Copper-catalyzed 1,2-amino oxygenation of 1,3-dienes: A chemo-, regio-, and site-selective three-component reaction with o-acylhydroxylamines and carboxylic acids

Article abstract of DOI:10.1021/acscatal.9b03076

A three-component reaction for 1,2-amino oxygenation of 1,3-dienes has been achieved using O-acyl hydroxylamines and carboxylic acids. The reaction occurs through copper-catalyzed amination of olefins followed by nucleophilic addition of carboxylic acids, offering high levels of chemo-, regio-, and site-selectivity. The method is effective for both terminal and internal 1,3-dienes, including those bearing multiple, unsymmetrical substituents. The amino oxygenation conditions also exhibited remarkable selectivity toward 1,3-dienes over alkenes, good tolerance of sensitive functional groups, and reliable scalability.

Full text of DOI:10.1021/acscatal.9b03076

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Article
Copper-Catalyzed 1,2-Amino Oxygenation of 1,3-Dienes:
A Chemo-, Regio-, and Site-Selective Three-Component
Reaction with O-Acylhydroxylamines and Carboxylic Acids
Brett N. Hemric, Andy Chen, and Qiu Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03076 • Publication Date (Web): 24 Sep 2019
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Page 1 of 8
ACS Catalysis
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Copper-Catalyzed 1,2-Amino Oxygenation of 1,3-Dienes: A Chemo-,
Regio-, and Site-Selective Three-Component Reaction with O-
Acylhydroxylamines and Carboxylic Acids
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Brett N. Hemric, Andy W. Chen, and Qiu Wang*
Department of Chemistry, Duke University, Durham, North Carolina 27708
KEYWORDS: alkene difunctionalization, amino oxygenation, copper catalysis, 1,3-diene
ABSTRACT: A three-component reaction for 1,2-amino oxygenation of 1,3-dienes has been achieved using O-acyl hydroxyla-
mines and carboxylic acids. The reaction occurs through copper-
catalyzed amination of olefins followed by nucleophilic addition of
carboxylic acids, offering high levels of chemo-, regio-, and site-
selectivity. The method is effective for both terminal and internal
1,3-dienes, including those bearing multiple, unsymmetrical sub-
stituents. The amino oxygenation conditions also exhibited remark-
able selectivity toward 1,3-dienes over alkenes, good tolerance of
sensitive functional groups, and reliable scalability.
O
Cu(OAc)2 (1 mol%)
O
R1
O
NR4R5
BzO
+
+
H
R2
NR4R5
R1
R3
DCE/2-MeTHF, 60 ºC
O
R2 R3
•
•
•
•
•
site- and regio-selective 1,2-addition
selectivity toward 1,3-dienes over alkenes
compatible with diverse, sensitive functional groups
broad scope of 1,3-dienes and carboxylic acids
>50 examples, including 2-mmol scale reaction in 79% yield
(A) Difunctionalization of 1,3-dienes: challenges in site- and regio-selectivity
INTRODUCTION
[N]
[O]
site selectivity
R2
R2
or
R1
R1
R1
R1
Difunctionalization of 1,3-dienes is fundamentally im-
portant as a powerful strategy to introduce molecular complex-
ity onto simple 1,3-diene skeletons and to create diverse, high-
ly valuable compounds from readily available materials.1 In
comparison to significant advances in the construction of new
carbon–carbon bonds from diene difunctionalization,1d,2 selec-
tive installation of two different heteroatoms onto 1,3-dienes
remains underdeveloped.3-4 For example, 1,2-amino oxygen
containing skeletons are ubiquitously found in natural prod-
ucts, bioactive compounds, and functional materials.5 Howev-
er, a modular and selective three-component amino oxygena-
tion reaction remains lacking and challenging. There are sev-
eral distinctive challenges to control site- and regioselectivity
in such a modular amino oxygenation of 1,3-dienes (Scheme
1A). First, 1,3-dienes possess two possible olefins at which to
react, leading to the potential for two distinct reaction sites.
Secondly, the conjugated nature of 1,3-dienes allows for either
direct 1,2-addition or conjugated 1,4-addition. Furthermore,
unless the reaction occurs in a concerted fashion, a stepwise
pathway for difunctionalization may allow for the resonance
of its intermediate, leading to the loss of the original geometry
of the unreacted olefin. Finally, a mixture of products resulting
from a non-selective reaction often presents another difficulty
in their separation under conventional means.
[O]
[N]
[O]
[O]
1,2 vs 1,4 addition
olefin geometry
R2
R2
R2
or
or
R1
R1
[N]
[N]
R1
[O]
[O]
R2
R2
[N]
[N]
(B) Current method: two-component reactions by tethering strategy
[4+2] cycloaddition: 1,4-addition
O
N
R2
O
N
R2
R1
R1
tethered nucleopile and electrophile: 1,2-addition
[N]
[O]
[N]
[O]
or
R1
[O]
[N]
Cu, Fe, or Pd catalyst
R1
R1
tethered diene and electrophile: both 1,2- and 1,4-addition
OR2
HN
OR2
PhI(OR2)2
O
R1
R1
+
R1
O
O
O
H2N
O
Rh catalyst
HN
O
(C) This work: a three-component, modular reaction initiated by copper-catalyzed amination
R4
N
O
O
R3
R1
R4
N
R5
R3
O
Several approaches have been developed to overcome these
challenges in amino oxygenation of 1,3-dienes (Scheme 1B).
