Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

Article abstract of DOI:10.1021/acscatal.9b04699

We report herein that a palladium catalyst in combination with a dual phosphine ligand system catalyzes alkylation of silyl enol ether and enamide with a broad scope of tertiary, secondary, and primary alkyl bromides under mild irradiation conditions by blue light-emitting diodes. The reactions effectively deliver α-alkylated ketones and α-alkylated N-acyl ketimines, and it is difficult to prepare the latter by other methods in a stereoselective manner. The α-alkylated N-acyl ketimine products can be further subjected to chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester to deliver chiral N-acyl-protected α-arylated aliphatic amines in high enantioselectivity up to 99% ee, thus providing a method for facile synthesis of chiral α-arylated aliphatic amines, which are of importance in medicinal chemistry research. The N-acetyl ketimine product also reacted smoothly with various types of Grignard reagents to afford sterically bulky N-acetyl α-tertiary amines in high yields. Theoretical studies in combination with experimental investigation provide understanding of the reaction mechanism with respect to the dual ligand effect and the irradiation effect in the catalytic cycle. The reaction is suggested to proceed via a hybrid alkyl Pd(I)-radical species generated by inner-sphere electron transfer of phosphine-coordinated Pd(0) species with alkyl bromide. This intriguing hybrid alkyl Pd(I)-radical species is elucidated by theoretical calculation to be a triplet species coordinated by three phosphine atoms with a distorted tetrahedral geometry, and spin prohibition rather than metal-to-ligand charge transfer contributes to the kinetic stability of the hybrid alkyl Pd(I)-radical species to impede alkyl recombination to generate Pd(II) alkyl intermediate.

Full text of DOI:10.1021/acscatal.9b04699

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Article
Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol
Ether and Enamide under Irradiation: Scope, Mechanism, and
The-oretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species
Bin Zhao, Rui Shang, Guang-Zu Wang, Shaohong Wang, Hui Chen, and Yao Fu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04699 • Publication Date (Web): 19 Dec 2019
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ACS Catalysis
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Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol
Ether and Enamide under Irradiation: Scope, Mechanism, and
Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species
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Bin Zhao,1 Rui Shang,*,1,2 Guang-Zu Wang,1 Shaohong Wang,3 Hui Chen,*,3 and Yao Fu*,1
1 Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion,
Anhui Province Key Laboratory of Biomass Clean Energy, iChEM, University of Science and Technology of China, Hefei,
Anhui 230026, China.
2 Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
3 Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Photochemistry, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China.
Supporting Information Placeholder
ABSTRACT: We report herein that a palladium catalyst in combination with a dual phosphine ligand system catalyzes alkylation of silyl
enol ether and enamide with a broad scope of tertiary, secondary, and primary alkyl bromides under mild irradiation conditions by blue light-
emitting diodes. The reactions effectively deliver -alkylated ketones and -alkylated N-acyl ketimines, it is difficult to prepare the latter by
other methods in a stereoselective manner. The -alkylated N-acyl ketimine products can be further subjected to chiral phosphoric acid-
catalyzed asymmetric reduction with Hantzsch ester to deliver chiral N-acyl-protected -arylated aliphatic amines in high enantioselectivity
up to 99% ee, thus providing a method for facile synthesis of chiral -arylated aliphatic amines, which are of importance in medicinal
chemistry research. The N-acetyl ketimine product also reacted smoothly with various types of Grignard reagents to afford sterically bulky
N-acetyl -tertiary amines in high yields. Theoretical studies in combination with experimental investigation provide understanding of the
reaction mechanism with respect to the dual ligand effect and the irradiation effect in the catalytic cycle. The reaction is suggested to proceed
via a hybrid alkyl Pd(I)-radical species generated by inner-sphere electron transfer of phosphine-coordinated Pd(0) species with alkyl
bromide. This intriguing hybrid alkyl Pd(I)-radical species is elucidated by theoretical calculation to be a triplet species coordinated by three
phosphine atoms with a distorted tetrahedral geometry, and spinprohibition rather than metal-to-ligand charge transfer contributes to the
kinetic stability of the hybrid alkyl Pd(I)-radical species to impede alkyl recombination to generate Pd(II) alkyl intermediate.
