Cooperative Light-Activated Iodine and Photoredox Catalysis for the Amination of Csp3 ?H Bonds

Article abstract of DOI:10.1002/anie.201703611

An unprecedented method that makes use of the cooperative interplay between molecular iodine and photoredox catalysis has been developed for dual light-activated intramolecular benzylic C?H amination. Iodine serves as the catalyst for the formation of a n

Full text of DOI:10.1002/anie.201703611

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Accepted Article
Title: Cooperative Light-Activated Iodine and Photoredox Catalysis for
the Amination of Csp3-H Bonds
Authors: Kilian Muniz, Markus Reiher, Christopher Stein, Peter Becker,
and Thomas Duhamel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703611
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10.1002/anie.201703611
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COMMUNICATION
Cooperative Light-Activated Iodine and Photoredox Catalysis for
the Amination of Csp3–H Bonds
Peter Becker,[a] Thomas Duhamel,[a,c] Christopher J. Stein,[b] Markus Reiher,*[b] Kilian Muñiz*[a,d]
Dedication ((optional))
Abstract: An unprecedented protocol for the cooperative interplay
between molecular iodine and photoredox catalysis under dual light-
activation for the intramolecular benzylic C–H amination is
presented. Iodine serves as a catalyst for the formation of a new C–
N bond by the activation of a remote Csp3–H bond (1,5-HAT
process) under visible light irradiation, while the organic photoredox
catalyst TPT effectively furnishes the re-oxidation of the molecular
iodine catalyst. To explain the compatibility of the two involved
photochemical steps, the key N–I bond activation was elucidated by
computational methods. The new cooperative catalysis provides
important implications for the combination of non-metallic main
group catalysis with photocatalysis.
which induces a selective 1,5-HAT process[7] to activate a remote
Csp3–H bond for the subsequent C–N bond formation. Although of
synthetic efficiency, the reaction requires stoichiometric amounts of
hypervalent iodine reagents indicating a clear disadvantage. Rovis
and Knowles independently reported a photoredox-based concept
for the generation of amidyl radicals and subsequent activation of
Csp3–H bonds by a 1,5-HAT process (Figure 1).[8,9] They extended
such processes by intermolecular radical interception with activated
alkenes. Within this new C–C bond forming approach, however, an
amination reaction is no longer feasible and the role of the amide is
restricted to the generation of the requisite radicals.
A fundamental goal in developing new catalytic processes is to
establish environmentally benign and effective conditions. The
activation of small organic molecules by photoredox catalytic
systems under visible light has opened up a whole new field in
catalysis leading to a plethora of effective transformations.[1] Here,
processes merging transition metal and photoredox catalysis are of
exceptional value as the utilization of stoichiometric amounts of
oxidizing reagents others than molecular oxygen is no longer
required.[2] Although this strategy has attracted the development of
organic transformations including C–H bond activations using a
number of metal catalysts,[3] no strategies for combining photoredox-
catalyzed re-oxidation with iodine redox catalysis has been reported
to date.[4] Devising a practical methodology for the functionalization
of non-activated Csp3–H bonds still represents a great challenge in
modern organic synthesis. While the transition-metal catalyzed C–H
bond transformation into new C–C and C–heteroatom bonds has
been established over the past years, this strategy usually requires
functional groups in close proximity to ensure regioselectivity and to
overcome activation barriers.[5] The modification of remote positions,
however, further increases difficulties related to C–H bond activation
concepts. Lately, our group developed the iodine catalyzed oxidative
Hofmann-Löffler reaction of sulfonamides for the formation of
pyrrolidines (Scheme 1).[6a] In this process, an in situ formed N–I
bond facilitates the formation of a nitrogen-centered amidyl radical,
Figure 1. Recent examples for the nitrogen-promoted application of 1,5-HAT
processes for the functionalization of remote Csp3–H bonds.
To further improve the photochemical amidyl radical-promoted
Csp3–H bond activation, we envisaged combining a 1,5-HAT
process and a subsequent cyclization reaction to re-establish
the original pathway to synthetically valuable pyrrolidines.
