Sp3 C-H Arylation and Alkylation Enabled by the Synergy of Triplet Excited Ketones and Nickel Catalysts

Article abstract of DOI:10.1021/jacs.8b07405

Triplet ketone sensitizers are of central importance within the realm of photochemical transformations. Although the radical-type character of triplet excited states of diaryl ketones suggests the viability for triggering hydrogen-atom transfer (HAT) and single-electron transfer (SET) processes, among others, their use as multifaceted catalysts in C-C bond-formation via sp³ C-H functionalization of alkane feedstocks still remains rather unexplored. Herein, we unlock a modular photochemical platform for forging C(sp³)-C(sp²) and C(sp³)-C(sp³) linkages from abundant alkane sp³ C-H bonds as functional handles using the synergy between nickel catalysts and simple, cheap and modular diaryl ketones. This method is distinguished by its wide scope that is obtained from cheap catalysts and starting precursors, thus complementing existing inner-sphere C-H functionalization protocols or recent photoredox scenarios based on iridium polypyridyl complexes. Additionally, such a platform provides a new strategy for streamlining the synthesis of complex molecules with high levels of predictable site-selectivity and preparative utility. Mechanistic experiments suggest that sp³ C-H abstraction occurs via HAT from the ketone triplet excited state. We believe this study will contribute to a more systematic utilization of triplet excited ketones as catalysts in metallaphotoredox scenarios.

Full text of DOI:10.1021/jacs.8b07405

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Article
sp3 C–H Arylation and Alkylation Enabled by the
Synergy of Triplet Excited Ketones and Nickel Catalysts
Yangyang Shen, Yiting Gu, and Ruben Martin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07405 • Publication Date (Web): 05 Sep 2018
Downloaded from http://pubs.acs.org on September 5, 2018
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sp3 C–H Arylation and Alkylation Enabled by the Synergy of Triplet
Excited Ketones and Nickel Catalysts
Yangyang Shen,†£ Yiting Gu†£ and Ruben Martin†§*
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Cataꢀ
lans 16, 43007 Tarragona, Spain
£ Universitat Rovira i Virgili, Departament de Química Analítica i Química Orgànica, c/Marcel·lí Domingo, 1, 43007 Tarraꢀ
gona, Spain
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§ICREA, Passeig Lluïs Companys, 23, 08010, Barcelona, Spain
ABSTRACT: Triplet ketone sensitizers are of central importance within the realm of photochemical transformations. Although
the radicalꢀtype character of triplet excited states of diaryl ketones suggests the viability for triggering hydrogenꢀatom transfer
(HAT) and singleꢀelectron transfer (SET) processes, among others, their use as multifaceted catalysts in C–C bondꢀformation via
sp3 C–H functionalization of alkane feedstocks still remains rather unexplored. Herein, we unlock a modular photochemical platꢀ
form for forging C(sp3)–C(sp2) and C(sp3)–C(sp3) linkages from abundant alkane sp3 C–H bonds as functional handles using the
synergy between nickel catalysts and simple, cheap and modular diaryl ketones. This method is distinguished by its wide scope
that is obtained from cheap catalysts and starting precursors, thus complementing existing innerꢀsphere C–H functionalization proꢀ
tocols or recent photoredox scenarios based on iridium polypyridyl complexes. Additionally, such a platform provides a new strateꢀ
gy for streamlining the synthesis of complex molecules with high levels of predictable siteꢀselectivity and preparative utility.
Mechanistic experiments suggest that sp3 C–H abstraction occurs via HAT from the ketone triplet excited state. We believe this
study will contribute to a more systematic utilization of triplet excited ketones as catalysts in metallaphotoredox scenarios.
INTRODUCTION
The photochemical behavior of diaryl ketones has undoubtꢀ
edly played an important role for the foundation of modern
molecular photochemistry.1 Over the course of the last centuꢀ
ry, diaryl ketones have gained a prominent role as photosensiꢀ
tizers in material science, biology, organic synthesis and
pharmacology.2 Indeed, diaryl ketones have found immediate
use in a wide number of phototherapeutic applications, for
example as UVꢀblocking agents to prevent polymer photodegꢀ
radation, or as sensitizers to transfer energy to DNA, among
others.3 The favorable photochemical properties of diaryl
ketones that allow such applications are commonly ascribed to
a longꢀlived triplet state4 generated by the excitation of an
electron from a nonꢀbonding orbital at the C=O bond to a
corresponding π* orbital (n,π*) followed by intersystem crossꢀ
ing (ISC).2,5 From a synthetic standpoint, the triplet excited
state of diaryl ketones (I) holds considerable potential to proꢀ
vide opportunities to build up molecular complexity. In a
formal sense, this triplet excited state behaves as a 1,2ꢀ
biradical, creating significant spin density on the oxygen atom.
Consequently, the (n,π*) triplet excited state possesses intriꢀ
guing electrophilic and radicalꢀtype properties, making it
particularly susceptible for radical addition, energy transfer
(ET), single electron transfer (SET) or hydrogen atom transfer
(HAT).1,6
Scheme 1. Triplet Photoexcited Diaryl Ketones.
Ar1
Ar2
O
O
—
—
O
ISC
Ar1
Ar2
Ar1
Ar2
I
light
singlet excited
state
ET, HAT
& SET
Convinced of the synthetic relevance of triplet excited keꢀ
tones,1,5 we turned our attention to unravel their potential as
catalysts for preparative purposes. A close look into the literaꢀ
ture, however, indicated that this might not be as straightforꢀ
ward as initially anticipated. Indeed, stoichiometric amounts
of diaryl ketones are frequently employed in photochemical
processes, suggesting that catalytic turnover might be at risk.1,5
Additionally, highꢀenergy UV irradiation is typically required
when using diaryl ketones as photosensitizers.1,5 This observaꢀ
tion is rather problematic due to the ability of a wide range of
functional groups to absorb in the UV region, which may lead
to deleterious side reactions arising from photoexcitation of
the substrate. However, it is also reasonable to expect that
facile tuning of the steric and electronic substituents of diaryl
ketones might have a profound impact on its photochemical
behaviour,7 changing the electronic configuration of the triplet
excited states while shifting the maximum (n,π*) absorption to
longer wavelengths.8
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Among various conceivable scenarios, the ability of triplet lived triplet excited I (τ [Ph2CO] = 6.5 ꢁs) along with the
formation of a ketyl radical II (Scheme 3).23 Concurrently,
oxidative addition of an organic halide to lowꢀvalent Ni(0)Ln
would give rise to an electrophilic Ni(II) entity (IV). Radical
recombination with III might generate discrete Ni(III) V speꢀ
cies, which would set the stage for C–C bondꢀforming reducꢀ
tive elimination to deliver the targeted C–H functionalization
product and Ni(I) intermediate VI. It is expected that the two
catalytic cycles could be interfaced under basic conditions24 by
a final SET from II (E1/2red (Ph2CO) = ꢀ2.20 V vs Ag/AgNO3 in
MeCN)25 to VI (Ered [NiI/Ni0] ≈ ꢀ1.13V vs Ag/AgNO3 in
DMF)26, thus recovering both the propagating diaryl ketone
and Ni(0)Ln catalysts.
