Visible-Light-Mediated Iodoperfluoroalkylation of Alkenes in Flow and Its Application to the Synthesis of a Key Fulvestrant Intermediate

Article abstract of DOI:10.1021/acs.orglett.9b01992

Two efficient continuous flow iodoperfluoroalkylation methods are described: using 0.05 mol % perylene diimide (PDI) photocatalyst under 450 nm irradiation or substoichiometric triethylamine under 405 nm irradiation. These methods enable dramatically elevated productivity versus batch processes. The triethylamine-mediated method is explored mechanistically and in substrate scope. The gram-scale synthesis of an active pharmaceutical ingredient side chain is also reported in flow, via a photochemical iodoperfluoroalkylation followed by hydrogenolysis.

Full text of DOI:10.1021/acs.orglett.9b01992

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Iodoperfluoroalkylation of Alkenes in Flow
and Its Application to the Synthesis of a Key Fulvestrant
Intermediate
Cristian Rosso,†,§ Jason D. Williams,†,‡ Giacomo Filippini,§ Maurizio Prato,§,∥,⊥
and C. Oliver Kappe*,†,‡
†Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
‡Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE),
Inffeldgasse 13, 8010 Graz, Austria
§Department of Chemical and Pharmaceutical Sciences, INSTM UdRTrieste, University of Trieste, Via Licio Giorgieri 1, 34127
Trieste, Italy
∥
̀
Nanobiotechnology Laboratory, CIC biomaGUNE, San Sebastian, Spain
⊥Ikerbasque, Basque Foundation for Science, Bilbao, Spain
S
* Supporting Information
ABSTRACT: Two efficient continuous flow iodoperfluoro-
alkylation methods are described: using 0.05 mol % perylene
diimide (PDI) photocatalyst under 450 nm irradiation or
substoichiometric triethylamine under 405 nm irradiation. These
methods enable dramatically elevated productivity versus batch
processes. The triethylamine-mediated method is explored mecha-
nistically and in substrate scope. The gram-scale synthesis of an
active pharmaceutical ingredient side chain is also reported in flow,
via a photochemical iodoperfluoroalkylation followed by hydro-
genolysis.
sensitizer (PDI, Scheme 1), in extremely low loading (0.05
luorination reactions have received significant interest in
Frecent years as a means to prepare high-value organic mol % = 500 ppm), under blue light irradiation.10
compounds.1 As a consequence of modified physicochemical
In order to transform the resulting perfluorinated com-
pounds 3 into suitable derivatives for the aforementioned
applications, a preparative scale process is necessary. Photo-
chemical transformations often have limited scale-up potential,
because they can be hampered by significant light attenuation,
as the size of a reaction vessel increases (as described by the
Beer−Lambert law).11 Continuous flow photochemistry can
alleviate this limitation by using a short irradiated path length,
which, when combined with the correct light source, can
improve photochemical efficiency, leading to shorter reaction
times and higher productivity.12 Many examples of other
photochemical fluorination processes have been demonstrated
in flow,13 offering efficient and selective reactivity, when
compared to their batch equivalents.
features, fluorinated molecules are broadly employed in
medicinal chemistry, agrochemistry, and materials science.2
Iodoperfluoroalkylation of olefins is a classical strategy for
accessing this class of compounds.3 Since the first examples in
the 1950s,4 atom-transfer radical addition (ATRA) method-
ologies have been studied using both thermal and photo-
chemical activation. In general, thermal activation requires
harsh reaction conditions5 and/or potentially explosive radical
initiators.6
With the recent resurgence of synthetic organic photo-
chemistry, a multitude of mild iodoperfluoroalkylation
protocols have been developed.3 In most cases these have
employed the following: expensive Ru/Ir/Cu metal com-
plexes;7 organic dyes, often in relatively high loading;8
a
Despite the industrial importance of the corresponding
products, a limited number of alkene perfluoroalkylations have
been performed in flow,14 and to the best of our knowledge,
none of these methods make use of UV or visible light
irradiation. Herein we report and exemplify two complemen-
significant excess of the perfluoroalkyl iodide reagent; or
several additives, under UV or visible light irradiation.9
A
further advance within this field involves metal-free photo-
catalytic systems capable of working under visible light
irradiation in low loadings. Recently, we reported an efficient
method for the iodoperfluoroalkylation of alkenes, driven by
the photochemical activity of a simple perylene diimide
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01992
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Iodoperfluoroalkylation of Alkenes in Batch and
Table 1. Flow Photochemical ATRA Optimization Studies
Flow
b
entry PDI wavelength (nm) concn (M) 2a (equiv) yield (%)
1
2
3
4
5
6
7
8
Y
N
Y
Y
Y
450
450
610
540
450
450
422
405
405
405
405
405
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.25
2
2
2
2
1.2
1.2
2
2
2
95
0
0
88
83
95 (90)
34
94
0
82
92
98 (95)
Y
N
N
N
N
N
N
c
9
10
11
1.2
1.2
1.2
d
d
12
a
Reaction conditions: 1-octene (1a), perfluorohexyl iodide (2a, 1.2 or
2 equiv), Et3N (0.2 equiv) and PDI (0.05 mol %) in CH3CN/
CH3OH (4:3). Reactions were performed using a 5 mL sample loop
b
and a 5 min residence time (0.56 mL/min). Yield was determined by
tary continuous flow iodoperfluoroalkylation protocols: using
PDI as a photocatalyst under blue light irradiation (450 nm)
or through the use of inexpensive triethylamine additive under
shorter wavelength blue light irradiation (405 nm, Scheme 1).
