Copper-catalyzed intermolecular oxyamination of olefins using carboxylic acids and O-benzoy I hydroxy lamines

Article abstract of DOI:10.3762/bjoc.12.4

This paper reports a novel approach for the direct and facile synthesis of 1, 2-oxyamino moieties via an intermolecular copper-catalyzed oxyamination of olefins. This strategy utilizes O-benzoylhydroxylamines as an electrophilic amine source and carboxyli

Full text of DOI:10.3762/bjoc.12.4

Copper-catalyzed intermolecular oxyamination of olefins
using carboxylic acids and O-benzoylhydroxylamines
Brett N. Hemric and Qiu Wang*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 22–28.
Department of Chemistry, Duke University, Durham, NC, USA
doi:10.3762/bjoc.12.4
Email:
Received: 30 October 2015
Accepted: 11 December 2015
Published: 07 January 2016
Qiu Wang* - qiu.wang@duke.edu
*
Corresponding author
This article is part of the Thematic Series "Copper catalysis in organic
synthesis".
Keywords:
copper; electrophilic amination; olefin oxyamination
Guest Editor: S. R. Chemler
©
2016 Hemric and Wang; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
This paper reports a novel approach for the direct and facile synthesis of 1,2-oxyamino moieties via an intermolecular copper-
catalyzed oxyamination of olefins. This strategy utilizes O-benzoylhydroxylamines as an electrophilic amine source and carboxylic
acids as a nucleophilic oxygen source to achieve a modular difunctionalization of olefins. The reaction proceeded in a regioselec-
tive manner with moderate to good yields, exhibiting a broad scope of carboxylic acid, amine, and olefin substrates.
Introduction
The 1,2-oxyamino motif is highly valuable and found in a vast able olefins in a single step, representing a powerful and
range of biologically active natural products, pharmaceuticals, appealing approach over multistep sequences [7-9]. Sharpless
and agrochemicals (Figure 1) [1,2]. Representative examples reported the first examples of this strategy using osmium
include salmeterol (Advair®), a β2-adrenergic receptor agonist tetroxide and amines to generate imido osmium intermediates
[
3]; lumefantrine, an antimalarial drug [4]; ifenprodil, an (Scheme 1A) [10-12]. Although this transformation has
N-methyl-D-aspartate (NMDA) antagonist [5]; and tebucona- received extensive application, the development of less toxic
zole, a commercial fungicide [6].
olefin oxyamination methods is greatly desired. In 2006, Stahl
and Liu reported a palladium-catalyzed introduction of phthal-
With the importance of 1,2-oxyamino motifs as privileged phar- imide (HNPhth) and acetate functionalities to terminal allylic
macophores, the development of facile and efficient access to and homoallylic ethers in the presence of an iodine oxidant
this class of molecules is highly valued. Toward this end, inter- (Scheme 1B) [13]. The Yoon lab also developed copper- and
molecular olefin oxyamination allows for direct and modular iron-catalyzed olefin difunctionalization reactions with oxaziri-
installation of both oxygen and amino groups to readily avail- dine derivatives to create 1,3-oxazolidines, which were readily
22

