Synthesis of 4-methoxy-3,5-dinitrobenzaldehyde: A correction to supposed tele nucleophilic aromatic substitution

Article abstract of DOI:10.1016/S0040-4039(03)00751-2

1,3-Dinitro-5-trichloromethylbenzene (2) was reacted with sodium methoxide in an attempt to prepare 4-methoxy-3,5-dinitrobenzaldehyde (7) via a reported tele nucleophilic aromatic substitution. The product from this reaction was methyl 3,5-dinitrobenzoate (5) and not the methoxy aldehyde as had been reported. The desired product was prepared by conventional nitration methodology from 4-methoxy-3-nitrobenzaldehyde.

Full text of DOI:10.1016/S0040-4039(03)00751-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3759–3761
Synthesis of 4-methoxy-3,5-dinitrobenzaldehyde: a correction to
supposed tele nucleophilic aromatic substitution
Keith A. Monk, Rogelio Siles, Kevin G. Pinney and Charles M. Garner*
Department of Chemistry and Biochemistry, Baylor University, PO Box 97348, Waco, TX 76798, USA
Received 28 January 2003; revised 20 March 2003; accepted 21 March 2003
Abstract—1,3-Dinitro-5-trichloromethylbenzene (2) was reacted with sodium methoxide in an attempt to prepare 4-methoxy-3,5-
dinitrobenzaldehyde (7) via a reported tele nucleophilic aromatic substitution. The product from this reaction was methyl
3,5-dinitrobenzoate (5) and not the methoxy aldehyde as had been reported. The desired product was prepared by conventional
nitration methodology from 4-methoxy-3-nitrobenzaldehyde. © 2003 Elsevier Science Ltd. All rights reserved.
The efficient synthesis of benzaldehydes containing
both the nitro and amine functionalities has become
very important to researchers in the area of drug dis-
covery. These compounds have presented promise in
the current therapy for Parkinson’s disease1 and as
precursors in the synthesis of cis-stilbenoid compounds
that have demonstrated to be valuable in the treatment
of certain cancers.2–5 Traditional nitrating procedures
often give low yields of a desired regioisomer and are
perhaps dangerous because of the potential for explo-
sive di- and tri-nitration products.
nes. These concepts6 were applied by Giannopoulos, et
al., in the synthesis of 4-methoxy-3,5-dinitrobenzalde-
hyde (7) and seemed to have potential as an alternative
to harsh nitrating procedures.
We wish to report a correction to the supposed6 prepa-
ration of 4-methoxy-3,5-dinitrobenzaldehyde via a tele
nucleophilic aromatic substitution reaction of 1,3-dini-
tro-5-trichloromethyl benzene (2). Compound 2 was
prepared in 87% yield by reaction with phosphorous
pentachloride in phenylphosphonic dichloride under
conditions described by Giannopoulos (Scheme 2).6 It
was reported there that reaction of 2 with sodium
methoxide in methanol yielded intermediate acetal 3,
which hydrolyzed to 4-methoxy-3,5-dinitrobenzalde-
hyde during purification by column chromatography.
However, the authors neither isolated nor characterized
the acetal 3. Under identical conditions,7 we isolated
compound 4, which was unambiguously identified by
1H NMR. The methoxy singlet at l 3.21 integrated to
nine protons and the aromatic region of the spectra
gave a doublet and triplet with J=2.1, suggesting meta
coupling. Hydrolysis of compound 4 using dilute HCl
afforded the methyl ester 5 in 60% yield. Once again the
1H NMR showed the aromatic protons as a doublet
Nucleophilic aromatic substitution has been reported in
both heterocyclic systems and carbocyclic systems
through the formation of a Meisenheimer complex
when at least two strongly electron-withdrawing groups
are positioned on the aromatic system.6,8,9 Cartwright
and co-workers reported an atypical reaction of 3-
trichloromethylpyridines (Scheme 1) termed tele nucle-
ophilic substitution.9 Nucleophilic attack occurs at the
6-position followed by displacement of chlorine and
1,5-hydrogen migration. When the nucleophile is
methoxide, subsequent nucleophilic attack will displace
the remaining chlorines giving the acetal. The
trichloromethyl group beta to the nitrogen is vital in the
formation of the 2-substituted-5-dichloromethyl pyridi-
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00751-2