Initial studies focused on the translation of our previously
reported process10 from batch to flow, using a commercially
available plate-based photoreactor (Corning Advanced-Flow
Lab Photo Reactor, 2.8 mL volume).15 The previous system,
which used sodium ascorbate as a substoichiometric electron
donor, was unsuitable for flow processing, due to its
heterogeneity. Accordingly, it was decided to employ triethyl-
amine (Et3N) as an alternative organic-soluble reductant.
Preliminary optimization (Table 1) was performed on the
iodoperfluoroalkylation of 1-octene (1a) by perfluorohexyl
iodide (2a, 2 equiv) in the presence of PDI (0.05 mol %) as
the photocatalyst and Et3N (0.2 equiv).16
Under blue light irradiation (450 nm) the ATRA product
3aa was observed in 95% yield, in a residence time of only 5
min (entry 1). A series of control experiments confirmed that
no reaction occurs in the absence of PDI (entry 2) nor when
using 610 nm (red) light (entry 3). However, green light (540
nm) was found to be marginally less effective in promoting the
reaction, resulting in an 88% yield of 3aa (entry 4). Reducing
the loading of perfluorohexyl iodide (2a, 1.2 equiv) lowered
the yield of 3aa to 83% (entry 5), but this was restored to its
original level (entry 6) by increasing the concentration to 0.2
M. Under these conditions, a 90% yield of the ATRA product
3aa was isolated, translating to a high throughput of 6.1 g h−1.
Upon undertaking a more detailed screen of irradiation
wavelengths, reactivity was observed even in the absence of
PDI, when using irradiation wavelengths of 422 nm or
shorter.16 This result can be attributed to the photoactivation
of perfluoroalkyl iodide 2a by Et3N, through the formation of a
halogen-bonded electron donor−acceptor (EDA) com-
plex.9a,c,17 Such complexes absorb most strongly in the deep
UV region, but can often be exploited at UVA or even some
visible wavelengths.
GC-FID vs n-dodecane as internal standard. Isolated yield is shown in
c
parentheses. Reaction was performed in the absence of Et3N.
d
Reaction was performed using only CH3CN as solvent.
Encouraged by this scenario, a second iodoperfluoro-
alkylation protocol was optimized under blue/purple light
irradiation, in the absence of any photocatalyst. Primary
investigations examined the wavelength-dependence, high-
lighting a complete lack of reactivity at 450 nm (entry 2),
moderate response at 422 nm (34% yield, entry 7), and finally
a 94% yield of 3aa at 405 nm (entry 8). A control experiment
ascertained the need for the amine additive, since no ATRA
product 3aa was detected in the absence of Et3N (entry 9).
Reducing the loading of perfluorohexyl iodide 2a (1.2 equiv)
decreased the yield of 3aa to 82% (entry 10), but was partially
restored by changing the solvent to only CH3CN (92%, entry
11). Finally, almost quantitative GC yield of 3aa was observed
by increasing the reaction concentration to 0.25 M, resulting in
a 95% isolated yield (entry 12). Thanks to the increased
reaction concentration allowed by this protocol, a further
increase in productivity was accessed, versus the PDI-catalyzed
method (7.6 g h−1 vs 6.1 g h−1). For this reason, and the
simplified reaction composition, we opted to further explore
this method under visible light (405 nm) irradiation. However,
in cases with light-sensitive substrates, the PDI-catalyzed
method may prove advantageous, since it allows reaction at
less energetic wavelengths, even down to green light (540 nm).
The synthetic potential of the catalyst-free flow procedure
was then examined (Scheme 2), demonstrating its generality
with respect to both the olefin (1) and perfluoroalkyl iodide
components (2). A standard residence time of 5 min was
found to be suitable for most alkene substrates when paired
with the highly reactive perfluoroalkyl iodide 2a. Less reactive
alkenes 1b and 1d required elongated residence times to reach
full conversion, whereby 3ba was isolated in a moderate 52%
yield as a 3:1 mixture of diastereomers. Diphenylacetylene
B
DOI: 10.1021/acs.orglett.9b01992
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
to prevent gassing out. These reagents warranted a larger
excess (4 equiv), but also afforded their corresponding
products with various alkenes (3ad to 3ie) in good to
excellent yields.