To foster such a reaction process, we pictured molecular iodine
playing an essential role in the cyclization step of the envisaged
process.[10] In a cooperative catalysis with two individual photo-
induced processes, the iodine catalyst would promote the
pyrrolidine formation via activation of the N–H bond with a
subsequent 1,5-HAT process, while the photoredox catalyst
would furnish the reoxidation of the iodine after the extrusion by
the cyclization event. Both catalysts, therefore, would be working
cooperatively and demonstrate the first example of photoredox-
catalyzed reoxidation of
a molecular homogeneous iodine
catalyst. Due to the consideration of metal-free processes using
iodine instead of transition-metal catalysts and iodine’s known
ability to quench metal-to-ligand charge-transfer (MLCT) excited
states of metal based photoredox catalysts,[11] organic dyes
were the preferred choice.[12]
To this end, a solution of the model substrate 1a, molecular
iodine (10 mol%) and photoredox catalyst (5 mol%) in DCE
under anhydrous or oxygen-free conditions was exposed to blue
light (λmax = 456 nm ± 12 nm) at room temperature. However, for
all reactions with different organic dyes (Eosin Y, Fukuzumi’s
catalyst, and TPT, Figure 2) only trace amounts of the desired
pyrrolidine 2a were detected (Table 1, entry 1).
[a]
[b]
Dr. P. Becker, T. Duhamel, Prof. Dr. K. Muñiz
Institute of Chemical Research of Catalonia (ICIQ),
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
C. J. Stein, Prof. Dr. M. Reiher
Laboratorium für Physikalische Chemie, ETH Zürich,
Vladimir-Prelog-Weg 2, 8093 Zürich (Switzerland)
Email: markus.reiher@phys.chem.ethz.ch
T. Duhamel
Facultad de Química, Universidad de Oviedo
C/Julián Clavería, 33006 Oviedo (Spain)
Prof. Dr. K. Muñiz
[c]
[d]
The first positive result was achieved when performing the
reaction in unpurified solvent with TPT[13] as the photoredox
catalyst of choice under air (20%, entry 2). A solvent mixture of
ICREA, Pg. Lluís Companys 23, 08010 Barcelona (Spain)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201703611
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COMMUNICATION
DCE and HFIP[14] dramatically improved the yield of 2a to 84%
(entry 3). When the TPT loading was reduced to 2 mol%, the
yield dropped to 58% (entry 4).
(entry 10). No pyrrolidine was formed in the absence of light
demonstrating that the reaction is indeed light-driven (entry 11).
At this point, it has to be stretched out that the intensity of the
LED light-source was determined crucial.[15] To finally
demonstrate the robustness of the process, a 2 mmol scale was
applied leading to 83% of 2a under standard conditions with a
slightly increased reaction time (entry 12).
Mechanistically, we propose a reaction sequence consisting
of two individual light-induced catalytic reactions within several
intertwined individual cycles (Figure 3). Raman spectroscopy
was employed to identify the active molecular iodine catalyst. A
rapid formation of hypoiodite[16] in the wet reaction media from
disproportionation of molecular iodine was observed, which
explains the requirement for water traces to initiate the
reaction.[15] This catalyst state is in agreement to Ishihara’s work
on related hypoiodite catalysis.[17] The concomitantly formed HI
essentially participates in the final catalyst reoxidation event
(cycle A).
Table 1. Screening of the conditions for the iodine/photoredox catalyzed
process.
TPT (x mol%)
Me
Me
Me Me
I2 (y mol%)
TsHN
Ph
Ph
HFIP/DCE, blue LED,
RT, 18 h
N
Ts
1a
2a
No.[a]
x
y
Solvent
Yield [%]
1[b,c]
2[c]
3
5
5
10
10
10
10
5
DCE
trace
20
DCE
5
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
HFIP/DCE
84
4
2
58
5
2
80
Ts
N
6
1
5
90
Ph
7
1
2
31[d]
76[d]
5[d]
Me
Me
2a
Me
Me
h!
