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Enantioselective Catalysis

Chemie

International Edition: DOI: 10.1002/anie.201910168
German Edition:
DOI: 10.1002/ange.201910168

Photochemical Asymmetric Nickel-Catalyzed Acyl Cross-Coupling
Eugenio Gandolfo, Xinjun Tang, Sudipta Raha Roy, and Paolo Melchiorre*
Abstract: Photochemical enantioselective nickel-catalyzed
cross-coupling reactions are difficult to implement. We report
a visible-light-mediated strategy that successfully couples symmetrical anhydrides and 4-alkyl dihydropyridines (DHPs) to
afford enantioenriched a-substituted ketones under mild conditions. The chemistry does not require exogenous photocatalysts. It is triggered by the direct excitation of DHPs, which
act as a radical source and as a reductant, facilitating the
turnover of the chiral catalytic nickel complex.

N

ickel catalysis has experienced great advances in the past
decade, with valuable cross-coupling processes being developed to produce natural products, polymers, and pharmaceuticals.[1] Recent efforts have also demonstrated how
nickel-catalyzed cross-coupling strategies can be used to
prepare chiral molecules.[2] For example, there are effective
methods for achieving enantioconvergent carbon–carbon
bond formation using racemic alkyl electrophiles and traditional[3] or reductive[4] cross-coupling processes (Figure 1 a).
However, these methods require highly nucleophilic organometallic reagents or stoichiometric reductants, respectively.
This reduces their practicality. Recently, the combination of
nickel catalysis and photoredox catalysis[5] has provided
a versatile tool to mitigate some of these issues (Figure 1 b).
This approach exploits the ability of visible-light-activated
photocatalysts to generate, on excitation, alkyl radicals upon
single-electron transfer (SET) activation of low-energy,
bench-stable substrates and under mild conditions.[6] Crucially, the photoredox catalyst also modulates the oxidation
state of nickel complexes by SET reduction, which is essential
for catalyst turnover. Despite the potential practical advantages of this approach, only a few asymmetric catalytic
examples has been developed to date.[7]

[*] Prof. Dr. P. Melchiorre
ICREA
Passeig Lluís Companys 23, 08010 Barcelona (Spain)
E. Gandolfo, Dr. X. Tang, Dr. S. Raha Roy, Prof. Dr. P. Melchiorre
ICIQ – Institute of Chemical Research of Catalonia, the Barcelona
Institute of Science and Technology
Avenida Països Catalans 16-43007, Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/profpaolo-melchiorre/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201910168.
 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial, and no
modifications or adaptations are made.

Our laboratory recently reported a complementary photochemical approach for nickel cross-coupling[8] that exploits
the direct excitation of 4-alkyl-1,4-dihydropyridines (DHPs,
1) to generate alkyl radicals.[9, 10] We demonstrated that the
excited state of DHPs acts simultaneously as a strong SET
reductant, thus modulating the nickel oxidation state, and as
a radical source. We recently wondered if the dual reactivity
profile of the excited 1 could be used to expand the potential
of asymmetric nickel-catalyzed cross-coupling technology.
Here, we detail how this design plan was translated in
experimental reality, leading to the development of a visiblelight-induced enantioselective process under mild conditions,
using readily available and stable reagents, and without the
need for exogenous photocatalysts (Figure 1 c).
The catalytic cycle of our proposed photochemical
asymmetric cross-coupling process is outlined in Figure 2.
We selected symmetrical anhydrides 2 as electrophiles
because nickel has a propensity to activate these substrates.[11]
The crucial mechanistic aspect is that, upon excitation, the
racemic alkyl-DHPs 1 can act as precursors of alkyl radicals
and as strong reducing agents (E (1 aC+/1 a*) % À1.6 V vs. Ag/
Ag+ in CH3CN, as estimated from electrochemical and
spectroscopic measurements applying the Rehm-Weller
approximation).[12] The latter property is essential to restore

1

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Angew. Chem. Int. Ed. 2019, 58, 1 – 6

Figure 1. a) Enantioconvergent nickel-catalyzed strategies via traditional nucleophile–electrophile coupling (left) and reductive (right)
cross-electrophile coupling. b) Enantioselective dual photoredox-nickel
catalysis approaches via radical manifolds. c) The proposed asymmetric catalytic cross-coupling strategy exploits the ability of 4-alkyl-1,4dihydropyridines (DHPs, 1) to generate radicals upon visible-light
excitation. X: halides and pseudo-halides; LG: leaving group; E:
electrophore.

