Alkylation of nitroarenes with Grignard reagents via oxidative nucleophilic substitution of hydrogen

Article abstract of DOI:10.1016/S0022-328X(00)00931-1

Alkylation of nitroarenes with Grignard reagents via oxidative nucleophilic substitution of hydrogen (ONSH) can be efficiently executed with potasium permanganate in liquid ammonia as an oxidative system for the σ^H adducts. The addition of RMgX to ArNO₂ of stoichiometry 1:1 is accompanied with a redox process apparently of stoichiometry 2:1. Because of that, real stoichiometry of the reaction between nitroarenes and Grignard reagents is ca. 1:1.5.

Full text of DOI:10.1016/S0022-328X(00)00931-1

Journal of Organometallic Chemistry 624 (2001) 167–171
www.elsevier.nl/locate/jorganchem
Alkylation of nitroarenes with Grignard reagents via oxidative
nucleophilic substitution of hydrogen
Mieczys*law Ma˛kosza *, Marek Surowiec
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, PL-01-224 Warsaw, Poland
Received 5 October 2000; accepted 6 December 2000
Dedicated to Professor Jean Normant on the occasion of his 65 birthday
Abstract
Alkylation of nitroarenes with Grignard reagents via oxidative nucleophilic substitution of hydrogen (ONSH) can be efficiently
executed with potasium permanganate in liquid ammonia as an oxidative system for the sH adducts. The addition of RMgX to
ArNO2 of stoichiometry 1:1 is accompanied with a redox process apparently of stoichiometry 2:1. Because of that, real
stoichiometry of the reaction between nitroarenes and Grignard reagents is ca. 1:1.5. © 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Grignard reagents; Nitro compounds; Alkylation; Oxydative nucleophilic substitution of hydrogen; Oxidation
the sH adducts and undesired side reactions. Perhaps
for this reason this procedure of oxidative alkylation
1. Introduction
does not assure high yields of the products.
Direct alkylation of nitroarenes via nucleophilic re-
placement of hydrogen can be executed on two princi-
pal ways — vicarious nucleophilic substitution (VNS)
or oxidative nucleophilic substitution (ONSH) [1,2].
Both of these reactions proceed via addition of carbon
nucleophiles to a nitroarene ring o- or p- to the nitro
group producing sH adducts, which are subsequently
converted into the final products. The VNS reaction
takes place when the carbon nucleophiles contain a
leaving group X at the carbanion center so the sH
adducts undergo base induced b-elimination of HX.
Alternatively the sH adducts of C-nucleophiles can be
oxidized with a variety of external oxidants to give
products of ONSH. Amongst numerous observations
of such processes of particular value are reactions of
alkyl magnesium halides with nitroarenes followed by
oxidation of the produced sH adducts with DDQ or
KMnO4 in aqueous acetone reported by Bartoli [3].
Although KMnO4 is an efficient strong oxidant, its
use in aqueous acetone could result in protonation of
Oxidation of sH adducts of ammonia or amide an-
ions is very efficiently executed with KMnO4 in liquid
ammonia, a system introduced by van der Plas for
oxidative amination of electrophilic heteroarenes [4].
We have found that KMnO4 in liquid ammonia oxi-
dizes efficiently sH adducts of the carbanions derived
from 2-phenyl propionitrile, and other nitriles to ni-
troarenes giving the ONSH products, often in quantita-
tive yields [5].
2. Results and discussion
Reported yields of oxidative alkylation of nitroarenes
with RMgX and aqueous KMnO4 are not always high,
whereas the relatively high price of DDQ and the
necessity to separate byproducts prevents its use in
preparative experiments. Moreover application of
KMnO4 in aqueous acetone for oxidation of the sH
adducts of MeMgCl to p-chloronitrobenzene and p-ni-
troanisole according to the procedure reported by Bar-
toli gave in our hands lower yields than these reported
(33 and 34%) instead of 40 and 56% respectively [3]. In
* Corresponding author. Tel.: +48-22-631-8788; fax: +48-22-632-
6681.