1
2
3
4
5
6
7
8
excited ketones I to trigger a HAT process is particularly
noteworthy.1,5 During this elementary step, a persistent ketyl
radical II and a transient nucleophilic radical III are formed.
While the former is inherently predisposed to SET with apꢀ
propriate electron acceptors, the latter is prone to C–C bondꢀ
formation in the presence of radical acceptors (Scheme 2). As
part of our ongoing interest in Ni and photoredox catalysis9
and prompted by the seminal studies of Chow and Murakami
on the photoreduction of Ni(acac)2 by triplet benzophenones10
and on the propensity of ketyl radicals to undergo SET proꢀ
cesses,11 we envisioned that nickel complexes could act both
as the electron and radical acceptors in Scheme 2, thus setting
the basis for turnover of the triplet ketone catalyst. If successꢀ
ful, a generic platform aimed at interfacing triplet excited
ketones and Ni catalysis might provide an enabling C–C bondꢀ
forming redox-neutral strategy from simple hydrocarbon
feedstocks by using sp3 C–H bonds as functional handles
without the need for sacrificial electron-donors or electron-
acceptors.12 We recognized that this scenario might offer new
reactivity within the field of triplet ketone catalysis while
complementing existing inner-sphere sp3 C–H functionalizaꢀ
tion techniques13 and recent outer-sphere metallaphotoredox
processes reported by MacMillan,14 Molander15 and Doyle16
based on Ir polypyridyl sensitizers. Unlike Ir photocatalysts
that are used as either SET or ET catalysts,17,18 however, the
utilization of simple and easilyꢀaccessible diaryl ketones as
photocatalysts offers the added value of activating sp3 C–H
bonds19 via HAT processes, thus expanding the boundaries of
metallaphotoredox processes.20 Herein, we describe our efforts
towards this goal, which have resulted in a practical, modular
and exceedingly tolerant platform for C–C bond construction
that streamlines synthetic sequences from native sp3 C–H
bonds, even in the context of lateꢀstage functionalization.
Control experiments and mechanistic studies suggest a mode
of action that might have relevance in other photocatalytic
bondꢀforming reactions.
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Scheme 3. Mechanistic Hypothesis.
ketone catalysts & Ni catalyst
R
Ar1
Ar2
H
X
X
O
L
L
R
Ni
+
light
triplet ketone
catalysis
Br
nickel catalysis
R
H
III
R
HAT
Ar1
Ar2
O
H
Ar1
Ar2
R
II
LnNi(I)Br
O
Triplet
catalysis
VI
I
SET
visible
light
R
O
Nickel
Ni(III)LnBr
catalysis
Ar2
Ar
V
LnNi(0)
Br
R
Br
L
L
Ni
III
IV
Scheme 2. Triplet Ketones as HAT & SET Catalysts.
Optimization of the reaction conditions. We began our
investigations by studying the sp3 C–H arylation of 4ꢀ
trifluoromethyl bromobenzene with tetrahydrofuran as both
C–H precursor and solvent under household compact fluoresꢀ
cent lamp (CFL) irradiation for 18 h (Table 1). We anticipated
that the electronic effects on the arene backbone of the diaryl
ketone might have a nonꢀnegligible influence on reactivity,7,8
(1) enhancing and shifting the (n,π*) absorption into the visiꢀ
ble light region, (2) tuning the rate of decay of the triplet exꢀ
cited state I, and/or (3) stabilizing the ketyl radical II that
results from the HAT process;27 the latter is particularly imꢀ
portant, as this putative reaction intermediate is critical for
turnover of the triplet ketone catalyst and nickel catalyst by a
final SET (Scheme 3). Therefore, we decided to investigate
the behaviour of a representative set of diaryl ketone catalysts
bearing different electronic effects.28 Under a catalytic regime
based on Ni(acac)2/L1 in tetrahydrofuran, it was quickly apꢀ
parent that electronic effects on the diaryl ketone were critical
for success. Among all diaryl ketones analysed, we found that
Ar1
sp3 C–H
functionalization
O
Ar2
R
H
I
alkane
O
+
HAT
C–C bond
formation
R
Ar1
Ar2
R
Ar1
Ar2
III
SET
O
base
H
H
II
+
base
electron
acceptor
RESULTS AND DISCUSSION
Mechanistic hypothesis. Under the premise that suitable
diaryl ketones might qualify as HAT & SET catalysts, we
initially focused our attention on the suitability of an integratꢀ
ed photocatalytic platform that enables C–C bondꢀformation
via the outer-sphere sp3 C–H functionalization of saturated
hydrocarbons in the absence of Ir polypyridyl complexes.21,22
Specifically, we hypothesized that an electronꢀrich carbonꢀ
centered radical III would be generated upon HAT from longꢀ
red
benchꢀstable A1 (E1/2 = ꢀ2.05 V vs Ag/AgNO3 in MeCN)25
possessing a “push-pull” structure provided promising results
en route to 1 (Table 1, entry 1). Interestingly, the utilization of
push A2 or pull A3 as catalysts resulted in a markedly lower
reactivity, thus arguing against a direct correlation between
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reaction rate and the Hammett parameter of the para-
substituent (entries 2 and 3).29 Similarly, lower yields were
Table 2. Optimization of the Reaction Conditions.
1
obtained with benzophenone (A4) (entry 4). Interestingly, A1-
A4 have similar absorption spectra; however, we found that
A1 possesses the maximum (n,π*) absorption at longer waveꢀ
lengths.28 Putting everything into perspective, the higher phoꢀ
tochemical reactivity of A1 can tentatively be interpreted on
the basis of a higher molar absorption coefficient in the visible
light region and the stability of the corresponding ketyl radiꢀ
cals with CF3ꢀsubstituted analogues.27,1
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Table 1. Electronic Effects on the Diaryl Ketone.
a
b
Reaction conditions: As Table 1, 60 h. GC yields with
c
dodecane as internal standard. Isolated yield, average of two
independent runs. d Mass balance accounts for reduced ArBr.
e
f
Mass balance accounts for homocoupling of ArBr.
