Catalytic Asymmetric Radical Diamination of Alkenes

Article abstract of DOI:10.1016/j.chempr.2017.10.008

Catalytic asymmetric diamination of alkenes is a highly attractive method for creating chiral vicinal diamines, which are ubiquitous in biologically active molecules and versatile ligands as well as organocatalysts. We report the use of O-acylhydroxylamines as dialkylaminyl radical precursors to trigger asymmetric diamination of alkene under Cu(I)/chiral phosphoric acid dual catalysis. This reaction allows for direct alkylamine incorporation and features high enantioselectivity, a broad substrate scope, wide functional-group tolerance, and mild reaction conditions, providing convenient and practical access to a wide range of highly enantio-enriched β-alkylamine-containing pyrrolidines. We have also achieved asymmetric azidoamination of alkenes by using azidoiodinane as an azidyl radical precursor, offering a complementary method for preparing diverse chiral β-amino pyrrolidines. The application of the resultant α-tertiary pyrrolidine-derived diamine was showcased to significantly promote the enantioselectivity of an asymmetric Michael reaction. Chiral vicinal diamines are characteristic and essential motifs embedded in numerous biologically active molecules. In addition, they are also the core scaffolds for a diverse range of chiral ligands, organocatalysts, and auxiliaries widely used in organic synthesis. For their preparation, asymmetric diamination of readily available alkenes constitutes an expedient and important method for accessing enantio-enriched vicinal diamines. However, none of the known strategies are able to directly introduce a protection-free alkyl amine moiety, mainly because of its strong coordination capability, mostly leading to transition-metal catalyst poisoning and susceptibility to oxidation. As a consequence, both the step economy and amine scope are compromised, thus limiting broad applicability. Here, we report the asymmetric radical diamination of alkenes under Cu(I)/chiral phosphoric acid dual catalysis, enabling direct incorporation of alkyl amine groups. Liu and colleagues describe the asymmetric radical diamination of alkenes triggered by intermolecular addition of dialkylaminyl or azidyl radical to the alkene under Cu(I)/chiral phosphoric acid dual catalysis. This reaction enables direct incorporation of alkylamine moieties and provides convenient and practical access to a wide range of highly enantio-enriched β-alkylamine-containing pyrrolidines. Moreover, the resulting α-tertiary pyrrolidine-derived diamine proves to significantly promote the enantioselectivity of an asymmetric Michael reaction.

Full text of DOI:10.1016/j.chempr.2017.10.008

Article
Catalytic Asymmetric Radical Diamination of
Alkenes
Fu-Li Wang, Xiao-Yang Dong,
Jin-Shun Lin, ..., Xian-Qi Guo,
Can-Liang Ma, Xin-Yuan Liu
liuxy3@sustc.edu.cn
HIGHLIGHTS
Asymmetric radical diamination
under copper/chiral phosphoric
acid dual catalysis
Direct incorporation of alkylamine
and azido moieties
Efficient synthesis of chiral
a-tertiary pyrrolidines
Demonstrated great potential for
application of diamine products
as organocatalysts
Liu and colleagues describe the asymmetric radical diamination of alkenes
triggered by intermolecular addition of dialkylaminyl or azidyl radical to the alkene
under Cu(I)/chiral phosphoric acid dual catalysis. This reaction enables direct
incorporation of alkylamine moieties and provides convenient and practical access
to a wide range of highly enantio-enriched b-alkylamine-containing pyrrolidines.
Moreover, the resulting a-tertiary pyrrolidine-derived diamine proves to
significantly promote the enantioselectivity of an asymmetric Michael reaction.
Wang et al., Chem 3, 1–12
December 14, 2017 ª 2017 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2017.10.008

