Direct Oxidation of Csp3?H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow

Article abstract of DOI:10.1002/chem.201805657

A fast, scalable, and safer C_sp³?H oxidation of activated and un-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp³?H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8–99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane.

Full text of DOI:10.1002/chem.201805657

A Journal of
Accepted Article
Title: Direct oxidation of Csp3-H bonds using in-situ generated
trifluoromethylated dioxirane in flow
Authors: Mathieu Lesieur, Claudio Battilocchio, Ricardo Labes, Jérôme
Jacq, Christophe Genicot, Steven Victor Ley, and Patrick
Pasau
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201805657
Link to VoR: http://dx.doi.org/10.1002/chem.201805657
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3
Direct oxidation of Csp -H bonds using in-situ generated
trifluoromethylated dioxirane in flow
Mathieu Lesieur,*[a] Claudio Battilocchio,[b][c] Ricardo Labes,[b] Jérôme Jacq,[a] Christophe Genicot,[a]
Steven V. Ley,*[b] and Pasau Patrick*[a]
Abstract: A fast, scalable and safer Csp3-H oxidation of activated and
un-activated aliphatic chain can be enabled by
butyl-3-(trifluoropentyl)dioxirane, 3). Specifically, limitations of this
method include low temperature (4 °C), long reaction time (72
hours), the use of HFIP (hexafluoro-2-propanol) as co-solvent and
iterative addition of reagents to achieve satisfactory yield.14
methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow
platform allows the in situ generation of TFDO gas and its rapid
reactivity toward tertiary and benzylic Csp3-H bonds. The process
exhibits a broad scope and good functional group compatibility (28
Photochemistry
Organometallic chemistry
examples,
8 - 99 %). The scalability of this methodology is
Chen-White catalyst (5 mol%)
AcOH, H2O2
O2, TBADT (2-5 mol%)
365 nm LED
demonstrated on 2.5 g scale oxidation of adamantane.
MeCN, RT, 30 min
MeCN/ HCl (1M), RT, 45 min
The development of new and powerful synthetic methodology for
direct Csp3-H oxidation of un-activated methylene and methine
systems is of considerable importance.1 More specifically, the
site-specific Csp3-H hydroxylation of valuable scaffolds bearing
further functional groups is of major current interest for both
academia and industry.2 Over the past decade, direct Csp3-H
oxidation has been investigated using transition metal complexes
(Ru, Fe, V, Co, Mn or Ir)3 and some organocatalysts4.
Unfortunately, specific challenges including cost of the catalyst,
complex synthetic design of the ligand, use of directing group,
harsh reaction conditions, functional group incompatibility and site
selectivity remain as major drawbacks to the field (Figure 1).5
Nowadays, new chemical methods such as chemo-catalytic
approaches,6 electrochemical oxidation7 or photochemical Csp3-H
hydroxylation in pure oxygen8 or using hydrogen peroxide9 offer
alternative approaches (Figure 1). Nevertheless, regio-selective
and stereo-selective oxidation of an un-activated Csp3-H bond
remains a challenging task.
or
RVC anode/Ni foam cathode
quinuclidine, Me4N.BF4, HFIP
1,1,1-trifluoroacetone (4)
NaHCO3 (1.5 M), Oxone (0.5M)
DCM/H2O, RT, <1.5 min
MeCN, 25 mA/mmol, RT, 3-21h
This study: Dioxirane generated oxidation of
activated and un-activated Csp3-H bond
Electrochemistry
Figure 1. Methods for the direct Csp3-H oxidation.
In recent years, continuous flow technologies have been
recognized as a powerful tool to generate in situ hazardous
reagents or unstable intermediates with an efficient mass and
heat transfer.15 Additionally, it offers other advantages in making
procedures more reproducible and scalable. With an interest in
further developing methods for Csp3-H oxidation, we sought to
develop an alternative direct Csp3-H oxidation using TFDO in a
rapid and safer continuous flow process.
Among existing Csp3-H oxidation strategies, the use of
strong oxidants such as dimethyldioxirane (DMDO, 1)10 and
methyl(trifluoromethyl)dioxirane (TFDO, 2)11, have a long history
of success on complex systems without the need for a directing
group. Regrettably, their use has been limited due to a long list of
disadvantages such as instability, volatility, laborious preparation,
safety requirements and scale limitations.12 Moreover, the use of
dioxirane for the direct Csp3-H oxidation requires precise control of
the temperature below 10 °C, a large excess of reagent and long
reaction times.13 For all these reasons, dioxiranes have only been
deployed on batch mode and limited to small scale application.
