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International Edition: DOI: 10.1002/anie.201812702
German Edition:
DOI: 10.1002/ange.201812702

Photochemistry

Reductive Cyclization of Unactivated Alkyl Chlorides with Tethered
Alkenes under Visible-Light Photoredox Catalysis
Miguel Claros, Felix Ungeheuer, Federico Franco, Vlad Martin-Diaconescu, Alicia Casitas,* and
Julio Lloret-Fillol*
Dedicated to Professor Pablo Espinet on the occasion of his 70th birthday
Abstract: The chemical inertness of abundant and commercially available alkyl chlorides precludes their widespread use
as reactants in chemical transformations. Presented in this
work is a metallaphotoredox methodology to achieve the
catalytic intramolecular reductive cyclization of unactivated
alkyl chlorides with tethered alkenes. The cleavage of strong
C(sp3)ÀCl bonds is mediated by a highly nucleophilic lowvalent cobalt or nickel intermediate generated by visible-light
photoredox reduction employing a copper photosensitizer. The
high basicity and multidentate nature of the ligands are key to
obtaining efficient metal catalysts for the functionalization of
unactivated alkyl chlorides.

Visible-light photoredox catalysis has opened novel and
milder approaches for CÀC and C–heteroatom (CÀHet)
bond-forming reactions through carbon-centered radicals.[1]
In this regard, organic halides are widely used electrophiles
that can be activated through reducing single-electron transfer (SET) reactions, and therefore serve as convenient
coupling partners. The continuous development of photoredox catalysts (PCs) have significantly expanded the reduction potential window (beyond À3 V vs. SCE),[2] facilitating
the cleavage of alkyl bromides,[3] activated alkyl chlorides and
aryl chlorides[2c, 4] by SET processes. Additionally, the synergistic merging of a photosensitizer and either a coordination
metal complex or silane has enabled the efficient activation of
alkyl bromides towards the generation of new CÀC or CÀHet

[*] M. Claros, Dr. F. Ungeheuer, Dr. F. Franco, Dr. V. Martin-Diaconescu,
Dr. A. Casitas, Prof. Dr. J. Lloret-Fillol
Institute of Chemical Research of Catalonia (ICIQ)
Barcelona Institute of Science and Technology
Avda. Països Catalans, 16, 43007 Tarragona (Spain)
E-mail: acasitas@iciq.es
jlloret@iciq.es
Prof. Dr. J. Lloret-Fillol
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluïs Companys, 23, 08010 Barcelona (Spain)
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.201812702.
 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 License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited, and is not used for commercial purposes.
Angew. Chem. Int. Ed. 2019, 58, 4869 –4874

bonds. This concept was recently be expanded to the
carboxylation of aryl chlorides.[5]
Although alkyl chlorides are available and bench-stable
feedstocks, their chemical inertness hinders their use as
electrophilic partners in transition metal catalyzed reactions.[6] Indeed, unactivated alkyl chlorides are beyond the
scope of current state-of-the-art photocatalytic methodologies. A direct homolytic cleavage of unactivated C(sp3)ÀCl
bonds, triggered by outersphere SET from current photosensitizers, is not feasible because of its extremely negative
redox potential values.[7, 8] Biologically relevant B12-dependent enzymes (that bear a cobalt corrinoid cofactor) and
methyl-coenzyme M reductase (MCR; containing a nickel
porphinoid F430 cofactor), and their synthetic models exhibit
an extreme nucleophilic reactivity.[9] Their ability to reach
oxidation state + 1 in basic ligand environments renders them
supernucleophiles. Mechanistic studies of catalytically activated alkyl chlorides, and stoichiometric dehalogenation
reactions of alkyl chlorides and bromides, with B12 and
methyl-coenzyme M reductase revealed the formation of Ccentered radical intermediates.[10] This finding set the foundation for the development of CÀC bond-forming reactions
by strong chemical reductants,[11] electrocatalysis,[12] and,
more recently, photocatalysis.[6c, 13]
Inspired by these precedents, we envision the in situ
photogeneration of low-valent cobalt and nickel complexes
that behave as supernucleophiles, capable of activating strong
C(sp3)ÀCl bonds under visible-light irradiation (Figure 1).
Herein, we disclose a new approach for the reductive
cyclization of unactivated alkyl chlorides, bearing tethered
alkenes, to form five-membered carbocycles with broad
functional-group tolerance at mild reaction conditions. The
combination of the photoredox catalyst PCCu and the
coordination cobalt or nickel complex [L1HM(OTf)](OTf)
(1HM, M = Co, Ni) enables reductive transformations that
operate via low-valent metal intermediates (see Table 1).[14]
We chose the hex-5-enyl halide 2 a as a suitable model
substrate for the desired transformation since the Thorpe–
Ingold effect provided by the dimalonate unit facilitates the
cyclization step (Table 1). After a systematic screening (see
Table SI.EP-1 in the Supporting Information), optimal reaction conditions yielded 83 % of the 5-exo-trig cyclic product
4 a when employing the PCCu/1HCo catalyst system in
combination with Et3N (14.4 equiv) in EtOH/MeCN (3:2)
and irradiating with blue-light-emitting diodes (1 W, 447 nm)
for 24 hours at 30 8C (Table 1, entry 1). The choice of EtOH as