E-mail address: icho-s@icho.edu.pl (M. Ma˛kosza).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00931-1

168
M. Ma˛kosza, M. Surowiec / Journal of Organometallic Chemistry 624 (2001) 167–171
Scheme 1.
are always present, thus the competing reaction in
stoichiometry 1:2 is apparently a redox process. This
supposition was supported by the reaction of 4-nitroan-
isole with the Grignard reagents. It is well-known that
product of partial reduction of this compound — p-
nitrosoanisole is more stable than p-chloronitrosoben-
zene. Indeed in this reaction we obtained nitrosoanisole
even upon oxidation of the reaction mixture with
KMnO4, whereas the starting nitroanisole was not
found in the reaction mixture (Scheme 1).
Next we studied how the yields of this reaction are
affected by the nature of R in RMgX and also by some
substituents in nitroarenes. Results of these experiments
are given in Table 1 (Scheme 2). We have found that
yields of products of ONSH were somewhat increased
when we used Grignard reagents containing longer R.
But when secondary Grignard reagents were used,
yields of the oxidative alkylation products were sub-
stantially lower, perhaps because they are stronger re-
ducting agents than the primary Grignard reagents. For
this reason we have not used tertiary Grignard reagents
in this reaction. Suprisingly yields of the reaction of
the reaction mixture we have found 4,4%-dichloro-2,2%-
dimethyl-azoxybenzene (5c) and 4,4%-dichloro-2-methyl-
azoxybenzene (5b) what indicates that the sH adducts
undergo other reactions than oxidation, thus search for
simple and efficient oxidation system was justified.
Since liquid ammonia decomposes the Grignard
reagents, the following procedure was elaborated for
oxidation of the sH adducts with KMnO4 in liquid
ammonia: first sH adducts were generated via addition
of RMgX to nitroarenes in THF solution at −70°C.
To this solution powdered KMnO4 was added and
subsequently ammonia was condensed. It was sufficient
to condense ca. 5 ml of ammonia for 10 ml of a THF
solution to assure an efficient oxidation process. In
preliminary control experiments yields of products of
oxidative alkylation in liquid ammonia were consis-
tently better than those reported by Bartoli.
An important question is the real stoichiometry of
the process. For oxidative alkylation of nitroarenes
with Grignard reagents Bartoli recommended the use of
a twofold excess of the latter, whereas in the paper by
Bentley nitroarenes and RMgX were used in ratio 1:1.5
[6].
One can assume that the reaction of ArNO2 with
RMgX follows two competing pathways: addition to
the ring producing sH adducts according to stoichiome-
try 1:1 and other processes such as addition to the NO2
group, reduction, etc. of stoichiometry 1:2 or more.
Using the standard procedure for oxidation of the sH
adducts for the reaction of p-chloronitrobenzene with
MeMgCl in ratio 1:1, 1:1.5, 1:2 we have obtained the
oxidative methylation product in yields of 52, 70 and
72%, respectively. Since the use of an excess, even
substantial, of MeMgCl does not result in decrease of
yield of the methylated product formed via oxidation of
the sH adducts, it appears that these two reactions
compete at an early stage and the sH adducts once
formed are not affected by an excess of MeMgCl. In
the reaction mixture only traces of methylated azoxy-
compounds produced from sH adducts (5b and 5c) as
well as significant amounts of product of reduction of
the starting nitroarene-4,4%-dichloro-azoxybenzene 5a
Table 1
Oxidative alkylation of nitroarenes with Grignard reagents and
KMnO4 in THF–liquid ammonia (Scheme 2)

M. Ma˛kosza, M. Surowiec / Journal of Organometallic Chemistry 624 (2001) 167–171
169
Scheme 2.
