Four-Component Photoredox-Mediated Azidoalkoxy-trifluoromethylation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b02152

We report herein an efficient four-component photoredox-catalyzed reaction. Under the optimized conditions using [Ru(bpy)₃(PF₆)₂] as the photocatalyst, a wide range of terminal and internal alkenes can efficiently undergo

Full text of DOI:10.1021/acs.orglett.9b02152

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Four-Component Photoredox-Mediated Azidoalkoxy-
trifluoromethylation of Alkenes
‡
§
‡
Guillaume Levitre,† Guillaume Dagousset,‡ Elsa Anselmi, Beatrice Tuccio, Emmanuel Magnier,
́
,†
́
and Geraldine Masson*
†
́
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite Paris-Sud, Universite Paris-Saclay, 1, av. de la Terrasse,
Gif-sur-Yvette 91198 Cedex, France
‡
́
Institut Lavoisier de Versailles, UMR 8180, Universite de Versailles-Saint-Quentin, Versailles 78035 Cedex, France
§
́
Aix-Marseille Universite-CNRS, Institut de Chimie Radicalaire (UMR 7273), Marseille F-13397 Cedex 20, France
S
* Supporting Information
ABSTRACT: We report herein an efficient four-component photoredox-catalyzed reaction. Under the optimized conditions
using [Ru(bpy)3(PF6)2] as the photocatalyst, a wide range of terminal and internal alkenes can efficiently undergo azidoalkoxy-
trifluoromethylation in the presence of Umemoto’s reagent, carbonyl compound, and TMSN3, giving rise to original and highly
complex molecules in a single operation.
he trifluoromethyl (CF3) group is an important structural
motif in a large number of pharmaceuticals, agro-
trifluoromethylation (Scheme 1).11 Based on this precedent
and our previous work,6e,j,7b,8e,9c,12 we questioned whether a
four-component reaction, in which both carbonyl and alkene
T
chemicals, and organic materials. Many research efforts have
been made to develop new efficient methods to incorporate
the CF3 group in the past years.1 Among the various
approaches, the photocatalyzed multicomponent trifluorome-
thylation reactions (PMCTRs) of alkenes have emerged as a
powerful and ecofriendly methodology from the viewpoint of
safety, simplicity, and efficiency.2−4 In addition, this strategy
offers access to diverse trifluoromethylated compounds in a
single step with high synthetic efficiency from three simple and
easily available reagents. In such a process, two bonds are
formed with the simultaneous incorporation of the CF3 group
with hydrogen,5 oxygen,6 nitrogen,6e,7 halogen,8 or carbon6e,9
into the alkenes. Despite the diversity, as far as we know, there
are few examples7a,10 in which more than three components
have been incorporated into the alkenes in order to generate
more elaborate trifluoromethylated products. The develop-
ment of such photocatalyzed multicomponent reactions is a
challenging task since one has to consider not only the
reactivity match of the components but also the reactivity of
the intermediates generated in situ and their compatibility.
Our group has previously developed a novel three-
component photoredox-mediated synthesis of CF3-containing
phthalans through an initial nucleophilic addition of azide to
vinylbenzaldehydes and a subsequent intramolecular oxy-
Scheme 1. Synthetic Approach of Four-Component
Azidoalkoxy-Trifluoromethylation of Alkenes
Received: June 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02152
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
functionalities would not be linked together, could be achieved.
This PMCTR might provide a facile route to highly
functionalized azidoalkoxy-trifluoromethylated compound 5
through a sequence of C−CF3, C−N, and C−O bond-forming
processes. Although conceptually appealing, the execution of
this four-component reaction is quite challenging. Indeed,
TMSN3 has a high propensity to trap the β-trifluoromethylated
carbocation 11 to form azidotrifluoromethylated compounds
10.1k,3,6e,7b,e,13 In addition, the α-azido alcohol which is
reversibly generated from aldehyde and an azide anion is a
short-lived species.14 For the reaction to succeed, the trapping
of 11 by the in situ generated α-azido alcohol has to occur at a
much faster rate than its trapping by the azide ion.
