Regioselectivity of nucleophilic substitution of the nitro group in 2,4,6-trinitrobenzamide

Article abstract of DOI:10.1016/S0040-4039(00)00750-4

Under the action of anionic nucleophiles RO- (R=Ph, HCF₂CF₂CH₂), R'S- (R'=Ph, PhCH₂, C₂H₅OC(O)CH₂), N₃ on 2,4,6-trinitrobenzamide in MeCN or DMF, the ortho-nitro group

Full text of DOI:10.1016/S0040-4039(00)00750-4

Tetrahedron Letters 41 (2000) 4973±4975
Regioselectivity of nucleophilic substitution of the nitro group
in 2,4,6-trinitrobenzamide
Tatyana K. Shkinyova, Igor L. Dalinger, Sergei I. Molotov and Svyatoslav A. Shevelev*
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 117913 Moscow,
Russian Federation
Received 7 March 2000; accepted 8 May 2000
Abstract
Under the action of anionic nucleophiles RO^ (R=Ph, HCF2CF2CH2), R0S^ (R0=Ph, PhCH2,
C2H5OC(O)CH2), N^3 on 2,4,6-trinitrobenzamide in MeCN or DMF, the ortho-nitro group is substituted
with high selectivity. Intramolecular cyclisation involving ortho-positioned fragments SX and -CONH2
(XˆC2H5OC(O)CH2, Cl) has been achieved with the formation of 2-ethoxycarbonyl-3-hydroxy-4,6-
dinitrobenzo[b]thiophene and 4,6-dinitro-2H-benzo[b]isothiazol-3-one correspondingly. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: nitro compounds; regioselection; benzoisothiazol; benzothiophenes.
The details of nucleophilic substitution of the nitro group in aromatic di- and polynitro-
compounds, though being of great importance, are little known, especially for compounds with
meta arranged nitro groups.1
Upon investigation of the chemistry of 2,4,6-trinitrobenzoic acid derivatives we have found
some interesting properties in the behaviour of 2,4,6-trinitrobenzamide (TNBA) in the reactions
of nucleophilic substitution. Upon reaction of TNBA with a range of anionic O-, S- and N-
nucleophiles (Nu^): RO^ (R=Ph, HCF2CF2CH2), R0S^ (R0=Ph, PhCH2, C2H5OC(O)CH2) in
MeCN (at 80±82ꢀC) or DMF (in the case of HCF2CF2CH2O^ at 75ꢀC and N^3 at 20ꢀC) selective
ortho-nitro group substitution, with the formation of the corresponding 2-Nu-4,6-dinitro-
benzamides (1), takes place in high yields (Scheme 1).
Nucleophiles RO^ and RS^ were generated in situ using a mixture of ROH or RSH with solid
K2CO3 (molar ratio TNB/ROH(RSH)/K2CO3 was 1:1:1). For azidation NaN3 (equimolar
amount) was employed and the reaction was continued until the full conversion of TNBA was
1
observed (6±10 h). According to the H NMR data, under such conditions, para-isomers are
either not formed at all (in the case of PhOH, PhSH, C2H5OC(O)CH2SH) or appeared in trace
* Corresponding author. Fax: +7(095)1355328; e-mail: shevelev@cacr.ioc.ac.ru
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00750-4

4974
^
Scheme 1. a: Nu^=PhO^; b: HCF2CF2CH2O^; c: PhS^; d: PhCH2S^; e: C2H5OC(O)CH2S^; f: N3
quantities; no more than 2% (in the case of HCF2CF2CH2OH, PhCH2SH). Only in the case of
NaN3 is the para-isomer formed in amounts of 5±7%.2
In the case of C2H5OC(O)CH2SH, when the process is carried out in re¯uxing MeCN, the
product of ortho-substitution 1e cyclises to form 2-ethoxycarbonyl-3-hydroxy-4,6-dinitro-
benzo[b]thiophene 22a (Scheme 1). At the same time, 1e can be obtained if the reaction is con-
ducted in 1-methyl-2-pyrrolidinone (NMP) at 20ꢀC.
We have found that the polarity increase of an aprotic solvent leads to an increase in an
amount of the para-isomer: in NMP, ortho/para ratio for PhOH was 4:1, for PhSH and
PhCH2SH=5:1 and for C2H5OC(O)CH2SH=6:1. However, even in these cases, the ortho-iso-
mers can be easily separated from para-isomers by means of crystallisation from an appropriate
solvent. After this, the yield of isolated ortho-isomers is 55±80%.
Thus obtained, are previously unknown, ortho-substituted benzamides 1 which are of interest
in the synthesis of benzannelated heterocycles with a novel combination of functional
substituents. The formation of benzothiophene 2 can serve as an example of this. Besides, we
have found, that upon treatment of sul®de 1d with SO2Cl2, the product 3 spontaneously cyclises
to form 4,6-dinitro-2H-benzo[d]isothiazol-3-one (4)3 (Scheme 2).
Scheme 2.
1
The structure of the compounds obtained was proven by H and 13C NMR spectroscopy,
mass-spectrometry, IR spectroscopy and elemental analysis.
Some preliminary considerations concerning the reasons for high selectivity of ortho-substitution
in TNBA. In some earlier works4,5 it was reported, that the turn of the nitro group's plane with
respect to the plane of aromatic ring under the in¯uence of a neighbouring group, favours the
substitution of this nitro group. This aids the transition from sp2 to sp3 hybridization of the carbon
atom at the formation of the ipso-s-complex of the nitro compound with a nucleophile (cf. see
Ref. 4). In accordance with quantum-chemical calculations (AM1, Chem3D Pro, version 5.0), the
2-NO2 group in TNBA is turned relative to the plane of aromatic ring by 68ꢀ, the 6-NO2- by 30ꢀ
and the 4-NO2 is in the plane of the aromatic ring, which probably governs the high regioselec-
tivity of ortho-substitution. The plane of the CONH2 fragment is turned by 62ꢀ which decreases
the steric hindrance of a nucleophile approach.