EtMgBr with nitroarenes were lower than those of
other primary reagents.
alkylmagnesium halide in THF (3 mmol) was added
dropwise during ca. 2.5 min. After 5 min powdered
KMnO4 (474 mg, 3 mmol) was added and subsequently
liquid NH3 (ca. 10 ml, −70°C) condensed in the
mixture. The reaction mixture was stirred for 15 min,
NH4Cl (318 mg, 6 mmol) was added and the cooling
bath was removed. To the mixture was added a satu-
rated solution of oxalic acid in aq. HCl (20 ml, 10%)
and the mixture was extracted with CH2Cl2 (4×10 ml).
The combined organic layers were dried over MgSO4
and filtered through silica gel. After evaporation of the
solvent the products were purifed by column chro-
matography on silica gel using hexane as an eluent.
It is well known that the reaction pattern of the
Grignard reagents is strongly affected by the degree of
covalent bonding C–Mg, association in solution, etc.
which can be changed using solvents of various solvat-
ing power or additives, such as DABCO, associating
with metal cations [7]. We have made some experiments
using DABCO, TMEDA and HMPT as additives to
the solution of the Grignard reagents before the reac-
tion with nitroarenes. It seems that only N,N,N%,N%-te-
tramethylethylenediamine (TMEDA) exerts moderate
effect on the reaction course (Table 1). When other
agents such as DABCO or HMPTA were used we have
not observed increase of yields of the ONSH products.
Addition of TMEDA to the Grignard reagents results
in precipitation of a partially insoluble complex.
In conclusion we have elaborated an efficient and
simple procedure for oxidative alkylation of nitroarenes
with the Grignard reagents and KMnO4 in liquid am-
monia as oxidant of the intermediate sH adducts.
3.1.1. 2-Methyl-4-chloronitrobenzene (3a)
1
Orange oil (lit. [3] oil). H-NMR (200 MHz, CDCl3)
l=7.96 (1H, d, J=7.81), 7.26–7.37 (2H, m), 2.61 (3H,
s).
3.1.2. 2-Ethyl-4-chloronitrobenzene (3b)
1
Orange oil (lit. [8] oil). H-NMR (200 MHz, CDCl3)
l=7.87 (1H, d, J=8.61), 7.25-7.38 (2H, m), 2.92 (2H,
q, J=7.51), 1.30 (3H, t, J=7.49).
3. Experimental
3.1.3. 2-n-Propyl-4-chloronitrobenzene (3c)
Orange oil. 1H-NMR (200 MHz, CDCl3) l=7.86
(1H, d, J=8.24), 7.25–7.60 (2H, m), 2.86 (2H, t,
J=7.69), 1.55–1.79 (2H, m), 1.00 (3H, t, J=7.36).
1
Melting points were uncorrected. H-NMR spectra
were recorded with a Varian Gemini 200 (200 MHz)
instrument. Chemical shifts are reported in ppm relative
to Me4Si as internal standard; coupling constants J are
in Hz. For column chromatography silica gel 230–400
mesh, Merck was used. THF was distilled over potas-
sium benzophenon ketyl before reaction. Starting ni-
3.1.4. 2-n-Butyl-4-chloronitrobenzene (3d)
Orange oil. 1H-NMR (200 MHz, CDCl3) l=7.86
(1H, d, J=8.93), 7.25–7.38 (2H, m), 2.88 (2H, t,
J=8.12), 1.55–1.72 (2H, m), 1.35–1.50 (2H, m), 0.95
(3H, t, J=7.19).
troarenes 1a, b,
d
were commercial products.
2-(4%-nitrophenyl)-1,3-dioxolane was prepared accord-
ing procedure reported by Bentley [5].
Satisfactory combustion analyses within 90.4 were
obtained for all compounds 3a–3k, 3n–3p, 4n–4p and
5c.
