Visible-Light-Induced Palladium-Catalyzed Generation of Aryl Radicals from Aryl Triflates

Article abstract of DOI:10.1002/anie.201915962

A mild visible-light-induced Pd-catalyzed intramolecular C?H arylation of amides is reported. The method operates by cleavage of a C(sp²)?O bond, leading to hybrid aryl Pd-radical intermediates. The following 1,5-hydrogen atom translocation, intramolecular cyclization, and rearomatization steps lead to valuable oxindole and isoindoline-1-one motifs. Notably, this method provides access to products with readily enolizable functional groups that are incompatible with traditional Pd-catalyzed conditions.

Full text of DOI:10.1002/anie.201915962

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Accepted Article
Title: Visible Light-Induced Palladium-Catalyzed Generation of Aryl
Radicals from Aryl Triflates
Authors: Vladimir Gevorgyan, Maxim Ratushnyy, Nikita Kvasovs, and
Sumon Sarkar
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915962
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10.1002/anie.201915962
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Visible Light-Induced Palladium-Catalyzed Generation of Aryl
Radicals from Aryl Triflates
Maxim Ratushnyy, Nikita Kvasovs‡, Sumon Sarkar‡, Vladimir Gevorgyan*
Dedication ((optional))
Abstract: Herein we report mild visible light-induced Pd-catalyzed
intramolecular C−H arylation of amides. The method operates via
cleavage of C(sp2) − O bond leading to hybrid aryl Pd-radical
intermediates. The following 1,5-HAT/ intramolecular cyclization/
rearomatization steps lead to valuable oxindole and isoindoline-1-
one motifs. Notably, this method provides access to products with
readily enolizable functional groups, incompatible with traditional Pd-
catalyzed conditions.
C(sp2)−I bond of vinyl iodides leading to formation of vinyl hybrid
Pd-radical intermediates.[6] Notably, these novel methods[7] rely
on the employment of organic halides,[8] predominantly iodides
and bromides, which limits synthetic applicability of this
approach. Potential employment of alternative aryl electrophiles
would substantially expand the toolbox of available substrates
for these transformations. Herein we report mild visible light-
induced[9] palladium-catalyzed fragmentation of C(sp2)−O bond
of aryl trifluoromethanesulfonates (triflates) 1[10] leading to the
formation of aryl hybrid palladium-radicals A1.[11] The latter, upon
a sequential 1,5-HAT (A1 → B1[12])/intramolecular cyclization
/rearomatization steps provided valuable oxindole products 2
(Scheme 1b).[13]
Encouraged by the successful cleavage of aryl halides,[3,5,14]
and inspired by work from Li’s group[15] on UV-light induced
transition metal-free fragmentation of (Csp2)−O bond (eq. 1), we
set to investigate the feasibility of generating hybrid aryl Pd-
radical intermediates from aryl triflates under visible light/Pd
conditions.
Aryl halides are essential substrates for a variety of Pd-
catalyzed transformations, which traditionally rely on the Pd(II)-
intermediates formed via two-electron oxidative addition
process.[1] Recently, a new approach involving intermediacy of
Pd(I)-species generated via a single electron transfer (SET) step
from photoexcited Pd(0)-complex to organohalide, emerged as
powerful and rapidly expanding area of Pd-catalysis.[2] Recently,
our group reported visible light-induced Pd-catalyzed cleavage
of C(sp2)−I bond of aryl iodides, leading to formation of aryl
hybrid Pd-radical intermediates A (Scheme 1a).[3] The latter
underwent selective 1,5-hydrogen atom translocation step
The intramolecular coupling of aryl triflates 1 was chosen for
this study. Hartwig reported[16] intramolecular 훼 -arylation of
amides as a powerful approach towards construction of oxindole
cores.[13b,c,d] Although high yielding and enantioselective, this
method relies on the employment of strong bases, what notably
diminishes the scope of this approach.
