Rapid synthesis of acridines using microwave

Article abstract of DOI:10.3987/COM-02-9493

Microwave irradiation for several minutes caused reaction of diarylamines with carboxylic acids in the presence of zinc chloride to give 9-substituted acridines in good yield.

Full text of DOI:10.3987/COM-02-9493

Heterocycles, Vol. 57, No. 7, 2002, pp.1299 - 1302, Received, 17th April, 2002
RAPID SYNTHESIS OF ACRIDINES USING MICROWAVE
Hideko Koshima* and Kosuke Kutsunai
Department of Applied Chemistry, Faculty of Engineering, Ehime University,
Matsuyama 790-8577, Japan
Abstract - Microwave irradiation for several minutes caused reaction of
diarylamines with carboxylic acids in the presence of zinc chloride to give 9-
substituted acridines in good yield.
Microwave-assisted organic synthesis has gained in popularity in recent years because microwave irradiation
was found to accelerate remarkably a wide variety of reactions.1,2 Heterocyclic compounds such as
quinolines and quinoxalines were also rapidly prepared by microwave heating.3-9 Acridines are materials
for some dyes and antiseptics. Further, acridine derivatives are useful for photoluminescence emitters as
well as electron acceptors in photochemical processes.10 Bernthsen reaction is known since many years ago,
which is acridine cyclization from diarylamines and carboxylic acids in the presence of zinc chloride as a
condensation agent.11 We report here that the reactions are completed by microwave irradiation for only
several minutes, despite conventional heating needs several hours.
H
N
N
R
microwave
+
RCOOH
ZnCl2
solvent-free
The reaction has been usually carried out under the conditions in the excess of carboxylic acid and zinc
chloride. In the context of our work on the reaction of diphenylamine (2) with acetic acid (1b) in the
absence of solvent, we first examined to what extent zinc chloride should be used as a condensation agent.
The every reaction temperature was measured by fiber thermometer and regulated to be kept in the range
200-210 °C by intermittent irradiation, typically one minute irradiation and 30 sec stopping. For 1:10
(equiv.) mixture of 2 and 1b, presence of 2, 3, 4, 5 and 10 (equiv.) times of zinc chloride completed the
reaction by 200 W microwave irradiation for 5 min. The reaction mixtures were submitted to silica gel
column chromatography to give 9-methylacridine (6b) as a sole product in 63, 74, 79, 74 and 73% isolated
yield, respectively. Next, 1 : 5 and 1 : 20 mixtures of 2 and 1b were irradiated in the presence of 4 times of
zinc chloride for 5 min to afford 6b in 70 and 71% yield, respectively. Thereafter, in the case of short
alkylcarboxylic acids (1a—f), 1 : 10 : 4 mixture of 2 : 1 : ZnCl2 was irradiated. On the other hand, for a
long alkylcarboxylic acid (1 g) and arylcarboxylic acids (1h—j), 1 :5 :4 mixture of 2 : 1 : ZnCl2 was adopted.
Such the excess of carboxylic acids probably played a role of solvents during the reactions, despite other
solvents were not added to the reaction mixtures.

Amine
Product
RCOOH
H
N
N
1a HCOOH
2
3
6
7
CH3COOH
1b
R
N
1c CH3CH2COOH
H
N
CH3(CH2 )2COOH
1d
(CH3)2C HCOOH
CH3(CH2 )8COOH
R
N
1e
1f
H
N
4
8
1g
CH3(CH2 )16COOH
R
H
N
N
R
1h
1i
COOH
COOH
5
R
N
9
MeO
O Me
N
H
O
R
10
COOH
1j
N
Table 1. Reaction of arylamines with carboxylic acids
Entry
Irrad. time (min)
Yield (%)
Amine
R–COOH
Acridine
1
2
3
2
2
2
1a
1b
1c
5
5
5
6a
6b
6c
63
79
86
4
5
2
2
1d
1e
5
5
6d
6e
87
85
6
2
1f
6
22
6
6f
76
1g
6g
7
8
9
2
3
4
37
77
72
1b
1b
1b
1c
1h
1i
7b
8b
9b
9c
6h
6
8
10
11
5
5
2
2
2
3
4
16
30
6
5
12
13
14
15
16
37
0 (23)
10
9
6i (10i)
6j
1j
15
1j
1j
7j
8j
7
53
26
14
Diphenylamine (2) easily reacted with a series of alkylcarboxylic acids (1a–f) by microwave irradiation for 5
min to give the corresponding 9-alkylacridines in high yields (Table 1, Entries 1-6). Reactivity of long
chain octadecanoic acid (1 g) decreased; even longer irradiation for 22 min resulted in 37% yield of 6 g (Entry
7). N-Phenyl-1-naphthylamine (3) and N-phenyl-2-naphthylamine (4) also revealed good reactivities with