For example, [4+2] cycloaddition of 1,3-dienes and nitroso
compounds allows for exclusive 1,4-addition, preserving al-
kene geometry via a concerted process, yet suffers from a nar-
row substrate scope.6 Site-selective 1,2-addition reactions for
terminal dienes or symmetrically-substituted dienes have been
BzO
OH
R1
R2
R5
Cu
R2
R4
[Cu]
via
chemo-, site-, and regio-
selective 1,2-addition
both terminal and
internal dienes
N
R5
R1
R2
Scheme 1. Amino Oxygenation Reactions of 1,3-Dienes.
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ACS Catalysis
achieved via a sophisticated strategy using tethered oxy-
Page 2 of 8
form both 1,2- and 1,4-addition products 4a and 4a’, as well as
4b resulting from the competitive trapping of benzoate which
was released from the O-benzoylhydroxylamine. Using cop-
per(II) acetate as a catalyst in dichloroethane (DCE) at 80 °C,
the reaction with stoichiometric amounts of each reactant pro-
vided 1,2-addition product 4a, with no detection of 1,4-
addition product 4a’ and only a trace amount of benzoate
trapped product 4b (entry 1). Probing the stoichiometric
amount of each reagent in this three-component reaction of-
fered several notable observations. Increasing the equivalents
of 1a gave an increased amount of 1,4 trapping (entry 2),
while increasing the equivalents of 2a or 3a led to more ben-
zoate trapped product (entries 3 and 4). Increasing the equiva-
lents of both 1a and 2a improved the reaction efficiency and
also inhibited the undesired benzoate trapping, yet at the cost
of poor 1,2- and 1,4-selectivity (entries 6 and 7). Remarkably,
reducing the catalyst loading from 20 mol % to even 1 mol %
did not diminish the reaction efficacy (entries 8 and 9). De-
creasing the reaction temperature resulted in a longer time yet
with little effect on the efficacy (entries 10 and 11). Surveying
different solvents revealed that etherated solvents, such as
dimethoxyethane (DME) and 2-methyltetrahydrofuran (2-
MeTHF) significantly reduced the formation of 1,4-addition
4a’ (entries 12 and 13). Yet the use of exclusively 2-MeTHF
as the solvent was found incompatible with many acid
sources.11 Finally, the conditions of a 1:1 co-solvent system of
DCE/2-MeTHF were found more generally effective for this
reaction (entry 14), which were adopted as standard conditions
in our studies.
1
2
3
4
5
6
7
8
gen/nitrogen sources, and afforded complementary regioselec-
tivity with different metal catalysts.7 In another example, rho-
dium-catalyzed amino oxygenation was achieved with
chemo- and site-selectivity through a diene-tethered nitrogen
group yet gave a nearly equal mixture of 1,2- and 1,4-addition
products.8 Despite these seminal developments, a three-
component modular and selective amino oxygenation reaction
incorporating a diverse range of 1,3-dienes remains lacking,
and is greatly desired.9
9
In this work, we have developed a copper-catalyzed three-
component 1,2-amino oxygenation reaction of 1,3-dienes,
using O-acyl hydroxylamines as the electrophilic nitrogen
source and carboxylic acids as the nucleophilic oxygen source
(Scheme 1C). The transformation is envisioned to be initiated
by a copper-catalyzed amination of dienes with electrophilic
O-acyl hydroxylamines10 followed by the nucleophilic addi-
tion of carboxylic acids. Such amination/oxygenation path-
ways are distinctly different from previous 1,3-diene methods
and thus would allow for a chemo-, regio- and site-selective
addition to 1,3-dienes. This study has demonstrated that such
an approach is effective on a wide range of 1,3-dienes, includ-
ing those substrates that are known to be challenging such as
those bearing multiple substituents and internal dienes. Inter-
estingly, these amino oxygenation conditions show remarkable
selectivity toward 1,3-dienes over non-conjugated olefins,
which are also known to undergo similar amino oxygenation
reactions.10 This method also tolerates a diverse scope of car-
boxylic acids, even those that contain sensitive functional
groups. Studies on the reaction pathways offer further mecha-
nistic insights on the radical intermediates and pathways under
reaction conditions.