KEWORDS: Palladium • Alkylation • Silyl Enol Ether • Enamide • Hybrid Alkyl Pd(I)-Radical Species
palladium catalysis, phosphine ligand was used in a much larger
ratio to palladium salts in the optimized reaction conditions
1. INTRODUCTION
With the easy availability of cheap light-emitting diodes,1 the
area of excited-state transition-metal catalysis2 under visible light
irradiation is attracting increasing attention and has seen substantial
development in the synthetic community. After photoexcitation of
a metal complex with visible light of certain wavelength, untapped
reactivity that was distinct from known thermal reactivity could be
discovered to enable new catalytic reactions. Recent studies have
revealed that even the most popular and heavily explored palladium
catalysts3 exhibit a blend of radical and organometallic reactivity
under irradiation by blue light-emitting diodes,1,4 which suppresses
the problematic -H elimination step of alkyl-Pd(II) species to
allow various alkylation reactions with broad scope.5 These
reactions were proposed to proceed through a putative hybrid alkyl
Pd(I)-radical species,6 which remains more elusive than the well-
defined palladium intermediates7 generated under thermal
conditions.
compared with the situation of thermal palladium catalysis,9 despite
the sacrificial amount necessary to reduce Pd(II) to Pd(0). Shang
and colleagues also discovered that applying a dual ligand is
sometimes crucial for the reactivity of excitation-state palladium
catalysis,5 which differs from the ligand requirement in thermal
palladium catalysis. We rationalized the intermediate to be a dual
phosphine ligand coordinated palladium(0) species to undergo
irradiation-induced inner-sphere electron transfer (ISET) to
generate a hybrid alkyl Pd(I)-radical species, which may be in
equilibrium with alkyl Pd(II) species4,10 through dissociation of the
monodentate phosphine ligand (Figure 1A).8d We hypothesized
that this reactivity of palladium species can be used for the
alkylations (especially tertiary alkylation) of silyl enol ether11 and
N-acyl enamide12 to deliver -alkylated ketone and -alkylated N-
acyl ketimine through a blend of radical and organometallic
reactivity (Figure 1B). Alkylation of N-acyl enamide with alkyl
bromide to generate -alkylate N-acyl imine, which is a useful
intermediate for further reduction or addition to deliver primary
amine after easy removal of N-acyl protection, has not been
successfully achieved. N-acyl-protected imines appear to be
With our continuing research interest in exploring palladium
catalysis under visible light excitation,5,8 we believe that
understanding the ligand configuration and reactivity control of
hybrid alkyl Pd(I)-radical species will facilitate discovery of new
reactivity. We note that in many recent reports of excitation-state
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difficult to prepare from the corresponding ketones, especially in a
(12 mol %) and Xantphos (6 mol %) as the dual phosphine ligand
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7
stereospecific manner.13
system to afford the desired N-acyl ketimine in 96% isolated yield
as single E-stereoisomer. The palladium catalyst, dual phosphine
ligand, base, and irradiation were all essential parameters (entries
1–5, in Table 1B). Using a single phosphine ligand system
containing the same amount of coordinative phosphine atoms
composed of either PPh3 (20 mol %) or Xantphos (12 mol %) was
ineffective (entries 6 and 7, in Table 1B).
8
9
Table 1. Key Parameters Controlling Tertiary Alkylation of
Silyl Enol Ether and Enamidea
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Figure 1. Working hypothesis of visible-light-induced palladium-
catalyzed synthesis of -alkylated ketone and imine via a hybrid alkyl
Pd(I)-radical species
We report herein that by using excited-state reactivity of
palladium catalyst in combination with two types of phosphine
ligands (Xantphos and PPh3) under irradiation of blue LEDs at
room temperature, alkylations of silyl enol ether and N-acyl
enamide were achieved with a broad scope of alkyl bromides
including all tertiary, secondary, and primary alkyls. Theoretical
study suggested that the reaction proceeds by irradiation-induced
ISET from dual phosphine-coordinated Pd(0) to activate alkyl
bromides to generate hybrid alkyl Pd(I)-radical species followed by
a process involving dissociation and association of monodentate
phosphine.8d The ligand structure and energy profiles of the
intriguing hybrid alkyl Pd(I)-radical species are elucidated. The
results presented here offer synthetic methods for preparation of -
alkylated ketone, -alkylated N-acetyl ketimines, and
enantiomerically pure -arylated aliphatic amines. The theoretical
explanation of the mechanism with respect to irradiation effect,
dual ligand effect, and the structure of hybrid alkyl Pd(I)-radical
species provides further guidance to design and explore palladium
catalysis under irradiation excitation.
