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Angewandte
Eine Zeitschrift der Gesellschaft Deutscher Chemiker
Chemie
www.angewandte.de
Akzeptierter Artikel
Titel: Direct C-H Arylation of Primary Amines via Organic Photoredox
Catalysis
Autoren: Kaila A. Margrey, Alison Levens, and David Nicewicz
Dieser Beitrag wurde nach Begutachtung und Überarbeitung sofort als
"akzeptierter Artikel" (Accepted Article; AA) publiziert und kann unter
Angabe der unten stehenden Digitalobjekt-Identifizierungsnummer
(DOI) zitiert werden. Die deutsche Übersetzung wird gemeinsam mit der
endgültigen englischen Fassung erscheinen. Die endgültige englische
Fassung (Version of Record) wird ehestmöglich nach dem Redigieren
und einem Korrekturgang als Early-View-Beitrag erscheinen und kann
sich naturgemäß von der AA-Fassung unterscheiden. Leser sollten
daher die endgültige Fassung, sobald sie veröffentlicht ist, verwenden.
Für die AA-Fassung trägt der Autor die alleinige Verantwortung.
Zitierweise: Angew. Chem. Int. Ed. 10.1002/anie.201709523
Angew. Chem. 10.1002/ange.201709523
Link zur VoR: http://dx.doi.org/10.1002/anie.201709523
http://dx.doi.org/10.1002/ange.201709523
10.1002/ange.201709523
Angewandte Chemie
COMMUNICATION
Direct Aryl C–H Amination using Primary Amines via Organic
Photoredox Catalysis
Kaila A. Margrey, Alison Levens, and David A. Nicewicz*
The construction of aryl C–N bonds is of particular
importance due to their prevalence in natural products,
pharmaceuticals, agrochemicals, and materials.1,2 Strategies for
the direct functionalization of carbon-hydrogen (C–H) bonds
have garnered much attention due to the ability to streamline
complex molecule synthesis in an atom-economical manner.3–5
Specifically, aromatic C–H functionalization bypasses the need
for employing a pre-oxidized arene coupling partner required for
conventional cross-couplings.
While several methodologies have been developed for
arene C–H amination,6–8 nitrogen coupling partners are
generally limited to electron-poor species, such as amides and
imides.9–12 Significant challenges exist for aromatic C–N
couplings using aliphatic amines, since many strategies for
functionalization of these substrates involve C–C bond
construction adjacent to nitrogen.13–16 Accordingly, C–H
amination of arenes with aliphatic amines has been
demonstrated only in select examples (Scheme 1).17 To achieve
C–N bond formation, the use of strongly acidic media and
prefunctionalized chloroamines, which suffer from limited
stability, are often required (eq. 1).18,19 To address these
shortcomings, we hoped to develop a direct aryl C–H amination
with aliphatic amines using a mild catalytic system.
Previously, our laboratory reported a method for direct C–
H amination of arenes and heteroarenes with nitrogencontaining heterocycles and ammonia surrogates, circumventing
the need for pre-oxidized coupling partners.20 This reaction
features a high degree of site selectivity, with monosubstituted
arenes favoring functionalization in the para position. This
approach exploits an acridinium photoredox catalyst capable of
oxidizing arenes through single electron transfer (SET) to
[*]
[**]
*
Kaila A. Margrey, Dr. Alison Levens, Prof. D. A. Nicewicz
Department of Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599-3290 (USA)
E-mail: nicewicz@unc.edu
This work was supported by the National Institutes of Health
(NIGMS) Award No. R01 GM098340 and an Eli Lilly Grantee Award
(D.A.N.).
generate the corresponding cation radicals, which then act as
electrophilic intermediates for nitrogenous nucleophiles.