Ts
8
0.5
-
5
2 TPT*
N
H
I
2 HI
2 TPT
Me
Me
C
IV
9
5
Ts
N
Ph
H2O
H
14[d]
---[e]
83[f]
2 TPT
1/2 O2 + 2 H+
10
11
12
1
-
A
III
Ph
h!
I2
B
1
5
HI
1,5-HAT
Me
Me
H2O
Ts
1
5
N
Me
Me
Ts
HOI
N
I
II
[a] All reactions were stirred for 18 h under blue light irradiation in 3 mL of
solvent (1:1) without external heating. Yields refer to isolated material after
purification. [b] Reaction performed under anhydrous or oxygen-free
conditions. [c] Eosin Y and Fukuzumi’s catalyst (depicted in Figure 2) led to
trace amounts of product. [d] Yields determined by NMR with 1,3,5-
trimethoxybenzene as internal standard. [e] Reaction performed in absence
of light. [f] Reaction performed at a 2 mmol scale, 22 h.
Initiation
Ph
I
Ph
1a
Ph
I
NH
H2O
Me Me
Ts
Figure 3. Proposed mechanism for the dual light-induced cooperative iodine
and photoredox catalyzed intramolecular amination of sulfonamides.
O
Ph
O
Mes
The active hypoiodite catalyst initiates the organic
transformation via N-iodination of the substrate 1a to form the
intermediate species I (cycle B).[18] Upon irradiation with visible
light, the N-iodinated species I collapses to generate the amidyl
radical species II. A subsequent 1,5-HAT process (III) within a
radical chain reaction generates an alkyliodide species IV.
Intramolecular isotope-labeling experiments[19] revealed the
hydrogen abstraction from II to III to be the rate-limiting step with
a kinetic isotope effect of 2.3.[15] The successful incorporation of
iodine into the carbon framework precludes the requirement for
intermolecular radical quenching.[8a,b] It drives the reaction to the
C–N bond formation, in which the sulfonamide attacks the
intermediary C–I bond in an intramolecular substitution reaction
to form the pyrrolidine 2a as the product. The extruded hydrogen
iodide is then effectively reoxidized by TPT to molecular iodine
in a single electron transfer process with molecular oxygen
(cycle C).[20] This context characterizes the new photocatalytic
iodine catalysis as an unprecedented iodine (-I/I) manifold and
for the first time demonstrates that a catalytic functionalization of
benzylic positions is possible without the involvement of
iodine(III) oxidation states.
O
Br
Br
Ph
Ph
N
Me
HO
O
OH
BF4
BF4
Br
Br
Fukuzumi’s catalyst
(Acr+-Mes)
TPT
Eosin Y
Figure 2. Organic dyes tested as photoredox catalysts.
However, a simultaneous reduction of the amount of iodine (5
mol%) led to similar yields (80%, entry 5), which indicates
absorption of visible light by iodine at high concentrations. With
only 5 mol% of iodine, the TPT loading was reduced to 1 mol%
leading to 90% of 2a (entry 6). A further reduction of iodine (2
mol%) led only to 31% yield (entry 7) accompanied by a large
amount of side products stemming from over-oxidation. When
0.5 mol% TPT was used, still 76% of 2a was formed (entry 8).
These results indicate an important role of the I2/TPT ratio to
effectively cooperate in the catalytic reaction. To probe the
necessity of both catalysts, control experiments were conducted.
With iodine alone, the formation of 5% of 2a was detected
equivalent of only a stoichiometric reaction (entry 9). When TPT
was added as single catalyst, 14% of pyrrolidine 2a was formed
accompanied by large amounts of decomposition products
The conceptually important feature of the reaction consists in the
compatibility of the dual role of light. First, there is its
participation within the photoredox catalysis, which provides the
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10.1002/anie.201703611
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terminal oxidant for the overall catalysis. Secondly, it is involved
in the homolytic cleavage of the N–I bond as the initial step
within the C–H bond functionalization. In order to understand
the molecular requirements for the elusive light-induced N–I
bond cleavage at stage I, theory was employed.
effects and the structural changes in both conformers have a
pronounced effect on the oscillator strengths.
