The Combination of Benzaldehyde and Nickel-Catalyzed Photoredox C(sp3)?H Alkylation/Arylation

Article abstract of DOI:10.1002/anie.201810526

Herein we report a highly selective photoredox C(sp³)?H alkylation/arylation of ethers through the combination of a photo-organocatalyst (benzaldehyde) and a transition-metal catalyst (nickel). This method provides a simple and general strategy for the C(sp³)?H alkylation/arylation of ethers. A selective late-stage modification of (?)-ambroxide has also been conducted to demonstrate the applicability of the method.

Full text of DOI:10.1002/anie.201810526

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Accepted Article
Title: The Combination of Benzaldehyde and Nickel-Catalyzed
Photoredox sp3-C-H Alkylation/Arylation
Authors: Lumin Zhang, Xiaojia Si, Yangyang Yang, Marc Zimmer, Sina
Witzel, Kohei Sekine, Matthias Rudolph, and A. Stephen K.
Hashmi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810526
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10.1002/anie.201810526
Angewandte Chemie International Edition
The Combination of Benzaldehyde and
Nickel-Catalyzed Photoredox sp3-C-H
Alkylation/Arylation
Lumin Zhang,[a] Xiaojia Si,[a] Yangyang Yang,[a] Marc Zimmer, [a] Sina Witzel,[a]
Kohei Sekine,[a]Matthias Rudolph,[a] A. Stephen K. Hashmi[a,b],
*
[a] M.Sc. L. M. Zhang, M.Sc. X. J. Si, M.Sc. Y. Y. Yang, M.Sc. M. Zimmer, M.Sc. S.
Witzel, Dr. K. Sekine, Dr. M. Rudolph, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Heidelberg University
Im Neuenheimer Feld 270
69120 Heidelberg
Germany
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department
Faculty of Science
King Abdulaziz University (KAU)
Jeddah 21589
Saudi Arabia
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10.1002/anie.201810526
Angewandte Chemie International Edition
ABSTRACT: Herein we report a highly selective photoredox sp3-C-H
alkylation/arylation of ethers via the combination of a photo-organocatalyst
(benzaldehyde) and a transition metal catalyst (nickel). This methodology provides
simple and general strategy for sp3-C-H alkylation/arylation of ethers, a selective late-
stage modification of (-)-Ambroxide has also been conducted to demonstrate the
applicability.
In modern organic chemistry, a selective functionalization of C-H bonds is one of the
most challenging transformations, traditional approaches often require pre-activation of
substrates, directing groups, stoichiometric additives or oxidants, to name just a few
drawbacks.[1] Along with the emergingXX of photocatalysis over the past decades,
which allows to achieve previously inaccessible transformations under mild conditions,
more recently, the strategy of combining photoredox (metal complex-based) with
transition-metal catalysis, namely metalla-photoredox, has emerged to be a
breakthrough for constructing C-C and C-heteroatom bonds in organic synthesis and
even allows late-stage functionalization of pharmaceutical compounds.[2] Although
numerous marvelous strategies concerning C-H functionalization have been reported,
to the best of our knowledge, the direct sp3-C-H alkylation by normal alkyl halides has
only been reported by MacMillan’s group, the strategy of polarity-match by combining
photoredox of an iridium complex Ir[dF(CF3)ppy]2(dtbbpy)PF6 (110 USD/ 100 mg
from Sigma Aldrich) with a nickel catalyst and a hydrogen-atom transfer catalyst
(quinuclidine) (Figure 1A).[3] With this in mind, the requirement for exploring new and
alternative methodologies for the direct sp3-C-H alkylation with alkyl halides is
desirable. Compared with relatively expensive metal-catalysts such as iridium,
ruthenium and dimeric gold used in photoredox, it is well known that the inexpensive
photo-organocatalysts can also absorb photons, and then activate substrates through
single electron transfer (SET), energy transfer or direct hydrogen atom transfer (DHAT)
processes. The process of DHAT, which can selectively cleave a C-H bond by forming
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10.1002/anie.201810526
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a carbon radical without the limitation of redox potentials, would open up enormous
opportunities for sp3-C-H alkylation and arylation.
