Copper-Catalyzed 1,2-Aminocyanation of Unactivated Alkenes via Cyano Migration

Article abstract of DOI:10.1021/acs.orglett.0c01217

A copper-catalyzed aminocyanation of alkenes has been achieved through distal cyano migration using O-benzoylhydroxylamines and N-fluorobenzenesulfonimides. This method offers a rapid approach to generate diverse β-amino and β-sulfonimido nitriles. These reactions feature mild conditions, tolerance of sensitive functional groups, and excellent regioselectivity. Mechanistic studies suggest that these transformations are initiated by a copper-catalyzed amination step followed by a cyano migration step.

Full text of DOI:10.1021/acs.orglett.0c01217

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Letter
Copper-Catalyzed 1,2-Aminocyanation of Unactivated Alkenes via
Cyano Migration
Yungeun Kwon and Qiu Wang*
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ABSTRACT: A copper-catalyzed aminocyanation of alkenes has
been achieved through distal cyano migration using O-benzoylhy-
droxylamines and N-fluorobenzenesulfonimides. This method
offers a rapid approach to generate diverse β-amino and β-
sulfonimido nitriles. These reactions feature mild conditions,
tolerance of sensitive functional groups, and excellent regioselectivity. Mechanistic studies suggest that these transformations are
initiated by a copper-catalyzed amination step followed by a cyano migration step.
Scheme 1. Strategies for Aminocyanation of Alkenes
lkene difunctionalization is a powerful synthetic method
that introduces two distinct functional groups simulta-
A
neously, which can transform simple feedstock alkenes into
richly functionalized valuable skeletons.1 With the well-known
importance of nitrogen-containing molecules in organic
synthesis, pharmaceuticals, and materials,2 great efforts have
been devoted to developing alkene amination functionalization
strategies, including diamination,3 aminooxygenation,4 and
aminohalogenation.5 Despite extensive progress in this area,
the aminocarbonation of alkenes remains underdeveloped.6
Moreover, the ubiquity of carbon−carbon and carbon−
nitrogen bonds in nature makes it highly desirable to develop
efficient methods for concurrent formation of these two
valuable bonds.
Alkene aminocyanation presents an efficient and direct
approach to the synthesis of a β-amino nitrile, which is an
important synthetic motif that can be transformed into diverse
functional groups including aldehydes, carboxylic acids,
amines, and amides.7 Toward this effort, several elegant
approaches have been reported to achieve 1,2-aminocyanation
of alkenes. For example, the Zhang and Wang groups have
independently reported a three-component aminocyanation or
azidocyanation, via the addition of nitrogen-centered radical
species to alkenes, generated from N-fluorobenzenesulfoni-
mide (NFSI) or trimethylsilyl azide, respectively. However,
most of these reactions are limited in scope of styrenyl alkenes
(Scheme 1A).8 Intramolecular aminocyanation of unactivated
alkenes has been achieved by palladium/Lewis acid catalysis,
affording various nitrile-containing azaheterocycles, including
indolines, pyrrolidines, sultams, and lactams (Scheme 1B).9
Furthermore, two-component azidocyanation reactions of
unactivated alkenes have been developed using azido radical
precursors through radical-mediated cyano migration (Scheme
1C).10 To the best of our knowledge, there has been no
aminocyanation of alkenes that directly installs electron-rich
amines reported. We envisioned such a 1,2-aminocyanation to
be achieved by using O-benzoylhydroxylamines as electron-
rich amine precursors, which would initiate a copper-catalyzed
amination of unactivated alkenes11 followed by an intra-
molecular cyano group migration10 (Scheme 1D). In this
paper, we report the development of the 1,2-aminocyanation of
unactivated alkenes using O-benzoylhydroxylamines and NFSI
as nitrogen precursors, achieving high regioselectivity and
broad scope.
