Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

Article abstract of DOI:10.1002/anie.201903801

A facile method for the regioselective hydrodifluoromethylation of alkenes is reported using difluoroacetic acid and phenyliodine(III) diacetate in tetrahydrofuran under visible-light activation. This metal-free approach stands out as it uses inexpensive reagents, does not require a photocatalyst, and displays broad functional group tolerance. The procedure is also operationally simple and scalable, and provides access in one step to high-value building blocks for application in medicinal chemistry.

Full text of DOI:10.1002/anie.201903801

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Accepted Article
Title: Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid
Authors: Claudio F. Meyer, Sandrine M. Hell, Antonio Misale, Andres A
Trabanco, and Veronique Gouverneur
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903801
Angew. Chem. 10.1002/ange.201903801
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10.1002/anie.201903801
Angewandte Chemie International Edition
COMMUNICATION
Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid
Claudio F. Meyer,[a,b] Sandrine M. Hell,[a] Antonio Misale,[b] Andrés A. Trabanco,[b] and Véronique
Gouverneur*[a]
Abstract:
A
facile
method
for
the
regioselective
using inexpensive difluoroacetic acid under visible light
activation.10 We were encouraged by studies demonstrating that
the photolysis of preformed hypervalent iodine (III) reagents
enables direct C-H difluoromethylation of heteroarenes.11
Hypervalent iodine (III) reagents are also suitable for the
hydroaryldifluoromethylation of alkenes under Ir-based
photoredox catalysis.12 These observations led us to consider
that visible light irradiation could enable hydrodifluoromethylation
of alkenes in the absence of photocatalyst using inexpensive
difluoroacetic acid and the oxidant phenyliodine(III) diacetate
(PIDA) in a solvent capable of hydrogen atom transfer e.g
tetrahydrofuran (THF).8,9 In this scenario, THF (α-C–H, BDE =
385 kJ/mol)13 would react with the carbon-centered radical
generated upon addition of CF2H radical onto the alkene. This
process would release a THF α-radical that could in turn activate
the in situ formed difluoromethylation I(III) reagent (Scheme 1B).
hydrodifluoromethylation of alkenes is reported using difluoroacetic
acid and phenyliodine(III) diacetate in tetrahydrofuran under visible
light activation. This metal-free approach stands out as it uses
inexpensive reagents, does not require a photocatalyst, and displays
broad functional group tolerance. The procedure is also operationally
simple and scalable, and allows access in one step to high value
building blocks for application in medicinal chemistry.
Fluorinated compounds are of high interest in drug
discovery due to the unique ability of fluorine to modulate the
lipophilicity, polarity, metabolic stability and solubility of potential
drug candidates, properties that directly influence bioavailability
and adsorption.1 The difluoromethyl group (CF2H) stands out as
a metabolically stable lipophilic bioisostere of weak hydrogen
bond donors such as alcohols, anilines, amines or thiophenols,
and as such has been used in a variety of drug molecules.2
Traditionally, the CF2H group is generated by deoxyfluorination
of an aldehyde with reagents such as N,N-dimethylaminosulfur
trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride
(Deoxo-Fluor®).3 These reagents react with alcohols, ketones
and carboxylic acids with poor selectivity, thereby imposing
extensive protecting group chemistry for molecules featuring
Dolbier 2015 - Hydrodifluoromethylation of electron-deficient alkenes (photoredox catalysis)
A
O
S
PC
R3Si-H
CF2H
CF2H
CF2H
+
Cl
CF2H
EWG
EWG
MeCN, hν
O
Qing 2015 - Two-step hydrodifluoromethylation of alkenes (photoredox catalysis)
PC
Zn, HCl
CF2Br
+
CF2Br2
R
R
R
DMF
THF, hν
these
functionalities.4
Furthermore,
the
exothermic
Qing 2016 - Hydrodifluoromethylation of alkenes (photoredox catalysis)
[Ph3PCF2Br]+Br-
decomposition of these reagents at elevated temperature or in
contact with water presents safety concerns, especially for large-
scale synthesis.5 In response to these challenges, late stage
difluoromethylation of (hetero)arenes,6 and new transformations
such as the hydrodifluoromethylation of alkene starting materials
have been developed. In 2015, Dolbier and co-workers
disclosed an elegant photocatalytic hydrodifluoromethylation of
electron deficient alkenes.7 Qing and co-workers reported that
hydrodifluoromethylation of a broader range of terminal alkenes
PC
R
[Ph3PCF2H]+X-
+
R
THF, hν
H2O, KI, PPh3
inexpensive
reagents
This work
• no photocatalyst
B
• no transition metal
• scalable (up to 10 g)
• broad FG tolerance
• operationally simple
H
O
PhI(OAc)2
THF, hν
hydrogen atom donor
CF2H
+
R
R
HO CF2H
is possible applying
a two steps sequence consisting of
Scheme 1. A. Known methods for the hydrodifluoromethylation alkenes. B.
