Nitromethane in polyphosphoric acid- A new reagent for carboxyamidation and carboxylation of activated aromatic compou

Article abstract of DOI:10.1080/00397911.2010.526284

A new method of carboxyamidation of aromatic compounds based on their reaction with nitromethane in polyphosphoric acid has been developed. Upon the hydrolysis of benzamides during the reaction mixture workup, the corresponding benzoic acids can be obtained. Taylor & Francis Group, LLC.

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Nitromethane in Polyphosphoric Acid—A
New Reagent for Carboxyamidation and
Carboxylation of Activated Aromatic
Compounds
Alexander V. Aksenov a , Nicolai A. Aksenov a , Oleg N. Nadein a &
Inna V. Aksenova a
a Stavropol State University, Stavropol, Russian Federation
Accepted author version posted online: 04 Aug 2011.Version of
record first published: 17 Oct 2011.
To cite this article: Alexander V. Aksenov , Nicolai A. Aksenov , Oleg N. Nadein & Inna V. Aksenova
(2012): Nitromethane in Polyphosphoric Acid—A New Reagent for Carboxyamidation and Carboxylation
of Activated Aromatic Compounds, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:4, 541-547
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Synthetic Communications1, 42: 541–547, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.526284
NITROMETHANE IN POLYPHOSPHORIC ACID––A
NEW REAGENT FOR CARBOXYAMIDATION
AND CARBOXYLATION OF ACTIVATED
AROMATIC COMPOUNDS
Alexander V. Aksenov, Nicolai A. Aksenov, Oleg N. Nadein,
and Inna V. Aksenova
Stavropol State University, Stavropol, Russian Federation
GRAPHICAL ABSTRACT
Abstract A new method of carboxyamidation of aromatic compounds based on their
reaction with nitromethane in polyphosphoric acid has been developed. Upon the hydrolysis
of benzamides during the reaction mixture workup, the corresponding benzoic acids can be
obtained.
Keywords Aromatic compounds; carboxyamidation; carboxylation; nitromethane;
polyphosphoric acid
INTRODUCTION
Amides are compounds of current industrial interest as intermediates in the
production of pharmaceuticals and dyes. For example, lidocaine is a widely used
anesthetic.[1]
Amides can be prepared by several well-established procedures including
acylation of amines, hydrolyses of nitriles, and rearrangement reactions such as
Schmidt and Beckmann procedures.[2]
For synthetic purposes, it is more efficient to start directly from arenes rather
than from carboxylic acids, their derivatives, or ketones, thereby bypassing some
steps. A direct carboxyamidation procedure has been reported, in which arenes con-
dense with trimethylsilylisocyanate in hydrochloric acid medium.[3a] Some methods
of carboxyamidation have been developed with various reagents in Friedel–Crafts
conditions.[3b,c]
Received September 16, 2010.
Address correspondence to Alexander V. Aksenov, Stavropol State University, St. Pushkina 1,
Stavropol 355009, Russian Federation. E-mail: alexaks05@rambler.ru; aksenov@stavsu.ru
541