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Article
Catalytic Asymmetric Radical
Diamination of Alkenes
Fu-Li Wang,1,2,3 Xiao-Yang Dong,1,3 Jin-Shun Lin,1,3 Yang Zeng,1 Guan-Yuan Jiao,1 Qiang-Shuai Gu,1
Xian-Qi Guo,1 Can-Liang Ma,1 and Xin-Yuan Liu1,4,
*
SUMMARY
The Bigger Picture
Chiral vicinal diamines are
Catalytic asymmetric diamination of alkenes is a highly attractive method for
creating chiral vicinal diamines, which are ubiquitous in biologically active
molecules and versatile ligands as well as organocatalysts. We report the use
of O-acylhydroxylamines as dialkylaminyl radical precursors to trigger asym-
metric diamination of alkene under Cu(I)/chiral phosphoric acid dual catalysis.
This reaction allows for direct alkylamine incorporation and features high enan-
tioselectivity, a broad substrate scope, wide functional-group tolerance, and
mild reaction conditions, providing convenient and practical access to a wide
range of highly enantio-enriched b-alkylamine-containing pyrrolidines. We
have also achieved asymmetric azidoamination of alkenes by using azidoiodi-
nane as an azidyl radical precursor, offering a complementary method for
preparing diverse chiral b-amino pyrrolidines. The application of the resultant
a-tertiary pyrrolidine-derived diamine was showcased to significantly promote
the enantioselectivity of an asymmetric Michael reaction.
characteristic and essential motifs
embedded in numerous
biologically active molecules. In
addition, they are also the core
scaffolds for a diverse range of
chiral ligands, organocatalysts,
and auxiliaries widely used in
organic synthesis. For their
preparation, asymmetric
diamination of readily available
alkenes constitutes an expedient
and important method for
accessing enantio-enriched
vicinal diamines. However, none
of the known strategies are able to
directly introduce a protection-
free alkyl amine moiety, mainly
because of its strong coordination
capability, mostly leading to
transition-metal catalyst
INTRODUCTION
Chiral vicinal diamines represent key structural elements in a large number of natural
products, pharmaceutical agents, and agrochemicals.1–8 They also constitute excel-
lent platforms for the development of chiral ligands, organocatalysts, and auxiliaries
with broad utility in asymmetric synthesis.9,10 Consequently, expedited assembly of
vicinal diamines from readily available precursors has long been recognized as a
preeminent goal in organic synthesis.1–8,11–13 In this regard, catalytic asymmetric
diamination of unactivated alkenes with transition-metal or aryliodine(I) catalysts
represents a straightforward and highly attractive method for creating such useful
vicinal diamine scaffolds, given the facile accessibility of alkene starting mate-
rials.14–25 However, the amine introduced by these asymmetric catalytic systems
has to be masked by electron-withdrawing protecting groups, and direct incorpora-
tion of free alkylamine has so far remained elusive (Scheme 1A).
poisoning and susceptibility to
oxidation. As a consequence,
both the step economy and amine
scope are compromised, thus
limiting broad applicability. Here,
we report the asymmetric radical
diamination of alkenes under
Cu(I)/chiral phosphoric acid dual
catalysis, enabling direct
Two major factors have contributed to the lack of development of asymmetric alkene
diamination with protection-free alkylamine.14–25 On the one hand, the high affinity
of a strongly Lewis-basic alkylamine for transition metal could lead to the formation
of stable amine-metal complexes, thus resulting in poisoning of transition-metal cat-
alysts. On the other hand, protection-free alkylamine is susceptible to oxidation
under reported oxidative diamination reaction conditions.14–25 As a result, success-
ful diamination of unactivated alkenes typically requires adequate electron-with-
drawing protecting groups to suppress undesired strong ligation and amine
oxidation, making these methods indirect for free amine synthesis and inconvenient
for subsequent amine transformation (Scheme 1A).
incorporation of alkyl amine
groups.
Chem 3, 1–12, December 14, 2017 ª 2017 Elsevier Inc.
1

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Scheme 1. Asymmetric Diamination of Alkenes for the Construction of Chiral Vicinal Diamines
To address these challenges, we became interested in the use of alkylaminyl
radical as a key reactive intermediate for direct diamination of unactivated al-
kenes.26–28 We envisioned that the Cu(I)-chiral phosphoric acid-catalyzed29–35 asym-
1Department of Chemistry, South University of
Science and Technology of China, Shenzhen
518055, China
metric radical diamination of alkenes with electrophilic aminating reagents such as
O-acylhydroxylamines,36–55 if successful, would provide a direct, convenient, and
powerful approach to enantio-enriched vicinal diamines bearing alkylamine moi-
eties (Scheme 1B).
2Key Laboratory and Institute of
Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
RESULTS AND DISCUSSION
3These authors contributed equally
4Lead Contact
Research Design
*Correspondence: liuxy3@sustc.edu.cn
https://doi.org/10.1016/j.chempr.2017.10.008
We expected a catalytic cycle wherein the copper-stabilized dialkylaminyl radical I
would be first generated from the reaction of O-acylhydroxylamine 2 with Cu(I)/CPA
2
Chem 3, 1–12, December 14, 2017

