Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unactivated Olefins

Article abstract of DOI:10.1016/j.chempr.2018.11.014

The integration of amidyl radicals with cross-coupling chemistry opens new avenues for reaction design. However, the lack of efficient methods for the generation of such radical species has prevented many such transformations from being brought to fruition. Herein, the amidoarylation of unactivated olefins by a cascade process from non-functionalized amides is reported by merging, for the first time, photoredox proton-coupled electron transfer (PCET) with nickel catalysis. This new technology grants access to an array of complex molecules containing a privileged pyrrolidinone core from alkenyl amides and aryl- and heteroaryl halides in the presence of a visible light photocatalyst and a nickel catalyst. Notably, the reaction is not restricted to amides—carbamates and ureas can also be used. Mechanistic studies, including hydrogen-bond affinity constants, cyclization rate measurements, quenching studies, and cyclic voltammetry, were central to comprehend the subtleties contributing to the integration of the two catalytic cycles. A rapid, highly diastereoselective amidoarylation of unactivated olefins was achieved to render medicinally privileged pyrrolidinone structures. Taking advantage of a photoredox proton-coupled electron transfer process, amidyl radicals were obtained from non-prefunctionalized N–H bonds under mild conditions, which were subsequently trapped by pendant olefins, delivering alkyl radicals for nickel-catalyzed cross-coupling. Mechanistic studies revealed the key balance between thermodynamically-driven radical generation and kinetically-driven cyclization, which led to expanding the scope toward urea and carbamate substrates. Rapid generation of molecular complexity and access to novel 3D chemical space is pivotal for successful and efficient drug discovery. Nickel/photoredox dual catalysis has arisen as an appealing strategy toward such a goal by rapidly introducing C_sp3 centers under mild reaction conditions. By taking advantage of a native amide group, we achieved an amidoarylation reaction of unactivated olefins, rendering a series of medicinally privileged structures in a highly atom-economical way. The reaction takes advantage of a photoredox proton-coupled electron transfer event to cleave the strong amidyl N–H bond homolytically. Subsequent regiospecific 5-exo-trig cyclization generates an alkyl radical. High functional group tolerance was achieved with excellent diastereoselectivities owing to the reaction's mild nature. Mechanistic studies showed the intricate relationship between the base stoichiometry and the N–H donor, as well as the key balance between kinetic and thermodynamic factors.

Full text of DOI:10.1016/j.chempr.2018.11.014

Article
Merging Photoredox PCET with Ni-Catalyzed
Cross-Coupling: Cascade Amidoarylation of
Unactivated Olefins
´
Shuai Zheng, Alvaro
Gutie´ rrez-Bonet, Gary A.
Molander
gmolandr@sas.upenn.edu
HIGHLIGHTS
Generation of C-centered radicals
via cleavage of strong X–H bonds
for cross-coupling
Rapid formation of new N–Csp3
and Csp2–Csp3 bonds from olefins
under mild conditions
Highly diastereoselective
synthesis of medicinally privileged
pyrrolidinone structures
Mechanism-driven scope
expansion toward carbamate and
urea motifs
A rapid, highly diastereoselective amidoarylation of unactivated olefins was
achieved to render medicinally privileged pyrrolidinone structures. Taking
advantage of a photoredox proton-coupled electron transfer process, amidyl
radicals were obtained from non-prefunctionalized N–H bonds under mild
conditions, which were subsequently trapped by pendant olefins, delivering alkyl
radicals for nickel-catalyzed cross-coupling. Mechanistic studies revealed the key
balance between thermodynamically-driven radical generation and kinetically-
driven cyclization, which led to expanding the scope toward urea and carbamate
substrates.
Zheng et al., Chem 5, 1–14
February 14, 2019 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.11.014

Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Article
Merging Photoredox PCET with Ni-Catalyzed
Cross-Coupling: Cascade Amidoarylation
of Unactivated Olefins
Shuai Zheng,1,2 Alvaro Gutie´ rrez-Bonet,1,2 and Gary A. Molander1,3,
´
*
SUMMARY
The Bigger Picture
Rapid generation of molecular
complexity and access to novel 3D
chemical space is pivotal for
successful and efficient drug
discovery. Nickel/photoredox
dual catalysis has arisen as an
appealing strategy toward such a
goal by rapidly introducing Csp3
centers under mild reaction
conditions. By taking advantage
of a native amide group, we
achieved an amidoarylation
reaction of unactivated olefins,
rendering a series of medicinally
privileged structures in a highly
atom-economical way. The
reaction takes advantage of a
photoredox proton-coupled
electron transfer event to cleave
the strong amidyl N–H bond
homolytically. Subsequent
The integration of amidyl radicals with cross-coupling chemistry opens new
avenues for reaction design. However, the lack of efficient methods for the gen-
eration of such radical species has prevented many such transformations from
being brought to fruition. Herein, the amidoarylation of unactivated olefins by
a cascade process from non-functionalized amides is reported by merging, for
the first time, photoredox proton-coupled electron transfer (PCET) with nickel
catalysis. This new technology grants access to an array of complex molecules
containing a privileged pyrrolidinone core from alkenyl amides and aryl- and
heteroaryl halides in the presence of a visible light photocatalyst and a nickel
catalyst. Notably, the reaction is not restricted to amides—carbamates and
ureas can also be used. Mechanistic studies, including hydrogen-bond affinity
constants, cyclization rate measurements, quenching studies, and cyclic voltam-
metry, were central to comprehend the subtleties contributing to the integra-
tion of the two catalytic cycles.
