Oxidative nucleophilic aromatic amination of nitrobenzenes

Article abstract of DOI:10.1039/c6cc02235a

Nitrobenzenes substituted with electron-acceptor groups such as halogen, nitro, trifluoromethyl, pentafluorosulfanyl, or cyano underwent oxidative nucleophilic substitution with lithium salts of arylamines to afford N-aryl-2-nitroanilines.

Full text of DOI:10.1039/c6cc02235a

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Oxidative nucleophilic aromatic amination of
nitrobenzenes†
Cite this:DOI: 10.1039/c6cc02235a
V. V. Khutorianskyi, M. Sonawane, M. Posta, B. Klepetarova and P. Beier*
´ˇ
ˇ
´
Received 14th March 2016,
Accepted 26th April 2016
DOI: 10.1039/c6cc02235a
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Nitrobenzenes substituted with electron-acceptor groups such as This redox process can take place in an intramolecular fashion
halogen, nitro, trifluoromethyl, pentafluorosulfanyl, or cyano under- leading to the nitroso product or the intermediate is subsequently
went oxidative nucleophilic substitution with lithium salts of arylamines transformed into a fused heterocyclic product.12 This is the case for
to afford N-aryl-2-nitroanilines.
the Wohl–Aue reaction of anilines with nitroarenes in the presence
of a base leading to phenazine derivatives.13 In 2010, Wrobel and
´
Many agrochemicals, pharmaceuticals, pigments, electronic Kwast have reported the reaction of anions of primary arylamines
materials, and conducting polymers contain aromatic amines.1 with nitrobenzenes affording N-aryl-2-nitrosoanilines (Scheme 1).14
Their synthesis is based on nitration of aromatics followed by The authors rationalized the formation of nitroso products by
reduction,1 transition-metal-catalysed2 or transition-metal-free3 the transformation of the initially formed sH adduct into the
amination of aryl halides or pseudohalides, addition to benzyne nitroaniline dianion (Scheme 1).
intermediates,4 or nucleophilic substitution of electron-deficient
Aside from the abovementioned processes, along with the
aromatic halides.5 In recent years, impressive achievements electrochemical oxidation of sH adducts formed from polynitro-
have been made in transition-metal-catalysed C–H amination aromatics and n-butylamine,15 there are only a few isolated
of (hetero)aromatics.6 Another route to the synthesis of arylamines examples of amination of nitrobenzenes and electron-deficient
from electron-poor aromatics is the nucleophilic substitution of nitrogen aromatics by SNAr or ONSH.16 There is no general
hydrogen.5,7 Certain requirements, however, must be met in order method for nucleophilic aromatic C–H amination. We hypothesized
to achieve an efficient substitution reaction. The equilibrium must that electron-deficient aromatics might undergo ONSH with
be shifted to the formation of a sH adduct. The sH adduct must be alkali metal salts of aromatic amines giving single-step transi-
amenable to oxidation under conditions that do not affect the tion metal-free access to aminated aromatic products.
´
nitrogen nucleophile. This process is generally known as oxidative
Based on the report of Wrobel and Kwast14 initial investiga-
nucleophilic substitution of hydrogen (ONSH).8 Alternatively, if the tions on the nucleophilic substitution of hydrogen were carried
nucleophile contains a leaving group connected directly to the out with 4-nitro-1-(pentafluorosulfanyl)benzene (1), aniline and
nitrogen atom, another reaction channel opens in the presence of t-BuOK in DMF (Table 1). The choice of this particular substrate
excess base – vicarious nucleophilic substitution (VNS).9 In rare for optimization was motivated by several factors. The SF5
cases, such as in the Chichibabin reaction of sodium amide with
pyridine or nitrobenzene, the hydride ion of the sH adduct is
eliminated in the form of H2.10
Early ONSH amination reactions of nitroaromatics and
heteroaromatics have relied on ‘spontaneous’ oxidation of the
sH adduct by oxygen dissolved in the reaction solvent or an
excess of nitrobenzene which gets reduced to nitrosobenzene.5,11
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
´
Republic, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
E-mail: beier@uochb.cas.cz
† Electronic supplementary information (ESI) available: Experimental procedures,
full characterization, and copies of NMR spectra of new compounds. CCDC
1438933. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c6cc02235a
Scheme 1 Formation of N-aryl-2-nitrosoanilines by the reaction of anions
of primary arylamines with nitrobenzenes.
