Unexpected nuclear formylation and acetylation of some nitroanilines with dimethyl sulfoxide in the presence of a strong base

Article abstract of DOI:10.1016/S0040-4039(00)01215-6

When treated with a strong base such as KO'Bu or NaH in dimethyl sulfoxide at room temperature, 2,4-dinitro-, 2-cyano-4-nitro- and 4-cyano-2-nitroanilines were found to undergo regiospecific acylation at the 3-position to afford the corresponding 3-formyl or 3-acetyl derivatives in fair to moderate yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01215-6

Tetrahedron Letters 41 (2000) 7093±7096
Unexpected nuclear formylation and acetylation of some
nitroanilines with dimethyl sulfoxide in the presence of a
strong base
Takehiko Kawakami and Hitomi Suzuki*
Department of Chemistry, School of Science, Kwansei Gakuin University, Uegahara, Nishinomiya 662-8501, Japan
Received 12 June 2000; revised 13 July 2000; accepted 14 July 2000
Abstract
When treated with a strong base such as KOtBu or NaH in dimethyl sulfoxide at room temperature, 2,4-
dinitro-, 2-cyano-4-nitro- and 4-cyano-2-nitroanilines were found to undergo regiospeci®c acylation at the
3-position to a€ord the corresponding 3-formyl or 3-acetyl derivatives in fair to moderate yields. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: acylation; sulfoxides; nitro compounds; arenes; carbanions.
Due to the inherent importance of carbonyl compounds as starting materials in organic
synthesis, the Friedel±Crafts type acylation has been widely employed as a tool for introducing
the carbonyl function into aromatic systems.1 This reaction proceeds via the electrophilic
pathway involving the acylium ion or its complex as the attacking species, so it fails when the
substrates bear electron-withdrawing substituent groups. This is the reason why nitrobenzene is
sometimes used as a reaction medium for the Friedel±Crafts reaction. In the last two decades,
however, several indirect methods have been developed for the introduction of the formyl group
into nitroarenes, which are based on the vicarious nucleophilic substitution of hydrogen with
anions of tris(phenylthio)methane,2 haloforms,3 chloromethyl phenyl sulfone4 and tris(benzo-
triazol-1-yl)methane.5 In the present paper, we wish to report the direct formylation and
acetylation of some nitroanilines with dimethyl sulfoxide (DMSO) in the presence of a strong
base at room temperature.
During the course of our ongoing program on the nucleophilic displacement reaction of
nitroarenes,6 we have come across an unusual acylation that took place at the most crowded site
of nitroanilines 1, when they were treated with potassium tert-butoxide or sodium hydride in
DMSO at room temperature. Thus, 2,4-dinitroaniline 1a underwent formylation at the 3-position
* Corresponding author. Tel: +81-798-54-6492; fax: +81-798-51-0914; e-mail: hsuzuki@kwansei.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01215-6