INTRODUCTION
The recent disclosure of nickel/photoredox dual catalysis has made cross-coupling
chemistry an even more important tool for synthetic chemists.1–7 Under mild condi-
tions with excellent functional group tolerance, these powerful methods have facil-
itated the construction of numerous challenging Csp2–Csp31–7 and Csp3–Csp38 bonds,
transformations that are crucial for success in modern drug discovery.9 Although
powerful and enabling, most of the radical precursors contain a traceless redox
handle previously introduced via multi-step synthesis1,2,6,7 that is homolytically
cleaved, generating the desired radical species. Ideally, if radicals were generated
from native functional groups benefiting from innate reactivity, excellent atom-
and step-efficiencies could be achieved on top of the many other existing advan-
tages associated with Ni/photoredox dual catalysis (e.g., mild reaction conditions,
good chemoselectivity, and reduced risks of side reactions).
regiospecific 5-exo-trig
cyclization generates an alkyl
radical. High functional group
tolerance was achieved with
excellent diastereoselectivities
owing to the reaction’s mild
nature. Mechanistic studies
showed the intricate relationship
between the base stoichiometry
and the N–H donor, as well as the
key balance between kinetic and
thermodynamic factors.
In this vein, significant achievements have been reached by merging hydrogen atom
transfer (HAT) of activated C–H bonds with Ni-catalyzed cross-coupling reactions.4,5
However, there has been a lack of reports in which heteroatom-centered radicals,
derived from the homolytic cleavage of heteroatom–hydrogen bonds, are used as
initial intermediates in a sequence of transformations, leading to subsequent
C
sp2–Csp3 bond construction.10 In fact, if the generation of such radicals could be
coupled with a cyclization onto naturally abundant olefins, one could not only main-
tain excellent atom economy while accessing privileged heterocyclic scaffolds, but
also transform relatively unreactive olefins to reactive, nucleophilic C-centered
Chem 5, 1–14, February 14, 2019 ª 2018 Elsevier Inc.
1

Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Prefunctionalized amides
Unfunctionalized amides
Multi-step preparation
Homolysis, radical-chain
UV-light, radical initiator, etc.
O
High oxidation potential and pKa
PT/ET or ET/PT
(strong oxidant/base)
O
O
Ar
ref 22-26
ref 15-18
Ar
Ar
R
N
R
N
R
N
LG
H
amidyl radical
LG: Cl, SPh, PTOC,
PCET (mild base & oxidant)
OAr, SO2Ar
R = H with
O
O
R =
Ar
X
H
cat. Ar'S
N
Ar
5-exo-trig
Ar1
R
N
X
EWG
R =
NiI
Ln
desired product
versus
from
EWG
O
previous
work
Ar
N
O
Ni-catalyzed
cross-coupling
Ar
N
O
N
X
Ar
LnNi0
termination
X
Ar1 Br
NiI
Ln
X
R
ref 14, 27, 29
this work
I
Scheme 1. Generation of Amidyl Radicals from Functionalized and Non-functionalized Amides
radicals, thereby providing new opportunities for rapidly increasing molecular
complexity via novel radical cyclization/cross-coupling paradigms.
Owing to the prevalence of nitrogen-containing heterocycles in Food and Drug
Administration-approved small-molecule drugs,11 an investigation was undertaken
to explore the applicability of amidyl radicals, generated via homolytic N–H cleav-
age, to synthesize nitrogen-containing heterocycles via a radical cyclization/cross-
coupling paradigm. The generation of amidyl radicals from N–H bonds has
previously posed significant challenges because of their high stability (bond-disso-
ciation free energy ꢀ100 kcal/mol).12–18 As a result, amidyl radical formation was
only achieved using strong oxidants (e.g., Dess-Martin periodinane,15 iodoxyben-
zoic acid,16 di-tert-butyl peroxide17) at high temperatures (Scheme 1),15–18 seriously
compromising the applicability of the developed methods. Alternatively, the use of
prefunctionalized amides19–21 (e.g., LG = Cl,22 SPh,23 PTOC [pyridine-2-thione-N-
oxycarbonyl],24 OAr,25 or SO2Ar26) made amidyl radicals more accessible under
various conditions (i.e., UV light, radical initiators, reductants). However, this
approach posed numerous disadvantages, such as the requirement for multi-step
syntheses of the amide derivatives, poor stability of the functionalized amides,
and the use of hazardous reagents, among others.
1Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia,
PA 19104-6323, USA
In a seminal publication, the Knowles group reported the generation of amidyl rad-
icals by merging concerted proton-coupled electron transfer (PCET) with photore-
dox catalysis (Scheme 1).14,27–29 After adoption of the biologically ubiquitous
PCET mechanism,30,31 this challenging bond disconnection was realized under
very mild conditions by emphasizing a much lower-barrier concerted pathway,
where charged intermediates are avoided.15–17 Mechanistic studies showed that
upon hydrogen bonding with a phosphate base, the amidyl radical was generated
2These authors contributed equally
3Lead Contact
*Correspondence: gmolandr@sas.upenn.edu
https://doi.org/10.1016/j.chempr.2018.11.014
2
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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
via single-electron transfer oxidation by the excited photocatalyst. Subsequent
addition of the amidyl radical across the pendant alkene resulted in a C-centered
radical, which was quenched via hydrogen atom abstraction or Giese-type addition
to a Michael acceptor.14,27,32
Being aware of the potential of alkene difunctionalization strategies for the rapid
construction of molecular complexity,15,33–36 a means was sought to use PCET to
expand the repertoire of current organic synthetic transformations in this realm.
