Photoactive electron donor-acceptor complex platform for Ni-mediated C(sp3)-C(sp2) bond formation

Article abstract of DOI:10.1039/d1sc00943e

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp3)-C(sp2) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor-acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp3)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

Full text of DOI:10.1039/d1sc00943e

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Photoactive electron donor–acceptor complex
platform for Ni-mediated C(sp3)–C(sp2) bond
formation†
Cite this: Chem. Sci., 2021, 12, 5450
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Lisa Marie Kammer,‡ Shorouk O. Badir,‡ Ren-Ming Hu and Gary A. Molander
A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp3)–C(sp2) linkages
is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE)
functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-
electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-
based radical generation through electron donor–acceptor (EDA) complex activation. This
homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric
metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp3)-
centered radical architectures (including primary, secondary, stabilized benzylic, a-oxy, and a-amino
systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction
conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.
Received 16th February 2021
Accepted 4th March 2021
DOI: 10.1039/d1sc00943e
rsc.li/chemical-science
manganese or zinc, functions as a terminal organic reductant in
the enantioselective cross-coupling of alkyl-N-hydroxyphthalimide
Introduction
esters (redox active esters, RAEs) with alkenyl bromides (Scheme
1A).7 These protocols, however, are complicated by the air-sensitive
nature of the organic super-electron-donor.8 Strategies utilizing
amines and tris(trimethylsilyl)silane as non-metallic reducing
agents have also been disclosed.9
Transition metal-catalyzed cross-couplings have become indis-
pensable tools for the rapid assembly of C(sp3)–C(sp2) linkages in
medicinal chemistry settings.1 Among these platforms, net-
reductive cross-electrophile couplings are particularly advanta-
geous because they facilitate the direct integration of alkyl elec-
trophiles,1f,j,2 bypassing the need for preformed, reactive carbon
nucleophiles.3 However, the vast majority of reductive cross-
coupling reactions rely on (super)stoichiometric loadings of
metal powders, including manganese and zinc as chemical
reductants, to restore the active catalyst.1f,j,2 In addition to safety
concerns with respect to metal waste disposal, the industry's
dependence on these reaction paradigms highlights the necessity
for inexpensive and scalable strategies for the incorporation of
abundant feedstocks in cross-coupling manifolds.1d,4 Recently,
several seminal studies have demonstrated the use of organic
reducing agents in cross-electrophile processes. Pioneering work
from Tanaka and colleagues showcased the use of tetrakis(dime-
thylamino)ethylene (TDAE) as a homogeneous organic reductant to
achieve the homo-coupling of aryl halides.5 Subsequently, the Weix
group utilized this reductant to activate C(sp3)-hybridized electro-
philes.2a,6 In 2017, Reisman demonstrated that TDAE, in place of
In recent years, photochemical methods have been enlisted
to assemble challenging structural motifs using excitable cata-
lysts under visible-light conditions. Such systems are inherently
mild, efficient at room temperature, and evade the need for
reactive additives (pyrophoric reagents, strong bases, harsh
oxidants and reductants).10 In these dual manifolds, the
reduced state of the photocatalyst has been proposed to restore
the catalytically active Ni0 species through single-electron
transfer (SET) events.11 However, the majority of these redox-
active auxiliaries are based on precious metals including
ruthenium and iridium, presenting limitations with respect to
scalability and sustainability.12 These processes are further
complicated by the oxidation/reduction steps of the photo-
catalyst. To establish a complementary reactivity mode, the
Melchiorre group elegantly reported the direct photoexcitation
of 4-alkyl-1,4-dihydropyridines (DHPs) to trigger the generation
of C(sp3)-centered radicals in the absence of external cata-
lysts.13,14 Although this advancement presented a milestone in
its own right, the scope of the radical precursor in the reported
Ni-catalyzed C(sp3)–C(sp2) cross-coupling was limited to
secondary and stabilized primary systems13a owing to competi-
tive C–H bond scission inherent to DHP feedstocks.15 In this
context, the generation of heteroatom- and unactivated carbon-
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA
† Electronic supplementary information (ESI) available: Experimental and
computational details, as well as spectral data. CCDC 2062315. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc00943e
‡ These authors contributed equally.
