2-(N-Hydroxylamino) sulfone synthesis by indium-iodine-triggered aza-Michael type addition of nitroarenes to vinyl sulfones

Article abstract of DOI:10.1016/j.tetlet.2008.11.046

One-pot reduction-triggered 1,4-addition reaction of various nitroarenes to the α,β-unsaturated sulfones was investigated. In the presence of indium/iodine in MeOH at room temperature, nitroarenes reduced in situ reacted with vinyl sulfones and produced β

Full text of DOI:10.1016/j.tetlet.2008.11.046

Tetrahedron Letters 50 (2009) 484–487
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Tetrahedron Letters
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2-(N-Hydroxylamino) sulfone synthesis by indium–iodine-triggered
aza-Michael type addition of nitroarenes to vinyl sulfones
Sun Jung Lee a, Jung June Lee a, Chong-Hyeak Kim b, Young Moo Jun a, Byung Min Lee b, Byeong Hyo Kim a,
*
a Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
b Korea Research Institute of Chemical Technology, Taejon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot reduction-triggered 1,4-addition reaction of various nitroarenes to the
a
,b-unsaturated sulfones
Received 25 October 2008
Accepted 13 November 2008
Available online 18 November 2008
was investigated. In the presence of indium/iodine in MeOH at room temperature, nitroarenes reduced
in situ reacted with vinyl sulfones and produced b-(N-hydroxylamino) sulfones in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
C–N bond formation derived from the aza-Michael additions of
amines or Michael additions of cyano compounds to conjugated
alkenones has been developed as a valuable synthetic tool for the
synthesis of b-aminocarbonyl or b-cyanocarbonyl compounds.1
Various examples of aza-Michael addition reactions under milder
conditions using various catalysts were recently shown in the liter-
ature.2 Those catalysts or promoters include palladium,2a BiX3
(X = NO3, OTf),2b,2c silica gel,2d Cu-nanoparticles,2e ionic liquids,2f
CAN,2g microwave irradiation,2h water,2i DBU,2j Amberlyst-15,2k
and pyrrolidine–thiourea.2l In addition, the Michael addition reac-
tions to vinyl sulfones are also well documented, as sulfones can
act as good activating groups for C–C bond-forming reactions.1
However, the aza-Michael addition reactions to vinyl sulfones are
barely studied. The recent application of aza-Michael addition
sphere.6b However, the indium-mediated reactions we developed
previously were mostly intramolecular, one-pot reductive reac-
tions followed by the C–N bond formation.
Building upon this concept, one-pot intermolecular reactions
between nitroarenes and Michael acceptors may also be possible
if the reaction conditions are properly controlled. Thus, here we
decided to investigate more challenging intermolecular one-pot
aza-Michael type addition reactions of nitroarenes to vinyl sulf-
ones, which can be a useful synthetic tool for making b-(N-hydrox-
ylamino) sulfones.
As mentioned above, our previous reductive heterocyclizations
of nitroarenes were accomplished via the reductive reaction of the
nitro group followed by cyclization to the properly ortho-substi-
tuted neighboring functional group. Similar to this intramolecular
reaction, the intermolecular type of the one-pot reductive 1,4-
addition reaction should be possible via (1) triggering with the
reductive reaction of the nitro group and (2) the 1,4-addition of
3
reactions for the preparation of amino sugars proves the useful-
ness of the reaction. In addition, double aza-Michael addition to vi-
nyl sulfone moieties was utilized for thiomorpholine 1,1-dioxide
ring formation,4a which is important for macrocyclic systems4b or
is a valuable sub-unit of an antibacterial agent.4c Those previous
studies encouraged us to attempt a new type of aza-Michael addi-
tion of nitroarenes to vinyl sulfones, that is, a one-pot reduction-
triggered process involving the reduction of nitroarenes and subse-
quent 1,4-addition to vinyl sulfones.
in situ formed nitrogen nucleophile to the
strate, if the timing of the reduction versus the in situ formed
nitrogen nucleophile to the ,b-unsaturated substrate is well man-
aged. Thus, we decided to examine the indium-mediated one-pot
1,4-addition reaction of nitroarenes with the ,b-unsaturated
substrate. ,b-Unsaturated sulfones were selected as model
a,b-unsaturated sub-
a
a
a
In our previous study of indium-mediated reductive hetero-
cyclizations of nitroarenes,5 it was found that reduced nitro groups
can trigger heterocyclization toward nitrogen-containing hetero-
cycles, such as 2,1-benzisoxazoles,5a benzimidazoles,5b quino-
compounds because (1) they are excellent Michael acceptors for
a number of nucleophiles such as amines, alcohols, and thiols
and (2) the resulting b-amino sulfone products are of interest for
physiological processes. Nevertheless, their synthetic methods
are relatively poorly documented in the literature.
lines,5c indazoles,5d,e and indoles,5f when there is
a proper
functional group at the ortho position. These reactions are note-
worthy as indium has been receiving increasing attention due to
environmental issues and the ease of reactions that obviate the
need for inflammable anhydrous organic solvents and inert atmo-
Thus, to discover the appropriate reaction conditions for the
reduction-triggered aza-Michael addition of nitroarenes to vinyl
sulfones, 1,4-addition reaction of nitrobenzene to methyl vinyl sul-
fone was examined using indium and a wide range of Lewis acids
or acid additives such as InCl3, I2, AcOH, and HI in various solvent
systems. Most of the reactions failed to show aza-Michael addition
products such as b-amino sulfone as a major product. In the case of
* Corresponding author. Tel.: +82 2 940 5247; fax: +82 2 942 4635.
E-mail address: bhkim@kw.ac.kr (B. H. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.046