10
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To examine the scope of this three-component reaction, we
started with different carboxylic acids (Table 2). First, a series
of substituted benzoic acids successfully delivered 1,2-
addition products. These reactions exhibited good tolerance of
functional groups, including nitro (4c), cyano (4d), alkoxy
(4e), acetate (4f), and even diazo group (4g), albeit in reduced
yields. Poly substituted benzoic acids were also effective (4h–
4i), and even steric hindrance had no effect on
Our studies began with amino oxygenation of (E)-1-phenyl-
1,3-butadiene 2a as the model reaction, with pentafluoroben-
zoic acid 1a as the nucleophilic oxygen source, and O-
benzoyl-N-hydroxylmorpholine 3a as the electrophilic nitro-
gen source (Table 1). We expected that the reaction might
Table 1. Condition Optimization for 1,2-Amino Oxygenation of (E)-1-Phenyl-1,3-butadiene.a
O
O
O
O
Cu(OAc)2
O
F5C6
Ph
O
O
F5C6
O
O
+
Ph
O
O
+
+
+
F5C6
OH
N
Ph
solvent, temp
BzO
N
N
N
Ph
Ph
4a (1,2-product)
4a' (1,4-product)
4b (BzO trapping)
1a
2a
3a
1a
2a
(equiv)
3a
Cu(OAc)2
(mol%)
temp
(°C)
80
80
80
80
80
80
80
80
80
60
40
60
60
60
60
time
(h)
2.0
0.5
2.0
0.5
2.0
0.5
0.5
0.5
0.5
2.5
24
4a
4a’
(%)b
0
19
1
4b
entry
solvent
(%)b
36
36
53
31
48
50
46
51
47
48
40
55
56
62d
0
(equiv)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
3
1
1
1
2
3
2
2
2
2
2
2
2
2
1
1
3
1
3
3
3
3
3
3
3
3
3
3
3
1
1
1
3
3
1
1
1
1
1
1
1
1
1
1
20
20
20
20
20
20
20
10
1
1
1
1
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0.07
0.01
0.12
0.27
1.53
0
0
0
0
0
0
0
12
20
16
18
21
21
4
2
7
0
DCE
DCE
DME
0
0
0
0
7
1.5
5
2-MeTHF
DCE/2-MeTHF (1:1)
DCE/2-MeTHF (1:1)
1
0
5
0
aReactions on 0.2 mmol scale. bDetermined by 19F NMR of the crude reaction with 1,2,4,5-tetrafluorobenzene as a quantitative internal standard. cDetermined by 1H
NMR of the crude reaction with dibromomethane as a quantitative internal standard. dIsolated yield.
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ACS Catalysis
Table 2. Scope of Carboxylic Acids in Amino Oxygenation
bearing sensitive functional groups that are known to interfere
with transition metals via strong coordination,13 such as cyclic
disulfide lipoic acid (4u), oxetanes (4v), and amino acid deriv-
atives (4w–4x), were all effective. Finally, the use of crushed
ibuprofen tablets in the reaction afforded desired product 4y in
46% yield, which proved the practicality of this transformation
and its good tolerance of impure material.
1
of 1,3-Dienes.
2
3
4
5
6
We briefly examined the scope for O-benzoyl-
hydroxylamines in the reaction (Table 3). Similar to the alkene
amino oxygenation reactions from our previous studies,10 pi-
perazine and piperidine derivatives proved to be the most
compatible in the reaction (5a–5c). Acyclic amines such as N-
methylbenzyl amine (5d), N-methylphenethyl amine (5e), and
diethyl amine (5f) were also compatible, whereas highly steri-
cally-hindered dicyclohexylamine was ineffective (5g). Func-
tional groups on the nitrogen source were well tolerated, such
as carbamate (5a) and ester (5b).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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53
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57
58
59
60
Table 3. Scope of O-Benzoylhydroxylamines in Amino Ox-
ygenation of 1,3-Dienes.
O
Cu(OAc)2
(1 mol %)
O
R
N
Ar
O
R
N
+
+
Ph
Ar
OH
DCE/2-MeTHF
BzO
R'
Ph
R'
60 ºC
1c (2 equiv)
2a (3 equiv) 3 (1 equiv)
5
O
Ar
O
O
O
X
Ar
O
Me
Ar
O
R
N
N
Ph
n
N
Ph
Ph
Ph
R
5a, X = NBoc, 61%
5b, X = CHCO2Et, 50%
5c, X = CH2, 40%
5d, n = 1, 36%a
5e, n = 2, 47%a
5f, R = Et, 30%a
5g, R = Cy, ND
Isolated yields as an average of two runs on 0.4 mmol scale. Ar
= 3,5-dinitrophenyl. aRun without 2-MeTHF.
Isolated yields as an average of two runs on 0.4 mmol scale.