3.1.5. 2-n-Decyl-4-chloronitrobenzene (3e)
Yellow crystals, m.p. 29–31°C (EtOH). 1H-NMR
(200 MHz, CDCl3) l=7.86 (1H, d, J=8.43), 7.26–
7.35 (2H, m), 2.87 (2H, t, J=7.86), 1.54–1.75 (2H, m),
1.16–1.53 (14H, m), 0.88 (3H, t, J=6.49).
3.1. General procedure for the reaction of nitroarenes
with the Grignard reagents
3.1.6. 2-Cyclohexyl-4-chloronitrobenzene (3f)
Yellow oil. 1H-NMR (200 MHz, CDCl3) l=7.68
(1H, d, J=8.62), 7.42 (1H, d, J=2.18), 7.23–7.31 (1H,
m), 2.90–3.14 (1H, m.), 1.05–1.95 (10H, m).
To a stirred solution of nitroarene (2 mmol) in THF
(20 ml) cooled to −70°C under argon a solution of

170
M. Ma˛kosza, M. Surowiec / Journal of Organometallic Chemistry 624 (2001) 167–171
3.1.7. 2-Methyl-4-methoxynitrobenzene (3g)
3.1.16. 2-n-Butyl-1-nitronaphtalene (3p)
Yellow oil. H-NMR (200 MHz, CDCl3) l=7.91–
7.83 (2H, m), 7.72–7.48 (3H, m), 7.75 (1H, d, J=8.54),
2.73 (2H, t, J=7.80), 1.77–1.60 (2H, m), 1.49–1.29
(2H, m), 0.93 (3H, t, J=7.25).
1
Colorless crystals, m.p. 43–44°C (EtOH), (lit. [3]
1
50–53°C). H-NMR (200 MHz, CDCl3) l=8.09 (1H,
d, J=9.40), 6.75–6.85 (2H, m), 3.88 (3H, s), 2.64 (3H,
s).
3.1.17. 4-n-Butyl-1-nitronaphtalene (4p)
Yellow oil (lit. [12] oil). H-NMR (200 MHz, CDCl3)
3.1.8. 2-Ethyl-4-methoxynitrobenzene (3h)
Yellow oil. H-NMR (200 MHz, CDCl3) l=8.03 (d,
1
1
l=8.62–8.56 (1H, m), 8.18–8.10 (2H, m), 7.75–7.58
(2H, m), 7.37 (1H, d, J=7.88), 3.13 (2H, t, J=7.70),
1.85–1.65 (2H, m), 1.59–1.35 (2H, m), 0.98 (3H, t,
J=7.24).
1H, J=9.57), 6.75–6.83 (m, 2H), 3.89 (s, 3H), 2.97 (q,
2H, J=7.40), 1.29, (t, 3H, J=7.46).
3.1.9. 2-n-Butyl-4-methoxynitrobenzene (3i)
1
Orange oil (lit. [3] oil). H-NMR (200 MHz, CDCl3)
3.1.18. 4,4%-Dichloro azoxybenzene (5a)
l=8.01 (1H, d, J=9.55), 6.83–6.75 (2H, m), 3.88 (3H,
s), 2.93 (2H, t, J=7.75), 1.53–1.75 (2H, m), 1.30–1.50
(2H, m), 0.95 (3H, t, J=7.19).
Orange crystals, m.p. 151–152°C (CHCl3), (lit. [10]).
MS(EI) m/z (relative intensity): 266 ([M+], 55), 250 (3),
237 (3), 125 (48), 111 (base). HRMS (EI): Calc. for
1
C12H8ON325Cl2 [M+]: 266.00137; Found: 266.00049. H-
3.1.10. 2-i-Propyl-4-methoxynitrobenzene (3j)
Orange oil. 1H-NMR (200 MHz, CDCl3) l=7.87
(1H, d, J=9.05), 6.92 (1H, d, J=2.73), 6.77 (1H, dd,
J=9.02, J=2.76), 3.88 (3H, s), 3.50–3.80 (1H, m),
1.29 (6H, d, J=6.81).