We began our study with examination of the intramolecular 훼-
arylation of triflate 1a (Table 1). While previously optimized
reaction conditions proved to be inefficient (entry 1),[3] we found
that oxindole 2a could be formed in low yield in N,N-
Dimethylformamide
(DMF)
when
Bis[(2-
diphenylphosphino)phenyl] ether (Dpephos) ligand was
employed. Further optimization revealed that this intramolecular
arylation proceeds better in the presence of NaI (entry 3).
Scheme 1. Aryl iodides and triflates in visible light-induced Pd-catalyzed
transformations.
Extensive
ligand
screening
provided
2,2’-
Bis(diphenylphosphino)-1,1’-binapthanlene
(rac-BINAP)
as
(HAT)[4] (B) followed by 훽-H elimination, leading to silyl enol
ethers[3] and desaturated amines[5] in efficient manner. This
strategy was also successfully translated onto fragmentation
superior ligand, leading to oxindole 2a in 41% yield. Screening
other additives, known to affect Pd-catalyzed transformations of
aryl triflates via stabilization of oxidative addition adduct,[17] did
not lead to reaction improvement (entries 5 and 6). Optimization
of solvents indicated that this reaction proceeds best in 1,4-
dioxane, leading to the oxindole 2a in 62% yield. Controlled
experiments confirmed that catalyst, light, and additive all are
essential for the success of this transformation (entries 8-9).
Additionally, performing reaction in the presence of radical
scavenger 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) (entry
[*]
M. Ratushnyy, N. Kvasovs, S. Sarkar, Prof. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 W. Taylor Street, Chicago, Illinois, 60607-7061 (USA)
Department of Chemistry and Biochemistry
University of Texas at Dallas
800 West Campbell, BSB13, Richardson, Texas, 75080 (USA)
Email: vlad@utdallas.edu
These authors contributed equally to this work
[‡]
Supporting information for this article is given via a link at the end of
the document
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less demanding n-pentyl moiety led to formation of acyclic
desaturated amide 2z’ as the major reaction product.
Table 1. Optimization of reaction parameters.[a]
Table 2. Scope of oxindoles.[a]
entry
1[c],[d]
2
ligand
additive
-
solvent
Benzene
DMF
yield, %[b]
Dtbdppf
0
Dpephos
Dpephos
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
-
11
30
41
18
19
62
<1
<1
5
3
NaI
DMF
4
NaI
DMF
5
NaCl
NaOAc
NaI
DMF
6
DMF
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
8[e]
9[f]
10[g]
NaI
NaI
NaI
[a] All reactions were performed on 0.1 mmol scale. [b] GC/MS yield. [c] 2
equiv. of Cs2CO3 were used. [d] 1-Diphenylphosphino-1’-(di-tert-
butylphosphino)ferrocene. [e] No Pd(OAc)2 was added. [f] No light, T = rt to
100 ℃. [g] 2 equiv. of TEMPO were added.
10) led to substantially diminished yield, thus indicating on
possible involvement of radical intermediates.
With the optimized conditions in hand, the scope of
intramolecular arylation reaction toward oxindole core[18] was
studied. Thus, reaction of triflate 1a led to the oxindole 2a in
60% yield. Introduction of various alkyl groups next to 휶-carbon
posed no problem, leading to oxindoles 2b-2d in 61%, 65%, and
69%, respectively. Substrates 1e-1g having halo- and ester
functional groups on the aromatic ring, both reacted well
providing products 2e-2g in good yields. Likewise, tricyclic
oxindole 2h was obtained in 64% yield. Alkyl substituents on the
aryl ring were also tolerated. The scope of this transformation
could further be expanded onto spirocyclic oxindole motifs, as
well. Thus, spiro cyclopropyl- (2k), cyclobutyl- (2l), cyclopentyl-
(2m), and cyclohexyl- (2n) oxindoles were synthesized efficiently
using this protocol. Norbornane derivative 1o reacted smoothly
leading to 2o in 70% yield. Incorporation of heteroatoms did not
alter the course of the reaction to give oxindoles 2p-2r in 85%,
65%, and 66% yield, respectively. Notably, base-sensitive
functionalities, such as ketone and ester are well tolerated under
these reaction conditions! Thus, oxindoles 2s and 2t,
possessing enolizable groups and thus, unavailable via the
traditional Pd-catalyzed methods,[14,16] were isolated in 50% and
71% yield, respectively. The transformation of cyclopentene
derivative 1u led to the corresponding oxindole 2u, albeit in
moderate yield. Varying the substitution pattern at N-atom led to
oxindoles 2v-2x in 71%, 59%, and 57% yields, respectively.