The scope of dienes was extensively examined in the amino
oxygenation reaction with 3a (Table 4). In comparison to the
model substrate 1-phenyl-1,3-butadiene 2a, different substitu-
ents on the aryl group were examined (6a–6j). While para-
substitution with methyl (6a), phenyl (6b), or electron-
withdrawing halogens (6e–6f) showed little effect on the reac-
tion, electron-donating groups, such as dimethylamino (6c)
and methoxy (6d) were found to be deleterious. Substituents at
the meta position, either electron donating methoxy (6g) or
electron-withdrawing trifluoromethyl (6h), showed no influ-
ence. For substituents at the ortho position, electron-donating
methoxy (6i) showed a decrease in the reaction yield, while
electron-withdrawing chloro (6j) did not. Besides 1-aryl-
dienes, 1-alkyl-substituted dienes were tested, providing 1,2-
addition products exclusively (6k–6l). Note that 1-methyl-1,3-
diene gave a mixture of 6l and 6l’ with a 5:1 ratio of site selec-
tivity, favoring the 1,2-addition at the unsubstituted olefin as
6a–6j. Interestingly, the reactions with 2-substituted dienes
successfully afforded 1,2-addition products (6m–6o), while
site selectivity favored the branched olefin. The site selectivity
of 6a–6l may largely result from steric influence of ssubstitu-
ent, which may impede the initial amination of the olefin. Ra-
ther, the site selectivity observed in the cases of 6m–6o might
be influenced by the nucleophilic trapping step that favors the
more stable intermediate bearing more substituents. Next, di-
substituted 1,3-dienes were examined. The reaction with 2,3-
dimethyl-1,3-butadiene 2p successfully provided 1,2-addition
product 6p while the reaction with 1-phenyl-3-methyl-1,3-
butadiene failed to deliver desired product 6q. The reactions
with 1,2-, and 1,2-disubstituted-dienes all gave amino
b
c
d
aRun with 3b. Run without 2-MeTHF. Run with 3c. Run with
e
f
3d. Determined by HPLC trace of the crude reaction. Run with
crushed ibuprofen. gDetermined by 1H NMR of the crude reaction.
the yield (e.g., 4i). A heteroaromatic carboxylic acid was also
tolerated (4j). We noticed that the reaction with benzoic acid
gave 4b in a slightly higher yield of 76% than others. Thus, we
decided to probe if matching the leaving group on the O-
benzoylhydroxylamine with the corresponding carboxylic acid
nucleophile could improve the yield. The use of pentafluoro-
benzoyl-derived 3b in the reaction of matching acid 1a
showed no effect on the formation of 4a. However, using
3,4,5-trimethoxybenzoyl-derived 3c in the reaction of match-
ing acid 1h led to a notable increase in the formation of 4h,
when compared to using the standard 3a, from 63% to 76%
yield. We next evaluated this reaction with a broad range of
diversely functionalized carboxylic acids. Acrylic acid and E-
cinnamic acid proved compatible in the reaction to form 4k–
4l, with the alkene group intact. Diene-bearing sorbic acid
afforded the desired product 4m while the poor yield suggest-
ed the conjugated diene system may undergo side reactions
under these conditions. Even propiolic acid gave rise to the
desired product 4n, with the terminal alkyne tolerated without
the canonic activation pathway under the reaction conditions.12
Simple alkyl carboxylic acids were found capable of providing
desired products 4o–4p in modest yields. When matching ac-
id-derived 3d was used instead of 3a for the formation of 4p,
an increased yield was also observed. Functionalized alkyl-
derived carboxylic acids were also tested, including alkyl hal-
ides (4q), thioethers (4r), and ketones (4s–4t). Even acids
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ACS Catalysis
Page 4 of 8
1
2
3
4
5
Table 4. Scope of Dienes in the Amino Oxygenation of 1,3-Dienes.
O
6
7
8
9
O
Cu(OAc)2 (1 mol %)
O
Ar
R1
O
O
+
+
Ar
1c (2 equiv)
dienes bearing a terminal olefin
OH
N
N
O
R1
DCE/2-MeTHF, 60 ºC
R2
BzO
R2
2 (3 equiv)
3a (1 equiv)
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R
O
O
O
O
Ph
O
R
O
Ph
O
O
Ar
O
O
Ar
O
N
O
Ar
O
N
O
Ar
O
O
N
N
N
N
Me
R
Me
6
6'
6m, R = Me, 73%c (6:1 6m:6m')b
6n, R =
, 61%c (3:1 6n:6n')b
6o, R = Ph, 39%a,c,d (8:1 6o:6o')b
6a, R = 4-Me, 52%
6b, R = 4-Ph, 56%
6c, R = 4-NMe2, ND
6d, R = 4-OMe, trace
6e, R = 4-Cl, 57%
6f, R = 4-Br, 64%
6g, R = 3-OMe, 63%
6h, R = 3-CF3 53%
6i, R = 2-OMe, 43%
6j, R = 2-Cl, 57%
6l
47%
6l'
(1.3:1 dr)b
6k, 49%a
x
CMe2
2
(14:1 E:Z)b
(5:1 6l:6l')b
O
O
O
O
O
Ar
O
O
Ar
O
O
Ar
O
O
Ar
O
O
N
Ar
O
O
N
N
N
N
Ph
Me
Ph
Me
Me
Me
6q, ND
C6H13
Ph
Ph
6p, 49%
6r, 32% (1.3:1 dr)e
6s, 49% (3:1 E:Z)b
6t, 59%
internal dienes
O
O
O
O
O
Ar
O
O
Ph
O
O
Ar
O
O
O
Ar
O
Ar
O
O
N
N
N
BzO
N
EtO
N
Me
Me Me
R
Me
Ph
Me
O
Me
Ph
R
OBz
6v, R = Ph, 59%c,e
6w, R = Me, 76%c(8:1)g
6u, 60%f (1:1 dr)b
6x
(1.4:1 dr)h
26%
6x’
6y, ND
(3.5:1 6x:6x’)h (1.9:1 dr)h
Isolated yields as an average of two runs on 0.4 mmol scale. Ar = 3,5-dinitrophenyl. aSecond run on 0.2 mmol scale. Determined by 1H
b
c
d
e
f
NMR of the crude reaction. Run without 2-MeTHF. Yield of major isomer. Determined by HPLC trace of the crude reaction. Starting
from 1.2:1 E:Z diene. gRatio of 1,2:1,4 addition products. hDetermined by 1H NMR of the crude reaction eluted through silica gel.