S. J. Lee et al. / Tetrahedron Letters 50 (2009) 484–487
485
Table 1
InCl3, the starting substrate was recovered typically with a low
yield of the 1,4-addition product [less than 15% at most; nitro-
benzene (1 equiv)/vinyl sulfone (1 equiv)/indium (4 equiv)/InCl3
(0.4 equiv) in THF/H2O (v/v = 5/1) at 50 °C]. In the case of AcOH
and HI [AcOH in MeOH at reflux and aqueous HI in benzene/1 drop
of aliquat 336 at reflux], the starting substrate disappeared after
several hours and the reaction produced lots of by-products with-
out the desired major products, presumably because of undesired
polymerization. However, some of the indium–iodine-mediated
reactions produced major products, which were seemingly the
expected 1,4-addition products of methyl vinyl sulfone and were
isolated by filtration, extraction, and flash column chromatogra-
phy. Unexpectedly, it was not N-[2-(methylsulfonyl)ethyl]benzen-
amine, that is, b-amino sulfone that was formed, but a different
type of product. Interestingly enough, it was instead the N-
hydroxy-N-[2-(methylsulfonyl)ethyl]benzenamine, b-(N-hydrox-
ylamino) sulfone, which is rarely seen in the literature. Indium
metal may initiate the reaction via a single electron transfer
(SET) reaction to the nitro group, which may result in a nitroso
intermediate. Then, repeated SET reaction of the in situ formed
radical anion species of nitrosobenzene, prior to conversion to the
amino group, may attack the electron-deficient olefin of the vinyl
sulfone to form the b-(N-hydroxylamino) sulfone, which is stable
enough to isolate by conventional column chromatography.
Although b-(N-hydroxylamino) sulfones are not well docu-
mented, such compounds have both N-hydroxylamine and sulfone
Indium-mediated reductive aza-Michael type addition of nitrobenzene to methyl
vinyl sulfone under various conditions
OH
N
In, I2
solvent / temp
Ph-NO2
+
SO2-CH3
Ph
SO2-CH3
1
2
Entry
Molar equiv
Solvent (mL)/temp (°C)
Time (h)
Yielda (%)
1
In
I2
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
3
2
3
4
3
3
3
3
3
3
3
3
3
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.4
1.2
0.8
0.8
0.8
0.8
0.8
1
1
1
1
1
1
1
1
1
1.5
2
1
1
1
CH2Cl2(3)/rt
THF(3)/rt
24
24
24
6
6
4
6
24
5
5
5
Traceb
Traceb
Traceb
82 (77)c
86
73
76
68
69
78
54
56
49
MeOH(3)/rt
MeOH(3)/rt
MeOH(3)/rt
MeOH(3)/50
MeOH(10)/rt
MeOH(3)/rt
MeOH(3)/rt
MeOH(3)/rt
MeOH(3)/rt
MeOH(10)/50
MeOH(3)–H2O(6)/rt
H2O(10)/rt
6
24
16
43
a
NMR yield with an internal standard.
Substrate (1, 1 mmol) was recovered (entry 1: 82%, entry 2: 76%, entry 3: 40%).
Isolated yield.
b
c
Table 2
Indium–iodine-triggered aza-Michael type addition of various nitroarenes (1 mmol) to vinyl sulfones (1 mmol) in the presence of indium (3 equiv), iodine (0.8 equiv) in methanol
at room temperature
OH
In (3 equiv), I2 (0.8 equiv)
MeOH (3 mL), rt
Ar NO2
1 mmol
+
CH2 CH SO2
1 mmol
R
Ar N CH2CH2 SO2
R
Entry
Ar–NO2
R
Time (h)
Product
Yielda (%)
1
2
3
CH3
CH2CH3
Ph
6
5
7
77
74
65
OH
N
NO2
SO2R
OH
N
NO2
4
5
6
CH3
CH2CH3
Ph
5
5
6
77
65
70
SO2R
Cl
Cl
OH
N
NO2
SO2R
7
8
9
CH3
CH2CH3
Ph
9
5
5
66
64
74
Cl
Cl
OH
N
NO2
Cl
10
11
12
CH3
CH2CH3
Ph
7
5
12
77
77
80
SO2R
Cl
OH
NO2
N
13
14
15
CH3
CH2CH3
Ph
5
6
9
62
SO2R
67
37 (72)b
OH
N
NO2
SO2R
16
17
18
CH3
CH2CH3
Ph
8
5
8
51
60
47 (65)b
(continued on next page)

