Semiheterogeneous Dual Nickel/Photocatalytic (Thio)etherification Using Carbon Nitrides

Article abstract of DOI:10.1021/acs.orglett.9b01957

A carbon nitride material can be combined with homogeneous nickel catalysts for light-mediated cross-couplings of aryl bromides with alcohols under mild conditions. The metal-free heterogeneous semiconductor is fully recyclable and couples a broad range of electron-poor aryl bromides with primary and secondary alcohols as well as water. The application for intramolecular reactions and the synthesis of active pharmaceutical ingredients was demonstrated. The catalytic protocol is applicable for the coupling of aryl iodides with thiols as well.

Full text of DOI:10.1021/acs.orglett.9b01957

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Semiheterogeneous Dual Nickel/Photocatalytic (Thio)etherification
Using Carbon Nitrides
,†
Cristian Cavedon,†,‡ Amiera Madani,†,‡ Peter H. Seeberger,†,‡ and Bartholomaus Pieber*
̈
†Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mu
Germany
̈
hlenberg 1, 14476 Potsdam,
‡
̈
Department of Chemistry and Biochemistry, Freie Universitat Berlin, Arnimallee 22, 14195 Berlin, Germany
S
* Supporting Information
ABSTRACT: A carbon nitride material can be combined
with homogeneous nickel catalysts for light-mediated cross-
couplings of aryl bromides with alcohols under mild
conditions. The metal-free heterogeneous semiconductor is
fully recyclable and couples a broad range of electron-poor
aryl bromides with primary and secondary alcohols as well as
water. The application for intramolecular reactions and the
synthesis of active pharmaceutical ingredients was demon-
strated. The catalytic protocol is applicable for the coupling of
aryl iodides with thiols as well.
Thermolysis of Ni(II) oxametallacycles, for example, results in
lkyl aryl ethers are a common structural motif in many
Aactive pharmaceutical ingredients (APIs), such as Fluox-
etine, Ketoconazole, Raloxifene, and Flecainide (Figure 1).1,2
β-hydride elimination of undesired carbonyl compounds,
whereas oxidation to Ni(III) complexes via single electron
transfer (SET) with stoichiometric oxidants can induce
reductive elimination resulting in C−O bond formation.14
Combining nickel with photoredox catalysis,15−17 enables the
coupling of aryl bromides with alcohols18,19 or water20 without
stoichiometric SET oxidants.
Photoredox catalysis is dominated by expensive, homoge-
neous iridium, and ruthenium complexes. Noble-metal-free,
homogeneous photoredox catalysts, such as boron-dipyrrome-
thene derivatives (BODIPY),20 require tedious purification
procedures and are prone to degradation.21 Heterogeneous
semiconductors are a recyclable alternative to common
homogeneous photoredox catalysts.22−25 CdSe quantum
dots26 and CdS27 were used for carbon−heteroatom couplings
via the dual nickel/photoredox catalytic approach. Cadmium,
however, is among the most toxic elements28 and strictly
regulated.29 Its application in the synthesis of APIs is therefore
not desirable.
Carbon nitride (CN) materials, a class of stable and metal-free
semiconductors with low toxicity30 that can be easily made from
commodity chemicals, are able to activate Ni complexes via
photosensitization.31 Here, we show that these materials are also
able to catalyze alkyl aryl ether synthesis, likely by triggering
reductive elimination via SET modification of the oxidation state
of Ni complexes.32
Figure 1. Examples of APIs containing the alkyl aryl ether motif.
