A new method for the selective amination of 1,3- and 1,4-dinitrobenzenes and protected nitroanilines leading to polyfunctional 1,3- and 1,4-disubstituted anilines

Article abstract of DOI:10.1055/s-2004-820043

The addition of functionalized arylmagnesium reagents to dinitrobenzenes and protected nitroanilines at -20°C in THF furnishes after a reductive workup polyfunctional diarylamines in 47-92% yield.

Full text of DOI:10.1055/s-2004-820043

LETTER
955
A New Method for the Selective Amination of 1,3- and 1,4-Dinitrobenzenes and
Protected Nitroanilines Leading to Polyfunctional 1,3- and 1,4-Disubstituted
Anilines
A
N
ewM
o
ethodfor th
a
e
Selective
n
A
minationo
n
f
1,3- and 1,
i
4-Dinit
s
robenzenes Sapountzis, Paul Knochel*
Department Chemie, Ludwig Maximilians Universität, Butenandtstrasse 5-13, 81377 München, Germany
Fax +49(89)218077679; E-mail: knoch@cup.uni-muenchen.de
Received 11 December 2003
functional diarylamines with up to 92% yield.10 We have
Abstract: The addition of functionalized arylmagnesium reagents
to dinitrobenzenes and protected nitroanilines at –20 °C in THF
furnishes after a reductive workup polyfunctional diarylamines in
47–92% yield.
observed that an excess (2 equiv) of the arylmagnesium
reagent (Ar1MgX) is necessary in order to obtain com-
plete conversion. This can be readily explained by consid-
ering the mechanism of this reaction.11,12 The first
equivalent of Grignard reagent is lost in the generation of
an intermediate arylnitroso species, which adds the
second equivalent of Ar1MgX providing the desired
diarylamine after reductive workup.
Key words: diarylamines, phenylenediamines, organomagnesium
reagents, arylation of amines, amination reaction
Nitroarenes are important synthetic intermediates and
their reactivity towards organometallics has been ex-
tensively studied.1 They are cheap and commercially
available starting materials and chemoselective trans-
formations of the nitro group leads to a number of useful
products.
Application of this methodology to dinitroarenes resulted
in a selective monoamination. Good yields are obtained
for both 1,3-dinitrobenzene and 1,4-dinitrobenzene
(Scheme 1 and Table 1).
The addition of phenylmagnesium chloride to 1,3-di-
nitrobenzene yields compound 1a in 67% yield and
addition to 1,4-dinitrobenzene generates compound 1b
which is isolated in 63%.
Selective mono-functionalization of dinitrobenzenes is a
longstanding problem in organic syntheses2,3 and has
attracted both academic and industrial interest. The
chemoselective differentiation between two nitrogen at-
oms in phenylenediamines is especially useful since this
moiety is present in numerous natural products and
biologically active molecules as well as in industrial
chemicals like dyes or polymers.4 Several N,N¢-substitut-
ed p-phenylenediamines are used as antidegradant and
antiozonant agents for diene rubber and are by far the
most effective and widely used radical scavengers in rub-
ber industry.5 To our knowledge, Pd-catalyzed amination
reactions do not allow in a general way the monofunction-
alization of aromatic dihalides or diamines, although this
method is widely used for the preparation of various aryl-
amines.6–8 Recently, we have reported that functionalized
arylmagnesium9 species react smoothly with various
nitrobenzenes providing after reductive work-up poly-
The Grignard reagent 2 can bear either electron-with-
drawing (Table 1, entries 3 and 4) or electron-donating
groups (Table 1, entries 5 and 6) and adds with good yield
to the dinitrobenzene of type 3. Thus, addition of 4-carbe-
thoxymagnesium bromide to 1,3- and 1,4-dinitrobenzene
provides after reductive workup the functionalized N-
phenylated nitroanilines 1c and 1d in 55% yield.13 The
more electron-rich p-methoxyphenylmagnesium bromide
provides the diarylamine 1e in good yield (65%) while the
addition to 1,4-dinitrobenzene gives compound 1f in 47%
yield (entries 5 and 6).
The use of a larger excess of Grignard reagent (4.6 equiv)
allowed reduction of both nitro groups in one step result-
ing in the 1,3-diamines of type 4 in good to excellent
H
N
NO2
MgCl
1) –20 °C, 2 h, THF
2) FeCl2, NaBH4
–20 °C to r.t., 2 h
NO2
FG
FG
NO2
1: 47–67 %
2: 2.3 equiv
3
m- or p-nitro
FG = H, OMe, CO2Et
Scheme 1
SYNLETT 2004, No. 6, pp 0955–0958
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820043; Art ID: G35103ST
© Georg Thieme Verlag Stuttgart · New York