486
S. J. Lee et al. / Tetrahedron Letters 50 (2009) 484–487
Table 2 (continued)
Entry
Ar–NO2
R
Time (h)
Product
Yielda (%)
19
20
21
CH3
CH2CH3
Ph
8
10
9
77
88
74
NO2
OH
N
SO2R
OH
NO2
N
SO2R
22
23
24
CH3
CH2CH3
Ph
7
4
11
55
74
34 (74)b
OH
N
NO2
25
26
27
CH3
CH2CH3
Ph
8
8
8
82
69
83
SO2R
OH
NO2
N
28
29
30
CH3
CH2CH3
Ph
4
4
6
78
69
68
SO2R
F
F
OH
N
NO2
SO2R
SO2R
31
32
33
CH3
CH2CH3
Ph
6
7
12
83
76
66
F
F
OH
N
NO2
F
34
35
36
CH3
CH2CH3
Ph
7
12
9
70
78
59
F
a
Isolated yield.
NMR yield with an internal standard.
b
groups in a molecule and have been reported in the recent litera-
ture as drug-like compounds7 or as potent inhibitors of matrix
metalloproteinases.8 Most early examples9 shown in the literature
focused on physical structural study rather than their application
to chemical or biological systems presumably because synthetic
methodology for b-(N-hydroxylamino) sulfone derivatives was
poorly developed. Thus, new synthetic methods for b-(N-hydroxyl-
amino) sulfone and tests on their biological and/or chemical activ-
ities are merited. Therefore, various reaction conditions were
carefully reinvestigated to optimize the reactions for the formation
of N-hydroxy-N-[2-(methylsulfonyl)ethyl]benzenamine, instead of
the typical aza-Michael addition product, N-[2-(methylsulfon-
yl)ethyl]benzenamine. The selected control experiments are sum-
marized in Table 1.
As shown in Table 1, reactions in aprotic solvent (entries 1 and
2) did not proceed well and mostly starting substrates were
recovered. However, by using protic solvents such as methanol
and/or water, the desired b-(N-hydroxylamino) sulfone was ob-
tained as a major product. Usually, methanol was better than
the methanol/water co-solvent (entry 13) and/or water (entry
14) presumably because of the poor solubility of nitroarene and
vinyl sulfone substrates. Thus, after the various reaction condi-
tions were examined, nitrobenzene (1 equiv)/vinyl sulfone
(1 equiv)/indium (3 equiv)/iodine (0.8 equiv) in methanol at room
temperature (entry 4) was deemed optimal in terms of yield and
cost-effectiveness.
sulfone with a reasonable yield, we next applied the optimized
reaction conditions to various substrates to test for general syn-
thetic utility. Thus, the aza-Michael type 1,4-addition of variously
substituted nitroarenes to selected vinyl sulfones (CH2@CH–SO2–
R, where R = methyl, ethyl, phenyl) was examined, and the results
are shown in Table 2. In most cases, the aza-Michael type 1,4-addi-
tion appears to be generally applicable, as most of the substrates
were consumed within 4–11 h to give the corresponding b-(N-
hydroxylamino) sulfones with reasonable yields. As shown in Table
2, most reactions performed with different nitrobenzene deriva-
tives seemed to be unaffected by the substitution. Electron-donat-
ing or electron-withdrawing groups did not show drastic influence
on product yield. Moreover, more or less sterically hindered sub-
strates such as 2-nitrotoluene (entries 19–21) or 1-ethyl-2-nitro-
benzene (entries 25–27) proceeded well and produced b-(N-
hydroxylamino) sulfones without retardation of the reaction or
yield reduction. Some of severe drops in the isolated yields (for
example, entries 15, 18, and 24) are attributed to difficulties in sep-
aration from overlapped residual phenyl vinyl sulfone (ꢀ5–10%)
that have almost the same Rf values with products, not because
of problems with reactivity, which is proven by their NMR yields
(entries 15, 18, and 24). The structures of b-(N-hydroxylamino)
sulfones were fully characterized by 1H NMR, 13C NMR, FTIR, MS,
HRMS.10 Furthermore, the structure of a representative com-
pound, 2-chloro-N-hydroxy-N-[2-(phenylsulfonyl)ethyl]benzen-
amine, was reconfirmed by X-ray crystallography as the product
is somewhat unexpected new type of material that is rarely
known.10 The molecular structure with an atom-labeling scheme
is shown in Figure 1.
As indium in the presence of iodine in methanol turned out to
have a reductive ability for nitroarene, and given that the reduced
intermediate can trigger the aza-Michael type 1,4-addition to vinyl

