Three-Component Aminoarylation of Electron-Rich Alkenes by Merging Photoredox with Nickel Catalysis

Article abstract of DOI:10.1002/anie.202101775

A three-component 1,2-aminoarylation of vinyl ethers, enamides, ene-carbamates and vinyl thioethers by synergistic photoredox and nickel catalysis is reported. 2,2,2-Trifluoroethoxy carbonyl protected α-amino-oxy acids are used as amidyl radical precursors. anti-Markovnikov addition of the amidyl radical to the alkene and Ni-mediated radical/transition metal cross over lead to the corresponding 1,2-aminoarylation product. The radical cascade, which can be conducted under practical and mild conditions, features high functional group tolerance and broad substrate scope. Stereoselective 1,2-aminoarylation is achieved using a L-(+)-lactic acid derived vinyl ether as the substrate, offering a novel route for the preparation of protected enantiopure α-arylated β-amino alcohols. In addition, 1,2-aminoacylation of vinyl ethers is achieved by using an acyl succinimide as the electrophile for the Ni-mediated radical coupling.

Full text of DOI:10.1002/anie.202101775

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Accepted Article
Title: Three-Component Aminoarylation of Electron-Rich Alkenes by
Merging Photoredox with Nickel Catalysis
Authors: Heng Jiang, Xiaoye Yu, Constantin Gabriel Daniliuc, and
Armido Studer
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Three-Component Aminoarylation of Electron-Rich Alkenes by
Merging Photoredox with Nickel Catalysis
Heng Jianga,b, Xiaoye Yua, Constantin G. Daniliuca and Armido Studera,*
Abstract: A three-component 1,2-aminoarylation of vinyl ethers,
enamides, ene-carbamates and vinyl thioethers by synergistic
photoredox and nickel catalysis is reported. 2,2,2-Trifluoroethoxy
carbonyl protected α-amino-oxy acids are used as amidyl radical
precursors. anti-Markovnikov addition of the amidyl radical to the
alkene and Ni-mediated radical/transition metal cross over lead to
the corresponding 1,2-aminoarylation product. The radical
cascade, that can be conducted under practical and mild
conditions, features high functional group tolerance and broad
substrate scope. Stereoselective 1,2-aminoarylation is achieved
using a L-(+)-lactic acid derived vinyl ether as the substrate,
offering a novel route for the preparation of protected enantiopure
α-arylated β-amino alcohols. In addition, 1,2-aminoacylation of
vinyl ethers is achieved by using an acyl succinimide as the
electrophile for the Ni-mediated radical coupling.
pharmaceuticals (see above).[2] As a rare example, the Mazet
group disclosed a Pd-catalysed aminoarylation of dihydrofurans
(Scheme 1d).[8] However, intermolecular three-component
variants are unknown.
Alkene 1,2-difunctionalization serves as a potent strategy to
prepare diverse compounds from easily accessible feedstock
chemicals.[1] Alkene 1,2-aminoarylation by sequential C−N and
C−aryl bond formation is of great interest because the constructed
2-arylethylamine backbone is a common structural motif in
alkaloids and pharmaceuticals (Scheme 1a).[2] Transition-metal
catalysed cyclizing 1,2-aminoarylation delivers N-heterocycles
bearing a benzyl substituent at the 2-position of the ring (Scheme
1b).[3] Such arylating cyclizations can also be achieved via
intramolecular amidyl radical cyclization and metal-mediated aryl
coupling.[4] Intermolecular amidyl radical addition to styrenes and
Cu-catalysed enantioselective arylation was reported by Liu
(Scheme 1c).[5] 1,2-Aminoarylation of aryl alkenes was realized
by Stephenson,[6] where C−N-bond formation was achieved by
amidation of a styrene radical cation with a sulfonamide and -
arylation occurred via a radical Smiles rearrangement. Reversed
regioselectivity for styrene aminoarylation can be obtained by
Meerwein type aryl radical addition and subsequent Ritter
amidation.[7]
However, known methods for intermolecular radical
aminoarylation mainly work on aryl alkenes and reactions with
electron-rich alkenes, such as vinyl ethers, enamides, and ene-
carbamates leading to -aryl--amino alcohols as well as -aryl-
-aminoalkylamines have not been reported. This is surprising
since such substructures are found widespread in
[*]
Dr. H. Jianga,b, Dr. X. Yua, Dr. C. G. Daniliuca, Prof. Dr. A. Studera
aOrganisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraß 40, 48149 Münster, Germany
E-mail: studer@uni-muenster.de
bSchool of Pharmacy, Shanghai Jiao Tong University
No. 800 Dongchuan Rd., 200240 Shanghai, China
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. 1,2-Aminoarylation of alkenes.
