Copper-Catalyzed Oxidative Oxyamination/Diamination of Internal Alkenes of Unsaturated Oximes with Simple Amines

Article abstract of DOI:10.1021/acscatal.6b02065

A convenient and versatile oxidative intra/intermolecular oxyamination and diamination of unactivated alkenes has been developed through copper-catalyzed radical reactions of β,γ- and γ,δ-unsaturated ketoximes with electron-rich aryl and aliphatic amines. These reactions were carried out by employing di-tert-butyl peroxide (DTBP) or air as the terminal oxidant, and a series of useful nitrogen-containing 4,5-dihydroisoxazoles and cyclic nitrones were formed.

Full text of DOI:10.1021/acscatal.6b02065

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Letter
Copper-Catalyzed Oxidative Oxyamination/Diamination of
Internal Alkenes of Unsaturated Oximes with Simple Amines
Rui-Hua Liu, Dian Wei, Bing Han, and Wei Yu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02065 • Publication Date (Web): 29 Aug 2016
Downloaded from http://pubs.acs.org on August 29, 2016
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Copper-Catalyzed Oxidative Oxyamination/Diamination of In-
ternal Alkenes of Unsaturated Oximes with Simple Amines
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RuiꢀHua Liu, Dian Wei, Bing Han*, and Wei Yu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, 730000 P. R. China
ABSTRACT: A convenient and versatile oxidative intra/interꢀmolecular oxyamination and diamination of unactivated alkenes has
been developed through copperꢀcatalyzed radical reactions of β,γꢀ and γ,δꢀunsaturated ketoximes with electronꢀrich aryl and aliphatꢀ
ic amines. These reactions were carried out by employing diꢀtertꢀbutyl peroxide (DTBP) or air as the terminal oxidant, and a series
of useful nitrogenꢀcontaining 4,5ꢀdihydroisoxazoles and cyclic nitrones were formed.
alkene, Cu, diamination, iminoxyl radicals, oxyamination
The vicinal oxyamination and diamination of unactivated alꢀ
kenes have received wide attention in recent years because
they provide rapid and efficient approaches towards structuralꢀ
ly important vicinal amino alcohol and diamine moieties.1 A
number of nitrogen sources such as ureas,2 amides,3 diaziriꢀ
dines,4 amidines,5 and azides6 have been explored for framing
these skeletons. However, the alkyl and arylamines, which are
abundant, cheap but important chemicals, are difficult to parꢀ
ticipate in these processes.7 To achieve this goal, several
methods have been developed, but they all require the use of
stoichiometric amount of environmentally unfriendly oxidants
such as hypervalent iodines7aꢀd (Scheme 1, a) and copper salts
(Scheme 1, b)3a or highly toxic heavy metal salts.7eꢀf Very reꢀ
cently, an elegant copperꢀcatalyzed alkene diamination and
oxyamination was reported by Wang et al., but their nitrogen
sources are only limited to secondary benzoyloxyamines.7iꢀj
Thus, more efficient and general catalytic methodologies for
the simple primary and secondary amineꢀinvolved oxyaminaꢀ
tion and diamination of unactivated alkenes are still in demand.