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Table 1: Optimization studies and control experiments.[a]

Entry
Figure 2. Proposed catalytic mechanism for the visible-light-driven
asymmetric nickel-catalyzed acyl cross-coupling process.

2

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the catalytically active nickel intermediate and to secure
turnover. In the first catalytic cycle, the excited-state intermediate 1* would reduce, by two discrete SET events, the NiII
precatalyst to afford the active Ni0 intermediate A (Ep(NiII/
Ni0) = À1.2 V versus SCE in DMF).[13] The resulting, highly
unstable radical cation 1C+ would then undergo homolytic
cleavage to generate a secondary C(sp3)-centered radical B.
Oxidative addition into the C(sp2)ÀO bond of the anhydride 2
would afford the NiII–acyl complex C, which would intercept
the stabilized secondary radical, leading to the NiIII intermediate D. Reductive elimination would then provide the
cross-coupling chiral ketone product 3. We anticipated that an
appropriate chiral ligand would provide control of the
stereoselectivity.[14] Finally, the generated NiI complex would
undergo SET reduction by the excited alkyl-DHPs 1*,
completing the nickel catalytic cycle while regenerating the
C(sp3) radical intermediate B.
To validate our plan, the commercially available and
stable butyric anhydride 2 a was selected as the acyl precursor
(Table 1). For the radical precursor, we chose the indolecontaining racemic DHP 1 a because this would form product
3 a bearing a stereogenic center a to the indole nitrogen. This
structural motif is synthetically interesting because it is found
in many natural products and pharmaceutical drugs.[15] However, it is a difficult target as testified to by the paucity of
asymmetric catalytic protocols available for the preparation
of enantioenriched N-alkylated indoles.[16] We conducted our
experiments in THF under irradiation by a single high-power
visible-light-emitting diode (LED, lmax = 405 nm) with an
irradiance of 75 mW cmÀ2, as controlled by an external power
supply (full details of the illumination set-up are reported in
the Supporting Information). By examining a range of
reaction parameters, we determined that NiCl2 and the
chiral box ligand L1[17] can accomplish the enantioconvergent
photochemical cross-coupling in good yield and high ee (3 a
formed in 65 % yield and 75 % ee; entry 1). Other nickel salts
provided slightly improved stereocontrol, but at the expense
of chemical yield (entries 2 and 3). Because of the good
compromise between reactivity and enantioselectivity, we
selected NiCl2 for further optimization. No improvement was
achieved with other solvents (entries 4 and 5) or chiral
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1
2
3
4
5
6
7
8
9

none
NiBr2 instead of NiCl2
NiCl2dme instead of NiCl2
acetonitrile instead of THF
dioxane instead of THF
L2 instead of L1
L3 instead of L1
no light
no catalyst NiCl2

[c]

65 (56)
53
48
43
38
31
34
0
0

ee [%]
75
80
80
28
77
12
0
–
–

[a] Reaction performed in THF [0.167 m] at 10 8C for 48 h on a 0.1 mmol
scale using 2 equiv of 1 a and 1 equiv of lutidine as base under
illumination by a single high-power (HP) LED (lmax = 405 nm) with an
irradiance of 75 mWcmÀ2. [b] Yield determined by 1H NMR analysis of
the crude mixture using mesitylene as the internal standard. [c] The
number in parentheses indicates the yield of the isolated 3 a after
chromatography purification on silica gel.

ligands, including representative examples that have been
useful in other nickel-catalyzed enantioconvergent crosscouplings (entries 6 and 7).[3, 4] Control experiments confirmed that the reaction could not proceed in the absence of
light or a nickel catalyst (entries 7 and 8).
Using the optimized conditions described in Table 1,
entry 1, we tested the generality of the photochemical crosscoupling process (Figure 3). We first evaluated the scope of
the radical precursors 1. Several halogen substituents on the
indole scaffold were tolerated well, affording the corresponding N-alkylated chiral indoles in good yields and stereoselectivity (products 3 b–d). A carbazole scaffold was also introduced within the final products, albeit at the expense of
stereoselectivity (adducts 3 e and 3 f). We then evaluated
different anhydrides as acyl coupling partners. Different
substitution patterns were tolerated, including an aryl moiety
(products 3 i, 3 k, 3 l), a ketone (3 h and 3 j), and an alkyl
chloride (3 g). We failed to synthesize DHP radical precursors
1 bearing a substitution pattern other than methyl. This
limitation is somehow mitigated by the ability to forge
a ketone moiety with a methyl a-stereogenic center. This is an
important synthetic achievement,[18] for which there are few
effective catalytic asymmetric protocols.
We then sought to extend the applicability of this photochemical cross-coupling strategy to the stereocontrolled
preparation of acyclic a,a-aryl,alkyl ketones, which are
versatile synthetic intermediates for the synthesis of natural
products and pharmaceutical agents.[19] This required the
preparation of racemic DHP radical precursors bearing both

