Cation Radical-Accelerated Nucleophilic Aromatic Substitution for Amination of Alkoxyarenes

Article abstract of DOI:10.1021/acs.orglett.0c01621

Nucleophilic aromatic substitution (SNAr) is a common method for arene functionalization; however, reactions of this type are typically limited to electron-deficient aromatic halides. Herein, we describe a mild, metal-free, cation-radical accelerated nucleophilic aromatic substitution (CRA-SNAr) using a potent, highly oxidizing acridinium photoredox catalyst. Selective substitution of arene C-O bonds on a wide array of aryl ether substrates was shown with a variety of primary amine nucleophiles. Mechanistic evidence is also presented that supports the proposed CRA-SNAr pathway.

Full text of DOI:10.1021/acs.orglett.0c01621

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Letter
Cation Radical-Accelerated Nucleophilic Aromatic Substitution for
Amination of Alkoxyarenes
Nicholas J. Venditto and David A. Nicewicz*
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ABSTRACT: Nucleophilic aromatic substitution (SNAr) is a
common method for arene functionalization; however, reactions
of this type are typically limited to electron-deficient aromatic
halides. Herein, we describe a mild, metal-free, cation-radical
accelerated nucleophilic aromatic substitution (CRA-SNAr) using a
potent, highly oxidizing acridinium photoredox catalyst. Selective
substitution of arene C−O bonds on a wide array of aryl ether
substrates was shown with a variety of primary amine nucleophiles.
Mechanistic evidence is also presented that supports the proposed
CRA-SNAr pathway.
difficult to carry through a synthesis due to their synthetic
lability over various other synthetic methods.8
nilines represent an important functional group in
Apharmaceutical, agrochemical, and materials industries.
These functionalities are present in a wide variety of bioactive
compounds.1 Additionally, the prevalence of anilines in
materials industries is ubiquitous, representing a common
structural motif found in organic dyes and conductive
polyaniline polymers.1 Due to their pervasiveness in industry
and their synthetic utility, the development of new aryl C−N
bond forming reactions is an important area of research.
Historically, benzenoid amination has been accomplished via
aromatic nitration to provide primary anilines.2,3 However,
these reactions require harsh conditions restricting functional
group tolerance and overall utility. Nucleophilic aromatic
substitution (SNAr), however, can be conducted under more
mild conditions. Classical SNAr reactions are widely used for
installing functional groups onto electron-poor halogenated
benzenoids and heteroaromatic systems and represent some of
the most used transformations in medicinal chemistry.3,4
Proceeding through either a Meisenheimer complex, or via a
concerted SN2-type mechanism, SNAr reactions require
strongly electron-withdrawing groups to be placed in the
ortho or para positions to a particular nucleofuge, typically
fluorine, to overcome the high energetic demand.3,5 The high
energetic demand of SNAr reactions typically limit this
transformation to electron-poor arenes, leaving SNAr of
electron-rich arenes as an area to still be explored.
In order to address substrate limitations, several reactions
have been developed that utilzie aryl ether electrophiles as
cross-coupling partners (Scheme 1A). These methods all
benefit from the commercial availability of a large number of
phenol and aryl ether starting materials stemming from their
prevalence in biomass, such as lignin.9 Aryl ethers are also less
synthetically labile than halides and can more efficiently be
carried through a synthesis without deleterious side reactivity.8
One such example of a transition metal mediated cross-
coupling reaction using aryl methyl ethers was developed by
Chatani and Tobisu.10 This method utilizes a catalytic quantity
of NHC ligated nickel complexes in the presence of
stoichiometric NaOtBu to affect formal aryl methyl ether
amination. However, this method is limited to heteroaryl and
π-extended aryl ethers and is only effective with secondary
amine cross-coupling partners.