4975
It must be noted that quantum-chemical calculations using this method quite adequately
re¯ects the known experimental data on the geometry of aromatic di- and polynitrocompounds
(to be published later).
Acknowledgements
This work was supported by the International Science and Technology Center (ISTC), Project
#419.
References
1. Terrier, F. Nucleophilic Aromatic Displacement: The In¯uence of the Nitro Group; VCH: Weinheim; New York,
1991.
2. General procedure for nucleophilic substitution. (a) Synthesis of 1a, 1c, 1d and 2. A mixture of K2CO3 (0.28 g, 2
mmol), 2 mmol of corresponding NuH and TNBA (0.51 g, 2 mmol) was re¯uxed in 20 mL of MeCN. After the
completion of the reaction the solvent was evaporated in vacuo and 20 mL of water was added to the residue. The
precipitate was ®ltered o€, washed with 5% HCl, water and recrystallised. (b) Synthesis of 1b, 1e and 1f. The
reaction was carried out under the same conditions in 5 mL of DMF (NMP for 1e). After the completion of the
reaction, the mixture was poured into water (70 mL), acidi®ed with HCl (pH=5±6), precipitate ®ltered o€ and
recrystallised. Compound 1a: Mp 173ꢀC (EtOH:H2O); H NMR (d6-DMSO) ꢀ 7.19±7.22 (m, 2H), 7.29±7.35 (m,
1
1H), 7.46±7.54 (m, 2H), 7.81 (s, 1H), 7.79 (s, 1H), 8.26 (s, 1H), 8.55 (s, 1H). Compound 1b: Mp 148ꢀC (MeCN); 1H
NMR (d6-DMSO) ꢀ 4.97 (t, 2H, J=13.65 Hz), 6.50 (t.t, 1H, J=3.37, 51.86 Hz), 7.96 (s, 1H), 8.14 (s, 1H), 8.43 (d,
1H, J=1.44 Hz), 8.51 (d, 1H, J=1.55 Hz). Compound 1c: Mp 248ꢀC (CHCl3); H NMR (d6-DMSO) ꢀ 7.51±7.65
1
(m, 5H), 7.68 (s, 1H), 8.09 (s, 1H), 8.32 (s, 1H), 8.58 (s, 1H). Compound 1d: Mp 170ꢀC (EtOH:H2O); H NMR
1
(d6-DMSO) ꢀ 4.99 (s, 2H), 7.27±7.96 (m, 5H), 7.97 (s, 1H), 8.15 (s, 1H), 8.41 (s, 1H), 8.55 (s, 1H). Compound 1e:
Mp 162ꢀC (H2O); H NMR (d6-DMSO) ꢀ 1.41 (t, 3H, J=5.85 Hz), 4.21±4.40 (m, 4H), 8.04 (s, 1H), 8.41 (s, 1H),
1
8.59 (s, 1H), 8.69 (s, 1H). Compound 1f: Mp 200ꢀC (H2O); 1H NMR (d6-DMSO) ꢀ 7.97 (s, 1H), 8.11 (s, 1H), 8.48
(d, 1H, J=1.45 Hz), 8.55 (d, 1H, J=1.56 Hz). Compound 2: Mp 164ꢀC (EtOH:H2O); 1H NMR (d6-DMSO) ꢀ 1.35
(t, 3H, J=4.40 Hz), 4.36 (q, 2H, J=4.40 Hz), 8.70 (s, 1H); 9.31 (s, 1H).
3. Compound 4: Mp 311ꢀC (EtOH:H2O); H NMR (d6-DMSO) ꢀ 8.66 (s, 1H), 9.34 (s, 1H).
1
4. Benedetti, F.; Marshall, D. R.; Stirling, C. J. M.; Leng, J. L. J. Chem. Soc., Chem. Commun. 1982, 918.
5. Rozhkov, V. V.; Kuvshinov, A. M.; Gulevskaya, V. I.; Chervin, I. I.; Shevelev, S. A. Synthesis 1999, 2065.