Indeed, this scenario to some extent mimics some stages of the dual catalysis that
we have been conducting with different radical precursors, whereby alkyl radicals
generated via reductive quenching of photocatalysts were merged with a nickel-
catalyzed cross-coupling cycle with different aryl electrophiles.1,2 Based on our
previous experience, a process was envisioned that would benefit from the rapid
5-exo-trig cyclization of amidyl radicals (k ꢀ 105 s
)
À1 37 generated via PCET to funnel
the resulting alkyl radical into a nickel-catalyzed cross-coupling cycle, resulting in the
introduction of biologically relevant pyrrolidinone cores11 onto aromatic backbones.
This novel photoredox PCET/Ni dual catalytic strategy would be expected to expe-
dite the synthesis of medicinally privileged N-containing heterocyclic scaffolds.
Importantly, there are several notable examples of bioactive molecules with this
structure, such as zolmitriptan and cytochalasin B (Figure 1). It is also worth noting
that, whereas other aminoarylation strategies rely on harsh reaction conditions38,39
or very reactive arylating reagents,40,41 this new strategy would benefit from the mild
reaction conditions associated with photoredox catalysis and PCET mechanisms,
providing ample opportunities for the high chemoselectivity profile required for
the late-stage construction of densely functionalized molecules. Moreover, the pro-
posed transformation would not necessarily be restricted to amides, so that carba-
mates and ureas could also be employed, expanding the array of heterocyclic cores
within range. Carbamates are particularly interesting, considering the tremendous
number of bioactive molecules containing allylic alcohols (Figure 1) that might be
engaged in this transformation through conversion to the carbamate, as well as
the ease of carbamate motif installation via quantitative alcoholysis of aryl isocya-
nates. Notably, thanks to the ease of oxazolidinone hydrolysis, ring-opened deriva-
tives would be readily accessible,16,42 resulting in a formal three-component
difunctionalization of unactivated olefins (Figure 1). Together with other derivatiza-
tion possibilities such as reduction,42,43 a series of cyclic or acyclicamido- or amino-
arylated backbones could be constructed.
RESULTS AND DISCUSSION
Reaction Discovery and Optimization
Prior to the search for suitable reaction conditions, an analysis was undertaken of the
possible challenges in developing this demanding, yet appealing, transformation.
Although 5-exo-trig cyclization was expected to be fast, a low thermodynamic
driving force (DGꢁ z À3 to À5 kcal/mol in the transformation of amidyl to 1ꢁ or 2ꢁ
alkyl radicals) was anticipated to be non-optimal for the reaction progress.12,44
Indeed, in a previous hydroamination study, a thiophenol HAT catalyst was
required to drive the transformation to completion.27 Moreover, the coexistence
of amidyl and alkyl radical species in the reaction medium could lead to selectivity
issues, depending on the affinity of the nickel complexes for these species and
the energy barrier of the subsequent step. This provided the potential for the gen-
eration of mixtures of N-arylated and olefin amidoarylated products.17 With these
challenges in mind, an investigation was begun using pent-4-enylanilide S1 and
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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Me
Accessible via amidoarylation
N
Me2N
Me
HN
OH
H
Me
OH
Ph
H
NH
O
HO
OH
HN
O
O
Morphine
(Pain medication)
O
O
O
Cytochalasin B
(actin polymerization inhibitor)
Zolmitriptan
(migraine treatment)
O
Synthesis and diversification of pyrrolidinone, oxazolidinone and
imidazolidinone backbones
HO
OH
OH
Ar
N
Y
D-Glucal
Reduction
(Oligosaccharide
building block)
Ar1
R1
ref. 42, 43
R3
O
O
Y = CR2, NR
Ar
R2
Ar
HO
N
H
H
N
Y
Y
PC Ni
Ar1
R1
HN
R3
R3
N
Me
R2
R2
Ar
H
HN
R1
H
Y
Hydrolysis
Elymoclavine
(Ergoline alkaloid)
Allylic alcohols suitable for
carbamate cyclization
ref. 16, 42
Y = O, NR
Ar1
R1
Y = CR2, O, NR
R3
R2
Figure 1. Biological Relevance, Diversification of ‘‘Lidinone’’ Derivatives, and Naturally Occurring Allylic Alcohols
4-bromobenzonitrile as reaction partners. Initial screening using a mildly oxidizing
Ir-photocatalyst (Ir-1) (E1/2* = 1.32 V versus standard carbon electrode [SCE]) and
the weak base Bu4N[OP(O) (OBu)2] (pKa = 1.72)45 led to a 29% yield of the expected
product 1 (Figure 2, entry 1). Ir-based photocatalysts with higher oxidizing power
(entries 2 and 3) gave lower yields or no product at all, likely owing to a poorer
rate match between the two catalytic cycles or relative instability of the photocata-
