Copper Nitrate-Mediated Selective Difunctionalization of Alkenes: A Rapid Access to β-Bromonitrates

Article abstract of DOI:10.1002/adsc.201900016

A regioselective copper nitrate-mediated difunctionalization of alkenes has been developed for the rapid synthesis of β-bromonitrates, where copper nitrate is used as an ideal nitrooxy source for the first time and the products will find many applications in organic synthesis as versatile synthons. Different from the general reports that copper nitrate acts as the nitro source, the given protocol provides a direct access to functionalized nitrates, with operational simplicity, good functional group tolerance and a wide substrate scope. (Figure presented.).

Full text of DOI:10.1002/adsc.201900016

Title: Copper Nitrate-Mediated Selective Difunctionalization of Alkenes:
A Rapid Access to β-Bromonitrates
Authors: Mingchun Gao, Kaijing Zhou, and Bin Xu
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper Nitrate-Mediated Selective Difunctionalization of
Alkenes: A Rapid Access to β-Bromonitrates
Mingchun Gao,a Kaijing Zhou,a and Bin Xua,b,*
a
Department of Chemistry, Innovative Drug Research Center, School of Materials Science and Engineering, Shanghai
University, Shanghai 200444, China
E-mail: xubin@shu.edu.cn; Fax: (+86)-21-66132830; Tel: (+86)-21-66132830
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Copper nitrate is a common inorganic salt, which
difunctionalization of alkenes has been developed for the has been proven to be a ubiquitous reactant in organic
Abstract.
A
regioselective copper nitrate-mediated
rapid synthesis of β-bromonitrates, where copper nitrate is
used as an ideal nitrooxy source for the first time and the
products will find many applications in organic synthesis as
versatile synthons. Different from the general reports that
copper nitrate acts as the nitro source, the given protocol
provides a direct access to functionalized nitrates, with
operational simplicity, good functional group tolerance and
a wide substrate scope.
synthesis due to its commercial availability, stability,
inexpensiveness and environmental-benign nature.[5]
Generally, copper nitrate is disclosed as the efficient
nitration reagent for arenes,[6] or as the catalyst or
Lewis acid to promote reactions.[5,7] An elegant
protocol has recently been developed for the
transformation of simple alkynes to nitrile oxide
dipoles with copper nitrate as the novel precursor of
the dipoles, which largely extends the synthetic
applications of copper nitrate in organic synthesis.[8]
Copper-catalyzed difunctionalization of carbon-
carbon multiple bonds represents one of the most
powerful and efficient tools for the construction of
organic compounds.[9] Recently, copper nitrate-
mediated chloronitration of alkynes was developed
by our group for the construction of polysubstituted
olefins,[10] where copper nitrate acts as the nitro
source and the crucial catalyst to activate the C≡C
triple bond as well (Scheme 1). Consequently, we
envisioned to realize the difunctionalization of
alkenes further in a similar strategy. Nevertheless,
several hurdles need to be overcome including the
inhibition of nitroolefins[11] formed as the by-product
during the reaction and the control of chemo- and
regioselectivity as well. Herein, we report a novel
Keywords: alkenes; β-bromonitrates; bromination;
copper nitrate; difunctionalization; nitrate compounds
Nitrate compounds have been widely found in
marketed drugs or pharmacologically active
molecules. For example, glycerol trinitrate (GTN)
and isosorbide mononitrate are well known for their
efficient treatment on cardio diseases, since the
released NO molecule from nitrates could reduce the
blood pressure through vasodilation. In addition,
nitrates occur as key building blocks for the rapid
construction of heterocyclic rings or function as
tentative hydroxy protecting groups.[1] Among them,
β-bromonitrates act as useful intermediates, allowing
the flexible transformation of functional groups.
Considering the great value on both medicinal and
synthetic chemistry, various methods to β-
bromonitrates have been reported and mainly focused
on nucleophilic substitution of appropriate halides
with silver nitrate,[2] nitration of alcohols with nitric
acid[3] or through difunctionalization of alkenes with
bromonium nitrate,[4a] mercury nitrate/halogen[4b,c] or
ceric ammonium nitrate (CAN)/potassium bromide
combination.[4d,e] However, some of these methods
suffer from complicated substrates, expensive or
toxic reagents, or harsh reaction conditions, which is
unbeneficial from the viewpoint of sustainable
development or substrate applicability.