oxygenation products 6r–6t with 1,2-addition selectively oc-
curring at the less substituted olefin site. It is worth noting that
in the reaction forming 6r, no amino oxygenation was ob-
substituted Z isomer, showed no detection of 1,2-addition
product (6aa) and gave nearly quantitative recovery of Z-2aa.
served on the isolated alkene, suggesting different reactivity
These results indicate the absence of reversibility in the amino
between 1,3-dienes and isolated alkenes.
addition to the diene and possibly the potentially impotent
nature of this Z-isomer under reaction conditions.
Reaction of internal 1,3-dienes, one of the most challenging
and complex systems, were next evaluated for efficiency and
selectivity. First, the formation of 6u in 60% yield was en-
couraging, as the comparable efficacy between 6u and 6t sug-
gests that the presence of methyl group did not impede the
reaction. The reactions of terminally fully substituted dienes
also delivered products 6v–6w successfully. The formation of
1,4-addition product 6w’ was observed (structure not shown),
which likely resulted from the isomerization of 1,2-addition
product 6w.11 A 1,4-non-symmetrically disubstituted-1,3-diene
was examined to evaluate the selectivity between two differen-
tially-substituted olefin sites. Despite the low yield, the for-
mation of 1,2-addition products 6x and 6x’ in a 3.5:1 ratio
suggested site selectivity in favor of the methyl-substituted
olefin, possibly because of the steric difference. Among an
extensive range of 1,3-dienes tested, electron-deficient dienes
were found ineffective, such as ethyl sorbate (6y).
O
Standard
Conditions
Ar
O
O
Ph
Ph
+
N
Me
Me
1c + 3a
Ph
Me
E-2z
(>95% E)a
(3.0 equiv)
6z
54%b
E-2z recovered
(>95% E)a
(7:1 E:Z)a
(1.7 equiv)
O
Standard
Conditions
Ar
O
O
Ph
Cl
Ph
Cl
+
N
Ph
1c + 3a
Cl
Z-2aa
(>95% Z)a
(3.0 equiv)
Z-2aa recovered
(>95% Z)a
6aa
ND
(2.9 equiv)
a
1
Ar = 3,5-dinitrophenyl. Ratio determined by H NMR of the
crude reaction. bAverage of two runs.
During our studies, we noticed some difference in reactivity
of E vs Z dienes in their reactions (Scheme 2). The reaction of
a methyl-substituted E isomer (E-2z) produced 1,2-addition
products 6z in a 7:1 ratio of the E:Z isomers along with recov-
ery of the E diene. The reaction of Z-2aa, a chloromethyl-
Scheme 2. Comparison of Diene Geometry in the Amino
Oxygenation of 1,3-Dienes.
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2
3
4
5
O
O
6
7
8
9
MeO
MeO
N
Cu(OAc)2 (1 mol %)
COOH
O
(A)
+
+
+
Ph
DCE, 60 ºC
O
O
O
O
O
O
N
MeO
N
Ph
HOOC
4z, 54%
7, NDa
1z (2 equiv)
2a (3 equiv)
3c (1 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
O
O
O
O
O
COOH
R
N
MeO
MeO
N
Cu(OAc)2 (1 mol %)
O
(B)
+
+
+
Ph
DCE, 60 ºC
N
O
O
O
R
R
MeO
Ph
4aa, R = H, 58%x
4ab, R = Me, 55%x
8a, R = H, traceb
8b, R = Me, tracec
1 (2 equiv)
2a (3 equiv)
3c (1 equiv)
O2N
NO2
O2N
NO2
O2N
COOH
Cu(OAc)2 (1 mol %)
O
(C)
+
+
+
+
Ph
Ph
N
DCE/2-MeTHF, 60 ºC
BzO
O
O
O
O
O
O
O2N
N
N
Ph
Ph
10, NDa
1c (2 equiv)
2a (3 equiv)
9 (3 equiv)
3a (1 equiv)
4c, 61%
a
b
1
Isolated yields as an average of two runs on 0.4 mmol scale. Ar = 3,5-dinitrophenyl. ND = Not detected by GCMS. Observed by H
NMR of the crude reaction (with the ratio of 4aa: 8a >40:1). cObserved by GCMS.
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Competition Experiments for the Amino Oxygenation of 1,3-Dienes or Alkenes.