Received: April 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01217
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Our exploration of the aminocyanation of alkenes began
with 2-hydroxy-2-methylhex-5-enenitrile 1a as the model
substrate and O-benzoyl-N-hydroxylmorpholine 2a as the
amine source (Table 1). The reaction with Cu(OTf)2 as
Scheme 2. Alkene Scope of Aminocyanation via 1,4- and
1,5-Migration
a
a
Table 1. Optimization for Aminocyanation of Alkene 1a
b
entry
additive
equiv
temp (°C)
3a (%)
1
2
3
4
5
6
7
8
−
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
60
60
60
60
60
60
60
60
80
100
80
80
7
0
0
5
18
16
13
37
48
41
59 (61)
51
pyridine
DIPEA
K2CO3
PPTS
HCOOH
BzOH
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
9
10
11
12
c
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (2.0 equiv),
b
1
Cu(OTf)2 (10 mol %), DCE (1.0 mL). Yields determined by H
NMR spectroscopy with CH2Br2 as an internal standard. Isolation
c
yield in parentheses. DIPEA = N,N-diisopropylethylamine, PPTS =
Pyridinium p-toluenesulfonate.
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (2.0 equiv),
catalyst in DCE gave the desired product 3a in 7% yield (entry
1). Using different copper catalysts or solvents did not improve
the yield.12 Screening various additives showed that Brønsted
acids generally enhanced the formation of 3a (entries 2−8).
Although the roles of the acids have yet to be fully understood,
one possibility is that the protonation of the amine would
prevent deactivation of the copper catalyst. Sulfonic acids
showed increased yields of 3a in comparison to other acids,
with p-toluenesulfonic acid (TsOH·H2O) being the most
effective additive (entry 8). We next studied the effect of
reaction temperatures (entries 9 and 10) and the equivalents of
TsOH·H2O (entries 11 and 12). The most effective conditions
were found to be at 80 °C with 1.5 equiv of TsOH·H2O,
affording 3a in 61% yield (entry 11). These conditions were
chosen as the standard conditions in our following studies.
With the standard aminocyanation conditions, we examined
the scope of alkenes in the aminocyanation reaction using 2a as
the amine source (Scheme 2). In comparison to model
substrate 1a, cyanohydrin 1b bearing a sterically hindered
cyclohexane did not deteriorate the reaction, giving 3b in 57%
yield. Phenyl-substituted cyanohydrin 1c also formed 3c in a
similar 62% yield. Furthermore, various substrates with
diversely substituted aryls were well tolerated, including an
electron-donating group (3d), electron-withdrawing group
(3e), chloride (3f), and sensitive iodide (3g) that tends to
react readily with copper catalysts. The presence of a methyl
substituent at the ortho-, meta-, and para-position did not
influence the outcome of the reactions, forming 3h−3j in
comparable yields. A thiophene-containing cyanohydrin was
also viable to give 3k, though less efficiently in 37% yield. The
reaction of cyanohydrin 1l bearing a geminal dimethyl group
on its backbone afforded 3l in 68% yield, suggesting the
favorable Thorpe−Ingold effect in the migration step. We also
Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1.0 mL).
Isolation yields shown.
investigated the influence of methyl substituents on double
bonds in the reactions of 1,1-disubstituted alkene and
trisubstituted alkene, which generated both 1,4-migration
products 3m and 3n in 32% and 24% yields, respectively.
The lower efficiency of these two reactions likely resulted from
the steric hindrance of the alkene substituents, which may
hamper the initial amination step. It is important to note that
the regioselectivity of 3n was achieved via 1,4-migration to a
less stable secondary radical intermediate, which competes
over a possible 1,5-migration onto a more stable tertiary radical
intermediate. Finally, the reaction of alkene 1a in 2 mmol scale
afforded 3a in 70% yield, demonstrating the scalability of this
transformation.
We then explored the feasibility of alkene aminocyanation
involving a possible 1,5-cyano migration. The reaction of 1o,
analogous to 1a, gave product 3o in 58% yield under standard
conditions, via the expected 1,5-cyano migration. Aryl-
substituted cyanohydrins also successfully formed the desired
products 3p−3r in 45−51% yields. These results supported the
generality of alkene aminocyanation reactions involving 1,5-
migration.