Scheme 1. Copper Nitrate-mediated Difunctionalization
Reactions.
1
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
copper nitrate-mediated difunctionalization of simple
alkenes to give β-bromonitrates selectively in good to
high yields under mild conditions (Scheme 1). To our
knowledge, the given approach represents the first
example for the construction of functionalized
nitrates with copper nitrate as an ideal nitrooxy
source, which is different from acting as the generally
reported nitro source.
Intriguingly, when NBS was used instead of SnBr2,
unexpected β-bromonitrate 2a was isolated in 39%
yield (entry 2), and the yield remained the same after
decreasing the amount of copper nitrate (entry 3).
Screening of solvents, such as DMF, DMSO, MeOH,
DCE, toluene, HOAc and dioxane, indicated dioxane
to be the superior choice, affording the product in
85% yield (entries 4–10). To our delight, increasing
the temperature could greatly shorten the reaction
time with a similar yield (entries 11 and 12).
Cu(NO3)2·3H2O was found to be the best nitrooxy
source, since ferric nitrate, cobalt nitrate, KNO3 or
CAN showed less or no effect on this transformation
At the outset of this study, following our previous
work,[10] we initiated the investigation by exploring
the reaction of 1a with copper nitrate trihydrate and
o
SnBr2 in acetonitrile at 60 C under air. However, we
failed to obtain the desired β-nitro bromide and the
reaction gave a complicated mixture (Table 1, entry1). (entries 13–16). Further optimization of the ‘Br’
source and its amount revealed that the nitrate
Table 1. Optimization of the Reaction Conditions.[a]
product 2a could be afforded in 86% yield in the
presence of 1.2 equivalents of NBS (entries 17–20).
No higher yield could be obtained under a nitrogen or
oxygen atmosphere (entries 21 and 22).
With the optimized conditions in hand, we next
examined the substrate scope of styrenes. As
illustrated in Table 2, a wide variety of substitution
patterns and functional groups were tolerated in this
reaction. Substrates with either electron-rich (2a, 2e,
2g–2i) or electron-deficient (2c, 2d, 2f, 2j) groups in
the para position gave the corresponding products in
moderate to excellent yields. The identity of 2h was
determined by spectral analysis and further confirmed
Yield[b]
(%)
‘ONO2’ source
‘Br’ source
(Y equiv))
Time
(h)
Temp
(oC)
Entry
Solvent
(X equiv)
Cu(NO3)2·3H2O
(1.5)
Cu(NO3)2·3H2O
(1.5)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Fe(NO3)3·9H2O
(0.7)
Co(NO3)2·6H2O
(1.0)
KNO3 (2.0)
CAN (0.33)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
1
2
SnBr2 (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
NBS (1.0)
CH3CN
CH3CN
CH3CN
DMF
60
60
60
60
60
60
60
60
60
60
70
80
80
80
5
4
trace
39
3
5
40
4
24
24
24
4
trace
trace
trace
59
Table 2. Substrate Scope of Substituted Styrenes.[a,b]
5
DMSO
MeOH
DCE
6
7
8
toluene
HOAc
4
74
9
24
48
42
2
trace
85
10
11
12
13
14
dioxane
dioxane
dioxane
dioxane
dioxane
82
83
30
4
51
50
15
16
NBS (1.0)
NBS (1.0)
DBDMH
(0.5)
dioxane
dioxane
80
80
18
2
33[c]
trace
17
18
19
20
21
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
80
80
80
80
80
80
6
1
75
72
Br2 (1.0)
KBr (1.0)
NBS (1.2)
NBS (1.2)
NBS (1.2)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
Cu(NO3)2·3H2O
(1.0)
24
1
trace
86
1
80[d]
80[e]
22
[a]
1
Reaction conditions: 1a (0.3 mmol), ‘ONO2’ source,
‘Br’ source, solvent (1.5 mL), under air. CAN = Cerium
ammonium nitrate. DBDMH = 1,3-Dibromo-5,5-dimethyl
hydantoin. DCE = Dichloroethane. NBS = N-Bromo
succinimide.
