Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides with Primary Aliphatic Amines by Organic Photoredox Catalysis

Article abstract of DOI:10.1002/chem.202002315

In this work, a mild and transition-metal-free approach for the nucleophilic aromatic substitution (S_NAr) of unactivated fluoroarenes with primary aliphatic amines to form aromatic amines is reported. This reaction is facilitated by the formati

Full text of DOI:10.1002/chem.202002315

Accepted Article
Accepted Article
Title: Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides
with Primary Aliphatic Amines via Organic Photoredox Catalysis
Authors: Shaolin Zhou, Weimin Shi, Jingjie Zhang, Fengqian Zhao,
Wei Wei, Fang Liang, and Yin Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.202002315
Link to VoR: https://doi.org/10.1002/chem.202002315
01/2020

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Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides
with Primary Aliphatic Amines via Organic Photoredox Catalysis
Weimin Shi,a Jingjie Zhang,a Fengqian Zhao,a Wei Wei,a Fang Liang,a Yin Zhang,a Shaolin Zhou*a,b
Abstract: Here, we report a mild and transition-metal-free approach
for the nucleophilic aromatic substitution (SNAr) of unactivated
fluoroarenes with primary aliphatic amines to form aromatic amines.
This reaction is facilitated by the formation of cationic fluoroarene
radical intermediates in the presence of an acridinium-based organic
photocatalyst under blue light irradiation. Various electron-rich and
electron-neutral fluoroarenes are competent electrophiles for this
transformation. A wide range of primary aliphatic amines, including
amino acid esters, dipeptides, and linear and branched amines are
suitable nucleophiles. The synthetic utility of this protocol is
demonstrated by the late-stage functionalization of several complex
drug molecules.
advances, however, either the strong basicities of these
reagents or the harsh reaction conditions resulted in limited
functional group tolerance. Therefore, there is still need for
improvement with regard to mild and transition-metal-free
conditions with broad functional group tolerance.
Aromatic amines are ubiquitous in natural products,
pharmaceuticals and pesticides;[1] hence, there is growing
demand to develop mild and cost-effective protocols for their
synthesis.[2] The classical nucleophilic aromatic substitution
(SNAr) of aryl halides (particularly aryl fluorides) with aliphatic
amines is a straightforward and well-documented protocol for
preparing aromatic amines.[3] This reaction commonly occurs by
the addition of aliphatic amines to aryl fluorides to form a
negatively charged Meisenheimer intermediate, and subsequent
elimination of HF delivers the products. Because the stabilization
of the Meisenheimer intermediate requires strongly electron-
withdrawing groups at the positions para and/or ortho to the
fluorine atom, the scope of this reaction is restricted to highly
electron-deficient aryl fluorides.[4]
Recent advances have begun to address the limited
substrate scope. The pioneering work by Shibata used Ru
catalysis,[5] while Wang employed Ni catalysis to facilitate the
amination of unactivated aryl fluorides with aliphatic amines at
elevated temperatures.[6] Although significant advances have
been made, both reactions rely on the use of transition-metal
catalysts, and the trapping and removal of these species might
be pose serious economic and environmental concerns for the
pharmaceutical industry.[7] As such, several other reports have
mainly focused on the use of alkali metal or other main group
metal reagents, such as LiHMDS,[8] BuLi,[9] NaOH,[10] K2CO3,[11]
and Mg(II)[12] and Pb(II)[13] amides. Despite these significant
Figure 1. Photocatalytic and electrophotocatalytic SNAr amination reactions with
unactivated aromatics.