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formation, we examined the feasibility of the proposed net-
reductive cross-electrophile coupling using 5-bromo-2-
cyanopyridine 1 and cyclohexyl-N-hydroxyphthalimide-ester 2
as model substrates (Table 1). From the outset of our investi-
gation, it was evident that the solvent plays a key role in this
process (entries 1–4), as it heavily affects the molecular
assembly and formation of EDA complexes. Once exciplex-
based charge transfer occurs, the resulting radical ion pair is
stabilized by interaction with solvent dipoles.18 In this vein,
dimethylacetamide (DMA) proved crucial to the success of this
photochemical method.
We then studied the inuence of the dihydropyridine (DHP)
backbone on the efficacy of the cross-coupling (Table 1, entries
5–7). To this end, we subjected four different DHP derivatives to
the reaction conditions to gain a deeper understanding of their
dual role in EDA complex photoactivation as well as the
reduction of Ni species through SET paradigms. It was
demonstrated that Hantzsch ester (HE) and cyano substitution
at C3 and C5 of the DHP (HE A, entry 5) promoted the reaction
most efficiently. For experimental simplicity, commercially
available and inexpensive Hantzsch ester HE was adopted as the
standard photoreductant. The C-4-substituted DHP (HE B, entry
6) resulted in diminished reactivity. Not surprisingly, 4,40-
dimethyl HE C (entry 7) led to no product formation. This result
can be rationalized by the lack of photooxidative aromatization
as an intrinsic driving force to supress a competitive back
electron transfer (BET) event from the radical ion pair, restoring
the ground-state EDA complex.16a,19 Finally, a ligand screen was
performed (Table 1, entries 10–12), demonstrating that 4,40-di-
tert-butyl-2,20-bipyridine (dtbpy), 2,20-bipyridine (bpy), and
electron-rich 4,40-dimethoxy-2,20-bipyridine (dMeObpy) func-
tion as viable ligand frameworks. Of note, modest conversion to
3 was observed using ligand-free nickel(II) bromide trihydrate.
Notably, the developed net-reductive photochemical condi-
tions are user-friendly, employing an air-stable nickel pre-
catalyst and a mild, homogeneous reductant (HE). Deviations
from the standard reaction setup are tolerated. For example,
modest product formation was observed when the reaction was
carried out under air (Table 1, entry 9). Similarly, although
superior reactivity was accomplished using purple Kessil irra-
diation (lmax ¼ 390 nm), affording a potent photoreductant
[Ered(HE*/HEc+) ¼ ꢀ2.28 V vs. SCE],20 comparable results were
achieved under blue light (entry 8, lmax ¼ 456 nm). Control
experiments demonstrated that all reaction parameters are key
to the formation of C(sp3)–C(sp2) linkages (Table 1, entries 14–
16).
Scheme 1 (A) Strategies toward net-reductive decarboxylative-based
cross-couplings. (B) Overview of electron donor–acceptor (EDA)
photoactivation. (C) Electron donor–acceptor (EDA) complex platform
for Ni-mediated alkyl transfer using HE as an organic photoreductant.
based radicals through direct visible-light excitation in Ni-
catalyzed cross-couplings remains underdeveloped.
Recently, synthetic methods driven by the photoactivity of
electron donor–acceptor (EDA) complexes (Scheme 1B) have
gained considerable momentum, including borylation, thio-
etherication, and sulfonylation.16 Inspired by this advance, we
examined the feasibility of EDA complex photoactivation as an
enabling technology in Ni-mediated C(sp3)–C(sp2) cross-
couplings (Scheme 1C). Under light irradiation at 390 nm,
a commercially available and inexpensive electron donor,
Hantzsch ester (HE, diethyl-1,4-dihydro-2,6-dimethyl-3,5-
pyridinedicarboxylate), serves as a potent organic photo-
reductant to deliver diverse radical architectures from carbox-
ylic acid feedstocks17 for further functionalization in Ni-
catalyzed cross-couplings. As part of its dual role, the excited
HE modulates the oxidation state of the transition-metal,
delivering catalytically active Ni(0) species, thus bypassing the
need for exogenous, expensive photocatalysts.
With suitable conditions established, we examined the scope
of the decarboxylative arylation employing a broad palette of
(hetero)aryl bromides (Scheme 2). In general, organic halides
substituted with electron-withdrawing groups exhibited excel-
lent reactivity, although electron-neutral and electron-donating
groups also afforded the desired products in modest yields.