Having identified the optimal conditions, we next inves-
tigated the scope of this four-component azidoalkoxy-
trifluoromethylation by varying the structure of carbonyl
components. As shown in Scheme 2, linear aldehydes 7b−e
a b
,
Scheme 2. Scope of Carbonyl Compounds
To test the feasibility of the proposed four-component
reaction, TMSN3 (2, 2 equiv) was added to a mixture of 2-
vinylnaphthalene (8a, 1 equiv) and phenylpropionaldehyde
(7a, 1 equiv) in DCM, in the presence of Ru(bpy)3(PF6)2 4
under blue LED light (Table 1). Our initial experiment failed,
Table 1. Survey of Reaction Conditions for the
Photocatalyzed Azidoalkoxy-Trifluoromethylation of 7a
a
b
b
entry
y equiv of 2
z equiv of 7a
yield 9a (%)
yield 10a (%)
1
2
3
4
5
2
2
3
5
5
5
5
5
5
5
1
3
4
6
5
6
6
6
6
6
0
65
25
37
10
30
37
35
-
-
36
19
61
39
18
20
-
a
c
e
General conditions: 3 (0.15 mmol), 8a (0.10 mmol), 2 (0.50 mmol),
7 (0.60 mmol), and 4 (0.05 equiv) in distillated CH2Cl2 (2.0 mL)
6
d
e
7
b
f
irradiated under blue LEDs at rt for 2.5 h. Yields refer to
8
g
chromatographically pure products. The dr’s were determined by
9
-
14
c
d
1H NMR analysis in all cases. With 1.5 equiv of 2. Reaction
performed with 1 mmol of 8a.
h
10
13
a
General conditions: 3 (0.15 mmol), 8a (0.10 mmol), 2 (0.y mmol),
7a (0.z mmol), and 4 (0.05 equiv) in distillated CH2Cl2 (2.0 mL)
irradiated under blue LEDs at rt for 2.5 h. Yields referred to
b
were all compatible, leading to the respective adducts in decent
yields (up to 77% yield) with moderate diastereoselectivities.
β-Branched aldehydes participated effectively in the four-
component reaction, leading to compound 9h in 68% yield,
while α-branched aldehydes were much less reactive (9i, 37%
yield). It is also worth noting that the process was compatible
with aldehydes bearing functional groups such as halogen or
silyl ether, affording the expected products 9f and 9g in 52 and
51% yields, respectively.15 However, the four-component
reaction with acetone 7j as a partner did not proceed, and
only the three-component product 10a was observed. We
found after further optimization that the three-component
undesired reaction was minimized when the amount of
TMSN3 was reduced to 1.5 equiv. Pleasingly, the reaction
was scaled up without any decrease in the yield. However,
hindered ketones such as pentan-3-one and cyclobutanone led
to much lower yields (9k and 9l) with concurrent increase of
10a.16
chromatographically pure product and 56:44 dr were determined by
c
d
1H NMR analysis. With 10 mol % of SnCl2. With 1 mol % of TfOH.
e
f
Formation of gem-diazide 10% yield. Without photocatalyst.
Without light. With Umemoto triflate salt.
g
h
affording only the azidotrifluoromethylated three-component
product 10a in 65% yield. Gratefully, when 2 equiv of TMSN3
and 3 equiv of aldehyde 7a were employed, we did isolate the
four-component adduct 9a as a mixture of two diaster-
eoisomers (36% yield), together with 10a (25% yield). Based
on this encouraging result, we speculated that the yield could
be further improved by adjusting the stoichiometry of TMSN3
and phenylpropionaldehyde (7a). Indeed, after a careful
screening, 5 equiv of TMSN3 and 6 equiv of 7a were optimal
for obtaining satisfactory yield of the desired four-component
product 9a. In this condition, the formation of three-
component product 10a was minimized (10%). Interestingly,
when a catalyst such as SnCl214b or TfOH14g was added, lower
yield of 9a was obtained (entries 6−7).
We next examined the scope of this four-component
reaction by varying the structure of alkenes (Scheme 3). A
variety of substituents such as bromine, chlorine, methyl, tert-
B
DOI: 10.1021/acs.orglett.9b02152
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of Alkene Compounds
Scheme 4. Control Experiments
Umemoto’s reagent 3, a slightly better conversion was noted.
Also, when the preformed trimethylsilylated azohydrin 12d14c
prepared by the reported procedure was used, the expected
azidoalkoxytrifluoromethylated product 9d was not formed,
and only a complex mixture was obtained. These results
suggest that the four-component reaction is unlikely to
proceed via a nucleophilic addition of 12 to 11. On the basis
of the above results as well as other reports,2−11 a plausible
reaction mechanism is shown in Scheme 5. First, irradiation
Scheme 5. Plausible Reaction Mechanism
a
General conditions: 3 (0.15 mmol), 8 (0.10 mmol), 2 (0.15 mmol),
7j (0.60 mmol), and 4 (0.05 equiv) in distillated CH2Cl2 (2.0 mL)
b
irradiated under blue LEDs at rt for 2.5 h. Yields refer to
chromatographically pure products. The dr’s were determined by
c
1H NMR analysis in all cases. Reactions performed with TMSCN
(0.15 mmol) as a nucleophile.