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
via a single electron transfer process (Scheme 1C).26–28,47,48,52 Subsequently, the
electrophilic dialkylaminyl radical I would undergo intermolecular addition to an
olefin acceptor to deliver two new C–N bonds, hopefully with a superior level of
enantiocontrol in the presence of Cu/CPA catalyst. Noteworthy is the dual role of
O-acylhydroxylamine 2 as both an alkylamine source and an oxidant in this process,
which would not only circumvent the catalyst poisoning associated with the use of a
free alkylamine but also dispense with excess external oxidants required in oxidative
diamination reactions, thus overcoming challenges in previous asymmetric diamina-
tion of alkenes.14–25 Here, we describe our efforts toward the development of asym-
metric radical diamination of alkenes with dialkylaminyl or azidyl radical species in
the presence of a dual Cu(I)/CPA catalytic system, affording a-tertiary pyrrolidines
bearing a b-alkylamine moiety with excellent yields and enantioselectivity. Such
enantio-enriched b-alkylamine-containing pyrrolidines have great potential for ap-
plications in asymmetric synthesis and medicinal chemistry.56–62
Optimization Study
We began our investigation by reacting N-alkenyl urea 1a and O-benzoyl hydroxyl-
morpholine 2a with Cu(CH3CN)4PF6 (10 mol %) and CPA (R)-A1 (15 mol %). To our
delight, the desired 1,2-diamination product 3A was obtained in 85% yield, albeit
with low enantioselectivity (13% ee) (Table 1, entry 1). Under these reaction condi-
tions, a variety of BINOL- and SPINOL-based CPAs63–71 were initially evaluated
(entries 1–6) and good results (52% ee, entry 4) were obtained with SPINOL-based
(S)-A4 with 4-Ph-phenyl groups at the 3,30-positions of the backbone. We next
screened a series of Cu(I) catalysts and organic solvents (entries 7–13) and found
that the use of Cu(CH3CN)4BF4 as catalyst in 1,4-dioxane was the best (57% yield
and 86% ee; entry 10). Fine-tuning of the electronic nature of the benzoyl group
of 2a–2d (entries 14–17) led to the identification of 2c bearing an OMe group at
the para position of the benzene ring as the optimal aminyl radical precursor,
because the use of 2c gave the best result with 3A in 75% yield and 84% ee with a
mixed solvent system of 1,4-dioxane/CHCl3 (1:4) (entry 16). In addition, the use of
˚
5 A molecular sieves improved the reaction efficiency remarkably (76% yield and
93% ee; entry 19). Furthermore, elongating the reaction time and increasing the
amount of 2c together with a lowered catalyst loading of CPA slightly boosted
both the reaction efficiency and enantioselectivity (entry 20).
Scope of the Investigation
With the optimal reaction conditions in hand, we first investigated the substrate
scope of the asymmetric radical alkene 1,2-diamination for urea aryl and tethering
groups (Figure 1; see also Figures S3–S46 and S152–S181). Typically, ureas 3A–3D
bearing electro-deficient aryl rings were viable substrates. Substrates containing
three- to seven-membered rings within the backbone were well tolerated to
produce spiro products 3E–3I in good yields with excellent ee. Interestingly,
geminal di-phenyl (1j) and di-ester (1k) groups in the tether had no significant influ-
ence on the reaction to give 3J and 3K in 81% and 62% yields with 95% and 94% ee,
respectively. It is more encouraging to note that the unbranched substrates 1l–1o
underwent the current reaction smoothly to give the corresponding products 3L–
3O in good enantioselectivities with an increased catalyst loading.
Next, a wide range of substrates with different alkenyl aryl rings were surveyed (Fig-
ure 2; see also Figures S47–S92 and S182–S213). It was found that meta or para
substitutions on the benzene ring generally did not significantly affect the enantio-
selectivity, whatever the electronic nature (91%–94% ee, 3P–3V). A bicyclic naphtha-
lene ring in 1t was also suitable for this reaction to provide comparable
Chem 3, 1–12, December 14, 2017
3

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Table 1. Screening of Reaction Conditions
Entry
1
CPA
2
Solvent
DCE
Yield (%)a
85
ee (%)b
13
(R)-A1
(R)-A2
(S)-A3
(S)-A4
(S)-A5
(R)-A6
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2c
2c
2c
2
DCE
73
8
3
DCE
72
33
4
DCE
82
52
5
DCE
65
26
6
DCE
78
ꢀ33
73
7
CHCl3
88
8
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
77
76
9
52
84
10c
11d
12e
13f
14c
15c
16c
17c
18c,h
19c,i
20c,j
57
86
32
81
34
85
42
80
g
–
71
84
g
–
68
80
g
–
75
84
g
–
65
77
1,4-dioxane
1,4-dioxane
1,4-dioxane
76
86
76
93
82
94
Abbreviations: CPA, chiral phosphoric acid; DCE, 1,2-dichloroethane; and MS, molecular sieves. Reaction
conditions: 1a (0.05 mmol), 2 (2 equiv), Cu(CH3CN)4PF6 (10 mol %), CPA (15 mol %), solvent (1.0 mL), 60ꢁC,
20 hr under argon.
aYield based on 1H NMR analysis of the crude product with CH2Br2 as an internal standard.
bEe value based on high-performance liquid chromatography analysis.
cCu(CH3CN)4BF4 (10 mol %).
dCuCl (10 mol %).
eCuBr (10 mol %).
fCuOAc (10 mol %).
g1,4-Dioxane/CHCl3 (1:4) was used.
h
ꢁ
˚
1.2 equiv of 2c was used with 4 A MS at 40 C for 40 hr.
i
j
ꢁ
˚
1.2 equiv of 2c was used with 5 A MS at 40 C for 40 hr.
ꢁ
˚
1.5 equiv of 2c and 10 mol % of (S)-A4 was used with 5 A MS at 40 C for 60 hr.
4
Chem 3, 1–12, December 14, 2017

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Figure 1. Substrate Scope for Urea Aryl and Tethering Groups
All the reactions were conducted on 0.1 mmol scale. All yields are isolated yields based on 1. Ee was determined by high-performance liquid
chromatography (HPLC) analysis. For 3B, the reaction was run for 80 hr. For 3L-O, 15 mol % Cu(CH3CN)4BF4 and 20 mol % (S)-A4 were used.
enantioselectivity with those obtained with other monocyclic aryl rings. Importantly,
many common functional groups, such as acid-sensitive acetal, oxidant-labile free
aldehyde, and potentially amine-reactive ester, were all well tolerated to give the
desired products 3W–3Y in 64%–70% yield and 86%–93% ee. In addition, extra dou-
ble and triple bonds in the substrates remained intact during the reaction to afford
corresponding highly enantio-enriched products 3Z and 3Za, respectively. To
further investigate the reaction scope, we tested the use of alkenyl-substituted
alkenes (dienes) as the substrate under the standard reaction conditions. To our
delight, the reaction gave the desired products 3Zb and 3Zc in 72% and 98% ee,
respectively. Heteroarene-substituted alkenes could also be used in the reaction
to give the desired products 3Zd and 3Ze in moderate yields with good to excellent
enantioselectivity. Such broad functional-group tolerance ensures great potential
for further versatile transformations. The absolute configuration of the chiral carbon
center in 3T has been determined to be S by X-ray crystallographic analysis (Figure 2;
see also Figure S1 and the Supplemental Information for details).
We then evaluated the scope for dialkylaminyl radical by using various O-benzoylhy-
droxylamines 2 (Figure 3; see also Figures S93–S110 and S214–S225). A wide range
of six-membered cyclic dialkylaminyl radicals, including piperidyl, 4-methoxy-piper-
idyl, 4-ethoxylcarbonyl-piperidyl, 4-methylsulfonyl-piperazyl, and 4-tosyl-piperazyl
ones, were all applicable to afford desired products 3Zf–3Zj in 44%–88% yields
Chem 3, 1–12, December 14, 2017
5

