Reductive Cyclization of Unactivated Alkyl Chlorides with Tethered Alkenes under Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201812702

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)?Cl bonds is mediated by a highly nucleophilic low-valent 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.

Full text of DOI:10.1002/anie.201812702

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Accepted Article
Title: Visible Light Reductive Cyclization of Unactivated Alkyl Chlorides
with Tethered Alkenes
Authors: Julio Lloret-Fillol, Miguel Claros, Felix Ungeheuer, Federico
Franco, Vlad Martin-Diaconescu, and Alicia Casitas
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812702
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Reductive Cyclization of Unactivated Alkyl Chlorides with
Tethered Alkenes under Visible-Light Photoredox Catalysis
Miguel Claros,[a] Felix Ungeheuer,[a] Federico Franco,[a] Vlad Martin-Diaconescu,[a]
Alicia Casitas,[a]* Julio Lloret-Fillol[a][b]
*
Dedication (We would like to dedicate this article 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. In this work, we present
a
metallaphotoredox methodology to achieve the catalytic
intramolecular reductive cyclization of unactivated alkyl chlorides with
tethered alkenes. The cleavage of strong Csp3-Cl bonds is mediated
by a highly nucleophilic low-valent cobalt or nickel intermediate
generated via visible light photoredox reduction employing a copper
photosensitizer. The high basicity and multidentate nature of the
ligands are key to obtain efficient metal catalysts for the
functionalization of unactivated alkyl chlorides.
Visible light photoredox catalysis has opened novel and
milder approaches for C-C and C-heteroatom (C-Het) 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
-3 V vs. SCE),[2] facilitating the cleavage of alkyl bromides,[3]
activated alkyl chlorides and aryl chlorides[2c],[4] via SET
Figure 1. Photocatalytic strategies towards reductive intramolecular cyclization
reactions of alkyl halides. Best performance is obtained with the PCCu/1HNi
catalyst system using i-Pr2NEt as electrondonor.
processes. Additionally, the synergistic merging of
a
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 Csp3-
Cl bonds under visible light irradiation (Figure 1). Herein, we
disclose a new approach for the reductive cyclization of
unactivated chloroalkanes bearing tethered alkenes to form 5-
membered carbocycles with broad functional group tolerance at
mild reaction conditions. 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]
photosensitizer and a coordination metal complex or silane has
enabled the efficient activation of alkyl bromides towards the
generation of new C-C or C-Het bonds. This concept could
recently be expanded for the carboxylation of Ar-Cl.[5]
Although alkyl chlorides are available, and bench-stable
feedstocks, the 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 Csp3-Cl bonds, triggered by
outer-sphere SET from current photosensitizers, is not feasible
due to 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 as 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 C-centered
radical intermediates.[10] This set the basis for the development of
C-C bond-forming reactions by strong chemical reductants,[11]
electrocatalysis,[12] and more recently photocatalysis.[6c, 13]
We chose hex-5-enyl halide 2a as a suitable model substrate
for the desired transformation since the Thorpe-Ingold effect
provided by the dimalonate unit facilitates the cyclization step.
After a systematic screening (see Table SI.EP-1), optimal
conditions yielded 83% of the 5-exo-trig cyclic product 4a
employing PCCu/1HCo catalyst system in combination with Et3N
(14.4 eq) in EtOH:MeCN (3:2) and irradiating with blue light-
emitting diodes (1 W, 447 nm) for 24 h at 30ºC (Table 1, entry 1).
The choice of EtOH as protic solvent was essential for achieving
high yields of 4a. For instance, 4a was obtained in low yields when
the reaction was performed in other solvent systems such as
MeCN, H2O/MeCN or MeOH/MeCN (17-27 %, Table 1, entries 2-
4). The use of i-Pr2NEt (11.4 eq) as electron donor (ED) slightly
decreased the yield of 4a to 78% (Table 1, entry 5).
[a] Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute
of Science and Technology, Avda. Països Catalans, 16, E-43007,
Tarragona, Spain. acasitas@iciq.es, jlloret@iciq.es.
[b] Catalan Institution for Research and Advanced Studies (ICREA),
Passeig Lluïs Companys, 23, E-08010, Barcelona, Spain.
