Knoevenagel condensation of aldehydes with Meldrum's acid in ionic liquids

Article abstract of DOI:10.1080/00397910802663345

The Knoevenagel condensation of Meldrum's acid with aromatic aldehydes proceeded efficiently in the recyclable ionic liquid [bmim]BF₄ at room temperature in the presence of catalytic amounts of piperidine.

Full text of DOI:10.1080/00397910802663345

General Issue
ARKIVOC 2011 (ix) 252-260
Synthesis of acridan-fused quinoxalines
Mahlegha Shamsi,a Mehdi M. Baradarani,a* Arash Afghan,b and John A. Joulec
aDepartment of Chemistry, Faculty of Science, University of Urmia, Urmia 57153-165, Iran
bDepartment of Chemical Engineering,Urmia University of Technology, Urmia 57155-419, Iran
cThe School of Chemistry, The University of Manchester, M13 9PL, UK
E-mail: mmbaradarani@yahoo.com
Abstract
The synthesis of acridan-fused quinoxalines, 10,14b-dihydro-1,6,14b-triazanaphth[a]-
aceanthrylenes, 10,14b-dihydro-1,2,6,14b-tetraazanaphth[a]aceanthrylene, 10,14b-dihydro-
1,5,6,14b-tetraazanaphth[a]aceanthrylene and the acridan-fused pyrazine, 2,3-dicyano-8,12b-
dihydro-1,4,12b-triazabenz[a]aceanthrylene, is described.
Keywords: acridan, quinoxaline, pyrazine, α-ketoamide, isatin, ortho-phenylenediamines, 2,3-
diaminopyridine
Introduction
Quinoxaline1 structural units are found frequently in biologically active substances, as recently
well summarised.2 Quinoxalines fused to other heterocyclic systems have been of particular
interest, for example antiviral indolo[2,3-b]quinoxalines3,4 2-p-chloroanilino-5-p-chlorophenyl-
3,5-dihydro-3-isopropyliminophenazine (chlofazimine) for treatment of leprosy,5 and the potent
Lck inhibitor N-(2-chloro-6-methylphenyl)-7,8-dimethoxyimidazo[1,5-a]quinoxalin-4-amine
(BMS 238497).6 The quinoxaline framework also figures largely in materials chemistry,7 again,
as well summarised previously.2
The standard route for the ring synthesis of quinoxalines involves the acid or Lewis acid
catalysed double condensation of a 1,2-diketone with an ortho-phenylenediamine. Many
protocols, differing mainly in the acidic catalyst used, have been described and are well
summarized in a report2 which introduced bismuth(III) triflate as a catalyst for carrying out the
condensation in water. Other combinations utilize the reaction of an ortho-phenylenediamine
with 1,2-difunctionalised components at a lower oxidation state, for example 2-hydroxy-ketones,
but these require the presence of an oxidant (sometimes just air). There are many examples of the
use of isatins (1H-indole-2,3-diones), which are, chemically speaking, α-keto-amides, in the ring
synthesis of quinoxalines,8 the earliest of which dates back to 1947.9
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We have previously described our investigations on the synthesis of some cyclooctane-based
pyrazines and quinoxalines.10 Here we detail our preparations of some acridan-fused
quinoxalines. The route is notable for the use of fused isatins as α-ketoamides, not 1,2-diketones,
in the quinoxaline ring formation.
Results and Discussion
Our route began with the assembly of the fused isatins 4a and 4b (Scheme 1). Acridones 1a and
1b were prepared by a standard route11 involving copper(II) oxide catalysed reactions of
aniline/2-methylaniline with 2-chlorobenzoic acid, then sulfuric acid promoted ring closure. The
acridones were efficiently reduced to the acridans (9,10-dihydroacridines) 2a and 2b by
treatment with sodium dissolving in n-butanol at 110 °C.12 Attempts to follow earlier work and
use lithium aluminium hydride13 or sodium amalgam14 resulted only in mixtures of starting
material and product. The acridans were unstable substances and spectroscopic measurements
were made rapidly as were the subsequent reactions of these two aromatic amines.
Reaction of the acridans with oxalyl chloride generated amide–acid chlorides 3a and 3b
which were ring closed to 4a and 4b by aluminium(III) chloride treatment at room temperature,
conditions which are milder than those used previously15 for a ring closure to 4a.