Scheme 2. Flow Photochemical ATRA Reaction Scope
For further mechanistic insight, we sought to confirm the
halogen-bonding activation of this ATRA reaction system. A
series of 19F NMR experiments were performed using different
ratios of perfluorohexyl iodide (2a) and Et3N in CD3CN,
whereby a Job plot analysis verified the formation of a 1:1
halogen-bonded complex.9a,c,17 Previous reports have implied
that involvement of solvent (THF) is required,9a which may
also be the case in our system. In addition, an association
constant of 1.57 M−1 was determined in CD3CN.16 This value
is consistent with previously reported halogen bond complexes
between perfluoroalkyl iodides and Et3N in Lewis basic
solvents.18 Moreover, the kinetic profile of the model reaction
revealed an induction period of at least 30 s, likely
corresponding to the time taken to cleave enough C−I
bonds for effective radical chain conjugation.16
Finally, we envisaged that this protocol could be used in the
preparation of a perfluorinated side chain, for active
pharmaceutical ingredient (API) preparation.19 In particular,
breast cancer drug Fulvestrant20 contains a perfluorinated side
chain, synthesized from intermediate alcohol 4 (Scheme 3),
a
Scheme 3. Fulvestrant Side Chain Preparation
a
Reaction conditions: alkene or alkyne (1, 1 equiv), perfluoroalkyl
iodide (2a−c: 1.2 equiv, or 2d−e: 4 equiv), and Et3N (0.2 equiv) in
CH3CN (0.25 M). Reactions were performed on 1.25 mmol (5 mL)
scale in 5 min residence time, unless otherwise specified. E/Z ratio
a
1
and d.r. determined by H NMR spectroscopy of the crude reaction
Reaction conditions: (a) as specified for 3ee in Scheme 2; (b) crude
mixture.
mixture from previous transformation, sparged with argon, added
Et3N (2 equiv) and diluted to 0.1 M in CH3CN, 50 °C, 20 bar
pressure, 1 mL/min flow rate; (c) crude mixture from previous
transformation, added benzoyl chloride (5 equiv) and pyridine (8
derivative 1h proved to be completely unreactive, as has been
observed previously for styrene-type substrates in ATRA
reactions.7a
b
equiv), stirred at rt for 16 h. Isolated yield (1.23 g) over three steps.
A slightly shorter perfluorinated chain (iodide 2b) provided
products 3ab and 3cb in synthetically useful yields. However,
the sterically hindered iodide 2c required longer residence
times to achieve good yields in both examined cases (3ac and
3dc). Furthermore, as the perfluoroalkyl chain on iodide
substrate 2 was shortened further, longer reaction times were
required due to the less polarized (and therefore stronger) C−
I bond. Gaseous iodide reagents 2d and 2e were used as
solutions in CH3CN and a small back pressure of 3 bar was
applied to the reactor (using a Zaiput back pressure regulator)
which, in turn, can be reached by hydrogenation/dehalogena-
tion (hydrogenolysis) of product 3ee or 3ie. During
commercial route development for Fulvestrant, the supply
and cost of intermediate 4 were noted as a main concern,19c
which highlights the need for a scalable synthesis, such as this
flow methodology.
The required dehalogenation reaction was carried out in a
continuous manner using an H-Cube Pro reactor equipped
with a platinum oxide hydrogenation catalyst cartridge. For this
manipulation, the crude mixture from the photochemical
C
DOI: 10.1021/acs.orglett.9b01992
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactor was diluted to 0.1 M (to avoid precipitation), sparged
with argon (to remove the excess of perfluoroalkyl iodide), and
additional Et3N (2 equiv) was added. Complete conversion of
3ee into the deiodinated product 4 was observed in less than 1
min residence time (50 °C, 20 bar). The obtained
pentafluoropentanol (4) is the desired side chain of
Fulvestrant,19c but due to its volatility, it was decided to
functionalize this intermediate further as its benzoyl ester 5 for
isolation. To demonstrate the scalability of this protocol, a
scale-out was successfully performed, allowing gram-scale
isolation of 5 (1.23 g, 73% yield over three steps), with a
single chromatographic purification step.
In summary, we report two complementary continuous flow
methods for the photochemical iodoperfluoroalkylation of
alkenes, with productivity up to 7.6 g h−1. The ATRA reaction
can be achieved under irradiation at 405 nm, using
substoichiometric loading of an inexpensive amine base.
Alternatively, reaction can also be achieved by irradiation at
a longer wavelength (450 nm), in the presence of a low loading
of PDI dye. In situations with light-sensitive substrates, this
method could also prove to be of importance. Mechanistic
insights were gained regarding the halogen-bond photo-
activation of perfluoroalkyl iodides by Et3N. Finally, a gram-
scale preparation of a fluorinated API intermediate was
demonstrated in two flow steps from inexpensive starting
materials.
the Corning Advanced-Flow lab photoreactor used in this
study in Graz.
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ACKNOWLEDGMENTS
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The CCFlow Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Science, Research and Economy (BMWFW), and
by State of Styria (Styrian Funding Agency (SFG). C.R. thanks
European Social Fund, Operational Programme 2014/2020 -
Friuli-Venezia Giulia (Regional Code FP1799043001) for a
fellowship. Part of this work was performed under the Maria de
Maeztu Units of Excellence Program from the Spanish State
Research Agency − Grant No. MDM-2017-0720. The authors
gratefully acknowledge Corning SAS for the generous loan of
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