Synergistic copper-TEMPO catalysis of intermolecular vicinal diamination of styrenes

Article abstract of DOI:10.1016/j.tetlet.2017.01.015

A copper-catalyzed, 2,2,6,6-tetramethyl piperidine N-oxy radical-assisted intermolecular diamination of styrenes with N-fluorobenzenesulfonimide has been developed. The current protocol proved amenable to a diverse array of styrenes via cascade radical addition to readily afford synthetically useful aromatic vicinal diamines with exclusive diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2017.01.015

Accepted Manuscript
Synergistic Copper-TEMPO catalysis of intermolecular vicinal diamination of
styrenes
Shiue-Shien Weng, Kun-Yi Hsieh, Zih-Jian Zeng, Jia-Wei Zhang
PII:
S0040-4039(17)30027-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.015
TETL 48518
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
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2 January 2017
4 January 2017
Please cite this article as: Weng, S-S., Hsieh, K-Y., Zeng, Z-J., Zhang, J-W., Synergistic Copper-TEMPO catalysis
of intermolecular vicinal diamination of styrenes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.01.015
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Tetrahedron Letters
Synergistic Copper-TEMPO catalysis of intermolecular vicinal diamination of
styrenes
Shiue-Shien Weng, Kun-Yi Hsieh, Zih-Jian Zeng, Jia-Wei Zhang
Department of Chemistry, ROC Military Academy, No.1, Wei-Wu Rd., Fengshan Dist, Kaohsiung City 830, Taiwan, ROC
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A copper-catalyzed, 2,2,6,6-tetramethyl piperidine N-oxy radical-assisted intermolecular
diaminaton of styrenes with N-fluorobenzenesulfonimide has been developed. The current
protocol proved amenable to a diverse array of styrenes via cascade radical addition to readily
afford synthetically useful aromatic vicinal diamines with exclusive diastereoselectivity.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Intermolecular diamination of styrenes
2,2,6,6-tetramethyl piperidine N-oxy radical
N-fluorobenzenesulfonimide
radical addition
vicinal diamines
Vicinal diamines are highly important functional groups in a
wide range of bioactive compounds and natural products. In
addition, functionalized 1,2-diamines have been broadly applied
as chiral ligands and auxiliaries.1 As a result, considerable efforts
have been directed toward the development of efficient methods
for their synthesis.2,3 Transition metal-catalyzed diamination of
amino-tethered alkenes has become the most popular approach
because it is currently the most efficient and shortest route for the
practical synthesis of 1,2-diamimes.4 In addition, the groups of
Chemler and Michael independently established a method for
accessing vicinal diamine-containing heterocycles via the copper-
and palladium-catalyzed oxidative diamination of anchored
amino alkenes using electron-deficient sulfonamides, anilines or
N-fluorobenzenesulfonimide (NFSI) as secondary intermolecular
aminative coupling sources.5,6 These two oxidative
transformations are of interest because high levels of
enantioselectivities can be introduced into the heterocycle
frameworks in the presence of suitable chiral auxiliaries.4-6 In
addition to these remarkable achievements, Shi and coworkers
developed a copper- or palladium-catalyzed enantioselective
intermolecular alkene diamination that uses diaziridines as the
oxidative nitrogen sources and provides an advanced solution for
circumventing the inherently more challenging intermolecular
version of this reaction.4,7 Furthermore, Mũniz reported the chiral
hypervalent iodine-mediated asymmetric diamination of alkenes,
which represents another straightforward route to the direct,
intermolecular installation of two amino groups across a double
bond.3
NFSI has recently been widely employed as an oxidative
nitrogen source in transition metal-catalyzed amination
reactions.6,8 The ability to easily produce the electrophilic
bissulfonylamidyl radical (·N(SO2Ph)2) via the oxidative addition
of Cu with NFSI provides an opportunity to use a cascade radical
reaction to conduct the vicinal aminative difunctionalization of
alkenes or alkynes (Scheme 1).9 Among these remarkable
achievements, the Cu(I)-catalyzed intermolecular aminoazidation
and diamination of alkenes to incorporate azidosilane and
reaction solvents have also been realized through the formation
of Si-F or B-F bonds in the second amination step.9e,f This
conceptually inspired us to further explore the utility of NFSI in
the field of aminative difunctionalization of alkenes. Herein, we
report a new Cu(I)-catalyzed intermolecular diamination of
styrenes that employs NFSI as the sole nitrogen source and
hexamethyldisilane (HMD) as an external fluoride radical
scavenger, with the assistance of the reductive 2,2,6,6-
tetramethyl piperidine N-oxy radical (TEMPO).10
N3
Previous work
R3
Me3SiN3
R1
R2
N(SO2Ph)2
R2
5 mol% CuCl
R3
R'(O)CHN
R1
R3
R1
R2
PhB(OH)2
R'CN
N(SO2Ph)2
This work
5 mol% CuCl
10 mol% TEMPO
N(SO2Ph)2
R2
R1
R1
Ar
R2
Ar
NFSI/TMD2
N(SO2Ph)2
Scheme 1. Copper-catalyzed vicinal diamination of alkenes.