542
A. V. AKSENOV ET AL.
Table 1. Synthesis of amides 3a–f
Entry
R1
R2
R3
R4
Product
Time (h) in PPA
Yield %
1
2
3
4
5
6
H
H
H
H
OH
OMe
H
H
H
3a
3b
3c
3d
3e
3f
7
7
5
5
8
6
46
71
62
67
48
49
OMe
H
H
OMe
H
OMe
H
OH
OMe
Me
OH
H
H
H
H
In the current article, we propose a new, convenient method of carboxyamidation
or carboxylation of aromatic compounds, suggesting reagent availability and experi-
mental simplicity based on the usage of nitromethane in polyphosphoric acid (PPA).
RESULTS AND DISCUSSION
The reaction of arenes (1a–f) with nitromethane (2) in PPAy at 90–95 ꢀC leads
to formation of benzamides (3a–f) with yields of 46–71% (Table 1, Scheme 1). Arenes
containing electron-donating groups such as hydroxy-, alkoxy- or alkyl-participate
in this reaction.
We have proposed that nitromethane in PPA medium forms diphosphorylated
aci-nitromethane 4, which is used for acylation of arenes 1a–f by means of a
Vilsmeier-type reaction with oximes 5a–f. Intermediate aldoximes 5a–f experience
dehydration with the formation of nitriles 6a–f, which hydrolyze in PPA into corre-
sponding amides 3a–f (Scheme 2).
An advantage of the suggested mechanism is the formation of mixed anhy-
drides of nitronic acids.[5] The existence of monoacyl anhydrides was proved by
spectroscopy methods,[5b] a reasoning for diacyl anhydrides had been provided,[5c]
and anhydrides obtained from secondary nitroalkanes were isolated.[5d]
It was reported,[6] that arenes can be acylated with sodium salts of nitroalkanes,
nitroacetic ester, or nitroacetophenone in trifluoromethanesulfonic acid (TFSA) with
formation of corresponding oximes. Intermediate nitriles such as 6b can be isolated
from PPA by distillation. The observed regioselectivity and a lack of ortho-products
in the cases of toluene, anisole, and phenol probably imply thermodynamic or orbital
control in this reaction.
It is well known that amides can undergo hydrolysis down to carboxylic acids
upon treatment with sodium nitrite in an acidic medium.[2a,7] On the basis of these
works, we have proposed that the investigated reaction may be used for the synthesis
of benzoic acids. When a reaction mixture treated with water was cooled down and
then sodium nitrite was added, corresponding benzoic acids 6 were formed with
38–64% yields (Scheme 3, Table 2).
In conclusion, it should be noted that the methods described here in allow
for relatively easy introduction of carbamoyl and carboxyl groups into activated
aromatic compounds.
yPPA containing 86% P2O5 was used; preparation according to Uhlig.[4]

CARBOXYLATION OF ACTIVATED AROMATIC COMPOUNDS
543
Scheme 1. Synthesis of amides 3a–f.
Scheme 2. Mechanism proposed for the reaction of arenes with nitromethane in PPA.
Scheme 3. Direct one-step carboxylation of arenes (1a–d).
Table 2. Synthesis of carboxylic acids 7a–d
Entry
R1
R2
R3
R4
Product
Time (h) in PPA
Yield %
1
2
3
4
H
H
H
H
OH
OMe
H
H
H
7a
7b
7c
7d
7
7
5
5
38
64
58
61
OMe
H
H
OMe
OMe
H
OMe
EXPERIMENTAL
Evaporation of solvents was carried out using a rotary evaporator under
reduced pressure (2–400 mbar) with a bath temperature of up to 60 ꢀC. Thin-layer
chromatography (TLC) was performed on silica-gel plates Silufol UV-254. In gen-
eral, the course of the reactions was followed by TLC. NMR spectra were obtained
1
on a Bruker AM-300 spectrometer H at 300 MHz using CDCl3, acetone-d6, or
dimethylsulfoxide (DMSO-d6) as solvent. Chemical shifts are expressed in parts

