Copper-Catalyzed Aminoheteroarylation of Unactivated Alkenes through Distal Heteroaryl Migration

Article abstract of DOI:10.1021/acscatal.1c01001

We report a copper-catalyzed aminoheteroarylation of unactivated alkenes to access valuable heteroarylethylamine motif. The developed reaction features a copper-catalyzed intermolecular electrophilic amination of the alkenes followed by a migratory heteroarylation. The method applies to alcohol-, amide-, and ether-containing alkenes, overcoming the common requirement of a hydroxyl motif in previous migratory difunctionalization reactions. This reaction is effective for the introduction of diverse aliphatic amines and has good functional group tolerance, which is particularly useful for rich functionalized heteroarenes. This migration-involved reaction was found well suited as a powerful ring-expansion approach for the construction of medium-sized rings that are in great demand in medicinal chemistry.

Full text of DOI:10.1021/acscatal.1c01001

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Research Article
Copper-Catalyzed Aminoheteroarylation of Unactivated Alkenes
through Distal Heteroaryl Migration
Yungeun Kwon,† Wei Zhang,† and Qiu Wang*
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ABSTRACT: We report a copper-catalyzed aminoheteroarylation of unactivated alkenes to access valuable heteroarylethylamine
motif. The developed reaction features a copper-catalyzed intermolecular electrophilic amination of the alkenes followed by a
migratory heteroarylation. The method applies to alcohol-, amide-, and ether-containing alkenes, overcoming the common
requirement of a hydroxyl motif in previous migratory difunctionalization reactions. This reaction is effective for the introduction of
diverse aliphatic amines and has good functional group tolerance, which is particularly useful for rich functionalized heteroarenes.
This migration-involved reaction was found well suited as a powerful ring-expansion approach for the construction of medium-sized
rings that are in great demand in medicinal chemistry.
KEYWORDS: unactivated olefin, copper, heteroaryl migration, N-centered radical, aminoheteroarylation
he heteroarylethylamine core is an important structural
Tmotif found prevalently in bioactive molecules and
pharmaceuticals, such as conserved in many opioid receptor
ligands (Figure 1).1 Their importance as medicinally privileged
functionality has motivated the development of effective
methods to access this structural motif in a rapid and diverse
manner. Toward this end, an appealing strategy is 1,2-
aminoheteroarylation of alkenes as a straightforward approach
that enables direct installation of an amino group and a
heteroaryl group on alkenes.2,3 Particularly, the intermolecular
aminoheteroarylation of unactivated alkenes presents a
general, desirable manner for the rapid and modular
construction of molecular diversity and complexity. A series
of methods have been developed on nitrogen-tethered
unactivated alkenes to afford azacyclic skeletons bearing
different aryl groups by an elegant amino cyclization and a
subsequent intermolecular C−C bond formation.4 Yet, for the
flexible installation of diverse amino functionalities, especially
aliphatic amines that feature attractive biological activities, a
few aminoheteroarylation reactions that involved an inter-
molecular C−N bond formation have been achieved (Scheme
1).5 A photo-catalyzed alkene aminopyridylation reaction was
reported to install secondary amides and 2-pyridyl groups
(Scheme 1a).5a The palladium-catalyzed aminoarylation
reaction reported by the Engle’s group was successful for an
intermolecular installation of amide, sulfonamides, and
imidazole (Scheme 1b).5b
Zhu’s group has developed a nickel-catalyzed reductive
aminoarylation for the preparation of aliphatic amines but only
on iodoarene-tethered alkenes (Scheme 1c).5e The versatile
assembly of diverse heteroarylethylamine motifs remains a
challenge for catalytic alkene aminoheteroarylation. To address
this problem, we envisioned an alkene amino migratory
heteroarylation strategy by leveraging temporary installation of
a heteroaryl group onto a remote carbonyl or iminyl group
(Scheme 1d). This paper reports the development of a copper-
catalyzed migratory aminoheteroarylation reaction for the
creation of diverse heteroarylethylamines motifs.
The key to the development of a new catalytic protocol is
use of O-benzoyl-N-hydroxylamines as electrophilic aminating
reagents8 in the copper-catalyzed amination step. This
intermolecular C−N bond formation not only enables the
Received: March 3, 2021
Revised: June 17, 2021
Published: July 2, 2021
https://doi.org/10.1021/acscatal.1c01001
© 2021 American Chemical Society
ACS Catal. 2021, 11, 8807−8817
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Figure 1. Heteroarylethylamines as an important motif commonly found in bioactive natural products and molecules.
Scheme 1. Aminoheteroarylation Reactions of Unactivated Alkenes via Intermolecular C−N Bond Formation
installation of diverse electron-rich aliphatic amines that were
problematic in most existing methods but also positions the
formation of carbon-radical intermediates that are expected to
undergo a distal migration for the assembly of the heteroarene.
Our work was inspired by radical-based functional group
migration-involved transformations, particularly alcohol-assis-
ted alkene migratory functionalization.6,7 Different from
previous migratory reactions, the catalytic protocol described
here is effective on alcohol-, amide-, and even ether-containing
alkenes, overcoming a common limitation for the requirement
of a hydroxyl moiety and presenting the synthetic potential for
broader applications. Furthermore, our method is well suited
for a rapid approach to access medium-sized rings via the form
of ring expansion, particularly for heteroarene-bearing
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a
medium-sized ketones that are highly valued in medicinal
chemistry, yet would be difficult to access otherwise.