We confirmed that the lowest excited states have mainly LUMO
character with complete active space self-consistent field
calculations[25] employing an active space consisting of 14
electrons in 16 orbitals, where the orbitals were selected with
our automated active space selection protocol.[26]
With this concise mechanistic explanation of the dual light-
activated iodine and photoredox catalyzed C–H amination and
the theoretical understanding of the photolytical cleavage of the
N–I bond in hand, we investigated the scope of the reaction
process (Figure 5).
The excitation energies for the ten lowest excited states of
species I were calculated with time-dependent density functional
theory (TDDFT) with the range-separated CAMY-B3LYP
functional[21] and environmental effects were included with a
continuum solvation model. We accounted for the pronounced
conformational freedom by carrying out TDDFT calculations on a
closed (A) and an open structure (B), that were both optimized
with DFT employing the PBE functional.[22] The energy of both
structures differs by less than 2.5 kcal/mol in favor of the open
conformation. With an empirical dispersion correction,[23] both
energies are almost identical with the closed conformation being
0.15 kcal/mol lower in energy. A table with energies and
oscillator strengths for all states and computational setups and
more details on the methodology are included in the Supporting
Information.[15]
Ts
Ts
Ts
N
N
N
X
Me
Me
Me
Me
Me
Me
Me
2b-e
2b (X = Me): 88%
2c (X = F): 90%
2f, 60%[a]
2d (X = Cl): 57%
2e (X = Br): 31%
2a, 90%
Ts
Ts
Ts
Ts
N
N
N
N
Ph
Ph
Ph
Me
Me
Me
2g, 90%[a]
2h, 81%
2i, 70%[b]
2j, 81%
Me
!
"
Ts
S
Ts
N
N
N
Ts
2k, 94%
2l, 73%
2m, 82%[c]
Me
Ph
O
Ms
Ns
O
S
O
S
N
S
N
N
N
O
Me
Me
Ph
Ph
Me
Me
Me
Me
Me
Ph
Me
2q, 60%
2p, 96%
2n, 92%
2o, 88%
O
O
Ph
Ph
2s, 82%[a]
CF3
SES
N
N
N
Ph
Ph
Me
Me
Me
Me
Me
Figure 4. N–I anti-bonding LUMO of intermediate species I in a closed (A) and
open (B) conformation. The orbitals were calculated with DFT employing the
range-separated CAMY-B3LYP functional.
2t, 70%[d]
Me
2r, 52%
Figure 5. Scope of the intertwined iodine and photoredox catalyzed cyclization.
Conditions: I2 (5 mol%), TPT (1 mol%), HFIP/DCE (3 mL), RT, blue light, 18 h.
All C–N bonds formed in this process are highlighted in blue. Yields are
generally stated as yields of isolated product obtained after purification by
column chromatography; [a] two rotamers were observed by NMR; [b] isolated
as 1:1 diasteromeric mixture; [c] isolated as a single diasteromer; [d] yield by
1H NMR with 1,3,5-trimethoxybenzene as internal standard.
The seven lowest excited states correspond to excitations into
the N–I anti-bonding lowest unoccupied molecular orbital
(LUMO) and therefore weaken this bond and facilitate bond
cleavage (Figure 4). Depending on the computational setup, the
transition energies of these excitations cover a range of 100-130
nm with the lowest transition energy around 380 nm. Several
effects shift the individual transition energies. One of them is the
conformational freedom of I, which causes a shift of up to 15 nm
for the open and closed structure considered in this study and
other conformers might further extend that range. Another effect
is the direct interaction of solvent molecules with I, that leads to
a significant broadening of the individual bands due to a plethora
of possible interactions. Furthermore, the error of TDDFT
transition energies lies typically in the range of 0.2 eV,[24] which
corresponds to about 30 nm in this wave length regime. These
effects, and the fact that the long reaction times do not require a
high efficiency of the photolytic reaction, explain the discrepancy
of the calculated lowest energy transitions and the LED wave
length. While we were mainly interested in identifying the
character of the excitations that cause the photolytic reaction, we
expect a higher efficiency of this reaction step for shorter wave
lengths. It should be noted that both the inclusion of solvent
The process features an effective procedure to yield various 2-
arylpyrrolidines in good to excellent yields. A series of substrates
with substituents in 4-position of the phenyl group are well
tolerated (2a-e, 31-90% yield), with only the 4-chloro or 4-
bromo-substituted substrates leading to decreased yields due to
over-oxidation (2d-e, 31-57% yield) by the photoredox catalyst.