2. RESULTS AND DISCUSSION
2.1. Alkylation of Silyl Enol Ether and Enamide
The optimized reaction conditions for alkylation of
trimethyl((1-phenylvinyl)oxy)silane
and
N-(1-
phenylvinyl)acetamide with tert-butyl bromide are shown in Table
1. For alkylation of silyl enol ether, a combination of Pd(PPh3)4 (5
mol %) and Xantphos (6 mol %) served as the optimal catalyst to
deliver the desired ketone product in 86% isolated yield after silica
gel column chromatography. Notably, the Heck-type product was
isolated in the absence of water using anhydrous dioxane. Water
(10 equiv) was added to hydrolyze the alkylated silyl enol ether in
situ to afford the ketone product. Dioxane was found to be the
optimal solvent (see Supporting Information for results of
screening solvents), and potassium acetate was found to be a mild
base to trap the trimethylsilyl group. The palladium catalyst and
irradiation by blue LEDs were essential for the reaction (entries 1
and 6 in Table 1A). The reaction proceeded in only 18% yield in
the absence of Xantphos (entry 2, in Table 1A). Using Pd(OAc)2 (5
mol %) and Xantphos (12 mol %) instead of Pd(PPh3)4 shut down
the reactivity, revealing the essential role of the dual phosphine
ligand system (entry 3, in Table 1A). Pd2(dba)3 (2.5 mol %) used
instead of Pd(PPh3)4 was not productive (entry 4, in Table 1A ).
KOAc as base is also crucial for the reaction to proceed (entry 5, in
Table 1A ). Other bidentate phosphine ligands such as DPE-Phos,
dppp, dppen, and triphos were all ineffective (Table 1A, bottom).
aReaction performed at room temperature (25±3 °C) for 24 h under argon
c
atmosphere. bYield of isolated product. Yield determined by 1H-NMR
using diphenylmethane as an internal standard.
The optimized reaction conditions for alkylation of silyl enol
ether and enamide were applicable for a broad scope of substrates.
The reaction scope with respect to alkylation of silyl enol ether is
shown in Scheme 1. A broad scope of tertiary and secondary alkyl
bromides including both cyclic and acyclic ones exhibited as
amenable substrates (1–14). Primary alkyl bromide (15) and
benzyl bromide (16) were also suitable substrates. The reaction
For alkylation of enamide shown in Table 1B, the optimal
condition uses Pd(OTfa)2 (5 mol %) as palladium source, and PPh3
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is compatible with various functional groups and substituents
such as ester (4), alkyl chloride (8), amide (12), ether (18),
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trifluoromethyl (19), cyano (21), aryl pinacol boronate (22), and
sulfone (24). Both electron-rich (18) and electron-deficient (19,
24, 28) silyl enol ethers exhibited as suitable substrates.
However, this reaction scope was limited to silyl enol ether
derived from aromatic and heteroaromatic ketones (29, 30).
Silyl enol ether derived from aliphatic ketones was an
incompatible substrate. Silyl enol ether derived from
benzylideneacetone afforded the desired product in moderate yield
(31). Sily enol ethers derived from -substituted acetophenones,
(e.g. propiophenone) were not successful probably because of the
increased steric hindrance.
The synthetic value of this excited-state palladium-catalysis
is highlighted by the synthesis of a broad scope of N-acyl-protected
ketimines from N-acyl enamides and alkyl bromides. N-acyl-
protected ketimines can be further (enantioselectively) reduced to
afford primary amine, which is a class of useful intermediates for
synthesis of bioactive compounds. Synthesis of N-acyl-protected
ketimine is challenging because of the weak nucleophilicity of
amide to condense with ketone. In addition, there is no efficient
synthetic method to access stereochemically pure N-acyl ketimine.
One study reported an isomerization-free method to access N-acyl
imines from hazardous secondary azides under light irradiation,15
but the compatibility of this method for the synthesis of -alkylated
ketimines with large steric hindrance was not demonstrated.
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Pd(OTfa)2 (5 mol %)
PPh3 (12 mol %)
Xantphos (6 mol %)
R'
R
HN
alkyl Br
0.2 mmol
N
R
KOAc (1.5 equiv)
dioxane (2.0 mL), r.t., 24 h
blue LEDs (456 nm)
alkyl
R'
(1.5 equiv)
Ac
Ac
Ac
Ac
N
N
N
Cl
N
Ph
Ph
32, 96%
Ph
Ph
Ph
34, 80%
35, 73%
33, 68%
Ph
O
Ac
Ac
O
Ac
Ac
N
O
N
O
N
N
Ph
Ph
O
Ph
Ph
38, 79%
39, 80%
37, 88%
36, 75%
Ac
H
H
O
N
Ac
Ac
N
N
Ph
Ph
H
Ph
H H
H H
COOEt
41, 73%, d.r. = 2.7:1
t-Bu
42, 82%, d.r. = 1.5:1
t-Bu
40, 73%
t-Bu
Ac
N
Ac
N
Ac
N
R
Ph
R = –F 43, 80%
–Cl 44, 92%
46, 99%
45, 93%
t-Bu
Ac
t-Bu
N
Me
Ac
N
O
Ac
N
t-Bu
49, 95%
MeOOC
O
Me
48, 88%
47, 97%
t-Bu
t-Bu
O
Ph
N
Ac t-Bu
O
Ph
N
N
F
O
aReaction conditions: alkyl halide (0.2 mmol), silyl enol ether (0.3 mmol),
Pd(PPh3)4 (5 mol %), Xantphos (6 mol %), KOAc (150 mol %), 1,4-dioxane
(2 mL), H2O (2.0 mmol), irradiation by blue LEDs (456 nm) at room
temperature for 24 h under argon atmosphere. Yield of isolated product.