O
Na, n-BuOH
(COCl)2, PhH, rt
110 °C
N
N
N
H
H
R
R
3 R
O
R
O
1
a
b
R
H
Me
2 R
a H
Cl
a
H
b Me
b
Me
AlCl3, CH2Cl2, rt
N
R
O
O
4
R
a H
b
Me
Scheme 1. Synthesis of 6H-pyrrolo[1,2,3-de]acridine-1,2-diones.
Two methods were investigated for the reaction of the arylamine-1,2-diamines with 4: (i)
heating at reflux in acetic acid or (ii) heating at 160 °C in acetic acid/methanol (1:9) with
ultrasound irradiation. The second of these methods is to be preferred since better yields were
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obtained in shorter reaction times. Reaction of 4b with 2,3-diaminomaleonitrile 5 gave the
pentacyclic pyrazine derivative 6 (Scheme 2). An alternative and reasonable structure for the
condensation product, 7, was clearly eliminated on the grounds of molecular weight, absence of
IR carbonyl or NH peaks, and the absence of an NMR signal for N-hydrogen. These criteria also
apply to the structure determinations of the other condensation products, 9 and 10/11, described
below.
MeOH/AcOH (9:1)
ultrasound, 160 °C
NH2
CN
NH2
CN
+
N
N
67%
Me
Me
4b
5
6
O
O
N
N
CN
CN
N
H
O
7 Me
N
NH
CN
CN
Scheme 2. Synthesis of 12-methyl-8H-pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine-2,3-
dicarbonitrile (6).
The hexacyclic quinoxalines 9a and 9b were similarly obtained by reactions of 4a and 4b,
respectively, with ortho-phenylenediamine 8a (Scheme 3). Isomeric mixtures were obtained
from the reactions between 4a and 4b with 4-methylbenzene-1,2-diamine 8b; compounds 9c/9d
and 9e/9f were formed in a 1:1 and 1:3 ratio respectively, but could not be separated by
chromatography. The ratios were determined by examination of the integrations of the 1H NMR
methyl signals, but we were not able to determine in the isomeric pair 9e/9f, which is the major
product.
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NH2
NH2
R2
MeOH/AcOH (9:1)
ultrasound, 160 °C
+
N
N
R1
R1
O
O
N
N
4 R1
a H
R2
H
9
a
R1 R3 R4
8
a
b
H H
Me H
H
H
b
c
d
e
f
b Me
Me
H Me H
H H Me
R3
R4
Me
Me
Me H
H
Me
Scheme 3. Synthesis of 5H-quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridines (9a-f).
The comparable condensation of 4a with pyridine-2,3-diamine gave a product which, by
analogy, we believe has the structure of either 10 or 11. On the grounds that one would speculate
that the first interaction would involve the more nucleophilic amino group (that at pyridine C-3)
with the more electrophilic carbonyl group (the ketone), we favour structure 10, but a definitive
decision awaits further experimentation.
NH2
N
NH2
+
N
N
N
MeOH/AcOH (9:1)
ultrasound, 160 °C
+
4a
10
11
1:1
O
O
N
N
N
N
N
N
Scheme 4. Synthesis of 5H-pyrido[2",3":5',6']pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine (10) or
5H-pyrido[3",2":5',6']pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine (11).
Conclusion
We have shown that the two carbonyl groups of 6H-pyrrolo[1,2,3-de]acridine-1,2-diones, one a
ketone and one anilide, will condense with arylamine-1,2-diamines, with loss of two molecules
of water, to generate a pyrazine ring.
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Experimental Section
General. Melting points were recorded on a Philip Harris C4954718 apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on a Bruker Avance AQS 300 MHz
spectrometer, at 300 MHz and 75 MHz respectively. Chemical shifts δ are in parts per million
(ppm) measured in CDCl3 and DMSO-d6 as solvents and relative to TMS as the internal
standard. Infrared spectra were recorded on a Thermonicolet-Nexus 670 FT-IR instrument. High
resolution mass spectra were recorded on an Agilent Technology (HP), MS Model: 5973
Network Mass, selective Detector Ion source: Electron Impact (EI) 70 eV, ion source
temperature: 230 ºC Analyzer: quadrupole, and relative abundances of fragments are quoted in
parentheses after the m/z values. A Cole-Parmer 600-Watt Ultrasonic Processor with US probe
was used for the ultrasonication and the reactions were carried out in a round-bottom flask.