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Figure 2. Substrate Scope for Alkenyl Aryl Rings
All the reactions were conducted on 0.1 mmol scale. All yields are isolated yields based on 1. Ee was determined by HPLC analysis. For 3Q, 3R, 3U, and
3V, the reaction was run for 80 hr.
with 90%–97% ee. In addition, a seven-membered dialkylaminyl radical derived from
1,4-diazepane was also viable, giving rise to the formation of 3Zk in 67% yield with
93% ee. Asymmetric diamination of alkene with an acyclic amine reagent such as
6
Chem 3, 1–12, December 14, 2017

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Figure 3. Substrate Scope for Dialkylaminyl Radical
All the reactions were conducted on 0.1 mmol scale. All yields are isolated yields based on 1h. Ee was determined by HPLC analysis. For 3Zg, 15 mol %
(S)-A4 was used.
N-fluorobenzenesulfonimide (NFSI) as the nitrogen source in the presence of the
Cu(I)/CPA catalytic system has been achieved in moderate yield with moderate
enantioselectivity, and is currently under further optimization in our laboratory
(Scheme S1 and Figures S111–S113, S226, and S227).
To expand the scope of other radical precursors of this methodology, we next
focused our attention on the azidyl radical generated from iodine(III) reagent azi-
doiodinane (4a). As expected, the reaction of substrate 1a with 4a in the presence
˚
of CuI (10 mol %) and (S)-A5 (10 mol %) with 1.2 equiv. of NaHCO3 and 4 A molecular
sieves in 1,4-dioxane at 25ꢁC for 24 hr delivered the desired azidoamination product
5A in 83% yield with 92% ee (Figure 4; see also Figures S114–S116, S228, and S229),
after systematic optimization of different reaction parameters (Table S1). Similar re-
sults were obtained in the reaction of a series of N-alkenyl ureas to afford the ex-
pected products 5B–5E (Figures S117–S127) in 75%–90% yields with 85–94% ee
(Figures S230–S237).
Mechanistic Study
To probe the reaction mechanism, a radical trapping experiment with 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) was conducted to reveal significant inhibition of
the desired reaction (Scheme S2, equation 1). This observation suggests that alkyla-
minyl radical I is likely generated in situ, which upon further addition to alkene gives
rise to alkyl radical II (Scheme 1C). Next, no reaction of 1a occurred in the absence of
O-benzoylhydroxylamine 2c under the otherwise standard conditions (Scheme S2,
equation 2). Thus, a mechanism involving an initial aminocupration followed by
Chem 3, 1–12, December 14, 2017
7

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Figure 4. Substrate Scope for Azidyl Radical
All the reactions were conducted on 0.1 mmol scale. All yields are isolated yields based on 1. Ee was determined by HPLC analysis.
homolysis of the resultant C–Cu bond and subsequent coupling with an alkylaminyl
radical is unlikely.47,72 Overall, all these experimental observations as well as previous
studies26–33,47,48,52 favor our initial mechanistic proposal involving a process initiated
by the intermolecular addition of aminyl radical to alkene, as shown in Scheme 1C.
Transformation and Application
To demonstrate the synthetic utilities of the current protocol, the urea group of 3A was
readily removed to give a-tertiary pyrrolidine-derived diamine 6 in 68% yield and the
enantiopurity was completely retained (Scheme 2, equation 1; see also Figures S128,
S129, S238, and S239). In addition, product 3A was also smoothly cyclized under
oxidative conditions to give bicyclic amine 7 in 96% yield as a 1:1 mixture of diastereo-
mers without obvious loss in enantiopurity (Scheme 2, equation 2; see also Figures
S130–S135, S240–S243, and S255–S258). The structure of 7 is the core component
of many biologically active compounds (Figure S2).56–60,73 Pyrrolidine tethered with
a tertiary amine moiety has been widely used as powerful organocatalysts.61,62,74–78
To further demonstrate the potential of the resulting a-tertiary pyrrolidine-derived
diamine as organocatalyst, the asymmetric Michael reaction of b-nitrostyrene with
propionaldehyde was investigated as a model reaction. To our delight, 6 as the cata-
lyst showed better enantioselectivity and diastereoselectivity (Figures S136–S139 and
S252–S254) than the commonly used (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine cata-
lyst 8 under otherwise identical reaction conditions (Scheme 2, equation 3).74 Most
importantly, the azido group in the resultant pyrrolidine-derived product can be
easily converted to a number of useful nitrogen-containing functional groups, such
as b-primary, secondary, or tertiary amine-containing pyrrolidines 10–12 in moderate
to good yields through simple and versatile transformations (Scheme 2, equation 4;
see also Figures S140–S148 and S244–S249). In addition, anti-diabetic analog 13
was obtained from 5A in 90% yield (Scheme 2, equation 5; see also Figures S2,
S149–S151, S250, and S251).73 No erosion of enantiomeric excess was observed in
any of these cases. These results clearly indicated great potential application in asym-
metric synthesis for these chiral diamine compounds.
Conclusion
We have developed an asymmetric radical diamination and azidoamination of
alkenes for the direct incorporation of alkylamine under Cu(I)/phosphoric acid dual
catalysis. This transformation enables facile access to enantio-enriched a-tertiary
8
Chem 3, 1–12, December 14, 2017