We next examined the amine scope of the aminocyanation
reaction (Scheme 3). In the reactions of alkene 1a, cyclic
amines bearing different functional groups were all introduced
successfully onto β-amino nitrile products, including piperidine
(4a), 3-methylpiperidine (4b), ethyl 4-piperidinecarboxylate
(4c), N-Cbz-piperazine (4d), and N-benzoylpiperazine (4e).
The reaction of 1a with acyclic hydroxylamine derived from
N,N-diethylamine required a lower temperature (40 °C) and
B
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a
a
Scheme 3. Amine Scope of Alkene Aminocyanation
Scheme 4. Mechanistic Investigations
a
b
Isolation yields shown. Reaction conditions: 5 (0.2 mmol, 1.0
equiv), 2a (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5
c
d
equiv), DCE (1.0 mL), 80 °C. Observed by LC-MS. Yield
1
determined by H NMR spectroscopy with CH2Br2 as an internal
standard. Reaction conditions: 1a (0.4 mmol, 1.0 equiv), 2a (2.0
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv),
Cu(OTf)2 (10 mol %), TsOH·H2O (1.5 equiv), DCE (1.0 mL).
e
equiv), TEMPO (1.0 equiv), Cu(OTf)2 (10 mol %), TsOH·H2O (1.5
b
c
Isolation yields shown. Reaction run at 40 °C. Reaction run at 60
°C. Reaction run without TsOH·H2O.
f
equiv), DCE (2.0 mL), 80 °C. Reaction conditions: 1a (0.2 mmol,
d
1.0 equiv), 2a (2.0 equiv), BHT (1.0 equiv), Cu(OTf)2 (10 mol %),
TsOH·H2O (1.5 equiv), DCE (1.0 mL), 80 °C.
Scheme 5. Proposed Reaction Pathways
afforded desired product 4f in 29% yield. Using a phenyl-
cyanohydrin derivative 1c in the reaction performed similarly,
with 4g formed in only 33% yield. On the other hand, the
aminocyanation reactions of substrate 1o involving 1,5-
migration were found to give piperidine (4h) and 3-
methylpiperidine (4i) products smoothly. Interestingly, NFSI
was found to be a viable nitrogen precursor and readily
afforded desired β-sulfonimide nitrile 4j, without the need for
TsOH·H2O.3c,13
In addition to 1,4- and 1,5-migratory aminocyanation
reactions, we also explored analogous reactions involving
possible 1,3- and 1,6-migration starting from 5a and 5b,
respectively (Scheme 4A). Although desired products 6a and
6b were observed by LC-MS, 7 and 8 were obtained as major
products which formed likely via an elimination pathway.
These results support a postulation that the 1,4- or 1,5-cyano
migration step may be assisted by the formation of five- or six-
membered intermediates (see Scheme 5), while 1,3- and 1,6-
migration would be more challenging owing to the disfavored
formation of four- or seven-membered ring intermediates.10
Control experiments were performed to probe the presence
of the radical intermediates under these reaction conditions,
with the addition of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) in the
reaction of 1a (Scheme 4B). In both cases, desired product 3a
was formed in significantly decreased yields. The formation of
TEMPO-trapped product (9) and two BHT-derived products
(10 and 11 where the nitrogen radical was trapped on the
aromatic ring or at the benzylic position possibly through
BHT-quinone methide) indicates the involvement of radical
intermediates in the reaction mechanism. Furthermore, the
formation of compounds 7, 8, and 9 indicates that this
aminocyanation reaction is initiated by the copper-catalyzed
aminyl radical addition to olefin.11c,d
Based on these experimental results, the possible reaction
pathways of this alkene aminocyanation reaction are outlined
in Scheme 5. One possibility is the initiation of the reaction by
the oxidative addition of O-benzyolhydroxylamine or NFSI to
the copper catalyst to generate an amino−Cu(III) complex,
which then adds onto the alkene. Alternatively, via a single-
electron transfer process, a N-centered radical intermediate
could be formed to promote radical addition to the olefin.