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Figure 1. Photocatalytic strategies towards reductive intramolecular
cyclization reactions of alkyl halides. Best performance is obtained
with the PCCu/1HNi catalyst system using iPr2NEt as an electron donor.
Table 1: Screening of conditions for the development of reductive
cyclization of alkyl chlorides with tethered alkenes.

Catalyst
1
2
3
4
5
6
7
8
9

Cosolv.

ED

Yield (Conv.) [%][a]

1HCo
1HCo
1HCo
1HCo
1HCo
1HNi
1HNi
Co(OTf)2(MeCN)2
Ni(OTf)2(MeCN)2

EtOH
–
H2O
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH

Et3N
Et3N
Et3N
Et3N
iPr2NEt
Et3N
iPr2NEt
Et3N
Et3N

83 (96)
17 (24)
22 (67)
27 (39)
78 (93)
74 (99)
96 (99)
5 (7)
1 (8)

Reaction conditions: substrate (10 mm), PC (PCCu, 2 mol %), Co or Ni
catalyst (5 mol %), electron donor (14.4 equiv. for Et3N or 11.4 equiv. for
iPr2NEt), cosolvent/MeCN (3:2), visible-light irradiation with blue LEDs
(1 W, 447 nm) for 24 h at 30 8C. [a] Conversion and yield were determined
by GC using biphenyl as an internal standard. Reactions run in triplicate.
ED = electron donor.

protic solvent was essential for achieving high yields of 4 a.
For instance, 4 a was obtained in low yields when the reaction
was performed in other solvent systems such as MeCN, H2O/
MeCN, or MeOH/MeCN (entries 2–4). The use of iPr2NEt
(11.4 equiv) as an electron donor (ED) slightly decreased the
yield of 4 a to 78 % (entry 5). Strikingly, the analogous nickel
complex [L1HNi(OTf)](OTf) (1HNi) in combination with
iPr2NEt yielded the desired product 4 a in 96 % yield
(entries 6 and 7). These observations are supported by the
fact that 1HNi shows faster kinetics for the formation of 4 a
than its cobalt analogue 1HCo (see Figure SI.EP-3). Singlepoint monitoring experiments of the catalytic reduction of 2 a

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throughout light-dark cycles show that the transformation is
light-mediated (see Figure SI.EP-4). Likewise, control experiments indicate that all reaction components are required for
its progression (see Table SI.EP-4). Furthermore, the role of
the photosensitizer was investigated in greater detail, and it is
particularly noteworthy that the combination of either 1HCo
or 1HNi with other PCs based on heavier transition metals,
such as Ir and Ru, afforded lower yields of 4 a (Figure 2).
Reactivity through Ni nanoparticles is discarded since mercury poisoning tests did not change the catalytic activity.
Single-point monitoring experiments of competition between
alkyl chlorides and bromides reveal that the activation of the
alkyl chlorides starts just after the complete consumption of
bromide substrate (see Figure SI.EP-6–8).
The use of the metallic precursor salts gave only trace
amounts of 4 a (Table 1, entries 8 and 9), highlighting the
importance of the L1H ligand for the cleavage of strong
C(sp3)ÀCl bonds. In this regard, we examined a variety of
cobalt and nickel complexes bearing different coordination
motifs for the reductive cyclization of 2 a under visible-light
irradiation (Figure 2). In general terms, pentacoordinate Co
complexes based on the triazacyclononane scaffold 1xCo (x =
H, MeOMeMe, CO2Et) showed higher catalytic activity than
the corresponding tetracoordinate 6xCo (70–83 % yield vs.
18–41 %, respectively). Tuning the electronic effects on the
ligand has a greater impact on the reactivity of 1xNi (varying
from 52 to 96 %) than for 1xCo. Other penta- and tetracoordinate Co and Ni complexes explored during this screening,
including complexes 5M, 7M, 8M, and 9M showed low to
moderate reactivity (16–68 %). We also explored a variety of
square-planar Co and Ni complexes that have been previously
employed towards the reduction of alkyl halides (see
Table SI.EP-3).[11, 16] Among the tested complexes, only
cobalt porphyrin (18Co) and Ni cyclam (10Ni) afforded 4 a
in good yields (Figure 2; see Table SI.EP-3). Finally, metal
catalysts based on commercially available ligands such as 4,4’di-tert-butyl-2,2’-dipyridyl (dtbbpy), terpyridine, and 1,4,7trimethyl-1,4,7-triazacyclononane afforded 4 a only in low
yields (2–42 %, see Table SI.EP-3). This study identifies that
the Co and Ni complexes with high coordination numbers, 4
and 5, bearing basic N-based ligands are remarkably active for
the activation of C(sp3)ÀCl bonds, showing moderate to high
catalytic activity. The importance of the catalytic system is
evidenced in the observation of the following unproductive
conditions: 1) Ni(COD)2 in combination with or without
stoichiometric amount of ligand L1H under photocatalytic
conditions and 2) 1HNi in combination with Zn or Mn as
reductants instead of the PC and electron donor (see
Table SI.EP-3).
The scope of the methodology was explored with the dual
catalytic system PCCu/1HM (M = Co, Ni) owing to its excellent
catalytic performance for the cyclization of the model
substrate 2 a (Table 2). The bimetallic catalyst PCCu/1HCo
enabled the formation of five-membered carbocyclic products
of different diethyl malonates (4 b–d) in 50–88 % yields as
well as fused bicyclic structures such as the [5,5] pyrrolizidinone 4 e (83 % yield) [5, 6] and (R)-carveol derivative 4 f (62 %
yield, over 2 steps). The preparation of carbocycles starting
from more challenging linear alkyl chlorides with PCCu/1HCo