Table 1. Optimization of Aminoheteroarylation of Alkene
Our studies began with the aminoheteroarylation reaction of
1-phenyl-1-(benzothiazolyl)pentenol 1a using O-benzoyl-N-
hydroxylmorpholine 2 as an amine precursor (Table 1). With
Cu(OTf)2 as the catalyst and TsOH·H2O as an additive, the
reaction at 80 °C readily proceeded to afford the desired
product 3a (entry 1). Yet, significant amounts of cyclization
and elimination byproducts were formed (see the Supporting
Information). To minimize these side reactions, shorter
reaction times and lower temperatures were tested (entries
2−4). When the reaction was run at 60 °C for 20 min, the
formation of 3a was improved to 73% yield (entry 3). We also
tested the reaction of 1-phenyl-1-(thiazolyl)pentenol 1b at
different temperatures (entries 5−7). The desired 1,2-
aminothiazole product 3b was formed in 77% yield most
effectively when the reaction was run at 80 °C for 5 min (entry
5). Control experiments showed that both copper catalyst and
the acid additive are imperative in this reaction (entries 8 and
9). Although we chose Cu(OTf)2 as standard conditions, the
reactions were also effective with other Cu(I) and Cu(II) salts
as the catalysts (see the Supporting Information).
b
entry
1a/1b
T (°C)
time
3a/3b (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1b
1b
1a
1a
80
80
60
40
80
60
40
60
60
1 h
20
66
70 (73)
5 min
20 min
4.5 h
5 min
20 min
5 h
c
65
c
cd
72 (77) (72)
65
66
trace
ND
e
8
f
20 h
72 h
9
a
Reaction conditions: 1a or 1b (0.2 mmol, 1.0 equiv), 2 (2.0 equiv),
Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), and 1,2-dichloro-
ethane (DCE) (1 mL). The conditions in bold gave best results.
Yields determined by H NMR spectroscopy with CH2Br2 as an
internal standard. Isolated yields in parentheses. Run on 2.0 mmol
b
1
c
d
e
f
scale. No acid was added. No copper catalyst was added.
a
Table 2. Generality of Amine Precursors in Aminoheteroarylation Reactions
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 4 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1 mL), and 80 °C. Isolated
b
c
d
e
f
yields shown. Run with 4f (3.0 equiv). Run at 40 °C. Run with 4j (4.0 equiv) and TsOH·H2O (3.0 equiv) at 60 °C. Run at 40 °C. Run with
4n (3.0 equiv) and TsOH·H2O (2.25 equiv) at 60 °C. Run with 1b (0.1 mmol, 1.0 equiv), 4o (3.0 equiv), and TsOH·H2O (6.0 equiv).
g
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a
Table 3. Heteroaryl Groups in Aminoheteroarylation Reactions
a
Reaction conditions: 7 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1 mL), and 80 °C. Isolated
b
c
d
yields shown. Run with 2 (3.0 equiv) and TsOH·H2O (3.0 equiv). Run with 7h (0.1 mmol, 1.0 equiv), and TsOH·H2O (3.0 equiv). Run with
7k (2.0 equiv), 2 (0.2 mmol, 1.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (0.6 equiv), DCE (2 mL), and 80 °C.
With effective conditions established, we studied the scope
of O-benzoylhydroxylamines for the aminoheteroarylation of
alkene (Table 2). Starting from 1a or 1b, the reactions using
piperidine and 3-methylpiperidine-derived hydroxylamines as
the amine precursors smoothly afforded benzothiazole- and
thiazole-containing amine products (5a−5b and 6a−6b),
respectively. Other six-membered cyclic amine precursors
bearing different functional groups were well tolerated,
providing a diverse range of β-aminoethyl thiazole derivatives
from the reactions of 1b, such as ester-containing piperidine
(6c), N-Bz- (6d), N-Cbz- (6e), and N-Boc-(6f) piperazines,
bridged bicyclic morpholine (6g) as well as thiomorpholine
(6h). Five- and seven-membered cyclic amine precursors,
specifically pyrrolidine and azepane, also participated in this
reaction, affording 6i and 6j in 20 and 45% yield, respectively.
The aminoheteroarylation reactions with N-Cbz- and N-Boc-
protected 1,4-diazepane precursors successfully delivered 6k
and 6l. The reaction was also applicable to acyclic amine
precursors, demonstrated in the formation of diethylamine 6m
and methylphenethylamine 6n in moderate yields. Noticeably,
primary amine was also successfully installed on the alkene to
give 6o in 69% yield.
We next examined the generality of this alkene migratory
difunctionalization strategy on diverse heteroarenes using
alkene substrates bearing different heteroaryl groups (Table
3). The reactions of various azoles were found to afford the
desired 1,2-amino azole products, including oxazole (8a),
benzoxazole (8b), imidazole (8c), benzimidazole (8d), and
4,5-dimethylthiazole (8e). Six-membered azaheteroaryl groups
were found to be effective in the formation of the 2-pyridyl
(8f), 4-pyridyl (8g), isoquinolinyl (8h) products, and more
electron-deficient pyrimidine (8i). Structurally, more complex
caffeine-containing product 8j was also formed in good yields.