Inspired by Ni-catalysed radical alkene difunctionalizations to
construct two geminal C−C bonds,[9] we envisioned that 1,2-
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aminoarylation of electron-rich alkenes could be realized by
synergistic photoredox/Ni-catalysis (Scheme 1d).[10] -Amido-oxy
acids were supposed to be potent amidyl radical precursors,
where N-radical generation can be achieved by SET oxidation
using a photoredox catalyst.[11] After regioselective addition of the
N-radical to the electron-rich alkene,[12] a Ni-mediated C-radical
arylation should terminate the sequence. The Ni-oxidation state
should be modulated by the photoredox catalyst.[13] Notably,
potential side reactions including direct two component C−N
coupling and C−O coupling of -amido-oxy acids with aryl
bromides leading to anilines or esters must be circumvented.[4a,14]
direct coupling to the corresponding anilide was almost entirely
suppressed (entry 4). Noteworthy, the Ir-based catalyst PC-II
gave a comparable yield, whereas with PC-III mainly the C−O
coupling product was obtained (see SI).[15] Only 7% of 4ad was
obtained with PC-IV. Other protecting groups were also examined.
(Perfluorophenyl)methyl carbamate 1f gave 4af in 62% yield
(entry 6), whereas Troc-protected 1e was not an efficient N-
radical precursor (4ae, entry 5). Hexafluoroisopropoxy carbonyl,
acetyl and phenyl sufonyl moieties were found to be inefficient N-
protecting groups for the aminoarylation reaction (4ag-4ai, entry
7-9). Replacing the N-methyl substituent by a methoxy carbonyl
(Moc) group also led to suppression of the 1,2-aminoarylation
(entry 10 and 11).
Table 1. Aminoarylation of 2a using different N-radical precursors 1 and 3a.[a]
Scheme 2. Variation of the aryl bromide. Reactions were performed under the
optimized conditions unless otherwise noted and isolated yields are provided.
Tfoc = 2,2,2-Trifluoroethoxy carbonyl. [a] Aryl chlorides were used instead of
aryl bromides.
[a] Reaction conditions: A mixture of 1 (2 equiv), 2a (4 equiv), 3a (1 equiv), 4-
CzIPN (2.5 mol%), Ni(dtbbpy)Br2 (10 mol%), Cs2CO3 (2 equiv) in CH3CN (0.1
M) was irradiated by two Kessil blue LEDs (45 W each) at 30 °C for 16 h.
Isolated yields are provided. [b] Identical yields were obtained with PC-I or PC-
II. [c] 2 mol% PC-III used. [d] 5 mol% PC-IV used.
The N-radical precursor 1d and acceptor 2a were chosen to
examine reaction scope with respect to the bromide component
(Scheme 2). Various electron withdrawing groups including acyl,
cyano, sulfonyl ester, formyl, trifluoromethyl and ester at the aryl
bromide are tolerated, providing 4b-4k in good to excellent yields
We commenced the study by using Cbz-protected N-radical
precursors 1a and 1b in combination with butyl vinyl ether (2a)
and methyl 4-bromobenzoate (3a) applying synergistic
photoredox and nickel catalysis (Table 1). The desired 4aa or 4ab
was not isolated with 4-CzIPN as the redox catalyst in
combination with Ni(dtbbpy)Br2 and Cs2CO3 in acetonitrile at room
temperature under blue light irradiation (entry 1 and 2). Tuning N-
radical reactivity by switching to the electron-deficient 2,2,2-
trifluoroethyloxy carbonyl protecting group provided traces of 4ac.
4-CF3CH2OC(O)NHC6H4CO2Me (27%) through direct C−N
coupling was formed as major compound (entry 3).[4a] To our
delight, the 1,2-aminoarylation compound 4ad was the major
product (85%) by using the N-radical precursor 1d,[11b],[14] and
(61-89%).
