Electrophilic nitration of electron-rich acetophenones

Article abstract of DOI:10.1007/s00706-005-0346-3

It is demonstrated that electron-rich disubstituted acetophenones react according to various electrophilic nitration conditions that generally lead to ipso substitution accompanying the conventional reaction. The hydroxy substituent does not seem prone to

Full text of DOI:10.1007/s00706-005-0346-3

Monatshefte f€ur Chemie 136, 1601–1606 (2005)
DOI 10.1007/s00706-005-0346-3
Electrophilic Nitration of Electron-Rich
Acetophenones
Natacha Malecki1, Pascal Carato1, Raymond Houssin1,
2
1;ꢀ
´
Philippe Cotelle , and Jean-Pierre Henichart
1
´
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite de Lille 2,
EA 2692, rue du Professeur Laguesse, BP 83, 59006 Lille, France
´
Laboratoire de Chimie Organique et Macromoleculaire, USTL,
2
UMR CNRS 8009, 59655 Villeneuve d’Ascq, France
Received December 6, 2004; accepted (revised) January 10, 2005
Published online August 12, 2005 # Springer-Verlag 2005
Summary. It is demonstrated that electron-rich disubstituted acetophenones react according to various
electrophilic nitration conditions that generally lead to ipso substitution accompanying the conven-
tional reaction. The hydroxy substituent does not seem prone to favor such behaviour.
Keywords. Nitration; Ipso substitution; Polysubstituted acetophenones.
Introduction
In the past, there have been regular references to the ipso electrophilic aromatic
substitution reaction [1–3] and a few authors have reported examples of it [4, 5].
Ipso substitution in which X is displaced by a nitro group has long been known
occurring in cases where X ¼ alkyl [6], acyl [7], or trialkylsilyl [8]. In cases where
it occurs in reactions other than nitration, such as bromination [9], it is called
‘‘non-conventional’’ [10]. This type of substitution may also be induced by radical
initiation [11]. We have recently demonstrated [12] that the nitration of electron-
rich benzoic acids and benzaldehydes occurs at the most reactive position whatever
that substituent, i.e. hydrogen, formyl, or carboxylic group. An ipso reaction has
also been reported in the case of the nitration of polymethoxyacetophenones under
concentrated nitric acid conditions [13].
In our general projects devoted to the synthesis of highly susbtituted
heterocycles [14], we required efficient syntheses of new, diversely substituted
ortho-aminoacetophenones. Therefore, we embarked on a systematic study of
the nitration of acetophenones substituted with a para nitrogen atom and a meta
oxygen atom. In this paper, we demonstrate that ipso substitution may be
ꢀ
Corresponding author. E-mail: henicha@pharma.univ-lille2.fr

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N. Malecki et al.
controlled depending on reaction conditions and the nature of the substituents
leading to highly polysubstituted anilines or acetophenones in satisfactory yields.
Results and Discussion
Three acetophenones, 6-acetyl-3-methyl-3H-benzoxazol-2-one (1) [15], 4-acetyl-
2-methoxy-N-methylaniline (2) and 4-acetyl-2-hydroxy-N-methylaniline (3) [16]
were subjected to five different nitration conditions. Structures of known com-
pounds were established by 2D NMR and results are reported in Tables 1–3.
Classical nitration conditions (methods A–C) were first tested using different co-
solvents and reaction temperatures. Tin(IV) chloride was used as catalyst under
Table 1. Nitration of 1
Method
Products (yield=%)a
Ab
Bc
Cd
De
Ef
0
16
0
76
50
0
0
0
48
0
0
0
14
50
0
a
Pure isolated products; b 68% HNO3, 0ꢁC, 3 h, see Experimental; c 68% HNO3, 8 eq, (CH3CO)2O,
d
0ꢁC, 3 h, see Experimental; 68% HNO3, 8 eq, H2SO4, CF3COOH, 0ꢁC, 1 h, see Experimental;
e
Fuming HNO3, SnCl4, CH2Cl2, ꢂ25ꢁC, 3 h, see Experimental; f Claycop (Aldrich, 26=30 nitrate=
clay), 1 eq, (CH3CO)2O, CH2Cl2, room temperature, 16 h, see Experimental
Table 2. Nitration of 2
Method
Products (yield=%)a
A
Bb
C
0
0
0
63
0
32
0
0
53
33
0
D
E
5
0
30
0
a
b
Footnotes as in Table 1 except for method B; 68% HNO3, 8 eq, (CH3CO)2O, ꢂ40ꢁC, 3 h,
see Experimental

