Arene Cyanation via Cation-Radical Accelerated-Nucleophilic Aromatic Substitution

Article abstract of DOI:10.1021/acs.orglett.9b02678

Herein we describe a cation radical-accelerated-nucleophilic aromatic substitution (CRA-S_NAr) of alkoxy arenes utilizing a highly oxidizing acridinium photoredox catalyst and acetone cyanohydrin, an inexpensive and commercially available cyanide source. This cyanation is selective for carbon-oxygen (C-O) bond functionalization and is applicable to a range of methoxyarenes and dimethoxyarenes. Furthermore, computational studies provide a model for predicting regioselectivity and chemoselectivity in competitive C-H and C-O cyanation of methoxyarene cation radicals.

Full text of DOI:10.1021/acs.orglett.9b02678

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Arene Cyanation via Cation-Radical Accelerated-Nucleophilic
Aromatic Substitution
Natalie Holmberg-Douglas and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: Herein we describe a cation radical-accelerated-
nucleophilic aromatic substitution (CRA-SNAr) of alkoxy
arenes utilizing a highly oxidizing acridinium photoredox
catalyst and acetone cyanohydrin, an inexpensive and
commercially available cyanide source. This cyanation is
selective for carbon−oxygen (C−O) bond functionalization
and is applicable to a range of methoxyarenes and
dimethoxyarenes. Furthermore, computational studies provide
a model for predicting regioselectivity and chemoselectivity in
competitive C−H and C−O cyanation of methoxyarene
cation radicals.
Scheme 1. Catalytic Approaches to Benzonitrile Synthesis
ryl nitriles are important functional groups within the
Astructures of pharmaceutical and agrochemical com-
pounds. Nitriles can serve as bioisosteres for hydroxy or
carbonyl moieties and have been implicated in key binding
interactions of aldosterone, aromatase, and phosphodiesterase
inhibitors.1 Moreover, benzonitriles serve as an effective
functional handle for the late stage installation of amides,2
amines,3 and esters.4
Classically, benzonitriles are synthesized via the Sandmeyer
reaction that converts anilines to highly reactive diazonium
intermediates. When using metal cyanides as nucleophiles, the
diazonium undergoes nucleophilic substitution to yield the
desired cyanoarene.5 While this transformation is utilized
extensively in preparative organic synthesis, diazonium salts
are prone to explosive decomposition making such trans-
formations difficult to scale. Modern approaches have since
focused on transition metal catalyzed cross-coupling methods
utilizing an aryl halide or pseudohalide (Scheme 1A).6 Despite
significant advances, these cross-coupling methods can suffer
from catalyst deactivation due to ligand displacement by cyanide
at the metal centers.7 Furthermore, these transformations are
limited to the availability of halogenated arene starting materials,
thus requiring prefunctionalization for more complex aromatic
substrates. Additionally, these preassembled leaving groups,
such as halides, triflates or other pseudohalides are synthetically
labile across many synthetic conditions, which may make late-
stage functionalization challenging.8
Current methods for the functionalization of aryl ethers
include substitution using alcohols, amines, sulfur and organo-
metallic nucleophiles.8−11 The synthesis of benzonitriles via aryl
ether substitution has only been reported using UV light to
promote the direct excitation of ortho- and para-substituted
dimethoxybenzenes in the presence of 1,4-dicyanobenzene.12
A
donor−acceptor π-complex between the two species is formed,
enabling nucleophilic cyanation and severely limits the scope of
this transformation. Reports of other C−C bond forming
A complementary and economically attractive alternative
functional handle is the alkoxy moiety. Aryl ethers are ubiquitous
in commercially available and naturally occurring molecules and
can also be easily prepared from phenols. Furthermore, methoxy
groups are tolerant of many harsh synthetic conditions, making
them ideal substrates for late stage functionalization.8
Received: July 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02678
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions via C−OMe cleavage are limited, likely due to the high
activation energy barrier for breaking the C−OMe bond.13
Recently, our group published a cation radical-accelerated-
nucleophilic aromatic substitution (CRA-SNAr) of methoxy or
benzyloxy-substituted arenes using azoles, ammonia, and
trifluoroethano as nucleophiles.14 Cyanide has shown to be a
competent nucleophile for arene C−H functionalization,15 thus
we believed we could extend the CRA-SNAr methodology for
the synthesis of benzonitriles. Herein, we report the use of
cyanide as a nucleophile in C−C bond formation for
benzonitrile synthesis utilizing a highly oxidizing acridinium
photoredox catalyst (Scheme 1B).16
We began by adapting our conditions previously developed
for arene C−H cyanation using TMSCN as the cyanide
source.15 Using 3,4-dimethoxybenzonitrile as a model substrate,
treatment with a catalytic quantity of acridinium salt Mes-Acr-
Ph+ under irradiation with 455 nm LEDs yielded the desired C−
O cyanation product in 18% yield as a mixture of two
regioisomers (Table 1, entry 1). In comparison to TMSCN,
The scope of this transformation was then examined using the
optimized conditions (Figure 1). Simple mono- and disub-
stituted arenes were investigated first. Arenes bearing 1,2-
dimethoxy substituents (1−5) were found to be the highest
yielding of this group. 2-Chloro substituted anisole derivatives
(6−8) also gave moderate to good yields of the desired product.
A variety of 1,2-dimethoxybenzophenone derivatives (12−17)
performed well with yields ranging from 48 to 83%. To our
surprise, selective cyanation was observed for 3-bromoveratrole
(9) and 1,2,3-trimethoxybenzene (10) yielding the products as
single regioisomers.
Aryl ethers bearing para-pyridine and pyrimidine substituents
(19−22) also produced the expected adducts, albeit in lower
yields. More complex substrates such as the noradrenaline (23)
and letrozole derivatives (24) also gave the desired benzonitrile
products in low to moderate yields.
The mass balance of this C−O cyanation reaction is excellent
with crude reaction mixtures typically consisting of only product
and unreacted starting material as the main chemical
components. Neither the inclusion of additional equivalents of
cyanohydrin nor extended reaction times were effective in
converting the remaining starting material to product,
suggesting that catalyst decomposition may be responsible.
The mass of a cyanide−acridinium adduct was detected by
HRMS supporting catalyst decomposition by adventitious
cyanide (Supporting Information, page 33).