Beilstein J. Org. Chem. 2016, 12, 22–28.
and by the Studer lab with the use of hypervalent iodo-azide
reagents [18]. Furthermore, the intramolecular oxyamination of
olefins with a tethered amino or oxygen functionality has been
achieved for the construction of a variety of 1,2-oxyamino prod-
ucts, using palladium [19,20], platinum [21], gold [22], copper
[
23-26], free-radical initiators [27-29], hypervalent iodine [30],
and electrochemical oxidation [31-33], as well as an analogous
intramolecular electrophilic amino lactonization from our group
[
34].
Despite these important achievements, current intermolecular
olefin oxyamination reactions are often restricted by the use of
specific amino and oxygen precursors, limiting the structural
diversity of 1,2-oxyamino products. For example, most oxyami-
nation methods are limited to the installation of amide or
sulfonamide derivatives. The direct installation of electron-rich
amino groups, especially tertiary cyclic amines, remains an
unsolved problem. Furthermore, most methods employ inflex-
Figure 1: Examples of valuable 1,2-oxyamino-containing molecules.
converted to the 1,2-oxyamino functionality (Scheme 1C) ible oxygen sources, such as TEMPO and acetate. Herein, we
14,15]. Recently, the Xu lab developed another iron-catalyzed envisioned that a copper-catalyzed intermolecular olefin
[
intermolecular olefin-oxyamination reaction with O-alkyl- oxyamination could be achieved using O-acylhydroxylamines
hydroxylamides to construct either 1,2-oxyamino or 2-oxazo- as an electrophilic amino precursor [35-39] and carboxylic acids
lidinone motifs (Scheme 1D) [16]. Metal-free intermolecular as a nucleophilic oxygen source (Scheme 1E). The proposed
oxyamination reactions have also been accomplished; exam- transformation, integrating an electrophilic amination with a
ples were reported by the Zhu lab with the use of peroxides [17] nucleophilic oxygenation, builds upon our recent development
Scheme 1: Strategies for intermolecular olefin oxyamination.
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Beilstein J. Org. Chem. 2016, 12, 22–28.
in copper-catalyzed olefin difunctionalization, such as copper- reactant was examined for this three-component transformation,
catalyzed diamination [40] and amino lactonization [34]. This decreasing the amount of 1a resulted in lower yields (Table 1,
strategy overcomes common issues of chemo- and regioselec- entry 2 vs 8), while decreasing the amount of 3a had no effect
tivity associated with adding two different nucleophiles and (Table 1, entry 2 vs 9). Increasing the amount of 2a led to a
simultaneously eliminates the need for an external oxidant. noticeable improvement (Table 1, entry 9 vs 12). Finally, the
Particularly advantageous is the direct addition of electron-rich optimal conditions were established with three equivalents of
amino groups, especially tertiary amines, which are difficult to both 1a and 2a, providing 4a in a clean 78% isolation yield
access by other known methods. Furthermore, O-acylhydroxyl- (Table 1, entry 13) [43].
amines are synthetically straightforward and benchtop stable,
serving as attractive amine precursors [41,42]. Overall, the With established oxyamination conditions in hand, the scope of
development of such a three-component transformation offers carboxylic acids in this transformation was examined using
an appealing oxyamination strategy complementary to existing olefin 2a and O-benzoylhydroxylamine 3a (Scheme 2). Both
methods.
aryl and alkyl carboxylic acid derivatives proved to be viable
substrates, smoothly providing 1,2-oxyamino products 4a–g.
Carboxylic acids containing a nitro group (4b), a halide group
Results and Discussion
Our investigation began with the use of pentafluorobenzoic acid (4d), or an allyl group (4f) were tolerated, demonstrating the
1a) as the oxygen source and 4-benzoyloxymorpholine (3a) as broad functional group compatibility of the reaction conditions.
(
the nitrogen source in the proposed intermolecular oxyamina- It is notable that higher efficiencies were observed in the reac-
tion of styrene (2a, Table 1). Copper was found to be effective tions with more acidic benzoic acids, indicating a correlation of
and critical to promote the formation of oxyamination product their reactivity to their acidity which remains to be further clari-
4
a with excellent regioselectivity, as 4a was not observed in the fied [44]. Furthermore, when trifluoroacetic acid was employed
absence of a catalyst (Table 1, entry 1). Among a variety of as an oxygen source, the free 1,2-amino alcohol 4g was
copper salts (Table 1, entries 2–7), Cu(OAc)2 proved superior isolated, possibly due to the labile hydrolysis of the trifluoro-
as a catalyst (Table 1, entry 2). When the stoichiometry of each acetate group.
Table 1: Optimization of copper-catalyzed intermolecular oxyamination.a
Entry
Reactants (equiv)
Catalyst
Timeb
4a (%)c
1a
2a
3a
1
2
3
4
5
6
7
8
9
2
1
1
1
1
1
1
1
1
1
1
2
2
3
2
2
2
2
2
2
2
2
1
1
2
1
1
–
24 h
0
2
2
2
2
2
2
1
2
3
1
2
3
Cu(OAc)2
Cu(OTf)2
CuCl2
15 min
15 min
15 min
15 min
15 min
60 min
15 min
15 min
15 min
15 min
15 min
15 min
63
45
60
Cu(TFA)2
Cu(OAc)
CuI
47
59
52
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
48
63
10
11
12
13
71
77
85
99 (78)d
aReaction conditions: 1a, 2a, 3a, catalyst (20 mol %), DCE (1.0 mL), 80 °C. bTime required for consumption of 2a. cOnly the indicated isomer was
observed. Yields determined by 1H NMR spectroscopy with CH2Br2 as a quantitative internal standard. dIsolated yield. OAc = acetate, OTf = trifluo-
romethanesulfonate, TFA = trifluoroacetate.
24

