Metal-Free C-O Bond Functionalization: Catalytic Intramolecular and Intermolecular Benzylation of Arenes

Article abstract of DOI:10.1021/acs.orglett.8b01495

A catalytic, metal-free intramolecular rearrangement of benzyl phenyl ethers using nitrosonium salt as a catalyst is described. The optimized reaction conditions enabled a catalytic and metal-free Friedel-Crafts alkylation reaction with benzylic alcohols, producing water as the stoichiometric byproduct. A comprehensive scope (>50 examples) for both approaches and application in drug synthesis were demonstrated. Mechanistic studies suggest a Lewis acid-based mechanism for the metal-free Friedel-Crafts reaction.

Full text of DOI:10.1021/acs.orglett.8b01495

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free C−O Bond Functionalization: Catalytic Intramolecular
and Intermolecular Benzylation of Arenes
Luis Bering,†,‡ Kirujan Jeyakumar,‡ and Andrey P. Antonchick*,†,‡
†Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund,
Germany
‡Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Straße 4a, 44227 Dortmund, Germany
S
* Supporting Information
ABSTRACT: A catalytic, metal-free intramolecular rear-
rangement of benzyl phenyl ethers using nitrosonium salt as
a catalyst is described. The optimized reaction conditions
enabled a catalytic and metal-free Friedel−Crafts alkylation
reaction with benzylic alcohols, producing water as the
stoichiometric byproduct. A comprehensive scope (>50 examples) for both approaches and application in drug synthesis were
demonstrated. Mechanistic studies suggest a Lewis acid-based mechanism for the metal-free Friedel−Crafts reaction.
he electrophilic activation of hydroxyl groups, as well as the
Tdevelopment of Friedel−Crafts reactions on nonactivated
systems, have been identified as top priorities in green chemistry
research.1 However, the direct employment of alcohols as
electrophiles represents a significant challenge.2 C−O bonds are
omnipresent in nature and the development of novel chemical
methods for transformation of C−O bonds to C−C bonds is
highly desired.3 Notably, nickel catalysis has emerged as a
powerful tool for C−O bond activation.4 In contrast to organo
halides, oxygen-containing compounds, such as alcohols, are
inexpensive, readily available, and nontoxic.5 Diarylmethanes are
important building blocks for pharmaceuticals, agrochemicals,
and materials.6 Cross-coupling methods enable the regioselec-
tive synthesis, but it requires additional activating groups on
both coupling partners.7 In 1952, Tarbell and Petropoulus
reported the transformation of benzyl phenyl ethers using
stoichiometric amounts of AlBr3 to a mixture of 2-benzylphenol
and phenol (Figure 1A).8 Later, different methods for the
synthesis of benzyl phenols have been described, but have
proven to be limited to electron-rich substrates and elevated
temperatures.9 Friedel−Craft reactions enable the efficient C−C
bond formation via functionalization of Csp2−H bonds, but
usually require metal-based Lewis acids, harsh reaction
Figure 1. Synthesis of diarylmethanes.
conditions, or lead to the undesired production of halohydric
acid as a byproduct.10 Recently, different strategies for the metal-
the application of electron-deficient boronic acids16 and, later,
free synthesis of diarylmethanes have been reported (Figure
Moran’s group demonstrated the super Brønsted acid-catalyzed
dehydrative Friedel−Crafts reaction of deactivated benzylic
alcohols.17 Nitrosonium salts were employed by us and others in
oxidative coupling, π-bond activation, and oxygenation.18
Notably, nitrosonium salts are inexpensive, stable, and non-
toxic.19 Reactive nitrogen−oxygen species are present in living
cells and play an important role in oxidative-stress response and
1B). Bode and co-workers demonstrated the arylation of benzyl
hydroxamates mediated by an excess of BF3·OEt2.11 Later, the
application of alkyl phosphates was reported.12 Paquin and co-
workers developed the Friedel−Crafts alkylation with benzyl
fluorides via the in situ generation of HF.13
Stephan’s group disclosed the activation of benzyl fluorides in
the presence of electrophilic organofluorides and stoichiometric
amounts of reductant.14 However, benzyl fluorides must be
generated from the corresponding alcohols using stoichiometric
amounts of fluorination reagent.15 Hall and co-workers explored
Received: May 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01495
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
as cell-signaling molecules.20 At present, the application in C−O
bond activation is limited to protecting group removal.21
Because of our ongoing interest in metal-free reaction
methodologies,22 we aimed to target the catalytic functionaliza-
tion of C−O bonds using nitrosonium salts. Herein, we report
the metal-free intramolecular rearrangement of benzyl phenyl
ethers using low loading of catalyst, which enabled a
intermolecular and catalytic synthesis of various diarylmethanes
from alcohols and arenes, producing water as the stoichiometric
byproduct (Figure 1C).