a
Table 1. Optimization for Catalytic SNAr Cyanation
Having evaluated the scope of this transformation, we sought
to investigate the mechanism and origins of regioselectivity of
this ipso-functionalization using a combination of experimental
and computational data. Examining the initial rates of a variety of
varying benzophenone derivatives, no linear free energy
relationship was observed. However, these experiments did
reveal an induction period (Supporting Information, pages
35−40). This is likely caused by a thermal barrier for the release
of cyanide from acetone cyanohydrin.
We previously reported that in the presence of a terminal
oxidant, nucleophilic attack of the anisole cation radical will
occur at the para- or ortho-position, which requires a second
irreversible oxidation to afford the C−H amination product.18
Without a terminal oxidant, however, the reaction pathway is
steered toward the ipso-product. Intriguingly, substrates which
underwent ipso-C−O cyanation efficiently were not competent
substrates under C−H cyanation conditions and vice versa. We
then sought to demonstrate that the absence of oxygen would
not simply allow a substrate to undergo ipso-substitution and
that the chemoselectivity is determined by the electronics of the
arene in the cation radical and ground state. To exemplify this,
we turned to computational modeling.
Our group has previously demonstrated that natural
population analysis (NPA) can be employed to computationally
predict the regioselectivity of cation radical mediated arene C−
H functionalization reactions.19 Upon oxidation, the ortho-,
para- and ipso-carbons of anisole are activated by an increase in
positive charge density, allowing for nucleophilic addition at
these positions.19 The difference between the predicted NPA
values of each carbon of the cation radical and ground state
arene were largely accurate in modeling the regioselectivity
observed for photoredox catalyzed C−H aminations. We elected
to apply this method to understand the chemoselectivity of
arene C−O cyanation. Utilizing the B3LYP/6-31-G+(d) level of
theory, the NPA for the arene neutral state and cation radical
state were determined for a variety of substrates. Comparing
these values with experimental results, we found that the largest
entry
solvent
MeCN
MeCN
DCE
DCE
DCE/TFE (3:1)
DCE/TFE(3:1)
DCE/HFIP (3:1)
DCE/TFE (3:1)
DCE/TFE (3:1)
base
yield (A:B)
b
1
10% v/v pH 8 buffer
10% v/v pH 8 buffer
10% v/v pH 8 buffer
33% NaHCO3(aq)
33% NaHCO3(aq)
NaHCO3 (5.0 equiv)
NaHCO3 (5.0 equiv)
NaHCO3 (5.0 equiv)
NaHCO3 (5.0 equiv)
18% (2.6:1)
24% (2.4:1)
24% (2.4:1)
35% (2.2:1)
80% (2.4:1)
90% (2.4:1)
53% (2.5:1)
n/a
2
3
4
5
6
7
c
8
d
9
n/a
a
b
Reactions run at 0.1 M with respect to substrate. TMSCN (4.0
equiv) used as a cyanide source. The reaction was run without LEDS.
No photocatalyst.
c
d
acetone cyanohydrin was found to be higher yielding and a more
economic cyanide source (entries 2−7). Other organic cyanide
sources or cyanide salts failed to improve the reaction yields
(Supporting Information, pages S7 and S8). A screen of
common organic and inorganic bases identified solid or aqueous
sodium bicarbonate as the optimal base for the generation of free
cyanide in situ (Supporting Information, pages S7 and S8).
Under these reaction conditions, the weak basicity of sodium
bicarbonate may improve reactivity by keeping the concen-
tration of the cyanide anion low, which helps to prevent
undesired degradation pathways via oxidation of the cyanide
anion by the photoredox catalyst.17 When examining solvents,
we found that the inclusion of 2,2,2-trifluoroethanol (TFE)
resulted in a significantly enhanced yield of the desired product
(Table 1, entries 5 and 6). In contrast, 1,1,1,3,3,3-hexafluor-
oisopropanol (HFIP) only marginally increased the yields
relative to those observed in DCE (entry 7). No reaction was
observed in the absence of irradiation or the acridinium
photoredox catalyst (entries 8 and 9, respectively).
B
DOI: 10.1021/acs.orglett.9b02678
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Letter
Figure 1. Scope of catalytic SNAr arene cyanation.
difference of NPA values between the cation radical and ground
state correlated experimentally to the favored major substitution
position (Figure 2). If the difference is greatest at the aryl C−O
product were isolated (∼<5%). Although this model predicted
meta-selectivity, the second largest difference was ortho-,
exemplifying that while there will be exceptions, nonetheless
this model provided insight into the chemo- and regioselectivity
of the cyanation.
To further understand the mechanism and thermodynamics
of this transformation, the overall change in Gibb’s free energy
for an example C−O cyanation was calculated (eq 1). Overall,
this reaction lacks a significant driving force as ΔG for 3,4-
dimethoxybenzonitrile is nearly thermoneutral (−0.3 kcal/mol).
It was observed that methoxyarenes bearing electron donating
and withdrawing groups in a 1,3 relationship were particularly
effective in this cyanation reaction. This increased reactivity
relative to other substrate classes may be due to enhanced
stability of the corresponding aryl radical intermediate via a
captodative-type effect (eq 2). After cyanide addition, the aryl
Figure 2. Prediction of chemoselectivity for benzonitrile synthesis via
photoredox catalysis.
position, ipso-substitution is preferred. Additionally, the largest
calculated NPA value in the cation radical arene correlated with
the minor isomer. This model successfully predicts the
regioselectivity for the cyanation of 3-bromoveratrole and
1,2,3-trimethoxybenzene.
We sought to demonstrate the predictive power of this
method by targeting a pharmaceutical molecule for functional-
ization and chose a letrozole precursor as a test case (25). This
model predicted the primary site of reactivity, the largest
difference in NPA, at the carbon meta to the methoxy group. In
the cation radical state, the most positive cation radical charge is
at the ipso-position. Under the optimized conditions for ipso-
substitution, both the ipso- product and ortho-C−H substituted
radical can be stabilized by both the electron donating and
withdrawing group, thus favoring C−O substitution; this is
supported by the NPA analyses in Figure 2.
This stabilization is further supported when comparing the
relative transition state energy for cyanide addition into veratrole
or 3,4-dimethoxymethylbenzoate cation radicals. The presence
of the para-electron withdrawing ester lowers the transition state
energy by 5.1 kcal/mol (Figure 3). Following the addition step
to afford this Meisenheimer-like intermediate, we postulate a
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Org. Lett. XXXX, XXX, XXX−XXX