7094
to give the corresponding aldehyde 3a. The product distribution was similar irrespective of the
bases employed. The acylation was always accompanied by methylation to a considerable extent
under the conditions employed (Scheme 1).
Scheme 1.
When 2,4-dinitroaniline 1a and potassium tert-butoxide were dissolved in DMSO in a ratio of
1:4 and stirred for 6 h under ambient conditions, 3-methyl-2,4-dinitroaniline 2a was obtained in
86% yield, as expected.7 Quenching of the reaction mixture with heavy water led to partial
deuteration of the methyl group, ruling out the possible operation of a free radical mechanism. In
anticipation of promoting the rate of methylation as well as the product yield, we carried out the
reaction under an atmosphere of oxygen.8 To our surprise, however, 3-amino-2,6-dinitro-
benzaldehyde 3a was isolated in 20% yield in addition to the expected 2a. Previously, Russell et
al. reported that nitrobenzene reacts with methylsul®nylmethyl anion under atmospheric
conditions to produce o- and p-nitrobenzoic acids.9 The observed discrepancy may be ascribed to
steric crowdedness around the reaction site, which would suppress oxidation of the initially
formed aldehyde 3a. With this assumption in mind, we next chose less crowded 2-cyano-4-
nitroaniline 1b and 4-cyano-2-nitroaniline 1c as the substrates. To our great surprise, these
compounds were found to undergo acetylation at the 3-position to give 3-acetyl-2-cyano-4-
nitroaniline 4b and 3-acetyl-4-cyano-2-nitroaniline 4c in 42 and 32% yields, respectively, in
addition to the corresponding methylation products 2b and 2c (Table 1). When the reaction of 1b
was carried out under oxygen, the yields of 2b and 4b were 23 and 44%, respectively. Under
argon, they were obtained in 26 and 38% yields, respectively. 2,4-Dinitroanisole and N,N-dime-
thyl-2,4-dinitroaniline failed to behave similarly, while 2,4-dicyanoaniline 1d and 2,4-dinitro-
phenol resulted in the recovery of the starting materials. When the N-acetyl derivative of
Table 1
Reaction of nitroanilines and related compounds with methylsul®nylmethyl anion

7095
nitroaniline 1a was subjected to the action of potassium tert-butoxide under similar conditions,
there resulted a complex mixture of products as a tarry matter. Therefore, the e€ective operation
of a push±pull electronic interaction, the presence of strongly electron-withdrawing substituent
groups close to the reaction site, and ease of formation of anilino anion seem to be crucial for the
present unusual acylation of nitroanilines with DMSO.
Based on the existing information, a possible mechanistic pathway to the unusual acylation
products 3 and 4 is illustrated in Scheme 2. Nitroaniline 1 ®rst deprotonates on the nitrogen to
generate the stabilized anion 5, which combines with methylsul®nylmethyl anion at the most
electropositive ring site to form the adduct ion 6. This ion undergoes isomerization to 7, followed
by the release of methylsul®nyl anion to a€ord the nitronate 8, which is protonated to give the
methylation product 2. Under an atmosphere of oxygen, the anion 8 would be oxidized to the
aldehyde anion 9.10 The formation of 9 is the common starting point for the following two dif-
ferent pathways a and b. When the substituent R at the 2-position of 9 is a nitro group, steric
congestion would disturb further transformation of the aldehyde function (path a). However,
when R is a cyano group, the second attack by methylsul®nylmethyl anion would take place at
the carbonyl function of 9 to produce the epoxide 10,12 which, in the presence of a strong base,
would undergo a Wittig-type rearrangement to give methyl ketone 4b via the enolate 11 (path
1
b).13 The progress of the reaction was monitored by H NMR, but we failed to observe any
intermediate stages de®nitely. We reserve a discussion of the acylation mechanism for future
publication.
Scheme 2.
The representative procedure for the acylation of nitroanilines 1 is as follows. A mixture of
2-cyano-4-nitroaniline (1b; 0.20 g, 1.2 mmol), potassium tert-butoxide (0.60 g, 5.4 mmol) and