S. J. Lee et al. / Tetrahedron Letters 50 (2009) 484–487
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10. Representative spectroscopic data of 2-chloro-N-hydroxy-N-[2-(phenyl-
sulfonyl)ethyl]benzenamine; mp 117–118.5 °C; TLC (30% ethyl acetate/
hexane) Rf 0.27; 1H NMR (400 MHz, CDCl3) d 7.90 (dd, 2H, J = 7.4, 1.2 Hz),
7.69–7.65 (m, 1H), 7.58–7.51 (m, 3H), 7.29–7.20 (m, 2H), 7.07 (td, 1H, J = 7.4,
1.6 Hz), 6.31 (s, 1H), 3.55–3.45 (m, 4H); 13C NMR (100 MHz, CDCl3) d 148.2,
138.9, 133.9, 130.0, 129.3, 127.9, 127.5, 126.2, 125.4, 120.7, 53.2, 52.6; IR (KBr)
3383, 3074, 2996, 2937, 1579, 1442, 1309, 1278, 1144 cmÀ1; GC–MS m/z (rel.
intensity) 295 (M+À16, 32), 153 (100), 135 (56), 118 (54), 99 (11), 77 (30);
HRMS (EI) calcd for C14H14ClNO3S 311.0383, found 311.0387. CCDC 702263
contains the supplementary crystallographic data for this compound. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
A typical procedure for aza-Michael type addition reactions is as
follows. Nitroarene (1 mmol) was added to a mixture of indium
powder (345 mg, 3.0 mmol) and iodine (203 mg, 0.8 mmol) in
MeOH (1 mL), and then vinyl sulfone (1 mmol) in MeOH (2 mL)
was added. The reaction mixture was stirred at room temperature
under a nitrogen atmosphere. After the reaction was complete, it
was diluted with diethyl ether (30 mL), filtered through Celite,
poured into saturated aqueous NaHCO3 solution (30 mL), and ex-
tracted with diethyl ether (30 mL Â 3). The combined organic ex-
tracts were dried over MgSO4, filtered, and concentrated. The
residue was eluted with ethyl acetate/hexane (v/v = 30/70) via sil-
ica gel (230–400 mesh) flash column chromatography to give the
corresponding b-(N-hydroxylamino) sulfone.
In conclusion, we have described a simple and efficient method
for one-pot reduction-triggered 1,4-addition reaction of various
nitroarenes to
a,b-unsaturated sulfones, forming the correspond-
ing b-(N-hydroxylamino) sulfone with good yields in the presence
of indium and iodine in methanol. These findings may serve as a
foundation for the development of new types of molecules.
Acknowledgments
This work was supported by the Korean Government through a
Korea Research Foundation Grant (MOEHRD, KRF-2005-C00250)
and partly by Kwangwoon University in the year 2008.
References and notes
1. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon
Press: Oxford, 1992; Chapters 2 and 6.