Strikingly, the analogous nickel complex [L1HNi(OTf)](OTf)
(1HNi) in combination with i-Pr2NEt yielded the desired product 4a
in 96% yield (Table 1, entries 6-7). These observations are
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supported by the fact that 1HNi shows faster kinetics for the
formation of 4a than its cobalt analogue 1HCo (Figure SI.EP-3).
Single point monitoring experiments of the catalytic reduction of
2a throughout light-dark cycles show that the transformation is
light-mediated (Figure SI.EP-4). Likewise, control experiments
indicate that all reaction components are required for its
progression (Table SI.EP-4). Furthermore, the role of the
photosensitizer was investigated in greater detail, and it is
particularly noteworthy that the combination of 1HCo or 1HNi with
other PC based on heavier transition metals, such as Ir and Ru,
afforded lower yields of 4a (Table 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).
butyl-2,2’-dipyridyl (dtbbpy), terpyridine and 1,4,7-trimethyl-1,4,7-
triazacyclononane afforded 4a 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 Csp3-Cl bonds,
showing moderate to high catalytic activity. The importance of the
catalytic system is evidenced in the observation of the following
unproductive conditions; i) Ni(COD)2 in combination with or
without stoichiometric amount of ligand L1H under photocatalytic
conditions and ii) 1HNi in combination with Zn or Mn as reduced
agents 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 model substrate 2a
(Table 2). The bimetallic catalyst PCCu/1HCo enabled the
formation of five-membered carbocyclic products of different
diethyl malonates (4b-d) in 50-88% yields as well as fused bicyclic
structures such as [5,5] pyrrolizidinone 4e (83% yield) and [5,6] (R)-
carveol derivative 4f (62% yield, over 2 steps) (4e-4f). The
preparation of carbocycles starting from more challenging linear
alkyl chlorides with PCCu/1HCo was troublesome, with the desired
product obtained only in low yields. Likewise, potential catalyst
18Co also gave low yields for the cyclization reaction of linear
substrates (Table SI.EP-4). Our group previously showed that
1HCo catalyzes dihydrogen formation when protic solvents are
used,[15a] which competes with the reductive cyclization (Figure
SI.EP-4). In contrast, 1HNi and 10Ni catalysts are not active
towards proton reduction under photocatalytic conditions,[15a]
which might contribute to the improved reactivity towards Csp3-Cl
bond cleavage.[17] We focused on 1HNi complex due to its slightly
higher efficiency in comparison to 10Ni (Table SI.EP-4). Starting
from diethyl malonate derivatives the corresponding carbocycles
could be obtained in yields ranging from 79-93%. We also
synthesized bicyclic structures 4e and 4f in 83% and 66% (over
two steps) yields respectively, and the preparation of indane
structure 4g in 52% isolated 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 (4b-4d, 4f, 4p,
4t-4w), alkenes (4f), nitriles (4i), carbamates (4e, 4j, 4r), ketones
(4s), alcohol protecting groups (MOM (4g), TBS (4o)), free
alcohols (4l, 4o), dioxolanes (4k), alkylboronates (4q) and
heteroaromatics as pyrrole (4m) and furan (4p).[17] Aromatic
halides as chlorine (4u) and fluorine (4w) are also compatible with
this methodology. The secondary alkyl chloride 2r yielded the
corresponding cyclic product 4r in 67% yield and the 2f
trisubstituted olefin forms a quaternary center in 4f in 66% isolated
yield. The cyclization reaction can be expanded to internal
alkynes which produces the desired cyclic products (4t-4w) in a
1:1 mixture of E/Z isomers with synthetically useful yields (72-83%
yield). In addition, we have scale up the reaction up to 5.1 mmol
using substrate 2a (1.2 g) with 81% yield of the desired product.
Table 1 Screening of conditions for the development of reductive cyclization of
alkyl chlorides with tethered alkenes.
Yield
Catalyst
Co-solv.
ED
(conv.)(%)a
83 (96)
1
2
3
1HCo
1HCo
1HCo
EtOH
-
Et3N
Et3N
Et3N
17 (24)
H2O
22 (67)
4
5
6
7
1HCo
1HCo
1HNi
1HNi
MeOH
EtOH
EtOH
EtOH
Et3N
i-Pr2NEt
Et3N
27 (39)
78 (93)
74 (99)
96 (99)
i-Pr2NEt
8
9
Co(OTf)2(MeCN)2
Ni(OTf)2(MeCN)2
EtOH
EtOH
Et3N
Et3N
5 (7)
1 (8)
Conditions: substrate (10 mM), PC (PCCu, 2 mol%), Co or Ni catalyst (5 mol%),
electron donor (14.4 eq. for Et3N or 11.4 eq. for i-Pr2NEt), co-solvent:MeCN (3:2),
a)
visible light irradiation with blue LEDs (1 W, 447 nm) for 24 h at 30ºC.