Iminoxyl radicals belong to a group of typical σꢀradicals
with the single electron spin delocalized on both the O and N
atoms.8 Iminoxyl radicals can be conveniently generated from
oximes via oxidation. Our recent studies demonstrate that the
readily prepared β,γꢀ and γ,δꢀunsaturated ketoximes can be
initiated to the corresponding iminoxyl radicals, which would
undergo radical cyclization to produce carbonꢀcentered radiꢀ
cals. Depending on the position of the tethered olefins, the
cyclization occur either in a Oꢀ5ꢀexoꢀtrig or Nꢀ5ꢀexoꢀtrig patꢀ
tern.9 The thusꢀformed Cꢀcentered radicals can be captured by
trapping agents such as 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinylꢀoxy
(TEMPO) and diethyl azodicarboxylate (DEAD). In this way,
dioxygenation, oxyamination, and diamination of unactivated
alkenes can be realized. Although these reactions are synthetiꢀ
cally useful, they have some limitations in scope due to the use
of expensive and structurally special radical traps. To overꢀ
come this obstacle, herein we wish to report a simple and effiꢀ
cient amineꢀinvolved catalytic radical method for the inꢀ
tra/intermolecular oxidative oxyamination and diamination of
β,γꢀ and γ,δꢀunsaturated ketoximes10 The reactions were realꢀ
ized by using diꢀtertꢀbutyl peroxide (DTBP) or air as the oxiꢀ
dant and Cu(OAc)2 as the catalyst, and through which a varieꢀ
ty of useful nitrogenꢀcontaining isoxazolines and cyclic
nitrones were obtained (Scheme 1, c). These heterocyclic
compounds possess broad biochemical and pharmaceutical
Scheme 1. Diamination and Oxyamination of Unactivated
Alkenes Employing Electronꢀrich Amines
properties.11 To the best of our knowledge, the current reacꢀ
tions constitute the first metalꢀcatalyzed oxidative oxyaminaꢀ
tion and diamination of unactivated alkenes with aryl and aliꢀ
phatic amines as the nitrogen source. This new protocol is
highly environmentally friendly as air can be used as the stoiꢀ
chiometric oxidant.
We commenced our study by the subjecting a mixture of
β,γꢀunsaturated ketoxime 1a and aniline 2a to the conditions of
o
DTBP and Cu2O in acetonitrile at 100 C under an argon atꢀ
mosphere for 1.5 h. To our delight, the desired oxyamination
product 3a was obtained in a yield of 44% (Table1, entry 1).
Several copper salts were then tested for their catalytic capaciꢀ
ty, and it was found that using Cu(OAc)2 as catalyst delivered
the best yield of 3a (72%) (Table 1, entries 2−5). The yield
can be further improved by the addition of 2,2′ꢀbipyridine, but
adding 1,10ꢀphenanthroline, 1,4ꢀdiazabicycloꢀoctane triethyꢀ
lenediamine (DABCO), or pyridine had no beneficial effect on
the reaction (Table 1, entries 6−9). Besides DTBP, tertꢀbutyl
hydroperoxide (TBHP), dicumyl peroxide (DCP) and tertꢀ
butyl peroxybenzoate (TBPB) can also act as the terminal
oxidant, but with them the yield was lower (Table 1, entries
10−12). No better yield was obtained when other solvents such
as toluene, benzotrifluoride and DMF were used (Table 1,
entries 13−15). Although using DTBP as oxidant gave a
satisfactory result (Table 1, entry 6, conditions A), we went on
with our exploration by using air as oxidant. From
economicand environmental points of view, air is an ideal
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Scheme 2. Scope of β,γꢀUnsaturated Oximesa,b,c
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Table 1. Optimization of the Reaction Conditionsa
1
2
3
4
5
6
7
8
9
entry
1
Cu
ligand
solvent oxidant yield (%)b
Cu2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DTBP
DTBP
DTBP
DTBP
DTBP
44
17
72
31
21
81
63
69
62
40
52
80
61
53
54
62
0
2
CuCl
3
Cu(OAc)2
CuBr2
4
10
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5
CuCl2
6
Cu(OAc)2
Cu(OAc)2
bpy
CH3CN DTBP
7
Phen
CH3CN
DTBP
DTBP
DTBP
TBHP
DCP
aAll reactions run in 0.3 M MeCN using oxime 1 (0.3 mmol),
8
Cu(OAc)2 DABCO CH3CN
Cu(OAc)2 pyridine CH3CN
ammine 2a (3 equiv), bpy (0.25 equiv), and Cu(OAc)2 (0.2 equiv)
9
o
at 100 C for 1.5 h. Conditions A: DTBP (3 equiv) used as the
b
c
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17
18c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
CH3CN
CH3CN
CH3CN
DMF
oxidant; Conditions B: Air used as the oxidant. Isolated yields.