General procedure for reduction of acridones to acridanes (9,10-dihydroacridines)
In a 250-mL round-bottomed flask, a mixture of acridone (1.5 mmol, 300 mg) and butanol (50
mL) was stirred for 2 h at 110 oC, then a mixture of sodium (6 g) in butanol (25 mL) was added
dropwise and the mixture was heated for 30 min at this temperature. After this time, excess
butanol was evaporated, water (100 mL) was added and product extracted into chloroform. The
organic layer was dried (Na2SO4), solvent evaporated and the residue was recrystallized from
EtOH to produce the pure acridan. The acridans were unstable substances tending to oxidize to
the corresponding acridine and were therefore utilised quickly for spectroscopic measurements
and for the subsequent synthetic steps.
o
1
9,10-Dihydroacridine (2a) (225 mg, yield 80%): mp 154-156 C; H-NMR (CDCl3): 4.08 (2H,
s), 5.96 (1H, br s, NH), 6.68 (2H, d, J=7.8 Hz), 6.9 (2H, dd, J1= 7.5 Hz, J2= 0.9 Hz), 7.08-7.13
(4H, m); 13C-NMR (CDCl3): 31.38, 113.43, 120.04, 120.99, 128.60, 140.13; FT-IR (KBr): 3373,
3039, 2933, 1581, 1477, 1453, 1297 cm-1; MS: m/z: 181 (M+), 180 (100), 152, 104, 90; Found:
M+ 181.0892, C13H11N requires M+ 181.0891.
o
1
4-Methyl-9,10-dihydroacridine (2b) (240 mg, yield 82%): mp 73-75 C; H-NMR (CDCl3):
2.30 (3H, s), 4.09 (2H, s), 5.94 (1H, s), 6.75-7.27 (7H, m); 13C-NMR (CDCl3): 16.94, 31.59,
113.89, 119.49, 120.13, 120.27, 120.38, 120.77, 126.50, 126.96, 128.31, 128.53, 138.32, 140.11;
FT-IR (KBr): 3391, 3039,1603,1588,1493, 1466, 1435, 1294, 750 cm-1; MS: m/z: 195 (M+), 194
(100), 180, 90; Found: M+ 195.1046, C14H13N requires M+ 195.1048.
General procedure for synthesis of 2-(acridin-10(9H)-yl)-2-oxoacetyl chlorides
Oxalyl chloride (5.5 mmol, 0.7 g) was added dropwise to a solution of the dihydroacridine (2.7
mmol) in benzene (10 mL) at 5 oC. The mixture was stirred for 2 h at room temperature, then the
benzene was evaporated leaving the residue as solid. It was not necessary to purify crude product
for subsequent reaction.
2-(Acridin-(9H)10-yl)-2-oxoacetyl chloride (3a) (620 mg, yield 85%): FT-IR (KBr): 2944,
1777, 1674, 1477, 1366, 1279, 758 cm-1.
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2-(4-Methylacridin-(9H)10-yl)-2-oxoacetyl chloride (3b) (617mg, yield 80%): FT-IR (KBr):
2940, 1775, 1671, 1475, 1369, 1284, 760 cm-1.
General procedure for synthesis of 6H-pyrrolo[1,2,3-de]acridine-1,2-diones
Sublimed aluminium chloride (3.1 mmol, 0.4 g) was slowly added to a solution of the 2-(acridin-
(9H)10-yl)-2-oxoacetyl chloride (1.2 mmol) in dichloromethane (20 mL). The reaction mixture
was stirred overnight at room temperature. Hydrochloric acid (2 M, 30 mL) was added. The
organic layer was separated, washed with KHCO3 (2 M. 20 mL) then water (20 mL). Finally the
dichloromethane was evaporated using a rotary evaporator. The residue was recrystallized from
ethanol.
o
6H-Pyrrolo[1,2,3-de]acridine-1,2-dione (4a) (155 mg, yield 55%): mp 208-210 C (lit.15 220-
221 °C); FT-IR (KBr): 2922, 1736, 1720, 1639, 1364, 758 cm-1; 1H-NMR (CDCl3): 4.20 (s, 2H),
7.17-7.34 (m, 4H), 7.45 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.5 Hz,1H), 8.67 (d, J=8.4Hz, 1H);
13CNMR (CDCl3): 28.25, 116.03, 117.60, 119.58, 121.12, 123.60, 125.44, 126.02, 128.07,
129.76, 132.19, 136.87, 145.57, 155.47 (C=O),184.55 (C=O); MS: m/z: 235 (M+), 207 (100),
192, 102; Found: M+ 235.0633, C15H9NO2 requires M+ 235.0633.