Conversion and yield were determined by GC using biphenyl as internal
standard by triplicates.
The use of the metallic salts gave only traces of 4a (Table 1,
entries 8-9), highlighting the importance of the L1H ligand for the
cleavage of strong Csp3-Cl bonds. In this regard, we examined a
variety of cobalt and nickel complexes bearing different
coordination motifs for the reductive cyclization of 2a under visible
light irradiation (Figure 2). In general terms, pentacoordinate Co
complexes based on 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 4a in
good yields (Figure 2, Table SI.EP-3). Finally, metal catalysts
based on commercially available ligands such as 4,4’-Di-tert-
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 chloromethyl β-keto ester 2t
gave the corresponding one-carbon expanded product 4t (49%
GC-yield, 33% isolated-yield) supporting the formation of alkyl
radical intermediates (Figure 3a).[15] Labeling experiments using
deuterated solvents are also in agreement with the formation of C-
centered radicals.
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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 by triplicates. 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 conditions: substrate (10 mM), PCCu (2 mol%), 1HNi or 1HCo (5 mol%), ED [Et3N (14.4 eq.) or i-Pr2NEt (11.4 eq.)],
EtOH:MeCN (3:2), visible light irradiation with blue LEDs (λ = 447 nm) at 30 ºC for 24 h. All are isolated yields averages of at least
3 reactions. Between parentheses are given the yield for 1HCo. b) Isolated yield over two steps.
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conditions, electrochemical studies and DFT modelling (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
i-Pr2NEt. 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 Ni(l) spin ½ species.
Equivalent features are reported for related Ni(I) complexes.[18a]
Spectroelectrochemical (SEC) experiments further corroborate
the formation of Ni(I) species; the same absorption band at 535
nm is obtained at the Ni(II/I) reduction wave (See Figure 4 and
SI.EP Section 13).
In the absence of a substrate, Cyclic Voltammetry (CV) of
1HNi shows a reversible Ni(II/I) wave at –1.08 V vs. SCE (ΔEp = 91
mV). Notably, the addition of varying amounts of 2a to the same
solution leads to a progressive loss of reversibility of the Ni(II/I)
feature. Moreover, the peak current of the forward peak slightly
increases, whereas a new anodic peak appears at –0.28 V vs.
SCE which is consistent with a reaction between the generated
Ni(I) species and 2a within the CV timescale (Figures SI.EP-27-
31). In agreement with CV data, UV-Vis -SEC experiments reveal
that the formation of Ni(I) species (max 535 nm) in the presence
2a (20 eq.) is inhibited (Figures SI.EP-35-41). The concomitant
growth of absorption bands at λmax 290 and 359 nm further
supports the formation of new species. Additionally, the in situ
photochemical generated Ni(I) showed a fast decay of the Ni(I)
signal upon addition of substrate 2a.
Figure 3. a) Ring expansion test, b) deuterium labeling experiments.
The photocatalytic reductive cyclization of 2j in EtOD:MeCN
(3:2) gave [D]-4j in 71% yield with less than 10% of deuterium
incorporation in position 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)-BDE(4j) = -3.1 kcal·mol-1, S.I. Theoretical
Studies (S.I.TS) Section 1.1-1.2). Under the same reaction
conditions, substrate 2n gave 79% yield of [D]-4n with complete
incorporation of the deuterium atom at C3 position (Scheme 3b,
BDE(CH3CH2OD)-BDE(4n) = 9.8 kcal·mol-1).[17] In this case, the
benzylic radical formed can be reduced during catalysis to the
corresponding radical anion (E1/2 = -1.6 V vs SCE calculated by
DFT, see S.I.TS Section 1.1-1.2), which then it is protonated by
the [D]-ethanol to give [D]-4n.