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K. A. Monk et al. / Tetrahedron Letters 44 (2003) 3759–3761
Scheme 2. Reagents and conditions: (a) PhP(O)Cl2, PCl5, reflux 15 h; (b) NaOCH3, CH3OH, rt; (c) dil. HCl, acetone.
References
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5. Cushman, M.; Nagarathnam, D.; Gopal, D.;
Scheme 3. Reagents and conditions: (a) fuming HNO3, conc.
H2SO4, 0°C.
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and triplet with J=2.1 Hz, indicative of meta coupling
rather than a long-range coupling between the aldehyde
and aromatic protons as reported.6 This result can be
attributed to a classical SN2 substitution reaction mech-
anism rather than a tele nucleophilic aromatic substitu-
tion mechanism.
mental for 1,3-dinitro-5-trichloromethylbenzene (2). To a
100 ml round-bottom flask was added 3,5-dinitrobenzoic
acid (5.0368 g, 23.7 mmol), and the flask was purged with
argon. Phenylphosphonic dichloride (3.70 ml, 26.1 mmol)
was added to the flask via syringe and the solution was
heated to 50°C. A CaCl2 drying tube was attached and
PCl5 was added to the flask portionwise over 1 h. After
addition was complete, the solution was refluxed for 16 h.
Phosphorous oxychloride was distilled off to give a
brown oil. The oil was transferred to a separatory funnel
containing 180 ml of 20% Na2CO3 solution. The product
was extracted with methylene chloride. The organic
phases were combined, dried with magnesium sulfate,
filtered, and solvent removed to give a pale yellow solid
(5.83 g, 87%, 98% pure by GC–MS). Rf (5% ethyl acetate/
Synthesis of 4-methoxy-3,5-dinitro benzaldehyde (7) by
conventional synthetic methodology (Scheme 3) was
successful in providing the desired compound. Com-
mercially available 3-nitro-4-methoxybenzaldehyde was
nitrated using fuming nitric acid in 48% yield.10 NMR
results were now entirely suggestive of compound 7,
with sharp singlets at l 4.1, 8.5, and 10.0, and integra-
tions of 3:2:1 for methoxy, aromatic, and aldehydic
1
hexanes)=0.50. H NMR (CDCl3, 300 MHz): 9.13–9.15
protons, respectively, consistent with
a literature
(m, 3H). 13C NMR (CDCl3, 75 MHz): 93.6, 120.4, 126.0,
147.7, 148.4. MS: 284 (M+), 249 (base peak). wmax
(Nujol): 1552, 1342 cm−1. Melting point: 73–75°C (lit.11
mp 76.5–77.5°C). Experimental for methyl-3,5-dini-
trobenzoate (5). To a 250 ml oven-dried round bottom
flask with stir bar was added 3,5-dinitro trichloromethyl-
benzene (5.75 g, 20.2 mmol). The flask was evacuated and
placed under an argon atmosphere. Spec. grade methanol
(150 ml) was transferred to the flask via cannula, and the
solution was stirred to dissolve all solid. The flask was
cooled in an ice bath to 0°C, and sodium methoxide
(12.03 g, 222 mmol) was added portionwise. The clear
solution turned to a cloudy orange and was stirred
report9 by which the desired compound was prepared in
a three-step procedure from 4-bromobenzaldehyde.
Acknowledgements
The authors are most appreciative of the generous
financial support provided by The Welch Foundation
(Grant No. AA-1278 to K.G.P., grant No. AA-1395 to
C.M.G.), Oxigene Inc., and Baylor University (Univer-
sity Research Committee Grant to K.G.P.).

K. A. Monk et al. / Tetrahedron Letters 44 (2003) 3759–3761
3761
overnight, warming from 0°C to room temperature under
argon. Solvent was removed and the flask was placed
under vacuum for 2 h. The compound was purified by
column chromatography using 5% ethyl acetate/hexanes,
giving 1,3-dinitro-5-trimethoxymethylbenzene (4, 5.18 g,
9. Crampton, M.; Ghariani, M.; Willison, M. J. Chem. Soc.,
Perkin Trans. 2 1974, 441–445.
10. Procedure adapted from Vogel’s Textbook of Practical
Organic Chemistry, 5th ed. 1989; pp. 854–856. Experi-
mental for 4-methoxy-3,5-dinitrobenzaldehyde (7). To a
100 ml round bottom flask containing a mixture of
4-methoxy-3-nitrobenzaldehyde (3.89 g, 21.5 mmol) and
25 ml concentrated sulfuric acid previously cooled to 0°C
in an ice bath, was added slowly a 0°C mixture of fuming
nitric acid (13.6 g, 217 mmol) and concentrated sulfuric
acid (15.9 g, 162 mmol). The reaction was stirred for 3.5
h and cautiously added to 100 ml of ice-water. After 1 h
at 0°C, the resultant mixture was filtered and the solid
was rinsed with ice-water (10 ml). Purification by flash
column chromatography (10% ethyl acetate/hexanes)
afforded the aldehyde as a pale yellow solid (2.31, 48%,
>99% pure by GC–MS). 1H NMR (CDCl3, 300 MHz):
4.14 (s, 3H), 8.51 (s, 2H), 10.02 (s, 1H). 13C NMR
(CDCl3, 75 MHz): 65.1, 129.1, 131.2, 145.6, 151.6, 186.6.
MS: 226 (M+), 196 (base peak). wmax (Nujol): 1531, 1462,
1377 cm−1. Melting point: 87–89°C (lit.9 mp 87°C).
11. Smith, W.; Chen, H.; Patterson, J. J. Org. Chem. 1961,
26, 4713–4715.
1
94%) as an orange oil. H NMR (CDCl3, 300 MHz): 3.21
(s, 9H), 8.76 (d, 2H, J=2.1), 9.07 (t, 1H, J=2.1). 13C
NMR (CDCl3, 75 MHz): 50.2, 113.1, 119.4, 127.9, 142.1,
148.6. This product was stirred in 50 ml of 1 M HCl and
25 ml of acetone overnight. The solution was extracted
with ethyl acetate, dried with magnesium sulfate, filtered,
and solvent was removed to give an orange solid. The
product was purified by column chromatography using
15% ethyl acetate/hexanes, collecting 2.520 g of pure
white solid (60%). Rf (15% ethyl acetate/hexanes)=0.39.
1H NMR (CDCl3, 300 MHz): 4.08 (s, 3H), 9.18 (d, 2H,
J=2.1 Hz), 9.24 (t, 1H, J=2.1 Hz). 13C NMR (CDCl3,
75 MHz): 53.6, 122.4, 129.5, 133.8, 148.7, 163.0. MS: 226
(M+), 195 (base peak). wmax (Nujol): 1728, 1543, 1302
.
cm−1 Melting point: 104–106°C (lit.12 mp 106.5–
106.8°C).
7. We have employed conditions identical to those reported,
but those described here give identical results in some-
what higher yields and/or purities.
8. Carwright, D.; Ferguson, J.; Giannopoulos, T.; Varvou-
nis, G.; Wakefield, B. Tetrahedron 1995, 51, 12791–12796.
12. Galetto, W. G.; Kepner, R. E.; Webb, A. D. Anal. Chem.
1966, 38, 34–36.