Direct coupling of nucleophiles with nitroaromatic compounds via fluoride-promoted oxidative nucleophilic aromatic substitution for hydrogen

Article abstract of DOI:10.1016/S0040-4039(01)00485-3

Useful yields are achieved in the regioselective direct coupling of amines, amides, and ketones with m-dinitrobenzene, 1-nitronaphthalene, and 1,3-dinitronaphthalene, through oxidatively activated nucleophilic aromatic substitution for hydrogen promoted by fluoride anions.

Full text of DOI:10.1016/S0040-4039(01)00485-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3439–3441
Direct coupling of nucleophiles with nitroaromatic compounds via
fluoride-promoted oxidative nucleophilic aromatic substitution for
hydrogen
Inma Huertas, Iluminada Gallardo and Jordi Marquet*
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 22 March 2001
Abstract—Useful yields are achieved in the regioselective direct coupling of amines, amides, and ketones with m-dinitrobenzene,
1-nitronaphthalene, and 1,3-dinitronaphthalene, through oxidatively activated nucleophilic aromatic substitution for hydrogen
promoted by fluoride anions. © 2001 Elsevier Science Ltd. All rights reserved.
Nucleophilic aromatic substitution is one of the most
widely used approaches for the functionalization of
aromatics and forms the backbone of numerous impor-
tant synthesis of pharmaceuticals and potential drugs.
However, new atomically efficient chemical reactions,
designed to avoid the use of chlorinated aromatics, are
required, mainly due to environmental reasons. In this
sense, we have focused our attention on nucleophilic
aromatic substitution for hydrogen reactions (NASH)1
as a means of generating functionalized aromatics with-
out the need for halogenated materials or intermedi-
ates.2,3 NASH reactions formally require the
replacement of a hydride ion and they occur ‘sponta-
neously’, consuming part of the starting material in the
oxidation of the anionic s-complex, or they are pro-
moted by the addition of external oxidants. Low yields
(with few exceptions)4 and lack of generality are the
main drawbacks of the first approach.1 We have
recently shown2 that the use of UV irradiation (to help
the redox step) and fluoride anions (to activate the
nucleophile in an essentially neutral medium)5 furnishes
useful yields of N-alkyl and N-acyl anilines,2a and
C-arylated ketones, esters and nitriles2b could be also
be furnished.
(and the anions of the substitution products) towards
oxidation. This, in connection with the often unfavor-
able position of the addition equilibrium and, hence,
low concentration of the sH adducts and high concen-
tration of the nucleophiles, leads to undesired oxidation
of nucleophiles and suppression of the ONASH reac-
tion. Therefore, the ONASH process only proceeds
satisfactorily with simple nucleophiles, such as OH− or
CN−, resistant to oxidation, or with very stabilized
anions, such as the 2-phenylpropionitrile carbanion.7
Very recently, we have described a successful oxidative
electrochemical approach to the cyanation of
nitroarenes.3
The removal of a proton and two electrons from s-
complexes has been shown to be facilitated in a class of
reaction referred to as vicarious nucleophilic substitu-
tion (VNS).8 These reactions require a good leaving
group, usually a halide, in a position a to the nucleo-
phile such that decomposition of the corresponding
s-complex results in b-elimination of HX. While this
class of reaction has provided useful mechanistic insight
and a significant synthetic utility, the requirement for
an auxiliary leaving group still persists.
The second approach, oxidative nucleophilic substitu-
tion of hydrogen (ONASH), is brought about by the
addition of an external oxidant. Although many exam-
ples of this transformation have been reported,6 it
suffers from significant limitations.6d The most impor-
tant of these is the sensitivity of the nucleophilic agents
Here, we describe how nucleophile activation by
fluoride anions can overcome many of the drawbacks
associated with oxidation of the nucleophile (or of the
anion of the final substitution product) in ONASH
reactions, thus broadening the synthetic scope of the
reaction. The fluoride anion is not easily oxidized (E°=
2.4 V versus NHE in acetonitrile),9 and its activity as a
nucleophile activating agent in aprotic solvents is not
due to anion generation (HF pKa=15 in DMSO)10 but
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00485-3