hydrobromodifluoromethylation with ozone-depleting CF2Br2
followed by Zn-mediated reductive debromination.8 The same
group subsequently reported a one step process exploiting the
reactivity of the difluoromethyl radical generated from
bromodifluoromethylphosphonium bromide and water. This
method requires three reagents including a phosphonium salt
that is not an atom economical source of CF2, and the
photocatalyst fac‐[Ir(ppy)3]; careful handling in a glovebox is also
necessary for this reaction to proceed (Scheme 1A).9
Streamlined novel process for the hydrodifluoromethylation of alkenes in the
absence of photocatalyst. EWG
= electron-withdrawing group. PC =
photocatalysis. DMF = dimethylformamide. THF = tetrahydrofuran.
Hex-5-enyl benzoate 1a was chosen as model substrate to
investigate the proposed decarboxylative hydrodifluoro-
methylation. Initial efforts focused on combining hypervalent
iodine oxidants 3a-3c with difluoroacetic acid
2 as the
difluoromethyl source in THF under visible light irradiation (blue
LEDs, λ = 450 nm) at 50 ºC. The desired hydrodifluoro-
methylated product 4a was observed with complete
regioselectivity, albeit in moderate yields (Table 1, entries 1-3).
Phenyliodine(III) diacetate 3a (PIDA) was the most efficient
oxidant affording 4a in 59%. The yield was not improved when
alternative non-protic solvents such as NMP, MTBE, MeCN,
DMF or DMA were used (Table 1, entries 4-8).14 Protic solvents
were not suitable (Table 1, entry 9),15 and the yield of 4a was not
increased in the presence of photocatalyst.16 Running the
reaction at higher concentration did not influence the reaction
outcome (Table 1, entry 10). When a second batch of PIDA was
added after 6 h, the yield of 4a was significantly improved (Table
1, entry 11). A control experiment showed that 4a was obtained
Our objective was to develop an operationally simple and
scalable process for the hydrodifluoromethylation of alkenes
[a]
[b]
C. F. Meyer, S. M. Hell, Prof. Dr. V. Gouverneur
University of Oxford, Oxford, Chemistry Research Laboratory
12 Mansfield Road, Oxford, OX1 3TA (UK)
veronique.gouverneur@chem.ox.ac.uk
C. F. Meyer, Dr. A. Misale, Dr. A. A. Trabanco
Discovery Chemistry
Janssen Research and Development, Toledo, E-45007 (Spain)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201903801
Angewandte Chemie International Edition
COMMUNICATION
in 21% yield when the reaction was performed in the absence of
light (Table 1, entry 12).17
difluoromethylation under the reaction conditions (4p-r). Alkynes
are suitable substrates as demonstrated with the isolation of 4s.
Alkene-containing biologically relevant molecules were
investigated next. Uracil derivative 4t was obtained in moderate
yield. N-Allyl caffeine 1u known to undergo facile
difluoromethylation at C8 was selected to study the
chemoselectivity of the reaction. Under our standard reaction
conditions, the hydrodifluoromethylated product 4u was formed
in 89% yield (19F NMR) with only trace amounts of product
Table 1. Optimization of the reaction conditions.[a]
resulting
from
competitive
C8-H
difluoromethylation.