NMR (200 MHz, CDCl3) l=8.25 (d, 2H, J=9.17),
8.16 (d, 2H, J=9.12), 7.48 (d, 2H, J=6.65), 7.44 (d,
2H, J=6.65).
3.1.19. 4,4%-Dichloro-2-methyl-azoxybenzene (5b)
Orange crystals, m.p. 146–147°C (EtOH). MS(EI)
m/z (relative intensity): 280 ([M+], 38), 265 (89), 245
(9), 228 (13), 111 (base). HRMS (EI): Calc. for
C13H10ON325Cl2 [M+]: 280.01702; Found: 280.01664.
3.1.11. 2-(2-Methyl-4-nitrophenyl)-1,3-dioxolane (3k)
Orange oil (lit. [6] oil). H-NMR (200 MHz, CDCl3)
l=7.98 (1H, d, J=8.98), 7.45–7.49 (2H, m), 5.83 (1H,
s), 4.04–4.14 (4H, m), 2.61 (3H, s).
1
2-Methyl-nitrobenzene (3l), 4-methyl-nitrobenzene
(4l), 2-i-propyl-nitrobenzene (3m), 4-i-propyl-nitroben-
zene (4m) were identical to commercial samples.
3.1.20. 4,4%-Dichloro-2,2%-dimethyl-azoxybenzene (5c)
Orange crystals, m.p. 99°C (MeOH). H-NMR (200
MHz, CDCl3) l=8.25 (d, 1H, J=8.55), 7.63 (d, 1H,
J=8.76), 7.22–7.34 (m, 4H), 2.49 (s, 3H), 2.36 (s, 3H).
1
3.1.12. 2-n-Butyl-nitrobenzene (3n)
1
Yellow oil (lit. [11] oil). H-NMR (200 MHz, CDCl3)
3.1.21. 4-Methoxynitrosobenzene (4)
l=7.90–7.83 (1H, m), 7.55–7.45 (1H, m), 7.38–7.26
(2H, m), 2.88 (2H, t, J=7.82), 1.72–1.52 (2H, m),
1.49–1.25 (2H, m), 0.94 (3H, t, J=7.15).
Green oil (lit. [9], m.p. 20–22°C). 1H-NMR (200
MHz, CDCl3) l=7.93 (2H, d, J=8.80), 7.03 (2H, d,
J=9.10), 3.95 (3H, s). MS(EI) m/z (relative intensity)
137 ([M+], base), 123 (6), 107 (43), 92 (78), 77 (81).
3.1.13. 4-n-Butyl-nitrobenzene (4n)
1
Yellow oil (lit. [11] oil). H-NMR (200 MHz, CDCl3)
3.2. General procedure for the reaction of nitroarenes
with Grignard reagents complexed with TMEDA
l=8.14 (2H, m), 7.33 (2H, m), 2.72 (2H, t, J=7.69),
1.72-1.52 (2H, m), 1.49–1.25 (2H, m), 0.94 (3H, t,
J=7.22).
To a stirred solution of alkylmagnesium halide (3
mmol) in THF (20 ml) was added dropwise during ca.
2.5 min TMEDA (6 mmol) and stirring was continued
for 15 min. The suspension was cooled to −70°C
under argon and a solution of nitroarene (2 mmol) in
THF (2 ml) was added dropwise during ca. 3 min. After
5 min powdered KMnO4 (474 mg, 3 mmol) was added
and subsequently liquid NH3 (ca. 10 ml, −70°C) con-
densed in the mixture. The reaction mixture was stirred
for 15 min and NH4Cl was added (318 mg, 6 mmol)
and cooling bath removed. The work-up was as in the
general procedure for reaction of nitroarenes with Grig-
nard reagents.