Biswas and co-workers have developed a metal-free
approach to aryl methyl ether functionalization by means of
triflic acid promoted oxocarbenium ion-catalyzed SNAr
(Scheme 1b).11 Conversely, base-promoted SNAr reactions
using aryl methyl ethers have been developed as well, using
strong bases such as stoichiometric n-butyl lithium, NaH-LiI
composites, and phosphazene superbase to generate reactive
Received: May 12, 2020
Transition metal cross-coupling reactions such as Buch-
wald−Hartwig and Ullmann couplings provide an alternative
avenue toward rapid access to aniline products.6,7 The
requirement of halogenated or pseudohalogenated cross-
coupling partners can prove to be problematic in late stage
functionalization, however, as these functional groups can be
https://dx.doi.org/10.1021/acs.orglett.0c01621
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Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Aryl Ether Amination Strategies
Table 1. Primary Amine CRA-SNAr Optimization
entry
solvent
ratio A/B
yield 1 (%)
1
2
3
4
5
6
7
8
9
1:1 DCE/TFE
2:1 DCE/TFE
1:2 DCE/TFE
TFE
MeCN
DCE
DCE
DCE
DCE
1:1
1:1
1:1
1:1
1:1
1:1
2:1
1:2
1:4
23
28
17
13
11
50
50
60 (52)
55
a
Reactions run on 0.1 mmol scale. Yields reported are NMR yields
with isolated yields in parentheses. NMR yields reported referenced to
a (Me3Si)2O internal standard.
product and the remaining aryl ether starting material.
Oxidative dimerization of benzylamine to N-benzyl phenyl-
methanimine was also observed as byproduct in 5% yield.
With optimized conditions in hand, the substrate scope was
explored (Figure 1). Several 2-chloro monomethoxy benze-
noids (1−3) afforded the desired secondary amine products in
moderate yields, using benzylic or heterobenzylic amine
coupling partners. Alternative ether leaving groups were
examined, and both benzyloxy and biaryl ether 4 and 5
afforded the resultant aniline in moderate yield. Electron-poor
leaving groups such as acetoxy, triflate, and tosylate were also
examined, but only returned starting material was observed.
Next, 1,2-dimethoxy-veratrole derived substrates were
tested. Amination of this class of arenes worked well overall,
giving synthetically useful yields ranging from 25% to 77%
yield (6−18). This class of 1,2-dimethoxy substrates bearing
an electron-withdrawing group para- to the nucleofuge was
particularly well-suited for CRA-SNAr giving the best yields.
This class of substrates may show increased yields due to
captodative-like stabilization of the radical intermediate formed
upon addition of the nucleophile to the arene cation radical.21
In all cases only one amination event was observed, with the
other methoxy group still intact.
Importantly, various functional groups were well-tolerated
including ketones, 7 and 13−17, generating the corresponding
products in 50% and to 77% yield. Benzoate and benzonitrile
substrates 8 and 9 also underwent the desired transformation
in synthetically useful yields of 71% and 62%. 4-Chlorovera-
trole 11 and aryl triflate 12 also underwent MeO-SNAr with
benzylamine, albeit with more moderate yields.
For all 3,4-dimethoxy arenes, preference for SNAr at C4 was
observed, with regioisomeric ratios ranging from 2:1−7:1 C4/
C3. This is in accordance with our previous ipso-substitution
work20,21 and follows computation trends identified using
natural population analysis (NPA) of electron density of the
ground and cation radical states of the arene, with the major
site of substitution having the largest difference in positive
charge density of the NPA values.21,22 Additionally, the
identity of the alkoxy group can improve regiocontrol in this
substrate class, increasing the C4/C3 ratio from 3.3:1 to ∼9:1
in favor of a methoxy leaving group over a benzyloxy (13−16).
Trimethoxy arenes also proved to be viable substrates, and
excellent regioselectivity was observed providing a single
amine anions (Scheme 1c).12−15 While noteworthy, the
substrate compatibility can be limited, demonstrating a need
for more mild reactions to access SNAr pathways.
Our group has developed a research program that utilizes
the reactivity of aryl cation radicals generated by highly potent
visible-light activated acridinium photoredox catalysts. Arene
cation radicals of aryl ethers have shown to be associated with
a significant increase in electrophilicity of the arene in the para,
ortho, and ipso positions, allowing for C−H functionalization
using azole, cyanide, primary amine, and fluoride nucleophiles
under oxidative conditions.16−19 By modifying the reaction
conditions to a redox neutral system, our group has been able
to show substitution at the ipso position using azoles,
ammonia, cyanide, and fluorine nucleophiles.20,21 Herein, we
describe the expansion of this methodology to primary amine
nucleophiles (Scheme 1d).