a
W. Shi, J. Zhang, F. Zhao, W. Wei, F. Liang, Y. Zhang, Prof. Dr. S.
Zhou
Recently, Nicewicz and coworkers disclosed a visible light
photocatalytic SNAr of aryl ether using azoles and ammonia
surrogates as nitrogen nucleophiles (Figure 1a).[14] This
reaction is thought to be facilitated by the formation of arene
cation radicals via photo-induced electron transfer. Very
recently, Li and coworkers could further extend this strategy to
aryl triflates using aliphatic nitriles as weaker nucleophiles
under UV light irradiation in the absence of any transition-metal
catalyst or photocatalyst (Figure 1b).[15] Remarkably, Lambert
and coworker demonstrated an electrophotocatalytic SNAr of
unactivated aryl fluorides with azoles as nucleophiles to
produce azolated arenes (Figure 1c).[16] In the course of our
Key Laboratory of Pesticide & Chemical Biology Ministry of
Education, College of Chemistry, CCNU-uOttawa Joint Research
Centre, Hubei International Scientific and Technological
Cooperation Base of Pesticide and Green Synthesis, Central China
Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
E-mail: szhou@mail.ccnu.edu.cn
b
Prof. Dr. S. Zhou
College of Materials and Chemical Engineering, Key Laboratory of
Inorganic Nonmetallic Crystalline and Energy Conversion Materials,
China Three Gorges University, Yichang, Hubei 443002, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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recent study on arene C-H amination with primary aliphatic
were investigated. Other solvents, such as CH2Cl2, acetonitrile
and ethanol, led to inferior results (entries 5-7). Gratifyingly, after
appropriate optimization of the ratio of 1a and 2a (1/1.5) and the
amines in the presence of a photoredox catalyst (Acr+-MesClO4 )
-
and
a
proton-reduction catalyst (Co(dmgH)2Cl2),[17] we
unexpectedly observed the reaction between 4-fluoroanisole (1a) reaction times, an excellent yield was eventually obtained (entry
and L-valine ethyl ester (2a) giving rise to substitutive
defluorination product 3aa (25% isolated yield) along with
8). Finally, additional control reactions indicated that both the
photocatalyst and light are crucial for this transformation (entries
desired C-H amination product 4 (13% isolated yield) (Figure 1d). 9-10).
We hypothesize that both products may result from the
competitive nucleophilic attack of the nitrogen atom of 2a on the
two possible electrophilic sites of fluoroarene radical cation
intermediate 5, which is formed by a photoinduced electron
transfer from 1a to the excited state photocatalyst acr-Mes-Me+*.
Nucleophilic attack at the ortho-position relative to the methoxy
group of radical cation 5 would produce C-H amination product 4
with the release of a molecule of hydrogen in the presence of
the proton-reduction catalyst Co(dmgH)2Cl2 (Scheme 1d, path a),
while nucleophilic ipso-attack of the fluorine atom on radical
cation 5 would generate substitutive defluorination product 3aa
with the loss of HF (Figure 1d, path b). We realized that if the
proton-reduction catalyst is omitted from the catalyst system, the
substitutive defluorination process would be the dominant
pathway, and this reaction can be regarded as an SNAr. With
this in mind and inspired by the pioneering works,[18] we describe
herein a mild and transition-metal-free approach for the SNAr of
(classically) unactivated fluoroarenes with primary aliphatic
amines in the presence of an acridinium-based organic
photocatalyst under blue light irradiation (Figure 1e).
Table 2. Scope of amines.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
DCE
Yield[b]
0%
1
2
Ir(dF(CF3)ppy)2(dtbbpy)PF6
Acr+-Mes-MeClO4
DCE
22%
31%
62%
26%
5%
-
-
3
Me2-Mes-Acr+BF4
DCE
-
4
t-Bu2-Mes-Acr+BF4
DCE
-
5
t-Bu2-Mes-Acr+BF4
DCM
CH3CN
EtOH
DCE
-
6
t-Bu2-Mes-Acr+BF4
-
7
t-Bu2-Mes-Acr+BF4
3%
[a] Unless otherwise stated, the reaction of 1a (0.1 mmol), amines 2 (0.15
-
mmol), t-Bu2-Mes-Acr+BF4 (5 mol%), and DCE (2.0 mL) was irradiated by
8[c]
9
t-Bu2-Mes-Acr+BF4
91%
0%
-
blue LED lamps (6 W) under Ar atmosphere at room temperature for 48 h.
-
Isolated yields. [b] 8 mol% of t-Bu2-Mes-Acr+BF4 was used and reaction run
--
DCE
for 72 h. [c] 5-mmol scale.
-
10[d]
t-Bu2-Mes-Acr+BF4
DCE
0%
Under the optimized conditions, the amine scope of this
reaction was examined by employing 1a as the aromatic
substrate (Table 2). A series of amino acid esters were
successfully employed as nitrogen nucleophiles. Amino acid
esters with normal alky and aryl side chains reacted smoothly
and delivered the arylated products in good to moderate yields
(3aa-3af). Benefiting from the mild and base-free reaction
conditions, this reaction was compatible with several sensitive
functional groups, including alcohol (3ag), phenol (3ah) and
indole (3ai) moieties. We were also pleased to find that a cyclic
dipeptide afforded arylated product 3aj in moderate yield,
highlighting the potential utility of our method in peptide
chemistry.-Branched and cyclic aliphatic amines were suitable
desired product (3ao), and an allylamine afforded a modest yield
[a] Unless otherwise stated, the reaction of 1a (0.1 mmol), 2a (0.3 mmol),
photocatalysts (5 mol%), and DCE (1 mL) was irradiated by blue LED lamps (6
W) under Ar atmosphere at room temperature for 24 h. [b] Yield was
determined via GC using tetradecane as an internal standard. [c] 2a (0.15
mmol) and reaction run for 48 h. [d] under darkness.