A worse result was obtained for 1-bromo-4-
chlorobenzene (4l, 33%) due to sluggish oxidative addition. Along
these lines, aryl bromides bearing electron donating groups did
not engage in the cascade due to failure of the oxidative addition
with Ni(0). For 4-bromoanisole, an additional ligand screening
was performed, but aminoarylation could not be achieved (see SI).
However, aminoarylation products were obtained in moderate to
good yields by using bromopyridines, providing an alternative
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pathway for alkene aminopyridination going beyond restrictions of
three-component Minisci reactions (4m-4t, 55-88%).[16] In
addition, halogenated pyrimidine, quinolone and benzothiazole
heterocycles engaged in the reaction and 4u-4w were isolated in
moderate yields (47-53%).
Next, the scope with respect to the alkene acceptor was examined
using 3a and 1d as reaction partners (Scheme 3). Ethyl,
cyclohexyl and tert-butyl vinyl ethers afforded very good results
(5a-5c, 81-87%), whereas phenyl vinyl ether provided a slightly
lower yield (5d, 65%). A free hydroxyl group was tolerated (see
5e, 77%). Aminoarylation of 3,4-dihydropyran provided 5f in 51%
yield with complete trans-selectivity. However, 1,2-disubstituted
linear vinyl ethers did not work, due to the slower initial N-radical
addition to the alkene (see SI). Consequently, direct amidation of
the aryl-Ni(II)-species is faster. This finding further underlines the
challenge of the introduced alkene aminoarylation. Ene-
carbamates (see 5g-5j and 5o) and N-vinyl amides (5k-5m)
served as N-radical acceptors to give protected -aryl--
aminoalkylamines. In this series, the less nucleophilic enamides
afforded lower yields. Notably, excellent diastereoselectivity was
obtained with the chiral N-vinyl oxazolidinone (see 5o). The
relative configuration was assigned by X-ray crystal structure
analysis.[17] Vinyl thioethers that are generally not compatible with
photoredox conditions also worked (5n, 53%). The N-methyl
group of 1d could be substituted by other alkyl groups such as
ethyl (5p), n-butyl (5q), benzyl (5r), cyclopropylmethyl (5s),
cyclohexylmethyl (5t) and 2-methoxyethyl (5u). Natural product
derivatives, including L-valinol (5v), (R)-3-hydroxybutyric acid
(5w), L-tyrosine (5x), (±)-isoborneol (5y), (–)-menthol (5z), D-
glucose (5aa) and estrone (5ab) derived vinyl ethers afforded the
aminoarylation products in good to satisfactory yields, albeit with
low or no stereoselectivity.
Scheme 3. Variation of the alkene 2. Reactions were performed under the
optimized conditions unless otherwise noted and isolated yields are provided.
Tfoc = 2,2,2-Trifluoroethoxy carbonyl. [a] 4'-Bromoacetophenone was used and
diastereoselectivity determined on 5f, obtained after Tfoc removal. [b] PC-II (2
mol%) was used. [c] Overall yield of 5h after Boc removal. [d] 6 equiv. 2a used.
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analysis on 11, obtained upon alcohol deprotection by
transesterification and cyclization under basic conditions.[17]
Scheme 4. Aminoacylation of alkene 2a. Reaction conditions: A mixture of 1d
(2 equiv), 2a (4 equiv), 6 (1 equiv), PC-II (2 mol%), Ni(bpy)Cl2 (20 mol%),
Cs2CO3 (2 equiv) in acetone (0.05 M) was irradiated by two Kessil blue LEDs
(45 W each) at 30 °C for 5 h. Isolated yields are provided.
After extensive reaction screening we found that acyl
succinimides 6 also engage as “electrophiles” in the three-
component coupling (Scheme 4).[18] Thus, N-alkylcarbonyl
succinimides 6a-6e reacted with the N-radical precursor 1d and
vinyl ether 2a in the presence of PC-II (2 mol%), Ni(bpy)Cl2 (20
mol%) and Cs2CO3 in acetone to the aminoacylation products 7a-
7e (55-61%). Aroyl succinimides 6f and 6g showed slightly lower
efficiencies, affording the protected -amino ketones 7f and 7g in
37 and 40% yields.
Scheme 6. Mechanistic studies and proposed catalysis cycle.
