Copper Nitrate Mediated Regio- and Stereoselective Difunctionalization of Alkynes: A Direct Approach to α-Chloro-β-nitroolefins

Article abstract of DOI:10.1021/acs.orglett.6b02464

An efficient copper nitrate mediated chloronitration reaction was developed for the direct synthesis of α-chloro-β-nitroolefins with high regio- and stereoselectivity from simple alkynes and low toxic stannous chloride. This protocol provides a direct access to polysubstituted alkenes with operational simplicity, good functional group tolerance, and a wide substrate scope. Various applications of given products allowed the straightforward assembly of molecular complexity and indicated them as promising and valuable building blocks in organic synthesis.

Full text of DOI:10.1021/acs.orglett.6b02464

Letter
pubs.acs.org/OrgLett
Copper Nitrate Mediated Regio- and Stereoselective
Difunctionalization of Alkynes: A Direct Approach to α‑Chloro-β-
nitroolefins
Mingchun Gao† and Bin Xu*,†,‡,§
†School of Materials Science and Engineering, Department of Chemistry, Innovative Drug Research Center, Shanghai University,
Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
§Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
Shanghai 200062, China
S
* Supporting Information
ABSTRACT: An efficient copper nitrate mediated chloronitration reaction was developed for the direct synthesis of α-chloro-β-
nitroolefins with high regio- and stereoselectivity from simple alkynes and low toxic stannous chloride. This protocol provides a
direct access to polysubstituted alkenes with operational simplicity, good functional group tolerance, and a wide substrate scope.
Various applications of given products allowed the straightforward assembly of molecular complexity and indicated them as
promising and valuable building blocks in organic synthesis.
Scheme 1. Copper Nitrate-Mediated Difunctionalization of
Alkynes
olysubstituted alkenes represent a class of versatile structural
Pmotifs that could easily be found in pharmacologically active
compounds,1a−c natural products,1b,d or functional materials.1e
Among them, α-chloro-β-nitroolefins occur as one of the most
useful building blocks with respect to their exceptionally rich
synthetic possibilities and various transformations of the func-
tional groups. Considering their great synthetic value, previous
methods for the synthesis of α-chloro-β-nitroolefins were mainly
concentrated onthe direct nitrationof olefinic chloridewith nitric
acid,2 eliminationofhydrochloridefromα-nitrodichloridesunder
basic conditions,2c,3 or addition of alkynes using nitryl chloride or
nitrosyl chloride as sources of chloro and nitro group.4 However,
these methods suffered from harsh reaction conditions or the use
of highly toxic reagents, which is unbeneficial and unfriendly from
the viewpoint of green chemistry and sustainable development.
Transition-metal-promoted difunctionalization of alkynes has
been widely investigated in the past several decades,5 which could
provide various polysubstituted alkenes with two distinct
functional groups installed in one pot. Thus, the development of
efficient syntheses of α-chloro-β-nitroolefins from readily
available starting materials through a direct difunctionalization
of alkynes will be an active and rewarding research area.
presenceofachlorosourceunderthepromotionofcoppernitrate.
Nevertheless, it will be a challenge to avoid the undesired
formation of 1,3-diynes via Glaser−Hay homocoupling reaction9
and the isoxazole byproducts that could be easily derived from the
annulation of copper nitrate and alkynes (Scheme 1).8 Also, more
attention should be paid to the difunctionalization of alkynes in a
regio- and stereoselective manner. Herein, we report a novel
copper nitrate trihydrate mediated chloronitration reaction from
simple alkynes and stannous chloride dihydrate to give
polysubstituted (E)-α-chloro-β-nitroolefins selectively under
mild conditions (Scheme 1). To the best of our knowledge, the
given approach represents the first example for the copper-
promoted difunctionalization of alkynes to α-chloro-β-nitro-
olefins with high regio- and stereoselectivities, where copper
nitratewasemployedtomediatethetransformationofalkynesand
asthenitrosourcewitheasilyavailablelowtoxicstannouschloride
as the crucial chlorine source.