47
ꢀW/cm2.
a
Reaction conditions: aryl bromide (0.30 mmol), Ni(acac)2
sp3 C–H arylation of saturated hydrocarbons aided by
triplet excited ketones and Ni catalysts. Encouraged by our
initial findings, we next turned our attention to study the genꢀ
erality of our sp3 C–H arylation. As evident from the results
compiled in Table 3, a wide variety of aryl bromides bearing
either electronꢀrich or electronꢀpoor substituents underwent
the targeted sp3 C–H arylation. Notably, our photochemical C–
H arylation displayed an excellent chemoselectivity profile,
and ketones (5), phenols (10, 14), primary alcohols (9), amides
(8, 29), nitriles (2, 22, 24), esters (3, 6, 7, 17, 26-29), alkynes
(7), alkenes (6, 18), anilines (11), acetals (16) and aldehydes
(20) could perfectly be tolerated. Likewise, aryl boronates
(12), organostannanes (13) or electrophilic sites that are susꢀ
ceptible to Niꢀcatalyzed crossꢀcoupling reactions such as aryl
chlorides (4, 14, 15) and aryl pivalates (15) were also accomꢀ
modated, thus providing an additional handle for further funcꢀ
tionalization.32 As shown for 25, the photochemical sp3 C–H
arylation could also be extended to vinyl bromides, albeit in
lower yields. Precursors derived from the chiral pool, such as
cholesterol (26), (L)–menthol (27), (D)–allofuranose (28) and
(D)–phenylglycine (29) were also within reach, showcasing
the preparative potential of this transformation. The ability to
easily scale up the reaction without noticeable erosion in yield
(3, 21, 37) constitute an additional bonus from a practical
standpoint. Notably, our protocol allowed for the coupling of a
wide variety of electronꢀpoor nitrogenꢀcontaining heterocyꢀ
cles, including pyridines (30-32), pyrimidines (33), and quinoꢀ
lines (36). Similarly, electronꢀrich heterocycles such as (benꢀ
zo)thiophenes (34, 35) and free indole do not interfere (37).
This finding showcases the complementarity of our photoꢀ
chemical technique with classical metallaphotoredox reactions
based on iridium polypyridyl complexes that typically result in
low yields when using electronꢀrich heterocycles as substrates
(10 mol%), 5,5’ꢀdimethylꢀ2,2’ꢀbipyridine (L1, 10 mol%), A
(10 mol%), Na2CO3 (0.30 mmol), THF (0.075M), CFL (32W)
at rt for 18 h. b GC yields using decane as internal standard.
Systematic evaluation of all other reaction parameters indiꢀ
cated that a cocktail consisting of Ni(acac)2, L1 (5,5’ꢀ
dimethylꢀ2,2’ꢀbipyridine), Na2CO3 and A1 under CFL irradiaꢀ
tion was particularly suited for our purposes, obtaining 1 in
95% isolated yield after 60 h (Table 2, entry 1).30 As expected,
the nature of the ligand had a nonꢀnegligible effect on reactiviꢀ
ty.28 Indeed, the utilization of otherwise related neocuproine
(L2), 2,2’ꢀbipyridine (L3) or even 4,4’ꢀditertbutylꢀ2,2’ꢀ
bipyridine (L4), a ligand commonly employed in the metalꢀ
laphotoredox arena, resulted in lower yields of 1 (entries 2ꢀ4).
As shown in entries 5ꢀ7, Ni(COD)2 and Ni(II) salts other than
Ni(acac)2 could also be employed as precatalysts, hence sugꢀ
gesting that acac does not play a critical role on the reaction
outcome (vide infra). Next, we turned our attention to study
the influence of the light source. The results are particularly
illustrative: (a) irradiation by a dark lamp (λmax = 365 nm) or
dark LED (390 nm) resulted in an enhanced rate acceleration
but with lower chemoselectivity profile (entry 8 and 10) to that
observed under CFL irradiation, and (b) 1 was selectively
observed under 34 W Kessil BlueꢀLEDs, albeit in lower yields
(entry 9). These results are particularly noteworthy, suggesting
that residual UV emission on fluorescent light bulbs cannot be
exclusively responsible for the observed selectivity and reacꢀ
tivity in the sp3 C–H arylation of tetrahydrofuran. Importantly,
87% yield of 1 was obtained under air (entry 11), thus constiꢀ
tuting an additional bonus from a practical standpoint while
complementing existing iridium polypyridyl photochemical
scenarios that commonly require exclusion of oxygen atmosꢀ
pheres.31 As expected, control experiments showed that all of
the parameters were crucial for the reaction to occur (entries
12ꢀ14). Note, however, that the absence of L1 gave rise to 1 in
35% yield, albeit with considerable amounts of homocoupling
product (entry 14).
due
to
competitive
SET
processes.14ꢀ16,20
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1
2
3
4
Table 3. Scope of (Hetero)Aryl Bromides.a,b
5
6
7
8
9
10
11
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60
a
Reaction conditions: as Table 2 (entry 1). b Isolated yields, average of at least two independent runs. c 10 mmol scale. d 4ꢀBrꢀ
e
C6H4N(TMS)2
(0.30
mmol)
was
used
as
masked
aniline.
20
mol%
of
A1.
With the results of Table 3 in hand, we wondered whether
our photochemical arylation could be extended to C–H precurꢀ
sors other than tetrahydrofuran. Gratifyingly, this was indeed
the case and a variety of cyclic ethers (38-40) and acyclic ether
analogues (41-44) could be employed as sp3 C–H functional
handles with equal ease (Table 4).33 Particularly noteworthy is
the coupling of 1,3ꢀdioxolane as C–H precursor (39), thus
representing a mild and complementary approach to introduce
the formyl group into arenes after routine hydrolytic
workup.22d,34 The ability to access 40 as a single diastereoisoꢀ
mer possessing a tetrasubstituted carbon center is equally
relevant; to the best of our knowledge, this example constiꢀ
tutes the first nickelꢀcatalyzed crossꢀcoupling reaction via
functionalization of stericallyꢀencumbered tertiary sp3 C–H
bonds possessing an αꢀheteroatom.35 As shown for 45 and
46,36 our protocol was not limited to ether motifs and the tarꢀ
geted sp3 C–H arylation could also be conducted with methylꢀ
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a
substituted benzene backbones, furnishing the corresponding
diarylmethanes in good yields.
Reaction conditions: as Table 2 (entry 1), in benzene as
b
1
2
3
4
5
6
7
8
solvent (0.075 M). Isolated yields, average of at two indeꢀ
pendent runs. c NaHCO3 (1 equiv). A1 (50 %) was used.
d
e
Table 4. Scope of Alkane sp3 C–H Precursors.a,b
Cyclohexane:benzene (1:1, 0.05 M).
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a
Reaction conditions: as Table 2 (entry 1). b Isolated yields,
average of at least two independent runs. c Using NaHCO3 (1.0
equiv). d 1.8:1 regioisomeric ratio. e 2.2:1 regioisomeric ratio.