We commenced our study with 1a (1 equiv) as the aromatic
substrate and 2a (3 equiv) as the nitrogen nucleophile in 1,2-
dichloroethane (DCE) under argon atmosphere with blue LED
irradiation (Table 1). Initially, several photocatalysts, including
-
-
Ir(dF(CF3)ppy)2(dtb-bpy)PF6, Acr+-MesClO4 , Me2-Mes-Acr+BF4
and t-Bu2-Mes-Acr+BF4- (entries 1-4), were evaluated, and t-Bu2-
Mes-Acr+BF4 was the most active photocatalyst, resulting in
-
desired product 3aa in moderate yield with no erosion of
-
enantiopurity (entry 4). Therefore, we chose t-Bu2-Mes-Acr+BF4
as the photocatalyst for further studies. Next, other solvents
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Table 3. Scope of fluoroarenes.[a]
(3ap). Notably, a secondary amine nucleophile derived from
azridine was arylated to give the corresponding arylated product
and delivered the arylated products in good to moderate yields
(3ak-3an). A linear amine reacted efficiently and produced (3aq).
However, no reactivity of other secondary amines， such as
pyrrolidine and piperidine (3ar and 3as)， was observed, which
may be a result of steric. Other weaker nitrogen nucleophiles,
such as aniline, benzamide, benzosulfonamide, didn’t lead to the
desired products under the optimal reaction conditions (3at-3av).
A 5-mmol scale reaction of 1a with 2a successfully afforded (3aa)
in 69% yield. Finally, the utility of this protocol was demonstrated
by the late-stage arylation of two primary amine-containing
drugs. Oseltamivir, an anti-influenza virus drug, can be arylated
with 1a in 60% yield (3aw). Sitagliptin, a dipeptidyl peptidase-4
inhibitor, afforded arylated product (3ax) in 69% yield.
After demonstrating the good performance of this protocol
towards a wide range of amine nucleophiles, we further explored
the scope of fluoroarenes using 2a as the nitrogen nucleophile
(Table 3). Silyl and aliphatic protected para-fluorophenolic ethers
can be efficiently converted to the desired aminated products
(3ba-3fa). Notably, this reaction is tolerant of alkyl chlorides
(3fa). para-Fluorinated diphenyl ether led to a moderate yield
(3ga). Interestingly, unprotected para-fluorophenol could also
undergo amination, albeit with lower reactivity (3ha). ortho-
Fluoroanisole afforded the corresponding aminated product in
good yield (3ia), while meta-fluoroanisole showed no reactivity
(3ta). The para- and ortho-monofluorinated anisole derivatives
containing functionalities such as methyl, chloride, bromide and
iodide can be converted to the desired aminated products in
modest to good yields (3ja-3pa), while 4-fluoroanisole bearing
mildly electron-withdrawing (trifluoromethyl, 3ua) and strongly
electron-withdrawing group (cyano, 3va), gave no product at all
(3ua and 3va). To probe the regioselectivity of the reaction, two
difluorinated anisole derivatives were chosen. Although no
selectivity was found with 2,4-difluoroanisole (1:1 3qa/3ra),
excellent para-selectivity was observed with 3,4-difluoroanisole
(3sa). The scope of fluoroarenes is not restricted to phenolic
ethers but extends to other electron-neutral and electron-rich
fluorinated aromatic compounds. Fluorinated diphenyl,
naphthalene, acetylaniline, methylsulfonylaniline, fluorene, N-
acetylcarbazole, 4-chromanol and phenyl sulphide delivered the
desired amination products in modest to moderate yields (3wa-
3Da). Finally, the utility of this protocol is highlighted by the late-
stage defluorinative amination of a pharmaceutical compound.
Ezetimibe, an inhibitor of tumor angiogenesis, can be aminated
with 3Ea in 59% yield.
Figure 2. Mechanistic study.
To obtain a better understanding of the reaction pathway, we
conducted the model reaction of 1a and 2a with two equivalent
of TEMPO as additive. The result showed that the yield of
substitutive defluorination product 3aa was significantly
decreased (36%), while the significant amount of C-H/N-H
coupled product 4 (37%) was obtained (Figure 2). The role of
[a] Unless otherwise stated, the reaction of fluoroarene 1 (0.1 mmol), 2a (0.15
mmol), t-Bu2-Mes-Acr+BF4- (5 mol%), and DCE (2.0 mL) was irradiated by
blue LED lamps (6 W) under Ar atmosphere at room temperature for 48 h.