lyst. Stronger bases favoring the formation of the corresponding amidate, such as
KOt-Bu (entry 4), proved unsuccessful in this case. However, higher amounts
of the phosphate base translated into higher yields (entry 6). The necessity for
superstoichiometric amounts of Bu4N[OP(O) (OBu)2] was further validated after
seeing failures at attempting to use it catalytically in combination with inorganic
bases to regenerate the former over the course of reaction (entry 5). Supporting
the initial mechanistic hypothesis, these conditions, along with the physical proper-
ties of the anilide (pKa of ꢀ2113 and redox potential of 1.78 V [versus SCE]), suggest
that the cleavage of the anilide N–H bond is most likely occurring via a concerted
PCET pathway. Both Ni(II) and Ni(0) sources rendered similar yields (entries 6 and
9). Consequently, well-defined Ni(dMeObpy) (H2O)2Br2 was used as the catalyst
precursor based on its stability, ease of preparation, and more convenient reaction
setup. Among the several bipyridyl-type ligands tested, dMeObpy clearly stood
4
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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
O
4-cyanobromobenzene (1.0 equiv)
Ni(dMeObpy)(H2O)2Br2 (6 mol %)
[Ir-1] (3 mol %)
O
Ph
Ph
MeO
MeO
N
N
H
Br
Ni
Br
N
N
OH2
OH2
Bu4N[OP(O)(OBu)2] (1 equiv)
DCE (0.05 M)
CN
blue LEDs, rt, 24 h
S1
1
Ni(dMeObpy)(H2O)2Br2
variation from standard conditionsa
none
yield (%)b
entry
-
PF6
CF3
1
2
3
29
25
0
F
R
[Ir-2] instead of [Ir-1]
N
N
[Ir-3] instead of [Ir-1]
F
F
Ir
N
4
5
6
t-BuOK instead of Bu4N[OP(O)(OBu)2]
0
N
2.5 equiv Cs2CO3 + 10 mol % Bu4N[OP(O)(OBu)2]
Bu4N[OP(O)(OBu)2] (2.5 equiv)
< 5
51
R
CF3
F
variation from entry 6a
yield (%)b
entry
Ir-photocatalyst
7
8
Ni(phen)Br2 instead of Ni(dMeObpy)Br2
Ni(dtbbpy)Br2 instead of Ni(dMeObpy)Br2
Ni(COD)2 + dMeObpy
45
42
50
[Ir-1]; R = H; EPC*/PC- = 1.32 V (SCE)
[Ir-2]; R = F; EPC*/PC- = 1.61 V (SCE)
[Ir-3]; R = CF3; EPC*/PC- = 1.68 V (SCE)
9
10
t-BuOH instead of DCE
68
11
t-BuOH/PhCF3 (2:1)
78
Figure 2. Optimization of Reaction Conditions
aReactions were performed on a 0.3-mmol scale. bYield of isolated product after column chromatography.
out, likely owing to easier oxidative addition with aryl halides because of its more
electron-rich nature.
Attempting to increase the reaction yield, we investigated the by-products gener-
ated over the course of the reaction. Among the few identified, chlorobenzonitrile
was, by far, predominant. We reasoned that the 1,2-dichloroethane (DCE) was
responsible for the formation of this by-product, being the only chloride source
present in the reaction medium.46 After confirming that aryl chlorides are inert
under reaction conditions, we examined other non-chlorinated solvents to
avoid the consumption of the aryl bromide and its deleterious effect on
yield. Upon testing numerous options, t-BuOH proved to be an excellent replace-
ment, affording considerably enhanced yields (entry 10). We suggest that
this improvement is likely due to an acidity enhancement of the N-H bond
by the t-BuOH. Finally, in an attempt to match DCE’s polarity, different binary
solvent systems with t-BuOH were tested. In the event, a 78% yield was obtained
using a 2:1 t-BuOH/PhCF3 mixture (entry 11), which came as no surprise consid-
ering the beneficial effects of a,a,a-trifluorotoluene in radical reactions.32 As
expected, control experiments showed the key role played by all of the reaction
components.47
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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
O
O
Ni(dMeObpy)(H2O)2Br2 (6 mol %)
Ar'
Ar'
N
Bu4N[OP(O)(OBu)2] (2.5 equiv)
R
CN
N
H
R
[Ir-1] (3 mol %)
t-BuOH/PhCF3 (2:1), rt
Br
CN
Ar
S1-S18
1-18
Scope of alkenyl amides
O
O
O
O
O
O
Me
Me
BocHN
Me
Ph
Ph
Ar
Ph
N
N
Ph
Ph
N
N
N
N
Ph
Me
Ar
Ar
Ar
Ar
Ar
4
66%
5
6
2
1
78%
3
73%
91%, dr = 5:1
41%, dr = 3:2
81%, dr = 2.4:1
O
O
F
O
N
Ar
O
F
O
Ph
Ar
N
N
Ph
Ph
Ar
N
N
Ph
Ar
N
Me
Ph
OH
Ph
O
Ar
Ar
10
11
12
49%
8
7
66%
9
54%, dr > 20:1
69%, dr > 20:1
(X-ray)
33%, dr > 20:1
72%, dr >20:1
(X-ray)
(X-ray)
(X-ray)
PMP Removal of 14
Scope of aniline
O
O
O
O
13 Me
50%
CAN (4.4 equiv)
MeCN:H2O (5:1)
14 OMe 56%, 58%a
N
OMe
NH
N
N
R
S
15
F
73%
16 CF3 29%b
17 CN 20%
Ar
18
46%
Ar
Ar
Ar
19
91%
14
Figure 3. Scope of N-Arylated Alkenyl Amides
Reaction conditions: amide S1–S18 (0.36 mmol, 1.2 equiv), 4-bromobenzonitrile (0.3 mmol, 1.0 equiv), Bu4N[OP(O) (OBu)2] (0.75 mmol, 2.5 equiv),
Ni(dMeObpy) (H2O)2Br2 (0.018 mmol, 6 mol %), [Ir-1] (0.009 mmol, 3 mol %), blue LED, 6 mL t-BuOH/PhCF3 (2:1). a Reaction run on 5 mmol scale. b [Ir-2]
was used.