Recently, Hilinski published a catalytic batch method for the in situ
formation of a less volatile but expensive reactive dioxirane (3-
A flow set up was investigated using adamantane (5a) as a
model substrate for the Csp3-H oxidation (Table 1). A solution of
adamantane (0.05 M) in dichloromethane containing 1,1,1-
trifluoroacetone (4, 1.0 M) was mixed with an aqueous solution of
NaHCO3 (1.5 M) and Oxone (0.5 M) in a sequential manner in
order to generate in situ the TFDO. The desired 1-adamantanol
(6a) can be efficiently obtained with a conversion of 93 % (Table
1, Entry 1) in an optimal residence time of 80 seconds. A better
mass transfer of the reaction mixture was observed with the use
of a coil reactor packed with glass beads (425 - 600 µm diameter)
compared to the conventional reactor (Table 1, Entry 2 vs. Entry
1). Decreasing the amount of the 1,1,1-trifluoroacetone (4, 0.5 M)
or increasing the quantity of adamantane (5a, 0.1 M) have,
respectively, an negative effect on the conversion (60 %, Table 1,
Entry 3 vs. Entry 1) and (62 %, Table 1, Entry 4 vs. Entry 1). An
excess of NaHCO3 (1.5 M) compared to Oxone (0.5 M) is required
to reach higher conversion (Table 1, Entry 5 vs. Entry 1), whereas
decreasing their flow rates showed inferior results (Table 1, Entry
6 vs. Entry 1). Moreover, the reactions proceeded at room
temperature, and under pressure, rendering the reaction
conditions simple and more reliable than in batch mode12d (Table
1, Entry 7 vs. Entry 1). Reducing the residence time to 32 seconds,
led to a lower conversion (79 %) (Table 1, Entry 8 vs. Entry 1).
[a]
Dr Mathieu Lesieur, Dr Jérôme Jacq, Dr Christophe Genicot and Dr
Patrick Pasau
UCB Biopharma, Avenue de l’industrie, 1420 Braine l’Alleud,
Belgium
E-mail: patrick.pasau@ucb.com
[b]
[c]
Dr Claudio Battilocchio, Dr Ricardo Labes and Pr Steven V. Ley
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, United Kingdom
E-Mail: svl1000@cam.ac.uk
Dr Claudio Battilocchio
Syngenta Crop Protection AG, Schaffhauserstrasse, CH-4332 Stein,
Switzerland
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10.1002/chem.201805657
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Finally, the use of the less volatile 1,1,1-trifluorobutanone (7) did
not provide a substantial improvement on the reaction outcome
(Table 1, Entry 9 vs. Entry 1) and no reaction was observed with
acetone as a source of dioxirane due to the formation of a
precipitate (Table 1, Entry 10 vs. Entry 1).
First of all, a panel of adamantane derivatives bearing various
substituents such as -H (5a), -Br (5b), -CN (5c), -OH (5d) and -
NHBOC (5f) was investigated. The Csp3-H oxidation was achieved
exclusively at the more sterically hindered Csp3-H site in moderate
to excellent yields (6d, 29 %), (6c, 54 %), (6b, 63 %), (6f, 64 %)
and (6a, 99 %).
Table 1. Optimization for the Csp3-H oxidation of adamantane (5a).
4 (1.0M)
in CDCl3
5 mL
loop
0.33 mL.min-1
4 (1.0M)
in DCM
5 mL, 25°C
glass beads reactor
0.33 mL.min-1
5a (0.05M)
aqueous phase
in DCM
5 mL, 25°C
glass beads reactor
Zaiput
NaHCO3 (1.5M)
1.67 mL.min-1
1.67 mL.min-1
in water
Residence time
80 seconds
75 psi
NaHCO3 (1.5M)
2
Oxone (0.5M)
in water
1.67 mL.min-1
1.67 mL.min-1
in water
Residence time
80 seconds
6a
Oxone (0.5M)
in water
Entry[a]
Deviation from above
Conv (%)[b]
1
2
/
93
87
No glass beads reactor
1,1,1-trifluoromethylketone
3
60
(4, 0.5 M)
4
5
Adamantane (5a, 0.1 M)
62
43
NaHCO3 (0.5 M)
Flow rate NaHCO3 and Oxone
at 0.333 mL.min-1
6
58
Scheme 1. Production of TFDO in flow.