Beilstein J. Org. Chem. 2016, 12, 22–28.
Scheme 2: Examples of carboxylic acids in the olefin oxyamination reaction. Reaction conditions: 1 (1.2 mmol, 3.0 equiv), 2a (3.0 equiv), 3a
1.0 equiv), Cu(OAc)2 (20 mol %), DCE (2.0 mL), 80 °C, 15 min. Isolated yields.
(
Next, the scope of O-benzoylhydroxylamines was examined than those from electron-deficient ones (i.e., 6c and 6f). The
with carboxylic acid 1a and olefin 2a (Scheme 3). In the reac- reactions with simple olefins also provided desired products, yet
tions with cyclic O-benzoylhydroxylamines, 5a–c were readily in poor yields (Table 2, entries 7 and 8). These results indicate
formed in good yields, while acyclic amine products 5d and 5e that olefin substrates capable of stabilizing a possible electron-
were formed less effectively. Likely, the electronic and steric deficient intermediate (carbon cation or radical) are likely
nature of the acyclic O-benzoylhydroxylamines may affect the favored in this transformation. Furthermore, 1,2-disubstituted
stability of the corresponding amino intermediates, and result in olefins were also viable substrates (Table 2, entries 9–11).
facile breakdown of the amine precursors to the corresponding Particularly exciting is the formation of 6j and 6k in excellent
free amine. It should be noted that the benzyl group on the diastereoselectivity. In contrast, acyclic 1,2-oxyamino product
amine 5e can be readily cleaved for the construction of a sec- 6i was formed as a 1:1 mixture of two diastereomers. These
ondary amine.
results suggest a contribution of the structural conformation to
the diastereoselective outcome of the reaction. Yet, 1,1-disubsti-
Finally, the scope of olefins for the transformation was exam- tuted olefins were not effective, likely due to the increased
ined including both aryl and alkyl olefins (Table 2). First, steric hindrance in the oxygenation step (Table 2, entry 12).
styrene derivatives bearing a variety of substitutions on the aryl
ring, including both electron-donating and electron-with- Currently, the mechanistic details of this copper-catalyzed
drawing groups, were all effective in providing the 1,2-oxyami- oxyamination reaction remain unclear. In the control experi-
nated products with exclusive regioselectivity (Table 2, entries ment with the absence of O-benzoylhydroxylamine, both
1
–6). Interestingly, the products derived from electron-rich carboxylic acid and olefin substrates were fully recovered,
styrene substrates (i.e., 6a, 6b, 6e) were formed in higher yields suggesting the critical role of O-benzoylhydroxylamine in the
Scheme 3: Examples of O-benzoylhydroxylamines in the olefin oxyamination reaction. Reaction conditions: 1a (1.2 mmol, 3.0 equiv), 2a (3.0 equiv),
3
(1.0 equiv), Cu(OAc)2 (20 mol %), DCE (2.0 mL), 80 °C, 15 min. Isolated yields.
25

Beilstein J. Org. Chem. 2016, 12, 22–28.
Table 2: Examples of olefins in intermolecular oxyamination reaction.a
Entry
Olefin
Product
Yield (%)b
1
2
3
4
5
6
6a, R = 2–OMe
6b, R = 3–OMe
6c, R = 3–F
6d, R = 4–Me
6e, R = 4–OMe
6f, R = 4–Cl
83
71
57
81
69
70
7
8
6g, R = CH2TMS
6h, R = TMS
19
9
9
6i
6j
69 (1:1 dr)c
10
89 (7:1 dr)c
1
1
2
6k
6l
35 (>20:1 dr)c
1
<15%d
aReaction conditions: 1a (1.2 mmol, 3.0 equiv), 2 (3.0 equiv), 3a (1.0 equiv), Cu(OAc)2 (20 mol %), DCE (2.0 mL), 80 °C, 15 min. bIsolated yields.
cdr = diastereomeric ratio, determined by 1H NMR of the crude reaction mixture. Major diastereomer shown. Relative stereochemistry of 6j deter-
mined by X-ray analysis. dProduct containing minor inseparable impurities.
activation of copper catalyst for the initiation of this reaction. carboxylic acids and O-benzoylhydroxylamines. This reaction
Further investigations are underway for a better understanding allows for rapid access to a variety of 1,2-oxyamino products in
of the reaction pathway.
a modular manner with excellent regioselectivity. It offers an
appealing oxyamination method, especially for the construction
of electron-rich tertiary amines. Future efforts will be under-
Conclusion
In summary, we have developed a copper-catalyzed three- taken for a better understanding of the reaction mechanism and
component intermolecular oxyamination of olefins using for the development of an asymmetric version.
26

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Supporting Information File 1
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