Nucleophilic substitution of alkyl halides with phenolates
(Williamson ether synthesis) traditionally used to synthesize
these scaffolds, suffers from functional group incompatibilities
due to the harsh conditions it requires. Catalytic strategies for
the synthesis of ethers were developed to overcome these
drawbacks. Copper can catalyze the coupling of phenols and aryl
halides (Ullmann-type reaction),3,4 as well as aryl boronic acids
and alcohols (Chan−Evans−Lam coupling).5 Palladium-cata-
lyzed O-arylations of alcohols via Buchwald−Hartwig-type
cross-coupling reactions broaden the substrate scope.6,7
Strongly basic conditions and well-designed biaryl phosphine
ligands are required for efficient cross-coupling reactions.8
Nickel catalysis gained increasing interest due to its
significantly higher abundance compared to noble metals.9,10
The low electronegativity of Ni enables facile oxidative addition
into carbon−halide bonds, whereas reductive elimination,
especially in case of C−O couplings, is difficult.11−13
The etherification of methyl 4-bromobenzoate with 1-hexanol
served as a model reaction for initial studies (Table 1). A careful
optimization of all reaction parameters showed that a carbon
Received: June 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01957
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimized Conditions and Control Experiments
Scheme 1. Scope and Limitations of the Semiheterogeneous
Etherification
a
b
b
b
entry
conditions
1 (%)
2 (%)
3 (%)
1
2
3
4
5
6
7
8
as shown
96
90
55
61
3
6
3
2
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1
CN-OA-m (1.66 mg mL−1
24 h
)
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
24 h with 10 mol % quinuclidine
methyl 4-chlorobenzoate
no light
no CN-OA-m
no NiBr2·3H2O
no dtbbpy
4
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
9
10
11
no BIPA
no degassing
a
Reaction conditions: methyl 4-bromobenzoate (0.3 mmol), 1-
hexanol (0.6 mmol), CN-OA-m (10 mg), NiBr2·3H2O (30 μmol),
dtbbpy (30 μmol), BIPA (1.5 mmol), MeCN (3.0 mL), white LEDs
b
at 40 °C for 48 h. Determined by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. n.d. = not detected.
nitride material prepared by polymerization of urea and oxamide
(CN-OA-m)33 in combination with catalytic amounts of NiBr2·
3H2O and di-tert-butylbipyridyl (dtbbpy) results in the selective
synthesis of the desired ether (1) after 48 h irradiation with
white LEDs in acetonitrile under mildly basic conditions (entry
1−2). The only side-products were small amounts of the
corresponding phenol (2) from the cross-coupling with water
and dehalogenated methyl benzoate (3). In homogeneous dual
catalysis, the addition of catalytic amounts of quinuclidine was
reported to accelerate the reaction.18,19 For similar reasons, an
amine-modified organonickel complex was used in combination
with photoredox catalysis for the synthesis of phenols from aryl
halides and water.20 The semiheterogeneous protocol did not
result in significant rate enhancement when 10 mol %
quinuclidine was added (entries 3−4). The utilization of 6,6′-
diamino-2,2′-bipyridyl instead of dtbbpy drastically reduced the
efficacy of the C−O coupling in our model system (see Table
S4). A reaction with methyl 4-chlorobenzoate as substrate
resulted in very low amounts of the desired ether product under
optimized conditions (Table 1, entry 5). No reaction was
detected in the case of the mesyltate, triflate, or tosylate
derivatives (see Table S10). Control experiments proved that
light, CN-OA-m, NiBr2·3H2O, dtbbpy, N-tert-butylisopropyl-
amine (BIPA), and oxygen-free conditions are essential for
successful C−O cross-couplings (entries 6−11).
With the optimized conditions in hand, the versatility of the
semiheterogeneous cross-coupling was investigated (Scheme 1).
Aryl bromides substituted with electron withdrawing groups in
para-position were generally isolated in good to excellent yields.
A broad range of functional groups including esters (1), nitriles
(4), aldehydes (5), ketones (6, 15), phenylboronic acid pinacol
esters (14), chlorides (10), and trifluoromethyl- (13) as well as
methylsulfonyl-groups (16) were tolerated. Substrates with
electron withdrawing meta-substituents (7, 8) did also yield the
desired products, although with lower efficiency. Ortho-
substituted aryl bromides (11, 12) resulted in a drastically
decreased reactivity. Coupling of 1,4-dibromobenzene with 1-
hexanol gave a selective monoetherification as the resulting aryl
alkyl ether (9) deactivates the second bromide functionality.
a
Reaction conditions: aryl bromide (1.2 mmol), alcohol (2.4−4.8
mmol), CN-OA-m (20 mg), NiBr2·3H2O (120 μmol), dtbbpy (120
μmol), BIPA (6.0 mmol), MeCN (6.0 mL), white LEDs at 40 °C.
b
1
Determined by H NMR using 1,3,5-trimethoxybenzene as internal
c
standard. DMF was used as solvent.