Note that copper(III) complex species readily undergo
reversible single-electron transfer to form copper(II) and the
corresponding radicals, which would be supported by the
formation of 7 and 8. The cyano migration step possibly occurs
C
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via the cyclic iminium radical intermediate (IV) followed by β-
cleavage, generating a more stable hydroxyalkyl radical (V).
Finally, the single-electron oxidation would transform this
radical to a carbocation, affording desired product 3 and
regenerating the copper catalyst (I).
In conclusion, we have developed a copper-catalyzed 1,2-
aminocyanation of alkenes by a distal cyano migration. These
reactions readily afford β-amino nitriles possessing an electron-
rich amine by using O-benzyolhydroxylamines, and are also
applicable to the synthesis of β-sulfonimido nitrile by using
NFSI. Mechanistic studies indicated the presence of nitrogen
and carbon radical intermediates under reaction conditions.
The transformation is likely initiated by a copper-catalyzed
amine addition to the alkene, followed by a 1,4- or 1,5-cyano
migration. In the future, we will investigate different alkene
aminocarbonation reactions involving other functional group
migrations.
̈
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01217.
Experimental procedures, condition optimization data,
compound characterization, and NMR spectra (PDF)
(4) See examples: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J.
Palladium-Catalyzed Ring-Forming Aminoacetoxylation of Alkenes. J.
Am. Chem. Soc. 2005, 127 (21), 7690−7691. (b) Fuller, P. H.; Kim, J.-
W.; Chemler, S. R. Copper Catalyzed Enantioselective Intramolecular
Aminooxygenation of Alkenes. J. Am. Chem. Soc. 2008, 130 (52),
17638−17639. (c) Lu, D.-F.; Zhu, C.-L.; Jia, Z.-X.; Xu, H. Iron(II)-
Catalyzed Intermolecular Amino-Oxygenation of Olefins through the
N−O Bond Cleavage of Functionalized Hydroxylamines. J. Am. Chem.
Soc. 2014, 136 (38), 13186−13189. (d) Zhu, H.; Chen, P.; Liu, G.
Pd-Catalyzed Intramolecular Aminohydroxylation of Alkenes with
Hydrogen Peroxide as Oxidant and Water as Nucleophile. J. Am.
Chem. Soc. 2014, 136 (5), 1766−1769. (e) Michaelis, D. J.; Shaffer, C.
J.; Yoon, T. P. Copper(II)-Catalyzed Aminohydroxylation of Olefins.
J. Am. Chem. Soc. 2007, 129 (7), 1866−1867.
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
Author
Yungeun Kwon − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
(5) See examples: (a) Chemler, S. R.; Bovino, M. T. Catalytic
Aminohalogenation of Alkenes and Alkynes. ACS Catal. 2013, 3 (6),
1076−1091. (b) Li, G.; Kotti, S. R. S. S.; Timmons, C. Recent
Development of Regio- and Stereoselective Aminohalogenation
Reaction of Alkenes. Eur. J. Org. Chem. 2007, 2007 (17), 2745−
2758. (c) Wu, T.; Yin, G.; Liu, G. Palladium-Catalyzed Intramolecular
Aminofluorination of Unactivated Alkenes. J. Am. Chem. Soc. 2009,
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G. Palladium-Catalyzed Intermolecular Aminofluorination of Styr-
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Chemler, S. R. Catalytic Enantioselective Alkene Aminohalogenation/
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01217
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support by Duke University
and the National Institutes of Health (GM118786). We thank
to Dr. Peter Silinski of the Department of Chemistry at Duke
University for the assistance with high-resolution mass
spectrometry.
(6) See examples: (a) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.; Li,
J.-H. Oxidative 1,2-Carboamination of Alkenes with Alkyl Nitriles and
Amines toward γ-Amino Alkyl Nitriles. Nat. Commun. 2017, 8 (1),
14720. (b) Qian, B.; Chen, S.; Wang, T.; Zhang, X.; Bao, H. Iron-
Catalyzed Carboamination of Olefins: Synthesis of Amines and
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