient
difluoromethylated benzyl alcohols. Indeed, NMR studies of
a crude reaction using 4-phenylbenzaldehyde as a substrate
revealed a difluorinated oxaphosphetane species B at room
3
1
temperature (Scheme 2c, P NMR, THF, d = À52.7 ppm, t,
2
19
2
JP-F = 76.0 Hz; F NMR, THF, d = À80.4 ppm, ddd, J
=
F-F
2
3
2
12.5 Hz, J = 70.9 Hz, J = 6.8 Hz, 1F; d = À103.5 ppm,
P-F
F-H
2 2 3 [25]
ddd, J = 212.6 Hz, J = 80.5 Hz, J = 13.1 Hz, 1F).
The P in B is more electron-deficient than typically observed
in OPAs,
F-F
P-F
F-H
V
[
25]
presumably due to the electron-withdrawing
difluoromethylene group. We then hypothesized that the
V
electrophilic P would be facile to the nucleophilic attack of
hydroxide (Scheme 2c). The expelled alkoxide would abstract
the hydroxyphosphorane proton to give phosphine oxide,
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Scheme 4. Substrate scope of continuous flow gem-difluoroalkenyla-
tion. Isolated yields were reported.
(7b–7d, 7 f–7g), electron-deficient (7e) and sterically hin-
dered aldehydes (7c–7d) proceeded efficiently with ClCF H.
2
In particular, the substrate containing an electron-rich
Scheme 3. Substrate scope of the continuous flow deuteriodifluorome-
thylation. Isolated product yields were reported. Deuterium incorpora-
tion levels are highlighted in parentheses. [a] 0.1m of aldehyde was
used. [b] C1-deuterated aldehyde was used. [c] A lower concentration
of aldehyde was used, see the Supporting Information for details.
allyloxy group (7 f) did not undergo competing gem-difluoro-
[
28]
cyclopropanation, thereby demonstrating chemoselectivity.
The scope of our flow reaction could be further expanded to
a- or b-substituted alkenyl aldehydes (7h–7i) while hetero-
cycles (dibenzofuran, thiophenes, carbarzole) were well
tolerated (7j–7m) under the continuous flow conditions.
The aldehyde derivative of the drug probenecid underwent
the gem-difluoroalkenylation smoothly to give 7n in 74%
isolated yield.
To demonstrate the synthetic utility of our deuteriodi-
fluoromethylation in a wider scope, we have carried out
derivatizations of product 6a (Scheme 5). Additional fluori-
nation on the a-deuteriodifluoromethylated benzyl alcohols
was possible using commercially available reagents and 8a
consumption and destruction of the gas as demonstrated by
[27]
Ley and co-workers.
Having established the hydrolysis–deuteration module,
we then turned our attention to develop a retro [2+2]
cycloaddition module for our system (Scheme 4). The reactor
coil for the heated fragmentation process was placed between
the OPA generation module and the back pressure regulator
(
BPR), as the utilization of a 50 PSI BPR would allow for the
[
29]
superheating of THF at 1008C without solvent vaporization.
This highlighted the utility of the flow apparatus in executing
reactions above the boiling point of the solvent and simulta-
neously maintaining homogeneity of a gas-liquid reaction.
The substrate scope of the continuous flow gem-difluoro-
alkenylation was then investigated and a broad scope of gem-
difluoroalkenes were obtained with a total residence time of
was isolated in 62% yield.
Amines are ubiquitous in
[
30]
pharmaceuticals and agrochemicals.
CÀN bond forming
reactions including Mitsunobu and Ritter reaction were
applicable and transformed 6a into 8b and 8c in excellent
yields, whereas the phthalimide in 8b could be removed to
give an amino group (-NH ). Dess–Martin oxidation of 6a
2
gave the a-CF D ketone 8d in 98% yield while the deuterium
2
1
6 minutes. gem-Difluoroalkenylation of both electron-rich
incorporation level was unaffected. We were also pleased to
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Acknowledgements
We thank Dr. Rachel L. Beingessner (MIT), Dr. Mohan
Kumar (MIT), Dr. Long V. Nguyen (MIT) and Dr. Timo-
thy M. Monos (MIT) for helpful discussions. This work was
supported by the Croucher Foundation (Hong Kong), and the
Defense Advanced Research Project Agency (DARPA)
under contract number ARO W911NF-16-2-0023.