Heteroaryl bromides (17, 18) were successfully coupled under
these conditions. Substrates lacking a strong electron with-
drawing group gave very low amounts of the desired C−O
coupling products (20, 21) within 48 h.
Electronic effects dictate the reactivity of para- and meta-
substituted aryl bromides, whereas steric effects influence the
reactivity of ortho-substituted analogs and are responsible for the
scope and limitations of aliphatic alcohols (Scheme 1). Coupling
of methyl 4-bromobenzoate with methanol (22) was completed
within 24 h under standard conditions and within 8 h when
MeOH was used as solvent (see the Supporting Information).
The semiheterogeneous methodology provides an effective
B
DOI: 10.1021/acs.orglett.9b01957
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
method to prepare deuterium-labeled anisoles (23) in excellent
yield. Primary alcohols with benzyl (24), allyl (26), nitrile (29),
trifluoromethyl (25), and tertiary amine (30) groups were
coupled with high selectivity. The secondary alcohols
isopropanol (31), cyclohexanol (32), and 1-phenylethanol
(33) reacted efficiently as well. Sterically encumbered secondary
(34, 35) and tertiary (36) alcohols resulted in low amounts of
the desired ether products within 48 h. Formation of diaryl
ethers from the reaction of aryl bromides and phenols was not
observed, presumably due to the low nucleophilicity of aromatic
alcohols.
Coupling of methyl 4-bromobenzoate with water as
nucleophile gave phenol 2 in moderate isolated yield by
switching to DMF as a solvent (for details, see Table S12). The
ortho-substituted, electron-rich aryl bromide 2-(2-
bromophenyl)ethanol did undergo an intramolecular C−O
coupling, resulting in 2,3-dihydrobenzofurane (37).34 An
analogous preparation of chromane and 1,4-benzodioxane was
not feasible (see Table S11). The reason for this remains
unclear, especially because chromanes were previously synthe-
sized by reductive elimination from the corresponding nickel(II)
oxametallacycles.14 The semiheterogeneous dual catalytic
reaction of 1,4-dibromobenzene and isopropylideneglycerol
afforded 38, a potential intermediate for the preparation of
ketoconazole (Figure 1), itraconazole, terconazole, and their
derivatives.35 The antidepressant Fluoxetine can be synthesized
using this method. N-Protected 3-methylamino-1-phenylpropa-
nol reacted with 1-bromo-4-(trifluoromethyl)benzene resulting
in N-acetyl fluoxetine (39) in 66%.
limited to primary and secondary thiols (40−42). Tertiary (43)
and aromatic thiols (44, 45) also gave the desired thioethers in
moderate isolated yields. This finding can be rationalized by the
formation of highly reactive thiyl radicals, which are proposed to
add to Ni(I) intermediates in the dual catalytic thioether
synthesis.38,39
The reaction rate was significantly increased by using blue
LEDs with higher light intensity (for details, see Supporting
Information). The coupling of methyl 4-bromobenzoate and
methanol, for example, was complete after 16 h instead of
24 using a modified setup. These intensified conditions were
used for studying the recyclability of the heterogeneous carbon
nitride material (Figure 2). CN-OA-m was recycled six times,
without losing its catalytic activity (Figure 2), proofing its high
potential for sustainable photocatalysis.
The same catalytic system was evaluated for the coupling of
thiols with aryl halides (Scheme 2).36−40 The reaction of aryl
a
Scheme 2. Scope of Semiheterogeneous Thioetherification
Figure 2. Recycling of CN-OA-m in the semiheterogeneous ether-
ification.