Yields in parentheses were obtained under conditions B. dThe
configuration of diastereomer was determined by coupling conꢀ
stants of 1H NMR and NOE.
TBPB
DTBP
DTBP
DTBP
air
Next, we explored the applicability of the protocol by
employing a vast variety of aromatic and aliphatic amines. Our
results show that both aromatic and aliphatic amines are good
aminating reagents under the standard reaction conditions
(Scheme 3). 4ꢀSubstituted anilines with a broad range of
PhCH3
PhCF3
CH3CN
CH3CN
CH3CN
DTBP
Cu(OAc)2
65
Scheme 3. Scope of Aminesa,b,c
aReaction conditions: 1a (1 equiv, 0.3 mmol), 2a (3 equiv, 0.9
mmol), copper salt (0.2 equiv, 0.06 mmol), oxidant (3 equiv, 0.9
o
mmol), ligand (0.25 equiv, 0.075 mmol), solvent (1 mL), 100 C,
1.5 h. bIsolated yield. DTBP = diꢀtertꢀbutylperoxide, TBHP = tertꢀ
butyl hydroperoxide, DCP = dicumyl peroxide, TBPB = tertꢀbutyl
peroxy benzoate, bpy
=
2,2′ꢀdipyridyl, Phen
=
1,10ꢀ
phenanthroline, DABCO = triethylenediamine. cCu(OAc)2 (3
equiv, 0.9 mmol) was used as the oxidant.
oxidant. Using air as the terminal oxidant would render this
protocol more attractive in practical synthesis and sustainable
chemistry. To our great delight, when the reaction was carried
out under the air atmosphere, 3a was obtained in 62% yield
(Table 1, entry 16, conditions B), along with a small amount
the oxygen captured isoxazoline (See Supporting
Information.). Our control experiment shows that copper was
essential for the reaction to take place. Without copper, no
compound 3a was detected under the otherwise same condiꢀ
tions (Table 1, entry 17). When a stoichiometric amount of
Cu(OAc)2 was used alone as oxidant, on the other hand, 3a
was obtained in a yield of 65% (Table 1, entry 18).
With the optimal conditions in hand, the scope of the reacꢀ
tion was then examined. Firstly various β,γꢀunsaturated ketoxꢀ
imes 1 was allowed to react with aniline 2a, and the results are
summarized in Scheme 2. The reaction proceeded well for
both aryl and alkyl substituted β,γꢀunsaturated ketoximes, deꢀ
livering the desired oxyamination products isoxazalines 3a−h
in good to excellent yields. Thiopheneꢀsubstituted β,γꢀunsaturꢀ
ated ketoxime was also suitable for the process, with the corꢀ
responding product 3i being generated in good yield. In addiꢀ
tion, this oxyamination method is applicable to 1,1ꢀdisubstitutꢀ
ed alkenes such as 3j. When the alkene moiety was merged
into a ring, as in the case of 1k, the reaction gave the oxyamiꢀ
nation product 3k in 21% yield, along with the isoxazolineꢀ
fused cyclopentanone 3k′ and cyclopentenone 3k′′ in 17% and
23% yields, respectively.12
aAll reactions run in 0.3 M MeCN using oxime 1a (0.3 mmol),
ammine 2 (3 equiv), bpy (0.25 equiv), and Cu(OAc)2 (0.2 equiv)
o
at 100 C for 1.5 h. Conditions A: DTBP (3 equiv) used as the
b
oxidant Conditions B: Air used as the oxidant. Isolated yields.
cYields in parentheses were obtained under conditions B.
electronic properties participated smoothly in the reaction,
affording the corresponding oxyamination products 3l−o in
good to excellent yields. Heterocyclic primary amines and
secondary anilines are also suitable for this transformation
(3p−r). Moreover, it is noteworthy that both primary and
secondary aliphatic amines, such as 1ꢀbutylamine, 1ꢀ
heptylamine, cyclohexylamine, piperidine, and morpholine,
which have seldom been employed in direct amination, are
good aminating reagents as well; with them the oxyamination
products 3s–w in moderated to good yields under both
conditions. Significantly, chiral amine such as (S)ꢀ1ꢀphenylꢀ
ethanamine was also suitable for the protocol, and gave the
chirality retained product 3x in 41% yield and 10% de
(Scheme 4).