Conflict of interest
The authors declare no conflict of interest.
Scheme 5. Transformation of product 6a. Reaction conditions: a) 6a
Keywords: chlorodifluoromethane · continuous flow ·
deuteration · difluoromethylation · gem-difluoroalkene
(
(
(
0.3 mmol), NEt (6 equiv), PBSF (2 equiv), NEt ·3HF (2 equiv), THF
3
3
0.25m), RT; b) 6a (0.3 mmol), PPh (1.1 equiv), phthalimide
3
1.1 equiv), DEAD (1.2 equiv), THF (0.15m), RT; c) 6a (0.3 mmol),
H SO (300 mL), MeCN (0.1m), 808C; d) 6a (0.3 mmol), Dess–Martin
2
4
periodinane (1.2 equiv), DCM (0.25m), RT; e) 6a (0.3 mmol), NBS
1 equiv), P(OPh) (1 equiv), DCM (0.3m), 408C; f) 6a (0.3 mmol),
[1] a) A. D. Kerekes, S. J. Esposite, R. J. Doll, J. R. Tagat, T. Yu, Y.
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Terracina, S. Lee, J. Jones, M. Liu, A. D. Basso, E. B. Smith, J.
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Narayanan, R. Unwalla, F. Lovering, R. A. Denny, H. Zhou,
M. E. Bunnage, ChemMedChem 2015, 10, 715; c) E. P. Gillis,
K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J.
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(
3
TsCl (1 equiv), DABCO (1.2 equiv), DCM (0.3m), RT.
find that 6a could be transformed to give the resulting
bromide 8e and tosylate 8 f in 60% and 72% yield,
respectively. Additionally, we studied the scalability of our
system and doubled the microreactor volumes and flow rates
(
Scheme 6). Product 6a was isolated in 70% overall yield
[
2] a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529; b) Y. Zafrani,
D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E.
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(
1.4 grams) within a total residence time of 14.9 minutes. The
À1
production rate increased from 0.832 mmolh (Scheme 3,
entry 6a) to 1.51 mmolh (Scheme 6).
À1
[
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Conclusion
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In conclusion, we have demonstrated the effective uti-
lization of chlorodifluoromethane gas in the continuous flow
synthesis of a-deuteriodifluoromethylated benzyl alcohols
and gem-difluoroalkenes. The use of a flow system enabled
efficient heat and mass transfer, and addressed several batch
limitations such as inadequate gas–liquid interfacial contact.
A broad scope of aldehydes with different conjugation,
electron richness and steric profiles were successfully dem-
onstrated as substrates, and a range of functional groups and
heteroarenes were well tolerated. We further demonstrated
the scale-up of our flow deuteriodifluoromethylation and the
derivatization of an a-deuteriodifluoromethyl benzyl alcohol
to a number of different products.
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3
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3
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Manuscript received: March 23, 2020
Revised manuscript received: May 13, 2020
Version of record online: && &&
,
&&&&
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Difluoromethylation
ClCF H gas is used in the continuous-
2
flow deuteriodifluoromethylation and
gem-difluoroalkenylation of aldehydes.
Mechanistic studies reveal the difluori-
nated oxaphosphetane intermediate can
proceed via alkaline hydrolysis in the
W. C. Fu, T. F. Jamison*
&&&& — &&&&
Deuteriodifluoromethylation and gem-
Difluoroalkenylation of Aldehydes Using
ClCF H in Continuous Flow
presence of D O to provide a-deuterio-
2
2
difluoromethylated benzyl alcohols or
undergo a retro [2+2] cycloaddition
under thermal conditions to provide the
gem-difluoroalkenylated product.
&
&&&
www.angewandte.org
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
These are not the final page numbers!