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
Scheme 2. Representative Product Transformation and Application
Abbreviations: DCE, 1,2-dichloroethane; DMAP, 4-dimethylaminepyridine; DTBP, di-tert-butyl peroxide; and THF, tetrahydrofuran.
pyrrolidines bearing a b-alkylamine moiety with high efficiency, remarkable enantio-
selectivity, excellent functional-group compatibility, and wide substrate scope.
Furthermore, the resultant a-tertiary pyrrolidine-derived diamine was showcased
to significantly promote the enantioselectivity of an asymmetric Michael reaction,
bringing about a different direction for the development of such organocatalysts.
Further studies including the expansion toward other substrate classes, product
application, and the development of a more challenging intermolecular asymmetric
version are ongoing in our laboratory.1–8
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
Chem 3, 1–12, December 14, 2017
9

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
DATA AND SOFTWARE AVAILABILITY
The data for the X-ray crystallographic structure of 3T have been deposited in the
Cambridge Crystallographic Data Center under accession number CCDC: 1542541.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, X-Ray
Crystallographic Data, 258 figures, 1 table, 2 schemes, and 1 data file and can be
found with this article online at https://doi.org/10.1016/j.chempr.2017.10.008.
AUTHOR CONTRIBUTIONS
F.-L.W., X.-Y.D., and J.-S.L. discovered the reaction. F.-L.W. and X.-Y.D. performed
the optimization. F.-L.W., X.-Y.D., Y.Z., G.-Y.J., X.-Q.G., and C.-L.M. investigated
the scope of the substrate, and G.-Y.J. and Q.-S.G. performed the application.
X.-Y.L. directed the project. X.-Y.L. wrote the manuscript with input from all authors.
All authors analyzed the results and commented on the manuscript.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (nos.
21722203, 21572096, and 21602098) and Shenzhen special funds for the develop-
ment of biomedicine, Internet, new energy, and new material industries
(JCYJ20170412152435366 and JCYJ20170307105638498) is greatly appreciated.
Received: June 29, 2017
Revised: September 4, 2017
Accepted: October 17, 2017
Published: November 9, 2017
REFERENCES AND NOTES
1. Bennani, Y.L., and Hanessian, S. (1997). trans-
1,2-Diaminocyclohexane derivatives as chiral
reagents, scaffolds, and ligands for catalysis:
applications in asymmetric synthesis and
molecular recognition. Chem. Rev. 97, 3161–
3196.
restricted diamines. Chem. Rev. 111, 5506–
5568.
16. Zhu, Y., Cornwall, R.G., Du, H., Zhao, B., and
Shi, Y. (2014). Catalytic diamination of olefins
via NꢀN bond activation. Acc. Chem. Res. 47,
3665–3678.
8. Chai, Z., Yang, P.-J., Zhang, H., Wang, S., and
Yang, G. (2017). Synthesis of chiral vicinal
diamines by silver(I)-catalyzed enantioselective
aminolysis of N-tosylaziridines. Angew. Chem.
Int. Ed. 56, 650–654.
17. Mun˜ iz, K., and Nieger, M. (2005).
Enantioselective catalytic diamination of
alkenes with a bisimidoosmium oxidant. Chem.
Commun. (Camb.), 2729–2731.
2. Lucet, D., Le Gall, T., and Mioskowski, C. (1998).
The chemistry of vicinal diamines. Angew.
Chem. Int. Ed. 37, 2580–2627.
9. Zhou, Q.-L. (2011). Privileged Chiral Ligands
and Catalysts (Wiley-VCH).
18. Sequeira, F.C., Turnpenny, B.W., and Chemler,
S.R. (2010). Copper-promoted and copper-
catalyzed intermolecular alkene diamination.
Angew. Chem. Int. Ed. 49, 6365–6368.
3. Viso, A., Ferna´ndez de la Pradilla, R., Garcı´a, A.,
and Flores, A. (2005). a,b-Diamino acids:
biological significance and synthetic
10. De Jong, S., Nosal, D.G., and Wardrop, D.J.
(2012). Methods for direct alkene diamination,
new & old. Tetrahedron 68, 4067–4105.
approaches. Chem. Rev. 105, 3167–3196.
19. Ingalls, E.L., Sibbald, P.A., Kaminsky, W., and
Michael, F.E. (2013). Enantioselective
palladium-catalyzed diamination of alkenes
using N-fluorobenzenesulfonimide. J. Am.
Chem. Soc. 135, 8854–8856.
4. Saibabu Kotti, S.R., Timmons, C., and Li, G.
(2006). Vicinal diamino functionalities as
privileged structural elements in biologically
active compounds and exploitation of their
synthetic chemistry. Chem. Biol. Drug Des. 67,
101–114.
11. Wang, J., Liu, X., and Feng, X. (2011).
Asymmetric Strecker reactions. Chem. Rev.
111, 6947–6983.
12. Noble, A., and Anderson, J.C. (2013). Nitro-
Mannich reaction. Chem. Rev. 113, 2887–2939.
20. Turnpenny, B.W., and Chemler, S.R. (2014).
Copper-catalyzed alkene diamination:
13. Cai, X.-H., and Xie, B. (2014). Recent advances
in asymmetric Strecker reactions. Arkivoc,
205–248.
5. Kizirian, J.-C. (2008). Chiral tertiary diamines in
asymmetric synthesis. Chem. Rev. 108,
140–205.
synthesis of chiral 2-aminomethyl indolines and
pyrrolidines. Chem. Sci. 5, 1786–1793.
21. Fu, S., Yang, H., Li, G., Deng, Y., Jiang, H., and
Zeng, W. (2015). Copper(II)-catalyzed
14. Cardona, F., and Goti, A. (2009). Metal-
catalysed 1,2-diamination reactions. Nat.
Chem. 1, 269–275.
6. Viso, A., Ferna´ndez de la Pradilla, R., Tortosa,
M., Garcı´a, A., and Flores, A. (2011). Update 1
of a,b-diamino acids: biological significance
and synthetic approaches. Chem. Rev. 111,
PR1–PR42.
enantioselective intramolecular cyclization of
N-alkenylureas. Org. Lett. 17, 1018–1021.
15. Muniz, K., and Martınez, C. (2013).
˜
´
Development of intramolecular vicinal
diamination of alkenes: from palladium to
bromine catalysis. J. Org. Chem. 78, 2168–
2174.
22. Mun˜ iz, K., Barreiro, L., Romero, R.M., and
7. Grygorenko, O.O., Radchenko, D.S.,
Volochnyuk, D.M., Tolmachev, A.A., and
Komarov, I.V. (2011). Bicyclic conformationally
Martınez, C. (2017). Catalytic asymmetric
´
diamination of styrenes. J. Am. Chem. Soc. 139,
4354–4357.
10
Chem 3, 1–12, December 14, 2017