3440
I. Huertas et al. / Tetrahedron Letters 42 (2001) 3439–3441
is due to its ability to form very strong hydrogen bonds,
even with hydrogens bonded to carbon.5 Activation of
the nucleophile is due to partial negative charge trans-
fer upon hydrogen-bond formation, and the tendency
of the hydrogen-bonded-complex to undergo oxidation
will probably be lower than the one of the free anion.
Therefore, we have explored the viability of ONASH
reactions of different nitroaromatic substrates with oxi-
dizable nucleophiles, activated by fluoride anions.
methanolic ammonia).11 Recently, we have described a
photochemical alternative that eludes the use of an
external oxidant and that gives similar results.2b In
experiments 5–7, carbon nucleophiles are used with
different results. Thus, ketones give rise to hydrogen-
substitution products in fair yields but acetonitrile fails
to do so.
The experiments with 1-nitronaphthalene and 1,3-dini-
tronaphthalene (Table 1, exp. 8–11) are very significant
and they help to understand the limits of the scope of
the reaction. Thus, electron-rich 1-nitronaphthalene
(when compared with m-DNB) reacts with a relatively
acidic nucleophile, such as acetone (pKa=26.5 in
DMSO),10 but fails (the starting material is recovered)
with a much less acidic nucleophile, such as n-butyl-
amine (pKa >35 in DMSO). This indicates that the
activation of the nucleophile through hydrogen-bond
formation with fluoride anions is very much dependent
on the acidity of the active hydrogens and, in each case,
a threshold exists that depends on the balance between
the electrophilicity12 of the aromatic compound and the
In Table 1 (Scheme 1) reactions of m-dinitrobenzene
(m-DNB), 1-nitronaphthalene, and 1,3-dinitronaph-
thalene with different nucleophiles in the presence of
KMnO4, as oxidant, and fluoride anions, as the nucleo-
phile activating agent, are described. Thus, in experi-
ments 1 and 2, excellent yields of regioselective hydro-
gen substitution by amines are obtained. The reactions
with amides also give fair to good yields of substitu-
tion products, and it is important to notice that these
experiments constitute a formal ‘chlorine free’ new
route to 2,4-dinitroaniline through hydrolysis of the
obtained amides (or treatment of the amides with
Table 1. Reactions of nitroaromatic compounds with nucleophiles in the presence of KMnO4 and fluoride anions (TBAF)
Exp.
Substrate
Nucleophile
Conditionsa
Product
Yield(%)b
1
2
3
4
5
6
7
8
m-Dinitrobenzene
m-Dinitrobenzene
m-Dinitrobenzene
m-Dinitrobenzene
m-Dinitrobenzene
m-Dinitrobenzene
m-Dinitrobenzene
1-Nitronaphthalene
1-Nitronaphthalene
1,3-Dinitronaphthalene
1,3-Dinitronaphthalene
CH3(CH2)3NH2
PhNH2
CH3CONH2
PhCONH2
CH3COCH2CH3
CH3CN
CH3COCH3
CH3(CH2)3NH2
CH3COCH3
CH3(CH2)3NH2
CH3COCH2CH3
DMF, 1.5 h, rt
DMF, 1 h, rt
DMF, 1 h, rt
DMF, 0.75 h, rt
1 h, rt
1 h, rt
20 min, rt
DMF, 1 h, rt
1.5 h, rt
DMF, 4.5 h, rt
1.5 h, rt
1a
1b
1c
1d
1ee
1f
1g
2a
2g
3a
3e
63c
75d
35d
61d
42
Traces
44
f
9
10
11
29g
34h
i
a Molar ratio of substrate/KMnO4=1:1. An excess of nucleophile (5 equiv.) was used in the reactions in DMF; in the others the nucleophile was
used as the solvent. 5 equiv. of FTBA·3H2O.
b Preparative yields of isolated products. For selected data of new compounds, see Ref. 14.
c N-(2,4-Dinitrophenyl)butyramide (8% yield) was also obtained.
d 2,4-Dinitrophenol was also obtained in 22, 23 and 13% yield in experiments 2–4, respectively.
e Compound 1e is a mixture of 1-(2,4-dinitrophenyl)butan-2-one and 3-(2,4-dinitrophenyl)butan-2-one.
f The starting material 1-nitronaphthalene was fully recovered.
g A small amount of the isomer 1-(4-nitronaphthalen-1-yl)acetone was also obtained.
h 53% of starting material was recovered.
i Extensive degradation of the reaction mixture was observed.
Nu
NuH
NO2
NO2
NuH
NO2
NO2
TBAF.3H2O
Nu
TBAF.3H2O
KMnO4
DMF
1
2
KMnO4
DMF
NO2
NO2
NO2
NuH
NO2
TBAF.3H2O
NO2
KMnO4
DMF
NO2
Nu
3
Scheme 1.