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Table 1 Optimization of addition of phenylanilide to 4-nitro-1-(pentafluorosulfanyl)benzene (1)
Entry
PhNH2 (equiv.)
Base (equiv.)
Solvent
Temp. (1C)
Time (min)
Quenching methoda
2a yieldb (%)
1
2
3
4
5
6
7
8
1
t-BuOK (3)
t-BuOK (3)
n-BuLi (1.2)
n-BuLi (2)
n-BuLi (4)
n-BuLi (8)
n-BuLi (4)
n-BuLi (4)
n-BuLi (4)
n-BuLi (4)
n-BuLi (4)
n-BuLi (4)
DMF
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
À65
3
2
5
5
5
AcOH
AcOH
36
28
41
55
64
51
83 (73)
46
42
1.5
1.2
2
4
8
4
4
4
4
À60
À70
KMnO4/NH3/NH4Cl
KMnO4/NH3/NH4Cl
KMnO4/NH3/NH4Cl
KMnO4/NH3/NH4Cl
KMnO4/NH3/NH4Cl
NH4Cl
KMnO4/NH4Cl
AgOAc/NH3/NH4Cl
CAN/NH3/NH4Cl
Pb(OAc)4/NH3/NH4Cl
À70
À70
À70
5
À110 to À120
À110 to À120
À110 to À120
À110 to À120
À110 to À120
À110 to À120
10
10
30
15
15
15
9
10
11
12
36
52
65
4
4
a
Quenching methods: AcOH – addition of AcOH (excess) and warming to rt; oxidant – addition of oxidant [KMnO4, AgOAc, CAN, or Pb(OAc)4]
(1.7 equiv.) at À110 1C; NH3 – addition of liquid NH3 at À110 1C, 5 min; NH4Cl – addition of solid NH4Cl and warming to rt. b 19F NMR yields using
4-(pentafluorosulfanyl)anisole as an internal standard; isolated yield in parentheses.
Table 2 Scope of the reaction of lithium salts of arylamines with 4-nitro-
1-(pentafluorosulfanyl)benzene (1)
group is a strongly electron withdrawing group with remarkable
stability, high dipole moment and lipophilicity. SF5-substituted
compounds are being intensively investigated as drug candidates,
agrochemicals, in materials sciences (polymers, ionic liquids, liquid
crystals, explosives), and also in catalysis.17 Compound 1 and
the corresponding meta-isomer are produced by fluorination of
nitrophenyl disulfides using elemental fluorine.18 In recent
years, investigations into nucleophilic aromatic substitutions
of 1 (and the meta-isomer) provided routes to the synthesis of a
variety of SF5-(hetero)aromatic compounds.19–23 In contrast to
the literature,14 the use of 1 did not provide any nitroso product.
Instead, 2a was formed in low yields (Table 1, entries 1 and 2).
Yields of 2a improved when n-BuLi in THF and KMnO4 in liquid
ammonia were used as oxidants (entry 3) – similar conditions to
ONSH of 1 with carbon nucleophiles.23 Further improvement
was observed upon increasing the amount of PhNHLi and
decreasing the temperature. Under optimized conditions (entry 7),
2a was isolated in 73% yield as an orange solid and fully
characterized including NMR spectroscopy and X-ray structure
Entry
Ar
2
Yielda (%)
1
2
3
4
5
6
7
8
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
73
73
70
59
66
72
58
68b
60
78
35
55
4-MeC6H4
4-(MeO)C6H4
2,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
3-BrC6H4
4-IC6H4
9
3-(CF3)C6H4
4-(HCRC)C6H4
4-(i-PrO2C)C6H4
1-Naphthyl
10
11
12
2j
2k
2l
a
b
Isolated yield. Along with side-product 2a (16% yield).
analysis (CCDC 1438933). Without KMnO4/NH3 (entry 8) the low stability, nucleophilicity, or high steric hindrance of their
reaction was considerably less efficient but still took place and lithium salts.
again, no nitroso product was observed. Upon using KMnO4 in
Examining the scope of the electrophilic reaction partner
the absence of liquid ammonia (entry 9) a very similar result was (electron-deficient aromatic) in the reaction with lithium anilide
obtained, indicating unavailability of the oxidant – perhaps due revealed that the nitro group and an additional electron-acceptor
to its low solubility. Other oxidants were tested (entries 10–12) group were necessary for the successful ONSH reaction (Table 3).
but none of them outperformed KMnO4.