Minisci (1966):
Me
FeSO4
H2SO4
+
Cl
N
H
Me
H2O
This Work:
MeO
+
H2N
R
Me
•Harsh conditions
Me •Prefunctionalized
N
chloroamine
(1)
H
•Reactive through
amine cation
21% yield
radical
2:1:1 p:m:o
Acridinium
Photoredox
Catalyst
MeO
N
H
R
(2)
O2
Scheme 1. Arene C–H amination with aliphatic nitrogen coupling partners
In designing a strategy to construct aryl C–N bonds using
aliphatic amines via photoredox catalysis (eq. 2), it is noteworthy
that both aliphatic amines and electron-rich arenes can be
oxidized by the acridinium photocatalyst to the corresponding
cation radicals (See Supporting Information, Table S1).21 To
examine whether aryl amination could occur using aliphatic
amines, irradiation (455 nm LEDs) of an arene and an amino
acid ester hydrochloride salt in the presence of acridinium
photocatalyst Me2-Mes-Acr+ in a mixture of 1,2-dichloroethane
(DCE) and pH 8 phosphate buffer afforded the aminated arene
products (Figure 1). A wide variety of amino acid ester
hydrochloride salts participated in the reaction, providing access
to N-arylated amino acids under mild conditions. When anisole
was used as the arene coupling partner, the ortho isomer was
favored in all cases in moderate to excellent yields (1a–14a),
complimentary to the aryl amination previously reported by our
laboratory. The regioselectivity could be reversed by employing
tert-butyldimethylsilyl (TBS) phenyl ether as the arene, favoring
the formation of the para isomer (1b–14b). In addition to amino
acids bearing hydrocarbon side chains, the reaction tolerated
additional functionality, with protected serine and threonine, NBoc lysine, and glutamic and aspartic acid esters all reacting
smoothly. Furthermore, amination products derived from
isoleucine and threonine (6a/b and 11a/b) formed as single
diastereomers, as observed by 1H NMR analysis, indicating that
amino acids do not epimerize during the reaction. Fourteen
amino acids were shown as coupling partners, highlighting the
generality of this approach.
Applying these conditions to other commercially available
amines, the pH 8 buffer could be omitted when using the free
base instead of the hydrochloride salt (15–26). The use of linear
aliphatic amines afforded products 16a and 16b in good yields,
despite the presence of a methylene adjacent to the nitrogen,
which is prone to oxidative degradation. Halogenated amine
coupling partners also provided the aminated products 17a and
17b in moderate yield. Allylamine afforded moderate to high
yields of 18a and 18b, and benzylamine derivatives were also
competent (19 and 20). Enantiopure (S)-α-methylbenzylamine
did not racemize over the course of the reaction, indicating that
even chiral benzylic amines retain stereochemical fidelity
throughout the transformation. This reaction was performed on
2.5 mmol scale using a flow apparatus, affording the desired
product in 61% yield. Amines bearing increased steric bulk also
participated in the reaction, however in diminished yield, with
tert-butylamine providing aniline 21 in 34% yield.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.
Accepted Manuscript
Abstract: The direct catalytic C–H amination of arenes is a powerful
synthetic strategy with useful applications in pharmaceuticals,
agrochemicals, and materials chemistry. Despite the advances in
catalytic arene C–H functionalization, the use of aliphatic amine
coupling partners is limited. Herein, we demonstrate the construction
of aryl C–N bonds to primary amines via a direct C–H
functionalization using an acridinium photoredox catalyst under an
aerobic atmosphere. A wide variety of primary amines, including
amino acids and more complex amines, are competent coupling
partners. Various electron-rich aromatics and heteroaromatics are
useful scaffolds in this reaction, as are complex, biologically active
arenes. We also describe the ability to functionalize arenes that are
not oxidized by an acridinium catalyst, such as benzene and toluene,
supporting a reactive amine cation radical intermediate.