———
 Corresponding author. Tel/fax: +886-07-742-6151; e-mail: wengss@mail.cma.edu.tw (S.-S. W)

2
Tetrahedron Letters
Table 1 Catalyst screening.a
bidentate and hindered 2,2,6,6-hexamethyl heptan-3,5-dione
5 mol% catalyst
(TMHD) ligand gave the highest yield (45%) of 1a (Table 1,
entry 9). Several effective fluoride scavengers were also
examined.9e Hexaphenyldisilane and bis(pinacolate)diboron
(B2Pin2) showed similar reactivity with HMD (Table 1, entries 10,
and 11), whereas nBuBF3K deactivated the reaction (Table 1,
entry 12). It is noteworthy that approximately 10-15 % of the
Ritter-type by-product was consistently observed in the
aforementioned Cu(I)-catalyzed manipulations.
N(SO2Ph)2
N(SO2Ph)2
1.0 equiv F-scavenger
+
Ph
NFSI
additive
Ph
CH3CN, 70 oC, 2h
1a
Entry
catalyst
F- scavenger (additive)
Yield(%)
1
CuCl2
(Me3Si)2
0 (18)b
24
23
19
27
28
36
39
45
44
40
34
49
55
53
57
61
66
2
CuCl
(Me3Si)2
3
CuBr
(Me3Si)2
O
O
4
CuI
(Me3Si)2
H3C
NH
N(SO2Ph)2
N(SO2Ph)2
5
CuCl/bipy
CuCl/phen
CuCl/2,6-lutidine
CuCl/BC
(Me3Si)2
6
(Me3Si)2
2
3
Figure 1. Undesired byproducts.
7
(Me3Si)2
To eliminate the undesired Ritter product, we envisaged that
an external reductant might suppress the oxidation of the α-
carbon radical by the high valent copper catalyst. Metal
reductants such as elemental Mn, Fe, and Mo(CO)6 were indeed
found to inhibit the Ritter-type side reaction, and the yield of
product 1a increased to 49-55 % (Table 1, entries 13-15).11
Furthermore, we noticed that N-oxy radicals have been
commonly used to reduce Cu(II) to the Cu(I);12 thus, 50 mol % of
reductive TEMPO was evaluated in the reaction. We observed
that the Ritter-type reaction was suppressed and that the yield
significantly improved to 57 % in the presence of TEMPO (Table
1, entry 16), although a trace amount of the oxyamination
product from TEMPO and the carbon radical was observed.9c
Lowering the amount of TEMPO to 0.15 equiv diminished the
undesired oxyamination coupling and increased the yield of 1a to
61 % (Table 1, entry 17). However, telomerization of styrene
under the reaction conditions was problematic, although TEMPO
is usually used to terminate polymerization,8b likely because all
of the TEMPO was oxidized by Cu(II) or NFSI during the
reaction.8b,11d The yield was further increased by the addition of 5
mol% of nBu4NCl, probably because the quaternary ammonium
salt might act as co-initiator to improve the amidyl radical
production (66 %, Table 1, entry 18).13 The best yield was
obtained upon increasing the loading of HMD to 1.5 equiv (Table
1, entry 19). Note that conducting the reaction in air inhibited the
desired transformation, and the oxyamination product 3 was
obtained in 14% yield (Table 1, entry 20). This result implies that
the isolation of 3 resulted from the trapping of oxygen by the
corresponding α-carbon-centered radical that is formed in the
second step. Finally, no reaction was observed in the absence of a
Cu(I) salt (Table 1, entry 21), and further optimization of the
reaction did not improve the yield (See Supplementary data,
Table S1).