More sterically-encumbered ortho-substituted aryl bromides (5,
9) did not hinder the cross-coupling efficacy. Furthermore,
substitution at the meta position (4, 6) is tolerated. Several
Discussion
Encouraged by the potential synthetic applications of harness- sensitive functional groups, including secondary sulfonamides
ing photoactive EDA complexes toward Ni-mediated bond (8, 19, 20, 31), ketones (4, 11, 18), trimethylsilylalkyne (9), and
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Table 1 Optimization of the reaction conditionsa
Deviation from std
conditions
Entry
3/IS ratiob
Entry
Deviation from std conditions
3/IS ratiob
1
2
3
4
5
6
7
8
None
DMSO
THF
MeCN
HE A
HE B
1.42 (79%)c
Traces
Traces
0.32
1.40
0.36
9
Under air
0.93
Traces
1.32
1.37
0.92
0
10
11
12
13
14
15
16
NiBr2(dMe-phen)
NiBr2(bpy)
NiBr2 (dMeObpy)
NiBr2$3H2O
No light
HE C
Blue Kessil
0
1.34
No Ni
No HE
0
Traces
a
Optimization reactions were performed using 1 (0.1 mmol), 2 (0.2 mmol), HE (0.2 mmol), and NiBr2(dtbpy) (10 mol%) in dry, degassed solvent (1.0
mL, 0.1 M) under purple Kessil irradiation for 24 h at rt. b Product to internal standard ratio (P/IS) was calculated using 1,3,5-trimethoxybenzene as
internal standard using LC-MS analysis of the crude reaction mixture. Isolated yield of 3 on 0.5 mmol scale.
c
terminal alkene (22) remained intact under the developed primary alkyl systems that lack any radical stabilizing groups
photoredox conditions. To this end, substrates 6, 9 and 22 can displayed exceptional reactivity (4–8, 11–18), providing
be further diversied via Kumada-, sila-Sonogashira-couplings, a clear advantage in terms of scope over previously reported
as well as Giese-type additions, respectively.21
protocols.13a Of note, medicinally relevant structures
Notably, several heteroarenes (electron-decient: 3, 12, 13, including thiophene (6–8), piperidine (23), and pyrrolidine
34 and electron-rich: 17, 18) were compatible structural motifs. (25) motifs were efficiently incorporated.
In particular, nitrogen-containing heteroaryl bromides,
To demonstrate the amenability of this cross-coupling for
including quinoline (13) and pyridine (3, 12, 34) scaffolds, late-stage functionalization, including glycodiversication of
reacted in a chemoselective fashion to yield C(sp3)–C(sp2) drug scaffolds, photoredox-generated glycosyl radicals were
linkages, despite their propensity to undergo visible light- successfully harnessed in this dual-catalytic manifold
mediated Minisci C–H alkylation with alkyl-N-hydroxyph- (Scheme 2). The desired C-aryl carbohydrates (31 and 32) were
thalimide-esters.22 This demonstrates a complementary reac- obtained in good yields and excellent diastereoselectivity (dr >
tivity mode to existing Minisci protocols, delivering linchpins 20 : 1). The relative conguration of the major diastereomer
that drive molecular complexity.23
32 was elucidated based on X-ray crystallography with the aryl
Next, the aliphatic photocoupling was evaluated with group cis with respect to the dimethyl acetal protecting group
respect to redox-active carboxylate derivatives (Scheme 2). (Scheme 2). Efficient decarboxylative arylation was observed
The reaction proceeded smoothly using a diverse array of with pharmaceutically relevant cores, displaying a high
proteinogenic and non-proteinogenic amino acids (21, 23, density of pendant functional groups, including indometh-
25–30). Bifunctional reagents, including Boc- (17, 23, 25–26, acin24 and loratadine25 precursors (33, 34). To evaluate the
29–30) and Fmoc-protected (28) amines, afforded the ary- amenability toward bioactive molecules further, carboxylic
lated products without compromising yields. The scope was acid derivatives stemming from dipeptide (36) and D-biotin
further extended to secondary, benzylic (35), and stabilized (37) were subjected to the reaction conditions. The corre-
a-oxy (19, 24, 31, 32) radical architectures. Remarkably, sponding cross-coupled products were obtained in moderate
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Scheme 2 Scope of the developed C(sp3)–C(sp2) cross-coupling. All values correspond to isolated yields after purification. Reaction conditions
as depicted in Table 1, entry 1 (0.5 mmol scale).
to high yields (65–86%). Finally, to demonstrate the versatility other electron acceptors including redox-active thiols (38a–
of EDA paradigms toward Ni-catalyzed bond-forming 39a)26 and pyridinium-activated amines (40a–41a)9b,16d,27 in the
processes, the cross-coupling was further extended to absence of external catalysts.