Even the adenosine-derived alkene was compatible with this
migration, furnishing the desired product 8k in 38% yield.
These examples have demonstrated the generality of this
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a
Table 4. Aminoheteroarylation of Alkenes Bearing Two Heteroaryl Groups
a
Reaction conditions: 9 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (0.3 mmol, 1.5 equiv), DCE (1 mL),
and 80 °C. Isolated yields shown.
migratory aminoheteroarylation strategy on a broad scope of
heteroarenes, including structurally complex ones that have
been less explored but are important such as caffeine and
adenosine derivatives. It should also be noted that electron-
rich heteroaryl groups were found unsuccessful under the
current conditions, as seen in the case of benzofuryl analogue
8l.
We further investigated alkene substrates bearing two
heteroaryl groups to evaluate the migration selectivity and
the impact of the second heteroaryl group (Table 4).
Subjecting bis-thiazole-containing alkene 9a to standard
reaction conditions led to the desired product 10a in 35%
yield, a significant drop in comparison to the formation of
analogous product 3b in 77% yield. Selective formation of β-
thiazolyl amine products 10b−10d revealed that thiazolyl
migration was favored over the migration of thienyl,
benzothienyl, and N-tosylindolyl group. Interestingly, benzo-
furyl- and thiazolyl-substituted substrate 9e afforded two
isomers in a 1:1.3 ratio that slightly favored the migration of
benzofuryl (10e′) over thiazolyl (10e). Note that benzofuryl
migration in the analogous phenyl-substituted product 8l was
unsuccessful. Thus, the change from phenyl to thiazolyl would
contribute to the viability of benzofuryl migration in forming
product 10e′. The reaction of pyridyl thiazole-containing
alkene 9f also gave two products 10f and 10f′ in a 6.3:1 ratio,
via the migration of thiazolyl and pyridyl, respectively. Finally,
imidazolyl thiazole-containing alkene 9g afforded both thiazole
(10g) and imidazole migration product (10g′) in comparable
yields. In comparison to the formation of 3b (77%), 8f (43%),
and 8c (41%) from mono-azaheteroaryl substrates, the poorer
yields observed in the formation of 10a (35%), 10f and 10f′
(9%) as well as 10g and 10g′ (36%) from bis-azaheteroaryl-
containing substrates indicated that the electronic nature of
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a
Table 5. Generality of Alkenes in Aminoheteroarylation Reactions
a
Reaction conditions: 11 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1 mL), and 80 °C. Isolated
b
yields shown. Detected by LC/MS.
nonmigratory substituent affects the efficiency of the
heteroaryl migration.
Cyclic alkene substrates were also evaluated. A α-tetralone-
derived precursor (as a mixture of 1:1 diastereomers)
delivered 12n in 69% yield (a mixture of 1:1 diastereomers),
which indicated that this migration process could occur via
both cis and trans fused (5:6) bicyclic transition states. Cyclic
internal alkenes successfully provided 1,2-aminothiazole
products 12o and 12p, via fused 5:6 and 5:5 bicyclic transition
states, respectively. The diminished yields of 12o−12p
resulted from competing pathways that led to intramolecular
aminooxygenation8b and aza-Wacker type9 byproducts.
We also examined alkenes 11q−11s under the standard
reaction conditions to gain more insight on the reactivity of
1,n-migration involved in this aminoheteroarylation trans-
formation. The formation of 12q and 12s, presumably via 1,3-
and 1,6-migration, was observed in a trace amount by LC/MS,
while aza-Wacker type allylic amination products were formed
instead. On the other hand, the 1,5-migration product 12r was
smoothly formed in 59% yield. These results support that the
readily formed five- and six-membered cyclic transition states
We also investigated the generality of alkenes in this
aminoheteroarylation reaction using different thiazole-bearing
unsaturated alcohols 11 (Table 5). First, all the reactions of 1-
phenyl-substiuted tertiary alcohols provided desired 1,2-
aminothiazole-containing products, regardless of the presence
of electron-donating or electron-withdrawing groups on the
phenyl ring (12a−12e). The alkyl-substituted tertiary alcohols
were also capable of delivering thiazole migration products
(12f−12j). The substrates bearing more sterically bulky alkyl
groups resulted in higher efficiencies, suggesting that the steric
bulkiness would facilitate the migration of neighboring thiazole
group. The backbone substituents of the alkenes were found to
affect the transformation dramatically, as seen in the cases of
12k−12l, wherein the varied gem-dimethyl position resulted
in steric interference hindering the migration step. This
reaction from 1,1-disubstituted alkene was capable of forming
quaternary carbon-containing product 12m in 64% yield.
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a
Scheme 2. Competing Reaction Pathways
a
Reaction conditions: 11 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1 mL), and 80 °C. Isolated
yields shown.
facilitated the 1,4- and 1,5-migratory aminoheteroarylation
reactions, while 1,3- and 1,6-migration is hampered by
unfavorable four- and seven-membered transition-state ring
formation.