Copper nitrate has been proven tobe an efficient catalyst in C−
H activation;6 in addition, it is also well-known as a common
nitration reagent for arenes.7 Recently, we have disclosed a novel
[2+2+1]cyclizationofalkynesandalkenestoisoxazolines,8 where
copper nitrate acts as both the activator of simple alkynes and the
nitrogen source. Inspired by previous works, we envisioned
synthesisofα-chloro-β-nitroolefinsselectivelyfromalkynesinthe
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02464
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
Cl source (X equiv)
solvent
temp (°C)
atm
time (h)
yield (%)
1
NaCl (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMF
60
60
60
60
60
60
60
60
60
60
60
60
40
30
40
40
40
40
40
40
air
air
air
air
air
air
air
air
air
air
air
air
air
air
N2
O2
N2
N2
N2
N2
21
21
7
69 (85:15)
50 (86:14)
66 (79:21)
42 (73:27)
80 (85:15)
30 (31:69)
83 (84:16)
trace
2
LiCl (2)
3
CuCl2·2H2O (1)
CuCl (2)
4
2
5
FeCl3 (0.7)
4
6
NCS (2)
7
7
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
SnCl2·2H2O (1)
1
8
1
9
1
0
10
11
12
13
14
15
16
17
18
19
20
DMSO
dioxane
DCE
1
0
1
52 (90:10)
trace
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
4
85 (88:12)
81 (91:9)
90 (88:12)
50 (90:10)
8
4
4
c
4
85 (88:12)
d
4
85 (87:13)
e
4
43 (94:6)
f
4
0
a
Reaction conditions: 1a (0.3 mmol), Cu(NO3)2·3H2O (0.45 mmol), Cl source (0.3 mmol), solvent (1.5 mL). DCE = 1,2-dichloroethane. NCS =
b
N-chlorosuccinimide. Isolated yield as mixture of E/Z isomers and the E/Z ratio given in the parenthese was determined by proton NMR.
c
d
e
f
Cu(NO3)2·3H2O (1.0 equiv) was used. Cu(NO3)2·3H2O (2.0 equiv) was used. Fe(NO3)3·9H2O (1.0 equiv) was used. KNO3 (3.0 equiv) was
used.
At the outset of this study, we started our investigation by
established protocol was not limited to a simple monosubstituted
benzene ring. For example, 3,4-dimethoxybenzene-containing
trisubstitutedalkene(2m)wasobtainedsmoothlyinthe(Z)-form
as the major product, and substrates bearing a naphthyl (2n) or
thienyl (2o) group could also be transformed into the
corresponding products in good yields. Notably, aliphatic alkynes
with tertiary alcohol substitutions proceeded gradually to afford
the corresponding alkenes with only one isomer isolated at
increased reaction temperature (2p and 2q), which may be due to
the coordination of the hydroxyl group to the copper salt.
Furthermore, successofthisconversioncouldbefurtherextended
to triisopropylsilylacetylene, and the product with both chlorine
and triisopropylsilyl groups assembled was obtained in moderate
yield (2r), which implied it was the key intermediate for further
transformations. Significantly, various internal alkynes afforded
thecorrespondingtetrasubstitutedalkenesingoodyields,albeitin
moderate stereoselectivities (2s−u). However, when SnF2 or
SnBr2 wasusedasthehalidesourceunderthestandardconditions,
the reactions failed to afford the desired product or led to a
complicated result. It should be noted that nitroalkene 3 could be
synthesized in moderate yield through the given chloronitration
reaction and successive Suzuki coupling reaction, which could be
further transformed into pharmacologically interesting 3-aryl-
substituted indole analogues (Scheme 3).10
exploring the reaction of 1a with copper nitrate trihydrate and
sodiumchlorideinacetonitrileat60°Cunderair. Intriguingly, the
desiredproduct2awasisolatedin69%yieldwithE/Zselectivityas
85/15 after 21 h (entry 1, Table 1). Encouraged by this result,
various Cl sources were tested, including LiCl, CuCl2·2H2O,
CuCl, FeCl3, NCS, and SnCl2·2H2O, and the stannous salt stood
outasthesuperiorchoiceduetoitshigheryieldandselectivitywith
shorter reaction time (entries 2−7). Screening of solvents such as
toluene,DMF,DMSO,dioxane,andDCEindicatedacetonitrileto
be the suitable choice (entries 8−12). The stereoselectivity was
increased at lower temperature, albeit with prolonged reaction
time (entries 13 and 14). Fortunately, the reaction conducted
undernitrogenatmosphereat40°Caffordedbetterresultsinhigh
yieldandgoodselectivity (entry15), whilelowyieldwasobserved
under an oxygen atmosphere (entry 16). Reducing or increasing
the amount of the copper salts failed to improve the reaction
(entries 17 and 18). No reaction or less effective results could be
observed when iron nitrate or potassium nitrate was used as the
nitration reagent (entries 19 and 20), which indicated that the
copper salt was crucial to the success of this reaction.