8
(Me3Si)2
9
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
CuCl/TMHD
(Me3Si)2
10
11
12
13
14
15
16
17
18
(Ph3Si)2
B2pin2
nBuBF3K
(Me3Si)2/0.5 eq Mn
(Me3Si)2/0.5 eq Fe
(Me3Si)2/0.5 eq Mo(CO)6
(Me3Si)2/0.5 eq TEMPO
(Me3Si)2/0.15 eq TEMPO
(Me3Si)2/0.15 eq TEMPO/
0.05 eq nBu4NCl
19
20
CuCl/TMHD
CuCl/TMHD
none
(Me3Si)2/0.15 eq TEMPO/
0.05 eq nBu4NCl
71d
(Me3Si)2/0.15 eq TEMPO/
0.05 eq nBu4NCl, Air
0 (14)e
0
21
(Me3Si)2/0.15 eq TEMPO/
0.05 eq nBu4NCl
a
Reaction conditions: styrene (0.5 mmol), NFSI (1.5 mmol,
3.0 equiv), (TMS)2 (0.5 mmol), catalyst (5 mol%), ligand: 5
mol%, 1 mL of CH3CN (0.5 M), 70 oC, N2 atmosphere, 2h.
bProduct 2 was obtained as the side-product.
c (Me3Si)2: hexamethyldisilane (HMD); phen: phenanthroline;
bipy: 2,2'-bipyridine; BC: bathocuproine; TfO: trifluoromethane
sulfonate; TMHD: 2,2,6,6-hexamethyl heptan-3,5-dione; B2pin2:
bis(pinacolate)diboron.
d 1.5 equiv of (Me3Si)2 was used.
Using the optimized reaction conditions (Table 1, entry 19),
the scope of the diamination of vinyl arenes was examined (Table
2). Electron-donating methyl and tert-butyl groups on the phenyl
ring were tolerated to afford the expected products 1b-e in 66-73
% yields, and the ortho-substituted methyl group (1b) led to a
slightly decreased yield due to the steric effect. The reaction of 4-
methoxystyrene was failed due to deprotection of the methoxy
group thus interfered the reaction. Other electron-rich groups
such as -OAc and -CH2OAc also reacted smoothly to provide
diamines 1g and 1h in high yields. However, 2-vinyl naphthalene
and the conjugated 4-phenyl-substituted styrene were found to be
less reactive, affording 1i and 1j in 58% and 62% yields. Chloro-
and bromo-substituted styrenes were particularly suitable
substrates for this transformation and provided the products 1k-n
in good to excellent yields (70-81%), even though the expected
steric effect was observed for 1k. Strongly electron-deficient
fluoro, trifluoromethyl (CF3-) and ortho-carboxylate groups
deactivated the reaction, although moderate to low yields (61 and
36 %) were still achieved upon prolonging the reaction time (1o-
q). A diastereoselective screening of this reaction toward β-
substituted styrenes and cyclic alkenes provided the trans-
e 14% of 3 was obtained as the main product.
Our initial studies focused on a model reaction of 1.0 equiv of
styrene, 3.0 equiv of NFSI, and 1.0 equiv of (Me3Si)2 in the
presence of various copper catalysts (5 mol%) in acetonitrile
under an N2 atmosphere (Table 1). Divalent copper was found to
be inactive toward the desired diaminative manipulation.
However, the participation of the solvent in the reaction resulted
in the formation of diamination product 2 as a by-product after
aqueous workup (18 %, Table 1, entry 1). This unexpected result
implied that an α-carbocation might be involved in the second
step via the oxidation of the high valent Cu(III) species after the
initial addition of the amidyl radical to the styrene.9f Cu(I)
catalysts showed mild catalytic activity to afford the desired
diamine product 1a in low yields after 2 h (Table 1, entries 2-4).