To probe radical intermediates that may be involved in the
migration step, control experiments were performed with 1b
and 11r under the standard reaction conditions, in the
presence of a radical scavenger (Scheme 3a). When 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was present, the
reactions of 1b and 11r provided the reduced yield of
migrated heteroarylation products and resulted in the
formation of TEMPO-trapped products 17 and 18,
respectively. The addition of 2,6-di-tert-butyl-4-methylphenol
(BHT) also deteriorated the formation of β-aminoethyl
thiazole product and gave rise to BHT-derivatives 19 and
20. The formation of 17−20 all implied the presence of
nitrogen- and carbon-radical species under the reaction
conditions. Based on these experimental results, a plausible
reaction mechanism is proposed for the aminoheteroarylation
reaction (Scheme 3b). The active Cu(I) catalyst can be
generated from the Cu(II) precatalyst through disproportio-
nation.10 The oxidative addition of O-benzoylhydroxylamine
to Cu(I) catalyst would generate an amide Cu(III) species (A)
or a Cu(II) nitrogen-based radical complex (A′). Subsequent
intermolecular amination of alkene 1b through either (A) or
(A′) would produce the corresponding Cu(III) species (B) or
a carbon radical (B′). Note that the electron-rich amine group
would be protonated in the presence of TsOH.11 The
migration of the heteroaryl group onto the carbon radical
During the investigation of these alkene aminoheteroar-
ylation reactions, we observed several possible competing
reaction pathways (Scheme 2). For example, subjecting
styrene-derived substrate 11t to standard reaction conditions
led to the formation of thiazolyl-substituted alkene 13 in 46%
yield, presumably owing to the elimination-prone ammonium
species under acidic conditions. Another common competing
pathway is the formation of cyclic ether products by an
intramolecular aminooxygenation reaction. For example, the
reaction of conjugated diene precursor 11u formed cyclic
ether 14 exclusively, with no desired product 12u observed.
The reaction of carvone derivative 11v also gave amino
oxycyclization product 15, as the migration would involve a
conformationally strained bicyclic transition state. Interest-
ingly, the reaction of another carvone derivative 11w provided
aza-Wacker type allylic amination product 16 as the major
product, when the oxycyclization was conformationally
disfavored. The unsuccessful migration of the thiazolyl group
placed at the opposite side of the alkene in both substrates 11v
and 11w supported the presence of five-membered cyclic
transition state for the 1,4-heteroaryl migration.
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Scheme 3. Mechanistic Studies on Aminoheteroarylation Reactions
a
b
Run under standard conditions with TEMPO (1.0 equiv). Run under standard conditions with BHT (1.0 equiv). Isolated yields shown.
may occur either through a cyclic Cu(III) intermediate (C) or
via an alkyl radical intermediate (C′). Subsequent C−C σ-
bond breaking would provide a hydroxyalkyl Cu(III)
intermediate (D) or a hydroxyalkyl radical (D′),12 finally
leading to the formation of the desired product by an
elimination step (from D) or a SET oxidation (from D′), as
well as the regeneration of the Cu(I) catalyst.
Based on the mechanistic hypothesis, we expect that this
aminoheteroarylation strategy was potentially extendable
beyond alcohol-containing alkenes in previous migratory
difunctionalization reactions. We examined the aminoheter-
oarylation conditions on alkene-containing α-tertiary amides
and ether derivatives (Scheme 4). Both sultam 21a and
phosphinamide 21b were found effective to promote the
migration functionalization in a manner analogous to tertiary
alcohols. N-sulfonylimine 22 from 21a was successfully
isolated in 41% yield, whereas N-phosphinylimine from 21b
was not stable under acidic conditions, with ketone product 3b
obtained in 52% yield. Furthermore, the reactions of analogous
methyl ethers 23a−23b also afforded the desirable products
3b and 8f. These examples demonstrated that this amino-
heteroarylation is applicable to nonalcohol substrates and is
not limited by the presence of a hydroxyl moiety which was
commonly required in previous migration methods. Excitingly,
this reaction proved to be a viable strategy for the synthesis of
cyclic ketone systems. Subjecting 24a and 24b to standard
conditions readily constructed eight- and nine-membered
cyclic amines 25a and 25b, respectively. Such ring-expansion
reactions present an attractive, useful approach to rapidly
access medium-sized nitrogen-containing ring systems known
to be synthetically challenging yet highly desirable in medicinal
chemistry.13
In summary, we have developed copper-catalyzed amino-
heteroarylation of alkenes for the synthesis of valuable
heteroarylethylamine motifs. This method features selective
migration, good tolerance of functional groups, as well as a
broad scope of alkenes, heteroarenes, and amines under mild
conditions. Mechanistic studies have implied the presence of
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a
Scheme 4. Expanding the Generality and Application of Alkene Aminoheteroarylation
a
b
Reaction conditions: alkene (1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE, and 80 °C. Run with 2 (3.0 equiv),
c
TsOH·H2O (2.0 equiv), DCE, and 80 °C. Run with 2 (5.3 equiv), TsOH·H2O (4.8 equiv), DCE, and 80 °C. Isolated yields shown.
nitrogen- and carbon-radical species under reaction conditions.