10.1002/ange.201709523
Angewandte Chemie
COMMUNICATION
455 nm LEDs
4:1 DCE: pH 8 Buffer
O2, 0.1 M, 4 h
R'O
1a; R = H; 45% yield; 1.3:1 o:p
1b; R = H; 49% yield; 1:1.8 o:p
2a; R = Me; 62% yield; 1.2:1 o:p
NH
CO2Me 2b; R = Me; 65% yield; 1:1.9 o:p
3a; R = i-Pr; 80% yield; 2.2:1 o:p
R
3b; R = i-Pr; 72% yield; 1:2.1 o:p
R'O
R'O
NHR
Ot-Bu
NH
BF4
R'O
NH
NH
CO2Me
CO2Et
Ph
Ph
8a; 77% yield; 1.5:1 o:p
8b; 85% yield; 1:1.4 o:p
9a; 78% yield; 2.0:1 o:p
9b; 74% yield; 1:2.0 o:p
R'O
NH
CO2Me
NHBoc
NH
CO2Me
CO2Me
CO2Me
12a; 75% yield; 1.7:1 o:p
12b; 62% yield; 1:2.3 o:p
15a; R = i-Pr; 53% yield;a,b 1.2:1 o:p
R'O
15b; R = i-Pr; 56% yield;a 1:1.8 o:p
16a; R = n-Pr; 56% yield;a 1.0:1 o:p
R'O
a
NH 16b; R = n-Pr; 61% yield; 1:1.8 o:p
R 17a; R = 3-Br-n-Pr; 58% yield;a,b 1.8:1 o:p
17b; R = 3-Br-n-Pr; 56% yield;a,b 1:1.4 o:p
18a; R = allyl; 34% yield;a 1.2:1 o:p
18b; R = allyl; 80% yield;a 1:2.2 o:p
Complex Amines: MeO
Me
Me
R'O
CO2Me
MeO
Me
R'O
NH
11a; 68% yield; 1.4:1 o:p
11b; 74% yield; 1:2.4 o:p
HN
Me
N
Ph
Ot-Bu
10a; 84% yield; 1.2:1 o:p
10b; 83% yield; 1:2.3 o:p
R
Me
4a; R = i-Bu; 81% yield; 1.5:1 o:p
4b; R = i-Bu; 89% yield; 1:2.4 o:p
5a; R = (S)-s-Bu; 69% yield; 2.0:1 o:p
5b; R = (S)-s-Bu; 82% yield; 1:1.7 o:p
6a; R = n-Bu; 88% yield; 1.5:1 o:p
6b; R = n-Bu; 89% yield; 1:2.0 o:p
7a; R = t-Bu; 48% yield; 5.5:1 o:p
7b; R = t-Bu; 33% yield; 1:1.2 o:p
NH
Me
Me
1-20a: R' = Me
1-20b: R' = TBS
R'O
NH
CO2t-Bu
Me2-Mes-Acr+
R'O
NH
R
CO2Me
13a; 72% yield; 1.3:1 o:p
13b; 77% yield; 1:2.8 o:p
19a; R = H; 90% yield;a 1.3:1 o:p
19b; R = H; 70% yield;a 1:1.8 o:p
20a; R = Me; 74% yield;a 1.4:1 o:p
(61% yield on 2.5 mmol scale)
20b; R = Me; 90% yield;a 1:1.2 o:p
14a; 69% yield; 1.2:1 o:p
14b; 70% yield; 1:2.0 o:p
MeO
NH
t-Bu
21; 34% yield;a,b 1.4:1 o:p
MeO
MeO
NH
R
CO2Me
Me
MeO
HN
NH
O
Ph
O
i-Pr
HN
CO2Et
Me
Me
22; R = H; 72% yield;a
single regioisomer
L-valyl-L-phenylalanine ethyl ester
gabapentin methyl ester
rimantidine
mexiletine
memantine
25; 34% yield;
27; 58% yield;b,c 3.2:1 o:p
24; 45% yield;a
26; 41% yield;a
23; R = Me; 37% yield;a
1.2:1 o:p
single regioisomer
single regioisomer
7.0:1 o:p
Figure 1. Products of C–H amination illustrating amine scope. Ratios refer to ortho:para (o:p) selectivity for the given adduct. Reactions were run in 4:1 DCE and
a
pH 8 phosphate buffer at 0.1 M concentration with respect to the arene limiting reagent. Reaction run in DCE at 0.1 M concentration with respect to the arene
b 1
c
limiting reagent H NMR yield of adduct Reaction run in DCE at 0.1 M concentration with respect to the arene limiting reagent for 14 h.