The sp3 C–H arylation could also be conducted in benzene as
solvent using 10ꢀ20 equiv of C–H precursor, giving rise to 1,
and 48-52 in good yields (Table 5). While in lower yields, the
reaction could also be executed with stoichiometric amounts
(2.0 equiv) of C–H precursor (1, 47), thus holding promise for
designing future photochemical sp3 C–H functionalizations
with improved practicality, flexibility and generality. Altꢀ
hough the results compiled in Tables 3ꢀ4 showed the viability
for a sp3 C–H arylation event with alkanes possessing low C–
H bondꢀdissociation energies, it was unclear whether such
technique could be extended to unactivated, yet particularly
strong, sp3 C–H bonds possessing high bondꢀdissociation
energies. Gratifyingly, we found that the sp3 C–H arylation of
cyclohexane is within reach (51, 52), constituting a stepꢀ
forward for the functionalization of particularly unactivated
sp3 C–H bonds.36,37
Figure 1. Late-stage Diversification and Site-Selectivity. a
As Table 2, with benzene as solvent (0.06M) and C–H precurꢀ
c
d
sor (10 equiv). b dr = 12:1. dr = 10:1. Minor regioisomer
corresponds to the arylation at the primary sp3 C–H bond.
Prompted by the generality of our photochemical sp3 C–H
arylation, we anticipated that our protocol might hold promise
to streamline the synthesis of complex molecules within the
context of lateꢀstage functionalization.38 To this end, we found
that (–)–Ambroxide underwent lateꢀstage sp3 C–H functionaliꢀ
zation with a different set of (hetero)aryl bromides in benzene
as solvent, giving rise to 53-55 in high yields and excellent
diastereoselectivities (Figure 1).39 We also found that the sp3
C–H arylation of NMP (Nꢀmethylpyrrolidone) with 3ꢀ
bromopyridine rapidly afforded Cotinine (56), a potential
therapeutic agent against Alzheimer´s disease,40 in high yields
and excellent siteꢀselectivity. Likewise, a variety of valuable,
yet not easily accessible, Cotinine analogues such as 5741 or
58-59 could also be accessed under otherwise identical reacꢀ
tion conditions from cheap starting precursors.
Table 5. sp3 C–H Arylation in Benzene as Solvent.a,b
Scheme 4. Enantioselective sp3 C–H Arylation.
Encouraged by our results, we wondered whether the merger
of triplet excited ketones and nickel catalysis might enable the
development of an asymmetric sp3 C–H arylation with approꢀ
priate chiral ligands. Gratifyingly, we found that 60 could be
accessed in moderate enantioselectivities and yields when
utilizing a Ni/L5 couple (Scheme 4).42 This result is particularꢀ
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ly noteworthy, as it constitutes the first example of an enanti-
tion products. Under these optimized reaction conditions, a
oselective C–C bond-forming reaction of native sp3 C–H
bonds within the metallaphotoredox arena.
wide variety of unactivated alkyl bromides possessing alkenes
(62), free alcohols (63), silyl ethers (64), esters (66), nitrogenꢀ
containing heterocycles (66), nitriles (70), amides (71, 73),
aldehydes (72) or ketones (74) could all be perfectly accomꢀ
modated. Although chemoselectivity issues arise in the presꢀ
ence of alkyl chlorides (67), exhaustive or selective sp3 C–H
alkylation could be accomplished when 1,6ꢀdibromohexane
was employed as substrate (68, 69). Notably, the sp3 C–H
alkylation could also be conducted with a variety of ethereal
C–H precursors (75-77). Although we anticipated that a C–C
bond reductive elimination between two fragments derived
from secondary sp3 C–H bonds would be even more problemꢀ
atic, we found that our protocol could be integrated with more
challenging secondary alkyl bromides (73, 74). As for the sp3
C–H arylation (Table 1), particularly noteworthy was the
ability to enable a rather challenging C(sp3)–C(sp3) bondꢀ
formation at unactivated sp3 C–H bonds possessing particularꢀ
ly high bondꢀdissociation energies (78-80). These results tacitꢀ
ly suggest that our Ni/A1 regime might complement existing
metallaphotoredox scenarios based on the utilization of noble
iridium polypyridyl photocatalysts for the functionalization of
1
2
3
4
5
6
7
8
sp3 C–H alkylation of saturated hydrocarbons. Taken toꢀ
gether, the data summarized above advocate the notion that the
interface between triplet excited ketones and nickel catalysis
might be a fertile ground within the sp3 C–H functionalization
arena. After establishing the ability to enable a sp3 C–H arylaꢀ
tion, we set out to investigate whether an otherwise related sp3
C–H alkylation would be within reach. We recognized that
such a platform might constitute an excellent opportunity to
couple two sp3 carbon fragments with readily accessible preꢀ
cursors and catalysts.43 Despite the lower propensity for
C(sp3)–C(sp3) bondꢀreductive elimination,44 and the natural
proclivity of transient alkyl metal species for parasitic hoꢀ
modimerization or βꢀhydride elimination, we found that a
regime based on Ni(acac)2, L4 (4,4’ꢀditerbutylꢀ2,2’ꢀ
bipyridine) and A1 was particularly suited for our purposes
(Table 6).28 Although the presence of CF3CO2Na was not
strictly necessary,45 its inclusion significantly improved both
the reaction rate and the yields of the targeted sp3 C–H alkylaꢀ
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60
sp3
CꢀH
via
HAT
process.14ꢀ16,34,43
Table 6. Scope of the sp3 C–H alkylation.a,b
a Reaction conditions: alkyl bromide (0.30 mmol), Ni(acac)2 (10 mol%), L6 (10 mol%), A1 (20 mol%), CꢀH precursor as solvent
(0.075 M), Na2CO3 (1.0 equiv), CF3CO2Na (1 equiv), CFL (32W), 25 ºC. b Isolated yields, average of at least two independent runs.
c
d
e
Without CF3CO2Na.
Benzene as cosolvent (1:1, 0.05 M), A1 (50 mol%).
NaHCO3 (1.0 equiv).
Mechanistic studies. The data summarized above provides
cleavage operates at the molecular level. Prompted by the
seminal studies from Chow10, Molander15 and Doyle16, we
turned our attention to unravelling the mode of action by
which A1 enable sp3 C–H arylation. Although we corroborated
by control experiments the efficient photoreduction of
Ni(acac)2 by A1 under CFL irradiation,28 various scenarios
compelling evidence that triplet excited ketone catalysts exꢀ
ploit an unrecognized opportunity in the field of metalꢀ
catalyzed sp3 C–H functionalization. However, it was unclear
whether the promiscuous photoreactivity of triplet excited
ketones would allow to understand how the C–H bondꢀ
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might a priori be conceivable for the results highlighted above
(Scheme 5): (a) singleꢀelectron oxidation of the arylꢀ
1
Ni(II)(L1)ꢀBr oxidative addition with A1* followed by
Ni(III)–Br homolysis and HAT towards III/V (path a);15,16 (b)
tripletꢀtriplet ET from A1* to the transient arylꢀNi(II)(L1)ꢀBr
oxidative addition complex followed by Ni(II)–Br homolysis
and HAT en route to III/VII (path b);15,16 (c) chargeꢀtransfer
(CT) from A1* to in situ generated arylꢀNi(II)(L1)ꢀacac, reꢀ
sulting in acac radical that triggers a HAT process followed by
recombination to end up in VII (path c);10 (d) tripletꢀtriplet ET
from A1* to arylꢀNi(II)(L1)ꢀBr species followed by σꢀbond
metathesis of the C–H precursor to deliver VII (path d)15 or
(e) generation of III upon HAT from A1* to ultimately generꢀ
ate V by recombination with arylꢀNi(II)(L1)ꢀBr (path e).