1b to afford 9-methylbenz[c]acridine (7b) and 9-methylbenz[a]acridine (8b) in more than 70% yield (Entries
8 and 9). Reaction of N,N'-diphenylbenzidine (5) with 1b and 1c gave 7,7' -bi-9-alkylacridyls (9b) and
(9c) in 16 and 30% yield, respectively (Entries 10 and 11).
On the other hand, arylcarboxylic acids (1h–g) (Entries 12-16) revealed lower reactivity than that of
alkylcarboxylic acids (1a–f) (Entries 1-6, 8 and 9). In particular, reaction of 2,6-dimethoxybenzoic acid
(1i) with 2 did not at all produce 9-2,6-dimethoxyphenylacridine (6i) but N,N-diphenyl-2' ,6' -
dimethoxyphenylamide (10i) in low yield (Entry13). It is understandable from the difficult rearrangement
due to the steric hindrance, based on the possible reaction mechanism as follows. First formation of amide
(10) by the condensation between carboxylic acid and amino group, then rearrangement of the acyl group to
the o-position of phenyl ring, and subsequent dehydrated cyclization affords 9-substituted acridine (6) as a
final product. In fact, at the initial reaction stage of 2 and 1b, N-phenylbenzamide (10b) was obtained as
an intermediate. Further irradiation decreased 10b and oppositely increased 6b, finally giving 6b alone
(Entry 2). Products 9-1-naphthylbenz[a]acridine (7j) and 9-1-naphthylbenz[c]acridine (8j) have an axial
chirality like binaphthol, confirmed by HPLC using chiral column (Entries 15 and 16).
N
N
8j
7j
Axial chirality
For a comparison, reaction by conventional heating at 200 °C was carried out; 1:10:4 mixture of 2 : 1b :
ZnCl2 completed the reaction after 8 h to give 6b in 82% yield. Similarly, heating of 1:5:4 mixture of 3 :
1j : ZnCl2 for 4 h produced 7j in 50% yield. As mentioned above, microwave irradiation for only 5 or 7
min completed the both reactions (Entries 2 and 15), despite the reaction temperature at 200-210 °C is similar
to the conventional heating at 200 °C. These results suggest that such the remarkable acceleration of
reactions by microwave irradiation might be caused from not only the rapid temperature rising but also some
other microwave effect, which is not however definitely clear at this time.
EXPERIMENTAL
1H-NMR spectra were measured on a JEOL JNM-GSX270 spectrometer with tetramethylsilane as an internal
standard. IR spectra were recorded on a JASCO FT/IR-300E spectrophotometer. Melting points were not
corrected. Elemental analysis was carried out with a Yanaco CHN Corder MT-5. All the reagents were
commercially available.
General procedure for preparation by microwave irradiation
Amine (2.0 mmol), carboxylic acid (10.0 or 20.0 mmol) and ZnCl2 (1.09 g, 8.0 mmol) were mixed in a test
tube, and the mixture was irradiated with 200 W microwave (2.45 GHz) at 200-210 °C for appropriate
minutes. After the reaction, aqueous ammonia (28%, 4 ml) was added to the mixture and stirred. The
slurry was filtered and the residue was washed with water until the filtrate was neutralized. The residue