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Figure 2. Catalysts studied for the cyclization of unactivated alkyl chlorides. [a] Conversion and yield were determined by GC using biphenyl as an
internal standard. Reactions run in triplicate. [b] Complex formed in situ in the reaction vessel. [c] Redox potentials are given vs. SCE.
Table 2: Substrate scope of the cyclization of unactivated alkyl chlorides.

Standard reaction conditions: substrate (10 mm), PCCu (2 mol %), 1HNi or 1HCo (5 mol %), ED [Et3N (14.4 equiv) or iPr2NEt (11.4 equiv.)], EtOH/
MeCN (3:2), visible-light irradiation with blue LEDs (l = 447 nm) at 30 8C for 24 h. All are those of isolated products and averages of at least three
reactions. Within parentheses are given the yield for 1HCo. [b] Yield of product isolated after two steps.

was troublesome, with the desired product obtained only in
low yields. Likewise, the potential catalyst 18Co also gave low
Angew. Chem. Int. Ed. 2019, 58, 4869 –4874

yields for the cyclization reaction of linear substrates (see
Table SI.EP-4). Our group previously showed that 1HCo

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catalyzes dihydrogen formation when protic solvents are
used,[15a] and competes with the reductive cyclization (see
Figure SI.EP-4). In contrast, 1HNi and 10Ni catalysts are not
active towards proton reduction under photocatalytic conditions,[15a] and might contribute to the improved reactivity
towards C(sp3)ÀCl bond cleavage.[17] We focused on 1HNi
complex because it is slightly more efficient in comparison to
10Ni (see Table SI.EP-4). Starting from diethyl malonate
derivatives the corresponding carbocycles could be obtained
in yields ranging from 79–93 %. We also synthesized 4 e and
4 f in 83 % and 66 % (over two steps) yields, respectively, and
the preparation of indane structure 4 g in 52 % yield.
Remarkably, the bimetallic PCCu/1HNi catalyst allowed the
cyclization of several linear hex-5-enyl chlorides with synthetically useful yields and exhibiting various degrees of
complexity as well as different functional groups. Owing to
the mildness of the reaction conditions, our photocatalytic
protocol is compatible with esters (4 b–d, 4 f, 4 p, 4 t–w),
alkenes (4 f), nitriles (4 i), carbamates (4 e, 4 j, 4 r), ketones
(4 s), alcohol protecting groups (MOM (4 g), TBS (4 o), free
alcohols (4 l, 4 o), dioxolanes (4 k), alkylboronates (4 q), and
heteroaromatics such as pyrrole (4 m) and furan (4 p).[17]
Aromatic halides having either a chlorine (4 u) and fluorine
(4 w) group are also compatible with this methodology. The
secondary alkyl chloride 2 r yielded the corresponding cyclic
product 4 r in 67 % yield and the 2 f trisubstituted olefin forms
a quaternary center in 4 f in 66 % yield. The cyclization
reaction can be expanded to internal alkynes which produces
the desired cyclic products (4 t–w) in a 1:1 mixture of E/Z
isomers with synthetically useful yields (72–83 % yield). In
addition, we scaled up the reaction up to 5.1 mmol using 2 a
(1.2 g) and obtained 81 % yield of the desired product.
The proposal of radical intermediates during the reaction
might explain the observed preference for the 5-exo-trig cyclic
product with our photocatalytic protocol. In this regard, the
Dowd–Beckwith ring-expansion reaction of the chloromethyl
b-keto ester 2 t gave the corresponding one-carbon expanded
product 4 t [49 % yield (GC), 33 % yield (isolated)], supporting the formation of alkyl radical intermediates (Figure 3 a).[15] Labeling experiments using deuterated solvents
are also in agreement with the formation of C-centered