OMe
50, 73%
52, 98%
51, 92%
reduced products
t-Bu
t-Bu
t-Bu
t-Bu
Ac
Ac
S
O
Scheme 1. Scope of Alkylation of Silyl Enol Ether for Synthesis
of -Alkylated Ketonesa
Ac
Ac
N
N
N
N
H
H
H
H
F3C
MeS
55, 87%b
56, 78%b
53, 86%b
54, 98%b
Tertiary alkylation can also be achieved using N-
(acyloxy)phthamide by slightly modifying the ligand system to use
Ni-Xantphos (eq. 3). However, because of the existence of a much
cheaper and more efficient reaction system using NaI/PPh3
developed previously,14 we did not expand further the scope using
the palladium system reported herein.
aReaction conditions: alkyl halide (0.2 mmol), enamide (0.3 mmol),
Pd(OTfa)2 (5 mol %), PPh3 (12 mol %), Xantphos (6 mol %), KOAc (150
mol %), 1,4-dioxane (2 mL), irradiation by blue LEDs (456 nm) at room
temperature for 24 h under argon atmosphere. Yield of isolated product.
1
b
Ratio of diastereomer measured by H-NMR analysis. Yield of isolated
product obtained after in situ reduction using NaBH4 (0.4 mmol) and acetic
acid (0.6 mmol) at room temperature for 3 h.
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Scheme 3. Chiral Phosphoric Acid-Catalyzed Enantioselective
Scheme 2. Reaction Scope of Stereoselective Synthesis of -
Reduction of N-Acyl Iminea
Alkylated Iminesa
1
2
3
4
5
6
7
8
9
Our method using irradiation-induced palladium catalysis
afforded a broad scope of -tertiary, secondary, and primary
alkylated N-acyl ketimines as pure stereoisomer (Scheme 2). The
geometric structure of the stereoisomer was determined to be E-
configuration by measuring single crystals of several products (45,
49, 51). The reaction is applicable to complicated steroid-derived
alkyl bromides to install imine functionality into steroid derivatives
(41, 42). Besides acetyl-protected ketimine, the reaction also
afforded ketimines protected by both electron-rich and electron-
deficient aroyl groups (51, 52). The generated ketimine product can
be in situ reduced by adding sodium borohydride and acetic acid at
room temperature to deliver -arylated aliphatic amines. Most
importantly, -alkylated N-acyl ketimine products can be subjected
to chiral phosphoric acid-catalyzed asymmetric reduction16 with
Hantzsch ester to deliver -arylated aliphatic amines in high
enantioselectivity up to 99% ee, providing a new method for facile
synthesis of chiral -arylated aliphatic amines of structure diversity
(Scheme 3). Although methods of chiral phosphoric acid-catalyzed
enantioselective reduction of imine have been reported,16a,17 they
reports mostly used N-p-methoxyphenyl (PMP)-protected imines,
which need further oxidation for deprotection. Moreover, the
substrates in these reports were limited to ketimines derived from
acetophenone derivatives,16a, 17a probably because of the synthetic
complexity of accessing -alkylated 1-arylethan-1-imine with
structure diversity.
As shown in Scheme 3, -tertiary alkylated ketimines (57–62),
-secondary alkylated ketimine (63), and -primary alkylated
ketimine (64) were all amenable substrates for asymmetric
reduction to afford 2-arylated N-acetyl aliphatic amines in good
yield and high enantioselectivity. Functional groups such as alkene
(62) and ester (61, 64) did not affect the high enantioselectivity.
When (R)-PA was used as catalyst, the absolute configuration of
product (57) and (61) was determined to be (S)-configuration by X-
ray crystallography. Changing the absolute configuration of chiral
phosphoric acid catalyst resulted in inversion of the absolute
configuration of the product with little effect on reaction efficiency
(57). These N-acetyl amines obtained in high ee and high yield are
easily subjected to hydrolysis to give free amine. Also, the N-acetyl
ketimine product reacted smoothly with various types of Grignard
reagents, including methyl (65), vinyl (66), benzyl (67), allyl (68),
phenyl (69), cyclohexyl (70), and isopropyl (71), to afford
sterically bulky N-acetyl -tertiary amines in high yields (Scheme
4).18
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2.2. Further Transformation of -Alkylated N-acyl
Ketimine Products
aReaction conditions: imine (0.2 mmol), Grignard reagent (200 mol % in
THF). Yield of isolated product.