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were prepared as the radical probe13 and then subjected to
Scheme 4. Chiral AmineꢀInvolved Reaction
1
conditions A as illustrated in Scheme 6. When 6 was allowed
to react with 2a under conditions A, the anticipated ringꢀ
opening amination product 8 was obtained in 31% yield along
with the ringꢀopening elimination product 1,3ꢀdiene 9 in 21%
yield (Scheme 6, eqn 1). The formation of the latter is
consistent with the fact that homoallylic carbon radicals
derived from ringꢀopening tend to undergo elimination to form
1,3ꢀdiene in the presence of copper salts.12c A similar result
was also obtained in the case of 7, where the ringꢀopening
amination product 10 was obtained in 48% yield accompanied
by the 1,3ꢀdiene 11 in trace amount (Scheme 6, eqn 2). In both
cases, no corresponding anilinomethylcyclopropane was
Cu(OAc)2 (0.2 equiv)
bpy (0.25 equiv), MeCN
OH
2
N
O
H
NH2
N
N
+
Ph
3
4
(S)
Conditions A: DTBP (3 equiv)
Ph
Ph
Ph
(S)-1-phenyl-
ethanamine
3x
1a
41% (10% de)
5
6
7
8
9
Encouraged by the success of oxyamination of β,γꢀ
unsaturated ketoximes, we wondered whether their γ,δꢀ
unsaturated counterparts could undergo diamination through
an analogous Nꢀatom 5ꢀexoꢀtrig cyclization as demonstrated in
our previous work.9 Gratifyingly, the desired intra/interꢀ
molecular diamination of unactivated alkenes could be easily
implemented by subjecting γ,δꢀunsaturated ketoximes and
amines to both conditions A and B. In this way, a variety of
useful nitrogenꢀcontaining cyclic nitrones 5a–z were obtained
as shown in the Scheme 5. Noticeably, the sterically hindered
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1
detected by H NMR analysis. Further evidence for the inꢀ
volvement of iminoxyl radicals came from the trapping experꢀ
iment with butylated hydroxytoluene (BHT). When 1.5 equiv
of BHT was added into the reaction system under standard
conditions A, the BHT−oxime adduct was detected in the
crude product by the ESIꢀHRMS measurement (Figure 1),14
while the yield of desired product was lowered to 51%
(Scheme 6, eqn 3).
Scheme 5. Scope of γ,δꢀUnsaturated Oximes and Aminesa,b,c
R4
Cu(OAc)2 (0.2 equiv)
bpy (0.25 equiv), MeCN
OH
N
O
N
R5
H
N
N
+
R4
R5
R1
A
Conditions : DTBP (3 equiv)
R1
Scheme 6. The Radical Probe and BHT Scavenging Experꢀ
iments
R2 R3
Conditions B: air
R2
R3
2
4
5
H
H
H
N
O
N
O
N
O
Ph
HO
Ph
N O
Ph
2a
Ph
N
N
X
N
N
O
N
Ph
eqn 1
N
+
N
Ph
Ph
A
conditions
H
Ph
Ph
8
, 31% (E/Z>20:1)
S
9, 21%
6
7
5g, 77% (68%)
5f, 59% (48%)
X = 4-H, 5a, 81% (71%)
O
N
4-MeO, 5b, 83% (73%)
4-Cl, 5c, 81% (67%)
4-CF3, 5d, 72% (66%)
O
N
HO
H
N
2a
O
N
H
eqn 2
eqn 3
+
Ph
Ph
O
N
N
A
conditions
N
Ph
Ph
N
H
5e
3-Br, , 81% (70%)
Ph
10, 48% (E/Z>20:1)
11
, trace
Ph
H
OH
O
N
n
N
X
5j, 55% (47%)
n = 1, 5h, 74% (66%)
1a
3a
, 51%
2a
+
+
Ph
A
conditions
5i
n = 2, , 70% (64%)
4-MeO, 5k, 83% (73%)
4-Me, 5l, 74% (67%)
4-Cl,
4-CF3, , 69% (56%)
4-NO2, , 61% (45%)
H
X =
H
N
BHT
O
N
O
N
N
O
5m
, 67% (62%)
Ph
Ph
O
O
5n
5o
5p
Ph
5r, 87% (71%)
2-Me, , 71% (62%)
5q, 78% (72%)
Cl
H
H
NH
O
N
O
N
N
N
N
N
Ph
Ph
Ph
Cl
5u, 52% (45%)
5s, 80% (65%)
5t, 46% (38%)
H
H
N
N
O
N
O
N
O
N
N
N
Ph
S
Ph
Ph
Figure 1. Analytical data of ESIꢀHRMS.