10-Methyl-6H-pyrrolo[1,2,3-de]acridine-1,2-dione (4b) (180 mg, yield 60%): mp 125-128 oC;
1
FT-IR (KBr): 1737, 1671, 1234, 1215, 1158, 767, 690 cm-1; H-NMR (CDCl3): 2.43 (3H, s),
3.80 (d, J= 16.5 Hz, 1H, CH2), 3.99 ( d, J=16.5 Hz, 1H, CH2) 7.12-7.21 (4H, m), 7.45 (d, J=7.2
Hz, 1H), 7.54 (d, J=7.2 Hz, 1H); 13C-NMR (CDCl3): 13.66, 34.12, 122.98, 124.87, 126.75,
127.70, 128.44, 129.01, 134.48, 134.94, 136.14, 138.45, 157.32 (C=O), 182.63 (C=O); MS: m/z:
249 (M+), 221 (100), 206; Found: M+ 249.0792, C16H11NO2 requires M+ 249.0790.
General procedures for synthesis of fused quinoxalines
Method 1:
A mixture of the dione (0.21 mmol) and ortho-phenylenediamine (0.21 mmol, 0.023 g) in acetic
o
acid-methanol (1:9, 10 mL) was irradiated with ultrasound at 160 C for the appropriate time.
After completion of reaction a precipitate had appeared. The solid obtained was filtered off,
washed with water and dried.
Method 2:
A mixture of the dione (0.21 mmol) and ortho-phenylenediamine (0.21 mmol, 0.023 g) in acetic
acid (10 mL) was heated at reflux for 6 h. During this time product precipitated and was filtered
off and washed with a mixture of water/acetone (1:1, 10 mL) and recrystallised from EtOH.
12-Methyl-8H-pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine-2,3-dicarbonitrile (6) as an
1
orange solid (method 1, reaction time: 10 min., 45 mg, yield 67%): mp 118-120 °C ; H-NMR
(CDCl3): 2.54 (s, 3H), 4.47 (s, 2H), 7.26-7.32 (m, 2H), 7.56 (t, J=7.5, 1H, H-12 or H-8), 7.62 (d,
J=6.9, 2H), 8.21 (d, J=7.8 Hz, 1H); 13C-NMR (CDCl3): 24.65, 31.14, 114.26, 114.54,
118.12,118.14,127.42, 120.78, 121.95, 125.77, 126.71, 127.61, 127.66, 129.72,132.25, 132.59,
134.14, 138.72, 139.30, 142.65; FT-IR (KBr): 2956, 2924, 2853, 2236, 1731, 1635, 1548, 1467,
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769 cm-1; MS: m/z: 321 (M+), 320, 305 (100); Found: M+ 321.1013, C20H11N5 requires M+
321.1014.
5H-Quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9a), yellow solid (Method 1, reaction
time: 15 min., 51 mg, yield 80%; Method 2, reaction time: 6 h, 38 mg, yield 60%): mp 288-289
°C (dec.); 1H-NMR (CDCl3): 4.55 (s, 2H), 7.20 (t, J=7.5 Hz, 1H, H-8), 7.35 (d, J=6.9 Hz, 1H, H-
9), 7.42 (t, J=6.9 Hz, 1H, H-13 or H-12), 7.48 (d, J=6.9 Hz, 1H, H-14), 7.49 (t, J=6.9 Hz, 1H, H-
13 or H-12), 7.72 (t, J=7.5 Hz, 1H, H-4 or H-3), 7.81 (t, J=7.8 Hz, 1H, H-4 or H-3), 8.25 (d,
13
J=8.1 Hz, 2H, H-5, H-2), 8.30 (d, J=8.4 Hz, 1H, H-11), 9.53 (d, J=8.4 Hz, 1H, H-7); C-NMR
(CDCl3): 29.42, 117.54, 118.29, 119.62, 120.20, 122.70, 123.38, 124.27, 126.71, 127,71, 128,35,
128.97, 129.11, 129.20, 129.63, 135.27, 138.88, 140.04; FT-IR (KBr): 3057, 1581, 1510, 1470,
1463, 1240, 745 cm-1; MS: m/z: 307 (M+), 306 (100). Found: M+ 307.1110, C21H13N3 requires
M+ 307.1109.