Substrate Scope Studies
Subsequently, the limits of this reaction were explored via substrate scope study. As
shown in Figure 3, substitutions from the a to the g positions on the amide are all
accommodated, allowing the synthesis of a tetra-substituted carbon center (7).
Notably, no significant Thorpe-Ingold effect was observed when comparing differ-
ently a-substituted substrates (1–3). A series of bicyclic (8, 10, 11), tricyclic (9), and
spirocyclic structures (4) were accessible from simple precursors. Remarkably,
when an endocyclic double bond was involved, the reaction in all cases showed dia-
stereoselectivities greater than 20:1 in favor of the trans product (8–11). Protic func-
tional groups such as hydroxy (10) and carbamate (5) did not pose a problem, nor did
activated a protons. Excellent regioselectivity was achieved, with no 6-endo-trig
cyclization observed in any of the substrates examined. A notable yield drop was
6
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Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Relative Cyclization Rate Studies
a
Ph
N
rel kc
Substrate
S54
X
CH2
O
R
H
O
0.29 0.02 M
0.32 0.01 M
0.014 0.001 M
kT
H
O
S55
Me
H
Ph
N
X
Bu3SnH
Ph
S56
O
O
Bu3Sn•
X
R
N
SPh
R
Ph
R
X
O
Ph
Bu3Sn-SPh
O
kT'
kc
N
N
R
R
-1
O
kc
H
Bu3Sn
X
H
Radical Clock
via:
O
O
O
O
Ph
Ni(dMeObpy)(H2O)2Br2 (6 mol %)
Bu4N[OP(O)(OBu)2] (2.5 equiv)
N
H
N
Ph
N
Ph
N
Ph
[Ir-1] (3 mol %)
t-BuOH/PhCF3 (2:1), rt
Ar
18% (53)
Starting materials recovered
S53
Scheme 2. Relative Cyclization Rate Studies and Radical Clock Experiment
aThe values reported are relative to kT. See Figure S1 for further details.
observed using an a,a-difluorosubstituted amide (12), most likely because of the
higher oxidation potential of this more electron-deficient amide (2.03 V versus
1.78 V for non-substituted pentenamide S1). In line with this observation, when a
more electron-deficient anilide was involved, a significantly lower yield was
observed (16, 17). The more oxidizing photocatalyst [Ir-2] had to be applied to
form 16, because [Ir-1] failed to give any product. We reasoned that the former
favored the amidyl radical formation, whereas the latter was not oxidizing enough
to accomplish the formation of that intermediate. Electron-neutral and electron-
rich anilines or heteroaryl amines (13–15, 18) delivered the corresponding products
in moderate to good yields. Considering that N-aryl amides are required to facilitate
the PCET step, para-methoxyphenyl (PMP) was incorporated as the aryl motif, which
allowed the synthesis of unsubstituted pyrrolidinones upon removal of the PMP
group with ceric ammonium nitrate (19).48 Moreover, a gram-scale reaction was car-
ried out without further optimization on the PMP-protected substrate (14) with no
erosion in the yield, thus establishing the scalability of this reaction.
Excellent functional group tolerance was observed when different aryl bromides
were subjected to the reaction conditions, including electron-deficient and elec-
tron-neutral substrates (20, 22–35, 37), featuring functional units such as aldehydes,
boronates, sulfones, amides, esters, trifluoromethoxy groups, and various halides.