956
I. Sapountzis, P. Knochel
LETTER
Table 1 Polyfunctional Amines of Type 1 Obtained by the Reaction of Arylmagnesium Halides 2 with Nitroarenes
Entry
1
Nitroarene 3
Grignard reagent 2
Product 1a
Yield (%)
67
MgCl
H
N
O2N
NO2
NO2
1a
2
3
4
63
O2N
O2N
O2N
MgCl
H
N
NO2
NO2
NO2
1b
55
55
MgCl
H
N
NO2
EtO2C
EtO2C
EtO2C
1c
MgCl
H
N
NO2
NO2
EtO2C
NO2
1d
5
6
64
47
O2N
O2N
MgCl
H
N
NO2
MeO
MeO
O
1e
MgCl
H
N
NO2
O
NO2
1f
7
8
73
58
H
N
O2N
O2N
N(Allyl)2
MgCl
MgCl
N(Allyl)2
1g
H
N
N(Allyl)2
N(Allyl)2
H
1h
9
75
67
O2N
O2N
N
Ph
MgCl
H
N
N
Ph
1i
10
MgCl
H
N
I
NMe2
Me
I
N
Me
1j
a Isolated yields; the dotted lines indicate the new C–N bond formed.
yields (Scheme 2). The reduction proceeds under very By using N-protected nitroanilines, better results are ob-
mild reaction conditions. Methoxy- or ester-functional- tained for protected 3-nitroanilines compared to the pro-
ized Grignard reagents can be used in this diamination tected 4-nitroanilines (Scheme 3, Table 1). Thus, addition
reaction as well providing products 4b and 4c, respec- of phenylmagnesium chloride to N,N-diallyl-4-nitro-
tively, in 63 and 72% yield (Scheme 2).
aniline (entry 8) affords the aromatic diimine 1h in 58%
yield whereas addition to N,N-diallyl-3-nitroaniline gives
Synlett 2004, No. 6, 955–958 © Thieme Stuttgart · New York

