Facile and mild displacement of nitrite ions in electron-deficient nitroarenes by alkyl or aryl thiols in the presence of magnesium methoxide as a solid base catalyst

Article abstract of DOI:10.1055/s-0032-1317079

The nucleophilic aromatic substitution reaction (Sr) between nitroarenes (having electron-withdrawing groups in the ortho or para position), and alkyl- or arylthiols using magnesium methoxide as a solid base catalyst is described. This method leads to the creation of a series of valuable compounds from arylsulfides via nucleophilic displacement of the nitro group with the sulfanyl moiety. This facile method is a synthetically useful process, and it is significant that the nucleophile is promoted effectively by magnesium methoxide as a base in N,N-dimethylformamide. The displacement of then nitrite ion occurred in the presence of a variety of functional groups that caused an electron-deficient ring such as aldehyde, ketone, ester, cyano, and nitro groups. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1317079

LETTER
▌2223
letter
Facile and Mild Displacement of Nitrite Ions in Electron-Deficient Nitroarenes
by Alkyl or Aryl Thiols in the Presence of Magnesium Methoxide as a Solid
Base Catalyst
Displacement of Nitrite Ion in Electron-Deficient Nitroarenes
Hossein Naeimi,* Mohsen Moradian
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317, Iran
Fax +98(361)5912397; E-mail: naeimi@kashanu.ac.ir
Received: 13.06.2012; Accepted after revision: 19.07.2012
lead to side reactions such as oxidation of the thiolate an-
Abstract: The nucleophilic aromatic substitution reaction (SNAr)
ion to sulfinate, nucleophilic attack on the functional
between nitroarenes (having electron-withdrawing groups in the
group, or reduction of the nitro substituent.5
ortho or para position), and alkyl- or arylthiols using magnesium
methoxide as a solid base catalyst is described. This method leads
to the creation of a series of valuable compounds from arylsulfides
via nucleophilic displacement of the nitro group with the sulfanyl
is high-yielding and is a facile procedure compared with
moiety. This facile method is a synthetically useful process, and it
is significant that the nucleophile is promoted effectively by mag-
nesium methoxide as a base in N,N-dimethylformamide. The dis-
placement of then nitrite ion occurred in the presence of a variety of
functional groups that caused an electron-deficient ring such as al-
We began our study by investigating the base and solvent
dehyde, ketone, ester, cyano, and nitro groups.
This study reports an improved method for SNAr reactions
of activated nitroarenes with thiols. The present reaction
similar reactions, and should prove to be an extremely
useful tool for formation of an sp2 carbon–sulfur covalent
bond.9
required for this reaction. The reaction of 2-nitrobenzalde-
hyde (1a) with thiophenol (2a) was chosen as a model re-
Key words: nitroarene, thiol, magnesium methoxide, aryl thioether
action. To our satisfaction an initial attempt in which a
mixture of substrates 1a and 2a was added to freshly pre-
A large amount of information is available on nucleophil-
ic aromatic substitution (SNAr) reactions where the nitro
group enables nucleophilic substitutions in the benzene
ring, thus altering the ortho and para positions of the nitro
group.1 In all of these reactions, the presence of nitro and
other electron-withdrawing groups on the benzene ring
activates other substituents, even nitro groups, at the ortho
and para positions for displacement with nucleophiles.2
Thus, this can result in the removal of a nitro group by a
nucleophile.3 Nucleophilic displacement of a nitro group
from a benzene ring carrying only one activating group
has rarely been observed.4 This is no doubt due to the fact
that it also has a very strong activating effect toward nu-
cleophilic displacement of other substituents on an aro-
matic nucleus. Baumann has shown that sodium α-toluene
thiolate reacts with methyl p-nitrobenzoate to form meth-
yl p-(benzylthio)benzoate, resulting in the loss of nitrite.5
Beck et al.6 have shown that, when a dipolar aprotic sol-
vent (DMF) is employed, the displacement of a nitro
group by thiolates occurs readily at room temperature. As
previously reported, it has been found that 4,4′-dinitro-
benzophenone readily undergoes replacement of the nitro
group by sodium phenoxide in dipolar aprotic solvents.7
Kornblum et al. reported the synthesis of aromatic sul-
fides via displacement of a nitro group with sodium thio-
lates in the presence of hexamethylphosphoramide
(HMPA).8 However, in all of these procedures, nucleo-