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
23. Du, H., Yuan, W., Zhao, B., and Shi, Y. (2007).
Catalytic asymmetric diamination of
conjugated dienes and triene. J. Am. Chem.
Soc. 129, 11688–11689.
38. Matsuda, N., Hirano, K., Satoh, T., and Miura,
M. (2012). Copper-catalyzed amination of
ketene silyl acetals with hydroxylamines:
53. Dong, X., Liu, Q., Dong, Y., and Liu, H. (2017).
Transition-metal-catalyzed
electrophilic amination: application of
O-benzoylhydroxylamines in the construction
of the C–N bond. Chem. Eur. J. 23, 2481–2511.
electrophilic amination approach to a-amino
acids. Angew. Chem. Int. Ed. 51, 11827–11831.
24. Xu, L., and Shi, Y. (2008). Chiral N-heterocyclic
carbene-Pd(0)-catalyzed asymmetric
diamination of conjugated dienes and triene.
J. Org. Chem. 73, 749–751.
54. He, J., Shigenari, T., and Yu, J.-Q. (2015).
Palladium(0)/PAr3-catalyzed intermolecular
amination of C(sp3)–H bonds: synthesis of
b-amino acids. Angew. Chem. Int. Ed. 54, 6545–
6549.
39. Rucker, R.P., Whittaker, A.M., Dang, H., and
Lalic, G. (2012). Synthesis of hindered anilines:
copper-catalyzed electrophilic amination of
aryl boronic esters. Angew. Chem. Int. Ed. 51,
3953–3956.
25. Cornwall, R.G., Zhao, B., and Shi, Y. (2013).
Catalytic asymmetric synthesis of cyclic
sulfamides from conjugated dienes. Org. Lett.
15, 796–799.
55. Lu, D.-F., Zhu, C.-L., Sears, J.E., and Xu, H.
(2016). Iron(II)-catalyzed intermolecular
aminofluorination of unfunctionalized olefins
using fluoride ion. J. Am. Chem. Soc. 138,
11360–11367.
40. Xiao, Q., Tian, L., Tan, R., Xia, Y., Qiu, D., Zhang,
Y., and Wang, J. (2012). Transition-metal-free
electrophilic amination of arylboroxines. Org.
Lett. 14, 4230–4233.
26. Xiong, T., and Zhang, Q. (2016). New amination
strategies based on nitrogen-centered radical
chemistry. Chem. Soc. Rev. 45, 3069–3087.
41. Nguyen, M.H., and Smith, A.B., III (2013).
Copper-catalyzed electrophilic amination of
organolithiums mediated by recoverable
siloxane transfer agents. Org. Lett. 15, 4872–
4875.
56. Sakai, R., Oiwa, C., Takaishi, K., Kamiya, H., and
Tagawa, M. (1999). Dysibetaine: a new
a,a-disubstituted a -amino acid derivative from
the marine sponge Dysidea herbacea.
Tetrahedron Lett. 40, 6941–6944.
27. Zhang, H., Pu, W., Xiong, T., Li, Y., Zhou, X.,
Sun, K., Liu, Q., and Zhang, Q. (2013). Copper-
catalyzed intermolecular aminocyanation and
diamination of alkenes. Angew. Chem. Int. Ed.
52, 2529–2533.
42. Zhu, S., Niljianskul, N., and Buchwald, S.L.
(2013). Enantio- and regioselective CuH-
catalyzed hydroamination of alkenes. J. Am.
Chem. Soc. 135, 15746–15749.
57. Thomson, C.G., Carlson, E., Chicchi, G.G.,
Kulagowski, J.J., Kurtz, M.M., Swain, C.J., Tsao,
K.-L.C., and Wheeldon, A. (2006). Synthesis and
structure–activity relationships of 8-azabicyclo
[3.2.1]octane benzylamine NK1 antagonists.
Bioorg. Med. Chem. Lett. 16, 811–814.
28. Zhang, H., Song, Y., Zhao, J., Zhang, J., and
Zhang, Q. (2014). Regioselective radical
aminofluorination of styrenes. Angew. Chem.
Int. Ed. 53, 11079–11083.
43. McDonald, S.L., and Wang, Q. (2014). Copper-
catalyzed a-amination of phosphonates and
phosphine oxides: a direct approach to
a-amino phosphonic acids and derivatives.
Angew. Chem. Int. Ed. 53, 1867–1871.
29. Lin, J.-S., Dong, X.-Y., Li, T.-T., Jiang, N.-C.,
Tan, B., and Liu, X.-Y. (2016). A dual-catalytic
strategy to direct asymmetric radical
aminotrifluoromethylation of alkenes. J. Am.
Chem. Soc. 138, 9357–9360.
58. Strachan, J.-P., Farias, J.J., Zhang, J., Caldwell,
W.S., and Bhatti, B.S. (2012). Diazaspirocyclic
compounds as selective ligands for the a4b2
nicotinic acetylcholine receptor. Bioorg. Med.
Chem. Lett. 22, 5089–5092.
44. Sakae, R., Hirano, K., and Miura, M. (2015).
Ligand-controlled regiodivergent Cu-
catalyzed aminoboration of unactivated
terminal alkenes. J. Am. Chem. Soc. 137, 6460–
6463.
30. Lin, J.-S., Wang, F.-L., Dong, X.-Y., He, W.-W.,
Yuan, Y., Chen, S., and Liu, X.-Y. (2017).
Catalytic asymmetric radical
59. Syed, Y.Y. (2015). Rolapitant: first global
approval. Drugs 75, 1941–1945.
aminoperfluoroalkylation and