Such an alkene migratory aminoheteroarylation reaction is also
well suited as a rapid approach to construct medium-sized
rings.
AUTHOR INFORMATION
Corresponding Author
■
Qiu Wang − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States;
orcid.org/0000-0002-6803-9556; Email: qiu.wang@
duke.edu
ASSOCIATED CONTENT
■
sı
Authors
* Supporting Information
Yungeun Kwon − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
Wei Zhang − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01001.
Condition optimizations; experimental procedures;
compound characterization; and NMR spectra (PDF)
Complete contact information is available at:
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(4) (a) Zeng, W.; Chemler, S. R. Copper(II)-Catalyzed
Enantioselective Intramolecular Carboamination of Alkenes. J. Am.
Chem. Soc. 2007, 129, 12948−12949. (b) Rosewall, C. F.; Sibbald, P.
A.; Liskin, D. V.; Michael, F. E. Palladium-Catalyzed Carboamination
of Alkenes Promoted by N-Fluorobenzenesulfonimide via C−H
Activation of Arenes. J. Am. Chem. Soc. 2009, 131, 9488−9489.
(c) Bagnoli, L.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Scarponi, C.;
Tiecco, M. Diastereoselective Synthesis of Hexahydro-3H-pyrrolyzin-
3-ones through Pd-Catalyzed Carboamination. J. Org. Chem. 2010,
75, 2134−2137. (d) Brenzovich, W. E., Jr.; Benitez, D.; Lackner, A.
D.; Shunatona, H. P.; Tkatchouk, E.; Goddard III, W. A.; Toste, F. D.
Gold-Catalyzed Intramolecular Aminoarylation of Alkenes: C−C
Bond Formation through Bimolecular Reductive Elimination. Angew.
Chem., Int. Ed. 2010, 49, 5519−5522. (e) Zhang, G.; Cui, L.; Wang,
Y.; Zhang, L. Homogeneous Gold-Catalyzed Oxidative Carboheter-
ofunctionalization of Alkenes. J. Am. Chem. Soc. 2010, 132, 1474−
1475. (f) Sahoo, B.; Hopkinson, M. N.; Glorius, F. Combining Gold
and Photoredox Catalysis: Visible Light-Mediated Oxy- and Amino-
arylation of Alkenes. J. Am. Chem. Soc. 2013, 135, 5505−5508.
(g) Faulkner, A.; Scott, J. S.; Bower, J. F. An Umpolung Approach to
Alkene Carboamination: Palladium Catalyzed 1,2-Amino-Acylation,
-Carboxylation, -Arylation, -Vinylation, and -Alkynylation. J. Am.
Chem. Soc. 2015, 137, 7224−7230. (h) Muriel, B.; Orcel, U.; Waser,
J. Palladium-Catalyzed Carboamination of Allylic Alcohols Using a
Trifluoroacetaldehyde-Derived Tether. Org. Lett. 2017, 19, 3548−
3551. (i) Yang, H.; Pathipati, S. R.; Selander, N. Nickel-Catalyzed
1,2-Aminoarylation of Oxime Ester-Tethered Alkenes with Boronic
Acids. ACS Catal. 2017, 7, 8441−8445. (j) Zheng, S.; Gutiérrez-
https://pubs.acs.org/10.1021/acscatal.1c01001
Author Contributions
†Y.K. and W.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from Duke
University and the National Institutes of Health
(GM118786). The authors thank Dr. Peter Silinski (Duke
University) for the assistance with high-resolution mass
spectrometry data.
REFERENCES
■
(1) (a) Kruegel, A. C.; Gassaway, M. M.; Javitch, J. A.; Sames, D.
Opioid Receptor Modulators. WO Patent WO2016086158A12016.
(b) Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.; Iversen,
L. L.; Kneen, C.; MacLeod, A. M.; Merchant, K. J.; Snow, R. J.;
Baker, R. Novel quinuclidine-based ligands for the muscarinic
cholinergic receptor. J. Med. Chem. 1990, 33, 1128−1138.
(c) Dean, D. K.; Lovell, P. J.; Takle, A. K. Imidazole Derivatives
and Their Use as Raf Kinase Inhibitors. WO Patent
WO2001038324A22001. (d) Gong, P. K.; Blough, E.; Brieaddy, L.
E.; Huang, X.; Kuhar, M. J.; Navarro, H. A.; Carroll, F. I. Synthesis,
Monoamine Transporter Binding, Properties, and Functional Mono-
amine Uptake Activity of 3β-[4-Methylphenyl and 4-Chlorophenyl]-
2β-[5-(Substituted phenyl)thiazol-2-yl]tropanes. J. Med. Chem. 2007,
50, 3686−3695.
́
Bonet, A.; Molander, G. A. Merging Photoredox PCET with Ni-
Catalyzed Cross-Coupling: Cascade Amidoarylation of Unactivated
Olefins. Chem 2019, 5, 339−352. (k) Angelini, L.; Davies, J.;
Simonetti, M.; Sanz, L. M.; Sheikh, N. S.; Leonori, D. Reaction of
Nitrogen-Radicals with Organometallics Under Ni-Catalysis: N-
Arylations and Amino-Functionalization Cascades. Angew. Chem.,
Int. Ed. 2019, 58, 5003−5007.