philes must be pre-prepared as sodium salts and this can
pared solid magnesium methoxide in dimethyl sulfoxide
(Table 1, entry 8) provided a good yield of the desired
coupling product.
In order to determine the appropriate base for this reac-
tion, several metal alkoxides and other organic and inor-
ganic bases were applied (Table 1, entries 2–7). When
sodium methoxide was used as a base the yield of 3a was
very low due to side reactions resulting from nucleophilic
attack of the methoxide (Table 1, entry 4). As can be seen
in Table 1, magnesium methoxide proved to be most effi-
cient among bases tested. This effect may be due to the
high basicity of magnesium methoxide in DMF. The use
of potassium carbonate and sodium carbonate resulted in
lower yields, and organic bases such as triethylamine
were far less effective (Table 1, entries 5–7).
Screening different solvents indicated that N,N-dimethyl-
formamide and dimethyl sulfoxide were the best choices,
although these solvents generally provided a lower yield
of adduct at room temperature; however, the reaction in
DMF was accelerated sixfold by increasing the tempera-
ture to 80 °C (Table 1, entries 1 and 9).
While a stoichiometric amount (0.5 mol) of magnesium
methoxide should be sufficient to achieve quantitative
conversion, using 1 mol of magnesium methoxide yielded
2-phenylthiobenzaldehyde in 87% yield. Substoichiomet-
ric amounts of the base resulted in poor conversions even
with prolonged reaction times.
Encouraged by the ease of this reaction, we next focused
on expanding the scope of the methodology. Table 2 high-
lights the broad range of the various electron-deficient
substrates that can be used to ease the SNAr reaction, in-
SYNLETT 2012, 23, 2223–2226
Advanced online publication: 31.08.2012
DOI: 10.1055/s-0032-1317079; Art ID: ST-2012-D0507-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2224
H. Naeimi, M. Moradian
LETTER
Table 1 Optimization Study of the Reactiona
Table 2 SNAr Reaction of Thiophenol with Electron-Deficient
Ringsa
O
SH
SH
EWG
O
base
EWG
+
Mg(OMe)2
solvent
NO2
+
S
DMF, 80 °C
O2N
PhS
1a
2a
3a
Entry
1
Substrate
Time (h)
Yield (%)b
Entry
Base
Solvent
Time
(°C)
Time
(h)
Yield
(%)b
O
4
4
87
88
1
2
Mg(OMe)2
Mg(OEt)2
Ca(OMe)2
Na(OMe)2
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
THF
80
80
80
80
80
80
80
80
r.t.
65
60
65
4
5
87
72
45
40c
13
7
NO2
O
3
7
2
3
O2N
O2N
4
4
O
5
4
5
6
84
85
6
Na2CO3
4
7
Et3N
4
<3
71
80
14
15
11
O
8
Mg(OMe)2
Mg(OMe)2
Mg(OMe)2
Mg(OMe)2
Mg(OMe)2
5
OMe
4
9
25
10
10
10
O2N
O2N
10
11
12
CN
5
6
6
5
78
81
MeOH
EtOH
NO2
NO2
a Reaction conditions: starting materials (2 mmol) were added to solid
magnesium methoxide (2 mmol) in related solvents (8 mL).
b Isolated yields.
c Moreover, a product yield of 32% including displacement of the
methoxide ion was obtained.
O
7
15
–
NO2
NO2
cluding a formyl group and other electron-withdrawing
groups such as ketone, nitro, and cyano groups (Table 2,
entries 3–6). It is worth noting that the SNAr reaction of
4-nitromethylbenzoate occurred without any byproducts
resulting from cleavage of the methyl ester linkage (Table
2, entry 4). The reaction of nitrobenzene and 3-nitrobenz-
aldehyde with 2a failed to afford the corresponding prod-
uct even at an elevated temperature (Table 2, entries 7 and
8).
8
9
15
20
–
COOH
Ph
<3
O2N
N
10
11
20
12
–
The reaction of 2-fluorobenzaldehyde with thiophenol
provided 2-phenylthiobenzaldehyde after 12 hours in only
14% yield, with 83% of 2-fluorobenzaldehyde recovered
(Table 2, entry 11). Substrates containing carboxylic acid
and imine moieties as electron-withdrawing groups did
not provide the desired coupling products (Table 2, entries
9 and 10).
NO2
O
F
14
a Reaction conditions: starting materials (2 mmol) were added to mag-
nesium methoxide (2 mmol) in DMF (8 mL) as solvent.
b Isolated yield.
Finally, we investigated the SNAr reaction of some nitro
substrates with 1,3-propanedithiol (Table 3) and 3-mer-
captopropanoic acid (Table 4) under the same reaction
conditions and in the presence of 2.5 equivalents of
Mg(OMe)2 as a solid base. However, the reaction of 1,3-
propanedithiol and 3-mercaptopropanoic acid with some
nitroarenes and magnesium methoxide led to related com-
pounds in high yield.
As illustrated in Table 4, the SNAr reaction 3-mercapto-
propanoic acid led to the corresponding adducts, although
with a longer reaction time (Table 4, entries 1–4).
In conclusion, we have successfully demonstrated that the
nucleophilic aromatic substitution reaction between elec-
tron-deficient nitroarens and thiol derivatives can be effi-
Synlett 2012, 23, 2223–2226
© Georg Thieme Verlag Stuttgart · New York

