Reduction of α,β-unsaturated nitroolefins into nitroalkanes with Hantzsch ester promoted by isothiouronium salts

Article abstract of DOI:10.1080/00397911.2019.1614627

α,β-Unsaturated nitroolefins were reduced into nitroalkanes with a Hantzsch ester, promoted by S-benzyl isothiouronium iodide. The reactions proceeded successfully to afford the desired products in high yields and with excellent chemoselectivity.

Full text of DOI:10.1080/00397911.2019.1614627

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Reduction of α,β-unsaturated nitroolefins into
nitroalkanes with Hantzsch ester promoted by
isothiouronium salts
Sungmin Kang, Haney Lee & Taek Hyeon Kim
To cite this article: Sungmin Kang, Haney Lee & Taek Hyeon Kim (2019): Reduction of α,β-
unsaturated nitroolefins into nitroalkanes with Hantzsch ester promoted by isothiouronium salts,
Synthetic Communications, DOI: 10.1080/00397911.2019.1614627
To link to this article: https://doi.org/10.1080/00397911.2019.1614627
Published online: 25 Jul 2019.
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https://doi.org/10.1080/00397911.2019.1614627
Reduction of a,b-unsaturated nitroolefins into nitroalkanes
with Hantzsch ester promoted by isothiouronium salts
Sungmin Kang, Haney Lee, and Taek Hyeon Kim
School of Chemical Engineering, College of Engineering, Chonnam National University, Gwangju,
Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 30 January 2019
a,b-Unsaturated nitroolefins were reduced into nitroalkanes with a
Hantzsch ester, promoted by S-benzyl isothiouronium iodide. The
reactions proceeded successfully to afford the desired products in
high yields and with excellent chemoselectivity.
KEYWORDS
Isothiouronium iodide;
reduction; nitroolefins
GRAPHICAL ABSTRACT
Introduction
Nitroalkanes are versatile and inexpensive candidates for feedstocks in organic synthesis,
and they are easily transformed into a wide variety of functional moieties such as nitrile
oxide, amine, and carbonyl group via the corresponding reactions.[1] Several synthetic
methods have been proposed for the reduction of a,b-unsaturated nitroolefins[2] into
nitroalkanes, but they have some drawbacks in chemoselective reactions.[3] Borohydride
is the most common reducing agent used to synthesize nitroalkanes from nitroolefins,
but a dimeric by-product is obtained because of the addition of the nitronate intermedi-
ate to the starting a,b-unsaturated nitroolefin. Reduction of nitroolefins with lithium
aluminum hydride also leads to the formation of by-products such as hydroxyl amines,
oximes, and amines.[3e]
Hantzsch esters have been identified as powerful biomimetic reducing agents[4] that
can overcome some of the drawbacks associated with typical reducing agents such as
metal hydrides and hydrogen gas/metal systems.[5] Selective reduction of nitroolefins
CONTACT Taek Hyeon Kim
thkim@jnu.ac.kr
School of Chemical Engineering, College of Engineering, Chonnam
National University, Gwangju 61186, Republic of Korea.
ß 2019 Taylor & Francis Group, LLC

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Scheme 1. Reduction of a,b-unsaturated nitroolefins using S-benzyl isothiouronium iodide.
into nitroalkanes has been carried out using Hantzsch esters, promoted by catalysts
such as acetic acid,[2b] silica gel,[2c,f] and thiourea.[2g,7b] During the course of our studies
on isothiouronium salts as novel combination catalysts with Hantzsch esters,[6] we dis-
covered that S-benzyl isothiouronium iodide was more effective than S-benzyl iso-
thiouronium chloride for the reductive amination of aldehydes.[6d] This recipe of
S-benzyl isothiouronium iodide and Hantzsch esters is herein applied to the reduction
of a,b-unsaturated nitroolefins into nitroalkanes, resulting in a more effective and che-
moselective combination. Isothiouronium units have recently been reported as a novel
class of hydrogen-bonding motifs for anion molecular recognition.[7] Some advantages
of the isothiouronium group as an anion-binding site are as follows: (i) the NH group
of isothiouronium is more acidic than that of thiourea, resulting in stronger hydrogen
bonding; (ii) the isothiouronium group can be easily prepared by the reaction of thio-
urea with general halides.[8] We demonstrate that isothiouronium iodide works as an
effective organocatalyst for the reduction of nitroolefins (Scheme 1).
Results and discussion
Hydrogen bonding between the isothiouronium catalyst and the nitro group might
mechanically decrease the lowest unoccupied molecular orbital (LUMO) activation
energy of the alkene, thus increasing the reaction rate (Scheme 1).[2g] Nitrostyrene 1a
was chosen for the model reaction (Table 1), which provided the corresponding nitroal-
kane in the presence of 0.1 equiv. isothiouronium iodide in 74% and 96% yields in
CH2Cl2 and CH3OH at 60 ꢀC, respectively (entries 1 and 2). Decreasing the catalyst
loading to 5 mol% led to a lower yield of 2a in 73% (entry 3). When the reaction was
carried out at room temperature, the yield was further reduced to 51% (entry 4). The
reaction executed under the same conditions but without the catalyst gave the product
in only 35% yield (entry 5). Therefore, 10 mol% catalyst loading was selected for further
investigation. Then, different solvents were screened to optimize the reaction. Methanol,
which dissolved the catalyst adequately, was selected as the best solvent, while benzene,
toluene, tetrahydrofuran, and dioxane, in which the catalyst was insoluble, were less
effective for this reaction. The most significant benefit of the isothiouronium catalyst
over thiourea was that it showed strong hydrogen-bonding interactions with the nitro
group even in a polar protic solvent such as methanol.[2g,8]