Tetrahydrofuran was critical for this reaction to be successful as
4u was not formed in CDCl3; this later solvent favored
difluoromethylation at the heteroarene albeit with poor
conversion (C8, 14%).16 Hydrodifluoromethylation of O-allyl-
estrone and Z-Phe-Leu-O-allyl proceeded in moderate yields (4v,
4w), with no erosion of diastereomeric ratio observed for 4w.
Vinclozolin (1x) and Bioallethrin (1y) afforded 4x and 4y isolated
in 89% and 43%, respectively. In terms of limitations, styrene
resulted in a mixture of products, and 1,2-disubstituted alkenes
were low yielding.16
entry
solvent
THF
oxidant
3a
yield [%]
59
1
2
THF
3b
3c
4[b]
27
3
THF
4
NMP
MTBE
MeCN
DMF
DMA
MeOH
THF
3a
41
O
R'
R'
PIDA (6.0 equiv)
+
CF2H
HO
CF2H
R
R
THF (0.07 M), 50 °C, 14 h
blue LEDs
5
3a
41
1a-1y
2 (6.0 equiv)
4a-y
substrate scope
O
O
Me
6
3a
12
FmocHN
CF2H
CF2H
CF2H
Ph
O
CF2H
Ph
O
4
4a 75% (62%)
4b 71% (57%)
4c 76% (64%)
7
3a
51
O
8
3a
40
N
H
HO
CF2H
O
O
CF2H
6
6
4f R = H 76% (64%)
4g R = Cl 73% (69%)
4h R= Br 65% (58%)
4i R = CN 79% (67%)
R
4d 79% (60%)a
4e 76% (72%)b
9
3a
2
10[c]
11[d]
12[e]
3a
60
O
CF2H
O
CF2H
O
CF2H
H
HO
THF
3a
77
4j 69% (61%)
4k 52% (51%)
O
4l 67% (55%)
O
CF2H
THF
3a
21
O
O
PhMe2Si
S
CF2H
Ph
CF2H
PhO2C
[a] 1a (0.1 mmol), oxidant (0.3 mmol), 2 (0.6 mmol), solvent (1.5 mL), blue
LED irradiation (λ = 450 nm) for 14 h. The yield was determined by 19F NMR
4m 83% (75%) dr 7:3
4n 66% (58%)
4o 92% (59%)
spectroscopy
using
trifluorotoluene
as
internal
standard.
[b]
O
O
H
Hydrotrifluoromethylation not observed. [c] THF (0.1 M). [d] A second portion
of 3a (0.3 mmol) was added after 6 h. [e] Reaction in the absence of light. THF
= tetrahydrofuran. NMP = N-methyl-2-pyrrolidone. MTBE = methyl tert-butyl
ether. DMF = dimethylformamide. DMA = dimethylacetamide.
N
CF2H
N
H
CF2H
N
H
CF2H
O
N
N
O
N
4p 77% (65%)
4q 67% (61%)
4r 56% (54%)
O
O
Me
O
N
With the optimized conditions in hand (Table 1, entry 11),
the generality of this new protocol for hydrodifluoromethylation
was studied. As illustrated in Scheme 2, a broad variety of
functional groups, such as esters, amides, alcohols, aldehydes,
halides and nitriles were tolerated, and the desired products 4a-i
N
Me
O
HF2C
N
HF2C
N
N
CF2H
8
N
O
N
Cl
4t 65% (61%)
O
Me
4s 46% (E/Z 85/15)c
4u 89% (50%)d
O
Ph
O
Me
O
H
N
H
CbzHN
O
CF2H
were
isolated
in
moderate
to
good
yields.