(2) (a) Jiang, H.; Studer, A. Intramolecular radical carboamination
of alkenes. Chem. Soc. Rev. 2020, 49, 1790−1811. (b) Schultz, D. M.;
Wolfe, J. P. Recent Developments in Pd-Catalyzed Alkene Amino-
arylation Reactions for the Synthesis of Nitrogen Heterocycles.
Synthesis 2012, 44, 351−361.
(5) (a) Moon, Y.; Park, B.; Kim, I.; Kang, G.; Shin, S.; Kang, D.;
Baik, M.-H.; Hong, S. Visible light induced alkene aminopyridylation
using N-aminopyridinium salts as bifunctional reagents. Nat.
Commun. 2019, 10, No. 4117. (b) Liu, Z.; Wang, Y.; Wang, Z.;
Zeng, T.; Liu, P.; Engle, K. M. Catalytic Intermolecular
Carboamination of Unactivated Alkenes via Directed Amino-
palladation. J. Am. Chem. Soc. 2017, 139, 11261−11270. (c) Matcha,
K.; Narayan, R.; Antonchick, A. P. Metal-Free Radical Azidoarylation
of Alkenes: Rapid Access to Oxindoles by Cascade C−N and C−C
Bond-Forming Reactions. Angew. Chem., Int. Ed. 2013, 52, 7985−
7989. (d) Li, Z.; Zhang, M.; Zhang, Y.; Liu, S.; Zhao, J.; Zhang, Q.
Multicomponent Cyclopropane Synthesis Enabled by Cu-Catalyzed
Cyclopropene Carbometalation with Organoboron Reagent: Enan-
tioselective Modular Access to Polysubstituted 2-Arylcyclopropyl-
amines. Org. Lett. 2019, 21, 5432−5437. (e) He, J.; Xue, Y.; Han, B.;
Zhang, C.; Wang, Y.; Zhu, S. Nickel-Catalyzed Asymmetric Reductive
1,2-Carboamination of Unactivated Alkenes. Angew. Chem., Int. Ed.
2020, 59, 2328−2332. (f) Ozols, K.; Onodera, S.; Woz′niak, Ł.;
Cramer, N. Cobalt(III)-Catalyzed Enantioselective Intermolecular
Carboamination by C−H Functionalization. Angew. Chem., Int. Ed.
2021, 60, 655−659.
(6) For recent reviews, see: (a) Chen, Z.; Zhang, X.; Tu, Y. Radical
aryl migration reactions and synthetic applications. Chem. Soc. Rev.
2015, 44, 5220−5245. (b) Li, W.; Xu, W.; Xie, J.; Yu, S.; Zhu, C.
Distal radical migration strategy: an emerging synthetic means. Chem.
Soc. Rev. 2018, 47, 654−667. (c) Wu, X.; Wu, S.; Zhu, C. Radical-
mediated difunctionalization of unactivated alkenes through distal
migration of functional groups. Tetrahedron Lett. 2018, 59, 1328−
1336. (d) Sivaguru, P.; Wang, Z.; Zanoni, G.; Bi, X. Cleavage of
carbon−carbon bonds by radical reactions. Chem. Soc. Rev. 2019, 48,
2615−2656. (e) Wu, X.; Zhu, C. Radical-Mediated Remote
Functional Group Migration. Acc. Chem. Res. 2020, 53, 1620−1636.
(f) Huynh, M.; Abreu, M. D.; Belmont, P.; Brachet, E. Frontispiece:
Spotlight on Photoinduced Aryl Migration Reactions. Chem. - Eur. J.
(3) (a) Ye, B.; Cramer, N. Chiral Cyclopentadienyl Ligands as
Stereocontrolling Element in Asymmetric C−H Functionalization.
Science 2012, 338, 504−506. (b) Ozols, K.; Jang, Y.; Cramer, N.
Chiral Cyclopentadienyl Cobalt(III) Complexes Enable Highly
Enantioselective 3d-Metal-Catalyzed C−H Functionalizations. J.
Am. Chem. Soc. 2019, 141, 5675−5680. (c) Wang, D.; Wu, L.;
Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. Asymmetric Copper-
Catalyzed Intermolecular Aminoarylation of Styrenes: Efficient
Access to Optical 2,2-Diarylethylamines. J. Am. Chem. Soc. 2017,
139, 6811−6814. (d) Monos, T. M.; McAtee, R. C.; Stephenson, C.
R. J. Arylsulfonylacetamides as bifunctional reagents for alkene
aminoarylation. Science 2018, 361, 1369−1373. (e) Liu, Z.; Liu, Z. An
Intermolecular Azidoheteroarylation of Simple Alkenes via Free-
Radical Multicomponent Cascade Reactions. Org. Lett. 2017, 19,
5649−5652. (f) Moon, Y.; Lee, W.; Hong, S. Visible-Light-Enabled
Ortho-Selective Aminopyridylation of Alkenes with N-Aminopyr-
idinium Ylides. J. Am. Chem. Soc. 2020, 142, 12420−12429.