Electron-rich aryl bromides were challenging, probably because of the more
demanding oxidative addition step, yet good yields could be achieved using the
corresponding aryl iodides (21, 36, and 49). Similarly, because of the more chal-
lenging oxidative addition, relatively electron-neutral (hetero)aryl bromides (e.g.,
23, 32, and 39) and ortho-substituted aryl bromides (33) exhibited diminished effi-
ciency, with the remaining anilide starting material and (hetero)aryl bromides recov-
ered after purification. Notably, aryl iodides only seemed to work on electron-rich
Chem 5, 1–14, February 14, 2019
7

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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
O
O
Ar
Ni(dMeObpy)(H2O)2Br2 (6 mol %)
Bu4N[OP(O)(OBu)2] (2.5 equiv)
Y
N
H
Y
R1
N
Ar
(Het)Ar
R1
[Ir-1] (3 mol %)
t-BuOH/PhCF3 (2:1), rt
Br
(Het)Ar
Y = CH2, O, NR
S20-S52
20-52
Scope of aryl halides
O
O
O
O
20 R = acetyl
68%
21
22
23
24
25
26
27
28
29
OMe
OCF3
Ph
CONMe2 72%
Br 55%
B(Neop) 55%
CO2Me
SO2Me
CHO
51%a
75%
31%
N
Ph
O
Ph
N
Ph
N
N
Ph
Cl
R
Ph
N
O
R
Cl
CHO
57%
72%
63%
30 R = OMe
78%
47%
36%
34
67%
35
64%
33
36%
31
32
Me
F
O
O
O
O
O
Ph
N
N
Ph
N
Ph
N
Ph
Ph
OAc
O
N
F
AcO
O
OAc
OAc
N
CN
N
N
OH
N
37
72%
36
58%,a dr = 1:1
38
80%
39
40%
40
61%
Ar = 4-benzonitrile
Scope of carbamates and ureas
O
O
O
O
O
O
43 R = H 64%(78%b)
Ph
O
O
R
O
O
N
N
N
44
45
46
47
acetyl 56%
Ph
N
Ph
N
Ph
Me
Me
Ar
OMe
Br
38%
59%
38%
Ar
Ar
Ar
Ar
CN
Me
48
42
41
22%
41a
37%
51%, dr > 20:1
32%
(X-ray)
O
O
O
N
R
O
O
O
N
Ph
N
N
H
Me
H
N
O
NMe2
Ph
Me
O
Ar
O
NBoc
O
Ar
N
H
Me
Me
Zolmitriptan
(migraine)
51 R = n-Bu
52
58%
53%
49
55%a
50
83%, dr > 20:1
Me
Zolmitriptan core
Novel Approach toward
C-Aryl-Amino Glycosides
8
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Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Figure 4. Scope of (Hetero)Aryl Halides, Carbamates, and Ureas
Reaction conditions: amide, urea, or carbamate S20–S52 (0.36 mmol, 1.2 equiv), (hetero)aryl halide (0.3 mmol, 1.0 equiv), Bu4N[OP(O) (OBu)2]
(0.75 mmol, 2.5 equiv), Ni(dMeObpy) (H2O)2Br2 (0.018 mmol, 6 mol %), [Ir-1] (0.009 mmol, 3 mol %), blue LED, 6 mL t-BuOH/PhCF3 (2:1). a (Hetero)aryl
b
iodide was applied. 7.5 equiv of base were used.
systems, whereas electron-neutral or electron-poor substrates rendered compro-
mised yields. Substructures with reducible functional groups or activated hydrogens
such as benzylic alcohols (40), saccharides (36), and aldehydes (29, 35) remained
intact under the reaction conditions, demonstrating the highly chemoselective na-
ture of this sequential transformation. In an effort to focus on more medicinally rele-
vant scaffolds, several electron-deficient (37–39) or electron-rich (49) heteroaryl
halides were tested, resulting in modest to high yields of the desired products.
To broaden the utility of this transformation, we tested b,g-unsaturated aryl carba-
mates and ureas in an attempt to provide an easy route toward oxazolidinone and
imidazolidinone scaffolds. Unfortunately, initial attempts with an O-allyl aryl carba-
mate produced a mixture of N-arylation (41a) and amidoarylation (41) products
(37% and 22% yield, respectively).47 To improve the reaction performance, an all-
substituted carbon was placed at the b-position (42) to favor the cyclization rate by
invoking the Thorpe-Ingold effect. In line with previous observations (1–3), the yield
enhancement was poor. However, N-arylated product was suppressed in this case.
Indeed, although a highly reversible amidyl radical addition to nickel has been
described,17 such transformations for carbamate-N radicals appear to be unknown.
As a more electron-rich motif compared with amides, nitrogen-based radicals
derived from carbamates would be expected to exhibit a higher nucleophilicity,
therefore favoring bonding with nickel. To minimize this putative reactivity, we
sought a designed motif to enhance the rate of 5-exo-trig cyclization. Considering
that the carbamate’s N–H bond-dissociation enthalpy (BDE) (ꢀ95 kcal/mol)13 is
lower than that of amides (ꢀ100 kcal/mol),12,14 it becomes evident that, from a
thermodynamic standpoint, generation of a primary alkyl radical via cyclization
(BDE of primary C–H ꢀ98 kcal/mol)44 is less favored for carbamates than for amides
(DGꢁ z 3 kcal/mol versus À2 kcal/mol). Owing to the BDE difference between pri-
mary and secondary C–H bonds (ꢀ4 kcal/mol lower for secondary C–H),44 we antic-
ipated that internal alkenes would react more smoothly. To test this hypothesis, we
carried out an indirect kinetic study using N-(phenylthiol)amides as the amidyl
radical precursors to determine the relative rate of radical cyclization (Scheme 2
and Figure S1).23,37 As shown, the cyclization rate for O-crotyl phenylcarbamate
(S55) was ꢀ25 times faster than for O-allyl phenylcarbamate (S56), thus supporting
the notion that generation of a secondary alkyl radical leads to a more efficient cycli-
zation step. Indeed, for both ureas and carbamates, satisfactory yields were ob-
tained when internal alkenes were used (43–52, Figure 4). Along this line, amino
aryl glycoside 50 derived from galactal was obtained in an 83% yield and excellent
diastereoselectivity, suggesting a more efficient cyclization step that can most likely
be attributed to stabilization of the generated a-oxy radical. The success of incorpo-
rating N-Boc-indole (49) provides an excellent starting point for the synthesis of
zolmitriptan analogs in a straightforward manner, thus highlighting a direct applica-
tion of this method. Interestingly, for the urea 52, one of the double bonds remained
unreacted without any observable intermolecular transformations.