R
O
O
Scheme 4. Synthesis of N-Acetyl -Tertiary amines from N-acyl
(R)-PA
(5.0 mol %)
alkyl
Ar
alkyl
Ar
P
R =
Ketimine Productsa
OH
O
Ac
Ac
HE (1.2 eq.)
DCM (2 mL)
r.t., 15 h
N
N
*
H
R
2.3. Possible Mechanism of the Reaction with Dual Ligand
Cooperation
0.2 mmol
(R)-PA
9-anthracenyl
t-Bu
t-Bu
t-Bu
Ac
N
Ac
Ac
N
N
H
H
H
Ph
(Np-)
58, 88% yield
94% ee
57, 84% yield
98% ee (S)b
59, 95% yield
99% ee
t-Bu
COOMe
O
Ac
H
N
N
H
Ac
O
t-Bu
61, 90% yield
60, 84% yield
91% ee
98% ee (S)
COOEt
Ph
Ac
Ac
Ac
Np
N
Np
N
Np
N
H
H
H
64, 85% yield
97% ee
63, 78% yield
d.r. = 1:1, 96% ee
62, 74% yield
99% ee
Scheme 5. Radical-Clock and Radical-Trapping Experiments
aReaction conditions: imine (0.2 mmol), (R)-PA (5 mol %, 0.01 mmol),
Hantzsch ester (120 mol %, 0.24 mmol), dichloromethane (2 mL). Yield of
isolated product. Condition for determination of enantiomeric excess:
HPLC, Daicel CHIRALPAK AD, hexane/2-propanol = 100/5 ~ 100/10,
flow rate 1.0 mL/min. bSingle crystal data shown in Supporting Information
(Table S9). (R)-isomer was obtained in 82% isolated yield and 98% ee.
when (S)-PA was used as catalyst.
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Although new catalytic reactivity of excited-state palladium
DFT calculations24 to support the proposed mechanism of
alkylation between enamine (a) and tert-butyl bromide (B) are
shown in Figure 3. In situ generated three-coordinated
Pd0(Xantphos)(PPh3) (A) complex is considered as the reference
structure for calculation. It is known that the phosphine-
coordinated Pd(0) species needs to overcome a high energy barrier
to undergo oxidative addition with tertiary alkyl bromide through a
three-centered transition state that resembles oxidative addition
with aryl halides.25 Activation of tert-butyl bromide (B) through
photoinduced ISET from A to generate ionized species (A1+B1)
requires overcoming an energy barrier of 57.9 kcal/mol, an energy
lower than the photon energy blue LEDs can provide (approx. 62.7
kcal/mol). DFT calculation and Marcus theory26 were applied to
compare the energy barriers for ISET from different Pd(0) species
to B, and the results revealed that A has the lowest energy barrier
(∆G = 57.9 kcal/mol, ∆G* = 58.3 kcal/mol) to activate B, while
Pd0(Xantphos) (A) and Pd0(PPh3)3 (A) have higher energy
barriers (∆G = 68.7 kcal/mol, ∆G* = 70.4 kcal/mol for A and ∆G
= 58.8 kcal/mol, ∆G* = 59.2 kcal/mol for A; see inset in Figure
3). These calculation results support that a Pd(0) species
coordinated by three phosphine atoms is responsible for the ET
process. Considering that ISET from A and A to B overcomes
similar energy barriers, the different outcomes using
Xantphos/PPh3 dual ligand and PPh3 alone could be attributed to a
better effect of Xantphos to stabilize hybrid alkyl Pd(I)-radical
species compared with PPh3 (cf. Figure 6A and 6C) . Fragmentation
of A1+B1 resulted in formation of hybrid alkyl Pd(I)-radical (C+D)
with energy release of 40.3 kcal/mol. C+D further overcomes a
small energy barrier to react with enamide to generate C+E by
releasing energy of 16.4 kcal/mol. The two doublet species C and
E collapse into a Pd(II) species G by dissociating PPh3 ligand. This
ligand dissociation process has an energy barrier of 17.2 kcal/mol.