7096
DMSO (5 ml) was stirred at room temperature under air. After 6 h, the colored solution was
diluted with 1 M HCl (30 ml) and the organic phase was extracted with CH2Cl2 (3Â30 ml). The
combined extracts were evaporated to leave a solid residue, which was chromatographed on silica
gel using a mixture of hexane±AcOEt as the solvent to elute 2-cyano-3-methyl-4-nitroaniline (2b;
59 mg, 0.33 mmol) and 3-acetyl-2-cyano-4-nitroaniline (4b; 0.11 g, 0.52 mmol) in this order.14
In summary, some nitroanilines of an extended capto-dative electronic structure have been
found to undergo direct formylation or acetylation at a crowded ring site by the action of a
strong base in DMSO at room temperature. Apparently limited in scope, the present reaction
o€ers a novel type of nucleophilic aromatic substitution that takes place in DMSO under strongly
basic conditions.15
References
1. For details of Friedel±Crafts acylation, see: Olah, G. A. Friedel±Crafts and Related Reactions, Vols. 1 and 3.
Wiley: New York, 1963±64.
2. (a) Makosza, M.; Winiarski, J. Chem. Lett. 1984, 1623. (b) Grobel, B.-T.; Seebach, D. Synthesis 1977, 357.
3. Makosza, M.; Owczarczyk, Z. J. Org. Chem. 1989, 54, 5094; Tetrahedron Lett. 1987, 28, 3021.
4. (a) Wulf, J. P.; Sienkiewicz, K.; Makosza, M.; Schmitz, E. Liebigs Ann. Chem. 1991, 537. (b) Makosza, M.;
Golinski, J.; Baran, J. J. Org. Chem. 1984, 49, 1488.
5. Katritzky, A. R.; Xie, L. Tetrahedron Lett. 1996, 37, 347.
6. Kawakami, T.; Suzuki, H. J. Chem. Soc., Perkin Trans. 1 2000, 1259, and papers cited therein.
7. Argabright, P. A.; Hofmann, J. E.; Schriesheim, A. J. Org. Chem. 1965, 30, 3233.
8. It appears that some oxygen is required, since under conditions where oxygen was excluded, the reaction was
sluggish and incomplete.
9. Russell, G. A.; Weiner, S. A. J. Org. Chem. 1966, 31, 248.
10. The decomposition of sulfoxide 6 to aldehyde 9 has formal analogy to the thermal decomposition of benzyl methyl
sulfoxide to benzaldehyde and methanethiol, which has been explained to proceed by way of benzyl
methylsulfenate.11
11. Carruthers, W.; Entwistle, I. D.; Johnstone, R. A. W.; Millard, B. J. Chem. Ind. 1966, 342.
12. Chaykovsky, M.; Corey, E. J. J. Org. Chem. 1963, 28, 254.
13. For a review of the Wittig rearrangement, see: Marshall, J. A. In Comprehensive Organic Chemistry, Vol. 3; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; p. 975.
14. Compound 2b. Mp 203±204ꢀC. H NMR (CDCl3, 200 MHz): ꢀ (ppm) 2.82 (s, 3H, Ar±CH3), 5.02 (br, 2H, Ar±
1
NH2), 6.65 (d, 1H, J=9.0, Ar±H), 8.11 (d, 1H, J=9.0, Ar±H), MS (EI, 70 eV): m/z 177 [M+] (83%), 160 (100%);
IR (KBr; ꢁ, cm^1): 2226 (CN), 1647 (CˆO), 1590, 1350 (NO2). Found: C, 54.07; H, 3.96; N, 23.54%. C8H7N3O2
requires: C, 54.24; H, 3.98; N, 23.72%. Compound 4b. Mp 158±159ꢀC. 1H NMR (DMSO-d6, 200 MHz): ꢀ (ppm)
2.63 (s, 3H, CO±CH3), 7.08 (d, 1H, J=9.7, Ar±H), 7.69 (d, 1H, J=9.7, Ar±H), 7.08 (br, 2H, Ar±NH2); MS (EI, 70
eV): m/z 205 [M+] (51%), 190 (100%), 176 (55%); IR (KBr; ꢁ, cm^1): 2207 (CN), 1655 (CˆO), 1526, 1332 (NO2).
Found: C, 52.99; H, 3.51; N, 20.25%. C9H7N3O3 requires: C, 52.69; H, 3.41; N, 20.48%.
15. For leading monographs on nucleophilic aromatic substitution of nitroarenes, see: (a) Churakhin, O.; Charushin,
V.; van der Plas, H. C. Nucleophilic Aromatic Substitution of Hydrogen; Academic: New York, 1994. (b) Terrier, F.
Nucleophilic Aromatic Displacement; VCH: New York, 1991.