The use of more highly substituted amines was demonstrated
with the addition of adamantylamine and memantine, antiParkinson and anti-Alzheimer pharmaceuticals, respectively,
affording 22 and 23 in modest to good yields and high ortho
selectivities with anisole.22 Furthermore, the antiviral
rimantidine23 produced aminated arene 24 as a single
regioisomer in 45% yield. Gabapentin methyl ester, a
pharmaceutical used to treat seizures,24 afforded aryl amine 25
in 34% yield, while anti-arrhythmic pharmaceutical mexiletine25
provided 26 in 41% yield as a single regioisomer. The coupling
of L-valyl-L-phenylalanine ethyl ester with anisole in 58% yield
(27) highlights the application of this methodology to peptidic
compounds.
With a wide variety of primary amines shown as competent
coupling partners, the arene scope was explored using valine
methyl ester hydrochloride as the amine component (Figure 2).
As discussed above, the regioselectivity of the amination could
be altered by changing the substituent on the phenolic ether.
Exposure of aliphatic (-Me, -Et, -t-Bu) and silyl protected (-TES, -
TBS, -TBDPS) phenolic ethers to the reaction conditions
demonstrated that increased steric demand leads to higher
amounts of the para adduct (3a/b, 28–31). Diphenyl ether,
diphenyl sulfide, and biphenyl underwent amination in modest to
good yields, also showing a preference for formation of the para
isomer (32–34). Furthermore, halogens were tolerated on the
arene to afford 35–38, using modified reaction conditions that
employ substoichiometric TEMPO as an additive, similarly to our
prior work.20 For these substrates, the major product resulted
from addition ortho to the methoxy substituent. Importantly, the
presence of a halogen in these products allows for subsequent
derivatization through cross-coupling reactions, highlighting the
utility of the present methodology in the synthesis of complex
benzenoids. 4-Alkyl substituents were also tolerated, with
amination of 4-isopropyl anisole proceeding in 43% yield (39) in
This article is protected by copyright. All rights reserved.
Accepted Manuscript
amine (3 equiv)
Me2-Mes-Acr+(5 mol %)
R'O
10.1002/ange.201709523
Angewandte Chemie
COMMUNICATION
Me
Me
1 equiv
NHR
Cl
C5
HN
C2
C4
Me
fenoprofen methyl ester
48; 73% yield;b,g 1:1:1 C4:C2:C8
HN
CO2Me
t-Bu2-Mes-Acr+
Me
t-Bu
N
Ph
BF4
E*red = + 2.15 V vs SCE
t-Bu
R
C2
C5
R
C4
HN
CO2Me
i-Pr
40; R = OMe; 49% yield;b
10.4:1 C4:C2
41; R = Me; 66% yield;a,b,e
10.1:1 C4:C5
R
Me
N
N
CO2Me
HN
CO2Me
i-Pr
i-Pr
i-Pr
Me
45; 60% yield;b
46; R = H; 64% yield;b single regioisomer
single regioisomer 47; R = Br; 66% yield;b,d single regioisomer
44; 60% yield;
1:5 o:pf
i-Pr
MeO2C
CO2Me
CO2Me
MeO
HN
CO2Me
i-Pr
i-Pr
HN
Me
Me
O
C8
HN
t-Bu
O
MeO2C C3
35; R = F; 35% yield;b
single regioisomer
OMe
36; R = Cl; 75% yield;b
20:1 C2:C3
37; R = Br; 57% yield;b,d
9.1:1 C2:C3
R
38; R = I; 33% yield;b,d
6.7:1 C2:C3
39; R = i-Pr; 43% yield;b
>10:1 regioselectivity
OMe
N
i-Pr
43; 78% yield;
1:2.3 o:pf
42; 63% yield;b
3.0:1 C4:C5
Complex Arenes:
i-Pr
Cl
CO2Me
i-Pr
H
N C2
OMe
NH
C4
Me
N
Ph
BF4
E*red = + 2.09 V vs SCE
O
MeO
Me
Me
455 nm LEDs
4:1 DCE: pH 8 Buffer
O2, 0.1 M, 4 h
3a; R = OMe; 80% yield; 2.2:1 o:p
28; R = OEt; 76% yield; 1.7:1 o:p
29; R = Ot-Bu; 82% yield; 1:1.3 o:p
NH
30; R = OTES; 77% yield; 1:1.7 o:p
CO2Me 3b; R = OTBS; 72% yield; 1:1.9 o:p