Mechanistic Insights
Although preliminary results pointed toward a mechanistic pathway in line with our
initial proposal (Scheme 1 and Figure 2), further experiments were conducted to
Chem 5, 1–14, February 14, 2019
9

Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
Figure 5. Measuring the Hydrogen-Bonding Affinity of Amides and Carbamates
See also Figures S12–S15 for further details.
substantiate the mechanism. As anticipated, control experiments excluding photo-
catalyst, nickel precatalyst, base, and light, gave no product (see Table S1).47
A
radical clock experiment (Scheme 2; see also Supplemental Information 4.2) led
exclusively to rearranged product 53, indicating the unlikelihood of undergoing
an energy transfer-mediated migratory insertion mechanism or alkene aminometa-
lation.35 Still, the crucial role for 2.5 equiv of Bu4N[OP(O) (OBu)2] base remained un-
clear. Cyclic voltammetry measurements showed that after addition of 2.5 equiv of
base, the redox potential of the amide dropped from 1.78 V to 1.27 V (versus SCE),
which is within the [Ir-1] photocatalyst excited state oxidative range, thus favoring a
PCET mechanistic scenario. However, this potential was also achieved with only 1
equiv of base.47 Stern-Volmer studies were carried out (see Supplemental Informa-
tion 4.6) with a fixed ratio of 1:2.5 (substrate/base) to mimic the reaction medium. A
linear relationship was observed. Although possessing a narrower linear range, the
quenching efficiency of the carbamate-base mixture (Stern-Volmer constant [KSV] =
19,000 G 2,000 MÀ1) was higher than that of amide-base (KSV = 8,200 G 700 MÀ1),
consistent with the relative ease of oxidation of the carbamate compared with that of
an amide (1.73 V versus SCE for allyl phenylcarbamate S41, 1.18 V after addition of
2.5 equiv of base; see Figures S2–S4). A linear correlation was found between vari-
able base loadings and quenching as well (KSV = 5,700 G 500 MÀ1 and 4,800 G 300
M
À1 for amides and carbamates, respectively; see Figures S5–S11).47
The differences in quenching efficiency in these two experimental sets (with amide
quenching being higher in the latter case) indicated that the base might have
different affinity for amides versus carbamates. Hydrogen-bonding affinity constants
were obtained via NMR titration (Figures 5 and S12–S15), with an amide affinity
almost 45-fold higher than that of the carbamate (33 G 4 MÀ1 for the amide and
0.74 G 0.05 MÀ1 for the carbamate).49 Interestingly, NMR titration showed a
behavior close to saturation for the amide at loadings higher than 2.5 equiv, whereas
for the carbamate, even upon addition of 5 equiv of base, no signs of saturation were
observed. Expecting that near-saturation conditions would be ideal for a PCET
mechanistic scenario, a reaction of carbamate S43 with 7.5 equiv of Bu4N[OP(O)
(OBu)2] was carried out,47 achieving a 14% yield increase within the same time frame
(Figure 4, 43). It is also noteworthy that, after adding t-BuOH to mimic the solvent
system used in the reaction, a significant N–H chemical shift change from 7.19 to
10
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Please cite this article in press as: Zheng et al., Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unac-
tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
via
radical addition
concerted PCET
O
Ar
LnNi0
D
e-
[PC]*
O
[PC]
O
N
photoexcitation
Ar
N
O
NiILn
III
Ar1 Br
H
Ar
oxidative
addition
N
Ar
N
[PC]*
Base
5-exo-trig
SET
I
Ar
O
O
II
N
[PC]
Ar
Br
NiIII
Base·H
N
PCET
Ar1
O
H
LnNiI Br
·-
IV
Ln
[B]-
[PC]
V
Ar
N
[B]·H
Ar
Ar1
reductive
elimination
S1·Base
adduct
N
O
II
1
Scheme 3. Proposed Catalytic Cycle and PCET Mechanism
9.14 ppm was observed, which suggested a beneficial N–H acidity enhancement in
the presence of t-BuOH (see Figure S16).47 Under such reaction conditions, the sub-
strate-base adduct would predominate and facilitate PCET, potentially via a proton
wire-type mechanism.50 Finally, kinetic isotope effects were measured with an
N-deuterated amide and carbamate. Although both the amide and the carbamate
revealed a small secondary kinetic isotope effect (KIE), the value for carbamate
(1.08 G 0.04) was still more significant than that for amide (1.02 G 0.02) (see Scheme
S1; Tables S2 and S3). Although small, KIEs are consistent with PCET processes,14
and these data could indicate different rate-limiting steps between carbamates
and amides. Further studies are required for a full understanding of such behavior.