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). Under
catalytic conditions, the photoreduced copper complex
(E1/2(PCCuI/0)= -1.69 V vs SCE see SI.EP-32)[14b] reduces 1HNi by
one electron forming new Ni(I) species (Ni(II/I) –1.08 V and -1.51 V
vs. SCE, for TfO- and Cl- complexes, respectively).[14b]
Thermodynamics discard a potential outer-sphere SET from
PCCu0 or its exited state (-1.02 V)[3e] to a Csp3-Cl bond (< -3 V vs
SCE).[8] EPR, UV-Vis and CV experiments suggest that the photo-
generated Ni(I) species can react with chloroalkanes. In
agreement is the low energy barriers (12.9 and 19.3 kcal·mol-1)
calculated by DFT for the reaction of 1HNiI (13) with 2x (3-
chloropropyl)benzene as
a challenging unactivated model
substrate). Based on DFT studies, we hypothesize two different
scenarios for the Csp3-Cl bond cleavage. First, the activation of
the Csp3-Cl bond via an oxidative addition by a SN2 mechanism
(OA-SN2) that generates the organometallic intermediate 14
(Figure 5, G‡ = 12.9 kcal·mol-1 and G = -3.0 kcal·mol-1, see
SI.TS section 1.3).[10, 18] Then, homolytic cleavage of the relatively
weak M-C bond (-0.5 kcal·mol-1 for 2x) could regenerate 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 (G = -30.7 kcal·mol-1), for which
homolytic cleavage of the M-C bond at room temperature is also
accessible (G = 22.1 kcal·mol for 2x).[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 Csp3-Cl bond can occur via
concerted halogen atom abstraction (CHAA) to generate directly
MII chloride complex and the corresponding organic radical 15
(Figure 5, G‡ = 19.3 and G = -1.4 kcal·mol-1 for 2x, see SI.TS
section 1.3).[20]
Figure 4. a) Calculated structure for the proposed Ni(I) intermediate 13; b) EPR
spectra of Ni(I) spin ½ 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. –1.1 V vs SCE, red line). Inset) CV of 1HNi; d)
Changes in UV-Vis spectrum of a reaction mixture containing PCCu (20 M) in
CH3CN:EtOH:i-Pr2NEt (2:3:0.1) by addition of 1HNi and 2a at 140 and 220 s after
the irradiation started (447 nm), respectively; A (Black line)) just before 1HNi
addition (final concentration 50 M). 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) 2a (final concentration 1 mM) added at B time (220 s). The green
trace decay is mainly due to the reaction of 2a with 1HNiI. Inset) UV-Vis traces
at  535 nm.
More insights into the reaction mechanism were obtained by
monitoring (UV-Vis and EPR) the reaction under relevant catalytic
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Figure 5. Hypothetical catalytic cycle for the visible light reductive cyclization of
unactivated alkyl chlorides with tethered alkenes. HAT and HC stands for
Hydrogen Atom Abstraction and Homolytic Cleavage.
In conclusion we have developed a robust and efficient visible
light metallaphotoredox methodology for the cleavage of
unactivated Csp3-Cl bonds under mild reaction conditions. The in
situ photogeneration of low-valent cobalt and nickel complexes
bearing pentacoordinate N-based ligands was key to observe
photocatalytic activity for the cleavage of studied strong Csp3-Cl
bonds. The catalytic system was used for the visible light
reductive cyclization that allows the construction of 5-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 exploits
the use of currently considered of particularly unreactive
molecules, as available feedstocks and biologically active
molecules containing alkyl chlorides.
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Acknowledgments
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SI.EP-21).
We thank the financial support from ICIQ Foundation, Cellex
Foundation, the European Research Council (ERC-CG-2014-
648304) to J. Ll.-F., MINECO (CTQ2016-80038-R), Juan de la
Cierva-Incorporación contract to A.C.. We also thank Catexel for
a generous gift of tritosyl-1,4,7-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.
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Keywords: Unactivated Chloroalkanes • Visible Light •
Photoredox Catalysis • Cyclizations • Dual Catalysis
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10.1002/anie.201812702
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Miguel Claros, Felix
Ungeheuer, Federico Franco,
Vlad Martin-Diaconescu,
Alicia Casitas*, Julio Lloret-
Fillol*
Page No. – Page No.
Reductive Cyclization of
Unactivated Alkyl Chlorides
with Tethered Alkenes under
Visible-Light Photoredox
Catalysis
Earth-abundant Transition Metal Catalysis Functional Group Tolerance
Functionalization of Chloroalkanes
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