[a]
Reaction conditions: 1 (0.3 mmol), Cu(NO3)2∙3H2O (0.3
[b] Isolated yield.
o
mmol), NBS (0.36 mmol), dioxane (1.5 mL), 80 C, under
[c] 0.3 equiv of Cu(NO3)2·3H2O was used.
[d] Under N2 atmosphere.
air atmosphere.
[b] Isolated yield.
[e] Under O2 atmosphere.
[c] 4.0 equiv of Cu(NO3)2∙3H2O was used.
2
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
by X-ray crystallographic analysis.[12] Notably, for
substrate 1k with both C=C double bond and C≡C
triple bond, the difunctionalization reaction occurred
selectively on the double bond with the triple bond
untouched. Meanwhile, meta- (1l and 1m), ortho-
(1n) and 3,4-dimethyl (1o) substituted styrenes were
all compatible with the reaction conditions and
converted to the corresponding products smoothly.
The substrate scope of the given approach is not
only limited to simple styrenes (Table 3). For
instance, naphthyl substituted product 2p was
afforded in good yield under the standard conditions.
Moreover, cyclic or acyclic internal alkenes also led
to the desired products (2q–2s) in good yields and
diastereoselectivities. The determining factor to
control the diastereoselectivity for internal alkenes
might be due to the steric effect. Success of this
conversion could be further extended to vinyl esters,
which afforded the corresponding α-acyloxy-β-
bromonitrates (2t–2v) in good yields.
Intriguingly, derivatives generated from product 2u
could be regarded as efficient NO releasing prodrugs
of Aspirin.[13] It should be noted that product 2v was
obtained from vinyl cinnamate, which suggested the
selective difunctionalization on the C=C double bond
adjacent to the oxygen atom, rather than the one
linked with the electron-withdrawing carbonyl group.
Significantly, the newly established protocol could
also be applied to alkyl substituted olefins, affording
corresponding β-bromonitrate products (2w–2y) in
good regioselectivities. Furthermore, modification to
the steroidal skeleton gave the estrone derivative 2z
in 79% yield, which highlighted the synthetic
application in late-stage functionalization of complex
molecules. Alternatively, when phenylacetylene was
employed instead of alkene substrates in acetonitrile
with 2.4 equivalents of N-bromosuccinimide, 2,2-
dibromo-1-phenylethan-1-one was obtained in 54%
yield.
The reaction could be conducted on gram scale to
provide the product 2a and 2s in good yield,
respectively. It is worth noting that the gram-scale
reaction for internal alkene 1s could also be carried
out in a stereoselective manner (Scheme 2).
Table 3. Substrate Scope of Olefins.[a,b]
Scheme 2. Gram-scale Reactions.
The applicability of β-bromonitrates with ortho-
OTIPS substitution, derived from 2-hydroxy-
acetophenones with five steps, has been well
demonstrated by Varvounis and co-worker.[2b] Further
synthetic utility of the given reaction was examined
next, as shown in Scheme 3. Owing to the synthetic
versatility of bromo atom and the nitrooxy group,
product 2a could be easily converted into vinyl azide
3 in the presence of sodium azide. Interestingly,
products 4 and 5 could be obtained selectively by
switching the amount of sodium thiocyanate and
reaction concentration. Furthermore, alcohols could
also act as good nucleophiles, with the alkoxy group
assembled on the benzylic position (6, 7) in excellent
yield. Alternatively, for substrate 2s with single
configuration, both bromo atom and nitrooxy group
would be substituted simultaneously to afford
dihydroacenaphthylene derivatives 8 and 9 in the
presence of sodium azide and potassium thiocyanate,
respectively.
[a]
Reaction conditions: 1 (0.3 mmol), Cu(NO3)2∙3H2O (0.3
o
mmol), NBS (0.36 mmol), dioxane (1.5 mL), 80 C, under
air atmosphere.
[b] Isolated yield.
[c]
The d.r. ratio was determined by proton NMR of
isolated product.
[d] 2.0 equiv of Cu(NO3)2∙3H2O was used.
[e] The ratio of isomers was determined by proton NMR.