Electrophilic Nitration of Electron-Rich Acetophenones
1603
Table 3. Nitration of 3
Method
Products (yield=%)a
Eb
0
45
a
Pure isolated products; b Claycop (Aldrich, 26=30 nitrate=clay), 1 eq, (CH3CO)2O, CH2Cl2, room
temperature, 16 h, see Experimental
mild conditions (ꢂ25ꢁC, methylene chloride) [17] in method D, whereas Claycop
(clay-supported cupric nitrate) was used in method E according to the Laszlo’s
procedure [18]. Details are given in footnotes of Table 1.
The results show that the reactivities of 1–3 are very different and depend
strongly on the reaction conditions. Compounds 1 and 2, which appear to be the
least reactive molecules of the series, give mainly, and in the case of 2, even
exclusively, products of ipso nitration. Reaction of 1 (Table 1) gives (i) 6-acetyl-
3-methyl-4-nitro-3H-benzoxazol-2-one (4) in only 14–16% yields using acetic
anhydride as solvent and nitric acid or Claycop as nitronium ion source (methods
B and E), (ii) 3-methyl-6-nitrobenzoxazolone (5) [19] as the main product (50%
yields, methods B and E) or as the sole product (76% yield, method A), whereas it
is recovered according to method D. Under more acidic conditions the ipso deriv-
ative 6 [20] was isolated in 48% yield (method C).
Whatever the conditions used, the ipso nitration of 2 occurred (Table 2) but the
structure of the products strongly depends on the reaction conditions. Whereas
Claycop (method E) gives the ipso nitration product 7 [21], the dinitro product 9
is obtained as the main compound using method C. Unexpectedly, 2-methoxy-4,5-
dinitro-N-methylaniline (8) is obtained in good yield using nitric acid in acetic
anhydride at ꢂ40ꢁC, whereas its 2,4-dinitro isomer 9 is the major product in the
other cases. These ipso reactions constitute the best method for obtaining these
dinitromethoxyanilines. The 2,4-dinitro isomer 9 has never been obtained using
this procedure and the 4,5-dinitro isomer 8 had previously been obtained by photo-
substitution (36% yield) from 4,5-dinitroveratrole [22].
Unlike the apparently dissimilar results, acetophenone 3, which is expected to
be the most reactive species, leads invariably (Table 3) to a dark residue from
which no organic compound could be isolated, except in the case of method E
where 2-acetoxy-4-acetyl-3,5-dinitro-N-methylaniline (11) was obtained in a mod-
erate yield. Whereas 3,4-dimethoxyacetophenone is efficiently nitrated at position
6 in good yield using the classical method A (68% nitric acid), the replacement of
the methoxy group at position 4 with a nitrogen atom dramatically increases the
reactivity of 1–3. Ipso nitration occurs almost exclusively for 1 and 2 whereas
compound 3 is too reactive to allow for the isolation of organic material. Even
milder conditions, i.e. Laszlo’s reagent, do not improve the yield in conventional

1604
N. Malecki et al.
nitration products from 1 or 2 whereas a dinitroacetophenone is cleanly obtained
from 3.
The generation of different dinitro compounds from 2 may be tentatively
explained by a difference in the order of occurrence of ipso nitration and conven-
tional electrophilic substitution. At low temperature (method B), conventional ni-
tration may occur first, ortho to the acetyl group (same position as in the case of
3,4-dimethoxyacetophenone) and, after that, ipso nitration leads to the 4,5-dinitro
derivative. Conversely, under the other reaction conditions, ipso nitration occurs first
and the second step is conventional nitration leading to the 2,4-dinitro compound.
In conclusion, we describe here the efficient preparation of some new, highly
substituted anilines that may lead to a diversity of heterocycles. In addition, the
yield of the known 2-methoxy-4,5-dinitro-N-methylaniline (8) was significantly
improved. These new examples illustrate the difficulties encountered when the
synthesis of highly substituted aryl compounds bearing electron-rich substituents
is envisaged.
Experimental
TLC analyses were performed on 3ꢃ10 cm plastic sheets precoated with silica gel 60F254 (Merck),
solvent system: ethyl acetate=cyclohexane. SiO2, 230–400 mesh (Merck), was used for flash column
chromatography. Melting points were obtained on a B€uchi 510 melting point apparatus. IR spectral
measurements were carried out with a Bruker Vector 22 spectrometer. 1H NMR spectra were obtained
on an AC 300P Bruker spectrometer in the appropriate solvent with TMS as internal reference. Mass
spectra were taken with a Finningan TSQ 700 apparatus. Elemental analyses were performed by the
´ ´
Service Central d’Analyse-Departement Analyse Elementaire, CNRS, F-69390 Vernaison and were
within 0.4% of the theoretical values.
Method A
Acetophenone (10 mmol) was added portionwise to 3 cm3 68% HNO3 (46 mmol) cooled to 0–5ꢁC.
The mixture was stirred for 3 h at this temperature. The solution was poured into 100 cm3 H2O, and the
pH was adjusted to 8 with 10% aqu. K2CO3. The solution was extracted with CH2Cl2. The organic
layer was dried (CaCl2) and evaporated under reduced pressure. The products were separated by
column chromatography and recrystallized.
Method B [23]
Nitric acid (68%, 5.30cm3, 80 mmol) cooled to 0–5ꢁC (ꢂ40ꢁC for 2) was added dropwise to a solution
of 10mmol acetophenone in 20 cm3 of acetic anhydride at the same temperature. The mixture was
stirred at 0–5ꢁC (ꢂ40ꢁC for 2) for 3 h. The precipitate was filtered, washed with H2O and ether. The
products were separated by column chromatography and recrystallized.
Method C [24]
A mixture of 68% HNO3 (5.30 cm3, 80 mmol) and 4 cm3 96% H2SO4 cooled to 0–5ꢁC was added
dropwise to a solution of 10mmol acetophenone in 5 cm3 TFA at the same temperature. The mixture
was stirred at 0–5ꢁC for 1 h. The solution was poured into 100 cm3 H2O. The precipitate was filtered
and washed with H2O. The products were separated by column chromatography and recrystallized.
Method D [17]
A solution of 10mmol acetophenone in 30cm3 CH2Cl2 was cooled to ꢂ25ꢁC. A mixture of 1.15 cm3
SnCl4 (30 mmol) and 1.30cm3 of fuming HNO3 (30 mmol) in 10cm3 CH2Cl2 was added. The solution