i-Pr
31; R = OTBDPS; 58% yield; 1:2.3 o:p
32; R = OPh; 84% yield; 1:2.2 o:p
33; R = SPh; 37% yield;a,b 1:4.4 o:p
34; R = Ph; 95% yield;c 1:2.1 o:p
Cl
R
Me2-Mes-Acr+
Me
MeO2C
CO2Me
C3
Cl
C2
MeO2C
NH
O
CO2Et
NH
O
O
Me Me
N
H
Me Me
CO2Me
Me Me
Cl
clofibrate
bezafibrate methyl ester
gemfibrozil methyl ester
49; 32% yield;b,h single regioisomer 50; 66% yield;a,b 8.7:1 C2:C3 51; 36% yield;a,b >10:1 regioselectivity
Figure 2. Product of C–H amination illustrating arene scope. Ratios refer to ortho:para (o:p) selectivity for the given isomer unless otherwise specified. Reactions
a 1
b
were run using Me2-Mes-Acr+ in 4:1 DCE and pH 8 phosphate buffer at 0.1 M concentration with respect to the arene limiting reagent. H NMR yield of adduct
c
d
Reactions run with 40 mol% TEMPO and 5 mol% t-Bu2-Mes-Acr+ for 15–26 h. Reaction run for 13 h Reactions were run in 4:1 trifluorotoluene and pH 8
e
f
g
phosphate buffer 10 equiv of meta-xylene was used with limiting amine o:p ratio determined after isolation Reaction was run with 3 equiv of tert-leucine methyl
h
ester hydrochloride 5 equiv of amine used
high selectivity for the C2 isomer. Additionally, 1,3-disubstituted
benzenes reacted well, with 1,3-dimethoxybenzene and metaxylene providing aminated products 40 and 41 in moderate to
good yields and excellent regioselectivity. 1,2-Disubstituted
arenes such as 2-chloroanisole also participated in the
amination, leading to product 42 in 63% yield. More complex
substrates bearing an additional aryl ring afforded anilines 43
and 44 in good yields, with functionalization only occurring on
the more electron-rich ring. Heterocycles also served as efficient
arene coupling partners, with 2,6-dimethoxypyridine and
N-methylindazole providing 45 and 46, respectively, as single
regioisomers in good yields. Moreover, amination of
halogenated heterocycles such as 7-bromo-N-methylindazole
afforded a single regioisomer (47) in good yield.
To highlight the derivatization of complex arenes using this
methodology, fenoprofen, a non-steroidal anti-inflammatory
drug, was subjected to amination with tert-leucine methyl ester,
affording 48 in 73% yield. Gemfibrozil, a lipid-lowering drug,26
also participated in the amination reaction, with valine methyl
ester, to give 49 as a single regioisomer in 32% yield. Clofibrate
and bezafibrate methyl ester, pharmaceuticals that are also
used to lower LDL cholesterol,27 were both functionalized in
moderate yields and good selectivity (50 and 51), further
illustrating the utility for late stage pharmaceutical derivatization.
In our previous work on arene functionalization, we
exploited electrophilic arene cation radicals generated by SET to
the acridinium photoredox catalyst. Since the present system
allows the primary amine to be oxidized to the amine cation
radical, we questioned whether arenes with oxidation potentials
above the reduction potential of the excited state acridinium
could undergo amination. Under slightly modified reaction
conditions, benzene (E1/2ox = +2.75 V vs. SCE) afforded aniline
52 in 40% yield, indicating a pathway for C–H amination not
accessible through an arene cation radical generated by the
acridinium catalyst (Figure 3). Toluene (E1/2ox = +2.42 V vs. SCE)
also underwent amination, affording 53 as a mixture of
regioisomers in 50% combined yield.