Scheme 2. Catalytic Rearrangement of Benzyl Ethers under
Optimized Reaction Conditions
a
We began our investigation by selecting benzyl phenyl ether
1a as a model substrate to avoid the restriction to electron-rich
starting materials. Multiparameter optimization for the rear-
rangement to benzyl phenol 2a was performed (see Tables S1−
S5 in the Supporting Information). Under the optimized
conditions, the rearranged product 2a was isolated in 84%
yield, with an ortho:para selectivity of 6:1 and short reaction
times while using only 0.5 mol % of nitrosonium tetrafluor-
oborate as catalyst in 2:1 dichloromethane/hexafluoro-isopro-
panol (Scheme 1). A notable feature of the developed reaction is
Scheme 1. Catalytic Rearrangement of Benzyl Ethers under
a
Optimized Reaction Conditions
a
a
Reaction conditions: 1a (1 mmol, 1 equiv), NOBF4 (5 μmol, 0.5 mol
Reaction conditions: 1 (0.5 mmol, 1 equiv), NOBF4 (2.5 μmol, 0.5
%), 2:1 DCM/HFIP (10 mL, 0.1 M). Yield is given for the isolated
product after column chromatography. o:p ratio according to GC-MS-
FID. Asterisk (*) denotes minor regioisomer. DCM = dichloro-
methane, HFIP = hexafluoroisopropanol. See the Supporting
Information (SI) for details.
mol %), 2:1 DCM/HFIP (5 mL, 0.1 M). Yields are given for isolated
products after column chromatography. The abbreviation “rr”
represents the regioisomer ratio, according to GC-MS-FID. Asterisk
(*) denotes minor regioisomer.
deactivating groups were well-tolerated, yielding products 2u
and 2v in high yields and selectivity. Finally, we also explored the
rearrangement of allylic groups. Geranylated products 2x and 2y
were isolated as single isomers, albeit in reduced yields.
the predominant formation of ortho-substituted product, while
intermolecular Friedel−Crafts alkylation of phenol usually gives
para-isomers.
With the optimized conditions in hand, we began to explore
the scope of the catalytic rearrangement for various benzyl
phenyl ethers (see Scheme 2). Using benzyl phenols substituted
at the 4-position of phenols, the desired products were isolated
in high yields with short reaction times and good to excellent
regioselectivity (2b−2e). The presence of methoxy groups on 3-
or 4-position of the phenol part yielded the benzyl phenols in
high yields, but as mixtures of regioisomers, which could be
separated in a straightforward manner (2f, 2g). A set of
polysubstituted phenols was employed, allowing the synthesis of
complex products with high selectivity and yield (2h−2j).
Substituted naphthols were successfully employed, yielding the
products 2k and 2l in good yield and excellent regioselectivity.
The rearrangement of ethers bearing substituents on the benzyl
moiety was successfully demonstrated. Functional groups with
electron-donating and electron-withdrawing effects were well
tolerated, yielding the desired products in high yields with
predominant formation of ortho-isomers (2m−2q). Substrates
with highly electron-withdrawing groups did not yield the
desired products. Furthermore, products 2r and 2s demonstrate
the compatibility of secondary benzyl groups, even with a
terminal double bond. Interestingly, the para regioisomer was
isolated as a major product. Next, a set of polysubstituted
starting materials were tested, bearing functional groups on the
phenol and benzyl moiety (2t−2v). It is noteworthy that even
After studying the scope of the catalytic rearrangement of
benzyl phenyl ethers, we aimed to develop an intermolecular
variant based on the developed reaction conditions. To our
delight, the direct employment of benzylic alcohols was found to
be suitable for the intermolecular Friedel−Crafts reaction using
a low loading of nitrosonium tetrafluoroborate (see Scheme 3).
Synthesis of diarylmethane (5a) was achieved in good yield
using benzene as a nucleophile and producing water as the
stoichiometric byproduct. We began to explore the scope of the
catalytic Friedel−Crafts reaction by testing secondary and
tertiary benzylic alcohols. Products 5b−5d were isolated in high
yields and with short reaction times. Electron-neutral and
deactivated diarylmethanes were successfully synthesized in
good yields, demonstrating no restriction to electron-rich
starting materials (5e−5i). Even polyhalogenated arenes (5j)
and benzylic alcohols (5k) yielded the desired products.
The combination of two electron-rich coupling partners
yielded products 5l−5o in high yield and selectivity. Notably,
this intermolecular reaction leads to predominant formation of
para-substituted products, while the earlier demonstrated
intramolecular transformation gave ortho-substituted products.
Furthermore, a set of diarylmethanes was successfully
synthesized using polysubstituted arenes as a coupling partner
(5p−5u). Arylation of dibenzylic alcohols was also demon-
strated and yielded diarylated products with good yield (5v, 5w).