Figure 3. a) Ring expansion test. b) Deuterium-labeling experiments.

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radicals. The photocatalytic reductive cyclization of 2 j in
EtOD/MeCN (3:2) gave [D]-4 j in 71 % yield with less than
10 % of deuterium incorporation at C1.[16] This result endorses
the formation of highly reactive alkyl radical intermediates
that engage into hydrogen-atom transfer (HAT) from the
solvent
([D]-ethanol,
BDE(CH3CH2OD)ÀBDE(4 j) =
À3.1 kcal molÀ1; see S.I.TS Section 1.1–1.2). Under the same
reaction conditions, 2 n gave 79 % yield of [D]-4 n with
complete incorporation of the deuterium atom at C3 (Figure 3 b, BDE(CH3CH2OD)ÀBDE(4 n) = 9.8 kcal molÀ1).[17] In
this case, the benzylic radical formed can be reduced during
catalysis to the corresponding radical anion (E1/2 = À1.6 V vs.
SCE calculated by DFT, see S.I.TS Section 1.1–1.2), which is
then protonated by the [D]-ethanol to give [D]-4 n.
More insight into the reaction mechanism was obtained by
monitoring (UV/Vis and EPR) the reaction under relevant
catalytic conditions, electrochemical studies, and DFT modelling (Figure 4; see SI.EP and SI.TS for details). Under light
irradiation, only significant changes in the UV/Vis and EPR
signals are observed in the presence of 1HNi, PCCu, and
iPr2NEt. A clear EPR signal with virtually axial symmetry is
formed (g-values 2.06, 2.08 and 2.29). The obtained g-values
combined with the appearance of an absorption band at
535 nm in the UV/Vis is consistent with the photogeneration
of a NiI spin 1=2 species. Equivalent features are reported for
related NiI complexes.[18a] Spectroelectrochemical (SEC)
experiments further corroborate the formation of NiI species.
The same absorption band at 535 nm is obtained at the NiII/I
reduction wave (SI.EP Section 13).

Figure 4. a) Calculated structure for the proposed NiI intermediate 13.
b) EPR spectra of NiI spin 1=2 species formed by irradiation. c) UV/Vis
SEC of 1HNi (4 mm in 0.2 m TBAH/CH3CN:EtOH (2:3)). Applied
potential from the 0 V (black line) to the NiII/I redox wave (ca. À1.1 V
vs. SCE, red line). Inset) CV of 1HNi; d) Changes in UV/Vis spectrum
of a reaction mixture containing PCCu (20 mm) in CH3CN:EtOH:
i-Pr2NEt (2:3:0.1) by addition of 1HNi and 2 a at 140 and 220 s after
the irradiation started (447 nm), respectively; A (black line) just before
1HNi addition (final concentration 50 mm). B (Red Line) 80 s after A
(1HNi addition) the light is switched off. C and D) 50 s after B with (C,
green line) and without (D, orange line) 2 a (final concentration 1 mm)
added at B time (220 s). The green trace decay is mainly due to the
reaction of 2 a with 1HNiI. Inset) UV/Vis traces at l 535 nm.

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In the absence of a substrate, cyclic voltammetry (CV) of
1HNi shows a reversible NiII/I wave at À1.08 V vs. SCE (DEp =
91 mV; Figure 4). Notably, the addition of varying amounts of
2 a to the same solution leads to a progressive loss of
reversibility of the NiII/I feature. Moreover, the peak current
of the forward peak slightly increases, whereas a new anodic
peak appears at À0.28 V vs. SCE which is consistent with
a reaction between the generated NiI species and 2 a within
the CV timescale (see Figures SI.EP-27–31). In agreement
with CV data, UV/Vis-SEC experiments reveal that the
formation of NiI species (lmax 535 nm) in the presence of 2 a
(20 equiv) is inhibited (see Figures SI.EP-35–41). The concomitant growth of absorption bands at lmax 290 and 359 nm
further supports the formation of new species. Additionally,
the in situ photochemical-generated NiI showed a fast decay
of the NiI signal upon addition of 2 a.
Based on these results, we have proposed a plausible
catalytic cycle for the visible-light reductive cyclization of
alkyl chlorides with the PCCu/1HNi catalytic system (Figure 5).