[f] The reaction was carried out in 1.0 mmol scale.
To define the possible intermediates and pathway,
a series of control experiments were carried out as
shown in Scheme 4. When a frequently used radical
3
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
substrate suggested hydroquinone could be
completely consumed with copper nitrate or NBS
(eqn (4)), which could explain for the trace amount
generation of product 2a in the presence of
hydroquinone. Furthermore, substrate 1ab could be
smoothly converted into product 2ab rather than the
cyclization product (eqn (5)).[14] Thus, based on these
results, we speculated that the reaction might mainly
undergo an ionic pathway.
Although the detailed reaction pathway remained
to be clarified, a plausible mechanism for this
reaction was proposed on the basis of above results
(Scheme 5). Initially, copper nitrate may act as a
Lewis acid to coordinate with one of the carbonyl
groups of NBS and generate complex A, where the
bromine atom is more electrophilic.[15] Treatment of
alkenes 1 with this bromination reagent A afforded an
ion pair B containing three-membered bromonium
ion and copper-coordinated imide anion. Finally, the
desired β-bromonitrates 2 could be obtained through
nucleophilic attack of dissociated nitrate anion to the
bromonium ion.
Scheme 3. Synthetic Applications of β-Bromonitrates.
o
Reaction Conditions: (a) NaN3, DMSO, 50 C, 1 h, 45%;
o
(b) NaSCN, DMSO (c = 0.033 M), 40 C, 45 h, 29%; (c)
NaSCN, DMSO (c = 0.1 M), 50 oC, 24 h, 75%; (d) MeOH,
o
Cu(NO3)2·3H2O, 60 C, 8 h, 96%; (e) Cu(NO3)2·3H2O,
o
o
glycol, 60 C, 11 h, 91%; (f) NaN3, DMSO, 40 C, 1 h,
58%; (g) KSCN, DMSO, 60 oC, 22 h, 33%.
clock substrate 1aa was conducted under
standard conditions, the ring-opening product
2aa was isolated in 43% yield (eqn (1)), which
could be produced through either radical or ionic
pathway. The reaction remained effective in the
presence of 1,4-dinitrobenzene (eqn (2)), however, no
desired product could be obtained when
hydroquinone was used as radical inhibitor (eqn (3)).
The result of control experiment without alkene
Scheme 5. Plausible Mechanism (Ligands are omitted for
clarity).
In summary, we have developed a novel and
efficient copper nitrate-mediated approach for the
direct synthesis of β-bromonitrates from bench stock
and readily available alkenes and N-bromo
succinimide, where copper nitrate is firstly described
as an ideal nitrooxy source. The reaction features a
wide substrate scope with good functional group
tolerance and mild reaction conditions. Further
applications of given products indicates them as
promising and valuable building blocks in synthetic
chemistry. In-depth investigation of this reaction is
currently studied in our laboratory.
Experimental Section
General procedure for the synthesis of β-bromonitrates
from alkenes: To a test tube, alkene 1 (0.3 mmol),
Cu(NO3)2·3H2O (72.5 mg, 0.3 mmol), N-bromo
succinimide (NBS) (64.1 mg, 0.36 mmol) in dioxane (1.5
o
mL) was added. The mixture was stirred at 80 C under an
air atmosphere. Upon completion monitored by TLC, the
reaction mixture was cooled down to room temperature
Scheme 4. Mechanistic Studies.
4
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
and purified by flash column chromatography on silica gel
to give the desired product 2.
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Acknowledgements
We thank the National Natural Science Foundation of China (No.
21871174, 21672136) and Innovation Program of Shanghai
Municipal Education Commission (No. 2019-01-07-00-09-
E00008) for financial support. The authors thank Profs. Qitao
Tan and Bingxin Liu for their helpful discussions, and Prof.
Hongmei Deng (Laboratory for Microstructures, SHU) and Mr.
Hui Wang for spectroscopic measurements.
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5
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10.1002/adsc.201900016
Advanced Synthesis & Catalysis
COMMUNICATION
Copper
Nitrate-Mediated
Selective
Difunctionalization of Alkenes: A Rapid Access to
β-Bromonitrates
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M. Gao, K. Zhou, B. Xu*
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