Isolated yield. [b] Reaction run at 50 ℃ for 72 h. [c] 8 mol% of t-Bu2-Mes-
Acr+BF4- was used and reaction run for 72 h. [d] 20 mol% of t-Bu2-Mes-
Acr+BF4- was used and reaction run for 72 h.
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TEMPO is to be believed to aromatize a radical intermediate (As
shown in Figure 1d, path a) by hydrogen atom abstraction,
which is in line with previous Nicewice’s report.[18a] This result
implies that a fluoroarene radical cation 5 may be involved in the
reaction pathway. Furthermore, Stern-Volmer quenching
experiments were performed to identify the primary radical
species involved in the reaction process. The results indicate
that both 1a (a comparable arene, anisole, has an oxidation
potential, Ep/2 = +1.87 V vs. SCE)[18a] and 2a (a comparable
amine, isopropylamine, has an oxidation potential, Ep/2 = +1.16 V
vs. SCE) can act as reductive quenchers for the excited state of
the photocatalyst t-Bu2-Mes-Acr+* (E1/2 red = +2.15 V vs.
SCE);[18a] however, 1a is more effective than 2a (see the
Supporting Information, Figure S1). These results suggest that a
fluoroarene radical cation and/or an aminium radical cation may
be involved in the reaction pathway. As we have shown, the use
regioselective nucleophilic attack of 5 by 2a at the carbon atom
bearing the fluorine would lead to 6. Then 6 is reduced by the t-
Bu2-Mes-Acr radical to regenerate the photocatalyst and
produce anion 7. Finally, anion 7 eliminates HF to give the
desired product 3aa.
In summary, we have developed a SNAr of unactivated
fluoroarenes with primary aliphatic amines in the presence of an
organic photocatalyst under blue light irradiation. The notable
features of this protocol include mild reaction conditions, wide
substrate scope, and excellently functional group tolerance. In
addition, the utility of this protocol has been demonstrated by the
late-stage functionalization of several complex drug molecules.
Further applications of this strategy towards other synthetically
important nitrogen-containing compounds are currently being
explored in our laboratory.
of
a
weaker
oxidizing
photocatalyst
such
as
Ir(dF(CF3)ppy)2(dtbbpy)PF6 (E1/2*III/II = +1.21 V vs SCE in
MeCN)[19] resulted in no product formation (table 1, entry 1),
which indicates that a fluoroarene radical cation is most likely
involved in the reaction mechanism and that the aminium radical
cation is unlikely. Additionally, we noted that the reaction of 1a
with 2a gives rise to product 3aa upon irradiation, while no
product was formed under darkness (ESI, Figure S2). Moreover,
the quantum yield of the model reaction of 1a and 2a was
determined to be 0.56 (see ESI). These results suggest that this
reaction should undergo a non-chain radical pathway.
Acknowledgements
Financial support was provided by the National Natural Science
Foundation of China (NNSFC) (no. 91956201), the Program of
Introducing Talents of Discipline to Universities of China (111
Program, B17019), and the Research Funds for the Central
Universities (no.CCNU20TS015 and CCNU18TS041). We thank
Profs. Wen-Jing Xiao, Liang-Qiu Lu and Jia-Rong Chen all from
CCNU, for helpful discussions.
Keywords: nucleophilic aromatic substitution • unactivated aryl
fluorides • primary aliphatic amines • visible light photocatalysis
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was proposed for this reaction by using la as the aromatic
substrate and 2a as the nitrogen nucleophile (Scheme 1).
Irradiation of t-Bu2-Mes-Acr+ forms an excited state
photocatalyst, t-Bu2-Mes-Acr+*, which could be reduced by 1a to
generate a t-Bu2-Mes-Acr radical and radical cation 5. Owing to
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radical cation relative to anisole radical cation,[14,
the
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
This work describes a mild and
Weimin Shi, Jingjie
transition-metal-free approachfor the
nucleophilic aromatic substitution
(SNAr) of non-activated fluoroarenes
with primary aliphatic amines to form
aromatic amines. The synthetic utility
of this protocol is demonstrated by the
late-stage functionalization of several
complex drug molecules complex drug
molecules.
Zhang, Fengqian Zhao,
Wei Wei, Fang Liang, Yin
Zhang, Shaolin Zhou
Page No. – Page No.
Nucleophilic Aromatic
Substitution of
Unactivated Aryl
Fluorides with Primary
Aliphatic Amines via
Organic Photoredox
Catalysis
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