Further exchange of bromide by acetate generates H and -H
elimination gives imine-coordinated Pd(0) species. PPh3
association to Pd(0) liberates the imine product and regenerates
triphosphine-coordinated Pd(0) species A for the next catalytic
cycle. Control calculation revealed that the generation of E-
ketimine is thermodynamically favored by 0.6 kcal/mol, which
explains the observed E-selectivity. A control experiment testing
compound 32 under standard reaction condition without addition
of alkyl bromide showed no stereoisomerization of E-ketimine,
revealing no palladium-catalyzed E/Z isomerization. The whole
catalytic cycle proceeds with a thermochemistry of the reaction A
(S0) + B + a + KOAc → A (S0) + c + KBr + HOAc, which equals
–7.2 kcal/mol. Besides the photoinduced ISET step, the energy
barriers of all the other steps in the catalytic cycle are lower than
20 kcal/mol, which is in accordance with the room temperature
condition. Irradiation plays an essential role in inducing ISET from
Pd(0) to activate alkyl bromide.
1
2
3
4
5
6
7
8
species for alkyl cross-coupling4,5,8 and C–H functionalization19
has been reported by several research groups recently, the reactive
alkyl palladium species under light irradiation remains elusive. It
has been claimed that catalyst under visible light irradiation
resembles a photoredox catalyst20 applied in recently popularized
photoredox chemistry.21 A Recent theoretical study by Rueping and
Cavallo22 and
a mechanistic investigation by Shang and
colleagues5,8 suggest that an ISET process between three
phosphine-atom-coordinated Pd(0) species and alkyl electrophiles
(alkyl bromide, or alkyl carboxylic acid N-hydroxyphthalimide
ester) to generate hybrid alkyl Pd(I)-radical followed by ligand
dissociation and association processes is more plausible. Through
radical clock experiments23 (Scheme 5A and 5B) and radical-
trapping experiment using TEMPO as scavenger (Scheme 5C), the
alkyl radical property of the intermediate was confirmed. For
enamide reaction, a control experiment showed that enamide
starting material did not isomerize to imine under the standard
reaction condition (eq. 4). We propose a reaction mechanism that
rationalizes the irradiation effect as well as the essential dual ligand
effect in Figure 2. As shown, the reaction starts with
photoactivation of a Pd(0) species three-coordinated by two
phosphine ligands (I). Visible light activation of I results in ISET
to activate alkyl bromide to generate hybrid alkyl Pd(I)-radical
species (II). Intermediate II reacts with silyl enol ether or enamide
to generate benzylic type radical, which has stronger coordination
ability toward palladium compared with saturated alkyls to replace
a monodentate phosphine ligand to generate intermediate IV, on
which -H elimination proceeds to give intermediate V.
Regeneration of I proceeds through association of monodentate
phosphine ligand to release product. DFT calculation is further
used to prove the possible reaction mechanism (Figure 3) and
elucidate the nature of the intriguing hybrid alkyl Pd(I)-radical
species (Figures 4–6).
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Figure 2. Proposed catalytic cycle.
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Figure 3. Computed energy profile for alkylation of enamide. Free energies in solution (in kcal/mol) at the M06/6-311+G(d,p)-SDD-
SMD(Dioxane)//B3LYP/6-31G(d)-LANL2DZ level are displayed.
t-Bu
PPh3
P
P
2.4. Theoretical Elucidation of Hybrid Alkyl Pd(I)-
Radical Species
PdII

G(kcal/mol)
Br
t-Bu
PPh3
Br
P
P
PdI
3.1
6.4
(1) The transformation between alkyl-Pd(II) and hybrid alkyl
Pd(I)-radical
3.3
TSKL
0.0
L
TSLM
-0.6
M
After clarifying the energy profile of the proposed reaction
mechanism, theoretical calculation was used to elucidate the
intriguing hybrid alkyl Pd(I)-radical species (C+D in Figure 3). The
existence of this species in irradiation-induced palladium catalysis
has been proposed, but was sometimes challenged because of the
high propensity of alkyl radical recombination to a d9 metal center.
We consider that three factors may contribute to stabilizing this
species to prevent alkyl recombination, 1) the dual ligand system,
2) a possible MLCT to ligand under irradiation, and 3) spin
prohibition. DFT and TD-DFT calculations were used to clarify
these issues. As shown in Figure 4, the transformation between
alkyl-Pd(II) species (K) and hybrid alkyl Pd(I)-radical (M) species
is a stepwise process involving L as intermediate, namely first
dissociation of PPh3 and then association with t-Bu•. The alkyl-
Pd(II) species K and hybrid alkyl Pd(I)-radical M have very close
stability, and the energy difference between them is only 0.6
kcal/mol. The barrier for transformation between K and M is
relatively small (about 6–7 kcal/mol), indicating the kinetic
easiness of this transformation.
t-Bu
PPh3
K
P
PPh3
Br
t-Bu
PPh3
PdI
P
P
P
Br
PdI
PdII
P
P
Br
t-Bu
Figure 4. Transformation energy profile between alkyl-Pd(II) (K)
and hybrid alkyl Pd(I)-radical species (M).