5w, 62% (43%)
5x, 42% (35%)
5v, 54% (47%)
O
N
O
O
N
N
N
Based on the aboveꢀmentioned study, an iminoxyl radical
mechanism is proposed to rationalize the present
oxyamination and diamination reactions as shown in Scheme 7.
A singleꢀelectron transfer process occurs firstly between Cu(II)
species A and oxime 1 or 4 to produce Cu(I) species B and the
iminoxyl radical. This minoxyl radical possesses an electronic
structure with singleꢀelectron spin density delocalized on both
the Oꢀatom and Nꢀatom (resonance structures C and D),9 and
it then undergoes dichotomous Oꢀ and Nꢀatom 5ꢀexoꢀtrig
radical cyclization depending on the position of the tethered
alkene, yielding the formed Cꢀcentered radicals E and F,
respectively. Meanwhile, the Cu(I) species B is oxidized by
DTBP or O2 to Cu (II) species A which then bind with the
amine to produce the intermediate [LnCu(II)–NRR′].
Ultimately, the intermolecular radical coupling takes place
Ph
Ph
5y, 51% (36%)
5z, 82% (73%)
aAll reactions run in 0.3 M MeCN using oxime 4 (0.3 mmol),
ammine 2 (3 equiv), bpy (0.25 equiv.), and Cu(OAc)2 (0.2 equiv)
at 100 C for 1.5 h. Conditions A: DTBP (3 equiv.) used as the
o
b
oxidant Conditions B: Air used as the oxidant. Isolated yields.
cYields in parentheses were obtained under conditions B.
arylamines, such as orthoꢀtoluidine, orthoꢀcumidine, 2,4ꢀ
dimethoxylphenylꢀamine, 2,4,6ꢀtrimethylphenylamine, and
2,5ꢀdichlorophenylamine are amenable to this reaction, giving
the diamination products 5p–t in moderate to good yield.
To confirm the iminoxyl radicals were involved in these
oxyamination and diamination reactions, compounds 6 and 7
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Page 4 of 6
Scheme 7. Proposed Mechanism
In summary, a novel, efficient and environmentally friendly
1
2
3
4
5
6
7
8
copperꢀcatalyzed direct oxidative strategy has been succesꢀ
sively developed for the oxyamination and diamination of
unactivated alkenes by using unsautrated ketoximes and simꢀ
ple amines as the readily accessible substrates and DTBP or
air as the oxidant. These reactions not only provide the first
example of metalꢀcatalyzed oxyamination and diamination of
unactive alkenes with the electronꢀrich amines as the nitrogen
source, but also make possible the facile synthesis of structurꢀ
ally important useful nitrogenꢀcontaining isoxazolines and
cyclic nitrones. Further studies on the mechanisms details
of this reaction and more iminoxyl radicalsꢀinvolved reactions
are underway in our laboratory.
