Efficient one-pot Friedel-Crafts acylation of benzene and its derivatives with unprotected aminocarboxylic acids in polyphosphoric acid

Article abstract of DOI:10.1080/00397910500522124

A number of aminobenzophenones have been synthesized by acylation of benzene and its derivatives with different 2-,3-,4-aminobenzoic and 4-aminophenyl-acetic acids in polyphosphoric acid via Friedel-Crafts reaction as compounds with expected antitumor activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500522124

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Efficient One‐Pot Friedel–Crafts Acylation of
Benzene and its Derivatives with Unprotected
Aminocarboxylic Acids in Polyphosphoric Acid
Iliyan Ivanov a , Stoyanka Nikolova a & Stela Statkova‐Abeghe a
a Department of Organic Chemistry , University of Plovdiv , Plovdiv, Bulgaria
Published online: 16 Aug 2006.
To cite this article: Iliyan Ivanov , Stoyanka Nikolova & Stela Statkova‐Abeghe (2006) Efficient One‐Pot
Friedel–Crafts Acylation of Benzene and its Derivatives with Unprotected Aminocarboxylic Acids in
Polyphosphoric Acid, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:10, 1405-1411
To link to this article: http://dx.doi.org/10.1080/00397910500522124
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Synthetic Communicationsw, 36: 1405–1411, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500522124
Efficient One-Pot Friedel–Crafts Acylation
of Benzene and its Derivatives with
Unprotected Aminocarboxylic Acids in
Polyphosphoric Acid
Iliyan Ivanov, Stoyanka Nikolova, and Stela Statkova-Abeghe
Department of Organic Chemistry, University of Plovdiv,
Plovdiv, Bulgaria
Abstract: A number of aminobenzophenones have been synthesized by acylation of
benzene and its derivatives with different 2-,3-,4-aminobenzoic and 4-aminophenyl-
acetic acids in polyphosphoric acid via Friedel–Crafts reaction as compounds with
expected antitumor activity.
Keywords: Aminobenzophenones, benzodiazepine intermediates, Friedel–Crafts
acylation, nonlinear optic, polyphosphoric acid
INTRODUCTION
Nonlinear optical techniques are moving toward the goal of integrated, small-
scale technology using high-intensity and broad spectrum band pass laser
light. Organic molecules with an open electron shell and a conjugated
donor-acceptor group often have large polarizabilities and hyperpolarizabil-
ities. Such molecules exhibit nonlinear optical properties.[1] The most
promising material of this type is 4-aminobenzophenone. These compounds
had interesting photochromic properties at different conditions. The
compounds change their color in a variety of solvents and pH values.
Similar photoproperties have been reported for 4-methoxybenzophenone,[2]
Received in Poland October 6, 2005
Address correspondence to Iliyan Ivanov, Department of Organic Chemistry,
University of Plovdiv, 24, Tsar Assen St., 4000, Plovdiv, Bulgaria. E-mail: ivanov@
argon.acad.bg
1405