(2) The possibility of MLCT state for Xantphos-Pd(I)-PPh3-Br
The possibility of MLCT between Xantphos and palladium
center to stabilize Xantphos-Pd(I)-PPh3-Br species was examined
by DFT calculations. We first attempted to obtain this MLCT state
in ground state DFT calculations. After swapping the orbitals for
getting the proper MLCT configuration of Xantphos-Pd(I)-PPh3-Br
as input for DFT calculation, we found that it was impossible to
obtain this MLCT state as the ground state, and the ligand π* orbital
of Xantphos was much higher in energy than the d-orbital of Pd(I).
This explains why the MLCT state cannot be obtained in ground-
state DFT calculations. We also tried TD-DFT calculations, and
found that the MLCT state was an excited state that was much
higher in energy than the ground state by 72.6 kcal/mol, an energy
even higher than the energy of irradiation photons (Figure 5),
Therefore, the MLCT state for Pd(I) species is unlikely to be
involved in the catalytic cycle. Based on the calculated energies,
we excluded the possibility of MLCT between Xantphos and Pd(I)
contributing to stabilize the hybrid alkyl Pd(I)-radical species.
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E (TD-DFT/M06) =
Eneries of singlet and triplet states of Pd(I)-(PPh3)3-Br/t-Bu• (M)
compared with K.
These calculation results shown in Figure 6A and Figure 6C
PPh3
Br
PPh3
Br
P
P
P
P
PdII
72.6 kcal/mol
PdI
1
2
3
4
5
6
7
8
9
revealed that Xantphos facilitates the formation of hybrid alkyl
Pd(I)-radical species, which explains the essential role of Xantphos
for these reactions.
Figure 5. TD-DFT calculation to locate the MLCT state for
Xantphos-Pd(I)-PPh3-Br species.
(3) The possibility of spin prohibition to enhance the kinetic
stability of hybrid alkyl Pd(I)-radical species (M)
Based on the above calculations, we conclude that Xantphos-
ligated
hybrid
alkyl
Pd(I)-radical
species
(M)
is
thermodynamically more favorable compared with alkyl-
recombined Pd(II) species (K), and spin prohibition rather than
MLCT contributes to the kinetic stability of M to impede alkyl
recombination.
As shown in Figure 4, with singlet hybrid alkyl Pd(I)-radical
species M, it is kinetically easy to form alkyl-Pd(II) species.
However, we found that triplet-state hybrid alkyl Pd(I)-radical
species M(triplet) is slightly more stable than the singlet one
(Figure 6A). In the triplet state, the formation of alkyl-Pd(II)
species from M(triplet) is not feasible, and geometry optimization
of alkyl-Pd(II) structure leads to spontaneous cleavage of the Pd–C
bond and release of t-Bu•. Therefore, it is possible for M(triplet) to
serve as a kinetically more stable form of hybrid alkyl Pd(I)-radical
species that has a longer lifetime. The optimized structure and
electron distribution of M(triplet) are shown in Figure 6B, where
the Pd(I) center is coordinated by three phosphine atoms with a
distorted tetrahedral geometry. Based on these results, we also
investigated the energy difference between Xantphos-Pd(I)-PPh3-
Br/t-Bu• intermediate (M) and Pd(I)-(PPh3)3-Br/t-Bu• intermediate
to understand the essential effect of Xantphos as ligand (Figure 6C).
As shown in Figure 6C, Pd(I)-(PPh3)3-Br/t-Bu• intermediate is +5.8
kcal/mol higher in energy compared with alkyl-recombined Pd(II)
intermediate K. The triplet state of M is +5.1 kcal/mol higher in
energy compared with K.
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3. CONCLUSION
In summary, alkylation of silyl enol ether and enamide with
tertiary, secondary, and primary alkyl bromides was achieved using
visible-light-induced palladium catalysis applying
a
dual
phosphine ligand system. The reactions effectively deliver -
alkylated ketones, as well as -alkylated N-acyl ketimine in a
stereoselective manner. The -alkylated N-acyl ketimine products
can be subjected to chiral phosphoric acid-catalyzed asymmetric
reduction with Hantzsch ester to deliver chiral -arylated N-acyl-
protected aliphatic amines in high enantioselectivity up to 99% ee.
The N-acetyl ketimine products also reacted with various Grignard
reagents to produce N-acetyl -tertiary amines in good yields.