(g) Zheng, D.; Studer, A. Asymmetric Synthesis of Heterocyclic γ-
Amino-Acid and Diamine Derivatives by Three-Component Radical
Cascade Reactions. Angew. Chem., Int. Ed. 2019, 58, 15803−15807.
(h) Chen, J.; Zhu, S.; Qin, J.; Chu, L. Intermolecular, redox-neutral
azidoarylation of alkenes via photoredox catalysis. Chem. Commun.
2019, 55, 2336−2339. (i) Lear, J. M.; Buquoi, J. Q.; Gu, X.; Pan, K.;
Mustafa, D. N.; Nagib, D. A. Multi-component heteroarene couplings
via polarity-reversed radical cascades. Chem. Commun. 2019, 55,
8820−8823. (j) Yang, Y.; Xu, C.; Xiong, Z.; Li, J. Visible light
photoredox alkylazidation of alkenes with sodium azide and
heteroarenium salts: entry to azido-containing 1,4-dihydropyridines.
Chem. Commun. 2020, 56, 9549−9552. (k) Prasad Hari, D.; Hering,
T.; König, B. The Photoredox-Catalyzed Meerwein Addition
Reaction: Intermolecular Amino-Arylation of Alkenes. Angew.
Chem., Int. Ed. 2014, 53, 725−728.
8816
https://doi.org/10.1021/acscatal.1c01001
ACS Catal. 2021, 11, 8807−8817

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
2021, 27, 3581−3607. (g) Wu, X.; Zhu, C. Recent Advances in
Alkoxy Radical-Promoted C−C and C−H Bond Functionalization
Starting from Free Alcohols. Chem. Commun. 2019, 55, 9747−9756.
(h) Tsui, E.; Wang, H.; Knowles, R. R. Catalytic generation of alkoxy
radicals from unfunctionalized alcohols. Chem. Sci. 2020, 11, 11124−
11141.
C.; Wang, Q. Copper-Catalyzed Decarboxylative Functionalization of
Conjugated β,γ-Unsaturated Carboxylic Acids. ACS Catal. 2020, 10,
13179−13185. (e) Kwon, Y.; Wang, Q. Copper-Catalyzed 1,2-
Aminocyanation of Unactivated Alkenes via Cyano Migration. Org.
Lett. 2020, 22, 4141−4145.
(9) Thomas, A. A.; Nagamalla, S.; Sathyamoorthi, S. Salient features
of the aza-Wacker cyclization reaction. Chem. Sci. 2020, 11, 8073−
8088.
(7) For selected examples, see: (a) Gao, P.; Shen, Y. W.; Fang, R.;
Hao, X. H.; Qiu, Z. H.; Yang, F.; Yan, X. B.; Wang, Q.; Gong, X. J.;
Liu, X. Y.; Liang, Y. M. Copper-Catalyzed One-Pot Trifluoromethy-
lation/Aryl Migration/Carbonyl Formation with Homopropargylic
Alcohols. Angew. Chem., Int. Ed. 2014, 53, 7629−7633. (b) Bunescu,
A.; Wang, Q.; Zhu, J. P. Copper-Catalyzed Cyanomethylation of
Allylic Alcohols with Concomitant 1,2-Aryl Migration: Efficient
Synthesis of Functionalized Ketones Containing an α-Quaternary
Center. Angew. Chem., Int. Ed. 2015, 54, 3132−3135. (c) Li, L.; Li,
Z.; Wang, F.; Guo, Z.; Cheng, Y.; Wang, N.; Dong, X.; Fang, C.; Liu,
J.; Hou, C.; Tan, B.; Liu, X. Radical aryl migration enables diversity-
oriented synthesis of structurally diverse medium/macro- or bridged-
rings. Nat. Commun. 2016, 7, No. 13852. (d) Gu, L.; Gao, Y.; Ai, X.;
He, C. Y.; Li, G.; Yuan, M.; He, Y. Direct alkylheteroarylation of
alkenes via photoredox mediated C−H functionalization. Chem.
Commun. 2017, 53, 12946−12949. (e) Wu, Z.; Wang, D.; Liu, Y.;
Huan, L.; Zhu, C. Chemo- and Regioselective Distal Heteroaryl ipso-
Migration: A General Protocol for Heteroarylation of Unactivated
Alkenes. J. Am. Chem. Soc. 2017, 139, 1388−1391. (f) Wu, X.; Wang,
M.; Huan, L.; Wang, D.; Wang, J.; Zhu, C. Tertiary-Alcohol-Directed
Functionalization of Remote C(sp3)−H Bonds by Sequential
Hydrogen Atom and Heteroaryl Migrations. Angew. Chem., Int. Ed.
2018, 57, 1640−1644. (g) Zheng, M. W.; Yuan, X.; Cui, Y.; Qiu, J.;
Li, G.; Guo, K. Electrochemical Sulfonylation/Heteroarylation of
Alkenes via Distal Heteroaryl ipso-Migration. Org. Lett. 2018, 20,
7784−7789. (h) He, Y.; Wang, Y.; Gao, J.; Zeng, L.; Li, S.; Wang, W.;
Zheng, X.; Zhang, S.; Gu, L.; Li, G. Catalytic, metal-free
alkylheteroarylation of alkenes via distal heteroaryl ipso-migration.