Ni/photoredox sp3 C-H alkylation (previous study)
Photochemistry of benzaldehyde and our hypothesis
Figure 1. Previous study about photoredox sp3-C-H alkylation catalyzed by nickel,
photochemistry of benzaldehyde and our hypothesis.
Benzaldehyde (51.8 USD/ 100 ml from Sigma Aldrich), same as other commonly used
carbonyl compounds such as benzophenones, acetophenones and quinones, which are
effective and productive photosensitizers and hydrogen abstractors for a variety of
hydrogen-donating solvents due to their low-lying and thermally accessible triplet
n,π*-states.[4] The photochemistry of benzaldehyde has been widely investigated
(Figure 1), ground state benzaldehyde going to singlet state by irradiation with UV light,
transferring to more reactive triplet state by ISC (inter-system crossing), then benzene
and CO are produced by going through Norrish I type reaction (Figure 1, path B).
Besides, this photoexcited benzaldehyde can undergoes HAT process either from
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10.1002/anie.201810526
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ground state benzaldehyde resulting in benzaldehyde and benzoin (Figure 1, path A) or
from hydrogen-donating solvent resulting α-hydroxybenzyl radicals and solvent
radicals. This α-hydroxybenzyl radicals would further abstract a hydrogen from solvent
to form benzyl alcohol or led to homocoupling products (Figure 1, path C). Given the
powerful hydrogen abstract performance of excited benzaldehyde, the α-hydroxybenzyl
radicals intermediate and THF radical formed after HAT process, we are wondering
whether this more general and simple photo-organocatalyst can merge with transition
metal catalysis for constructing C-C and C-heteroatom bonds or not? Herein, we
designed a novel combination of a nickel catalyst and a photo-organocatalyst
(benzaldehyde), which might act both as photosensitizer and HAT catalyst in
challenging sp3-C-H alkylation reactions.
Table 1. Select optimization results and control studiesa
a 0.2 mmol scale in THF (1.0 ml), N2, 72 h; b Using 1,3,5-trimethoxybenzene as the internal standard;
c THF (1.0 mmol, 10.0 equiv) in acetone (1.0 ml), 96h; d Replace benzaldehyde with other relevant
photosensitizers. e Benzaldehyde replaced by p-OMe-PHO and irradiated by CFL light source.
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On the basis of our mechanistic assumption, this novel photoredox coupling between
(3-bromopropyl)benzene and THF has been initiated by using NiBr2•glyme and 4,4′-di-
tert-butyl-2,2′-bipyridyl (dtbbpy) as nickel catalyst, benzaldehyde as both
photosensitizer and hydrogen abstractor, in combination with K2HPO4 as base and
under irradiation with UVA light. To our delight, the desired sp3-sp3-coupling product
could be isolated in 92% yield after reaction optimization (see supporting information).
Furthermore, a series of control experiments were conducted to confirm the necessity
of each component. As the experimental results in Table 1 indicate, UVA light,
benzaldehyde, precatalyst NiBr2•glyme, the ligand dtbbpy and the base K2HPO4 are all
critical for the reaction (entries 1-6). Only a trace of the desired product can be detected
in the absence of K2HPO4, which would be consistent with our hypothesis of electron
transfer between the ketyl anion radical and the nickel catalyst (entry 6). That other
known photosensitizers with ketyl structure weren’t efficient in this reaction could
result from steric bulk compared with benzaldehyde (entries 8 and 9). Benzaldehydes
with different substituents are less efficient than benzaldehyde (entries 10 and 11). No
reaction was detected when using p-OMe-PCHO as photosensitizer with CFL as light
source in our reactions (entry 12)[4h]. Our reaction can also proceed well using 10.0
equivalents of THF with acetone as solvent, 83% yield were obtained after extending
the reaction time (entry 7).