2
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Scheme 6. Ruling Out the Intermediacy of Br Radicals.
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Scheme 5. Proposed Pathways for sp3 C–H Cleavage.
Next, we turned our attention to explore the viability of a
tripletꢀtriplet ET followed by σꢀbond metathesis (Scheme 5,
pathway d). If such a pathway intervenes, we anticipated that
exposure of 1ꢀbromoꢀ4ꢀ(trifluoromethyl)benzene in THF
under UVꢀirradiation with Ni/L1 in the absence of A1 might
result in nonꢀnegligible amounts of sp3 C–H arylation. Howꢀ
ever, not even traces of 1 were observed under irradiation by a
dark lamp (λmax = 365 nm).50 Further support for the lack of σꢀ
bond metathesis is evident from the sp3 C–H arylation of a
mixture of cis/trans 2,5ꢀdimethyl tetrahydrofuran (1:1 ratio)
with methyl 4ꢀbromobenzoate (Scheme 7). A statistical mixꢀ
ture of products was anticipated for a mechanism consisting of
a concerted σꢀbond metathesis; on the contrary, a non-
concerted scenario by capturing radical intermediates generatꢀ
ed by SET or HAT would be expected to exert a certain conꢀ
trol on diastereoselectivity. As shown in Scheme 7, 40 was
obtained as a single diastereoisomer, suggesting that pathways
other than σꢀbond metathesis seem to be the most plausible
avenue for our sp3 C–H arylation event.51
At first sight, it is not particularly straightforward to rigorꢀ
ously distinguish between the mechanistic scenarios highlightꢀ
ed in Scheme 5. Although HAT might indeed occur via broꢀ
mine radicals that are released from in situ generated arylꢀ
Ni(II)(L1)ꢀBr complexes (pathways a & b),15,16 we believe that
this manifold makes a minor contribution to productive sp3 C–
H arylation, if any. Taking into consideration the mismatch of
bondꢀdissociation energies (BDE)46 of H–Br (87 Kcal/mol)
and the C–H bond of cyclohexane (98 Kcal/mol), one might
argue that the sp3 C–H arylation of the latter with bromoarenes
should a priori not take place (Scheme 8). However, the sucꢀ
cessful formation of 51-52 (Table 3) and 78-80 (Table 4)
indicates otherwise. The interpretation for the lack of Ni–
halogen homolysis gains credence by the nonꢀnegligible reacꢀ
tivity found when promoting the sp3 C–H arylation of both
tetrahydroduran (C–H: 85 Kcal/mol) and cyclohexanes (C–H:
98 Kcal/mol) with iodoarenes (H–I: 71 Kcal/mol) as subꢀ
strates, delivering 3 and 51 in moderate yields. Furthermore,
deuterium labelling studies showed an exothermic radical sp3
C–H abstraction.48 Putting everything into perspective, these
experiments suggest that a pathway consisting of the intermeꢀ
diacy of halogen radical species may not be populated.49
Scheme 7. Assessing Intramolecular σ-Bond Metathesis.
Although the available data likely indicates that scenarios
based on bromine radicals (Scheme 5, pathway a & b) or σꢀ
bond metathesis (pathway d) might not be operative, a clearꢀ
cut choice between the two remaining options (pathways c &
e) still remained elusive. Aiming at shedding light into such
overly complex reaction, we set out to explore the reactivity of
the putative arylꢀNi(II)(L1)ꢀBr oxidative addition complex
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(Figure 2). To this end, simple exposure of 4ꢀtrifluoromethyl
Na(acac)52 whereas an improved turnover number (TON) was
1
2
3
4
5
6
7
8
bromobenzene to Ni(COD)2 and L1 in THF at rt resulted in
Ni-1, the structure of which was univocally confirmed by Xꢀ
ray diffraction (Figure 2, top).28 Particularly noteworthy was
the observation that Ni-1 underwent the targeted sp3 C–H
arylation of tetrahydrofuran en route to 1 only in the presence
of A1 under CFL irradiation. Indeed, control experiments
revealed that no reaction occurred in the absence of A1 whereꢀ
as exclusive homodimerization was observed if Ni-1 was
exposed under UVA irradiation (λmax = 365 nm), thus providꢀ
ing additional evidence that a σꢀbond metathesis regime
(pathway d) might not be operative.
observed in the absence of such additive, leaving a reasonable
doubt that pathway c (Scheme 7) based on a CT event might
be operative. As a consequence, the presence of acac in our
catalytic protocol does not have an influence on product forꢀ
mation, suggesting that acac may merely facilitate the initial
photoreduction of Ni(acac)2 to deliver the catalytically compeꢀ
tent nickel intermediates. In line with this context, it is worth
noting that no significant deleterious effect was observed
when replacing Ni(acac)2 by other Ni(II) precatalysts28 or
Ni(COD)2 (Table 2, entry 5). Although our empirical observaꢀ
tions may not be taken as a definitive proof that other pathꢀ
ways might not be populated,53 the available data is consistent
with pathway e based on a HAT process from the triplet excitꢀ
ed state of A1 followed by SET to recover back the propagatꢀ
ing A1 and lowꢀvalent Ni(0)L species (Scheme 4). Unfortuꢀ
nately, it was not possible to unambiguously unravel the most
basic features of such intertwined scenarios, as the interaction
of A1 and Ni-1 in either THF or benzene was exacerbated by
the high absorption of Ni-1 in the (n,π*) excitation region of
A1. Additionally, SternꢀVolmer analysis or flash photolysis
could not be conducted due the propensity of Ni-1 to decomꢀ
position pathways, even under highly diluted conditions.54,55
Aimed at providing indirect evidence about the mode of action
of A1, we decided to monitor a stoichiometric reaction of Ni-1
and A1 in dioxane by EPR spectroscopy with constant irradiaꢀ
tion (>300 nm) (Figure 2, bottom). A direct comparison with
the known g-values on related scenarios10b,28 revealed the
formation of Ni(I) intermediates and the corresponding ketyl
radical together with the corresponding sp3 C–H arylation of
dioxane (83).28 Taken together, these control mechanistic
experiments contribute to the perception that a HAT & SET
pathway seems the most plausible avenue for the merger of
triplet excited ketones and Ni catalysis.