Val-OMe•HCl (1 equiv)
t-Bu2-Mes-Acr+ (5 mol %)
TEMPO (40 mol %)
NHR
455 nm LEDs
2:2:1 DCE: arene: pH 8 Buffer
O2, 0.1 M, 15 h
CO2Me
N
H
i-Pr
Me
NH
CO2Me
i-Pr
52; 40% yield
53; 50% yield; 1.2:1:2.1 o:m:p
Figure 3. Amination of benzene and toluene. Reactions were run in 2:2:1
DCE, arene, and pH 8 phosphate buffer at 0.1 M concentration with respect to
the amine limiting reagent.
This article is protected by copyright. All rights reserved.
Accepted Manuscript
Val-OMe•HCl (3 equiv)
Mes-Acr+ (5 mol %)
10.1002/ange.201709523
Angewandte Chemie
COMMUNICATION
R
H
N H
R
NH2
NH2
+e–
E1/2red* = +2.15 V
hν
Mes-Acr+
via: R
When arene
E1/2ox ≤ E*red, Mes-Acr+
–e
–
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
NH
[12]
[13]
[14]
HOO
HOO
O2
Mes-Acr+*
[1]
[11]
R
–H+
Mes-Acr•
–e–
Keywords: organocatalysis · photoredox catalysis · synthesis
O2
HOO
+e–
[15]
[16]
O2
HOO
via:
NH2
or NH2 When arene
E1/2ox > E*red, Mes-Acr+ R
R
Figure 4. Proposed mechanism for direct C–H amination with primary amines
via photoredox catalysis.
In conclusion, we have developed a direct aryl C–H
amination via photoredox catalysis using primary amines.
Further work will be required to extend this protocol to
secondary amines. This methodology is mild and compatible
with a variety of functional groups on both the arene and the
amine, and enables extension of the arene coupling partners to
non-activated aromatics such as benzene.
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
Acknowledgements
[25]
This work was supported by the National Institutes of Health
(NIGMS) Award No. R01 GM120186 and an Eli Lilly Grantee
Award (D.A.N.). A.L. thanks the American Australian Association
for a Chevron Fellowship. This research made use of an
Edinburgh FLS920 emission spectrometer funded by the UNC
EFRC: Center for Solar Fuels, an Energy Frontier Research
Center funded by the U.S. Department of Energy, Office of
Science, Office of Basic Energy Sciences under Award Number
DE-SC0001011. We thank Cole Cruz for his assistance with
spectroscopic measurements. We thank the University of North
Carolina’s Department of Chemistry Mass Spectrometry Core
Laboratory for its assistance with mass spectrometry analysis.
[26]
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This article is protected by copyright. All rights reserved.
Accepted Manuscript
Based on these experiments, we hypothesized that for
benzene and toluene, the reaction can proceed through an
amine cation radical intermediate. The reaction begins with
excitation of Mes-Acr+ with 455 nm LEDs to Mes-Acr+* (Figure
4). The excited state of the catalyst oxidizes the amine to the
cation radical, generating Mes-Acr•. The addition of the arene
forms a cyclohexadienyl radical intermediate that can be
rearomatized using molecular oxygen as originally proposed by
Fukuzumi.28 However, since several arenes in Figure 2 possess
similar oxidation potentials to those of the amine coupling
partner, an arene cation radical could also account for the
observed reactivity.20 As determined by Stern-Volmer
fluorescence quenching analysis (see Supporting Information,
Figure S1), amines and electron-rich arenes both quench the
acridinium excited state, but insufficiently electron-rich arenes
such as toluene do not. Based on these results, insufficiently
electron-rich arenes such toluene cannot undergo amination
through an arene cation radical and instead react via an amine
cation radical pathway. For electron-rich arenes, neither reactive
intermediate can be excluded since both the amine and the
arene quench the acridinium excited state.
10.1002/ange.201709523
Angewandte Chemie
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MeO
+
H2N
organic photooxidant
Me
455 nm LEDs
O2
74 Examples
32–95% yield
MeO
NH
Me
74% yield
•Wide variety of primary amines
including amino acids
•Regiochemistry influenced by
arene substitution
•Stereochemistry preserved
•Scalable through flow
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