1-Methyl-5H-quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9b), purple solid (Method 1,
reaction time: 10 min., 47 mg, yield 70%; Method 2, reaction time: 6 h, 33 mg, yield 50%): mp
219-220 °(.dec)C ; 1H-NMR (CDCl3): 2.24 (s, 3H, CH3), 4.01 (d, J=17.7 Hz, 1H, CH2), 4.20 (d,
J= 17.7 Hz, 1H, CH2), 7.21-7.56 (m, 7H), 7.95 (dd, J1=6.9 Hz, J2=2.4 Hz, H-2 or H-5), 8.33 (d,
J=8.1 Hz, 1H), 8.57 (dd, J1=6 Hz, J2=2.4 Hz,1H); 13C-NMR (CDCl3): 21.11, 32.90, 114.29,
115.16, 119.78, 122.78, 124.78, 125.49, 125.56, 125.82, 126.68, 126.78, 129.56, 130.79, 130.99,
131.72, 131.93, 143.97; FT-IR (KBr): 3049, 2913, 1600, 1582, 1405, 1241, 817, 746 cm-1; MS:
m/z: 321 (M+), 320, 305(100); Found: M+ 321.1268, C22H15N3 requires M+ 321.1266.
12-Methyl-5H-quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9c) and 11-Methyl-5H-
quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9d) obtained in a ratio of 1:1 (the isomers
could not be separated); yellow solid (Method 1, reaction time: 10 min., 57 mg, yield 85%;
1
Method 2, reaction time: 6 h : 49 mg, yield 73%): mp 189-190 ° ;(.dec)C H-NMR (CDCl3):
2.65 (s, 0.5x3H, CH3), 2.66 (s, 0.5 x3H, CH3), 4.50 (s, 2H), 7.1 4-7.46 (m, 4H), 7.16 (t, J=7.5,
1H, H-8 ), 7.55 (dd, J1=8.4 Hz, J2=1.2 Hz, 1H, H-14 or H-11), 7.62 (dd, J1=8.4 Hz, J2=1.8 Hz,
1H, H-14 or H-11), 8.01 (s, 0.5x1H), 8.05 (s, 0.5x1H), 8.11 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.4 Hz,
1H), 8.20 (d, J=8.4 Hz,1H, H-3), 9.46 (d, J=4.2 Hz, 1H, H-7), 9.49 (d, J=4.2 Hz, 1H, H-7); 13C-
NMR (CDCl3): 29.40, 29.69, 117.40, 117.47, 118.37, 119.49, 119.92, 120.05, 122.61, 122.67,
123.19, 123.24, 124.08, 124.12, 127.38, 127.63, 127.83, 128.11, 128.26, 128.64, 128.70, 128.83,
128.95, 129.56, 131.18, 135.307, 136.85, 137.23, 138.28, 138.84, 139.45; FT-IR (KBr): 3060,
2921, 2852, 1582, 1467, 1405, 1177, 1116, 746 cm-1; MS: m/z: 321 (M+), 320, 285 (100). Found:
M+ 321.1265, C22H15N3 requires M+ 321.1266.
1,12-Dimethyl-5H-quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9e) and 1,11-dimethyl-
5H-quinoxalino[2',3':4,5]pyrrolo[3,2,1-de]acridine (9f) obtained in a ratio of 1:3 or 3:1 (by
integration of the methyl signals) (the isomers could not be separated), yellow solid (Method 1,
reaction time: 5 min., 56 mg, yield 80%; Method 2, , reaction time: 5 h , 49 mg, yield 70%): mp
1
251-252 °(.dec)C ; H-NMR (CDCl3): 2.23 (s, 3H for one isomer), 2.24 (s, 3H for one isomer),
2.61 (s, 3H for one isomer) 2.65 (s, 3H for one isomer), 4.00 (d, J=17.4 Hz, 1H, CH2), 4.20 (d,
J=17.4 Hz,1H, CH2), 7.72 (d, Jm=0.9 Hz, H-2 or H-5), 7.81 ( d, J=8.4 Hz, H-7(7b)), 8.31 (d,
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13
J=8.4 Hz, H-4,H-3), 8.37 (d, Jm=0.9 Hz, H-5 or H-2), 8.42 (d, J=8.4 Hz, H-7(6b)); C-NMR
(CDCl3): 21.07, 21.11, 21.77, 21.95, 30.89, 32.90, 114.57, 115.08, 119.23, 119.64, 122.61,
122.69, 125.48, 125.79, 126.16, 126.61, 126.74, 126.94, 129.30, 129.38, 130.75, 130.99, 131.92,
135,48; FT-IR (KBr): 3057, 1581, 1510, 1470, 1463, 1408, 1240, 745 cm-1; MS: m/z: 335 (M+),
334, 319 (100), 304; Found: M+ 335.1419, C23H17N3 requires M+ 335.1422.