I. Huertas et al. / Tetrahedron Letters 42 (2001) 3439–3441
3441
activity of the nucleophile (directly related to the
acidity).
3. Gallardo, I.; Guirado, G.; Marquet, J. Chem. Eur. J.
2001, 7, 1759.
4. (a) Hamana, M.; Iwasaki, G.; Saeki, S. Heterocycles
1982, 17, 177; (b) Iwasaki, G.; Hamana, M.; Saeki, S.
Heterocycles 1982, 19, 162; (c) Iwasaki, G.; Wada, K.;
Saeki, S.; Hamana, M. Heterocycles 1984, 22, 1811.
5. Clark, J. H. Chem. Rev. 1980, 80, 429.
6. (a) Wozniak, M.; Van der Plas, H. C.; Tormula, M.; Van
Vedhuizen, A. Recl. Trav. Chim. Pays-Bas 1983, 102,
511; (b) Van der Plas, H. C.; Wozniak, M. Croat. Chem.
Acta 1986, 59, 33; (c) Wozniak, M.; Grzegozek, M.
Liebigs Ann. Chem. 1993, 823; (d) Makosza, M.; Stalin-
ski, K. Chem. Eur. J. 1997, 3, 2025.
7. (a) Makosza, M.; Stalinski, K. Synthesis 1998, 1631; (b)
Makosza, M.; Stalinski, K. Tetrahedron 1998, 54, 8797;
(c) Makosza, M.; Stalinski, K.; Klepka, C. Chem Com-
mun. 1996, 837.
8. Makosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
282 and references cited therein.
9. Eberson, L. Acta Chem. Scand. 1984, B38, 1984.
10. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
11. Stern, M. K.; Cheng, B. K. J. Org. Chem. 1993, 58, 6883.
12. A simple ordering of electrophilicity can be achieved by
considering the energies of the LUMO orbitals of the
nitroaromatic compounds calculated using the semi-
empirical AM1 method implemented in the MOPAC
package: 1,3-dinitronaphthalene, ELUMO=−2.06 eV; m-
dinitrobenzene, ELUMO=−1.91 eV; 1-nitronaphthalene,
On the other hand, the experiments with 1,3-dini-
tronaphthalene afford information about the existence
of two additional thresholds in our reactions. Thus, this
substrate is more electrophilic than 1-nitronaphthalene
and m-DNB,12 and, in this case, the substitution with a
ketone (butanone, exp. 11, Table 1) fails but the start-
ing material is not recovered and extensive degradation
is observed. This is very similar to what occurs in
experiment 6 (Table 1) with m-DNB when acetonitrile
is used as the nucleophile. We attribute this behavior to
the acidity of the final substitution products, that would
not be stable in the reaction mixture, undergoing oxida-
tion in the presence of KMnO4. In experiment 10,
another interesting feature of these reactions can be
established. Thus, even though 1,3-dinitronaphthelene
is the most electrophilic substrate among the three
studied, and that the reaction with n-butylamine is very
clean, it is rather slow (only 66% conversion after 4.5
h). This behavior is attributed to the fact that the
s-adduct intermediate in the case of 1,3-dinitronaph-
thalene has a high redox potential, practically at the
limit of the oxidizing power of KMnO4 in DMF.13
The results reported in Scheme 1 and Table 1 broaden
considerably the usefulness of the ONASH reaction,
allowing the introduction of typical carbon and nitro-
gen nucleophiles in aromatic rings in a very simple way.
ELUMO=−1.30 eV.
13. E°(MnO4−)=−0.6 V (versus SCE in DMF), see: Bock,
H.; Jaculi, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 305.
Using cyclic voltammetry we have measured Epc=0.8 V
(versus SCE) for s-adducts of 1,3-dinitronaphthalene and
Epc=0.6 V (versus SCE) for s-adducts of m-DNB, with
amines.
Acknowledgements
Financial support from DGI (MCiT of Spain) through
the project BQU2000-0336 and from ‘Generalitat de
Catalunya’ through the project 1999SGR00090 are
gratefully acknowledged. The authors would also like
to thank G. Guirado for the help with the cyclic
voltammetry measurements.
14. Selected data for 1-(1-nitronaphthalen-2-yl)acetone, 2g:
lH (250 MHz, CDCl3): 2.24 (s, 3H), 3.88 (s, 2H), 7.30
(dd, J 8.5, 1.0, 1H), 7.56 (m, 2H), 7.85 (m, 3H); lC (62.5
MHz): 29.77, 46.51, 121.78, 124.68, 125.03, 127.30,
127.87, 128.04, 128.79, 131.18, 133.04, 147.72, 203.28; IR:
w 1714, 1519, 1344, 1316 cm−1; mp 75–76°C. Anal. calcd
for C12H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C,
68.18; H, 4.84; N, 6.01. Selected data for N-butyl-(2,4-
dinitronaphthalen-1-yl)amine, 3a: lH (250 MHz, CDCl3):
0.95 (t, J 7.3, 3H), 1.47 (m, 2H), 3.89 (q, J 6.8, 2H), 7.56
(t, J 7.2, 1H), 7.80 (t, J 7.2, 1H), 8.32 (dd, J 8.6, 0.7, 1H),
8.75 (dd, J 8.6, 0.7, 1H), 9.16 (s, 1H), 9.73 (broad s, 1H);
lC (62.5 MHz): 13.59, 19.87, 33.50, 50.93, 123.68, 124.48,
124.87, 126.09, 126.21, 128.33, 129.92, 132.77, 135.34,
152.14; IR: w 1587, 1548, 1402 cm−1; mp 74–76°C. Anal.
calcd for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53.
Found: C, 58.14; H, 5.28; N, 14.39.
References
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