LETTER
Displacement of Nitrite Ions in Electron-Deficient Nitroarenes
2225
Table 3 SNAr Reaction of Nitro Substrates with 1,3-Propanedithiola
Table 4 SNAr Reaction with 3-Mercaptopropanoic Acida
HO
EWG
HS
EWG
S
O
EWG
OH
S
S
Mg(OMe)2
+
Mg(OMe)2
DMF
+
DMF, 80 °C
NO2
O
NO2
HS
EWG
EWG
HS
Entry
1
Nitro substrate
Time (h)
Yield (%)b
80
Entry
1
Nitro substrate
Time (h)
7
Yield (%)b
O
O
10
10
81
85
NO2
NO2
O
O
2
3
7
8
2
73
O2N
O2N
O
NO2
77
78
3
4
10
10
71
82
NO2
O2N
O
O
OMe
O2N
4
8
a Reaction conditions: 3-mercaptopropanoic acid (2.0 mmol) and ni-
tro substrate (2.0 mmol) were added to magnesium methoxide (5.0
mmol) in DMF (10 mL).
O2N
O2N
CN
b Isolated yield.
5
6
9
8
71
76
NO2
NO2
2-(Phenylthio)benzaldehyde (Table 2, Entry 1)
Yellow oil. IR (thin film): 3060 (HAr), 2846, 2738 (HCO), 1686
(C=O), 1584, 1445 (C=C, Ar), 1392, 1299, 1195, 751, 694 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 10.38 (s, 1 H, HC=O), 7.88 (s, 1 H,
Ar), 7.26–7.43 (m, 7 H, Ar), 7.10 (s, 1 H, Ar). 13C NMR (100 MHz,
CDCl3): δ = 126.3, 128.4, 129.7, 130.3, 131.9, 133.1, 133.2, 133.7,
134.1, 141.5, 191.4. MS: m/z (%) = 215 (1.5) [M + 1]+, 215 (12)
[M+], 185 (45), 109 (74), 105 (23), 76 (100). Anal. Calcd for
C13H10OS (214.28): C, 72.8; H, 4.7. Found: C, 72.7; H, 4.6.
a Reaction conditions: 1,3-propanedithiol (2.0 mmol) and nitro sub-
strate (4.0 mmol) were added to magnesium methoxide (5.0 mmol) in
DMF (10 mL).
b Isolated yield.
ciently performed via deprotonation using magnesium
methoxide as the base. This novel C–S bond-formation re-
action provides moderate to excellent yields of the corre-
sponding thioether adducts under mild conditions and
short reaction times. The versatility of this reaction al-
lowed us to efficiently prepare novel thioether com-
pounds, which are subsequently evaluated as novel
xenobiotics.
Acknowledgment
The authors are grateful to the University of Kashan for supporting
this work (grant No. 159148/2).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2223–2226

2226
H. Naeimi, M. Moradian
LETTER
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Synlett 2012, 23, 2223–2226
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