Table 2. Scope with respect to the alkyl and aryl bromidea
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10.1002/anie.201810526
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aIsolated yields. 0.2 mmol scale. 72-96 h.
With optimized conditions in hand, we next sought to determine the generality with
respect to the bromide components in this photoredox sp3-C-H alkylation/arylation
reaction. As shown in Table 2, functional groups such as aryl, heteroaryl, esters, ethers,
OTBS, boronic esters, acetals, amides (3aa-3af, 3ah, 3ak-3al) were all compatible. We
also found that the coupling occurred selectively at the bromide-bearing carbon when
1-bromo-3-chloropropane was subjected to the same reaction condition, yielding 3ag
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10.1002/anie.201810526
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in 83% yield. Cyclic substrates with sterically demanding also gave the coupling
product (3ai, 36% yield). Secondary-secondary C-C coupling can also be achieved with
high levels of efficiency, which has been a challenge for a long time in the area of cross-
coupling (3aj). Further exploration of the scope demonstrated that these reaction
conditions tolerated a variety of aryl and heteroaryl bromides. For aryl bromide
containing either an electron-withdrawing substituent (trifluoromethyl) or electron-
donating substituent (methoxy) the corresponding sp3 C-H coupling products were
isolated in high yields (3am-3ao). Notably, even medically relevant heteroaromatic
coupling partners, which are notoriously problematic in many photoredox coupling
technologies, performed well under our reaction conditions including thiazoles,
benzothiazoles, furans, pyridines, quinolones, pyrimidines (3ap-3au, 74-82% yield).
Table 3. Scope with respect to the ethera
aIsolated yields. 0.2 mmol scale. 72 and 96 h.
We next evaluated ether coupling partners in this sp3-sp3-cross-coupling reaction. As
shown in Table 3, along with THF, both commonly used cyclic and acyclic ether all
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performed well under identical conditions, providing primary, secondary coupling
products. For symmetric cyclic ethers, such as cyclobutane (3ba), tetrahydropyran
(3ca), dioxane (3da), it is appreciable that the reaction only occurred at the position
adjacent to the oxygen-atom. The diminished reactivity of cyclobutane and
tetrahydropyran compare with THF would be influenced by both ring strain and
stereoelectronic factors as well. In the case of the diether 1,4–dioxane, although it have
comparable steric demands, the second oxygen atom in this molecule wouldn’t favor
radical formation by either stereoelectronic or direct mesomeric interactions.[5]
Symmetric acyclic ether also compatible to this sp3-sp3-photoredox coupling condition
with moderate yield for 3ea and 3fa. For substrate 3fa, a selectivity between methyl
and methylene group is occurred, giving the linear product preferentially (1.4:1,
branched: linear) in a combined 48% yield. Furthermore, in the case of unsymmetric
substrates, both cyclic 3ga and acyclic 3ha ethers are all preformed in good yields, 82%
and 80%, respectively.
Figure 3. Results with other substrates.
While having succeed in the reaction of photoredox sp3 C-H alkylation by the
combination of benzaldehyde and a nickel catalyst, extensive future work has to be
conducted in order to gain detailed insight into the mechanism. Other substrates, such
as benzyl and vinyl bromides, do not efficiently couple under our reaction conditions
(Figure 3).
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10.1002/anie.201810526
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Figure 4. Selective late-stage modification of the natural product (-)-Ambroxide by sp3-
C-H alkylation and arylation.
In conclusion, a simple photoredox sp3-C-H alkylation/arylation was achieved by the
combination of a quite inexpensive photo-organocatalyst benzaldehyde, the transition
metal nickel and UVA light. The applications clearly suggest that our strategy is a
promising synthetic method and late-stage modification tool for natural products.
Detailed studies of the mechanism and other new combinations of photo-
organocatalysts and transition metals are currently ongoing.
Keywords: benzaldehyde, nickel catalysis, sp3 C-H alkylation/arylation, photoredox
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