after drying was extracted with ethyl acetate. The solvent was dried over magnesium sulfate and evaporated
under reduced pressure. Products were separated by silica gel column chromatography using toluene and
ethyl acetate. Several products were submitted to HPLC using chiral column (Daicel, Chiralpak AD) and
hexane : 2-propanol (98 : 2) to detect two enantiomeric peaks; the retention times were 5.0 and 5.6 min for 7j
and 11.6 and 16.6 min for 8j.
9-1-Naphthylbenz[a]acridine (7j)
mp 223.4-225.7 °C (from MeCN); 1H-NMR (CDCl3) δ 9.64 (d, 1H, J = 8.6 Hz), 8.47 (d, 1H, J = 8.6 Hz),
8.10 (d, 1H, J = 8.1 Hz), 8.03 (d, 1H, J = 8.1 Hz), 7.69-7.84 (m, 5H), 7.39-7.55 (m, 5H), 7.22 (t, 2H, J
= 9.0 Hz), 7.08 (d, 1H, J = 8.6 Hz); IR (KBr) no NH band. Anal. Calcd for C27H17N: C, 91.24; H, 4.82;
N, 3.94. Found: C, 91.27; H, 4.65; N, 3.99.
9-1-Naphthylbenz[c]acridine (8j).
mp 203.3-205.9°C (from MeCN); 1H-NMR (CDCl3) δ 8.34 (d, 1H, J = 8.6 Hz), 8.05-8.17 (m, 4H), 7.87
(d, 1H, J = 8.6 Hz), 7.69-7.82 (m, 4H), 7.52 (t, 1H, J = 6.2 Hz), 7.20-7.43 (m, 5H), 6.93 (t, 1H, J = 7.5
Hz) ; IR (KBr) no NH band. Anal. Calcd for C27H17N: C, 91.24; H, 4.82; N, 3.94. Found: C, 91.45; H,
4.65; N, 3.73.
7,7'-Bi-9-ethylacridyl (9c).
1
mp 211.7-214.1 °C (from MeCN); H-NMR (CDCl3) δ 8.58 (s, 2H), 8.40 (d, 2H, J = 8.6 Hz), 8.24-8.32
(m, 6H), 7.81 (t, 2H, J = 7.8 Hz), 7.60 (t, 2H, J = 7.8 Hz), 3.78 (q, 4H, J = 7.5 Hz), 1.57 (t, 6H, J = 7.5
Hz); IR (KBr) no NH band. Anal. Calcd for C30H24N2: C, 87.35; H, 5.86; N, 6.79. Found: C, 87.51; H,
5.65; N, 6.66.
REFERENCES
1.
2.
3.
'Microwave-Enhanced Chemistry: Fundamentals, Sample Preparation, and Application,' ed. by H. M.
(Skip) Kingston and S. J. Haswell, American Chemical Society, Washington, DC 1997.
'Microwaves: Theory and Application in Materials Processing IV,' ed. by D. E. Clark, W. H. Sutton,
and D. A. Lewis, The American Ceramic Society, Ohio, 1997.
A. K. Bose, M. S. Manhas, M. Ghosh, V. S. Raju, K. Tabei, and Z. Urbanczyk-Lipkowska,
Heteocycles, 1990, 3 0, 741.
4.
5.
6.
7.
8.
9.
J. F. Pilard, B. Klein, F. Texier-Boullet, and J. Hamelin, Synlett, 1992, 219.
D. Villemin and B. Martin, Synth. Commun., 1995, 2 5, 2319.
R. S. Varma, J. Heterocycl. Chem., 1999, 3 6, 1565.
B. C. Ranu, A. Hajra, and U. Jana, Tetrahedron Lett., 2000, 4 1, 531.
E. Vazquez, A. de la Hoz, A. Moreno, and S. Stone-Elander, Heterocycles, 2001, 5 5, 109.
J. H. M. Lange, P. C. Verveer, S. J. M. Osnabrug, and G. M. Visser, Tetrahedron Lett., 2001, 42,
1367.
10. ' Photoinduced Electron Transfer, Part C,' ed. by M. A. Fox and M. Chanon, Elsevier, Amsterdam,
1988.
11. (a) A. Bernthsen, Ann., 1878, 192, 1. (b) A. Bernthsen, Ann., 1884, 224, 1.