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Yield [%][b]

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an aryl and alkyl moiety. A quick re-optimization of the
reaction conditions identified NiBr2 as the best catalyst to
promote the asymmetric acyl cross-coupling using anhydrides,
which afforded the target chiral a-aryl ketones 4 with high
enantioselectivity (Figure 4).[20] Concerning the radical precursor, this protocol offered a wide scope since alkyl chains of
different length could be readily accommodated (products
4 a–d). A variety of a-methyl a-aryl ketones were synthesized
with high stereocontrol and good chemical yield. The process
tolerated aromatic rings adorned with electron-donating and
electron-withdrawing groups at the para position (4 g–i). A
meta-substituted ring decreased the yield (4 f), while orthosubstitution suppressed the reactivity (result not shown,
a complete list of unsuccessful substrates is reported in
Figure S6 of the Supporting Information). A naphthyl ring
was also tolerated (4 e).
A wide functional group tolerance was achieved for the
acyl fragment. For example, an olefin was included in the final
product (4 k) without the occurrence of side reactions.
Angew. Chem. Int. Ed. 2019, 58, 1 – 6

Figure 4. Synthesis of a-aryl ketones: survey of the DHPs 1 and
anhydrides 2 that can participate in the photochemical nickel-catalyzed
asymmetric cross-coupling. Reaction performed at 10 8C for 18 h on
a 0.1 mmol scale using THF as solvent (0.6 mL), 2 equiv of 1, 1 equiv
of lutidine under illumination by a single high-power (HP) LED
(lmax = 405 nm) with an irradiance of 75 mWcmÀ2. Ac: acetyl.

In summary, we have shown that the excited state
chemistry of DHPs 1 can be combined with a chiral nickel
catalyst. We have used this approach to stereoselectively
couple radicals with symmetric anhydrides. The resulting
chiral ketones, which contain different groups at the astereogenic center, including an (1H-indol-1-yl) moiety, are
synthesized with good stereocontrol. We believe that this
visible-light-mediated strategy, which does not require external photoredox catalysts, can provide a reliable platform for
other applications in enantioselective catalytic cross-coupling
processes.

Acknowledgements
Financial support was provided by MICIU (CTQ2016-75520P), the AGAUR (Grant 2017 SGR 981), and the European
Research Council (ERC-2015-CoG 681840 – CATA-LUX).

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Figure 3. Synthesis of N-alkylated chiral indoles: survey of the DHPs
1 and anhydrides 2 that can participate in the photochemical nickelcatalyzed asymmetric cross-coupling. Reaction performed at 10 8C for
48 h on a 0.1 mmol scale using THF as solvent (0.6 mL), 2 equiv of 1,
1 equiv of lutidine under illumination by a single high-power (HP) LED
(lmax = 405 nm) with an irradiance of 75 mWcmÀ2. Ac: acetyl.

Chemie

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Conflict of interest
The authors declare no conflict of interest.

[8]

Keywords: asymmetric catalysis · cross-coupling ·
nickel catalysis · photochemistry · radical chemistry

[9]

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literature, see Ref. [4a].
Manuscript received: August 9, 2019
Revised manuscript received: September 17, 2019
Accepted manuscript online: September 18, 2019
Version of record online: && &&, &&&&

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[17] Chiral box ligands have shown a remarkable ability to infer high
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Enantioselective Catalysis
E. Gandolfo, X. Tang, S. Raha Roy,
P. Melchiorre*
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Photochemical Asymmetric NickelCatalyzed Acyl Cross-Coupling

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Light it up: Photochemical enantioselective nickel-catalyzed cross-coupling reactions are difficult to implement. A visiblelight-mediated strategy is reported that
couples anhydrides 2 and 4-alkyl dihydropyridines 1 (DHPs) to afford enantioenriched a-amino and a-aryl ketones

under mild conditions. The chemistry,
which does not require exogenous photocatalysts, is triggered by the direct
excitation of DHPs, which generate radicals while facilitating the turnover of the
nickel catalyst.

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