Higher efficiencies were observed when CuCl was used with
basic ligands, especially with hindered ligands (Table 1, entries
5-8).8 Similar to the previously reported results obtained for the
Cu(I)-catalyzed carboamination of alkenes,9g the use of acidic

diamines 1r-1t in good yields (72-77% yields) with complete
trans selectivity. We further applied the current protocol to the
unprotected (E)-4-(4-fluorophenyl)but-3-en-1-ol, which was
efficiently difunctionalized to the hydroxyl-tethered cis-
platinum precursor 1u with exclusive diastereocontrol and 70%
yield.14 The bissulfonamide groups of 1s can be readily removed
by treating 1s with NaOH in reflux ethanol to afford the
disulfonamide 4 and subsequently desulfonylation of 4 by
Na/naphthalene to provide diamine 5 in 84% yield (Scheme 2).15
We next explored the scope of α-disubstituted styrenes and
activated α,β-unsaturated alkenes (Scheme 3). α-Methyl styrene
and α-phenyl styrene were found to undergo elimination to afford
enamines 6 and 7 in 77 and 84 % yield, respectively.9c
Interestingly, α,β-unsaturated alkenes such as ethyl acrylate,
methyl vinyl ketone, and vinyl nitrile did not proceed through the
desired diamination manipulation, and the hydroamination
products 8, 9, and 10 were instead isolated in high yields.
Unactivated aliphatic alkenes unfortunately reacted via the
precedented carboamination pathway to provide sultams 11a-c in
56-68% yield.9g Even the tertiary α-disubstituted 2-methyl
hexene, which was expected to produce a more stable tertiary α-
carbon radical, also underwent carboamination to give a 71 %
yield of sultam 11d.
1
The relative stereoconfiguration of 1s was determined by H
NMR after deprotection, and that of 1t was determined by X-ray
crystallography.16 The stereoconfigurations of 1r and 1u were
deduced by analogy to 1s.
O
CH2
Table 2 Scope of diamination of vinyl arenes.a
Ph
Ph
N(SO2Ph)2
N(SO2Ph)2
6, 77%
Ph
EtO
N(SO2Ph)2
5mol% CuCl/TMHD
N(SO2Ph)2
8, 81%
7, 84%
15 mol% TEMPO
R1
R1
Ar1
3.0 equiv NFSI
+
Ar1
1.5 equiv (Me3Si)2
5 mol% nBu4NCl
CH3CN, 70 oC, 2h
N(SO2Ph)2
SO2
O
N(SO2Ph)2
NC
N(SO2Ph)2
N
N(SO2Ph)2
CH3
N(SO2Ph)2
R1
R2
SO2Ph
N(SO2Ph)2
H3C
H3C
11a, 64%, R1=H, R2=CH2Ph
10, 71%
9, 74%
N(SO2Ph)2
1d, 70%
11b, 56%, R1=H, R2=(CH2)5CH3
11c, 68%, R1=H, R2=cyclohexyl
11d, 71%, R1=CH3, R2=(CH2)3CH3
N(SO2Ph)
2 H3C
N(SO2Ph)2
1b, 66%
1c, 73%
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
Scheme 3.
N(SO2Ph)2
N(SO2Ph)2
The ability of a limited amount of TEMPO (15 mol%) to
suppress the Ritter by-product that resulted from the oxidation of
carbon radical further proves the synergistic role of TEMPO in
assisting the catalytic turnover of the Cu(I) catalyst (Table 1,
entries 17-19). We envisaged that cooperative redox coupling
between TEMPO, TEMPO+, and HMD might also be involved in
the catalytic turnover process because HMD was previously
reported to be a radical or anionic reducing reagent.17 Control
reactions revealed that TEMPO+ could be reduced to TEMPO in
the presence of HMD and Cu(I) catalyst to give a quantitative
yield of HN(SO2Ph)2, as shown in Eq(1). In contrast,
HN(SO2Ph)2 was obtained in only 62% yield and TEMPO was
not produced in the reaction conducted in the absence of HMD.
This result indirectly proved the role of HMD in the reduction of
TEMPO+. In addition, the inactive Cu(II) catalyst became
reactive towards diamination (Eq. 2) upon reduction to Cu(I) by
TEMPO, although with low efficiency (compared with Table 1,
entry 1).
N(SO2Ph)2
1g, 74%
AcO
H3CO
t Bu
1f, 0%
1e, 71%
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
Ph
1h, 73%
1i, 58%
1j, 62%
OAc
N(SO2Ph)2
Cl
N(SO2Ph)2
N(SO2Ph)2
Cl
N(SO2Ph)2
1m, 77%
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
1k, 70%
Cl
1l, 76%
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
F3C
Br
F
1p, 36%c
1o, 54%b
1n, 81%
H3CO
O
N(SO2Ph)2
Ph
N(SO2Ph)2
N(SO2Ph)2
1.5equiv
(Me3Si)2
CH3
+
5 mol% CuCl
HN(SO2Ph)2
quant.