OH
O2N
NO2
O
t-Bu
t-Bu
t-Bu
O2N
COOH
Cu(OAc)2 (1 mol %)
O
t-Bu
+
+
+
+
Ph
N
O
DCE, 60 ºC
BzO
O
O
O
Me
O2N
N
N
N
BHT (1 equiv)
Ph
Ph
O
1c (equiv)
2a (equiv)
3a (equiv)
4c
11
11%
ND
--
12
2
0
2
0
3
3
0
0
1
1
1
1
30%
--
--
10%
45%
48%
46%
--
--
Isolated yields on 0.4 mmol scale. Ar = 3,5-dinitrophenyl.
Scheme 4. Radical Trapping Experiments for the Amino Oxygenation of 1,3-Dienes.
We next examined the selectivity between 1,3-dienes and
alkenes under copper-catalyzed amino oxygenation conditions
by a number of competition experiments (Scheme 3). First, in
the reaction with 4-vinylbenzoic acid, 4-vinylbenzoate 4z was
formed as 1,2-addition to diene 2a while the styrene-addition
product 7 was not observed (Scheme 3A). Secondly, in the
reactions of 2-vinylbenzoic acids, 4aa and 4ab were formed as
the 1,2-addition products to diene 2a, in 58% and 55% yields,
respectively (Scheme 3B). We detected only trace amounts of
8a and 8b, the amino lactonization products resulting from
alkene addition. These results suggest that the intermolecular
amino oxygenation of 1,3-diene 2a occurs even faster than the
intramolecular amino oxygenation of alkenes under such con-
ditions. When both the model diene (2a) and styrene (9) were
present under the reaction conditions, the diene addition prod-
uct 4c was formed with no detection of the alkene addition
product 10 (Scheme 3C). Note that the formation of 4c in 61%
yield in this competitive experiment is comparable to its for-
mation of 63% yield in the reaction with the absence of alkene
9 (Table 2). All these results suggest the remarkable selectivity
of this amino oxygenation reaction favoring 1,3-dienes over
alkenes, even when expedient intramolecular trapping of al-
kenes was possible.
Our previous studies on copper-catalyzed amino oxygena-
tion of alkenes using O-benzoyhydroxylamines have suggest-
ed the presence of radical pathways under similar reaction
conditions.10 To probe the involvement of any possible radical
intermediates in the reaction of dienes, the reaction of diene 2a
was performed in the presence of radical scavengers (Scheme
4). With the presence of one equivalent of butylated hydroxy-
toluene (BHT) as a radical scavenger in the reaction of 2a, the
desired product 4c was obtained in a decreased 30% yield,
along with the formation of two BHT-derived products, 11 and
12. The control experiments in the absence of diene 2a, acid
1c, or both were conducted. The formation of 12 was con-
firmed independent from the reaction of 1,3-dienes. On the
other hand, the formation of the 1,4-aminocarbonation addi-
tion product 11 suggested the formation of an allylic radical
intermediate after the initial amination step of 1,3-diene and
the involvement of resonance through the conjugated system,
providing additional insights on the pathways in this reaction.
Further studies for a better understanding of observed selectiv-
ity will be disclosed in future work.
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a) Standard Conditions,
BzOH, 3a, 1.5 h
of 1,3-Dienes. Tetrahedron Lett. 2018, 59, 347–355; (d) Wu, X.;
OH
O
Gong, L. Z., Palladium(0)-Catalyzed Difunctionalization of 1,3-
Dienes: From Racemic to Enantioselective. Synthesis 2019, 51, 122–
134.
Ph
N
Ph
b) KOH, EtOH, 86 ºC, 5 h
2a
13
7
8
9
68% (0.2 mmol scale)
79% (2.0 mmol scale)
2. Selected examples: (a) Sato, Y.; Takimoto, M.; Hayashi, K.;
Katsuhara, T.; Takagi, K.; Mori, M., Novel Stereoselective
Cyclization via -Allylnickel Complex Generated from 1,3-Diene and
Hydride Nickel-Complex. J. Am. Chem. Soc. 1994, 116, 9771–9772;
(b) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I., Pd(II)-
Catalyzed Intermolecular 1,2-Diamination of Conjugated Dienes. J.
Am. Chem. Soc. 2005, 127, 7308–7309; (c) Liao, L. Y.; Jana, R.;
Urkalan, K. B.; Sigman, M. S., A Palladium-Catalyzed Three-
Component Cross-Coupling of Conjugated Dienes or Terminal
Alkenes with Vinyl Triflates and Boronic Acids. J. Am. Chem. Soc.
2011, 133, 5784–5787; (d) Wu, X.; Lin, H. C.; Li, M. L.; Li, L. L.;
Han, Z. Y.; Gong, L. Z., Enantioselective 1,2-Difunctionalization of
Dienes Enabled by Chiral Palladium Complex-Catalyzed Cascade
Arylation/Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137,
13476–13479; (e) Sardini, S. R.; Brown, M. K., Catalyst Controlled
Regiodivergent Arylboration of Dienes. J. Am. Chem. Soc. 2017, 139,
9823–9826; (f) Bao, X.; Yokoe, T.; Ha, T. M.; Wang, Q.; Zhu, J. P.,
Copper-Catalyzed Methylative Difunctionalization of Alkenes. Nat.