7
8
5°C
58
79
Reactor volume = 2 mL
In the same way, trans-decaline (5g) and trans-hydrindane
(5h) afforded the Csp3-H oxidation products 6g and 6h at the
tertiary position with an isolated yield of 74 % and 98 %,
respectively. Interestingly, product of tertiary hydroxylation
remote position are strongly preferred over proximal oxidable
position. For example, Csp3-H oxidation products of 5i can be
obtained with an isolated yield of 68 % (6i) and 7 % (6i’) with a
ratio of (91:9) toward the remote Csp3-H bond. Lower yields were
obtained for substrates (5j) and (5k) bearing only one hindered
proximal tertiary carbon (6j, 21 % and 6k, 8 %). Importantly, the
retention of configuration was achieved on the L-menthyl-acetate
scaffold (5l). As previously described, the Csp3-H oxidation
occurred, preferentially, at the two tertiary remote positions with
an isolated yield of 18 % (6l) and 21 % (6l’), without racemization,
suggesting no deviation from the current mechanistic
understanding of dioxirane hydroxylation.18 Product 6m can be
selectively oxidized on the tertiary position with an isolated yield
of 31 %. Notably, increasing the residence time and the
concentration of 1,1,1-trifluoroacetone (4) by a factor of 2 showed
higher isolated yield in the desired product (75 %). Activated
methylenes, such as benzylic Csp3-H bonds bearing cyclohexyl
(5n) and cyclobutyl (5o) ring can be oxidized, at the tertiary
carbon, with an isolated yield of 42 % and 51 %, respectively.
Regio-selectivity was investigated with substrate (4-
methylcyclohexyl)benzene (5p) bearing an activated benzylic
position and an un-activated Csp3-H bond.
1,1,1-trifluorobutanone
9
67
<5
(7, 0.5 M)
10
acetone
[a] Reaction condition: 0.25 mmol scale reaction. Reaction carried out at 0.05
M concentration of 5a and 1.0 M of 4 in DCM, 1.5 M concentration of NaHCO3
in water and 0.5 M concentration of Oxone in water, 5 mL glass beads reactor,
residence time: 80 seconds, 25 °C. [b] Conversion determined by 1H NMR,
average of two reactions.
To confirm the in situ formation of TFDO (2) in the reaction,
a solution of CDCl3 containing 1,1,1-trifluoroacetone (1.0 M) was
mixed with an aqueous solution of NaHCO3 (1.5 M) and Oxone
(0.5 M) using the flow set up depicted in Scheme 1. After a
continuous phase separation, using the Zaiput unit, and collection
of the organic phase, 19F and HMBC H/13C NMR spectroscopy
1
revealed the formation of TFDO (2) (19F NMR = -87.3 ppm).16
Furthermore, titration of the organic phase, revealed a molarity of
TFDO (2) around 0.05 M (5 % yield)17,18 This results emphasise
the benefit of the flow procedure to achieve a safe, faster and
higher TFDO concentration than reported in batch mode (2 %
yield).12d
With the optimized conditions in hand, the scope for this
transformation was explored as shown in Scheme 2. As expected,
investigations of the substrate scope of this new flow method
revealed a strong preference for hydroxylation of tertiary centers.
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10.1002/chem.201805657
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5 mL
loop
4 (2.0M)
in DCM
0.33 mL.min-1
5 (0.05M)
in DCM
5 mL, 25°C
glass beads reactor
75 psi
NaHCO3 (1.5M)
1.67 mL.min-1
1.67 mL.min-1
in water
Residence time
80 seconds
6
Oxone (0.5M)
in water
Scheme 2. Substrate scope for the direct Csp3-H oxidation using TFDO.[a] [a] Reaction conditions: 0.25 mmol scale reaction. Reaction carried out at 0.05 M
concentration of 5 and 2.0 M of 4 in DCM, 1.5 M concentration of NaHCO3 in water and 0.5 M concentration of Oxone in water, 5 mL glass beads reactor, residence
time: 80 seconds, 25 °C. Isolated yield after chromatography, average of two reactions. [b] Reaction carried out at 0.05 M concentration of 5 and 4.0 M of 4 in DCM,
1.5 M concentration of NaHCO3 in water and 0.5 M concentration of Oxone in water, 20 mL helicoidal static-mixer coil reactor, residence time: 160 seconds, 25 °C.