544
A. V. AKSENOV ET AL.
per million (ppm) downfield from tetramethylsilane (TMS), which was used as an
internal standard. Infrared (IR) spectra were recorded on a Perkin-Elmer Fourier
transform (FT–IR) spectrometer. Melting points of small samples were obtained
after recrystallization; solvents are given in parentheses. Microanalyses were carried
out on a C,H,N-1 elemental analyzer. Chemicals were obtained from commercial
sources, we used without purification, and were of reagent quality or better.
Typical Procedure: Preparation of Benzamides 3a–f
Corresponding aromatic compounds 1a–f (1 mmol) and nitromethane 2
(0.244 g, 4 mmol) in PPA (3–4 g) were stirred at 90–95 ꢀC for 5–8 h (Table 1). The
reaction mixture was poured in cold water (10 mL) with intense stirring. The result-
ing mixture was extracted by CH2Cl2 (10 ꢁ 30 mL). The solution was evaporated
under vacuum; the residue was purified by crystallization from water.
Data
4-Hydroxybenzamide (3a). Mp 160–162 ꢀC. Lit.[8] mp 159–161 ꢀC. 1H NMR
(300 MHz, DMSO-d6): d 6.28 (br. s, 2H, NH2); 7.03 (d, J ¼ 8.6 Hz, 2H, H-3=5); 7.84
(d, J ¼ 8.6 Hz, 2H, H-2=6); 9.87 (br. s, 1H, OH). IR (KBr): 3617, 3412 (NH), 1651
(CONH), 1612 (CONH) cmꢂ1. Anal. calcd. for C7H7NO2 (%): C, 61.31; H, 5.14;
N, 10.21. Found: C, 61.48; H, 5.11; N, 10.15.
4-Methoxybenzamide (3b). Mp 166–167 ꢀC. Lit.[8] mp 165–166 ꢀC. 1H NMR
(300 MHz, CDCl3): d 3.84 (s, 3 H, OMe); 5.93 (br. s, 2 H, NH2); 6.94 (d, J ¼ 8.7 Hz,
2 H, H-3=5); 7.79 (d, J ¼ 8.7 Hz, 2 H, H-2=6). IR (KBr): 3390, 3170 (NH), 1660
(CONH), 1618 (CONH) cmꢂ1. Anal. calcd. for C8H9NO2 (%): C, 63.57; H, 6.00;
N, 9.27. Found: C, 63.71; H, 5.93; N, 9.20.
1
2,5-Dimethoxybenzamide (3c). Mp 141–142 ꢀC. Lit.[9] mp 141–142 ꢀC. H
NMR (300 MHz, acetone-d6): d 3.82 (s, 3 H, OMe); 3.91 (s, 3 H, OMe); 6.41 (br. s,
1 H, NH); 6.92 (d, J ¼ 9.0 Hz, 1 H, H-3); 7.01 (dd, J ¼ 9.0, 3.1 Hz, 1 H, H-4); 7.75
(d, J ¼ 3.1 Hz, 1 H-6); 7.84 (br s, 1 H, NH). IR (KBr): 3386, 3180 (NH), 1664
(CONH), 1619 (CONH) cmꢂ1. Anal. calcd. for C9H11NO3 (%): C, 59.66; H, 6.12;
N, 7.73. Found: C, 59.78; H, 6.08; N, 7.65.
3,4-Dimethoxybenzamide (3d). Mp 162–163 ꢀC. Lit.[10] mp 162.5-163.5 ꢀC.
1H NMR (300 MHz, DMSO-d6): d 3.89 (s, 6 H, OMe); 5.94 (br. s, 2 H, NH); 6.87
(d, J ¼ 8.8 Hz, 1 H, H-5); 7.37 (dd, J ¼ 8.8, 2.5 Hz, 1 H, H-6); 7.44 (d, J ¼ 2.5 Hz,
1 H, H-2). IR (KBr): 3386, 3180 (NH), 1664 (CONH), 1619 (CONH) cmꢂ1. Anal.
calcd. for C9H11NO3 (%): C, 59.66; H, 6.12; N, 7.73. Found: C, 59.81; H, 6.03;
N, 7.67.
1
4-Methylbenzamide (3e). Mp 159–160 ꢀC. Lit[8] mp 157–159 ꢀC. H NMR
(300 MHz, CDCl3): d 2.42 (s, 3 H, Me); 5.80 (br. s, 2 H, NH2); 7.26 (d, J ¼ 7.8 Hz,
2 H, H-3=5); 7.72 (d, J ¼ 7.8 Hz, 2 H, H-2=6). IR (KBr): 3341, 3170 (NH), 1670
(CONH), 1612 (CONH) cmꢂ1. Anal. calcd. for C8H9NO (%): C, 71.09; H, 6.71;
N, 10.36. Found: C, 71.27; H, 6.64; N, 10.29.