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To gain insight into the mechanism of this photochemical excited HE as an organic single-electron donor in this system
net-reductive cross-coupling, we analysed the reaction compo- (Scheme 3A).
nents by UV/vis absorption spectroscopy (Fig. 1). In line with
To probe the formation of alkyl radical intermediates,
seminal reports,16 although cyclohexyl-N-hydroxyphthalimide- TEMPO trapping experiments were performed. The corre-
ester shows absorption in the visible light region, mixtures of sponding TEMPO-adduct was isolated in 63% yield and
the RAE and HE in DMA at 0.2 M display a signicant bath- conrmed via HRMS analysis (Scheme 3B, bottom right). Stoi-
ochromic shi (Fig. 1B, brick red and blue lines).
chiometric experiments with Ni complex 46, synthesized
The absorption band (brick red line) stems from the through oxidative addition of 4-bromobenzotriuoride to
formation of a new molecular aggregation, a colored EDA Ni(cod)2/dtbpy, revealed that C(sp3) alkyl transfer does not
complex (Fig. 1A), exhibiting a wavelength band tailing to occur in the absence of HE, thus highlighting the likelihood of
500 nm. Preliminary studies revealed an association constant of EDA complex activation for effective cross-coupling (Scheme 3B,
2.04 Mꢀ1 of HE with 2, indicating a plausible EDA complex bottom le). As anticipated, Ni complex 46 is catalytically active
association event prior to homolytic fragmentation (Fig. 1C). in the reaction, delivering the desired arylated product in 77%
Analysis of this complex using Job's method29 revealed a 1 : 1 yield (Scheme 3B, bottom le).
stoichiometry of the most absorbing species (Fig. 1D). Notably,
Furthermore, negligible conversion of 42 was observed in the
concentration is a crucial parameter for effective cross- presence of stoichiometric amounts of Ni(COD)2/dtbpy; traces
coupling. A dilute reaction mixture (10ꢀ4 M) exhibits a blue- of homocoupling or alkene-side products, if any, were detected
shied absorption band, indicating the inhibition of EDA in the crude mixture, ruling out the role of Ni as a catalytic
complex formation (see ESI†). Furthermore, a DMA solution of reductant toward redox-active esters (Scheme 3B, top right).
HE was found to absorb visible light (l > 400 nm), indicating Finally, it is worth noting that reduction of redox-active esters
selective photoexcitation of this species at 390 nm to generate with photoredox catalysts is reported in the presence of HE as
a potent reducing agent (Fig. 1B, purple line). Under the opti- a hydrogen atom transfer (HAT) donor.30 A model reaction in
mized reaction conditions, near full recovery of pyridine was the absence of Ni/dtbpy and aryl halide afforded the hydro-
observed (relative to 2.0 equiv. of HE), demonstrating the role of alkylated product in 70% yield with full recovery of pyridine
Fig. 1 (A) Visual appearance of reaction components and mixtures thereof. (B) UV/vis absorption spectra measured in DMA (0.1 M) unless
otherwise noted. Ni complex ¼ NiBr2(dtbpy), aryl bromide ¼ 4-bromobenzonitrile, and RAE ¼ cyclohexyl-N-hydroxyphthalimide ester. Mixture
refers to a DMA solution of all reaction components. (C) Benesi–Hildebrand plot.28 (D) Job plot29 for a mixture of N-(cyclohexyl)-hydroxyph-
thalimide ester (2) and HE in DMA (0.2 M).
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charge transfer provides an enormous rate enhancement over
intermolecular SET, we cannot rule out the intervention of some
direct electron transfer from the photoexcited Hantzsch ester to
initiate radical formation from the RAE. This high-energy,
C(sp3)-hybridized intermediate can suffer two potential fates.