Notably, this transformation was capable of delivering the 3-
monosubstituted oxindole 2y, though in moderate 40% yield.
However, the replacement of bulky tert-butyl group with sterically
[a] Reaction conditions: 1 0.1 mmol, Pd(OAc)2 0.01 mmol, rac-BINAP 0.02
mmol, NaI 0.2 mmol, Cs2CO3 0.125 mmol, 1,4-dioxane 0.1 M, 34 W blue
LED. [b] NMR yield. [c] 훼: 훽, 3:1.
Notably, the developed method for synthesis of oxindoles 2
operates under electronically-matched scenario, where
a
translocated electrophilic radical B1 cyclizes at an electron-rich
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aromatic ring (Scheme 1b). We hypothesized that the analogous
cyclization under electronically-inversed scenario (A2→B2)
Table 3. Scope of isoindoline-1ones.[a]
preservation of the deuterium label at about 47%. Indeed,
experiments with triflate 1a-D completely supported the above
projections, leading to the oxindole 2a-D with 48% deuterium
incorporation at the aromatic ring. Furthermore, cyclization of the
alternatively D-labeled triflate 1a’-D reacting via the same
intermediate B1-D was examined, which produced the single
reaction product−oxindole 2a-D. As in the previous experiment,
an excellent agreement between predicted and observed levels
of deuterium label incorporation was observed. These
deuterium-labeling experiments ruled out a potential direct C–H
activation mechanism (1a’-D  i  2a-D),[21] according to which
a complete preservation of the D-label at the C2 position should
be observed (eq. 3).
[a] Reaction conditions: 1 0.1 mmol, Pd(OAc)2 0.01 mmol, rac-BINAP 0.02
mmol, NaI 0.2 mmol, Cs2CO3 0.125 mmol, 1,4-dioxane 0.1 M, 40 W blue
LED. [b] 훼: 훽, 2.5:1. [c] 훼: 훽, 2:1.
should be possible, thus leading to useful isoindoline-1-one
products 4.[19] Therefore, cyclization of benzamide[20] 3a was
tested under the optimized reaction conditions. To our delight,
isoindoline-1-one 4a was isolated in 69% yield (Table 3).
Reactions of differently substituted benzamides (3b-g, 3i),
featuring alkyl, methoxy, halo-, trifluoromethyl, and naphthyl
groups proceeded smoothly providing the corresponding
isoindoline-1-ones in moderate to good yields. The protocol also
proved efficient for cyclization of cyclohexyl- and isobutyl amides
leading to products 4h and 4j in 71% and 73% yields.
Next, we turned our attention to the mechanism of this
intramolecular C−H alkylation reaction. As mentioned above
(Table 1, entry 10), the reaction was sensitive to the presence of
a radical scavenger, leading to dramatic decrease of the
reaction yield. Additional evidence supporting radical nature of
this transformation was obtained via following deuterium
labelling experiments (eq. 2). Intramolecular arylation of
deuterated triflate 1a-D was investigated first. It was expected
that upon C–O bond fragmentation and a subsequent 1,5-HAT,
the B1-D intermediate would be produced. In the absence of any
stereoelectronic factors, it was expected to display equal
probability for cyclization at either C2 or C6 position of the
aromatic ring, thus leading to the oxindole 2a-D with a statistical
Scheme 2. Proposed mechanism.
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In addition, the radical nature of this transformation was
further confirmed by a radical clock experiment with triflate 1aa
producing the ring-opened dienamide 2aa (eq. 4) and by the
spin-trap experiments with DMPO.[22]
We thank Prof.