3.1.14. 2-n-Butyl-6-chloro-nitrobenzene (3o)
Yellow oil. H-NMR (200 MHz, CDCl3) l=7.37–
7.32 (2H, m), 7.28–7.20 (1H, m), 2.58 (2H, t, J=7.74),
1.68–1.51 (2H, m), 1.46–1.23 (2H, m), 0.92 (3H, t,
J=7.21).
1
3.1.15. 4-n-Butyl-2-chloro-nitrobenzene (4o)
Yellow oil. 1H-NMR (200 MHz, CDCl3) l=7.83
(1H, d, J=8.31), 7.35 (1H, d, J=1.75), 7.21 (1H, dd,
J=8.33, J=1.80), 2.67 (2H, t, J=7.61), 1.71–1.54
(2H, m), 1.46–1.23 (2H, m), 0.94 (3H, t, J=7.22).

M. Ma˛kosza, M. Surowiec / Journal of Organometallic Chemistry 624 (2001) 167–171
171
Bosco, J. Org. Chem. 45 (1980) 522. (c) G. Bartoli, M. Bosco, J.
Org. Chem. 47 (1982) 5227.
Acknowledgements
[4] (a) A. Counotte-Potman, H.C. van der Plas, J. Heterocyclic
Chem. 18 (1981) 123. (b) H.C. van der Plas, M. Woz´niak,
Croatica Chemica Acta 59 (1986) 33.
The authors thank the State Committee for Scientific
Research for financial support of this work (grant no.
PBZ 6.01).
[5] (a) M. Ma˛kosza, K. Stalin´ski, Chem. Eur. J. 3 (1997) 2025. (b)
M. Ma˛kosza, K. Stalin´ski, Tetrahedron 54 (1998) 8797. (c) M.
Ma˛kosza, K. Stalin´ski, Synthesis 11 (1998) 1631.
[6] J.S. Bentley, D.J. Milner, J. Organomet. Chem. 447 (1993) 1.
[7] (a) C. Chevrot, K. Kham, J. Perichon, J.F. Fauvarque, J.
Organomet. Chem. 161 (1978) 139. (b) J. Ducom, B. Denise, J.
Organomet. Chem. 26 (1971) 305. (c) H.L. Lewis, T.I. Brown, J.
Am. Chem. Soc. 92 (1970) 4664. (d) D.J. Peterson, J. Org. Chem.
32 (1967) 1717.
[8] K. Altau, J.G. Beasley, H.J. Pine, R.H. Crawford, J. Chem. Eng.
Data 8 (1963) 122.
[9] C.A. Leigh, M.B. Geiger, J. Am. Chem. Soc. 54 (1932) 3064.
[10] G.A. Olah, K. Dunne, D.P. Kelly, Y.K. Mo, J. Am. Chem. Soc.
94 (1972) 7438.
References
[1] (a) M. Ma˛kosza, J. Winiarski, Acc. Chem. Res. 20 (1987) 282.
(b) M. Ma˛kosza, K. Wojciechowski, Liebigs Annalen Receuil
(1997) 1805. (c) M. Ma˛kosza, Russ. Chem. Bull. 45 (1996)
491. (d) M. Ma˛kosza, K. Stalin´ski, Polish J. Chem. 73 (1999)
151.
[2] (a) F. Terrier, Nucleophilic Aromatic Displacement, Verlag
Chemie, Weinheim, 1991. (b) O.N. Chupakhin, V.N. Charushin,
H.C. van der Plas, Nucleophilic Aromatic Substitution of Hy-
drogen, Academic Press, San Diego, 1994.
[11] P. Laszlo, J. Vandormael, Chem. Lett. (1988) 1843.
[12] A.W. Da˛browski, A.P. Gierientiew, A.M. Jurkiewicz, Zh. Obsch.
Khim. 27 (1957) 421.
[3] (a) G. Bartoli, Acc. Chem. Res. 17 (1984) 109. (b) G. Bartoli, M.
.