Chem. Commun. 2018, 54, 7499−7502. (i) Wang, M.; Wu, Z.; Zhang,
B.; Zhu, C. Azidoheteroarylation of unactivated olefins through distal
heteroaryl migration. Org. Chem. Front. 2018, 5, 1896−1899. (j) Zou,
Z.; Zhang, W.; Wang, Y.; Kong, L.; Karotsis, G.; Wang, Y.; Pan, Y.
Electrochemically Promoted Fluoroalkylation−Distal Functionaliza-
tion of Unactivated Alkenes. Org. Lett. 2019, 21, 1857−1862.
(k) Chang, X.; Zhang, Q.; Guo, C. Electrochemical Reductive Smiles
Rearrangement for C−N Bond Formation. Org. Lett. 2019, 21, 10−
13. (l) Ning, Y.; Mekareeya, A.; Babu, K. R.; Anderson, E. A.; Bi, X.
Silver-Catalyzed C- to N-Center Remote Arene Migration. ACS Catal.
2019, 9, 4203−4210. (m) Sarkar, S.; Banerjee, A.; Yao, W.; Patterson,
E. V.; Ngai, M. Photocatalytic Radical Aroylation of Unactivated
Alkenes: Pathway to β-Functionalized 1,4-, 1,6-, and 1,7-Diketones.
ACS Catal. 2019, 9, 10358−10364. (n) Zhao, Q.; Hao, W.; Shi, H.;
Xu, T.; Tu, S.; Jiang, B. Photocatalytic Annulation−Alkynyl Migration
Strategy for Multiple Functionalization of Dual Unactivated Alkenes.
Org. Lett. 2019, 21, 9784−9789. (o) Liu, C.; Jiang, Q.; Lin, Y.; Fang,
Z.; Guo, K. C- to N-Center Remote Heteroaryl Migration via
Electrochemical Initiation of N Radical by Organic Catalyst. Org. Lett.
2020, 22, 795−799. (p) Tian, T.; Wang, X.; Lv, L.; Li, Z. Iron-
catalyzed acylation-functionalization of unactivated alkenes with
aldehydes. Chem. Commun. 2020, 56, 14637−14640. (q) Zhang,
H.; Kou, L.; Chen, D.; Ji, M.; Bao, X.; Wu, X.; Zhu, C. Radical-
Mediated Distal Ipso-Migration of O/S-Containing Heteroaryls and
DFT Studies for Migratory Aptitude. Org. Lett. 2020, 22, 5947−5952.
(8) (a) Hemric, B. N.; Shen, K.; Wang, Q. Copper-Catalyzed Amino
Lactonization and Amino Oxygenation of Alkenes Using O-
Benzoylhydroxylamines. J. Am. Chem. Soc. 2016, 138, 5813−5816.
(b) Hemric, B. N.; Chen, A.; Wang, Q. Copper-Catalyzed Modular
Amino Oxygenation of Alkenes: Access to Diverse 1,2-Amino
Oxygen-Containing Skeletons. J. Org. Chem. 2019, 84, 1468−1488.
(c) Hemric, B. N.; Chen, A.; Wang, Q. Copper-Catalyzed 1,2-Amino
Oxygenation of 1,3-Dienes: A Chemo-, Regio-, and Site-Selective
Three-Component Reaction with O-Acylhydroxylamines and Carbox-
ylic Acids. ACS Catal. 2019, 9, 10070−10076. (d) Zhang, W.; Wang,
(10) Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I. Copper-
Promoted Functionalization of Organic Molecules: from Biologically
Relevant Cu/O2 Model Systems to Organometallic Transformations.
Chem. Rev. 2019, 119, 2954−3031.
(11) Although the roles of acid additive such as TsOH in this
reaction remain to be fully understood, the acid additive likely
contributes to the protonation of amine intermediate/product to
release the coordination of copper-catalyst to the amine group. The
acid may have additional roles of facilitating the N−O cleavage of
BzO−NRR’ or the migration of heteroaryl group, although the
protonation is not required in either N−O bond cleavage or the
migration step.
(12) We can’t exclude the involvement of the protonated heteroaryl
form in the migration step with the presence of TsOH·H2O under
standard reactions. Yet the migration of heteroaryl groups does not
necessarily require the protonation, which was supported by the
formation of 10e′, control experiment with NSFI in the absence of
TsOH (see the SI), and related migration reactions such as those in
ref 7.
(13) (a) Clarke, A. K.; Unsworth, W. P. A happy medium: the
synthesis of medicinally important medium-sized rings via ring
expansion. Chem. Sci. 2020, 11, 2876−2881. (b) Zhao, C.; Ye, Z.;
Ma, Z.; Wildman, S. A.; Blaszczyk, S. A.; Hu, L.; Guizei, I. A.; Tang,
W. A general strategy for diversifying complex natural products to
polycyclic scaffolds with medium-sized rings. Nat. Commun. 2019, 10,
No. 4015. (c) Zhang, T. Y. Heterocyclic Chemistry in the 21st Century:
A Tribute to Alan Katritzky, Scriven, E.; Ramsden, C. A., Eds.;
Academic Press, 2017; Vol. 121, pp 1−12.
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