B
DOI: 10.1021/acs.orglett.8b01495
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Letter
Scheme 3. Scope of the Catalytic Intermolecular Friedel−
Scheme 4. Metal-Free Drug Synthesis Using the Developed
Reaction Conditions
a
Crafts Alkylation
synthesized using stoichiometric amounts of aluminum
chloride.23
Next, we studied the mechanism for the intermolecular
Friedel−Crafts alkylation reaction (see Table S7 in the
Supporting Information). Oxidation of reactive nitrogen−
oxygen species appeared to be unlikely, because of the inefficient
performance of nitric acid. NOCl as catalyst yielded the desired
product unaffectedly, which supports a Lewis acid-based
mechanism. Notably, when hydrochloric acid or nitric acid
were used respectively, only small amounts of product were
isolated. The presence of the nitrosonium ion in solution
appeared to be crucial for the reaction. Furthermore, the
reaction was not affected by the radical trap BHT (Scheme S1 in
the Supporting Information). The formation of a benzylic cation
appeared to be reasonable, since racemization was observed
upon functionalization of enantiopure starting material (see
Scheme S2 in the Supporting Information). The proposed
course of reaction is outlined in Figure 2. Nitrosonium
a
Reaction conditions: 3 (0.2 mmol, 1 equiv), 4 (2.5 equiv or 10
equiv) NOBF4 (10 μmol, 5 mol %), 1:1 DCE/HFIP (2 mL, 0.1 M).
Yields are given for isolated products after column chromatography.
The abbreviation “rr” represents the regioisomer ratio, according to
1H NMR. Asterisk (*) denotes minor regioisomer. Abbreviations:
Mes = mesityl; Naph = 1-naphthyl.
Figure 2. Proposed reaction mechanism for the intermolecular
Friedel−Crafts alkylation reaction.
tetrafluoroborate activates the benzylic alcohol by generating
intermediate A. The formation of intermediate B is followed by
intermolecular SEAr with the arene nucleophile. The released
NO+ species are scavenged by HBF4 to generate water and to
maintain the catalytic cycle. We also compared the developed
system for the Friedel−Crafts alkylation reaction with other acid
catalysts, including triflic acid and HBF4. However, no acid was
able to outperform nitrosonium tetrafluoroborate (see Table S6
in the Supporting Information).
In summary, we have developed a catalytic and metal-free
intramolecular rearrangement of benzyl phenyl ethers using low
loading of nitrosonium tetrafluoroborate as a catalyst under mild
conditions. A broad substrate scope was demonstrated revealing
good functional group tolerance, predictable selectivity, and
short reaction times. Furthermore, the developed reaction
conditions were converted to the catalytic and metal-free
Friedel−Crafts alkylation for the synthesis of various diaryl-
Afterward, we moved our attention to the coupling of complex
starting materials embedding heterocycles. Functionalization of
indoles was successfully achieved in good to excellent yield (5x−
5z). Impressively, synthesis of oxindole 5aa with a quaternary
carbon proceeded with perfect yield and regioselectivity, using
anisole and 3-hydroxy-2-oxindole derivative as coupling
partners. Incorporation of heterocyclic moieties such as
benzothiophene, chromone, and furan was achieved in good
to excellent yield (5ab−5ad). In addition, we targeted the
functionalization of natural products. Product 5ae was
synthesized regioselectively in 92% yield by means of late-
stage functionalization of unprotected estrone. To further prove
the utility of the developed reaction conditions, we targeted the
metal-free synthesis of drugs (see Scheme 4). Phenprocoumon
(5af) and Nafenopin (5ag) were synthesized in satisfying yields
as single regioisomers. Notably, Nafeonpin is commonly
C
DOI: 10.1021/acs.orglett.8b01495
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
(8) Tarbell, D. S.; Petropoulos, J. C. J. Am. Chem. Soc. 1952, 74, 244−
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01495.
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General experimental procedures, detailed optimization
studies, details on control experiments, mechanistic
studies, and biological methods and characterization of
starting materials and products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andrey.antonchick@mpi-dortmund.mpg.de.
ORCID
̈
(11) Schafer, G.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 10913−
10916.
(12) Pallikonda, G.; Chakravarty, M. J. Org. Chem. 2016, 81, 2135−
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(13) Champagne, P. A.; Benhassine, Y.; Desroches, J.; Paquin, J.-F.
Angew. Chem., Int. Ed. 2014, 53, 13835−13839.
Andrey P. Antonchick: 0000-0003-0435-9443
Notes
The authors declare no competing financial interest.
́
(14) Zhu, J.; Perez, M.; Stephan, D. W. Angew. Chem., Int. Ed. 2016,
55, 8448−8451.
ACKNOWLEDGMENTS
■
(15) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F.
Org. Biomol. Chem. 2015, 13, 2243−2246.
A.P.A. acknowledges the support of DFG (Heisenberg Scholar-
ship No. AN 1064/4-1) and the Boehringer Ingelheim
Foundation (Plus 3). L.B. is supported by the Verband der
Chemischen Industrie e.V.
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