Beginning with conditions previously reported by our group
for CRA-SNAr, optimization commenced with 4-(tert)butyl-2-
chloroanisole and benzylamine as the amine coupling partner
using a catalytic amount of acridinium salt di-tBu-Mes-Acr
(E*red = +2.15 V vs SCE). For significant conversion to 1 to
occur, 2 equiv of the primary amine were required, while 1,2-
dichloroethane proved to be the optimal solvent. Solvent and
concentration optimization studies indicated that a 0.1 M DCE
solvent system afforded the desired product in 52% isolated
yield (Table 1). Screening other acridinium photoredox
catalysts reveled that the (tert)butyl groups were necessary
for optimal aniline formation to occur. Additionally, the
reaction was run with an acridinium catalyst with a less
oxidizing excited state (hexa-OMe-Mes-Acr E*red = +1.65 V vs
SCE) and no reaction was observed (see Supporting
Information for details). The mass balance for this reaction
is excellent, with the reaction mixture consisting of primarily
B
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a
b
Figure 1. Primary amine CRA-SNAr scope. 2-Picolylamine used in cases where purification proved difficult with other amine nucleophiles. 64%
yield on 1.0 mmol scale using continuous flow setup. cFrom (R)-1-phenethan-1-amine. dAmine source was HBr salt. Reaction run in a 4:1 DCE/
e
aqueous pH 8 phosphate buffer solution. Amine source was HCl salt. Reaction run in a 4:1 DCE/aqueous pH 8 phosphate buffer solution.
isomer at the 2 (or 4) position, following the same
regioselectivity trends as dimethoxy arenes (19−22).21 Addi-
tionally, heterocyclic compounds were also tolerated as
demonstrated by quinoline (23) and isoquinoline (24), albeit
with lower yields but with complete regiocontrol and, in the
case of the Cl-substituted quinolone, complete chemo-
selectivity.
The reaction also proceeded efficiently with a variety of
primary amines. Halogenated benzyl amines worked effectively
as nucleophiles (25 and 26) providing aniline products with a
useful functional handle for downstream cross-coupling
C
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Figure 2. (a) Catalyst fluorescence quenching data. (b) Stern−Volmer quenching analysis. (c) Proposed mechanism.
reactions. Unfortunately, attempts to employ secondary amines
were unsuccessful in this transformation.
Phenethylamine, a prominent structural motif in many
psychoactive compounds, was also effective albeit in more
moderate yields affording the corresponding aniline (32) in
46% yield.25 Aniline formation using 3-bromopropyl amine
(33), ethanolamine (34), glycine (35), and aminoacetaldehyde
dimethyl acetal (36) was also observed, demonstrating
functional group compatibility. Lastly, heterocycle-containing
primary amines (pyridine, pyrazine, and furan) were
competent nucleophiles, affording products 37−39 in
moderate to good yield.
Time-resolved Stern−Volmer quenching analysis was further
utilized to compare the rates of quenching of the aniline
products to those of the reactants (Figure 2b). These studies
revealed that the rate of quenching of the aniline products is
significantly faster than that of both the substrate and the
primary amine reactants. In particular, 7 quenched slightly
faster than the diffusion limit of DCE, which has been shown
to be possible in cases where the Marcus inverted region is
suppressed.26 The oxidation potentials of the aniline products
are significantly lower than that of the parent substrate as well,
demonstrating that quenching of the catalyst by these aniline
compounds is both thermodynamically and kinetically favored
to oxidation of the substrate. This may lead to product
Employing (R)-1-phenylethan-1-amine as the nucleophile
resulted in similar reactivity to the other benzylamine
nucleophiles, affording 61% of the desired aniline (27).
Unfortunately, this reaction proceeded with complete race-
mization, most likely due to oxidation of the amine or aniline
product followed by formation of an α-amino radical.23,24
Based on this result it is somewhat surprising that a
cyclopropyl ring is tolerated (28), affording 46% of the
desired aniline, suggesting that α-amino radical formation in
this substrate is less favorable.
Next, other more oxidizable amines were employed as
nucleophiles. Propyl (29), allyl (30), and propargyl (31)
amine gave 65%, 71%, and 50%, yields respectively. These
primary amine nucleophiles are more oxidizable than both
benzylamine (+1.80 V vs SCE) and 3,4-dimethoxy-
acetophenone (+1.60 V vs SCE), demonstrating that the
reaction can proceed even with competitive oxidation of the
primary amine. Additionally, Stern−Volmer analysis demon-
strated that the rates of photoinduced electron transfer (kq)
kinetically favor oxidation of the arene (Figure 2a).
D
https://dx.doi.org/10.1021/acs.orglett.0c01621
Org. Lett. XXXX, XXX, XXX−XXX