60. Martirosyan, A.H., Gasparyan, S.P., Alexanyan,
M.V., Harutyunyan, G.K., Panosyan, H.A., and
Schinazi, R.F. (2016). Anti-human
aminodifluoromethylation of alkenes to
versatile enantioenriched-fluoroalkyl amines.
Nat. Commun. 8, 14841–14851.
45. Shi, S.-L., and Buchwald, S.L. (2015). Copper-
catalysed selective hydroamination reactions
of alkynes. Nat. Chem. 7, 38–44.
immunodeficiency activity of novel
2-arylpyrrolidine analogs. Med. Chem. Res. 26,
101–108.
31. Zhu, R., and Buchwald, S.L. (2013).
Enantioselective functionalization of radical
intermediates in redox catalysis: copper-
catalyzed asymmetric oxytrifluoromethylation
of alkenes. Angew. Chem. Int. Ed. 52, 12655–
12658.
46. Yang, Y., Shi, S.-L., Niu, D., Liu, P., and
Buchwald, S.L. (2015). Catalytic asymmetric
hydroamination of unactivated internal olefins
to aliphatic amines. Science 349, 62–66.
61. Mukherjee, S., Yang, J.W., Hoffmann, S., and
List, B. (2007). Asymmetric enamine catalysis.
Chem. Rev. 107, 5471–5569.
47. Shen, K., and Wang, Q. (2015). Copper-
catalyzed diamination of unactivated alkenes
with hydroxylamines. Chem. Sci. 6, 4279–4283.
62. Moyano, A., and Rios, R. (2011). Asymmetric
organocatalytic cyclization and cycloaddition
reactions. Chem. Rev. 111, 4703–4832.
32. Zhu, R., and Buchwald, S.L. (2015). Versatile
enantioselective synthesis of functionalized
lactones via copper-catalyzed radical
oxyfunctionalization of alkenes. J. Am. Chem.
Soc. 137, 8069–8077.
48. Hemric, B.N., Shen, K., and Wang, Q. (2016).
Copper-catalyzed amino lactonization and
amino oxygenation of alkenes using
O-benzoylhydroxylamines. J. Am. Chem. Soc.
138, 5813–5816.
63. Phipps, R.J., Hamilton, G.L., and Toste, F.D.
(2012). The progression of chiral anions from
concepts to applications in asymmetric
catalysis. Nat. Chem. 4, 603–614.
33. Wang, D., Wang, F., Chen, P., Lin, Z., and Liu,
G. (2017). Enantioselective copper-catalyzed
intermolecular amino- and azidocyanation of
alkenes in a radical process. Angew. Chem. Int.
Ed. 56, 2054–2058.
64. Brak, K., and Jacobsen, E.N. (2013).
Asymmetric ion-pairing catalysis. Angew.
Chem. Int. Ed. 52, 534–561.
49. Pirnot, M.T., Wang, Y.-M., and Buchwald, S.L.
(2016). Copper hydride catalyzed
hydroamination of alkenes and alkynes.
Angew. Chem. Int. Ed. 55, 48–57.
34. Sibi, M.P., Manyem, S., and Zimmerman, J.
(2003). Enantioselective radical processes.
Chem. Rev. 103, 3263–3295.
65. Mahlau, M., and List, B. (2013). Asymmetric
counteranion-directed catalysis: concept,
definition, and applications. Angew. Chem. Int.
Ed. 52, 518–533.
50. Shi, S.-L., Wong, Z.L., and Buchwald, S.L. (2016).
Copper-catalysed enantioselective
stereodivergent synthesis of amino alcohols.
Nature 532, 353–356.
35. Zhang, L., and Meggers, E. (2003). Steering
asymmetric Lewis acid catalysis exclusively with
octahedral metal-centered chirality. Acc.
Chem. Res. 50, 320–330.
66. Chen, D.-F., Han, Z.-Y., Zhou, X.-L., and Gong,
L.-Z. (2014). Asymmetric organocatalysis
combined with metal catalysis: concept, proof
of concept, and beyond. Acc. Chem. Res. 47,
2365–2377.
51. Zhu, S., Niljianskul, N., and Buchwald, S.L.
(2016). A direct approach to amines with
remote stereocentres by enantioselective CuH-
catalysed reductive relay hydroamination. Nat.
Chem. 8, 144–150.
36. Seko, S., and Kawamura, N. (1996). Copper-
catalyzed direct amination of nitrobenzenes
with O-alkylhydroxylamines. J. Org. Chem. 61,
442–443.
67. Parmar, D., Sugiono, E., Raja, S., and Rueping,
M. (2014). Complete field guide to asymmetric
BINOL-phosphate derived Brønsted acid and
metal catalysis: history and classification by
mode of activation; Brønsted acidity, hydrogen
bonding, ion pairing, and metal phosphates.
Chem. Rev. 114, 9047–9153.
52. Ren, S., Song, S., Ye, L., Feng, C., and Loh, T.-P.
(2016). Copper-catalyzed oxyamination of
electron deficient alkenes with
37. Berman, A.M., and Johnson, J.S. (2004).
Copper-catalyzed electrophilic amination of
diorganozinc reagents. J. Am. Chem. Soc. 126,
5680–5681.
N-acyloxyamines. Chem. Commun. 52, 10373–
10376.
Chem 3, 1–12, December 14, 2017
11