LETTER
A New Method for the Selective Amination of 1,3- and 1,4-Dinitrobenzenes
957
H
H
MgCl
N
N
O2N
NO2
1) –20 °C, 2 h, THF
2) FeCl2, NaBH4
–20 °C to r.t., 2 h
FG
FG
FG
4
2: 4.6 equiv
FG: H, OMe, CO2Et
3
FG = H:
FG = OMe:
4a; 92 %
4b; 63 %
FG = CO2Et: 4c; 72 %
Scheme 2
H
N
NO2
MgCl
1) –20 °C, 2 h, THF
2) FeCl2, NaBH4
–20 °C to r.t., 2 h
NPG
FG
FG
NPG
1: 58–75 %
2: 2.3 equiv
3
FG = H, I, OMe, CO2Et PG = Me, allyl,
benzimine
Scheme 3
Tetrahedron 1987, 43, 351. (c) Kuo, E.; Srivastava, S.;
Cheung, C. K.; Le Noble, W. J. Synth. Commun. 1985, 15,
599.
the corresponding 1,3-substituted diamine 1g in 73%
yield (entry 7). A variety of common protecting groups
like a benzimine (entry 9), a bis-allylamine (entries 7 and
8) or a dimethylmethylamine (entry 10) have been used.
In case of the benzimine a reduction to the benzyl group
is observed under reaction conditions providing the di-
amine 1j in 75% yield (entry 9).
(4) (a) Thomas, G. Medicinal Chemistry; Wiley-VCH:
Weinheim, 2000. (b) Bellmann, E.; Shaheen, S.;
Thayumanavan, S.; Barlow, S.; Grubbs, R.; Marder, S.;
Kippelen, B.; Peyghambarian, N. Chem. Mater. 1998, 10,
1668. (c) Rondestvedt, C. S. J. Org. Chem. 1977, 42, 1786.
(5) (a) Cataldo, F. Polym. Degrad. Stab. 2001, 72, 287.
(b) Cataldo, F. Eur. Polym. J. 2002, 38, 885. (c) Rakovsky,
S.; Zaikov, G. Kinetics and Mechanism of Ozone Teactions
with Organic and Polymeric Compounds in Liquid Phase;
Nova Science: New York, 1998.
(6) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727. (b) Wolter, M.; Klapars,
A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. (c) Shen, R.;
Porco, J. A. Org. Lett. 2000, 2, 1333. (d) Kalinin, A. V.;
Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999,
64, 2986. (e) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (f) For an
excellent overview see: Modern Amination Methods; Ricci,
A., Ed.; Wiley-VCH: Weinheim, 2000.
In summary, we have demonstrated that the addition of
various Grignard reagents to nitroarenes can be applied to
dinitroarenes and protected nitroanilines leading to a gen-
eral access of phenylenediamine derivatives. Extensions
of this method are currently underway.
Acknowledgment
We thank Aventis Pharma (Frankfurt a. M.) for a fellowship to I. S.
We thank the Fonds der Chemischen Industrie for the generous
support of research. We also thank the BASF AG, Degussa AG,
Chemetall GmbH and Bayer AG for generous gifts of chemicals.
(7) (a) Lipshutz, B. H.; Ueda, H. Angew. Chem. Int. Ed. 2000,
39, 4492; Angew. Chem. 2000, 112, 4666. (b) Desmarets,
C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001, 42, 247.
(8) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(b) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
(c) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. (d) Lam, P.
Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122,
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(9) For reviews, see: (a) Jensen, A. E.; Dohle, W.; Sapountzis,
I.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002,
565. (b) Rottländer, M.; Boymond, L.; Berillon, L.;
Leprêtre, A.; Varchi, G.; Avolio, S.; Laaziri, H.; Quéguiner,
G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem.–Eur. J. 2000,
6, 767. (c) Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem. Int. Ed. 2003, 42, 4302; Angew. Chem. 2003,
115, 4438.
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958
I. Sapountzis, P. Knochel
LETTER
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(13) Typical Procedure: Preparation of ethyl 4-(3-nitro-
phenylamino)benzoate (1d): In a dry and argon flushed 25
mL flask, equipped with a magnetic stirrer and a septum,
ethyl 4-iodobenzoate (952 mg, 3.45 mmol) was dissolved in
dry THF (8 mL), cooled to –20 °C and i-PrMgCl (3.6 mmol,
0.85 M in THF) was added dropwise. The I/Mg-exchange
was complete after 30 min (as indicated by GC analysis of
reaction aliquots) and 1,3-nitrobenzene (252 mg, 1.5 mmol)
was added. After 2 h of stirring at –20 °C, the reaction
mixture was quenched with EtOH (2 mL) and FeCl2 (378
mg, 3 mmol) and NaBH4 (57 mg, 1.5 mmol) were added.
After 2 h stirring at r.t., the reaction mixture was poured onto
brine (25 mL). The aqueous phase was extracted with Et2O
(3 × 40 mL) and the organic fractions were washed with 2 M
NaOH (30 mL), brine (30 mL), dried (Na2SO4) and
concentrated in vacuo. Flash chromatography purification
on silica gel (pentane/Et2O = 4:1) furnished 1d as red
crystals (245 mg, 55% yield).
Synlett 2004, No. 6, 955–958 © Thieme Stuttgart · New York