The
Me
H
H
hydrodifluoromethylation of alkenes containing a carboxylic acid
or aldehyde was successful affording 4l and 4k in moderate
yields; such functional groups would require protecting group
chemistry with deoxyfluorination chemistry. Alkene 1d with a
pending alcohol functionality afforded the tetrahydrofuranyl ether
4d, so in situ deprotection is necessary to isolate the alcohol 4e
in 72% yield. A methylene cyclobutane derivative underwent
hydrodifluoromethylation in good yield (4m), and electron
deficient alkene such as phenylvinylsulfone led to 4n in 58%
yield. The incorporation of difluoromethyl groups onto a vinyl
silane was also successful (4o). Heteroarenes are well tolerated
O
CF2H
Me
4w 62% (51%)
from Z-Phe-Leu-O-Allyl
4v 60% (42%)
from O-Allyl-estrone
CF2H
Me Me
Me
O
O
Cl
Cl
Me
Me
O
CF2H
N
O
Me
O
O
4x 96% (89%)
from Vinclozolin
4y 62% (43%)
from Bioallethrin
Scheme 2. Substrate scope. Reaction conditions: alkene 1a-y (0.3 mmol), 2
(1.8 mmol), 3a (0.9 mmol), THF (4.5 mL), blue LED irradiation (λ = 450 nm),
50 °C, 14 h. After 6 h a second portion of 3a (0.9 mmol) was added. Yields
determined by 19F NMR spectroscopy using trifluorotoluene as internal
standard, yields of isolated products in brackets. [a] The starting material is 7-
octen-1-ol. [b] HCl (conc. 0.5 mL) was added after completion of the reaction.
[c] The starting material is N-propargylphtalimide (1s). [d] In CDCl3, the C8-H
difluoromethylated product is obtained in 14% yield.
and
did
not
undergo
competitive
heteroaryl
C-H
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10.1002/anie.201903801
Angewandte Chemie International Edition
COMMUNICATION
TEMPO (6.0 equiv)
2 (6.0 equiv),
3a (6.0 equiv)
With the aim of scaling up our reaction from milligram to
multigram, we selected alkene starting materials that are
converted into valuable difluoromethylated building blocks for
application in medicinal chemistry (Scheme 3). 4,4-
A
B
C
D
Me
Me
O
O
+
HF2C
N
Ph
O
Ph
O
CF2H
THF (0.07 M)
50 °C, 14 h
blue LEDs
O
3
4
Me Me
4ab 51%
1a
4a nd
Difluorobutan-1-amine is
a
known compound previously
2 (6.0 equiv)
3a (6.0 equiv)
prepared in five steps applying deoxyfluorination chemistry.18
Pleasingly, the hydrodifluoromethylation of t-butyl allyl N-
carbamate 1z was accomplished in one step on a 10 g scale
affording 4z isolated in 68% yield (9.2 g). For this process, the
concentration was increased from 0.07 M to 0.13 M, and three
equivalents of PIDA 3a was sufficient. Similar conditions
enabled the multigram synthesis of azetidine 4aa (8.9 g, 67%).19
HF2C
N
N
THF (0.07 M)
50 °C, 14 h
blue LEDs
Ts
Ts
1ac
4ac 78% (dr 2:1)
2 (6.0 equiv)
3a (6.0 equiv)
O
O
N
N
CF2H
[D8]THF (0.07 M)
50 °C, 14 h
blue LEDs
H
H
D
1e
[D]4e 37% (D/H 40/60)
2 (6.0 equiv)
3a (6.0 equiv)
O
O
S
O
O
S
O
S
O
CF2H
THF (0.07 M)
50 °C, 14 h
blue LEDs
+
O
1n
1d
4n 66%
5n (25%)
2 (6.0 equiv)
3a (6.0 equiv)
E
F
HO
CF2H
5
O
O
5
THF (0.07 M)
50 °C, 14 h
blue LEDs
4d 79%
Scheme 3. Scale-up synthesis of building blocks highly valuable for medicinal
chemistry.
O
I(OAc)2
I
O
CF2H
HO
CHF2
A series of experiments were performed to gain more
insight into the reaction mechanism. Addition of the radical
quencher 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) inhibited
the formation of product 4a affording instead the TEMPO adduct
4ab in 51% yield (Scheme 4A). Next, when diene 1ac was
submitted to the reaction conditions, the cyclized product 4ac
was obtained in 78% yield (Scheme 4B). Collectively, these data
are consistent with the presence of a CF2H radical intermediate
2
2
O
3d
3a
-AcOH
hν
PhI
O
O
PhI
+
+
O
9
O
CHF2
O
CF2H
6
CO2
and strongly suggest
a
radical-based mechanism. The
3d
hydrodifluoromethylation of 1e in [D8]THF led to the desired
product in 37% yield with 40% deuterium incorporation,
indicating that THF acts as hydrogen atom donor (Scheme 4C).