Theoretical studies provided mechanistic understanding of the
reaction mechanism with respect to the dual ligand effect and
irradiation effect in the catalytic cycle. The reaction is suggested to
proceed via a hybrid alkyl Pd(I)-radical species generated by ISET
from dual phosphine ligand-coordinated Pd(0) species to alkyl
bromide. This intriguing hybrid alkyl Pd(I)-radical species was
elucidated by theoretical calculation to be a triplet species
coordinated by three phosphine atoms with a distorted tetrahedral
geometry, which is energetically slightly favored compared with
the corresponding alkyl-recombined Pd(II) species. Spin
prohibition rather than MLCT contributes to the stability of hybrid
alkyl Pd(I)-radical species to impede alkyl recombination. The
discovered reactions add examples to the repertoire of excited-state
palladium catalysis. It is hoped that the theoretically elucidated
structure and reactivity of hybrid alkyl Pd(I)-radical species as well
as the dual ligand effect will provide guidance in related fields for
the discovery of new reactivity of excited-state transition metal
catalysis under visible light.
A
PPh3

G (kcal/mol)
P
P
PdI
Br
t-Bu
-0.6
M
spin-
prohibited
0.0
-2.0
K
K (triplet)
M (triplet)
t-Bu
P
t-Bu
P
P
PdII
PdII
PPh3
PPh3
Br
PPh3
P
Br
P
PdI
Br
P
not exist
t-Bu
Xantphos
P
P
B
t-Bu
Br
P
PdI
P
ASSOCIATED CONTENT
PPh3
M (triplet)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: rui@chem.s.u-tokyo.ac.jp (R.S.); chenh@iccas.ac.cn
(H.C.); fuyao@ustc.edu.cn (Y. F.)
C

G (kcal/mol)
+5.8
M’
+5.1
Notes
M’ (triplet)
0.0
K’
PPh3
Ph3P
Ph3P
The authors declare no competing financial interest.
PPh3
PdI
Ph3P
Ph3P
Ph3P
PdI
t-Bu
Br
PdII
Supporting Information
Br
Ph3P
PPh3
t-Bu
Br
t-Bu
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental details and characterization data for all products
(PDF).
Crystallographic data for 45 (CIF)
Crystallographic data for 49 (CIF)
Crystallographic data for 51 (CIF)
Crystallographic data for 57 (CIF)
Crystallographic data for 61 (CIF)
Figure 6. The triplet M(triplet) as a more stable hybrid alkyl Pd(I)-
radical species (M) to avoid the kinetically active singlet M. (A)
The Spin-Prohibition effect to kinetically stabilize triplet hybrid
alkyl Pd(I)-radical species. (B) Computed structure and d-orbital
electron distribution of triplet hybrid alkyl Pd(I)-radical species.
Orbitals indicating spin delocalization on Pd(I) radical species. (C)
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V., Catalysis with Palladium Complexes Photoexcited by Visible Light.
Angew. Chem. Int. Ed. 2019, 58, 11586–11598.
ACKNOWLEDGMENTS
1
2
3
4
5
6
7
8
(5) (a) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y., Irradiation-induced
Heck Reaction of Unactivated Alkyl Halides at Room Temperature. J.
Am. Chem. Soc. 2017, 139, 18307–18312. (b) Kurandina, D.; Parasram,
M.; Gevorgyan, V., Visible Light-induced Room-temperature Heck
This work was supported by National Key R&D Program of China
(2018YFB1501600, 2017YFA0303502), National Natural Science
Foundation of China (21572212, 21732006, 51821006,
51961135104, 21833011), Strategic Priority Research Program of
CAS (XDB20000000, XDA21060101), HCPST (2017FXZY001),
KY (2060000119). Calculations were conducted on the
supercomputing system in the Supercomputing Center of USTC.
Reaction
of
Functionalized
Alkyl
Halides
with
Vinyl
Arenes/heteroarenes. Angew. Chem. Int. Ed. 2017, 56, 14212–14216. (c)
Kurandina, D.; Rivas, M.; Radzhabov, M.; Gevorgyan, V., Heck
Reaction of Electronically Diverse Tertiary Alkyl Halides. Org. Lett.
2018, 20, 357–360. (d) Wang, G.-Z.; Shang, R.; Fu, Y., Irradiation-
induced Palladium-catalyzed Direct C–H Alkylation of Heteroarenes
with Tertiary and Secondary Alkyl Bromides. Synthesis 2018, 50, 2908–
2914. (e) Koy, M.; Sandfort, F.; Tlahuext-Aca, A.; Quach, L.; Daniliuc,
C. G.; Glorius, F. Palladium-catalyzed Decarboxylative Heck-type
Coupling of Activated Aliphatic Carboxylic Acids Enabled by Visible
Light. Chem. Eur. J. 2018, 24, 4552–4555. (f) Koy, M.; Bellotti, P.
Katzenburg, F.; Daniliuc, C. G.; Glorius, F. Synthesis of All-carbon
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