Analysis of the recycled photocatalyst showed Ni deposition
(see the Supporting Information). Attempts to use the recycled
photocatalyst in absence of additional Ni(II) salts showed that
the immobilized Ni species is not catalytically active in the
model reaction.
In conclusion, a dual Ni/photocatalytic C−O coupling was
developed using a carbon nitride semiconductor as recyclable
photocatalyst with low toxicity. The semiheterogeneous nickel/
carbon nitride catalysis is an inexpensive, sustainable alternative
to homogeneous protocols. The method selectively couples a
broad range of electron-poor aryl bromides with primary and
secondary alcohols as well as water in good to excellent isolated
yields. The application of this protocol for intramolecular
reactions and API synthesis was demonstrated. The same
catalytic protocol can be utilized to couple aryl iodides with
thiols.
a
Reaction conditions: methyl 4-iodobenzoate (1.2 mmol), thiol (2.4
mmol), CN-OA-m (20 mg), NiBr2·3H2O (120 μmol), dtbbpy (120
μmol), BIPA (6.0 mmol), MeCN (6.0 mL), white LEDs at 40 °C.
bromides and thiols usually requires strongly reducing photo-
redox catalysts,39 whereas aryl iodides can be successfully
coupled using weaker reductants.38 When the optimized
semiheterogeneous protocol (the conduction band minimum
of CN-OA-m was reported to be at −1.6 V vs Ag/AgCl33) was
applied on the reaction of methyl 4-bromobenzoate with methyl
3-mercaptopropionate, only 4% of the desired thioether were
formed after 48 h (Table S15). The analogous reaction using
methyl 4-iodobenzoate went to completion within 48 h resulting
in 79% isolated yield of the desired thioether (40). When 2-
mercaptoethanol was used, a selective C−S bond formation
(41), with no detectable amount of the corresponding
etherification product was obtained. In contrast to the C−O
coupling, the semiheterogeneous C−S bond formation is not
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01957.
Experimental procedures and characterization data
(PDF)
C
DOI: 10.1021/acs.orglett.9b01957
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bartholomaeus.pieber@mpikg.mpg.de.
ORCID
(19) Zhu, B.; Yan, L.-K.; Geng, Y.; Ren, H.; Guan, W.; Su, Z.-M. Chem.
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264−267.
̈
Bartholomaus Pieber: 0000-0001-8689-388X
Author Contributions
̈
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The manuscript was written through contributions of all
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The authors declare no competing financial interest.
A version of this research was previously posted to ChemRxiv:
Cavedon, Cristian; Madani, Amiera; Seeberger, Peter H.; Pieber,
(26) Caputo, J. A.; Frenette, L. C.; Zhao, N.; Sowers, K. L.; Krauss, T.
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55, 4853−4856.
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Bartholomaus (2019): Semi-Heterogeneous Dual Nickel/
Photocatalytic (Thio)Etherification using Carbon Nitrides.
ChemRxiv. Preprint. June 6, 2019. https://doi.org/10.26434/
chemrxiv.8231144.v1
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the Max-Planck Society for generous
financial support. B.P. acknowledges financial support by a
Liebig Fellowship of the German Chemical Industry Fund
(Fonds der Chemischen Industrie, FCI). A.M. and B.P.
acknowledge the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germany’s Excellence
Strategy−EXC 2008/1 (UniSysCat)−390540038 for financial
support. We thank our colleagues Xuan Pham (FU Berlin) and
Katharina ten Brummelhuis (MPIKG) for analytical support.
́
(30) Dong, Q.; Mohamad Latiff, N.; Mazanek, V.; Rosli, N. F.; Chia,
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(32) The etherification was proposed to proceed via SET oxidation/
reduction of Ni intermediates (ref 18). However, a photosensitization
pathway cannot be excluded: Welin, E. R.; Le, C.; Arias-Rotondo, D.
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