Commun. 2018, 9, 3725.
3. Examples of diamination of 1,3-dienes, see: (a) Sharpless, K. B.;
Singer, S. P., 1,2-Diamination of 1,3-Dienes by Imido Selenium-
Compounds. J. Org. Chem. 1976, 41, 2504–2506; (b) Akermark, B.;
Backvall, J. E.; Lowenborg, A.; Zetterberg, K., Palladium(Ii)-
Promoted 1,4-Diamination of 1,3-Dienes – Stereochemistry of
Amination of a -Allylpalladium Complex. J. Organomet. Chem.
1979, 166, C33–C36; (c) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-
Milburn, K. I., Pd(II)-Catalyzed Intermolecular 1,2-Diamination of
Conjugated Dienes. J. Am. Chem. Soc. 2005, 127, 7308–7309. (d)
Yuan, W. C.; Du, H. F.; Zhao, B. G.; Shi, Y. A., A Mild Cu(I)-
Catalyzed Regioselective Diamination of Conjugated Dienes. Org.
Lett. 2007, 9, 2589–2591; (e) Zhao, B. G.; Peng, X. G.; Cui, S. L.;
Shi, Y. A., Cu(I)-Catalyzed Regioselective Diamination of
Conjugated Dienes via Dual Mechanistic Pathways. J. Am. Chem.
Soc. 2010, 132, 11009–11011; (f) Wu, Z. X.; Wen, K.; Zhang, J. G.;
Zhang, W. B., Pd(II)-Catalyzed Aerobic Intermolecular 1,2-
Diamination of Conjugated Dienes: A Regio- and Chemoselective
[4+2] Annulation for the Synthesis of Tetrahydroquinoxalines. Org.
Lett. 2017, 19, 2813–2816.
4. Difunctionalization of 1,3-dienes for installation other
heteroatoms, see examples: (a) Sleet, C. E.; Tambar, U. K., Copper-
Catalyzed Aminothiolation of 1,3-Dienes via a Dihydrothiazine
Intermediate. Angew. Chem. Int. Ed. 2017, 56, 5536–5540; (b) Lu, D.-
F.; Zhu, C.-L.; Sears, J. D.; Xu, H., Iron(II)-Catalyzed Intermolecular
Aminofluorination of Unfunctionalized Olefins Using Fluoride Ion. J.
Am. Chem. Soc. 2016, 138, 11360–11367.
5. (a) Ager, D. J.; Prakash, I.; Schaad, D. R., 1,2-Amino Alcohols
and Their Heterocyclic Derivatives as Chiral Auxiliaries in
Asymmetric Synthesis. Chem. Rev. 1996, 96, 835–875; (b) O'Brien,
P., Sharpless Asymmetric Aminohydroxylation: Scope, Limitations,
and Use in Synthesis. Angew. Chem. Int. Ed. 1999, 38, 326–329; (c)
Bergmeier, S. C., The Synthesis of Vicinal Amino Alcohols.
Tetrahedron 2000, 56, 2561–2576; (d) Donohoe, T. J.; Callens, C. K.
A.; Flores, A.; Lacy, A. R.; Rathi, A. H., Recent Developments in
Methodology for the Direct Oxyamination of Olefins. Chem. Eur. J.
2011, 17, 58–76.
Scheme 5. Rapid Synthesis of the 1,2-Amino Alcohol via
Amino Oxygenation Reaction/Hydrolysis Sequence.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
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41
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43
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45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
Finally, a representative example for the synthetic utility of
this method is highlighted in its application for a rapid entry to
amino alcohol 13, by the amino oxygenation of diene 2a and
subsequent hydrolysis (Scheme 5). Note that the formation of
13 in 79% yield on the 2.0 mmol-scale reaction is more effi-
cient than the reaction on the 0.2 mmol-scale in 68% yield,
further demonstrating the scalability and practicality of the
reaction protocol.
In conclusion, we have developed a copper-catalyzed, three-
component 1,2-amino oxygenation reaction of 1,3-dienes. The
reaction proceeds through a copper-catalyzed amination of the
diene followed by a rapid nucleophilic trapping by the carbox-
ylic acid. The amino oxygenation conditions show remarkable
selectivity toward 1,3-dienes over alkenes, excellent tolerance
of sensitive functional groups, and reliable scalability. This
method is general and applicable to an extensive range of ter-
minal and internal 1,3-dienes as well as a wide range of car-
boxylic acids, presenting high levels of chemo-, regio-, and
site-selectivity. Further studies for a better understanding of
the selectivity will be disclosed in our future work.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, additional
screening data, and characterization data including NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*qiu.wang@duke.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors acknowledge financial support from Duke University,
the National Institutes of Health (GM118786), and the GAANN
fellowship from US Department of Education (P200A150114) to
B.N.H. The authors thank Dr. Peter Silinski (Duke University
Mass Spectrometry Facility) and Dr. Michael Walla (University
of South Carolina Mass Spectrometry Facility) for assistance with
high-resolution mass spectrometry. The authors thank Dr. Ben
Bobay and the Duke University NMR Center for assistance with
NMR experimentation. The authors also thank Colton Ku and
Jiaqi Zhao for collaborative efforts on O-benzoylhydroxylamine
synthesis.