With the optimized conditions in hand, we next examined the
substratescopeofalkynes.AsillustratedinScheme2,awidevariety
ofsubstitutionpatternsandfunctionalgroupsweretolerated. Aryl
acetylenes bearing either electron-withdrawing or -donating
groups in the para position of the aryl ring were smoothly
converted into the corresponding products in moderate to
excellent yields with excellent stereoselectivities (2a−f). Sub-
stratescontainingdifferentsubstitutions,suchasalkyl(2g),alkoxy
(2k), halides (2h and 2l), nitrile (2i), and sulfamide (2j), were
compatible with this reaction as well, regardless of their different
electronic properties and meta- or ortho- substitutions. The newly
A gram-scale synthesis of the product 2a was next carried out
underthestandardconditions(Scheme4).Pleasingly,theproduct
couldbeisolatedpredominantlyinitsE-isomerin76%yield,which
could be further purified to give 2a with single configuration
through recrystallization. The identity of 2a was determined by
spectral analysis and further confirmed by X-ray crystallographic
analysis.11
B
DOI: 10.1021/acs.orglett.6b02464
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a
Scheme 2. Substrate Scope of Alkynes
Scheme 5. Application of α-Chloro-β-nitroolefin Product
(4) or aryl amines (5), and the absolute configuration of 4 was
further determined by X-ray crystallography.11 The reason for the
configuration retention may be attributed to an elimination−
addition mechanism.12 However, alkene 6 was obtained in (Z)-
form when sodium thiocyanate was used as the nucleophile,11
owing toa fast configuration rotation ofthe intermediate from the
(E)- to (Z)-form.13 Furthermore, the well-documented Suzuki
reaction proceeded smoothly, with the corresponding product 7
obtained in almost quantitive yield.
To define the possible intermediates and pathway, several
control experiments were carried out as shown in Scheme 6. The
desired alkene product 2a was not observed when β-nitro- (eq 1)
orα-chloro-(eq2)substitutedalkenewasusedasstartingmaterial
in the absence of copper nitrate or stannous chloride, which
suggested that the above two proposed intermediates could be
a
Reaction conditions: 1 (0.3 mmol), Cu(NO3)2·3H2O (0.45 mmol),
SnCl2·2H2O (0.3 mmol), CH3CN (1.5 mL), 40 °C, N2 atmosphere.
Isolated yield as mixture of E/Z isomers, and the E/Z ratio was
b
determined by 1H NMR spectroscopy. The E/Z ratio was determined
c
d
e
by 19F NMR spectroscopy. 30 °C. 60 °C. 80 °C.
Scheme 3. Difunctionalization/Suzuki Stepwise Reaction
Scheme 6. Mechanistic Studies
Scheme 4. Gram-Scale Reaction
To illustrate the synthetic utility and demonstrate the broad
application prospect of the reaction, further transformations of
given product were investigated (Scheme 5). A series of
nucleophiles were first introduced. Intriguingly, products were
isolated in (E)-form from nitrogen nucleophiles, such as aliphatic
C
DOI: 10.1021/acs.orglett.6b02464
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Scheme 7. Plausible Mechanism (Ligands Are Omitted for
Clarity)
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21272149 and 21672136) and the Innovation Program of
Shanghai Municipal Education Commission (No. 14ZZ094) for
financial support. We thank Prof. Hongmei Deng (Laboratory for
Microstructures, SHU) for NMR spectroscopic measurements.
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nitrate mediated approach for the direct access of synthetic
interesting polysubstituted α-chloro-β-nitroolefins from simple
alkynes and low toxic stannous chloride. The reaction featured a
wide substrate scope with functional groups tolerated. Various
applications of given products allowed the straightforward
assembly of molecular complexity and indicated them as
promising and valuable building blocks in organic synthesis.
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Experimental procedures and characterization data for all
compounds (PDF)
X-ray data for compound (E)-2a (CIF)
X-ray data for compound 4 (CIF)
X-ray data for compound 6 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xubin@shu.edu.cn.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b02464
Org. Lett. XXXX, XXX, XXX−XXX