Also, substrates bearing 2- or 3-substituted arenes form
pyrrolidines 2f-g in 60-90% yield demonstrating that steric
factors only play a minor role. A possible Thorpe-Ingold-effect
was shown to have little influence on the reaction since different
substitution pattern in β-position of the amide were successfully
tolerated (2h-j,m, 70-81%). Substrates with a phenyl backbone
were subjected to the reaction conditions effectively yielding
previously inaccessible isoindolines (2k-l, 73-94%). Different
sulfonyl groups are also well tolerated in this process leading to
60-96% of the desired pyrrolidines 2n-r. For the first time
benzamide and trifluoroacetamide derivatives are also
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10.1002/anie.201703611
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COMMUNICATION
[6]
For recent reports on the Hofmann-Löffler reaction, see: a) C. Martínez,
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yields (70-82%).[27] In contrast to the previously described
iodine(I/III) approach for the Hofmann-Löffler reaction, the
intermediary benzyliodide of the iodine(-I/I) approach holds a
weaker nucleofug requiring additional activation by the benzylic
position to allow the internal substitution by the amide
nucleophile.
In summary, we have introduced a novel concept of a dual light-
activated cooperative iodine- and photoredox catalysis and
applied it to the intramolecular amination of remote sp3 C–H
bonds. The iodine acts as the primary catalyst allowing the
activation of the sp3 C–H bond by a light-induced homolytic
cleavage of in situ-generated N–I bonds followed by a 1,5-HAT
process. After recombination of the radicals and an
intramolecular substitution, the molecular iodine catalyst is
photoredox-catalytically reoxidized in a second light-induced
process. The key step of the reaction, the cleavage of the
intermediary N–I bond, has been rationalized by computational
methods, while the presence of the active iodine species,
hypoiodite, has been determined by Raman spectroscopy.
[7]
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Financial support was provided by the Spanish Ministry for
Economy and Competitiveness and FEDER (CTQ2014-56474R
grant to K. M., and Severo Ochoa Excellence Accreditation
2014-2018 to ICIQ, SEV-2013-0319) and the Schweizerischer
Nationalfonds (No. 20020_169120 to M. R.). P. B. and C. J. S.
gratefully acknowledge the Alexander von Humboldt Foundation
for a postdoctoral fellowship, and the Fonds der Chemischen
Industrie for a Kekulé fellowship. The authors are grateful to the
CERCA Programme of the Government of Catalonia and to
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[15] Please see supporting information for more experimental details.
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stoichiometric radical recombination from III to IV.
COST Action CA15106 “C
Synthesis (CHAOS)”.
–
H
Activation in Organic
Keywords: photoredox catalysis • iodine catalysis • 1,5-HAT
process • cooperative catalysis • C–H bond amination
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10.1002/anie.201703611
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Peter Becker, Thomas Duhamel,
Christopher J. Stein, Markus Reiher,*
Kilian Muñiz*
Page No. – Page No.
More light, more possibilities! A dual light-activated intertwined iodine and
photoredox-catalyzed process for the amination of remote sp3 C–H bond has been
developed. While iodine promotes the activation of the sp3 C–H bond, the dye TPT
efficiently acts as photoredox catalyst to regenerate the molecular iodine catalyst.
The compatibility of the two processes is explained based on calculations.
This article is protected by copyright. All rights reserved.