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Table 1. Optimization of reaction conditions for the model reaction.
Entry
Catalyst loading (mol%)
Solvent
Time (h)
Temperature (oC)
Yield of 2a (%)
1
2
3
4
5
10
10
5
10
0
CH2Cl2
MeOH
MeOH
MeOH
MeOH
12
7
7
24
7
Reflux
60
60
RT
60
74 (0)a
96 (45)a
73
51
35
aYields in the parentheses were obtained from using the excess tetrabutylammonium acetate (1.5 equiv.).
To examine the hydrogen bonding between the nitrostyrene substrate and the cata-
lyst, excess acetate anion, which is known to bind strongly with the isothiouronium ion,
was added to the reaction mixture.[9] The reaction gave very low yields of the products
(entries 1 and 2), implying that the acetate anion hampered the binding between the
catalyst and the nitro group. On the basis of the experimental results, we propose that
the isothiouronium ion intensely promotes the reduction via hydrogen bonding with
the nitro group.
After establishing the optimal reaction conditions, we next investigated the reduction
of a variety of nitroolefin substrates in methanol at 60 ꢀC (Table 2). This protocol
worked well for nitroolefins containing aromatic (entries 1–8) and heterocyclic (entries
9 and 10) substrates. Electron-withdrawing and electron-donating substituents at differ-
ent positions on the aromatic ring of the nitroolefins were investigated, and in all cases,
the desired products were obtained in high yields, regardless of the type of substituent
and substituent position. It is noteworthy to mention that, nitro (entry 1), cyano
(entry 6), and carbonyl (entry 7) substituents on the aromatic ring were not reduced at
all. Additionally, in a nitroolefin with two conjugated carbon–carbon double bonds,
only the double bond adjacent to the nitro group was selectively reduced even when the
excess reducing agent was employed (entry 8). a,b-Unsaturated carbonyl compounds
such as cyclohexenone and cinnamaldehyde did not react under these conditions, and
the starting material was recovered. This result indicated that the present protocol
allows for the chemoselective reduction of a,b-unsaturated nitroolefins.
Conclusion
In summary, we have developed a highly chemoselective method for the reduction of
a,b-unsaturated nitroolefins into nitroalkanes, promoted by S-benzyl isothiouronium
iodide. S-Substituted isothiouronium organocatalysts might work well even in polar
protic solvents such as methanol via effective hydrogen bonding.

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Table 2. The reaction scope for the reduction of nitroolefins.
Entry
Nitroolefins 1 Nitroalkanes 2 Reaction time (h)
Yield (%)
96a
1
2
3
7
2a
2b
1a
1b
16
5
81b
76
2c
Br
CI
1c
CI
4
6
76
2d
1d
5
6
7
9
6
7
79
95
82
OMe
2e
2f
1e
1f
NC
2g
2h
1g
1h
1i
8
9
22
9
51
91
85
2i
2j
N
10
9
S
1j
aIsothiouronium chloride and isothiouronium bromide gave 78% and 83% yields, respectively.
bIsothiouronium chloride and isothiouronium bromide gave 63% and 81% yields, respectively.
Experimental detail
All reagents and solvents were purchased and used without further purification. Air-
and moisture-sensitive reactions were carried out under a nitrogen atmosphere. TLC
1
was developed on Merck silica gel 60 F254 aluminum sheets. H NMR (300 MHz) and

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13C NMR (75 MHz) spectra were recorded in CDCl3 (solvent). Chemical shifts are pre-
sented in parts per million (ppm), downfield from tetramethylsilane as the internal
standard. HRMS profiles were recorded on a Micromass Q-TOF instrument (ESp
ion mode).
General procedure for the reduction of nitroolefins into nitroalkanes
To a mixture of nitroolefins 1 (0.70 mmol) and Hantzsch ester (0.20 g, 0.77 mmol) in
methanol (5 mL), S-benzyl isothiouronium iodide (21 mg, 0.07 mmol) was added and
stirred at 60 ꢀC for 5–22 h. The methanolic mixture was concentrated, and then, cold
CH2Cl2 was added. The isothiouronium iodide was precipitated out, filtered, and
washed three times with CH2Cl2. The filtrate was concentrated and purified using flash
column chromatography to provide the desired nitroalkanes 2. All the nitroalkanes
obtained herein were characterized by their NMR spectra, which were compared with
the literature data.[6c]
Selected product
1-Aceto-3-(2-nitroethyl)benzene (2 g).[5c]
1
Colorless oil; IR (neat): ꢀmax ¼ 1681, 1547, 1267 cmꢁ1; H NMR (300 MHz, CDCl3):
d ¼ 2.60 (s, 3H), 3.38 (t, J ¼ 7.2 Hz, 2H), 4.65 (t, J ¼ 7.2 Hz, 2H), 7.20–7.90 (m, 4 H);
13C NMR (75 MHz, CDCl3): d ¼ 26.62, 33.18, 75.87, 127.59, 128.21, 129.32, 133.18,
136.41, 137.93, 197.69; HRMS (ESI) calcd. for C10H12NO3 [M þ Hþ]: 194.0817,
found: 194.0817.
1
Full experimental details, H, and 13C NMR spectra. This material can be found in
the “Supplementary Content” section of this article’s webpage.
Acknowledgments
The spectral data were obtained from the Korea Basic Science Institute, Gwangju branch.
Funding
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea funded by the Ministry of Education (2018R1D1A3B07040876).
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