Electrophilic Nitration of Electron-Rich Acetophenones
1605
was stirred at ꢂ25ꢁC for 3 h and hyrolyzed with 30cm3 H2O. The organic layer was washed with 5%
aqu. K2CO3, dried (CaCl2) and evaporated under reduced pressure. The products were purified by
column chromatography and recrystallized.
Method E [18]
Acetophenone (10 mmol) was dissolved in 30cm3 CH2Cl2 before Claycop (mixture of Cu(NO2)2 ꢄ H2O
and Montmorillonite K10 (26=30)) (10 mmol) and 9.40cm3 of acetic anhydride (100 mmol) were
added. The mixture was stirred for 16 h at room temperature. The solution was filtered and evaporated
under reduced pressure. The products were purified by column chromatography and recrystallized.
4-Acetyl-2-methoxy-N-methylaniline (2, C10H13NO2)
Sodium hydride was added at room temperature to a solution of 3-hydroxy-4-methylaminoacetopheno-
ne [25] (0.5g, 30mmol) in THF. After stirring for 30min, 0.23 cm3 of iodomethane (36mmol) were
added. After 24 h, the mixture was poured into 50cm3 H2O and extracted with ether. The organic layer
was dried (CaCl2) and evaporated under reduced pressure to give 0.33 g of orange solid (61%).
Mp 105–106ꢁC (cyclohexane); 1H NMR (300 MHz, DMSO-d6): ꢀ ¼ 2.55 (s, 3H, COCH3), 2.90 (d, 3H,
J ¼ 4.9 Hz, NCH3), 3.90 (s, 3H, OCH3), 4.85 (bs, 1H, NH), 6.50 (d, 1H, J ¼ 8.3 Hz, H-5), 7.40 (dd, 1H,
J ¼ 1.6 Hz, H-2), 7.55 (dd, 1H, J ¼ 8.3Hz, 1.6 Hz, H-6); IR (KBr): ꢁꢀ¼ 3381, 1649 cmꢂ1
6-Acetyl-3-methyl-4-nitro-3H-benzoxazol-2-one (4, C10H8N2O5)
.
Yellow solid; chromatography eluent: CH2Cl2, petroleum ether 1=1; Rf ¼ 0.5 (CH2Cl2); Mp 175–
1
176ꢁC (EtOH); H NMR (300MHz, CDCl3): ꢀ ¼ 2.65 (s, 3H, COCH3), 3.70 (s, 3H, NCH3), 8.05
(d, 1H, J ¼ 1.6 Hz, H-7), 8.45 (d, 1H, J ¼ 1.6 Hz, H-5); IR (KBr): ꢁꢀ¼ 1760, 1680 cmꢂ1
.
2-Acetoxy-4-acetyl-3,5-dinitro-N-methylaniline (11, C11H11N3O7)
Yellow solid; chromatography eluent: EtOAc, cyclohexane 1=1; Rf ¼ 0.7 (EtOAc); Mp 155–156ꢁC
(EtOH 95%); 1H NMR (300 MHz, CDCl3): ꢀ ¼ 1.97 (bs, 1H, NH), 2.36 (s, 3H, COCH3), 2.71 (s, 3H,
COCH3), 3.24 (s, 3H, NCH3), 8.36 (s, 1H, H-5); IR (KBr): ꢁꢀ¼ 1715, 1685, 1535, 1345cmꢂ1; MS
(70 eV): m=z ¼ 297 (Mþ).
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