N
N(SO2Ph)2
1s, 77%
N(SO2Ph)2
N(SO2Ph)2
N(SO2Ph)2
1q, 61%c
1.0 equiv NFSI
O
(1)
(2)
86 %
CH3CN, 70 oC, 1h
N
O
1r, 72%
-
BF4
HN(SO2Ph)2
62%
N(SO2Ph)2
N(SO2Ph)2
OH
N(SO2Ph)2
N(SO2Ph)2
5mol% CuCl2/TMHD
N(SO2Ph)2
15 mol% TEMPO
Ph
F
3.0 equiv NFSI
+
Ph
1.5 equiv (Me3Si)2
CH3CN, 70 oC, 2h
1u, 70%b
47%
1t, 73%
On the basis of the previous investigations and our
experimental observations, a possible mechanism is proposed
(Scheme 4).8b,9 First, the oxidation of Cu(I) with NFSI affords a
Cu(III)-bissulfonamide adduct, which transforms to the isomeric
Cu(II)-stabilized amidyl radical through a redox equilibrium. The
corresponding amidyl radical subsequently adds to the styrene to
provide an α-carbon-centered radical, which then couples with an
additional amidyl radical to complete the diamination
manipulation. Reduction of the Cu(II) species is performed by
TEMPO via a single electron transfer (SET) process that
simultaneously eliminates Me3Si-F by incorporating HMD2,
thereby regenerating the Cu(I) catalyst for the next catalytic cycle.
a
Reaction conditions: Vinyl arene (0.5 mmol), NFSI (1.5
mmol), (TMS)2 (0.75 mmol), CuCl (5 mol%), TMHD: 5 mol%,
15 mol% TEMPO, 1 mL of CH3CN (0.5 M), 70 oC, N2
atmosphere, 2h.
bReaction time: 20 h.
c Reaction time: 3 h.
NHSO2Ph
N(SO2Ph)2
Ph
NH2
Na/Naphthalene
THF/0oC to rt
NaOH/EtOH
reflux, 6 h
78%
Ph
Ph
Ph
Ph
Ph
84%
NHSO2Ph
N(SO2Ph)2
5
NH2
4
1s
In conclusion, we have demonstrated the copper-catalyzed
deamination of styrenes with NFSI as the sole nitrogen source
under the assistance of a reductive TEMPO co-catalyst. The
current protocol works for a variety of styrenes to give exclusive
diastereoselectivity and offers excellent advantages including
Scheme 2. Deprotection of bissulfonamide groups of 1s.

4
Tetrahedron Letters
mild reaction conditions, and operational simplicity, and has the
potential to be widely adopted in future applications.
TEMPO+
Me3Si-F
CuICl
1/2(Me3Si)2
TEMPO
Ph
Cl
F-CuII
+
Cl
F-CuIII-N(SO2Ph)2
N(SO2Ph)2
Cl
F-CuII
+
N(SO2Ph)2
N(SO2Ph)2
Ph
N(SO2Ph)2
N(SO2Ph)2
Ph
Scheme 4. proposed catalytic cycle.
Acknowledgments
This work was supported by the Ministry of Science and Technology ROC, Taiwan (MOST-103-2113-M-145-001),
and the authors declare no competing financial interest. We thank Center for Resources and Development (CRRD),
Kaohsiung Medical University for the services in NMR analysis.
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Supplementary Material
1
Supplementary material (Full characterization data and H, 13C NMR spectra for all compounds related to this article can be
found at http://dz.doi.org/

Graphical Abstract
Synergistic Copper-TEMPO catalysis of
intermolecular vicinal diamination of
styrenes
Leave this area blank for abstract info.
Shiue-Shien Weng, Kun-Yi Hsieh, Zih-Jian Zeng, Jia-Wei Zhang
N(SO2Ph)2
R2
5 mol% CuCl
15 mol% TEMPO
R1
R1
Ar
R2
Ar
F-N(SO2Ph)2/(Me3Si)2
5 mol% nBu4NCl
N(SO2Ph)2
36-81% yield
exclusive trans diastereoselectivities

5
Highlights
1. Cu(I)-catalyzed intermolecular N-,N-bond
installation across a double bond.
2. N-Fluorobenzenesulfonimide as the only
nitrogen source.
3. Reductive N-oxy radical and hexamethyldisilane
benefit the catalytic turnover.