The pentafluorosulfanyl group of 1 could be replaced by a
With the optimal set of reaction conditions the scope of the trifluoromethyl or a cyano group while still affording the products
new amination process was explored using a range of aromatic of ONSH in good yields (entries 1 and 2). 1,4-Dinitrobenzene as well
amines (Table 2). Both aromatic amines with electron donating and as 1,2-derivative reacted largely in SNAr of the nitro group rather
withdrawing groups reacted equally well affording products 2 in than in an ONSH fashion (entries 3 and 4). Remarkably, 1-fluoro-4-
good to high yields. Functional groups such as halogen or nitrobenzene provided solely the ONSH product 7 (entry 5) so
ethynyl were tolerated. In the case of 4-iodoaniline (entry 8) did the other halo nitrobenzenes (entries 6 and 7). More
partial deiodination was observed while the yield of 2k (entry 11) activated 2,4-difluoro-1-nitrobenzene afforded the product of
was reduced due to competing amide formation. Some aryl- SNAr of fluorine rather than substitution of hydrogen (entry 8).
amines proved to be unreactive such as 2- or 4-nitroaniline, 4-Fluoro-1-nitro-2-(trifluoromethyl)benzene yielded a mixture of
2-aminopyridine, and 2,6-dimethylaniline, presumably due to ONSH and SNAr products (entry 9) while the 4-bromo derivative
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Table 3 Scope of the reaction of lithium anilide with electron-deficient
aromatics
Scheme 2 Simplified mechanism of aromatic substitutions of substituted
nitrobenzenes with lithium salts of anilines.
Entry
1
Substrate
Product and yielda (%)
The only heterocyclic substrate tested 4-methyl-3-nitropyridine,
on the other hand, provided the ONSH product substituted in
the para-position (entry 14). Substrates such as nitrobenzene,
4-(cyanomethyl)nitrobenzene and 1,4-bis(trifluoromethyl)benzene
(not shown in Table 3) were unreactive presumably as a result of
their insufficient electron-acceptor character.
2
3
Generally accepted mechanisms of SNAr and ONSH processes5
applied to reactions of nitrobenzenes with lithium anilide are
shown in Scheme 2. Reversible addition of lithium anilide to the
ortho-position leads to the formation of a deep purple sH-complex.
Hydride elimination from the sH adduct is not favourable and the
rearomatization takes place by the action of an oxidant in an
irreversible process eventually affording the ONSH product. In
contrast, SNAr of the nitro group favoured with polynitro aromatics
and in polar solvents is initiated by reversible addition in the ipso-
position, followed by nitrite elimination.
In conclusion, ONSH of electron-acceptor group substituted
nitrobenzenes with lithium salts of arylamines afforded N-aryl-
2-nitroanilines. This aromatic amination process showed a
broad scope for arylamines in reactions with 4-nitro-1-(penta-
fluorosulfanyl)benzene. Similarly, nitrobenzenes substituted with
halogen, nitro, CF3, CN, and SF5 groups as well as 4-methyl-3-
nitropyridine underwent efficient substitution of hydrogen with
lithium salt of aniline. Ortho- and para-dinitrobenzenes, however,
reacted in SNAr of a nitro group. Products of the ONSH process are
attractive push–pull benzene derivatives with two electron-acceptor
groups and one amino electron-donor group.
4
5
6b
7b
8
9
10
11b
12
Financial support from the Academy of Sciences of the
Czech Republic (Research Plan RVO: 61388963) and the Grant
Agency of the Czech Republic (P207/12/0072) is gratefully
acknowledged.
13
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