To elucidate the mechanism, control experiments were conducted.
Aminoarylation did not occur in the absence of either photoredox
or nickel catalyst. The N-radical could not be generated from the
NH-amide, as demonstrated by replacing 1d with 12. Neither the
aminoarylation product 4a nor the aniline byproduct was formed
(Scheme 6). Replacing acid 1d with the methyl ester 13 did not
give any transformation, showing that amidyl radical generation
does not occur via homolytic or reductive N−O bond cleavage.
Based on these results and previous reports, the following
mechanism is proposed. The catalysis cycle starts by photo-
excitation of 4-CzIPN upon irradiation to generate the excited
Scheme 5. Preparation of an optically pure protected -amino alcohol.
redox catalyst which oxidizes carboxylate A,[21] formed by
Considering the enantioselective aminoarylation of butyl vinyl
ether (2a), all attempts using chiral Ni-ligands failed. We therefore
followed the chiral auxiliary approach and sought to prepare an
optically pure protected amino alcohol through diastereoselective
aminoarylation of readily accessed L-(+)-lactic acid derived vinyl
ether 8.[19] Acceptor 8 underwent aminoarylation to ester 9 with
complete stereoselectivity (Scheme 8). The chiral auxiliary was
removed in a two-step sequence by first cleaving the tert-butyl
ester (TFA) and subsequent radical decarboxylative oxidation to
give the optically pure protected β-amino alcohol 10.[20] The
absolute configuration was assigned by X-ray crystal structure
deprotonation of 1, to generate the carboxyl radical B and the
[22]
reduced 4-CzIPN
.
Sequential fragmentation of CO2 and
acetone generates the electrophilic N-radical C,[11] which then
adds to alkene 2 to provide the radical D. 4-CzIPN gets
oxidized by Ni(I) to close the photoredox cycle, thereby generating
a Ni(0)-species that undergoes an oxidative addition with the aryl
bromide to provide a Ni(II)-Ar intermediate. Trapping of the radical
D with the Ni(II)-Ar complex leads to the Ni(III) species E.
Reductive elimination gives 4 or 5 along with a Ni(I) species,
closing the nickel catalysis cycle.[13] Aminoacylation works in
analogy by replacing the bromoarene with the acylated
succinimide.
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[6]
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In summary, we reported a three-component aminoarylation of
electron rich alkenes through synergistic photoredox/nickel
catalysis. 2,2,2-Trifluoroethoxy carbonyl protected -amino oxy
acids are used as N-radical precursors and bromoarenes serve
as the electrophilic coupling partners. Compared with traditional
strategies such as addition of a Grignard reagent to glycine
aldehyde derivatives,[23] this three component cascade features
mild conditions and broad scope, providing a practical approach
to the modular synthesis of -aryl--amino alcohols and -aryl--
aminoalkylamines. Optically pure -aryl--amino alcohols can be
prepared using cheap lactic acid as a chiral auxiliary. By using N-
acylated succinimides as reaction partners, -aminoketones are
accessible.
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Acknowledgements
This work was supported by the European Research Council
(ERC Advanced Grant agreement No.692640) and Alexander von
Humboldt Foundation (postdoctoral fellowship to X. Y.). We thank
Prof. Zhankui Sun (Shanghai Jiao Tong University) for assistance
during revision.
Conflict of Inerest
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The authors declare no conflict of interest.
Keywords: Aminoarylation of alkenes • synergistic catalysis •
amidyl radical • photoredox catalysis • nickel catalysis
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10.1002/anie.202101775
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
H. Jiang, X. Yu, C. G. Daniliuc, A.
Studer*
Page No. – Page No.
Three-Component Aminoarylation of
Electron-Rich Alkenes by Merging
Photoredox with Nickel Catalysis
1,2-aminoarylation of vinyl ethers, enamides, ene-carbamates and vinyl thioethers by synergistic
photoredox and nickel catalysis is reported. The radical cascade features high functional group tolerance
and broad substrate scope. By using the chiral auxiliary approach, stereoselective 1,2-aminoarylation is
achieved. Using the same strategy, 1,2-aminoacylation of vinyl ethers is achieved by using an acyl
succinimide as the electrophile for the Ni-mediated radical coupling step.
This article is protected by copyright. All rights reserved.