1406
I. Ivanov, S. Nikolova, and S. Statkova-Abeghe
4-aminobenzophenone,[1] and ketoprofen[3] in a variety of solvents and pH
values. For example, in air and under normal light conditions, 4-aminobenzo-
phenone undergoes a color change from colorless to a deep pink color.[1]
Benzophenone derivatives are also widely used in sunscreen lotions for
ultraviolet A (UVA) protection.[4]
Besides, some benzophenones possess biological activity as sultam deriva-
tives, for example, antitumor and anticonvulsive[5] activity against RNA virus
hepatitis C.[6] They showed excellent cytotoxic activities against a panel of
human cancer cell lines including multidrug-resistant cell lines.[7] 2-(4-Amino-
phenyl)-1-phenyl-ethanone also possess in vivo and in vitro activity as inhibitor
of acyl-CoA–cholesterol acyltransferase (ACAT).[8] Besides benzophenones
were intermediates in the synthesis of benzodiazepine derivatives[9] and were
investigated in the research laboratories of Hoffman–La Roche.[10]
RESULTS AND DISCUSSION
In view of these observations, we had to synthesize different aminobenzo-
phenones as compounds with interesting photochromic properties at
different conditions and expected biological activity. Direct synthesis of ami-
nobenzophenones by Friedel–Crafts acylation involves problems. Acylation
of methoxybenzene with 4-nitrobenzoyl chloride followed by reduction of
obtained 4-nitro-4-methoxybenzophenone gave 4-amino-4-methoxybenzo-
phenone.[11] Some authors used a reaction of 4-substituted (chloro or nitro)
anilines with benzoyl chlorides in the presence of zinc chloride under
drastic conditions (heating at 200 to 2308C).[8]
The Friedel–Crafts acylation of activated benzene rings with various
acylating agents such as benzamide, benzonitrile, ethyl benzoate, and
benzoic acid in the presence of polyphosphoric acid (PPA) is the most used
method for direct synthesis of aromatic ketones.[7,12] In a search of a new
approach to isoquinolines we investigated the reaction of carboxylic acids,
their esters, and anhydrides with 2-(3,4-dimethoxyphenyl)-ethylamine (homo-
veratrylamine) and its derivatives in PPA.[13] We found that this reaction
afforded the corresponding 3,4-dihydroisoquinolines in good yields and
purity.
In this article we applied this reaction to the synthesis of (4-aminophe-
nyl)-(3,4-dimethoxyphenyl)-methanone (4-amino-30,40-dimethoxybenzophe-
none), known compound,[14] at first.
We found that when the dichloromethane solution of 4-aminobenzoic
acid was carefully mixed in the presence of PPA, the ammonium salt 2 was
obtained. Then adding of 1,2-dimethoxybenzene (veratrol) into the reaction
mixture and heating at 808C for 2 h led to the product with high yield (ꢀ79%)
and purity (Scheme 1). These results prompted us to prepare differently
substituted benzophenones (Table 1).

Friedel–Crafts Acylation of Benzene
1407
Scheme 1.
We found that benzophenones obtained from substituted benzenes with
activated aromatic rings were prepared with higher yields than the same
products prepared with unsubstituted benzene.
In conclusion we report for the first time application of carboxylic acids
with unprotected amino groups in a Friedel–Crafts reaction with benzene and
its derivatives. The synthesized compounds have potential biological activity.
Some of them also possess interesting photochromic properties. This property
Table 1. Friedel–Crafts reaction of benzene and its derivatives with unprotected
aminocarboxylic acids 4a–l
.
Entry
R
R1
R2
Yield, %
4a
4b
4c
2-NH2-C6H4
H
H
48
75
77
MeO
MeO
H
MeO
4d
4e
4f
3-NH2-C6H4
H
H
49
76
78
MeO
MeO
H
MeO
4g
4h
4i
4-NH2-C6H4
H
H
50
75
78
MeO
MeO
H
MeO
4g
4k
4l
4-NH2-C6H4CH2
H
H
52
76
78
MeO
MeO
H
MeO

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I. Ivanov, S. Nikolova, and S. Statkova-Abeghe
of aminobenzophenones made them appropriate to use in nonlinear optics and
in sunscreen lotions for UVA protection.
EXPERIMENTAL
¨
Melting points were determined on a Boetius hostage apparatus and are uncor-
rected. 1H NMR and 13C NMR were measured in Bruker-250 device by using
CDCl3 as solvent. Chemical shifts (d, ppm) were referenced to the chemical
shifts of either TMS (d ¼ 0.00 ppm) as an internal standard, and coupling
constants are indicated in Hz. Mass spectra were recorded on a Jeol JMS-
D300 spectrometer (70 eV). All new compounds had correct parent ion
peaks by mass spectrometry. Polyphosphoric acid was obtained from 85%
phosphoric acid and P2O5 (1:1 w/w).
General Procedure for the Preparation of Products 4a–l
Corresponding aminocarboxylic acid 3 mmol was dissolved in CH2Cl2 (3–
5 mL) in an open flask, and polyphosphoric acid (10 g) was added. Then
3 mmol of benzene (or its substituted derivatives) was added. The mixture
was stirred carefully at 808C for 2 h and then poured on crushed ice. The
solution was carefully alkalized with 25% ammonia and then extracted with
CH2Cl2 (3 ꢀ 20 mL). The combined extracts were dried (Na2SO4) and
filtrated on a short column with basic Al2O3. The products, after evaporation
of the solvent, were purified by recrystallization from MeOH.
Data
(2-Aminophenyl)-phenyl-methanone (4a): known compound, mp 103–
1078C (lit.[15] mp 105–1068C).
(2-Aminophenyl)-(4-methoxyphenyl)-methanone (4b): known compound,
mp 79–808C (lit.[16] mp 78–808C).
(2-Aminophenyl)-(3,4-dimethoxyphenyl)-methanone(4c):knowncompound,
mp 74–768C (lit.[17] mp 74–768C).
(3-Aminophenyl)-phenyl-methanone (4d): mp 109–109.58C; 1H NMR
(CDCl3): 7.76–6.69 (m, 9H, Ar); 3.83 (br s, 2H, NH2); 13C NMR (CDCl3):
194.7, 162.3; 151.4, 132.5, 131.9, 130.8, 129.6, 120.2, 113.6, 55.3. MS m/z:
197 (Mþ); anal. calcd. for C13H11NO: C, 79.17; H, 5.62; N, 7.10. Found: C,
79.31; H, 5.73; N, 7.23.
(3-Aminophenyl)-(4-methoxyphenyl)-methanone (4e): mp 114–1168C;
1H NMR (CDCl3): 7.84–6.91 (m, 8H, Ar); 3.85 (s, 3H, OMe); 3.78 (br s,