Moreover, the hydrodifluoromethylation of the electron-deficient
alkene 1n afforded the THF adduct 5n in addition to the desired
product of hydrodifluoromethylation 4n, a result consistent with
the formation of a nucleophilic THF α-radical (Scheme 4D).
Reaction of alcohol 1d under the standard reaction conditions
afforded the THF protected ether 4d in 79% yield; an
electrophilic tetrahydrofuran-derived oxonium ion is therefore
present that can react with the alcohol group (Scheme 4E).
Based on these experiments, a reaction mechanism is proposed
in Scheme 4F. The exchange of difluoroacetic acid 2 with the
acetate group on 3a affords 3d.20 Photolysis under blue light
exposure releases 6 that can undergo decarboxylation to
generate •CF2H. This radical would be well-suited to add
regioselectively to the alkene substrate. The resultant carbon
radical 7 would subsequently react with THF to afford the
product of net hydrodifluoromethylation. Hydrogen atom
abstraction from tetrahydrofuran releases the THF α-radical 8
that could undergo single electron transfer to 3d with
concomitant release of the oxonium ion 9, iodobenzene,
difluoroacetate, and radical 6 for further alkene functionalization.
Hydromethylation was not observed as expected considering the
superior stability of •CF2H with respect to •CH3.21
O
F
H
F
8
H
CF2H
R
4
R
O
CF2H
R
H
7
Scheme 4. Mechanistic considerations. Yields were determined by 19F NMR
spectroscopy using trifluorotoluene as internal standard. Yields of isolated
products are shown in brackets. dr = diastereomeric ratio. nd = not detected.
In conclusion, we have developed a new streamlined
protocol for the hydrodifluoromethylation of alkenes as part of
our recent late stage fluorination program aimed at avoiding
operationally complex, over-engineered, and costly processes.22
Difluoroacetic acid was used as an inexpensive difluoromethyl
radical source and phenyliodine(III) diacetate as oxidant, both
reagents used in excess to maximize yields. These mild
conditions tolerate a wide array of functional groups. This novel
reaction was applied to the multigram-synthesis of
pharmaceutically relevant building blocks providing shorter and
safer synthetic routes compared to synthesis relying on classical
deoxyfluorination protocols.
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10.1002/anie.201903801
Angewandte Chemie International Edition
COMMUNICATION
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Acknowledgements
The authors gratefully acknowledge Dr. Daniel Oehlrich, Dr.
Aldo Peschiulli and Dr. Natan Straathof for helpful discussions,
and Dr. Alejandro Diéguez-Vázquez for assistance with the
scale-up experiments. This project has received funding from
the European Union’s Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie grant agreement
No 721902.
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The authors declare no conflict of interest.
Keywords: difluoroacetic acid • hydrodifluoromethylation •
hypervalent Iodine • photochemistry • radicals
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10.1002/anie.201903801
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Claudio F. Meyer, Sandrine M. Hell,
Antonio Misale, Andrés A. Trabanco,
Véronique Gouverneur*
H
no photocatalyst
O
PhI(OAc)2
CF2H
no transition metal
scalable (up to 10 g)
broad FG tolerance
operationally simple
+
R
R
HO CF2H
THF, hν
27 examples
high value
products
Page No. – Page No.
Hydrodifluoromethylation of Alkenes
with Difluoroacetic Acid
readily available
starting materials
inexpensive
reagents
Terminal alkenes undergo net hydrodifluoromethylation in the presence of an
excess of difluoroacetic acid and phenyliodine(III) diacetate in tetrahydrofuran
applying visible light irradiation (λ = 450 nm). This highly practical protocol
telescopes access to biorelevant building blocks that would require multiple
synthetic steps applying deoxyfluorination chemistry.
This article is protected by copyright. All rights reserved.