Paradimitratos (UTD) for the help with EPR experiments.
Anvar Zakhidov (UTD) and Dr. Alexios
Keywords: triflate • radical • palladium • homolysis • light
Based on the preliminary mechanistic studies, we postulate
the formation of a key hybrid aryl Pd-radical intermediate A1 in
this transformation (Scheme 2). A consecutive 1,5-HAT step in
the latter produces the translocated hybrid alkyl radical B1, which,
upon intramolecular cyclization at the aromatic ring (C1) and a
subsequent rearomatization is converted to the oxindole product
2a. At present, the details of the C−O bond fragmentation step,
as well as the precise role of NaI, remain unclear. We foresee
generation of intermediate A1 via several alternative scenarios.
According to the path A, a SET between aryl triflate 1a and
active photoexcited Pd-complex[23] leads to the formation of aryl
triflate radical-anion (not shown), which upon cleavage of the
C−O bond leads to A1. In path B, oxidative addition of Pd-
catalyst onto 1a leads to the adduct D1, which then experiences
visible light-induced homolysis of C−Pd bond, thus leading to A1.
Alternatively, ligand exchange between D1 and NaI arrives at a
more stable aryl−Pd−I intermediate E1.[17] As in the previous
case, irradiation-induced homolysis of C−Pd bond converts E1
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a reductive elimination of the
intermediate E1 generates aryl iodide 5. The latter undergoes
SET with photoexcited Pd-catalyst,[3,5] leading to hybrid aryl Pd-
radical A1 (path D). It should be mentioned that several
additional mechanistic experiments, including EPR study on
model substrates, rate comparison of stoichiometric reactions
with palladium, and monitoring parallel reactions at the early
stages, point out on the feasibility of all four scenarios.[22]
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fragmentation of C−O bond may be reliably ruled out. Evidently,
more detailed mechanistic studies are required to set up a
precise mechanism for this novel transformation.
[5]
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In summary, we demonstrated that combination of visible light
and palladium catalysis can efficiently fragment the C(sp2)−O
bond of readily available aryl triflates, leading to the aryl hybrid
Pd-radicals. Involvement of the latter in the successive 1,5-HAT/
cyclization/ rearomatization events afforded diversely substituted
oxindole and isoindoline-1-one products. Advantageous
engagement of Pd(0)/Pd(I)/Pd(II) manifold over the traditional
Pd(0)/Pd(II) cycle allowed for the formation of oxindole products
with base-sensitive functionalities, incompatible with traditional
Pd-catalyzed conditions. Although, the involvement of hybrid Pd-
radicals is well supported, the details of C − O bond
fragmentation step as well as the role of NaI remain unclear at
this point. Apparently, more detailed mechanistic study is
required to elucidate the precise mechanism of this
transformation. It is believed that this method will find
applications in synthesis.
[8]
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This research was supported by the National Institutes of Health
(GM120281), National Science Foundation (CHE-1936422), and
Welch Foundation (Chair, AT-0041).
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10.1002/anie.201915962
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Maxim Ratushnyy, Nikita Kvasovs,
Sumon Sarkar, Vladimir Gevorgyan*
R1
N
R1
R2
R2
R3
Pd(I)X
OTf
H
Page No. – Page No.
H
Pd-cat.
O
N
visible light
R
R
T
Visible Light-Induced Palladium-
Catalyzed Homolysis of C−O Bond in
Aryl Triflates
T
R
R
R3
34 examples
39 to 85% yields
O
Text for Table of Contents
C−O activation: Mild visible light-induced Pd-catalyzed intramolecular C−H arylation of amides is reported. The method features activation of
C(sp2)−O bond leading to hybrid aryl Pd-radical intermediates. The following 1,5-HAT/ intramolecular cyclization/ rearomatization steps lead to
valuable N-containing heterocyclic cores. Notably, this method provides access to products with readily enolizable functional groups,
incompatible with traditional Pd-catalyzed conditions.
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