[c] 0.125 mmol scale reaction. Reaction carried out at 0.025 M concentration of 5 and 2.0 M of 4 in DCM. [d] 1.25 mmol scale reaction. Reaction carried out at 0.025
M concentration of 5 and 4.0 M of 4 in DCM. [e] 5.0 M of 4 in DCM.
The benzylic position was preferentially oxidized with an
isolated yield of 27 % toward the un-activated methine position
(6p’, 9 %) with a ratio of (6p:6p’ = 3:1). Interestingly, indole
derivative bearing a sulfonyl chloride functionality (5q) can be
tolerated. Hydroxylation reaction occurred on the benzylic
position with an isolated yield of 24 %. The reaction was also
achieved on a 1.25 mmol scale reaching an isolated yield of 56 %
with an increase of the 1,1,1-trifluoroacetone (4) by a factor of 2.
Secondary Csp3-H bond oxidation was evaluated using few
substrates bearing un-activated and activated positions. The
reaction on ibuprofen methyl ester (5r) led to oxidation on both
benzylic and tertiary Csp3-H in a 3:2 ratio favouring the tertiary
position. In the case of protected phthalimide-methyl ester
scaffold bearing a cyclohexyl ring (5s), a mixture (1/1) of two
regio-isomer ketone 6s and 6s’ was obtained in low yield 8 % in
both cases. The excellent potential of TFDO to oxidize secondary
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alcohols was also demonstrated with camphor (95 %, 6t) and on
1-adamantanone (98 %, 6u). In general, a variety of functionalities
are well tolerated under the reaction conditions. For example,
ester, nitrile, carbamate, phthalimide, ketone and sulfonyl chloride
remain intact during the reaction, except for non-protected
primary amine (6e) which are oxidized to the nitro derivative,
quantitatively which is an interesting reaction in its own right.
Natural products such as sclareolide (5v) and cholestane (5w)
bearing multiple oxidative sites were studied. In the case of the
sclareolide, the Csp3-H oxidation was selectively observed at the
secondary carbon position C2 whereas for cholestane the
transformation occurred preferentially at the terminal tertiary
position.
Acknowledgements
Acknowledgements Text The authors gratefully acknowledge the
Walloon region (Belgium) – DG06 (Convention n°7240) for
funding.
Keywords: oxidation • Flow • TFDO • dioxirane • Oxone
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Figure 2. Retrosynthetic step for the synthesis of Adapalene18
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steady state in standard conditions provided the desired product
6a with similar yield (96 %) to the smaller scale reaction with this
particular reactor design (Scheme 3).
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6.7 mL.min-1
4 (1.5M)
in DCM
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in water
2.7 mL.min-1
5a (0.05M)
in DCM
2 X 20 mL, 25°C
helicoidal static-mixer reactor
(2.5 g, 18.3 mmol)
NaHCO3 (1.5M)
75 psi
13.3 mL.min-1
13.3 mL.min-1
in water
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Residence time
80 seconds
6a, 96% yield
Oxone (0.5M)
in water
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In summary, the development of
a
new general
trifluoromethylated dioxirane-mediated Csp3-H oxidation method
has been enabled in a fast, efficient and simple fashion through a
continuous flow process. This practical method employs
inexpensive reagents and can be applied to a wide panel of
substrates bearing a large range of functionalities. The flow
conditions provide a scalable and safer solution for transforming
simple aliphatic compounds to complex materials.
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[18] See Supporting Information for experimental details.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Faster, Safer, Scalable: A
continuous flow concept
allowed the direct Csp3-H
oxidation of activated and
un-activated aliphatic chain
via in situ formation of
TFDO. The reported
Mathieu Lesieur, Claudio Battilocchio, Ricardo Labes, Jérôme
Jacq, Christophe Genicot, Steven V. Ley,* and Pasau Patrick*
in-situ
or
Page No. – Page No.
25°C, 80 seconds
Direct oxidation of Csp3-H bonds using in-situ generated
trifluoromethylated dioxirane in flow
✓
✓
✓
Fast
Safer
Scalable
28 examples (8 - 99%)
procedure depicted a broad
scope and good functional
group compatibility (28
examples, 8-99 %).
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