6. (a) Gouverneur, V.; McCarthy, S. J.; Mineur, C.; Belotti, D.;
Dive, G.; Ghosez, L., New Acylnitroso Compounds for the
Asymmetric Oxyamination of Dienes. Tetrahedron 1998, 54, 10537–
10554; (b) Bollans, L.; Bacsa, J.; Iggo, J. A.; Morris, G. A.;
Stachulski, A. V., The Acyl Nitroso Diels-Alder (Anda) Reaction of
Sorbate Derivatives: An X-Ray and 15N NMR Study with an
Application to Amino-Acid Synthesis. Org. Biomol. Chem. 2009, 7,
4531–4538; (c) Scholz, S.; Plietker, B., Fe-Catalyzed Reductive NO–
REFERENCES
1. Selected recent reviews: (a) Cho, H. Y.; Morken, J. P., Catalytic
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Chem. Res. 2014, 47, 3665–3678; (c) Xiong, Y.; Sun, Y. W.; Zhang,
G. Z., Recent Advances on Catalytic Asymmetric Difunctionalization
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9
Bond Cleavage
–
a
Route to the Diastereoselective 1,4-
Aminohydroxylation of 1,3-Dienes. Org. Chem. Front. 2016, 3,
1295–1298.
7. (a) Michaelis, D. J.; Ischay, M. A.; Yoon, T. P., Activation of N-
Sulfonyl
Oxaziridines
Using
Copper(II)
Catalysts:
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Alkene Oxyamination with Nitrenes. Chem. Eur. J. 2014, 20, 8929–
8933; (b) Sun, X.; Li, X. Y.; Song, S.; Zhu, Y. C.; Liang, Y. F.; Jiao,
N.,
Mn-Catalyzed
Highly
Efficient
Aerobic
Oxidative
Hydroxyazidation of Olefins: A Direct Approach to Beta-Azido
Alcohols. J. Am. Chem. Soc. 2015, 137, 6059–6066; (c) Legnani, L.;
Morandi, B., Direct Catalytic Synthesis of Unprotected 2-Amino-1-
Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine.
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Benzoylhydroxylamines. J. Am. Chem. Soc. 2016, 138, 5813–5816;
(b) Hemric, B. N.; Wang, Q., Copper-Catalyzed Intermolecular
Oxyamination of Olefins Using Carboxylic Acids and O-
Benzoylhydroxylamines. Beil. J. Org. Chem. 2016, 12, 22–28; (c)
Hemric, B. N.; Chen, A. W.; Wang, Q., Copper-Catalyzed Modular
Amino Oxygenation of Alkenes: Access to Diverse 1,2-Amino
Oxygen-Containing Skeletons. J. Org. Chem. 2019, 84, 1468–1488.
11. See the Supporting Information for more details.
12. Shimizu, Y.; Kanai, M., Recent Progress in Copper-Catalyzed
Difunctionalization of Unactivated Carbon-Carbon Multiple Bonds.
Tetrahedron Lett. 2014, 55, 3727–3737.
13. (a) Bichler, P.; Love, J. A., Organometallic Approaches to
Carbon-Sulfur Bond Formation. In C–X Bond Formation, Vigalok,
A., Ed. Springer: Berlin, Heidelberg, 2010; Vol. 31, pp 39–64; (b)
Uyeda, C.; Tan, Y. C.; Fu, G. C.; Peters, J. C., A New Family of
Nucleophiles for Photoinduced, Copper-Catalyzed Cross-Couplings
via Single-Electron Transfer: Reactions of Thiols with Aryl Halides
under Mild Conditions (0 C). J. Am. Chem. Soc. 2013, 135, 9548–
9552; (c) Malapit, C. A.; Howell, A. R., Recent Applications of
Oxetanes in the Synthesis of Heterocyclic Compounds. J. Org. Chem.
2015, 80, 8489–8495; (d) Sakurai, T.; Yamauchi, O.; Nakahara, A.,
Mixed-Ligand Copper(II) Complexes of Alpha-Amino-Acids with
Ligand-Ligand Interactions. Bull. Chem. Soc. Jpn. 1976, 49, 169–173.
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Cu(OAc)2 (1 mol%)
DCE/2-MeTHF, 60 ºC
O
R1
O
NR4R5
BzO
+
+
H
R2
O
NR4R5
R1
R3
R2 R3
•
•
•
•
•
site- and regio-selective 1,2-addition
selectivity toward 1,3-dienes over alkenes
compatible with diverse, sensitive functional groups
broad scope of 1,3-dienes and carboxylic acids
>50 examples, including 2-mmol scale reaction in 79% yield
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