LnCuI
B
1
4
or
DTBP
Ln =
N
N
or O2
LnCuII
R'
N
3
5
or
A
R
O-atom
5-exo-trig
O
R
N R'
N
O
CuIII
N
F E
( )
Ln CuII
Ln
H
R
R
n
R
n = 0
G
C
H
N
2
E
path a
path b
R
R'
DTBP
LnCuII
LnCuI
or O2
A
B
9
O
N
O
R
G'
n = 1
N
10
11
12
13
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R
N
R'
N-atom
5-exo-trig
n
Ln CuI
D
F
3 or 5
ASSOCIATED CONTENT
between E or F and intermediate [LnCu(II)–NRR′] to produce
the desired products 3 or 5 with Cu(I) species B being reꢀ
leased.15,16
Supporting Information. Detailed experimental procedures and
spectral data for all products are provided. This material is availaꢀ
ble free of charge via the Interꢀnet at http://pubs.acs.org.
Prior mechanistic study reveals that there exist two
pathways for the reaction of Cꢀcentered radicals with
[LnCu(II)–NRR′] species. One is that a Cꢀradical first couples
with Cu(II)ꢀatom to form a Cu(III) species; the Cu(III) species
then undergoes reductive elimination (Scheme 7, path a).15
The other is the direct coupling of Cꢀradical with Nꢀatom of
the [LnCu(II)–NRR′] intermediate (Scheme 7, path b). This
latter process is recently proposed by Warren et. al.16 The
mechanistic and DFT studies by Warren et. al. reveal that a
[(Cl2NN)Cu(II)–HNArCl3] (Cl2NN = (2,6ꢀdichlorophenꢀyl)
((2Z,4E)ꢀ4ꢀ((2,6ꢀdichlorophenyl) imino) pentꢀ2ꢀenꢀ2ꢀyl)
amide, ArCl3 = 2,4,6ꢀtrichlorophenyl) species possesses an
electronic structure with the singleꢀelectron spin delocalized
on both the Nꢀatom from the aniline and the Cuꢀatom; the
trapping of a carbonꢀcentered radical by such a species at the
Nꢀcenter is thermodynamically more favorable (ꢁG = ꢀ4.0
kcal/mol) than the capture at the Cuꢀcenter (ꢁG = +20.8
kcal/mol). In Scheme 7, the [LnCu(II)–NRR′] species can be
drawn as the resonance structures G and G′, and thus trapping
of E or F by the nitrogen would also deliver 3 or 5. Warren’s
study shows that in case that the singleꢀelectron spin appears
on the nitrogen atom in the [LnCu(II)–NHAr] intermediate,
bimolecular N–N radical coupling might occur to give the
hydrazine ArNH–NHAr, which is apt to be further oxidized to
diazene ArN=NAr.17bꢀd In our trapping experiment with BHT
(Scheme 6, eqn 3), we detected both hydrazine PhNH–NHPh
and diazene PhN=NPh in the ESIꢀHRMS spectra (Figure 2),
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hanb@lzu.edu.cn; yuwei@lzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Nos.
21422205, 21272106, and 21632001), the Program for New Cenꢀ
tury Excellent Talents in University (NCETꢀ13ꢀ0258), the
Changjiang Scholars and Innovative Research Team in University
(IRTꢀ15R28), the “111” project, and the Fundamental Research
Funds for the Central Universities (Nos. lzujbkyꢀ2016ꢀct02 and
lzujbkyꢀ2016ꢀct08) for financial support.
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ABSTRACT: A convenient and versatile oxidative intra/interꢀmolecular oxyamination and diamination of unactivated alkenes has
been developed through copperꢀcatalyzed radical reactions of β,γꢀ and γ,δꢀunsaturated ketoximes with electronꢀrich aryl and aliphatꢀ
ic amines. These reactions were carried out by employing diꢀtertꢀbutyl peroxide (DTBP) or air as the terminal oxidant, and a series
of useful nitrogenꢀcontaining 4,5ꢀdihydroisoxazoles and cyclic nitrones were formed.
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