Chemie

the divalent metal catalyst while forming C-centered radical
intermediates (15).[19] A single-electron reduction of complex
alkyl-MIII to form 17 is favorable (DG = À30.7 kcal molÀ1), for
which homolytic cleavage of the MÀC bond at room temperature is also accessible (DG = 22.1 kcal mol for 2 x).[12a] Finally,
the radical generated can be trapped by the tethered alkene to
form the kinetically favored 5-exo-trig carbocyclic compound
(16). Alternatively, the activation of the C(sp3)ÀCl bond can
occur by concerted halogen atom abstraction (CHAA) to
generate directly MII chloride complex and the corresponding
organic radical 15 (Figure 5, DG° = 19.3 and DG = À1.4 kcal
molÀ1 for 2 x; see SI.TS section 1.3).[20]
In conclusion we have developed a robust and efficient
visible-light metallaphotoredox methodology for the cleavage
of unactivated C(sp3)ÀCl bonds under mild reaction conditions. The in situ photogeneration of low-valent cobalt and
nickel complexes bearing pentacoordinate N-based ligands
was key to the observed photocatalytic activity for the
cleavage of strong C(sp3)ÀCl bonds studied. The catalytic
system was used for the visible-light reductive cyclization,
allowing the construction of five-membered carbocycles
employing alkyl chlorides as convenient starting materials
with a broad functional-group tolerance. We envision that the
catalyst design principles found herein will trigger the
development of novel visible-light synthetic protocols that
exploit the use of currently considered unreactive molecules,
as available feedstocks and biologically active molecules
containing alkyl chlorides.

Acknowledgements

Figure 5. Hypothetical catalytic cycle for the visible-light reductive
cyclization of unactivated alkyl chlorides with tethered alkenes.
HAT = hydrogen atom abstraction, HC = homolytic cleavage.

Under catalytic conditions, the photoreduced copper complex
(E1/2(PCCuI/0) = À1.69 V vs. SCE see SI.EP-32)[14b] reduces
1HNi by one electron, forming new NiI species (NiII/I À1.08 V
and À1.51 V vs. SCE, for TfOÀ and ClÀ complexes, respectively).[14b] Thermodynamics discard a potential outersphere
SET from PCCu0 or its exited state (À1.02 V)[3e] to a C(sp3)ÀCl
bond (< À3 V vs. SCE).[8] EPR, UV/Vis, and CV experiments
suggest that the photogenerated NiI species can react with
alkyl chlorides. In agreement is the low-energy barriers (12.9
and 19.3 kcal molÀ1) calculated by DFT for the reaction of
1HNiI (13) with 2 x (3-chloropropyl)benzene as a challenging
unactivated model substrate). Based on DFT studies, we
hypothesize two different scenarios for the C(sp3)ÀCl bond
cleavage. First, the activation of the C(sp3)ÀCl bond by an
oxidative addition through an SN2 mechanism (OA-SN2) that
generates the organometallic intermediate 14 (Figure 5,
DG° = 12.9 kcal molÀ1 and DG = À3.0 kcal molÀ1; see SI.TS
section 1.3).[10, 18] Then, homolytic cleavage of the relatively
weak MÀC bond (À0.5 kcal molÀ1 for 2 x) could regenerate
Angew. Chem. Int. Ed. 2019, 58, 4869 –4874

We acknowledge financial support from the ICIQ Foundation, Cellex Foundation, the European Research Council
(ERC-CG-2014-648304) to J. Ll.-F., MINECO (CTQ201680038-R), and the Juan de la Cierva-Incorporación contract
to A.C. We also thank Catexel for a generous gift of tritosyl1,4,7-triazacyclononane. We thank Dr. Arnau Call for preparing some cobalt complexes employed in the screening of
catalysts. We also thank Prof. R. Martin and Dr. M. Suero for
the thoughtful discussions.

Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclizations · haloalkanes · photochemistry ·
reaction mechanisms · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2019, 58, 4869 – 4874
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Manuscript received: November 5, 2018
Revised manuscript received: January 26, 2019
Accepted manuscript online: February 1, 2019
Version of record online: March 7, 2019

 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2019, 58, 4869 –4874