5H-Pyrido[2",3":5',6']pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine
(10)
or
5H-
pyrido[3",2":5',6']pyrazino[2',3':4,5]pyrrolo[3,2,1-de]acridine (11): red solid by Method 1
(reaction time: 30 min.) (39 mg, yield 60%): mp >300 °(.dec)C ; 1H-NMR (CDCl3): 4.56 (s, 2H),
7.17-7.60 (m, 4H), 7.70-7.74 (m, 1H), 7.68-7.74 (m, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.65 (dt,
13
J1=8.4, J2=1.8, 1H), 9.17 (m, 1H), 9.65 (d, J=8.1 Hz, 1H); C-NMR (CDCl3): 29.68, 118.55,
120.56, 122.21, 123.93, 124.97, 128.11, 128.32 129.66, 129.88, 132.21, 133.15, 138.22, 140.38,
142.04, 143.22, 145.37, 146.95, 153.51, 154.02; FT-IR (KBr): 3057, 2923, 2852, 1601, 1493,
1400, 1245, 752 cm-1; MS: m/z: 308 (M+), 307 (100). Found: M+ 308.1062, C20H12N4 requires
M+ 308.1062.
Acknowledgements
The authors are grateful to the University of Urmia for financial support of this work. We also
thank Mr. M. Qavidel for measuring the NMR spectra.
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Agents Chemother. 1988, 32, 1720; (b) Harmenberg, J.; Åkesson-Johansson, A.; Gräslund,
A.; Malmfors, T.; Bergman, J.; Wahren, B.; Åkerfeldt, S.; Lundblad, L.; Cox, S. Antiviral
Res. 1991, 15, 193.
5. Arbiser, J. L.; Moschella, S. L. J. Am. Acad. Dermatol. 1995, 32, 241; Morrison, N. E.;
Morley, G. M. Int. J. Lepr., 1976, 44, 133.
6. Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Wang, B.; Sundeen, J. E.; Barrish, J. C. J. Org.
Chem. 2004, 69, 977.
7. See for example, Danel, A.; Gondek, E.; Kityk, I. Opt. Mater. 2009, 32, 267
8. Some recent representative examples are: (a) Shibinskaya, M. O.; Lyakhov, S. A.; Mazepa,
A. V.; Andronati, S. A.; Turov, A. V.; Zholobak, N. M.; Spivak, N. Ya. Eur. J. Med. Chem.
2010, 45,1237; (b) Alsubari, A.; Bouhfid, R.; Essassi, El M. Arkivoc 2009, xii, 337; (c)
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Manna, K.; Agrawal, Y. K. Bioorg. Med. Chem. Lett. 2009, 19, 2688; (d) Driller, K. M.;
Libnow, S.; Hein, M.; Harms, M.; Wende, K.; Lalk, M.; Michalik, D.; Reinke, H.; Langer,
P. Org. Biomol. Chem. 2008, 6, 4218.; (e) Jaouen, A.; Helissey, P.; Desbene-Finck, S.;
Giorgi-Renault, S. Heterocycles 2008, 75, 2745.
9. Buu-Hoi, N.P.; Royer, R.; Jouin, J. J.; Lecocq, J.; Guettier, D. Bull. Soc. Chim. Fr. 1947,
128.
10. Alamdari, M. H.; Helliwell, M.; Baradarani, M. M.; Joule, J. A. Arkivoc 2008, xiv, 166.
11. Allen, C. F. H.; McKee, G. H. W., Org. Synth., Coll. Vol. 2 1943, 15.
12. A recent paper (Sourdon, V.; Mazoyer, S.; Pique, V.; Galy, J.-P. Molecules 2001, 6, 673.)
states that “a solution of sodium dissolved in butan-1-ol” was used for reduction of acridone
to acridan. This is clearly in error. Our reduction utilized dissolving metal (sodium) in
butanol for the purpose achieving yields of 80 and 82% for acridan and 4-methylacridan
respectively.
13. Yano, T.; Yamaguchi, T.; Yamamoto, Y. Chem. Lett. 2009, 38, 794.
14. Acheson, R. M.; Harvey, C. W. C. J. Chem. Soc., Perkin Trans. 1 1976, 465.
15. Hess, B. A.; Corbino, S., J. Heterocycl. Chem., 1971, 8, 161.
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