Please cite this article in press as: Wang et al., Catalytic Asymmetric Radical Diamination of Alkenes, Chem (2017), https://doi.org/10.1016/
j.chempr.2017.10.008
68. Yang, Z.-P., Zhang, W., and You, S.-L. (2014).
Catalytic asymmetric reactions by metal and
chiral phosphoric acid sequential catalysis.
J. Org. Chem. 79, 7785–7798.
aminohalogenation/cyclization involving
atom transfer. Angew. Chem. Int. Ed. 51, 3923–
3927.
76. Mase, N., Tanaka, F., and Barbas, C.F., III
(2004). Synthesis of b-hydroxyaldehydes with
stereogenic quaternary carbon centers by
direct organocatalytic asymmetric Aldol
reactions. Angew. Chem. Int. Ed. 43, 2420–
2423.
73. Ackermann, J., Amrein, K., Kuhn, B., Mayweg,
A.V., and Neidhart, W. (2009). Imidazolidinone
derivatives as 11b-HSD1 inhibitors. Patent WO
2009/132986, filed April 21, 2009, and
69. Akiyama, T., and Mori, K. (2015). Stronger
Brønsted acids: recent progress. Chem. Rev.
115, 9277–9306.
77. Mase, N., Thayumanavan, R., Tanaka, F., and
Barbas, C.F., III (2004). Direct asymmetric
organocatalytic Michael reactions of
a,a-disubstituted aldehydes with
published November 5, 2009.
70. James, T., van Gemmeren, M., and List, B.
(2015). Development and applications of
disulfonimides in enantioselective
74. Betancort, J.M., and Barbas, C.F., III (2001).
Catalytic direct asymmetric Michael reactions:
taming naked aldehyde donors. Org. Lett. 3,
3737–3740.
b-nitrostyrenes for the synthesis of quaternary
carbon-containing products. Org. Lett. 6,
2527–2530.
organocatalysis. Chem. Rev. 115, 9388–9409.
71. Wang, Z., Hong, W.-X., and Sun, J. (2016).
Organocatalytic enantioselective
desymmetrization of meso-aziridines and
prochiral azetidines. Curr. Org. Chem. 20,
1851–1861.
78. Mase, N., Watanabe, K., Yoda, H., Takabe, K.,
Tanaka, F., and Barbas, C.F., III (2006).
Organocatalytic direct Michael reaction
of ketones and aldehydes with
75. Betancort, J.M., Sakthivel, K., Thayumanavan,
R., Tanaka, F., and Barbas, C.F., III (2004).
Catalytic direct asymmetric Michael reactions:
addition of unmodified ketone and aldehyde
donors to alkylidene malonates and nitro
olefins. Synthesis, 1509–1521.
b-nitrostyrene in brine. J. Am. Chem. Soc. 128,
4966–4967.
72. Bovino, M.T., and Chemler, S.R. (2012).
Catalytic enantioselective alkene
12
Chem 3, 1–12, December 14, 2017