CARBOXYLATION OF ACTIVATED AROMATIC COMPOUNDS
545
3,4-Dihydroxybenzamide (3f). Mp 216–218 ꢀC. Lit.[11] mp 212 ꢀC. 1H NMR
(300 MHz, DMSO-d6): d 5.92 (br. s, 2 H, NH2); 6.81 (d, J ¼ 8.1 Hz, 1 H, H-5); 7.23
(dd, J ¼ 8.1, 2.1 Hz, 1 H, H-6); 7.38 (d, J ¼ 2.1 Hz, 1 H, H-2). IR (KBr): 3610, 3190
(NH), 1660 (CONH), 1615 (CONH) cmꢂ1. Anal. calcd. for C7H7NO3 (%): C,
54.90; H, 4.61; N, 9.15. Found: C, 55.08; H, 5.55; N, 9.02.
4-methoxybenzonitrile (6b). Anisole 1b (1.08 g, 10 mmol) and nitromethane
2 (2.44 g, 40 mmol) in PPA (30–35 g) was stirred at 90–95 ꢀC for 7 h. After the reflux,
4-methoxybenzonitrile was distilled from the reaction mixture collecting the fraction
with bp 200–260 ꢀC. 4-Methoxybenzonitrile 6b was purified by crystallization from
alcohol with water.
1
Mp 59–61 ꢀC. Lit.[12] mp 60 ꢀC. H NMR (300 MHz, CDCl3): d 3.86 (s, 3 H,
OMe); 6.96 (d, J ¼ 8.8 Hz, 2 H, H-3=5); 7.59 (d, J ¼ 8.8 Hz, 2 H, H-2=6). IR (KBr):
2218 (CN) cmꢂ1. Anal. calcd. for C8H7NO (%): C, 72.17; H, 5.30; N, 10.52. Found:
C, 72.30; H, 5.26; N, 10.52.
Typical Procedure: Preparation of Benzoic Acids 7a–d
Corresponding aromatic compound 1a–d (1 mmol) and nitromethane 2
(0.244 g, 4 mmol) in PPA (3–4 g) was stirred at 90–95 ꢀC for 5–8 h (Table 2). The
reaction mixture was poured in water (30 mL) with intense stirring and then cooled
to 0 ꢀC, and sodium nitrite (0.069 g, 1 mmol) was added. The reaction mixture was
stirred at this temperature for 15 min, and benzoic acids 7a–d were precipitated.
The resulting mixture was extracted by CH2Cl2 (10 ꢁ 30 mL). The solution was eva-
porated under vacuum; the residue was purified by crystallization from water.
Data
4-Hydroxybenzoic acid (7a). Mp 212–214 ꢀC. Lit.[13] mp 211–213 ꢀC. 1H
NMR (300MHz, DMSO-d6): d 6.84 (d, J ¼ 8.7 Hz, 2 H, H-3=5); 7.81 (d, J ¼ 8.7 Hz,
2 H, H-2=6); 10.20 (br. s, 1 H, OH); 12.40 (br. s, 2 H, COOH). IR (KBr): 3393
(OH), 1677 (CO) cmꢂ1. Anal. calcd. for C7H6O3 (%): C, 60.87; H, 4.38. Found: C,
61.02; H, 4.33.
1
4-Methoxybenzoic acid (7b). Mp 182–184 ꢀC. Lit.[14] mp 183–184 ꢀC. H
NMR (300 MHz, DMSO-d6): d 3.84 (s, 3 H, OMe); 7.04 (d, J ¼ 8.7 Hz, 2 H, H-3=5);
7.93 (d, J ¼ 8.7 Hz, 2 H, H-2=6); 12.70 (br. s, 2 H, COOH). IR (KBr): 1688 (CO)
cmꢂ1. Anal. calcd. for C8H8O3 (%): C, 63.15; H, 5.30. Found: C, 63.30; H, 5.24.
2,5-Dimethoxybenzoic acid (7c). Mp 74–76 ꢀC. Lit[13] mp 74–76 ꢀC. 1H
NMR (300 MHz, CDCl3): d 3.79 (s, 3 H, OMe); 4.03 (s, 3 H, OMe); 6.97 (d,
J ¼ 9.0 Hz, 1 H, H-3); 7.12 (dd, J ¼ 9.0, 2.5 Hz, 1 H, H-4); 7.68 (d, J ¼ 2.5 Hz, 1 H);
11.00 (br. s, 2 H, COOH). IR (KBr): 1664 (CO) cmꢂ1. Anal. calcd. for C9H10O4
(%): C, 59.34; H, 5.53. Found: C, 59.44; H, 5.48.
3,4-Dimethoxybenzoic acid (7d). Mp 178–179 ꢀC. Lit.[13] mp 176–178 ꢀC.
1H NMR (300 MHz, CDCl3): d 3.94 (s, 3 H, OMe); 3.98 (s, 3 H, OMe), 6.93 (d,
J ¼ 8.4 Hz, 1 H, H-5); 7.61 (d, J ¼ 1.9 Hz, 1 H); 7.78 (dd, J ¼ 8.4, 1.9 Hz, 1 H, H-4);

546
A. V. AKSENOV ET AL.
8.60 (br. s, 2 H, COOH). IR (KBr): 1677 (CO) cmꢂ1. Anal. calcd. for C9H10O4 (%):
C, 59.34; H, 5.53. Found: C, 59.47; H, 5.47.
ACKNOWLEDGMENT
This work was supported by the Federal Program ‘‘Scientific and Scientific-
Pedagogical Personnel of Innovative Russia’’ (Grant No. 16.740.11.0162).
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