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CONCLUSION
In summary, we have designed a catalytic platform that emꢀ
ploys a synergistic combination of nickel salts and diaryl
ketone catalysts for the utilization of saturated feedstocks as
functional handles in sp3 C–H arylation and alkylation events
with aryl or alkyl halides as starting precursors. This dual
catalytic scenario makes use of simple, modular and versatile
triplet diaryl ketones as catalysts to activate sp3 C–H bonds,
even in the context of lateꢀstage functionalization or in an
asymmetric manner. The available data suggest that the merꢀ
ger of cheap, modular and widely accessible triplet excited
ketones and nickel catalysts might represent a powerful alterꢀ
native to classical innerꢀsphere sp3 C–H functionalization
techniques or existing photochemical metallaphotoredox sceꢀ
narios based on commonly employed iridium polypyridyl
photoredox catalysts. Mechanistic experiments suggest a new
activation mode by which triplet excited ketones serve as both
HAT and SET catalysts, with catalytic turnover effected by an
intertwined scenario with nickel catalysts. We expect that the
broader consequences of this concept will foster systematic
investigations for a more prolific use of simple ketones as
photocatalysts for streamlining synthetic sequences that rapidꢀ
ly buildꢀup molecular complexity from simple chemical feedꢀ
stocks.
Figure 2. Mechanistic Experiments with Ni-1. All reactions
were conducted with Ni-1:A1 in a 1:1 ratio. a GC yields, using
decane as internal standard. b Exclusive homodimerization was
observed in the crude mixtures.
In line with our expectations, Ni-1 turned out to be catalytiꢀ
cally competent, furnishing 3 in 35% yield together with nonꢀ
negligible amounts of 1 derived from Ni-1 (Figure 2, middle).
At present, the markedly decrease in reactivity of Ni-1 when
compared to our in situ protocol based on Ni(acac)2/L1 can
tentatively be attributed to (a) the stunning absorption of Ni-1
in the visible light region,28 and/or (b) the absence of acac
anion, as the photoreduction of Ni(acac)2 via chargeꢀtransfer
(CT) might have a direct correlation with the generation of
acacꢀradical species (Scheme 5, pathway c).10 The latter asꢀ
sumption was assessed by conducting the sp3 C–H arylation of
methyl 4ꢀbromobenzoate and Ni-1 (1 mol%) with or without
additional Na(acac) (20 mol%). Although in lower yields, the
results are particularly illustrative (Figure 2, middle); specifiꢀ
cally, significant inhibition was observed in the presence of
ASSOCIATED CONTENT
Supporting Information
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Photocycloaddition Reactions of 2(1H)ꢀQuinolones Induced
The Supporting Information is available free of charge on
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the ACS Publications website.
Experimental procedures, spectral and crystallographic data
(PDF)
Data for Ni-1 (CCDC 1851145) (CIF)
AUTHOR INFORMATION
Corresponding Author
9
* rmartinromo@iciq.es
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Funding Sources
The authors declare no competing financial interest.ꢀ
ACKNOWLEDGMENT
We thank ICIQ, MINECO (CTQ2015ꢀ65496ꢀR), & Severo
Ochoa Accreditation SEVꢀ2013ꢀ0319 for support. We also
thank the ICIQ XꢀRay Diffraction Unit and insightful disꢀ
cussions with Dr. Francisco Juliá. Y. S. and Y. G. thank
China Scholarship Council (CSC) and MINECO for preꢀ
doctoral fellowships.
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9
24) For acidity of ketyl radicals: (a) Kalinowski, M. K.;
Grabowski, Z. R.; Pakula, B. Reactivity of Ketyl Free Radiꢀ
cals. Part 1.ꢀAcid Dissociation of Aromatic Ketyls and Pinaꢀ
cols. Trans. Faraday. Soc., 1966, 62, 918. (b) Lund, T.;
Wayner, D. D. M. Jonsson, M.; Larsen, A.; Daasbjerg, K. Oxꢀ
idation Potentials of αꢀHydroxyl Radicals in Acetonitrile Obꢀ
tained by Photomodulated Voltammetry. J. Am. Chem. Soc.
2001, 123, 12590. (b) Tang, X.; Studer, A. Alkene 1,2ꢀ
Difuntionalization by Radical Alkenyl Migration. Angew.
Chem. Int. Ed. 2018, 57, 814.
25) Leigh, W. J.; Arnold, D. R.; Humphreys, R. W. R.; Wong, P.
C. Merostabilization in Radical Ions, Triplets, and Biradicals.
4. Substituent Effects on the HalfꢀWave Reduction Potentials
and n, π* Triplet Energies of Aromatic Ketones. Can. J.
Chem. 1980, 58, 2537.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
26) For Ered[NiI/Ni0] vs Ag/AgNO3, see: (a) Börjesson, M.; Moraꢀ
gas, T.; Martin, R. NiꢀCatalyzed Carboxylation of Unactivatꢀ
ed Alkyl Chlorides with CO2. J. Am. Chem. Soc. 2016, 138,
7504. For Ered[NiI/Ni0] vs SCE, see: (b) Klein, A.; Kaiser, A.;
Sarkar, B.; Wanner, M.; Fiedler, J. The Electrochemical Beꢀ
haviour of Organonickel Complexes: Monoꢀ, Diꢀ and Trivaꢀ
lent Nickel. Eur. J. Inorg. Chem. 2007, 965. (c) Cannes, C.;
Labbé, E.; Durandetti, M.; Devaud, M.; Nédélec, J. Y. Nickꢀ
elꢀCatalyzed Electrochemical Homocoupling of Alkenyl Halꢀ
ides: Rates and Mechanisms. J. Electroanal. Chem. 1996,
412, 85.
19) For ketoneꢀcatalyzed sp3 CꢀH functionalization using visible
light sources: (a) Xia, J.ꢀB.; Zhu, C.; Chen. C. Visible Lightꢀ
Promoted MetalꢀFree C–H Activation: Diarylketoneꢀ
Catalyzed Selective Benzylic Monoꢀ and Difluorination. J.
Am. Chem. Soc. 2013, 135, 17494. (b) Xia, J.ꢀB.; Zhu, C.;
Chen. C. Visible LightꢀPromoted MetalꢀFree sp3ꢀCꢀH Fluoriꢀ
nation. Chem. Commun., 2014, 50, 11701. (c) Paul, S.; Guin,
J. Radical C(sp3)ꢀH Alkenylation, Alkynylation and Allylaꢀ
tion of Ethers and Amides Enabled by Photocatalysis. Green
Chem. 2017, 19, 2530.
20) For reviews on dual catalysis in photochemical events: (a)
Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
MacMillan, D. W. C. The Merger of Transition Metal and
Photocatalysis. Nat. Rev. Chem. 2017, 1, 0052. (b) Levin, M.