Based on previous computational studies,11 one plausible
mechanistic pathway involves initial radical combination with
a Ni0 species, generating a NiI intermediate that engages in
oxidative addition with the aryl halides to produce high valent
NiIII species II. Subsequent reductive elimination from this
complex yields the desired cross-coupled product and the cor-
responding LnNiI species IV. At this juncture, a key SET event
from the excited state HE [Ered(HE*/HEc+) ¼ ꢀ2.28 V vs. SCE20]
to Ni [Ered(NiI/Ni0) ¼ ꢀ1.17 V vs. SCE in THF10d] regenerates the
active Ni0 catalyst. However, a process that involves initial
oxidative addition of the aryl halides to Ni0 species V, affording
aryl-NiII complex VII, cannot be ruled out based on stoichio-
metric experiments with Ni complex 46 (Scheme 3B). In this
scenario, VII would engage the radical to generate NiIII complex
II, which would then be carried on through the catalytic cycle.
Conclusion
In summary, we have demonstrated the implementation of an
electron donor–acceptor (EDA) complex platform toward Ni-
catalyzed C(sp3)–C(sp2) bond formation, circumventing the
need for exogenous photocatalysts, additives, and stoichio-
metric metal reductants. Under the developed conditions, the
generation of heteroatom- and unactivated carbon-based radi-
cals through direct visible-light excitation of diverse electron
acceptors is feasible, providing a clear advantage in terms of
scope over previously reported photochemical systems.13 Upon
light irradiation at 390 nm, excited HE functions as a potent
organic photoreductant exhibiting a dual role: generation of
reactive C(sp3)-hybridized radicals through EDA complex acti-
vation as well as restoration of the desired catalytically active
Ni(0) species through SET paradigms. This decarboxylative
cross-electrophile arylation is amenable to the synthesis of
peptidomimetics, drug-like molecules, and the diaster-
eoselective functionalization of carbohydrates. The commercial
availability of carboxylic acids and related electron acceptor
species facilitates the rapid incorporation of diverse carbon-
and heteroatom-based radical architectures with high func-
tional group tolerance. Key mechanistic and spectroscopic
studies highlight the necessity for EDA photoactivation for
efficient alkyl transfer and help inform the design of improved
EDA-based paradigms in Ni-catalyzed cross-couplings.
Scheme 3 (A) Investigation of HE as electron donor. (B) Mechanistic
experiments. [a]Isolated yield on 0.3 mmol scale, [b]analysed via GC-MS
analysis, [c]NMR yield, *1.0 equiv. of 42. (C) Proposed mechanism.
(Scheme 3B, top le). These ndings demonstrate that the rate
of alkyl radical addition to aryl-Ni(II) species VII must be faster
than hydrogen atom abstraction from HE.
Based on these experiments, we propose a mechanistic
scenario involving the intermediacy of an EDA complex between
the electron-decient, aliphatic redox-active esters and the
electron-rich HE (Scheme 3C). Photoirradiation at 390 nm
triggers an intra-complex SET event, generating a dihydropyr-
idine radical cation and a phthalimide radical anion. The latter
species undergoes decarboxylative fragmentation to yield an
alkyl radical Ic. Although the absorptivity of the EDA complex is
signicantly greater than that of the Hantzsch ester itself, and
although the entropic advantage inherent in intra-complex
Author contributions
Shorouk O. Badir conceived the topic. Lisa Marie Kammer,
Shorouk O. Badir, and Ren-Ming Hu completed experiments
with input from Gary A. Molander. Shorouk O. Badir and Lisa
Marie Kammer prepared the manuscript with input from Gary
A. Molander.
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L. K. G. Ackerman and D. J. Weix, J. Am. Chem. Soc., 2016,
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There are no conicts to declare.
Acknowledgements
The authors are grateful for nancial support provided by
NIGMS (R35 GM 131680 to G. M.). Shorouk O. Badir is sup-
ported by the Bristol-Myers Squibb Graduate Fellowship for
Synthetic Organic Chemistry. The NSF Major Research Instru-
mentation Program (award NSF CHE-1827457), the NIH
supplement awards 3R01GM118510-03S1 and 3R01GM087605-
06S1, as well as the Vagelos Institute for Energy Science and
Technology supported the purchase of the NMRs used in this
study. We thank Dr Charles W. Ross, III (UPenn) for mass
spectral data and Dr Patrick Carroll (UPenn) for X-ray crystal-
lography data. Merck is acknowledged for donation of aryl
halide informer sets. Access to a UV/vis spectrophotometer was
provided by the Petersson lab (UPenn). We thank Kessil for
donation of lamps.
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