Based on the previous empirical evidence gathered and precedent litera-
ture,14,16,18,32,51 we propose a mechanistic scenario (Scheme 3) initiated by forma-
tion of an amidyl radical (II) via PCET as suggested by cyclic voltammetry, NMR
experiments, and Stern-Volmer studies. Next, a fast 5-exo-trig cyclization follows,
the rate of which is related to the nature of the newly formed alkyl radical and
N–H BDE, as evidenced by indirect kinetic studies. Once the alkyl radical I is formed,
it enters the nickel-catalytic cycle, forming Ni(I)-complex III, which undergoes oxida-
tive addition with the aryl halide.52 Next, the resultant high-valent Ni(III) intermedi-
ate IV undergoes reductive elimination, delivering the final product 1 along with a
Ni(I)-halide complex (V). Both catalytic cycles are simultaneously closed by reduction
of the Ni(I)-halide with the reduced form of the photocatalyst. Even though the key
organonickel intermediates in the proposed mechanism proved challenging to
isolate because of their highly reactive nature, their existence is in line with prelim-
inary mechanistic investigations as well as previous computational studies on nickel/
photoredox dual-catalyzed cross-coupling.52
Conclusion
A photoredox PCET/Ni dual-catalyzed amidoarylation of unactivated olefins has
been disclosed, forging highly functionalized 5-membered heterocyclic systems un-
der mild reaction conditions from readily available precursors. This method merges
Chem 5, 1–14, February 14, 2019
11

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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
the concept of concerted PCET with a nickel-catalyzed cross-coupling process for
the first time, taking advantage of photocatalytic activation of strong N–H bonds as-
sisted by a phosphate H-bond acceptor, followed by rapid 5-exo-trig cyclization and
alkyl-aryl single-electron cross-coupling. Relative cyclization rates for amides and
carbamates were studied, the latter being disclosed for the first time, which allowed
the introduction of carbamates and ureas into the protocol. Stern-Volmer studies,
NMR titration experiments, cyclic voltammetry, and control experiments point to-
ward a concerted PCET mechanism. This transformation adds to the repertoire of
alkene difunctionalization processes in a manner that is exceedingly functional
group tolerant, using readily available alkenyl amides, carbamates, and ureas, and
takes advantage of the tens of thousands of commercially available (hetero)aryl bro-
mides and iodides to expand chemical space.
EXPERIMENTAL PROCEDURES
A general procedure for photoredox PCET/Ni-catalyzed amidoarylation of unactivated
olefins is as follows. An 8.0-mL screw-cap vial containing a stirring bar was charged with
Ni(dMeObpy) (H2O)2(Br)2 (8.5 mg, 0.018 mmol, 6 mol %), [Ir{dF(CF3)2ppy}2(bpy)]PF6
(9.0 mg, 0.009 mmol, 3 mol %), amide (0.36 mmol, 1.2 equiv), aryl bromide (if solid,
0.3 mmol, 1.0 equiv), and Bu4N[(n-BuO)2P(O)O] (338.8 mg, 0.75 mmol, 2.5 equiv).
Next the vial was closed, and three vacuum/argon cycles were carried out. Under an
inert atmosphere, a 2:1 mixture of pre-degassed, anhydrous t-BuOH/PhCF3 was
added (6.0 mL, 0.05 M) followed by addition of the aryl bromide (if liquid). After
covering the cap with Parafilm, the reaction was placed 3 cm from the light source in
a blue LED bay (blue LED strip, ꢀ5 W in total) and stirred at room temperature
until complete (a fan was added ꢀ30 cm from above to disperse any heat coming
from the blue LEDs). When completed, the reactions were taken to dryness and
purified by column chromatography using an automated system (hexane/EtOAc
gradient), delivering the corresponding pure product.
Other experimental details, characterization data (Figures S17–S177 and Tables S4–
S39), and procedures are provided in Supplemental Information.
DATA AND SOFTWARE AVAILABILITY
Crystallographic data for the structures reported in this paper have been deposited
at the Cambridge Crystallographic Data Center (CCDC), with accession numbers
CCDC: 1854737 (Ni(dMeObpy) (H2O) (CH3CN)2Br2), 1854738 (8), 1854742 (10),
1854739 (48), 1854740 (11), and 1854741 (9).
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 177
figures, 1 scheme, 39 tables, and 6 data files and can be found with this article online
at https://doi.org/10.1016/j.chempr.2018.11.014.
ACKNOWLEDGMENTS
The authors are grateful for the financial support provided by NIGMS (no. R01 GM
113878). We thank the NIH (no. S10 OD011980) for supporting the University of
Pennsylvania (UPenn) Merck Center for High Throughput Experimentation, which
funded the equipment used in screening efforts. Kai Chen (Caltech) is acknowledged
for helpful discussion of the manuscript. The authors thank Dr. Jun Gu (UPenn) for
assistance with the NMR studies, and Drs. P.J. Carroll and M.R. Gau (UPenn) for crys-
tallographic analysis of compounds 8–11, 48, and the Ni-precatalyst.
12
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tivated Olefins, Chem (2018), https://doi.org/10.1016/j.chempr.2018.11.014
AUTHOR CONTRIBUTIONS
A.G.-B. conceived the project; S.Z. and A.G.-B. designed the experiments; S.Z. and
A.G.-B. carried out the experiments under the guidance of G.A.M.; S.Z. and A.G.-B.
prepared the manuscript with input from G.A.M.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: September 11, 2018
Revised: October 19, 2018
Accepted: November 20, 2018
Published: January 3, 2019
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