D.; Kim, S.; Toste, F. D. Photoredox Catalysis Unlocks Sinꢀ
gleꢀElectron Elementary Steps in Transition Metal Catalyzed
CrossꢀCoupling. ACS Cent. Sci. 2016, 2, 293. (c) Hopkinson,
M. N.; Sahoo, B.; Li, J.ꢀL.; Glorius, F. Dual Catalysis Sees
the Light: Combining Photoredox with Organoꢀ, Acids, and
TransitionꢀMetal Catalysis. Chem. Eur. J. 2014, 20, 3874. (d)
Skubi, K. L.; Blum, T. R.; Yoon, T. P. dual catalysis strateꢀ
gies in photochemical synthesis. Chem. Rev. 2016, 116,
10035. (e) Marzo, L.; Pagore, S. K.; Reiser, O.; König, B.
VisibleꢀLight Photocatalysis: Does It Make A Difference in
Organic Synthesis? Angew. Chem. Int. Ed. 2018, 57, 2.
21) For recent reviews on organic photocatalysts, see: (a)
Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalyꢀ
sis. Chem. Rev., 2016, 116, 10075. (b) Majek, M.; von
Wangelin, A. J. Mechanistic Perspectives on Organic Photoꢀ
redox Catalysis for Aromatic Substitutions. Acc. Chem. Res.,
2016, 49, 2316. (c) Chen, C. The Past, Present, and Future of
the Yang Reaction. Org. Biomol. Chem. 2016, 14, 8641. (d)
Ravelli, Fagnoni, M.; Albini, A. Photoorganocatalysis. What
for? Chem. Soc. Rev., 2013, 42, 97. (e) Fagnoni, M.; Dondi,
D.; Ravelli, D.; Albini, A. Photocatalysis for the Formation of
the CꢀC Bond. Chem. Rev. 2007, 107, 2725.
27) Selected references: (a) Demeter, A.; Horváth, K.; Böör, K.;
Molnár, L.; Soós, T.; Lendvay, G. Substituent effect on the
photoreduction kinetics of benzophenone. J. Phys. Chem. A.,
2013, 117, 10196. (b) Jacques, P.; Lougnot, D. J.; Fouassier,
J. P.; Scaiano, J. C. Location Effects upon the Kinetic Behavꢀ
ior of Benzophenone in Micellar Solution. Chem. Phys. Lett.
1986, 127, 469. (c) refs 8, 18cꢀd and 24.
28) See Supporting information for details.
29) See for example: (a) Zhang, X.; Wang, C. –J.; Liu, L. –H.;
Jiang, Y. –B. J. Phys. Chem. B., 2002, 106, 12432. (b) Wagꢀ
ner, P. J.; Truman, R. J.; Scaiano, J. C. J. Am. Chem. Soc.
1985, 107, 7093. (c) Wintgens, V.; Valat, P.; Kossanyi, J.;
Demeter, A.; Biczók, L.; Bérces, T. J. Photochem. Photobiol.
A., 1996, 93, 109. (d) ref. 25.
30) For a nonꢀphotocatalytic C–H arylation of THF requiring
stoichiometric amounts of diꢀtert-butyl peroxide: Liu, D.; Liu,
C.; Li, H.; Lei, A. Direct Functionalization of Tetrahydrofuꢀ
ran and 1,4ꢀDioxane: NickelꢀCatalyzed Oxidative C(sp3)ꢀH
Arylation. Angew. Chem. Int. Ed. 2013, 52, 4453.
31) For a discussion on the intriguing role of oxygen in Ir photoꢀ
redox/nickel catalysis: Oderinde, M. S.; VarelaꢀAlvarez, A.;
Aquila, B.; Robbins, D. W. Effects of Molecular Oxygen,
Solvent, and Light on IridiumꢀPhotoredox/Nickel Dualꢀ
Catalyzed CrossꢀCoupling Reactions. J. Org. Chem. 2015, 80,
7642.
32) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Adꢀ
vances in Homogeneous Nickel Catalysis. Nature 2014, 509,
299ꢀ309. (b) Diederich, F.; Meijere, A., Eds. Metal-Catalyzed
Cross-Coupling Reactions; WileyꢀVCH: Weinheim, 2004.
33) Barry, J. T.; Berg, D. J.; Tyler, D. R. Radical Cage Effects;
Comparison of Solvent Bulk Viscosity and Microviscosity in
Predicting the Recombination Efficiencies of Radical Cage
Pairs. J. Am. Chem. Soc. 2016, 138, 9389.
22) For nonꢀnoble metalꢀbased photocatalysts in arylation reacꢀ
tions initiated by SET: (a) Luo, J.; Zhang, J. DonorꢀAcceptor
Fluorophores for VisibleꢀLightꢀPromoted Organic Synthesis:
Photoredox/Ni Dual Catalytic C(sp3)ꢀC(sp2) CrossꢀCoupling.
ACS Catal., 2016, 6, 873. (b) McTiernan, C. D.; Leblanc, X.;
Scaiano, J. C. Heterogeneous TitiniaꢀPhotoredox/Nickel Dual
Catalysis: Decarboxylative CrossꢀCoupling of Carboxylic Acꢀ
ids with Aryl Iodides. ACS Catal., 2017, 7, 2171. (c) Matsui,
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34) Nielsen, M. K.; Shields, B. J.; Liu, J.; Williams, M. J.;
tion times, however, small amounts of reduced arene could be
observed in the crude mixtures (see ref. 28). For selected
mechanistic considerations with either bipyridine or phosꢀ
phine ligands, see: (a) ref. 16. (b) Tsou, T. T.; Kochi, J. K.
Mechanism of Oxidative Addition. Reaction of Nickel(0)
Complexes with Aromatic Halides. J. Am. Chem. Soc. 1979,
101, 6319. (c) FunesꢀArdoiz, I.; Nelson, D. J.; Maseras, F.
Halide Abstraction Competes with Oxidative Addition in the
Reactions of Aryl Halides with [Ni(PMenPh(3ꢀn)4]. Chem. Eur.
J. 2017, 23, 16728.
Zacuto, M. J.; Doyle, A. G. Mild, RedoxꢀNeutral Formylation
of Aryl Chlorides via Photocatalytic Generation of Chlorine
radicals. Angew. Chem. Int. Ed. 2017, 56, 7191.
1
2
3
4
5
6
7
35) For an elegant formation of quaternary centers by Ir photoreꢀ
dox initiated by SET from stoichiometric organotrifluoroboꢀ
rates: Primer, D. N.; Molander, G. A. Enabling the Crossꢀ
Coupling of Tertiary Organoboron Nucleophiles through Radꢀ
icalꢀmediates Alkyl Transfer. J. Am. Chem. Soc. 2017, 139,
9847.
8
9
36) For photoreduction of benzophenone in toluene and cycloꢀ
hexane, see: Walling, C.; Gibian, M. J. Hydrogen Abstraction
Reactions by the Triplet States of ketones. J. Am. Chem. Soc.
1965, 87, 3361.
37) Bicyclohexyl and cyclohexylbenzene were observed in the
crude mixtures, thus explaining the lower efficiency en route
to 51 and 52. See ref. 36.
38) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska,
S. W. The Medicinal Chemist’s Toolbox for Late Stage Funcꢀ
tionalization of drugꢀlike molecules. Chem. Soc. Rev. 2016,
45, 546.
39) Unreacted Ambroxide was recovered unaltered.
40) Echeverria, V.; Zeitlin, R. Cotinine: A Potential New Theraꢀ
peutic Agent against Alzheimer’s Disease. CNS Neuroscience
& Therapeutics 2012, 18, 517.
41) According to eBioChem, USBiological, GENTAUR or Toꢀ
ronto Research Chemicals, 57 costs approximately 60$/mg.
The utilization of our protocol, however, allows for preparing
57 at 10 mmol scale from cheap and simple precursors.
42) Modest results were found when using commonly employed
Pyrox, Box or Phoxꢀtype ligands. For a recent enantioselecꢀ
tive Ni/photoredox decarboxylative arylation, see: Zuo, Z.;
Cong, H.; Choi, L. J.; Fu, G. C.; MacMillan, D. W. C. Enanꢀ
tioselective Decarboxylative Arylation of αꢀAmino Acids via
the Merger of Photoredox and Nickel Catalysis. J. Am. Chem.
Soc. 2016, 138, 1832.
43) For a recent technique based on Irꢀpolypyridyl complexes: (a)
Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W.
C. Selective sp3 C–H alkylation via PolarityꢀMatchꢀBased
CrossꢀCoupling. Nature 2017, 547, 79ꢀ83. (b) For a single exꢀ
ample of an alkylation event in moderate yields, see ref. 34.
44) Choi, J.; Fu, G. C. Transition MetalꢀCatalyzed AlkylꢀAlkyl
Bond Formation: Another Dimension in CrossꢀCoupling
Chemistry. Science 2017, 356, 152.
45) At present, we believe that the inclusion of CF3CO2Na could
increase the electrophilicity of the putative alkylꢀNi(II) broꢀ
mide by anion exchange to facilitate the interception with the
in situ generated alkyl radical via HAT, thus preventing paraꢀ
sitc βꢀhydride elimination or homocoupling events.
46) Xue, X.ꢀS.; Ji, P.; Zhou, B.; Cheng, J.ꢀP. The Essential Role
of Bond Energetics in CꢀH Activation/Functionalization.
Chem. Rev. 2017, 117, 8622.
48) (a) Deneś, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl
Radicals in Organic Synthesis. Chem. Rev. 2014, 114, 2587.
(b) Simmons, E. M.; Hartwig, J. F. On the Interpretation of
Deuterium Kinetic Isotope Effects in CꢀH Bond Functionaliꢀ
zations by TransitionꢀMetal Complexes. Angew. Chem. Int.
Ed. 2012, 51, 3066.
49) For the generation of halogen radical from high valent Ni
complex, see: Mondal, P.; Pirovano, P.; Das, A.; Farquhar, E.
R.; McDonald, A. R. Hydrogen Atom Transfer by A Highꢀ
Valent Nickel Chloride Complex. J. Am. Chem. Soc. 2018,
140, 1834.
50) These results are in sharp contrast to a recent arylation of tolꢀ
uene under UV irradiation, see: Ishida, N.; Masuda, Y.; Ishiꢀ
kawa, N.; Murakami, M. Cooperative of A NickelꢀBipyridine
Complex with Light for Benzylic CꢀH Arylation of Toluene
Derivatives. Asian. J. Org. Chem. 2017, 6, 669.
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42
43
44
45
46
47
48
49
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52
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51) In this context, not even traces of intramolecular sp3 C–H
functionalization were observed en route to either 68 or 81
and 82 using 2,2’ꢀdibromoꢀ1,1’ꢀbiphenyl as starting precursor
(see Supporting information for details). Although the siteꢀ
selectivity observed for 42 or 43 favoring secondary vs primaꢀ
ry sp3 C–H sites may argue against a σꢀbond metathesis reꢀ
gime, we cannot rigorously rule out this pathway due to the
reversibility of high valent Ni–C bonds. For a computational
study, see: Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Moꢀ
lander, G. A. NickelꢀCatalyzed CrossꢀCoupling of Photoreꢀ
doxꢀGenerated Radicals: Uncovering a General Manifold for
Stereoconvergence in NickelꢀCatalyzed CrossꢀCouplings. J.
Am. Chem. Soc. 2015, 137, 4896.
52) In line with this notion, the sp3 C–H arylation of THF with 4ꢀ
trifluoromethyl bromobenzene was inhibited in the presence
of Naꢀacac (1 equiv). See ref. 28 for details.
53) For a fundamental study of photochemical properties of biꢀ
pyridine ligated Ni(II) complex, see: Shields, B. J.; Kudisch,
B.; Scholes, G. D.; Doyle, A. G. LongꢀLived ChargeꢀTransfer
States of Ni(II) Aryl Halide Complexes Facilitate Bimolecular
Photoinduced Electron Transfer. J. Am. Chem. Soc. 2018,
140, 3035.
54) It is worth considering the quenching rate of triplet benzopheꢀ
none by Ni(acac)2 (2.9*109 Mꢀ1secꢀ1 in MeOH) and nPr2O
(9.2*106 Mꢀ1secꢀ1 in bencene). See: (a) Guttenplan, J.; Cohen,
S. G. Triplet Energies, Reduction Potential, and Ionization
potentials in CarbonylꢀDonor Partial ChargeꢀTransfer Interacꢀ
tions. J. Am. Chem. Soc. 1972, 94, 4040. (b) ref. 10b. Altꢀ
hough tentative, these quenching rates might be responsible
for the observed efficiency of our Ni/A1 regime
47) Oxidative addition of aryl bromides or iodides to Ni(0) may a
priori occur via radical cage mechanisms en route to arylꢀ
Ni(II) halide complexes or by the formation of Ni(I) halide
species with concomitant formation of aryl radicals capable of
triggering HAT with C–H donors. In line with this context, it
is worth noting that trace amounts of reduced arene were obꢀ
served when using aryl iodides as substrates in THF (or d8-
THF), suggesting that the latter pathway does not intervene
under our standard reaction conditions; after prolonged reacꢀ
55) Although Ni-1 turned out to be particularly prone to decomꢀ
position pathways, the presence of an aryl bromide signifiꢀ
cantly increased its stability.
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Ni catalyst / Ligand
sp3 C–H precursor
&
sp3 C–H arylation
ketone catalysts
R
H
R
59 examples
up to 98% yield
Ar1
Ar2
X
X
O
L
L
+
Ni
light
sp3 C–H alkylation
triplet ketone
catalysis
Br
nickel catalysis
R
20 examples
up to 84% yield
organic bromide
R1
Excellent chemo- & site-selectivity
Wide scope & mild conditions
Late-stage functionalization
R2
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