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Figure 3. Relative transition state energies for cyanide addition into veratrole (left) or 3,4-dimethoxymethylbenzoate (right) cation radicals calculated
using DFT (B3LYP, 6-31+g(d) basis set).
similar mechanistic pathway as before: loss of methoxide and
single electron reduction to furnish the final product.14
In conclusion, we have developed a photoredox-catalyzed
ipso-cyanation of aryl ethers. These mild conditions utilize a
highly oxidizing, transition metal-free photoredox catalyst and
have been successfully demonstrated for the cyanation of
methoxyarenes and dimethoxyarenes in moderate to excellent
yields. This method uses mild reactions conditions for the
synthesis of benzonitriles via selective SNAr C−OMe bond
cleavage. In addition, we have provided a method for predicting
the chemoselectivity of benzonitrile synthesis via photoredox
catalysis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02678.
Experimental procedures and supporting H and 13C
NMR spectra (PDF)
1
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nicewicz@unc.edu.
ORCID
David A. Nicewicz: 0000-0003-1199-9879
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for support from Eli Lilly (Eli Lilly Grantee
Award to D.A.N.). This work was performed in part at the Mass
Spectrometry Core Laboratory at UNC Chapel Hill (NSF Grant
CHE-1726291). Photophysical measurements were performed
in the AMPED EFRC Instrumentation Facility established by
the Alliance for Molecular PhotoElectrode Design for Solar
Fuels (AMPED), an Energy Frontier Research Center (EFRC)
funded by the U.S. Department of Energy, Office of Science,
Office of Basic Energy Sciences under Award DE-SC0001011.
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