butyl, and acetate at different positions of the aromatic ring of
styrenes were tolerated, affording the expected four-compo-
nent adducts 9m−s in up to 67% yield. 1,1-Disubstituted
alkene was also compatible with this transformation, providing
the desired trifluoromethylated tertiary azido-ether 9s in 44%
yield. Remarkably, this process could also be successfully
extended to internal alkenes. For instance, trans-β-methylstyr-
ene, stilbene, as well as cyclic indene smoothly reacted to
afford the corresponding azidoalkoxy-trifluoromethylated
products 9t−9v, respectively, in 58−51% yields, with
diastereomeric ratios from 52:48 to 92:8. It is also worth
noting that only small amounts of three-component trifluor-
omethylated azides 10a were isolated in all cases (<10%), thus
pointing out the high selectivity in favor of the four-component
transformation. On the other hand, the reaction was not
limited to styrenes as dihydropyran was azidoalkoxytrifluor-
omethylated, furnishing the corresponding product 9w albeit
with moderate yield.17 To our delight, TMSCN could be
efficiently used instead of TMSN3, leading to cyanoalkoxy-
trifluoromethylation of 9w in 59% yield.
In order to understand the mechanism of the current four-
component reaction, a set of control experiments were
performed (see Supporting Information). The conversion of
aldehyde 7a into the corresponding trimethylsilylated azohy-
drin 12a (Scheme 4) was studied by 1H NMR monitoring of a
reaction mixture containing 7a and TMSN3 in DCM. It
revealed that in both cases the addition of TMSN3 was very
slow, and only a trace of 12a was observed after 24 h. When
the same reaction was carried out in the presence of the
2+
with visible light excites Ru(bpy)3 into a strong reductant
species *Ru(bpy)32+, which performs a single electron transfer
(SET) to generate ·CF3 from Umemoto’s reagent 3 (see
Supporting Information for Stern−Volmer experiments and for
ST/EPR experiments).4,6−9,11
Subsequent regioselective addition of electrophilic ·CF3 to
alkene 8 leads to the radical species 13, which can be further
oxidized into cation 11 by SET from Ru(bpy)33+. Then, the
corresponding cation 11 can act as an electrophilic species
assisting the nucleophilic attack of TMSN3 to carbonyl
compound 7 with the tetrafluoroborate counteranion acting
as the source of fluoride ion.18 To support this assumption, an
additional experiment using Umemoto triflate salt 3b was
performed (Table 1, entry 10) where only a little amount of 9a
(14%) and 10a (13%) was recovered.
In conclusion, we have successfully developed an efficient
azidoalkoxy-trifluoromethylation reaction. A wide range of
terminal and internal alkenes as well as a variety of carbonyl
compounds are compatible with this MCR, affording the
corresponding trifluoromethylated compounds in up to 77%
yield. Importantly, this radical/cationic process represents an
efficient and straightforward example of four-component
photoredox-mediated reaction. Extension of this new concept
C
DOI: 10.1021/acs.orglett.9b02152
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Carbon Bond Forming Reactions via Photogenerated Intermediates.
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of photoredox MCTR is currently underway in our laboratory
and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02152.
(3) For selected reviews on photocatalyzed muticomponent
trifluoromethylation, see: (a) Koike, T.; Akita, M. New Horizons of
Photocatalytic Fluoromethylative Difunctionalization of Alkenes.
Chem. 2018, 4, 409−437. (b) Oh, E. H.; Kim, H. J.; Han, S. B.
Recent Developments in Visible-Light-Catalyzed Multicomponent
Trifluoromethylation of Unsaturated Carbon−Carbon Bonds. Syn-
thesis 2018, 50, 3346−3358. (c) Dagousset, G.; Carboni, A.; Masson,
G.; Magnier, E. Visible Light-Induced (Per)fluoroalkylation by Photo-
redox Catalysis; Elsevier S&T Books, 2017; pp 389−426. (d) Koike,
T.; Akita, M. Recent Developments in Visible-Light-Catalyzed
Multicomponent Trifluoromethylation of Unsaturated Carbon−
Carbon Bonds. Acc. Chem. Res. 2016, 49, 1937−1945. (e) Chatterjee,
T.; Iqbal, N.; You, Y.; Cho, E. J. Controlled Fluoroalkylation
Reactions by Visible-Light Photoredox Catalysis. Acc. Chem. Res.
2016, 49, 2284−2294. (f) Koike, T.; Akita, M. A Versatile Strategy for
Difunctionalization of Carbon−Carbon Multiple Bonds by Photo-
redox Catalysis. Org. Chem. Front. 2016, 3, 1345−1349.
Experimental procedures, characterization data, and
NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: geraldine.masson@cnrs.fr. Fax: (+33)1 69077247.
ORCID
Guillaume Dagousset: 0000-0001-8720-3828
Emmanuel Magnier: 0000-0003-3392-3971
Geraldine Masson: 0000-0003-2333-7047
́
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank ICSN and CNRS for financial support and doctoral
fellowships to G.L. G.D. thanks the Labex Charm3at (ANR-11-
LABX-0039) for a postdoctoral fellowship.
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F
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