Friedel–Crafts Acylation of Benzene
1409
2H, NH2); 13C NMR (CDCl3): 195.7, 163.1, 146.9, 139.3, 132.4, 130.2, 128.9,
120.2, 119.6, 118.4, 115.6, 113.4, 111.4, 55.5. MS m/z: 227 (Mþ); anal. calcd.
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 74.12; H, 5.92; N, 6.31.
(3-Aminophenyl)-(3,4-dimethoxyphenyl)-methanone (4f): mp 107–1098C;
1H NMR (CDCl3): 7.46–6.82 (m, 7H, Ar); 3.92 (s, 6H, 2 ꢀ OMe); 3.84 (br
s, 2H, NH2); 13C NMR (CDCl3): 195.7, 152.8, 148.8, 146.4, 139.2, 130.2,
128.8, 125.4, 120.6, 118.3, 115.6, 112.0, 109.6, 56.0. MS m/z: 257 (Mþ);
anal. calcd. for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.12; H,
6.03; N, 5.57.
(4-Aminophenyl)-phenyl-methanone (4g): known compound mp 107–
1108C (lit.[18] mp 106–1078C).
(4-Aminophenyl)-(4-methoxyphenyl)-methanone (4h): known compound[11]
mp 105–1088C.
(4-Aminophenyl)-(3,4-dimethoxyphenyl)-methanone
(4i):
known
compound[14] mp 191–1928C; H NMR (CDCl3): 7.58–6.60 (m, 7H, Ar);
5.15 (br s, 2H, NH2); 3.84 (s, 6H, 2 ꢀ OMe); 13C NMR (CDCl3): 193.4,
151.1, 132.1, 126.3, 123.7, 55.5, 39.6. MS m/z: 257 (Mþ); anal. calcd. for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.15; H, 6.03; N, 5.58.
1
2-(4-Aminophenyl)-1-phenyl-ethanone (4g): mp 97–998C; 1H NMR
(CDCl3): 7.78–6.97 (m, 9H, Ar); 4.15 (br s, 2H, NH2); 3.81 (s, 2H, CH2);
13C NMR (CDCl3): 194.5, 162.3, 151.4, 131.5, 131.9, 130.8, 129.6, 120.2,
113.6, 55.3, 44.6. MS m/z: 211 (Mþ); anal. calcd. for C14H13NO: C, 79.59;
H, 6.20; N, 6.63. Found: C, 79.73; H, 6.35; N, 6.75.
2-(4-Aminophenyl)-1-(4-methoxyphenyl)-ethanone (4k): known compound[19]
mp 89–908C (lit. mp 89–928C).
2-(4-Aminophenyl)-1-(3,4-dimethoxyphenyl)-ethanone (4l): mp 162–
1
1658C; H NMR (CDCl3): 7.65–6.59 (m, 7H, Ar); 4.10 (s, 2H, CH2); 3.91
(s, 6H, 2 ꢀ OMe); 3.60 (br s, 2H, NH2); 13C NMR (CDCl3): 194.7, 162.3,
156.7, 151.4, 132.5, 128.8, 127.7, 120.2, 113.6, 55.5. MS m/z: 271 (Mþ);
anal. calcd. for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.97; H,
6.44; N, 5.30.
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